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Co-delivery of doxorubicin and curcumin via cRGD-peptide modified PEG-PLA self-assembly nanomicelles for lung cancer therapy

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Chinese Chemical Letters 2022年第5期33卷 2507-2511页

作者： Yunchu Zhang Tingting Li Yuzhu Hu Jing Chen Yihong He Xiang Gao yan Zhang Department of Thoracic Oncology Cancer CenterState Key Laboratory of BiotherapyWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China

Lung cancer is the most common malignancy in the world, with a high mortality rate. Nevertheless,therapies to act effectively against lung cancer remain elusive. So far, chemotherapy is still the frontline treatment of lung cancer. Doxorubicin(DOX) is a broad-spectrum anti-tumor drug. However, DOX often has serious side effects and causes multi-drug resistance, which greatly limits its clinical *** this work, biodegradable methoxy poly(ethylene glycol)-poly(lactic acid)(MPEG-PLA) and cyclo(ArgGly-Asp-D-Phe-Lys)(c RGD) polypeptide modified PEG-PLA(c RGD-PEG-PLA) copolymers were used for the co-delivery of curcumin(CUR) and DOX(CUR-DOX/c RGD-M). The particle size of the self-assembled drugloaded nanomicelle approximately was 27.4 nm and the zeta potential was -2.7mV. Interestingly, CUR can enhance the uptake of DOX by Lewis lung carcinoma(LL/2) cells. The experimental results in vivo and in vitro showed that CUR-DOX/c RGD-M combination therapy could promote apoptosis of lung cancer cells, and conspicuously inhibit the tumor growth. Our data indicate that CUR-DOX/c RGD-M will be biodegradable and sustainable, which may have potential clinical application value in the treatment of lung cancer.

关键词： Doxorubicin Curcumin Lung cancer Nanomicelle Co-delivery

Neonatal Exposure to Propofol Interferes with the Proliferation and Differentiation of Hippocampal Neural Stem Cells and the Neurocognitive Function of Rats in Adulthood via the Akt/p27 Signaling Pathway

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Biomedical and Environmental Sciences 2022年第4期35卷 283-295页

作者： MIAO Hui Hui LIU Wen Bo JIAO Xin Hao SHAO Ke Jie YUAN Ying Xuan SHA Sha ZHANG Qi Qi yan Jing SUN Yin Ying ZHOU Cheng Hua WU Yu Qing Department of Anesthesiology Beijing Shijitan HospitalCapital Medical UniversityBeijing 100038China Jiangsu Province key laboratory of Anesthesiology Xuzhou Medical UniversityXuzhou 221004JiangsuChina Jiangsu key laboratory of New drug Research and Clinical Pharmacy Xuzhou Medical UniversityXuzhou 221004JiangsuChina NMPA key laboratory for Research and Evaluation of Narcotic and Psychotropic drugs Xuzhou Medical UniversityXuzhou 221004JiangsuChina

Objective Neonatal exposure to propofol has been reported to cause neurotoxicity and neurocognitive decline in adulthood;however,the underlying mechanism has not been *** SD rats were exposed to propofol on postnatal day 7(PND-7).Double-immunofluorescence staining was used to assess neurogenesis in the hippocampal dentate gyrus(DG).The expression of pAkt and p27 were measured by western *** Morris water maze,novel object recognition test,and object location test were used to evaluate neurocognitive function 2-month-old *** Phosphorylation of Akt was inhibited,while p27 expression was enhanced after neonatal exposure to *** also inhibited proliferation of neural stem cells(NSCs)and decreased differentiation to neurons and ***,the neurocognitive function in 2-month-old rats was *** significance,intra-hippocampal injection of the Akt activator,SC79,attenuated the inhibition of p-AKT and increase of p27 ***79 also rescued the propofol-induced inhibition of NSC proliferation and *** propofol-induced neurocognition deficit was also partially reversed by *** Taken together,these results suggest that neurogenesis is hindered by neonatal propofol ***,neonatal propofol exposure was shown to suppress the proliferation and differentiation of NSCs by inhibiting Akt/p27 signaling pathway.

关键词： Propofol Neurogenesis Hippocampal dentate gyrus Akt p27

Co-delivery of enzymes and photosensitizers via metal-phenolic network capsules for enhanced photodynamic therapy

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Chinese Chemical Letters 2022年第4期33卷 1917-1922页

作者： Qian Wang Zhiliang Gao Kaijie Zhao Peiyu Zhang Qi-Zhi Zhong Qun Yu Shumei Zhai Jiwei Cui key laboratory of Colloid and Interface Chemistry of the Ministry of Education School of Chemistry and Chemical EngineeringShandong UniversityJi’nan 250100China ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and the Department of Chemical EngineeringThe University of MelbourneParkvilleVIC 3010United States State key laboratory of microbial Technology Shandong UniversityQingdao 266237China

The intrinsic hypoxic tumor microenvironment and limited accumulation of photosensitizers(PSs) result in unsatisfied efficiency of photodynamic therapy(PDT).To enhance the PDT efficiency against solid tumors,a functional oxygen self-supplying and PS-delivering nanosystem is fabricated via the combination of catalase(CAT),chlorin e6(Ce6) and metal-phenolic network(MPN) *** is demonstrated that the CAT encapsulated in the capsules(named CCM capsules) could catalyze the degradation of hydrogen peroxide(H;O;) to produce molecular oxygen(O;),which could be converted into cytotoxicity reactive oxygen species(ROS) by surface-loaded Ce6 under 660 nm laser irradiation,leading to synergistic anticancer effects in vitro and in ***,the application of CCM capsule could be a promising strategy to improve PDT effectiveness.

关键词： Metal-phenolic network(MPN) Photodynamic therapy(PDT) Capsule Oxygen self-supply drug delivery

Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

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药物分析学报:英文版 2023年第7期13卷 776-787页

作者： Xiangyi Wang Jin Zhang Kailu Zheng Qianqian Du Guocai Wang Jianpeng Huang yanhe Zhou yan Li Hongtao Jin Jiuming He State key laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China NMPA key laboratory of Safety Research and Evaluation of Innovative drug Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China Beijing key laboratory of New drug Mechanisms and Pharmacological Evaluation Study Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China New drug Safety Evaluation Center Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted ***,metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and ***,choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types,and a choline-modified strategy for small molecule-drug conjugates(SMDCs)design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy,instead of directly inhibiting choline *** a proof-of-concept,choline-modified SMDCs were designed,screened,and investigated for their druggability in vitro and in *** strategy improved tumor targeting,preserved tumor inhibition and reduced toxicity of paclitaxel,through targeted drug delivery to tumor by highly expressed choline transporters,and site-specific release by *** study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.

关键词： Mass spectrometry imaging Spatially resolved metabolomics Small molecule-drug conjugate Tumor metabolism Targeted tumor therapy

Human organoids in basic research and clinical applications

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Signal Transduction and Targeted Therapy 2022年第6期7卷 2010-2026页

作者： Xiao-yan Tang Shanshan Wu Da Wang Chu Chu Yuan Hong Mengdan Tao Hao Hu Min Xu Xing Guo yan Liu Institute for Stem Cell and Neural Regeneration School of PharmacyState Key Laboratory of Reproductive MedicineKey Laboratory of Targeted Intervention of Cardiovascular DiseaseCollaborative Innovation Center for Cardiovascular Disease Translational MedicineNanjing Medical UniversityNanjingChina Department of Neurobiology School of Basic Medical SciencesNanjing Medical UniversityNanjingChina

Organoids are three-dimensional(3D)miniature structures cultured in vitro produced from either human pluripotent stem cells(hPSCs)or adult stem cells(AdSCs)derived from healthy individuals or patients that recapitulate the cellular heterogeneity,structure,and functions of human *** advent of human 3D organoid systems is now possible to allow remarkably detailed observation of stem cell morphogens,maintenance and differentiation resemble primary tissues,enhancing the potential to study both human physiology and developmental *** they are similar to their original organs and carry human genetic information,organoids derived from patient hold great promise for biomedical research and preclinical drug testing and is currently used for personalized,regenerative medicine,gene repair and transplantation *** recent decades,researchers have succeeded in generating various types of organoids mimicking in vivo ***,we provide an update on current in vitro differentiation technologies of brain,retinal,kidney,liver,lung,gastrointestinal,cardiac,vascularized and multi-lineage organoids,discuss the differences between PSC-and AdSC-derived organoids,summarize the potential applications of stem cell-derived organoids systems in the laboratory and clinic,and outline the current challenges for the application of organoids,which would deepen the understanding of mechanisms of human development and enhance further utility of organoids in basic research and clinical studies.

关键词： organs clinical generating

Hypoxia-inducible factor upregulation by roxadustat attenuates drug reward by altering brain iron homoeostasis

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Signal Transduction and Targeted Therapy 2023年第10期8卷 4949-4963页

作者： Pengju yan Ningning Li Ming Ma Zhaoli Liu Huicui yang Jinnan Li Chunlei Wan Shuliu Gao Shuai Li Longtai Zheng John LWaddington Lin Xu Xuechu Zhen Jiangsu key laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences Soochow UniversitySuzhou 215123China CAS key laboratory of Animal Models and Human Disease Mechanisms and KIz-sU Joint Laboratory of Animal Model and Drug Developmentand Laboratory of Learning and MemoryKunming Institute of Zoologythe Chinese Academy of SciencesKunming 650223China School of Pharmacy and Biomolecular Sciences RCSI University of Medicine and Health SciencesDublin 2Ireland

Substance use disorder remains a major challenge,with an enduring need to identify and evaluate new,translational targets for effective ***,we report the upregulation of Hypoxia-inducible factor-1α(HIF-1α)expression by roxadustat(Rox),a drug developed for renal anemia that inhibits HIF prolyl hydroxylase to prevent degradation of HIF-1α,administered either systemically or locally into selected brain regions,suppressed morphine(Mor)-induced conditioned place preference(CPP).

关键词： drug morphine anemia

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

Study of the inflammatory activating process in the early stage of Fusobacterium nucleatum infected PDLSCs

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International Journal of Oral Science 2023年第1期15卷 113-126页

作者： Yushang Wang Lihua Wang Tianyong Sun Song Shen Zixuan Li Xiaomei Ma Xiufeng Gu Xiumei Zhang Ai Peng Xin Xu Qiang Feng Department of Implantology School and Hospital of StomatologyCheeloo College of MedicineShandong University&Shandong Key Laboratory of Oral Tissue Regeneration&Shandong Engineering Laboratory for Dental Materials and Oral Tissue RegenerationJinanChina Department of Human Microbiome School and Hospital of StomatologyCheeloo College of MedicineShandong University&Shandong Key Laboratory of Oral Tissue Regeneration&Shandong Engineering Laboratory for Dental Materials and Oral Tissue RegenerationJinanChina Department of Orthodontics School and Hospital of StomatologyCheeloo College of MedicineShandong University&Shandong Key Laboratory of Oral Tissue Regeneration&Shandong Engineering Laboratory for Dental Materials and Oral Tissue RegenerationJinanChina State key laboratory of microbial technology Shandong UniversityQingdaoChina

Fusobacterium nucleatum(***)is an early pathogenic colonizer in periodontitis,but the host response to infection with this pathogen remains *** this study,we built an *** infectious model with human periodontal ligament stem cells(PDLSCs)and showed that *** could inhibit proliferation,and facilitate apoptosis,ferroptosis,and inflammatory cytokine production in a dose-dependent *** *** adhesin Fad A acted as a proinflammatory virulence factor and increased the expression of interleukin(IL)-1β,IL-6 and *** study showed that Fad A could bind with PEBP1 to activate the Raf1-MAPK and IKK-NF-κB signaling ***-course RNA-sequencing analyses showed the cascade of gene activation process in PDLSCs with increasing durations of *** ***κB1 and NFκB2 upregulated after 3 h of ***-infection,and the inflammatory-related genes in the NF-κB signaling pathway were serially elevated with *** computational drug repositioning analysis,we predicted and validated that two potential drugs(piperlongumine and fisetin)could attenuate the negative effects of ***,this study unveils the potential pathogenic mechanisms of *** and the host inflammatory response at the early stage of *** infection.

关键词： inflammatory drugs PDL

Study on improving hematopoietic function of rats with blood deficiency syndrome by Shengxuebao mixture

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Traditional Medicine Research 2024年第8期9卷 35-46页

作者： yan Shu Hong-Na Liu yang Zhao Jin-Yi Cao Yue Chen Yi Qiao Hui Guo Zhi-Fu yang College of Pharmacy Shaanxi University of Chinese MedicineXianyang 712046China Tsing Hua De Ren Xi’an Happiness Pharmaceutical Co. Ltd.Xi’an 710400China Department of Pharmacy Xijing HospitalFourth Military Medical UniversityXi’an 710000China State key laboratory of Oral&Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral DiseasesShaanxi Engineering Research Center for Dental Materials and Advanced ManufactureDepartment of PharmacySchool of Stomatologythe Fourth Military Medical UniversityXi’an 710000China

Background:Shengxuebao mixture(SXBM)is a novel herbal drug approved by China State Food and drug Administration for the treatment of Leukopenia and iron deficiency anemia caused by radiotherapy and ***:To explore the mechanism of SXBM in treating blood deficiency syndrome(BDS).Firstly,network pharmacology and in vivo experiments were used to screen candidate targets and important signaling pathways of SXBM,GO functional enrichment and KEGG pathway analysis were ***,a BDS rat model was established to verify the results of the analysis of network pharmacological *** and routine peripheral blood examination were *** expressions of tumor necrosis factor-α,interleukin(IL)-6,HIF-1αand NF-κB were detected by Western blot,and the expressions of IL-6,IL-1βwere detected by ***:62 bioactive components,66 potential targets and 131 signaling pathways of BDS were successfully identified by network *** docking simulation techniques showed that key targets tumor necrosis factor-α,IL-6,IL-1βcan dock well with crucial components,and the BDS-related signaling pathways HIF-1 and JAK-STAT play a vital *** combined model experiment of acetylphenylhydrazine and cyclophosphamide showed that the model group had obvious blood deficiency,and the histopathology and blood routine were effectively restored after *** findings indicate that SXBM’s therapeutic effect on BDS primarily involves the mediation of the HIF-1α/NF-κB signaling pathway and the regulation of hematopoietic factor ***:This study not only affirmed the protective properties of SXBM against BDS but also provided insights into a potential mechanism for blood replenishment in the treatment of BDS using SXBM.

关键词： network pharmacology molecular docking technology blood deficiency syndrome hematopoietic factors HIF-1α/NF-κB