Melatonin Receptor 1B and Corticosteroid Receptor Polymorphisms in Infertile Women with Implantation Failure and Miscarriages.

BACKGROUND: The development of assisted reproductive techniques has significantly improved fertility chances in many women, but recurrent implantation failure (RIF) and miscarriages (RM) might preclude successful pregnancy. Alterations in the intrinsic secretory patterns of melatonin and cortisol influence reproduction in humans, and imperfection of receptor - dependent signaling may additionally compromise the hormonal effects. Therefore, the present study aims to investigate the influence of certain melatonin and cortisol receptor polymorphisms in infertile women. METHODS: A total of 111 female infertile patients suffering from implantation failure and/or miscarriages were genotyped for MTNR1B rs1562444, MTNR1Brs10830962, GCCR rs41423247, and GCCR ER22/23EK variants. Additionally, 106 female volunteers were genotyped for the same polymorphisms. RESULTS: The allele and genotype distribution of the investigated polymorphisms did not differ between infertile women and the control group. Significantly more women with history of RIF have MTNR1B rs1562444 G-allele-containing genotypes in comparison to AA carriers (19.3% vs. 3.6%, p = 0.004). The minor allele of the ER22/23EK variant was more frequent in infertile patients with three or more unsuccessful implantation attempts than in other women (12.5% vs. 2.4%, p = 0.025). CONCLUSIONS: Melatonin receptor 1B polymorphisms might affect embryo implantation and early pregnancy loss, while their influence on late pregnancy complications needs further evaluation. The possible association between the cortisol receptor ER22/23EK variant and recurrent implantation failure might help to differentiate women who could benefit from corticosteroid treatment.

Oxidative Stress, Reductive Stress and Antioxidants in Vascular Pathogenesis and Aging.

This review is focused on the mechanisms that regulate health, disease and aging redox status, the signal pathways that counteract oxidative and reductive stress, the role of food components and additives with antioxidant properties (curcumin, polyphenols, vitamins, carotenoids, flavonoids, etc.), and the role of the hormones irisin and melatonin in the redox homeostasis of animal and human cells. The correlations between the deviation from optimal redox conditions and inflammation, allergic, aging and autoimmune responses are discussed. Special attention is given to the vascular system, kidney, liver and brain oxidative stress processes. The role of hydrogen peroxide as an intracellular and paracrine signal molecule is also reviewed. The cyanotoxins ß-N-methylamino-l-alanine (BMAA), cylindrospermopsin, microcystins and nodularins are introduced as potentially dangerous food and environment pro-oxidants.

Nutritional Management of Thyroiditis of Hashimoto.

Since the thyroid gland is one of the organs most affected by autoimmune processes, many patients with thyroiditis of Hashimoto (TH) seek medical advice on lifestyle variance and dietary modifications to improve and maintain their hyroid function. In this review, we aim to present and discuss some challenges associated with the nutritional management of TH, focusing on environmental and dietary deficits, inflammatory and toxic nutrients, cyanotoxins, etc. We discuss the relationships among different diets, chronic inflammation, and microbiota, and their impact on the development and exacerbation of TH in detail. We share some novel insights into the role of vitamin D and melatonin for preserving thyroid function during chronic inflammation in autoimmune predisposed subjects. A comprehensive overview is provided on anti-inflammatory nutrients and ecological diets, including foods for cleansing and detoxification, which represent strategies to prevent relapses and achieve overall improvement of life quality. In conclusion, data from biomedical and clinical studies provide evidence that an appropriate dietary and lighting regimen could significantly improve the function of the thyroid gland and reduce the reactivity of autoantibodies in TH. Compliance with nutritional guidelines may help TH patients to reduce the need for medicines.

Membrane Melatonin Receptors Activated Cell Signaling in Physiology and Disease.

The pineal hormone melatonin has attracted great scientific interest since its discovery in 1958. Despite the enormous number of basic and clinical studies the exact role of melatonin in respect to human physiology remains elusive. In humans, two high-affinity receptors for melatonin, MT1 and MT2, belonging to the family of G protein-coupled receptors (GPCRs) have been cloned and identified. The two receptor types activate Gi proteins and MT2 couples additionally to Gq proteins to modulate intracellular events. The individual effects of MT1 and MT2 receptor activation in a variety of cells are complemented by their ability to form homo- and heterodimers, the functional relevance of which is yet to be confirmed. Recently, several melatonin receptor genetic polymorphisms were discovered and implicated in pathology-for instance in type 2 diabetes, autoimmune disease, and cancer. The circadian patterns of melatonin secretion, its pleiotropic effects depending on cell type and condition, and the already demonstrated cross-talks of melatonin receptors with other signal transduction pathways further contribute to the perplexity of research on the role of the pineal hormone in humans. In this review we try to summarize the current knowledge on the membrane melatonin receptor activated cell signaling in physiology and pathology and their relevance to certain disease conditions including cancer.

What could microRNA expression tell us more about colorectal serrated pathway carcinogenesis?

In the last two decades, the vision of a unique carcinogenesis model for colorectal carcinoma (CRC) has completely changed. In addition to the adenoma to carcinoma transition, colorectal carcinogenesis can also occur via the serrated pathway. Small non-coding RNA, known as microRNAs (miRNAs), were also shown to be involved in progression towards malignancy. Furthermore, increased expression of certain miRNAs in premalignant sessile serrated lesions (SSLs) was found, emphasizing their role in the serrated pathway progression towards colon cancer. Since miRNAs function as post-transcriptional gene regulators, they have enormous potential to be used as useful biomarkers for CRC and screening in patients with SSLs particularly. In this review, we have summarized the most relevant information about the specific role of miRNAs and their relevant signaling pathways among different serrated lesions and polyps as well as in serrated adenocarcinoma. Additional focus is put on the correlation between gut immunity and miRNA expression in the serrated pathway, which remains unstudied.

Comparative studies of different cryopreservation methods for mesenchymal stem cells derived from human fetal liver.

Fetal stem cells possess some intriguing characteristics, which delineate them as promising cellular therapeutics. They are less immunogenic, at lower stage of differentiation and have higher potential for repopulation and migration. Furthermore, the fetal stem cells secrete a set of cytokines and growth factors, which stimulate the regeneration of the recipient tissue. The present study indicated that the adhesive fraction of human fetal liver cells possessed the morphological characteristics of mesenchymal stem cells, as well as potential to differentiate into adipocyte and osteoblast lineages. The immunophenotypic analysis showed that the cells expressed CD13, CD73, CD90 and CD105 (typical for mesenchymal stem cells) and lacked the haematopoietic lineage markers CD34 and CD45. Addressing the issue of the low-temperature storage of the human fetal liver cells, four different methods for cryopreservation were assessed: conventional slow freezing, program freezing and two vitrification protocols. The obtained results demonstrated that the cells were cryotolerant and maintained their properties and differentiation potential after thawing. Program freezing showed to be the most efficient method for cryopreservation of the investigated cells.

Nitric oxide stimulates the production of atrial natriuretic peptide and progesterone by human granulosa luteinized cells with an antiapoptotic effect.

OBJECTIVE: To study the effect of nitric oxide (NO) on atrial natriuretic peptide (ANP) and progesterone (P) production by human granulose luteinized cells (GLC) in vitro and to elucidate their role on the survival of cultured cells. METHODS: Human GLCs were cultured in HAM's F10/10% FCS as monolayers for 24 h. Subsequently GLCs were treated for 24 h with 0.5 mM Sodium Nitroprusside (SNP, NO donor) and 0.5 mM Aminoglutethimide (AG , P450scc inhibitor). The levels of ANP and P were measured in supernatants of cultured cells by proANP(1-98) kit and RIA, respectively. Caspase-3 activity was determined by Ac-DEVD-pNA as substrate. RESULTS: The production of ANP and P was increased by NO as compared to control cells (p<0.05). AG diminished the production of P compared to SNP (p<0.05). The caspase-3 activity was significantly lower in SNP treated cells (p<0.05) and increased significantly after AG treatment compared to control cells (p<0.05). CONCLUSION: NO generated by SNP in human GLCs culture stimulated the production of ANP and P. The higher levels of ANP and P were closely related to significantly lower caspase-3 activity thus showing the role of ANP, P and NO on the survival of preovulatory human follicle.

Melatonin secretion and non-specific immune responses are differentially expressed in corticotropin-dependent and corticotropin-independent Cushing's syndrome.

BACKGROUND: This study was done to clarify the relation between melatonin secretion and the hypothalamic-pituitary-adrenal axis. MATERIAL/METHODS: In this clinical study using a follow-up approach, we investigated the circadian melatonin secretion and immune parameters of patients with corticotropin-dependent (Cushing's disease) and corticotropin-independent Cushing's syndrome. Plasma hormone concentrations, interleukin 1-beta (IL-1beta) and total immunoglobulin E (IgE) were determined before surgical treatment and during remission of the syndrome 1 year later. RESULTS: Patients with Cushing's disease showed mean nocturnal and diurnal melatonin plasma values similar to those of healthy controls. Only the midday level of patients (taken at 12:00) was significantly higher in comparison to controls (35.44+/-19.5 pg/mL vs 17.14+/-3.58 pg/mL; P<0.05). In contrast, patients with corticotropin-independent Cushing's syndrome had significantly lower mean nocturnal and significantly higher mean diurnal melatonin levels (52.8+/-17.7 pg/mL and 59.2+/-28.7 pg/mL, respectively; P<0.05 and P<0.05) as compared with corresponding values for controls (101.4+/-43.1 pg/mL and 28.9+/-11.7 pg/mL, respectively). In the last group of patients, significantly higher mean IL1beta and plasma IgE concentrations (3.30+/-1.72 pg/mL and 527.8+/-474.0 IU/mL, respectively) were observed compared with controls (1.43+/-0.95 pg/mL and 35.7+/-32.1 IU/mL, respectively) (P<0.05). Remission of the hypercortisolism in these patients resulted in restoration of circadian melatonin secretion and significant reductions in plasma IL1beta and total IgE levels. CONCLUSIONS: Our results demonstrate a specific mode of melatonin secretion and different nonspecific immune responses in the 2 investigated forms of hypercortisolism, specifically, corticotropin-dependent and corticotropin-independent Cushing's syndrome.

Mitochondria are involved in stress response of A549 alveolar cells to halothane toxicity.

During inhalation anaesthesia lung epithelial cells are directly exposed to halogenated hydrocarbons such as halothane. Information about the effects of volatile anaesthetics on lung cells is rather limited although their noxious effect on the A549 alveolar cells has been shown recently. The present study indicated that halothane decreases cell viability, impairs DNA integrity and provokes stress-induced apoptosis in A549 cells when applied at clinically relevant concentrations. Data obtained clearly demonstrated intensive expression of anti-apoptotic Bcl-2 protein during treatment with all tested concentrations. In post-treatment periods the increased DNA injury was accompanied by reduction of Bcl-2 expression. We concluded that the in vitro effect of halothane on lung cells involved alteration in the expression of proteins of the mitochondrial apoptotic pathway.