August 2010 Blog with Durk and Sandy

What a glorious morning this is!

— Samuel Adams, to John Hancock at the Battle of Lexington, Massachusetts, 1775

 

Advertisements ... contain the only truths to be relied on in a newspaper.

— Thomas Jefferson to Nathaniel Macon, 1819. Memorial Edition 15:179

 

Perhaps an editor might begin a reformation in some such way as this. Divide his paper into four chapters, heading the 1st, Truths, 2nd, Probabilities, 3rd, Possibilities, 4th, Lies. The first chapter would be very short, as it would contain little more than authentic papers and information from such sources as the editor would be willing to risk his own reputation for their truth. The second would contain what, from a mature consideration of all circumstances, his judgment should conclude to be probably true. This, however, should rather contain too little than too much. The third and fourth should be professedly for those readers who would rather have lies for their money than the blank paper they would occupy.

— Thomas Jefferson to John Norvell, 1807. Memorial Edition 11:225

 

Science is the great antidote to the poison of enthusiasm and superstition.

— Adam Smith, 1776

D&S Comment: 
But be careful what you call science.

Alzheimer’s DiseaseFish Oil and EGCG Act Synergistically 
To Inhibit Cerebral Amyloid Beta Deposits

A 2010 paper¹ reports that in a mouse (Tg2576) model of Alzheimer’s disease, oral co-treatment with fish oil (8 mg/kg/day) and EGCG (epigallocatechin gallate, 62.5 mg/kg/day or 12.5 mg/kg/day) at 8 months of age for 6 months enhanced the production of soluble amyloid precursor protein (sAPP) that is produced via the non-amyloidogenic pathway where APP is cleaved by alpha secretase. The non-amyloidogenic pathway prevents the generation of amyloid beta and, therefore, is protective against Alzheimer’s disease (AD).

To produce the EGCG-enriched mouse food, 20 mg (low dose) or 100 mg (high dose) of the >97% EGCG was mixed with 400 g chow. (Mice eat about 5 g of food a day, while humans eat about 500 g of food a day.) 12.8 mg of fish oil was added to 400 g of the chow containing the added EGCG as described in the paper. The result was that each mouse ingested 0.25 mg of fish oil plus 1.875 mg of EGCG (high dose) or 0.25 mg of fish oil plus 0.375 mg of EGCG (low dose).

The low oral dose of EGCG alone (12.5 mg/kg/day) does not itself reduce amyloid beta deposits. However, in the mice treated with this dose of EGCG plus the fish oil, there was a marked reduction of amyloid beta deposits. The researchers found significantly elevated plasma and brain levels of free EGCG in mice co-treated with fish oil, “suggesting a mechanism of increased bioavailability conferred by the addition of fish oil to EGCG.” The authors further conclude that “moderate supplementation with EGCG and fish oil [have] significant therapeutic potential for the treatment of AD.” (Notice, they suggest TREATMENT of AD, not just risk reduction. The FDA forbids — in violation of the First Amendment — mention of any treatment effect for a dietary supplement in an ad or on a label, as that converts it magically into an unapproved new drug.)

1. Giunta et al. Fish oil enhances anti-amyloidogenic properties of green tea EGCG in Tg2576 mice. Neurosci Lett 8(471):134-8 (2010).

Predicting Future Cognitive Decline

Markers Help Predict Future Cognitive Decline 
In Individuals Without Dementia

In a new paper,¹ researchers investigated possible markers for helping anticipate future cognitive decline in people who currently have no signs of dementia. They used data from 2312 male and female subjects aged 50–80 participating in the Aspirin for Asymptomatic Atherosclerosis Trial, a large prospective study based in central Scotland. The results showed that increased levels of plasma fibrinogen (which increases with aging and is associated with greater “stickiness” of blood) and C-reactive protein (CRP, a marker for inflammation) were associated with poorer general cognitive ability, nonverbal reasoning, executive function (CRP only), processing speed, and mental flexibility after 5 years of follow-up and after adjustment for age and sex. They also found significant associations between CRP and fibrinogen and 5-year decline in executive function and nonverbal reasoning, respectively. The researchers reported that baseline plasma viscosity was associated with late-life general cognitive ability, processing speed, and mental flexibility, and with estimated lifetime cognitive decline and 5-year decline in mental flexibility. Since plasma fibrinogen is a major determinant of blood viscosity, the fact that the effects of increasing blood viscosity followed in the same direction as increasing fibrinogen is not surprising. However, adjusting for fibrinogen levels did not account for all of the changes due to increasing blood viscosity, so (as the authors suggest) other factors active in regulation of blood viscosity may be involved.

The researchers note that the effect sizes for the association between inflammatory markers (CRP) and cognitive ability were small, but the results were consistent with other studies. Though causality is still difficult to assess (for example, it may be that poorer cognitive ability in earlier life may be linked to conditions that increase inflammation in later life), it still may be useful to include tests for CRP, fibrinogen, and blood viscosity in your regular tests for assessing your state of cognitive decline in aging.

1. Marioni et al. Peripheral levels of fibrinogen, C-reactive protein, and plasma viscosity predict future cognitive decline in individuals without dementia.Psychosom Med 71(8):901-6 (2009).

Alzheimer’s Disease and ApoE4

ApoE4 Found to be Carried by VLDL and Is Possibly 
Converted by VLDL Into a More Pathogenic Form

An interesting 2010 paper¹ reports that “after every meal, VLDL fluidity is increased causing apoE4 associated with VLDL to assume a more expanded conformation, potentially enhancing the pathogenicity of apoE4 in vascular tissue.” The researchers found that “[l]ike the native apoE proteins, spin-labeled apoE4 preferentially associated with VLDL and apoE3-like protein with HDL after a moderately high-fat meal.”

As the authors explain, apoE4 is pro-inflammatory and associated with increased risks of both atherosclerosis and Alzheimer’s disease. Following a meal, there is a state of increased lipolysis (fat breakdown into fatty acids). “During lipolysis, fatty acids accumulate at the lipoprotein surface because the rate of fatty acid transfer is much slower than lipolysis.”¹ The result is an accumulation of fatty acids on the lipoprotein surface that could mediate changes in lipoprotein fluidity. Indeed, as postprandial increases in lipid levels have been “implicated in the development of atherosclerosis via repetitive injury to the arterial endothelium,” the authors suggest that it is important to understand how changes in lipoprotein fluidity resulting from an accumulation of fatty acids might affect apoE isoforms and their conformation in modulating proinflammatory processes important in atherosclerosis.

The authors find that apoE4 assumes a more linear conformation on VLDL particles as a result of increased fatty acids in VLDL due to lipolysis and that the increase in free fatty acid content is accompanied by an increase in lipid fluidity. They suggest that the dramatically changed conformation of apoE4 in postprandial VLDL may be associated with the contribution of apoE4 to atherosclerosis, but that further research will be needed to determine whether this is the case.

If the hypothesis that altered conformation of apoE4 associated with VLDL is associated with greater apoE4 pathogenicity in vascular tissues is correct, it may be useful for that reason alone to keep VLDL levels low. Fortunately, niacin very effectively reduces lipolysis as well as LDL, VLDL, and triglyceride levels. We both take 12 capsules a day of our Niacin Easy 200™ capsules (2.4 grams of niacin a day). It is important to remember that doses of niacin greater than 800 mg a day can, in some sensitive individuals, cause liver damage. If you wish to take higher doses than that, you will need to have yourself tested regularly for liver enzyme levels (as we do) to detect any possible liver damage as a result of high dose niacin which, when detected early, quickly returns to normal when niacin is discontinued.

1. Tetali et al. VLDL lipolysis products increase VLDL fluidity and convert apolipoprotein E4 into a more expanded conformation. J Lipid Res 51(6):1273-1283 (2010).

Chronic Obstructive Pulmonary Disease

Decreased Histone Deacetylase Activity Results in 
Resistance to Antiinflammatory Effect of 
Corticosteroids in COPD

COPD (which is usually but not always caused by cigarette smoking) is associated with chronic severe airway inflammation (greater in patients with advanced disease) that is resistant to the antiinflammatory effects of corticosteroids. It has been recently discovered that histone deacetylase 2 (HDAC2) activity is reduced in the lungs of COPD patients^1-3 and this is thought to possibly play a key role in the severe inflammation in COPD that is difficult to control. Normally, corticosteroids recruit HDAC2 to an activated coactivator complex, which then switches off the process that allows gene transcription and synthesis of inflammatory proteins.¹ However, in those with impaired HDAC2 activity, corticosteroids may not be effective in reducing inflammatory protein synthesis. So whereas treatment with corticosteroids can reduce inflammation in asthma, in COPD they usually provide much less benefit.¹

“Gene expression is mediated via histone deacetylases (HDACs) and other corepressors. In asthma, there is an increase in HAT [histone acetyltransferase] activity and some reduction in HDAC activity, which is restored by corticosteroid therapy. ... In chronic obstructive pulmonary disease, there is a reduction in HDAC2 activity and expression, which may account for the amplified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrosative stress as a result of cigarette smoking and severe inflammation, and may also occur in severe asthma, smoking asthmatic patients, and cystic fibrosis.”² Histones are proteins that surround DNA, regulating access to genes to either allow or prevent transcription. Histone deacetylases, by removing acetyl groups from hyperacetylated histones, suppress gene transcription.²

Carbonyl Compounds Antagonize HDAC1, HDAC2, and HDAC3

A 2010 paper⁴ has now reported that alkylation (carbonylation) of conserved cysteines in the protein structure of certain HDACs (HDAC1, HDAC2, and HDAC3) antagonizes their transcriptional repressor function. Carbonyl compounds that result from protein and lipid oxidation processes can act as powerful inducers of the formation of AGEs (advanced glycation endproducts, markers of carbonyl stress), implicated as causative factors in cardiovascular disease, cancer, complications of diabetes, and aging (AGEs increase with age). Hence, one potential way to help prevent the decrease in HDAC2 in COPD is to take supplements that scavenge carbonyls involved in the formation of AGEs. Our AGEless™ formulation contains several natural products that potently scavenge carbonyl compounds and/or inhibit the formation of and/or damage caused by AGEs including thiamine,¹¹ pyridoxine hydrochloride, bentofiamine (lipid soluble thiamine),¹² carnosine,^4a histidine,^4b alpha-lipoic acid,^4c and rutin. L-arginine (which we take as part of our InnerPower Plus™ formulation) has also been shown to attenuate the accelerated age-dependent accumulation of AGEs in hamsters with hyperglycemia and hyperlipidemia.^4d [See “Reducing Glycation Reactions for Better Health and Longer Life” in the February, 2008 issue of Life Enhancement.]

Curcumin has also been found to restore corticosteroid function in human monocytes exposed to oxidants in vitro by maintaining HDAC2.⁵ The authors of this paper propose that “[c]urcumin may therefore have potential to reverse steroid resistance, which is common in patients with COPD and asthma.”

The methylxanthine theophylline (with a related chemical structure to caffeine) has also been reported to induce histone deacetylase (HDAC) activity at low doses in human studies^6,7 to decrease inflammatory gene expression.

Green and black tea extracts have been reported to have trapping effects on peroxidation-derived carbonyl substances in seal blubber oil.⁹ (Just in case you are enjoying a meal of seal blubber any time soon.) The researchers were studying whether green and black tea extracts could stabilize marine oils from lipid peroxidation that created carbonyls. The extracts did in fact reduce significantly the production of acrolein and malondialdehyde, two reactive carbonyl species, resulting from lipid peroxidation in the seal blubber oil.

Cruciferous vegetables (such as broccoli and cauliflower) induce elevated levels of carbonyl-metabolizing enzymes, thus providing protection against carbonyl stress.¹⁰

Cinnamon proanthocyanidins have been found to be potent scavengers of dicarbonyls and to inhibit the formation of three typical AGEs (pentosidine, methylglyoxal, and N-(carboxymethyl)lysine.¹³

Finally, it is interesting to note that histone deacetylase,³ which is one of the HDACs with reduced activity as a result of carbonylation,⁴ has been reported to have a “unique role” in maintaining cardiac energy metabolism in mice.⁸ COPD patients are at increased risk of cardiovascular disease; it would be interesting to know whether HDAC3 activity is also reduced in COPD.

References

1. Barnes et al. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J 25(3):552-63 (2005). 
2. Ito et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 352(19):1967-76 (2005). 
3. Barnes et al, Hypothesis: Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. Lancet 363(9410):731-3 (2004). 
4. Doyle and Fitzpatrick. Redox signaling, alkylation (carbonylation) of conserved cysteines inactivates Class I histone deacetylases 1, 2, and 3 and antagonizes their transcriptional repressor function. J Biol Chem 285(23):17417-24 (2010). 
4a. Hipkiss. On the enigma of carnosine’s anti-ageing actions. Exp Gerontol 44(4):237-42 (2009). 
4b. Lee et al. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol 513(1-2):145-50 (2005). 
4c. Bierhaus et al. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes 46(9):1481-90 (1997). 
4d. Georgescu and Popov. Age-dependent accumulation of advanced glycation endproducts is accelerated in combined hyperlipidemia and hyperglycemia, a process attenuated by L-arginine. J Amer Aging Assoc 23(1):33-40 (2000). 
5. Meja 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). 
6. Ito et al. A molecular mechanism of action of theophylline: induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci USA 99(13):8921-6 (2002). 
7. Cosio et al. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 200(5):689-95 (2004). 
8. Montgomery et al. Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J Clin Invest 118(11):3588-97 (2008) doi:10.1172/JCI35847. 
9. Zhu et al. Trapping effects of green and black tea extracts on peroxidation-derived carbonyl substances of seal blubber oil. J Agric Food Chem 57(3):1065-9 (2009). 
10. Ellis. Reactive carbonyls and oxidative stress: potential for therapeutic intervention. Pharmacol Ther 115(1):13-24 (2007). 
11. Shangari et al. Hepatocyte susceptibility to glyoxal [a reactive dicarbonyl] is dependent on cell thiamin content. Chem Biol Interact 165(2):146-154 (2007). “Under thiamin deficient conditions a non-toxic dose of glyoxal (2mM) became cytotoxic ...” 
12. Stirban et al. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care 29(9):2064-71 (2006). 
13. Peng et al. Beneficial effects of cinnamon proanthocyanidins on the formation of specific advanced glycation endproducts and methylglyoxal-induced impairment on glucose consumption. J Agric Food Chem 58(11):6692-6 (2010).

 

Prostate Cancer, Breast Cancer, 
Alzheimer’s Disease

Carbonyl Compounds Increased in Brain in 
Preclinical Alzheimer’s Disease 
Carbonyl Compound Useful as a Predictive Biomarker 
of Prostate Carcinoma Relapse After Surgery 
Early Increase of AGEs (Marker of the Carbonyl 
Stress) in Breast Cancer

Two new papers^1-2 underline the participation of carbonyl compounds (products of lipid peroxidation) in two serious medical conditions, Alzheimer’s disease and prostate cancer.

Researchers studying possible predictive markers for tumor recurrence in prostate cancer have found that “relapse might be predicted with 90% accuracy if tumour-positive surgical margins, stage of disease and the intensity of acrolein presence in tumour stroma were taken together.”¹ As the authors explain, acrolein is one of the major toxic by-products of smoke and one of the main reasons for death following smoke inhalation. The authors note that acrolein may be of particular importance for the prostate because this aldehyde is a toxic oxidation product of the polyamines spermine and spermidine, found abundantly in the prostate; these polyamines are involved in the regulation of cellular proliferation and differentiation and can even induce cell death.

In another paper,² increased levels of 4-hydroxynonenal and acrolein have been found in the brains of preclinical Alzheimer’s disease (AD), individuals who have normal neuropsychological test scores in the absence of symptoms of AD but abundant AD pathology at autopsy. Increased levels of these highly reactive carbonyl compounds have also been found in areas of the brain vulnerable to AD in late-stage AD as well as in mild cognitive impairment.²

The authors conclude that “[o]verall, our data suggest that lipid peroxidation occurs early in the progression of AD, further supporting the hypothesis that oxidative stress is an early event in the pathogenesis of AD.”

In an earlier paper,³ “breast cancer patients had an early increase of AGEs (marker of the carbonyl stress) followed by further increase of AGEs and elevation of AOPP (marker of oxidative stress) in patients with progressive disease.”

References

1. Custovic et al. Lipid peroxidation product acrolein as a predictive biomarker of prostate carcinoma relapse after radical surgery. Free Radic Res 44(5):497-504 (2010).
2. Bradley et al. Increased levels of 4-hydroxynonenal and acrolein in the brain in preclinical Alzheimer disease. Free Radic Biol Med 48(12):1570-6 (2010).
3. Tesarova et al. Carbonyl and oxidative stress in patients with breast cancer — is there a relation to the stage of the disease? Neoplasma 54(3):219-24 (2007).

 

Weight Control, Diabetes Inhibition of Starch Digestion by Black Tea

A 2010 paper¹ reports on a comparison of green (nonfermented), oolong (semifermented), and black (fully fermented) teas on their ability to inhibit human salivary alpha-amylase (HSA) and mammalian alpha-glucosidase (AGH), two enzymes that digest starch, with the alpha-glucosidase in the small intestine completing the process to produce glucose that is actively transported into the bloodstream. The fully fermented black tea was most effective at inhibiting HSA and AGH, with IC50 (concentration required to inhibit 50% of the enzymatic activity) reported to be 0.42 to 0.67 and 0.56 to 0.58 mg of tea leaves/mL, respectively. The use of alpha-amylase and alpha-glucosidase inhibitors has been shown to be beneficial in the treatment of type 2 diabetes.¹ This is essentially a way to produce a low glycemic index (GI) meal from a higher GI meal containing starch.

The paper¹ also reports other natural inhibitors of alpha-amylase and alpha-glucosidase that include cumin seeds, mulberry leaves, and mangosteen pericarp. However, tea is particularly useful as it is easy to incorporate into a daily regimen that includes frequent servings.

In this study, the effects of the teas on the two enzymes was investigated using real food (rice noodles — the scientists who performed this study were located in Singapore, so they chose a popular starchy Asian food) in a simulated digestion experiment. One of the black teas (LB) was reported to reduce rice noodle digestion by 28% (30 mg of tea leaves/mL).

As the authors explain, “[b]lack tea may be inferior to acarbose [a drug that inhibits the two enzymes] in terms of delaying starch digestion. However, treatment with the latter often leads to adverse health effects (such as flatulence, diarrhea and abdominal pain) among diabetic patients.”¹ The adverse effects are caused by microbial digestion of the undigested starch that reaches the large intestine. Additional experiments by the authors¹ found that theaflavins (found in black but not green teas) were far more potent in inhibiting HSA and AGH than catechins (plentiful in green but not black teas).

1. Koh et al. Evaluation of different teas against starch digestibility by mammalian glycosidases. J Agric Food Chem 58(1):148-54 (2010).

Fat Reduction
Consumption of Acetic Acid (Vinegar) Suppresses Body Fat Accumulation in Mice
A recent paper1 reports beneficial health effects of consumption of acetic acid (main component, after water, of vinegar*) by mice. The authors report earlier studies by their group that showed reduction of hyperglycemia in diabetic mice,2 reduction of serum cholesterol and triacylglycerols (triglycerides) in rats fed a cholesterol-rich diet3 and antihypertensive effects of acetic acid and vinegar on spontaneously hypertensive rats.4 In their new paper,1 they studied the effect of acetic acid on the accumulation of body fat and liver lipids.

* Typical commercial vinegar contains about 5% acetic acid.

The high-fat diet-induced obese mice were intragastrically administered with water or 0.3 or 1.5% acetic acid for 6 weeks. (Not too much fun for the mice, but perhaps less awful than drinking vinegar. Important for the experimental analysis, though, because the researchers could be sure of exactly how much of the stuff each mouse consumed.) By the end of the study, the incremental ratios of body weight gain were 37.3% for the control group, 29.5% for the low-dose acetic acid group, and 27.7% for the high-dose acetic acid group. Tissue weight/body weight ratios of liver, total white adipose tissue, and mesenteric white adipose tissue in both the high and low-dose groups were significantly lower as compared to the control group. There was no significant difference in the gastrocnemius muscle weight between the three groups.

The researchers determined that “the main mechanism by which AcOH [acetic acid] intake suppressed body fat accumulation in this study is suggested to be upregulation of fatty acid oxidation ... .”1 They analyzed for SREBP-1, an enzyme that regulates gene expression of lipogenic (fat manufacturing) enzymes and PPARalpha, a gene that regulates fatty acid oxidation, in the liver, where (the authors explain) almost all acetate in the portal circulation is metabolized. They also looked at possible changes in other lipogenic enzymes, including FAS (fatty acid synthase) and ACC; however, they found no changes in these.

What the researchers found was that PPARalpha gene expression in both the high and low-dose groups was significantly upregulated. Uncoupling protein 2 (UCP2), which plays a role in thermogenesis (metabolizing fats to produce heat) was also elevated.

Thus, the Old Wives’ Tale about the weight-reducing effect of vinegar was true in the case of mice and probably would work similarly in humans. (Vinegar has been found in human studies to improve insulin sensitivity to a high-carbohydrate meal in subjects with insulin resistance or type 2 diabetes2 as well as in healthy subjects.3) The moral of this story is that just because something is an Old Wives’ Tale doesn’t prove that it isn’t true but until you have some experimental measurements, you certainly shouldn’t count on it being true. A reasonable dose would be 1 to 2 tablespoons of vinegar per day diluted with about ten times as much water before swallowing, taken with meals.

Also, see our earlier article “Effects of acetic acid (vinegar) on glycemic and insulinemic response to food: inhibitory effects on digestive and other enzymes” published in Vol. 9 No. 2 (April 2006) of this newsletter.

References

Kondo et al. Acetic acid upregulates the expression of genes for fatty acid oxidation enzymes in liver to suppress body fat accumulation. J Agric Food Chem 57(13):5982-6 (2009).
Johnston et al. Vinegar improves insulin sensitivity to a high-carbohydrate meal in subjects with insulin resistance or type 2 diabetes. Diabetes Care 27(1):281-2 (Jan. 2004).
Granfeldt et al. Vinegar supplementation lowers glucose and insulin responses and increases satiety after a bread meal in healthy subjects. Eur J Clin Nutr 59(9):983-8 (Sept. 2005).

 

Fat Reduction

Consumption of Acetic Acid (Vinegar) Suppresses Body Fat Accumulation in Mice

A recent paper¹ reports beneficial health effects of consumption of acetic acid (main component, after water, of vinegar*) by mice. The authors report earlier studies by their group that showed reduction of hyperglycemia in diabetic mice,² reduction of serum cholesterol and triacylglycerols (triglycerides) in rats fed a cholesterol-rich diet³ and antihypertensive effects of acetic acid and vinegar on spontaneously hypertensive rats.⁴In their new paper,¹ they studied the effect of acetic acid on the accumulation of body fat and liver lipids.

 

---

* Typical commercial vinegar contains about 5% acetic acid.

 

---

 

The high-fat diet-induced obese mice were intragastrically administered with water or 0.3 or 1.5% acetic acid for 6 weeks. (Not too much fun for the mice, but perhaps less awful than drinking vinegar. Important for the experimental analysis, though, because the researchers could be sure of exactly how much of the stuff each mouse consumed.) By the end of the study, the incremental ratios of body weight gain were 37.3% for the control group, 29.5% for the low-dose acetic acid group, and 27.7% for the high-dose acetic acid group. Tissue weight/body weight ratios of liver, total white adipose tissue, and mesenteric white adipose tissue in both the high and low-dose groups were significantly lower as compared to the control group. There was no significant difference in the gastrocnemius muscle weight between the three groups.

The researchers determined that “the main mechanism by which AcOH [acetic acid] intake suppressed body fat accumulation in this study is suggested to be upregulation of fatty acid oxidation ... .”¹ They analyzed for SREBP-1, an enzyme that regulates gene expression of lipogenic (fat manufacturing) enzymes and PPARalpha, a gene that regulates fatty acid oxidation, in the liver, where (the authors explain) almost all acetate in the portal circulation is metabolized. They also looked at possible changes in other lipogenic enzymes, including FAS (fatty acid synthase) and ACC; however, they found no changes in these.

What the researchers found was that PPARalpha gene expression in both the high and low-dose groups was significantly upregulated. Uncoupling protein 2 (UCP2), which plays a role in thermogenesis (metabolizing fats to produce heat) was also elevated.

Thus, the Old Wives’ Tale about the weight-reducing effect of vinegar was true in the case of mice and probably would work similarly in humans. (Vinegar has been found in human studies to improve insulin sensitivity to a high-carbohydrate meal in subjects with insulin resistance or type 2 diabetes² as well as in healthy subjects.³) The moral of this story is that just because something is an Old Wives’ Tale doesn’t prove that it isn’t true but until you have some experimental measurements, you certainly shouldn’t count on it being true. A reasonable dose would be 1 to 2 tablespoons of vinegar per day diluted with about ten times as much water before swallowing, taken with meals.

Also, see our earlier article “Effects of acetic acid (vinegar) on glycemic and insulinemic response to food: inhibitory effects on digestive and other enzymes” published in Vol. 9 No. 2 (April 2006) of this newsletter.

References

1. Kondo et al. Acetic acid upregulates the expression of genes for fatty acid oxidation enzymes in liver to suppress body fat accumulation. J Agric Food Chem 57(13):5982-6 (2009).
2. Johnston et al. Vinegar improves insulin sensitivity to a high-carbohydrate meal in subjects with insulin resistance or type 2 diabetes. Diabetes Care 27(1):281-2 (Jan. 2004).
3. Granfeldt et al. Vinegar supplementation lowers glucose and insulin responses and increases satiety after a bread meal in healthy subjects. Eur J Clin Nutr59(9):983-8 (Sept. 2005).

I regret to say that we of the FBI are powerless to act in cases of oral-genital intimacy, unless it has in some way obstructed interstate commerce.— J. Edgar Hoover

Good News! We Win Yet Another First Amendment Suit Against the FDA!! Free Speech Lives!!!

As the FDA continues its longstanding efforts to censor truthful information (“claims”) on the labels or in ads for dietary supplements and foods in violation of the First Amendment to the U.S. Constitution, we became plaintiffs in another lawsuit against the FDA (Alliance for Natural Health US et al v. Kathleen Sebelius et al, Civil Action No. 09-01470 (ESH)). In this case, the FDA had refused to permit truthful health claims that selenium may reduce the risk of cancers, that selenium may produce anticarcinogenic effects in the body, that selenium may reduce the risk of prostate cancer and a variety of other cancers (lung and respiratory tract, colon and digestive tract, thyroid, brain, liver, and breast). The United States District Court for the District of Columbia found on May 27, 2010 that the FDA IS subject to the strictures of the First Amendment and has failed to follow that standard, holding its suppression of the ten selenium-cancer risk reduction claims unconstitutional. Pearson v. Shalala (U.S. Circuit Court of Appeals for the District of Columbia, 164 F.3d 650, 652) 1999, continues to dog the FDA, costing them heavily in legal expenses and curtailing their illegitimate use of censorship to prevent communication of truthful information by dietary supplement and food manufacturers and vendors. To see the entire court decision, go to www.emord.com.

We believe that an important factor in helping win this case was including an argument we proposed that PROVED that the FDA had lied (we made sure the word “lie” was used) to the Court; the FDA claimed that it could not draw scientific conclusions from the many in vitro and animal studies we included in our petition for health claims on the effects of selenium in various cancers, while in fact the FDA REQUIRES in vitro and animal studies prior to permitting human studies in the drug approval process. While in vitro and animal studies do not prove that a particular treatment will work in humans, it can suggest that it MAY work in humans. Hence, scientific conclusions can be and are drawn by the FDA on in vitro and animal studies.

Judges do not like to be lied to.

Glioblastoma

Experimental Treatment That May Never Be Approved by the FDA

Dichloroacetate (DCA) is an analog of acetic acid in which chlorine atoms replace two of the three hydrogen atoms on the methyl group.¹ It has interesting metabolic effects. DCA interferes with glycolysis, an inefficient ATP generating pathway that is relied upon by most cancer cells for their energy needs. By inhibiting the mitochondrial enzyme pyruvate dehydrogenase kinase, DCA alters carbohydrate metabolism so that cells have to increase energy production by oxidative phosphorylation rather than glycolysis. This eliminates advantages that glycolytic metabolism provides to cancer cells; for example, glycolytic enzymes are reported to have direct antiapoptotic (reducing programmed cell death) actions, lactic acid produced by glycolysis promotes angiogenesis and interstitial matrix breakdown (hence, promoting metastasis) and decreased mitochondrial glucose oxidation is associated with inhibition of mitochondria-dependent apoptosis.² DCA had already been tested for treatment of lactic acidosis in humans and seemed to be relatively safe.^3,4 A recent study of five patients with glioblastoma multiforme (a devastating form of brain cancer, in which patients usually live no more than a year after diagnosis) showed beneficial effects with DCA treatment.²“All except patient 3 were clinically stable at month 15 of DCA therapy and alive at month 18 (telephone follow-up).”² The same authors had previously published a study showing DCA treatment in rats with human tumors shrunk the tumors.

Unfortunately, DCA is not approved for the treatment of cancer in the U.S. and, worse yet, the drug is off patent and is therefore an “orphan.” Nobody is likely to be willing to spend the hundreds of millions of dollars on large clinical trials that would be required by the FDA for approval to treat glioma. Hence, there is a fair amount of activity among glioma patients (as reported in various web sites) to get and use the drug without waiting for approval.⁵ Needless to say, there is considerable controversy surrounding this “self-approval” by patients, even including the lead author of paper #2, who worries that people are not only placing themselves in danger, they may also be jeopardising the conduction of clinical trials that would determine whether the drug actually works. We disagree with this attitude entirely. A drug approval process that requires dying people to simply roll over and die rather than to seek out and try a potential (even risky) treatment is a drug approval process that needs to be given the boot. Whose life is it, anyway? In fact, it would be hard to respect somebody who didn’t make an effort (not necessarily by taking DCA) to save his own life.

Researchers will, in our opinion, still be able to recruit subjects to participate in clinical trials by providing extra value to patients in the form of tests to evaluate ongoing effectiveness and to catch early signs of toxicity that a patient might not notice on his own. In the case of glioma, you still have the problem in the usual design for a clinical trial of requiring people to take a chance on getting a placebo or “standard care” (a death sentence) to compare with the outcome of experimental treatments. We would advocate instead using “historical controls” for such comparisons, thus allowing all subjects the opportunity to try (for better or for worse) an experimental therapy and to do so at three different dosage levels.

That brings up the question of what alternatives to the current regulatory approach to off-patent drugs discovered to have new uses might be appropriate. An editorial in the 20 May 2010 Nature suggested that perhaps the “government” (with your money) could pay for clinical trials (terrible idea) or that, as the editorial says it is done in Europe, add an extra year of patent exclusivity if new uses are found for an off-patent previously approved drug (this would be ineffective, as a year is unlikely to allow recovery of the immense costs for clinical trials). What we suggest is that, once a drug has been approved for safety, any new uses should be considered matters between patients and doctors without any need for FDA approval. Of course, we believe it should be understood that in the use of drugs for unapproved uses, the patient takes his chances with his own life and the doctor takes his chances with his reputation and conscience with no liability for the drug manufacturer (except for defective products that cause injury).

References

1. Linda Geddes. Cancer therapy: When all else fails. NewScientist.com (28 March 2007).
2. Michelakis et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2:31ra34 (2010) DOI: 10.1126/scitranslmed.3000677.
3. Stacpoole et al. Treatment of lactic acidosis with dichloroacetate. N Engl J Med 309(7):390-6 (1983).
4. Curry. Lactate-lowering effect of dichloroacetic acid: a model for investigation of anxiolytic drugs? Psychopharmacol Bull 25(2):202-3 (1989).
5. Helen Pearson. Cancer patients opt for unapproved drug. Nature 446(7135):474-5 (29 March 2007). Two websites are mentioned in this 2007 article: www.thedcasite.com (still there as of June 15, 2010) and buydca.com (access forbidden as of June 15, 2010); of course, the two of us cannot vouch for ANYTHING said or sold at these websites.)

Psychobiochemistry

Testosterone Decreases Trust in 
Human Social Relationships

A very interesting new paper¹ appeared this month in the Proceedings of the National Academy of Sciences on the subject of the effect of testosterone on human trust. While the hormone oxytocin has been associated with bonding and increased trust in humans, including both men³ and women, as well as other mammals, testosterone is now identified as increasing social vigilance and decreasing interpersonal trust in humans. The researchers suggest that testosterone “may have antagonistic properties with oxytocin.”

The authors used a facial trustworthiness test to assess how much trust different individuals attached to different nonfamiliar human faces. This test is said to be “highly validated” when unconfounded by rewards and that “these judgments are also highly correlated with investments in an economic-trust task.”¹

Twenty-four healthy young women were the subjects (mean age 20.2) in this study. The authors explain that they did not include men because the kinetic parameters (quantity and time course) for inducing neurophysiological effects after a single sublingual administration of 0.5 mg (500 mcg) of testosterone have been established in women, but are unknown in men. The testosterone was administered sublingually because, if swallowed it would be destroyed in the first pass through the liver.

As the researchers point out, trust is an important factor in human society (human relationships, including commerce, could not exist without a certain degree of trust), but that too much trust could lead to costly interactions with individuals who are not trustworthy. “Thus, those who are willing to believe what others say, or fail to probe the motivations underlying their actions, may fall prey to considerable economic and social costs.”¹ Because humans are not only social but also compete for resources, there has to be a balance between trust and vigilance. Or, as the authors memorably put it, testosterone is a “steroid hormone with potentially toxic consequences for human sociality [that] might counteract the maladaptive aspects of trust.”

A recent study,² as cited by the authors of paper #1, showed “higher trustworthiness ratings to unfamiliar others after oxytocin administration compared with placebo, demonstrating the validity of using a comparable paradigm for measuring trustworthiness.”¹

The results of the study¹ showed a significant overall reduction in trustworthiness ratings after testosterone as compared with placebo. “The hormone acted selectively on our high-trusting subjects, defensibly to down-regulate their trust to a level more advantageous in the competition for resources.”¹ However, as the authors explain, the down-regulation of trust after testosterone administration in the present study “was restricted to high-trusting, thus most socially naive half of our subject group, and may for that reason be adaptive in the competition for status and resources.” “A socially vigilant stance is vital for gaining and maintaining dominance or leadership ...”

References

1. Bos et al. Testosterone decreases trust in socially naive human. Proc Natl Acad Sci USA 107(22):9991-5 (June 1, 2010).
2. Theodoridou et al. Oxytocin and social perception: oxytocin increases perceived facial trustworthiness and attractiveness. Horm Behav 56(1):128-132 (2009).
3. Kosfeld et al. Oxytocin increases trust in humans. Nature 435(7042):673-6 (2005).