MAP3K8 Regulates Cox-2-Mediated Prostaglandin E2 Production in the Lung and Suppresses Pulmonary Inflammation and Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by exuberant deposition of extracellular matrix components, leading to the deterioration of lung architecture and respiratory functions. Profibrotic mechanisms are controlled by multiple regulatory molecules, including MAPKs, in turn regulated by multiple phosphorylation cascades. MAP3K8 is an MAPK kinase kinase suggested to pleiotropically regulate multiple pathogenic pathways in the context of inflammation and cancer; however, a possible role in the pathogenesis of IPF has not been investigated. In this report, MAP3K8 mRNA levels were found decreased in the lungs of IPF patients and of mice upon bleomycin-induced pulmonary fibrosis. Ubiquitous genetic deletion of Map3k8 in mice exacerbated the modeled disease, whereas bone marrow transfer experiments indicated that although MAP3K8 regulatory functions are active in both hematopoietic and nonhematopoietic cells, Map3k8 in hematopoietic cells has a more dominant role. Macrophage-specific deletion of Map3k8 was further found to be sufficient for disease exacerbation thus confirming a major role for macrophages in pulmonary fibrotic responses and suggesting a main role for Map3k8 in the homeostasis of their effector functions in the lung. Map3k8 deficiency was further shown to be associated with decreased Cox-2 expression, followed by a decrease in PGE2 production in the lung; accordingly, exogenous administration of PGE2 reduced inflammation and reversed the exacerbated fibrotic profile of Map3k8 -/- mice. Therefore, MAP3K8 has a central role in the regulation of inflammatory responses and Cox-2-mediated PGE2 production in the lung, and the attenuation of its expression is integral to pulmonary fibrosis development.

Therapeutic Effects of Micronutrient Supplements on Sperm Parameters: Fact or Fiction?

BACKGROUND: Despite the limited evidence about the effect of micronutrient supplementation on the semen quality, many micronutrient supplements have been used to improve male fertility. Approximately, 40%- 50% of male infertility cases in general and up to 80% in men with idiopathic infertility cases are caused by oxidative stress and decreased level of seminal total antioxidant capacity. OBJECTIVE: To investigate the beneficial effects of micronutrient supplementation on sperm concentration, motility and morphology. METHODS: A PubMed, Google Scholar, Embase data, Web of Science and Cochrane Library database extensive research of the randomized controlled studies utilizing micronutrient vitamins and supplements was performed. RESULTS: The existent international literature is rather heterogeneous and a definitive is difficult to be drawn. Several micronutrients have beneficial effects on sperm parameters. Rational use of micronutrients might be helpful for infertile patients. CONCLUSION: Further randomized, controlled clinical trials are required to elucidate the efficacy and safety of micronutrients and propose proper protocols for their use. A well-rounded, balanced diet is more preferable than the widespread use of micronutrient supplements beyond the recommended doses. Future studies should concern the pregnancy rate as a primary outcome in their designs. Further research should be done to determine the appropriate antioxidant compounds, the duration of the treatment, as well as a certain dose of antioxidants in clinical practices. The pre-treatment evaluation of the seminal oxidative status is also an important parameter to proceed with micronutrient supplementation without the risk of reductive stress. Under these conditions, supplements could support the quality of sperm and help to alleviate male infertility.

Effects of phosphodiesterase-5 inhibitors on Leydig cell secretory function in oligoasthenospermic infertile men: a randomized trial.

OBJECTIVE: to evaluate the effects of phosphodiesterase-5 inhibitors (PDE5-i) on Leydig cell secretory function (LCSF). PATIENTS AND METHODS: in all, 75 men with oligoasthenospermia were treated daily for 12 weeks with either vardenafil (23 men, group A), sildenafil (25 men, group B) or l-carnitine (26 men, group C); a further group of 22 men with oligoasthenospermia (group D) received no treatment. Serum levels of insulin-like-3 peptide (INSL3) were evaluated before and after the end of the treatment in each of groups A, B and C, respectively. Serum INSL3 levels were measured in each participant of group D before and after the 12-week experimental period. RESULTS: within group A and B, the peripheral serum mean INSL3 concentration, sperm concentration, percentage of motile spermatozoa, and percentage of morphologically normal spermatozoa were significantly greater after PDE5-i treatment than before. CONCLUSION: we suggest that PDE5-i enhances LCSF, as the mean INSL3 concentration was significantly greater after PDE5-i administration than before, within groups A and B. This enhancement in LCSF might contribute to the increase in sperm concentration and sperm motility after administration of PDE5-i.

Post-fertilization effects of chronic renal failure in male rats.

We evaluated the potential for growth and intrauterine development of embryos generated from the fertilization of oocytes with spermatozoa recovered from animals with chronic renal failure (CRF). Group A included sham-operated rats (n = 28), group B1 involved CRF rats that had undergone erythropoietin plus bromocryptine treatment (n = 28), and group B2 included CRF rats that had received normal saline. Embryos derived from the in vitro fertilization of oocytes with spermatozoa recovered from rats of group A or group B1 or group B2 were transferred to female recipients. We induced CRF in a group of rats (group B; n = 56; the total kidney volume was reduced to one-sixth with two operations). One week after the second operation, the rats of group B were randomly divided into group B1 (they subsequently received bromocryptine plus erythropoietin) and group B2 (they received injections of saline). Nine weeks after the second operation, the fertility of each male rat was assessed by mating tests and in vitro fertilization of oocytes. The mean litter size was significantly smaller in the subpopulation of fertile animals in group B2 than in the fertile rats of group B1 and in the fertile rats of group B1 than in the fertile rats of group A. Per cent of transferred blastocysts that developed into alive offspring were significantly lower in group B2 than in group B1 and in group B1 than in group A. Epididymal spermatozoa demonstrated a significantly larger DNA-oxidative damage in group B2 than in group B1 and in group B1 than in group A. These findings demonstrate that sperm-DNA damage because of CRF development is accompanied by a defect in the development of embryos generated in vitro. We may suggest that bromocryptine and erythropoietin protecting sperm DNA from oxidative damage improve reproductive potential in rats with CRF.