MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

nemoci-sympt/BAKTERIALNI-INFEKCE/chlamydie/anti-infecni-vlivy

Inhibice Chlamyd. pneumonia infekce


Cytokines

  • Potentiators of the cellular immune response
    • Subsequent inhibition of replication of several species of Chlamydiae
  • IFN-? and TNF-?
    • Human cytokines that can restrict the intracellular replication of Chlamydiae in
      • Epithelial cells
      • Human monocyte-derived macrophages [12]

TNF

  • Multifunctional cytokine
  • Regulate inflammation and defense against infectious agents including Chlamydiae [12]

TNF-? inhibitors

  • Treatment strategy for several inflammatory diseases
    • Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis
    • Cause immunosuppression = increased risk of infection
      • Enhanced fungal growth in human monocytes and alveolar macrophages [12]
      • Enhanced growth of Chlamydia trachomatis in human epithelial cell lines [12]
  • Inhibition of TNF-? during chlamydial infection
    • Impairs the expression of these costimulatory molecules and their functions [12]

IFN-gamma

  • Stimulation of host cells by IFN-gamma
    • Inhibits growth of C. pneumoniae
      • By induction of indoleamine 2,3-dioxygenase (IDO) activity
  • Higher doses (2 ng·mL-1)
    • Completely inhibited the growth of Chlamydia in vitro [22]
  • Lower doses (0.2 ng·mL-1)
    • Persistent infection was established [22]
  • Removal of IFN-gamma
    • Resulted in infectious progeny from these aberrant forms [22]
  • Plays a role in the NO production [38]
  • Inhibition of tryptophan [38]
    • Activation of the host tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) [39]
  • Preexposure of epithelial cells for 24 h to high concentrations of IFN-?
    • Inhibited inclusion formation by
      • C. trachomatis serovar L2 (111)
      • C. psittaci 6BC
      • C. pneumoniae BAL-37 [38]
  • IFN-?-induced persistent chlamydiae were enlarged and aberrant [39]
    • Could be reversed by the addition of tryptophan [39]
    • Important link between IFN-? and differential tissue tropisms among C. trachomatis serovars [39]
      • Availability of exogenous indole
      • Ability of the infecting strain to use it k synteze tryptofanu [39]
  • IFN gamma dělá
    • Depleci tryptofanu [39]
    • Induce nitric oxide synthase effector pathway [39]
      • NO potlačuje růst C.p.
    • Iron deprivation [39]

Marked upregulation observed at 24 h of infection:

  • no significant decreases in bacterial protein expression due to IFN-gamma treatment
    • Major outer membrane protein (MOMP)
    • Heat shock protein 60 (Hsp-60/GroEL)
    • Functions in DNA replication (GyrA)
    • Transcription (RpoA, PnP)
    • Translation (Rrf)
    • Glycolysis (PgK, GlgP)
    • Type III secretion (SctN) [21]
  • Altered gene transcription profile by IFN-? treatment [21] :
    • Cell division-related genes (i.e., ftsK and ftsW) is downregulated [21]
    • Upregulation genes for proteins
      • With functions in cell wall structure (ompA and ompB)
      • Glycolysis (pyk)
      • Peptidoglycan synthesis (nlpD)
  • May allow the organism to resist [21]


Aspirin

  • At high doses (1 and 2 mM)
  • Inhibited the formation of chlamydial inclusion bodies and proliferation
    • In HEp-2 cells
  • Might be associated with the
    • Inhibition of host-cell metabolism
    • Including depletion of essential factors during chlamydial growth
  • Inhibition of chlamydial growth by aspirin was overcome when tryptophan was added [35]
    • no significant effect of tryptophan addition alone on chlamydial growth in the absence of aspirin [35]
  • Aspirin způsobuje depleci nitrobuněčného tryptofanu ??? To by bylo dosti nežádoucí u jedinců bez C.p. infekce... ?? To by si buňky nemohly syntetizovat melatonin a rychleji by stárnuly ? Jak to je?


Strategie

  • Cílem této rešerše tedy je postupně hledat a doplňovat maximum informací o účinných látkách (a jejich dostupnosti), které by byly nějakým způsobem účinné v potlačování či eliminaci infekce Chlamydia pneumonia a zvyšovaly tak efektivitu antibioticé terapie a snižovaly riziko vzniku rezistence, recidivy atp. V idálním případě, aby byly netoxické a daly se dlouhodbě užívat. (Za bezpečnost uvedených informací nemohu nijak ručit, je to pouhý výsledek hledání v textech na internetu bez možnosti ověřování - indicie k dalšímu ověření).
  • "By combining compounds that target and disrupt bacterial cellular membranes with compounds which neutralize bacterial virulence mechanisms while supporting the host body’s immune responses it should be possible to completely neutralize infective bacteria." [62]
  • "Allow prolonged treatment periods where necessary, while avoiding the ability of a specific pathogen to adapt and develop resistance to treatment, thereby providing relief from chronic conditions." [62]
  • Opravdu je zajímavé sledovat, že kde co, co vychází, že funguje dobře ve zpomalení a oddálení progrese aterosklerozy, jako přírorní léčba protrahovaného kašle nebo postinfekčního astmatu, tak nějakým způsobem inhibuje C. pneumonia.
  • Epidemie astmatu a dalších nemocí......asi není divu, že se tomu tak děje, když se dnes předepisují lokální a inhalační kortikoidy skoro uplne na potkání na skoro uplně všechno. Pak bakterie tyou Chlamydie může infikovat a přecházet do chronicity a více do těla mnohem snáze a více.

Abecední seznam dohledaných látek s prokázanou účinností proti Chlamydia pneumonia


ACC

  • Extracellular forms - EB - may be depleted by giving N-acetyl cysteine [27]
  • Thiol-containing amino acid
  • Readily absorbed
  • Non-toxic
  • Ability of this molecule to destroy chlamydial elementary bodies
  • Powerful antioxidant
    • Replenishes intracellular glutathione
  • May also be effective in inactivating fungal gliotoxins

Destroying the elementary bodies

  • C.p. possess cysteine-rich proteins on the surface membrane of the spore-like EB
  • Cysteine contains a sulfhydryl ( —S-H ) group
    • Disulphide bond ( —S-S— ) can form between two cysteine molecules
    • Such cross-linking bonds are common within and between the EB surface proteins
    • Thought to preserve the integrity and shape of the EB
    • These disulphide bonds are accessible for cleavage
  • Reduction of these bonds
    • Disrupts the integrity of the EB's surface
      • May be the mechanism how EB rapidly opens within the endosome
      • Chlamydial body must avoid fusion with the host lysosome or it will be killed
  • Chlamydial surface proteins
    • Must be opened
      • Up just prior to or
      • During attachment to the host cell [27]
      • [Raulston JE et al., Surface accessibility of the 70-kilodalton Chlamydia trachomatis heat shock protein following reduction of outer membrane protein disulfide bonds. Infect Immun. 2002; 70(2): 535-43.]
  • Mechanisms of chlamydial attachment to the host cell membrane
    • Entry into the cell
    • Ability to rapidly open
    • Subvert host cellular activities
    • Ability to evade host-defences
    • Track actively across the host cytoplasm taking what it needs
    • Induce endosomal formation
    • Once the EB is in the endosome, time is of the essence [27]
    • It has only a limited amount of preformed proteins
    • It must get to work metabolizing as fast as possible [27]
  • Were the EB coat to be opened up before achieving attachment to a nutrient-rich host cell
    • Unprotected EB would perish through starvation [27]
  • EBs may accumulate in extracellular spaces awaiting their chance to enter host cells
    • May be analogous to the 'acellular (or extracellular) load' seen in HIV infections [Chuck Stratton, personal communication.] [27]
  • N-acetyl cysteine
    • A thiol antioxidant
    • Good candidate for the reduction of disulphide bonds in EB coating proteins
    • Readily available as a health supplement without the need for prescription [27]

Penicillamine (dimethyl cysteine)

  • Reduces disulphide bonds
  • Inactivates EBs in vitro
  • Prevents the initiation of infection in vivo

Amoxycillin

  • B-lactam antibiotic
  • Also effective in inactivating EBs in vivo
  • Penicillamine is one of its major metabolites [Chuck Stratton, personal communication.] [27]

The NAC Test

  • One indirect indicator of chronic infection
  • Ability of NAC to rupture the extracellular Elementary Body by opening up surface disulphide bonds in the organism’s geodesic coat
  • The release of naked bacterial components causes local inflammatory symptoms
  • EBs are more numerous in primary respiratory infections
    • Acellular load of EBs is likely to be highest around respiratory structures
  • Daily administration of 2.4 G of NAC will cause, after a few days
    • Sinusitis-like symptoms
    • With watery mucous
    • Cough productive of a clear, moderately viscous sputum
  • Systemic symptoms — 'NAC flu' — may also occur
  • If symptoms are severe
    • Dose of NAC may be cut down to 600mg
  • Symptoms wane
    • After a few days if the chlamydial load is small
  • If the load is large, may continue for a month or more
  • NAC is unlikely to produce die-off reactions with any other genus [27]

NAC's other valuable properties

  • Ability to replenish depleted glutathione in an animal model with defective transporter neuronal proteins is dramatic.
    • [Aoyama K, Suh SW, Hamby AM, Liu J, Chan WY, Chen Y, Swanson RA. Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nat Neurosci. 2005 Nov 27; {Epub ahead of print}] [27]
    • Major oxidative stress is a cause of cell-death in MS
    • NAC's antioxidant benefits may not be limited to the replenishment of depleted glutathione.
      • [Gosset P, Wallaert B, Tonnel AB, Fourneau C. Thiol regulation of the production of TNF-alpha, IL-6 and IL-8 by human alveolar macrophages. Eur Respir J. 1999 Jul;14(1):98-105.] [27]
  • Preventing further new infections with C. pneumoniae
    • Averting the risk of MS relapse which this can produce [27]
  • Ameliorating intracellular infections
    • Such as influenza A
    • Known to precede MS relapse too [27]
  • Modulating the immune response
    • Cells more resistant to the effects of proinflammatory cytokines such as TNF-a [27]
  • Chelates heavy metals [27]
  • Moderate the effect of endotoxins made by chlamydiae [27]
  • May be of particular importance in demyelinating conditions
    • Moderate lipid peroxidation
    • May also moderate the induction of ceramide production by TNF alpha and consequent cell-death
      • [Singh I, Pahan K, Khan M, Singh AK. Cytokine-mediated induction of ceramide production is redox-sensitive. Implications to proinflammatory cytokine-mediated apoptosis in demyelinating diseases. J Biol Chem. 1998 Aug 7;273(32):20354-62.]
    • Thiol depletion of itself could induce ceramide production independently of TNFalpha
      • 'NAC, which has been used to block the cytokine-induced ceramide production in this study and to inhibit cytokine-mediated induction of inducible nitric oxide synthase in a previous study
      • Enters the cell readily
      • Serves both as a scavenger of ROS and a precursor of GSH, the major intracellular thiol [27]
    • May be beneficial in restoring cellular redox and in inhibition of cytokine-mediated induction of inducible nitric oxide synthase and breakdown of sphingomyelin
      • Reducing NO-mediated cytotoxicity
      • Reducing ceramide-mediated apoptosis in neuroinflammatory diseases [27]
  • Persons with a high EB load
    • Variety of symptoms as the EBs are ruptured and endotoxin and other bacterial material are released
      • Pain round the eyes and over the sinuses
      • Wheezing
      • Sputum production
      • Joint pain
      • Pain in soft tissues
      • Abdominal discomfort
    • Symptoms tend to last a month or so [27]

N-acetyl cysteine and Gliotoxin

  • Poisonous metabolite secreted by Candida sp. [27]
  • In preventing the establishment of fungal infections such as candidiasis
    • [Shah DT, Larsen B. Clinical isolates of yeast produce a gliotoxin-like substance. Mycopathologia. 1991 Dec;116(3):203-8.] [27]
  • Mycotoxins which cause damage to the immune system
  • Provoking caspase-mediated apoptosis in monocytes and macrophages
  • Gliotoxin molecules contain a highly active surface disulphide bond
    • Being reduced, damages host proteins by altering their structure
  • Gliotoxin may also deplete host glutathione
    • Removing host antioxidant potential
    • Increasing free radical damage
  • Molecule has been shown to oscillate between oxidized and reduced forms
    • With the production of unstable peroxides
  • Gliotoxin may be fundamental to the establishment of chronic colonization
    • Locally high levels are found, for instance, in the genital tract of women with severe vaginal candidiasis
      • [Shah DT, Glover DD, Larsen B. In situ mycotoxin production by Candida albicans in women with vaginitis. Gynecol Obstet Invest. 1995; 39(1): 67-9.]
  • Gliotoxin is a potent neurotoxin
  • May alter gut motility [27]
  • Impairs the efficiency of host polymorphonuclear neutrophils [27]
    • [Shah DT, Jackman S, Engle J, Larsen B. Effect of gliotoxin on human polymorphonuclear neutrophils. Infect Dis Obstet Gynecol. 1998; 6(4): 168-75.]
  • Intestinal gliotoxin may cause dysfunction of the gut barrier by damaging enterocytes
    • [Upperman JS, Potoka DA et al., Mechanism of intestinal-derived fungal sepsis by gliotoxin, a fungal metabolite. J Pediatr Surg. 2003 Jun; 38(6): 966-70.]
  • Gliotoxin is a virulence factor in other fungal infections such as invasive aspergillosis [27]
  • N-acetyl cysteine
    • May be expected to neutralize gliotoxin by opening the disulphide bond
    • Has been shown to be protective in vitro.
      • [Zhou X, Zhao A, Goping G, Hirszel P. Gliotoxin-induced cytotoxicity proceeds via apoptosis and is mediated by caspases and reactive oxygen species in LLC-PK1 cells. Toxicol Sci. 2000 Mar; 54(1): 194-202.]
    • It probably acts by opening the gliotoxin disulphide bond
  • Dithiothreitol also opens available disulphide bonds
    • Protected gut cells from gliotoxin-mediated apoptosis
  • Not all orally taken N-acetyl cysteine is absorbed
    • That which remains in the gut may be useful in counteracting gliotoxin produced by intestinal candida
  • NAC does not possess intrinsic activity against the yeast itself
    • Candida albicans is not inhibited even by high concentrations (> 100 mg/L) of NAC [Wheldon D: unpublished data.] [27]
  • Good overview of gliotoxin and related mycotoxins
    • [Gardiner DM, Waring P, Howlett BJ. The epipolythiodioxopiperazine (ETP) class of fungal toxins: distribution, mode of action, functions and biosynthesis. Microbiology. 2005 Apr;151 (Pt 4): 1021-32.] the full text of which is available as a pdf file.
  • Gliotoxin- protein, toxic to the glial (gliocyte) classes astrocytes and oligodendrocytes
    • Found in the CSF of persons with MS
      • [Menard A, Amouri R, Dobransky T, et al., A gliotoxic factor and multiple sclerosis. J Neurol Sci. 1998 Feb 5; 154 (2) : 209-21.]
  • Other sulphur-containing organic molecules have anti-candidal activity
    • Allicin, which is found in garlic
      • [Yamada Y, Azuma K. Evaluation of the in vitro antifungal activity of allicin. Antimicrob Agents Chemother. 1977 Apr;11(4):743-9.]
  • N-acetyl cysteine and selenium
    • Seem to be useful supplements for restoring GSH stores
    • Important in regeneration of other antioxidants [40]

Glutathion - redukovaný - GSH

  • GSH is a tripeptide composed of
    • Glutamate
    • Cysteine
    • Glycine
  • Must be made in the body
  • Glutamate and glycine
    • Well represented in the diet [40]
  • Cysteine
    • Concentration in the diet is limiting factor in the synthesis of glutathione
    • Best form of supplementation is N-acetyl cysteine (NAC)
      • Safer than cysteine [40]
  • Supplementation of diet with NAC in MS patients
    • Elevates levels of GSH peroxydase
      • [Mai J et al., High dose antioxidant supplementation to MS patients. Effects on glutathione peroxidase, clinical safety, and absorption of selenium. Biol Trace Elem Res. 1990 Feb;24(2):109-17.]

GSH peroxydase

  • Selenium is required for the synthesis
  • Levels are low in patients with MS
  • Supplementation with selenium normalized the low levels [40]

2-methoxy-alpha-naphthoflavone

Synonyma

  • 2'-METHOXY-7,8-BENZOFLAVONE
  • 2''-METHOXY-A-NAPHTHOFLAVONE
  • 2'-METHOXY-ALPHA-NAPHTHOFLAVONE [69]
  • CBNumber: CB7195095
  • Molecular Formula: C20H14O3 [69]

Popis

  • Formula Weight: 302.32 [69]

Synthetic flavone derivative

  • Alpha-Naphthoflavone = 7,8-benzoflavone = 2-phenyl-benzo(h)chromen-4-one
  • Can be prepared from 2-naphthol and cinnamaldehyde [72]

Účinky 7,8-benzoflavone

  • One of the most potent inhibitors of breast cancer resistance protein (BCRP)
  • Rats
    • Nonlinear pharmacokinetics of 7,8-benzoflavone
    • Dose-dependent bioavailability
    • Linear absorption
    • Nonlinear elimination [71]

.benzoflavone.jpg


Podpůrná terapie a opatření


Treatment and prevention

  • Charles W. Stratton, MD William M. Mitchell, MD PhD Vanderbilt University School of Medicine Nashville, Tennessee 37232
  • Antiporphyric regimen and vitamin B12 therapy
    • Minimizes cellular damage and facilitates cellular repair
    • Following initiation of the antiporphyric regimen, the first atb added [31]






B-Complex Vitamins

  • Glucose is needed by host cells that are infected by chlamydiae
    • Assisted by taking B-complex vitamins [31]




Folic acid

  • 400 mcg twice per day [31]



B-1




B-2




B-5

  • Pantothenate 100 mg twice per day [31]



B-6




B-12

  • 5000 mcg sublingual three to six per day [31]
  • Initially 4000 - 5000 micrograms several times a day
  • Reducing to once daily after three months
  • There is often a functional B12 deficit
  • Hyperhomocysteinaemia
    • Frequently accompanies chronic Chl pneumoniae infection
    • Is thought to cause connective tissue damage
    • Potent neurotoxin with activity against cortical and hippocampal neurones
      • [1. Kruman II, Culmsee C, Chan SL, et al., Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 2000;20:6920-6:]
      • [2. Den Heijer T, Vermeer SE, Clarke R, Oudkerk M, Koudstaal PJ, Hofman A, et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 2002;126:170-5:]
      • [3. Leblhuber F, Walli J, Artner-Dworzak E, Vrecko K, Widner B, Reibnegger G, et al. Hyperhomocysteinemia in dementia. J Neural Tansm 2000;107:1469-74.]
  • An excellent review of Vitamin B12 and multiple sclerosis can be recommended here:
    • [Miller A, Korem M, Almog R, Galboiz Y. Vitamin B12, demyelination, remyelination and repair in multiple sclerosis. J Neurol Sci 2005 Jun 15;233(1-2):93-7.]



Vitamins C

  • 1 gram twice per day [31]
  • Nechala jsme si dát infuzi vit. C 7,5 g i.v. s glutathionem. Celých cca 7-10 dní jsem neměla obtíže s bolestí kloubů a šíje, než se to začalo zase pomalo vracet. Opakovaně mě přepadává skoro žravost citrusů. Nějaká souvislost s tím zjevně bude.



Vitamin E

  • 400 units twice per day [31]



L-carnitine

  • 500 mg twice per day [31]
  • Ten jsem zkusila, opravdu se mi potom výborně běhalo, byl to citelný zdroj energie
  • Treatment of MS patients with ALC
    • Decreased CSF levels of NO reactive metabolites and protein nitration
    • Increased content of GSH and GSH/GSSG ratio
  • Nitrosative stress is a major consequence of NO produced in MS-affected CNS
  • Possible important role for acetylcarnitine in protecting brain
  • Protect against acoustic damage to the inner ear in an animal model [40]
    • [Kopke R et al., Prevention of impulse noise-induced hearing loss with antioxidants. Acta Otolaryngol. 2005 Mar;125(3):235-43.]
  • ALC in the treatment of mild cognitive impairment and mild Alzheimer's disease showed significant efficacy vs. placebo.
    • [Ames BN, Liu J. Delaying the mitochondrial decay of aging with acetylcarnitine. Ann N Y Acad Sci. 2004 Nov;1033:108-16. Review.]
  • Efficacious in alleviating pain in patients with established diabetic neuropathy - improved:
    • Nerve fiber regeneration
    • Vibration perception [40]
    • [Sima AA et al., Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care. 2005 Jan;28(1):89-94.]
  • Found to protect against damage caused by beta-amyloid (Abeta)
    • ALC attenuated oxidative stress and cell death induced by beta-amyloid neurotoxicity [40]
    • [Dhitavat S, Ortiz D, Shea TB, Rivera ER. ALC protects against amyloid-beta neurotoxicity: roles of oxidative buffering and ATP levels. Neurochem Res. 2002 Jun;27(6):501-5.]
  • Oxidative damage to nucleic acids (8-hydroxyguanosine and 8-hydroxy-2'-deoxyguanosine) increased with age in the hippocampus
    • Occurred predominantly in RNA
    • ALC and / or a-lipoic acid significantly reduced the extent of oxidized RNA
      • Combination being the most effective [40]
      • [Liu J et al., Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-a -lipoic acid. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2356-61. Erratum in: Proc Natl Acad Sci U S A 2002 May 14;99(10):7184-5.]



Ubiquinone -coenzyme Q10

  • 30 mg twice per day [31]
  • Lipid-soluble molecule
  • Active in the hydrophobic core of the phospholipid bilayer of the inner membrane of mitochondria
  • Electron transfer within the electron transport chain
  • Important antioxidant within the mitochondrion.
  • Ability of the body to synthesize CoC10 begins to diminish surprisingly early in adult life
    • [Kalen A et al., Age-related changes in the lipid compositions of rat and human tissues. Lipids. 1989 Jul;24(7):579-84.] By mid-life most people are dependent on dietary sources.
  • Lipid peroxidation diminishes CoC10 levels in cells
    • [Forsmark-Andree P et al., Lipid peroxidation and changes in the ubiquinone content and the respiratory chain enzymes of submitochondrial particles. Free Radic Biol Med. 1997;22(3):391-400.]
  • When CoC10 levels become low:
    • Lipid peroxidation ++
    • CoQ10 depletion +++
    • Resulting in mitochondrial damage
  • Q10 supplementation
    • Doubles the number of ubiquinol-10-containing low-density lipoprotein (LDL) molecules [40]
    • May therefore have an inhibitory effect on LDL oxidation [40]
      • [Aejmelaeus R et al., Ubiquinol-10 and total peroxyl radical trapping capacity of LDL lipoproteins during aging: the effects of Q-10 supplementation. Molecular Aspects of Medicine 18(Suppl.) (1997), s113-s120.]
  • Protected against toxic damage to neurones in animal studies [40]
    • [Beal MF et al., Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate. Ann Neurol. 1994 Dec;36(6):882-8]
  • Protected against neurological damage caused by endotoxins [40]
    • [Chuang YC et al., Neuroprotective effects of coenzyme Q10 at rostral ventrolateral medulla against fatality during experimental endotoxemia in the rat. Shock. 2003 May;19(5):427-32.]
  • Combination found to improve and stabilize vision in age-related macular degeneration (AMD):
    • Acetyl L-carnitine
    • CoQ10
    • N-3 oils
      • [Feher J et al., Improvement of visual functions and fundus alterations in early age-related macular degeneration treated with a combination of acetyl L-carnitine, n-3 fatty acids, and coenzyme Q10. Ophthalmologica. 2005 May-Jun;219(3):154-66.]
    • One factor of AMD is chronic infection with Chlamydia pneumoniae
      • [Ishida O et al., Is Chlamydia pneumoniae infection a risk factor for age related macular degeneration? Br J Ophthalmol. 2003 May;87(5):523-4; Kalayoglu MV et al., Serological association between Chlamydia pneumoniae infection and age-related macular degeneration. Arch Ophthalmol. 2003 Apr;121(4):478-82; Robman L et al., Exposure to Chlamydia pneumoniae Infection and Progression of Age-related Macular Degeneration. Am J Epidem 2005 161(11):1013-1019.]
    • AMD is a disorder characterized by mitochondrial depletion and damage [40]
      • [Feher J et al., Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration.Neurobiol Aging. 2005 Jun 22.]




Biotin

  • 5 mg twice per day [31]
  • Cofactor in the synthesis of fatty acids, including myelin
  • 2015 pilot study of high-dose supplementation in persons with progressive MS
    • Surprising improvement in function in those with cord lesions
    • Improvement took 2 - 8 months to become manifest
    • [Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: A pilot study. Mult Scler Relat Disord 2015; 4: 159-169]
    • Dose used was 100 - 300 milligrams daily
  • Biotin is harmless
  • Only the pure form, unmixed with other supplements, should be taken
  • Sedel F, Bernard D, Mock DM, Tourbah A. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. 2016 Nov;110(Pt B):644-653 [40]

Alpha-lipoic acid - ALA

  • 400 mg twice per day [31]
  • mitochondrial energy production
  • Powerful antioxidant
  • Can be synthesized in the body
  • In conditions of chronic oxidative stress it may become depleted
  • Redukovaná forma ALA
    • Dihydrolipoic acid (DHLA)
  • ALA scavenges hydroxyl radicals
    • Hypochlorous acid
    • Peroxynitrite
    • Singlet oxygen [40]
  • DHLA
    • Scavenges superoxide and peroxyl radicals
    • Can regenerate
  • [reviewed by Packer L et al., Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition. 2001 Oct;17(10):888-95.]
  • Chelate to inorganic mercury
  • Increase the biliary excretion of mercury [40]
    • [Gregus Z et al., Effect of lipoic acid on biliary excretion of glutathione and metals. Toxicol Appl Pharmacol. 1992 May;114(1):88-96.]
  • Ameliorate oxidative damage caused by cadmium [40]
    • [Bludovska M et al., The influence of a-lipoic acid on the toxicity of cadmium. Gen Physiol Biophys. 1999 Oct;18 Spec No:28-32]

Vitamin D

  • 4000 iu is recommended [42]
    • Less may be needed in infections other than MS [42]
  • 1. D3 - cholecalciferol
    • Generated in the skin
    • Little biological activity
    • 2. 25(OH)D3
      • Vznikl alpha-hydroxylací in the liver
    • 3. 1,25(OH)2D3 - dihydroxy cholekalciferol
      • V ledvinách
      • Regulováno PTH
      • Greatest biological activity
  • MS has a geographical distribution
    • Incidence is lower in those who have a diet high in fish oils
    • Accords with the amount of sunlight received
      • With latitude
      • Cultural dictates, etc.
  • Vitamin D deficiency is common in MS
    • Bone mass density (BMD) lower in women with MS against controls
    • Parathyroid hormone (PTH) was frankly elevated in 13% of patients
      • Negatively correlated with
        • 25-hydroxycholecalciferol levels
        • BMD
  • calcium and vitamin D deficits increase
    • The risk of malignancies
      • Colon
      • Breast
      • Prostate gland
    • Chronic inflammatory
    • Autoimmune diseases
      • Insulin-dependent diabetes mellitus
      • Inflammatory bowel disease
      • Multiple sclerosis
    • Metabolic disorders
      • Metabolic syndrome
      • Hypertension [46]
  • Intake of vitamin D from supplements was inversely associated with risk of MS
  • Supplementation with Vitamin D in MS
    • Followed by elevation TGF-b [46]
      • Broadly anti-inflammatory signalling protein
      • Promote wound healing
      • Inhibit macrophage and lymphocyte proliferation
  • Supplementation with Vitamin D, calcium and magnesium
    • Decrease of relapse rate in young people with RRMS [46]
  • 1,25(OH)2D3 directly induces specific antimicrobial gene expression and activity [46]
    • Production of cathelicidins
      • Marked antimicrobial activity
      • Promote wound healing
      • Re-epthelialization of breaks in the skin
      • Absent in chronic (non-healing) ulcers
      • Activity against intracellular bacteria
        • Demonstrated in Mycobacterium tuberculosis [46]
    • Active in the innate defence system of the gut
      • Lining the mucosa
      • Preventing attachment by epithelial-adherent bacterial pathogens
    • Active in vitro against Herpes Simplex Virus
      • Cathelicidin deficiency in eczema herpeticum [46]
  • Safe upper limit of supplementation in adults is officially declared to be 50 micrograms (2,000 IU) [46]
  • 100 micrograms (4000 iu.) may be safely given
    • In older persons may be necessary [46]
    • Absence of toxicity in trials on healthy adults vitamin D dose > or = 250 microg/d (10,000 IU vitamin D3)
      • [Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6-18.]
  • High dose Vitamin D important to those receiving (je možná fotoxicita):
    • Doxycycline
    • Minocycline [46]
  • It is important to take the D3 form [46]

Magnesium

  • 300mg [42]

Calcium

  • 500mg
  • Calcium salts should be taken remote from doxycycline as it can interfere with absorption [42]

Bioflavinoids - proanthocyanidins

Pygnoginol

Quercetin

  • Very effective antioxidants [31]


Selenium

  • 100 mcg twice per day
  • Should be taken with the vitamin E [31]


L-Glutamine

  • 2 - 4 grams twice per day [31]


Querceten

  • 400 - 500 mg twice per day [31]


Glucosamine

  • 750 - 1000 mg two or three times per day [31]


Chondroitin sulfate

  • 250 - 500 mg twice per day [31]
  • Tohle mi na kloubní bolesti pomáhá. Když to pár týdnů nemám, je to horší. Tak nějak sama poksu omyl sem dospěla k tomu, že tohle musím tu a tam prostě zobat a ještě s hořčíkem a vit. D a vápníkem tu a tam k tomu, abych ty kloubní potíže držela nějak rozumně a nezhoršovalo se to. Jen poslední dobou se to zhoršilo tak rychle, že tohle přestalo fungovat.






Antiporphyrinic Drugs

Benzodiazapine Drugs

  • Xanax (0.5 mg three or four times per day) if panic attacks [31]
  • Restoril (30 mg at night) If insomnia [31]
  • Hydroxychloroquine Hydroxychloroquine (100 - 200 mg once or twice per day) often used to treat porphyria [31]
    • For patients with symptoms of porphyria, a single 100 mg dose of hydroxychloroquine may be tried
      • If this trial dose relieves the symptoms, hydroxychloroquine may be continued
      • Dose must be adjusted for each patient
      • Most patients do well on 100 mg once per day [31]

Oral Activated Charcoal

  • Absorbs fat-soluble porphyrins [31]
  • Binds these porphyrins in the gastrointestinal tract
    • Prevents them from being reabsorbed in the small intestine
  • Start with 2 grams (eight 250 mg capsules) of activated charcoal three times per day on an empty stomach
  • Gradually increase to 4 grams taken three times per day
  • Much more activated charcoal can be safely taken
    • 20g 6xd po 9 měs. bylo without any adverse side effects [31]
  • Important on a completely empty stomach without any food, vitamins, or medications
    • 2 hours before or 2 hours after charcoal ingestion [31]

Subtle and unrecognized vitamin B12 deficiency at the cellular level

  • Functional B12 deficiency:
    • Vitamin B12 level (usually normal or low)
    • Serum homocysteine
    • Methylmalonate levels
      • One or both metabolites will be elevated [31]
  • Can corrected by high-dose vitamin B12 therapy
  • 1. Vitamin B12 Therapy Prior to Chlamydial Therapy Adults
    • First several days 6,000 mcg of i.m./s.c.
    • Each of the next 3 weeks 6,000 mcg is given once per week [31]
  • 2. Vitamin B12 Therapy During Chlamydial Therapy
    • Increased need for vitamin B12
    • 6,000 mcg of parental vitamin B12 (3,000 mcg in each anterior thigh) once per week
    • In addition 5,000 mcg of sublingual vitamin B12 three times each day [31]
  • 3 Vitamin B12 Therapy Post Chlamydial
    • Vitamin B12 and serum homocysteine/methylmalonate levels should be rechecked
    • If the methylmalonate level remains elevated, continued vitamin B12 deficiency
    • P.o. 5,000 mcg of cobalamin 3xd should be continued
    • After several months, 6,000 mcg of parental vitamin B12 may be given [31]

Vlastní dojem

  • To je jak záplatovat děravou loď. Výčet samých super věcí, ale kolik bych toho musela celkem denně sníst a kolik by mě to všechno stálo. Už teď sem si připadala skoro jako blázen s pocitem, že toho mám moc. Je to výzva ke zdravým potravinám, kvantům zeleniny a ovoce, bylinek ale ne k ládování se bílým pečivem a těstovinami a polykání doslova haldy drahých tabletek z lékárny, které stejně neřeší samotnou podstatu problému. Jen jakási nouzová pomoc k překlenutí nějaké příšerné krize, ale tohle není to řešení. Ok. Vše se točí kolem záchrany neuronů a prevence zhoršení funkce mozku. V případě neurologických obtíží a denerace tedy zcela na místě. S tímhle ohledem mi to dává větší smysl než megadávky kortikoidů. Tohle aspoň dává smysl. Neřekla bych ani popel.

Melatonin

  • Indole
  • Hormone biosynthesized from L-tryptophan within the pineal gland in the brain [40]
  • Regulate sleep [40]
  • Numerous and diverse actions in the cell [40]
  • Potent antioxidant [40]
  • Protecting mitochondria from oxidative stress [40]
  • Acts directly on the electron transport chain [40]
    • Increasing ATP synthesis [40] [40]
    • Preventing the oxidative damage associated with such an increase [40]
  • Restored levels of the important antioxidant glutathione [40] [40]
  • Able to pass into any tissue, cell or cell compartment with ease [40]
  • Normal dietary constituent [40]
    • Walnuts are a particularly rich source [40]
    • Dietary MEL can markedly influence blood-levels [40]
  • Protects against endotoxin-induced lipid peroxidation [40]
  • Stimulate some important antioxidative enzymes [40]
    • Superoxide dismutase
    • Glutathione peroxidase [40]
    • Glutathione reductase [40]
  • Effective in reducing macromolecular damage [40]
    • Paraquat toxicity [40]
    • Potassium cyanide administration [40]
    • Lipopolysaccharide treatment [40]
    • Kainic acid injection [40]
    • Carcinogen administration [40]
    • Carbon tetrachloride poisoning, etc. [40] [40]
    • Reducing the oxidation of macromolecules that occurs during strenuous exercise or ischemia-reperfusion [40]
  • Effective in reducing neuronal damage [40]
  • no toxicity [40]
  • Crosses morphophysiological barriers and enters subcellular compartments [40] [40]
  • Inhibit the production of endotoxin-induced Tumour Necrosis Factor alpha. [40]
  • Immunoregulatory effects via T-helper 2 (Th2) cell products [40]
    • Deve[40]lopment of septic shock associated with endotoxemia
  • Diminished levels of MEL in the ventricular CSF of those who had died with Alzheimer's disease [40]
  • Uniformly low in those who had died with advanced dementia, irrespective of their age. [40]
  • MEL depletion was found to be a very early event in the development of AD. [40]
  • A loss of the diurnal rhythm of MEL levels may precede the first clinical signs of the AD [40]
  • MEL ameliorated evening agitation [40]
  • Improved cognitive and non-cognitive functions in patients with AD [40]
    • It took several weeks for benefits to appear [40]
      • Action other than sedation, which is immediate
  • Sleep disorders are common in MS, with a flattening of the normal circadian sleeping/waking rhythm [40]
    • Wakefulness at night [40]
    • Tendency to somnolence during the day [40]
    • May be due to decreased nocturnal biosynthesis of MEL [40]
  • Decreased MEL biosynthesis is associated with pineal calcification. [40]
    • Pineal calcification is common in MS. [40]
    • MEL levels were found to be lower than daytime levels in 11 of 25 patients with MS
  • MEL is a major antioxidant in the brain [40]
    • Chronic depletion would be expected to allow widespread oxidative damage in the CNS [40]
  • Correct disordered steroid metabolism [40]
    • Hypothalamic - pituitary - adrenal (HPA) axis activation of the HPA axis in MS [40]
      • Activation of corticotropin releasing hormone (CRH) neurons [40]
      • + cortisol in the cerebrospinal fluid [40]
      • + basal cortisol levels increased in the CSF of MS patients [40]
        • Can be damaging, particularly to the hippocampus [40]
    • Dietary MEL reduced hypothalamic CRH [40]
  • MEL attenuates the adrenocortical response to stress [40]
    • Influences the biosynthesis, release and glucocorticoid responsiveness of hypothalamic ACTH secretagogues [40]
  • Depression can be set in motion by dysregulation of the HPA axis [40]

Lactobacillus acidophilus

  • Daily, either as a supplement or in capsules
  • To maintain bowel flora in the face of antibiotic treatment [42]

6,2-Dimethoxyflavone

Synonyma

  • PubChem CID: 676288
  • 6,2'-dimethoxyflavone
  • ST055984
  • 6-methoxy-2-(2-methoxyphenyl)chromen-4-one
  • 6-methoxy-2-(2-methoxyphenyl)-4H-chromen-4-one
  • 156464-92-5
  • ZINC00039291
  • Molecular Formula: C17H14O4

Popis

  • Molecular Weight: 282.295 g/mol

Příbuzné látky (jsou jich tisíce)

5-Hydroxy-6,2'-dimethoxyflavone

  • From Primula denticulata = Prvosenka zoubkatá
  • Isolated from the leaf exudate [70]
    • 5-hydroxyflavone
    • 2‘-hydroxyflavone
    • 5,2‘-dihydroxyflavone
    • 5,8-dihydroxyflavone
  • Induced little apoptosis, low toxicity
  • Primula flavonoids
    • Possessed strong cytostatic properties even at low concentrations
      • Human acute myeloid leukemia cells [73]
    • The cell cycle distribution showed a characteristic time-dependent shift
      • Short-lived effect of the test compounds in the exposed cells [73]

5,6,2'-trimethoxyflavone

  • Sargentia greggii [70]

6-Methylcoumarin

Synonyma

  • 6-MC
  • Pralina
  • Toncair
  • 6-Methyl
  • Toncarine
  • FEMA 2699
  • Cocodescol
  • NCI-C55812

Výskyt

  • Not found in nature [74]

Použití

  • Flavor: Dry herbaceous coconut
  • One of the most important constituent of coconut flavours
  • Used effectively in:
    • Nut, caramel, butter, date, fig, root beer etc. [74]
  • Frequently used in various vanilla compositions
  • Extra ordinary stability towards heat
    • Excellent for flavour meant for baked goods
  • Concentration in finished products is usually less then 30 ppm [74]

7-dimethylamino-3-thenoylcoumarin

Synonyma

  • 7-(diethylamino)-3-(thiophen-2-ylcarbonyl)-2H-chromen-2-one
  • CBNumber: CB2342193
  • Molecular Formula: C18H17NO3S [75]

Popis

  • Yellow powder [75]

Varování

  • May cause eye and skin irritation
  • May cause respiratory and digestive tract irritation
  • The toxicological properties of this material have not been fully investigated [75]

Dietní doporučení



High Carbohydrate Diet

  • Cca 70% of the daily caloric intake of complex carbohydrates
    • Bread, potato, rice, and pasta [31]
  • Remaining 30% of calories in protein and fat
    • White fish or chicken [31]
  • Proboha proč tohle??? To mi vysvětlí jak?

Glucose

  • Important source of cellular energy reduced with chlamydial infections
  • Increasing the availability of glucose provides optimal conditions for the cells to produce energy [31]
  • Takhle jíst, tak ze mě bude za chvíli tak akorát tlustá koule. Ale je pravda, že když jsem zkoušla jíst jenom 2x denně a otužovat se, tak sem to přehnala a obtíže s bolestí krční ptáteře se mi skoro skokově zhoršily a místo toho, abych byla odolnější, tak sem se pak cítila zchátralejší a zdegenerovanější. Oboje působí imunosupresivně. Zjevně nemám zánět autouimunitní, ale infekční a reakce jsou opačné.
  • Občas abych se vydržela v práci soustředit, piju čaj a kávu a nepomáhá to jako dřív, ale čokoláda a sladkosti ano i za cenu toho, že po tom fakt tloustnu. Občas se však stává, že už nepomůže ani sníst těch sladkostí hodně. To je asi jeden z momentů, kdy si clovek rika, ze uz to zacina byt vazny. Vsechny tyhle symptomy zmizely skoro okamzite do ruhého dne po nasazení Azitromycinu. Nic se nezhorsilo.
    • Augmentin, ktery jsem uzivala cca měsíc před Azitromycinem na doporučení lékaře, kdy všichni ostatní členové rodiny měli výtěry pozitivní na Streptokoka A a já sem se cítila unavená a zadýchávala jsem se, mi sice první dva dny mírně snížil únavu a zadýchávání se, ale dalších 5 dní, co sem ho užívala, se už stav neměnil a vliv na schopnost vydržet se soustředit, stahující se šíji a míru kloubních bolestí to nemělo skoro žádný nebo jen minimální.

Sucrose

  • Mixture of glucose and fructose
  • Not the best way to increase the glucose availability [31]

Fructose

  • Excess of fructose may temporarily reduce the availability of glucose at the cellular level
  • Should be avoided as much as possible [31]






Avoid Alcohol

  • Well-known aggravator of porphyria
  • Should be avoided as much as possible [31]

High Oral Fluid Intake

  • water
    • Bicarbonated water
    • "sports-drinks" [water with glucose and salts]
    • Helps flush water-soluble porphyrins
  • Dehydration
    • Concentrates porphyrins
    • Makes patients more symptomatic [31]
  • The color of the urine should always be almost clear rather than dark yellow
  • Voda pomáhá od kde čeho...





Avoid Red Meats

  • Including beef and dark turkey, tuna and salmon
    • Contain tryptophan
      • Should be avoided as much as possible [31]
  • Tole by mi dávalo smysl. Když jsem si dávala L-tryptofan na zlepšení kvality spánku (ráno sem se cítívala málo odpočatá), asi mě potom bolely klouby a svaly ještě víc, ale nedávala jsem si to dohromady. Že mám po proteinových nápojích asi silnější potíže se zánětem, toho jsem si pak už všimla. Že proteiny dodají sílu zánětu ať už je jakéhokoliv původu není těžké si představit.
  • V různých studiích o chlamdyiích sem vyčetla, že try je pro ně důležitý zdroj a že naše buňky se s nima o to přetahují. Pro Chl. je trp tak důležitý pro jejich replikaci, že zásoby trp v různých buňkách určují i tropismus toho, ve kterých buňkách se chlamydie budou nebo nebudou množit. Typicky trp musí být v buňkách, které si potřebují syntetizovat hodně melatoninu jako hlavního nejsilnějšího antioxidantu - a to jsou typicky buňky epitelů, sliznic, kůže a mozku, imunitního syst. atd. - dle toho, jak musí být schopné čelit ox. stresu. Otázka zrychleného stárnutí, oxidačního stresu a degenerace je tedy ve vztahu k chlamydiím velmi přiléhavá.






Avoid Milk Products

  • Contain lactose and lactoferrin [31]
  • A tohle je proč? Dříve jsem po některém mléku mívala jen ataky astmatu. To pak zmizelo po vyléčení se z Chlamydie. To už je cca 10 let. Nyní se stává, že občas po některém mléku (s kávou - v jiné podobě už ho nepiju) se mi totálně rozhodilo soustředění se, až jako šum v hlavě s bolestí šíje a až snad i hlavy, kterou jsem ještě nezanala. Myslela jsem si, že je to důsledek nějakého antigenu v mléce, reaktivní plicní zahlenění a následná hyperventilace a její důsledky na schopnost se soustředit. Kontrola dechu mi však moc nepomáhala. Párkrát jsem na to konto lehnula na gauč a usnula. Proč to je? Jaké to má souvislosti ?


C. pneumoniae vaccine

  • Vaccine offering long-lasting immunity in humans is not yet available
  • Identifying antigens that may elicit protective immunity
  • Need to confer stronger immunity than natural infection
    • Re-infection in humans after previous C. pneumoniae exposure is common [14]
    • Memory immunity elicited by C. pneumoniae appears to be short-lived and only partial [22]
  • Obligate intracellular pathogen may escape humoral immune defences [14]
  • Cellular immune responses
    • CD8+ T-cells
      • Appear to be necessary for protection against primary infection, as well as re-infection [14]
  • DNA immunization
    • Plasmid DNA encoding the antigen of choice
    • Injected into muscle
      • Where synthesis of the antigen takes place
    • Plasmid DNA itself constitutes a powerful T-helper cell adjuvant
      • Has immunostimulatory motifs
  • Tested DNA vaccines in animal models for several C. pneumoniae proteins
      • MOMP (major outer membrane protein)
      • Omp2
      • CHsp60 [14]
    • Were able to induce only partial protective immunity against C. pneumoniae challenge [14]
  • Recombinant protein vaccine
    • Induced an immune response able to completely eliminate C. pneumoniae infection in mice
    • The antigen, LcrE
      • Component of the chlamydial type III secretion system
    • Induced
      • CD4+ and CD8+ T-cell activation
      • Type I cytokine secretion
      • Neutralizing antibodies
      • Reduced the day 7 lung bacterial burden
        • To a level undetectable by conventional immunohistochemistry and barely detectable by PCR amplification
    • Inoculum remained present in unvaccinated mice and in those vaccinated with other chlamydial proteins
    • Thorpe et al. [14]

  • Vaccine Development and Field Trials Workshop Group
    • Clinical trials for a C. pneumoniae vaccine
    • Seroepidemiological studies suggest that children begin to seroconvert at approx. 5 years of age
    • Prophylactic use, the vaccine would need to be administered in infancy
    • A vaccine for therapeutic use in older subjects
      • Would be difficult to target and evaluate
        • Appropriate markers for identifying patients with chronic infection are not yet available

  • Outer membrane protein (MOMP)3 of C. trachomatis
    • Surface-exposed protein
    • Target for neutralizing Abs
    • Has made it the focus for vaccine development [22]

B2M – beta-2-microglobulin:

  • Enhanced severity of infection of TAP1-/-/beta2-microglobulin -/- mice (Rottenberg et al, 1999) [153]

BRCA1 – breast cancer 1, early onset

  • Reduced expression in isolated C.pneumoniae positive human atherosclerotic plaques (Ja et al, 2011) [153]

Bicyclic 9a-azalide derivatives

C4A complement component 4A and C4B complement component 4B (Chido blood group)

  • Deficiency in humans predisposes to chlamydial infections (Kozlov et al, 2001) [153]

CCND1 – cyclin D1

  • Upregulated by IFN- gamma
  • Induced persistent C. pneumoniae infection in HL cells (Mannonen et al, 2007) [153]

CD8A CD8B

  • Enhanced severity of infection of CD8-/- mice (Rottenberg et al, 1999)

CFP Properdin

  • Binds to C.Pneumoniae and promotes
    • Complement activation
    • Depositing complement components C3 and C9 on the bacterial surface (Cortes et al, 2011) [153]

CXCL9 chemokine (C-X-C motif) ligand 9

  • Alias:CMK, Humig, MIG, SCYB9, crg-10
    • Has antichlamydial activity
      • CXCL*, CXCL10 and CXCL11 induced by infection (Balogh et al, 2011) [153]

Chondroitin sulfate A

  • C. pneumoniae and C. trachomatis attachment inhibited by exogenous Csa (suggesting attachment to recptors containg Csa) (Yan et al, 2006) [153]

Echinacea

  • Stimuluje Th1 imunitu

Escherichia coli heat-labile enterotoxin

  • Th1-enhancing genetic adjuvant [122]
Umí E. coli ve střevě produkovat tohle ? Pomohlo by to v případě chronické infekce ?

Ethambutol


HMGCR – 3-hydroxy-3-methylglutaryl-CoA reductase

  • Inhibition reduces Chlamydia pneumoniae-induced cell interaction and activation (Dechend et al, 2003) [153]

Heparin

  • Binds to bacterial OmcB (Stephens et al, 2001) [153]

IDO1

  • Restricts bacterial growth
    • Via diversion of tyryptophan metabolism to the kynurenine pathway
      • A common bacterial defence mechanism (Njau et al, 2009) [153]

IFN-gamma

  • Antichlamydial effect of interferon-gamma In macrophages enhanced by
    • Interleukin-1 (IL-1)
    • Lipopolysaccharide (LPS)
    • LPS -max. at 100 ng/ml
    • TNF-alpha -max. at ng/ml
      • By increasing indoleamine 2,3-dioxygenase (IDO) activity in a dose-dependent manner [118]
  • Tumor necrosis factor-alpha (TNF-alpha)
    • Inhibited chlamydial growth in a dose-dependent manner
      • Only in IFN-treated macrophages [118]
  • Excess tryptophan
    • Reversed the effect of combined cytokine treatment
    • IDO alone was responsible for chlamydial inhibition [118]
  • Depletion of intracellular tryptophan pools
    • By IFN-gamma–induced activation of the indoleamine 2,3-dioxygenase (IDO)
      • Supposed to be of uppermost importance in C. trachomatis persistence [118]
  • An increased survival of genital C. trachomatis strains in an IFN-?–rich environment
    • Documented to facilitate the development of chronic infections
  • IFN-gamma–mediated mechanisms that inhibit chlamydial growth reported
    • All of them are mediated by the JAK-STAT signaling pathways [118]
  • IFN-gamma can induce indoleamine 2,3-dioxygenase (IDO) activity in aortic smooth muscle cells
    • IDO-mediated increase in tryptophan catabolism
      • Resulted in a dose-dependent marked inhibition of C. pneumoniae replication
        • Marked inhibition of C. pneumoniae growth [119]
        • Capable of maintaining intracellular viability for long periods of time but unable to infect other host cells [119]
  • Low levels of IFN-? induced an altered life cycle of C. pneumoniae,
    • With subsequent recovery of an infectious organism through the addition of excess tryptophan [119]
  • Undergo similar morphological alterations in the presence of ampicillin
    • Found to be noninfectious in the presence of ampicillin
    • Infectious elementary bodies were regenerated once the antibiotic was removed [119]
  • Animals lacking IFN-gamma signaling
    • Bacterial loads are higher
    • Clearance of organisms is greatly hampered [120]
  • IFN-gamma is a critical cytokine in
    • Protection against infection
    • Reduction of pulmonary C. pneumoniae loads (Rottenberg et al., 2000) [132]





IFNG interferon, gamma

  • Intra-nasal bacterial inoculation increases plasma levels of IL2, IL5, IL6, IL10, IL12, GM-CSF (= CSF2) , IFN-gamma, and serum amyloid A (Campbell et al, 2010) [153]

IFNGR1 – interferon gamma receptor 1

  • IFN-gamma-/- or IFN-gamma receptor (R)-/- mice
    • Are highly susceptible to infection with C. pneumoniae (Rothfuchs et al, 2006) [153]

IGF2R mannose 6 -phosphate IGF2 receptor

  • Used in epithelial cells (Puolakkainen et al, 2005) [153]
  • Retinoic acid
    • Also inhibits chlamydial growth via this receptor Puolakkainen et al, 2008 [153]


IGFBP6 – insulin-like growth factor binding protein 6

  • Upregulated by IFN- gamma -induced persistent C. pneumoniae infection in HL cells (Mannonen et al, 2007.) [153]

IL7R interleukin 7 receptor

  • Upregulated by IFN- gamma -induced persistent C. pneumoniae infection in HL cells (Mannonen et al, 2007.) [153]

Production of mucosal antibody

  • Protective (Penttiläet al., 2006; Rodríguez et al., 2006) [132]

Isonicotinic acid congeners

  • Effective against the replicating and cryptic stationary phases of Chlamydia (and possibly against some other stages of the cryptic phase)
  • Comprises
    • Isonicotinic acid congeners

      • Isoniazid (INH) - most preferred

      • Isonicotinic acid (also known as niacin)

      • Nicotinic acid

      • Pyrazinamide

      • Ethionamide

      • Aconiazide

      • Niacin

  • Currently considered effective only for mycobacterial infections
  • In combination with other antibiotics, are particularly effective against Chlamydia
  • Isonicotinic acid congeners
    • Target the constitutive production of catalase and peroxidase
      • Characteristic of microorganisms, such as mycobacteria, that infect monocytes and macrophages
      • Chlamydia can also successfully infect monocytes and macrophages
  • H to eradicate Chlamydia from macrophages and monocytes subsequently assists these cells in their role of fighting infection
  • However, these agents appear to be less effective, in vitro, against the cryptic phase
    • Ethambutol, INH and other isonicotinic acid congeners ideally should be used in combination with agents that target other phases of the chlamydial life cycle
  • Isonicotinic acid congeners
    • Excellent agents for the long term therapy of chronic/systemic chlamydial infection generally
      • In particular to chlamydial infection of endothelial and smooth muscle cells in human blood vessels
  • INH and its congeners can be used to clear infection from monocytes and/or macrophages
  • When monocytes and macrophages are infected by Chlamydia
    • Become debilitated and cannot properly or effectively fight infection
    • Is believed that, if the chlamydial infection, per se, is cleared from these cells, then the monocytes and macrophages can resume their critical roles fighting chlamydial or other infection(s)
  • Patient responsiveness to combination therapy can be optimized by the inclusion of isonicotinic acid congeners
  • Accordingly, one aspect of the invention provides a specific method for reempowering monocytes or macrophages that have been compromised by a Chlamydia infection
    • Compromised macrophages or monocytes can be activated by treating the chlamydial infection by contacting the infected macrophages and/or monocytes with an antichlamydial agent
www.google.com/patents/EP0981372A2

LCN2 lipocalin 2

  • Involved in host defence against Chlamydia
    • Presumably by limiting the availability of iron to the pathogen (Bellmann-Weiler et al, 2012) [153]

LDLR low density lipoprotein receptor

  • Delivery of C.pneumoniae to the vessel wall aggravates atherosclerosis in LDLr knockout mice (Hauer et al, 2006.) [153]

LTA – lymphotoxin alpha (TNF superfamily, member 1)

  • Inhibits C. pneumoniae growth in HEp-2 cells (Matsushima et al, 1999) [153]

Leucine, isoleucine, methionine and phenylalanine

  • Inhibit the growth of C.trachomatis and C.Pneumoniae [153]

Melatonin and serotonin

  • Inhibit chlamydial infection, not by effects on the bacterium itself, but via host receptors for these transmitters
  • Buspirone (HTR1A partial agonist)
    • Partially decreased infection
  • NAN190 (HTR1A and HTR1F agonist)
    • Partially decreased infection
  • Melatonin agonist IIK7 ( MTRN1A and MTNR1B agonist) and antagonist, luzindole
    • Decreased chlamydial infection as effectively as melatonin (Rahman et al, 2005) [153]
  • GPR50 dimerises with melatonin receptors [153]
  • Melatonin and serotonin
    • Reduced chlamydial infection
      • But not other bacterial growth tested [163]
  • melatonin limited infection of all three chlamydiae
    • Effects were not recovered by tryptophan supplementation !!! [163]
  • Melatonin treatment only of host cells could diminish infection
    • Infection reduction was neutralized by a pertussis toxin !!
  • Inhibition mechanisms of chlamydial infection by melatonin and serotonin
    • Appear to be different from those of IFN-gamma
    • Involve specific G-protein-coupled receptors [163]
  • Melatonin
    • Inhibit early progression of the chlamydial development cycle
      • Establishment of intracellular infection
      • And/or conversion from elementary body to reticulate body [163]
  • Utilization of melatonin, serotonin or their derivatives
    • May be advantageous for harmless prevention of chlamydial infection [163]
Další z vysvětlení proč málo spánku vede k vyššímu výskytu všech možných nemocí a úmrtí na ně a proč dobrá nálada - bez deprese - je prventivní faktor kardiovaskulárních chorob i Alzheimerovy nemoci.


NOS2 nitric oxide synthase 2, inducible

  • Nitric oxide prevents chlamydial infection of macrophages (Carratelli et al, 2005) [153]

Nitric oxide

  • Limits chlamydial growth (Carratelli et al, 2005) [153]

Nitroglycerin

  • Uvolňuje NO do krve a dělá vazodilataci cév

Doměnky

  • Tím, že dokáže vyprovokovat účinnější nitrboněčné zabíjení Chlamydia pneumonia a tedy i zánět / destrukci infikovaných buněk
    • Může v případě pokročilé aterosklerozy způsobit / urychlit prasknutí aterosklertického plátu a tepennou embolizaci
    • Proto nejspíš ani když dělá vazodilataci, ve studíích nevyjde, že by jeho užívání prodlužovalo život
      • Benefit je vynulován rizikem potenciace zánětu

Vlastní zkušenost s požitím 0,5 mg nitroglycerinu

  • Cca do 15 minut na mne přišla taková příjemná svalová únava asi jako když přijdu po celodenním výletě domů a nabaštím se 2 litrů teplé plévky
  • Po chvíli přišla i silná touha spát a lehká bolest hlavy s neschopností se soustředit na cokoliv náročnějšího a na cca 30 minut mě to skolilo do postele
  • Dalších x hodin jsem pak byla unavená, měla jsem těžké nohy a ruce a cítila jsem lehkou bolest v hlavě
  • Bolest v hlavě byla v cévách
  • Zajímavé je, že to byla prostorově lokalizovatelná bolest do přesných míst uvnitř v hlavě
    • Myslím, že bych uměla určit i přesné souřadnice těch míst
    • A pocitově bych řekla, že to bylo v průběhu 1-2 tepen v levé hemisféře kdesi uvnitř v hloubce a pak v jedné větvi na rozhraní čelního a temporálního laloku
  • Tuto bolest v této lokalizaci jsem již cítila dříve - například při infekci a teplotě nebo při cukání hlavou ze strany na stranu při pozici hlavou dolů
    • Pocitově jsou to asi místa v cévách, kde mi asi doutná nějaký zánět v endotelu a cévy zde jsou lehce propustnější nebo reaktivnější
  • V souladu s mnoha dalšími informacemi mi toto nepřipadá jako nemožné ani nelogické
  • Asi je to něco, co by popsala většina lidí v populaci a lékaři by se tím nechtěli nijak zabývat nebo to má asi skoro každý desítky let před tím,
    • Než se tam nějaká ateroskleroza rozvine do nějaké výrzanější podoby
  • Hodně zajímavé bylo pozorovat, že je to levá část mozku, zatímco pravostranně nebyly ždáné potíže

Nystatin

  • Blokuje cholesterol dependentní vstup C. pneumonie do epitelových buněk [153]

Purus Meda PM Chlamydil Extra 60 tbl.

  • Tužebník jilmový (Filipendula ulmaria) 127.5 mg
  • Lapačo červené (Tabebuia impetiginosa, extrakt) 82 mg
  • Bakopa drobnolistá (brahmi, Bacopa monieri, extrakt) 35 mg
  • Kočičí dráp (Vilcacora, Řemdihák plstnatý, Uncaria tomentosa, Cat´s Claw) 10 mg
  • Propolis Moravia PM® 8.3 mg
  • Selen (seleničitan sodný, selenan sodný) 0.05 mg
  • Vrba bílá (Salix alba, extrakt z kůry)
  • Olše lepkavá (Alnus glutinosa, extrakt z kůry)
.chlamidyl.jpg


PTGS2 a selective cox-2 inhibitor PTPBS

  • Inhibits C. pneumoniae growth in vitro
  • But does not prevent infection or eradicate C. pneumoniae from host cells (Yan et al, 2008.) [153]

RARA or RARB

  • Retinoic acid inhibits chlamydial growth via a RAR receptor (Puolakkainen et al, 2008) [153]

RIPK2 – receptor-interacting serine-threonine kinase 2

  • Essential for host defense against C.Pneumoniae lung infection (Shimada et al, 2009) [153]

Retinoic acid

  • Inhibits chlamydial growth via IGF2R mannose 6 -phosphate IGF2 receptor (Puolakkainen et al, 2008) [153]

Spectinomycin

  • Potent inhibitor of bacterial protein synthesis
  • Unique mechanism of action
  • Excellent safety index
  • Lacks antibacterial activity against most clinically important pathogens
  • Novel series of N-benzyl substituted 3'-(R)- 3'-aminomethyl-3'-hydroxy spectinomycins
    • Developed based on a computational analysis of the aminomethyl spectinomycin binding site and structure guided synthesis
  • Compounds had ribosomal inhibition values comparable to spectinomycin
    • Increased potency against common respiratory tract pathogens
      • Streptococcus pneumoniae
      • Haemophilus influenzae
      • Legionella pneumophila
      • Moraxella catarrhalis
      • Sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis
  • Compound 1
    • Exhibited excellent chemical stability
      • Superior to spectinomycin [167]
    • no significant interaction with a panel of human receptors and drug metabolism enzymes suggesting low potential for adverse reactions PMID:25995221 [167]

TAP1 – transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)

  • Enhanced severity of infection of TAP1-/-/beta2-microglobulin -/- mice (Rottenberg et al, 1999) [153]

TMBIM4 transmembrane BAX inhibitor motif containing 4

  • Knock-down in infected A549 cells increases number of C. pneumoniae genomes and bacterial growth (Markkula et al, 2012) [153]

TNF

  • Restricts chlamydial growth via activation of IDO1 (Njau et al, 2009) [153]

VDR Vitamin D receptor

  • Chlamydial infection is enhanced in VDR knockout mice (He et al, 2013) [153]

Vaccine - heptavalent CTL epitope minigene (CpnCTL7)

  • Conferred equal protection in the lungs of both aged and young mice
  • Was partially effective in protecting against C. pneumoniae spread to the cardiovascular system of young mice
    • But failed to provide cardiovascular protection in aged animals [123]
  • Vaccine strategies that target the generation of a C. pneumoniae-specific CTL response
    • Can protect the respiratory system of both young and aged animals
    • May not be adequate to prevent dissemination of C. pneumoniae to the cardiovascular system or control replication in those tissues in aged animals [123]

XIAP X-linked inhibitor of apoptosis

  • Knockout sensitises mice to infection (Prakash et al, 2010) [153]





Acacetin

Synonyma

  • 5,7-Dihydroxy-4'-methoxyflavone
  • Linarigenin
  • CAS 480-44-4
  • C16H12O5
  • Acacetine
  • 4'-methoxyapigenin
  • Buddleoflavonol
  • 5,7-dihydroxy-2-(4-methoxyphenyl)chromen-4-one
  • Acacetine
  • 4'-methoxyapigenin
  • Linarisenin
  • Akatsetin
  • 5,7-dihydroxy-2-(4-methoxyphenyl)-4h-chromen-4-one
  • Apigenin 4'-methyl Ether
  • 5,7-dioxy-4'-methoxyflavone
  • Apisenin 4'-methyl Ether
  • Apigenin 4'-dimethyl Ether
  • Flavone, 5,7-dihydroxy-4'-methoxy-
  • 4'-methoxy-5,7-dihydroxyflavone
  • 4h-1-benzopyran-4-one, 5,7-dihydroxy-2-(4-methoxyphenyl)-
  • 5,7-dihydroxy-2-(4-methoxyphenyl)-4-benzopyrone
  • Acaceztin
  • 4'-methylapigenin
  • 4'-o-methylapigenin [78]

Vznik

  • The enzyme apigenin 4'-O-methyltransferase uses:
    • S-adenosyl methionine
    • 5,7,4'-trihydroxyflavone (apigenin) to produce: [76]
      • S-adenosylhomocysteine
      • 4'-methoxy-5,7-dihydroxyflavone (acacetin) [76]
  • Umí to i některé E. coli z různých flavonoidů
  • Semisynthesis of linarin and acacetin from the Citrus flavonoid diosmin
    • Performed via first intermediate 3'-O-phenyltetrazolyl ether of diosmin
      • Linarin completely inhibited the growth oc Chlamydia pneumonia at 100 µM. [60]
  • Lze zakoupit i syntetický v kapslích !!!

Metabolismus

Výskyt v přírodě

  • Acinos
  • Agastache mexicana [81]
  • Agastache rugosa
    • Indigenous Korean Mint, Agastache rugosa
  • Achillea fragrantissima (Forssk.) Sch. Bip.
  • Achillea pannonica Scheele
  • Ajuga nipponensis
  • Alternanthera tenella Colla
  • Anoda cristata
    • Edible plant
  • Anthemideae
  • Anthuriumversicolor leaves
  • Aquilaria sinensis
  • Arrabidaea chica
  • Artemisia capillaris
  • Artemisia ordosica II
  • Artemisia sacrorum Ledeb
  • Artemisia sphaerocephala
  • Artemisia vestita
  • Avena fatua L.
  • Artemisia afra
  • Atriplex semibacata R .BR.
  • Asplenium normale fern [76]
  • Baccharis articulata (Lam.) Pers. (Asteraceae)
  • Baccharis dracunculifolia D. C. (Asteraceae).
  • Betula pendula (silver birch tree)
  • Biebersteinia orphanidis listy - obsahují i luteolin [89]
  • Brickellia cavanillesii (Cass.) A. Gray
  • Bryophyllum pinnatum
  • Buddleja albiflora
  • Buddleja davidii
  • Buddleja lindleyana Fruits
  • Buddleja officinalis
  • Buddleia officinalis Maxim
  • Calamintha officinalis Moench leaves
  • Capparis tenera -roots
  • Carthamus tinctorius L. - Safflower leaves, seeds obs. i luteolin
  • Caenorhabditis elegans
  • Calamintha
  • Calea urticifolia
  • Carthamus tinctorius - i luteolin a quercetin
  • Cirsium japonicum DC. extract
  • Cirsium rhinoceros
  • Cirsium rivulare (Jacq.) All.
  • Cirsium setosum (Willd.)
  • Citrus medica Fruit
  • Clerodendron trichotomum
  • Clerodendrum inerme leaves
  • Clinopodium
  • Combretum caffrum (Combretaceae)
  • Combretum vendae (Combretecacea)
  • Couepia bracteosa fruit
    • Major phenolic compound was acacetin sulphate (one methoxy and two OH groups) (62%) in the shells
  • Curvularia lunata
  • Dendranthema indicum
  • Dendranthema morifolium
  • Dendranthema zawadskii var. latilobum Kitamura (Asteraceae).
  • Dendrolobium triangulare
  • Desmodii Styracifolii Herba
  • Dianthus versicolor Fisch
  • Discocleidion rufescens
  • Distictella elongata (Vahl) Urb. (Bignoniaceae)
  • Dodonaea viscosa
  • Dracocephalum foetidum.
  • Dracocephalum moldavica L. (Lamiaceae)
  • Dracocephalum peregrinum
  • Dryoathyrium boryanum (Willd.) Ching.
  • Elsholtzia bodinieri Vaniot
  • Eremosparton songoricum
  • Euphorbia lunulata
  • Fagonia arabica
  • Fatsia japonica Leaves
  • Ficus hirta
  • Ficus lyrata-
  • Garcinia nervosa var. pubescens King.
  • Ginkgo biloba leaves
  • Hemistepta lyrata
  • Hemistepta lyrata Bunge
  • Heteroplexis micocephal
  • Humulus lupulus
  • Hyssopus cuspidatus
  • Chaenomeles sinensis
  • Chenopodium quinoa Willd - quinoa
  • Chromolaena odorata
  • Chrozophora tinctoria (L.) Raf.
  • Chrysanthemum boreale
  • chrysanthemum Hebei balmy
  • Chrysanthemum indicum
  • Chrysanthemum morifolium -Leaves of "Chuju"
  • Chrysanthemum morifolium Ramat
  • Chrysanthemum sinense
  • Juglandaceae
  • Kumquat
  • Launaea spinosa
  • Lemon verbena extract
  • Leucas aspera
  • Linaria kurdica subsp. eriocalyx.
  • Lygodium japonicum
  • Mentha arvensis
  • Mentha haplocalyx
  • Menta aravensis (corn mint) [60]
  • Micromeria
  • Moringa peregrina (Forssk.) Fiori. (family: Moringaceae)
  • Mosla scabra
  • Onopordum alexandrinum
  • Otanthus maritimus
  • Paraquilegia microphylla
  • Pedicularis densispica
  • Phlomis aurea
  • Phoradendron brachystachyum DC Nutt (Viscaceae)
  • Piper aduncum Leaves
  • Piper ossanum
  • Piper umbellatum
  • Platycladus orientalis (Linnaeus) Franco
  • Pogostemon cablin
  • Potentilla anserina L.
  • Potentilla evestita
  • Propolis
  • Propolis from Central Chilean matorral
  • Prunella vulgaris
  • Pseudostellaria heterophylla
  • Robinia pseudoacacia (black locust - false acacia )
  • Ruta graveolens - rue
  • Saussurea tridactyla -traditional Chinese medicine Xuelianhua [80]
  • Satureja
  • Satureja khuzistanica
  • Scoparia dulcis
  • Scrophularia kakudensis Franch
  • Scutellaria barbata D. Don
  • Solanum lyratum - Lilek potměchuť
  • Sphallerocarpus gracilis Stems and Leave
  • Striga asiatica
  • S. lutea
  • Thistles - Korean
  • Torilis radiata Moench (Apiaceae)
  • Trifolium repens (white clover) shoots and roots of
  • Trollius chinensis Bunge
  • Trollius ledebourii
  • Turpinia arguta
  • Turnera diffusa (Damiana shrub )
  • Valeriana jatamansi
  • Valeriana hardwickii
  • Valeriana wallichii rhizome extract
  • Vernonia schreb
  • Wissadula periplocifolia (L.) C. Presl (Malvaceae)
  • Yinqiaosan powder
  • Ziziphora clinopodioides Lam. (Lamiaceae)



ACEI

  • ACE catalyzes the generation of angiotensin II
    • Mediates the activation of the renin-angiotensin system (RAS)
      • Implicated in many types of cardiovascular disease
  • ACEI anti-inflammatory
  • Can restrict the vascular remodeling processes during
    • Vascular injury
    • Atherosclerosis
    • Aneurysm formation
  • Protective effects on aortic rupture
  • ARBs block the angiotensin II receptor type 1
    • Causing vasodilation

ACC

Synonyma

  • N-acetylcysteine
  • NAC
  • C5H9–NO3S

NAC a chlamydie

  • ROS scavenging agents ascorbic acid and N-acetylcysteine do not suppress C. pneumoniae growth in epithelial cells [105]
  • Extracellular forms - EB - may be depleted by giving N-acetyl cysteine [27]
  • Thiol-containing amino acid
  • Readily absorbed
  • Non-toxic
  • Ability of this molecule to destroy chlamydial elementary bodies
  • Powerful antioxidant
    • Replenishes intracellular glutathione
  • May also be effective in inactivating fungal gliotoxins

Incubation of cells with NAC

  • An increase in the infectivity of C. trachomatis
  • Size of chlamydial inclusions in NAC-treated cells signi?cantly increased
  • Low GSH impairs the effective reduction of disul?de bonds at the initial stage of infection
    • Reduction of disul?de bonds in cysteine-rich proteins in the chlamydial outer envelopemight be essential for the entry of elementary bodies into the cell
  • Similar with other infectious agents
    • Low GSH levels inhibited or decreased replication and decreased their cytotoxic effect of:
      • Human echovirus 9
      • HIV-1
      • In?uenza A virus
      • Hepatitis C virus [106]

Destroying the elementary bodies

  • C.p. possess cysteine-rich proteins on the surface membrane of the spore-like EB
  • Cysteine contains a sulfhydryl ( —S-H ) group
    • Disulphide bond ( —S-S— ) can form between two cysteine molecules
    • Such cross-linking bonds are common within and between the EB surface proteins
    • Thought to preserve the integrity and shape of the EB
    • These disulphide bonds are accessible for cleavage
  • Reduction of these bonds
    • Disrupts the integrity of the EB's surface
      • May be the mechanism how EB rapidly opens within the endosome
      • Chlamydial body must avoid fusion with the host lysosome or it will be killed
  • Chlamydial surface proteins
    • Must be opened
      • Up just prior to or
      • During attachment to the host cell [27]
      • [Raulston JE et al., Surface accessibility of the 70-kilodalton Chlamydia trachomatis heat shock protein following reduction of outer membrane protein disulfide bonds. Infect Immun. 2002; 70(2): 535-43.]
  • Mechanisms of chlamydial attachment to the host cell membrane
    • Entry into the cell
    • Ability to rapidly open
    • Subvert host cellular activities
    • Ability to evade host-defences
    • Track actively across the host cytoplasm taking what it needs
    • Induce endosomal formation
    • Once the EB is in the endosome, time is of the essence [27]
    • It has only a limited amount of preformed proteins
    • It must get to work metabolizing as fast as possible [27]
  • Were the EB coat to be opened up before achieving attachment to a nutrient-rich host cell
    • Unprotected EB would perish through starvation [27]
  • EBs may accumulate in extracellular spaces awaiting their chance to enter host cells
    • May be analogous to the 'acellular (or extracellular) load' seen in HIV infections [Chuck Stratton, personal communication.] [27]
  • N-acetyl cysteine
    • A thiol antioxidant
    • Good candidate for the reduction of disulphide bonds in EB coating proteins
    • Readily available as a health supplement without the need for prescription [27]

Penicillamine (dimethyl cysteine)

  • Reduces disulphide bonds
  • Inactivates EBs in vitro
  • Prevents the initiation of infection in vivo

Amoxycillin

  • B-lactam antibiotic
  • Also effective in inactivating EBs in vivo
  • Penicillamine is one of its major metabolites [Chuck Stratton, personal communication.] [27]

The NAC Test

  • One indirect indicator of chronic infection
  • Ability of NAC to rupture the extracellular Elementary Body by opening up surface disulphide bonds in the organism’s geodesic coat
  • The release of naked bacterial components causes local inflammatory symptoms
  • EBs are more numerous in primary respiratory infections
    • Acellular load of EBs is likely to be highest around respiratory structures
  • Daily administration of 2.4 G of NAC will cause, after a few days
    • Sinusitis-like symptoms
    • With watery mucous
    • Cough productive of a clear, moderately viscous sputum
  • Systemic symptoms — 'NAC flu' — may also occur
  • If symptoms are severe
    • Dose of NAC may be cut down to 600mg
  • Symptoms wane
    • After a few days if the chlamydial load is small
  • If the load is large, may continue for a month or more
  • NAC is unlikely to produce die-off reactions with any other genus [27]

NAC's other valuable properties

  • Ability to replenish depleted glutathione in an animal model with defective transporter neuronal proteins is dramatic.
    • [Aoyama K, Suh SW, Hamby AM, Liu J, Chan WY, Chen Y, Swanson RA. Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nat Neurosci. 2005 Nov 27; {Epub ahead of print}] [27]
    • Major oxidative stress is a cause of cell-death in MS
    • NAC's antioxidant benefits may not be limited to the replenishment of depleted glutathione.
      • [Gosset P, Wallaert B, Tonnel AB, Fourneau C. Thiol regulation of the production of TNF-alpha, IL-6 and IL-8 by human alveolar macrophages. Eur Respir J. 1999 Jul;14(1):98-105.] [27]
  • Preventing further new infections with C. pneumoniae
    • Averting the risk of MS relapse which this can produce [27]
  • Ameliorating intracellular infections
    • Such as influenza A
    • Known to precede MS relapse too [27]
  • Modulating the immune response
    • Cells more resistant to the effects of proinflammatory cytokines such as TNF-a [27]
  • Chelates heavy metals [27]
  • Moderate the effect of endotoxins made by chlamydiae [27]
  • May be of particular importance in demyelinating conditions
    • Moderate lipid peroxidation
    • May also moderate the induction of ceramide production by TNF alpha and consequent cell-death
      • [Singh I, Pahan K, Khan M, Singh AK. Cytokine-mediated induction of ceramide production is redox-sensitive. Implications to proinflammatory cytokine-mediated apoptosis in demyelinating diseases. J Biol Chem. 1998 Aug 7;273(32):20354-62.]
    • Thiol depletion of itself could induce ceramide production independently of TNFalpha
      • 'NAC, which has been used to block the cytokine-induced ceramide production in this study and to inhibit cytokine-mediated induction of inducible nitric oxide synthase in a previous study
      • Enters the cell readily
      • Serves both as a scavenger of ROS and a precursor of GSH, the major intracellular thiol [27]
    • May be beneficial in restoring cellular redox and in inhibition of cytokine-mediated induction of inducible nitric oxide synthase and breakdown of sphingomyelin
      • Reducing NO-mediated cytotoxicity
      • Reducing ceramide-mediated apoptosis in neuroinflammatory diseases [27]
  • Persons with a high EB load
    • Variety of symptoms as the EBs are ruptured and endotoxin and other bacterial material are released
      • Pain round the eyes and over the sinuses
      • Wheezing
      • Sputum production
      • Joint pain
      • Pain in soft tissues
      • Abdominal discomfort
    • Symptoms tend to last a month or so [27]

N-acetyl cysteine and Gliotoxin

  • Poisonous metabolite secreted by Candida sp. [27]
  • In preventing the establishment of fungal infections such as candidiasis
    • [Shah DT, Larsen B. Clinical isolates of yeast produce a gliotoxin-like substance. Mycopathologia. 1991 Dec;116(3):203-8.] [27]
  • Mycotoxins which cause damage to the immune system
  • Provoking caspase-mediated apoptosis in monocytes and macrophages
  • Gliotoxin molecules contain a highly active surface disulphide bond
    • Being reduced, damages host proteins by altering their structure
  • Gliotoxin may also deplete host glutathione
    • Removing host antioxidant potential
    • Increasing free radical damage
  • Molecule has been shown to oscillate between oxidized and reduced forms
    • With the production of unstable peroxides
  • Gliotoxin may be fundamental to the establishment of chronic colonization
    • Locally high levels are found, for instance, in the genital tract of women with severe vaginal candidiasis
      • [Shah DT, Glover DD, Larsen B. In situ mycotoxin production by Candida albicans in women with vaginitis. Gynecol Obstet Invest. 1995; 39(1): 67-9.]
  • Gliotoxin is a potent neurotoxin
  • May alter gut motility [27]
  • Impairs the efficiency of host polymorphonuclear neutrophils [27]
    • [Shah DT, Jackman S, Engle J, Larsen B. Effect of gliotoxin on human polymorphonuclear neutrophils. Infect Dis Obstet Gynecol. 1998; 6(4): 168-75.]
  • Intestinal gliotoxin may cause dysfunction of the gut barrier by damaging enterocytes
    • [Upperman JS, Potoka DA et al., Mechanism of intestinal-derived fungal sepsis by gliotoxin, a fungal metabolite. J Pediatr Surg. 2003 Jun; 38(6): 966-70.]
  • Gliotoxin is a virulence factor in other fungal infections such as invasive aspergillosis [27]
  • N-acetyl cysteine
    • May be expected to neutralize gliotoxin by opening the disulphide bond
    • Has been shown to be protective in vitro.
      • [Zhou X, Zhao A, Goping G, Hirszel P. Gliotoxin-induced cytotoxicity proceeds via apoptosis and is mediated by caspases and reactive oxygen species in LLC-PK1 cells. Toxicol Sci. 2000 Mar; 54(1): 194-202.]
    • It probably acts by opening the gliotoxin disulphide bond
  • Dithiothreitol also opens available disulphide bonds
    • Protected gut cells from gliotoxin-mediated apoptosis
  • Not all orally taken N-acetyl cysteine is absorbed
    • That which remains in the gut may be useful in counteracting gliotoxin produced by intestinal candida
  • NAC does not possess intrinsic activity against the yeast itself
    • Candida albicans is not inhibited even by high concentrations (> 100 mg/L) of NAC [Wheldon D: unpublished data.] [27]
  • Good overview of gliotoxin and related mycotoxins
    • [Gardiner DM, Waring P, Howlett BJ. The epipolythiodioxopiperazine (ETP) class of fungal toxins: distribution, mode of action, functions and biosynthesis. Microbiology. 2005 Apr;151 (Pt 4): 1021-32.] the full text of which is available as a pdf file.
  • Gliotoxin- protein, toxic to the glial (gliocyte) classes astrocytes and oligodendrocytes
    • Found in the CSF of persons with MS
      • [Menard A, Amouri R, Dobransky T, et al., A gliotoxic factor and multiple sclerosis. J Neurol Sci. 1998 Feb 5; 154 (2) : 209-21.]
  • Other sulphur-containing organic molecules have anti-candidal activity
    • Allicin, which is found in garlic
      • [Yamada Y, Azuma K. Evaluation of the in vitro antifungal activity of allicin. Antimicrob Agents Chemother. 1977 Apr;11(4):743-9.]
  • N-acetyl cysteine and selenium
    • Seem to be useful supplements for restoring GSH stores
    • Important in regeneration of other antioxidants [40]

Glutathion - redukovaný - GSH

  • GSH is a tripeptide composed of
    • Glutamate
    • Cysteine
    • Glycine
  • Must be made in the body
  • Glutamate and glycine
    • Well represented in the diet [40]
  • Cysteine
    • Concentration in the diet is limiting factor in the synthesis of glutathione
    • Best form of supplementation is N-acetyl cysteine (NAC)
      • Safer than cysteine [40]
  • Supplementation of diet with NAC in MS patients
    • Elevates levels of GSH peroxydase
      • [Mai J et al., High dose antioxidant supplementation to MS patients. Effects on glutathione peroxidase, clinical safety, and absorption of selenium. Biol Trace Elem Res. 1990 Feb;24(2):109-17.]

GSH peroxydase

  • Selenium is required for the synthesis
  • Levels are low in patients with MS
  • Supplementation with selenium normalized the low levels [40]

Pokles závislostí - kouření

  • N-acetylcysteine or NAC tablets found a drop in tobacco use among highly addicted smokers [94]

ACC a kardiovaskulární choroby

  • Preventive effects of NAC on dyslipidemic profile and alleviation of hyperglycemia in rats [92]
  • Beneficial effects on sucrose-induced insulin resistance
  • NAC reduced the feed-efficiency and the body weight gain [92]
  • Oxidative modification of low-density lipoprotein (LDL) producing oxidized-LDL (ox-LDL)
    • Key step in the sequence of events leading to atherosclerosis [92]
  • NAC secondary metabolites, as occurred with S-methylcysteine sulfoxide metabolites
    • Could have properties depressing hepatic cholesterol synthesis [92]
  • NAC enhanced GSH-reductase activity
    • Thus shifting the NADPH, a co-factor for lipid synthesis, to GSSG reduction [92]

Výskyt - Acetylcystein

  • Allium species
    • Česnek
    • Cibule [92]
    • ACC considered responsible, at least in part, for onion and garlic beneficial effects in warding off illnesses and cardiovascular protection [92]
  • leafy green vegetables [94]

Výskyt - Cysteine

  • Present in most high protein foods
  • meat (including pork and poultry)
  • eggs
  • dairy
  • red peppers
  • garlic, onions
  • broccoli
  • brussels sprout
  • oats
  • granola
  • wheat germ
  • sprouted lentils [93]
  • poultry
  • quinoa
  • buckwheat
  • Raw cow’s milk (or rather, milk whey) - highly bioactive proteins:
      • Lactoferrin
      • Serum albumin
      • Alpha lactalbumin
    • Contain exceptional amounts of cysteine in the form that can enter cells
      • Cysteine molecule is bonded with another cysteine molecule by a disulfide bond or bridge [94]
        • These disulfide bonds are very fragile and easily denatured by heat and mechanical stress [94]







Ag+

    • Chlamydia pneumonia a její závislost na Na+ cyklu
    • Primary Na+ pump, NQR
  • Antibacterial effects of silver salts first noticed long ago
  • NQR has been recently recognized as one of the targets of Ag+ ions
  • Two independent studies, nanomolar concentrations of Ag+ ions
    • Inhibit energy-dependent Na+ transport in inside-out vesicles
      • Alkalophilic Bacillus sp. strain FTU
    • Inhibit purified NQR
      • V. alginolyticus
    • Irreversibly bind to the beta subunit of NQR (NqrF or Nqr6)
      • Enzyme denaturation
      • The loss of its flavin adenine dirucleotide cofactor
  • Half-maximal inhibition of the enzyme activity at concentrations between 0.5 and 2 nM Ag+
    • Making NQR one of the most vulnerable targets of Ag+ ions

Alpha-naphtoflavone

Synonyma

  • 7,8-benzoflavone
  • 2-phenyl-benzo(h)chromen-4-one

Výskyt

  • Syntetický
  • From 2-naphthol and cinnamaldehyde [106]

Účinky

  • Potent inhibitor of the enzyme aromatase
  • Cause abnormal testicular development in young chickens [106]

Apigenin

Synonyma

  • 4',5,7-trihydroxyflavone
  • 5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one
  • Chamomile
  • Spigenin
  • Versulin
  • 4',5,7-Trihydroxyflavone
  • Apigenol
  • Apigenine
  • Pelargidenon 1449
  • 5,7-Dihydroxy-2-(4-hydroxyphenyl)-4-benzopyrone
  • 2-(p-Hydroxyphenyl)-5,7-dihydroxychromone
  • 5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one [109]


Použití

  • Used to dye wool [108]
  • Heřmánkový čaj:
    • Soothing qualities as a sedative
    • Mild analgesic
    • Sleep medication [109]

Vznik

  • Apigenin is the 3'-hydroxylated metabolite of chrysin [109]

Metabolismus

  • The main in vitro metabolite of apigenin
    • In rat liver Aroclor 1254-induced microsomes
      • 3'-hydroxylated compound, luteolin

Výskyt

  • Apigenin is found in many fruits and vegetables
  • Bacopa Monnieri - kotvičník zemní
  • Celeriac - celer bulva - kořen
  • Celery - celer nať
  • Grapefruit
  • Plant-derived beverages - rostlinné nápoje
  • Cibule
  • Pomeranče
  • Čaj
  • Mladý ječmen
  • Víno a pivo z přírodních ingrediencí
  • Červené víno
  • Rozmarýn
  • Oregáno
  • Thymus
  • Bazalka
  • Coriandr
  • Jetel
  • Meduňka lékařská - Melissa officinalis -Lemon Balm
  • Artičoky
  • Špenát
  • Máta peprná
  • Lékořice [110]
  • Čínské zelí (187.0 mg/kg) [111]
  • Paprika roční - Bell pepper (272.0 mg/kg)
  • česnek (217.0 mg/kg)
  • belimbi fruit - bilimbi, cucumber tree - Averrhoa bilimbi - karambola tupá (458.0 mg/kg)
  • Hrách setý (176.0 mg/kg)
  • snake gourd - Trichosanthes anguina - Vlasokvět ... (42.4 mg/kg)
  • Guáva (579.0 mg/kg)
  • wolfberry leaves - Lycium barbarum or Lycium chinense - Goji (547.0 mg/kg)
  • celer nať (338.5 mg/kg)
  • daun turi - Sesbania grandiflora - sesbánie velkokvětá (39.5 mg/kg)
  • Kadok - Piper sarmentosum - thajský listový pepřovník (34.5 mg/kg) [111]
  • Beach naupaka - Scaevola sericea - shoot [112]
  • Paprika roční - Chili papričky - Capsicum annuum
  • Chinese violet - Asystasia gangetica [112]
  • Sweet bitter leaf - Vernonia hymenolepis
  • Weed passion flower - Passiflora foetida - mučenka smrdutá [112, 115]
  • Turnera aphrodisiaca - Damiána
  • Oxalis pes-caprae L. leaf extract - šťavel kozí noha, kyslička
  • Artemisia campestris L. from Eastern Morocco - pelyněk ladní, palina poľná
  • Cyclotrichium origanifolium (Labill.) Manden and Scheng - Calamintha florida Boiss. - cosi hluchavkovitého
  • Azorella compacta - azorela nahloučená
  • Vitex peduncularis Wall. ex Schauer
  • Agastache rugosa - Agastache vrásčitá, Agastache svraskalá
  • Paeonia ostii - pivoňka
  • Pistacia atlantica Desf. fruits - řečík atlasský, pistácia
  • Sojové boby listy
  • Šalvěj
  • Beach naupaka - Scaevola sericea - Vějířovka takada
  • Hrách setý - Pisum sativum
  • Celer - Apium graveolens [114, 115]
  • Paprika roční - Bell pepper - Capsicum annum [114]
  • Česnek - Allium sativum [114]
  • belimbi listy - Averrhoa belimbi - karambola tupá [114]
  • Chili papričky výhonky paprika roční - Capsicum annuum [115]
  • Chinese violet shoot- Asystasia gangetica [115]
  • Petržel- Petroselium crispum [115]
  • Rozmarýn - Rosmarinus officinalis [115]
  • snakegourd - Trichosanthes anguina [114]
  • Guáva - Psidium guajava [114]
  • wolfberry listy - Lycium chinense - kustovnice čínská [114]
  • Celer - Apium graveolens [114]
  • daun turi - Sesbania grandiflora - sesbánie velkokvětá [114]
  • Kadok - Piper sarmentosum - thajský listový pepřovník [114]

.apigenin.jpg

Chamomile tea

  • Abundant in the flowers of chamomile plants
  • Chamomile aromatic oil extracted from the flowers or leaves of the daisy-like plants including
    • German chamomile (Matricaria recutita)
    • Roman or English chamomile (Chamaemelum nobile) [109]
  • Extracts, oils and teas made from chamomile

Parsley

  • Appears to be absorbable by humans after intake of parsley (Petroselinum crispum)
    • 20 g parsley- urinary excretion of apigenin was significantly higher
    • Half-life for apigenin was calculated to be on the order of 12 hr
    • Individual variation in the bioavailability and excretion of apigenin [109]
  • Oral bolus of 2 g blanched parsley ( 65.8 +- 15.5 umol apigenin) per kilogram body weight
    • Maximum apigenin plasma concentration of 127 +- 81 nmol/L reached after 7.2 +- 1.3 hr
    • Plasma apigenin concentration
      • Rose after bolus ingestion
      • Fell within 28 hr under the detection limit (2.3 nmol/L) [109]
  • Average apigenin content in 24-hour urine was 144 +- 110 nmol/24 hr
  • Detected in red blood cells
    • Without showing dose-response characteristics [109]

Chrysanthemum morifolium

  • Extract (CME) (200 mg/kg)
  • Luteolin and apigenin
    • Plasma concentrations of luteolin and apigenin peak
      • At 1.1 and 3.9 hr after dosing [109]
    • AUC for luteolin and apigenin
      • 23.03 and 237.6 ug h/mL [109]
    • Total recovery of the dose was 37.9% luteolin
      • 6.6% in urine
      • 31.3% in feces [109]
    • Total recovery of the dose was 45.2% apigenin
      • 16.6% in urine
      • 28.6% in feces [109]
  • Cumulative luteolin and apigenin excreted in the bile was 2.05% and 6.34%
  • apigenin may be absorbed more efficiently than luteolin
  • Luteolin and apigenin have a slow elimination phase
  • Possible accumulation of the two flavonoids in the body can be hypothesized [109]

Hypericum perforatum





Naturally occurring glycosides formed by the combination of apigenin with sugars include:

Apiin (apigenin 7-O-apioglucoside)

  • Parsley
  • Celery

Apigetrin (apigenin 7-glucoside)

  • Found in Dandelion coffee
  • Teucrium gnaphalodes

Vitexin (apigenin 8-C-glucoside)

  • Vitexin inhibits thyroid peroxidase thus contributing to goiter
  • Passion flower
  • Vitex agnus-castus (chaste tree or chasteberry)
  • Phyllostachys nigra bamboo leaves
  • Pearl millet (Pennisetum millet)
  • Hawthorn

Isovitexin (apigenin 6-C-glucosid, homovitexin, saponaretin)

  • passion flower
  • Cannabis
  • Açaí palm

Rhoifolin (apigenin 7-O-neohesperidoside)

  • Boehmeria nivea
  • China grass or ramie (leaf)
  • Citrus limon
  • Canton lemon (leaf)
  • Citrus x aurantium,
  • bigarade or bitter orange (plant)
  • Citrus x paradisi
  • grapefruit (leaf)
  • Ononis campestris
  • cammock (shoot)
  • Sabal serratula
  • Serenoa - sabal fruit (plant)

Schaftoside (apigenin 6-C-glucoside 8-C-arabinoside) +++





Ascorbic acid

  • A common reducing agent
  • Decreased the infectivity by 27.9% (not statistically significant)
  • Inhibitory effect upon the acute infection model, on the other hand, might depend on intracellular mechanisms.
  • Extracellular EB form of the bacterium is known to be sensitive to reducing agents (Kim et al., 2009; Di Pietro et al., 2013)

Aspirin

  • At high doses (1 and 2 mM)
  • Inhibited the formation of chlamydial inclusion bodies and proliferation
    • In HEp-2 cells
  • Might be associated with the
    • Inhibition of host-cell metabolism
    • Including depletion of essential factors during chlamydial growth
  • Inhibition of chlamydial growth by aspirin was overcome when tryptophan was added [35]
    • no significant effect of tryptophan addition alone on chlamydial growth in the absence of aspirin [35]
  • Aspirin způsobuje depleci nitrobuněčného tryptofanu ??? To by bylo dosti nežádoucí u jedinců bez C.p. infekce... ?? To by si buňky nemohly syntetizovat melatonin a rychleji by stárnuly ? Jak to je?


Lyophilized azithromycin formulation

  • Invention provides among other things a stable, sterile pharmaceutical formulation
  • Comprising lyophilized azithromycin and ethanol
  • Method of treating a disease in a patient [149]

Bacteriopheges in Chlamydias -Microviridae

  • Genetically and structurally related to
    • Phages of Spiroplasma melliferum
    • Bdellovibrio bacteriovorus
    • More distantly to the coliphage phiX174 [148]
  • Infect the genus Chlamydia
  • Polyhedral
  • Non-enveloped,
  • Prokaryotic viruses
  • 1 icosahedral symmetry
  • Cca 30 nm in diameter
  • Single-stranded DnA (ssDnA)
  • Capsid consists of 12 pentagonal trumpet-shaped pentomers
  • Subfamily
    • Gokushovirinae
      • Infect obligate intercellular parasitic bacteria
        • Bdellovibrio spp.
        • Chlamydia spp. [148]
    • Microvirus
    • Alpavirinae [148]
  • Participate in the synthesis of glycogen
  • Encode proteins responsible for their virulence
  • C. suis
    • Plasmid is integrated in a genomic island
    • Contains the tetracycline-resistance gene [146]
  • Bacteriophages specific for chlamydia (chlamydiaphages) were detected only in six species:
    • C. psittaci,
    • C. abortus,
    • C. felis,
    • C. caviae
    • C. pecorum
    • C. pneumoniae [146]
  • Cause inhibition of the developmental cycle
  • Delay transformation of reticulate bodies (RBs) into elementary bodies (EBs)
    • Reducing the possibility of infecting other cells in time [146]
  • Plasmids and bacteriophages can be used in the diagnostics of chlamydioses
    • Plasmids already used for detection of chlamydial infections [146]
  • Bacteriophages could be used as therapeutic agents to replace antibiotics [146]

Phi-CPAR39 = phi-Cpn1 Bacteriophage from Chlamydia pneumoniae

  • Chlamydia pneumoniae AR39 is naturally infected by the bacteriophage phi-CPAR39
  • Phage genome encodes six ORFs:
    • ORF8
    • ORF4
    • ORF5,
    • Viral protein (VP) 1
    • VP2
    • VP3 [133]
  • Phi-CPAR39 infection:
    • Suppressed C. pneumoniae protein synthesis
    • Suppressed polymorphic membrane protein 10 - protein Pmp10
      • Could not be detected in phage-infected C. pneumoniae inclusions (Hoestgaard-Jensen et al. 2011) [148]
        • Lower production
        • Or faster degradation (Hoestgaard-Jensen et al. 2011) [148]
    • Secreted chlamydial protein Cpn0796 was hardly expressed [133]
      • Cpn0796 was also nearly absent in phage—infected inclusions [148]
    • Secreted chlamydial protein Cpaf was expressed, but not secreted
      • Cpaf is synthesised, but not secreted into the cytoplasm of the host cell (Hoestgaard-Jensen et al. 2011) [148]
      • Was accumulating in the chlamydial envelope (Hoestgaard-Jensen et al. 2011) [148]
    • Inclusion membrane protein, IncA
      • Surround the phage-infected abnormal reticulate bodies (RB)
      • Located in the inclusion membrane
      • Secreted by the type 3 secretion (T3S) system [133]
    • Is likely that the T3S is disrupted in the phage-infected chlamydiae
      • Accumulates around the infected RB [133]
  • Limited genetic variation in Chlamydia pneumoniae
  • One strain (AR39) containing a 4,524 nucleotide single-stranded DNA bacteriophage
  • PCR, reverse transcription (RT)-PCR, and Western blotting
    • Presence and functional expression of PhiCpn1 in C. pneumoniae strain AR39
    • Absence in strain CWL029 [133]
  • Unique among chlamydiaphages because it does not lyse the membranes
  • Phage-infected abnormally large C. pneu-moniae AR39 RB [148]
  • Infection variously affects synthesis of membrane proteins which are secreted by C. pneumoniae
    • Pmp 10
    • Cpn0796
    • Cpaf
    • Inc [148]

Viral protein 1 (Vp1)

  • Generated recombinant viral protein 1 (Vp1) from PhiCpn1 in Escherichia coli
    • Vp1 antigen is highly immunogenic in mice
    • Murine antisera readily recognize native Vp1 from C. pneumoniae strain AR39 elementary bodies (EB)
  • Developed an enzyme-linked immunosorbent assay (ELISA)
    • To measure antibodies to recombinant Vp1 in human sera
      • 32 patients with abdominal aortic aneurysm (AAA) and 40 controls
        • 61 had C. pneumoniae EB antibodies shown by ELISA
        • Antibodies to Vp1 were found in 39 of the 61 (64%) seropositive individuals
          • Significantly correlated with AAA (adjusted odds ratio, 13.9; 95% confidence interval)
            • Phage-containing strains of C. pneumoniae
              • Uncommonly found by isolation
              • May commonly infect individuals with vascular disease [134]
  • VP1 major viral capsid proteins of phi-CPG1 (guinea pig-infecting C. psittaci) and phi-AR39 (C. pneumoniae)
    • Almost identical [147] [148] vP1 sequences
    • Both able to infect Chlamydia caviae and C. pneumoniae [148]

Chp1 - Chlamydia phage 1

  • First-known representative of chlamydiaphages
  • Discovered in Chlamydia psittaci isolates

Chp2

  • Double stranded replicative form DNA has been isolated
  • Homologs of microvirus proteins A and C are present
  • DNA replication is thought to occur via a similar mechanism
  • Capsid formation in the genus Chlamydiamicrovirus are not known
    • Probably not resemble microviruses morphogenesis
      • Chlamydiamicroviruses lack external scaffolding and major spike proteins
  • Vp3 has been demonstrated to be an internal scaffold protein
  • Chp-2 viral lifecycle has been characterized
    • Tightly regulated with the developmental cycle of its host [141]
  • Chlamydiamicroviruses probably recognize a protein receptor [141]
  • VP1 of ovine C. psittaci phage Chp2
    • High rate of nucleotide sequence change localized to a region encoding the "IN5" loop of the protein
      • V.s. potential receptor-binding site [147]
  • Chp2, whose vP1 sequences differs, may also infect
    • C. caviae
    • Other Chlamydia species (everson et al. 2002),
    • Receptors for these phages have not been identified
    • Chlamydial host range for the various chlamydiaphages
      • Varied
      • But all are lytic for their respective hosts (Rank et al. 2009) [148]
  • Infection with Chp2 has a strong impact on the development of C. abortus
    • Inhibiting bacterial cell division of the bacteria
      • Transformation of RB to eB is blocked
      • Enlargement of reticulate bodies without cellular divisions [148]
    • Hour 36 and 48 post-infection, rapid replication of Chp2 genome occurs
      • Expression of viral proteins and the replication of the host chromosome
      • Leads to chlamydia cell lysis
        • Accompanied by the appearance of paracrystalline structures [148]
  • Bacteriophage life cycle is coordinated with the developmental cycle of its bacterial host
  • Phage infection takes place upon eBs differentiation into metabolically active RBs [148]
    • Lysis of the inclusion membrane
    • Releasing abundant phage progeny in the inclusion
    • Changed bacteria are released into the cytosol of host cell [148]

Chp3 - Chlamydia phage 3

  • First bacteriophage isolated from elementary bodies of C. pecorum from sheep
  • Host range is limited to
    • C. abortus
    • C. caviae,
    • C. pecorum,
    • C. felis [148]

Chp4 - Chlamydia phage 4

  • Originating from C. abortus [148]

Phi-CPG1 - Guinea pig Chlamydia phage

  • Lytic phage
  • Infects Chlamydia caviae
    • Guinea pig inclusion conjunctivitis strain
  • Genome has five open reading frames (ORFs):
    • ORFs 1–3 encode capsid proteins Vp1, Vp2 and Vp3,
    • ORFs 4–5 encode proteins VG4 and VG5
  • Capsid protein Vp1 plays a crucial role in the
    • Adhesion
    • Invasion of Chlamydia
  • Genome-wide analysis
    • Similarity of 83–95% among the six chlamydiaphage Vp1 capsid proteins [135]
  • Vp1 capsid proteins of phi-CPG1 pretreatment
    • Prevented C. trachomatis induced cytotoxicity in host cells
    • Reversed chlamydial
      • Suppression of host cell proapoptotic p53 protein
      • Induction of antiapoptotic cIAP 2 and Mcl 1 gene expression
    • Has a clear inhibitory effect on C. trachomatis growth in vitro [135]
    • Decrease in the number of C. trachomatis inclusion bodies during infection
    • Inhibitory effects on the proliferation of C. trachomatis in the mouse genital tract
    • C. trachomatis-induced host cell apoptosis was detected following Vp1 treatment [135]

Baicalin

Popis

  • Flavone

Výskyt

  • Derived from Radix scutellariae
    • Dried root of the medicinal plant Scutellariae baicalensis [62]

Použití

  • Oriental medicine

Chlamydie

  • Antimicrobial and anti-inflammatory activities
  • Inhibit several strains of C. pneumoniae
    • In vitro
    • In vivo [62]
  • Baicalin successfully blocked the infection of Hep-2 cells (C. trachomatis)
    • Down-regulate chlamydia protease-like activity factor (CPAF), který:
      • Degrade host transcription factors
  • Baicalin target and down-regulate the production of CPAF
    • Immune system may more effectively detect the chlamydial infection [62]
  • CPAF is synthesized as a proenzyme by chlamydiae
    • Has to be processed into intramolecular dimers to acquire proteolytic activity [62]
  • Baikalin dělá down regulation of CPAF
    • May reduce host inflammation [62]
    • May allow the hosts immune system to more effectively detect the chlamydial infection [92]





BASANT

  • Polyherbal formulation
  • Cream or tablet as a vaginal microbicide
  • Cream has gone through Phase II clinical trials in India
  • BASANT showed antimicrobial activity against sexually transmitted serovars of C. trachomatis
  • no known side effects of BASANT
  • Equally effective as a cream or tablet [96]
  • HeLa cells were infected with C. trachomatis serovar D and exposed to BASANT solutions
    • Preinkubace:
      • Complete inhibition was achieved with 15 min incubation at a concentration of 65 µg/mL
      • 30 min incubation at 35 µg/mL
      • 60 min incubation at 15 µg/mL [96]
    • Post-incubation exposure
      • Minimum inhibitory concentration (MIC) was determined to be ~9 µg/mL
      • C. trachomatis isolates from a doxycycline treatment failure patient, the MIC was 30 µg/mL [96]
  • BASANT is comprised of:
    • Aloe vera
    • curcumin
    • Saponins from S. mukerossi
    • Amla (Phyllanthus emblica)
  • Components have a synergistic effect
  • Enhances the properties of each ingredient
  • Broadens the spectrum of treatable infections

A. vera

  • Wound healing properties
  • Inhibit HIV and HPV [96]

Curcumin

  • Antiseptic
  • Anti-inflammatory
  • Antitumor properties [96]

Amla - Indian goosbery

  • Antioxidant
  • Anti-inflammatory
  • Antimutagenic properties [96]

Berberine

  • Inhibits Chlamydia pneumoniae infection-induced vascular smooth muscle cell migration
    • Through downregulating MMP3 and MMP9 via PI3K [104]
  • Matrix metalloproteinases (MMPs)
    • Important roles in VSMC migration
  • C. pneumoniae infection could induce VSMC migration through Matrigel-coated membrane (P<0.05)
    • Can be significantly inhibited by the broad-spectrum MMP inhibitor
  • C. pneumoniae infection upregulated both mRNA and protein expressions of
    • MMP3
    • MMP9 [104]
  • berberine significantly attenuated C. pneumoniae infection-induced VSMC migration
  • berberine suppressed the protein expressions of MMP3 and MMP9 caused by C. pneumoniae infection
    • In a dose-dependent manner
  • C. pneumoniae infection-induced increase in the phosphorylation level of Akt at Ser473
    • Was inhibited by the treatment with berberine [104]

Methoxy psoralen

Výskyt:

  • bergamotový olej
  • citrus
  • grep
  • petržel
  • celer naťový
  • pastyňák
  • fík listy a míza

Betablokátroy

Nipradilol

Nebivolol

  • Inhibited the development of atherosclerosis
  • Increased plasma nitrates
  • Endothelial reactivity and aortic eNOS expression

NO

  • Obviously, nitric oxide (NO) is beneficial to the vessels in atherosclerosis.
  • NO kills C.pneumonia

Betaglukany

  • Aktivují makrofágy a neutrofily k zabíjení buněk označ. protilátkami
  • Zesílení účinku protilátek
  • Antioxidační působení
  • Posiluje tvorbu kolagenu
  • Snižuje cholesterol

Betulin

Popis

  • Natual triterpene compound

Chlamydia

  • Inhibit intracellular Chlamydia in one in vitro study
  • Protects plants against bacteria and viruses
  • Betulin and its derivatives to be highly active inhibitors of C. pneumoniae (Salin et al., 2010)
  • Betulin dioxime
    • Had a minimal inhibitory concentration (MIC) of 1 µM against CWL-029
    • Was active with nanomolar concentrations
  • Found in several medicinal herbs [139]

A synthesized betulin derivative, betulin dioxime

  • IC50 value of 0.29 µM against strain CWL-029 (Salin et al., 2011a)
    • Effect comparable with that of MPA (IC50 value in nanomolar range)
  • MIC value of 1 µM against strain CWL-029
  • Against a clinical isolate CV6 and had a MIC value of 2.2 µM
  • LogP value of 4.9
    • Potential problems in solubility (Salin et al., 2010)
  • LogP value higher than 2.5
    • Likely to cross blood brain barrier
      • Adverse effects ?

Použití rostlin s betulinem

  • Help to significantly reduce their chronic symptoms of
    • Fatigue
    • Arthritis
    • Inflammation
    • Asthmatic shortness of breath [64]

Výskyt v přírodě

  • In several medicinal herbs
  • Birch bark
    • Betulin derivatives for potential use against C. pneumoniae in vitro
    • Five promising compounds
      • Betulin dioxime
        • Minimum inhibitory concentration (MIC) of 1 mM against the CWL-029 C. pneumoniae strain
          • 50% inhibition achieved at 290 nM [96]
        • A clinical isolate confirmed the antichlamydial activity, with an MIC of 2.2 mM [96]

Biochanin A


Popis

  • A methylated isoflavone
    • Greater efficacy of biochanin A was attributed to the presence of a methylated hydroxyl group.
      • Digestive demethylation and conversion to genistein [96]

Antichlamydiální účinky

  • Potent inhibitor of C. pneumoniae growth [60]
  • Biochanin A exert more potent antichlamydial effects than its unmethylated counterpart genistein [60] [104]
  • Compared with formononetin, genistein, daidzein, genistin, and daidzin for their antichlamydial effect
    • Against both C. trachomatis and C. pneumoniae in vitro.
      • Formononetin and daidzein exhibited no inhibition of C. trachomatis
      • C. pneumoniae was more susceptible to inhibition
  • Biochanin A exhibited the greatest antichlamydial activity overall
    • Significantly suppressed inclusion counts
    • Decreased the mean bacterial inclusion size in C. trachomatis-infected cell cultures
    • Prevented the formation of C. pneumoniae inclusions at concentrations of 25 µM or higher
    • Prevented the formation of new infectious progeny [60]
  • Potent Chlamydia growth inhibitor
    • IC50?=?12 µM on C. pneumoniae inclusion counts
    • 6.5 µM on infectious progeny production of infected epithelial cell cultures
  • Permeation of biochanin A across porcine buccal mucosa without detectable metabolism [102]

Výskyt

  • Main isoflavone component of red clover

Blokáda aromatic amino acid hydrolase, Cpn1046

  • Asi zabrání růstu C.p. bych si tak myslela

Blueberry

  • Found to suppress C. pneumoniae growth in an epithelial cell line [60]

Bylinné čaje s účinnými látkami proti Chlamydia pneumonia

  • Kombinace bylin, které obsahují různé typy látek, které mají prokázanou účinnost proti Chlamydia pneumonia
    • Popřípadě schopnost stimulovat imunitní systém např. k tvorbě interferonu aj.
    • Zároveň obsahují i antioxidanty
  • K dennímu popíjení a nosním lavážím / výplachům konvičkou
  • Vhodným doplňkem antibiotické léčby, který má potenciál:
    • Zvýšit účinnost antibiotické terapie
    • Snížit riziko vzniku rezistence Chlamydia pneumonia
  • Dávka na 3-6 měsíců k dennímu popíjení cca litru čaje
  • Možnost zprostředkování individuálně sestaveného čaje z rukou fytofarmakologa MUDr. Landy
    • Tel. 775 999 882, dana.manaskova@volny.cz

Caffeic acid



Catechins

  • Membrane Disruption
  • Type of flavan-3-ol
  • Ubiquitous constituents of vascular plants
  • Tea polyphenol extract
    • Inhibitory effect on C. trachomatis and C. pneumoniae [62]
  • Inhibitory concentrations required were relatively high
  • Damage or disrupt the permeability of lipid bilayers [62]
  • Inhibit
    • Influenza virus
    • Vibrio cholerae
    • Staphylococcus aureus
    • Campylobacter jejuni
    • C. coli and others [62]
  • water based tea leaf extracts
    • boiling tea leaves in water
    • Adequate to achieve useful antichlamydial properties
  • Complete inhibition of C. trachomatis
    • Polyphenon 70S extract concentrations of 0.4 mg/mL and above
  • This tea extract comprised a range of tea polyphenols:
    • Epigallocatechin
    • Epicatechin
    • Epigallocatechin gallate (EGCg) (dominant)
    • Epicatechin gallate
    • Gallocatechin gallate
  • Simple extraction process produce an EGCg concentration of 2.1 to 2.4 mg/mL
    • May be high enough to provide antichlamydial activity when used for washing infected regions [62::
.catechins.jpg

  • C. pneumoniae and C. trachomatis are sensitive to catechins from tea extracts [62]
  • Catechins cause cytoplasmic membrane damage
    • Disrupting the permeability of lipid bilayers
  • Polyphenon 70S
    • Tea polyphenol extract from a green tea high in catechins
    • On C. pneumoniae- and C. trachomatis-infected human cells
      • Complete inhibition of C. pneumoniae
        • 1.6 mg/mL Polyphenon 70S for the strain AC-43
        • 0.8 mg/mL for the Ar-39 strain [96]
      • Complete inhibition of C. trachomatis
        • 1.6 mg/mL for serovar D
        • 0.4 mg/mL for the L2 strain [96]
    • Epigallocatechin, epicatechin, epigallocatechin gallate, epicatechin gallate, and gallocatechin gallate
      • Epigallocatechin gallate is the dominant constituent
        • Major antimicrobial effects [96]
    • Toxic to human cells post-inoculation with the bacteria
      • At 0.25 mg/mL for treatment [96]
    • Non-toxic when treatment began pre-inoculation
  • Five biosynthesized tea polyphenols
    • Active against C. trachomatis
    • (-)-epicatechin (EC) was the least toxic
    • Inhibitory effect on the proliferation of C. trachomatis in vitro [96]
    • High compared to antibiotics
    • Not currently suitable for treating systemic infections
    • Modification of the catechin structure to reduce the required dose and toxicity may help [96]


Cathelicidin peptides

  • SMAP-29 (sheep)
    • Most active against C. trachomatis
    • Also active against C. pneumoniae and C. felis [96]
  • LL-37 (humans)
  • BMAP-27 (cattle)
  • BMAP-28 (cattle)
  • BAC-7 (cattle)
  • PG-1 (pigs)
    • Resulted in an increase in the number of inclusions in some animal chlamydial species at a concentration of 80 µg/mL
    • PG-1 pretreatment facilitates the entry of C. abortus into host cells [96]
  • Found in lysosomes of
    • Macrophages
    • Polymorphonuclear leukocytes (PMNs)
    • Keratinocytes [96]
  • Tested against a total of 25 strains from the chlamydial species:
    • C. trachomatis, C. pneumoniae, C. felis, C. abortus, C. psittaci, and C. pecorum
    • C. pneumoniae strains were less susceptible to peptides than C. trachomatis
    • Most animal Chlamydiae were not sensitive to cathelicidins at concentrations of around 10 to 80 µg/mL [96]
  • Natural defense compounds in mammalian leukocytes
    • Lead compounds for antichlamydial use (Donati et al., 2005)
    • Chlamydial plasmid-encoded virulence factor Pgp3
      • Neutralize the antichlamydial activity of human cathelicidin LL-37 (Hou et al., 2015).

Cationic antimicrobial peptides (AMPs)

  • Class of naturally occurring anti-infective agents
  • Essentially contributing to the innate immunity of all multicellular organisms
  • Most AMPs reflects their ability to disrupt bacterial membranes
    • Selective interaction
      • Higher negatively charged outer surface
      • Lack of cholesterol
  • Inherent activity to the gram-negative outer membranes
    • Targeting C. pneumoniae in its nonreplicative form
  • Ability of a cathelicidin-type AMP present in leukocytes to suppress C. pneumoniae infectivity when EBs are treated with the peptide [60]
  • Nature as peptides = limitations in:
    • Oral bioavailability
    • Inability to penetrate eukaryotic cell membranes
    • Pharmacophore model for the synthesis of peptidomimetics has been applied
      • Given amount and topological distribution of charges, allowing the design of small molecules fulfilling these requirements
        • Series of beta2,2-amino acid derivatives has been synthesized
          • Effective against both gram-negative and gram-positive bacteria
          • Passively diffuse through phospholipid membranes [60]
        • Two of them are able to disrupt the C. pneumoniae replication cycle even after the entry of the bacterium into epithelial cells [60]
        • Destabilization of elementary bodies
        • Targeting of the inclusion membrane in the early stages of infection [60]
  • Interact with negatively charged microbial membranes
    • Permeabilizing the membrane phospholipid bilayer
      • Lysis and the death of microbes (Hancock et al., 2002)
  • Several plant peptides showed activity against Chlamydia trachomatis (Balogh et al., 2014)

CD8+ T cells

  • Peptide-specific IFN-gamma-secreting CD8+ T cells
  • In local and systemic compartments after primary infection
  • Expanded after pathogen re-exposure [120]
  • Were cytotoxic
  • Displayed a memory phenotype
  • Secreted IFN-gamma and TNF-alpha, but not IL-4 [120]
  • Lysed Cpn-infected macrophages
  • Lytic activity was inhibited by brefeldin A
  • Cpn peptide-specific CD8+ CTL suppressed chlamydial growth in vitro
    • By direct lysis of infected cells
    • By secretion of IFN-gamma and other soluble factors [120]
  • CD8+ CTL protect against Cpn [120]
  • CD8+ T cells are necessary for protection from both primary and reinfection [124]

8 Cpn-infected mice

  • Generate pathogen-specific CD8+ CTL with a type 1 cytokine secretion
    • Effector cells recognize multiple MHC class I-restricted epitopes from Cpn Ags endogenously processed by productively infected macrophages
  • Cpn peptide-specific CD8+ CTL and their soluble factors significantly inhibit chlamydial growth in vitro [120]
  • Peak inflammatory responses
    • Stronger and emerge faster after reinfection than after primary infection
    • Fewer pulmonary bacteria are recovered from Cpn-reinfected mice than from infected animals
    • = Cpn infection induces immunoprotective responses [120]

Typ imunity Th1 / Th2

  • CD8+ T cells are thought to contribute to protection by modifying the CD4+ T cell cytokine pattern
    • from a Th2 to a protective Th1 phenotype [120]
  • Speculations that Cpn-specific IFN-?-producing CD8+ T cells contribute to the type 1 cytokine milieu
    • Required to control early Cpn growth in the lungs of infected mice [120]
Spekulace moje
  • dnešní očkování (bez Th1 protiváhy např. v očkování proti Tbc) u dětí způsobují nadbytek Th2 imunitního nastavení
  • nejen, že podporují častějších vznik alergií, ale asi i onoho postinfekčního astmatu - nebo-li chronické chlamydiální infekce, což je dál fatálně zazděno inhalačními kortikoidy
  • Slyšela jsem říkat několik pediatrů odpůrců očkování, že po očkování jsou děti náchylnější k tomu být více nemocné - respirační infekce. Co když je to právě ona větší náchylnost k Chlamydia pneumonia...
    • Najdu nějakou práci prokazuící, že očkované děti mají častěji právě astma nebo dokonce postinfekční astma ?

Každý pacient s aterosklerozou či astmatem aj. projevy infekce Chlamydia pneumonia...

  • By neměl dostat žádnou medikaci, která oslabí / sníží počty CD8+ buněk !
    • Například kortikoidy / něteré typy imunosupresiv
      • Dle mého selského rozumu pak lze pak očekávat zhoršení chronického stavu
  • Protizánětlivá terapie bude snižovat plicní a cévní poranění aj. symotomy, ale nesmí snižovat CD8 T buněčnou imunitu !!!
    • To by byl ochod s čertem a dočasná úleva od symptomů záněty by byla draze vykoupena následnou progresí základní příčiny - infekce

Potencionální výroba vakcíny proti Chlamydia pneumonia

  • Stimuluje CD8+ bu
    • Identification of 18 H-2b-restricted Tc1 epitope-bearing sequences in the first 12 bona fide [120]
  • Následuje lysis of infected cells
  • Secretion of soluble factors
    • Including IFN-? [120]
  • Pro protektivní imunitu je tedy klíčové aby infikované APC buňky - makrofágy
    • Zpracovaly antigen chlamydií a vystavily na HLA rec. 1. třídy na povrch sekvence antigenu tak, aby došlo k aktivaci T-buněk
    • Jedinci s různými typy HLA 1 - MHC I. receptory to budou umět různě efektivně
      • Genetická dispozice k přechodu do chronicity a progresi infekce nebo naopak k odolnosti
  • Při tvorbě vakcíny = hledání nejlepšího chlamydiálního antigenu, popř. jeho sekvence pro nejsilnější aktivaci CD8+ T-buněk
    • V pročítaném článku našli jako potencionálně efektivní:
      • Membrane proteins specific to Chlamydia
      • Chaperones
      • Ags unique to Cpn
      • Orthologs in other chlamydial species
    • A specific, H-2b-restricted, and CD8+ T cell-dependent CTL response
      • Detected for 18 peptides in 12 Cpn Ags
        • 7 represent sequences within five outer membrane protein complex Ags, namely, Omp2, MOMP, OmpB, Omp85 homolog, and Omp5 (Pmp10)
      • Four chaperones
        • Only a peptide from DnaK (41) elicited recall CD8+ CTL responses
          • Associated with the outer membranes of C. trachomatis [120]




Cecropin

  • Peptide found in cecropia moths (Hyalophora cecropia)
  • Broad-spectrum antimicrobial activity
  • Cecropin-based topical microbicide
  • Gel formulations of cecropin peptides D2A21 and D4E1
    • Equally effective against two C. trachomatis strains
      • Addition of 10% human blood did not alter the results significantly
      • PH values above and below 7 reduced D2A21 activity
        • 2% D2A2 gel formulation remained effective with experimental pH variation [96]
  • D2A21 exposure for 90 min
    • C. trachomatis EB membranes had been disrupted
      • Leaking of cytoplasm [96]
  • Inhibits microbial growth due to the creation of pores or channels through the bacterial membrane
  • Broad-spectrum microbial inhibitory activity
    • Release of mitochondrial respiratory control
    • Inhibition of protein import
    • Inhibition of bacterial respiration [96]

Červené víno

  • Red wine extract has been shown to suppress C. pneumoniae growth [60]

CH-005

  • Polyherbal composition
  • Broad-spectrum antimicrobial against reproductive tract infections and sexually transmitted pathogens
  • Purified saponins from:
    • S. mukorossi
    • Mentha citrata oil
    • Natural polycationic polymer
  • Mouse model study, topical application of either CH-005 or Praneem
    • Effective in blocking the vaginal transmission of C. trachomatis
      • CH-005 - 4.17% transmission rate
      • Praneem - 13.9% transmission rate [96]

Chaga mushroom

  • Chinese name: Bai Hua Rong
  • Purifies the blood and relieves pain
  • Over five hundred years in Russia
  • Contains betulin and betulinic acid
  • Inhibit C. pneumonia
  • Over two hundred different compounds that have
    • Anti-cancer
    • Anti-bacterial
    • Anti-viral
    • Anti-inflammatory
    • Immunostimulating
    • Cytotoxic
    • Anti-platelet aggregation
    • Anti-diabetic
    • Anti-dementia properties [64]
  • Burned topically on the skin
    • To treat arthritis inflammation
      • Similar to moxabustion in Chinese medicine [64]
  • Effective in reducing several kinds of cancers:
    • Lung
    • Colon
    • Hodgkin’s lymphoma
    • Carcinoma [64]
  • Inhibits
    • HIV26
  • Scavenges free radicals
  • Reduces oxidative stress [64]

Coumarine 106


Coumarins

.coumarins.jpg

.coumarins-syntet.jpg


COX inhibitors selective

  • Can inhibit the infectivity of C. pneumoniae
    • By inhibiting the growth and maturation [99]
  • Growth can be only delayed by selective COX inhibitors
    • It can recover to normal level once the drugs were removed [99]
  • Chlamydial infection causes a 10-fold increase of the expression of the cyclooxygenase-2 (Cox-2) mRNA
    • In the peripheral blood monocytes [99]
  • Cox catalyses the biosynthesis of prostaglandins (PGs) from arachidonic acid such as:
    • Prostacyclin (PGI2)
    • Thromboxane A2 (TXA2)
    • Prostaglandin E2 (PGE2) [99]
  • Increased biosynthesis of PGI2 and TXA2
    • Associated with atherosclerosis

2 isoforms of the COX COX-1 and COX-2

  • Expressed or overexpressed in human atherosclerotic lesions
    • Especially COX-2 only in atheromatous, not in normal arteries [99]
  • Ibuprofen and diclofenac
    • Found to reduce C. pneumoniae-induced ROS production in monocytes
      • Might limit the LDL oxidation as well as the foam cell formation [105]

COX-1

  • Constitutively expressed in most tissues [99]
  • Activated platelets
    • Relatively large amount of COX-1 [99]

COX-2

  • Inflammatory response follows cell activation in:
    • Endothelial cells
    • Macrophages/foam cells
    • Smooth muscle cells [99]
  • Enhanced expression of Cox-2 and prostaglandin E2 (PGE2) in monocytic cells
    • Associated with increased plaque instability in human atheromas [99]
  • Cox 2 inhibitors slow down the progression of
    • Alzheimer’s disease
    • Growth of cancers [99]

Aspirin

  • Acetylating a serine residue positioned in the channel
    • Ser 529 of COX-1
    • Ser516 of COX-2 [99]
  • Covalently modifies COX
  • Irreversibly inactivating it
    • Block generation of prostaglandins and thromboxane A2 [99]
      • Prevents the access of the substrate to the catalytic site of the enzyme [99]
  • Antiplatelet, antithrombotic
  • Improves endothelial dysfunction
  • Enhances the vasodilation in response to acetylcholine in patients with atherosclerosis
  • Decrease
    • The expression of COX-2
    • Thickness of aorta plaque
    • Artery stenosis
    • Proportion occupied by atheroma in the intima [99]
  • Delays the development of atherosclerosis significantly [99]
  • Snižuje riziko
    • Stroke
    • Thrombosis
    • Alzheimer’s disease [99]
    • Cancer [99]
  • Inhibit the growth of C. pneumoniae !!! [99]

Nimesulide

  • 30% reduction in atherosclerosis [99]

Rofecoxib

  • In patients with ACS lowers the levels of :
  • May lead to the retardation of coronary atherosclerosis and coronary events [99]
  • Removed from the US market in 2004 due to increased cardiovascular risk [99]

Celecoxib

  • Warned to have anincreased cardiovascular risk [99]
    • With higher doses [99]






Curcumin

  • Preventing the NOX-mediated ROS production
    • By inhibiting protein kinase C [105]

Cytokines

  • Potentiators of the cellular immune response
    • Subsequent inhibition of replication of several species of Chlamydiae
  • IFN-gamma and TNF-alpha
    • Human cytokines that can restrict the intracellular replication of Chlamydiae in
      • Epithelial cells
      • Human monocyte-derived macrophages [12]

TNF

  • Multifunctional cytokine
  • Regulate inflammation and defense against infectious agents including Chlamydiae [12]

TNF-alpha inhibitors

  • Treatment strategy for several inflammatory diseases
    • Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis
    • Cause immunosuppression = increased risk of infection
      • Enhanced fungal growth in human monocytes and alveolar macrophages [12]
      • Enhanced growth of Chlamydia trachomatis in human epithelial cell lines [12]
  • Inhibition of TNF-alpha during chlamydial infection
    • Impairs the expression of these costimulatory molecules and their functions [12]
  • Synergistic effect with IFN-gamma
    • Reducing the concentration of IFN-gamma necessary to restrict intracellular growth
    • tryptophan reversed the inhibitory effects of IFN-gamma and TNF-alpha
      • V.s. indoleamine-2,3-dioxygenase pathway in the restriction process [57]

IFN-gamma

  • Stimulation of host cells by IFN-gamma
    • Inhibits growth of C. pneumoniae
      • By induction of indoleamine 2,3-dioxygenase (IDO) activity
  • Higher doses (2 ng·mL-1)
    • Completely inhibited the growth of Chlamydia in vitro [22]
  • Lower doses (0.2 ng·mL-1)
    • Persistent infection was established [22]
  • Removal of IFN-gamma
    • Resulted in infectious progeny from these aberrant forms [22]
  • Plays a role in the NO production [38]
  • Inhibition of activity of indoleamine 2,3-dioxygenase
    • One of the major mechanisms responsible for the anti-C. pneumoniae activity induced by gamma interferon [53]
  • Inhibition of tryptophan [38]
    • Activation of the host tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) [39]
  • Preexposure of epithelial cells for 24 h to high concentrations of IFN-alpha
    • Inhibited inclusion formation by
      • C. trachomatis serovar L2 (111)
      • C. psittaci 6BC
      • C. pneumoniae BAL-37 [38]
  • IFN-alpha-induced persistent chlamydiae were enlarged and aberrant [39]
    • Could be reversed by the addition of tryptophan [39]
    • Important link between IFN-alpha and differential tissue tropisms among C. trachomatis serovars [39]
      • Availability of exogenous indole
      • Ability of the infecting strain to use it k synteze tryptofanu [39]
  • IFN gamma dělá
    • Depleci tryptofanu [39]
    • Induce nitric oxide synthase effector pathway [39]
      • NO potlačuje růst C.p.
    • Iron deprivation [39]

Marked upregulation observed at 24 h of infection:

  • no significant decreases in bacterial protein expression due to IFN-gamma treatment
    • Major outer membrane protein (MOMP)
    • Heat shock protein 60 (Hsp-60/GroEL)
    • Functions in DNA replication (GyrA)
    • Transcription (RpoA, PnP)
    • Translation (Rrf)
    • Glycolysis (PgK, GlgP)
    • Type III secretion (SctN) [21]
  • Altered gene transcription profile by IFN-alpha treatment [21] :
    • Cell division-related genes (i.e., ftsK and ftsW) is downregulated [21]
    • Upregulation genes for proteins
      • With functions in cell wall structure (ompA and ompB)
      • Glycolysis (pyk)
      • Peptidoglycan synthesis (nlpD)
  • May allow the organism to resist [21]

Různé koncentrace IFN gamma

  • High IFN-gamma concentrations
    • Irreversibly inhibits chlamydial replication
  • Lower concentrations
    • Induce the formation of persistent forms
  • Production of IFN-gamma by Cpn-specific CD8+ T cells
    • Critical to achieve the local threshold concentration [59]
  • Persistent Cpn infection in humans and rodents
    • May be due to a suboptimal CD8+ T cell response
    • We believe that an efficacious anti-Cpn CD8+ CTL response can be induced through vaccination [59]

Vitamín D

  • Antimicrobial peptides, cathelicidins (LL-37)
    • Induces apoptosis of infected cells via:
      • Enhanced LL-37-induced mitochondrial membrane depolarisation
      • Release of cytochrome c
        • Activation of caspases -9 and -3 [67]
  • Human Cathelicidin LL-37
    • Preferentially Promotes Apoptosis of Infected Airway Epithelium
  • Cpni
    • Interferes with NF-KappaB regulation
      • Degradation of BH3-only proteins such as
        • Bim, Puma, Bad, Bik, Bmf, Noxa, and tBid
          • Inhibit proapoptotic Bax and Bak [67]
  • Chlamydia Inhibit Host Cell Apoptosis by Degradation of Proapoptotic BH3-only Proteins
  • Persistent infection resulted in the
    • Upregulation of the NF-kappaB regulated inhibitor of apoptosisi protein 2 (cIAP-2)
      • Not inhibitor of apoptosis protein 1 (cIAP-1) [67]
  • Silencing of either cIAP-1 or cIAP-2
    • Sensitized infected cells to apoptosis [67]
  • NF-kappaB and inhibitor of apoptosis proteins
    • Required for apoptosis resistance of epithelial cells persistently infected with Chlamydophila pneumoniae [67]
  • This action occurs directly through Vitamin D Receptors (VDRs)
    • On numerous cell types in the body
  • VDR signalling and NF-KappaB activation in various cell types:
    • 20-Hydroxycholecalciferol
      • Decreases NF-?B Activity by Increasing I?B? Levels in Human Keratinocytes [67]
    • Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor
    • Involvement of different nuclear hormone receptors in butyrate-mediated inhibition of inducible NF kappa B signalling [67]
  • Symptoms of secondary pophryia can also be dramatically increased
    • Vitamin D3 levels should therefore be increased very slowly when treating a C. pneumoniae infection [67]

Dermaseptins

  • Family of peptides isolated from skin of the Phyllomedusa genus of frogs
  • Dermaseptin S4 and derivatives:
    • D4D20S4
    • K4K20S4
      • Provided 96% inhibition after 48 h at 5 µg/mL.
    • S4 (5–28)
    • S4 (1–12)
      • Provided 81% inhibition after 48 h at a concentration of 5 µg/mL [96]
  • 50% cytotoxic concentration (CC50) was determined to be higher than 25 µg/mL for each peptide
    • Except for S4, which appeared to be more toxic [96]

Desert truffle - Terfezia claveryi

  • Mycorrhizal fungus, or dark brown truffle
  • Native to the Arabian Peninsula
  • Ethnobotanical therapeutics in Bahrain
    • Aqueous extracts in treating trachoma - C. trachomatis infection
  • protein extracted from T. claveryi
    • Antimicrobial activity against a wide spectrum of bacteria and against C. trachomatis in particular
  • Al-Marzooky in 1981 used sterilized aqueous extracts of T. claveryi to treat patients with trachoma
    • Found to be effective
    • Slower acting than conventional antibiotic treatment
  • Effective in treating a broad range of bacterial infections as well as other diseases
    • Many potential uses in medicine
  • Naturally occurring antichlamydial alkaloid [7]
  • In the form of quaternary ammonium salt
  • May be extracted from a range of plants [29]

DTT

  • Disturb the assembly of MOMP and other disulfide-bridged protein in Chlamydia (Jones 1983; Hackstadt et al.,1985).

Flavanones

.flavanones.jpg

Flavones

  • Flavones baical in and luteolin
    • Indirect mechanisms
      • Negation of the antiapoptotic effect of chlamydia
      • Improved pathogen identification [62]
.flavones.jpg

Flavonoids syntethic

.flavonoids-syntetic.jpg

Flavonoidy



Flavonols

  • Flavan-3-ol catechins are proposed to primarily rupture cell membranes
.flavonols.jpg

Gallates

  • Dodecyl gallate
  • Methyl gallate
  • Octyl gallate
  • Propyl gallate
  • (-)-Epicatechin gallate
  • Alkyl gallates
    • Synthetic derivatives of gallic acid
    • Commonly used as antioxidant additives in various foodstuffs [100]

.gallates.jpg

Genistein


Heparan sulfate-like glycosaminoglycans

  • Perhaps inhibit the attachment of C. pneumoniae EBs onto the host cells [98]
  • Heparan sulfate or heparin as receptors
    • C.p. bind the outer membrane proteins to them
      • Therefore the exogenous heparan sulfate-like compounds could inhibit the infectivity of chlamydiae [99]
  • The heparan sulfate-like compounds proposed to act as atrimolecular bridge between chlamydiae and the host cells
    • Differences in ability to utilize GAGs in attachmen
      • C. trachomatis LGV
        • May use the heparan sulfate-like GAGs on hostcells as receptors
      • C. trachomatis E
        • May use other mechanisms
        • Infektivita C. trachomatis E on HeLa cells can be inhibited by chondroitin sulfate A [99]
  • Exogenous heparin
    • Can inhibit the infectivity of chlamydial trachoma biovar effectively
      • But not so effectively as to inhibit the attachment to the host cell [99]

Heparin

  • Glycosaminoglycan (GAG)
  • Alternating copolymer of an uronic acid and an amino sugar
  • Heterogeneous chains with varying molecular weights and anticoagulation activity
  • Activate antithrombin III (ATIII)
    • Dramatically enhancing its ability to inhibit thrombin andfactor Xa
  • Heparin chains can be cleaved
    • Heparin depolymerization
    • Cleavage produces low molecular weight heparins (LMWHs)
      • Different lengths of heparin chains, molecular weights and anticoagulant activity [99]
  • Unfractionated heparin and LMWHs
    • Bound to the protein core in proteoglycans, which are present in the extracellular matrix [99]
  • Several pathogenic microbes have learned to exploit them as receptors for their attachment to their target cells
    • Antiviral activities of heparin and its derivatives been found for many years
      • Extremely potent inhibitory effect on the infectivity of herpes simplex virus (HSV) in vitro
        • Confirmed with different strains of HSV, different tissue culture and different media [99]
      • Inhibitory effect on thehuman papillomavirus
      • Human munodeficiencyvirus (HIV) infection
        • Altering HIV envelope reduction
          • By protein disulfide-isomerase [99]
        • Direct effect on the interaction of the envelope with cell-surface components [99]
  • Chlamydiae invade eukaryotic cells by binding heparan sulfate or heparin with their outer membrane proteins [99]
  • Anti-cancer activities
    • Inhibit the metastasis
      • By inhibiting selectin-mediated interactions of tumor cells with leukocytes, platelets, and endothelial cells
        • Mediate the initial steps of hematogenous metastasis [99]
  • LMWHs offer a number of potential advantages over unfractionated heparin
    • Higher antithrombotic activity
      • Inhibiting a small amount of factor Xa [99]
  • Heparan sulfate-like GAGs
    • Used by C. trachomatis asreceptors when attaching to its host cells
  • Exogenousheparan sulfate-like GAGs
    • Inhibit infectivity of both C. trachomatis and C.pneumoniae

LMWH Clexane (enoxaparin)

    • Shown the strongest inhibitory effect on the infectivity of C. trachomatis [99]


IL6 interleukin 6

  • Polymorphism modifies chlamydial growth (Poikonen et al 2009) [153]

Indoleamine-2,3-dioxygenase (IDO) AKTIVACE

  • C.p. has no tryptophan-synthesis pathway
  • Decrease in intracellular pools of tryptophan aktivací IDO
  • Substantially reduces chlamydial survival in host cells
...nebo vede k perzistenci (?)

INP0007 (compound C1), INP0010, and INP0400

  • Inhibitors of Yersinia type III secretion
  • May target a bacterial-specific factor related to the type III secretion system
    • Directly abrogate chlamydial growth in eukaryotic cells [54]

Isoflavones

.isoflavones.jpg

Zkoumané kombinace léčivých látek

Kortikoid + resveratrol + polyfenol

Glucocorticoid

  • Methylprednisolone
    • Preferred over hydrocortisone (HCT)
      • Does not increase the oxidant activity of macrophages and peroxidation of lipids [68]
      • At low concentrations
        • Avoid side-stimulating effects on reactive oxygen production by monocytes
        • Avoid reactivation of the endocellular micro-organisms - especially Chlamydiae
          • In the range of about 10~6 M - 10"8 M
            • 10~7 M being preferred [68]
  • Prednisolone or hydrocortisone
    • In a concentration range of about 10-6 to about 10"7 M [68]

Stilbene-type phytoalexin

  • E.g. resveratrol, piceatanol or their respective salts
  • Low concentration range 10"s M - 10"6 M [68]
    • To avoid and/or to reduce estrogenic effects [68]
      • Most preferred concentration is 10"6 M [68]

Resveratrol or his acceptable forms

  • Cis or trans form
  • Ester, an amide, a mono- or disaccharide conjugate of resveratrol
  • Acceptable salt or its metabolite
  • In vivo, resveratrol can be metabolized into piceatanol [68]

Polyphenol

  • One or more
  • Remarkably improved the effectiveness of the above compositions
  • Especially flavonoids such as:
    • Flavan-3-ol (formula 1)
    • Isoflavan-3-ol derivatives such as:
      • Catechin,
      • Epicatechin,
      • Gallocatechin
      • Leucocyanidin [68]
  • Flavanone (formula 2) derivatives such as:
    • Rutin, [68]
    • Quercetin,
    • Hesperidin,
    • Kaempferin,
    • Myricetin,
    • apigenin,
    • Diosmin,
    • Luteolin,
    • Fisetin,
    • Troxerutin [68]

Rutin

  • Long known to be non-toxic
  • Present in:
    • Grapes
    • Wine
      • Especially in red wine
    • Many plants
      • Polygonum cuspidatum
  • Flavonoid prevent and/or reduce rapid degradation of stilbene-type phyto-alexins such as resveratrol
  • Rutin and/or quercetin
    • Very little effect on its own
    • But high ability to regenerate compounds such as resveratrol [68]
      • Low as 10~6 M were found sufficient
    • More effective composition - synergický efekt
  • Particularly suitable for the treatment and/or prevention of atherosclerosis from infectious origin
    • Preferably human atherosclerosis from infectious origin by endocellular micro-organisms such as
      • Chlamydiae
      • Mycoplasmae
      • Bartonellae
      • CMV [68]

Navrhovaná strategie terapie

1. antibiotic (macrolide) 10 dní + kompozitum

Composition 6 weeks.

3. 10 dní antibiotic + composition

4. Composition 6 weeks

  • Atd.
  • Continued until the return of CRP to normal blood value
    • Abnormal state of muscle fatigue - indication for blood CRP concentration measurement
  • For months or years, depending from one patient to another [68]


Li+

  • A number of Na+-dependent bacterial permeases, including
    • NhaA-
    • NhaB-type Na+/H+ antiporters, can use Li+ instead of Na+
      • Li+ is effectively exported from the cell
        • Decreases its toxicity
  • Growth inhibition of wild-type E. coli
    • Required as high as 700 mM Li+ in the medium
  • ?nhaA ?nhaB double mutant
    • Could not grow even in the presence of 30 mM Li+
  • P. aeruginosa is also Li+ sensitive
  • NQR does not seem to use Li+ as substrate
    • Some data suggest that Li+ inhibits this enzyme
    • If so, Li+ might have potential as drug against Na+ cycle-dependent bacteria;
  • Li+ is mildly toxic for humans - used in the treatment of bipolar affective disorder
    • Affect thyroid function
      • Hypothyroidism
      • Goiter

Lichořeřešnice


Ligustrum seed - Nu zhen zi14

  • Sweet, bitter, and cool
  • Used to strengthen the liver, kidneys, and vital essence or jing
  • Contains betulin
    • Inhibits C. pneumonia
  • Used to treat dizziness, tinnitus, vertigo, premature gray hair, and soreness and weakness of the low back and knees
  • Suitable for use over a long period
  • Is very safe [64]
  • Suited for symptoms of dryness and excess internal heat
    • Menopause, irritability, tidal fever, hot flashes
    • Thirst, night sweats, mood swings,
    • Bones that feel like they are being steamed
    • Helps with eye problems like diminished vision, blurred vision, and dry eyes [64]
  • Increases white blood cells
    • Neutrophils
  • Increases the production of blood
  • Used to reduce plasma glucose levels in diabetes
  • Reduces plasma cholesterol and triglyceride levels
  • Reduces inflammation, swelling, and permeability of vessels
  • Lowers elevated liver enzyme levels and prevents liver damage [64]
  • Inhibitory effect against
    • Staphylococcus aureus
    • Bacillus dysenteriae
    • Salmonella typhi
    • Pseudomonas aeruginosa
    • E. coli
  • Contraindicated for patients with internal cold symptoms in the stomach
    • Diarrhea
  • Caution with insulin, sulfonylureas, and other antidiabetic medications
    • Hypoglycemia [64]

Lotus rhizome node

  • Chinese name: Ou jie
  • Sweet, astringent, and neutral
  • Chinese food recipes for centuries
  • Contains betulin
    • Effective at inhibiting C. pneumonia [64]
  • Stop bleeding disorders
  • Restrain blood leakage
  • Disperse blood stasis (hypercoagulation)
  • Raw herb clears heat and cools the blood
  • Lotus rhizome node has been used to treat symptoms of
    • Coughing up blood (hemoptysis)
    • Vomiting of blood (hematemesis)
    • Nose bleeds (epistaxis)
    • Blood in the urine (hematuria)
    • Blood in the stools (hematochezia) [64]
  • Lotus rhizome node is effective at treating
    • Bleeding hemorrhoids
    • Bleeding from the eyes
    • Nasal polyps [64]

Luteolin

Antichlamydial activity

  • Flavonol present in +++apples, broccholi, parsley and several other dietary plants+++ [60]
  • Pokles relative number of C. pneumoniae-positive animals [60]
  • Vyšší C. pneumoniae-specific IgG titer [60]
  • High antichlamydial activity [60]
  • Multifaceted and often cell-type dependent modification of eukaryotic cells
    • Seen in both luteolin treatment and C. pneumoniae infection [60]
  • ROS scavenging agents ascorbic acid and N-acetylcysteine
    • Do not suppress C. pneumoniae growth in epithelial cells [60]
  • Luteolin and other related compounds
    • Not directly linked to their ability to scavenge ROS
    • Involve additional molecular targets [60]
  • Mice with acute C. pneumoniae infection
    • Luteolin significantly decreased the bacterial load
      • In the lungs
      • Antibody titers in the bloodstream
    • Diminished the inflammatory changes in histological samples of the lung [60]
    • Similar results with a phenol-rich extract of corn mint [60]
  • Luteolin suppress p38, ERK1/2 and JNK activation in various cell types
    • Resist C. pneumoniae infection
  • Highly active in reducing C. pneumoniae inclusion counts (MIC 9 µM)
    • Also when administered to the infected cells 2 h post inoculation
      • Time point in which EB internalization has already occurred [61]
  • calcium modulating effects of luteolin and other flavonoids
    • Induce or inhibit apoptosis in a cell type-dependent manner [61]
  • Endothelial cells
    • Luteolin blocks Ca2+ influx upon pathogenic stimuli
    • Protecting these cells from apoptosis [61]
    • Asi nevýhodné v chronické fázi
  • Luteolin and octyl gallate, for instance, suppress Ca2+ influx [104]
    • While quercetin and morin stimulate it [104]
  • Suppression of NF-kB-mediated cascades
    • Can inhibit phosphorylation cascades and proinflammatory cytokine and chemokine production
  • Directly reduces the natural inflammatory process [62]
    • May cause a reduction in the body’s immune response
  • Observed reduction in C. pneumoniae-specific antibodies found in serum also suggests a decrease in the natural immune response
  • Reductions of the presence of chlamydia in lung tissue were still observed
  • Luteolin v.s. induces cellular apoptosis
    • Via interference with the mitochondrial pathway
    • Counteracts the reported the ability of C. pneumoniae to inhibit apoptosis [62]
  • Luteolin is highly active in reducing C. pneumoniae inclusion counts (MIC 9 µM)
    • Also when administered to the infected cells 2 h post inoculation
      • Time point in which EB internalization has already occurred [104]
  • Proposed that luteolin negates the antiapoptotic effect of chlamydia
    • Leads to apoptosis of the infected host cells
    • Release of intracellular chlamydial particles
      • Vulnerable to the hosts natural antimicrobial defenses [62]
  • Quercetin and luteolin and an alkyl gallate, octyl gallate, in a mouse model
    • Lowest presence of C. pneumoniae in lung tissue was detected in mice treated with luteolin
    • Luteolin negates the antiapoptotic effect of chlamydia
      • By inducing cellular apoptosis
        • Via interference with the mitochondrial pathway
          • Allowing the chlamydial infection to become vulnerable to the hosts natural immune responses [92]
  • Luteolin and quercetin
    • Effective in both suppressing the lung inflammatory response
    • Decreasing the chlamydial load in lung tissue
  • Luteolin treatment
    • Lowered the levels of C. pneumoniae-specific antibodies in serum.

.luteolins.jpg


Další účinky luteolinu

  • Adipocytes
    • Ca influx into adipocytes is enhanced by luteolin
    • Leading to mitochondria apoptotic mediator release [61]
      • "Jablko aj. potraviny s luteolinem usnadňují hubnutí"
  • Luteolin moduluje dráhy:
    • Phosphatidylinsitide-3-kinase (PI3K) pathway
    • Bcl-2 family proteins [61]

Metabolismus

  • The bioavailability at the inflammatory foci
    • Might also be better than that of quercetin
    • Free luteolin aglycone can be found in plasma
    • Together with its main metabolite, luteolin monoglucuronide [100]
  • Luteolin monoglucuronide
    • Hydrolysed to free luteolin by the ß-glucuronidase of neutrophils at the site of inflammation
  • Glucuronides, are not as efficient as the unconjugated compounds [100]

Výskyt luteolinu

  • Brokolice (74.5 mg/kg dry weight) [111]:
  • Zelené chili (33.0 mg/kg) [111]:
  • Chili papričky patačí oko - paprika křovinatá (1035.0 mg/kg) [111]:
  • Cibule (391.0 mg/kg) [111]:
  • Belimbi plody - bilimbi, cucumber tree - Averrhoa bilimbi - karambola tupá (202.0 mg/kg) [111]:
  • Belimbi listy (464.5 mg/kg) [111]:
  • Hrách setý (11.0 mg/kg) [111]:
  • Mrkev (37.5 mg/kg) [111]:
  • Ředkev bílá (9.0 mg/kg) [111]:
  • Celer (80.5 mg/kg) [111]:
  • Limau purut leaves - Kaffir sitrus indonesian lime leaves, wild lime - kaffir lime listy (30.5 mg/kg) [111]:
    • Nejedná se o limetku, ale o příbuzný druh
  • dried asam gelugur - Garcinia atroviridis (107.5 mg/kg) [111]:
  • Ashitaba - Angelica keiskei [112]
  • Beach naupaka - Scaevola sericea - Vějířovka takada [112]
  • Celer - Apium graveolens [112]
  • Paprika roční - Chili - Capsicum annuum [112]
  • Chinese violet - Asystasia gangetica [112]
  • Chinese wedelia - Wedelia chinensis - Wedelia calendulacea [112]
  • Smetanka lékařská - pampeliška - Dandelion - Taraxacum officinale [112]
  • Frog fruit - Phyla nodiflora - Lippia Nodiflora - phyla, lipie [112]
  • Rozmarýn - Rosmarinus officinalis [112]
  • Soneysuckle - Lonicera japonica - zimolez japonský [112]
  • Sweet bitter leaf - Vernonia hymenolepis [112]
  • Mrkev
  • Jablko
  • Olivový olej
  • Šalvěj
  • Tymián
  • Verbena citrónová - aloisie - Lemon verbena – Lippia citriodora
  • Mexické oregano
  • Artočok
  • Semínka celeru
  • Jalovcové bobule
  • Čekanka salátová
  • Celer naťový
  • Čili papričky
  • Petržel
  • Máta peprná
  • fazol obecná
  • Mrkev
  • Bílá ředkev
  • Celer - Apium graveolens [114, 115] +++
  • daun turi - Sesbania grandiflora - sesbánie velkokvětá [115]
  • asam gelugor - Garcinia atroviridus - Malajské ovoce asam gelugur [114]
  • belimbi fruit - bilimbi, cucumber tree - Averrhoa bilimbi - karambola tupá [114]
  • Ashitaba - Angelica keiskei [115]
  • Baobab tree - Adansonia digitata - Baobab prstnatý [115]
  • Beach naupaka - Scaevola sericea - Vějířovka takada [115]
  • Chinese violet - Asystasia gangetica [115]
  • Chinese wedelia - Wedelia chinensis [115]
  • Smetanka lékařská - pampeliška - Dandelion - Taraxacum officinale [115]
  • paprika roční bell pepper - někdy ano [114]

M6P-PAA

  • A ligand binding to mannose receptor
  • Active against C. trachomatis and Chlamydia pneumoniae
    • With 72% decrease in infectivity
      • Compared to infected control to the latter pathogen (Kuo et al., 2007)
  • Inhibition was shown in vivo in a mouse model.
  • Chlamydial mannose oligosaccharide
    • Mediate attachment and infectivity of Chlamydia trachomatis and Chlamydia pneumoniae in vitro
  • Mannose receptor inhibiting ligands
    • Affect the attachment and entry to the host cell
  • M6P-PAA for topical use
    • For example in mouthwashes for preventing pneumonia

Mastné kyseliny


Lauric acid

  • 12-carbon saturated fatty acid (12:0)
  • C. trachomatis can be inactivated
    • Exposure for 10 min to 10 mM (final concentration) [62]

Capric acid (10:0) and

  • C. trachomatis can be inactivated
    • Exposure for 10 min to 10 mM (final concentration)
  • High antibacterial activity against C. trachomatis
  • no activity against HSV-1 under the same conditions [62]
  • EBs were exposed to lipid before inoculation
    • After 5 min exposure, EB viability was shown to decrease
    • After 10 min was completely lost [62]
  • Irreversible deactivation of C. trachomatis EBs
    • Combined with the observed cell rupture
    • Disintegration after 10 min
    • V.s. disrupting the outer membrane [62]
  • Capric acid was the least active of the three lipids, losing most of its activity when diluted [96]

Monocaprin

  • The most active, monocaprin
  • 1 MK z capric acid
  • C. trachomatis can be inactivated
    • 10 mM for 10 min to (final concentration) [62]
    • 5 mM concentration caused a greater than 100,000-fold inhibition of C. trachomatis when exposed for five minutes [96]
  • Monocaprin at 30 µg/mL was 50% effective when incubated with C. trachomatis for two hours [96]
  • EBs exposed to monocaprin for 1, 5, and 10 min
    • After 10 min exposure, the EBs were irreversibly deactivated
    • Rupture and disintegrate [96]
  • Monocaprin potent inactivators of:
    • C. trachomatis
    • HSV-2
    • Human immunodeficiency virus in vitro [62]
  • Greater inhibitory effect against chlamydia than nonoxynol-9
  • Low level of toxicity in vivo at relevant concentrations [62::

Mnoho dalších mk - zanedbatelný efekt

  • Caprylic acid (8:0)
  • Monocaprylin (8:0)
  • monolaurin (12:0),
  • Myristic acid (14:0)
  • Palmitoleic acid (16:1)
  • Monopalmitolein (16:1)
  • Oleic acid (18:1)
  • Monoolein (18:1) at concentrations of 20 mM (final concentration, 10 mM) [62]

Linoleic acid

  • Disrupted:
    • Viral envelope of vesicular stomatitis virus
    • Cellular membrane on Vero cells [62]


Nonoxynol-9

  • Detergent
    • Studován jako prevention of STDs
    • Toxic in cell cultures
    • Cause irritation of mucosal tissues with frequent application

Synthetic lipids

  • Derived from human breast milk

2-O-octyl-sn-glycerol

  • Most active
  • Completely inhibited the growth of C. trachomatis
  • At a concentration of 7.5 mM for 120 min

Less activity

  • 1-O-octyl-
  • 1-O-heptyl-
  • 2-O-hexyl-
  • 1-O-hexyl-sn-glycerol
    • 50 mM 1-O-hexyl-sn-glycerol for 90 min
      • EBs appeared to be hollow shells
      • With the cell membrane ruptured
      • Cytoplasmic contents having leaked out [62]

2-O-octyl-sn-glycerol

  • Synthetic lipid
  • Developed from naturally occurring human breast milk lipids
  • Effective inhibitory agent against C. trachomatis
  • Complete growth inhibition occurred after two hours of contact with a 7.5 mM concentration of 2-O-octyl-sn-glycerol [96]
  • Some specific antichlamydial effects
  • Inhibitory activity against
    • Escherichia coli
    • Salmonella enteritidis
    • Staphylococcus epidermidis [62]
  • Disruption of the chlamydial lipid membrane [62]

3-O-octyl-sn-glycerol [3-OG] + Antimicrobial peptide, WLBU2

  • Two components combined showed synergy, with significantly increased inhibitory activity
  • Potential for the development of a topical microbicide [96]

Hinokitiol

  • Tropolone-related compound
  • In the heartwood of trees in the Cupresseceae family
  • Antimicrobial activity against
    • Staphylococcus aureus
    • Schistosoma mansoni [96]
  • Found to be active against C. trachomatis
    • MIC of 32 µg/mL in vitro
    • MIC was significantly greater than for hinokitiol against S. aureus or the MICs of antibiotics [96]
  • High concentrations of hinokitiol are cytotoxic [96]



Mateřídouška


Melatonin

  • Reduced chlamydial infection
    • But not other bacterial growth tested here [97]
  • melatonin limited infection of all three chlamydiae
  • Effects were not recovered by tryptophan supplementation
  • Melatonin treatment only of host cells could diminish infection
    • Infection reduction was neutralized by a pertussis toxin
  • Inhibition mechanisms of chlamydial infection appear to be different from those of IFN-gamma
    • Involve specific G-protein-coupled receptors [97]
  • Melatonin is deemed to inhibit early progression of the chlamydial development cycle
    • Establishment of intracellular infection
    • Conversion from elementary body to reticulate body [97]
  • Utilization of melatonin, serotonin or their derivatives
    • May be advantageous for harmless prevention of chlamydial infection [97]

Melittin

  • Principle active component of bee venom
  • Potential treatment for C. trachomatis infections [96]
  • Known to be cytotoxic
  • Main antichlamydial mechanism is its direct cytotoxic effect
  • Secondary mechanism may be due to lowering the transmembrane potential of a transfected cell
    • Which disturbs chlamydial adhesion to the cell
  • In vivo mouse studies
    • Half of infected mice were free from infection 3–4 weeks after exposure [96]

Mifepristone

  • Steroid receptor antagonist RU486
    • RU486 is an antiprogestin with
    • High affinity for the progesterone receptor
      • Competitive binding to the intracellular progesterone receptor :53::
  • C. pneumoniae growth in epithelial HEp-2 cells inhibited
    • In a dose-dependent manner
    • Marked destruction of infecting organisms [53]
  • Cycloheximide
    • Host cell protein synthesis inhibitor
    • Did not alter the inhibition of C. pneumoniae growth by RU486
  • Binding of RU486 to C. pneumoniae organisms in cells at 24 h after infection
  • RU486 may directly bind to the bacteria within cells and cause the destruction of C. pneumoniae [53]
  • Concentration of RU486 required to be effective against C. pneumoniae growth without cytotoxicity to the target cells
    • Was 2 µM [53]
  • P.o. RU486 at up to 800 mg
    • Rapidly absorbed from the GIT
    • Average maximum plasma concentration of RU486
      • Is 2.5 mg/liter (5.8 µM)
        • Effective concentr. can be reached in vivo [53]
  • Addition of an excess (up to 100 µg/ml) of tryptophan to RU486-treated cells infected with C. pneumoniae
    • no alteration of the inhibition of bacterial growth induced by RU486 [53]
  • Assessed by RT-PCR, the treatment of infected cells with RU486
    • Significant decrease in bacterial transcripts [53]
  • Neovlivňuje elementary bodies [53]
  • Nenašli DNA sequence similar to the progesterone receptor in the C. pneumoniae whole genome [53]
  • RU486 has a hydrophobic characteristic
    • Directly cross a cell membrane without interception by a receptor [53]
  • RU486 showed an ability to inhibit C. pneumoniae replication in human monocytic and lymphoid cells
    • Similar to that observed in epithelial cells [53]
  • It is likely that the inhibitory effect of RU486 on bacterial growth is specific to C. pneumoniae [53]
  • Steroid receptor antagonist mifepristone inhibits the growth of C. pneumoniae (Yamaguchi et al., 2008)
  • více zde

Mint species - Mentha species

  • Found to suppress C. pneumoniae growth in an epithelial cell line [60]
  • Being present in most species in relatively high amounts:
    • 7% of cafeinic acid derivatives
    • Eriocitrin
    • Luteolin
    • Rosmarinic acid [98]

Corn mint (Mentha arvensis L.)

  • High antichlamydial activity
  • Traditional use for treating respiratory tract symptoms
  • Diminishes Acute Chlamydia pneumoniae Infection in Vitro and in Vivo
  • Antichlamydial effect of corn mint
    • Characterized in a mouse model of acute C. pneumoniae infection
    • Decrease in the number of C. pneumoniae-positive animals
    • C. pneumoniae-specific IgG antibodies
    • Main antichlamydial components of the extract :
      • Linarin (acacetin-7-O-rutinoside)
        • Linarin completely inhibited the growth at 100 µM
      • Rosmarinic acid [60]
      • acacetin
      • acacetin-acetylglucoside-rhamnoglycoside [98]
  • Mouse model of C. pneumoniae infection - corn mint (Mentha arvensis, L.) extract
    • Diminish the inflammatory parameters relate to C. pneumoniae infection
    • Genome equivalents (Salin et al., 2011b).
  • Both the mint extracts and pure compounds exhibited high levels of inhibitory activity in vitro, with low host cell toxicity.
  • Mouse model, intraperitoneally administered corn mint extracts
    • Reduced inflammatory symptoms
    • Not as effective as antibiotics in clearing the infection
  • In vitro study on the effect of seven peppermint (Mentha × piperita L.) tea extracts
    • On C. pneumoniae-infected human cells
    • All seven tea extracts were active against C. pneumoniae
  • Peppermint teas contain secondary metabolites predominantly were related to higher antichlamydial activity:
    • Catechins
    • Glycosides of flavanones and flavones
      • Luteolin
      • apigenin glycoside
      • Rosmarinic acid [96]
  • M. arvensis and its main components alone could serve as a potential source of health-promoting agents against C. pneumoniae infection when consumed in suf?cient amounts or as part of a polyphenol-rich diet. [98]
    • Extract was able to diminish the in?ammatory parameters related to C. pneumoniae infection in vivo at a biologically relevant dose and thus could help to prevent some of the long-te rm harmful e?ects of C. pneumoniae infection. [98]
  • Also another species of Menthae, Mentha arvensis (L.) has been shown to
have antichlamydial activity (Salin et al., 2011b). The aqueous methanol extract fromSchisandra chinensis inhibited the growth of Chlamydia pneumoniae and Chlamydiatrachomatis in a dose-dependent manner (II).

Mitochondrie dobře fungující


Morin

  • Quercetin and morin stimulate it Ca2+ influx [61]

Výskyt:

  • Jahody
  • Listy stromu moringa
  • Akridokarpus východní (Acridocarpus orientalis)
  • Listy guávy (Psidium guajava)
  • Morušovité:
    • Moruše bílá a černá – listy a plody
    • Maklura oranžová – indiánské pomeranče (Maclura pomifera)
    • Moruše barvířská (Maclura tinctoria )
    • Maclura cochinchinensis Heartwood

Mycophenolic acid

  • A clinically approved drug with known antibacterial activities
  • Antichlamidyal properties [60]
  • The most active compound, mycophenolic acid, had an IC50 value in the nanomolar range [60]
    • IC50 value 0.3 µM [117]

Myricetin

Výskyt:

  • brokolice
  • sladká paprika
  • fazol obecná
  • čísnké zelí
  • černý čaj
  • česnek [114]
  • zelí [114]
  • čínské zelí [114]
  • zelené čili [114]
  • červené čili [114]
  • bell pepper - Capsicum annum - paprika roční Bell pepper [114]
  • bird chili - Capsicum frutescens - paprika křovitá [114]
  • belimbi plody a listy - Averrhoa belimbi - karambola tupá [114]
  • yam stalk - Colocasia esculenta - Kolokázie jedlá [114]
  • cashew výhonky - Anacardium occidentale - Ledvinovník západní - výhonky kešu oříšků [114]
  • mungo výhonky - Phaseolusaureus [114]
  • lady’s fingers - Hibiscus esculentus - Ibišek jedlý - plody okra [114]
  • French bean - Phaseolusvulgaris - fazol obecná [114]
  • French peas - Pisum sativum - hrách setý [114]
  • brinjal - Solanum melongena - lilek vejcoplodý [114]
  • angular loofah - Luffa acut angula [114]
  • snake gourd - Trichosanthes anguina - Vlasokvět ... [114]
  • guava - Psidium guajava - Guáva [114]
  • daun turi - Sesbania grandifolia - Sesbánie velkokvětá [114]
  • pandan leaves - Pandanus odorus - pandán vonný / voňavý [114]
  • lemon grass - Cymbopogon citratus - voňatka citronová, "citronová tráva" [114]
  • semambu leaves - Calamus scipronum - listy stromu neem - nimba [114]
  • kesom listy - Polygonum minus - redesno menší [114]
  • maman - Gynandropsis gynandra - Luštěnice trnitá [114]
  • Kadok - Piper sarmentosum - thajský listový pepřovník [114]
  • asam gelugor - Garcinia atroviridus - Malajské ovoce asam gelugur [114]
  • černý čaj - Camellia chinensis [114]

Nafamostat mesylate

  • serine protease inhibitor
  • Antimicrobial properties and effectiveness in Chlamydia-induced arthritis

Naringin


Niacin

  • Isonicotinic acid congeners

Nitroimidazoles and nitrofurans

  • Initial phase of Chlamydia infection is susceptible to the antimicrobial effects of
    • Nitroimidazoles,
    • Nitrofurans
    • Other agents directed against anaerobic metabolism in bacteria
  • Transition of the chlamydial EB to an RB - "cryptic" growth phase
  • Replicating chla- mydial microorganism, which uses host cell energy
    • Electrons and electron transfer proteins
    • Nitroreductases
  • Synthetic antimicrobial agents
  • Grouped together because both are nitro (NO2-) containing ringed structures
  • Have similar antimicrobial effects
  • Effects require degradation of the agent within the microbial cell such that electrophilic radicals are formed
  • These reactive electophilic intermediates then damage nucleophilic protein sites including
    • Ribosomes, DNA and RNA
  • Nitroimidazoles and nitrofurans currently are not considered to possess antimicrobial activity against members of the Chlamydia species
    • Due to the fact that conventional susceptibiUty testing methods only test for effect on the replicating form of Chlamydia species !!!

Examples of suitable nitroimidazoles

  • Include, but are not limited to:

Metronidazole

  • Is most preferred

Tinidazole,

Bamnidazole,

Benznidazole,

Flunidazole,

Ipronidazole,

Misonidazole,

Moxnidazole,

Ronidazole,

Sulnidazole

Metabolites, analogs and. derivatives of them thereof.


Examples of nitrofurans

  • That can be used include, but are not limited to:

Nitrofurantoin

  • Preferred within the class of nitrofurans

Nitrofurazone

Niiurtimox

Nifuratel

Nifuradene

Nifurdazil

Nifurpirinol

Nifuratrone

Furazolidone

Their metabolites, analogs and derivatives thereof


www.google.com/patents/EP0981372A2

Nitric oxide (NO)

  • Inhibiting C. pneumoniae from infecting macrophage J774 cells
  • Ability of NO to directly damage isolated C. pneumoniae cells
  • Infected cells exposed to recombinant murine gamma interferon (MurIFN-?)
    • Activate inducible nitric oxide synthase (iNOS)
      • Increased production of NO
        • Reduced viability of the infected cells [96]
  • 2-(N,N-diethylamino)-diazenolase-2-oxide
    • Complex of diethylamine with NO
      • Can be used to generate a controlled release of NO in solution [96]
    • Added to cells before infection or during chlamydial cultivation
      • Increase in NO concentration resulted in C. pneumoniae inhibition in a dose-dependent manner [96]
  • Host immune response to chlamydial infection triggers cellular pathways which activate NO release
    • Subsequently lead to the inhibition of chlamydial growth [96]
  • Cellular NO production
    • Implications for the role of symbiotic microbes in the control of pathogenic microbial infections [96]
    • Wide range of host symbiotic microbiota are known to produce NO as a cellular metabolite [96]

Host microbiome

  • Plays a significant role in the inhibition of pathogenic microbial infections [96]

Octyl gallate

  • Suppress Ca2+ influx [61]
  • Doxycycline–octyl gallate combinations
    • Antagonizing or indifferent rather than additive or synergistic effects for all the concentration combinations

Ozonoterapie

  • Centrum léčby bolesti Chodov

Peppermint tea

  • Seven commercial peppermint tea water extracts
    • Inhibited the growth of Chlamydia pneumoniae clinical respiratory isolate K7 at 250.0 ug/ml (n = 3) (I).
    • Tea samples inhibited the chlamydial growth in the range of 20.7% to 69.5%
  • The tea samples which had the highest antichlamydial activity were high in contents of luteolin and apigenin glycosides.

Peptides

  • Direct relation to having antichlamydial properties
  • Short chains of amino acid monomers linked by peptide (amide) bonds
  • Membrane disruption [62]

Cecropin Peptides—Membrane Disruption

  • Two cecropin peptides
    • D2A21
    • D4E1 [62]
  • Antichlamydia trachomatis activity
    • Completely inhibit C. trachomatis EBs in vitro
  • Could be formulated into effective topical microbicides
  • Group of antibacterial peptides
    • In the pupae of the cecropia moth
    • Identified in other insects
      • Bactericidin
      • Moricin
      • Sarcotoxin [62]
    • In pig intestines
      • Cecropin P
    • In tunicates [62]
  • Also against
    • Human immunodeficiency virus,
    • N. gonorrhoeae
    • Gardnerella vaginalis
    • Trichomonas vaginalis
    • Candida albicans [62]
  • When incorporated into a 2% gel formulation and in the vaginal and anogenital tract
    • Only the peptide D2A21 inhibit C. trachomatis
    • Membrane lysis or disruption
      • For 90 min
      • Cell membranes appear to have ruptured
      • Cytoplasmic contents have leaked out, leaving empty hollow shells [62]
  • Postinoculation assays
    • D2A21 failed to inhibit C. trachomatis
      • Does not penetrate eukaryotic cells
        • May not be effective against RB stage [62]

2-amino-phenoxazine-3-one (phenoxazine derivate, Phx-3)

  • Found in various insects, and among mould metabolite [55]
  • Biosensor for detecting nicotinamide adenine dinucleotide [55]
  • Anti-tumour activity
    • Via inhibition of cellular proliferation [55]
  • Inhibits proliferation of viruses
    • Poliovirus
    • Human immunodeficiency virus in vitro [55]
  • Human monocytic THP-1 cells
  • Human epithelial HEp-2 cells
  • Phx-3 significantly inhibited growth of C. pneumoniae in THP-1 and HEp-2 cells
  • Decrease in the number of bacterial 16S rRNA transcripts
  • Phx-3 induces bacterial destruction in most of the inclusion bodies in these cells
  • Addition of tryptophan to the culture slightly blocked the growth inhibition of C. pneumoniae by Phx-3
  • Results suggest that Phx-3 inhibits C. pneumoniae replication in human monocytic cells as well as epithelial cells
    • Partially depending on the tryptophan-metabolic pathway of host cells [54]
  • 10 uM as most effective concentration
    • For inhibiting C. pneumoniae growth
    • Without significant cell toxicity [55]

Phenolic compounds

  • Most potent antichlamydial compounds in the epithelial cell model [61]

Alvesalo et al.

  • Determine the antichlamydial activity of 57 natural flavonoids and other natural polyphenols
  • And structurally similar synthetic compounds
  • Against C. pneumoniae in a human cell line (HL)
  • All of the compounds were found to be non-toxic to host cells
    • 37% (21/57) of the compounds - highly active
    • 28% (16/57) active,
    • 11% (6/57) moderately active
    • 24% (14/57) inactive
  • Most active group:
    • Gallates
    • Flavones
    • Flavonols
    • Synthetic flavonoids
    • Natural coumarins [62]
  • Synthetic coumarins had the greatest number of compounds with no activity [62]
.phenolic-acid.jpg

.kom.jpg


Quercetin, rhamnetin, morin, and octyl gallate

  • HL cells were incubated for 24 h with each compound prior to infection C. pneumoniae
  • Pretreatment process decreased the infectivity of C. pneumoniae to 0%–50% of that in untreated controls
    • Accumulate in cells or on cell membranes
    • Maintain antimicrobial properties
  • Cell culturing process
    • Infectivity was even lower
      • Ranging from 0% to 32% [62]
  • Variation in compound activity can be attributed to the presence of sugars
    • All of the compounds exhibiting over 70% antichlamydial inhibition are free from sugars
    • All compounds with 50% inhibition or less contain one or more sugar moieties [62]

Quercetin, rhamnetin, morin

  • Same basic three-ring structure
  • Penetrate phospholipid membranes [62]

Praneem

  • Polyherbal composition
  • Effective against C. trachomatis
  • Three antimicrobial products: a cream, a pessary, and an insertable tablet
    • Polyherbal cream treats local, not systemic
      • Useful for preventing the spread of infections
      • Treating some symptoms
  • Contains saponins extracted from:
    • the pericarp of reetha tree (Sapindus mukorossi) fruit
    • quinine hydrochloride
    • purified extract from neem (Azadirachta indica) seeds as the main active ingredient
      • Contain water-soluble polysaccharides that stimulate antitumor and antiviral cytokines
        • Including gamma-interferon
          • Cause cell-mediated immune responses [96]
  • Lack of side effects

Phase I clinical trials

  • Daily topical application of 5 mL of the cream for eight days
    • Resulted in C. trachomatis being cleared from the cervicovaginal region of every subject studied







Probiotika - produkce NO

  • Probiotic feed supplements
    • Reduce rates of chlamydial congenital infections in swine
  • C. suis isolate, S-45, is identical to C. trachomatis serovar D
    • Concern for zoonotic infection
      • Limiting the spread of C. suis infection in swine is important for human safety
  • The large-scale antibiotic treatment of swine is undesirable

Enterococcus faecium

  • Beneficial effects as a probiotic feed supplement
    • Pregnant C. suis-positive
      • Sows for thirteen weeks and then for eight weeks after giving birth
        • Rate of piglets born infected was reduced from 85% to 60%
        • Appearance of infection was delayed
  • E. faecium may function as an antibiotic by
    • Reducing the proliferation of bacteria
    • Inhibiting host cell infection
    • Facilitating a more rapid clearance of the infection
    • Balance the native microbial population of the swine digestive tract
      • Beneficial for maintaining the hosts innate defense system [85].

Laktobacily

  • Antichlamydial effect of various lactobacilli on C. trachomatis
  • Vaginal lactobacilli - brevis and salivarius [96]
    • Both lactobacilli had an adverse effect on
      • Chlamydial EBs
      • Chlamydial adsorption to epithelial cells
      • Intracellular phases of chlamydial replication

Lactobacillus brevis

  • Significantly more effective than L. salivarius
  • Inhibited the development of persistent forms of C. trachomatis induced by coinfection with herpes simplex virus type 2 (HSV-2) [96]

Lactobacillus salivarius [96]

Lactobacillus gasseri

Lactobacillus jensenii

Lactobacillus vaginalis

Lactobacillus crispatus

  • All lactobacilli exerted a strong inhibitory effect
    • L. crispatus exhibited the highest efficacy
  • L. crispatus and its supernatant
    • no cytotoxic effect on the epithelial cells or macrophages
    • Inhibited the adhesion of C. trachomatis cells to human epithelial cells or macrophages
    • Inhibited C. trachomatis infectivity
  • The immunomodulatory effect of L. crispatus significantly:
    • Reduced the production of the pro-inflammatory cytokines, IL-6, IL-8, and TNF-alpha
    • Increased the production of the anti-inflammatory cytokine, IL-10
  • Commonly resides in the urogenital microbiome of healthy women
    • Increasing the presence of such microbes can play an important role in protecting the genitourinary tract

Lactic acid

  • Lactobacilli cellular metabolite
  • Chlamydial inhibition was shown to be due to
    • Acidic pH conditions arising from lactic acid production [96]
  • Greater antichlamydial activity was correlated to:
    • Increased cellular metabolites resulting in a lower pH
      • Acidic conditions produced by lactic acid production are necessary for chlamydial inhibition
    • Increased lactobacilli consumption of glucose
  • Lactobacilli supernatants exhibited greater inhibition than only lactic acid
    • Synergism with other lactobacilli metabolites [96]


Protegrin-1

  • Granulocyte- and epithelium-derived antimicrobial peptide
  • Strongest antichlamydial activity
  • Inhibiting infectivity by 50% at a concentration of 6 µg/mL [96]
  • Specific peptide/bacteria interactions are complex and remarkably specific
  • Protegrins may have a broader antimicrobial activity than defensins
  • Moderate-sized cationic peptides may be useful in microbicide preparations designed to prevent chlamydial infection [96]

Protilátky proti MOMP C.p.

  • Immunoprecipitation of C. pneumoniae with GZD1E8 and RR-402 MAbs
  • Both antibodies GZD1E8 and RR-402 recognize the MOMP of C. pneumoniae
    • protein is localized on the surface of the organism
  • Human sera from C. pneumoniae-positive donors
    • Consistently recognize the MOMP by immunoprecipitation
  • MOMP of C. pneumoniae is an immunogenic protein [133]

GZD1E8

  • Species-specific monoclonal antibody (MAb),
    • Recognizes a conformational epitope on the surface of C. pneumoniae
    • Potent in the neutralization of C. pneumoniae infectivity in vitro [133]

RR-402

  • Very similar characteristics
  • Antigenic determinant recognized by RR-402 has yet to be identified [133]




3'-pyridyl oxindole compound

  • Inhibited PknD autophosphorylation and phosphorylation of CdsD
  • Inhibitor of Janus kinase 3 (JAK3)
  • Inhibits C. pneumoniae PknD activity
    • Prevented PknD autophosphorylation
    • Prevented phosphorylation of CdsD
      • Type III secretion apparatus protein [54]
  • Retarded C. pneumoniae growth
  • Significantly reduced the amount of infectious C. pneumoniae produced
    • V.s. important role in chlamydial replication [54]
  • Significantly retarded the growth rate of C. pneumoniae
    • Presence of very small inclusions
    • Reduced number of bacteria seen by electron microscopy
    • Lacked persistent bodies (PB) [54]
      • Induction of persistence was not the cause of reduced chlamydial growth [54]
    • Failed to produce inclusions
      • V.s. blocks an essential step in the production of infectious chlamydial EB [54]
  • Not toxic to HeLa cells
  • Did not block activation of the MEK/ERK pathway required for chlamydial invasion
  • Did not block intracellular replication of either Chlamydia trachomatis serovar D or Salmonella enterica sv. Typhimurium
    • Specific for C. pneumoniae [54]

Quercetin and its 7-methylated analogue rhamnetin

  • Rhamnetin completely blocks infective EB production at concentration 0.5 M
  • Only partial suppression in the infective yield is seen with quercetin treatment [60]
  • Methylated rhamnetin and unmethylated quercetin [60]
    • Methoxy group in the A-ring of rhamnetin [62]
      • More hydrophobic [62]
    • Quercetin and morin stimulate it Ca2+ influx [61]
  • Rhamnetin is able to completely block the production of infective chlamydial EBs [62]
  • Quercetin and morin result in inclusions being observed after repassage [62]
  • resveratrol and quercetin improved the antichlamydial effect of clarithromycin and ofloxacin (Rizzo et al., 2014)
  • resveratrol and quercetin alone inhibit intracellular C. pneumoniae growth.
  • Quercetin reduces the infectivity by 79%.
    • During the infection 50 µM quercetin was shown to inhibit the growth of C. pneumoniae by 90% (Alvesalo et al., 2006b).

Výskyt

  • Cibulové listy (1497.5 mg/kg quercetin, 391.0 mg/kg luteolin, and 832.0 mg/kg kaempferol) [111]
  • Semambu listy - listy stromu neem (2041.0 mg/kg) [111, 115]
  • bird chili - čili papričky ptačí oči (1663.0 mg/kg) [111]
  • černý čaj (1491.0 mg/kg) [111]
  • papaya výhonky (1264.0 mg/kg) [111]
  • guáva (1128.5 mg/kg) [111]
  • brokolice
  • sladká paprika
  • fazol obecná
  • česnek
  • mrkev
  • sojové výhonky
  • Ailanthus prickly ash - Zanthoxylum ailanthoides - žlutodřev [115]
  • Calamus scipronum - druh palmy [115]
  • kesom listy - Polygonum minus - redesno menší [115]
  • Amaranth - Amaranthus mangostanus - laskavec ... [115]
  • Amaranth, livid - Amaranthus lividus - laskavec bledý [115]
  • Amaranth, redroot - Amaranthus retroflexus - laskavec srstnatý [115]
  • Amaranth, spleen - Amaranthus dubius - laskavec pochybný [115]
  • Aromatic turmeric - Curcuma aromatica [115]
  • Ashitaba - Angelica keiskei [115]
  • Baobab tree - Adansonia digitata - Baobab prstnatý [115]
  • Chinese boxthorn - Lycium chinense - Kustovnice čínská [115]
  • Chinese cedar - Toona sinensis - Česnekovník čínský [115]
  • Chinese foldwing - Dicliptera chinensis [115]
  • Cluster bean, Guar - Cyamopsis tetragonoloba [115]
    • Zdroj guarové gumy (boby) a jedlých lusků +++
  • Comfrey výhonky- Symphytum officinale - kostival lékařský [115]
  • Coriander výhonky- Coriandrum sativum - koriandr [115]
  • Cowpea leaf- Vigna unguiculata - vigna čínská [115]
  • Cucumber, spiny bitter - Momordica cochinchinensis - Momordika indočínská [115]
  • Drumstick - Moringa oleifera - Moringa olejodárná [115]
  • Duck's tongue grass - Monochoria vaginalis [115]
  • Eggplant, nakati leaf, plod - Solanum zuccagnianum - Solanum aethiopicum L. - lilek, baklažán [115]
  • Feather cockscomb výhonky - Celosia argentea - Nevadlec hřebenitý [115]
  • Fishwort - Houttuynia cordata - Touleň srdčitá [115]
  • Garden chrysanthemum výhonky- Chrysanthemum coronarium - Čínská jedlá chryzantéma [115]
  • Gynura, white výhonky - Gynura oralis [115]
  • Hairy beggarticks výhonky- Bidens pilosa - Dvouzubuec chlupatý [115]
  • India gourd výhonky, bud- Cucurbita maxima - Tykev velkoplodá - dýně obrovská [115]
  • Indian cress květy -Tropaeolum majus - lichořeřišnice větší [115]
  • Indian mulberry výhonky- Morinda citrifolia - nooni - rojok barvířský [115]
  • Ivy gourd výhonky - Coccinia grandis - břečťan tykev, dítě meloun, malá tykev, Pán prsty, tindora [115]
  • Jute výhonky- Corchorus capsularis - jutovník tobolkatý [115]
  • Jute mallow výhonky- Corchorus olitorius - jutovník olivovitý [115]
  • Jute, wild výhonky - Corchorus trilocularis - hutovník trojoký [115]
  • Kangkong, red stem - Ipomoea aquatica - povijnice vodní [115]
  • Komatsuna výhonky- forage turnips- Brassica campestris - Brukev řepák, brukev řepka ladní [115]
  • Lablab - Lablab purpureus - Lablab purpurový [115]
  • Nightshade výhonky - Solanum nigrum - lilek černý - divoká odrůda [115]
  • Nightshade, African výhonky- Solanum scabrum - lilek borůvkovitý [115]
  • Nightshade, African výhonky - Solanum villosum - lilek žlutý [115]
  • Okra fruit-Abelmoschus esculentus - okra [115]
  • Orach výhonky- Atriplex hortensis - lebeda zahradní [115]
  • Pilose beggarticks výhonky- Bidens bipinnata - dvouzubec dvoj... [115]
  • Sesame výhonky- Eurca sp. - sezamové výhonky [115]
  • Sesbania, red flower- Sesbania grandiflora - sesbánie velkokvětá [115]
  • Sorrel výhonky- Rumex acetosa - šťovík kyselý [115]
  • Spider plant výhonky - Kaffir cabbage - Cleome gynandra [115]
  • květák [114]
  • kailan - Brassica alboglabra - brukev čínská [114]
  • red chili - Capsicum annum - Paprika roční červená čilli [114]
  • bell pepper - Capsicum annum - Paprika roční bell pepper [114]
  • bird chili - Capsicum frutescens - paprika křovitá [114]
  • Chinese chives - Allium odorum - česnek vonný [114]
  • onion listy - Allium fistulosum - Cibule zimní - ošlejch [114]
  • garlic - Allium sativum - česnek setý [114]
  • belimbi listy - Averrhoa belimbi - karambola tupá [114]
  • tapioca výhonky - Manihot utilissima - maniok obecný [115]
  • papaya výhonky - Carica papaya - Papája obecná [115]
  • cashew výhonky - Anacardium occidentale - Ledvinovník západní - výhonky kešu oříšků [115]
  • fern výhonky - Diplazium esculentum - kapraď jedlý [115]
  • soja klíčky - Glycinemax [115]
  • mungo klíčky - Phaseolus aureus [114]
  • lady’s fingers - Hibiscus esculentus - Ibiškovec jedlý, ibišek jedlý - plody okra [114]
  • French bean - Phaseolus vulgaris - fazol obecná [114]
  • French peas - Pisum sativum - hrách setý [114]
  • angular loofah - Luffa acut- angula - teroi [114]
  • carrot - Daucus carota - mrkev [114]
  • white radish - Raphanus sativus - Ředkev setá bílá / olejnatá [114]
  • red spinach - Amaranthus gangeticus - laskavec trojbarvý pravý [114]
  • Kangkung - Ipomoea aquatica - povijnice vodní / povojník [114]
  • wolfberry listy - Lycium chinense - kustovnice čínská [114]
  • limau - purut listy - Citrus hystrix - limetka [114]
  • maman - Gynandropsis gynandra - Luštěnice trnitá [114]
  • Kadok - Piper sarmentosum - thajský listový pepřovník [114]
  • cekur manis - Sauropus androgynus [114]
  • selom - Oenantheja vanica [114]
  • pegaga - Hydrocotyle asiatica - Centella asiatica - pupečník, gotu kola [114]
  • bungakantan - Phaeomeria speciosa [114]
  • asam gelugor - Garcinia atroviridus - Malajské ovoce asam gelugur [114]
  • turmeric - Curcuma longa - kurkuma [114]
  • mint - Mentha arvensis - máta rolní [114]
  • černý čaj

Rapamycin - rapamune - sirolimus

Popis

  • Produced by Streptomyces hygroscopicus
    • A streptomycete isolated from a soil sample from Easter Island (Rapa Nui) [99]

Antichlamydiální účinky

  • Macrolide antibiotics
  • Can inhibit the infectivity of C. neumoniae [99]
    • By inhibiting the growth and maturation [99]
  • Rapamycin inhibited the maturation of chlamydial EBs
    • Infectivity fell down further even when the rapamycin was removed [99]
  • Morphological changes of inclusions of C. pneumoniae
    • During the phase of growth caused less inclusion counts
    • Smaller inclusion size
    • Less chlamydial particles in the inclusions
    • More non-infective RBs
    • Elongated RBs [99]
      • Blocked by rapamycin and stopped in the G1 phase [99]

Immunosuppressive

  • Reverses the acute rejection of heart, kidney and pancreas allograft [99]
  • C. pneumoniae infection is an additional factor for chronic allograft rejection [99]
    • Worsen the prognosis in lung, liver and heart transplantation [99]

Antiproliferative

  • Makes it useful in eluting stents for resisting in-stent restenosis [99]

Další indikace

  • Ocular ischemia
  • Acute lymphoblastic leukemia [99]
  • Epstein Barr virus B-cell lymphomas
  • Kaposi sarcoma [99]

Antimigratory


Mechanismus účinku

  • Vzba na intracellular receptor FK506 binding protein (FKBP12)
  • Blocking signals induced by the mammalian target of rapamycin (mTOR)
  • Arresting cell cycle progression in T lymphocytes from G1 to S phase transition [99]
  • Inhibiting mRNA and protein expression of
    • Inflammatory cytokines IL-6, tumor necrosis factor-alpha, IL-8, monocyte chemoattractant protein-1
    • Inhibiting lipid uptake together with increasing cholesterol efflux [99]
  • Rapamycin-coated eluting-stents can inhibit intimal thickening in patients with coronary artery disease
  • Prevent neointima formation
  • Reduce the risk of in-stent restenosis (Eisenberg & Konnyu 2006).
  • Reduce atherosclerotic lesion size in apoE-null mice
  • Neointimal proliferation is the principal mechanism underlying in-stent restenosis
    • Result of endothelial damage after stent expansion
    • Proliferation and migration of smooth muscle cells
    • Deposition of the extracellular matrix [99]
  • Stents coated with antiproliferative agents such as rapamycin have shown remarkable zlepšení [99]

Everolimus

  • Derivative of rapamycin
  • Similar effect
  • Selective clearance of macrophages in atherosclerotic plaques
    • By autophagy
      • May be another novel mechanism of anti-atherosclerotic effects of rapamycin

Autophagy

  • One of the cell death mechanisms in VSMCs
  • Involved in the progression of atherosclerosis
  • Relationship between mTOR and autophagy
    • TOR-ATG1 [99]

Resveratrol

  • Prevent the NOX-mediated ROS production by inhibiting protein kinase C
    • In C. pneumoniae-infected monocytes
  • Inhibit ROS production by directly decreasing NOX activity [106]
  • Effectiveness in preventing the atherogenic changes induced by C. pneumoniae has been confirmed
    • Decrease in superoxide anion
    • Decrease of oxLDL production
    • Decrease number of foam cells [106]
  • resveratrol and quercetin improved the antichlamydial effect of clarithromycin and ofloxacin (Rizzo et al., 2014)


Rhamnetin

  • Rhamnetin completely blocks infective EB production at concentration 0.5 M
    • Whereas only partial suppression in the infective yield is seen with quercetin [104]
  • Especially rhamnetin, were active also against the inactive chlamydial elementary bodies (EBs)

Roquefort cheese

  • protein extract from Roquefort cheese
  • Inhibits the propagation of C. pneumoniae
    • In a human HL cell line
    • In a dose-dependent manner
    • Significant reduction in the infective progeny formation
      • protein extract range of 0.12–0.5 µg/mL
  • Moreover, short term feeding of mice with Roquefort cheese
    • 2x 10 mg per mouse with an interval of 24 h
      • Inhibition of the migration of peritoneal leukocytes
        • By intraperitoneal injection of E. coli lipopolysaccharide
      • Reduction in neutrophil count
      • Relative increase in peritoneal macrophages
  • Could promote regenerative processes at the site of inflammation
  • May contribute to the low prevalence of cardiovascular mortality in France
    • Consumption of fungal fermented cheeses is the highest in the world [61]
  • The genome of Penicillium roqueforti
    • Major fungus used for Roquefort production
    • Does not contain genes encoding penicillin biosynthesis [61]
  • Roquefortine
    • Believed to have antibacterial activity [61]
  • Crude Roquefort cheese homogenate had noticeable cytotoxicity
    • Organic substances of low molecular weight
      • Mycophenolic acid
      • Putrescine
      • Tyramine
      • Others ::61]
  • Only purified protein fraction of Roquefort cheese have reproducible and dose-dependent antichlamydial activity [61]

Rotenone

  • Toxin
  • Riziko vzniku Prakinsonovy choroby

V přírodě

  • Yam bean - mexický tuřín
  • organický insecticid – při pěstování salátů a rajčat
  • haiari / ? Muricopsis haidari - druh mořského šneka
  • Dalbergia monetaria druh liány
  • nekoe
  • Fabaceae family - luštěniny
  • Derris eliptica - kožnatec vejčitý
  • koželusk
  • Barbasco - Lonchokarp - timbo - pea (Leguminosae) family Lonchocarpus nicou
    • Z čeledi bobovité
  • pyrethrum - Chrysanthemum - římbaba
    • z květů chryzantémy (Chrysanthemum cinerariaefolium)




Rutin


Schisandra chinensis (Turczaninow) Baillon

  • “Wu Wei Zi” in Mandarin

Schisandra lignans

  • Liana native to the forests of Eastern Asia (Hancke et al ., 1999)
  • Produces bright red fruits spherical in shape and growing in clusters.
  • Various different synonyms in the literature

S. chinensis

  • Known for its use in Traditional Chinese Medicine (TCM) — and overall in Far East, ethnopharmacologically
    • Disorders of the reproductive, respiratory, nervous, and digestive systems (Hancke et al., 1999; Panossian & Wikman, 2008)
  • In Russia, the fruits of S. chinensis are considered a stimulant and adaptogen
  • Constituents of S. chinensis berries four classes:
    • Dibenzocyclooctadiene lignans
      • Dominant secondary metabolite
      • Predominantly dibenzocyclooctadiene in structure
        • Majority of the declared biological activities (Lu & Chen, 2009)
          • Schisandrin
          • Schisandrin B
    • Monoterpenes
    • Sesquiterpenes
    • Various structures (Opletal et al., 2004)
  • Neuro-, cyto- and hepatoprotective, as well as anti-cancer and anti-inflammatory effects
    • Schisandrin or schisandrin B at 5 and 6.25 µM concentrations in cell models
    • Schisandrin B at 1–30 mg/kg in animal models
      • Lowest concentrations to give statistically significant results.
  • Anti-viral activities
  • Anti-HIV activity (Chen et al., 1997; Yangetal., 2010)
    • Lowest EC 50 values 0.005 µ g/ml for gomisin G (Chen et al., 1997)
    • 1.4µ g/ml for new lignans identified in the same study (Yang et al., 2010)
  • Inhibition of HSV-2 and adenovirus (Songet al., 2013)
    • Lowest EC 50 values for HSV-2 and adenovirus were 5.85 µg/ml and 22.10 µg/ml respectively with new lignans identified in the same study (Song et al., 2013)
  • Inhibition of Epstein–Barr virus early antigen activation (Chen et al ., 2002)
  • Schisandra chinensis(Turcz.) Baill. is used in TCM for chronic cough (Chinese pharmacopoeia, 2010)
  • Clinical study results have suggested that a tincture of Schisandra fruit has alleviating effect on the symptoms of pneumonia (Pavluschenkoet al., 1981, reviewed in Panossian & Wikman, 2008)
  • Reduced prevalence of influenza in study subjects treated with Schisandra tincture (Panossian & Wikman, 2008)
  • Schisandra chinensis protecting effect in alveolar inflammation.
  • Extract prevented airway inflammation both in vitro and in vivo (Bae et al ., 2012), In human alveolar epithelial cells
.schisandrin.jpg
.schisandrin2.jpg

  • Aqueous methanol extract of Schisandra chinensis berries to the Chlamydia infected host cells and the respiratory pathogen cultures (II)
  • Concentrations of the extract were 10, 25, 50, 100 and 250 µg/ml in each experiment
  • Extract inhibited all the chlamydial species and strains in a dose-dependent manner
  • MIC values against C. pneumoniae strains CV6 and K7 were bellow 100 µg/ml
    • C. trachomatis was less susceptible with the MIC value exceeding 250 µg/ml
  • Remarkable differences in the antichlamydial activities of Schisandra lignans
  • In all of the experiments schisandrin B inhibited chlamydial growth
    • Remarkably more than schisandrin with an over two-fold lower IC50 value against C. pneumoniae
  • Schisandrin had virtually no activity on the growth of C. trachomatis
  • All of the six Schisandra lignans inhibited the growth of C. pneumoniae and C. trachomatis in a dose-dependent manner
    • Three of them having a MIC value of 50 µM against C. pneumoniae
    • One of them, schisandrin C, a MIC value of 25 µM
.schis.jpg

  • Inhibition at the first passage at 25 and 50 µM were
    • Lowest with schisandrin (26.3% at highest)
    • Highest with schisandrin C (99.5%, 25 µM)
    • Schisandrin B, schisandrin C and schisantherin A (100.0%, 50 µM), each
  • Schisandrin C showed the highest inhibition percentages at both concentrations and both passages.
.schiz-cas.jpg

.schiz-cykl.jpg

.schis-c.jpg

  • Schisandra lignans did not show growth inhibition of these bacteria
    • Common gram-negative
      • Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa)
    • Gram-positive
      • Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermis

Scopoletin

Výskyt

  • čekanka
  • tonkové boby
  • levandule
  • jetel
  • jahody
  • skořice
  • maniok, mouka z manioku - gari
  • noni (Morinda citrifolia)
  • kopřiva dvoudomá
  • mučenka
  • brunfelsie
  • kalina slivoňolistá (Viburnum prunifolium)
  • lilek černý (Solanum nigrum)
  • pískavice řecké seno
  • ocet
  • pampeliška a pampelišková káva


Serotonine

  • Reduced chlamydial infection
    • But not other bacterial growth tested here [97]
  • Ligands of melatonin and serotonin receptors also hampered infection [97]
  • Inhibition mechanisms of chlamydial infection appear to be different from those of IFN-gamma
    • Involve specific G-protein-coupled receptors [97]
  • Utilization of melatonin, serotonin or their derivatives
    • May be advantageous for harmless prevention of chlamydial infection [97]


Schisandrin B

  • Found to suppress C. pneumoniae growth
  • Dibenzocyclooctadiene lignin
    • Together with its close structural analogues
  • Dominant chemical components in the fruit extract of Schisandra chinensis (Turcz. Baill.)
    • Commonly known as:
      • wu wei zi
      • five-flavour berry
  • Extensively applied adaptogenic and liver-protecting medication in eastern medicine
  • S. chinensis fruit extract
    • Used to alleviate respiratory tract symptoms
      • Especially prolonged coughing [60]
  • Antichlamydial activity of the extract has also been demonstrated [60]
  • Traditional indication of the extract fits well with the typical clinical manifestation of C. pneumoniae infections [60]
  • Lignans from Schisandra chinensis berries
    • Antioxidative and cytoprotective properties
    • Antibacterial properties of six dibenzocyclooctadiene lignans
    • Chlamydia pneumoniae and Chlamydia trachomatis in human epithelial cells [101]
    • All six lignans inhibited
      • C. pneumoniae inclusion formation
      • Infectious progeny production [101]
  • Schisandrin B
    • Inhibited C. pneumoniae inclusion formation even when administered 8?h post infection
  • Lignan-pretreated C. pneumoniae elementary bodies
    • Impaired inclusion formation capacity [101]
  • Substitution pattern of methylenedioxy, methoxy and hydroxyl groups of the lignans
    • Had a profound impact on the antichlamydial activity [101]
  • None of the compounds showed inhibition on seven other bacteria
    • Selectivity of the antibacterial effect [101]
  • Administering simultaneously did not affected the inhibitory activity the lignans.
  • Inhibition of the growth of Chlamydia was highest with 50 µM schisandrin B
.schiza.jpg

  • Inhibitory effect of schisandrin and schisandrin B
    • Dramatically drops when they are administered at 24 h p.i.
  • Inhibitory effect of the Schisandra lignans on C. pneumoniae
EB pretreatment is significant, it can be concluded that these lignans have inhibiting effecton the EBs which is not dependent on the host cell. However, as the inhibition is remarkablyhigher during the infection, the effect is not specifically targeted to the EBs residing outsidethe host cell.
  • 25 µM schisandrin A and schisandrin B
    • Reduced the amount of basal intracellular ROS levels by 30.5% and 32.3%
  • 50 µM schisandrin B did not have this effect
    • Also smaller with schisandrin A
  • Cellular basal levels of ROS were elevated by schisandrin B in lymphocytes (Checker et al., 2012)
    • Differing results - to a different cell lines ?
  • During the Chlamydia pneumoniae infection (MOI 1.0) only 50 µM schisandrin B modestly reduced the amount of ROS (6.5% )
  • ROS reducing activity of schisandrin B
    • Higher when the basal ROS levels were measured
  • ROS levels are normally elevated 1 hour after the first contact between Chlamydia and the host cell
    • Administration of schisandrin B after 8 hours p.i. still shows efficient inhibition of the infection
  • Schisandrin B has been shown to inhibit the production of ROS in microglia (Zeng et al., 2012)
    • NADPH oxidase-dependent superoxide O2 and ROS formation were LPS induced
    • ROS production in microglia was induced with LPS produced by Escherichia coli.
  • Schisandrin B has been shown to
    • Induce apoptosis in human lung adenocarcinoma A549 cells
      • Inducing pro-apoptotic components Bax
      • Cytochrome C
      • Caspase-3 and -9
      • Decreasing Bcl-2
      • Proliferating cell nuclear antigen (PCNA) expression (Lv et al., 2015)
  • Schisandrin B was
  • Schisandra lignans upregulate heat shock proteins Hsp25, Hsp70 and Hsp72 (Chiu& Ko, 2004; Wu et al., 2004)
    • C. pneumoniae downregulates these genes 12 hours post infection
      • Time point where Schisandra lignans display antichlamydial activity
  • Phosphorylation of certain kinases - upregulated or downregulated by Schisandra lignans / C. pneumoniae
    • Often with opposing effects
    • Targets of the antichlamydial mechanism of action of Schisandra lignans

Toxicita a NÚ

  • Schisandrin - reduced the viability of the growing cells by 18.9%
  • Most of the lignans did not affect the host cell viabilities at the studied concentrations
  • Lignans in vitro cell models and in vivo animal studies considered non-toxic
    • Rats (schisandrin B 30 mg/kg/day × 2, intraperitoneally)
    • Mice (schisandrin B 3 mmol/kg/day × 3, orally, schisandrin 100 mg/kg)
    • Dogs (10 mg/kg daily for 4 weeks) (Chang et al., 1986; Ip & Ko., 1996; Lee et al., 2012)
  • USSR herbal products of Schisandra chinensis
    • Well tolerated by healthy volunteers (reviewed in Hancke et al., 1999 and Panossian & Wikman, 2008)
  • Schisandrin induce adverse effects in healthy humans
    • 153 healthy human subjects
    • Doses of 3.6 mg (n = 17)
    • 5 mg (n = 44)
    • 10 mg (n = 47)
    • 20 mg (n = 45)
  • Only
    • Four subjects experienced excitation
    • Three complained of depression
  • No drug dependency or significant adverse effects in a study of 1200 patients
  • 1162 individuals
    • Infusions of Schisandra chinensis leaves regularly for 8 months
    • Only 38 patients (3.3%) had ceased taking the infusions because of excitation
  • no adverse effects
    • 415 patients taking Schisandra chinensis seed extract for 1 month during influenza epidemic

Necitliví mikrobi at 50 µM

  • The Schisandra extract did not affect the growth of
    • Gram-positive
      • Streptococcus pneumoniae
      • S. pyogenes
      • Bacillus subtilis,
      • Staphylococcus aureus
      • S. epidermidis concentrations.
    • Gram-negative
      • Klebsiella pneumoniae
      • Enterobacter aerogenes
      • Escherichia coli
      • Pseudomonas aeruginosa
      • Proteus mirabilis

Splynutí Chlamydiálních inkluzí s endozomy infikovaných buněk a jejich rozštěpení

  • To by bylo elegantní řešení, které by ničilo i perzistentní formy infekce
  • Možná by i stačilo, aby se toto dělo jen v části infikovaných buňkách a následná vyprovokovaná imunitní reakce by již byla dostatečně silná
  • Má acetylcystein schopnost dostatečně narušit obal chlamydiálních inkluzí například v endotelu cév ?
  • Podaří se mi najít něco na tohle téma ?

Statiny

  • 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors
  • Inhibiting the conversion of acetyl CoA and acetoacetyl CoA to mevalonate
  • Preventing the formation of the isoprenoids [99]

Druhy

Pravastatin

Simvastatin

  • Effect on the microbe itself, reducing viable C. pneumoniae counts in mice [99]
  • Decrease viable chlamydial counts
  • Increase inflammatory cell infiltrates in lung tissue
  • Antichlamydial and proinflammatory effects during acute chlamydial infection [100]

Atorvastatin

Rosuvastatin

Fluvastatin

  • Limit oxLDL uptake in C. pneumoniae-infected endothelial cells
    • By inhibiting LOX-1 scavenger receptor activity
      • Partially regulated by ROS
      • Preventing the endothelial dysfunction and progression of atherosclerotic lesion [105]

Lovastatin

Cerivastatin

  • Indirect inhibitory effect of on C. pneumoniae infection [99]
  • Inhibit C. pneumoniae-induced oxidative stress in
    • Macrophages, VSMCs, endothelial cells
    • Preventing the inflammation
      • Consequently the atherosclerosis development and progression [105]

Antichlamydiální účinky

  • C pneumoniae can be transmitted from macrophages to VSMCs
  • VSMCs showed an activation profile typical of atherosclerosis
    • Rac1 and RhoA prenylation
    • Nuclear transcription factor-kappa B activation
    • Reactive oxygen species production
    • Chemokine production
  • Statin reduces macrophage-mediated C pneumoniae–induced signaling and transmission [63]
    • 250 nmol/L reduced the C pneumoniae transmission to VSMCs by one third [63]
  • Statin reduced membrane-bound RhoA [63]
  • Infection sharply increased ROS
    • Statin decreased this response
      • It was restored by mevalonate in statintreated cells [63]
  • Statin treatment reduced NF-kappa B activation [63]
  • Atorvastatin and Rho GTPase inhibitors reduce C pneumoniae–induced NF-kappa B activation [63]
  • Statins induced VSMC apoptosis by downregulation of Bcl-2 expression and Rho A prenylation
    • Rho family GTPase activity was essential for invasion
    • Pan-Rho GTPase inhibitor compactin blocked infection of HEp2 cells [63]
  • Reduce the intracellular growth of Salmonella entericain vitro and in vivo
  • Attenuate the replication of C. pneumoniae

Stilbene

.stiblene.jpg

Stimulace Th1 imunity, CD8+ cytotoxických lymfocytů a sekrece IFN gamma

  • IFN gamma potlačí množivost chlamydií - zastabilizují stav
  • Mezi tím CD8+ mohou postupně zabíjet infikované buňky - pomalu nás z toho dostávají
  • Cesta - čím vším toto podpořit a čemu se vyhnout a to dlouhodobě


Thiol-disulfide

  • Exchange agents
  • Include, but are not limited to:
    • 2,3-dimercaptosuccinic acid (DMSA; also referred to herein as "succimer")
    • D,L,-ß,ß-dimethylcysteine (also known as penicillamine)
    • ß-lactam agents (e.g., penicillins, penicillin G, ampicillin and amoxicillin, which produce penicillamine as a degradation product)
    • Cycloserine
    • Dithiotreitol
    • Mercaptoethylamine (e.g., mesna, cysteiamine, dimercaptol)
    • N- acetylcysteine
    • Tiopronin
    • Glutathione
  • A particularly effective extracellular antichlamydial agent within this class is DMSA
    • Chelating agent
      • Four ionizable hydrogens
      • Two highly charged carboxyl groups
        • Prevent its relative passage through human cell membranes
          • DMSA thus remains in the extracellular fluid
          • Can readily encounter extracellular EBs
  • The two thiol (sulfhydryl) groups on the succimer molecule (DMSA) are
    • Able to reduce disulfide bonds in the MOMP of EBs located in the extracellular milieu
  • Penicillamine can also be used as a disulfide reducing agent to eliminate chlamydial EBs
  • Use of penicillamine may cause undesirable side effects
  • Alternative, those ß-lactam agents which are metabolized or otherwise converted to penicillamine-like agents in vivo (i.e., these agents possess a reducing group)
    • Can be orally administered to the human or animal as a means of providing a controlled release of derivative pemciUamine
      • By non-enzymatic acid hydro lysis of the penicillin, under physiologic conditions
  • Clavulonic acid is not required for this hydrolysis or for using ß-lactam agents to create penicillamine in vivo

Thyme - tymián


Transferrins

  • Family of iron-binding glyco-proteins
  • Found in milk, tears, saliva, and vaginal secretions
  • Both bactericidal and bacteriostatic
  • Various transferrins on inhibiting poultry-related C. psittaci infections [96]

Ovotransferrin (ovoTF)

  • More effective in inhibiting irreversible attachment and cell entry by C. psittaci
  • Binding of bacterial lipopolysaccharides leading to the bacterial membrane becoming more rigid
    • Interference with the actin host cell recruitment pathway
      • By disrupting the stability of bacterial T3SS translocon proteins
      • By disrupting secretion of Type III secretion effector proteins [96]
    • May occur due to proteolytic degradation of the Type III secretion effector proteins
      • A key step in host cell internalization of the bacteria [96]
  • OvoTF did not prevent infection
  • Severity of infection was significantly diminished
  • Iron sequestration is involved in the in vivo antibacterial activity
    • May also be the underlying mechanism
      • OvoTFs activating both innate and adaptive immune responses [96]
  • OvoTF treatment reduced the shedding of C. psittaci into the air
    • Reducing the risk of zoonotic transmission
  • Respiratory disease was delayed for the first half of the brood period
    • Resulting in a 46% reduction in mortality [96]

Human lactoferrin (hLF)

Bovine lactoferrin (bLF)



Umbelliferone


Antigen LcrE

  • Induced
    • CD4+ and CD8+ T cell activation
    • Type 1 cytokine secretion
    • Neutralising antibodies [127]
  • Was completely effective in eliminating infection in mice
  • Highly conserved and essential to all Chlamydial species
  • Discovery of an effective vaccine for Chlamydiae pneumoniae has potential wide benefits for human health
    • © 2006 Elsevier Ltd. [127]

Další kandidátní antigeny pro tvrobu vakcíny

  • Chlamydia pneumoniae (Cpn) genome scan
    • Described 53 recombinant proteins which elicited antibodies binding to purified Cpn cells
      • 6 proteins can also induce in vitro neutralizing antibodies
          • Assessed by immunoblot analysis of 2DE Cpn protein maps [128]
        • 4 of these antigens (Pmp2, Pmp10, OmpH-like and enolase) could inhibit Cpn dissemination in a hamster model !!! [128]
  • Cpn proteins are immunoaccessible in infectious EBs
    • Recommend further investigation on their value as vaccine components [128]

Vakcína proti Chlamydia trachomatis

Další myší vakcína

  • 2016
  • BD584 antigen reduced chlamydia symptoms by up to 95 percent
  • Immunized female mice with a novel antigen called BD584
    • Made up of three T3SS proteins from C. trachomatis: CopB, CopD, and CT584 [131]



Xanthotoxin - Methoxsalen - Ammoidin:

Výskyt:
  • bergamotový olej
  • andělika lékařská kořen
  • pastyňák
  • bolševník velkolepý


C. pneumoniae vaccine

  • To avoid the use of antibiotics, several research teams are trying to develop vaccines
    • Unsuccessful because Chlamydiae are not very antigenic [67]
  • Vaccine offering long-lasting immunity in humans is not yet available
  • Identifying antigens that may elicit protective immunity
  • Need to confer stronger immunity than natural infection
    • Re-infection in humans after previous C. pneumoniae exposure is common [14]
    • Memory immunity elicited by C. pneumoniae appears to be short-lived and only partial [22]
  • Obligate intracellular pathogen may escape humoral immune defences [14]
  • Cellular immune responses
    • CD8+ T-cells
      • Appear to be necessary for protection against primary infection, as well as re-infection [14]
  • DNA immunization
    • Plasmid DNA encoding the antigen of choice
    • Injected into muscle
      • Where synthesis of the antigen takes place
    • Plasmid DNA itself constitutes a powerful T-helper cell adjuvant
      • Has immunostimulatory motifs
  • Tested DNA vaccines in animal models for several C. pneumoniae proteins
      • MOMP (major outer membrane protein)
      • Omp2
      • CHsp60 [14]
    • Were able to induce only partial protective immunity against C. pneumoniae challenge [14]
  • Recombinant protein vaccine
    • Induced an immune response able to completely eliminate C. pneumoniae infection in mice
    • The antigen, LcrE
      • Component of the chlamydial type III secretion system
    • Induced
      • CD4+ and CD8+ T-cell activation
      • Type I cytokine secretion
      • Neutralizing antibodies
      • Reduced the day 7 lung bacterial burden
        • To a level undetectable by conventional immunohistochemistry and barely detectable by PCR amplification
    • Inoculum remained present in unvaccinated mice and in those vaccinated with other chlamydial proteins
    • Thorpe et al. [14]

  • Vaccine Development and Field Trials Workshop Group
    • Clinical trials for a C. pneumoniae vaccine
    • Seroepidemiological studies suggest that children begin to seroconvert at approx. 5 years of age
    • Prophylactic use, the vaccine would need to be administered in infancy
    • A vaccine for therapeutic use in older subjects
      • Would be difficult to target and evaluate
        • Appropriate markers for identifying patients with chronic infection are not yet available

  • Outer membrane protein (MOMP)3 of C. trachomatis
    • Surface-exposed protein
    • Target for neutralizing Abs
    • Has made it the focus for vaccine development [22]

Yersinia type III secretion system

  • Small inhibitory molecules
  • N’-(3,5-dibromo-2-hydroxybenzylidene)-4-nitrobenzohydrazide
  • Purinergic receptor P2X7R
  • Able to disrupt the progression of the chlamydial developmental cycle
  • Directly inhibit the chlamydial infection as well as antibiotics [99]

Zoledronic acid

  • Significant anti-proliferative effect on SaOS-2 cell line ( osteoblast-like cells) infected by C. pneumoniae
    • Time- and dose-dependent manner [103]
  • Zoledronic acid induced growth inhibition of C. pneumoniae
  • C. pneumoniae-infection of SaOS-2 cells induced a significant gene expression of proinflammatory cytokines
    • TNF-alfa, IL-6, IL-8 and IL-12 [103]
  • Zoledronic acid could facilitate C. pneumoniae-mediated immune response
    • Novel immune regulator in promoting host defense against C. pneumoniae infection [103]


Podpůrná terapie a opatření - prevence a potlačení neurozánětu, podpora neroregenerace

Charles W. Stratton, MD William M. Mitchell, MD PhD Vanderbilt University School of Medicine Nashville, Tennessee 37232

  • Antiporphyric regimen and vitamin B12 therapy
    • Minimizes cellular damage and facilitates cellular repair
    • Following initiation of the antiporphyric regimen, the first atb added [31]
Pokud tomu rozumím dobře, tak následující seznam je jakýsi protizánětlivý regenerační protokol sestaven z maximálního množství kde čeho, o čem se ví, že působí protektivně a regeneračně na neurony a myelinové pochvy. Celý tento protokol byl psán jako součást alternativní oficiálně neuznávané léčby rotroušené sklerozy s cílem léčit to nikoliv jako autoimunitu, ale infekci Chlamydií pneumonia. Jinými slovy zbavit se imunosupresivních kortikoidů a naopak nasadit antibiotika účinná na Chlamydii. Bylo však potřeba něčím nahradit ten protizánětlivý účinek kortikoidů a maximálně zamezit případnému poškození mozku zánětem a oxidačním stresem z infekce i z reakce na mrtvé chlamydie.
Pokud se prokáže, že RS a další nemoci jsou skutečně spjaté s infekcí Chlamydia pneumonia (mnohé studie to dost jasně naznačují), nikoliv pouze s autoimunitou, která může být i druhotná, znamenala by v takovém případě léčba kortikoidy potencionálně fatální chybu.
Volba mezi terapií imunosupresivy nebo antibiotiky. V současné době jsou standardem imunosupresiva, nejčastěji v podobě kortikoidů.
Pokud existují pacienti, kteří se z RS vyléčili bez kortikoidů, pomocí antibiotik a protizánětlivých potravních doplňků, považuji to za úspěch hodný korunovace - ne-li Nobelovy ceny. Kdybych měla RS, hledala bych lékaře, který s tím má tu zkušenost a chtěla bych se léčit u něho i kdybych kvůli tomu musela odjet na druhou stranu země. Zatím jsem nikoho hledat nezkoušela, takže ani netuším, jak moc je to obtíné nebo snadné. Toto jsou jen mé osobní názory, žádná doporučení a vlastní zkušenost s tím nemám. Následující informace jsem si pouze poznamenala, protože mě toto téma zajímá.

B-Complex Vitamins

  • Glucose is needed by host cells that are infected by chlamydiae
    • Assisted by taking B-complex vitamins [31]

Folic acid

  • 400 mcg twice per day [31]

B-1

B-2

B-5

  • Pantothenate 100 mg twice per day [31]

B-6

B-12

  • 5000 mcg sublingual three to six per day [31]
  • Initially 4000 - 5000 micrograms several times a day
  • Reducing to once daily after three months
  • There is often a functional B12 deficit
  • Hyperhomocysteinaemia
    • Frequently accompanies chronic Chl. pneumoniae infection !!!
    • Is thought to cause connective tissue damage
    • Potent neurotoxin with activity against cortical and hippocampal neurones
      • [1. Kruman II, Culmsee C, Chan SL, et al., Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 2000;20:6920-6:]
      • [2. Den Heijer T, Vermeer SE, Clarke R, Oudkerk M, Koudstaal PJ, Hofman A, et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 2002;126:170-5:]
      • [3. Leblhuber F, Walli J, Artner-Dworzak E, Vrecko K, Widner B, Reibnegger G, et al. Hyperhomocysteinemia in dementia. J Neural Tansm 2000;107:1469-74.]
  • An excellent review of Vitamin B12 and multiple sclerosis can be recommended here:
    • [Miller A, Korem M, Almog R, Galboiz Y. Vitamin B12, demyelination, remyelination and repair in multiple sclerosis. J Neurol Sci 2005 Jun 15;233(1-2):93-7.]

Subtle and unrecognized vitamin B12 deficiency at the cellular level

  • Functional B12 deficiency:
    • Vitamin B12 level (usually normal or low)
    • serum homocysteine
    • methylmalonate levels
      • One or both metabolites will be elevated [31]
  • Can corrected by high-dose vitamin B12 therapy
  • 1. Vitamin B12 Therapy Prior to Chlamydial Therapy Adults
    • First several days 6,000 mcg of i.m./s.c.
    • Each of the next 3 weeks 6,000 mcg is given once per week [31]
  • 2. Vitamin B12 Therapy During Chlamydial Therapy
    • Increased need for vitamin B12
    • 6,000 mcg of parental vitamin B12 (3,000 mcg in each anterior thigh) once per week
    • In addition 5,000 mcg of sublingual vitamin B12 three times each day [31]
  • 3 Vitamin B12 Therapy Post Chlamydial
    • Vitamin B12 and serum homocysteine/methylmalonate levels should be rechecked
    • If the methylmalonate level remains elevated, continued vitamin B12 deficiency
    • P.o. 5,000 mcg of cobalamin 3xd should be continued
    • After several months, 6,000 mcg of parental vitamin B12 may be given [31]
  • Píchnula jsem si na to konto zkusmo 5 x 1000 ug i.m. vit. B12 (bez ohledu na to, kolik ho mám nebo nemám v krvi) a bylo to uplně skvělé. Vidím, že jsem mohla i mnohem větší dávky, ale nejsem nijak zvlásť nemocný člověk a nemám žádné neurologické obtíže. Najednou mě však zcela nečekaně přestávaly bolet klouby. Výborně mi to fungovalo proti bolestem kloubů !!! Ano, svaly krční páteře se už tolik nestahují a soustředí se mi na práci již mnohem lépe a nemám návaly hladu a pocitu na padnutí. Dokonce nemám ani zvýšené chutě na sladké a netloustnu (nejím však pečivo ani jiné škroboviny). Paměť je snad také lepší. Přineslo to úlevu a přitom vidím, jak to zaktivovalo imunitní systém a jak mi najednou na kůži hnisá kde co jak za mlada. Není-li riziko, že má pacient někde nádor, vřele doporučuji. Samozřejmě když už to do sebe člověk píchne, má smysl to dále podpořit dalšími vit. řady B, vč. kyseliny listové, aby se účinek ještě zvýšil.


Vitamins C

  • 1 gram twice per day [31]
  • Nechala jsme si dát infuzi vit. C 7,5 g i.v. s glutathionem. Celých cca 7-10 dní jsem neměla obtíže s bolestí kloubů a šíje, než se to začalo zase pomalo vracet. Opakovaně mě přepadává skoro žravost citrusů. Nějaká souvislost s tím zjevně bude. Kdaždopádně pro imunitu velmi důležité.

Vitamin E

  • 400 units twice per day [31]

L-carnitine

  • 500 mg twice per day [31]
  • Ten jsem zkusila, opravdu se mi potom výborně běhalo, byl to citelný zdroj energie
  • Treatment of MS patients with ALC
    • Decreased CSF levels of NO reactive metabolites and protein nitration
    • Increased content of GSH and GSH/GSSG ratio
  • Nitrosative stress is a major consequence of NO produced in MS-affected CNS
  • Possible important role for acetylcarnitine in protecting brain
  • Protect against acoustic damage to the inner ear in an animal model [40]
    • [Kopke R et al., Prevention of impulse noise-induced hearing loss with antioxidants. Acta Otolaryngol. 2005 Mar;125(3):235-43.]
  • ALC in the treatment of mild cognitive impairment and mild Alzheimer's disease showed significant efficacy vs. placebo.
    • [Ames BN, Liu J. Delaying the mitochondrial decay of aging with acetylcarnitine. Ann N Y Acad Sci. 2004 Nov;1033:108-16. Review.]
  • Efficacious in alleviating pain in patients with established diabetic neuropathy - improved:
    • Nerve fiber regeneration
    • Vibration perception [40]
    • [Sima AA et al., Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care. 2005 Jan;28(1):89-94.]
  • Found to protect against damage caused by beta-amyloid (Abeta)
    • ALC attenuated oxidative stress and cell death induced by beta-amyloid neurotoxicity [40]
    • [Dhitavat S, Ortiz D, Shea TB, Rivera ER. ALC protects against amyloid-beta neurotoxicity: roles of oxidative buffering and ATP levels. Neurochem Res. 2002 Jun;27(6):501-5.]
  • Oxidative damage to nucleic acids (8-hydroxyguanosine and 8-hydroxy-2'-deoxyguanosine) increased with age in the hippocampus
    • Occurred predominantly in RNA
    • ALC and / or a-lipoic acid significantly reduced the extent of oxidized RNA
      • Combination being the most effective [40]
      • [Liu J et al., Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-a -lipoic acid. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2356-61. Erratum in: Proc Natl Acad Sci U S A 2002 May 14;99(10):7184-5.]

Ubiquinone -coenzyme Q10

  • 30 mg twice per day [31]
  • Lipid-soluble molecule
  • Active in the hydrophobic core of the phospholipid bilayer of the inner membrane of mitochondria
  • Electron transfer within the electron transport chain
  • Important antioxidant within the mitochondrion.
  • Ability of the body to synthesize CoC10 begins to diminish surprisingly early in adult life
    • [Kalen A et al., Age-related changes in the lipid compositions of rat and human tissues. Lipids. 1989 Jul;24(7):579-84.] By mid-life most people are dependent on dietary sources.
  • Lipid peroxidation diminishes CoC10 levels in cells
    • [Forsmark-Andree P et al., Lipid peroxidation and changes in the ubiquinone content and the respiratory chain enzymes of submitochondrial particles. Free Radic Biol Med. 1997;22(3):391-400.]
  • When CoC10 levels become low:
    • Lipid peroxidation ++
    • CoQ10 depletion +++
    • Resulting in mitochondrial damage
  • Q10 supplementation
    • Doubles the number of ubiquinol-10-containing low-density lipoprotein (LDL) molecules [40]
    • May therefore have an inhibitory effect on LDL oxidation [40]
      • [Aejmelaeus R et al., Ubiquinol-10 and total peroxyl radical trapping capacity of LDL lipoproteins during aging: the effects of Q-10 supplementation. Molecular Aspects of Medicine 18(Suppl.) (1997), s113-s120.]
  • Protected against toxic damage to neurones in animal studies [40]
    • [Beal MF et al., Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate. Ann Neurol. 1994 Dec;36(6):882-8]
  • Protected against neurological damage caused by endotoxins [40]
    • [Chuang YC et al., Neuroprotective effects of coenzyme Q10 at rostral ventrolateral medulla against fatality during experimental endotoxemia in the rat. Shock. 2003 May;19(5):427-32.]
  • Combination found to improve and stabilize vision in age-related macular degeneration (AMD):
    • Acetyl L-carnitine
    • CoQ10
    • N-3 oils
      • [Feher J et al., Improvement of visual functions and fundus alterations in early age-related macular degeneration treated with a combination of acetyl L-carnitine, n-3 fatty acids, and coenzyme Q10. Ophthalmologica. 2005 May-Jun;219(3):154-66.]
    • One factor of AMD is chronic infection with Chlamydia pneumoniae
      • [Ishida O et al., Is Chlamydia pneumoniae infection a risk factor for age related macular degeneration? Br J Ophthalmol. 2003 May;87(5):523-4; Kalayoglu MV et al., Serological association between Chlamydia pneumoniae infection and age-related macular degeneration. Arch Ophthalmol. 2003 Apr;121(4):478-82; Robman L et al., Exposure to Chlamydia pneumoniae Infection and Progression of Age-related Macular Degeneration. Am J Epidem 2005 161(11):1013-1019.]
    • AMD is a disorder characterized by mitochondrial depletion and damage [40]
      • [Feher J et al., Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration.Neurobiol Aging. 2005 Jun 22.]

Biotin

  • 5 mg twice per day [31]
  • Cofactor in the synthesis of fatty acids, including myelin
  • 2015 pilot study of high-dose supplementation in persons with progressive MS
    • Surprising improvement in function in those with cord lesions
    • Improvement took 2 - 8 months to become manifest
    • [Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: A pilot study. Mult Scler Relat Disord 2015; 4: 159-169]
    • Dose used was 100 - 300 milligrams daily
  • Biotin is harmless
  • Only the pure form, unmixed with other supplements, should be taken
  • Sedel F, Bernard D, Mock DM, Tourbah A. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. 2016 Nov;110(Pt B):644-653 [40]

Alpha-lipoic acid - ALA

  • 400 mg twice per day [31]
  • mitochondrial energy production
  • Powerful antioxidant
  • Can be synthesized in the body
  • In conditions of chronic oxidative stress it may become depleted
  • Redukovaná forma ALA
    • Dihydrolipoic acid (DHLA)
  • ALA scavenges hydroxyl radicals
    • Hypochlorous acid
    • Peroxynitrite
    • Singlet oxygen [40]
  • DHLA
    • Scavenges superoxide and peroxyl radicals
    • Can regenerate
  • [reviewed by Packer L et al., Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition. 2001 Oct;17(10):888-95.]
  • Chelate to inorganic mercury
  • Increase the biliary excretion of mercury [40]
    • [Gregus Z et al., Effect of lipoic acid on biliary excretion of glutathione and metals. Toxicol Appl Pharmacol. 1992 May;114(1):88-96.]
  • Ameliorate oxidative damage caused by cadmium [40]
    • [Bludovska M et al., The influence of a-lipoic acid on the toxicity of cadmium. Gen Physiol Biophys. 1999 Oct;18 Spec No:28-32]

Vitamin D

  • 4000 iu is recommended [42]
    • Less may be needed in infections other than MS [42]
  • 1. D3 - cholecalciferol
    • Generated in the skin
    • Little biological activity
    • 2. 25(OH)D3
      • Vznikl alpha-hydroxylací in the liver
    • 3. 1,25(OH)2D3 - dihydroxy cholekalciferol
      • V ledvinách
      • Regulováno PTH
      • Greatest biological activity
  • MS has a geographical distribution
    • Incidence is lower in those who have a diet high in fish oils
    • Accords with the amount of sunlight received
      • With latitude
      • Cultural dictates, etc.
  • Vitamin D deficiency is common in MS
    • Bone mass density (BMD) lower in women with MS against controls
    • Parathyroid hormone (PTH) was frankly elevated in 13% of patients
      • Negatively correlated with
        • 25-hydroxycholecalciferol levels
        • BMD
  • calcium and vitamin D deficits increase
    • The risk of malignancies
      • Colon
      • Breast
      • Prostate gland
    • Chronic inflammatory
    • Autoimmune diseases
      • Insulin-dependent diabetes mellitus
      • Inflammatory bowel disease
      • Multiple sclerosis
    • Metabolic disorders
      • Metabolic syndrome
      • Hypertension [46]
  • Intake of vitamin D from supplements was inversely associated with risk of MS
  • Supplementation with Vitamin D in MS
    • Followed by elevation TGF-b [46]
      • Broadly anti-inflammatory signalling protein
      • Promote wound healing
      • Inhibit macrophage and lymphocyte proliferation
  • Supplementation with Vitamin D, calcium and magnesium
    • Decrease of relapse rate in young people with RRMS [46]
  • 1,25(OH)2D3 directly induces specific antimicrobial gene expression and activity [46]
    • Production of cathelicidins
      • Marked antimicrobial activity
      • Promote wound healing
      • Re-epthelialization of breaks in the skin
      • Absent in chronic (non-healing) ulcers
      • activity against intracellular bacteria
        • Demonstrated in Mycobacterium tuberculosis [46]
    • Active in the innate defence system of the gut
      • Lining the mucosa
      • Preventing attachment by epithelial-adherent bacterial pathogens
    • Active in vitro against Herpes Simplex Virus
      • Cathelicidin deficiency in eczema herpeticum [46]
  • Safe upper limit of supplementation in adults is officially declared to be 50 micrograms (2,000 IU) [46]
  • 100 micrograms (4000 iu.) may be safely given
    • In older persons may be necessary [46]
    • Absence of toxicity in trials on healthy adults vitamin D dose > or = 250 microg/d (10,000 IU vitamin D3)
      • [Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6-18.]
  • High dose Vitamin D important to those receiving (je možná fotoxicita):
    • Doxycycline
    • Minocycline [46]
  • It is important to take the D3 form [46]

Magnesium

  • 300mg [42]

Calcium

  • 500mg
  • Calcium salts should be taken remote from doxycycline as it can interfere with absorption [42]

Bioflavinoids - proanthocyanidins

Já už nově vím, že mnohé fungují nejen jako antioxidanty, ale i jako antibioticky účinné látky proti Chlamydia pneumonia

Pygnoginol

Quercetin

  • Very effective antioxidants [31]


Selenium

  • 100 mcg twice per day
  • Should be taken with the vitamin E [31]

L-Glutamine

  • 2 - 4 grams twice per day [31]

Querceten

  • 400 - 500 mg twice per day [31]

Glucosamine

  • 750 - 1000 mg two or three times per day [31]

Chondroitin sulfate

  • 250 - 500 mg twice per day [31]
  • Tohle mi na kloubní bolesti pomáhá. Když to pár týdnů nemám, je to horší. Tak nějak sama poksu omyl sem dospěla k tomu, že tohle musím tu a tam prostě zobat a ještě s hořčíkem a vit. D a vápníkem tu a tam k tomu, abych ty kloubní potíže držela nějak rozumně a nezhoršovalo se to. Jen poslední dobou se to zhoršilo tak rychle, že tohle přestalo fungovat.

Antiporphyrinic Drugs

Benzodiazapine Drugs

  • Xanax (0.5 mg three or four times per day) if panic attacks [31]
  • Restoril (30 mg at night) If insomnia [31]
  • Hydroxychloroquine Hydroxychloroquine (100 - 200 mg once or twice per day) often used to treat porphyria [31]
    • For patients with symptoms of porphyria, a single 100 mg dose of hydroxychloroquine may be tried
      • If this trial dose relieves the symptoms, hydroxychloroquine may be continued
      • Dose must be adjusted for each patient
      • Most patients do well on 100 mg once per day [31]

Oral Activated Charcoal

  • Absorbs fat-soluble porphyrins [31]
  • Binds these porphyrins in the gastrointestinal tract
    • Prevents them from being reabsorbed in the small intestine
  • Start with 2 grams (eight 250 mg capsules) of activated charcoal three times per day on an empty stomach
  • Gradually increase to 4 grams taken three times per day
  • Much more activated charcoal can be safely taken
    • 20g 6xd po 9 měs. bylo without any adverse side effects [31]
  • Important on a completely empty stomach without any food, vitamins, or medications
    • 2 hours before or 2 hours after charcoal ingestion [31]

Melatonin

  • Indole
  • Hormone biosynthesized from L-tryptophan within the pineal gland in the brain [40]
  • Regulate sleep [40]
  • Numerous and diverse actions in the cell [40]
  • Potent antioxidant [40]
  • Protecting mitochondria from oxidative stress [40]
  • Acts directly on the electron transport chain [40]
    • Increasing ATP synthesis [40] [40]
    • Preventing the oxidative damage associated with such an increase [40]
  • Restored levels of the important antioxidant glutathione [40] [40]
  • Able to pass into any tissue, cell or cell compartment with ease [40]
  • Normal dietary constituent [40]
    • Walnuts are a particularly rich source [40]
    • Dietary MEL can markedly influence blood-levels [40]
  • Protects against endotoxin-induced lipid peroxidation [40]
  • Stimulate some important antioxidative enzymes [40]
    • Superoxide dismutase
    • Glutathione peroxidase [40]
    • Glutathione reductase [40]
  • Effective in reducing macromolecular damage [40]
    • Paraquat toxicity [40]
    • Potassium cyanide administration [40]
    • Lipopolysaccharide treatment [40]
    • Kainic acid injection [40]
    • Carcinogen administration [40]
    • Carbon tetrachloride poisoning, etc. [40] [40]
    • Reducing the oxidation of macromolecules that occurs during strenuous exercise or ischemia-reperfusion [40]
  • Effective in reducing neuronal damage [40]
  • no toxicity [40]
  • Crosses morphophysiological barriers and enters subcellular compartments [40] [40]
  • Inhibit the production of endotoxin-induced Tumour Necrosis Factor alpha. [40]
  • Immunoregulatory effects via T-helper 2 (Th2) cell products [40]
    • Deve[40]lopment of septic shock associated with endotoxemia
  • Diminished levels of MEL in the ventricular CSF of those who had died with Alzheimer's disease [40]
  • Uniformly low in those who had died with advanced dementia, irrespective of their age. [40]
  • MEL depletion was found to be a very early event in the development of AD. [40]
  • A loss of the diurnal rhythm of MEL levels may precede the first clinical signs of the AD [40]
  • MEL ameliorated evening agitation [40]
  • Improved cognitive and non-cognitive functions in patients with AD [40]
    • It took several weeks for benefits to appear [40]
      • Action other than sedation, which is immediate
  • Sleep disorders are common in MS, with a flattening of the normal circadian sleeping/waking rhythm [40]
    • Wakefulness at night [40]
    • Tendency to somnolence during the day [40]
    • May be due to decreased nocturnal biosynthesis of MEL [40]
  • Decreased MEL biosynthesis is associated with pineal calcification. [40]
    • Pineal calcification is common in MS. [40]
    • MEL levels were found to be lower than daytime levels in 11 of 25 patients with MS
  • MEL is a major antioxidant in the brain [40]
    • Chronic depletion would be expected to allow widespread oxidative damage in the CNS [40]
  • Correct disordered steroid metabolism [40]
    • Hypothalamic - pituitary - adrenal (HPA) axis activation of the HPA axis in MS [40]
      • Activation of corticotropin releasing hormone (CRH) neurons [40]
      • + cortisol in the cerebrospinal fluid [40]
      • + basal cortisol levels increased in the CSF of MS patients [40]
        • Can be damaging, particularly to the hippocampus [40]
    • Dietary MEL reduced hypothalamic CRH [40]
  • MEL attenuates the adrenocortical response to stress [40]
    • Influences the biosynthesis, release and glucocorticoid responsiveness of hypothalamic ACTH secretagogues [40]
  • Depression can be set in motion by dysregulation of the HPA axis [40]

Lactobacillus acidophilus

  • Daily, either as a supplement or in capsules
  • To maintain bowel flora in the face of antibiotic treatment [42]

Dietní doporučení



High Carbohydrate Diet

  • Cca 70% of the daily caloric intake of complex carbohydrates
    • Bread, potato, rice, and pasta [31]
  • Remaining 30% of calories in protein and fat
    • White fish or chicken [31]
  • Proboha proč tohle??? To mi vysvětlí jak?

Glucose

  • Important source of cellular energy reduced with chlamydial infections
  • Increasing the availability of glucose provides optimal conditions for the cells to produce energy [31]
  • Takhle jíst, tak ze mě bude za chvíli tak akorát tlustá koule. Ale je pravda, že když jsem zkoušla jíst jenom 2x denně a otužovat se, tak sem to přehnala a obtíže s bolestí krční ptáteře se mi skoro skokově zhoršily a místo toho, abych byla odolnější, tak sem se pak cítila zchátralejší a zdegenerovanější. Oboje působí imunosupresivně. Zjevně nemám zánět autouimunitní, ale infekční a reakce jsou opačné.
  • Občas abych se vydržela v práci soustředit, piju čaj a kávu a nepomáhá to jako dřív, ale čokoláda a sladkosti ano i za cenu toho, že po tom fakt tloustnu. Občas se však stává, že už nepomůže ani sníst těch sladkostí hodně. To je asi jeden z momentů, kdy si clovek rika, ze uz to zacina byt vazny. Vsechny tyhle symptomy zmizely skoro okamzite do ruhého dne po nasazení Azitromycinu. Nic se nezhorsilo.
    • Augmentin, ktery jsem uzivala cca měsíc před Azitromycinem na doporučení lékaře, kdy všichni ostatní členové rodiny měli výtěry pozitivní na Streptokoka A a já sem se cítila unavená a zadýchávala jsem se, mi sice první dva dny mírně snížil únavu a zadýchávání se, ale dalších 5 dní, co sem ho užívala, se už stav neměnil a vliv na schopnost vydržet se soustředit, stahující se šíji a míru kloubních bolestí to nemělo skoro žádný nebo jen minimální.

Sucrose

  • Mixture of glucose and fructose
  • Not the best way to increase the glucose availability [31]

Fructose

  • Excess of fructose may temporarily reduce the availability of glucose at the cellular level
  • Should be avoided as much as possible [31]






Avoid Alcohol

  • Well-known aggravator of porphyria
  • Should be avoided as much as possible [31]

High Oral Fluid Intake

  • water
    • Bicarbonated water
    • "sports-drinks" [water with glucose and salts]
    • Helps flush water-soluble porphyrins
  • Dehydration
    • Concentrates porphyrins
    • Makes patients more symptomatic [31]
  • The color of the urine should always be almost clear rather than dark yellow
  • Voda pomáhá od kde čeho...





Avoid Red Meats

  • Including beef and dark turkey, tuna and salmon
    • Contain tryptophan
      • Should be avoided as much as possible [31]
  • Tole by mi dávalo smysl. Když jsem si dávala L-tryptofan na zlepšení kvality spánku (ráno sem se cítívala málo odpočatá), asi mě potom bolely klouby a svaly ještě víc, ale nedávala jsem si to dohromady. Že mám po proteinových nápojích asi silnější potíže se zánětem, toho jsem si pak už všimla. Že proteiny dodají sílu zánětu ať už je jakéhokoliv původu není těžké si představit.
  • V různých studiích o chlamdyiích sem vyčetla, že try je pro ně důležitý zdroj a že naše buňky se s nima o to přetahují. Pro Chl. je trp tak důležitý pro jejich replikaci, že zásoby trp v různých buňkách určují i tropismus toho, ve kterých buňkách se chlamydie budou nebo nebudou množit. Typicky trp musí být v buňkách, které si potřebují syntetizovat hodně melatoninu jako hlavního nejsilnějšího antioxidantu - a to jsou typicky buňky epitelů, sliznic, kůže a mozku, imunitního syst. atd. - dle toho, jak musí být schopné čelit ox. stresu. Otázka zrychleného stárnutí, oxidačního stresu a degenerace je tedy ve vztahu k chlamydiím velmi přiléhavá.






Avoid Milk Products

  • Contain lactose and lactoferrin [31]
  • A tohle je proč? Dříve jsem po některém mléku mívala jen ataky astmatu. To pak zmizelo po vyléčení se z Chlamydie. To už je cca 10 let. Nyní se stává, že občas po některém mléku (s kávou - v jiné podobě už ho nepiju) se mi totálně rozhodilo soustředění se, až jako šum v hlavě s bolestí šíje a až snad i hlavy, kterou jsem ještě nezanala. Myslela jsem si, že je to důsledek nějakého antigenu v mléce, reaktivní plicní zahlenění a následná hyperventilace a její důsledky na schopnost se soustředit. Kontrola dechu mi však moc nepomáhala. Párkrát jsem na to konto lehnula na gauč a usnula. Proč to je? Jaké to má souvislosti ?


Shrnutí

  • The following compounds fulfilled the criteria with 100% growth inhibition of
    • C. pneumoniae clinical isolate K7 (Kajaani 7):
  • acacetin
  • apigenin
  • Coumarin 106
  • 7-diethylamino-3-thenoylcoumarin
  • Dodecyl gallate
  • Luteolin
  • Methoxy sporalen
  • Methyl gallate
  • Morin,
  • Myricetin
  • Octyl gallate
  • Propyl gallate
  • Rhamnetin
  • Rotenone (Alvesalo et al., 2006b)
  • Biochanin A (Hanski et al., 2014)
  • Schisandrin A
  • Schisandrin B
  • Schisandrin C
  • Not as potent inhibitors of the growth of C. pneumoniae as MPA:
    • 2-arylbenzimidazole 42 (Keurulainen et al., 2010),
    • Benzimidazole MB4 (Alvesalo et al., 2006a)
    • Biochanin A (Hanski et al., 2014),
    • Linarin (Salin et al., 2011b)
    • Luteolin (Alvesalo et al., 2006b)
.souhrn.jpg

O úroveň výše

Poslední aktualizace: 18. 12. 2022 1:30:20