Download Natural Gene Therapies in Down Syndrome

Natural Gene Support
Therapies in
Down Syndrome
Dr Bill Deagle MD DABFP FCFP CCFP AAEM A4M
www.NutriMedical.com
The NutriMedical Report
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and Hrs 1 and 2 Stream 4
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and
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Kelsea Deagle Makes
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Presentations Arrays of
Individuals who have
Downs Syndrome Unwellness
What is Down
Syndrome?
• An Gene Dosage Syndrome of
Oxidative, Folic Acid, Heat
Shock Protein, and Nerve
Synaptic Protein Imbalances
• Delayed myelination, with
increased synaptic and DNA and
toxicity increased thyroid and
mitochondrial dysfunction
Why does an extra gene
cause abnormal neural and
organ development?
• Genes code for proteins and enzymes for
structure and function  Tau Proteins
Plaque / Lack of Neurotransmitters /
Reduced Dendritic Interconnections
• Genes that increase oxidative protein and
cellular membrane damage  Secondary to
NO/OONO Peroxynitrate Metabolic
Pathway Induction
Which genes are the key factors
causing the Down Syndrome spectrum
of illness?
• Cq21 – Cq22 long arm of
Chromosome 21
• Gene Dosage of Five Genes ++
• 1] Cytathionine Beta Synthetase 
Folate trapping and Homocysteine
Elevation
• 2] SOD 1 Zinc / Copper Superoxide
Dismutase  NO/OONO
Peroxynitrate Synthase Free Radical
Glial Cell Neuron Damage  Neuron
apoptosis and dendrite and synapse
atrophy
Which genes are the key factors
causing the Down Syndrome
spectrum of illness?
• 3] BACE, an aspartyl protease,
has been identified as the betasecretase  Amyloid Beta Tau
Protein Excess with Plaque
formation  Alzheimer’s type
• 4] MNB Minibrain also
colocalizes with dynamin 1
(DYRK1A), a substrate of MNB
kinases  Regulate Dendrite
Differentiation
Which genes are the key factors
causing the Down Syndrome
spectrum of illness?
• 5] TT2F/h Gene Chr21 cells in
early differentiating neurons 
Affect Neuronal Outgrowth,
Proliferation and Differentiation
Lets look at the Past &
Future Down Syndrome
Natural Support!
• Dr Henry Turkel and Schmid
formulas
• Dr Harrell’s formula
• Kent McLeod ICMT MSB Plus
Formulas
• Dr David Steenblock DO –
Mesenchymal and Umbilical
Cord Adult Stem Cell Therapy
Natural Metabolic
Support Principals:
• 1] Correct Deficiencies – Mg, Zn, Se,
Folinic Acid …
• 2] Detoxify Heavy Metals – Mercury,
Aluminum…
• 3] Protect Mitochondrial and Cellular
Membranes – e.g. Long Acting ALA,
Tocotrienols, C3, Quercetin , CoQ10,
Propionyl L-Carnitine …
• 4] Support Neurotransmitters –
Glycerophosphocholine …
• 5] Antipathogenics & Probiotics
• 6] Oral and Systemic Enzymatics
DOWNS SYNDROME
NATURAL SUPPORT:
• CARNOSINE – ECOLOGICAL – 10
CAPS
• NutriTRALA – powder 10 tablets
• DIGESTICOL – GEN+ - 10 CAPSULES
• COGNITION IGNITION – ALLIMAX –
10 CAPS
• COGNITIVE NUTRITION –
ECOLOGICAL – 10 CAPS
DOWNS SYNDROME
NATURAL SUPPORT:
• C3 Curcumin Complex –
ECOLOGICAL – 10 CAPS
• QUERCETIN-C – ECOLOGICAL –
10 CAPS
• INOSINE – ECOLOGICAL – 10
CAPS
• SELENIUM CRUCIFERATE –
ECOLOGICAL – 10 CAPS
DOWNS SYNDROME
NATURAL SUPPORT
• MITOCARNITNE – ECOLOGICAL
– 10 CAPS
• MITOCHONDRIAL CATALYSTS –
ECOLOGICAL - 10 CAPS
• URIDINE – ECOLGICAL – 10
CAPS
• CoQ10Supreme – puncture one
softgel with mixing formula
from power
DOWNS SYNDROME
NATURAL SUPPORT
• Mountain Red Deer Velvet –
AlliMax - 10 capsules
• Stem Cell Mobilizer –
NutriMedical – 10 tabs as
powder
• MULTIVITAMINs Plus Minerals
FOR CHILDREN / ADULT
NATURAL SOURCE – GROWN BY
NATURE – 10 tabs as powder
DOWNS SYNDROME
NATURAL SUPPORT
• B12 Folic Acid Spray ECOLOGICAL
or Methylcobamin + Folate or Folinic
Acid Supplement – take twice per
day orally
• Her Majesty Royal Jelly –Ecological one softgel puncture and mix
• Krill Oil Softgels 3 per 70 kg
proportional – puncture and mix
• Neuromins – Ecological – 1 to 2
softgels – puncture and mix
DOWNS SYNDROME
NATURAL SUPPORT
• Green Tea Polyphenon - Douglas
Labs – 10 CAPS
• Resveratrol – ECOLOGICAL – 10
CAPS
• Thiamine - TTFD fat soluble
form Tetrahydrofurfurul
disulfide B1 Thiamine Ecological Formulas – 10 CAPS
DOWNS SYNDROME
NATURAL SUPPORT +
• NutriDine 1 to 5 drops topical or
orally per day – NutriMedical
• Super Silver 5 mls per day –
maintenance and use for
infection control With
• AlliUltra Drops – 1 to 4 drops per
day - AlliMax
MONITORING OF
METABOLIC RESPONSE:
• Adjust dosages based on Blood and
Urine Oxymarkers, Amino Acids and
Organic Acids – Genova Labs
• Stool CSDA Comprehensive
Digestive Stool Analysis
• MRI Scan with T1 Weighted Myelin
Study
• QEEG – QUANTITATIVE EEG
SPECTRAL SCAN STUDY
Can cognitive deterioration associated
with Down syndrome be reduced?
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Med Hypotheses. 2005;64(3):524-32
Can cognitive deterioration associated with Down syndrome be reduced?
• Thiel R,
• Fowkes SW.
Center for Natural Health Research, Down Syndrome-Epilepsy Foundation, 1248 E. Grand Avenue,
Suite A, Arroyo Grande, CA 93420, USA. [email protected]
Individuals with Down syndrome have signs of possible brain damage prior to birth. In addition to
slowed and reduced mental development, they are much more likely to have cognitive
deterioration and develop dementia at an earlier age than individuals without Down syndrome.
Some of the cognitive impairments are likely due to post-natal hydrogen peroxide-mediated
oxidative stress caused by overexpression of the superoxide dismutase (SOD-1) gene, which is
located on the triplicated 21st chromosome and known to be 50% overexpressed. However, some
of this disability may also be due to early accumulation of advanced protein glycation endproducts, which may play an adverse role in prenatal and postnatal brain development. This paper
suggests that essential nutrients such as folate, vitamin B6, vitamin C, vitamin E, selenium, and
zinc, as well as alpha-lipoic acid and carnosine may possibly be partially preventive. Acetyl-Lcarnitine, aminoguanidine, cysteine, and N-acetylcysteine are also discussed, but have possible
safety concerns for this population. This paper hypothesizes that nutritional factors begun
prenatally, in early infancy, or later may prevent or delay the onset of dementia in the Down
syndrome population. Further examination of these data may provide insights into nutritional,
metabolic and pharmacological treatments for dementias of many kinds. As the Down syndrome
population may be the largest identifiable group at increased risk for developing dementia,
clinical research to verify the possible validity of the prophylactic use of anti-glycation nutrients
should be performed. Such research might also help those with glycation complications
associated with diabetes or Alzheimer's.
PMID: 15617860 [PubMed - indexed for MEDLINE]
Redox balance in patients with Down's
syndrome before and after dietary
supplementation with alpha-lipoic acid and Lcysteine.
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Int J Clin Pharmacol Res. 2003;23(1):23-30
Redox balance in patients with Down's syndrome before and after dietary
supplementation with alpha-lipoic acid and L-cysteine.
• Gualandri W,
• Gualandri L,
• Demartini G,
• Esposti R,
• Marthyn P,
• Volonte S,
• Stangoni L,
• Borgonovo M,
• Fraschini F.
University of Milan, Milan, Italy.
The aim of the present study was to investigate the possible normalizing effect of
antioxidants on certain parameters indicative of oxidative stress in Down's syndrome
(DS). The study was performed in pediatric patients with DS with proven redox
imbalance, who were advised to take a dietary supplementation composed of alphalipoic acid and L-cysteine for several treatment cycles (one treatment cycle = 30 days
dietary supplementation plus 30 days wash-out). Serum thiol groups, serum total and
septic reactive oxygen species (ROS) and total antioxidant status of serum were
determined before and after dietary supplementation, using commercially available kits.
In all the evaluable patients (n = 20), after 3.8 +/- 1.1 treatment cycles, thiol group serum
concentrations and total antioxidant status of serum significantly increased (p < 0.0001
for both parameters) in comparison with basal values, while serum total and septic ROS
significantly decreased (p < 0.0001 for both parameters). On the basis of these results it
is impossible to demonstrate the clinical effects of the biochemical normalization
obtained in patients with DS after supplying alpha-lipoic acid and L-cysteine. These data
suggest that delaying the clinical expression of redox imbalance in patients with DS
might be feasible by normalizing their redox balance.
PMID: 14621070 [PubMed - indexed for MEDLINE]
Peroxynitrate NO/ONOO-Cycle
Biochemistry
-Dr Bill Deagle MD
Nutraceuticals Protocol:
• Peroxynitrate Protocol VCM Vicious Metabolic Cycles,
Cytokine Release and Tissue Inflammatory Cellular
Damage:
• Acetyl L-carnitine - Allergy Research Group
• B12 methylcobalamin & folic acid - Liposomal B12 /
Folate - Ecological Formulas
• reduced L-Glutathione - Ecological Formulas
• Tocotrienols and Gamma Tocopherol - Allergy Research
Group
• Curcumin and C3 Curcumin Complex- Ecological
Formulas
• Boswellia Serrata – BioInflammatory Caps & Functional
Food – BioGenesis Nutraceuticals
• Coenzyme Q10 - Allergy Research Group or Ecological
Formulas
• Lutein - Allergy Research Group
Peroxynitrate NO/ONOO-Cycle
Biochemistry
-Dr Bill Deagle MD
Nutraceuticals Protocol:
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Phosphatidyl Serine - ProHealth
Super Oxide Dismutase SOD - Douglas Labs
Alpha R Lipoic Acid - BioGenesis
Omega 3,6,9 Fatty Acids and Carrier molecules Krill Oil - ProHealth or International Health
Taurine - Ecological Formulas Potassium &
Magnesium Taurate
Proanthocyanidins - Grape Seed Extract - Douglas
Labs
Spirulina & Chlorella - Use the quick search box on
www.NutriMedical.com
Organic Magnesium - Grown By Nature
B Complex - Grown By Nature
L-Carnosine - Ecological Formulas
Peroxynitrate NO/ONOO-Cycle
Biochemistry
-Dr Bill Deagle MD
Nutraceuticals Protocol:
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Inosine - Ecological Formulas
Organic Vitamin C - Grown By Nature or Ecological Formulas
Tapioca or Cassava Vitamin C
Antioxidant High ORAC - URI The Feast, Beyond Berries and
Antioxidant and Grown By Nature Antioxidant
Zinc - Grown By Nature
Thiamine - TTFD fat soluble form Tetrahydrofurfurul disulfide B1
Thiamine - Ecological Formulas
Alkalinizing Agents - BioAlkalinizer - BioGenesis, Electrolyzed
Plus Water - RPA Biotech and Quantum Energy Wands - Global
Light
Branch Chain Amino Acids - Jomar Labs
Pyridoxal 5'Phosphate B6 - Allergy Research Group or Ecological
Formulas
Green Tea Polyphenon - Douglas Labs
Resveratrol - Red Wine Grape Skin polyphenols - Longevinex Purity Products
SPECIFIC NUTRIENTS:
www.NutriMedical.com 0r
888-212-8871
• Essential Minerals – Selenium, Zinc,
Magnesium ++
• B complex – TTFD Tetrahydrofurfuryl
Disulfide B1 Thiamine – Fat Soluble
topically and orally
• Vitamin E and K – Tocotrienols,
Tocopherols and K1 and K2 – 7Menidione
SPECIFIC NUTRIENTS:
www.NutriMedical.com 0r
888-212-8871 :
• Antioxidants – Free Radical
Scavengers – Numerous
• Reduced L-Glutathione & IGA
Intracellular Glutathione Agonist &
NAC – N-Acetyl Cysteine - Ecological
Formulas
• C3 Curcumin Complex – Ecological
Formulas
• Quercetin – Ecological Formulas
SPECIFIC NUTRIENTS:
www.NutriMedical.com 0r
888-212-8871
• Energetic cofactors:
• Alpha-lipoic acid – NutriTRALA
– timed release ALA –
Glutathione Peroxidase Support
• Coenzyme Q10 – CoQ10Supreme
– Non-polymerizing CoQ10
• Nicotinamide Adenine
Dinucleotide & Reduced NADH.
SPECIFIC NUTRIENTS:
www.NutriMedical.com 0r
888-212-8871 :
• Additional nutrients that can
improve cognition include:
• Acetyl L-carnitine
• Omega-3 fatty acid, and DHA
Docosahexanoic Acid
• Krill Oil with Astaxanthine Fatty Acid
Antioxidant
• Glycerophosphocholine and
Phosphatidylserine.
SPECIFIC NUTRIENTS:
www.NutriMedical.com 0r
888-212-8871 :
• Dimethylaminoethanol DMAE –
Synaptic Acetylcholine support
• Propionyl L-Carnitine – Mitocarnitine,
Mitochondrial Catalysts and Uridine
 Ecological Formulas
• Folinic Acid – Activated Folate via 5Methyl Folate Reductase
• Calcium Betonite Clay orally and
topically in baths for gastrointestinal
heavy metals and chemical
detoxification
SPECIFIC NUTRIENTS:
www.NutriMedical.com 0r
888-212-8871 :
• Digestive Enzymes – Protein, Fats
and Especially Carbohydrates
• Trace Ionic Minerals with Fulvic
Acid– Mineral Pure – URI
International & Living Minerals
Probiotics
• Detoxified PSP-Iodine Complex –
NutriDine – NutriMedical
• TMG – Trimethyl Glycine – Methyl
Donor to help rebuild myelin nerve
sheaths
SPECIFIC NUTRIENTS:
www.NutriMedical.com 0r
888-212-8871
• Mountain Red Deer Velvet – IGF1 and
IGF2 Growth Factors and
• Stem Cell Mobilizer – Dr Steenblocks
Formula for Stem Cell Support
• Almost 300 synergistic tissue stem
cell and organ rejuvenation natural
molecules
• Tiaga Tea – NK Natural Killer
Immune Cell Stimulation against
infection and pre-cancer cells
SPECIFIC NUTRIENTS:
www.NutriMedical.com 0r
888-212-8871
• ALLICIN – Oral and Topical to
prevent Otitis Media, Gut Dysbiosis
with Yeast, Bacterial pathogens and
parasites and total body steal
infections with viruses, bacteria and
fungi – AlliMax and AlliUltra liquid
and capsules
• Super Silver – American Biotech –
Silver Sol – Antipathogenic Antiviral
Antibacterial Antiparasitic and AntiLyme ++
Yes, you may need help!
• SPECIFIC NUTRIENTS All @:
www.NutriMedical.com 0r 888-212-8871
• Nutraceuticals Consult with Dr Bill Deagle
MD @ 888-212-8871 or email
[email protected]
• Listen to “The NutriMedical Report”
Mondays to Fridays 2 to 4 PM CST and
Sundays 8 to 10 PM CST
• www.NutriMedical.com Windows Media
Button Galaxy Satellite 32 Kbyte Feed
• Free Radio Archives on Lower Right Main
Page Button on www.NutriMedical.com
Professional Section of
Down Syndrome Metabolic
Research:
• Review these studies to see the
correlation to nutrient
metabolic and gene interactions
• Epigenesis is the key to natural
metabolic support
• Functional Medicine Studies –
Oxymarkers, Amino Acids,
Organic Acids, QEEG, MRI T1 +
Neurodegeneration From
Mitochondrial Insufficiency
• Kidd PM. Neurodegeneration from mitochondrial
insufficiency: nutrients, stem cells, growth factors, and
prospects for brain rebuilding using integrative
management. Altern Med Rev 2005; 10(4): 268-293.
• Support for mitochondria can reduce electron leakages
and reactive oxygen free radical species. Forms of
dementia, including Down syndrome are associated with
impairments of the mitochondrial citric acid cycle and
oxidative phosphorylation enzymes. Nutients involved in
mitochondrial metabolism can provide clinical benefit.
These include essential minerals, B complex, vitamin E
and K, antioxidants and energetic cofactors (alpha-lipoic
acid, coenzyme Q10), nicotinamide adenine dinucleotide,
reduced NADH. Additional nutrients that can improve
cognition include acetyl L-carnitine, omega-3 fatty acid,
glycerophosphocholine and phosphatidylserine. Stem
cells and growth factors also encourage optimism
regarding brain regeneration.
Abnormal Neuronal
Networks and Altered
Gene Proteins
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Altered gene products and aberrant protein expression
were observed in TT2F/hChr21 cells
Kadota M, Nishigaki R, Wang CC, Toda T, Shirayoshi Y,
Inoue T, Gojobori T, Ikeo K, Rogers MS, Oshimura M.
Proteomic signatures and aberrations of mouse
embryonic stem cells containing a single human
chromosome 21 in neuronal differentiation: an in vitro
model of Down syndrome.
Neuroscience 2004; 129(2): 325-35. The authors utilized
an in vitro neuronal differentiation system of mouse
embryonic stem cells containing a single human
chromosome 21. The authors observed altered gene
products and aberrant protein expression from
TT2F/hChr21 cells in early differentiating neurons that
may affect neuronal outgrowth, proliferation and
differentiation and produce developmental abnormalities
in neural patterning and neural networks, characteristic
of Down syndrome.
STEM CELLS Model of
Down Syndrome
Development and Therapy
•
Stem cells offer a novel model system to study
development disorders like Down's syndrome
•
Bhattacharyya A, Svendsen CN. Human neural stem cells:
a new tool for studying cortical development in Down's
syndrome. Genes Brain Behav 2003; 2(3): 179-86.
The clinical characteristics of Down syndrome or trisomy
21 include mental retardation, craniofacial abnormalities,
clinical defects of the heart, gut and immune system, and
an increased risk of other diseases, including leukemia
and Alzheimer's disease. The neurological
characteristics of Down syndrome are established during
the prenatal and early postnatal period in humans. Stem
cells now allow the generation of human neural tissue in
culture and offer a novel model system to study
alterations in developmental disorders such as Down
syndrome.
•
Amyloid-beta Protein
Deposits and Down
Syndrome
• Amyloid-beta protein deposits and Down Syndrome
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Barbiero L, Benussi L, Ghidoni R, Alberici A, Russo C,
Schettini G, Pagano SF, Parati EA, Mazzoli F, Nicosia F,
Signorini S, Feudatari E, Binetti G. BACE-2 is
overexpressed in Down's syndrome. Exp Neurol 2003;
182(2): 335-45.
Amyloid-beta protein deposits in the brain (and perhaps
cardiovascular system) are a complication in patients
with Down syndrome. The amyloid-beta peptide is
generated by gamma and beta secretases. Recently
BACE, an aspartyl protease, has been identified as the
beta-secretase. The BACE-2 gene resides on
chromosome 21 in the Down syndrome region. The
authors measured the levels of BACE-2 mRNA expression
and found a 2.6-fold increase in Down syndrome patients
compared to normal controls. The authors suggest that
BACE-2 overexpression can play a role in plaque
formation in Down syndrome patients.
Overexpression of
MNB/DYRK1A in Down
Syndrome
•
BMC Cell Biol. 2003 Sep 10;4:12.
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Hammerle B, Carnicero A, Elizalde C, Ceron J, Martinez S,
Tejedor FJ. Expression patterns and subcellular
localization of the Down syndrome candidate protein
MNB/DYRK1A suggest a role in late neuronal
differentiation. Eur J Neurosci 2003; 17(11): 2277-86.
The minibrain (MNB) gene belongs to a protein kinase
family and may play several roles during brain
development. In humans, MNB has been mapped within
the Down syndrome critical region of chromosome 21 and
is overexpressed in the Down syndrome embryonic brain.
MNB also colocalizes with dynamin 1 (DYRK1A), a
substrate of MNB kinases. The authors propose that MNB
kinase is involved in signaling pathways that regulate
dendrite differentiation, in which MNB/DYRK1A may
contribute to the development of Down syndrome
neuropathologies.
Heat Shock Protein 60 and
Mitochondrial Function in
Down Syndrome
• J Alzheimers Dis. 2002 Dec;4(6):479-86.
• Bozner P, Wilson GL, Druzhyna NM, Bryant-Thomas
TK, LeDoux SP, Wilson GL, Pappolla MA. Deficiency
of chaperonin 60 in Down's syndrome. J Alzheimers
Dis 2002; 4(6): 479-86.
• The mitochondria and oxidative stress may be
involved in the pathogenesis of both Down
syndrome and Alzheimer's disease. Heat Shock
Protein 60 is important in mitochondrial function.
The authors discovered a defective basal
expression and 35% reduction of a major
mitochondrial heat shock protein, chaperonin 60
(Cpn60) in Down syndrome patients. The authors
suggest that this defect may play a role in the
neuropathology of Down Syndrome.
VACCINATION
DANGERS!
• The safest vaccine stays in the
bottle
• NEVER give Vaccines with Mercury
Thiomersal, Aluminum,
Formaldehyde or Toxic Adjuvants
• All Multiple dose bottles must be
assumed to be having toxic
preservatives and adjuvants
Natural Molecular
Therapies of Down
Syndrome Research:
• 1] Correct Deficiencies – Mg, Zn, Se,
Folinic Acid …
• 2] Detoxify Heavy Metals – Mercury,
Aluminum…
• 3] Protect Mitochondrial and Cellular
Membranes – e.g. ALA, Tocotrienols, C3,
Quercetin …
• 4] Support Neurotransmitters –
Glycerophosphocholine …
• 5] Antipathogenics & Probiotics
• 6] Oral and Systemic Enzymatics
Frequency of Down's syndrome
and neural-tube defects in the
same family.
• Lancet. 2003 Apr 19;361(9366):1331-5
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Barkai G,
• Arbuzova S,
• Berkenstadt M,
• Heifetz S,
• Cuckle H.
Danek Gertner Institute of Human Genetics, Sheba Medical Centre, Tel Hashomer,
and Sackler School of Medicine, Tel Aviv University, 52621, Tel Aviv, Israel.
[email protected] <[email protected]>
BACKGROUND: There is evidence that some mothers of infants with Down's
syndrome have abnormal metabolism of folate and methyl, as well as mutations in
folate genes, which are features that are also seen in neural-tube defects (NTD).
We therefore investigated whether Down's syndrome and NTD arise more often in
the same family than would be expected from the incidence of each disorder
considered separately. METHODS: We studied two series of families using
information obtained from medical records about maternal age, pregnancy
outcome, congenital malformations, and karyotype: the first, 493 families from
Israel who were at high risk of NTD (445 with a history of NTD and 48 with
isolated hydrocephalus); and the second, 516 families from the Ukraine at high
risk of Down's syndrome. FINDINGS: In the families at risk of NTD, there were a
total of 11 pregnancies affected by Down's syndrome in 1492 at-risk pregnancies
(compared with 1.87 expected on the basis of maternal age), which was a
significant increase (p<0.00001). In the families at risk of Down's syndrome, there
were seven NTD pregnancies in 1847 at risk, compared with 1.37 expected
(p<0.001). INTERPRETATION: In this study, we provide direct evidence of a link
between Down's syndrome and NTD. Folate supplementation before conception
has the potential to reduce the frequency of Down's syndrome.
PMID: 12711468 [PubMed - indexed for MEDLINE]
Maternal use of nutritional
supplements during the first month of
pregnancy and decreased risk of
Down's syndrome: case-control study.
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• Nutrition. 2005 Jun;21(6):774.
Maternal use of nutritional supplements during the first month of pregnancy and
decreased risk of Down's syndrome: case-control study.
• Czeizel AE,
• Puho E.
Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary.
[email protected]
OBJECTIVE: We studied the association between the use of nutritional supplements
during the first gestational month and the origin of Down's syndrome. METHODS: We
compared 781 subjects with Down's syndrome caused by pure trisomy 21 with their
matched controls who had no defect. We also compared subjects who had Down's
syndrome with groups of 22 843 patient controls (i.e., subjects with other congenital
abnormalities) and 38 151 population controls (without defects). Subjects with Down's
syndrome and other congenital abnormalities were identified in the large populationbased dataset of the Hungarian Congenital Abnormality Registry between 1980 and
1996, and matched population controls were selected from the National Birth Registry.
There were three sources of exposure data: 1) prospective and medically recorded data
based on prenatal logbooks, 2) retrospective maternal information based on
questionnaires, and 3) home visits in non-respondent cases of Down's syndrome and
congenital abnormalities. A possible association between the use of nutritional
supplements, mainly folic acid and antioxidant vitamins C and E, during the first month
of pregnancy and the incidence of Down's syndrome was studied. RESULTS: A significant
protective effect was seen with large doses of folic acid ( approximately 6 mg/d) and iron
(150-300 mg/d of ferrous sulfate) during the first gestational month against Down's
syndrome (adjusted odds ratio 0.4, 95% confidence interval 0.2 to 0.7 for both). In
general, folic acid and iron were used together, so it was difficult to separate these
effects due to the limited number of subjects and controls. Only iron alone showed a
protective effect against Down's syndrome (odds ratio 0.4, 95% confidence interval 0.1
to 0.9). The use of antioxidant vitamins was a rare event in the first month of pregnancy.
CONCLUSION: Pharmacologic doses of folic acid and iron appear to have a preventive
effect against Down's syndrome.
PMID: 15925294 [PubMed - indexed for MEDLINE]
Autosomal trisomy and
maternal use of
multivitamin supplements
• Am J Med Genet A. 2004 Mar 1;125(2):113-6
•
•
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• Botto LD,
• Mulinare J,
• Yang Q,
• Liu Y,
• Erickson JD.
National Center on Birth Defects and Developmental Disabilities,
Centers for Disease Control and Prevention, Atlanta, Georgia 30333,
USA. [email protected]
Recent reports suggest that women carrying certain polymorphisms
of folate genes associated with suboptimal folate status might be at
increased risk for having a child with Down syndrome or other
autosomal trisomies, and hypothesized that maternal use of
multivitamin supplements might reduce such risk. To evaluate this
hypothesis, we examined data from a population-based case-control
study, and contrasted cases of Down syndrome, trisomy 18, and
trisomy 13, with unaffected controls. Periconceptional multivitamin
use, compared to no such use, was associated with an odds ratio
(OR) of 0.9 (95% confidence interval [CI], 0.6-1.3) for having a
pregnancy affected by an autosomal trisomy. The OR was 0.8 (95%
CI, 0.5-1.3) for Down syndrome and 1.4 (95% CI, 0.5-3.6) for trisomies
13 and 18, with little variation by maternal race or age.
Periconceptional multivitamin use was not associated with a major
reduction in the risk for common autosomal trisomies.
PMID: 14981710 [PubMed - indexed for MEDLINE]
Aminoacid profile and oxidative status in
children affected by Down syndrome before
and after supplementary nutritional
treatment.
• Ital J Biochem. 2003 Jun;52(2):72-9
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Ciaccio M,
• Piccione M,
• Giuffre M,
• Macaione V,
• Vocca L,
• Bono A,
• Corsello G.
Cattedra di Biochimica Clinica, Facolta di Medicina e Chirurgia, Sezione di
Biochimica Medica, Dipartimento di Biotecnologie Mediche e Medicina Legale,
Universita degli Studi di Palermo, Palermo, Italy. [email protected]
Down syndrome is the most common autosomal aberration among liveborns,
characterised by several clinical features and metabolic disturbances. Aminoacid
pathways abnormalities and defective oxidative balance are the most common
metabolic problems in Down Syndrome. To evaluate the biochemical responses
of children with Down Syndrome to a nutritional regimen supplemented with
aminoacids, vitamins and polyunsaturated fatty acids, we submitted 86 subjects
divided in two groups (0-6 and 6-12 years) to the dosage of plasma levels of
aminoacids, antioxidant enzymes activities and reactive oxygen species, before
and after 12 months of such nutritional supplementation and in relation to normal
controls. The results obtained showed a tendency towards the values of normal
subjects with statistically significant differences. Although other studies must be
performed to confirm and define such report, our experience supports the
usefulness of a nutritional supplementation with aminoacids, vitamins and
polyunsaturated fatty acids, also considering the absence of side effects.
PMID: 14677423 [PubMed - indexed for MEDLINE]
Redox balance in patients with Down's
syndrome before and after dietary
supplementation with alpha-lipoic acid and Lcysteine.
• Int J Clin Pharmacol Res. 2003;23(1):23-30
• Gualandri W,
•
•
•
• Gualandri L,
• Demartini G,
• Esposti R,
• Marthyn P,
• Volonte S,
• Stangoni L,
• Borgonovo M,
• Fraschini F.
University of Milan, Milan, Italy.
The aim of the present study was to investigate the possible normalizing effect of
antioxidants on certain parameters indicative of oxidative stress in Down's syndrome
(DS). The study was performed in pediatric patients with DS with proven redox
imbalance, who were advised to take a dietary supplementation composed of alphalipoic acid and L-cysteine for several treatment cycles (one treatment cycle = 30 days
dietary supplementation plus 30 days wash-out). Serum thiol groups, serum total and
septic reactive oxygen species (ROS) and total antioxidant status of serum were
determined before and after dietary supplementation, using commercially available kits.
In all the evaluable patients (n = 20), after 3.8 +/- 1.1 treatment cycles, thiol group serum
concentrations and total antioxidant status of serum significantly increased (p < 0.0001
for both parameters) in comparison with basal values, while serum total and septic ROS
significantly decreased (p < 0.0001 for both parameters). On the basis of these results it
is impossible to demonstrate the clinical effects of the biochemical normalization
obtained in patients with DS after supplying alpha-lipoic acid and L-cysteine. These data
suggest that delaying the clinical expression of redox imbalance in patients with DS
might be feasible by normalizing their redox balance.
PMID: 14621070 [PubMed - indexed for MEDLINE]
Serum lipid resistance to oxidation and uric
acid levels in subjects with Down's syndrome
• Physiol Res. 2000;49(2):227-31 .
•
•
•
• Nagyova A,
• Sustrova M,
• Raslova K.
Institute of Preventive and Clinical Medicine, Bratislava, Slovak Republic.
[email protected]
In subjects with Down's syndrome (DS) increased oxidative stress and
consequent oxidative cell damage have been reported. The aim of this study was
to assess whether the excessive production of free oxygen radicals in these
subjects can affect the copper-induced lipid oxidation resistance measured in
fresh whole serum. Since a significant elevation of serum uric acid levels, which
is an efficient hydrophilic antioxidant, has been repeatedly reported in subjects
with DS, we studied the association between increased serum uric acid levels
and lipid resistance to oxidation measured directly in serum samples by
monitoring the change in absorbance at 234 nm. The group of subjects with
Down's syndrome consisted of 25 individuals (aged 18+/-5 years). Control group
included brothers and sisters of subjects with DS (n = 25, aged 17+/-7 years). In
subjects with DS, the serum lipid resistance to oxidation (lag time) was
significantly higher than in controls (p<0.05) and a concomitant increase in serum
uric acid levels was observed (p<0.001). A significant positive correlation
between lag time and serum uric acid concentration was found in subjects with
DS (r = 0.48, p<0.05), while the positive correlation in the control group was not
significant. The results suggest that increased serum uric acid levels repeatedly
observed in subjects with DS may be associated with an enhanced resistance of
serum lipids to oxidation which is thought to play an important role in the
atherogenic process.
PMID: 10984088 [PubMed - indexed for MEDLINE]
Uric acid and allantoin levels in Down
syndrome: antioxidant and oxidative
stress mechanisms?
• Clin Chim Acta. 2004 Mar;341(1-2):139-46
•
•
•
•
•
•
•
•
•
•
•
•
Zitnanova I,
Korytar P,
Aruoma OI,
Sustrova M,
Garaiova I,
Muchova J,
Kalnovicova T,
Pueschel S,
Durackova Z.
Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of
Medicine, Comenius University, Sasinkova 2, 813 72 Bratislava, Slovak Republic.
[email protected]
BACKGROUND: Down syndrome (DS) is a chromosomal abnormality (trisomy 21) leading
to mental retardation, to the characteristic change of individual's phenotype and to the
pathological features of Alzheimer disease. Patients with DS have elevated ratio of
superoxide dismutase to (catalase plus glutathione peroxidase) with respect to controls
in all age categories suggesting that oxidative imbalance contributes to the clinical
manifestation of accelerated aging. RESULTS: We report that persons with DS have
elevated uric acid levels compared with controls, 348.56+/-22.78 versus 284.00+/-20.86
micromol/l (p=0.018). The levels of hypoxanthine and xanthine in DS children (6.35+/-0.31
and 1.02+/-0.23 micromol/l) were significantly lower than in controls (7.83+/-0.59 and
2.43+/-0.66 micromol/l). This result suggests increased conversion of hypoxanthine and
xanthine to uric acid with subsequent free radical-dependent oxidation of uric acid to
allantoin, mechanisms potentiated by the oxidative stress in DS. Allantoin is a
nonenzymatic oxidative product of uric acid in human. In DS individuals, the levels of
allantoin were significantly higher than those in healthy controls (18.58+/-2.27 and
14.07+/-1.07 micromol/l, respectively, p=0.03). CONCLUSIONS: Our data supported the
presumption of increased oxidative stress in DS.
PMID: 14967170 [PubMed - indexed for MEDLINE]
Concentrations of serum lipids in children
with Down's syndrome]
[Article in Spanish]
• Arch Biol Med Exp (Santiago). 1991;24(1):49-55.
•
[Article in Spanish]
•
•
Unidad de Genetica, Hospital Luis Calvo Mackenna.
The level of blood lipids in children with Down's syndrome was
determined with the purpose of establishing possible differences in
total cholesterol, triglyceride and HDL-cholesterol levels with those
of healthy children. LDL-cholesterol fraction was calculated. Blood
samples were obtained from 66 healthy children (controls) and 72
patients who suffered from clinically diagnosed Down's syndrome. All
the children were grouped according to age. The variables of body
weight, height, and blood lipids gave a distribution of values that
allows one to distinguish the group of children with Down's syndrome
from the normal group. The values obtained for triglycerides, total
cholesterol, and LDL-cholesterol ranged higher, with a constant
deficit of HDL-cholesterol in all age groups. The lipid pattern
encountered in the Down's syndrome patient suggests the existence
of unknown, possibly genetically determined mechanisms, that
provoke a disorder in lipid metabolism.
PMID: 1845017 [PubMed - indexed for MEDLINE]
•
•
•
•
•
•
Zamorano A,
Guzman M,
Aspillaga M,
Avendano A,
Gatica M.
Lipids and lipoproteins in
persons with Down's
syndrome.
• J Intellect Disabil Res. 1992 Aug;36 ( Pt 4):365-9
•
•
•
•
•
•
Pueschel SM,
Craig WY,
Haddow JE.
Department of Pediatrics, Rhode Island Hospital, Brown University
School of Medicine, Providence 02903.
This study was designed to investigate whether the observed
decreased prevalence of coronary artery disease in individuals with
Down's syndrome may be explained by their serum lipid and
lipoprotein profiles. Twenty-seven persons with Down's syndrome and
23 non-affected control individuals were enrolled in this study. Their
fasting venous blood was analysed for total cholesterol, triglyceride,
LDH cholesterol, HDL cholesterol, apo B and apo AI. The results
revealed no significant differences between the study and control
group with regard to total cholesterol, LDL cholesterol, apo B and the
apo B:apo AI ratio. However, triglyceride levels were significantly
increased, and serum HDL cholesterol, apo AI and HDL
cholesterol:total cholesterol ratio were significantly decreased in
patients with Down's syndrome when compared with the control
group. The latter observations are all associated with an increased
risk for coronary artery disease. Therefore, it is concluded that the
decreased prevalence of coronary artery disease in individuals with
Down's syndrome cannot be explained by the lipid and lipoprotein
levels observed in this study population.
PMID: 1388078 [PubMed - indexed for MEDLINE]
Alpha-tocopherol and alpha-lipoic acid
enhance the erythrocyte antioxidant defence
in cyclosporine A-treated rats.
Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):68-73
•
•
•
•
•
•
Lexis LA,
Fassett RG,
Coombes JS.
Physiology Laboratory, School of Community Health, Faculty of Health Studies, Charles Sturt
University, Albury, 2640, Australia. [email protected]
The aim of this study was to determine the effects of dietary antioxidant supplementation
with alpha-tocopherol and alpha-lipoic acid on cyclosporine A (cyclosporine)-induced
alterations to erythrocyte and plasma redox balance. Rats were randomly assigned to either
control, antioxidant (alpha-tocopherol 1000 IU/kg diet and alpha-lipoic acid 1.6 g/kg diet),
cyclosporine (25 mg/kg/day), or cyclosporine + antioxidant treatments. Cyclosporine was
administered for 7 days after an 8 week feeding period. Plasma was analysed for alphatocopherol, total antioxidant capacity, malondialdehyde, and creatinine. Erythrocytes were
analysed for glutathione, methaemoglobin, superoxide dismutase, catalase, glutathione
peroxidase, glucose-6-phosphate dehydrogenase, alpha-tocopherol and malondialdehye.
Cyclosporine administration caused a significant decrease in superoxide dismutase activity
(P<0.05 control versus cyclosporine) and this was improved by antioxidant supplementation
(P<0.05 cyclosporine versus cyclosporine + antioxidant; P<0.05 control versus cyclosporine +
antioxidant). Animals receiving cyclosporine and antioxidants showed significantly increased
(P<0.05) catalase activity compared to both groups not receiving cyclosporine. Cyclosporine
administration induced significant increases in plasma malondialdehyde and creatinine
concentration (P<0.05 control versus cyclosporine). Antioxidant supplementation prevented
the cyclosporine induced increase in plasma creatinine (P<0.05 cyclosporine versus
cyclosporine + antioxidant; P>0.05 control versus cyclosporine + antioxidant), however,
supplementation did not alter the cyclosporine induced increase in plasma malondialdehyde
concentration (P>0.05 cyclosporine versus cyclosporine + antioxidant). Antioxidant
supplementation resulted in significant increases (P<0.05) in plasma and erythrocyte alphatocopherol in both of the supplemented groups compared to non-supplemented groups. In
conclusion, dietary supplementation with alpha-tocopherol and alpha-lipoic acid enhanced
the erythrocyte antioxidant defence and reduced nephrotoxicity in cyclosporine treated
animals.
PMID: 16433894 [PubMed - indexed for MEDLINE]
Influence of alpha-lipoic acid on lipid
peroxidation and antioxidant defence system
in blood of insulin-resistant rats.
• Diabetes Obes Metab. 2004 May;6(3):200-7.
•
•
•
•
•
Thirunavukkarasu V,
Anuradha CV.
Department of Biochemistry, Faculty of Science, Annamalai University, Chidambaram, Tamil
Nadu, India.
BACKGROUND: High fructose feeding induces insulin resistance and hyperinsulinaemia in
rats. A role for oxidative stress in the occurrence of insulin resistance has been suggested by
several workers. AIM: The aim of this study was to investigate the effect of alpha-lipoic acid
(LA) on oxidant-antioxidant balance in rats fed on a high-fructose diet that showed
characteristic features of insulin resistance. METHODS: Male Wistar rats weighing 150-170 g
were divided into seven groups. The control group received the control diet containing
starch. The fructose group was given a high-fructose diet (>60% of total calories). The third
and fourth groups were given fructose diet and were administered two different doses of LA
at a low dose (35 mg/kg body weight) and high dose (70 mg/kg body weight) using olive oil as
vehicle. The fifth group received fructose diet and olive oil. The sixth group received control
diet and was administered LA (70 mg/kg body weight). And, the seventh group received the
control diet and olive oil. Products of lipid peroxidation and activities of enzymic
antioxidants, namely superoxide dismutase, catalase, glutathione peroxidase, glutathione-Stransferase and glutathione reductase, in red blood cells were assayed. Levels of nonenzymic antioxidants alpha-tocopherol, ascorbic acid and reduced glutathione were
determined in plasma. RESULTS: The levels of lipid peroxides, diene conjugates and
thiobarbituric acid-reactive substances were significantly higher in fructose-fed rats.
Inadequate antioxidant system was observed in high-fructose-fed rats. Treatment of fructose
rats mitigated the imbalance between peroxidation and antioxidant defence system at both
the doses tested. Increases in glucose, triglycerides, free fatty acids, insulin and insulin
resistance were observed in fructose-fed rats. LA administration prevented these alterations
and improved insulin sensitivity. Significant positive correlations were obtained between
insulin resistance and lipid peroxidation indices. CONCLUSIONS: Increased lipid peroxidation
and deficient antioxidant system are observed in high-fructose-fed rats. LA administration
preserves the antioxidant system and lowers lipid peroxidation. The findings suggest an
interrelationship between lipid peroxidation and insulin resistance.
PMID: 15056128 [PubMed - indexed for MEDLINE]
Coenzyme Q10 absorption and
tolerance in children with Down
syndrome: a dose-ranging trial.
• Pediatr Neurol. 2006 Jul;35(1):30-7.
•
•
•
• Miles MV,
• Patterson BJ,
• Schapiro MB,
• Hickey FJ,
• Chalfonte-Evans M,
• Horn PS,
• Hotze SL.
Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital
Medical Center, Ohio 45229, USA. [email protected]
Controlled studies of coenzyme Q(10) dosing and tolerance have been reported in
adults, but not in pediatric patients. This study compares low- and high-dose
coenzyme Q(10) (LiQ-NOL syrup) absorption and tolerance in children with Down
syndrome. After a 1-month low-dose (1.0 mg/kg/day) run-in period, all participants
received high-dose coenzyme Q(10) (10.0 mg/kg/day) for two additional months (in
randomized sequence as one daily dose or split into two daily doses). Chemistry
profiles and complete blood counts were determined just before and at the study
completion. Plasma coenzyme Q(10) concentrations were determined initially and
at each study visit. Parents reported adverse events and study drug evaluations
using standardized forms. Most of the 16 children who completed this study
tolerated high-dose coenzyme Q(10) well. Uncooperative behavior resulted in
premature withdrawal of two participants, and may have been treatment-related.
Pre- and posttreatment laboratory test changes were considered to be clinically
nonsignificant. Study results indicate that high-dose coenzyme Q(10) (10
mg/kg/day) is well-absorbed and well-tolerated by most children with Down
syndrome, and appears to provide plasma concentrations which are comparable
to previous adult studies administering much higher coenzyme Q(10) dosages.
PMID: 16814082 [PubMed - indexed for MEDLINE]
Effects of metabolic modifiers such as
carnitines, coenzyme Q10, and PUFAs
against different forms of neurotoxic insults:
metabolic inhibitors, MPTP, and
methamphetamine.
• Ann N Y Acad Sci. 2005 Aug;1053:183-91
•
•
•
•
Virmani A,
• Gaetani F,
• Binienda Z.
Research and Development, Sigma-Tau Health Science, Via Treviso 4, Pomezia 00040, Italy.
[email protected]
A number of strategies using the nutritional approach are emerging for the protection of the brain
from damage caused by metabolic toxins, age, or disease. Neural dysfunction and metabolic
imbalances underlie many diseases, and the inclusion of metabolic modifiers may provide an
alternative and early intervention approach that may prevent further damage. Various models
have been developed to study the impact of metabolism on brain function. These have also proven
useful in expanding our understanding of neurodegeneration processes. For example, the
metabolic compromise induced by inhibitors such as 3-nitropropionic acid (3-NPA), rotenone, and
1-methyl-4-phenylpyridinium (MPP+) can cause neurodegeneration in animal models and these
models are thought to simulate the processes that may lead to diseases such as Huntington's and
Parkinson's diseases. These inhibitors of metabolism are thought to selectively kill neurons by
inhibiting various mitochondrial enzymes. However, the eventual cell death is attributed to
oxidative stress damage of selectively vulnerable cells, especially highly differentiated neurons.
Various studies indicate that the neurotoxicity resulting from these types of metabolic
compromise is related to mitochondrial dysfunction and may be ameliorated by metabolic
modifiers such as L-carnitine (L-C), creatine, and coenzyme Q10, as well as by antioxidants such
as lipoic acid, vitamin E, and resveratrol. Mitochondrial function and cellular metabolism are also
affected by the dietary intake of essential polyunsaturated fatty acids (PUFAs), which may
regulate membrane composition and influence cellular processes, especially the inflammatory
pathways. Cellular metabolic function may also be ameliorated by caloric restriction diets. L-C is
a naturally occurring quaternary ammonium compound that is a vital cofactor for the
mitochondrial entry and oxidation of fatty acids. Any factors affecting L-C levels may also affect
ATP levels. This endogenous compound, L-C, together with its acetyl ester, acetyl-L-carnitine
(ALC), also participates in the control of the mitochondrial acyl-CoA/CoA ratio, peroxisomal
oxidation of fatty acids, and production of ketone bodies. A deficiency of carnitine is known to
have major deleterious effects on the CNS. We have examined L-C and its acetylated derivative,
ALC, as potential neuroprotective compounds using various known metabolic inhibitors, as well
as against drugs of abuse such as methamphetamine.
PMID: 16179522 [PubMed - indexed for MEDLINE]
Role of carnitine esters in
brain neuropathology.
• Mol Aspects Med. 2004 Oct-Dec;25(5-6):533-49.
•
•
•
•
•
Virmani A,
Binienda Z.
Scientific Affairs, Sigma-tau HealthScience, Pomezia 00040, Italy. [email protected]
L-Carnitine (L-C) is a naturally occurring quaternary ammonium compound endogenous in
all mammalian species and is a vital cofactor for the mitochondrial oxidation of fatty
acids. Fatty acids are utilized as an energy substrate in all tissues, and although glucose
is the main energetic substrate in adult brain, fatty acids have also been shown to be
utilized by brain as an energy substrate. L-C also participates in the control of the
mitochondrial acyl-CoA/CoA ratio, peroxisomal oxidation of fatty acids, and the
production of ketone bodies. Due to their intrinsic interaction with the bioenergetic
processes, they play an important role in diseases associated with metabolic
compromise, especially mitochondrial-related disorders. A deficiency of carnitine is
known to have major deleterious effects on the CNS. Several syndromes of secondary
carnitine deficiency have been described that may result from defects in intermediary
metabolism and alterations principally involving mitochondrial oxidative pathways.
Mitochondrial superoxide formation resulting from disturbed electron transfer within the
respiratory chain may affect the activities of respiratory chain complexes I, II, III, IV, and
V and underlie some CNS pathologies. This mitochondrial dysfunction may be
ameliorated by L-C and its esters. In addition to its metabolic role, L-C and its esters
such as acetyl-L-carnitine (ALC) poses unique neuroprotective, neuromodulatory, and
neurotrophic properties which may play an important role in counteracting various
disease processes. Neural dysfunction and metabolic imbalances underlie many
diseases, and the inclusion of metabolic modifiers may provide an alternative and early
intervention approach, which may limit further developmental damage, cognitive loss,
and improve long-term therapeutic outcomes. The neurophysiological and
neuroprotective actions of L-C and ALC on cellular processes in the central and
peripheral nervous system show such effects. Indeed, many studies have shown
improvement in processes, such as memory and learning, and are discussed in this
review.
PMID: 15363640 [PubMed - indexed for MEDLINE]
Therapeutic effects of L-carnitine and
propionyl-L-carnitine on
cardiovascular diseases: a review.
•
•
•
•
•
Ann N Y Acad Sci. 2004 Nov;1033:79-91.
Ferrari R,
•
•
•
•
•
Merli E,
Cicchitelli G,
Mele D,
Fucili A,
Ceconi C.
Chair of Cardiology, University Hospital of Ferrara, Gussago (Brescia), Italy. [email protected]
Several experimental studies have shown that levocarnitine reduces myocardial injury after ischemia and
reperfusion by counteracting the toxic effect of high levels of free fatty acids, which occur in ischemia, and by
improving carbohydrate metabolism. In addition to increasing the rate of fatty acid transport into
mitochondria, levocarnitine reduces the intramitochondrial ratio of acetyl-CoA to free CoA, thus stimulating
the activity of pyruvate dehydrogenase and increasing the oxidation of pyruvate. Supplementation of the
myocardium with levocarnitine results in an increased tissue carnitine content, a prevention of the loss of
high-energy phosphate stores, ischemic injury, and improved heart recovery on reperfusion. Clinically,
levocarnitine has been shown to have anti-ischemic properties. In small short-term studies, levocarnitine acts
as an antianginal agent that reduces ST segment depression and left ventricular end-diastolic pressure. These
short-term studies also show that levocarnitine releases the lactate of coronary artery disease patients
subjected to either exercise testing or atrial pacing. These cardioprotective effects have been confirmed
during aortocoronary bypass grafting and acute myocardial infarction. In a randomized multicenter trial
performed on 472 patients, levocarnitine treatment (9 g/day by intravenous infusion for 5 initial days and 6
g/day orally for the next 12 months), when initiated early after acute myocardial infarction, attenuated left
ventricular dilatation and prevented ventricular remodeling. In treated patients, there was a trend towards a
reduction in the combined incidence of death and CHF after discharge. Levocarnitine could improve ischemia
and reperfusion by (1) preventing the accumulation of long-chain acyl-CoA, which facilitates the production of
free radicals by damaged mitochondria; (2) improving repair mechanisms for oxidative-induced damage to
membrane phospholipids; (3) inhibiting malignancy arrhythmias because of accumulation within the
myocardium of long-chain acyl-CoA; and (4) reducing the ischemia-induced apoptosis and the consequent
remodeling of the left ventricle. Propionyl-L-carnitine is a carnitine derivative that has a high affinity for
muscular carnitine transferase, and it increases cellular carnitine content, thereby allowing free fatty acid
transport into the mitochondria. Moreover, propionyl-L-carnitine stimulates a better efficiency of the Krebs
cycle during hypoxia by providing it with a very easily usable substrate, propionate, which is rapidly
transformed into succinate without energy consumption (anaplerotic pathway). Alone, propionate cannot be
administered to patients in view of its toxicity. The results of phase-2 studies in chronic heart failure patients
showed that long-term oral treatment with propionyl-L-carnitine improves maximum exercise duration and
maximum oxygen consumption over placebo and indicated a specific propionyl-L-carnitine effect on peripheral
muscle metabolism. A multicenter trial on 537 patients showed that propionyl-L-carnitine improves exercise
capacity in patients with heart failure, but preserved cardiac function.
PMID: 15591005 [PubMed - indexed for MEDLINE]
Nitric oxide and cellular stress response in
brain aging and neurodegenerative disorders:
the role of vitagenes.
•
In Vivo. 2004 May-Jun;18(3):245-67.
Calabrese V,
•
•
•
•
•
•
Boyd-Kimball D,
Scapagnini G,
Butterfield DA.
Section of Biochemistry and Molecular Biology, Department of Chemistry, Faculty of Medicine, University of
Catania, Catania, Italy. [email protected]
Nitric oxide and other reactive nitrogen species appear to play crucial roles in the brain such as
neuromodulation, neurotransmission and synaptic plasticity, but are also involved in pathological processes
such as neurodegeneration and neuroinflammation. Acute and chronic inflammation result in increased
nitrogen monoxide formation and nitrosative stress. It is now well documented that NO and its toxic
metabolite, peroxynitrite, can inhibit components of the mitochondrial respiratory chain leading to cellular
energy deficiency and, eventually, to cell death. Within the brain, the susceptibility of different brain cell
types to NO and peroxynitrite exposure may be dependent on factors such as the intracellular reduced
glutathione and cellular stress resistance signal pathways. Thus neurons, in contrast to astrocytes, appear
particularly vulnerable to the effect of nitrosative stress. Evidence is now available to support this scenario
for neurological disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease,
multiple sclerosis and Huntington's disease, but also in the brain damage following ischemia and
reperfusion, Down's syndrome and mitochondrial encephalopathies. To survive different types of injuries,
brain cells have evolved integrated responses, the so-called longevity assurance processes, composed of
several genes termed vitagenes and including, among others, members of the HSP system, such as HSP70
and HSP32, to detect and control diverse forms of stress. In particular, HSP32, also known as heme
oxygenase-1 (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1
induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin,
could represent a protective system potentially active against brain oxidative injury. Increasing evidence
suggests that the HO-1 gene is redox-regulated and its expression appears closely related to conditions of
oxidative and nitrosative stress. An amount of experimental evidence indicates that increased rate of free
radical generation and decreased efficiency of the reparative/degradative mechanisms, such as proteolysis,
are factors that primarily contribute to age-related elevation in the level of oxidative stress and brain
damage. Given the broad cytoprotective properties of the heat shock response there is now strong interest
in discovering and developing pharmacological agents capable of inducing such a response. These findings
have led to new perspectives in medicine and pharmacology, as molecules inducing this defense mechanism
appear to be possible candidates for novel, cytoprotective strategies. Particularly, manipulation of
endogenous cellular defense mechanisms such as the heat shock response, through nutritional antioxidants
or pharmacological compounds, represents an innovative approach to therapeutic intervention in diseases
causing tissue damage, such as neurodegeneration. Consistent with this notion, maintenance or recovery of
the activity of vitagenes may possibly delay the aging process and decrease the occurrence of age-related
diseases with resulting prolongation of a healthy life span.
PMID: 15341181 [PubMed - indexed for MEDLINE]
Redox regulation of heat shock protein
expression by signaling involving nitric oxide
and carbon monoxide: relevance to brain
aging, neurodegenerative disorders, and
longevity.
• Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):444-77
•
•
•
•
•
•
•
•
Calabrese V,
Butterfield DA,
Scapagnini G,
Stella AM,
Maines MD.
Section of Biochemistry and Molecular Biology, Department of Chemistry, Faculty of
Medicine, University of Catania, Catania, Italy.
Increased free radical generation and decreased efficiency of the reparative/degradative
mechanisms both primarily contribute to age-related elevation in the level of oxidative
stress and brain damage. Excess formation of reactive oxygen and nitrogen species can
cause proteasomal dysfunction and protein overloading. The major neurodegenerative
diseases are all associated with the presence of abnormal proteins. Different integrated
responses exist in the brain to detect oxidative stress which is controlled by several
genes termed vitagenes, including the heat shock protein (HSP) system. Of the various
HSPs, heme oxygenase-I (HO-1), by generating the vasoactive molecule carbon
monoxide and the potent antioxidant bilirubin, could represent a protective system
potentially active against brain oxidative injury. The HO-1 gene is redox regulated and its
expression is modulated by redox active compounds, including nutritional antioxidants.
Given the broad cytoprotective properties of the heat shock response, there is now
strong interest in discovering and developing pharmacological agents capable of
inducing the heat shock response. These findings have opened up new neuroprotective
strategies, as molecules inducing this defense mechanism can be a therapeutic target to
minimize the deleterious consequences associated with accumulation of
conformationally aberrant proteins to oxidative stress, such as in neurodegenerative
disorders and brain aging, with resulting prolongation of a healthy life span.
PMID: 16677090 [PubMed - indexed for MEDLINE]
Acetylcarnitine and cellular stress response:
roles in nutritional redox homeostasis and
regulation of longevity genes.
• J Nutr Biochem. 2006 Feb;17(2):73-88. Epub 2005 Oct
18.
•
•
•
• Calabrese V,
• Giuffrida Stella AM,
• Calvani M,
• Butterfield DA.
Department of Chemistry, Biochemistry and Molecular Biology Section, Faculty of Medicine,
University of Catania, 95100 Catania, Italy. [email protected]
Aging is associated with a reduced ability to cope with physiological challenges. Although the
mechanisms underlying age-related alterations in stress tolerance are not well defined, many
studies support the validity of the oxidative stress hypothesis, which suggests that lowered
functional capacity in aged organisms is the result of an increased generation of reactive oxygen
and nitrogen species. Increased production of oxidants in vivo can cause damage to intracellular
macromolecules, which can translate into oxidative injury, impaired function and cell death in
vulnerable tissues such as the brain. To survive different types of injuries, brain cells have
evolved networks of responses, which detect and control diverse forms of stress. This is
accomplished by a complex network of the so-called longevity assurance processes, which are
composed of several genes termed vitagenes. Among these, heat shock proteins form a highly
conserved system responsible for the preservation and repair of the correct protein conformation.
The heat shock response contributes to establishing a cytoprotective state in a wide variety of
human diseases, including inflammation, cancer, aging and neurodegenerative disorders. Given
the broad cytoprotective properties of the heat shock response, there is now a strong interest in
discovering and developing pharmacological agents capable of inducing the heat shock response.
Acetylcarnitine is proposed as a therapeutic agent for several neurodegenerative disorders, and
there is now evidence that it may play a critical role as modulator of cellular stress response in
health and disease states. In the present review, we first discuss the role of nutrition in carnitine
metabolism, followed by a discussion of carnitine and acetyl-l-carnitine in mitochondrial
dysfunction, in aging, and in age-related disorders. We then review the evidence for the role of
acetylcarnitine in modulating redox-dependent mechanisms leading to up-regulation of vitagenes
in brain, and we also discuss new approaches for investigating the mechanisms of lifetime
survival and longevity.
PMID: 16413418 [PubMed - indexed for MEDLINE]
Homocysteine concentrations in
adults with trisomy 21: effect of B
vitamins and genetic polymorphisms.
• Am J Clin Nutr. 2004 Dec;80(6):1551-7.
•
•
•
• Fillon-Emery N,
• Chango A,
• Mircher C,
• Barbe F,
• Blehaut H,
• Herbeth B,
• Rosenblatt DS,
• Rethore MO,
• Lambert D,
• Nicolas JP.
Faculte de Medecine, Laboratory of Medical Biochemistry, Vandoeuvre-Les-Nancy, France.
BACKGROUND: The effects of supplementation with B vitamins and of common polymorphisms in
genes involved in homocysteine metabolism on plasma total homocysteine (tHcy) concentrations
in trisomy 21 are unknown. OBJECTIVES: We aimed to determine the effects of orally
administered folic acid and of folic acid combined with vitamin B-12, vitamin B-6, or both on tHcy
in adults with trisomy 21. The study was also intended to analyze the possible influence of gene
polymorphisms. DESIGN: One hundred sixty adults with trisomy 21 and 160 healthy, unrelated
subjects aged 26 +/- 4 y were included. Plasma tHcy, red blood cell folate, serum folate, and
vitamin B-12 were measured. Genotyping for the common methylenetetrahydrofolate reductase
(MTHFR) 677C-->T, MTHFR 1298A-->C, cystathionine beta-synthase 844Ins68, methionine
synthase 2756A-->C, methionine synthase reductase 66A-->G, and reduced folate carrier 80G-->A
polymorphisms was carried out. RESULTS: The mean tHcy concentration (9.8 +/- 0.7 micromol/L)
of cases who did not use vitamins was not significantly different from that of controls (9.4 +/- 0.3
micromol/L). Plasma tHcy concentrations (7.6 +/- 0.3 mmol/L) in cases who used folic acid were
significantly lower than in cases who did not. Folic acid combined with vitamin B-12 did not
significantly change tHcy concentrations compared with those in cases who used only folic acid.
Folic acid combined with vitamins B-6 and B-12 significantly lowered tHcy (6.5 +/- 0.5 micromol/L).
The difference in tHcy according to MTHFR genotype was not significant. However, tHcy
concentrations were slightly higher in TT homozygotes among the controls but not among the
cases. CONCLUSION: This study provides information on the relation between several
polymorphisms in genes involved in homocysteine and folate metabolism in adults with trisomy
21.
PMID: 15585767 [PubMed - indexed for MEDLINE]
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