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A pancreatic player in dementia:pathological role for islet amyloid polypeptide accumulation in the brain

Neural Regeneration Research 2023年第10期18卷 2141-2146页

作者： Angelina S.Bortoletto Ronald J.Parchem Center for cell and Gene Therapy Stem Cell and Regenerative Medicine CenterDepartment of NeuroscienceDepartment of Molecular and Cellular BiologyTranslational Biology and Molecular Medicine ProgramMedical Scientist Training ProgramBaylor College of MedicineHoustonTXUSA

Type 2 diabetes mellitus patients have a markedly higher risk of developing *** multiple factors contribute to this predisposition,one of these involves the increased secretion of amylin,or islet amyloid polypeptide,that accompanies the pathophysiology of type 2 diabetes *** amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia,including Alzheimer’s disease and vascular dementia,but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are *** this review,we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage,ultimately leading to the clinical symptoms of *** discuss the evidence for islet amyloid polypeptide deposition in the brain,islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration,neuroinflammation caused by islet amyloid polypeptide deposition,vascular damage induced by islet amyloid polypeptide accumulation,and islet amyloid polypeptide-induced *** are very few therapies approved for the treatment of dementia,and of these,clinical responses have been controversial at ***,investigating new,targetable pathways is vital for identifying novel therapeutic strategies for treating *** such,we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.

关键词： Alzheimer’s disease amylin amyloid dementia diabetes human islet amyloid polypeptide islet amyloid polypeptide protofibrils type 2 diabetes mellitus vascular dementia

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Unveiling blood pressure-associated genes in aortic cells through integrative analysis of GWAS and RNA modification-associated variants

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Chronic Diseases and Translational Medicine 2024年第2期10卷 118-129页

作者： Huan Zhang Yuxi Chen Peng Xu Dan Liu Naqiong Wu Laiyuan Wang Xingbo Mo Jiangsu Key laboratory of Preventive and Translational Medicine for Geriatric Diseases Department of EpidemiologySchool of Public HealthMedical College of Soochow UniversitySuzhouJiangsuChina Cardiometabolic Center Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Key laboratory of Cardiovascular Epidemiology&Department of Epidemiology State Key Laboratory of Cardiovascular DiseaseFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina MOE Key laboratory of Geriatric Diseases and Immunology School of Public HealthCenter for Genetic Epidemiology and GenomicsMedical College of Soochow UniversitySuzhouJiangsuChina

Background Genome-wide association studies(GWAS)have identified more than a thousand loci for blood pressure(BP).Functional genes in these loci are cell-type *** aim of this study was to elucidate potentially functional genes associated with BP in the aorta through the utilization of RNA modification-associated single-nucleotide polymorphisms(RNAm-SNPs).Methods Utilizing large-scale genetic data of 757,601 individuals from the UK Biobank and International Consortium of Blood Pressure consortium,we identified associations between RNAm-SNPs and *** association between RNAm-SNPs,gene expression,and BP were *** A total of 355 RNAm-SNPs related to m6A,m1A,m5C,m7G,and A-to-I modification were associated with *** related genes were enriched in the pancreatic secretion pathway and renin secretion *** BP GWAS signals were significantly enriched with m6A-SNPs,highlighting the potential functional relevance of m6A in physiological processes influencing ***,m6A-SNPs in CYP11B1,PDE3B,HDAC7,ACE,SLC4A7,PDE1A,FRK,MTHFR,NPPA,CACNA1D,and HDAC9 were *** methylation and differential expression of the BP genes in FTO-overexpression and METTL14-knockdown vascular smooth muscle cells were ***-SNPs were associated with ascending and descending aorta diameter and the genes showed differential methylation between aortic dissection(AD)cases and *** scRNA-seq study,we identified ARID5A,HLA-DPB1,HLA-DRA,IRF1,LINC01091,MCL1,MLF1,MLXIPL,NAA16,NADK,RERG,SRM,and USP53 as differential expression genes for AD in aortic *** The present study identified RNAm-SNPs in BP loci and elucidated the associations between the RNAm-SNPs,gene expression,and *** identified BP-associated genes in aortic cells were associated with AD.

关键词： aortic dissection blood pressure genome-wide association study RNA modification single-cell

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STING signaling in islet macrophages impairs insulin secretion in obesity

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Science China(Life Sciences) 2024年第2期67卷 345-359页

作者： Ze Hong Saihua Chen Jing Sun Dan Cheng Hanli Guo Jiahao Mei Xiang Zhang Munire Maimaiti Haiping Hao Peng Cao Haiyang Hu Chen Wang School of Pharmacy Nanjing University of Chinese MedicineNanjing 210023China State Key laboratory of Natural Medicines Department of Life Science and TechnologyChina Pharmaceutical UniversityNanjing 211198China School of Life Sciences Westlake UniversityHangzhou 310012China

The innate immune regulator stimulator of interferon genes(STING)mediates self-DNA sensing and leads to the induction of type I interferons and inflammatory cytokines,which promotes the progression of various inflammatory and autoimmune *** immune system plays a critical role in regulating obesity-induced islet dysfunction,whereas the potential effect of STING signaling is not fully ***,we demonstrate that STING is mainly expressed and activated in islet macrophages upon high-fat diet(HFD)***^(-/-)alleviates HFD-induced islet inflammation by inhibiting the expression of pro-inflammatory cytokines and the infiltration of ***,palmitic acid incubation promotes mitochondrial DNA leakage into the cytosol and subsequently activates STING pathway in ***,STING activation in macrophages impairs glucose-stimulated insulin secretion by mediating the engulfment ofβcell insulin secretory *** inhibiting STING activation enhances insulin secretion to control ***,our results reveal a regulatory mechanism in controlling the islet inflammation and insulin secretion in dietinduced obesity and suggest that selective blocking of the STING activation may be a promising strategy for treating type 2 diabetes.

关键词： STING obesity type 2 diabetes insulin macrophages islet

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The short and long-term effect of polystyrene nanoplastics on nitrifying sludge at high nitrite concentrations

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Journal of Environmental Sciences 2024年第1期135卷 222-231页

作者： Xiaolong Wang Jialu Huang Zhiqiang Qi Ruiqin Kang Chao Du Da Li School of Chemical and Environmental Engineering Anyang Institute of TechnologyAnyang 455000China Henan Licheng Environmental Technology Co. Ltd.Anyang 455000China State Key laboratory of Urban Water Resource and Environment School of EnvironmentHarbin Institute of TechnologyHarbin 150090China

The effect of nanoplastics(NPs)on nitrite oxidation bacteria(NOB)community in treating high-strength wastewater remains unclear,which seriously affects the stability of nitrogen removal *** this study,highly active nitrifying sludge was enriched and exposed to 50nm polystyrene NPs(PS-NPs)for short-term(1,100,500,and 1000 mg/L,1.5 hr)and long-term(1,10,100 mg/L,40 days)at high nitrite *** contrast to previous studies,our results showed that the exposures to PS-NPs had little effect on nitrifying *** long-term exposure,the protein/polysaccharide ratios in extracellular polymeric substances(EPS)were positively correlated with PS-NPs concentrations(0.78–0.99).The produced reactive oxygen species(ROS)were gradually removed,and PS-NPs higher than 10 mg/L caused damage to membrane ***-term exposure for 40 days increased the community diversity and caused significant differences between the control and exposed *** control group were dominated by Nitrobacter and Exiguobacterium,while the exposure group was dominated by Bacillus,Mycobacterium,and Nitrospira.A noticeable shift in the NOB community from Nitrobacter(26.5%to 3.4%)to Nitrospira(1.61%to 14.27%)was observed.A KEGG analysis indicated a decrease in cell growth and death,cell motility and energy *** appeared that NOB could adapt to PS-NPs stress through enhanced secretion and removal of oxidative ***,this study provided new insights into the response mechanism of NOB to PS-NPs exposure.

关键词： Nanoplastics Nitrifying activity Extracellular polymeric substance(EPS) Exposure Community analysis

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Cisplatin-induced activation of TGF-βsignaling contributes to drug resistance

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Oncology Research 2024年第1期32卷 139-150页

作者： SAYAKA IMATSUJI YUKIKO UJIE HIROYUKI ODAKE MASAYA IMOTO SUSUMU ITOH ETSU TASHIRO Department of Biosciences and Informatics Faculty of Science and TechnologyKeio UniversityYokohama223-8522Japan Department of Neurology Juntendo University Graduate School of MedicineTokyo113-8421Japan laboratory of Biochemistry Showa Pharmaceutical UniversityTokyo194-8543Japan

Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer ***,the mechanism of EMT induction in the process of acquiring anti-cancer drug resistance remains *** address this issue,we obtained a number of cisplatin-resistant clones from LoVo cells and found that almost all of them lost cell-cell *** these clones,the epithelial marker E-cadherin was downregulated,whereas the mesenchymal marker N-cadherin was ***,the expression of EMT-related transcription factors,including Slug,was *** the other hand,the upregulation of other mesenchymal marker Vimentin was weak,suggesting that the mesenchymal-like phenotypic changes occurred in these cisplatin-resistant *** mesenchymal-like features of cisplatin-resistant clones were partially reversed to parental epithelial-like features by treatment with transforming growth factor-β(TGF-β)receptor kinase inhibitors,indicating that TGF-βsignaling is involved in cisplatin-induced the mesenchymallike phenotypic ***,cisplatin was observed to enhance the secretion of TGF-βinto the culture media without influencing TGF-βgene *** results suggest that cisplatin may induce the mesenchymal-like phenotypic changes by enhancing TGF-βsecretion,ultimately resulting in drug resistance.

关键词： Cisplatin EMT Chemo-resistance TGF-β

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The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1951-1964页

作者： Longsheng Wang Jie Zhang Wenxin Zhang Mingming Zheng Hongjie Guo Xiaohui Pan Wen Li Bo Yang Ling Ding Zhejiang Province Key laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China The Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Nanhu Brain-Computer Interface Institute Hangzhou 311100China

Adenosine(Ado)is significantly elevated in the tumor microenvironment(TME)compared to normal *** binds to adenosine receptors(AdoRs),suppressing tumor antigen presentation and immune cell activation,thereby inhibiting tumor adaptive *** downregulates major histocompatibility complex II(MHC II)and co-stimulatory factors on dendritic cells(DCs)and macrophages,inhibiting antigen *** suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor(TCR)binding and signal *** also inhibits chemokine secretion and KCa3.1 channel activity,impeding effector T cell trafficking and infiltration into the tumor ***,Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion,upregulating immune checkpoint proteins,and enhancing immune-suppressive cell *** Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other *** and clinical development of inhibitors targeting Ado generation or AdoRs is ***,this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity,as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.

关键词： Adenosine Adenosine receptors Adenosine-generating enzymes Tumor microenvironment Immune suppression Immune escape Clinical treatment Targeting drugs

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Lactobacillus acidophilus FCQHC4L1 strengthens the intestinal mucus barrier and inhibits endoplasmic reticulum stress

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Food Science and Human Wellness 2024年

作者： Yuli Qi Leilei Yu Fengwei Tian Wei Chen Xiaoming Liu Qixiao Zhai State Key laboratory of Food Science and Technology Jiangnan University National Engineering Research Center for Functional Food Jiangnan University School of Food Science and Technology Jiangnan University

Mucin 2 (MUC2) is a critical component of the intestinal mucus barrier. Lactic acid bacteria (LAB) strains can improve mucosal homeostasis. In this study， we determined the expression of Muc2 induced by dead bacteria and cell-free conditioned medium (CM) of 50 LAB strains in the human goblet cell line， LS174T. Dead bacteria or CM of LAB affected the Muc2 expression in a species- and strain-specific manner under homeostasis. Next， LAB strains with different regulatory abilities were selected， gavaged into mice， and exposed to dextran sodium sulfate (DSS) after 1 week. Different LAB strains inhibited intestinal injury to different degrees， with Lactobacillus acidophilus FCQHC4L1 exerting the most potent effect. FCQHC4L1 significantly decreased the secretion of pro-inflammatory factors， promoted the expression and secretion of mucin， and inhibited colitis development. This strain also regulated the gut microbiota and increased the secretion of butyric acid. Moreover， CM of FCQHC4L1 inhibited endoplasmic reticulum (ER) stress and ameliorated the abnormal expression of MUC2 by suppressing the activation of the GRP78/ATF6 and GRP78/IRE1/XBP1 signaling pathways. Our results highlight the potential of FCQHC4L1 as a therapeutic agent for strengthening the mucus barrier and improving the gut health.

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Novel Pt(IV) complex OAP2 induces STING activation and pyroptosis via mitochondrial membrane remodeling for synergistic chemo-immunotherapy

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1742-1758页

作者： Renming Fan Ruizhuo Lin Shuo Zhang Aohua Deng Yongrui Hai Junyan Zhuang Yang Liu Maosheng Cheng Gaofei Wei Institute of Medical Research Northwestern Polytechnical UniversityXi'an 710072China Research&Development Institute of Northwestern Polytechnical University in Shenzhen Shenzhen 518057China Key laboratory of Structure-Based Drug Design and Discovery Ministry of EducationSchool of Pharmaceutical EngineeringShenyang Pharmaceutical UniversityShenyang 110016China

Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.

关键词： Anti-tumor drug Prodrug Platinum Chemo-immunotherapy Mitochondrial membrane modeling STING Pyroptosis mtDNA

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SEC1A and SEC6 synergistically regulate pollen tube polar growth

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Journal of Integrative Plant biology 2023年第7期65卷 1717-1733页

作者： Tingting Fan Yuemin Fan Yang Yang Dong Qian Yue Niu Lizhe An Yun Xiang MOE Key laboratory of cell Activities and Stress Adaptations School of Life SciencesLanzhou UniversityLanzhou 730000China

Pollen tube polar growth is a key physiological activity for angiosperms to complete double fertilization, which is highly dependent on the transport of polar substances mediated by secretory *** exocyst and Sec1/Munc18(SM) proteins are involved in the regulation of the tethering and fusion of vesicles and plasma membranes, but the molecular mechanism by which they regulate pollen tube polar growth is still unclear. In this study, we found that loss of function of SEC1A, a member of the SM protein family in Arabidopsis thaliana, resulted in reducing pollen tube growth and a significant increase in pollen tube width. SEC1A was diffusely distributed in the pollen tube cytoplasm, and was more concentrated at the tip of the pollen tube. Through coimmunoprecipitation-mass spectrometry screening,protein interaction analysis and in vivo microscopy,we found that SEC1A interacted with the exocyst subunit SEC6, and they mutually affected the distribution and secretion rate at the tip of the pollen tube. Meanwhile, the functional loss of SEC1A and SEC6 significantly affected the distribution of the SNARE(soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex member SYP125 at the tip of the pollen tube, and led to the disorder of pollen tube cell wall components. Genetic analysis revealed that the pollen tube-related phenotype of the sec1a sec6 double mutant was significantly enhanced compared with their respective single mutants. Therefore, we speculated that SEC1A and SEC6 cooperatively regulate the fusion of secretory vesicles and plasma membranes in pollen tubes, thereby affecting the length and the width of pollen tubes.

关键词： pollen tube SEC1A SEC6 SYP125 vesicle secretory

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A crucial role of neutrophil extracellular traps in pulmonary infectious diseases

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Chinese Medical Journal Pulmonary and Critical Care Medicine 2024年第1期2卷 34-41页

作者： Ting Pan Jae Woo Lee Shanghai Key laboratory of Lung Inflammation and Injury Department of Pulmonary MedicineZhongshan HospitalFudan UniversityShanghai 200032China Department of Anesthesiology University of California Los AngelesLos AngelesCA 90230USA

Neutrophil extracellular traps(NETs),extrusions of intracellular DNA with attached granular material that exert an antibacterial effect through entangling,isolating,and immobilizing microorganisms,have been extensively studied in recent *** primary role of NETs is to entrap and facilitate the killing of bacteria,fungi,viruses,and parasites,preventing bacterial and fungal *** formation has been described in many pulmonary diseases,including both infectious and *** are considered a double-edged *** innate immune cells,neutrophils release NETs to kill pathogens and remove cellular ***,the dele-terious effects of excessive NET release in lung disease are particularly important because NETs and by-products of NETosis can directly induce epithelial and endothelial cell death while simultaneously inducing inflammatory cytokine secretion and immune-mediated ***,NET formation must be tightly regulated to preserve the anti-microbial capability of NETs while minimizing damage to the *** this review,we summarized the recent updates on the mechanism of NETs formation and pathophysiology associated with excessive NETs,aiming to provide insights for research and treatment of pulmonary infectious diseases.

关键词： Pulmonary infectious diseases Neutrophils Neutrophil extracellular traps(NETs) NETosis

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