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A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3232-3250页

作者： Ping Yu Tanwei Gu Yueyang Rao Weimin Liang Xi Zhang Huanguo Jiang Jindi Lu Jianglian She Jianmin Guo Wei Yang Yonghong Liu Yingfeng Tu Lan Tang Xuefeng Zhou guangdong provincial key laboratory of New drug Screening Guangdong-Hong Kong-Macao Joint Laboratory for New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China CAS key laboratory of Tropical Marine Bio-Resources and Ecology Guangdong Key Laboratory of Marine Materia MedicaSouth China Sea Institute of OceanologyChinese Academy of SciencesGuangzhou 510301China NMPA key laboratory for research and evaluation of drug Metabolism School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China guangdong Lewwin Pharmaceutical research Institute Co. Ltd.Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and ResearchGuangdong Engineering Research Center for Innovative Drug Evaluation and ResearchGuangzhou 510990China

Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its *** study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)***,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS *** to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed *** developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 *** encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,*** main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated *** summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.

关键词： Acute kidney injury Piericidin glycoside Peroxiredoxin 1 Nanodrug Kim-1 targeted ADME Marine drug druggability

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Preparation of baicalin colon-targeted granules and its intervention effect on ulcerative colitis in rats

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Particuology 2024年第2期85卷 13-21页

作者： Yongqing Huang Yuxin Zhou Yao Shen Jin Wang Liangliang Zhou Zhenhua Chen Jiangxi provincial key laboratory of drug Design and evaluation School of PharmacyJiangxi Science and Technology Normal UniversityNanchang330013China

Baicalin(BA)is a flavonoid extracted from the dried root of Scutellaria baicalensis Georgi with excellent antioxidant and anti-inflammatory biological *** this study,Eudragit S100 was used as the colonic target material to prepare BA colonic targeting granules(EBCGs)based on plasticizer dry powder coating technology to improve the targeting transportation performance of *** vitro studies showed that EBCGs with pH-sensitive properties were successfully prepared by plasticizer dry powder coating,and in vivo animal imaging studies showed that EBCGs could deliver BA to the colon and inhibit the release of BA in the upper gastrointestinal tract(GIT).In vivo studies showed that EBCGs had good therapeutic effects in colitis,which reduced expression levels of tumor necrosis factor alpha(TNF-α)and interleukin-1β(IL-1β)and increased superoxide dismutase(SOD)activities in the colonic tissues of rats with *** conclusion,Eudragit S100 could be used for the preparation of multi-unit oral colon-targeted formulations by plasticizer dry powder coating technology,and our prepared EBCGs had good colon-targeting properties,which could improve the therapeutic effect and provide a potential application for ulcerative colitis(UC).

关键词： Plasticizer dry powder coating Colon-targeted granulesIn vivo imaging Ulcerative colitis

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Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

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Acta Pharmaceutica Sinica B 2024年第2期14卷 517-532页

作者： Shuang Xiang Xiaoyun Lu International Cooperative laboratory of Traditional Chinese Medicine Modernization and Innovative drug Discovery of Chinese Ministry of Education(MOE) Guangdong Provincial Key Laboratory of New Drug Design and EvaluationGuangzhou City Key Laboratory of Precision Chemical Drug DevelopmentSchool of PharmacyJinan UniversityGuangzhou 510632China

Neurotrophic receptor kinase(NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors,and tropomyosin receptor kinase(TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these ***,two generations TRK inhibitors have been *** representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target ***,xDFG(TRKAG667C/A/S,homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib,and overcoming these resistances represents a major unmet clinical *** this review,we summarize the acquired resistance mechanism of the first-and second-generation TRK inhibitors,and firstly put forward the emerging selective type Ⅱ TRK inhibitors to overcome xDFG mutations mediated ***,we concluded our perspectives on new challenges and future directions in this field.

关键词： NTRK fusions TRK kinase clinical resistance xDFG mutations Selective type II inhibitors

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Effect of lens surgery on health-related quality of life in preschool children with congenital ectopia lentis

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International Journal of Ophthalmology(English edition) 2024年第1期17卷 66-72页

作者： Yan-Qiao Huang Qian-Zhong Cao Yi-Yao Wang Yi-Jing Zhou Dan-Ying Zheng State key laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceGuangdong Provincial Clinical Research Center for Ocular DiseasesGuangzhou 510060Guangdong ProvinceChina

AIM:To evaluate the effect of lens surgery on health-related quality of life(HRQoL)of preschool children with congenital ectopia lentis(CEL).METHODS:A prospective self-controlled study was conducted in Zhongshan Ophthalmic *** aged from 5 to 7y whom were diagnosed with CEL and underwent phacoemulsification with scleral-fixated posterior chamber intraocular lens implantation and their parents were enrolled in this *** of them completed the child and proxy(parental)PedsQL™4.0 before and after the *** preoperative scores were compared to their postoperative *** analyses were performed based on gender and preoperative bilateral presenting visual acuity of the ***:Thirty-two children with CEL successfully underwent surgery without any complications,among whom 8 had monocular surgery and 24 had binocular *** and postoperative questionnaires were completed by 32 child-parent *** intervention could significantly improve the vision of affected children(Pevaluation,the preoperative score reported by parents of girls was higher than parents of boys(P=0.041),and the postoperative score of girls was higher than that of boys(P=0.036).CONCLUSION:CEL is associated with significantly worse quality of life in preschool *** intervention can significantly improve the HRQoL in affected children from both personal and family perspective.

关键词： congenital ectopia lentis surgical intervention health-related quality of life preschool children

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Evolving roles of glycosylation in the tug-of-war between virus and host

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National Science Review 2024年第5期11卷 100-104页

作者： Xiaofeng Zhai Yanqiu Yuan Wan-Ting He Ying Wu Yi Shi Shuo Su Quansheng Du Yang Mao Academy for Advanced Interdisciplinary Studies Engineering Laboratory of Animal Immunity of Jiangsu Province College of Veterinary MedicineNanjing Agricultural University State key laboratory of Anti-Infective drug Discovery and Development School of Pharmaceutical SciencesSun Yat-sen University School of Pharmacy China Pharmaceutical University guangdong provincial key laboratory of drug non-clinical evaluation and research School of Pharmaceutical Sciences Sun Yat-sen University CAS key laboratory of Pathogen Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Department of Interdisciplinary Sciences National Natural Science Foundation of China

Covering the surface of both host cells and enveloped viruses, glycans are inevitable biomolecules for investigating virus–host interactions. However, due to the intricate role of glycans in the viral–host relationship, few glycanrelated molecular mechanisms have been harnessed for antiviral therapies. The intricacy arises from multiple factors.

关键词： VACCINE BINDING PROTEIN

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Engineered extracellular vesicles efficiently deliver CRISPR-Cas9 ribonucleoprotein(RNP)to inhibit herpes simplex virus1 infection in vitro and in vivo

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1362-1379页

作者： Yuanda Wan Liren Li Ruilin Chen Jiajia Han Qiyun Lei Zhipeng Chen Xiaodong Tang Wenyu Wu Shuwen Liu Xingang Yao NMPA key laboratory for research and evaluation of drug Metabolism Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Center of clinical Pharmacy Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China State key laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangzhou 510060China key laboratory of Infectious Diseases research in South China(Southern Medical University) Ministry of EducationGuangzhou 510515China

Extracellular vesicles(EVs)have recently emerged as a promising delivery platform for CRISPR/Cas9 ribonucleoproteins(RNPs),owing to their ability to minimize off-target effects and immune ***,enhancements are required to boost the efficiency and safety of Cas9 RNP enrichment within *** response,we employed the Fc/Spa interaction system,in which the human Fc domain was fused to the intracellular domain of PTGFRN-Δ687 and anchored to the EV ***,the B domain of the Spa protein was fused to the C domain of cargos such as Cre or *** to the robust interaction between Fc and Spa,this method enriched nearly twice the amount of cargo within the *** loaded with spCas9 RNP targeting the HSV1 genome exhibited significant inhibition of viral replication in vitro and in ***,following neuron-targeting peptide RVG modification,the in vivo dosage in neural tissues substantially increased,contributing to the clearance of the HSV1 virus in neural tissues and exhibiting a lower off-target *** findings establish a robust platform for efficient EV-based SpCas9 delivery,offering potential therapeutic advantages for HSV1 infections and other neurological disorders.

关键词： Extracellular vesicles CRISPR/Cas9 Ribonucleoproteins PTGFRN Fc/Spa HSV1 Neuron-targeting Delivery

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Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathway

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2992-3008页

作者： Shicheng Fan Yue Gao Pengfei Zhao Guomin Xie Yanying Zhou Xiao Yang Xuan Li Shuaishuai Zhang Frank JGonzalez Aijuan Qu Min Huangb Huichang Bi NMPA key laboratory for research and evaluation of drug Metabolism&guangdong provincial key laboratory of New drug Screening&guangdong-Hongkong-Macao Joint laboratory for New drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China guangdong provincial key laboratory of New drug Design and evaluation School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Physiology and Pathophysiology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA The State key laboratory of Chemical Oncogenomics School of Chemical Biology and BiotechnologyShenzhen Graduate School of Peking UniversityShenzhen 518055China

Fenofibrate,a peroxisome proliferator-activated receptor α(PPARα)agonist,is widely prescribed for hyperlipidemia *** studies also showed that it has therapeutic potential in various liver ***,its effects on hepatomegaly and liver regeneration and the involved mechanisms remain ***,the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice,which was dependent on hepatocyteexpressed PPARα.Yes-associated protein(YAP)is pivotal in manipulating liver growth and *** further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination,promoting its K63-linked ubiquitination,and enhancing the interaction and transcriptional activity of the YAP-TEAD *** inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced *** factors,such as MYC,KRT23,RAS,and RHOA,might also participate in fenofibrate-promoted hepatomegaly and liver *** studies demonstrate that fenofibratepromoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling,with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.

关键词： Fenofibrate PPARa Hepatomegaly Partial hepatectomy Liver regeneration YAP TEAD Ubiquitination

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Total Synthesis of Laurane and Guaiane Sesquiterpenoids via Oxidative Nazarov Reaction

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Chinese Journal of Chemistry 2024年第11期42卷 1267-1274页

作者： Yuye Chen Wenqing Chen Zhiting Zhang Jing Xu Shenzhen Grubbs Institute and Department of Chemistry and Guangming Advanced research Institute and guangdong provincial key laboratory of Catalysis and Shenzhen key laboratory of Small Molecule drug Discovery and Synthesis Southern University of Science and TechnologyShenzhenGuangdong518055 China

As one of the most common structural motifs in natural products,cyclopentenones usually can be fabricated by Nazarov cyclization using divinyl ketones or functionalized tertiary divinyl carbinols(TDCs)as ***,straightforward method for transforming unfunctionalized TDCs to their corresponding cyclopentenones is currently ***,we wish to report the total syntheses of four structurally distinct terpenoids,namely laurane-type marine sesquiterpenoids isolaurene,debromoaplysin and aplysin,and guaiane sesquiterpenoid guaiadienone A,all using a novel synthetic method,named oxidative Nazarov cyclization,as the key *** work demonstrated our robust method is suitable for synthesizing various highly substituted cyclopentenones.

关键词： Total synthesis Synthetic methods Sesquiterpenoids Oxidative Nazarov reaction Electrocyclization Oxoammonium salt Pericyclic reaction Annulation

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Deciphering the high-carbonization-temperature triggered enzymatic activity of wool-derived N,S-co-doped carbon nanosheets

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Chinese Chemical Letters 2024年第3期35卷 182-188页

作者： Jiachen Zhao Deshuai Yu Jianmin Chen Shihao Lin Yonghua Tang Chaoyu Fan Dongfang Zhou Youhui Lin Department of Physics Research Institute for Biomimetics and Soft MatterFujian Provincial Key Laboratory for Soft Functional Materials ResearchXiamen UniversityXiamen 361005China School of Pharmacy and Medical Technology Putian UniversityPutian 351100China key laboratory of Mental Health of the Ministry of Education NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China key laboratory of Pharmaceutical Analysis and laboratory Medicine(Putian University) Fujian Province UniversityPutian 351100China

It is well-established that high carbonization temperature will trigger the enzyme-like activity of carbon-based ***,the catalytic mechanism is still ambiguous,which hinders the further rational design of nanomaterials as enzyme ***,N,S-rich carbonized wool nanosheets(CWs)were synthesized at different pyrolysis *** expected,only CWs treated with high-temperature possess intrinsic oxidase-and peroxidase-like ***,density functional theory(DFT)calculations demonstrate that graphitic nitrogen and the co-existence of nitrogen and sulfur in the carbon matrix serve as the active sites for the enzyme-like *** importantly,combining theoretical calculations and experimental observations,the high-temperature triggered catalytic mechanism can be ascribed to the fact that an appropriate high-temperature maximizes the graphitization degree to a certain extent,at which most of the catalytic active sites are well retained rather than ***,coupling with excellent photothermal conversion efficiency and catalytic performance,CWs can be applied to photothermal-catalytic cancer therapy under near-infrared region(NIR)light *** believe this work will contribute to understanding the catalytic mechanism of carbon-based nanozymes and promote the development of new biomedical and pharmaceutical applications.

关键词： Carbon-based nanozyme Catalytic mechanism Density functional theory High-temperature carbonization

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Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

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Acta Pharmaceutica Sinica B 2024年第2期14卷 533-578页

作者： Xiaopeng Peng Zhihao Hu Limei Zeng Meizhu Zhang Congcong Xu Benyan Lu Chengpeng Tao Weiming Chen Wen Hou Kui Cheng Huichang Bi Wanyi Pan Jianjun Chen College of Pharmacy Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of EducationGannan Medical UniversityGanzhou 314000China College of Basic Medicine Gannan Medical UniversityGanzhou 314000China guangdong provincial key laboratory of New drug Screening NMPA Key Laboratory for Research and Evaluation of Drug MetabolismSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators(e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges,including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result,the design of new epigenetic modulators(e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging(Hy T) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review,we aim to provide an in-depth illustration of new degrading strategies(2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

关键词： Epigenetic Degrader PROTAC Molecularglue Hydrophobic tagging

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