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Id2 epigenetically controls CD8^(+)T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex

Cellular & Molecular Immunology 2024年第3期21卷 292-308页

作者： Yiming Li Mingwei Han Haolin Wei Wan Huang Zhinan Chen Tianjiao Zhang Meirui Qian Lin Jing Gang Nan Xiuxuan Sun Shuhui Dai Kun Wang Jianli Jiang Ping Zhu Liang Chen department of Cell Biology of National Translational Science Center for Molecular medicine and department of Clinical Immunology of Xijing Hospital Fourth Military Medical UniversityXi’anShaanxi 710032China State Key Laboratory of New Targets Discovery and Drug Development for Major diseases GanzhouJiangxi341000Xi’anShaanxi 710032China School of medicine Shanghai UniversityShanghai 200444China

CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))*** of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell ***,the role of Id2 in CD8^(+)T-cell exhaustion is ***,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm *** deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor ***,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase ***,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog *** LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing *** of LSD1 increases the abundance of Slamf6^(+)Tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T *** study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

关键词： Id2 T-cell exhaustion Epigenetic modification Immune evasion

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Protective mechanism of quercetin in alleviating sepsis-related acute respiratory distress syndrome based on network pharmacology and in vitro experiments

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World Journal of Emergency medicine 2024年第2期15卷 111-120页

作者： Weichao Ding Wei Zhang Juan Chen Mengmeng Wang Yi Ren Jing Feng Xiaoqin Han Xiaohang Ji Shinan Nie Zhaorui Sun department of Emergency medicine Jinling HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing 210002China department of Emergency medicine Jinling Clinical Medical College of Nanjing University of Chinese MedicineNanjing 210002China department of Emergency medicine the Affiliated Hospital of Xuzhou Medical UniversityXuzhou 221002China department of Emergency medicine Xuzhou Municipal Hospital Affiliated to Xuzhou Medical UniversityXuzhou 221000China

BACKGROUND:Sepsis-related acute respiratory distress syndrome(ARDS)has a high mortality rate,and no effective treatment is available *** is a natural plant product with many pharmacological activities,such as antioxidative,anti-apoptotic,and anti-inflammatory *** study aimed to elucidate the protective mechanism of quercetin against sepsis-related ***:In this study,network pharmacology and in vitro experiments were used to investigate the underlying mechanisms of quercetin against sepsis-related *** targets and signaling pathways of quercetin against sepsis-related ARDS were screened and were verified by in vitro ***:A total of 4,230 targets of quercetin,360 disease targets of sepsis-related ARDS,and 211 intersection targets were obtained via database *** the 211 intersection targets,interleukin-6(IL-6),tumor necrosis factor(TNF),albumin(ALB),AKT serine/threonine kinase 1(AKT1),and interleukin-1β(IL-1β)were identified as the core targets.A Gene Ontology(GO)enrichment analysis revealed 894 genes involved in the inflammatory response,apoptosis regulation,and response to *** Encyclopedia of Genes and Genomes(KEGG)enrichment analysis identified 106 *** eliminating and generalizing,the hypoxia-inducible factor-1(HIF-1),TNF,nuclear factor-κB(NF-κB),and nucleotide-binding and oligomerization domain(NOD)-like receptor signaling pathways were *** docking revealed that quercetin had good binding activity with the core ***,quercetin blocked the HIF-1,TNF,NF-κB,and NODlike receptor signaling pathways in lipopolysaccharide(LPS)-induced murine alveolar macrophage(MH-S)*** also suppressed the inflammatory response,oxidative reactions,and cell ***:Quercetin ameliorates sepsis-related ARDS by binding to its core targets and blocking the HIF-1,TNF,NF-κB,and NOD-like receptor signaling pathways to reduce inflammation,cell apoptosis,and oxidative

关键词： Quercetin Sepsis-related acute respiratory distress syndrome Network pharmacology

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New insights into astrocyte diversity from the lens of transcriptional regulation and their implications for neurodegenerative disease treatments

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Neural Regeneration Research 2024年第11期19卷 2335-2336页

作者： Ibrahim Olabayode Saliu Guoyan Zhao department of Genetics Washington University School of MedicineSt.LouisMOUSA department of Neurology Department of Pathology and ImmunologyWashington University School of MedicineSt.LouisMOUSA

Astrocytes are a major glial cell type in the central nervous system,and they provide trophic and metabolic support to *** addition to these roles,they play crucial roles in modulating synaptic functions,development,and pruning(Brandebura et al.,2023).Astrocytes become reactive(activated)by undergoing morphological,molecular,and functional alterations in response to neuropathology such as in injuries and neurodegenerative diseases(NDs)(Escartin et al.,2021).

关键词： degenerative injuries

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Succinylation modification:a potential therapeutic target in stroke

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Neural Regeneration Research 2024年第4期19卷 781-787页

作者： Jie Lian Wenwu Liu Qin Hu Xiaohua Zhang department of Neurosurgery Ren Ji HospitalShanghai Jiao Tong University School of Medicine department of Diving and Hyperbaric medicine Naval Medical CenterNaval Medical University

Stroke is a leading cause of mortality and disability *** cell death triggered by the compromised supply of blood oxygen and glucose is one of the major pathophysiology of strokeinduced brain *** mitochondrial energy metabolism is observed minutes after stroke and is closely associated with the progression of ***,a new type of posttranslational modification,known as lysine succinylation,has been recognized to play a significant role in mitochondrial energy metabolism after ***,the role of succinylation modification in cell metabolism after stroke and its regulation are not well *** aimed to review the effects of succinylation on energy metabolism,reactive oxygen species generation,and neuroinflammation,as well as Sirtuin 5 mediated desuccinylation after *** also highlight the potential of targeting succinylation/desuccinylation as a promising strategy for the treatment of *** succinylation level is dynamically regulated by the nonenzymatic or enzymatic transfer of a succinyl group to a protein on lysine residues and the removal of succinyl catalyzed by *** evidence has suggested that succinylation can regulate the metabolic pathway through modulating the activity or stability of metabolic ***,especially Sirtuin 5,are characterized for their desuccinylation activity and have been recognized as a critical regulator of metabolism through desuccinylating numerous metabolic *** between succinylation and desuccinylation has been implicated in the pathophysiology of *** agents that enhance the activity of Sirtuin 5 have been employed to promote desuccinylation and improve mitochondrial metabolism,and neuroprotective effects of these agents have been observed in experimental stroke ***,their therapeutic efficacy in stroke patients should be validated.

关键词： mitochondria metabolism neuroprotection sirtuin 5 stroke succinylation modification

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Vanillylacetone attenuates cadmium chloride-induced hippocampal damage and memory loss through upregulation of nuclear factor erythroid 2-related factor 2 gene and protein expression

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Neural Regeneration Research 2024年第12期19卷 2750-2759页

作者： Fahaid H.A.L-Hashem Salah O.Bashir Amal F.Dawood Moutasem S.Aboonq Ismaeel Bin-Jaliah Abdulaiziz M.Al-Garni Mohamed D.Morsy department of Physiology College of MedicineKing Khalid UniversityAbhaSaudi Arabia department of Basic Medical Sciences College of MedicinePrincess Nourah bint Abdulrahman UniversityP.O.Box 84428Riyadh 11671Saudi Arabia department of Physiology College of MedicineTaibah UniversityAl-Madinah Al-MunawwarahSaudi Arabia department of medicine College of MedicineKing Khalid UniversityAbhaSaudi Arabia

Memory loss and dementia are major public health concerns with a substantial economic *** stress has been shown to play a crucial role in the pathophysiology of hippocampal damage-induced memory *** investigate whether the antioxidant and anti-inflammatory compound vanillyla cetone(zingerone) can protect against hippocampal damage and memory loss induced by cadmium chloride(CdCl_(2)) administration in rats,we explo red the potential involvement of the nuclear factor erythroid 2-related factor 2(Nrf2) signaling pathway,which is known to modulate oxidative stress and *** healt hy male Wistar rats were divided into five groups:vehicle-treated(control),vanillylacetone,CdCl_(2),vanillylacetone+ CdCl_(2),vanillylacetone+ CdCl_(2)+ brusatol(a selective pharmacological N rf2inhibitor) *** effectively attenuated CdCl_(2)-induced damage in the dental gyrus of the hippocampus and improved the memory function assessed by the Morris Water Maze ***,vanillylacetone markedly decreased the hippocampal tissue levels of inflammatory biomarkers(interleukin-6,tumor necrosis factor-α,intracellular cell adhesive molecules) and apoptosis biomarkers(Bax and cleaved caspase-3).The control and CdCl_(2)-treated groups treated with va nillylacetone showed reduced generation of reactive oxygen species,decreased malondialdehyde levels,and increased superoxide dismutase and glutathione activities,along with significant elevation of nuclear Nrf2 mRNA and protein expression in hippocampal *** the protective effects of vanillylacetone we re substantially blocked by the co-administration of brusatol(a selective N rf2 inhibitor).Va nillylacetone mitigated hippocampal damage and memory loss induced by CdCl_(2),at least in part, by activating the nuclear transcription factor ***,vanillylacetone exerted its potent antioxidant and antiinflammatory actions.

关键词： hippocampus neuroprotective Nrf2 gene oxidative stress vanillylacetone

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Simulation-based assessment for the emergency medicine milestones: a national survey of simulation experts and program directors

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World Journal of Emergency medicine 2024年第4期15卷 301-305页

作者： Afrah A Ali Ashley Crimmins Hegang Chen Danya Khoujah department of Emergency medicine University of Maryland School of MedicineBaltimore 21201USA department of Epidemiology and Public Health University of Maryland School of MedicineBaltimore 21201USA department of Emergency medicine AdventHealth TampaTampa 33606USA

The focus of outcome-based education has shifted from the process of training to the end“product”of *** has necessitated a reframing of the teaching,learning,and ***,in 2013,the Accreditation Council for Graduate Medical Education(ACGME)implemented the educational milestones for all accredited residencies and fellowship programs.[1]The milestones have been described as“developmentally based,specialty-specific achievements that residents are expected to demonstrate at established intervals as they progress through training.”[1]Milestones are based on the six core competencies established by the ACGME and American Board of Medical Specialties(ABMS),which consist of medical knowledge(MK),patient care(PC),interpersonal and communication skills(ICS),practice-based learning and improvement(PBLI),professionalism(PROF),and systems-based practice(SBP).[2,3]ACGME,in conjunction with the American Board of Emergency medicine(ABEM),drafted 23 detailed subcompetencies relevant to emergency medicine(EM).[4]

关键词： Miles milestone education

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Fangji Fuling Decoction Alleviates Sepsis by Blocking MAPK14/FOXO3A Signaling Pathway

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Chinese Journal of Integrative medicine 2024年第3期30卷 230-242页

作者： WANG Yi CHEN Ming-qi DAI Lin-feng ZHANG Hai-dong WANG Xing department of Critical Care medicine Changzhou Hospital of Traditional of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineChangzhouJiangsu Province213000China department of Critical Care medicine Jiangsu Province Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineNanjing210029China

Objective:To examine the therapeutic effect of Fangji Fuling Decoction(FFD) on sepsis through network pharmacological analysis combined with in vitro and in vivo ***:A sepsis mouse model was constructed through intraperitoneal injection of 20 mg/kg lipopolysaccharide(LPS).RAW264.7 cells were stimulated by 250 ng/m L LPS to establish an in vitro cell *** pharmacology analysis identified the key molecular pathway associated with FFD in *** ectopic expression and depletion experiments,the effect of FFD on multiple organ damage in septic mice,as well as on cell proliferation and apoptosis in relation to the mitogen-activated protein kinase 14/Forkhead Box O 3A(MAPK14/FOXO3A) signaling pathway,was ***:FFD reduced organ damage and inflammation in LPS-induced septic mice and suppressed LPS-induced macrophage apoptosis and inflammation in vitro(P<0.05).Network pharmacology analysis showed that FFD could regulate the MAPK14/FOXO signaling pathway during *** confirmed by in vitro cell experiments,FFD inhibited the MAPK14 signaling pathway or FOXO3A expression to relieve LPS-induced macrophage apoptosis and inflammation(P<0.05).Furthermore,FFD inhibited the MAPK14/FOXO3A signaling pathway to inhibit LPS-induced macrophage apoptosis in the lung tissue of septic mice(P<0.05).Conclusion:FFD could ameliorate the LPS-induced inflammatory response in septic mice by inhibiting the MAPK14/FOXO3A signaling pathway.

关键词： sepsis Fangji Fuling Decoction mitogen-activated protein kinase 14/Forkhead Box O 3A signaling pathway inflammatory response apoptosis lung injury Chinese medicine

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Neuroprotective effects of chaperone-mediated autophagy in neurodegenerative diseases

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Neural Regeneration Research 2024年第6期19卷 1291-1298页

作者： Qi Jia Jin Li Xiaofeng Guo Yi Li You Wu Yuliang Peng Zongping Fang Xijing Zhang department of Anesthesiology and Perioperative medicine and department of Intensive Care Unit Xijing Hospital The Fourth Military Medical University department of Critical Care medicine Translational Research Institute of Brain and Brain-Like Intelligence Shanghai Fourth People's Hospital School of Medicine Tongji University

Chaperone-mediated autophagy is one of three types of autophagy and is characterized by the selective degradation of proteins. Chaperone-mediated autophagy contributes to energy balance and helps maintain cellular homeostasis, while providing nutrients and support for cell survival. Chaperone-mediated autophagy activity can be detected in almost all cells, including neurons. Owing to the extreme sensitivity of neurons to their environmental changes, maintaining neuronal homeostasis is critical for neuronal growth and survival. Chaperone-mediated autophagy dysfunction is closely related to central nervous system diseases. It has been shown that neuronal damage and cell death are accompanied by chaperone-mediated autophagy dysfunction. Under certain conditions, regulation of chaperone-mediated autophagy activity attenuates neurotoxicity. In this paper, we review the changes in chaperone-mediated autophagy in neurodegenerative diseases, brain injury, glioma, and autoimmune diseases. We also summarize the most recent research progress on chaperone-mediated autophagy regulation and discuss the potential of chaperone-mediated autophagy as a therapeutic target for central nervous system diseases.

关键词： chaperone-mediated autophagy neurodegenerative disease neuronal homeostasis neuroprotection

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Identifying the effective combination of acupuncture and traditional Chinese medicinal herbs for postmenopausal osteoporosis therapy through studies of their molecular regulation of bone homeostasis

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Journal of Traditional Chinese medicine 2024年第1期44卷 212-219页

作者： REN Ping WANG Quanwu BAI Wei SUN Miao LIU Zheling GAO Ming WANG Liang PENG Bo XU Liguang department of Health Management the Third Affiliated Clinical Hospital of Changchun University of Chinese MedicineChangchun 130117China department of Dirty Tuina the affiliated Hospital to Changchun University of Chinese MedicineChangchun 130117China department of Acupuncture the affiliated Hospital to Changchun University of Chinese MedicineChangchun 130117China department of Rehabilitation medicine the 924th Hospital of the PLA Joint Logistic Support ForceFoshan 528226China department of College of Acupuncture and Massage Changchun University of Chinese MedicineChangchun 130117China

Worldwide,as the population age,osteoporosis is becoming increasingly common,and osteoporotic fractures have a significant economic *** women are the most susceptible to developing osteoporosis and the most critical time to prevent it is during the perimenopausal and early menopausal *** this regard,we hypothesize rational combination of acupuncture and Traditional Chinese medicine(TCM)in the form of herbal extract could prevent osteoporosis in *** deficiency during menopause causes low-level inflammation that stimulates the formation of osteoclasts,the boneresorbing cells,and simultaneously inhibits the viability and function of osteoblasts,the bone-forming *** most potent inflammatory cytokine in skeletal homeostasis is the receptor activator of nuclear factor kappa B ligand(RANKL)that stimulates osteoclast ***,the canonical Wnt pathway is essential for osteoblastogenesis and bone formation,and estrogen deficiency leads to diminished functioning of this *** and acupuncture could target the RANKL and the Wnt pathway in favorable ways to prevent the accelerated bone loss experienced during the early menopausal stage and promote the gain in bone mass in postmenopausal *** this review,we propose a rational combination of specific TCM and acupuncture targeting those signaling molecules/pathways by the drugs that are in clinical use for the treatment of postmenopausal *** rational approach revealed that Danshen(Radix Salviae Miltiorrhizae)could exert a synergistic effect with *** then propose a translational path for developing the putative combination in women with postmenopausal osteoporosis to curtail the risk of osteoporotic fractures.

关键词： medicine traditional osteogenic anti-resorptive review

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Effects of mesenchymal stem cell on dopaminergic neurons,motor and memory functions in animal models of Parkinson's disease:a systematic review and meta-analysis

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Neural Regeneration Research 2024年第7期19卷 1584-1592页

作者： Jong Mi Park Masoud Rahmati Sang Chul Lee Jae Il Shin Yong Wook Kim department and Research Institute of Rehabilitation medicine Yonsei University College of MedicineSeoulSouth Korea department of Physical Education and Sport Sciences Faculty of Literature and Human SciencesLorestan UniversityKhoramabadIran department of Pediatrics Yonsei University College of MedicineSeoulSouth Korea

Parkinson’s disease is chara cterized by the loss of dopaminergic neurons in the substantia nigra pars com pacta,and although restoring striatal dopamine levels may improve symptoms,no treatment can cure or reve rse the disease *** cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson’s *** stem cells are considered a promising option due to fewer ethical concerns,a lower risk of immune rejection,and a lower risk of *** performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function,memory,and preservation of dopamine rgic neurons in a Parkinson’s disease animal *** searched bibliographic databases(PubMed/MEDLINE,Embase,CENTRAL,Scopus,and Web of Science)to identify articles and included only pee r-reviewed in vivo interve ntional animal studies published in any language through J une 28,*** study utilized the random-effect model to estimate the 95%confidence intervals(CI)of the standard mean differences(SMD)between the treatment and control *** use the systematic review center for laboratory animal expe rimentation’s risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment.A total of 33studies with data from 840 Parkinson’s disease model animals were included in the *** with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational *** the stem cell types,the bone marrow MSCs with neurotrophic factor group showed la rgest effect size(SMD[95%CI]=-6.21[-9.50 to-2.93],P=0.0001,I^(2)=0.0%).The stem cell treatment group had significantly more tyrosine hydroxylase positive dopamine rgic neurons in the striatum([95%CI]=1.04[0.59 to 1.49],P=0.0001,I^(2)=65.1%)and substantia nigra(SMD[95%CI]=1.38[0.89 to 1.87],P=0.0001,I^(2)=75.3%),indicating a

关键词： animal animal experimentation mesenchymal stem cells models Parkinson’s disease stem cell transplantation

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