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

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

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Targeting RAF dimers in RAS mutant tumors:From biology to clinic

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1895-1923页

作者： Huanhuan Yin Qiulin Tang Hongwei Xia Feng Bi division of Abdominal Cancer Department of Medical OncologyCancer Center and Laboratory of Molecular Targeted Therapy in OncologyWest China HospitalSichuan UniversityChengdu 610041China

RAS mutations occur in approximately 30%of tumors worldwide and have a poor prognosis due to limited *** targeting of KRAS G12C has achieved significant success in recent years,but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations.A highly promising approach is to target the MAPK pathway downstream of RAS,with a particular focus on RAF ***-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a ***,their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF *** address the issue of RAF dimerization,type II RAF inhibitors have emerged as leading *** clinical studies have shown the initial effectiveness of these agents against RAS mutant ***,type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant *** review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations,as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.

关键词： RAS mutations RAF dimerization RAF inhibitors Cancer therapy Drug resistance

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Elevated Kallistatin promotes the occurrence and progression of non-alcoholic fatty liver disease

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1730-1744页

作者： Zhenzhen Fang Gang Shen Yina Wang Fuyan Hong Xiumei Tang Yongcheng Zeng Ting Zhang Huanyi Liu Yanmei Li Jinhong Wang Jing Zhang Anton Gao Weiwei Qi Xia Yang Ti Zhou Guoquan Gao department of biochemistry Zhongshan School of MedicineSun Yat-Sen UniversityGuangzhou 510080China department of VIP Medical Center the Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510080China Physical Examination Center the Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 510080China department of clinical laboratory Guangzhou First People's HospitalGuangzhou 510080China Guangdong Key laboratory of Liver Disease Research the Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou 51008China department of Health Sciences College of Health SolutionsArizona State UniversityTempeUSA Guangdong Engineering&Technology Research Center for Gene Manipulation and Biomacromolecular Products Sun Yat-Sen UniversityGuangzhou 510080China Guangdong Province Key laboratory of Diabetology Guangzhou 510o80China Guangdong Province Key laboratory of Brain Function and Disease Zhongshan School of MedicineSun Yat-Sen UniversityGuangzhou 510080China

Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide,and the development of nonalcoholic steatohepatitis(NASH)might cause irreversible hepatic ***(HLP)is the leading risk factor for *** study aims to illuminate the causative contributor and potential mechanism of Kallistatin(KAL)mediating HLP to NAFLD.221 healthy control and 253 HLP subjects,62 healthy control and 44 NAFLD subjects were *** plasma KAL was significantly elevated in HLP subjects,especially in hypertriglyceridemia(HTG)subjects,and positively correlated with liver ***,KAL levels of NAFLD patients were significantly *** transgenic mice induced hepatic steatosis,inflammation,and fibrosis with time and accelerated inflammation development in high-fat diet(HFD)*** contrast,KAL knockout ameliorated steatosis and inflammation in high-fructose diet(HFruD)and methionine and choline-deficient(MCD)diet-induced NAFLD ***,KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase(ATGL)and comparative gene identification 58(CGl-58)by LRP6/Gas/PKA/GSK3βpathway through down-regulating peroxisome proliferator-activated receptor(PPARy)and up-regulating kruppel-like factor four(KLF4),***-58 is bound to NF-kB p65 in the cytoplasm,and diminishing CGl-58 facilitated p65 nuclear translocation and TNFa ***,hepatic CGl-58-overexpress reverses NASH in KAL transgenic ***,free fatty acids up-regulated KAL against thyroid hormone in ***,Fenofibrate,one triglyceride-lowering drug,could reverse hepatic steatosis by down-regulating *** results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.

关键词： GSK3β inflammation elevated

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GTF2H4 regulates partial EndMT via NF-κB activation through NCOA3 phosphorylation in ischemic diseases

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The Innovation 2024年第2期5卷 27-41页

作者： Zheyan Fang Gang Zhao Shuang Zhao Xueting Yu Runyang Feng You-en Zhang Haomin Li Lei Huang Zhenyang Guo Zhentao Zhang Mukaddas Abdurahman Hangnan Hong Peng Li Bing Wu Jinhang Zhu Xin Zhong Dong Huang Hao Lu Xin Zhao Zhaoyang Chen Wenbin Zhang Junjie Guo Hongchao Zheng Yue He Shengying Qin Haojie Lu Yun Zhao Xiangdong Wang Junbo Ge Hua Li department of Cardiology Zhongshan HospitalFudan UniversityShanghai Institute of Cardiovascular DiseasesShanghai 200032China department of Cardiology Zhongshan HospitalFudan UniversityShanghai 200032China department of Medical Examination Shanghai Xuhui District Central HospitalShanghai 200031China department of Cardiology and Institute of clinical medicine Renmin HospitalHubei University of MedicineShiyan 442000China clinical Data Center Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China department of Molecular Celland Cancer BiologyUniversity of Massachusetts Chan Medical SchoolWorcesterMA 01605USA Bio-X Institute Key Laboratory for The Genetics of Developmental and Neuropsychiatric DisordersShanghai Jiao Tong UniversityShanghai 200030China department of Cardiology Heart Center of Fujian ProvinceFujian Medical University Union HospitalFuzhou 350001China department of Cardiology Sir Run Run Shaw Hospitalaffiliated with Zhejiang University School of MedicineHangzhou 310020China department of Cardiology The Affiliated Hospital of Qingdao UniversityQingdao 266003China department of Cardiology Shanghai Xuhui District Central HospitalShanghai 200031China department of Cardiology Shanghai Eighth People’s HospitalShanghai 200235China department of Chemistry and Institutes of Biomedical Sciences Fudan UniversityShanghai 200032China State Key laboratory of Cell Biology Shanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 200031China School of Life Science and Technology Shanghai Tech University100 Haike RoadShanghai 201210China Key laboratory of Systems Health Science of Zhejiang Province School of Life ScienceHangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China department of Pulmonary and Critical Care medicine Zhongshan Hospital

Partial endothelial-to-mesenchymal transition(EndMT)is an intermediate phenotype observed in endothelial cells(ECs)undergoing a transition toward a mesenchymal state to support neovascularization during(patho)physiological ***,we investigated the occurrence of partial EndMT in ECs under hypoxic/ischemic conditions and identified general transcription factor IIH subunit 4(GTF2H4)as a positive regulator of this *** addition,we discovered that GTF2H4 collaborates with its target protein excision repair cross-complementation group 3(ERCC3)to co-regulate partial ***,by using phosphorylation proteomics and site-directed mutagenesis,we demonstrated that GTF2H4 was involved in the phosphorylation of receptor coactivator 3(NCOA3)at serine 1330,which promoted the interaction between NCOA3 and p65,resulting in the transcriptional activation of NF-κB and the NF-kB/Snail signaling axis during partial *** vivo experiments confirmed that GTF2H4 significantly promoted partial EndMT and angiogenesis after ischemic ***,our findings reveal that targeting GTF2H4 is promising for tissue repair and offers potential opportunities for treating hypoxic/ischemic diseases.

关键词： ischemic activation GTF

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Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

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Acta Pharmaceutica Sinica B 2024年第1期14卷 87-109页

作者： Letian Song Shenghua Gao Bing Ye Mianling Yang Yusen Cheng Dongwei Kang Fan Yi Jin-Peng Sun Luis Menéndez-Arias Johan Neyts Xinyong Liu Peng Zhan department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Shenzhen Research Institute of Shandong University Shenzhen 518057China The Key laboratory of Infection and Immunity of Shandong Province Department of PharmacologySchool of Basic Medical SciencesShandong UniversityJinan 250012China Key laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Centro de Biologı´a Molecular“Severo Ochoa”(Consejo Superior de Investigaciones Cientı´ficas&Autonomous University of Madrid) Madrid 28049Spain KU Leuven Department of Microbiology and ImmunologyRega Institute for Medical ResearchLaboratory of Virology and ChemotherapyLeuven 3000Belgium

The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life *** covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic *** antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable *** non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available *** viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.

关键词： COVID-19 SARS-CoV-2 Main protease Non-covalent inhibitors Medicinal chemistry strategies

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Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses

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Cancer Communications 2024年第2期44卷 287-293页

作者： Kouya Shiraishi Atsushi Takahashi Yukihide Momozawa Yataro Daigo Syuzo Kaneko Takahisa Kawaguchi Hideo Kunitoh Shingo Matsumoto Hidehito Horinouchi Akiteru Goto Takayuki Honda Kimihiro Shimizu Masahiro Torasawa Daisuke Takayanagi Motonobu Saito Akira Saito Yuichiro Ohe Shun-ichi Watanabe Koichi Goto Masahiro Tsuboi Katsuya Tsuchihara Sadaaki Takata Tomomi Aoi Atsushi Takano Masashi Kobayashi Yohei Miyagi Kazumi Tanaka Hiroyuki Suzuki Daichi Maeda Takumi Yamaura Maiko Matsuda Yoko Shimada Takaaki Mizuno Hiromi Sakamoto Teruhiko Yoshida Yasushi Goto Tatsuya Yoshida Taiki Yamaji Makoto Sonobe Shinichi Toyooka Kazue Yoneda Katsuhiro Masago Fumihiro Tanaka Megumi Hara Nobuo Fuse Satoshi S.Nishizuka Noriko Motoi Norie Sawada Yuichiro Nishida Kazuki Kumada Kenji Takeuchi Kozo Tanno Yasushi Yatabe Kuniko Sunami Tomoyuki Hishida Yasunari Miyazaki Hidemi Ito Mitsuhiro Amemiya Hirohiko Totsuka Haruhiko Nakayama Tomoyuki Yokose Kazuyoshi Ishigaki Toshiteru Nagashima Yoichi Ohtaki Kazuhiro Imai Ken Takasawa Yoshihiro Minamiya Kazuma Kobayashi Kenichi Okubo Kenji Wakai Atsushi Shimizu Masayuki Yamamoto Motoki Iwasaki Koichi Matsuda Johji Inazawa Yuichi Shiraishi Hiroyoshi Nishikawa Yoshinori Murakami Michiaki Kubo Fumihiko Matsuda Yoichiro Kamatani Ryuji Hamamoto Keitaro Matsuo Takashi Kohno division of Genome Biology National Cancer Center Research InstituteTokyoJapan department of clinical Genomics National Cancer Center Research InstituteTokyoJapan laboratory for Statistical Analysis Center for Integrative Medical SciencesRIKENYokohamaJapan department of Genomic medicine Research InstituteNational Cerebral and Cardiovascular CenterOsakaJapan laboratory for Genotyping Development Center for Integrative Medical SciencesRIKENYokohamaJapan Center for Antibody and Vaccine Therapy Research HospitalInstitute of Medical ScienceThe University of TokyoTokyoJapan department of Medical Oncology and Cancer Center and Center for Advanced Medicine against CancerShiga University of Medical ScienceOtsuJapan division of Medical AI Research and Development National Cancer Center Research InstituteTokyoJapan Center for Genomic medicine Graduate School of MedicineKyoto UniversityKyotoJapan department of Medical Oncology Japanese Red Cross Medical CenterTokyoJapan department of Thoracic Oncology National Cancer Center Hospital EastJapan department of Thoracic Oncology National Cancer Center HospitalTokyoJapan department of Cellular and Organ Pathology Graduate School of MedicineAkita UniversityAkitaJapan department of Respiratory medicine Tokyo Medical and Dental UniversityBunkyo-kuTokyoJapan division of General Thoracic Surgery Department of SurgeryShinshu University School of MedicineMatsumotoNaganoJapan department of General Surgical Science Division of General Thoracic SurgeryGunma University Graduate School of MedicineIntegrative Center of General SurgeryGunma University HospitalGunmaJapan department of Gastrointestinal Tract Surgery Fukushima Medical University School of MedicineFukushimaJapan StaGen Co. LtdTokyoJapan division of Thoracic Surgery National Cancer Center HospitalTokyoJapan department of Thoracic Surgery National Cancer Center Hospital EastChibaJapan division of Translational Informatics Exploratory Oncology Research and Clinical Trial Center(EPOC

Dear editor,Lung carcinoma is responsible for the highest fatal-ity rate among cancer-related deaths globally,with lung adenocarcinoma(LADC)emerging as the prevailing sub-type.

关键词： adenocarcinoma lung Lung

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Charting epimutation dynamics in human hematopoietic differentiation Xiaohuan Qina

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Blood Science 2024年第3期6卷 1-10页

作者： Jiayi Lu Peng Wu Chunyong Zhang Lei Shi Ping Zhu State Key laboratory of Experimental Hematology National Clinical Research Center for Blood DiseasesHaihe Laboratory of Cell EcosystemDepartment of Stem Cell and Regenerative MedicineInstitute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjinChina The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease(Ministry of Education)Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina

DNA methylation plays a critical role in hematopoietic *** is a stochastic variation in DNA methylation that induces epigenetic ***,the effects of epimutations on normal hematopoiesis and hematopoietic diseases remain *** this study,we developed a Julia package called EpiMut that enabled rapid and accurate quantification of *** was used to evaluate and provide an epimutation landscape in steady-state hematopoietic differentiation involving 13 types of blood cells ranging from hematopoietic stem/progenitor cells to mature *** showed that substantial genomic regions exhibited epigenetic variations rather than significant differences in DNA methylation levels between the myeloid and lymphoid *** dynamics of epimutations were observed during the differentiation of each ***,we found that epimutation significantly enriched signals associated with lineage ***,epimutations in hematopoietic stem cells(HSCs)derived from various sources and acute myeloid leukemia were related to the function of HSCs and malignant cell *** together,our study comprehensively documented an epimutation map and uncovered its important roles in human hematopoiesis,thereby offering insights into hematopoietic regulation.

关键词： DNA methylation Epimutation Hematopoietic differentiation Hematopoietic stem cell

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Solid-state atomic hydrogen as a broad-spectrum RONS scavenger for accelerated diabetic wound healing

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National Science Review 2024年第2期11卷 196-206页

作者： Man Luo Qin Wang Gang Zhao Wei Jiang Cici Zeng Qingao Zhang Ruyu Yang Wang Dong Yunxi Zhao Guozhen Zhang Jun Jiang Yucai Wang Qing Zhu Key laboratory of Precision and Intelligent Chemistry School of Chemistry and Materials Science University of Science and Technology of China department of Radiology The First Affiliated Hospital of University of Science and Technology of China Division of Life Sciences and Medicine University of Science and Technology of China Shenzhen Senior High School Institute of Intelligent Innovation Henan Academy of Sciences

Hydrogen therapy shows great promise as a versatile treatment method for diseases associated with the overexpression of reactive oxygen and nitrogen species（RONS）. However, developing an advanced hydrogen therapy platform that integrates controllable hydrogen release, efficient RONS elimination, and biodegradability remains a giant technical challenge. In this study, we demonstrate for the first time that the tungsten bronze phase H0.53WO3（HWO） is an exceptionally ideal hydrogen carrier, with salient features including temperature-dependent highly-reductive atomic hydrogen release and broad-spectrum RONS scavenging capability distinct from that of molecular hydrogen. Moreover, its unique p H-responsive biodegradability ensures post-therapeutic clearance at pathological sites. Treatment with HWO of diabetic wounds in an animal model indicates that the solid-state atomic H promotes vascular formation by activating M2-type macrophage polarization and anti-inflammatory cytokine production, resulting in acceleration of chronic wound healing. Our findings significantly expand the basic categories of hydrogen therapeutic materials and pave the way for investigating more physical forms of hydrogen species as efficient RONS scavengers for clinical disease treatment.

关键词： atomic hydrogen RONS scavenger inflammatory regulation diabetic wound healing hydrogen therapy

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Environmentally friendly polylysine gauze dressing for an innovative antimicrobial approach to infected wound management

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Chinese Chemical Letters 2024年第10期35卷 309-314页

作者： Yaxian Liang Qingyi Li Liwei Hu Ruohan Zhai Fan Liu Lin Tan Xiaofei Wang Huixu Xie State Key laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesWest China College of StomatologySichuan UniversityChengdu 610041China College of Biomass Science and Engineering Key Laboratory of Biomass Fibers for Medical Care in Textile IndustrySichuan UniversityChengdu 60065China division of Thyroid Surgery Department of General SurgeryLaboratory of Thyroid and Parathyroid DiseaseFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan University.Chengdu 610041China

Infections frequently occur after skin injuries,posing a significant challenge in current clinical *** changing dressings to minimize wound infections and adhesions results in large amounts of medical ***,developing environmentally friendly multifunctional dressings has considerable application and translational *** study aimed to prepare a wound dressing with favorable antimicrobial properties and biosafety by grafting a natural antimicrobial peptide,polylysine,onto a traditional cotton textile *** cotton textile dressing offers excellent moisture absorption and softness,while polylysine provides excellent biocompatibility,a broad antimicrobial spectrum,and high ***,both materials are natural and biodegradable,making them ideal for environmentally friendly wound dressings.

关键词： Polylysine Modified cotton dressing Antimicrobial Environmentally friendly Infected wound management

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A retrospective analysis of carbapenem-resistant Acinetobacter baumannii infections in critically ill patients:Experience at a tertiary-care teaching hospital ICU

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Journal of Intensive medicine 2024年第2期4卷 181-186页

作者： Leyla Ferlicolak Neriman Defne Altintas Fugen Yoruk department of Internal medicine division of Intensive Care Unit Ankara University Faculty of MedicineAnkaraTurkey department of Infectious Diseases and clinical Microbiology Ankara University Faculty of MedicineAnkaraTurkey

Background Acinetobacter baumannii is a clinically significant pathogen with a high incidence of multidrug resistance that is associated with life-threatening nosocomial ***,we aimed to provide an insight into the clinical characteristics and outcomes of a unique group of *** infections in which the isolates were resistant to carbapenems and most other antibiotic groups in a tertiary-care intensive care unit(ICU).Methods We performed a retrospective observational study in which records of patients hospitalized in the ICU between June 1,2021 and June 1,2023 were *** checked the clinical,laboratory,and microbiological records of all adult patients who had carbapenem-resistant ***(CRAB)*** antibiotic treatments and definitive antibiotic treatments after culture positivity and susceptibility test results were recorded.C-reactive protein(CRP)and procalcitonin levels and leukocyte counts were *** of ICU stay and 30-day mortality were defined as the outcome *** During the study period,57 patients were diagnosed with CRAB *** respiratory tract was the leading infection site(80.7%).In non-survivors,bloodstream infections(21.9%vs.4.0%P=0.05)and colistin-resistant(col-R)CRAB infections(43.8%vs.24.0%,P=0.12)were more common than in survivors,but these parameters were not statistically *** length of ICU stay was not different between survivors and ***,the rate of col-R among CRAB clinical isolates was 35.1%.The 30-day mortality in all patients with CRAB infection was 56.1%.Mortality in col-R CRAB and colistin-susceptible(col-S)CRAB infections was 70.0%and 48.6%,respectively(P=0.12).Prior carbapenem use was 56.1%.Prior colistin use before col-R and col-S CRAB infections was not significant(35.0%vs.27.0%,P=0.53).Conclusions Our study provides real-world data on highly resistant *** infections and shares the characteristics of infections with such resistant stra

关键词： Mortality Colistin-resi stant Gram-negative bacteria MDR Intensive care unit

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