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The gasdermin family:emerging therapeutic targets in diseases

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1905-1937页

作者： Chenglong Zhu Sheng Xu Ruoyu Jiang Yizhi Yu Jinjun Bian Zui Zou Faculty of Anesthesiology Changhai HospitalNaval Medical UniversityShanghai 200433China School of Anesthesiology Naval Medical UniversityShanghai 200433China national key laboratory of immunity&inflammation Naval Medical UniversityShanghai 200433China d 4 Department of Biochemistry and Molecular Biology College of Basic Medical SciencesNaval Medical UniversityShanghai 200433China

The gasdermin(GSDM)family has garnered significant attention for its pivotal role in immunity and disease as a key player in *** recently characterized class of pore-forming effector proteins is pivotal in orchestrating processes such as membrane permeabilization,pyroptosis,and the follow-up inflammatory response,which are crucial self-defense mechanisms against irritants and *** have been implicated in a range of diseases including,but not limited to,sepsis,viral infections,and cancer,either through involvement in pyroptosis or independently of this *** regulation of GSDM-mediated pyroptosis is gaining recognition as a promising therapeutic strategy for the treatment of various *** strategies for inhibiting GSDMD primarily involve binding to GSDMD,blocking GSDMD cleavage or inhibiting GSDMD-N-terminal(NT)oligomerization,albeit with some off-target *** this review,we delve into the cutting-edge understanding of the interplay between GSDMs and pyroptosis,elucidate the activation mechanisms of GSDMs,explore their associations with a range of diseases,and discuss recent advancements and potential strategies for developing GSDMD inhibitors.

关键词： diseases therapeutic immunity

Advances in the study of mitophagy in osteoarthritis

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第3期25卷 197-211页

作者： Hong CAO Xuchang ZHOU Bowen XU Han HU Jianming GUO Miao WANG Nan LI Jun ZOU Department of Sport Rehabilitation Shanghai University of SportShanghai 200438China national key laboratory of immunity and inflammation Naval Medical UniversityShanghai 200433China School of Sport Medicine and Rehabilitation Beijing Sport UniversityBeijing 100084China

Osteoarthritis(OA),characterized by cartilage degeneration,synovial inflammation,and subchondral bone remodeling,is among the most common musculoskeletal disorders globally in people over 60 years of *** initiation and progression of OA involves the abnormal metabolism of chondrocytes as an important pathogenic *** degeneration features mitochondrial dysfunction as one of the important causative factors of abnormal chondrocyte ***,maintaining mitochondrial homeostasis is an important strategy to mitigate *** is a vital process for autophagosomes to target,engulf,and remove damaged and dysfunctional mitochondria,thereby maintaining mitochondrial *** studies have revealed a strong association between mitophagy and OA,suggesting that the regulation of mitophagy may be a novel therapeutic direction for *** reviewing the literature on mitophagy and OA published in recent years,this paper elaborates the potential mechanism of mitophagy regulating OA,thus providing a theoretical basis for studies related to mitophagy to develop new treatment options for OA.

关键词： Mitophagy Osteoarthritis Chondrocyte Mitochondria Apoptosis

Nutritional competition within tumor microenvironment dictates anti-tumor immunity

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national Science Review 2024年第2期11卷 98-100页

作者： Yankang Fei Xuetao Cao Juan Liu national key laboratory of immunity and inflammation Institute of Immunology Naval Medical University Department of Immunology Chinese Academy of Medical Sciences Institute of Immunology College of Life Sciences Nankai University

The crosstalk between metabolism and immunity has emerged as an essential regulator of tumor immune escape, and targeting immunometabolic pathways holds great potential for cancer immunotherapy [1]. Abnormal metabolic...

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Recombinant adeno-associated virus 8-mediated inhibition of microRNA let-7a ameliorates sclerosing cholangitis in a clinically relevant mouse model

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World Journal of Gastroenterology 2024年第5期30卷 471-484页

作者： Hui Hua Qian-Qian Zhao Miriam Nkesichi Kalagbor Guo-Zhi Yu Man Liu Zheng-Rui Bian Bei-Bei Zhang Qian Yu Yin-Hai Xu Ren-Xian Tang Kui-Yang Zheng Chao Yan Jiangsu key laboratory of immunity and Metabolism Department of Pathogenic Biology and ImmunologyNational Demonstration Center for Experimental Basic Medical Science EducationLaboratory of Infection and ImmunityXuzhou Medical UniversityXuzhou 221004Jiangsu ProvinceChina Department of laboratory Medicine The Affiliated Hospital of Xuzhou Medical UniversityXuzhou 221002Jiangsu ProvinceChina

BACKGROUND Primary sclerosing cholangitis(PSC)is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment *** adeno-associated virus(rAAV)provides a promising platform for gene therapy on such kinds of diseases.A microRNA(miRNA)let-7a has been reported to be associated with the progress of PSC but the potential therapeutic implication of inhibition of let-7a on PSC has not been *** To investigate the therapeutic effects of inhibition of a miRNA let-7a transferred by recombinant adeno-associated virus 8(rAAV8)on a xenobiotic-induced mouse model of sclerosing *** A xenobiotic-induced mouse model of sclerosing cholangitis was induced by 0.1% 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine(DDC)feeding for 2 wk or 6 wk.A single dose of rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo into mice onset of DDC *** sacrifice,the liver and the serum were collected from each *** hepatobiliary injuries,hepatic inflammation and fibrosis were *** targets of let-7a-5p and downstream molecule NF-κB were detected using Western *** rAAV8-mediated anti-let-7a-5p sponges can depress the expression of let-7a-5p in mice after DDC feeding for 2 wk or 6 *** reduced expression of let-7a-5p can alleviate hepato-biliary injuries indicated by serum markers,and prevent the proliferation of cholangiocytes and biliary ***,inhibition of let-7a mediated by rAAV8 can increase the expression of potential target molecules such as suppressor of cytokine signaling 1 and Dectin1,which consequently inhibit of NF-κB-mediated hepatic *** Our study demonstrates that a rAAV8 vector designed for liver-specific inhibition of let-7a-5p can potently ameliorate symptoms in a xenobiotic-induced mouse model of sclerosing cholangitis,which provides a possible clinical translation of PSC of human.

关键词： Primary sclerosing cholangitis Recombinant adeno-associated virus 8 Let-7a-5p Therapeutic effects inflammation

An antibiotic-free platform for eliminating persistent Helicobacter pylori infection without disrupting gut microbiota

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3184-3204页

作者： Yongkang Lai Tinglin Zhang Xiaojing Yin Chunping Zhu Yiqi Du Zhaoshen Li Jie Gao Department of Gastroenterology Shanghai Changhai HospitalNaval Medical UniversityShanghai 200433China Changhai Clinical Research Unit Shanghai Changhai HospitalNaval Medical UniversityShanghai 200433China Department of Gastroenterology Ganzhou People’s Hospital Affiliated to Nanchang UniversityGanzhou 341000China national key laboratory of immunity and inflammation Naval Medical UniversityShanghai 200433China Shanghai key laboratory of Nautical Medicine and Translation of Drugs and Medical Devices Shanghai 200433China

Helicobacter pylori(***)infection remains the leading cause of gastric adenocarcinoma,and its eradication primarily relies on the prolonged and intensive use of two ***,antibiotic resistance has become a compelling health issue,leading to *** eradication treatment failure ***,the powerlessness of antibiotics against biofilms,as well as intracellular *** and the long-term damage of antibiotics to the intestinal microbiota,have also created an urgent demand for antibiotic-free ***,we describe an antibiotic-free,multifunctional copperorganic framework(HKUST-1)platform encased in a lipid layer comprising phosphatidic acid(PA),rhamnolipid(RHL),and cholesterol(CHOL),enveloped in chitosan(CS),and loaded in an ascorbyl palmitate(AP)hydrogel:AP@CS@Lip@*** platform targets inflammatory sites where *** aggregates through electrostatic ***,hydrolysis by matrix metalloproteinases(MMPs)releases CS-encased nanoparticles,disrupting bacterial urease activity and membrane ***,RHL disperses biofilms,while PA promotes lysosomal acidification and activates host autophagy,enabling clearance of intracellular ***,AP@CS@Lip@HKUST-1 alleviates inflammation and enhances mucosal repair through delayed Cu^(2+) release while preserving the intestinal ***,this platform presents an advanced therapeutic strategy for eradicating persistent *** infection without inducing drug resistance.

关键词： Helicobacter pylori infection Antibiotic-free Biofilms Autophagy Gastric mucosal repair Drug resistance Intestinal microbiota Anti-inflammation

The anti-inflammatory effects of exercise on autoimmune diseases:A 20-year systematic review

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Journal of Sport and Health Science 2024年第3期13卷 353-367,I0001页

作者： Beibei Luo Dao Xiang Xiaorong Ji Xuan Chen Rui Li Shuxin Zhang Yujun Meng David C.Nieman Peijie Chen School of Exercise and Health Shanghai University of SportShanghai 200438China Shanghai key laboratory of Human Performance Shanghai University of SportShanghai 200438China Department of Diving and Hyperbaric Medicine Naval Medical CenterShanghai 200433China national key laboratory of immunity and inflammation Naval Medical UniversityShanghai 200433China Human Performance laboratory Appalachian State UniversityNorth Carolina Research CampusKannapolisNC 28081USA Research Institute for Doping Control Shanghai University of SportShanghai 200438China

Background:The anti-inflammatory effect of exercise may be an underlying factor in improving several autoimmune *** aim of this systematic review was to examine the evidence on the role of exercise training in mitigating inflammation in adolescents and adults with autoimmune ***:PubMed,Web of Science,and Embase databases were systematically reviewed for related studies published between January 1,2003,and August 31,*** randomized and non-randomized controlled trials of exercise interventions with autoimmune disease study participants that evaluated inflammation-related biomarkers were *** quality of evidence was assessed using the Tool for the assEssment of Study qualiTy and reporting in EXercise scale and Cochrane bias risk ***:A total of 14,565 records were *** screening the titles,abstracts,and full texts,87 were eligible for the systematic *** studies were conducted in 25 different countries and included a total of 2779 participants(patients with autoimmune disease,in exercise or control groups).Overall,the evidence suggests that inflammation-related markers such as C-reactive protein,interleukin 6,and tumor necrosis factor a were reduced by regular exercise *** exercise interventions combined with multiple exercise modes were associated with greater ***:Regular exercise training by patients with autoimmune disease exerts an anti-inflammatory *** systematic review provides support for the promotion and development of clinical exercise intervention programs for patients with autoimmune *** patients with autoimmune disease can safely adopt moderate exercise training protocols,but changes in inflammation biomarkers will be modest at *** exercise interventions are ineffective or even modestly but transiently pro-inflammatory.

关键词： Autoimmune diseases Cytokines inflammation Physical activity Training

Current understanding of ELF4 deficiency:a novel inborn error of immunity

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World Journal of Pediatrics 2024年第5期20卷 444-450页

作者： Hong-Qiang Du Xiao-Dong Zhao Department of Rheumatology&Immunology National Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChongqing Key Laboratory of Child Rare Diseases in Infection and ImmunityChildren’s Hospital of Chongqing Medical UniversityZhongshan Er Road 136Yuzhong DistrictChongqingChina

Background ELF4 deficiency has been recently recognized as a novel disorder within the spectrum of inborn errors of immunity(IEIs),specifically categorized as a“disease of immune dysregulation.”Cases of this condition,reported by our team and others,are very limited *** such,our current knowledge of this new disease remains *** review aims to provide a brief overview of the clinical manifestations,pathogenesis,and treatment strategies for this novel *** sources A comprehensive review was conducted after an extensive literature search in the PubMed/Medline database and websites concerning transcriptional factor ELF4 and reports concerning patients with ELF4 *** search strategy was“ELF4 OR ETS-related transcription factor Elf-4 OR EL4-like factor 4 OR myeloid Elf-1-like factor”as of the time of manuscript *** The current signature manifestations of ELF4 deficiency disorder are recurrent and prolonged oral ulcer,abdominal pain,and diarrhea in pediatric *** some cases,immunodeficiency and autoimmunity can also be *** Sanger sequencing or whole exome sequencing can be used to detect variation in ELF4 *** blotting for ELF4 expression of the patient’s cells can confirm the pathogenic effect of the *** fully confirm the pathogenicity of the variant,further functional test is strongly *** and biologics are the mainstream management of ELF4 deficiency *** Pediatric males presenting with recurring ulcerations in digestive tract epithelium with or without recurrent fever should be suspected of *** atypical presentations are prominent,variations in ELF4 gene should be carefully evaluated functionally due to the complex nature of ELF4 *** of treating DEX includes use of glucocorticoid and biologics and more precise treatment needs more patients to identify and further mechanistic study.

关键词： ELF4 transcription factor Immune dysregulation Inborn errors of immunity Mechanism Recurrent infections

Eosinophils promote CD8+ T cell memory generation to potentiate anti-bacterial immunity

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1230-1243页

作者： Jun Zhou Jiaqi Liu Bingjing Wang Nan Li Juan Liu Yanmei Han Xuetao Cao Institute of Immunology Zhejiang University School of MedicineHangzhou 310058China national key laboratory of immunity and inflammation Institute of ImmunologyNaval Medical UniversityShanghai 200433China Department of Immunology Center for ImmunotherapyInstitute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing 100005China Institute of Immunology College of Life SciencesNankai UniversityTianjin 300071China

Memory CD8+T cell generation is crucial for pathogen elimination and effective vaccination against *** cellular and molecular circuitry that underlies the generation of memory CD8+T cells remains *** can modulate inflammatory allergic responses and interact with lymphocytes to regulate their functions in immune *** we report that eosinophils are required for the generation of memory CD8+T cells by inhibiting CD8+T cell ***-deficient mice display significantly impaired memory CD8+T cell response and weakened resistance against Listeria monocytogenes(L.m.)***,eosinophils secrete interleukin-4(IL-4)to inhibit JNK/Caspase-3 dependent apoptosis of CD8+T cells upon *** in ***,active eosinophils are recruited into the spleen and secrete more IL-4 to suppress CD8+T cell apoptosis during early stage of *** in *** transfer of wild-type(WT)eosinophils but not IL-4-deficient eosinophils into eosinophil-deficient mice could rescue the impaired CD8+T cell memory ***,our findings suggest that eosinophil-derived IL-4 promotes the generation of CD8+T cell memory and enhances immune defense against *** study reveals a new adjuvant role of eosinophils in memory T cell generation and provides clues for enhancing the vaccine potency via targeting eosinophils and related cytokines.

关键词： impaired immunity spleen

Metabolic plasticity of T cell fate decision

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Chinese Medical Journal 2024年第7期137卷 762-775页

作者： Xiaoli Pan Jiajia Wang Lianjun Zhang Guideng Li Bo Huang national key laboratory of immunity and inflammation Suzhou Institute of Systems MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeSuzhouJiangsu 215123China key laboratory of Synthetic Biology Regulatory Element Suzhou Institute of Systems MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeSuzhouJiangsu 215123China Department of Immunology&national key laboratory of Medical Molecular Biology Institute of Basic Medical SciencesChinese Academy of Medical Sciences(CAMS)&Peking Union Medical CollegeBeijing 100005China Department of Biochemistry&Molecular Biology Tongji Medical CollegeHuazhong University of Science&TechnologyWuhanHubei 430030China

The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T *** antigen exposure,T cells undergo metabolic reprogramming,leading to the development of functional effectors or memory ***,within the tumor microenvironment(TME),metabolic stress impairs CD8+T cell anti-tumor immunity,resulting in exhausted *** studies suggested that targeting T cell metabolism could offer promising therapeutic opportunities to enhance T cell *** this review,we provide a comprehensive summary of the intrinsic and extrinsic factors necessary for metabolic reprogramming during the development of effector and memory T cells in response to acute and chronic inflammatory ***,we delved into the different metabolic switches that occur during T cell exhaustion,exploring how prolonged metabolic stress within the TME triggers alterations in cellular metabolism and the epigenetic landscape that contribute to T cell exhaustion,ultimately leading to a persistently exhausted *** the intricate relationship between T cell metabolism and cancer immunotherapy can lead to the development of novel approaches to improve the efficacy of T cell-based treatments against cancer.

关键词： T cell immunotherapy T cell differentiation T cell exhaustion Metabolic reprogramming Tumor microenvironment