1,721,049 research outputs found
DNA methylation alterations caused by Leishmania infection may generate a microenvironment prone to tumour development
Full text linkDNA methylation is an epigenetic signature consisting of a methyl group at the 5’ cytosine of CpG dinucleotides. Modifications in DNA methylation pattern have been detected in cancer and infectious diseases and may be associated with gene expression changes. In cancer development DNA methylation aberrations are early events whereas in infectious diseases these epigenetic changes may be due to host/pathogen interaction. In particular, in leishmaniasis, a parasitic disease caused by the protozoan Leishmania, DNA methylation alterations have been detected in macrophages upon infection with Leishmania donovani and in skin lesions from patients with cutaneous leishmaniasis. Interestingly, different types of cancers, such as cutaneous malignant lesions, lymphoma and hepatocellular carcinoma, have been diagnosed in patients with a history of leishmaniasis. In fact, it is known that there exists an association between cancer and infectious diseases. Leishmania infection may increase susceptibility to develop cancer, but the mechanisms involved are not entirely clear. Considering these aspects, in this review we discuss the hypothesis that DNA methylation alterations induced by Leishmania may trigger tumorigenesis in long term infection since these epigenetic modifications may enhance and accumulate during chronic leishmaniasis
Common fragile sites on human chromosomes represent transcriptionally active regions: evidence from camptothecin
No full textCellular processes involved in the expression of fragile sites (FS) have been investigated by studying the possible modulation of their induction by camptothecin, a specific topoisomerase I inhibitor. Expression of FS was induced by aphidicolin and then camptothecin was administered to cultures during G2 phase. Under these conditions, a very high number of chromosome aberrations were obtained: R-bands carrying FS were specifically involved in breakage and, in particular, the common FS (cFS) bands already expressed in aphidicolin-treated cultures were the most affected. These data show that the expressed FS are preferential targets of camptothecin, that is, regions where topoisomerase I-cleavable complexes are formed. This allows us to hypothesize that cFS could represent the cytogenetic expression of transcriptionally active regions. These treatments were able to induce, besides the known FS, four new FS, namely 1p34, 6p21, 6q25, and 15q15
Correlation between major histocompatibility complex (MHC)-class II and type 1 diabetes
No full textThe autoimmune disease type 1 diabetes (T1D) results from a T lymphocyte-dependent, selective destruction of the insulin-producing pancreatic beta-cells and subsequent irreversible insulin deficiency. The disease is caused by a combination of genetic and environmental factors. Numerous genetic, structural and biological studies have provided a convincing case that in human T1D and in its murine model, the non obese diabetes (NOD) mouse, the major histocompatibility complex (MHC) class II molecules, HLA-DQB1 and -DRB1 and their murine orthologues, IA and IE, are the major genetic determinants. The two loci act as a complex superlocus, with both haplotype- and genotype-specific effects. In humans the HLA class II molecule-association with the disease is constituted by a two-sided gradient from positively associated-high risk to negatively associated-low risk molecules. Very low risk corresponds to dominant protection from the disease. The protein structure of DQ/IA and DR/IE molecules have been established. Molecular modeling work revealed that there are marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules show conserved similarities that differ with the shared structural patterns observed between the protective molecules. The available data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall these observations suggest shared pathways in human and murine T1D
Zinc status and autoimmunity: A systematic review and meta-analysis
Full text linkZinc is an essential trace element for living organisms and their biological processes. Zinc plays a key role in more than 300 enzymes and it is involved in cell communication, proliferation, differentiation and survival. Zinc plays also a role in regulating the immune system with implications in pathologies where zinc deficiency and inflammation are observed. In order to examine the experimental evidence reported in the literature regarding zinc levels in the body of patients with autoimmune disorders compared to control individuals, a systematic review and meta-analysis were performed. From 26,095 articles identified by literature search, only 179 of them were considered potentially relevant for our study and then examined. Of the 179 articles, only 62 satisfied the inclusion criteria. Particularly for Fixed Model, Zn concentration in both serum (mean effect = -1.19; confidence interval: -1.26 to -1.11) and plasma (mean effect = -3.97; confidence interval: -4.08 to -3.87) samples of autoimmune disease patients was significantly lower than in controls. The data presented in our work, although very heterogeneous in the manner of collecting and investigating samples, have proved to be extremely consistent in witnessing a deficiency of zinc in serum and plasma of patients compared to controls
DNA methylation alterations at RE1-silencing transcription factor binding sites and their flanking regions in cancer
Full text linkAbstract Background DNA methylation changes, frequent early events in cancer, can modulate the binding of transcription factors. RE1-silencing transcription factor (REST) plays a fundamental role in regulating the expression of neuronal genes, and in particular their silencing in non-neuronal tissues, by inducing chromatin modifications, including DNA methylation changes, not only in the proximity of its binding sites but also in the flanking regions. REST has been found aberrantly expressed in brain cancer and other cancer types. In this work, we investigated DNA methylation alterations at REST binding sites and their flanking regions in a brain cancer (pilocytic astrocytoma), two gastrointestinal tumours (colorectal cancer and biliary tract cancer) and a blood cancer (chronic lymphocytic leukemia). Results Differential methylation analyses focused on REST binding sites and their flanking regions were conducted between tumour and normal samples from our experimental datasets analysed by Illumina microarrays and the identified alterations were validated using publicly available datasets. We discovered distinct DNA methylation patterns between pilocytic astrocytoma and the other cancer types in agreement with the opposite oncogenic and tumour suppressive role of REST in glioma and non-brain tumours. Conclusions Our results suggest that these DNA methylation alterations in cancer may be associated with REST dysfunction opening the enthusiastic possibility to develop novel therapeutic interventions based on the modulation of this master regulator in order to restore the aberrant methylation of its target regions into a normal status
An INSIG2 polymorphism affects glucose homeostasis in Sardinian obese children and adolescents
No full textAllelic variants of a single nucleotide polymorphism (SNP), rs7566605, located approximately 10 kb upstream of the INSIG2 gene have been found in association with body weight and with other clinical features related to obesity in some populations but not in others. Our objective was to test the association of this SNP in obese children and adolescents from the genetically isolated population of Sardinia. We tested the association of rs7566605 with body mass index (BMI) and with serum glucose and insulin concentrations and a surrogate measure of insulin resistance (HOMA-IR) in a cohort of 747 Sardinian obese children and adolescents. A case control analysis was performed using 548 ethnically-matched healthy controls. Allelic frequencies of the SNP were similar between patients and controls. Mean glucose and insulin concentration and mean HOMA-IR values were significantly higher in patients carrying the CC genotype than in the CG and GG carriers. In the patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), allele C was significantly more frequent than in controls. Although INSIG2 polymorphisms do not consistently associate with BMI, the observation of an association with glucose concentration would support a role for this gene in the metabolic complications of obesity
The role of the rs9939609 FTO gene polymorphism on BMI is age-dependent
No full textBackground: In a large sample of obese Sardinian children and controls we have confirmed that the rs9939609 variant of the FTO gene is strongly associated with BMI, with a frequency of the A allele of 55% in patients’ and of 43% in controls’ chromosomes. It has been recently suggested that this association may be age-dependent.
Objective: Aim of this study is to evaluate whether this association is uniformly present in all ages.
Methods: 1004 Sardinian obese children and adolescents were genotyped for rs9939609 by using TaqMan probes (472 boys and 532 girls, age 1-20 y). Association analyses were performed by chi-square test (2x1 table), after evaluation of the sample statistical power. Association analyses were then repeated separately in four age groups: ≤ 5 years, 6-10, 11-15 and ≥ 16.
Results: In the whole dataset the A allele was significantly more frequent (54.6%) than the T variant (P = 3.3 x 10-5). Analysis in the different age groups showed that the A allele was associated to obesity only in the age groups 6-10 years (55.4%, P = 8.2 x 10-4) and 11-15 years (56.1%, P = 7.1 x 10-4). In the older subjects the frequency of the two alleles was almost the same (A allele frequency = 49.5%), while in children ≤ 5 years the T allele was even more frequent than the A allele (44.0%), similarly to a group of lean controls.
Conclusions: Our preliminary results seem to confirm that the effect of the FTO rs9939609 A variant is age-dependent. It may be speculated that the effects of the FTO gene variants predominate in the age groups which escape control of food intake, either by the parents (≤5 years) or self-control (≥16 years). This is in line with the theory that FTO exerts its effect by an action on feeding behavior
rs9939609 in the FTO gene is associated with obesity but not with several biochemical parameters in Sardinian obese children
No full textSeveral studies have reported an association of the intronic single nucleotide polymorphism (SNP) rs9939609 of the fat mass and obesity-associated (FTO) gene with obesity and with a number of obesity-related features. We studied the association of rs9939609 with obesity in 912 obese children and adolescents (426 males and 486 females, mean ± SD age 10.5 ± 3.3 years) and in 543 normal weight subjects. A number of biochemical and clinical parameters was also evaluated in 700 of these patients. In the obese group, mean body mass index standard deviation score (BMI-SDS) was similar between the three genotypes. The A allele was present in 55% of the patients' and in 43% of controls' chromosomes. The distribution of heterozygotes was similar between patients and controls (47%), while the distribution of AA homozygotes was significantly higher in patients (31% vs. 20%). Logistic regression analysis on the genotypes yielded a χ(2) of 35.5 with an odds ratio of 1.6 (CI = 1.3-1.8), P < 1 × 10(-5) . None of the clinical and metabolic parameters tested was associated with the genotype. In conclusion, we have confirmed the strong association between FTO and obesity, and shown that only AA homozygotes are predisposed to develop obesity while TT homozygotes might be protected. Finally, we found no association between rs9939609 and a number of obesity-related abnormalities
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