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  • Inflammation is a useful natural reaction that the body has in response to injury and certain other conditions. Chronic inflammation, however, can be more destructive than beneficial. Indeed, when we hear the word inflammation, we tend to associate with conditions like arthritis and other more serious issues. Nevertheless, there are many common causes of inflammation that are not associated with disease states. These include eating diets high in certain inflammation-promoting foods (e.g., polyunsaturated fats, simple carbohydrates— especially refined sugars1, common allergens like casein and gluten2), being in colder temperatures3, experiencing menopause (with hormone fluctuations)4, experiencing psychological stress5 and exposure to environmental toxins.6

    Ramifications Of Inflammation
    That being said, there can still be ramifications associated with common, non-disease types of inflammation, even low-grade systemic inflammation. Examples include but are not limited to everyday aches and pains, alterations in digestion and absorption7, behavioral changes8, minor disruption in microcirculation and blood flow over the course of the aging process9, and a minor negative impact on immune health.10 In addition, obesity is associated with inflammation.

    Specifically, overweight and obese children and adults have elevated serum levels of C-Reactive Protein and other known markers of inflammation. This is not to say that inflammation causes obesity, but rather the reverse: obesity causes low-grade systemic inflammation. While obesity is commonly thought of as adipose tissue, it is also associated with fat storage in other tissues—including the liver and skeletal muscle. This may lead to insulin resistance and may also stimulate inflammation. Obesity also changes the type of chemicals that our fat cells secrete, which may include the secretion of several pro-inflammatory mediators.11 Since chronic inflammation is closely associated with cardiovascular risk factors, including cardiovascular and non-cardiovascular causes of death, this may help explain the increased risk of diabetes, heart disease, and many other chronic diseases in the obese.12

    Anti-Inflammatory Nutraceuticals
    One of the strategies to help decrease inflammation is the use of anti-inflammatory nutraceuticals—and there are many from which to choose. Following is a discussion of some of my favorite anti-inflammatory nutraceuticals, which includes resveratrol, grape seed extract, calcium fructoborate, turmeric (curcumin) and ginger.

    Resveratrol (RSV), a natural substance found in grapes, peanuts and Japanese Knotweed (Polygonum cuspidatum), made a big splash when it was introduced into the dietary supplement market because it was considered to contribute to the “French paradox,” the unexpectedly low rate of death from cardiovascular disease in the Mediterranean population, despite a diet that is relatively high in saturated fat. Since then research has demonstrated other benefits for RSV, among them its effectiveness as an anti-inflammatory agent. This was seen in a randomized, placebo-controlled study13 investigating the effectiveness of 40 mg RSV or placebo daily (for six weeks) on oxidative and inflammatory stress in normal subjects. The results were that RSV significantly reduced oxidative stress (P < 0.05) and also significantly suppressed levels of several inflammatory markers, including TNF-alpha, IL-6, and C-Reactive Protein (P <). There was no change in these indices in the control group given placebo.

    Grape Seed Extract And Resveratrol
    Grape seed extract contains phenolic compounds known as oligomeric proanthocyanidins (OPC). These OPC have significant antioxidant properties.14 In addition, they also appear to have significant anti-inflammatory properties—at least when combined with RSV. In a triple-blind, randomized, placebo-controlled, one-year follow-up, 3-arm pilot clinical trial15, 75 stable–coronary artery disease (CAD) patients received a combination of grape seed phenolics (i.e. OPC) and RSV, grape seed extract alone, or a placebo. The daily doses of the combination were as follows: 139 mg of grape seed OPC for the first six months, and then doubled for the following six months, which would require about 293 mg (a grape seed extract providing 95 percent OPC, 146.32 mg is required to yield 139 mg OPC); RSV was eight mg and 16 mg for the first six months and the remaining six months, respectively. The daily dose of grape seed OPC alone was 151 mg during six months, and then doubled for the following six months. The results showed that after one year, in contrast to the placebo and grape seed extract only groups, the combination group showed an increase of the antiinflammatory serum adiponectin (9.6 percent, p = 0.01).

    In addition, in the combination group six key inflammation factors were significantly improved (p < 0.05) without any adverse effects.

    Using the same dosage strategy and group types as in the last study, a randomized placebo-controlled, triple-blind, dose–response, 1-year follow-up study16 with three parallel arms was conducted in 35 in hypertensive male patients with type 2 diabetes mellitus (T2DM). Results showed that after 12 months there was a significant reduction in levels of the inflammatory markers ALP (p = 0.02) and IL-6 (p = 0.00) in the combination group. In addition, the production of proinflammatory cytokines was also reduced significantly.

    Calcium Fructoborate
    Calcium fructoborate (CF) is a form of the mineral boron, known for its role in bone health—but it is also good for joints and inflammation. A double-blind, placebo-controlled study17 examined the effect of 108 mg CF twice a day in patients with knee osteoarthritis (OA). Results showed that in the CF group, pain scores at Day seven dropped to 82 percent of the Day one value (from 74.0 to 59.9, p<0.05). By Day 14, the pain score reduced to 71 percent of the baseline (from 74.4 to 52.2, p<0.01). In contrast, there was no significant reduction in pain scores in the placebo group on either Day seven or Day 14. Other measures of pain were also significantly reduced (p< 0.05) on Day seven and Day 14 (p< 0.01). In addition, blood level of C-Reactive Protein were reduced up to 37 percent compared to Day one baseline levels in 79 percent of subjects. Interestingly, the study also showed that blood level of vitamin D was increased more than 19 percent compared to baseline, but not in the placebo group. The CF was well tolerated by all study subjects with no reports of adverse effect.

    Calcium Fructoborate And Resveratrol
    A 60-day, randomized, double-blinded, active-controlled, parallel clinical trial18 was conducted in three groups of subjects to evaluate the effects of oral supplementation with CF (112 mg/day), RSV (20 mg/day), and their combination (RSV – 20 mg/day + CF – 112 mg/day) for 60 days on the clinical and biological statuses of patients with stable angina pectoris. Of the total number of subjects included in study (n = 166), 87 completed the test treatment study period and 29 followed in parallel their usual medical care and treatment. Results showed that there was a significant decrease of high-sensitivity C-Reactive Protein in all groups at the 30-day and 60-day visits. At 60 days, this decrease was greater for CF (39.7 percent), followed by RSV + CF (30.3 percent). Markers for congestive heart failure were significantly lowered by RSV (59.7 percent) and by CF (52.6 percent). However, their combination induced a decrease of 65.5 percent. The improvement in the quality of life was best observed for subjects who received the RSV + CF mixture.

    Turmeric (Curcumin)
    Turmeric, a member of the ginger family, has been used as a traditional remedy in Chinese and Ayurvedic medicine as well as for condiment and flavoring purposes for over 2,000 years, based on records dating back to 600 BCE.19 Its primary active constituent is the flavonoid curcumin (diferuloylmethane), which is responsible for the plant’s yellow color and the compound providing most of its medicinal qualities.20,21 Certainly, research has demonstrated that the curcumin molecules inhibit 5-lipoxygenase (LOX) and cyclooxygenase (COX), resulting in a well-established anti-inflammatory action.22,23,24 This ability to help relieve common, everyday inflammation has been demonstrated in a significant number of published human clinical studies on curcumin.25,26,27,28,29,30,31,32,33,34,35

    Although it’s probably more known for its anti-nausea properties (i.e., treatment of motion sickness and morning sickness), Ginger is also an effective anti-inflammatory herb that has historically been used for arthritis and rheumatism. In a study of patients with rheumatoid arthritis, osteoarthritis and muscular discomfort, the majority experienced (to varying degrees) relief of pain and swelling. None of the patients reported adverse effects during the period of ginger consumption, which ranged from three months to 2.5 years.36

    Another double-blind trial found ginger extract to be more effective than placebo at relieving pain in people with OA of the hip or knee.37 Likewise, in another doubleblind study ginger was significantly more effective than a placebo in pain relief and overall improvement.38 Ginger is considered to exert its anti-inflammatory activity by inhibiting COX-2 and lipoxygenase pathways.39

    Inflammation may be present in disease or non-disease states. In either case, resveratrol, grape seed extract, calcium fructoborate, turmeric (curcumin) and ginger may be helpful in reducing markers of inflammation, reducing pain, and improving other parameters of health.


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    14. Feringa HH, Laskey DA, Dickson JE, Coleman CI. The effect of grape seed extract on cardiovascular risk markers: a meta-analysis of randomized controlled trials. J Am Diet Assoc. 2011 Aug;111(8):1173–81.
    15. Tomé-Carneiro J, Gonzálvez M, Larrosa M, Yáñez-Gascón MJ, García-Almagro FJ, Ruiz-Ros JA, Tomás-Barberán FA, García-Conesa MT, Espín JC. Grape resveratrol increases serum adiponectin and down regulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease. Cardiovasc Drugs Ther. 2013 Feb;27(1):37–48.
    16. Tomé-Carneiro J, Larrosa M, Yáñez-Gascón MJ, Dávalos A, Gil-Zamorano J, Gonzálvez M, García-Almagro FJ, Ruiz Ros JA, Tomás-Barberán FA, Espín JC, García-Conesa MT. One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacol Res. 2013 Jun;72:69–82.
    17. Reyes-Izquierdo T, et al. Short-term Intake of Calcium Fructoborate Improves WOMAC and McGill Scores and Beneficially Modulates Biomarkers Associated with Knee Osteoarthritis: A Pilot Clinical Double-blinded Placebocontrolled Study. Am J Biomed Sci. 2012; doi: 10.5099.
    18. Militaru C, Donoiu I, Craciun A, Scorei ID, Bulearca AM, Scorei RI. Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life. Nutrition. 2013 Jan;29(1):178–83.
    19. Curcuma longa (turmeric). Monograph. Altern Med Rev 2001;6 Suppl:S62–6.
    20. Chattopadhyay I, Biswas K, Bandyopadhyay U, Banerjee RK. Turmeric and curcumin: Biological actions and medicinal applications. Current Science. 2004;87(1):44–53.
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    22. Chandra D, Gupta S. Anti-inflammatory and anti-arthritic activity of volatile oil of Curcuma longa (Haldi). Ind J Med Res 1972; 60:138–42.
    23. Arora R, Basu N, Kapoor V, et al. Anti-inflammatory studies on Curcuma longa (turmeric). Ind J Med Res 1971;59:1289–95.
    24. Mukhopadhyay A, Basu N, Ghatak N, et al. Antiinflammatory and irritant activities of curcumin analogues in rats. Agents Actions 1982; 12:508–15.
    25. Satoskar RR, Shah SJ, Shenoy SG. Evaluation of antiinflammatory property of curcumin (diferuloyl methane) in patients with postoperative inflammation. Int J Clin Pharmacol Ther Toxicol 1986;24:651–54.
    26. Deodhar SD, Sethi R, Srimal RC. Preliminary study on antirheumatic activity of curcumin (diferuloyl methane). Indian J Med Res 1980;71:632–4.
    27. Kulkarni RR, Patki PS, Jog VP, et al. Treatment of osteoarthritis with a herbomineral formulation: a doubleblind, placebo controlled, cross-over study. J Ethnopharmacol 1991;33:91–5.
    28. Lal B, Kapoor AK, Asthana OP, et al. Efficacy of curcumin in the management of chronic anterior uveitis. Phytother Res 1999;13:318–22.
    29. Mombaerts I , Goldschmeding R, Schlingemann RO, Koornneef L. What is orbital pseudotumour? Surv Ophthalmol 1996;41:66–78.
    30. Lal B, Kapoor AK, Agrawal PK, et al. Role of curcumin in idiopathic inflammatory orbital pseudotumours. Phytother Res 2000;14:443–7.
    31. Prucksunand C, Indrasukhsri B, Leethochawalit M, Hungspreugs K. Phase II clinical trial on effect of the long turmeric (Curcuma longa Linn) on healing of peptic ulcer. Southeast Asian J Trop Med Public Health 2001;32:208–15.
    32. Camilleri M. Dyspepsia, irritable bowel syndrome, and constipation: review and what’s new. Rev Gastroenterol Disord 2001;1:2–17.
    33. Barbara G, De Giorgio R, Stanghellini V, et al. A role for inflammation in irritable bowel syndrome? Gut 2002;51:i41–4.
    34. Bundy R, Walker AF, Middleton RW, Booth J. Turmeric extract may improve irritable bowel syndrome symptomology in otherwise healthy adults: a pilot study. J Altern Complement Med 2004;10:1015–8.
    35. Hanai H, Iida T, Takeuchi K, et al. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006;4:1502–6.
    36. Srivastava KC, Mustafa T. Ginger (Zingiber officinale) inrheumatism and musculoskeletal disorders. Med Hypotheses 1992; 39:342–8.
    37. Bliddal H, Rosetzsky A, Schlichting P, et al. A randomized, placebo-controlled crossover study of ginger extracts and buprofen in osteoarthritis. Osteoarthritis Cartilage 2000;8:9–12.
    38. Altman RD, Marcussen KC. Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum 2001; 44:2531– 8.
    39. Srivastava KC, Mustafa T. Ginger (Zingiber officinale) and rheumatic disorders. Medical Hypotheses 1989; 29:25–8.
  • A common nutritional complaint regarding American eating habits is that the culture tends toward a mono-diet, meaning that only a handful of foods account for most of the diet. Favored foods typically include, either directly or in derived and hidden forms, corn, wheat, soy, potatoes, canola oil and a few other items along with foods based on these as feed, such as the meat, fish and fowl raised on them. There are a number of reasons for the narrowness of this range, one of the most powerful being subsidies to agriculture. Staple crops and foods are subsidized and relatively inexpensive whereas fresh fruit and vegetables along with most foods not on the favored lists of subsidies are expensive. One result is what economists term "externalities," in this case costs borne by individuals and society, such as poor health, higher medical and medical insurance costs along with shorter life spans. In contrast to the results of typical American eating habits, experience commonly demonstrates that merely increasing the range of food choices with an emphasis on fresh as opposed to canned, frozen and preserved foods can introduce considerable benefits. Similar benefits sometimes can be achieved through the proper use of dietary supplements with the catch, however, that not all supplements match the purposes for which they are being taken. (Note: some foods do well frozen, such as corn, peas and many fruits, especially berries; canning is more limited, but includes, for example, tomatoes. However, most vegetables need to start off fresh!)

    Foods Rescue the Prostate

    It is not necessary to consume large amounts of exotic nutrients to obtain significant benefits. In 2013 a group of British researchers performed a six month long experiment in which 203 adult males with prostate cancer consumed either a placebo or a simple supplement mixture consisting of powdered pomegranate, turmeric, green tea and broccoli.1 Only the green tea was an extract, and even then providing roughly the same amount of actives as found in a cup or two of brewed green tea. Consumed three times a day, the active arm was comprised of:

    • broccoli powder (Brassica oleracea) 100 mg
    • turmeric powder (Curcuma longa) 100 mg
    • pomegranate whole fruit powder (Punica granatum) 100 mg
    • green tea 5:1 extract (Camellia sinensis) 20 mg, equivalent to 100 mg of crude green tea

    After six months, the researchers found that prostate-specific antigen (PSA) levels, a possible marker for prostate cancer, were 63 percent lower among those taking the supplement than among those taking the placebo. This significant result was achieved with really quite tiny amounts of everyday foods and, except in the case of the green tea, these were not even extracts.

    A number of studies have demonstrated that quite a range of compounds found in everyday foods are protective not just against prostate cancer, but also against many other cancers, as well. As another example, ursolic acid (found in apple peels and rosemary herb) in combination with turmeric’s ingredient curcumin or resveratrol (found in grapes and berries) blocks the uptake of glutamine by cancer cells yet do not interfere with the metabolism of normal cells—glutamine is a nutrient cancer cells need in order to grow.

    Plant Colors, Plant Nutrients and Nutritional Synergy
    red beetsCurrent government health recommendations include five servings per day of fruit and vegetables along with the suggestion that nine servings would be better. Unfortunately, this type of recommendation tends to be a bit misleading in that some fruits and vegetables are vastly more nutritious than others. For instance, cabbages in general are sources of compounds including isothiocyanates and indoles. However, cabbage-family members such as bok choy are comparatively light in nutrition compared with purple cabbage, which is rich in anthocyanidins as well as the expected precursors of sulforaphane. Similarly, leaf lettuces tend to be much more nutrient rich than is head lettuce. Below is a rough overview of some of the phytonutrients matched to associated colors in plants. There is a large degree of overlap and many phytonutrient polyphenols are almost colorless in the amounts found in foods. We tend to not associate black tea and coffee with nutrition, but the former is a source of theaflavin and the latter, if not overly roasted and freshly brewed, is a good source of chlorogenic acids.

    Red—lycopene, associated with tomatoes, pink grapefruit and watermelon; anthocyanidins (cyanidin literally meaning "red color") associated with berries, other highly colored fruit, beets

    Red/Purple—anthocyanidins, resveratrol and related compounds found in berries, other highly colored fruit, beets and eggplant, also found in black and other beans, black rice

    Yellow/Orangealpha- and beta-carotene, beta-cryptoxanthin; sources include carrots, citrus fruit, squashes, sweet potatoes, cantaloupes; hesperidin and diosmin are found in citrus fruit; rutin, related to hesperidin, is found in buckwheat

    Yellow/Green—lutein, zeaxanthin, quercetin, catechin, epicatechins, ellagic acid, isothiocyanates and indoles found in peppers, kale, cabbage, many other green vegetables, green tea; the best single source of highly bioavailable lutein and zeaxanthin is the yolk of eggs from hens allowed to eat grass and insects

    White/Green—allicin and related compounds, rutin in garlic and onions; isothiocyanates and indoles are found in cabbage family members, including cauliflower; many flavonoids; quercetin glycosides, phloretin glycoside (apple skin), chlorogenic acid and epicatechin found in "white" fruits (apples, pears), eggplant, green tea, freshly brewed coffee (chlorgenic acid)

    Various polyphenols and other phytonutrients provide benefits, many of which overlap, but some of which are special to one or another family of compounds. One huge payoff from variety is that there can be unexpected synergisms. This is an issue dealt with in these pages several years ago in the article, "Beyond Synergy—the Entourage Effect in Nutrition and Herbalism." (Total Health, September 2015) It is worth repeating here a key example described in that essay.

    At the 219th American Chemical Society National Meeting held in San Francisco on March 26–30, 2000 researchers associated with the company Polyphenolics presented studies that supported supplementing the diet with special plant-derived nutrients and consuming more whole fruits and vegetables. One of my associates pointed out that antioxidant vitamins are present in the human body at levels typically twenty to several hundred times the level of plant polyphenols. This is one reason that so much less research has focused on the antioxidant vitamins in foods and relatively little research has been done on the antioxidant roles of the other compounds present. By 2000, however, it already was becoming clear that these non-vitamin plant antioxidants have an impact on the antioxidant status of the body that is much beyond their representation in the blood and tissues. For instance, at the conference it was explained that an extract from grape seeds given to human volunteers led to a much greater increase in the antioxidant capacity of the subjects’ blood than was theoretically possible based on the compound alone. This was a finding that called for explanation. A second set of tests helped to clarify the result of the first—the same grape seed extract demonstrated significant synergism when tested in vitro with the antioxidant vitamins C and E, either alone or in combination.

    To establish a quantitative baseline for the antioxidant power of each of the compounds, tests used the standard cupric ion generation of oxidation to look at the impact of combining our grape seed extract (Vixox Gold™) with vitamins C and E to gauge the synergy of the combinations. Vitamin C, vitamin E and grape seed extract were each tested individually to determine their effects at several concentrations. These baselines were added to yield the "Sum of Individual Inhibitions" which then was compared with the "Actual Inhibitions When Tested Together." The Actual Inhibitions minus the Sum of Individual Inhibitions times 100 yielded the percent of Synergism. This series of in vitro tests thus allowed the investigator to elegantly demonstrate the concentrations of maximal synergism amongst the three antioxidants. Strong synergism was shown for Vinox Gold™ plus vitamin C, for Vinox Gold™ plus vitamin E, and, finally, for Vinox Gold™ plus vitamin C and vitamin E.

    Synergisms in the ranges shown here are good examples of why it is that consuming a diet rich in fruit and vegetables is so much more successful in terms of health than is eating a diet based on refined carbohydrates, protein and fats.

    Cautionary Tales Regarding Supplements

    Refining the "big three" macronutrients and then "adding back" nutrients/micronutrients loses the benefits of the plant compounds that otherwise are present in the original sources of carbohydrates and in partially refined oils, such as olive and sesame oils. Supplements are useful, but they do not take the place of fresh food properly prepared in a diet emphasizing adequate variety. Moreover, there are other reasons for being careful about the use of non-food interventions.

    Synergistic Ratios of Antioxidants

    A good example, one that shows the overlap of how we sometimes use over-the-counter drugs and nutrients, is drawn from sports. Almost all of us, whether inclined towards athletics or not, have experience with soreness from exercise beyond our current level of physical preparation. "Weekend warriors" are familiar with this and so are high school, college and professional athletes. To overcome soreness from exertion beyond our capacity, it is common to take pain relievers. Hard physical training even in healthy you individuals, of course, is itself associated with post-exercise soreness.

    To prevent this, researchers at various centers have explored whether taking aspirin or similar compounds can prevent the development of post-exercise soreness. The findings of these experiments were that taking aspirin or some other non-steroidal anti-inflammatory can, in fact, mitigate the development of soreness. That was the positive finding. The not-so-positive finding was that this approach also prevented improvements based on training or overload effects! It turned out that a certain amount of local damage to the tissues caused by overload is required to induce improvements in exercise capacity based on training.

    That was a bit of a surprise even if, in scientific terms, it also was a very interesting and useful finding. More surprising still were the results of a variation on the theme of using NSAIDs prophylactically to prevent muscle pain. Researchers reasoned that tissue damage was due to, among other things, localized oxidative challenge associated with tissue damage. Instead of NSAIDs, classic powerful antioxidant vitamins and compounds were provided: vitamin C, E and N-acetyl cysteine (NAC). As was the case with the pre-workout use of NSAIDs, these antioxidants taken in quantity before training sessions did reduce soreness. Just as in the case of the NSAIDs, they also reduced the benefits of training.

    More recently still, reports have emerged showing that very high dose resveratrol (250 mg) interferes with the benefits of exercise training.2 This finding is not limited to resveratrol and potentially extends to quite a number of nutrients:

    "support for beneficial effects of resveratrol in human [sic] is weak and studies even show that resveratrol supplementation, similarly to supplementation with other antioxidants, can counteract the positive effects of physical activity. Regular physical activity remains the most effective way of maintaining and improving vascular health status and caution should be taken regarding potential interference of supplements on training adaptations."3

    It should be pointed out that such negative findings are balanced by other positive findings. In another study with older individuals 65–80 years of age, 500 mg per day resveratrol, although it did not improve cardiovascular risks compared to exercise alone, did improve the number of functional mitochondria in muscle and "subjects that [sic] were treated with RSV had an increase in knee extensor muscle peak torque (8 percent), average peak torque (14 percent), and power (14 percent) after training, whereas exercise did not increase these parameters in the placebotreated older subjects."4,5

    These findings can be reconciled in a variety of ways. For instance, one implication is that high dose resveratrol might be cycled to improve muscle quality and function, then removed from the cycle to allow for the emergence of other benefits. Those readers interested in further exploring the use of antioxidants in exercise and aging might do well to consult "Oxidative stress: role of physical exercise and antioxidant nutraceuticals in adulthood and aging."6

    A second and more serious type of caveat emptor case involves taking a cocktail of supplements and finding that one of these undoes the benefits of the others. Several years back, a group of researchers at Georgetown University Medical Center, of whom I was one, examined whether avoiding insulin resistance, which is associated with aging, might lengthen life span in rodents as indicated by previous studies using caloric-restricted animals. We assessed whether consuming niacin-bound chromium (NBC) alone or in a formula containing other so-called "insulin sensitizers" would overcome various manifestations of aging and extend life span in Zucker Fatty Rats (ZFR).7 As we report in the abstract of our research, we "compared many metabolic parameters of ZFR fed NBC alone (n=12) or NBC in a unique formula (n=10) to a control group (n=10). In addition to NBC, the formula contained Allium sativum, Momordica charantia, Trigonella foenum-graecum and Gymnema sylvestre. The formula group received roughly ½ as much NBC daily as the NBC group. At week 44, all rats still lived, and no abnormalities in blood count (CBC), renal, or liver functions were found. In the two treatment groups compared to control, circulating glucose levels were significantly lower, with a trend toward lower HbA1C. Relatively elevated cholesterol and triglyceride concentrations occurred in the formula group. Compared to control, the NBC group had increased average lifespan (21.8%), median lifespan (14.1%), 30th percentile survival (19.6%), and maximum lifespan (22%). Despite similar beneficial effects on the glucose and blood pressure systems, a difference in aging was also found when the NBC group was compared to the formula group. When all rats in the other two groups had died, four in the NBC group continued to live at least a month longer."

    The fact that the life extension benefits of supplementation with chromium were undone by the inclusion of the other ingredients despite similar improvements in markers, such as blood glucose and blood pressure, was the source of considerable discussion in our group. My position at the time was and remains that the "insulin sensitizer" approach is beneficial. However, one of the ingredients in the formula, Gymnema sylvestre, is not an insulin sensitizer; instead, it is an inducer of insulin release from the pancreas, thus can elevate insulin levels or prevent a lowering of such levels even in conjunction with better insulin sensitivity. Elevated levels of circulating insulin are damaging the arteries and to many systems of the body regardless of any apparent benefit in terms of lowering circulating glucose and HbA1C. Adding this inappropriate ingredient to the mix negated benefits in terms of actual final endpoints, in this case extended lifespan, as opposed to improving mere markers.

    The American diet notoriously tends to be restricted in terms of the range and types of foods included. Surprisingly small changes in the diet that increase the variety of polyphenols and other nutrients, mostly plant-derived, can lead to quite outsized effects in terms of benefits. As described above in one example, plant nutrients equal to a small portion of a well-designed curry plus a cup of green tea yielded significant returns in terms of prostate health. Dietary supplements can be useful aids to enlarging the range of nutrients consumed each day, but supplements do not take the place of fresh food properly prepared and eaten in variety. Moreover, supplement interactions are not always obvious and need to be observed carefully.

    1. van Die MD, Williams SG, Emery J, Bone KM, Taylor JM, Lusk E, Pirotta MV. A Placebo-Controlled Double-Blinded Randomized Pilot Study of Combination Phytotherapy in Biochemically Recurrent Prostate Cancer. Prostate. 2017 May;77(7):765 –75.
    2. Gliemann L, Schmidt JF, Olesen J, Biensø RS, Peronard SL, Grandjean SU, Mortensen SP, Nyberg M, Bangsbo J, Pilegaard H, Hellsten Y. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J Physiol. 2013 Oct 15;591(20):5047–59.
    3. Gliemann L, Nyberg M, Hellsten Y. Effects of exercise training and resveratrol on vascular health in aging. Free Radic Biol Med. 2016 Sep;98:165–76.
    4. Alway SE, McCrory JL, Kearcher K, Vickers A, Frear B, Gilleland DL, Bonner DE, Thomas JM, Donley DA, Lively MW, Mohamed JS. Resveratrol Enhances Exercise-Induced Cellular and Functional Adaptations of Skeletal Muscle in Older Men and Women. J Gerontol A Biol Sci Med Sci. 2017 Nov 9;72(12):1595 –1606.
    5. Pollack RM, Barzilai N, Anghel V, Kulkarni AS, Golden A, O’Broin P, Sinclair DA, Bonkowski MS, Coleville AJ, Powell D, Kim S, Moaddel R, Stein D, Zhang K, Hawkins M, Crandall JP. Resveratrol Improves Vascular Function and Mitochondrial Number but Not Glucose Metabolism in Older Adults. J Gerontol A Biol Sci Med Sci. 2017 Nov 9;72(12):1703 – 09.
    6. Simioni C, Zauli G, Martelli AM, Vitale M, Sacchetti G, Gonelli A, Neri LM. Oxidative stress: role of physical exercise and antioxidant nutraceuticals in adulthood and aging. Oncotarget. 2018 Mar 30;9(24):17181– 98.
    7. Preuss HG, Echard B, Clouatre D, Bagchi D, Perricone NV. Niacin-bound chromium increases life span in Zucker Fatty Rats. J Inorg Biochem. 2011 Oct;105(10):1344 – 9.
  • Well over a decade ago, resveratrol made its introduction into the dietary supplement marketplace. Initially, excitement about resveratrol was based upon the consideration that intake of it and other polyphenol compounds from red wine may contribute to the “French paradox”—the unexpectedly low rate of death from cardiovascular disease in the Mediterranean population despite the relatively higher intake of saturated fats.1 Then, excitement increased with the understanding that resveratrol helped activate the SIRT 1 gene, associated with longevity.2 Since that time, interest in resveratrol has continued to expand due to human research demonstrating its effectiveness for inflammation, immune health/breast cancer prevention, muscle health, cognitive health, weight loss, blood sugar/ insulin resistance, non-alcoholic fatty liver disease, and more. These benefits will be the focus of this article.

    Resveratrol Background
    Before jumping into a discussion about the fascinating human research, however, let's take a moment to review just what resveratrol is, in case you're unfamiliar with it. Resveratrol is a type of natural phenol by several plants in response to injury or attack by pathogens.3,4 These plants include grapes, peanuts5 and Japanese Knotweed (Polygonum cuspidatum).6 Resveratrol helps provide protection to the plants, at least in part, due to its demonstrated antioxidant properties.7 These antioxidant properties benefit humans too, as shown in research where resveratrol provided a direct antioxidant effect against free radicals, and facilitated an increase in vitamin E8—another powerful antioxidant.

    There are two primary isomers (i.e. two forms) of resveratrol, trans- and cis-. To be clear, trans-resveratrol has been unequivocally shown to have much greater activity than cis-resveratrol.9 Consequently, when purchasing a resveratrol product, make sure to check the supplement facts panel to verify that the product contains trans-resveratrol. If just"resveratrol" is listed, without the trans-designation, or if cis-resveratrol is listed, you would be better off choosing a different product that lists trans-resveratrol. In any case, for ease of reading, I will drop references to trans- in the rest of this article, although it can be assumed that any mention of resveratrol will actually refer to trans-resveratrol.

    Cardiovascular Health
    As its first claim to fame, resveratrol has been found to have activity that may have protective effects on the cardiovascular system. In both test-tube and animal research, resveratrol has been shown to inhibit platelet aggregation (i.e. the clumping together of blood platelets). This has value since excessive or inappropriate aggregation of platelets can lead to formation of blood clots and subsequent blockages in blood vessels that result in insufficient blood flow, heart attack or stroke.10 Resveratrol can also promote vasodilation (a relaxed and expanded state of the artery that accommodates increased blood flow) by enhancing the production of a naturally occurring substance in the body called nitric oxide.11

    More importantly, human clinical research12 has demonstrated that 100 mg/day of resveratrol significantly reduced arterial stiffness (a major indicator of atherosclerosis) compared to placebo, and also lowered systolic blood pressure by 5.5 points in patients with type 2 diabetes. Another human study,13 which used a much higher dose (2.3 g) in older adults, found that resveratrol not only improved vascular function more than placebo, but also increased the number of mitochondria.those parts of the cells that help to generate energy for our body! Another interesting cardiovascular benefit is resveratrol's effect on Apolipoprotein B (ApoB), a primary component of many lipoproteins such as LDL (the gbad cholesterolh) that are involved in atherosclerosis and cardiovascular disease. In human clinical research14 on overweight or obese individuals with mild hypertriglyceridemia, 1000 mg/day of resveratrol for one week followed by 2000 mg/day for two weeks reduced ApoB production rate by an impressive 22 percent. In addition, flowmediated dilatation (a measure of arterial circulation and endothelial function) was increased in human studies15,16,17 where 10 mg to 270 mg/day of resveratrol was given. In one of the studies,18 LDL cholesterol levels were also significantly decreased.

    In addition to showing anti-inflammatory effects in in-vitro and animal studies, resveratrol has also been shown to comprehensively suppress oxidative and inflammatory stress with as little as 40 mg/day in normal human subjects.19 This included the reduction of inflammatory markers such as TNF-alpha, IL-6, and C-reactive protein, with no changes in the placebo group. Similarly, in postmenopausal women with osteoarthritis pain, 75 mg of resveratrol twice daily significantly reduced pain and improved total well-being.20

    Ulcerative colitis (UC), a chronic inflammatory bowel disease, has also responded to treatment with resveratrol. In one study21 with 56 UC patients, those receiving 500 mg/day of resveratrol had significant symptom improvement, reduced malondialdehyde (a highly reactive oxidative stress compound), and increased superoxide dismutase (SOD), and total antioxidant capacity. In another human study22 with 50 UC patients, 500 mg/day of resveratrol also reduced the activity of inflammatory compounds, including TNF-α, hs-CRP, and activity of NF-κB. Furthermore, in a study23 of firefighters, supplementation with 100 mg/day resveratrol for 90 days, plasma biomarkers of inflammation were reduced after a physical fitness test, including IL-6 and TNF-α. This adds further credence to resveratrol's anti-inflammatory effects.

    Immune Health/Breast Cancer Prevention
    resveratrol's effect on immune health can be as fundamental as increasing certain circulating immune cells, or as profound at reducing the risk of breast cancer. For example, human research24 was conducted to assess the effects of repeated doses of resveratrol (1000 mg/day for 28 days) on circulating immune cells in healthy individuals. The results were that resveratrol was safe and well tolerated and was associated with significant increases in the numbers of circulating gamma delta T cells (functioning as a first line of defense and a bridge between innate and adaptive responses) and regulatory T cells—demonstrating that resveratrol has clear biological effects on human circulating immune cells.

    With regard to breast cancer prevention, resveratrol may help in a couple of ways. First, resveratrol has been shown to have a dose-dependent effect on reducing the formation of mammary tumors in-vitro as a result of down-regulating DNA methyltransferases. To see if it had a similar effect in humans, a study25 was conducted in which 39 adult women at increased breast cancer risk received a placebo, 5 or 50 mg of resveratrol twice daily for 12 weeks. Results were that there was indeed decrease in methylation of the tumor suppressor gene with increasing levels of resveratrol (P = .047).

    In another study26 of 34 overweight, postmenopausal women (BMI ≥ 25 kg/m2), the clinical effect of resveratrol on systemic sex steroid hormones were investigated, since high estrogen levels may contribute to breast cancer. The subjects received 1 g of resveratrol daily for 12 weeks. The results were that resveratrol supplementation led to an average of 73 percent increase in urinary 2-hydroxyestrone (the "good estrogen") levels leading to a favorable change in estrogen ratios that are less conducive to the development of breast cancer. This research demonstrated that among overweight and obese postmenopausal women, a daily 1 g dose of resveratrol has favorable effects on estrogen metabolism.

    Muscle Health
    In a 12-week study,27 older men and women (aged 65.80 years) exercised and took either a placebo or 500 mg/day of resveratrol to determine if resveratrol would have additive effects to those of exercise. Results showed that exercise added to resveratrol treatment increased the number of mitochondria, and improved muscle fatigue resistance more than placebo and exercise treatments. In addition, subjects treated with resveratrol had an increase in muscular torque and power after training, whereas exercise did not increase these parameters in the placebo-treated older subjects. Furthermore, exercise combined with resveratrol significantly improved muscle fiber. Together, these data suggest that resveratrol combined with exercise might provide a better approach for reversing sarcopenia than exercise alone.

    Cognitive Health
    Research suggests that resveratrol may have cognitive health benefits in people with and without dementia. For example, the ongoing dysfunction of small blood vessels in patients with type 2 diabetes mellitus (T2DM) may impair the ability of cerebral vessels to supply blood to various brain regions, thereby increasing risks of dementia. To determine if resveratrol could benefit cerebral circulation, a study28 was conducted in which 36 dementia-free, non-insulin dependent T2DM older adults (49–78 years old) consumed single doses of resveratrol (0, 75, 150, and 300 mg) at weekly intervals. Results were that 75–300 mg of resveratrol enhanced vasodilator responsiveness in cerebral vessels.

    In another study,29 80 post-menopausal women aged 45–85 years received resveratrol or placebo for 14 weeks to examine the effect on cognitive performance and other parameters. Results were that compared to placebo, significant improvements were observed in the performance of cognitive tasks in the domain of verbal memory (p = 0.041) and in overall cognitive performance (p = 0.020). Mood also tended to improve in multiple measures. These results indicate that regular consumption of a modest dose of resveratrol can enhance both cerebrovascular function and cognition in post-menopausal women, potentially reducing their heightened risk of accelerated cognitive decline and offering a promising therapeutic treatment for menopauserelated cognitive decline.

    To test30 whether supplementation of resveratrol (200 mg/ day for 26 weeks) would enhance memory performance in older adults, 23 healthy overweight older individuals were pairwise matched to 23 participants that received placebo (total n = 46, 18 females, 50–75 years). Results showed a significant effect of resveratrol on retention of words over 30 min compared with placebo (p = 0.038), significant increases in hippocampal functional connectivity, decreases in glycated hemoglobin (HbA1c) and body fat, and increases in leptin compared with placebo (all p < 0.05). This study provides initial evidence that supplementary resveratrol improves memory performance in association with improved glucose metabolism in older adults, providing a basis for helping to maintain brain health during aging.

    To determine the effects of oral resveratrol on localized cerebral blood flow, a study31 was conducted with which 22 healthy human adults received placebo and two doses (250 and 500 mg) of resveratrol in counterbalanced order on separate days. After a 45-min resting absorption period, the participants performed a selection of cognitive tasks. Resveratrol administration resulted in dose-dependent increases in cerebral blood flow during task performance, and enhanced oxygen extraction. These results showed that single doses of orally administered resveratrol can modulate cerebral blood flow variables.

    Finally, a clinical study32 was conducted to determine if up to 1 g of resveratrol twice daily could benefit Alzheimer's disease (AD) patients. The results demonstrated that resveratrol decreased CSF MMP9 (a biomarker for confirmed AD), modulates neuro-inflammation, and induces adaptive immunity— suggesting that resveratrol may be a viable target for treatment or prevention of neurodegenerative disorders.

    Weight Loss
    One of the reasons that resveratrol has received widespread interest is because of its ability to mimic effects of calorie restriction. To gain more insight into this effect on adipose tissue, a study33 was conducted in which healthy obese subjects were supplemented with 150 mg/day of resveratrol or placebo for 30 days. Results showed that resveratrol significantly decreased the size of adipocytes (fat cells), with a shift toward reducing the proportion of large and very-large adipocytes and an increase in small adipocytes. Furthermore, lysosomal/phagosomal pathway and transcription factor EB were up-regulated reflecting an alternative pathway of lipid breakdown by autophagy.

    Similarly,34 T2DM patients received 3 g resveratrol or placebo daily for 12 weeks. Results were that there was a significant increase in both SIRT1 expression and resting metabolic rate compared with the placebo group. In patients with T2DM, treatment with resveratrol helped regulate energy expenditure, suggesting that resveratrol may have beneficial exercise-mimetic effects.

    Again,35 healthy, obese subjects were treated with placebo and 150 mg/day resveratrol for 30 days. The results were that resveratrol increased SIRT1 and improved the muscle's use of fatty acids as an energy fuel, demonstrating that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction. Given these results, one might think that resveratrol may aid in weight loss—and indeed this has been shown to be the case in clinical research.

    Orlistat is an over-the-counter drug (also known as Alli®) designed to treat obesity by reducing the absorption of fats from the human diet. A study36 was conducted to evaluate the efficacy of combining orlistat with resveratrol in 84 obese subjects over a 6-month period. The subjects consumed a diet with 500 fewer calories than their usual diet for two weeks, and were randomly assigned to four groups, placebo, resveratrol, orlistat, or the O-R combination, and they consumed the energyreduced diet for 6-months. Results were significant weight loss of 15 lbs in the O-R group compared with 7.7 lbs in the placebo group. Significant decreases in BMI, waist circumference, fat mass, triglycerides, leptin, and leptin/adiponectin ratio were observed with the O-R combination, indicating that it was the most effective weight loss treatment.

    In another study,37 24 patients with metabolic syndrome received resveratrol (500 mg) three times per day before meals for 90 days. Resveratrol administration resulted in significant differences in total weight (P=0.007), body mass index (BMI) (P=0.006), fat mass (P=0.001), and waist circumference (P=0.004). In conclusion, administration of resveratrol significantly decreased weight, BMI, and fat mass.

    Blood Sugar/Insulin Resistance
    A study38 was conducted using 480 mg/day of resveratrol or placebo for four weeks on 43 patients with diabetes who also had chronic periodontitis (i.e. gum disease). Results were that serum levels of fasting insulin and insulin resistance were significantly lower in the resveratrol group compared with control group. With regard to periodontal disease, there was also a significant difference in the gum pocket depth between intervention and control groups with resveratrol. The researchers recommended that resveratrol supplementation might be beneficial as adjuvant therapy along with non-surgical periodontal treatment in insulin resistance and improving periodontal status among patients with diabetes with periodontal disease.

    Another human clinical trial39 was conducted in 32 over-weight, older adults (average age: 73 years). Participants received placebo, 300 mg/day of resveratrol, or 1000 mg/day of resveratrol for 90 days. Results were that, compared to placebo, glucose levels were significantly lower at after treatment among participants receiving either dose of resveratrol (P<0.05), and were well tolerated.

    In this study,40 62 patients with T2DM received either an oral hypoglycemic medication, or an oral hypoglycemic medication along with 250 mg/day of resveratrol. Results were that supplementation with resveratrol for three months significantly improved the mean hemoglobin A1c (P<0.05), a measure of long-term glucose control, systolic blood pressure (P<0.05), total cholesterol (P<0.05), and total protein (P<0.05) in T2DM. The researchers concluded that oral supplementation with resveratrol was effective in improving glycemic control and may be a potential adjuvant for the treatment and management of diabetes.

    In a pilot study,41 subjects with impaired glucose tolerance (aged 72 ± 3 years) received 1, 1.5, or 2 g/day of resveratrol for four weeks. After four weeks of resveratrol supplementation, results showed that post-meal (P=0.003) and 3-hour glucose levels (P=0.001) declined. Researchers concluded that, at doses between 1 and 2 g/day, resveratrol improves insulin sensitivity and post-meal plasma glucose in subjects with impaired glucose tolerance. Likewise, in a 4-week study,42 T2DM patients received 10 mg/day resveratrol or a placebo. Results showed that, after the fourth week, resveratrol significantly improved insulin sensitivity, which might be due to a resveratrol-induced decrease in oxidative stress that leads to a more efficient insulin-signaling pathway.

    Non-Alcoholic Fatty Liver Disease
    Nonalcoholic fatty liver disease (NAFLD) refers to the accumulation of fat in the liver of people who drink little or no alcohol. Unfortunately, NAFLD is common—with easily one-third of all American adults being affected43—and often causes no signs and symptoms, and sometimes no complications. In more serious cases, however, the fat that accumulates in NAFLD can cause liver inflammation and scarring.44 In addition, NAFLD is usually associated with insulin resistance, central obesity, reduced glucose tolerance, T2DM and high triglyceride levels.

    In a clinical study,45 50 NAFLD patients received either a 500 mg/day of resveratrol or a placebo for 12 weeks. Both groups were advised to follow an energy-balanced diet and physical activity recommendations. Results were that resveratrol supplementation reduced alanine aminotransferase (a marker for NAFLD) and hepatic steatosis (fatty liver) significantly more than placebo (P<0E05).

    In another study,46 60 NAFLD patients received two 150 mg resveratrol capsules twice daily for three months. Results were that, compared with the placebo group, resveratrol significantly decreased aspartate aminotransferase, glucose and low-density lipoprotein cholesterol (P.0.001) alanine aminotransferase, total cholesterol (P=0.002), and insulin resistance (P=0.016). The researchers concluded that resveratrol supplementation might benefit patients with NAFLD.

    Other Resveratrol Benefits
    In addition to the aforementioned applications for resveratrol, there are additional benefits for this nutraceutical as well. Two such benefits are related to bone health, and for those who are smokers.

    In a clinical study,47 66 middle-aged, obese subjects with metabolic syndrome (average age: 49.3 } 6.3 years) received oral treatment with 1,000 mg or 150 mg of resveratrol, or a placebo daily for 16 weeks to assess changes in the bone turnover marker bone alkaline phosphatase (BAP), and bone mineral density (BMD). Results were that BAP increased dose dependently with resveratrol (P<0.001), compared with placebo. Lumbar spine trabecular volumetric bone mineral density also increased dose dependently with resveratrol (P=0.036), with a significant increase of 2.6 percent in the 1,000 mg resveratrol group compared with placebo (P=0.043). In addition, changes in BAP and bone mineral density were positively correlated (P=0.027).

    Smokers typically experience a state of low-grade systemic inflammation and oxidant-antioxidant imbalance. To determine whether resveratrol has beneficial effects on markers of inflammation and oxidative stress, a study48 was conducted with 50 healthy adult smokers who alternatively were given 500 mg/ day of resveratrol and placebo. Results were that resveratrol significantly reduced the inflammatory marker C-reactive protein (CRP), triglyceride concentrations, and increased Total Antioxidant Status (TAS) values. The researchers concluded that, because resveratrol has anti-inflammatory, anti-oxidant, and hypotriglyceridemic effects, its supplementation might beneficially affect the increased cardiovascular risk of healthy smokers.

    Improving The Bioavailability And Efficacy Of Resveratrol

    Now that we've reviewed some of the many benefits associated with resveratrol supplementation, let's briefly consider ways to improve the bioavailability and efficacy of this valuable nutraceutical. First, take resveratrol on an empty stomach. The reason for this recommendation is a study showing that the absorption rate of resveratrol following an oral 400 mg singledose was significantly delayed by the presence of food.49

    Second, resveratrol may work better when taken together with pterostilbene (a related antioxidant) and quercetin (a flavonoid). In this study,50 the antioxidant activities of resveratrol, pterostilbene and quercetin, and the effect of their combination were investigated in human blood cells in-vitro. When used together, the combination protected the blood cells against destruction and against depletion of the important antioxidant, glutathione. Also, the combination of resveratrol with quercetin or pterostilbene synergistically inhibited oxidative injury of membrane lipids. These protective effects may partially explain the health benefit of these bioactive microcomponents when together in the diet.

    The value of supplementation with resveratrol has moved beyond the "French paradox" and the activation of the SIRT 1 gene, associated with longevity. Human clinical research has demonstrated efficacy of resveratrol for inflammation, immune health/breast cancer prevention, muscle health, cognitive health, weight loss, blood sugar/insulin resistance, non-alcoholic fatty liver disease, and more.

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    2. Borra MT, Smith BC, Denu JM.Mechanism of human SIRT1 activation by resveratrol. J Biol Chem. 2005 Apr 29;280(17):17187–95. 3. Higdon J, Drake VJ, Steward WP. Resveratrol. Micronutrient Information Center. Linus Pauling Institute, Oregon State University, Corvallis, OR; 2016.
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    4. Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: A molecule whose time has come? And gone? Clin Biochem 1997;30:91–113.
    5. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nature reviews. Drug Discovery 2006; 5(6):493–506.
    6. Bradamante S, Barenghi L, Villa A. Cardiovascular protective effects of resveratrol. Cardiovasc Drug Rev 2004; 22(3):169–188.
    7. Apostolidou C, Adamopoulos K, Iliadis S, Kourtidou-Papadeli C. Alterations of antioxidant status in asymptomatic hypercholesterolemic individuals after resveratrol intake. Int J Food Sci Nutr. 2015 Aug;67(5):541–52.
    8. Anisimova NY, Kiselevsky MV, Sosnov AV, Sadovnikov SV, Stankov IN, Gakh AA. Trans-, cis-, and dihydro-resveratrol: a comparative study. Chem Cent J. 2011 Dec 20;5:88.
    9. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nature reviews. Drug Discovery 2006; 5(6):493–506.
    10. Wallerath T, Deckert G, Ternes T, et al. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 2002; 106(13):1652–8.
    11. Imamura H, Yamaguchi T, Nagayama D, Saiki A, Shirai K, Tatsuno I. Resveratrol Ameliorates Arterial Stiffness Assessed by Cardio-Ankle Vascular Index in Patients With Type 2 Diabetes Mellitus. Int Heart J. 2017 Aug 3;58(4):577–83.
    12. Pollack RM, Barzilai N, Anghel V, Kulkarni AS, Golden A, O’Broin P, Sinclair DA, Bonkowski MS, Coleville AJ, Powell D, Kim S, Moaddel R, Stein D, Zhang K, Hawkins M, Crandall JP. Resveratrol Improves Vascular Function and Mitochondrial Number but Not Glucose Metabolism in Older Adults. J Gerontol A Biol Sci Med Sci. 2017 Nov 9;72(12):1703–9.
    13. Dash S, Xiao C, Morgantini C, Szeto L, Lewis GF. High-dose resveratrol treatment for 2 weeks inhibits intestinal and hepatic lipoprotein production in overweight/obese men. Arterioscler Thromb Vasc Biol. 2013 Dec;33(12):2895–901.
    14. Wong RH, Berry NM, Coates AM, Buckley JD, Bryan J, Kunz I, Howe PR. Chronic resveratrol consumption improves brachial flow-mediated dilatation in healthy obese adults. J Hypertens. 2013 Sep;31(9):1819–27.
    15. Magyar K, Halmosi R, Palfi A, Feher G, Czopf L, Fulop A, Battyany I, Sumegi B, Toth K, Szabados E. Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc. 2012;50(3):179–87.
    16. Wong RH1, Howe PR, Buckley JD, Coates AM, Kunz I, Berry NM. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis. 2011 Nov;21(11):851–6.
    17. Magyar K, Halmosi R, Palfi A, Feher G, Czopf L, Fulop A, Battyany I, Sumegi B, Toth K, Szabados E. Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc.2012;50(3):179–87.
    18. Ghanim H, Sia CL, Abuaysheh S, Korzeniewski K, Patnaik P, Marumganti A, Chaudhuri A, Dandona P. An antiinflammatory and reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum containing resveratrol. J Clin Endocrinol Metab. 2010 Sep;95(9):E1-8.
    19. Wong RHX, Evans HM, Howe PRC. Resveratrol supplementation reduces pain experience by postmenopausal women. Menopause. 2017 Aug;24(8):916–22.
    20. Samsamikor M, Daryani NE, Asl PR, Hekmatdoost A. Resveratrol Supplementation and Oxidative/Anti-Oxidative Status in Patients with Ulcerative Colitis: A Randomized, Double-Blind, Placebo-controlled Pilot Study. Arch Med Res.2016 May;47(4):304–9.
    21. Samsami-Kor M, Daryani NE, Asl PR, Hekmatdoost A. Anti-Inflammatory Effects of Resveratrol in Patients with Ulcerative Colitis: A Randomized, Double-Blind, Placebo-controlled Pilot Study. Arch Med Res. 2015 May;46(4):280–5.
    22. Macedo RC, Vieira A1, Marin DP2, Otton R3. Effects of chronic resveratrol supplementation in military firefighters undergo a physical fitness test--a placebo-controlled, double blind study. Chem Biol Interact. 2015 Feb 5;227:89–95.
    23. Espinoza JL, Trung LQ, Inaoka PT, Yamada K, An DT, Mizuno S, Nakao S, Takami A. The Repeated Administration of Resveratrol Has Measurable Effects on Circulating T-Cell Subsets in Humans. Oxid Med Cell Longev. 2017;2017:6781872.
    24. Zhu W, Qin W, Zhang K, Rottinghaus GE, Chen YC, Kliethermes B, Sauter ER. Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer. Nutr Cancer. 2012 Apr;64(3):393–400.
    25. Chow HH, Garland LL, Heckman-Stoddard BM, Hsu CH, Butler VD, Cordova CA, Chew WM, Cornelison TL. A pilot clinical study of resveratrol in postmenopausal women with high body mass index: effects on systemic sex steroid hormones. J Transl Med. 2014 Aug 14;12:223.
    26. Alway SE, McCrory JL, Kearcher K, Vickers A, Frear B, Gilleland DL, Bonner DE, Thomas JM, Donley DA, Lively MW, Mohamed JS. Resveratrol Enhances Exercise-Induced Cellular and Functional Adaptations of Skeletal Muscle in Older Men and Women. J Gerontol A Biol Sci Med Sci. 2017 Nov 9;72(12):1595–1606.
    27. Wong RH, Nealon RS, Scholey A, Howe PR. Low dose resveratrol improves cerebrovascular function in type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis. 2016 May;26(5):393–9.
    28. Evans HM, Howe PR, Wong RH. Effects of Resveratrol on Cognitive Performance, Mood and Cerebrovascular Function in Post-Menopausal Women; A 14-Week Randomised Placebo-Controlled Intervention Trial. Nutrients.2017 Jan 3;9(1). pii: E27.
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    32. Konings E, Timmers S, Boekschoten MV, Goossens GH, Jocken JW, Afman LA, Müller M, Schrauwen P, Mariman EC, Blaak EE. The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men. Int J Obes (Lond). 2014 Mar;38(3):470–3.
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    35. Arzola-Paniagua MA, García-Salgado López ER, Calvo-Vargas CG, Guevara-Cruz M. Efficacy of an orlistat-resveratrol combination for weight loss in subjects with obesity: A randomized controlled trial. Obesity (Silver Spring). 2016 Jul;24(7):1454–63.
    36. Méndez-del Villar M, González-Ortiz M, Martínez-Abundis E, Pérez-Rubio KG, Lizárraga-Valdez R. Effect of resveratrol administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Metab Syndr Relat Disord. 2014 Dec;12(10):497–501.
    37. Zare Javid A, Hormoznejad R, Yousefimanesh HA, Zakerkish M, Haghighi-Zadeh MH, Dehghan P, Ravanbakhsh M. The Impact of Resveratrol Supplementation on Blood Glucose, Insulin, Insulin Resistance, Triglyceride, and Periodontal Markers in Type 2 Diabetic Patients with Chronic Periodontitis. Phytother Res. 2017 Jan;31(1):108–114.
    38. Anton SD, Embry C, Marsiske M, Lu X, Doss H, Leeuwenburgh C, Manini TM. Safety and metabolic outcomes of resveratrol supplementation in older adults: results of a twelve-week, placebo-controlled pilot study. Exp Gerontol. 2014 Sep;57:181–7.
    39. Bhatt JK, Thomas S, Nanjan MJ. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr Res. 2012 Jul;32(7):537–41.
    40. Crandall JP, Oram V, Trandafirescu G, Reid M, Kishore P, Hawkins M, Cohen HW, Barzilai N. Pilot study of resveratrol in older adults with impaired glucose tolerance. J Gerontol A Biol Sci Med Sci. 2012 Dec;67(12):1307–12.
    41. Brasnyó P, Molnár GA, Mohás M, Markó L, Laczy B, Cseh J, Mikolás E, Szijártó IA, Mérei A, Halmai R, Mészáros LG, Sümegi B, Wittmann I. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr. 2011 Aug;106(3):383–9.
    42. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity. Hepatology2004;40(6):1387–95.
    43. Sanyal AJ. American Gastroenterological Association: AGA technical review on nonalcoholic fatty liver disease (national guidelines). Gastroenterology 2002; 123:1705–25.
    44. Faghihzadeh F, Adibi P, Hekmatdoost A. The effects of resveratrol supplementation on cardiovascular risk factors in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled study. Br J Nutr.2015 Sep 14;114(5):796–803.
    45. Chen S, Zhao X, Ran L, Wan J, Wang X, Qin Y, Shu F, Gao Y, Yuan L, Zhang Q, Mi M. Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial. Dig Liver Dis. 2015 Mar;47(3):226–32
    46. Ornstrup MJ, Harsløf T, Kjær TN, Langdahl BL, Pedersen SB. Resveratrol increases bone mineral density and bone alkaline phosphatase in obese men: a randomized placebo-controlled trial. J Clin Endocrinol Metab. 2014 Dec;99(12):4720–9.
    47. Bo S, Ciccone G, Castiglione A, Gambino R, De Michieli F, Villois P, Durazzo M, Cavallo-Perin P, Cassader M.Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial. Curr Med Chem. 2013;20(10):1323–31.
    48. Vaz-da-Silva M, Loureiro AI, Falcao A, Nunes T, Rocha JF, Fernandes-Lopes C, Soares E, Wright L, Almeida L, Soares-da-Silva P. Effect of food on the pharmacokinetic profile of trans-resveratrol. Int J Clin Pharmacol Ther. 2008 Nov;46(11):564–70.
    49. Mikstacka R, Rimando AM, Ignatowicz E. Antioxidant effect of trans-resveratrol, pterostilbene, quercetin and their combinations in human erythrocytes in vitro. Plant Foods Hum Nutr. 2010 Mar;65(1):57–63
  • As pointed out last year in a review of pollen extract for prostate support, benign prostatic hyperplasia (BPH, formerly called hypertrophy), involves a renewed growth in the number of prostate cells late in life.1 Unfortunately, of men between the age of 40 and 59, nearly 60 percent can be shown to already be suffering from benign prostatic hyperplasia. This usually does not present a noticeable problem until after the age of 50; by the age of 80, however, some 85 percent of all men suffer from one or more symptoms of BPH. The primary effect of BPH is a progressive decrease in the ability to empty the bladder as the prostate enlarges and applies pressure to the urethra.

    BPH is hardly the lone prostate and sex hormone related issue that can be troubling to men. Aside from prostate cancer, which for most men is so slow growing as to not be life threatening, many men are concerned about low testosterone, which has its own repercussions. Two of the repercussions of low testosterone are a low level of muscle-maintaining free testosterone and elevated levels of estrogen produced from testosterone by a pathway referred to as the aromatase pathway. Fortunately, there are a number of safe natural compounds that can help to regulate both sides of this equation.

    Protective herbs and nutrients have counterparts that increase the risks of various conditions. Some of these potentially damaging compounds are prescriptions given for unrelated conditions and this provides a rationale for being cautious about prescription drugs. What you do not know definitely can hurt!


    In 2013, experts slammed a claimed fish oil/omega-3 fatty acid intake link to prostate cancer as “scaremongering.” The trial in question purported to find increased risks for total prostate cancer as well as increased risks of both low-grade and high-grade prostate cancer, an increase of 71 percent in this latter category.2 The responses were quick and brutal. One nutritionist (Duffy MacKay, vice president of scientific and regulatory affairs at the for Responsible Nutrition (CRN)) pointed out, quite correctly, that the findings of this study were based on blood level differences so small that “[t]his change [of 0.2%] literally could have occurred if somebody ate a fish sandwich on their way to get their blood drawn.”3 Both the consumers of the low and the high levels of long chain omega-3 fatty acids were within the normal blood range.

    Others pointed out that the findings of the study clearly imply that men in countries with high levels of consumption of seafood, such as Scandinavia and Japan, should exhibit high levels of prostate cancer, yet the opposite is the case. Alan Ruth, PhD, CEO of the Irish Health Trade Association observed, “[i]n a 2010 meta-analysis of 31 studies published in the American Journal of Clinical Nutrition, the risks of prostate cancer diagnosis calculated for high fish consumption ranged from a 61% decrease in risk to a 77% increase in risk, and several showed no significant differences in risk at all…In the same meta-analysis, pooled data from four studies on fish consumption and death from prostate cancer (rather than diagnosis of prostate cancer) found a 63% decrease in risk for high fish consumption.”4

    Especially interesting in this dust-up is the recent attempt to rehabilitate omega-6 fatty acids. In pre-modern times, the intake of omega-3 to omega-6 fatty acids in the diet typically was in the range of one-to-two, whereas today in the United States it regularly may be as low as one-to-twentyfive, with prostate cancer rates climbing steadily over the last 60 years. In this instance, a headline is revealing: “Corn oil, omega-6 could speed up prostate cancer.”5 Journal article titles are more prosaic, yet just as damning: “A high ratio of dietary n-6/n-3 polyunsaturated fatty acids is associated with increased risk of prostate cancer.”6

    Barry Sears, who has written for years on the health effects of fatty acids, both good and bad, tartly comments in his blog, “Omega-3 fatty acids and prostate cancer? Oh, really?”7 Among other things, Sears demonstrates how easily a statistically significant blood reading of fatty acid profiles can be attached to otherwise clinically irrelevant findings. The take away message in this case is that the experience around the world repeatedly has been that prostate risks, especially death from prostate cancer, are lower in matched populations that consume more fish. There is nothing in recently published research that should make us doubt that improving the omega-3 to omega-6 ratio in our diets is a good goal at which to aim.

    Grape Skin Extract & Resveratrol
    In many areas in the US and the United Kingdom (Scotland has not yet opted out of the Union), one cannot visit a doctor without being queried about alcohol intake and then the required lecture on the evils of alcohol. The distinction as to the source of alcohol in the diet routinely drops out despite the fact that red wine has been recognized in Europe for centuries as exhibiting various health benefits and little downside as long as consumed in moderation. It turns out that red wine, often thought of in terms of the heart, may benefit the prostate, as well.

    The trick to the studies is that the researchers must work vigorously to screen for the different sources of alcohol over the course of a man’s life. If this is done, then the research is likely to confirm that a glass of red wine per day may be protective against the risk of prostate cancer.8 Less clear is which compounds in red wine are protective. Perhaps many are. A recent study on grape skin extract and resveratrol identified several protective mechanisms of action.9 Some of the factors linked to resveratrol have been known for years, whereas other mechanisms and, similarly, the benefits of other red wine compounds, are being vigorously researched. Grape seed components (proanthocyanidins) are another example of a source of anti-cancer benefits.10 Given the huge volume of papers being published today on the healthprotective benefits of red wine and its ingredients, it is a reasonable conclusion that most men may benefit from one or two glasses of red wine per day consumed with meals.

    Quercetin & EGCG
    The dietary bioflavonoid quercetin is well known to readers of this magazine, as is epigallocathechin gallate (EGCG). Both compounds are considered to be health protective and quercetin, in particular, is known to improve the uptake (bioavailability) and the benefits of many other compounds found in the diet and in herbs. Papers routinely show greater efficacy or even benefits where none initially were found, when quercetin is combined with resveratrol, with sulphorafane, with EGCG, etc. One of the more interesting recent findings is that these combinations sometimes not only can help to prevent the transformation of cells from precarcinogenic stages to active cancer, but also can interfere with or eliminate entirely cancer stem-cell characteristics. Cancer stem cells are the ultimate source of cancer self-renewal, so this action by the combination of quercetin and EGCG is a warm recommendation.11

    Bitter Melon
    Bitter melon has received quite a bit of publicity recently with regard to pancreatic cancer. It would be unfortunate were the exploration to end there. Several researchers have reported that treatment of bitter-melon-related products in a number of cancer cell lines induces cell cycle arrest and apoptosis without affecting normal cell growth.12 Researches targeted specifically at prostate cancer have demonstrated that the impact of bitter melon extends to this area.13 Admittedly, bitter melon is not a staple at the American table. Perhaps that should change. See my earlier article, “Going WILD with Bitter Melon for Blood Sugar Support.”14

    Pomegranate is a fruit long associated with healing and medicine. Indeed, the pomegranate is on the crest-of-arms of the British Royal Society of Medicine and of many other ancient organizations devoted to healing. A quick look at the PubMed database shows that the keywords “pomegranate” and “prostate” bring up 60 studies. Many of these studies have been promising, especially when pomegranate was added to other ingredients with related and differing mechanisms of action. For instance, in 2013 the polyphenol rich whole food supplement Pomi-T® (pomegranate seeds, green tea, broccoli, and turmeric) was reported to have a direct anti-cancer effect in men with prostate cancer.15 These results were confirmed in a larger clinical trial published in 2014.16

    Thymoquinone and Black Seed
    Few Americans have heard either of black seed or thymoquinone (TQ). The former is famous for healing in the areas in which it grows naturally, meaning much of the eastern Mediterranean through the Near and Middle East all the way to India. Mohammed is reputed to have said that the seed cures every condition except death itself.

    With regard to the prostate, black seed is useful for both BPH and in preventing prostate cancer induction. One of the important ingredients in black seed oil, thymoquinone, promotes healthy apoptosis in prostate cells and therefore helps the body to regulate the size and health of the prostate.17,18 Similar effects have been found in, for example, breast cancer, so TQ has a broad spectrum of applications.19

    Cactus Flower
    A couple of decades back, the herbal extract chrysin was introduced to the athletics and body building world as an answer to improving free testosterone levels and reducing the pathway (aromatase) that transforms testosterone to estrogen. Chrysin has some benefits, as long as one does not expect too much and is willing to focus on the anxiolytic qualities of the compound (found in passion flower). However, much more successful compounds for this purpose of increasing free testosterone, and so forth, have been found. One of these is an extract of cactus flower (Opuntia ficus-indica).

    I ran across this almost a decade ago being sold in Germany and Israel for BPH,20 but at the time could not find a reliable source of supply. Since then, a friend with whom I was working took this item and continued to dig until he found a reliable source that he could market as increasing serum free testosterone levels and reducing aromatase (reducing estrogen production and inhibiting the binding of dihydrotestosterone/DHT.) As my friend writes at his website, based on preliminary laboratory research, “Opuntia flower extract (1 mg/ml concentration) inhibited over 80% of the activity of 5-alpha reductase in human prostate tissue homogenate and inhibited over 80% of aromatase activity in human placenta tissue homogenate.”21 This particular product also contains supporting ingredients, such as an extract of stinging nettle root.

    Some Prostate-Questionable Foods and Pharmaceuticals Now for a few items that men may want to remove from their daily habits or environment.

    • Non-and low-fat milk (but not whole milk or other dairy products) intake by men is linked to higher rates of prostate cancer22
    • Long-term use of statins increases the risk of prostate cancer23
    • Oral contraceptive use is associated with prostate cancer—this refers to these contraceptives getting into the environment at large and not to use by one’s partner24

    There are protective foods, nutrients and herbs of which men should take advantage to maintain and regain prostate health as well as improve other parameters of health and performance. Omega-3 fatty acids and the active compounds found in red wine (grape skin anthocyanidins and other compounds, resveratrol, grape seed proanthocyanidins, quercetin), green tea (EGCG) and bitter melon are on this short list. More exotic are black seed and thymoquinone as well as cactus flower extract. For the most part, these can be characterized as special foods since they can be consumed over the long term and have few or no downsides even when consumed chronically in large amounts. Indeed, this should be the goal—a little prevention is always worth a whole lot of cure.

    1. 1. F. Hinman, Benign Prostatic Hypertrophy. New York: Springer-Verlag, 1983.
    2. 2. Brasky TM, Darke AK, Song X, Tangen CM, Goodman PJ, Thompson IM, Meyskens FL Jr, Goodman GE, Minasian LM, Parnes HL, Klein EA, Kristal AR. Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Natl Cancer Inst. 2013 Aug 7;105(15):1132– 41. doi: 10.1093/jnci/djt174.
    3. 3. Experts slam omega-3 link to prostate cancer as overblown ‘scaremongering.’
    4. 4. Ibid.
    5. 5.
    6. 6. Williams CD, Whitley BM, Hoyo C, Grant DJ, Iraggi JD, Newman KA, Gerber L, Taylor LA, McKeever MG, Freedland SJ. A high ratio of dietary n-6/n-3 polyunsaturated fatty acids is associated with increased risk of prostate cancer. Nutr Res. 2011 Jan;31(1):1–8. doi: 10.1016/j.nutres.2011.01.002.
    7. 7.
    8. 8. A glass of red wine a day keeps prostate cancer away?
    9. 9. Hudson TS, Hartle DK, Hursting SD, Nunez NP, Wang TT, Young HA, Arany P, Green JE. Inhibition of prostate cancer growth by muscadine grape skin extract and resveratrol through distinct mechanisms. Cancer Res. 2007 Sep 1;67(17):8396–405.
    10. 10. Raina K, Singh RP, Agarwal R, Agarwal C. Oral grape seed extract inhibits prostate tumor growth and progression in TRAMP mice. Cancer Res. 2007 Jun 15;67(12):5976-82.
    11. 11. Tang SN, Singh C, Nall D, Meeker D, Shankar S, Srivastava RK. The dietary bioflavonoid quercetin synergizes with epigallocathechin gallate (EGCG) to inhibit prostate cancer stem cell characteristics, invasion, migration and epithelial-mesenchymal transition. J Mol Signal. 2010 Aug 18;5:14. doi: 10.1186/1750–2187–5–14.
    12. 12. Nerurkar P, Ray RB. Bitter melon: antagonist to cancer. Pharm Res. 2010 Jun;27(6):1049–53. doi: 10.1007/s11095–010–0057–2.
    13. 13. Ru P, Steele R, Nerurkar PV, Phillips N, Ray RB. Bitter melon extract impairs prostate cancer cell-cycle progression and delays prostatic intraepithelial neoplasia in TRAMP model. Cancer Prev Res (Phila). 2011 Dec;4(12):2122–30. doi: 10.1158/1940–6207.
    14. 14.
    15. 15. Goodman A. High Marks for Nutritional Supplement in Patients with Localized Prostate Cancer. Value-Based Cancer Care. September 2013 Vol 4, No 7.
    16. 16. Thomas R, Williams M, Sharma H, Chaudry A, Bellamy P. A doubleblind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer-the UK NCRN Pomi-T study. Prostate Cancer Prostatic Dis. 2014 Mar 11. doi: 10.1038/pcan.2014.6.
    17. 17. Kaseb AO, Chinnakannu K, Chen D, Sivanandam A, Tejwani S, Menon M, Dou QP, Reddy GP. Androgen receptor and E2F-1 targeted thymoquinone therapy for hormone-refractory prostate cancer. Cancer Res. 2007 Aug 15;67(16):7782–8.
    18. 18. Kumar AP, Sethi G, Tan KH. Thymoquinone: potential cure for inflammatory disorders and cancer. Biochem Pharmacol. 2012 Feb 15;83(4):443–51. doi: 10.1016/j.bcp.2011.09.029.
    19. 19. Rajput S, Kumar BN, Sarkar S, Das S, Azab B, Santhekadur PK, Das SK, Emdad L, Sarkar D, Fisher PB, Mandal M. Targeted apoptotic effects of thymoquinone and tamoxifen on XIAP mediated Akt regulation in breast cancer. PLoS One. 2013 Apr 17;8(4):e61342. doi: 10.1371/journal.pone.0061342.
    20. 20. Palevitch D., Earon G., Levin I., Treatment of benign prostatic hypertrophy with Opuntia ficus-indica (L.) Miller. Journal of herbs, spices & medicinal plants. J. herbs spices med. plants 1993;2(1):45–49.
    21. 21. drawing upon Jonas A, Rosenblat G, Krapf D, Bitterman W, Earon G, Neeman I. Efficacy of cactus flowers miller treatment in benign prostatic hyperplasia due to inhibition of 5a reductase activity, aromatase activity and lipid peroxidation. HerbaMed paper; undated. Available at:
    22. 22. Park SY, Murphy SP, Wilkens LR, Stram DO, Henderson BE, Kolonel LN. Calcium, vitamin D, and dairy product intake and prostate cancer risk: the Multiethnic Cohort Study. Am J Epidemiol. 2007 Dec 1;166(11):1259–69.
    23. 23. Chang CC, Ho SC, Chiu HF, Yang CY. Statins increase the risk of prostate cancer: a population-based case-control study. Prostate. 2011 Dec;71(16):1818–24. doi: 10.1002/pros.21401.
    24. 24. Margel D, Fleshner NE. Oral contraceptive use is associated with prostate cancer: an ecological study. BMJ Open. 2011 Nov 14;1(2):e000311. doi:10.1136/bmjopen–2011–000311.