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C-X-C chemokine receptor type 5+CD8+T cells as immune regulators in hepatitis Be antigen-positive chronic hepatitis B under interferonalpha treatment

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World Journal of Gastroenterology 2025年第3期31卷 73-83页

作者： Zhen-Yu Xu zhong-Shang Dai guo-zhong gong Min Zhang Department of Infectious Diseases Second Xiangya HospitalCentral South UniversityChangsha 410011Hunan ProvinceChina Institute of Hepatology and Department of Infectious Diseases The Second Xiangya HospitalCentral South UniversityChangsha 410011Hunan ProvinceChina

BACKGROUND C-X-C chemokine receptor type 5(CXCR5)+CD8+T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell *** their importance,the specific role of CXCR5+CD8+T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully *** study aims to elucidate the relationship between CXCR5+CD8+T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for *** To elucidate the relationship between CXCR5+CD8+T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for *** This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-α*** were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×104 copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of *** samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8+T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell *** Patients with CHB exhibited significantly lower levels of circulating CXCR5+CD8+T cells compared to healthy controls(P<0.01).Notably,CXCR5+CD8+T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.62

关键词： C-X-C chemokine receptor type 5 Programmed death-ligand 1 Interleukin-21 Pegylated interferon-alpha Chronic hepatitis B

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Diagnosis and management of fulminant Wilson's disease: a single center's experience

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World Journal of Pediatrics 2016年第2期12卷 209-214页

作者： Yi Tian guo-zhong gong Xu Yang Feng Peng Liver Disease Research Center Second Xiangya Hospital of Central South UniversityChangsha 410011China

Background: Medical therapy is rarely effective inpatients with fulminant Wilson's disease (FWD). Livertransplantation is limited by the lack of donor liver inmost patients with FWD at the time of diagnosis. NewWilson's index, model for end-stage liver disease (MELD)and Child-Pugh score are useful tools for decisionmakingof liver transplantation;however, none of them isan independent decisive tool. It is worthwhile to explorea more effective and practical therapeutic strategy andreevaluate the prediction systems for patients with ***: Nine patients with FWD associated withhemolytic crisis and fulminant hepatic failure (FHF) wereinvestigated. The clinical presentation, prognostic scoreand medical therapies of the patients were ***: In 7 of the 9 patients with FWD who receivedthe comprehensive therapy of corticosteroid, copperchelatingagent (dimercaptopropansulfonate sodium)and therapeutic plasma exchange (TPE), 6 patientsrecovered from FHF. The remaining one had beenimproved through the comprehensive therapy but died ofsepticemia 51 days later. Two patients with spontaneousbacterial peritonitis (SBP) died from liver failure inthree or five hospital days without plasma exchangeor chelating therapy. All of the 9 patients with FWDpresented with acute hepatic failure, severe jaundice andmild to severe hemolytic anemia. No marked differencein the incidence of severe hemolytic anemia was detectedbetween the survival and deceased groups. However,the incidence and the degree of hepatic encephalopathy(HE) in the non-survival group were higher than thosein the survival group. Unlike the deceased group, thesurvival group had no complications induced by bacterialinfection. Compared to new Wilson's index, Child-Pughscore and MELD score, the variation of prothrombinactivity (PTA) between the survival and deceased groupswas more ***: For patients with FWD, the episodeof severe hepatic encephalopathy or/and spontaneousbacterial peritonitis indica

关键词： decoppering dimercaptopropansulfonate sodium fulminant hepatic failure therapeutic plasma exchange Wilson's disease

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Cationic liposome-mediated transfection of CD40 ligand gene inhibits hepatic tumor growth of hepatocellular carcinoma in mice

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2009年第1期10卷 7-13页

作者： Yong-fang JIANG Jing MA Yan HE Yong-hong ZHANG Yun XU guo-zhong gong Center for Liver Diseases the Second Xiangya Hospital Central South University Changsha 410011 China

Objective: To evaluate the efficacy of cationic liposome-mediated CD40 ligand (CD40L) gene therapy for hepato- cellular carcinoma. Methods: 1×106 of parental H22 cells or H22 cells transfected with the expression vector containing murine CD40L cDNA encoding the entire coding region (pcDNA3.1+-mCD40L) were inoculated subcutaneously into the left flanks of syngenic BALB/C mice. The tumor-bearing mice (tumor nodules 10 mm in maximal diameter) received the treatment of the intratumoral injection of pcDNA3.1+-mCD40L/Transfectam, pcDNA3.1+, or phosphate-buffered saline (PBS), or no treatment. The mice were monitored for tumor growth weekly. We examined mCD40L messenger ribonucleic acid (mRNA) expression by reverse transcription polymerase chain reaction (RT-PCR) and the histologic changes in tumors at two weeks after intratumoral injection using immunohistochemical staining of tumor tissues. Results: All mice inoculated with parental H22 cells developed a tumor subcutaneously, and the tumor size increased progressively within three weeks. However, the mice receiving H22-CD40L cells exhibited complete regression of the tumor two weeks after tumor cell inoculation. The tumor-bearing animals with the treatment of pcDNA3.1+ or PBS, or without treatment had progressive tumor growth, while those mice treated with pcDNA3.1+-mCD40L exhibited a significant inhibition of tumor growth. RT-PCR analysis showed that 783-bp fragments cor- responding to the mCD40L mRNA were amplified only from pcDNA3.1+-mCD40L treated tumors. The tumor samples from pcDNA3.1+-mCD40L-treated mice showed significant lymphocyte infiltration, apoptotic bodies, and confluent necrosis in the tumor tissues. Conclusion: The tumorigenicity of CD40L-expressing cells was abrogated when the cells were implanted subcu- taneously. In vivo gene therapy of established liver tumor nodules in mice by the intratumoral injection of pcDNA3.1+-mCD40L led to significant tumor inhibition. There was mCD40L mRNA expression in the

关键词： CD40 ligand gene Hepatocellular carcinoma (HCC) Cationic liposome Transfection

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Novel HBV mutations and their value in predicting efficacy of conventional interferon

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Hepatobiliary & Pancreatic Diseases International 2017年第2期16卷 189-196页

作者： Da-Xian Wu Xiao-Yu Fu guo-zhong gong Ke-Wei Sun Huan-Yu gong Ling Wang Juan Wu De-Ming Tan Department of Infectious Diseases Xiangya Hospital Central South University Key Laboratory of Viral Hepatitis of Hunan Province Department of Infectious Diseases The Second Xiangya Hospital Central South University Department of Infectious Diseases The First Affiliated Hospital Hunan University of Chinese Medicine Department of Infectious Diseases The Third Xiangya Hospital Central South University

BACKGROUND： Accumulating studies assessing the impacts of hot spot mutations on conventional interferon（IFN） efficacy come to discrepant conclusions; studies regarding the mutations in S and RT regions are also unclear. The present study aimed to evaluate the impacts of HBV mutations on the efficacy of conventional IFN. METHODS： A total of 126 patients who received conventional IFN treatment for 48 weeks were enrolled. Biochemical and serological parameters were routinely tested. The sequences of HBV from 78 serum samples were amplified by nested-PCR; mutations were identified with sequence scanner V1.0 after ABI 3730 xl direct sequencing, HBV genotypes were determined according to RT gene sequences utilizing NCBI Genotyping Tool which was based on phylogenetic ***： The baseline DNA levels of virological response（VR） group were significantly lower than those of no VR group [7.13±0.76 vs 7.69±0.56 lg（copies/m L）, P=0.001]. The baseline ALT levels were significantly higher in the HBe Ag clearance group（204.72±88.65 vs 162.80±85.81 IU/L, P〈0.05） andHBe Ag seroconversion group（204.89 ±95.68 vs 166.75±84.43 IU/L, P〈0.05）. Females and lower BMI levels（20.01±2.33 vs 21.65±3.66 kg/m^2, P〈0.05） were prone to acquired biochemical response（BR）. PC-W28STOP（ntG 1896A） was significantly higher in the combined response（CR） group than that in the no CR group（91.7% vs 39.7%, P=0.001）. Multivariate logistic regression analysis showed that baseline DNA, PC-P159T（ntC2288A）, BCP-N118T（ntA 1726C） and BCP-L134L（ntA 1775C/G/T） influenced VR independently. PC-G182C（nt G2357T）, PC-S64A/T（nt T2003G/A） and BMI were independent influence factors for HBe Ag clearance, HBe Ag seroconversion and BR, respectively. The new predicting model concluded that baseline DNA and new mutations for VR were established successfully, and ROC analysis showed that AUC was 0.842（P〈0.001） with a sensitivity of 0.652 and a specificity of ***： PC-P159T（ntC 2288A）, BCP-N118T（ntA 1726C）, BCP-

关键词： hepatitis B virus interferon mutation treatment efficacy

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Hepatitis B virus-persistent infection and innate immunity defect: Cell-related or virus-related?

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World Journal of Clinical Cases 2018年第9期6卷 233-241页

作者： Jian Tang Zhen-Yu Wu Rong-Juan Dai Jing Ma guo-zhong gong Department of Infectious Disease the Second Xiangya Hospital Central South University Department of Infectious Disease the First Affiliated Hospital of University of South China

The outcomes of hepatitis B virus(HBV) infection are closely related to the age at which infection was acquired. Infection acquired in adult life tends to be selflimited, in contrast to perinatal acquirement, for which chronic persistence of the HBV is a general outcome. Innate immunity plays an indispensable role in early virus infection, facilitating virus clearance. However, it has been reported that HBV is under-recognized and poorly eliminated by the innate immune system in the early stages of infection, possibly explaining the long-lasting persistence of viremia afterwards. Furthermore, due to the existence of covalently closed circular DNA, chronic HBV clearance is very difficult, even when patients are given interferon-α and nucleotide/nucleoside analogs for antiviral therapy. The mechanism by which HBV evades innate immune recognition and establishes persistent infection remains a subject of debate. Besides, some researchers are becoming more interested in how to eradicate chronic HBV infection by restoring or boosting innate immunity. This review aimed to summarize the current knowledge on how intrahepatocyte signaling pathways and innate immune cells act after the onset of HBV infection and how these actions are related to the persistence of HBV. We anticipate the insights presented herein to be helpful for future development of novel immune therapeutic strategies to fight HBV infection.

关键词： Hepatitis B virus Innate immunity Immune evasion Pattern recognition receptor Toll-like receptor Natural killer cells Kupffer cells Dendritic cells

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Hepatitis C Virus non-structural 5A abrogates signal transducer and activator of transcription-1 nuclear translocation induced by IFN-α through dephosphorylation

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World Journal of Gastroenterology 2007年第30期13卷 4080-4084页

作者： guo-zhong gong Jie Cao Yong-Fang Jiang Yang Zhou Bo Liu Institute of Hepatology and Department of Infectious Diseases The Second Xiangya Hospital Central South University Changsha 410011 Hunan Province China

AIM： To study the effect of Hepatitis C virus nonstructural 5A （HCV NSSA） on IFNα induced signal transducer and activator of transcription-1 （STAT1） phosphorylation and nuclear translocation.METHODS： Expression of STAT1 Tyr701 phosphorylation at different time points was confirmed by Western blot, and the time point when p-STAT1 expressed most, was taken as the IFN induction time for further studies. Immunocytochemistry was used to confirm the successful transient transfection of NS5A expression plasmid. Immunofluorescene was performed to observe if there was any difference in IFNα-induced STAT1 phosphorylation and nuclear translocation between HCV NSSA-expressed and non-HCV NSSA-expressed cells. Western blot was used to compare the phosphorylated STAT1 protein of the cells.RESULTS： Expression of HCV NS5A was found in the cytoplasm of pCNS5A-transfected Huh7 cells, but not in the PRC/ CMV transfected or non-transfected cells, STAT1 Tyr701 phosphorylation was found strongest in 30 min of IFN induction, STAT1 phosphorylation and nuclear import were much less in the presence of HCV NS5A protein in contrast to pRC/CMV-transfected and non-transfected cells under fluorescent microscopy, which was further confirmed by Western blot.CONCLUSION： HCV NSSA expression plasmid is successfully transfected into Huh7 cells and HCV NS5A protein is expressed in the cytoplasm of the cells. IFN-α is able to induce STAT1 phosphrylation and nuclear translocation, and this effect is inhibited by HCV NS5A protein, which might be another possible resistance mechanism to interferon alpha therapy.

关键词： Hepatitis C virus nonstructural protein 5A IFN-α Signal transducer and activator of transcription (STAT1) Phosphorylation Nuclear translocation

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HCV replication in PBMC and its influence on interferon therapy

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World Journal of Gastroenterology 2003年第2期9卷 291-294页

作者： guo-zhong gong Li-Ying Lai Yong-Fang Jiang Yan He Xian-Shi Su Center for Liver Diseases, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China Center for Liver Diseases Second Xiangya Hospital Xiangya Medical School Central South University 86 Middle Renmin Street Changsha 410011 Hunan Province China. guozhong_gong@***

AIM: To study hepatic virus C (HCV) RNA and HCV proteinexpression in peripheral blood mononuclear cells (PBMCs)of patients with HCV infection, and explore the relationshipbetween the HCV RNA in the PBMCs and response tointerferon (IFN) ***: Type-specific primers were designed and RT-nested PCR was used to detect the plus- and minus- strandsof HCV RNA in PBMCs of 54 patients with HCV infection;Indirect immunofluorescence assay was applied to identifyHCVNS5 protein expression in PBMCs; 6 month-, 3 MU-IFNregiment was administrated to observe the responses toIFN in 35 chronic hepatitis C patients with different HCVRNA status in ***: HCV plus strand RNA was found in 10 of 19(52.6 %) acute hepatitis C patients and 22 of 35 (62.9 %)chronic hepatitis C patients. HCV minus strand RNA wasdetected in 14 of 35 (40.0 %) chronic hepatitis C patients,but only one patient (5.3 %) with acute HCV infection wasfound to be minus HCV RNA positive. Though no HCV NS5protein expression was found in the examined 10 cases ofacute HCV infection, it was positive in 17 of 20 (85.0 %)chronic hepatitis C patients by indirect immunofluoresenceassay. There are significant differences of positive rate of theminus-strand and HCVNS5 protein between acute and chronichepatitis C groups(u=2.07, P＜0.05and u=4.43, P＜0.01respectively). The patients with minus-strand HCV RNAshowed a significantly lower 6-month sustained response (SR-6) to IFN compared to those without minus-strand HCVRNAin PBMCs (biologically 14.3 % vs 42.8 %, X2=4.12, P＜0.05and virologically 7.1% vs23.9 %, X2=4.24, P＜0.05).CONCLUSION: HCV is capable of infecting and replicatingin PBMCs, and HCVNS5 protein was expressed in *** patients with minus strand HCV RNA in PBMCs showeda significantly lower 6-month sustained response to IFN,suggesting that minus-strand HCV RNA in PBMCs may beone of the factors influencing response to IFN therapy.

关键词：外周血单核细胞丙型肝炎病毒病毒复制干扰素免疫疗法

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CD40配体基因对实验性肝细胞癌的治疗作用

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世界华人消化杂志 2005年第11期13卷 1287-1290页

作者：蒋永芳何艳张永红许允龚国忠中南大学湘雅二医院肝痛研究中心湖南省长沙市410011

目的:探讨鼠CD40配体基因体内抗肿瘤作用方法:转染和未转染质粒pcDNA3.1+-mCD40L的H22细胞(1×106)分别种植到同源Balb/c小鼠左侧腹皮下.荷瘤小鼠(瘤结节最大直径约10mm)瘤结节内直接注射pcDNA3.1+-mCD40L/脂质体复合物(治疗组)或者pcDN... 详细信息

目的:探讨鼠CD40配体基因体内抗肿瘤作用方法:转染和未转染质粒pcDNA3.1+-mCD40L的H22细胞(1×106)分别种植到同源Balb/c小鼠左侧腹皮下.荷瘤小鼠(瘤结节最大直径约10mm)瘤结节内直接注射pcDNA3.1+-mCD40L/脂质体复合物(治疗组)或者pcDNA3.1+、脂质体、培养基(对照组).每周测量各组小鼠皮下肿瘤结节的平均直径的大小,绘制肿瘤生长曲线.RT-PCR法检测治疗组肿瘤组织mCD40LmRNA的表达.常规组织HE染色观察治疗组肿瘤组织病理变化.结果:注射转染了质粒的H22细胞的Balb/c小鼠皮下一直未见瘤结节出现.治疗组荷瘤小鼠瘤结节生长受到明显的抑制,而对照组小鼠瘤结节生长没有抑制.用RT—PCR法从pcDNA3.1+-mCD40L治疗组的小鼠肿瘤组织中扩增出783bp大小片段产物.病理检查发现治疗组肿瘤组织中有明显淋巴细胞浸润、大量凋亡小体和片状坏死.结论:质粒pcDNA3.1+-mCD40L转染后使H22细胞致瘤性明显下降.直接瘤内注射pcDNA3.1+-mCD40L能使荷瘤Balb/c小鼠瘤结节生长明显抑制.质粒pcDNA3.1+-mCD40L治疗组肿瘤组织中有mCD40LmRNA的表达和明显的炎症反应以及肿瘤细胞凋亡、坏死明显增加.

关键词： CD40配体基因实验性肝细胞癌治疗作用 pcDNA3 荷瘤Balb/c小鼠 H22细胞 RT-PCR法肿瘤组织脂质体复合物 PCR法检测组织病理变化淋巴细胞浸润肿瘤细胞凋亡荷瘤小鼠 mRNA 治疗组直接注射作用方法平均直径皮下肿瘤

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BIBR1532 inhibits proliferation and metastasis of esophageal squamous cancer cells by inducing telomere dysregulation

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World Journal of Gastrointestinal Oncology 2025年第1期17卷 214-225页

作者： Qin Wang Qing-Rong Li Lei Xu Zi-Chun Yuan Xiao Liu Mao-Ju Tang Man Luo Xiao-Wu zhong Qiang Ma Xiao-Lan guo Department of Clinical Laboratory Affiliated Hospital of North Sichuan Medical CollegeNanchong 637000Sichuan ProvinceChina School of Laboratory Medicine&Translational Medicine Research Center North Sichuan Medical CollegeNanchong 637000Sichuan ProvinceChina

BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a malignant tumor with high morbidity and mortality,and easy to develop resistance to chemotherapeutic *** are DNA-protein complexes located at the termini of chro-mosomes in eukaryotic cells,which are unreplaceable in maintaining the stability and integrity of ***,an RNA-dependent DNA polymerase,play vital role in telomere length maintain,targeting telomerase is a promising therapeutic strategy for ***150 and KYSE410 cells were cultured and exposed to various concentrations of *** viability was assessed at 48 hours and 72 hours to determine the IC50 *** effects of BIBR1532 on ESCC cell proliferation,migration,and cellular senescence were evaluated using the cell counting kit-8 assay,plate colony formation assay,scratch assay,transwell assay,andβ-galactosidase staining,*** blotting was performed to detect the expression of RESULTS The IC50 values for KYSE150 and KYSE410 cells after 48 hours of BIBR1532 exposure were 48.53μM and 39.59μM,*** values decreased to 37.22μM and 22.71μM,respectively,following a longer exposure of 72 ***1532 exhibited dose-dependent effects on KYSE150 and KYSE410 cells,including decreased hTERT expression,inhibition of proliferation and metastasis,and induction of cellular ***,BIBR1532 upregulated the expression of the DDR protein,γ-H2AX,and activated the ataxia telangiectasia and Rad3-related protein(ATR)/check point kinase 1(CHK-1)and ataxia-telangiectasia mutated gene(ATM)/CHK2 ***1532 downregulated the expression of telomere-binding proteins,including telomeric-repeat binding factor 1(TRF1),TRF2,protection of telomeres 1,and TIN2-interacting protein *** a nude mouse xenograft model,BIBR1532 significantly suppressed tumor growth,reduced hTERT expression,and increasedγ-H2AX protein *** and eosin staining of various organs,including the heart,liver,s

关键词： Esophageal squamous cell carcinoma BIBR1532 Human telomerase reverse transcriptase DNA damage response Telomere-binding proteins

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Prediction and stratification for the surgical adverse events after minimally invasive esophagectomy:A two-center retrospective study

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World Journal of Gastroenterology 2025年第3期31卷 50-61页

作者： Qi-Hong zhong Jiang-Shan Huang Fei-Long guo Jing-Yu Wu Mao-Xiu Yuan Jia-Fu Zhu Wen-Wei Lin Sui Chen Zhen-Yang Zhang Jiang-Bo Lin Department of Thoracic Surgery Fujian Medical University Union HospitalFuzhou 350001Fujian ProvinceChina The Graduate School Fujian Medical UniversityFuzhou 350001Fujian ProvinceChina Department of Thoracic Surgery Affiliated Hospital of Jinggangshan UniversityJi’an 343000Jiangxi ProvinceChina

BACKGROUND Minimally invasive esophagectomy(MIE)is a widely accepted treatment for esophageal cancer,yet it is associated with a significant risk of surgical adverse events(SAEs),which can compromise patient recovery and long-term *** preoperative identification of high-risk patients is critical for improving *** To establish and validate a risk prediction and stratification model for the risk of SAEs in patients with *** This retrospective study included 747 patients who underwent MIE at two centers from January 2019 to February *** were separated into a train set(n=549)and a validation set(n=198).After screening by least absolute shrinkage and selection operator regression,multivariate logistic regression analyzed clinical and intraoperative variables to identify independent risk factors for SAEs.A risk stratification model was constructed and validated to predict the probability of *** SAEs occurred in 10.2%of patients in train set and 13.6%in the validation *** with SAE had significantly higher complication rate and a longer hospital stay after *** key independent risk factors identified included chronic obstructive pulmonary disease,a history of alcohol consumption,low forced expiratory volume in the first second,and low albumin *** stratification model has excellent prediction accuracy,with an area under the curve of 0.889 for the training set and an area under the curve of 0.793 for the validation *** The developed risk stratification model effectively predicts the risk of SAEs in patients undergoing MIE,facilitating targeted preoperative interventions and improving perioperative management.

关键词： Surgical adverse events Minimally invasive esophagectomy Esophageal cancer Stratification model Perioperative management

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