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Bioinformatics analysis and experimental validation of cystathionine-gamma-lyase as a potential prognosis biomarker in hepatocellular carcinoma

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BIOCELL 2024年第3期48卷 463-471页

作者： YANAN MA SHANSHAN WANG huiguo ding Department of Gastroenterology and Hepatology Beijing You’an Hospital Affiliated with Capital Medical UniversityBeijing100069China Beijing Institute of Hepatology Beijing You’an Hospital Affiliated with Capital Medical UniversityBeijing100069China

Background:Hepatocellular carcinoma(HCC)is a common malignant tumor with poor prognosis and high mortality worldwide.Although cystathionine-gamma-lyase(CSE)plays an important role in the development of multiple tumors,the clinical implication and potential mechanisms of CSE in HCC development remain elusive.Methods:In our study,the CSE expression in HCC was analyzed in Gene Expression Omnibus(GEO)and The Cancer Genome Atlas(TCGA)datasets and further conﬁrmed by RT-qPCR and immunohistochemistry assays in HCC samples.Furthermore,the associations between CSE expression and HCC malignancy as well as survival were analyzed in GSE14520 and validated in HCC patients.Finally,the biological functions of CSE in HCC cells was assessed by CCK-8,ﬂow cytometry and Western blotting.Results:Lower transcriptional and proteomic CSE expressions were found in HCC tissues in contrast to adjacent normal tissues.Decreased CSE mRNA expression was signiﬁcantly associated with advanced clinicopathological features and poor outcomes in HCC patients from public database and our cohort.Following univariate and multivariate analyses of GSE14520 data showed that CSE expression was an independent prognostic indicator for the overall survival(OS)and recurrence-free survival(RFS)of HCC patients.In vitro experiments further explained that CSE might trigger HCC cell apoptosis by H2S.Conclusion:In summary,the present study identiﬁed the relationship between CSE expression and HCC malignancy as well as OS and RFS,indicating that CSE might be a potential prognostic biomarker and a novel therapeutic target for HCC.

关键词： Hepatocellular carcinoma Cystathionine-gamma-lyase Hydrogen sulfide Prognosis Apoptosis

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Role of Hydrogen Sulfide and Hypoxia in Hepatic Angiogenesis of Portal Hypertension

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Journal of Clinical and Translational Hepatology 2023年第3期11卷 675-681页

作者： Huaxiang Yang Mingjie Tan Zhuqing Gao Shanshan Wang Lingna Lyu huiguo ding Department of Gastroenterology and Hepatology Beijing You’an Hospital Affiliated to Capital Medical UniversityBeijingChina Cell Biology Laboratory Beijing Institute of HepatologyBeijingChina

The pathogenesis of portal hypertension remains unclear,and is believed to involve dysfunction of liver sinusoidal endotheli-al cells(LSEC),activation of hepatic stellate cells(HSC),dys-regulation of endogenous hydrogen sulfide(H_(2)S)synthesis,and hypoxia-induced angiogenic responses.H_(2)S,a novel gas transmitter,plays an important role in various pathophysi-ological processes,especially in hepatic angiogenesis.Inhibi-tion of endogenous H_(2)S synthase by pharmaceutical agents or gene silencing may enhance the angiogenic response of en-dothelial cells.Hypoxia-inducible factor-1(HIF-1)is the main transcription factor of hypoxia,which induces hepatic angio-genesis through up-regulation of vascular endothelial growth factor(VEGF)in HSC and LSEC.H_(2)S has also been shown to be involved in the regulation of VEGF-mediated angiogen-esis.Therefore,H_(2)S and HIF-1 may be potential therapeutic targets for portal hypertension.The effects of H_(2)S donors or prodrugs on the hemodynamics of portal hypertension and the mechanism of H_(2)S-induced angiogenesis are promising areas for future research.

关键词： Hydrogen sulfide Hypoxia Hypoxia-inducible factor Angiogen-esis Portal hypertension

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肝硬化门静脉血栓防治的新靶点

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中华肝脏病杂志 2024年第6期32卷 484-488页

作者：王宇威丁惠国首都医科大学附属北京佑安医院肝病消化中心北京100000

门静脉血栓(PVT)分为肝硬化性PVT和非肝硬化性PVT。PVT发病率在肝硬化不同临床阶段差别较大,总体发病率约为13.92%,而肝硬化脾切除术后PVT患病率高达60%。肝硬化性PVT的发病机制尚不明确,但Janus激酶/信号转导与转录激活子信号通路活化... 详细信息

门静脉血栓(PVT)分为肝硬化性PVT和非肝硬化性PVT。PVT发病率在肝硬化不同临床阶段差别较大,总体发病率约为13.92%,而肝硬化脾切除术后PVT患病率高达60%。肝硬化性PVT的发病机制尚不明确,但Janus激酶/信号转导与转录激活子信号通路活化、血管性血友病因子表达增加、肠道菌群及其代谢产物三甲胺-N-氧化物在肝硬化血管内皮细胞损伤、PVT形成中具有重要作用,可能是肝硬化性PVT防治的新靶点。

关键词：肝硬化门静脉血栓治疗危险因素肠道菌群预防靶点

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肝硬化门静脉血栓形成风险监测及抗凝管理

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实用肝脏病杂志 2024年第1期27卷 3-6页

作者：靳珂珂丁惠国首都医科大学附属北京佑安医院肝病消化中心北京市100069

门静脉血栓形成(portal vein thrombosis,PVT)指形成于门静脉主干、肝内门静脉分支、肠系膜静脉或脾静脉的血栓[1]。PVT是肝硬化患者常见且严重的并发症之一。失代偿期肝硬化患者PVT患病率高于代偿期肝硬化患者(9.36%对5.24%,P=0.04),并... 详细信息

门静脉血栓形成(portal vein thrombosis,PVT)指形成于门静脉主干、肝内门静脉分支、肠系膜静脉或脾静脉的血栓[1]。PVT是肝硬化患者常见且严重的并发症之一。失代偿期肝硬化患者PVT患病率高于代偿期肝硬化患者(9.36%对5.24%,P=0.04),并发PVT者发生静脉曲张破裂出血(EVB)的比例显著高于无PVT者(47.33%对19.63%,P<0.001)[2]。当肝移植患者并发血栓延伸至肠系膜上静脉(superior mesenteric vein,SMV)时,术后病死率增加[3]。PVT形成会影响肝脏血流,增加门静脉压力,进而可能增加EVB、腹水、肠缺血坏死等临床并发症的风险。但是,关于肝硬化并发PVT形成的危险因素、对门静脉高压相关并发症、肝病进展和病死率的影响仍未完全阐明,肝硬化并发PVT患者的风险监测及抗凝治疗仍有待进一步研究。

关键词：肝硬化门静脉血栓形成危险因素抗凝治疗

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USP21 deubiquitylates Nanog to regulate protein stability and stem cell pluripotency

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Signal Transduction and Targeted Therapy 2016年第1期1卷 42-51页

作者： Xingyu Liu Yuying Yao huiguo ding Chuanchun Han Yuhan Chen Yuan Zhang Chanjuan Wang Xin Zhang Yiling Zhang Yun Zhai Ping Wang Wenyi Wei Jing Zhang Lingqiang Zhang Department of Hepatology and Gastroenterology Beijing Youan HospitalCapital Medical UniversityBeijingChina State Key Laboratory of Proteomics Beijing Proteome Research CenterBeijing Institute of Radiation MedicineCollaborative Innovation Center for Cancer MedicineBeijingChina Institute of Cancer Stem Cell Dalian Medical UniversityDalianChina College of Life Sciences Xiamen UniversityXiamenChina Department of Orthopedics the General Hospital of Chinese People’s Liberation ArmyBeijingChina Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghaiChina Department of Pathology Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMassachusettsUSA Department of Microbiology and Immunology Indiana University School of MedicineIndianapolisIndianaUSA

The homeobox transcription factor Nanog has a vital role in maintaining pluripotency and self-renewal of embryonic stem cells(ESCs).Stabilization of Nanog proteins is essential for ESCs.The ubiquitin–proteasome pathway mediated by E3 ubiquitin ligases and deubiquitylases is one of the key ways to regulate protein levels and functions.Although ubiquitylation of Nanog catalyzed by the ligase FBXW8 has been demonstrated,the deubiquitylase that maintains the protein levels of Nanog in ESCs yet to be defined.In this study,we identify the ubiquitin-specific peptidase 21(USP21)as a deubiquitylase for Nanog,but not for Oct4 or Sox2.USP21 interacts with Nanog protein in ESCs in vivo and in vitro.The C-terminal USP domain of USP21 and the C-domain of Nanog are responsible for this interaction.USP21 deubiquitylates the K48-type linkage of the ubiquitin chain of Nanog,stabilizing Nanog.USP21-mediated Nanog stabilization is enhanced in mouse ESCs and this stabilization is required to maintain the pluripotential state of the ESCs.Depletion of USP21 in mouse ESCs leads to Nanog degradation and ESC differentiation.Overall,our results demonstrate that USP21 maintains the stemness of mouse ESCs through deubiquitylating and stabilizing Nanog.

关键词： Nanog maintain stabilization

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Chronological dating and tectonic implications of late Cenozoic volcanic rocks and lacustrine sequence in Oiyug Basin of southern Tibet

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Science China Earth Sciences 2008年第2期51卷 275-283页

作者： CHEN HeHai HAN JingTai ding ZhongLi SUN huiguo GUO ZhengFu Institute of Geology and Geophysics Chinese Academy of SciencesBeijing 100029China Beilun Entry-exit Inspection and Quarantine Bureau of China Ningbo 315800China

Reconstruction of uplift history of the Tibetan Plateau is crucial for understanding its environmental impacts. The Oiyug Basin in southern Tibet contains multiple periods of sedimentary sequences and volcanic rocks that span much of the Cenozoic and has great potential for further studying this issue. However, these strata were poorly dated. This paper presents a chronological study of the 145 m thick and horizontally-distributed lacustrine sequence using paleomagnetic method as well as a K-Ar dating of the underlying volcanic rocks. Based on these dating results, a chronostratigraphic framework and the basin-developmental history have been established for the past 15 Ma, during which three tectonic stages are identified. The period of 15-8.1 Ma is characterized by intense volcanic activities involving at least three major eruptions. Subsequently, the basin came into a tectonically quiescent period and a lacustrine sedimentary sequence was developed. Around 2.5 Ma, an N-S fault occurred across the southern margin of the basin, leading to the disappearance of the lake environment and the development of the Oiyug River. The Gyirong basin on northern slope of the Himalayas shows a similar basin developmental history and thus there is a good agreement in tectonic activities between the Himalayan and Gangdise orogenic belts. Therefore, the tectonic evolution stages experienced by the Oiyug Basin during the past 15 Ma could have a regional significance for southern Tibet. The chronological data obtained from this study may provide some constraints for further studies with regard to the tectonic processes and environmental changes in southern Tibetan Plateau.

关键词： southern Tibet Oiyug Basin late Cenozoic paleomagnetic dating K-Ar dating

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马来酸阿伐曲泊帕治疗肝硬化合并血小板减少症的临床疗效观察

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北京医学 2024年第1期46卷 1-4页

作者：武永乐易银张金赫张世斌李鹏丁惠国董培玲首都医科大学附属北京佑安医院肝病消化中心 100069 内蒙古自治区通辽市传染病医院检验科

目的探讨马来酸阿伐曲泊帕治疗肝硬化合并血小板减少症(thrombocytopenia,TCP)患者的临床疗效。方法选取2022年1—12月首都医科大学附属北京佑安医院肝硬化伴重度TCP(PLT<50×10~9/L)患者151例,患者均接受马来酸阿伐曲泊帕治疗,检测... 详细信息

目的探讨马来酸阿伐曲泊帕治疗肝硬化合并血小板减少症(thrombocytopenia,TCP)患者的临床疗效。方法选取2022年1—12月首都医科大学附属北京佑安医院肝硬化伴重度TCP(PLT<50×10~9/L)患者151例,患者均接受马来酸阿伐曲泊帕治疗,检测患者治疗后30 d内PLT。根据治疗后30 d内PLT结果分为PLT达标组(n=117,PLT≥50×10~9/L)和未达标组(n=34,PLT <50×10~9/L),采用多因素logistic回归方程分析马来酸阿伐曲泊帕治疗肝硬化合并TCP患者PLT达标率的影响因素。结果 151例患者中男112例(74.2%)、女39例(25.8%),平均年龄(57.2±19.3)岁,PLT达标率为77.5%。多因素回归分析结果显示,年龄≥60岁(OR=3.432,95%CI:1.464~8.044)、肝功能Child-Pugh分级C级(OR=9.416,95%CI:2.416~36.695)的患者,应用马来酸阿伐曲泊帕治疗后的PLT达标率较低。达标组23例患者治疗后的PLT增长曲线结果显示,17例(73.9%)患者的PLT在治疗第15天内达峰值。结论马来酸阿伐曲泊帕治疗肝硬化TCP的临床疗效较好。高龄、肝功能差是马来酸阿伐曲泊帕治疗肝硬化合并TCP患者PLT达标率的危险因素。

关键词：马来酸阿伐曲泊帕肝硬化血小板减少症

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胆源性肝脏疾病消化内镜的诊断与治疗

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中华肝脏病杂志 2022年第7期30卷 690-695页

作者：梁雪莹丁惠国首都医科大学附属北京佑安医院肝病消化中心北京100069

胆源性肝脏疾病指肝内外胆管系统病变或胆管上皮细胞损伤,导致肝功能异常和肝脏炎症及纤维化,主要表现为慢性胆汁淤积性肝病。常见原因包括原发性胆汁性胆管炎、原发性硬化性胆管炎、进行性家族性肝内胆汁淤积症、肝移植术后胆管并发症... 详细信息

胆源性肝脏疾病指肝内外胆管系统病变或胆管上皮细胞损伤,导致肝功能异常和肝脏炎症及纤维化,主要表现为慢性胆汁淤积性肝病。常见原因包括原发性胆汁性胆管炎、原发性硬化性胆管炎、进行性家族性肝内胆汁淤积症、肝移植术后胆管并发症、药物或严重感染所致的胆管消失综合征等。瘙痒和黄疸是最突出症状,影响患者的生活质量。逆行十二指肠镜胰胆管造影术、胆胰子镜直视系统(SpyGlass)等内镜检查,可显著提高原发性硬化性胆管炎、免疫球蛋白G4相关胆管炎与胆管癌的早期鉴别诊断能力,实现精准细胞学及活组织检查。经内镜鼻胆管引流术、球囊扩张术及胆管内支架置入术可显著改善瘙痒症状、肝脏生物化学指标和预后。因此,消化内镜在胆源性肝脏疾病诊断与治疗中显示了重要价值和应用前景。

关键词：超声内镜胆源性肝脏疾病胆汁淤积性肝病逆行十二指肠镜胰胆管造影术胆胰子镜直视系统

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重视应急附条件获批治疗新型冠状病毒感染药物的安全管理

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药物不良反应杂志 2023年第1期25卷 2-5页

作者：曾阿娟韩莹丁惠国首都医科大学附属北京佑安医院肝病消化中心北京100069 首都医科大学附属北京佑安医院肝病中心二科北京100069

目前,我国应急附条件批准(CMA)3种抗新型冠状病毒药物,包括莫诺拉韦、奈玛特韦/利托那韦和阿兹夫定。这些药物存在临床有效性和安全性数据相对不足的现状。莫诺拉韦不是主要的药物代谢酶或转运体的抑制剂或诱导剂,发生药物相互作用的可... 详细信息

目前,我国应急附条件批准(CMA)3种抗新型冠状病毒药物,包括莫诺拉韦、奈玛特韦/利托那韦和阿兹夫定。这些药物存在临床有效性和安全性数据相对不足的现状。莫诺拉韦不是主要的药物代谢酶或转运体的抑制剂或诱导剂,发生药物相互作用的可能性较小,对需要长期药物治疗的慢性病患者可能更有利。Paxlovid中的利托那韦是药物代谢关键酶—CYP3A4强抑制剂,可与众多治疗心律失常、糖尿病、神经系统疾病等的药物发生相互作用,导致治疗基础疾病的药物安全风险增加。阿兹夫定药品说明书记载的生殖和遗传毒性令人担忧。实现对3种药物的安全管理需要我国政府、医院管理者、临床医师和药师等的共同努力,包括完善药物CMA相关管理法规,加强对这些药物有效性、安全性监测,进行真实世界临床研究,监测病毒的变异及其耐药等。

关键词：新型冠状病毒感染抗病毒药安全药物相互作用奈玛特韦利托那韦莫诺拉韦阿兹夫定

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Baseline Characteristics and Treatment Patterns of the Patients Recruited to the China Registry of Hepatitis B

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Journal of Clinical and Translational Hepatology 2019年第4期7卷 322-328页

作者： Shan Shan Hong You Junqi Niu Jia Shang Wen Xie Yuexin Zhang Xun Li Hong Ren Hong Tang huiguo ding Xihong Wang Yuemin Nan Xiaoguang Dou Tao Han Lingyi Zhang Xiaoqing Liu Cunliang Deng Jilin Cheng Xiaozhong Wang Qing Xie Shumei Lin Yan Huang Youqing Xu Yong Xiong Wu Li Xuebing Yan Hongxin Piao Wenxiang Huang Qinghua Lu Weijin Gong Shiping Li Xiaoxuan Hu Xiaolan Zhang Shourong Liu Yufang Li Dongliang Yang Hai Li Caixia Yang Mingliang Cheng Liaoyun Zhang Huanwei Zheng Xinhua Luo Feng Lin Lei Wang Guanghua Xu Xiaoyuan Xu Lai Wei Jinlin Hou Zhongping Duan Hui Zhuang Xizhong Yang Yuanyuan Kong Jidong Jia the CR-HepB study group,Beijing,China Liver Research Center Beijing Friendship HospitalCapital Medical UniversityBeijing Key Laboratory of Translational Medicine on Liver CirrhosisNational Clinical Research Center for Digestive DiseasesBeijingChina Department of Hepatology First Hospital of Jilin UniversityChangchunJilinChina Department of Infectious Diseases Henan Provincial People's HospitalZhengzhouHenanChina Center of Liver Diseases Beijing Ditan HospitalCapital Medical UniversityBeijingChina Department of Infectious Diseases First Affiliated Hospital of Xinjiang Medical UniversityUrumqiXinjiangChina Department of General Surgery The First Hospital of Lanzhou UniversityLanzhouGansuChina Department of Infectious Diseases The Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina Center of Infectious Diseases West China Hospital of Sichuan UniversityChengduSichuanChina Department of Gastroenterology and Hepatology Beijing Youan HospitalCapital Medical UniversityBeijingChina Center of Infectious Diseases The Third People's Hospital of TaiyuanTaiyuanShanxiChina Department of Traditional and Western Medical Hepatology The Third Hospital of Hebei Medical UniversityShijiazhuangHebeiChina Department of Infectious Diseases Shengjing Hospital of China Medical UniversityShenyangLiaoningChina Department of Hepatology Tianjin Third Central HospitalTianjin Medical UniversityTianjinChina Department of Hepatology Lanzhou University Second HospitalLanzhouGansuChina Department of Infectious Diseases Peking Union Medical College HospitalBeijingChina Department of Infectious Diseases The Affiliated Hospital of Southwest Medical UniversityLuzhouGansuChina Department of Gastroenterology Shanghai Public Health Clinical CenterShanghaiChina Department of Hepatology Xinjiang Uygur Autonomous Region Traditional Chinese Medicine HospitalUrumqiXinjiangChina Department of Infectious Diseases Shanghai Ruijin HospitalJiao Tong University School of MedicineShanghaiChina Department of Infectious Diseases Th

Background and Aims: Chronic hepatitis B virus(HBV)in-fection remains a major public health problem globally.Here,we describe the baseline characteristics and treatment pro-files of HBV-infected patients recruited to the China Registry of Hepatitis B.Methods: Inclusion criteria were patients with different stages of chronic HBV infection and complete key data.Exclusion criteria were patients with hepatocellular car-cinoma.The baseline clinical,laboratory and treatment pro-files were analyzed.Results: Finally,40,431 patients were included.The median age was 43 years,with 65.2%being men and 51.3%being positive for hepatitis B e antigen(HBeAg).The most common initial diagnosis was chronic hep-atitis B(81.0%),followed by cirrhosis(9.3%),inactive carrier of hepatitis B surface antigen(HBsAg)(6.7%),and immune tolerant phase of hepatitis B infection(3.0%).Among the 21,228 patients who were on treatment,88.0%,10.0%and 2.0%received nucleos(t)ide analogues(NAs),interferon or combination of NAs and interferon,respectively.The propor-tion of patients who received preferred NAs(entecavir or te-nofovir disoproxil fumarate)had increased from 13.5%in 2003 to 79.7%in 2016.Conclusions: We concluded that middle-aged men accounted for most of the patients with chronic hepatitis B in this cross-sectional study.About half of the patients were HBeAg-positive.NAs were the most com-monly used therapy,and use of the preferred NAs had steadily increased in the past decade.

关键词： Hepatitis B Treatment Registry

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