Handan Ak

Mitochondrial DNA polymorphisms associated with longevity in the Turkish population.

The accumulation of mutations in mitochondrial DNA is a widely recognized mechanism for aging and age related diseases. However, studies indicate that some mutations could be beneficial to longevity by slowing down the function of the electron transport chain, reducing free radical production. In this study, we re-sequenced the entire mitochondrial DNA from 50 individuals and examined aging-related variations in the Turkish population. We evaluated sequence data by comparing whole SNP frequencies, individual SNP frequencies, the effect of SNPs, SNP accumulation in certain mtDNA regions and haplotype profiles between elderly and control groups. The frequency of total mitochondrial SNPs was significantly higher in nonagenarians than controls (p=0.0094). Furthermore, non-coding, synonymous and tRNA mutations were more prevalent in the 90+ group compared to controls (p=0.0001, p<0.001, p=0.0096, respectively). A73G and C152T polymorphisms were significantly associated with longevity in the Turkish population (p=0.0086 and p=0.004, respectively). Additionally, C150T was specific to the 90+ group, but the difference failed to reach statistical significance (p=0.053). We also detected a novel transversion in the ATPase6 gene (C8899A) that was negatively associated with longevity (p=0.0016). Examining the distribution of SNPs among genes and functionally associated gene regions revealed a significant accumulation of mutations in the D-loop region and genes encoding Complex I subunits (ND1-6) (p<0.0001, p=0.0302, respectively). Moreover, there was an increase in the non-synonymous mutation frequency of Complex I genes in aged subjects (p<0.0001). Haplotype H was also significantly increased in the control group (p=0.0405). Overall, our findings support a role for mitochondrial genome variations and the functionality of oxidative phosphorylation in longevity. In this report, we sequenced the whole mtDNA of the Turkish population for the first time.

The effect of calcitriol on endoplasmic reticulum stress response.

Calcitriol, the active form of vitamin D, is known for its anticancer properties including induction of apoptosis, inhibition of angiogenesis, and metastasis. Calcitriol also increases intracellular calcium triggering apoptosis in a calpain-dependent manner. Since the main storage unit for cellular calcium is endoplasmic reticulum (ER) and a decrease in ER calcium levels might induce ER stress associated cell death, we hypothesized that the cellular actions of calcitriol occur via ER stress. We have evaluated induction of ER stress by assessing BIP expression and XBP-1 splicing in breast cancer cell lines (MCF-7 and MDA-MB-231) and mammary epithelial cell line MCF10A. Our results suggest that cytotoxic concentrations of calcitriol induce an ER stress related response indicated as increased BIP levels and XBP-1 splicing not only in breast cancer cells but also in mammary epithelial cell line. However, vehicle treatment also induced a similar response de-emphasizing the importance of such effect. Calcitriol also failed to activate calpains, further weakening the idea of ER stress as the main mechanism for apoptotic effects of calcitriol. Taken together our results suggest an association between ER stress and vitamin D signaling. However present data indicates that ER stress by itself is not sufficient to explain anticancer properties of calcitriol.

Is overactive bladder microvasculature disease a component of systemic atheroscleorosis

To evaluate the relationship between overactive bladder (OAB) and systemic atherosclerosis in a cohort of women.

High concentration calcitriol induces endoplasmic reticulum stress related gene profile in breast cancer cells

Calcitriol, the active form of vitamin D, is known for its anticancer properties including induction of apoptosis as well as the inhibition of angiogenesis and metastasis. Understanding the mechanisms of action for calcitriol will help with the development of novel treatment strategies. Since vitamin D exerts its cellular actions via binding to its receptor and by altering expressions of a set of genes, we aimed to evaluate the effect of calcitriol on transcriptomic profile of breast cancer cells. We previously demonstrated that calcitriol alters endoplasmic reticulum (ER) stress markers, therefore in this study we have focused on ER-stress-related genes to reveal calcitriols action on these genes in particular. We have treated breast cancer cell lines MCF-7 and MDA-MB-231 with previously determined IC50 concentrations of calcitriol and evaluated the transcriptomic alterations via microarray. During analysis, only genes altered by at least 2-fold with a P value < 0.05 were taken into consideration. Our findings revealed an ER-stress-associated transcriptomic profile induced by calcitriol. Induced genes include genes with a pro-survival function (NUPR1, DNAJB9, HMOX1, LCN2, and LAMP3) and with a pro-death function (CHOP (DDIT3), DDIT4, NDGR1, NOXA, and CLGN). These results suggest that calcitriol induces an ER-stress-like response inducing both pro-survival and pro-death transcripts in the process.

Microarray gene expression analysis of uterosacral ligaments in uterine prolapse.

OBJECTIVES Pelvic organ prolapse (POP) is a major health problem that impairs the quality of life with a wide clinical spectrum. Since the uterosacral ligaments provide primary support for the uterus and the upper vagina, we hypothesize that the disruption of these ligaments may lead to a loss of support and eventually contribute to POP. DESIGN AND METHODS In this study, we therefore investigated whether there are any differences in the transcription profile of uterosacral ligaments in patients with POP when compared to those of the control samples. Seventeen women with POP and 8 non-POP controls undergoing hysterectomy for benign conditions were included in the study. Affymetrix® Gene Chip microarrays (Human Hu 133 plus 2.0) were used for whole genome gene expression profiling analysis. RESULTS There was 1 significantly down-regulated gene, NKX2-3 in patients with POP compared to the controls (p=4.28464e-013). KIF11 gene was found to be significantly down-regulated in patients with ≥3 deliveries compared to patients with <3 deliveries (p=0.0156237). UGT1A1 (p=2.43388e-005), SCARB1 (p=1.19001e-006) and NKX2-3 (p=2.17966e-013) genes were found to be significantly down-regulated in the premenopausal patients compared to the premenopausal controls. UGT1A1 gene was also found to be significantly down-regulated in the post menopausal patients compared to the postmenopausal controls (p=0.0005). CONCLUSION This study provides evidence for a significant down-regulation of the genes that take role in cell cycle, proliferation and embryonic development along with cell adhesion process on the development of POP for the first time.

TPH1 A218 allele is associated with suicidal behavior in Turkish population

BACKGROUND Serotonergic dysfunction is implicated in depression, psychiatric disorders and suicidal behaviors. The first and rate-limiting step in the synthesis of serotonin is catalyzed by tryptophan hydroxylase (TPH) which is encoded by TPH1 and THP2 genes. Genetic association studies have revealed contradictory results about the effect of the TPH1 A218C (rs1800532) polymorphism on suicidal behavior in different populations. MATERIAL AND METHOD In this study, we investigated A218C polymorphism in 109 suicide attempters and 98 healthy controls. Socio-demographic characteristics of participants were obtained through questionnaire. DNA was extracted from peripheral blood and genotyping was performed by Real Time PCR. Fishers exact test was used to evaluate the significance of the difference among the independent variables. Hardy-Weinberg equilibrium was tested using Pearsons goodness-of-fit chi-squared test. RESULTS The frequency of A allele was significantly higher in suicide attempters than controls (46.33% vs. 35.71%, p=0.0357). However, there were no differences in genotype frequencies of this locus between participants having attempted suicide and controls (p>0.05). Among males, frequencies of CC genotype and C allele were found to be significantly higher in controls (p=0.0125, p=0.0298). With regard to the female subjects and female controls, no significant association was detected between suicidal behavior and genotype/allele frequencies (p>0.05). CONCLUSION Our results provide evidence that A allele of TPH1 A218C polymorphism may be associated with suicidal behavior in Turkish population.

Big data aware diabetes management: Requirements, solutions and reviews

The convergence of IoT, cloud computing and big data creates new opportunities for diabetes management. There are many research projects on diabetes management in the literature. They are generally based on web application architectures and rely on traditional data management systems. This paper firstly describes the big data characteristics and then discusses the perspectives of healthcare systems should have. After briefing the requirements of diabetes management in big data era, big data awareness matrix for diabetes management is presented. Existing solutions are revisited in the light of the matrix and a general review of diabetes management is concluded with the convergent technologies.