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Immune checkpoint inhibitors:breakthroughs in cancer treatment

Cancer Biology & medicine 2024年第6期21卷 451-472页

作者： Xueqing Kong Jinyi Zhang Shuwei Chen Xianyang Wang Qing Xi Han Shen Rongxin Zhang Laboratory of Immunology and Inflammation School of Life Sciences and BiopharmaceuticsGuangdong Pharmaceutical UniversityGuangzhou 510006China Department of Biology School of Life Sciences and BiopharmaceuticsGuangdong Pharmaceutical UniversityGuangzhou 510006China

Over the past two decades,immunotherapies have increasingly been considered as first-line treatments for most *** such treatment is immune checkpoint blockade(ICB),which has demonstrated promising results against various solid tumors in clinical *** antibodies(mAbs)are currently available as immune checkpoint inhibitors(ICIs).These ICIs target specific immune checkpoints,including cytotoxic T-lymphocyte-associated antigen-4(CTLA-4)and programmed cell death protein 1(PD-1).Clinical trial results strongly support the feasibility of this immunotherapeutic ***,a substantial proportion of patients with cancer develop resistance or tolerance to treatment,owing to tumor immune evasion mechanisms that counteract the host immune ***,substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1,anti-programmed cell death ligand 1(anti-PD-L1),and anti-CTLA-4 ***,several immune checkpoint molecular targets have been identified,such as T cell immunoreceptor with Ig and ITIM domains(TIGIT),mucin domain containing-3(TIM-3),lymphocyte activation gene-3(LAG-3),V-domain immunoglobulin suppressor of T cell activation(VISTA),B and T lymphocyte attenuator(BTLA),and signal-regulatory proteinα(SIRPα).Functional m Abs targeting these molecules are under ***-4,PD-1/PD-L1,and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of *** review discusses these structures,as well as clinical progress in m Abs targeting these immune checkpoint molecules and their potential applications.

关键词： Immunotherapy cancer ICIs PD-1 CTLA-4

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Lactate regulates major zygotic genome activation by H3K18 lactylation in mammals

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National Science Review 2024年第2期11卷 124-134页

作者： Jingyu Li Weibo Hou Qi Zhao Wei Han Hongdi Cui Songling Xiao Ling Zhu Jiadan Qu Xiaoyu Liu Weitao Cong Jingling Shen Yuzheng Zhao Shaorong Gao Guoning Huang Qingran Kong Chongqing Key Laboratory of Human Embryo Engineering Center for Reproductive Medicine Chongqing Health Center for Women and ChildrenWomen and Children's Hospital of Chongqing Medical University Oujiang Laboratory Zhejiang Provincial Key Laboratory of Medical Genetics Key Laboratory of Laboratory MedicineMinistry of EducationSchool of Laboratory Medicine and Life Sciences Wenzhou Medical University Frontier Science Center for Stem Cell Research School of Life Sciences and Technology Tongji University school of Pharmaceutical Science Wenzhou Medical University Institute of life sciences College of Life and Environmental Sciences Wenzhou University Optogenetics&Synthetic Biology Interdisciplinary Research Center State Key Laboratory of Bioreactor Engineering Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism School of Pharmacy East China University of Science and Technology

Lactate is present at a high level in the microenvironment of mammalian preimplantation embryos in vivo and in vitro. However, its role in preimplantation development is unclear. Here, we report that lactate is highly enriched in the nuclei of early embryos when major zygotic genome activation(ZGA) occurs in humans and mice. The inhibition of its production and uptake results in developmental arrest at the 2-cell stage, major ZGA failure, and loss of lactate-derived H3K18lac, which could be rescued by the addition of Lac-Co A and recapitulated by overexpression of H3K18R mutation. By profiling the landscape of H3K18lac during mouse preimplantation development, we show that H3K18lac is enriched on the promoter regions of most major ZGA genes and correlates with their expressions. In humans, H3K18lac is also enriched in ZGA markers and temporally concomitant with their expressions. Taken together, we profile the landscapes of H3K18lac in mouse and human preimplantation embryos, and demonstrate the important role for H3K18lac in major ZGA, showing that a conserved metabolic mechanism underlies preimplantation development of mammalian embryos.

关键词： mammalian preimplantation development lactate epigenetic remodeling histone lactylation zygotic genome activation

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Cannabinoids and endocannabinoids as therapeutics for nervous system disorders:preclinical models and clinical studies

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Neural Regeneration Research 2024年第4期19卷 788-799页

作者： R.Scott Duncan Sean M.Riordan Matthew C.Gernon Peter Koulen Department of Ophthalmology School of MedicineUniversity of Missouri Department of Biomedical sciences School of MedicineUniversity of Missouri

Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human *** have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human *** of these include central nervous system(CNS)diseases and dysfunctions such as forms of epilepsy,multiple sclerosis,Parkinson’s disease,pain and neuropsychiatric *** addition,the endogenously produced cannabinoid lipids,endocannabinoids,are critical for normal CNS function,and if controlled or modified,may represent an additional therapeutic avenue for CNS *** review discusses in vitro cellular,ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS *** addition,the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS *** and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.

关键词： anandamide cannabidiol cannabinoid endocannabinoid epilepsy multiple sclerosis neurodegeneration neuroprotection tetrahydrocannabinol

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HUNK inhibits cargo uptake and lysosomal traffic in the caveolar pathway via the AGAP3/ARF6

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Science Bulletin 2024年第2期69卷 173-178页

作者： Siyuan Jiang Xiaoqi Han Tihui Liu Ying He Zidong Zhao Tongfeng Liu Shuwen Cheng Jihang Zhang Liqiang Duan Yajuan Liu Tianyou Cheng Yong Liu Qinong Ye Shan Gao Zhongda Hospital Medical SchoolAdvanced Institute for Life and HealthSoutheast UniversityNanjing 20096China Medical school of Guizhou University Guiyang 550025China Shanxi Academy of Advanced Research and Innovation Taiyuan 030032China Zhongda Hospital School of Life Sciences and TechnologyAdvanced Institute for Life and HealthSoutheast UniversityNanjing 210096China Nanjing University Medical school Nanjing 210046China Hubei Key Laboratory of Cell Homeostasis College of Life SciencesTaiKang Center for Life and Medical SciencesWuhan UniversityWuhan 430072China Department of Medical Molecular Biology Beijing Institute of BiotechnologyCollaborative Innovation Center for Cancer MedicineBeijing 100850China

Endocytosis is a crucial cellular process that takes up cargos by enclosing them in membrane-bound vesicles,and transports cargos to different parts of the cell,such as the lysosomes[1].Endocytosis is classified into several mechanistically and morphologically pathways,including clathrin-mediated endocytosis(CME)and caveolae-mediated endocytosis(CavME)[1,2].

关键词： endocytosis cargo uptake

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STING signaling in islet macrophages impairs insulin secretion in obesity

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Science China(life sciences) 2024年第2期67卷 345-359页

作者： Ze Hong Saihua Chen Jing Sun Dan Cheng Hanli Guo Jiahao Mei Xiang Zhang Munire Maimaiti Haiping Hao Peng Cao Haiyang Hu Chen Wang school of Pharmacy Nanjing University of Chinese MedicineNanjing 210023China State Key Laboratory of Natural medicines Department of Life Science and TechnologyChina Pharmaceutical UniversityNanjing 211198China school of life sciences Westlake UniversityHangzhou 310012China

The innate immune regulator stimulator of interferon genes(STING)mediates self-DNA sensing and leads to the induction of type I interferons and inflammatory cytokines,which promotes the progression of various inflammatory and autoimmune *** immune system plays a critical role in regulating obesity-induced islet dysfunction,whereas the potential effect of STING signaling is not fully ***,we demonstrate that STING is mainly expressed and activated in islet macrophages upon high-fat diet(HFD)***^(-/-)alleviates HFD-induced islet inflammation by inhibiting the expression of pro-inflammatory cytokines and the infiltration of ***,palmitic acid incubation promotes mitochondrial DNA leakage into the cytosol and subsequently activates STING pathway in ***,STING activation in macrophages impairs glucose-stimulated insulin secretion by mediating the engulfment ofβcell insulin secretory *** inhibiting STING activation enhances insulin secretion to control ***,our results reveal a regulatory mechanism in controlling the islet inflammation and insulin secretion in dietinduced obesity and suggest that selective blocking of the STING activation may be a promising strategy for treating type 2 diabetes.

关键词： STING obesity type 2 diabetes insulin macrophages islet

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Seeing is believing: observation of migrasomes

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Biophysics Reports 2024年第2期10卷 67-81页

作者： Yuwei Huang Li Yu school of Basic Medical sciences Translational Medicine Institute Xi'an Jiaotong University State Key Laboratory of Membrane Biology Tsinghua University-Peking University Joint Center for Life SciencesBeijing Frontier Research Center for Biological Structure School of Life Sciences Tsinghua University

Migrasomes are a novel type of cell organelle that form on the retraction fibers at the rear of migrating cells. In recent years, numerous studies have unveiled the mechanisms of migrasome formation and have highlighted significant roles of migrasomes in both physiological and pathological *** upon the strategies outlined in published works and our own research experiences, we have compiled a comprehensive set of protocols for observing migrasomes. These step-by-step instructions encompass various aspects such as cell culture, labeling, imaging, in vitro reconstitution, and statistical analysis. We believe that these protocols serve as a valuable resource for researchers exploring migrasome biology.

关键词： Migrasome Labeling Imaging In vitro reconstitution

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Epigenetic modification in liver fibrosis:Promising therapeutic direction with significant challenges ahead

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1009-1029页

作者： Runping Liu Yajing Li Qi Zheng Mingning Ding Huiping Zhou Xiaojiaoyang Li school of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 102400China school of life sciences Beijing University of Chinese MedicineBeijing 102400China Department of Microbiology and Immunology Virginia Commonwealth UniversityRichmondVA 22460USA

Liver fibrosis,characterized by scar tissue formation,can ultimately result in liver ***’s a major cause of morbidity and mortality globally,often associated with chronic liver diseases like hepatitis or alcoholic and non-alcoholic fatty liver ***,current treatment options are limited,highlighting the urgent need for the development of new *** a reversible regulatory mechanism,epigenetic modification is implicated in many biological processes,including liver *** the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases,although the current evidence is still *** review provides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifications,including DNA methylation,histone modification,and RNA modification,in liver fibrotic *** potential cooperation of different epigenetic modifications in promoting fibrogenesis was also ***,available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were *** summary,elucidating specific druggable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.

关键词： Liver fibrosis Epigenetics regulation DNA methylation Histone acetylation Histone methylation mRNA methylation Non-coding RNA Drug development

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Design of antiviral AGO2-dependent short hairpin RNAs

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Virologica Sinica 2024年第4期39卷 645-654页

作者： Yuanyuan Bie Jieling Zhang Jiyao Chen Yumin Zhang Muhan Huang Leike Zhang Xi Zhou Yang Qiu Key Laboratory of Virology and Biosafety Wuhan Institute of VirologyChinese Academy of SciencesWuhan 430071China State Key Laboratory of Virology Wuhan Institute of VirologyChinese Academy of SciencesWuhan 430071China University of Chinese Academy of sciences Beijing 100049China school of life sciences Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230027China

The increasing emergence and re-emergence of RNA virus outbreaks underlines the urgent need to develop effective *** interference(RNAi)is a sequence-specific gene silencing mechanism that is triggered by small interfering RNAs(siRNAs)or short hairpin RNAs(shRNAs),which exhibits significant promise for antiviral ***2-dependent shRNA(agshRNA)generates a single-stranded guide RNA and presents significant advantages over traditional siRNA and *** this study,we applied a logistic regression algorithm to a previously published chemically siRNA efficacy dataset and built a machine learning-based model with high predictive *** this model,we designed siRNA sequences targeting diverse RNA viruses,including human enterovirus A71(EV71),Zika virus(ZIKV),dengue virus 2(DENV2),mouse hepatitis virus(MHV)and severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),and transformed them into *** validated the performance of our agshRNA design by evaluating antiviral efficacies of agshRNAs in cells infected with different *** the agshRNA targeting EV71 as an example,we showed that the anti-EV71 effect of agshRNA was more potent compared with the corresponding siRNA and ***,the antiviral effect of agshRNA is dependent on AGO2-processed guide RNA,which can load into the RNA-induced silencing complex(RISC).We also confirmed the antiviral effect of agshRNA in ***,this work develops a novel antiviral strategy that combines machine learning-based algorithm with agshRNA design to custom design antiviral agshRNAs with high efficiency.

关键词： AgshRNA Antiviral strategy Machine learning model

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Fusobacterium nucleatum-induced imbalance in microbiome-derived butyric acid levels promotes the occurrence and development of colorectal cancer

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World Journal of Gastroenterology 2024年第14期30卷 2018-2037页

作者： Qi-Long Wu Xiao-Ting Fang Xin-Xin Wan Qing-Yong Ding Yan-Jun Zhang Ling Ji Yong-Liang Lou Xiang Li school of Laboratory medicine and life sciences Wenzhou Medical UniversityKey Laboratory of Laboratory MedicineMinistry of EducationWenzhou 325035Zhejiang ProvinceChina Department of Health Inspection and Quarantine School of Laboratory Medicine and Life SciencesWenzhou 325035Zhejiang ProvinceChina school of Laboratory medicine and life sciences Wenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical GeneticsMinistry of EducationWenzhou 325035Zhejiang ProvinceChina Department of General Surgery The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325035Zhejiang ProvinceChina school of Laboratory medicine and life sciences Institute of One HealthWenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical GeneticsMinistry of EducationWenzhou 325035Zhejiang ProvinceChina Department of Health Inspection and Quarantine School of Laboratory Medicine and Life SciencesInstitute of One HealthWenzhou Medical UniversityZhejiang Provincial Key Laboratory of Medical GeneticsMinistry of EducationWenzhou 325035Zhejiang ProvinceChina

BACKGROUND Colorectal cancer(CRC)ranks among the most prevalent malignant tumors *** reports suggest that Fusobacterium nucleatum(***)contributes to the initiation,progression,and prognosis of ***,a short-chain fatty acid derived from the bacterial fermentation of soluble dietary fiber,is known to inhibit various *** study is designed to explore whether *** influences the onset and progression of CRC by impacting the intestinal metabolite butyric *** To investigate the mechanism by which *** affects CRC occurrence and *** Alterations in the gut microbiota of BALB/c mice were observed following the oral administration of ***,DLD-1 and HCT116 cell lines were exposed to sodium butyrate(NaB)and *** in vitro to examine the effects on proliferative proteins and mitochondrial *** Our research indicates that the prevalence of *** in fecal samples from CRC patients is significantly greater than in healthy counterparts,while the prevalence of butyrate-producing bacteria is notably *** mice colonized with ***,the population of butyrate-producing bacteria decreased,resulting in altered levels of butyric acid,a key intestinal metabolite of *** to NaB can impair mitochondrial morphology and diminish mitochondrial membrane potential in DLD-1 and HCT116 CRC ***,this leads to modulated production of adenosine triphosphate and reactive oxygen species,thereby inhibiting cancer cell ***,NaB triggers the adenosine monophosphate-activated protein kinase(AMPK)signaling pathway,blocks the cell cycle in HCT116 and DLD-1 cells,and curtails the proliferation of CRC *** combined presence of *** and NaB attenuated the effects of the *** employing small interfering RNA to suppress AMPK,it was demonstrated that AMPK is essential for NaB’s inhibition of CRC cell *** F.n

关键词： Colorectal cancer Fusobacterium nucleatum Butyric acid Gut microbiota Adenosine monophosphate-activated protein kinase signal pathway

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Genomic analysis of Nypa fruticans elucidates its intertidal adaptations and early palm evolution

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Journal of Integrative Plant Biology 2024年第4期66卷 824-843页

作者： Weihong Wu Xiao Feng Nan Wang Shao Shao Min Liu Fa Si Linhao Chen Chuanfeng Jin Shaohua Xu Zixiao Guo Cairong Zhong Suhua Shi Ziwen He State Key Laboratory of Biocontrol and Guangdong Provincial Key Laboratory of Plant Resources School of Life SciencesSun Yat-sen UniversityGuangzhou 510275China Greater Bay Area Institute of Precision medicine School of Life SciencesFudan UniversityGuangzhou 511462China Hainan Academy of Forestry(Hainan Academy of Mangrove) Haikou 571100China

Nypa fruticans(Wurmb),a mangrove palm species with origins dating back to the Late Cretaceous period,is a unique species for investigating long-term adaptation strategies to intertidal environments and the early evolution of ***,we present a chromosome-level genome sequence and assembly for *** integrated the genomes of *** and other palm family members for a comparative genomic analysis,which confirmed that the common ancestor of all palms experienced a whole-genome duplication event around 89 million years ago,shaping the distinctive characteristics observed in this *** also inferred a low mutation rate for the *** genome,which underwent strong purifying selection and evolved slowly,thus contributing to its stability over a long evolutionary ***,ancient duplicates were preferentially retained,with critical genes having experienced positive selection,enhancing waterlogging tolerance in ***,we discovered that the pseudogenization of Early Methionine-labelled 1(EM1)and EM6 in *** underly its crypto-vivipary characteristics,reflecting its intertidal *** study provides valuable genomic insights into the evolutionary history,genome stability,and adaptive evolution of the mangrove *** results also shed light on the long-term adaptation of this species and contribute to our understanding of the evolutionary dynamics in the palm family.

关键词： crypto-vivipary genome stability long-term adaptation mangrove Nypa fruticans palm

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