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SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2702-2715页

作者： Hye Jin Shin Wooseong Lee Keun Bon Ku Gun Young Yoon Hyun-Woo Moon Chonsaeng Kim Mi-Hwa Kim Yoon-Sun Yi Sangmi Jun Bum-Tae Kim Jong-Won Oh Aleem Siddiqui Seong-Jun Kim Department of Convergent Research of Emerging Virus infection Korea Research Institute of Chemical TechnologyDaejeon 34114Republic of Korea Gyeongnam Biohealth Research Center Gyeongnam Branch InstituteKorea Institute of ToxicologyJinju 52834Republic of Korea Center for Research Equipment Korea Basic Science InstituteCheongjuChungcheongbuk-do 28119Republic of Korea Department of Biotechnology Yonsei UniversitySeoul 03722Republic of Korea Division of Infectious Diseases School of MedicineUniversity of CaliforniaSan DiegoLa JollaCA 92093USA Present address:Department of microbiology Chungnam National University School of MedicineDaejeon 35015Republic of Korea

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is a‘highly transmissible respiratory pathogen,leading to severe multiorgan ***,knowledge regarding SARS-CoV-2-induced cellular alterations is *** this study,we report that SARSCoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral ***-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNAnucleocapsid cluster,thereby abnormally promoting mitochondrial elongation and the OXPHOS process,followed by enhancing ATP ***,SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking,contributing to abnormal OXPHOS process and viral *** EGFR inhibitors remarkably reduce SARS-CoV-2 propagation,among which vandetanib exhibits the highest antiviral *** of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation,thereby resulting in the reduction of SARS-CoV-2 ***,oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung *** also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern,including alpha,beta,delta and omicron,in in vitro cell culture *** together,our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation,suggesting that EGFR is an attractive host target for combating COVID-19.

关键词： alterations aberrant thereby

Management of cytomegalovirus infection after liver transplantation

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World Journal of Transplantation 2024年第3期14卷 30-39页

作者： Zeynep Burcin Yilmaz Funda Memisoglu Sami Akbulut Infectious Diseases and clinical microbiology Inonu University Faculty of MedicineMalatya 44280Türkiye Surgery and Liver Transplant Institute Inonu University Faculty of MedicineMalatya 44280Türkiye

Cytomegalovirus(CMV)infection is one of the primary causes of morbidity and mortality following liver transplantation(LT).Based on current worldwide guidelines,the most effective strategies for avoiding post-transplant CMV infection are antiviral prophylaxis and pre-emptive ***-IgG serology is the established technique for pretransplant screening of both donors and *** clinical presentation of CMV infection and disease exhibits variability,prompting clinicians to consistently consider this possibility,partic-ularly within the first year post-transplantation or subsequent to heightened *** annual symposia to discuss CMV prevention and how treatment outcomes can be improved,evidence on the incorporation of immune functional tests into clinical practice is presented,and the results of studies with new antiviral treatments are *** there are ongoing studies on the use of letermovir and maribavir in solid organ transplantation,a consensus reflected in the guidelines has not been *** the most appro-priate strategy at the individual level appears to be the key to enhancing *** prevention strategies reduce the risk of CMV disease,the disease can still occur in up to 50%of high-risk patients.A balance between the risk of infection and disease development and the use of immunosuppressants must be considered when talking about the proper management of CMV in solid organ transplant *** objective of this study was to establish a compre-hensive framework for the management of CMV in patients who have had LT.

关键词： Liver transplantation Cytomegalovirus Antiviral prophylaxis Preemptive treatment Valganciclovir Ganciclovir

Targeting miRNA by CRISPR/Cas in cancer:advantages and challenges

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Military Medical Research 2024年第3期11卷 345-373页

作者： Bashdar Mahmud Hussen Mohammed Fatih Rasul Snur Rasool Abdullah Hazha Jamal Hidayat Goran Sedeeq Hama Faraj Fattma Abodi Ali Abbas Salihi Aria Baniahmad Soudeh Ghafouri-Fard Milladur Rahman Mark C.Glassy Wojciech Branicki Mohammad Taheri Department of Biomedical Sciences Cihan University-ErbilErbilKurdistan Region 44001Iraq Department of clinical Analysis College of PharmacyHawler Medical UniversityErbilKurdistan Region 44001Iraq Department of Pharmaceutical Basic Science Faculty of PharmacyTishk International UniversityErbilKurdistan Region 44001Iraq Medical Laboratory Science Lebanese French UniversityErbilKurdistan Region 44001Iraq Department of biology College of EducationSalahaddin University-ErbilErbilKurdistan Region 44001Iraq Department of Medical Laboratory Science Komar University of Science and TechnologySulaymaniyah 46001Iraq Department of Medical microbiology College of Health SciencesHawler Medical UniversityErbilKurdistan Region 44001Iraq Department of biology College of ScienceSalahaddin University-ErbilErbilKurdistan Region 44001Iraq Center of Research and Strategic Studies Lebanese French UniversityErbil 44001Iraq Institute of Human Genetics Jena University Hospital07747 JenaGermany Department of Medical Genetics School of MedicineShahid Beheshti University of Medical SciencesTehran 374-37515Iran Department of clinical Sciences MalmöSection for SurgeryLund University22100 MalmöSweden Translational Neuro-Oncology Laboratory San Diego(UCSD)Moores Cancer CenterUniversity of CaliforniaSan DiegoCA 94720USA Faculty of biology Institute of Zoology and Biomedical ResearchJagiellonian University31-007 KrakówPoland Urology and Nephrology Research Center Shahid Beheshti University of Medical SciencesTehran 374-37515Iran

Clustered regulatory interspaced short palindromic repeats(CRISPR)has changed biomedical research and provided entirely new models to analyze every aspect of biomedical sciences during the last *** the study of cancer,the CRISPR/CRISPR-associated protein(Cas)system opens new avenues into issues that were once unknown in our knowledge of the non-coding genome,tumor heterogeneity,and precision ***/Cas-based geneediting technology now allows for the precise and permanent targeting of mutations and provides an opportunity to target small non-coding RNAs such as microRNAs(miRNAs).However,the development of effective and safe cancer gene editing therapy is highly dependent on proper design to be innocuous to normal cells and prevent introducing other *** study aims to highlight the cutting-edge approaches in cancer-gene editing therapy based on the CRISPR/Cas technology to target miRNAs in cancer ***,we highlight the potential challenges in CRISPR/Cas-mediated miRNA gene editing and offer advanced strategies to overcome them.

关键词： CRISPR CRISPR/Cas9 CRISPR/Cas12 Gene editing miRNAs Cancer therapy

Translating bacteriophage-derived depolymerases into antibacterial therapeutics:Challenges and prospects

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Acta Pharmaceutica Sinica B 2024年第1期14卷 155-169页

作者： Honglan Wang Yannan Liu Changqing Bai Sharon Shui Yee Leung School of Pharmacy the Chinese University of Hong KongHong Kong SARChina Emergency Medicine clinical Research Center Beijing Chao-Yang HospitalCapital Medical UniversityBeijing 100020China Department of Respiratory Shenzhen University General HospitalShenzhen University Clinical Medical AcademyGuangdong 518055China

Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and *** depolymerases are enzymes responsible for degrading diverse bacterial surface *** are exploited as antibiofilm agents and antimicrobial adjuvants while rarely inducing bacterial resistance,making them an invaluable asset in the era of antibiotic *** depolymerases have been investigated preclinically,with evidence indicating that depolymerases with appropriate dose regimens can safely and effectively combat different multidrug-resistant pathogens in animal infection ***,some formulation approaches have been developed for improved stability and activity of ***,depolymerase formulation is limited to liquid dosage form and remains in its infancy,posing a significant hurdle to their clinical translation,compounded by challenges in their applicability and *** development must address these obstacles for clinical ***,after unravelling the history,diversity,and therapeutic use of depolymerases,we summarized the preclinical efficacy and existing formulation findings of recombinant ***,the challenges and perspectives of depolymerases as therapeutics for humans were assessed to provide insights for their further development.

关键词： Phage-derived polysaccharide depolymerases Bacteriophage proteins Bacterial capsules Polysaccharide capsules Antibiotic resistance Biofilms Antibacterial therapy Antimicrobial adjuvants Combination treatment

Experts’Consensus on the Management of Respiratory Disease Syndemic

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China CDC weekly 2024年第8期6卷 131-138页

作者： Weizhong Yang Zhongjie Li Ting Yang Yanming Li Zhengde Xie Luzhao Feng Zhibin Peng Jue Liu School of Population Medicine and Public Health Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina State Key Laboratory of Respiratory Health and Multimorbidity BeijingChina Key Laboratory of Pathogen infection Prevention and Control Peking Union Medical CollegeMinistry of EducationBeijingChina National Center for Respiratory Diseases State Key Laboratory of Respiratory Health and MultimorbidityNational Clinical Research Center for Respiratory DiseasesInstitute of Respiratory MedicineChinese Academy of Medical SciencesDepartment of Pulmonary and Critical Care MedicineCenter of Respiratory MedicineChina-Japan Friendship HospitalBeijingChina Department of Pulmonary and Critical Care Medicine National Center of GerontologyBeijing HospitalInstitute of Geriatric MedicineChinese Academy of Medical SciencesBeijingChina Beijing Key Laboratory of Pediatric Respiratory infection Diseases Key Laboratory of Major Diseases in ChildrenMinistry of EducationNational Clinical Research Center for Respiratory DiseasesResearch Unit of Critical Infection in ChildrenChinese Academy of Medical Sciences2019RU016National Key Discipline of Pediatrics(Capital Medical University)Beijing Pediatric Research InstituteBeijing Children's HospitalCapital Medical UniversityNational Center for Children's HealthBeijingChina Chinese Center for Disease Control and Prevention BeijingChina Department of Epidemiology and Biostatistics School of PublicHealthKey Laboratory of Epidemiology of Major DiseasesMinistry of EducationPeking University Health Science Center-Weifang Joint Research Center for Maternal and Child HealthPeking UniversityBeijingChina

The global burden of respiratory diseases is a significant and increasing threat to individuals *** 2017,there were 544.9 million cases of chronic respiratory diseases,a 39.8%increase since 1990(1).These diseases were the third leading cause of global mortality in 2017,accounting for 7.0%of all deaths,an 18.0%increase compared to 1990.

关键词： diseases respiratory mortality

Human chemerin induces eryptosis at concentrations exceeding circulating levels

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BIOCELL 2024年第8期48卷 1197-1208页

作者： MARYNA TKACHENKO ANATOLII ONISHCHENKO LILIYA TRYFONYUK DMYTRO BUTOV KATERYNA KOT VIKTORIIA NOVIKOVA LIWEI FAN VOLODYMYR PROKOPIUK YURII KOT ANTON TKACHENKO Department of Internal Medicine No.2 Clinical Immunology and AllergologyKharkiv National Medical UniversityKharkiv61022Ukraine Research Institute of Experimental and clinical Medicine Kharkiv National Medical UniversityKharkiv61022Ukraine Institute of Health National University of Water and Environmental EngineeringRivne61022Ukraine Department of Infectious Diseases and Phthisiology Kharkiv National Medical UniversityKharkiv61022Ukraine Biochemistry Department V.N.Karazin Kharkiv National University Ministry of Education and Science of UkraineKharkiv61022Ukraine Department of Chemistry BiochemistryMicrobiology and Food HygieneState Biotechnological UniversityKharkiv61022Ukraine clinical Research Innovation Lab Floor 26 Block D Qidi Technology Building 8Tsinghua Technology ParkBeijing100084China Department of Cryobiochemistry Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of UkraineKharkiv61015Ukraine

Introduction:Human chemerin is an adipokine that regulates chemotaxis,inflammation,and glucose *** addition,accumulating evidence suggests that chemerin promotes apoptosis,autophagy,and ***,there are no data on its impact on *** current study aimed to analyze the effects of human active Glu^(21)-Ser^(157) chemerin on eryptosis in *** and Methods:Human chemerin 0-2-10-50μg/mL was incubated for 24 h with human erythrocytes(hematocrit 0.4%)obtained from eight healthy *** cytometry-based determination of phospholipid scrambling,reactive oxygen species(ROS)production,and intracellular Ca^(2+)levels was *** supplement data on ROS and Ca^(2+)signaling in chemerin-mediated eryptosis,incubation in the presence or absence of antioxidants vitamin C and N-acetylcysteine and Ca^(2+)-binding agent EGTA was carried out,*** microscopy-based techniques were used to detect reactive nitrogen species(RNS)generation,involvement of caspase-3 and caspase-8,as well as the state of lipid order in cell membranes of erythrocytes exposed to human Glu^(21)-Ser^(157) ***:Our observations suggest that human Glu^(21)-Ser^(157) chemerin had no impact on eryptosis parameters at 2μg/***,chemerin stimulated phosphatidylserine externalization,ROS production,and Ca^(2+)accumulation at higher concentrations suggesting activation of ***^(2+)uptake turned out to be at least partly required for chemerin-mediated ***-mediated erythrotoxicity was additionally mediated by RNS,caspase-3,and ***,Glu^(21)-Ser^(157) chemerin promoted reduction in the liquid-ordered phase of cell membranes in ***:The present study first discloses that human chemerin can induce eryptosis via Ca^(2+)-dependent mechanisms at concentrations noticeably exceeding circulating ***,chemerin-induced eryptosis can hardly contribute to eryptosis-mediated anemia in disease

关键词： Adipokine Cell death Chemerin Oxidative stress Eryptosis

Durable and enhanced immunity against SARS-CoV-2 elicited by manganese nanoadjuvant formulated subunit vaccine

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Signal Transduction and Targeted Therapy 2024年第1期9卷 47-50页

作者： Mengyu Guo Mingjing Cao Jiufeng Sun Ziwei Chen Xin Wang Lianpan Dai George F.Gao Yuliang Zhao Yaling Wang Chunying Chen CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety&CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology of ChinaBeijingChina Guangdong Provincial Institute of Public Health Guangdong Provincial Center for Disease Control and PreventionGuangzhouChina CAS Key Laboratory of Pathogen microbiology and Immunology Institute of MicrobiologyBeijingChina

Dear editor,Vaccines are the most efficient and effective means to prevent infectious diseases,but improving the long-term protective efficacy is still a major challenge in contemporary vaccine development.1 The waning immunity varies depending on the diversification of the pathogen and the number of booster doses.1 Strategies to overcome this warrant is using adjuvants that amplify the immune response,and drive the production of memory B and T cells or long-lived plasma cells that recognize the pathogen for durable protection.2–4 Although existing adjuvants have achieved promising results,research on generating durable protective immunity is lacking in promoting vaccine development and staying ahead of global pandemics such as coronavirus disease 2019(COVID-19).The precisely designed nanoadjuvants can enhance lymph node targeting and increase antigenpresenting cell(APCs)uptake,achieving the co-delivery of adjuvants and antigens and activating innate and adaptive immune responses.5 Previously,we reported a manganese nanoadjuvant(MnARK)and receptor-binding domain(RBD)monomer antigen formulated nanovaccine.6 MnARK transported antigens to lymph nodes,activated the STING pathway,elicited strong neutralizing abilities and increased immune memory T cell percentage against the infection of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).6 Regarding the long-term protection potential of MnARK for subunit vaccine development,we further explored the durable immune regulation abilities of MnARK to a SARS-CoV-2 RBD dimer antigen,which has been used in an approved COVID-19 subunit vaccine ZF2001 with aluminum adjuvant(alum).7,8 TEM result revealed that RBD dimer could interact with BSA on MnARK surface and epitope can be well preserved(Supplementary Fig.1a).The size and zeta potential of MnARK-RBD dimer nanovaccine was~58 nm and-14 mV,respectively(Supplementary Fig.1b,c).

关键词： manganese immunity protective

Occurrence of K1 and K2 serotypes and genotypic characteristics of extended spectrumβ-lactamases-producing Klebsiella pneumoniae isolated from selected hospitals in Malaysia

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Asian Pacific Journal of Tropical Medicine 2024年第1期17卷 30-38页

作者： Nurul Syazrah Anuar Hazmin Hazman Sharven Raj Jeyakumar Mohd Nasir Mohd Desa Hasni Idayu Saidi Siti Norbaya Masri Nur Afiza Aziz Nurshahira Sulaiman Department of Biomedical Science Faculty of Medicine and Health SciencesUniversiti Putra Malaysia43400UPM SerdangSelangorMalaysia Department of Medical microbiology Faculty of Medicine and Health SciencesUniversiti Putra Malaysia43400UPM SerdangSelangorMalaysia microbiology Unit Department of PathologyHospital Sultanah AminahJalan Persiaran Sultan Abu Bakar80100 Johor BahruJohorMalaysia

Objective:To determine the distribution,phenotypic and genetic background of extended spectrumβ-lactamases(ESBL)-producing Klebsiella(K.)pneumoniae clinical isolates associated with K1 and K2 serotypes in two selected hospitals in ***:A total of 192 *** isolates were collected and subjected to antibiotic susceptibility,hypermucoviscosity test and multiplex PCR to detect the presence of K1-and K2-serotype associated *** sequence typing(MLST)was performed on ESBL-producing *** isolates presented with K1 and K2 serotypes,followed by phylogenetic ***:A total of 87 out of 192(45.3%)of the *** isolates collected were ESBL ***,only 8.3%(16/192)and 10.9%(21/192)of the total isolates were detected to carry K1-and K2-serotype associated genes,*** analysis showed that K1 and K2 capsular serotypes were not significantly associated with ESBL phenotype(P=0.196).However,they were significantly associated with hypervirulent,as demonstrated by the positive string test(P<0.001).MLST analysis revealed that ST23 as the predominant sequence type(ST)in the K1 serotype,while the ST in the K2 serotype is more ***:Although the occurrence of ESBL-producing isolates among the hypervirulent strains was low,their coexistence warrants the need for continuous *** showed that these isolates were genetically heterogeneous.

关键词： Extended spectrumβ-lactamases Klebsiella pneumoniae Capsular serotypes Genotypic

An Update on the clinical Pipelines of New Antibacterial Drugs Developed in China

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Engineering 2024年第7期38卷 52-68页

作者： Xinyi Yang Congran Li Xiukun Wang Zhonghui Zheng Peiyi Sun Chunjie Xu Luni Chen Jiandong Jiang Staffan Normark Birgitta Henriques-Normark Xuefu You Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Division for Medicinal Microorganism-Related Strains CAMS Collection Center of Pathogenic MicroorganismsChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Shandong Xinhua Pharmaceutical Co. Ltd.Zibo 255005China Department of microbiology Tumor and Cell BiologyKarolinska InstitutetStockholm SE-17177Sweden State Key Laboratory of Bioactive Substances and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China clinical microbiology Karolinska University HospitalBioclinicumStockholm SE-17176Sweden

Antibacterial resistance is a global health threat that requires further concrete action on the part of all *** this context,one of the biggest concerns is whether enough new antibacterial drugs are being discovered and *** several high-quality reviews on clinical antibacterial drug pipelines from a global perspective were published recently,none provides comprehensive information on original antibacterial drugs at clinical stages in *** this review,we summarize the latest progress of novel antibacterial drugs approved for marketing and under clinical evaluation in China since *** was obtained by consulting official websites,searching commercial databases,retrieving literature,asking personnel from institutions or companies,and other means,and a considerable part of the data covered here has not been included in other *** of June 30,2023,a total of 20 antibacterial projects from 17 Chinese pharmaceutical companies or developers were identified and *** them,two new antibacterial drugs that belong to traditional antibiotic classes were approved by the National Medical Products Administration(NMPA)in China in 2019 and 2021,respectively,and 18 antibacterial agents are in clinical development,with one under regulatory evaluation,five in phase-3,six in phase-2,and six in *** of the clinical candidates are new analogs or monocomponents of traditional antibacterial pharmacophore types,including two dual-acting hybrid antibiotics and a recombinant antibacterial ***,despite there being 17 antibacterial clinical candidates,our analysis indicates that there are still relatively few clinically differentiated antibacterial agents in stages of clinical development in ***,Chinese pharmaceutical companies and institutions will develop more innovative and clinically differentiated candidates with good market potential in the future research and development(R&D)of original antibacterial drugs.

关键词： Antimicrobial resistance New antibiotics clinical pipelines WHO priority pathogens National Mega-Project for Innovative Drugs