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Cellular interplay to 3D in vitro microphysiological disease model:cell patterning microbiota-gut-brain axis

Bio-Design and Manufacturing 2024年第3期7卷 320-357页

作者： Kamare Alam Lakshmi Nair Souvik Mukherjee Kulwinder Kaur Manjari Singh Santanu Kaity Velayutham Ravichandiran Sugato Banerjee Subhadeep Roy department of pharmacology and Toxicology National Institute of Pharmaceutical Education and ResearchKolkataWest Bengal 700054India department of pharmaceutical sciences Assam UniversitySilchar 788011India department of pharmaceutical sciences Guru Ghasidas UniversityKoniBilaspur 495009C.G.India school of Pharmacy and Biomolecular sciences RCSI University of Medicine and Health SciencesDublin D02 YN77Ireland Tissue Engineering Research Group Department of Anatomy and Regenerative MedicineRCSI University of Medicine and Health SciencesDublin D02 YN77Ireland department of Pharmaceutics National Institute of Pharmaceutical Education and ResearchKolkataWest Bengal 700054India department of Natural Products National Institute of Pharmaceutical Education and ResearchKolkataWest Bengal 700054India

The microbiota-gut-brain axis(MGBA)has emerged as a key prospect in the bidirectional communication between two major organ systems:the brain and the *** between the two organ systems allows the body to function without disease,whereas dysbiosis has long-standing evidence of etiopathological *** most common communication paths are the microbial release of metabolites,soluble neurotransmitters,and immune ***,each pathway is intertwined with a complex *** the emergence of in vitro models and the popularity of three-dimensional(3D)cultures and Transwells,engineering has become easier for the scientific understanding of neurodegenerative *** paper briefly retraces the possible communication pathways between the gut microbiome and the *** further elaborates on three major diseases:autism spectrum disorder,Parkinson’s disease,and Alzheimer’s disease,which are prevalent in children and the *** diseases also decrease patients’quality of ***,understanding them more deeply with respect to current advances in in vitro modeling is crucial for understanding the *** of MGBA in the laboratory uses many molecular technologies and biomaterial *** and organoids provide a more realistic picture of the cell and tissue structure than *** them with the Transwell system offers the advantage of compartmentalizing the two systems(apical and basal)while allowing physical and chemical cues between ***-edge technologies,such as bioprinting and microfluidic chips,might be the future of in vitro modeling,as they provide dynamicity.

关键词： Microbiota-gut-brain axis Neurodegeneration 3D disease model Organoid Transwell system

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A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT

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Chinese Journal of Natural Medicines 2024年第2期22卷 112-126页

作者： REN Boxue LI Yang DI Lei CHENG Ranran LIU Lijuan LI Hongmei LI Yi TANG Zhangrui YAN Yongming LU Tao FU Rong CHENG Yongxian WU Zhaoqiu State Key Laboratory of Natural Medicines Department of PharmacologySchool of PharmacyChina Pharmaceutical UniversityNanjing 211198China Institute for Inheritance-Based Innovation of Chinese Medicine School of Pharmaceutical SciencesShenzhen University Health Science CenterShenzhen 518060China

The tumor suppressor protein p53 is central to cancer biology,with its pathway reactivation emerging as a promising therapeutic strategy in *** study introduced LZ22,a novel compound that selectively inhibits the growth,migration,and metastasis of tumor cells expressing wild-type p53,demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant ***22’s mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 *** interaction disrupted the MDM2-p53 binding,consequently stabilizing p53 by shielding it from proteasomal ***22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling ***,LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT,effectively reducing tumor cell migration and distal ***,LZ22 administration in tumor-bearing mice did not manifest notable side *** findings position LZ22 as a structurally unique reactivator of p53,offering therapeutic promise for the management of human cancers with wild-type TP53.

关键词： LZ22 Wild-type p53 p53 Reactivator Snail-driven EMT Tumor growth and metastasis

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Antitumor effects of a novel photosensitizer-mediated photodynamic therapy and its influence on the cell transcriptome

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Oncology Research 2024年第5期32卷 911-923页

作者： JINGJING CHEN DAN WANG ZEQUN WANG MENGYUAN HAN HOUQING YIN WENTING ZHOU RIBAI YAN YAN PAN department of pharmacology School of PharmacyChangzhi Medical CollegeChangzhiChina2 Department of PharmacologySchool of Basic Medical SciencesHealth Science CenterPeking UniversityBeijingChina3 Beijing Key Laboratory of Tumor Systems BiologyPeking UniversityBeijingChina4 Department of PharmacologyXinjiang Medical UniversityUrumqiChina5 School of Pharmaceutical SciencesPeking UniversityBeijingChina

Photodynamic therapy(PDT)is a promising cancer *** study investigated the antitumor effects and mechanisms of a novel photosensitizer meso-5-[ρ-diethylene triamine pentaacetic acid-aminophenyl]−10,15,20-triphenyl-porphyrin(DTP)mediated PDT(DTP-PDT).Cell viability,reactive oxygen species(ROS),and apoptosis were measured with a Cell Counting Kit-8 assay,DCFH-DA fluorescent probe,and Hoechst staining,*** apoptosis-and autophagy-related proteins were examined using western *** sequencing was used to screen differentially expressed mRNAs(DERs),and bioinformatic analysis was performed to identify the major biological events after *** results show that DTP-PDT inhibited cell growth and induced ROS generation in MCF-7 and SGC7901 *** ROS scavenger N-acetyl-L-cysteine(NAC)and the P38 MAPK inhibitor SB203580 alleviated DTP-PDT-induced ***-PDT induced cell apoptosis together with upregulated Bax and downregulated Bcl-2,which could also be inhibited by NAC or *** level of LC3B-Ⅱ,a marker of autophagy,was increased by DTP-PDT.A total of 3496 DERs were obtained after *** Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that DERs included those involved in cytosolic ribosomes,the nuclear lumen,protein binding,cell cycle,protein targeting to the endoplasmic reticulum,and ribosomal DNA *** Ontology and Reactome enrichment analyses indicated that DERs were associated with a variety of cancers and cell cycle ***-protein interaction results demonstrated that cdk1 and rps27a ranked in the top 10 interacting ***,DTP-PDT could inhibit cell growth and induce cell apoptosis and autophagy,partly through ROS and the P38 MAPK signaling *** associated with the cell cycle,ribosomes,DNA replication,and protein binding may be the key changes in DTP-PDT-mediated cytotoxicity.

关键词： Photodynamic therapy ROS Apoptosis Autophagy Bioinformatic analysis

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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 *** 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 *** 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 *** review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and ***,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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mIgM-mediated splenic marginal zone B cells targeting of folic acid for immunological evasion

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Acta Pharmaceutica Sinica B 2024年第2期14卷 808-820页

作者： Huan Wang Zhuxuan Jiang Zhiwei Guo Gan Luo Tianhao Ding Changyou Zhan department of pharmacology School of Basic Medical Sciences&Department of PharmacyShanghai Pudong HospitalFudan UniversityShanghai 200032China department of pharmaceutical sciences School of PharmacyNaval Medical UniversityShanghai 200433China Shanghai Engineering Research Center for Synthetic Immunology Fudan UniversityShanghai 200032China

Folic acid is a fully oxidized synthetic folate with high bioavailability and stability which has been extensively prescribed to prevent congenital *** we revealed the immunosuppressive effect of folic acid by targeting splenic marginal zone B(MZB)*** acid demonstrates avid binding with the Fc domain of immunoglobulin M(IgM),targeting IgM positive MZB cells in vivo to destabilize IgM-B cell receptor(BCR)complex and block immune *** induced anergy of MZB cells by folic acid provides an immunological escaping window for *** conjugation of folic acid with therapeutic proteins and antibodies induces immunological evasion to mitigate the production of anti-drug antibodies,which is a major obstacle to the long-term treatment of biologics by reducing curative effects and/or causing adverse *** acid acts as a safe and effective immunosuppressant via IgM-mediated MZB cells targeting to boost the clinical outcomes of biologics by inhibiting the production of anti-drug antibodies,and also holds the potential to treat other indications that adverse immune responses need to be transiently shut off.

关键词： Membrane-bound IgM Anti-drugantibodies Bcell anergy Folic acid Marginal zoneBcells Bcell receptor Biologics Targeting

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Repurposing lansoprazole to alleviate metabolic syndrome via PHOSPHO1 inhibition

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1711-1725页

作者： Yingting Wu Jiaqi Xin Xinyu Li Ting Yang Yi Liu Yongsheng Zhao Wen Xie Mengxi Jiang department of pharmacology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China department of Traditional Chinese Medicine Capital Medical UniversityBeijing 100069China Center for Pharmacogenetics and department of pharmaceutical sciences University of PittsburghPittsburghPA 15261USA Advanced Innovation Center for Human Brain Protection Capital Medical UniversityBeijing 100069China

Drug repurposing offers an efficient approach to therapeutic *** this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gastrointestinal *** went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity,insulin resistance,and hepatic stea-tosis in *** with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes,and induced cold tolerance in cold-exposed mice,suggesting the activity of LPZ in promoting adipose thermogenesis and energy ***,LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1(PHOSPHOI)and produces metabolic benefits in a PHOS-PHO1-dependent *** results suggested that LPZ may stimulate adipose thermogenesis by inhi-biting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid(2-AG-LPA)to 2-arachidonoylglycerol(2-AG)and reduce the activity of the thermogenic-suppressive cannabinoid recep-tor *** summary,we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome,and identified a potential metabolic basis by which LPZ improves energy metabolism.

关键词： Lansoprazole Proton pump inhibitors Adipose thermogenesis Energy expenditure Metabolic syndrome PHOSPHO1 inhibitor Cannabinoid receptor signaling Drug repurposing

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Site-specific incorporation of reduction-controlled guest amino acids into proteins for cucurbituril recognition

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Chinese Chemical Letters 2024年第5期35卷 193-196页

作者： Zhen Dai Linzhi Tan Yeyu Su Kerui Zhao Yushun Tian Yu Liu Tao Liu College of Chemistry State Key Laboratory of Elemento-Organic ChemistryNankai UniversityTianjin 300071China State Key Laboratory of Natural and Biomimetic Drugs Department of Molecular and Cellular PharmacologySchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China

Protein recognition using host-guest recognition approach is of great interest but has been limited mainly to the protein N-terminal ***,we site-specific incorporated two novel non-canonical amino acids containing supramolecular guest motifs into protein via an expanded genetic *** Staudinger reduction reactions,the encoded unnatural residues on protein becoming activated and can be specifically recognized by cucurbit[7]uril(CB[7])and cucurbit[8]uril(CB[8]).We demonstrated that enzyme containing guest amino acid incorporated near the active site can be reversibly regulated by CB[7]recognition,and CB[8]recognition induces protein *** amino acids will make useful addition to the supramolecular toolbox for protein targeting using molecular recognition approaches.

关键词： Protein recognition Host-guest recognition Non-canonical amino acids Staudinger reduction Expanded genetic code

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Activation of glutamatergic neurons in the somatosensory cortex promotes remyelination in ischemic vascular dementia

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Fundamental Research 2024年第1期4卷 188-198页

作者： Yi-Ting Zhou Da-Dao An Yi-Xin Xu Ying Zhou Qing-Qing Li Hai-Bin Dai Xiang-Nan Zhang Yi Wang Min Lou Zhong Chen Wei-Wei Hu department of pharmacology and department of Pharmacy of the Second Affiliated Hospital NHC and CAMS Key Laboratory of Medical NeurobiologySchool of Basic Medical SciencesCollege of Pharmaceutical SciencesZhejiang University School of MedicineHangzhou 310058China department of Pharmacy Sir Run Run Shaw HospitalHangzhou 310012China Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province School of Pharmaceutical SciencesZhejiang Chinese Medical UniversityHangzhou 310053China department of Neurology the Second Affiliated Hospital of Zhejiang UniversitySchool of MedicineHangzhou 310003China

Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia,however no effective treatments are ***,based on magnetic resonance imaging studies of patients with white matter damage,we found that this damage is associated with disorganized cortical *** a mouse model,optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell(OPC)proliferation,remyelination in the corpus callosum,and recovery of cognitive ability after cerebral *** therapeutic effect of such stimulation was restricted to the upper layers of the cortex,but also spanned a wide time window after ***,enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic ***,skin stroking,an easier method to translate into clinical practice,activated the somatosensory cortex,thereby promoting OPC proliferation,remyelination and cognitive recovery following cerebral *** summary,we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral *** should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.

关键词： Chronic cerebral hypoperfusion Optogenetic stimulation Oligodendrocyte progenitor cellIschemic vascular dementia Glutamatergic neuron Remyelination

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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 ***,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 *** 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 *** 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 *** fast onset property of crocin was verified through multicenter ***,crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on *** 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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Targeting BCL9/BCL9L enhances antigen presentation by promoting conventional type 1 dendritic cell(cDC1)activation and tumor infiltration

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2804-2818页

作者： Fenglian He Zhongen Wu Chenglong Liu Yuanyuan Zhu Yan Zhou Enming Tian Rina Rosin-Arbesfeld Dehua Yang Ming-Wei Wang Di Zhu department of pharmacology Minhang Hospitaland Key Laboratory of Smart Drug DeliveryShanghai Engineering Research Center of Immune TherapySchool of PharmacyFudan UniversityShanghai 201203China The national Center for Drug Screening and the CAS Key Laboratory of Receptor Research Shanghai Institute of Materia MedicaChinese Academy of Sciences(CAS)Shanghai 201203China department of Microbiology and Immunology Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael department of pharmacology School of Basic Medical SciencesFudan UniversityShanghai 200032China Research Center for Deepsea Bioresources SanyaChina department of Chemistry School of ScienceThe University of TokyoTokyoJapan Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education School of PharmacyHainan Medical UniversityHaikouChina Shandong Academy of pharmaceutical Science JinanChina

Conventional type 1 dendritic cells(cDC1)are the essential antigen-presenting DC subset in antitumor *** B-cell lymphoma 9 and B-cell lymphoma 9-like(BCL9/BCL9L)inhibits tumor growth and boosts immune responses against ***,whether oncogenic BCL9/BCL9L impairs antigen presentation in tumors is still not completely ***,we show that targeting BCL9/BCL9L enhanced antigen presentation by stimulating cDC1 activation and infiltration into *** inhibition of BCL9/BCL9L with a novel inhibitor hsBCL9z96 or Bcl9/Bcl9l knockout mice markedly delayed tumor growth and promoted antitumor CD8^(+)T cell ***,targeting BCL9/BCL9L promoted antigen presentation in *** is due to the increase of cDC1 activation and tumor infiltration by the XCL1-XCR1 ***,using single-cell transcriptomics analysis,we found that Bcl9/Bcl9l deficient cDC1 were superior to wild-type(WT)cDC1 at activation and antigen presentation via NF-κB/IRF1 ***,we demonstrate that targeting BCL9/BCL9L plays a crucial role in cDC1-modulated antigen presentation of tumor-derived antigens,as well as CD8^(+)T cell activation and tumor *** BCL9/BCL9L to regulate cDC1 function and directly orchestrate a positive feedback loop necessary for optimal antitumor immunity could serve as a potential strategy to counter immune suppression and enhance cancer immunotherapy.

关键词： immunity Targeting markedly

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