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Open access

Terezia Valkovicova, Martina Skopkova, Juraj Stanik and Daniela Gasperikova


MODY (Maturity Onset Diabetes of the Young) is a type of diabetes resulting from a pathogenic effect of gene mutations. Up to date, 13 MODY genes are known. Gene HNF1A is one of the most common causes of MODY diabetes (HNF1A-MODY; MODY3). This gene is polymorphic and more than 1200 pathogenic and non-pathogenic HNF1A variants were described in its UTRs, exons and introns. For HNF1A-MODY, not just gene but also phenotype heterogeneity is typical. Although there are some clinical instructions, HNF1A-MODY patients often do not meet every diagnostic criteria or they are still misdiagnosed as type 1 and type 2 diabetics. There is a constant effort to find suitable biomarkers to help with in distinguishing of MODY3 from Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). DNA sequencing is still necessary for unambiguous confirmation of clinical suspicion of MODY. NGS (Next Generation Sequencing) methods brought discoveries of multiple new gene variants and new instructions for their pathogenicity classification were required. The most actual problem is classification of variants with uncertain significance (VUS) which is a stumbling-block for clinical interpretation. Since MODY is a hereditary disease, DNA analysis of family members is helpful or even crucial. This review is updated summary about HNF1A-MODY genetics, pathophysiology, clinics functional studies and variant classification.

Open access

Dmytro O. Minchenko


Objective. The development of obesity and its metabolic complications is associated with dysregulation of various intrinsic mechanisms, which control basic metabolic processes through changes in the expression of numerous regulatory genes.

Methods. The expression level of HLA-DRA, HLA-DRB1, HLA-G, HLA-F, and NFX1 genes as well as miR-190b was measured in the blood of obese adolescents without signs of resistance to insulin and with insulin resistance in comparison with the group of relative healthy control individuals without signs of obesity.

Results. It was shown that obesity without signs of insulin resistance is associated with upregulation of the expression level of HLA-DRA and HLA-DRB1 genes, but with down-regulation of HLA-G gene expression in the blood as compared to control group of relative healthy adolescents. At the same time, no significant changes were observed in the expression level of HLA-F and NFX1 genes in the blood of this group of obese adolescents. Development of insulin resistance in obese individuals leads to significant down-regulation of HLA-DRA, HLA-DRB1, HLA-G, and HLA-F gene expressions as well as to up-regulation of NFX1 gene as well as microRNA miR-190b in the blood as compared to obese patients without signs of insulin resistance.

Conclusions. Results of this study provide evidence that obesity affects the expression of the subset of genes related to immune response in the blood and that development of insulin resistance in obese adolescents is associated with strong down-regulation of the expressions of HLA-DRA, HLA-DRB1, HLA-F, and HLA-G genes, which may be contribute to the development of obesity complications. It is possible that transcription factor NFX1 and miR-190b participate in downregulation of HLA-DRA gene expression in the blood of obese adolescents with insulin resistance.

Open access

Shokoufeh Taherkhani, Fatemeh Moradi, Masoumeh Hosseini, Mohsen Alipour and Hadi Feizi


Objective. Ghrelin, a 28 amino acid peptide, has diverse physiological roles. Phosphatidylino-sitol-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) are involved in some of the recognized actions of ghrelin. It has been shown that ghrelin upregulates HOXB4 gene expression but the real mechanism of this effect is not clear.

Methods. Rat bone marrow stromal cells (BMSCs) were cultured in DMEM. BMSCs were treated with ghrelin (100 μM) for 48 h. Real-time PCR for HOXB4 was performed from Control (untreated BMSCs), BG (BMSCs treated with 100 µM ghrelin), PD (BMSCs treated with 10 µM PD98059, a potent inhibitor of mitogen-activated protein kinase, and 100 µM ghrelin), LY (BM-SCs treated with 10 µM LY294002, a strong inhibitor of phosphoinositide 3-kinase, and 100 µM ghrelin) and SY (BMSCs treated with 10 µM LY294002 plus 10 µM PD98059, and 100 µM ghrelin) groups. Relative gene expression changes were determined using Relative expression software tool 9 (REST 9).

Results. HOXB4 gene has been overexpressed in ghrelin-treated BMSCs (p<0.05). PI3K inhi-bition by LY294002 significantly downregulated the ghrelin-induced overexpression of HOXB4 (p<0.05).

Conclusion. We can conclude that ghrelin, through PI3K/Akt pathway, may improve BMSC transplantation potency by reducing its apoptosis. Moreover, upregulating HOXB4 in BMSC and its possible differentiation to HSCs might in the future open the doors to new treatment for hematologic disorders. Therefore, activating the PI3K/Akt pathway, instead of using a non-specific inducer, could be the principal point to increase the efficiency of BMSC-based cell therapies in the future.

Open access

Alexandra Padova, Ivana Rokytova, Boris Mravec, Richard Kvetnansky and Peter Vargovic


Objectives. Despite extensive research efforts, mechanisms participating on development of Alzheimer’s disease (AD) are covered only partially. Data from the last decades indicate that various stressors, as etiological factors, may play a role of in the AD. Therefore, we investigated the effect of two acute stressors, immobilization (IMO) and lipopolysaccharide (LPS), on the AD-related neuropathology.

Methods. Adult C57BL/6J mice males were exposed to a single IMO stress or a single intraperitoneal injection of LPS (250 µg/kg body weight). After terminating the experiments, the brains were removed and their cortices isolated. Gene expression of pro-inflammatory cytokines, as well as expression of genes implicated in the AD neuropathology were determined. In addition, mediators related to the activation of the microglia, monocytes, and perivascular macrophages were determined in brain cortices, as well.

Results. In comparison with the control animals, we found increased gene expression of proinflammatory mediators in mice brain cortex in both IMO and LPS groups. In stressed animals, we also showed an increased expression of genes related to the AD neuropathology, as well as positive correlations between genes implicated in AD development and associated neuroinflammation.

Conclusions. Our data indicate that acute exposure to a strong IMO stressor, composed of the combined physical and psychological challenges, induces similar inflammatory and other ADrelated neuropathological changes as the immune LPS treatment. Our data also indicate that cytokines are most likely released from the peripheral immune cells, as we detected myeloid cells activity, without any microglia response. We hypothesize that stress induces innate immune response in the brain that consequently potentiate the expression of genes implicated in the AD-related neuropathology.

Open access

Ana B. Segarra, Isabel Prieto, Magdalena Martinez-Canamero, Jose-Ignacio Ruiz-Sanz, M. Begona Ruiz-Larrea, Marc De Gasparo, Inmaculada Banegas, Stefan Zorad and Manuel Ramirez-Sanchez


Objective. Enkephalins are neuropeptides involved in functions such as pain modulation and/ or cognitive processes. It has been reported that dietary fat modifies enkephalins in the brain. Since enkephalins are hydrolyzed by enkephalinases, the study of the influence of dietary fats, differing in their degree of saturation, on brain fatty acids content and enkephalinase activity is important to understand its regulatory role on neuropeptides under different type of diets.

Methods. We analyzed enkephalinase activity, assayed with alanine-β-naphthylamide as sub-strate, in frontal cortex of adult male rats fed diets supplemented with fish oil, olive oil or coconut oil, which markedly differed in the saturation of their fatty acids.

Results. Rats fed a diet enriched with coconut oil had lower soluble enkephalinase activity than the group fed olive oil (p<0.01) and fish oil (p<0.05) whereas rats fed a diet enriched with fish oil had lower membrane-bound enkephalinase activity than the group fed with olive (p<0.001) or coconut oil (p<0.05). Significant negative correlations were observed between certain fatty acids and enkephalinase activities in the groups fed with olive and coconut oils. No correlations were observed in the group fed with fish oil.

Conclusions. Dietary fat modifies enkephalinase activity in the frontal cortex depending on the degree of saturation of the used oil. It is postulated that the functions, in which enkephalins are involved, such as pain modulation or cognitive functions, may also be affected according to the type of oil used in the diet.

Open access

Nasim Malekmohamadi, Alireza Abdanipour, Mehrdad Ghorbanlou, Saeed Shokri, Reza Shirazi, Eva Dimitriadis and Reza Nejatbakhsh


Objective. Stem cell therapy, specifically, pre-induction of mesenchymal stem cells toward male germ-like cells may be useful in patients with azoospermia. The aim of this study was to evaluate in vitro differentiation of mouse bone marrow-derived mesenchymal stem cells (BMSCs) into male germ-like cells by indirect co-culture with testicular cells in the presence of bone morphogenetic protein 4 (BMP4).

Methods. Experimental groups included: control (mouse BMSCs), treatment group-1 (BMSCs treated with BMP4), treatment group-2 (indirect co-culture of BMSCs with mouse testicular cells in the presence of BMP4) and treatment group-3 (indirect co-culture of BMSCs with testicular cells). BMSCs-derived male germ-like cells were evaluated by the expression of Dazl, and Stra8 using RT-qPCR.

Results. Stra8 gene expression was significantly increased in the treatment group-2 and Dazl gene was significantly increased in the treatment group-1 compared to other groups. In conclusion, indirect co-culturing of BMSCs with testicular cells and BMP4 leads to the differentiation of BMSCs into male germ-like cells which express specific male germ-like genes. Testicular cells released factors that contributed to the differentiation of BMSCs into male germ progenitor cells.

Conclusion. This study suggests that mesenchymal stem cells may be differentiated into male germ-like cells and therefore, may be a novel treatment option for men with azoospermia.

Open access

Jana Osacka, Lubica Horvathova, Alena Cernackova and Alexander Kiss


Objective. Prolonged treatment with neuroleptics has been shown to induce FosB/ΔFosB expression in several brain regions including the medial prefrontal cortex, dorsomedial and dorsolateral striatum, ventrolateral and dorsolateral septum, nucleus accumbens shell and core, and the hypothalamic paraventricular nucleus (PVN). Some of these regions are known to be also stress responsive. This study was designed to determine whether repeated clozapine (CLZ) administration for 7 consecutive days to Wistar rats may modify FosB/ΔFosB expression in the above-mentioned brain areas induced by acute stress or novel stressor that followed 13-day chronic mild stress preconditioning.

Methods. Following experimental groups were used: unstressed animals treated with vehicle/ CLZ for 7 days; 7-day vehicle/CLZ-treated animals on the last day exposed to acute stress – forced swimming (FSW); and animals preconditioned with stress for 13 days treated from the 8th day with vehicle/CLZ and on the 14th day exposed to novel stress – FSW.

Results. In the unstressed animals CLZ markedly increased FosB/ΔFosB immunoreactivity in the ventrolateral septum and PVN. FSW elevated FosB/ΔFosB expression in the medial prefrontal cortex, striatum, and septum. CLZ markedly potentiated the effect of the FSW on FosB/ΔFosB expression in the PVN, but suppressed it in the dorsomedial striatum. Novel stress with stress preconditioning increased FosB/ΔFosB immunoreactivity in the prefrontal cortex, striatum, ventrolateral septum, and the PVN. In the nucleus accumbens the effect of the novel stressor was potentiated by CLZ.

Conclusion. Our data indicate that CLZ may modulate the acute as well as novel stress effects on FosB/ΔFosB expression but its effect differs within the individual brain regions.

Open access

Nazli Khajehnasiri, Homayoun Khazali, Farzam Sheikhzadeh and Mahnaz Ghowsi


Objective. The hypothalamic arcuate nucleus proopiomelanocortin (POMC) and neuropeptide Y (NPY) circuitries are involved in the inhibition and stimulation of the appetite, respectively. The aim of this study was to investigate the effects of one-month lasting high-intensity exercise on the POMC mRNA and NPY mRNA expression in the above-mentioned brain structure and appetite and food intake levels.

Methods. Fourteen male Wistar rats (250±50 g) were used and kept in the well-controlled conditions (22±2 °C, 50±5% humidity, and 12 h dark/light cycle) with food and water ad libitum. The rats were divided into two groups (n=7): 1) control group (C, these rats served as controls) and 2) exercised group (RIE, these rats performed a high-intensity exercise for one month (5 days per week) 40 min daily with speed 35 m/min. The total exercise time was 60 min. The body weight and food intake were recorded continuously during the experiments.

Results. The results showed relative mRNA expression of POMC and NPY estimated in the hypothalamic arcuate nucleus. There were no significant differences in the NPY and POMC mRNAs expression levels and food intake between C and RIE groups.

Conclusions. The present data indicate that one-month regular intensive exercise did not alter the levels of NPY and POMC mRNAs expression (as two important factors in the regulation of appetite) in the hypothalamic arcuate nucleus and food intake suggesting that this type of exercise itself is not an appropriate procedure for the body weight reduction.

Open access

Hisham El Falougy, Barbora Filova, Daniela Ostatnikova, Zuzana Bacova and Jan Bakos


Current understanding of the neuroanatomical abnormalities in autism includes gross anatomical changes in several brain areas and microstructural alterations in neuronal cells as well. There are many controversies in the interpretation of the imaging data, evaluation of volume and size of particular brain areas, and their functional translation into a broad autism phenotype. Critical questions of neuronal pathology in autism include the concept of the reversible plasticity of morphological changes, volume alterations of brain areas, and both short- and long-term consequences of adverse events present during the brain development. At the cellular level, remodeling of the actin cytoskeleton is considered as one of the critical factors associated with the autism spectrum disorders. Alterations in the composition of the neuronal cytoskeleton, in particular abnormalities in the polymerization of actin filaments and their associated proteins underlie the functional consequences in behavior resulting in symptoms and clinical correlates of autism spectrum disorder. In the present review, a special attention is devoted to the role of oxytocin in experimental models of neurodevelopmental disorders manifesting alterations in neuronal morphology.

Open access

Camile Wunsch, Thais Fernanda Dornelles, Pricila Girardi, Marcelo Emilio Arndt, Julia Pasqualini Genro and Veronica Contini


Objective. Genetic variants in the transcription factor 7-like 2 (TCF7L2) gene have been described as the most noteworthy ones regarding the type 2 diabetes mellitus (T2DM) liability. This work is aimed to evaluate the association between rs12255372 and rs7903146 polymorphisms and T2DM in patients with cardiovascular disease (CAD) risk.

Methods. A sample of six hundred and forty-seven patients that underwent the coronary angiography in a Cardiac Catheterization Lab was evaluated. The patients were investigated for the presence of T2DM and coronary stenosis. The TCF7L2 polymorphisms were genotyped by real-time PCR and the haplotype analysis was performed with the MLOCUS software. All genetic tests were carried out by considering the haplotype combinations in patients divided into three groups: 0 – carrying none disease risk allele, 1 – carrying one or two risk alleles and 2 – carrying three or four risk alleles.

Results. No significant associations between TCF7L2 risk haplotypes and the presence of T2DM or CAD were detected.

Conclusions. Our results indicate that the TCF7L2 rs12255372 and rs7903146 polymorphisms do not influence T2DM in Brazilian patients with the high risk for CAD. Therefore, we assume that these variants may only be relevant for a specific subgroup of T2DM patients or some particular human population.