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Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice

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Zoological Research 2024年第3期45卷 551-566页

作者： Chen Ling Su-Su Liu Yu-Ya Wang Gui-Tao Huo Yan-Wei Yang Nan Xu Hong Wang Yong Wu Yu-Fa Miao Rui Fu Yu-Wei Zhao Chang-Fa Fan College of Life Sciences Northwest UniversityProvincial Key Laboratory of Biotechnology of Shaanxi ProvinceXi’anShaanxi 710069China Division of Animal Model Research Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China National center for Safety evaluation of drugs National Institutes for Food and Drug Control(NIFDC)Beijing 100176China Division of HIV/AIDS and Sexually Transmitted Virus Vaccines Institute for Biological Products ControlNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China Division of Laboratory Animal Monitoring Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China

Hepatocellular carcinoma(HCC),a prevalent solid carcinoma of significant concern,is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic *** etiology and pathological progression of non-alcoholic steatohepatitis(NASH)-related HCC is multifactorial and ***,no single animal model can accurately mimic the full NASH-related HCC pathological progression,posing considerable challenges to transition and mechanistic ***,a novel conditional inducible wild-type human HRAS overexpressed mouse model(HRAS-HCC)was established,demonstrating 100%morbidity and mortality within approximately one month under normal dietary and lifestyle *** symptoms of HCC such as ascites,thrombus,internal hemorrhage,jaundice,and lung metastasis were successfully replicated in ***-depth pathological features of NASH-related HCC were demonstrated by pathological staining,biochemical analyses,and typical marker gene *** murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival,further confirming the accuracy and reliability of the *** on protein-protein interaction(PPI)network and RNA sequencing analyses,we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis,with subsequent progression to ***,our study successfully duplicated natural sequential progression in a single murine model over a very short period,providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

关键词： HRAS THBS1 HCC driver factor NASH Fibrosis Cirrhosis HCC Treatment evaluation

Cyclocarysaponins A–J, dammarane-type triterpenoid glycosides from the leaves of Cyclocarya paliurus

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Chinese Journal of Natural Medicines 2024年第10期22卷 955-964页

作者： XI Huiting YUAN Mingming XIE Jianhua WANG Yuanxing state Key Laboratory of food Science and Resources Nanchang University Jiangxi Institute for drug Control NMPA Key Laboratory of Quality Evaluation of Traditional Chinese Patent Medicine Jiangxi Provincial Engineering Research Center of Drug and Medical Device Quality

Ten previously undescribed dammarane-type triterpenoid glycosides, cyclocarysaponins A–J(1–10), were isolated from the leaves of Cyclocarya paliurus(Batal.) Iljinskaja. The structures of these compounds were characterized through detailed spectroscopic analysis, including 1D and 2D nuclear magnetic resonance(NMR) and high-resolution electrospray ionization mass spectrometry(HR-ESI-MS). The cytotoxic activities of all isolates were assessed against five human cancer cell lines(Bel-7402, Caski, BGC-823, A2780, and HCT-116). Of the tested compounds, compounds 1, 7, and 9 exhibited selective cytotoxicity against one or more human cancer cell lines.

关键词： Cyclocarya paliurus Cyclocarysaponin Cytotoxic activities Juglandaceae Triterpenoid glycosides

Recombinant adeno-associated virus 8 vector in gene therapy:Opportunities and challenges

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Genes & Diseases 2024年第1期11卷 283-293页

作者： Liyuan Zhao Zixuan Yang Minhui Zheng Lei Shi Mengyun Gu Gang Liu Feng Miao Yan Chang Fanghua Huang Naping Tang Anhui University of Traditional Chinese Medicine HefeiAnhui 230000China Yangtze Delta drug Advanced Research Institute Yangtze Delta Pharmaceutical CollegeNantongJiangsu226133China Shanghai Innostar Bio-Technology Co. LtdChina State Institute of Pharmaceutical IndustryShanghai 201203China Innostar Bio-tech Nantong Co. Ltd.NantongJiangsu 226133China center for drug evaluation National Medical Products AdministrationBeijing 100022China

In recent years,significant breakthroughs have been made in the field of gene ***-associated virus(AAV)is one of the most promising gene therapy vectors and a powerful tool for delivering the gene of *** the AAV vectors,AAV serotype 8(AAv8)has attracted much attention for its efficient and stable gene transfection into specific ***,recombinant AAv8 has been widely used in gene therapy research on a va-riety of diseases,including genetic diseases,cancers,autoimmune diseases,and viral diseases.

关键词： AAV8 Adeno-associated virus Gene therapy Primates

Worm-like micelles facilitate the intestinal mucus diffusion and drug accumulation for enhancing colorectal cancer therapy

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Chinese Chemical Letters 2024年第6期35卷 427-432页

作者： Yihan Zhou Duo Gao Yaying Wang Li Liang Qingyu Zhang Wenwen Han Jie Wang Chunliu Zhu Xinxin Zhang Yong Gan state Key Laboratory of drug Research and center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China University of Chinese Academy of Sciences Beijing 100049China NMPA Key Laboratory for Quality Research and evaluation of Pharmaceutical Excipients National Institutes for Food and Drug ControlBeijing 100050China School of Pharmacy Shanghai University of Traditional Chinese MedicineShanghai 201203China

Local delivery of nanoparticles holds promise for colorectal cancer(CRC)***,the presence of the mucus layer on the epithelium poses a significant challenge to drug delivery,thereby adversely affecting treatment *** is crucial to develop efficient drug delivery carriers that can effectively overcome mucus barriers to treat colorectal ***,we utilized poly(1,4-butadiene)-b-poly(ethylene oxide)polymers to prepare four distinct geometries of polymeric micelles,namely linear micelles(LMs),worm-like micelles(WLMs),large spherical micelles(LSMs),and small spherical micelles(SSMs)to investigate the influence of shape effects on overcoming colonic mucosal *** found that the carriers exhibited diverse shapes while maintaining comparable physicochemical *** these,WLMs had an aspect ratio similar to segmented filamentous bacteria,which exhibited superior mucus penetration ability,leading to prolonged drug release kinetics and faster entry into epithelial cells compared to ***,rectally administrated 10-hydroxycamptothecin-loaded WLMs traversed the colorectal mucus in orthotopic CRC nude mice model,penetrated and accumulated within tumor tissue,and effectively aggregated within cancer cells,thereby inducing significantly robust antitumor outcomes in *** findings underscore the significance of shape design in overcoming colonic mucosal absorption barriers,offering a novel approach for the development of drug delivery carriers tailored for effective tumor therapy.

关键词： Worm-like micelles Mucus penetration Shape dependent Transmucosal delivery Colorectal cancer

Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathway

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2992-3008页

作者： Shicheng Fan Yue Gao Pengfei Zhao Guomin Xie Yanying Zhou Xiao Yang Xuan Li Shuaishuai Zhang Frank JGonzalez Aijuan Qu Min Huangb Huichang Bi NMPA Key Laboratory for Research and evaluation of drug Metabolism&Guangdong Provincial Key Laboratory of New drug Screening&Guangdong-Hongkong-Macao Joint Laboratory for New drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Guangdong Provincial Key Laboratory of New drug Design and evaluation School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Physiology and Pathophysiology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China Laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA The state Key Laboratory of Chemical Oncogenomics School of Chemical Biology and BiotechnologyShenzhen Graduate School of Peking UniversityShenzhen 518055China

Fenofibrate,a peroxisome proliferator-activated receptor α(PPARα)agonist,is widely prescribed for hyperlipidemia *** studies also showed that it has therapeutic potential in various liver ***,its effects on hepatomegaly and liver regeneration and the involved mechanisms remain ***,the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice,which was dependent on hepatocyteexpressed PPARα.Yes-associated protein(YAP)is pivotal in manipulating liver growth and *** further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination,promoting its K63-linked ubiquitination,and enhancing the interaction and transcriptional activity of the YAP-TEAD *** inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced *** factors,such as MYC,KRT23,RAS,and RHOA,might also participate in fenofibrate-promoted hepatomegaly and liver *** studies demonstrate that fenofibratepromoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling,with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.

关键词： Fenofibrate PPARa Hepatomegaly Partial hepatectomy Liver regeneration YAP TEAD Ubiquitination

Ononin inhibits triple-negative breast cancer lung metastasis by targeting the EGFR-mediated PI3K/Akt/mTOR pathway

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Science China(Life Sciences) 2024年第9期67卷 1849-1866页

作者： Kumar Ganesan Cong Xu Jianming Wu Bing Du Qingqing Liu Yue Sui Cailu Song Jinhui Zhang Hailin Tang Jianping Chen School of Chinese Medicine LKS Faculty of MedicineThe University of Hong KongHong Kong 999077China School of Pharmacy Southwest Medical UniversityEducation Ministry Key Laboratory of Medical ElectrophysiologySichuan Key Medical Laboratory of New Drug Discovery and Druggability EvaluationLuzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia MedicaSouthwest Medical UniversityLuzhou 646000China College of food Science South China Agricultural UniversityGuangzhou 510642China state Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou 510080China

The spreading of cancer cells from the primary tumor site to other parts of the body,known as metastasis,is the leading cause of cancer recurrence and mortality in patients with triple-negative breast cancer(TNBC).Overexpression of epidermal growth factor receptor(EGFR)is observed in approximately 70%of TNBC *** is crucial for promoting tumor metastasis and associated with poor ***,it is vital to identify effective therapeutic strategies targeting EGFR ***,an isoflavonoid found in various plants,such as clover and soybeans,has been shown to have anticancer properties in several *** the present study,we aimed to investigate the effects of ononin on TNBC lung metastasis and the associated molecular *** used various assays,including cell viability,colony formation,Transwell,wound healing,ELISA,Western blotting,and staining techniques,to achieve this *** results demonstrated that ononin effectively suppressed cellular proliferation and induced apoptosis,as evidenced by the cell viability assay,colony formation assay,and expression of apoptosis markers,and reduced the metastatic capabilities of TNBC *** effects were achieved through the direct suppression of cell adhesion,invasiveness and ***,in TNBC xenograft lung metastatic models,ononin treatment significantly reduced tumor growth and lung ***,ononin reversed the epithelial-mesenchymal transition(EMT)by downregulating the expression of EMT markers and matrix metalloproteinases,as confirmed by Western blot ***,ononin treatment reduced EGFR phosphorylation and suppressed the PI3K,Akt,and m TOR signaling pathways,which was further confirmed using EGFR agonists or ***,ononin treatment did not exert any toxic effects on liver or kidney *** conclusion,our findings suggest that ononin is a safe and potentially therapeutic treatment for TNBC metastasis that targets the EGFRm

关键词： ononin TNBC breast cancer lung metastasis EGFR PI3k/Akt EMT therapeutic effect

Clinical characteristics and outcomes of hospitalized kidney transplant recipients with COVID-19 infection in China during the Omicron wave:a single-center cohort study

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第6期25卷 529-540页

作者： Duo LV Xishao XIE Qinyun YANG Zhimin CHEN Guangjun LIU Wenhan PENG Rending WANG Hongfeng HUANG Jianghua CHEN Jianyong WU Department of Clinical Pharmacy the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Zhejiang Provincial Key Laboratory for drug evaluation and Clinical Research Hangzhou 310003China Kidney Disease center the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Key Laboratory of Kidney Disease Prevention and Control Technology Zhejiang ProvinceHangzhou 310003China Institute of Nephrology Zhejiang UniversityHangzhou 310003China Zhejiang Clinical Research center of Kidney and Urinary System Disease Hangzhou 310003China The Third Grade Laboratory under the National state Administration of Traditional Chinese MedicineHangzhou 310003China Information center the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Background:Following the short-term outbreak of coronavirus disease 2019(COVID-19)in December 2022 in China,clinical data on kidney transplant recipients(KTRs)with COVID-19 are ***:We conducted a single-center retrospective study to describe the clinical features,complications,and mortality rates of hospitalized KTRs infected with COVID-19 between Dec.16,2022 and Jan.31,*** patients were followed up until Mar.31,***:A total of 324 KTRs with COVID-19 were *** median age was 49 *** median time between the onset of symptoms and admission was 13 ***,azvudine,and nirmatrelvir/ritonavir were administered to 67(20.7%),11(3.4%),and 148(45.7%)patients,***-nine(9.0%)patients were treated with more than one antiviral ***-eight(14.8%)patients were treated with tocilizumab and 53(16.4%)patients received baricitinib *** acute kidney injury(AKI)occurred in 81(25.0%)patients and 39(12.0%)patients were admitted to intensive care *** infections were observed in 55(17.0%)***(15.4%)patients lost their *** 28-d mortality rate of patients was 9.0%and 42(13.0%)patients died by the end of *** Cox regression analysis identified that cerebrovascular disease,AKI incidence,interleukin(IL)-6 level of>6.8 pg/mL,daily dose of corticosteroids of>50 mg,and fungal infection were all associated with an increased risk of death for hospitalized ***:Our findings demonstrate that hospitalized KTRs with COVID-19 are at high risk of *** administration of immunomodulators or the late application of antiviral drugs does not improve patient survival,while higher doses of corticosteroids may increase the death risk.

关键词： Coronavirus disease 2019(COVID-19) Kidney transplant Hospitalization Mortality

Early-phase clinical trials of anti-HIV drugs——understanding and discussion

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Science China(Life Sciences) 2009年第6期52卷 521-527页

作者： LI YaJie,ZHAO Ming & ZHAO DeHeng center for drug evaluation,state food and drug administration,Beijing 100038,China center for drug evaluation State Food and Drug Administration Beijing 100038 China

Innovative anti-HIV drugs developed by local sponsors in China have come into the stage of early-phase clinical *** to systemically design the clinical trials of innovative anti-HIV drugs still remains a challenge for *** article references the literature and the experience of reviewers,to introduce general considerations concerning early-phase clinical trials of innovative anti-HIV drugs.

关键词： HIV tolerance dose exploration drug-drug interaction drug resistance

Status and developmental trends in recombinant collagen preparation technology

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Regenerative Biomaterials 2024年第2期3卷 17-36页

作者： Xiaolei Guo Yuan Ma Hang Wang Hongping Yin Xinli Shi Yiqin Chen Guobiao Gao Lei Sun Jiadao Wang Yunbing Wang Daidi Fan center for Medical Device evaluation National Medical Products AdministrationBeijing 100081China state Key Laboratory of Tribology Tsinghua UniversityBeijing 100084China school of Life Science and Technology China Pharmaceutical UniversityNanjing 210009China National Engineering Research center for Biomaterials&College of Biomedical Engineering Sichuan UniversityChengdu 610064China Biotech.&Biomed.Research Institute Northwest UniversityXi'an 710127China

Recombinant collagen is a pivotal topic in foundational biological research and epitomizes the application of critical bioengineer-ing *** technological advancements have pro-found implications across diverse areas such as regenerative medicine,organ replacement,tissue engineering,cosmetics and ***,recombinant collagen and its preparation methodologies rooted in genetically engineered celis mark pivotal milestones in medical product *** article pro-vides a comprehensive overview of the current genetic engi-neering technologies and methods used in the production of recombinant collagen,as well as the conventional production process and gquality control detection methods for this ***,the discussion extends to foresee the strides in physical transfection and magnetic control sorting studies,envisioning an enhanced preparation of recombinant collagen-seeded cells to further fuel recombinant collagen production.

关键词： recombinant collagen preparation genetic engineering collagen characterization physical transfection seed cell sorting