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).

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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

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DAMP’s:Damage-Associated Molecular Patterns

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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.

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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

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Gut-brain-microbiome Influences

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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.

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Model of

development

of Parkinson’s

disease

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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

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Increasedoxidative

stress

Then:

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Increased

need for

glutathione

Oxidation-Reduction cycle

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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

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Detoxification Pathways 18

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Role in development of cancer

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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

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Neurodegeneration22

Peacock BN, Gherezghiher TB, Hilario JD, Kellermann GH. New insights into

Lyme disease. Redox Biology. 2015;5:66-70.

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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

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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.

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26

Diabetes

and

Cardiac

Disease

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Support for chronic disease

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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

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Support for mitochondrial

dysfunction

Repair mitochondrial membrane

Phospholipids

30

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Repair mitochondrial membranePhospholipids

Support mitochondrial functionCoQ10/UbiquinolCarnitineNADHAlpha-lipoic acidB vitaminsVitamin E

SUPPORT FOR MITOCHONDRIAL

DYSFUNCTION

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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

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ATP Fuel® Clinical Research Highlights

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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

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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

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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.

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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

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Tri-Fortify™clinical research summary

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Tri-Fortify™ clinical research summary

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Tri-Fortify™ clinical research summary

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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)

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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

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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

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H2 Absorb™for a healthier life

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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

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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

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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

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CytoQuel®Human Clinical Research

The health improvements

included:

Pain reduction

Reduced blood pressure

Improved activities of daily

living and wellness

Reduced serum cytokine

level

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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.

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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

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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*

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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

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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

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Dr. Debby Hamilton, MD, MPH

Researched Nutritionals

dhamilton@researchednutritionals.com

www.researchednutritionals.com

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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)

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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.

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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.

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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.

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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.

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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.

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