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Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites

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Cancer Communications 2024年第1期44卷 47-75页

作者： Ji Eon Kim So-Young Park Chulhwan Kwak Yoonji Lee Dae-Geun Song Jae Woo Jung Haesong Lee Eun-Ae Shin Yangie Pinanga Kyung-hee Pyo Eun Hae Lee Wonsik Kim Soyeon Kim Chang-Duck Jun Jeanho Yun Sun Choi Hyun-Woo Rhee Kwang-Hyeon Liu Jung Weon Lee Department of pharmacy College of PharmacySeoul National UniversitySeoulRepublic of Korea Research Institute of Pharmaceutical Sciences College of PharmacySeoul National UniversitySeoulRepublic of Korea BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit College of Pharmacy and Research Institute of Pharmaceutical SciencesKyungpook National UniversityDaeguRepublic of Korea Department of Chemistry Seoul National UniversitySeoulRepublic of Korea College of pharmacy Chung-Ang UniversitySeoulRepublic of Korea Natural Product Informatics Research Center Korea Institute of Science and Technology(KIST)Gangneung-siGangwon-doRepublic of Korea School of Life Sciences Gwangju Institute of Science and Technology(GIST)GwangjuRepublic of Korea Department of Biochemistry College of MedicineDong-A UniversityBusanRepublic of Korea Global AI Drug Discovery Center College of Pharmacy and Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoulRepublic of Korea Interdisciplinary program in Genetic Engineering Seoul National UniversitySeoulRepublic of Korea

Background:Transmembrane 4 L six family member 5(TM4SF5)translocates subcellularly and functions metabolically,although it is unclear how intracellu-lar TM4SF5 translocation is linked to metabolic *** is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of ***:Here,we explored the metabolic significance of TM4SF5 localization at mitochondria-lysosome contact sites(MLCSs),using in vitro cells and in vivo animal systems,via approaches by immunofluorescence,proximity labelling based proteomics analysis,organelle reconstitution ***:Upon extracellular glucose repletion following depletion,TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506-binding protein 8(FKBP8)and lysosomal *** labeling showed molecular clustering of phospho-dynamic-related protein I(DRP1)and certain mitophagy receptors at TM4SF5-enriched MLCSs,leading to mitochondrial fis-sion and ***4SF5 bound NPC intracellular cholesterol transporter 1(NPC1)and free cholesterol,and mediated export of lysosomal cholesterol to mitochondria,leading to impaired oxidative phosphorylation but intact tri-carboxylic acid(TCA)cycle andβ-*** mouse models,hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria,both with positive relations to liver ***:Our findings suggested that TM4SF5-enriched MLCSs regu-late glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming,presumably while hepatocellular carcinogenesis,recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial repro-gramming to support biomolecule synthesis in addition to glycolytic energetics.

关键词： cholesterol fluorescent imaging glucose catabolism hepatocellular carcinogenesis mem-brane contact sites mitochondria function mitophagy oxidative phosphorylation protein-protein interaction tetraspanin

Investigation of the active ingredients and mechanism of Shuangling extract in dextran sulfate sodium salt induced ulcerative colitis mice based on network pharmacology and experimental verification

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Journal of Traditional Chinese Medicine 2024年第3期44卷 478-488页

作者： CHU Mengzhen WANG Yu LIN Zhijian Lyu Jintao ZHANG Xiaomeng ZHANG Bing Department of Clinical Chinese pharmacy School of Chinese Materia MedicaBeijing University of Chinese Medicine

OBJECTIVE: To explore the pharmacodynamic effects and potential mechanisms of Shuangling extract against ulcerative colitis(UC). METHODS: The bioinformatics method was used to predict the active ingredients and action targets of Shuangling extract against UC in mice. And the biological experiments such as serum biochemical indexes and histopathological staining were used to verify the pharmacological effect and mechanism of Shuangling extract against UC in mice. RESULTS: The Shuangling extract reduced the levels of seruminterleukin-1β(IL-1β), tumor necrosis factor-α(TNF-N), interleukin-6(IL-6) and other inflammatory factors in UC mice and inhibited the inflammatory response. AKT Serine/threonine Kinase 1 and IL-6 may be the main targets of the anti-UC action of Shuangling extract, and the TNF signaling pathway, Forkhead box O signaling pathway and T-cell receptor signaling pathway may be the main signaling pathways. CONCLUSION: The Shuangling extract could inhibit the inflammatory response induced by UC and regulate intestinal immune function through multiple targets and multiple channels, which provided a new option and theoretical basis for anti-UC.

关键词： Shuangling extract colitis, ulcerative molecular docking simulation network pharmacology pharmacodynamic study

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Advanced nano drug delivery systems for neuroprotection against ischemic stroke

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Chinese Chemical Letters 2024年第2期35卷 151-162页

作者： Chenchen Xie Jun Liao Ning Zhang Yuhan Sun Yi Li Liyan Xiong Yingnan Zhang Xiaoyan Liu Wei Su Heming Chen Ping Zeng Xiaoqing Zhang Ying Lu Tingfang Wang Chuan Zhang Shanghai Engineering Research Center of Organ Repair School of MedicineShanghai UniversityShanghai 200444China Department of Pharmaceutical Science School of PharmacyNaval Medical UniversityShanghai 200433China Department of pharmacy the International Peace Maternity and Child Health HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200030China School of pharmacy Shanghai Jiao Tong UniversityShanghai 200040China

Ischemic stroke(IS)represents a significant threat to brain health due to its elevated mortality and disability *** efficacy of small-molecule neuroprotective agents has been impeded by challenges associated with traversing the blood-brain barrier(BBB)and limited ***,advanced nano drug delivery systems hold promise for overcoming these obstacles by facilitating efficient transportation across the BBB and maintaining optimal drug *** review aims to explore advanced neuroprotective nano drug delivery systems as a means of effectively administering neuroprotective agents to the brain using pharmaceutical approaches in the treatment of *** examining these systems,researchers and clinicians can gain valuable insights and innovative concepts,illuminating the potential of advanced neuroprotective nano drug delivery *** these advancements can drive the progress of pioneering and efficacious therapeutic interventions for IS.

关键词： Target Blood-brain barrier Ischemic stroke Nano drug delivery Neuroprotection

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The effect of lengths of branched-chain fatty alcohols on the efficacy and safety of docetaxel-prodrug nanoassemblies

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1400-1411页

作者： Shuo Wang Tian Liu Yuetong Huang Chaoying Du Danping Wang Xiyan Wang Qingzhi Lv Zhonggui He Yinglei Zhai Bingjun Sun Jin Sun Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China School of pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China School of Medical Devices Shenyang Pharmaceutical UniversityShenyang 110016China School of pharmacy Binzhou Medical UniversityBinzhou 256600China

The self-assembly prodrugs are usually consisted of drug modules,activation modules,and assembly *** the balance between efficacy and safety by selecting suitable modules remains a challenge for developing prodrug *** study designed four docetaxel(DTX)prodrugs using disulfide bonds as activation modules and different lengths of branched-chain fatty alcohols as assembly modules(C_(16),C_(18),C_(20),and C_(24)).The lengths of the assembly modules determined the self-assembly ability of prodrugs and affected the activation modules’*** extension of the carbon chains improved the prodrugs’self-assembly ability and pharmacokinetic behavior while reducing the cytotoxicity and increased cumulative *** use of C_(20) can balance efficacy and *** results provide a great reference for the rational design of prodrug nanoassemblies.

关键词： Prodrugs Nanoassemblies Self-assembly Branched-chain fatty alcohols Disulfide bond Docetaxel Efficacy Safety

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Sustained adenosine release:Revealing its impact on osteogenic signalling pathways of human mesenchymal stromal cells

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Engineered Regeneration

Engineered Regeneration 2024年第2期5卷 255-268页

作者： Hadi Hajiali Jane McLaren Cristina Gonzalez-García Salah Abdelrazig Dong-Hyun Kim Matthew J.Dalby Manuel Salmerón-Sánchez Felicity R.A.J.Rose School of pharmacy Nottingham Biodiscovery InstituteUniversity of NottinghamNottinghamUK Healthcare Technologies Institute School of Chemical EngineeringUniversity of BirminghamBirminghamUK Centre for the Cellular Microenvironment University of GlasgowGlasgowUK Centre for Analytical Bioscience Advanced Materials&Healthcare Technologies DivisionSchool of PharmacyUniversity of NottinghamNottinghamUK Marine Microbiomics Program in BiologyDivision of Science and MathematicsNew York University Abu Dhabi(NYUAD)P.O.Box 129188Abu DhabiUnited Arab Emirates

Non-healing fractures,a global health concern arising from trauma,osteoporosis,and tumours,can lead to severe ***,integral to cellular energy metabolism,gains prominence in bone regeneration via adeno-sine A2 B receptor *** study introduces a controlled-release system for localized adenosine delivery,fostering human mesenchymal stromal cell(hMSC)differentiation into functional bone *** study investi-gates how the ratio of lactic acid to glycolic acid in microparticles can influence adenosine release and explores the downstream effects on gene expression and metabolic profiles of osteogenic differentiation in hMSCs cultured in growth and osteoinductive *** into adenosine-modulated signalling pathways during MSC differenti-ation,with osteogenic factors,provide a comprehensive understanding of the pathways *** gene expression and metabolic profiles unravels adenosine’s regulatory mechanisms in MSC *** adenosine release from microparticles induces mineralization,synergizing with osteogenic media supplements,showcasing the potential of adenosine for treating critical bone defects and metabolic *** study high-lights the efficacy of a polymeric microparticle-based delivery system,offering novel strategies for bone *** adenosine’s roles and associated signalling pathways advances our comprehension of molecular mech-anisms steering bone regeneration,propelling innovative biomaterial,combined with metabolites,approaches for clinical use.

关键词： Adenosine release Osteogenic signalling pathways Human mesenchymal stromal cells Bone regeneration

Balancing efficacy and safety of doxorubicin-loaded albumin nanoparticles utilizing pH-sensitive doxorubicin-fatty acid prodrugs

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Nano Research 2024年第7期17卷 5491-5500页

作者： Yuanhao Yu Shiyi Zuo Jiaxuan Song Lingxiao Li Tian Liu Jiayu Guo Yaqiao Li Danping Wang Qi Lu Helin Wang Dun Zhou Zhonggui He Xiaohong Liu Bingjun Sun Jin Sun School of pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Department of pharmacy The First Affiliated Hospital of Jinzhou Medical UniversityJinzhou 121001China Joint International Research Laboratory of Intelligent Drug Delivery Systems Ministry of EducationShenyang 110016China

Albumin nanoparticles(ANPs)offer unique advantages for antitumor drug delivery system,including non-immunogenicity and inherent tumor-targeting *** present,only a few products,such as ABRAXANE®and FYARRO™,have been approved for clinical *** poor affinity of doxorubicin(DOX)for albumin,coupled with its numerous severe adverse reactions,poses challenges in the fabrication of desirable albumin nanoparticles loaded with *** this study,we developed prodrugs by conjugating fatty acids of varying lengths with *** aim was to investigate the balance between efficacy and safety through the selection of appropriate *** synthesized five pH-sensitive doxorubicin-fatty acid *** to free DOX,all DOX prodrug ANPs exhibited a uniform size distribution with desirable sizes of 150 ***,DOX prodrugs with hydrazone bonds remained intact in blood circulation while releasing DOX within tumor ***,the characteristics of prodrug ANPs were considerably influenced by the length of fatty acids,impacting their in vivo pharmacokinetics,antitumor effectiveness and tumor *** research offers a detailed understanding of the length of fatty acid influence on DOX-fatty acid prodrug-based ANPs,and it builds a good platform for creating ANPs which prioritize high drug loading,high efficiency,and minimal side effects.

关键词： fatty acid prodrug albumin doxorubicin pH-sensitive bond nanomedicines

Regulatory factors of Nrf2 in age-related macular degeneration pathogenesis

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International Journal of Ophthalmology(English edition) 2024年第7期17卷 1344-1362页

作者： Zi-Ling Hu Yu-Xuan Wang Zi-Yue Lin Wen-Shuo Ren Bo Liu Hui Zhao Qiong Qin Five Year program of Ophthalmology and Optometry 2019 Beijing Tong Ren HospitalCapital Medical UniversityBeijing 100054China Four Year program of Traditional Chinese pharmacy 2020 School of Traditional Chinese MedicineCapital Medical UniversityBeijing 100069China School of Traditional Chinese Medicine Capital Medical UniversityBeijing 100069China Beijing Key Laboratory of TCM Collateral Disease Theory Research Beijing 100069China Five Year program of Ophthalmology and Optometry 2021 School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China Biochemistry&Molecular Biology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China

Age-related macular degeneration(AMD)is a complicated disease that causes irreversible visual *** evidences pointed retinal pigment epithelia(RPE)cells as the decisive cell involved in the progress of AMD,and the function of anti-oxidant capacity of PRE plays a fundamental physiological *** factor erythroid 2 related factor 2(Nrf2)is a significant transcription factor in the cellular anti-oxidant system as it regulates the expression of multiple anti-oxidative *** functions of protecting RPE cells against oxidative stress(OS)and ensuing physiological changes,including inflammation,mitochondrial damage and autophagy dysregulation,have already been *** the roles of upstream regulators of Nrf2 could provide further insight to the OS-mediated AMD *** the first time,this review summarized the reported upstream regulators of Nrf2 in AMD pathogenesis,including proteins and miRNAs,and their underlying molecular mechanisms,which may help to find potential targets via regulating the Nrf2 pathway in the future research and further discuss the existing Nrf2 regulators proved to be beneficial in preventing AMD.

关键词： Nrf2 upstream regulators retinal pigment epithelia age-related macular degeneration oxidative stress

Dysregulation of RNA modification systems in clinical populations with neurocognitive disorders

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Neural Regeneration Research 2024年第6期19卷 1256-1261页

作者： Helen M.Knight Merve Demirbugen ?z Adriana PerezGrovas-Saltijeral Division of Cells Organisms and Molecular Genetics School of Life Sciences University of Notingham Department of Pharmaceutical Toxicology Faculty of Pharmacy Ankara University

The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms. Methylation of N6 adenosine(m6A) and C5 cytosine(m5C) bases occur on mRNAs, tRNA, mt-tRNA, and rRNA species as well as non-coding RNAs. With emerging knowledge of RNA binding proteins that act as writer, reader, and eraser effector proteins, comes a new understanding of physiological processes controlled by these systems. Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain, give rise to different forms of disease. In this review, we discuss accumulating evidence that changes in the m6A and m5C methylation systems contribute to neurocognitive disorders. Early studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m6A RNA reader protein. Subsequently, familial mutations within the m6A writer gene METTL5, m5C writer genes NSUN2, NSUN3, NSUN5, and NSUN6, as well as THOC2 and THOC6 that form a protein complex with the m5C reader protein ALYREF, were recognized to cause intellectual development disorders. Similarly, differences in expression of the m5C writer and reader effector proteins, NSUN6, NSUN7, and ALYREF in brain tissue are indicated in individuals with Alzheimer’s disease, individuals with a high neuropathological load or have suffered traumatic brain injury. Likewise, an abundance of m6A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases, Alzheimer’s disease, and individuals with high cognitive reserve. m6A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson’s disease tissue, whilst modified RNAs are misplaced within diseased cells, particularly where synapses are located. In parahippocampal brain tissue, m6A modification is en

关键词： 5-methylcytosine methylation Alzheimer's disease cognitive diseases epitranscriptomics intellectual disability Lewy body diseases N6 adenosine RNA modification

Metformin:A promising clinical therapeutical approach for BPH treatment via inhibiting dysregulated steroid hormones-induced prostatic epithelial cells proliferation

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Journal of Pharmaceutical Analysis 2024年第1期14卷 52-68页

作者： Tingting Yang Jiayu Yuan Yuting Peng Jiale Pang Zhen Qiu Shangxiu Chen Yuhan Huang Zhenzhou Jiang Yilin Fan Junjie Liu Tao Wang Xueyan Zhou Sitong Qian Jinfang Song Yi Xu Qian Lu Xiaoxing Yin Jiangsu Key Laboratory of New Drug Research and Clinical pharmacy Xuzhou Medical UniversityXuzhouJiangsu221004China Department of pharmacy Affiliated Lianyungang Hospital of Xuzhou Medical UniversityLianyungangJiangsu222061China Department of pharmacy The Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsu221006China New Drug Screening Center Jiangsu Center for Pharmacodynamics Research and EvaluationChina Pharmaceutical UniversityNanjing210009China School of Life Sciences University of EssexEssex CO43SQUnited Kingdom Department of Urology The Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsu221006China Department of pharmacy Affiliated Hospital of Jiangnan UniversityWuxiJiangsu214000China

The occurrence of benign prostate hyperplasia(BPH)was related to disrupted sex steroid hormones,and metformin(Met)had a clinical response to sex steroid hormone-related gynaecological ***,whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains ***,our clinical study showed that along with prostatic epithelial cell(PEC)proliferation,sex steroid hormones were dysregulated in the serum and prostate of BPH *** the major contributor to dysregulated sex steroid hormones,elevated dihydrotestosterone(DHT)had a significant positive relationship with the clinical characteristics of BPH *** of adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor(AR)-mediated Yes-associated protein(YAP1)-TEA domain transcription factor(TEAD4)***’s anti-proliferative effects were blocked by AMPK inhibitor or YAP1 overexpression in DHT-cultured BPH-1 *** findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

关键词： Metformin Benign prostatic hyperplasia Sex steroid hormones homeostasis Proliferation DHT YAP1-TEAD4 heterodimer