OBJECTIVE To investigate the effects of astragaloside IV(which can be extracted from the traditional Chinese medicine Astragalus membranaceus)on lipid and glucose metabolism in acute myocardial infarction(AMI).METHODS...OBJECTIVE To investigate the effects of astragaloside IV(which can be extracted from the traditional Chinese medicine Astragalus membranaceus)on lipid and glucose metabolism in acute myocardial infarction(AMI).METHODS Model of heart failure(HF)after AMI was established with ligation of left anterior descending artery on Sprague-Dawley(SD)rats.The rats were divided into three groups:sham,model and astragaloside IV treatment group.Twenty-eight days after treatment(astragaloside IV,20 mg·kg-1 daily),hematoxylin-eosin(HE)staining was applied to visualize cardiomyocyte morphological changes.High performance liquid chromatography(HPLC)was performed to assess the contents of adenosine phosphates in heart.Positron emission tomography and computed tomography(PET-CT)was conducted to evaluate the cardiac glucose metabolism.Expressions of key molecules such as peroxisome proliferatoractivated receptor γ(PPARγ),sterol carrier protein 2(SCP2)and long chain acyl CoA dehydrogenase(ACADL)were measured by Western blotting and immunohistochemistry.Oxygen-glucose deprivation-reperfusion(OGD/R)-induced H9C2 injury cardiomyocyte model was adopted for potential mechanism research in vitro.RESULTS Treatment with astragaloside Ⅳ rescued hearts from structural and functional damages as well as inflammatory infiltration.Levels of adenosine triphosphate(ATP)and energy charge(EC)in astragaloside IV group were also up-regulated compared to model group.Further results demonstrated that critical enzymes both in lipid metabolism and glucose metabolism compro mised in model group compared to sham group.Intriguingly,astragalosideⅣcould up-regulate critical enzymes including ACADL and SCP2 in lipid metabolism accompanying with promoting effect on molecules in glycolysis simultaneously.Results on upstreaming signaling pathway demonstrated that astragaloside Ⅳ could dramatically increase the expres sions of PPARγ.In vitro study suggested the efficacy of astragalosideⅣcould be blocked by T0070907,a selective PPARγ inhibitor.CONCLUSION Astragaloside IV has cardioprotective effect in improving cardiac function and energy metabolism through regulating lipid and glucose metabolism.The effects may be mediated by PPARγ pathway.展开更多
Objective To observe the effects of Danggui Shaoyao powder(DSP)on hepatic lipid metabolism and further explore its mechanism of action by peroxisome proliferator-activated receptor(PPARγ)-liver X receptor(LXRα)-aden...Objective To observe the effects of Danggui Shaoyao powder(DSP)on hepatic lipid metabolism and further explore its mechanism of action by peroxisome proliferator-activated receptor(PPARγ)-liver X receptor(LXRα)-adenosine triphosphate(ATP)-binding cassette transporter A1(ABCA1)pathway regulation.Methods Eight C57BL/6J male mice were selected as the control group,and 24 ApoE^(−/−)male mice were randomly divided into the atherosclerosis model(AS)group,atorvastatin calcium(AC)group,and DSP group(n=8 each group).To establish an AS model,ApoE^(−/−)mice were fed a high-fat diet for 16 weeks.Pathologic changes in the aortic vasculature and liver were identified using Oil Red O staining.Triglyceride(TG),cholesterol(TC),and low-density lipoprotein cholesterol(LDL-C)levels were determined in the livers using a single-reagent GPO-PAP method.Fluorescence quantitative polymerase chain reaction and western blot were used to observe and evaluate the mRNA and protein expression of the PPARγ-LXRα-ABCA1 intermediates in the liver.Results After 16 weeks of a high-fat diet,ApoE−/−mice showed more Oil Red O staining in the aorta and liver compared to the CONT group.Compared to the AS group,the DSP and AC treatment reduced aortic plaque and hepatic lipid deposition to varying degrees.Furthermore,DSP significantly reduced the hepatic lipid area in ApoE^(−/−)mice(P<.001)and decreased the levels of TG,TC,and LDL-C in liver(P<.001,P=.027,P<.001,respectively).DSP also significantly increased the levels of PPARγ,LXRα,ABCA1,and ABCG1 mRNA expression,as well as the PPARγ,LXRα,ABCA1,and ABCG1 protein expression in liver.Conclusion DSP improved hepatic lipid metabolism via PPARγ-LXRα-ABCA1 pathway modulation for AS treatment.展开更多
Dietary parboiled rice(PR)has a low risk of disease,but little is known about the contribution of PR to the prevention of hyperlipidemia.The potential role and underlying mechanisms of PR in hyperlipidemia were evalua...Dietary parboiled rice(PR)has a low risk of disease,but little is known about the contribution of PR to the prevention of hyperlipidemia.The potential role and underlying mechanisms of PR in hyperlipidemia were evaluated in this study.Male C57BL/6J mice were fed with a normal diet,high-fat diet(HFD)containing refined rice(HFDRR)or PR(HFDPR).It was found that PR intervention improved lipid accumulation in mice.Transcriptomic data analysis revealed that 27 genes were up-regulated(mostly involved in lipid breakdown)and 86 genes were down-regulated(mostly involved in inflammatory responses)in the HFDPR group compared to the HFDRR group.And 15 differentially expressed genes(DEGs)were validated by quantitative real-time PCR(RT-qPCR),while protein interaction network showed that protein tyrosine phosphatase receptor type C(PTPRC)has a central role.The gut microbiota of mice was also altered after different dietary treatments,with higher ratio of Firmicutes and Bacteroidetes,increased abundances of Ruminococcaceae,Lachnospiraceae,Christensenellaceae,Porphyromonadaceae,Rikenellaceae and Prevotellaceae,and decreased abundances of Lactobacillaceae,Peptostreptococcaceae,Erysipelotrichaceae and Actinobacteria in the HFDRR group.In addition,it was observed that PPAR signaling pathway may act as a bridge between DEGs and differential gut microbiota.These results suggested that PR can prevent hyperlipidemia by modulating liver genes and gut microbiota.展开更多
BACKGROUND In degenerative intervertebral disc(IVD),an unfavorable IVD environment leads to increased senescence of nucleus pulposus(NP)-derived mesenchymal stem cells(NPMSCs)and the inability to complete the differen...BACKGROUND In degenerative intervertebral disc(IVD),an unfavorable IVD environment leads to increased senescence of nucleus pulposus(NP)-derived mesenchymal stem cells(NPMSCs)and the inability to complete the differentiation from NPMSCs to NP cells,leading to further aggravation of IVD degeneration(IDD).Urolithin A(UA)has been proven to have obvious effects in delaying cell senescence and resisting oxidative stress.AIM To explore whether UA can alleviate NPMSCs senescence and to elucidate the underlying mechanism.METHODS In vitro,we harvested NPMSCs from rat tails,and divided NPMSCs into four groups:the control group,H2O2 group,H2O2+UA group,and H2O2+UA+SR-18292 group.Senescence-associatedβ-Galactosidase(SA-β-Gal)activity,cell cycle,cell proliferation ability,and the expression of senescence-related and silent information regulator of transcription 1/PPAR gamma coactivator-1α(SIRT1/PGC-1α)pathway-related proteins and mRNA were used to evaluate the protective effects of UA.In vivo,an animal model of IDD was constructed,and Xrays,magnetic resonance imaging,and histological analysis were used to assess whether UA could alleviate IDD in vivo.RESULTS We found that H2O2 can cause NPMSCs senescence changes,such as cell cycle arrest,reduced cell proliferation ability,increased SA-β-Gal activity,and increased expression of senescence-related proteins and mRNA.After UA pretreatment,the abovementioned senescence indicators were significantly alleviated.To further demonstrate the mechanism of UA,we evaluated the mitochondrial membrane potential and the SIRT1/PGC-1αpathway that regulates mitochondrial function.UA protected mitochondrial function and delayed NPMSCs senescence by activating the SIRT1/PGC-1αpathway.In vivo,we found that UA treatment alleviated an animal model of IDD by assessing the disc height index,Pfirrmann grade and the histological score.CONCLUSION In summary,UA could activate the SIRT1/PGC-1αsignaling pathway to protect mitochondrial function and alleviate cell senescence and IDD in vivo and vitro.展开更多
Insulin resistance(IR) has been considered to be an important causative factor of metabolic syndrome(Met S). The present study investigated whether pomegranate peel polyphenols(PPPs) could prevent the development of M...Insulin resistance(IR) has been considered to be an important causative factor of metabolic syndrome(Met S). The present study investigated whether pomegranate peel polyphenols(PPPs) could prevent the development of Met S by improving IR in rats. Male Sprague-Dawley(SD) rats were fed high fat diet(HFD) to induce Met S and supplemented with different dosages of PPPs for 12 weeks. The results showed that HFD-induced insulin resistant rats had disordered metabolism of blood glucose, blood lipid, and terrible muscle fiber morphology when compared with normal diet-fed rats, but PPPs treatment at a dosage of 300 mg/kg·day significantly reversed these negative effects. Moreover, in skeletal muscle tissue of insulin resistant rats, PPPs treatments significantly increased the protein expressions of insulin receptor(Ins R) and phosphorylated insulin receptor substrate 1(IRS-1), stimulated peroxisome proliferator activated receptor gamma(PPARγ) and phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT/PKB) signaling pathway, and aggrandized the protein levels of phosphorylated glycogen synthase kinase-3β(GSK-3β) and glucose transporter 4(GLUT4). Our results suggest that PPPs possess of the beneficial effects on alleviating IR by enhancing insulin sensitivity and regulating glucose metabolism.展开更多
Dysregulation of microRNAs(miRNAs)in adipocytes plays a critical role in the pathogenesis of obesity.However,the signaling mechanisms regulating miRNAs production in adipose tissue remain largely unclear.Here,we show ...Dysregulation of microRNAs(miRNAs)in adipocytes plays a critical role in the pathogenesis of obesity.However,the signaling mechanisms regulating miRNAs production in adipose tissue remain largely unclear.Here,we show that adipose tissue-specific knockout of Ras homolog enriched in brain(Rheb),a direct upstream activator of mTOR,increases miR-182-5p level in mouse subcutaneous white adipose tissues.Interestingly,the inhibition of mTOR signaling by rapamycin has no effect on miR-182-5p level in primary subcutaneous white adipocytes,suggesting the presence of a mTOR-independent mechanism regulating Rheb-mediated miR-182-5p expression.Consistent with this view,Rheb-ablation activates the cAMP/PPARγsignaling pathway.In addition,treatment of white adipocytes with pioglitazone,a PPARγagonist,dramatically upregulates miR-182-5p levels.Our study reveals a unique mechanism by which Rheb regulates miR-182-5p in adipocytes.Given that increasing miR-182-5p in adipose tissue promotes beige fat development,our study also suggests a unique mechanism by which Rheb promotes thermogenesis and energy expenditure.展开更多
Tumor immunotherapy has achieved breakthroughs in a variety of tumors. However, the systemic absence of T cells in tumors and immunosuppressive tumor microenvironment so far limits the efficacy of immunotherapy to a s...Tumor immunotherapy has achieved breakthroughs in a variety of tumors. However, the systemic absence of T cells in tumors and immunosuppressive tumor microenvironment so far limits the efficacy of immunotherapy to a small population of patients. Therefore, novel agents to increase T-cell tumor infiltration are urgently needed in the clinic. We recently found that inhibition of the ADP-ribosylation factor 1 (Arf1)-mediated lipid metabolism not only kills cancer stem cells (CSCs) but also elicits an anti-tumor immune response. In this study, we revealed a mechanism that targeting Arf1 promotes the infiltration of cytotoxic T lymphocytes (CTLs) into tumors through the C-C chemokine ligand 5 (CCL5)- C-C chemokine receptor type 5 (CCR5) pathway. We found that blockage of Arf1 induces the production of the unsaturated fatty acid (PE 18:1) that binds and sequestrates peroxisome proliferator- activated receptor-γ (PPARγ) from the PPARγ-nuclear factor-κB (NF-κB) cytoplasmic complex. The released NF-κB was then phospho-rylated and translocated into the nucleus to regulate the transcription of chemokine CCL5. CCL5 promoted infiltration of CTLs for tumor regression. Furthermore, the combination of the Arf1 inhibitor and programmed cell death protein 1 (PD-1) blockade induced an even stronger anti-tumor immunity. Therefore, targeting Arf1 represents a novel anti-tumor immune approach by provoking T-cell tumor infiltration and may provide a new strategy for tumor immunotherapy.展开更多
Goldfish comprise around 300 different strains with drastically altered and aesthetical morphologies making them suitable models for evolutionary developmental biology.The dragon-eye strain is characterized by protrud...Goldfish comprise around 300 different strains with drastically altered and aesthetical morphologies making them suitable models for evolutionary developmental biology.The dragon-eye strain is characterized by protruding eyes(analogous to those of Chinese dragons).Although the strain has been selected for about 400 years,the mechanism of its eye development remains unclear.In this study,a stable dragon-eye goldfish strain with a clear genetic background was rapidly established and studied.We found that upregulation of the PPAR signaling pathway accompanied by an increase in lipid accumulation might trigger the morphological and structural transformation of the eye in dragon-eye goldfish.At the developmental stage of proptosis(eye protrusion),downregulation of the phototransduction pathway was consistent with the structural defects and myopia of the dragon-eye strain.With the impairment of retinal development,cytokine-induced inflammation was activated,especially after proptosis,similar to the pathologic symptoms of many human ocular diseases.In addition,differentially expressed transcription factors were significantly enriched in the PAX and homeobox families,two well-known transcription factor families involved in eye development.Therefore,our findings reveal the dynamic changes in key pathways during eye development in dragon-eye goldfish,and provide insights into the molecular mechanisms underlying drastically altered eyes in goldfish and human ocular disease.展开更多
In gliomas, the canonical Wingless/Int(WNT)/b-catenin pathway is increased while peroxisome proliferator-activated receptor gamma(PPAR-c) is downregulated.The two systems act in an opposite manner. This review foc...In gliomas, the canonical Wingless/Int(WNT)/b-catenin pathway is increased while peroxisome proliferator-activated receptor gamma(PPAR-c) is downregulated.The two systems act in an opposite manner. This review focuses on the interplay between WNT/b-catenin signaling and PPAR-c and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/bcatenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis,tumor growth, and angiogenesis. Activation of PPAR-c agonists inhibits various signaling pathways such as the JAK/STAT, WNT/b-catenin, and PI3 K/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/b-catenin pathway through the upregulation of PPAR-c 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.展开更多
As an ultrasmall derivative of black phosphorus(BP)sheets,BP quantum dots(BP-QDs)have been effectively used in many fields.Currently,information on the cardiotoxicity induced by BP-QDs remains limited.We aimed to eval...As an ultrasmall derivative of black phosphorus(BP)sheets,BP quantum dots(BP-QDs)have been effectively used in many fields.Currently,information on the cardiotoxicity induced by BP-QDs remains limited.We aimed to evaluate BP-QD-induced cardiac toxicity in mice.Histopathological examination of heart tissue sections was performed.Transcriptome sequencing,real-time quantitative PCR(RT–qPCR),western blotting,and enzyme-linked immunosorbent assay(ELISA)assays were used to detect the m RNA and/or protein expression of proinfammatory cytokines,nuclear factor kappa B(NF-κB),phosphatidylinositol3 kinase-protein kinase B(PI3K-AKT),peroxisome proliferator-activated receptor gamma(PPARγ),and glucose/lipid metabolism pathway-related genes.We found that heart weight and heart/body weight index(HBI)were significantly reduced in mice after intragastric administration of 0.1 or 1 mg/kg BP-QDs for 28 days.In addition,obvious infammatory cell infiltration and increased cardiomyocyte diameter were observed in the BP-QD-treated groups.Altered expression of proinfammatory cytokines and genes related to the NF-κB signaling pathway further confirmed that BP-QD exposure induced infammatory responses.In addition,BP-QD treatment also affected the PI3K-AKT,PPARγ,thermogenesis,oxidative phosphorylation,and cardiac muscle contraction signaling pathways.The expression of genes related to glucose/lipid metabolism signaling pathways was dramatically affected by BP-QD exposure,and the effect was primarily mediated by the PPAR signaling pathway.Our study provides new insights into the toxicity of BP-QDs to human health.展开更多
基金National Natural Science Foundation of China(81530100,81673802,81673712,81822049)。
文摘OBJECTIVE To investigate the effects of astragaloside IV(which can be extracted from the traditional Chinese medicine Astragalus membranaceus)on lipid and glucose metabolism in acute myocardial infarction(AMI).METHODS Model of heart failure(HF)after AMI was established with ligation of left anterior descending artery on Sprague-Dawley(SD)rats.The rats were divided into three groups:sham,model and astragaloside IV treatment group.Twenty-eight days after treatment(astragaloside IV,20 mg·kg-1 daily),hematoxylin-eosin(HE)staining was applied to visualize cardiomyocyte morphological changes.High performance liquid chromatography(HPLC)was performed to assess the contents of adenosine phosphates in heart.Positron emission tomography and computed tomography(PET-CT)was conducted to evaluate the cardiac glucose metabolism.Expressions of key molecules such as peroxisome proliferatoractivated receptor γ(PPARγ),sterol carrier protein 2(SCP2)and long chain acyl CoA dehydrogenase(ACADL)were measured by Western blotting and immunohistochemistry.Oxygen-glucose deprivation-reperfusion(OGD/R)-induced H9C2 injury cardiomyocyte model was adopted for potential mechanism research in vitro.RESULTS Treatment with astragaloside Ⅳ rescued hearts from structural and functional damages as well as inflammatory infiltration.Levels of adenosine triphosphate(ATP)and energy charge(EC)in astragaloside IV group were also up-regulated compared to model group.Further results demonstrated that critical enzymes both in lipid metabolism and glucose metabolism compro mised in model group compared to sham group.Intriguingly,astragalosideⅣcould up-regulate critical enzymes including ACADL and SCP2 in lipid metabolism accompanying with promoting effect on molecules in glycolysis simultaneously.Results on upstreaming signaling pathway demonstrated that astragaloside Ⅳ could dramatically increase the expres sions of PPARγ.In vitro study suggested the efficacy of astragalosideⅣcould be blocked by T0070907,a selective PPARγ inhibitor.CONCLUSION Astragaloside IV has cardioprotective effect in improving cardiac function and energy metabolism through regulating lipid and glucose metabolism.The effects may be mediated by PPARγ pathway.
基金supported by the National Natural Science Foundation of China(82074325).
文摘Objective To observe the effects of Danggui Shaoyao powder(DSP)on hepatic lipid metabolism and further explore its mechanism of action by peroxisome proliferator-activated receptor(PPARγ)-liver X receptor(LXRα)-adenosine triphosphate(ATP)-binding cassette transporter A1(ABCA1)pathway regulation.Methods Eight C57BL/6J male mice were selected as the control group,and 24 ApoE^(−/−)male mice were randomly divided into the atherosclerosis model(AS)group,atorvastatin calcium(AC)group,and DSP group(n=8 each group).To establish an AS model,ApoE^(−/−)mice were fed a high-fat diet for 16 weeks.Pathologic changes in the aortic vasculature and liver were identified using Oil Red O staining.Triglyceride(TG),cholesterol(TC),and low-density lipoprotein cholesterol(LDL-C)levels were determined in the livers using a single-reagent GPO-PAP method.Fluorescence quantitative polymerase chain reaction and western blot were used to observe and evaluate the mRNA and protein expression of the PPARγ-LXRα-ABCA1 intermediates in the liver.Results After 16 weeks of a high-fat diet,ApoE−/−mice showed more Oil Red O staining in the aorta and liver compared to the CONT group.Compared to the AS group,the DSP and AC treatment reduced aortic plaque and hepatic lipid deposition to varying degrees.Furthermore,DSP significantly reduced the hepatic lipid area in ApoE^(−/−)mice(P<.001)and decreased the levels of TG,TC,and LDL-C in liver(P<.001,P=.027,P<.001,respectively).DSP also significantly increased the levels of PPARγ,LXRα,ABCA1,and ABCG1 mRNA expression,as well as the PPARγ,LXRα,ABCA1,and ABCG1 protein expression in liver.Conclusion DSP improved hepatic lipid metabolism via PPARγ-LXRα-ABCA1 pathway modulation for AS treatment.
基金financially supported by Key Project of State Key R&D Program,China (2022YFF1100200)the Program for Science&Technology Innovation Platform of Hunan Province (2019TP102)+3 种基金Natural Science Foundation of Hunan Province (2021JJ31075,2019JJ50984)Natural Science Foundation of Changsha City (kq2014275)Scientific Innovation Fund for Postgraduates of Central South University of Forestry and Technology (CX20200699,CX202102067)Postgraduate Scientific Research Innovation Project of Hunan Province (CX20201018,CX20210899,CX20220701 and CX20220720)。
文摘Dietary parboiled rice(PR)has a low risk of disease,but little is known about the contribution of PR to the prevention of hyperlipidemia.The potential role and underlying mechanisms of PR in hyperlipidemia were evaluated in this study.Male C57BL/6J mice were fed with a normal diet,high-fat diet(HFD)containing refined rice(HFDRR)or PR(HFDPR).It was found that PR intervention improved lipid accumulation in mice.Transcriptomic data analysis revealed that 27 genes were up-regulated(mostly involved in lipid breakdown)and 86 genes were down-regulated(mostly involved in inflammatory responses)in the HFDPR group compared to the HFDRR group.And 15 differentially expressed genes(DEGs)were validated by quantitative real-time PCR(RT-qPCR),while protein interaction network showed that protein tyrosine phosphatase receptor type C(PTPRC)has a central role.The gut microbiota of mice was also altered after different dietary treatments,with higher ratio of Firmicutes and Bacteroidetes,increased abundances of Ruminococcaceae,Lachnospiraceae,Christensenellaceae,Porphyromonadaceae,Rikenellaceae and Prevotellaceae,and decreased abundances of Lactobacillaceae,Peptostreptococcaceae,Erysipelotrichaceae and Actinobacteria in the HFDRR group.In addition,it was observed that PPAR signaling pathway may act as a bridge between DEGs and differential gut microbiota.These results suggested that PR can prevent hyperlipidemia by modulating liver genes and gut microbiota.
基金National Natural Science Foundation of China,No.81972136Young Medical Scholars Major Program of Jiangsu Province,No.QNRC2016342+1 种基金Key Funding Project of Maternal and Child Health Research of Jiangsu Province,No.F201801and Highlevel Health Professionals"Six projects"Top-notch Talent Research Program of Jiangsu Province,No.LGY2019035.
文摘BACKGROUND In degenerative intervertebral disc(IVD),an unfavorable IVD environment leads to increased senescence of nucleus pulposus(NP)-derived mesenchymal stem cells(NPMSCs)and the inability to complete the differentiation from NPMSCs to NP cells,leading to further aggravation of IVD degeneration(IDD).Urolithin A(UA)has been proven to have obvious effects in delaying cell senescence and resisting oxidative stress.AIM To explore whether UA can alleviate NPMSCs senescence and to elucidate the underlying mechanism.METHODS In vitro,we harvested NPMSCs from rat tails,and divided NPMSCs into four groups:the control group,H2O2 group,H2O2+UA group,and H2O2+UA+SR-18292 group.Senescence-associatedβ-Galactosidase(SA-β-Gal)activity,cell cycle,cell proliferation ability,and the expression of senescence-related and silent information regulator of transcription 1/PPAR gamma coactivator-1α(SIRT1/PGC-1α)pathway-related proteins and mRNA were used to evaluate the protective effects of UA.In vivo,an animal model of IDD was constructed,and Xrays,magnetic resonance imaging,and histological analysis were used to assess whether UA could alleviate IDD in vivo.RESULTS We found that H2O2 can cause NPMSCs senescence changes,such as cell cycle arrest,reduced cell proliferation ability,increased SA-β-Gal activity,and increased expression of senescence-related proteins and mRNA.After UA pretreatment,the abovementioned senescence indicators were significantly alleviated.To further demonstrate the mechanism of UA,we evaluated the mitochondrial membrane potential and the SIRT1/PGC-1αpathway that regulates mitochondrial function.UA protected mitochondrial function and delayed NPMSCs senescence by activating the SIRT1/PGC-1αpathway.In vivo,we found that UA treatment alleviated an animal model of IDD by assessing the disc height index,Pfirrmann grade and the histological score.CONCLUSION In summary,UA could activate the SIRT1/PGC-1αsignaling pathway to protect mitochondrial function and alleviate cell senescence and IDD in vivo and vitro.
基金supported by the National Natural Science Foundation of China (31871801, 32001679)the Science and Technology Research of Shaanxi Province (2020QFY08-03)+1 种基金Forestry Science and Technology Programs of Shaanxi Province (SXLK20200213)Fundamental Research Funds for the Central Universities (GK201604013)。
文摘Insulin resistance(IR) has been considered to be an important causative factor of metabolic syndrome(Met S). The present study investigated whether pomegranate peel polyphenols(PPPs) could prevent the development of Met S by improving IR in rats. Male Sprague-Dawley(SD) rats were fed high fat diet(HFD) to induce Met S and supplemented with different dosages of PPPs for 12 weeks. The results showed that HFD-induced insulin resistant rats had disordered metabolism of blood glucose, blood lipid, and terrible muscle fiber morphology when compared with normal diet-fed rats, but PPPs treatment at a dosage of 300 mg/kg·day significantly reversed these negative effects. Moreover, in skeletal muscle tissue of insulin resistant rats, PPPs treatments significantly increased the protein expressions of insulin receptor(Ins R) and phosphorylated insulin receptor substrate 1(IRS-1), stimulated peroxisome proliferator activated receptor gamma(PPARγ) and phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT/PKB) signaling pathway, and aggrandized the protein levels of phosphorylated glycogen synthase kinase-3β(GSK-3β) and glucose transporter 4(GLUT4). Our results suggest that PPPs possess of the beneficial effects on alleviating IR by enhancing insulin sensitivity and regulating glucose metabolism.
基金supported by grants 82170886 and 81800758 from the National Nature Science Foundation of Chinapartially supported by the Fundamental Research Funds for the Central Universities of Central South University(2021zzts1048)。
文摘Dysregulation of microRNAs(miRNAs)in adipocytes plays a critical role in the pathogenesis of obesity.However,the signaling mechanisms regulating miRNAs production in adipose tissue remain largely unclear.Here,we show that adipose tissue-specific knockout of Ras homolog enriched in brain(Rheb),a direct upstream activator of mTOR,increases miR-182-5p level in mouse subcutaneous white adipose tissues.Interestingly,the inhibition of mTOR signaling by rapamycin has no effect on miR-182-5p level in primary subcutaneous white adipocytes,suggesting the presence of a mTOR-independent mechanism regulating Rheb-mediated miR-182-5p expression.Consistent with this view,Rheb-ablation activates the cAMP/PPARγsignaling pathway.In addition,treatment of white adipocytes with pioglitazone,a PPARγagonist,dramatically upregulates miR-182-5p levels.Our study reveals a unique mechanism by which Rheb regulates miR-182-5p in adipocytes.Given that increasing miR-182-5p in adipose tissue promotes beige fat development,our study also suggests a unique mechanism by which Rheb promotes thermogenesis and energy expenditure.
基金This work was financially supported by grants from the National Natural Science Foundation of China(NSFC:92057205 and 32150710518 to S.X.H.,and 82203511 to Y.W.)Greater Bay Area Institute of Precision Medicine(Guangzhou),Fudan University,China.
文摘Tumor immunotherapy has achieved breakthroughs in a variety of tumors. However, the systemic absence of T cells in tumors and immunosuppressive tumor microenvironment so far limits the efficacy of immunotherapy to a small population of patients. Therefore, novel agents to increase T-cell tumor infiltration are urgently needed in the clinic. We recently found that inhibition of the ADP-ribosylation factor 1 (Arf1)-mediated lipid metabolism not only kills cancer stem cells (CSCs) but also elicits an anti-tumor immune response. In this study, we revealed a mechanism that targeting Arf1 promotes the infiltration of cytotoxic T lymphocytes (CTLs) into tumors through the C-C chemokine ligand 5 (CCL5)- C-C chemokine receptor type 5 (CCR5) pathway. We found that blockage of Arf1 induces the production of the unsaturated fatty acid (PE 18:1) that binds and sequestrates peroxisome proliferator- activated receptor-γ (PPARγ) from the PPARγ-nuclear factor-κB (NF-κB) cytoplasmic complex. The released NF-κB was then phospho-rylated and translocated into the nucleus to regulate the transcription of chemokine CCL5. CCL5 promoted infiltration of CTLs for tumor regression. Furthermore, the combination of the Arf1 inhibitor and programmed cell death protein 1 (PD-1) blockade induced an even stronger anti-tumor immunity. Therefore, targeting Arf1 represents a novel anti-tumor immune approach by provoking T-cell tumor infiltration and may provide a new strategy for tumor immunotherapy.
基金supported by the Strategic Priority Research Program of Chinese Academy of Sciences(XDB31000000)the National Natural Science Foundation of China(31930111)+2 种基金the China Agriculture Research System(CARS-45-07)the Autonomous Project of the State Key Laboratory of Freshwater Ecology and Biotechnology(2019FBZ04)supported by the Wuhan Branch,Supercomputing Centre,Chinese Academy of Sciences,China。
文摘Goldfish comprise around 300 different strains with drastically altered and aesthetical morphologies making them suitable models for evolutionary developmental biology.The dragon-eye strain is characterized by protruding eyes(analogous to those of Chinese dragons).Although the strain has been selected for about 400 years,the mechanism of its eye development remains unclear.In this study,a stable dragon-eye goldfish strain with a clear genetic background was rapidly established and studied.We found that upregulation of the PPAR signaling pathway accompanied by an increase in lipid accumulation might trigger the morphological and structural transformation of the eye in dragon-eye goldfish.At the developmental stage of proptosis(eye protrusion),downregulation of the phototransduction pathway was consistent with the structural defects and myopia of the dragon-eye strain.With the impairment of retinal development,cytokine-induced inflammation was activated,especially after proptosis,similar to the pathologic symptoms of many human ocular diseases.In addition,differentially expressed transcription factors were significantly enriched in the PAX and homeobox families,two well-known transcription factor families involved in eye development.Therefore,our findings reveal the dynamic changes in key pathways during eye development in dragon-eye goldfish,and provide insights into the molecular mechanisms underlying drastically altered eyes in goldfish and human ocular disease.
文摘In gliomas, the canonical Wingless/Int(WNT)/b-catenin pathway is increased while peroxisome proliferator-activated receptor gamma(PPAR-c) is downregulated.The two systems act in an opposite manner. This review focuses on the interplay between WNT/b-catenin signaling and PPAR-c and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/bcatenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis,tumor growth, and angiogenesis. Activation of PPAR-c agonists inhibits various signaling pathways such as the JAK/STAT, WNT/b-catenin, and PI3 K/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/b-catenin pathway through the upregulation of PPAR-c 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.
基金supported by the National Natural Science Foundation of China (Nos.32071301 and 31971234)。
文摘As an ultrasmall derivative of black phosphorus(BP)sheets,BP quantum dots(BP-QDs)have been effectively used in many fields.Currently,information on the cardiotoxicity induced by BP-QDs remains limited.We aimed to evaluate BP-QD-induced cardiac toxicity in mice.Histopathological examination of heart tissue sections was performed.Transcriptome sequencing,real-time quantitative PCR(RT–qPCR),western blotting,and enzyme-linked immunosorbent assay(ELISA)assays were used to detect the m RNA and/or protein expression of proinfammatory cytokines,nuclear factor kappa B(NF-κB),phosphatidylinositol3 kinase-protein kinase B(PI3K-AKT),peroxisome proliferator-activated receptor gamma(PPARγ),and glucose/lipid metabolism pathway-related genes.We found that heart weight and heart/body weight index(HBI)were significantly reduced in mice after intragastric administration of 0.1 or 1 mg/kg BP-QDs for 28 days.In addition,obvious infammatory cell infiltration and increased cardiomyocyte diameter were observed in the BP-QD-treated groups.Altered expression of proinfammatory cytokines and genes related to the NF-κB signaling pathway further confirmed that BP-QD exposure induced infammatory responses.In addition,BP-QD treatment also affected the PI3K-AKT,PPARγ,thermogenesis,oxidative phosphorylation,and cardiac muscle contraction signaling pathways.The expression of genes related to glucose/lipid metabolism signaling pathways was dramatically affected by BP-QD exposure,and the effect was primarily mediated by the PPAR signaling pathway.Our study provides new insights into the toxicity of BP-QDs to human health.