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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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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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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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dbSCI:A manually curated database of SARS-CoV-2 Inhibitors for COVID-19

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BIOCELL 2023年第2期47卷 367-371页

作者： QIANG WANG GUO ZHAO LONGXIANG XIE XUAN LI XIXI YU QIONGSHAN LI BAOPING ZHENG ZULIPINUER WUSIMAN XIANGQIAN GUO Institute of Biomedical Informatics School of SoftwareBioinformatics CenterHenan Provincial Engineering Center for Tumor Molecular MedicineSchool of Basic Medical SciencesAcademy for Advanced Interdisciplinary StudiesHenan UniversityKaifeng475004China

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the pathogen of the ongoing coronavirus disease 2019(COVID-19)global pandemic.Here,by centralizing published cell-based experiments,clinical trials,and virtual drug screening data from the NCBI PubMed database,we developed a database of SARS-CoV-2 Inhibitors for COVID-19,dbSCI,which includes 234 SARS-CoV-2 Inhibitors collected from publications based on cell-based experiments,81 drugs of COVID-19 in clinical trials and 1305 potential SARS-CoV-2 Inhibitors from bioinformatics analyses.dbSCI provides four major functions:(1)search the drug target or its inhibitor for SARS-CoV-2,(2)browse target/inhibitor information collected from cell experiments,clinical trials,and virtual drug screenings,(3)download,and(4)submit data.Each entry in dbSCI contains 18 types of information,including inhibitor/drug name,targeting protein,mechanism of inhibition,experimental technique,experimental sample type,and reference information.In summary,dbSCI provides a relatively comprehensive,credible repository for Inhibitors/drugs against SARS-CoV-2 and their potential targeting mechanisms and it will be valuable for further studies to control COVID-19.

关键词： SARS-CoV-2 COVID-19 Inhibitors Drugs Database

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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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Protein kinase Inhibitors affect spermatogenic functions and blood testis barrier remodelling:A scoping review

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Asian pacific Journal of Reproduction 2023年第3期12卷 97-108页

作者： Oyovwi Mega Obukohwo Onome Bright Oghenetega Falajiki Yewande Faith Emojevwe Victor Rotu Arientare Rume Joseph Gregory Uchechukwu Oyeleke Abiodun Abioye Department of Physiology Faculty of Basic Medical SciencesAdeleke UniversityEdeOsun StateNigeria Department of Physiology School of Basic Medical ScienceBabcock UniversityIllisan-RomoOgun StateNigeria Department of Physiology University of Medical SciencesOndo StateNigeria Department of Physiology University of IbadanIbadanOyo StateNigeria Department of Medical Laboratory Science Adeleke UniversityEdeOsun StateNigeria Department of Physiology Federal University Oye-EkitiNigeria

Objective:To identify the role of protein kinase in male reproduction in animal models and human spermatogenic function.Methods:This study assessed the protein kinase of male reproduction in animal models and human using different reviewed paper indexed in PubMed,Science Direct,EBSCO,Scopus,Cochrane Library,Sage Journals,and Google Scholar.Data were charted based on author,year of publication published between 1893 and 2023,country,purpose,data collection,key findings,and research focus/domain.Results:The MAPK pathway contributed to the growth,maturation,and functionality of male germ cells.We also found out that certain influencing factors categorized into hormonal/non hormonal factors and chemotoxicant,as well as heat stress expressed an inhibitory mechanism on protein kinase,thus affecting spermatogenic functions and maintenance/remodeling of the blood testis barrier,as well as the physiology of the Sertoli cells necessary for nutritional support of spermatogenesis.However,activating protein kinases pathway like the mTOR pathway as well as increased expression of peroxiredoxin-4 and L-carnitine mediated protein kinases may be useful for treating or managing male reproductive dysfunction.Conclusions:Protein kinase plays an important role in spermatogenic functions and blood testis remodeling in animal and human.Its assessment provides essential information that can guide treatment strategies aimed at improving male reproductive potential.Taken together,these recent advances highlight a future therapeutic intervention in assessing male reproductive potential.It might also be possible to look at potential targets for male contraceptives in the MAPK pathway.

关键词： Spermatogenesis Protein kinase Inhibitors Sertoli cells Capacitation mTOR

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Epigenetic therapies in acute myeloid leukemia: the role of hypomethylating agents, histone deacetylase Inhibitors and the combination of hypomethylating agents with histone deacetylase Inhibitors

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Chinese Medical Journal 2020年第6期133卷 699-715页

作者： Qing-Yu Xu Li Yu Department of Hematology-Oncology International Cancer CenterShenzhen University General HospitalShenzhen University Health Science CenterShenzhenGuangdong 518000China Department of Hematology and Oncology Medical Faculty MannheimHeidelberg UniversityMannheim 68169Germany

Epigenetic regulation includes changes of DNA methylation and modifications of histone proteins and is essential for normal physiologic functions,especially for controlling gene expression.Epigenetic dysregulation plays a key role in disease pathogenesis and progression of some malignancies,including acute myeloid leukemia(AML).Epigenetic therapies,including hypomethylating agents(HMAs)and histone deacetylase(HDAC)Inhibitors,were developed to reprogram the epigenetic abnormalities in AML.However,the molecular mechanisms and therapeutic effects of the two agents alone or their combination remain unknown.An overview of these epigenetic therapies is given here.A literature search was conducted through PubMed database,looking for important biological or clinical studies related to the epigenetic regimens in the treatment of AML until October 15th,2019.Various types of articles,including original research and reviews,were assessed,identified,and eventually summarized as a collection of data pertaining the mechanisms and clinical effects of HMAs and HDAC Inhibitors in AML patients.We provided here an overview of the current understanding of the mechanisms and clinical therapeutic effects involved in the treatment with HMAs and HDAC Inhibitors alone,the combination of epigenetic therapies with intensive chemotherapy,and the combination of both types of epigenetic therapies.Relevant clinical trials were also discussed.Generally speaking,the large number of studies and their varied outcomes demonstrate that effects of epigenetic therapies are heterogeneous,and that HMAs combination regimens probably contribute to significant response rates.However,more research is needed to explore therapeutic effects of HDAC Inhibitors and various combinations of HMAs and HDAC Inhibitors.

关键词： Acute myeloid leukemia Decitabine 5-azacytidine Histone deacetylase Inhibitors Intensive chemotherapy

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The spatiotemporal evolution of EGFR C797S mutation in EGFR-mutant non-small cell lung cancer:opportunities for third-generation EGFR Inhibitors re-challenge

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Science Bulletin 2019年第8期64卷 499-503页

作者： Yi-Chen Zhang Qing Zhou Zhi-Hong Chen Ming-Feng Zhang Jin-Ji Yang Hai-Yan Tu Xu-Chao Zhang Chong-Rui Xu Hong-Hong Yan Xiao-Xiao Peng Xiao-Yan Bai Shao-Kun Chuai Jun-Yi Ye Yi-Long Wu The Second School of Clinical Medicine Southern Medical University Guangdong Lung Cancer Institute Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences Burning Rock Biotech

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase Inhibitors (TKIs) have demonstrated impressive activity in EGFR T790M-positive non-small cell lung cancer (NSCLC) progressed from prior EGFR-TKI... 详细信息

关键词： cis The spatiotemporal evolution of EGFR C797S mutation in EGFR-mutant non-small cell lung cancer:opportunities for third-generation EGFR Inhibitors re-challenge

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