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The Underlying Pathology of Chronic Disease
DEBBY HAMILTON, M.D., MPH
RESEARCHED NUTRITIONALS
1
Oxidative stress: a
disturbance in the
balance between
the production of
reactive oxygen
species (free
radicals) and
antioxidant
defenses
Oxidative Stress 2
Mitochondrial
Function
1. ATP production-
produce energy for
the cell
2. Initiating and
performing
apoptosis and cell
death
3. Calcium
homeostasis
4. Iron homeostasis
3
Oxidative Stress Damage to Mitochondria
Mitochondrial DNA (mtDNA)
Mitochondrial lipids
Cardiolipin: releases cytochrome C into
cytosol starts apoptosis
Mitochondrial protein
alteration
Aconitase:
•key role in Krebs cycle transfer citrate to isocitrate
•Inactivation of Fe-S releases Fe and H2O2 leading to formation of hydroxyl radical
Uncoupling protein 2
•Role of mitochondria in toxic oxidative stress. Farris MW. Et al. Molecular Interventions. 2005 April. Vol 5(2).
4
Causes of
Mitochondrial Dysfunction
and Oxidative Stress
Mitochondrial
Dysfunction
Medicines
Poor Nutrition
Stress
Pesticides
(Glyphosate)
Heavy Metals
Environmental toxins
Oxidative Stress
Medicines
Poor Nutrition
Stress
Pesticides
(Glyphosate)
Heavy Metals
Environmental Toxins
5
Oxidative
Stress
leads to
Inflammation
6
DAMP’s:Damage-Associated Molecular Patterns
7
Picca A, Lezza AMS, Leeuwenburgh C, Pesce V, Calvani R, Landi F, Bernabei R, Marzetti E. Fueling Inflamm-Aging through Mitochondrial Dysfunction: Mechanisms and Molecular Targets. International Journal of Molecular Sciences. 2017; 18(5):933.
8
NF-kB: Nuclear Factor Kappa B
Transcription Factor
Activated by oxidative stress
Increase in pro-inflammatory
cytokines
causing increase of lymphocytes
and chemokines
Leading to more free radicals
(oxidative stress)
More tissue damage
Inflammation
9
Gut-brain-microbiome Influences
10
Disrupted Gut-Brain-Microbiome 11
Disrupted Gut-Brain-Microbiome in
Autism Spectrum Disorder
40 autistic subjects (36 out of 40 autistic subjects were classified as severe ASDs, Childhood Autism Rating Scale (CARS) value >37) and 40 neurotypical controls
Analysis of gut microbiota
Results:
Candida was more than double in the autistic than neurotypical subjects
Significant increase in the Firmicutes/Bacteroidetes ratio in autistic subjects due to a reduction of the Bacteroidetes relative abundance
Strati F. et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 2017. 5:24.
12
Model of
development
of Parkinson’s
disease
13
Houser MC. Et al. The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis? NPJ Parkinson's Dis. 2017;3:3
Terlecky SR, Terlecky LJ, Giordano CR. Peroxisomes, oxidative stress, and inflammation. World J Biol Chem 2012; 3(5): 93-97
14
Increasedoxidative
stress
Then:
15
Increased
need for
glutathione
Oxidation-Reduction cycle
16
What are the functions of Glutathione?
1. Master Antioxidant
2. Reduces Free Radicals
3. Detoxifies Chemicals
4. Chelates Heavy Metals
5. Protects Mitochondrial DNA
6. Cellular Anti-inflammatory compound
7. Storage and transport of cysteine
8. Enhances immune function
and transport of cysteine
17
Detoxification Pathways 18
19
Role in development of cancer
20
Oxidativestress, mitochondrial dysfunction and, inflammationcommon events in skin of patients with Fibromyalgia. Sanchez-Dominguez B. Mitochondrion. 2015 Mar;21:69-75.
Recent studies have shown some evidence demonstrating that oxidative stress, mitochondrial dysfunction andinflammation may have a role in the pathophysiology of fibromyalgia.
Skin biopsies from patients showed a significant mitochondrial dysfunctionwith reduced mitochondrial chain activities and bioenergetics levels and increased levels of oxidative stress.
OS, mitochondrial dysfunction and inflammation as interdependent events in the pathophysiology of FM
21
Neurodegeneration22
Peacock BN, Gherezghiher TB, Hilario JD, Kellermann GH. New insights into
Lyme disease. Redox Biology. 2015;5:66-70.
23
Oxidative stress and mitochondrial dysfunction in sepsis.Galley HF. BR. Jr of Anesth. 2011 Jul;107(1):57-64.
Sepsis-related
organ dysfunction remains
the most common cause of
death in the intensive care
unit (ICU)
Marked oxidative stress as a
result of the inflammatory
responses inherent with
sepsis initiates changes
in mitochondria function
which may result in organ
damage
24
Oxidative stress induced mitochondrial dysfunction drives inflammationand airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease. Wiegman CH. J Allerg Clin Immun. 015 Sep;136(3):769-80..
Mitochondrial dysfunction in
patients with COPD is
associated with
excessive mitochondrial ROS levels
enhanced inflammation and cell hyperproliferation.
Targeting mitochondrial ROS
represents a promising
therapeutic approach in
patients with COPD.
25
26
Diabetes
and
Cardiac
Disease
27
Support for chronic disease
28
Support for chronic disease
Repair and support mitochondria
•Membrane repair
•Support nutrients in ATP production from breakdown of macronutrients to Krebs cycle to oxidative phosphorylation
1
Decrease causes of oxidative stress and inflammation
2
Increase anti-oxidants to counteract oxidative stress including activating Nrf2
3
Decrease inflammation through down regulating inflammatory mediators and improving microbiome
4
29
Support for mitochondrial
dysfunction
Repair mitochondrial membrane
Phospholipids
30
31
Repair mitochondrial membranePhospholipids
Support mitochondrial functionCoQ10/UbiquinolCarnitineNADHAlpha-lipoic acidB vitaminsVitamin E
SUPPORT FOR MITOCHONDRIAL
DYSFUNCTION
32
ATP Fuel® 33
Phospholipid delivery system for mitochondrial membrane repair plus optimization of Krebs Energy Cycle
Top mitochondrial nutrients:
Unique Phospholipid Matrix: repair mitochondrial membrane
Stabilized NADH
CoQ10
Carnitine
Vitamin E
Alpha-ketoglutaric acid
ATP Fuel® Clinical Research Highlights
58 patient (Lyme, CFS, Fibromyalgia) study
31% fatigue reduction
30% cognitive function improvement
Published in peer reviewed journals
International Journal of Clinical Medicine
Functional Foods in Health & Disease
34
ATP Fuel® Clinical Research Highlights
35
15%
22%
31%
0%
5%
10%
15%
20%
25%
30%
35%
Day 7 Day 30 Day 60
Fatigue Reduction
ATP Fuel®Optimized energy for serious mitochondrial needs
36
Suggested Use:
Take five capsules 30 minutes beforebreakfast and five capsules 30 minutesbefore lunch or dinner (ten capsules perday) for the first two months, and fivecapsules 30 minutes before breakfast inmonth 3 and beyond.
It is important to keep with the protocolfor the first two months so that enoughcell membranes are repaired — which willallow the patient to feel the difference.This equates to 2 bottles per month foreach of the first two months, and 1 bottleper month thereafter.
Support
for
oxidative
stress
Anti-oxidants to combat oxidative stress
Glutathione
Molecular Hydrogen (H2 : Hydrogen gas)
Vitamin E: mixed tocopherols and tocotrienols
Curcumin
Tea: EGCG
Resveratrol
N-acetyl-cysteine
37
Sinha R. Et al. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. European Journal of Clinical Nutrition advance online publication, 30 August 2017; doi:10.1038/ejcn.2017.132.
A clinical trial using Tri-
Fortify™ liposomal
glutathione showed
efficacy in raising
intracellular reduced
glutathione levels (GSH)
along with natural killer
cell function while also
decreasing oxidative
stress markers.
38
Glutathione
liposomal delivery
Liposomal technology (continued)
Body recognizes the liposome as self
Absorption begins with membranes vs. going through digestive tract
Unique liposome structure allows it to combine effectively with the body's natural fluids and penetrate its protective membranes
Most nutrients require the stomach acids to break them down into smaller molecules so they may be absorbed
Oral glutathione, not in liposomes, must go through stomach acids, reducing absorption potential
39
Tri-Fortify™clinical research summary
40
Tri-Fortify™ clinical research summary
41
Tri-Fortify™ clinical research summary
42
Tri-Fortify™ liposomal glutathione
Available in two natural flavors:
Watermelon
Orange
450 mg of glutathione per serving
50 mg of vitamin C
Proven Heat Stable
3rd party lab tested
1040F/400C / 75% humidity – 90 days
Result: exceed label claim
GMO-free (3rd party lab tested)
43
Molecular Hydrogen: H2
Hydrogen gas is very stable molecule
Neutralizes harmful free radicals, including the hydroxyl radical1
Hydrogen electron donation turns hydroxyl into water
Diffuses across membranes, including mitochondria, due to its small size2
Most antioxidant supplements are limited in their cellular distributions and are poorly taken up by organelles like mitochondria 3
Hydrogen has the ability to effectively penetrate biomembranes and infiltrate into organelles, such as mitochondria and the nucleus 3
In contrast to many antioxidants, H2 also has the advantage of being able to penetrate the blood-brain barrier 3
Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals, Ikuroh Ohsawa, et al. Nature Medicine Vol 13, No. 6, June 2007
2 Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine, Ohta S., Pharmacology & Therapeutics, Volume 144, Issue 1, October 2014, Pages 1–11
3Clinical Effects of Hydrogen Administration: From Animal and Human Diseases to Exercise
Medicine, Nicolson G. et al., International Journal of Clinical Medicine, 2016, 7, 32-76
44
Molecular Hydrogen: H2
Summary
Anti-oxidant for dangerous hydroxyl radical without destroying free radicals needed for metabolism
Activates Nrf2 anti-oxidant cascade including glutathione peroxidase, catalase, and superoxide dismutase (SOD)
Decreases pro-inflammatory cytokines through cell signaling
Promotes mitochondrial ATP energy function
1Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine, Ohta S., Pharmacology & Therapeutics, Volume 144, Issue 1, October 2014, Pages 1–11
2Clinical Effects of Hydrogen Administration: From Animal and Human Diseases to Exercise Medicine, Nicolson G. et al., International Journal of Clinical Medicine, 2016, 7, 32-76
45
H2 Absorb™for a healthier life
46
Support for inflammation and abnormal cytokines
Glutathione
Molecular Hydrogen (H2 : Hydrogen gas)
Vitamin E: mixed tocopherols and tocotrienols
Curcumin
Tea: EGCG
Resveratrol
N-acetyl-cysteine
Probiotics
47
Nrf2: Nuclear Factor 2
Master regulator of the
antioxidant system
Mechanism: A Nrf2
activator releases protein
into the cell nucleus where
it binds to DNA and
activates anti-oxidant
enzymes such as catalase,
glutathione peroxidase,
and superoxide dismutase
and these enzymes can
neutralize up to 1 million
free radicals
48
CytoQuel®Human Clinical Research
A human clinical pilot study was undertaken in a
population of twenty individuals with chronic pain
The results from this open-label 8-week pilot study
showed robust changes on a number of health-
related parameters within two weeks that
continued to improve over the course of the study
49
CytoQuel®Human Clinical Research
The health improvements
included:
Pain reduction
Reduced blood pressure
Improved activities of daily
living and wellness
Reduced serum cytokine
level
50
CytoQuel® - 55% Pain Reduction51
40% decreasep value = 0.009
55% decreasep value = 0.011
0
1
2
3
4
5
6
7
Week 0 Week 2 Week 8
Scal
e (
0-1
0)
Primary pain in the past 24 hourswhile not active
CytoQuel - 3 caps daily
CytoQuel® - 65% Pain Reduction52
65% decreasep value = 0.0006
0
1
2
3
4
5
6
7
8
Week 0 Week 2 Week 8
Scal
e (
0-1
0)
Primary pain in the past 24 hourswhile active
CytoQuel - 3 caps daily
43% decreasep value = 0.006
CytoQuel® 44% Improved Sleep Quality 53
*
0
1
2
3
4
5
6
7
8
9
Week 0 Week 2 Week 8
Scal
e (
0-1
0)
Quality of sleep without the use of sleep aids
CytoQuel - 3 caps daily
44% Improvementp value 0.024
CytoQuel®: healthy cytokine and
inflammation support
Black Tea Extract
Much stronger antioxidant than green tea
Highest EGCG Content - 50%
CurcuWin®
46X absorption of standard curcumin*
35X absorption of BCM-95®*
6X absorption of Meriva®*
Delta Gold® Tocotrienols
Pure delta & gamma
No tocopherols = better absorption
N-Acetyl-cysteine (NAC)
Resveratrol (Natural Trans-Resveratrol)
* Comparative Absorption of Curcumin Formulations. Jager R. Et al Nutr J 2014 Jan 24;13(1):11.
54
Probiotics: Immune
modulation
Soil-based (spore)
Bacillus (ex: Bacillus subtilis, Bacillus coagulans)
Spore form survives stomach acid and bile acid1
Leave spore form in intestine, produce lactic acid which has anti-bacterial properties to prevent growth of pathogenic bacteria
Dairy-free (no dairy allergy concern)
Before processed foods, soil based bacteria part of our normal microbiome
Colonize intestine sooner
Dairy-based lactic acid bacteria
Lactobacillus and Bifidobacterium
Need to take high CFU- do not survive stomach acid well
55
Genomic
Sequencing
Genomic Sequencing: the order of the DNA nucleotides
For Probiotics: genomic sequencing identifies specific strain of probiotic.
Not just lactobacillus acidophilus or bacillus subtilis but lactobacillus acidophilus strain X and bacillus subtilis strain Y
*Important: Can do research on genomic sequenced specific strain of a probiotic to guarantee efficacy and safety*
56
CoreBioticTM
*Key Concepts*
Soil-based (spore)
Normal part of the human microbiome
Spore forming probiotics survive stomach acid
Leave the spore form in the intestine and produce lactic acid
Inhibit growth of harmful organisms by competitive inhibition, natural anti-bacterial compounds, increasing lactic acid
Helpful for IBS symptoms, cholesterol and triglyceride metabolism
Each strain has been clinically researched and genomically sequenced to ensure efficacy and safety
57
Summary: Support for
mitochondrial dysfunction,
oxidative stress and Inflammation
ATP Fuel® - repair mitochondrial membranes and support mitochondrial function
CytoQuel® - support healthy cytokine activity and manage oxidative stress and inflammation
H2Absorb™ -manage oxidative stress and inflammation, mitochondrial function
Tri-Fortify™ -Liposomal glutathione
CoreBiotic™ - soil based probiotics
Additional support:
CoQ10 Power™
Ribose Cardio™
C-RLA™: Liposomal vitamin C and R-lipoic acid
58
Dr. Debby Hamilton, MD, MPH
Researched Nutritionals
dhamilton@researchednutritionals.com
www.researchednutritionals.com
59
References for Glutathione
Cooke RW. Et al Reduction of oxidative stress marker in lung fluid of preterm infants after
administration of intra-tracheal liposomal glutathione. Bio Neonate. 2005;87(3):178-80.
Hauser AR. Et al. Randomized, double-blind, pilot evaluation of intravenous glutathione in
Parkinson's disease. Mov Disord. 2009 May 15;24(7):979-83. doi: 10.1002/mds.22401.
James J. Et al. Am J Clin Nutr 2004;80:1611-161
Kern JK. Et al. A clinical trial of glutathione supplementation in autism spectrum disorders. Med
Sci Monit. 2011; 17(12): CR677–CR682
Madrigal JL. Et al. glutathione depletion, lipid peroxidation and mitochondrial dysfunction are
induced by chronic stress in rat brain. Neuropsychopharm. 2001. 24(4).
Marí M. et al. Mitochondrial Glutathione, a Key Survival Antioxidant. Antioxidants & Redox
Signaling. 2009;11(11):2685-2700.
Morris G. et al. The glutathione system: a new drug target in neuroimmune disorders. Mol
Neurobiol. 2014 Dec;50(3):1059-84.
Sechi G. Et al. Reduced intravenous glutathione in the treatment of early Parkinson's disease
Prog Neurospychopharm Biol Psych. 1996 Oct;20(7):1159-70.
Sinha R. Et al. Oral supplementation with liposomal glutathione elevates body stores of
glutathione and markers of immune function. European Journal of Clinical Nutrition advance
online publication, 30 August 2017; doi:10.1038/ejcn.2017.132. (Tri-Fortify™ study)
60
References for Molecular Hydrogen
Ichihara, M., et al., Beneficial biological effects and the underlying mechanisms of molecular
hydrogen - comprehensive review of 321 original articles. Med Gas Res, 2015. 5: p. 12.
Ohta, S., Molecular hydrogen as a preventive and therapeutic medical gas: initiation,
development and potential of hydrogen medicine. Pharmacol Ther. 2014.
Molecular hydrogen foundation: www.molecularhydrogenfoundation.com
Yu, J., et al., Molecular hydrogen attenuates hypoxia/reoxygenation injury of intrahepatic
cholangiocytes by activating Nrf2 expression. Toxicol Lett. 2015. 238(3): p. 11-19.
Ohno, K., M. Ito, and M. Ichihara, Molecular hydrogen as an emerging therapeutic medical
gas for neurodegenerative and other diseases. Oxidative Medicine and Cellular Longevity.
2012. 2012: p. 353152.
Dixon, B.J., J. Tang, and J.H. Zhang, The evolution of molecular hydrogen: a noteworthy
potential therapy with clinical significance. Med Gas Res. 2013. 3(1): p. 10.
Dohi, K., et al., Molecular Hydrogen in Drinking Water Protects against Neurodegenerative
Changes Induced by Traumatic Brain Injury. PLoS One. 2014. 9(9): p. e108034.
Saitoh Y, et al. Biological safety of neutral-pH hydrogen-enriched electrolyzed water upon
mutagenicity, genotoxicity, and subchronic oral toxicity. Toxicology and Industrial Health.
2010. 26(4):203-216.
61
References for combination of
ingredients in CytoQuel®
Resveratrol, Curcumin, Vitamin E, Tea (EGCG), and N-Acetyl-Cysteine
Pocernich CB. Et al. Nutritional approaches to modulate oxidative stress in
Alzheimer’s disease. Curr Alz Res. 2011 Aug;8(5):452-69.
Resveratrol and tea extract (EGCG)
Vacca RA. Et al. Plant polyphenols as natural drugs for the management of Down Syndrome and related disorders. Neurosci Biobehav Rev. 2016 Dec;71:865-877.
Resveratrol and N-Acetyl-Cysteine
Collins JA Et al. Resveratrol and N-Acetyl cysteine influence redox balance in equine articular chondrocytes under acidic and very low oxygen conditions. Free Radic Biol Med. 2015 Sep;86:57-64.
Curcumin and Resveratrol
Cucolas C. Et al. Resveratrol and curcumin as protective agents in an experimental rat model of intestinal ischemia and reperfusion. Can J Physiol Pharmacol 2016 May
Rangarajan P et al. Role of dietary phenols in mitigating microglia mediated neuroinflammation. Neuromolecular Med 2016 Sep.
Zaky A. Et al. A combination of resveratrol and curcumin is effective against Aluminum Chloride induced neuroinflammation in rats. J. Alzheimer’s Dis. 2017 Feb 7.
62
References for combination of
ingredients in CytoQuel®
Resveratrol, curcumin, and tea extract(EGCG)
Dominiak K. Et al. Critical need for clinical trials: an example of a pilot human intervention trial of a mixture of natural agents protecting lymphocytes against TNF-alpha induced activation of NF-kB. Pharm Res. 2010 June;27(6)
Moline S. Et al. Polyphenols in dementia. From molecular basis to clinical trials. Life Sci. 2016 Sep 15;161:69-77.
Niedzwiecki R. Et al. Anti-cancer efficacy of polyphenols and their combinations. Nutrients. 2016 Sep 9;8(9).
Scapaggnini G. et al. Modulation of Nrf2/ARE pathways by food polyphenols: A nutritional neuroprotective strategy for cognitive and neurodegenerative disorders. Mol Neurobiol. 2011. 44:192-201.
Resveratrol, Curcumin, and EGCG and Tocotrienols
Dandawak PR. Et al. Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. Semin Cancer biol. 2016 Oct;40-41:192-208.
Subramaniam D. Et al. Targeting cancer stem cells for chemoprevention of pancreatic cancer. Curr Med Chem. 2017 Jan 26.
63
References for Probiotics:
CoreBiotic™
Bonomo R. Et al. Secretory immunity in the local digestive functions. Use of spores of B. subtilis
in some forms of disease with IgA deficiency and hypogammaglobulinemia. Chemioter
Antimicrob. 1980;3:237–240.
Ciprandi G. Et al. In vitro effects of Bacillus subtilis on the immune response. Chemioterapia.
1986;5:404–407.
Hun L. Et al. Bacillus coagulans significantly improved abdominal pain and bloating in
patients with IBS. Postgrad Med. 2009. 121:119-124.
Hyronimus B. Et al. Acid and bile tolerance of spore-forming lactic acid bacteria. In J Food
Microbiol. 2000. PMID:11078170.
Labellearte G. Et al. Tolerance and Efficacy of the Probiotic DE-111™ Delivered in Capsule
Form. Department of Biology, University of Wisconsin- La Crosse.
Majeed M. Et al. Bacillus coagulans MTCC 5856 supplementation in the management of
diarrhea predominant Irritable Bowel Syndrome: a double blind randomized placebo
controlled pilot clinical study. Nutr J. 2016 Feb 27;15:21.
Majeed M. Et al. Double-Blind, Placebo-Controlled, Parallel Study Evaluating the Safety of
Bacillus coagulans MTCC 5856 in Healthy Individuals. J Clin Toxicol 2016.
64
References for Probiotics:
CoreBiotic™
Thomas CM Et al. Probiotics-Host Communication: Modulation of Signaling Pathways in the
Intestine. Gut Microbes 1.3 (2010): 148–163. PMC. Web. 24 Feb. 2015.
Sudha RM. Et al. Effect of supplementation of Bacillus coagulans Unique IS-2(ATCC pat-11748)
on hypercholesterolemic subjects: a clinical study. Inter. J. Probiotics Prebiotics 2011. 6(2):89-
94
Sudha RM. Et al. Clinical study of Bacillus coagulans Unique IS-2 (ATCC PTA-11748) in the
treatment of patients with bacterial vaginosis. Indian J. Microbiol. 2012. 52(3):396-399.
65
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