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Correlative factors of poor prognosis and abnormal cellular immune function in patients with Alzheimer’s disease

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World Journal of Clinical Cases 2024年第6期12卷 1063-1075页

作者： Hua Bai Hong-Mei Zeng Qi-Fang Zhang Yue-Zhi Hu Fei-Fei Deng department of Neurology The Third Affiliated Hospital of Guizhou Medical University in ChinaDuyun 558099Guizhou ProvinceChina department of Neurology Guizhou Medical UniversityDuyun 558099Guizhou ProvinceChina Key laboratory of medical molecular biology Guizhou Medical UniversityGuiyang 550004Guizhou ProvinceChina

BACKGROUND Alzheimer’s disease(AD)is a serious disease causing human dementia and social *** quality of life and prognosis of AD patients have attracted much *** role of chronic immune inflammation in the pathogenesis of AD is becoming more and more *** To study the relationship among cognitive dysfunction,abnormal cellular immune function,neuroimaging results and poor prognostic factors in *** A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November *** cognitive dysfunction performance characteristics,laboratory test data and neuroimaging data from medical records within 24 h of admission,including Mini Mental State Examination Scale score,drawing clock test,blood T lymphocyte subsets,and neutrophils and lymphocyte ratio(NLR),disturbance of consciousness,extrapyramidal symptoms,electroencephalogram(EEG)and head nucleus magnetic spectroscopy(MRS)and other *** logistic regression analysis was used to determine independent prog-nostic *** modified Rankin scale(mRS)was used to determine whether the prognosis was *** correlation between drug treatment and prognostic mRS score was tested by the rank sum *** Univariate analysis showed that abnormal cellular immune function,extrapyramidal symptoms,obvious disturbance of consciousness,abnormal EEG,increased NLR,abnormal MRS,and complicated pneumonia were related to the poor prognosis of AD *** logistic regression analysis showed that the decrease in the proportion of T lym-phocytes in the blood after abnormal cellular immune function(odd ratio:2.078,95%confidence interval:1.156-3.986,P<0.05)was an independent risk factor for predicting the poor prognosis of *** number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score(r=0.578,P<0.05).CONCLUSION The decrease in the proportion of T

关键词： Alzheimer’s disease Cellular immunity Prognosis T lymphocytes Magnetic resonance spectroscopy

Endogenous retrovirus activation: potential for immunology and clinical applications

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National Science Review 2024年第4期11卷 21-23页

作者： Jundan Yu Peishan Qiu Jingwen Ai Bo Liu Guan-Zhu Han Fan Zhu Wenhong Zhang Jie Cui department of Infectious Diseases Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response National Medical Center for Infectious Diseases Huashan Hospital Shanghai Medical College Fudan University CAS Key laboratory of molecular Virology &Immunology Shanghai Institute of Immunity and Infection Chinese Academy of Sciences University of Chinese Academy of Sciences Shanghai Huashen Institute of Microbes and Infections College of Life Sciences Nanjing Normal University State Key laboratory of Virology and department of medical Microbiology School of Basic Medical SciencesWuhan University The Institute of Infection and Health Research Fudan University Key laboratory of medical molecular Virology(MOE/MOH) Shanghai Medical CollegeFudan University laboratory for Marine biology and Biotechnology Qingdao Marine Science and Technology Center

Endogenous retroviruses (ERVs), the remnants of ancient retrovirus infections, constitute approximately 8% of the human genome and play important roles in human evolution, development,and diseases. Multiple drugs, such as DNA methyltransferase inhibitors and lysine-specific histone demethylase 1inhibitors, reactivate ERVs, induce viral mimicry and trigger innate immune responses to enhance tumor immunogenicity.

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Hepatic Zbtb18 (Zinc Finger and BTB Domain Containing 18) alleviates hepatic steatohepatitis via FXR (Farnesoid X Receptor)

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Signal Transduction and Targeted Therapy 2024年第2期9卷 766-781页

作者： Lei Zhang Jiabing Chen Xiaoying Yang Chuangpeng Shen Jiawen Huang Dong Zhang Naihua Liu Chaonan Liu Yadi Zhong Yingjian Chen Kaijia Tang Jingyi Guo Tianqi Cui Siwei Duan Jiayu Li Shangyi Huang Huafeng Pan Huabing Zhang Xiaoqiang Tang Yongsheng Chang Yong Gao State Key laboratory of Traditional Chinese Medicine Syndrome Science and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina Key laboratory of Immune Microenvironment and Disease(Ministry of Education) Tianjin Key Laboratory of Cellular Homeostasis and DiseaseDepartment of Physiology and PathophysiologyTianjin Medical UniversityTianjinChina Jiangsu Key laboratory of Immunity and Metabolism Department of Pathogen Biology and ImmunologyJiangsu International Laboratory of Immunity and MetabolismXuzhou Medical UniversityXuzhouChina department of Endocrinology The First Clinical CollegeGuangzhou University of Chinese MedicineGuangdongChina The Fourth Clinical medical College of Guangzhou University of Chinese Medicine ShenzhenChina Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor Nanjing University of Chinese MedicineNanjingChina department of Biochemistry and molecular biology Metabolic Disease Research CenterSchool of Basic MedicineAnhui Medical UniversityHefeiChina Key laboratory of Birth Defects and Related Diseases of Women and Children of MOE State Key Laboratory of BiotherapyWest China Second University HospitalSichuan UniversityChengduChina

A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease(NAFLD),coupled with hepatitis and insulin *** the details of the underlying mechanisms are not fully ***,we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of *** Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation(FAO),and induced insulin ***,hepatic Zbtb18 overexpression alleviated hepato-steatosis,insulin resistance,and hyperglycemia in mice fed on a high-fat diet(HFD)or in diabetic ***,in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor(FXR)mediated FAO and Clathrin Heavy Chain(CLTC)protein hinders NLRP3 inflammasome *** key mechanism by which hepatocyte’s Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR’s deletion and forced expression in mice and cultured mouse primary hepatocytes(MPHs).Moreover,CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in ***,Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression,which inhibits NLRP3 inflammasome’s activity alleviating inflammatory stress and insulin resistance,representing an attractive remedy for hepatic steatosis and fibrosis.

关键词： hepatic Hepatic impaired

The antiviral treatment should be initiated before the development of cirrhosis

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Hepatobiliary Surgery and Nutrition 2024年第1期13卷 136-138页

作者： Qiao Tang Peng Hu department of Infectious Diseases Institute for Viral HepatitisThe Key Laboratory of Molecular Biology for Infectious DiseasesChinese Ministry of EducationThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina

Hepatitis B virus(HBV)infection increases the risk of liver fibrosis,cirrhosis and hepatocellular carcinoma(HCC)(1).International guidelines recommend antiviral treatment for eligible patients to prevent the development of HCC and the progression of liver ***,there is discrepancy in these guidelines regarding treatment recommendations for patients with compensated cirrhosis and low-level viremia(LLV),defined as serum HBV-DNA level of 20-2,000 IU/mL(2-4).And data on the natural history of untreated compensated cirrhotic patients with LLV is limited.

关键词： Low-level viraemia maintained virological response(MVR) untreated hepatocellular carcinoma(HCC) decompensated cirrhosis

Rhodium-catalyzed enantioselective in situ C(sp^(3))-H heteroarylation by a desymmetrization approach

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Chinese Chemical Letters 2024年第10期35卷 218-222页

作者： Yujia Shi Yan Qiao Pengfei Xie Miaomiao Tian Xingwei Li Junbiao Chang Bingxian Liu State Key laboratory of Antiviral Drugs NMPA Key Laboratory for Research and Evaluation of Innovative DrugSchool of Chemistry and Chemical EngineeringHenan Normal UniversityPingyuan LaboratoryXinxiang 453007China department of pathophysiology School of Basic Medical SciencesZhengzhou UniversityZhengzhou 450001China

A rhodium-catalyzed desymmetrization reaction for enantioselective methyl C-H arylation is achieved by utilizing an in situ arylating reagent via nucleophilic cyclization of o-aminoaryl *** reaction results in chiral indoles containing all-carbon quaternary stereocenters under atmospheric conditions,with a wide range of substrates exhibiting good enantioselectivity(44 examples).Mechnism and DFT studies show that the stereocontrol is reasonably achieved through the collaborative control of a large silicon substituted chiral ligand and C-H···π,LP···πinteractions between aryl rings of the carboxylate group and the *** experiments demonstrate that Rh-aryl bond formation via in situ nucleophilic cyclization is more critical for reaction efficiency than via C-H activation of the nucleophilic cyclization byproduct.

关键词： Heteroarylation C(sp^(3))-H activation Enantioselective Desymmetrization πInteractions

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Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma

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National Science Review 2024年第5期11卷 170-185页

作者： Yong Zhou Shanlan Mo Heyang Cui Ruifang Sun Weimin Zhang Xiaofei Zhuang Enwei Xu Hongyi Li Yikun Cheng Yongsheng Meng Meilin Liu Ting Yan Huijuan Liu Ling Zhang Bin Yang Yanfeng Xi Shubin Wang Xiaolong Cheng Shuai Cheng Li Zhihua Liu Qimin Zhan Zheng Hu Yongping Cui Cancer Institute Department of Pathology Peking University Shenzhen Hospital Shenzhen Peking University-the Hong Kong University of Science and Technology(PKU-HKUST) Medical Center Institute of Cancer ResearchShenzhen Bay Laboratory Key laboratory of Cellular Physiology of the Ministry of Education Department of Pathology Shanxi Medical University City University of Hong Kong Shenzhen Research Institute CAS Key laboratory of Quantitative Engineering biology Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of Sciences department of Surgery Faculty of Medicine The Chinese University of Hong Kong department of Tumor Biobank Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University Key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute Research Unit of molecular Cancer Research Chinese Academy of Medical Sciences department of Thoracic Surgery Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University department of Pathology Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University College of Letters & Science University of California Berkeley State Key laboratory of molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College

Esophageal squamous cell carcinoma（ESCC） is a poor-prognostic cancer type with extensive intra-and inter-patient heterogeneity in both genomic variations and tumor microenvironment（TME）. However, the patterns and drivers of spatial genomic and microenvironmental heterogeneity of ESCC remain largely unknown. Here, we generated a spatial multi-omic atlas by whole-exome, transcriptome, and methylome sequencing of 507 tumor samples from 103 patients. We identified a novel tumor suppressor PREX2,accounting for 22% of ESCCs with frequent somatic mutations or hyper-methylation, which promoted migration and invasion of ESCC cells in vitro. Analysis of the TME and quantification of subclonal expansion indicated that ESCCs undergo spatially directed evolution, where subclones mostly originated from the tumor center but had a biased clonal expansion to the upper direction of the ***, we found upper regions of ESCCs often underwent stronger immunoediting with increased selective fitness, suggesting more stringent immune selection. In addition, distinct TMEs were associated with variable genomic and clinical outcomes. Among them, hot TME was associated with high immune evasion and subclonal heterogeneity. We also found that immunoediting, instead of CD8+T cell abundance, acts as an independent prognostic factor of ESCCs. Importantly, we found significant heterogeneity in previously considered potential therapeutic targets, as well as BRCAness characteristics in a subset of patients, emphasizing the importance of focusing on heterogeneity in ESCC targeted ***, these findings provide novel insights into the mechanisms of the spatial evolution of ESCC and inform precision therapeutic strategies.

关键词： squamous cell carcinoma heterogeneity multi-omics evolution tumor microenvironment

Syrosingopine,an anti-hypertensive drug and lactate transporter(MCT1/4)inhibitor,activates hepatic stellate cells and exacerbates liver fibrosis in a mouse model

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Genes & Diseases 2024年第4期11卷 28-30页

作者： Meichun Guo Yannian Gou Xiangyu Dong Jiamin Zhong Aohua Li Ailing Hao Tongchuan He Jiaming Fan Ministry of Education Key laboratory of Diagnostic Medicine and the School of Laboratory Diagnostic MedicineChongqing Medical UniversityChongqing 400016China molecular Oncology laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA

Syrosingopine is an anti-hypertensive drug and can cause high intracellular lactate levels and end-product inhibition of lactate dehydrogenase by inhibiting the lactate transporters MCT1 and *** studies have shown that syrosingopine plays an essential role in the process of glycolytic blockade,ATP depletion,and cell death in cancer due to high intracellular levels of lactate.

关键词： hypertensive MCT1 drug

Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

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Acta Pharmaceutica Sinica B 2024年第1期14卷 87-109页

作者： Letian Song Shenghua Gao Bing Ye Mianling Yang Yusen Cheng Dongwei Kang Fan Yi Jin-Peng Sun Luis Menéndez-Arias Johan Neyts Xinyong Liu Peng Zhan department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Shenzhen Research Institute of Shandong University Shenzhen 518057China The Key laboratory of Infection and Immunity of Shandong Province Department of PharmacologySchool of Basic Medical SciencesShandong UniversityJinan 250012China Key laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Centro de Biologı´a molecular“Severo Ochoa”(Consejo Superior de Investigaciones Cientı´ficas&Autonomous University of Madrid) Madrid 28049Spain KU Leuven Department of Microbiology and ImmunologyRega Institute for Medical ResearchLaboratory of Virology and ChemotherapyLeuven 3000Belgium

The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life *** covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic *** antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable *** non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available *** viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.

关键词： COVID-19 SARS-CoV-2 Main protease Non-covalent inhibitors Medicinal chemistry strategies

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An engineered DNA aptamer-based PROTAC for precise therapy of p53-R175H hotspot mutant-driven cancer

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Science Bulletin 2024年第13期69卷 2122-2135页

作者： Lingping Kong Fanlu Meng Ping Zhou Ruixin Ge Xiaoshan Geng Zhihao Yang Guo Li Linlin Zhang Jing Wang Jinfeng Ma Cheng Dong Jun Zhou Sijin Wu Diansheng Zhong Songbo Xie department of medical Oncology Tianjin Medical University General HospitalTianjin 300052China Center for Cell Structure and Function Collaborative Innovation Center of Cell Biology in Universities of ShandongCollege of Life SciencesShandong Normal UniversityJinan 250014China The Province and Ministry Co-sponsored Collaborative Innovation Center for medical Epigenetics Key Laboratory of Immune Microenvironment and Disease(Ministry of Education)School of Basic Medical SciencesTianjin Medical UniversityTianjin 300070China Tianjin Key laboratory of Lung Cancer Metastasis and Tumor Microenvironment Lung Cancer InstituteTianjin Medical University General HospitalTianjin 300052China Haihe laboratory of Cell Ecosystem State Key Laboratory of Medicinal Chemical BiologyCollege of Life SciencesNankai UniversityTianjin 300071China Wisdom Lake Academy of Pharmacy Xi’an Jiaotong-Liverpool UniversitySuzhou 215028China department of Ophthalmology Tianjin Medical University General HospitalLaboratory of Molecular OphthalmologyTianjin Key Laboratory of Ocular TraumaTianjin Medical UniversityTianjin 300052China

Targeting oncogenic mutant p53 represents an attractive strategy for cancer treatment due to the high frequency of gain-of-function mutations and ectopic expression in various cancer *** extensive efforts,the absence of a druggable active site for small molecules has rendered these mutants therapeutically *** we develop a selective and effective proteolysis-targeting chimera(PROTAC)for p53-R175H,a common hotspot mutant with dominant-negative and oncogenic *** a novel iterative molecular docking-guided post-SELEX(systematic evolution of ligands by exponential enrichment)approach,we rationally engineer a high-performance DNA aptamer with improved affinity and specificity for *** this resulting aptamer as a binder for PROTACs,we successfully developed a selective p53-R175H degrader,named ***53m induces the ubiquitin–protea some-dependent degradation of p53-R175H while sparing wildtype ***,dp53m demonstrates significant antitumor efficacy in p53-R175H-driven cancer cells both in vitro and in vivo,without ***,dp53m significantly and synergistically improves the sensitivity of these cells to cisplatin,a commonly used chemotherapy *** findings provide evidence of the potential therapeutic value of dp53m in p53-R175H-driven cancers.

关键词： P53 Aptamer PROTAC Cancer Drug resistance