The journey of a thousand miles begins by finding your shoes.— Lao-Tzu (first century BC)Advertisement: Stock up and save. Limit: one
Sign in a Japanese amusement park: Those who suffer from high blood pressure, mental disease, horrifying of heights, and liquor heads are refused.— (Above two found in the 2012 Anguished English Desk Calendar)
I know you lawyers can, with ease Twist words and meanings as you please.— Benjamin Franklin (Poor Richard’s Almanack, 1740)
The mass of the law is, to be sure, accumulating with an almost incredible rapidity ... It is impossible not to look without some discouragement upon the ponderous volumes, which the next half century will add to the groaning shelves of our jurists.— Joseph Story (1779-1845) Address before Suffolk Bar, Sept. 4, 1821
We were thinking about what a tremendous difference it makes to your sense of well-being and happiness when future opportunities shrink because of general economic decline. It may be true that (as indicated by some scientific studies), at least once you reach a certain level of wealth such that you needn’t be concerned with the basic needs of shelter and food, increasing income doesn’t add much (or nearly as much) to happiness as it does when your wealth is below the basic level of sustenance. However, it occurred to us that a major effect that loss of opportunity to increase wealth has is to limit future options and, thus, to shrink the future. Just as youth is generally thought of as an open door to an expandable future (as compared to middle or old age), so wealth also opens the way to myriad future options that would otherwise be unavailable.
We were thinking about those who have saved enough wealth so that they needn’t be too concerned about a foreseeable even fairly near term economic collapse in the United States, at least in terms of their basic survival and even allowing for fairly comfortable living. What effect would the general deterioration in economic conditions have on the well-being and happiness of these pretty well off people? We realized that it would dramatically reduce the sense of an open future associated with a vibrant free economy such as the United States has long been and that the sense of an open future is an important part of happiness. Yet, if one were able to develop sources of increased income, it would greatly mitigate this sense of a lost open future and, hence, ameliorate the loss of happiness that accompanies a shrunken future.
So, yes, money can buy happiness in a very real and very important sense.
Yet more evidence emerges supporting the hypothesis that excess inflammatory gene activity is a major causative factor in aging.
While inflammatory pathways are a critical part of immune function, adequate regulatory control to prevent excessive inflammation is important in the prevention of chronic inflammation-associated diseases such as atherosclerosis and diabetes. Recent studies indicate that human centenarians are able to maintain immune function while avoiding excessive inflammatory activity.1 In fact, “older humans and mice show higher levels of inflammation and oxidative stress in their leukocytes [white blood cells], coincident with the impaired immune responses.”1
A recent paper1 investigated the relationship between preserved immune functions and controlled oxidative stress in successful aging using a natural long-lived mouse model. NF-kappaB (nuclear factor kappa B) is an important mediator of the effects of inflammation and oxidative stress on immune function. The activity of this factor is increased in many chronic inflammatory diseases, including multiple sclerosis and sepsis. It is also reported to be downregulated by glutathione precursors such as
A recent paper2 reviewed the effects of NF-kappaB signaling in the aging process. Here, the authors explain that chronic activation of NF-kappaB signaling “has the capacity to induce the senescent phenotype associated with aging. Interestingly, several longevity genes such as SIRT1, SIRT6, and FoxOs can clearly suppress NF-kappaB signaling and in this way delay the aging process and extend lifespan.”2 Of particular interest, they report that “… de Magalhaes et al [see ref 3] performed a meta-analysis of age-related expression profiles of 27 datasets from mice, rats, and humans. The most common agerelated genetic signature involved the overexpression of inflammation and immune response genes and also the genes linked to the function of lysosomal system. This indicates that the entropy [disorganization] related to aging process activates the innate immunity system. This process is called
The response of the lymphocytes to stimulation by the T-cell mitogen Con A was preserved in the extreme long-lived as compared with adults, whereas old animals had a significantly decreased response.1 Phagocytosis, an important function of macrophages, was reduced in old and very old animals as compared to adults. However, the peritoneal macrophages from the extreme long-lived animals had intact phagocytic function.
Importantly, the levels of GSSG (oxidized form of glutathione) in peritoneal leukocytes from old animals was increased compared to adult levels, but there was no such increase in the extreme long-lived animals, indicating that they had superior antioxidative capacities.1
“The results show a low level of basal NF-kappaB activation in cells from adult and extreme long-lived animals. However, leukocytes from both old and very old animals showed greater activation of NF-kappaB compared with the adult animals, suggesting chronic activation of this transcription factor in resting leukocytes with aging, but not in those animals that achieved extreme old age.” “… persistent high NF-kappaB activation in basal conditions could be deleterious and has been related to a wide range of aging-related diseases, such as
Most of the mice, however, never made it to extreme old age just as few people live to 100 and beyond. “… only 1 of 10 individuals analyzed from the old and very old age groups ultimately achieved extreme longevity (138 and 132 weeks, respectively), and interestingly these two mice were the ones showing controlled NF-kappaB activation in their leukocytes.” “Importantly, extreme long-lived mice maintained their NK [natural killer] cytotoxic activity, a finding also reported for human centenarians.”
One recent paper5 suggests that, inhibition of NF-kappaB, activated in influenza-infected lung epithelial cells and playing a key role in the inflammatory response to influenza infections, could be part of a practical strategy to improve survival during flu epidemics. One way that NF-kappaB increases inflammatory activity is to promote the transcription of a number of proinflammatory cytokines.3
NF-kappaB as a Mediator of Stress
Finally, it is interesting to note that NF-kappaB is identified as a “critical mediator of stress-impaired neurogenesis and depressive behavior.”5b Hence, it may be particularly helpful during these stressful times to take supplements that inhibit NF-kappaB signaling.
Modulation of NF-kappaB Levels with Supplements
Supplements that have been reported to inhibit NF-kappaB include metabolites of omega-3 fatty acids (called resolvins and protectins).6 quercetin,7 EGCG,8 the amino acid cysteine,9 and others.
1. Arranz et al. Preserved immune functions and controlled leukocyte oxidative stress in naturally long-lived mice: possible role of nuclear factor kappa B. J Gerontol A Biol Sci Med Sci 65A(9):941-50 (2010).
2. Salminen and Kaarniranta. NF-kappaB signaling in the aging process. J Clin Immunol29:397-405 (2009).
3. De Magalhaes et al. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25:875-81 (2009) doi:10.1093/bioinformatics/btp073.
4. Weindruch et al. Microarray profiling of gene expression in aging and its alteration by caloric restriction in mice. J Nutr 131:918S-23S (2001).
5. McCarty et al. Practical strategies for targeting NFkappaB and NADPH oxidase may improve survival during lethal influenza epidemics. Med Hypotheses 74:18-20 (2010).
5b. 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. Kaarniranta and Salminen. NF-kappaB signaling as a putative target for w-3 metabolites in the prevention of age-related macular degeneration (AMD). Exp Gerontol44:685-8 (2009).
7. Min et al. Quercetin inhibits expression of inflammatory cytokines through attenuation of NFkappaB and p38 MAPK in HMC-1 human mast cell line. Inflamm Res 56:210-5 (2007).
8. Giakoustidis et al. Inhibition of intestinal ishemia/reperfusion induced apoptosis and necrosis via down-regulation of the NF-kappaB, c-Jun, and caspace-3 expression by epigallocatechin-3-gallate administration. Free Radic Res 42(2):180-8 (2008).
9. Mihm et al. Inhibition of HIV-1 replication and NF-kappaB activity by cysteine and cysteine derivatives. AIDS 5:497-503 (1991).
10. Spencer et al. Constitutive activation of NF-kappaB in an animal model of aging. Int Immunol 9(10):1581-8 (1997).
A press release dated 29 Sept. 2011 from the Federation of American Societies for Experimental Biology (publishers of the FASEB Journal)* reports on research1 that “suggests that rats fed homobrassinolide, found in the mustard plant, produced an anabolic effect, and increased appetite and muscle mass, as well as the number and size of muscle fibers.” Moreover, the researchers found that homobrassinolide treatment produced anabolic effects and improved physical fitness in healthy animals without detrimental androgenic effects.1
*Contact: Cody Mooneyhan, firstname.lastname@example.org, (301)-634-7104
Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal said, “[t]he temptation is to see this discovery as another quick fix to help you go from fat to fit, and to a very small degree, this may be true. In reality, however, this study identifies an important drug target for a wide variety of conditions that cause muscle wasting.”
The paper1 explains that very little is known about the effects of brassinosteroids in animals. “A natural brassinosteroid and its synthetic derivatives were found to inhibit herpes simplex virus type 1 (HSV-1) and arenavirus, measles, Junin, and vesicular stomatitis virus replication in cell culture.” Moreover, the paper cites studies in which natural brassinosteroids have also been shown to inhibit growth of several human cancer cell lines without affecting the growth of normal cells.
Investigation of the mechanisms of growth promotion by homobrassinolide (HB) have revealed an association with the increased synthesis of nucleic acids and proteins.1 The researchers note that IGF-1 (insulin-like growth factor-1) has “both an anabolic effect on protein synthesis and an anticatabolic effect on protein degradation in skeletal muscle, similar to insulin.”1 “HB at concentrations of 0.3–20 µM inhibited protein degradation dose dependently, and its activity reached a plateau between 3 and 10 µM.” “Insulin at 10 nM served as positive control in this assay; it reduced protein degradation by 13.0 ± 1.6%.” This compared to 1 µM HB, which decreased protein degradation by 8.2 ± 0.6% above control levels.
The researchers explain that IGF-1 inhibits protein degradation in myotubes through PI3K/Akt/GSK-3beta- and PI3K/Akt/mTOR-dependent mechanisms, identifying Akt as the key intermediate in the IGF-1 signaling pathway regulating downstream targets for protein synthesis and degradation. Similar results were found for HB as for IGF-1, though the effect of HB on Akt phosphorylation “is not as robust as that described for IGF-1.”
Importantly, the researchers found that HB showed no significant binding to the androgen receptor from concentrations of 0.01 µM up to 10 µM. They were, thus, able to conclude that “our data demonstrate that oral application of HB triggers an anabolic response with minimal or no androgenic side effects.”
THE NATIONAL MUSTARD MUSEUM (7477 Hubbard Ave., Middleton, WI 53562; 800-438-6878) is our favorite source of a wide variety of mustards; you won’t find most of these at your local supermarket. The store/catalog has many hundreds of different kinds in their hilarious catalog. (This is an unsolicited plug!) Our favorite mustard sauce available at this store (goes great on chicken, fish, and egg dishes) is the Key Lime Mustard Sauce.
Chronic obstructive pulmonary disease (COPD) is already relatively common (with 80,000,000 suffering from the disease in 2005 and 3,000,000 dying from it at that time) and the World Health Organization warns that COPD may become the third leading cause of death by 2030 (which may be true, but we always take such long-term predictions with a large grain of salt, however, especially when they come from public or quasi-public—that is politically motivated—agencies with a vested interest in scaring people into putting more money into the agencies’ budgets.) But, getting back to the facts … COPD is becoming increasingly viewed not just as a respiratory disorder but as a systemic disease, involving skeletal muscle wasting, diaphragmatic dysfunction, and systemic inflammation.1 It is largely caused by inhalation of smoke from tobacco and cooking fires and of air pollutants from automotive, industrial, and power generation activities. The disease is progressive and treatments are relatively ineffective, with some patients requiring lung transplantation.
Recent studies in a mouse model of COPD, however, point the way to an effective therapy.1 Excitingly, the researchers publishing this paper found a way to protect mice from developing emphysema and pulmonary hypertension, but even to REVERSE established disease in the animals. Importantly, it was discovered that “… smoke exposure caused emphysema and pulmonary hypertension in wild-type mice and in mice lacking eNOS [the endothelial form of nitric oxide synthase], but not in mice lacking iNOS [inducible nitric oxide synthase].”1 In other words, iNOS was part of the process by which the smoke exposure caused emphysema and pulmonary hypertension. “Moreover, when the authors administered an iNOS inhibitor after 8 months of smoke exposure, the treatment reversed the lung damage within 3 months.”
A CURATIVE APPROACH
The substance used in the reported paper to inhibit iNOS was the iNOS inhibitor N6-(iminoethyl)-L-lysine (hereafter called L-NIL). The authors refer to their use of L-NIL to restore lung structure and function when wild-type mice were treated with L-NIL after FULL establishment of emphysema (i.e. initiation of L-NIL treatment after 8 months of chronic smoke exposure for an additional 3 month period) as a CURATIVE APPROACH, not the sort of description you see routinely used in highly respected journals such as Cell, in which this paper was published.
The authors suggest that ONOO– (peroxynitrite, formed by the chemical reaction of nitric oxide and superoxide radicals in mitochondria) “is a possible candidate for mediating the effects of iNOS upregulation on lung vasculature and parenchyma.”1 “The increased levels of nitrotyrosine, present as a possible consequence of ONOO– generation (as reported in ref 2), in WT mice following tobacco-smoke exposure were in accordance with our hypothesis that ONOO-upregulation is a key step in vascular remodeling and emphysema pathogenesis.”
More About ONOO– and Its Inhibition
ONOO– is chemically created by the reaction of nitric oxide with superoxide radicals, especially in the presence of a deficiency of arginine or a deficiency of the mitochondrial cofactor tetrahydrobiopterin. Under those conditions, you get was is called “uncoupling” in the mitochondria, where instead of generating nitric oxide from the interaction of arginine and nitric oxide synthase, the mitochondria generate superoxide radicals, which can lead to a plethora of adverse effects due to scavenging of nitric oxide (and the consequent reduced availability of nitric oxide) by superoxide and the powerful prooxidant effects of ONOO–.
A Natural Product That Downregulates iNOS in a Mouse Model of Asthma
As so frequently happens in the large scientific literature, more than one group is studying a particular phenomenon of interest at the same time, such as researchers seeking methods for controlling and producing the effects of iNOS. iNOS is an important part of the proinflammatory processes that, as part of the immune system, are key factors in preventing and fighting off infections. Hence, like so many other things, you do not want to inhibit iNOS too much, but just enough to prevent the adverse effects of excess inflammation. That balancing act is one reason that medicine is an art as well as a science. No two people will respond exactly the same to any pharmacological agent, such as an iNOS inhibitor, and thats why you need the help of an experienced doctor to help you use powerful medicinal agents.
As it happens, a paper was published in Planta Medica3 at almost the same time as the paper on the inhibition of iNOS as a potential curative approach to COPD (at least in mice). The new paper described the effects of grape seed proanthocyanidins (grapeseed proanthocyanidin extract, or GSPE) in a mouse model of asthma. As the authors report, nitric oxide (NO) plays an important role in the pathophysiology of asthma.3 “Increased NO level is found to be positively related to asthmatic airway inflammation and hyperresponsiveness. iNOS is also increased in asthmatic tissues, representing airway eosinophilic cells, T helper (Th) 2 cells, and mast cell infiltration.” Glucocorticoids (with their often powerful anti-inflammatory effects) are the first choice of asthma therapy, but “no significative curative effect is observed among those with severe asthma or steroidal resistance. In addition, years of steroid therapy cannot guarantee that asthmatic patients regain normal bronchial reactivity. It is therefore safe to say that an alternative anti-inflammatory treatment of asthma is badly needed.”
In the abstract of the new paper,3 the authors state that “[a]dministration of GSPE REMARKABLY suppressed airway resistance and reduced the total inflammatory cell and eosinophil counts in BALF.” See, for example, Fig. 3B. Also, Fig. 4B shows that infiltrating macrophages and neutrophils around the bronchi showed positive iNOS protein expression in the tissues of animals where inflammatory activation was induced by OVA (ovalbumin) as compared to animals not so sensitized. “GSPE treatment dramatically decreased them [the i-NOS stained cells in the OVA-induced inflammatory lung tissue].”
The authors make some comments on the safety of GSPE supplements. They note, for example, that a 3 month study of oral toxicity of 2.5% grape seed extract caused no adverse effects. Japanese researchers reported that no evidence showed acute oral toxicity in rats at dosages of 2 and 4 g/kg. “However, high-dose GSPE could cause apoptotic cell injury via effector caspase-3 activation and subsequent induction of reactive oxygen species generation.”2 (The general rule is that nothing is perfectly safe and that “the dose makes the poison.”) In their study,2 the authors found no significant cytotoxicity in GSPE-treated mice.
Other Natural Products Can Inhibit iNOS Under Certain Experimental Conditions
Quite a few studies (mostly in vitro)4 have identified natural products with anti-iNOS activity that include: naringenin (found in orange peel), kaempferol (found in broccoli and tea), quercetin (found in onion, broccoli, apples, and berries)—we include quercetin in our high potency multivitamin, multimineral, antioxidant formulation (128 mg in the daily recommended dosage of 12 capsules)—and silymarin. Our recent PubMed search of gamma tocopherol peroxynitrite also suggests that gamma tocopherol as protective against peroxynitrite (see, for example, refs 4b, 4c). Of course, to evaluate whether the iNOS inhibiting activity would be adequate to mitigate various disease conditions would require careful study of the literature for dosage used, type of cell cultures and/or animals involved, toxicity, and many other factors.
And, finally, as is mentioned in a recent paper,5 “[t]here are not however, many anti-inflammatory drugs that specifically target NOS or more specifically, iNOS, although there are various studies and trial that are investigating the effect of iNOS inhibition in various inflammatory conditions such as sepsis and other chronic illnesses including cancer.”
1. Seimetz et al. Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice. Cell 147:293-305 (2011).
2. Szabo et al. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 6:662-80 (2007).
3. Zhou et al. Grape seed proanthocyanidin extract attenuates airway inflammation and hyperresponsiveness in a murine model of asthma by downregulating inducible nitric oxide synthase. Planta Med 77:1575-81 (2011).
4. Pan et al. Modulation of inflammatory genes by natural dietary bioactive compounds. J Agric Food Chem 57:4467-77 (2009).
4b. McCarty. Gamma tocopherol may promote effective NO synthase function by protecting tetrahydrobiopterin from peroxynitrite. Med Hypotheses 69(6):1367-70 (2007).
4c. Ferroni et al. Phenolic antioxidants and the protection of low density lipoprotein from peroxynitrite-mediated oxidations at physiologic CO2. J Agric Food Chem 52(10):2866-74 (2004).
5. Liu et al. Targeting cyclooxygenase and nitric oxide pathway cross-talk: a new signal transduction pathway for developing more effective anti-inflammatory drugs. Curr Signal Transduct Ther 4:66-75 (2009).
It’s late fall and the Indians on the Northern Cheyenne Indian Reservation in Montana asked their new chief if the coming winter was going to be cold or mild. Since he was a chief in a modern society, he had never been taught the old ways. When he looked at the sky, he couldn’t tell what the winter was going to be like.
Nevertheless, to be on the safe side, he told his tribe that the winter was indeed going to be cold and that the members of the tribe should collect firewood to be prepared.
But, being a practical leader, after several days, he got an idea.
He got on the phone and called the National Weather Service and asked.
“Is the coming winter going to be cold?”
“It looks like this winter is going to be quite cold,” the meteorologist at the weather service responded.
So the chief went back to his people and told them to collect even more firewood in order to be prepared.
A week later, he called the National Weather Service again. “Does it still look like it is going to be a very cold winter?”
“Yes,” the man at National Weather Service again replied, “it’s going to be a very cold winter.”
The chief again went back to his people and ordered them to collect every scrap of firewood they could find. Two weeks later, the chief called the National Weather Service again.
“Are you absolutely sure that the winter is going to be very cold?” “Absolutely,” the man replied. “It’s looking more and more like it is going to be one of the coldest winters we’ve ever seen.”
“How can you be so sure?” the chief asked.
The weatherman replied, “The Indians are collecting a shitload of firewood.”
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