April 2011 Blog with Durk and Sandy

“There are countless suns and countless earths all rotating around their suns in exactly the same way as the seven planets of our system. We see only the suns because they are the largest bodies and are luminous, but their planets remain invisible to us because they are smaller and non-luminous.”— Giordano Bruno, 1584

“The budget should be balanced, the Treasury should be refilled, public debt should be reduced, the arrogance of officialdom should be tempered and controlled, and the assistance to foreign lands should be curtailed lest Rome become bankrupt. People must again learn to work, instead of living on public assistance.”— Cicero, 55 BC

“Logic will get you from A to B. Imagination will take you everywhere.”— Albert Einstein

“It is difficult to imagine that a nation which began, at least in part, as the result of opposition to a British mandate giving the East India Company a monopoly and imposing a nominal tax on all tea sold in America would have set out to create a government with the power to force people to buy tea in the first place.”— District Court Judge Roger Vinson in his ruling declaring the individual mandate to purchase health insurance in Obamacare (and, hence, the entire Act) unconstitutional

Comparison of Efficacy of Turmeric and Curcumin 
in Immunological Measures and Gene Regulation

We have long been interested in assessing the differences between ingesting healthful substances as parts of a whole food or an herb as compared to taking them as an individual ingredient.

A new paper¹ examined the comparative efficacy of extract of turmeric rhizome (ETE, prepared as an ethanolic extract of raw turmeric) as compared to commercially obtained curcumin, the yellow component of turmeric that has been widely studied for beneficial effects (such as antioxidant, neuroprotection, memory enhancement, cancer preventive, and anti-inflammatory). There has been little published comparing the effects of turmeric and curcumin, so we were especially interested in the results. The two were compared for immunostimulatory, anti-inflammatory, and antioxidant properties in a mouse model. In addition they were compared for gene expression of perforin (a pore forming protein important in T-cell mediated cytoxicity), IL-2, IL-6, TNF (a powerful inflammatory cytokine), and iNOS (the inducible form of nitric oxide synthase, which plays an important role in many inflammatory conditions).

Results included: Turmeric extract “caused a heightened expression of perforin, the effector molecule to carry out T-cell mediated immunity. It was almost double to that with curcumin which could not elicit the response beyond controls.” The better efficacy of turmeric extract for immunostimulation “was also observed when we measured the expression of concerned gemes, such as IL-2, IL-6 and perforin in assay ...” In fact, “[f]or the expression of IL-2, IL-6 and [as mentioned in quote above] perforin curcumin could not elicit response beyond controls.” “This seems notable to establish superiority of ETE in induction of certain immunologically important genes over curcumin.”

Both ETE and curcumin significantly downregulated the inflammatory cytokine TNF-alpha expression in mouse splenic T-cells.

The foot pads of mice were injected with an inflammatory agent, 2,4-dinitrofluorobenzene, to induce swelling and redness. Turmeric extract was found to inhibit generation of superoxide and hydrogen peroxide in cells from these mice significantly more effectively than curcumin, while the turmeric extract and curcumin inhibited hydroxyl radicals equivalently. “The percentage of inhibition in [superoxide] generation with ETE treatment was almost double to that of curcumin treated ones. The ETE also could inhibit [copper chloride]-ascorbate derived hydrogen peroxide generation in murine [mouse] lymphocytes by higher percentage over control; whereas the percentage of inhibition with curcumin treatment was even lower than the alcohol control.” “Thus, ETE is found to be effective antioxidant, at times better than curcumin.”

Photographs of mouse paws showed the results of the delayed hypersensitivity reaction induced by the 2,4-dinitrofluorobenzene. The paws of the animals receiving turmeric extract looked less swollen than those that received curcumin.

The results of this study provide some support for what the authors call “the general belief with Ayurvedic practioners” that a crude extract of turmeric is more effective than the purified compound curcumin in curing human ailments. Of course, the “general belief” of anyone is only anecdotal until supported by hard data.

The authors also note that “it is an age old common practice in India to have oral uptake of 5–10 g of turmeric rhizome with molasses in the morning in empty stomach.” Too bad they didn’t mention what it is that people get or expect to get from this supplementation.

A separate study² published the same year as the one above reported findings on comparative antioxidant capacities of curcumin and extract of Curcuma longa(turmeric). Because Curcuma longa has a content of 31.9% curcumin and the purity of their curcumin standard was 70%, the authors “normalized the results of antioxidant capacity to the curcumin content.” “The results expressed in this way showed the increased antioxidant activity of curcumin in C. longa extract in comparison to that in the curcumin standard in DPPH- and ABTS-scavenging assays, peroxidation of DOPC liposomes and FRAP assay. These results emphasize the role of synergistic effects of other constituents of C. longa extract on the antioxidant activity of curcumin.

However, the authors note, the curcumin standard they used was only 70% pure, with other curcuminoids in the remaining 30%. Thus, they recalculated the results on the basis of total curcuminoid content and found similar antioxidant results for turmeric extract and the curcumin standard in the ABTS test. What this suggests to us is that pure curcumin (which, unlike the curcumin “standard” used in this study, wouldn’t include other curcuminoids found in turmeric) would be, in the tests as listed above, less effective than turmeric. However, the curcumin standard did have much higher antioxidant activity than the extract in a model of enzymatic lipid peroxidation (LOX catalyzed linoleic acid hydroperoxide formation).

Another paper,³ this one published in 2002, adds to the data by reporting that dietary supplementation with an antioxidant-rich hydroalcoholic extract of the curcuma rhizome (turmeric) in human subjects resulted in a decrease in total blood lipid peroxides as well a decrease in HDL and LDL-lipid peroxidation.

They report³ that these anti-atherogenic effects were accompanied by a turmeric antioxidant-induced normalization of the plasma levels of fibrinogen (a pro-clotting factor) and the apoB/apoA ratio, suggesting additional anti-atherogenic effects.

There wasn’t a direct comparison of the effects of curcumin and turmeric in this paper, however, but the authors’ review of the literature (some of the research was carried out by the authors and others at their lab) suggests that “the main antioxidant from Curcuma, i.e., curcumin or 1,7-bis-(-4-hydroxy- 3-methoxyphenyl)-1,6-heptadiene-2,5-dione, as well as a hydro-alcoholic extract of the dry Curcuma rhizome are powerful anti-inflammatory, immunomodulating, tumor-preventing and antiatherogenic drugs [sic] suitable for clinical testing in order to assess their probable therapeutic potential.” “The curcuma antioxidants might be especially useful as antiatherogenic agents in those processes linked to a marked increase in blood lipid peroxidation such as myocardial infarction, diabetes, and dislipemias in women after menopause.”

Hopefully, we will see more research comparing the effects of the complex mixture of constituents in turmeric to that of curcumin to help untangle these complex comparisons. The difficulty of attributing the source of benefits is one reason that researchers prefer to study a single entity rather than mixtures, yet mixtures are potentially sources of benefits beyond that of a single component. The FDA compounds the problem of getting information on mixtures by refusing to accept any data on beneficial results derived from mixtures in the determination of qualified health claims for dietary supplements and foods on the basis that it is unclear what is responsible for the benefits. What we are likely to see in further detailed comparisons of turmeric and curcumin, we think, is differences in efficacy that are dependent upon what biochemical processes are being examined, ie. sometimes turmeric may be more efficacious and other times curcumin may.

On the basis of the limited information currently available, we prefer to supplement with turmeric root powder to get the full spectrum of curcuminoids as compared to curcumin alone. For optimal effects, we suggest taking powdered turmeric with meals. We have a glass of wine with lunch and dinner (Durk) or just with dinner (Sandy), and the wine, acting as a delightful hydroalcoholic extracting agent, may further the beneficial effects of turmeric as well as providing benefits of its own (such as increasing HDL and decreasing insulin resistance).

References

1. Chakravarty et al. Comparison of efficacy and turmeric and commercial curcumin in immunological functions and gene regulation. Int J Pharmacol 5(6):333-45 (2009).
2. Rackova et al. Comparative study of two natural antioxidants, curcumin and Curcuma longa extract. J Food Nutr Res 48(3):148-52 (2009).
3. Miquel et al. The curcuma antioxidants: pharmacological effects and prospects for future clinical use. A review. Arch Gerontol Geriatr 34:37-46 (2002).

Dietary Intake of Docosahexaenoic Acid (DHA) 
Provides More Neuroprotection in Transgenic 
Mice That Can Convert Omega-6 Fatty Acids to 
Omega-3 Fatty Acids

A very recent study¹ reports on the neuroprotective effects of DHA in a mouse Parkinson’s disease model. The unique aspect of this experiment was that the mice were transgenically altered to express an n-3 fatty acid desaturase that allowed the mice to convert n-6 polyunsaturated fatty acids into n-3 polyunsaturated fatty acids, something that neither mice nor humans can do under normal conditions.

The authors had recently published a report in which they identified a “remarkable” neuroprotective effect of omega-3 (n-3) polyunsaturated acids (PUFA) in a mouse model of Parkinson’s disease. They found that consumption of an n-3 PUFA-enriched diet for 10 months led to higher levels of DHA (docosahexaenoic acid) in the brain which protected from the detrimental effects of MPTP, a free radical neurotoxin (including protection against MPTP inducing the development of a Parkinson’s disease-like condition). They reported that increased expression of BDNF (brain-derived neurotrophic factor, important in learning and memory and neurogenesis) was an important factor in this protection by DHA.

As mice, like humans, are unable to convert n-6 PUFA to n-3 PUFA, the researchers incorporated the missing n-3 PUFA desaturase into a transgenic mouse called the FAT-1 mouse. The FAT-1 mouse is a mouse model now being used to study various diseases such as liver cancer and atherosclerotic lesions for beneficial effects of increased production of n-3 fatty acids. In the new study, the authors compared the protective effects of the increased n-3 PUFA in the FAT-1 mouse to the protective effects of DHA supplementation with dietary intake of DHA in non-transgene mice.

The results showed that, “the increase in brain DHA provided by FAT-1 was insufficient to induce a frank neuroprotective effect against MPTP neurotoxicity, in comparison to the effects reached with DHA dietary supplements.” “Nevertheless the strong correlations between nigral [area of brain most strongly affected by MPTP] constituents and DHA levels found in the present study reinforce the hypothesis that n-3 PUFAs are beneficial against MPTP-induced denervation. They also support the implication of n-3 PUFAs in reducing inflammatory processes. Overall, the present data combined with our previous work strongly suggest that dietary intervention with preformed DHA [as found in diet or dietary supplements] constitutes a potent method to achieve neuroprotective levels in the brain, particularly in the context of PD [Parkinson’s disease].”

We take 9 capsules a day (Durk) or 8 capsules a day (Sandy) of our high-potency omega-3 formulation for our hearts and minds, which provides about 2 grams a day of DHA. We recommend 1 gram of DHA per day for most people.

References

1. Bousquet et al. Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson’s disease. J Lipid Res 52:263-71 (2011).

Post-Operative Cognitive Decline 
Associated with a Cytokine Cascade Triggered 
by Tumor Necrosis-Factor-Alpha

Post-operative cognitive decline has been for many years a little known (by potential surgical patients) risk of operations. It is particularly common following open heart surgery, such as bypasses and opening blocked arteries with balloons. We had a good friend who had a heart transplant and was reported by those living in close proximity to him to have had a mental decline afterward from which he never recovered; he died a couple of years later.

A new paper¹ reports on mechanisms underlying postoperative cognitive decline. As the authors point out, “[c]ritical illness and postoperative recovery are often associated with cognitive decline, including memory dysfunction, especially in the elderly …” The incidence of postoperative delirium reportedly ranges from “28 to 92% in hospitalized medical patients, depending on age, patient comorbidity, and the type of surgery …” though this acute confusion state is said to be typically limited in duration and potentially reversible. However, postoperative cognitive dysfunction is a longer lasting type of damage detected through a battery of neuropsychological tests. “After major noncardiac surgery, POCD [post-operative cognitive dysfunction] occurs in 7 to 26% of patients, and is independently associated with poor short-term and long-term outcomes, including an increased risk of mortality, inability to cope independently, premature unemployment, and possible permanent dementia.” The authors used a mouse model of orthopedic surgery to search for underlying immune and inflammatory mechanisms for this serious problem.

The researchers report that following surgery under general anesthesia, TNF-alpha (tumor necrosis factor alpha, a major inflammatory cytokine) was the first cytokine to be released and peaked at 30 minutes after surgery. In contrast, they note, other important proinflammatory cytokines such as IL-1beta and IL-6 were not detected until 6 hours postoperatively.

Moreover, the authors found that preoperative administration of a TNF-alpha antibody “effectively reduced the amount of systemic IL-1beta both at 6 and 24 hours following surgery.” Administering the TNF-alpha antibody 1 hour AFTER surgery had no effect. Although the inflammatory cytokine IL-1beta at low levels is important for hippocampal learning and memory, high levels are reported to interfere with long-term potentiation and synaptic plasticity.¹

The authors note that: “Therapy with TNF-alpha inhibitors is clinically well established and already offers beneficial effects in inflammatory conditions, such as rheumatoid arthritis, Crohn’s disease, and ankylosing spondylitis, and may thus be useful for the prevention of postoperative cognitive decline in susceptible individuals.”

Natural products that attenuate the effects of TNF-alpha include quercetin² (as contained, for example, in our high potency antioxidants, multivitamin, multimineral formulation, the herbal Cat’s Claw,³ xanthohumol (as found in hops),⁴ fish oil⁵ (as is found in our premium blend of omega-3 fatty acids derived from coldwater fish, highly concentrated and purified), and N-acetylcysteine.⁶

References

1. Terrando et al. Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci USA 107(47):20518-22 (2010).
2. Chuang et al. Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-alpha-mediated inflammation and insulin resistance in primary human adipocytes. Am J Clin Nutr 92:1511-21 (2010).
3. Sandoval et al. Cat’s Claw inhibits TNFalpha production and scavenges free radicals: role in cytoprotection. Free Radic Biol Med 29(1):71-8 (2000).
4. Lupinacci et al. Xanthohumol from hop (Humulus lupulus L.) is an efficient inhibitor of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha release in LPS-stimulated RAW 264.7 mouse macrophages and U937 human monocytes. J Agric Food Chem 57:7274-81 (2009).
5. Grimble et al. The ability of fish oil to suppress tumor necrosis factor alpha production by peripheral blood mononuclear cells in healthy men is associated with polymorphisms in genes that influence tumor necrosis factor alpha production. Am J Clin Nutr 76:454-9 (2002).
6. Muscari et al. Long-term treatment with N-acetylcysteine, but not caloric restriction, protects mesenchymal stem cells of aged rats against tumor necrosis factor-induced death. Exp Gerontol 41:800-4 (2006).

Correlated Genotypes in Friendship Networks

You are probably more closely related to your friends than you realize. A new paper1 reports on a study of six available genotypes from the National Longitudinal Study of Adolescent Health to test for genetic similarity between friends. Friendship in humans is unusual compared to other mammalian species in that humans can form stable, nonreproductive unions (e.g., having nothing to do with kinship) to one or more friends.

As the study’s authors note, genetic associations have long been postulated in human self-selected social groups but there has been little evidence to support these suppositions.

A study in laying hens cited in paper #12 found that the feather condition of an individual was strongly influenced by the genotypes of its neighbors. In fact, in that study the average phenotypic (gene expression) effects of the “social” genes were more than two times greater than the genes with a direct effect on an individual’s own genome. “Interestingly, some of the genes with indirect or associative effects in hens involve the serotonin pathway, which has also been shown to influence social behavior in humans.”1

Moreover, the new paper notes that people tend to associate with other people they resemble, a process called “homophily” (“birds of a feather flock together”), whereas people may also choose friends who are different from themselves in certain selected traits, a process called “heterophily” (“negatives attract”).

The authors began their study with the accepted notion that people with similar genotypes may become associated because of living physically close to them (population stratification). “However, no work has yet established that, net of such stratification, there are any genes that are correlated (either positively or negatively) between individuals in nonreproductive, friendship unions. To study whether such correlation exists, we analyzed two independent samples with information about respondents’ genes and about respondents’ friendship ties and social networks: the National Longitudinal Study of Adolescent Health (Add Health) and the Framingham Heart Study Social Network (FHS-Net).”

“In Add Health, subjects were genotyped for one marker each in the DRD2, DRD4, CYP246, MAOA, SLC6A3, and SLC6A4 genes.” The DRD2 and DRD4 are genes for two different dopamine receptors, important in behavior such as reward. The DRD2 dopamine receptor, for example, has been associated with alcoholism1 (and perhaps other forms of addiction). CYP246 is linked to detoxification of otherwise damaging substances. Figures 1 and 2 of the paper1 illustrate how genotypes for DRD2 and CYP246 were distributed in the largest connected component of the friendship network in Add Health. “Notably significant clusters of similar genotypes for DRD2 suggest the possibility of homophily, but the substantial absence of any connection between individuals with minor alleles of CYP246 suggests possible heterophily.”

The authors summarize: “An important implication of these results is that genetic structure in human populations may result not only from the formation of reproductive unions, but also from the formation of friendship unions within a population.” As an example, they explain that an individual who is susceptible to alcoholism might choose friends with the same genotype (homophily) who would be more likely to influence her to drink and that, if so, an association between alcoholism and genotype that does not take account of the influence of friends’ genotypes could overstate the effect of an individual’s genes.

“In some sense, humans might be ‘metagenomic’ not just with respect to the microbes within them, but also with respect to the humans around them.”

We speculate that the attraction of people with different CYP246 variants might provide an advantage to a social group by having members with different abilities to deal with food toxins, thus reducing the risk of a sudden population collapse from a food toxin to which all were susceptible.

References

Fowler et al. Correlated genotypes in friendship networks. Proc Natl Acad Sci USA 108(5):1993-7 (2011).
Biscarini et al. Across-line SNP association study for direct and associative effects on feather damage in laying hens. Behav Genet 40:715-27 (2010).