Peroxisome proliferator-activated receptor-γ (PPARγ) plays a protective role against brain injury after stroke in mice. However, the relationship between PPARγ gene polymorphisms and the functional outcome of acute ischemic stroke (AIS) remains unknown. 8822 patients from The Third China National Stroke Registry (CNSR-III) after whole-genome sequencing, two functional single nucleotide polymorphisms(SNPs) in PPARγ, rs1801282 C > G and rs3856806 C > T, were further analysed. The primary outcome was neurological functional disability at three months. Of the 8822 patients, 968 (11.0%) and 3497 (39.6%) were carriers of rs1801282 and rs3856806, respectively. Carriers of rs3856806 showed reduced risks for three-month neurological functional disability (OR, 0.84; 95% CI, 0.73-0.98; p = 0.02) and reduced risks for higher infarct volume (OR 0.90, 95% CI, 0.81-0.99, p = 0.04). They also had a reduced risk of neurological functional disability only in case of lower baseline IL-6 levels (OR 0.64, 95% CI 0.48-0.84, Pinteraction = 0.01). Carriers of rs1801282 had a reduced risk for three-month neurological functional disability (OR 0.77, 95% CI, 0.61-0.99, p = 0.04). Our study suggested that PPARγ polymorphisms are associated with a reduced risk for neurological functional disability and higher infarct volume in AIS. Therefore, PPARγ can be a potential therapeutic target in AIS.

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.

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.

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.

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.

https://www.crd.york.ac.uk/prospero/, identifier [CRD42022319347].

Published researches have suggested some associations between PPAR-γ and ischemic stroke (IS) development. This meta-analysis was conducted to evaluate the association between PPAR-γ gene polymorphisms and IS risk.

A systematic search was conducted in PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and WanFang databases. The pooled association of odd ratios (ORs) and its 95% confidence interval (CI) was calculated to assess the IS risk of PPAR-γ rs1801282 C/G and rs3856806 C/T polymorphisms. Furthermore, the heterogeneity test, cumulative analyses, sensitivity analyses, and publication bias were conducted.

Sixteen publications with 3786 cases and 5343 controls were identified. Overall findings indicated that rs1801282 C/G polymorphism may be associated with an increased risk for IS (GG vs. CC: OR = 2.17 95%CI = 1.09-4.35, p = .03, I²  = 0%; GG vs. CC+CG: OR = 2.15, 95%CI = 1.07-4.32, p = .03, I²  = 0%). The similar results were also found in the subgroup analysis. In addition, no significant association was observed between rs3856806 C/T polymorphism and IS risk.

In conclusion, our study showed that PPAR-γ rs1801282 C/G polymorphism probably plays an important role in IS occurrence. The result should be verified with more studies in the future.

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.

Role of peroxisome proliferator-activated receptors (PPARs) in the pathophysiology of stroke and protective effects of PPAR ligands have been widely investigated in the last 20 years. Activation of all three PPAR isoforms, but especially PPAR-γ, was documented to limit postischemic injury in the numerous in vivo, as well as in in vitro studies. PPARs have been demonstrated to act on multiple mechanisms and were shown to activate multiple protective pathways related to inflammation, apoptosis, BBB protection, neurogenesis, and oxidative stress. The aim of this review was to summarize two decades of PPAR research in stroke with emphasis on in vivo animal studies. We focus on each PPAR receptor separately and detail their implication in stroke. This review also discusses recent clinical efforts in the field and the epidemiological data with regard to role of PPAR polymorphisms in susceptibility to stroke, and tries to draw conclusions and describe future perspectives.

Diabetic mellitus-induced erectile dysfunction (DMED) represents a significant complication associated with diabetes mellitus (DM) that greatly affects human life quality. Various reports have highlighted the involvement of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in the regulation of mitochondrial fatty acid oxidation, which has also been linked with DM. Through bioinformatics analysis, HMGCS2 was determined to be a novel target among DM patients suffering from erectile dysfunction (ED), and enriched in the Ras/ERK/PPAR signaling axis. Owing to the fact that the key mechanism HMGCS2 involved in DM remains largely unknown, we set out to investigate the role of the Ras/MAPK/PPARγ signaling axis and HMGCS2 in the corpus cavernosal endothelial cells (CCECs) of rats with DMED.

Firstly, bioinformatics analysis was used to screen out differentially expressed genes in DMED. Then, to investigate the influence of the Ras/MAPK/PPARγ signaling axis and HMGCS2 on DMED, a rat model of DMED was established and injected with Simvastatin and si-Hmgcs2. The individual expression patterns of Ras, MAPK, PPARγ and HMGCS2 were determined by RT-qPCR, immunohistochemistry and western blot analysis methods. Afterwards, to investigate the mechanism of Ras/MAPK/PPARγ signaling axis and HMGCS2, CCECs were isolated from DMED rats and transfected with agonists and inhibitors of the Ras/MAPK/PPARγ signaling axis and siRNA of HMGCS2, with their respective functions in apoptosis and impairment of CCECs evaluated using TUNEL staining and flow cytometry.

Microarray analysis and KEGG pathway enrichment analysis revealed that Ras/ERK/PPAR signaling axis mediated HMGCS2 in DMED. Among the DMED rats, the Ras/MAPK/PPAR signaling axis was also activated while the expression of HMGCS2 was upregulated. The activation of Ras was determined to be capable of upregulating ERK expression which resulted in the inhibition of the transcription of PPARγ and subsequent upregulation of HMGCS2 expression. The inhibited activation of the Ras/ERK/PPAR signaling axis and silencing HMGCS2 were observed to provide an alleviatory effect on the injury of DMED while acting to inhibit the apoptosis of CCECs.

Collectively, the key findings suggested that suppression of the Ras/MAPK/PPARγ signaling axis could downregulate expression of HMGCS2, so as to alleviate DMED. This study defines the potential treatment for DMED through inhibition of the Ras/MAPK/PPARγ signaling axis and silencing HMGCS2.

The serum level of osteoprotegerin (encoded by OPG or TNFRSF11B) was previously shown to be increased in patients with ischemic stroke. A single nucleotide polymorphism rs3134069 in the TNFRSF11B gene was previously associated with ischemic stroke in a population of diabetic patients in Italy. It remains to be determined whether rs3134069 is associated with ischemic stroke in the general population or populations without diabetes.

We genotyped rs3134069 and performed a case-control association study to test whether rs3134069 is associated with ischemic stroke in 2 independent Chinese Han populations, including a China-Central population with 1629 cases and 1504 controls and a China-Northern population with 1206 cases and 720 controls.

rs3134069 showed significant association with ischemic stroke in the China-Central population (P = 9.24 × 10^-3, odds ratio [OR] = 1.50). The association was replicated in the independent China-Northern population (P = 2.45 × 10^-4, OR = 1.53). The association became more significant in the combined population (P = 7.09 × 10^-6, OR = 1.41). The associations remained significant in the male population, female population, and population without type 2 diabetes. Our expression quantitative trait loci analysis found that the minor allele C of rs3134069 was significantly associated with a decreasedexpression level of TNFRSF11B (P = .002).

This study demonstrates that rs3134069 in TNFRSF11B increases risk of ischemic stroke by decreasing TNFRSF11B expression.

Peroxisome proliferator-activated receptor gamma (PPARG) is a transcription factor involved in atherosclerosis and related diseases. In this study, we aimed to investigate whether PPARG C161T was associated with lipid levels and large-artery atherosclerosis (LAA) ischemic stroke in a Han Chinese population in Guangdong province.

The genotype PPARG C161T in 149 LAA ischemic stroke patients and 125 healthy controls was examined by polymerase chain reaction-restriction fragment length polymorphism (RFLP) assay. Associations with LAA ischemic stroke were analyzed for PPARG C161T genotype, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), and a logistic regression analysis was performed to identify risk factors for LAA ischemic stroke.

The frequency of CC was higher than that of CT + TT and was significantly associated with LAA ischemic stroke. In both the LAA and control groups, TC and LDL-C levels were significantly higher in the CC type than the CT + TT, but TG and HDL-C levels were comparable. The only verified independent risk factors for LAA ischemic stroke were ischemic heart disease (OR: 2.784, 95% CI: 1.377-5.632; p = 0.004) and systolic blood pressure (OR: 1.014, 95% CI: 1.001-1.026; p = 0.029); the PPARG C161T allele was not independently associated with an increased risk of LAA ischemic stroke (OR = 0.697, 95% CI: 0.372-1.305; p = 0.260).

In this Han population, PPARG C161T CT/TT was associated with LAA ischemic stroke and lower levels of blood TC and LDL-C, but was not an independent risk factor for LAA ischemic stroke.