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A zebrafish tufm mutant model for the COXPD4 syndrome of aberrant mitochondrial function

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Journal of Genetics and Genomics 2024年第9期51卷 922-933页

作者： Ting Li Tursunjan Aziz Guangyuan Li Lin Zhang Jihua Yao Shunji Jia School of Life Sciences Fudan UniversityShanghai 200438China State Key Laboratory of Membrane biology Tsinghua-Peking Center for Life SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China State Key Laboratory of molecular Developmental biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China

Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular *** in the TUFM gene are known to cause combined oxidative phosphorylation deficiency 4(COXPD4),a rare mitochondrial disorder characterized by a comprehensive quantitative deficiency in mitochondrial respiratory chain(MRC)*** development of a reliable animal model for COXPD4 is crucial for elucidating the roles and mechanisms of TUFM in disease pathogenesis and benefiting its medical *** this study,we construct a zebrafish tufm−/−mutant that closely resembles the COXPD4 syndrome,exhibiting compromised mitochondrial protein translation,dysfunctional mitochondria with oxidative phosphorylation defects,and significant metabolic suppression of the tricarboxylic acid *** this COXPD4 zebrafish model,we comprehensively validate the clinical relevance of TUFM mutations and identify probucol as a promising therapeutic approach for managing *** data offer valuable insights for understanding mitochondrial diseases and developing effective treatments.

关键词： Tufm Mitochondria COXPD4 Disease model Zebrafish

Ultra-high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry-characterized extract of Aerides odorata Lour alleviates paracetamol-induced hepatotoxicity in animal model evidenced by biochemical,molecular,and computational studies

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Animal Models and Experimental Medicine 2024年第4期7卷 497-522页

作者： A.M.Abu Ahmed Md.Atiar Rahman Farjana Sharmen A.S.M.Ali Reza Md.Shahidul Islam Md.Mamunur Rashid Md.Khalid Juhani Rafi Tanvir Ahmed Siddiqui Md.Muzahid Ahmed Ezaj Srabonti Saha Md.Nazim Uddin Walla Alelwani Department of Genetic Engineering and Biotechnology University of ChittagongChittagongBangladesh Department of biochemistry and molecular biology University of ChittagongChittagongBangladesh Department of Pharmacy International Islami University ChittagongChittagongBangladesh Institute of Food Science and Technology Bangladesh Council of Scientific and Industrial ResearchDhakaBangladesh Department of biochemistry College of ScienceUniversity of JeddahJeddahSaudi Arabia

Background:Many kinds of orchids have significant health benefits although ade-quate research on their biological functions is yet to be carried *** study inves-tigated the paracetamol-induced liver damage-protecting effect of epiphytic Aerides odorata methanol extract(AODE).Methods:The protective effects of AODE were studied by analyzing its effect on liver function parameters,messenger RNA(mRNA)expression,and tissue histopatho-logical *** results were confirmed by ligand-receptor interaction of molecular docking and multitarget interaction of network pharmacological ***:AODE significantly(p<0.05)minimized the dose-dependent increase in acid phosphatase,aspartate aminotransferase,alanine aminotransferase,alkaline phos-phatase,γ-glutamyl transferase,lactate dehydrogenase,and total bilirubin compared to the reference drug *** level decreased,and the antioxidant genes catalase(CAT),superoxide dismutase(SOD),β-actin,paraoxonase-1(PON1),and phosphofructokinase-1(PFK-1)were upregulated in AODE-treated paracetamol-intoxicated rats.A total of 376 compounds comprising phenols and flavonoids were identified using ultra-high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry(UPLC-qTOF-MS).The online toxicity assessment using SwissADME and admetSAR exhibited drug-like,nontoxic,and potential pharmaco-logical ***,in silico analysis showed that isoacteoside,one of the identified compounds,exhibited the best docking score(−11.42)with the liver pro-tein human pituitary adenylate cyclase-1(Protein Data Bank ID:3N94).Furthermore,network pharmacology analysis identified the top 10 hub genes,namely AKT1(protein kinase B),CTNNB1(catenin beta-1),SRC(proto-oncogene c-Src),TNF(tumor necrosis factor),EGFR(epidermal growth factor receptor),HSP90AA1(heat shock protein 90α),MAPK3(mitogen-activated protein kinase 3),STAT3(signal transducer and activator of transcription 3),CASP3(caspase protein),

关键词： Aerides odorata animal model mRNA expression PCM-induced hepatotoxicity UPLC-qTOF-MS

Chemoproteomics reveals the epoxidase enzyme for the biosynthesis of camptothecin in Ophiorrhiza pumila

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Journal of Integrative Plant biology 2024年第6期66卷 1044-1047页

作者： Tong Zhang Yan Wang Shiwen Wu Ernuo Tian Chengshuai Yang Zhihua Zhou Xing Yan Pingping Wang CAS‐Key Laboratory of Synthetic biology CAS Center for Excellence in MolecularPlant SciencesChinese Academy of SciencesShanghai 200032China University of Chinese Academy of Sciences Beijing 100049China

Camptothecin is one of the most commonly used anticancer drugs worldwide,yet the downstream biosynthetic route from strictosidine to camptothecin has remained unclear for more than half a ***,we searched for proteins involved in camptothecin biosynthesis from the camptothecin-producing plant Ophiorrhiza pumila by chemoproteomics and identified Op CYP716E111.

关键词： camptothecin strict drugs

Identification of crucial roles of transcription factor IhfA on high production of free fatty acids in Escherichia coli

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Synthetic and Systems Biotechnology 2024年第1期9卷 144-151页

作者： Lixia Fang Ziyi Han Xueru Feng Xueyan Hao Mengxiao Liu Hao Song Yingxiu Cao Frontiers Science center for Synthetic biology and Key Laboratory of Systems Bioengineering(Ministry of Education) School of Chemical Engineering and TechnologyTianjin UniversityTianjin300072China Frontiers research Institute for Synthetic biology Tianjin UniversityChina

Transcription factor engineering has unique advantages in improving the performance of microbial cell factories due to the global regulation of gene *** analyses and reverse engineering enable learning and subsequent incorporation of novel design strategies for further ***,we identify the role of the global regulator IhfA for overproduction of free fatty acids(FFAs)using CRISPRi-facilitated reverse engineering and cellular physiological *** the differentially expressed genes in the ihfAL􀀀strain,a total of 14 beneficial targets that enhance FFAs production by above 20% are identified,which involve membrane function,oxidative stress,and *** membrane-related genes,the engineered strains obtain lower cell surface hydrophobicity and increased average length of membrane lipid *** oxidative stress-related genes,the engineered strains present decreased reactive oxygen species(ROS)*** gene modulations enhance cellular robustness and save cellular resources,contributing to FFAs *** study provides novel targets and strategies for engineering microbial cell factories with improved FFAs bioproduction.

关键词： Free fatty acids CRISPRi ihfA Cell membrane ROS

Role of fullerenols derivative 3HFWC in the treatment of Alzheimer's disease

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Neural Regeneration research 2024年第8期19卷 1641-1642页

作者： Sanja Ivkovic Djuro Koruga Department of molecular biology and Endocrinology “VINCA”Institute of Nuclear Sciences-National Institute of Republic of SerbiaUniversity of BelgradeBeogradSrbija TFT Nano center BelgradeSerbia

Fullerenes:The extensive development of nanoscience that has marked this century continues to evolve,producing new materials,structures,and devices for the treatments of diverse *** are a family of nanoparticles with great applicative promise due to their small size(approximately 1 nm in diameter),structure,and capacity to cross biological barriers.

关键词： treatment evolve size

Mechanistic study of lipid metabolism disorders in diabetic kidney disease treated with GLQMP based on network pharmacology,molecular docking and in vitro experiments

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Traditional Medicine research 2024年第2期9卷 42-51页

作者： Shu-Man Liu Zi-Jie Yan Man Xiao Yi-Qiang Xie College of Traditional Chinese Medicine Hainan Medical UniversityHaikou 571199China Key Laboratory of biochemistry and molecular biology Hainan Medical UniversityHaikou 571199China.

Background:In this study,we used network pharmacology and molecular docking combined with vitro experiments to explore the potential mechanism of action of Gualou Qumai pill(GLQMP)against ***:We screened effective compounds and drug targets using Chinese medicine systemic pharmacology database and analysis platform and Chinese medicine molecular mechanism bioinformatics analysis tools;and searched for DKD targets using human online Mendelian genetics and gene *** potential targets of GLQMP for DKD were obtained through the intersection of drug targets and disease *** software was applied to build herbal medicine-active compound-target-disease networks and analyze them;protein-protein interaction networks were analyzed using the STRING database platform;gene ontology and Kyoto Encyclopedia of Genes and Genomes were used for gene ontology and gene and genome encyclopedia to enrich potential targets using the DAVID database;and the AutoDock Vina 1.1.2 software for molecular docking of key targets with corresponding key *** vitro experiments were validated by CCK8,oil red O staining,TC,TG,RT-qPCR,and Western ***:Through network pharmacology analysis,a total of 99 potential therapeutic targets of GLQMP for DKD and the corresponding 38 active compounds were obtained,and 5 core compounds were *** constructing the protein-protein interaction network and performing network topology analysis,we found that PPARA and PPARG were the key targets,and then we molecularly docked these two key targets with the 38 active compounds,especially the 5 core compounds,and found that PPARA and PPARG had good binding ability with a variety of *** vitro experiments showed that GLQMP was able to ameliorate HK-2 cell injury under high glucose stress,improve cell viability,reduce TC and TG levels as well as decrease the accumulation of lipid droplets,and RT-qPCR and Western blot confirmed that GLQMP was able to promote the expressi

关键词： Gualou Qumai pill diabetic kidney disease disorder of lipid metabolism network pharmacology molecular docking

CMKLR1 senses chemerin/resolvin E1 to control adipose thermogenesis and modulate metabolic homeostasis

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Fundamental research 2024年第3期4卷 575-588页

作者： Zewei Zhao Siqi Liu Bingxiu Qian Lin Zhou Jianglin Shi Junxi Liu Lin Xu Zhonghan Yang Department of biochemistry Molecular Cancer Research CenterSchool of MedicineSun Yat-sen UniversityShenzhenGuangdong 518107China Department of biochemistry Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouGuangdong 510080China School of Public Health Sun Yat-sen UniversityGuangzhouGuangdong 510080China

Induction of beige fat for thermogenesis is a potential therapy to improve homeostasis against obesity.β3-adrenoceptor(β3-AR),a type of G protein-coupled receptor(GPCR),is believed to mediate the thermogenesis of brown fat in ***,β3-AR has low expression in human adipose tissue,precluding its activation as a standalone clinical *** study aimed at identifying a potential GPCR target to induce beige *** found that chemerin chemokine-like receptor 1(CMKLR1),one of the novel GPCRs,mediated the development of beige fat via its two ligands,chemerin and resolvin E1(RvE1).The RvE1 levels were decreased in the obese mice,and RvE1 treatment led to a substantial improvement in obese features and augmented beige fat ***,despite sharing the same receptor as RvE1,the chemerin levels were increased in obesogenic conditions,and chemerin treatment led to an augmented obese phenotype and a decline of beige fat ***,RvE1 and chemerin induced or restrained the development of beige fat,respectively,via the mechanistic target of rapamycin complex 1(mTORC1)signaling *** further showed that RvE1 and chemerin regulated mTORC1 signaling differentially by forming hydrogen bonds with different binding sites of *** conclusion,our study showed that RvE1 and chemerin affected metabolic homeostasis differentially,suggesting that selectively modulating CMKLR1 may be a potential therapeutic target for restoring metabolic homeostasis.

关键词： Obesity Insulin resistance Thermogenesis CMKLR1 Resolvin E1 Chemerin

Revealing Tissue Heterogeneity and Spatial Dark Genes from Spatially Resolved Transcriptomics by Multiview Graph Networks

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research 2024年第2期6卷 629-645页

作者： Ying Li Yuejing Lu Chen Kang Peiluan Li Luonan Chen School of Mathematics and Statistics Henan University of Science and TechnologyLuoyang471023China Longmen Laboratory LuoyangHenan471003China Key Laboratory of Systems biology Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesShanghai201100China Key Laboratory of Systems Health Science of Zhejang Province Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou310000China School of Life Science and Technology ShanghaiTech UniversityShanghai201100.China

Spatially resolved transcriptomics(SRT)is capable of comprehensively characterizing gene expression patterns and providing an unbiased image of spatial *** fully understand the organizational complexity and tumor immune escape mechanism,we propose stMGATF,a multiview graph attention fusion model that integrates gene expression,histological images,spatial location,and gene *** better extract information,stMGATF exploits SimCLRv2 for visual feature exaction and employs edge feature enhanced graph attention networks for the learning potential embedding of each view.A global attention mechanism is used to adaptively integrate 3 views to obtain low-dimensional *** to diverse SRT datasets,stMGATF is robust and outperforms other methods in detecting spatial domains and denoising data even with different resolutions and *** particular,stMGATF contributes to the elucidation of tissue heterogeneity and extraction of 3-dimensional expression ***,considering the associations between genes in tumors,stMGATF can identify the spatial dark genes ignored by traditional methods,which can be used to predict tumor-driving transcription factors and reveal tumor immune escape mechanisms,providing theoretical evidence for the development of new immunotherapeutic strategies.

关键词： Spatial integrate driving

Biallelic variants in RBM42 cause a multisystem disorder with neurological,facial,cardiac,and musculoskeletal involvement

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Protein & Cell 2024年第1期15卷 52-68页

作者： Yiyao Chen Bingxin Yang Xiaoyu Merlin Zhang Songchang Chen Minhui Wang Liya Hu Nina Pan Shuyuan Li Weihui Shi Zhenhua Yang Li Wang Yajing Tan Jian Wang Yanlin Wang Qinghe Xing Zhonghua Ma Jinsong Li He-Feng Huang Jinglan Zhang Chenming Xu Institutes of Biomedical Sciences Fudan UniversityShanghai 200032China bstetrics and Gynecology Hospital Institute of Reproduction and DevelopmentFudan UniversityShanghai 200011China Intermational Peace Matermity and Child Health Hospital School of MedicineShanghai Jiao Tong UniversityShanghai 200030China Shanghai Key Laboratory of Embryo Original Diseases Shanghai 200030China State Key Laboratory of Cell biology Shanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCAS Center for Excellence in Molecular Cell ScienceUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China State Key Laboratory of Rice biology the Key Laboratory of Molecular Biology of Crop Pathogens and InsectsInstitute of BiotechnologyZhejiang UniversityHangzhou 310058China Verna and Marrs McLean Department of biochemistry and molecular biology Baylor College of MedicineHoustonTX 77030USA Children's hospital of Fudan University Shanghai 201102China School of Life Science and Technology Shanghai Tech UniversityShanghai 201210China School of Life Science Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024ZhejiangChina research Units of Embryo Original Diseases Chinese Academy of Medical Sciences(No.2019RU056)Shanghai 200011China

Here,we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 *** patient is a 2-year-old female with severe central nervous system(CNs)abnormalities,hypotonia,hearing loss,congenital heart defects,and dysmorphic facial *** whole-exome sequencing(WEs)reveals that the patient has two compound heterozygous variants,c.304C>T(p.R102*)and c.1312G>A(p.A438T),in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein *** p.A438T variant is in the RRM domain which impairs RBM42 pro-tein stability in ***,p.A438T disrupts the interaction of RBM42 with hnRNP K,which is the causa-tive gene for Au-Kline syndrome with overlapping disease characteristics seen in the index *** human R102*or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout△FgRbp1 in Fusarium while it was rescued by the wild-type(WT)human RBM42.A mouse model carying Rbm42 compound heterozygous variants,c.280C>T(p.Q94*)and c.1306_1308delinsACA(p.A436T),demonstrated gross fetal develop-mental defects and most of the double mutant animals died by ***-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing(As).Overall,we present clinical,genetic,and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.

关键词： RBM42 gene RNA-binding protein neurodevelopmental disorder Au-Kline syndrome alternative splicing