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Targeting carnitine palmitoyl transferase 1A(CPT1A)induces ferroptosis and synergizes with immunotherapy in lung cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1675-1689页

作者： Lei Ma Chong Chen Chunxing Zhao Tong Li Lingyu Ma Jiayu Jiang Zhaojun Duan Qin Si Tsung-Hsien Chuang Rong Xiang Yunping Luo Department of Immunology Institute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China Collaborative Innovation Center for Biotherapy Institute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China Department of Lung Cancer Surgery Tianjin Medical University General HospitalTianjin 300052China Immunology Research Center National Health Research InstitutesZhunanMiaoliTaiwanROC Department of Immunology Nankai UniversityTianjin 300071China

Despite the successful application of immune checkpoint therapy,no response or recurrence is typical in lung *** stem cells(CSCs)have been identified as a crucial player in immunotherapy-related ***,a form of cell death driven by iron-dependent lipid peroxidation,is highly regulated by cellular metabolism remolding and has been shown to have synergistic effects when combined with *** adaption of CsCs drives tumor resistance,yet the mechanisms of their ferroptosis defense in tumor immune evasion remain ***,through metabolomics,transcriptomics,a lung epithelialspecific Cptla-knockout mouse model,and clinical analysis,we demonstrate that CPT1A,a key rate-limiting enzyme of fatty acid oxidation,acts with L-carnitine,derived from tumor-associated macrophages to drive ferroptosis-resistance and CD8^(+)T cells inactivation in lung ***,CPT1A restrains ubiquitination and degradation of c-Myc,while c-Myc transcriptionally activates CPT1A *** CPT1A/c-Myc positive feedback loop further enhances the cellular antioxidant capacity by activating the NRF2/GPX4 system and reduces the amount of phospholipid polyunsaturated fatty acids through ACSL4 downregulating,thereby suppressing ferroptosis in ***,targeting CPT1A enhances immune checkpoint blockadeinduced anti-tumor immunity and tumoral ferroptosis in tumor-bearing *** results illustrate the potential of a mechanismguided therapeutic strategy by targeting a metabolic vulnerability in the ferroptosis of CsCs to improve the efficacy of lung cancer immunotherapy.

关键词： immunotherapy metabolism peroxidation

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Si-Wu-Tang attenuates liver fibrosis via regulating lncRNA H19-dependent pathways involving cytoskeleton remodeling and ECM deposition

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Chinese Journal of Natural Medicines 2024年第1期22卷 31-46页

作者： QU Jiaorong XUE Xiaoyong WANG Zhixing MA Zhi JIA Kexin LI Fanghong ZHANG Yinhao WU Ruiyu ZHOU Fei ZHAO Piwen LI Xiaojiaoyang school of Life Sciences Beijing University of Chinese MedicineBeijing 100029China school of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China State Key Laboratory of medical Molecular Biology Department of Molecular Biology and BiochemistryInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100005China

Liver fibrosis is a dynamic wound-healing response characterized by the agglutination of the extracellular matrix(ECM).Si-Wu-Tang(SWT),a traditional Chinese medicine(TCM)formula,is known for treating gynecological diseases and liver *** previous studies demonstrated that long non-coding RNA H19(H19)was markedly upregulated in fibrotic livers while its deficiency markedly reversed ***,the mechanisms by which SWT influences H19 remain ***,we established a bile duct ligation(BDL)-induced liver fibrosis model to evaluate the hepatoprotective effects of SWT on various cells in the *** results showed that SWT markedly improved ECM deposition and bile duct reactions in the ***,SWT relieved liver fibrosis by regulating the transcription of genes involved in the cytoskeleton remodeling,primarily in hepatic stellate cells(HSCs),and influencing cytoskeleton-related angiogenesis and hepatocellular *** modulation collectively led to reduced ECM *** extensive bioinformatics analyses,we determined that H19 acted as a miRNA sponge and mainly inhibited miR-200,miR-211,and let7b,thereby regulating the above cellular regulatory ***,SWT reversed H19-related miRNAs and signaling pathways,diminishing ECM deposition and liver ***,these protective effects of SWT were diminished with the overexpression of H19 in *** conclusion,our study elucidates the underlying mechanisms of SWT from the perspective of H19-related signal networks and proposes a potential SWT-based therapeutic strategy for the treatment of liver fibrosis.

关键词： Liver fibrosis LncRNA H19 Si-Wu-Tang miRNAs Cytoskeleton ECM deposition

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Drug repurposing screening and mechanism analysis based on human colorectal cancer organoids

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Protein & Cell 2024年第4期15卷 285-304页

作者： Yunuo Mao Wei Wang Jingwei Yang Xin Zhou Yongqu Lu Junpeng Gao Xiao Wang Lu Wen Wei Fu Fuchou Tang school of Life Sciences Biomedical Pioneering Innovation CenterDepartment of General SurgeryThird HospitalPeking UniversityBeijing 100871China Beijing Advanced Innovation Center for Genomics(ICG) Ministry of Education Key Laboratory of Cell Proliferation and DifferentiationBeijing 100871China peking-Tsinghua Center for Life Sciences Peking UniversityBeijing 100871China peking university Third Hospital Cancer Center Beijing 100871China The Research Center of Stem Cell and Regenerative Medicine School of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Colorectal cancer(CRC)is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be ***,we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original *** efficiently identify repurposed drugs for CRC,we developed a robust organoid-based drug screening *** combining the repurposed drug library and computation-based drug prediction,335 drugs were tested and 34 drugs with anti-CRC effects were *** importantly,we conducted a detailed transcriptome analysis of drug responses and divided the drug response signatures into five representative patterns:differentiation induction,growth inhibition,metabolism inhibition,immune response promotion,and cell cycle *** anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft(PDOX)system in *** found that fedratinib,trametinib,and bortezomib exhibited effective anticancer ***,the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were *** study offers an innovative approach for drug discovery,and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC.

关键词： colorectal cancer organoids drug repurposing patient-derived organoids-based xenograft mechanism of action

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A homing rescue gene drive with multiplexed gRNAs reaches high frequency in cage populations but generates functional resistance

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Journal of Genetics and Genomics 2024年第8期51卷 836-843页

作者： Shibo Hou Jingheng Chen Ruobing Feng Xuejiao Xu Nan Liang Jackson Champer Center for Bioinformatics Center for Life SciencesSchool of Life SciencesPeking UniversityBeijing 100871China

CRISPR homing gene drives have considerable potential for managing populations of medically and agriculturally significant *** operate by Cas9 cleavage followed by homology-directed repair,copying the drive allele to the wild-type chromosome and thus increasing in frequency and spreading throughout a ***,resistance alleles formed by end-joining repair pose a significant *** address this,we create a homing drive targeting the essential hairy gene in Drosophila *** resistance alleles are recessive lethal,while drive carriers have a recoded“rescue”version of *** drive inheritance rate is moderate,and multigenerational cage studies show drive spread to 96%–97%of the ***,the drive does not reach 100%due to the formation of functional resistance alleles despite using four *** alleles have a large deletion but likely utilize an alternate start ***,revised designs targeting more essential regions of a gene may be necessary to avoid such functional *** of the rescue element’s native 3'UTR with a homolog from another species increases drive inheritance by 13%–24%.This was possibly because of reduced homology between the rescue element and surrounding genomic DNA,which could also be an important design consideration for rescue gene drives.

关键词： Genedrive Homing drive Rescueelement Population modification Multiplexed gRNAs Resistance alleles Cage study

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China stroke surveillance report 2021

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Military medical Research 2024年第3期11卷 374-399页

作者： Wen-Jun Tu Long-De Wang 无 Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijing 100070China school of Public Health Peking UniversityBeijing 100191China Special Writing Group of China Stroke Surveillance Report

Since 2015,stroke has become the leading cause of death and disability in China,posing a significant threat to the health of its citizens as a major chronic non-communicable *** to the China Stroke High-risk Population Screening and Intervention Program,an estimated 17.8 million[95%confidence interval(CI)17.6–18.0million]adults in China had experienced a stroke in 2020,with 3.4 million(95%CI 3.3–3.5 million)experiencing their first-ever stroke and another 2.3 million(95%CI 2.2–2.4 million)dying as a ***,approximately 12.5%(95%CI 12.4%–12.5%)of stroke survivors were left disabled,as defined by a modified Rankin Scale score greater than 1,equating to 2.2 million(95%CI 2.1–2.2 million)stroke-related disabilities in *** the population ages and the prevalence of risk factors like diabetes,hypertension,and hyperlipidemia continues to rise and remains poorly controlled,the burden of stroke in China is also increasing.A large national epidemiological survey initiated by the China Hypertension League in 2017 showed that the prevalence of hypertension was 24.7%;the awareness,treatment,and control rates in hypertensive patients were:60.1%,42.5%,and 25.4%,respectively.A nationally representative sample of the Chinese mainland population showed that the weighted prevalence of total diabetes diagnosed by the American Diabetes Association criteria was 12.8%,suggesting there are 120 million adults with diabetes in China,and the awareness,treatment,and control rates in diabetic patients were:43.3%,49.0%,and 49.4%,***“Sixth National Health Service Statistical Survey Report in 2018”showed that the proportion of the obese population in China was 37.4%,an increase of 7.2 points from *** from 1599 hospitals in the Hospital Quality Monitoring System and Bigdata Observatory Platform for Stroke of China(BOSC)showed that a total of 3,418,432 stroke cases[mean age±standard error(SE)was(65.700±0.006)years,and 59.1%were male]were admitted dur

关键词： Stroke Epidemiological characteristics Treatment Prognosis China

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DLX3(Q178R)mutation delays osteogenic differentiation via H19/miR-29c-3p/KDM5B axis in TDO-iPSCs-derived MSCs

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Genes & Diseases 2024年第4期11卷 49-52页

作者： Liying Dong Na Zhao Dongmei Wang Meng Wang Yixin Zhang Liangjie Sun Chong Ding Yixiang Wang Zeyun Ma Central Laboratory Peking University School and Hospital of StomatologyBeijing 100081China Department of Oral and Maxillofacial Surgery Peking University School and Hospital of StomatologyBeijing 100081China National Engineering Laboratory for Digital and Material Technology of Stomatology Peking University School and Hospital of StomatologyBeijing 100081China Beijing Key Laboratory of Digital Stomatology Peking University School and Hospital of StomatologyBeijing 100081China The Second Clinical Division Peking University School and Hospital of StomatologyBeijing 100081China Department of VIP Service Peking University School and Hospital of StomatologyBeijing 100081China Department of Restorative Dentistry and Biomaterials Sciences Harvard School of Dental MedicineBostonMA 02115USA Department of Prosthodontics Fudan UniversityShanghai 200001China Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Shanghai Stomatological HospitalFudan UniversityShanghai 200001China

Tricho-dento-osseous(TDO)syndrome is a rare autosomal dominant disease resulting from distal-less homeobox 3(DLX3)mutation.1,2 Accumulative bone density in alveolar bone is a clinically favorable phenotype for TDO ***... 详细信息

关键词： patients clinically alveolar

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Cervical cancer prevention in China: where are we now, and what's next?

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Cancer Biology & Medicine 2024年第3期21卷 213-217页

作者： Huijiao Yan Qiankun Wang Youlin Qiao school of Population Medicine and Public Health Chinese Academy of Medical Sciences and Peking Union Medical CollegeBejing 100730China Department of Cancer Epidemiology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBejing 100021China

Cervical cancer(CC) epidemiology CC, the fourth most frequently diagnosed malignancy in women worldwide, is a major global health challenge, particularly in low-resource regions. Approximately 88.1% of the 604,000 CC new cases occurred in low-and middle-income countries in 2020, and more than 90% of the 342,000 CC deaths occurred in low-and middle-income countries in 2020~1.

关键词： prevention Cervical epidemiology

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DEAD-box helicase 17(DDX17)protects cardiac function by promoting mitochondrial homeostasis in heart failure

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2774-2790页

作者： Mingjing Yan Junpeng Gao Ming Lan Que Wang Yuan Cao Yuxuan Zheng Yao Yang Wenlin Li Xiaoxue Yu Xiuqing Huang Lin Dou Bing Liu Junmeng Liu Hongqiang Cheng Kunfu Ouyang Kun Xu Shenghui Sun Jin Liu Weiqing Tang Xiyue Zhang Yong Man Liang Sun Jianping Cai Qing He Fuchou Tang Jian Li Tao Shen The Key Laboratory of Geriatrics Beijing Institute of GeriatricsInstitute of Geriatric MedicineChinese Academy of Medical SciencesBeijing Hospital/National Center of Gerontology of National Health CommissionBeijing 100730China peking university Fifth school of Clinical Medicine Beijing 100730China Department of Laboratory Medicine Huashan HospitalShanghai Medical CollegeFudan UniversityShanghai 200040China Biomedical Pioneering Innovation Center School of Life SciencesPeking UniversityBeijing 100871China Emergency Center Zhongnan Hospital of Wuhan UniversityWuhan 430071China Department of Cardiology Beijing HospitalNational Center of GerontologyInstitute of Geriatric MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China Graduate school of peking Union medical College Beijing 100730China Department of Health Care Beijing HospitalNational Center of GerontologyInstitute of Geriatric MedicineChinese Academy of Medical SciencesBeijing 100730China peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100871China Department of Pathology and Pathophysiology and Department of Cardiology at Sir Run Run Shaw Hospital Zhejiang University School of MedicineHangzhou 310058China Department of Cardiovascular Surgery Peking University Shenzhen HospitalShenzhen 518036China Experimental Technology Center for Life Sciences at Beijing Normal university Beijing 100875China

DEAD-box helicase 17(DDX17)is a typical member of the DEAD-box family with transcriptional cofactor *** DDX17 is abundantly expressed in the myocardium,its role in heart is not fully *** generated cardiomyocyte-specific Ddx17-knockout mice(Ddx17-cKO),cardiomyocyte-specific Ddx17 transgenic mice(Ddx17-Tg),and various models of cardiomyocyte injury and heart failure(HF).DDX17 is downregulated in the myocardium of mouse models of heart failure and cardiomyocyte ***-specific knockout of Ddx17 promotes autophagic flux blockage and cardiomyocyte apoptosis,leading to progressive cardiac dysfunction,maladaptive remodeling and progression to heart *** of DDX17 expression in cardiomyocytes protects cardiac function under pathological *** studies showed that DDX17 can bind to the transcriptional repressor B-cell lymphoma 6(BCL6)and inhibit the expression of dynamin-related protein 1(DRP1).When DDX17 expression is reduced,transcriptional repression of BCL6 is attenuated,leading to increased DRP1 expression and mitochondrial fission,which in turn leads to impaired mitochondrial homeostasis and heart *** also investigated the correlation of DDX17 expression with cardiac function and DRP1 expression in myocardial biopsy samples from patients with heart *** findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway in heart failure.

关键词： DDX17 homeostasis cardiac

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Crosstalk among Oxidative Stress,Autophagy,and Apoptosis in the Protective Effects of Ginsenoside Rb1 on Brain Microvascular Endothelial Cells:A Mixed Computational and Experimental Study

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Current medical Science 2024年第3期44卷 578-588页

作者： Yi-miao LUO Shu-sen LIU Ming ZHAO Wei WEI Jiu-xiu YAO Jia-hui SUN Yu CAO Hao LI Department of Geriatrics Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan)Beijing100901China Department of Integration of Chinese and Western Medicine Peking University Health Science CenterBeijing100191China school of Pharmacy Harbin University of CommerceHarbin150028China Xiyuan Hospital China Academy of Chinese Medical ScienceBeijing100901China Wangjing Hospital China Academy of Chinese Medical ScienceBeijing100102China

Objective Brain microvascular endothelial cells (BMECs) were found to shift from their usually inactive state to an active state in ischemic stroke (IS) and cause neuronal damage. Ginsenoside Rb1 (GRb1),a component derived from medicinal plants,is known for its pharmacological benefits in IS,but its protective effects on BMECs have yet to be explored. This study aimed to investigate the potential protective effects of GRb1 on BMECs. Methods An in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model was established to mimic ischemia-reperfusion (I/R) injury. Bulk RNA-sequencing data were analyzed by using the Human Autophagy Database and various bioinformatic tools,including gene set enrichment analysis (GSEA),Gene Ontology (GO) classification and enrichment analysis,Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis,protein-protein interaction network analysis,and molecular docking. Experimental validation was also performed to ensure the reliability of our findings. Results Rb1 had a protective effect on BMECs subjected to OGD/R injury. Specifically,GRb1 was found to modulate the interplay between oxidative stress,apoptosis,and autophagy in BMECs. Key targets such as sequestosome 1 (SQSTM1/p62),autophagy related 5 (ATG5),and hypoxia-inducible factor 1-alpha (HIF-1α) were identified,highlighting their potential roles in mediating the protective effects of GRb1 against IS-induced damage. Conclusion GRbl protects BMECs against OGD/R injury by influencing oxidative stress,apoptosis,and autophagy. The identification of SQSTM1/p62,ATG5,and HIF-1α as promising targets further supports the potential of GRb1 as a therapeutic agent for IS,providing a foundation for future research into its mechanisms and applications in IS treatment.

关键词： ischemic stroke ginsenoside Rb1 brain microvascular endothelial cells oxidative stress autophagy apoptosis bioinformatic analysis

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The meta-analyses on effectiveness and safety of colorectal cancer screening

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Chinese medical Journal 2024年第12期137卷 1471-1473页

作者： Pei Li Xueyang Zeng Zuoxiang Liu Jichun Yang Yueying Li Le Gao Hongmei Zeng Lin Zhang Feng Sun Department of Epidemiology and Biostatistics School of Public HealthPeking UniversityBeijing 100191China peking Union medical College Beijing 100005China Centre for Safe Medication Practice and Research Department of Pharmacology and PharmacyLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina Department of Cancer Registry National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China school of Population Medicine and Public Health Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China

To the Editor:The colorectal cancer(CRC)is the fourthmost common cause of cancer deaths in China that was treated as a public health threat,accounting for approximately 10%of all the cancer-caused mortalities each year.[1]It usually takes decades to develop from a polyp to full CRC,[2]which allows a time window for detecting precancerous lesions and taking early steps for preventions and treatments.

关键词： colorectal prevention cancer

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