MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

nemoci-sympt/METABOLISMUS/downuv-syndrom/zvysene

Whole-blood 5-hydroxyindole (5-hi) levels

  • Average blood 5-hi level was depressed in phenylketonuria and Down's syndrome
  • Elevated in the severely retarded
  • The csf 5-hi levels were within or above normal limits in Down's syndrome and the severely retarded.
  • Beim Down Syndrom fiel ein deutlicher Abfall der 5-hi-Blutspiegel rnit zunehmendem Alter auf.
  • 5-hi-Blutspiegei beim Down Syndrom und bei den schwer Retardierten keinen genauen Hinweis auf den Serotonin Metabolismus im Gehirn gibt

Alkaline phosphatase


APP triplication

  • Overexpression of APP
    • Integral membrane protein
    • Concentrated in neuronal synapses
    • Consequent overproduction of amyloid beta (Aß)-peptide
      • Considered one of the major toxic players in the early onset of AD neuropathology in DS population (Hartley et al., 2015; Wiseman et al., 2015).
  • www.frontiersin.org/articles/10.3389/fnins.2020.00670/full

Abeta

  • Jako zdroj oxidačího stresu v CNS
  • Can cause increased production of hydrogen peroxide and lipid peroxides (Behl et al. 1994)
  • Three possible sources can be envisaged
    • Iron release from aconitase (Longo et al. 2000) - increased in fetal DS brain (Bajo et al. 2002)
    • Binding to advanced glycation end products receptor (Yan et al. 1997) - also increased in fetal DS brain (Odetti et al. 1998)
    • Aß-mediated generation of hydrogen peroxide through its interaction with copper (Huang et al. 1999)


Adipokine production


Autoimunity

  • Medullary thymocytes from DS patients
    • Show altered the mRNA levels of the autoimmune regulator (AIRE) gene, sited on HSA21
      • Resulting in the consequent deregulated expression of INSULIN and CHRNA1genes (Gimenez-Barcons et al., 2014)
  • www.frontiersin.org/articles/10.3389/fnins.2020.00670/full

Cystathione beta-synthase - CBS

  • Overexpression of the gene causes a “functional” folic acid deficiency
    • Serum levels are normal but the body "can’t use all of it" and is unable to repair damaged DNA.
    • Supplementation supposedly alleviates
    • Theory has yet to be demonstrated in a scientific study
  • FDA funded such a study, which should be completed in 1999
    • It is not clear that cystathione beta-synthase levels are elevated in Down syndrome
    • One study showed increased amounts, but two others did not
  • quackwatch.org/11ind/down/

  • Activity of the enzyme cystathionine beta-synthase (CBS)
    • Encoded on chromosome 21 (21q22.3)
  • Associated with the level of intelligence and with neuropsychiatric disorders (Abbott et al., 1987; Barbaux et al., 2000)
  • Concentration of CBS investigated in postmortem brains of DS persons (Ichinohe et al., 2005)
    • Concentration of CBS was 3x higher x normal individuals
  • CBS catalyzes:
    • Conversion of homocysteine and serine into cystathionine
      • Dipeptide is further metabolized into the amino acids cysteine
        • Eventually to taurine
  • In humans
    • Sole source of homocysteine is through dietary intake of the essential amino acid methionine (Selhub et al., 1999; Ward et al., 2000).
  • Over-expression of CBS in persons with DS
    • May alter homocysteine metabolism
      • Resulting in a metabolic imbalance
        • Folate-dependent resynthesis of methionine is compromised
          • May be in favour of the transsulfuration pathway, leading eventually to increased levels of taurine (Huxtable, 1992)
  • Due to the dosage effect of CBS
    • A decrease in plasma concentration of serine was found in DS persons
    • Increase in plasma lysine
      • Explained by generalized premature aging in DS, was observed (Mircher et al., 1997)
  • Concentrations of taurine and glycine
    • Are significantly increased in DS persons

  • Overexpression of CBS is responsible for reduced homocysteine levels together with reduced mitochondrial function
    • Accumulation of Krebs cycle intermediaries in DS human dermal fibroblasts (Panagaki et al., 2019)
  • Szabo et al. showed that increased production of H2S is responsible for mitochondrial deficits
    • In particular by inhibiting complex IV (Panagaki et al., 2019)
  • Both cytosolic and mitochondrial CBS protein levels, as well as H2S cellular levels
    • Are markedly elevated in DS fibroblasts
  • Extracellular flux analysis of DS cells showed a significant impairment of
    • mitochondrial complexes activities
    • Oxygen consumption
    • ATP generation
    • Also affected proliferation rate
  • Specific activity of Complex IV
    • Significantly inhibited in DS cells
  • Inhibition of CBS by aminooxyacetate (AOAA)
    • Interferes with the pyridoxal phosphate in the catalytic site
    • Restored Complex IV activity
    • Ameliorated mitochondrial electron transport and cell proliferation
  • Similar effects were also obtained by CBS normalization by siRNA (Panagaki et al., 2019)
  • Increased urinary thiosulfate [a stable degradation product of hydrogen sulfide (H2S)]
  • Circulating sulfhemoglobin (addition of H2S to hemoglobin) levels
    • Have already been detected in subjects with DS (Szabo, 2020).
  • Reduced rate of energy metabolism due to mitochondrial dysfunction
    • Significantly impairs neuronal functions, as well as neuronal development and survival (Mattson et al., 2008)
  • ATP production and redox homeostasis in brain mitochondria are essential to sustain neural developmental processes (Mattson et al., 2008).
  • Mitochondrial deficits in DS is mainly the result of reduced efficiency to produce ATP through OXPHOS
    • Decreased respiratory capacity
    • Disruption of membrane potential and mitochondrial dynamics Valenti et al. (2018)
    • Associated with increased oxidative stress (Perluigi and Butterfield, 2012).

Intracellular neuronal chloride
i
levels

  • Determines the efficacy of GABAergic inhibition:
    • High levels
      • Can reverse the polarity of GABA actions from inhibition to excitation
      • Immature neurons that have high (Cl-)i levels and excitatory actions of GABA
      • Seizures, brain trauma,
      • Spinal cord lesions,
      • Cerebrovascular infarcts
      • Chronic pain
    • Low Cl-
      • Adult neurons
      • Inhibitory actions of GABA
  • Polarity shift of the actions of GABA impact sensory and integrative properties of the brain
    • And exert major deleterious effects
      • Pharmacological treatments that restore physiological (Cl-)i levels and GABAergic inhibition in pathological conditions.

Ceramide synthase

  • Zvýšená aktivita

Cholesterol


Citrate

Creatine

  • Is phosphorylated in mitochondria by ATP derived from oxidative phosphorylation and the phosphocreatine
    • Subsequently exported outside mitochondria
      • Used by the cytosolic creatine kinase to resupply ATP for muscle activity
  • Plasma accumulation of creatine, probably due to the OXPHOS impairment
    • Could account for the muscle weakness, another typical DS phenotype.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC5813015/

Cysteine

DM

  • The prevalence of childhood-onset autoimmune diabetes in the DS
    • More than fourfold that of the general population
    • Arise from the trisomy of genes on chromosome 21 (Bergholdt et al., 2006; Johnson et al., 2019)
  • Type 2 diabetes mellitus (T2DM)
    • Increased frequency at a relatively early age in DS subjects (Alexander et al., 2016)
  • DS subjects show an increased rate of non-alcoholic fatty liver disease (NAFLD)
    • Closely associated with insulin resistance (Williams et al., 2011; Loomba et al., 2012)
  • Several known proteins encoded by HSA21 such as
    • BACE2 (Esterhazy et al., 2011)
      • Gain-of-function experiments in INS1E cell cultures decreased cell proliferation and insulin secretion
        • Along with increased mitochondrial metabolism and ROS levels (Alcarraz-Vizan et al., 2015)
      • Loss of function experiments improved insulin secretory response in rat pancreatic ß-cells (Alcarraz-Vizan et al., 2015).
    • RCAN1 (Peiris et al., 2016; Seo et al., 2019),
    • DYRK1A (Rachdi et al., 2014a)
  • Expressed in peripheral organs
  • Related to diabetes phenotypes
    • Besides the HLA region of chromosome 6, chromosome 21 may contain also candidate genes which overdose and may contribute to the metabolic disruptions, thus conferring increased TD1 risk in DS.
  • www.frontiersin.org/articles/10.3389/fnins.2020.00670/full

DYRK1A kinase [Dual specificity Tyrosine(Y) Regulated Kinase 1A]

  • Overexpression
  • Could reduce availability of tyrosine
  • This gene is fundamental for normal neurogenesis
  • Overexpressed in fetuses and adults with DS
  • Triplicated gene DYRK1A is involved in brain developmental alterations in DS derives from evidence that:
    • Dyrk1A transgenic mice exhibit brain and behavioral abnormalities that are similar to those of DS
    • Dyrk1A transgenic mice exhibit neurogenesis alterations
      • Confirming the role of DYRK1A in this process
  • www.tandfonline.com/doi/full/10.1080/23262133.2016.1270383

Pharmacological inhibition of DYRK1A in both mice and human cells

  • Leads to proliferation of beta-cell (Wang et al., 2015; Belgardt and Lammert, 2016)
    • Improves glycemic control in mice (Liu et al., 2020)
  • Dyrk1A is highly expressed and induces the expression and nuclear accumulation of p27Kip1 in the adipose tissue and pancreas (Rachdi et al., 2014b)

Mice overexpressing Dyrk1A

  • Increased beta-cell mass
  • Improved glucose homeostasis (Rachdi et al., 2014a)
    • Probably mediated by p27Kip1
      • Acts as a negative regulator of proliferation via the inhibition of cyclin-CDK activity (Lloyd et al., 1999)
  • Mice overexpressing Dyrk1A are characterized by
    • Reduced fat mass,
    • Increased Thr(P) (356)-GSK3beta in the white adipose tissue
    • Downregulation of adipogenic proteins (Song et al., 2015)
  • DYRK1A specifically inhibits GSK3beta (Song et al., 2015)
    • Transcription factor associated with adiposity and obesity (Pearce et al., 2004)

Dyrk1A haploinsufficiency in mice

  • Produces severe glucose intolerance
  • Reduced beta-cell mass
  • Decreased ß-cell proliferation (Rachdi et al., 2014b).
  • XDyrk1A resides within the so-called Down Syndrome Critical Region (DSCR) of human chromosome 21 (refs 5,6,7)
    • A genomic region that has an important role in DS manifestations
  • Overexpression of Dyrk1A alone
    • Is sufficient to induce brain morphology alterations
    • As well as neurological and motor disorders that may be reminiscent of the learning deficits and altered motor skill acquisition seen in patients with DS
  • Aberrant phosphorylation of NFATc transcription factors
    • Components of the calcineurin/NFAT (nuclear factor of activated T cell) signalling pathway
    • Proposed to have a role in the pathogenesis of DS
  • Nfatc1-/--knockout mouse embryos and Nfatc2-/-; Nfatc3-/-; Nfatc4-/- triple-knockout mouse embryos
    • Exhibit cardiac development defects similar to those seen in DS
  • Nfatc2-/-; Nfatc4-/- double-knockout mice
    • Decreased muscular strength, increased sociability and decreased anxiety-related behaviour that are similar to those seen in DS.
  • Dyrk1A in one allele (Dyrk1A+/- mice)
    • Also show profound phenotypic abnormalities
    • Reduced viability, smaller body size, disproportionate decrease in the size of the midbrain and hindbrain regions
    • Changes in pyramidal cell structure and neuromotor and cognitive impairment
  • Mice homozygous for targeted disruption of Dyrk1A (Dyrk1A-/--null mice)
    • Embryonic lethal
  • Dyrk1A has distinctively strong dose effects
    • Excess or a deficit of the kinase activity is detrimental for the normal functioning of the brain and the body.

Down syndrome critical region-1 (DSCR-1) (mRNA)

  • DSCR-1 is a developmentally regulated gene involved in neurogenesis
  • Over-expression may contribute to brain abnormalities through
    • Inhibition of calcineurin-dependent gene transcription (Fuentes et al. 2000)
  • DS region was first defined as lying between DS21S17 and Ets2 (4.8 Mb)
  • Restricted to the
    • 2.5-Mb carbonyl reductase,
    • Transcription factor ERG (CBR-ERG) region (Pritchard and Kola 1999; Shapiro 1999; Galdzicki et al. 2001)
  • Associated with numerous features of DS
    • Genes from the DS critical region, including
      • DSCR1
      • Sim (in mouse model of DS) are found to be over-expressed, whereas rets is unaffected.
  • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

Ethanolamine, glutamate + glutamine and phenylacetylglycine

Ets-2

  • Pokles mRNA Baffico et al. (1989)
  • Pokles proteinu Engidawork et al. (2001a)
  • Human Ets-2 is a proto-oncogene and transcription factor
  • Defines the distal limit of the Down syndrome critical region
  • Coded by the ets-2 gene
    • Member of the ets-2 gene family identified on the basis of homology to the v-ets oncogene isolated from
      • E26 erythroblastosis virus (Raouf and Seth 2000)
  • Ubiquitous distribution of Ets-2, including the brain (Bhat et al. 1987; Baffico et al. 1989)
  • Role in leukaemia and organogenesis
  • Encoding gene is located on chromosome 21
  • Development of skeletal abnormalities resembling those of DS in transgenic mice over-expressing Ets-2 (Sumarsono et al. 1996)
    • Strengthened this view
  • Neither Ets-2 message (Baffico et al. 1989) nor Ets-2 protein levels (Engidawork et al. 2001a) are significantly different between control and DS fetal brain
    • In contrast to what would be expected from a gene dosage effect
  • Discrepancy emphasizes that extra gene load is not always associated with gain of function.
Může tedy rozhodovat míra metylace/demetylace. Demetylace asi může být rizikový stav u jedinců s DS... (?)

FTCD - formimidoyltransferase cyclodeaminase

  • On Hsa21
    • Only one enzyme gene
    • Located on 21q22.3
    • Encoding for the formimidoyltransferase cyclodeaminase
  • FTCD enzyme is involved in the most common inborn error of folate metabolism
    • Due to an autosomal recessive disorder causing a glutamate formiminotransferase deficiency
  • This enzyme catalyzes two reactions of the histidine metabolism
    • Degradation of N-formimino-L-glutamic acid to form 5,10-methenyltetrahydrofolate, L-glutamate, and ammonia
      • (KEGG pathway 2.1.2.5, Supplementary Table S4)
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC5813015/

Disorders of phenylalanine and tyrosine metabolism in Down's syndrome

  • Article in Russian, A M Shaposhnikov, S E Khal'chitskii, E I Shvarts; PMID: 154771

Phenylalanine !!

  • Was increased in blood serum in mongolism
  • 4 patients with mongolism and 10 healthy persons
    • Loaded with 1-phenylalanine
      • Content of the amino acid in blood serum of patients exceeded 1.5-2-fold that found in healthy persons
      • Within 4 and 6 hrs after the treatment
  • Hydroxylation rate of phenylalanine
    • Was lower in mongolism as compared to normal state
  • Corresponded to the rate of phenylalanine hydroxylation in
    • Atypical homo- and heterozygote patients bearing "phenylketonuria" gene
    • In patients with viral hepatitis

Tyrosine

  • Was distinctly higher in the impaired patients within 2-6 hrs after the loading
    • As compared with the healthy persons
  • Tyrosine was increased only slightly in patients with mongolism during the loading
  • Excretion of homogentisinic acid with urine was decreased

Activity of phenylalanine hydroxylase system

  • Is impaired in liver tissue in mongolism
  • Excretion of phenylpyruvic acid with urine
    • Was not observed in the patients and healthy persons both before and during the amino acid loading.
  • The data obtained suggest that impairment of phenylalanine and tyrosine turnover in mongolism
    • Appears to be
      • One of the factors responsible for disturbance of neurotransmitter synthesis
      • To be related to development of mental retardation.
  • pubmed.ncbi.nlm.nih.gov/154771/
Vyplývá z toho že může mít smysl omezovat bohaté zdroje fenyalaninu a ev. zařadit suplementaci "Large neutral aminoacids" - vleké neutrální aminokyseliny, které soutěží s fenylalaninem o vstup do mozku. Dále je důležité okontrolovat, aby nebyla hypofunkce štítnice - "ani subklinická"

Moderate form of hyperphenylalaninaemia



Formimidoyltransferase cyclodeaminase (FTCD)

  • Another gene located on the long arm of HSA21
  • Participates in histidine and folate metabolism
  • Essential for purine, pyrimidines, and amino acids biosynthesis.
  • Aberrant metabolism of adenosine, homocysteine, and folate
    • Also observed in DS (Patterson, 2009; Gross et al., 2019).

G6PDH

  • Was also significantly increased
  • G6PDH fuels the first reaction of the pentose phosphate pathway
    • To synthesise ribose as the sugar components of nucleotides and to maintain a continuous supply of NADPH as the obligatory substrate for the glutathione system protecting cells against oxidative stress (Lukaszewicz-Hussain, 2003; Sailaja et al., 2003)

Altered GABAergic transmission through Cl- permeable GABAA receptors (GABAARs)

  • Contributes considerably to learning and memory deficits in DS mouse models
  • GABAAR signaling was found to be excitatory rather than inhibitory
  • Reversal potential for GABAAR-driven Cl- currents (ECl) was shifted toward more positive potentials in the hippocampi of adult DS mice.
  • GABA is excitatory in adult DS mice
    • Identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.
  • Excitation/inhibition imbalance has been attributed to the developmental profiles of NKCC1 and KCC2 protein expression (Ben-Ari et al., 2012).
  • www.nature.com/articles/nm.3827

NKCC1 cotransporter

  • Hippocampal expression of the cation Cl- cotransporter NKCC1 was increased in both trisomic mice and individuals with DS.
  • Notably, NKCC1 inhibition by the FDA-approved drug bumetanide
    • Restored ECl,
    • Synaptic plasticity
    • Hippocampus-dependent memory in adult DS mice
  • www.nature.com/articles/nm.3827

  • GABA inibice

    • Deficits in Cognition and Synaptic Plasticity in a Mouse Model of Down Syndrome Ameliorated by GABAB Receptor Antagonists
    • Signaling through postsynaptic GABAB receptors is significantly increased in the dentate gyrus of Ts65Dn mice, a genetic model of DS
    • GABAB receptor antagonist CGP55845 restored memory of Ts65Dn mice
    • www.jneurosci.org/content/32/27/9217.short

    GIRK2

    Glutamatergic

    • Reported to be increased by some, if not all, authors (Brooksbank et al. 1989; Bar-Peled et al. 1991; Arai et al. 1996; Oka and Takashima 1999; Lubec et al. 2001b)
    • Increased expression of metabotropic glutamate receptor 5 (Oka and Takashima 1999)
      • Appears to be neuroprotective
        • Possibly through modulation of APP processing, NMDA toxicity and maturation of neurite growth.
    • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

    Glutamine


    Glutathione peroxidase (GPX1)

    Guanosinc triphosphate in the purine pool

    • H2S blokuje enzymy vazbou na železo
      • fenylalanin dehydrogenaza v sobě taky má atom železa
      • Možná je to jeden z možných způsobů, proč je u Downova syndromu popsaná nižší aktivita PAH
        • A proč to některé studie popisují, jiné ne

    H2S

    • Increased production of H2S
      • Responsible for mitochondrial deficits
        • By inhibiting complex IV (Panagaki et al., 2019) !!!
    • Confirmed that both cytosolic and mitochondrial CBS protein levels, as well as H2S cellular levels, are markedly elevated in DS fibroblasts.
    • Significant impairment of mitochondrial complexes activities and oxygen consumption, and of ATP generation,
      • Also affected proliferation rate (!!! mozek !!!)

    HMG14

    • Zvýšení mRNA Epstein (2001)
    • HMG14 zvýšení protein Epstein (2001)

    Homovanillic acid

    • Monoamine metabolites
      • 5-hydroxyindoleacetic acid was not altered
      • Homovanillic acid was significantly increased
    • Healthy DS persons of older age:
      • Compromised homocysteine metabolism
      • Enhanced turnover of dopamine
    • HVA concentrations are signifi- cantly increased, which is an indication of a higher turnover of dopamine that was reported previously also in cerebrospinal fluid studies in persons with DS (Kay et al., 1987; Schapiro et al., 1987).
    • www.ncbi.nlm.nih.gov/pmc/articles/PMC2794348/

    Inhibitory neurons increase


    Instability of the upper cervical-spine

    70 children with Down Syndrome (22 boys and 48 girls)

    • Ages ranging between five and seventeen years
    • X-ray study of this region in lateral projection in neutral position and flexion-extension of the neck
    • Distance between the anterior arch of the atlas and odontoid process as well as the displacement of the basion in relation to the first cervical vertebrae were examined
    • 12 patients (17.14 percent) exhibited motion alterations of the region studied
      • Atlanto-axial instability in 8 cases (interval bigger than 4.5 mm)
      • Atlanto-occipital instability in 4 cases
    • pubmed.ncbi.nlm.nih.gov/2144107/
    • Může to souviset s overexpresí metaloproteinázy 9 (?) - degraduje vazivo a extracelulární matrix...

    Intersectin (mRNA)

    • Intersectin gene is widely expressed in fetal as well as adult tissues
    • Codes for two isoforms, short and long, by alternative splicing
    • Long isoform is brain specific
      • Takes part in synaptic vesicle recycling activities
      • Over-expressed in brain of DS fetuses compared with controls (Pucharcós et al. 1999)
    • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

    Insulin resistance

    Isoleucine, leucine, phenylalanine and cystine

    • Down's syndrome, where Alzheimer-type histology appears
    • Consistently at an early age
    • There was a definite type of abnormality, raised concentrations of:

    Krebs cycle intermediaries

    • Accumulation in DS human dermal fibroblasts (Panagaki et al., 2019).

    Krebsův cyklus metabolity

    • DS/normal ratio in plasma:
      • 1.23 (pyruvate)
      • 1.47 (succinate)
      • 1.39 (fumarate)
      • 1.33 (lactate)
      • 1.4 (formate)
    • Several significantly altered metabolites are produced at the beginning or during the Krebs cycle.
    .plasma.jpg

    .plasma-fast.jpg

    .urine.jpg

    .urine-fast.jpg
    • Important to underline that the increment of
      • Pyruvate,
      • Succinate,
      • Formate
      • Creatine
    • Are significant alterations suggest a systematic imbalance of the Krebs cycle
      • Different pathways of mitochondrial metabolism
      • Several works have pointed out the role of mitochondria in DS
    • Krebs cycle is a central metabolic pathway for regulation of cell metabolism and energy homeostasis
    • Accumulation of intermediate metabolites of Krebs cycle
      • Could suggest a systematic imbalance of this cycle in DS

    Impairment of certain enzymes of Krebs cycle

    Kyselina močová

    L-glutamate

    • Increased level in DS urine of the fasting group subjects
      • Not significant
    • Further study is needed in this regard by analyzing other metabolites

    Lactate

    • The increase of plasma lactate we found in DS samples
      • Increase of basal levels of lactate found in fibroblasts from DS patients
    • DS cells, in which the OXPHOS is impaired
      • Activate glycolysis for their energy demands
    • Consistently, also in another neurodevelopmental disease such as
      • Autism spectrum disorder
        • Associated with mitochondrial metabolism impairment
          • Abnormal levels of metabolites associated with activation of glycolysis like serum lactate and pyruvate were found
    • www.ncbi.nlm.nih.gov/pmc/articles/PMC5813015/

    Leucine, isoleucine, cysteine, and phenylalanine

    • At age vulnerable to Alzheimer’s changes higher levels !!
    Jestli by dy fenyketonurickou dietu neměli držet i dementnící senioři...

    Lysine

    • Increased concentration in patients above 10 years old
    • Possibly associated to accelerated aging Caracausi et al. (2018).
    • Increased plasma lysine concentration in patients above 10 years old, possibly due to premature aging
    • www.ncbi.nlm.nih.gov/pmc/articles/PMC5813015/

    Metabolites related to the methylation cycle

    • Such as cysteine, cystathionine, choline and dimethylglycine
      • Concentrations were found to be significantly elevated in DS plasma by MS analysis
    • S-adenosylhomocysteine and S-adenosylmethionine plasma level
      • However were found to be decreased in a previous report
    • www.ncbi.nlm.nih.gov/pmc/articles/PMC5813015/

    NKCC1


    Natural antibodies

    • Against intestinal antigens are low
    • In the presence of cow's milk, abnormally high titres against casein and beta-lactoglobulin were present = tvaroh může být problém a mléko obecně
    • High levels of IgG antibodies against gliadin have been observed = syndrom zvýšené střevní propustnosti

    Neopterin

      • Was increased in persons with DS
    • High concentrations of neopterin as seen in DS is consistent with the impaired immune function that was reported in persons with DS (Nespoli et al., 1993; Park et al., 2000).
    • www.ncbi.nlm.nih.gov/pmc/articles/PMC2794348/


    Olig1 and Olig2

    • Two genes that are triplicated in Down syndrome and in Ts65Dn mice
    • Overexpressed in the Ts65Dn forebrain
    • Genetic approach to normalize the dosage of these two genes
      • Rescued the inhibitory neuron phenotype in the Ts65Dn brain
      • Suggest a mechanistic relationship between triplicated genes and these brain abnormalities in the Ts65Dn mouse.
    • www.nature.com/articles/nn.2600

    Overexpression of the Hsa21 gene NRIP1 (21q11.2–21q21.1)


    Parathyroid hormone (PTH)

    • Able to inhibit proximal reabsorption of ions such as Ca and Na
    • Induce salivary secretion of these electrolytes
    • Elevated salivary levels of Ca and Na
      • Might reflect high PTH levels which have been found in individuals with DS
    • High salivary calcium concentrations
      • Are suggested as an indicator of osteoporosis and orthopedic problems and low bone mineral density (BMD)
        • Are among the most frequently encountered problems in people with DS
    • Therefore high salivary calcium levels might represent low calcium concentrations in the extracellular fluid
      • Leading to increase in PTH levels
        • Thereby reducing BMD in people with DS

    Paradentoza

    • Supra- and subgingival calculus
    • Gingival inflammation
    • Periodontal pockets (greater than or equal to 5 mm)
    • Alveolar bone loss
    • In children (10-19 yr) with Down's syndrome (D-S) roentgenologic examination
      • Alveolar bone loss was diagnosed in 39% of the D-S children x 3% control group (P less than 0.001)
    • Early signs of periodontitis are frequently seen in D-S children
      • As early as 11 yr of age and the lesions are first diagnosed in the mandibular anterior region

    Peroxiredoxins


    Phenylacetylglycine, trimethylamine-N-oxide (TMAO) and tyrosine

    • Takže nějaký odpadní produkt z fenylalaninu je v moči vyšší (?)
    • A že vázne metabolismus i už hotového tyrozinu (?)

    Phenylalanine and tyrosine


    Phenylpyruvate

    • Conducted on amniotic fluid samples from fetuses with DS x controls
    • MS analysis showing an elevation of phenylpyruvate that inhibits the metabolism of tetrahydrobiopterin
    • Takže v podstatě keton fenylalaninu, který se hromadí i u fenyletonurie a ještě ke všemu působí sekundární poruchu biopterinového metabolismu, což může mít za následek deficit monoaminových neurotransmiterů - již prenatálně



    Phenylpyruvate

    • Amniotic fluid samples from fetuses with DS
      • Compared with those of non-syndromic fetuses
    • MS analysis
      • Elevation of phenylpyruvate that inhibits the metabolism of tetrahydrobiopterin
    • www.ncbi.nlm.nih.gov/pmc/articles/PMC5813015/


    Phosphate

    Phosphofructokinase (PFK)

    • Regulatory enzyme in glycolysis
    • Catalyzes the phosphorylation of fructose-6-phospate to fructose-1, 6-bisphosphate (Uyeda, 1979).
    • Increased glucose utilization in the brain
      • Observed in young DS adult brain that likely contributes to cognitive disabilities.
    • Aberrant glucose metabolism is already pronounced in developmental period
      • May contribute to learning disabilities
    • HSA21 also encodes for phosphofructokinase (PFK)
    • Regulatory enzyme in glycolysis
    • Catalyzes the phosphorylation of fructose-6-phospate to fructose-1, 6-bisphosphate (Uyeda, 1979)

    Transgenic mice that overexpress PFK liver type (Tg- PFKL)

    • Showed alteration in glucose metabolism
    • Increased metabolic flux in brain
    • Reduced clearance from blood (Peled-Kamar et al., 1998)
    • Increased glucose utilization in the brain of Tg-PFKL mice is similar to the observed faster glucose metabolism in young DS adult brain
      • Likely contributes to cognitive disabilities
    • PFK specific activity is twofold higher in the brains of embryonic Tg-PFKL mice (Elson et al., 1994)
      • Suggesting that aberrant glucose metabolism is already pronounced in developmental period
    • www.frontiersin.org/articles/10.3389/fnins.2020.00670/full

    Pyruvate

    • Metabolites found increased are
      • Pyruvate
      • Fumarate
      • Succinate
      • Lactate
      • Formate
      • Creatine
    • Abnormal levels of metabolites associated with activation of glycolysis like serum lactate and pyruvate were found


    Regulator of calcineurin 1 (RCAN1)

    • Plays a role in cell growth and immune responses but has also a role in cognition (Dierssen et al., 2011; Mendez-Barbero et al., 2013)

    S-adenosylhomocysteine and S-adenosylmethionine

    • Significant increase (Obeid et al., 2012)
      • Though a previous study showed to be decreased (Pogribna et al., 2001).
    • Levels of these metabolites seem to be strongly associated with triplication of CBS (Skovierova et al., 2016).

    S100beta (mRNA and protein)

    • S100beta protein exhibits a lifelong over-expression in DS brain (Griffin et al. 1998)
    • MRNA is also documented to be increased in fetal DS brain (Epstein 2001)
    • S100beta is synthesized and released by astrocytes in response to serotonin (5-HT)-mediated stimulation of 5-HT1A receptors
    • Appears to be an important neurotrophic agent during normal fetal brain development
      • Effects on neuroblasts and glia (Azmitia et al. 1992)
    • Early over-expression of S100beta may therefore indicate a potential role of this protein in dendritic abnormalities and mental retardation.
    • It can provide an important clue to the link between 5-HT and DS (Whitaker-Azmitia 2001)
    • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

    SOD

    • Zvýšená aktivita při trizomii 21
    • 1. SOD
      • Catalyses the dismutation of the superoxide anion (O2-) to H2O2
    • 2. glutathione peroxidase (GPx) and catalase (CAT)
    • Activity of the first-step (SOD) and second-step (GPx, CAT) antioxidant enzymes
      • must be balanced to prevent cell damage by oxidative stress (Crosti et al., 1989)
    • Excess H2O2 produced by the action of SOD
      • Would induce a significant increase in the catalytic activity of GPx
      • Not observed significant changes in the activity of CAT (Brugge et al., 1999; Muchova et al., 2001).

    Animal cells, human erythrocytes

    • The principal antioxidant enzyme for the detoxification of H2O2 has long been considered to be GPx
      • Catalase has much lower affinity for H2O2 than does GPx
    • Glutathione peroxidases (GPx) are selenium-dependent enzymes
      • Reduced glutathione (GSH) is used as a cosubstrate to metabolise H2O2 to H2O and oxidised glutathione (GSSG)
    • Oxidised glutathione (GSSG) can be reduced back to GSH by the enzyme GSH reductase (GR)
      • Requiring NADPH regenerated by glucose 6-phosphate dehydrogenase (G6PDH) (Jollow & Mcmillan 2001; Lukaszewicz-Hussain, 2003)
        • G6PDH je zvýšená
    Tohle všechno bude zvýšeně potřebovat, aby kompenzoval zvýšenou akci SOD1

    • Cu/Zn superoxide dismutase (SOD1) is coded on chromosome 21 and it is overexpressed (~50%) resulting in an increase of reactive oxygen species (ROS) due to overproduction of hydrogen peroxide (H 2 O 2 ).
    • ROS leads to oxidative damage of DNA, proteins and lipids
    • A number of animal studies have shown that an increase inSOD is associated with increased rates of lipid peroxidationin the brain
    • A 36% increase in lipid peroxidation was also demonstrated in the cerebral cortex of fetuses with DS
      • Who were incubated in vitro with iron and ascorbate
      • Compared with infants without DS
    • Neurons of fetuses with DS were also more likely to undergo apoptotic degeneration
      • Prevented by the addition of antioxidants
    • Higher levels of the products of lipid peroxidation
      • Have also been reported in the blood or urine of indi-viduals with DS than in individuals without
    • Compensatory increase in the activity of glutathioneperoxidase and the hexose monophosphate shunt
      • However, the 50% increase in activity of SOD is muchhigher than the percentage increase usually reported in activ-ity of GSH-P
        • = oxidační stres
    • Cells with ahigh SOD:GSH-Px ratio are more likely to undergo apoptosiswhen challenged with hydrogen peroxid
    • onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-8749.2000.tb00072.x
    • Superoxide dismutase [Cu–Zn] (SOD)-1 (de Haan et al. 1997) mRNA are increased in fetal DS brain
      • Levels of the corresponding proteins are comparable to those in controls (Arai et al. 1996; Griffin et al. 1998; Engidawork et al. 2001a; Gulesserian et al. 2001).
    • Buňka to může ještě kompenzovat posttranslační regulací a nadbytečné proteiny ještě zlikvidovat dřív než začnou škodit. Budou tedy zvýšené nároky na proteazom a ubiqitinizaci (koenzym Q). S přibývajícím věkem a třeba demetylací DNA a rostoucím množstvím balastních proteinů to pak buňky nedají a mohou začít vznikat ony proteinopatie s inkluzemi sražených proteinů - třeba toho A-beta proteinu aj.
    • Asi by z toho vyšlo, že během stárnutí by mohli profitovat z tu a tam aktivace autofagocytózy... napadají mne alfa a beta cyklodextriny.
    • Oxidative stress is one of the most likely factors for neurotoxicity in DS (Busciglio and Yankner 1995)
    • Was thought to emanate primarily from over-expression of SOD-1 and lack of a corresponding increase in hydrogen peroxide-handling enzymes,
      • Catalase
      • Glutathione peroxidase (de Haan et al. 1997)
    • Expression of catalase is unaltered in fetal DS brain (Gulesserian et al. 2001)
      • But it is SOD-1 activity (Brooksbank and Balazs 1984) rather than expression (Gulesserian et al. 2001) that was increased.
    • This suggests that increased activity might not be linked to over-expression
      • Probably attributed to enzymatic modification.
    • Increased SOD-1 activity might be a consequence rather than an antecedent of oxidative stress
    • SOD-1 activity can later have a positive reinforcing effect.
    • There are other possible primary causes of oxidative stress in fetal DS.
      • Peroxiredoxins
      • Abeta
    • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

    Scleraxis

    Serotonergic markers

    • Reported to be increased by some, if not all, authors (Brooksbank et al. 1989; Bar-Peled et al. 1991; Arai et al. 1996; Oka and Takashima 1999; Lubec et al. 2001b)
    • Over-expression of 5-HT1A receptors (Bar-Peled et al. 1991)
      • May indicate the involvement of this receptor in developmental disorders
        • Associated with release of S100beta
    • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

    Succinate

    Synaptojanin (protein)

    • Highly abundant polyphosphoinositide phosphatase
    • Over-expressed in fetal DS brain (Arai et al. 2002)
    • Modulates synaptic transmission
    • Plays a role in clathrin-mediated synaptic vesicle endocytosis and signalling
    • Over-expression may form the neurochemical basis for impaired synaptic functions in DS brain
    • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

    TMAO

    • Increases in urine
    • Not processed by enzymes produced by human genes
    • Hypothesized to play a role of the human microbiota
    • TMAO is a gut-microbiota-dependent metabolite
    • Role in the onset of cardiovascular diseases + kidney diseases
    • Analyzed the gut microbiota (GM) in DS subjects
      • Premature aging that occurs in the DS may be due to changes in GM
    • Deterioration of GM plays an important role in the aging of the general population as well
    • DS GM is predominantly composed of
      • Firmicutes,
      • Actinobacteria
      • Bacteroidetes
    • Most represented families in DS GM were
      • Ruminococcaceae (39%)
      • Clostridiales (9%)
      • These bacteria are positively associated with TMAO levels
    • www.ncbi.nlm.nih.gov/pmc/articles/PMC5813015/

    Taurin


    Trp-ratio

    • Increased in the DS group
    • Suggests an enhanced availability of tryptophan for the synthesis of serotonin in the central nervous system
    • Whether central serotonergic neurotransmission is increased in DS persons cannot be concluded from this
      • Especially since the plasma concentration of 5-HIAA is not changed
        • Only a very weak and indirect measure of central serotonergic activity (Lambert et al., 1995)
    • www.ncbi.nlm.nih.gov/pmc/articles/PMC2794348/

    Urinary thiosulfate

    • Increased in subjects with DS (Szabo, 2020)

    Urine tyrosyl radical

    Zánět


    Overexpression of the c-ets-2-encoded protein

    • Stimulated cell proliferation and abolished their serum requirement
    • C-ets-2 transfected cells formed colonies in semisolid medium and induced tumors in nude mice
      • C-ets-2 can be a transforming gene when overexpressed in these cells
    • Member of the c-ets gene family has transforming and mitogenic activity
    • Location in the minimal Down syndrome region on chromosome 21 implicates its involvement in the phenotypic changes associated with Down syndrome.
    • pubmed.ncbi.nlm.nih.gov/2813360/

    DS and epilepsy: a nutritional connection?

    Higher levels of circulating cholesterol, (LDL), TG

    • With respect to age-matched controls (Zamorano et al., 1991; Adelekan et al., 2012; Buonuomo et al., 2019).

    Upregulation of lymphocyte beta-adrenergic receptor in Down's syndrome

    • A biological marker of a neuroimmune deficit
    • A nebo známka deficitu adrenergní stimulace a hladin noradrenalinu, dopaminu a adrenalinu celkově...
    • Beta 2-adrenergic receptor (B2AR) system in peripheral blood monocytes (PBMC) of 12 pre-pubertal (six boys and six girls) individuals
      • Significant increase in B2AR binding capacity of PBMC from DS subjects (Bmax = 5258 +/- 470 sites/cell) compared to the values measured in the control population of retarded children (Bmax = 1965 +/- 280 sites/cell)
    • pubmed.ncbi.nlm.nih.gov/1318320/
    • Podporou metabolismu biopterinu (syntézy nerutransmiterů) by se mohlo podpořit i imunita, tonus svaloviny, vývoj mozku, funkce mitochondrií... stav celkově, včetně toho, že by klesnul i mírně zvýšený fenylalanin (?)



    Screening metabolomu DS pacientů

    • Considering the samples from all subjects, independently from their fasting state showed significantly increased levels in DS with a DS/CTRL (zdravé kontroly) ratio nad 1 :
      • Acetate,
      • Pyruvate,
      • Acetone,
      • Creatine,
      • Formate,
      • Acetoacetate,
      • Unk3
      • Succinate
    • www.nature.com/articles/s41598-020-67195-z
    • Significantly increased concentrations (p-value after FDR correction < 0.05)
      • Acetate;
      • Pyruvate;
      • Succinate;
      • Formate
      • Creatine
    • All of them are involved in energy production.
    • Acetate
      • Fundamental in supporting acetyl-coenzyme A metabolism and thus Krebs cycle progression and lipogenesis
    • Pyruvate and succinate
    • Succinate
      • Levels increase in DS samples (p-value after FDR correction <0.0001 in both “all samples” and “fasting samples” groups) with a DS/CTRL ratio close to 3:2 (1.37 in “all samples” and 1.57 in “fasting samples” groups).
      • Alterations of succinate metabolism may play a role in the development of ID, but to date there is no strong evidence.
    • Formate
      • Necessary for the formylation of mitochondrial tRNAs21
      • For the formylation of tetrahydrofolate during the folic acid cycle and the purine synthesis pathway
    • Creatine
      • Used by muscles for the production of ATP
    • Dependence of the levels of the metabolites on the enzyme concentration is complex and not easily interpretable
      • Ratio DS/CRTL near to 3:2 (1.5) or 2:3 (0.67) is observed for a certain set of molecules

    Some enzymes which metabolize succinate are involved in developmental delay and brain injuries:

    • Succinic semialdehyde dehydrogenase (SSADH) deficiency
      • Caused by a mutation of the ALDH5A1 gene (6p22.3)
        • Determines an increase of gamma-aminobutyric acid (GABA) and gamma-hydroxybutyric acid levels
      • These alterations cause developmental delay, hypotonia, hyporeflexia, ataxia, neuropsychiatric problems, and epilepsy

    Alterations of activities for the Krebs cycle enzymes also observed in some brain disorders such as Alzheimer’s disease, Huntington’s disease

    • Increase of succinate dehydrogenase and malate dehydrogenase
    • Decrease of the pyruvate dehydrogenase complex, isocitrate dehydrogenase, and the alpha-ketoglutarate dehydrogenase complex
      • Suggesting that a mitochondrial alteration occurs
      • Measures to improve tricarboxylic acid cycle metabolism might lessen the effects of the diseases

    Metabolic pathways in DS

    • Observed that some correlations are strong/moderate (r > 0.4 or r < -0.4) and significant (p < 0.05) in CTRL samples
      • But lose their significance or weaken their correlation in DS samples = porucha souvislosti met. drah u DS
        • = loss of correlations among strictly related metabolites (from a biochemical point of view)
        • Metabolites involved in the Krebs cycle (pyruvate, citrate and succinate)
        • Formate and lactate and amino acids like alanine, threonine and tyrosine
    • Statistically significant correlations found only in DS samples = ne u zdravých, kde je výkyv metabolicky kompezován
    • Confirmed the dysregulation of some metabolic pathways
      • Inverse correlation between lactate and succinate characteristic of CTRL (zdravých) samples becomes direct in DS samples (=více succinátu, více laktátu a naopak)

    Triplication of some microRNAs (miRNAs), in particular miR-155

    • Modulate target genes leading to:
      • Changes of neurochemical metabolites
      • mitochondrial deficits,
      • Other pathological conditions observed in DS individuals (Quinones-Lombrana and Blanco, 2015).
      • Responsive to dosage that may contribute to defects in behavior and cognition and other DS pathological features (Vacano et al., 2012; Gupta et al., 2016).

    Oxidační stres a IQ

    • Some evidence of an association between mental development in DS and oxidative stress
    • Highly significant positive correlation between GSH-Px activity and IQ in 22 individuals with DS
    • GSH-Px may play an important role in preserving the cerebral status of individuals with DS
    • As GSH-Px is an endogenous antioxidant
      • Supplement-ing individuals with DS with exogenous antioxidants may offer similar protection to their cerebral status.
    • This is sup-ported by the protective effect of antioxidants on DS neurons in culture

    A randomised controlled trialof vitamin E in Alzheimer’s disease

    In vitro

    • Increased chromosomal damagereduced by 50% in vitro by the addition of vitamin E

    V plodpvé vodě

    Were found to be significantly accumulated:

    • Calumenin,
    • Nucleophosmin,
    • Elongation factor 1-beta,
    • Cathepsin D,
    • Platelet-activating factor acetylhydrolase IB subunit beta,
    • 14-3-3 protein beta/alpha

    Neurotoxic tryptophan catabolites

    • Trisomy 21 drives production of neurotoxic tryptophan catabolites via the interferon-inducible kynurenine pathway
    • [August 2018]

    In human cells with T21 and a mouse model of DS

    • T21 disrupts tryptophan catabolism toward
      • Increased production of kynurenine (KYN)
          • And its neurotoxic derivative quinolinic acid
    • Stimulation of IFN signaling leads to
      • tryptophan depletion
      • Over-production of KYN
      • Super-induction of IDO1
        • The rate-limiting enzyme in the KYN pathway
    • = než tryptofan, tak raději suplementovat melatonin na noc
    • = žádné echinacey aj. stimulátory IFN gamma

    Zánět


O úroveň výše

Poslední aktualizace: 30. 9. 2024 22:17:27