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Centenarians Have Preserved Immune Functions But a Lower Expression of Genes Inducing Inflammation in Durk Pearson & Sandy Shaw’s® Life Extension NewsTM, Volume 14 No. 5 • November 2011
Article:
"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 N-acetylcysteine, which can prevent excessive oxidative stress and inflammation in animal models. However, these authors wanted to look at specific models of long-lived animals (animals living naturally long periods of time as compared to others of their species, analogously to human centenarians) to assess the degree of NF-kappaB activity in leukocytes in old individuals. They chose to look at Mus musculus, a type of mouse that can be extremely long lived (for a mouse), with 7–10% of the females reaching 125 ± 4 weeks of age.
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 inflammaging … .” The NF-kappaB system responds, not only to immune attacks, but to other signals such as oxidative stress, hypoxia, and genotoxic stress.2 Not unsurprisingly, caloric restriction studies in organisms ranging from yeast to mammals can prevent the appearance of the age-related proinflammatory gene expression profile.4
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 atherosclerosis.”1,10
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."
Article at:
http://www.life-enhancement.com/magazine/article/2546-centenarians-have-preserved-immune-functions-but-a-lower-expression-of-genes-inducing-inflammation
Centenarians as a model for healthy aging in PubMed, Franceschi C1, Bonafè M., Department of Experimental Pathology, University of Bologna, Bologna, Italy, April 2003
Abstract:
For over 10 years we have studied centenarians as a model to address the biological basis of aging and longevity, with particular attention to immunology and genetics. The most important findings can be summarized as follows. (i) Human immunosenescence represents a complex remodelling, whereby clonotypical immunity deteriorates, while ancestral, innate immunity is largely preserved. (ii) Continuous exposure to antigens causes a lifelong, chronic antigenic stress, which is responsible, together with the involution of the thymus, for the accumulation of memory/effector T cells and the exhaustion of naïve T cells. (iii) Aging is characterized by a peculiar chronic inflammatory status that we propose to call 'inflammaging', which appears to be under genetic control, is detrimental for longevity and is more evident in men than in women. Inflammaging, i.e. the up-regulation of a variety of anti-stress responses at the cellular and molecular level, is the consequence of the ability of the body to adapt to and counteract the effects of a variety of stressors, which causes the accumulation of molecular and cellular scars. Inflammaging is considered the common and most important driving force of age-related pathologies, such as neurodegeneration, atherosclerosis, diabetes and sarcopenia, among others, all of which share an inflammatory pathogenesis. (iv) Possible strategies to counteract the major effects of immunosenescence and inflammaging, such as the systematic reduction of the lifelong antigenic load, the elimination of chronic infections, thymic rejuvenation and preventative treatment with anti-inflammatory drugs in people with a pro-inflammatory genotype, are envisaged.
Article at:
http://www.ncbi.nlm.nih.gov/pubmed/12653662
Centenarians as a model for healthy aging at PubMed.com,
Franceschi C1, Bonafè M., Department of Experimental Pathology, University of Bologna, Bologna, Italy, April 2003
Abstract:
For over 10 years we have studied centenarians as a model to address the biological basis of aging and longevity, with particular attention to immunology and genetics. The most important findings can be summarized as follows. (i) Human immunosenescence represents a complex remodelling, whereby clonotypical immunity deteriorates, while ancestral, innate immunity is largely preserved. (ii) Continuous exposure to antigens causes a lifelong, chronic antigenic stress, which is responsible, together with the involution of the thymus, for the accumulation of memory/effector T cells and the exhaustion of naïve T cells. (iii) Aging is characterized by a peculiar chronic inflammatory status that we propose to call 'inflammaging', which appears to be under genetic control, is detrimental for longevity and is more evident in men than in women. Inflammaging, i.e. the up-regulation of a variety of anti-stress responses at the cellular and molecular level, is the consequence of the ability of the body to adapt to and counteract the effects of a variety of stressors, which causes the accumulation of molecular and cellular scars. Inflammaging is considered the common and most important driving force of age-related pathologies, such as neurodegeneration, atherosclerosis, diabetes and sarcopenia, among others, all of which share an inflammatory pathogenesis. (iv) Possible strategies to counteract the major effects of immunosenescence and inflammaging, such as the systematic reduction of the lifelong antigenic load, the elimination of chronic infections, thymic rejuvenation and preventative treatment with anti-inflammatory drugs in people with a pro-inflammatory genotype, are envisaged.
Article at:
http://www.ncbi.nlm.nih.gov/pubmed/12653662
Chronic Inflammation Associated With Worse Outcomes in Aging at fightaging.org, no author, 18 September 2013
Excerpt:
"Chronic inflammation is not a good thing, but it becomes worse with age even for those in the best of health, a result of the decline of the immune system into progressively worse states of malfunction. There are plenty of ways to accelerate this decline into inflammation, however, such as by becoming overweight, as visceral fat tissue generates inflammation via a range of signaling processes."
Quote:
"The importance of chronic inflammation as a determinant of aging phenotypes may have been underestimated in previous studies that used a single measurement of inflammatory markers. We assessed inflammatory markers twice over a 5-year exposure period to examine the association between chronic inflammation and future aging phenotypes in a large population of men and women.
We obtained data for 3044 middle-aged adults (28.2% women) who were participating in the Whitehall II study and had no history of stroke, myocardial infarction or cancer at our study's baseline (1997-1999). Interleukin-6 was measured at baseline and 5 years earlier. Cause-specific mortality, chronic disease and functioning were ascertained from hospital data, register linkage and clinical examinations. We used these data to create 4 aging phenotypes at the 10-year follow-up (2007-2009): successful aging (free of major chronic disease and with optimal physical, mental and cognitive functioning), incident fatal or nonfatal cardiovascular disease, death from noncardiovascular causes and normal aging (all other participants).
Of the 3044 participants, 721 (23.7%) met the criteria for successful aging at the 10-year follow-up, 321 (10.6%) had cardiovascular disease events, 147 (4.8%) died from noncardiovascular causes, and the remaining 1855 (60.9%) were included in the normal aging phenotype. After adjustment for potential confounders, having a high interleukin- 6 level (greater than 2.0 ng/L) twice over the 5-year exposure period nearly halved the odds of successful aging at the 10-year follow-up and increased the risk of future cardiovascular events and noncardiovascular death. Chronic inflammation, as ascertained by repeat measurements, was associated with a range of unhealthy aging phenotypes and a decreased likelihood of successful aging."
Article at:
https://www.fightaging.org/archives/2013/09/chronic-inflammation-associated-with-worse-outcomes-in-aging.php
Centenarians at longerhealthylife.net, no author, no date
Excerpts:
"Starting closer to us, human centenarians (living over 100 years) have been studied to determine what characteristic biologic factor(s) leads to long life. These people are a very widely varying group. Diets of these centenarians have considerable variation with no food outstanding as a common source of their longevity. Some smoke, some drink, some are good tempered, and some are mean as nails. Cholesterol levels vary considerably. The oldest ever recorded (well documented) was Jean Calumet of France who died at 122 years of age. She smoked and drank all of her life until about 100 years of age. She claimed that chocolate had kept her alive so long. We can set the maximum human life span by this 122 years of age, as we have no other documented examples of greater human life span.
The only common finding shared by all centenarians(besides being from relatively long lived families is 1.) a very well preserved insulin response to rising dietary incoming blood sugar with a rather Low Body Mass Index (=weight divided by (height)^2 in kilogram/meter system-meaning that they were relatively slim) AND 2.) a much lower rate of chronic inflammatory activation with age ."
"[b]This absence of age adjusted higher levels of resistance to insulin and lower chronic inflammation levels in centenarians is critical[/b].
This better handling of glucose compares to the far more common finding of a continual rise in insulin resistance with rising fasting insulin levels and some rise in fasting blood glucose levels in normal middle aged humans. Insulin sensitivity and insulin resistance are both focused on the ability to handle an increased level of glucose entering the blood stream from meal with low insulin levels (low insulin resistance = high Insulin sensitivity). Conversely, very high blood circulating insulin levels are harmful. High insulin resistance in response to rising blood sugar means that cells are not as sensitive to low level of insulin to absorb the blood sugar. This forces the body to produce and release into the blood stream much more insulin. Insulin resistance means the body does not efficiently remove glucose from the blood stream. Higher blood stream levels of glucose damage proteins by complex free radial mechanisms. AIn addition to better control over glucose by low levels of insulin, centenarians also have lower levels of blood circulating triglycerides (triglycerides are are the typical fats and oils we buy in the market). Centenarian's levels of insulin and triglyceride have risen over life, just like other people, but not as much as others. Notable among centenarians is the post mortem finding of virtually no evidence of Alzheimer's disease or similar dementia manifestations "
"While most centenarians show various levels of age associated diseases, some CENTENARIAN humans show no known diseases of age that are common in much younger humans. Now we are beginning to realize that we are PREMATURELY dying by an INFLAMMATION driven age-associated diseases is not necessary."
Article at:
http://longerhealthylife.net/SUBS%20(Read%20More...)/Centenarians.html
You may be interested in the following:
BBC Documentary: Visions of the Future - The Biotech Revolution (1 hr video)
No, however having said that, my brother has a PhD in pharmacology and has done research and been a division manager of several pharmaceutical companies. My cousin has a PhD in biological toxins. So, I get some excellent 'dumps' and feedback regarding the field of autoimmunity and biological responses. BTW, my brother said it is not surprising that pharmaceuticals have poured a lots of money in the area of autoimmunity (but the yields have been dismal)---so my interest in anatabine citrate as an investment area. Obviously big Pharma must think autoimmune disorders and inflammatory inhibitors are key areas of research or they wouldn't throw large sums of money at it. FYI, my degree is in Electrical Engineering and only in the last 10 years have I become interested in biology and in particular, synthetic biology.(fascinating). I don't represent STSI, but I own some stock in my portfolio, hence my sharing of DD on this discussion board. I find autoimmune disorders as related to chronic inflammation the new frontier in biology, not to mention the connection with cardiovascular and cancer diseases. I hope answers from all this research will solve the trillion dollar question about disease and life itself. I personally think prevention of chronic inflammation will be a key for longer and healthier lives. Only time will tell if STSI is part of that future.
The Drug That Could Reverse Alzheimer's in Yahoo News from the The Daily Beast, By Elizabeth Lopatto, 24 May 2014
Article:
"A drug in early animal trials has shown promising results, appearing to reverse the symptoms of Alzheimer’s disease in mice.
Additionally, in mice, the treatment reduced inflammation in parts of the brain that are associated with memory and learning, according to a study led by Susan Farr of Saint Louis University School of Medicine, published in the Journal of Alzheimer’s Disease.
The mice were engineered to produce a mutant form of human beta amyloid, one of the proteins associated with Alzheimer’s disease. In a previous study, the researchers had tested mice that naturally overproduced mouse beta amyloid; this step was to see if the drug would work with the human version. Both types of mice showed impaired learning as they aged, much like humans with Alzheimer’s disease.
Two groups of mice were tested: the mutants, and wild-type mice. The wild-type mice were given random compounds, along with half of the mutants. The other half of the mutants received the experimental drug, called antisense oligonucleotide or OL-1. They were then tested in mazes, to see how well they learned and remembered while exploring a new location, and in recognizing objects. The genetically engineered mice that received OL-1 did about as well as the wild mice.
“It reversed learning and memory deficits and brain inflammation in mice that are genetically engineered to model Alzheimer’s disease,” Farr said in a statement released by the school. “Our current findings suggest that the compound is a potential treatment for Alzheimer’s disease.”
About 5 million Americans who are 65 or older have Alzheimer’s disease now, and that number may rise to 16 million in 2050, according to the Alzheimer’s Association, an advocacy organization for the disease. There is no cure.
Four drugs are currently used in Alzheimer’s disease: Aricept, Exelon, Reminyl, and Namenda. They all temporarily treat symptoms of memory loss, but lose effectiveness as the disease progresses.
Unlike these drugs, OL-1 doesn’t target symptoms. Its molecules bind to messenger RNA, allowing certain genes to be “turned off.” Here, the blockage of RNA prevents extra amyloid from being produced by targeting its precursor protein and making less of it. The hope is that by lowering the amount of amyloid, fewer mind-robbing plaques would appear—either slowing the disease’s progression or halting it entirely.
OL-1 hasn’t been through the toxicity trials needed to determine if it’s safe for human use. Many promising treatments for diseases don’t make it past this step into Phase 1 testing in humans. And even that’s just the beginning. Only about 10 percent of drugs tested in Phase 1 go on to make through the FDA, according to a January article in Nature Biotechnology.
In fact, more than 100 drugs for Alzheimer’s disease have either failed in development or been abandoned. Beta amyloid, which OL-1 is meant to lower, was first implicated in the disease at its identification by Alois Alzheimer in 1906. Many researchers believe that the dementia from Alzheimer’s disease is caused by an accumulation of beta amyloid in the brain, forming plaques that choke healthy cells, leading to the loss of neurons and, eventually, problems with thought.
Previous drugs targeting amyloid precursor protein, or APP, have failed. Eli Lilly & Co.’s drug to inhibit one of the chemicals that slices APP into beta amyloid not only failed in a final-stage trial, it was worse for patients than a placebo. Another drug company, Myriad, tried a similar route, and also failed in clinical testing.
Article at:
http://news.yahoo.com/drug-could-reverse-alzheimers-023433680--politics.html
My comments: Compare to Anatabine abstract in PubMed.
Abstract:
"Anatabine lowers Alzheimer's Aß production in vitro and in vivo.
Paris D1, Beaulieu-Abdelahad D, Bachmeier C, Reed J, Ait-Ghezala G, Bishop A, Chao J, Mathura V, Crawford F, Mullan M.
Author information
Abstract
Brain Aß accumulation represents a key pathological hallmark in Alzheimer's disease. In this study, we investigated the impact of anatabine, a minor alkaloid present in plants of the Solanacea family on Aß production in vitro using a cell line overexpressing the human amyloid precursor protein (APP) and in vivo using a transgenic mouse model of Alzheimer's disease. In vitro, anatabine lowers Aß1?40 and Aß1?42 levels in a dose dependent manner and reduces sAPPß production without impacting sAPPa levels suggesting that anatabine lowers Aß production by mainly impacting the ß-cleavage of APP. Additionally, we show that anatabine lowers NF?B activation at doses that inhibit Aß production in vitro. Since NF?B is known to regulate BACE-1 expression (the rate limiting enzyme responsible for Aß production), we determined the impact of anatabine on BACE-1 transcription. We show that anatabine inhibits BACE-1 transcription and reduces BACE-1 protein levels in human neuronal like SHSY-5Y cells suggesting that the Aß lowering properties of anatabine are mediated via a regulation of BACE-1 expression. In vivo, we show that an acute treatment with anatabine for four days significantly lowers brain soluble Aß1?40 and Aß1?42 levels in a transgenic mouse model of Alzheimer's disease. Altogether our data suggest that anatabine may represent an interesting compound for regulating brain Aß accumulation.
Copyright © 2011 Elsevier B.V. All rights reserved."
Abstract at"
http://www.ncbi.nlm.nih.gov/pubmed/21958873
Biotech's breathless quarter of IPOs brings in $2.1B for R&D in Fierce Biotech, April 7, 2014 | By Damian Garde
Excerpt:
"More than 45 life sciences companies had made their way onto the public markets in the preceding year, banking more than $3 billion in the process, and many at the industry's annual sewing circle believed biotech was about to see its shadow on Wall Street. Furthermore, rumor had it at least 25 upstarts were already embarking on road shows and wooing underwriters, all looking to squeeze out of a shrinking window before it snapped shut and burst the biotech bubble in the process.
But then that's not quite how things turned out.
Instead, a galling 29 life sciences outfits went public in the first quarter, taking home $2.1 billion to fund high-tech gene silencing, me-too pain drugs and what might boil down to a gussied-up formulation of plain old bleach, to name just three.
My comments:
If you explore each of these start-ups, all focus on a specific disease or phase of a disease. Anatabine Citrate has opportunities in a whole range of applications that relate to inhibition of chronic inflammation, the common root of many autoimmune, cardiovascular, and cancer diseases.
Article at:
http://www.fiercebiotech.com/special-report/biotechs-breathless-quarter-ipos-brings-21b-rd/2014-04-07#ixzz32e1aqILG
Subscribe at FierceBiotech
Teva keeps the faith after another rebuke for Copaxone's heir
May 23, 2014 | By Damian Garde
Excerpts:
"Teva's ($TEVA) $4-billion-a-year multiple sclerosis treatment Copaxone is slated to lose patent protection next year, and the Israeli drugmaker is struggling to move the needle on its planned replacement, enduring another rejection from European reviewers."
"In its first rejection of the drug, CHMP highlighted safety risks that cropped up in animal studies and weren't quelled by later human trials, pointing out that exposure to laquinimod was tied to a higher occurrence of cancers and some dangers for pregnant women. On the efficacy side, the committee was satisfied with the treatment's ability to slow the progression of MS-related disability but unimpressed with its effect on relapses.
Laquinimod has endured two Phase III missteps on its way to regulatory trouble, failing to significantly reduce relapse rates in MS patients. Teva is now in the midst of a third late-stage trial, dubbed CONCERTO, studying the treatment's effects on disability progression. Data from that study will likely support Teva's second go at EU approval, and the company has said it expects to win U.S. approval by 2018.
Article at:
http://www.fiercebiotech.com/story/teva-keeps-faith-after-another-rebuke-copaxones-heir/2014-05-23#ixzz32dyxnSIc
Subscribe at FierceBiotech
Clinical Trials for Alzheimer's Disease in Pharma, no date, no author
Excerpt:
The 108 clinical trials listed here include 65 that have not yet started recruiting patients or are just now seeking volunteers to participate and another 43 that are active, but not recruiting new patients. This information is potentially valuable to patients still seeking possible treatments for Alzheimer’s disease. It provides a new therapeutic option to discuss with physicians. Those interested in obtaining more information about certain trials can use the URL code listed for each trial to log onto www.clinicaltrials.gov, the clinical trials database of the National Institutes of Health.
Report at:
http://www.phrma.org/alzheimers-disease-clinical-trials#sthash.dXxw7tAG.dpuf
Drugs and Treatments for Autoimmune Diseases: Global Markets in BCC Research, October 2011, no author
REPORT HIGHLIGHTS:
The global market for autoimmune treatments reached at $34 billion in 2010, it is expected to reach at $38.9 billion by 2011 and it will further grow to $55 billion by 2016 at a compounded annual growth rate (CAGR) of 7.2%.
U.S being the largest market for autoimmune treatments holds 43% share in the global market, it will sustain its position and will hold 44% market share in 2016.
Europe remains the second largest market for autoimmune treatments holds 27% share in the global market, it will sustain its position and will hold 28% market share in 2016.
Article at:
http://www.bccresearch.com/market-research/healthcare/autoimmune-diseases-drugs-treatment-markets-hlc091a.html
Specialty Drugs are Forecasted to be 50 Percent of All Drug Expenditures in 2018 in Compendium Blog, S. Johnson No external funding provided for this research 1
, B. Gunderson1
, K. Bowen1
, C. I. Starner1, 2
, P. P. Gleason1, 2
Prime Therapeutics, Eagan, MN, USA; 2
University of Minnesota College of Pharmacy, Minneapolis, MN, USA
Conclusions:
• Currently approximately four of five prescriptions are filled
with a generic drug at a cost of less than $20. In the coming
years, new generic drug market entrants are limited.
• Due to the increased use of generics, continued
pharmaceutical manufacturer annual double digit price
increases, increasing utilization, and future pipeline of new
specialty drugs, specialty drug expenditures are expected to
be 50 percent of all drug expenditures by 2018.
• The current top specialty category is autoimmune with the
top expenditure drug on both the medical and pharmacy
benefits. Health insurers and pharmacy benefit managers
will need to focus initially on the autoimmune category to
ensure expenditures are managed.
• Health insurers will need to increase their vigilance
of specialty drugs and focus on four management
opportunities: drug distribution channel, utilization
management, contracting activities, and coordination
of care.
Article at:
http://cdn2.content.compendiumblog.com/uploads/user/e7c690e8-6ff9-102a-ac6d-e4aebca50425/accf0d87-0d14-4aa7-bbf3-193b90c8d68c/File/1f8476cb4a60eb472893ddf381c9c3ec/prediction_that_by_2018__more_than_50_percent_of_all_drug_expenditures_will_be_specialty.pdf
The Fastest-Growing Therapeutic Class: Autoimmune Agents in Cutting Edge Information, no author, no date
Article:
"Though oncologics dominate the market with a whopping $52.37 billion in 2009 sales, they are the second-fastest growing therapeutic class. What wins the award as the number one fastest growing therapeutic class?
According to a recent article by Fierce Pharma, Autoimmune agents take the cake. Growing at a faster overall pace than its contenders over 5 years (2005 to 2009), this therapeutic class dominates with an annual growth rate of 17.86 percent (the oncologics market averages a 15.75 percent annual growth). This is nothing new to our analysts, who have stayed on the “cutting edge” of this therapeutic class since before the release of our Autoimmune Market Forecast to 2014 study.
Our research indicates that of 14 brands already at or expected to reach blockbuster status, half generate at least $3 billion annually. Nine mid-level products will generate $400 million, at minimum, by 2014. For autoimmune drugs, reaching blockbuster-level success is an expectation as much as a goal. If you are interested in finding out more about the other therapeutic areas we have researched, let me refer you to our growing collection of market forecasting reports. We’re currently focused on several of the majors: oncology, diabetes and neurodegenerative."
Article at:
http://www.cuttingedgeinfo.com/2010/the-fastest-growing-therapeutic-class-autoimmune-agents/#sthash.dolpRLvD.dpuf
The top 10 pharma companies by 2013 revenue in Fierce Pharma, March 4, 2014
Excerpt:
"The earnings reports for the biggest of Big Pharma are all in. Bayer reported last week, making it possible to see how they stacked up as they came into the new year. There are no big surprises. Pfizer ($PFE) and Merck & Co. ($MRK), with ongoing patent issues and reorganizations, saw their positions fall a couple of notches, and AbbVie ($ABBV), having been spun off from Abbott Laboratories ($ABT) at the beginning of the year, didn't quite make the top 10. Its disappearance allowed Eli Lilly & Co. ($LLY) to make the list. It also helped Bayer HealthCare move up a couple of notches. Here's last year's special report if you make comparisons.
After the major patent crashes of 2012, last year was more of a transitional period. Johnson & Johnson ($JNJ), Novartis ($NVS), Roche ($RHHBY), GlaxoSmithKline ($GSK), Eli Lilly and Bayer saw their revenues rise, although only J&J and Bayer had an appreciable change. Bayer's pharma revenues, combined with its consumer health unit, saw revenue growth of 7.6% based on dollars. J&J's number was up 6.7%, driven in large part by its pharma division. The others were flat or had growth of less than 3%.
Pfizer, Sanofi ($SNY), Merck & Co. and AstraZeneca ($AZN) were on the revenue-eroding end of the spectrum. Patent losses on blockbusters figured into most of the declines. Merck, whose revenues were off 6.8%, lost the patent on Singulair. Pfizer, which has yet to get past the sales erosion from the 2011 patent loss of Lipitor, saw its revenues fade 6%. Interestingly, Lipitor generics also rained on AstraZeneca's revenue parade, cutting sales of its cholesterol-lowering drug Crestor by 9% for the year; AZ's revenues were off 8% across the board. Sanofi's revenues were down 5.7%, undermined by a host of issues, including the patent loss on Plavix.
Still, you have to keep this all in perspective. Those numbers are nothing compared to the 17% revenue free falls that both AstraZeneca and Bristol-Myers Squibb ($BMY), which doesn't make this year's list, reported last year. As I said, it was a transitional year.
My comments:
There is a box in the article with links to the top 10, you might want to check out how many and who are focused on autoimmune, cardiovascular, and cancer diseases (think chronic inflammation).
Article at:
http://www.fiercepharma.com/special-reports/top-10-pharma-companies-2013-revenue#ixzz32drg2EMi
Subscribe at FiercePharma
Baffling Chronic Fatigue Syndrome Set for Diagnostic Overhaul
Researchers might soon redefine the mysterious condition, while the latest findings point to the role of brain inflammation
May 16, 2014 |By Katherine Harmon Courage in Scientific American
Article:
"More than one million people in the U.S. suffer from a poorly understood, difficult-to-diagnose condition that can leave them debilitated by unshakable exhaustion, pain, depression and cognitive trouble. Researchers, however, are still unsure what causes chronic fatigue syndrome (CFS), how to treat it, how best to diagnose it and even what to call it.
A new study is now providing hope for better understanding—and potentially better diagnosing—the disease. It has revealed a striking pattern of brain inflammation in CFS patients. Meanwhile, diagnosis and definition of the disease could soon be getting a major overhaul as a new $1-million Institute of Medicine (IOM) study gets underway at the request of the U.S. Department of Health and Human Services (HHS). Is the exhausting search for answers about CFS finally coming to an end?
In your head
Chronic fatigue syndrome was first formally described in the late 1980s. Soon thereafter it was lumped in with another perplexing condition known as myalgic encephalomyelitis (ME), which had been classified as a disease of the nervous system in the 1960s. A precise definition and diagnosis of CFS—sometimes called CFS/ME—has largely eluded doctors and researchers, however. Its subjectively described symptoms seem untestable: everyone is exhausted from time to time; many people suffer from occasional aches and pains; and, sure, we all have foggy days as well as down ones.
A large obstacle is that, unlike cancers or high blood pressure, researchers have no particular biomarkers that would allow them to test for the condition. Doctors rely exclusively on patient reports of the severity and duration of the symptoms—usually requiring the symptoms to be present for at least six consecutive months—along with the presence of extreme post-physical or mental exertion, fatigue and unrefreshing sleep, to diagnose the condition. Remissions and relapses confound clinicians further.
A change might be on the distant horizon, however, thanks in part to a new study of the brains of patients living with CFS.
Doctors have long suspected brain inflammation as a potential cause, but no definite traces of it had been detected. New research, in the June issue of the Journal of Nuclear Medicine, shows for the first time distinct increases in inflammation in particular regions of CFS patients' brains.
Yasuyoshi Watanabe, director of the RIKEN Center for Life Science Technologies and professor of physiology at Osaka City University Graduate School of Medicine, and his colleagues studied positron emission tomography (PET) scans of the brains of 10 health controls and nine patients with CFS. "Many researchers and clinicians, including our group, thought of this before, but apparently no one tried it using PET," Watanabe says.
The research team found increases in inflammatory markers in regions including the amygdala, thalamus and midbrain in CFS patients who had more severe cognitive troubles. They found more of these markers in thalamus and cingulate cortex in individuals who reported worse pain. And they found higher traces of inflammation in the hippocampus in patients with severe depression.
More than a decade ago, Watanabe's group found tantalizing suggestions that certain neurotransmitters were not being synthesized as well in people with CFS. These patients also had lower levels of serotonin transporters in particular brain areas. Other research had found higher levels of inflammatory cell-signaling proteins called cytokines circulating in the blood. All of these results led Watanabe to look closer for inflammation.
These PET-scan correlations do not precisely explain the symptoms, Watanabe notes. And only a handful of patients were in the study. But the work opens a new trail researchers can follow. Watanabe and his team are now looking into the amount of neuroinflammation in patients with CFS as well as the levels of circulating cytokines, which could both lead to the development of tests for the condition. Having a biologically based test could help those who do have the disease as well as patients who might have a different condition that has similar symptoms, such as depression, fibromyalgia or late-stage Lyme disease, which would be managed differently and potentially be cured with antidepressants, pain relievers or antibiotics. "Most important," Watanabe says, is "how to treat [CFS] patients and how to prevent this disorder." Currently, clinicians can only try to treat the symptoms—not the disease—with medications or lifestyle recommendations. "We are now planning to study therapeutics, such as anti-inflammatory agents, including herbal medicine," which might treat the underlying pathology, Watanabe says.
By any other name
Watanabe's study, and other new and forthcoming findings, however, may not be included in the current IOM review of the disease. "It is possible that the committee could examine new research that comes out during the study," says Jennifer Walsh, a spokesperson for the IOM. But, she notes, it depends on the study.
The study committee members will largely be assessing major research efforts and definitions developed previously for the disorder. "There were a number of case definitions that had come up over the years," says Nancy Lee, director of the Office on Women's Health at HHS and the department's designated federal officer of the Chronic Fatigue Syndrome Advisory Committee. Bringing so much of the work together to come up with a unified definition would help researchers not only better understand the illness, as well as help to convey information to clinicians so they can make faster, more definitive diagnoses. As Lee points out, "most U.S. physicians do not have a good understanding of how to make the diagnosis of ME/CFS." The IOM will try to develop new evidence-based criteria for diagnosing CFS, decide whether the condition should be renamed and come up with a way to best get the new recommendations to health care providers. It will not, however, be making recommendations on treatment, for now. The report is due by spring 2015.
The group's conclusions could have far-reaching consequences for how patients are diagnosed and treated in the U.S. and worldwide. Another recent study in Australia, published April 30 in the journal of Health and Quality of Life Outcomes, showed a large discrepancy in severity of illness for 45 CFS patients and 30 healthy volunteers who met the U.S. Centers for Disease Control and Prevention criteria set in 1994 versus international standards revised in 2011. Better definitions could prevent some patients from being underdiagnosed."
Article at:
http://www.scientificamerican.com/article/baffling-chronic-fatigue-syndrome-set-for-diagnostic-overhaul/?&WT.mc_id=SA_WR_20140523
NF-kB: Dr. Jekyll or Mr. Hyde? in Margaret's Corner-LIVING WITH SMOLDERING MYELOMA IN TUSCANY, blog by Margaret, January 2008
(Buddhahead's comment: hopefully easier to understand than academia papers?)
Article:
"A blog reader and I recently had an interesting exchange about this transcription factor, which is so important in myeloma…in a negative sense, unfortunately. Our discussion gave me the incentive to read more about it. My good friend Sherlock (grazie!) sent me a study published in January (2008) in “Experimental Biology and Medicine,” titled “Nuclear Factor-kB Activation: From Bench to Bedside,” and co-authored by Prof. B. Aggarwal (abstract: http://tinyurl.com/2m6j2g).
This transcription factor, discovered in 1986, was called NF-kB “because it was found in the nucleus bound to an enhancer element of the immunoglobulin kappa light chain gene in B cells.” Okay, wrap your brain around that! But seriously, if you reread the quote slowly, it begins to make sense: it’s a thingie (protein complex or transcription factor) sticking to the “kappa” gene inside a B cell’s nucleus.
Under normal circumstances, our immune system needs NF-kB to fight off diseases and infections. And until it is needed, this transcription factor follows my cats’ example and takes a lot of very long naps. I don’t want to go into its mechanisms of action (complicated stuff!), at least not today. Let it suffice that, once it has accomplished its task, it settles back down for another nap.
The study informs us that NF-kB is present in every type of cell, not just B cells as was first thought. Researchers have in fact discovered that it is located in the cytoplasm (the watery environment surrounding the cell nucleus) of all types of animal (from the fruit fly to us) cells. Another important finding is that it moves, or translocates, to the cell nucleus only when activated. Otherwise, it stays in, or (once it has finished its task) goes back to, the cytoplasm.
Things change with cancer. That’s when NF-kB turns into Mr. Hyde: it goes bonkers for a variety of reasons and ends up being active ALL the time, or constitutively active. And when this happens, NF-kB remains inside the cell nucleus, that is, it doesn’t return to the cytoplasm. No more naptime!
Skipping the technical parts about heterodimers, polyubiquitination and nuclear localization sequences (!), let me get to what we are really interested in: how does this transcription factor get activated in cancer cells? The study provides an answer: “NF-kB is activated by many divergent stimuli, including proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), epidermal growth factor (EGF), T- and B-cell mitogens, bacteria and lipopolysaccharides (LPS), viruses, viral proteins, double-stranded RNA, and physical and chemical stresses.” Radiation and chemotherapy also activate NF-kB. Speaking of which, the study tells us also that "Cells that express constitutively activated NF-kB are resistant to various chemotherapeutic agents and radiation treatment.” Vicious circle?
Another key sentence: “In tumor cells, different types of molecular alterations may result in impaired regulation of NF-kB activation. In such cases, NF-kB loses its transient nature of activation and becomes constitutively activated. This leads to deregulated expression of NF-kB– controlled genes.” NF-kB, the study continues, plays a critical role in cancer cell survival, inflammation, growth and so on. It regulates genes that are implicated in cancer cell proliferation, including TNF-alpha, IL-6, to name just a couple that we know are essential growth factors in multiple myeloma. It also regulates some of the cell cycle-regulatory proteins such as cyclin D1, also involved in myeloma (see my page on Ursolic Acid or my December 4 2007 post for more info on this gene, which has recently been associated with disease activity and progression).
Activated NF-kB is also implicated in the control of anti-apoptotic genes, that is, genes that keep cancer cells healthy and alive, such as survivin and Bcl-2 (again, see my post on ursolic acid). Furthermore, it regulates matrix metalloproteinases, or MMPs, which are proteases (protein-dissolving enzymes) that, among other things, promote cancer cell growth and angiogenesis. Okay, so there is no question that constitutively active NF-kB is not a good thing.
That’s enough for today, but I would like to end with a question: if we systemically inhibit NF-kB in order to stop our cancer from progressing, doesn’t that leave us more susceptible to infections? (More on this topic SOON!)"
Article at:
http://margaret.healthblogs.org/2008/01/22/nf-kb-dr-jekyll-or-mr-hyde/
NF-?B Regulates Spatial Memory Formation and Synaptic Plasticity through Protein Kinase A/CREB Signaling
Barbara Kaltschmidt1, Delphine Ndiaye2, Martin Korte3,†, Stéphanie Pothion4, Laurence Arbibe2,‡, Maria Prüllage1, Julia Pfeiffer1, Antje Lindecke1, Volker Staiger3, Alain Israël2, Christian Kaltschmidt1,* and Sylvie Mémet2, 1Institut für Neurobiochemie, Universität Witten/Herdecke, Stockumer Strasse 10, D-58448 Witten, Germany
2Unité de Biologie Moléculaire de l'Expression Génique, URA CNRS 2582, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France
3Max-Planck-Institut für Neurobiologie, Department of Cellular and Systems Neurobiology, Am Klopferspitz 18a, D-82152 Martinsried, Germany
4Key-Obs SA, Centre d'Innovation, 16 rue Léonard de Vinci, 45074 Orléans Cedex 2, France in Molecular and Cellular Biology, American Society for Microbiology, April 2006
ABSTRACT:
"Synaptic activity-dependent de novo gene transcription is crucial for long-lasting neuronal plasticity and long-term memory. In a forebrain neuronal conditional NF-?B-deficient mouse model, we demonstrate here that the transcription factor NF-?B regulates spatial memory formation, synaptic transmission, and plasticity. Gene profiling experiments and analysis of regulatory regions identified the a catalytic subunit of protein kinase A (PKA), an essential memory regulator, as a new NF-?B target gene. Consequently, NF-?B inhibition led to a decrease in forskolin-induced CREB phosphorylation. Collectively, these results disclose a novel hierarchical transcriptional network involving NF-?B, PKA, and CREB that leads to concerted nuclear transduction of synaptic signals in neurons, accounting for the critical function of NF-?B in learning and memory."
Article at:
http://mcb.asm.org/content/26/8/2936
Role of NF-kappaB-associated factors in T cell development and function by Lee, Joon Hyung, Ph.D., THE PENNSYLVANIA STATE UNIVERSITY, Dec 2013
Abstract:
The immune system is a defensive mechanism that protects an organism from disease by identifying and neutralizing invading pathogens. The proper functioning of the mammalian immune system requires participation and cooperation of different immune cell types, with the ability to distinguish self from non-self. Despite its protective functions, the immune system can also be a double-edged sword, as aberrant activation of the immune system can cause chronic inflammation and autoimmune diseases. Therefore, it is important to understand the mechanism by which immune responses are generated and regulated. Various intracellular signal transduction pathways and transcription factors are involved in the activation and regulation of immune responses.
NF-?B is a key transcription factor in the immune system that regulates the development, function, homeostasis, and survival of various immune cells. NF-?B activation typically occurs after a stimulatory signal received at the cell surface is relayed to NF-?B through complex intracellular signaling pathways. Therefore, the outcome of NF-?B activation is critically determined by the function of molecules involved in the NF-?B signaling pathways. This thesis addresses the role of NF-?B-associated molecules in the development, differentiation, and function of T cells. Our studies show that CYLD, a negative regulator of NF-?B activation, is critical for development of natural killer T (NKT) cells. In addition, Carma1, a key molecule involved in the T cell receptor-mediated NF-?B activation, is required for the development of suppressive regulatory T cells (Tregs). Lastly, p105, a NF-?B precursor molecule with NF-?B inhibitor function, plays an important role in the regulation of T cell homeostasis and prevention of chronic inflammation. The major findings are summarized below.
1. CYLD regulates IL-7 signaling and ICOS expression in the development of natural killer T cells. Natural killer T (NKT) cells modulate immune responses against pathogens and tumors. Utilizing CYLD-deficient mice, we show that CYLD, a deubiquitylase that negatively regulates NF?B activation, plays a critical role in NKT cell development. Unlike most of the known regulators of NKT cell development, CYLD is dispensable for NKT cell maturation but is required for the survival of immature NKT cells. The survival defect of immature NKT cells was associated with decreased expression of ICOS, a costimulatory molecule required for the survival and homeostasis of NKT cells, and signaling attenuation of an NKT-survival cytokine, IL-7. CYLD positively regulate ICOS expression and IL-7 signaling by preventing hyper-activation of NF-?B in immature NKT cells. Thus, CYLD regulates NKT cell development through a mechanism involving modulation of IL-7 signaling and ICOS expression.
2. Carma1 regulates development of regulatory T cells in the thymus. Regulatory T cells (Tregs) play a critical role in the preservation of self-tolerance and prevention of autoimmunity. We show that Carma1, a signaling molecule involved in the T cell receptor (TCR)-mediated NF-?B activation, is essential for development of Tregs in the thymus. Carma1 deficiency leads to attenuation of IL-2 signaling, a cytokine that is critical for the development of Tregs in the thymus. This IL-2 signaling defect in Carma1-knockout mice is associated with low expression of IL-2 receptor ß subunit (IL2Rß). Thus, Carma1 regulates thymic Treg development through modulation of IL-2 signaling via the IL-2Rß.
3. NF-kappa B1 p105 regulates T cell homeostasis and prevents chronic inflammation. NF-?B transcription factors are regulated by a family of inhibitors called I?Bs. NF-?B1 precursor, p105, contains I?B-like domain in their C-terminal and can function as NF-?B inhibitors. In this study, we show that p105 plays an important role in the regulation of T cell homeostasis and prevention of chronic inflammation. Mice that express mature NF-?B1, p50, in the absence of p105, spontaneously develop T cell-mediated intestinal inflammation. Consistent with the inflammatory phenotype, p105-deficient mice have increased frequency of memory/effector T cells in the peripheral lymphoid organs. Additionally, p105 deficiency renders CD4 + T cells more resistant to Treg-mediated suppression, while promoting differentiation of inflammatory Th17 CD4+ helper cells. Therefore, p105 plays critical roles in the regulation of T cell homeostasis and differentiation and the control of chronic inflammation."
Article at:
http://gradworks.umi.com/35/76/3576201.html
Molecular network of ChIP-Seq-based NF-?B p65 target genes involves diverse immune functions relevant to the immunopathogenesis of multiple sclerosis in Multiple Sclerosis and Related Disorders
Volume 3, Issue 1 , Pages 94-106, Jun-Ichi Satoh, January 2014
Abstract
Background
The transcription factor nuclear factor-kappa B (NF-?B) acts as a central regulator of immune response, stress response, cell proliferation, and apoptosis. Aberrant regulation of NF-?B function triggers development of cancers, metabolic diseases, and autoimmune diseases. We attempted to characterize a global picture of the NF-?B target gene network relevant to the immunopathogenesis of multiple sclerosis (MS).
Methods
We identified the comprehensive set of 918 NF-?B p65 binding sites on protein-coding genes from chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset of TNFa-stimulated human B lymphoblastoid cells. The molecular network was studied by a battery of pathway analysis tools of bioinformatics.
Results
The GenomeJack genome viewer showed that NF-?B p65 binding sites were accumulated in promoter (35.5%) and intronic (54.9%) regions with an existence of the NF-?B consensus sequence motif. A set of 52 genes (5.7%) corresponded to known NF-?B targets by database search. KEGG, PANTHER, and Ingenuity Pathways Analysis (IPA) revealed that the NF-?B p65 target gene network is linked to regulation of immune functions and oncogenesis, including B cell receptor signaling, T cell activation pathway, Toll-like receptor signaling, and apoptosis signaling, and molecular mechanisms of cancers. KeyMolnet indicated an involvement of the complex crosstalk among core transcription factors in the NF-?B p65 target gene network. Furthermore, the set of NF-?B p65 target genes included 10 genes among 98 MS risk alleles and 49 molecules among 709 MS brain lesion-specific proteins.
Conclusions
These results suggest that aberrant regulation of NF-?B-mediated gene expression, by inducing dysfunction of diverse immune functions, is closely associated with development and progression of MS.
Article at:
http://www.msard-journal.com/article/PIIS2211034813000473/abstract
Upstream Signal Transduction of NF-kB Activation
Fei Chen§, Jacquelyn Bower, Laurence M. Demers¶, and Xianglin Shi
The Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505, USA; ¶Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA, December 2001
Abstract:
NF-kB is a transcription factor governing the expression of genes involved in the immune response, embryo or cell lineage development, cell apoptosis, cell cycle progression, inflammation, and oncogenesis. During past few years, tremendous attention has been focused on the upstream signaling pathways leading to the activation of this transcription factor. Many of these signaling molecules can serve as potential pharmaceutical targets for the specific inhibition of NF-kB activation and the subsequent interference of disease processes. However, how these molecules interact with each other is still a debatable issue. Since many nodal signal molecules in this pathway relay more than one of the upstream signals to their downstream targets, it has been speculated that the transmission of signals involves a network, rather than a linear sequence in the activation of NF-kB. Thus, elucidation of the detailed relationships among the upstream signaling molecules of NF-kB activation will be important in developing pharmaceutical inhibitors that specifically inhibit the activation of NF-kB. Such inhibitors would be predicted to have powerful anti-inflammatory and/or anti- carcinogenic effects
Article at:
http://atlasgeneticsoncology.org/Deep/NFKBID20033.html
NF-?B Activation Inhibitors in EMD Millipore, no author, no date
Excerpts:
"Stimulation of cells by inflammatory cytokines, UV light, or reactive oxygen species leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of I?B, which frees NF-?B from the NF-?B-I?B complex. NF-?B then translocates to the nucleus where it binds to ?B enhancer elements of pro-inflammatory target genes to induce transcription. NF-?B is highly activated at sites of inflammation in diverse diseases and induces transcription of pro-inflammatory cytokines, chemokines, adhesion molecules, MMPs, COX-2, and inducible nitric oxide (iNOS). Hence, NF-?B has been considered as a desirable target for therapy in various inflammatory diseases. In most cancer cells, NF-?B is constitutively active and resides in the nucleus. In some cases, this may be due to chronic stimulation of the IKK pathway, while in others the gene encoding I?Ba may be defective. Such continuous nuclear NF-?B activity not only protects cancer cells from apoptotic cell death, but may even enhance their growth activity. "
"[b]Designing antitumor agents to block NF-?B activity or to increase sensitivity to conventional chemotherapy may have great therapeutic value."
Article at:
http://www.emdmillipore.com/life-science-research/nf-%CE%BAb-activation/c_6Cub.s1LUxkAAAEWxWEfVhTm?PortalCatalogID=merck4biosciences&CountryName=United+States+of+America
Advances in the Treatment of Ovarian Cancer -- A Potential Role of Anti-inflammatory Phytochemicals in Discovery Medicine, Author(s): Sophie S Chen, Agnieszka Michael, Simon A Butler-Manuel
Specialty: Biophysics, Biochemistry, Molecular Biology
Institution: Department of Research & Development, Ovarian and Prostate Cancer Research Trust Laboratory
Address: Guildford, Surrey, GU2 7YG, United Kingdom
Published on January 16, 2012
Abstract:
Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies worldwide. The five-year survival rates for stage IIIC and IV patients are 29% and 13%, respectively. Type-2 EOC cells have been found to be associated with this late stage disease. In contrast, women diagnosed in stage 1 disease, which mostly exhibits type-1 cells, have a high 5-year survival rate (90%). Recent progress in understanding the pathogenesis of EOC and inflammatory signaling pathways revealed that type-2 cells frequently express a deleted or mutated TP53 (60-80%), or aberrations in BRCA1 (30-60%) and BRCA2 (15-30%). The deletion or mutation of TP53 results in a dysregulated inflammatory signal network and contributes to an immunosuppressive microenvironment. Thus, to be effective, EOC therapy may be necessary to cover two areas: (1) direct cytotoxic killing of cancer cells; (2) reversion of the immunosuppressive microenvironment. Presently the first strategy is advancing rapidly while the second strategy remains behind. Isolation and characterization of cancer stem cells (CSCs) have helped to confirm the dynamic role of the tumor microenvironment in promoting cancer metastasis and recurrence. Based on widely published in vitro and mouse-model data, some anti-inflammatory phytochemicals appear to exhibit activity in modulating the tumor microenvironment. Specifically, apiegenin, baicalein, curcumin, EGCG, genistein, luteolin, oridonin, quercetin, and wogonin repress NF-kappaB (NF-?B, a proinflammatory transcription factor) and inhibit proinflammatory cytokines such as TNF-a and IL-6. Additionally, most of these phytochemicals have been shown to stabilize p53 protein, sensitize TRAIL (TNF receptor apoptosis-inducing ligand) induced apoptosis, and prevent or delay chemotherapy-resistance. Recent studies further indicate that apigenin, genistein, kaempferol, luteolin, and quercetin potently inhibit VEGF production and suppress ovarian cancer cell metastasis in vitro. Lastly, oridonin and wogonin were suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted. .
Article at:
http://www.discoverymedicine.com/tag/nf-kappab/
Ubiquitin signaling in the NF-?B pathway in UT Southwestern Medical Center, Zhijian "James" Chen Lab, no author, no date
Excerpt:
"IkB ubiquitination, IKK and IkB ubiquitin ligase
NF-?B is a transcription factor that regulates a plethora of genes in response to diverse stimuli. Aberrant regulation of NF-?B has been linked to many human diseases, such as cancer and autoimmune diseases. NF-?B is normally sequestered in the cytoplasm by proteins of the IkB family. Upon stimulation, distinct signaling cascades converge on the IkB kinase complex (IKK), which phosphorylates IkBs and targets these inhibitors for degradation by the ubiquitin proteasome pathway. NF-?B then enters the nucleus to turn on downstream target genes.
Article at:
http://www.utsouthwestern.edu/labs/chen-james/research/ubiquitin-signalling.html
A role for transcription factor NF-?B in autoimmunity: possible interactions of genes, sex, and the immune response in Advances in Physiology Education, American Physiological Society,
Elizabeth Dale , Miriam Davis , Denise L. Faustman, 1 December 2006
ABSTRACT:
Sex hormones have long been implicated in autoimmune diseases because women account for 80% of cases. The mechanism of hormonal action in autoimmunity is unknown. Drawing on genetic studies of autoimmune disease, this article discusses how both genes and sex hormones may exert their effects through the same general mechanism, dysregulation of transcription factor NF-?B, an immunoregulatory protein. Gene and hormone alterations of the NF-?B signaling cascade provide a unifying hypothesis to explain the wide-ranging human and murine autoimmune disease phenotypes regulated by NF-?B, including cytokine balance, antigen presentation, lymphoid development, and lymphoid repertoire selection by apoptosis.
Article at:
http://advan.physiology.org/content/30/4/152
Regulation of nuclear factor-?B in autoimmunity in Cell Press Trends in Immunology, Shao-Cong Sunemail, Jae-Hoon Chang, Jin Jin, June 2013
Summary:
"Nuclear factor (NF)-?B transcription factors are pivotal regulators of innate and adaptive immune responses, and perturbations of NF-?B signaling contribute to the pathogenesis of immunological disorders. NF-?B is a well-known proinflammatory mediator, and its deregulated activation is associated with the chronic inflammation of autoimmune diseases. Paradoxically, NF-?B plays a crucial role in the establishment of immune tolerance, including both central tolerance and the peripheral function of regulatory T (Treg) cells. Thus, defective or deregulated activation of NF-?B may contribute to autoimmunity and inflammation, highlighting the importance of tightly controlled NF-?B signaling. This review focuses on recent progress regarding NF-?B regulation and its association with autoimmunity."
Article at:
http://www.cell.com/trends/immunology/abstract/S1471-4906(13)00013-6
Mayo Clinic researchers find new molecule to target in pancreatic cancer treatment in Mayo Clinic WorldPharmaNews, 04 JANUARY 2013, no author
Excerpts:
"Researchers at Mayo Clinic in Florida have identified a new target to improve treatment of pancreatic ductal adenocarcinoma cancer, which accounts for more than 95 percent of pancreatic cancer cases. This fast-growing, often lethal cancer is resistant to conventional chemotherapy. The findings are published in the Jan. 3 online issue of PLOS ONE.
The researchers decoded a molecular pathway that is switched "on" at all times, promoting accelerated growth of pancreatic tumors, and that discovery revealed ways to disable the pathway. They say one strategy could involve the use of the drug bortezomib, which is already approved for several human blood cancers.
"Targeting this pathway to decrease the proliferation of cancer cells may represent a new strategy for pancreatic cancer therapy," says the study's senior investigator, Peter Storz, Ph.D., a biochemist and molecular biologist at Mayo Clinic.
One feature of pancreatic cancer is increased activity of the transcription factor NF-kB, which turns on expression of genes that keep the cells proliferating and protect them from death. There are two pathways, known as the classical and alternative, by which NF-kB can be activated, and the researchers looked at the alternative pathway - one in which NF-kB is activated differently, and which switches on other genes, compared to the classical signaling pathway. Both the classical and alternative pathways are active in pancreatic cancer.
The research team discovered that increased activity of the alternative NF-kB pathway results from suppression of TNF receptor-associated factor 2, or TRAF2. Loss of TRAF2 promotes fast growth of pancreatic tumors and correlates with increased aggressiveness, Dr. Storz says."
Article at:
http://www.worldpharmanews.com/research/2307-mayo-clinic-researchers-find-new-molecule-to-target-in-pancreatic-cancer-treatment
Alzheimer’s Burden Will Balloon if New Treatments Are Not Found in Pharma, no date, no author
Excerpt:
" A new report from the Alzheimer’s Association examines the future impact of Alzheimer’s disease (AD) and the potential impact of new treatments. The study finds that on our current trajectory Alzheimer’s disease in adults over 65 will cost $1 trillion per year by 2050 and a total of $20 trillion in the next 40 years. Medicare spending on AD will rise 600% while costs to Medicaid, other payers and patients will each rise 400%. The number of patients with AD will increase from 5.1 million today to 13.5 million in 2050.
New disease-modifying treatments could change that trajectory. A new treatment that delays the onset of disease by 5 years would push back the growth in new cases reducing the number of people with the disease by 43% and saving $447 billion a year by 2050. A treatment that slows the progression of AD by 5 years would reduce the number of people in the severe stage of the disease by over 80% and save $197 billion a year by 2050.
The study included medical costs to Medicare, Medicaid, private payers, and patients, but did not account for the additional burden on family caregivers and the cost of lost productivity, so the full societal benefits of effective treatments would be even higher.
Article at:
http://www.phrma.org/rx-minute-alzheimer%E2%80%99s-burden-will-balloon-if-new-treatments-are-not-found#sthash.GpbadTxH.dpuf
MY VIEW
After reviewing hundreds of articles from a database of millions in a meta search on chronic inflammation, nf-kb, autoimmune diseases, cardiovascular diseases, and cancers, some signficant points stand out and reach a common thread amongst many of the articles and research papers available online.
The race is on for an anti-inflammatory that can suppress nf-kb in a time varient manner and with minimal side-effects. The efficacy and flexibility of use for different applications are prime considerations in this search. Nf-kb appears to be the key inflammation modulator in focus today and for the foreseeable future. This could be the 'BIG KAHUNA' of modern medicine.
The race is in almost every medical discipline because 'chronic inflammation' is a common denominator to many autoimmune, cardiovascular, and cancer diseases. Major pharmaceuticals, small and large biotech firms, and government/university research organizations are in this race to find the 'holy grail.'
The current yields for promising therapeutics is going from poor to worse. Patent expirations are driving major drug manufacturers to seek new drugs from both within and without. Small biotechs are being bought out, teamed with, and licensed from, in the early stages of drug development to keep major pharmaceutical pipelines filled and alive. Some large pharmas are trying buyouts and mergers with like sized firms to keep their piplines filled.
With a dwindling pipelines, pharmaceuticals are raising prices of their current and new patent products into the astronomical range. Patients, hospitals, and government are raising their voices in anger.
Increases in diabetes, Alzheimers, cardiovascular diseases, cancers, and autoimmune disorders are surfacing issues connected with diet, stress, and environment for closer scrutiny and review. The complexity of diet (especially sugar), herbicides, pesticides, pollution, and genetically engineered foods as inflammatory triggers are being looked at in much greater detail.
Lack of 'transparent' data from pharmaceutical clinical trials are undergoing severe criticism and review. Many trials appear for short durations whereas problems manifest themselves in the longer term where data is lacking or non-existent. Researchers complain that clinical data is not open for review. Pharmaceuticals retort that the data is proprietary to keep competitors from gaining any advantage. Research institutions performing this research are restricted by contractual agreements and non-disclosure clauses.
Problems with serious side-effects and efficacy yields are making new drugs (with attendant high prices) questionable as to whether or not they can be economically used in the future. Older drugs are being looked at for 'new' applications.
The issue of whether or not the FDA is serving the best interest of the consumer is being severely tested. Employees in the FDA seek jobs in the pharmaceutical industry and employees of pharmaceuticals seek jobs with the FDA. The incestuous relationship between the FDA and the large drug companies makes their objectivity to regulate the drug industry questionable and needs review in the near future.
Criminal and civil transgressions by financial institutions are being exposed daily, the question is how large and caustic are these issues.
Are neutraceuticals and vitamins coming to an end with the FDA micromanaging all facets of their efficacy, marketing, and manufacture? Neutraceutical and vitamin companies complain that their products are being treated as drugs with attendant constraints and testing required. These small companies find themselves being driven out of business by the FDA actions.
MY OPINION: STSI/Roskamp appear to be in the sweet spot of the chronic inflammation/anti-inflammatory /nf-kb suppression arena with their patented application/process to manufacture anatabine citrate and their variants. Their research data shows anatabine to have high efficacy with minimal side-effects, making it stand out against the many anti-inflammatory peers being investigated. The success for reducing CRP (inflammation) and Thyroiditis are a beginning. With Dr Mullan's focus on Alzheimers and autoimmune diseases, his small team of scientists have as good a chance as any others of succeeding where many have already failed. Dr Mullan's team of 'experienced' researchers realize they don't have money to burn but if their research and findings are successful, it is very probable that a business arrangement with a large pharmaceutical is in their future to market their success. I personally think Anatabloc has a place as a 'pre-autoimmune' neutraceutical, prevention is more important than cure where the diseases linked to inflammation are life threatening.
Negative regulation of NF-?B and its involvement in rheumatoid arthritis in Arthritis Research & Therapy, Geert van Loo12 and Rudi Beyaert12, Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, B-9052 Ghent, Belgium, Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium, 2011
Abstract:
"The transcription factor NF-?B plays crucial roles in the regulation of inflammation and mmune responses, and inappropriate NF-?B activity has been linked with many autoimmune and inflammatory diseases, including rheumatoid arthritis. Cells employ a multilayered control system to keep NF-?B signalling in check, including a repertoire of negative feedback regulators ensuring termination of NF-?B responses. Here we will review various negative regulatory mechanisms that have evolved to control NF-?B signalling and which have been implicated in the pathogenesis of rheumatoid arthritis."
Conclusions:
"The NF-?B family of transcription factors plays crucial roles in the inflammatory processes in RA leading to cartilage and bone destruction. Keeping NF-?B activation under control can thus be very important for the design of specific therapeutics. The existence of multiple negative regulators ensuring a tight regulation of the NF-?B pathway, however, raises the question of the specific role of each of these regulators and the relationship between them. In addition, given the number of miRNAs in humans and the multiple mRNAs they target, intense complexity can be expected. How all these regulatory signals are themselves regulated will be an important question in order to clarify how NF-?B signalling is organised, and, more importantly, how this knowledge may lead to new treatments for inflammatory diseases such as RA."
Article at:
http://arthritis-research.com/content/13/3/221
Enbrel Warning in WebMD Rx List, no author, no date
"Etanercept (trade names Enbrel) is a biopharmaceutical that treats autoimmune diseases by interfering with tumor necrosis factor (TNF; a soluble inflammatory cytokine) by acting as a TNF inhibitor. It has U.S. F.D.A. approval to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF-alpha is the "master regulator" of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha.[1]"(Wikipedia)
Excerpt:
"WARNINGS
SERIOUS INFECTIONS AND MALIGNANCIES
Serious Infections
Patients treated with Enbrel are at increased risk for developing serious infections that may lead to hospitalization or death [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
Enbrel should be discontinued if a patient develops a serious infection or sepsis.
Reported infections include:
Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before Enbrel use and during therapy. Treatment for latent infection should be initiated prior to Enbrel use.
Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.
The risks and benefits of treatment with Enbrel should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Enbrel, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Malignancies
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including Enbrel.
"What are the possible side effects of etanercept (Enbrel, Enbrel Prefilled Syringe, Enbrel SureClick)?
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
fever, night sweats, weight loss, tiredness;
feeling full after eating only a small amount;
pain in your upper stomach that may spread to your shoulder;
easy bruising or bleeding, pale skin, feeling light-headed or short of breath, rapid heart rate; or
nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools,..."
Article at:
http://www.rxlist.com/enbrel-drug.htm
Rigel Shoots Out the Lights in Forbes, Melanie Lindner, 12/13/2007
Excerpt:
"Autoimmune diseases plague millions of Americans, but Rigel might have discovered a treatment to alleviate their suffering.
Rigel Pharmaceuticals skyrocketed after the company announced that its latest rheumatoid arthritis medication is showing positive results in a mid-stage study. Rigel climbed 224.4%, or $17.95, to $25.95, setting a new 52-week high for the South San Francisco-based company.
Rheumatoid arthritis is an autoimmune disease that causes chronic inflammation of the joints. It affects more than 2 million people in the United States.
Rigel’s experimental drug, known as candidate R788 or tamatinib fosdium, was given to 189 rheumatoid arthritis patients. The patients received one of three doses of tamatinib fosdium. According to Rigel’s study, the 100-milligram and 150-milligram doses showed positive results as early as one week after beginning the oral treatment. The 50-milligram dose did not appear to be effective."
Article at:
http://www.forbes.com/2007/12/13/rigel-pharmaceuticals-closer-markets-equity-cx_ml_1213markets36.html
Is Alzheimer's Really a Type of Diabetes? in NextAvenue, Gary Drevitch, October 17, 2012
Excerpts:
"We know that exercising and maintaining a healthy weight can help ward off dementia. We also know that people with Type 2 diabetes appear to be at least twice as likely to develop Alzheimer's disease than others. And now a provocative thesis suggests that Alzheimer's itself should be thought of as "Type 3" diabetes, or "diabetes of the brain." It's a theory that offers cause for both encouragement and concern.
A recent article by Brown Medical School neuropathologist Suzanne de la Monte in the Journal of Alzheimer's Disease detailed the connection between insulin and Alzheimer's. "Many of the unexplained features of Alzheimer's, such as cell death and tangles in the brain, appear to be linked to abnormalities in insulin signaling," she explained in a statement. "This demonstrates that the disease is most likely a neuroendocrine disorder, or another type of diabetes."
"Like Alzheimer's, diabetes has no cure. According to the American Diabetes Association, there are already nearly 26 million diabetics in the country, a number that is growing. Many diabetics do not develop Alzheimer's, but there is measurable overlap and the rates of both diseases are rising. If fatty foods provoke insulin resistance in our brains, then, as New Scientist magazine put it in a recent cover story about the link between diabetes and Alzheimer's, "we may be unwittingly poisoning our brains every time we chow down on burgers and fries."
In the New Scientist article, SUNY-Albany neuroscientist Ewan McNay said: "The epidemic of Type 2 diabetes, if it continues on its current trajectory, is likely to be followed by an epidemic of dementia. That's going to be a huge challenge to the medical and care systems."
"Traditional understanding of Alzheimer's has focused on beta amyloid plaques in the brain, but exactly how those plaques amass has challenged scientists. "I believe it starts with insulin resistance," de la Monte has said. "Once it gets going you are going to need to attack on multiple fronts."
The news that Alzheimer's could be a type of diabetes may not appear to be encouraging, but de la Monte offers a bit of hope. "If you could target the disease early," she has said, "you could prevent the further loss of neurons. But you would have to target not just the loss of insulin but the resistance of its receptors in the brain."
Article at:
http://www.nextavenue.org/blog/alzheimers-really-type-diabetes
New Discovery May Reveal A Pathway To Longer Life in Forbes,
Gary Drevitch Gary, Gary Drevitch is senior Web editor for Next Avenue’s Caregiving and Health & Well-Being channels. Follow Gary on Twitter @GaryDrevitch., 5/06/2013
Excerpts:
"Researchers at New York City’s Albert Einstein College of Medicine have found that the brain region known as the hypothalamus controls aging throughout the body and that switching a pathway within it off or on can extend (or shorten) the life spans of laboratory mice."
"The hypothalamus is tiny, Cai said, “but it is a very crucial structure in the brain in terms of regulation of life-supporting activities,” like metabolism, reproduction and growth. He believes inflammation in the hypothalamus has a major effect on how we grow older."
“As people age you can detect inflammatory changes in various tissues,” Cai said. “Inflammation is also involved in various age-related diseases, such as metabolic syndrome, cardiovascular disease, neurological disease and many types of cancer.”
"Cai’s team had previously studied the link between inflammation in the hypothalamus and metabolic syndrome, a combination of health problems that can put you at higher risk for diabetes or heart disease. This time they focused on a specific protein complex they had identified as central to that inflammation. They discovered it was virtually inactive in young mice, but became much more active in the hypothalamus as mice grew older.
In the study, the researchers showed that stimulating the protein accelerated aging, causing earlier death. “The mice showed a decrease in muscle strength and size, in skin thickness and in their ability to learn — all indicators of aging,” Cai said. “Activating this pathway promoted systemic aging that shortened the lifespan.”
It also shut down the mice’s reproductive systems, a further indication that the buildup of inflammation in the hypothalamus triggers the aging process.
Crucially, the team also demonstrated that blocking the protein’s activity slowed aging and increased life spans by about 20 percent. “What’s exciting,” Cai said, “is that it’s possible — at least in mice — to alter signaling within the hypothalamus to slow down the aging process and increase longevity.”"
"Experts commenting on the discovery called it a major breakthrough. Other researchers are now expected to follow Cai’s lead in pursuing treatments that exploit the hypothalamus’ role in aging.
“This earns a spot in the top 10 or 15 leads that should earn a lot of attention,” University of Michigan gerontologist Richard Miller, who did not participate in the research, told The Scientist. In the study, “many different aspects of aging are being slowed together,” he noted. “That means that whatever they’re working on is somehow slowing that basic aging process itself.”"
Article at:
http://www.forbes.com/sites/nextavenue/2013/05/06/new-discovery-may-reveal-a-pathway-to-longer-life/
How Stress And Sleep Loss Are Shortening Your Life in Forbes, Melanie Haiken, 7/05/2012
Excerpts:
"Stress Sabotages Your Immune System, Too
This isn’t news; study after study has shown that stress raises our risk of cancer, heart disease, allergies, and susceptibility to colds and flu. What’s new is that researchers at Carnegie Mellon think they now know how this works. The key, they say, is cortisol, the stress hormone released whenever we feel fear, worry, or anxiety. Cortisol is supposed to give us a jolt of energy, enabling us to react to and run away from the lion as it were. But it appears that when our systems are constantly bathed in cortisol, the body loses its ability to regulate inflammation.
Here’s how it works. Cortisol has a secondary function of controlling the body’s inflammatory response to immune system triggers. But over time, with constant exposure to stress and therefore cortisol, tissues become less sensitive to cortisol, releasing less of their anti-inflammatory substances. (A similar process occurs with diabetes, as chronically elevated insulin leads to insulin resistance.)"
"So what does it all mean? That when you get stressed out and stop sleeping, or stop sleeping well, you get sick. (Think back to college, when you’d get a horrible flu or even pneumonia or mono, right after finals were over.) That probably doesn’t seem that concerning; we’ve dealt with the post-all-nighter flu all our lives. But this year has also seen convincing research that the body’s immune response is key to protecting us from serious disease, such as cancer, and that inflammation is a key precursor to heart attack, stroke, diabetes, and other life-threatening diseases. In fact, ongoing research is underway to document the effects of stress and sleep loss on shortening lifespan."
Article at:
http://www.forbes.com/sites/melaniehaiken/2012/07/05/how-stress-and-sleep-loss-are-shortening-your-life/
If All Roads Lead to Inflammation, How Do We Get to Health? in Forbes, Alice Walton, 10/19/2011
Excerpts:
"The problems arise in the aftermath of inflammation – especially chronic inflammation – and our healthy cells can take the brunt. When the immune system kicks into gear, white blood cells and their byproducts can saturate a region and leave healthy tissue overwrought and stressed. Katz says that “our healthy tissues are potential collateral damage – victims of friendly fire – as the immune system does its job defending us from pathogens, and rogue cells. The term is descriptive, and derives more from observation than any genuine insights about physiology.”
In other words, it is difficult to know all the myriad events that are occurring in previously healthy tissue that has suffered the aftermath of inflammation, but the end product is not good.
To put it plainly, chronic inflammation can provide the framework for, if not outright cause, a lot of the major chronic disease states. Katz says that “inflammation – the actions of white blood cells, and the molecules they produce (including oxygen free radicals) – is directly implicated in the progression of most chronic diseases.” This isn’t dramatic, it’s intuitive, he says, because “the process is fundamental, just like oxidation. There are ‘final common pathways’ that unify all of the ways we, and our parts, can fail.”
So what are the diseases that all stem from inflammation? Some of the ones most people are aware are linked are heart disease, type 2 diabetes, and stroke. These diseases are all strongly connected to metabolic syndrome, a pesky intermingling of risk factors like being overweight (particularly having belly fat), being sedentary, and having high blood fats, blood pressure, and cholesterol. Inflammation seems to be the common denominator, possibly the result of the body being subject to these variables over many years.
Other diseases linked to inflammation are less obvious, but just as disturbing – like cancer, Alzheimer’s disease, and, oddly, depression.
While one’s risk for cancer comes in part from the genes, there is, for better or for worse, more to the picture than genes. The inflammatory status in the body, which can be the result of various lifestyle factors, has a lot to do with cancer risk. The cancer-inflammation connection could work in a variety of ways: one possibility is that an inflamed environment presents the opportunity for potentially cancerous cells to take root and grow. Some evidence has shown that certain immune cells are actually hijacked by cancer cells to become their partners in crime. Other studies have shown bacterial and viral infections are strongly linked to cancer; certain inflammatory diseases like crohn’s disease, also linked to bacterial infection, are known to increase one’s risk for cancer.
Not surprisingly, but unfortunately, inflammation can also affect the brain, and when it does, it seems to lead to some dire consequences. For example, Alzheimer’s disease develops when plaques accumulate in the brain and cannot be cleared away efficiently: it’s thought that the particles that are byproducts of inflammation are at least in part responsible for the formation of these plaques, and studies have shown that the markers of inflammation pepper the brains of Alzheimer’s patients.
Depression is another disorder that has recently been connected with brain inflammation. Some researchers have suggested that depression in an adaptive mechanism to address severe psychological stress. The brain responds to serious psychological assaults with inflammation, say the researchers, and depression becomes the brain’s ineffective, pathological attempt to quell it. Other studies have found that markers of inflammation are actually present more often in the brains of depressed people. Finally, omega-3 fatty acids, which have been shown to reduce inflammation (mainly pertaining to heart risk) by suppressing the inflammatory markers, have also been shown to help treat depression.
A lingering question is, why does inflammation produce disease A in one person, and disease B in another? Katz suggests that it’s for the “same reason why no two car crashes produce exactly the same injury. It depends how your ‘situated’ relative to the traumatic force in both cases.” There are a slew of variables involved in the picture that inflammation paints in the body: And how inflammation manifests “depends on your genes, cell surface antigens, behaviors that protect against or exacerbate inflammatory injury, etc. You start with different substrate, and apply the same kind of force – you get different outcomes, because the interaction between the two differs.” Hopefully more research will elucidate why inflammation is linked to Alzheimer’s in Peter, and cardiovascular disease in Paul.
Luckily, we’re not totally powerless over our inflammatory status. We may not be able to do much about infections that lead to it, but we do have a lot of power to change the other culprits in our lives. Katz stresses the idea that inflammation is extraordinarily lifestyle-dependent – and because this is true, we have a great capacity to reduce our risk for major disease. “When we over-burden our system with toxins – from bad food, tobacco smoke, etc. – we create imbalances in immune function and the hormones that regulate it, and can generate a constant excess of immune system activity, or inflammation. This is a key element in the progression of chronic disease, and it is, by and large, preventable.”
Until there is a magic pill to restore us to our uninflamed states, it’s probably a good idea to start on the job yourself. While it’s not always fun, changing little (or big) habits here and there will not only make you feel better now, but it could reduce your risk for disease in the future."
Article at:
http://www.forbes.com/sites/alicegwalton/2011/10/19/all-roads-lead-to-inflammation-so-can-we-ever-get-healthy/
Mayo Clinic researchers find new molecule to target in pancreatic cancer treatment in World Pharma News, 04 JANUARY 2013, no author
Excerpt:
"One feature of pancreatic cancer is increased activity of the transcription factor NF-kB, which turns on expression of genes that keep the cells proliferating and protect them from death. There are two pathways, known as the classical and alternative, by which NF-kB can be activated, and the researchers looked at the alternative pathway - one in which NF-kB is activated differently, and which switches on other genes, compared to the classical signaling pathway. Both the classical and alternative pathways are active in pancreatic cancer.
The research team discovered that increased activity of the alternative NF-kB pathway results from suppression of TNF receptor-associated factor 2, or TRAF2. Loss of TRAF2 promotes fast growth of pancreatic tumors and correlates with increased aggressiveness, Dr. Storz says.
They tested this discovery in 55 human samples of pancreatic cancer, and found that in 69 percent, TRAF2 wasn't functioning properly and there were higher levels of other molecules participating in the alternative pathway. A cocktail of drugs that includes chemotherapy, bortezomib and other inhibitors of molecules activated along the pathway may help pancreatic cancer patients, Dr. Storz says."
Article at:
http://www.worldpharmanews.com/research/2307-mayo-clinic-researchers-find-new-molecule-to-target-in-pancreatic-cancer-treatment
Chronic Inflammation An American Epidemic in International Wellness Directory, no date, no author
Excerpt:
"Inflammation is a part of the body’s natural defense system against injury and disease.
Chronic inflammation, on the other hand, is a disease. The system has gotten hung up, and instead of protecting the organism (our bodies) it starts to kill the organism, slowly but surely.
Today modern medicine is starting to admit that chronic inflammation is the main contributing factor to all chronic degenerative diseases, and the root cause of the two greatest killers in America: Cancer and Heart Disease. Indeed, chronic inflammation might just be the root cause of all degenerative disease.
Article at:
http://www.mnwelldir.org/docs/terrain/chronic_inflammation.htm
You can't access because it is a 'secure' site that requires authorization and login. However, you can reach Star Scientific and Roskamp:
Star Scientific at:
http://www.starscientific.com/
Star Scientific re Rock Creek:
http://www.starscientific.com/index.php?s=129
Roskamp Institute at:
http://www.rfdn.org/
5 Juices With More Sugar Than Soda in Time.com, Men's Health@MensHealthMag May 18, 2014
Excerpts:
"That "health" drink is anything but
Lovers of bottled fruit juices may have to rethink their infatuation. A new report from researchers at the University of Glasgow in the U.K. equated your glass of fruit juice to your can of soda—just with a few more vitamins. And your perception of how healthy juice actually is can be way off as well. When researchers polled more than 2,000 adults, people underestimated the sugar content in juice by a whopping 48 percent."
"1. Ocean Spray 100% Cranberry Juice"
Though it boasts “no sugar added,” the juice is sweetened with grape and apple juice concentrates, contributing to 36 g of sugar per cup."
"2. Tropicana Berry Punch"
"With only 5 percent juice in the blend and high fructose corn syrup listed as the second ingredient, this juice drink will add 29 g of sugar to your day in just one cup."
"3. Minute Maid Enhanced Pomegranate Blueberry"
"Contains 29 g of sugar per cup from a blend of five fruit juices from concentrate: apple, grape, pomegranate, blueberry, and raspberry. "
"4. Jamba Juice Kale Orange Power"
"However, the juice is made with more OJ and banana than the green stuff, and the sugar content is 40 g per 16 oz cup."
"5. Welch’s Essentials Orange Pineapple Apple Juice Cocktail"
"The label boasts “no high fructose corn syrup” and that’s true, but it also contains added sugar for a total of 31 g per cup."
FYI 4 grams equals 1 teaspoon, trans fats and sugar, particularly fructose, will increase inflammation
Article at:
http://time.com/103898/5-juices-with-more-sugar-than-soda/