Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pathways leading from obesity to the manifestations of metabolic syndrome involve a number of metabolic risk factors, as well as adipokines, mediators of inflammatory response, thrombogenic and thrombolytic parameters, and vascular endothelial reactivity. Increased adipose tissue mass contributes to augmented secretion of proinflammatory adipokines, particularly tumor necrosis factor-alpha (TNF alpha), along with diminished secretion of the "protective" adiponectin. In our view, TNF alpha and adiponectin are antagonistic in stimulating nuclear transcription factor-kappa B (NF-kappa B) activation. Through this activation, TNF alpha induces oxidative stress, which exacerbates pathological processes leading to oxidized low-density lipoprotein and dyslipidemia, glucose intolerance, insulin resistance, hypertension, endothelial dysfunction, and atherogenesis. NF-kappa B activation further stimulates the formation of additional inflammatory cytokines, along with adhesion molecules which promote endothelial dysfunction. Elevated free fatty acid, glucose, and insulin levels enhance this NF-kappa B activation and further downstream modulate specific clinical manifestations of metabolic syndrome.
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PMID:A novel pathway to the manifestations of metabolic syndrome. 1498 Dec 9

Chronic ethanol abuse is associated with liver injury, neurotoxicity, hypertension, cardiomyopathy, modulation of immune responses and increased risk for cancer, whereas moderate alcohol consumption exerts protective effect on coronary heart disease. However, the signal transduction mechanisms underlying these processes are not well understood. Emerging evidences highlight a central role for mitogen activated protein kinase (MAPK) family in several of these effects of ethanol. MAPK signaling cascade plays an essential role in the initiation of cellular processes such as proliferation, differentiation, development, apoptosis, stress and inflammatory responses. Modulation of MAPK signaling pathway by ethanol is distinctive, depending on the cell type; acute or chronic; normal or transformed cell phenotype and on the type of agonist stimulating the MAPK. Acute exposure to ethanol results in modest activation of p42/44 MAPK in hepatocytes, astrocytes, and vascular smooth muscle cells. Acute ethanol exposure also results in potentiation or prolonged activation of p42/44MAPK in an agonist selective manner. Acute ethanol treatment also inhibits serum stimulated p42/44 MAPK activation and DNA synthesis in vascular smooth muscle cells. Chronic ethanol treatment causes decreased activation of p42/44 MAPK and inhibition of growth factor stimulated p42/44 MAPK activation and these effects of ethanol are correlated to suppression of DNA synthesis, impaired synaptic plasticity and neurotoxicity. In contrast, chronic ethanol treatment causes potentiation of endotoxin stimulated p42/44 MAPK and p38 MAPK signaling in Kupffer cells leading to increased synthesis of tumor necrosis factor. Acute exposure to ethanol activates pro-apoptotic JNK pathway and anti-apoptotic p42/44 MAPK pathway. Apoptosis caused by chronic ethanol treatment may be due to ethanol potentiation of TNF induced activation of p38 MAPK. Ethanol induced activation of MAPK signaling is also involved in collagen expression in stellate cells. Ethanol did not potentiate serum stimulated or Gi-protein dependent activation of p42/44 MAPK in normal hepatocytes but did so in embryonic liver cells and transformed hepatocytes leading to enhanced DNA synthesis. Ethanol has a 'triangular effect' on MAPK that involve direct effects of ethanol, its metabolically derived mediators and oxidative stress. Acetaldehyde, phosphatidylethanol, fatty acid ethyl ester and oxidative stress, mediate some of the effects seen after ethanol alone whereas ethanol modulation of agonist stimulated MAPK signaling appears to be mediated by phosphatidylethanol. Nuclear MAPKs are also affected by ethanol. Ethanol modulation of nuclear p42/44 MAPK occurs by both nuclear translocation of p42/44 MAPK and its activation in the nucleus. Of interest is the observation that ethanol caused selective acetylation of Lys 9 of histone 3 in the hepatocyte nucleus. It is plausible that ethanol modulation of cross talk between phosphorylation and acetylations of histone may regulate chromatin remodeling. Taken together, these recent developments place MAPK in a pivotal position in relation to cellular actions of ethanol. Furthermore, they offer promising insights into the specificity of ethanol effects and pharmacological modulation of MAPK signaling. Such molecular signaling approaches have the potential to provide mechanism-based therapy for the management of deleterious effects of ethanol or for exploiting its beneficial effects.
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PMID:MAP kinase signaling in diverse effects of ethanol. 1502 49

The causal relation of total Homocysteine (tHcy) to coronary heart diseases (CHD) is unclear. In vitro studies suggest a proinflammatory effect. Among 32,826 women from the Nurses' Health Study who provided blood samples in 1989-1990, 237 CHD events were documented during 8 years of follow-up. The cases (1:2) were matched to controls on age, smoking, and month of blood draw. Plasma tHcy was inversely associated with blood levels of folate (partial r = -0.3, P < 0.0001) and B1(2) (r = -0.2, P < 0.0001) and with dietary intake of folate (r = -0.1, P < 0.01) and B(2) vitamin (r = -0.1, P = 0.01). tHcy was positively associated with soluble tumor necrosis receptor (sTNF-R) 1 and 2 (partial r = 0.2, P < 0.0001). In a multivariate model adjusted for age, smoking, BMI, parental history, hypertension, diabetes, postmenopausal hormone use, physical activity and alcohol intake, the relative risk of CHD between the extreme quartiles of tHcy was 1.66 (95% CI; 1.05-2.64, P trend = 0.02). The association was not appreciably attenuated after further adjustments for sTNF-R1, sTNF-R2, CRP, or Total Cholesterol:/HDL-c ratio. tHcy is an independent risk predictor of CHD and modestly associated with TNF-receptors. However, the inflammatory biomarkers measured could not explain its role in CHD.
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PMID:Homocysteine as a risk factor for coronary heart diseases and its association with inflammatory biomarkers, lipids and dietary factors. 1553 Sep 13

The metabolic syndrome is a cluster of interrelated common clinical disorders, including obesity, insulin resistance, glucose intolerance, hypertension, and dyslipidemia (hypertriglyceridemia and low HDL cholesterol levels). According to recently defined criteria, the metabolic syndrome is prevalent and is associated with a greater risk of atherosclerotic cardiovascular disease than any of its individual components. Primary defects in energy balance that produce obesity (and visceral adiposity in particular) are sufficient to drive all aspects of the syndrome. Increased free fatty acids and lipid accumulation in certain organs are mediators of insulin resistance. Obesity also leads to a proinflammatory and prothrombotic state that potentiates atherosclerosis. Pathways leading directly from adiposity to the genesis of dyslipidemia and hypertension have been elucidated. Recent knowledge implies a role for fat-derived "adipokines," including TNF alpha and adiponectin, as pathogenic contributors or protective factors. Current therapies include diet and exercise as well as agents indicated for the treatment of individual components of the syndrome. Future therapies may accrue from the aggressive pursuit of newer molecular drug targets that have the potential to prevent or treat multiple aspects of the metabolic syndrome.
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PMID:Metabolic syndrome: a clinical and molecular perspective. 1566 May 1

Heme oxygenase (HO) has been shown to be important for attenuating the overall production of reactive oxygen species (ROS) through its ability to degrade heme and to produce carbon monoxide (CO), biliverdin/bilirubin, and the release of free iron. Excess free heme catalyzes the formation of ROS, which may lead to endothelial cell (EC) dysfunction as seen in numerous pathological conditions including hypertension and diabetes, as well as ischemia/reperfusion injury. The upregulation of HO-1 can be achieved through the use of pharmaceutical agents, such as metalloporphyrins and some HMG-CoA reductase inhibitors. Among other agents, atrial natriretic peptide and donors of nitric oxide (NO) are important modulators of the heme-HO system, either through induction of HO-1 or the biological activity of its products. Gene therapy and gene transfer, including site- and organ-specific targeted gene transfer, have become powerful tools for studying the potential role of HO-1/HO-2 in the treatment of various cardiovascular diseases as well as diabetes. HO-1 induction by pharmacological agents or gene transfer of human HO-1 into endothelial cells (ECs) in vitro increases cell-cycle progression and attenuates Ang II, TNF-, and heme-mediated DNA damage; administration in vivo acts to correct blood pressure elevation following Ang II exposure. Moreover, site-specific delivery of HO-1 to renal structures in spontaneously hypertensive rats (SHR), specifically to the medullary thick ascending limb of the loop of Henle (mTALH), has been shown to normalize blood pressure and provide protection to the mTAL against oxidative injury. In other cardiovascular situations, delivery of human HO-1 to hyperglycemic rats significantly lowers superoxide (O(2)(-)) levels and prevents EC damage and sloughing of vascular EC into the circulation. In addition, administration of human HO-1 to rats in advance of ischemia/reperfusion injury considerably reduces tissue damage. The ability to upregulate HO-1 through pharmacological means or through the use of gene therapy may offer therapeutic strategies for cardiovascular disease in the future. This review discusses the implications of HO-1 delivery during the early stages of cardiovascular system injury or in early vascular pathology and suggests that pharmacological agents that regulate HO activity or HO-1 gene delivery itself may become powerful tools for preventing the onset or progression of certain cardiovascular pathologies.
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PMID:Heme oxygenase and the cardiovascular-renal system. 1592 76

Hypertension in pregnancy (HP), one of the most common causes of perinatal deaths, is a multifactorial disease with genetic and environmental factors involved in its etiology. We have carried out molecular epidemiologic research with the purpose of (1) identifying gene variants associated with HP in Japanese women, and (2) analyzing the genetic and environmental factors involved in the pathophysiology of the disease. Self-administered questionnaires were returned by the subjects between 1 and 6 months after delivery. The candidate genetic variants were identified by use of a PCR-RFLP method. T235 of AGT, C1166 of AT1 and Asp298 of NOS3 were respectively associated with HP, although no significant associations were found between the common genetic variants and HP in ACE, FV, MTHFR, B3AR, TNF-A, PAI-1, GSTP1, mEH, and LPL. In analyses using genetic, environmental and lifestyle factors, 5 factors before pregnancy and 4 factors during pregnancy were significantly associated with HP in univariate analysis. Further multivariate analysis revealed 3 factors before pregnancy, i.e. "prepregnancy BMI > or = 24 kg/m(2)", "family history of hypertension" and "TT genotype of AGT", and 2 factors during pregnancy, i.e. "mentally stressful condition" and "salty dishes preferred". Dividing the subjects into 2 subgroups according to whether they possessed "TT genotype of AGT" or not, we identified acquired risk factors before and during pregnancy for HP in each groups. The multivariate analysis identified "mentally stressful condition" as a potent significant risk factor during pregnancy in the former subgroup. However, there were no significant risk factors concerning and "mental stress" in the latter subgroup. Through further exploration of the risk factors associated with HP, we hope to provide useful suggestions about the development of new and effective preventive measures for a range of multifactorial diseases.
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PMID:Genetic and environmental factors associated with the development of hypertension in pregnancy. 1636 2

In 2005, new data on the prognostic value of blood pressure measurement in the home and by ambulatory recordings were published from the Italian (PAMELA) and Japanese (OHASAMA) registers. The ambulatory BP has a greater prognostic value than that measured in the physician's office in hypertensive patients whereas the difference in prognostic value is less in normotensive patients. The prevalence of masked hypertension is estimated at 15 to 26% with reference to the diastolic and systolic BP. The cardiovascular risk is significantly higher in patients with permanent or masked hypertension compared with normotensive subjects and "white coat" hypertensive patients. The ASCOT trial showed that in primary prevention of hypotensive patients with more than 3 associated cardiovascular risk factors, a strategy based on amlodipine secondarily associated with a diuretic, provided better control of the blood pressure than that of a betablocker secondarily associated with a diuretic: the therapeutic trial was negative with respect to the primary criterion including fatal coronary events and non-fatal myocardial infarction but the trial was stopped prematurely because of a significant reduction in cardiovascular and global mortality in the amlodipine-perindopril arm compared with the atenolol-thiazide arm. The metaregression of Verdecchia confirmed that the reduction of the BP remains the essential beneficial factor of antihypertensive therapy, but suggested that; in addition to the reduction of the blood pressure, ACE inhibitors provided better protection against coronary disease than calcium antagonists whereas the calcium antagonists were superior to ACE inhibitors for prevention of stroke. The endothelium is confirmed as a potential therapeutic target. Endothelial dysfunction has been demonstrated in resistance and conduction vessels. The study of antihypertensive therapy on endothelial vasodilation is a new pharmacological approach which may help differentiate the benefits of different classes. New data has documented the relations between inflammation, the vessel and hypertension, and different cytokines hs-CRP, ICAM1, IL6, TNF alpha and MCP-1 may be implicated. The new HAS 2005 recommendations for the management of adult hypertensive patients have been published recently; they are an updated reference for the optimisation of treatment in everyday clinical practice in France. The value of auto-measurement and ambulatory BP recording, the necessary estimation of global cardiovascular risk, the use of the 5 classes of antihypertensive drugs having shown a reduction in cardiovascular morbid-mortality, constitute the key points of these recommendations. Finally, data is now available concerning the incidence of hypertension in France in a working population (IPHAF study) and is estimated at 3% in men and 1.34% in women.
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PMID:[The best of hypertension 2005]. 1647 62

Recombinant human TNF (rhTNF) has a selective effect on endothelial cells in tumour angiogenic vessels. Its clinical use has been limited because of its property to induce vascular collapsus. TNF administration through isolated limb perfusion (ILP) for regionally advanced melanomas and soft tissue sarcomas of the limbs was shown to be safe and efficient. When combined to the alkylating agent melphalan, a single ILP produces a very high objective response rate. ILP with TNF and melphalan provided the proof of concept that a vasculotoxic strategy combined to chemotherapy may produce a strong anti-tumour effect. The registered indication of TNF-based ILP is a regional therapy for regionally spread tumours. In soft tissue sarcomas, it is a limb sparing neoadjuvant treatment and, in melanoma in-transit metastases, a curative treatment. Despite its demonstrated regional efficiency TNF-based ILP is unlikely to have any impact on survival. High TNF dosages induce endothelial cells apoptosis, leading to vascular destruction. However, lower TNF dosage produces a very strong effect that is to increase the drug penetration into the tumour, presumably by decreasing the intratumoural hypertension resulting in better tumour uptake. TNF-ILP allowed the identification of the role of alphaVbeta3 integrin deactivation as an important mechanism of antiangiogenesis. Several recent studies have shown that TNF targeting is possible, paving the way to a new opportunity to administer TNF systemically for improving cancer drug penetration. TNF was the first agent registered for the treatment of cancer that improves drug penetration in tumours and selectively destroys angiogenic vessels.
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PMID:Recombinant human tumor necrosis factor: an efficient agent for cancer treatment. 1693 77

The distribution of fat in obese persons is related to the risk of developing various metabolic disorders, such as glucose intolerance, dyslipidemia and hypertension, and the combination of these conditions is known as the metabolic syndrome. The aim of this study was to investigate the role of subcutaneous fat in regulating insulin resistance and its influence on TNF-alpha expression in visceral fat, by using mice that were subjected to subcutaneous lipectomy with or without subsequent fat transplantation. After partial subcutaneous lipectomy, mice showed significantly greater accumulation of visceral fat compared with sham-operated control mice. Lipectomy led to higher plasma insulin and lower plasma glucose levels after loading with glucose and insulin, respectively, compared with the levels in control mice. Insulin-induced phosphorylation of IRS-1 was decreased in the skeletal muscles of lipectomized mice. Subcutaneous transplantation of fat pads into lipectomized mice reversed the above-mentioned changes indicating insulin resistance in these animals. The fat storage area of adipocytes and TNF- alpha expression by adipocytes in visceral fat were significantly higher in the lipectomized mice than in controls, while subcutaneous transplantation of fat reduced both the fat storage area and TNF-alpha expression. The insulin resistance of lipectomized mice was also ameliorated by systemic neutralization of TNF-alpha activity using a specific antibody. These findings obtained in mice subjected to subcutaneous lipectomy with/without subsequent fat transplantation indicate that subcutaneous fat regulates systemic insulin sensitivity, possibly through altering fat storage and the expression of TNF-alpha by adipocytes in visceral fat. The balance between accumulation of subcutaneous fat and visceral fat may be important with respect to the occurrence of systemic insulin resistance in the metabolic syndrome.
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PMID:Subcutaneous fat modulates insulin sensitivity in mice by regulating TNF-alpha expression in visceral fat. 1707 71

Inflammation plays an important role in the pathogenesis of atherosclerosis and coronary syndromes; moreover, various lines of evidence suggest that genetic factors contribute significantly to the risk of coronary artery disease (CAD). Through its effects on endothelial function, coagulation, insulin resistance and lipid metabolism, the proinflammatory cytokine TNF could be involved in cardiovascular pathophysiology. The aim of our study is to analyze whether TNF gene promoter (-308 G/A; -857 G/A) and TNF receptor polymorphisms (TNFR1 MspA1 I exon 1 and TNFR2 Nla III exon 6) show involvement in CAD predisposition in a group of Italian patients compared with healthy controls. Genotyping was performed by PCR-RFLP. Consecutive Italian patients with angiographically proven CAD (n= 248) were compared with controls (n=241), matched for age, sex and geographical origins. CAD patients showed a higher frequency of the TNF -308 A allele than healthy controls (p=0.046). After stratification according to risk factors for CAD, our analysis revealed that CAD patients with diabetes (p=0.042) and CAD patients without hypertension (p= 0.0495) displayed a higher frequency of the TNF -308 AA genotype compared with healthy controls. Our data stress the inflammatory nature of CAD and show a possible involvement of TNF -308G/A promoter polymorphisms in the predisposition to the development of this disease. The less frequent A allele seems to be a predisposing factor for development of CAD in particular pathological settings associated with the disease itself, such as diabetes.
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PMID:Inflammation and atherosclerosis: the role of TNF and TNF receptors polymorphisms in coronary artery disease. 1734 38


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