Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-alcoholic fatty liver disease (NAFLD) has become the most common form of hepatic disorders in the developed world. NAFLD is part of the metabolic syndrome with insulin resistance as a primary underlying derangement. The natural history of NAFLD may extend from simple steatosis over steatohepatitis into cirrhosis and hepatocellular carcinoma. Among numerous factors shaping these transitions, uncoupling protein-2 (UCP2) may theoretically contribute to every stage of this disease. UCP2 is a recently identified fatty acid-responsive mitochondrial inner membrane carrier protein showing wide tissue distribution with a substantially increased presence in fatty liver. The biological functions of UCP2 are not fully elucidated and the greater part of our current knowledge has been obtained from animal experiments. These data suggest a role for UCP2 in lipid metabolism, mitochondrial bioenergetics, oxidative stress, apoptosis, and even carcinogenesis. Available evidence is reviewed and new concepts are considered to appraise the potential role of UCP2 in the pathogenesis of NAFLD.
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PMID:Uncoupling protein-2 and non-alcoholic fatty liver disease. 1597 Apr 80

The metabolic syndrome, defined as a cluster of visceral obesity, insulin resistance, dyslipidemia and elevated blood pressure, is associated with pro-thrombotic, pro-atherogenic and inflammatory risk factors that predispose to cardiovascular disease. Although activators of the peroxisome proliferator-activated receptors (PPARalpha,gamma,delta) in various combinations are under development for treating the metabolic syndrome, they are hampered by adverse effects related to increased adipogenesis, weight gain, fluid overload and carcinogenesis. The recent discovery that telmisartan and irbesartan, antihypertensive angiotensin II type 1 receptor (AT1-R) blockers (ARBs), were uniquely capable of activating PPARgamma, has provided a novel approach to addressing the multifactorial components of the metabolic syndrome. Both drugs have established favorable safety profiles and can activate PPARgamma at concentrations potentially achievable at therapeutic doses. Emerging studies have revealed that both these drugs have beneficial metabolic profiles. This information provides a strategic rationale and pharmacological platform for the development of novel dual ARB/PPARgamma agonists to target the metabolic syndrome and its cardiovascular sequelae, for which therapy is presently insufficient or non-existent. Beneficial effects of these agents include increased energy expenditure, improved lipid profile, increased insulin sensitivity, blood pressure reduction, and amelioration of the associated pro-inflammatory and pro-atherogenic risk profiles. The potential benefit for treatment of the metabolic syndrome, cardiovascular protection, and prevention of related end-organ complications could be of immense clinical value.
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PMID:Treating the metabolic syndrome using angiotensin receptor antagonists that selectively modulate peroxisome proliferator-activated receptor-gamma. 1629 56

The metabolic syndrome, a cluster of metabolic abnormalities linked to insulin resistance, has attracted much interest as a risk factor for cardiovascular disease and type 2 diabetes. Hyperinsulinemia is also a postulated biological risk factor for colorectal carcinogenesis. We therefore here examined the relation between the metabolic syndrome and colorectal adenoma development. The study subjects were 756 cases of colorectal adenoma and 1751 controls with no polyps who underwent total colonoscopy during the period January 1995 to March 2002 at two Self Defense Forces (SDF) hospitals in Japan. The metabolic syndrome was defined with reference to abdominal obesity in combination with any two of the following conditions: elevated triglycerides (150 mg/dL); lowered HDL cholesterol (<40 mg/dL); elevated blood pressure (systolic blood pressure 130 mmHg and/or diastolic blood pressure 85 mmHg); and raised fasting glucose (110 mg/dL). Abdominal obesity was defined as a waist circumference of 85 cm or more(Japanese criterion) or 90 cm (Asian criterion). Statistical adjustment was made for age, hospital, and rank in the SDF. The metabolic syndrome was found to be associated with a moderately increased risk of colorectal adenomas whether either of the Japanese and Asian criteria was used; adjusted odds ratios with the Japanese and Asian criteria were 1.38 (95% confidence interval [CI] 1.13-1.69) and 1.48 (95% CI 1.13-1.93), respectively. Increased risk was more evident for proximal than distal colon or rectal adenomas, and was almost exclusively observed for large lesions (5 mm in diameter). Thus the metabolic syndrome appears to be an important entity with regard to the prevention of colorectal cancer, as well as cardiovascular disease and type 2 diabetes.
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PMID:The metabolic syndrome is associated with increased risk of colorectal adenoma development: the Self-Defense Forces health study. 1643 97

Prostate cancer, the third most common cancer in men worldwide, varies substantially according to geographic region and race/ethnicity. Obesity and associated endocrine variation are foremost among the risk factors that may underlie these regional and ethnic differences. The association between obesity and prostate cancer incidence is complex and has yielded inconsistent results. Studies that have linked obesity with prostate cancer mortality, advanced stage disease, and higher grade Gleason score, however, have produced more consistent findings, indicating that obesity may not necessarily increase the risk of prostate cancer, but may promote it once established. Additionally, metabolic syndrome, which includes disturbed glucose metabolism and insulin bioactivity, may also be associated with prostate carcinogenesis. Adipokines, defined as biologically active polypeptides produced by adipose tissue, have been linked with a number of carcinogenic mechanisms, including angiogenesis, cell proliferation, metastasis, and alterations in sex-steroid hormone levels. A number of emerging studies have implicated the role of adipokines in prostate carcinogenesis. This review explores the specific roles of several adipokines as putative mediating factors between obesity and prostate cancer with particular attention to leptin, interleukin-6 (IL-6), heparin-binding epidermal growth factor-like growth factor (HB-EGF), vascular endothelial growth factor (VEGF) and adiponectin.
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PMID:Obesity, adipokines, and prostate cancer (review). 1646 80

WNT signals are context-dependently transduced to canonical and non-canonical signaling cascades. We cloned and characterized wild-type human WNT10B, while another group cloned aberrant human WNT10B with Gly60Asp amino-acid substitution. Proto-oncogene WNT10B is expressed in gastric cancer, pancreatic cancer, breast cancer, esophageal cancer, and cervical cancer. Because WNT10B blocks adipocyte differentiation, coding SNP of WNT10B gene is associated with familial obesity. In 2001, we reported WNT10B upregulation by TNFalpha. Here, comparative integromics analyses on WNT10B orthologs were performed to elucidate the transcriptional mechanism of WNT10B. Chimpanzee WNT10B and cow Wnt10b genes were identified within NW_001223159.1 and AC150975.2 genome sequences, respectively, by using bioinformatics (Techint) and human intelligence (Humint). Chimpanzee WNT10B and cow Wnt10b showed 98.7% and 95.1% total-amino-acid identity with human WNT10B, respectively. N-terminal signal peptide, 24 Cys residues, two Asn-linked glycosylation sites, and Gly60 of human WNT10B were conserved among mammalian WNT10B orthologs. Transcription start site of human WNT10B gene was 106-bp upstream of NM_003394.2 RefSeq 5'-end. Number of GC di-nucleotide repeats just down-stream of WNT10B transcription start site varied among primates and human population. Comparative genomics analyses revealed that double AP1-binding sites in the 5'-flanking promoter region and NF-kappaB-binding site in intron 3 were conserved among human, chimpanzee, cow, mouse, and rat WNT10B orthologs. Because TNFalpha signaling through TNFR1 and TRADD/RIP/TRAF2 complex activates JUN kinase (JNK) and IkappaB kinase (IKK) signaling cascades, conserved AP1- and NF-kappaB-binding sites explain the mechanism of TNFalpha-induced WNT10B upregulation. TNFalpha-WNT10B signaling loop is the negative feedback mechanism of adipogenesis to prevent obesity and metabolic syndrome. On the other hand, TNFalpha-WNT10B signaling loop is implicated in carcinogenesis. Inhibitors of TNFalpha-WNT10B signaling loop could be utilized for the prevention or treatment of cancer associated with chronic inflammation, such as gastric, liver, breast and pancreatic cancer.
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PMID:AP1- and NF-kappaB-binding sites conserved among mammalian WNT10B orthologs elucidate the TNFalpha-WNT10B signaling loop implicated in carcinogenesis and adipogenesis. 1733 47

Genetic factors, Helicobacter pylori infection, salt over-uptake, decreased vegetable/fruit consumption, smoking, and metabolic syndrome are risk factors of human gastric cancer. Germline mutations of CDH1 gene, and SNPs of PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 and RUNX3 genes are associated with gastric cancer. Helicobacter pylori activates CagA-SHP2-ERK and peptidoglycan-NOD1-NFkappaB signaling cascades in gastric epithelial cells using type IV secretion system, and also TRAF6-MAP3K7-NFkappaB and TRAF6-MAP3K7-AP-1 signaling cascades in epithelial and immune cells through lipopolysaccharide recognition by TLR2 or TLR4. IL-1beta, IL-6, IL-8, TNFalpha and IFNgamma are elevated in gastric mucosa with Helicobacter pylori infection. IL-6 and TNFalpha induce upregulation of WNT5A and WNT10B, respectively. WNT signals are transduced to beta-catenin-TCF/LEF, RhoA, JNK, PKC, NFAT, and NLK signaling cascades. WNT-beta-catenin-TCF/LEF signaling induces upregulation of MYC, CCND1, WISP1, FGF20, JAG1 and DKK1 genes. Notch signals are transduced to CSL-NICD-MAML and NFkappaB signaling cascades. FGF signals are transduced to ERK, PI3K-AKT, PKC, and NFAT signaling cascades. Helicobacter pylori infection induces SHH upregulation in parietal cell lineage, while BMP signals induce IHH upregulation in pit cell lineage. Hedgehog signals induce upregulation of GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1 genes. JAG1 and JAG2 activate Notch signaling, while DKK1 and SFRP1 inhibit WNT signaling. Stem cell signaling network, consisting of WNT, Notch, FGF, Hedgehog and BMP signaling pathways, is activated during chronic Helicobacter pylori infection. Epigenetic silencing of SFRP1 gene occurs in the earlier stage of carcinogenesis in the stomach, while amplification and overexpression of FGFR2 gene in the later stage. Dysregulation of the stem cell signaling network due to the accumulation of germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration gives rise to gastric cancer. SNP typing and custom-made microarray analyses on genes encoding stem cell signaling molecules could be utilized for the personalized medicine.
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PMID:Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. 1756 83

To clarify the role of metabolic factors in endometrial carcinogenesis, we conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), and examined the relation between prediagnostic plasma lipids, lipoproteins, and glucose, the metabolic syndrome (MetS; a cluster of metabolic factors) and endometrial cancer risk. Among pre- and postmenopausal women, 284 women developed endometrial cancer during follow-up. Using risk set sampling, 546 matched control subjects were selected. From conditional logistic regression models, high-density lipoprotein cholesterol (HDL-C) levels were inversely associated with risk body mass index (BMI)-adjusted relative risk (RR) for top versus bottom quartile 0.61 (95% confidence intervals (CI) 0.38-0.97), P(trend) = 0.02). Glucose levels were positively associated with risk (BMI-adjusted RR top versus bottom quartile 1.69 (95% CI 0.99-2.90), P(trend) = 0.03), which appeared stronger among postmenopausal women (BMI-adjusted RR top versus bottom tertile 2.61 (95% CI 1.46-4.66), P(trend) = 0.0006, P(heterogeneity) = 0.13) and never-users of exogenous hormones (P(heterogeneity) = 0.005 for oral contraceptive (OC) use and 0.05 for hormone replacement therapy-use). The associations of HDL-C and glucose with risk were no longer statistically significant after further adjustment for obesity-related hormones. Plasma total cholesterol, Low-density lipoprotein cholesterol (LDL-C), and triglycerides were not significantly related to overall risk. The presence of MetS was associated with risk (RR 2.12 (95% CI 1.51-2.97)), which increased with the number of MetS factors (P(trend) = 0.02). An increasing number of MetS factors other than waist circumference, however, was marginally significantly associated with risk only in women with waist circumference above the median (P(interaction) = 0.01). None of the associations differed significantly by fasting status. These findings suggest that metabolic abnormalities and obesity may act synergistically to increase endometrial cancer risk.
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PMID:Metabolic syndrome, plasma lipid, lipoprotein and glucose levels, and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). 1791 5

The obesity is the second most frequent cause of death which can be prevented. It elevates the risk of cardiovascular diseases, diabetes mellitus type 2, cancers and premature mortality. Overweight and obesity responsible for 14% of cancer caused death in males, and 20% in females, respectively. Authors review the connection between obesity, metabolic syndrome and related metabolic alterations with colorectal cancers. They summarize the role of inflammation, hyperinsulinemia, insulin-like growth factor-I and adipokines in the colorectal carcinogenesis.
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PMID:[Role of obesity in colorectal carcinogenesis]. 1805 94

Incidences of breast cancer, type 2 diabetes, and metabolic syndrome have increased over the past decades with the obesity epidemic, especially in industrialized countries. Insulin resistance, hyperinsulinemia, and changes in the signaling of growth hormones and steroid hormones associated with diabetes may affect the risk of breast cancer. We reviewed epidemiologic studies of the association between type 2 diabetes and risk of breast cancer and the available evidence on the role of hormonal mediators of an association between diabetes and breast cancer. The combined evidence supports a modest association between type 2 diabetes and the risk of breast cancer, which appears to be more consistent among postmenopausal than among premenopausal women. Despite many proposed potential pathways, the mechanisms underlying an association between diabetes and breast cancer risk remain unclear, particularly because the 2 diseases share several risk factors, including obesity, a sedentary lifestyle, and possibly intake of saturated fat and refined carbohydrates, that may confound this association. Although the metabolic syndrome is closely related to diabetes and embraces additional components that might influence breast cancer risk, the role of the metabolic syndrome in breast carcinogenesis has not been studied and thus remains unknown.
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PMID:Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence. 1826 76

Although obesity has been consistently linked to an increased risk of several malignancies, including cancers of the colon, gallbladder, kidney, and pancreas, its role in prostate cancer etiology remains elusive. Data on the association between obesity and prostate cancer incidence are inconsistent, and in some studies obesity is associated with an increase in risk of high-grade prostate cancer but with a decrease in risk of low-grade tumors. In contrast, obesity has been consistently associated with an increased risk of prostate cancer aggressiveness and mortality. The differential effects of obesity on subtypes of prostate cancer suggest etiologic heterogeneity in these tumors and complex interactions between androgen metabolism and several putative risk factors, including insulin resistance, diabetes, inflammation, and genetic susceptibility, on prostate cancer risk. Data on the role of abdominal obesity, insulin resistance, and metabolic syndrome in prostate cancer etiology are limited. Obesity has been shown to be associated with a state of low-grade chronic inflammation, and insulin resistance and the metabolic syndrome are associated with adverse metabolic profiles and with higher circulating concentrations of inflammation-related markers, including leptin, interleukin-6, and tumor necrosis factor-, many of which have been shown to enhance tumor growth. Thus, whether obesity and metabolic syndrome modulate the risk of prostate cancer through chronic inflammation needs to be investigated further. Given that the prevalence of obesity and metabolic syndrome is increasing worldwide and that the world population is aging, the roles of obesity and metabolic syndrome in prostate carcinogenesis warrant further clarification.
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PMID:Obesity, metabolic syndrome, and prostate cancer. 1826 78


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