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An Update on the Clinical Pipelines of New Antibacterial Drugs Developed in China

Engineering 2024年第7期38卷 52-68页

作者： Xinyi Yang Congran Li Xiukun Wang Zhonghui Zheng Peiyi Sun Chunjie Xu Luni Chen Jiandong Jiang Staffan Normark Birgitta Henriques-Normark Xuefu You Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Division for Medicinal Microorganism-Related Strains CAMS Collection Center of Pathogenic MicroorganismsChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Shandong Xinhua Pharmaceutical Co. Ltd.Zibo 255005China department of microbiology Tumor and Cell BiologyKarolinska InstitutetStockholm SE-17177Sweden State Key Laboratory of Bioactive Substances and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Clinical microbiology Karolinska University HospitalBioclinicumStockholm SE-17176Sweden

Antibacterial resistance is a global health threat that requires further concrete action on the part of all *** this context,one of the biggest concerns is whether enough new antibacterial drugs are being discovered and *** several high-quality reviews on clinical antibacterial drug pipelines from a global perspective were published recently,none provides comprehensive information on original antibacterial drugs at clinical stages in *** this review,we summarize the latest progress of novel antibacterial drugs approved for marketing and under clinical evaluation in China since *** was obtained by consulting official websites,searching commercial databases,retrieving literature,asking personnel from institutions or companies,and other means,and a considerable part of the data covered here has not been included in other *** of June 30,2023,a total of 20 antibacterial projects from 17 Chinese pharmaceutical companies or developers were identified and *** them,two new antibacterial drugs that belong to traditional antibiotic classes were approved by the National medical Products Administration(NMPA)in China in 2019 and 2021,respectively,and 18 antibacterial agents are in clinical development,with one under regulatory evaluation,five in phase-3,six in phase-2,and six in *** of the clinical candidates are new analogs or monocomponents of traditional antibacterial pharmacophore types,including two dual-acting hybrid antibiotics and a recombinant antibacterial ***,despite there being 17 antibacterial clinical candidates,our analysis indicates that there are still relatively few clinically differentiated antibacterial agents in stages of clinical development in ***,Chinese pharmaceutical companies and institutions will develop more innovative and clinically differentiated candidates with good market potential in the future research and development(R&D)of original antibacterial drugs.

关键词： Antimicrobial resistance New antibiotics Clinical pipelines WHO priority pathogens National Mega-Project for Innovative Drugs

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Screening of Rodents from Rural Communities of Lagos and Ogun State Nigeria of Lassa Virus RNA

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Open Journal of medical microbiology 2024年第2期14卷 120-130页

作者： Fatai Sarafa Emmanuel Tochukwu Onyeje Joseph Ojonugwa Shaibu Olumuyiwa Babalola Salu Rosemary Ajuma Audu Sunday Aremu Omilabu department of medical microbiology and Parasitology College of Medicine University of Lagos Lagos Nigeria Centre for Human Virology and Genomics Research Microbiology Department Nigerian Institute of Medical Research Lagos Nigeria Centre for Human and Zoonotic Virology Central Research Laboratory and Department of Medical Microbiology and Parasitology College of Medicine University of Lagos Lagos Nigeria

Background: In recent times, there has been an increase in the number of Lassa fever cases resulting from the several episodes of Lassa fever epidemics ravaging Nigeria and other West African countries. The presence of Lassa virus in rodents other than the major reservoir (Mastomys natalensis) has been a public health concern as to the actual burden of the disease. It is therefore of a public health necessity to explore the LASV RNA habouring potential of several species of rodents in endemic as well as non-endemic areas for proper prevention of emergence of outbreaks in non-endemic areas. Objectives: The aim of this study was to detect the presence of LASV RNA in different species of rodents in Ikorodu, Lagos state and Abeokuta, Ogun state. Methods: A total of ninety one (91) rodents were captured from Ikorodu, Lagos State (61 rodents) and Abeokuta, Ogun State (30 rodents), euthanized, bled, and plasma obtained for the detection of LASV RNA by Reverse Transcriptase Polymerase Chain Reaction. Results: A total of 91 rodents consisting of 77 Rattus rattus and 14 Crocidura spp. The S segment of LASV RNA was not in any of the 91 rodents’ plasma samples. Conclusion: The rodents captured within the rural communities of Ikorodu, Lagos State and Abeokuta, Ogun State were found not to habour the LASV RNA. This study is limited by the relatively small sample size. Similar studies should be encouraged both in endemic and non-endemic areas in order to understand the actual burden of Lassa fever as well as put into check future epidemics.

关键词： Lassa Virus Lassa Fever Mastomys natalensis Transmission Lagos State Ogun State

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Retrospective study of the incidence, risk factors, treatment outcomes of bacterial infections at uncommon sites in cirrhotic patients

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World Journal of Hepatology 2024年第3期16卷 418-427页

作者： Sophie Schneitler Christina Schneider Markus Casper Frank Lammert Marcin Krawczyk Sören L Becker Matthias Christian Reichert Institute of medical microbiology and Hygiene Saarland UniversityHomburg 66421Germany department of Medicine II Saarland University Medical CenterHomburg 66421Germany Health Sciences Hannover Medical SchoolHannover 30625Germany Laboratory of Metabolic Liver Diseases Department of GeneralTransplant and Liver SurgeryCentre for Preclinical ResearchMedical University of WarsawWarsaw 02-097Poland

BACKGROUND Bacterial infections(BI)negatively affect the natural course of *** most frequent BI are urinary tract infections(UTI),pneumonia,and spontaneousbacterial peritonitis(SBP).AIM To assess the relevance of bacterial infections beyond the commonly recognized types in patients with cirrhosis and to investigate their relationship with other clinical *** We retrospectively analyzed patients with cirrhosis and BI treated between 2015 and 2018 at our tertiary care *** were classified as typical and atypical,and clinical as well as laboratory parameters were compared between the two *** In a cohort of 488 patients with cirrhosis,we identified 225 typical BI(95 UTI,73 SBP,72 pulmonary infections)and 74 atypical BIs,predominantly cholangitis and soft tissue infections(21 each),followed by intra-abdominal BIs(n=9),cholecystitis(n=6),head/throat BIs(n=6),osteoarticular BIs(n=5),and endocarditis(n=3).We did not observe differences concerning age,sex,or etiology of cirrhosis in patients with typical vs atypical *** BIs were more common in patients with more advanced cirrhosis,as evidenced by Model of End Stage Liver Disease(15.1±7.4 vs 12.9±5.1;P=0.005)and Child-Pugh scores(8.6±2.5 vs 8.0±2;P=0.05).CONCLUSION Atypical BIs in cirrhosis patients exhibit a distinct spectrum and are associated with more advanced stages of the ***,the work-up of cirrhosis patients with suspected BI requires detailed work-up to elucidate whether typical BI can be identified.

关键词： Bacterial infection Empirical antibiotic therapy End-stage liver disease Escherichia coli Multi-resistant pathogens

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Targeting miRNA by CRISPR/Cas in cancer:advantages and challenges

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Military medical Research 2024年第3期11卷 345-373页

作者： Bashdar Mahmud Hussen Mohammed Fatih Rasul Snur Rasool Abdullah Hazha Jamal Hidayat Goran Sedeeq Hama Faraj Fattma Abodi Ali Abbas Salihi Aria Baniahmad Soudeh Ghafouri-Fard Milladur Rahman Mark C.Glassy Wojciech Branicki Mohammad Taheri department of Biomedical Sciences Cihan University-ErbilErbilKurdistan Region 44001Iraq department of Clinical Analysis College of PharmacyHawler Medical UniversityErbilKurdistan Region 44001Iraq department of Pharmaceutical Basic Science Faculty of PharmacyTishk International UniversityErbilKurdistan Region 44001Iraq medical Laboratory Science Lebanese French UniversityErbilKurdistan Region 44001Iraq department of Biology College of EducationSalahaddin University-ErbilErbilKurdistan Region 44001Iraq department of medical Laboratory Science Komar University of Science and TechnologySulaymaniyah 46001Iraq department of medical microbiology College of Health SciencesHawler Medical UniversityErbilKurdistan Region 44001Iraq department of Biology College of ScienceSalahaddin University-ErbilErbilKurdistan Region 44001Iraq Center of Research and Strategic Studies Lebanese French UniversityErbil 44001Iraq Institute of Human Genetics Jena University Hospital07747 JenaGermany department of medical Genetics School of MedicineShahid Beheshti University of Medical SciencesTehran 374-37515Iran department of Clinical Sciences MalmöSection for SurgeryLund University22100 MalmöSweden Translational Neuro-Oncology Laboratory San Diego(UCSD)Moores Cancer CenterUniversity of CaliforniaSan DiegoCA 94720USA Faculty of Biology Institute of Zoology and Biomedical ResearchJagiellonian University31-007 KrakówPoland Urology and Nephrology Research Center Shahid Beheshti University of Medical SciencesTehran 374-37515Iran

Clustered regulatory interspaced short palindromic repeats(CRISPR)has changed biomedical research and provided entirely new models to analyze every aspect of biomedical sciences during the last *** the study of cancer,the CRISPR/CRISPR-associated protein(Cas)system opens new avenues into issues that were once unknown in our knowledge of the non-coding genome,tumor heterogeneity,and precision ***/Cas-based geneediting technology now allows for the precise and permanent targeting of mutations and provides an opportunity to target small non-coding RNAs such as microRNAs(miRNAs).However,the development of effective and safe cancer gene editing therapy is highly dependent on proper design to be innocuous to normal cells and prevent introducing other *** study aims to highlight the cutting-edge approaches in cancer-gene editing therapy based on the CRISPR/Cas technology to target miRNAs in cancer ***,we highlight the potential challenges in CRISPR/Cas-mediated miRNA gene editing and offer advanced strategies to overcome them.

关键词： CRISPR CRISPR/Cas9 CRISPR/Cas12 Gene editing miRNAs Cancer therapy

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Cmtm4 deficiency exacerbates colitis by inducing gut dysbiosis and S100a8/9 expression

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Journal of Genetics and Genomics 2024年第8期51卷 811-823页

作者： Qiao Meng Jing Ning Jingjing Lu Jing Zhang Ming Zu Jing Zhang Xiurui Han Huiling Zheng Yueqing Gong Xinyu Hao Ying Xiong Fang Gu Wenling Han Weiwei Fu Jun Wang Shigang Ding department of Gastroenterology Peking University Third HospitalBeijing 100191China Beijing Key Laboratory for Helicobacter Pylori Infection and Upper Gastrointestinal Diseases(BZ0371) Beijing 100191China CAS Key Laboratory of Pathogenic microbiology and Immunology Institute of MicrobiologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100101China department of Immunology School of Basic Medical SciencesPeking University Health Science CenterNHC Key Laboratory of Medical Immunology(Peking University)Beijing 100191China Peking University Center for Human Disease Genomics Beijing 100191China

The dysfunction of innate immunity components is one of the major drivers for ulcerative colitis(UC),and increasing reports indicate that the gut microbiome serves as an intermediate between genetic mutations and UC ***,we find that the IL-17 receptor subunit,CMTM4,is reduced in UC patients and dextran sulfate sodium(DSS)-induced *** deletion of CMTM4(Cmtm4^(-/-))in mice leads to a higher susceptibility to DSS-induced colitis than in wild-type,and the gut microbiome significantly changes in *** causal role of the gut microbiome is confirmed with a cohousing *** further identify that S100a8/9 is significantly up-regulated in Cmtm4^(-/-)colitis,with the block of its receptor RAGE that reverses the phenotype associated with the CMTM4 ***4 deficiency rather suppresses S100a8/9 expression in vitro via the IL17 pathway,further supporting that the elevation of S100a8/9 in vivo is most likely a result of microbial *** together,the results suggest that CMTM4 is involved in the maintenance of intestinal homeostasis,suppression of S100a8/9,and prevention of colitis *** study further shows CMTM4 as a crucial innate immunity component,confirming its important role in UC development and providing insights into potential targets for the development of future therapies.

关键词： Ulcerative colitis CMTM4 Gut microbiota IL-17 receptor C(IL-17RC) S100a8/9

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Adeno-associated virus as a delivery vector for gene therapy of human diseases

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1808-1840页

作者： Jiang-Hui Wang Dominic J.Gessler Wei Zhan Thomas L.Gallagher Guangping Gao Horae Gene Therapy Center University of Massachusetts Chan Medical SchoolWorcesterMA01605USA department of microbiology and Physiological Systems University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Centre for Eye Research Australia Royal Victorian Eye and Ear HospitalEast MelbourneVIC3002Australia Ophthalmology Department of SurgeryUniversity of MelbourneEast MelbourneVIC3002Australia department of Neurological Surgery University of Massachusetts Chan Medical SchoolWorcesterMA01605USA department of Neurosurgery University of MinnesotaMinneapolisMN55455USA department of Medicine University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Li Weibo Institute for Rare Diseases Research University of Massachusetts Chan Medical SchoolWorcesterMA01605USA

Adeno-associated virus(AAV)has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different *** AAV(rAAV)has been engineered for enhanced specificity and developed as a tool for treating various ***,as rAAV is being more widely used as a therapy,the increased demand has created challenges for the existing manufacturing *** rAAV-based gene therapy products have received regulatory approval,but there continue to be concerns about safely using high-dose viral therapies in humans,including immune responses and adverse effects such as genotoxicity,hepatotoxicity,thrombotic microangiopathy,and *** this review,we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing *** discuss how rAAVs are being employed in ongoing clinical trials for ocular,neurological,metabolic,hematological,neuromuscular,and cardiovascular diseases as well as *** outline immune responses triggered by rAAV,address associated side effects,and discuss strategies to mitigate these *** hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.

关键词： diseases specificity approval

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To Analyze the Sensitivity of RT-PCR Assays Employing S Gene Target Failure with Whole Genome Sequencing Data during Third Wave by SARS-CoV-2 Omicron Variant

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Advances in microbiology 2024年第5期14卷 247-255页

作者： Pooja Patel Yogita Mistry Monika Patel Summaiya Mullan Viral Research and Diagnostic Laboratory Department of Microbiology Government Medical college Surat India

Introduction: Omicron is a highly divergent variant of concern (VOCs) of a severe acute respiratory syndrome SARS-CoV-2. It carries a high number of mutations in its spike protein hence;it is more transmissible in the community by immune evasion mechanisms. Due to mutation within S gene, most Omicron variants have reported S gene target failure (SGTF) with some commercially available PCR kits. Such diagnostic features can be used as markers to screen Omicron. However, Whole Genome Sequencing (WGS) is the only gold standard approach to confirm novel microorganisms at genetically level as similar mutations can also be found in other variants that are circulating at low frequencies worldwide. This Retrospective study is aimed to assess RT-PCR sensitivity in the detection of S gene target failure in comparison with whole genome sequencing to detect variants of Omicron. Methods: We have analysed retrospective data of SARS-CoV-2 positive RT-PCR samples for S gene target failure (SGTF) with TaqPath COVID-19 RT-PCR Combo Kit (ThermoFisher) and combined with sequencing technologies to study the emerged pattern of SARS-CoV-2 variants during third wave at the tertiary care centre, Surat. Results: From the first day of December 2021 till the end of February 2022, a total of 321,803 diagnostic RT-PCR tests for SARS-CoV-2 were performed, of which 20,566 positive cases were reported at our tertiary care centre with an average cumulative positivity of 6.39% over a period of three months. In the month of December 21 samples characterized by the SGTF (70/129) were suggestive of being infected by the Omicron variant and identified as Omicron (B.1.1.529 lineage) when sequence. In the month of January, we analysed a subset of samples (n = 618) with SGTF (24%) and without SGTF (76%) with Ct values Conclusions: During the COVID-19 pandemic, it took almost more than 15 days to diagnose infection and identify pathogen by sequencing technology. In contrast to that molecular assay provided qu

关键词： SARS-CoV-2 S Gene Target Failure Whole Genome Sequencing Omicron

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Syringa pubescens Turcz ethyl acetate extract improves non-alcoholic steatohepatitis by regulating the Nrf2， IκBα and TGF-β1 signaling pathways

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Food Science and Human Wellness 2024年

作者： Weidong Xu Yanfang Wu Jiameng Zhang Zichen Zhang Xinyi Guan Suya Zhang Xinsheng Wang Pu Liu Enguo Fan College of Chemistry and Chemical Engineering， Henan University of Science and Technology College of Basic medical and Forensic Medicine， Henan University of Science and Technology department of microbiology and Parasitology， Institute of Basic medical Sciences， Chinese Academy of medical Sciences/School of Basic Medicine， Peking Union medical College

The flower of Syringa pubescens Turcz. （SP）， was used as both medicine and food in China， exhibited a variety of biological activities. However， it remains unknown whether SP has an effect on ameliorative nonalcoholic fatty liver disease （NASH）. In this study， the improvement of SP ethyl acetate extract （SPE） on NASH was evaluated and the potential mechanisms were explored. The glycosides of SPE were determined by an HPLC method. HepG2 cell lines were treated with free fatty acid to clarify the improvement effect and mechanisms of SPE on NASH in vitro. C57BL/6J mice were treated by 60 kcal% high-fat diet （HFD） combined with carbon tetrachloride (CCl4) to establish the NASH model in vivo. The results showed SPE could inhibited the hepatic injury and lipid steatosis by decreasing the levels of ALT， AST， TG and TC in vitro and vivo. The SPE suppressed the oxidative stress and inflammation by restraining the generation of ROS， MDA， IL-1β， IL-6 and TNF-α and enhancing the activity of antioxidant enzymes including SOD， CAT and GSH-Px in NASH model. Moreover， SPE declined the level of fibrosis markers including HYP， Col Ⅰ and α-SMA in HFD combined CCl4（HC）-induced mice. Mechanically， SPE inhibited hepatocellular Keap1 expression and promoted Nrf2 nuclear translocation， which suppressing the phosphorylation of IκBα/NF-κB. In addition， SPE down-regulated the level of TGF-β1 and phosphorylation of Smad2 to mitigate fibrosis. In brief， SPE could significantly alleviate lipid accumulation， oxidative stress， inflammation and fibrosis via regulating Nrf2/HO-1， IκBα/NFκB and TGF-β1/Smad2 pathways in the progression of NASH， which indicated that SPE had the potential to be a novel and effective drug or food supplements for the improvement of NASH.

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Predictors of cerebrospinal fluid GeneXpert MTB/RIF positivity in patients with tuberculous meningitis:A prospective cohort study

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Asian Pacific Journal of Tropical Medicine 2024年第10期17卷 465-472页

作者： Priyanka Gupta Neeraj Kumar Ravindra Kumar Garg Hardeep Singh Malhotra Imran Rizvi Rajesh Verma Praveen Kumar Sharma Ravi Uniyal Shweta Pandey Amita Jain Parul Jain department of Neurology King George’s Medical UniversityLucknowIndia department of microbiology King George’s Medical UniversityLucknowIndia

Objective:To identify the clinical,laboratory,and radiological markers that could predict a positive GeneXpert result in patients suspected of tuberculous ***:In this prospective,observational study,patients with tuberculous meningitis were systematically *** clinical,laboratory[including cerebrospinal fluid(CSF)microscopy,culture,and GeneXpert],and neuroimaging factors were *** participants were administered anti-tuberculous treatment and corticosteroids.A six-month follow-up was done to evaluate the ***:Of the 116 patients studied,54(46.6%)tested positive for GeneXpert,while 62(53.4%)were *** cranial nerve involvement(OR 3.71,95%CI 1.052-13.09,P=0.04)and the presence of basal exudates on neuroimaging(OR 5.22,95%CI 2.03-13.42,P=0.001)emerged as independent predictive factors for a positive GeneXpert result.A positive CSF GeneXpert result(P=0.002)and drug resistance(P=0.004)were significantly linked to adverse ***,a high score on the medical Research Council stageⅢ(OR 5.64,95%CI 1.18-26.87,P=0.03)and elevated CSF cell counts(OR 1.002,95%CI 1.00-1.001,P=0.03)were identified as independent predictors of poor ***:Third cranial nerve involvement and the presence of basal exudates were significant indicators of a positive GeneXpert *** stageⅢdisability and elevated CSF cell counts predicted poor outcomes.

关键词： Tuberculous meningitis Mycobacterium tuberculosis Cerebrospinal fluid Ziehl-Neelsen staining GeneXpert

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Transforming growth factor-beta 1 enhances discharge activity of cortical neurons

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Neural Regeneration Research 2025年第2期20卷 548-556页

作者： Zhihui Ren Tian Li Xueer Liu Zelin Zhang Xiaoxuan Chen Weiqiang Chen Kangsheng Li Jiangtao Sheng department of microbiology and Immunology Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular ImmunopathologyShantou University Medical CollegeShantouGuangdong ProvinceChina department of Neurosurgery First Affiliated Hospital of Shantou University Medical CollegeShantouGuangdong ProvinceChina

Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system *** neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types ***-gated sodium channels(VGSCs)are essential ion channels for the generation of action potentials in neurons,and are involved in various neuroexcitation-related ***,the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain *** this study,we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from *** found that TGF-β1 increased VGSC current density in a dose-and time-dependent manner,which was attributable to the upregulation of Nav1.3 *** VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase(PD98059),p38 mitogen-activated protein kinase(SB203580),and Jun NH2-terminal kinase 1/2 inhibitor(SP600125).Interestingly,TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical *** findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2-JNK-MAPK pathway,which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological ***,this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.

关键词： central nervous system cortical neurons ERK firing properties JNK Nav1.3 p38 transforming growth factor-beta 1 traumatic brain injury voltage-gated sodium currents

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