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Neuroscience Bulletin 2020年第11期36卷 1242-1258页

作者： James Morgan Mariana Alves Giorgia Conte Aida Menendez-Mendez Laura de Diego-Garcia Gioacchino de leo Edward Beamer Jonathon Smith Annette Nicke Tobias Engel Department of Physiology and Medical Physics Royal College of Surgeons in IrelandDublin D02 YN77Ireland FutureNeuro Science Foundation Ireland Research Centre for Chronic and Rare Neurological DiseasesRoyal College of Surgeons in IrelandDublin D02 YN77Ireland Walther Straub Institute of Pharmacology and Toxicology Faculty of MedicineLudwig-Maximilians-Universitat Miinchen80336 MunichGermany

Mounting evidence suggests that the ATP-gated P2X7 receptor contributes to increased hyperexcitability in the *** increased expression of P2X7 in the hippocampus and cortex following status epilepticus and during epilepsy has been repeatedly demonstrated,the cell type-specific expression of P2X7 and its expression in extra-hippocampal brain structures remains incompletely *** this study,P2X7 expression was visualized by using a transgenic mouse model overexpressing P2X7 fused to the fluorescent protein *** results showed increased P2X7-EGFP expression after status epilepticus induced by intra-amygdala kainic acid and during epilepsy in different brain regions including the hippocampus,cortex,striatum,thalamus and cerebellum,and this was most evident in microglia and *** of P2X7-EGFP with cell type-specific markers was not detected in neurons or *** data suggest that P2X7 activation is a common pathological hallmark across different brain structures,possibly contributing to brain inflammation and neurodegeneration following acute seizures and during epilepsy.

关键词： Purinergic signaling P2X7 Green fluorescence protein Status epilepticus Epilepsy Cell typespecific expression

Silymarin,boswellic acid and curcumin enriched dietetic formulation reduces the growth of inherited intestinal polyps in an animal model

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World Journal of Gastroenterology 2020年第14期26卷 1601-1612页

作者： Bruna Girardi Maria Pricci Floriana Giorgio Mariano Piazzolla Andrea Iannone Giuseppe Losurdo Mariabeatrice Principi Michele Barone Enzo Ierardi Alfredo Di leo ThD SpA Correggio 42015Italy Gastroenterology Section Department of Emergency and Organ TransplantationUniversity of BariBari 70124Italy

BACKGROUND Some substances of plant origin have been reported to exert an effect in reducing intestinal neoplasm development,especially in animal *** polyposis coli multiple intestinal neoplasia-ApcMin/+is the most studied murine model of genetic intestinal *** To assess whether an enriched nutritional formulation(silymarin,boswellic acid and curcumin)with proven“in vitro”and“in vivo”anti-carcinogenetic properties may prevent inherited intestinal cancer in animal *** Forty adenomatous polyposis coli multiple intestinal neoplasia-ApcMin/+mice were used for the study of cancer *** were divided into two groups:20 assumed standard and 20 enriched *** the 110th d animals were *** each group,four subgroups received intraperitoneal bromodeoxyuridine injection at different times(24,48,72 and 96 h before the sacrifice)in order to assess epithelial ***,we evaluated the following parameters:Intestinal polypoid lesion number and size on autoptic tissue,dysplasia and neoplasia areas by histological examination of the whole small intestine,inflammation by histology and cytokine mRNA expression by real-time polymerase chain reaction,bromodeoxyuridine and TUNEL immunofluorescence for epithelial turnover and apoptosis,***,we performed western blotting analysis for the expression of estrogen alpha and beta receptors,cyclin D1 and cleaved caspase 3 in normal and polypoid *** Compared to standard,enriched diet reduced the total number(203 vs 416)and the mean±SD/animal(12.6±5.0 vs 26.0±8.8;Phed diet group a reduction in polyp size was observed(Phistological inflammation and pro-inflammatory cytokine expression were similar in both *** of low-grade dysplasia(Phed diet *** was observed in 100%in standard and 85%in enriched formulation assumin

关键词： Intestinal cancer Familial adenomatous polyposis Chemopreventive diet Apc^Min/+mice Boswellia Curcumin

In vitro 3D phenotypic drug screen identifies celastrol as an effective in vivo inhibitor of polycystic kidney disease

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Journal of Molecular Cell Biology 2020年第8期12卷 644-653页

作者： Tijmen h.Booij Wouter N.leonhard hester Bange Kuan Yan Michiel Fokkelman Anna J.Plugge Kimberley A.M.Veraar Johannes G.Dauwerse Gerard J.P.van Westen Bob van de Water leo S.Price Dorien j.M.Peters Division of Toxicology Leiden Academic Centre for Drug Research(LACDR)Leiden UniversityLeidenThe Netherlands Present address:NEXUS Personalized health Technologies ETH ZurichSwitzerland Department of human Genetics Leiden University Medical Center(LUMC)LeidenThe Netherlands OcellO B.V. LeidenThe Netherlands Division of Medicinal Chemistry Leiden Academic Centre for Drug Research(LACDR)LeidenThe Netherlands

Polycystic kidney disease(PKD)is a prevalent genetic disorder,characterized by the formation of kidney cysts that progressively lead to kidney *** currently available drug tolvaptan is not well tolerated by all patients and there remains a strong need for alternative *** signalling rewiring in PKD that drives cyst formation is highly complex and not fully *** a consequence,the effects of drugs are sometimes difficult to *** previously established a high-throughput microscopy phenotypic screening method for quantitative assessment of renal cyst ***,we applied this 3D cyst growth phenotypic assay and screened 2320 small drug-like molecules,including approved *** identified 81 active molecules that inhibit cyst ***-parametric phenotypic profiling of the effects on 3D cultured cysts discriminated molecules that showed preferred pharmacological effects above genuine toxicological ***,a triterpenoid from Tripterygium wilfordii,was identified as a potent inhibitor of cyst growth in *** an in vivo iKspCre-Pkd1^lox,lox mouse model for PKD,celastrol inhibited the growth of renal cysts and maintained kidney function.

关键词： PKD celastrol pyrvinium pamoate high-content screening 3D

Ex vivo response to mucosal bacteria and muramyl dipeptide in inflammatory bowel disease

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World Journal of Gastroenterology 2016年第44期22卷 9734-9743页

作者： Claudia Loganes Erica Valencic Alessia Pin Elisa Marini Stefano Martelossi Samuele Naviglio Luigina De leo Tarcisio Not Lorenzo Monasta Alberto Tommasini Annalisa Marcuzzi Department of Medicine Surgery and Health Sciences University of Trieste Strada di Fiume Institute for Maternal and Child health - IRCCS "Burlo Garofolo"

AIM To evaluate how mucosal bacteria impact on the spontaneous and muramyl dipeptide(MDP)-induced inflammation in Crohn's disease(CD) and ulcerative colitis(UC).METhODS Colonic mucosal biopsies were collected from children with active or remissive CD, UC and controls. Two tissue samples were taken from inflamed mucosal segments(in patients with active disease) or from noninflamed mucosa [in patients in remission or in healthy controls(hC)]. Experiments were performed in the presence or absence of antibiotics, to assess whether the disease-associated microbiota can modulate the cytokine response ex vivo. For this purpose, each specimen was half-cut to compare spontaneous and MDP-induced inflammation in the presence of live bacteria(LB) or antibiotics. After 24 h of culture, an array of 17 cytokines was assessed in supernatants. Statistical analyses were performed to find significant differences in single cytokines or in patterns of cytokine response in the different groups. RESULTS We demonstrated that subjects with CD display a spontaneous production of inflammatory cytokines including granulocyte-colony stimulating factor(G-CSF), interleukin(IL) 6, IL8, IL10 and IL12, that was not significantly influenced by the addition of antibiotics. UC specimens also displayed a trend of increased spontaneous secretion of several cytokines, which however was not significant due to broader variability among patients. After the addition of antibiotics, spontaneous IL8 secretion was significantly higher in UC than in controls. In hC, a trend towards the weakening of spontaneous IL8 production was observed in the presence of live mucosal bacteria with respect to the presence of antibiotics. In contrast, in the presence of LB UC showed an increasing trend of spontaneous IL8 production, while MDP stimulation resulted in lower IL8 production in the presence of antibiotics. We also showed that subjects with CD seem to have a lowered production of IL8 in response to MDP in the presence

关键词： Gut-microbiota Crohn’s disease Ulcerative colitis Cytokines Inflammation

5-Methylcytosine RNA Methylation in Arabidopsis Thaliana

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Molecular Plant 2017年第11期10卷 1387-1399页

作者： Xuean Cui Zhe Liang Lisha Shen Qian Zhang Shengjie Bao Yuke Geng Bin Zhang Vonny leo Leah A. Vardy Tiegang Lu Xiaofeng Gu hao Yu Biotechnology Research Institute Chinese Academy of Agricultural Sciences Beijing 100081 China Department of Biological Sciences and Temasek Life Sciences Laboratory National University of Singapore 117543 Singapore Singapore Institute of Medical Biology Agency for Science Technology and Research (A^+STAR) 8A Biomedical Grove #06-06 Immunos 138648 Singapore Singapore

5-Methylcytosine （m^5C） is a well-characterized DNA modification, and is also predominantly reported in abundant non-coding RNAs in both prokaryotes and eukaryotes. however, the distribution and biological functions of m^5C in plant mRNAs remain largely unknown. here, we report transcriptome-wide profiling of RNA m^5C in Arabidopsis thaliana by applying m^5C RNA immunoprecipitation followed by a deep- sequencing approach （m^5C-RIP-seq）. LC-MS/MS and dot blot analyses reveal a dynamic pattern of m^5C mRNA modification in various tissues and at different developmental stages, m^5C-RIP-seq analysis identified 6045 m^5C peaks in 4465 expressed genes in young seedlings. We found that m^5C is enriched in coding sequences with two peaks located immediately after start codons and before stop codons, and is associated with mRNAs with low translation activity. We further demonstrated that an RNA （cytosine-5）-methyl- transferase, tRNA-specific methyltransferase 4B （TRM4B）, exhibits m^5C RNA methyltransferase activity. Mutations in TRM4B display defects in root development and decreased m^5C peaks. TRM4B affects the transcript levels of the genes involved in root development, which is positively correlated with their mRNA stability and m^5C levels. Our results suggest that m^5C in mRNA is a new epitranscriptome marker inArabidopsis, and that regulation of this modification is an integral part of gene regulatory networks underlying plant development.

关键词： 5-methylcytosine (m^5C) Arabidopsis RNA methylation TRM4B root development