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Narciclasine induces colon carcinoma cell apoptosis by inhibiting the IL-17A/Act1/TRAF6/NF-kB signaling pathway

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Genes & diseases 2024年第5期11卷 428-441页

作者： Huiming Deng Qiang Liu Siman Yu Lifan Zhong Lianfang Gan Huiquan Gu Qianru Wang Ruxin Cheng Yong Liu Li Liu Ling Huang Ronghua Xu Department of Gastrointestinal Surgery Huazhong University of Science and Technology Union Shenzhen HospitalShenzhenGuangdong 518000China Research center for Drug Safety Evaluation of Hainan Province HaikouHainan 571199China Department of Pharmacology Hainan Medical UniversityHaikouHainan 571199China Department of Pathology Guangzhou Panyu Central HospitalGuangzhouGuangdong 511400China Hainan Province Key Laboratory for Drug Preclinical Study of Pharmacology and Toxicology Research Hainan Medical UniversityHaikouHainan 571199China Hainan center for Drug and Medical Device Evaluation and Service Hainan Medical Products AdministrationHaikouHainan 570216China

IL-17 A is a promoter of colorectal cancer initiation and *** is a polyhydroxy alkaloid compound isolated from Narcissus plants,which has potent anti-inflammatory and antitumor *** effects of narciclasine on colorectal tumors were evaluated,with a focus on IL-17 *** reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in murine *** results of flow cytometry on JC-1 and Annexin V/PI revealed that narciclasine significantly reduced the mitochondrial membrane potential and induced apoptosis,findings confirmed by western blotting results of reduced Bcl2 and enhanced Bax expression,as well as accumulation of cleaved Caspase-3,Caspase-8,Caspase-9,and cytoplasmic *** narciclasine incubation,IL-17 A,Act1,and TRAF6 were down-regulated,while p-P65(Ser536)accumulated in the cytoplasm,a finding confirmed by laser scanning confocal ***17A substitution could partly reverse these narciclasine effects while they were elevated by IL17A ***,IL-17 A,Act1,and TRAF6 were significantly expressed to greater extents in human colorectal cancer compared to normal adjacent tissue specimens and were closely linked with a poor *** study provided evidence that narciclasine may be a useful therapeutic drug for colorectal cancer treatment through its actions in down-regulating the L-17A/Act1/TRAF6/NF-kB anti-apoptotic signaling pathway.

关键词： Act1 Apoptosis Colonrectal cancer IL-17A Narciclasine NF-kB

5S-Heudelotinone alleviates experimental colitis by shaping the immune system and enhancing the intestinal barrier in a gut microbiota-dependent manner

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2153-2176页

作者： Qing Meng Jianshuang Guo Ke Lv Yang Liu Jin Zhang Mingyue Li Xirui Cheng Shenghua Chen Xiaoguang Huo Quan Zhang Yue Chen Jing Li State Key Laboratory of Medicinal Chemical Biology College of PharmacyNankai UniversityTianjin 300353China College of Chemistry and Frontiers Science center for New Organic Matter Haihe Laboratory of Sustainable Chemical TransformationsNankai UniversityTianjin 300071China Accendatech Company Ltd.Tianjin 300193China

Aberrant changes in the gut microbiota are implicated in many diseases,including inflammatory bowel disease(IBD).Gut microbes produce diverse metabolites that can shape the immune system and impact the intestinal barrier integrity,indicating that microbe-mediated modulation may be a promising strategy for preventing and treating *** fecal microbiota transplantation and probiotic supplementation are well-established IBD therapies,novel chemical agents that are safe and exert strong effects on the gut microbiota are urgently ***,we report the total synthesis of heudelotinone and the discovery of 5S-heudelotinone(an enantiomer)as a potent agent against experimental colitis that acts by modulating the gut microbiota.5S-Heudelotinone alters the diversity and composition of the gut microbiota and increases the concentration of short-chain fatty acids(SCFAs);thus,it regulates the intestinal immune system by reducing proinflammatory immune cell numbers,and maintains intestinal mucosal integrity by modulating tight junctions(TJs).Moreover,5S-heudelotinone(2)ameliorates colitis-associated colorectal cancer(CAC)in an azoxymethane(AOM)/dextran sulfate sodium(DSS)-induced in situ carcinoma ***,these findings reveal the potential of a novel natural product,namely,5S-heudelotinone,to control intestinal inflammation and highlight that this product is a safe and effective candidate for the treatment of IBD and CAC.

关键词： 5S-heudelotinone Total synthesis inflammatory bowel disease Gut microbiota Short-chain fatty acids Immune system Intestinal barrier Drug discovery

Express,on of the novel adipokine ClqTNF-related protein 4 （CTRP4） suppresses colitis and colitis- associated colorectal cancer in mice

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Cellular & Molecular Immunology 2016年第5期13卷 688-699页

作者： Yang Luo Xiaotong Wu Zhuang Ma Weifeng Tan Lanlan Wang Daxiang Na Guoying Zhang Ang Yin He Huang Dan Xia Yingmei Zhang Xueying Shi Lu Wang Department of Immunology Key Laboratory of Medical Immunology (Ministry of Health) School of Basic Medical Sciences Peking University Health Science Center Beijing 100191 China Department of Pathology School of Basic Medical Sciences Peking University Health Science Center Beijing 100191 China These authors contributed equally to the article. Correspondence: Dr L Wang MD PhD Department of Immunology Key Laboratory of Medical Immunology (Ministry of Health) School of Basic Medical Sciences Peking University Health Science Center 38# Xueyuan Road Beijing 100191 China

inflammatory bowel disease （IBD） is an important factor in the induction of colon cancer, but its mechanism is unclear. Colitis and colitis-associated colorectal cancer （CAC） models induced using both dextran sulfate sodium （DSS） and the azoxymethane/DSS protocol were established in wild-type （WT） and CTRP4 transgenic （CTRP4-tg） C57BL6/J mice. Body weight, stool consistency and the presence of blood in the stool were analyzed; tumor quantity, size and histological characteristics were analyzed during the development of CAC. The CTRP4-tg mice exhibited significantly reduced colitis and developed far fewer macroscopic tumors; these tumors were smaller in size, and a majority of the colon tumors in these mice were restricted to the superficial mucosa. Tumors of lower grades were observed in the CTRP4-tg mice. Interleukin-6 was markedly downregulated in the CTRP4-tg mice during CAC tumorigenesis. The phosphorylation of ERK, signal transducer and activator of transcription 3 and Akt in the colon and the proliferation of intestinal epithelial cells were decreased in the CTRP4-tg mice. The injection of recombinant CTRP4 protein significantly reduced the colitis symptoms of the WT mice. CTRP4 plays an important role in inflammation and inflammation-associated colon tumorigenesis, and our research may provide a novel method for the treatment of IBD and CAC.

关键词： CAC CTRP4 DSS/AOM IBD

Promising Effects of Zerumbone on the Regulation of Tumor-promoting Cytokines Induced by TNF-α-activated Fibroblasts

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Current Medical Science 2020年第6期40卷 1075-1084页

作者： Zahra Radaei Alireza Zamani Rezvan Najafi Massoud Saidijam Farid Azizi Jalilian Razieh Ezati Ghasem Solgi Razieh Amini Department of Immunology School of MedicineRamadan University of Medical SciencesHamadan 65178Iran Research center for Molecular Medicine Hamadan University of Medical SciencesHamadan 65178Iran Department of Microbiology School of MedicineHamadan University of Medical SciencesHamadan 65178Iran Institute of Medical Biotechnology National Institute of Genetic Engineering and BiotechnologyTehran 14965Iran

Inflammation plays an important role in the development of several *** cytokines,including tumor necrosis factor-α(TNF-α),are associated with the induction of *** inflammation contributes to the progression of cancer through several mechanisms,including increased cytokine production and activation of transcription factors,such as nuclear factor-κB(NF-κB).Zerumbone(ZER),a component of subtropical ginger(Zingiber zerumbet Smith),seems to have anti-inflammatory,anti-cancer,and antioxidant *** this study,we aimed to explore the protective function and mechanisms of ZER against TNF-α-induced cancer-promoting *** found that the viability of stimulated human fibroblast cell lines was reduced after treatment with ZER(IC50=18µmol/L),compared to un-stimulated fibroblasts(IC50=40µmol/L).Besides,ZER inhibited mRNA expression and protein secretion of transforming growth factor-β(TGF-β),interleukin-33(IL-33),monocyte chemoattractant protein-1(MCP-1),and stromal cell-derived factor 1(SDF-1),which were produced by TNF-α-induced fibroblasts,as measured by quantitative real time-PCR(qRT-PCR)and ELISA *** mRNA expression levels of TGF-β,IL-33,SDF-1,and MCP-1 showed 8,5,2.5,and 4-fold reductions,***,secretion of TGF-β,IL-33,SDF-1,and MCP-1 was reduced to 3.65±0.34 ng/mL,6.3±0.26,1703.6±295.2,and 5.02±0.18 pg/mL,respectively,compared to the untreated *** addition,the conditioned media(CM)of TNF-α-stimulated fibroblasts increased the NF-κB expression in colorectal cancer cell lines(HCT-116 and Sw48),while in the vicinity of ZER,the expression of NF-κB was *** the significant effects of ZER,this component can be used as an appropriate alternative herbal treatment for cancer-related chronic inflammation.

关键词： inflammation zerumbone activated fibroblasts tumor necrosis factor-α(TNF-α) nuclear factor-κB(NF-κB)

Advancements of Macrophages Involvement in Pathological Progression of Colitis-Associated colorectal cancer and Associated Pharmacological Interventions

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Chinese Journal of Integrative Medicine 2024年第6期30卷 565-576页

作者： KE Jun-yu SONG Jin-bin LI Long HE Zhen-fan HUANG Zhuo-jian LIU Zheng-lin CHEN Gui-rong WANG Hai-yan WEN Su-ru ZHOU Heng-li MA Hui-lin DU Qun WU Yong-qiang LI Yan-wu CHEN Xin-lin School of Basic Medical Sciences Guangzhou University of Chinese MedicineGuangzhou510006China Department of Surgery II Gaozhou Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese MedicineGaozhou525200China Science and Technology Innovation center Guangzhou University of Chinese MedicineGuangzhou510405China The First Clinical Medical College of Guangzhou University of Traditional Chinese Medicine Guangzhou510405China

Intestinal macrophages play crucial roles in both intestinal inflammation and immune homeostasis. They can adopt two distinct phenotypes, primarily determined by environmental cues. These phenotypes encompass the classically activated pro-inflammatory M1 phenotype, as well as the alternatively activated anti-inflammatory M2 phenotype. In regular conditions, intestinal macrophages serve to shield the gut from inflammatory harm. However, when a combination of genetic and environmental elements influences the polarization of these macrophages, it can result in an M1/M2 macrophage activation imbalance, subsequently leading to a loss of control over intestinal inflammation. This shift transforms normal inflammatory responses into pathological damage within the intestines. In patients with ulcerative colitis-associated colorectal cancer (UC-CRC), disorders related to intestinal inflammation are closely correlated with an imbalance in the polarization of intestinal M1/M2 macrophages. Therefore, reinstating the equilibrium in M1/M2 macrophage polarization could potentially serve as an effective approach to the prevention and treatment of UC-CRC. This paper aims to scrutinize the clinical evidence regarding Chinese medicine (CM) in the treatment of UC-CRC, the pivotal role of macrophage polarization in UC-CRC pathogenesis, and the potential mechanisms through which CM regulates macrophage polarization to address UC-CRC. Our objective is to offer fresh perspectives for clinical application, fundamental research, and pharmaceutical advancement in UC-CRC.

关键词： macrophage ulcerative colitis colon cancer Chinese medicine

Artificial intelligence and machine learning in colorectal cancer

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Artificial Intelligence in Gastrointestinal Endoscopy 2022年第3期3卷 31-43页

作者： Muhammad Awidi Arindam Bagga Internal Medicine Beth Israel Lahey HealthBurlingtonMA 01805United States Internal Medicine Tufts Medical CenterBostonMA 02111United States

colorectal cancer(CRC)is a heterogeneous illness characterized by various epigenetic and microenvironmental changes and is the third-highest cause of cancer-related death in the *** intelligence(AI)with its ability to allow automatic learning and improvement from experiences using statistical methods and Deep learning has made a distinctive contribution to the diagnosis and treatment of several cancer *** review discusses the uses and application of AI in CRC screening using automated polyp detection assistance technologies to the development of computer-assisted diagnostic algorithms capable of accurately detecting polyps during colonoscopy and classifying ***,we summarize the current research initiatives geared towards building computer-assisted diagnostic algorithms that aim at improving the diagnostic accuracy of benign from premalignant *** the evolving transition to more personalized and tailored treatment strategies for CRC,the review also discusses the development of machine learning algorithms to understand responses to therapies and mechanisms of resistance as well as the future roles that AI applications may play in assisting in the treatment of CRC with the aim to improve disease *** also discuss the constraints and limitations of the use of AI *** the medical profession remains enthusiastic about the future of AI and machine learning,large-scale randomized clinical trials are needed to analyze AI algorithms before they can be used.

关键词： Artificial intelligence Machine learning Colonic polyps colorectal neoplasms Computer-aided diagnosis precision oncology

Intravenous immune globulin suppresses angiogenesis in mice and humans

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Signal Transduction and Targeted Therapy 2016年第1期1卷 141-148页

作者： Reo Yasuma Valeria Cicatiello Takeshi Mizutani Laura Tudisco Younghee Kim Valeria Tarallo Sasha Bogdanovich Yoshio Hirano Nagaraj Kerur Shengjian Li Tetsuhiro Yasuma Benjamin J Fowler Charles B Wright Ivana Apicella Adelaide Greco Arturo Brunetti Balamurali K Ambati Sevim Barbasso Helmers Ingrid E Lundberg Ondrej Viklicky Jeanette HW Leusen J Sjef Verbeek Bradley D Gelfand Ana Bastos-Carvalho Sandro De Falco Jayakrishna Ambati Department of Ophthalmology and Visual Sciences University of KentuckyLexingtonKYUSA Department of Ophthalmology Nagoya University Graduate School of MedicineNagoyaJapan Angiogenesis Lab Institute of Genetics and Biophysics—CNRNaplesItaly Bio-Ker MultiMedica GroupNaplesItaly Department of Physiology University of KentuckyLexingtonKYUSA Department of Advanced Biomedical Sciences University of Naples‘Federico II’NaplesItaly CEINGE—Biotecnologie Avanzate s.c.ar.l.NaplesItaly Department of Ophthalmology and Visual Sciences Moran Eye CenterUniversity of Utah School of MedicineSalt Lake CityUTUSA Department of Ophthalmology Veterans Affairs Salt Lake City Healthcare SystemSalt Lake CityUTUSA Rheumatology Unit Department of MedicineKarolinska InstitutetKarolinska University HospitalStockholmSweden Department of Nephrology Institute for Clinical and Experimental MedicinePrague 4Czech Republic Immunotherapy Laboratory Laboratory for Translational ImmunologyUniversity Medical Center UtrechtUtrechtThe Netherlands Department of Human Genetics Leiden University Medical CenterLeidenThe Netherlands Department of Biomedical Engineering University of KentuckyLexingtonKYUSA Department of Microbiology Immunologyand Molecular GeneticsUniversity of KentuckyLexingtonKYUSA IRCCS MultiMedica MilanoItaly

Human intravenous immune globulin(IVIg),a purified IgG fraction composed of~60%IgG1 and obtained from the pooled plasma of thousands of donors,is clinically used for a wide range of *** biological actions of IVIg are incompletely understood and have been attributed both to the polyclonal antibodies therein and also to their IgG(IgG)Fc ***,we demonstrated that multiple therapeutic human IgG1 antibodies suppress angiogenesis in a target-independent manner via FcγRI,a high-affinity receptor for *** we show that IVIg possesses similar anti-angiogenic activity and inhibited blood vessel growth in five different mouse models of prevalent human diseases,namely,neovascular age-related macular degeneration,corneal neovascularization,colorectal cancer,fibrosarcoma and peripheral arterial ischemic *** was mediated by the Fc region of IVIg,required FcγRI and had similar potency in transgenic mice expressing human Fcγ***,IVIg therapy administered to humans for the treatment of inflammatory or autoimmune diseases reduced kidney and muscle blood vessel *** data place IVIg,an agent approved by the US Food and Drug Administration,as a novel angioinhibitory drug in doses that are currently administered in the clinical *** addition,they raise the possibility of an unintended effect of IVIg on blood vessels.

关键词： doses inhibited degeneration

The novel Adipokine C1qTNF-related protein 4(CTRP4) expression suppresses colitis and colitis-associated colorectal cancer in mice

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The novel Adipokine C1qTNF-related protein 4(CTRP4) expressi...

Actinidia chinensis polysaccharide interferes with the epithelial-mesenchymal transition of gastric cancer by regulating the nuclear transcription factor-κB pathway to inhibit invasion and metastasis

第十届全国免疫学学术大会

作者： Yang Luo Wu Xiaotong Ma Zhuang Tan Weifeng Wang Lanlan Na Daxiang Zhang Guoying Yin Ang Huang He Xia Dan Zhang Yingmei Shi Xueying Wang Lu Department of Immunology Key Laboratory of Medical Immunology(Ministry of Health)School of Basic Medical SciencesPeking University Health Science Center

Object:inflammatory bowel disease(IBD)is an important factor in the induction of colon cancer,but the mechanism is ***:Colitis and colitis-associated colorectal cancer(CAC)models induced using dextran sulfate sodium(DSS)and the azoxymethane(AOM)/DSS protocol were established in wild-type(WT)and CTRP4 transgenic(CTRP4-tg)C57BL6/J *** body weight,stool consistency and the presence of blood in the stool were observed and analyzed,the tumor quantity and size,the histological characteristic of the tumors were analyzed during CAC ***:The CTRP4-tg mice exhibited significantly reduced colitis and developed far fewer macroscopic tumors;these tumors were of smaller size,and a majority of the colon tumors in these mice were restricted to the superficial *** highly differentiated tumors were also observed in these ***-6 was markedly downregulated in the CTRP4-tg mice during CAC *** phosphorylation of ERK,STAT3 and Akt in the colon and the proliferation of intestinal epithelial cells were decreased in the CTRP4-tg *** injection of WT mice with recombinant CTRP4 protein significantly reduced their colitis ***:CTRP4 plays an important role in inflammation and inflammation-associated colon tumorigenesis,and may represent a novel target for the treatment of inflammatory bowel disease and CAC.

关键词： CTRP4 IBD CAC DSS/AOM

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Journal of Traditional Chinese Medicine 2024年第5期44卷 896-905页

作者： ZHANG Guangshun XU Xiaonan XU Chuyun LIAO Guanghui XU Hao LOU Zhaohuan ZHANG Guangji School of Pharmaceutical Sciences Zhejiang Chinese Medical UniversityHangzhou 310053China Key Labortary of Blood-stasis-toxin Syndrome of Zhejiang Province Hangzhou 310053China School of Basic Medical Sciences Zhejiang Chinese Medical UniversityHangzhou 310053China Traditional Chinese Medicine"Preventing Disease"Wisdom Health Project Research center of Zhejiang Hangzhou 310053China the First Affiliated Hospital of Zhejiang Chinese Medical University Hangzhou 310053China

OBJECTIVE:To investigate the mechanisms of the effect of Actinidia chinensis polysaccharide(ACPS)on the invasion and metastasis of gastric cancer ***:BGC-823-Luc gastric cancer cells stably transfected with a luciferase gene were used to establish an insitutransplanted tumor mouse model.A live mouse imaging system was used to observe tumor growth,and hematoxylin and eosin staining was applied to analyze tissue *** and scratch wound assays were performed to examine the invasive and migratory ability of BGC-823 ***,confocal microscopy,immunohistochemistry,and Western blot assays were used to analyze the expressions of the nuclear transcription factor-κB(NF-κB)signaling pathway and epithelial-mesenchymal transition(EMT)-related ***:ACPS significantly inhibited the growth of subcutaneously transplanted BGC-823-Luc gastric cancer tumors in nude mice and reduced inflammatory cell infiltration in tumor *** inhibited Epidermal Growth Factor-induced invasion,migration,and morphological changes in the cytoskeleton of *** inhibited gastric cancer EMT and decreased the expression of matrix metallopeptidase 9,N-cadherin and p-NF-κB p65 in transplanted tumor *** inhibited the expression of matrix metalloproteinases and vascular adhesion factors in BGC-823 cells,promoted p65-NF-κB nuclear translocation,and regulated proteins associated with the NF-κB p65 ***:ACPS inhibited gastric cancer invasion and metastasis both in vivo and in vitro,which evidenced the inhibition of gastric cancer EMT via regulating the NF-κB inflammatory pathway.

关键词： stomach neoplasms invasion neoplasm metastasis epithelial-mesenchymal transition NF-kappa B signal transduction Actinidia chinensis polysaccharide