Tinnitus is a phantom auditory sensation often accompanied by hearing loss,cognitive impairments,and psychological disturbances in various populations.Dysfunction of KCNQ2 and KCNQ3 channelsvoltage-dependent potassium...Tinnitus is a phantom auditory sensation often accompanied by hearing loss,cognitive impairments,and psychological disturbances in various populations.Dysfunction of KCNQ2 and KCNQ3 channelsvoltage-dependent potassium ion channels-in the cochlear nucleus can cause tinnitus.Despite the recognized significance of KCNQ2 and KCNQ3 channels in the auditory cortex,their precise relationship and implications in the pathogenesis of tinnitus remain areas of scientific inquiry.This study aimed to elucidate the pathological roles of KCNQ2 and KCNQ3 channels within the auditory cortex in tinnitus development and examine the therapeutic potential of mid-infrared photons for tinnitus treatment.We utilized a noise-induced tinnitus model combined with immunofluorescence,electrophysiological recording,and molecular dynamic simulation to investigate the morphological and physiological alterations after inducing tinnitus.Moreover,invivo irradiation was administered to verify the treatment effects of infrared photons.Tinnitus was verified by deficits of the gap ratio with similar prepulse inhibition ratio and auditory brainstem response threshold.We observed an important enhancement in neuronal excitability in the auditory cortex using patch-clamp recordings,which correlated with KCNQ2 and KCNQ3 channel dysfunction.After irradiation with infrared photons,excitatory neuron firing was inhibited owing to increased KCNQ2 current resulting from structural alterations in the filter region.Meanwhile,deficits of the acoustic startle response in tinnitus animals were alleviated by infrared photons.Furthermore,infrared photons reversed the abnormal hyperexcitability of excitatory neurons in the tinnitus group.This study provided a novel method for modulating neuron excitability in the auditory cortex using KCNQ2 channels through a nonthermal effect.Infrared photons effectively mitigated tinnitus-related behaviors by suppressing abnormal neural excitability,potentially laying the groundwork for innovative therapeutic approaches for tinnitus treatment.展开更多
Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the developme...Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the development ofHCC.TheWarburg effect has recently been confirmed to occur in a variety of cancers,including HCC.However,little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells.In this study,we sought to better understand how methyltransferase 5,N6-adenosine(METTL5)controls the development of HCC and theWarburg effect.Methods:In the current study,quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines.Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecularmechanism of HCC.Glutathione-S-transferase pulldown,coimmunoprecipitation,RNA sequencing,non-targeted metabolomics,polysome profiling,and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells.Results:We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC.Mechanistically,upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A(LDHA),enolase 1(ENO1),triosephosphate isomerase 1(TPI1),solute carrier family 2 member 1(SLC2A1),and pyruvate kinase M2(PKM2).The c-Box and ubiquitin binding domain(UBA)regions of ubiquitin specific peptidase 5(USP5)binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc.Further study revealed that METTL5 controled the USP5 translation process,which in turn regulated the ubiquitination of c-Myc.Furthermore,we identified cAMP responsive element binding protein 1(CREB1)/P300 as a critical transcriptional regulator ofMETTL5 that promoted the transcription of METTL5 in HCC.In patient-derived tumor xenograft(PDX)models,adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice.Conclusions:These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth,suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.展开更多
Deregulated telomere length is a causative factor in many physiological and pathological processes,including aging and cancer.Many studies focusing on telomeres have revealed important roles for cooperation between th...Deregulated telomere length is a causative factor in many physiological and pathological processes,including aging and cancer.Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length.However,it remains largely unknown whether and how aging-related stresses,such as deregulated protein homeostasis,impact telomere length.Here,we explored the possible roles of aminoacyl tRNA synthetases(AARSs),key enzymes catalyzing the first reactions in protein synthesis,in regulating telomere length and aging.We selected seryl tRNA synthetase(SerRS)since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis.In this study,we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells.In the nucleus,SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1.We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres,resulting in progressive telomere shortening.Our data suggested a possible molecular link between protein synthesis and telomere length control,the deregulation of which may be associated with aging and cancer.展开更多
Diabetic nephropathy(DN)has become the leading cause of end-stage renal disease with high morbidity and mortality among individuals with diabetes mellitus.Although functional alterations of renal infiltrating immune c...Diabetic nephropathy(DN)has become the leading cause of end-stage renal disease with high morbidity and mortality among individuals with diabetes mellitus.Although functional alterations of renal infiltrating immune cells have been reported as part of the pathological mechanism of DN,the understanding of the immune response underlying peripheral blood mononuclear cells(PBMCs)in DN remains limited.Here,single-cell RNA sequencing(scRNA-seq)was used toprofile the transcriptomic signatures of PBMCs from DN patients.展开更多
基金supported by the Beijing Science and Technology New Star Program(grant number Z2011-00006820133)National Key Research and Development Program(grant numbers 2022YFC2402704 and 2022YFC2402701)the National Natural Science Foundation of China(grant numbers 82201299 and 81970890).
文摘Tinnitus is a phantom auditory sensation often accompanied by hearing loss,cognitive impairments,and psychological disturbances in various populations.Dysfunction of KCNQ2 and KCNQ3 channelsvoltage-dependent potassium ion channels-in the cochlear nucleus can cause tinnitus.Despite the recognized significance of KCNQ2 and KCNQ3 channels in the auditory cortex,their precise relationship and implications in the pathogenesis of tinnitus remain areas of scientific inquiry.This study aimed to elucidate the pathological roles of KCNQ2 and KCNQ3 channels within the auditory cortex in tinnitus development and examine the therapeutic potential of mid-infrared photons for tinnitus treatment.We utilized a noise-induced tinnitus model combined with immunofluorescence,electrophysiological recording,and molecular dynamic simulation to investigate the morphological and physiological alterations after inducing tinnitus.Moreover,invivo irradiation was administered to verify the treatment effects of infrared photons.Tinnitus was verified by deficits of the gap ratio with similar prepulse inhibition ratio and auditory brainstem response threshold.We observed an important enhancement in neuronal excitability in the auditory cortex using patch-clamp recordings,which correlated with KCNQ2 and KCNQ3 channel dysfunction.After irradiation with infrared photons,excitatory neuron firing was inhibited owing to increased KCNQ2 current resulting from structural alterations in the filter region.Meanwhile,deficits of the acoustic startle response in tinnitus animals were alleviated by infrared photons.Furthermore,infrared photons reversed the abnormal hyperexcitability of excitatory neurons in the tinnitus group.This study provided a novel method for modulating neuron excitability in the auditory cortex using KCNQ2 channels through a nonthermal effect.Infrared photons effectively mitigated tinnitus-related behaviors by suppressing abnormal neural excitability,potentially laying the groundwork for innovative therapeutic approaches for tinnitus treatment.
基金the Ethics Committee of Zhongnan Hospital ofWuhan University(permit number:KELUN2017082 and KELUN2020100)The tissue samples were obtained with written informed consent from each patient.All animal experiments were approved in accordance with the guidelines of the Animal Ethics and Welfare Committee of Wuhan University of Zhongnan Hospital(permit number:ZN2022005).
文摘Background:Hepatocellular carcinoma(HCC)is one of the most prevalent cancers in the world,with a high likelihood of metastasis and a dismal prognosis.The reprogramming of glucosemetabolism is critical in the development ofHCC.TheWarburg effect has recently been confirmed to occur in a variety of cancers,including HCC.However,little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells.In this study,we sought to better understand how methyltransferase 5,N6-adenosine(METTL5)controls the development of HCC and theWarburg effect.Methods:In the current study,quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines.Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecularmechanism of HCC.Glutathione-S-transferase pulldown,coimmunoprecipitation,RNA sequencing,non-targeted metabolomics,polysome profiling,and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells.Results:We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC.Mechanistically,upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A(LDHA),enolase 1(ENO1),triosephosphate isomerase 1(TPI1),solute carrier family 2 member 1(SLC2A1),and pyruvate kinase M2(PKM2).The c-Box and ubiquitin binding domain(UBA)regions of ubiquitin specific peptidase 5(USP5)binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc.Further study revealed that METTL5 controled the USP5 translation process,which in turn regulated the ubiquitination of c-Myc.Furthermore,we identified cAMP responsive element binding protein 1(CREB1)/P300 as a critical transcriptional regulator ofMETTL5 that promoted the transcription of METTL5 in HCC.In patient-derived tumor xenograft(PDX)models,adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice.Conclusions:These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth,suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81772974)the Natural Science Foundation of Tianjin City(18JCQNJC12600)+1 种基金the Project of Science and Technology Assistance in Developing Countries(KY201501006)the Ph.D.Candidate Research Innovation Fund of Nankai University.
文摘Deregulated telomere length is a causative factor in many physiological and pathological processes,including aging and cancer.Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length.However,it remains largely unknown whether and how aging-related stresses,such as deregulated protein homeostasis,impact telomere length.Here,we explored the possible roles of aminoacyl tRNA synthetases(AARSs),key enzymes catalyzing the first reactions in protein synthesis,in regulating telomere length and aging.We selected seryl tRNA synthetase(SerRS)since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis.In this study,we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells.In the nucleus,SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1.We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres,resulting in progressive telomere shortening.Our data suggested a possible molecular link between protein synthesis and telomere length control,the deregulation of which may be associated with aging and cancer.
基金supported by the Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties(China)(No.SZGSP001)Shenzhen Governmental Sustainable Development Fund(Guangdong,China)(No.KCXFZ20201221173612034)+3 种基金the National Natural Science Foundation of China(China)(No.82170842)the Natural ScienceFoundation of Shenzhen City(China)(No.KCXFZ20201221173600001)Guangdong Basic and Applied Basic Research Foundation(China)(No.2021A1515012164)Shenzhen Key Laboratory of Kidney Diseases(No.ZDSYS20150430161-6234)。
文摘Diabetic nephropathy(DN)has become the leading cause of end-stage renal disease with high morbidity and mortality among individuals with diabetes mellitus.Although functional alterations of renal infiltrating immune cells have been reported as part of the pathological mechanism of DN,the understanding of the immune response underlying peripheral blood mononuclear cells(PBMCs)in DN remains limited.Here,single-cell RNA sequencing(scRNA-seq)was used toprofile the transcriptomic signatures of PBMCs from DN patients.
