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A novel strategy for treating oncogene-mutated tumors by targeting tumor microenvironment and synergistically enhancing anti-PD-1 immunotherapy

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Cancer Communications 2024年第3期44卷 438-442页

作者： Yingqiang Liu Linjiang Tong Mengge Zhang Qi Zhang Qiupei Liu Fang Feng Yan Li Mengzhen Lai Haotian Tang Yi Chen Meiyu Geng Wenhu Duan Jian Ding Hua Xie division of Antitumor Pharmacology&State Key Laboratory of drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiP.R.China University of Chinese Academy of Sciences BeijingP.R.China Department of Chemical and Environmental Engineering University of Nottingham Ningbo ChinaNingboZhejiangP.R.China Zhongshan Institute for drug discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdongP.R.China Shandong Laboratory of Yantai drug discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantaiShandongP.R.China Small-Molecule drug Research Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiP.R.China

Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune *** in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor(EGFR)are among the most frequent gain-of-function alterations[1].After many years of in-depth research,inhibitors targeting EGFR or KRAS mutations have been successfully developed,however,their clinical benefit is relatively limited,and they will inevitably encounter the challenge of drug *** emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors.

关键词： alterations KRAS sarcoma

Advancements in nanotechnology for the delivery of phytochemicals

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Journal of Integrative Medicine 2024年第4期22卷 385-398页

作者： Divya Chauhan Pavan K.Yadav Nazneen Sultana Arun Agarwal Saurabh Verma Manish K.Chourasia Jiaur R.Gayen division of Pharmaceutics and Pharmacokinetics Central Drug Research InstituteCouncil of Scientific and Industrial ResearchLucknow 226031Uttar PradeshIndia Academy of Scientific and Innovative Research Ghaziabad 201002Uttar PradeshIndia

Phytosomes(phytophospholipid complex) are dosage forms that have recently been introduced to increase the stability and therapeutic effect of herbal medicine. Currently, bioactive herbs and the phytochemicals they contain are considered to be the best remedies for chronic diseases. One promising approach to increase the efficacy of plant-based therapies is to improve the stability and bioavailability of their bio-active ingredients. Phytosomes employ phospholipids as their active ingredients, and use their amphiphilic properties to solubilize and protect herbal extracts. The unique properties of phospholipids in drug delivery and their use in herbal medicines to improve bioavailability results in significantly enhanced health benefits. The introduction of phytosome nanotechnology can alter and revolutionize the current state of drug delivery. The goal of this review is to explain the application of phytosomes, their future prospects in drug delivery, and their advantages over conventional formulations.

关键词： Phytochemical bioavailability drug delivery system Phytosome Plant extracts

Multitarget Thiol-Activated Tetrapyridyl Gold(Ⅲ)Complexes for Hypoxic Cancer Therapy

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CCS Chemistry 2024年第3期6卷 783-797页

作者： Xue-Quan Zhou Selda Abyar Imma Carbo-Bague Lan Wang Sebastian Türck Maxime ASiegler Uttara Basu Ingo Ott Rongfang Liu Adriaan PIJzerman Sylvestre Bonnet Institute of biopharmaceutical and Health Engineering Tsinghua Shenzhen International Graduate School(SIGS)Tsinghua UniversityShenzhen 518055 Leiden Institute of Chemistry Leiden University2333 CC Leiden Department of Chemistry Simon Fraser UniversityBurnabyBritish Columbia V5A 1S6 Institute of Medicinal and Pharmaceutical Chemistry Technische Universität Braunschweig38106 Braunschweig Department of Chemistry Johns Hopkins UniversityBaltimoreMaryland 21218 division of drug discovery&Safety Leiden Academic Centre for Drug ResearchLeiden University2333 CC Leiden

Gold complexes have emerged as promising anticancer metallodrugs due to their efficient thioredoxin reductase(TrxR)inhibition,which disturbs the redox balance of cancer ***,in this model,the role of the ligand(s)coordinated to gold is often *** this work,we present a series of tetrapyridyl Au(Ⅲ)complexes that exhibit thiol-induced release of a Au(Ⅰ)ion and a tetrapyridyl *** formation of a free Au(Ⅰ)center is responsible for the expected TrxR ***,the released ligand,which was visible in cells due to its intense blue fluorescence,showed excellent binding properties to the hERG potassium ***,these ligands ended up in the lysosomes,resulting in significant lysosome ***,the Au(Ⅲ)complexes presented in this work showed broad-spectrum anticancer properties,both in hypoxic 2D monolayers and 3D tumor *** suggest that the interaction of the released Au(Ⅰ)center and the tetrapyridyl ligand with two different protein targets may combine into prodrugs that overcome hypoxia-induced drug deactivation.

关键词： anticancer Au(Ⅲ)complexes enzyme inhibtion potassium channel affinity lysosome damage cell imaging prodrug

Photocatalytic Site-Selective Cascade Radical Addition of Biaryl Ynones for the Construction of Spiro-and Fused Carbon Rings

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Chinese Journal of Chemistry 2024年第14期42卷 1599-1605页

作者： Kairui Liu Chunhang Zhao Liji Gu Xiang Li Jiali Yan Siqi Lao Weiwei Huan Yan Zhang Key Laboratory of the Ministry of Education for Advanced Catalysis Materials and Drug Discovery&Innovation CenterCollege of Chemistry and Materials ScienceZhejiang Normal UniversityJinhuaZhejiang321004 China Zhejiang Provincial Key Laboratory of Chemical Utilization of Forestry biomass College of Chemistry and Materials EngineeringZhejiang A&F UniversityHangzhouZhejiang311300 China

Functionalized free radical addition/cyclization reactions represent an efficient way for introducing new functionality or coupling fragments to *** are good regional selectivity radical acceptors in organic synthesis,and many of bio-relevant cyclic compounds could be easily obtained by direct radical cyclization ***,we report a photocatalytic cascade radical addition of biaryl ynones,for the divergent synthesis of privileged carbon ***,further transformation of the multi-functional group product into a variety of other derivatives demonstrates the synthetic value of this developed method.

关键词： Ynones Photocatalysis Cascade cyclization Alkoxycarbonyl radical Dearomatization Biaryls Regioselectivity Radical reactions

Characterization of a pangolin SARS-CoV-2-related virus isolate that uses the human ACE2 receptor

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Science China(Life Sciences) 2024年第7期67卷 1502-1513页

作者： Luo-Yuan Xia Xue-Feng Wang Xiao-Ming Cui Yi-Ming Zhang Zhen-Fei Wang En-Tao Li Chang-Fa Fan Ke Song Yuan-Guo Li Run-Ze Ye Fang-Xu Li Dai-Yun Zhu Jie Zhang Zhuang-Zhuang Shi Ming-Zhu Zhang Liang-Jing Li Shi-Jing Shen Song Jin Ya-Wei Zhang Wei-Guang Fu Lin Zhao Wen-Hao Wang Tie-Cheng Wang You-Chun Wang Jia-Fu Jiang Yan-Ling Hu Na Jia Yu-Wei Gao Wu-Chun Cao Institute of EcoHealth School of Public HealthCheeloo College of MedicineShandong UniversityJinan 250012China Changchun Veterinary Research Institute Changchun 130122China State Key Laboratory of Pathogen and biosecurity Beijing Institute of Microbiology and EpidemiologyBeijing 100071China division of Animal Model Research Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug ControlBeijing 102629China National Institutes for Food and drug Control Beijing 102629China Life Sciences Institute Guangxi Medical UniversityNanning 530020China College of Life Sciences Shandong Normal UniversityJinan 250014China Research Unit of discovery and Tracing of Natural Focus Diseases Chinese Academy of Medical SciencesBeijing 100071China

Various SARS-CoV-2-related coronaviruses have been increasingly identified in pangolins,showing a potential threat to *** we report the infectivity and pathogenicity of the SARS-CoV-2-related virus,PCoV-GX/P2V,which was isolated from a Malayan pangolin(Manis javanica).PCoV-GX/P2V could grow in human hepatoma,colorectal adenocarcinoma cells,and human primary nasal epithelial *** replicated more efficiently in cells expressing human angiotensin-converting enzyme 2(hACE2)as SARS-CoV-2 *** intranasal inoculation to the hACE2-transgenic mice,PCoV-GX/P2V not only replicated in nasal turbinate and lungs,but also caused interstitial pneumonia,characterized by infiltration of mixed inflammatory cells and multifocal alveolar *** population immunity established by SARS-CoV-2 infection and vaccination may not protect people from PCoV-GX/P2V *** findings further verify the hACE2 utility of PCoV-GX/P2V by in vivo experiments using authentic viruses and highlight the importance for intensive surveillance to prevent possible cross-species transmission.

关键词： pangolin SARS-CoV-2-related virus infectivity pathogenicity human cell lines human ACE2 receptor hACE2-transgenic mice

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Small molecule conjugates with selective estrogen receptor β agonism promote anti-aging benefits in metabolism and skin recovery

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2137-2152页

作者： Tarik Zahr Vijay K.Boda Jian Ge Lexiang Yu Zhongzhi Wu Jianwen Que Wei Li Li Qiang Naomi Berrie Diabetes Center Columbia UniversityNew YorkNY 10032USA Department of Molecular Pharmacology and Therapeutics Columbia UniversityNew YorkNY 10032USA Department of Pharmaceutical Sciences College of PharmacyUniversity of Tennessee Health Science CenterMemphisTN 38163USA drug discovery Center College of PharmacyUniversity of Tennessee Health Science CenterMemphisTN 38163USA division of Digestive and Liver Diseases Columbia UniversityNew YorkNY 10032USA Center for Human Development Columbia UniversityNew YorkNY 10027USA Department of Pathology and Cell biology Columbia UniversityNew YorkNY 10032USA Department of Medicine Columbia UniversityNew YorkNY 10032USA

Estrogen is imperative to mammalian reproductivity,metabolism,and ***,the hormone activating estrogen receptor(ERs)αcan cause major safety concerns due to the enrichment of ERαin female tissues and certain *** contrast,ERβis more broadly expressed in metabolic tissues and the ***,it is desirable to generate selective ERβagonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERα***,we report the design and production of small molecule conjugates containing selective non-steroid ERβagonists Gtx878 or *** of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity,visceral adipose integrity,skeletal muscle function,and skin health,with validation in *** further uncovered the benefits of ERβconjugates in the skin using two inducible skin injury mouse models,showing increased skin basal cell proliferation,epidermal thickness,and wound ***,our ERβ-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.

关键词： Estrogen receptorβ Aging Metabolism Skin injury Muscle metabolism Small molecule conjugates Regeneration Adiposity

Disruption of cyclin D1 degradation leads to the development of mantle cell lymphoma

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2977-2991页

作者： Ke Lu Ming Zhang Hongyu Qin Siyu Shen Haiqing Song Hua Jiang Chunxiang Zhang Guozhi Xiao Liping Tong Qing Jiang Di Chen Research Center for Computer-aided drug discovery Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Faculty of Pharmaceutical Sciences Shenzhen Institute of Advanced TechnologyShenzhen 518055China Oncology Department Johns Hopkins University School of MedicineBaltimoreMD 21205USA division of Spine Surgery the First Affiliated Hospital of Guangxi Medical UniversityNanning 530021China division of Sports Medicine and Adult Reconstructive Surgery Department of Orthopedic SurgeryNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolState Key Laboratory of Pharmaceutical BiotechnologyNanjing UniversityNanjing 210008China Wenzhou Institute University of Chinese Academy of SciencesWenzhou 325000China Department of Cardiology Basic Medicine Innovation Center for Cardiometabolic Diseases of Ministry of EducationInstitute of Cardiovascular Researchthe Affiliated HospitalSouthwest Medical UniversityLuzhou 646000China School of Medicine Southern University of Science and TechnologyShenzhen 518055China

Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of ***,we demonstrated that cyclin D1 is SUMOylated,and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin *** generated cyclin D1 mutant mice with mutations in the SUMOylation site,phosphorylation site,or both sites of cyclin D1,and found that double mutant mice developed a Mantle cell lymphoma(MCL)-like *** showed that arsenic trioxide(ATO)enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes,leading to MCL cell *** of severe combined immunodeficiency(SCID)mice grafted with MCL cells with ATO resulted in a significant reduction in tumor *** this study,we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.

关键词： Cyclin D1 SUMOylation Mantle cell lymphoma Arsenic trioxide SENP2 Proteasome degradation

Chemical biology investigation of a triple-action,smart-decomposition antimicrobial booster based-combination therapy against“ESKAPE”pathogens

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Science China Chemistry 2024年第9期67卷 3071-3082页

作者： Min Wang Huangsheng Pu Yangfan Xu Chenxuan Wu Yuanxin Gu Qingyun Cai Guoxing Yin Peng Yin Chunhui Zhang Wing-Leung Wong Muyang Wan Yugang Bai Xinxin Feng State Key Laboratory of Chem-/bio-Sensing and Chemometrics Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biologyand School of Chemistry and Chemical EngineeringHunan UniversityChangsha 410082China College of biology Hunan UniversityChangsha 410082China College of Advanced Interdisciplinary Studies&Hunan Provincial Key Laboratory of Novel Nano Optoelectronic Information Materials and Devices National University of Defense TechnologyChangsha 410073China Nanhu Laser Laboratory National University of Defense TechnologyChangsha 410073China Key Laboratory of Chemical biology and Traditional Chinese Medicine Research(Ministry of Education) College of Chemistry and Chemical EngineeringHunan Normal UniversityChangsha 410081China State Key Laboratory of Chemical biology and drug discovery Department of Applied Biology and Chemical TechnologyThe Hong Kong Polytechnic UniversityHong Kong SAR 999077China Hunan Provincial Key Laboratory of Anti-Resistance Microbial drugs The Third Hospital of Changsha(The Affiliated Changsha Hospital of Hunan University)Changsha 410015China

The global antibiotic resistance crisis necessitates urgent *** innovative approach involves potentiating antibiotics and non-antibiotic drugs with adjuvants or boosters.A major drawback of these membrane-active boosters is their limited biocompatibility,as they struggle to differentiate between prokaryotic and eukaryotic *** study reports the chemical biology investigation of a dual-action oligoamidine(OA1)booster with a glutathione-triggered decomposition ***1,when combined with other antimicrobial molecules,exhibits a triple-targeting mechanism including cell membrane disruption,DNA targeting,and intracellular enzyme *** multi-targeting mechanism not only enhances the in vitro and in vivo eradication of antibiotic-resistant“ESKAPE”pathogens,but also suppresses the development of bacterial ***,OA1 maintains its activity in bacterial cells by creating an oxidative environment,while it quickly decomposes in mammalian cells due to high glutathione *** mechanistic insights and design principles may provide a feasible approach to develop novel antimicrobial agents and effective anti-resistance combination therapies.

关键词： antimicrobial booster oligoamidine membrane disruption DNA targeting triggered degradation anti-resistance

A novel saliva-based miRNA profile to diagnose and predict oral cancer

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International Journal of Oral Science 2024年第1期16卷 97-109页

作者： Jaikrishna Balakittnen Chameera Ekanayake Weeramange Daniel F.Wallace Pascal H.G.Duijf Alexandre S.Cristino Gunter Hartel Roberto A.Barrero Touraj Taheri Liz Kenny Sarju Vasani Martin Batstone Omar Breik Chamindie Punyadeera Saliva&Liquid biopsy Translational Laboratory Griffith Institute for Drug DiscoveryGriffith UniversityNathanQLDAustralia Department of Medical Laboratory Sciences Faculty of Allied Health SciencesUniversity of JaffnaJaffnaSri Lanka Menzies Health Institute Griffith UniversityGold CoastQLDAustralia School of biomedical Sciences Faculty of HealthQueensland University of TechnologyBrisbaneQLDAustralia Centre for Cancer biology Clinical and Health SciencesUniversity of South Australia&SA PathologyAdelaideSAAustralia Institute of Clinical Medicine Faculty of MedicineUniversity of OsloOsloNorway Department of Medical Genetics Oslo University HospitalOsloNorway Griffith Institute for drug discovery Griffith UniversityNathanQLDAustralia QIMR Berghofer Medical Research Institute Statistics UnitBrisbaneQLDAustralia School of Public Health The University of QueenslandBrisbaneQLDAustralia School of Nursing Queensland University of TechnologyBrisbaneQLDAustralia eResearch Research InfrastructureAcademic DivisionQueensland University of TechnologyBrisbaneQLDAustralia Department of Anatomical Pathology Royal Brisbane and Women’s HospitalHerstonQLDAustralia Faculty of Medicine The University of QueenslandBrisbaneQLDAustralia Royal Brisbane and Women’s Hospital Cancer Care ServicesHerstonQLDAustralia Department of Otolaryngology Royal Brisbane and Women’s HospitalHerstonQLDAustralia Department of Oral and Maxillofacial Surgery Royal Brisbane and Women’s HospitalHerstonQLDAustralia

Oral cancer (OC) is the most common form of head and neck cancer. Despite the high incidence and unfavourable patient outcomes, currently, there are no biomarkers for the early detection of OC. This study aims to discover, develop, and validate a novel saliva-based microRNA signature for early diagnosis and prediction of OC risk in oral potentially malignant disorders (OPMD).The Cancer Genome Atlas (TCGA) miRNA sequencing data and small RNA sequencing data of saliva samples were used to discover differentially expressed miRNAs. Identified miRNAs were validated in saliva samples of OC (n=50), OPMD (n=52), and controls(n=60) using quantitative real-time PCR. Eight differentially expressed miRNAs (miR-7-5p, miR-10b-5p, miR-182-5p, miR-215-5p,miR-431-5p, miR-486-3p, miR-3614-5p, and miR-4707-3p) were identified in the discovery phase and were validated. The efficiency of our eight-miRNA signature to discriminate OC and controls was:area under curve (AUC):0.954, sensitivity:86%, specificity:90%,positive predictive value (PPV):87.8%and negative predictive value (NPV):88.5%whereas between OC and OPMD was:AUC:0.911,sensitivity:90%, specificity:82.7%, PPV:74.2%and NPV:89.6%. We have developed a risk probability score to predict the presence or risk of OC in OPMD patients. We established a salivary miRNA signature that can aid in diagnosing and predicting OC,revolutionising the management of patients with OPMD. Together, our results shed new light on the management of OC by salivary miRNAs to the clinical utility of using miRNAs derived from saliva samples.

关键词： specificity salivary diagnosis