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Do Microglia in the Hypothalamus Drive Aging? in ALZFORUM NETWORKING FOR A CURE,03 May 2013
Excerpts:
"Microglia have taken center stage in Alzheimer’s disease (AD) research recently. Not only have genetics studies pinpointed variants in the microglial receptor TREM2 as major risk factors for AD (see ARF related news story), but tuning down microglial cytokines has been shown to reduce plaque buildup (see ARF related news story), and a new network analysis links microglial dysfunction with AD pathology (see upcoming ARF Webinar). Could microglia also accelerate aging, the strongest risk factor for AD? In the May 1 Nature, Dongsheng Cai and scientists at the Albert Einstein College of Medicine, Bronx, New York, report that microglial inflammation in the hypothalamus of mice caused overall senescence, shortened lifespan, and weakened cognition. Conversely, quelling glial activation slowed aging and raised performance on cognitive tests. This study could have implications for the treatment of age-associated disorders, such neurodegeneration, cardiovascular disease, and diabetes, wrote the authors."
"Almond sized, the human hypothalamus releases hormones for growth, reproduction, and metabolism. Cai’s group previously showed that inflammation in the hypothalamus contributes to the development of obesity, glucose intolerance, and hypertension—all metabolic syndrome components associated with aging and Alzheimer's disease. These disorders came about upon activation of a central regulator of immunity—a proinflammatory transcription factor called nuclear factor ?B (NF-?B), and its upstream I?B kinase-ß (IKK-ß (see Li et al., 2012; Zhang et al., 2008; and Purkayastha et al., 2011). NF-?B is elevated in the brains of those who died with AD (see Terai et al., 1996) and has been reported to exacerbate Aß pathology under pathological conditions (see Chami et al., 2012). Cai and colleagues wondered if NF-?B signaling might be tied to aging."
"Microglia appeared to be initial players in this aging process. The number of microglia with activated NF-?B grew with age in the hypothalamus, and they overproduced inflammatory cytokines such as tumor necrosis factor-a. TNF-a is both induced by and activates NF-?B in a feed-forward loop. TNF-a also activates IKK-ß. Nearby hypothalamic neurons later upped their own NF-?B and TNF-a production, implying that the microglial output led to inflammatory neuron changes.
Could reining in microglia control aging? When the researchers knocked out IKK-ß in hypothalamic microglia of middle-aged mice, microglia numbers held steady with age, while TNF-a remained low. When they got older, these knockouts outperformed wild-type controls on the Morris water maze test and retained more muscle strength, bone mass, and skin thickness. Their maximum lifespan stretched to about 1,100 days, around 10 percent longer than the wild-type. Together, the results suggest that microglial IKK-ß accelerates aging.
How does microglial NF-?B signaling reduce lifespan? Looking for the downstream effects, the researchers found that gonadotropin-releasing hormone (GnRH), which regulates sex hormones and reproduction, was diminished. Does its reduction accelerate aging? Levels of the hormone fell in the hypothalamus with age—a decline prevented by inhibition of IKK-ß and NF-?B, and enhanced by their activation. GnRH replacement therapy seemed to turn back the clock. Both wild-type and IKK-ß knockout mice injected subcutaneously with GnRH for up to eight weeks showed fewer signs of age and performed better on cognitive tests than untreated controls. This youthening may be related to neurogenesis, which declines with age. When injected into the hypothalamus of old mice, GnRH seemed to promote differentiation of new neurons—indicated by BrdU labeling. This is the first time GnRH has been tied to neurogenesis, Cai said. The new cells would have to be tested with appropriate markers to be sure it was true neurogenesis, wrote Gerd Kempermann, Center for Regenerative Therapies, Dresden, Germany, to Alzforum in an e-mail.
Treatments that target GnRH could translate to humans if scientists find a safe, efficacious method, said Cai. Such therapies might help prevent age-related disorders, including diabetes, cardiovascular disease, and neurodegenerative disease. “People tend to think about aging as a passive, chaotic deterioration of tissues,” Cai told Alzforum. “We provide a new view—it includes a brain-controlled process.”
The suggestion that the aging process is driven by the integration of immune and hormonal responses is a new paradigm, wrote Dana Gabuzda and Bruce Yankner of Harvard Medical School, Boston, in an accompanying editorial. It “raises the intriguing possibility that hypothalamic regulation could be therapeutically manipulated to have broad effects on the aging process.”
In addition to the reported effects on aging, the hypothalamus coordinates energy metabolism and stress responses, wrote Mark Mattson, National Institute on Aging, Baltimore, Maryland, to Alzforum in an e-mail (see full comment below). It would be interesting to explore how these pathways influence each other, he added. Metabolic syndrome and stress are both potential risk factors for AD (see ARF related news series).
This study provides some of the first evidence in a mammalian system that one entity centrally regulates the aging process. “I think the brain is going to turn out to be more important than any other tissue for mammalian aging,” said Leonard Guarente, Massachusetts Institute of Technology, Cambridge. He and colleagues recently reported that length of circadian periods, which are regulated by a portion of the hypothalamus, determine lifespan in mice (see Libert et al., 2012). “Maybe we’ve underestimated the importance of the hypothalamus,” he said.—Gwyneth Dickey Zakaib."
Article at:
http://www.alzforum.org/news/research-news/do-microglia-hypothalamus-drive-aging
Biology of Inflammation Dr. Jekyll or Mr. Hyde? White blood cells with a split personality: macrophages, in Centre d'Immunologie de Marseille-Luminy (CIML Immunology), Dr Toby Lawrence, no date
Excerpt:
"The mechanisms that put an end to the inflammatory process are poorly understood but are potentially defective during chronic inflammation and may be hijacked by invaders to avoid our défenses. These endogenous anti-inflammatory mechanisms are the focus of the research team of Toby Lawrence.
"Sometimes, bacterial or viral infections or repeated tissue injury persist for several years. Our immune system has continued the fight, but in vain. This eventually causes important collateral damage, including cancer," says Toby Lawrence. "This state of chronic inflammation in effect creates an environment conducive to the development of malignant tumors: activated cells and their continued production of proinflammatory compounds promote the growth, of cancer cells and eventually malignant tumors. Our hypothesis is that the same mechanisms to halt the acute inflammatory response are hijacked by pathogens and cancer cells to evade attack by our immune system."
The macrophage: Doctor Jekyll and Mister Hyde
in inflammation and cancer
San Diego State University Structural Biochemistry Laboratory, Dr Tom Huxford, Research, no date
Excerpt:
"In this laboratory we use our knowledge and experience in the area of protein structure and function to determine the chemical mechanisms employed by interesting biological factors. The major focus of the laboratory is in understanding regulation in the transcription factor NF-kappaB signal transduction pathway. NF-kappaB is a relatively small class of proteins that respond to diverse stimuli by activating the expression of numerous genes. NF-kappaB responsive genes include many of the key components of the cellular survival program including inflammatory cytokines, mediators and effectors of both innate and adaptive immunity, and inhibitors of apoptosis. Although proper NF-kappaB function is integral to a cell's ability to fight off infection and respond to stress, too much of an NF-kappaB response can contribute to states of chronic inflammation such as arthritis, asthma, multiple sclerosis, and colitis. Recently, it has been shown that chronically inflamed tissues can serve as hotbeds for tumor formation. Cellular processes that recognize and kill tumors in healthy tissues fail to function effectively under the influence of the NF-kappaB cell survival program. Chronic inflammation due to hyperactive NF-kappaB has also been shown to contribute to sclerotic formation in arteries and heart disease.
Article at:
http://www-rohan.sdsu.edu/~thuxford/Research.html
NF-kappaB signalling pathway in Neurological diseases in Frontiers
Jun Yan, University of Queensland, Centre for for Clinical Research, The University ofQueensland., Australia
Deadline for full article submission: 14 May 2014
Post:
"The ubiquitous transcription factor Nuclear Factor-kappa B (NF-kappa B) plays an important role in controlling gene expression in cellular inflammation, immunity, cell proliferation and apoptosis. In mammals, NF-kappa B comprises of a family of five protein subunits, NF-kB1 (p50/p105), NF-kB2 (p52/p100), p65 (RelA), RelB and c-Rel. These NF-kappa B subunits share an N-terminal Rel Homology Domain (RHD) of about 300 amino acid, which contain regions for the dimerization of NF-kappa B subunits, nuclear translocation and DNA binding.
In most unstimulated cells the majority of NF-kappaB subunits, either hetero- or homo-dimers, are retained in an inactive form in the cytoplasm through association with members of a family of inhibitory proteins, known as IkB. IkB proteins all contain an ankyrin repeat of 30-33 amino acids, which can bind the NF-kappa B RHD region. Cellular exposure to a variety of stimuli leads to a rapid phosphorylation, ubiquitination and proteolytic degradation of IkB freeing NF-kappa B dimers to translocate to the nucleus and initiate gene transcription. The degradation of IkB is achieved through the actions of the IkB kinase (IKK) complex. Target gene specificity is determined by the specific NF-kappa B complexes present in different cell types, the kB target site binding specificities of different NF-kappa B complexes and the particular protein-protein interactions and post-translational modifications that NF-kappa B complexes can undergo in different contexts.
Extracellular stimuli that can induce NF-kappa B activation include proinflammatory cytokines (e.g. TNF), bacteria, physiological stress conditions, physical and oxidative stress, environmental factors, therapeutically used drugs, modified proteins, apoptotic mediators, mitogens, growth factors and hormones, and chemical agents, many of which have been implicated in the development of autoimmune and inflammatory diseases.
The reports of the involvement of NF-kappa B in chronic inflammatory diseases have dramatically increased in recent years. Diseases such as, Multiple Sclerosis, Rheumatoid Arthritis, Atherosclerosis, Chronic-inflammatory Demyelinating Polyradiculoneuritis, Asthma, Inflammatory Bowel Disease, Helicobacter pylori -associated gastritis and Systemic Inflammatory Response Syndrome (SIRS).
This research topic aims to explore the effects of the NF-kappa B signalling pathway in the pathogenesis of neurological diseases, and investigate NF-kappa B regulation in context of disease and genetic factors influencing the NF-kappa B pathway. Most importantly it is aimed to foster discussion on NF-kappa B related therapeutic design in neurological diseases. Research work and review articles are all encouraged for submission."
Article at:
http://www.frontiersin.org/molecular_neuroscience/researchtopics/nf-kappab_signalling_pathway_i/2354
NF-?B pathway in colitis-associated cancers in Translational Gastrointestinal Cancer, November 29 2012
Emilie Viennois1, Fengyuan Chen1, Didier Merlin1
1Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA; 2Department of Gastroenterology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, People’s Republic of China; 3Veterans Affairs Medical Center, Decatur, GA, USA
Abstract:
Colitis-associated cancer is the subtype of colorectal cancer that is associated with inflammatory bowel diseases including ulcerative colitis and Crohn’s disease. Colorectal cancer is one of the most commonly diagnosed cancers, and is the third leading cause of cancer death in developed countries. Of the signaling pathways involved in colonic inflammation, that triggered by NF-?B plays a key role. A relationship between inflammation and cancer is now well documented. Moreover, the association between NF-?B activity and cancer development has been intensively investigated. The present review focuses on the activity of the NF-?B signaling pathway in colitis-associated carcinogenesis. The pivotal roles played by this pathway in apoptosis, tumor promotion, and tumor maintenance strongly suggest that inhibitors of the pathway would be powerful anti-cancer agents."
Article at:
http://www.amepc.org/tgc/article/view/1254/1878
Pipeline report in Drug Topics, FEB 14, 2013
Excerpts:
"Without a drug that truly modifies, if not halts, the progression of Alzheimer’s disease, caring for patients in the United States alone is expected to top $1 trillion annually by 2020."
"Abbott’s — now AbbVie’s — injectable biologic drug Humira (adalimumab) probably won’t ever unseat Pfizer’s Lipitor as the best-selling drug of all time, but it may come close. Sales in 2012 are likely to approach $9 billion, only $4 billion away from Lipitor’s staggering $13 billion in annual sales during its heyday."
"Cancer: improving on innovation- The National Cancer Institute estimated that 76,250 new cases of melanoma will be diagnosed in the United States this year, and almost 10,000 patients will die from the disease. Yervoy, a monoclonal antibody and CTLA-4 inhibitor, works in only about one in four patients, but it works well in those patients. Zelboraf is faster-acting and has excellent response rates due to its companion diagnostic, but only around half of the patient population carries the BRAF mutation."
"Diabetes: Incremental improvement
Unfortunately for type 1 diabetes patients, there isn’t much to get excited about in terms of new pharmaceutical products, at least in the short term.
"Despite a crowded landscape — if an SGLT2 inhibitor is approved, it will face off against GLP-1 receptor agonists such as Novo Nordisk’s Victoza (liraglutide [rDNA origin] injection) and Amylin/Alkermes Bydureon (exenatide), and DPP4s like Merck’s Januvia (sitagliptin), BMS/AZ’s Onglyza (saxagliptin) and Lilly/Boehringer Ingelheim’s Tradjenta (linagliptin) — there’s room to grow, with the market for type 2 diabetes drugs nearly doubling, from $26 billion in 2011 to $50 billion in 2022, according to Decision Resources."
Article at:
http://drugtopics.modernmedicine.com/drug-topics/news/user-defined-tags/specialty-pharmacy/pipeline-report#sthash.tVJXxYfn.dpuf
Alzheimer Disease & Pipeline Drugs Market Analysis and 2018 Forecasts in the Business Journal April 7, 2014
Article:
"/PRNewswire-iReach/ -- Alzheimer's disease drug market is on the curvature stage. Since 2003, there is not any single "magic bullet" launched in the market to prevent or cure it. However, all current marketed products are going to be generic in the next 3-4 years. There are high unmet medical needs. The current unmet needs represent a huge opportunity for pharmaceutical companies which are developing targeted novel therapies. If successful, they will be in a position to command premium prices and tap the existing opportunity. Lot of drugs has failed in Phase III stage thus putting a greater impact on Alzheimer's disease drug market.
From the year 2009 Alzheimer's disease drug market is declining and it is expected to fall till 2016. But with the expected launch of some Alzheimer's drugs from the year 2017 onwards, Alzheimer's disease drug market is expected to revive in the coming years. However due to absence of exact potential drugs there will always remain a huge Unmet Alzheimer's Drug Market. For the year 2018 Alzheimer 's disease Drug Market will be just 10% of Unmet Alzheimer's Disease Drug Market.
This report provides a comprehensive assessment of the fast-evolving, high-growth Global Alzheimer's Disease Market. This 110 page report with 29 Figures and 11 Tables studies the Global Alzheimer's Disease Drug Market."
BTW, if you are curious enough to want to buy a copy of the report, they go for $1475 a copy for single users.
Article at:
http://www.bizjournals.com/prnewswire/press_releases/2014/04/07/MN99417
Right again! You're on a run. I use it also. Why don't you try? Lots of good info, maybe too much now that everybody is investigating inflammation and it's connections to various diseases and disorders, especially cancers and cardiovascular diseases---not to mention the autoimmune disorders and their connection with NF-kB Look at my post #18904 at:
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=101821284
Millions of possibilities!
Let's let the experts review your comment: "Just because you may fight inflammation does not mean you fight cancer. There are lots of things that fight inflammation and inhibit NF-KB."
From Cancer Research UK article dated Feb 1, 2013: "So how does inflammation lead to cancer?
Here’s the current thinking.
When a tiny tumour starts growing from a few rogue cells, it can scavenge enough oxygen and nutrients from its surroundings. But as it grows bigger, demand starts to outstrip supply, and things start getting desperate.
As they struggle to survive, and as they accumulate more and more genetic faults, the cancer cells release chemical signals that lure immune cells called macrophages and granulocytes to infiltrate the tumour.
Once inside the tumour’s inner sanctum, these cells secrete molecules (called cytokines) that kick-start the growth of blood vessels (angiogenesis), which ferry in much-needed oxygen and nutrients.
Other cytokines encourage growth of a sort of cellular ‘pillow’ called the stroma against which the tumour rests. Meanwhile, other inflammatory cells spritz the tumour with molecules (free radicals) that further damage their DNA. Inflammation might also fire the starting gun for metastasis by producing chemicals that help tumour cells nibble through the molecules tethering them to their surroundings.
Taken together, it’s clear that fledgling tumours hijack inflammation and use it to accelerate the progression towards full-blown cancer. As one of our own experts once commented: “If genetic damage is the match that lights the fire, inflammation may provide the fuel that feeds the flames.”"
There are other research articles that pretty much say the same thing. Sounds to me that fighting inflammation DOES fight cancer.
Your comment: "There are lots of things that fight inflammation and inhibit NF-KB."
Yes, but are they as good as Anatabloc? Researchers have found several natural and drug products that might find application, but if you look carefully, many lack strong efficacy and/or have potentially dangerous side effects. Even simple things like Aspirin to expensive things like Statins. The race has been on over the last several years to find the product that is effective and safe. Maybe they need to do a metasearch like me?
From the New England Journal of Medicine: Nuclear factor-?B—a pivotal transcription factor in chronic inflammatory diseases
by Ambili Ranjith
"Because currently available antioxidants, such as vitamins C and E and acetylcysteine, are relatively weak, more potent and long-lasting antioxidants are needed. Aspirin and sodium salicylate also inhibit the activation of NF-kB, albeit only in relatively high concentrations,"
There is also a school of thought that Statins reduce inflammation but they originally were meant to lower Cholesterol, which appears to be the wrong thing to do.
From Alzheimers and Dementia Weekly: The Bad & The Good in Statins & Alzheimer's
“Statins are widely used in the older population to reduce the risk of cardiovascular disease. But recent reports of statin-associated cognitive impairment have led the US Food and Drug Administration (FDA) to list statin-induced cognitive changes, especially for the older population, in its safety communications.”
And your post that looks like it got deleted that I am a pumper, you finally got one correct!
Slang word 'pumper': "To fill with enthusiasm, strength, and energy"
I like that definition, thank you, happy skiing!
Inflammation and ovarian cancer--current views at pubmed.com, April 2013
Kisielewski R1, Tolwinska A, Mazurek A, Laudanski P.
Department of Gynecology and Gynecological Oncology, Medical University of Bialystok, Poland.
Abstract:
Ovarian cancers pose the greatest challenge for gynecological oncology. They are a heterogeneous, rapidly progressing and highly lethal group of malignancies and their etiology is still poorly understood. Among many hypotheses, explaining the pathogenesis of malignant tumors, chronic inflammation seems to play a significant role, which was proved in cervical, hepatic and esophageal cancers. The processes of inflammation and carcinogenesis are very much alike. Their similarity was experimentally confirmed by epidemiological, immunological, biochemical and genetic studies. Additionally this view is supported by indirect epidemiological and clinical evidence linking ovarian cancer with pelvic inflammatory disease, endometriosis or polycystic ovary syndrome. Chronic inflammation is a key factor in the pathogenesis of these illnesses. Moreover ovulation involving repeated damage and repair of the ovarian surface epithelium is in fact an inflammatory process. In this review, we focus on the role of inflammation in cancer initiation, promotion and progression with special emphasis on the ovarian cancer. We discuss the potential involvement of the fallopian tubes, endometriosis and microenvironment of tumors represented by cytokines, chemokines, growth factors and various enzymes that destroy the extracellular matrix. Considering that molecular biology is currently rapidly evolving, we focus on the function of the mammalian target of rapamycin (mTOR) kinase and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) in the pathophysiology of inflammation and cancer.
Article at:
http://www.ncbi.nlm.nih.gov/pubmed/23700863
Everything you wanted to know about Cancer--Cancer Facts and Figures 2014, American Cancer Society
Data at:
http://d2j7fjepcxuj0a.cloudfront.net/wp-content/uploads/2014/02/2014_ACS_Statistics.pdf
Chronic Inflammation, Arizona Center for Advanced Medicines, no date
Excerpts:
"Inflammation
Chronic inflammation feeds a smorgasbord of chronic diseases. If you don't have a chronic disease yourself, you know someone who does. An estimated 80 percent of visits to doctor's offices are for issues
CHRONIC DISEASE
• Persistent or recurring disease, usually affecting a person for three months or longer
• Generally triggered by diet and environmental contaminants
• Standard medicine believes such diseases can be managed but rarely cured
• Includes allergies, Alzheimer's, arthritis, asthma, cancer, COPD, Crohn's, chronic fatigue, cystic fibrosis, diabetes, emphysema, fibromyalgia, Gulf War Syndrome, heart disease and stroke, high blood pressure, Lyme, lupus, multiple sclerosis, obesity, osteoporosis, depression, anxiety, PTSD, and more
relating to chronic disease. The CDC tells us 7 of every 10 Americans die of a chronic disease.
Chronic inflammation gradually destroys an otherwise beautiful machine."
"The Persistent Stimulus
Inflammation goes chronic when there is a persistent stimulus. The stimulus might come from an army of free radicals launched every day when we eat foods made with processed vegetable oils – French fries, fried food, non-fat dried milk, powdered coffee creamer, most salad dressings, crackers, cookies, chips, and a plethora of other processed and convenience foods. The stimulus might be an allergy to wheat (gluten) which inflames the gut. Or a low-grade, lingering infection. Or a growing body burden of heavy metals, pesticides, and chemicals. Or a low-grade, lingering infection from an old injury or from a root canal. There is a lot of opportunity in today's contaminated, junk food-filled world for a combination of factors to constantly irritate the body's normal functions."
"Medical schools don't teach much about the inflammatory effects of food, toxic chemicals, or EMF so the medical profession has been slow to appreciate the extent of the problem. "Researchers are linking inflammation to an ever-wider array of chronic illnesses," reported Newsweek's Anne Underwood in 2005. "Suddenly medical puzzles seem to be fitting together, such as why hypertension puts patients at increased risk of Alzheimer's, or why rheumatoid-arthritis sufferers have higher rates of sudden cardiac death. They're all connected on some fundamental level."[1]
"Heart Attacks, Cancer, Alzheimers, Arthritis...
Dr. Barry Marshall and Dr. Robin Warren turned medical dogma on its head by proving that bacteria – not stress – caused ulcers. The pair proved the bacterium Helicobacter pylori causes inflammation, then ulcers.
Dr Marshall and Dr Warren
Their work has stimulated research into microbes as possible reasons for other chronic inflammatory conditions, such as Crohn's disease, ulcerative colitis, rheumatoid arthritis and atherosclerosis, the Nobel assembly said in its citation. Chronic inflammation has a damaging effect on arteries, which can lead to high cholesterol, heart attacks and strokes. Microorganisms cause inflammation within blood vessels. The inside of the arteries come under attack. Immune cells are dispatched to fight the inflammation, and then cholesterol is laid down over the wound like a Band-Aid. However, the inflammation is still active under that Band-Aid. In time, the Band-Aid bulges. In time, maybe a small part of the blood vessel gives way. Whoops! Now the body has to put a finger in the dyke. It uses a blood clot to do that. But if the clot breaks loose and goes to the brain, you have a stroke. If it goes to the heart, you have a heart attack.
Statin drugs, the best selling drugs worldwide, were developed to limit cholesterol. Now you can see why suppressing cholesterol production is not a good way to address the problem. Recently, we are hearing that statins' best asset may be their anti-inflammatory properties. That would be a better approach, but there are better ways to reduce inflammation. Statins' side effects include muscle weakness and mental problems. And, although drugs can suppress the inflammation, they do not put out the fire. They don't bring a cure.
Chronic inflammation depresses the immune system and helps promote the formation of cancerous tumors. A substantial body of evidence supports the conclusion that chronic inflammation can predispose an individual to cancer as demonstrated by the association between chronic inflammatory bowel diseases and the increased risk of colon carcinoma. The longer the inflammation persists, the higher the risk of associated carcinogenesis.[2]
Chronic inflammation destroys nerve cells in the brains of Alzheimer's patients. The inflammation in a joint can eat away at cartilage and you've got a serious case of arthritis. In Rheumatoid Arthritis, the inflammation is systemic, eating away at the entire body, an autoimmune disorder. Inflammation of kidneys is known as nephritis and may cause kidney failure or high blood pressure. Unchecked inflammation in the pancreas can cause both pancreatitis, a potentially fatal disease, and type 1 diabetes, in which the pancreatic islet cells that produce insulin are destroyed. Inflammation of the small airways that transport air to the lungs may cause an asthma attack or chronic bronchitis.
What determines how inflammation will affect you? Your genes play a part. If arthritis runs in your family, then you very possibly have a genetic weak link in that regard and you are likely prone to arthritis. For someone else, the genetic weak link may make them prone to cancer or Crohn's Disease.
"
"The Obesity Connection
overweight manThe correlation between type 2 diabetes and obesity is so well established that some researchers refer to the two collectively as "diabesity." When you gain weight, fat cells become more biochemically active, churning out inflammatory compounds. As obesity ratchets up inflammation, inflammation in turn promotes insulin resistance, a central feature of diabetes and the metabolic syndrome that precedes it.
Some of the excess weight comes from excess calories, and some comes from toxins stored in our fat cells.
Our bodies have become virtual dumping grounds for the tens of thousands of toxic compounds that invade our everyday world, setting the stage for a slow decline in health. The EPA estimates there are more than 20,000 chemicals that our bodies cannot metabolize. Unable to be excreted from the body, chemicals find their way into our liver, and then migrate to fat cells throughout the body where they are stored. Studies show that most of us have between 400 and 800 chemical residues stored in our cells.
Exercise and weight loss work to reduce inflammation in the fat cells and liver. But it gets complicated – no wonder so many people have trouble shedding pounds.
In a 2004 study published in the International Journal of Obesity, 15 obese people lost an average of 23 pounds on a 15-week diet. When researchers compared blood samples at the end of the diet with ones taken before the diet began, they found two differences: Concentrations of leptin – the hormone that usually keeps hunger in check – were 33% lower. And concentrations of industrial chemicals called organochlorines were 23% higher."
"C-Reactive Protein
Cytokines are a tool of the immune system, dispatched during inflammatory reactions. Cytokines are thought to play a central role in the occurrence of disease.
Cytokines are a diverse group of soluble proteins and peptides that mediate interactions between cells directly, and regulate processes taking place in the extracellular environment.
Pro-inflammatory cytokines that feed chronic diseases:
• TNF-a tumor necrosis factor-alpha
• IL-6 interleukin-6
• IL-1(b) interleukin-1 beta
• IL-8 interleukin-6 A critical inflammatory marker is C-reactive protein. This marker measures inflammation in the arteries that can cause heart attacks. A New England Journal of Medicine study showed that people with high levels of C-reactive protein were almost three times as likely to die from a heart attack [2a]. C-reactive protein is regulated by proinflammatory cytokines, such as interleukins 1b and 6.
In a study published in the July 18, 2001 issue of the Journal of the American Medical Association, a group from the famous Women's Health Study was evaluated to ascertain what risk factors could predict future development of Type II diabetes [2b]. The findings showed that baseline levels of C-reactive protein and interleukin-6 were significantly higher among those who subsequently developed diabetes compared to those who did not.
In January, 2003, the American Heart Association and Centers for Disease Control & Prevention (CDC) jointly endorsed the C-reactive protein test to screen for coronary-artery inflammation to identify those at risk for heart attack."
"Food is Information
farmFood is the real key to chronic inflammation.
Consider what our great-grandmother had to eat; she lived in a time when chronic inflammation and chronic diseases were not rampant. Everything came from a farmer's field, nothing from a food chemist's laboratory. Nothing was homogenized, refined, or processed. There was no need for "nutrition labels" because food was not so altered and compromised it had to have labels. "
"Getting a Bum Steer on Diet
One reason chronic inflammation is rampant is because for decades, the public has gotten bad nutrition advice. "Butter is bad for you, eat margarine," says the American Heart Association. Problem is, margarine is a lethal tub of trans fats. But the corn oil industry gave a lot of money to the AHA. In fact, 2007 was "a record corporate sponsorship year," exceeding goals.
"Corporate Gifts brought in more than $60 million. We renewed eight Pharmaceutical Roundtable members for four-year commitments and a total of nearly $19 million, bringing the membership to nine companies with both Merck and Merck/Schering-Plough renewing under separate memberships. AstraZeneca and Merck also committed to three-year national sponsorships of Start!"[9]
That association with drug makers might be why the AHA gave a big thumbs up to statin drugs based on the 2008 Crestor study funded by AstraZeneca. The AHA did not mention, for example, the report in the July 2008 issue of Mayo Clinic Proceedings where researchers found that fish oils and yeast rice supplements lowered bad cholesterol better than statins."
Article at:
http://www.arizonaadvancedmedicine.com/articles/inflammation.html
The Role of Inflammation in Cancer at Qiagen website, no date
Excerpt:
"Highlights
Precancerous inflammation can cause increased genetic and epigenetic damage
Aberrant oncogenic signaling can induce inflammation
The inflammatory response in cancer tissues elicits tumor tissue remodeling and metastases
Summary:
Cancer related inflammation can fall into one of two categories: 1. precancerous inflammation lesions and 2. Inflammation that is present in almost all cancer tissues including those that have no precancerous inflammation lesions. The connection between inflammation and cancer can be thought of as consisting of two pathways: an extrinsic mechanism, where a constant inflammatory state contributes to increased cancer risk (such as inflammatory bowel disease); and an intrinsic mechanism, where acquired genetic alterations (such as activation of oncogenes) trigger tumor development"
Article at:
http://www.sabiosciences.com/pathwaymagazine/minireview/cancerinflammation.php
Liver cancer due to chronic inflammation: Tumour growth follows programmed cell death (apoptosis) in Medical Press, Helmholtz Zentrum Muenchen - German Research Centre for Environmental Health, no date
Article:
"The death of numerous liver cells in the context of chronic inflammation due to apoptosis, a form of programmed cell death, can promote the formation of tumour cells in the liver. This insight significantly contributes to a better understanding of cellular processes in liver cancer development and thereby opens up new therapeutic approaches. A research team including scientists from the Helmholtz Zentrum München has reported this in the current issue of the scientific journal Cell Reports.
Liver cancer (Hepatocellular Carcinoma, HCC) usually arises as the result of a chronic, inflammatory liver disease. The most common causes here are excessive alcohol consumption as well as a high-fat diet and also chronic infection with the hepatitis viruses B and C. In the course of the inflammatory process, the liver cells (hepatocytes) die more frequently due to programmed cell death. The result is increased cell growth, also referred to as compensatory proliferation, which can lead to tumour development.
A distinction is made between the two most important forms of self-induced cell death, namely apoptosis (programmed cell death) and necroptosis (programmed necrosis), which are based on different cellular mechanisms. Until now, it was not clear which form of cell death is decisive for the development of malignant liver tumours. The team working with Professor Dr. Tom Luedde from the RWTH Aachen University Hospital and Professor Dr. Mathias Heikenwälder from the Institute of Virology at the Helmholtz Zentrum München (HMGU) has now been able to verify that apoptosis precedes the development of abnormal liver cells. The scientists, including Florian Reisinger from the Institute of Virology (HMGU) and Dr. Kristian Unger from the Research Unit Radiation Cytogenetics (HMGU) showed this using mouse models. Moreover they discovered that in contrast, necroptosis prevents uninhibited cell proliferation and consequently the development of liver cancer.
These findings could form the basis for new approaches to therapy for liver cancer, which until now has been a form of cancer that cannot be adequately treated and that kills 800,000 patients around the world each year. "We now know which cellular signalling pathways are involved in liver tumour development", explains Heikenwälder. "In a further step we want to develop new treatment options, for example, by attempting to pharmaceutically block the apoptosis itself or its signalling pathways. But any new therapy can also cause undesirable effects: In our experiments, we saw that blocking apoptosis under inflammatory conditions can result in bililary obstruction (cholestasis) in the context of liver inflammation."
In upcoming investigations, the scientists want to verify their findings on the development of liver cancer and search for active substances that inhibit apoptosis while simultaneously causing the mildest possible side effects. The objective is to further develop the acquired knowledge in the sense of translational research in order to provide concrete benefits for society."
Article at:
http://medicalxpress.com/news/2013-08-liver-cancer-due-chronic-inflammation.html
Also available in Science Daily dated August 30.2013 at:
http://www.sciencedaily.com/releases/2013/08/130830091802.htm
Physiology of the Skin: Aging and Inflammation
By: Peter T. Pugliese, MD, and Michael Pugliese, Posted: February 28, 2012, from the March 2012 issue of Skin Inc. magazine.
Excerpts:
"Despite many years of intense research on the cause of aging, it is still not fully understood, although general consensus is that chronic inflammation appears to be a major underlying factor. It is known that aging is a complex process that has both genetic and environmental components. It is also known that, in many cases, aging is not always systemic. The process of aging results in an increase of inflammatory cytokines, which are chemicals that are cell signals responsible for many of the degenerative diseases that are associated with aging.1 Rheumatoid arthritis is a classic chronic inflammatory disease associated with excess levels of cytokines that include tumor necrosis factor-alpha (TNF-a), interleukin-6 and NF-kappaB (NF-kB), which are known to cause or contribute to the inflammatory syndrome. In this article, the three known causes of chronic inflammatory disease associated with aging will be addressed, including NF-kB, oxidative damage and the effects of ultraviolet (UV) light on the skin."
"NF-kB is a critical compound in body protection, and in the initiation of inflammation. When it is in excess or if it is stimulated by some pathological condition, it can produce both acute and chronic inflammation.2 One of the compounds that is capable of stimulating NF-kB production is known as an advanced glycation end product (AGE). Glycation is the binding of a protein molecule to a glucose molecule, or a fat molecule, resulting in the formation of abnormal protein structures. Many known age-related diseases, such as cataracts and neurological impairment, are at least partially attributable to glycation. These glycation end products contain reactive chemical groups that can combine with proteins and lipids, and cause insoluble complexes.3 These complexes, while biologically active, are physiologically abnormal and thus are capable of entering into cellular reactions that are related to the production of inflammatory components, particularly the cytokines. Foods that are cooked above 140°C will undergo glycation. Frying, baking, broiling and roasting all are done at temperatures in excess of 300°"
"Oxidative damage
Free radical damage was one of the first processes associated with aging; it actually goes back to the 1950s when Denham Harman, MD, PhD, first proposed oxidation as a mechanism for tissue destruction. The aging process is a deterioration of metabolic balance, or homeostasis; therefore, aging is accompanied by an alteration in the impairment of physiological systems, such as the immune system. One target of oxidative damage within the cell is an organelle known as the mitochondria, which applies the major portion of energy to the cell and also consumes more than 90% of the oxygen coming into the body. It is interesting that this oxidation-mitochondrial process is associated with aging, and that the age-related changes of immune functions have their basis in oxidative and inflammatory stress situations. These have among their intracellular mechanisms the activation of NF-kB in immune cells. Now the relationship between oxidation and immune function can be seen, as can the relationship between that process and the production of NF-kB in immune cells. This association adds a great deal of weight to a relatively new theory of aging known as oxidation-inflammation.5"
"Chronic oxidative stress affects all cells, especially cells of the nervous, endocrine and immune systems, as well as the communication between them, and all the processes that involve cellular regulation. Once biological homeostasis is upset, the preservation of health is at peril. A key involvement of the immune system in the aging process of the organism concerns the rate of aging—because there is a relation between the degree of oxidative damage and the functional capacity of the immune cells—and therefore the longevity of individuals. More than 40 years ago, the immune system was proposed as a major target of aging and, only now, are scientists beginning to see the relationship between the immune system and the process of aging linked together by oxidative damage.6 The addition of adequate amounts of antioxidants in the diet improves immune function, decreasing oxidative stress and, consequently, increasing longevity.
Certain neurodegenerative diseases, such as Alzheimer’s disease and multiple sclerosis as well as amyotrophic lateral sclerosis, have been associated with oxidative damage. A major target of oxidative damage is the mitochondria, since approximately 95% of the body’s intake of oxygen must pass through the mitochondria in the process of oxidative metabolism. Because the mitochondria supplies the major portion of energy to the cell, and therefore to the body, any process that damages mitochondria will have a major impact on the body physiology."
"UV damage the skin
There is no question that UV rays have a very adverse effect on skin. Both the epidermis and dermis can be severely damaged by excessive exposure to energy in the range of 290–400 nm, which covers both the UVA and UVB spectra. The skin is one of the major target organs of UV exposure. Within this, the immune system is particularly vulnerable. In the presence of an inflammatory reaction, which is the body’s response to infection or injury, there can be an actual accentuation of the inflammatory mechanism, such that it amplifies the defensive response, which can result in molecular damage to not only DNA, but also to other proteins, such as enzymes and immune-response proteins.8 Some of these responses can actually produce immune suppression, as well as cancer and classic photoaging."
"Although this cross-linking is an enzymatic process, there is also associated nonenzymatic cross-linking that appears to be due to glycation. Both of these processes are characteristic of photodamaged skin. The amount of UV light reaching the dermis depends not only on the duration of exposure, but also on the intensity of the radiation. For example, UVA, although it penetrates deeper into the dermis than UVB, is more frequently associated with collagen damage and aging changes, while UVB damages the epidermis most frequently and is a major cause of skin cancer. The radiation intensity from UVB is 1,000 times stronger than that of UVA radiation. Skin changes resulting from chronic UV exposure show classic collagen changes with the increased levels of collagen Type III, along with abnormal, thickened, tangled and nonfunctional elastic fibers. Eventually these tissue changes result in tissue that is degenerated into a nonfibrous, amorphous mass—a finding known histologically as solar elastosis.10 It is this process that produces classic sun-damaged skin seen in inveterate sun worshipers. The bottom line is that there is no safe way to tan, because increased pigmentation appears to be a sign that some degree of inflammation has taken place"
Article at:
http://www.skininc.com/skinscience/physiology/140766633.html?page=3
NF-kappaB as a therapeutic target in chronic inflammation: recent advances. S S Makarov, Attagene Inc, in Research Gate, no date
Abstract:
The family of nuclear factor kappaB (NF-kappaB) transcription factors is a topic of intense interest in the biomedical community stemming from the role NF-kappaB plays in almost every aspect of cell regulation: stress responses, immune cell activation, apoptosis, proliferation, differentiation and oncogenic transformation. The objective of this article is to provide an overview of recent developments in the field with an emphasis on the role of NF-kappaB in chronic inflammation, and to discuss the feasibility of therapeutic approaches based on the specific suppression of the NF-kappaB pathway
Article at:
http://www.researchgate.net/publication/12254037_NF-kappaB_as_a_therapeutic_target_in_chronic_inflammation_recent_advances
Requires membership to see full article
Inflammation Keywords Search Entries---The following lists in descending order by keyword type the number of entries using Google Only (no metasearch engine). Kind of interesting how much info is on the net regarding inflammation and it's various sub-categories.---OVERWHELMING!
SEARCH KEYWORDS ENTRIES
Heart Disease 279,000,000
Cancer 176,000,000
Cardiovascular Disease 41,300,000
Inflammation 336,000,000
Inflammation Cancer 58,500,000
Inflammation Autoimmune 13,200,000
Inflammation Cardiovascular 9,640,000
Inflammation Alzheimers Disease 4,730,000
Chronic Inflammation 14,900,000
Chronic Inflammation Cancer 13,300,000
Chronic Inflammation Regulation 8,910,000
Chronic Inflammation Diseases 6,340,000
Chronic Inflammation Alzheimers 5,400,000
Chronic Inflammation Cardiovascular 4,270,000
NF-kB 5,950,000
NF-kB inflammation 1,950,000
Anatabloc 75,300
Anatabine 39,300
Anatabine Citrate 6,190
The Inflammation and Breast Cancer Connection, March 11th 2013, by Helayne Waldman, Ed.D, M.S
Excerpts:
"New studies continually increase our understanding of the complex inflammatory process and how it relates to breast cancer. In 2010 several piece of the puzzle came together when researchers at Thomas Jefferson University reported they could definitively show that inflammation in the breast is key to the development and progression of breast cancer. (Liu, et al. 2010)"
"We've known for quite some time that inflammation and cancer have shared some sort of functional relationship. In fact, it was in 1863 that a German pathologist named Rudolph Virchow first hypothesized that the origin of cancer was at sites of chronic inflammation. Now it seems that modern science has caught up with the observations of the 19th Century. It wasn't easy.
It took 12 years and the creation of a highly sophisticated transgenic mouse for researchers to finally prove that inflammation in the breast is fundamental to the growth and progression of breast cancer. (Liu, et al., 2010) The researchers in this study specifically inactivated the nfKappaB inflammatory pathway to test its effect on breast cancer – not an easy task, as this pathway is involved in several functions that actually helped keep the mice alive. They had to find a way to turn off inflammation in the breasts only. And, ingeniously, they did, paving the way to their discovery.
A noteworthy 2009 study also confirmed a link between chronic inflammation and breast cancer recurrence. (Pierce, et al. 2009) In this study, scientists at the Fred Hutchinson Cancer Research Center at the University of Washington noted that women with high levels of two markers of inflammation?C-reactive protein and serum amyloid A?were two to three times more likely to die early or have their cancer return than women with lower level
Although many inflammatory substances have shown to have a relationship with cancer, three of the most widely researched compounds to date are known as COX, LOX and nfKappaB. While the particulars of each chemical are not critical for this discussion, it is critical is to understand the need to keep a balance between the "pro-inflammatory" and "anti-inflammatory" forces at work in our bodies.
Inflammation Enables Angiogenesis
Another important characteristic of chronic inflammation is its relationship to angiogenesis—the development of new blood vessels. While the COX and LOX enzymes promote inflammation, hormone like chemicals from these enzymes play a major role in creating new blood vessels. While this is a natural and normal process, it's also a process that gets hijacked even by tumors too small to detect, to build a blood supply to feed their growing needs. Likewise, these new blood vessels transport nutrients and oxygen to the inflamed tissue by way of inflammatory cells. This process is a recipe for chronic inflammation, each process promoting the other.
On the flip side, research suggests that compounds that block inflammation also inhibit angiogenesis, so by inhibiting one you are affecting both. (Jackson, et al. 1997)"
Article at:
http://www.greenmedinfo.com/blog/inflammation-and-breast-cancer-connection?page=2
Heart surgeon speaks out on what really causes heart disease, Dr. Dwight Lundell, PreventDisease, Thu, 01 Mar 2012
Excerpts:
"We physicians with all our training, knowledge and authority often acquire a rather large ego that tends to make it difficult to admit we are wrong. So, here it is. I freely admit to being wrong. As a heart surgeon with 25 years experience, having performed over 5,000 open-heart surgeries, today is my day to right the wrong with medical and scientific fact.
I trained for many years with other prominent physicians labelled "opinion makers." Bombarded with scientific literature, continually attending education seminars, we opinion makers insisted heart disease resulted from the simple fact of elevated blood cholesterol.
The only accepted therapy was prescribing medications to lower cholesterol and a diet that severely restricted fat intake. The latter of course we insisted would lower cholesterol and heart disease. Deviations from these recommendations were considered heresy and could quite possibly result in malpractice. "
"It Is Not Working!
These recommendations are no longer scientifically or morally defensible. The discovery a few years ago that inflammation in the artery wall is the real cause of heart disease is slowly leading to a paradigm shift in how heart disease and other chronic ailments will be treated.
The long-established dietary recommendations have created epidemics of obesity and diabetes, the consequences of which dwarf any historical plague in terms of mortality, human suffering and dire economic consequences.
Despite the fact that 25% of the population takes expensive statin medications and despite the fact we have reduced the fat content of our diets, more Americans will die this year of heart disease than ever before.
Statistics from the American Heart Association show that 75 million Americans currently suffer from heart disease, 20 million have diabetes and 57 million have pre-diabetes. These disorders are affecting younger and younger people in greater numbers every year.
Simply stated, without inflammation being present in the body, there is no way that cholesterol would accumulate in the wall of the blood vessel and cause heart disease and strokes. Without inflammation, cholesterol would move freely throughout the body as nature intended. It is inflammation that causes cholesterol to become trapped.
Inflammation is not complicated -- it is quite simply your body's natural defence to a foreign invader such as a bacteria, toxin or virus. The cycle of inflammation is perfect in how it protects your body from these bacterial and viral invaders. However, if we chronically expose the body to injury by toxins or foods the human body was never designed to process,a condition occurs called chronic inflammation. Chronic inflammation is just as harmful as acute inflammation is beneficial.
What thoughtful person would willfully expose himself repeatedly to foods or other substances that are known to cause injury to the body? Well, smokers perhaps, but at least they made that choice willfully.
The rest of us have simply followed the recommended mainstream diet that is low in fat and high in polyunsaturated fats and carbohydrates, not knowing we were causing repeated injury to our blood vessels. This repeated injury creates chronic inflammation leading to heart disease, stroke, diabetes and obesity.
Let me repeat that: The injury and inflammation in our blood vessels is caused by the low fat diet recommended for years by mainstream medicine.
What are the biggest culprits of chronic inflammation? Quite simply, they are the overload of simple, highly processed carbohydrates (sugar, flour and all the products made from them) and the excess consumption of omega-6 vegetable oils like soybean, corn and sunflower that are found in many processed foods. "
"Take a moment to visualize rubbing a stiff brush repeatedly over soft skin until it becomes quite red and nearly bleeding. you kept this up several times a day, every day for five years. If you could tolerate this painful brushing, you would have a bleeding, swollen infected area that became worse with each repeated injury. This is a good way to visualize the inflammatory process that could be going on in your body right now.
Regardless of where the inflammatory process occurs, externally or internally, it is the same. I have peered inside thousands upon thousands of arteries. A diseased artery looks as if someone took a brush and scrubbed repeatedly against its wall. Several times a day, every day, the foods we eat create small injuries compounding into more injuries, causing the body to respond continuously and appropriately with inflammation.
While we savor the tantalizing taste of a sweet roll, our bodies respond alarmingly as if a foreign invader arrived declaring war. Foods loaded with sugars and simple carbohydrates, or processed with omega-6 oils for long shelf life have been the mainstay of the American diet for six decades. These foods have been slowly poisoning everyone. "
"How does eating a simple sweet roll create a cascade of inflammation to make you sick?
Imagine spilling syrup on your keyboard and you have a visual of what occurs inside the cell. When we consume simple carbohydrates such as sugar, blood sugar rises rapidly. In response, your pancreas secretes insulin whose primary purpose is to drive sugar into each cell where it is stored for energy. If the cell is full and does not need glucose, it is rejected to avoid extra sugar gumming up the works.
When your full cells reject the extra glucose, blood sugar rises producing more insulin and the glucose converts to stored fat.
What does all this have to do with inflammation? Blood sugar is controlled in a very narrow range. Extra sugar molecules attach to a variety of proteins that in turn injure the blood vessel wall. This repeated injury to the blood vessel wall sets off inflammation. When you spike your blood sugar level several times a day, every day, it is exactly like taking sandpaper to the inside of your delicate blood vessels.
While you may not be able to see it, rest assured it is there. I saw it in over 5,000 surgical patients spanning 25 years who all shared one common denominator -- inflammation in their arteries.
Let's get back to the sweet roll. That innocent looking goody not only contains sugars, it is baked in one of many omega-6 oils such as soybean. Chips and fries are soaked in soybean oil; processed foods are manufactured with omega-6 oils for longer shelf life. While omega-6's are essential -they are part of every cell membrane controlling what goes in and out of the cell -- they must be in the correct balance with omega-3's.
If the balance shifts by consuming excessive omega-6, the cell membrane produces chemicals called cytokines that directly cause inflammation.
Today's mainstream American diet has produced an extreme imbalance of these two fats. The ratio of imbalance ranges from 15:1 to as high as 30:1 in favor of omega-6. That's a tremendous amount of cytokines causing inflammation. In today's food environment, a 3:1 ratio would be optimal and healthy.
To make matters worse, the excess weight you are carrying from eating these foods creates overloaded fat cells that pour out large quantities of pro-inflammatory chemicals that add to the injury caused by having high blood sugar. The process that began with a sweet roll turns into a vicious cycle over time that creates heart disease, high blood pressure, diabetes and finally, Alzheimer's disease, as the inflammatory process continues unabated.
There is no escaping the fact that the more we consume prepared and processed foods, the more we trip the inflammation switch little by little each day. The human body cannot process, nor was it designed to consume, foods packed with sugars and soaked in omega-6 oils.
There is but one answer to quieting inflammation, and that is returning to foods closer to their natural state. To build muscle, eat more protein. Choose carbohydrates that are very complex such as colorful fruits and vegetables. Cut down on or eliminate inflammation- causing omega-6 fats like corn and soybean oil and the processed foods that are made from them.
One tablespoon of corn oil contains 7,280 mg of omega-6; soybean contains 6,940 mg. Instead, use olive oil or butter from grass-fed beef.
Animal fats contain less than 20% omega-6 and are much less likely to cause inflammation than the supposedly healthy oils labelled polyunsaturated. Forget the "science" that has been drummed into your head for decades. The science that saturated fat alone causes heart disease is non-existent. The science that saturated fat raises blood cholesterol is also very weak. Since we now know that cholesterol is not the cause of heart disease, the concern about saturated fat is even more absurd today.
The cholesterol theory led to the no-fat, low-fat recommendations that in turn created the very foods now causing an epidemic of inflammation. Mainstream medicine made a terrible mistake when it advised people to avoid saturated fat in favor of foods high in omega-6 fats. We now have an epidemic of arterial inflammation leading to heart disease and other silent killers.
What you can do is choose whole foods your grandmother served and not those your mom turned to as grocery store aisles filled with manufactured foods. By eliminating inflammatory foods and adding essential nutrients from fresh unprocessed food, you will reverse years of damage in your arteries and throughout your body from consuming the typical American diet."
Article at:
http://www.sott.net/article/242516-Heart-surgeon-speaks-out-on-what-really-causes-heart-disease
Another cause of inflammation? Ecosystem and Food Supply Threatened by Gross Underestimate of Toxicity of Neonicotinoid Pesticides, June 18, 2013 by Dr Mercola
Excerpts:
"Research has shown that many pesticides are neurotoxic and can cause disruptions to your neurological system and your brain. The reason why neurotoxins still enjoy widespread use on our food supply is really more about the bottom line for farming operations than it is about the science of human health.
Research has clearly and consistently linked pesticide exposure to Parkinson’s disease. The Environmental Protection Agency (EPA) also considers 30 percent of insecticides to be carcinogenic.
All of these toxic chemicals are permitted on farms growing conventional and genetically engineered crops, and a large number of them can end up on your plate when you purchase conventionally-grown fruits and vegetables and/or processed foods.
But pesticides also have a dramatic impact on the health of our ecosystem. Neonicotinoids, such as Imidacloprid and Clothianidin, kill insects by attacking their nervous systems. These are known to get into pollen and nectar, and can damage beneficial insects such as bees.
These toxic chemicals have been implicated as one of the primary culprits in the mass die-offs of bees, and have subsequently been banned in some countries. The United States, however, is not among these countries...
But the effects of neonicotinoids do not end there. According to recent research by the American Bird Conservancy (ABC), the use of neonicotinoids in seed treatments is also responsible for the death of birds, terrestrial and aquatic invertebrates and other wildlife."
"Disturbingly, the US Environmental Protection Agency (EPA) has not adequately assessed the toxicity of neonicotinoids. Part of the problem, according to the featured report, is that the EPA is “using scientifically unsound, outdated methodology that has more to do with a game of chance than with a rigorous scientific process.” This has led the agency to grossly underestimate the toxicity of these chemicals. Furthermore3:
“The report also charges that there is no readily available biomarker for neonicotinoids as there is for cholinesterase inhibitors such as the organophosphorous pesticides. ‘It is astonishing that EPA would allow a pesticide to be used in hundreds of products without ever requiring the registrant to develop the tools needed to diagnose poisoned wildlife. It would be relatively simple to create a binding assay for the neural receptor which is affected by this class of insecticides,’ said Dr. Mineau.”
Dr. Mineau urges the EPA to require pesticide registrants to also provide the diagnostic tools necessary to diagnose cases of wildlife poisonings. So far, neonicotinoids have garnered the most attention and criticism for their role in bee die-offs—a worldwide phenomenon that took off once these newer pesticides became widely used. As stated by ABC4:
“The serious risk to bees should not be understated, as one-third of the US diet depends on these insect pollinators. The ABC assessment makes clear, however, that the potential environmental impacts of neonicotinoids go well beyond bees.”
"Pesticides Again Tied to Parkinson's Disease
A recent meta-analysis published in the journal Neurology6, examined data from 104 studies published between 1975 and 2011, in search for a potential link between pesticides and Parkinson's disease. As many previous studies, it found one... Parkinson’s disease is a neurological disorder in which neurons in a region within your brain responsible for normal movement begin to die, causing the telltale shaking and rigidity associated with the disease. There’s currently no known cure, which makes preventing the disease all the more important. Mounting evidence suggests avoiding pesticides is an important part of prevention. As reported by Reuters7:
“In 2011, a study of US farm workers from National Institutes of Health found some pesticides that are known to interfere with cell function were linked to the development of Parkinson's disease. Another study that was published in 2012 also reported that people with Parkinson's disease were more likely to report exposure to pesticides, compared to people without the condition.”
In this latest analysis, exposure to pesticides was linked to a 58 percent increased risk of developing Parkinson’s. Some pesticides were clearly worse than others. Paraquat (a non-selective plant killer) and two fungicides, maneb and mancozeb, were found to double your risk. One of the study’s authors told Reuters that8:"
(Bayer, Dow, and the Japanese keiretsu companies are the major producers of Neonicotinoid)
Article at:
http://articles.mercola.com/sites/articles/archive/2013/06/18/neonicotinoid-pesticide.aspx
Further reading:
http://en.wikipedia.org/wiki/Neonicotinoid
http://thecelebritycafe.com/feature/2014/05/honeybee-colony-collapse-due-insecticide-study-says
Chronic Inflammation NF-kB meta searches: Over 2 million hits of articles, research, dissertations, papers, conferences, and websites on the subject. The elephant in the room is: reducing chronic inflammation by targeting NF-kB. Chronic inflamation is implicated in autoimmune disorders, chronic diseases, heart diseases and cancers. Only in the last couple of years, there has been an explosion in the information available about the chronic inflammation NF-kB connection. Prevention appears to be the keyword for today's focus.
The biggest investments/research for pharmaceuticals appears to be in cancer, heart, and Alzheimers/dementia related research. Chronic inflammation is implicated in all three areas. Chronic inflammatory disease is the new kid on the block and researchers all over the globe are investigating it's complex interactions, therapies, and possibilities. Almost all researchers are focused on the NF-kB link and there must be a reason.
I think STSI and Rosenkamp are at the 'sweetspot' of this arena. Like the history of Alexander Fleming's discovery of penicillin, the finding of anti-inflammatory solutions will probably be the next great thing in medicine.
Inflammation 101: The Fuel That Feeds Cancer
Published November 11, 2012 by Brian D. Lawenda, M.D.
Excerpts:
"Chronic Inflammation: Whereas acute inflammation protects us from our hostile environment, “chronic” inflammation (a prolonged state of low-level, smoldering inflammation, lasting months-to-years) can hurt or even kill us. This difference is one of the most important discoveries of modern medicine. We now recognize that chronic inflammation is involved in the development and progression of almost every chronic disease…including cancer. The role of chronic inflammation is particularly poignant in the autoimmune and chronic infectious diseases, where the involved tissues are flooded with persistent chemical and protein signaling to repair and grow. Chronic inflammation can also significantly reduce your body’s sensitivity to insulin, leading to persistently elevated levels of blood sugar, increased production of insulin and insulin-like growth factor 1 (IGF-1), metabolic syndrome, type 2 diabetes and obesity. All of these factors have been shown to increase the risk of cancer development, progression and recurrence."
"The Role of Nuclear Factor Kappa-B (NF-kB) in Cancer When immune cells first detect any signs of tissue injury or stress, they activate a cellular protein, called nuclear factor kappa-B (or NF-kB.) This protein is the main ‘switch’ that turns on the inflammation in the tissues. Activated NF-kB signals the cell (via many pathways, including through the activation of inflammasomes) to begin to produce numerous proteins involved in inflammation and tissue repair. So far so good, as long as the growth signals are not happening in precancerous or cancerous tissues… During chronic inflammatory conditions, inflamed tissues are predisposed to developing and accumulating DNA damage at a greater rate than non-inflamed tissues. This is due to the production of large amounts of free radicals in inflamed tissues [in fact, billions of DNA mutations develop in our cells each day as a result of free radical injury and toxic exposures.] When these highly-reactive chemicals interact with DNA, they can create DNA mutations. As long as the cell is able to either repair these DNA mutations (most cells have built-in DNA repair mechanisms) or signal the cell to undergo a process of cell suicide (“apoptosis”), precancerous cells will not develop. However, during constant exposure to NF-kB directed signals (which happens during chronic inflammation), both apoptosis and DNA repair mechanisms are shut down. This leads to an accumulation of cells with genetic mutations. If these cells develop enough mutations, they can transform into precancerous cells and, eventually, cancer cells. In the presence of chronic inflammation, precancerous and cancerous tissues are signaled to divide, grow and even invade into surrounding tissues (including blood and lymph vessels, which gives them access to the rest of the body; this is referred to as “metastatic” spread.) These inflammatory signals also inactivate immune cells in the area, preventing them from being able to identify and attack the newly formed cancer cells. One of the sneaky things that cancer cells learn to do to ensure their own growth and survival, is that they can activate their own NF-kB. This enables them to turn on all of the same inflammatory proteins in the surrounding tissues, thereby hijacking the body’s tissue repair and growth mechanisms. Experiments have shown that inflammasome activation involves NF-kB through a multi-step process. When the immune cells (macrophages) identify any tissue injury or oxidative stress, they first activate NF-kB. Activated NF-kB then signals the cells to form inflammasome protein complexes (steps 1 and 2), which are now ready (or ‘primed) to further respond to the tissue injury or oxidative stress. At this step (step 3), the activated inflammasome signals the cell to produce and release inflammatory protein (i.e. IL-1, etc.)"
"Testing for Systemic Inflammation
Most conventionally trained physicians do not assess systemic inflammatory serum markers in their day-to-day practice, as they are considered non-specific (many conditions can lead to ‘above normal’ levels.) Nevertheless, I believe that they can be generally helpful in determining if anti-inflammatory lifestyle changes and interventions are having a positive effect.
The following two blood tests are inexpensive and are good markers of systemic inflammation:
High-sensitivity C-reactive protein (CRP)
Optimum levels in males: Under 0.55 mg/L
Optimum levels in females: Under 1.50 mg/L
Fibrinogen
Optimum levels: 200 – 300 mg/dL
Article at:
http://www.integrativeoncology-essentials.com/2012/11/inflammation-101-the-fuel-that-feeds-cancer/#sthash.Ri6956bL.dpuf
Inflammation and Cancer in Natural Health 365 Where the Experts Speak Out, Thu. Nov. 3, 2011
Article:
"(NaturalHealth365) Nuclear factor-kappaB is a complex of potent proteins, which are kept in an inactive form in the cytoplasm of the cell. When the cell is stressed in some way the cell tries to protect itself. The stresses come from: radiation, toxic chemicals, and nutritional depletion, high carbohydrates, and lack of exercise.
Considering NF-kB regulates the expression of almost 400 different genes, the activation of NF-kB through a whole host of stresses isn’t desirable. NF-kB stimulates genes to produce inflammatory cytokines and other molecules that promote cancer. Because of the strong link of NF-kB with different stress signals, it has been named the “smoke-sensor” of the body.
Activated NF-kB fragments trigger cell differentiation. This means more cells goes from a resting state to a proliferation state, making more copies of the cell. When NF-Kb is activated cells develop survival techniques and resist both cell suicide and chemotherapy drugs. The bottom line is that NF-kB when activated promotes malignancy.
NF-Kb and Inflammation
Some recent studies have tied chronic inflammation to the expression of nuclear factor-kappaB (NF-kappaB). NF-kappa B (NF-KB) acts like a switch to turn on genes that produce inflammation. NF-kappaB’s expression increases in maturing individuals. This may be the reason cancer rates rise with age.
NF-kB is the premium regulator of the cancer-causing process. Once NF-kB triggers the events that link inflammation with the development of cancer, it continues to contribute to cancer cells ability to grow and spread.
It is a fact that most to all cancers have abnormally high levels of active NF-kB, which keeps them in a state of inflammation. Why this is the smoking gun: inflammation is a must in order for cancer cells to proliferate and spread.
What Turns on NF-Kb?
By understanding what turns on nuclear factor-kappa beta and its role in inflammation will assure both health and longevity. Since inflammation is responsible for a host of chronic conditions such as type 2 diabetes, heart disease, arthritis, asthma, and Alzheimer’s it is imperative that we understand the common denominator. NF-kB is the sensor that detects threats like free radicals and infections and in response turns on the genes in charge of inflammation.
There is also very good research that tracks the dietary connection to NF-kB signaling. Most of the research into this explores the role that high-glycemic index carbohydrates have. These foods have been showed to increase the NF-kappa B levels. Any sudden spike in glucose will raise the NF-kB level.
The current thinking is that a high-carb combined with a high fat diet will cause inflammation. While the evidence for low carb even with high fat may reduce NF-kappaB.
What Turns Off NF-Kb?
What blocks NF-kB will block a host of chronic conditions. It is estimated that anywhere from 67%to 90% of cancers are preventable. The consensus is health is dependent on lifestyle factors. Phytochemicals in fruits, vegetables, and spices turn off the inflammatory responses. So, it is no surprise that NF-kB is suppressed by a whole food diet.
Antioxidants are being studied for their NF-kB-blocking ability. These include vitamins C and E, carotenoids, glutathione, lipoic acid, flavonoids, polyphenols, selenium, zinc, milk thistle, curcumin, garlic extract, ginger, isoflavones found in the bean family and omega-3 fatty acids. Besides all the above, there is now growing evidence that vitamin D, ashwagandha and pomegranate extracts have NF-kB blocking activity.
While the pharmaceutical industry looks to turn off the cancer switch, we have the ability to start our own campaign to turn off the inflammatory response. At our disposal is a simple, precise and economical way to design our own cancer prevention program. This is a methodical approach that can save lives. The challenge is to apply this knowledge and move towards better health.
Article at:
http://www.naturalhealth365.com/cancer_treatments/inflammation-and-cancer.html
NF-?B and its relevance to arthritis and inflammation
Rachel E. Simmonds and Brian M. Foxwell
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, no date
Abstract:
In the synovial cells of patients with rheumatoid arthritis (RA), activation of the NF-?B pathway results in the
transactivation of a multitude of responsive genes that contribute to the inflammatory phenotype, including
TNFa from macrophages, matrix metalloproteinases from synovial fibroblasts and chemokines that recruit
immune cells to the inflamed pannus. This is largely a consequence of activation of the ‘canonical’ NF-?B
pathway that involves heterodimers of p50/p65. Whilst much information on the role of NF-?B in inflammation
has been gleaned from genetic deficiency of the respective genes in mice, important differences exist in the
signalling networks between human and murine immune cells and immortalised cell lines. Despite these
differences at the molecular level, the importance of NF-?B in inflammation is undisputed and inhibition of the
pathway is widely believed to have great potential as a therapeutic target in RA. Commercial effort has gone
into developing inhibitors of NF-?B activation. However, inhibition of the NF-?B activation can result in an
exacerbation of inflammation if TNFa production by macrophages is not controlled. It will be important that
such inhibitors are carefully monitored before their long term use in chronic inflammatory conditions such as
RA.
Article at:
http://epubs.surrey.ac.uk/129804/3/Simmonds_and_Foxwell.pdf
NF-?B controls the global pro-inflammatory response in endothelial cells: evidence for the regulation of a pro-atherogenic program in Nucleic Acids Research, August 30, 2005
Sybille Kempe, Hans Kestler1, Andrea Lasar and Thomas Wirth*, Department of Physiological Chemistry, University of Ulm Albert Einstein Allee 11, Ulm 89081, Germany
1Department of Neuroinformatics and Internal Medicine I, University of Ulm Albert Einstein Allee 11, Ulm 89081, Germany
Abstract:
Activation of the transcription factor NF-?B is critical for the tumor necrosis factor-a (TNF-a)-induced inflammatory response. Here we report the complete gene expression profile from activated microvascular endothelial cells emphasizing the direct contribution of the NF-?B pathway. Human microvascular endothelial cell line-1 (HMEC-1) cells were modified to express dominant interfering mutants of the IKK/NF-?B signaling module and expression profiles were determined. Our results provide compelling evidence for the virtually absolute dependence of TNF-a-regulated genes on NF-?B. A constitutively active IKK2 was sufficient for maximal induction of most target genes, whereas a transdominant I?Ba suppressed gene expression. Several genes with a critical role in atherogenesis were identified. The endothelial lipase (EL) gene, a key enzyme involved in lipoprotein metabolism, was investigated more in detail. Binding sites interacting with NF-?B in vitro and in vivo were identified and co-transfection experiments demonstrated the direct regulation of the EL promoter by NF-?B. We conclude that targeting the IKK/NF-?B pathway or specific genes downstream may be effective for the control or prevention of chronic inflammatory diseases such as atherosclerosis.
Article at:
http://nar.oxfordjournals.org/content/33/16/5308.full
Celebrating 25 years of NF-?B in Nature Immunology 12, 681 (2011)
Article:
"Few proteins have had as profound an influence on immunity and biology as the transcription factor NF-?B.
Systems analyses and bioinformatics metadata mining are commonly used today as state-of-the-art approaches for identifying nodal components, whether proteins, genes or regulatory pathways, that intersect to affect biological processes or influence phenotypes. This approach allows connections to be made where none are readily apparent. Twenty-five years ago, using a simple gel-electrophoresis mobility-shift assay, Ranjan Sen and David Baltimore identified a DNA-binding factor that has since been found to be ancient and evolutionarily conserved and to be linked to many biological pathways. It influences cellular development, innate and adaptive immune responses, the induction of inflammatory mediators and wound repair, and, when dysregulated, can lead to various forms of cancer, autoimmunity and chronic inflammatory syndromes. This factor is NF-?B.
The first paper, published in the journal Cell (46, 705–716 (1986)), reported the identification of DNA-binding activity in B lymphocytes that specifically recognizes an enhancer element found in the gene encoding the immunoglobulin-? light chain. Shortly thereafter, Sen and Baltimore presented evidence that this activity is inducible and that its expression is not restricted to the B cell lineage (Cell 47, 921–928 (1986)). This second paper is chock-full of hints about signaling pathways (activation by lipopolysaccharide and phorbol esters) and means of regulation (no requirement for de novo protein synthesis, which suggests the existence of preformed complexes in cells awaiting the proper stimulus) and the possibility that a labile repressor may govern the DNA-binding activity. Since then, the molecule responsible for this activity, known as nuclear factor-?B. (NF-?B) but actually a family of five related Rel-family proteins, has emerged as the central orchestrator of inflammation and immune responses and has been shown to have a critical role in homeostasis of cells of the immune system by maintaining the expression of prosurvival genes. So far, over 35,000 articles have been published that involve some aspect of NF-?B biology. Many more are sure to follow.
This issue of Nature Immunology marks the seminal discovery of NF-?B by presenting a series of six specially commissioned reviews in the Focus on 25 Years of NF-?B (www.nature.com/ni/focus/NF-kB/index.html). In the focus overview, David Baltimore outlines five states associated with NF-?B biology: latency, induction, response, resolution and pathology. He also points out holes in the present state of knowledge—for example, how particular stimuli can trigger unique subsets of NF-?B target-gene expression, whereas other stimuli activate different sets of targets. Context is surely key, for the constellation of other factors induced in the cell at the time and for the duration of the signal; for the array of cis-recognition sites found in the regulatory regions of the target genes and the transcription factors that associate with these sites; and for the diversity of covalent modifications to NF-?B itself. Here, systems biology might provide hints about the 'logic' of the regulation of gene expression by NF-?B.
In a historical commentary, Ranjan Sen recounts the discovery of NF-?B during a search for factors that influence the recombination and transcription of immunoglobulin genes in cells of the B lineage. Elucidation of how the immunoglobulin gene enhancers function could provide insight into the regulatory mechanisms that govern gene activity. The trick was to break the problem down into smaller component parts to allow delineation of the enhancer sites through the use of restriction endonucleases and to determine which nuclear factors bind.
Steve Smale discusses the regulatory hierarchy that governs target-gene selection by NF-?B to ensure proper gene expression. In particular, he reviews the chromatin landscapes present in regulatory loci of NF-?B target genes and how the specificity of the response is governed by stimulus-induced chromatin remodeling. That is, the binding sites themselves must be made accessible before NF-?B, and associated partner proteins can activate or, in some cases, repress gene transcription.
Sankar Ghosh and colleagues review the multiple signaling pathways that activate NF-?B and how other signaling pathways intersect to influence the ensuing NF-?B response. Many factors seem to converge on NF-?B, and sorting out the mechanisms by which the specificity of the response is maintained is a daunting task. A commonality in the activation scheme is the ubiquitin-dependent assembly of multiprotein kinase complexes that inactivate the inhibitor I?B that tethers cytosolic NF-?B. These complexes are themselves subject to multiple layers of regulation by ubiquitin-editing enzymes. The exact nature of many of these complexes and the scenarios that drive their interaction remain a focus of ongoing research.
Jurgen Ruland discusses the mechanisms by which NF-?B signaling is terminated to prevent potential tissue pathology due to prolonged expression of inflammatory mediators. Because the response activated by NF-?B is so potent, tight regulation is needed. Fortunately, many of the NF-?B target genes encode inhibitors of the signaling pathways, which allow the inflamed tissues to reset to normal function, in a classic feedback-inhibition way, once the danger has passed.
Finally, Yinon Ben-Neriah and Michael Karin delve into the pathologies associated with NF-?B dysregulation. They discuss the way many cancers can arise after excessive activation of the innate immune response, a scenario in which wound-healing processes can evade normal tissue growth–control mechanisms. Notably, they point to the anti-inflammatory and antitumorigenic roles of NF-?B, as certain mutations in the gene encoding NF-?B or inhibition of NF-?B itself can lead to more severe disease in some settings.
Clearly, despite 25 years of research centered on NF-?B, much remains unknown. Further research will no doubt identify additional regulatory modules that either activate or repress NF-?B or its target genes. Gaining insight into these processes and understanding how they contribute to human health and disease should remain a top priority."
Article at:
http://www.nature.com/ni/journal/v12/n8/full/ni0811-681.html
Contribution of ER and NF-?B to endocrine resistance in inflammatory breast cancer in Future Medicine,January 2014
Leen Sas*1,2, Peter B Vermeulen1, Peter van Dam1,2, Luc Y Dirix1, Filip Lardon2 & Steven J Van Laere1,3
SUMMARY:
Inflammatory breast cancer (IBC) is a very aggressive form of breast cancer with a high mortality rate. Most patients have lymph node metastasis at the time of diagnosis and 30% of patients already have metastases in distant organs. IBC is normally treated with multimodality therapy. Endocrine therapy is administered in cases of ER-positive tumors. Nevertheless, IBC has a high HOXB13:Il17RB ratio, predicting a poor response to tamoxifen treatment. These data suggest a possible role for IBC as a model for endocrine resistance. Previous studies have shown that NF-?B, a transcription factor regulating different cellular processes, is more highly activated in IBC than in non-IBC, while ER is often downregulated in this tumor type. This article summarizes the activity of ER and NF-?B in IBC and their possible contribution to endocrine resistance in this breast cancer subtype.
Article at:
http://www.futuremedicine.com/doi/abs/10.2217/bmt.13.72
The Inflammation Link: NF-?B Remains a Difficult but Intriguing Target in OncOnline, ane de Lartigue, PhD
Published in Oncline: Friday, June 28, 2013
Excerpts:
"Second-generation proteasome inhibitors act at a lower concentration with lower toxicity and can be administered orally. These include carfilzomib (Kyprolis), which was recently approved for the treatment of patients with multiple myeloma who have received at least two prior therapies, including bortezomib, following clinical trials in which nearly one-quarter of patients experienced complete or partial disappearance of their tumors with a median duration of response of 7.8 months."
"Other strategies to target NF-?B activation include using inhibitors of the upstream signaling pathways mentioned above. Many of these were not conceived as NF-?B inhibitors but have subsequently shown NF-?B inhibitory activity. Among them is an antibody against the ligand that binds to RANK, one of the main activators of NF-?B signaling. Denosumab (Xgeva) has been approved since 2010 for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
NF-?B undergoes numerous types of posttranslational modification, including acetylation, which regulates its activity. The histone deacetylase enzyme HDAC3 acts directly on Rel-A to enable its association with I?Ba, and the sirtuins are a family of deacetylase enzymes, with several members that act on NF-?B. Thus, HDAC inhibitors provide a potential therapeutic means of indirectly inhibiting NF?B. Vorinostat (Zolinza) and romidepsin (Istodax) are two such agents, both approved for the treatment of cutaneous T-cell lymphoma. Sirtuin inhibitors have also drawn a significant amount of attention and are currently in preclinical development.
Nonsteroidal anti-inflammatory drugs such as ibuprofen, aspirin, and indomethacin have been shown to suppress NF-?B activation, though their exact mechanism of action is not fully understood. A number of natural products with anti-inflammatory properties are also potent inhibitors of NF-?B. These include the polyphenolic compounds curcumin and resveratrol, which are undergoing phase II and phase I clinical testing, respectively, in a number of different cancer types.
Finally, since the noncanonical NF-?B pathway was discovered, it has been increasingly recognized as an important arm of NF-?B signaling. The activity of IKKß inhibitors has been shown to be somewhat limited in vivo; this could be because these inhibitors only target the canonical pathway, and there may be compensatory activity by the noncanonical pathway. With this in mind, a dual inhibitor of both pathways is being developed, which targets all five members of the NF-?B gene family. PBS-1086 is currently being examined in preclinical studies and has demonstrated potent cytotoxicity in multiple myeloma cell lines."
Article at:
http://www.onclive.com/publications/oncology-live/2013/june-2013/the-inflammation-link-nf-b-remains-a-difficult-but-intriguing-target/3#sthash.D7LrvB17.dpuf
NF-kappaB-dependent MicroRNA-425 upregulation promotes gastric cancer cell growth by targeting PTEN upon IL-1ß induction, 2014
Jun Ma1†, Jun Liu1†, Zhiming Wang3, Xixi Gu1, Yue Fan1, Wen Zhang1, Lili Xu1, Jianjun Zhang2* and Dingfang Cai1* in Molecular Cancer
* Corresponding authors: Jianjun Zhang zjjshuobo@163.com - Dingfang Cai dingfangcai@163.com
† Equal contributors
Author Affiliations
1 Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China
2 Department of Oral & Maxillofacial-Head Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
3 Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, PR China
Abstract:
Overexpression of the proinflammatory cytokine IL-1ß is associated with diverse diseases, including cancer. Alteration of microRNAs has been observed in cancer cells exposed to proinflammatory cytokines, yet their function in inflammation stress remains elusive. Here, we show that IL-1ß induces the upregulation of miR-425, which negatively regulates phosphatase and tensin homolog expression by targeting its 3’ UTR. An increase in miR-425 depends on IL-1ß-induced NF-kappaB activation, which enhances miR-425 gene transcription upon IL-1ß induction. Consequently, repression of phosphatase and tensin homolog by miR-425 promotes gastric cancer cell proliferation, which is required to protect cells from cisplatin-induced apoptosis. Taken together, our data support a critical role for NF-kappaB-dependent upregulation of miR-425, which represents a new pathway for the repression of phosphatase and tensin homolog activation and the promotion of cell survival upon IL-1ß induction.
Article at:
http://www.molecular-cancer.com/content/13/1/40
University of Glasgow, Institute of Infection, Immunity and Inflammation, Dr Ruaidhri Carmody Senior Lecturer (Immunology), no date
Excerpt:
"Since its discovery some 20 years ago, the NF-?B family of proteins has become one of the most important transcription factors relevant to human health and disease. This is due in large part to its pleiotropic effects, its tightly regulated inducibility and its central role in the control of immunity and inflammation. While intense study of the receptor associated events leading to NF-?B activation has resulted in the identification of a complex cytoplasmic regulatory network, comparatively little is known about the regulation of NF-?B nucleus. My research interests lie in identifying key nuclear events that shape the transcriptional outcome of receptor activated NF-?B. We identified the nuclear I?B protein Bcl-3 as a key regulator of NF-?B transcriptional activity during Toll-like receptor signalling. The interaction of Bcl-3 with NF-?B p50 homodimers prevents their ubiquitination and proteasomal degradation, leading to the formation of a stable repressor complex. This Bcl-3:p50 homodimer complex competes with transcriptionaly competent NF-?B dimers for a finite number of DNA binding sites, thereby negatively regulating gene transcription. This Bcl-3:p50 homodimer complex is also of critical importance in promoting a non-responsive state in macrophage following chronic or repeated stimulation through Toll-like receptors, termed tolerance, which is essential for limiting inflammation-induced injury to host tissue. We are very interested in identifying and understanding additional regulators of Toll-like receptor tolerance at the transcriptional level.
More recently, we have identified the first de-ubiquitinase enzyme for NF-?B, Ubiquitin Specific Protease 7, and revealed that the balance of ubiquitination and de-ubiquitination of the NF-?B subunit p65 in the nucleus is fundamental to the control of target gene transcription.
We continue to identify nuclear regulatory events which shape the activity of NF-?B. In addition to revealing fundamental aspects of the control of transcription during inflammation our work also identifies novel therapeutic targets relevant to the treatment of inflammatory disease."
Article at:
http://www.gla.ac.uk/researchinstitutes/iii/staff/ruaidhricarmody/
Role of NF-?B in immune and inflammatory responses in the gut
M F NEURATH, C BECKER, K BARBULESCU
Laboratory of Immunology,
I. Medical Clinic,
University of Mainz,
Langenbeckstrasse,
55101 Mainz, Germany
Dr M F Neurath.
Abstract:
NF-?B is a pleiotropic transcription factor with key functions in the intestinal immune system. NF-?B family members control transcriptional activity of various promoters of proinflammatory cytokines, cell surface receptors, transcription factors, and adhesion molecules that are involved in intestinal inflammation. The perpetuated activation of NF-?B in patients with active inflammatory bowel disease suggests that regulation of NF-?B activity is a very attractive target for therapeutic intervention. Such strategies include antioxidants, proteasome inhibitors, inhibition of NF-?B by adenoviral I?Ba expression vectors, and antisense DNA targeting of NF-?B. These approaches will hopefully permit the design of new treatment strategies for chronic intestinal inflammation.
NF-kappaB, inflammation, and metabolic disease by R. G. Baker, M. S. Hayden, S. Ghosh in Cell Metab 01/2011; 13:11-22.
ABSTRACT:
Metabolic disorders including obesity, type 2 diabetes, and atherosclerosis have been viewed historically as lipid storage disorders brought about by overnutrition. It is now widely appreciated that chronic low-grade inflammation plays a key role in the initiation, propagation, and development of metabolic diseases. Consistent with its central role in coordinating inflammatory responses, numerous recent studies have implicated the transcription factor NF-kappaB in the development of such diseases, thereby further establishing inflammation as a critical factor in their etiology and offering hope for the development of new therapeutic approaches for their treatment.
NEW TOBACCO DERIVED SUPPLEMENT THAT REDUCES HASHIMOTO'S ANTIBODIES
11/17/2013 by Dr Izabella Wentz (thanks to a_brown3 on the clown board)
Article:
"In doing research for my own thyroid condition, I found that smoking tobacco reduced the risk of Hashimoto’s, but that it often made the outcomes of Graves' disease much worse. I have heard from many former smokers who reported that indeed their Hashimoto's symptoms started around the time they stopped smoking.
When I started researching lifestyle interventions for Hashimoto's, this one really irked me. I mean here I was, a non-smoker and being a health conscious person put me at greater risk of developing Hashimoto's. When I decided to write my book, I almost didn't want to reveal that there was indeed a connection, I mean, smoking is terrible for us, and the last thing I wanted to do was to encourage anyone to start smoking or prevent them from quitting. While I tried many interventions in an effort to heal myself, I never did take up smoking! Of course the risks would outweigh the benefits, but I kept this nugget of information in the back of my mind, and wondered what about smoking reduced the incidence of Hashimoto’s... until I came across a new supplement last year.
Anatabine
I came across some research from John Hopkins that showed anatabine reduced the incidence and severity of Hashimoto’s in mice (Caturegli, et.al, July 2012). Mice models for Hashimoto's are often used to learn more about how the condition affects humans, and benefits in mice often translate to benefits in humans.
I came to learn that Anatabine is a naturally occurring alkaloid found in the Nightshade plant family (tomato, tobacco, peppers) that is available as a dietary supplement. Anatabine has anti-inflammatory effects and reduces the expression of cytokines (IL-18, IL-1R2) associated with the development of Th-1 mediated autoimmunity. This makes sense, as Hashi's is often a Th-1 condition, and Graves' is a Th-2 condition.
Hot off the presses, released on October 31st!
A brand new randomized, double-blind and placebo controlled study (this time in humans) followed a total of 146 patients with Hashimoto's for 3 months. Seventy of those patients were treated with Anatabine at a dose of 9-24mg per day, while the rest were treated with placebo.
The results showed a statistically significant reduction in Thyroglobulin antibodies (TgAb's) at weeks 4, 8, and 12. TgAb's reduced by an average of 46 points in the treatment group compared to a reduction by 4 points in the placebo group. 50% of patients reduced their antibodies by at least 25 points, while 25% reduced their TG antibodies by at least 100 points.
All of the patients in the study were euthyroid, meaning their TSH, T4, T3 were within range, either because they were taking levothyroxine or because they were in the early stages of Hashimoto's. Anatabine did not affect the levels of TSH, T4 or T3, but the patients who were taking levothyroxine seemed to have a greater reduction in antibodies that patients that were not.
Dizziness, nausea, tingling and headaches were some of the more common side effects.
Discussion
The authors suggested that Anatabine may affect Thyroglobulin secretion, resulting in a drop of Thyroglobulin specific antibodies.
Surprisingly, the study did not find a statistically significant reduction in TPO antibodies. The authors of the study noted that TG antibodies are often the first antibodies to come down, followed by TPO antibodies and thought that perhaps more time was needed to see a statistically significant drop in TPO antibodies.
I found the same to be true in my case as well. My TG antibodies completely went away after my first lifestyle changes, but the TPO antibodies were slower to budge and took a longer time to reduce.
Additionally, while this was not shared in the study results, the manufacturer did share some preliminary results on TPO levels last January on their healthcare professional portal. One patient who was studied had an enormous drop in antibody levels after she took a dose of 0.12 mg/kg per day of anatabine for sixteen days. Her TPO antibodies reduced from 3655 IU to 300 IU.
I personally tried Anatabine for three months last year when I was in the middle of my root cause search and it actually lowered my TPO antibodies by about 50% (I didn't have anymore TG antibodies at the time).
What I found particularly interesting is that not everyone responds the same to Anatabine, the study noted that not everyone had a drop in TG antibodies, and some had a greater drop than others did. Of course, this makes sense as not everyone has the same root cause.
How to use it
Doses of 0.12 mg/kg per day to 0.267mg/kg per day have been studied and found to be safe and effective in reducing TPO antibodies. This dose would equal to about 5 mg–12 mg per day for a 100-pound woman. Anatabine has a half-life of about eight hours, and should be dosed six to eight hours apart to ensure a constant level in the body.
Anatabine should be started at a low dose of 1–2 mg per day and gradually increased to the target dose over a week. The onset of action should be seen within a couple of days to a few weeks. Early research suggests that anatabine must be taken continuously to exert its effect on the immune system.
Side effects of headache, nausea, vomiting, and changes in liver function have been observed when doses were started too high. Some individuals with Hashimoto’s may have a nightshade sensitivity, and as anatabine is a tobacco alkoloid there is potential of cross reactivity.
Anatabine lozenges are available from Rock Creek Pharmaceuticals, as Anatabloc®. This supplement can be bought over the counter, however, the manufacturing process and clinical research is pharmaceutical grade. I recommend the non-flavored lozenges for those who may be sensitive to the original minty formulation. The company is currently working on additional hypoallergenic products. Healthcare professionals can request free samples through www.anatabloc.com
When to use it
Anatabine has anti-inflammatory properties, and has been shown to detoxify endotoxin, a toxin produced by our opportunistic gut bacteria (the bad guys that can outnumber the good guys). In my opinion, anatabine may likely be helpful for those with a dysbiosis or low alkaline phosphatase; alkaline phosphatase is an enzyme we all have that helps us detoxify our opportunistic bacteria and is deficient in many with Hashimoto's and some other autoimmune conditions. Smoking, for example, has been found to increase alkaline phosphatase, so while I have not been able to find research on the effects on Anatabine on alkaline phosphatase, perhaps Anatabine works in a similar way?
This supplement may be a helpful tool in reducing inflammation and antibodies while searching for why the immune system is imbalanced. I would recommend it for someone who has already gone through an elimination diet and has already identified their food sensitivites, as the Anatabine may falsely block inflammatory reactions we experience with foods.
It may be of particular benefit for those former smokers who felt their condition got worse after they quit smoking, or for those with particularly high Thyroglobulin antibodies. It may also be something to consider for those who want to quit smoking but are concerned about the impact of smoking cessation on Hashimoto's.
Remember, just as with any supplement, Anatabine is not a cure, but rather a tool to help in your healing journey as you work to discover your root cause(s). Wishing you all the best in your journey and continue to DIG-AT-IT!
PS. You can also download a free Thyroid Diet Guide, 10 Thyroid friendly recipes, and the Nutrient Depletions and Digestion chapter for free by going to www.thyroidpharmacist.com/gift . You will also receive occasional updates about new research, resources, giveaways and helpful information.
For future updates, make sure to follow us on Facebook!
Sincerely,
Your Thyroid Pharmacist
Izabella Wentz, PharmD
Article at:
http://www.thyroidpharmacist.com/1/post/2013/11/new-tobacco-derived-supplement-that-reduces-hashimotos-antibodies.html#comments
FDA targets prescription drug shortages October 31, 2013|By Monte Morin in Los Angeles times. (Similar article in Readers Digest--implied that drug prices too low so manufacturers didn't want to increase manufacturing or improve supplies, no shortage of expensive prescription drugs)
Excerpt:
"From 2010 to 2012, the nation experienced 546 drug shortages, 399 of which involved sterile, injectable drugs. Most of these shortages were caused by quality and manufacturing issues, according to the FDA. Others were caused by a lack of raw materials and components from suppliers."
Article at:
http://articles.latimes.com/2013/oct/31/science/la-sci-sn-fda-targets-prescription-drug-shortages-20131031
Current shortages:
http://www.ashp.org/drugshortages/current/
Multiple Facets of NF-?B in the Heart To Be or Not to NF-?B
Joseph W. Gordon, James A. Shaw, Lorrie A. Kirshenbaum in Circulation Research From the Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre (J.W.G., J.A.S., L.A.K.) and Departments of Physiology (L.A.K.) and Pharmacology & Therapeutics (L.A.K.), Faculty of Medicine University of Manitoba, Winnipeg, Canada.
Abstract:
"The progression from cardiac injury to symptomatic heart failure has been intensely studied over the last decade, and is largely attributable to a loss of functional cardiac myocytes through necrosis, intrinsic and extrinsic apoptosis pathways and autophagy. Therefore, the molecular regulation of these cellular programs has been rigorously investigated in the hopes of identifying a potential cell target that could promote cell survival and/or inhibit cell death to avert, or at least prolong, the degeneration toward symptomatic heart failure. The nuclear factor (NF)-?B super family of transcription factors has been implicated in the regulation of immune cell maturation, cell survival, and inflammation in many cell types, including cardiac myocytes. Recent studies have shown that NF-?B is cardioprotective during acute hypoxia and reperfusion injury. However, prolonged activation of NF-?B appears to be detrimental and promotes heart failure by eliciting signals that trigger chronic inflammation through enhanced elaboration of cytokines including tumor necrosis factor a, interleukin-1, and interleukin-6, leading to endoplasmic reticulum stress responses and cell death. The underlying mechanisms that account for the multifaceted and differential outcomes of NF-?B on cardiac cell fate are presently unknown. Herein, we posit a novel paradigm in which the timing, duration of activation, and cellular context may explain mechanistically the differential outcomes of NF-?B signaling in the heart that may be essential for future development of novel therapeutic interventions designed to target NF-?B responses and heart failure following myocardial injury."
Article at:
http://circres.ahajournals.org/content/108/9/1122.full
How to Prevent Vaccine Injury By Dr. Tyler Keliiheleua|December 21st, 2013 in Byron J Richards Wellness Resources.
Excerpts:
"It is a colossal failure on the part of our government not to warn parents of the actual risks associated with vaccines. The blind insistence that vaccines are safe and effective is not supported by science, at least for a significant number of our children. There are now 25,000 children per year who develop autism (one in 150), a problem that has expanded in direct proportion to the increase in vaccinations. How do you know if your child is at risk?"
"Scientists at the National Institutes of Health3 freely acknowledge that the pro-inflammatory effects of adjuvants in vaccines “underlie many of the observed toxic effects.” The new science shows very clearly that all the inflammation generated by adjuvants is actually not necessary for activating the immune response."
"What Does NF-kappaB Have to Do With It?
Nuclear Factor kappa-B is the “brain” residing within every cell of your body, including cells of your nervous system. It is a gene transcription factor, meaning that it tells your cells how to behave depending on what is happening. When everything runs smoothly, NF-kappaB has its feet up on the lawn chair in a relaxed mode of operation. Under stress NF-kappaB initiates survival strategies. NF-kappaB is the main regulator of all inflammatory and immune responses, and is intimately involved with the healthy function of your nervous system. NF-kappaB is an active intelligence within your cells. The last thing you would ever want to do is mess up NF-kappaB.
Adjuvants, due to their intentionally inflammatory mode of operation, activate NF-kappaB. This is done to ramp-up the immune system so it can “see” the weakened virus in the vaccine. The million dollar question is: “How much NF-kappaB activation can children take before their NF-kappaB systems overheat and set a fire in their brain called autism?” When NF-kappaB overheats it generates large amounts of inflammatory immune system messengers (like TNFa and IL6) and massive numbers of free radicals that damage nerve cells.
If a child is already acutely inflamed then the NF-kappaB pump has already been primed and the risk for vaccine injury is greater. Acute inflammation is caused by illness, injury, surgery, poor diet, and stress at home. This problem is magnified if the child had a history of inflammation while in the womb, was born prematurely, or had health struggles during the first few years of life. Even a previous round of vaccines can prime the inflammatory NF-kappaB pump. Environmental toxicity is another factor that cannot be ignored, as is the health of the mother prior to and during pregnancy. A mother’s obesity and eating habits have a significant effect on the nerve health of her child.
The main point to understand is that if the NF-kappaB system is already on the edge of overheating due to other factors, then the intentional pushing of this system with vaccines poses a serious risk to the child. Multiple vaccines given at one time, with multiple pro-inflammatory adjuvants, obviously increase the risk. Any person who objectively reviews the science on this issue could reach no other conclusion.
The issue of NF-kappaB is so important that the next generation of vaccines5 will utilize it in an attempt to make less toxic vaccines6 (the laser-guided approach rather than the shotgun). While NF-kappaB-targeted vaccines will be less blatantly toxic, making them free of adverse side effects is another story altogether. Manipulating NF-kappaB is playing with the essence of the life force of a cell. At any given time numerous on’s and off’s relate to how NF-kappaB naturally works to maintain health. The new vaccines will turn on the inflammatory aspect of NF-kappaB, which could easily upset the applecart in some other needed aspect of health.
No matter how good research scientists are at developing new vaccines, there will always be a percentage of at-risk-already-inflamed children who are likely to respond in a poor manner. Vaccine safety is not just about better vaccines; it’s also about protecting those who are most likely to have poor reactions to them. It is not possible to have a good public health policy for disease prevention that fails to take this fact into account."
Article at:
http://www.wellnessresources.com/tips/articles/how_to_prevent_vaccine_injury/
NF-KB AND INFLAMMATION in Natural Family Health Clinic, By Dr. Tyler Keliiheleua|December 21st, 2013
Article:
"For years natural health practitioners have understood the connection between underlying inflammatory conditions and the development and presence of chronic disease. Most of us have benefited from the temporary use of anti-inflammatory medication(s) such as Tylenol and Ibuprofen. Further you have likely heard about anti-inflammatory foods such as fish oil, flax seed or ginger.
NF-KB
NF-KB is the latest evolution in our growing understanding of inflammatory processes and their relationship to chronic disease. Though all inflammation ultimately creates the same outcome in the body the NF-KB inflammatory pathway has two distinct features. 1) It can be induced by a number of different mechanisms including insulin surges, trans fat or modified fat, high blood pressure, fat cells adn the cytokines they secrete, … 2) It is self-perpetuating. This has a couple of profound implications. First, the typical modern lifestyle creates many opportunities for the induction of this inflammatory mechanism. Second, once induced without direct intervention is likely to continue in perpetuity. Fortunately the literature has also showed us two of the most powerful anti0inflammatory compounds available that directly and synergistically dampen NF-KB expression.
Turmeric
Curcuminoids are the ac
Resveratrol
Longevity.
Synergistic effect
Though each of these compounds has been found to have powerful anti-inflammatory effects when studied in combination the effect is amplified greatly. This means we can multiply our clinical effectiveness by applying both of these compounds together.
Article at:
http://www.naturalfamilyhealthclinic.com/nf-kb-and-inflammation/
Chronic Inflammation, NF-kB, and Cancer by M. Bokulich
From: Science & Medicine: Volume 10 Number 3: Page 180 (June 2005)
Abstract:
The inflammatory microenvironment is characterized by the presence of activated macrophages and other immune cell types, which secrete a host of proinflammatory factors, such as cytokines, chemokines, and proteases. In chronic inflammation, this unabated immune response stimulates the proliferation of mutated cells, enhances their survival, and promotes angiogenesis, invasion, and metastasis. By regulating the expression of various factors that modulate the inflammatory processes, the transcription factor NF-kB appears to play a central role. Blocking NF-kB may offer a therapeutic option against cancer.
Article at:
http://www.sciandmed.com/sm/journalviewer.aspx?issue=1171&article=1701&action=1
Brain Inflammation, Autism and NFkB Posted on June 18, 2012 in: the medicine and science of autism
Abstract:
"It is becoming clear that inflammation plays a significant role in a number of neurological and psychiatric conditions. Post mortem brain samples in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia and most recently autism spectrum condition, all exhibit neuroglial activation and inflammatory markers within the CSF. Many questions remain about the underlying molecular mechanisms. By adding the pro-inflammatory cytokine, TNF-a, to mouse brain tissue we demonstrated that the frontal lobes and temporal region, areas involved in higher functions such as memory and learning, are most susceptible to cytokine-induced inflammation via the NF-?B signalling pathway. We observed direct correlations between the volumetric increase and molecular expression indicating that therapeutic targets in these lobes may require different approaches when treating conditions with a central neuroinflammatory component."
Article at:
http://asdresearchinitiative.wordpress.com/2012/06/18/brain-inflammation-autism-and-nfkb/
Inhibition of canonical NF-kB and suppression of inflammation and cancer growth by designed inhibitor DHMEQ In the Russian Journal: Creative oncology and surgery, January 29,2012 by K. Horie, K. Umezawa
Department of Applied Chemistry,
Faculty of Science and Technology,
Keio University,
Japan
Kana Horie,
biochemist, post-graduate student Keio University,
Yokohama 223-0061, Japan,
Excerpts:
"NF-kB is a transcription factor and considered to be involved in the mechanisms of inflammation and cancer. NF-kB is classified into canonical and noncanonical NF-kB. Canonical NF-kB is mainly involved in natural immunity and general inflammation, while noncanonical one in B-cell maturation and autoimmune diseases. In one hand, we have designed the new NF-kB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) based on the structure of an antibiotic epoxyquinomicin. DHMEQ showed potent anti-inflammatory and anticancer activities in many animal models. DHMEQ directly binds to a specific cysteine residue of Rel family proteins to inhibit their DNA-binding activity. However, it often inhibits nuclear translocation of NF-kB. In this article, we describe biological activities of DHMEQ and the mechanism of inhibition especially how it inhibits noncanonical NF-kB."
"NF-kB is often excessively activated in human solid tumor and leukemias. Activation of NF-kB in cancer cells may enhance cancer progression through the activation of cancer cell growth, apoptotic resistance, and increased metastatic activity. DHMEQ has potent anticancer effect on various animal models,"
"Thus, DHMEQ was very effective to suppress many inflammation and cancer models in animals. It showed no toxicity. It is not sufficiently soluble to water, but its soluble conjugate is being developed."
Article at:
http://eoncosurg.com/inhibition-of-canonical-nf-kb-and-uppression-of-inflammation-and-cancer-growth-by-designed-inhibitor-dhmeq