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  • Epitaph: Dipak K. Das, PhD, Renowned Red Wine Pill Researcher

    September 25, 2013: by Bill Sardi

    The poverty in India has led to the common practice that Hippocrates embraced: “Let food be thy medicine and medicine thy food.” Many East Indian medical researchers fondly embrace this idea as it is a customary part of the gastronomy of this still impoverished country.

    Having visited there twice to attend recent scientific research symposiums, first in Chennai (the old Madras) and then Kolkata (the old Calcutta), it is clearly evident that spices added to many East Indian dishes serve as medicine. Many households there cannot afford western medicines. Aspirin, as cheap as it may seem, is not popular there. The herb holy basil serves as the aspirin of India.

    Then it came as no surprise, over a period of 27 years of research, that Dipak K. Das, born in Kolkata, West Bengal, India, graduate of Jadavapur University (1971) who earned his PhD at New York University (1982), began to delve into the use of natural molecules in his life-long study of cardioprotection, which is defined as “all mechanisms and means that contribute to the preservation of the heart by reducing or even preventing myocardial (muscle) damage.”

    Most of Dr. Das’ research work originated from the Cardiovascular Research Center at the University of Connecticut. Dr. Das would go on to write over 500 research reports including 117 on the red wine molecule resveratrol, which represented a rather late flurry of activity in his research career.

    He also served as editor-in-chief of the journal Antioxidants & Redox Signaling as well as co-editor of other journals in cardiology and even reviewer for National Institutes of Health research grants.

    Dr. Das demonstrates most damage occurs after a heart attack

    In the early stages of his laboratory research (all of his work was performed on animals) he carefully documented the role of both endogenous (internally produced) antioxidants such as catalase, glutathione and superoxide dismutase and exogenous (dietary acquired) antioxidants during a heart attack.

    He demonstrated that most of the damage to heart muscle after a heart attack (blockage of delivery of oxygenated blood via coronary arteries) did not take place when the heart attack occurred but later when a clot would dissolve or be mechanically removed, thus reinstating oxygen delivery to heart muscle. Oxygen, as essential as it is for life, is also the source for tissue-damaging unstable electrons that are known as oxygen free radicals.

    Advocated antioxidants

    While Dr. Das suggested antioxidants be employed prior to reinstatement of blood circulation to the heart (called reperfusion) in 1986, this idea has yet to be put into practice.

    It was in that same year Dr. Das utilized mepacrine, a synthetic substitute for quinine, to protect the heart after a heart attack. This appears to be his first attempt at utilizing molecules to limit heart muscle damage following a heart attack.

    Studies involving natural molecules

    Three years later Dr. Das successfully attempted to employ nicotinic acid (niacin, aka vitamin B3) to limit damage caused by an intentionally induced heart attack in a laboratory animal. It was his first experiment using a natural molecule.

    Then Dr. Das began a long series of studies that showed natural molecules could be used to prevent reperfusion injury to the heart and even protect the heart prior to a heart attack.

    Among the list of natural molecules successfully tested were IP6 rice bran extract, L-arginine, coenzyme Q10, red wine, grape seed, resveratrol (red wine molecule), alcohol, tomato juice, fresh-crushed garlic (via hydrogen sulfide gas), tocotrienols (isoforms of vitamin E from palm oil), carnitine, fresh broccoli, calendula, and raw eggplant.

    Issued early warning over use of anti-inflammatory drugs

    In 2002 warnings were issued over mortal heart attacks associated with the use of non-steroidal anti-inflammatory drugs such as Vioxx. But it was Dipak Das who sounded the alarm in 1990 when he clearly demonstrated that the use of ibuprofen, a similar COX-2 inhibiting anti-inflammatory drug, causes further damage to the already oxygen-starved (ischemic) heart.

    Pre-dated a modern discovery that iron overload increases cardiac risks

    While modern cardiology embraces the cholesterol theory of heart disease, Dr. Das showed that iron overload may be instrumental for the susceptibility of heart muscle to injury. That idea has only been recently re-validated.

    Red wine molecules: the dose determines the effect

    Before he would retire from his life-long work, he wanted to see theoretical research in the animal laboratory become applied research in the cardiology clinic. He wanted to define the proper doses and available brands of resveratrol pills that met safety and dosage requirements. Early in the new century he had already demonstrated how resveratrol protected animal hearts prior to an intentionally induced heart attack.

    Dr. Das explained that resveratrol worked within a certain dosage range. It had already been established by other researchers that 3-5 glasses of red wine providing 180-300 milligrams of red wine solids (known as polyphenols) optimally reduced the risk for coronary artery disease mortality. Dr. Das found a similar dosage range, 175-350 mg of resveratrol, reduced the area of damage in rodent heart muscle during an induced heart attack.

    In a subsequent experiment, an even lower dose of resveratrol (100 mg-Longevinex®) when combined with other synergistic natural molecules, was found by Dr. Das to further reduce damage to heart over what plain resveratrol accomplished.

    This dosage discovery was delivered at a time when a well-known Harvard researcher was saying it would take 1000 milligrams of resveratrol, about what would be found in 1000 glasses of red wine, to replicate the same effects achieved in the animal lab. But mega-doses produced negative or null effects. The Harvard professor may have been intentionally leading consumers away from taking available resveratrol pills to wait for a drug version of the molecule that was advertised as being 1000-times stronger. That drug never materialized.

    Hormesis and biology’s first demonstrated L-shaped risk curve

    This protective effect from a mild dose of resveratrol is known as hormesis, and Dr. Das demonstrated this effect vividly in his laboratory investigations. (Hormesis is defined a mild biological stressor that triggers internal antioxidants.) Dr. Das showed that higher doses of resveratrol actually had a detrimental effect. He emphasized, “the most important point about resveratrol is… a very low concentration.”

    With hormesis in mind, Dr. Das conducted an unprecedented experiment where a commercially available resveratrol pill (Longevinex®) was found to reduce the risk for heart damage at a 100 mg dose but as the dose increased to 2800 mg, unlike with plain resveratrol, there was no deleterious effect (2800 mg of resveratrol “kills” the rodent heart).

    Hormesis is graphically shown to produce a U-shaped risk curve, with risks for mortality declining on a graph and then rising with increased dose. But Longevinex® remained effective and never exhibited any cytotoxicity (cell killing effect) even at high doses. It was the first L-shaped risk curve ever exhibited in biology. Just another in the long list of unparalleled experiments he conducted.

    Dr. Das explains a puzzling phenomenon

    Dr. Das went on to explain a rather puzzling phenomenon involving resveratrol. Whereas in the back of the eyes resveratrol inhibits abnormal new blood vessel formation (angiogenesis) that can invade and destroy the visual center of the eye (the macula), in the heart resveratrol surprisingly did the opposite – promoted new blood vessels so as to create collateral circulation and to hasten healing of damaged heart muscle following a heart attack. Dr. Das showed that in oxygen-starved heart muscle, resveratrol triggered angiogenesis (new blood vessels) via a growth factor known as vascular endothelial growth factor (VEGF).

    Dr. Das always took the time to stay up to date with recent advancements in biomedical research. He was particularly interested in microRNAs (miRNAs) as it is possible for one miRNA to target a messenger RNA (mRNA) in the heart and a different mRNA in another site, such as the eye. (MicroRNA is a way of measuring the biological activation of genes). He believed that miRNAs may be a key to understanding this puzzling phenomenon.

    Making stem cell therapy work

    Once heart muscle cells are damaged, they are repaired ever so slowly. New heart muscle cells take a prolonged time (maybe years) to regenerate. So once damaged, a scarred heart remains that is less than a full-functioning heart.

    In recent times investigators have injected stem cells into damaged animal hearts to determine if they would differentiate into new cardiomyocytes (heart muscle cells). But the experiments were largely disappointing. Injected stem cells didn’t survive.

    But Dr. Das pre-instilled resveratrol into animals prior to an experimentally induced heart attack and then injected stem cells. When this was done, stem cells survived and produced daughter cells. This remarkable discovery has obvious application for all stem cell therapies.

    Molecular preconditioning

    Dr. Das was trying to convince cardiologists of a practice known as cardiac preconditioning. Cardiac surgeons sometimes practice this by applying prolonged pressure to an appendage (arm or leg) away from the heart with a blood pressure cuff, which in turn induces oxygen-deprivation in that tissue which then triggers activation of protective internal antioxidants.

    This is known as remote ischemic cardiac preconditioning and is practiced in the hospital in an effort to reduce cardiac arrest on the operating table. Dr. Das successfully demonstrated cardiac preconditioning could be accomplished molecularly, without mechanical oxygen deprivation. He noted in 2008 that the idea of preconditioning had been around for 20 years and is known “as the most powerful mechanism known to date for limiting infarct (heart attack) size (area of damaged heart muscle).” His goal was to precondition at-risk subjects so they would never experience a mortal heart attack. Resveratrol was shown by Dr. Das to be an effective preconditioning agent.

    A preventive cardiologist in Ft. Lee, New Jersey, Nate Lebowitz MD, attests to the successful use of resveratrol (Longevinex®) on a fragile 90-year old patient who had a totally blocked coronary artery but experienced no damage to that area of his heart. The patient was not healthy enough to undergo invasive treatment. This case was well documented. Resveratrol theoretically reduced oxygen demand in the heart. The patient fully recovered without any heart muscle damage and was demonstrated to be an effective preconditioning agent.

    Dr. Das vindicated over allegations of scientific fraud

    Just freshly retired, charges of scientific fraud were lodged by his university. Western blot tests, a measure of proteins made by genes, were said to be fabricated.

    Dr. Das was pilloried in the court of public opinion. Hundreds of news agencies declared his guilt before he had even stood trial. At trial, Dr. Das was never given an opportunity to defend himself.

    His university withdraw a website that made many unsubstantiated allegations against him. Kindred resveratrol researchers noted that Dr. Das’ published papers had been validated by many other independent researchers.

    The tell-tale experiment that would either validate or nullify Dr. Das’ discoveries was conducted by National Institute of Health (NIH) researchers. Dr. Das had reported on gene activity in resveratrol-treated hearts as graphically displayed by western blot images (alleged to be altered).

    NIH investigators, using the same tissue samples from animal hearts that Dr. Das used, performed a more sophisticated microRNA analysis.

    MicroRNA results paralleled the Western Blot testing performed in Dr. Das’ laboratory. But the charges were never dropped and Dr. Das faced expulsion from his university position.

    In the wake of this decision, many of his research papers were retracted. Dr. Das later filed a $35 million defamation case against his university. That case is still pending. Offers to fund the case against the university have been received to clear his name of unjust charges.

    It is clear that millions of lives have been lost with failure to put into practice many of the discoveries made by Dipak K. Das. Ranging from mistaken use of anti-inflammatory drugs, failure to employ antioxidants when restoring circulation to the heart following a heart attack, to failed survival of instilled stem cells because they were not accompanied by antioxidant pre-treatment, modern medicine now attempts to erase much of this noble researcher’s science, falsely claiming it was fabricated. Few if any cardiologists prescribe resveratrol pills even though “cardiac preconditioning” is the most advantageous approach to saving lives.

    Dr. Dipak Kumar Das, 67, died at his home in West Hartford, Connecticut on Sept. 19, 2013. He is survived by his wife, son and daughter and many brothers and sisters. – By Bill Sardi, Resveratrol Partners LLC

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