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Inhibition of ASCT2 induces hepatic stellate cell senescence with modified proinflammatory secretome through an IL-1α/NF-κB feedback pathway to inhibit liver fibrosis

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3618-3638页

作者： Feixia Wang Zhanghao Li Li Chen Ting Yang Baoyu Liang Zili Zhang Jiangjuan Shao Xuefen Xu Guoping Yin Shijun Wang Hai Ding Feng Zhang Shizhong Zheng Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica School of PharmacyNanjing University of Chinese MedicineNanjing 210023China Department of General Surgery Nanjing Hospital Affiliated to Nanjing University of Chinese MedicineNanjing 210003China Department of Anesthesiology Nanjing Hospital Affiliated to Nanjing University of Chinese MedicineNanjing 210003China College of Traditional Chinese Medicine Shandong University of Traditional Chinese MedicineJinan 250035China

Senescence of activated hepatic stellate cells(aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression.Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype(SASP).But little is known about how alanine-serine-cysteine transporter type-2(ASCT2),a high affinity glutamine transporter,affects HSC senescence and SASP during liver fibrosis.Here,we identified ASCT2 is mainly elevated in aHSCs and positively correlated with liver fibrosis in human and mouse fibrotic livers.We first discovered ASCT2 inhibition induced HSCs to senescence in vitro and in vivo.The proinflammatory SASP were restricted by ASCT2 inhibition at senescence initiation to prevent paracrine migration.Mechanically,ASCT2 was a direct target of glutaminolysisdependent proinflammatory SASP,interfering IL-1α/NF-κB feedback loop via interacting with precursor IL-1α at Lys82.From a translational perspective,atractylenolide Ⅲ is identified as ASCT2 inhibitor through directly bound to Asn230 of ASCT2.The presence of -OH group in atractylenolide Ⅲ is suggested to be favorable for the inhibition of ASCT2.Importantly,atractylenolide Ⅲ could be utilized to treat liver fibrosis mice.Taken together,ASCT2 controlled HSC senescence while modifying the proinflammatory SASP.Targeting ASCT2 by atractylenolide Ⅲ could be a therapeutic candidate for liver fibrosis.

关键词： Hepatic stellate cells Senescence SASP ASCT2 Precursor IL-1α NF-κB Atractylenolide III Liver fibrosis

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Methionine metabolism in chronic liver diseases:an update on molecular mechanism and therapeutic implication

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Signal Transduction and Targeted Therapy 2021年第1期6卷 17-25页

作者： Zhanghao Li Feixia Wang Baoyu Liang Ying Su Sumin Sun Siwei Xia Jiangjuan Shao Zili Zhang Min Hong Feng Zhang Shizhong Zheng Department of Pharmacology Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaNanjing University of Chinese MedicineNanjing 210023China Department of Pharmacology Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineNanjing University of Chinese MedicineNanjing 210023China Department of Pharmacology State Key Laboratory Cultivation Base for TCM Quality and EfficacyNanjing University of Chinese MedicineNanjing 210023China

As one of the bicyclic metabolic pathways of one-carbon metabolism,methionine metabolism is the pivot linking the folate cycle to the transsulfuration pathway.In addition to being a precursor for glutathione synthesis,and the principal methyl donor for nucleic acid,phospholipid,histone,biogenic amine,and protein methylation,methionine metabolites can participate in polyamine synthesis.Methionine metabolism disorder can aggravate the damage in the pathological state of a disease.In the occurrence and development of chronic liver diseases(CLDs),changes in various components involved in methionine metabolism can affect the pathological state through various mechanisms.A methionine-deficient diet is commonly used for building CLD models.The conversion of key enzymes of methionine metabolism methionine adenosyltransferase(MAT)1 A and MAT2A/MAT2B is closely related to fibrosis and hepatocellular carcinoma.In vivo and in vitro experiments have shown that by intervening related enzymes or downstream metabolites to interfere with methionine metabolism,the liver injuries could be reduced.Recently,methionine supplementation has gradually attracted the attention of many clinical researchers.Most researchers agree that adequate methionine supplementation can help reduce liver damage.Retrospective analysis of recently conducted relevant studies is of profound significance.This paper reviews the latest achievements related to methionine metabolism and CLD,from molecular mechanisms to clinical research,and provides some insights into the future direction of basic and clinical research.

关键词： synthesis. linking donor

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Contingency management strategies of the Nursing Department in centralized rescue of patients with coronavirus disease 2019

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International Journal of Nursing Sciences 2020年第2期7卷 139-142页

作者： Huafen Wang Jiehui Feng Lewen shao Jianhua Wei Xiaoyan Wang Xiaowei Xu Rongya shao Meiyun Zhang jiangjuan He Xuehong Zhao Tingbo Liang The Department of Nursing The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina The Department of Heart Vascular Surgery The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina Surgery Intensive Care Unit The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina The Department of Infectious Disease The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina The Department of Hepatopancreatobiliary Surgery The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina

Objectives:This article aims to summarize a series of contingency management strategies of the Nursing Department in the centralized treatment of patients with coronavirus disease 2019(COVID-19).Methods:The strategies of the Nursing Department included an early warning for prevention and control,taking functions of vertically commanding and horizontally coordinating,and reasonably allocating nursing workforce,to facilitate centralized treatment work in the in-hospital fever clinic,isolation wards and ICU,and referral and admission of critical patients.Five special groups were established in charge of training and examination,management and supervision,psychological support,logistical support,and reporting and publicity,respectively.Results:It was achieved that no deaths from critical patients and no medical staff,no other patients were infected.Conclusion:Through the implementation of these strategies,safe and efficient centralized treatment was ensured timely,orderly and sustainably.

关键词： Contingency management COVID-19 Infectious disease control Nursing administration research Public health emergencies

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CTB induces mitochondrial apoptosis in hepatoma cells by p53 mitochondrial translocation dependent on Drp1-mediated mitochondrial fission

CTB induces mitochondrial apoptosis in hepatoma cells by p53...

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中国化学会第十四届全国生物无机化学学术会议

作者： Jiangjuan Shao Zijian Guo Feng Zhang Shizhong Zheng Xiaoyong Wang College of Pharmacy Nanjing University of Chinese Medicine State Key Laboratory of Coordination Chemistry School of Chemistry and Chemical Engineering Nanjing University State Key Laboratory of Pharmaceutical Biotechnology School of Life Sciences Nanjing University

Copper complexes are potential anticancer drugs by virtue of their available redox properties, low toxicity and physiological distribution. A copper(Ⅱ) complex, [Cu(ttpy-tpp)Br]Br(simplified as CTB), is a newly synthesized mitochondrion-targeting copper complex that triphenylphosphine(TPP) is introduced into it for its mitochondrion-targeting ability and lipophilic character. CTB can cross the cytoplasmic and mitochondrial membranes of tumor cells and influence the mitochondrial membrane potential more profoundly than the anticancer drug cisplatin. Nevertheless, the mechanism by which CTB targets mitochondria to exert a stronger anti-tumor effect is not fully understood, and further exploration is needed. The aim of this study is to investigate the relevance of mitochondrial dysfunction and apoptosis for the antitumor activity of CTB in hepatocellular carcinoma cells. Our results indicated that CTB suppressed the proliferation of hepatoma cells and induced apoptosis. In addition, mitochondrial damage, the loss of mitochondrial membrane potential, and the disturbance of energy metabolism were observed in the cells treated with CTB, while the activation of Bax and caspase-3/9, and inhibition of Bcl-2 were detected. This finding indicates that CTB-induced apoptosis is associated with mitochondrial pathway and occurs through a caspase-dependent way. Simultaneously, we also detected that the mitochondrial translocation of p53, mitochondrial division and elevated Drp1 protein levels in CTB-treated cells. In conclusion, our results demonstrate that CTB promotes mitochondrial apoptosis in hepatocellular carcinoma cells by inducing p53 mitochondrial translocation, and that this process relies on mitochondrial division controlled by Drp1. Our findings suggest that CTB merits further evaluation as a chemotherapeutic agent for human liver cancer.

关键词： Copper complex p53 mitochondrial translocation mitochondrial apoptosis Drp1 hepatoma cell

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Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway

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Journal of Clinical and Translational Hepatology 2023年第1期11卷 26-37页

作者： Li Chen Siwei Xia Shuqi Wang Yuanyuan Zhou Feixia Wang Zhanghao Li Yang Li Desong Kong Zili Zhang Jiangjuan Shao Xuefen Xu Feng Zhang Shizhong Zheng Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica School of PharmacyNanjing University of Chinese MedicineNanjingJiangsuChina Chinese Medicine Modernization and Big Data Research Center Nanjing University of Chinese MedicineNanjingJiangsuChina

Background and Aims:Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease.The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.Methods:The relationship between the cGAS-stimulator of interferon genes(STING)pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database.Histopathology,immunohistochemistry,fluorescence staining,Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers.Molecular docking was performed to evaluate the relationship between naringenin and cGAS,and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro.Results:Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease.Naringenin ameliorated liver injury and liver fibrosis,decreased collagen deposition and cGAS expression,and inhibited inflammation in carbon tetrachloride(CCl4)-treated mice.Molecular docking found that cGAS may be a direct target of naringenin.Consistent with the in vivo results,we verified the inhibitory effect of naringenin on activated hepatic stellate cells(HSCs).By using the cGAS-specific agonist double-stranded(ds)DNA,we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA.We verified that naringenin inhibited the cGAS-STING pathway,thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.Conclusions:Interrupting the cGAS-STING pathway helped reverse the fibrosis process.Naringenin has potential as an antihepatic fibrosis drug.

关键词： Liver fibrosis cGAS Naringenin Inflammation Hepatic stellate cells

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O-GlcNAcylation Coordinates Glutaminolysis by Regulating the Stability and Membrane Trafficking of ASCT2 in Hepatic Stellate Cells

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Journal of Clinical and Translational Hepatology 2022年第6期10卷 1107-1116页

作者： Feixia Wang Li Chen Biyun Zhang Zhanghao Li Min Shen Li Tang Zili Zhang Jiangjuan Shao Feng Zhang Shizhong Zheng Shanzhong Tan Department of Integrated TCM and Western Medicine Nanjing Hospital Affiliated to Nanjing University of Chinese MedicineNanjingJiangsuChina Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica Nan-jing University of Chinese MedicineNanjingJiangsuChina Department of Nuclear Medicine Jiangsu Province Hospital of Chinese MedicineAffiliated Hospital of Nanjing University of Chinese MedicineNanjingJiangsuChina

Background and Aims:Recognition of excessive activa-tion of hepatic stellate cells(HSCs)in liver fibrosis prompt-ed us to investigate the regulatory mechanisms of HSCs.We aimed to examine the role of O-GlcNAcylation modifica-tion of alanine,serine,cysteine transporter 2(ASCT2)in HSCs and liver fibrosis.Methods:The expression of O-Glc-NAcylation modification in fibrotic mice livers and activated HSCs was analyzed by western blotting.Immunoprecipita-tion was used to assess the interaction of ASCT2 and O-Glc-NAc transferase(OGT).In addition,ASCT2 protein stability was assayed after cycloheximide(CHX)treatment.The O-GlcNAcylation site of ASCT2 was predicted and mutated by site-directed mutagenesis.Real-time PCR,immunofluores-cence,kit determinations and Seahorse assays were used to clarify the effect of ASCT2 O-GlcNAcylation on HSC glu-taminolysis and HSC activation.Western blotting,immuno-chemistry,and immunohistofluorescence were used to ana-lyze the effect of ASCT2 O-GlcNAcylation in vivo.Results:We observed significantly increased O-GlcNAcylation modi-fication of ASCT2.ASCT2 was found to interact with OGT to regulate ASCT2 stability.We predicted and confirmed that O-GlcNAcylation of ASCT2 at Thr122 site resulted in HSCs activation.We found Thr122 O-GlcNAcylation of ASCT2 me-diated membrane trafficking of glutamine transport and attenuated HSC glutaminolysis.Finally,we validated the expression and function of ASCT2 O-GlcNAcylation after in-jection of AAV8-ASCT2 shRNA in CCl4-induced liver fibrosis mice in vivo.Conclusions:Thr122 O-GlcNAcylation regu-lation of ASCT2 resulted in stability and membrane traf-ficking-mediated glutaminolysis in HSCs and liver fibrosis.Further studies are required to assess its role as a putative therapeutic target.

关键词： ASCT2 O-GlcNacylation Stability Trafficking Liver fibrosis

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雨课堂在无机化学课程教学中的运用

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卫生职业教育 2020年第1期38卷 57-58页

作者：邵江娟李顺利陈瑞南京中医药大学药学院江苏南京210023 南京师范大学化学与材料科学学院江苏南京210023

雨课堂依托于微信平台,通过连接教师与学生的手机,提供课前、课上、课后、课外等方面的实时互动服务,成为一种新的混合式教学载体。本文以无机化学课程为例,对雨课堂在教学中的运用进行探讨。

关键词：雨课堂无机化学混合式教学

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雷公藤甲素壳聚糖纳米粒的制备与初步评价

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辽宁中医杂志 2016年第4期43卷 806-808,I0003页

作者：陈瑞赵群邵江娟王耀帅南京中医药大学药学院江苏南京210023 南京中医药大学第二临床医学院江苏南京210023

目的:制备包载雷公藤甲素的壳聚糖纳米粒系统(triptolide-chitosan nanoparticles,TP-CS NPs),并考察其理化性质及体外释药性能。方法:采用非溶剂辅助络合-化学交联法制备壳聚糖纳米粒。利用透射电镜、粒度仪、HPLC法等对制备的纳米粒... 详细信息

目的:制备包载雷公藤甲素的壳聚糖纳米粒系统(triptolide-chitosan nanoparticles,TP-CS NPs),并考察其理化性质及体外释药性能。方法:采用非溶剂辅助络合-化学交联法制备壳聚糖纳米粒。利用透射电镜、粒度仪、HPLC法等对制备的纳米粒性质进行表征。结果:制得的纳米粒呈球形,平均粒径为(151.2±5.4)nm,Zeta电位(20.1±1.2)m V,纳米粒收率(78.0±3.3)%,包封率(77.0±1.2)%,载药量(2.0±0.4)%,体外模拟释药结果表明载药纳米粒药物释放速率在24 h内持续稳定。结论:非溶剂辅助络合-化学交联法制备的雷公藤甲素壳聚糖纳米粒简便可靠,体外释药具有明显的缓释作用。

关键词：雷公藤甲素壳聚糖纳米粒非溶剂辅助络合法药物缓释

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