The Role of Sirtuins in the Pathogenesis of Psoriasis.

Psoriasis is the most common chronic inflammatory skin disease with a genetic basis. It is characterised by keratinocyte hyperproliferation, parakeratosis and inflammatory cell infiltration. Psoriasis negatively affects a patient's physical and emotional quality of life. Sirtuins (SIRTs; silent information regulators) are an evolutionarily conserved group of enzymes involved in the post-translational modification of proteins, including deacetylation, polyADP-ribosylation, demalonylation and lipoamidation. SIRTs are involved in a number of cellular pathways related to ageing, inflammation, oxidative stress, epigenetics, tumorigenesis, the cell cycle, DNA repair and cell proliferation, positioning them as an essential component in the pathogenesis of many diseases, including psoriasis. Activation of SIRT1 counteracts oxidative-stress-induced damage by inhibiting the mitogen-activated protein kinases (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways and may mitigate pathological events in psoriasis. There is a significant reduction in the expression of SIRT1, SIRT2, SIRT3, SIRT4 and SIRT5 and an increase in the expression of SIRT6 and SIRT7 in psoriasis. The aim of the review is to draw the attention of physicians and scientists to the importance of SIRTs in dermatology and to provide a basis and impetus for future discussions, research and pharmacological discoveries to modulate SIRT activity. In light of the analysis of the mode of action of SIRTs in psoriasis, SIRT1-SIRT5 agonists and SIRT6 and SIRT7 inhibitors may represent new therapeutic options for the treatment of psoriasis.

The Involvement of Semaphorins in the Pathogenesis of Skin Diseases.

Semaphorins belong to a group of membrane and secretory proteins that act as ligands for several receptor families and are involved in modulating cell signaling pathways. They bind multimeric receptor complexes on the cell membrane to exert their effects and initiate unique intracellular signal transduction cascades. These proteins can influence several processes that are very important for cell function, such as cell division and differentiation. Semaphorins are involved in cell migration, apoptosis, cell adhesion, aggregation, and numerous immune processes due to their immunoregulatory effects. Semaphorins are expressed in keratinocytes, which is why they have become a target for studies on the pathogenesis of skin diseases. Most studies to date on the role of semaphorins in the pathogenesis of skin diseases have been carried out in cellular or animal models, and there are few clinical studies evaluating the role of semaphorins in the pathogenesis and therapy of skin diseases. In this narrative review, we summarized the current state of knowledge on the role of semaphorins in the pathogenesis of skin diseases and their potential importance as targets for therapy. We also tried to present the key findings and weaknesses of previous research in this field. The novelty of this article lies in the comprehensive presentation of the role of semaphorins in the pathogenesis of skin diseases, including the results of studies on cell cultures and animal models, elucidating the mechanisms and signaling pathways through which semaphorins affect the development of skin diseases, as well as on the presentation of the results of existing clinical trials evaluating the role of semaphorins in the pathogenesis of skin diseases, and as potential therapeutic targets.

Role of miRNA in Melanoma Development and Progression.

Melanoma is one of the most aggressive and progressive skin cancers. It develops from normal pigment-producing cells known as melanocytes, so it is important to know the mechanism behind such transformations. The study of metastasis mechanisms is crucial for a better understanding the biology of neoplastic cells. Metastasis of melanoma, or any type of cancer, is a multi-stage process in which the neoplastic cells leave the primary tumour, travel through the blood and/or lymphatic vessels, settle in distant organs and create secondary tumours. MicroRNA (miRNA) can participate in several steps of the metastatic process. This review presents the role of miRNA molecules in the development and progression as well as the immune response to melanoma.

Role of Adiponectin in the Pathogenesis of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic chronic inflammatory autoimmune joint disease, characterized by progressive articular damage and joint dysfunction. One of the symptoms of this disease is persistent inflammatory infiltration of the synovial membrane, the principle site of inflammation in RA. In the affected conditions, the cells of the synovial membrane, fibroblast-like synoviocytes and macrophage-like synovial cells, produce enzymes degrading cartilage and underlining bone tissue, as well as cytokines increasing the infiltration of immune cells. In patients with RA, higher levels of adiponectin are measured in the serum and synovial fluid. Adiponectin, a secretory product that is mainly white adipose tissue, is a multifunctional protein with dual anti-inflammatory and pro-inflammatory properties. Several studies underline the fact that adiponectin can play an important pro-inflammatory role in the pathophysiology of RA via stimulating the secretion of inflammatory mediators. This narrative review is devoted to the presentation of recent knowledge on the role played by one of the adipokines produced by adipose tissue-adiponectin-in the pathogenesis of rheumatoid arthritis.

CCL2, CCL5, IL4 and IL15 Gene Polymorphisms in Women with Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is a glucose intolerance that occurs during pregnancy. Several studies suggest that inflammation contributes to pregnancy-induced insulin resistance and the development of glucose intolerance. The aim of this study is to examine the association between the CCL2, CCL5, IL4 and IL15 gene polymorphisms and the development of GDM. This study included 411 pregnant women who underwent a 75 g oral glucose tolerance test at 24-28 weeks of gestation. Participants were categorised into 2 groups according to results of the oral glucose tolerance test (OGTT). The GDM group included 204 pregnant women who were diagnosed with GDM. The normal glucose tolerance group included 207 pregnant women with normal values in the OGTT. To discriminate the CCL2 rs1024611 and rs4586, CCL5 rs2107538, IL4 rs2243250, IL15 rs2857261 and rs2254514 alleles, TaqMan® Pre-Designed SNP Genotyping Assays were used. GDM was significantly associated with genotypes and alleles of the CCL2 rs1024611 and rs4586 polymorphisms, while there was no statistically significant association between the CCL5 rs2107538, IL4 rs2243250, IL15 rs2857261, and rs2254514 gene polymorphisms and GDM. In a multivariate regression analysis, age and BMI before pregnancy were independent significant predictors of a higher risk of GDM, while a lower number of G alleles CCL2 rs1024611 was protective against GDM. Moreover, women with the GG CCL2 rs1024611 and CC rs4586 genotype tended to have lower body mass and BMI increases during pregnancy, as well as lower newborn body mass. The results of our study suggest an association between CCL2 gene polymorphisms and GDM.

STAT4 gene polymorphism in patients after renal allograft transplantation.

INTRODUCTION: STAT4 (signal transducer and activator of transcription 4) is involved in the regulation of innate and adaptive immune responses. Some studies have suggested that STAT4 may be involved in the immune response after graft transplantation. Several polymorphisms in the STAT4 gene have been identified. The most commonly studied polymorphism in the STAT4 gene is rs7574865. In our study, we examined whether this polymorphism is associated with the early and late functions of renal allografts. MATERIAL AND METHODS: A total of 270 recipients of first renal transplants were included in the study. Single nucleotide polymorphisms (SNPs) within the STAT4 gene were genotyped using TaqMan genotyping assays. RESULTS: There were no statistically significant associations between the STAT4 gene rs7574865 polymorphism and delayed graft function, acute rejection, chronic allograft dysfunction, post-transplant diabetes mellitus, or creatinine serum concentrations after transplantation. CONCLUSIONS: Our results suggest a lack of association between the STAT4 rs7574865 SNP and kidney allograft function in the Polish population.

The Effect of Oral Isotretinoin Therapy on Meibomian Gland Characteristics in Patients with Acne Vulgaris.

INTRODUCTION: The aim of the study was to determine the effect of oral isotretinoin therapy on the functional and morphological condition of the anterior segment of the eye, with particular emphasis on the meibomian glands. METHODS: Twenty-four patients (48 eyes) with a diagnosis of acne vulgaris were involved in the survey. All patients underwent a thorough ophthalmological examination at three time points: before therapy, 3 months after the start of therapy, and 1 month after the completion of isotretinoin therapy. The physical examination included the following elements: blink rate, analysis of the lid margin abnormality score (LAS), tear film break-up time (TFBUT) and Schirmer's test, meibomian gland loss (MGL), and the evaluation of the meibum quality score (MQS) and meibum expressibility score (MES). Additionally, the total score of an ocular surface disease index (OSDI) questionnaire was analysed. RESULTS: In comparison with pretreatment values, significant increases in OSDI during and after the treatment (p = 0.003 and p = 0.004, respectively) were observed. Substantial deterioration during the treatment was observed for MGL (p < 0.0001), MQS (p < 0.001) and LAS (p < 0.0001), while an improvement in those parameters after isotretinoin cessation was observed (p = 0.006, p = 0.02 and p = 0.0003, respectively). The frequency of using artificial eye drops was positively associated with MGL during (Spearman's rank correlation coefficient (Rs) = + 0.31; p = 0.03) and after the cessation of the therapy (Rs = + 0.28; p = 0.04). Meibomian gland atrophy correlated significantly with MQS during (Rs = + 0.29; p = 0.04) and after treatment (Rs = + 0.38; p = 0.008). The decrease in TFBUT values correlated with increased LAS (Rs = - 0.31; p = 0.03) during the course of isotretinoin usage. We found no changes in Schirmer's test or blink rates. CONCLUSION: Isotretinoin therapy leads to increased ocular complaints related to lipid tear film component dysfunction. This is due to reversible changes in meibomian gland morphology and function observed during drug usage.

Adiponectin, Leptin and Resistin in Patients with Psoriasis.

Psoriasis is a common chronic, inflammatory skin disease characterised by keratinocyte hyperproliferation, parakeratosis, and T-cell infiltration. Adipose tissue has an endocrine function, producing an abundance of cytokines and adipokines. It has also been described that the major adipokines, leptin, resistin, and adiponectin, may be involved in the pathogenesis of psoriasis. The aim of the study was to examine the plasma levels of adiponectin, leptin, and resistin in patients with psoriasis and their correlations with disease activity parameters: Psoriasis Activity Severity Index (PASI), Dermatology Life Quality Index (DLQI), and Body Surface Area (BSA) index, as well as selected clinical parameters. The study included 53 patients with the plaque type and 31 healthy controls. The plasma concentrations of adiponectin were significantly lower in patients with psoriasis (p < 0.001) than in the control group. The plasma concentrations of leptin were higher in patients with psoriasis, however, due to high intra-patient variability of leptin plasma concentrations these differences did not reach statistical significance (p = 0.2). The plasma concentrations of resistin were significantly increased in patients with psoriasis compared to healthy controls (p = 0.02). There were no statistically significant correlations between adiponectin and leptin plasma concentrations and values of PASI, DLQI, and BSA. The resistin plasma concentrations correlated significantly with DLQI values. Additionally, we examined the correlations between adiponectin, leptin, and resistin plasma concentrations, and selected clinical parameters. Plasma concentrations of adiponectin correlated significantly with CRP values and ALT values. Leptin plasma concentrations correlated significantly with creatinine values. The results of our study confirm the role of adiponectin, leptin, and resistin in the pathogenesis of psoriasis.

Role of Janus Kinase Inhibitors in Therapy of Psoriasis.

Janus kinases inhibitors are molecules that target Janus kinases-signal transducers and activators of transcription (JAK/STAT). They inhibit this intracellular signal pathway, blocking the gene transcription of crucial proinflammatory cytokines that play a central role in the pathogenesis of many inflammatory and autoimmune diseases, including psoriasis. This process reduces psoriatic inflammation. The JAK inhibitors are divided into two generations. The first generation of JAK inhibitors blocks two or more different Janus kinases. The second generation is more specified and blocks only one type of Janus kinase and has less side effects than the first generation. Tofacitinib, ruxolitinib and baricitinib belong to first generation JAK inhibitors and decernotinib and filgotinib belong to second group. This narrative review summarizes the role of Janus kinase inhibitors in the therapy of psoriasis. Oral JAK inhibitors show promise for efficacy and safety in the treatment of psoriasis. Studies to date do not indicate that JAK inhibitors are superior to recent biologic drugs in terms of efficacy. However, JAK inhibitors, due to their lack of increased incidence of side effects compared to other biologic drugs, can be included in the psoriasis treatment algorithm because they are orally taken. Nevertheless, further studies are needed to evaluate long-term treatment effects with these drugs.

Over-Expression of Allograft Inflammatory Factor-1 (AIF-1) in Patients with Rheumatoid Arthritis.

Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic protein that is encoded by the AIF1 gene. The main functions of AIF-1 are the activation of macrophages and enhancing the production of pro-inflammatory cytokines. To date, three different AIF-1 isoforms have been identified. In this study, we examined the expression of AIF-1 isoforms on the level of mRNA, and we compared the percentage of AIF-1-positive white blood cells (WBCs) in blood and AIF-1/CD68 cells in the synovial membranes in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). We examined 15 patients with RA and 15 patients with OA who had previously undergone knee arthroplasty. Peripheral blood and synovial membranes (SMs) were collected from these patients during knee arthroplasty. We identified three AIF-1 mRNA expression variants in peripheral mononuclear cells (PBMCs) and SMs from patients in both groups. Spearman's rank correlation coefficient tests showed strong, positive, and significant correlations between the three AIF-1 mRNA expression variants in PBMCs and/or SMs in patients with RA and OA. There were no statistically significant correlations for any of the AIF-1 mRNA expression variants between PBMCs and SMs in patients with RA and OA. We observed a statistically significant increased percentage of AIF-1-positive cells in patients with RA in comparison to patients with OA. The percentage of AIF-1-positive cells in the blood of patients with RA and OA was 1.35 ± 0.81% and 0.71 ± 0.25% (p < 0.01), respectively, whereas the percentage of AIF-1/CD68-positive WBC cells in the SMs was 24.05 ± 7.17% and 4.78 ± 1.52% (p < 0.001), respectively. In conclusion, three AIF-1 mRNA expression variants occurred in PBMCs and SM cells in patients with RA and OA. The AIF-1 mRNA expression levels of the variants correlated with each other in PBMCs and SM cells, but there were no statistically significant correlations for AIF-1 mRNA expression variants between PBMCs and SM cells in patients with RA and OA. Both in the blood and SMs, we observed an increased percentage of AIF-1-positive cells in patients with RA in comparison to patients with OA. The above results suggested that AIF-1 was the cytokine involved in the pathogenesis of RA. The precise knowledge of the role of AIF-1 in RA pathogenesis and the development of inflammatory response requires further investigations.

Ficolin-2 Gene rs7851696 Polymorphism is Associated with Delayed Graft Function and Acute Rejection in Kidney Allograft Recipients.

Ficolin-2 is an activator of the complement system that acts via the lectin pathway. Complement activation plays a substantial role in the renal injury inherent to kidney transplantation. In this study, we examined the associations between ficolin-2 gene polymorphisms in exon 8 and kidney allograft function. This study comprised 270 Caucasian deceased-donor renal transplant recipients. The following parameters were recorded in each case: delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction. Among patients with DGF, we observed a significantly increased frequency of rs7851696 GT and TT genotypes as well as T allele (TT + GT vs GG OR 1.98, 95% CI 1.12-3.48, p = 0.02; T vs G OR 2.08, 95% CI 1.27-3.41, p = 0.005). There was also an increased frequency of rs4521835 GG and TG genotypes as well as G alleles; however, these differences were on the borderline of statistical significance (GG + TG vs TT, OR 1.75, 95% CI 0.98-3.12, p = 0.07; G vs T OR 1.45, 95% CI 1.00-2.09, p = 0.050). In addition, we observed an increased frequency of acute allograft rejection in carriers of ficolin-2 rs7851696 T alleles on the borderline of statistical significance (TT + GT vs GG OR 1.75, 95% CI 0.97-3.16, p = 0.08), but the frequency of T allele was significantly higher in patients with AR (T vs G OR 1.71, 95% CI 1.02-2.87, p = 0.048). The results of our study suggest that ficolin-2 rs7851696 gene polymorphism influences kidney allograft functions, with T allele increasing the risk of DGF and AR.

Genetic factors in pathogenesis of diabetes mellitus after kidney transplantation.

Posttransplant diabetes mellitus (PTDM) is one of the major metabolic complications after transplantation of solid organs including the kidney. This type of diabetes mellitus affects allograft survival, cardiovascular complications and overall patient survival. The modifiable risk factors that contribute to PTDM include obesity, some viral infections (eg, hepatitis C virus, cytomegalovirus) and especially immunosuppressive drugs including corticosteroids, tacrolimus, cyclosporine and sirolimus. Currently, predisposing genetic factors have been considered important in PTDM development. The commonly evaluated genetic determinants include genes encoding transcription factors, cytokines, chemokines, adipokines, ionic channels, glucose transporters, cytochrome P450 enzymes and other enzymes metabolizing drugs, drug transporters. Unfortunately, the results of studies are inconclusive and differ between populations. There is a need for large genome-wide association study to identify the genetic risk factors associated with PTDM development.

Serum and peritoneal fluid concentrations of soluble human leukocyte antigen, tumor necrosis factor alpha and interleukin 10 in patients with selected ovarian pathologies.

BACKGROUND: Although immune system plays a key role in the pathogenesis of both endometriosis and ovarian cancer, its function is different. Therefore, we hypothesized, that selected immune parameters can serve as diagnostic markers of these two conditions. The aim of this study was to compare serum and peritoneal fluid concentrations of sHLA-G, IL-10 and TNF-alpha in women with selected ovarian pathologies: benign serous cysts, endometrioma and malignant tumors. Clinical significance of using them for diagnostic purposes in women with serous ovarian cysts, endometriosis, and ovarian cancer, which in the future may improve the early diagnosis of ovarian diseases. CASE PRESENTATION: The study included women treated surgically for benign serous ovarian cysts, ovarian endometrioma and serous ovarian adenocarcinomas. Peripheral blood and peritoneal fluid samples were obtained intraoperatively. Patients with benign serous cysts, endometrioma and ovarian malignancies did not differ significantly in terms of their serum and peritoneal fluid concentrations of sHLA-G. Ovarian cancer patients presented with significantly higher median serum concentrations of IL-10 and TNF-alpha than other study subjects. Median concentrations of IL-10 and TNF-alpha in peritoneal fluid turned out to be the highest in ovarian cancer patients, followed by women with endometrioma and subjects with benign serous cysts. All these intergroup differences were statistically significant. Irrespective of the group, median concentrations of sHLA-G, IL-10 and TNF-alpha in peritoneal fluid were higher than serum levels of these markers. CONCLUSIONS: Elevated serum and peritoneal fluid concentrations of IL-10 and TNF-alpha distinguish ovarian malignancies and endometriomas from benign serous ovarian cysts. In contrast to endometriosis, ovarian malignancies are characterized by elevated peritoneal fluid concentrations of IL-10 and TNF-alpha, elevated serum concentrations of IL-10 and low serum levels of TNF-alpha. Serum and peritoneal fluid concentrations of sHLA-G have no diagnostic value in differentiating between ovarian malignancies and endometriomas.

Morphology of the epithelial cells and expression of androgen receptor in rat prostate dorsal lobe in experimental hyperprolactinemia.

The effect of hyperprolactinemia on the prostate has not been well investigated. Since androgens play an important role in prostate development, growth and function, the goal of the present study was to estimate the influence of hyperprolactinemia on expression of the androgen receptor (AR) in rat epithelial cells of prostate dorsal lobe and on morphology of these cells. Studies were performed on sexually mature male Wistar rats. The experimental group rats received metoclopramide (MCP) intraperitoneally to provoke hyperprolactinemia. The control group animals were given saline in the same way. For light and electron microscopy the prostate dorsal lobes were obtained routinely. To evaluate the intensity of immunohistochemical reaction for AR in epithelial cells, the optical density was measured and computer-assisted image analysis system was used. Morphological observations of the dorsal lobe epithelial cells were carried out in transmission electron microscope. MCP caused over twofold increase in prolactin (PRL) serum levels. In rats with hyperprolactinemia, the testosterone levels (T) were twofold decreased. The intensity of immunohistochemical reaction for AR in epithelial cells of dorsal lobe in the experimental group was significantly lower than in the control group. In the dorsal lobe epithelial cells of experimental group animals, the transmission electron microscopy (TEM) revealed highly dilated RER cisternae and reduced number of microvilli on the cellular surface when compared to the control group. The results show that hyperprolactinemia in male rats causes morphological abnormalities in the dorsal lobe of prostate. The abnormalities are caused by elevated prolactin either directly or indirectly through decreased level of testosterone. Decreased expression of AR in epithelial cells of prostate dorsal lobe is likely to be caused by decreased testosterone level.

The effect of gene polymorphisms on patient responses to rheumatoid arthritis therapy.

INTRODUCTION: Rheumatoid arthritis (RA) is a systemic disease leading to joint destruction. The therapy of RA is mainly based on disease-modifying anti-rheumatic drugs (DMARDs) and biological drugs. The response to treatment is different among patients. Therefore, we have searched for factors that may predict the efficacy and toxicity during therapy in individual patients. AREAS COVERED: This review presents the role of genetic polymorphisms as predictors of the efficacy and toxicity during the therapy of RA patients with DMARDs (methotrexate, leflunomide, sulfasalazine) and biological drugs (anti-TNF-alpha antagonists, Tocilizumab, Rituximab). EXPERT OPINION: Despite studies having shown an association between genetic polymorphisms and response to therapy in RA patients, the majority of these findings are still inconclusive and inconsistent. We are still far from applying pharmacogenetic tests in routine clinical practice that can predict the outcome of treatment. Several factors, such as small sample size with low statistical power, variability in the outcome definitions and the heterogeneity of the cohorts, limited number of tested single nucleotide polymorphisms (SNPs), small effect for the selected variant, and a lack of consideration of epigenetic factors, may contribute to the inconsistency observed and may lead to limited success in personalizing therapy.

Effects of an immunosuppressive treatment on the rat prostate.

The aim of this study was to determine the influence of different combinations of immunosuppressive drugs on the morphology, ultrastructure, and expression of proliferating cell nuclear antigen and cytoskeleton proteins in the rat dorsolateral prostate. The studies were conducted on 48 male Wistar rats. The animals were divided into eight groups: a control group and seven experimental groups. For 6 months, the animals in the experimental groups were administered a combination of drugs including rapamycin (Rapa), cyclosporin A, tacrolimus (Tac), mycophenolate mofetil, and prednisone (Pred), according to the standard three-drug regimens for immunosuppressive therapy used in clinical practice. An evaluation of the morphology and ultrastructure was conducted, and a quantitative evaluation of the expression of proliferating cell nuclear antigen and desmin- and cytokeratin-positive cells with weak, moderate, and strong expression was performed. The combination of Rapa, Tac, and Pred caused the smallest morphological and ultrastructural changes in the rat prostate cells. In the case of rats whose treatment was switched to Rapa monotherapy, a decreased percentage of proliferating cells of both the glandular epithelium and the stroma was found. Decreases in body weight and changes in the expression of cytokeratin and desmin were observed in all the experimental rats. The combination of Rapa, Tac, and Pred would seem to be the most beneficial for patients who do not suffer from prostate diseases. Our results justify the use of inhibitors of the mammalian target of Rapa in the treatment of patients with prostate cancer. The changes in the expression of cytoskeleton proteins may be the result of direct adverse effects of the immunosuppressive drugs, which are studied in this article, on the structure and organization of intermediate filament proteins.

Vitamin D3 stimulates embryonic stem cells but inhibits migration and growth of ovarian cancer and teratocarcinoma cell lines.

BACKGROUND: Deficiency in Vitamin D3 (cholecalciferol) may predispose to some malignancies, including gonadal tumors and in experimental models vitamin D3 has been proven to inhibit the growth of cancer cells. To learn more about the potential role of vitamin D3 in cancerogenesis, we evaluated the expression and functionality of the vitamin D receptor (VDR) and its role in metastasis of ovarian cancer cells and of murine and human teratocarcinoma cell lines. METHODS: In our studies we employed murine embrynic stem cells (ESD3), murine (P19) and human (NTERA-2) teratocarcimona cells lines, human ovarian cancer cells (A2780) as well as purified murine and human purified very small embryonic like stem cells (VSELs). We evaluated expression of Vitamin D3 receptor (VDR) in these cells as well as effect of vitamin D3 exposure on cell proliferation and migration. RESULTS: We here provide also more evidence for the role of vitamin D3 in germline-derived malignancies, and this evidence supports the proposal that vitamin D3 treatment inhibits growth and metastatic potential of several germline-derived malignancies. We also found that the ESD3 murine immortalized embryonic stem cell line and normal, pluripotent, germline-marker-positive very small embryonic-like stem cells (VSELs) isolated from adult tissues are stimulated by vitamin D3, which suggests that vitamin D3 affects the earliest stages of embryogenesis. CONCLUSIONS: We found that however all normal and malignant germ-line derived cells express functional VDR, Vitamin D3 differently affects their proliferation and migration. We postulate that while Vitamin D3 as anticancer drug inhibits proliferation of malignant cells, it may protect normal stem cells that play an important role in development and tissue/organ regeneration.

Histological changes of testes in growth hormone transgenic mice with high plasma level of GH and insulin-like growth factor-1.

INTRODUCTION: Overexpression of growth hormone (GH) leads to increase in insulin-like growth factor-1 (IGF-1) plasma level, stimulation of growth and increase in body size, organomegaly and reduced body fat. The action of GH affects all the organs and transgenic mice that overexpress bovine GH (bGH mice) serve as convenient model to study somatotropic axis. Male mice overexpressing GH are fertile, however, they show reduced overall lifespan as well as reproductive life span. The aim of the study was to evaluate the morphology and expression of androgen receptor (AR) and luteinizing hormone receptor (LHR) of bGH mice testes. MATERIAL AND METHODS: The experiment was performed on 6 and 12 month-old bGH male mice and 6 and 12 month-old wild type (WT) littermates (8 animals in each group). The morphology of testes was evaluated on deparaffinized sections stained by the periodic acid-Schiff (PAS) method. Expression of AR and LHR was investigated by immunohistochemistry and diameters of seminiferous tubules (ST) were measured on round cross sections of ST. RESULTS: We noted larger testes in 6-month bGH mice as compared to normal WT littermates. The morpho-logical observations revealed essentially normal structure of Leydig cells, seminiferous epithelium and other morphological structures. However, some changes like tubules containing only Sertoli cells, tubules with arrested spermatogenesis or vacuoles in seminiferous epithelium could be attributed to the overexpression of GH. In contrast to WT mice, 12 month-old bGH mice displayed first symptoms of testicular aging. The immunoexpres-sion of AR and LHR was decreased in 12 month-old bGH males as compared to 12 month-old WT mice and younger animals. CONCLUSION: Chronic exposure to elevated GH level accelerates testicular aging and thus potentially may change response of Leydig cells to LH and Sertoli and germ cells to testosterone.

Caloric restriction increases ratio of estrogen to androgen receptors expression in murine ovaries--potential therapeutic implications.

Both estrogens and androgens are involved in the development and normal functioning of the ovaries. It is also known that ovarian function is regulated by diet. The goal of this study was to estimate the expression of sex hormone receptors in ovaries of mice that were on a 9-month caloric restriction (alternate-day feeding) as compared to normal control animals fed ad libitum. We found that prolonged caloric restriction in mouse ovaries led to increased expression of estrogen receptors (ERs) but did not affect expression of the androgen receptor (AR). This increase in ER:AR ration as result of caloric restriction may lead to higher sensitivity to estrogens and upon return to normal diet may increase ovulation. Thus our observation shed more light on a role of beneficial effect of calorie restriction on female reproduction.

The influence of immunosuppressants on the morphology, proliferating cell nuclear antigen (PCNA) and apoptosis in the rat ventral prostate.

AIM: Analysis of the impact of immunosuppressants on apoptosis and PCNA in the rat ventral prostate. METHOD: The studies were performed on 48 male Wistar rats. The animals were divided into a control group and 7 experimental groups. For 6 months, the rats were administered drugs such as: rapamycin (Rapa), cyclosporin A (CsA), tacrolimus (Tac), mycophenolate mofetil (MMF) and glucocorticosteroids (GS). During section of the rats, prostate ventral lobes were obtained. Morphological evaluation (HE, PAS), TUNEL assay, PCNA expression analysis and quantitative image computer analysis were performed. RESULTS: The highest percentage of apoptosis in epithelial cells was observed in groups which received two combinations of drugs: (V) CsA, MMF, GS and (VII) Tac, MMF, GS. A much lower percentage of apoptotic epithelial cells was found in the groups where the treatment schemes included rapamycin throughout the duration of the study. Interestingly, the conversion of the treatment to rapamycin caused a significant reduction of apoptosis in epithelial cells as well as in proliferation in both epithelial and stromal cells. CONCLUSIONS: On one hand, the obtained results may explain the anticancer activity of rapamycin in reducing the proliferation of epithelial cells, and on the other hand the adverse effect of rapamycin in the form of reduced regeneration of these cells. Taking into account the prostate in isolation from other organs/systems, the dosage scheme with Rapa, Tac and GS would appear to be the most favorable, due to the smallest morphological changes.