1,720,986 research outputs found
Pharmacogenetics of glucocorticoid response
No full textGlucocorticoids (GC) are first-line treatment in a number of inflammatory, autoimmune and neoplastic diseases. Despite their extensive therapeutic use and the proven effectiveness, considerable clinical evidence of wide inter-individual differences
in GC efficacy and side effects among patients has been reported. 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. The glucocorticoid
receptor (GR) is crucial for the effects of GCs: mutations in the GR gene (NR3C1) 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 hormone-free GR in the cytosol, and several factors involved in the transcriptional machinery and chromatin remodelling, that are critical for the
hormonal control of target genes transcription in the nucleus. Polymorphisms in genes involved in the pharmacokinetics and/or pharmacodynamics of these hormones have also been suggested as other possible candidates of interest that could play a role in the
observed inter-individual differences, because of their influence on drug disposition. The best characterized example is the drug efflux pump P-glycoprotein (P-gp), a membrane transporter that acts lowering GC intracellular concentration. This protein is encoded by
the ABCB1/MDR1 gene that presents different known polymorphic sites. 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 great variability in GC
response. The goal of this review is to emphasize the current knowledge on this topic and to underlie the role of genetics in predicting GC clinical response. The ambitious prospective of pharmacogenomic studies is to achieve an individualized therapy, giving to physicians a reliable tool based on the patient genetic profile
Glucocorticoids in Pediatric Gastrointestinal Disorders
No full textPediatric Inflammatory Bowel Disease
Inflammatory bowel diseases (IBDs) are the most frequent chronic gastrointestinal disorders in pediatric age. They include two disease entities – Crohn’s disease (CD) and ulcerative colitis (UC) – which, although different in their pathogenesis, show common clinical characteristics such as chronic inflammation at different levels of the gastrointestinal tract and alternation between active and inactive phases. The incidence of IBD is increasing in recent years, particularly among children and adolescents, and it is currently estimated that 20–30 % of patients with IBD experience the onset of symptoms when they are under 20 years of age [1–3]. In childhood, IBDs are gener- ally more extended, more severe, and progress more rapidly than in adulthood. Moreover, therapy in children with IBD is more aggressive than in adults: Indeed, about 80 % of children need steroids, and about 30 % are subjected to an intestinal resection during a 5-year follow-up. Quality of life is severely affected in IBD, espe- cially for pediatric patients, owing to the chronic character of the disease that implies frequent hospitalizations and aggressive therapies, with a significant risk of side effects and a considerable impact on health care costs. IBD can result in loss of education and difficulty in gaining employment or insurance; overall, 15 % of patients with IBD are unable to work after 5–10 years of disease. Depressive disorders and low social func- tioning are also common among these patients, and the disease can also cause growth failure or retarded sexual development in young people [4–7]. It was recently reported that the mean individual annual costs in European countries amount to US4,600 for UC, and pediatric cases cost even more than adult ones [8]
Selective resistance to different glucocorticoids in severe autoimmune disorders
No full textResistance to glucocorticoids often occurs in patients with severe inflammatory disorders. Occasionally, this resistance could be overcome by switching to a different glucocorticoid, but the mechanisms of this selectivity are not clear. We studied this condition in three patients with severe inflammatory disorders, who responded satisfactorily to betamethasone, but could not be switched to equipotent doses of methylprednisolone or prednisone. While betamethasone displayed similar activity on lymphocyte proliferation in cells obtained from the three patients and controls, higher concentrations of methylprednisolone were needed to inhibit proliferation in patients' cells. In a competition study, the concentration of methylprednisolone that inhibited 50\% of specific [(3)H]dexamethasone binding was increased in patients' lymphocytes. Higher Rhodamine-123 efflux was demonstrated in CD4 T cells from two patients, suggesting that an increased activity of membrane transporters could be responsible for the selective response to different glucocorticoids, even if P-glycoprotein and MRP1 expression was not increased
ABCB1 gene polymorphisms and expression of P-glycoprotein and long term prognosis in colorectal cancer
No full textBACKGROUND: P-glycoprotein (Pgp), encoded by the ATP-binding cassette B1 (ABCB1) gene, is an efflux transporter located on the luminal side of intestinal epithelial cells, which protects the gut from endogenous and exogenous toxins. The association of two ABCB1 polymorphisms with the occurrence of colon cancer and long-term prognosis was evaluated in a selected patient population. The expression of Pgp in neoplastic and normal intestinal mucosa was also studied. PATIENTS AND METHODS: Archival material from 51 patients, in Dukes stage B2 or C, treated for 6 months with 5-fluorouracil plus leucovorin was retrieved. The G2677T and C3435T polymorphisms were studied and immunohistochemical analysis of the tumor and adjacent normal tissue was performed. RESULTS: The distribution of wild-type and polymorphic genotypes was similar in the patients and controls and in the patients who relapsed and those who remained event-free for 5 years. Cox proportional hazard model indicated an increased probability of relapse for older patients (p = 0.042) and C stage tumors (p = 0.030). Pgp expression was significantly lower in cancer tissue compared to normal mucosa (p < 0.001) and was related to grading, being lower in poorly-differentiated tumors (p < 0.05); however, no relationship was seen between Pgp expression, genotype and long-term prognosis. CONCLUSION: G2677T and C3435T polymorphisms are not associated with colon cancer risk and prognosis in a selected patient population
MicroRNAs as tools to predict glucocorticoid response in inflammatory bowel diseases.
No full textIn 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
Glucocorticoid Receptor Interacting Co-regulators: Putative Candidates for Future Drug Targeting Therapy
No full textGlucocorticoids (GCs) are largely used in different inflammatory, autoimmune and proliferative diseases. To date their mechanism of action is not completely clear and more studies are necessary, in particular to explain the great interindividual variability in clinical response. In this panorama the glucocorticoid receptor (GR) has an important role: in fact it regulates the pharmacological response thanks to the capability to interact with different molecules (DNA, RNA, ncRNA and proteins) that are known to influence its activity. In this review our aim is to highlight the knowledge about the role of protein-protein, RNA-protein interactions and epigenetic modifications on the GR and the consequent response to GCs. The characteristics of these interactions with the GR and their effects on the pharmacological activity of GCs will be examined. This information could contribute to the prediction of individual sensitivity to steroids through the identification of new markers of GC resistance. In addition this knowledge may be used in developing new strategies for targeted therapy
Role of MDR1 gene polymorphisms in gingival overgrowth induced by cyclosporine in transplant patients.
No full textBACKGROUND AND OBJECTIVE:
The aim of the present study was to determine the association between genotypes of the MDR1 gene, encoding P-glycoprotein, and gingival overgrowth in transplant patients treated with cyclosporine, and to evaluate the effect of periodontal treatment in these patients.
MATERIAL AND METHODS:
Fifty transplant patients receiving therapy with cyclosporine and suffering from gingival overgrowth were subjected to nonsurgical periodontal treatment and received oral hygiene instructions. Hyperplastic index, periodontal probing depths, bleeding and plaque scores were recorded at baseline and after 3 and 6 mo. Patients were dichotomized into two groups: those with a hyperplastic index of or = 30% (clinically significant gingival overgrowth). MDR1 C3435T and G2677T polymorphisms were evaluated in all patients and in 100 controls.
RESULTS:
At baseline, 32 patients (64%) had minimal gingival overgrowth and 18 patients (36%) had clinically significant gingival overgrowth. The mutated C3435T genotype was significantly more frequent in the second group (p < 0.019). The significant association between gingival overgrowth and the 3435TT genotype was confirmed by logistic regression analysis (p < 0.031). The differences in hyperplastic index, observed at baseline between patients with the TT genotype and those with the CC/CT genotype disappeared in the second and third evaluation. The mean monthly change of the square root of the gingival overgrowth scores for all patients, assessed using linear models, was significantly different from baseline (-0.17 points per month, p < 0.00001); and this was particularly evident in subjects with renal transplant (-1.62, p < 0.01).
CONCLUSION:
Aetiological periodontal and self-performed maintenance therapy is effective in reducing gingival overgrowth, particularly in subjects with the 3435TT genotype and in patients with renal transplant
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