Variability, Expression, and Methylation of IL-6 and IL-8 Genes in Bladder Cancer Pathophysiology.

Bladder cancer (BC) is the 10th most common form of cancer globally, but its complete aetiology is still unknown. Nevertheless, there is evidence that chronic inflammation plays a role in the development and progression of BC. Therefore, the presented study aimed to detect a potential association between selected single nucleotide polymorphisms (SNPs)-rs1800797 and rs2069845 in IL-6 and rs2227307 in IL-8-and BC development, as well as to identify the impact of BC on the level of expression and methylation of IL-6 and IL-8 promoters in PBMCs with the use of the TaqMan SNP genotyping assay, TaqMan gene expression assay, and methylation-sensitive high-resolution melting techniques. We did not find any association between the genotypes and combined genotypes of all studied polymorphisms and the occurrence of BC. However, we found that BC patients were characterised by decreased IL-6 and IL-8 mRNA expression levels compared to the controls. Additionally, the methylation status of the IL-6 promoter was higher in controls than in BC patients. Our findings suggest that inflammation may be involved in the development and progression of BC.

Agomelatine Changed the Expression and Methylation Status of Inflammatory Genes in Blood and Brain Structures of Male Wistar Rats after Chronic Mild Stress Procedure.

The preclinical research conducted so far suggest that depression development may be influenced by the inflammatory pathways both at the periphery and within the central nervous system. Furthermore, inflammation is considered to be strongly connected with antidepressant treatment resistance. Thus, this study explores whether the chronic mild stress (CMS) procedure and agomelatine treatment induce changes in TGFA, TGFB, IRF1, PTGS2 and IKBKB expression and methylation status in peripheral blood mononuclear cells (PBMCs) and in the brain structures of rats. Adult male Wistar rats were subjected to the CMS and further divided into matched subgroups to receive vehicle or agomelatine. TaqMan gene expression assay and methylation-sensitive high-resolution melting (MS-HRM) were used to evaluate the expression of the genes and the methylation status of their promoters, respectively. Our findings confirm that both CMS and antidepressant agomelatine treatment influenced the expression level and methylation status of the promoter region of investigated genes in PBMCs and the brain. What is more, the present study showed that response to either stress stimuli or agomelatine differed between brain structures. Concluding, our results indicate that TGFA, TGFB, PTGS2, IRF1 and IKBKB could be associated with depression and its treatment.

Variation of genes encoding nitric oxide synthases and antioxidant enzymes as potential risks of multiple sclerosis development: a preliminary study.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by a variable clinical course and diverse pathophysiology, including nitrative and oxidative stresses as well as inflammation. We aimed to detect the potential association between five selected single-nucleotide polymorphisms (SNPs) in genes encoding nitric oxide synthetases as well as antioxidant enzymes and the development of MS in a Polish population. Genomic DNA was isolated from peripheral blood collected from 142 MS patients and 140 controls. Using Taq-Man® probes, we genotyped the following SNPs: rs1879417 in NOS1, and rs2297518 in NOS2 as well as rs4880 in SOD2, rs7943316 in CAT, rs713041 in GPX4. In the case of rs2297518, the C/C genotype and C allele SNP were associated with an enhanced occurrence of MS, while the C/T, T/T genotypes, and T allele of the same polymorphism reduced this risk. Moreover, the C/C homozygote and C allele of the rs4880 SNP reduced MS risk, while the T allele increased the risk. In addition, the A/T heterozygote of rs7943316 polymorphism was associated with an increased risk of MS occurrence. We also detected that the C/C genotype and C allele of rs713041 decreased the risk of MS, whereas the T/T genotype and T allele increased this risk. In conclusion, the results of our study suggest some links between polymorphic variability in the nitrative/oxidative stress-related genes and the risk of MS development in the Polish population.

The role of oxidative and nitrosative stress and the tryptophan catabolites pathway in the pathogenesis of depression / Rola stresu oksydacyjnego i nitracyjnego oraz szlaku katabolitów tryptofanu w patogenezie depresji.

Depression is the most common mental illness, affecting approximately 350 million people around the world. Despite numerous studies, the etiology of this disease remains unclear. Previous studies suggest the involvement of interrelated biochemical pathways, i.e. oxidative and nitrative stress as well as abnormalities of the tryptophan catabolites pathway (TRYCATs) in the depression development. Therefore, the aim of this study was to explain the role of oxidative and nitrative stress as well as disorders in the course of the TRYCATs pathway in the molecular basis of depression. In this study, an attempt was made to determine the effect of single nucleotide polymorphisms, located in genes, encoding enzymes involved in oxidative and nitrative stress, and the TRYCATs pathway on the incidence of depression. Moreover, using an in vivo model of depression, the impact of chronic mild stress stimuli on mRNA expression and protein amount as well as the degree of methylation of the promoter regions of genes encoding enzymes involved in the studied pathways was assessed. The obtained results clearly confirmed the studied biochemical pathways are involved in the development of depression at the molecular level.

Clinical Potential of Fruit in Bladder Cancer Prevention and Treatment.

Bladder cancer (BC) is the most common tumor of the urinary system in the world. Moreover, despite using anticancer therapies, BC is also characterized by a high recurrence risk. Among numerous risk factors, cigarette smoking, occupational exposure to certain aromatic compounds, and genetic factors contribute most strongly to BC development. However, the epidemiological data to date suggests that diet quality may influence some carcinogenic factors of BC and, therefore, might have a preventative effect. Adequate consumption of selected fruits with scientifically proven properties, including pomegranates and cranberries, can significantly reduce the risk of developing BC, even in those at risk. Therefore, in this article, we aim to elucidate, using available literature, the role of fruits, including pomegranates, cranberries, citrus fruits, cactus pears, and apples, in BC prevention and treatment. Previous data indicate the role of compounds in the above-mentioned fruits in the modulation of the signaling pathways, including cell proliferation, cell growth, cell survival, and cell death.

Probiotics in the Prevention of the Calcium Oxalate Urolithiasis.

Nephrolithiasis ranks third among urological diseases in terms of prevalence, making up about 15% of cases. The continued increase in the incidence of nephrolithiasis is most probably due to changes in eating habits (high protein, sodium, and sugar diets) and lifestyle (reduced physical activity) in all developed countries. Some 80% of all kidney stones cases are oxalate urolithiasis, which is also characterized by the highest risk of recurrence. Frequent relapses of nephrolithiasis contribute to severe complications and high treatment costs. Unfortunately, there is no known effective way to prevent urolithiasis at present. In cases of diet-related urolithiasis, dietary changes may prevent recurrence. However, in some patients, the condition is unrelated to diet; in such cases, there is evidence to support the use of stone-related medications. Interestingly, a growing body of evidence indicates the potential of the microbiome to reduce the risk of developing renal colic. Previous studies have primarily focused on the use of Oxalobacterformigenes in patients with urolithiasis. Unfortunately, this bacterium is not an ideal probiotic due to its antibiotic sensitivity and low pH. Therefore, subsequent studies sought to find bacteria which are capable of oxalate degradation, focusing on well-known probiotics including Lactobacillus and Bifidobacterium strains, Eubacterium lentum, Enterococcus faecalis, and Escherichia coli.

The Green Anti-Cancer Weapon. The Role of Natural Compounds in Bladder Cancer Treatment.

Bladder cancer (BC) is the second most common genitourinary cancer. In 2018, 550,000 people in the world were diagnosed with BC, and the number of new cases continues to rise. BC is also characterized by high recurrence risk, despite therapies. Although in the last few years, the range of BC therapy has considerably widened, it is associated with severe side effects and the development of drug resistance, which is hampering treatment success. Thus, patients are increasingly choosing products of natural origin as an alternative or complementary therapeutic options. Therefore, in this article, we aim to elucidate, using the available literature, the role of natural substances such as curcumin, sulforaphane, resveratrol, quercetin, 6-gingerol, delphinidin, epigallocatechin-3-gallate and gossypol in the BC treatment. Numerous clinical and preclinical studies point to their role in the modulation of the signaling pathways, such as cell proliferation, cell survival, apoptosis and cell death.

The Molecular Aspect of Nephrolithiasis Development.

Urolithiasis is the third most common urological disease after urinary tract infections and prostate diseases, and it is characterised by an occurrence rate of about 15%, which continues to rise. The increase in the incidence of kidney stones observed in recent decades, is most likely caused by modifications in dietary habits (high content of protein, sodium and sugar diet) and lifestyle (reduced physical activity) in all industrialised countries. Moreover, men are more likely than women to be diagnosed with kidney stones. A growing body of evidence suggests that inflammation, oxidant-antioxidant imbalance, angiogenesis, purine metabolism and urea cycle disorders may play a crucial role in nephrolithiasis development. Patients with urolithiasis were characterised by an increased level of reactive oxygen species (ROS), the products of lipid peroxidation, proinflammatory cytokines as well as proangiogenic factors, compared to controls. Furthermore, it has been shown that deficiency and disorders of enzymes involved in purine metabolism and the urea cycle might be causes of deposit formation. ROS generation suggests that the course of kidney stones might be additionally potentiated by inflammation, purine metabolism and the urea cycle. On the other hand, ROS overproduction may induce activation of angiogenesis, and thus, allows deposit aggregation.

Oxidative stress parameters as biomarkers of bladder cancer development and progression.

The epidemiological studies confirm that the overproduction of free radical is an important factor of cancer induction as well as development, and loss of antioxidant systems efficiency is associated with an increased risk of carcinogenesis. While bladder cancer is the fourth most common type of cancer all over the world, there is little evidence of the advancing changes in oxidative/nitrative stress during the progression of bladder cancer. Our study aimed to investigate the plasma levels of typical markers of oxidative/nitrative stress depending on the clinical classification of bladder cancer differentiation and infiltration degree. We examined 40 patients with newly diagnosed bladder cancer and 20 healthy volunteers as a control group. We analysed the plasma levels of protein carbonyls, thiol groups, 3-nitrotyrosine, lipid peroxidation, as well as non-enzymatic plasma antioxidant capacity using DPPH· and ABTS·+ radicals. We confirmed that all analysed biomarkers are higher in enrolled BC patients than in healthy subjects. Furthermore, our findings demonstrate a positive correlation between the degree of bladder cancer progression and the level of oxidative stress, but no correlation in the case of NT-3. Based on obtained results, we might conclude that during carcinogenesis of the bladder increased oxidative damage of biomolecules is manifested. This indicates the participation of oxidative stress in the development of bladder cancer, and it is important the ensure the proper antioxidant protection.

Chronic Mild Stress and Venlafaxine Treatment Were Associated with Altered Expression Level and Methylation Status of New Candidate Inflammatory Genes in PBMCs and Brain Structures of Wistar Rats.

Preclinical studies conducted to date suggest that depression could be elicited by the elevated expression of proinflammatory molecules: these play a key role in the mediation of neurochemical, neuroendocrine and behavioral changes. Thus, this study investigates the effect of chronic mild stress (CMS) and administration of venlafaxine (SSRI) on the expression and methylation status of new target inflammatory genes: TGFA, TGFB, IRF1, PTGS2 and IKBKB, in peripheral blood mononuclear cells (PMBCs) and in selected brain structures of rats. Adult male Wistar rats were subjected to the CMS and further divided into matched subgroups to receive vehicle or venlafaxine. TaqMan gene expression assay and methylation-sensitive high-resolution melting (MS-HRM) were used to evaluate the expression of the genes and the methylation status of their promoters, respectively. Our results indicate that both CMS and chronic treatment with venlafaxine were associated with changes in expression of the studied genes and their promoter methylation status in PMBCs and the brain. Moreover, the effect of antidepressant administration clearly differed between brain structures. Summarizing, our results confirm at least a partial association between TGFA, TGFB, IRF1, PTGS2 and IKBKB and depressive disorders.

The Interplay between Oxidative Stress, Inflammation and Angiogenesis in Bladder Cancer Development.

In 2018, 550,000 people were diagnosed with bladder cancer (BC), of which nearly 200,000 people died. Moreover, men are 4 times more likely than women to be diagnosed with BC. The risk factors include exposure to environmental and occupational chemicals, especially tobacco smoke, benzidine and genetic factors. Despite numerous studies, the molecular basis of BC development remains unclear. A growing body of evidence suggests that inflammation, oxidant-antioxidant imbalance and angiogenesis disorders may play a significant role in the development and progression of bladder cancer. The patients with bladder cancer were characterised by an increased level of reactive oxygen species (ROS), the products of lipid peroxidation, proinflammatory cytokines and proangiogenic factors as compared to controls. Furthermore, it was shown that polymorphisms localised in genes associated with these pathways may modulate the risk of BC. Interestingly, ROS overproduction may induce the production of proinflammatory cytokines, which finally activated angiogenesis. Moreover, the available literature shows that both inflammation and oxidative stress may lead to activation of angiogenesis and tumour progression in BC patients.

Single-Nucleotide Polymorphisms in Oxidative Stress-Related Genes and the Risk of a Stroke in a Polish Population-A Preliminary Study.

The present preliminary case-control study was undertaken to detect the potential association of six single nucleotide polymorphisms (SNPs) in oxidative stress-related genes: SOD2 (c.47T > C; rs4880), CAT (c.-89A > T; rs7943316), GPX4 (c.660T > A; rs713041), NOS1 (g.117803515C > T; rs1879417) and NOS2 (c.1823C > T; rs2297518 and c.-227G > C; rs10459953) and the occurrence of a stroke. The SNPs were determined using the TaqMan® Allelic Discrimination Assay in 107 patients with strokes and 107 age- and sex-matched individuals who had not experienced cerebrovascular accidents. The T alleles of the rs4880 were positively correlated with a stroke (bootstrap OR 1.31; 1.07-1.59 95% CI). In the case of the rs713041, an association with the T allele was found (bootstrap OR 1.36; 1.12-1.67). In addition, the occurrence of a stroke was associated with the presence of the C allele of the rs1879417 (bootstrap OR 1.32; 1.09-1.61). We also found that the C/C genotype and C allele of the rs2297518 increased the risk of a stroke (bootstrap ORs 7.00; 4.34-11.29 and 4.96; 3.88-6.34, respectively). Moreover, the C allele of the rs10459953 was associated with an increased occurrence of this disease (bootstrap OR 1.31; 1.08-1.60). These results indicated that genetics variants in the SOD2, GPX4, NOS1 and NOS2 might be associated with susceptibility to strokes in the Polish population.

Disturbance of cellular homeostasis as a molecular risk evaluation of human endothelial cells exposed to nanoparticles.

Even though application of nanoparticles in medicine seems to provide unique solutions for drug delivery and diagnosis diseases, understanding interactions between nanoscale materials and biological systems is imperative. Therefore, this study determined the effect of different types of nanoparticles (NPs) on human endothelial cells and examined the types of toxicity responses they can induce. Four different types of NPs were tested (PLA/MMT/TRASTUZUMAB, PLA/EDTMP, PLGA/MDP, and Pluronic F127 MICELLES), representing three putative areas of application: anticancer therapy, scintigraphy, and cosmetology. The experiments were performed on immortalized human umbilical vein endothelial cells (HUVEC-STs). Light contrast phase microscopy as well as cell viability assays showed that only Pluronic F127 MICELLES decreased the number of HUVEC-STs in contrast to PLA/MMT/TRASTUZUMAB, PLA/EDTMP, and PLGA/MDP NPs, which altered cell morphology, but not their confluency. The tested NPs induced not only DNA strand-breaks and alkali-labile sites, but also internucleosomal DNA fragmentation, visualized as a DNA ladder pattern typical of apoptosis. Moreover, generation of free radicals and subsequent mitochondrial membrane potential collapse showed the significance of free radical production during interactions between NPs and endothelial cells. High concentrations of NPs had different degrees of toxicity in human endothelial cells and affected cell proliferation, redox homeostasis, and triggered mitochondrial dysfunction.

Doxorubicin-transferrin conjugate alters mitochondrial homeostasis and energy metabolism in human breast cancer cells.

Doxorubicin (DOX) is considered one of the most powerful chemotherapeutic agents but its clinical use has several limitations, including cardiomyopathy and cellular resistance to the drug. By using transferrin (Tf) as a drug carrier, however, the adverse effects of doxorubicin as well as drug resistance can be reduced. The main objective of this study was to determine the exact nature and extent to which mitochondrial function is influenced by DOX-Tf conjugate treatment, specifically in human breast adenocarcinoma cells. We assessed the potential of DOX-Tf conjugate as a drug delivery system, monitoring its cytotoxicity using the MTT assay and ATP measurements. Moreover, we measured the alterations of mitochondrial function and oxidative stress markers. The effect of DOX-Tf was the most pronounced in MDA-MB-231, triple-negative breast cancer cells, whereas non-cancer endothelial HUVEC-ST cells were more resistant to DOX-Tf conjugate than to free DOX treatment. A different sensitivity of two investigate breast cancer cell lines corresponded to the functionality of their cellular antioxidant systems and expression of estrogen receptors. Our data also revealed that conjugate treatment mediated free radical generation and altered the mitochondrial bioenergetics in breast cancer cells.

The Effect of Chronic Mild Stress and Escitalopram on the Expression and Methylation Levels of Genes Involved in the Oxidative and Nitrosative Stresses as Well as Tryptophan Catabolites Pathway in the Blood and Brain Structures.

Previous studies suggest that depression may be associated with reactive oxygen species overproduction and disorders of the tryptophan catabolites pathway. Moreover, one-third of patients do not respond to conventional pharmacotherapy. Therefore, the study investigates the molecular effect of escitalopram on the expression of Cat, Gpx1/4, Nos1/2, Tph1/2, Ido1, Kmo, and Kynu and promoter methylation in the hippocampus, amygdala, cerebral cortex, and blood of rats exposed to CMS (chronic mild stress). The animals were exposed to CMS for two or seven weeks followed by escitalopram treatment for five weeks. The mRNA and protein expression of the genes were analysed using the TaqMan Gene Expression Assay and Western blotting, while the methylation was determined using methylation-sensitive high-resolution melting. The CMS caused an increase of Gpx1 and Nos1 mRNA expression in the hippocampus, which was normalised by escitalopram administration. Moreover, Tph1 and Tph2 mRNA expression in the cerebral cortex was increased in stressed rats after escitalopram therapy. The methylation status of the Cat promoter was decreased in the hippocampus and cerebral cortex of the rats after escitalopram therapy. The Gpx4 protein levels were decreased following escitalopram compared to the stressed/saline group. It appears that CMS and escitalopram influence the expression and methylation of the studied genes.

The Impact of Chronic Mild Stress and Agomelatine Treatment on the Expression Level and Methylation Status of Genes Involved in Tryptophan Catabolic Pathway in PBMCs and Brain Structures.

Depression is the serious mental disorder. Previous studies suggest that the development mechanism of depression may be associated with disorders of the tryptophan catabolic pathway (TRYCAT). Thus, this study investigates the effect of agomelatine treatment on the expression and methylation status of genes involved in TRYCAT in the brain and blood of rats exposed to a chronic mild stress (CMS). Separate groups of rats were exposed to CMS for two or seven weeks; the second group received vehicle or agomelatine for five weeks. After completion of both stress conditions and treatment, the expression levels of messenger RNA (mRNA) and protein, as well as the methylation status of promoters, were measured in peripheral blood mononuclear cells (PBMCs) and in brain structures with the use of TaqMan Gene Expression Assay, Western blot, and methylation-sensitive high-resolution melting techniques. In PBMCs, Kmo mRNA expression increased in the group after CMS, while this effect was normalized by agomelatine therapy. In brain, KatI and KatII expression changed following CMS exposure. Moreover, CMS decreased the methylation status of the second Tdo2 promoter in the amygdala. Protein expression of Tph1, Tph2, Ido1, and KatII changed in the group after CMS and agomelatine administration, most prominently in the basal ganglia, cerebral cortex, hippocampus, and amygdala. The results indicate that CMS and agomelatine affect the mRNA and protein expression, as well as the methylation of promoters of genes involved in the tryptophan catabolic pathway.

The Changes of Expression and Methylation of Genes Involved in Oxidative Stress in Course of Chronic Mild Stress and Antidepressant Therapy with Agomelatine.

Preclinical studies conducted so far suggest that oxidative stress processes may be associated with the mechanism of depression development. This study shows the effects of chronic administration of agomelatine on expression and the methylation status of Sod1, Sod2, Gpx1, Gpx4, Cat, Nos1, and Nos2 in the brain stricture and blood in the chronic mild stress (CMS) animal model of depression. The animals were exposed to the CMS procedure and treatment with agomelatine (10 mg/kg/day, IP) for five weeks and then were sacrificed. TaqMan Gene Expression Assay, Western blot, and methylation-sensitive high-resolution melting techniques were used to evaluate mRNA and protein expression of the genes, and the methylation status of their promoters. Gpx1, Gpx4, and Sod2 expression in the PBMCs and Sod1 and Sod2 expression in the brain were reduced in the stressed group after agomelatine administration. CMS caused an increase in the methylation of the third Gpx4 promoter in peripheral blood mononuclear cells and Gpx1 promoter in the cerebral cortex. Additionally, stressed rats treated with agomelatine displayed a significantly lower Gpx4 level in the hypothalamus. The results confirm the hypothesis that the CMS procedure and agomelatine administration change the expression level and methylation status of the promoter region of genes involved in oxidative and nitrosative stress.

The Effect of Chronic Mild Stress and Venlafaxine on the Expression and Methylation Levels of Genes Involved in the Tryptophan Catabolites Pathway in the Blood and Brain Structures of Rats.

A growing body of evidence suggests that depression may be associated with impairment of the tryptophan catabolites (TRYCATs) pathway. The present study investigated the effects of the chronic administration of venlafaxine on the expression and methylation status of Katl, Tph1/2, Ido1, Kmo and Kynu in the brain and blood of rats exposed to the CMS model of depression. The rats were subjected to the CMS procedure for 2 or 7 weeks and administered venlafaxine (10 mg/kg/day, IP) for 5 weeks. mRNA and protein expression and the methylation status of gene promoters in PBMCs and six brain structures were evaluated and analysed using the TaqMan Gene Expression Assay and Western blotting, and methylation-sensitive high-resolution melting (MS-HRM), respectively. We found that the CMS procedure increased KatI expression in the midbrain and KatII expression in the midbrain and the amygdala, while venlafaxine administration decreased KatII expression in the hypothalamus and the cerebral cortex. The methylation status of the Tph1 and Kmo promoters in peripheral blood mononuclear cells (PBMCs) was significantly increased in the stressed group after antidepressant therapy. The protein levels of Tph1 and Ido1 were decreased following venlafaxine administration. Our results confirmed that CMS and venlafaxine modulate the expression levels and methylation status of genes involved in the TRYCATs pathway.

Effects of venlafaxine on the expression level and methylation status of genes involved in oxidative stress in rats exposed to a chronic mild stress.

Recent human and animal studies indicate that oxidative and nitrosative stress may play a role in the aetiology and pathogenesis of depression. This study investigates the effect of chronic administration of the serotonin-norepinephrine reuptake inhibitor, venlafaxine, on the expression and methylation status of SOD1, SOD2, GPx1, GPx4, CAT, NOS1 and NOS2 in the brain and blood of rats exposed to a chronic mild stress (CMS) model of depression. Separate groups of animals were exposed to CMS for 2 or 7 weeks; the second group received saline or venlafaxine (10 mg/kg/d, IP) for 5 weeks. After completion of both stress conditions and drug administration, the mRNA and protein expression of selected genes and the methylation status of their promoters were measured in peripheral mononuclear blood cells (PBMCs) and in brain structures (hippocampus, amygdala, hypothalamus, midbrain, cortex, basal ganglia) with the use of TaqMan Gene Expression Assay, Western blot and methylation-sensitive high-resolution melting techniques. CMS caused a decrease in sucrose consumption, and this effect was normalized by fluoxetine. In PBMCs, SOD1, SOD2 and NOS2 mRNA expression changed only after venlafaxine administration. In brain, CAT, Gpx1, Gpx4 and NOS1 gene expression changed following CMS or venlafaxine exposure, most prominently in the hippocampus, midbrain and basal ganglia. CMS increased the methylation of the Gpx1 promoter in PBMCs, the second Gpx4 promoter in midbrain and basal ganglia, and SOD1 and SOD2 in hippocampus. The CMS animals treated with venlafaxine displayed a significantly higher CAT level in midbrain and cerebral cortex. CMS caused an elevation of Gpx4 in the hippocampus, which was lowered in cerebral cortex by venlafaxine. The results indicate that CMS and venlafaxine administration affect the methylation of promoters of genes involved in oxidative and nitrosative stress. They also indicate that peripheral and central tissue differ in their response to stress or antidepressant treatments. It is possible that that apart from DNA methylation, a crucial role of expression level of genes may be played by other forms of epigenetic regulation, such as histone modification or microRNA interference. These findings provide strong evidence for thesis that analysis of the level of mRNA and protein expression as well as the status of promoter methylation can help in understanding the pathomechanisms of mental diseases, including depression, and the mechanisms of action of drugs effective in their therapy.

Novel association between TGFA, TGFB1, IRF1, PTGS2 and IKBKB single-nucleotide polymorphisms and occurrence, severity and treatment response of major depressive disorder.

BACKGROUND: Activation of the immune system might affect the severity of depressive episodes as well as response to the antidepressant treatment. The purpose of this study was to investigate whether the occurrence of variant alleles of analyzed SNPs are involved in prevalence and progression of depression. Moreover, selected genes and SNPs have not been investigated in context of the disease severity and treatment. Therefore, six polymorphisms were selected: g.41354391A>G-TGFB1 (rs1800469), g.132484229C>A-IRF (rs2070729), g.186643058A>G-PTGS2 (rs5275), g.186640617C>T-PTGS2 (rs4648308), g.70677994G>A-TGFA (rs2166975) and g.42140549G>T-IKBKB (rs5029748). METHODS: A total of 360 (180 patients and 180 controls) DNA samples were genotyped using TaqMan probes. RESULTS: We observed that A/G of the rs2166975 TGFA, A/C of rs2070729 IRF1 and G/T of rs5029748 IKBKB were associated with an increased risk of depression development while the T/T of rs5029748 IKBKB, T/T of rs4648308 PTGS2 and G/G of rs2166975 TGFA reduced this risk. We also stratified the study group according to gender and found that genotype A/G and allele G of the rs2166975 TGFA, G/T of rs5029748 IKBKB as well as C allele of rs4648308 PTGS2, homozygote A/A and allele A of rs5275 PTGS2 were associated with increased risk of depression development in men while homozygote G/G of rs5275 PTGS2 decreased this risk. Moreover, C/T of rs4648308 PTGS2 and A/G of rs5275 PTGS2 was positively correlated with the risk of the disease occurrence in women. Furthermore, a gene-gene analysis revealed a link between studied polymorphisms and depression. In addition, A/A of rs1800469 TGFB1 was associated with earlier age of onset of the disease while G/G of this SNP increased severity of the depressive episode. Interestingly, A/C of rs2070729 IRF1 and T/T of rs5029748 IKBKB may modulate the effectiveness of selective serotonin reuptake inhibitors therapy. In conclusion, studied SNPs may modulate the risk of occurrence, age of onset, severity of the disease and response to the antidepressant treatment.