Though many have tried, no one has ever yet explained away the decisive fact that science, which can do so much, cannot decide what it ought to do.
— Joseph Wood Krutch, “The Loss of Confidence” in The Measure Of Man (1954)
(D&S: It may have something to do with the undeniable fact that “science” makes no decisions at all and that scientists as a whole are unlikely to agree on anything involving subjective values.)
As Charles Darwin once said, “Mathematics seems to endow one with something like a new sense.”
Darwin would have been amazed at the incredible increase in the rates of computational power since his time. “In our recent past, it took 30 years to determine the complete DNA sequence of a cold virus genome. Today a virus of the same size can be sequenced in minutes. We can now read more than 500 billion bases in a week, compared to 25,000 in 1990 and 5 million in 2000.”
— quotes from Perdue, “Mathematics Transforming Bioresearch,” Genetic Engineering & Biotechnology News May 1, 2012 genengnews.com
Being able to redesign systems whether it’s with genetics or whether it’s with drugs is going to be at the heart of the new kind of medicine that will emerge from systems biology—P4 Medicine —that is, predictive, personalized, preventive, and participatory medicine.
Dr. Hood gives an example of how personalized medicine can work. “A friend of mine at Microsoft had a defect in vitamin D transporters and was suffering from osteoporosis. To reverse his osteoporosis, all he had to do was take 20 times the normal amount of vitamin D.”
— LeRoy Hood, quoted in above article
(D&S: Fortunately for Dr. Hood’s friend, he didn’t have to wait for umpteen years for FDA approval for the vitamin D remedy because of vitamin D availability as a dietary supplement. A lot of others are not so lucky.)
The great book of nature can be read only by those who know the language in which it was written. And this language is mathematics.
— Galileo“52% Say States Should Be Allowed to Overrule Feds on Drug Approval”
In a telephone survey of 1,000 likely U.S. voters conducted on May 12, 2012, Rasmussen Reports found that 52% “believe that if a state government feels a drug has benefits in some circumstances, it should be able to approve sale of that drug within its borders” even when the FDA has already denied approval. 32% disagreed, while 16% were not sure.
(D&S: The Tenth Amendment to the U.S. Constitution provides that: “The powers not delegated to the United States by the Constitution, nor prohibited by it to the States, are reserved to the States respectively, or to the people.” There is NO power delegated to the United States to regulate the practice of medicine just as there is NO power delegated to the U.S. to determine what you can or cannot eat. Nobody is likely to imagine that there could not be costly errors made in a system free of FDA drug approval, but the costs of these errors have to be compared not to perfect decision-making but to the existing flawed and very expensive system of FDA drug approval.
Does the Tenth Amendment have any effect on federal government action today? Surprisingly, it does. See the special article at the end of this issue on a 2011 U.S. Supreme Court decision where the Court unanimously upheld the right of a woman to challenge her criminal conviction under a federal statute on the basis of the Tenth Amendment!)
The invention of M. de Montgolfier has given such a shock to the French that it has restored vigor to the aged, imagination to the peasants and constancy to our women.
— A witticism of the first manned balloon flight (Paris, Nov. 21, 1783) reported by Simon Schama (FASEB J, May 2012)
(D&S: Sounds like something France could really use today, at least with respect to restoring vigor to the aged and imagination to its inhabitants.)
“Hydrogen Therapy” Update
Here we continue our ongoing series in which we follow the development of an emerging field of medical therapy in which hydrogen is used to treat diseases, especially those linked to oxidative stress or inflammation. The hydrogen is administered by being inhaled as gas, consumed in hydrogen dissolved in water or saline, or—the way we use it—by eating certain prebiotic foods that stimulate particular gut bacteria to produce hydrogen that circulates throughout the body, eventually being excreted by exhalation through the lungs. A growing number of studies involving animals or humans have shown promise for this simple to use and nontoxic treatment for such conditions as metabolic syndrome (diabetes), ischemia-reperfusion injury (as occurs in heart attacks and strokes), protection against radiation, cognitive impairment in senescence-accelerated mice, atherosclerosis in mouse models of the disease, hemorrhagic strokes, and protection against the development of Parkinson’s disease in animal models, to name some of the published research.
For those who want to read our initial introduction to this new, interesting field of medicine, you can access our article “Hydrogen Therapy” [See article in the June issue of Life Enhancement]. Briefly, hydrogen is a potent but selective antioxidant that scavenges the highly toxic hydroxyl radical (for which it is widely believed that there is no known endogenous protective mechanism) and peroxynitrite, a powerful oxidant that is created by the chemical combination of nitric oxide and superoxide in the body. Hydrogen has little effect, however, on reactive oxygen species such as superoxide and hydrogen peroxide that are important (at low concentrations) as signaling molecules; to scavenge these may not be desirable yet can occur when targeted by most antioxidants that cannot discriminate between different ROS.
Another advantage of hydrogen as an antioxidant is that it easily passes through membranes, reaches all tissues, and enters mitochondria where most of the reactive oxygen species are created and often escape control. Many antioxidants cannot easily enter mitochondria and do not provide much if any protection there. For that reason, there are scientists working on mitochondria-targeted antioxidants specifically for the purpose of overcoming this limitation. Hydrogen, however, is an antioxidant that is already able to enter mitochondria.
Incredibly, in a paper* new to us (though pretty old, having been published in 1969), the author notes that “[t]he presence of a high concentration of hydrogen (H2) in human flatus was first reported over 100 years ago.”**
Hydrogen Improves Obesity and Diabetes by Inducing FGF21 and Stimulating Energy Metabolism in Mice
A particularly interesting recent study in the field of hydrogen therapy is the one we describe here. Though this published paper1 appeared only last year, it represents early work in the attempt by scientists to discover mechanisms (other than its antioxidant and antiinflammatory effects) to explain hydrogen’s therapeutic benefits. It is the first paper that we know of reporting that hydrogen induces fibroblast growth factor 21 (FGF21) in db/db mice (obese because they lack leptin receptors) which, if verified, would be very exciting because FGF21 has been found to regulate energy metabolism. In rodents and rhesus monkeys with diet-induced or genetic obesity and diabetes, for example, systemic administration of FGF21 has been found to exert strong antihyperlipidemic and triglyceride- lowering effects and leads to body weight reduction.2
The researchers,1 knowing that oxidative stress is a major causative factor in diabetes, studed whether hydrogen (administered by dissolving hydrogen in the animals’ drinking water) might be beneficial in an animal model of diabetes, the db/db mouse which lacks leptin receptors. The mice were divided into three groups: the first group could drink water without hydrogen ad lib, the second group received drinking water 100% saturated in dissolved hydrogen (0.8 mmol/l) and the third group received drinking water with 10% of the saturated level of dissolved hydrogen (0.08 mmol/l). The mice in the third group began the experimental regimen at 6 weeks of age. The mice drinking the water with 10% or 100% saturated with hydrogen had modest but significant reductions in body weights at 18 weeks of age as compared with the controls (drinking water containing no hydrogen). Body fat was also substantially lower in the mice consuming water 100% saturated with hydrogen. The authors reasoned that, “[s]ince the consumed amounts and volumes of diet and water did not differ among groups, it is suggested that H2 [hydrogen] consumption stimulates energy metabolism to suppress the gain of fat and body weights.”1
The researchers further found that plasma levels of glucose and insulin were significantly reduced in the 100% hydrogen in water administered group and triglycerides were reduced in both the 100% and 10% hydrogen in water-administered groups. The authors examined the effects of genes involved in the regulation of gluconeogenesis and found that FGF21, which contributes to the regulation of energy metabolism, had increased mRNA expression in the liver after hydrogen administration. Thus, the authors conclude, “the induction of hepatic [liver] FGF21 contributes to the lowering effect on plasma glucose and triglyceride levels.” Moreover, they found that the “H2-drinking db/db mice consumed more O2, 10%, and produced more CO2, 10%, than db/db mice without H2-water during both night and day.” This suggests that hydrogen consumption stimulated energy metabolism in the mice.
As we noted at the start, these are newly reported findings and we certainly hope to see follow up that attempts to replicate and extend this work. As we mentioned, FGF21 is a potent metabolic regulator, which has been reported to activate AMPK (a major metabolic energy sensor and master regulator of metabolic homeostasis) and SIRT1 (a putative longevity gene), in adipocytes (fat cells) that results in enhanced mitochondrial oxidative function (as indicated by increased oxygen consumption).2
FGF21 is also reported to regulate the activity of PPARgamma, which is the key mediator of the physiologic and pharmacologic actions of thiazolidinediones (a major class of antidiabetic drugs, such as Pioglitazone).3 In a commentary4 accompanying a very recent paper, new data were described suggesting that FGF21 promotes the “browning” of white fat (i.e., inducing white fat to take on the properties of thermogenic brown fat) by enhancing “PPARgamma coactivator 1alpha activity, potentially through inducing its post-translational modifications.”4 The commentary to the paper4 notes that “circulating FGF21 concentration also increases in overweight patients with various features of the metabolic syndrome, potentially hinting at the existence of an obesity-induced FGF-21 resistant state,”(see also 4b,4c) although the authors point out that this hypothetical FGF-21 resistant state is debated.
Improved Outcome in Hemorrhagic Strokes in Mice Inhaling Hydrogen Gas
Two recent papers describe the results of short periods of inhaling hydrogen gas in mouse models of hemorrhagic stroke. In the first paper,5 an intracerebral hemorrhage (ICH) was induced by injecting bacterial collagenase into the right basal ganglia of anesthetized CD1 male mice. As expected, the mice had brain edema and impaired functional performance. The 30 animals were divided into controls (which breathed room air), a group treated with hydrogen inhalation for one hour and then tested at 24 hours after ICH for neurological deficits (including tests for beam balance and wire hanging) and brain edema, and a group treated with 2 hours of hydrogen inhalation and tested at 72 hours after ICH for the same parameters.
Hydrogen leaves the body rapidly, mostly via exhalation through the lungs. Hence, a one hour or even two hour inhalation of hydrogen would not be around very long. It is remarkable to us that they found improvements in the experimental animals: ICH caused a significant increase in water content (edema) of the ipsilateral basal ganglia of all collagenase-injected animals. one hour of hydrogen inhalation resulted in a significant decrease in brain water content vs. room air treated animals, while the animals that had two hours of hydrogen inhalation showed no significant effect on brain water content (the authors offered no explanation for this discrepancy, but the small numbers of animals in the study may have been responsible). At 72 hours, the animals treated with one hour of hydrogen inhalation showed only a tendency (that is, the difference was not statistically significant) towards reducing brain water content. Similarly, the one hour hydrogen inhalation resulted in attenuation of the ICH-induced neurological deficits when measured at 24 hours after ICH, but showed only a tendency (not statistically significant) toward an improvement in the animals breathing hydrogen for two hours and examined at 72 hours.
In the other study,6 researchers conducted a similar experiment, this time with 137 adult male Sprague-Dawley rats. The scientists in the second study6 included one of the same authors, John H. Zhang, of the other study;5 it was a year later and Dr. Zhang had apparently become the director of the lab during that period. The rats had subarachnoid hemorrhages induced by endovascular perforation while under general anesthesia. The animals breathed 2.9% hydrogen gas for two hours after perforation. Brain edema and blood-brain barrier disruption that resulted from the hemorrhage was significantly improved at 24 hours but not at 72 hours. They also observed amelioration of oxidative stress injury in lipids, proteins, and DNA. After seeing the results of their first study, you have to wonder why they did not increase the period of time during which the animals were breathing hydrogen. As it is, they did two very similar experiments and got about the same result, very short term improvements.
* Levitt. Production and excretion of hydrogen gas in man. NEJM 281(3):122-127 (1969)
** Ruge E. Beitrage, zur Kenntniss der Darmgase, Chem Zentrabl 7:347-351 (1862).
1. Kamimura et al. Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity 19(7):1396-1403 (2011).
2. Chau et al. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway. Proc Natl Acad Sci USA 107(28):12553-8 (2010).
3. Dutchak et al. Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones. Cell 148:556-67 (2012).
4. Canto and Auwerx. FGF21 takes a fat bite. Science 336:675-6 (2012).
4b. Fisher et al. Obesity is an FGF21 resistant state. Diabetes 59:2781-9 (2010).
4c. Domouzoglou and Maratos-Flier. Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis. Am J Clin Nutr 93(suppl):901S-5S (2011).
5. Manaenko et al. Hydrogen inhalation is neuroprotective and improves functional outcomes in mice after intracerebral hemorrhage. In: Zhang and Colohan, eds. Intracerebral Hemorrhage Research, Acta Neurochinurgica Supplementum, Vol. 111, Springer-Verlag/Wien 2011 DOI: 10.1007/978-3-7091-0693-8_30
6. Zhan et al. Hydrogen gas ameliorates oxidative stress in early brain injury after subarachnoid hemorrhage in rats. Crit Care Med 40(4):1-6 (2012).
Why is [it] that nobody understands me, and everybody likes me?
— Albert Einstein, in an interview in The New York Times, 3/12/1944
(D&S: Could this be the FACEBOOK question of the century?)
Chronic Intake of Red Wine Polyphenols By Young Rats Protects Against Aging-Induced Decline in Physical Performance and Endothelial Dysfunction
After our discussion (see last issue of this newsletter) of a study in which people displayed increased creativity as a result of consuming alcohol to reach 0.07 blood level (a little less than the 0.08 level set for legally drunk), you may be thinking “uh oh, here we go again.” But, no, this study1 involved the consumption of powdered French red wine POLYPHENOLS (RWP), with small amounts of alcohol as solvent. One liter of red wine was said to produce 2.9 grams of phenolic extract, which contained 471 mg/g of total phenolic compounds expressed as gallic acid equivalent.1
The rats were divided into four groups that received the following treatments: controls (3% ethanol, solvent), RWPs at 25 mg/kg/day in 3% ethanol, RWPs at 75 mg/kg/day in 3% ethanol and a group receiving RWPs at 100 mg/kg/day in 3% ethanol plus apocynin (an antioxidant and inhibitor of NADPH oxidase, an enzyme that is a causative factor in some diseases by being a major source of oxidative stress. The researchers note that “[t]hese treatments correspond to human equivalent doses of 284, 851, and 1135 mg [of the RWP]., respectively, for a 70 kg. adult.” The solvent, RWPs and apocynin were given to the rats in their drinking water starting at week 16 until week 40.
As the authors explain, “[v]ascular aging appears to be initiated by an increased oxidative stress involving superoxide anions, which, in turn, inactivate NO [nitric oxide].” [Adequate amounts of NO are critical for vasodilatory function in blood vessels.] “Potential sources of superoxide anions in old arteries include NADPH oxidase, mitochondrial respiration chain, xanthine oxidase, and uncoupled eNOS.” In this paper,1the authors observed that aging in their subject mice was associated with blunted endothelium-dependent relaxations, oxidative stress, and an upregulation of eNOS [endothelial nitric oxide synthase] and arginase. (Arginase is an enzyme that competes with eNOS for arginine and, when levels of arginase are increased, it can reduce the availability of arginine for the synthesis of nitric oxide by eNOS). Insufficient availability of arginine can induce the uncoupling of eNOS (resulting in the generation of superoxide anions instead of nitric oxide). These are all changes linked to endothelial dysfunction.
NADPH Oxidase Involved in Endothelial Dysfunction Accompanying Aging
Indicating that the enzyme NADPH oxidase was involved in the age-associated endothelial dysfunction was the increase with aging in the NADPH oxidase p22phox and nox1 subunits, combined with the improvement in endothelial dysfunction derived by the mice receiving the NADPH oxidase inhibitor apocynin. (The supplementation with RWPs also resulted in improved endothelial function.) “Regular administration of either RWPs (25 and/or 75 mg./kg./day) or apocynin (100 mg./kg./day) in the drinking water from week 16 until week 40 improved the aging-induced impairment of both the NO and the EDHF-mediated component of the relaxation to ACh [acetylcholine].”1 Moreover, “[i]ntake of either RWPs (25 and 75 mg./kg./day) or apocynin (100 mg/kg/day) prevented the aging-induced vascular oxidative stress and normalized the expression of eNOS and peroxynitrites.”1
Improvement in Physical Performance
The researchers kept track of the physical capabilities of the mice by assessing endurance capacity on a treadmill. Unsurprisingly, they observed a decrease in physical performance on the treadmill as a result of aging, with the old rats having an endurance capacity of 6.0 ± 0.6 min. as compared to 16.7 ± 0.9 min. for the young rats. “The aging-related physical impairment is partially but significantly improved by the RWPs treatment at a dose of 75 mg/kg/day (9.9 ± 1.3 min., n=6) but not 25 mg./kg./day (5.2 ± 1.0 min., n=4), and also by the apocynin treatment (10.9 ± 1.1 min., n=5).”1 The improvement with apocynin indicates that NADPH oxidase played an important role in the decreased vascular response with aging as a source of superoxide anions. Uncoupled eNOS is another source of superoxide anions in old arteries.
- Dal-Ros et al. Chronic intake of red wine polyphenols by young rats prevents aging-induced endothelial dysfunction and decline in physical performance: role of NADPH oxidase. Biochem Biophys Res Commun 404:743-749 (2011)
We hope to explain the universe in a single, simple formula that you can wear on your T-shirt.
— Leon Lederman, in “Quark City” by
Richard Wolkomir, Omni Feb. 1984
(D&S: Mmmmm. That sounds good, and maybe the formula could become the basis of a new bubble on the stock market.)
Increased Expression of Brain-Derived Neurotrophic Factor (BDNF) Famously Increases Neurogenesis in the Hippocampus and Improves Cognition
But, New Report Finds That Increased Expression of BDNF Under Stressful Conditions Has Opposite Effects in Amygdala and Hippocampus
It might have seemed (for a little while, anyway) that increasing the expression of the neurotrophin BDNF might be an unalloyed great idea, as it was shown to enhance cognition by inducing neurogenesis when its expression was increased in the hippocampus. Now, new results1 show that things are not that simple (but then they rarely are).
On the basis of earlier studies, chronic administration of antidepressants were found to prevent stress-induced decrease in the level of BDNF and the increase of dendritic atrophy in the hippocampus. From this, the “neurotrophic hypothesis” of depression developed, that attributed depression to decreased neurotrophic support in the hippocampus and that restoring the neurotrophic support (such as by increasing BDNF levels) in that area of the brain would correct the symptoms of depression.1 The results of the new paper1 found, though, that chronic immobilization stress in eight week old adult male Wistar rats reduced BDNF expression in the CA3 area of the hippocampus but INCREASED the expression of BDNF in the BLA (basolateral amygdala), a different area of the brain that is particularly involved in emotional responses to stress, such as anxiety and fear. Under the conditions of chronic immobilization stress (CIS), there is dendritic atrophy in CA3 pyramidal neurons of the rodent hippocampus while, at the same time, there is a strengthening of synaptic connectivity through dendritic growth and spinogenesis in BLA.
These changes are called plastic remodeling and can last for some time. “... exposure to 10 days of chronic immobilization stress elicits dendritic hyertrophy [enhanced growth] in BLA principal neurons that lasts till at least 21 days after the termination of stress.”1 Meanwhile, the CA3 atrophy in the hippocampus is reported to be able to reverse these changes within the same period of post-stress recovery.1 In fact, the researchers explain that even a single 2 hour episode of immobilization that causes no dendritic atrophy in the BLA one day later can still result in a significant increase in spine density ten days later.
The authors also say, “in [mice genetically engineered to overexpress BDNF], overexpression of BDNF also causes spinogenesis in the BLA. Moreover, BLA spinogenesis is also triggered by chronic stress in control mice [that express BDNF at normal levels] but is occluded by BDNF overexpression, thereby suggesting a role for BDNF signaling in stress-induced plasticity in the amygdala.”1 As the authors point out, these differential changes in the two brain areas pose a “significant challenge for pharmacological interventions aimed at countering the effects of stress on amygdala and hippocampus.” They suggest that further elucidation of the mechanisms involved would be helpful in designing better treatments for stress-related psychiatric conditions such as post-traumatic stress disorder characterized by impaired cognition and high levels of fear and anxiety.
- Lakshminarasimhan and Chattarji. Stress leads to contrasting effects on the levels of brain derived neurotrophic factor in the hippocampus and amygdala. PLoS ONE 7(1):e30481 (Jan. 2012).
Recent Results Highlight Importance of BDNF in
Maintaining Youthful Cognitive Abilities
In a recent paper,1 researchers report that the age-dependent deficits in long-term synaptic plasticity and loss of dendritic spines in the hippocampus of aged Fisher 344 rats were closely associated with reduced histone acetylation. Histones are proteins surrounding DNA that, by various chemical modifications, such as acetylation, determine whether genes are available for expression or are prevented from being expressed. In this paper,1 the aging deficits were linked to upregulation of HDAC2, a particular histone deacetylase, and decreased expression of a histone acetyltransferase. The researchers found that a key gene, BDNF, was affected by these changes and that these cognitive deficits could be rescued by enhancing BDNF and TrkB (BDNF receptor) expression via HDAC inhibition or by directly activating trkB receptors.
The authors suggest that “epigenetic or pharmacological enhancement of BDNF-trkB signaling could be a promising strategy for reversing cognitive aging.”
- Zeng et al. Epigenetic enhancement of BDNF signaling rescues synaptic plasticity in aging. J Neurosci 31(49):17800-10 (2011).
APOE epsilon 4, Risk Factor for Alzheimer’s Disease:
Why Is It Still in the Gene Pool?
You have to wonder why the well known risk factor for Alzheimer’s disease, APOEepsilon4, is still around. Since it hasn’t disappeared from the gene pool, one has to assume that it is providing something beneficial, at least under certain conditions. An example of a genetic disease that has disastrous effects when an individual inherits two copies of the defective gene, but where there are benefits (a reduced risk of getting malaria) for those with just one copy of the defective gene is sickle cell anemia. Protection against malaria would have been, at least in the areas with endemic malaria, an important advantage. Otherwise, over time, for genes with adverse effects that do not also provide survival advantages at least under some conditions, one would expect they would end up disappearing from the gene pool.
A new paper1 reports that, interestingly, the APOE epsilon4 gene is associated with higher vitamin D levels in mice genetically engineered to carry the gene and also in humans that have the APOEepsilon4 gene. In fact, the paper reports that “[i]n Europe, the epsilon4 allele distribution is positively correlated with geographical latitude, with a >4-fold higher frequency in the north than in the south (e.g., 22.7% in Finland vs. 5.2% in Sardinia.” This would correlate well with the amount of vitamin D created in the skin as a result of sun UVB exposure, with the exposure reduced as one moved farther north. The authors propose, therefore, that “[t]he current investigations suggest the APOE epsilon4 allele as a novel genetic modulator of vitamin D status.”(1) Moreover, patients with Alzheimer’s disease are reported to have a high prevalence of vitamin D deficiency and vitamin D is reported to improve cognition in some AD patients.1a
In fact, a paper published in 19412 reported that people in the United States who lived at higher latitudes, such as in New Hampshire, Vermont, and Massachusetts had overall greater risks of dying of cancer as compared with men and women of similar ages who lived in southern states, such as Texas, Georgia, and Alabama. Vitamin D deficiency has been associated with many types of cancer.2a
In addition, some data have been published on the risk of disease (other than Alzheimer’s disease) for those carrying the APOEepsilon4 allele as compared to those who don’t, such as increased injury following brain trauma. There is an awful lot of downside with this allele. If one needs additional vitamin D, and many people do, taking supplemental vitamin D3 is easy and inexpensive, while having the “advantage” of higher vitamin D levels as a result of carrying the APOEepsilon4 allele is, at least nowadays, no advantage at all.
In fact, a new report3 has just been published on APOE4, in which the “bad” form of APOE has been found to weaken the blood-brain barrier as a result of dysregulation of an inflammatory protein (cyclophilin A) in mice genetically engineered to express human APOE4, whereas this did not happen to mice carrying APOE2 or APOE3. However, as the authors of the commentary accompanying the new paper3a pointed out, “... as it is the lack of APOE3 rather than the presence of APOE4 that triggers the inflammatory response, the role of this pathway in the many patients with Alzheimer’s disease who carry one copy of APOE4 and one of APOE3 is unclear.”
1. Huebbe et al. APOEepsilon4 is associated with higher vitamin D levels in targeted replacement mice and humans. FASEB J 25:3262-3270 (2011).
1a. Lu’o’ng et al. The beneficial role of vitamin D in Alzheimer’s disease. Am J Alzheimers Dis Other Demen 26(7):511-20 (2011 Nov).
2. Apperly. The relation of solar radiation to cancer mortality in North America. Cancer Res 1:191-5 (1941) (2A) See, for example, Tuohimaa. Vitamin D, aging, and cancer. Nutr Rev 66(Suppl 2):5147-52 (2008).
3. Bell et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485:512-6 (24 May 2012).
3a. Carmeliet and de Strooper. A breach in the blood-brain barrier. Nature 485:451-2 (2012)
Effects of Different Ratios of Omega 6/Omega 3
Polyunsaturated Fatty Acids on Infarct Size
After a Heart Attack in Rats
Researchers hypothesized, on the basis that dietary omega-6 fatty acids and omega-3 fatty acids could modulate the balance between pro- and anti-inflammatory mechanisms, that a decrease in the ratio of omega-6/omega-3 (that is, an increase in omega-3 fatty acids as compared to omega-6 fatty acids) in the diet, without altering the content in total fat, proteins, or carbohydrates, would result in a reduction in infarct size (the amount of heart tissue killed) in a myocardial infarction (MI).1 They also hypothesized that the decreased omega-6/omega-3 in the diet would diminish the apoptosis (cell death) that occurred in the amygdala and hippocampus of the brain following reperfusion (restoration of blood flow) after the MI.
Three month old male Sprague Dawley rats were fed diets with one of three possible ratios of omega-6/omega-3 fatty acids for two weeks: 1:5, 1:1, or 5:1.
After that, the researchers induced myocardial infarction (heart attack) in the animals while the animals were under anesthesia by occluding the left anterior descending coronary artery; then, after 40 minutes of ischemia, there was 15 minutes of reperfusion, after which the animals were killed and heart and brain tissues prepared for examination.
Infarct size was significantly reduced by 32% in groups 1:5 and 1:1 as compared to group 5:1 omega6/omega3 ratios. The plasma levels of the proinflammatory cytokine TNF-alpha (tumor necrosis factor alpha), released following myocardial infarction (MI) was significantly increased in the 5:1 diet group as compared to the two other groups. Various brain areas were examined—the dentate gyrus, areas CA1 and CA3 and the lateral and medial amygdala—with particular attention paid to the limbic system where damage following an MI (from reduced blood flow and the release of inflammatory cytokines) is thought to be a causative factor in the depression that often follows an MI. In fact, after 15 minutes of reperfusion, caspase-3 activity (a mediator of apoptosis) was significantly reduced in the groups receiving high omega-3 polyunsaturated diets (1:1 and 1:5).
The researchers, taking all the results into consideration, concluded that “the 1:1 ratio is optimal for heart health.” (This conclusion, though, was derived from the parameters measured following MI in their 3 month old male Sprague Dawley rats, not from a study of heart health in general.)
The authors add, as a potential explanation of some of the results, that the omega-3 polyunsaturated fatty acids have antiapoptotic effects. For example, docosahexaenoic acid (DHA) is precursor for the antiinflammatory neuroprotectin D and systemic DHA administration after middle cerebral artery occlusion has been reported to increase levels of circulating neuroprotectin D. Interestingly, neuroprotectin D1 has been identified as an inhibitor, at very low doses, of inflammatory pain.2 In fact, the DHA derived NPD1 was first identified in resolving inflammatory exudates in mouse brain, as well as in experimental stroke, where it was found to provide potent protective actions (neuroprotection).2
In another study,3 human subjects that had lower levels of DHA in red blood cells (those in the lowest quartile when compared to those in higher quartiles) had significantly smaller brain volumes and also had significantly lower scores on tests of visual memory, executive function, and abstract thinking.3
An earlier study4 reported that a marker of inflammation (hs-CRP, high sensitivity assay C-reactive protein) was modestly but significantly elevated in autopsy samples from patients dying suddenly with severe coronary artery disease and that the association of hs-CRP with sudden death in heart disease patients was independent of age, smoking, and body mass index.
Actually, we don’t know anybody (including ourselves) who eats a diet (or even a diet plus supplementation) so enriched in omega-3 fatty acids as to reach a 1:5, let alone a 1:1 ratio. But the results of this study suggest that, if a heart attack is going to take place, you are going to be a lot better off if you have an omega-6/omega-3 ratio that is better (that is, lower) than the typical 16:1 in the average North American’s diet.1
- Rondeau et al. Effects of different dietary omega-6/3 polyunsaturated fatty acid ratios on infarct size and the limbic system after myocardial infarction. Can J Physiol Pharmacol 89:169-76 (2011).
- Park et al. Resolving TRPV1- and TNF-alpha-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J Neurosci31(42):15072-85 (2011).
- Tan et al. Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging. Neurology 78:658-64 (2012).
- Burke et al. Elevated C-reactive protein values and atherosclerosis in sudden coronary death: association with different pathologies. Circulation 105:2019-23 (2002).
No Statistically Significant Linear Relationship
Between Oxidative Stress and Abnormal Lipid Profile
in Human Subjects with Coronary Artery Disease
An interesting paper1 published the results of an examination of 42 known human cases of coronary artery disease (CAD) (outpatients who had just survived a heart attack) for markers of oxidative stress (assessed by measuring MDA, malondialdehyde, a lipid peroxidation product) and lipid profile parameters (standard risk factors that include HDL cholesterol, LDL cholesterol, and triglycerides). The CAD outpatients were compared to 33 age- and sex-matched healthy controls who were evaluated for the same parameters.
The major finding of this study was that although, as expected, there was increased oxidative stress as well as significantly abnormal measures of HDL, LDL, and triglycerides in the CAD patients who had just survived a heart attack as compared to the healthy controls, there was a highly statistically insignificant correlation between MDA level and each lipid profile parameter in the CAD cases. This suggests, the researchers say, that “increased oxidative stress and abnormal lipid profile are two independent risk factors in the pathomechanism of atherogenesis.”1
This finding is potentially of considerable interest and, if verified with a larger sample size, may help explain why antioxidants have not, in very large human clinical trials, been consistently effective in reducing the risk of developing heart disease. In these large trials, there generally haven’t been measurements to establish participants’ baseline and later levels of oxidative stress. If one is going to test the hypothesis that the reduction of oxidative stress by antioxidants could reduce the risk of (say) heart disease, then it hardly makes sense to run the study without measuring oxidative stress.
In the previously conducted large trials, it was difficult to interpret the results because it was unclear what part oxidative stress was playing in the disease process. (It still is, which is why measurements assessing changes in oxidative stress are so important.) Clearly, a great deal more is going on in CAD than just oxidative stress and antioxidants can often do a great deal more than just suppressing the generation of and/or chemical reactions of ROS, such as acting as signaling molecules in the expression of genes that might be relevant to CAD. Indeed, in the design of these costly studies, researchers need to take into account that the proper dosage level of antioxidants is unlikely to be the same for the diverse mechanisms by which antioxidants could affect the course of a disease.
The authors1 suggest that their findings should be verified by a study with a larger sample size. We hope this is done. It would also be useful to include more than just a single marker for the formation of lipid peroxide breakdown products (MDA) to assess oxidative stress.
- Rao and Kiran. Evaluation of correlation between oxidative stress and abnormal lipid profile in coronary artery disease. J Cardiovasc Dis Res 2(1):57-60 (2011) www.jcdronline.com DOI: 10.4103/0975-3583.78598.
Potential Efficacy of Curcumin
In Treatment of Inflamed Tendons
An in vitro study of cultured human tendon cells (tenocytes) derived from a healthy finger tendon of a single male middle aged donor during tendon-rupture surgery was conducted in order to study in detail the mechanism of curcumin in the inflammatory signaling of the proinflammatory cytokine IL-1beta and to investigate whether curcumin might antagonize the catabolic effects of this and other powerful inflammatory cytokines by suppressing the activation of NFkappaB—a master regulator of inflammation—as well as NFkappaB-induced gene expression. By following a complex map of inflammatory regulation using amazingly sophisticated experimental tools, the researchers were able to determine that curcumin regulates a series of inflammatory mediators and predict that “curcumin might have prophylactic potential for the treatment of tendinitis.”1 Curcumin and related curcuminoids are found in turmeric, a yellow spice used in generous quantities in curry dishes.
The researchers explain that “[t]endinopathy is accompanied by inflammation and degradation of the tendon extracellular matrix ... [where] pro-inflammatory cytokines such as IL-1beta may initiate a cascade of events leading to tendon destruction and loss of biomechanical structural integrity.” Part of the destruction involves a catabolic process in which there is down-regulation of structural components such as collagen types I and III, decorin, and tenomodulin in tenocytes; the latter are all suppressed by IL-1beta. The authors consider the control of IL-1beta to possibly be “critical” for protecting tendons from pathological inflammatory processes that involve subsequent activation of specific transcription factors such as NF-kappaB.
The authors found that “curcumin suppresses the activation of NF-kappaB in human tenocytes in vitro and inhibits the expression of NF-kappaB gene products, including COX-2 [an inflammatory enzyme], MMPs [matrix degrading enzymes], Bax, and caspase-3.” (Bax and caspase-3 are involved in the process of apoptosis, programmed cell death.) “Curcumin at concentrations of
Furthermore, the authors explain that in human phase I clinical trials, oral doses of curcumin have been found to be safely administered at doses of 0.2–12 g/day with no dose limiting toxicity, being eliminated within 12 hours. They also cite a phase II study of curcumin that reported biological activity in patients with pancreatic cancer.
This paper is a good example of the sort of sophisticated and exquisitely designed study that can isolate the contribution of various aspects of a complex interaction to identify what is causing what so as to potentially control disease. And all this for the sake of helping people deal with inflamed tendons!
The work was funded by the Biotechnology and Biological Sciences Research Council and The Wellcome Trust, UK.
- Buhrmann et al. Curcumin modulates nuclear factor kappaB (NF-kappaB)-mediated inflammation in human tenocytes in vitro. J Biol Chem 286(32):28556-66 (2011).
Sometimes Big Things Can Happen
What If The Tenth Amendment Won Big Time
At the U.S. Supreme Court ... Would You Know?
The Tenth Amendment of the United States Constitution states: “The powers not delegated to the United States by the Constitution, nor prohibited by it to the States, are reserved to the States respectively, or to the people.”
The Tenth Amendment isn’t the sort of thing you expect to see being supported at the U.S. Supreme Court. In fact, it is one of those things you expect to have faded into oblivion along with a lot of (most of) the rest of the Constitution. Well, something funny happened on the way to oblivion ...
The Tenth Amendment was supported in a UNANIMOUS U.S. Supreme Court decision Bond v. United States, No. 09–1227, decided June 16, 2011.
The case itself was a pretty unlikely basis for a momentous decision. In Carol Anne Bond, Petitioner v. United States, Bond had admitted to attacking a former close friend she suspected of having an affair with her husband (and of becoming pregnant by him) with a noxious chemical, as well as smearing the chemical on surfaces the woman was likely to come into contact with. She was indicted under a Federal statute, but appealed, her attorney arguing that the statute exceeded Congress’ constitutional authority under the Tenth Amendment to enact as it involved entirely local matters that should have been dealt with by state law. In fact, Bond would have faced a much lower period of imprisonment under state, as opposed to Federal, law. Bond was ruled by the Third Circuit to lack standing in her Tenth Amendment challenge to her conviction under Federal law.
The appeal to the U.S. Supreme Court reversed the Third Circuit and held: “Bond has standing to challenge the federal statute on grounds that the measure interferes with the powers reserved to States. Pp. 3–14.”
The language used to explain how the Court reached its decision (the unanimous decision was delivered by Justice Anthony Kennedy) included some remarkable and quite revolutionary stuff. For example:
“The indicted defendant, petitioner here, sought to argue the invalidity of the statute. She relied on the Tenth Amendment, and by extension, on the premise that Congress exceeded its powers by enacting it in contravention of basic federalism principles. The statute, 18 U.S.C. §229, was enacted to comply with a treaty, but petitioner contends that, at least in the present instance, the treaty cannot be the source of congressional power to regulate or prohibit her conduct.”
“The Court of Appeals held that because a State was not a party to the federal criminal proceeding, petitioner had no standing to challenge the statute as an infringement upon the powers reserved to the States.”
“Federalism has more than one dynamic. It is true that the federal structure serves to grant and delimit the prerogatives and responsibilities of the States and the National Government vis-a-vis one another. The allocation of powers in our federal system preserves the integrity, dignity, and residual sovereignty of the States. The federal balance is, in part, an end in itself, to ensure that States function as political entities in their own right.”
“But that is not its exclusive sphere of operation. Federalism is more than an exercise in setting the boundary between different institutions of government for their own integrity. ‘State sovereignty is not just an end in itself: “Rather, federalism secures to citizens the liberties that derive from the diffusion of sovereign power.’“ [case citations follow but have been deleted here.]
“Federalism also protects the liberty of all persons within a State by ensuring that laws enacted in excess of delegated governmental power cannot direct or control their actions. By denying any one government complete jurisdiction over all the concerns of public life, federalism protects the liberty of the individual from arbitrary power. When government acts in excess of its lawful powers, that liberty is at stake.”
“An individual has a direct interest in objecting to laws that upset the constitutional balance between the National Government and the States when the enforcement of those laws causes injury that is concrete, particular, and redressable. Fidelity to principles of federalism is not for the States alone to vindicate.”
“The principles of limited national powers and state sovereignty are intertwined. While neither originates in the Tenth Amendment, both are expressed by it. Impermissible interference with state sovereignty is not within the enumerated powers of the National Government [case cited here] and action that exceeds the National Government’s enumerated powers undermines the sovereign interests of States. See United States v. Lopez, 514 U.S. 549, 564 (1995) The unconstitutional action can cause concomitant injury to persons in individual cases.”
“There is no basis in precedent or principle to deny petitioner’s standing to raise her claims.”
This decision is really worth reading in its entirety. Something has happened at the U.S. Supreme Court—and though we certainly can’t read the minds of the Justices, reading the words delivered in this opinion was enough to knock us off our chairs. There is a breathtaking emotional content in this decision affirming that federalism exists (and note the reference to U.S. v. Lopez, where a federal law banning the possession of a gun within a certain distance of a school was ruled by the U.S. Supreme Court as an unconstitutional overreach under the Commerce Clause), that federalism is very important to individual liberty, and that the powers of the National Government are limited under the terms of the Tenth Amendment.
Yikes! The Tenth Amendment lives!!
If the scale of a country renders it unmanageable, there are two possible responses. One is a breakup of the nation; the other a radical decentralization of power.
— Gar Alperovitz, The New York Times (10 Feburary 2007) (as quoted in Thomas N. Naylor, “Secession” (2008)