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Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

Acta Pharmaceutica Sinica B 2024年第1期14卷 87-109页

作者： Letian Song Shenghua Gao Bing Ye Mianling Yang Yusen Cheng Dongwei Kang Fan Yi Jin-Peng Sun Luis Menéndez-Arias Johan Neyts Xinyong Liu Peng Zhan department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Shenzhen Research Institute of Shandong University Shenzhen 518057China The Key Laboratory of Infection and Immunity of Shandong Province Department of PharmacologySchool of Basic Medical SciencesShandong UniversityJinan 250012China Key Laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Centro de Biologı´a molecular“Severo Ochoa”(Consejo Superior de Investigaciones Cientı´ficas&Autonomous University of Madrid) Madrid 28049Spain KU Leuven Department of Microbiology and ImmunologyRega Institute for Medical ResearchLaboratory of Virology and ChemotherapyLeuven 3000Belgium

The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life *** covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic *** antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable *** non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available *** viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.

关键词： COVID-19 SARS-CoV-2 Main protease Non-covalent inhibitors Medicinal chemistry strategies

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Pull the fuzes:Processing protein precursors to generate apoplastic danger signals for triggering plant immunity

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Plant Communications 2024年第8期5卷 113-136页

作者： Daniele Del Corpo Daniele Coculo Marco Greco Giulia De Lorenzo Vincenzo Lionetti department of biology and Biotechnology“Charles Darwin ”Sapienza University of RomeRomeItaly

The apoplast is one of the first cellular compartments outside the plasma membrane encountered by phytopathogenic microbes in the early stages of plant tissue *** have developed sophisticated surveillance mechanisms to sense danger events at the cell surface and promptly activate ***,a fine tuning of the activation of immune pathways is necessary to mount a robust and effective defense *** endogenous proteins and enzymes are synthesized as inactive precursors,and their post-translational processing has emerged as a critical mechanism for triggering alarms in the *** this review,we focus on the precursors of phytocytokines,cell wall remodeling enzymes,and *** physiological events that convert inactive precursors into immunomodulatory active peptides or enzymes are *** review also explores the functional synergies among phytocytokines,cell wall damage-associated molecular patterns,and remodeling,highlighting their roles in boosting extracellular immunity and reinforcing defenses against pests.

关键词： apoplast immunity activation post-translational processing cell wall proteases pro-peptides proenzymes phytocytokines cell-wall remodeling enzymes phytopathogenic microbes plant immunity

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MicroRNA-630:A promising avenue for alleviating inflammation in diabetic kidney disease

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World Journal of Diabetes 2024年第7期15卷 1398-1403页

作者： Javier Donate-Correa Ainhoa González-Luis Jésica Díaz-Vera Juan Ramón Hernandez-Fernaud Research Unit University Hospital Nuestra Señora de Candelaria(UHNSC)Santa Cruz de Tenerife 38010Spain department of Biochemistry MicrobiologyCell Biology and GeneticsInstituto de Tecnologías BiomédicasUniversidad de La LagunaSanta Cruz de Tenerife 38000Spain

Diabetic kidney disease(DKD)is one of the complications of diabetes,affecting millions of people *** relentless progression of this condition can lead to kidney failure,requiring life-altering interventions such as dialysis or *** evidence suggests that immunologic and inflammatory elements play an important role in initiating and perpetuating the damage inflicted on renal tissues,exacerbating the decline in organ ***-like receptors(TLRs)are a family of receptors that play a role in the activation of the innate immune system by the recognition of pathogen-associated molecular *** data from in vitro and in vivo studies have highlighted the critical role of TLRs,mainly TLR2 and TLR4,in the pathogenesis of *** the diabetic milieu,these TLRs recognize diabetic-associated molecular signals,triggering a proinflammatory cascade that initiates and perpetuates inflammation and fibrogenesis in the diabetic *** non-traditional strategies targeting TLR signaling with potential therapeutic implications in DKD have been *** of these approaches is the use of microRNAs,small non-coding RNAs that can regulate gene *** editorial comments on the results of this approach carried out in a rat model of diabetes by Wu et al,published in this issue of the World Journal of *** results of the experimental study by Wu et al shows that microRNA-630 decreased levels compared to non-diabetic ***,microRNA-630 exerted anti-inflammatory effects in the kidneys of diabetic rats through the modulation of *** findings indicate that the microRNA-630/TLR4 axis might represent a pathological mechanism of DKD and a potential therapeutic target capable of curbing the destructive inflammation characteristic of DKD.

关键词： Diabetes Diabetic kidney disease Inflammation Toll-like receptor 4 microRNA-630

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The ubiquitin codes in cellular stress responses

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Protein & cell 2024年第3期15卷 157-190页

作者： Xiangpeng Sheng Zhixiong Xia Hanting Yang Ronggui Hu Key Laboratory of Systems Health Science of Zhejiang Province School of Life ScienceHangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China State Key Laboratory of molecular biology Shanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesShanghai 200031China State Key Laboratory of Animal Disease Control Harbin Veterinary Research InstituteChinese Academy of Agricultural SciencesHarbin 150069China department of Neurology State Key Laboratory of Medical NeurobiologyInstitute for Translational Brain ResearchMOE Frontiers Center for Brain ScienceZhongshan HospitalFudan UniversityShanghai 200032China

Ubiquitination/ubiquitylation,one of the most fundamental post-translational modifications,regulates almost every critical cellular process in *** evidence has shown that essential components of numerous biological processes undergo ubiquitination in mammalian cells upon exposure to diverse stresses,from exogenous factors to cellular reactions,causing a dazzling variety of functional *** forms of ubiquitin sig-nals generated by ubiquitylation events in specific milieus,known as ubiquitin codes,constitute an intrinsic part of myriad cellular stress *** ubiquitination events,leading to proteolytic turnover of the substrates or just switch in functionality,initiate,regulate,or supervise multiple cellular stress-associated responses,supporting adaptation,homeostasis recovery,and survival of the stressed *** this review,we attempted to summarize the crucial roles of ubiquitination in response to different environmental and intracellular stresses,while discussing how stresses modulate the ubiquitin *** review also updates the most recent advances in understanding ubiquitination machinery as well as different stress responses and discusses some important questions that may warrant future investigation.

关键词： ubiquitin E3 ligase environmental stresses intercellular stresses stress response homeostasis

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Improving colorectal cancer screening programs

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World Journal of Gastroenterology 2024年第22期30卷 2849-2851页

作者： Oscar J Cordero Lucia Mosquera-Ferreiro Iria Gomez-Tourino department of Biochemistry and molecular biology University of Santiago de CompostelaSantiago de Compostela 15782Spain Centre for Research in molecular Medicine and Chronic Diseases(CiMUS) University of Santiago de CompostelaSantiago de Compostela 15782GaliciaSpain

In this editorial we comment on the article by Agatsuma et al published in the World Journal of *** suggest policies for more effective colorectal *** is the main policy that has led to lower mortality rates in later years among the population that was eligible for *** is the gold standard tool for screening and has preventive effects by removing precancerous or early malignant ***,colonoscopy is an invasive process,and fecal tests such as the current hemoglobin immunodetection were developed,followed by endoscopy,as the general tool for population screening,avoiding logistical and economic *** so,participation and adherence rates are *** screening options are being developed with the idea that if people could choose between the ones that best suit them,participation in population-based screening programs would *** tests,such as a recent one that detects cell-free DNA shed by tumors called circulating tumor DNA,showed a similar accuracy rate to stool tests for cancer,but were less sensitive for advanced precancerous *** the time when the crosstalk between the immune system and cancer was being established as a new hallmark of cancer,novel immune system-related biomarkers and information on patients’immune parameters,such as cell counts of different immune populations,were studied for the early detection of colorectal cancer,since they could be effective in asymptomatic people,appearing earlier in the adenoma-carcinoma development compared to the presence of fecal ***26,for example,detected 80.37%of advanced *** reach as many eligible people as possible,starting at an earlier age than current programs,the direction could be to apply tests based on blood,urine or salivary fluid to samples taken during routine visits to the primary health system.

关键词： Mortality rates Colorectal cancer Screening Biomarker Fecal hemoglobin immunodetection Soluble sCD26 Colonoscopy Immunoscores

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Efficient scar-free knock-ins of several kilobases in plants by engineered CRISPR-Cas endonucleases

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molecular Plant 2024年第5期17卷 824-837页

作者： Tom Schreiber Anja Prange Petra Schafer Thomas Iwen Ramona Grutzner Sylvestre Marillonnet Aurelie Lepage Marie Javelle Wyatt Paul Alain Tissier department of cell and Metabolic biology Leibniz Institute of Plant BiochemistryWeinberg 306120 Halle(Saale)Germany Limagrain Centre de RechercheRoute d’EnnezatCS 9012663720 ChappesFrance

In plants and mammals,non-homologous end-joining is the dominant pathway to repair DNA doublestrand breaks,making it challenging to generate knock-in *** this study,we identified two groups of exonucleases from the herpes virus and the bacteriophage T7 families that conferred an up to 38-fold increase in homology-directed repair frequencies when fused to Cas9/Cas12a in a tobacco mosaic virus-based transient assay in Nicotiana *** achieved precise and scar-free insertion of several kilobases of DNA both in transient and stable transformation *** Arabidopsis thaliana,fusion of Cas9 to a herpes virus family exonuclease led to 10-fold higher frequencies of knock-ins in the first generation of *** addition,we demonstrated stable and heritable knock-ins in wheat in 1%of the primary *** together,our results open perspectives for the routine production of heritable knock-in and gene replacement events in plants.

关键词： homology-directed repair knockin gene replacement CRISPR-Cas 50 exonuclease plants

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Comments on‘Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer’

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Journal of molecular cell biology 2024年第3期16卷 61-63页

作者： Xinyuan Tong Ningxia Zhang Yun Xue Hongbin Ji Key Laboratory of Multi-cell Systems Shanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesShanghai 200031China department of Respiratory and Critical Care Medicine The Fourth Affiliated HospitalZhejiang University School of MedicineYiwu 322000China School of Life Science Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China School of Life Science and Technology ShanghaiTech UniversityShanghai 200120China

Cancer plasticity is a new cancer hallmark and serves as a rising mechanism of resistance to targeted therapy(Hanahan,2022).Lung adenocarcinoma(ADC)and squamous cell carcinoma(SCC)are two distinct subtypes of non-small cell lung cancer(NSCLC),characterized by different cell origins,histopathological features,and drug ***,there is a small subtype of NSCLC termed adenosquamous cell carcinoma(AdSCC),which exhibits mixed adenomatous and squamous pathologies and frequently contains identical mutations.

关键词： squamous LKB1 lung

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Neuroinflammation revisited through the microglial lens

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Neural Regeneration Research 2025年第7期20卷 1989-1990页

作者： Renato Socodato João B.Relvas Institute of Research and Innovation in Health(i3S)and Institute for molecular and cell biology(IBMC) University of PortoPortoPortugal department of Biomedicine Faculty of Medicine of the University of Porto(FMUP)PortoPortugal

Neuroimmunology is emerging as a pivotal field,shedding light on the intricate dialogues between the central nervous system(CNS)and the immune *** exploration is particularly significant in understanding microglia,the CNS’s innate immune cells,beyond the conventional conflation of“neuroinflammation”and“microglial activation.”This conflation has clouded the true complexity of these processes,potentially stalling scientific progress and the development of new *** challenge the long-standing perspectives that have oversimplified these interactions,advocating for a deeper exploration of the dynamic relationship between neuroinflammation and microglial *** dissecting specific molecular pathways,we aim to illuminate their elaborate roles in neuroinflammatory responses,especially in the context of Alzheimer’s disease(AD).Here,neuroinflammation is not merely a passive observer or a direct antagonist but a complex agent in the disease’s *** article calls for a significant paradigm shift towards an integrative,multi-omics approach to *** such a comprehensive framework is crucial for advancing our understanding of neuroinflammatory conditions and paving the way for targeted therapeutic strategies for brain diseases.

关键词： inflammation simplified activation

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Extracellular vesicles-coupled miRNAs from oviduct and uterus modulate signaling pathways related to lipid metabolism and bovine early embryo development

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Journal of Animal Science and Biotechnology 2024年第4期15卷 1528-1549页

作者： Rosane Mazzarella Karina Canon‑Beltran Yulia N.Cajas Meriem Hamdi Encina M.Gonzalez Juliano C.da Silveira Claudia L.V.Leal D.Rizos department of Animal Reproduction INIA-CSICMadridSpain department of Biochemistry and molecular biology Veterinary FacultyComplutense University of Madrid(UCM)MadridSpain department Agrarian Production Technical University of MadridUPMMadridSpain Departamento de Ciencias Biologicas Universidad Tecnica Particular de LojaUTPLLojaEcuador department of Anatomy and Embryology FV-UCMMadridSpain department of Veterinary Medicine FZEA-USPPirassunungaBrazil

Background Extracellular vesicles(EVs) present in oviductal(OF) and uterine fluid(UF) have been shown to enhance bovine embryo quality during in vitro culture by reducing lipid contents and modulating lipid metabolism-related genes(LMGs), while also influencing cell proliferation, suggesting their involvement on the regulation of different biological pathways. The regulation of signaling pathways related to cell differentiation, proliferation, and metabo-lism is crucial for early embryo development and can determine the success or failure of the pregnancy. Bioactive molecules within EVs in maternal reproductive fluids, such as micro RNAs(miRNAs), may contribute to this regulatory process as they modulate gene expression through post-transcriptional *** This study evaluated miRNA cargo in OF-EVs from the early luteal phase and UF-EVs from the mid-luteal phase, coinciding with embryo transit within oviduct and uterus in vivo, and its possible influence on LMGs and sign-aling pathways crucial for early embryo development. A total of 333 miRNAs were detected, with 11 exclusive to OF, 59 to UF, and 263 were common between both groups. From the 20 differentially expressed miRNAs, 19 up-regulated in UF-EVs(bta-miR-134, bta-miR-151-3p, bta-miR-155, bta-miR-188, bta-miR-181b, bta-miR-181d, bta-miR-224, bta-miR-23b-3p, bta-miR-24-3p, bta-miR-27a-3p, bta-miR-29a, bta-miR-324, bta-miR-326, bta-miR-345-3p, bta-miR-410, bta-miR-652, bta-miR-677, bta-miR-873 and bta-miR-708) and one(bta-miR-148b) in OF-EVs. These miRNAs were predicted to modulate several pathways such as Wnt, Hippo, MAPK, and lipid metabolism and degradation. Differ-ences in miRNAs found in OF-EVs from the early luteal phase and UF-EVs from mid-luteal phase may reflect differ-ent environments to meet the changing needs of the embryo. Additionally, miRNAs may be involved, particularly in the uterus, in the regulation of embryo lipid metabolism, immune system, and *** Our study su

关键词： Embryo-maternal interaction Epigenetic Exosomes Mammalian Preimplantation Reproductive fluids

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Smooth muscle cell-specific genetic targeting by Myh11-driven Cre(ER)knockin mice

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Science China(Life Sciences) 2024年第10期67卷 2280-2282页

作者： Enci Wang Ximeng Han Haixiao Wang Kathy O.Lui Bin Zhou Lixin Wang department of Vascular Surgery Zhongshan HospitalFudan UniversityShanghai 200032China department of Cardiology Shanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai 200030China Pediatric Research Institute The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhou 325027China department of Chemical Pathology and Li Ka Shing Institute of Health SciencesPrince of Wales HospitalThe Chinese University of Hong KongHong Kong 999077China New Cornerstone Investigator Institute State Key Laboratory of Cell BiologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 200031China department of Vascular Surgery(Xiamen) Zhongshan hospitalFudan UniversityXiamen 361015China

Dear editor,Site specific recombinases have been widely used for genome engineering in cardiovascular research(Fu et al.,2024;Huang et al.,2023;Xue et al.,2022).In particular,Cre is the most broadly used recombinase for cell type-specific lineage tracing and gene manipulation in *** smooth muscle cell(SMC)-specific targeting,several SMC promoters including Myh11(smooth muscle myosin heavy chain),Acta2(smooth muscle a-2 actin),and SM22a(Tagln)have been used to drive Cre or CreER.

关键词： cardiovascular manipulation

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