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MicroRNAs as tools to predict glucocorticoid response in inflammatory bowel diseases

World Journal of Gastroenterology 2013年第44期19卷 7947-7954页

作者： sara de iudicibus Marianna Lucafò Stefano Martelossi Chiara Pierobon Alessandro Ventura Giuliana decorti Institute for Maternal and Child Health IRCCS Burlo Garofolo 34137 Trieste Italy department of Medical Surgical and Health Sciences University of Trieste 34127 Trieste Italy department of Life Sciences University of Trieste 34127 Trieste Italy

In spite of the introduction in therapy of highly effective biological agents,glucocorticoids(GCs)are still employed to induce remission in moderate to severe inflammatory bowel diseases(IBD),but considerable inter-individual differences in their efficacy and side effects have been *** effectiveness of these drugs is indeed very variable and side effects,particularly severe in pediatric patients,are common and often unpredictable:the understanding of the complex gene regulation mediated by GCs could shed light on the causes of this *** this context,microRNAs(miRNAs)represent a new and promising field of *** are small non-coding RNA molecules that suppress gene expression at post-transcriptional level,and are fine-tuning regulators of diverse biological processes,including the development and function of the immune system,apoptosis,metabolism and *** data have implicated the deregulated expression of certain miRNA networks in the pathogenesis of autoimmune and inflammatory diseases,such as *** is a great interest in the identification of the role of miRNAs in the modulation of pharmacological response;however,the association between miRNA and GC response in patients with IBD has not yet been evaluated in a prospective clinical *** identification of miRNAs differently expressed as a consequence of GC treatment in comparison to diagnosis,represents an important innovative approach that could be translated into clinical *** this review we highlight the altered regulation of proteins involved in GC molecular mechanism by miRNAs,and their potential role as molecular markers useful for predicting in advance GC response.

关键词： Glucocorticoids Inflammatory bowel diseases MicroRNA Molecular markers Pharmacogenomics

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Pharmacogenetics of azathioprine in inflammatory bowel disease: A role for glutathione-S-transferase?

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World Journal of Gastroenterology 2014年第13期20卷 3534-3541页

作者： Gabriele Stocco Marco Pelin Raffaella Franca sara de iudicibus Eva Cuzzoni Diego Favretto Stefano Martelossi Alessandro Ventura Giuliana decorti department of Life Sciences University of TriesteI-34127 TriesteItaly Institute for Maternal and Child Health IRCCS Burlo Garofolo I-34137 TriesteItaly department of Medical Surgical and Health SciencesUniversity of TriesteI-34127 TriesteItaly

Azathioprine is a purine antimetabolite drug commonly used to treat inflammatory bowel disease (IBD). In vivo it is active after reaction with reduced glutathione (GSH) and conversion to mercaptopurine. Although this reaction may occur spontaneously, the presence of isoforms M and A of the enzyme glutathione-S-transferase (GST) may increase its speed. Indeed, in pediatric patients with IBD, deletion of GST-M1, which determines reduced enzymatic activity, was recently associated with reduced sensitivity to azathioprine and reduced production of azathioprine active metabolites. In addition to increase the activation of azathioprine to mercaptopurine, GSTs may contribute to azathioprine effects even by modulating GSH consumption, oxidative stress and apoptosis. Therefore, genetic polymorphisms in genes for GSTs may be useful to predict response to azathioprine even if more in vitro and clinical validation studies are needed.

关键词： Inflammatory bowel disease Azathioprine Pharmacogenetics Glutathione-S-transferase Pediatric patients

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Thiopurine metabolites variations during co-treatment with aminosalicylates for inflammatory bowel disease:Effect of N-acetyl transferase polymorphisms

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World Journal of Gastroenterology 2015年第12期21卷 3571-3578页

作者： Gabriele Stocco Eva Cuzzoni sara de iudicibus Diego Favretto Noelia Malusà Stefano Martelossi Elena Pozzi Paolo Lionetti Alessandro Ventura Giuliana decorti department of Life Sciences University of Trieste School in Sciences of Reproduction and development University of Trieste Institute for Maternal and Child Health IRCCS Burlo Garofolo department of Prevention Sanitary Services Agency Number esearch Children’s Hospital "Meyer" department of Medical Surgical and Health Sciences University of Trieste

AIM: To evaluate variation of the concentration of thiopurine metabolites after 5-aminosalicylate(5-ASA) interruption and the role of genetic polymorphisms of N-acetyl transferase(NAT) 1 and 2. METHODS: Concentrations of thioguanine nucleotides(TGN) and methymercaptopurine nucleotides(MMPN), metabolites of thiopurines, were measured by high performance liquid chromatography in 12 young patients(3 females and 9 males, median age 16 years) with inflammatory bowel disease(6 Crohn's disease and 6 ulcerative colitis) treated with thiopurines(7 mercaptopurine and 5 azathioprine) and 5-ASA. Blood samples were collected one month before and one month after the interruption of 5-ASA. DNA was extracted and genotyping of NAT1, NAT2, inosine triphosphate pyrophosphatase(ITPA) and thiopurine methyl transferase(TPMT) genes was performed using PCR assays. RESULTS: Median TGN concentration before 5-ASA interruption was 270 pmol/8 x 108 erythrocytes(range: 145-750); after the interruption of the aminosalicylate, a 35% reduction in TGN mean concentrations(absolutemean reduction 109 pmol/8 × 108 erythrocytes) was observed(median 221 pmol/8 × 108 erythrocytes, range: 96-427, P value linear mixed effects model 0.0011). demographic and clinical covariates were not related to thiopurine metabolites concentrations. All patients were wild-type for the most relevant ITPA and TPMT variants. For NAT1 genotyping, 7 subjects presented an allele combination corresponding to fast enzymatic activity and 5 to slow activity. NAT1 genotypes corresponding to fast enzymatic activity were associated with reduced TGN concentration(P value linear mixed effects model 0.033), putatively because of increased 5-ASA inactivation and consequent reduced inhibition of thiopurine metabolism. The effect of NAT1 status on TGN seems to be persistent even after one month since the interruption of the aminosalicylate. No effect of NAT1 genotypes was shown on MMPN concentrations. NAT2 genotyping revealed that 6 patients

关键词： Thiopurines Aminosalicylates Inflammatory bowel di

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Molecular mechMolecular mechanism of glucocorticoid resistance in inflammatory bowel disease

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World Journal of Gastroenterology 2011年第9期17卷 1095-1108页

作者： sara de iudicibus Raffaella Franca Stefano Martelossi Alessandro Ventura Giuliana decorti department of Reproduction and development University of Trieste Institute for Maternal and Child Health IRCCS Burlo Garofolo department of Life Sciences University of Trieste

Natural and synthetic glucocorticoids (GCs) are widely employed in a number of inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in moderate to severe active Crohn’s disease and ulcerative colitis. despite their extensive therapeutic use and the proven effectiveness, considerable clinical evidence of wide inter-individual differences in GC efficacy among patients has been reported, in particular when these agents are used in inflammatory diseases. In recent years, a detailed knowledge of the GC mechanism of action and of the genetic variants affecting GC activity at the molecular level has arisen from several studies. GCs interact with their cytoplasmic receptor, and are able to repress inflammatory gene expression through several distinct mechanisms. The glucocorticoid receptor (GR) is therefore crucial for the effects of these agents: mutations in the GR gene (NR3C1, nuclear receptor subfamily 3, group C, member 1) are the primary cause of a rare, inherited form of GC resistance; in addition, several polymorphisms of this gene have been described and associated with GC response and ***, the GR is not self-standing in the cell and the receptor-mediated functions are the result of a complex interplay of GR and many other cellular partners. The latter comprise several chaperonins of the large cooperative hetero-oligomeric complex that binds the hormonefree GR in the cytosol, and several factors involved in the transcriptional machinery and chromatin remodeling, that are critical for the hormonal control of target genes transcription in the nucleus. Furthermore, variants in the principal effectors of GCs (e.g. cytokines and their regulators) have also to be taken into account for a comprehensive evaluation of the variability in GC response. Polymorphisms in genes involved in the transport and/or metabolism of these hormones have also been suggested as

关键词： Glucocorticoids Inflammatory bowel disease Pharmacogenomics

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Failure of interferon-γ pre-treated mesenchymal stem cell treatment in a patient with crohn's disease

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World Journal of Gastroenterology 2015年第14期21卷 4379-4384页

作者： Andrea Taddio Alberto Tommasini Erica Valencic Ettore Biagi Giuliana decorti sara de iudicibus Eva Cuzzoni Giuseppe Gaipa Raffaela Badolato Alberto Prandini Andrea Biondi Alessandro Ventura Institute for Maternal and Child Health-IRCCS "Burlo Garofolo" -Trieste and University of Trieste Institute for Maternal and Child Health-IRCCS "Burlo Garofolo"-Trieste "Matilde Tettamanti" Research Centre Laboratory of Cell Therapy "Stefano Verri"Paediatric ClinicUniversity of Milano-BicoccaSan Gerardo Hospital department of Life Sciences University of Trieste Clinical department of Medical Surgical and Health SciencesUniversity of Trieste department of Clinical and Experimental Sciences Institute of Molecular Medicine "Angelo Nocivelli"University of Brescia

Mesenchymal stem cells(MSC) are cells of stromal origin which exhibit unlimited self-renewal capacity and pluripotency in *** has recently been observed that MSC may also exert a profound immunosuppressive and anti-inflammatory effect both in vitro and in vivo with consequent potential use in autoimmune *** present the case of a patient suffering from childhood-onset, multidrug resistant and steroiddependent Crohn's disease who underwent systemic infusions of MSC, which led to a temporary reduction in CCR4, CCR7 and CXCR4 expression by T-cells, and a temporary decrease in switched memory B-cells, In addition, following MSC infusion, lower doses of steroids were needed to inhibit proliferation of the patient's peripheral blood mononuclear *** these changes, no significant clinical benefit was observed, and the patient required rescue therapy with infliximab and subsequent autologous hematopoietic stem cell *** results of biological and in vitro observations after MSC use and the clinical effects of infusion are discussed, and a brief description is provided of previous data on MSC-based therapy in autoimmune disorders.

关键词： Autoimmune disease Crohn’s disease Interferon-γ pr

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