Effect and Mechanism of Total Saponins from Panax Japonicus on White Adipose Tissue Browning/Brown Adipose Tissue Activation in High-fat Diet-induced Mice / 中国实验方剂学杂志

ObjectiveTo investigate the effect and mechanism of total saponins from Panax japonicus （TSPJ） on white adipose tissue （WAT） browning/brown adipose tissue （BAT） activation in C57BL6/J male mice fed on a high-fat diet （HFD）. MethodThirty-two C57BL6/J male mice （8-week-old） were randomly divided into a normal group， a model group， a low-dose TSPJ group， and a high-dose TSPJ group. The mice in the low-dose and high-dose TSPJ groups were given TSPJ for four months by gavage at 25， 75 mg·kg-1·d-1， respectively， and those in the other groups were given 0.5% sodium carboxymethyl cellulose （CMC-Na） accordingly. After four months of feeding， all mice were placed at 4 ℃ for acute cold exposure， and the core body temperature was monitored. Subsequently， all mice were sacrificed， and BAT and inguinal WAT （iWAT） were separated rapidly to detect the corresponding indexes. Hematoxylin-eosin （HE） staining was used to observe the morphological changes in each group. The effect of TSPJ on the mRNA expression of uncoupling protein 1 （UCP1）， fatty acid-binding protein 4 （FABP4）， cytochrome C （CytC）， PR domain-containing protein 16 （PRDM16）， elongation of very long chain fatty acids protein 3 （ELOVL3）， peroxisome proliferator-activated receptor γ （PPARγ）， and peroxisome proliferator-activated receptor-γ coactivator-1α （PGC-1α） in iWAT and BAT was detected by Real-time polymerase chain reaction （Real-time PCR）. Western blot was also used to detect the protein expression of UCP1， PRDM16， PPARγ， and PGC-1α in BAT and iWAT of each group. The effect of TSPJ on UCP1 expression in BAT and iWAT was detected by immunohistochemistry. Result① Compared with the model group， TSPJ could decrease the body weight and proportions of iWAT and BAT in the HFD-induced mice （P<0.05， P<0.01）. ② The body temperature of mice in the model group decreased compared with that in the normal group in the acute cold exposure tolerance test （P<0.05）. The body temperature in the high-dose TSPJ group increased compared with that in the model group （P<0.01）. ③ Compared with the normal group， the model group showed increased adipocyte diameter in iWAT and BAT and decreased number of adipocytes per unit area. Compared with the model group， the TSPJ groups showed significantly reduced cell diameter and increased number of cells per unit area， especially in the high-dose TSPJ group. ④ Compared with the normal group， the model group showed decreased mRNA expression of FABP4， UCP1， CytC， PRDM16， ELOVL3， PGC-1α， and PPARγ in adipose tissues of mice （P<0.05， P<0.01）. Compared with the model group， after intervention with TSPJ， the mRNA expression was significantly up-regulated （P<0.05， P<0.01）. ⑤ Compared with the normal group， the model group showed decreased protein expression of UCP1， PRDM16， PPARγ， and PGC-1α in adipose tissues of mice （P<0.05， P<0.01）. Compared with the model group， after intervention with TSPJ， the protein expression increased significantly （P<0.05， P<0.01）. ConclusionTSPJ could induce the browning of iWAT/BAT activation and enhance adaptive thermogenesis in obese mice induced by HFD. The underlying mechanism may be attributed to the activation of the PPARγ/PGC-1α signaling pathway.

Role of melatonin receptor 1B gene polymorphism and its effect on the regulation of glucose transport in gestational diabetes mellitus / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Melatonin receptor 1B (MT2, encoded by the MTNR1B gene), a high-affinity receptor for melatonin, is associated with glucose homeostasis including glucose uptake and transport. The rs10830963 variant in the MTNR1B gene is linked to glucose metabolism disorders including gestational diabetes mellitus (GDM); however, the relationship between MT2-mediated melatonin signaling and a high birth weight of GDM infants from maternal glucose abnormality remains poorly understood. This article aims to investigate the relationship between rs10830963 variants and GDM development, as well as the effects of MT2 receptor on glucose uptake and transport in trophoblasts. TaqMan-MGB (minor groove binder) probe quantitative real-time polymerase chain reaction (qPCR) assays were used for rs10930963 genotyping. MT2 expression in the placenta of GDM and normal pregnant women was detected by immunofluorescence, western blot, and qPCR. The relationship between MT2 and glucose transporters (GLUTs) or peroxisome proliferator-activated receptor γ (PPARγ) was established by western blot, and glucose consumption of trophoblasts was measured by a glucose assay kit. The results showed that the genotype and allele frequencies of rs10830963 were significantly different between GDM and normal pregnant women (P<0.05). The fasting, 1-h and 2-h plasma glucose levels of G-allele carriers were significantly higher than those of C-allele carriers (P<0.05). Besides, the protein and messenger RNA (mRNA) expression of MT2 in the placenta of GDM was significantly higher than that of normal pregnant women (P<0.05). Melatonin could stimulate glucose uptake and GLUT4 and PPARγ protein expression in trophoblasts, which could be attenuated by MT2 receptor knockdown. In conclusion, the rs10830963 variant was associated with an increased risk of GDM. The MT2 receptor is essential for melatonin to raise glucose uptake and transport, which may be mediated by PPARγ.

Effect of total flavonoids of buckwheat flower and leaf on myocardial cell apoptosis and Wnt/β-catenin/PPARγ pathway in arrhythmic rats / 中国中药杂志

This paper aimed to investigate the effect of total flavonoids of buckwheat flower and leaf on myocardial cell apoptosis and Wnt/β-catenin/peroxisome proliferator-activated receptor γ(PPARγ) pathway in arrhythmic rats. SD rats were randomly divided into a control group, a model group, a low-dose(20 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a medium-dose(40 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a high-dose(80 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a propranolol hydrochloride(2 mg·kg~(-1)) group, with 12 rats in each group. Except the control group, rats in other groups were prepared as models of arrhythmia by sublingual injection of 1 mL·kg~(-1) of 0.002% aconitine. After grouping and intervention with drugs, the arrhythmia, myocardial cells apoptosis, myocardial tissue glutathione peroxidase(GSH-Px), catalase(CAT), malondialdehyde(MDA), serum interleukin-6(IL-6), prostaglandin E2(PGE2) levels, myocardial tissue apoptosis, and Wnt/β-catenin/PPARγ pathway-related protein expression of rats in each group were measured. As compared with the control group, the arrhythmia score, the number of ventricular premature beats, ventricular fibrillation duration, myocardial cell apoptosis rate, MDA levels in myocardial tissues, serum IL-6 and PGE2 levels, Bax in myocardial tissues, and Wnt1 and β-catenin protein expression levels increased significantly in the model group, whereas the GSH-Px and CAT levels, and Bcl-2 and PPARγ protein expression levels in myocardial tissues reduced significantly. As compared with the model group, the arrhythmia score, the number of ventricular premature beats, ventricular fibrillation duration, myocardial cell apoptosis rate, MDA leve in myocardial tissues, serum IL-6 and PGE2 levels, Bax in myocardial tissues, and Wnt1 and β-catenin protein expression levels reduced in the drug intervention groups, whereas the GSH-Px and CAT levels and Bcl-2 and PPARγ protein expression levels in myocardial tissues increased. The groups of total flavonoids of buckwheat flower and leaf were in a dose-dependent manner. There was no significant difference in the levels of each index in rats between the propranolol hydrochloride group and the high-dose group of total flavonoids of buckwheat flower and leaf. The total flavonoids of buckwheat flower and leaf inhibit the activation of Wnt/β-catenin pathway, up-regulate the expression of PPARγ, reduce oxidative stress and inflammatory damage in myocardial tissues of arrhythmic rats, reduce myocardial cell apoptosis, and improve the symptoms of arrhythmia in rats.

Effects of Shenqi Gualou Xiebai Banxia Decoction （参芪瓜蒌薤白半夏汤） on PPARγ， Bile Acids， and Blood Lipids in Mouse Models of Atherosclerosis / 中医杂志

ObjectiveTo explore the mechanism of Shenqi Gualou Xiebai Banxia Decoction （参芪瓜蒌薤白半夏汤， SGXBD） in the treatment of atherosclerosis. MethodsThirty Apolipoprotein E gene knockout （ApoE-/-） mice were randomly divided into five groups： model group， rosuvastatin group， low-， moderate-， and high-dose SGXBD， with six mice in each group. They were fed a high-fat diet to prepare for atherosclerosis model. Another six C57BL/6J wild-type mice were set as the blank group. After modeling， the low-， moderate-， and high-dose SGXBD groups were gavaged with 6.46， 12.92， and 25.84 g/（kg·d） of SGXBD， respectively. The rosuvastatin group was given 1.55 mg/（kg·d） of rosuvastatin tablets by gavage. The blank group and model group were given 0.5 ml saline by gavage. After four weeks， the total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， and high-density lipoprotein cholesterol （HDL-C） in the serum of each group were detected， as well as TC and TG in the liver. The serum bile acid level was detected by enzyme cycling colorimetry. The mRNA and protein expression of peroxisome proliferator-activated receptor γ （PPARγ）， sterol regulatory element-binding protein 2 （SREBP2）， 3-hydroxy-3-methylglutaryl-CoA reductase （HMGCR）， and cholesterol 7α-hydroxylase （CYP7A1） in the liver were detected by real-time RT-PCR and Western blot. ResultsCompared with the blank group， the model group showed significant increases in serum TG， TC， and LDL-C levels， and significant decreases in HDL-C and bile acid levels； the levels of TG and TC in the liver， as well as the expression of SREBP2 and HMGCR proteins and mRNA in the liver significantly increased， while the expression of PPARγ and CYP7A1 proteins and mRNA significantly decreased （all P＜0.01）. Compared with the model group， the rosuvastatin group and high-dose SGXBD group showed significant decreases in serum TG， TC， and LDL-C levels and liver TG and TC levels， and significant increases in bile acid levels； the expression of PPARγ and CYP7A1 proteins and mRNA increased， while the expression of SREBP2 and HMGCR proteins and mRNA decreased； the low-dose SGXBD group showed significant decreases in serum TC and LDL-C levels and liver TC level （P＜0.05 or P＜0.01）. Compared with the rosuvastatin group， the low-dose SGXBD group had a significantly higher liver TC level， while the high-dose SGXBD group had a significantly lower liver TC level， CYP7A1 mRNA level， and PPARγ protein expression level， and a significantly higher SREBP2 protein expression level （P＜0.05 or P＜0.01）. Compared with the low- and moderate-dose groups， the high-dose SGXBD group had significantly lower serum TG and liver TC levels （P＜0.05）. ConclusionSGXBD may improve blood lipid levels and exhibit anti-atherosclerotic effects by regulating the protein level of PPARγ and simultaneously affecting the synthesis of liver cholesterol and the conversion of cholesterol to bile acids.

Effect of Five Huoxue Huayu Prescriptions on Blood Lipid Metabolism， Liver Tissue and ABCA1 and PPARγ Expression in New Zealand Rabbits with Blood Stasis Syndrome / 中国实验方剂学杂志

ObjectiveTo observe the effects of five Huoxue Huayu prescriptions on blood lipid metabolism， liver tissue and adenosine triphosphate binding cassette transporter A1 （ABCA1） and peroxisome proliferator-activated receptor γ（PPARγ） expression in New Zealand rabbits with blood stasis syndrome， and to compare their differences in order to provide laboratory evidence for clinical selection of prescriptions and drugs. MethodSeventy New Zealand rabbits were randomly divided into normal group （n=10） and model group （n=60）. The blood stasis syndrome was modeled by the method of starvation+high-fat feed+adrenaline. After the models were successfully established， they were randomly divided into Xuefu Zhuyutang（3.55 g·kg-1·d-1） group， Danshenyin（1.962 g·kg-1·d-1） group， Shixiaosan（0.56 g·kg-1·d-1） group， Huoluo Xiaolingdan（2.80 g·kg-1·d-1） group， and Taohong Siwutang（2.66 g·kg-1·d-1） group， and were given corresponding compound prescriptions by gavage. The normal group and model group were given the same dose of distilled water. After the treatment of 30 consecutive days， blood was taken from the abdominal aorta to detect the content of total cholesterol （TC）， triglycerides （TG）， high-density lipoprotein cholesterol （HDL-C）， low-density lipoprotein cholesterol（LDL-C） and apolipoprotein A1 （ApoA1）. Hematoxylin-eosin（HE） staining was used to observe the changes in liver tissue. Real-time polymerase chain reaction （Real-time PCR） and Western blot were used to detect the mRNA and protein expression of ABCA1 and PPARγ in liver tissue， respectively. ResultCompared with the conditions in the normal group， increased mRNA and protein levels of HDL-C， LDL-C， TG， TC， and PPARγ （P<0.01）， decreased ApoA1 level （P<0.05） and decreased mRNA and protein levels of ABCA1 （P<0.01） were found in the model group. Compared with the conditions in the model group， the HDL-C level in the five Huoxue Huayu prescriptions was lowered （P<0.05）， and lowered TG level in Xuefu Zhuyutang group and Shixiaosan group （P<0.05）， decreased LDL-C and TC levels in Shixiaosan group （P<0.05）， and increased ApoA1 level in the Huoluo Xiaolingdan group （P<0.01） and Taohong Siwutang group （P<0.05） were observed. Furthermore， the mRNA and protein levels of ABCA1 in Xuefu Zhuyutang group， Shixiaosan group， Huoluo Xiaolingdan group and Taohong Siwutang group were elevated （P<0.05， P<0.01）， and the elevated levels were higher than that of Danshenyin group （P<0.05）. The mRNA level of PPARγ in the five Huoxue Huayu prescriptions was reduced （P<0.01）， and its protein level was also decreased in Xuefu Zhuyutang group， Shixiaosan group， Huoluo Xiaolingdan group and Taohong Siwutang group （P<0.01）. ConclusionThe five Huoxue Huayu prescriptions had a certain therapeutic effect on dyslipidemia，which might be achieved by up-regulating the expression of ApoA1 and ABCA1 to promote the production of HDL-C and strengthen the excretion of dysfunctional HDL-C. And Xuefu Zhuyutang had the optimal effect in lowering lipid.

Isoflavones from Sojae Semen Praeparatum Regulate Lipid Metabolism in Atherosclerotic Mice Through PPARγ/LXRα/ABCA1 Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo study the effect of isoflavones from Sojae Semen Praeparatum （ISSP） on lipid metabolism in atherosclerotic mice， and decipher the underlying mechanism via the peroxisome proliferator-activated receptor gamma/liver X receptor alpha/ATP-binding cassette transporter A1 （PPARγ/LXRα/ABCA1） signaling pathway. MethodFifty ApoE-/- mice were randomly assigned into the model group， western medicine （atorvastatin calcium， 3.03 mg·kg-1） group， and low-， medium-， and high-dose ISSP （2.5， 5， 10 mg·kg-1， respectively） groups， with 10 rats in each group. Atherosclerosis model mice were established by bilateral ovariectomy and feeding high-fat diet. Another 10 ApoE-/- mice receiving ovariectomy and high-fat diet were taken as the sham group. Some mice died of postoperative infection， and finally 6 mice were included in each group. One week after operation， each group was administrated with corresponding drugs or equivalent amount of normal saline. After 12 weeks， the levels of triglyceride （TG）， total cholesterol （TC）， high-density lipoprotein cholesterol （HDL-C）， low-density lipoprotein cholesterol （LDL-C）， and non-esterified fatty acids （NEFAs） in serum and liver tissue were measured. The levels of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in serum were detected by enzyme-linked immunosorbent assay （ELISA）. Hematoxylin-eosin （HE） staining and oil red O staining were used for observation of aortic plaque formation and liver lipid deposition. The mRNA and protein levels of PPARγ， LXRα， ABCA1， and ATP-binding cassette transporter G1 （ABCG1） in liver were determined by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot. ResultCompared with the sham group， the modeling of atherosclerosis increased the aortic plaque area （P<0.01）， elevated the serum TC， TG， LDL-C， TNF-α， and IL-6 levels （P<0.01）， decreased the level of HDL-C （P<0.01）， increased the liver index （P<0.05） and the levels of TC， TG， and NEFAs in liver （P<0.01）， and caused obvious hepatic fat vacuoles and lipid deposition. In addition， the modeling down-regulated the mRNA levels of PPARγ， LXRα， ABCA1 in liver （P<0.05， P<0.01），and regulated the mRNA and protein levels of ABCG1（P<0.05， P<0.01）. Compared with the model group， atorvastatin calcium and middle-， high-dose ISSP reduced the serum TC， TG， LDL-C， TNF-α， and IL-6 levels （P<0.01）， decreased the liver index （P<0.01）， alleviated the liver fat vacuoles and lipid deposition， and increased the levels of TC， TG， and NEFAs in the liver （P<0.05， P<0.01）. Furthermore， they up-regulated the mRNA and protein levels of PPARγ， LXRα， ABCA1， and ABCG1 in the liver （P<0.05， P<0.01）. ConclusionISSP may regulate lipid metabolism through PPARγ/LXRα/ABCA1 signaling pathway to down-regulate the expression of inflammatory cytokines in serum and alleviate liver lipid deposition， thereby suppressing the formation of atherosclerotic plaque.

Effect of Hei Xiaoyaosan on Neuroinflammation in AD Model Rats： Based on Wnt/β-catenin Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo explore whether Hei Xiaoyaosan can inhibit the inflammatory response in the hippocampi of Alzheimer's disease （AD） rats by regulating and activating the Wnt/β-catenin signaling pathway to improve the cognitive and memory dysfunction. MethodAmong the 90 male Wistar rats， 12 were randomly selected as the blank group （normal saline） and 12 as the sham operation group （normal saline）. For the remainder， amyloid β-protein42 （Aβ42） was injected in the left and right hippocampus to induce AD， and then the AD rats were randomized into model group， low-， medium-， and high-dose Hei Xiaoyaosan groups （corresponding doses of Hei Xiaoyaosan， ig）， and donepezil group （donepezil hydrochloride，ig）， with 12 in each group. The administration lasted 42 days. The pathological changes of hippocampal CA1 region was observed based on Nissl staining. The escape latency on the 1st to 5th day in Morris water maze was recorded and the spatial memory on the 6th day was tested. Enzyme-linked immunosorbent assay （ELISA） was employed to detect the expression of interleukin （IL）-6， IL-10， and tumor necrosis factor-α （TNF-α） in rat hippocampus and serum， Western blotting to examine the protein expression of glycogen synthase kinase-3β （GSK-3β）， β-catenin， and peroxisome proliferator-activated receptor gamma （PPARγ）， and real-time polymerase chain reaction （Real-time PCR） to determine the mRNA expression of rat GSK-3β， β-catenin， and PPARγ. ResultCompared with the blank group， the number of neurons in the hippocampal CA1 area of model group was significantly reduced， the arrangement was uneven， the cell body was damaged more obviously， and the Neisser body was unclear. The treatment group was significantly prolonged （P<0.01）， and the number of crossing stations was significantly reduced （P<0.01）， the levels of IL-10 in serum and hippocampus of rats in the model group were significantly decreased， while the levels of IL-6 and TNF-α were significantly increased （P<0.01）， the GSK-3β protein and mRNA in the model group were significantly increased， and the protein expressions of β-catenin and PPARγ were significantly decreased （P<0.01）， and the difference was more obvious. The number of neurons in the donepezil group was more distributed， neatly arranged， the structure was intact， and the Nissl bodies were clear and definite， the escape latency on the 3rd to 5th days in middle and high dose groups of Hei Xiaoyaosan and the donepezil group was significantly shortened （P<0.01）， the number of crossing platforms increased significantly （P<0.01）， the expression levels of IL-10 in the rat hippocampus and serum were significantly increased， while IL-6 and TNF-α were significantly decreased （P<0.01）， GSK-3β in the rat hippocampus was significantly increased. The expressions of GSK-3β protein and mRNA were significantly decreased， while the expression levels of β-catenin and PPARγ protein and mRNA were significantly increased （P<0.01）. There was no significant difference in each index between the donepezil hydrochloride group and the high-dose Hei Xiaoyaosan group. ConclusionHei Xiaoyaosan can inhibit the inflammatory response in the hippocampus of AD rats by regulating the Wnt/β-catenin signaling pathway， thereby alleviating the cognitive and memory impairment of AD rats.

PPARγ2 functions as a tumor suppressor in a translational mouse model of human prostate cancer / 亚洲男科学杂志(英文版)

Peroxisome proliferator-activated receptors γ (PPARγ) is a master regulator that controls energy metabolism and cell fate. PPARγ2, a PPARγ isoform, is highly expressed in the normal prostate but expressed at lower levels in prostate cancer tissues. In the present study, PC3 and LNCaP cells were used to examine the benefits of restoring PPARγ2 activity. PPARγ2 was overexpressed in PC3 and LNCaP cells, and cell proliferation and migration were detected. Hematoxylin and eosin (H&E) staining was used to detect pathological changes. The genes regulated by PPARγ2 overexpression were detected by microarray analysis. The restoration of PPARγ2 in PC3 and LNCaP cells inhibited cell proliferation and migration. PC3-PPARγ2 tissue recombinants showed necrosis in cancerous regions and leukocyte infiltration in the surrounding stroma by H&E staining. We found higher mixed lineage kinase domain-like (MLKL) and lower microtubule-associated protein 1 light chain 3 (LC3) expression in cancer tissues compared to controls by immunohistochemistry (IHC) staining. Microarray analysis showed that PPARγ2 gain of function in PC3 cells resulted in the reprogramming of lipid- and energy metabolism-associated signaling pathways. These data indicate that PPARγ2 exerts a crucial tumor-suppressive effect by triggering necrosis and an inflammatory reaction in human prostate cancer.

Pharmacological Activation of RXR-α Promotes Hematoma Absorption via a PPAR-γ-dependent Pathway After Intracerebral Hemorrhage / 神经科学通报·英文版

Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH. Our results showed that pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in microglia/macrophages, neurons, and astrocytes. Mechanistically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, as well as reducing neuroinflammation by modulating microglia/macrophage reprograming from the M1 into the M2 phenotype. Furthermore, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662. In conclusion, the pharmacological activation of RXR-α confers robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.

Role of PPARγ/CD36 signaling pathway in macrophage lipid metabolism after Mycobacterium tuberculosis infection / 中华微生物学和免疫学杂志

Objective:To investigate the role of peroxisome proliferator-activated receptor γ (PPARγ)/CD36 signaling pathway in macrophage lipid metabolism after Mycobacterium tuberculosis ( Mtb) infection. Methods:THP-1-derived macrophages were infected with Mtb. Four groups were included in this study, which were control group, Mtb infection group, Mtb+ rosiglitazone (ROZ, PPARγ agonist) group and Mtb+ GW9662 (PPARγ antagonist) group. Western blot and RT-PCR were used to detect the expression of PPARγ in macrophages at protein and mRNA levels, respectively. The lipids in cells were detected by oil red O staining. The concentrations of total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL-C) and high density lipoprotein (HDL-C) in the supernatant of cell culture were detected by automatic biochemical analyzer. The expression of CD36 was detected by immunohistochemistry. CCK-8 was used to detect the proliferation rate of macrophages. Results:Mtb infection significantly increased the expression of PPARγ in macrophages ( P<0.001), promoted intracellular lipid aggregation and CD36 expression and decreased the levels of TC, TG, LDL-C and HDL-C in the supernatant of cell culture ( P<0.001) and cell proliferation rate ( P<0.001). PPARγ agonist significantly enhanced the intracellular lipid accumulation and CD36 expression that were induced by Mtb infection and down-regulated the lipid level in the supernatant of cell culture and cell proliferation rate, while PPARγ antagonist reversed the above effects. Conclusions:PPARγ played a role in lipid metabolism in Mtb-infected macrophages through affecting CD36 expression.

Mechanism of Magnoliae Officinalis Cortex in treatment of peptic ulcer based on network pharmacology and molecular docking / 中国中药杂志

Magnoliae Officinalis Cortex(Houpo) can treat peptic ulcer disease(PUD), the mechanism of which remains unclear. In this study, network pharmacology and molecular docking were employed to predict the mechanism of Houpo in the treatment of PUD. Through literature review and TCMSP screening, 15 main active ingredients were obtained. The SwissTargetPrediction database was used to predict the potential targets of the ingredients, and Therapeutic Target Database(TTD), DrugBank, and Human Phenotype Ontology(HPO) to screen the disease-related targets. A total of 49 potential targets were obtained by the intersection of active ingre-dients-related targets and disease-related targets. Cytoscape 3.6.1 was employed to construct the protein-protein interaction network for the targets with high confidence(score>0.700) screened out by STRING. The DAVID database was used for GO and KEGG pathway enrichment of potential targets. GO enrichment analysis showed that the treatment mechanism was mostly related to nuclear receptor activity, ligand-activated transcription factor activity, and G protein-coupled acetylcholine receptor activity. KEGG enrichment analysis found that Houpo could regulate material metabolism, endocrine system, p53 signaling pathway, and PPAR signaling pathway. Molecu-lar docking verified that all 15 ingredients had good binding activities with key targets(CHRM1, CHRM2, FABP1, mTOR, and STAT3). The results mean that Houpo can treat PUD by participating in cell metabolism, inhibiting inflammatory cytokines, and regulating cell proliferation and apoptosis.

Effect of electroacupuncture on lung dysplasia in rats with intrauterine growth restriction induced by maternal food restriction / 中国针灸

OBJECTIVE@#To investigate the protective effect of electroacupuncture (EA) at "Zusanli" (ST 36) in pregnant rats on lung dysplasia of newborn rats with intrauterine growth restriction (IUGR) induced by maternal food restriction.@*METHODS@#Twenty-four female SD rats were randomly divided into a control group, a control+EA group, a model group and a model+EA group, 6 rats in each group. From the 10th day into pregnancy to the time of delivery, the rats in the model group and the model+EA group were given with 50% dietary restriction to prepare IUGR model. From the 10th day into pregnancy to the time of delivery, the rats in the control+EA group and the model+EA group were treated with EA at bilateral "Zusanli" (ST 36), once a day. The body weight of offspring rats was measured at birth, and the body weight and lung weight of offspring rats were measured on the 21st day after birth. The lung function was measured by small animal lung function detection system; the lung tissue morphology was observed by HE staining; the content of peroxisome proliferator activated receptor γ (PPARγ) in lung tissue was detected by ELISA.@*RESULTS@#Compared with the control group, the body weight at birth as well as the body weight, lung weight, lung dynamic compliance (Cdyn) and PPARγ at 21 days after birth in the model group were significantly decreased (@*CONCLUSION@#EA at "Zusanli" (ST 36) may protect the lung function and lung histomorphology changes by regulating the level of PPARγ of lung in IUGR rats induced by maternal food restriction.

Updated research progress of selective PPARγ modulators / 药学学报

Thiazolidinediones (TZDs) are currently the only recognized insulin sensitizers available for the clinical treatment of type 2 diabetes. Although their advantages are recognized, the profiles of numerous adverse effects hinder the continued use of these drugs. Peroxisome proliferator-activated receptor γ (PPARγ) is known as a receptor for TZDs, and its underlying mechanisms of pharmacological actions and adverse effects have been deeply explored. To maximally preserve the PPARγ-mediated insulin sensitizing effects and reduce the occurrence of related adverse effects, the concept of "selective PPARγ modulators (SPPARMs)" has been proposed and developed, guiding the development of new drugs. In this review, we summarize the recent research progress in the definition of SPPARMs, the candidate classification and the molecular underpinnings, as well as present the discovery of the YR series compounds as an example, and discuss the potential application prospects of SPPARMs.

Pharmacological Activation of RXR-α Promotes Hematoma Absorption via a PPAR-γ-dependent Pathway After Intracerebral Hemorrhage / 神经科学通报·英文版

Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH. Our results showed that pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in microglia/macrophages, neurons, and astrocytes. Mechanistically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, as well as reducing neuroinflammation by modulating microglia/macrophage reprograming from the M1 into the M2 phenotype. Furthermore, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662. In conclusion, the pharmacological activation of RXR-α confers robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.

Improvement effect and mechanism of ethanol extract from Citri Reticulatae Pericarpium on triglyceride in hyperlipidemia model rat / 中国中药杂志

The aim of this paper was to study the improvement effect of ethanol extract from Citri Reticulatae Pericarpium(CRP) on triglyceride of hyperlipidemia model rats, and to explore the possible mechanism. SD rats were randomly divided into normal group, model group, positive control group, and high, medium and low-dose CRP ethanol extract groups, with 10 rats in each group. During the experiment, except for the normal group that was fed with distilled water and ordinary feed, rats in the other groups were given different concentrations of alcohol and fed with high-sugar and fat diets. All rats were given free diets. While being modeled, each group was administered with 0.01 mL·g~(-1) by gavage once a day for six weeks. Blood samples were collected after two weeks, four weeks and six weeks of drug treatment. After the completion of the experiment, blood, liver and adipose tissue were collected. Triglyceride(TG), alanine aminotransferase(ALT), aspartate aminotransferase(AST), alkaline phosphatase(ALP) in serum, TG in liver tissue and TG in fecal were detected. Free fatty acid(FFA) and triglyceride-related hydrolase, such as adipose tiglyceride lipase(ATGL), lipoprotein lipase(LPL), hepatic lipase(HL), hormone-sensitive triglyceride lipase(HSL) were detected by ELISA. The mRNA expressions of peroxisome proliferators-activated receptors(PPARγ), sterol regulatory element binding protein 1 c(SREBP-1 c) and farnesoid X receptor(FXR) were determined by RT-PCR. Compared with the model group, each administration group could reduce TG levels in serum and liver to varying degrees, reduce serum ALT, AST, ALP activities, significantly reduce free fatty acid content in serum, significantly increase triglyceride metabolism-related enzymes, including fat ATGL, LPL and liver HL content, and significantly reduced the content of fat HSL. According to the study of transcriptional regulation genes relating to triglyceride metabolism, extract from CRP could significantly increase the mRNA expressions of PPARγ and FXR. In conclusion, ethanol extract from CRP could ob-viously reduce the TG level of hyperlipidemia model rats, and might reduce plasma TG content by increasing PPARγ-LPL/ATGL and FXR-HL triglyceride hydrolysis pathways.

Effect of fucoxanthin on insulin resistance in obese mice induced by high fat diet / 中国中药杂志

The aim of this paper was to study the effect and mechanism of fucoxanthin on insulin resistance of obese mice induced by high-fat diet. Fifty C57 BL/6 J male mice were randomly divided into control group and high-fat diet group. The insulin resistance model was induced with high-fat diet for 12 weeks, and model mice were randomly divided into model group, fucoxanthin-0.2% group, fucoxanthin-0.4% group and metformin group. After dietary treatment for 6 weeks, the body weight and epididymal fat weight in each group were measured. Fasting blood glucose(FBG), fasting insulin(FINS), total cholesterol(TC), triglyceride(TG), low-density lipoprotein(LDL-C) and high-density lipoprotein(HDL-C) were measured, and insulin resistance index(HOMA-IR) was calcula-ted. The pathological morphology in liver was observed by hematoxylin eosin staining, and the expressions of some key proteins in insulin receptor substrate 1(IRS-1)/posphoinositide 3-kinase(PI3 K)/serine-threonine kinase(Akt) and peroxisome proliferators-activated receptor-γ(PPARγ)/sterol regulatory element binding protein-1(SREBP-1)/fatty acid synthetase(FAS) pathways in liver were detected by Western blot. According to the findings, compared with the model group, levels of body weight, epididymal fat weight, FBG, FINS, TC, TG, LDL-C and HOMA-IR, as well as protein expressions of PPARγ, SREBP-1 and FAS in liver were significantly reduced(P<0.05 or P<0.01), while level of HDL-C and protein expressions of p-IRS-1, IRS-1, PI3 K and p-Akt in liver were signi-ficantly increased after treatment with fucoxanthin(P<0.05 or P<0.01). And the pathological changes of liver tissue in fucoxanthin-treated mice were also improved obviously. The results showed that fucoxanthin could improve obesity, hyperglycemia and hyperlipidemia, and alleviate insulin resistance in obese mice, and its mechanism is possibly related to the regulation of IRS-1/PI3 K/Akt and PPARγ/SREBP-1/FAS pathways.

Silencing of DsbA-L gene impairs the PPARγ agonist function of improving insulin resistance in a high-glucose cell model / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Disulfide-bond A oxidoreductase-like protein (DsbA-L) is a molecular chaperone involved in the multimerization of adiponectin. Recent studies have found that DsbA-L is related to metabolic diseases including gestational diabetes mellitus (GDM), and can be regulated by peroxisome proliferator-activated receptor γ (PPARγ) agonists; the specific mechanism, however, is uncertain. Furthermore, the relationship between DsbA-L and the novel adipokine chemerin is also unclear. This article aims to investigate the role of DsbA-L in the improvement of insulin resistance by PPARγ agonists in trophoblast cells cultured by the high-glucose simulation of GDM placenta. Immunohistochemistry and western blot were used to detect differences between GDM patients and normal pregnant women in DsbA-L expression in the adipose tissue. The western blot technique was performed to verify the relationship between PPARγ agonists and DsbA-L, and to explore changes in key molecules of the insulin signaling pathway, as well as the effect of chemerin on DsbA-L. Results showed that DsbA-L was significantly downregulated in the adipose tissue of GDM patients. Both PPARγ agonists and chemerin could upregulate the level of DsbA-L. Silencing DsbA-L affected the function of rosiglitazone to promote the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)/AKT pathway. Therefore, it is plausible to speculate that DsbA-L is essential in the environment of PPARγ agonists for raising insulin sensitivity. Overall, we further clarified the mechanism by which PPARγ agonists improve insulin resistance.

Study on pathogenesis of mice model of coronary heart disease with phlegm-blood stasis syndrome based on PPARγ pathway / 中草药

Objective: To explore the pathogenesis of phlegm-blood stasis syndrome in mice model of coronary heart disease based on PPAR gamma pathway. Methods: Healthy SPF C57BL/6J mice were used in the control group and the sham operation group, and ApoE-/-mice were used in the blood stasis group, phlegm turbid group and phlegm-blood stasis group. The phlegm turbid group and the phlegm-blood stasis group were fed with high-fat diet for 12 weeks, and the other groups were fed with normal feed for 12 weeks. At the end of the 8th week, the left anterior descending coronary artery was ligated in the blood stasis group and the phlegm-blood stasis group. The sham operation group was not ligated. The levels of IL-6, ET, Ang II and PPARγ in serum were measured by enzyme linked immunosorbent assay, the levels of PPARγ, ABCA1 and CD36 protein in liver tissue were detected by Western blotting, and the levels of CD40, MMP-9 and NF-κB protein in aorta were detected by immunohistochemistry. Results: Compared with sham operation group, there was no significant change in serum IL-6, the content of serum ET in the group of phlegm and blood stasis was increased significantly (P < 0.01), the content of Ang II in blood stasis group was increased significantly (P < 0.05), the content of serum Ang II in phlegm turbid group and phlegm-blood stasis group was increased significantly (P < 0.01), and the content of PPARγ was decreased. In liver tissue, the expression levels of PPARγ and ABCA1 protein in blood stasis group, phlegm turbid group and phlegm-blood stasis group were decreased significantly (P < 0.01), the expression of CD36 protein was increased. CD40, MMP-9 and NF-κB levels in aorta tissue were increased significantly (P < 0.01). Conclusion: The phlegm-blood stasis syndrome of coronary heart disease can cause more serious atherosclerotic plaque in the course of its onset. Its mechanism may be through activating PPARγ pathway.

Effect of salvianolic acid B on high-glucose induced renal tubular epithelial-mesenchymal transition in rats and its mechanism / 中国中药杂志

The aim of this paper was to observe the effect of salvianolic acid B(Sal B) on high-glucose induced renal tubular epithelial-mesenchymal transition(EMT) in rats, and to explore its possible mechanisms of prevention and treatment of diabetic nephropathy. The rat renal tubular epithelial NRK-52 E cells were cultured in vitro. The cells were divided into control group, high glucose group, high glucose+10 μmol·L~(-1)Sal B group(Sal B), the above 3 groups were set at 6, 12, 24 and 48 h for dynamic observation; high glucose+Sal B different concentration(1, 5, 10 μmol·L~(-1)) groups, high glucose+5.0 μmol·L~(-1) pioglitazone group, high glucose+10 μmol·L~(-1)Sal B+5 μmol·L~(-1)GW9662 group. The protein expression levels of PPARγ, PTEN, α-SMA, E-cadherin and PI3 K/Akt signaling molecules were determined by Western blot. The mRNA expression of PPARγ and PTEN were detected by Real-time PCR. The viabi-lity of NRK52 E cells was determined by MTT assay. The results showed that as compared with control group, the mRNA and protein expression levels of PPARγ and PTEN in high glucose group gradually reduced, the protein expression levels of α-SMA and p-Akt~((Thr308))gradually increased, and the protein expression of E-cadherin gradually reduced(P<0.05). As compared with high glucose group, when increases in Sal B doses, the mRNA and protein expression levels of PPARγ, PTEN in high glucose + different concentrations of Sal B groups gradually increased, the protein expression levels of α-SMA and p-Akt~((Thr308)) gradually reduced, and the protein expression of E-cadherin gradually increased(P<0.05), however, the effect of 1 μmol·L~(-1)concentration of Sal B on the expression of PPARγ mRNA and protein and PTEN mRNA was not significantly different. As compared with high glucose group, the mRNA and protein expression levels of PPARγ mRNA(except 6 h) and protein(except 6 h), PTEN mRNA(except 6 h) and protein(except 6, 12 h) kept increasing, the protein expression levels of α-SMA and p-Akt~((Thr308))(except 6 h) continued to reduce, the protein expression of E-cadherin kept increasing in high glucose+10 μmol·L~(-1) Sal B dynamic observation group(P<0.05). As compared with high glucose group, Sal B and the pioglitazone(PIO) can greatly enhance the expression of PPARγ, PTEN at mRNA and protein levels, enhance the expression of E-cadherin at protein levels, and reduce the expression of α-SMA, p-Akt~((Thr308))protein level(P<0.05), there was no significant difference between the two groups. However, the expression levels of PPARγ and PTEN mRNA and protein, E-cadherin, α-SMA and p-Akt(Thr308) protein in the Sal B+GW9662 control group were not statistically significant compared with the high glucose group. The effect of Sal B was blocked by the PPARγ antagonist GW9662. It can be concluded that Sal B can suppress the NRK52 E cells induced by high-glucose EMT. The mechanism may be related to the activation of PPARγ with Sal B, and the up-regulation of PTEN expression, and thereby inhibiting the fibrosis effect of PI3 K/Akt signaling pathway.

Effects and Mechanism Study of Pioglitazone on High Glucose-induced Epithelial-mesenchymal Transition in Renal Tubular Epithelial Cells of Rat / 中国药房

OBJECTIVE：To investigate the effects o f pioglitazone （PIO）on high glucose-induced epithelial-mesenchymal transition（EMT）in renal tubular epithelial cells of rat and its possible mechanism ，and to provide theoretic reference and new target for the prevention and treatment of diabetic nephropathy. METHODS ：The rat renal tubular epithelial NRK- 52E cells were randomly divided into control group （5.5 mmol/L glucose ），high-glucose group （30 mmol/L glucose ），PIO intervention group （30 mmol/L glucose+ 5.0 μmol/L PIO），GW9662 intervention group （30 mmol/L glucose+ 5.0 μmol/L PIO+5.0 μmol/L specific anta- gonist GW 9662）. The cells of the first 3 groups were detected at 6，12，24，48 h of culture ，while those in GW 9662 intervention group were detected at 48 h of culture. mRNA expression of PTEN and PPARγ were detected by real-time PCR. The protein expression of PTEN ，PPARγ，α-SMA and E-cadherin as well as the changes of PI 3K/AKT signaling pathway were determined by Western blotting assay. RESULTS ：With the extension of culture time ，compared with control group ，the mRNA and protein expression of PPARγ（except for protein expression at 6 h）and PTEN in high-glucose group reduced significantly ，while the protein expression of α-SMA and p-AKT （Thr308）increased significantly ，and the protein expression of E-cadherin reduced significantly （P＜0.05），showing time-dependent trend. Compared with high-glucose group ，the mRNA and the protein expression （except for 6 h） of PPAR γ and PTEN were increased significantly in PIO intervention group ， while the protein expression of α-SMA and p-AKT （Thr308） were decreased significantly，and the protein expression of E-cadherin wasincreased significantly （P＜0.05）， showing time-dependent trend. There was no statistical significance in mRNA and protein expression of PPAR γ and PTEN，protein expression of E-cadherin ，α-SMA and p-AKT （Thr308） between GW 9662 intervention group and high-glucose group ；the effect of PIO was blocked by PPAR γ antagonist GW9662. CONCLUSIONS ：PIO may up-regulate the expression of PTEN by activating PPARγ，inhibit PI 3K/AKT signaling pathway so as to inhibit the occurrence of EMT of renal tubular epithelial cells .