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G Allele of the rs1801282 Polymorphism in PPARγ Gene Confers an Increased Risk of Obesity and Hypercholesterolemia, While T Allele of the rs3856806 Polymorphism Displays a Protective Role Against Dyslipidemia: A Systematic Review and Meta-Analysis.
Li, S, He, C, Nie, H, Pang, Q, Wang, R, Zeng, Z, Song, Y
Frontiers in endocrinology. 2022;:919087
Abstract
BACKGROUND The relationships between the rs1801282 and rs3856806 polymorphisms in nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) gene and obesity indexes as well as serum lipid levels have been extensively investigated in various studies, but the results were inconsistent and even contradictory. METHODS PubMed, Google Scholar, Embase, Cochrane Library, Web of Science, Wanfang, CNKI and VIP databases were searched for eligible studies. The random-effTPDEects model was used, and standardized mean difference (SMD) with 95% confidence interval (CI) was calculated to estimate the differences in obesity indexes and serum lipid levels between the subjects with different genotypes in a dominant model. Heterogeneity among studies was assessed by Cochran's x2-based Q-statistic test. Publication bias was identified by using Begg's test. RESULTS One hundred and twenty studies (70,317 subjects) and 33 studies (18,353 subjects) were identified in the analyses for the rs1801282 and rs3856806 polymorphisms, respectively. The G allele carriers of the rs1801282 polymorphism had higher levels of body mass index (SMD = 0.08 kg/m2, 95% CI = 0.04 to 0.12 kg/m2, p < 0.001), waist circumference (SMD = 0.12 cm, 95% CI = 0.06 to 0.18 cm, p < 0.001) and total cholesterol (SMD = 0.07 mmol/L, 95% CI = 0.02 to 0.11 mmol/L, p < 0.01) than the CC homozygotes. The T allele carriers of the rs3856806 polymorphism had lower levels of low-density lipoprotein cholesterol (SMD = -0.09 mmol/L, 95% CI = -0.15 to -0.03 mmol/L, p < 0.01) and higher levels of high-density lipoprotein cholesterol (SMD = 0.06 mmol/L, 95% CI = 0.02 to 0.10 mmol/L, p < 0.01) than the CC homozygotes. CONCLUSIONS The meta-analysis suggests that the G allele of the rs1801282 polymorphism confers an increased risk of obesity and hypercholesterolemia, while the T allele of the rs3856806 polymorphism displays a protective role against dyslipidemia, which can partly explain the associations between these polymorphisms and cardiovascular disease. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/, identifier [CRD42022319347].
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No Relevant Pharmacokinetic Drug-Drug Interaction Between the Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin and Lobeglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, in Healthy Subjects.
Kim, YK, Hwang, JG, Park, MK
Drug design, development and therapy. 2021;:1725-1734
Abstract
PURPOSE Combination therapy with insulin-independent sodium-glucose cotransporter 2 inhibitors and thiazolidinedione drugs, such as lobeglitazone, has been reported to elicit potential additive efficacy in glycemic control in type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetic (PK) drug-drug interactions between empagliflozin and lobeglitazone in healthy subjects. SUBJECTS AND METHODS A randomized, open-label, multiple-dose study was conducted in 30 healthy subjects using a three-treatment, six-sequence, three-way crossover design. Subjects received one of the following treatments once daily for 5 days in each period: 25 mg empagliflozin, 0.5 mg lobeglitazone sulfate, or a combination. Serial blood sampling before every dose and up to 24 h after the last dose was performed during each treatment period. The PK parameters were estimated using noncompartmental methods with the plasma empagliflozin and lobeglitazone concentrations. The absence of a PK interaction was construed as the 90% confidence interval (90% CI) of maximum concentration at steady state (Cmax,ss) and area under the concentration-time curve over the dosing interval (AUCtau) for combination therapy-to-monotherapy ratios within the limits of 0.80-1.25. RESULTS The steady-state plasma empagliflozin and lobeglitazone concentration-time profiles of combination therapy and monotherapy were comparable in the 25 subjects who completed the study. Coadministration of empagliflozin with lobeglitazone did not affect empagliflozin PK (with 90% CIs of 0.956-1.150 and 0.945-1.133 for Cmax,ss and AUCtau, respectively). Likewise, empagliflozin did not affect lobeglitazone Cmax,ss or AUCtau (with 90% CIs of 0.869-0.995 and 0.851-1.018, respectively). All treatment groups tolerated mild adverse events well. CONCLUSION The lack of PK interactions between lobeglitazone and empagliflozin in combination therapy, along with their good tolerability, indicates that the two drugs can be coadministered without dose adjustment. TRIAL REGISTRATION NUMBER NCT02854748, Registered on August 7, 2016.
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Association between PPAR-γ2 gene polymorphisms and diabetic retinopathy risk: a meta-analysis.
Li, XF, Jiang, GB, Cheng, SY, Song, YF, Deng, C, Niu, YM, Cai, JW
Aging. 2021;(4):5136-5149
Abstract
A close association between peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) and the development of diabetic retinopathy (DR) has been previously suggested. Herein, a meta-analysis was conducted to explore the association between PPAR-γ2 polymorphisms and DR risk by performing a systematic search and quantitative analysis. Overall, fourteen articles involving 10,527 subjects were included. The pooled results did not reveal an association between PPAR-γ2 rs1801282 C/G and DR susceptibility in the overall population (e.g., the dominant model: CG+GG vs. CC, OR=0.85, 95% CI=0.69-1.06, P=0.15, I2=62.9%). Furthermore, heterogeneity tests, cumulative analyses, sensitivity analyses, and publication bias analyses were conducted and showed that the results were robust. Similarly, race-based subgroup analyses and other subgroup analyses did not reveal an association between the rs1801282 C/G and DR susceptibility. In addition, no significant association was observed between PPAR-γ2 rs3856806 C/T polymorphism and DR risk (e.g., the dominant model: CT+TT vs. CC, OR=1.12, 95%CI=0.91-1.37, P=0.28, I2=27.0%). Overall, based on the current sample size and the level of evidence presented in the study, the results suggest that PPAR-γ2 gene polymorphisms are not associated with DR risk.
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Formononetin protects against ox-LDL-induced endothelial dysfunction by activating PPAR-γ signaling based on network pharmacology and experimental validation.
Zhang, B, Hao, Z, Zhou, W, Zhang, S, Sun, M, Li, H, Hou, N, Jing, C, Zhao, M
Bioengineered. 2021;(1):4887-4898
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Abstract
Formononetin (FMNT), a flavonoid identified from the Chinese herb Astragalus membranaceus, possesses anti-inflammatory or anti-oxidative properties in different human diseases. This study aims to comprehensively elucidate the function of FMNT in atherosclerosis and its underlying mechanisms. Online public databases were used to identify the drug-disease targets. Protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were applied to explore the potential targets and signaling pathways involved in FMNT against atherosclerosis. Human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low-density lipoprotein (ox-LDL) to construct an atherosclerosis cell model in vitro. Endothelial cell function was assessed via examining cell proliferation, inflammatory factors, oxidative markers, reactive oxygen species (ROS), and apoptosis. Western blot was performed to detect the expression of cyclooxygenase-2 (COX-2), endothelial nitric oxide synthase (eNOS), cleaved caspase-3, and peroxisome proliferator-activated receptor-γ (PPAR-γ). A total of 39 overlapping target genes of FMNT and atherosclerosis were identified. Through the PPI network analysis, 14 hub genes were screened and found to be closely relevant to inflammation, oxidative stress, and apoptosis. Results of KEGG pathway assays indicated that lots of targets were enriched in PPAR signaling. Functionally, FMNT could protect against ox-LDL-induced inflammatory reaction, oxidative stress, and apoptosis in HUVECs. Moreover, FMNT attenuated ox-LDL-mediated inactivation of PPAR-γ signaling. GW9662, a PPAR-γ antagonist, reversed the inhibitory effect of FMNT on ox-LDL-induced endothelial injury. In conclusion, FMNT alleviates ox-LDL-induced endothelial injury in HUVECs by stimulating PPAR-γ signaling, providing a theoretical basis for employing FMNT as a potential drug to combat atherosclerosis.Abbreviations: FMNT formononetin; PPI: protein-protein interaction; GO: Gene Ontology; KEGG Kyoto Encyclopedia of Genes and Genomes; HUVECs: human umbilical vein endothelial cells; ox-LDL: oxidized low-density lipoprotein; COX-2: cyclooxygenase-2; eNOS: endothelial nitric oxide synthase; PPAR-γ: peroxisome proliferator-activated receptor-γ; CVD: cardiovascular disease; TCM: traditional Chinese medicines; OGDR oxygen-glucose deprivation/reoxygenation; ROS: reactive oxygen species; FBS: fetal bovine serum; CCK-8: cell counting kit-8; EdU: 5-Ethynyl-2'-deoxyuridine; SOD: antioxidant enzymes superoxide dismutase; MDA: malondialdehyde; DCFH-DA: 2',7'-dichlorofluorescein-diacetate; PVDF polyvinylidene fluoride; ANOVA one-way analysis of variance; PPARs: peroxisome proliferation-activated receptors.
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Diet and PPARG2 Pro12Ala Polymorphism Interactions in Relation to Cancer Risk: A Systematic Review.
Tran, L, Bobe, G, Arani, G, Zhang, Y, Zhang, Z, Shannon, J, Takata, Y
Nutrients. 2021;(1)
Abstract
Peroxisome proliferator-activated receptor-γ2 gene Pro12Ala allele polymorphism (PPARG2 Pro12Ala; rs1801282) has been linked to both cancer risk and dietary factors. We conducted the first systematic literature review of studies published before December 2020 using the PubMed database to summarize the current evidence on whether dietary factors for cancer may differ by individuals carrying C (common) and/or G (minor) alleles of the PPARG2 Pro12Ala allele polymorphism. The inclusion criteria were observational studies that investigated the association between food or nutrient consumption and risk of incident cancer stratified by PPARG2 Pro12Ala allele polymorphism. From 3815 identified abstracts, nine articles (18,268 participants and 4780 cancer cases) covering three cancer sites (i.e., colon/rectum, prostate, and breast) were included. CG/GG allele carriers were more impacted by dietary factors than CC allele carriers. High levels of protective factors (e.g., carotenoids and prudent dietary patterns) were associated with a lower cancer risk, and high levels of risk factors (e.g., alcohol and refined grains) were associated with a higher cancer risk. In contrast, both CG/GG and CC allele carriers were similarly impacted by dietary fats, well-known PPAR-γ agonists. These findings highlight the complex relation between PPARG2 Pro12Ala allele polymorphism, dietary factors, and cancer risk, which warrant further investigation.
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PPARγ-A Factor Linking Metabolically Unhealthy Obesity with Placental Pathologies.
Kwiatkowski, S, Kajdy, A, Stefańska, K, Bednarek-Jędrzejek, M, Dzidek, S, Tousty, P, Sokołowska, M, Kwiatkowska, E
International journal of molecular sciences. 2021;(23)
Abstract
Obesity is a known factor in the development of preeclampsia. This paper links adipose tissue pathologies with aberrant placental development and the resulting preeclampsia. PPARγ, a transcription factor from the ligand-activated nuclear hormone receptor family, appears to be one common aspect of both pathologies. It is the master regulator of adipogenesis in humans. At the same time, its aberrantly low activity has been observed in placental pathologies. Overweight and obesity are very serious health problems worldwide. They have negative effects on the overall mortality rate. Very importantly, they are also conducive to diseases linked to impaired placental development, including preeclampsia. More and more people in Europe are suffering from overweight (35.2%) and obesity (16%) (EUROSTAT 2021 data), some of them young women planning pregnancy. As a result, we will be increasingly encountering obese pregnant women with a considerable risk of placental development disorders, including preeclampsia. An appreciation of the mechanisms shared by these two conditions may assist in their prevention and treatment. Clearly, it should not be forgotten that health education concerning the need for a proper diet and physical activity is of utmost importance here.
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The Interplay of WNT and PPARγ Signaling in Vascular Calcification.
Reinhold, S, Blankesteijn, WM, Foulquier, S
Cells. 2020;(12)
Abstract
Vascular calcification (VC), the ectopic deposition of calcium phosphate crystals in the vessel wall, is one of the primary contributors to cardiovascular death. The pathology of VC is determined by vascular topography, pre-existing diseases, and our genetic heritage. VC evolves from inflammation, mediated by macrophages, and from the osteochondrogenic transition of vascular smooth muscle cells (VSMC) in the atherosclerotic plaque. This pathologic transition partly resembles endochondral ossification, involving the chronologically ordered activation of the β-catenin-independent and -dependent Wingless and Int-1 (WNT) pathways and the termination of peroxisome proliferator-activated receptor γ (PPARγ) signal transduction. Several atherosclerotic plaque studies confirmed the differential activity of PPARγ and the WNT signaling pathways in VC. Notably, the actively regulated β-catenin-dependent and -independent WNT signals increase the osteochondrogenic transformation of VSMC through the up-regulation of the osteochondrogenic transcription factors SRY-box transcription factor 9 (SOX9) and runt-related transcription factor 2 (RUNX2). In addition, we have reported studies showing that WNT signaling pathways may be antagonized by PPARγ activation via the expression of different families of WNT inhibitors and through its direct interaction with β-catenin. In this review, we summarize the existing knowledge on WNT and PPARγ signaling and their interplay during the osteochondrogenic differentiation of VSMC in VC. Finally, we discuss knowledge gaps on this interplay and its possible clinical impact.
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[Huangqin Qingre Chubi Capsules in improving oxidative stress of patients with ankylosing spondylitis via activating PPARγ mediated AMPK/FOXO3a pathway].
Huang, D, Liu, J, Zong, RK, Wan, L
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica. 2020;(2):451-456
Abstract
To investigate the efficacy of Huangqin Qingre Chubi Capsules(HQC) in patients with ankylosing spondylitis(AS) and its effect on oxidative stress, and to explore its possible mechanism. Fifty-eight cases of AS patients were randomly divided into HQC group and salazosulfapyridine(SASP) group. Another 30 healthy people were employed as a control group. Superoxide dismutase(SOD), total antioxidant capacity(TAOC), malondialdehyde(MDA), lipid peroxidatio(LPO), interleukin-1β(IL-1β), IL-10, IL-4, and tumor necrosis factor-α(TNF-α) were detected by ELISA. The mRNA expression levels of AMP-activated protein kinase(AMPK-α), forkhead box O3a(FOXO3a), manganese superoxide dismutase(MnSOD), and peroxisome proliferator-activated receptor gamma(PPARγ) were detected by Real-time fluorescence quantitative polymerase chain reaction(RT-qPCR). The protein expression levels of AMPK-α, FOXO3a, p-FOXO3a, MnSOD, and PPARγ were detected by Western blot. A questionnaire was used to evaluate the disease activity score and observe the clinical efficacy of HQC in AS patients. The levels of MDA, LPO, TNF-α, and IL-1β were significantly increased in the peripheral blood of AS patients, and SOD, TAOC, IL-4, IL-10 levels were significantly decreased. After HQC treatment, scores of disease active indexes were all decreased, and its clinical efficacy was significantly higher than that in SASP group. After HQC treatment, TAOC, SOD, IL-4, IL-10 were increased and MDA, LPO, TNF-α, IL-1β were decreased; mRNA levels of AMPK-α, FOXO3a, MnSOD, PPARγ and protein levels of AMPK-α, FOXO3a, p-FOXO3a, MnSOD, PPARγ were increased(P<0.01 or P<0.05). HQC can effectively improve the clinical symptoms and oxidative stress of AS patients, and its mechanism may be related to activating PPARγ and up-regulating AMPK/FOXO3a signal pathway.
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Associations between peroxisome proliferator-activated receptor γ (PPAR-γ) polymorphisms and serum lipids: Two cross-sectional studies of community-dwelling adults.
Matsunaga, T, Naito, M, Yin, G, Hishida, A, Okada, R, Kawai, S, Sasakabe, T, Kadomatsu, Y, Tsukamoto, M, Kubo, Y, et al
Gene. 2020;:145019
Abstract
Dyslipidemia is a well-established risk factor for cardiovascular disease. Experimental studies have reported that peroxisome proliferator-activated receptor γ (PPAR-γ) regulates adipocyte differentiation, lipid storage, and glucose metabolism. Therefore, we examined the associations between PPAR-γ polymorphisms (rs1801282, rs3856806, rs12497191, rs1151999, and rs1152003) and serum lipids in two cross-sectional studies. In the Shizuoka area of the Japan Multi-Institutional Collaborative Cohort Study, we examined 4,952 participants (3,356 men and 1,596 women) in a baseline survey and 2,245 participants (1,550 men and 695 women) in a second survey 5 years later. Outcome measures were the prevalence of dyslipidemia (low-density lipoprotein-cholesterol [LDL-C] ≥ 140 mg/dl, high-density lipoprotein-cholesterol < 40 mg/dl, triglycerides ≥ 150 mg/dl, and/or use of cholesterol-lowering drugs) and the prevalence of high LDL-C (LDL-C ≥ 140 mg/dl and/or use of cholesterol-lowering drugs). Multivariate odds ratios (ORs) were estimated by using unconditional logistic regression models. A total of 2,114 and 1,431 individuals (42.7% and 28.9%) had dyslipidemia and high LDL-C in the baseline survey, respectively, as did 933 and 716 (41.6% and 31.9%), respectively, in the second survey. In the baseline study, compared with major allele homozygotes, minor allele homozygotes of rs3856806 and rs12497191 had a 42% (OR, 0.58; 95% confidence interval (CI), 0.39-0.85) and 23% (OR, 0.77; 95% CI, 0.60-0.99) lower risk of dyslipidemia, respectively, after adjustment for potential confounding factors. In addition, minor allele homozygotes of rs3856806 had a 45% (OR, 0.55; 95% CI, 0.35-0.86) lower risk of high LDL-C. Similar risk reductions were found in the second survey. In conclusion, rs3856806 and rs12497191 polymorphisms may be related to a lower risk of dyslipidemia and high LDL-C.
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The Oxidation of Phytocannabinoids to Cannabinoquinoids.
Caprioglio, D, Mattoteia, D, Pollastro, F, Negri, R, Lopatriello, A, Chianese, G, Minassi, A, Collado, JA, Munoz, E, Taglialatela-Scafati, O, et al
Journal of natural products. 2020;(5):1711-1715
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Abstract
Spurred by a growing interest in cannabidiolquinone (CBDQ, HU-313, 2) as a degradation marker and alledged hepatotoxic metabolite of cannabidiol (CBD, 1), we performed a systematic study on the oxidation of CBD (1) to CBDQ (2) under a variety of experimental conditions (base-catalyzed aerobic oxidation, oxidation with metals, oxidation with hypervalent iodine reagents). The best results in terms of reproducibility and scalability were obtained with λ5-periodinanes (Dess-Martin periodinane, 1-hydroxy-1λ5,2-benziodoxole-1,3-dione (IBX), and SIBX, a stabilized, nonexplosive version of IBX). With these reagents, the oxidative dimerization that plagues the reaction under basic aerobic conditions was completely suppressed. A different reaction course was observed with the copper(II) chloride-hydroxylamine complex (Takehira reagent), which afforded a mixture of the hydroxyiminodienone 11 and the halogenated resorcinol 12. The λ5-periodinane oxidation was general for phytocannabinoids, turning cannabigerol (CBG, 18), cannabichromene (CBC, 10), and cannabinol (CBN, 19) into their corresponding hydroxyquinones (20, 21, and 22, respectively). All cannabinoquinoids modulated to a various extent peroxisome proliferator-activated receptor gamma (PPAR-γ) activity, outperforming their parent resorcinols in terms of potency, but the iminoquinone 11, the quinone dimers 3 and 23, and the haloresorcinol 12 were inactive, suggesting a specific role for the monomeric hydroxyquinone moiety in the interaction with PPAR-γ.