Peroxisome proliferator-activated receptor agonists:A new hope towards the management of alcoholic liver disease

In this editorial,we examine a paper by Koizumi et al,on the role of peroxisome proliferator-activated receptor(PPAR)agonists in alcoholic liver disease(ALD).The study determined whether elafibranor protected the intestinal barrier and reduced liver fibrosis in a mouse model of ALD.The study also underlines the role of PPARs in intestinal barrier function and lipid homeostasis,which are both affected by ALD.Effective therapies are necessary for ALD because it is a critical health issue that affects people worldwide.This editorial analyzes the possibility of PPAR agonists as treatments for ALD.As key factors of inflammation and metabolism,PPARs offer multiple methods for managing the complex etiology of ALD.We assess the abilities of PPARα,PPARγ,and PPARβ/δagonists to prevent steatosis,inflammation,and fibrosis due to liver diseases.Recent research carried out in preclinical and clinical settings has shown that PPAR agonists can reduce the severity of liver disease.This editorial discusses the data analyzed and the obstacles,advantages,and mechanisms of action of PPAR agonists for ALD.Further research is needed to understand the efficacy,safety,and mechanisms of PPAR agonists for treating ALD.

Dual peroxisome proliferator-activated receptorα/δagonists:Hope for the treatment of alcohol-associated liver disease?

In this letter,we review the article“Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease”.We focus specifically on the detrimental effects of alcohol-associated liver disease(ALD)on human health.Given its insidious onset and increasing incidence,increasing awareness of ALD can contribute to reducing the prevalence of liver diseases.ALD comprises a spectrum of several different disorders,including liver steatosis,steatohepatitis,fibrosis,cirrhosis,and hepatocellular carcinoma.The pathogenesis of ALD is exceedingly complex.Previous studies have shown that peroxisome proliferator-activated receptors(PPARs)regulate lipid metabolism,glucose homeostasis and inflammatory responses within the organism.Additionally,their dysfunction is a major contributor to the progression of ALD.Elafibranor is an oral,dual PPARαandδagonist.The effectiveness of elafibranor in the treatment of ALD remains unclear.In this letter,we emphasize the harm of ALD and the burden it places on society.Furthermore,we summarize the clinical management of all stages of ALD and present new insights into its pathogenesis and potential therapeutic targets.Additionally,we discuss the mechanisms of action of PPARαandδagonists,the significance of their antifibrotic effects on ALD and future research directions.

Germ cell-specific deletion of Pex3 reveals essential roles of PEX3-dependent peroxisomes in spermiogenesis

Peroxisomes are organelles enclosed by a single membrane and are present in various species.The abruption of peroxisomes is correlated with peroxisome biogenesis disorders and single peroxisomal enzyme deficiencies that induce diverse diseases in different organs.However,little is known about the protein compositions and corresponding roles of heterogeneous peroxisomes in various organs.Through transcriptomic and proteomic analyses,we observed heterogenous peroxisomal components among different organs,as well as between testicular somatic cells and different developmental stages of germ cells.As Pex3 is expressed in both germ cells and Sertoli cells,we generated Pex3 germ cell-and Sertoli cell-specific knockout mice.While Pex3 deletion in Sertoli cells did not affect spermatogenesis,the deletion in germ cells resulted in male sterility,manifested as the destruction of intercellular bridges between spermatids and the formation of multinucleated giant cells.Proteomic analysis of the Pex3-deleted spermatids revealed defective expressions of peroxisomal proteins and spermiogenesis-related proteins.These findings provide new insights that PEX3-dependent peroxisomes are essential for germ cells undergoing spermiogenesis,but not for Sertoli cells.

Peroxisome proliferator-activated receptors as targets to treat metabolic diseases:Focus on the adipose tissue,liver,and pancreas

The world is experiencing reflections of the intersection of two pandemics:Obesity and coronavirus disease 2019.The prevalence of obesity has tripled since 1975 worldwide,representing substantial public health costs due to its comorbidities.The adipose tissue is the initial site of obesity impairments.During excessive energy intake,it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs.The pancreas is one of the organs most affected by obesity.Once lipotoxicity becomes chronic,there is an increase in insulin secretion by pancreatic beta cells,a surrogate for type 2 diabetes mellitus(T2DM).These alterations threaten the survival of the pancreatic islets,which tend to become dysfunctional,reaching exhaustion in the long term.As for the liver,lipotoxicity favors lipogenesis and impairs beta-oxidation,resulting in hepatic steatosis.This silent disease affects around 30%of the worldwide population and can evolve into end-stage liver disease.Although therapy for hepatic steatosis remains to be defined,peroxisome proliferator-activated receptors(PPARs)activation copes with T2DM management.Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways,leading to insulin resistance relief,improved thermogenesis,and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation.This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases,focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.

Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease （NAFLD） is highly prevalent and can result in nonalcoholic steatohepatitis （NASH） and progressive liver disease including cirrhosis and hepatocellular carcinoma. A growing body of literature implicates the peroxisome proliferators- activated receptors （PPARs） in the pathogenesis and treatment of NAFLD. These nuclear hormone receptors impact on hepatic triglyceride accumulation and insulin resistance. The aim of this review is to describe the data linking PPARα and PPART to NAFLD/NASH and to discuss the use of PPAR ligands for the treatment of NASH.

Role of Oxidative Stress in Non-genotoxic Carcinogenesis with Special Reference to Liver Tumors Induced by Peroxisome Proliferators

Peroxisome proliferators (POPs), such as hypolipidemic drugs or industrial phthalate ester plasticizers, are widely known as non-genotoxic hepatocarcinogens in rodents. As one of the possible mechanisms of POP-induced carcinogenesis, the 'Oxidative Stress' theory has been postulated. In this review, in order to reconsider the significance of 'Oxidative Stress' to POP-induced carcinogenesis, we focus on in vivo studies examining formation of 8-hydroxydeoxyguanosine (8-OH -dG), a marker of oxidative DNA damage with mutagenic potential, after treatment of rodents with POPs. Some studies clearly demonstrated that 8-OH-dG levels in the liver DNA were increased by POP-treatments. These findings suggest that 'Oxidative Stress' could contribute as one factor to POP-induced carcinogenesis. Furthermore, we refer to other multiple biological changes caused by POP-treatment presumably contributing to the carcinogenic mechanisms, and consider possible roles of 'Oxidative Stress' in the carcinogenesis process

Construction and Evaluation of Merged Pharmacophore Based on Peroxisome Proliferator Receptor-Alpha Agonists

Pharmacophore is a commonly used method for molecular simulation, including ligand-based pharmacophore （LBP） and structure-based pharmacophore （SBP）. LBP can be utilized to identify active compounds usual with lower accuracy, and SBP is able to use for distin- guishing active compounds from inactive compounds with frequently higher missing rates. Merged pharmacophore （MP） is presented to integrate advantages and avoid shortcomings of LBP and SBP. In this work, LBP and SBP models were constructed for the study of per- oxisome proliferator receptor-alpha （PPARα） agonists. According to the comparison of the two types of pharmacophore models, mainly and secondarily pharmacological features were identified. The weight and tolerance values of these pharmacological features were adjusted to construct MP models by single-factor explorations and orthogonal experimental design based on SBP model. Then, the reliability and screening efficiency of the best MP model were validated by three databases. The best MP model was utilized to compute PPARα activity of compounds from traditional Chinese medicine. The screening efficiency of MP model outperformed individual LBP or SBP model for PPARα agonists, and was similar to combinatorial screening of LBP and SBP. However, MP model might have an advantage over the combination of LBP and SBP in evaluating the activity of compounds and avoiding the inconsistent prediction of LBP and SBP, which would be beneficial to guide drug design and optimization.

Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease

Intrahepatic fat deposition has been demonstrated in patients with nonalcoholic fatty liver disease(NAFLD). Genetic and environmental factors are important for the development of NAFLD. Diseases such as obesity, diabetes, and hypertension have been found to be closely associated with the incidence of NAFLD. Evi-dence suggests that obesity and insulin resistance are the major factors that contribute to the development of NAFLD. In comparing the factors that contribute to the buildup of excess calories in obesity, an imbalance of energy homeostasis can be considered as the basis. Among the peripheral signals that are generated to regulate the uptake of food, signals from adipose tissue are of major relevance and involve the maintenance of energy homeostasis through processes such as lipo-genesis, lipolysis, and oxidation of fatty acids. Advances in research on adipose tissue suggest an integral role played by adipokines in NAFLD. Cytokines secreted by adipocytes, such as tumor necrosis factor-α, transform-ing growth factor-β, and interleukin-6, are implicated in NAFLD. Other adipokines, such as leptin and adiponectin and, to a lesser extent, resistin and retinol binding protein-4 are also involved. Leptin and adiponectin can augment the oxidation of fatty acid in liver by activating the nuclear receptor super-family of transcription fac-tors, namely peroxisome proliferator-activated receptor(PPAR)-α. Recent studies have proposed downregula-tion of PPAR-α in cases of hepatic steatosis. This re-view discusses the role of adipokines and PPARs with regard to hepatic energy metabolism and progression of NAFLD.

Association of β3 Adrenergic Receptor and Peroxisome Proliferator-activated Receptor Gamma 2 Polymorphisms With Insulin Sensitivity:A Twin Study

Objective To study the effect of β3 adrenergic receptor （β3AR） Trp64Arg and peroxisome proliferator activated receptor gamma 2 （PPAR72） Prol2Ala polymorphisms on insulin resistance. Methods One hundred and eight dizygotic twin pairs were enrolled in this study. Microsatellite polymorphism was used to diagnose zygosity of twins. Insulin sensitivity was estimated with logarithm transformed homeostasis model assessment （HOMA）. PCR-RFLP analysis was performed to detect the variants. As a supplement to the sib-pair method, identity by state （IBS） was used to analyze the association of polymorphisms with insulin sensitivity. Results The genotype frequencies of Trp64Trg, Trp64Arg, and Arg64Arg were 72.3%, 23.8%, and 3.9%, respectively, while the genotype frequencies of Pro12Pro, Pro12Ala, and Ala12Ala were 89.9%, 9.6%, and 0.5%, respectively. For β3AR Trp64Arg the interclass co-twin correlations of Waist-to-hip ratio （WHR）, blood glucose （GLU）, and insulin （INS）, homeostasis model assessment insulin resistance index （HOMA-IR） of the twin pairs sharing 2 alleles of IBS were greater than those sharing 0-1 allele of IBS, and HOMA4R had statistic significance. For PPAR3t2 Prol2Ala most traits of twin pairs sharing 2 alleles of IBS had greater correlations and statistic significance in body mass index （BMI）, WHR, percent of body fat （PBF） and GLU, but there were low correlations of either insulin or HOMA-IR of twin pairs sharing 1 or 2 alleles of IBS. The combined effects of the two variations showed less squared significant twin-pair differences of INS and HOMA-IR among twins sharing 4 alleles of IBS. Condusions β3AR Trp64Arg and PPAR）,2 Pro 12Ala polymorphisms might be associated with insulin resistance and obesity, and there might be slight synergistic effects between this two gene loci, and further studies are necessary to confirm this finding.

Effect of insulin and metformin on methylation and glycolipid metabolism of peroxisome proliferator-activated receptor γcoactivator-1A of rat offspring with gestational diabetes mellitus

Objective:To discuss the effect of insulin and metformin on amethylation and glycolipid metabolism of peroxisome proliferator-activated receptor γ coactivator-1A(PPARGC1A) of rat offspring with gestational diabetes mellitus(GDM).Methods:A total of 45 pregnant rats received the intraperitoneal injection of streptozotocin to establish the pregnant rat model of GDM.A total of 21 pregnant rats with GDM were randomly divided into three groups,with 7ruts in each group,namely the insulin group,metformin group and control group.Rats in the insulin group received the abdominal subcutaneous injection of 1 mL/kg recombinant insulin glargine at 18:00 every day.Rats in the metformin group received the intragastric infusion of metformin hydrochloride at 18:00 every day,with the first dose of 300 mg/kg.The doses of two groups were adjusted every 3 d to maintain the blood glucose level at 2.65-7.62 mmol/L.Rats in the control group received the intragastric infusion of 1 mL normal saline at 18:00 every day.After the natural delivery of pregnant rats.10 offspring rats were randomly selected from each group.At birth,4 wk and 8 wk after the birth of offspring rats,the weight of offspring rats was measured.The blood glucose level of offspring rats was measured at 4wk and 8 wk,while the level of serum insulin,triglyceride and leptin was measured at 8 wk.Results:The weight of offspring rats at birth in the insulin group and metformin group was significantly lower than the one in the control group(P<0.05),and there was no significant difference at 4 wk and 8 wk among three groups(P>0.05).The fasting blood glucose and random blood glucose in the insulin group and metformin group at 4 wk and 8 wk were all significantly lower than ones in the control group(P<0.05);there was no significant difference between the insulin group and metformin group(P>0.05).The expression of PPARGC1 A mRNA in the insulin group and metformin group was significantly higher and the methylation level of PPARGC1 A was significantly lower than the one in the control group(P<0.05),but there was no significant difference between the insulin group and metformin group(P>0.05).Insulin and leptin at 8 wk in the insulin group and metformin group were significantly higher,while triglyceride was significantly lower than the one in the control group(P<0.05);triglyceride level of rats in the insulin group was significantly higher than the one in the metformin group(P<0.05).There was no significant difference in insulin and leptin level of offspring rats between the insulin group and metformin group(P>0.05).Conclusions:GDM can induce the methylation of PPARGC1 A of offspring rats to reduce the expression of PPARGC1 A mRNA and then cause the disorder of glycolipid metabolism when the offspring rats grow up;the insulin or metformin in the treatment of pregnant rats with GDM can reduce the methylation level of PPARGC1 A and thus improve the abnormal glycolipid metabolism of offspring rats.

Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease(NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors(PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation(mitochondrial and peroxisomal)and microsomal omega-oxidation, being markedly decreased by high-fat(HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.

Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome

Metabolic syndrome(MetS) and type 2 diabetes mellitus(T2DM) are the serious public health problems worldwide.Moreover,it is estimated that MetS patients have about five-fold greater risk of the T2 DM development compared with people without the syndrome.Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2 DM.All three members of the peroxisome proliferator-activated receptor(PPAR) nuclear receptor subfamily,PPARα,PPARp/5 and PPARγ are critical in regulating insulin sensitivity,adipogenesis,lipid metabolism,and blood pressure.Recently,more and more studies indicated that the gene polymorphism of PPARs,such as Leu^(162)Val and Val^(227)Ala of PPARα,+294T> C of PPARβ/δ,Pro^(12)Ala and C1431 T of PPARγ,are significantly associated with the onset and progressing of MetS and T2 DM in different population worldwide.Furthermore,a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes.However,given the complexity pathogenesis of metabolic disease,it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes.Thus,gene-gene interactions and gene-environment interactions associated with T2 DM and MetS need future comprehensive studies.

Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ2 in patients with fatty liver diseases

AIM:To test the occurrence of the Pro12Ala mutation of the peroxisome proliferator-activated receptor-γ (PPARγ)2-gene in patients with non-alcoholic fatty liver disease (NAFLD) or alcoholic fatty liver disease (AFLD).METHODS:DNA from a total of 622 specimens including 259 blood samples of healthy blood donors and 363 histologically categorized liver biopsies of patients with NAFLD (n=263) and AFLD (n=100) were analyzed by Real-time polymerase chain reaction using allele-specific probes.RESULTS:In the NAFLD and the AFLD collective,3% of the patients showed homozygous occurrence of the Ala12 PPARγ2-allele,differing from only 1.5% cases in the healthy population.In NAFLD patients,a high incidence of the Ala12 mutant was not associated with the progression of fatty liver disease.However,we observed a significantly higher risk (odds ratio=2.50,CI:1.05-5.90,P=0.028) in AFLD patients carrying the mutated Ala12 allele to develop inflammatory alterations.The linkage of the malfunctioning Ala12-positive PPARγ2 isoform to an increased risk in patients with AFLD to develop severe steatohepatitis and fibrosis indicates a more prominent anti-inflammatory impact of PPARγ2 in progression of AFLD than of NAFLD.CONCLUSION:In AFLD patients,the Pro12Ala single nuclear polymorphism should be studied more extensively in order to serve as a novel candidate in biomarker screening for improved prognosis.

Peroxisome proliferator-activated receptor gamma inhibits hepatic fibrosis in rats

BACKGROUND:Hepatic fibrosis is a necessary step in the development of hepatic cirrhosis.In this study we used lentiviral vector-mediated transfection technology to evaluate the effect of peroxisome proliferator-activated receptor gamma(PPAR-γ) on rat hepatic fibrosis. METHODS:Hepatic fibrosis in rats was induced by CCl4 for 2 weeks(early fibrosis)and 8 weeks(sustained fibrosis).The rats were randomly divided into four groups:normal control, fibrosis,blank vector,and PPAR-γ.They were infected with the recombinant lentiviral expression vector carrying the rat PPAR-γgene by portal vein injection.The liver of the rats was examined histologically and hydroxyproline was assessed.In vitro primary hepatic stellate cells(HSCs)were infected with the recombinant lentiviral expression vector carrying the rat PPAR-γgene.The status of HSC proliferation was measured by the MTT assay.The protein levels of PPAR-γ,α-smooth muscle actin(α-SMA)and type I collagen expression were evaluated by the Western blotting method. RESULTS:In vitro studies revealed that expression of PPAR-γ inhibited expression ofα-SMA and type I collagen in activated HSCs(P<0.01)as well as HSC proliferation(P<0.01).In vivo experiments indicated that in the early hepatic fibrosis group,the hydroxyproline content and the level of collagen I protein in the liver in the PPAR-γtransfected group were not significantly different compared to the hepatic fibrosis group and the blank vector group;whereas the expressions of PPAR-γ andα-SMA were different compared to the hepatic fibrosis group(P<0.01).In the sustained hepatic fibrosis group,there were significant differences in the hydroxyproline content and the expression of PPAR-γ,α-SMA,and type I collagen between each group.CONCLUSION:PPAR-γcan inhibit HSC proliferation and hepatic fibrosis,and suppressα-SMA and type I collagen expression.

Peroxisome proliferator activated receptor-γ and the ubiquitin-proteasome system in colorectal cancer

Peroxisome proliferator activated receptor-γ (PPARγ), a transcription factor of the nuclear receptor superfamily plays a significant role in colorectal cancer pathogenesis. In most experimental systems PPARγ activation has tumor suppressing effects in the colon. PPARγ is regulated at multiple levels by the ubiquitin-proteasome system (UPS). At a first level, UPS regulates PPARγ transcription. This regulation involves both PPARγ transcription specific factors and the general transcription machinery. At a second level UPS regulates PPARγ and its co-factors themselves, as PPARγ and many co-factors are proteasome substrates. At a third level of regulation, transduction pathways working in parallel but also having interrelations with PPARγ are regulated by the UPS, creating a network of regulation in the colorectal carcinogenesisrelated pathways that are under UPS control. Activation of PPARγ transcription by direct pharmacologic activators and by stabilization of its molecule by proteasome inhibitors could be strategies to be exploited in colorectal cancer treatment.

Peroxisome proliferator-activated receptor γ and colorectal cancer

Peroxisome proliferator-activated receptors(PPARs) are members of the nuclear hormone receptor superfamily and ligand-activated transcription factors.PPARγ plays an important role in adipocyte differentiation,lipid storage and energy dissipation in adipose tissue,and is involved in the control of inflammatory reactions as well as in glucose metabolism through the improvement of insulin sensitivity.Growing evidence has demonstrated that activation of PPARγ has an antineoplastic effect in tumors,including colorectal cancer.High expression of PPARγ is detected in human colon cancer cell lines and adenocarcinoma.This review describes the molecular mechanisms by which PPARγ regulates tumorigenesis in colorectal cancer,and examines current clinical trials evaluating PPARγ agonists as therapeutic agents for colorectal cancer.

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.

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.

Troglitazone, a peroxisome proliferator-activated receptor γ ligand, induces growth inhibition and apoptosis of HepG2 human liver cancer cells

AIM: To examine the effect of troglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) ligand, on the proliferation and apoptosis of human liver cancer cells. METHODS: Liver cancer cell line HepG2 was cultured and treated with troglitazone. Cell proliferation was detected by 3-(4-,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay; apoptosis was detected by flow cytometry and terminal deoxynucleotidyl transferase- mediated nick end labeling of DNA fragmentation sites (TUNEL) assay; and apoptosis-related protein was detected by immunocytochemistry and Western blotting. RESULTS: Troglitazone inhibited growth and induced apoptosis of HepG2 cells in a dose-dependent manner, and induced activation of caspase-3 expression. Troglitazone not only drove apoptosis-inhibiting factor survivin to translocate incompletely from the nucleus to the cytoplasm, but also inhibited expression of survivin, while it did not affect expression of apoptosis-promoting factor Bax. CONCLUSION: PPARγ ligands inhibit growth and induce apoptosis of liver cancer cells, and may have applications for the prevention and treatment of liver cancer.

Peroxisome proliferator-activated receptor-γ is essential in the pathogenesis of gastric carcinoma

AIM： To investigate whether peroxisome proliferatoractivated receptor γ （PPAR-γ） is expressed in human gastric carcinoma and whether PPAR-γ, is a potential target for gastric carcinoma therapy. METHODS： PPAR-γ protein in gastric carcinoma was examined by immunohistochemistry. In the gastric carcinoma cell line MGCS03, PPAR-7, survivin, Skp2 and p27 protein and mRNA were examined by Western blotting and real-time reverse transcription-polymerase chain reaction, respectively; proliferation was examined by MTT; apoptosis was examined by chromatin staining with Hoechst 33342 and fluorescence activated cell sorting （FACS）. and cell cycle was examined by FACS; the knockdown of PPAR-γ was done by RNA interference. RESULTS： A high level of expression of PPAR-γ was observed in human gastric carcinoma and in a human gastric carcinoma cell line MGCS03. The PPAR-γ agonist 15-deoxy-△12,14-prostaglandin J2 （15d-PGJ2）inhibited growth, and induced apoptosis and G1/G0 cell cycle arrest in MGC803 cells in a concentration-dependent and time-dependent manner. The effect of 15d-PGJ2 on MGC803 cells was not reversed by the selective and irreversible antagonist GW9662 for PPAR-γ. Furthermore, survivin and Skp2 expression were decreased, whereas p27 expression was enhanced following 15d-PGJ2 treatment in a dose-dependent manner in MGC803 cells. Interestingly, we also found that small interfering RNA for PPAR-γ inhibited growth and induced apoptosis in MGC803 cells. The inhibition of PPAR-γ function may be a potentially important and novel modality for treatment and prevention of gastric carcinoma. CONCLUSION： A PPAR-γ agonist inhibited growth of human gastric carcinoma MGC803 cells by inducing apoptosis and G1/G0 cell cycle arrest with the involvement of survivin, Skp2 and p27 and not via PPAR-γ.