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3-Hydroxybutyrate ameliorates insulin resistance by inhibiting pparγSer273 phosphorylation in type 2 diabetic mice

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Signal Transduction and Targeted Therapy 2023年第6期8卷 3158-3167页

作者： Yudian Zhang Zihua Li Xinyi Liu Xinyu Chen Shujie Zhang Yuemeng Chen Jiangnan Chen Jin Chen Fuqing Wu Guo-Qiang Chen School of Life Sciences Tsinghua UniversityBeijing100084P.R.China Department of Medical Genetics and Cell Biology School of Basic Medical Science of Ningxia Medical UniversityYinchuanNingxia750004P.R.China Center for Synthetic and Systems Biology Tsinghua UniversityBeijing100084China MOE Key Lab of Industrial Biocatalysis Dept of Chemical EngineeringTsinghua UniversityBeijing100084P.R.China

3-Hydroxybutyrate(3HB)is a small ketone body molecule produced endogenously by the body in the *** studies have shown that 3HB can reduce blood glucose level in type 2 diabetic(T2D)***,there is no systematic study and clear mechanism to evaluate and explain the hypoglycemic effect of *** we demonstrate that 3HB reduces fasting blood glucose level,improves glucose tolerance,and ameliorates insulin resistance in type 2 diabetic mice through hydroxycarboxylic acid receptor 2(HCAR2).Mechanistically,3HB increases intracellular calcium ion(Ca^(2+))levels by activating HCAR2,thereby stimulating adenylate cyclase(AC)to increase cyclic adenosine monophosphate(cAMP)concentration,and then activating protein kinase A(PKA).Activated PKA inhibits Raf1 proto-oncogene serine/threonine-protein kinase(Raf1)activity,resulting in a decrease in extracellular signal-regulated kinases 1/2(ERK1/2)activity and ultimately inhibiting peroxisome proliferator-activated receptorγ(pparγ)Ser273 phosphorylation in *** of pparγSer273 phosphorylation by 3HB altered the expression of pparγregulated genes and reduced insulin ***,3HB ameliorates insulin resistance in type 2 diabetic mice through a pathway of HCAR2/Ca^(2+)/cAMP/PKA/Raf1/ERK1/2/pparγ.

关键词： pparγ thereby ketone

pparγ: the dominant regulator among ppars in dry eye lacrimal gland and diabetic lacrimal gland

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International Journal of Ophthalmology(English edition) 2020年第6期13卷 860-869页

作者： Peng-Yue Mu Chen-Chen Chu Di Yu Yan Shao Shao-Zhen Zhao Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science Eye Institute and School of OptometryTianjin Medical University Eye Hospital

AIM: To investigate the regulatory roles of the members of the peroxisome proliferator-activated receptor(ppar)family in lacrimal gland dysfunction under conditions of desiccating stress or ***: Quantitative polymerase chain reaction(qPCR) was used to examine the expression of ppars in the cornea, conjunctiva, meibomian gland, and lacrimal gland in adult rats. The rats were divided into 3 groups:a control group, dry eye group, and diabetic group. The phenol red threads test, tear film break-up time(BUT) test and fluorescein staining were carried out to evaluate the development of dry eye. Based on bioinformatics research,qP CR was used to examine the expression level of pparγ,tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β),interleukin-6(IL-6), sirtuin 1(Sirt1), myeloid differentiation factor 88(MyD88) and transforming growth factor-β(TGF-β)in the lacrimal ***: pparα and pparβ/δ were mainly expressed in the conjunctiva and the lacrimal gland, ***, pparγ was expressed in both the conjunctiva and lacrimal gland, at much higher levels than those measured for pparα and pparβ/δ. Dry eye rats and diabetic rats both showed decreased tear secretion, shortened BUT,and increased corneal staining. Significant changes in gene expression were observed compared with the control group. In the lacrimal glands of dry eye rats and diabetic rats, expression of pparγ decreased(Pppars, pparγ might play a dominant role in the regulation of metabolic-and inflammatorysignaling pathways on the ocular surfaces and in lacrimal glands. Down-regulation of pparγ is highly relevant to lacrimal gland dysfunction under desiccating-stress and diabetic conditions. pparγ, thus, is a potential therapeutic target in the treatment of environment-or diabetes-induced dry eye diseases.

关键词： dry eye diabetes pparγ rat lacrimal gland

pparγLBD and its ligand specificity reveal a selection of potential partial agonist:Molecular dynamics based T2D drug discovery initiative

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BIOCELL 2021年第4期45卷 953-961页

作者： BIDYUT MALLICK ASHISH RANJAN SHARMA MANOJIT BHATTACHARYA SANG-SOO LEE CHIRANJIB CHAKRABORTY Department of Applied Science Galgotias College of Engineering and TechnologyKnowledge Park-IIGreater Noida201306India Institute for Skeletal Aging&Orthopedic Surgery Hallym University-Chuncheon Sacred Heart HospitalChuncheon-si24252Korea Department of Zoology Fakir Mohan UniversityVyasa ViharBalasore756020India Department of Biotechnology School of Life Science and BiotechnologyAdamas UniversityKolkata700126India

pparγis a peroxisome proliferator-activated receptor(ppar)family protein and is a target for type 2 diabetes(T2D).In this paper,we have performed a molecular docking analysis between ligand molecules(CID9816265,CID11608015,CID20251380,CID20251343,CID20556263,CID624491,CID42609928,and CID86287562)and pparγto determine the ligand *** also helps to understand the ligand-binding domain(LBD)activity of pparγduring the binding of the ***,a molecular dynamics simulation study was performed to determine the ligand biding stability in the pparγ*** ligand specificity informed us about the potentiality of selecting a partial *** study also shows the binding conformation of Ceramicine B having hydrogen bonding affinity with a tricyclic polar head and stabilized theβ-sheet *** the other hand,the tricyclic polar head of nimbolide also formed hydrogen bonding(Ser342),but it shows a lesser degree of stabilization in theβ-sheet *** shows the binding conformation of partial agonist(pparγ)in the Pocket-II of pparγLBD,which has a significant role in stabilizing theβ-sheet *** might help to regulate ERK/Cdk5 mediated phosphorylation of *** study helps us understand the valid pose of a set of ligands confirmation and target protein conformation using docking and molecular dynamics *** in silico study will also help to initiate a drug discovery process of T2D.

关键词： pparγ Partial agonist Molecular simulation T2D Drug discovery

Ginsenoside Rb1 improves brain,lung,and intestinal barrier damage in middle cerebral artery occlusion/reperfusion(MCAO/R)micevia the pparγsignaling pathway

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Chinese Journal of Natural Medicines 2022年第8期20卷 561-571页

作者： SU Lin-Jie REN Yu-Chuan CHEN Zhuo MA Hui-Fen ZHENG Fan LI Fang ZHANG Yuan-Yuan GONG Shuai-Shuai KOU Jun-Ping Jiangsu Key Laboratory of TCM Evaluation and Translational Research Department of Pharmacology of Chinese Materia MedicaSchool of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing 211198China

Ischemic stroke causes brain inflammation and multi-organ injury,which is closely associated with the peroxisome proliferator-activated receptor-gamma(pparγ)signaling *** studies have indicated that ginsenoside Rb1(GRb1)can protect the integrity of the blood-brain barrier after *** the current study,a mouse model of middle cerebral artery occlusion/reperfusion(MCAO/R)was established to determine whether GRb1 can ameliorate brain/lung/intestinal barrier damage via the pparγsignaling ***(2,3,5-triphenyltetrazolium chloride,hematoxylin,and eosin)and Doppler ultrasonography were employed to detect pathological *** breakdown was investigated with the leakage of Evans Blue dye and the expression of TJs(tight junctions)and AJs(adherent junctions).Western blot and immunofluorescence were used to determine the levels of cell junction proteins,pparγand NF-κ*** showed that GRb1 significantly mitigated multi-organ injury and increased the expression of cerebral microvascular,pulmonary vascular,and intestinal epithelial *** brain,lung,and intestinal tissues,GRb1 activated pparγ,decreased the levels of phospho-NF-κB p65,and inhibited the production of proinflammatory cytokines,thereby maintaining barrier ***,co-treatment with GRb1 and the pparγantagonist GW9662 reversed the barrier-protective effect of *** findings indicated that GRb1 can improve stroke-induced brain/lung/intestinal barrier damagevia the pparγpathway.

关键词： Focal ischemic stroke Brain/lung/intestinal barriers Ginsenoside Rb1 pparγ

Acetylated-pparγexpression is regulated by different P53 genotypes associated with the adipogenic differentiation of polyploid giant cancer cells with daughter cells

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Cancer Biology & Medicine 2023年第1期20卷 56-76页

作者： Kexin Zhang Xiaohui Yang Minying Zheng Yidi Ning Shiwu Zhang Tianjin Union Medical Center Tianjin 300122China Nankai University School of Medicine Nankai UniversityTianjin 300071China

Objective:Polyploid giant cancer cells(PGCCs)with daughter cells express epithelial–mesenchymal transition(EMT)-associated *** malignant tumor cells with EMT properties can transdifferentiate into mature tumor *** this study,we elucidated the potential for,and underlying mechanism of,adipogenic differentiation of PGCCs with daughter cells(PDCs).Methods:Cobalt chloride was used to induce PGCC formation in HEY(wild-type P53)and MDA-MB-231(mutant P53)cells;these cells were then cultured in adipogenic differentiation *** red O staining was used to confirm adipogenic differentiation,and the cell cycle was detected with flow *** expression of adipogenic differentiation-associated proteins and P300 histone acetyltransferase activity were compared before and after adipogenic *** xenograft models were used to confirm the adipogenic differentiation of ***:PDCs transdifferentiated into functional *** different cell cycle distributions were observed in PDCs after adipogenic *** expression levels of pparγ,Ace-pparγ,and Ace-P53 were higher in PDCs after adipogenic differentiation than in cells before adipogenic ***-pparγand FABP4 expression increased in HEY cells and decreased in MDA-MB-231 PDCs after p53 knockdown.A485 treatment increased Ace-P53,Ace-pparγ,and FABP4 expression in HEY PDCs by inhibiting SUMOylation of *** MDA-MB-231 PDCs,A485 treatment decreased Ace-P53,Ace-pparγ,and FABP4 *** experiments also confirmed the adipogenic differentiation of ***:Acetylation of P53 and pparγplays an important role in the adipogenic differentiation of PDCs.

关键词： PGCCs adipogenic differentiation pparγ post-translational modification P53 genotype

Oroxyloside protects against dextran sulfate sodium-induced colitis by inhibiting ER stress via pparγ activation

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Chinese Journal of Natural Medicines 2024年第4期22卷 307-317页

作者： TAO Lei DOU Renjie CHEN Xueming CAO Yu DAI Zhen HU Ziyan MA Zhi GE Xiaoming ZHANG Ling WANG Xiaoping Nanjing Institute for Food and Drug Control Nanjing 211198China State Key Laboratory of Natural Medicines School of Basic Medicine and Clinical PharmacyChina Pharmaceutical UniversityNanjing 211198China

Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease (IBD), may result from immune system dysfunction, leading to the sustained overproduction of reactive oxygen species (ROS) and subsequent cellular oxidative stress damage. Recent studies have identified both peroxisome proliferator-activated receptor-γ (pparγ) and endoplasmic reticulum (ER) stress as critical targets for the treatment of IBD. Oroxyloside (C22H20O11), derived from the root of Scutellaria baicalensis Georgi, has traditionally been used in treating inflammatory diseases. In this study, we investigated the molecular mechanisms by which oroxyloside mitigates dextran sulfate sodium (DSS)-induced colitis. We examined the effects of oroxyloside on ROS-mediated ER stress in colitis, including the protein expressions of GRP78, p-PERK, p-eIF2α, ATF4, and CHOP, which are associated with ER stress. The beneficial impact of oroxyloside was reversed by the pparγ antagonist GW9662 (1 mg·kg^(−1), i.v.) in vivo. Furthermore, oroxyloside decreased pro-inflammatory cytokines and ROS production in both bone marrow-derived macrophages (BMDM) and the mouse macrophage cell line RAW 264.7. However, pparγ siRNA transfection blocked the anti-inflammatory effect of oroxyloside and even abolished ROS generation and ER stress activation inhibited by oroxyloside in vitro. In conclusion, our study demonstrates that oroxyloside ameliorates DSS-induced colitis by inhibiting ER stress via pparγ activation, suggesting that oroxyloside might be a promising effective agent for IBD.

关键词： Oroxyloside ER stress pparγ Colitis

Irisin regulates pancreatic lipases through pparγ-PGCα-FNDC5 pathway

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Genes & Diseases 2023年第1期10卷 29-32页

作者： Horwitz Avital Birk Ruth Faculty of Health Sciences Ariel UniversityAriel 40700Israel

Irisin,a secreted myokine actively cleaved from fibronectin type III domain-containing protein 5(FNDC5),plays a crucial role in whole-body *** date,irisin receptor has not been identified,and its signal transduction i... 详细信息

关键词： pparγ mostly identif

Pravastatin activates pparα/pparγexpression in the liver and gallbladder epithelium of hamsters

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Hepatobiliary & Pancreatic Diseases International 2011年第2期10卷 185-190页

作者： Seok Ho Dong Jin Lee Dong Hee Koh Min Ho Choi Hyun Joo Jang Sea Hyub Kae Division of Gastroenterology Department of Internal MedicineKyung Hee University College of Medicine Division of Gastroenterology Department of Internal MedicineHallym University College of Medicine

BACKGROUND:Our earlier study with cultured gallbladder epithelial cells demonstrated that statins(HMG-CoA reductase inhibitors)activate the expression of pparαand pparγ, consequently blocking the production of pro-inflmmatory *** present study used hamsters to investigate the effects of pavastatin on pparα/pparγexpression in the liver and gallbladder epithelium,and to determine whether pravastatin suppresses cholesterol crystal formation in the gallbladder. METHODS:A total of 40 Golden Syrian male hamsters(4 weeks old)were randomly assigned to four groups(basal diet control; basal diet+pavastatin;high cholesterol diet;high cholesterol diet+pravastatin).All hamsters were 11 weeks old at the end of the *** liver,gallbladder and bile were harvested. Immunohistochemical staining and Western blotting for pparαand pparγwere performed in the liver and gallbladder. A drop of fresh bile was examined for cholesterol crystals under a microscope. RESULTS:In the gallbladder and liver of the hamsters, pravastatin activated the pparαand pparγexpression of gallbladder epithelial cells and hepatocytes,and particularly the response of pparγwas much stronger than that of pparα. Pravastatin suppressed the formation of cholesterol gallstones or crystals in the gallbladder. CONCLUSION:Pravastatin is an effective medication to activate ppars(especially pparγ)in the liver and the gallbladder epithelium of hamsters,and contributes to the prevention of gallstone formation.

关键词： pravastatin pparα pparγ hamster gallstone

Ginsenoside Rg1 protects against ischemia-induced neuron damage by regulating the rno-miRNA-27a-3p/pparγaxis

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BIOCELL 2023年第7期47卷 1583-1594页

作者： YUE GUAN TINGTING ZHANG JIANAN YU JIAWEI LIU WENYUAN LI YUJIA ZHENG JIALE WANG YUE LIU FENGGUO ZHAI Department of Clinical Medicine Heilongjiang Nursing CollegeHarbin150001China Department of Neurology Hongqi Hospital of Mudanjiang Medical UniversityMudanjiang157011China Department of Pharmacology Mudanjiang Medical UniversityMudanjiang157011China Department of Organic Chemistry Mudanjiang Medical UniversityMudanjiang157011China Department of Anatomy Mudanjiang Medical UniversityMudanjiang157011China Department of Rehabilitation Science Kobe University Graduate School of Health SciencesKobe654-0142Japan Institute of Natural Medicine Mudanjiang Medical UniversityMudanjiang157011China

A preliminary miRNA screening showed that expression levels of rno-miRNA-27a-3p were significantly increased in the serum and brain tissues of rats undergoing cerebral *** recent years,there is evidence of the protective capacity of the saponins extracted from panax ginseng and its primary active ingredient ginsenosideRg1oncerebral ischemic ***:Fetal rat neurons(FRNs)were cultured in glucose-and-serumfree medium and exposed to hypoxia to establish a cerebral ischemia model in vitro(oxygen and glucose deprivation model,OGD).Antioxidant indexes(CAT,SOD),inflammatory markers(MPO,TNF-αand IL-6),and the expression of apoptosis and proliferation associated proteins(NF kB-p65,Caspase 3-cleaved,BCL-2)were ***:Pre-treatment of Rg1(30–100μg/mL)could effectively inhibit the decline of antioxidant indexes(CAT,SOD)and increase in inflammatory markers(MPO,TNF-αand IL-6),and effectively inhibited the apoptosis in FRNs induced by OGD in a gradient-dependent *** mechanism analysis showed that the role of Rg1 in protecting against ischemia-induced neuron damage depends on its indirect up-regulation of ppar protein via suppression of ***,these effects of Rg1 could be reversed by exogenous rno-miRNA-27a-3p and ppar gene silencing in FRNs exposed to ***:To summarize,our study demonstrates that Rg1 could effectively attenuate neuronal damage caused by cerebral ischemia via the rno-miRNA-27a-3p/pparγ***,clarification of the novel mechanism will certainly improve our previous understanding of the role of Rg1 and enhancing its level in treatments for alleviating ischemic brain injury.

关键词： Ginsenoside Rg1 rno-miRNA-27a-3p pparγ Cerebral ischemia Neuron OGD