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Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction

Signal Transduction and Targeted Therapy 2022年第2期7卷 502-518页

作者： Zhen Wang Fan-lian Zeng Ya-wen Hu Xiao-yan Wang Fu-lei Zhao Pei Zhou Jing Hu Yuan-yuan Xiao Zhong-lan Hu Ming-feng Guo Xiao-qiong Wei Xiao Liu Nong-yu Huang Jun Zhang Shu-wen Chen Juan Cheng Hua-ping Zheng Hong Zhou Qi-xiang Zhao Chen Zhang Yan Hao Song Zou Yi-yue Gui Jia-dong Yu Lin-na Gu Cheng-cheng Yue Hao-zhou Zhang Wen-ling Wu Yi-fan Zhou Xi-kun Zhou Guo-bo Shen Xiu Teng Jiong Li State Key Laboratory of Biotherapy and Cancer Center West China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengduSichuan 610041China Department of Liver Surgery&Liver Transplantation West China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuan 610041China Laboratory of Liver Surgery West China HospitalSichuan UniversityChengduSichuan 610041China Department of Obstetrics and Gynecology West China Second University HospitalSichuan UniversityChengdu 610041China Key Laboratory of Birth Defects and Related Diseases of Women and Children Ministry of EducationSichuan UniversityChengdu 610041China Department of Cardiovascular Medicine West China HospitalSichuan UniversityChengduSichuan 610041China Laboratory of Human Disease and Immunotherapies West China HospitalSichuan UniversityChengduSichuan 610041China

Interleukin-37b(hereafter called IL-37)was identified as fundamental inhibitor of natural and acquired immunity.The molecular mechanism and function of IL-37 in colorectal cancer(CRC)has been elusive.Here,we found that IL-37 transgenic(IL-37tg)mice were highly susceptible to colitis-associated colorectal cancer(CAC)and suffered from dramatically increased tumor burdens in colon.Nevertheless,IL-37 is dispensable for intestinal mutagenesis,and CRC cell proliferation,apoptosis,and migration.Notably,IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models.CD8^(+)T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice,enabling tumor evasion of immune surveillance.The dysfunction led by IL-37 antagonizes IL-18–induced proliferation and effector function of CD8+T cells,which was dependent on SIGIRR(single immunoglobulin interleukin-1 receptor-related protein).Finally,we observed that IL-37 levels were significantly increased in CRC patients,and positively correlated with serum CRC biomarker CEA levels,but negatively correlated with the CD8+T cell infiltration in CRC patients.Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancerimmunity cycle as therapeutic targets in CRC.

关键词： immunity cytotoxic Interleukin

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"Moonlighting" at the power plant: how mitochondria facilitate serial killing by CD8^(+) cytotoxic T cells

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Signal Transduction and Targeted Therapy 2022年第1期7卷 15-16页

作者： Dimitrios Mougiakakos Sascha Kahlfuss Department of Hematology Oncologyand Stem Cell TransplantationOtto-von-Guericke University MagdeburgMagdeburgGermany Institute of Molecular and Clinical Immunology Medical FacultyOtto-von-Guericke University MagdeburgMagdeburgGermany Institute of Medical Microbiology and Hospital Hygiene Medical FacultyOtto-von-Guericke University MagdeburgMagdeburgGermany Health Campus Immunology InfectiologyInflammation(GC-I3)Medical FacultyOtto-von-Guericke UniversityMagdeburgGermany Center for Health and Medical Prevention(CHaMP) Otto-von-Guericke UniversityMagdeburgGermany

Griffiths and colleagues rece ntly dem on strated in Science^(1) that mitochondrial translation is required by CD8^(+)cytotoxic T cells(CTLs)to facilitate serial killing of target cells.CD8^(+)CTLs provide immunity to viruses and tumors by acting as serial killers that eliminate infected or transformed target cells one after another.To achieve that,CTLs utilize a cytotoxic protein machinery that involves perforin and granzymes to activate effector caspases and to induce apoptosis in target cells.

关键词： cytotoxic immunity lighting

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Intrinsic PD-L1 promotes antitumor activity of CD8^(+)cytotoxic T lymphocytes via in cis interaction with CD80

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Cancer Communications 2022年第8期42卷 784-788页

作者： Yuming Ding Chaojia Chen Shuaiya Ma Xue Sheng Fangcheng Zhao Jiali Peng Haoqing Dong Chunhong Ma Chunyang Li Cheeloo College of Medicine Shandong UniversityJinanShandong 250012P.R.China Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical SciencesShandong UniversityJinanShandong 250012P.R.China Shandong Key Laboratory of Gynecologic Oncology Qilu Hospital of Shandong UniversityJinanShandong 250012P.R.China Key Laboratory of Infection and Immunity of Shandong Province School of Basic Medical SciencesShandong UniversityJinanShandong 250012P.R.China Key Laboratory for Experimental Teratology of Ministry of Education and Department of Histology and Embryology School of Basic Medical SciencesShandong UniversityJinanShandong 250012P.R.China

Dear Editor,Programmed cell death-ligand 1(PD-L1)on tumor cells can inhibit CD8+cytotoxic T lymphocyte(CTL)-mediated antitumor response by trans-engagement with programmed death protein 1(PD-1).Besides tumor cells,PD-L1 is expressed on T cells.However,the intrinsic role of PD-L1 in T cells has not been widely studied.PD-L1 expression is essential for the survival of activated CD8+T cells,and PD-L1 blockade at the contraction stage reduced the number of effector T cells[1].CD8+T cell responses to influenza virus infection were also impaired in PD-L1-deficient mice[2].

关键词： cytotoxic impaired death

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Seven drimane-type sesquiterpenoids from an earwig-associated Aspergillus sp.

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Chinese Journal of Natural Medicines 2023年第1期21卷 58-64页

作者： SALMAN Khan ZHU Hongjie SUN Ziqian LI Yilin WANG Lan WANG Rong GUO Zhikai JIAO Ruihua State Key Laboratory of Pharmaceutical Biotechnology Institute of Functional BiomoleculesSchool of Life SciencesNanjing UniversityNanjing 210093China Hainan Key Laboratory of Tropical Microbe Resources Institute of Tropical Bioscience and BiotechnologyChinese Academy of Tropical Agricultural SciencesHaikou 571101China Key Laboratory for Biology and Genetic Resources of Tropical Crops of Hainan Province Hainan Institute for Tropical Agricultural ResourcesHaikou 571101China Hainan Academy of Ocean and Fisheries Sciences Hainan Tropical Ocean UniversityHaikou 571126China

Drimane-type sesquiterpenoids are widely distributed in fungi.From the ethyl acetate extract of the earwig-derived Aspergillus sp.NF2396,seven new drimane-type sesquiterpenoids,named drimanenoids A−G(1−7),were isolated.Their structures were elucidated by diverse spectroscopic analysis including high-resolution ESI-MS,one-and two-dimensional NMR spectroscopy.Drimanenoids A−F(1−6)are new members of drimane-type sesquiterpenoid esterified with unsaturated fatty acid side chain at C-6.Drimanenoids C(3),D(4)and F(6)showed antibacterial activity against five types of bacteria with different inhibition diameters.Drimanenoid D(4)exhibited moderate cytotoxicity against human myelogenous leukemia cell line K562 with an IC_(50) value of 12.88±0.11μmol·L^(−1).

关键词： Fungus Sesquiterpenoids Drimane-type Antibacterial cytotoxic Aspergillus sp.

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Ursolic acid: An overview on its cytotoxic activities against breast and colorectal cancer cells

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Journal of Integrative Medicine 2019年第3期17卷 155-160页

作者： Eric Wei Chiang Chan Chu Yong Soon Joash Ban Lee Tan Siu Kuin Wong Yew Woh Hui Faculty of Applied Sciences UCSI University School of Science Monash University Sunway Xiamen University Malaysia Bandar Sunsuria

Ursolic acid(UA) is a pentacyclic triterpene of the ursane type. As a common chemical constituent among species of the family Lamiaceae, UA possesses a broad spectrum of pharmacological properties. This overview focuses on the anticancer properties of UA against breast cancer(BC) and colorectal cancer(CRC)that are most common among women and men, respectively. In vitro studies have shown that UA inhibited the growth of BC and CRC cell lines through various molecular targets and signaling pathways.There are several in vivo studies on the cytotoxic activity of UA against BC and CRC. UA also inhibits the growth of other types of cancer. Studies on structural modifications of UA have shown that the –OH groups at C3 and at C28 are critical factors influencing the cytotoxic activity of UA and its derivatives.Some needs for future research are suggested. Sources of information were from ScienceDirect, Google Scholar and PubMed.

关键词： Ursolic acid cytotoxic Molecular targets Signaling pathways

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Natural epitope variants of the hepatitis C virus impair cytotoxic T lymphocyte activity

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World Journal of Gastroenterology 2010年第16期16卷 1953-1969页

作者： Shuping Wang Rico Buchli Jennifer Schiller Jianen Gao Rodney S VanGundy William H Hildebrand David D Eckels Department of Pathology University of Utah Pure Protein L.L.C. Oklahoma CityOK 73104United States Jennifer SchillerJianen GaoDepartment of PediatricsMedical College of Wisconsin Department of Pediatrics Medical College of Wisconsin Pure Protein L.L.C. Department of Microbiology and Immunology Health Sciences CenterUniversity of Oklahoma

AIM:To understand how interactions between hepatitis C virus(HCV) and the host's immune system might lead to viral persistence or effective elimination of HCV.METHODS:Nucleotides 3519-3935 of the non-structural 3(NS3) region were amplified by using reverse transcription polymerase chain reaction(PCR).PCR products of the HCV NS3 regions were integrated into a PCR T7TOPO TA vector and then sequenced in both directions using an automated DNA sequencer.Relative major histocompatibility complex binding levels of wild-type and variant peptides were performed by fluorescence polarization-based peptide competition assays.Peptides with wild type and variant sequences of NS3 were synthesized locally using F-moc chemistry and purified by high-performance liquid chromatography.Specific cytotoxic T lymphocytes(CTLs) clones toward HCV NS3 wild-type peptides were generated through limiting dilution cloning.The CTL clones specifically recognizing HCV NS3 wild-type peptides were tested by tetramer staining and flow cytometry.Cytolytic activity of CTL clones was measured using target cells labeled with the fluorescence enhancing ligand,DELFIA EuTDA.RESULTS:The pattern of natural variants within three human leukocyte antigen(HLA)-A2-restricted NS3 epitopes has been examined in one patient with chronic HCV infection at 12,28 and 63 mo post-infection.Results obtained may provide convincing evidence of immune selection pressure for all epitopes investigated.Statistical analysis of the extensive sequence variation found within these NS3 epitopes favors a Darwinian selection model of variant viruses.Mutations within the epitopes coincided with the decline of CTL responses,and peptide-binding studies suggested a signif icant impact of the mutation on T cell recognition rather than peptide presentation by HLA molecules.While most variants were either not recognized or elicited low responses,such could antagonize CTL responses to target cells pulsed with wild-type peptides.CONCLUSION:Cross-recognition of CTL epitopes from wild-type and n

关键词： Epitopes Human T Cells cytotoxic Anergy Viral

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cytotoxic, genotoxic and apoptotic effects of naringenin-oxime relative to naringenin on normal and cancer cell lines

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Asian Pacific Journal of Tropical Biomedicine 2016年第10期6卷 872-880页

作者： Abdurrahim Kocyigit Ismail Koyuncu Murat Dikilitas Fatemeh Bahadori Baki Turkkan Department of Medical Biochemistry Faculty of Medicine Bezmialem Vakif University Department of Biology Faculty of Arts and Sciences Harran University Department of Plant Protection Faculty of Agriculture Harran University Department of Pharmaceutical Biotechnology Faculty of Pharmacy Bezmialem Vakif University Department of Chemistry Faculty of Arts and Sciences Harran University

Objective: To assess and compare the cytotoxic, genotoxic, apoptotic and reactive oxygen species(ROS) generating effects of naringenin(NG) and its new derived compound naringenin-oxime(NG-Ox) on MCF-7, HT-29, PC-12 cancer and L-929 normal cell lines.Methods: The cells were incubated with different doses of NG-Ox and NG(50–1 000 mmol/L) for 24 h. The cell viability was assessed based on ATP cell viability assay.Intracellular accumulation of ROS was determined using the fluorescent probes 2070-dichlorodihydrofluorescin diacetate. Genotoxic effects were evaluated by alkaline single cell gel electrophoresis assay(comet assay) and, the apoptotic effect was evaluated by acridine orange staining at below the IC50 levels.Results: Both NG-Ox and NG exhibited cytotoxic, genotoxic and apoptotic effects and resulted in increased ROS values in a dose-dependent manner. The effects were more pronounced on cancer cell lines. The cytotoxic, genotoxic and apoptotic effects of NG-Ox were higher than that of NG in all cell lines. Significant correlations were observed between cell viability, DNA damage, apoptosis and ROS, in all cell lines exposed to either NG-Ox or NG.Conclusions: This study showed that both NG-Ox and NG possess cytotoxic, genotoxic and apoptotic activities through the production of ROS on cells, NG-Ox being the more effective one. Therefore, derived compound of NG might be used as antiproliferative agents for the treatment of cancer.

关键词： Naringenin Naringenin-oxime cytotoxic Genotoxic Apoptosis Reactive oxygen species Comet assay

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cytotoxic, kinetics of inhibition of carbohydrate-hydrolysing enzymes and oxidative stress mitigation by flavonoids roots extract of Dicoma anomala(Sond.)

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Asian Pacific Journal of Tropical Medicine 2018年第1期11卷 24-31页

作者： Fatai Oladunni Balogun Anofi Omotayo Tom Ashafa Phytomedicine and Phytopharmacology Research Group Department of Plant Sciences University of the Free StateQwaQwa Campus Phytomedicine and Phytopharmacology Research Group Department of Plant Sciences University of the Free State QwaQwa Campus

Objective: To investigate the free radical scavenging, antidiabetic, kinetics and cytotoxic potentials of flavonoids extract of Dicoma anomala root by using standard methods. Methods:Antioxidant activity of the flavonoids was investigated at scavenging free radicals such as 1,1-diphenyl-2-picrylhydrazyl, nitric oxide, hydroxyl radical, reducing capabilities, 2,2-azinobis(3-ethylbenzothiazoline-6) sulfonic acid as well as metal chelating capability at different concentrations(0.125-1.000 mg/mL) while the antidiabetic activity was evaluated via the inhibition and kinetics of carbohydrate digestive enzymes including, alpha glucosidase, sucrase and maltase. Brine shrimp lethality assay was also employed to examine the cytotoxic effects of the extract by using different range of concentrations(0.125-2.000 mg/mL). Results: The study revealed the best antioxidant activity of the extract in 1,1-diphenyl-2-picrylhydrazyl,2,2-azino-bis(3-ethylbenzothiazoline-6) sulfonic acid and nitric oxide having IC_(50) values of(386.90±4.91),(736.00±38.12),(629.30±9.62) μg/mL respectively compared with quercetin(standard) with IC_(50) [(522.20±12.38),(1 021.00±15.61) and(1 075.00±29.35) μg/mL]respective values while it was insignificantly(P>0.05) at par with quercetin for reducing power. Similarly, the extract exhibited a moderate inhibition of alpha glucosidase(43.1%),sucrase(33.4%) and maltase(29.9%) activities which were significantly(Pcytotoxic effect of the flavonoids with LC_(50) value 0.510 mg/mL. Conclusions: The results obtained from this study are suggestive of the antioxidative, antidiabe

关键词： Antioxidative Antihyperglycaemic cytotoxic Dicoma anomala Flavonoids Kinetics

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Tagetones A and B, new cytotoxic monocyclic diterpenoids from flowers of Tagetes minuta

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Chinese Journal of Natural Medicines 2017年第7期15卷 546-549页

作者： Sabrin Ragab Mohamed Ibrahim Gamal Abd Allah Mohamed Department of Pharmacognosy and Pharmaceutical Chemistry College of Pharmacy Taibah University Al-Madinah Al-Munawarah 30078 Saudi Arabia Department of Natural Products and Alternative Medicine Faculty of Pharmacy King Abdulaziz University Jeddah 21589 Saudi Arabia

Tagetones A(1) and B(2), two new monocyclic diterpenoids were isolated from the n-hexane fraction of fresh flowers of Tagetes minuta L.(Asteraceae). Their structures were established by multiple spectroscopic methods(IR, HR-ESI-MS, and 1D-, and 2D-NMR), in addition to comparison with literature data. Compound 1 showed cytotoxic activity towards MCF7 and A549 cancer cells with IC_(50) values being 4.68 and 4.24 μmol·L^(-1), respectively, compared to doxorubicin(IC_(50) 0.13 and 1.12 μmol·L^(-1), respectively). Compound 2 also exhibited significant activity against HCT116 cancer cells(IC_(50), 6.30 μmol·L^(-1)).

关键词： Tagetes minuta Asteraceae Monocyclic diterpenoids Tagetones cytotoxic

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cytotoxic and antibacterial substances against multi-drug resistant pathogens from marine sponge symbiont:Citrinin,a secondary metabolite of Penicillium sp.

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Asian Pacific Journal of Tropical Biomedicine 2013年第4期3卷 291-296页

作者： Ramesh Subramani Rohitesh Kumar Pritesh Prasad William Aalbersberg Centre for Drug Discovery and Conservation Institute of Applied SciencesThe University of the South Pacific.Laucala CampusSuva.Fiji Islands

Objective:To Isolate,purify,characterize,and evaluate the bioaclive compounds from the sponge-derived fungus Penicillium sp.FF001 and to elucidate its structure.Methods:The fungal strain FF001 with an interesting bioactivity profile was isolated from a marine Fijian sponge Melophlus sp.Based on conidiophores aggregation,conidia development and mycelia morphological characteristics,the isolate FF001 was classically identified as a Penicillium sp.The bioactive compound was identified using various spectral analysis of UV,high resolution electrospray ionization mass spectra,1H and 13C NMR spectral data.Further minimum inhibitory concentrations(MICs)assay and brine shrimp cytotoxicity assay were also carried out to evaluate the biological properties of the purified compound.Results:Bioassay guided fractionation of the EtOAc extract of a static culture of this Penicillium sp.by different chromatographic methods led the isolation of an antibacterial,anticryptococcal and cytotoxic active compound,which was identified as citrinin(1).Further,citrinin(1)is reported for its potent antibacterial activity against methicillin-resistant Staphylococcus aureus(S.aureus),rifampicin-resistant 5.aureus,wild type S.aureus and vancomycin-resistant Enterococcus faecium showed MICs of 3.90,0.97,1.95 and7.81μg/mL,respectively.Further citrinin(1)displayed significant activity against the pathogenic yeast Cryptococcus neoformans(MIC 3.90μg/mL),and exhibited cytotoxicity against brine shrimp larvae LD_(50)of 96μg/mL.Conclusions:Citrinin(1)is reported from sponge associated Penicillium sp.from this study and for its strong antibacterial activity against multi-drug resistant human pathogens including cytotoxicity against brine shrimp larvae,which indicated that sponge associated Penicillium spp.are promising sources of natural bioactive metabolites.

关键词： Penicillium sp. Sponge derived Citrinin Multi-drug resistant Antimicrobial cytotoxic activity

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