protandim: pubmed.gov clinical studies and more
TRANSCRIPT
PROTANDIM, NRF2 ACTIVATOR Peer-‐Reviewed Studies, WWW.PUBMED.GOV
Updated January 22, 2015 1. UNIVERSITY OF COLORADO – OXIDATIVE STRESS
The induction of human superoxide dismutase and catalase in vivo: a fundamentally new approach to antioxidant therapy, Free Radical Biology & Medicine Jan. 2006 http://www.ncbi.nlm.nih.gov/pubmed/16413416
Protandim® is not an antioxidant supplement. It is an Nrf2 Activator. This DNA pathway up and down regulates 500 of the 25,000 genes in our body. These genes are called the survival genes. After 120 days, Superoxide Dismutase (SOD) increased by 30 % (+ / -‐ 10%); Catalase increased 54% (+/ -‐ 15%). These indirect antioxidant enzymes neutralize 1,000,000 free radicals per second every second. Oxidative Stress levels are subsequently reduced in every mammal by an average of 40% in 30 days and up to 70% in 120 days -‐ 100% of the time. Oxidative Stress is related to over 250 age-‐related diseases. The study indicated no evidence of toxicity = Protandim is a safe nutraceutical supplement.
2. LOUISIANA STATE UNIVERSITY – SKIN CANCER Protandim, a fundamentally new antioxidant approach in chemoprevention using mouse two-‐stage skin carcinogenesis as a mode, PLoS One, April 2009 http://www.ncbi.nlm.nih.gov/pubmed/19384424
• The group without Protandim® all developed Cancer. • In the group that received Protandim®:
o 33% developed NO Cancer at all o The remaining developed 40% Less aggressive Cancer with fewer, smaller tumors
3. UNIVERSTIY OF COLORADO -‐ GLUTATHIONE Synergistic induction of heme oxygenase-‐1 by the components of the antioxidant supplement Protandim, Free Radical Biology & Medicine Feb. 2009 http://www.ncbi.nlm.nih.gov/pubmed/19056485
Protandim®, up regulates the enzyme Glutathione by 300% in 30 days. Glutathione is the Master Antioxidant in our bodies. It is a powerful Anti-‐inflammatory agent that crosses the brain barrier & gut barrier (very few things in our bodies can do this). It also detoxifies our liver & kidneys. This study explored whether components of Protandim acted in a synergistic manner in certain cells, specifically if it would induce heme oxygenase. When each component was tested alone, only curcumin showed minimal induction. Together, all five major ingredients in Protandim®,’s patented formula, produced a strong, synergistic induction MUCH greater than the sum of its parts.
4. VIRGINIA COMMONWEALTH UNIVERSITY Chronic Pulmonary Artery Pressure Elevation Is Insufficient to Explain Right Heart Failure http://www.ncbi.nlm.nih.gov/pubmed/19884466, Circulation, Nov 2009
This study used a lab model of pulmonary hypertension in rats to explore factors contributing to heart failure in animals. Pulmonary hypertension was induced in rats through a drug and by creating an oxygen-‐poor environment. • The animals pre-‐treated with Protandim® experienced strong cardio-‐protective effects. • Protandim® protected the animals’ hearts by increasing the expression of protective
genes and preventing the formation of scar tissue. • Protandim® preserved heart functions and demonstrated strong cardio-‐protective
effects in an animal model of lung disease. • Osteopontins levels reduced by more than 50%; heart output preserved and cardiac
fibrosis (Harding of the Arteries) was prevented in animals. “This study showed that induction of Nrf2 by Protandim® prevents cardiac oxidative stress, preserves HO-‐1 and VEGF expression and myocardial capillary density, and prevents RV failure without modifying lung angioproliferation. The restoration of Nrf2 and HO-‐1 signaling can prevent maladaptive RV remodeling and preserve heart (RV) function.”
5. HARVARD UNIVERSITY – MUSCULAR DYSTROPHY
The Dietary Supplement Protandim Decreases Plasma Osteopontin and Improves Markers of Oxidative Stress in Muscular Dystrophy Mdx Mice, Journal of Dietary Supplements, June 2010 http://www.ncbi.nlm.nih.gov/pubmed/20740052 Protandim® IMPROVES markers of Oxidative Stress and Fibrosis in muscular dystrophy mice.
Oxidative damage is thought to be a pertinent factor in the development of Duchenne Muscular Dystrophy (DMD), the most common and lethal neuromuscular disorder in children. Researchers used surrogate markers and functional measurers in a dystrophin-‐deficient mouse model of DMD to determine whether Protandim provides any benefit. After six months on Protandim®, researchers saw a 48 % average decrease in plasma TBARS (oxidative stress) and a 57 % decrease in plasma osteopontin as well as a 35 % increase in beneficial protective plasma PON1 activity. • Osteopontin (OPN) is a pleiotropic protein with important roles in inflammation and
immunity that has been suggested as a candidate biomarker for disease activity in multiple sclerosis (MS)
• PON1 Paraoxonase: An enzyme associated with high-‐density lipoprotein (HDL) that is believed to protect against the oxidation of low-‐density lipoprotein (LDL) and hence to affect the risk of coronary artery disease
6. LOUISANA STATE UNIVERSITY – TUMOR SUPPRESSION IN SKIN CANCER
The chemopreventive effects of Protandim: modulation of p53 mitochondrial translocation and apoptosis during skin carcinogenesis, PLoS One, July 2010 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011902
Chemopreventative Effects of Protandim® Examined Further in New Peer-‐Reviewed Study; Protandim's ability to modulate relationship between superoxide dismutase and tumor suppressor p53 believed responsible for reduction of skin cancers in mice.
“MnSOD is a highly inducible protein, and when induced by dietary compounds such as Protandim®, is effective in the suppression of tumor promotion. The results from this study further confirmed and extended our previous findings that Protandim® modulates tumorigenesis via the induction of endogenous antioxidant enzymes. In addition, Protandim® utilizes multiple mechanisms to modulate cell proliferation and apoptosis in vivo and in vitro which both contribute to tumorigenesis. Therefore, these results further demonstrate the effectiveness of multi-‐modal antioxidant base therapies in chemoprevention.” (Excerpt from study)
The induction of MnSOD (Manganese Superoxide Dismutase) is gaining interest as an effective novel mechanism of chemoprevention, being that it is the ONLY antioxidant enzyme that when over expressed suppresses tumor formation. MnSOD also has the ability to modulate multiple pathways contributing to skin carcinogenesis.
7. OHIO STATE UNIVERSITY – CORONARY BYPASS GRAFTS
Protandim attenuates intimal hyperplasia in human saphenous veins cultured ex vivo via a catalase-‐dependent pathway, Free Radical Biology and Medicine, March 2011 http://www.ncbi.nlm.nih.gov/pubmed/21167278
This study examined the biochemical mechanisms that underlie the ability of Protandim® to suppress intimal hyperplasia-‐over-‐proliferation of cells that line the vessel wall, a common adverse event that limits the effectiveness of vascular surgery. Treatment of human saphenous veins with Protandim® blocked intimal hyperplasia and reduced cellular proliferation to that of freshly isolated human saphenous veins. Protandim® prevents the proliferation of cells that can cause re-‐blockage of vessels following coronary artery bypass surgery, stenting, and carotid endarterectomy.
8. LOUISIANA STATE UNIVERSITY -‐ SKIN CANCER & MnSOD The Role of Manganese Superoxide Dismutase in Skin Cancer, Enzyme Research, March 23, 2011 http://www.ncbi.nlm.nih.gov/pubmed/21603266
This study used a two-‐part model to test the effectiveness of Protandim® in chemoprevention. In one approach, researchers applied an SOD mimetic topically to mouse skin. In another approach, Protandim® decreased tumor incidence and multiplicity by 33% and 57 % respectively. “Protandim® may be a novel approach to chemoprevention.”
9. UNIVERSITY OF COLORADO – PIVOTAL NRF2 ACTIVATION AND GENE EXPRESSION STUDY Oxidative stress in health and disease: The therapeutic potential of Nrf2 activation, Molecular Aspects of Medicine, August 2011 http://www.ncbi.nlm.nih.gov/pubmed/22020111
**A MUST read for healthcare professionals**
“Nrf2 is referred to as the "master regulator" of the antioxidant response, modulating the expression of hundreds of genes, including not only the familiar antioxidant enzymes, but large numbers of genes that control seemingly disparate processes such as immune and inflammatory responses, tissue remodeling and fibrosis, carcinogenesis and metastasis, and even cognitive dysfunction and addictive behavior. Thus, the dysregulation of Nrf2-‐regulated genes provides a logical explanation for the connections, both direct and indirect, between observable oxidative stress and perhaps 200 human diseases involving these various physiological processes, each reflecting a network involving many gene products.” (Excerpt from Abstract)
This study involved using a Bioassay of the AREc32 cell line to which scientists added solutions containing either Protandim® , sulforaphane, bardoxolone methyl, or dimethyl fumarate. Each of which are known Nrf2 activators. The test was to determine the extent of each item’s ability to activate the Nrf2 pathway leading to gene expression within the cells. The tests were conducted three times. RESULTS:
• “Luciferase activity is increased up to 100-‐fold by Protandim® at 30 lg/ml, the most
potent Nrf2 activator that we have observed.” (p 237) • “As seen here, the two important parameters Cmax and FImax are easily observed. The
greatest FImax was observed with Protandim at 135-‐fold” (p 239) • “Among the 10 genes most highly upregulated by Protandim® are a number of notables
that encode antioxidant and anti-‐inflammatory proteins.” (p 240)
• “Pathway analysis of results shows significant modulation by Protandim® of pathways involving not only antioxidant enzymes, but of those related to colon cancer, cardiovascular disease, and Alzheimer disease.”
• Of the 66 Protandim-‐regulated genes that are associated with Alzheimer disease, only five (SOD1, NQO1, HMOX1, GLRX, and TXN) appear to be in the antioxidant family. Protandim® upregulated ALL five of them… (p 243)
In addition to the discussion of the therapeutic potential of Nrf2 activation for cardiovascular disease, colon cancer, and Alzheimer’s, the study discusses the therapeutic potential as it relates to other diseases such as renal failure, multiple sclerosis, type II diabetes, etc. The study also includes a table indicating the specific genes and by how much Protandim® up or down regulates each gene. Dr. Joe McCord Overview of Nrf2 Study-‐https://www.youtube.com/watch?v=wzZKCyyXBME
10. UNIVERSITY OF COLORADO, SCHOOL OF MEDICINE – ALCOHOL ABUSE AND LUNG INJURY Protandim does not influence alveolar epithelial permeability or intrapulmonary oxidative stress in human subjects with alcohol use disorders, American Journal of Physiology: Lung Cellular and Molecular Physiology, April 2012 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3330762/
“Alcohol use disorders (AUDs), including alcohol abuse and dependence, have been linked to the development of acute lung injury (ALI). Prior clinical investigations suggested an association between AUDs and abnormal alveolar epithelial permeability mediated through pulmonary oxidative stress that may partially explain this relationship. We sought to determine if correcting pulmonary oxidative stress in the setting of AUDs would normalize alveolar epithelial permeability in a double-‐blinded, randomized, placebo-‐controlled trial of Protandim, a nutraceutical reported to enhance antioxidant activity. We randomized 30 otherwise healthy AUD subjects to receive directly observed inpatient oral therapy with either Protandim (1,350 mg/day) or placebo. Subjects underwent bronchoalveolar lavage (BAL) and blood sampling before study drug administration and after 7 days of therapy……These results suggest that Protandim for 7 days in individuals with AUDs who are newly abstinent does not alter alveolar epithelial permeability. However, our work demonstrates the feasibility of safely conducting clinical trials that include serial bronchoscopies in a vulnerable population at risk for acute lung injury.”(Abstract)
11. COLORADO STATE UNIVERSITY -‐ NRF2 AND CORONARY ARTERY PROTECTION Phytochemical Activation of Nrf2 Protects Human Coronary Artery Endothelial Cells against an Oxidative Challenge, Oxidative Medicine and Cellular Longevity, March 2012
http://www.ncbi.nlm.nih.gov/pubmed/22685617
Activation of NF-‐E2-‐related factor 2 (Nrf2) is a potential therapeutic intervention against endothelial cell oxidative stress and associated vascular disease. The study was done to determine if treatment with Protandim® would induce Nrf2 nuclear localization and phase II antioxidant enzyme protein in human coronary artery endothelial cells (HCAECs), protecting against an oxidant challenge in an Nrf2-‐ dependent manner.
RESULTS:
• Protandim® treatment induced Nrf2 nuclear localization, and HO-‐1 (778% of control ± 82.25 P < 0.01), SOD1 (125.9% of control ± 6.05 P < 0.01), NQO1 (126% of control ± 6.5 P < 0.01), and GR (119.5% of control ± 7.00 P < 0.05) protein expression in HCAEC (human artery cells).
• Protandim® induces Nrf2 nuclear localization and antioxidant enzyme expression. Protection of Human Coronary Artery Endothelial Cells HCAEC from an oxidative challenge is Nrf2 dependent.
12. COLORADO STATE UNIVERSITY – NRF2 AND CARDIOMYOCYTE PROTECTION Upregulation of phase II enzymes through phytochemical activation of Nrf2 protects cardiomyocytes against oxidant stress, Free Radical Biology and Medicine, March 2013 http://www.ncbi.nlm.nih.gov/pubmed/23201694
Oxidative stress has been linked to cardiovascular disease. The purpose of the experiments in this study was to determine if treatment of cardiomyocytes with Protandim® would activates Nrf2, induce phase II detoxification enzymes, and protect cardiomyocytes from oxidant-‐induced apoptosis in a Nrf2-‐dependent manner. **They wanted to know if Protandim would protect heart cells from oxidative damage.
• The result – “phytochemical treatment [with Protandim® ] was found to be a more robust activator of Nrf2 than oxidant treatment, supporting the use of the phytochemicals as a potential treatment to increase antioxidant defenses and protect heart cells against an oxidative challenge.
13. UNIVERSITY OF COLORADO -‐ ACUTE MOUNTAIN SICKNESS AND NRF2 ACTIVATION Nrf2 activation: A potential strategy for the prevention of acute mountain sickness, Free Radical Biology and Medicine, Oct. 2013 http://www.ncbi.nlm.nih.gov/pubmed/23722164
“Reactive oxygen species (ROS) formed during acute high altitude exposure contribute to cerebral vascular leak and development of acute mountain sickness (AMS). Nuclear factor (erythroid-‐derived 2)-‐related factor 2 (Nrf2) is a transcription factor that regulates expression of greater than 90% of antioxidant genes, but prophylactic treatment with Nrf2 activators has not yet been tested as an AMS therapy. We hypothesized that prophylactic activation of the antioxidant genome with Nrf2 activators would attenuate high-‐altitude-‐induced ROS formation and cerebral vascular leak and that some drugs currently used to treat AMS symptoms have an additional trait of Nrf2 activation. …….Of nine drugs tested, with the exception of dexamethasone, only drugs that showed the ability to activate Nrf2 (Protandim, methazolamide, nifedipine, amlodipine, ambrisentan, and sitaxentan) decreased high-‐altitude-‐induced cerebral vascular leak in vivo.” (Excerpt from Abstract)
BIOGEN IDEC – NRF2 ACTIVATORS BG-‐12 (TECFIDERA) AND PROTANDIM Nrf2 activators: a novel strategy to promote oligodendrocyte survival in multiple sclerosis?, October 21, 2011 J. Lim, S. van der Pol, J. Drexhage, E. de Vries, J. van Horssen (Amsterdam, NL) Objectives: To investigate the potential of different Nrf2 activators to boost antioxidant enzyme expression in oligodendrocytes and protect them from reactive oxygen species (ROS)-‐mediated cell death. Background: Oligodendrocyte damage and loss are key features of Multiple Sclerosis (MS) pathology and oligodendrocytes are particularly vulnerable to ROS-‐induced oxidative damage and cell death. Hence, a potential therapeutic strategy to protect these cells from ROS-‐mediated damage is urgently needed. To date, several compounds, including fumurate derivative BG-‐12, tert-‐Butylhydroquinone (tBHQ), sulforaphane (SFN) and protandim have potential anti-‐inflammatory and neuroprotective properties. These compounds are thought to exert their protective function via activation of the nuclear-‐factor-‐E2-‐related factor-‐2 (Nrf2) transcriptional pathway, which is involved in the production of antioxidant enzymes necessary for oxidative stress defense. We postulate that distinct Nrf2 activators boost antioxidant enzyme production in oligodendrocytes and limit ROS-‐mediated oligodendrocyte cell death. Methods: Primary rat oligodendrocytes and rat and human oligodendrocyte cell lines were treated with different concentrations of BG-‐12, tBHQ, SFN and protandim. Next, we analyzed the expression of Nrf2-‐mediated antioxidant enzymes by PCR and Western blot techniques. To study the beneficial effects of the different Nrf2 activators, we first incubated the oligodendrocytes with Nrf2 activators and subsequently exposed them to various concentrations of hydrogen peroxide and measured oligodendrocyte cell survival. Results: 1. BG-‐12, tBHQ, SFN and Protandim are well-‐tolerated and strongly induce Nrf2-‐driven antioxidant enzyme production in oligodendrocytes, with protandim showing the most potent induction. 2. Nrf2 activators are able to protect oligodendrocytes against ROS-‐induced cytotoxicity. Conclusions: Our findings indicate that several Nrf2 activators are able to significantly increase antioxidant enzyme production in oligodendrocytes. Interestingly, Protandim, a dietary supplement consisting of herbal ingredients, was the most potent inducer and therefore may be the most suited as a therapeutic strategy. Importantly, Nrf2-‐mediated antioxidant enzyme expression in oligodendrocytes resulted in enhanced oligodendrocyte survival during an oxidative attack. Dr. J. van Horssen received research grants from BiogenIdec
MAYO CLINIC – PROTANDIM APPROACH TO TREATING OVARIAN CANCER Translational Studies of Protandim(RTM) as a Candidate Nutraceutical Approach to Treating Ovarian Cancer by Prasongsook, Naiyarat, M.S., COLLEGE OF MEDICINE – MAYO CLINIC, 2014, 98 pages; 1555561 Abstract Background: Nutraceutical approaches are increasing in cancer patients. We encountered a recurrent ovarian cancer patient who incurred durable tumorregression and decreasing CA-‐125 with initiation of the nutraceutical Protandim, a combination of five phytochemical extracts (ashwagandha,bacopa, green tea, milk thistle, turmeric). Preclinical studies were undertaken to investigate Protandim and its constituent anticancer effects and underlying mechanism(s). Methods: In vitro ovarian cancer models were used to assess Protandim effects. Colony forming assays, Hoechst nuclear/Trypan exclusion staining, immunoblotting, and flow cytometric methods were used to assess cytotoxic and to identify mechanism (s) of action. Combined effects of Protandim components were assessed by the methods of Chou and Talalay; ex vivo myeloma patient model was used to assess cancer selectivity. In vivo studies assessed tolerability and toxicity effect of Protandim. Results: Anticancer effects of Protandim demonstrated induction of necrotic-‐morphological cell death. Ex vivo assays showed Protandim to selectively kill freshly collected patient myeloma cells, relatively sparing paired patient normal bone marrow cells. Immunoblotting and flow cytometric experiments indicated that Protandim induced cellular reactive oxygen species (ROS) level. Similar cytotoxic effects in wild-‐type and Rho-‐MOLT4 cells indicated non-‐mitochondrial mediated ROSinduction. Assessment of the combined effects of Protandim constituents showed antagonism or additivity. In vivo studies showed no Protandim toxicities in mice. Conclusions: Protandim has promising activity in ovarian cancer models, associated with induction of non-‐mitochondrial mediated-‐ ROS and necrosis. Protandim is well-‐tolerated in mice, and has anti-‐cancer selectivity. Further investigations to more specifically assess molecular mechanism and in vivo efficacy are presently underway.
1ST ANNUAL CONFERENCE: THE KEAP1/NRF2 PATHWAY IN HEALTH AND DISEASE,
CAMBRIDGE, UK JANUARY 2015
22nd Annual World Congress on Anti-‐Aging Medicine
December 11-‐13, 2014 Las Vegas, NV
This year’s conference highlights include:
• Metabolic Syndrome • Hormonal Health • Diagnostic Testing and Interpretations • Stress and the Immune Response • Function Neurology • The Science of Stem Cells • PRP-‐new research and applications • Clinical and Aesthetic Advancements • Skin technology, skin tightening therapies and procedures • Nutrient Strategies • Endocrine System • Lifestyle Factors • Chronic Stress, Oxidative Stress • Lifestyle effects on sex and stress hormones
PRODUCT SHOWCASE In addition to the education offered at this event, A4M’s product showcase features the most cutting edge products and services designed to keep the frontline physician improving their patient care and increasing their practice revenue. The product showcase will take place during the breaks of the CME presentations and will include demonstrations from diagnostic labs, weight loss management firms, clinics, nutraceutical companies, and compounding pharmacies, among others.
Topic: Protandim and Nrf2 Triggering -‐ a fundamentally different approach to cellular protection Presented by: Shawn Talbott, PhD Sponsored by: LifeVantage
