October 2013 Blog with Durk and Sandy

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APPETIZERS

The following short excerpt is from Freehold by Michael Z. Williamson (Baen, 2004):

Background: UN vs. FREEHOLD, a former Earth colony, now an independent planet being invaded by the UN, which expects the yokels to roll over and play dead. But, unfortunately for the UN, FREEHOLD isn’t Earth.

The convoy was four vehicles with UN markings. One was a Mk 17 Infantry Light Armored Wheeled Assault Vehicle, the others simply multipurpose vehicles with heavy weapons mounted. They stopped in front of the farm and several people dismounted. They approached the door and met Dak at the steps as he came out.

“Yes?” he asked, bluntly and without any friendship.

The one in civilian clothes spoke, “I am Lynet Krishnamurti with the United Nations Readjustment Task Force. I am here to give you an informational package on the recent improvements we are implementing.”

“Thanks, but we don’t need any improvements. I have the latest gear I can afford.” Dak replied. He wanted them to leave quickly.

“Well, that’s the point,” Krishnamurti said, “One of the benefits the UN offers is investment capital to buy better equipment. We also guarantee reparations not covered by insurance, accident insurance … many benefits. This package is on hard copy and on datachip, compatible with most systems.”

“And what does this cost me?” Dak asked, trying to sound like a suspicious bumpkin.

“It’s free. The UN provides it as a service to all agrobusiness operations.”

“Well, if I need it, I’ll call you. Thanks. Is that it?”

“I’m also here to assess your hectareage,” Krishnamurti admitted.

“Not sure. Probably six or seven thousand.” He knew to the millimeter what he planted, but he wasn’t about to admit it. “Why?”

“We need an accurate measure to assess commercial property taxes. The package also contains information on tha—.”

“Property tax?” Dak acted confused. “It’s my property and a gift from the Lord. Why should I pay tax on it?” Krishnamurti looked exasperated. Was every one of these peasants utterly ignorant of basic principles? They wrangled for long segs, while the troops looked amused. They’d seen it all before.

“So let me get this straight,” Dak was trying desperately but successfully to avoid hysterical laughter at his guest’s discomfort. “In exchange for taxing the property the Lord gave me to clear and use and taking a whopping chunk of my income from said property, and dictating what I grow, how I grow it, what equipment to use, and how to wipe my nose most likely, you’ll grant me a ‘free’ loan at interest to buy the equipment I wouldn’t need without your regulations? And I’ll have to spend an extra four days a week, unpaid, doing bookkeeping to prove it to you?”

“Un, put that way it sounds stupid,” she said.

To find out how this all ends up, you’ll need to read the book. We both read it and highly recommend it for those who see where the American political class is heading, don’t like it, and would enjoy reading fiction where people like us and (hopefully) you fight back and WIN!

Politics is the art of looking for trouble, finding it whether it exists or not, diagnosing it incorrectly, and applying the wrong remedy. .
— Ernest Benn

TThen you add two forkfuls of cooking oil.
— Julia Child

He who joyfully marches in rank and file has already earned my contempt. He has been given a large brain by mistake, since for him the spinal cord would suffice.
— Albert Einstein

… the human gut microbiome contributes 36% of the small molecules that are found in human blood …
— Leroy Hood, cofounder and president of the Institute for Systems Biology (Science 8 June 2012)

The National Park Service, administered by the U.S. Department of the Interior, asks us, “Please Do Not Feed the Animals.” Their stated reason for the policy is: “The animals will grow dependent on handouts and will not learn to take care of themselves.”
— Attributed to The National Park Service as reported in Casey’s Daily Dispatch 6/28/13

CARDIOVASCULAR PROTECTION

Lipid Accumulation in Vascular Endothelial Cells Induced by Palmitate, a Saturated Fatty Acid, Markedly Reduced by Green Tea Polyphenol EGCG

A new paper1 reports another potentially important beneficial effect of the major polyphenol in green tea, epigallocatechin gallate (EGCG). EGCG is shown to stimulate autophagy (a form of self-disassembly or “self-eating” that is required to maintain homeostasis) that degrades lipid droplets induced by palmitate in primary bovine aortic endothelial cells (BAEC). The accumulation of lipids in vascular endothelial cells is a major part of the process promoting atherosclerosis.

A large epidemiological study in Japan2 with an 11-year followup reported in a 2006 paper that green tea consumption was associated with reduced mortality due to cardiovascular disease but not with mortality due to cancer.

In the new study, the authors investigated whether EGCG could normalize the palmitate impairment of autophagy flux that prevents lipid accumulation in vascular endothelial cells by degrading lipid droplets and, if so, to identify the mechanism for this action. As the authors describe their findings:

“Excess intake of lipid causes obesity and ectopic lipid accumulation, which is implicated as one of the causes for cardiometabolic syndrome. Fatty acid overload increases intracellular lipid droplets, and the presence of lipid droplets in non-adipose tissue [such as muscle] plays a role in various pathophysiologies.” Their experimental results suggest, the authors say, that “the effect of EGCG in reduction of lipid droplets is mainly dependent on degradation but not inhibition of formation. These results suggest that EGCG decreases accumulation of lipid droplets through facilitation of lysosomal degradation, which may contribute to prevention of lipotoxicity [toxicity to cells by fatty acid overload] in vascular endothelial cells.”

Intensive investigation of possible mechanisms led the authors to conclude that EGCG induces autophagy through a CA2+/CaMKKbeta/AMPK mediated mechanism, which reduced palmitate-induced accumulation of lipid droplets in endothelial cells. Autophagy is a major mechanism by which old organelles (such as mitochondria) and damaged molecular debris are degraded and the basic components made available for reuse. It is also a way to regulate the turnover of supplies of resources for more efficient use. In the case of lipids, autophagy may have “important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.”4“Decreased autophagy in the liver with ageing may contribute to hepatic [liver] lipid accumulation that occurs along with an increased incidence of the metabolic syndrome in aged humans.”4

Earlier papers that led up to this new paper1 include references #2 and #3 listed below, where two scientific groups reported an inhibitory effect of EGCG on lipid accumulation in adipocytes (fat cells). The new findings explain how autophagy plays a key role in EGCG inhibition of lipid accumulation in vascular cells which links the EGCG protection to a reduced risk of cardiovascular disease, whereas the two earlier papers reported that EGCG decreased lipid accumulation in adipocytes (fat cells), which is particularly associated with reduction of the risk of metabolic syndrome that includes obesity and insulin resistance.

Whichever way you look at it, EGCG has become something of a phenomenon if you want to maintain a healthier life (healthspan) for longer. It has earned a place as a basic component for your cabinet of medical supplies. Don’t leave home without it!

References

  1. Kim et al. Epigallocatechin gallate stimulates autophagy in vascular endothelial cells: a potential role for reducing lipid accumulation. J Biol Chem. 288:22693-705 (2013).
  2. Moon et al. Inhibitory effect of (-)-epigallocatechin-3-gallate on lipid accumulation of 3T3-L1 cells. Obesity. 15(11):2571-82 (2007).
  3. Lee et al. Inhibitory effects of green tea catechin on the lipid accumulation in 3T3-L1 adipocytes. Phytother Res. 23:1088-91 (2009).
  4. Singh et al. Autophagy regulates lipid metabolism. Nature. 458:1131-5 (2009).

MECHANISM OF SYSTEMIC AGING
CONTROLLED BY THE HYPOTHALAMUS

​A new paper1 reports the important discovery that activation of innate immunity in the hypothalamus plays a key role in aging. The researchers found that “through activating or inhibiting immune pathway IKK-beta and NF-kappaB in the hypothalamus of mice, we were able to accelerate or decelerate the ageing process, leading to shortened or increased lifespan.”

The researchers found that there was a direct link between IKK-beta and NF-kappaB activation and gonadotropin-releasing hormone (GnRH) decline. GnRH regulates the release of sex hormones and, hence, controls reproduction. The researchers found that GnRH release decreased in GT1-7 cells, a cell line of GnRH neurons, after IKK-beta and NFkappaB activation, but increased after IKK-beta and NFkappaB inhibition. Focusing on the effect of GnRH on aging, the scientists found that delivering the hormone into the third ventricle of the hypothalamus of old mice caused increased adult neurogenesis, whereas neurogenesis normally declines with age. In fact, administration of GnRH via peripheral injections (that is, outside of the brain) ameliorated age-related cognitive decline. (The authors note that certain areas of the brain that are sensitive to GnRH are actually located outside of the blood-brain barrier, thus permitting GnRH to reach the brain from the periphery. The mechanism for the peripheral anti-aging effects of GnRH requires additional study.)

The scientists found, further, that reduced hypothalamic release of GnRH also contributed to other aspects of aging, including declining muscle strength, skin atrophy, bone loss, memory impairment, in addition to (as noted above) adult neurogenesis.

The researchers discovered that while NFkappaB signaling increased in many regions of the brain in aging mice, this increase was greatest in the hypothalamus. Part of their earlier work that led up to this latest discovery revealed that “infection-unrelated inflammatory changes in the mediobasal hypothalamus contribute to the development of various metabolic syndrome components, and the molecular basis is mediated crucially by NF-kappaB and its upstream IKK-beta.”1

Earlier work has also reported NFkappaB involvement in aging processes. For example, another recent paper2 found that the mechanism by which DNA damage drives aging is due in part to NFkappaB activation. A recent review3 reported that transcriptional activation of NFkappaB is increased in a variety of tissues with aging and associated with age-related degenerative diseases such as Alzheimer’s disease, diabetes, and osteoporosis. The review also reports that inhibition of NFkappaB in mouse models has been shown to delay onset of age-related symptoms and pathologies.

Moreover, NFkappaB has been implicated in aging in much earlier work. One paper from 19974 reported that “NFkappaB … exists in a constitutively activated state in cells obtained from the major lymphoid organs of aged animals.” One earlier paper5 found that overnutrition activated hypothalamic IKKbeta/NF-kappaB at least in part by elevated endoplasmic reticulum stress, a mechanism that has also been identified in diabetes. Yet another paper6 reports that depressive-like behaviors in mice subjected to chronic unpredictable stress are mediated by NFkappaB signaling in the adult hippocampus.

Hydrogen Modulation of NF-KappaB Reported In Three Papers

Research on the mechanisms of hydrogen therapy is in early stages, but three papers have reported it to modulate NF-kappaB activation. In one paper,7 hydrogen-rich saline was tested as a treatment in a rat model of amyloid-beta-induced Alzheimer’s disease. Amyloid beta has been found to induce neuronal cell death via ROS (reactive oxygen species) mediated by NF-kappaB activation. In this study,7 NF-kappaB activation in the hippocampus was inhibited by the hydrogen-rich saline. In another paper,8 hydrogen-rich saline prevented neointima (atherosclerotic plaque) formation that followed carotid balloon injury by suppressing ROS and the TNF-alpha/NF-kappaB pathway. In another paper,9 NF-kappaB activation increased early and transiently in response to ventilator-induced lung injury in mice, providing protection against apoptosis and inflammation. This is an example of how timing can be a key factor in determining the effect of a powerful molecule such as NF-kappaB. As the authors comment, “[t]he function of NF-kappaB activation during VILI [ventilator-induced lung injury] has not been fully elucidated and conflicting roles for NF-kappaB, protective and injurious, have been proposed.”9 On the one hand, NF-kappaB triggers upregulation of genes involved in inflammation, infection, and stress responses and, on the other hand, it mediates a cellular survival mechanism against apoptotic cell death. Hence, an early transient increased activation of NF-kappaB might provide a protective effect against the early stages of induced cell death and, if not prolonged, not increase inflammatory and stress responses. Further research is required to unravel the complex timing process.

Finally, a new paper10 reported that treatment of TNF-alpha-induced cell injury in neonatal rat osteoblasts (bone forming cells) with hydrogen dissolved in vehicle inhibited the TNF-alpha-induced activation of the NF-kappaB pathway. This resulted in reduced oxidative stress, preservation of mitochondrial function, suppression of inflammation, and enhancement of nitric oxide availability. The authors note that circulating NO level is reduced and correlated with osteoporosis in aged rats and ovariectomized rats, suggesting (they propose) that hydrogen might be a useful way to treat osteoporosis.

Natural Products That Inhibit IkappaB Kinase (IKKbeta)

Other natural products have been reported to inhibit IKKbeta and/or NFkappaB. For example, the anti-inflammatory parthenolide, a major component of the medicinal herb Feverfew has been reported to directly bind to and inhibit IKKbeta11 and that this results in the inactivation of NFkappaB.

As NFkappaB is involved in many functions, including importantly beneficial activities (such as cellular pro-survival pathways), the key to the use of NFkappaB suppression for optimal anti-aging is to target it to reduce its activity in areas such as the hypothalamus, where overactivity links it to aging-induced changes. Hydrogen easily passes the blood-brain barrier to enter the hypothalamus.

Toll-Like Receptors Play a Crucial Role in the Signaling Pathways Which Lead to Nf-Kappab Activation

Toll-like receptors are molecules that, as part of the innate immune system, recognize structures of microbes (such as LPS, lipopolysaccharide, a component of Gram-negative bacterial cell walls, viral or bacterial nucleic acids, and proteins unique to microbes), thereby activating immune system response. Importantly, “Toll-like receptors (TLRs) play a crucial role in the signaling pathways which lead to NFkappaB activation. TLR4 is considered the lipopolysaccharide (LPS) receptor.”12 A new paper12 ­reports that molecules that activate the mu opioid receptor (such as morphine) decreases TLR4 in mouse macrophages, thus acting as a powerful immunesuppressive agent. In fact, the paper12 reports, “[a] series of studies have demonstrated that MOR [mu opioid receptor] activation is responsible for most of the immunosuppressive effects of opioids.”

We report this interesting and important link between toll-like receptors, opioids, and NF-kappaB, but do not propose that mu opioid agonists (such as morphine) be used to reduce the activation of TLRs for the purpose of decreasing NF-kappaB signaling and reducing immune system inflammation. The risk there is, aside from opioid addiction, that too much suppression of TLRs could increase the risk of infection. As the authors12note, excessive immunosuppression is a risk when using opioids such as morphine for pain control. We think that the use of hydrogen therapy or other natural products that modulate the effects of NF-kappaB, such as parthenolide (from the herb feverfew),13offer a safer approach to decreasing excessive activation of NF-kappaB.

References

  1. Zhang et al. Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH. Nature. 497:211-6 (2013).
  2. Tilstra et al. NFkappaB inhibition delays DNA damage-induced senescence and aging in mice. J Clin Invest. 122(7):2601-12 (2012).
  3. Tilstra et al. NF-kappaB in aging and disease. Aging Dis. 2(6):449-65 (2011).
  4. Spencer et al. Constitutive activation of NF-kappaB in an animal model of aging. Int Immunol. 9(10):1581-8 (1997).
  5. Koo et al. Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci USA. 107(6):2669-74 (2010).
  6. Zhang et al. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell. 135:61-73 (2008).
  7. Wang et al. Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-kappaB activation in a rat model of amyloid-beta-induced Alzheimer’s disease. Neurosci Lett. 491:127-132 (2011).
  8. Qin et al. Hydrogen-rich saline prevents neointima formation after carotid balloon injury by suppressing ROS and the TNF-alpha/NF-kappaB pathway. Atherosclerosis. 220:343-50 (2012).
  9. Huang et al. Hydrogen inhalation reduced epithelial apoptosis in ventilator-induced lung injury via a mechanism involving nuclear factor-kappa B activation. Biochem Biophys Res Commun. 408:253-8 (2011).
  10. Cai et al. Treatment with hydrogen molecule alleviates TNF-alpha-induced cell injury in osteoblast. Mol Cell Biochem. 373:1-9 (2013).
  11. Kwok et al. The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. Chem Biol. 8:759-66 (2001).
  12. Franchi et al. Mu opioid receptor activation modulates Toll like receptor 4 in murine macrophages. Brain Behav Immun. 26:480-8 (2012).
  13. Dai et al. The NF-kappaB inhibitor parthenolide interacts with histone deacetylase to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells. Br J Haematol. 151(1):70-83 (2010).

CHRONIC RED WINE CONSUMPTION BY MIDDLE AGED MEN REDUCES PLASMA LPS, AN IMPORTANT SOURCE OF INFLAMMATION

The researchers were investigating the effect on LPS concentrations and on the gut microbiota of chronic red wine consumption and acute red wine intake in middle-aged men on a diet high in fat. It has been shown that even a single high fat meal can result in a significant increase in absorption of LPS from the gastrointestinal tract in a small trial of 12 healthy men.2B Studies in animal models of high fat diet-induced obesity have reported increased plasma LPS concentration as an early event in the development of diabetes.3We have written before on how LPS, lipopolysaccharide (a component of bacterial cell wall), is a major source of inflammatory stimulation of the immune system and probably a key element in the aging process.1 A new paper2 reports that chronic red wine consumption by middle aged men increases certain gut microbes and that this increase was correlated negatively with LPS concentrations. The resident gut microbiota appears to play an important role in supplying LPS to plasma in metabolic endotoxemia2 and could, therefore, be a major supplier of inflammatory immune system stimuli.

While the investigators didn’t find a significant difference between LPS or LPS-binding protein (LBP) concentrations between subjects who were taking chronic red wine, dealcoholized red wine, or gin for 20 days,* they did observe significant increases in the amounts of Bifidobacterium and Prevotella gut microbes in subjects consuming chronic red wine, where these increases were correlated negatively with LPS concentration. An earlier paper4 had also reported that increases in bifidobacteria in mice fed a high fat diet supplemented with a prebiotic, oligofructose, resulted in reduced inflammation and decreased endotoxemia (LPS).

* The subjects drank 272 ml/day of red wine (250 ml is about a cup), dealcoholized red wine (272 ml/day), or gin (100 ml/day) during the 20 day study.

Interestingly, the researchers2 found that there was an enhanced postprandial lipid response to a meal induced by red wine but, despite that, a moderate dose of red wine prevented the increase in NF-kappaB activation ordinarily induced by a high fat meal. As suggested by the paper reported above, aging is associated with increased expression of NF-kappaB and decreased expression of this molecule (particularly in the hypothalamus) may be an effective way to slow aging.

References

1. Finch and Crimmins. Inflammatory exposure and historical changes in human life-spans. Science. 305:1736-9 (2004).
2. Clemente-Postigo et al. Effect of acute and chronic red wine consumption on lipopolysaccharide concentrations. Am J Clin Nutr. 97:1053-61 (2013).
2B. Erridge et al. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr. 86:1286-92 (2007).
3. Cani et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 56:1761-72 (2007).

EXTRACELLULAR SUPEROXIDE DISMUTASE (EC-SOD) PROTECTS AGAINST ATHEROSCLEROSIS AND SUPPORTS HIPPOCAMPAL NEUROGENESIS

EC-SOD May Be Induced by Natural Hypo­methylation Agents Such as Curcumin and EGCG

Extracellular superoxide dismutase (EC-SOD) is part of the superoxide defense system present in the vascular wall that plays an important role in normal redox homeostasis by regulating superoxide activity there, for example, by reducing atherogenic superoxide oxidation of low density lipoprotein (LDL). A new paper1 now reports that EC-SOD can be induced by 5-azacytidine, a DNA methyltransferase inhibitor commonly used in experimental research. Curcumin (along with other curcuminoids, major active components of turmeric root) and EGCG have also been identified as DNA methyltransferase inhibitors (hypomethylation agents)1A,1B and, hence, might also be able to induce EC-SOD activity.

EC-SOD has become the subject of increasing numbers of research publications as a result of its important anti-inflammatory action against superoxide in the vascular system. In fact, EC-SOD acts as an important anti-inflammatory and anti-oxidative stress agent in monocytes and macrophages that are observed to accumulate in atherosclerotic plaques and to act as promoters of atherosclerosis.1

A large literature is evolving to explain the regulation of genetic expression via epigenetics, a modification of histone proteins associated with DNA that alters the histones without changing the chemical structure of the DNA itself. The researchers1here observed changes in DNA methylation in the promoter and coding regions of EC-SOD that “suggest the strong possibility that DNA methylation within promoter and coding regions might regulate cell-specific expression of EC-SOD in human monocytic cells.”1

Another epigenetic modification, histone acetylation, is also involved in gene regulation. Here the researchers studied the effects of histone acetylation/deacetylation, mediated by histone acetyltransferase (HAT) and/or histone deacetylase (HDAC) on EC-SOD expression. They found that TPA (12-0-tetra-decanoylphorbol-13-acetate) treatment significantly decreased the expression of EC-SOD in U937 cells but increased it in THP-1 cells, determining the effect of histone modification, especially H3 and H4 acetylation, in TPA-inducible EC-SOD expression in THP-1 cells.

The most interesting findings here were the ones related to increased EC-SOD expression by decreasing methylation of its promoter and coding regions because of the possibility of using easily available and safe natural products curcumin (found in turmeric root with related curcuminoids) and EGCG as hypomethylating agents. As the authors1® explain, “the presence of a high level of EC-SOD throughout the vessel walls can contribute to the regulation of nitric oxide-derived vasodilation by preventing the formation of peroxynitrite.” Moreover, they say, “it has been shown that EC-SOD protects arteries from ischemia-induced cytotoxicity and reduces infarct sizes.” Note that hydrogen selectively destroys peroxynitrite.

EC-SOD Promotes Long-Term Survival of Newborn Neurons

A paper from last year2 reported that EC-SOD was important in a mouse model of neurogenesis by comparing mice in which EC-SOD was either knocked out, was normal in wild type (WT) mice, or was overexpressed in other mice. EC-SOD was important in progenitor cell proliferation, dendritic development, and long-term survival of newborn neurons. The study also “suggested that maintenance of the dendritic system following cranial irradiation was important for preservation of neurocognitive functions.”2

In a 2013 review paper,3 researchers noted that “… increasing SOD3 [EC-SOD] levels in various experimental disease models, e.g., chemically induced diabetes, hypertension, and inflammatory arthritis, reduced oxidative stress and improved disease state, thereby placing SOD3 as a central therapeutic target.”

References
1. Kamiya et al. Epigenetic regulation of extracellular-superoxide dismutase in human monocytes. Free Radic Biol Med. 61:197-205 (2013).
1A. Liu et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19:706-9 (2009).
1B. Fang et al. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 63:7563-70 (2003).
2. Zou et al. Extracellular superoxide dismutase is important for hippocampal neurogenesis and preservation of cognitive functions after irradiation. Proc Natl Acad Sci USA. 109(52):21522-7 (2012).
3. Frank et al. Targeting the redox balance in inflammatory skin conditions. Int J Molec Sci. 14:9126-67 (2013).

GENE EXPRESSION PROFILING REVEALS SOME DIFFERENCES BETWEEN SODIUM SELENITE, SELENOMETHIONINE AND YEAST-DERIVED SELENIUM FOLLOWING INGESTION IN THE MOUSE

Gene expression profiling has become a valuable tool in uncovering mechanisms of action of genes and nutrients that affect their expression. In this new study,1 scientists examined the effects of three forms of selenium used to supplement a base diet at 1 mg/kg diet of added selenium as compared to the base diet deficient in selenium (<0.01 mg/kg diet). The subjects were weanling mice. They received either the base diet without added selenium or the selenium supplemented base diet for 100 days.

The three forms of selenium were reported to be equally effective in activating standard measures of selenium, such as expression of genes encoding selenoproteins. The gene expression profile revealed that sodium selenite and yeast-derived selenium had similar profiles and different from that of selenomethionine. The most interesting/revealing result of the study was that sodium selenite changed the expression of far more genes than the other two forms in the cerebral cortex and gastrocnemius (muscle) and slightly more genes in the intestine than the other two forms.

In the liver, the yeast-derived selenium changed the expression of more genes than the other two forms. For example, in the gastrocnemius, sodium selenite changed the expression of 1082 genes while yeast-derived selenium changed the expression of 637 genes and selenomethionine changed the expression of 148 genes. In the cerebral cortex, the genes changed were 1166, 832, and 421 for selenite, yeast-derived selenium, and selenomethionine. We were quite surprised, wondering why there would be such a large difference in the number of expressed genes (particularly in muscle). Moreover, the DNA damage response gene Gadd45b had a lowered expression in response to yeast-derived selenium in all tissues, while sodium selenite reduced its expression in cortex and gastrocnemius, and selenomethionine reduced its expression only in cortex. The authors also point out that the overlap of changes in gene expression that were changed in the same direction was greater for sodium selenite and yeast-derived selenium than any other pair of treatments. There is a complete list of the individual genes changed in expression by more than one diet for all four tissues in Online Resources 1–4, which we have not reported here.

The authors point out that the results of this study clearly show that research based upon different forms of selenium cannot be considered equivalent and that “the published data regarding the effect of selenium should be re-evaluated with respect to the source of selenium that was administered.”1

Note that the most common form of natural dietary selenium is sodium selenite. Importantly, the prostate cancer killing effect of selenium was strongest for sodium selenite as reported in a recent paper.2

References

  1. Barger et al. Gene expression profiling reveals differential effects of sodium selenite, selenomethionine, and yeast-derived selenium in the mouse. Genes Nutr. 7:155-165 (2012).
  2. Olm et al. Extracellular thiol-assisted selenium uptake dependent on the xc- cystine transporter explains the cancer-specific cytotoxicity of selenite. Proc Natl Acad Sci USA. 106(27):11400-5 (2009).

PROTECTIVE EFFECTS OF ASTAXANTHIN ON CAPILLARY BLOOD FLOW IN MUSCLES OF MOUSE MODEL OF COUCH POTATOES

Despite the proven benefits of exercise, there are still an awful lot of people who don’t exercise, including those who don’t think they have the time or others that simply don’t enjoy exercising. For those people (and we include ourselves among those who would rather spend our time reading, writing, or thinking than doing boring exercises), protecting our muscles from atrophy due to being sedentary is an important priority in maintaining good health. A new paper1 reports protective effects against decreased capillary blood flow in the muscles of rats as a result of disuse by the carotenoid astaxanthin.

The researchers explain that capillary regression in skeletal muscles is associated with decreased muscular activity as a result of increased oxidative stress and this results in reduced blood flow in the affected muscles. The researchers hypothesized that astaxanthin, a powerful antioxidant that is stronger than vitamin E under a number of stress conditions, might reduce this oxidative stress and ameliorate the capillary regression associated with muscle disuse.

They used a common experimental model of muscular disuse where the hindlimbs of the rats were suspended by the tail so that there was no weight bearing on the hindlimbs and, hence, those muscles were not subject to contractions that activate pathways induced by exercise. The effects are very similar to extended bedrest. The researchers explain that these “unloaded” hindlimbs have been shown to have lower levels of VEGF (vascular endothelial growth factor) that supports the blood vessels that, in active muscles, maintain blood flow.

The results showed that the VEGF protein level was lower in the hindlimb suspended group than in both control groups (in one of the control groups, rats were not hindlimb suspended and in the other control group, rats were not hindlimb suspended but did receive astaxanthin supplementation), but that the VEGF protein level in the hindlimb suspended rats supplemented with astaxanthin, the VEGF level was not different from the two control groups. In fact, the authors found that all angiogenic (blood vessel growth promoting) factors, except ANG-2, were higher in the the hindlimb suspended + astaxanthin group than the hindlimb suspended (no astaxanthin) group. The decreased angiogenic factors in the hindlimb suspended group that did not receive astaxanthin resulted in regression of capillaries.

In this study, astaxanthin treatment prevented the decrease in capillary volume and shift towards smaller diameter capillaries that occurred in the disused hindlimb muscles but did not prevent the decrease in muscle mass that resulted from the decreased hindlimb loading. Therefore, the mechanisms responsible for the decreased capillary capacity and the decreased muscle mass must be different.

Though the researchers did not examine the effects of astaxanthin on blood vessel capacity in the heart in this experiment, it would be of considerable interest to see whether astaxanthin would help maintain capillary volume in the heart of sedentary animals or people. Exercise is known to provide beneficial results to heart capillary blood flow (collateral blood flow) and this may very well be due to similar angiogenic factors as astaxanthin maintained in the hindlimb suspension model.

Reference

  1. Kanazashi et al. Protective effect of astaxanthin on capillary regression in atrophied soleus muscle of rats. Acta Physiol (Oxf). 207:405-15 (2013).

ASTAXANTHIN IMPROVES SWIMMING ENDURANCE IN MICE AND DECREASES FAT ACCUMULATION, POSSIBLY BY INCREASING UTILIZATION OF FAT AS AN ENERGY SOURCE

The carotenoid astaxanthin has been reported to increase endurance capacity in male mice exercised to exhaustion.1 The mice were supplemented with astaxanthin by stomach intubation in doses of 1.2, 6, or 30 mg/kg body weight 5 days a week for 5 weeks or they received vehicle (olive oil). In another experiment, the mice received the same amount of astaxanthin or vehicle by the same route and had a weight attached to their tails, swimming to exhaustion. In experiment 3, the mice had to swim for a predetermined amount of time and were assessed for blood concentrations of exercise-induced metabolites.

In the control group, plasma glucose was decreased by 15 minutes of swimming exercise, but in the astaxanthin groups (receiving 6 mg/kg or 30 mg/kg) the plasma glucose was significantly higher than in the control group. This may suggest that the animals receiving astaxanthin used more fat as an energy fuel, thus sparing glycogen. The researchers in fact observed significantly higher levels of liver and muscle glycogen in the astaxanthin groups than in the control group after swimming for 15 minutes. That, and the lower levels of blood lactate in the astaxanthin groups also suggested a decrease in glucose utilization.

Reference

  1. Ikeuchi et al. Effect of astaxanthin supplementation on exercise-induced fatigue in mice. Biol Pharm Bull. 29(10):2106-10 (2006).

COENZYME Q10 MAY BE AN EFFECTIVE
TREATMENT FOR OSTEOPOROSIS

A new paper1 reports findings for the first time on the beneficial effects of CoQ10 on bone, in which it enhanced bone-forming osteoblast differentiation while inhibiting osteoclast (bone resorbing cells) differentiation. These findings, while discovered in in vitro cell culture experiments, could be of particular value to postmenopausal osteoporosis that develops as a result of estrogen deficiency if the effects prove to work similarly in vivo.

At a dose of 100 μM, CoQ10 decreased the number of osteoclasts in cell culture to approximately 87.3% of controls (didn’t receive CoQ10).

The CoQ10 was found to work by its effects on specific bone signaling pathways. For example, RANKL (receptor activator of nuclear factor kappa B ligand) is released by preosteoblasts, which activates its receptor RANK that is expressed on osteoclasts with the monocyte/macrophage colony-stimulating factor (M-CSF) for osteoclastogenesis. Osteoclasts are bone cells that demineralize bone, hence decrease bone mineral density. The inhibition of the RANKL-induced osteoclast differentiation is one of the mechanisms for CoQ10 increase of bone formation. Another natural product that is reported to suppress RANKL-induced osteoclast differentiation is alpha lipoic acid.1

CoQ10 increased osteoblast differentiation by enhancing alkaline phosphatase (ALP) activity. “CoQ10 enhanced not only early osteoblastic biomarkers like ALP and Col1, but also late osteoblastic biomarkers such as BSP and matrix minralization through transcription factors Runx2 and OSX. In this way, CoQ10 acts as an enhancer for all stages of osteoblast differentiation.”1

The researchers suggest that further study be done to determine what the optimal dose of CoQ10 for bone formation should be. In the meantime, CoQ10 is quite safe. Sandy, for example, takes 100 mg. CoQ10 a day.

The authors sum up the results of their study: “… CoQ10 may have great therapeutic implications in treating osteoporosis and other bone diseases.”

Reference

  1. Moon et al. Coenzyme Q10 regulates osteoclast and osteoblast differentiation. J Food Sci. 78(5):H785-891 (2013).

SURPRISE! KAPPA OPIOID RECEPTORS MEDIATE THE
ANTIDEPRESSANT-LIKE ACTIVITY OF HESPERIDIN IN MICE

Who would have thought it? That hesperidin could exhibit anti-depressant effects in mice subjected to the forced swim test and do so by interacting with the kappa opioid receptor. But that’s one thing about biomedical science—there are always lots of surprises.

The kappa opioid receptor is one of the three currently known opioid receptors, that also include mu and delta opioid receptors. Hesperidin, a naturally occurring flavonone glycoside, is found in rich quantities in citrus fruits and has been reported to have antioxidant, neuroprotective, and anticancer effects. An earlier paper2 reported that in traditional Mexican medicine, infusion of flowers of the Citrus genera are used as a sedative to treat insomnia. This paper2 explored the sedative effects of Citrus; the authors reported that, in an earlier study, hesperidin in the methanol extract of Citrus sinensis was identified as the sedative active principle of the plant. Others had described the involvement of opioid receptors to the behavioral and antinociceptive (anti-pain) effects of hesperidin.

The immobility period of the mice subjected to the forced swim test (freezing as a result of fear) was significantly reduced by treatment with hesperidin at doses of 0.1, 0.3, and 1 mg/kg.1 Pretreatment with naloxone (a nonselective opioid receptor antagonist) reversed the antidepressant-like effect of hesperidin in that study.

References

  1. Filho et al. Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test. Eur J Pharmacol. 698:286-91 (2013).
  2. Guzman-Gutierrez and Navarrete. Pharmacological exploration of the sedative mechanism of hesperidin identified as the active principle of Citrus sinensisflowers. Planta Med. 75:295-301 (2009).

NEGATIVE EFFECT OF MARKETS ON MORAL VALUES

Of Mice And Men And Markets

A new paper studied the effect of markets on moral values by setting up a moneymaking experiment in trade whereby it would cost people money to avoid harms to third parties. The researchers found that the more the number of people involved in a market trade, the less money people would forego to avoid harms to third parties. They concluded, therefore, that markets had a negative effect on moral principles.

The experiment went like this: a buyer and seller, each in possession of a mouse, could divide a sum of money and keep the proceeds. (The mouse was left over from an experiment and, in the usual course of events, would be euthanized at that point, but for the sake of this experiment would be allowed to live if the owner of the mouse were willing to forego a certain amount of a sum of money (the price for allowing the mouse to live).) The idea was to see what effect being in a moneymaking trade arrangement, a market, would have on the price people were willing to pay to allow the mouse to live.

The experimenters obviously considered it moral to be willing to forego some money to keep the mouse alive, but immoral to simply keep the money and let the mouse die. (As part of the experiment, the participants watched a short movie of how a mouse would die, so nobody had any illusions. For the mouse, the outcome was a matter of life or death.) We would have preferred it if the researchers had called the decision to keep a mouse alive a personal value rather than a matter of morality, as we do not agree that allowing a mouse to die is immoral. (Such values are intensely subjective. In the Jaine moral system, for example, it would be considered immoral to kill even an ant.)

In the individual decision option, Option A, a mouse would be allowed to live but the participant would receive no money. Option B meant that the mouse would die but the participant would receive 10 euros. There were 124 participants in the individual decision option, of which 45.9% were willing to allow the mouse to die in order to get 10 euros. In the bilateral market (2 participants traded for prices), 72.2% of sellers were willing to let the mouse die for prices below or equal to 10 euros. This difference was statistically significant from the individual decision option. In the multilateral market (where there were 7 bidders), 75.9% of sellers were willing to kill a mouse for less than or equal to 10 euros. This, too, was statistically significantly different from the individual decision option.

The more bidders, the lower the average price offered in exchange for allowing the mouse to live. (In a separate experiment, people could either keep and spend a coupon or take a certain amount of money. The effects of numbers of bidders in this condition revealed no significant price trend.) The authors conclude, therefore, that the market had the effect (and the larger the market, the greater the effect) of reducing the price paid for a moral outcome (allowing the mouse to live).

The authors sum it up: “We therefore agree with the statement quoted at the beginning that we as a society have to think about where markets are appropriate—and where they are not.”

We offer the following comments:

Power Law

The decreasing price paid as the number of bidders increases looks a lot like a power law, which is a characteristic of self-organizing systems as described in the book Ubiquity by Mark Buchanan (Three Rivers Press, 2000). As explained in Ubiquity, for example, if you look at a sandpile on which grains of sand are being dropped one by one, eventually at some point you will have an avalanche. If you double the amount of energy released by the avalanche, the avalanche becomes four times less likely. You see the same pattern with earthquakes: the larger the earthquake, the less likely that size event will occur, consistent with the mathematical power law you see with avalanches.

Thus, we propose that the higher the number of bidders in the market, the lower the price paid to avoid harms to third parties, is a power law, something that is mathematically built into markets as self-organizing systems. It is not that people become less moral as the number of bidders increases; it is that the likelihood of the decision of each individual determining the average price becomes less and less as the number of bidders increases.

Political Decision Making vs. Markets

The researchers wonder, as indicated in their summation, whether under some circumstances decisions should be made by a different mechanism than markets. Whether a political process would result in a more “moral” outcome than a market is we believe questionable. The more voters, the less likely that your decision will affect the outcome of an election and, hence, the less likely that voters will concern themselves with harms to third parties. Moreover, the less likely that your decision will decide the outcome of an election, the less likely you will have an incentive to be well informed before you vote, the “rational ignorance” problem. The authors note that, “it is a pervasive feature of market interaction to impose costs on uninvolved third parties.” We agree. Yet, there can be no doubt that the production of externalities (costs to uninvolved third parties) is a pervasive feature of political processes.

Moreover, there may be costs in the use of politics as a way of making decisions by large numbers of people that go beyond that of markets. Even as the authors themselves noted, not all the participants chose to take part in the bidding of their experimental market.* In politics, you can refuse to vote but the outcome of the election (the decisions of other people) will be imposed upon you anyway, whereas refusing to enter the bidding in a market transaction allows you to opt out, at least in part, of the costs of whatever other people decide. In the usual trade, opting out means you can keep your money and use it for something else.

 

* “22.2% of all traders in the bilateral market never traded, while in the multilateral market, 24.1% never traded. … 27.1% of subjects [in the individual decision option] were unwilling to kill their mouse even for the maximum offered monetary amount of 50 euros.”

 

Reference

  1. Falk and Szech. Morals and Markets. Science. 340:707-11 (2013)
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