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

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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Amphotericin B release rate is the link between drug status in the liposomal bilayer and toxicity

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Asian Journal of Pharmaceutical Sciences 2022年第4期17卷 544-556页

作者： Yuri Svirkin Jaeweon Lee Richard Marx Seongkyu Yoon Nelson Landrau Md Abul Kaisar Bin Qin Jin H.Park Khondoker Alam Darby Kozak Yan Wang Xiaoming Xu Jiwen Zheng Benjamin Rivnay Landrau Scientific Innovations LeominsterMAUnited States of America University of Massachusetts Lowell LowellMAUnited States of America Office of research and Standards Office of Generic DrugsCenter for Drug Evaluation and ResearchU.S.Food and Drug AdministrationSilver SpringMDUnited States of America Office of Testing and research Office of Pharmaceutical QualityCenter for Drug Evaluation and ResearchU.S.Food and Drug AdministrationSilver SpringMDUnited States of America Office of Science and Engineering Laboratories Center for Devices and Radiological HealthU.S.Food and Drug AdministrationSilver SpringMDUnited States of America

Amphotericin B(AmB)is an amphiphilic drug commonly formulated in liposomes and administered intravenously to treat systemic fungal *** studies on the liposomal drug product have shed light on the AmB aggregation status in the bilayer,which heat treatment(curing)*** toxicity was found related to aggregation status-loose aggregates significantly more toxic than tight aggregates-the precise mechanism linking aggregation and toxicitywas notwell *** study directlymeasured drug release rate fromvarious AmB liposomal preparations made with modified curing protocols to evaluate correlations among drug aggregation state,drug release,and in vitro ***–Vis spectroscopy of these products detected unique curing-induced changes in the UV spectral features:a∼25nm blue-shift of the main absorption peak(λ_(max))in aqueous buffer and a decrease in the OD_(346)/OD_(322) ratio upon thermal curing,reflecting tighter *** vitro release testing(IVRT)data showed,by applying and fitting first-order release kinetic models for one or two pools,that curing impacts two significant changes:a 3–5-fold drop in the overall drug release rate and a ten-fold decrease in the ratio between the loosely aggregated and the tightly aggregated,more thermodynamically stable drug *** kinetic data thus corroborated the trend independently deduced from the UV–Vis spectral *** in vitro toxicity assay indicated a decreased toxicity with curing,as shown by the significantly increased concentration,causing half-maximal potassium release(TC50).The data suggest that the release of AmB requires dissociation of the tight complexes within the bilayer and that the reduced toxicity relates to this slower rate of *** study demonstrates the relationship between AmB aggregation status within the lipid bilayer and drug release(directly measured rate constants),providing a mechanistic link between aggregation status and in vitro toxicity in the lip

关键词： Amphotericin B UV–Vis Spectrum drug Release In Vitro Toxicity Aggregation Status Liposomes

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The investigation of the stability of DNA-b-PPO vesicles formed through frame guided assembly

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Science China Chemistry 2018年第12期61卷 1568-1571页

作者： Bo Bian Yi-Yang Zhang Yuan-Chen Dong Fen Wu Chao Wang Shuo Wang Yun Xu Dong-Sheng Liu Department of Chemistry Tsinghua University College of Chemistry and Materials Engineering Wenzhou University center for Medical Device evaluation China Food and Drug Administration (CFDA)

Frame-guided assembly is a novel assembly method which can control the shape and size of vesicles accurately. It has been reported that the DNA-b-PPO vesicles could be stable over two weeks. In this communication we have introduced restriction sites of EcoR1 in the interior DNA scaffold to the formed vesicles in order to further study their stability. Dynamic light scattering(DLS), transmission electron microscope(TEM) and fluorescence spectrum were used to characterize the digestion process. The final results revealed that the vesicles were still stable even after two weeks cultivated with EcoR1, which suggests potential in future biological applications.

关键词： frame-guided assembly vesicles stability restriction sites EcoR1

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Synthesis and Crystal Structure of Dehydroandrographolide Dipolycyclophosphate

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Chinese Journal of Structural Chemistry 2005年第10期24卷 1198-1202页

作者： XU Hai-Wei WANG Jun-Feng LIU Hong-Min ZHANG Jian-Ye New drug research ＆ Development center Zhengzhou University Zhengzhou 450052 China

The title compound was synthesized and characterized by IR, NMR, HRSI-MS and MS, and its crystal structure was determined by single-crystal X-ray diffraction. The crystal is of orthorhombic system （C40H52O11P2, Mr= 770.76）, space group P21212, with a = 22.562（5）, b = 29.224（6）, c = 7.1953（14） A, V = 4744.2（16） A^3, Z = 4, Dc = 1.079 g/cm^3, F（000） = 1640 and μ = 0.141 mm^-1. The final R = 0.0758 and wR = 0.1778 for 2794 observed reflections with I 〉 20（I）. Intermolecular hydrogen bonds are found between the O atom of carbonyl group and H atoms of olefinic carbon. The absolute configuration of this molecule was confirmed by comparison with that of the original material.

关键词： crystal structure andrographolide cyciophosphate synthesis

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De novo strategy with engineering a multifunctional bacterial cellulose-based dressing for rapid healing of infected wounds

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Bioactive Materials 2022年第7期7卷 212-222页

作者： Chen Zhou Zhifei Yang Xiaowei Xun Le Ma Zejing Chen Xiaoming Hu Xidong Wu Yizao Wan Haiyong Ao Jiangxi Key Laboratory of Nanobiomaterials&Institute of Advanced Materials East China Jiaotong UniversityNanchang330000China Department of drug safety evaluation Jiangxi Testing Center of Medical DeviceNanchang330000China

The treatment and healing of infected skin lesions is one of the major challenges in *** solve this problem,collagen I(Col-I)and the antibacterial agent hydroxypropyltrimethyl ammonium chloride chitosan(HACC)were composited into the bacterial cellulose(BC)three-dimensional network structure by a novel membrane-liquid interface(MLI)culture,and a Col-I/HACC/BC(CHBC)multifunctional dressing was *** water absorption rate and water vapor transmission rate of the obtained CHBC dressing were 35.78±2.45 g/g and 3084±56 g m^(-2)⋅day^(-1),*** water retention of the CHBC dressing was significantly improved compared with the BC caused by the introduced Col-I and *** vitro results indicated that the combined advantages of HACC and Col-I confer on CHBC dressings not only have outstanding antibacterial properties against Staphylococcus aureus(***)compared with BC and CBC,but also exhibit better cytocompatibility than BC and HBC to promote the proliferation and spread of NIH3T3 cells and *** importantly,the results of in vivo animal tests demonstrated that the CHBC dressings fully promoted wound healing for 8 days and exhibited shorter healing times,especially in the case of wound *** skin regeneration effects and higher expression levels of collagen during infection were also shown in the CHBC *** believe that CHBC composites with favorable multifunctionality have potential applications as wound dressings to treat infected wounds.

关键词： Bacterial cellulose Quaternized chitosan Multifunctional dressing Antibacterial activity Healing promotion

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Total glucosides of Rhizoma Smilacis Glabrae:a therapeutic approach for psoriasis by regulating Th17/Treg balance

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Chinese Journal of Natural Medicines 2023年第8期21卷 589-598页

作者： TANG Yingzhan YU Jingyi ZHAO Wen LIU Juyan PENG Hongying ZHANG Haoran JIANG Zhenzhou YU Qinwei ZHANG Luyong New drug screening center Jiangsu Center for Pharmacodynamics Research and EvaluationChina Pharmaceutical UniversityNanjing 210009China Guangzhou Baiyunshan Jingxiutang Pharmaceutical Co. Ltd.Guangzhou 510130China Guangzhou Pharmaceutical Holdings Co. Ltd.Guangzhou 510103China center for drug research and Development Guangdong Pharmaceutical UniversityGuangzhou 510006China

Total glucosides of Rhizoma Smilacis Glabrae(RSG)are selective immunosuppressants that exhibit primary efficacy in the treatment of rheumatoid arthritis through targeted inhibition of activated T *** this study,we aimed to investigate the potential application of RSG in the treatment of psoriasis and elucidate its mechanism of action and material *** findings revealed significant improvements upon administration of RSG in an imiquimod(IMQ)-induced psoriasis *** improvements were characterized by a remarkable increase in the number of tail scales in mice and a substantial amelioration of skin erythema,ulceration,and *** transcriptome sequencing and T-cell flow sorting assay,we identified notable effects of RSG on the modulation of various cellular ***,RSG prominently down-regulated the Th17/Treg ratio in damaged skin tissues and reduced the proportion of G2 phase ***,RSG exhibited a stimulatory effect on the proliferation and differentiation of epithelial *** particular interest,we discovered thatβ-sitosterol,sitostenone,stigmasterol,smiglanin,and cinchonain Ib displayed potent inhibitory effects on the IL-17-mediated inflammatory response in HaCaT *** summary,our study highlights the therapeutic potential of RSG in the treatment of psoriasis,attributed to its ability to regulate the Th17/Treg *** findings contribute to the development of new indications for RSG and provide a solid theoretical foundation for further exploration in this field.

关键词： Psoriasis Rhizoma Smilacis Glabrae Th17/Treg balance Inflammation Epithelium development

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A novel inhibitor of ARfl and ARv7 induces protein degradation to overcome enzalutamide resistance in advanced prostate cancer

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Acta Pharmaceutica Sinica B 2022年第11期12卷 4165-4179页

作者： Yan Li Ya Chu Guangjiang Shi Xiaobin Wang Wanli Ye Chun Shan Dajia Wang Di Zhang Wei He Jingwei Jiang Shuqian Ma Yuhong Han Zhili Zhao Shijia Du Zhen Chen Zhiyu Li Yong Yang Chen Wang Xi Xu Hongxi Wu center for New drug safety evaluation and research State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 211198China School of Life Science and Technology China Pharmaceutical UniversityNanjing 211198China School of Pharmacy China Pharmaceutical UniversityNanjing 211198China Jiangsu Key Lab of drug Screening China Pharmaceutical UniversityNanjing 211198China

Enzalutamide(ENZ) is a second-generation androgen receptor(AR) antagonist used for the treatment of castration-resistant prostate cancer(CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance(ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR(ARfl)or dominantly active androgen receptor splice variant 7(ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.

关键词： drug resistance Enzalutamide Castration-resistant prostate cancer Androgen receptorsplice variant7 Heterodimers Degradation

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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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Potential herb-drug interactions between anti-COVID-19 drugs and traditional Chinese medicine

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Acta Pharmaceutica Sinica B 2023年第9期13卷 3598-3637页

作者： Ling Ye Shicheng Fan Pengfei Zhao Chenghua Wu Menghua Liu Shuang Hu Peng Wang Hongyu Wang Huichang Bi NMPA Key Laboratory for research and evaluation of drug Metabolism&Guangdong Provincial Key Laboratory of 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

Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread *** treatments against COVID-19 remain urgently in need although vaccination significantly reduces the incidence,hospitalization,and *** present,antiviral drugs including Nirmatrelvir/Ritonavir(Paxlovid^(TM)),Remdesivir,and Molnupiravir have been authorized to treat COVID-19 and become more globally *** the other hand,traditional Chinese medicine(TCM)has been used for the treatment of epidemic diseases for a long ***,various TCM formulae against COVID-19 such as Qingfei Paidu decoction,Xuanfei Baidu granule,Huashi Baidu granule,Jinhua Qinggan granule,Lianhua Qingwen capsule,and Xuebijing injection have been widely used in clinical practice in China,which may cause potential herb-drug interactions(HDIs)in patients under treatment with antiviral drugs and affect the efficacy and safety of ***,information on potential HDIs between the above anti-COVID-19 drugs and TCM formulae is lacking,and thus this work seeks to summarize and highlight potential HDIs between antiviral drugs and TCM formulae against COVID-19,and especially pharmacokinetic HDIs mediated by metabolizing enzymes and/or *** well-characterized HDIs could provide useful information on clinical concomitant medicine use to maximize clinical outcomes and minimize adverse and toxic effects.

关键词： COVID-19 Antiviral drugs Anti-COVID-19 drugs Nirmatrelvir/Ritonavir(Paxlovid^(TM)) Remdesivir Molnupiravir Traditional Chinese medicine Pharmacokinetics Herb-drug interaction

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The role of neutrophils in triptolide-induced liver injury

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Chinese Journal of Natural Medicines 2018年第9期16卷 653-664页

作者： WANG Xin-Zhi ZHANG Shen-Ye XU Yao ZHANG Lu-Yong JIANG Zhen-Zhou Jiangsu Key Laboratory of drug Screening Jiangsu Center for Pharmacodynamics Research and Evaluation China Pharmaceutical University Nanjing 210009 China Faculty of Health and Medical Science University of Copenhagen Copenhagen Denmark Key Laboratory of drug Quality Control and Pharmacovigilance China Pharmaceutical University Ministry of Education Nanjing 210009 China Jiangsu Key Laboratory of Traditional Chinese Medicine evaluation and Translational research Nanjing 210009 China

Triptolide(TP) induces severe liver injury, but its hepatotoxicity mechanisms are still unclear. Inflammatory responses may be involved in the pathophysiology. Neutrophils are the first-line immune effectors for sterile and non-sterile inflammatory responses. Thus, the aim of the present study was to investigate the neutrophilic inflammatory response in TP-induced liver injury in C57 BL/6 mice. Our results showed that neutrophils were recruited and accumulated in the liver, which was parallel to or slightly after the development of liver injury. Neutrophils induced release of myeloperoxidase and up-regulation of CD11 b, which caused cytotoxicity and hepatocyte death. Hepatic expressions of CXL1, TNF-α, IL-6, and MCP1 were increased significantly to regulate neutrophils recruitment and activation. Up-regulation of toll like receptors 4 and 9 also facilitated neutrophils infiltration. Moreover, neutrophils depletion using an anti-Gr1 antibody showed mild protection against TP overdose. These results indicated that neutrophils accumulation might be the secondary response, not the cause of TP-induced liver injury. In conclusion, the inflammatory response including neutrophil infiltration may play a role in TP-induced hepatotoxicity, but may not be severe enough to cause additional liver injury.

关键词： Triptolide Liver injury Inflammatory response Neutrophil Depletion

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