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MiR-4465-modified mesenchymal stem cell-derived small extracellular vesicles inhibit liver fibrosis development via targeting LOXL2 expression

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第7期25卷 594-604页

作者： Yanjin WANG Yifei CHEN Fuji YANG Xiaolong YU Ying CHU Jing ZHOU Yongmin YAN Jianbo XI Department of laboratory medicine Wujin Hospital Affiliated with Jiangsu UniversityJiangsu UniversityChangzhou 213017China Department of laboratory medicine School of MedicineJiangsu UniversityZhenjiang 212013China Changzhou Key laboratory of molecular Diagnostics and Precision Cancer medicine Wujin Clinical College of Xuzhou Medical UniversityChangzhou 213017China

Liver fibrosis is a significant health burden,marked by the consistent deposition of ***,the currently available treatment approaches for this condition are far from *** oxidase-like protein 2(LOXL2)secreted by hepatic stellate cells(HSCs)is a crucial player in the cross-linking of matrix collagen and is a significant target for treating liver *** stem cell-derived small extracellular vesicles(MSC-sEVs)have been proposed as a potential treatment option for chronic liver *** studies have found that MSC-sEV can be used for microRNA delivery into target cells or *** is currently unclear whether microRNA-4465(miR-4465)can target LOXL2 and inhibit HSC ***,it is uncertain whether MSC-sEV can be utilized as a gene therapy vector to carry miR-4465 and effectively inhibit the progression of liver *** study explored the effect of miR-4465-modified MSC-sEV(MSC-sEVmiR-4465)on LOXL2 expression and liver fibrosis *** results showed that miR-4465 can bind specifically to the promoter of the LOXL2 gene in ***,MSC-sEVmiR-4465 inhibited HSC activation and collagen expression by downregulating LOXL2 expression in ***-sEVmiR-4465 injection could reduce HSC activation and collagen deposition in the CCl4-induced mouse ***-sEVmiR-4465 mediating via LOXL2 also hindered the migration and invasion of HepG2 *** conclusion,we found that MSC-sEV can deliver miR-4465 into HSC to alleviate liver fibrosis via altering LOXL2,which might provide a promising therapeutic strategy for liver diseases.

关键词： Mesenchymal stem cell(MSC) Small extracellular vesicle(sEV) MicroRNA-4465(miR-4465) Hepatic stellate cell(HSC) Liver fibrosis

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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

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Emerging role of regulated cell death in intestinal failure-associated liver disease

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 228-233页

作者： Si-Yang Cheng Lu Jiang Ying Wang Wei Cai Department of pediatric Surgery Xinhua HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200092China Shanghai Key laboratory of pediatric Gastroenterology and Nutrition Shanghai 200092China Shanghai Institute for pediatric Research Shanghai 200092China Division of pediatric Gastroenterology and Nutrition Xinhua HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200092China

Intestinal failure-associated liver disease(IFALD)is a common complication of long-term parenteral nutrition that is associated with significant morbidity and *** is mainly characterized by cholestasis in children and steatohepatitis in ***,there is no effective approach to prevent or reverse the *** cell death(RCD)represents a fundamental biological paradigm that determines the outcome of a variety of liver *** cell death is reclassified into several types,based on the mechanisms and morphological *** evidence has linked different modes of RCD,such as apoptosis,necroptosis,ferroptosis,and pyroptosis to the pathogenesis of liver *** studies have shown that different modes of RCD are present in animal models and patients with *** the pathogenic roles of cell death may help uncover the underlying mechanisms and develop novel therapeutic strategies in *** this review,we discuss the current knowledge on how RCD may link to the pathogenesis of *** highlight examples of cell death-targeted interventions aiming to attenuate the disease,and provide perspectives for future basic and translational research in the field.

关键词： Parenteral nutrition Apoptosis Necroptosis Cholestasis Steatosis

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Pyruvate kinase M in germ cells is essential for sperm motility and male fertility but not spermatogenesis

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Asian Journal of Andrology 2024年第2期26卷 212-219页

作者： Gao-Qing Qian Xiao-Chen Wang Xi Zhang Bin Shen Qiang Liu State Key laboratory of Reproductive medicine and Offspring Health Nanjing Medical UniversityNanjing 211166China Shanghai Key laboratory of Reproductive medicine Department of HistoembryologyGenetics and Developmental BiologyShanghai Jiao Tong University School of MedicineShanghai 200025China State Key laboratory of molecular Biology Shanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 200031China

Male germ cells employ specific metabolic pathways throughout their developmental *** a previous study,we discovered heightened expression of pyruvate kinase M(PKM),a pivotal glycolytic enzyme,in spermatogonia and *** gain deeper insights into PKM's roles in spermatogenesis,sperm function,and male fertility,we engineered a conditional-knockout mouse model(Pkm-vkO mice)to selectively disrupt the Pkm gene within germ *** maintaining regular testicular histology and sperm morphology,the male Pkm-vko mice were infertility,characterized by significant impairments in sperm motility and adenosine triphosphate(ATP)*** addition,Pkm-null spermatozoa exhibited similar deficits in protein tyrosine phosphorylation linked to capacitation,as well as compromised performance in in vitro fertilization *** conclude,PKM's presence is not obligatory for the entirety of spermatogenesis in male germ cells;however,it emerges as a critical factor influencing sperm motility and overall male fertility.

关键词： glycolysis male fertility pyruvate kinase M sperm motility spermatogenesis

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Longitudinal changes in body weight of breastfeeding mothers in the first year after delivery and its relationship with human milk composition:a combined longitudinal and cross-sectional cohort study

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Food Science and Human Wellness 2024年第1期13卷 254-264页

作者： Huijuan Ruan Yajie Zhang Qingya Tang Xuan Zhao Xuelin Zhao Yi Xiang Wei Geng Yi Feng Wei Cai Department of Clinical Nutrition Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China Shanghai Key laboratory of pediatric Gastroenterology and Nutrition Shanghai Institute of Pediatric ResearchShanghai 200092China Department of pediatric Surgery Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China

Objective:Postpartum weight retention(PPWR)is a common problem among women after *** main objectives of this study are to understand the changes in body weight of breastfeeding mothers during long-term follow-up and preliminarily explore the relationship between maternal body weight and human milk composition,including macronutrients,leptin,and ***:The study included a longitudinal cohort(122 mothers),and a cross-sectional cohort(37 mothers).The human milk,maternal weight,and dietary surveys were collected in the longitudinal cohort at different follow-up time points(1-14 days postpartum,2-4 months postpartum,5-7 months postpartum,and 12-17 months postpartum).The maternal body weight was analyzed using the responses in the survey questionnaires.A milk analyzer based on the mid-infrared spectroscopy(MIRS)was used to determine milk composition,and nutrition analysis software evaluated dietary *** the cross-sectional cohort,participating mothers were asked to provide blood and human milk samples and pertinent information related to maternal body *** body composition was measured by bioelectrical impedance analysis(BIA),while ELISA analyzed leptin and adiponectin in milk and ***:At 5-7 months postpartum,the PPWR of breastfeeding mothers was(2.46±3.59)*** 12-17 months postpartum,the PPWR was(0.98±4.06)*** was found to be negatively correlated with milk fat content within 14 days postpartum and positively correlated at 2-4 months *** addition,the maternal weight and body muscle mass were positively correlated with leptin and adiponectin in *** leptin was positively correlated with the mother’s body weight,body mass index(BMI),FAT percentage,and body fat mass,while plasma adiponectin did not correlate with any *** results also indicate that the PPWR did not correlate with leptin and adiponectin in plasma or ***:Breastfeeding mothers may retain considerable weight gai

关键词： Human milk Milk composition Body weight Body mass index(BMI) Weight gain Postpartum weight retention

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The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer

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Research 2024年第1期2023卷 119-130页

作者： Ding Ding Haitao Zhao Dali Wei Qinglai Yang Cai Yang Ruowen Wang Yumei Chen Lianghua Li Shuxian An Qian Xia Gang Huang Jianjun Liu Zeyu Xiao Weihong Tan Institute of molecular medicine(IMM) Renji HospitalState Key Laboratory of Oncogenes and Related GenesShanghai Jiao Tong University School of Medicineand College of Chemistry and Chemical EngineeringShanghai Jiao Tong UniversityShanghai 200240China Department of Nuclear medicine Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China Center for molecular Imaging Probes Cancer Research InstituteUniversity of South ChinaHengyangHunan 421001China The Key laboratory of Zhejiang Province for Aptamers and Theranostics Zhejiang Cancer HospitalHangzhou Institute of Medicine(HIM)Chinese Academy of SciencesHangzhouZhejiang 310022China molecular Science and Biomedicine laboratory(MBL) State Key Laboratory of Chemo/Biosensing and ChemometricsCollege of Chemistry and Chemical EngineeringHunan UniversityChangshaHunan 410082China Shanghai Key laboratory of molecular Imaging Shanghai University of Medicine and Health SciencesShanghai 201318China Department of Pharmacology and Chemical Biology Shanghai Jiao Tong University School of MedicineShanghai200127China

Serving as targeting ligands,aptamers have shown promise in precision ***,the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’clinical *** bridge this gap,here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68(^(68)Ga)radiolabeled *** specificity and binding affinity of a radiolabeled aptamer,named ^(68)Ga[Ga]-NOTA-SGC8,were maintained as proven in *** preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity,potential mutation risks,or genotoxicity at high dosage(40 mg/kg).Based on this result,a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles,as well as biosafety,of the radiolabeled SGC8 aptamer in the human *** advantage of the cutting-edge total-body PET,the aptamers’distribution pattern in the human body was acquired in a dynamic fashion.

关键词： metabolism dosage Whole

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EGFR-targeted and gemcitabine-incorporated chemogene for combinatorial pancreatic cancer treatment

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Nano Research 2024年第2期17卷 848-857页

作者： Miao Xie Qiushuang Zhang Yuanyuan Guo Lijuan Zhu Xinyuan Zhu Chuan Zhang School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative MoleculesInstitute of Molecular MedicineSixth people’s HospitalSchool of MedicineShanghai Key Laboratory for Molecular Engineering of Chiral DrugsShanghai Jiao Tong UniversityShanghai 200240China Department of Radiology Shanghai Jiao Tong University Affiliated Sixth People’s HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200233China Institute of molecular medicine Shanghai Jiao Tong University Affiliated Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China

Pancreatic cancer stands out as a recognized intractable tumor due to its high malignancy and mortality rates,which are largely attributed to the insensitivity of current clinical chemotherapies or *** chemo and gene therapy that integrates different therapeutic targets,may increase the chemosensitivity of pancreatic cancer and synergistically enhance the antitumor ***,conventional co-delivery of gene and chemo drugs is intensively dependent on complex nanoparticle delivery systems,thus would be limited by unstable drug packaging,nonspecific biodistribution,and biosafety ***,we rationally designed an epidermal growth factor-receptor(EGFR)-targeted and gemcitabine-incorporated oligonucleotide(termed as chemogene)with anti-Bcl-2 sequence,which achieves simple and precise integration of gemcitabine into a gene regulative agent,as well as the EGFR-targeted delivery for pancreatic cancer *** solid-phase synthesis,gemcitabine,as the first-line chemodrug for pancreatic cancer,is introduced to the antisense oligonucleotide to replace all cytosine nucleosides to obtain the gemcitabine-integrated chemogene(Ge-ASO^(Bcl-2)).Thereafter,Ge-ASO^(Bcl-2)is covalently coupled with EGFR nanobody to construct the final targeted chemogene without any exogenous ***,this nanobody-conjugated chemogene exhibits remarkable tumor targeting capability and antitumor effects both in vitro and in vivo,which initiates a first step toward the application of combinatorial chemo and gene therapy for future pancreatic cancer treatment.

关键词： antisense oligonucleotide chemogene nanobody drug delivery system pancreatic cancer

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Multi-omics integration reveals potential stage-specific druggable targets in T-cell acute lymphoblastic leukemia

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Genes & Diseases 2024年第5期11卷 374-389页

作者： Zijun Yan Jie Xia Ziyang Cao Hongyang Zhang Jinxia Wang Tienan Feng Yi Shu Lin Zou Clinical Research Unit Shanghai Children’s HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200062China Institute of pediatric Infection Immunityand Critical Care MedicineShanghai Jiao Tong University School of MedicineShanghai 200062China Center for Clinical molecular laboratory medicine of Children’s Hospital of Chongqing Medical University Chongqing 400014China Clinical Research Institute Shanghai Jiao Tong University School of MedicineShanghai 200025China Bioinformatics and BioMedical Bigdata Mining laboratory School of Big HealthGuizhou Medical UniversityGuiyangGuizhou 554300China

T-cell acute lymphoblastic leukemia(T-ALL),a heterogeneous hematological malignancy,is caused by the developmental arrest of normal T-cell *** development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this *** this study,we performed multi-omics integration analysis,which included mRNA expression,chromatin accessibility,and gene-dependency database analyses,to identify potential stage-specific druggable targets and repositioned drugs for this *** multi-omics integration helped identify 29 potential pathological genes for *** genes exhibited tissue-specific expression profiles and were enriched in the cell cycle,hematopoietic stem cell differentiation,and the AMPK signaling *** these,four known druggable targets(CDK6,TUBA1A,TUBB,and TYMS)showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in *** TUBA1A expression level was higher in the early T cell precursor(ETP)-ALL cells,while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-positive ***6 exhibited a U-shaped expression pattern in malignant T cells along the naıve to maturation ***,mebendazole and gemcitabine,which target TUBA1A and TYMS,respectively,exerted stage-specific inhibitory effects on T-ALL cell lines,indicating their potential stage-specific antileukemic role in ***,our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.

关键词： Multi-omics Stage-specific druggable targets Targeted therapeutic strategies T-cell acute lymphoblastic leukemia Drug repositioning

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Reduced expression of semaphorin 3A in osteoclasts causes lymphatic expansion in a Gorham-Stout disease(GSD)mouse model

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第1期25卷 38-50页

作者： Dongfang ZHANG Hao XU Chi QIN Kangming CAI Jing ZHANG Xinqiu XIA Jingwen BI Li ZHANG Lianping XING Qianqian LIANG Wensheng WANG laboratory of molecular medicine College of Life Science and State Key Laboratory of Cell Differentiation and RegulationHenan Normal UniversityXinxiang453007China Longhua Hospital&Spine Institute Shanghai University of Traditional Chinese MedicineShanghai200032China Key laboratory of Theory and Therapy of Muscles and Bones Ministry of Education(Shanghai University of Traditional Chinese Medicine)Shanghai201203China Department of Pathology and laboratory medicine University of Rochester Medical CenterRochester14642USA

Gorham-Stout disease(GSD)is a sporadic chronic disease characterized by progressive bone dissolution,absorption,and disappearance along with lymphatic vessel infiltration in bone-marrow *** the osteolytic mechanism of GSD has been widely studied,the cause of lymphatic hyperplasia in GSD is rarely *** this study,by comparing the RNA expression profile of osteoclasts(OCs)with that of OC precursors(OCPs)by RNA sequencing,we identified a new factor,semaphorin 3A(Sema3A),which is an osteoprotective factor involved in the lymphatic expansion of *** to OCPs,OCs enhanced the growth,migration,and tube formation of lymphatic endothelial cells(LECs),in which the expression of Sema3A is low compared to that in *** the presence of recombinant Sema3A,the growth,migration,and tube formation of LECs were inhibited,further confirming the inhibitory effect of Sema3A on LECs in *** an LEC-induced GSD mouse model,the effect of Sema3A was examined by injecting lentivirus-expressing Sema3A into the tibiae in *** found that the overexpression of Sema3A in tibiae suppressed the expansion of LECs and alleviated bone loss,whereas the injection of lentivirus expressing Sema3A short hairpin RNA(shRNA)into the tibiae caused GSD-like *** staining further demonstrated that OCs decreased and osteocalcin increased after Sema3A lentiviral treatment,compared with the *** on the above results,we propose that reduced Sema3A in OCs is one of the mechanisms contributing to the pathogeneses of GSD and that expressing Sema3A represents a new approach for the treatment of GSD.

关键词： Semaphorin 3A Gorham-Stout disease Osteoclast Osteolysis Lymphatic endothelial cell

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Self-assembled amphiphilic NIR-Ⅱ emissive nano-micelles for imaging-guided photothermal therapy of colorectal cancer

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Science China Chemistry 2024年第8期67卷 2767-2774页

作者： Axin He Fangfang Xia Da Han Qinglai Yang Weihong Tan Institute of molecular medicine(IMM) Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200240China Center for molecular Imaging Probe Hunan Province Key Laboratory of Cancer Cellular and Molecular PathologyCancer Research InstituteHengyang Medical SchoolUniversity of South ChinaHengyang 421001China The Key laboratory of Zhejiang Province for Aptamers and Theranostics Zhejiang Cancer Hospital Hangzhou Institute of Medicine(HIM)Chinese Academy of SciencesHangzhou 310022China molecular Science and Biomedicine laboratory(MBL) State Key Laboratory of Chemo/Biosensing and ChemometricsCollege of Chemistry and Chemical EngineeringCollege of BiologyAptamer Engineering Center of Hunan ProvinceHunan UniversityChangsha 410082China

Colorectal cancer(CRC) is one of the major causes of cancer-related mortality worldwide. Most near-infrared(NIR) agents used in clinical CRC treatment are at NIR-I(700–900 nm) window, which has limitations on deep tissue, and fluorescent probes in the second NIR(1,000–1,700 nm) allow high-resolution bioimaging with deep tissue penetration. However, existing NIR-II fluorophores used in clinical are still rare. Herein, based on shielding-donor-acceptor-donor-shielding(S-D-A-D-S) scaffold, we developed an organic small-molecule fluorophore IR-BTGP with NIR-II emission for imaging-guided photothermal therapy(PTT) in CRC mice model. Amphiphilic IR-BTGP can be self-assembled into spherical nano-micelles, which presents reliable water solubility and photothermal conversion efficiency(30.2%). In vitro experiments indicate that cancer cells treated with IRBTGP were significantly killed upon 808 nm light irradiation. Furthermore, in vivo NIR-II fluorescence imaging confirms that IR-BTGP accumulates in the tumor region. Remarkably, a significant tumor inhibition rate(78.5%) was observed in tumorbearing mice when treated with IR-BTGP plus 808 nm irradiation. Therefore, this work shows that IR-BTGP holds great promise as an NIR-II fluorescence imaging-guided PTT platform for CRC in the future.

关键词： photothermal therapy(PTT) second near-infrared(NIR-Ⅱ)imaging organic molecule

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