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Bacteria-mediated tumor-targeted delivery of tumstatin(54-132)significantly suppresses tumor growth in mouse model by inhibiting angiogenesis and promoting apoptosis

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Frontiers of Medicine 2022年第6期16卷 873-882页

作者： Feifei Bao Mengjie Liu Wenhua Gai Yuwei Hua Jing Li Chao Han Ziyu Zai Jiahuang Li Zichun Hua The State Key Laboratory of pharmaceutical Biotechnology School of Life SciencesNanjing UniversityNanjing210023China changzhou high-tech research institute of nanjing university and Jiangsu target pharma laboratories inc. Changzhou213164China

Tumor growth is an angiogenesis-dependent process and accompanied by the formation of hypoxic *** is a tumor-specific angiogenesis inhibitor that suppresses the proliferation and induces the apoptosis of tumorous vascular endothelial ***20009,an attenuated Salmonella typhimurium strain,preferentially accumulates in the hypoxic areas of solid *** this study,a novel Salmonella-mediated targeted expression system of tumstatin(VNP-Tum5)was developed under the control of the hypoxia-induced J23100 promoter to obtain anti-tumor efficacy in *** with VNP-Tum5 effectively suppressed tumor growth and prolonged survival in the mouse model of B16F10 ***-Tum5 exhibited a higher efficacy in inhibiting the proliferation and inducing the necrosis and apoptosis of B16F10 cells in vitro and in vivo compared with VNP(control).VNP-Tum5 significantly inhibited the proliferation and migration of mouse umbilical vascular endothelial cells to impede ***-Tum5 downregulated the expression of anti-vascular endothelial growth factor A,platelet endothelial cell adhesion molecule-1,phosphorylated phosphoinositide 3 kinase,and phosphorylated protein kinase B and upregulated the expression of cleaved-caspase 3 in tumor *** study is the first to use tumstatin-transformed VNP20009 as a tumor-targeted system for treatment of melanoma by combining anti-tumor and anti-angiogenic effects.

关键词： Salmonella VNP20009 tumstatin B16F10 melanoma apoptosis angiogenesis

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A Convenient Fluorescent-labeled Assay for in vitro Measurement of DNA Mismatch Repair Activity

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Biomedical and Environmental Sciences 2010年第6期23卷 496-501页

作者： SHI-YING LI XIANG-YU ZHANG XIN ZHANG YAN LAN ZI-CHUN HUA The State Key Laboratory of pharmaceutical Biotechnology and Jiangsu Center of Hepatobiliary Diseases School of Stomatology and Affiliated Stomatological Hospital Nailing University Nanjing 210093 Jiangsu China changzhou high-tech research institute of nanjing university and changzhou target pharma laboratories inc. Changzhou 213164 Jiangsu China

Objective The assay of DNA mismatch repair （MMR） activity can be used as a biomarker for environmental condition detection and human disease diagnosis. Radioactive 32p-endlabeled DNA containing mismatch is extensively used as the substrate for MMR activity analyses. The aim of the present study is to develop a simple non-radioactive, but equally specific and sensitive method for the MMR activity assay. Methods A fluorescent label was chosen to replace the radioactive isotope label. Sensitive evaluation of the fluorescent label was carried out for the first time, and then the fluorescent label was compared with the isotope label in the MMR activity and DNA binding assays. Result LOD （limit of detection） of the fluorescent label was about 0.1 fmol and the relative signal strength displayed a pretty good linear relationship. Moreover, the fluorescent label method has equivalent sensitivity and performance as compared with the classical radioactive method in experiments. Conclusion In light of the sensitivity, reproducibility, safety, rapidity and long lifespan of the fluorescent label, this improved method can be applied to evaluation of biologic and toxic effects of environmental pollutants on man and other forms of life.

关键词： Fluorescent label MMR activity EMSA TDG

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Phosphatidylserine externalized on the colonic capillaries as a novel pharmacological target for IBD therapy

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Signal Transduction and targeted Therapy 2021年第7期6卷 2186-2195页

作者： Xuerui Zhang Lulu Song Lin Li Banghui Zhu Lina Huo Zhaoqing Hu Xinran Wang Jie Wang Mengyue Gao Jing Zhang Zichun Hua The State Key Laboratory of pharmaceutical Biotechnology School of Life SciencesNanjing UniversityNanjingChina changzhou high-tech research institute of nanjing university and Jiangsu target pharma laboratories inc ChangzhouChina School of Biopharmacy China Pharmaceutical UniversityNanjingChina

Inflammatory bowel disease(IBD)is a chronic and relapsing disorder for many people associated with poor *** there are some clinical drugs for IBD treatment,the development of effective therapeutics on IBD patients has always been ***,we show that externalized phosphatidylserine(PS)is observed on the surface of colonic *** A5(ANXA5)with high affinity for PS has a good targeting to the colon and effectively alleviates experimental *** contrast,ANXA5 mutant(A5m)lacking the PS-binding ability,has no accumulation in the colon and no therapeutic effects on *** investigations indicate that ANXA5 reduces the inflammatory cell infiltration by inhibiting endothelial cell activation dependent on PS-binding *** the inc.easing of PS exposure on activated HUVECs(human umbilical vein endothelial cells),ANXA5 binding induces the internalization of TLR4 via PS-dependent *** provide new insights on the molecular mechanism of ANXA5 for its anti-inflammatory *** data suggest that PS-externalization is a potential target of ANXA5 aiming at targeted drug delivery(TDD)for IBD treatment.

关键词： colonic colon drugs

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A bacteria-based system expressing anti-TNF-αnanobody for enhanced cancer immunotherapy

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Signal Transduction and targeted Therapy 2023年第5期8卷 2064-2067页

作者： Lina Liu Xing Liu Wenjie Xin Lulu Zhou Baolian Huang Chao Han Zhiting Cao Zichun Hua The State Key Laboratory of pharmaceutical Biotechnology School of Life SciencesNanjing UniversityNanjing210023JiangsuChina School of Biopharmacy China Pharmaceutical UniversityNanjing210023JiangsuChina changzhou high-tech research institute of nanjing university and Jiangsu targetpharma laboratories inc. Changzhou213164JiangsuChina

Dear Editor,As a successful drug for inflammatory diseases,the application of TNF-αinhibitor on cancer therapy is limited by repeated administration and off-target effects.1 A body of evidence indicated that the anti-tumor efficacy of TNF-αinhibitor is unsatisfactory,though repeated administration was used to improve its efficacy in tumor-treating fields,it will also lead to severe side effects and high cost.2,3,4 Hence,an efficient and highly targeted TNF-αantibody delivery system is worth developing.

关键词： cancer diseases immunotherapy

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Salmonella flagella confer anti-tumor immunological effect via activating Flagellin/TLR5 signalling within tumor microenvironment

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Acta pharmaceutica Sinica B 2021年第10期11卷 3165-3177页

作者： Jianxiang Chen Yiting Qiao Guo Chen Cunjie Chang Heng Dong Bo Tang Xiawei Cheng Xiufeng Liu Zichun Hua School of Life Sciences Nanjing UniversityNanjing 210023China changzhou high-tech research institute of nanjing university and Jiangsu target pharma laboratories inc. Changzhou 213164China College of pharmacy School of MedicineHangzhou Normal UniversityHangzhou 311100China Department of Hepatology the Affiliated Hospital of Hangzhou Normal UniversityHangzhou Normal UniversityHangzhou 310003China Division of Hepatobiliary and Pancreatic Surgery Department of Surgerythe First Affiliated HospitalSchool of MedicineZhejiang University School of Biopharmacy China Pharmaceutical UniversityNanjing 211198China

Salmonella:mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models,but the detailed mechanism remains *** this report,the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma *** flagella are key inducers of the host immune response during bacterial infection,flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer *** results showed that flagellum-deficient strains failed to induce significant anti-tumor effects,even when more bacteria were administered to offset the difference in invasion *** mainly activate immune cells via Flagellin/Toll-like receptor 5(TLR5)signalling ***,we showed that exogenous activation of TLR5 signalling by recombinant Flagellin and exogenous expression of TLR5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against *** study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/TLR5 signalling pathway during Salmonella-mediated cancer therapy,thereby suggesting the potential application of TLR5 agonists in the cancer immune therapy.

关键词： Bacteria-mediated cancer therapy Salmonella VNP20009 Flagellum Flagellin TLR5 NF-kB Cancer immune therapy

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RIP3 deficiency attenuated hepatic stellate cell activation and liver fibrosis in schistosomiasis through JNK-cJUN/Egr1 downregulation

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Signal Transduction and targeted Therapy 2022年第7期7卷 2151-2153页

作者： Li-Jun Song Xu-Ren Yin Sheng-Wen Guan Hong Gao Pan-Pan Dong Cong-Jin Mei Ying-Ying Yang Ying Zhang Chuan-Xin Yu Zi-Chun Hua School of Life Sciences and the State Key Laboratory of pharmaceutical Biotechnology Nanjing UniversityNanjingPR China Key Laboratory of National Health and Family Planning Commission on Parasitic Disease Control and Prevention Jiangsu Provincial Key Laboratory on Parasite and Vector Control TechnologyJiangsu Institute of Parasitic DiseasesWuxiPR China Public Health research Center at Jiangnan university WuxiPR China Department of Pathology Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingPR China School of Biopharmacy China Pharmaceutical UniversityNanjingPR China changzhou high-tech research institute of nanjing university and Jiangsu targetpharma laboratories inc ChangzhouPR China

Dear Editor,Activated hepatic stellate cells(HSCs)synthesizing a large amount of extracellular matrix(ECM)are the key events to hepatic fibrosis.1 However,there are no effective drugs for curing liver fibrosis in the clinic.1 Therefore,clarifying the formation mechanism of liver fibrosis is of great importance for finding anti-liver fibrosis drug ***,an inc.easing amount of research has shown that necroptosis regulated by receptor-interacting protein kinase 3(RIP3)plays an important role in inflammatory disease injury and could be used as a drug target.2 We found that RIP3 was highly expressed in liver tissues of wildtype(WT)mice infected with Schistosoma japonicum(***),mainly at 6 w(weeks)and 8 w post-infection(Fig.1a)。

关键词： RIP3 hepatic liver

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