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...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.展开更多
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 ...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.展开更多
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 fir...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.展开更多
Objective To explore Effects of marine collagen peptides （MCPs） on markers of metablic nuclear receptors, i.e peroxisome proliferator-activated receptor （PPARs）, liver X receptor （LXRs） and farnesoid X receptor ...Objective To explore Effects of marine collagen peptides （MCPs） on markers of metablic nuclear receptors, i.e peroxisome proliferator-activated receptor （PPARs）, liver X receptor （LXRs） and farnesoid X receptor （FXRs） in type 2 diabetic patients with/without hypertension. Method Study population consisted of 200 type 2 diabetic patients with/without hypertension and 50 healthy subjects, all of whom were randomly assigned to MCPs-treated diabetics （n=50）, placebo-treated diabetics （n=50）, MCPs-treated diabetics with hypertension （n=50）, placebo-treated diabetics with hypertension （n=50）, and healthy controls （n=50）. MCPs or placebo （water-soluble starch） were given daily before breakfast and bedtime over three months. Levels of free fatty acid, cytochrome P450, leptin, resistin, adiponectin, bradykinin, NO, and Prostacyclin were determined before intervention, and 1.5 months, and 3 months after intervention. Hypoglycemia and the endpoint events during the study were recorded and compared among the study groups. Result At the end of the study period, MCPs-treated patients showed marked improvement compared with patients receiving placebo. The protection exerted by MCPs seemed more profound in diabetics than in diabetics with hypertension. In particular, after MCPs intervention, levels of free fatty acid, hs-CRP, resistin, Prostacyclin decreased significantly in diabetics and tended to decrease in diabetic and hypertensive patients whereas levels of cytochrome P450, leptin, NO tended to decrease in diabetics with/without hypertension. Meanwhile, levels of adiponectin and bradykinin rose markedly in diabetics following MCPs administration. Conclusion MCPs could offer protection against diabetes and hypertension by affecting levels of molecules involved in diabetic and hypertensive pathogenesis. Regulation on metabolic nuclear receptors by MCPs may be the possible underlying mechanism for its observed effects in the study. Further study into its action may shed light on development of new drugs based on bioactive peptides from marine sources.展开更多
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 an...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.展开更多
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 tissue...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.展开更多
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 populatio...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.展开更多
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,...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.展开更多
Peroxisome proliferator-activated receptor gamma(PPARγor PPARG)is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily.It plays a master role in the differentiation and prolif...Peroxisome proliferator-activated receptor gamma(PPARγor PPARG)is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily.It plays a master role in the differentiation and proliferation of adipose tissues.It has two major isoforms,PPARγ1 and PPARγ2,encoded from a single gene using two separate promoters and alternative splicing.Among them,PPARγ2 is most abundantly expressed in adipocytes and plays major adipogenic and lipogenic roles in the tissue.Furthermore,it has been shown that PPARγ2 is also expressed in the liver,specifically in hepatocytes,and its expression level positively correlates with fat accumulation induced by pathological conditions such as obesity and diabetes.Knockout of the hepatic Pparg gene ameliorates hepatic steatosis induced by diet or genetic manipulations.Transcriptional activation of Pparg in the liver induces the adipogenic program to store fatty acids in lipid droplets as observed in adipocytes.Understanding how the hepatic Pparg gene expression is regulated will help develop preventative and therapeutic treatments for non-alcoholic fatty liver disease(NAFLD).Due to the potential adverse effect of hepatic Pparg gene deletion on peripheral tissue functions,therapeutic interventions that target PPAR g for fatty liver diseases require fine-tuning of this gene's expression and transcriptional activity。展开更多
Background:Liver regeneration is a fundamental process for sustained body homeostasis and liver function recovery after injury.Emerging evidence demonstrates that myeloid cells play a critical role in liver regenerati...Background:Liver regeneration is a fundamental process for sustained body homeostasis and liver function recovery after injury.Emerging evidence demonstrates that myeloid cells play a critical role in liver regeneration by secreting cytokines and growth factors.Peroxisome proliferator-activated receptorα(PPARα),the target of clinical lipid-lowering fibrate drugs,regulates cell metabolism,proliferation,and survival.However,the role of myeloid PPARαin partial hepatectomy(PHx)-induced liver regeneration remains unknown.Methods:Myeloid-specific PPARa-deficient(Ppara^(Mye−/−))mice and the littermate controls(Ppara^(fl/fl))were subjected to sham or 2/3 PHx to induce liver regeneration.Hepatocyte proliferation and mitosis were assessed by immunohistochemical(IHC)staining for 5-bromo-2'-deoxyuridine(BrdU)and Ki67 as well as hematoxylin and eosin(H&E)staining.Macrophage and neutrophil infiltration into livers were reflected by IHC staining for galectin-3 and myeloperoxidase(MPO)as well as flow cytometry analysis.Macrophage migration ability was evaluated by transwell assay.The mRNA levels for cell cycle or inflammation-related genes were measured by quantitative real-time RT-PCR(qPCR).The protein levels of cell proliferation related protein and phosphorylated signal transducer and activator of transcription 3(STAT3)were detected by Western blotting.Results:Ppara^(Mye−/−)mice showed enhanced hepatocyte proliferation and mitosis at 32 h after PHx compared with Ppara^(fl/fl)mice,which was consistent with increased proliferating cell nuclear antigen(Pcna)mRNA and cyclinD1(CYCD1)protein levels in Ppara^(Mye−/−)mice at 32 h after PHx,indicating an accelerated liver regeneration in Ppara^(Mye−/−)mice.IHC staining showed that macrophages and neutrophils were increased in Ppara^(Mye−/−)liver at 32 h after PHx.Livers of Ppara^(Mye−/−)mice also showed an enhanced infiltration of M1 macrophages at 32 h after PHx.In vitro,Ppara-deficient bone marrow-derived macrophages(BMDMs)exhibited markedly enhanced migratory capacity and upregulated M1 genes Il6 and Tnfa but downregulated M2 gene Arg1 expressions.Furthermore,the phosphorylation of STAT3,a key transcript factor mediating IL6-promoted hepatocyte survival and proliferation,was reinforced in the liver of Ppara^(Mye−/−)mice after PHx.Conclusions:This study provides evidence that myeloid PPARαdeficiency accelerates PHx-induced liver regeneration via macrophage polarization and consequent IL-6/STAT3 activation,thus providing a potential target for manipulating liver regeneration.展开更多
OBJECTIVE To investigate the anti-proliferative effect of rosiglitazone and its relationship to peroxisome proliferator-activated receptor γ （PPARγ） in human breast cancer cell line MDA-MB-231 and evaluate the pot...OBJECTIVE To investigate the anti-proliferative effect of rosiglitazone and its relationship to peroxisome proliferator-activated receptor γ （PPARγ） in human breast cancer cell line MDA-MB-231 and evaluate the potential application value of rosiglitazone for breast cancer therapy. METHODS The cytostatic effect of rosiglitazone on MDA- MB-231 cells was measured by the MTT assay. Cell-cycle kinetics was assessed by flow cytometry. Apoptotic cells were determined by the TUNEL assay. MDA-MB-231 cells were treated with rosiglitazone or in combination with the PPARy antagonist GW9662 to investigate the effect of rosiglitazone on cell proliferation and its relationship to PPARγ. RESULTS The results showed that rosiglitazone could inhibit growth of MDA-MB-231 cells in a dose- and time-dependent manner with an IC50 value of 5.2 μmol/L at 24 h after the drug was added into the culture. Cell cycle analysis showed that the percentage of G0/G1 phase cells increased, S phase cells decreased, and cells were arrested in G1 phase with increasing concentrations of rosiglitazone. Detectable signs of apoptotic cell death caused by rosiglitazone occurred at a concentration of 100 μmol/L and the apoptotic rate was （18 ± 3）%. PPARγ selective antagonist GW9662 could partially reverse the inhibitory effect of rosiglitazone on proliferation of MDA-MB-231 cells. CONCLUSION It was concluded that rosiglitazone can inhibit growth of MDA-MB-231 cells via PPARy activation and a high concentration of rosiglitazone can also induce MDA-MB-231 cell apoptosis. These results suggest that PPARy represents a putative molecular target for chemopreventive therapy and rosiglitazone may be effective in the treatment of breast cancer.展开更多
Objective:To investigate the peroxisome proliferator-activated receptor-γ (peroxisome)in patients with type 2 diabetes mellitus.Proliferators-activated receptors-γ ,PPARs-γ (γ )gene.polymorphisms about serum lipof...Objective:To investigate the peroxisome proliferator-activated receptor-γ (peroxisome)in patients with type 2 diabetes mellitus.Proliferators-activated receptors-γ ,PPARs-γ (γ )gene.polymorphisms about serum lipofuscin and leptin.Methods:One humdred and twenty patients with type 2 diabetes admitted to our hospital from June 2015 to June 2018 were selected.The patients were divided into an obese group and a non-obese group of 60 patients each according to their waist circumference.A polymerase chain reaction-length polymorphism protocol was implemented in all patients to explore the PPAR-γ gene polymorphism and blood glucose,lipid,adiponectin and leptin levels were measured in both groups.Results:PPAR-γ gene polymorphisms in type 2 diabetic patients were dominated by wild-type homozygous;The levels of total cholesterol,triglyceride and LDL cholesterol in the obese group were significantly higher than those in the non-obese group,while the levels of HDL cholesterol were lower than those in the non-obese group.There is significant difference in comparison between groups(P<0.05)Those canrying the A alele had a significant lipid disorder profile and decreased adiponectin levels.Conclusions:PPAR-γ gene polymorphisms in type 2 diabetes are not significantly associated with adiponectin and leptin,and only in the obese group,the patients with the Allele A showed significant dyslipidemia and a declining trend of adiponectin levels.展开更多
Nutrient metabolism is regulated by several factors.Social determinants of health with or without genetics are the primary regulator of metabolism,and an unhealthy lifestyle affects all modulators and mediators,leadin...Nutrient metabolism is regulated by several factors.Social determinants of health with or without genetics are the primary regulator of metabolism,and an unhealthy lifestyle affects all modulators and mediators,leading to the adaptation and finally to the exhaustion of cellular functions.Hepatic steatosis is defined by presence of fat in more than 5%of hepatocytes.In hepatocytes,fat is stored as triglycerides in lipid droplet.Hepatic steatosis results from a combination of multiple intracellular processes.In a healthy individual nutrient metabolism is regulated at several steps.It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component.Several hormones,peptides,and genes have been described that participate in nutrient metabolism.Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP.As of now several publications have revealed very intricate regulation of nutrient metabolism,where most of the regulatory factors are tied to each other bidirectionally,making it difficult to comprehend chronological sequence of events.Insulin hormone is the primary regulator of all nutrients’metabolism both in prandial and fasting states.Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes;metabolic,inflammation and repair,and cell growth and regeneration.Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands,adiponectin,leptin,and adiponutrin.Insulin hormone has direct effect on these final modulators.Whereas blood glucose level,serum lipids,incretin hormones,bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle.The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease(MASLD)that help us understand the disease natural course,risk stratification,role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine.PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states;MASLD,cardiovascular disease and cancer.More than 1000 publications including original research and review papers were reviewed.展开更多
基金supported by Intervento cofinanziato dal Fondo di Sviluppo e Coesione 2007-2013–APQ Ricerca Regione Puglia "Programma regionale a sostegno della specializzazione intelligente e della sostenibilitàsociale ed ambientale-FutureInResearch".Project ID:I2PCTF6
文摘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.
文摘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.
文摘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.
基金grants from the National Key Technology R&D Program (No. 2006BAD27B01)Chinese Center for Disease Control and Prevention Dalone Foundation of Dietary Nutrition (No. DIC-200710)a grant from Shenzhen Bureau of Science Technology & Information (No. 200802002)
文摘Objective To explore Effects of marine collagen peptides （MCPs） on markers of metablic nuclear receptors, i.e peroxisome proliferator-activated receptor （PPARs）, liver X receptor （LXRs） and farnesoid X receptor （FXRs） in type 2 diabetic patients with/without hypertension. Method Study population consisted of 200 type 2 diabetic patients with/without hypertension and 50 healthy subjects, all of whom were randomly assigned to MCPs-treated diabetics （n=50）, placebo-treated diabetics （n=50）, MCPs-treated diabetics with hypertension （n=50）, placebo-treated diabetics with hypertension （n=50）, and healthy controls （n=50）. MCPs or placebo （water-soluble starch） were given daily before breakfast and bedtime over three months. Levels of free fatty acid, cytochrome P450, leptin, resistin, adiponectin, bradykinin, NO, and Prostacyclin were determined before intervention, and 1.5 months, and 3 months after intervention. Hypoglycemia and the endpoint events during the study were recorded and compared among the study groups. Result At the end of the study period, MCPs-treated patients showed marked improvement compared with patients receiving placebo. The protection exerted by MCPs seemed more profound in diabetics than in diabetics with hypertension. In particular, after MCPs intervention, levels of free fatty acid, hs-CRP, resistin, Prostacyclin decreased significantly in diabetics and tended to decrease in diabetic and hypertensive patients whereas levels of cytochrome P450, leptin, NO tended to decrease in diabetics with/without hypertension. Meanwhile, levels of adiponectin and bradykinin rose markedly in diabetics following MCPs administration. Conclusion MCPs could offer protection against diabetes and hypertension by affecting levels of molecules involved in diabetic and hypertensive pathogenesis. Regulation on metabolic nuclear receptors by MCPs may be the possible underlying mechanism for its observed effects in the study. Further study into its action may shed light on development of new drugs based on bioactive peptides from marine sources.
基金the grants from the National Natural Science Foundation of China (No. 30671904 and No. 30670949)the Doctor Subjects Foundation of the Ministry of Education of the People's Republic of China (No. 20060558010).
文摘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.
基金grants from the National Natural Science Foundation of China(No.81560222)the Guizhou Science and Technology Foundation(No.[2017]7187,and No.[2013]2043).
文摘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.
文摘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.
基金Project (No. SP 135/14-1) supported by the Deutsche Forschungs-gemeinschaft,Germany
文摘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.
基金This work was supported by USA National Institutes of Health(NIH)grant,R01DK093774 to Y.K.Lee.
文摘Peroxisome proliferator-activated receptor gamma(PPARγor PPARG)is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily.It plays a master role in the differentiation and proliferation of adipose tissues.It has two major isoforms,PPARγ1 and PPARγ2,encoded from a single gene using two separate promoters and alternative splicing.Among them,PPARγ2 is most abundantly expressed in adipocytes and plays major adipogenic and lipogenic roles in the tissue.Furthermore,it has been shown that PPARγ2 is also expressed in the liver,specifically in hepatocytes,and its expression level positively correlates with fat accumulation induced by pathological conditions such as obesity and diabetes.Knockout of the hepatic Pparg gene ameliorates hepatic steatosis induced by diet or genetic manipulations.Transcriptional activation of Pparg in the liver induces the adipogenic program to store fatty acids in lipid droplets as observed in adipocytes.Understanding how the hepatic Pparg gene expression is regulated will help develop preventative and therapeutic treatments for non-alcoholic fatty liver disease(NAFLD).Due to the potential adverse effect of hepatic Pparg gene deletion on peripheral tissue functions,therapeutic interventions that target PPAR g for fatty liver diseases require fine-tuning of this gene's expression and transcriptional activity。
基金supported by National Natural Science Foundation of China(81370521,81670400,and 91739120)National Key R&D Program of China(2017YFC0211600)+1 种基金Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan(CIT&TCD20190332)The Key Science and Technology Project of Beijing Municipal Institutions(KZ202010025032).
文摘Background:Liver regeneration is a fundamental process for sustained body homeostasis and liver function recovery after injury.Emerging evidence demonstrates that myeloid cells play a critical role in liver regeneration by secreting cytokines and growth factors.Peroxisome proliferator-activated receptorα(PPARα),the target of clinical lipid-lowering fibrate drugs,regulates cell metabolism,proliferation,and survival.However,the role of myeloid PPARαin partial hepatectomy(PHx)-induced liver regeneration remains unknown.Methods:Myeloid-specific PPARa-deficient(Ppara^(Mye−/−))mice and the littermate controls(Ppara^(fl/fl))were subjected to sham or 2/3 PHx to induce liver regeneration.Hepatocyte proliferation and mitosis were assessed by immunohistochemical(IHC)staining for 5-bromo-2'-deoxyuridine(BrdU)and Ki67 as well as hematoxylin and eosin(H&E)staining.Macrophage and neutrophil infiltration into livers were reflected by IHC staining for galectin-3 and myeloperoxidase(MPO)as well as flow cytometry analysis.Macrophage migration ability was evaluated by transwell assay.The mRNA levels for cell cycle or inflammation-related genes were measured by quantitative real-time RT-PCR(qPCR).The protein levels of cell proliferation related protein and phosphorylated signal transducer and activator of transcription 3(STAT3)were detected by Western blotting.Results:Ppara^(Mye−/−)mice showed enhanced hepatocyte proliferation and mitosis at 32 h after PHx compared with Ppara^(fl/fl)mice,which was consistent with increased proliferating cell nuclear antigen(Pcna)mRNA and cyclinD1(CYCD1)protein levels in Ppara^(Mye−/−)mice at 32 h after PHx,indicating an accelerated liver regeneration in Ppara^(Mye−/−)mice.IHC staining showed that macrophages and neutrophils were increased in Ppara^(Mye−/−)liver at 32 h after PHx.Livers of Ppara^(Mye−/−)mice also showed an enhanced infiltration of M1 macrophages at 32 h after PHx.In vitro,Ppara-deficient bone marrow-derived macrophages(BMDMs)exhibited markedly enhanced migratory capacity and upregulated M1 genes Il6 and Tnfa but downregulated M2 gene Arg1 expressions.Furthermore,the phosphorylation of STAT3,a key transcript factor mediating IL6-promoted hepatocyte survival and proliferation,was reinforced in the liver of Ppara^(Mye−/−)mice after PHx.Conclusions:This study provides evidence that myeloid PPARαdeficiency accelerates PHx-induced liver regeneration via macrophage polarization and consequent IL-6/STAT3 activation,thus providing a potential target for manipulating liver regeneration.
文摘OBJECTIVE To investigate the anti-proliferative effect of rosiglitazone and its relationship to peroxisome proliferator-activated receptor γ （PPARγ） in human breast cancer cell line MDA-MB-231 and evaluate the potential application value of rosiglitazone for breast cancer therapy. METHODS The cytostatic effect of rosiglitazone on MDA- MB-231 cells was measured by the MTT assay. Cell-cycle kinetics was assessed by flow cytometry. Apoptotic cells were determined by the TUNEL assay. MDA-MB-231 cells were treated with rosiglitazone or in combination with the PPARy antagonist GW9662 to investigate the effect of rosiglitazone on cell proliferation and its relationship to PPARγ. RESULTS The results showed that rosiglitazone could inhibit growth of MDA-MB-231 cells in a dose- and time-dependent manner with an IC50 value of 5.2 μmol/L at 24 h after the drug was added into the culture. Cell cycle analysis showed that the percentage of G0/G1 phase cells increased, S phase cells decreased, and cells were arrested in G1 phase with increasing concentrations of rosiglitazone. Detectable signs of apoptotic cell death caused by rosiglitazone occurred at a concentration of 100 μmol/L and the apoptotic rate was （18 ± 3）%. PPARγ selective antagonist GW9662 could partially reverse the inhibitory effect of rosiglitazone on proliferation of MDA-MB-231 cells. CONCLUSION It was concluded that rosiglitazone can inhibit growth of MDA-MB-231 cells via PPARy activation and a high concentration of rosiglitazone can also induce MDA-MB-231 cell apoptosis. These results suggest that PPARy represents a putative molecular target for chemopreventive therapy and rosiglitazone may be effective in the treatment of breast cancer.
基金Xi'an Science and Technology Plan Project(2017114SF/YX008(5))National Science Foundation Youth Science Fund Project(81800711)。
文摘Objective:To investigate the peroxisome proliferator-activated receptor-γ (peroxisome)in patients with type 2 diabetes mellitus.Proliferators-activated receptors-γ ,PPARs-γ (γ )gene.polymorphisms about serum lipofuscin and leptin.Methods:One humdred and twenty patients with type 2 diabetes admitted to our hospital from June 2015 to June 2018 were selected.The patients were divided into an obese group and a non-obese group of 60 patients each according to their waist circumference.A polymerase chain reaction-length polymorphism protocol was implemented in all patients to explore the PPAR-γ gene polymorphism and blood glucose,lipid,adiponectin and leptin levels were measured in both groups.Results:PPAR-γ gene polymorphisms in type 2 diabetic patients were dominated by wild-type homozygous;The levels of total cholesterol,triglyceride and LDL cholesterol in the obese group were significantly higher than those in the non-obese group,while the levels of HDL cholesterol were lower than those in the non-obese group.There is significant difference in comparison between groups(P<0.05)Those canrying the A alele had a significant lipid disorder profile and decreased adiponectin levels.Conclusions:PPAR-γ gene polymorphisms in type 2 diabetes are not significantly associated with adiponectin and leptin,and only in the obese group,the patients with the Allele A showed significant dyslipidemia and a declining trend of adiponectin levels.
文摘Nutrient metabolism is regulated by several factors.Social determinants of health with or without genetics are the primary regulator of metabolism,and an unhealthy lifestyle affects all modulators and mediators,leading to the adaptation and finally to the exhaustion of cellular functions.Hepatic steatosis is defined by presence of fat in more than 5%of hepatocytes.In hepatocytes,fat is stored as triglycerides in lipid droplet.Hepatic steatosis results from a combination of multiple intracellular processes.In a healthy individual nutrient metabolism is regulated at several steps.It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component.Several hormones,peptides,and genes have been described that participate in nutrient metabolism.Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP.As of now several publications have revealed very intricate regulation of nutrient metabolism,where most of the regulatory factors are tied to each other bidirectionally,making it difficult to comprehend chronological sequence of events.Insulin hormone is the primary regulator of all nutrients’metabolism both in prandial and fasting states.Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes;metabolic,inflammation and repair,and cell growth and regeneration.Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands,adiponectin,leptin,and adiponutrin.Insulin hormone has direct effect on these final modulators.Whereas blood glucose level,serum lipids,incretin hormones,bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle.The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease(MASLD)that help us understand the disease natural course,risk stratification,role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine.PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states;MASLD,cardiovascular disease and cancer.More than 1000 publications including original research and review papers were reviewed.
