November 2011 Blog with Durk and Sandy

November 02, 2011

November 2011 Blog with Durk and Sandy

Iron Deficiency in Obese Mexican Women and Children—
Association with Inflammation But Not Iron Intake

Another interesting link between inflammation and disease risk was reported in a recent paper.1 The authors studied why obese individuals may be at increased risk of iron deficiency and found (using data from the 1999 Mexican Nutrition Survey) that the risk of iron deficiency in obese Mexican women and children was 2–4 times that of normal-weight individuals at similar dietary intakes of iron. However, their data reported that CRP (C-reactive protein, a marker of inflammation) concentrations in obese women and children were 4 times those of their normal weight counterparts and that CRP (but NOT iron intake) was a strong negative predictor of iron status, independently of BMI (body mass index).

Though the study was cross-sectional, not longitudinal, so that cause and effect could not be determined (from these data), nevertheless the authors propose a possible mechanism for the link between inflammation and iron deficiency: “[I]n obesity, increased proinflammatory cytokines, such as leptin, interleukin- 6, and CRP, may stimulate hepcidin production by the liver and adipose tissue. Hepcidin excess has been suggested to decrease dietary iron absorption ... Moreover, lipocalin-2, an iron-binding protein upregulated by inflammation, might also be responsible for iron sequestration within the adipocytes.”1

Reference

  1. Cepeda-Lopez et al. Sharply higher rates of iron deficiency in obese Mexican women and children are predicted by obesity-related inflammation rather than by differences in dietary iron intake. Am J Clin Nutr 93:975-83 (2011).

Immune Gene Upregulation in Aging Mouse Brain Parallels 
Declines in Cognition, Motivation, and Locomotion

In a new paper1 researchers studied declines in cognitive performance resulting from age-related changes in the prefrontal cortex (PFC) of mice. As they note, this brain region is particularly sensitive to age-related decline, as reflected in deficits in cognition, motivation, and locomotor behavior. The mouse PFC is functionally and anatomically homologous to the PFC in higher mammals.1

The researchers1 explain: “There is substantial evidence that aging is associated with increases in peripheral gene upregulation and that this is, in turn, associated with cognitive dysfunction.” Thus, they examined the levels of pro-inflammatory cytokines in the serum of mice. “Aging was associated with upregulation of numerous CD antigens, chemokine related genes, complement genes, genes in the JAK-STAT and/or interferon signaling pathway, cellular adhesion genes, MHC related genes, and Toll-like receptors in the CD11b+ cells.” Toll-like receptor2 was shown in Table 3 to be one of the upregulated genes.

“Immune gene upregulation, especially within the CNS [central nervous system], has been demonstrated to impair a variety of cognitive domains, including learning, memory, and attention. While this study is the first, to our knowledge, to relate behavior with whole genome expression changes within the PFC of rodents, others have investigated PFC related behavior under inflammatory conditions. For example, rats given chronic ventricular administration of lipopolysaccharide (LPS), a potent activator of innate immunity, are significantly impaired in PFC dependent spatial working memory tasks. Similarly, there is evidence that age-related neuroimmune gene upregulation in humans is associated with cognitive decline.”1

Reference

  1. Bordner et al. Parallel declines in cognition, motivation, and locomotion in aging mice: Exp Gerontol 46:643-59 (2011).

The Brain Glucose Transporter GLUT-1 Also Transports Dehydroascorbic Acid Into the Brain Where It is Reduced To Ascorbic Acid

An early paper1 reporting on the transport of glucose into the brain found that the tight interendothelial cell junctions of the blood-brain barrier prevent the entry into the brain of water-soluble substances such as glucose. So how does the brain, highly dependent upon glucose as a fuel for energy production, get its glucose? Answer: Glucose is actively transported across the blood-brain barrier by a transporter similar to the one that delivers glucose to erythrocytes (red blood cells).1b “It has been shown that essentially 100% of glucose transporter binding sites at the blood-brain barrier can be accounted for by the GLUT-1 [glucose transporter 1] isoform; and that the GLUT-1 gene is expressed selectively in microvascular endothelium in the brain with minimal, if any, expression of this gene in neurons in vivo.”2

Interestingly, GLUT-1 not only transports glucose into the brain, but also delivers dehydroascorbic acid (the oxidized form of vitamin C) across the blood-brain barrier into the brain, where it is rapidly reduced to ascorbate.3 “Recent evidence indicates that dehydroascorbic acid crosses the blood-brain barrier via GLUT1 and is rapidly reduced to ascorbate and thus trapped within the brain. This trapping mechanism may contribute to the high vitamin C levels in the brain without the participation of an active transport mechanism.”3

GLUT-1 Expression Decreased in Aged Rats But Increased in Aged Rats by Alpha Lipoic Acid

In another paper,4 it was reported that there is an age-related decrease in GLUT-1 expression in rats in studies comparing the GLUT-1 induced uptake of glucose by leukocytes (white blood cells) in aged compared to young rats. This is thought to be a contributing factor to age-related decline of phagocytic immune function.4 Data4 also showed that administration of alpha lipoic acid to aged rats for 14 days caused an increase in the expression of GLUT-1 when compared to aged control rats (which had a decreased expression of GLUT-1 compared to young rats).

Another paper5 reports that there is an age-associated decline in ascorbic acid concentration, recycling (recycling of ascorbic acid from dehydroascorbic acid) and biosynthesis in rat hepatocytes (liver cells). In this paper, the authors found that that (R)-alpha-lipoic acid almost completely reversed the age-associated decline in ascorbic acid concentration (including decreased recycling of dehydroascorbic acid to ascorbic acid) in the rat hepatocytes. Another paper6 reports further on the role of alpha-lipoic acid dependent regeneration of ascorbic acid from dehydroascorbic acid in rat liver mitochondria.

A paper2 reporting on a congenital condition in which GLUT-1 deficiency in humans exists, resulting in low levels of glucose in the cerebrospinal fluid as well as impaired transport of dehydroascorbic acid notes: “It has been suggested that in tissues dependent on GLUT-1 for glucose transport the antioxidant thioctic acid [also called alpha lipoic acid] may be of benefit, as it can translocate GLUT-1 from intracellular pools to the plasma membrane in response to insulin; and benefit has been reported.”

In the earlier paper1 mentioned above, the authors explained that an explanation for the relatively high density of the glucose transporter protein in brain microvessels is that brain microvessels constitute less than 1% of the brain’s weight, yet must transport all the glucose needed for oxidative metabolism of the whole brain. Thus, “the density of the glucose transporter moiety in brain capillaries is 10 to 20 times higher than the density of the transporter in membranes of other mammalian tissues such as adipocytes [fat cells] and myocytes [muscle cells].”1 GLUT-1 is reduced in specific regions of the brain, including the hippocampus, during normal aging. Thus, preventing age-associated reduction in GLUT-1 expression may help prevent the burden of age-associated reduced energy and antioxidant supplies.

Finally, another recent paper7 reports on the regulation of glucose transporters in the ischemic brain (resulting from stroke and other forms of occlusion of blood vessels delivering nutrients to the brain). As the paper reports, “... glucose transport becomes the limiting step [in brain metabolism] in certain steps, such as cerebral ischemia, in which brain glucose fluctuations are primarily associated with blood brain barrier (BBB) permeability and subsequently with GLUT transcriptional and translational expression changes.”

In this paper7 the authors review recent papers on the neuroprotective potential of GLUT upregulation in ischemic stroke, where evidence suggests neuroprotective effects of augmented GLUTs. They note that the upregulation of GLUTs takes place naturally as a result of cerebral ischemia as a protective response. Some natural substances have been associated with this GLUT upregulation. For example, they report that one study found that VITAMIN E (400–600 μg/day) given freely in drinking water for one week before middle carotid artery occlusion-induced ischemia and for an additional 5 weeks after occlusion reduced the brain infarct volume (brain cells killed by the ischemia) by about 50% and reduced the space navigation disability in rats. Induced expression of GLUT3 mRNA and protein expression was reported.

Aged Garlic Extract

Treatment with aged garlic extract before the onset of ischemia has been shown to be beneficial in counteracting cerebral damage.7 Recently, the authors7 evaluated the effect of aged garlic extract on GLUT1 and GLUT3 mRNA expression in rats subjected to middle carotid artery occlusion for 2 hours. “We observed that GLUT1 (2.43 ± 0.77 fold) and GLUT3 (3.16 ± 0.48 fold) increase after 1 hour and return to basal level after 2 hours of reperfusion.” They also report two other studies in which VITAMIN E or QUERCETIN were shown to induce an increase in GLUT expression.

Finally, the paper7 also reported work in which other researchers found that ESTRADIOL pretreatment reduced the ischemic damage (by greater than 50%) following middle carotid artery occlusion in rat. “In the penumbral ischemic region, where cortical tissues are supplied primarily by the anterior cerebral artery but also, to small extent, by the middle cerebral artery, E2 [17-beta estradiol] treatment caused an increase in GLUT1 protein (23.3%) compared with GLUT1 at the lesion side of OVX [ovariectomized] rats.”7

“... glucose transport activity is probably one of the most important mechanisms for the enhanced hypoxic tolerance induced by hypoxic preconditioning. Yu et al demonstrated that preconditioned neuronal and astroglial hippocampal cultures showed an increase in GLUT expression.”7

References

1. Kalaria et al. The glucose transporter of the human brain and blood-brain barrier. Ann Neuro 24:757-64 (1988). 
1b. Montel-Hagen et al. Erythocyte GLUT1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C. Cell 132:1039-48 (2008). 
2. Gordon and Newton. Glucose transporter type 1 (GLUT-1) deficiency. Brain Dev27:477-80 (2003). 
3. Klepper et al. Deficient transport of dehydroascorbic acid in the glucose transporter protein syndrome. Ann Neurol 44:286-7 (1998). 
4. Palaniyappan and Alphonse. Immunomodulatory effect of DL-alpha-lipoic acid in aged rats. Exp Gerontol 46:709- 15 (2011). 
5. Lykkesfeldt et al. Age-associated decline in ascorbic acid concentration, recycling, and biosynthesis in rat hepatocytes—reversal with (R)-alpha-lipoic acid supplementation. FASEB J 12:1183-9 (1998). 
6. Xu and Wells. Alpha-lipoic acid dependent regeneration of ascorbic acid from dehydroascorbic acid in rat liver mitochondria. J Bioenerg Biomembr 28(1):77-85 (1996). 
7. Espinoza-Rojo et al. Glucose transporters regulation on ischemic brain: possible role as therapeutic target. Cent Nerv Syst Agents Med Chem 10:317-325 (2010).

Looking for a Few Good Laughs

We are always on the lookout for funny/amusing quotes and funny brief items to report here to lighten an unavoidably technical publication. However, it seems to be getting more and more difficult to find genuinely funny things to include. Even The Wall Street Journal has become mostly full of grim news and gloomy uninspiring editorials. If you run into some funny stuff that you think we might like to include in this newsletter (or that might just contribute a chortle or even a guffaw to our day), please feel free to send it to us care of Life Enhancement Products. Thank you.

I’m deeply honoured, but a bit confused. I was only ever a B-cup.
— Diana Rigg, on being voted the sexiest television star ‘of all time’ by Americans, The Times, 3 May 1999

(D&S Comment: Don’t make the mistake of confusing cup size with being sexy.)

My only solution for the problem of habitual accidents ... is to stay in bed all day. Even then, there is always the chance that you will fall out.
— Robert Benchley
When politics are used to allocate resources, the resources all end up being allocated to politics.
— P. J. O’Rourke
For new drugs, the proper comparison is not risk versus benefit but rather risk versus risk—that is, the risk of doing nothing (which may have a deadly outcome), versus the risk of taking a preventive drug for long periods.
— Michael B. Sporn
Another canard is that cancer prevention efforts are not cost-effective. The argument is that the number of lives saved with a preventive drug would be too small with respect to the total number of people who need treatment. But this is a curious perspective. The number of houses destroyed by fire is trivial compared with the total number of houses, and yet almost every homeowner insures against fire. The conceptual problem here is that everyone doesn’t die of cancer in a short period; this is a lifetime problem.
— Michael B. Sporn, professor of pharmacology, Dartmouth Medical School, Hanover, NH in “The Big C—for Chemoprevention” in the 24 March 2011 Nature
... we will unshackle you ... but you must stand or fall on your own just like the rest of us on Main Street.
— Sarah Palin, from her speech of 9/3/11 outlining a five point plan to revive America’s economy, in which her attack on “crony capitalism” was especially notable

“Crony capitalism” is not capitalism at all, but a form of state fascism in which taxpayer money is distributed to favored big businesses and big banks; “crony capitalism” shows up in the agendas of the leading Republican candidates (including Romney and Perry) for President. We don’t trust these guys with our money any more than Obama and won’t vote for them. (Actually, we don’t entirely trust anyone running for President and would rather not vote for any of them.)

Americans Getting Inadequate Amounts of Some Vitamins and Minerals

Despite being relatively well off, many Americans do not get adequate quantities of certain vitamins and minerals in their diets and may need to either alter their diet to counter these deficiencies or to add supplements to their daily regimen. Data were analyzed from the NHANES data for 2003–2004 and 2005–2006 in a published study.1Various USDA food composition databases were used to determine the micronutrients derived from foods consumed by NHANES participants and reported in the 24-hour recall dietary interview. The first dietary interview was done in person, while a second was obtained by telephone interview.

A bit confusing in this paper was the use of different estimates of dietary adequacy. The EAR (estimated average requirement), AI (adequate intake) and the DRI (Dietary Reference Intake) were three such measures. As reported here,1 only 3 and 35% of Americans assessed by the NHANES data had total usual intakes of potassium and vitamin K, respectively, greater than the adequate intake. “The percentage of individuals aged ≥2 y with total usual nutrient intake, including that from foods and dietary supplements, falling below the EAR was considerable for vitamin D (70%), vitamin E (60%), calcium (38%), vitamin A (34%), vitamin C (25%), and magnesium (45%) (Table 1).” “Less than 3% of the population had total usual intakes that exceeded the AI [adequate intake] for potassium ...” “... very few individuals obtained the recommended level of potassium.”

What stands out most clearly to us in this report is the remarkable deficiency of potassium intake by most Americans assessed by NHANES data. It is very important to get adequate amounts of potassium, either from the diet or via supplementation for, among other things, maintaining normal blood pressure. The modern American diet contains too high a ratio of sodium to potassium when compared to the Paleolithic human diet. While the nagging nanny state agencies are trying to get Americans to decrease their sodium intake by constant messages haranguing the public or by regulation (coercion) of the food industry, we think it is far more important from the point of view of improving the health of Americans to increase the potassium intake. For example, a recent paper2 reports that low serum potassium appears to be independently associated with incident type 2 diabetes and low dietary potassium is more common in African Americans than in whites. Hence, the authors suggest that “[l]ow serum potassium concentrations in African Americans may contribute to their excess risk of type 2 diabetes relative to whites.”

We recommend taking potassium bicarbonate (such as our potassium supplement). Take 2 capsules two to four times daily with meals. Two capsules provide a total of 2.7 grams of potassium bicarbonate (containing 1.05 grams of elemental potassium); take with meals to avoid possible stomach ache. As we have reported before (see “Potassium Bicarbonate Supplementation” and “Potassium Bicarbonate for Reduced Blood Pressure and Increased Muscle Mass” in the April 2009 issue of Life Enhancement), potassium bicarbonate has been shown to reduce blood pressure, whereas other forms of potassium have not.

References

  1. Fulgoni et al. Foods, fortificants, and supplements: where do Americans get their nutrients? J Nutr Aug. 26, 2011 doi: 10.3945/jn.111.142257.
  2. Chatterjee et al. Serum potassium and the racial disparity in diabetes risk: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr 93:1087-91 (2011).

Is Your Current Body Weight a Threat To Your Health

A database of consumer attitudes toward making modifications in diet and exercise has been included in Porter Novelli’s ConsumerStyles database. Since 2000, the statement—“My current body weight is a threat to my health.”—has been included. In the year 2000, 29% of the total population [represented by the poll] agreed with that statement, with 71% disagreeing or remaining neutral. As the percentage of overweight and obese adults has increased since 2000 (and is still increasing), one might wonder what the latest such poll has reported. Incredibly, in 2010 the responses were identical to those in 2000! (as reported pp. 20–21 in the Apr. 2011 Food Technology)

 

Why Are Rates of Diabetes Higher in Americans 
As Compared to Brits of Similar Weight

An interesting report1 described how the U.S. has higher rates of diabetes than the English in the old-age population. The authors used data from the English Longitudinal Study of Aging (ELSA) and the American National Health and Nutrition Examination Survey (NHANES) for 1999–2006 (time comparable with ELSA) to study this risk differential.

The higher rates of diabetes in the U.S. were largely accounted for by raised waist circumference and not BMI (body mass index) differences especially among women. (In fact, remarkably, American women were less overweight—32.1% as compared with 38.7% of English women—and more of normal weight—35.0% compared with 30.8%—as represented by BMI distributions.) Approximately three quarters of the country differences for women and 38% among men can be explained by the different waist sizes. “Even among those with normal weight, the fraction with raised waist risk was not trivial for US women—40.6% of Americans who were neither overweight nor obese were categorised as high waist risk compared with 8.9% among equivalent English women.”1

Interestingly, one of the findings was that there was a significant role for height, as well as waist size, in diabetes risk. “Adult stature reflects childhood growth patterns and an association of short stature with type 2 diabetes indicates that impaired childhood growth leads to adult insulin resistance and diabetes.”1

A Link Between Shorter Stature and Inflammation

One of the papers we cited in our report (see above) on exposure to stimulants of inflammatory signaling via Toll-like receptors2 (Crimmins and Finch, 2006), in fact, provides detailed analysis of the authors’ hypothesis that lifelong exposure to inflammatory stimuli contributes importantly to the risk of age-related diseases, including insulin resistance and diabetes. In their analysis, reduced growth in childhood (and, hence, shorter stature) can result from increased exposure to inflammatory stimuli such as infectious disease, leading to differences in cohorts which tend to be exposed to similar infectious milieu. “If infections occur during development, substantial energy is reallocated at the expense of growth, as required by the body for immune defense reactions and for repair. In adults, the fever associated with severe infections increases resting metabolic rates by 25–100%.”2

References

  1. Banks et al. What explains the American disadvantage in health compared with the English? the case of diabetes. J Epidemiol Community Health (2010) doi:10.1136/jech.2010.108415.
  2. Crimmins and Finch. Infection, Inflammation, Height, and Longevity. Proc Natl Acad Sci USA 103(2):498-503 (2006).

Sorry—No Chuckles or Giggles here ... 
But You Might Like to Know Why the Value of 
the Dollar Keeps Falling ...

Partial Audit of the Federal Reserve Results Posted on Senator Bernie Sanders’ Webpage On July 21, 2011

This is a clear case of socialism for the rich and rugged, you’re-on-your-own individualism for everyone else.
— Bernie Sanders (I-VT)

The first ever GAO (Government Accountability Office) audit of the Federal Reserve was carried out in the past few months due to the Ron Paul, Alan Grayson Amendment to the Dodd-Frank bill, which passed last year. It is said that Jim DeMint, a Republican Senator, and Bernie Sanders, an Independent (but self-proclaimed socialist) Senator led the charge for a Federal Reserve audit in the Senate, but watered down the original language of the House bill (HR1207) so that a complete audit would not be carried out. However, the results of the first audit in the Federal Reserve’s nearly 100 year history were posted on Senator Sander’s webpage on July 21, 2011.

$16,000,000,000,000 Secretly Given Out to U.S. Banks and Corporations and Foreign Banks

From the period between December 2007 and June 2010, the Federal Reserve had secretly bailed out many of the world’s banks, corporations, and governments. Virtually none of the money has been returned and it was loaned out at 0% interest.

To keep $16,000,000,000,000 in perspective, remember that the Gross Domestic Product of the U.S. is only $14.12 trillion. Moreover, the entire national debt of the U.S. over its 200+ history is $14.5 trillion. The $16,000,000,000,000 distributed by the Fed without oversight by Congress was created out of thin air (thin paper, actually) that will, because it increases the number of U.S. dollars without increasing the goods and services available to be purchased by U.S. dollars, reduce the value of dollars (e.g., how much a dollar will buy).

The list of institutions that received the most money from the Federal Reserve can be found on page 131 (http://www.scribd.com/doc/60553686/GAO-Fed-Investigation#outer page 144) of the GAO Audit includes: Citigroup: $2.5 trillion Morgan Stanley: $2.04 trillion Merrill Lynch: $1.949 trillion Bank of America: $1.344 trillion Barclays PLC (United Kingdom): $868 billion Bear Stearns: $853 billion Royal Bank of Scotland (UK): $541 billion JP Morgan Chase: $391 billion Deutsche Bank (Germany): $354 billion UBS (Switzerland): $287 billion Credit Suisse (Switzerland): $262 billion Lehman Brothers: $183 billion Bank of Scotland (United Kingdom): $181 billion BNP Paribas (France): $175 billion and many many more including banks in Belgium of all places

http://www.scribd.com/doc/60553686/GAO-Fed-Investigation#outer page 144

View the 266-page GAO audit of the Federal Reserve (July 21st, 2011):

http://www.scribd.com/doc/60553686/GAO-Fed-Investigation

Source:

http://www.gao.gov/products/GAO-11-696 FULL PDF

on GAO server:

http://www.gao.gov/new.items/d11696.pdf

Suggestion: Our tryptophan or 5-hydroxytryptophan formulations help prevent anger and aggressive impulsive acts from taking over your mindset when you read about these criminals/traitors at the Fed.

Inflammatory Exposure via Stimulants of Toll-Like 
Receptors in Foods: Possible Effects on Risk of 
Disease and Life Expectancy

We have written in earlier newsletters on the hypothesis,1 supported by increasing amounts of data, that exposure to inflammatory stimuli from infections and other sources (including non-infectious sources such as tissue damage2a and oxidative stress2b) contributes importantly to reducing life expectancy. As proposed by Finch and Crimmins,1 the “reduction in lifetime exposure to infectious diseases and other sources of inflammation—a cohort mechanism—has also made an important contribution to the historical decline in old-age mortality.” In a later paper,3 Crimmins and Finch explain: “It is well known that the survivors of birth cohorts with lowered early age mortality due to infections experienced lower mortality throughout adult life.” In the same paper,3 they note that “In highly infectious environments, children are exposed to high inflammation levels, which promote the process of atherosclerosis even without exposure to high-fat diets.” Surprisingly (and in support of the hypothesis that lifelong exposure to inflammation promotes atherosclerosis), they also note3 that “... Fogel showed that cardiovascular disease was twice as prevalent among older Army veterans born before 1845 vs. veterans born in the early 20th century.”

Much has been discovered on the transduction pathways responsible for inflammatory signaling. “A major family of innate immune sensors involved in the induction of inflammatory signaling in response to bacterial products [such as LPS, lipopolysaccharides], the Toll-like receptors (TLRs), has been shown to play a key role in the promotion of [insulin resistance and atherosclerosis].”4

An interesting new paper4 now reports that stimulants of Toll-like receptors TLR-2 and TLR-4 are found abundantly in certain foods (minimally processed vegetables), thus providing another and perhaps unexpected source of exposure to increased inflammation. In the new paper, the authors, explain that “stimulation of TLR2- or TLR4- signaling promotes both atherosclerosis and insulin resistance in mice.” The researchers wanted to learn whether humans might be exposed to ligands (activators) of TLR2 or TLR4.

The authors report:4 “[w]e showed recently that a variety of common foodstuffs can contain relatively high levels of stimulants of TLR2 or TLR4, and that these stimulants were likely to be bacterial lipopeptides and lipopolysaccharides (LPS), respectively. While the highest levels of TLR-stimulants were found in processed meat and dairy products, the fresh fruits and vegetables examined in the previous study tended to contain only very low or undetectable levels of these agents. Since minimally processed vegetables, which are defined as being fresh but otherwise physically altered from their original state, and certain other vegetable products such as bean sprouts and cress can contain a relatively high bacterial load relative to unprocessed vegetables, we here examined the potential of extracts of MPVs [minimally processed vegetables] and related products to stimulate TLR2 and TLR4 signaling using a recently developed quantitative bioassay.”

The MPVs they studied included samples of grated carrot, diced onion, sliced apple, mixed leaf salad, and baby spinach, each packaged under a modified atmosphere) and three classes of other vegetable products they considered to be likely to contain a high microbial load (including bean sprouts, water cress and salad cress). They found, for example, that TLR stimulants were abundant in processed (diced) onion and grated carrot, but undetectable in the whole unprocessed forms. “Stimulants of TLR2 or TLR4 were not detectable in chopped onion or carrot on the day of preparation, but tended to increase with time from 4 days onward when stored exposed to air at 5 degrees C.”4

The authors explain4 that “... certain vegetable products, such as bean sprouts and cress tend to contain a relatively high microbial load even in the absence of processing, as a result of susceptibility of these products to microbial growth ... Alternatively, for those vegetables which are otherwise resistant to microbial growth in the whole or unpeeled form (such as onion and carrot) it is possible that TLR-stimulants accumulate in these products as a result of microbial growth subsequent to the processing and storage of these products.” “This notion is consistent with the well-established principle that damage to the protective outer layers of vegetables markedly diminishes their resistance to microbial growth.”

“As humans are responsive to doses of LPS [lipolysaccharides] at least 250-fold lower than those required to elicit inflammation in mice, it is tempting to speculate that the occasional ingestion of certain MPVs could result in an oral LPS dose sufficient to promote systemic inflammatory signaling in human subjects.”4

The obvious conclusion of the report on Toll-like receptor stimulants in minimally processed vegetables is that one should use these processed veggies, such as chopped onion and diced carrots, soon after preparing them and perhaps avoid minimally processed foods of this type that are stored for extended periods of time. Of course, sterile foods, such as canned and fully cooked, avoid these problems.

Natural Products That Suppress Signaling by Toll-Like Receptors

LEM1111_NFKB_thumb_260.jpg
Mechanism of NF-κB action.

There are also nutrients that provide protection against inflammatory Toll-like receptor signaling. A recent paper5 reports in a study of thirty two patients with severe multiple trauma (mostly from automobile accidents) on the effects of w-3 polyunsaturated fats on inflammatory signaling in peripheral blood mononuclear cells (PBMCs) from the patients. “The results showed that the mRNA and protein expression of TLR2 and TLR4 in PBMCs was significantly lower in w-3 PUFA group as compared with control group at 5th and 7th day [after initiation of w-3 PUFA supplementation].” “It was concluded that w-3 PUFA can remarkably decrease the expression of TLR2, TLR4, and some related inflammatory factors in NF-kappaB signaling pathway in PBMCs of patients with severe multiple trauma, which suggests that w-3 PUFA may suppress the excessive inflammatory response mediated by the TLRs/NF-kappaB signaling pathway.”

Another paper6 reported that plant proanthocyanidins from cranberries, tea, and grapes “... inhibit LPS interaction with TLR4/MD2, an activity that also mediates the inhibition of LPS- induced NF-kappaB activation.” (The authors explain6 that LPS binding to MD2 is a prerequisite for TLR4 signaling activity and LPS endocytosis [LPS being taken up by cells].)

References

1. Finch and Crimmins. Inflammatory exposure and historical changes in human life-spans. Science 305:1736-9 (2004). 
2a. McDonald et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330:362-6 (2010). 
2b. Gill et al. Linking oxidative stress to inflammation: Toll- like receptors. Free Radic Biol Med 48:1121-32 (2010). 
3. Crimmins and Finch. Infection, inflammation, height, and longevity. Proc Natl Acad Sci USA 103(2):498-503 (2006). 
4. Erridge. Stimulants of Toll-like receptor (TLR)-2 and TLR-4 are abundant in certain minimally-processed vegetables. Food Chem Toxicol 49:1464-7 (2011). 
5. Yi et al. Effect of w-3 polyunsaturated fatty acid on Toll-like receptors in patients with severe multiple trauma. J Huazhong Univ Sci Technolog Med Sci [paper in English] 31(4):504-8 (2011). 
6. Delehanty et al. Binding and neutralization of lipopolysaccharides by plant proanthocyanidins. J Nat Prod 70:1718-24 (2007).

 

Remarkable New Findings: When Fish Oils Meet 
Cannabis Receptors: A Result is Powerful 
Protection of the Brain Against Neuroinflammation

Here’s some really good news. Maybe even a little bit funny (read on). A remarkable new paper1 reports sensational brain protective effects of naturally formed bioactive oxygenated derived products of DHA (docosahexaenoic acid, a long chain polyunsaturated fatty acid found in fish oils). In the paper, the authors did a sophisticated analysis of a series of docosahexaenoyl ethanolamide (DHEA) products derived from DHA that have profound anti-inflammatory and organ-protective properties in the brain.

Fascinatingly, DHA (docosahexaenoic acid) is thought to be converted in the brain to DHEA (docosahexaenoyl ethanolamide) by the same pathway as N-acyl-arachidonoyl ethanolamide (AEA, anandamide), an endocannabinoid (a natural endogenous cannabinoid that activates the same receptors, CB1 and CB2, as the active ingredients in cannabis). Note: the initials DHEA are also used by scientists as an acronym to represent dehydroepiandrosterone, which is entirely different from the DHEA that is discussed in this new paper; this is unfortunate because of the danger of confusion, so keep in mind as you read this paper review that DHEA (docosahexaenoyl ethanolamide) has nothing to do with the other DHEA (dehydroepiandrosterone).

The authors1 suggest that the newly identified bioactive products from DHEA “may underlie some of the beneficial effects of DHA [docosahexaenoic acid] administration.” The experimental work was done in male FVB mice.

The paper1 reports that these newly identified enzymatic oxidation products from DHEA are activators of CB2 cannabis receptors (CB2 is a potent anti-inflammatory cannabinoid receptor that does not have psychotropic effects), with enhanced potencies that are in the nanomolar range.

The authors explained that the production of N-acyl ethanolamide is enhanced during stroke, so they examined whether DHEA had biological effects in platelet-leukocyte aggregate formation in human whole blood. “Platelet-leukocyte aggregate formation is a component of many vascular diseases, stroke, diabetes, and hypertension. Specifically, increased platelet-leukocyte aggregates were suggested as an early marker for acute myocardial infarction [heart attack] and are increasingly regarded as a cardiovascular risk factor. Also, patients with elevated circulating platelet-monocyte aggregates may reflect a pro-atherogenic phenotype [e.g., a vulnerability to develop atherosclerosis].” Moreover, they note that platelet-leukocyte aggregates stimulate the production of pro-inflammatory cyokines such as IL-1beta, IL-8, MCP-1, MIP-1b, PAF [platelet activating factor], and matrix metallopoteinase plus procoagulant tissue factors. As the authors had identified 10,17-diHDHEA and 15-HEDPEA as two major DHEA-derived products produced by isolated human PMN, they assessed the effects of these two substances in PAF (platelet activating factor)-stimulated platelet-monocyte aggregate formation. The results showed that both were potent signals and, “at concentrations as low as 10 pm [picomole, 10–12 mole], each decreased 100 nm PAF-stimulated platelet-monocyte aggregate formation ~30% in human whole blood. The 10,17-diHDHEA also decreased PAF-stimulated platelet-PMN aggregates by 25–35%.” Thus, these compounds are among the most potent biochemicals known.

The authors also assessed the effect of the DHEA-derived products on ischemia-reperfusion injury, which results when blood flow is reduced or stopped and then fully restored as in a heart attack. “[T]he prevention of PMN activation or accumulation in ischemia organ reduces tissue injury after reperfusion.” They found that 15-HEDPEA, which effectively stopped PMN chemotactic migration (neutrophil migration into ischemic tissues is responsible for much of the ischemia-reperfusion tissue damage) decreased PMN infiltration in lung by ~50%. “It is noteworthy that aberrant and excessive leukocytic infiltration is also associated with other diseases, including arthritis and psoriasis.”

Another paper2 reports that a CB2-selective agonist (activator of the CB2 cannabinoid receptor), JWH-015, reduced the migration of human monocytes in response to inflammatory signals and thus CB2 agonists may have a therapeutic effect in chronic inflammatory conditions such as atherosclerosis. In atherosclerosis, a crucial part of the process of development and progression is a result of the recruitment of inflammatory cells into the arterial intima.2

All This and Neurogenesis, Too!

Moreover, a recent paper3 found that docosahexaenoyl ethanolamide promotes the development of hippocampal neurons. “We found active biosynthesis of DEA (N-docosahexaenoyl ethanolamide) in developing hippocampi as well as the hippocampal neuronal culture. Treatment of hippocampal neurons with DEA promoted neurite growth, synaptogenesis and expression of glutamate receptor subunits and enhanced glutamatergic synaptic activity as in the case with DHA [docosahexaenoic acid], but at substantially lower concentrations. Our results suggest that DEA is an active component of DHA-mediated hippocampal development.”3 The authors3 also note that the content of docosahexaenoyl ethanolamide in the pig brain was increased by dietary inclusion of DHA (docosahexaenoic acid) as reported in a study by others.

References

  1. Yang et al. Decoding functional metabolomics with docosahexaenoyl ethanolamide (DHEA) identifies novel bioactive signals. J Biol Chem286(36):31532-41 (2011).
  2. Montecucco et al. CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways. Am J Physiol Heart Circ Physiol 294:H1145-55 (2008).
  3. Kim et al. N-Docosahexaenoylethanolamide promotes development of hippocampal neurons. Biochem J 435:327-36 (2011).



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