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Chinese Journal of Cancer Research 2022年第4期34卷 415-421页

作者： Limin Zou Yueli Qi Ling Tang Yu Du Meiyi Xiang Xiaoming Chen Jun Ma Zhimin Yang Office of Clinical evaluation 1 Center for Drug EvaluationNational Medical Products AdministrationBeijing 100022China Office of Management and Communication Center for Drug EvaluationNational Medical Products AdministrationBeijing 100022China Harbin Institute of Hematology and Oncology Harbin 150010China

Several phosphoinositide 3-kinase(PI3 K) inhibitors are currently approved to treat hematolymphatic malignant diseases worldwide, and many drugs that have the same target are in the clinical research stage. In March 2022,duvelisib became the first PI3 K inhibitor approved in China indicated for the treatment of hematolymphatic malignant diseases. Meanwhile, linperlisib and copanlisib have almost completed the technical review of the clinical specialty. The center for drug evaluation(CDE) of the China National Medical Products Administration(NMPA) found that class I PI3 K inhibitors can cause various degrees of immune-related adverse events, which are associated with action mechanisms, affecting the benefit-risk assessment of the drugs. On April 21, 2021, the United States Food and drug Administration(FDA) convened the Oncologic drugs Advisory Committee(ODAC)meeting to discuss the safety of PI3 K inhibitors indicated for hematolymphatic malignancies and their related risk of death. The hematological tumor group of CDE of the China NMPA summarized and combined the data on PI3 K inhibitors listed or under technical review for marketing authorization applications and found that such products may have unique efficacy and safety characteristics in Chinese patients with malignant lymphoma.

关键词： Class I PI3K inhibitors efficacy hematolymphatic malignancies safety

Commentary:brain endothelial GSDMD as a novel target for brain disorders associated with BBB damage

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Chinese Journal of Natural Medicines 2024年第7期22卷 580-581页

作者： LIU Kui PANG Tao State Key Laboratory of Natural Medicines New Drug Screening and Pharmacodynamics Evaluation CenterChina Pharmaceutical UniversityNanjing 210009China

The blood-brain barrier(BBB)is a highly selective and critical interface between the blood and the central nervous system(CNS),essential for maintaining the microenvironment necessary for normal brain function and homeostasis[1].The BBB is primarily formed by brain endothelial cells(bECs),pericytes,and astrocytes,and it operates in concert with microglia/macrophages and neurons[2,3]to constitute the neurovascular unit(Fig.1).Disruption of the BBB or the presence of systemic inflammation can precipitate or exacerbate various CNS pathologies,including Alzheimer’s disease[4],amyotrophic lateral sclerosis[5],Huntington’s disease[6]and multiple sclerosis.

关键词： Brain endothelial cells GSDMD Blood-brain barrier Natural products Neuroinflammation Brain disorders

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

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

重组生物技术制品生产工艺变更的病毒安全性风险再评估策略

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Engineering 2024年第1期32卷 14-17页

作者： Wenbo Sai Dongchen Jia Hao Chen Wei Wei center for drug evaluation National Medical Products AdministrationBeijing 100076China

In the manufacturing of biotechnology drug products,the viral safety control strategy is a critical pharmaceutical quality management framework that contains three key elements:prevention,testing,and *** prevention strategy involves rigorous screening for any adventitious virus contamination in the raw materials,reagents,and endogenous/adventitious virus contamination in the cell banks.

关键词： prevention testing remove

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

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

Aerobic respiration Lactococcus lactis ameliorate Salmonella induced infection and intestinal dysfunctions by oxygen-scavenging and maintaining immune balance and regulating intestinal microbiota

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Food Science and Human Wellness 2024年

作者： Yulong Zhang Han Yang Zhiliang Cheng Hui Ha Fei Liu Yuehua Jiao Key Laboratory of Dairy Science， Ministry of Education， Food College， Northeast Agricultural University center of drug Safety evaluation， Heilongjiang University of Chinese Medicine

Salmonella grows better under aerobic conditions as a facultative anaerobic foodborne pathogenic bacteria. The oxygen-scavenging activity of Lactococcus lactis in the intestinal tract is a promising strategy for preventing Salmonella infection. In this study， the aerobic respiration requirement and preventive mechanism of Lactococcus lactis subsp. lactis (L. lactis) KLDS 4.0325 in murine models infected by Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) SL1344 were investigated. Results indicate that L. lactis KLDS 4.0325 is capable of aerobic respiratory metabolism in the host intestine when exogenous heme exists， and decrease intestinal oxygen concentration， which in turn trigger autophagy of intestinal cells to reduce S. Typhimurium load， improve gut microbiota composition， alleviate intestinal barrier injury and inflammation response. These results suggest that aerobic respiration L. lactis KLDS 4.0325 can prevent S. Typhimurium infection in a new way in which by restoring intestinal cell hypoxia， maintaining immune balance and regulating intestinal flora.

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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

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