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Neural Regeneration Research 2025年第7期20卷 2011-2012页

作者： Sharon J.Brown Rafael J.Yáñez-Muñoz Heidi R.Fuller School of Pharmacy and Bioengineering Keele UniversityKeeleUK Wolfson center for Inherited Neuromuscular Disease TORCH BuildingRJAH Orthopaedic HospitalOswestryUK *** Center of Gene and Cell TherapyDepartment of Biological SciencesSchool of Life Sciences and the EnvironmentRoyal Holloway University of LondonEghamUK

Spinal muscular atrophy(SMA)is a genetic condition that results in selective lower motor neuron loss with concomitant muscle weakness and *** genetic cause of SMA was understood in 1995 when loss or impairment of the survival motor neuron 1(SMN1)gene was identified as the main contributing factor(Lefebvre et al.,1995).This,in combination with the discovery that humans have a“back-up”gene,SMN2,which can produce low levels(approximately 10%)of the full-length functional SMN protein,has led to the generation of SMA-specific gene *** was traditionally classified according to age of symptom onset and developmental milestones achieved,with life expectancy and severity varying between ***,SMN2 copy number is used as a proxy for the prediction of disease severity,with higher SMN2 copy number typically being associated with reduced severity of SMA,although this relationship is not absolute:some individuals with low SMN2 copy number have less severe SMA phenotypes and vice ***,the etiology of SMA is further complicated by other factors,such as non-typical nucleotide variants and SMN2-independent modifiers of disease severity.

关键词： atrophy traditionally absolute

LIM kinases in synaptic plasticity and their potential as therapeutic targets

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Neural Regeneration Research 2020年第8期15卷 1471-1472页

作者： Éva Halász Ellen Townes-Anderson Weiwei Wang Department of Pharmacology Physiology and NeuroscienceGraduate School of Biomedical SciencesRutgersThe State University of New JerseyNewarkNJUSA grousbeck gene therapy center Schepens Eye Research Institute and Massachusetts Eye and EarHarvard Medical SchoolBostonMAUSA

LIM domain kinases(LIMKs),which modulate cytoskeletal dynamics,are found throughout the central nervous *** synaptic junctions between neurons show structural alteration or plasticity during neurodevelopment,learning and memory formation,or after injury and disease;in some cases completely new connections form,while others are *** remodeling is under the control of the actin cytoskeleton and therefore is influenced by the activity of LIMKs(Scott and Olson,2007).Recent reports discussed in this perspective shed light on the potential role of LIMK in hippocampal dendritic spines and photoreceptor presynaptic terminals and illustrate the importance of LIMK in nerve cell function.

关键词： function. plasticity potential

Targeting the insulin-like growth factor pathway in hepatocellular carcinoma

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World Journal of Hepatology 2014年第10期6卷 716-737页

作者： Mónica Enguita-Germán Puri Fortes Department of Hepatology and gene therapy Center for Applied Medical Research

Hepatocellular carcinoma(HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor(IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed suchas monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor Ⅱ rather than insulin growth factor Ⅰ. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-Ⅰ signaling pathway for hepatocellular carcinoma treatment.

关键词： Hepatocellular carcinoma Insulin Insulinlike growth factor Insulinlike growth factor receptor therapy Tyrosine kinase inhibitor Antibody therapy

Cloning and characterization of a novel hepatitis B virus core binding protein C12

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World Journal of Gastroenterology 2005年第36期11卷 5666-5671页

作者： Yin-Ying Lu Jun Cheng Yong-Ping Yang Yan Liu Lin Wang Ke Li Ling-Xia Zhang gene therapy Research center Institute of Infectious Diseases The 302 Hospital of PLA 100 Xisihuanzhong Road Beijing 100039 China

AIM： To elucidate the biological function of HBV core antigen （HBcAg） on pathogenesis of hepatitis B, a novel gene C12 coding for protein with unknown function interacting with HBcAg in hepatocytes was identified and characterized. METHODS： HBcAg bait plasmid pGBKT7-HBcAg was constructed and transformed into yeast AH109, then the transformed yeast was mated with yeast Y187 containing liver complementary DNA （cDNA） library plasmid in 2xYPDA medium. Diploid yeast was plated on synthetic dropout nutrient medium （SD/-Trp-Leu-His-Ade） and synthetic dropout nutrient medium （SD/-Trp-Leu-His-Ade） containing X-α-gal for screening twice. After extracting and sequencing of plasmid from blue colonies, we isolated a cDNA clone encoding a novel protein designated as C12 that directly interacted with HBcAg. The interaction between HBcAg and C12 was verified again by re-mating. pEGFP-N1-C12 fluorescent protein fusion gene was transfected in 293 and L02 cell, and observed by fluorescent microscope. M-FI reduction assay was used to study the action of C12 protein effect on metabolism of mammal cell. Yeast two-hybrid and cDNA microarray were performed to search binding protein and differential expression genes regulated by C12 protein. RESULTS： C12 gene was screened and identified by yeast two-hybrid system 3. The interaction between HBcAg and the novel protein coded by the new gene C12 was further confirmed by re-mating. After 48 h, fluorescence of fusion protein could be observed steadily in the 293 and L02 cell plasma. Under MTT assay, we found that the expression of C12 did not influence the growth of liver cells. Seventeen differential expression genes in HepG2 cells transfected with C12 protein expression plasmid by cDNA microarray, of which 16 genes were upregulated and 1 gene was downregulated by C12 protein. Twenty-one colonies containing 16 different genes coding for C12 protein binding proteins were isolated by yeast two-hybrid, there were 2 new genes with unknown function.

关键词： Hepatitis B virus core antigen Yeast two-hybrid cDNA microarray MTT assay

Inhibition of Bcl-2 expression by a novel tumor-specific RNA interference system increases chemosensitivity to 5-fluorouracil in Hela cells

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Acta Pharmacologica Sinica 2006年第2期27卷 242-248页

作者： Sheng-lin HUANG Yi WU Hai YU Ping ZHANG Xing-qian ZHANG Lei YING Han-fang ZHAO Research center for Human gene therapy,Department of Biochemistry and Molecular Biology.Shanghai Jiao Tong University School of Medicine,Shanghai 200025.China Department of Biochemistry and Molecular Biology Research Center for Human Gene Therapy Shanghai Jiao Tong University School of Medicine Shanghai China

Aim:RNA interference(RNAi)has been proposed as a potential treatment forcancer,but the lack of cellular targets limits its use in cancer gene *** technology has achieved direct tumor-specific gene silencing using *** the present study we attempt to develop a tumor-specific RNAi system usingthe human telomerase reverse transcriptase(hTERT)promoter:furthermore,weanalyzed its inhibitive effect on Bcl-2 ***:The vectors contain-ing a small hairpin RNA(shRNA)to target exogenous reporters[firefly luciferaseand enhanced green fluorescent protein(EGFP)]and endogenous gene(Bcl-2)were *** expression was determined by dual luciferase *** transcription-polymerase chain reaction(RT-PCR),fluorescence micros-copy and fluorescence-activated cell sorting(FACS)were used to measure EGFPexpression,Inhibition of Bcl-2 was evaluated by RT-PCR and Western *** proliferation and viability were measured by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide(MTT)*** was used to analyzethe cell cycle distribution ***:We showed that with the hTERTpromoter directly driving shRNA transcription,expression of the exogenous re-porters(LUC and EGFP)in tumor cells,but not normal cells,was specificallyinhibited in *** hTERT promoter-driven shRNA also depressed the expres-sion of *** of Bcl-2 did not affect cell proliferation,but increased thechemosensitivity of HeLa cells to ***:The present studydescribes an efficient RNAi system for gene silencing that is specific to tumorcells using the hTERT *** of Bcl-2 by using this system sen-sitized HeLa cells to *** system may be useful for RNAi therapy.

关键词： RNA interference telomerase promoter regions (genetics) Bcl-2 fluorouracil gene therapy

Booming cancer immunotherapy fighting tumors

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Science China(Life Sciences) 2017年第12期60卷 1445-1449页

作者： Dan Li Wei Wang Lab of gene and Cell therapy Cancer CenterCollaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengdu610041China.

In 2013,cancer immunotherapy led the annual breakthroughs in *** fact,immunotherapy is one of the hotspots in cancer therapy,and can date back to the Coley vaccine in *** in biotechnology and bio-engineering,especially research and development（R＆D）in the fields of therapeutic antibodies,checkpoint inhibitors,and engineered T cells,helped overcome the problems in tumor therapies,leading to increasing research focus on cancer immunotherapy.

关键词： Booming cancer immunotherapy fighting tumors

Combination therapy of murine liver cancer with IL-12 gene and HSV-TK gene

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Chinese Journal of Cancer Research 2000年第3期12卷 26-29页

作者：唐展云孙文长陈诗书 Research center for Human gene therapy Shanghai Second Medical University Shanghai China

Objective: To investigate the synergistic anti-tumor effects of murine IL-12 gene and HSV-TK gene therapy in mice bearing liver cancer. Methods: Mouse liver cancer MM45T. Li (H-2d) cells were transfected with retroviral vector containing IL-12 gene or HSV-TK gene insert. gene-modified liver cancer cells, MM45T. Li/IL-12 and MM45T. Li/TK, with stable expression of IL-12 and TK were obtained. Balb/c mice were inoculated subcutaneously with 2′105 MM45T. Li cells. When the tumor reached a size of 0.5-1.0 cm, a mixture of ***/TK cells and 60Co-irradiated MM45T. Li/IL-12 cell were injected intratumoraly. Ganciclovir (GCV) was injected ip (40 ***-1.d-1) for 10 days. Intratumoral injection of 60Co-irradiated MM45T. Li/IL-12 cells was repeated twice in one week apart. Mice with distant tumors were treated according to the same protocol. CTL activity of spleen cells was measured by 51Cr-release assay and phenotype of tumor infiltrating lymphocytes by immunohistochemical staining. Results: In mice treated with MM45T. Li/IL-12 or MM45T. Li/TK+GCV individually led to moderate reduction in tumor growth, but neither could eradicate the tumor completely, while in 60% of mice treated with a mixture of MM45T. Li/IL-12 and MM45T. Li/TK cells plus GCV, complete tumor regression was observed, with no tumor recurrence for two months. The growth of distant tumor was also inhibited significantly in mice similarly treated. Most of the mice received combined gene therapy plus GCV had abundant CD4+, CD8+T lymphocyte infiltration. Their CTL activity was significantly higher than in mice received single gene therapy. Conclusion Combination therapy with IL-12 gene and HSV-TK gene plus GCV is effective for mouse liver cancer.

关键词： Liver cancer Interleukin-12 HSV-TK gene therapy

Stem cell-based regenerative opportunities for the liver: State of the art and beyond

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World Journal of Gastroenterology 2015年第43期21卷 12334-12350页

作者： Eleftheria Tsolaki Evangelia Yannaki gene and Cell therapy center Hematology Department-BMT UnitGeorge Papanicolaou Hospital Department of Medicine University of Washington

The existing mismatch between the great demand for liver transplants and the number of available donor organs highlights the urgent need for alternative therapeutic strategies in patients with acute or chronic liver failure. The rapidly growing knowledge on stem cell biology and the intrinsic repair processes of the liver has opened new avenues for using stem cells as a cell therapy platform in regenerative medicine for hepatic diseases. An impressive number of cell types have been investigated as sources of liver regeneration: adult and fetal liver hepatocytes,intrahepatic stem cell populations,annex stem cells,adult bone marrow-derived hematopoietic stem cells,endothelial progenitor cells,mesenchymal stromal cells,embryonic stem cells,and induced pluripotent stem cells. All these highly different cell types,used either as cell suspensions or,in combination with biomaterials as implantable liver tissue constructs,have generated great promise for liver regeneration. However,fundamental questions still need to be addressed and critical hurdles to be overcome before liver cell therapy emerges. In this review,we summarize the state-of-the-art in the field of stem cell-based therapies for the liver along with existing challenges and future perspectives towards a successful liver cell therapy that will ultimately deliver its demanding goals.

关键词： Stem cells Liver regeneration Liver cirrhosis Acut

Chronic inhibition of cyclic guanosine monophosphate-specific phosphodiesterase 5 prevented cardiac fibrosis through inhibi- tion of transforming growth factor 13-induced Smad signaling

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Frontiers of Medicine 2014年第4期8卷 445-455页

作者： Wei Gong＊ Mengwen Yan Junxiong Chen Sandip Chaugai Chen Chen Daowen Wang Department of Internal Medicine and gene therapy center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China

Recent evidences suggested that cyclic guanosine monophosphate-specific phosphodiesterase 5 （PDE5） inhibitor represents an important therapeutic target for cardiovascular diseases. Whether and how it ameliorates cardiac fibrosis, a major cause of diastolic dysfunction and heart failure, is unknown. The purpose of this study was to investigate the effects of PDE5 inhibitor on cardiac fibrosis. We assessed cardiac fibrosis and pathology in mice subjected to transverse aortic constriction （TAC）. Oral sildenafil, a PDE5 inhibitor, was administered in the therapy group. In control mice, 4 weeks of TAC induced significant cardiac dysfunction, cardiac fibrosis, and cardiac fibroblast activation （proliferation and transformation to myofibroblasts）. Sildenafil treatment markedly prevented TAC-induced cardiac dysfunction, cardiac fibrosis and cardiac fibroblast activation but did not block TAC-induced transforming growth factor-β0 （TGF-β1） production and phosphorylation of Smad2/3. In isolated cardiac fibroblasts, sildenafil blocked TGF-β1-induced cardiac fibroblast transformation, proliferation and collagen synthesis. Furthermore, we found that sildenafil induced phosphorylated cAMP response element binding protein （CREB） and reduced CREB-binding protein 1 （CBP1） recruitment to Smad transcriptional complexes. PDE5 inhibition prevents cardiac fibrosis by reducing CBP1 recruitment to Smad transcriptional complexes through CREB activation in cardiac fibroblasts.

关键词： PDE5 cardiac fibrosis TGF-β CREB

Preparation of human single chain Fv antibody against hepatitis C virus E2 protein and its identification in immunohistochemistry

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World Journal of Gastroenterology 2002年第5期8卷 863-867页

作者： Yan-Wei Zhong Jun Cheng Gang Wang Shuang-Shuang Shi Li Li Ling-Xia Zhang Ju-Mei Chen gene therapy Research center,Institute of Infectious Diseases,302 Hospital of PLA,26 Fengtai Road,Beijing 100039,China gene therapy Research center Institute of Infectious Diseases 302 Hospital of PLA 26 Fengtai Road Beijing 100039 China. zyw@***

AIM: To screen human single chain Fv antibody (scFv)against hepatitis C virus E2 antigen and identify its applicationin ***: The phage antibody library was panned by HCVE2 antigen, which was coated in microtiter plate. After fiverounds of biopanning,56 phage clones were identified specificto HCV E2 antigen. The selected scFv clones were digestedby SfiI/NotI and DNA was sequenced. Then it was subclonedinto the vector pCANTABSE for expression as E-taggedsoluble scFv. The liver tissue sections from normal personand patients with chronic hepatitis B and chronic hepatitis Cwere immunostained with HCV E2 scFv ***: The data of scFv-E2 DNA digestion and DNAsequencing showed that the scFv gene is composed of 750bp. ELISA and immunohistochemistry demonstrated that thehuman single chain Fy antibody against hepatitis C E2 antigenhas a specific binding character with hepatitis virus E2 antigenand paraffin-embedded tissue, but did not react with liver tissuesfrom healthy persons or patients with chronic hepatitis ***: We have successfully screened andidentified HCV E2 scFv and the scFv could be used in theimmunostaining of liver tissue sections from patients withchronic hepatitis C.

关键词：丙型肝炎病毒E2 人体单克隆抗体Fv 免疫组织化学鉴定慢性丙型肝炎