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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 | Induced pluripotent stem cells for therapy personalization in pediatric patients:Focus on drug-induced adverse events显示文摘Adverse drug reactions(ADRs)are major clinical problems,particularly in special populations such as pediatric patients.Indeed,ADRs may be caused by a plethora of different drugs leading,in some cases,to hospitalization,disability or even death.In addition,pediatric patients may respond differently to drugs with respect to adults and may be prone to developing different kinds of ADRs,leading,in some cases,to more severe consequences.To improve the comprehension,and thus the prevention,of ADRs,the set-up of sensitive and personalized assays is urgently needed.Important progress is represented by the possibility of setting up groundbreaking patient-specific assays.This goal has been powerfully achieved using induced pluripotent stem cells(iPSCs).Due to their genetic and physiological species-specific differences and their ability to be differentiated ideally into all tissues of the human body,this model may be accurate in predicting drug toxicity,especially when this toxicity is related to individual genetic differences.This review is an up-to-date summary of the employment of iPSCs as a model to study ADRs,with particular attention to drugs used in the pediatric field.We especially focused on the intestinal,hepatic,pancreatic,renal,cardiac,and neuronal levels,also discussing progress in organoids creation.The latter are three-dimensional in vitro culture systems derived from pluripotent or adult stem cells simulating the architecture and functionality of native organs such as the intestine,liver,pancreas,kidney,heart,and brain.Based on the existing knowledge,these models are powerful and promising tools in multiple clinical applications including toxicity screening,disease modeling,personalized and regenerative medicine. | Elena Genova Federica Cavion Marianna Lucafò Luigina De Leo Marco Pelin Gabriele Stocco Giuliana Decorti | 2019 | World Journal of Stem Cells2019，11，12： | 4 |
| 4 | 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 |
| 5 | Failure of interferon-γ pre-treated mesenchymal stem cell treatment in a patient with crohn's disease显示文摘Mesenchymal stem cells(MSC) are cells of stromal origin which exhibit unlimited self-renewal capacity and pluripotency in vitro.It 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 disorders.We 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 cells.Despite these changes, no significant clinical benefit was observed, and the patient required rescue therapy with infliximab and subsequent autologous hematopoietic stem cell transplantation.The 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. | 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 | 2015 | World Journal of Gastroenterology2015，21，14： | 2 |
| 6 | 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 |
| 7 | Ultrasound-assisted extraction coupled with under vacuum distillation of flavour compounds from spearmint (carvone-rich) plants: Comparison with conventional hydrodistillation 显示文摘 | Porto C D Decorti D | 2009 | Ultrasonics sonochemistry2009，16，6： | 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 | Targeting faraesyl-transferase as a novel therapeutic strategy for mevalonate kinase deficiency: in vitro and in vivo approaches 显示文摘 | De Leo L Marcuzzi A Decorti G | 2010 | Pharmacol Res2010，61，6： | 1 |
| 10 | Ultrasoundassisted extraction coupled with under vacuum distillation of flavour compounds from spearmint (carvone-rich) plants: Comparison with conventional hydrodistillation显示文摘 | Porto Carla Da Decorti Deborha | 2009 | Ultrasonics Sonochemistry2009，16，6： | 1 |
| 11 | COSIMO:A cognitive simulation model of human decision making and behavior in accident management of complex plants显示文摘 | CACCIABUE P C DECORTIS F DROZDOWICZ B | 1992 | IEEE Transactions on Systems Man and Cybernetics1992，22，5： | 1 |
| 12 | Effects of melatonin on doxorubicin cytotoxicity in sensitive and pleiotropically resistant tumor cells显示文摘 | Granzotto M Rapozzi V Decorti G | 2001 | J Pineal Res2001，31，3： | 1 |
| 13 | Comparison of ultrasound-assisted extraction with conventional extraction methods of oil and polyphenols from grape (Vitis vinifera L) seeds显示文摘 | PORTO D C PORRETTO E DECORTI D | 2013 | Uhrason Sonochem2013，20，4： | 1 |
| 14 | Endocytosis of gentamicin in a proximal tubular renal line显示文摘 | Decorti G Malusa N Furlan G | 1999 | Life Sci1999，65，11： | 1 |
| 15 | Female steroid hormones modulate receptors for nerve growth factor in rat dorsal root ganglia 显示文摘 | LANLUA P DECORTI F GANGULA P R | 2001 | Biol Reprod2001，64，1： | 1 |
| 16 | Ultrasound-assisted extraction coupled with under vacuum distillation of flaw)ur compounds from spearmint (carw~ne-rich) planls:Comparison with conventional hydrodistillation 显示文摘 | Da Porto C Decorti D | 2009 | Ultrasonic Sonochemistry2009，16，6： | 1 |
| 17 | Ultrasound-assisted extraction coupled with under vacuum distillation of flavour compounds from spearmint ( carvone-rich ) plants: Comparison with conventional hydrodistillation 显示文摘 | Da Porto C Decorti D | 2009 | Ultrasonics Sonochemistry2009，16，6： | 1 |
| 18 | Female steroid hormones modulate receptors for nerve growth factor in rat dorsal root ganglia显示文摘 | LANLUA P DECORTI F GANGULA P R | 2001 | Biol Reprod2001，64，1： | 1 |
| 19 | Targeting farnesyl-trans- ferase as a novel therapeutic strategy for mevalonate kinase defi- ciency: in vitro and in vivo approaches 显示文摘 | De Leo L Marcuzzi A Decorti G | 2010 | Pharmacol Res2010，61，6： | 1 |
| 20 | Adriamycin-induced histamine release from heart tissue in vitro显示文摘 | DECORTI G CANDUSSIO L KLUGMANN F B | 1991 | Cancer Chemother Pharmacol1991，40，4： | 1 |
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