Effects of Complement Regulators and Chemokine Receptors in Type 2 Diabetes.

CD55 and CD59 are complement regulatory proteins suggested to be related with progression of diabetes and its complications. The stromal cell-derived factor 1 (SDF-1) and C-X-C chemokine receptor type 4 (CXCR-4) are chemokine proteins. We aimed to investigate the relation of CD55 and CD59 expression levels and polymorphisms of SDF-1 and CXCR-4 with type 2 diabetes mellitus (T2DM) and its complications. Seventy-five T2DM patients and 73 controls were enrolled. Expression levels of CD55 and CD59 were measured by FACS Calibur; qRT-PCR was used to determine SDF-1 and CXCR-4 gene polymorphisms. CD55 and CD59 expressions in patients with nephropathy, retinopathy and cardiovascular disease were significantly lower than controls. Frequency of CXCR-4 T allele carrying was high in patients and created 1.6 fold risk for the disease (p = .07). CXCR-4 a allele carriers had decreased nephropathy; although there was no statistical significance in carrying CXCR-4 T allele, presence of nephropathy was approximately 2 times higher (p = .254). The nephropathy risk increased 10-fold in CXCR-4 TT genotype carriers (p = .02). All SDF-1 CC genotype carriers had retinopathy, so, it was considered that the CC genotype was effective in retinopathy development (p = .031). For the presence of cardiovascular disease, significant difference was observed for SDF-1 genotypes. Increased cardiovascular risk of 5- and 1.9-fold in SDF-1 T (p = .007) and CXCR-4 T (p = .216) allele carriers, respectively, was observed. We suggest that CD55 and CD59 protein levels and SDF-1 and CXCR-4 have predictive importance in process, complications and tendency of T2DM.

Relationship between MCP1 (-2518A>G) gene variants and ovarian cancer in Turkish population.

The monocyte chemoattractant protein-1 (MCP-1) gene polymorphism(-2518A>G)  in the regulatory region of the MCP-1 protein has been reported to be associated with cancer risk. In this study we aimed to investigate the relationship of MCP-1 (-2518A>G) gene polymorphism and ovarian cancer. MCP-1 genotyping was performed using polymerase chain reaction from blood samples ofovarian cancer patient (n=56) and a control groups (n=52).There was a significant difference in MCP1 (-2518A>G) genotypes between the patient and control groups (p=0.049; x2=6.042). AA carriers were significantly higher in the control group (p=0.014) whereas AG genotype and G allele carriers were significantly higher in the ovarian cancer group (p=0.029, p=0.014, respectively). This study suggests that MCP-1 (-2518A>G) AG genotype and G allele could be considered as risk factor for susceptibility to ovarian cancer.

Effects of genetic variants of CCR5 chemokine receptors on oral squamous cell carcinoma.

We aimed to evaluate the effect of genetic variants of the chemokine C-C motif receptor (CCR5) in the pathogenesis of oral squamous cell carcinoma (OSCC). A total of 127 patients diagnosed with OSCC and 104 healthy individuals were included in the study. The polymorphisms CCR5 59029 and CCR5-delta32 were assessed with the polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) method from peripheral blood samples of both groups. There was a statistically significant difference between the control and patient groups for CCR5 59029 A/G genotypes (P < 0.01). Individuals carrying the CCR5 59029 G allele (GG +AG genotypes) had a 2.84-fold increased risk for OSCC (P < 0.0001), and the CCR5 59029 AA genotype frequency was higher in the control group than in the patient group (P < 0.0001). The CCR5-delta 32 genotype frequencies did not differ significantly between controls and cases (P > 0.05). CCR5 59029 GG and CCR5-delta32 DD + ID genotype frequencies were significantly increased in Grade II-III OSCC patients compared with Grade I-II OSCC patients. In conclusion, these results suggested that the G allele of the CCR5 59029 polymorphism might be a risk factor due to the loss of receptor function that might cause increased inflammation leading to the development of OSCC.

MCP-1 and CCR2 gene variants in oral squamous cell carcinoma.

AIM: We aimed to investigate a possible association of the MCP-1 and CCR2 polymorphisms with the risk of developing oral squamous cell carcinoma (OSCC). METHODS: MCP-1 A2518G and CCR2 V64I gene polymorphisms were performed by polymerase chain reaction and restriction fragment length polymorphism, in 129 patients with OSCC and 140 healthy control subjects. RESULTS: Individuals who had G allele and GG genotype of MCP-1, and 64I allele and wt/64I genotype of CCR2 had increased risk for OSCC (P<0.05.) In contrast, individuals with CCR2 wt/wt genotype seem to be protected from OSCC (P < 0.01). Haplotype analysis revealed that MCP-1G: CCR2 64I haplotype frequencies were significantly higher in patients than those of controls (P = 0.001). CONCLUSIONS: We can suggest that the G allele of MCP-1 and 64I allele of CCR2 may be risk factors for OSCC.

XPD and hOGG1 gene polymorphisms in reperfusion oxidative stress.

Knee replacement surgery is an ischemia/reperfusion model, as it uses tourniquet applied to the knee area to stop the blood flow during the operation. Fifty patients that were undergoing elective arthroscopic knee surgery were included in our study. Human 8-oxoguanine glycosylase 1 (hOGG1) is an enzyme to repair specific DNA lesions and a good marker of hydroxyl radical damage to DNA. XPD is another DNA repair gene. We investigated the effect of hOGG1 (Ser326Cys) and XPD (Lys751Gln) polymorphisms on the oxidative stress level after reperfusion. To evaluate oxidative stress conditions, we measured 8-hydroxyguanosine and malondialdehyde (MDA) levels. Polymorphism analyses were done by PCR-RFLP; serum 8-hydroxyguanosine and MDA levels were determined by enzyme-linked immunoassay. There were no significant differences between serum MDA and 8-hydroxyguanosine levels in the samples taken before and after tourniquet application; none of these parameters were related with hOGG1 genotypes. However, we observed increased MDA levels after tourniquet application in M allele carriers for the XPD gene; this could mean that M allele carriers are more prone to DNA damage due to oxidative activity.

Hesperidin promotes programmed cell death by downregulation of nongenomic estrogen receptor signalling pathway in endometrial cancer cells.

Endometrial carcinoma (EC) is the most common malignant gynecologic tumor in women. EC is thought to be caused by increasing estrogen levels relative to progesterone in the body. Hesperidin (Hsd), a biologically active flavonoid, could be extracted from Citrus species. It has been recently shown that Hsd could exert anticarcinogenic properties in different cancer types. However, the effects of Hsd and its molecular mechanisms on EC remain unclear. In this study, the antiproliferative, apoptotic and genomic effects of Hsd in EC and its underlying mechanisms were identified. We found that Hsd significantly suppressed the proliferation of EC cells in dose and time dependent manner. Mechanistic studies showed that Hsd could contribute apoptosis by inducing externalization of phosphatidyl serine (PS), caspase-3 activity and loss of mitochondrial membrane (MMP). Furthermore, we examined that Hsd could also significantly upregulate the expression of proapoptotic Bax subgroup genes (Bax and Bik) while downregulating the anti-apoptotic protein Bcl-2 in EC cell lines. According to GO enrichment and KEGG pathway analysis of differentially expressed genes in Hsd treated EC cells, we identified that Hsd could promote cell death via downregulation of estrogen receptor I (ESRI) that was directly related to ERK/MAPK pathway. Taken together, our study first showed that Hsd could be an antiestrogenic compound that could modulate nongenomic estrogen receptor signaling through inhibition of EC cell growth. Our findings may provide us a novel growth inhibitory agent for EC treatment after verifying its molecular mechanism with in vivo studies.

Identification of gene variants related to the nitric oxide pathway in patients with acute coronary syndrome.

Dysfunction of vascular endothelium is known to have an essential role in the atherosclerotic process by releasing mediators including nitric oxide (NO). Nitric oxide maintains endothelial balance by controlling cellular processes of vascular smooth muscle cells. Evidence suggests that variations in the NO pathway could include atherosclerotic events. The objective of this study was to determine the possible effects of genes on the nitric oxide pathway in the development of acute coronary syndrome (ACS). The blood samples of 100 patients with ACS and 100 controls were collected at Istanbul University, Department of Cardiology. DNA samples were genotyped by using Illumina Cyto-SNP-12 BeadChip. The additive model and Correlation/Trend Test were selected for association analysis. Afterwards, a Q-Q graphic was drawn to compare expected and obtained values. A Manhattan plot was produced to display p-values that were generated by -log10(P) function for each SNP. The p-values under 1×10(-4) were selected as statistically significant SNPs while p-values under 5×10(-2) were considered as suspicious biomarker candidates. Nitric oxide pathway analysis was then used to find the single nucleotide polymorphisms (SNPs) related to ACS. As a result, death-associated protein kinase 3 (DAPK) (rs10426955) was found to be most statistically significant SNP. The most suspicious biomarker candidates associated with the nitric oxide pathway analysis were vascular endothelial growth factor A (VEGFA), methionine sulfoxide reductase A (MSRA), nitric oxide synthase 1 (NOS1), and GTP cyclohydrolase I (GCH-1). Further studies with large sample groups are necessary to clarify the exact role of nitric oxide in the development of disease.

Oral squamous cell carcinoma and serum paraoxonase 1.

BACKGROUND: Serum paraoxonase 1 is involved in mechanisms that protect cells from oxidative stress damage. This study aimed to investigate the correlation between serum paraoxonase 1 activity and polymorphisms in patients with oral squamous cell carcinoma. METHODS AND MATERIALS: Fifty-seven patients with oral squamous cell carcinoma and 59 matched healthy controls participated in the study. Serum paraoxonase 1 activity and polymorphisms in blood samples were compared with results for polymerase chain reaction and restriction fragment length polymorphism tests. RESULTS: Mean serum paraoxonase 1 activity levels were lower in patients than controls (mean ± standard deviation, 21.9 ± 5 units/l and 120.4 ± 2 units/l, respectively) (p = 0.001). The serum paraoxonase 1 192 glutamine polymorphism was more common in patients than controls. CONCLUSION: Patients with oral squamous cell carcinoma had significantly lower serum paraoxonase 1 activity levels and a greater prevalence of the serum paraoxonase 1 192 glutamine allele, compared with controls. Serum paraoxonase 1 may play a role in the aetiology of oral squamous cell carcinoma.