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Mitochondrial transplantation confers protection against the effects of ischemic stroke by repressing microglial pyroptosis and promoting neurogenesis

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Neural Regeneration Research 2024年第6期19卷 1325-1335页

作者： Li Sun Zhaoyan Zhao Jing Guo Yuan Qin Qian Yu Xiaolong Shi Fei Guo Haiqin Zhang Xude Sun Changjun Gao Qian Yang Department of Experimental Surgery The Second Affiliated Hospital of Air Force Medical University Department of Anesthesiology The Second Affiliated Hospital of Air Force Medical University

Transferring healthy and functional mitochondria to the lateral ventricles confers neuroprotection in a rat model of ischemia-reperfusion injury. Autologous mitochondrial transplantation is also beneficial in pediatric patients with cardiac ischemia-reperfusion injury. Thus, transplantation of functional exogenous mitochondria may be a promising therapeutic approach for ischemic disease. To explore the neuroprotective effect of mitochondria transplantation and determine the underlying mechanism in ischemic stroke, in this study we established a photo-thrombosis-induced mouse model of focal ischemia and administered freshly isolated mitochondria via the tail vein or to the injury site(in situ). Animal behavior tests, immunofluorescence staining, 2,3,5-triphenyltetrazolium chloride(TTC) staining, mRNA-seq, and western blotting were used to assess mouse anxiety and memory, cortical infarct area, pyroptosis, and neurogenesis, respectively. Using bioinformatics analysis, western blotting, co-immunoprecipitation, and mass spectroscopy, we identified S100 calcium binding protein A9(S100A9) as a potential regulator of mitochondrial function and determined its possible interacting proteins. Interactions between exogenous and endogenous mitochondria, as well as the effect of exogenous mitochondria on recipient microglia, were assessed in vitro. Our data showed that:(1) mitochondrial transplantation markedly reduced mortality and improved emotional and cognitive function, as well as reducing infarct area, inhibiting pyroptosis, and promoting cortical neurogenesis;(2) microglial expression of S100A9 was markedly increased by ischemic injury and regulated mitochondrial function;(3) in vitro, exogenous mitochondria enhanced mitochondrial function, reduced redox stress, and regulated microglial polarization and pyroptosis by fusing with endogenous mitochondria; and(4) S100A9 promoted internalization of exogenous mitochondria by the microglia, thereby amplifying their pro-prolifera

关键词： ischemic stroke microglia mitochondria transplantation neurogenesis pyroptosis

A Transformer-Based Ensemble Framework for the Prediction of Protein-Protein Interaction Sites

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Research 2024年第2期2023卷 703-718页

作者： Minjie Mou Ziqi Pan Zhimeng Zhou Lingyan Zheng Hanyu Zhang Shuiyang Shi Fengcheng Li Xiuna Sun Feng Zhu College of Pharmaceutical Sciences The Second Affliated HospitalZhejiang University School of MedicineNational Key Laboratory of Advanced Drug Delivery and Release SystemsZhejiang UniversityHangzhou 310058China Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University Alibaba-Zhejiang University Joint Research Center of Future Digital HealthcareHangzhou 330110China

The identification of protein-protein interaction (PPI) sites is essential in the research of protein function and the discovery of new drugs. So far, a variety of computational tools based on machine learning have been developed to accelerate the identification of PPI sites. However, existing methods suffer from the low predictive accuracy or the limited scope of application. Specifically, some methods learned only global or local sequential features, leading to low predictive accuracy, while others achieved improved performance by extracting residue interactions from structures but were limited in their application scope for the serious dependence on precise structure information. There is an urgent need to develop a method that integrates comprehensive information to realize proteome-wide accurate profiling of PPI sites. Herein, a novel ensemble framework for PPI sites prediction, EnsemPPIS, was therefore proposed based on transformer and gated convolutional networks. EnsemPPIS can effectively capture not only global and local patterns but also residue interactions. Specifically, EnsemPPIS was unique in (a) extracting residue interactions from protein sequences with transformer and (b) further integrating global and local sequential features with the ensemble learning strategy. Compared with various existing methods, EnsemPPIS exhibited either superior performance or broader applicability on multiple PPI sites prediction tasks. Moreover, pattern analysis based on the interpretability of EnsemPPIS demonstrated that EnsemPPIS was fully capable of learning residue interactions within the local structure of PPI sites using only sequence information. The web server of EnsemPPIS is freely available at http://***/ensemppis.

关键词： residue extracting ensemble

The role of proteasomes in tumorigenesis

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Genes & Diseases 2024年第4期11卷 155-169页

作者： Xiangyi Zhou Ruqing Xu Yue Wu Li Zhou Tingxiu Xiang Department of Oncology The First Affliated Hospital of Chongqing Medical UniversityChongqing 400016China Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment Chongqing University Cancer HospitalChongqing 400030China

Protein homeostasis is the basis of normal life activities,and the proteasomefamily plays an extremely important function in this *** proteasome 2os is a concentric circle structure with twoαrings and twoβrings *** proteasome 2os can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits(such as 19S,11S,and 200 PA),which is performed by its active subunitβ1,β2,andβ*** proteasome can degrade misfolded,excess proteins tomaintain *** the same time,it can be utilized by tumors to degrade over-proliferate and unwanted proteins to support their *** can affect the development of tumors from several aspects including tumor signaling pathways such as NF-kB and p53,cell cycle,immune regulation,and drug ***-encoding genes have been found to be overexpressed in a variety of tumors,providing a potential novel target for cancer *** addition,proteasome inhibitors such as bortezomib,carfilzomib,and ixazomib have been put into clinical application as the first-line treatment of multiple *** and more studies have shown that it also has different therapeutic effects in other tumors such as hepatocellular carcinoma,non-small cell lung cancer,glioblastoma,and ***,proteasome inhibitors are not much effective due to their tolerance and singleness in other ***,further studies on their mechanisms of action and drug interactions are needed to investigate their therapeutic potential.

关键词： Bortezomib Cancer therapy Immunoproteasome Multiplemyeloma Proteasome 20S Proteasome inhibitor Thymoproteasom

Single-cell transcriptomic analysis reveals transcript enrichment in oxidative phosphorylation,fluid sheer stress,and inflammatory pathways in obesity-related glomerulopathy

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Genes & Diseases 2024年第4期11卷 314-326页

作者： Yinyin Chen Yushun Gong Jia Zou Guoli Li Fan Zhang Yiya Yang Yumei Liang Wenni Dai Liyu He Hengcheng Lu Department of Nephrology Hunan Provincial People's HospitalThe First Affliated Hospital of Hunan Normal UniversityHunan Clinical Research Center for Chronic Kidney DiseaseChangshaHunan 410000China Department of Nephrology The Second Xiangya Hospital of Central South UniversityHunan Key Laboratory of Kidney Disease and Blood PurificationChangshaHunan 410011China Cardiovascular Research Institute of Jiangxi Province Jiangxi Provincial People's HospitalThe First Affiliated Hospital of Nanchang Medical CollegeNanchangJiangxi 330006China

Obesity-related glomerulopathy(ORG)is an independent risk factor for chronic kid-ney disease and even progression to end-stage renal *** have been undertaken to elucidate the mechanisms underlying the development of ORG and substantial advances have been made in the treatment of ORG,but relatively little is known about cell-specific changes in gene *** define the transcriptomic landscape at single-cell resolution,we analyzed kidney samples from four patients with ORG and three obese control subjects without kidney disease using single-cell RNA *** report for the first time that immune cells,including T cells and B cells,are decreased in ORG *** analysis indicated that SPP1 was significantly up-regulated in T cells and B *** gene is related to inflammation and cell *** of differential gene expression in glomerular cells(endothelial cells,mesangial cells,and podocytes)showed that these cell types were mainly enriched in genes related to oxidative phosphorylation,cell adhesion,thermogenesis,and inflammatory pathways(PI3K-Akt signaling,MAPK signaling).Furthermore,we found that the podocytes of ORG patients were enriched in genes related to the fluid shear stress ***,an evaluation of cell-cell communications revealed that there were interactions between glomerular parietal epithelial cells and other cells in ORG patients,with major interactions between parietal epithelial cells and ***,our identification of molecular events,cell types,and differentially expressed genes may facilitate the development of new preventive or therapeutic approaches for ORG.

关键词： Fluid shear stress Inflammation Obesity-related glomerulopathy Oxidative phosphorylation Single-cell RNA seq

Exogeneous metal ions as therapeutic agents in cardiovascular disease and their delivery strategies

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Regenerative Biomaterials 2024年第2期3卷 1-16页

作者： Xiaoqian Hong Geer Tian Yang Zhu Tanchen Ren Department of Cardiology of the second affliated hospital and State Key Laboratory of Transvascular Implantation Devices Cardiovascular Key Laboratory of Zhejiang ProvinceZhejiang University School of MedicineHangzhou 310o09China Binjiang Institute of Zhejiang University Hangzhou 310053China MOE Key Laboratory of Macromolecular Synthesis and Functionalization Department of Polymer Science and EngineeringZhejiang UniversityHangzhou 310027China

Metal ions participate in many metabolic processes in the human body,and their homeostasis is crucial for *** cardiovascular diseases(CVDs),the equilibriums of metal ions are frequently interrupted,which are related to a variety of disturbances of physiological processes leading to abnormal cardiac *** supplement of metal ions has the potential to work as therapeutic strategies for the treatment of *** with other therapeutic drugs,metal ions possess broad availability,good stability and safety and diverse drug delivery *** delivery strategies of metal ions are important to exert their ther-apeutic effects and reduce the potential toxic side effects for cardiovascular applications,which are also receiving increasing *** local delivery strategies for metal ions based on various biomaterials are constantly being *** this review,we comprehensively summarized the positive roles of metal ions in the treatment of cVDs from three aspects:protecting cells from oxidative stress,inducing angiogenesis,and adjusting the functions of ion *** addition,we introduced the transferability of metal ions in vascular reconstruction and cardiac tissue repair,as well as the currently available engineered strategies for the precise delivery of metal ions,such as integrated with nanoparticles,hydrogels and scaffolds.

关键词： metal ions cardiovascular disease tissue engineering oxidative stress angiogenesis ion channel

New roles of tumor-derived exosomes in tumor microenvironment

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Chinese Journal of Cancer Research 2024年第2期36卷 151-166页

作者： Shiqian Chen Jinzhe Sun Huan Zhou Hongbin Lei Dan Zang Jun Chen Department of Oncology the Second Hospital of Dalian Medical UniversityDalian 116023China Department of Radiotherapy the Second Hospital of Dalian Medical UniversityDalian 116023China

Throughout tumorigenesis, the co-evolution of tumor cells and their surrounding microenvironment leads to the development of malignant phenotypes. Cellular communication within the tumor microenvironment(TME) plays a critical role in influencing various aspects of tumor progression, including invasion and metastasis. The release of exosomes, a type of extracellular vesicle, by most cell types in the body, is an essential mediator of intercellular communication. A growing body of research indicates that tumor-derived exosomes(TDEs) significantly expedite tumor progression through multiple mechanisms, inducing epithelial-mesenchymal transition and macrophage polarization, enhancing angiogenesis, and aiding in the immune evasion of tumor cells. Herein, we describe the formation and characteristics of the TME, and summarize the contents of TDEs and their diverse functions in modulating tumor development. Furthermore, we explore potential applications of TDEs in tumor diagnosis and treatment.

关键词： Tumor-derived exosomes tumorigenesis tumor microenvironment diagnosis treatment

Increased N6-methyladenosine is related to the promotion of the methyltransferase METTL14 in ovarian aging

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Genes & Diseases 2024年第3期11卷 151-154页

作者： Chunfeng Qian Zhenxing Liu Yonghong Qian Jie Ding Rulei Chen Han Su Minghong Shen Hong Li Boxian Huang State Key Laboratory of Reproductive Medicine and Offspring Health Suzhou Affliated Hospital of Nanjing Medicine and Offspring HealthSuzhou Affiliated Hospital of Nanjing Medical UniversitySuzhouMunicipal HospitalGusu SchoolNanjing Medical UniversitySuzhouJiangsu 215002China Department of Gynecology Affliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Municipal HospitalGusu School of Nanjing Medical UniversitySuzhouJiangsu 215002China Department of Pathology Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou Municipal HospitalGusu School of Nanjing Medical UniversitySuzhouJiangsu 215002China

The ovary is a vital female reproductive organ that functions to produce oocyte gametes and cyclically expressed sex hormones to maintain reproductive capacity and hormone *** aging,characterized by declines in follicle quantity and oocyte quality,leads to premature ovarian failure,premature ovarian insufficiency,or diminished ovarian reserve,thus contributing to female *** gene-expression signatures from RNA transcriptional level and post-transcriptional regulation are relative to oocyte quality and reproductive age.

关键词： promotion signature maintain

Recent advances in promising drugs for primary prevention of gastroesophageal variceal bleeding with cirrhotic portal hypertension

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Hepatobiliary & Pancreatic Diseases International 2024年第1期23卷 4-13页

作者： Ji-Yao Sheng Zi-Fan Meng Qiao Li Yong-Sheng Yang Department of Hepatobiliary and Pancreatic Surgery the Second Hospital of Jilin UniversityChangchun 130041China Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases the Second Hospital of Jilin UniversityChangchun 130041China

Background:Gastroesophageal variceal bleeding is one of the most severe complications of patients with *** primary prevention drugs,including non-selectiveβ-blockers,have effectively reduced the incidence of bleeding,their efficacy is limited due to side effects and related *** recent advances in precision medicine,precise drug treatment provides better treatment *** sources:Literature search was conducted in PubMed,MEDLINE and Web of Science for relevant articles published up to May *** on clinical trials was obtained from https://***/and http://***/.Results:The in-depth understanding of the pathogenesis and advances of portal hypertension has enabled the discovery of multiple molecular targets for promising *** to the site of action,these drugs could be classified into four classes:intrahepatic,extrahepatic,both intrahepatic and extrahepatic targets and *** these classes of drugs offer advantages over traditional treatments in prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal ***:This review classified and summarized the promising drugs,which prevent gastroesophageal variceal bleeding by targeting specific markers of pathogenesis of portal hypertension,demonstrating the significance of using the precision medicine strategy to discover and develop promising drugs for the primary prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.

关键词： Cirrhotic portal hypertension Target drug Primary prevention Bleeding

Dry eye disease in systemic lupus erythematosus: a cross sectional study

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International Journal of Ophthalmology(English edition) 2024年第7期17卷 1255-1261页

作者： Sui-Fang Kang Ying-Xue Wang Qi-Chen Zhang Zhi-Lun Wang Guo-Ling Chen Department of Ophthalmology the Second Hospital of Shandong UniversityJinan 250033Shandong ProvinceChina Department of Rheumatology the Second Hospital of Shandong UniversityJinan 250033Shandong ProvinceChina

AIM:To explore ocular surface manifestations of dry eye disease(DED)and its influencing factors in systemic lupus erythematosus(SLE)***:Ophthalmological examinations were conducted in SLE patients(n=43)and controls(n=41),including Ocular Surface Disease Index(OSDI),objective scatter index(OSI),tear meniscus height(TMH),lipid layer thickness(LLT),non-invasive Keratograph tear breakup time(NIKBUT),corneal fluorescein score(CFS),Schirmer I *** was diagnosed according to the Tear Film and Ocular Surface Society Dry Eye Workshop II *** patients were further divided into DED group and non-DED group,the disease activity,clinical manifestations and laboratory investigations were compared between the two *** disease activity was evaluated by Systemic Lupus Erythematosus Disease Activity Index 2000(SLEDAI-2K).Receiver operative characteristic(ROC)curve and multiplefactor binary logistic regression were ***:SLE patients showed higher OSDI[9.1(2.8-15.9)vs 6.3(2.2-7.5),P=0.035],higher OSI[1.67(1.09-2.60)vs 0.96(0.87-1.60),P=0.001],higher CFS[1(0-2)vs 0(0-1),P=0.001],lower LLT[65(42-100)vs 100(79.5-100),P=0.010],and lower NIKBUT[8.03(4.02-9.73)vs 9.67(5.26-12.71),P=0.030]than *** 32.6%of SLE patients had DED,which was higher than 12.2%of healthy *** group showed higher SLEDAI-2K score[9.7±6.1 vs 5.4±3.4,P=0.025],higher anti-cardiolipin antibody(ACL)[8.7(3.5-13.2)vs 3.6(2.0-6.9),P=0.035],and higher proportion of patients with cutaneous eruption[42.9%vs 6.9%,P=0.015]than non-DED *** to multiple-factor binary logistic regression analysis,the SLEDAI-2K score(OR=1.194,P=0.041)and cutaneous eruption(OR=7.094,P=0.045)could be consider as risk factors for DED in SLE *** ROC curve of the combined factors including age,disease duration,SLEDAI-2K score,ACL,and cutaneous eruption was analyzed,with a sensitivity of 0.786,a specificity of 0.793,and an area under curve of ***:Ocular surface affec

关键词： autoimmune disease systemic lupus erythematosus dry eye disease