Role of PIAS-regulated SUMOylation of PPARγ in endogenous protective mechanism against endotoxin-induced acute lung injury in mice / 中华麻醉学杂志

Objective:To evaluate the role of small ubiquitin-associated modifier (SUMO) E3 ligase (PIAS)-regulated SUMOylation of peroxisome proliferator-activated receptor γ (PPARγ) in the endogenous protective mechanism against endotoxin-induced acute lung injury (ALI) in mice.Methods:Experiment Ⅰ Twenty-four clean-grade wild type male C57BL/6 mice, aged 6-8 weeks, weighing 18-22 g, were divided into 4 groups ( n=6 each) using a random number table method: control group (C group), ALI group, ALI+ PPARγ inducer TZD group (ALI+ T group) and ALI+ TZD+ SUMOylation inhibitor anacardic acid group (ALI+ T+ A group). Lipopolysaccharide (LPS) 15 mg/kg was injected into the tail vein to develop the ALI model. In ALI+ T+ A group, anacardic acid 5 mg/kg was intraperitoneally injected at 1 h before LPS administration. In ALI+ T group and ALI+ T+ A group, TZD 50 mg/kg was intraperitoneally injected at 30 min before LPS administration. The mice were sacrificed at 12 h after LPS administration, and the lung tissues were obtained to examine the pathological changes which were scored and to determine the wet/dry (W/D) weight ratio, and expression of PIAS1, PIAS2, PIAS3 and PIASy protein and mRNA (by Western blot or polymerase chain reaction). Experiment Ⅱ Mouse alveolar macrophages (MH-S cells) were cultured in vitro and divided into 4 groups ( n=5 each) using a random number table method: control group (C group), LPS group, LPS+ PIAS2 siRNA group (L+ P group) and LPS+ Con siRNA group (L+ C group). Cells were routinely cultured in group C. Cells were stimulated with 10 μg/ml LPS to develop the model of endotoxin challenge. PIAS2 siRNA 50 nmol/L and Con siRNA 50 nmol/L were transfected at 48 h before LPS was added in L+ P group and L+ C group, respectively. The cells were collected at 24 h of incubation with LPS to determine the cell viability, levels of M1 and M2 alveolar macrophages (by flow cytometry), expression of PIAS2 and PPARγ (by Western blot), co-expression of PPARγ-SUMO1 (by immunoprecipitation) and expression of tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) mRNA (by polymerase chain reaction). The ratio of M1/M2 was calculated. Results:Experiment Ⅰ Compared with C group, the lung injury scores and W/D ratio were significantly increased, and the expression of PIAS2 protein and mRNA was up-regulated in the other three groups ( P<0.05). Compared with ALI group, the lung injury scores and W/D ratio were significantly decreased, and the expression of PIAS2 protein and mRNA was up-regulated in ALI+ T group and ALI+ T+ A group ( P<0.05). Compared with ALI+ T group, the lung injury scores and W/D ratio were significantly increased, and the expression of PIAS2 protein and mRNA was down-regulated in ALI+ T+ A group ( P<0.05). There was no significant difference in the expression of PIAS1, PIAS3 and PIASy protein and mRNA in lung tissues among the four groups ( P>0.05). Experiment Ⅱ Compared with C group, the cell viability was significantly decreased, the expression of PPARγ and co-expression of PPARγ-SUMO1 was up-regulated, the levels of M1 and M2 macrophages and M1/M2 ratio were increased, the expression of TNF-α mRNA was up-regulated, and the expression of IL-10 mRNA was down-regulated in the other three groups, and PIAS2 expression was significantly up-regulated in L group and L+ C group ( P<0.05). Compared with L group, the cell viability was significantly decreased, the expression of PIAS2 and PPARγ and PPARγ-SUMO1 co-expression were down-regulated, the M1 macrophage level and M1/M2 ratio were increased, TNF-α mRNA expression was up-regulated, and the expression of IL-10 mRNA was down-regulated in L+ P group ( P<0.05), and no significant change was found in the parameters mentioned above in L+ C group ( P>0.05). Compared with L+ C group, the cell viability was significantly decreased, the expression of PIAS2 and PPARγ and co-expression of PPARγ-SUMO1 were down-regulated, the level of M1 alveolar macrophages and M1/M2 ratio were increased, the expression of TNF-α mRNA was down-regulated, and the expression of IL-10 mRNA was up-regulated in L+ P group ( P<0.05). Conclusions:PIAS2-regulated SUMOylation of PPARγ is the endogenous protective mechanism against endotoxin-induced ALI in mice, which may be related to inhibition of macrophage polarization into M1 type and alleviation of inflammatory responses.

Breaking blood expelling stasis method accelerates hematoma resolution after hyperacute intracerebral hemorrhage and its potential mechanism / 中国医师杂志

Objective:To explore the efficacy of breaking blood expelling stasis method accelerates hematoma resolution after intracerebral hemorrhage (ICH) and its potential mechanism.Methods:63 ICH patients confirmed by computer tomography (CT) scan from August 2019 to February 2020 were selected as the research objects and randomly divided into control group ( n=29, routine treatment plus placebo) and observation group ( n=34, routine treatment plus breaking blood expelling stasis granules). The changes of neurological function and hematoma volume were observed before and after treatment. At the same time, the ICH rat model was constructed to observe the changes of neurobehavior and hematoma volume after the intervention of breaking blood expelling stasis granules. The expressions of peroxidase proliferator-activated-receptor γ(PPARγ), CD11b and CD36 in the surrounding tissues of hematoma were detected by Western blot on the third day after the intervention. Results:After two weeks of treatment, the National Institutes of Health Stroke Scale (NIHSS) score and hematoma volume of the two groups decreased (all P<0.05), and the NIHSS score and hematoma volume of the observation group were significantly lower than those of the control group (all P<0.05). In addition, the changes of NIHSS score and hematoma volume in the observation group before and after treatment were significantly greater than those in the control group ( P<0.01). In animal experiments, the hematoma volume in the breaking blood expelling stasis group on the 14th day after ICH was significantly smaller than that in the ICH group [(9.8±4.9)mm 3 vs (17.6±6.4)mm 3,P<0.05], and the reduction of hematoma in the breaking blood expelling stasis group on the 7th and 14th day was significantly larger than that in the ICH group [(4.6±2.9)mm 3 vs (-2.1±1.6)mm 3, (14.3±3.8)mm 3 vs (4.2±2.8)mm 3, all P<0.01]. The percentage of right turn on 3rd, 7th and 14th day and the modified Neurological Severity Score (mNSS) on 7th and 14th day in the breaking blood expelling stasis group were lower than those in the ICH group (all P<0.05). Western blot analysis showed that the expressions of CD11b, CD36 and PPARγ in the breaking blood expelling stasis group on the third day after ICH were significantly higher than those in the ICH group (CD11b: 0.78±0.12 vs 0.49±0.11, P<0.05; CD36: 1.16±0.16 vs 0.80±0.11, P<0.05; PPARγ: 0.78±0.11 vs 0.37±0.10, P<0.01). Conclusions:Breaking blood expelling stasis can effectively accelerate intracerebral hematoma clearance and improve neurological outcome after ICH, and the mechanism maybe probably mediated by activating PPARγ and enhanced CD36, CD11b upregulation on microglia/macrophages, which resulting in facilitating erythrocyte endogenous phagocytosis.

Relationship between HO-1 and PPARγ during alveolar macrophage polarization in a mouse model of endotoxin-induced acute lung injury / 中华麻醉学杂志

Objective:To evaluate the relationship between heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor γ (PPARγ) during alveolar macrophage polarization in a mouse model of endotoxin-induced acute lung injury (ALI).Methods:Thirty clean-grade male C57BL/6 mice (24 wide-type mice and 6 HO-1 knockout mice), aged 6-8 weeks, weighing 18-22 g, were studied.Wide-type mice were divided into 4 groups ( n=6 each) using a random number table method: control group (C group), ALI group, ALI+ HO-1 agonist hemin group (ALI+ H group), and ALI+ hemin+ PPARγ antagonist T0070907 group (ALI+ H+ T group).HO-1 knockout mice in which the ALI model was developed served as ALI+ HO-1 -/- group.ALI model was developed by injecting lipopolysaccharide (LPS) 15 mg/kg via the tail vein in anesthetized animals.T0070907 1.5 mg/kg was intraperitoneally injected at 1 h before LPS administration in ALI+ H+ T group, and hemin 50 mg/kg was intraperitoneally injected at 30 min before LPS administration in ALI+ H group and ALI+ H+ T group.Mice were sacrificed at 12 h after LPS administration, and lung tissues were obtained to measure the wet to dry weight ratio (W/D ratio), to observe pathological changes which were scored, and to determine the F4/80+ /CD86+ labeled M1 alveolar macrophages and the F4/80+ /CD206+ labeled M2 alveolar macrophages (by flow cytometry), contents of M1 macrophage-related genes inducible nitric oxide synthase (iNOS) and M2 macrophage-related genes Arginase-1 (Arg-1) (by enzyme-linked immunosorbent assay), and the expression of HO-1 and PPARγ (by Western blot). Results:Compared with C group, the lung injury score, W/D ratio, levels of CD86 and CD206, and contents of iNOS and Arg-1 were significantly increased, and PPARγ expression was up-regulated in the other four groups ( P<0.05), and HO-1 protein expression was up-regulated in ALI, ALI+ H and ALI+ H+ T groups ( P<0.05).Compared with ALI group, the lung injury score, W/D ratio, and levels of CD86 and iNOS were significantly increased, the levels of CD206 and Arg-1 were decreased, and the expression of HO-1 and PPARγ was down-regulated in ALI+ HO-1 -/- group, the lung injury score, W/D ratio and levels of CD86 and iNOS were significantly decreased, the levels of CD206 and Arg-1 were increased, and the expression of HO-1 and PPARγ was up-regulated in ALI+ H group ( P<0.05), and no significant change was found in the parameters mentioned above in ALI+ H+ T group ( P>0.05).Compared with ALI+ H group, the lung injury score, W/D ratio and levels of CD86 and iNOS were significantly increased, the levels of CD206 and Arg-1 were decreased, the expression of PPARγ was down-regulated ( P<0.05), and no significant change was found in the expression of HO-1 in ALI+ H+ T group ( P>0.05). Conclusions:HO-1 can up-regulate the expression of PPARγ, inhibit the polarization of alveolar macrophages toward M1 phenotype and promote the polarization toward M2 phenotype, thus playing an endogenous protective role in endotoxin-induced ALI in mice.

Type II diabetes mellitus and obesity: Common links, existing therapeutics and future developments

Type II diabetes mellitus (T2DM) and obesity are two common pathophysiological conditions of metabolic syndrome(MetS), a collection of similar metabolic dysfunctions due to sedentary lifestyle and overnutrition. Obesity arises fromimproper adipogenesis which otherwise has a crucial role in maintaining proper metabolic functions. Downstream eventsarising from obesity have been linked to T2DM. The nuclear receptor peroxisome proliferator activator gamma (PPAR-c),responsible for maintaining lipid and glucose homeostasis, is down-regulated under obesity leading to a weakened insulinsensitivity of the human body. In course of our review we will outline details of the down-regulation mechanism, provide anoverview of the current clinical therapeutics and their shortcomings. Toxicity studies on the seminal drug troglitazone,belonging to the most effective glitazone anti-diabetic category, is also discussed. This will lead to an overview aboutstructural adaptations on the existing glitazones to alleviate their side effects and toxicity. Finally, we forward a concept ofnovel therapeutics mimicking the glitazone framework, based on some design concepts and preliminary in silico studies.These could be later developed into dual acting drugs towards alleviating the deleterious effects of obesity on normalglucose metabolism, and address obesity in itself.

Study on the polymorphism of PPAR-γgene and preeclampsia susceptibility / 中国医师杂志

Objective To investigate the correlation between peroxisome proliferator-activated re-ceptor-gamma ( PPAR-γ) gene polymorphism and preeclampsia ( PE) . Methods 110 PE patients and 110 normal pregnants who delivered in our hospital from May 2016 to October 2018 were selected as the study subjects. Detection of two loci of PPAR-γ gene by SNaPshot technique: rs10865710 and rs4684847. Re-sults ⑴ rs10865710:The genotype frequencies of CC, CG and GG in the control group were 44. 55％, 42. 73％ and 12. 73％, respectively, and those in the PE group were 31. 82％, 44. 55％ and 23. 64％, re-spectively. There was a critical difference in the distribution of genotype frequencies between the two groups (x2 =5. 975, P=0. 050); The frequencies of C and G alleles were 65. 91％ and 34. 09％ in the control group, 54. 09％ and 45. 91％ in the PE group, respectively. There was significant difference in the fre-quency distribution of C and G alleles between the two groups (x2 =6. 402, P=0. 015). ⑵ rs4684847:the genotype frequencies of CC, CT and TT in control group were 94. 55％, 5. 45％, 0, and those in PE group were 84. 55％, 15. 45％ and 0, respectively,with significant difference in the distribution of genotype frequencies between the two groups (x2 =5. 875, P =0. 015). The frequencies of C and T alleles in control group were 97. 27%, 2. 73% and those in PE group were 92. 27% and 7. 73%, respectively,with significant difference in allele frequency distribution between the two groups (x2 = 5. 551, P = 0. 030). ⑶ The frequency of GG genotype and G allele at rs10865710 locus in PE group was significantly higher than that in control group [OR (95% CI) =2. 600 (1. 190 - 5. 679), P = 0. 021; OR (95% CI) = 1. 64 (1. 117 -2. 411), P =0. 015]. The frequencies of CT genotype and T allele at rs4684847 locus in PE group were significantly higher than those in control group [OR (95% CI) =3. 168 (1. 199 -8. 374), P =0. 026; OR (95% CI) =2. 987 (1. 155 -7. 726), P =0. 030]. Conclusions The single nucleotide polymorphisms of PPAR-γ gene rs10865710 and rs4684847 may be related to the susceptibility to preeclampsia in Chinese population.

Mannosylerythritol lipids ameliorate ultraviolet A-induced aquaporin-3 downregulation by suppressing c-Jun N-terminal kinase phosphorylation in cultured human keratinocytes

Mannosylerythritol lipids (MELs) are glycolipids and have several pharmacological efficacies. MELs also show skin-moisturizing efficacy through a yet-unknown underlying mechanism. Aquaporin-3 (AQP3) is a membrane protein that contributes to the water homeostasis of the epidermis, and decreased AQP3 expression following ultraviolet (UV)-irradiation of the skin is associated with reduced skin moisture. No previous study has examined whether the skin-moisturizing effect of MELs might act through the modulation of AQP3 expression. Here, we report for the first time that MELs ameliorate the UVA-induced downregulation of AQP3 in cultured human epidermal keratinocytes (HaCaT keratinocytes). Our results revealed that UVA irradiation decreases AQP3 expression at the protein and messenger RNA (mRNA) levels, but that MEL treatment significantly ameliorated these effects. Our mitogen-activated protein kinase inhibitor analysis revealed that phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase or p38, mediates UVA-induced AQP3 downregulation, and that MEL treatment significantly suppressed the UVA-induced phosphorylation of JNK. To explore a possible mechanism, we tested whether MELs could regulate the expression of peroxidase proliferator-activated receptor gamma (PPAR-γ), which acts as a potent transcription factor for AQP3 expression. Interestingly, UVA irradiation significantly inhibited the mRNA expression of PPAR-γ in HaCaT keratinocytes, whereas a JNK inhibitor and MELs significantly rescued this effect. Taken together, these findings suggest that MELs ameliorate UVA-induced AQP3 downregulation in HaCaT keratinocytes by suppressing JNK activation to block the decrease of PPAR-γ. Collectively, our findings suggest that MELs can be used as a potential ingredient that modulates AQP3 expression to improve skin moisturization following UVA irradiation-induced damage.

Opposite Interplay Between the Canonical WNT/β-Catenin Pathway and PPAR Gamma: A Potential Therapeutic Target in Gliomas / 神经科学通报·英文版

In gliomas, the canonical Wingless/Int (WNT)/β-catenin pathway is increased while peroxisome proliferator-activated receptor gamma (PPAR-γ) is downregulated. The two systems act in an opposite manner. This review focuses on the interplay between WNT/β-catenin signaling and PPAR-γ and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/β-catenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis, tumor growth, and angiogenesis. Activation of PPAR-γ agonists inhibits various signaling pathways such as the JAK/STAT, WNT/β-catenin, and PI3K/Akt pathways, which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin, and sulforaphane downregulate the WNT/β-catenin pathway through the upregulation of PPAR-γ and thus appear to provide an interesting therapeutic approach for gliomas. Temozolomide (TMZ) is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.

Relationship between effect of PPARγ in pulmonary vascular remodeling and NOX-4 in rats with pulmonary hypertension / 中华麻醉学杂志

Objective To evaluate the relationship between the effect of peroxisome proliferator-activated receptor-γ (PPARγ) in pulmonary vascular remodeling and NADPH oxidase 4 (NOX-4) in rats with pulmonary hypertension.Methods Thirty-two healthy adult male Sprague-Dawley rats,aged 2 months,weighing 200-250 g,were divided into 4 groups (n =8 each) using a random number table method:control group (group C),pulmonary arterial hypertension group (group PH),PPARγ agonist rosiglitazone treatment group (group R),and PPARγ antagonist GW9662 treatment group (group G).In group PH,monocrotaline 60 mg/kg was injected subcutaneously in the neck and back to induce pulmonary hypertension.The suspension of rosiglitazone and normal saline 5 mg · kg-1 · d-1 and GW9662 solution 2 mg · kg-1 · d-1 were administered by intragastric gavage after injecting monocrotaline,in group R and group G,respectively,for 4 consecutive weeks.The mean pulmonary arterial pressure (mPAP) was measured at 4 weeks after establishing the model.The animals were then sacrificed,and the lungs were removed for microscopic examination of the pathological changes (with a light microscope) and for determination of the expression of PPARγ and NOX-4 protein and mRNA in lung tissues (by real-time polymerase chain reaction or Western blot).The percentage of media thickness of pulmonary arterioles was calculated.Results Compared with group C,the mPAP and percentage of media thickness of pulmonary arterioles were significantly increased,the expression of PPARγ protein and mRNA was down-regulated,and the expression of NOX-4 protein and mRNA was up-regulated in PH,R and G groups (P＜0.05).Compared with group PH,the mPAP and percentage of media thickness of pulmonary arterioles were significantly decreased,the expression of PPARγ protein and mRNA was up-regulated,and the expression of NOX-4 protein and mRNA was down-regulated in group R,and the mPAP and percentage of media thickness of pulmonary arterioles were significantly increased,the expression of PPARγ protein and mRNA was down-regulated,and the expression of NOX-4 protein and mRNA was up-regulated in group G (P＜0.05).Conclusion The mechanism of endogenous protective effect of PPARγ in the development of pulmonary hypertension and pulmonary vascular remodeling may be related to down-regulating the expression of NOX-4 in rats.

Effect of Pioglitazone in Combination with Moderate Dose Statin on Atherosclerotic Inflammation: Randomized Controlled Clinical Trial Using Serial FDG-PET/CT

BACKGROUND AND OBJECTIVES: Non-statin therapy plus lower intensity statin might be an alternative in patients with coronary artery disease (CAD). A recent data suggested an anti-inflammatory therapy can reduce recurrent cardiovascular events and pioglitazone is also an intriguing inflammatory-modulating agent. However, limited data exist on whether pioglitazone on top of statins further attenuates plaque inflammation. METHODS: Statin-naïve patients with stable CAD and carotid plaques of ≥3 mm were randomly prescribed moderate dose atorvastatin (20 mg/day), or moderate dose atorvastatin plus pioglitazone (30 mg/day) for 3 months. The primary endpoint was the change in the arterial inflammation of the carotid artery measured by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) during 3 months. RESULTS: Of the 41 randomized patients, 33 underwent an evaluation by fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT; 17 atorvastatin plus pioglitazone and 16 atorvastatin patients). The addition of pioglitazone significantly improved the insulin sensitivity and increased the high-density lipoprotein cholesterol after 3 months. Although a reduction in the (FDG) uptake by pioglitazone on top of atorvastatin in carotid arteries with plaque showed marginally statistical significance in the entire patient group (atorvastatin plus pioglitazone; −0.10±0.07 and atorvastatin −0.06±0.04, p=0.058), pioglitazone showed a further reduction of the fluorodeoxyglucose (FDG) uptake among patients who had a baseline FDG uptake above the median (atorvastatin plus pioglitazone; −0.14±0.04 and atorvastatin −0.03±0.03, p < 0.001). CONCLUSIONS: Pioglitazone demonstrated marginally significant anti-inflammatory effects in addition to moderate dose atorvastatin. This may have been due to the lack of power of the study. However, pioglitazone may have an anti-inflammatory effect in those patients with high plaque inflammation (Trial registry at ClinicalTrials.gov, NCT01341730).

The role of peroxisome proliferator-activated receptor gamma in prostate cancer / 亚洲男科学杂志(英文版)

Despite great progress in the detection and treatment of prostate cancer, this disease remains an incredible health and economic burden. Although androgen receptor (AR) signaling plays a key role in the development and progression of prostate cancer, aberrations in other molecular pathways also contribute to the disease, making it essential to identify and develop drugs against novel targets, both for the prevention and treatment of prostate cancer. One promising target is the peroxisome proliferator-activated receptor gamma (PPARγ) protein. PPARγ was originally thought to act as a tumor suppressor in prostate cells because agonist ligands inhibited the growth of prostate cancer cells; however, additional studies found that PPARγ agonists inhibit cell growth independent of PPARγ. Furthermore, PPARγ expression increases with cancer grade/stage, which would suggest that it is not a tumor suppressor but instead that PPARγ activity may play a role in prostate cancer development and/or progression. Indeed, two new studies, taking vastly different, unbiased approaches, have identified PPARγ as a target in prostate cancer and suggest that PPARγ inhibition might be useful in prostate cancer prevention and treatment. These findings could lead to a new therapeutic weapon in the fight against prostate cancer.

Troglitazone Inhibits Matrix Metalloproteinase-9 Expression and Invasion of Breast Cancer Cell through a Peroxisome Proliferator-Activated Receptor γ-Dependent Mechanism / 한국유방암학회지

PURPOSE: Peroxisome proliferator-activated receptor γ (PPARγ) is involved in the pathology of numerous diseases including atherosclerosis, diabetes, obesity, and cancer. Matrix metalloproteinases (MMPs) play a significant role in tissue remodeling related to various processes such as morphogenesis, angiogenesis, tissue repair, invasion, and metastasis. We investigated the effects of PPARγ on MMP expression and invasion in breast cancer cells. METHODS: MCF-7 cells were cultured and then cell viability was monitored in an MTT assay. Western blotting, gelatin zymography, real-time polymerase chain reaction, and luciferase assays were performed to investigate the effect of the synthetic PPARγ ligand troglitazone on MMP expression. Transcription factor DNA binding was analyzed by electrophoretic mobility shift assay. A Matrigel invasion assay was used to assess the effects of troglitazone on MCF-7 cells. RESULTS: Troglitazone did not affect MCF-7 cell viability. 12-O-tetradecanoylphorbol-13-acetate (TPA) induced MMP-9 expression and invasion in MCF-7 cell. However, these effects were decreased by troglitazone. TPA increased nuclear factor κB and activator protein-1 DNA binding, while troglitazone inhibited these effects. The selective PPARγ antagonist GW9662 reversed MMP-9 inhibition by troglitazone in TPA-treated MCF-7 cells. CONCLUSION: Troglitazone inhibited nuclear factor κB and activator protein-1-mediated MMP-9 expression and invasion of MCF-7 cells through a PPARγ-dependent mechanism.

Effect of pioglitazone on expression of p38 mitogen-activated protein kinase in myocardium of rats following I/R injury / 中华老年心脑血管病杂志

Objective To study the effect of pioglitazone,a member of the thiazolidinedione (TZD) class with hypoglycemic action to treat diabetes,on expression of p38 mitogen-activated protein kinase in myocardium of rats following I/R injury.Methods Twenty-four healthy SD rats were randomly divided into sham group,I/R injury group,pioglitazone treatment group and pioglitazone+peroxisome proliferator-activated receptors-γ specific antagonist GW9662 treatment group (6 in each group).A rat I/R injury model was established by ligating the left anterior descending coronary artery.Apoptosis of myocardial cells was assayed by Terminal dUTP deoxynucleotidyl transferase nick end labeling.Expression of p-p38 protein was detected by Western blot.Results The apoptosis index of myocardial cells was significantly lower in sham operation group and piogl itazone treatment group than in I/R injury group and was significantly higher in pioglitazone+ GW9662 treatment group than in pioglitazone treatment group (8.6％±4.3％,21.4％±8.8％ vs 40.1％±12.3％,P＜0.05;37.0％-10.5％ vs 21.4％±8.8％,P＜0.05).The expression level of p-p38 was significantly lower in sham operation group and pioglitazone treatment group than in I/R injury group and was significantly higher in pioglitazone+GW9662 treatment group than in pioglitazone treatment group (P＜0.05).Conclusion Pioglitazone can inhibit I/R injury-induced apoptosis of myocardial cells by downregulating the expression of p-p38 protein.

Total synthesis of cyclodepsipeptide Hikiamides A-C / 中国药科大学学报

@#Total synthesis of cyclodepsipeptide Hikiamides A-C was described. Fragment convergent condensation method was applied for the preparation of Hikiamides A-C, starting from Commercially available amino acid such as L-N-Boc-Phe-OH, L-N-Boc-Trp-OH, L-N-Cbz-Van-OH etc. Tripeptide fragments(compounds 5a/5b)and dipeptide fragments(compounds 8a/8b)were first prepared. The subsequent condensation of the resulted two fragments provided protected linear pentapetides(compounds 9a/9b/9c); Finally, the linear pentapetide was cyclized by a mixed condensing agents comprised of PyBOP and HBTU. Hikiamides A-C was obtained with total yields of 9%, 11% and 6. 5%, respectively. Compared with the natural source, this method has the advantages of low cost, convenient operation and high yield, which effectively solves the problem of low isolated yield of Hikiamides A-C from Fusarium sp.

Protective effect of Astragaloside Ⅳ on the oxygenation induced by RAW264.7 murine macrophage / 国际中医中药杂志

Objective To investigate the protective effect and mechanism of Astragaloside Ⅳ (AS-Ⅳ) on hypoxia/re-oxygenation induced by RAW264.7 murine macrophages.Methods The hypoxia/re- oxygenation induced RAW264.7 murine macrophages served as a model of I/R injury. The cells were divided into the control group, the model group, and the AS-Ⅳ group. The cell morphological changes of each group were observed directly under inverted microscope. Inducible nitric oxide synthase (iNOS), cluster of differentiation 206 (CD206), and peroxisome proliferator activated receptor-γ (PPAR-γ) were separately examined by RT-PCR, Western blot analysis and immunofluorescence staining.Results Compared with the model group, the numbers of cell in AS-Ⅳ group significantly increased , and the cell physiological status were much better. Compared with the model group, the iNOS immunofluorescence semi quantitative (0.62 ± 0.02 vs. 1.32 ± 0.09), the expression of mRNA (1.51 ± 0.07 vs. 3.46 ± 0.39), and protein (2.30 ± 0.14 vs. 5.16 ± 0.49) significantly reduced in AS-Ⅳ group (P<0.01). The CD206 immunofluorescence semi quantitative (1.01 ± 0.03 vs.0.61 ± 0.01), the expression of mRNA (0.91 ± 0.03 vs.0.51 ± 0.01), and protein (0.61 ± 0.04 vs.0.19 ± 0.01) significantly reduced in AS-Ⅳ group (P<0.01). Compared with the model group, the PPAR-γ immunofluorescence semi quantitative (0.60 ± 0.14 vs. 0.34 ± 0.03), mRNA (2.00 ± 0.14 vs.1.04 ± 0.03), andprotein (0.67 ± 0.05 vs.0.19 ± 0.01) significantly increased (P<0.01). Conclusions The AS-Ⅳ could attenuate ischemia-reperfusion injury by altering macrophages phenotype through upregulation PPAR-γ.

Roles of phosphatidylinositol 3-kinase/protein kinase B signaling pathway in skeletal muscle, peroxisome proliferator-activated receptor γ and phosphatase and tension homologue deleted on chromosome 10 in regulating insulin sensitivity of rats with fetal growth restriction / 中华围产医学杂志

Objective To investigate the roles of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and its regulatory protein peroxisome proliferator-activated receptor γ (PPAR γ) and phosphatase and tension homologue deleted on chromosome 10 (PTEN) in regulating insulin sensitivity in rats with fetal growth restriction (FGR).Methods Sixteen pregnant rats were randomly divided into two groups including FGR and control groups on the 12th day of pregnancy (eight in each group).The FGR group was given low protein diet (8％ of casein) and restriction diet to establish the neonatal rat model of FGR.All maternal rats after delivery and newborn rats after weaning on 21 days after born were fed with normal diet.Each time blood samples were collected from eight newborn rats of each group to measure levels of fasting plasma glucose (FPG) and fasting insulin(FINS) at the time points of 21 days,two and four months after birth.Then insulin resistance index (IRI) and insulin sensitivity index (ISI) were calculated to evaluate insulin sensitivity.Expression of PI3K,AKT,PPAR γγ,PTEN and glucose transporters 4 (GLUT4) in skeletal muscle at mRNA and protein levels were measured at 21 days,two and four months after birth with real time fluorescence polymerase chain reaction and Western blot,respectively.Relationships between the expression of key molecules of PI3K/AKT signaling pathway and insulin sensitivity were analyzed.T-test,and Pearson's correlation analysis were used for statistical analysis.Results (1) The average birth weight of newborn rats in the FGR group was lower than that of the control group [(4.37± 0.69) vs (7.03±0.55) g,t=-20.75,P＜0.05].The incidence of FGR in the FGR group was 93.33％ (70/75).(2) Compared with normal offspring,those in the FGR group showed significantly increased FPG [two months after birth:(5.53± 0.58) vs (7.49 ± 0.38) mmol/L,t=8.08;four months afterbirth:(6.35±0.66) vs (8.94±0.90) mmol/L,t=6.58],FINS [two months afterbirth:(9.18±0.66) vs (14.67± 1.90) mU/L,t=7.71;four months after birth:(33.08±2.76) vs (56.33±2.81) mU/L,t=16.71] and IR1 (two months after birth:2.25±0.31 vs 4.90±0.81,t=8.63;four months after birth:9.30±0.90 vs 22.44±3.10,t=1 1.51),but decreased ISI (two months after birth:0.020 ± 0.002 vs 0.009± 0.001,t=-10.1 4;four months after birth:0.005±0.000 vs 0.002 ±0.000,t=-14.91) at two and four months after birth (all P＜0.05).(3) Compared with normal offspring,those in the FGR group showed decreased expression of PI3K (21 days after birth:0.082±0.028 vs 0.019±0.004,t=-6.29;two months after birth:0.020±0.003 vs 0.010±0.005,t=-4.78;four months after birth:0.014±0.004 vs 0.003±0.001,t=-7.87) and GLUT4 (21 days after birth:0.132±0.057 vs 0.041 ±0.019,t=-4.32;two months after birth:0.183±0.084 vs 0.069±0.017,t=-3.74;four months after birth:0.248±0.069 vs 0.113±0.040,t=-4.74) at mRNA level at 21 days,two and four months after birth (all P＜0.05).Compared with normal offspring,decreased expression of PPAR γ (two months after birth:0.028±0.002 vs 0.012±0.005,t=-3.70;four months after birth:0.030±0.008 vs 0.012±0.005,t=-3.80) and increased expression of PTEN (two months after birth:0.020±0.004 vs 0.045±0.014,t=5.09;four months after birth:0.023±0.007 vs 0.034±0.009,t=2.57) at mRNA level were observed in offspring of the FGR group at two and four months after birth (all P＜0.05).(4) Compared with normal offspring,expression of PI3K protein (21 days after birth:0.22±0.01 vs 0.17±0.02,t=-6.62;two months after birth:0.27±0.03 vs 0.16±0.02,t=-7.25;four months after birth:0.18±0.01 vs 0.09±0.02,t=-9.79) and GLUT4 protein (21 days after birth:0.21 ±0.01 vs 0.03±0.01,t=-27.29;two months after birth:0.10±0.01 vs 0.06t±0.01,t=-3.90;four months after birth:0.13 ±0.01 vs 0.08± 0.02,t=-8.10) decreased in offspring in the FGR group at 21 days,two and four months after birth (all P＜0.05).Compared with normal offspring,those in the FGR group showed decreased expression of PPAR γ protein (two months after birth:0.10 ± 0.01 vs 0.07± 0.01,t =-7.29;four months after birth:0.09±0.01 vs 0.08±0.01,t=-2.83),but increased expression of PTEN at protein level (two months after birth:0.10±0.01 vs 0.15±0.02,t=6.01;four months after birth:0.09±±0.01 vs 0.13±0.02,t=5.51) at two and four months after birth (all P＜0.05).(5) The IRI levels in offsprings in the FGR group were negatively correlated with the expression of PI3K,GLUT4 and PPAR γ at protein level (two months after birth:r=-0.90,-0.92 and-0.79;four months after birth:r=-0.92,-0.75 and-0.73,all P＜0.05),but positively correlated with the expression of PTEN at protein level (r=0.87 and 0.86,both P＜0.05) at two and four months after birth.Conclusions The abnormal expression of the key molecules of PI3K/AKT signaling pathway precedes the decrease of insulin sensitivity in newborn rats with FGR and the expression regulatory protein PPAR γ and PTEN are also changed,suggesting that these molecules may induce the impairment of insulin sensitivity in rats with FGR and be involved in the development of insulin resistance.

DHEA and frontal fibrosing alopecia: molecular and physiopathological mechanisms

Abstract The transforming growth factor-beta 1 (TGFβ1) promotes fibrosis, differentiating epithelial cells and quiescent fibroblasts into myofibroblasts and increasing expression of extracellular matrix. Recent investigations have shown that PPAR (peroxisome proliferator-activated receptor*) is a negative regulator of fibrotic events induced by TGFβ1. Dehydroepiandrosterone (DHEA) is an immunomodulatory hormone essential for PPAR functions, and is reduced in some processes characterized by fibrosis. Although scarring alopecia characteristically develops in the female biological period in which occurs decreased production of DHEA, there are no data in the literature relating its reduction to fibrogenic process of this condition. This article aims to review the fibrogenic activity of TGFβ1, its control by PPAR and its relation with DHEA in the frontal fibrosing alopecia.

The significance of PPARγexpression in lung tissue of rats with hypoxic pulmonary hypertension / 天津医药

Objective To investigate the significance of peroxisome proliferator-activated receptor (PPAR)γexpression in the lung tissue of rats with chronic hypoxic pulmonary hypertension (HPAH). Methods Forty male Sprague-Dawley rats were randomly divided into four groups (n=10 for each group):normal control group (NC), hypoxia control group-one-week (HC-1w), hypoxia control group-two-week (HC-2w) and hypoxia control group-three-week (HC-3w). Normal control group was raised under normal oxygen condition in ventilated animal cage for three weeks. The other HC groups were placed in a low oxygen chamber (O2 concentration of 10%) from 9:00 AM-5:00 PM (8 h/d) everyday by one week, two weeks and three weeks. The mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure (RVSP) were detected. The index of right ventricular hypertrophy RV/(LV+S) was measured by dissecting rat heart. The morphological changes of the small pul-monary arteries were observed by HE staining, and the percentage of vascular wall thickness (WT%) was calculated. The ex-pression level of PPARγprotein was detected by Westren blot assay. Results The mPAP, RVSP and RV/(LV+S) were sig-nificantly higher in HC groups than those of NC group (P<0.05). The morphology of pulmonary arteries showed vessel wall thickening and vessel lumina stenosis in HC groups compared with that of NC group. The PPARγexpression in lung tissue was significantly lower in HC groups than that of NC group, and the downward trend was more obvious with the extension of time. Conclusion PPARγplays an important role in the occurrence and development of chronic hypoxic pulmonary hyper-tension.

Association between Pro12Ala polymorphism of peroxisome proliferator activated receptorγ2 gene and gestational diabetes mellitus：a meta-analysis / 中华围产医学杂志

ObjectiveTo evaluate the association between Pro12Ala polymorphism in peroxisome proliferator activated receptorγ2 (PPARγ2) gene and gestational diabetes mellitus(GDM).Methods Publications on genetic association studies of PPARγ2 and GDM were searched using the PubMed database, The HuGE Navigator, China National Knowledge Infrastructure (CNKI), Wanfang database and VIP Science from the inception of the databases to December 1, 2014. Two reviewers independently selected literature according to the inclusion and exclusion criteria, extracted data and assessed the quality of the data using the Newcastle-Ottawa Scale (NOS) standard. Meta-analysis was performed using RevMan 5.3 software.ResultsOverall, 13 eligible articles were identified, including seven in English and six in Chinese, with a total of 2 787 GDM cases and 5 408 healthy controls. Quality assessment showed that the quality of the 13 articles was all good, with NOS≥5. (1) Pro12Ala polymorphism in PPARγ2 (allele Ala or genotype Ala/Ala or Pro/Ala) was shown to be highly associated with GDM occurrence on general evaluation, with anOR(95%CI) of 0.74(0.60-0.93) in the allele model and 0.79(0.65-0.96) in the dominant genetic model (P0.05, respectively), although there was still a significant correlation in polymerase chain reaction-restriction fragment length polymorphism with anOR(95%CI) of 0.58(0.43-0.79) in the allele model and 0.62(0.45-0.85) in the dominant genetic model (P<0.01, respectively).ConclusionsThe Ala allele and the Ala/Ala or Pro/Ala genotypes of the Pro12Ala polymorphism in PPARγ2 can decrease the risk of GDM. However, there are differences in the results which are affected by the genotype analysis method or races.

Effects of PPARγon malignant arrhythmia in myocardial ischemia/reperfusion model rats / 天津医药

Objective To investigate the effects of peroxisome proliferator activated receptor gamma (PPARγ) on malignant arrhythmia in myocardial of ischemia/reperfusion(I/R) rats. Methods Twenty-four SD rats were randomly divided into four groups:Sham group, I/R group, rosiglitazone (ROS) group and PPARγ inhibitor GW9662 (GW) group. The myocardial I/R injury was induced by ligation of the left anterior descending coronary artery, with ischemia for 30 min and reperfusion for 2 h. The whole process limb Ⅱ lead electrocardiogram was applied to observe the frequency of malignant arrhythmia and record the corrected changes of QT(QTc) interval. RT-PCR was used to detect the expression of PPARγ mRNA. Results There were 5 cases of malignant arrhythmia in ROS group, 2 in I/R and 1 in GW group, 0 was found in Sham group. There was a prolongation of the QTc interval in ROS group than the other groups after ischemic stage (P＜0.05). Compared with I/R group and ROS group, the QTc intervals were shorten in ischemia 30 min and reperfusion process in GW group (P＜0.05). Compared with sham group, the expression of PPARγ mRNA was significantly increased in other three groups (P＜0.05). The expression level of PPARγ mRNA was the highest in ROS group. The expression level of PPARγ mRNA was reduced in GW group compared with that of I/R group and ROS group (P＜0.05). Conclusion Over expression of PPARγ may lead to the occurrence of malignant arrhythmia in myocardial ischemia/reperfusion rats.

Effect of telmisartan on serum adiponectin, urine microalbumin of obese mice / 中华肾脏病杂志

Objective To evaluate the effect of telmisartan on serum adiponectin and urine microalbumin(mAlb) level by administrating it to mice with simple obesity, so as to explore new therapies for obesity-related kidney diseases.Method A total of 24 8-week-old male OB mice and 8 8-week-old male C57 mice were selected for this study.The genetic background of OB mouse was C57 mouse, but the lepin gene was deleted in OB mouse.OB mice were randomly divided into 3 groups by body weight and fed with high-fat diet for 12 weeks: model group (M group), telmisartan group (T1 group) and losartan group (T2 group).C57 mice acted as control and were fed with general diet for 12 weeks.Serum adiponectin and blood glucose levels were measured before and after treatment.24 h urine was collected to measure urine mAlb.Quantitative real-time PCR (qRT-PCR) was used to measure the expression level of peroxisome proliferators-activated receptors gamma mRNA(PPARγ mRNA).HE stain was used to observe the morphological changes of kidney and measure the glomerular diameter.Body weight, serum adiponectin level, blood glucose level, urine mAlb level, expression level of kidney PPARγ mRNA, kidney wet weight and glomerular diameter of 4 groups were compared and a correlation analysis was carried out by Person correlation coefficient.Results Compared with C group, the urine mAlb level in M group increased (P＜0.01), serum adiponectin level and the expression level of kidney PPARγ mRNA in M group decreased (P ＜ 0.01);The urine mAlb level was negatively correlated with serum adiponectin level and expression of kidney PPARγmRNA (r=-0.773,P ＜ 0.01;r=-0.469, P ＜ 0.01).The urine mAlb level in T1 group was lower than M group (P ＜ 0.05),serum adiponectin level and expression of kidney PPARγmRNA in T1 group were higher than M group (P ＜ 0.05).Compared with T2 group, the urine mAlb level in T1 group decreased, serum adiponectin level and expression of kidney PPARγ mRNA in T1 group increased (P ＜ 0.05);Compared with M group, the urine mAlb level in T2 group decreased (P=0.01).The morphological changes of kidney:glomerular volume increase and focal segmental sclerosis were found in some mice in M group and T2 group.No glomerular volume increase and focal segmental sclerosis were observed in T1 group.Conclusions Telmisartan can reduce urine microalbumin, whose mechanism might be that telmisartan can active the PPARγand promote the level of serum adiponectin.