OBJECTIVE Basic fibroblast growth factor(b FGF)and platelet-derived growth factor(PDGF)produced by hepatocellular carcinoma(HCC)cells are responsible for the cell growth.Accumulating evidence shows that insulin-like g...OBJECTIVE Basic fibroblast growth factor(b FGF)and platelet-derived growth factor(PDGF)produced by hepatocellular carcinoma(HCC)cells are responsible for the cell growth.Accumulating evidence shows that insulin-like growth factor-binding protein-3(IGFBP-3)suppresses HCC cell proliferation in both IGF-dependent and independent manners.The present study is to investigate whether treatment with exogenous IGFBP-3 inhibits bF GF and PDGF production and the cell proliferation of HCC cells.METHODS Cell Counting Kit 8 assay were designed to detect HCC cell proliferation,transcription factor early growth response-1(EGR1)involving in IGFBP-3 regulation of b FGF and PDGF were detected by RT-PCR and Western blot assays.Western blot assay was adopted to detect the IGFBP-3 regulating insulin-like growth factor 1 receptor(IGF-1R)signaling pathway.RESULTS The present study demonstrates that IGFBP-3 suppressed IGF-1-induced b FGF and PDGF expression while it does not affect their expression in the absence of IGF-1.To delineate the underlying mechanism,Western-blot and RT-PCR assays confirmed that the transcription factor early growth response protein 1(EGR1)is involved in IGFBP-3 regulation of b FGF and PDGF.IGFBP-3 inhibition of type 1 insulin-like growth factor receptor(IGF1R),ERK and AKT activation is IGF-1-dependent.Furthermore,transient transfection with constitutively activated AKT or MEK partially blocks the IGFBP-3 inhibition of EGR1,b FGF and PDGF expression.CONCLUSION In conclusion,these findings suggest that IGFBP-3suppresses transcription of EGR1 and its target genes b FGF and PDGF through inhibiting IGF-1-dependent ERK and AKT activation.It demonstrates the importance of IGFBP-3 in the regulation of HCC cell proliferation,suggesting that IGFBP-3 could be a target for the treatment of HCC.展开更多
Mammary epithelial cells with lactational function can be a valuable cellular model for research of the development and regulation of the mammary gland.This paper describes some aspects of function of an epithelial ce...Mammary epithelial cells with lactational function can be a valuable cellular model for research of the development and regulation of the mammary gland.This paper describes some aspects of function of an epithelial cell line from the mammary gland of the dairy goat.SDS-PAGE,triglyceride and lactose content of cultured cells were used to assess synthetic function of cells and the effects of exposure to insulin and prolactin.Results show that goat mammary epithelial cells can synthesize fat,proteins and lactose when they were cultured in DMEM-F12 medium with added EGF,IGF-1,ITS and FBS.There were no obvious changes after 48h treatment with additional insulin.Prolactin added to the basal medium significantly increased synthesis of proteins and lactose.A mammary gland epithelial cell line from goats which has lactational function has been established.This outcome provides a valuable and convenient model system.展开更多
A new six intraperitoneal injection insulin-mimetic vanadyl(Ⅱ) compounds [(VD3^-1)(VO^+2)(AAn^-1)](where(n=1~6);AA1=isoleucine, AA2=threonine, AA3=proline, AA4=phenylalanine, AA5=lysine and AA6=glutamine) were synthe...A new six intraperitoneal injection insulin-mimetic vanadyl(Ⅱ) compounds [(VD3^-1)(VO^+2)(AAn^-1)](where(n=1~6);AA1=isoleucine, AA2=threonine, AA3=proline, AA4=phenylalanine, AA5=lysine and AA6=glutamine) were synthesized by the chemical reactions between vitamin D3(VD3), VOSO4 and amino acids(AAn) with equal molar ratio 1∶1∶1 in neutralized media. The structures of these complexes were elucidated by spectroscopic methods like, infrared and solid reflectance spectroscopes. Magnetic moments and electronic spectra reveal square pyramid geometrical structure of the complexes. The infrared spectra assignments of these complexes revealed that the chelation towards vanadyl(Ⅳ) ions existed via deprotonation of the hydroxyl group of VD3 drug ligand and so amino acids act as bidentate ligand via N-amino and O-carboxylate groups. The anti-diabetic efficiency of these complexes were evaluated against streptozotocin induced diabetic male albino rats.展开更多
OBJECTIVE To investigate the role of active component of Isatidis Radix on insulin resistance in the diabetes mellitus rat.METHODS To induce diabetic rat model with long-term high sugar and high fat plus low-dose stre...OBJECTIVE To investigate the role of active component of Isatidis Radix on insulin resistance in the diabetes mellitus rat.METHODS To induce diabetic rat model with long-term high sugar and high fat plus low-dose streptozotocin(25 mg·kg-1).Then rats were randomly divided into 6 groups:control group,model group,rosiglitazone maleate group(0.3mg·kg-1),high(100mg·kg-1),middle(50mg·kg-1)and low(25 mg·kg-1)active component of Isatidis Radix group.Drugs were adiministered orally once a day.After four weeks,following substances were measured:serum fasting blood glucose,total cholesterol,triglycerides,high density lipoprotein,low density lipoprotein,free fatty acids,fasting insulin,insulin index,pathological observation and immunohistochemistry technology of pancreas islet.RESULTS High and middle active component of Isatidis Radix group could decrease serum FBG,TC,TG,LDL,FFA,FINS and increase serum HDL,ISI;the damage of the pancreas islet has been restoration partly.CONCLUSION Active component of Isatidis Radix could improve insulin resistance in diabetic rats,which might be related to improvement of the function of pancreas islet.展开更多
OBJECTIVE To investigate the effect of Pandanus amaryllifolius leaf in high-fat diet-induced insulin resistance in mice model.METHODS To induce obesity,male ICR mice were fed with a high-fat diet(45%fat)for six weeks....OBJECTIVE To investigate the effect of Pandanus amaryllifolius leaf in high-fat diet-induced insulin resistance in mice model.METHODS To induce obesity,male ICR mice were fed with a high-fat diet(45%fat)for six weeks.The mice were divided into four groups(n=8):non-obese control mice were treated with 5% gum arabic and obese mice were treated with Pandanus amaryllifolius(125and 250mg·kg-1·d-1),or 5% gum arabic.After six weeks of treatments,the fasting blood glucose,serum insulin,OGTT and fat cell protein expression of glucose transporter 4(GLUT4)were determined.RESULTS Administration of Pandanus amaryllifolius showed significantly(P<0.05)reduced the high blood glucose,inhibited the abnormal increase in blood glucose level during OGTT,and decreased the high level of serum insulin.Moreover,it is interesting that the protein expression of GLUT4 was effectively increased by Pandanus amaryllifolius.CONCLUSION These findings demonstrate that the extract from Pandanus amaryllifolius leaf possesses antihyperglycemic action in obese mice by improving insulin sensitivity and stimulating GLUT4 expression in adipose tissue.展开更多
OBJECTIVE To investigate the effect of phosphotyrosine interaction domain containing 1(PID1,NYGGF4)on promotion of IR and HCC,and explore its underlying mechanisms.METHODS Lentivirus were used to mediate the knockdown...OBJECTIVE To investigate the effect of phosphotyrosine interaction domain containing 1(PID1,NYGGF4)on promotion of IR and HCC,and explore its underlying mechanisms.METHODS Lentivirus were used to mediate the knockdown of PID1 in HFD induced IR mouse model as well as ob/ob mice.Intraperitoneal glucose and insulin tolerance were performed 4 weeks after lentivirus injection.Hydrodynamics-based transfection was applied to inducethe liver specific overexpression of PID1.Flow cytometry was exerted to detect the proportion and function of immune cells.qR T-PCR and Western blot were used to detect the expression of downstream pathways of PID1.Immunoprecipitation was used to determine the receptor of PID1.Chromatin immunoprecipitation(ChI P)was operated to measure the modification of H3K4me3 of PID1 promoter.RESULTS PID1 restriction improved insulin resistance,hyperglycemia and fatty liver.Conversely,hepatic knockdown of PID1 attenuated liver xenografted tumor growth.Moreover,PID1 liver-specific protooncogenes via hydrodynamics-based transfection established a primary hepatocellular carcinoma mouse model,induced an immunosuppressive environment,with the reduction of CD3^+,CD4^+,CD8^+T cel s,retarded maturation of dendritic cel s(DCs),pronounced differentiation of regulatory T cells(Tregs),and recruitment of MDSC.In addition,PID1 overexpression activated proliferation related genes,promoted anti-inflammatory genes,suppressed pro-inflammatory genes,induced glycolysis and lipid metabolism genes to facilitate tumorigenesis in liver.Importantly,PID1 exerted its tumor-promoting function through binding to epidermal growth factor receptor(EGFR)and activation of downstream MAPK pathway.As such,PID1 exist trimethylation of histone H3 at lysine 4(H3K4me3)modification and IR up-regulated the expression of PID1 by activation the H3K4me3 modification.CONCLUSION PID1 is a new gene that exerts both liver cancer-promoting and insulin resistance inducing function.IR accelerates liver cancer development and progressionpartially dependent on the activation of PID1.展开更多
Increased circulating branched-chain amino acids(BCAAs)have been involved in the pathogenesis of obesity and insulin resistance.However,evidence relating berberine(BBR),gut microbiota,BCAAs,and insulin resis⁃tance is ...Increased circulating branched-chain amino acids(BCAAs)have been involved in the pathogenesis of obesity and insulin resistance.However,evidence relating berberine(BBR),gut microbiota,BCAAs,and insulin resis⁃tance is limited.Here,we showed that BBR could effectively rectify steatohepatitis and glucose intolerance in high-fat diet(HFD)-fed mice.BBR reorganized gut microbiota populations under both the normal chow diet(NCD)and HFD.Particu⁃larly,BBR noticeably decreased the relative abundance of BCAA-producing bacteria,including order Clostridiales;fami⁃lies Streptococcaceae,Clostridiaceae,and Prevotellaceae;and genera Streptococcus and Prevotella.Compared with the HFD group,predictive metagenomics indicated a reduction in the proportion of gut microbiota genes involved in BCAA biosynthesis but the enrichment genes for BCAA degradation and transport by BBR treatment.Accordingly,the elevated serum BCAAs of HFD group were significantly decreased by BBR.Furthermore,the Western blotting results implied that BBR could promote the BCAA catabolism in the liver and epididymal white adipose tissues of HFD-fed mice by acti⁃vation of the multienzyme branched-chain α-ketoacid dehydrogenase complex,whereas by inhibition of the phosphoryla⁃tion state of BCKDHA(E1α subunit)and branched-chain α-ketoacid dehydrogenase kinase.The ex vivo assay further confirmed that BBR could increase BCAA catabolism in both AML12 hepatocytes and 3T3-L1 adipocytes.Finally,data from healthy subjects and diabetics confirmed that BBR could improve glycemic control and modulate circulating BCAAs.Besides,functional microbiomics integrated high-throughput microbial genomics,metabolomics and molecular biotechnology has also been successfully applied to reveal the anti-obesity mechanism of hydroxysafflor yellow A.展开更多
Insulin sensitizing medicines are currently limited, and identification of new drug candidate is a chal- lenge. Protein tyrosine phosphatase 1B （PTP1 B） negatively regulates insulin signaling pathway, and its inhibi...Insulin sensitizing medicines are currently limited, and identification of new drug candidate is a chal- lenge. Protein tyrosine phosphatase 1B （PTP1 B） negatively regulates insulin signaling pathway, and its inhibition is anticipated to improve insulin resistance. This study investigated the pharmacological profiles of compound CX08005, a new PTP1B inhibitor, with therapeutic potential for insulin resistance in vivo and in vitro, respective- ly. Recombinant human PTP1B protein was used to measure the enzyme activity. The docking simulation was per- formed to explore the interactions between the compound and the protein. The insulin sensitivity was evaluated in Diet-induced obesity mice and/or T2DM KKAy mice by glucose tolerance test （GTT）, the blood glucose level, glucose stimulated insulin secretion （GSIS）, homeostasis model assessment of insulin resistance index （HOMA-IR） and the whole-body insulin sensitivity （ISwb） index, respectively. The hyperinsulinemic-euglycemic clamp was performed to evaluate the insulin stimulated glucose disposal both in whole body and in insulin-sensitive tissues （muscle and fat）. Furthermore, its direct effect in muscle, fat and liver cells was observed. We found that CX08005 was a competitive inhibitor of PTP1B with dose-dependent activity （IC50=5.95 × 10^-7 M）. Docking simulation demonstrated that CX08005 binds to PTP1B at the catalytic P-loop through hydrogen bonds. In DIO mice, treatment with CX08005 effectively ameliorated glucose intolerance in a dose-dependent manner （50- 200 mg. kg^-1 · d^-l）, and decreased HOMA-IR values. We also demonstrated that oral administration of 50 mg ~ kg^-1· d^-1 CX08005 improved hyperglycemia, hyperinsulinemia, HOMA-IR and ISwb in KKAy mice. In hyperin- sulinemic-euglycemic clamp test, CX08005 increased glucose infusion rate and glucose uptake in muscle and fat of DIO mice. In 3T3-L1 adipocytes and C2C12 myotubes, CX08005 enhanced insulin-induced glucose uptake. In HepG2 hepatocyte, CX08005 enhanced insulin-stimulated tyrosine phosphorylation of IRβ/IRS1 in a dose-depend- ent manner, respectively; furthermore, the phosphorylation of several downstream molecules, including Akt, Foxol and GSK3β was also increased, indicating this compound could augment insulin＇s ability to suppress hepatic glu- cose output （HGO）. Our results strongly suggest that compound CX08005 directly enhances insulin action in vitro and in vivo with therapeutic potential for insulin resistance.展开更多
Parenteral route of insulin administration has been the mode of treatment for all Type 1 diabetics and Type 2 diabetics with complications.Patient compliance has really been a major concern for this route of administr...Parenteral route of insulin administration has been the mode of treatment for all Type 1 diabetics and Type 2 diabetics with complications.Patient compliance has really been a major concern for this route of administration.Several alternative routes of administration are under consideration for effective glycemic control,including oral,inhaled,buccal,nasal,and patch routes.One of the approaches involving inhaled insulin has now reached the market.Several other candidates may reach the market in the near future,the promising one being oral insulin.展开更多
OBJECTIVE To explorethe correlation betweenhypoxiaand insulin resistance bythe blood gas index in high-fat diets-induced obese rat model.METHODS 36% of high-fat diets were fed to SD male rats for 12 weeks.The model gr...OBJECTIVE To explorethe correlation betweenhypoxiaand insulin resistance bythe blood gas index in high-fat diets-induced obese rat model.METHODS 36% of high-fat diets were fed to SD male rats for 12 weeks.The model group was divided into IR group and non-IR group with the HOMA-IR index of the 12th week,and the abdominal aorta blood was taken for blood gas analysis.RESULTS The HOMA-IR index,Hct,ctHb and ctO_2 in IR group were significantly higher than those in normal group andnon-IR group(P>0.05),simultaneously no significant difference in pO_2,pCO_2 and sO_2 between tree groups.CONCLUSION Circulating blood of obese rat with insulin resistance is normoxia,accompanied by higher Hct,tHb and ctO_2,which may be due to the higher blood viscositand the selfregulation of chronic hypoxia in the body.展开更多
OBJECTIVE To investigate the effect of phosphotyrosine interaction domain containing1(PID1,NYGGF4) onpromotion of IR and HCC,and explore its underlying mechanisms.METHODS Lentivirus were used to mediate the knockdown ...OBJECTIVE To investigate the effect of phosphotyrosine interaction domain containing1(PID1,NYGGF4) onpromotion of IR and HCC,and explore its underlying mechanisms.METHODS Lentivirus were used to mediate the knockdown of PID1 in HFD induced IR mouse model as well as ob/ob mice.Intraperitoneal glucose and insulin tolerance were performed 4 weeks after lentivirus injection.Hydrodynamics-based transfection was applied to induce the liver specific overexpression of PID1.Flow cytometry was exerted to detect the proportion and function of immune cells.qRT-PCR and Western blot were used to detect the expression of downstream pathways of PID1.Liquid chromatographymass spectrometry(LC-MS) and co-immunoprecipitation(Co-IP) were conducted to identify proteins interacting with PID1.Chromatin immunoprecipitation(ChIP) was operated to measure the modification of H3K4me3 of PID1 promoter.RESULTS PID1 restriction improved insulin resistance,hyperglycemia and fatty liver.Conversely,hepatic knockdown of PID1 attenuated liver xenografted tumor growth.Moreover,PID1 liver-specific protooncogenes via hydrodynamics-based transfection established a primary hepatocellular carcinoma mouse model,induced an immunosuppressive environment,with the reduction of CD3+,CD4+,CD8+T cells,retarded maturation of dendritic cells(DCs),pronounced differentiation of regulatory T cells(Tregs),and recruitment of MDSC.In addition,PID1 overexpression activated prolifer.ation related genes,promoted anti-inflammatory genes,suppressed pro-inflammatory genes,induced glycolysis and lipid metabolism genes to facilitate tumorigenesis in liver.Importantly,PID1 exerted its tumor-promoting function through binding to epidermal growth factor receptor(EGFR) and activation of downstream KRAS/ERK pathway.As such,PID1 exist trimethylation of histone H3 at lysine 4(H3K4me3)modification and IR up-regulated the expression of PID1 by activation the H3K4me3 modification.CONCLUSION PID1 is a new gene that exerts both liver cancer-promoting and insulin resistance inducing function.IR accelerates liver cancer development and progression partially dependent on the activation of PID1.展开更多
基金supported by National Natural Science Foundation of China(81502123 and81330081)Natural Science Foundation of Anhui Province(1308085QH130)Anhui Province Nature Science Foundation in University(KJ2014A119)
文摘OBJECTIVE Basic fibroblast growth factor(b FGF)and platelet-derived growth factor(PDGF)produced by hepatocellular carcinoma(HCC)cells are responsible for the cell growth.Accumulating evidence shows that insulin-like growth factor-binding protein-3(IGFBP-3)suppresses HCC cell proliferation in both IGF-dependent and independent manners.The present study is to investigate whether treatment with exogenous IGFBP-3 inhibits bF GF and PDGF production and the cell proliferation of HCC cells.METHODS Cell Counting Kit 8 assay were designed to detect HCC cell proliferation,transcription factor early growth response-1(EGR1)involving in IGFBP-3 regulation of b FGF and PDGF were detected by RT-PCR and Western blot assays.Western blot assay was adopted to detect the IGFBP-3 regulating insulin-like growth factor 1 receptor(IGF-1R)signaling pathway.RESULTS The present study demonstrates that IGFBP-3 suppressed IGF-1-induced b FGF and PDGF expression while it does not affect their expression in the absence of IGF-1.To delineate the underlying mechanism,Western-blot and RT-PCR assays confirmed that the transcription factor early growth response protein 1(EGR1)is involved in IGFBP-3 regulation of b FGF and PDGF.IGFBP-3 inhibition of type 1 insulin-like growth factor receptor(IGF1R),ERK and AKT activation is IGF-1-dependent.Furthermore,transient transfection with constitutively activated AKT or MEK partially blocks the IGFBP-3 inhibition of EGR1,b FGF and PDGF expression.CONCLUSION In conclusion,these findings suggest that IGFBP-3suppresses transcription of EGR1 and its target genes b FGF and PDGF through inhibiting IGF-1-dependent ERK and AKT activation.It demonstrates the importance of IGFBP-3 in the regulation of HCC cell proliferation,suggesting that IGFBP-3 could be a target for the treatment of HCC.
基金supported by Innovation Team Project of Northeast Agricultural Vniversity(XLT005-1-2)Research Fund for the Doctoral Program of Heilongjiang Educational Committee(HLJBSDJI2004-15)
文摘Mammary epithelial cells with lactational function can be a valuable cellular model for research of the development and regulation of the mammary gland.This paper describes some aspects of function of an epithelial cell line from the mammary gland of the dairy goat.SDS-PAGE,triglyceride and lactose content of cultured cells were used to assess synthetic function of cells and the effects of exposure to insulin and prolactin.Results show that goat mammary epithelial cells can synthesize fat,proteins and lactose when they were cultured in DMEM-F12 medium with added EGF,IGF-1,ITS and FBS.There were no obvious changes after 48h treatment with additional insulin.Prolactin added to the basal medium significantly increased synthesis of proteins and lactose.A mammary gland epithelial cell line from goats which has lactational function has been established.This outcome provides a valuable and convenient model system.
文摘A new six intraperitoneal injection insulin-mimetic vanadyl(Ⅱ) compounds [(VD3^-1)(VO^+2)(AAn^-1)](where(n=1~6);AA1=isoleucine, AA2=threonine, AA3=proline, AA4=phenylalanine, AA5=lysine and AA6=glutamine) were synthesized by the chemical reactions between vitamin D3(VD3), VOSO4 and amino acids(AAn) with equal molar ratio 1∶1∶1 in neutralized media. The structures of these complexes were elucidated by spectroscopic methods like, infrared and solid reflectance spectroscopes. Magnetic moments and electronic spectra reveal square pyramid geometrical structure of the complexes. The infrared spectra assignments of these complexes revealed that the chelation towards vanadyl(Ⅳ) ions existed via deprotonation of the hydroxyl group of VD3 drug ligand and so amino acids act as bidentate ligand via N-amino and O-carboxylate groups. The anti-diabetic efficiency of these complexes were evaluated against streptozotocin induced diabetic male albino rats.
基金The project supported by Spark Technology Project by Jiangsu Province(BE2004339)
文摘OBJECTIVE To investigate the role of active component of Isatidis Radix on insulin resistance in the diabetes mellitus rat.METHODS To induce diabetic rat model with long-term high sugar and high fat plus low-dose streptozotocin(25 mg·kg-1).Then rats were randomly divided into 6 groups:control group,model group,rosiglitazone maleate group(0.3mg·kg-1),high(100mg·kg-1),middle(50mg·kg-1)and low(25 mg·kg-1)active component of Isatidis Radix group.Drugs were adiministered orally once a day.After four weeks,following substances were measured:serum fasting blood glucose,total cholesterol,triglycerides,high density lipoprotein,low density lipoprotein,free fatty acids,fasting insulin,insulin index,pathological observation and immunohistochemistry technology of pancreas islet.RESULTS High and middle active component of Isatidis Radix group could decrease serum FBG,TC,TG,LDL,FFA,FINS and increase serum HDL,ISI;the damage of the pancreas islet has been restoration partly.CONCLUSION Active component of Isatidis Radix could improve insulin resistance in diabetic rats,which might be related to improvement of the function of pancreas islet.
基金The project supported by Faculty of Medicine,Thammasat University Thailand
文摘OBJECTIVE To investigate the effect of Pandanus amaryllifolius leaf in high-fat diet-induced insulin resistance in mice model.METHODS To induce obesity,male ICR mice were fed with a high-fat diet(45%fat)for six weeks.The mice were divided into four groups(n=8):non-obese control mice were treated with 5% gum arabic and obese mice were treated with Pandanus amaryllifolius(125and 250mg·kg-1·d-1),or 5% gum arabic.After six weeks of treatments,the fasting blood glucose,serum insulin,OGTT and fat cell protein expression of glucose transporter 4(GLUT4)were determined.RESULTS Administration of Pandanus amaryllifolius showed significantly(P<0.05)reduced the high blood glucose,inhibited the abnormal increase in blood glucose level during OGTT,and decreased the high level of serum insulin.Moreover,it is interesting that the protein expression of GLUT4 was effectively increased by Pandanus amaryllifolius.CONCLUSION These findings demonstrate that the extract from Pandanus amaryllifolius leaf possesses antihyperglycemic action in obese mice by improving insulin sensitivity and stimulating GLUT4 expression in adipose tissue.
基金supported by National Natural Science Foundation of China(81673440,81273521,and 91229114)
文摘OBJECTIVE To investigate the effect of phosphotyrosine interaction domain containing 1(PID1,NYGGF4)on promotion of IR and HCC,and explore its underlying mechanisms.METHODS Lentivirus were used to mediate the knockdown of PID1 in HFD induced IR mouse model as well as ob/ob mice.Intraperitoneal glucose and insulin tolerance were performed 4 weeks after lentivirus injection.Hydrodynamics-based transfection was applied to inducethe liver specific overexpression of PID1.Flow cytometry was exerted to detect the proportion and function of immune cells.qR T-PCR and Western blot were used to detect the expression of downstream pathways of PID1.Immunoprecipitation was used to determine the receptor of PID1.Chromatin immunoprecipitation(ChI P)was operated to measure the modification of H3K4me3 of PID1 promoter.RESULTS PID1 restriction improved insulin resistance,hyperglycemia and fatty liver.Conversely,hepatic knockdown of PID1 attenuated liver xenografted tumor growth.Moreover,PID1 liver-specific protooncogenes via hydrodynamics-based transfection established a primary hepatocellular carcinoma mouse model,induced an immunosuppressive environment,with the reduction of CD3^+,CD4^+,CD8^+T cel s,retarded maturation of dendritic cel s(DCs),pronounced differentiation of regulatory T cells(Tregs),and recruitment of MDSC.In addition,PID1 overexpression activated proliferation related genes,promoted anti-inflammatory genes,suppressed pro-inflammatory genes,induced glycolysis and lipid metabolism genes to facilitate tumorigenesis in liver.Importantly,PID1 exerted its tumor-promoting function through binding to epidermal growth factor receptor(EGFR)and activation of downstream MAPK pathway.As such,PID1 exist trimethylation of histone H3 at lysine 4(H3K4me3)modification and IR up-regulated the expression of PID1 by activation the H3K4me3 modification.CONCLUSION PID1 is a new gene that exerts both liver cancer-promoting and insulin resistance inducing function.IR accelerates liver cancer development and progressionpartially dependent on the activation of PID1.
文摘Increased circulating branched-chain amino acids(BCAAs)have been involved in the pathogenesis of obesity and insulin resistance.However,evidence relating berberine(BBR),gut microbiota,BCAAs,and insulin resis⁃tance is limited.Here,we showed that BBR could effectively rectify steatohepatitis and glucose intolerance in high-fat diet(HFD)-fed mice.BBR reorganized gut microbiota populations under both the normal chow diet(NCD)and HFD.Particu⁃larly,BBR noticeably decreased the relative abundance of BCAA-producing bacteria,including order Clostridiales;fami⁃lies Streptococcaceae,Clostridiaceae,and Prevotellaceae;and genera Streptococcus and Prevotella.Compared with the HFD group,predictive metagenomics indicated a reduction in the proportion of gut microbiota genes involved in BCAA biosynthesis but the enrichment genes for BCAA degradation and transport by BBR treatment.Accordingly,the elevated serum BCAAs of HFD group were significantly decreased by BBR.Furthermore,the Western blotting results implied that BBR could promote the BCAA catabolism in the liver and epididymal white adipose tissues of HFD-fed mice by acti⁃vation of the multienzyme branched-chain α-ketoacid dehydrogenase complex,whereas by inhibition of the phosphoryla⁃tion state of BCKDHA(E1α subunit)and branched-chain α-ketoacid dehydrogenase kinase.The ex vivo assay further confirmed that BBR could increase BCAA catabolism in both AML12 hepatocytes and 3T3-L1 adipocytes.Finally,data from healthy subjects and diabetics confirmed that BBR could improve glycemic control and modulate circulating BCAAs.Besides,functional microbiomics integrated high-throughput microbial genomics,metabolomics and molecular biotechnology has also been successfully applied to reveal the anti-obesity mechanism of hydroxysafflor yellow A.
文摘Insulin sensitizing medicines are currently limited, and identification of new drug candidate is a chal- lenge. Protein tyrosine phosphatase 1B （PTP1 B） negatively regulates insulin signaling pathway, and its inhibition is anticipated to improve insulin resistance. This study investigated the pharmacological profiles of compound CX08005, a new PTP1B inhibitor, with therapeutic potential for insulin resistance in vivo and in vitro, respective- ly. Recombinant human PTP1B protein was used to measure the enzyme activity. The docking simulation was per- formed to explore the interactions between the compound and the protein. The insulin sensitivity was evaluated in Diet-induced obesity mice and/or T2DM KKAy mice by glucose tolerance test （GTT）, the blood glucose level, glucose stimulated insulin secretion （GSIS）, homeostasis model assessment of insulin resistance index （HOMA-IR） and the whole-body insulin sensitivity （ISwb） index, respectively. The hyperinsulinemic-euglycemic clamp was performed to evaluate the insulin stimulated glucose disposal both in whole body and in insulin-sensitive tissues （muscle and fat）. Furthermore, its direct effect in muscle, fat and liver cells was observed. We found that CX08005 was a competitive inhibitor of PTP1B with dose-dependent activity （IC50=5.95 × 10^-7 M）. Docking simulation demonstrated that CX08005 binds to PTP1B at the catalytic P-loop through hydrogen bonds. In DIO mice, treatment with CX08005 effectively ameliorated glucose intolerance in a dose-dependent manner （50- 200 mg. kg^-1 · d^-l）, and decreased HOMA-IR values. We also demonstrated that oral administration of 50 mg ~ kg^-1· d^-1 CX08005 improved hyperglycemia, hyperinsulinemia, HOMA-IR and ISwb in KKAy mice. In hyperin- sulinemic-euglycemic clamp test, CX08005 increased glucose infusion rate and glucose uptake in muscle and fat of DIO mice. In 3T3-L1 adipocytes and C2C12 myotubes, CX08005 enhanced insulin-induced glucose uptake. In HepG2 hepatocyte, CX08005 enhanced insulin-stimulated tyrosine phosphorylation of IRβ/IRS1 in a dose-depend- ent manner, respectively; furthermore, the phosphorylation of several downstream molecules, including Akt, Foxol and GSK3β was also increased, indicating this compound could augment insulin＇s ability to suppress hepatic glu- cose output （HGO）. Our results strongly suggest that compound CX08005 directly enhances insulin action in vitro and in vivo with therapeutic potential for insulin resistance.
基金support from Swedish Medical Research Council,Svenskadiabetes Forbundet,Barndiabetesfonden,Svenskadiabetes StiftelsenKarolinska Institute and Karolinska University Hospital to Carani B.Sanjeevi
文摘Parenteral route of insulin administration has been the mode of treatment for all Type 1 diabetics and Type 2 diabetics with complications.Patient compliance has really been a major concern for this route of administration.Several alternative routes of administration are under consideration for effective glycemic control,including oral,inhaled,buccal,nasal,and patch routes.One of the approaches involving inhaled insulin has now reached the market.Several other candidates may reach the market in the near future,the promising one being oral insulin.
基金supported by National Natural Science Foundation of China(81560744)
文摘OBJECTIVE To explorethe correlation betweenhypoxiaand insulin resistance bythe blood gas index in high-fat diets-induced obese rat model.METHODS 36% of high-fat diets were fed to SD male rats for 12 weeks.The model group was divided into IR group and non-IR group with the HOMA-IR index of the 12th week,and the abdominal aorta blood was taken for blood gas analysis.RESULTS The HOMA-IR index,Hct,ctHb and ctO_2 in IR group were significantly higher than those in normal group andnon-IR group(P>0.05),simultaneously no significant difference in pO_2,pCO_2 and sO_2 between tree groups.CONCLUSION Circulating blood of obese rat with insulin resistance is normoxia,accompanied by higher Hct,tHb and ctO_2,which may be due to the higher blood viscositand the selfregulation of chronic hypoxia in the body.
基金supported by National Natural Science Foundation of China(816734408127352191229114)
文摘OBJECTIVE To investigate the effect of phosphotyrosine interaction domain containing1(PID1,NYGGF4) onpromotion of IR and HCC,and explore its underlying mechanisms.METHODS Lentivirus were used to mediate the knockdown of PID1 in HFD induced IR mouse model as well as ob/ob mice.Intraperitoneal glucose and insulin tolerance were performed 4 weeks after lentivirus injection.Hydrodynamics-based transfection was applied to induce the liver specific overexpression of PID1.Flow cytometry was exerted to detect the proportion and function of immune cells.qRT-PCR and Western blot were used to detect the expression of downstream pathways of PID1.Liquid chromatographymass spectrometry(LC-MS) and co-immunoprecipitation(Co-IP) were conducted to identify proteins interacting with PID1.Chromatin immunoprecipitation(ChIP) was operated to measure the modification of H3K4me3 of PID1 promoter.RESULTS PID1 restriction improved insulin resistance,hyperglycemia and fatty liver.Conversely,hepatic knockdown of PID1 attenuated liver xenografted tumor growth.Moreover,PID1 liver-specific protooncogenes via hydrodynamics-based transfection established a primary hepatocellular carcinoma mouse model,induced an immunosuppressive environment,with the reduction of CD3+,CD4+,CD8+T cells,retarded maturation of dendritic cells(DCs),pronounced differentiation of regulatory T cells(Tregs),and recruitment of MDSC.In addition,PID1 overexpression activated prolifer.ation related genes,promoted anti-inflammatory genes,suppressed pro-inflammatory genes,induced glycolysis and lipid metabolism genes to facilitate tumorigenesis in liver.Importantly,PID1 exerted its tumor-promoting function through binding to epidermal growth factor receptor(EGFR) and activation of downstream KRAS/ERK pathway.As such,PID1 exist trimethylation of histone H3 at lysine 4(H3K4me3)modification and IR up-regulated the expression of PID1 by activation the H3K4me3 modification.CONCLUSION PID1 is a new gene that exerts both liver cancer-promoting and insulin resistance inducing function.IR accelerates liver cancer development and progression partially dependent on the activation of PID1.
