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Pathology of pain and its implications for therapeutic interventions

Signal Transduction and Targeted Therapy 2024年第7期9卷 2851-2899页

作者： Bo Cao Qixuan Xu Yajiao Shi Ruiyang Zhao Hanghang Li Jie Zheng Fengyu Liu You Wan Bo Wei Department of General Surgery First Medical CenterChinese PLA General HospitalBeijing 100853China medical School of Chinese PLA Beijing 100853China Neuroscience research institute and Department of Neurobiology School of Basic Medical SciencesKey Laboratory for NeuroscienceMinistry of Education/National Health CommissionPeking UniversityBeijing 100191China

Pain is estimated to affect more than 20%of the global population,imposing incalculable health and economic *** pain management is crucial for individuals suffering from ***,the current methods for pain assessment and treatment fall short of clinical *** from advances in neuroscience and biotechnology,the neuronal circuits and molecular mechanisms critically involved in pain modulation have been *** research achievements have incited progress in identifying new diagnostic and therapeutic *** this review,we first introduce fundamental knowledge about pain,setting the stage for the subsequent *** review next delves into the molecular mechanisms underlying pain disorders,including gene mutation,epigenetic modification,posttranslational modification,inflammasome,signaling pathways and *** better present a comprehensive view of pain research,two prominent issues,sexual dimorphism and pain comorbidities,are discussed in detail based on current *** status quo of pain evaluation and manipulation is summarized.A series of improved and innovative pain management strategies,such as gene therapy,monoclonal antibody,brain-computer interface and microbial intervention,are making strides towards clinical *** highlight existing limitations and future directions for enhancing the quality of preclinical and clinical *** to decipher the complexities of pain pathology will be instrumental in translating scientific discoveries into clinical practice,thereby improving pain management from bench to bedside.

关键词： pain thereby summarized

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Tirofiban combined with Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction (STRATEGY): protocol for a multicentre, randomised controlled trial

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Stroke & Vascular Neurology 2024年第1期9卷 75-81,I0047-I0052页

作者： Xiaoling Liao Shuo Feng Yicong Wang Yuesong Pan Weiqi Chen Hui Qu Xingquan Zhao Liping Liu Yongjun Wang Yilong Wang Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina China National Clinical research Center for Neurological Diseases Beijing TiantanHospitalCapital Medical UniversityBeijingChina Chinese institute for Brain research BeijingChina National Center for Neurological Diseases BeijingChina Advanced Innovation Center for Human Brain Protection Capital Medical UniversityBeijingChina Beijing Laboratory of Oral health Capital Medical UniversityBeijingChina

Background Perforating artery territorial infarction(PAI)caused by branch atheromatous disease(BAD)is prone to recurrence and early progression without an effective and well-documented antiplatelet treatment ***,an adjunctive antiplatelet agent,has shown great potential to treat acute ischaemic ***,whether the combination of tirofiban and aspirin can improve the prognosis of PAI remains *** To explore an effective and safe antiplatelet regimen for reducing the risk of recurrence and early neurological deterioration(END)in PAI caused by BAD by comparing the tirofiban and aspirin combination with placebo and aspirin *** Tirofiban combined with Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction(STRATEGY)trial is an ongoing multicentre,randomised,placebo-controlled trial in *** patients shall be randomly assigned to receive standard aspirin with tirofiban or placebo on the first day and standard aspirin from days 2 to *** primary endpoint is a new stroke or END within 90 *** primary safety endpoint is severe or moderate bleeding within 90 *** The STRATEGY trial will assess whether tirofiban combined with aspirin is effective and safe in preventing recurrence and END in patients with *** registration number NCT05310968.

关键词： Aspirin regimen centre

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Ciclopirox inhibits SARS-CoV-2 replication by promoting the degradation of the nucleocapsid protein

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2505-2519页

作者： Xiafei Wei Yuzheng Zhou Xiaotong Shen Lujie Fan Donglan Liu Xiang Gao Jian Zhou Yezi Wu Yunfei Li Wei Feng Zheng Zhang institute for Hepatology National Clinical Research Center for Infectious DiseaseShenzhen Third People's HospitalSouthern University of Science and TechnologyShenzhen 518112China Guangzhou Laboratory Guangzhou Medical UniversityGuangzhou 511495China State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China

The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long *** its vital role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)assembly and host inflammatory response,it remains an unexplored target for drug *** this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell *** significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP *** induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower *** condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP *** results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.

关键词： SARS-CoV-2 Nucleocapsid protein Viral replication Ciclopirox Abnormal aggregation Protein degradation Autophagy-lysosome Drug target

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The lactylation index predicts the immune microenvironment and prognosis of pan-cancer patients

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BIOCELL 2024年第8期48卷 1223-1239页

作者： XUEJIA ZHAI JIE LIU JINWEI XIAO TAO ZHANG JUN WANG JIANJUN LI SHICANG YU Department of Oncology Southwest HospitalThird Military Medical University(Army Medical University)Chongqing400038China Department of Stem Cell and Regenerative Medicine Institute of Pathology and Southwest Cancer CenterSouthwest HospitalThird Military Medical University(Army Medical University)Chongqing400038China Key Laboratory of cancer Immunopathology Ministry of EducationChongqing400038China International Joint research Center for Precision Biotherapy Ministry of Science and TechnologyChongqing400038China Jin-feng Laboratory Chongqing401329China

Background:Protein lactylation is a new way for the“metabolic waste”lactic acid to perform novel ***,our understanding of the contribution of protein lactylation to both tumor progression and therapeutic interventions remains *** construction of a scoring system for lactylation to predict the prognosis of pancancer patients and to evaluate the tumor immune microenvironment(TIME)would improve our understanding of the clinical significance of ***:Consensus clustering analysis of lactylation-related genes was used to cluster 177 pancreatic adenocarcinoma(PAAD)***,a scoring system was developed using the least absolute shrinkage and selection operator(LASSO)*** validation and external validation were both conducted to assess and confirm the predictive accuracy of the scoring ***,leucine rich repeat containing 1(LRRC1),a newly discovered lactylation-related gene,was analyzed in PAAD in ***:Utilizing the profiles of 332 lactylation-related genes,a total of 177 patients with PAAD were segregated into two distinct ***^(high) patients had a poorer prognosis than LacCluster^(low) *** the differential analysis between the LacCluster^(high) and LacCluster^(low) groups,we identified additional genes associated with *** genes were then integrated to construct the LacCluster-enhanced system,which enabled more accurate prognosis prediction for patients with ***,a lactylation index containing three genes(LacI-3)was constructed using LASSO *** was done to enhance the usability of the LacCluster-enhanced system in the *** to those in the LacI-3^(high) subgroup,patients in the LacI-3^(low) subgroup exhibited increased expression of immune checkpoint-related genes,more immune cell infiltration,lower tumor mutation burdens,and better prognoses,indicating a“hot tumor”***,knocking down the expression of LRRC1,

关键词： Pancreatic adenocarcinoma Pan-cancer Lactylation Prognosis Tumor immune microenvironment LRRC1

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TOPK Inhibition Enhances the Sensitivity of Colorectal cancer Cells to Radiotherapy by Reducing the DNA Damage Response

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Current medical Science 2024年第3期44卷 545-553页

作者： Shi-gui PANG Xin ZHANG Zhao-xin LI Li-fei HE Feng CHEN Ming-long LIU Ying-ze HUANG Jian-mei MO Kong-lan LUO Juan-juan XIAO Feng ZHU Department of Oncology The Affiliated Hospital of Guilin Medical UniversityGuilin541001China cancer research institute The Affiliated Hospital of Guilin Medical UniversityGuilin541001China Translational medical Center Huaihe HospitalHenan UniversityKaifeng475000China Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair The Affiliated Hospital of Guilin Medical UniversityGuilin541001China

Objective Abnormal expression of T-lymphokine-activated killer cell-originated protein kinase(TOPK)was reported to be closely related to the resistance of prostate cancer to radiotherapy and to targeted drug resistance in lung ***,the role of TOPK inhibition in enhancing radiosensitivity of colorectal cancer(CRC)cells is *** study aimed to evaluate the radiosensitization of TOPK knockdown in CRC *** The expression of TOPK was detected in CRC tissues by immunohistochemistry,and the effect of TOPK knockdown was detected in CRC cells by Western ***-8 and clonogenic assays were used to detect the growth and clonogenic ability of CRC cells after TOPK knockdown combined with radiotherapy in CRC ***,proteomic analysis showed that the phosphorylation of TOPK downstream proteins changed after *** damage was detected by the comet *** in the DNA damage response signaling pathway were analyzed by Western blotting,and apoptosis was detected by flow *** The expression of TOPK was significantly greater in CRC tissues at grades 2–4 than in those at grade *** irradiation,CRC cells with genetically silenced TOPK had shorter comet tails and reduced expression levels of DNA damage response-associated proteins,including phospho-cyclin-dependent kinase 1(p-CDK1),phospho-ataxia telangiectasia-mutated(p-ATM),poly ADP-ribose polymerase(PARP),and meiotic recombination 11 homolog 1(MRE11).Conclusions TOPK was overexpressed in patients with moderately to poorly differentiated ***,TOPK knockdown significantly enhanced the radiosensitivity of CRC cells by reducing the DNA damage response.

关键词： T-lymphokine-activated killer cell-originated protein kinase colorectal cancer DNA damage response radiosensitivity

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Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia

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Genes & Diseases 2024年第1期11卷 413-429页

作者： Dongsheng Zhang Wenjuan Tang Haitao Niu William Tse Hai-Bin Ruan Helmut Dolznig Thomas Knosel Friedrich Karl-Heinz Madeleine Themanns Jiang Wang Mingquan Song Lee Denson Lukas Kenner Richard Moriggl Yi Zheng Xiaonan Han Division of Hematology and Oncology Division of Cancer BiologyDepartment of MedicineMetroHealth Medical Center(MHMC)Case Western Reserve University(CWRU)School of MedicineClevelandOH 44109USA cancer Genomics and Epigenomics program Case Comprehensive Cancer CenterCase Western Reserve University(CWRU)ClevelandOH 44106USA Division of Gastroenterology Hepatology and NutritionCincinnati Children’s Hospital Medical Center(CCHMC)CincinnatiOH 45229USA Children’s Hospital of Fudan University Shanghai 201102China School of Medicine Jinan UniversityGuangzhouGuangdong 510632China Laboratory Animal Science(ILAS) Chinese Academy of Medical Science(CAMS)and Peking Union Medical College(PUMC)Beijing 100006China Department of Integrative Biology and Physiology University of Minnesota Medical SchoolMinneapolisMI 55455USA institute of medical Genetics Medical University of ViennaVienna 1040Austria institute of Pathology Ludwig-Maximilians-University MunichMunich 80539Germany institute of Biochemistry II University Hospital JenaJena 07743Germany Laboratory Animal Pathology University of Veterinary Medicine ViennaVienna 1210Austria Department of Pathology University of CincinnatiCincinnatiOH 45221USA Department of Gastroenterology The Affiliated Hospital of Qingdao UniversityQingdaoShandong 266005China Department of Pathology Medical University of ViennaVienna 1040Austria Ludwig Boltzmann institute for cancer research Vienna 1090Austria medical University of Vienna Vienna 1040Austria institute of Animal Breeding and Genetics University of Veterinary Medicine ViennaVienna 1210Austria Division of Experimental Hematology CCHMCCincinnatiOH 45229USA

CDC42 controls intestinal epithelial(IEC)stem cell(IESC)*** aberrant CDC42 initiates intestinal inflammation or neoplasia is *** utilized models of inflam-matory bowel diseases(IBD),colorectal cancer,aging,and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and *** specimens were collected to determine the levels of CDC42 in IBD or colorectal ***42 floxed mice were crossed with Villin-Cre,Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2,or Bmi1-CreERT2 mice to generate Cdc42 deficient ***,colitis,aging,and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation,IESC/progenitor regenerative capacity,and IEC *** studies revealed that increased CDC42 in colorectal cancer correlated with lower survival;in contrast,lower levels of CDC42 were found in the inflamed IBD *** Cdc42 depletion significantly reduced Lgr5+IEsCs,increased progenitors'hyperplasia,and induced mucosal inflammation,which led to crypt *** Cdc42 depletion markedly enhanced irra-diation-or chemical-induced *** or inhibition of Cdc42 reduced colonic Lgr5+IESC *** conclusion,depletion of Cdc42 reduces the IESC regeneration and IEC repair,leading to prolonged mucosal *** monogenic loss of Cdc42 in-duces mucosal inflammation,which could result in intestinal neoplasia in the context of aging.

关键词： Cell divisioncycle 42(CDC42) Colitis Colorectal cancer(CRC) Inflammatory bowel diseases(IBD) Intestinal epithelial cell(IEC) Intestinal epithelial stem cell(IESC) Irradiation

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Roles of THEM4 in the Akt pathway:a double-edged sword

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第7期25卷 541-556页

作者： Wen XIE Weidong LIU Lei WANG Bin ZHU Cong ZHAO Ziling LIAO Yihan LI Xingjun JIANG Jie LIU Caiping REN NHC Key Laboratory of Carcinogenesis Department of NeurosurgeryXiangya HospitalCentral South UniversityChangsha 410008China National Clinical research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangsha 410008China The Key Laboratory of Carcinogenesis and cancer Invasion of the Ministry of Education Cancer Research InstituteSchool of Basic Medical ScienceCentral South UniversityChangsha 410078China Department of Critical Care Medicine Hainan Hospital of Chinese PLA General HospitalHainan Province Clinical Medical CenterSanya 572013China

The protein kinase B(Akt)pathway can regulate the growth,proliferation,and metabolism of tumor cells and stem cells through the activation of multiple downstream target genes,thus affecting the development and treatment of a range of *** superfamily member 4(THEM4),a member of the thioesterase superfamily,is one of the Akt kinase-binding *** studies on the mechanism of cancers and other diseases have shown that THEM4 binds to Akt to regulate its ***,THEM4 was considered an endogenous inhibitor of Akt,which can inhibit the phosphorylation of Akt in diseases such as lung cancer,pancreatic cancer,and liver cancer,but subsequently,THEM4 was shown to promote the proliferation of tumor cells by positively regulating Akt activity in breast cancer and nasopharyngeal carcinoma,which contradicts previous *** these two distinct views,this review summarizes the important roles of THEM4 in the Akt pathway,focusing on THEM4 as an Akt-binding protein and its regulatory relationship with Akt phosphorylation in various diseases,especially *** work provides a better understanding of the roles of THEM4 combined with Akt in the treatment of diseases.

关键词： Protein kinase B(Akt) Thioesterase superfamily member 4(THEM4) Tumor proliferation Tumor metastasis

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Disulfiram ameliorates STING/MITA-dependent inflammation and autoimmunity by targeting RNF115

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Cellular & Molecular Immunology 2024年第3期21卷 275-291页

作者： Zhi-Dong Zhang Chang-Rui Shi Fang-Xu Li Hu Gan Yanhong Wei Qianhui Zhang Xin Shuai Min Chen Yu-Lin Lin Tian-Chen Xiong Xiaoqi Chen Bo Zhong Dandan Lin Department of Gastrointestinal Surgery Medical Research InstituteFrontier Science Center of Immunology and MetabolismZhongnan Hospital of Wuhan UniversityWuhan UniversityWuhan430071China Department of Virology College of Life SciencesWuhan UniversityWuhan430072China TaiKang Center for Life and medical Sciences Wuhan UniversityWuhan430071China Wuhan research Center for Infectious Diseases and cancer Chinese Academy of Medical SciencesWuhan430071China Department of Rheumatology and Immunology Zhongnan Hospital of Wuhan UniversityWuhan430071China cancer Center Renmin Hospital of Wuhan UniversityWuhan430060China

STING(also known as MITA)is an adaptor protein that mediates cytoplasmic DNA-triggered signaling,and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe ***,we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram(DSF).Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1^(–/–)mice and STING^(N153S/WT) bone marrow chimeric *** addition,knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α,IFN-γand proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus(SLE)who exhibit high concentrations of dsDNA in peripheral ***,knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1^(–/–)***,knockout of RNF115 inhibits the activation and Golgi localization of STINGN153S as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or *** together,these findings highlight the RNF115-mediated cell type-specific regulation of STING and STINGN153S and provide potential targeted intervention strategies for STING-related autoimmune diseases.

关键词： STING/MITA Disulfiram RNF115 SLE Autoimmunity

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Subsequent strategies and underlying mechanism of acquired resistance to PD-1 axis inhibitors in advanced non-small cell lung cancer

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Chinese medical Journal 2024年第7期137卷 880-882页

作者： Huilan Wang Xinyu Cheng Fan Yang Lu Chen Anmei Zhang Liangzhi Zhong Haixia Long Bo Zhu Zhongyu Wang institute of cancer Xinqiao HospitalThird Military Medical UniversityChongqing 400037China Chongqing Key Laboratory of Immunotherapy Chongqing 400037China

To the Editor:With the widespread application of immune checkpoint inhibitors(ICIs)in clinical practice,acquired resistance(AR)to programmed death-1(PD-1)/programmed death ligand 1(PD-L1)axis inhibitors in advanced nonsmall cell lung cancer(NSCLC)develops and limits the durability of *** is a clinical condition in which a patient initially responds to ICIs but relapses and progresses after a period of *** rates of AR have not been routinely reported in lung cancer but typically range from 12.9%to 64%.[1]However,studies on subsequent management strategies and the mechanism of AR to PD-1/PD-L1 axis inhibitors in lung cancer are *** main exploratory strategies are immunotherapy rechallenge and the combination of ICIs with other therapies,including local therapy,chemotherapy,antiangiogenetic treatment,and cytotoxic T lymphocyte antigen 4(CTLA-4)inhibitors.[2]The purpose of this study was to characterize the clinical patterns of AR and compare different subsequent therapies and outcomes in NSCLC patients after AR to PD-1/PD-L1 ***,we explored the underlying mechanism of AR by analyzing the alterations in next-generation sequencing(NGS)data before and after AR.

关键词： routine alterations resistance

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Molecular quantification of herbs(Herb-Q):a pyrosequencingbased approach and its application in Pinellia ternata

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Chinese Journal of Natural Medicines 2024年第7期22卷 663-672页

作者： PEI Yifei LIU Ziyi YU Dade ZHANG Xiangyu SUN Wei CHEN Xiaofang FENG Xue LI Xiwen institute of Chinese Materia Medica China Academy of Chinese Medical SciencesBeijing 100700China Bijie institute of Traditional Chinese Medicine Bijie 551700China The Key Laboratory for health Industry of Bijie Bijie Medical CollegeBijie 551700China

Variations in herb dosage due to species adulteration and dosing inaccuracies can substantially affect clinical safety and *** species quantification remains challenging,as current methods often yield inconsistent *** study introduces a novel pyrosequencing-based technique,termed herb molecular quantification(Herb-Q),designed to precisely quantify herbal *** evaluated its effectiveness using Pinellia ternata and five of its ***,we assessed commonly used DNA barcodes with sequences from a public database,identifying two candidate regions,Maturase K(matK)and internal transcribed spacer 2(ITS2),for screening specific single nucleotide polymorphism(SNP)loci,allowing for species-specific *** loci were validated by amplifying and sequencing genomic material from collected *** validation studies showed that Herb-Q demonstrated excellent linearity,accuracy,repeatability,and detection *** established quantitative standard curves with high R^(2)values(>0.99)to enable precise species quantification,which were combined with external standards to provide clear and accurate visual quantification *** average bias in quantifying the tuber of *** was 2.38%,confirming that Herb-Q can accurately identify and quantify herbal product ***,the entire quantification process took less than 4 *** study presents a novel,rapid method for accurately quantifying species in herbal products and advances the application of DNA barcoding from species identification to quantitative detection.

关键词： Quantification Adulterant DNA barcodes Single nucleotide polymorphism

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