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Maric G.,University of Belgrade | Gazibara T.,University of Belgrade | Zaletel I.,University of Belgrade | Labudovic Borovic M.,University of Belgrade | And 4 more authors.
Acta Physiologica Hungarica | Year: 2014

Eating process is an aggregate of complex and different forms of behavior. Its regulation is based on energy homeostasis and appetite control which includes two components: the homeostatic and the hedonistic control. Important signals in appetite regulation are gut-derived hormones. They are produced by enteroendocrine cells in response to nutrient and energy intake, and achieve their effects by influencing brain structures involved in food intake regulation. The key brain structure involved in this process is the hypothalamus. Gut hormones reach the hypothalamus from the circulation or by the vagal nerve via the nucleus of the solitary tract. Among gut peptides, ghrelin is the only orexigenic hormone, leading to an increase in food intake and body weight. All others, such as cholecystokinin, glucagon like peptide-1, oxyntomodulin, peptide tyrosine tyrosine or pancreatic polypeptide, are anorexigenic, leading to decrease in food intake. Also, gut-derived endocannabinoids exert orexigenic effect on appetite. Keeping in mind the growing problem of obesity, the crucial issue when considering gut derived peptides is to understand their mechanisms of acting because of potential role in clinical therapy, and discovering long-lasting gut peptides or their analogues, with no or minimal side effects. © 2014 Akadémiai Kiadó, Budapest.

Objective: Vascular endothelial growth factor A (VEGF) and its receptor KDR play central roles in angiogenesis and vascular repair, which occur in diabetic vascular complications, such as MI. The aim of our study was to investigate if polymorphisms rs2071559 and rs2305948 in the kinase insert domain-containing receptor (KDR) gene are associated with myocardial infarction (MI) in Caucasians with type 2 diabetes (T2DM). Design and methods: The association of KDR - 604T>C (rs2071559) and 1192G>A (rs2305948) polymorphisms was tested in a case-control cross-sectional study including 171 subjects with T2DM and MI compared to 855 subjects with T2DM without coronary artery disease (CAD). In addition, VEGF serum levels were analyzed in 98 subjects with type 2 diabetes without CAD. Results: A significantly higher frequency of the CC genotype of the KDR - 604T>C (rs2071559) polymorphism was found in diabetic patients with MI compared to diabetic patients without CAD (27.5% vs. 21.1%, p = 0.04). On the other hand, the 1192G>A (rs2305948) polymorphism was not associated with MI in subjects with type 2 diabetes. Significantly higher VEGF serum levels were found in subjects with the - 604CC genotype compared to those with other (CT + TT) genotypes (73.8 ± 22.1 ng/l vs. 58.1 ± 18.5 ng/l; p < 0.01). Multiple logistic regression analysis adjusted for age, arterial hypertension, LDL cholesterol, HDL cholesterol and hsCRP revealed that carriers of the - 604CC genotype (rs2071559) had a 1.6-fold higher risk for MI (OR = 1.6; 95% CI = 1.1-2.1; p = 0.022). Conclusion: The present study demonstrates that the CC genotype of the KDR - 604T>C polymorphism (rs2071559) is a possible risk factor for MI in Caucasians with T2DM. © 2014 The Canadian Society of Clinical Chemists.

Vukojevic K.,University of Split | Vukojevic K.,University of Mostar | Petrovic D.,Institute of Histology and Embryology | Saraga-Babic M.,University of Split
Gene Expression Patterns | Year: 2010

Expression of the neural crest marker nestin was studied in glial and neuronal progenitors of developing human spinal ganglia using immunohistochemistry in 10 conceptuses, 5-10 weeks old. Quantification was performed by counting the ratio of positive cells in the total cell number, expressed as mean ± SD and by the Mann-Whitney test. Strong expression of nestin in the 5th-6th developmental week (56%) decreased to 49% in the foetal period. During the same period, number of PGP9.5-positive cells increased from 38% to 42%. At earliest stages, the number of cells expressing GFAP was two folds higher (21%) than S100 (11%). During further development, their number nearly levelled (23% and 28%, respectively), and finally reached level of 25% for GFAP and 40% for S100. While expression of nestin was constantly higher in the dorsal parts of spinal ganglia, number of PGP9.5-, GFAP- and S100-positive cells was higher in their ventral parts, thus indicating ventral to dorsal direction of spinal ganglia differentiation. Co-localization of nestin and GFAP or nestin and S100 was observed during the whole investigate period, while PGP9.5 did not co-localize with nestin. Some ganglion cells simultaneously co-expressing GFAP and S100 might be satellite cells and immature Schwann cells. We suggest that some nestin-positive cells might be capable to differentiate into neurons during the earliest stages of development. Gangliogenesis seems to be important process during the whole ganglion development. Continuous presence of neural crest cells during development might be important in regenerative processes following damage of the spinal ganglia. © 2009 Elsevier B.V. All rights reserved.

Marzese D.M.,John Wayne Cancer Institute | Scolyer R.A.,Royal Prince Alfred Hospital | Scolyer R.A.,University of Sydney | Scolyer R.A.,Melanoma Institute Australia | And 14 more authors.
Neuro-Oncology | Year: 2014

Background: The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets. Methods: Genome-wide DNA methylation analyses of MBMs (n = 15) and normal brain tissues (n = 91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues (99 MBMs and 43 extracranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing. Results: MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN, and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. Of MBMs, 46.1% and 28.8% had BRAF and NRAS missense mutations, respectively. Compared with lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified 2 clinically relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis. Conclusions: Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes. © The Author(s) 2014.

Avramovic V.,Institute of Histology and Embryology | Petrovic V.,Institute of Histology and Embryology | Jovic M.,Institute of Histology and Embryology | Vlahovic P.,Center for Medical Biochemistry
Acta Otorhinolaryngologica Italica | Year: 2015

During chronic tonsillitis, the relationship between proliferation and apoptosis of lymphocytes in tonsillar follicles can be disturbed, which gives rise to attenuation of tonsil immunocompetence and diminishing its contribution in systemic immunity. In this study, we have quantified the cells expressing the markers of proliferation and apoptosis in the follicles of the palatine tonsil. Six tonsils from patients aged 10-29 years with hypertrophic tonsillitis and five tonsils from patients aged 18-22 years with recurrent tonsillitis were studied. The sections of paraffin blocks of tonsillar tissue were stained by the immunohistochemical LSAB/HRP method with the utilisation of antibodies for: Ki-67 antigen-cell marker of proliferation; Bcl-2 and survivin anti-apoptotic factors and Fas/CD95, caspase-3 and Bax pro-apoptotic factors. The size of lymphoid follicles, i.e. mean follicle area and number of lymphoid follicle immunopositive cells per mm2 of a slice area, i.e. numerical areal density were determined by the quantitative image analysis. The localisation of Ki-67, Bcl-2, survivin, Fas/CD95, caspase-3 and Bax- immunopositive cells inside the palatine tonsil was similar in both types of tonsillitis. The number of Ki-67 immunopositive cells was significantly (p < 0.01) larger in the tonsils with hypertrophic tonsillitis (14681.4 ± 1460.5) in comparison to those with recurrent tonsillitis (12491.4 ± 2321.6), although the number of survivin and caspase-3 immunopositive cells was significantly (p < 0.05) larger in recurrent tonsillitis (survivin, 406.9 ± 98.4; caspase-3, 350.4 ± 119.4) when compared to those with hypertrophic tonsillitis (survivin, 117.4 ± 14.5; caspase-3, 210 ± 24). Our results show that the rate of the proliferation and apoptosis of follicular lymphocytes is different in various types of tonsillitis. This suggests that the immunological potential of the palatine tonsil varies in patients with hypertrophic and recurrent tonsillitis, which in practice poses a dilemma over the choice of conservative or surgical treatment. © 2015, Pacini Editore S.p.A. All rights reserved.

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