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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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Narciclasine induces colon carcinoma cell apoptosis by inhibiting the IL-17A/Act1/TRAF6/NF-kB signaling pathway

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Genes & Diseases 2024年第5期11卷 428-441页

作者： Huiming Deng Qiang Liu Siman Yu Lifan Zhong Lianfang Gan Huiquan Gu Qianru Wang Ruxin Cheng Yong Liu Li Liu Ling Huang Ronghua Xu Department of Gastrointestinal Surgery Huazhong University of Science and Technology Union Shenzhen HospitalShenzhenGuangdong 518000China research center for drug Safety evaluation of Hainan Province HaikouHainan 571199China Department of Pharmacology Hainan Medical UniversityHaikouHainan 571199China Department of Pathology Guangzhou Panyu Central HospitalGuangzhouGuangdong 511400China Hainan Province Key Laboratory for drug Preclinical Study of Pharmacology and Toxicology research Hainan Medical UniversityHaikouHainan 571199China Hainan center for drug and Medical Device evaluation and Service Hainan Medical Products AdministrationHaikouHainan 570216China

IL-17 A is a promoter of colorectal cancer initiation and *** is a polyhydroxy alkaloid compound isolated from Narcissus plants,which has potent anti-inflammatory and antitumor *** effects of narciclasine on colorectal tumors were evaluated,with a focus on IL-17 *** reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in murine *** results of flow cytometry on JC-1 and Annexin V/PI revealed that narciclasine significantly reduced the mitochondrial membrane potential and induced apoptosis,findings confirmed by western blotting results of reduced Bcl2 and enhanced Bax expression,as well as accumulation of cleaved Caspase-3,Caspase-8,Caspase-9,and cytoplasmic *** narciclasine incubation,IL-17 A,Act1,and TRAF6 were down-regulated,while p-P65(Ser536)accumulated in the cytoplasm,a finding confirmed by laser scanning confocal ***17A substitution could partly reverse these narciclasine effects while they were elevated by IL17A ***,IL-17 A,Act1,and TRAF6 were significantly expressed to greater extents in human colorectal cancer compared to normal adjacent tissue specimens and were closely linked with a poor *** study provided evidence that narciclasine may be a useful therapeutic drug for colorectal cancer treatment through its actions in down-regulating the L-17A/Act1/TRAF6/NF-kB anti-apoptotic signaling pathway.

关键词： Act1 Apoptosis Colonrectal cancer IL-17A Narciclasine NF-kB

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Oral peptide therapeutics for diabetes treatment: State-of-the-art and future perspectives

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2006-2025页

作者： Bingwen Ding Zhu Zhu Cong Guo Jiaxin Li Yong Gan Miaorong Yu State Key Laboratory of drug research and center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China School of Pharmacy Henan UniversityKaifeng 475004China NMPA Key Laboratory for Quality research and evaluation of Pharmaceutical Excipients National Institutes for Food and Drug ControlBeijing 100050China

Diabetes,characterized by hyperglycemia,is a major cause of death and disability ***,such as insulin and glucagon-like peptide-1(GLP-1)analogs,have shown promise as treatments for diabetes due to their ability to mimic or enhance insulin's actions in the *** to subcutaneous injection,oral administration of anti-diabetic peptides is a preferred ***,biological barriers significantly reduce the efficacy of oral peptide *** advancements in drug delivery systems and formulation techniques have greatly improved the oral delivery of peptide therapeutics and their efficacy in treating *** review will highlight(1)the benefits of oral anti-diabetic peptide therapeutics;(2)the biological barriers for oral peptide delivery,including pH and enzyme degradation,intestinal mucosa barrier,and biodistribution barrier;(3)the delivery platforms to overcome these biological ***,the review will discuss the prospects in this *** information provided in this review will serve as a valuable guide for future developments in oral anti-diabetic peptide therapeutics.

关键词： Oral peptides Diabetes Delivery platforms Insulin Glucagon-like peptide-1 Biodistribution Biological barriers Targeted delivery

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Macrophage senescence in health and diseases

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1508-1524页

作者： Longling Wang Wenxiang Hong Hong Zhu Qiaojun He Bo Yang Jiajia Wang Qinjie Weng center for drug Safety evaluation and research Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Nanhu Brain-Computer Interface Institute Hangzhou 311100China Taizhou Institute of Zhejiang University Taizhou 318000China The Second Affiliated Hospital Zhejiang University School of MedicineHangzhou 310009China

Macrophage senescence,manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype,has long been consid-ered *** senescence of macrophages may lead to maladaptation,immune dysfunction,and finally the development of age-related diseases,infections,autoimmune diseases,and ***,it is a ubiquitous,multi-factorial,and dynamic complex phenomenon that also plays roles in remodeled processes,including wound repair and *** this review,we summarize some general molecular changes and several specific biomarkers during macrophage senescence,which may bring new sight to recognize senescent macrophages in different ***,we take an in-depth look at the functional changes in senescent macrophages,including metabolism,autophagy,polarization,phagocytosis,antigen presentation,and infiltration or ***,some degenerations and diseases associated with senescent macrophages as well as the mechanisms or relevant genetic regulations of senescent macrophages are integrated,not only emphasizing the possibility of regulating macrophage senescence to benefit age-associated diseases but also has an implication on the finding of potential tar-gets ordrugs clinically.

关键词： Macrophages Senescence Molecular changes Functional alterations Aging tissues Age-associated diseases drug treatment Genetic regulation

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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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Clinical characteristics and pharmacokinetics of PAXLOVID in COVID-19 patients with hematological tumor

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Medical Review 2024年第2期4卷 169-171页

作者： Wei Liu Ping Yang Ping Yang Li Yang Hongmei Jing Libo Zhao Rongsheng Zhao Department of Pharmacy Peking University Third HospitalBeijing 100191China Therapeutic drug Monitoring and Clinical Toxicology center of Peking University Beijing 100191China Institute for drug evaluation Peking University Health Science CenterBeijingChina NMPA Key Laboratory for research and evaluation of Generic drugs Beijing 100191China Department of Pharmacy Peking University Third HospitalBeijingChina Therapeutic drug Monitoring and Clinical Toxicology center of Peking University BeijingChina NMPA Key Laboratory for research and evaluation of Generic drugs BeijingChina Department of Hematology Peking University Third HospitalBeijingChina.

To the editor:Since the onset of COVID-19,several new treatments have been studied,but only a few have received approval for clinical ***,a challenge we still face is that in real-world medical practice,the patient population may differ from those in clinical *** instance,prolonged viral elimination has become an issue in immunocompromised patients[1,2]

关键词： patients clinical Clinical

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In situ autophagy regulation in synergy with phototherapy for breast cancer treatment

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2317-2332页

作者： Huijuan Zhang Xiangyang Xuan Yaping Wang Zijun Qi Kexuan Cao Yingmei Tian Chaoqun Wang Junbiao Chang Zhenzhong Zhang Lin Hou School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases Zhengzhou 450001China Collaborative Innovation center of New drug research and Safety evaluation Zhengzhou 450001China School of Chemistry and Molecular Engineering Zhengzhou UniversityZhengzhou 450001China

Autophagy is an important factor in reducing the efficacy of tumor phototherapy(including PTT and PDT).Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/*** project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor *** achieve this goal,we first synthesized TRANSFERRIN(Tf)biomimetic mineralized nano-tellurium(Tf-Te)as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te *** autophagy inhibitor hydroxychloroquine(HCQ)and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/*** entering breast cancer cells through the“self-guidance system”,Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation,to efficiently induce PTT/PDT ***,the disulfide bond broke down in response to GSH,and the nanoparticles disintegrated to release Fe2+and HCQ at fixed *** simultaneously induce lysosomal alkalinization and increased osmotic pressure,effectively inhibit autophagy,and synergistically enhance the therapeutic effect of *** vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6%on 4T1 tumor-bearing *** multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.

关键词： Autophagy Tumor phototherapy Synergistic sensitization HCQ TRANSFERRIN Disulfide bond reconstruction GSH Biomimetic mineralized nano-tellurium

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pH-controlled reversible sol-gel inversion by cerous phosphate nanofibers for hemostasis

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Rare Metals 2024年第10期43卷 5141-5151页

作者： Tuo Su Jun-Chen Xu Wei Yu Dan Su Di-Er Shi Yi-Chao Pang Yao Ying Wang-Chang Li Juan Li Jing-Wu Zheng Liang Qiao Sheng-Lei Che Jing Yu research center of Magnetic and Electronic Materials College of Materials Science and EngineeringZhejiang University of Technology State Key Laboratory for Diagnosis and Treatment of Infectious Diseases Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang University Key Laboratory of drug Safety evaluation and research of Zhejiang Province Department of Clinical MedicineHangzhou Medical College Department of Chemistry Zhejiang University Clinical Medical College Yangzhou University

Developing biomimetic soft materials that display stimuli responsiveness using solely inorganic materials has been regarded as a challenge owing to that such materials?properties typically vary from those of living ***,biomimetic soft materials have been developed using organic materials or inorganic materials modified with organic small *** this study,we prepared cerium phosphate nanofibers （CePO4NFs） by using inorganic agents only without further *** CePO4NFs demonstrate sol-ge switching properties in response to pH value,allowing them to form a gel under high hydroxide ion （OH-） concentrations and turn back into sol under low *** formation of gel could be ascribed to the physical cross-linking of the nanofibers induced by the attractive electrostatic force of OH-and surface Ce3+.As a result,CePO4NFs are able to form a gel when in contac with blood of high pH value for *** specific clotting mechanism makes them better candidates for hemostasis of heavy bleeding.

关键词： Cerium phosphate nanofibers Hemostasis pH-responsive Reversible Sol-gel switching

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Cyclocarysaponins A–J, dammarane-type triterpenoid glycosides from the leaves of Cyclocarya paliurus

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Chinese Journal of Natural Medicines 2024年第10期22卷 955-964页

作者： XI Huiting YUAN Mingming XIE Jianhua WANG Yuanxing State Key Laboratory of Food Science and Resources Nanchang University Jiangxi Institute for drug Control NMPA Key Laboratory of Quality Evaluation of Traditional Chinese Patent Medicine Jiangxi Provincial Engineering Research Center of Drug and Medical Device Quality

Ten previously undescribed dammarane-type triterpenoid glycosides, cyclocarysaponins A–J(1–10), were isolated from the leaves of Cyclocarya paliurus(Batal.) Iljinskaja. The structures of these compounds were characterized through detailed spectroscopic analysis, including 1D and 2D nuclear magnetic resonance(NMR) and high-resolution electrospray ionization mass spectrometry(HR-ESI-MS). The cytotoxic activities of all isolates were assessed against five human cancer cell lines(Bel-7402, Caski, BGC-823, A2780, and HCT-116). Of the tested compounds, compounds 1, 7, and 9 exhibited selective cytotoxicity against one or more human cancer cell lines.

关键词： Cyclocarya paliurus Cyclocarysaponin Cytotoxic activities Juglandaceae Triterpenoid glycosides

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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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