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High-throughput screening of novel TFEB agonists in protecting against acetaminopheninduced liver injury in mice

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Acta Pharmaceutica Sinica B 2024年第1期14卷 190-206页

作者： Xiaojuan Chao Mengwei Niu Shaogui Wang Xiaowen Ma Xiao Yang Hua Sun Xujia Hu Hua Wang Li Zhang Ruili Huang Menghang Xia Andrea Ballabio Hartmut Jaeschke Hong-Min Ni Wen-Xing Ding Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKS 66160USA NMPA Key laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key laboratory of New Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Department of Oncology the First Affiliated Hospital of Anhui Medical UniversityAnhui Medical UniversityHefei 230032China National Center for Advancing translational Sciences National Institutes of HealthBethesdaMD 20892USA Telethon Institute of genetics and Medicine TIGEMPozzuoliNaples 80131Italy Medical genetics Department of Translational MedicineFederico II UniversityNaples 80131Italy Department of Molecular and Human genetics Baylor College of MedicineHoustonTX 77030USA Department of Internal Medicine Division of GastroenterologyHepatology&MotilityUniversity of Kansas Medical CenterKansas CityKS 66160USA

Macroautophagy(referred to as autophagy hereafter)is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and *** studies showed that autophagy protects against acetaminophen(APAP)-induced injury(AILI)via selective removal of damaged mitochondria and APAP protein *** lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with *** the present study,we showed that transcription factor EB(TFEB),a master transcription factor for lysosomal biogenesis,was impaired by APAP resulting in decreased lysosomal biogenesis in mouse *** loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI,***,overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2(NRF2)activation to protect against *** also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB *** these agonists,salinomycin,an anticoccidial and antibacterial agent,activated TFEB and protected against AILI in *** conclusion,genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.

关键词： Autophagy DILI Drug screening Hepatotoxicity Lysosome Mitochondria Mitophagy NRF2

Apoer2/Lrp8:the undercover cop of synaptic homeostasis

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Neural Regeneration Research 2024年第12期19卷 2563-2564页

作者： Gordon C.Werthmann Joachim Herz Department of Molecular genetics and Center for translational Neurodegeneration Research University of Texas Southwestern Medical Center at DallasDallasTXUSA Department of Neuroscience Department of Neurology University of Texas Southwestern Medical Center at Dallas DallasTXUSA

Apolipoprotein E receptor 2(ApoER2)is a receptor for the protein ApoE,the most common genetic risk factor for late-onset Alzheimer's disease(AD).It is also a key modulator of syna ptic homeostasis,in part through its effect on the expression of neuronal genes including those implicated in AD and other neuropsychiatric *** this perspective,we highlight several genes affected by ApoER2 and its alternatively spliced forms and how aberrant expression can be rescued by the reintroduction of the ApoER2 intracellular domain in the mouse hippocampus.

关键词： homeostasis ApoE Alzheimer

METTL14 downregulation drives S100A4^(+)monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2176-2192页

作者： Yue-fan Wang Wen-li Zhang Zhi-xuan Li Yue Liu Jian Tan Hao-zan Yin Zhi-chao Zhang Xian-jie Piao Min-hao Ruan Zhi-hui Dai Si-jie Wang Chen-yang Mu Ji-hang Yuan Shu-han Sun Hui Liu Fu Yang The Third Department of Hepatic Surgery Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University200438 ShanghaiChina The Department of Medical genetics Naval Medical University200433 ShanghaiChina translational Medicine Research Center Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital100048 BeijingChina The Department of Pharmaceutical Analysis School of PharmacyNaval Medical University200433 ShanghaiChina Key laboratory of Biosafety Defense Ministry of Education200433 ShanghaiChina Shanghai Key laboratory of Medical Biodefense 200433 ShanghaiChina

Without intervention,a considerable proportion of patients with metabolism‐associated fatty liver disease(MAFLD)will progress from simple steatosis to metabolism‐associated steatohepatitis(MASH),liver fibrosis,and even hepatocellular ***,the molecular mechanisms that control progressive MAFLD have yet to be fully ***,we unraveled that the expression of the N6-methyladenosine(m6A)methyltransferase METTL14 is remarkably downregulated in the livers of both patients and several murine models of MAFLD,whereas hepatocyte-specific depletion of this methyltransferase aggravated lipid accumulation,liver injury,and ***,hepatic Mettl14 overexpression alleviated the above pathophysiological changes in mice fed on a high-fat diet(HFD).Notably,in vivo and in vitro mechanistic studies indicated that METTL14 downregulation decreased the level of GLS2 by affecting the translation efficiency mediated by YTHDF1 in an m6A-depedent manner,which might help to form an oxidative stress microenvironment and accordingly recruit Cx3cr1^(+)Ccr2^(+)monocyte-derived macrophages(Mo-macs).In detail,Cx3cr1^(+)Ccr2^(+)Mo-macs can be categorized into M1-like macrophages and S100A4-positive macrophages and then further activate hepatic stellate cells(HSCs)to promote liver *** experiments revealed that CX3CR1 can activate the transcription of S100A4 via CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1^(+)Ccr2^(+)*** of METTL14 or GLS2,or interfering with this signal transduction pathway such as inhibiting MyD88 could ameliorate liver injuries and *** together,these findings indicate potential therapies for the treatment of MAFLD progression.

关键词： S100A4 MyD88 metabolism

Weakened tanning ability is an important mechanism for evolutionary skin lightening in East Asians

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Journal of genetics and Genomics 2024年第7期51卷 703-713页

作者： Youwei Pu Siyu Pu Yanyan Chen Qinghong Kong Xuyang Liu Qi Zhao Ke Xu Jiuming Liu Mengyuan Li Xiaoyu Xu Xiaoyang Qiao Bing Su Jing Chen Zhaohui Yang Tianjian laboratory of Advanced Biomedical Sciences Academy of Medical ScienceZhengzhou UniversityZhengzhouHenan 450052China Department of Pediatric Surgery and laboratory of Pediatric Surgery West China HospitalSichuan UniversityChengduSichuan 610041China Guizhou Provincial College-based Key Lab for Tumor Prevention and Treatment with Distinctive Medicines Zunyi Medical UniversityZunyiGuizhou 563000China Yunnan Key laboratory of Primate Biomedical Research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnan 650500China State Key laboratory of Genetic Resources and Evolution Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650223China Center for Excellence in Animal Evolution and genetics Chinese Academy of SciencesKunmingYunnan 650223China

The evolution of light-skin pigmentation among Eurasians is considered as an adaptation to the high-latitude *** Asians are ideal populations for studying skin color evolution because of the complex environment of East ***,we report a strong selection signal for the pigmentation gene phenylalanine hydroxylase(PAH)in light-skinned Han Chinese *** intron mutation rs10778203 in PAH is enriched in East Asians and is significantly associated with skin color of the back of the hand in Han Chinese males(P<0.05).In vitro luciferase and transcription factor binding assays show that the ancestral allele of rs10778203 could bind to SMAD2 and has a significant enhancer activity for ***,the derived T allele(the major allele in East Asians)of rs10778203 decreases the binding activity of transcription factors and enhancer ***,the derived T allele of rs10778203 shows a weaker ultraviolet radiation response in A375 cells and zebrafish ***,rs10778203 decreases melanin production in transgenic zebrafish embryos after ultraviolet B(UVB)***,PAH is a potential pigmentation gene that regulates skin tanning *** selection has enriched the adaptive allele,resulting in weakened tanning ability in East Asians,suggesting a unique genetic mechanism for evolutionary skin lightening in East Asians.

关键词： East Asians PAH Skin pigmentation Natural selection Genetic adaptation

CD36 promotes tubular ferroptosis by regulating the ubiquitination of FSP1 in acute kidney injury

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Genes & Diseases 2024年第1期11卷 449-463页

作者： Yixin Ma Lili Huang Zheng Zhang Pengfei Yang Qingsong Chen Xujia Zeng Fangyan Tan Chunxia Wang Xiongzhong Ruan Xiaohui Liao Department of Nephrology The Second Affiliated HospitalChongqing Medical UniversityChongqing 400010China Department of Cell Biology and genetics Chongqing Medical UniversityChongqing 400016China Centre for Nephrology Royal Free and University College Medical SchoolUniversity College LondonRoyal Free CampusRowland Hill StreetLondon NW32PFUnited Kingdom Centre for Lipid Research Key Laboratory of Molecular Biology on Infectious DiseasesMinistry of EducationChongqing Medical UniversityChongqing 400016China Kuanren laboratory of translational Lipidology Centre for Lipid ResearchSecond Affiliated Hospital of Chongqing Medical UniversityChongqing 400010China

Reactive oxidative species(ROos)production-driven ferroptosis plays a role in acute kidney injury(Akl).However,its exact molecular mechanism is poorly *** receptor CD36 has important roles in oxidizing lipids,lipid accumulation,metabolic syndrome,and insulin resistance in chronic kidney disease,but its roles remain unexplored in *** present study investigated the role and mechanism of CD36 in regulating proximal tubular cell ferroptosis and *** expression of CD36 was found to be significantly up-regulated in AKI renal tissues and correlated with renal function,which might serve as an independent biomarker for AKl ***,in adult mice subjected to AKl,deletion of CD36(CD36-/-)induced tubular cell Ros accumulation,ferroptosis activation,and renal ***,combining LC-MS/MS,co-IP,and ubiquitination analyses revealed that CD36 could specifically bind to ferroptosis suppressor protein 1(FSP1)and regulate its ubiquitination at sites K16 and K24,leading to FSP1 degradation and progression of ferroptosis in *** present results emphasize a novel mechanism of CD36 in cisplatin-induced *** discovery of the special CD36 roles in promoting ferroptosis and AKI development by regulating the ubiquitination of FSP1 in proximal tubular cells may be potential therapeutic targets for ***,CD36 may play a key role in the progression of ***,targeting CD36 may provide a promising treatment option for AKI.

关键词： Acute kidney injury CD36 Ferroptosis FSP1 Ubiquitin-dependent degradation

Contactin-associated protein-like 2(CNTNAP2)mutations impair the essentialα-secretase cleavages,leading to autism-like phenotypes

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1625-1636页

作者： Qing Zhang Mengen Xing Zhengkai Bao Lu Xu Yang Bai Wanqi Chen Wenhao Pan Fang Cai Qunxian Wang Shipeng Guo Jing Zhang Zhe Wang Yili Wu Yun Zhang Jia-Da Li Weihong Song Oujiang laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Zhejiang Key Laboratory of Alzheimer's DiseaseZhejiang Provincial Clinical Research Center for Mental DisordersSchool of Mental Health and Wenzhou Kangning HospitalThe Second Affiliated Hospital and Yuying Children's HospitalInstitute of AgingWenzhou Medical UniversityWenzhouZhejiang 325035China Townsend Family Laboratories Department of PsychiatryBrain Research CenterThe University of British Columbia2255 Wesbrook MallVancouverBC V6T 1Z3Canada Chongqing Key laboratory of translational Medical Research in Cognitive Development and Learning and Memory Disorders Ministry of Education Key Laboratory of Child Development and DisordersChildren's Hospital of Chongqing Medical UniversityChongqing 400014China Center for Medical genetics Hunan Key Laboratory of Animal Models for Human DiseasesHunan Key Laboratory of Medical GeneticsHunan International Scientific and Technological Cooperation Base of Animal Models for Human DiseasesSchool of Life SciencesCentral South UniversityChangsha 410078 HunanChina The National Clinical Research Center for Geriatric Disease Xuanwu HospitalCapital Medical UniversityBeijing 100053Chin

Mutations in the Contactin-associated protein-like 2(CNTNAP2)gene are associated with autism spectrum disorder(ASD),and ectodomain shedding of the CNTNAP2 protein plays a role in its ***,key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown,and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain *** this report we showed that CNTNAP2 undergoes sequential cleavages by furin,ADAM10/17-dependent a-secretase and presenilindependent *** identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96,and the main a-cleavage product C79 by ADAM10 is required for the subsequent y-secretase cleavage to generate CNTNAP2 intracellular domain(CICD).ASD-associated CNTNAP2 mutations impair the a-cleavage to generate C79,and the inhibition leads to ASDIlike repetitive and social behavior abnormalties in the Cntnap2l1254T knock-in ***,exogenous expression of 79 improves autism-ike phenotypes in the Cntnap2^(11254T) knock-in and Cntnap2^(-/-)knockout *** data demonstrates that the a-secretase is essential for CNTNAP2 processing and its *** study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis,and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.

关键词： NAP2 cleavage subsequent

Somatic CDKN2A copy number variations are associated with the prognosis of esophageal squamous cell dysplasia

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Chinese Medical Journal 2024年第8期137卷 980-989页

作者： Zhiyuan Fan Jing Zhou Yuan Tian Yu Qin Zhaojun Liu Liankun Gu Sanford M.Dawsey Wenqiang Wei Dajun Deng National Central Cancer Registry National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Key laboratory of Carcinogenesis and translational Research(MOE/Beijing) Division of EtiologyPeking University Cancer Hospital and InstituteBeijing 100142China Division of Cancer Epidemiology and genetics National Cancer InstituteBethesdaMDUSA Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical UniversityNanjingJiangsu 211166China

Background:Somatic copy number variations(SCNVs)in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell ***,whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia(ESCdys)is *** study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate(m/M)***:This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China(Ci County,Hebei Province;Yanting,Sichuan Province;Linzhou,Henan Province;Yangzhong,Jiangsu Province;and Feicheng,Shandong Province)from 2005 to *** DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients,and a quantitative polymerase chain reaction assay,P16-Light,was used to detect CDKN2A copy *** cumulative regression and progression rates of ESCdys were evaluated using competing risk ***:A total of 205 patients with baseline m/M ESCdys were *** proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts(18.8%[13/69]vs.35.0%[28/80]vs.51.8%[29/56],P<0.001).In the univariable competing risk analysis,the cumulative regression rate was statistically significantly lower(P=0.008),while the cumulative progression rate was higher(P=0.017)in ESCdys patients with CDKN2A deletion than in those without CDKN2A ***2A deletion was also an independent predictor of prognosis in ESCdys(P=0.004)in the multivariable ***:The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification.

关键词： Somatic copy number variations Esophageal squamous cell carcinoma Esophageal neoplasms Squamous intraepithelial lesions DNA copy number variations Prognosis Prospective study

DNA methylation of SMPD3-based diagnostic biomarkers of NASH and mild fibrosis

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Genes & Diseases 2024年第1期11卷 99-102页

作者： Na Wu Mofan Feng Siran Yue Xinyu Shi Nan Tang Yalan Xiong Jianying Wang Lei Zhang Hualing Song Yi Shi Guang He Guang Ji Baocheng Liu Shanghai Innovation Center of Traditional Chinese Medicine Health Service School of Public HealthShanghai University of Traditional Chinese MedicineShanghai 201203China Institute of Digestive Diseases Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersShanghai Jiao Tong UniversityShanghai 200030China Institute for Advancing translational Medicine in Bone and Joint Diseases School of Chinese MedicineHong Kong Baptist UniversityHong Kong SAR 999077China

Non-alcoholic fatty liver disease(NAFLD)is a liver condition that is widely prevalent across the world.A considerable number of people with NAFLD have the potential to progress to a more severe form of the condition known as nonalcoholic steatohepatitis(NASH),accompanied by bridging *** advancement is more likely if the patient has metabolic risk factors such as obesity or type 2 diabetes that deteriorate over ***,even slight inflammation or fibrosis in NAFLD can significantly increase the likelihood of progression compared to steatosis *** underscores the importance of revising the present methods of monitoring NAFLD patients to ensure early detection and effective management of the disease.

关键词： NAFLD inflammation NASH

Mitigating growth-stress tradeoffs via elevated TOR signaling in rice

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Molecular Plant 2024年第2期17卷 240-257页

作者： Wei Li Jiaqi Liu Zeqi Li Ruiqiang Ye Wenzhen Chen Yuqing Huang Yue Yuan Yi Zhang Huayi Hu Peng Zheng Zhongming Fang Zeng Tao Shiyong Song Ronghui Pan Jian Zhang Jumim Tu Jen Sheen Hao Du State Key laboratory of Rice Biology College of Agriculture and BiotechnologyZhejiang UniversityYu-Hang-Tang Road No.866Hangzhou 310058China ZJU-Hangzhou Global Scientific and Technological Innovation Center Zhejiang UniversityHangzhou 311215China Hainan Institute of Zhejiang University Sanya 572025China National Key laboratory of Plant Molecular genetics CASCenter for Excellence in Molecular Plant SciencesShanghai lnstitute of Plant Physiology and EcologyChineseAcademy of SciencesShanghai 200032China Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region(Ministry of Education) College of Agricultural SciencesGuizhouUniversityGuiyang 550025China State Key laboratory of Rice Biology and Breeding China National Rice Research InstituteHangzhou 311400China Department of Molecular Biology and Center for Computational and Integrative Biology Massachusetts General Hospitaland Department of GeneticsHarvard Medical SchoolBostonMA02114USA

Rice production accounts for approximately half of the freshwater resources utilized in agriculture,result-ing in greenhouse gas emissions such as methane(CH4)from flooded paddy *** address this chal-lenge,environmentally friendly and cost-effective water-saving techniques have become widely adopted in rice ***,the implementation of water-saving treatments(WsTs)in paddy-field rice has been associated with a substantial yield loss of up to 50%as well as a reduction in nitrogen use efficiency(NUE).In this study,we discovered that the target of rapamycin(TOR)signaling pathway is compromised in rice under *** profiling-coupled transcriptome sequencing(polysome-seq)analysis unveiled a substantial reduction in global translation in response to WST associated with the downregulation of TOR ***,biochemical,and genetic analyses revealed new insights into the impact of the positive TOR-S6K-RPS6 and negative TOR-MAF1 modules on translation repression under ***,ammonium exhibited a greater ability to alleviate growth constraints under WsT by enhancing TOR signaling,which simultaneously promoted uptake and utilization of ammonium and nitrogen *** further demonstrated that TOR modulates the ammonium transporter AMT1;1 as well as the amino acid permease APP1 and dipeptide transporter NPF7.3 at the translational level through the 5'untranslated ***,these findings reveal that enhancing TOR signaling could mitigate rice yield penalty due to WST by regulating the processes involved in protein synthesis and *** study will contribute to the breeding of new rice varieties with increased water and fertilizer utilization efficiency.

关键词： target of rapamycin TOR water-saving rice low-carbon agriculture drought nitrogen use efficiency NUE