Peroxisome Proliferator-activated Receptor-γ2 Pro12Ala and C-689T Polymorphisms and Haplotypes Affect the Profiles of Coronary Heart Disease in Diabetic Chinese People

Objectives Peroxisome proliferator-activated receptor-γ2（PPARγ2） variant Pro12Ala was demonstrated with risk of coronary heart disease （CHD） and type 2 diabetes mellitus （T2DM）. Another variant C-689T in the promoter was reported with lower receptor activity but lack of reports on association between C-689T and CHD or T2DM. Methods A total of 351 subjects without CHD and T2DM （controls） and 125 patients with CHD and T2DM （cases） were enrolled in our case-control study. Polymerase chain reaction-restricted fragments length polymorphism （PCR-RFLP） was used to detect Pro12Ala and C-689T polymorphisms. And effects on CHD merged with T2DM of the two polymorphisms were analyzed in individual and haplotype analyses. Results In the study, Pro12Pro, Pro12Ala and Ala12Ala genotype frequencies were 92.9%, 6.8% and 0.3% in controls; 92.8%, 7.2% and 0.0% in cases respectively whilst CC, CT and TT genotype frequencies were 93.4%, 6.3% and 0.3% in controls; 92.8%, 7.2% and 0.0% in cases respectively. Pro12Ala and C-689T polymorphisms were in strong linkage disequilibrium （D＇=0.81, P=0.000） and the observed haplotype frequency of Pro-C, Pro-T, Ala-C and Ala-T was 0.957, 0.006, 0.008 and 0.028 respectively. No significant associations were detected between the two polymorphisms and CHD merged with T2DM in either individual or haplotype analyses. In subjects with obesity [body mass index （BMI）≥25 kg/m^2], we found that both Pro12Ala and C-689T polymorphisms were associated with BMI. In haplotype analyses, we found that Pro12Ala and C-689T haplotypes had associations with systolic blood pressure in total population, with BMI, waist circle and total cholesterol（TC） in obesity subgroup and with fasting blood glucose and TC in males. Conclusions PPARγ2 Pro12Ala and C-689T polymorphisms and haplotypes affect the profiles of CHD merged with T2DM in Chinese Han people.

Functional Variant of C-689T in the Peroxisome Proliferator-Activated Receptor-γ2 Promoter is Associated with Coronary Heart Disease in Chinese Nondiabetic Han People

Objective To investigate the association between the polymorphism of C-689T in the peroxisome proliferator-activated receptor-γ2 （PPARγ2） promoter and coronary heart disease （CHD）. Methods This case-controlled study was conducted in nondiabetic Chinese Han people, which enrolled 455 patients with CHD （cases） and 693 subjects without CHD （controls）. Data of clinical indexes were collected, including height, body weight, waist circumstance, systolic blood pressure （SBP）, diastolic blood pressure （DBP）, smoking, drinking, physical activity, as well as body mass index （BMI）. Fasting blood glucose （FBG）, plasma total cholesterol （TC） and triglyceride （TG） levels were measured. Polymerase chain reaction-restricted fragments length polymorphism （PCR-RFLP） was used to determine the PPARγ2 promoter C-689→T substitution. The genotype distribution of PPARγ2 promoter C-689T, allelic frequency, clinical indexes, and laboratorial measurements were compared between the two groups. The effect of genotype on the risk of CHD was assessed using univariate and multivariate regression model. Results The genotype frequencies of CC, CT and TT in PPARγ2 promoter C-689T were 89.7%, 9.9% and 0.4% in the case group, and 93.1%, 6.6% and 0.3% in the control group, respectively （CC vs. CT＋TT, χ^2= 6.243, P=0.041）. Carriers of -689T allele （n=95） had significantly higher TC level than non-carriers （n=1053） （5.12±1.26 vs. 4.76±1.22 mmol/L, P=0.001）. Male carriers of -689T allele （n=51） were significantly higher in waist circumference, body weight, TC and TG than male non-carriers （n=656） （all P〈0.05）. In subjects whose BMI was over 25 kg/m2, carriers of -689T allele （n=82） had significantly higher levels of waist circumference, BMI, SBP and TC than non-carriers （n=231） （all p〈0.05）. The -689T allele was an independent risk factor for CHD （OR=1.668, 95%CI： 1.031-2.705, P=0.037） after adjusting for age, gender, waist circumference, body weight, BMI, smoking, physical activities, SBP, DBP, FBG, TC and TG level. Conclusion These data support the hypothesis that the -689T allele is associated with an increased risk of CHD, in Chinese Han people and correlates significantly with the profiles of CHD-related risk factors.

Decreased hepatic peroxisome proliferator-activated receptor-γ contributes to increased sensitivity to endotoxin in obstructive jaundice

AIM: To investigate the role of hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) in increased susceptibility to endotoxin-induced toxicity in rats with bile duct ligation during endotoxemia.METHODS: Male Sprague-Dawley rats were subjected to bile duct ligation (BDL). Sham-operated animals served as controls. DNA binding were determined by polymerase chain reaction, Western blotting analysis,and electrophoretic mobility shift assay, respectively.BDL and sham-operated rats received a non-lethal dose of intraperitoneal lipopolysaccharide (LPS) injection (3 mg/kg, i.p.). Additionally, the potential beneficial effects of the PPAR-γ agonist rosiglitazone were determined in BDL and sham-operated rats treated with a non-lethal dose of LPS. Survival was assessed in BDL rats treated with a non-lethal dose of LPS and in sham-operatedrats treated at a lethal dose of LPS (6 mg/kg, i.p.).RESULTS: PPAR-γ activity in rats undergoing BDL wassignificantly lower than in the sham-controls. Hepatic PPAR-γ gene expression was downregulated at both them RNA and protein levels. In a parallel group, serumlevels of pro-inflammatory cytokines were nearly unde-tectable in the sham-operated rats. When challenged with a non-lethal dose of LPS (3 mg/kg), the BDL ratshad approximately a 2.4-fold increase in serum IL-6,a 2.7 fold increase in serum TNF-α, 2.2-fold increasein serum IL-1 and 4.2-fold increase in serum ALT. Thesurvival rate was significantly lower as compared with that in sham-operated group. Additionally, rosiglitazone significantly reduced the concentration of TNF-α, IL-1β, IL-6 and ALT in sham-operated rats, but not in BDL rats, in response to LPS (3 mg/kg). Also, the survival was improved by rosiglita zone in sham-operated rats challenged with a lethal dose of LPS, but not in BDL rats, even with a non-lethal dose of LPS (3 mg/kg).CONCLUSION: Obstructive jaundice downregulates hepatic PPAR-γ expression, which in turn may contributeto hypersensitivity towards endotoxin.

Peroxisome proliferator-activated receptor-γ 34C>G polymorphism and colorectal cancer risk: A meta-analysis

AIM: To investigate the association between peroxisome proliferator-activated receptor-γ (PPAR-γ ) gene polymorphism 34 C>G and colorectal cancer (CRC),a meta-analysis review was performed in this report.METHODS: A systematic literature search and selection of eligible relevant studies were carried out.Nine independent studies with a total number of 4533 cases and 6483 controls were included in the meta-analysis on the association between polymorphism 34 C>G and CRC.RESULTS: There was no evidence for the association between PPAR-γ 34 C>G and CRC if all of the subjects in the nine studies were included.However,CG + GG showed a marginally significant difference from CC (OR = 0.84,95% CI: 0.69-1.01,P = 0.07) in random-effect model.Stratified meta-analysis indicated that PPAR-γ 34 C>G was associated with colon cancer (OR = 0.8,95% CI: 0.65-0.99,P = 0.04) in random-effect model,and the G allele decreased colon cancer risk.No significant association was observed between PPAR-γ 34 C>G and rectal cancer.CONCLUSION: PPAR-γ 34 C>G is associated with colon cancer risk,but not associated with CRC and rectal cancer risk.

Peroxisome proliferator-activated receptor gamma as a therapeutic target for hepatocellular carcinoma:Experimental and clinical scenarios

Hepatocellular carcinoma(HCC)is the most common type of liver cancer worldwide.Viral hepatitis is a significant risk factor for HCC,although metabolic syndrome and diabetes are more frequently associated with the HCC.With increasing prevalence,there is expected to be>1 million cases annually by 2025.Therefore,there is an urgent need to establish potential therapeutic targets to cure this disease.Peroxisome-proliferator-activated receptor gamma(PPARγ)is a ligand-activated transcription factor that plays a crucial role in the pathophysiology of HCC.Many synthetic agonists of PPARγsuppress HCC in experimental studies and clinical trials.These synthetic agonists have shown promising results by inducing cell cycle arrest and apoptosis in HCC cells and preventing the invasion and metastasis of HCC.However,some synthetic agonists also pose severe side effects in addition to their therapeutic efficacy.Thus natural PPARγagonists can be an alternative to exploit this potential target for HCC treatment.In this review,the regulatory role of PPARγin the pathogenesis of HCC is elucidated.Furthermore,the experimental and clinical scenario of both synthetic and natural PPARγagonists against HCC is discussed.Most of the available literature advocates PPARγas a potential therapeutic target for the treatment of HCC.

An innovative approach for the treatment of Alzheimer's disease: the role of peroxisome proliferator-activated receptors and their ligands in development of alternative therapeutic interventions

Alzheimer＇s disease is a multifactorial pathology, for which no cure is currently available. Nowadays, researchers are moving towards a new hypothesis of the onset of the illness, linking it to a metabolic impairment, q-his innovative approach will lead to the identification of new targets for the preparation of new effective drugs. Peroxisome proliferator-activated receptors and their ligands are the ideal candidates to reach the necessary breakthrough to defeat this complicate disease.

Differential Mechanisms of the Effect of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Bleomycin-Induced Lung Fibrosis

Background and Objectives: Peroxisome proliferator-activated receptor-g (PPAR-g) is a nuclear receptor whose activation regulates inflammation and fibrosis in various organs. We aimed to investigate the effect of two PPAR-g ligands, telmisartan and rosiglitazone, on lung injury and fibrosis induced by intratracheal bleomycin (BLM). Methods: Lung injury and fibrosis was induced in female C57Bl/6 mice by intratracheal instillation of 1.0 mg/kg of BLM. Some of the animals received rosiglitazone intraperitoneally or telmisartan in drinking water. Bronchoalveolar lavage (BAL) was performed 2, 7, 14 or 21 days after BLM instillation for cell counting and measurement of mediators in the lung. In a separate series, the lungs were sampled for collagen assay and histopathological evaluation. Results: Treatment with rosiglitazone or telmisartan significantly attenuated the BLM-induced increases in lung collagen content, pathological score, and inflammatory cells in BAL fluid. Rosiglitazone significantly suppressed BLM-induced elevation of TGF-b1, MCP-1, and IL-6 levels in the lung. In contrast, telmisartan made no changes in these cytokines, whereas it mitigated the BLM-induced increase in prostaglandin F2a in the lung. Higher concentrations of rosiglitazone and telmisartan attenuated proliferation of lung fibroblasts in vitro. Conclusions: Two PPAR-g ligands, rosiglitazone and telmisartan, exert protective effects on BLM-induced lung fibrosis through the suppression of different profibrotic mediators.

Potential effects of curcumin on peroxisome proliferatoractivated receptor-γ in vitro and in vivo

Natural peroxisome proliferator-activated receptor-γ(PPAR-γ) agonists are found in food and may be important for health through their anti-inflammatory properties. Curcumin(Cur) is a bright yellow spice, derived from the rhizome of Curcuma longa Linn. It has been shown to have many biological properties that appear to operate through diverse mechanisms. Some of these potentially beneficial effects of Cur are due to activation of the nuclear transcription factor PPAR-γ. It is reported(using in vitro and in vivo models) that Cur plays a potential role against several diseases. In this review article, we present the current literature on the effects of Cur on the modulation of inflammatory processes that are mediated through PPAR-γ.

High density lipoprotein suppresses lipoprotein associated phospholipase A2 in human monocytes-derived macrophages through peroxisome proliferator-activated receptor-γ pathway

Background Lipoprotein-associated phospholipase A2 （Lp-PLA2） is mainly secreted by macrophages, serving as a specific marker of atherosclerotic plaque and exerting pro-atherogenic effects. It is known that high-density lipoprotein （HDL） plays an important role against atherosclerosis by inhibiting pro-inflammatory factors, however, the relationship between HDL and Lp-PLA2 remains elusive. Methods In this study, reverse transcription-polymerase chain reaction （RT-PCR）, Western blotting, and a platelet-activating factor （PAF） acetylhydrolase assay were performed to determine the Lp-PLA2 mRNA level, protein expression and activity in human monocyte-derived macrophages upon HDL treatment of different concentrations and durations. To investigate the underlying mechanism of HDL-induced Lp-PLA2 action, pioglitazone, a peroxisome proliferator-activated receptor-γ （PPARy） ligand, was introduced to human monocyte-derived macrophages and mRNA and protein levels of Lp-PLA2, as well as its activity, were determined. Results Lp-PLA2 mRNA levels, protein expression and activity were significantly inhibited in response to HDL treatment in a dose and time dependent manner in human monocyte-derived macrophages. Pioglitazone treatment （1-10 ng/ml） upregulated the Lp-PLA2 mRNA level, protein expression and activity in human monocyte-derived macrophages, while the effects were markedly reversed by HDL. In addition, pioglitazone resulted in a significant increase in PPARy phosphorylation in human monocyte-derived macrophages, which could be inhibited by HDL. Conclusion These findings indicate that HDL suppresses the expression and activity of Lp-PLA2 in human monocyte-derived macrophages, and the underlying mechanisms may be mediated through the PPARγ pathway.

Association between peroxisome proliferator-activated receptor-γ coactivator-1α gene polymorphisms and type 2 diabetes in southern Chinese population:role of altered interaction with myocyte enhancer factor 2C

Background Some single nucleotide polymorphisms （SNPs） in the peroxisome proliferator-activated receptor-y coactivator （PGC）-1α gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1α and type 2 diabetes in the southern Chinese population and to determine whether the common variants： Gly482Ser and Thr394Thr, in the PGC-1α gene have any impacts on interaction with myocyte enhancer factor （MEF） 2C. Methods The SNPs in all exons of the PGC-1α gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism （PCR-SSCP） and direct sequencing. Thereafter, 263 type 2 diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP）. A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1α gene alter the interaction with MEF2C. Results Three frequent SNPs （Thr394Thr, Gly482Ser and Thr528Thr） were found in exons of the PGC-1α gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls （40.1% vs 29.3%, P〈0.01）. Even in controls, the 482Ser（A） carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly（G） carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr （A） had a synergic effect on the interaction between 482Ser variant and MEF2C. Conclusions The results suggested that the 482Ser variant of PGC-1α conferred the susceptibility to type 2 diabetes in the southern Chinese population. The underlying mechanism may be attributable, at least in part, to the altered interaction between the different variants （Gly482Ser, Thr394Thr） in the PGC-1α gene and MEF2C.

Construction and identification of the recombinant adenovirus vector carrying a small interfering RNA targeting the peroxisome proliferator-activated receptor-γ

Background Steroid-induced osteonecrosis of the femoral head （ONFH） is a common clinical disease,with a high disability rate.At present,efficient prevention and treatment of steroid-induced ONFH is still lacking.The peroxisome proliferator-activated receptor-γ （PPARγ） is recognized as an important pathogenic gene for the development of steroid-induced ONFH.RNA interference （RNAi） is a tool for functional gene analysis,which has been successfully used to down-regulate the levels of specific target proteins.Therefore,down-regulation of PPARγ expression by RNAi may prevent the incidence of steroid-induced ONFH.Methods According to the principles of siRNA design,three duplex siRNA sequences （971-989,1253-1271 and 1367-1385） derived from the PPARy gene （NM_001082148） were synthesized.These duplexes were annealed,purified and ligated into 1.0-cytomegalovirus （CMV） shuttle vector.The shuttle vector was transfected into HEK293 cells.The HEK293 generated recombinant adenovirus vector carrying PPARγ siRNA sequences was purified and the titer of recombinant adenovirus was determined.Results After the annealing of single-strand DNA oligo encoding short hairpin RNA （shRNA） sequences,products were identified by gel electrophoresis.These products were ligated into the 1.0-CMV shuttle vector and the recombinant shuttle vectors 1.0-CMV-971,1.0-CMV-1253 and 1.0-CMV-1367 were constructed.These sequences of these recombinant vectors were confirmed.We then successfully constructed the recombinant adenovirus vector carrying siRNA targeting PPARγ.After purification,the virus titer was higher than 1010 plaque forming unit （PFU）/ml.Conclusion In this study,three recombinant adenovirus shuttle vectors carrying siRNA targeting PPARγ,including shuttle vectors 1.0-CMV-971,1.0-CMV-1253 and 1.0-CMV-1367,were successfully constructed and high titers of recombinant adenovirus were obtained.

Expression of peroxisome proliferator-activated receptor γ,E-cadherin and matrix metalloproteinases-2 in gastric carcinoma and lymph node metastases

Background Peroxisome proliferator activated receptor γ （PPARγ） is a ligand-activated transcription factor. Activation of PPARγ has recently been demonstrated to inhibit various tumor cells growth, progression and metastasis. E-cadherin-mediated cell adhesion system is now considered to be an “invasion suppressor system” in cancer tissues. Matrix metalloproteinases-2 （MMP-2） is a prerequisite for metastasizing tumor cells. However their correlation is still unknown in gastric carcinoma. The aim of this study was to assess the expression of PPAR7, E-cadherin, MMP-2 and their correlation in gastric carcinoma and metastases. Methods Gastric carcinoma tissues and their corresponding lymph nodes with metastases and the adjacent non-tumor tissues were obtained from 54 patients with gastric cancer who underwent gastrectomy. Expression of PPARγ, E-cadherin and MMP-2 was assessed by immunohistochemical staining. Results The nuclear expression level of PPARγ in neoplastic cells was significantly lower than that in the normal controls （P〈0.001）, with the expression of PPARγ being weaker in primary tumors compared with that in metastases. In all neoplastic cells, E-cadherin was expressed with abnormal patterns （cytoplasm pattern, cytoplasm and membrane pattern or absent）, compared with normal cells where E-cadherin was expressed with a normal pattern （membrane pattern）. Compared with the normal tissues, the expression level of E-cadherin decreased in primary tumors and further decreased in metastases （P〈0.001）. Membrane staining of MMP-2 was detected in the foveolar epithelia of normal gastric mucosa, whereas predominant cytoplasm staining of MMP-2 was found in malignant tissues. The expression of MMP-2 was stronger in metastatic tissues than in primary tumors. In neoplastic foci the expression of PPARγ was negatively correlated with MMP-2 expression （P〈0.05）. However, there was no correlation between E-cadherin and PPARγ or MM P-2 expression. Conclusions Down-regulation of PPARγ and E-cadherin and up-regulation of MMP-2 in neoplastic foci might be helpful to gastric carcinogenesis and metastases. An inverse relationship between PPARγ and MMP-2 in human gastric carcinoma suggests that PPARγ might modulate MMP-2 expression and affect gastric cancer metastases.

Inhibition of peroxisome proliferator-activated receptor-γ in steroid-induced adipogenic differentiation of the bone marrow mesenchymal stem cells of rabbit using small interference RNA

Background Steroids inhibit osteogenic differentiation and decrease bone formation while concomitantly inducing adipose deposition in osteocytes.This leads to the fatty degeneration and necrosis of bone cells commonly seen in osteonecrosis of the femoral head.The peroxisome proliferator-activated receptor-γ （PPARγ） is an adipogenic transcription factor linked to the development of this disease and responsible for inducing adipogenesis over osteogenesis in bone marrow mesenchymal stem cells （BMSCs）.The aim of this study was to assess whether adipogenic differentiation could be suppressed,and thus osteogenic potential retained,by inhibiting PPARy expression in BMSCs.Methods Cells from the bone marrow of New Zealand rabbits were treated with 10-7 mol/L dexamethasone and infected with one of three small interference RNA （siRNA） adenovirus vectors （S1,S2,and S3） or non-targeting control siRNA （Con） and compared with dexamethasone-treated （model） and untreated （normal） cells.Cells were grown for 21 days and stained with Sudan Ⅲ for adipocyte formation.At various time points,cells were also assessed for changes in PPARγ,osteocalcin （OC）,Runx2,alkaline phosphatase （ALP） activity,and triglyceride （TG） content.Results Dexamethasone-treated model and control groups showed a significant increase in fatty acid-positive staining,which was inhibited in cells treated with PPARγ siRNA-treated,similar to normal untreated cells.All three siRNA groups significantly inhibited PPARγ mRNA and protein,adipocyte number,and TG content compared with the dexamethasonetreated model and control groups,matching that seen in normal cells.OC and Runx2 mRNA and protein,as well as ALP activity,were significantly higher in cells treated with siRNA against PPARγ,similar to that seen in the normal cells.These osteogenic markers were significantly lower in the dexamethasone-treated cell cultures.Conclusions The siRNA adenovirus vector targeting PPARγ can efficiently inhibit steroid-induced adipogenic differentiation in rabbit BMSCs and retain their osteogenic differentiation potential.

Conjugated linoleic acid isomers and their precursor fatty acids regulate peroxisome proliferator-activated receptor subtypes and major peroxisome proliferator responsive element-bearing target genes in HepG2 cell model

The purpose of this study was to examine the induction profiles （as judged by quantitative reverse tran- scription polymerase chain reaction （qRT-PCR）） of peroxisome proliferator-activated receptor （PPAR） α,β, y subtypes and major PPAR-target genes bearing a functional peroxisome proliferator responsive element （PPRE） in HepG2 cell model upon feeding with cis-9,trans-11-octadecadienoic acid （9-CLA） or trans-10,cis-12-octadecadienoic acid （10-CLA） or their precursor fatty acids （FAs）. HepG2 cells were treated with 100 pmol/L 9-CLA or 10-CLA or their precursor FAs, viz., oleic, linoleic, and trans-11-vaccenic acids against bezafibrate control to evaluate the induc- tion/expression profiles of PPAR （α, β, γ subtypes and major PPAR-target genes bearing a functional PPRE, i.e., fatty acid transporter （FAT）, glucose transporter-2 （GLUT-2）, liver-type FA binding protein （L-FABP）, acyl CoA oxidase-1 （ACOX-1）, and peroxisomal bifunctional enzyme （PBE） with reference to β-actin as house keeping gene. Of the three housekeeping genes （glyceraldehyde 3-phosphate dehydrogenase （GAPDH）, β-actin, and ubiquitin）, β-actin was found to be stable. Dimethyl sulfoxide （DMSO）, the common solubilizer of agonists, showed a significantly higher induction of genes analyzed, qRT-PCR profiles of CLAs and their precursor FAs clearly showed upregulation of FAT, GLUT-2, and L-FABP （-0.5-.0-fold）. Compared to 10-CLA, 9-CLA decreased the induction of the FA metabolizing gene ACOX-1 less than did PBE, while 10-CLA decreased the induction of PBE less than did ACOX-I. Both CLAs and precursor FAs upregulated PPRE-beadng genes, but with comparatively less or marginal activation of PPAR subtypes This indicates that the binding of CLAs and their precursor FAs to PPAR subtypes results in PPAR activation, thereby induction of the target transporter genes coupled with downstream lipid metabolising genes such as ACOX-1 and PBE. To sum up, the expression profiles of these candidate genes showed that CLAs and their precursor FAs are involved in lipid signalling by modulating the PPAR a, 13, or ~ subtype for the indirect activation of the PPAR-target genes, which may in turn be responsible for the supposed health effects of CLA, and that care should be taken while calculating the actual fold induction values of candidate genes with reference to housekeeping gene and DMSO as they may impart false positive results.

Electroacupuncture alleviates diabetic peripheral neuropathy through modulating mitochondrial biogenesis and suppressing oxidative stress

BACKGROUND Peripheral neuropathy caused by diabetes is closely related to the vicious cycle of oxidative stress and mitochondrial dysfunction resulting from metabolic abnormalities.The effects mediated by the silent information regulator type 2 homolog-1(SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α(PGC-1α)axis present new opportunities for the treatment of type 2 diabetic peripheral neuropathy(T2DPN),potentially breaking this harmful cycle.AIM To validate the effectiveness of electroacupuncture(EA)in the treatment of T2DPN and investigate its potential mechanism based on the SIRT1/PGC-1αaxis.METHODS The effects of EA were evaluated through assessments of metabolic changes,morphological observations,and functional examinations of the sciatic nerve,along with measurements of inflammation and oxidative stress.Proteins related to the SIRT1/PGC-1αaxis,involved in the regulation of mitochondrial biogenesis and antioxidative stress,were detected in the sciatic nerve using Western blotting to explain the underlying mechanism.A counterevidence group was created by injecting a SIRT1 inhibitor during EA intervention to support the hypothesis.RESULTS In addition to diabetes-related metabolic changes,T2DPN rats showed significant reductions in pain threshold after 9 weeks,suggesting abnormal peripheral nerve function.EA treatment partially restored metabolic control and reduced nerve damage in T2DPN rats.The SIRT1/PGC-1αaxis,which was downregulated in the model group,was upregulated by EA intervention.The endogenous antioxidant system related to the SIRT1/PGC-1αaxis,previously inhibited in diabetic rats,was reactivated.A similar trend was observed in inflammatory markers.When SIRT1 was inhibited in diabetic rats,these beneficial effects were abolished.CONCLUSION EA can alleviate the symptoms of T2DNP in experimental rats,and its effects may be related to the mitochondrial biogenesis and endogenous antioxidant system mediated by the SIRT1/PGC-1αaxis.

Advances in Studies of Chiglitazar Sodium,a Novel PPAR Pan-Agonist,for the Treatment of Type 2 Diabetes Mellitus

Chiglitazar sodium is a new peroxisome proliferator-activated receptor(PPAR)pan-agonist with independent intellectual property rights in China.It can treat type 2 diabetes mellitus and regulate metabolism by modestly activating PPARα,PPARγ,and PPARδto improve insulin sensitivity,regulate blood glucose,and promote fatty acid oxidation and utilization.Chiglitazar sodium has a significant insulin-sensitizing effect and is advantageous in reducing fasting and postprandial blood glucose levels,particularly at the 48 mg dose in patients with concomitant high triglycerides in terms of blood glucose and triglyceride level control.

Tagging single nucleotide polymorphisms in the PPAR-γ and RXR-α gene and type 2 diabetes risk:a case-control study of a Chinese Han population

Peroxisome proliferator-activated receptor （PPAR-γ）,which is mainly involved in adipocyte differentiation, has been suggested to play an important role in the pathogenesis of insulin resistance and atherosclerosis. We investigated the frequencies of two common tagging polymorphisms of the PPAR-γ gene and two of PPAR-α with minor allele frequency （MAF）≥ 0.05 in the Chinese Han population and analyzed the correlation between the different genotypes and the risk of type 2 diabetes mellitus （T2DM）. TaqMan assay was performed to test the genotypes in T2DM patients （n = 1,105） and normal controls （n = 1,107）. Serum adiponectin concentration was measured by ELISA kit. The variant genotypes rs17817276GG, rs3856806CT and rs3856806CT/TT of PPAR-γ were associated with T2DM, P = 0.023,0.037 and 0.018, respectively. Furthermore, the prevalence of haplotype GT in PPAR-γ was less frequent in the case subjects （0.3%） than in the controls （1.9%） [P 0.001,OR（95%CI）=0.13 （0.06-0.31）]. Patients with genotype TT of rs3856806 had a higher serum level of adiponectin than those with the genotype CC and CT （P = 0.031 and 0.038, respectively）. There was no statistically significant difference between patients and controls in genotype distribution of rs6537944 and rs1045570 of the RXR-α gene. The present study suggests that the variant genotypes in the PPAR-γ gene could decrease the risk for the development of T2DM in the Chinese Han population.

Activating PPARy Increases NQO1 and γ-GCS Expression via Nrf2 in Thrombin-activated Microglia

The present study aimed to explore the molecular mechanisms underlying the increase of nicotinamide adenine dinucleotide phosphate:quinine oxidoreductase 1(NQO1)and y-glutamylcysteine synthetase(γ-GCS)in brain tissues after intracerebral hemorrhage(ICH).The microglial cells obtained from newborn rats were cultured and then randomly divided into the normal control group(NC group),model control group(MC group),rosiglitazone(RSG)intervention group(RSG group),retinoic-acid intervention group(RSG+RA group),and sulfbraphane group(RSG+SF group).The expression levels of NQO1,γ-GCS,and nuclear factor E2-related factor 2(Nrf2)were measured by real-time polymerase chain reaction(RT-PCR)and Western blotting,respectively.The results showed that the levels of NQO1,γ-GCS and Nrf2 were significantly increased in the MC group and the RSG group as compared with those in the NC group(P<0.01).They were found to be markedly decreased in the RSG+RA group and increased in the RSG+SF group when compared with those in the MC group or the RSG group(P<0.01).The RSG+SF group displayed the highest levels of NQO1,γ-GCS,and Nrf2 among the five groups.In conclusion,a medium dose of RSG increased the anti-oxidative ability of thrombinactivated microglia by increasing the expression of NQO1 and γ-GCS.The molecular mechanisms underlying the increase of NQO1 and γ-GCS in thrombin-activated microglia may be associated with the activation of Nrf2.

The Influence of the Pro12Ala Mutation of PPARγ2 Receptor Gene on β-cells Restoration and Insulin Resistance in Type 2 Diabetes with Hypertension

The aim of this investigation was to determine whether a PPAR72 Prol2Ala polymorphism was associated with insulin resistance, β-cellfunction and hypertension in Chinese populations. 289 unrelated Chinese subjects first diagnosed Type 2 diabetes （HbAC1〈6.0） were investigated, including 132 hypertensive diabetic （HTD） subjects, 157 normotensive diabetic （NTD） subjects. Blood pressure and anthropometric measurements were collected from all participants, as well as several venous blood samples during oral glucose tolerance test （OGTT）. Biochemical measurements （high-density lipoprotein （HDL） and low-density lipoprotein-cholesterol （LDL）, triglycerides） and PPARγ2 Pro12Ala genotype were also determined. And insulin resistance and β-cells function was assessed by HOMA-IR and HOMA-β respectively. The frequency of subjects bearing the Pro12Ala was lower in the hypertension group （3. 03 %） than in the non-hypertension group （5.7 %） （P〈0.05） after adjusted for age, BMI and gender. Hypertensive diabetic Pro12Ala subjects had lower fasting plasma glucose level （P=0. 0127）, and better glucose tolerance 60 min after oral glucose （P=0. 0361）. Moreover, plasma insulin concentrations at 60 min was lower than those without A variant （P = 0. 0275）, and both hypertensive Ala/Pro in HOMA-β （P ： 0. 0455） and AUC for insulin （P=0. 0473） were higher, and HOMA-IR was lower （P=0. 0375） as compared with hypertensive Pro/Pro subjects. No association was observed between Prol2Ala genotype and BMI, total cholesterol, HDL- cholesterol or triglycerides in either group. Our findings suggested that the Ala 12 allele of the PPARγ2 gene may improve insulin resistance and ameliorate β-cell function reserves in T2DM with hypertension, and protect patients from hypertension in T2DM. As an important thrifty gene, environment factors may exerts an effect of PPARγ2 on glucose homeostasis and insulin resistance.

Mitofusin2 Decreases Intracellular Cholesterol of Oxidized LDL-Induced Foam Cells from Rat Vascular Smooth Muscle Cells

Mitofusin2 （Mfn2） plays a pivotal role in the proliferation and apoptosis of vascular smooth muscle cells （VSMCs）. The purpose of this study was to investigate the effects of Mfn2 on the traffick- ing of intracellular cholesterol in the foam ceils derived from rat VSMCs （rVSMCs） and also to investigate the effects of Mfn2 on the expression of adenosine triphosphate-binding cassette subfamily A member 1 （ABCA1）, adenosine triphosphate-binding cassette subfamily G member 1 （ABCG1） and peroxisome proliferator-activated receptor gamma （PPARy）. The rVSMCs were co-cultured with oxi- dized low density lipoprotein （LDL, 80 ~tg/mL） to produce foam cells and cholesterol accumulation in cells. Before oxidized LDL treatment, different titers （20, 40 and 60 pfu/cell） of recombinant adenovirus containing Mfn2 gene （Adv-Mfn2） were added into the culture medium for 24 h to transfect the Mfn2 gene into the rVSMCs. Then the cells were harvested for analyses. The protein expression of Mfn2 was significantly higher in Adv-Mfn2-transfected group than in untransfected group （P〈0.05）, and the ex- pression levels significantly increased when the titer of Adv-Mfn2 increased （P〈0.05）. At 24 or 48 h af- ter oxidized LDL treatment, rVSMCs became irregular and their nuclei became larger, and their plasma abounded with red lipid droplets. However, the number of red lipid droplets was significantly decreased in Adv-Mfn2-transfected group as compared with untransfected group. At 48 h after oxidized LDL treatment, the intracellular cholesterol in rVSMCs was significantly increased （P〈0.05）, but it was sig- nificantly decreased in Adv-Mfn2-transfected group as compared with untransfected group （P〈0.05）, and it also significantly decreased when the titer of Adv-Mfn2 increased （P〈0.05）. The mRNA and pro- tein expression levels of ABCA1 and ABCG1 were significantly increased in Adv-Mfn2-transfected group as compared with untransfected group （P〈0.05）. Though the mRNA and protein expression levels of PPARy was not significantly increased （P〉0.05）, the phosporylation levels of PPARy were signifi- cantly decreased in Adv-Mfn2-transfected group as compared with untransfected group （P〈0.05）. These results suggest that the transfection of Adv-Mfn2 can significantly reduce intracellular cholesterol in oxidized LDL-induced rVSMCs possibly by decreasing PPAR＇/phosporylation and then increasing pro- tein expression levels of ABCAI and ABCG1, which may be helpful to suppress the formation of foam cells.