Chronic inflammation plays a pivotal role in insulin resistance and type 2 diabetes,yet the mechanisms are not completely understood.Here,we demonstrated that serum LPS levels were significantly higher in newly diagno...Chronic inflammation plays a pivotal role in insulin resistance and type 2 diabetes,yet the mechanisms are not completely understood.Here,we demonstrated that serum LPS levels were significantly higher in newly diagnosed diabetic patients than in normal control.miR-145 level in peripheral blood mononuclear cells decreased in type 2 diabetics.LPS repressed the transcription of miR-143/145 cluster and decreased miR-145 levels.Attenuation of miR-145 activity by anti-miR-145 triggered liver inflammation and increased serum chemokines in C57BL/6 J mice.Conversely,lentivirus-mediated miR-145 overexpression inhibited macrophage infiltration,reduced body weight,and improved glucose metabolism in db/db mice.And miR-145 overexpression markedly reduced plaque size in the aorta in ApoE−/−mice.Both OPG and KLF5 were targets of miR-145.miR-145 repressed cell proliferation and induced apoptosis partially by targeting OPG and KLF5.miR-145 also suppressed NF-κB activation by targeting OPG and KLF5.Our findings provide an association of the environment with the progress of metabolic disorders.Increasing miR-145 may be a new potential therapeutic strategy in preventing and treating metabolic diseases such as type 2 diabetes and atherosclerosis.展开更多
Infertility is a severe public health problem worldwide that prevails up to 15% in reproductive-age couples,and male infertility accounts for half of total infertility.Studies on genetically modified animal models hav...Infertility is a severe public health problem worldwide that prevails up to 15% in reproductive-age couples,and male infertility accounts for half of total infertility.Studies on genetically modified animal models have identifed lots of genes involved in the pathogenesis of male infertility.The underlying causes,however,remain largely unclear.In this study,we provide evidence that EMCIO,one subunit of endoplasmic reticulum (ER)membrane protein complex (EMC),is required for male fertility.EMC10 is significantly decreased in spermatozoa from patients with asthenozoospermia and positively associated with human sperm motility. Male mice lacking Emc10 gene are completely sterile.Emc10-null spermatozoa exhibit multiple defects including abnormal morphology,decreased motility,impaired capacitation,and impotency of acrosome reaction,thereby which are incapable of fertilizing intact or ZP-free oocytes.However,intracytoplasmic sperm injection could rescue this defect caused by EMC10 deletion. Mechanistically,EMC10 deficiency leads to inactivation of Na/K-ATPase,in turn giving rise to an increased level of intraceltutar Na^+ in spermatozoa,which contributes to decreased sperm motility and abnormal morphology.Other mechanistic investigations demonstrate that the absence of EMC10 results in a reduction of HCO3^- entry and subsequent decreases of both cAMP-dependent protein kinase A substrate phosphorylation and protein tyrosine phosphorytation.These data demonstrate that EMC10 is indispensable to mate fertility via maintaining sperm ion balance of Na^+ and HCO3^-,and also suggest that EMC10 is a promising biomarker for male fertility and a potential pharmaceutical target to treat male infertility.展开更多
基金National Natural Science Foundation of China （39925018, 90508002 , 30121001） Chinese Academy of Science （KSCX 1-R65 and RSCX2-H10）+2 种基金 National Basic Research Program of China （973 project, 2002CB713700） American Cancer Society （RPG-99-173-01） a Gcc Breast Cancer Research award and National Institutes of Health grants DK56292 and CA89019 to XY （a GCC Eminent Scholar） and NS36194 （JW）.
基金This work was supported by grants from the National Natural Science Foundation of China(81270902,81381220308,and 30230380).
文摘Chronic inflammation plays a pivotal role in insulin resistance and type 2 diabetes,yet the mechanisms are not completely understood.Here,we demonstrated that serum LPS levels were significantly higher in newly diagnosed diabetic patients than in normal control.miR-145 level in peripheral blood mononuclear cells decreased in type 2 diabetics.LPS repressed the transcription of miR-143/145 cluster and decreased miR-145 levels.Attenuation of miR-145 activity by anti-miR-145 triggered liver inflammation and increased serum chemokines in C57BL/6 J mice.Conversely,lentivirus-mediated miR-145 overexpression inhibited macrophage infiltration,reduced body weight,and improved glucose metabolism in db/db mice.And miR-145 overexpression markedly reduced plaque size in the aorta in ApoE−/−mice.Both OPG and KLF5 were targets of miR-145.miR-145 repressed cell proliferation and induced apoptosis partially by targeting OPG and KLF5.miR-145 also suppressed NF-κB activation by targeting OPG and KLF5.Our findings provide an association of the environment with the progress of metabolic disorders.Increasing miR-145 may be a new potential therapeutic strategy in preventing and treating metabolic diseases such as type 2 diabetes and atherosclerosis.
基金the National Basic Research Program (2014CB943103 to Y.Z.,2015CB943003 to Q.D.)the National Natural Science Foundation of China (31471104 and 31671203 to Y.Z.,81370753 to Q.D.,81070647 and 81370936 to X.W.)+1 种基金This work was also sponsored by grants from Shanghai Pujiang Program (16PJ1401700 to X.W.)Science and Technology Commission of Shanghai Municipality (16140901200 to X.W.).
文摘Infertility is a severe public health problem worldwide that prevails up to 15% in reproductive-age couples,and male infertility accounts for half of total infertility.Studies on genetically modified animal models have identifed lots of genes involved in the pathogenesis of male infertility.The underlying causes,however,remain largely unclear.In this study,we provide evidence that EMCIO,one subunit of endoplasmic reticulum (ER)membrane protein complex (EMC),is required for male fertility.EMC10 is significantly decreased in spermatozoa from patients with asthenozoospermia and positively associated with human sperm motility. Male mice lacking Emc10 gene are completely sterile.Emc10-null spermatozoa exhibit multiple defects including abnormal morphology,decreased motility,impaired capacitation,and impotency of acrosome reaction,thereby which are incapable of fertilizing intact or ZP-free oocytes.However,intracytoplasmic sperm injection could rescue this defect caused by EMC10 deletion. Mechanistically,EMC10 deficiency leads to inactivation of Na/K-ATPase,in turn giving rise to an increased level of intraceltutar Na^+ in spermatozoa,which contributes to decreased sperm motility and abnormal morphology.Other mechanistic investigations demonstrate that the absence of EMC10 results in a reduction of HCO3^- entry and subsequent decreases of both cAMP-dependent protein kinase A substrate phosphorylation and protein tyrosine phosphorytation.These data demonstrate that EMC10 is indispensable to mate fertility via maintaining sperm ion balance of Na^+ and HCO3^-,and also suggest that EMC10 is a promising biomarker for male fertility and a potential pharmaceutical target to treat male infertility.
