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EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors

Signal Transduction and Targeted Therapy 2024年第2期9卷 679-692页

作者： Keith Al-Hasani Safiya Naina Marikar Harikrishnan Kaipananickal Scott Maxwell Jun Okabe Ishant Khurana Thomas Karagiannis Julia J.Liang Lina Mariana Thomas Loudovaris Thomas Kay Assam El-Osta Epigenetics in Human Health and Disease Program Baker Heart and Diabetes Institute75 Commercial RoadMelbourne 3004 VICAustralia Department of Diabetes Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia Epigenetics in Human Health and Disease Laboratory Central Clinical SchoolMonash UniversityMelbourne 3004 VICAustralia School of Science STEM CollegeRMIT UniversityMelbourne 3001 VICAustralia Immunology and Diabetes Unit St Vincent’s Institute of Medical ResearchFitzroy 3065 VICAustralia Department of Medicine and Therapeutics The Chinese University of Hong KongSha TinHong Kong SAR Hong Kong Institute of Diabetes and Obesity Prince of Wales HospitalThe Chinese University of Hong Kong3/F Lui Che Woo Clinical Sciences Building30-32-Ngan Shing StreetSha TinHong Kong SAR Li Ka Shing Institute of Health Sciences The Chinese University of Hong KongSha TinHong Kong SAR Biomedical Laboratory Science Department of TechnologyFaculty of HealthUniversity College CopenhagenCopenhagenDenmark

β-cells are a type of endocrine cell found in pancreatic islets that synthesize,store and release insulin.In type 1 diabetes(T1D),T-cells of the immune system selectively destroy the insulin-producingβ-cells.Destruction of these cells leads to a lifelong dependence on exogenous insulin administration for survival.Consequently,there is an urgent need to identify novel therapies that stimulateβ-cell growth and induceβ-cell function.We and others have shown that pancreatic ductal progenitor cells are a promising source for regeneratingβ-cells for T1D owing to their inherent differentiation capacity.Default transcriptional suppression is refractory to exocrine reaction and tightly controls the regenerative potential by the EZH2 methyltransferase.In the present study,we show that transient stimulation of exocrine cells,derived from juvenile and adult T1D donors to the FDAapproved EZH2 inhibitors GSK126 and Tazemetostat(Taz)influence a phenotypic shift towards aβ-like cell identity.The transition from repressed to permissive chromatin states are dependent on bivalent H3K27me3 and H3K4me3 chromatin modification.Targeting EZH2 is fundamental toβ-cell regenerative potential.Reprogrammed pancreatic ductal cells exhibit insulin production and secretion in response to a physiological glucose challenge ex vivo.These pre-clinical studies underscore the potential of small molecule inhibitors as novel modulators of ductal progenitor differentiation and a promising new approach for the restoration ofβ-like cell function.

关键词： EZH2 struction inhibitors

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Efficacy of interleukin-17 inhibitors on radiographic progression in psoriatic arthritis:A systematic review and meta-analysis

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Chinese Medical Journal 2024年第4期137卷 473-475页

作者： Han-Lei Jiang Yu Du Qiang Tong Sheng-Ming Dai Department of Rheumatology and Immunology Shanghai Sixth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200233China

To the Editor:Psoriatic arthritis(PsA)is a highly heterogeneous inflammatory arthritis.It occurs in up to 30%of patients with psoriasis and can have severe impacts on peripheral joints,spine,tendon insertions,and fingers. ^([1])Radiographic progression is currently the preferred method for assessing structural damage of PsA. ^([2])Biologic treatment options for PsA include tumor necrosis factor-αinhibitors(TNFi),interleukin-12/23 inhibitors,and interleukin-17(IL-17)inhibitors.The therapeutic effects of IL-17 inhibitors on structural damage were not consistent over multiple trials.Therefore,a systematic review and meta-analysis of the available randomized controlled trials(RCTs)was conducted to quantify the overall effect of IL-17 inhibitors on structural damage in PsA.This study was registered with PROSPERO(No.CRD42022301774).

关键词： damage analysis inhibitors

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Cardiovascular toxicity with CTLA-4 inhibitors in cancer patients:A meta-analysis

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Cancer Innovation 2024年第3期3卷 49-64页

作者： Huiyi Liu Lu Fu Shuyu Jin Xingdong Ye Yanlin Chen Sijia Pu Yumei Xue Department of Cardiology Guangdong Cardiovascular InstituteGuangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdongChina The Second School of Clinical Medicine Southern Medical UniversityGuangzhouGuangdongChina School of Medicine South China University of TechnologyGuangzhouGuangdongChina Guangdong Provincial Key Laboratory of Clinical Pharmacology Research Center of Medical SciencesGuangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouGuangdongChina

Background:With the emergence of cytotoxic T lymphocyte-associated protein-4(CTLA-4)inhibitors,the outcomes of patients with malignant tumors have improved significantly.However,the incidence of cardiovascular adverse events has also increased,which can affect tumor treatment.In this study,we evaluated the incidence and severity of adverse cardiovascular events caused by CTLA-4 inhibitors by analyzing reported trials that involved CTLA-4 inhibitor therapy.Methods:Randomized clinical trials published in English from January 1,2013,to November 30,2022,were searched using the Cochrane Library and PubMed databases.All included trials examined all grade and grades 3–5 cardiac and vascular adverse events.These involved comparisons of CTLA-4 inhibitors to placebo,CTLA-4 inhibitors plus chemotherapy to chemotherapy alone,CTLA-4 inhibitors combined with PD-1/PD-L1 inhibitors to PD-1/PD-L1 inhibitors alone,and CTLA-4 inhibitors plus target agent to PD-1/PD-L1 inhibitors plus target agent.The odds ratio(OR)and corresponding 95%confidence intervals(CIs)were calculated using the Mantel-Haenszel method.Results:Overall,20 trials were included.CTLA-4 inhibitors significantly increased the incidence of all-grade cardiovascular toxicity(OR=1.33,95%CI:1.00–1.75,p=0.05).The incidence of all-grade cardiovascular toxicity increased in malignant tumor patients who received single-agent CTLA-4 inhibitors(OR=1.73,95%CI:1.13–2.65,p=0.01),as well as the incidence rate of grades 3–5 cardiovascular adverse events(OR=2.00,95%CI:1.08–3.70,p=0.03).Compared with the non-CTLA-4 inhibitor group,CTLA-4 inhibitors plus chemotherapy,PD-1/PD-L1 inhibitors,or target agent did not significantly affect the incidence of cardiac and vascular toxicity.The incidence of grades 3–5 cardiac failure,hypertension,pericardial effusion,myocarditis,and atrial fibrillation were much higher among patients exposed to CTLA-4 inhibitor,but the data were not statistically significant.Conclusion:Our findings suggest that the incidence rate of all cardiovascular toxicity an

关键词： cardiovascular toxicity CTLA-4 inhibitors malignancies

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Role of marine natural products in the development of antiviral agents against SARS‑CoV‑2:potential and prospects

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Marine Life Science & Technology 2024年第2期6卷 280-297页

作者： D.P.Nagahawatta N.M.Liyanage Thilina U.Jayawardena H.H.A.C.K.Jayawardhana Seong‑Hun Jeong Hyung‑Jun Kwon You‑Jin Jeon Department of Marine Life Sciences Jeju National UniversityJeju 690-756Republic of Korea Department of Chemistry Biochemistry and PhysicsUniversitédu QuébecàTrois-RivièresTrois-RivièresQC G8Z 4M3Canada Marine Science Institute Jeju National UniversityJeju 63333Republic of Korea Functional Biomaterial Research Center Korea Research Institute of Bioscience and BiotechnologyJeongeup-siRepublic of Korea

A novel coronavirus,known as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has surfaced and caused global concern owing to its ferocity.SARS-CoV-2 is the causative agent of coronavirus disease 2019;however,it was only discovered at the end of the year and was considered a pandemic by the World Health Organization.Therefore,the develop-ment of novel potent inhibitors against SARS-CoV-2 and future outbreaks is urgently required.Numerous naturally occurring bioactive substances have been studied in the clinical setting for diverse disorders.The intricate infection and replication mechanism of SARS-CoV-2 offers diverse therapeutic drug targets for developing antiviral medicines by employing natural products that are safer than synthetic compounds.Marine natural products(MNPs)have received increased attention in the development of novel drugs owing to their high diversity and availability.Therefore,this review article investigates the infection and replication mechanisms,including the function of the SARS-CoV-2 genome and structure.Furthermore,we highlighted anti-SARS-CoV-2 therapeutic intervention efforts utilizing MNPs and predicted SARS-CoV-2 inhibitor design.

关键词： SARS-CoV-2 Marine natural products Drug targets inhibitors

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Empagliflozin reduces brain pathology in Alzheimer's disease and type 2 diabetes

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Neural Regeneration Research 2024年第6期19卷 1189-1190页

作者： Carmen Hierro-Bujalance Monica Garcia-Alloza Division of Physiology School of MedicineUniversidad de Cadiz Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA) Salus Infirmorum-Universidad de Cadiz

Alzheimer’s disease(AD) and type 2 diabetes(T2D): More than 55 million people suffer from dementia, and it is expected that over 150 million people will suffer from this disease by 2050. AD is the most common type of dementia and while aging remains the main risk factor to suffer it, previous studies have also shown that metabolic disorders, and T2D specifically, are also major contributors(Wang et al., 2012).

关键词： inhibitors

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Arf6 as a therapeutic target:Structure,mechanism,and inhibitors

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Acta Pharmaceutica Sinica B 2023年第10期13卷 4089-4104页

作者： Dejuan Sun Yuanyuan Guo Piyu Tang Hua Li Lixia Chen Wuya College of Innovation Key Laboratory of Structure-Based Drug Design&DiscoveryMinistry of EducationShenyang Pharmaceutical UniversityShenyang 110016China College of Pharmacy Fujian University of Traditional Chinese MedicineFuzhou 350122China

ADP-ribosylation factor 6(Arf6),a small G-protein of the Ras superfamily,plays pivotal roles in multiple cellular events,including exocytosis,endocytosis,actin remodeling,plasma membrane reorganization and vesicular transport.Arf6 regulates the progression of cancer through the activation of cell motility and invasion.Aberrant Arf6 activation is a potential therapeutic target.This review aims to understand the comprehensive function of Arf6 for future cancer therapy.The Arf6 GEFs,protein structure,and roles in cancer have been summarized.Comprehending the mechanism underlying Arf6-mediated cancer cell growth and survival is essential.The structural features of Arf6 and its efforts are discussed and may be contributed to the discovery of future novel protein-protein interaction inhibitors.In addition,Arf6 inhibitors and mechanism of action are listed in the table.This review further emphasizes the crucial roles in drug resistance and attempts to offer an outlook of Arf6 in cancer therapy.

关键词： Arf6 Mechanism Structure inhibitors Drug resistance

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A CRISPR-Cas9 screen shows the combination efficacy of lenvatinib plus epidermal growth factor receptor inhibitors for treatment of liver cancer

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Cancer Biology & Medicine 2022年第2期19卷 136-139页

作者： Yuchen Guo Yangyang Zhou Wenxin Qin State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University School of MedicineShanghai 200032China

Recently,in cooperation with the Netherlands Cancer Institute,we demonstrated that epidermal growth factor receptor(EGFR)activation limited the response of liver cancer to lenvatinib.The original article was published in Nature as a cover story,which resulted in considerable attention from major scientific journals.Here,we were invited by Cancer Biology&Medicine to provide comments on preclinical and clinical findings about the combination of lenvatinib plus EGFR inhibitors as a promising strategy for hepatocellular carcinoma(HCC)treatment.Primary liver cancer represents the sixth most common malignancy and the third leading cause of cancer-related mortality worldwide,with an estimated 906,000 new cases and 830,000 deaths in 20201.

关键词： treatment finding inhibitors

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Discovery of CECR2 Bromodomain inhibitors with High Selectivities over BPTF Bromodomain

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Chinese Journal of Chemistry 2022年第17期40卷 2072-2080页

作者： Haibo Lu Shijia Zu Zhe Duan Yueyao Feng Jie Wang Jingyi Ma Qi Li Dongying Chen Bo Li Kaixian Chen Cheng Luo Jin Lin Tian Lu Hua Lin Biomedical Research Center of South China College of Life SciencesFujian Normal UniversityFuzhouFujian350117 China School of Pharmacy Fudan University826 Zhangheng RoadShanghai201203 China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of Sciences555 Zuchongzhi RoadShanghai201203 China University of Chinese Academy of Sciences 19 Yuquan RoadBeijing100049 China School of Pharmacy Nanchang UniversityNanchangJiangxi330006 China Laboratory of Pharmaceutical Analysis Shanghai Institute of Materia MedicaChinese Academy of Sciences555 Zuchongzhi RoadZhangjiang Hi-Tech ParkShanghai201203 China School of Pharmacy Fujian Medical UniversityFuzhouFujian350122 China Guizhou University of Traditional Chinese Medicine GuiyangGuizhou550025 China

Cat's eye syndrome chromosome candidate 2 bromodomain(CECR2 BRD)and Bromodomain PHD transcription factor bromodomain(BPTF BRD)are the same subfamily proteins,both of which are highly conserved in sequence and binding pockets.Challenges remain in the development of small molecules to inhibit one of the two bromodomains(BRDs),in view of each subtype may possess unique physiological and pathological functions.There is still a lack of effective selective inhibitors of CECR2 BRD,which makes it difficult to fully understand the pathogenesis of CECR2-BRD in diseases,especially cancers.Herein,we report our efforts to discover a series of highly selective CECR2 BRD inhibitors over BPTF BRD based on TP-248.Structure-based molecular optimization led to the discovery of DC-CEi-26,whose IC_(50) for CECR2 BRD was 96.7±14.9 nmol/L and selectivity was up to 590×over BPTF BRD.DC-CEi-26 showed weak potencies for other classic BRDs in different subfamily,which may serve as a chemical probe for CECR2 BRD biological research.

关键词： CECR2 bromodomain BPTF bromodomain inhibitors Structure-activity relationships chemical probe

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Identification of a class of potent USP25/28 inhibitors with broad-spectrum anti-cancer activity

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Signal Transduction and Targeted Therapy 2023年第1期8卷 3-5页

作者： Jin Peng Kun Jiang Xiao Sun Lingzhi Wu Jiewei Wang Xiaomei Xi Xu Tan Tingbo Liang Changheng Tan Pumin Zhang Zhejiang Provincial Key Laboratory of Pancreatic Diseases The First Affiliated Hospital of Zhejiang UniversityHangzhouZhejiang 310003China Shanghai Institute of Materia Medica Shanghai 200216China Chaser Therapeutics Inc.HangzhouZhejiang Province 310018China Beijing Advanced Innovation Center for Structural Biology School of Pharmaceutical SciencesTsinghuaPeking Center for Life SciencesTsinghua UniversityBeijingChina

Dear Editor,An increasing body of evidence suggests that USP28 could be a target for cancer treatment^(1-4).To identify its inhibitors,we screened a 100-thousand synthetic compound library and found 3 lead compounds,CT1001-1003,that showed significant inhibitory activity(Supplementary Fig.1a).The optimization of these compounds led to CT1018,a much stronger inhibitor(Supplementary Fig.1b).

关键词： cancer spectrum inhibitors

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Design,synthesis and SAR study of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors

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Chinese Chemical Letters 2022年第6期33卷 2969-2974页

作者： Dandan Liu Huan Ge Fangling Xu Yufang Xu Wenjun Liu Honglin Li Lili Zhu Yanyan Diao Zhenjiang Zhao Shanghai Key Laboratory of New Drug Design School of PharmacyEast China University of Science and TechnologyShanghai 200237China Research and Development Department Jiangzhong Pharmaceutical Co.Ltd.Nanchang 330096China

The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms(MPNs).At present,there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic.In this paper,a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design,synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib.Among them,21 b exhibited high inhibitory activity against JAK2 with an IC_(50)of 9 nmol/L,moreover,it showed 276-and 184-fold selectivity over JAK1 and JAK3,respectively.Besides,21 b had a significant antiproliferative activity against HEL cells,and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway.These results indicated that2-aminopyridine compound 21 b had the potential to be developed as a selective JAK2 inhibitor for further study.

关键词： JAK2 Selectivity inhibitors Cancer Structure-activity relationships

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