Foreskin neurovascular structure: A histological analysis comparing 0-3 years and 6-11 years children.

BACKGROUND: Circumcision is a surgical operation that is frequently performed throughout the world due to religious, cultural, and medical reasons. The best age for circumcision is still debatable, with different procedures depending on geography, culture, and surgeon preference. OBJECTIVE: This study aims to immunohistochemical examination using S100 staining and histologically evaluate the neurovascular structures in foreskin samples obtained from children aged 0-3 years and 6-11 years. The goal is to provide guidance in determining an appropriate age for circumcision based on these data. STUDY DESIGN: Concerns regarding potential effects on glans sensitivity and sexual function led to the investigation and comparison of sensory innervation in the foreskin of children aged 0-3 and 6-11 years, a total 54 samples, divided into pre-phallic (0-3 years) and post-phallic (6-11 years) groups, were examined. The mean number of Meissner and Pacinian corpuscles, Ruffini endings, free nerve endings and the diameters of arteries were investigated. RESULTS: Our findings show that compared to the 6-11 age group, the 0-3 age group had considerably lower sensory innervation in terms of, Meissner's corpuscles, Pacinian corpuscles, Ruffini endings and free nerve endings. Additionally, the diameter of arteries was noticeably smaller in the 0-3 age group. CONCLUSIONS: In conclusion, this study supports the idea that circumcision performed in the early years of life may be associated with less adverse effects on neurovascular structures.

Effect of pioglitazone on the expression of ubiquitin proteasome system and autophagic proteins in rat pancreas with metabolic syndrome.

The metabolic syndrome (MetS) and pathologies associated with metabolic dysregulations a worldwide growing problem. Our previous study demonstrated that pioglitazone (PGZ) has beneficial effects on metabolic syndrome associated disturbances in the heart. However, mechanism mediating the molecular alterations of Ubiquitin proteasome system (UPS) and autophagy has not been investigated in rat pancreas with metabolic syndrome. For this reason, we first aimed to detect whether MetS effects on the expression of UPS (p97/VCP, SVIP, Ubiquitin) and autophagic (p62, LC3) proteins in rat pancreas. The second aim of the study was to find impact of pioglitazone on the expression of UPS and autophagic proteins in MetS rat pancreas. To answer these questions, metabolic syndrome induced rats were used as a model and treated with pioglitazone for 2 weeks. Pancreatic tissue injuries, fibrosis and lipid accumulation were evaluated histopathologically in control, MetS and MetS-PGZ groups. Apoptosis and cell proliferation of pancreatic islet cells were assessed in all groups. UPS and autophagic protein expressions of pancreas in all groups were detected by using immunohistochemistry, double-immunfluorescence and Western blotting. Compared with the controls, the rat fed with high sucrose exhibited signs of metabolic syndrome, such as higher body weight, insulin resistance, higher triglyceride level and hyperglycaemia. MetS rats showed pancreatic tissue degeneration, fibrosis and lipid accumulation when their pancreas were examined with Hematoxilen-eozin and Mallory trichrome staining. Metabolic, histopathologic parameters and cell proliferation showed greater improvement in MetS-PGZ rats and pioglitazone decreased apoptosis of islet cells. Moreover, SVIP, ubiquitin, LC3 and p62 expressions were significantly increased while only p97/VCP expression was significantly decreased in MetS-rat pancreas compared to control. PGZ treatment significantly decreased the MetS-induced increases in autophagy markers. Additionally, UPS and autophagy markers were found to colocalizated with insulin and glucagon. Colocalization ratio of UPS markers with insulin showed significant decrease in MetS rats and PGZ increased this ratio, whereas LC3-insulin colocalization displayed significant increase in MetS rats and PGZ reversed this effect. In conclusion, PGZ improved the pancreatic tissue degeneration by increasing the level of p97/VCP and decreasing autophagic proteins, SVIP and ubiquitin expressions in MetS-rats. Moreover, PGZ has an effect on the colocalization ratio of UPS and autophagy markers with insulin.

Ubiquitin proteasome system and autophagy associated proteins in human testicular tumors.

Ubiquitin proteasome sytem (UPS) and autophagy govern protein quality control by degradation and clearance of damaged proteins. Many proteins working in these pathways such as p97/VCP, Ubiquitin (Ub), Jab1/CSN5, p62, LC3B and Beclin 1 are known to be essential for different pathological conditions, especially in cancer, but their expression in human testicular tumors has not been characterized yet. In the present study, we aimed to investigate the expression of UPS (p97/VCP, Ubiquitin, Jab1/CSN5) and autophagic (p62, LC3B, Beclin 1) proteins in human testicular tumors and cancer adjacent normal testicular tissues. We used an immunohistochemical staining technique. 120 cases of testicular germ and non-germ cell tumors, which are 42 seminomas, 31 embryonal carcinomas, 11 yolk sac tumors, 25 intratubular germ cell neoplasms, 6 Leydig cell tumors, 5 Sertoli cell tumors, were collected and evaluated on tissue microarray. For the first time, the expression of p97/VCP, Ub, Jab1/CSN5, p62, LC3B and Beclin 1 in different type of human testicular tumors has been confirmed. We found that p97/VCP, Ub and Jab1/CSN5 were frequently expressed at higher levels in testicular tumours. In contrast to UPS markers, p62, LC3B and Beclin 1 showed significantly diminished expressions in testicular tumors. Accordingly, a negative correlation between p97/VCP and autophagic markers (p62 and LC3B) was found, suggesting a relationship between UPS and autophagy in different type of testicular tumors. The current results displayed elevated level of p97/VCP, Ub and Jab1/CSN5 expressions in contrast to the diminished expression of p62, LC3B and Beclin 1 in human testicular tumors, thereby supporting a correlation between p97/VCP and autophagic markers in testicular tumors.

Ultrastructural and morphometric alterations to the peripheral nerve following the administration of immunosuppressive agent tacrolimus (FK506).

Tacrolimus, a widely used immunosuppressive drug for preventing graft rejection following organ transplantation, was reported to develop neurotoxic side effects ranging from mild to severe symptoms in the literature. Rats were randomly divided into three groups as control and 2-week and 3-week treatment groups and received a 2 mg/kg/day tacrolimus by oral gavage. Animals were sacrificed and sciatic nerves obtained from all groups were fixed and processed for light and electron microscopic investigations. The myelinated fiber diameter, axon diameter, G-ratio (axon diameter/myelinated fiber diameter), and myelin thickness were also determined. The data obtained in the control and tacrolimus-treated groups were compared.The control group sciatic nerve fascicles showed normal morphology with myelinated and unmyelinated fibers. Experimental groups exhibited axonal dilatation, irregularly thickened and vacuolated myelin sheaths with separation of myelin layers. The morphometric analysis showed that the myelinated fibers of the 2-week tacrolimus-treated group displayed a moderate increase in the myelin thickness and axon and fiber diameter in comparison with the control and 3-week tacrolimus-treated groups. The G-ratio was found to be in normal range in all groups and there were no statistically significant difference.The present study indicates that the treatment with tacrolimus may produce a mild degenerative change but prolonged drug administration for 3 weeks led to improvement in morphometric and morphologic data and the normal G-ratio values, suggesting that the regeneration capacity of the myelinated fibers maintains their normal function to transmit nerve impulses.

Inhibition of p97/VCP function leads to defective autophagosome maturation, cell cycle arrest and apoptosis in mouse Sertoli cells.

p97/valosin-containing protein (VCP) is expressed in many cells and plays critical functions in a broad range of diverse cellular processes. Because it is expressed in the mouse testes, predominantly in Sertoli cells, and is known to play a critical role in autophagy and apoptosis in different cell types, we set out to investigate its function in autophagosome maturation, apoptosis and cell cycle arrest in a mouse Sertoli cell line. To study the mechanism of p97/VCP action, p97/VCP siRNA and a specific p97/VCP inhibitor, N2,N4-dibenzylquinazoline-2,4-diamine (DBeQ), were used in the mouse 15P1 Sertoli cell line. Loss of p97/VCP activity due to DBeQ exposure and silencing of p97/VCP (siVCP) expression results in autophagosome (LC3 and p62) accumulation in the cytoplasm of Sertoli cells. The coexpression of autophagosomal and lysosomal markers (LAMP1 and LAMP2) was reduced in cells in which p97/VCP expression had been inactivated. To better understand in which step of autophagy p97/VCP functions, the interaction between autophagosomal and autolysosomal markers was studied by coimmunoprecipitation and colocalization experiments. The interaction between autophagosomal markers and lysosomal markers decreased in siVCP-expressing and DBeQ-exposed cells. Moreover, the expression of siVCP and DBeQ exposure caused cytoplasmic vacuolation, induced caspase 3-7-mediated cell death and decreased cell cycle progression in mouse Sertoli cells. Taken together, the results show that p97/VCP is essential for autophagosome maturation and cell survival in mouse Sertoli cells. When these functions are prevented, impaired autophagy and apoptosis may have a detrimental effect on germ cells and cause male infertility.

Pioglitazone provides beneficial effect in metabolic syndrome rats via affecting intracellular Na+ Dyshomeostasis.

Metabolic syndrome, is associated impaired blood glucose level, insulin resistance, and dyslipidemia caused by abdominal obesity. Also, it is related with cardiovascular risk accumulation and cardiomyopathy. The hypothesis of this study was to examine the effect of thiazolidinediones such as pioglitazone on intracellular Na+ homeostasis in heart of metabolic syndrome male rats. Abdominal obesity and glucose intolerance had measured as a marker of metabolic syndrome. Intracellular Na+ concentration ([Na+]i) at rest and [Na+]i during pacing with electrical field stimulation were determined in freshly isolated cardiomyocytes. Also, TTX-sensitive Na+- channel current (INa) density and I-V characteristics of these channels were measured to understand [Na+]i homeostasis. We determined the protein levels of Na+/Ca2+ exchanger and Na+-K+ pump to understand the relation between [Na+]i homeostasis. High sucrose intake significantly increased body mass and blood glucose level of the rats in the metabolic syndrome group as compared with control group. There was a decrease in INa density and there were differences in points on activation curve of INa. Basal [Na+]i in metabolic syndrome group significantly increased but there was a significantly decrease in [Na+]i in stimulated cardiomyocytes in metabolic syndrome. Furthermore, pioglitazone induced decreases in the basal [Na+]i and preserved the decrease in INa and [Na+]i in stimulated cardiomyocytes to those of controls. Histologically, metabolic syndrome affected heart and associated tissues together with many other organs. Results of the present study suggest that pioglitazone has significant beneficial effects on metabolic syndrome associated disturbances in the heart via effecting Na+ homeostasis in cardiomyocytes.