Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-alpha expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-alpha production in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-alpha production. Dominant negative AMP-activated protein kinase (AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-alpha production. Adiponectin induced cyclooxygenase (COX)-2-dependent synthesis of prostaglandin E(2) in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-alpha production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms.
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PMID:Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. 1621 Oct 35

Pyruvic acid, an intermediate metabolite of glucose, an effective scavenger of reactive oxygen species (ROS), inhibits tumor necrosis factor-alpha production and NF-kappaB signaling pathways, reduces circulating levels of HMGB1 (high mobility group B1), decreases COX-2 (cyclo-oxygenase-2), iNOS (inducible nitric oxide synthase), and IL-6 (interleukin-6) mRNA expression in liver, ileal mucosa, and colonic mucosa in animal models with endotoxemia. These studies suggest that pyruvate has potent anti-oxidant and anti-inflammatory actions. Insulin influences the production of pyruvate by its action on glucose metabolism and pyruvate is an insulin secretagogue. This suggests that in metabolic syndrome X, obesity, hypertension, diabetes mellitus, and cancer (where insulin resistance is common due to enhanced TNF-alpha production) pyruvate plays a role. This may have relevance to the use of glucose-insulin-potassium regimen in these clinical conditions, sepsis, and cancer.
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PMID:Pyruvate is an endogenous anti-inflammatory and anti-oxidant molecule. 1664 87

Obesity is an important risk factor for esophageal adenocarcinoma (EAC), and elevated serum leptin is characteristic of obesity. We hypothesized that leptin may have biological effects in promoting esophageal adenocarcinoma and examined the effects of leptin on the OE33 Barrett's-derived EAC line. Proliferation was assessed by dimethylthiazoldiphenyltetra-zoliumbromide and 5-bromo-2'-deoxyuridine incorporation assays and apoptosis by ELISA of intracellular nucleosomes. Intracellular signaling was examined using specific pharmacological inhibitors and direct detection of phosphorylated active kinases. Expression of the long and short leptin receptors by OE33 cells was confirmed by RT-PCR, Western blotting and immunocytochemistry. Leptin stimulated OE33 cell proliferation in a dose-dependent manner and inhibited apoptosis. These effects were dependent on cyclooxygenase (COX)-2 and replicated by adding prostaglandin E2 (PGE2). The effects of PGE2 and leptin were abolished by the EP-4 antagonist AH23848. ERK, p38 MAPK, phosphatidylinositol 3'-kinase/Akt, and Janus tyrosine kinase (JAK)-2 were activated upstream of COX-2 induction, whereas the epidermal growth factor receptor and c-Jun NH2-terminal kinase (JNK) were downstream of COX-2. The activation of ERK and Akt but not p38 MAPK was JAK2 dependent. PGE2 stimulated phosphorylation of JNK in an EGF receptor-dependent manner, and activation of the epidermal growth factor receptor required protein kinase C, src, and matrix metalloproteinase activities. We conclude that leptin stimulates cell proliferation and inhibits apoptosis in OAC cells via ERK, p38 MAPK, phosphatidylinositol 3'-kinase/Akt, and JAK2-dependent activation of COX-2 and PGE2 production. Subsequent PGE2-mediated transactivation of the epidermal growth factor receptor and JNK activation are essential to the leptin effects. These effects may contribute to the greatly increased risk of esophageal adenocarcinoma in obesity.
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PMID:Leptin stimulates proliferation and inhibits apoptosis in Barrett's esophageal adenocarcinoma cells by cyclooxygenase-2-dependent, prostaglandin-E2-mediated transactivation of the epidermal growth factor receptor and c-Jun NH2-terminal kinase activation. 1674 Sep 77

Colorectal cancer is a major cause of mortality and whilst up to 80% of sporadic colorectal tumours are considered preventable, trends toward increasing obesity suggest the potential for a further increase in its worldwide incidence. Novel methods of colorectal cancer prevention and therapy are therefore of considerable importance. Non-steroidal anti-inflammatory drugs (NSAIDs) are chemopreventive against colorectal cancer, mainly through their inhibitory effects on the cyclooxygenase isoform COX-2. COX enzymes represent the committed step in prostaglandin biosynthesis and it is predominantly increased COX-2-mediated prostaglandin-E2 (PGE2) production that has a strong association with colorectal neoplasia, by promoting cell survival, cell growth, migration, invasion and angiogenesis. COX-1 and COX-2 inhibition by traditional NSAIDs (for example, aspirin) although chemopreventive have some side effects due to the role of COX-1 in maintaining the integrity of the gastric mucosa. Interestingly, the use of COX-2 selective NSAIDs has also shown promise in the prevention/treatment of colorectal cancer while having a reduced impact on the gastric mucosa. However, the prolonged use of high dose COX-2 selective inhibitors is associated with a risk of cardiovascular side effects. Whilst COX-2 inhibitors may still represent viable adjuvants to current colorectal cancer therapy, there is an urgent need to further our understanding of the downstream mechanisms by which PGE2 promotes tumorigenesis and hence identify safer, more effective strategies for the prevention of colorectal cancer. In particular, PGE2 synthases and E-prostanoid receptors (EP1-4) have recently attracted considerable interest in this area. It is hoped that at the appropriate stage, selective (and possibly combinatorial) inhibition of the synthesis and signalling of those prostaglandins most highly associated with colorectal tumorigenesis, such as PGE2, may have advantages over COX-2 selective inhibition and therefore represent more suitable targets for long-term chemoprevention. Furthermore, as COX-2 is found to be overexpressed in cancers such as breast, gastric, lung and pancreatic, these investigations may also have broad implications for the prevention/treatment of a number of other malignancies.
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PMID:Mediators of PGE2 synthesis and signalling downstream of COX-2 represent potential targets for the prevention/treatment of colorectal cancer. 1685 32

Guggulu, the gum resin from Commiphora mukul, is one of the components of various formulations of traditional Ayurvedic medicine to treat inflammation, obesity, and lipid disorders. In most preparations of Ayurvedic medicine in India, guggulu is boiled prior to its use. Therefore, guggulu was boiled with H2O prior to extractions in our study. Bioassay-guided isolation of compounds from the hexane-soluble portion of the MeOH extract of guggulu yielded cembrenoids, 1-6, a bicyclic diterpene, 7, guggulusterone derivatives, 8-11, myrrhanone derivatives, 12, myrrhanol derivative, 13, and a lignan, 14. The structures of these compounds were confirmed by spectroscopic methods. Compounds 5, 6, 7, 10, and 12-14 are novel. These compounds were assayed for lipid peroxidation and cyclooxygenase (COX) enzyme inhibitory activities. At 100 ppm, compounds 3, 6, and 14 inhibited the lipid peroxidation by 79, 57, and 58%, respectively, and the rest of isolated compounds showed 20-40% inhibitory activity with respect to the controls. In COX-1 and COX-2 enzyme inhibitory assays, compound 3 showed 79 and 83%, and compound 8 gave 67 and 54% of inhibition, respectively, at 100 ppm. All fourteen compounds inhibited COX-1 enzyme at 100 ppm. The lipid peroxidation and COX enzyme inhibitory activities exhibited by compounds isolated from C. mukul may substantiate its use in traditional medicine.
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PMID:Bioactive terpenoids and guggulusteroids from Commiphora mukul gum resin of potential anti-inflammatory interest. 1719 20

Obesity increases the risk of colon cancer. Hyperleptinemia is characteristic of obesity and leptin has been reported to be a colonic growth factor. We have examined the involvement of the cyclo-oxygenase (COX) pathways in the proliferation and anti-apoptotic effects of leptin. Leptin stimulated proliferation in HT-29 colon cancer cells: this was unaffected by inhibition of COX-1, COX-2, protein kinase C, or the epidermal growth factor receptor. Leptin did not increase COX-2 mRNA or COX-derived prostaglandin E2 production. Celecoxib induced apoptosis in a COX-independent manner. Leptin reduced both serum starvation- and celecoxib-induced apoptosis. Inhibition of ERK, p38 MAP kinase, and nuclear factor (NF)-kappaB abolished the growth-promoting and anti-apoptotic effects of leptin. Treatment of HT-29 cells with leptin stimulated phosphorylation of ERK and p38 MAP kinase and nuclear translocation of active NF-kappaB. We conclude that leptin stimulates colon cancer proliferation via COX-independent pathways and reduces celecoxib-induced apoptosis via ERK, p38 MAP kinase, and NF-kappaB pathways.
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PMID:Cyclo-oxygenase-independent inhibition of apoptosis and stimulation of proliferation by leptin in human colon cancer cells. 1740 16

It is now recognized that cross-talk between adipocytes and adipose tissue stromal cells such as macrophages contributes to local and systemic inflammation. One factor from adipocytes that may participate in this interaction and that is frequently elevated in inflammatory conditions such as obesity, insulin resistance, and type 2 diabetes is free fatty acids (FFA). To investigate the potential for FFA to enhance macrophage inflammation, we exposed U937 macrophages to physiological levels (150 microM) of FFA. Palmitic acid (PA), the predominant saturated FFA released from adipose tissue, but not unsaturated FFA, induced an approximately 6-fold (p<0.05) increase in IP-10 gene expression (and 2- to 4-fold increases in IL-8, MCP-1, COX-2, and MIG). PA also induced an approximately 2-fold increase (p<0.05) in active NF-kappaB, and two structurally distinct NF-kappaB inhibitors effectively blocked PA-induced IP-10 gene expression. Conditioned medium from PA-treated cells increased lymphocyte migration 41% (p<0.05) which was significantly reduced by IP-10-neutralizing antibody. These results suggest that elevated concentrations of PA commonly present in obese and insulin resistant individuals can increase NF-kappaB-mediated expression of IP-10 in macrophages. These events in turn may lead to an increasing feed-forward loop of chronic inflammation.
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PMID:Palmitic acid induces IP-10 expression in human macrophages via NF-kappaB activation. 1746 67

Obesity and gastro-oesophageal reflux are the main predisposing factors for oesophageal adenocarcinoma. We have examined the effects of transient acid exposure and leptin on OE33 oesophageal adenocarcinoma cells. Leptin and acid individually stimulated proliferation and inhibited apoptosis and the combination was synergistic. Leptin receptor protein levels were unchanged by acid exposure. The COX-2 inhibitor NS 398 blocked the effects of acid and leptin but while both acid and leptin individually significantly increased PGE2 production and COX-2 mRNA levels, the combination was not more effective than either stimulant alone. Leptin synergistically enhanced acid-stimulated EGFR and ERK phosphorylation but did not further increase JNK or p38 MAP kinase phosphorylation. Specific EGFR and ERK inhibitors reduced the effects of leptin and acid alone and in combination. The combination of increased circulating leptin levels in obesity and transient reflux of gastric acid may promote oesophageal carcinogenesis by increasing proliferation and inhibiting apoptosis.
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PMID:Leptin synergistically enhances the anti-apoptotic and growth-promoting effects of acid in OE33 oesophageal adenocarcinoma cells in culture. 1761 45

Obesity is a leading risk factor for type 2 diabetes (T2D). Aging is associated with an increase in T2D incidence, which is not totally explained by the much lower prevalence of obesity in the elderly. Low-grade inflammation in adipose tissue (AT) contributes to insulin resistance and T2D. Thus, we determined whether inflammatory responses are up-regulated with age in AT. The results showed that visceral AT from old C57BL mice had significantly higher mRNA expression of the proinflammatory cytokines IL-1beta, IL-6, TNF-alpha, and COX-2 and lower expression of anti-inflammatory PPAR-gamma than those of young mice. We further showed that adipocytes (AD) and not stromal vascular cells including macrophages (Mphi) were the cells responsible for this higher inflammatory state of the aged AT, suggesting that the age-associated increase in AT inflammation is distinguished from that seen in obesity, in which Mphi are the main contributors. However, peritoneal Mphi of either age (young or old) produced more TNF-alpha and IL-6 after incubation in old AD-conditioned medium compared with young AD-conditioned medium. This suggests that in addition to producing more inflammatory cytokines, AD from old mice induce a higher inflammatory response in other cells. Sphingolipid ceramide was higher in old compared with young AD. Reducing ceramide levels or inhibiting NF-kappaB activation decreased cytokine production, whereas the addition of ceramide increased cytokine production in young AD to a level comparable to that seen in old AD, suggesting that ceramide-induced activation of NF-kappaB plays a key role in AT inflammation.
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PMID:Aging up-regulates expression of inflammatory mediators in mouse adipose tissue. 1787 82

Optimum but balanced food intake maintains healthy growth and disease-free lifespan. However, imbalanced and over-nutrition promotes obesity, diabetes, malignancy, osteoporosis, infectious diseases, etc. In 1936, McCay reported that calorie restriction prevents weight gain and extend lifespan in rodents. In early 1970, Dr. Good at University of Minnesota and Dr. Walford at UCLA began studies in mice by reducing protein and calorie intake and studying their impact on immune function. Dr. Good's group (Jose, Fernandes, Kramer, Cooper, Day, etc.) reported changes in humoral and cellular immunity at present known as innate and adaptive immune function. Later, much interest was devoted by late Dr. Good on studying the role of calorie restriction (CR) and the role of zinc on immunity, particularly their role on aging, autoimmunity, and malignancy. Both functional role of T-cells, NK-cells and B-cells and their interaction during CR was studied extensively. We recently decided to pursue the beneficial effects of n-3 fatty acids (fish oil) with and without CR on controlling autoimmune-disease in NZB x NZW F1 mice. Our results indicated that n-3 FA when fed ad-libitum prolongs lifespan higher than commonly consumed n-6 FA (corn oil) in these mice. Moreover, n-3 FA + CR is found to be more effective than n-6 FA + CR. Some of the beneficial changes by n-3 FA include enhancing antioxidant enzymes and lowering Th-1/Th-2 cytokines, adhesion molecules, COX-2/PGE(2) levels, pro-inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha etc. The decreased pro-inflammatory cytokines were also found to protect against bone loss in OVX mice. Further, Fat-1 transgenic mice (which make n-3 FA endogenously in vivo from n-6 FA) when fed CR revealed decreased NF-kappaB and AP-1 activity and increased expression of life-prolonging gene SIRT1. Also CR and n-3 FA decreases body weight and increases insulin sensitivity, as well. Thus, to prevent obesity decreased calorie intake with n-3 FA supplement is far more effective and may have protection against CVD, malignancy, autoimmunity, and osteoporosis. The CR studies undertaken in primates and recently in humans are showing very encouraging results. In order to understand more precisely the role of diet and nutrition, new approaches exploring the link through nutrigenomics, proteomics and metabolomics may soon provide insight into controlling age-related diseases by following a balanced food intake.
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PMID:Progress in nutritional immunology. 1825 5


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