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It is estimated that by the year 2050 the elderly (aged 65 or older) population will double the population of children (aged 0-14) for the first time in history. The expansion of the elderly population has already taken a toll on health care systems. In order to alleviate the health care costs and increase the quality of living in the aging population, it is crucial to explore methods that may retard or reverse the deleterious effects of aging. Inflammation and oxidative stress play important roles in brain aging. Inflammatory markers, as well as cellular and molecular oxidative damage, increase during normal brain aging. This increase is accompanied by the concomitant decline in cognitive and motor performance in the elderly population, even in the absence of neurodegenerative diseases. Epidemiological studies have shown that consumption of diets rich in antioxidant and anti-inflammatory agents, such as those found in fruits and vegetables, may lower the risk of developing age-related neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Research from our laboratory suggests that dietary supplementation with fruit or vegetable extracts can decrease the age-enhanced vulnerability to oxidative stress and inflammation. Additional research suggests that the polyphenolic compounds found in fruits such as blueberries may exert their beneficial effects through signal transduction and neuronal communication. Thus, nutritional intervention may exert therapeutic protection against age-related deficits and neurodegenerative diseases [ABSTRACT FROM AUTHOR]

Atherosclerosis is the primary cause of coronary and cardiovascular diseases (CVD). Epidemiological studies have revealed several important environmental (especially nutritional) factors associated with atherosclerosis. However, progress in defining the cellular and molecular interactions involved has been hindered by the etiological complexity of the disease. Nevertheless, our understanding of CVD has improved significantly over the past decade owing to the availability of new randomized trial data. In particular, the failure of antioxidant and anti-inflammatory treatments to consistently reduce the rate of CVD complications suggests that theories of atherosclerosis may have considerably exaggerated the importance of oxidized lipoprotein and vascular inflammation. In that context, one new and basic question is whether the biology of essential dietary lipids may help us understand the role of the inflammatory process in CVD. Essential dietary lipids of the omega-6 and omega-3 families are the precursors of major mediators of inflammation such as eicosanoids that regulate the production of inflammatory cytokines and the expression of some major inflammation genes. On the other hand, non-essential lipids (omega-9 and saturated fatty acids) interfere with biological activities of essential lipids. Finally, essential omega-3 and omega-6 fatty acids have different, often antagonistic, effects on inflammation, and their effects can vary according to the type of cells and target organs involved, as well as their respective amounts in the diet. Because of the extreme complexity in the etiology of CVD, the best strategy may be to monitor the main features of dietary patterns, such as the Mediterranean diet, that are known to be associated with a low prevalence of both CVD and chronic inflammatory diseases [ABSTRACT FROM AUTHOR]

Parkinson's disease∈dexParkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra∈dex substantia nigra (SN). Several pathogenic mechanisms have been implicated in the demise of these cells, including dopamine∈dexdopamine-dependent oxidative stress, mitochondrial dysfunction, excitotoxicity, and proteasomal impairment. In recent years, the involvement of neuroinflammatory processes in nigral degeneration has gained increasing attention. Not only have activated microglia∈dexmicroglia and increased levels of inflammatory mediators been detected in the striatum of PD patients, but a large body of animal studies points to a contributory role of inflammation in dopaminergic cell loss. For example, post-mortem examination of human subjects exposed to the parkinsonism-inducing toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine∈dex methyl-4-phenyl-1,2,3,6- tetrahydropyridine, revealed the presence of activated microglia decades after drug exposure, suggesting that even a brief pathogenic insult can induce an ongoing inflammatory response. Perhaps not surprisingly, non-steroidal anti-inflammatory drugs have been shown to reduce the risk of developing PD. In the past few years, various pathways have come to light that could link neurodegeneration and microglial activation, finally ascribing a pathogenic trigger to the chronic inflammatory response characteristic of PD [ABSTRACT FROM AUTHOR]

Epidemiologic and laboratory studies suggest that non-steroidal anti-inflammatory drug (NSAID) use reduces the risk of Alzheimer's disease (AD). Initial reports in the early 1990's indicated that a history of arthritis, a presumed surrogate of NSAID use, was associated with a lower risk of AD. [1] These reports were followed by epidemiologic studies in which NSAID use was assessed directly and the majority of these reports confirmed the inverse association with risk for AD. [2,3] Postmortem studies in humans [4], studies in animal models of AD [5,6], and in vitro studies [7,8] generally support the notion that NSAIDs can reduce the deleterious inflammation which surrounds amyloid beta (Aβ) plaques in the AD brain. In addition, some studies conducted in vitro and in rodents point to a subgroup of NSAIDs that may work by inhibiting amyloidogenic APP metabolism rather than through traditional anti-inflammatory mechanisms. [9-11] This novel property of NSAIDs is currently being explored in epidemiologic studies. Results from randomized clinical trials of NSAIDs and established AD and one trial on secondary prevention have not been promising and there have been no prevention trials completed. The feasibility of using NSAIDs as a chemopreventive agent in AD is discussed [ABSTRACT FROM AUTHOR]

Large bowel cancer is one of the most common human malignancies in western countries, including North America. Several epidemiological studies have detected decreases in the risk of colorectal cancer in individuals who regularly use aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical trials with NSAIDs in patients with familial adenomatous polyposis have demonstrated that treatment with NSAIDs causes regression of pre-existing adenomas. Preclinical efficacy studies using realistic laboratory animal models have provided scientifically sound evidence as to how NSAIDs act to retard, block, and reverse colonic carcinogenesis. Selective COX-2 inhibitors (celecoxib) as well as naturally occurring anti-inflammatory agents (curcumin) have proven to be effective chemopreventive agents against colonic carcinogenesis. There is growing optimism for the view that realization of preventive concepts in large bowel cancer will also serve as a model for preventing malignancies of the prostate, the breast, and many other types of cancer. There is increasing interest in the use of combinations of low doses of chemopreventive agents that differ in their modes of action in order to increase their efficacy and minimize toxicity. Preclinical studies conducted in our laboratory provide strong evidence that the administration of combinations of chemopreventive agents (NSAIDs, COX-2 inhibitors, DFMO, statins) at low dosages inhibit carcinogenesis more effectively and with less toxicity than when these agents are given alone [ABSTRACT FROM AUTHOR]

Clinical investigations have demonstrated a relationship between the extended use of rofecoxib and increased risk for atherothrombotic events. This has led to the removal of rofecoxib from the market and explicit cardiovascular safety warnings for other COX-2 selective and non-selective agents that remain on the market. Early explanations for the cardiotoxicity of rofecoxib, such as the relative cardioprotective effect of comparator agents (naproxen) or an ‘‘imbalance'' between thromboxane and prostacyclin biosynthesis due to an absence of concomitant aspirin use, have not been substantiated by the evidence. New experimental findings indicate that the cardiotoxicity of rofecoxib is not a general class effect but may be due to its intrinsic chemical structure and unique primary metabolism. Specifically, rofecoxib has been shown to increase the susceptibility of human LDL and cell membrane lipids to oxidative modification, a hallmark feature of atherosclerosis. Rofecoxib was also found to promote the non-enzymatic formation of isoprostanes from biological lipids, which act as important mediators of inflammation in the atherosclerotic plaque. The explanation for such cardiotoxicity is that rofecoxib forms a reactive maleic anhydride in the presence of oxygen due to its chemical structure and primary metabolism (cytoplasmic reductase). By contrast, adverse effects on rates of LDL and membrane lipid oxidation were not observed with other chemically distinct (sulfonamide) COX-2 inhibitors under identical conditions. These findings provide a compelling rationale for distinguishing the differences in cardiovascular risk among COX-selective inhibitors on the basis of their intrinsic physico-chemical properties [ABSTRACT FROM AUTHOR]

Significant use of selective cyclooxygenase-2 (COX-2) blocking agents prescribed for the treatment of arthritis during 1999 to 2005 facilitates epidemiologic investigations to illuminate their chemopreventive effects against human cancer. We therefore conducted a set of case control studies of selective COX-2 blocking agents to determine their chemopreventive potential for the four major cancers: breast, prostate, colon, and lung. Newly diagnosed cases (323 breast cancer patients, 229 prostate cancer patients, 326 colon cancer patients, and 486 lung cancer patients) were ascertained during 2002 to September 30, 2004, at The James Cancer Hospital and Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio. All cases of invasive cancer were confirmed by examination of the pathology report. Healthy controls without cancer were ascertained from hospital screening clinics during the same time period. Controls were frequency matched at a rate of 2:1 to the cases by age, gender, and county of residence. We collected information on type, frequency, and duration of use of selective COX-2 inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Other potentially important risk factors (smoking, drinking, body mass, medical history, blood pressure and cholesterol medications, family history of cancer, occupational history, and reproductive history for women) were also recorded for each subject. Estimates of odds ratios were obtained with adjustment for age and other potential confounders using logistic regression analysis. Use of selective COX-2 inhibitors resulted in a significant risk reduction for each type of cancer (71% for breast cancer, 55% for prostate cancer, 70% for colon cancer, and 79% for lung cancer) and an overall 68% risk reduction for all four cancers. This investigation demonstrates that COX-2 blocking agents have strong potential for the chemoprevention of cancers of the breast, prostate, colon and lung [ABSTRACT FROM AUTHOR]

The development of drugs that selectively inhibit cyclooxygenase-2 (COX-2) demonstrates translational research from bench to bedside based on underlying knowledge of micro-cellular structure and function. However, theoretical concerns about potentially pro-thrombotic effects of selective COX-2 inhibitors coupled with observations of increased cardiovascular risk have produced significant consternation and lead to the withdrawal of two of these agents from the market. A number of questions remain unanswered. It appears clear that both selective and non-selective COX inhibitors are associated with increases in blood pressure. In addition, blood pressure is often increased after starting nonsteroidal therapy, and we know that even small increases in blood pressure in subjects with pre-existing vascular disease are associated with substantial increases in the risk of cardiovascular morbidity. Given this line of reasoning, one might hypothesize that the observed increases in the risk of cardiovascular events associated with COX-inhibitors are largely due to increases in blood pressure in populations of subjects who are already at high risk. But can we generalize that the adverse cardiovascular effects observed forrofecoxib and valdecoxib are sufficient to indict the entire class of COX-2 inhibitors, or is this not a class effect, but dependent upon the degree of COX-2 selectivity? In either case, it seems prudent to recommend that subjects who are at higher risk for a cardiovascular event and receiving a COX-inhibitor should also be treated with low dose ASA with close follow up of blood pressure and efficacious use of anti-hypertensive medications. Finally, modest dietary salt restriction may help lessen the effects of COX-inhibitors on blood pressure [ABSTRACT FROM AUTHOR]

The data that have accumulated in recent years underscore the importance of carefully weighing the risks and benefits of traditional NSAIDs and COX-2 selective inhibitors before making therapeutic decisions for the management of chronic arthritis. In clinical practice, the majority of patients with moderate to severe arthritis who might benefit from NSAID or COX-2 therapy are likely to be elderly and, therefore, at higher risk for gastrointestinal and cardiovascular adverse events than younger persons. Thus, these patients are more likely to be taking low-dose aspirin and using over-thecounter NSAIDs for pain. Selecting a combination of therapies that provides relief from arthritis-related symptoms, minimizes cardiovascular risk, and preserves the gastrointestinal mucosa is complex. Factors to consider include the interference of certain NSAIDs, such as ibuprofen or naproxen, with the antiplatelet effects of aspirin; direct effects of non-selective NSAIDs and of COX-2 selective inhibitors on fluid retention and blood pressure; emerging data about cardiovascular risks associated with these drugs; differences between these agents with regard to associated gastrointestinal adverse event rates; and the feasibility of coadministration of anti-inflammatory therapies with gastro-protective agents [ABSTRACT FROM AUTHOR]

In the last decade, the potential role of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) in brain diseases has been extensively studied. COX-2 over-expression has been associated with neurotoxiticy in acute conditions, such as hypoxia/ischemia and seizures, as well as in inflammatory chronic diseases, including Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD). However, the role played by COX-2 in neurodegenerative diseases is still controversial and further clinical and experimental studies are warranted. In addition, the emerging role of COX-2 in behavioural and cognitive functions strongly indicates that studies aimed at improving our knowledge of the physiological role of COX-2 in the central nervous system are crucial to fully understand the pros and cons of its manipulation in disabling neurological diseases [ABSTRACT FROM AUTHOR]

Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that aberrant induction of COX-2 and up-regulation of the prostaglandin cascade play a significant role in carcinogenesis, and reciprocally, blockade of the process has strong potential for cancer prevention and therapy. Supporting evidence includes the following: [1] expression of constitutive COX-2-catalyzed prostaglandin biosynthesis is induced by most cancer-causing agents including tobacco smoke and its components (polycylic aromatic amines, heterocyclic amines, nitrosamines), essential polyunsaturated fatty acids (unconjugated linoleic acid), mitogens, growth factors, proinflammatory cytokines, microbial agents, tumor promoters, and other epigenetic factors, [2] COX-2 expression is a characteristic feature of all premalignant neoplasms, [3] COX-2 expression is a characteristic feature of all malignant neoplasms, and expression intensifies with stage at detection and cancer progression and metastasis, [4] all essential features of carcinogenesis (mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis, and immunosuppression) are linked to COX-2-driven prostaglandin (PGE-2) biosynthesis, [5] animal studies show that COX-2 up-regulation (in the absence of genetic mutations) is sufficient to stimulate the transformation of normal cells to invasive cancer and metastatic disease, [6] non-selective COX-2 inhibitors, such as aspirin and ibuprofen, reduce the risk of human cancer and precancerous lesions, and [7] selective COX-2 inhibitors, such as celecoxib, reduce the risk of human cancer and precancerous lesions at all anatomic sites thus far investigated. Results confirming that COX-2 blockade is effective for both cancer prevention and therapy have been tempered by observations that some COX-2 inhibitors pose a risk to the cardiovascular system, and more studies are needed in order to determine if certain of these drugs can be taken at dosages that prevent cancer without increasing cardiovascular risk. It is emphasized that the "inflammogenesis model of cancer" is not mutually exclusive and may in fact be synergistic with the accumulation of somatic mutations in tumor suppressor genes and oncogenes or epigenetic factors in the development of cancer [ABSTRACT FROM AUTHOR]

Insulin resistance, both in nondiabetic and diabetic subjects, is frequently associated with obesity, particularly with an excess of central fat. With the growing prevalence of obesity, scientific interest in the biology of adipose tissue has been extended to the secretory products of adipocytes, since they are increasingly shown to influence several aspects in the pathogenesis of obesity-related diseases Until relatively recently, the role of fat itself in the development of obesity and its consequences was considered to be a passive one; adipocytes were considered to be little more than storage cells for fat. It is now clear that, in addition to storing calories as triglycerides, they also secrete a large variety of proteins, including cytokines, chemokines and hormone-like factors, such as leptin, adiponectin and resistin. This production of pro-atherogenic chemokines by adipose tissue is of particular interest since their local secretion, e.g. by perivascular adipose depots, may provide a novel mechanistic link between obesity and the associated vascular complications Recent research has revealed many functions of adipocytokines extending far beyond metabolism, such as immunity, cancer and bone formation. This remarkable understanding is allowing us to more clearly define the role that adipocytes play in health and in obesity and how inflammatory mediators act as signaling molecules in this process Moreover, on a molecular level, we are beginning to comprehend how such variables as hormonal control, exercise, food intake, and genetic variation interact and result in a given phenotype, and how pharmacological intervention may modulate adipose tissue biology [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis and osteoarthritis are painful and debilitating diseases with complex pathophysiology. There is growing evidence that pro-inflammatory cytokines (e.g., interleukin-1 and tumor necrosis factor alpha) and mediators (e.g., prostaglandins, leukotrienes, and nitric oxide) play critical roles in the development and perpetuation of tissue inflammation and damage in joint tissues such as articular cartilage and meniscus. While earlier studies have generally focused on cells of the synovium (especially macrophages), there is increasing evidence that chondrocytes and meniscal cells actively contribute to inflammatory processes. In particular, it is now apparent that mechanical forces engendered by joint loading are transduced to biological signals at the cellular level and that these signals modulate gene expression and biochemical processes. Here we give an overview of the interplay of cytokines and mechanical stress in the production of cyclooxygenases and prostaglandins; lipoxygenases and leukotrienes; and nitric oxide synthases and nitric oxide in arthritis, with particular focus on the interactions of these pathways in articular cartilage and meniscus [ABSTRACT FROM AUTHOR]

Historically, anti-inflammatory drugs had their originsin the serendipitous discovery of certain plants and their extracts being applied for the relief of pain, fever and inflammation. When salicylates were discovered in the mid-19th century to be the active components of Willow Spp., thisenabled these compounds to be synthesized and from this,acetyl-salicylic acid or Aspirin trademark was developed.Likewise, the chemical advances of the 19th-20th centuries leadto development of the non-steroidal anti-inflammatory drugs(NSAIDs), most of which were initially organic acids, but laternon-acidic compounds were discovered. There were two periods ofNSAID drug discovery post-World War 2, the period up to the 1970'swhich was the pre-prostaglandin period and thereafter up to the latter part of the last century in which their effects on prostaglandin production formed part of the screening in thedrug-discovery process. Those drugs developed up to the 1980-late90's were largely discovered empirically following screening for anti-inflammatory, analgesic and antipyretic activities inlaboratory animal models. Some were successfully developed thatshowed low incidence of gastro-intestinal (GI) side effects (theprincipal adverse reaction seen with NSAIDs) than seen with their predecessors (e.g. aspirin, indomethacin, phenylbutazone); the GIreactions being detected and screened out in animal assays. In the1990's an important discovery was made from elegant molecular andcellular biological studies that there are two cyclo-oxygenase(COX) enzyme systems controlling the production of prostanoids [prostaglandins (PGs) and thromboxane (TxA2) ]; COX-1that produces PGs and TxA2 that regulategastrointestinal, renal, vascular and other physiological functions, and COX-2 that regulates production of PGs involved in inflammation, pain and fever. The stage was set in the 1990's forthe discovery and development of drugs to selectively controlCOX-2 and spare the COX-1 that is central to physiological processes whose inhibition was considered a major factor indevelopment of adverse reactions, including those in the GI tract.At the turn of this century, there was enormous commercialdevelopment following the introduction of two new highly selectiveCOX-2 inhibitors, known as coxibs (celecoxib and rofecoxib) whichwere claimed to have low GI side effects. While found to have fulfilled these aims in part, an alarming turn of events tookplace in the late 2004 period when rofecoxib was withdrawn worldwide because of serious cardiovascular events and other coxibs were subsequently suspected to have this adverse reaction, although to a varying degree. Major efforts are currently underwayto discover why cardiovascular reactions took place with coxibs, identify safer coxibs, as well as elucidate the roles of COX-2 andCOX-1 in cardiovascular diseases and stroke in the hope that there may be some basis for developing newer agents (e.g. nitricoxide-donating NSAIDs) to control these conditions The discovery of the COX isoforms led to establishing their importance in many non-arthritic or non-pain states where there isan inflammatory component to pathogenesis, including cancer, Alzheimer's and other neurode generative diseases. The applications of NSAIDs and the coxibs in the prevention and treatment of theseconditions as well as aspirin and other analogues in the prevention of thrombo-embolic diseases now constitute one of the major therapeutic developments of the this century. Moreover, new anti-inflammatory drugs are being discovered and developed based ontheir effects on signal transduction and as anti-cytokine agents andthese drugs are now being heralded as the new therapies to controlthose diseases where cytokines and other non-prostaglandin components of chronic inflammatory and neurode generative diseasesare manifest.… [ABSTRACT FROM AUTHOR]