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Inhalable metal–organic framework-mediated cuproptosis combined with PD-L1 checkpoint blockade for lung metastasis synergistic immunotherapy

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2281-2297页

作者： Chongzheng Yan Ying Liu Guozhi Zhao Huatian Yang Huaiyou Lv Genju Li Yuhan Li Yaqing Fu Fengqin Sun Yafei Feng Yizhe Li Zhongxi Zhao Department of Pharmaceutics Key Laboratory of Chemical Biology of Ministry of EducationSchool of Pharmaceutical SciencesCheelloo College of MedicineShandong UniversityJinan 250012China Key University Laboratory of Pharmaceutics&Drug Delivery Systems of Shandong Province School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Cuproptosis shows enormous application prospects in lung metastasis treatment.However,the glycolysis,Cu^(+)efflux mechanisms,and insufficient lung drug accumulation severely restrict cuproptosis efficacy.Herein,an inhalable poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate)(OPDEA)-coated copper-based metal–organic framework encapsulating pyruvate dehydrogenase kinase 1 siRNA(siPDK)is constructed for mediating cuproptosis and subsequently promoting lung metastasis immunotherapy,namely OMP.After inhalation,OMP shows highly efficient lung accumulation and long-term retention,ascribing to the OPDEA-mediated pulmonary mucosa penetration.Within tumor cells,OMP is degraded to release Cu2+under acidic condition,which will be reduced to toxic Cu^(+)to induce cuproptosis under glutathione(GSH)regulation.Meanwhile,siPDK released from OMP inhibits intracellular glycolysis and adenosine-5ʹ-triphosphate(ATP)production,then blocking the Cu^(+)efflux protein ATP7B,thereby rendering tumor cells more sensitive to OMP-mediated cuproptosis.Moreover,OMP-mediated cuproptosis triggers immunogenic cell death(ICD)to promote dendritic cells(DCs)maturation and CD8^(+)T cells infiltration.Notably,OMP-induced cuproptosis up-regulates membrane-associated programmed cell death-ligand 1(PD-L1)expression and induces soluble PD-L1 secretion,and thus synergizes with anti-PD-L1 antibodies(aPD-L1)to reprogram immunosuppressive tumor microenvironment,finally yielding improved immunotherapy efficacy.Overall,OMP may serve as an efficient inhalable nanoplatform and afford preferable efficacy against lung metastasis through inducing cuproptosis and combining with aPD-L1.

关键词： Cuproptosis Immunogenic cell death PD-L1 checkpoint blockade Copper-based metal-organic framework Immunotherapy Tumor microenvironment Transmucosal deliveryLung metastasis

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An efficient approach for the treatment of radioactive waste perfluoropolyether lubricants via a synergistic effect of thermal catalysis and immobilization

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Journal of Environmental sciences 2024年第2期136卷 512-522页

作者： Xinhang Du Wenhua Tong Xinyu Zhou Jia Luo Yuqiu Liu Yabo Wang Panyu Li Yongkui Zhang Department of pharmaceutical&Biological Engineering School of Chemical EngineeringSichuan UniversityChengdu 610065China

Perfluoropolyether(PFPE)lubricants are a kind of high-molecular polymer with many excellent properties.However,the use of PFPEs in the nuclear industry can lead to partial decomposition and carrying radionuclides,resulting in a large amount of radioactive waste PFPE lubricants annually.Moreover,radioactive waste PFPE lubricants are difficult to be effectively treated due to their high stability,the risk of possible leakage of radionuclides,and hypertoxic fluorine-containing by-products.In this study,without any precedent,a strategy of Mn O_(2)-catalyzed decomposition and Na_(2)CO_(3)-immobilized conversion was proposed for PFPE lubricant decomposition and fluorine immobilization simultaneously based on the Lewis acid-base and oxygen vacancies concept.A high fluorine conversion efficiency of 95.4%was achieved.Meanwhile,the mechanism of decomposition suggested that Mn O_(2)mainly provided Lewis acid sites and attacked the(basic)fluorine or oxygen atoms in PFPE molecules.The decomposition of PFPE chains was proceed down and volatile fluorine-containing gas was released by partial electron transfer,intramolecular disproportionation reaction,and unzipping fashion.Subsequently,gas by-products could be further oxidized and then immobilized into fluoride salts by carbonate solid absorbents.Overall,this study provides a simple,safe,and potentially practical strategy for the harmless conversion of refractory fluorinated organic wastes,especially perfluoropolymers.

关键词： Perfluoropolyether lubricants Catalyzed decomposition Fluorine-containing gas Immobilized conversion Fluoride

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Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 667-681页

作者： Yue Zhang Jingwen Gao Na Li Peng Xu Shimeng Qu Jinqian Cheng Mingrui Wang Xueru Li Yaheng Song Fan Xiao Xinyu Yang Jihong Liu Hao Hong Ronghao Mu Xiaotian Li Youmei Wang Hui Xu Yuan Xie Tianming Gao Guangji Wang Jiye Aa Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics State Key Laboratory of Natural MedicinesResearch Unit of PK-PD Based Bioactive Components and Pharmacodynamic Target Discovery of Natural Medicine of Chinese Academy of Medical SciencesChina Pharmaceutical UniversityNanjing 210009China Key Laboratory of Drug Monitoring and Control Drug Intelligence and Forensic CenterMinistry of Public SecurityBeijing 100193China school of Pharmacy China Pharmaceutical UniversityNanjing 211198China school of Foreign Languages China Pharmaceutical UniversityNanjing 211198China Department of Neurobiology School of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China Department of Pharmacology China Pharmaceutical UniversityNanjing 211198China school of pharmaceutical sciences Zhengzhou UniversityZhengzhou 450001China

Studies have suggested that the nucleus accumbens(NAc)is implicated in the pathophysiology of major depression;however,the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated.Here,we identified a specific reduction of cyclic adenosine monophosphate(cAMP)in the subset of dopamine D1 receptor medium spiny neurons(D1-MSNs)in the NAc that promoted stress susceptibility,while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors.Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons(D2-MSNs)of depressed mice,however,the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs.We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration,but not a lower dose.The fast onset property of crocin was verified through multicenter studies.Moreover,crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN.These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc,and provide a potential rapid antidepressant drug candidate,crocin.

关键词： CAMP Nucleus accumbens Depression D1-MSN D2-MSN

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Understanding the Novel Approach of Nanoferroptosis for Cancer Therapy

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Nano-Micro Letters 2024年第9期16卷 501-556页

作者： Afsana Sheikh Prashant Kesharwani Waleed H.Almalki Salem Salman Almujri Linxin Dai Zhe‑Sheng Chen Amirhossein Sahebkar Fei Gao Department of Pharmaceutics School of Pharmaceutical Education and ResearchJamia HamdardNew Delhi 110062India Department of Pharmacology and Toxicology Faculty of PharmacyUmm Al-Qura UniversityMakkahSaudi Arabia Department of Pharmacology College of PharmacyKing Khalid University61421 Asir‑AbhaSaudi Arabia State Key Laboratory of Southwestern Chinese Medicine Resources Pharmacy SchoolChengdu University of Traditional Chinese MedicineChengdu 611130People’s Republic of China Department of pharmaceutical sciences College of Pharmacy and Health SciencesSt.John’s UniversityNew York 11439USA Biotechnology Research Center Pharmaceutical Technology InstituteMashhad University of Medical SciencesMashhadIran Applied Biomedical Research Center Mashhad University of Medical SciencesMashhadIran

As a new form of regulated cell death,ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer cells.The molecular mechanism of ferroptosis depends on the induction of oxidative stress through excessive reactive oxygen species accumulation and glutathione depletion to damage the structural integrity of cells.Due to their high loading and structural tunability,nanocarriers can escort the delivery of ferro-therapeutics to the desired site through enhanced permeation or retention effect or by active targeting.This review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and metastasis.Additionally,we discussed the effect of ferroptosis-mediated therapy using nanoplatforms and their chemical basis in overcoming the barriers to cancer therapy.

关键词： Ferroptosis Nanoparticles Ferrotherapy Cancer Genes Nanotechnology Toxicity Reactive oxygen species

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Combatting Pathogenic Bacteria with Synthetic Immunotherapeutics from Chitosan:Antibody Recruiting at Engineered Bacterial Surface with Peptidoglycan Analogs

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CCS Chemistry 2024年第6期6卷 1448-1457页

作者： Yuan Xu Shihao Song Hongwei Duan Yinyue Deng Xue-Wei Liu school of Chemistry Chemical Engineering and BiotechnologyNanyang Technological UniversitySingapore 637371 Key Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical SciencesHainan UniversityHaikou 570228 school of pharmaceutical sciences(Shenzhen) Shenzhen Campus of Sun Yat-sen UniversitySun Yat-sen UniversityShenzhen 518107

The emergence of microbial drug resistance,coupled with the paucity of new antibiotics poses an impending threat to public health.In this work,we drew inspiration from synthetic peptidoglycan oligomers and successfully constructed antibody-recruiting peptidoglycan analogs,2a-d,with excellent safety profiles and high efficiencies in recruiting antibodies across different conditions.Further,we demonstrated that these peptidoglycan analogs could be readily incorporated into bacteria cell walls,whereby both simple monoclonal and pooled human serum antibodies effectively congregated to the surfaceengineered bacteria,leading to the complete extermination of the engineered bacterial cells both in vitro and in vivo.Our peptidoglycan analog agents for recruiting endogenous antibodies to combat pathogenic bacteria enable further development of promising broad-spectrum immunotherapeutics.

关键词： chitosan bacterial infection endogenous antibodies bacterial surface engineering peptidoglycan analogs

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Progress in experimental models to investigate the in vivo and in vitro antidiabetic activity of drugs

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Animal Models and Experimental Medicine 2024年第3期7卷 297-309页

作者： Yasodha Krishna Janapati Sunil Junapudi school of Pharmacy&Health sciences United States International University-AFRICA(USIU-A)NairobiKenya Department of pharmaceutical Chemistry Geethanjali College of PharmacyKeesaraIndia

Diabetes mellitus is one of the world's most prevalent and complex metabolic disorders,and it is a rapidly growing global public health issue.It is characterized by hyperglycemia,a condition involving a high blood glucose level brought on by deficiencies in insulin secretion,decreased activity of insulin,or both.Prolonged effects of diabetes include cardiovascular problems,retinopathy,neuropathy,nephropathy,and vascular alterations in both macro-and micro-blood vessels.In vivo and in vitro models have always been important for investigating and characterizing disease pathogenesis,identifying targets,and reviewing novel treatment options and medications.Fully understanding these models is crucial for the researchers so this review summarizes the different experimental in vivo and in vitro model options used to study diabetes and its consequences.The most popular in vivo studies involves the small animal models,such as rodent models,chemically induced diabetogens like streptozotocin and alloxan,and the possibility of deleting or overexpressing a specific gene by knockout and transgenic technologies on these animals.Other models include virally induced models,diet/nutrition induced diabetic animals,surgically induced models or pancreatectomy models,and non-obese models.Large animals or non-rodent models like porcine(pig),canine(dog),nonhuman primate,and Zebrafish models are also outlined.The in vitro models discussed are murine and human beta-cell lines and pancreatic islets,human stem cells,and organoid cultures.The other enzymatic in vitro tests to assess diabetes include assay of amylase inhibition and inhibition ofα-glucosidase activity.

关键词： animal models diabetes mellitus typeⅠ diabetes mellitus typeⅡ in vitro and in vivo models

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Genetic analysis of transcription factors in dopaminergic neuronal development in Parkinson’s disease

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Chinese Medical Journal 2024年第4期137卷 450-456页

作者： Yuwen Zhao Lixia Qin Hongxu Pan Tingwei Song Yige Wang Xiaoxia Zhou Yaqin Xiang Jinchen Li Zhenhua Liu Qiying Sun Jifeng Guo Xinxiang Yan Beisha Tang Qian Xu Department of Neurology Xiangya HospitalCentral South UniversityChangshaHunan 410008China Department of Neurology The Second Xiangya HospitalCentral South UniversityChangshaHunan 410011China Bioinformatics Center National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan 410008China Department of Geriatrics Xiangya HospitalCentral South UniversityChangshaHunan 410008China Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics School of Life SciencesCentral South UniversityChangshaHunan 410008China Key Laboratory of Hunan Province in Neurodegenerative Disorders Central South UniversityChangshaHunan 410008China

Background:Genetic variants of dopaminergic transcription factor-encoding genes are suggested to be Parkinson’s disease(PD)risk factors;however,no comprehensive analyses of these genes in patients with PD have been undertaken.Therefore,we aimed to genetically analyze 16 dopaminergic transcription factor genes in Chinese patients with PD.Methods:Whole-exome sequencing(WES)was performed using a Chinese cohort comprising 1917 unrelated patients with familial or sporadic early-onset PD and 1652 controls.Additionally,whole-genome sequencing(WGS)was performed using another Chinese cohort comprising 1962 unrelated patients with sporadic late-onset PD and 1279 controls.Results:We detected 308 rare and 208 rare protein-altering variants in the WES and WGS cohorts,respectively.Gene-based association analyses of rare variants suggested that MSX1 is enriched in sporadic late-onset PD.However,the significance did not pass the Bonferroni correction.Meanwhile,72 and 1730 common variants were found in the WES and WGS cohorts,respectively.Unfortunately,single-variant logistic association analyses did not identify significant associations between common variants and PD.Conclusions:Variants of 16 typical dopaminergic transcription factors might not be major genetic risk factors for PD in Chinese patients.However,we highlight the complexity of PD and the need for extensive research elucidating its etiology.

关键词： Parkinson’s disease Transcription factors Dopaminergic neurons Genetic Variants

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PCDH17 restricts dendritic spine morphogenesis by regulating ROCK2-dependent control of the actin cytoskeleton,modulating emotional behavior

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Zoological Research 2024年第3期45卷 535-550页

作者： Laidong Yu Fangfang Zeng Mengshu Fan Kexuan Zhang Jingjing Duan Yalu Tan Panlin Liao Jin Wen Chenyu Wang Meilin Wang Jialong Yuan Xinxin Pang Yan Huang Yangzhou Zhang Jia-Da Li Zhuohua Zhang Zhonghua Hu Hunan Key Laboratory of Molecular Precision Medicine Department of Critical Care MedicineXiangya HospitalCentral South UniversityChangshaHunan 410008China Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics School of Life SciencesCentral South UniversityChangshaHunan 410008China National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangshaHunan 410008China Hunan Provincial Clinical Research Center for Critical Care Medicine Xiangya HospitalCentral South UniversityChangshaHunan 410008China Hunan Key Laboratory of Animal Models for Human Diseases School of Life SciencesCentral South UniversityChangshaHunan 410008China MOE Key Lab of Rare Pediatric Diseases School of Life SciencesCentral South UniversityChangshaHunan 410008China Department of Neurosciences University of South China Medical SchoolHengyangHunan 421001China

Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function.Synaptic abnormalities,such as defects in the density and morphology of postsynaptic dendritic spines,underlie the pathology of various neuropsychiatric disorders.Protocadherin 17(PCDH17)is associated with major mood disorders,including bipolar disorder and depression.However,the molecular mechanisms by which PCDH17 regulates spine number,morphology,and behavior remain elusive.In this study,we found that PCDH17 functions at postsynaptic sites,restricting the number and size of dendritic spines in excitatory neurons.Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety-and depression-like behaviors in mice.Mechanistically,PCDH17 interacts with actin-relevant proteins and regulates actin filament(F-actin)organization.Specifically,PCDH17 binds to ROCK2,increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3(Ser3).Inhibition of ROCK2 activity with belumosudil(KD025)ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression,suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development.Hence,these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior,providing pathological insights into the neurobiological basis of mood disorders.

关键词： Synapse development Dendritic spine Mood disorder Actin cytoskeleton Animal behavior

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Identification of depressive symptoms: A cause-and-effect based machine learning study

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中华医学杂志(英文版) 2024年第10期137卷 1258-1260页

作者： Wang Tiantian Zhang Zijian Zhang Xilin Xue Chuang Cheng Tingting Department of Radiation Oncology Xiangya Hospital Central South University Changsha Hunan China National Clinical Research Center for Geriatric Disorders Xiangya Hospital Changsha Hunan China school of Science Hunan University of Technology and Business Changsha Hunan China school of Mathematical sciences University of Science and Technology of China Hefei Anhui China Department of Physiotherapy Treatment Center Affiliated Mental Health Center &amp Hangzhou Seventh People’s Hospital Zhejiang University School of Medicine Hangzhou Zhejiang China Department of General Practice Xiangya Hospital Central South University Changsha Hunan China

As society continues to advance, individuals are increasingly exposed to various stressors in their personal and professional lives. The World Health Organization claims that nearly 1 billion people worldwide suffer from mental disorders in 2019, including 14 %of the world's adolescents.[1] Depression among Chinese adults is a serious public health challenge that requires urgent attention. Due to the combined influence of various life stresses and unhealthy lifestyles, individuals face a significantly increased risk of developing depression.[2] Depression is often misdiagnosed because its symptoms overlap with those of other mental health conditions. A misdiagnosis of depression can have a significant impact on all aspects of an individual's life. In children, a misdiagnosis can lead to inappropriate academic interventions or unnecessary treatments that can adversely affect their school life and overall well-being. For adults, a misdiagnosis can strain relationships, undermine productivity, and lead to longterm emotional distress due to ineffective treatment.

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Role of adhesion molecules in cancer and targeted therapy

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Science China(Life sciences) 2024年第5期67卷 940-957页

作者： Chunmei Fan Fang Xiong Shanshan Zhang Zhaojian Gong Qianjin Liao Guiyuan Li Can Guo Wei Xiong He Huang Zhaoyang Zeng NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangsha 410000China Department of Histology and Embryology Xiangya School of MedicineCentral South UniversityChangsha410013China Department of Stomatology Xiangya HospitalCentral South UniversityChangsha 410078China Department of Oral and Maxillofacial Surgery The Second Xiangya HospitalCentral South UniversityChangsha 410011China Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education Cancer Research InstituteCentral South UniversityChangsha 410078China

Adhesion molecules mediate cell-to-cell and cell-to-extracellular matrix interactions and transmit mechanical and chemical signals among them.Various mechanisms deregulate adhesion molecules in cancer,enabling tumor cells to proliferate without restraint,invade through tissue boundaries,escape from immune surveillance,and survive in the tumor microenvironment.Recent studies have revealed that adhesion molecules also drive angiogenesis,reshape metabolism,and are involved in stem cell self-renewal.In this review,we summarize the functions and mechanisms of adhesion molecules in cancer and the tumor microenvironment,as well as the therapeutic strategies targeting adhesion molecules.These studies have implications for furthering our understanding of adhesion molecules in cancer and providing a paradigm for exploring novel therapeutic approaches.

关键词： adhesion molecules tumor microenvironment invasion and metastasis reshaping metabolism angiogenesis immune evasion tumor stemness therapeutic strategy

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