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| 1 | Molecular mechanism of glucocorticoid resistance in inflammatory bowel disease显示文摘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 toxicity.However, 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 other possible candidates of interest that could play a role in the observed inter-individual differences in efficacy and toxicity. The best-characterized example is the drug efflux pump P-glycoprotein, a membrane transporter that extrudes GCs from cells, thereby lowering their intracellular concentration. This protein is encoded by the ABCB1/ MDR1 gene; this gene presents different known polymorphic sites that can influence its expression and function. This editorial reviews the current knowledge on this topic and underlines the role of genetics in predicting GC clinical response. The ambitious goal of pharmacogenomic studies is to adapt therapies to a patient’s specific genetic background, thus improving on efficacy and safety rates. | Sara De Iudicibus Raffaella Franca Stefano Martelossi Alessandro Ventura Giuliana Decorti | 2011 | World Journal of Gastroenterology2011，17，9： | 14 |
| 2 | Thiopurine metabolites variations during co-treatment with aminosalicylates for inflammatory bowel disease:Effect of N-acetyl transferase polymorphisms显示文摘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 presented a genotype corresponding to fast enzymatic activity and 6 to slow activity; NAT2 genotypes were not related to thiopurine metabolites concentration in this study. CONCLUSION: NAT1 genotype affects TGN levels in patients treated with thiopurines and aminosalicylates and could therefore influence the toxicity and efficacy of these drugs; however the number of patients evaluated is limited and this has to be considered a pilot study. | Gabriele Stocco Eva Cuzzoni Sara De Iudicibus Diego Favretto Noelia Malusà Stefano Martelossi Elena Pozzi Paolo Lionetti Alessandro Ventura Giuliana Decorti | 2015 | World Journal of Gastroenterology2015，21，12： | 5 |
| 3 | MicroRNAs as tools to predict glucocorticoid response in inflammatory bowel diseases显示文摘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 reported.The 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 variability.In this context,microRNAs(miRNAs)represent a new and promising field of research.miRNAs 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 inflammation.Emerging data have implicated the deregulated expression of certain miRNA networks in the pathogenesis of autoimmune and inflammatory diseases,such as IBD.There 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 study.The 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 practice.In 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. | Sara De Iudicibus Marianna Lucafò Stefano Martelossi Chiara Pierobon Alessandro Ventura Giuliana Decorti | 2013 | World Journal of Gastroenterology2013，19，44： | 4 |
| 4 | Crohn's disease and Takayasu's arteritis: An uncommon association显示文摘Takayasu’s arteritis(TA)and Crohn’s disease(CD)are two rare autoimmune disorders;however some reports describe the presence of both diseases in the same patient.This finding has suggested the possibility that both diseases could share some common etiologic origin.We describe a case of a 13-year-old male affected by CD characterized by fever,diarrhea,weight loss,abdominal pain and elevation of inflammatory markers.Clinical and histological features from colonic specimens were consistent with CD.Treatment with steroids and azathioprine was started,however disease flared every time steroids were tapered.One year later,while still on treatment,he came back to our attention for dyspnea at rest and at night,tiredness and weakness.At physical examination a diastolic heart murmur was found as well as a left carotid artery bruit.A transthoracic echocardiography showed mild aortic valve insufficiency,left ventricular hypertrophy and a dilated ascending aorta with same findings at the aortic arch.A computed tomography scan showed abdominal aortathickening,dilated thoracic aorta and the presence of a thoracic aortic aneurysm.TA associated with CD was diagnosed and medical treatment with cyclophosphamide,steroids and aminosalicylic acid was started,with good clinical response at 6 mo follow-up.We discuss the presence of possible common causes for the two diseases and the importance of differential diagnosis in those patients characterized for intractable disease. | Andrea Taddio Massimo Maschio Stefano Martelossi Egidio Barbi Alessandro Ventura | 2013 | World Journal of Gastroenterology2013，19，35： | 3 |
| 5 | Pharmacogenetics of azathioprine in inflammatory bowel disease: A role for glutathione-S-transferase?显示文摘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.reserved. | Gabriele Stocco Marco Pelin Raffaella Franca Sara De Iudicibus Eva Cuzzoni Diego Favretto Stefano Martelossi Alessandro Ventura Giuliana Decorti | 2014 | World Journal of Gastroenterology2014，20，13： | 2 |
| 6 | Heterozygous nucleotide-binding oligomerization domain-2 mutations affect monocyte maturation in Crohn's disease显示文摘瞄准:在 Crohn 的疾病(CD ) 调查单核白血球的函数病人并且相关这与联系疾病的核苷酸绑定 oligomerization domain-2 (NOD2 ) 基因变体。方法:从 47 个连续地提交的 CD 病人和 9 健康供血者的单核白血球与 interleukin (IL ) 是有教养的 -4 和 granulocyte 巨噬细胞刺激殖民地的因素(GM-CSF ) ,并且与脂肪的多糖(LPS ) 或 muramyldipeptide (MDP ) 刺激了, NOD2 的通常认为的 ligand。结果:我们发现从 CD 病人的单核白血球区分了在试管内到成熟树枝状的房间(DC ) ,由免疫显型和形态学决定了。NOD2 遗传型在所有题目被估计,并且我们观察到在 NOD2 的不成熟、刺激 LPS 的 DC 上的高 CD86 表示变异 CD 病人,作为与 wtNOD2 CD 病人和控制相比。由对比,导致到成熟, MDP 源于变异 NOD2 的题目的 DC 的 CD86 表示层次比得上正常题目的那些。在耐心房间的文化的 IL-12p70 的数量与 MDP 比在在 LPS 治疗,然而并非术后疗法以后的控制大。结论:我们的结果建议在 NOD2 基因与变化从病人获得的 DC 显示高 CD86 表示描绘的激活的显型,但是当与终端相比区别分阶段执行时,有减少的回答到 MDP。我们推测单核白血球的改变的区别可能导致在发炎和单核白血球的杀死的能力之间的不平衡,并且可能与 CD 的致病相关。 | Marilena Granzotto Elisa Fabbro Massimo Maschio Stefano Martelossi Sara Quaglia Alberto Tommasini Gianni Presani Alessandro Ventura | 2007 | World Journal of Gastroenterology2007，13，46： | 2 |
| 7 | Acute and recurrent pancreatitis in children : exploring etiological factors 显示文摘 | Minen F De Cunto A Martelossi S | 2012 | Scand J Gastroenterol2012，47，12： | 1 |
| 8 | Inflammatory bowel disease显示文摘 | Gabriele Stocco Giuliana Decorti Fiora Bartoli Stefano Martelossi Alessandro Ventura | 2007 | The Lancet . 2007 (9584)2007，，9584： | 1 |
| 9 | Alagille syndrome: a new missense mutation detected by whole-exome sequencing in a case previously found to be negative by DHPLC and MLPA显示文摘 | Vozzi D Licastro D Martelossi S | 2013 | Mol Syndromol2013，4，4： | 1 |
| 10 | TPMT genotype and the use of thiopurines in paediatric inflammatory bowel disease显示文摘 | STOCCO G MARTELOSSI S BARABINO A | 2005 | Dig Liver Dis2005，37，12： | 1 |
| 11 | Glutathione-S-transferase geno- types and the adverse effects of azathioprine in young patients with in- flammatory bowel disease显示文摘 | Stocco G Martelossi S Barabino A | 2007 | lnflamm Bowel D/s2007，13，1： | 1 |
| 12 | Efficacy and safety of thalidomide in children and young adults with intractable inflamma- tory bowel disease: Long-term results 显示文摘 | Lazzerini M Martelossi S Marchetti F | 2007 | Aliment Pharmacol Ther2007，25，4： | 1 |
| 13 | Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: a randomized clinical trial显示文摘 | Lazzerini M Martelossi S Magazzfl G | 2013 | JAMA2013，310，21： | 1 |
| 14 | Efficacy of long-term treatment with thalidomide in children and young adults with Crohn disease: preliminary results显示文摘 | Facchini S Candusso M Martelossi S | 2001 | J Pediatr Gastroenterol Nutr2001，32，： | 1 |
| 15 | Effect of thalidomide on clinical remission in children and adoles- cents with refractory Crohn disease: a randomized clinical trial显示文摘 | Lazzerini M Martelossi S Magazz~ G | 2013 | JAMA2013，310，20： | 1 |
| 16 | Inflammatory bowel disease显示文摘 | Gabriele Stocco Giuliana Decorti Fiora Bartoli Stefano Martelossi Alessandro Ventura | 2007 | The Lancet2007，，9584： | 1 |
| 17 | Efficacy and safety of thalidomide in children and young adults with intractable inflammatory bowel disease: long-term results 显示文摘 | azzerini M Martelossi S Marchetti F | 2007 | Aliment Pharmacol Ther2007，25，4： | 1 |
| 18 | Efficacy and safety of thalidomide in children and young adults with intractable inflammatory bowel disease: long-term results显示文摘 | Lazzerini M Martelossi S Marchetti F | 2007 | Aliment Pharmacol Ther2007，25，4： | 1 |
| 19 | Genetic Predictors of Glucocorticoid Response in Pediatric Patients With Inflammatory Bowel Diseases显示文摘 | Sara De Iudicibus Gabriele Stocco Stefano Martelossi Margherita Londero Egle Ebner Alessandra Pontillo Paolo Lionetti Arrigo Barabino Fiora Bartoli Alessandro Ventura Giuliana Decorti | 2011 | Journal of Clinical Gastroenterology2011，，1： | 1 |
| 20 | Alagille syndrome : a new mis- sense mutation detected by whole-exome sequencing in a case previously found to be negative by DHPLC and MLPA显示文摘 | Vozzi D Lieastro D Martelossi S | 2013 | Mol Syndromol2013，4，4： | 1 |
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