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1.
In silico identification of potential drug compound against Peroxisome proliferator-activated receptor-gamma by virtual screening and toxicity studies for the treatment of Diabetic Nephropathy.
Singh, S, Mohanty, A
Journal of biomolecular structure & dynamics. 2018;(7):1776-1787
Abstract
Diabetic Nephropathy is a serious complication of diabetes mellitus. Current therapeutic strategies of Diabetic Nephropathy are based on control of modifiable risks like hypertension, glucose levels, and dyslipidemia. Peroxisome proliferator activated receptor-gamma (PPAR-γ) is implicated in several metabolic syndromes including Diabetic Nephropathy, besides obesity, insulin insensitivity, dislipidemia, inflammation, and hypertension. In the present study, virtual screening of 617 compounds from two different public databases was done against PPAR-γ with an objective to find a possible lead compound. Two softwares, PyRx and iGEMDOCK, were used to achieve the docking accuracy in order to avoid loss of candidate compounds. Rosiglitazone (used to treat Diabetic Nephropathy) was taken as the standard compound. A total of 30 compounds with good binding affinity with PPAR-γ were selected for further filtering, on the basis of absorption, distribution, metabolism, excretion, and toxicity (ADMET). The interaction profiling of these 30 compounds, showed a minimum of one and maximum of three interactions with reference to rosiglitazone (SER-289, HIS-449, HIS-323, TYR-473). The fulfilling of ADMET analysis criteria of 30 compounds led to the selection of four compounds (ZINC ID 00181552, 00276456, 00298314, 00448009). Molecular dynamics simulation of these lead compounds in complex with PPAR-γ revealed that three of the four compounds formed a stable complex in the ligand-binding pocket of PPAR-γ during 20-ns simulation. Hence, these three (ZINC ID 00181552, 00276456, 00298314) of the four compounds are potential candidates for experimental validation of biological activity against PPAR-γ in future drug discovery studies.
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2.
Effects of telmisartan on fat distribution: a meta-analysis of randomized controlled trials.
Choi, GJ, Kim, HM, Kang, H, Kim, J
Current medical research and opinion. 2016;(7):1303-9
Abstract
OBJECTIVES Several meta-analyses have confirmed the positive metabolic effects of telmisartan, an angiotensin II receptor blocker that can also act as a partial peroxisome proliferator-activated receptor-γ agonist, compared to those of other angiotensin II receptor blockers. These effects include decreased fasting glucose, glycosylated hemoglobin, interleukin-6, and tumor necrosis factor-α levels. However, no systemic analysis of telmisartan's effects on body fat distribution has been performed. We performed a meta-analysis of randomized controlled telmisartan trials to investigate its effects on body weight, fat distribution, and visceral adipose reduction. RESEARCH DESIGN AND METHODS A literature search was performed using Embase, MEDLINE, and the Cochrane Library between January 1966 and November 2013. Randomized controlled trials in English and meeting the following criterion were included: random assignment of hypertensive participants with overweight/obesity, metabolic syndrome, or glucose intolerance to telmisartan or control therapy group. RESULTS Of 651 potentially relevant reports, 15 satisfied the inclusion criterion. While visceral fat area was significantly lower in the telmisartan group than in the control group (weighted mean difference = -18.13 cm(2), 95% C.I. = -27.16 to -9.11, Pχ(2) = 0.19, I(2) = 41%), subcutaneous fat area was similar (weighted mean difference =2.94 cm(2), 95% C.I. = -13.01 to 18.89, Pχ(2) = 0.30, I(2) = 17%). Total cholesterol levels were significantly different between the groups (standardized mean difference = -0.24, 95% C.I. = -0.45 to -0.03, Pχ(2) = 0.0002, I(2) = 67%). LIMITATIONS Limitations include: (1) limited number of studies, especially those evaluating fat distribution; (2) different imaging modalities to assess visceral fat area (V.F.A.) and subcutaneous fat area (S.F.A.); (3) observed heterogeneity. CONCLUSION The findings suggest that telmisartan affected fat distribution, inducing visceral fat reduction, and thus could be useful in hypertensive patients with obesity/overweight, metabolic syndrome, or glucose intolerance.
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3.
The role of PPARgamma in cardiovascular diseases.
Kvandová, M, Majzúnová, M, Dovinová, I
Physiological research. 2016;(Suppl 3):S343-S363
Abstract
The peroxisome proliferator-activated receptors (PPAR) belong to the nuclear superfamily of ligand-activated transcription factors. PPARgamma acts as a nutrient sensor that regulates several homeostatic functions. Its disruption can lead to vascular pathologies, disorders of fatty acid/lipid metabolism and insulin resistance. PPARgamma can modulate several signaling pathways connected with blood pressure regulation. Firstly, it affects the insulin signaling pathway and endothelial dysfunction by modulation of expression and/or phosphorylation of signaling molecules through the PI3K/Akt/eNOS or MAPK/ET-1 pathways. Secondly, it can modulate gene expression of the renin- angiotensin system - cascade proteins, which potentially slow down the progression of atherosclerosis and hypertension. Thirdly, it can modulate oxidative stress response either directly through PPAR or indirectly through Nrf2 activation. In this context, activation and functioning of PPARgamma is very important in the regulation of several disorders such as diabetes mellitus, hypertension and/or metabolic syndrome.
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4.
Effects of Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ2 gene on metabolic syndrome risk: a meta-analysis.
Zhang, R, Wang, J, Yang, R, Sun, J, Chen, R, Luo, H, Liu, D, Cai, D
Gene. 2014;(1):79-87
Abstract
BACKGROUND Associations between peroxisome proliferator-activated receptor γ2 (PPARγ2) gene polymorphism and metabolic syndrome risk remained controversial and ambiguous. Thus, we performed a meta-analysis to assess the association between Pro12Ala polymorphism in PPARγ2 gene and metabolic syndrome susceptibility. METHODS An electronic literature search was conducted on Medline, OVID, Cochrane Library database, and the China National Knowledge Internet up to March 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strength of association in the fixed or random effects model. RESULTS Ten studies involving a total of 4456 cases and 10343 controls were included in this meta-analysis. No statistical evidence of association was found between Pro12Ala polymorphism and metabolic syndrome risk in all genetic models (homozygote model: OR=0.83, 95% CI=0.62-1.12; heterozygote model: OR=1.04, 95% CI=0.94-1.14; dominant model: OR=1.02, 95% CI=0.93-1.12; recessive model: OR=0.83, 95% CI=0.62-1.11). No statistical evidence of significant association was observed when stratified by ethnicity, definition of metabolic syndrome, source of control groups and quality score of the selected articles. All in all, the results did not support a major role of the Pro12Ala variant of the PPARγ2 gene in metabolic syndrome risk. CONCLUSIONS This meta-analysis suggested that the effect of Pro12Ala polymorphism in PPARγ2 gene may not be related to metabolic syndrome as an entity. However, Pro12Ala may affect the single component of metabolic syndrome. A large, well designed study is required to more adequately assess the role for Pro12Ala polymorphism on metabolic syndrome.
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5.
FTO T/A and peroxisome proliferator-activated receptor-γ Pro12Ala polymorphisms but not ApoA1 -75 are associated with better response to lifestyle intervention in Brazilians at high cardiometabolic risk.
Curti, ML, Rogero, MM, Baltar, VT, Barros, CR, Siqueira-Catania, A, Ferreira, SR
Metabolic syndrome and related disorders. 2013;(3):169-76
Abstract
BACKGROUND The role of obesity-related polymorphisms on weight loss and inflammatory responses to interventions is unclear. We investigated associations of certain polymorphisms with response to a lifestyle intervention. METHODS This 9-month intervention on diet and physical activity included 180 Brazilians at high cardiometabolic risk, genotyped for the fat mass and obesity-associated (FTO) T/A, peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala, and ApoA1 -75G/A polymorphisms. Changes in metabolic and inflammatory variables were analyzed according to these polymorphisms. RESULTS The intervention resulted in lower energy intake and higher physical activity. Anthropometric measurements, 2-hr plasma glucose, insulin, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) improved significantly for the total sample, and these benefits were similar among genotypes. Only variant allele carriers of FTO T/A decreased fasting plasma glucose after intervention (99.9±1.3 to 95.6±1.4 mg/dL, P=0.021). Mean blood pressure reduced after intervention in variant allele carriers of the PPARγ Pro12Ala (109.4±2.1 to 101.3±2.1 mmHg, P<0.001). Improvement in lipid variables was not significant after adjustment for medication. Only the reference genotype of PPARγ Pro12Ala increased apolipoprotein A1 (ApoA1) after intervention (134.3±2.4 to 140.6±2.3 mg/dL, P<0.001). Only variant allele carriers of FTO reduced C-reactive protein (CRP) concentration (0.366±0.031 to 0.286±0.029 mg/dL, P=0.023). CONCLUSION In Brazilian individuals, the FTO T/A polymorphism induces a favorable impact on inflammatory status and glucose metabolism. The reference genotype of PPARγ Pro12Ala seems to favor a better lipid profile, while the variant allele decreases blood pressure. Our data did not support benefits of the variant allele of ApoA1 -75G/A polymorphism. Further studies are needed to direct lifestyle intervention to subsets of individuals at cardiometabolic risk.
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6.
Interaction of PPARG Pro12Ala with dietary fat influences plasma lipids in subjects at cardiometabolic risk.
AlSaleh, A, O'Dell, SD, Frost, GS, Griffin, BA, Lovegrove, JA, Jebb, SA, Sanders, TAB
Journal of lipid research. 2011;(12):2298-2303
Abstract
The PPARγ2 gene single nucleotide polymorphism (SNP) Pro12Ala has shown variable association with metabolic syndrome traits in healthy subjects. The RISCK Study investigated the effect of interaction between genotype and the ratio of polyunsaturated:saturated (P:S) fatty acid intake on plasma lipids in 367 white subjects (ages 30-70 years) at increased cardiometabolic risk. Interaction was determined after habitual diet at recruitment, at baseline after a 4-week high-SFA (HS) diet, and after a 24-week reference (HS), high-MUFA (HM), or low-fat (LF) diet. At recruitment, there were no significant associations between genotype and plasma lipids; however, P:S × genotype interaction influenced plasma total cholesterol (TC) (P = 0.02), LDL-cholesterol (LDL-C) (P = 0.002), and triglyceride (TG) (P = 0.02) concentrations. At P:S ratio ≤ 0.33, mean TC and LDL-C concentrations in Ala12 allele carriers were significantly higher than in noncarriers (respectively, P = 0.003; P = 0.0001). Significant trends in reduction of plasma TC (P = 0.02) and TG (P = 0.002) concentrations occurred with increasing P:S (respectively, ≤0.33 to >0.65; 0.34 to >0.65) in Ala12 allele carriers. There were no significant differences between carriers and noncarriers after the 4-week HS diet or 24-week interventions. Plasma TC and TG concentrations in PPARG Ala12 allele carriers decrease as P:S increases, but they are not dependent on a reduction in SFA intake.
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7.
PPARγ2 gene Pro12Ala and PPARα gene Leu162Val single nucleotide polymorphisms interact with dietary intake of fat in determination of plasma lipid concentrations.
Alsaleh, A, Frost, GS, Griffin, BA, Lovegrove, JA, Jebb, SA, Sanders, TA, O'Dell, SD, ,
Journal of nutrigenetics and nutrigenomics. 2011;(6):354-66
Abstract
BACKGROUND/AIMS: The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of lipid metabolism, activated by unsaturated fatty acids. We investigated independent and interactive effects of PPARγ2 gene PPARG Pro12Ala (rs1801282) andPPARαgene PPARA Leu162Val (rs1800206) genotypes with dietary intake of fatty acids on concentrations of plasma lipids in subjects of whom 47.5% had metabolic syndrome. METHODS The RISCK study is a parallel design, randomised controlled trial. Plasma lipids were quantified at baseline after a 4-week high saturated fatty acids diet and after three parallel 24-week interventions with reference (high saturated fatty acids), high monounsaturated fatty acids and low-fat diets. Single nucleotide polymorphisms were genotyped in 466 subjects. RESULTS At baseline, the PPARG Ala12allele was associated with increased plasma total cholesterol (n = 378; p = 0.04), LDL cholesterol (p = 0.05) and apoB (p =0.05) after adjustment for age, gender and ethnicity. At baseline, PPARA Leu162Val × PPARG Pro12Ala genotype interaction did not significantly influence plasma lipid concentrations. After dietary intervention, gene-gene interaction significantly influenced LDL cholesterol (p =0.0002) and small dense LDL as a proportion of LDL (p = 0.005) after adjustments. CONCLUSIONS Interaction between PPARG Pro12Ala and PPARA Leu162Val genotypes may influence plasma LDL cholesterol concentration and the proportion as small dense LDL after a high monounsaturated fatty acids diet.
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8.
PPARγ Pro12Ala and ACE ID polymorphisms are associated with BMI and fat distribution, but not metabolic syndrome.
Passaro, A, Dalla Nora, E, Marcello, C, Di Vece, F, Morieri, ML, Sanz, JM, Bosi, C, Fellin, R, Zuliani, G
Cardiovascular diabetology. 2011;:112
Abstract
BACKGROUND Metabolic Syndrome (MetS) results from the combined effect of environmental and genetic factors. We investigated the possible association of peroxisome proliferator-activated receptor-γ2 (PPARγ2) Pro12Ala and Angiotensin Converting Enzyme (ACE) I/D polymorphisms with MetS and interaction between these genetic variants. METHODS Three hundred sixty four unrelated Caucasian subjects were enrolled. Waist circumference, blood pressure, and body mass index (BMI) were recorded. Body composition was estimated by impedance analysis; MetS was diagnosed by the NCEP-ATPIII criteria. A fasting blood sample was obtained for glucose, insulin, lipid profile determination, and DNA isolation for genotyping. RESULTS The prevalence of MetS did not differ across PPARγ2 or ACE polymorphisms. Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but lower systolic blood pressure compared with Pro/Pro homozygotes. A significant PPARγ2 gene-gender interaction was observed in the modulation of BMI, fat mass, and blood pressure, with significant associations found in women only. A PPARγ2-ACE risk genotype combination for BMI and fat mass was found, with ACE DD/PPARγ2 Ala subjects having a higher BMI (p = 0.002) and Fat Mass (p = 0.002). Pro12Ala was independently associated with waist circumference independent of BMI and gender. CONCLUSIONS Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but not a worse metabolic profile, possibly because of a more favorable adipose tissue distribution. A gene interaction exists between Pro12Ala and ACE I/D on BMI and fat mass. Further studies are needed to assess the contribution of Pro12Ala polymorphism in adiposity distribution.
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9.
Changes in insulin resistance and cardiovascular risk induced by PPARgamma activation have no impact on RBP4 plasma concentrations in nondiabetic patients.
Pfützner, A, Schöndorf, T, Hanefeld, M, Lübben, G, Kann, PH, Karagiannis, E, Wilhelm, B, Forst, T
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2009;(3):202-6
Abstract
Retinol binding protein 4 (RBP4) has recently been suggested as a good biomarker for insulin resistance and the metabolic syndrome. With this study, we wanted to investigate the effect of pioglitazone (PIO) and simvastatin (SIMVA) on insulin resistance and RBP4 plasma concentrations in nondiabetic patients with metabolic syndrome and increased risk for cardiovascular complications. The prospective, parallel, randomized, double-blind clinical trial was performed with 125 nondiabetic patients with increased cardiovascular risk (78 females, 47 males, age (mean+/-STD): 58.6+/-7.8 years, BMI: 30.8+/-4.2 kg/m (2)). They were randomized to either receive PIO (45 mg)+placebo, SIMVA (40 mg)+placebo, or PIO+SIMVA for 3 months. Key outcome measures were the HOMA (IR)-Score, an oral glucose tolerance test, adiponectin, hsCRP, and RBP4 at baseline and endpoint. No correlation could be detected between the HOMA (IR) values or the impaired fasting glucose tolerance status and RBP-4. Treatment with PIO alone or in combination with SIMVA resulted in a significant improvement of the HOMA (IR)-Score and the adiponectin values, while no change in HOMA (IR) and a decrease in adiponectin (p<0.05) were observed with SIMVA monotherapy. Reductions of hsCRP were seen in all three treatment arms (p<0.001). No changes of the plasma RBP4 concentrations were observed in any of the treatment groups (PIO: 35.6+/-7.2/36.3+/-8.7 ng/ml, PIO+SIMVA 36.5+/-10.8/36.5+/-8 ng/ml, SIMVA 36.1+/-8.1/36.6+/-11.1 ng/ml, all n.s. vs. baseline). Despite a partial or comprehensive improvement in insulin resistance and/or cardiovascular risk indicators in all treatment arms, no change in RBP4-levels could be observed. The regulation of RBP4 expression and secretion occurs through biochemical pathways independent from those influenced by pioglitazone or simvastatin.
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10.
The effects of telmisartan and amlodipine on metabolic parameters and blood pressure in type 2 diabetic, hypertensive patients.
Negro, R, Hassan, H
Journal of the renin-angiotensin-aldosterone system : JRAAS. 2006;(4):243-6
Abstract
INTRODUCTION Hypertension in type 2 diabetes represents a strong risk factor for cardiovascular events. Either calcium channel blockers or angiotensin receptor blockers (ARBs) may reduce insulin resistance. One of the ARBs, telmisartan (Telm) acting as a PPARgamma agonist, significantly reduces HbA(1C) levels. The aim of this study was the comparison of the effects on glycaemic control of amlodipine (Aml) and Telm in hypertensive type 2 diabetic patients. MATERIALS AND METHODS Forty diabetic hypertensive subjects were assigned to two groups. Group A: rosiglitazone (RSG) 4 mg + Telm 80 mg; Group B: RSG 4 mg + Aml 10 mg. All the patients were already treated with metformin, but not with antihypertensive drugs. RESULTS After four months treatment, both groups showed a significant reduction of mean blood pressure (Group A: - 13.5%; Group B: - 13.3%) and a positive influence on glycaemic control and insulin resistance. Lower values of glucose, HbA1C, HOMA index and higher adiponectin levels were observed in Group A compared to Group B. Conclusions. In type 2 diabetic hypertensive patients, the association of Telm 80 mg and RSG 4 mg seems to display a metabolic advantage compared to Aml 10 mg. The simultaneous beneficial effects on blood pressure and insulin sensitivity may confer make Telm particularly suitable in the treatment of the metabolic syndrome.