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Protective role of fruits of Rosa odorata var. gigantea against WIRSinduced gastric mucosal injury in rats by modulating pathway related to inflammation, oxidative stress and apoptosis

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Chinese Herbal Medicines 2024年第2期16卷 263-273页

作者： Xinnan Liu Zhen Yuan Lifei Luo Teng Wang Feng Zhao Jingze Zhang Dailin Liu National key laboratory of Chinese Medicine Modernization Tianjin University of Traditional Chinese MedicineTianjin 301617China Tianjin Modern Innovation Chinese Medicine Technology Co. Ltd.Tianjin 300380China School of Pharmacy Key Laboratory of Molecular Pharmacology and Drug EvaluationMinistry of EducationCollaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of ShandongYantai UniversityYantai 264005China

Objective: Rosa odorata var. gigantea is a popular medicinal plant. Some studies have demonstrated that ethanolic extract of the fruits of R. odorata var. gigantea(FOE) has gastroprotective properties. The aim of this study was to investigate the gastroprotective activity of FOE on water immersion restrained stress(WIRS)-induced gastric mucosal injury in a rat model and elucidate the possible molecular mechanisms ***: A rat stress ulcer model was established in this study using WIRS. After rats were treated with FOE orally for 7 d, the effect of FOE treatment was analyzed by hematoxylin and eosin(H&E) staining, and the changes of inflammatory factors, oxidative stress factors, and gastric-specific regulatory factors and pepsin in the blood and gastric tissues of rats were examined by ELISA assay. Molecular mechanism of FOE was investigated by immunohistochemical assay and Western ***: Compared with the WIRS group, FOE could diminish both the macroscopic and microscopic pathological morphology of gastric mucosa. FOE significantly preserved the antioxidants glutathione peroxidase(GSH-PX), superoxide dismutase(SOD) and catalase(CAT) contents;anti-inflammatory cytokines interleukin-10(IL-10) and prostaglandin E2(PGE2) levels as well as regulatory factors tumor necrosis factor-a(TGF-a) and somatostatin(SS) contents, while decreasing malondialdehyde(MDA), nitric oxide synthase(i NOS), tumor necrosis factor(TNF-a), interleukin-1β(IL-1β), interleukin-6(IL-6), gastrin(GAS)and endothelin(ET) levels. Moreover, FOE distinctly upregulated the expression of Nrf2, HO-1, Bcl2 and proliferating cell nuclear antigen(PCNA). In addition, FOE activated the expression of p-EGFR and downregulated the expression of NF-ΚB, Bax, Cleaved-caspase-3, Cyto-C and Cleaved-PARP1, thus promoting gastric mucosal cell ***: The current work demonstrated that FOE exerted a gastroprotective activity against gastric mucosal injury induced by WIRS. The underlying mecha

关键词： anti-apoptosis anti-inflammation anti-oxidation gastric mucosal injury Rosa odorata Sweet var.gigantea(Coll.et Hemsl.)Rehd.et Wils water immersion restrained stress

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Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1726-1741页

作者： Yanjiang Xing Yangfeng Hou Tianfei Fan Ran Gao Xiaohang Feng Bolun Li Junling Pang Wenjun Guo Ting Shu Jinqiu Li Jie Yang Qilong Mao Ya Luo Xianmei Qi Peiran Yang Chaoyang Liang Hongmei Zhao Wenhui Chen Jing Wang Chen Wang State key laboratory of Respiratory Health and Multimorbidity Institute of Basic Medical SciencesChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100005China Department of Lung Transplantation National Center for Respiratory MedicineNational Clinical Research Center for Respiratory DiseasesChina–Japan Friendship HospitalInstitute of Respiratory MedicineChinese Academy of Medical SciencesBeijing 100029China Haihe laboratory of cell Ecosystem Chinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin 300051China The State key laboratory of Complex Severeand Rare DiseasesInstitute of Basic Medical SciencesChinese Academy of Medical SciencesDepartment of PathophysiologyPeking Union Medical CollegeBeijing 100005China Department of Pharmacy West China HospitalSichuan UniversityChengdu 610044China

Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A–D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH;however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA–CREB–BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

关键词： Phosphodiesterase 4B Pulmonary hypertension Endothelial-to-mesenchymal transition

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Bimetallic nanoparticles as cascade sensitizing amplifiers for low-dose and robust cancer radio-immunotherapy

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1787-1800页

作者： Yupeng Wang Lina Wang Tao Li Min Ouyang Hejian Xiong Dongfang Zhou Department of Ultrasonic Diagnosis Zhujiang HospitalKey Laboratory of Mental Health of the Ministry of EducationNMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Testing and Analysis Center Hebei Normal UniversityShijiazhuang 050024China Department of Mechanical Engineering The University of Texas at DallasRichardsonTX 75080USA

Radiotherapy(RT)is one of the most feasible and routinely used therapeutic modalities for treating malignant *** particular,immune responses triggered by RT,known as radio-immunotherapy,can partially inhibit the growth of distantly spreading tumors and recurrent ***-ever,the safety and efficacy of radio-immunotherapy is impeded by the radio-resistance and poor immu-nogenicity of ***,we report oxaliplatin(IV)-iron bimetallic nanoparticles(OXA/Fe NPs)as cascade sensitizing amplifiers for low-dose and robust *** OXA/Fe NPs exhibit tumor-specific accumulation and activation of OXA(I)and Fe^(2+)in response to the reductive and acidic microenvironment within tumor *** cascade reactions of the released metallic drugs can sensitize RT by inducing DNA damage,increasing ROS and O_(2) levels,and amplifying the immunogenic cell death(ICD)effect after RT to facilitate potent immune *** a result,OXA/Fe NPs-based low-dose RT triggered a robust immune response and inhibited the distant and metastatic tumors effectively by a strong abscopal ***,a long-term immunological memory effect to protect mice from tumor rechal-lenging is ***,the bimetallic NPs-based cascade sensitizing amplifier system offers an effi-cient radio-immunotherapy regimen that addresses the key challenges.

关键词： Bimetallic nanoparticles Radio-immunotherapy Cascade sensitizing amplifier,Oxaliplatin Fenton-typeHaber-Weiss reaction Radiosensitization Immunogenic cell death Radio-resistance

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Enhanced optical imaging and fluorescent labeling for visualizing drug molecules within living organisms

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2428-2446页

作者： Ting Sun Huanxin Zhao Luyao Hu Xintian Shao Zhiyuan Lu Yuli Wang Peixue Ling Yubo Li Kewu Zeng Qixin Chen School of Pharmaceutical Sciences National Key Laboratory of Advanced Drug Delivery SystemMedical Science and Technology Innovation CenterShandong First Medical University&Shandong Academy of Medical SciencesJinan 250062China Departments of Diagnostic Radiology SurgeryChemical and Biomolecular Engineeringand Biomedical EngineeringYong Loo Lin School of Medicine and College of Design and EngineeringNational University of SingaporeSingapore 119074Singapore Institute of Biochemical and Biotechnological drugs School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China key laboratory of Biopharmaceuticals Postdoctoral Scientific Research WorkstationShandong Academy of Pharmaceutical ScienceJinan 250098China State key laboratory of Natural and Biomimetic drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China School of Life Sciences Science and Technology Innovation CenterShandong First Medical University&Shandong Academy of Medical SciencesJinan 250062China School of Chinese Materia Medica Tianjin University of Traditional Chinese MedicineTianjin 301617China Tianjin Pharmaceutical DA REN TANG Group Corporation Limited Traditional Chinese Pharmacy Research Institute Tianjin 300457China key laboratory of Systems Bioengineering(Ministry of Education) School of Chemistry Engineering and TechnologyTianjin UniversityTianjin 300072China

The visualization of drugs in living systems has become key techniques in modern *** advancements in optical imaging technologies and molecular design strategies have revolutionized drug *** the subcellular level,super-resolution microscopy has allowed exploration of the molecular landscape within individual cells and the cellular response to *** beyond subcellular imaging,researchers have integrated multiple modes,like optical near-infrared II imaging,to study the complex spatiotemporal interactions between drugs and their *** combining these visualization approaches,researchers gain supplementary information on physiological parameters,metabolic activity,and tissue composition,leading to a comprehensive understanding of drug *** review focuses on cutting-edge technologies in drug visualization,particularly fluorescence imaging,and the main types of fluorescent molecules ***,we discuss current challenges and prospects in targeted drug research,emphasizing the importance of multidisciplinary cooperation in advancing drug *** the integration of advanced imaging technology and molecular design,drug visualization has the potential to redefine our understanding of pharmacology,enabling the analysis of drug micro-dynamics in subcellular environments from new perspectives and deepening pharmacological research to the levels of the cell and organelles.

关键词： Optical imaging Drug visualization Fluorophore labeling Therapeutics

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Degradation of FAK-targeting by proteolytic targeting chimera technology to inhibit the metastasis of hepatocellular carcinoma

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Oncology Research 2024年第4期32卷 679-690页

作者： XINFENG ZHANG SHUANG LI MEIRU SONG YUE CHEN LIANGZHENG CHANG ZHERUI LIU HONGYUAN DAI YUTAO WANG GANGQI YANG YUN JIANG YINYING LU The PLA 307 Clinical College of Anhui Medical University The Fifth Clinical Medical College of Anhui Medical UniversityHefei230032China Liver Tumor Diagnosis and Research Center 5th Medical Center of the PLA General HospitalBeijing100039China Department of Infection Diseases Guizhou Medical UniversityGuiyang550025China 4302 Clinical Medical School Peking UniversityBeijingChina cell and Gene therapy Innovation Center Beijing Lotuslake BiomedicalScience and Technology ParkBeijing102206China State key laboratory of Chemical Oncogenomics and the Institute of Biopharmaceutical and Health Engineering(iBHE) Shenzhen International Graduate SchoolTsinghua UniversityShenzhen518055China

Liver cancer is a prevalent malignant cancer,ranking third in terms of mortality *** and recurrence primarily contribute to the high mortality rate of liver *** carcinoma(HCC)has low expression of focal adhesion kinase(FAK),which increases the risk of metastasis and ***,the efficacy of FAK phosphorylation inhibitors is currently ***,investigating the mechanisms by which FAK affects HCC metastasis to develop targeted therapies for FAK may present a novel strategy to inhibit HCC *** study examined the correlation between FAK expression and the prognosis of ***,we explored the impact of FAK degradation on HCC metastasis through wound healing experiments,transwell invasion experiments,and a xenograft tumor *** expression of proteins related to epithelial-mesenchymal transition(EMT)was measured to elucidate the underlying *** results showed that FAK PROTAC can degrade FAK,inhibit the migration and invasion of HCC cells in vitro,and notably decrease the lung metastasis of HCC in *** expression of E-cadherin and decreased expression of vimentin indicated that EMT was ***,degradation of FAK through FAK PROTAC effectively suppressed liver cancer metastasis,holding significant clinical implications for treating liver cancer and developing innovative anti-neoplastic drugs.

关键词： Hepatocellular carcinoma(HCC) Focal adhesion kinase(FAK) Proteolytic targeting chimera technology(PROTAC) Epithelial-mesenchymal transformation(EMT) Metastasis

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Sulforaphane ameliorates non-alcoholic steatohepatitis by KLF4-mediated macrophage M2 polarization

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Food Science and Human Wellness 2024年第5期13卷 2727-2740页

作者： Xianghui Huang Jia Xu Ye Xu Bingxin Huangfu Feng Zhang Yanzhou Hu Ruxin Gao Xinxin Ren Boyang Zhang Kunlun Huang Xiaoyun He key laboratory of Precision Nutrition and Food Quality Key Laboratory of Functional DairyMinistry of EducationCollege of Food Science and Nutritional EngineeringChina Agricultural UniversityBeijing 100083China key laboratory of Safety Assessment of Genetically Modified Organism(Food Safety) the Ministry of Agriculture and Rural Affairs of the P.R.ChinaBeijing 100083China

Non-alcoholic fatty liver disease (NAFLD) has become a global issue and a severe threat to public ***, to date, no approved therapeutic drugs have been developed. Dietary interventions with naturalproducts have shown promise in preventing and treating NAFLD. Sulforaphane (SFN) is a phytocompoundwith antioxidant and anti-inflammatory properties, and previous research has demonstrated that SFN canameliorate hepatic lipid accumulation and inflammation. However, the molecular mechanisms underlying thesebeneficial effects remain unclear. In this study, we confirmed the protective effects of SFN on excessive lipidaccumulation and inflammatory injury in a high-fat, high-fructose diet-induced non-alcoholic steatohepatitis(NASH) mouse model. We found that SFN attenuates the inflammatory injury in a macrophage cell line andthe liver of NASH mice, owing to the promotion of M1-type macrophage polarization toward the M2-type andthe regulation of inflammatory mediators. Further analysis demonstrated that this SFN-induced macrophageM2-type polarization occurs in a Krüppel-like factor 4 (KLF4)-dependent manner. In summary, we uncovereda new mechanism of action underlying SFN activity and provide evidence that dietary intervention with SFNmight be protective against NASH.

关键词： Non-alcoholic steatohepatitis(NASH) Krüppel-like factor 4 Nuclear translocation Chemokine Lipid metabolism

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Exploring a novel class tryptophan hydroxylase 1 inhibitor derived from Sambucus williamsii Hance for the osteoporosis treatment

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Acupuncture and Herbal Medicine 2024年第1期4卷 102-112页

作者： Yu-Xin Zhu Zi-Ling Tang Lu Lu Zuo-Cheng Qiu Dabo Pan Yang Yu Hui-Hui Xiao Man-Sau Wong State key laboratory of Chinese Medicine and Molecular Pharmacology(Incubation) The Hong Kong Polytechnic University Shenzhen Research InstituteShenzhenChina Guangzhou key laboratory of Formula-Pattern of Traditional Chinese Medicine School of Traditional Chinese MedicineJinan UniversityGuangzhouChina Guangdong Provincial key laboratory of Pharmacodynamic Constituents of TCM and New drugs Research College of PharmacyJinan UniversityGuangzhouChina Department of Food Science and Nutrition The Hong Kong Polytechnic UniversityHong KongChina Research Center for Chinese Medicine Innovation The Hong Kong Polytechnic UniversityHong KongChina

Objective:Gut-derived serotonin strongly inhibits bone formation by inhibiting osteoblast *** previous study demonstrated that the lignan-rich fraction prepared from Sambucus willimasii Hance,a folk herbal medicine used to treat bone fractures and joint diseases in China,exerted bone-protective effects,and its actions were modulated by suppressing the synthesis of gut-derived serotonin via the inhibition of intestinal tryptophan hydroxylase 1(TPH-1).However,there is no direct evidence for the action of lignans on *** study aimed to verify the direct action of lignans on the TPH-1 and its influence on serotonin synthesis and bone ***:Molecular docking and surface plasmon resonance were performed to determine the affinities of lignans to *** cell viability and the protein activity and expression of TPH-1 were measured in RBL2H3 *** serum serotonin level and bone mineral density upon lignan treatment in ovariectomized mice were ***:The lignans showed high binding scores and binding affinities to TPH-1,inhibited the activity and protein expression of TPH-1,suppressed the serum serotonin levels in ovariectomized mice as well as promoted bone mineral ***:This is the first study to report that lignans are novel TPH-1 inhibitors and that these lignans could be potential agents for the management of serotonin-related diseases,including osteoporosis.

关键词： Lignan Osteoporosis Sambucus williamsii Hance Serotonin TPH-1 inhibitor

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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

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Integrin α6:a potential target for cancer molecular imaging and targeting therapy

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Malignancy Spectrum 2024年第1期1卷 30-45页

作者： Xin-Ling Li Zhuo-Lun Shen Qiao-Li Wang Jia-Cong Ye Wen-Biao Zhang Ying-He Li Guo-Kai Feng Mu-Sheng Zeng State key laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineGuangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapySun Yat-sen University Cancer CenterGuangzhouGuangdongChina

As a major kind of cell surface adhesion molecules with signal transduction function,integrins play a major role in tumorigenesis and tumor *** role of integrins in tumor cells and the tumor microenvironment has been extensively *** the integrin family,integrinαvβ3 is the most studied integrin in the past 20 *** of preclinical and clinical studies have been conducted,which showed clinical benefits of targeting integrinαvβ3 in tumor imaging and ***,the focus of interest is gradually shifting from integrinαvβ3 toward other integrin ***α6 is expressed in many malignant tumors,such as colorectal cancer,head and neck squamous cell carcinoma,breast cancer,pancreatic cancer,and liver cancer,and its expression is correlated with poor survival of the *** studies have shown that tumor molecular imaging agents and therapeutic drugs targeting integrinα6 have excellent safety and efficacy in preclinical mouse models,encouraging clinical translation of this promising *** this review,we briefly overview the physiological and pathological function of integrinα6 and highlight the recent advances in integrinα6-targeted imaging and therapeutics in tumors.

关键词： tumor imaging tumor therapy tumor microenvironment molecular imaging integrin

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Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases

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Journal of Pharmaceutical Analysis 2023年第6期13卷 545-562页

作者： Jiuping Zeng Mingxing Li Qianyun Zhao Meijuan Chen Long Zhao Shulin Wei Huan Yang Yueshui Zhao Anqi Wang Jing Shen Fukuan Du Yu Chen Shuai Deng Fang Wang Zhuo Zhang Zhi Li Tiangang Wang Shengpeng Wang Zhangang Xiao Xu Wu laboratory of Molecular Pharmacology Department of PharmacologySchool of PharmacySouthwest Medical UniversityLuzhouSichuan646000China cell therapy&cell drugs of luzhou key laboratory LuzhouSichuan646000China South Sichuan Institute of Translational Medicine LuzhouSichuan646000China Department of Spleen and Stomach Diseases The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical UniversityLuzhouSichuan646000China School of Medicine Chengdu UniversityChengdu610106China State key laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao999078China Department of Oncology The Affiliated Hospital of Southwest Medical UniversityLuzhouSichuan646000China

As a ligand-dependent transcription factor,retinoid-associated orphan receptor gt(RORγt)that controls T helper(Th)17 cell differentiation and interleukin(IL)-17 expression plays a critical role in the progression of several inflammatory and autoimmune *** emerging novel approach to the therapy of these diseases thus involves controlling the transcriptional capacity of RORγt to decrease Th17 cell development and IL-17 *** RORγt inhibitors including both antagonists and inverse agonists have been discovered to regulate the transcriptional activity of RORγt by binding to orthosteric-or allosteric-binding sites in the ligand-binding *** of small-molecule inhibitors have entered clinical ***,in current review,the role of RORγt in Th17 regulation and Th17-related inflammatory and autoimmune diseases was ***,the recently developed RORγt inhibitors were summarized,with an emphasis on their optimization from lead compounds,efficacy,toxicity,mechanisms of action,and clinical *** limitations of current development in this area were also discussed to facilitate future research.

关键词： T helper 17 RORγt Small-molecule inhibitor Inflammatory disease Autoimmune disease

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