March 2013 Blog with Durk and Sandy

Appetizers

The main difference for the history of the world if I had been shot rather than Kennedy is that Onassis probably wouldn’t have married Mrs. Khrushchev.

— Nikita Khrushchev

After The Wizard of Oz I was typecast as a lion, and there aren’t all that many parts for lions.

— Bert Lahr

A lady came up to me on the street and pointed at my suede jacket. “You know a cow was murdered for that jacket?” she sneered. I replied in a psychotic tone, “I didn’t know there were any witnesses. Now I’ll have to kill you, too.”

— Jake Johannsen

Never go to a doctor whose office plants have died.

— Erma Bombeck

How small of all that human hearts endure That part which laws or kings can cause or cure!

— Samuel Johnson

Feeling Burned Out?

Reduced Sensitivity to Glucocorticoid Feedback Regulation of Inflammatory Cytokines in Vitally Exhausted Men

In our article on leptin and increased body fat (Durk & Sandy Life Extension Newsletter,Oct. 2012), we noted that leptin, a negative feedback adiposity signal, is less effective in the presence of inflammatory conditions.A One source of inflammation is stress.^1,2Researchers found that male industrial employees suffering from vital exhaustion (a combination of unusual fatigue, loss of energy, and irritability) have high levels of inflammatory cytokines such as IL-1beta, TNF-alpha, IL-6, and C-reactive protein (CRP).¹ In another study,² researchers reported that daily social interactions that are negative and competitive are associated with increased proinflammatory cytokine activity. Under these inflammatory conditions, one would expect leptin signaling to be impaired, resulting in weight gain and reduced satiety.

The authors of the paper on vital exhaustion in men¹ report that the increased inflammatory responses of activated monocytes are generally normalized by glucocorticoid feedback regulation, but there is a reduced release of endogenous cortisol in individuals with vital exhaustion. Hence, these individuals, because of inadequate glucorticoids, do not adequately downregulate inflammatory responses and, thus, have increased plasma levels of inflammatory cytokines, such as those listed in the paragraph just above. As the authors of paper #1 explained, “... more dexamethasone [a glucocorticoid] was required to suppress IL-6 release in response to the same LPS stimulus in highly exhausted subjects as compared with nonexhausted individuals.” Inadequate shutting down of monocyte release of proinflammatory cytokines in response to LPS (lipopolysaccharide, a bacterial cell wall component that strongly stimulates immune system activation) can result in a chronic inflammatory state such as is associated with obesity and an increased risk of cardio­vascular disease.

Consumption of Hydrogen (in Water) Prevents Stress-Induced Impairments in Hippocampus-dependent Learning in Mice

We continue our Hydrogen Therapy Series here with a paper that found protection by hydrogen against stress-induced learning impairments in mice.

A recent paper³ reports that mice subjected to 4 to 8 weeks of chronic physical restraint stress had a variety of cognitive impairments and significantly increased oxidative stress in the brain, which is a known inducer of inflammation. Consistently with increased inflammation, there was a decline in the proliferation of neural progenitors (neurogenesis) in the stressed mice.

Treating the stressed mice with hydrogen-saturated water was able to restore neurogenesis and improve their performance in passive avoidance learning, novel recognition test, and in the Morris Water Maize test (where the mice have to find a hidden platform in a tank of water to avoid having to continually tread water).

Supplementation with long chain oligosaccharides (a form of inulin) is one way to provide a food that humans cannot digest for consumption by resident bacteria in the lower intestine that they can use to produce hydrogen. Data indicate that hydrogen is produced and released over a longer period of time than when hydrogen is ingested in water or saline or when hydrogen is inhaled as a gas. Some of the hydrogen is consumed by other resident bacteria, but most diffuses out of the lower intestine and throughout the body, passing through the blood-brain barrier and even reaching into mitochondria, before being exhaled out from the lungs.

We are particularly impressed by the ability of hydrogen to reach into cellular compartments (especially mitochondria, subject to considerable oxidative stress) that many antioxidants are unable to do. Many other supplements have been reported to have potent antiinflammatory effects, though not necessarily including data on the ability to pass into mitochondria; a few examples are foods such as fruits,⁴ berries,⁴ whole grains,⁴ and fatty fish,⁴ as well as nutrients such as choline⁵ and betaine,⁵ and herb/spice constituents including curcumin,⁶ epigallocatechin gallate (EGCG),⁷ and cinnamon.⁸

References

1. Chen et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med. 12(4):425 (2006). 
   1. Wirtz et al. Reduced glucorticoid sensitivity of monocyte interleukin-6 production in male industrial employees who are vitally exhausted. Psychosomatic Medicine.65:672-8 (2003). 
   2. Chiang et al. Negative and competitive social interactions are related to heightened proinflammatory cytokine activity.Proc Natl Acad Sci USA. 109(6):1878-82 (2012). 
   3. Nagata et al. Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology. 34:501-8 (2009). 
   4. Wu and Schauss. Mitigation of inflammation with foods. J Agric Food Chem. 60:6703-17 (2012). 
   5. Detopoulou et al. Dietary choline and betaine intakes in relation to concentration of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr. 87:424-30 (2008). 
   6. Shehzad et al. New mechanisms and the anti-inflammatory riule of curcumin in obesity and obesity-related metabolic diseases. Eur J Nutr. 50:151-61 (2011). 
   7. Kumaran et al. Attenuation of the inflammatory changes and lipid anomalies by epigallocatechin-3-gallate in hypercholesterolemic diet fed aged rats. Exp Gerontol.44:745-51 (2009). 
   8. Kim et al. Suppression of age-related inflammatory NF-kappaB activation by cinnamaldehyde. Biogerontology. 8:545-54 (2007).

Restoration of Glucocorticoid Sensitivity to Downregulation of Monocyte Release of Pro-Inflammatory Cytokines in Patients with COPD and Asthma

As explained above, in vitally exhausted men, monocytes are insensitive to glucorticoid-induced downregulation of proinflammatory cytokine secretion. Interestingly, histone deacetylase-2 (HDAC2), “a critical component of corticosteroid anti-inflammatory action, is impaired in lungs of patients with COPD and correlates with disease severity.”⁹ “... curcumin acts at a post-translational level by maintaining both HDAC2 activity and expression, thereby reversing steroid insensitivity by either CSE [cigarette smoke extract] or oxidative stress in monocytes. Curcumin may therefore have potential to reverse steroid resistance, which is common in patients with COPD and asthma.”⁹ The similarity of this mechanism to the glucorticoid insensitivity to suppressing proinflammatory cytokine release in monocytes of men with vital exhaustion hints (but does not prove) that HDAC2 may be involved in the glucocorticoid insensitivity that was found in vital exhaustion and, therefore, curcumin may be able to restore glucocorticoid sensitivity in that disorder as was found in COPD patients.

Another activator of HDAC2 is sulforaphane (found in cruciferous vegetables, such as broccoli). It has been reported to reactivate HDAC2 in alveolar macrophages via activation of Nrf2 (a major regulator of antioxidant genes) and thus restore sensitivity to corticosteroid downregulation of proinflammatory cytokine release.¹⁰

Another paper¹¹ reports that “[l]ow subbronchodilator doses of theophylline can also act as corticosteroid-sparing drugs in asthmatics.” The authors note that although curcumin and low-dose theophylline “appear to restore corticosteroid [antiinflamatory] function and may initially provide therapeutic potential, they lack specificity [e.g., they affect other chemical pathways] and the mechanism of their action is unknown.”

9. Mela et al. Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. 39(3):312-23 (2008). 
   10. Malhotra et al. Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticoid sensitivity in macrophages from COPD patients. J Clin Invest. 121:4289-302 (2011). 
   11. Marwick et al. Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy. Expert Opin Ther Targets.11(6):745-55 (2007).

Acute Psychological Stress in Men: Higher Body Mass Index Associated with Reduced Glucocorticoid Inhibition of Inflammatory Cytokines

“Our data suggest that with increasing BMI, glucocorticoids are less able to inhibit TNF-alpha [tumor necrosis factor-alpha, a proinflammatory cytokine] production following stress. This might suggest a new mechanism linking BMI with elevated risk for adverse cardiovascular outcomes following stress.”¹²

A recent paper reports on reduced ability of glucocorticoid feedback signaling to inhibit inflammation (as assessed by monocyte TNF-alpha production) following experimental stresses (the Trier Social Stress Test, which is a combination of a mock job interview and mental arithmetic task) in 42 male subjects aged 21-65.¹² This is a lot less stress than vital exhaustion (as discussed above), but the decrease in glucocorticoid feedback signaling against inflammation (as indicated by reduction of monocyte TNF-alpha production) was similar. Although increased BMI was associated with reduced effectiveness of glucocorticoid suppression of TNF-alpha production under conditions of stress, baseline gluco­corticoid sensitivity was not associated with BMI.¹² “... mental stress might increase cardiovascular risk in overweight persons by lowering the capacity of GCs [glucocorticoids] to down-regulate monocyte cytokine release.”¹² A likely mechanism is leptin resistance, which, as noted above, is increased under proinflammatory conditions and also in obesity, which would link inflammation with increased adiposity and BMI. However, leptin was not discussed in this paper.¹²

12. Wirtz et al. Higher body mass index (BMI) is associated with reduced gluco­corticoid inhibition of inflammatory cytokine production following acute psychosocial stress in men. Psychoneuroendocrinology. 33:1102-10 (2008).

To trace something unknown back to something known is alleviating, soothing, gratifying, and gives moreover a feeling of power. Danger, disquiet, anxiety attend the unknown —the first instinct is to eliminate these distressing states. First principle: any explanation is better than none ... The cause-creating drive is thus conditioned and excited by the feeling of fear.

— Friedrich Nietzsche

Anthocyanins to Prevent Obesity and Diabetes Anthocyanins Enhance Secretion of the Adipocytokines Leptin and Adiponectin Without Activating PPARgamma-induced Lipogenesis

Thiazolidinedione drugs used to treat diabetes (example: pioglitazone) are powerful activators of PPARgamma, which can potently increase insulin sensitivity, but unfortunately also activate PPARgamma target genes that increase lipogenesis (fat synthesis), thereby inducing weight gain as an undesirable side effect. A 2004 paper¹reported that anthocyanins (colored molecules such as cyanidin or cyanidin 3-glucoside found in blueberries and many other blue or purple fruits and vegetables but not beets) are able to increase the release of adipocytokines (specifically adiponectin and leptin) from rat adipocytes (fat cells) that enhance insulin sensitivity without activating PPARgamma induced lipogenesis, by a mechanism that may be different from that of thiazolidinediones. As the authors summarize: “[t]hese data suggest that anthocyanins have a potency of unique therapeutic advantage and also have important implications for preventing obesity and diabetes.”¹

The researchers also report that in another study, the gene expression of adiponectin was upregulated in white adipose tissue in mice fed an anthocyanin supplemented diet. As we mentioned in the article just above, leptin acts as a signal that reduces food intake and increases energy expenditure. In an earlier study,² some of the same researchers that published paper #1 found that purple corn color, enriched with the anthocyanin cyanidin 3-O-beta-D-glucoside, prevented obesity and ameliorated hyperglycemia in mice fed a high fat diet. In that paper, the scientists also reported that dietary anthocyanin normalized hypertrophy of the adipocytes in the epididymal white adipose tissues. Hypertrophy of adipocytes, an increase in the size of fat cells, results in larger, more insulin resistant cells.

Anthocyanins Effective at Nanomolar Quantities

In a different paper,³ scientists found that anthocyanins were protective against oxidative stress induced by high doses of glucose in pancreatic mouse beta-cells despite their very low bioavailability because they are bioactive at NANOMOLAR quantities. Thus, very small amounts were required and could be effective intracellularly even at their low bioavailability. “Mouse pancreatic beta-cells (TC-3) were treated with chokeberry anthocyanins [chokeberries are purple/dark blue colored like blueberries or bilberries] at concentrations between 0 and 3 nM, expressed as cyanidin 3-galactoside. ... the viability and proliferation of TC-3 cells is stimulated by all tested anthocyanin concentrations.” “Our data shows that the oxidative stress induced by 100 mM glucose determined a significant decrease (50%) of GSH [glutathione]. The intracellular GSH level increased significantly (25%) in cells preincubated with 0.2 nM chokeberry anthocyanins compared to glucose (100 mM) treated cells, but remain under the normal GSH levels in untreated pancreatic beta-cells. The GSH level in cells treated with the highest concentration of chokeberry anthocyanins (1.0 nM) and 100 mM glucose was restored, being even HIGHER than for untreated cells.”³ (emphasis added)

These protective effects of chokeberry anthocyanins at such low concentrations are remarkable and, although this paper did not report changes induced by the anthocyanins in inflammatory cytokines, oxidative stress induced by high levels of glucose is known to be associated with increased inflammation. Hence, anthocyanins would likely have anti-diabetic effects, as has been reported in other studies (cited in paper #3).

In paper #1, the researchers explain that “[a]nthocyanins are the largest group of water-soluble pigments in the plant kingdom. They are widely distributed in the human diet through crops, beans, fruits, vegetables, and red wine, suggesting that we ingest significant amounts of anthocyanins from plant-based daily diets.” The authors reported that in four of their earlier papers (citations provided in paper #1), they showed that in addition to antioxidant properties, cyanidin 3-O-beta-D-glucoside, a typical anthocyanin, also had anti-inflammatory properties based on in vitro and in vivo studies.

References

1. Tsuda et al. Anthocyanin enhances adipocytokine secretion and adipocyte-specific gene expression in isolated rat adipocytes. Biochem Biophys Res Commun. 316:149-157 (2004). 
   2. Tsuda et al. Dietary cyanidin 3-O-beta-D-glucoside-rich purple corn color prevents obesity and ameliorates hyperglycemia in mice. J Nutr.133:2125-30 (2003). 
   3. Rugina et al. Protective effect of chokeberry anthocyanin-rich fraction at nanomolar concentrations against oxidative stress induced by high doses of glucose in pancreatic beta-cells. Bul UASVM, Vet Med. 68(1):313-9 (2011).

Chronic Inflammation and Superoxide Radicals Produced by NADPH Oxidase Are Reported to be the Main Determinants of Physical Frailty in Older Adults

A new study¹ reports that physical frailty (assessed on the basis of gait speed) in 280 ambulatory elderly (over 60 years of age) is associated with superoxide anion overproduction by NADPH oxidase and low-grade chronic inflammation.

In the studied group, 64% of patients had a walking speed less than 0.8 meter/second. The higher prevalence of slow walkers in the subjects studied here as compared to some other studies is, the authors explain, probably due to the fact that 37% of the subjects were more than 83 years old. “Our group had already shown that inflammation and oxidative stress are linked in older people by reciprocal activations. Indeed, inflammation is accompanied by activation of NADPH oxidase, particularly through TNF-alpha, leading to overproduction of superoxide anion in stressful situations.”¹

References

1. Baptista et al. Low-grade chronic inflammation and superoxide anion production by NADPH oxidase are the main determinants of physical frailty in older adults. Free Radic Res.46(9):1108-14 (2012).

Procyanidins from Grapes Shown to Be Inhibitors of Human Endothelial NADPH Oxidase

A very useful new paper² reports that procyanidin-rich grape pomace, a commonly available by-product of the wine industry processing of grapes, was found to be a natural inhibitor of NADPH oxidase.

As explained by the authors,² NADPH oxidase expression and superoxide anion production were shown to correlate with the severity of atherosclerosis, plaque stability, oxidative stress in coronary artery disease, and plasma metalloproteinase-9 levels, suggesting that NADPH oxidase could be a target for reducing the risk of atherosclerosis. The authors, however, state that there are no inhibitors of this enzyme that can be used in therapeutics, nor are there any specific inhibitors of the enzyme isoforms. Thus, the researchers initiated this study hoping to identify a safe, natural inhibitor of NADPH oxidase; they focused on three different procyanidin-rich fractions from an aqueous extract of grape pomace that included skin, seeds, and a small number of stems. These were compared to the effects of two known NADPH oxidase inhibitors diphenylene iodonium (DPI) and apocynin.

Interestingly, there was a differential effect of the grape procyanidin-rich fractions on NADPH oxidase and on superoxide anion, in that the F4, F5, and F6 procyanidin fractions (10–100 ng/ml) inhibited NADPH oxidase activity in a concentration-dependent manner, yet only the highest concentrations of these fractions were effective as superoxide scavengers. Thus, the effects as superoxide scavengers and as inhibitors of NADPH oxidase were independent effects.

In addition, the researchers found that the three grape pomace procyanidin fractions were effective inhibitors of NADPH oxidase in living HUVEC (human umbilical vein endothelial cells), being active at both the extra- and intracellular level.

The authors claim that “[t]he NADPH oxidase inhibition activity described in our work for procyanidins from grape pomace has not been reported before, despite the inhibitor activity on this oxidase having been described for other components of grapes.” They cite, for example, a study in which polyphenols from grape extracts reduced NADPH oxidase subunit expression in human neutrophil mononuclear cells and in an endothelial cell line.

We are delighted that grape procyanidins were effective as NADPH oxidase inhibitors, as we have been on the lookout for a safe, effective and potent natural inhibitor of this enzyme for some time. The enzyme is hyperactive in the production of oxidative stress associated with many serious conditions, including cardiovascular disease and diabetes, and NADPH oxidase is the major source of superoxide anions in the vasculature.²

2. Alvarez et al. Procyanidins from grape pomace are suitable inhibitors of human endothelial NADPH oxidase.J Cell Biochem.

The Hydrogen Therapy Series Continued Measurement of Hydrogen Gas Emitted From the Skin During Inhalation of Hydrogen-Rich Air

As we have mentioned, after the production of hydrogen in the lower intestinal tract by resident microbes, the hydrogen diffuses throughout the body and is exhaled from the lungs. But the gas also leaves the body by being released from the skin, as discussed in a paper¹ presented in a poster session on May 15, 2011 at a scientific c-onference held at the Colorado Convention Center. The researchers propose that the measurement of this skin-emitted hydrogen is a convenient way to monitor the increase and then decrease of hydrogen following the inhalation of hydrogen gas. The “skin gases were obtained from perfusion gas passing through a chamber covered by the palm and the forearm skin gas in a Tedlar bag.”¹ This would also appear to be a useful way to monitor hydrogen gas production by the resident microbiota in the lower digestive tract.

The poster reported that “[t]o reach the equilibrium levels of skin H2 during H2inhalation, at least 30 min. was needed, whereas the skin H2 rapidly decreased after the cessation of H2 inhalation and recovered to the baseline level within 10 to 20 min.” The production by resident microbiota of hydrogen gas by processing of a meal containing indigestible carbohydrates that reach the lower digestive tract can result in increasing hydrogen gas for hours before decreasing to baseline levels. The ability to monitor this increase and the following decrease by skin-emitted hydrogen could be very convenient and likely to be relatively inexpensive. The hydrogen flow through the skin would also provide significant protection against exposure to the skin of environmental substances that increase oxidative stress and inflammation (particularly when it involves hydroxyl radicals and peroxynitrite) such as radiation, ultraviolet light, or ozone.

References

1. Shimouchi and Nose. Changes in Hydrogen Gas Release from the Skin During Inhalation of Hydrogen-rich Air. Am J Respir Crit Care Med.183:A1682 (2011).

Hydrogen and Radiation Protection

A new paper,² published Sept. 2012, reports (“for the first time”) the protective effect of hydrogen gas in irradiated cells and in mice. “A randomised, placebo-controlled investigation also showed consumption of H2 can improve the quality of life of patients treated with radiotherapy for liver tumours. These encouraging results suggested that H2 has a potential as a radioprotective agent with efficacy and non-toxicity.”

The researchers note that, as we have mentioned before, hydroxyl radical is the determinant species for reactions with biological molecules. “It was estimated that 60–70% of the IR [irradiation]-induced cellular damage was caused by hydroxyl radical.”² “Studies in the late damages in cardiac myocyte and pulmonary alveoli showed pretreatment of H2 significantly suppressed the radiation-induced fibrosis.”² For survivors of cancers treated with radiotherapy, late appearing damage can show up years or even decades after the radiation treatment, with serious life-shortening effects such as accelerated atherosclerosis or fibrosis. Hence, hydrogen could be a useful method of reducing these late effects.

2. Chuai et al. Molecular hydrogen and radiation protection. Free Radic Res.46(9):1061-7 (2012).

Hepatic Oxidoreduction-Related Genes Are Upregulated in Rats By Hydrogen-Saturated Drinking Water

This recent paper³ reports on an experiment in which rats drank hydrogen-saturated water for four weeks and resulting gene changes in the liver were studied with DNA microarrays. “Our major finding in the present study was that drinking of hydrogen water altered the hepatic gene expression profile. Taken together with previous studies, the hepatic oxidoreduction-related gene uprregulation observed in this study appears to confirm the findings reported to date concerning the antioxidant effect of hydrogen water.”

Interestingly, the researchers observed upregulation of genes for cholesterol biosynthesis. However, they also observed that primary bile acid synthesis pathway and steroid hormone biosynthesis pathway-related genes such as Cyp27A1, Cyp3A2, and Hsd17b6 were upregulated in the hydrogen water-drinking group.

This suggests, they propose, that pathways of cholesterol catabolism (disposal) were promoted by the hydrogen water, which resulted (as a compensatory effect) in upregulation of the genes for cholesterol synthesis to normalize levels of cholesterol.

Another result was the decrease of liver TBARS (a measure of lipid peroxidation) detected by DNA microarray analysis, indicating reduction of oxidative stress by hydrogen water.

3. Nakai et al. Hepatic oxidoreduction-related genes are upregulated by administration of hydrogen-saturated drinking water. Biosci Biotechnol Biochem.75(4):774-6 (2011).

Medium Chain Triglycerides 
Wash ’Em Down With Niacin

Coconut Oil Increases Tomato Carotenoid Uptake as Compared to Safflower Oil in Mongolian Gerbils Fed Whole Tomato Powder

A new study¹ reports beneficial effects in accumulating carotenoids from a “salad” of powdered tomatoes for Mongolian gerbils eating a diet of 10% whole tomato powder along with a 20% safflower oil diet or an 18% coconut oil plus a 2% safflower oil diet (the latter was added to prevent essential fatty acid deficiency). The authors report that Mongolian gerbils are a good rodent model for humans ingesting tomatoes as “the lipoprotein profiles of the gerbil are more similar to humans than most other rodents, making carotenoid metabolism findings more relevant than those results in other species.” In addition, gerbils are reported to accumulate tomato carotenoids in levels proportionate to humans.¹ Coconut oil is a good source of medium chain triglyceride fats, while safflower oil is the most commonly used vegetable oil in commercial salad dressings. The purpose of the study was to determine how the coconut oil plus low-dose safflower oil compared to the high-safflower oil for the tissue uptake of carotenoids from the powdered tomatoes. The authors note that recent studies have suggested that the combination of carotenoids derived from whole tomato powder may be more effective in disease prevention than lycopene alone.¹ Tomatoes are known to contain the carotenoids phytoene, phytfluene, alpha-carotene, Z-carotene, and beta-carotene, as well as lycopene and lutein.

The results showed that “the coconut oil feeding resulted in significantly increased tomato carotenoid bioaccumulation compared to safflower oil in all tissues measured except the spleen and skin. Increased tissue accumulation may have been a result of increased solubility of tomato carotenoids in the intestinal lumen, portal absorption of medium-chain fatty acids, a cholesterol-mediated change in the flux of carotenoids between the liver and peripheral tissues, facilitated carotenoid cellular uptake by specific fatty acids, or the combination of the four.”¹

Also observed was that serum cholesterol in the coconut-oil fed animals was significantly higher than that of the safflower-fed animals. The safflower oil-fed gerbils, however, had significantly higher liver cholesterol than the coconut-oil fed animals. These findings are consistent with what is known of the fatty acid content of these oils. You can avoid the increase in serum or liver cholesterol levels by not adding vegetable oils at all to your salad or using a smaller quantity than fed to the gerbils, but then you might absorb smaller amounts of the carotenoids than the gerbils did in this study. We get around this by both using smaller amounts of oil and eating larger amounts of carotenoid containing veggies (as well as taking supplements that contain particular carotenoids of interest, such as lycopene, lutein, zeaxanthin, and astaxanthin). And, of course, we both take niacin.

Keeping Cholesterol Under Control with Niacin

Another solution to high cholesterol levels that doesn’t require you to meddle with your salad is niacin and, as we explain below, the mechanism(s) responsible for the remarkable effectiveness if niacin in lowering LDL and increasing HDL is, despite decades of research, still unknown.

Durk’s Familial Hypercholesterolemia Succumbs to Niacin

We both take niacin on a daily basis, but it has been even more important for Durk who, before finding out about niacin quite a few years ago, had always had a problem with hypercholesterolemia, which ran in his family.

But How Does Niacin Work?

The mystery of how niacin works is under intensive investigation (even by pharmaceutical companies, hoping to find out mechanisms that it can use to design patentable drugs for the treatment of hypercholesterolemia in the many patients who are not treated effectively by statin drugs). Yet, as the years go by, one mechanism after another that is thought to explain how niacin works ends up explaining something but not how niacin works. A paper published two months ago² explains that the GPR109A receptor that is activated by niacin (the “niacin receptor”) and was thought to be the reason for niacin’s decrease in triglycerides and LDL cholesterol and the increase in HDL cholesterol was found to be responsible for niacin’s antilipolytic effect but not for it’s effects on triglycerides or LDL or HDL. Hence, as reported in a commentary on the new niacin GPR109A findings,³ “[b]ecause the increase in HDL-C is regarded as the most important beneficial effect of nicotinic acid [niacin], the finding that it does not involve GPR109A questions the rationale for the development of synthetic GRP109A agonists; accordingly, most drug companies have stopped their GPR109A agonist programs.” However, the commentary also explains that there is reason to believe that the “increases in HDL-C may not be responsible for the long-term effects of nicotinic acid on the development of cardiovascular diseases.”

As the commentary explains, nicotinic acid has anti-inflammatory effects which do not involve GPR109A and has been shown to release adiponectin, the antiinflammatory cytokine released by fat cells. Moreover, the paper² that was the subject of the commentary found that most effects of niacin on plasma lipid levels are not mediated by the GPR109A receptor. New data, the commentary³ suggests, points to the possibility that GPR109A may be of use in the treatment of diseases involving inflammation and immunological processes.

The niacin mystery lingers, tantalizingly. The title of the commentary paper,³appropriately points out “It Ain’t Over ’Til the Fat Lady Sings.”

References

1. Conlon et al. Coconut oil enhances tomato carotenoid tissue accumulation compared to safflower oil in the mongolian gerbil. J. Agric. Food Chem.60:8386-94 (2012). 
   2. Lauring et al. Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. ­www.ScienceTranslationalMedicine.org4(148):148ra115 (22 Aug. 2012). 
   3. Offermanns. It Ain’t Over ’Til the Fat Lady Sings. ­www.ScienceTranslationalMedicine.org4(148):148fs30 (22 Aug. 2012).

Transported to a surreal landscape, a young girl kills the first woman she meets and then teams up with three complete strangers to kill again. 
— Marin County (Calif.) newspaper’s TV listing for The Wizard of Oz

Why We Recommend 
Supplementation with L-Arginine 
(and Also Histidine)

Serum Levels of Histidine and Arginine Significantly 
Lower in Obese as Compared to Non-Obese Women: 
These Amino Acids Are Negatively Associated 
With Inflammation and Oxidative Stress in Obese Women

A recent paper¹ reports that, in a study of 235 obese women compared to 217 non-obese women controls, six amino acids (but especially histidine and arginine) were found to be significantly lower in the obese women. Importantly, both histidine and arginine were negatively associated with inflammation and oxidative stress in the obese women, while in the non-obese controls, histidine was negatively associated with oxidative stress.

We both take histidine (250 mg. three or four times a day) as an ingredient in a formulation we designed for reducing the formation of AGEs (advanced glycation endproducts).^2,3 Inhibiting the formation of AGEs is a mechanism which we consider a very likely part of histidine’s anti-inflammatory and anti-oxidative stress effects. We also take arginine, 6–12 grams/day. Arginine can also provide protection against inflammation and oxidative stress via its conversion to nitric oxide, a critical factor in regulating vasodilation and blood pressure,⁴ as well as protecting against AGE formation.⁵

References

1. Niu et al. Histidine and arginine are associated with inflammation and oxidative stress in obese women. Brit J Nutr.108:57-61 (2012). 
   2. Lee et al. Histidine and carnosine dellay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol.513:145-50 (2005). 
   3. Hobart et al. Anti-crosslinking properties of carnosine: significance of histidine. Life Sci.75:1379-89 (2004). 
   4. Giugliano et al. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine: evidence for reduced availability of nitric oxide during hyperglycemia. Circulation. 95:1783-90 (1997). 
   5. Radner et al. L-arginine reduces kidney collagen accumulation and N-epsilon-(carboxymethyl)lysine in the aging NMRI-mouse. J Gerontol. 49(2):M44-6 (1994).

Low Plasma Levels of L-Arginine in Patients with Major Depression

This recent paper⁶ reports on an investigation of the mechanisms that might explain why major depression (MD) is an independent cardiovascular risk factor. It was a small study involving 19 subjects with MD (34 ± 4 years) and 19 control subjects (34 ± 3 years). The researchers examined L-arginine influx, NO (nitric oxide) synthase activity and intracellular cGMP levels in platelets, as well as systemic factors including eNOS, iNOS, arginase, soluble guanylate cyclase, platelet aggregation and the systemic amino acid profile in both MD subjects and controls.

The results included: L-arginine influx in platelets was reduced in MD as compared to controls, from 46.2 ± 9.5 to 20.02 ± 2.12 pmol/10000000000 cells. NOS activity and intracellular cGMP were diminished in MD. The concentration of plasma L-arginine was reduced by 20% in the MD patients.

The reduced availability of arginine and reduced activity of the nitric oxide signaling pathway could be an important contributor to the increased risk of cardiovascular disease in MD patients. It is known that a deficiency of arginine can result in uncoupling of nitric oxide synthase and the subsequent production of superoxide radicals rather than nitric oxide.⁷ However, this was a small study and should, therefore, be interpreted with this limitation in mind.

6. Pinto et al. Low plasma levels of L-arginine, impaired intraplatelet nitric oxide and platelet hyperaggregability: implications for cardiovascular risk in depressive patients. J Affect Disord. 140(2):187-92 (2012). 
   7. van der Zwan et al. Systemic inflammation is linked to low arginine and high ADMA plasma levels resulting in an unfavourable NOS substrate-to-inhibitor ratio: the Hoorn Study.Clin Sci (London). 121:71-8 (2011).

Plasma Arginine Concentrations Reduced in Cancer Patients

Another paper⁸ reports an association of low plasma concentrations of L-arginine with cancer. The researchers measured plasma arginine concentrations in patients with various types of tumors, hypothesizing that L-arginine concentrations would be lower than those in age- and sex-matched control subjects. Indeed, L-arginine concentrations were found to be significantly lower than in the controls in patients with the cancers they studied: breast cancer, colonic cancer, and pancreatic cancer.

The researchers propose that disturbances of L-arginine metabolism could “contribute to the cascade of metabolic events leading to cancer cachexia.”⁸ In addition, they explain, “[i]t was recently shown that the high arginase activity of tumors is a mechanism of tumor-induced immunosuppression through depletion of arginine concentrations in the microenvironment of the tumor.”⁸

8. Vissers et al. Plasma arginine concentrations are reduced in cancer patients: evidence for arginine deficiency? Am J Clin Nutr.81:1142-6 (2005).

In the economic sphere an act, a habit, an institution, a law produces not only one effect, but a series of effects. Of these effects, the first alone is immediate, it appears simultaneously with its cause; IT IS SEEN. The other effects emerge only subsequently; THEY ARE NOT SEEN; we are fortunate if we FORESEE them.

... it almost always happens that when the immediate consequence is favorable, the later consequences are disastrous, and vice versa. Whence it follows that the bad economist pursues a small present good that will be followed by a great evil to come, while the good economist pursues a great good to come, at the risk of a small present evil.

— From an essay by Frederic Bastiat in 1850, 
“That Which is Seen and That Which is Unseen”

Ultra Easy Monetary Policy and the Law of Unintended Consequences

Stimulative monetary policies are commonly referred to as “Keynesian.” However it is important to note that Keynes himself was not convinced of the effectiveness of easy money in restoring real growth in the face of a Deep Slump. This is one of the principal insights of the General Theory.

... the Austrian school of [economic] thought, spearheaded by von Mises and Hayek, warned that credit driven expansions would eventually lead to a costly misallocation of real resources (‘malinvestments’) that would end in crisis. Based on his experience during the Japanese crisis of the 1990’s, Koo (2003) pointed out that an overhang of corporate investment and corporate debt could also lead to the same result (‘a balance sheet recession’).

— William R. White, 
currently the chairman of the 
Economic Development and Review Committee at the OECD in Paris 
(http://dallasfed.org/assets/documents/institute/wpapers/2012/0126.pdf)

 

Dietary Help for Stressed Mice and Humans

Antidepressant Effects of Whey Protein Isolate in Mice Under Chronic Unpredictable Stress

A 2011 paper¹ reports significant effects of whey protein isolate in significantly reducing depressive behavior in mice subjected to the chronic unpredictable stress (CUS) model, where the mice (except for the controls) were exposed to various types of stress (one per day in random order for 24 days). One group of the mice were treated with the selective serotonin reuptake inhibitor drug fluoxetine (Prozac^®) (10 mg/kg po), while four other groups of mice received whey protein isolate (WPI) at dose levels of 75, 150, and 300 mg/kg po. The stress tests included commonly used tests such as the tail suspension test, the forced swimming test, and the open field test. Depression-like behavior included reductions in the activity of the mice (ambulation, rearing and grooming frequencies) and increased latency (“freezing”) in the open field test. Fluoxetine treatment restored the normal value of ambulation in the stressed mice, including the grooming frequency and and rearing frequency. WPI at both 75 mg/kg po and at 150 mg/kg po normalized the ambulation and grooming frequencies. “WPI, on the other hand, normalized all the four parameters and gave results that were comparable to those of fluoxetine (10 mg/kg).”¹

Chronic Unpredictable Stress Effects on Brain Serotonin, Norepinephrine, and Dopamine

The CUS model was reported to cause a significant decrease in the neurotransmitters serotonin, norepinephrine, and dopamine in the brains of the mice. There was a significant decrease of 44.83%, 36.13%, and 63.33%, respectively, as compared to the normal control levels. Fluoxetine elevated the levels of serotonin (117.24%), norepinephrine (94.45%), and dopamine (101.33%) compared to the normal controls. WPI (75, 150, and 300 mg/kg) significantly increased serotonin (130.77%, 138.46%, and 146.15%), and increased norepinephrine (146.91%, 156.74%, and 165.45%) and increased dopamine (172%, 172.67%, and 218.67%) compared to the normal control values.¹

Protection Against Oxidative Stress in the Brain by Whey Protein Isolate

The 75 and 150 mg/kg dose WPI did not have a significant effect on glutathione compared to the depressed group but both these doses did reduce the malondialdehyde (MDA) levels. The 300 mg/kg dose of WPI resulted in a significant increase in glutathione, with an effect similar to that of fluoxetine; it also significantly decreased the MDA level down to 47.64% as compared to the depressed group.

Alpha-lactalbumin, An Important Constituent of Whey, Benefitted Rats in Earlier Studies

Two earlier studies were reported to show that rats fed am alpha-lactalbumin rich diet showed elevated brain levels of tryptophan and serotonin levels after acute and chronic administration.^2,3 In an additional study⁴ rats on alpha-lactalbumin had enhanced serotonin release and also anxiolytic (reduced anxiety) and rewarding effects. As the authors of paper #1 explained, whey protein is rich in the amino acids tryptophan, glutamine, phenylalanine, and tyrosine. While tryptophan is precursor to the neurotransmitter serotonin, phenylalanine and tyrosine are precursors to both norepinephrine and dopamine.

... And Reduced Pain in Mice

An additional paper⁵ reported that alpha-lactalbumin derived from bovine milk reduced pain in mice in several commonly used pain models (such as the acetic acid-induced writhing test) and also reduced inflammation in mice by inhibiting COX2 and phospholipase A2. The authors of this paper conclude that “[t]hese results suggest that alpha-lactalbumin can be a safe and useful natural drug for patients with severe pain that requires anti-inflammatory drugs.”

References

1. Ahmed et al. Pharmacological study of the possible antidepressant activity of whey protein isolate in mice. Aust J Basic Appl Sci. 5(12):2649-59 (2011). 
   2,3. Choi et al. Meal ingestion, amino acids and brain neurotransmitters: effects of dietary protein source on serotonin and catecholamine synthesis rates, Physiol Behav.98:156-62 (2009); Choi et al. The chronic ingestion of diets containing different proteins produces marked variations in brain tryptophan and serotonin synthesis in the rat. Neurochem Res.36:559-65 (2011). 
   4. Orosco et al. Alphalactalbumin-enriched diets enhance serotonin release and induce anxiolytic and rewarding effects in the rat. Behav Brain Res.148:1-10 (2004). 
   5. Yamaguchi et al. Novel functions of bovine milk-derived alpha-lactalbumin: anti-nociceptive and anti-inflammatory activity caused by inhibiting cyclooxygenase-2 and phospholipase A2. Biol Pharm Bull. 32(3):366-71 (2009).

Alpha-Lactalbumin, a Whey Protein With High Tryptophan Content, Improved Coping Ability in Stress-Vulnerable Human Subjects

In the study described above, mice were protected against chronic unpredictable stress by whey protein isolate. Now, in a human study (10 men, 19 women) were subjected to experimental stress and received either a casein based diet or a alpha-lactalbumin-enriched whey protein diet.⁶ The diets were isoenergetic and contained equal amounts of protein, carbohydrate, and fat.

The human version of experimental stress included 18 successive 1 minute trials in which each subject had to do mental arithmetic under time constraints while at the same time receiving different levels of industrial noise (65, 70, or 80 dB) through headphones. Additional stress was added by changing the “criterion” (the specified number of calculations that had to be solved correctly in order to supposedly have the opportunity to control the noise level) so that all subjects continued to fail each trial and thus lost the “opportunity” to control the noise level. Perhaps they would have preferred the tail suspension test. …

One of the results of the experiment was that there was a significant 48% increase in the plasma ratio of tryptophan to other large neutral amino acids (which compete with tryptophan for transport into the brain) after the alpha-lactalbumin diet as compared to the casein diet. This meant that there was more tryptophan available for entry into the brain (for conversion to serotonin) with the alpha-lactalbumin diet. The latter diet also decreased the increased cortisol released in HS subjects during acute experimental stress.

Concerning mood, “we indeed found that only in HS subjects [high stress vulnerable subjects] did feelings of depression tend to be lower after experimental stress with consumption of the alpha-lactalbumin diet compared with the casein diet. In HS subjects who showed a physiologic stress response, this dietary effect on depression was significant (P=0.007). It is important, however, not to draw strong conclusions concerning the clinical implications of this observation because the dietary effects of mood seem to be small. We also found that HS subjects reported more depressive moods at baseline than did LS subjects. This seems to agree with the observation that experiences of chronic stress may lower mood and reflect a vulnerability to depression.”⁶

“... the present data show that an alpha-lactalbumin-enriched whey protein diet may reduce in stress-vulnerable subjects the negative consequences of experimental stress on cortisol secretion and mood, probably by enhancing brain serotonin mechanisms that are involved in adaptation to stress.” The authors propose, therefore, that a tryptophan-enriched whey protein diet in healthy but stress vulnerable subjects could improve ability to cope with stress.

6. Markus et al. The bovine protein alpha-lactalbumin increases the plasma ratio of tryptophan to the other large neutral amino acids, and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress. Am J Clin Nutr. 71:1536-44 (2000).