Androgênios e o trato reprodutor masculino: ações clássicas e perspectivas atuais

Androgens are steroid hormones that play key roles in the development and maintenance of male phenotype and reproductive function. These hormones also affect the function of several non-reproductive organs, such as bone and skeletal muscle. Endogenous androgens exert most of their effects by genomic mechanisms, which involve hormone binding to the androgen receptor (AR), a ligand-activated transcription factor, resulting in the modulation of gene expression. AR-induced non-genomic mechanisms have also been reported. A large number of steroidal and non-steroidal AR-ligands have been developed for therapeutic use, including the treatment of male hypogonadism (AR agonists) and prostate diseases (AR antagonists), among other pathological conditions. Here, the AR gene and protein structure, mechanism of action and AR gene homologous regulation were reviewed. The AR expression pattern, its in vivo regulation and physiological relevance in the developing and adult testis and epididymis, which are sites of sperm production and maturation, respectively, were also presented.Os androgênios são hormônios esteroides com papel fundamental no desenvolvimento e na manutenção do fenótipo masculino e da função reprodutiva. Esses hormônios também afetam a função de diversos tecidos não reprodutivos, como, por exemplo, o ósseo e musculoesquelético. Os androgênios endógenos exercem a maioria de suas funções por mecanismo genômico, que envolve a ligação do hormônio ao receptor de androgênio (RA), um fator de transcrição ativado por ligante, o que resulta no controle da expressão gênica. Mecanismos não genômicos também têm sido associados aos efeitos induzidos pelo RA. Um grande número de ligantes do RA, esteroidais e não esteroidais, tem sido desenvolvido para o uso terapêutico, incluindo o tratamento do hipogonadismo masculino (agonistas do RA) e de doenças da próstata (antagonistas do RA), entre outras condições patológicas. Neste trabalho, foram discutidas as características estruturais básicas do RA (gene e proteína), os mecanismos de ação desse receptor, bem como aspectos relacionados à sua regulação homóloga. O padrão de expressão do RA, sua regulação in vivo e relevância fisiológica durante o desenvolvimento e a vida adulta na função do testículo e epidídimo, tecidos responsáveis pela produção e maturação de espermatozoides, respectivamente, também foram discutidos.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de FarmacologiaUNIFESP, EPM, Depto. de FarmacologiaSciEL

Interacting Proteins on Human Spermatozoa: Adaptive Evolution of the Binding of Semenogelin I to EPPIN

Semenogelin I (SEMG1) is found in human semen coagulum and on the surface of spermatozoa bound to EPPIN. The physiological significance of the SEMG1/EPPIN interaction on the surface of spermatozoa is its capacity to modulate sperm progressive motility. The present study investigates the hypothesis that the interacting surface of SEMG1 and EPPIN co-evolved within the Hominoidea time scale, as a result of adaptive pressures applied by their roles in sperm protection and reproductive fitness. Our results indicate that some amino acid residues of SEMG1 and EPPIN possess a remarkable deficiency of variation among hominoid primates. We observe a distinct residue change unique to humans within the EPPIN sequence containing a SEMG1 interacting surface, namely His92. In addition, Bayes Empirical Bayes analysis for positive selection indicates that the SEMG1 Cys239 residue underwent positive selection in humans, probably as a consequence of its role in increasing the binding affinity of these interacting proteins. We confirm the critical role of Cys239 residue for SEMG1 binding to EPPIN and inhibition of sperm motility by showing that recombinant SEMG1 mutants in which Cys239 residue was changed to glycine, aspartic acid, histidine, serine or arginine have reduced capacity to interact to EPPIN and to inhibit human sperm motility in vitro. In conclusion, our results indicate that EPPIN and SEMG1 rapidly co-evolved in primates due to their critical role in the modulation of sperm motility in the semen coagulum, providing unique insights into the molecular co-evolution of sperm surface interacting proteins

Lipopolysaccharide and lipotheicoic acid differentially modulate epididymal cytokine and chemokine profiles and sperm parameters in experimental acute epididymitis

Bacterial infections are the most prevalent etiological factors of epididymitis, a commonly diagnosed inflammatory disease in the investigation of male infertility factors. The influence of early pathogenic mechanisms at play during bacterial epididymitis on reproductive outcomes is little understood. We report here that experimental epididymitis induced in rats by Gram-negative (LPS) and Gram-positive (LTA) bacterial products resulted in differential patterns of acute inflammation in the cauda epididymis. LPS elicited a strong inflammatory reaction, as reflected by upregulation of levels of mRNA for seven inflammatory mediators (Il1b, Tnf, Il6, Ifng, Il10, Nos2 and Nfkbia), and tissue concentration of six cytokines/chemokines (IL1A, IL1B, IL6, IL10, CXCL2 and CCL2) within the first 24 h post-treatment. Conversely, LTA induced downregulation of one (Nfkbia) and upregulation of six (Il1b, Il6, Nos2, Il4 Il10 and Ptgs1) inflammatory gene transcripts, whereas increased the tissue concentration of three cytokines/chemokines (IL10, CXCL2 and CCL2). The stronger acute inflammatory response induced by LPS correlated with a reduction of epididymal sperm count and transit time that occurred at 1, 7, and 15 days post-treatment. Our study provides evidence that early epididymal inflammatory signaling events to bacterial activators of innate immunity may contribute to the detrimental effects of epididymitis upon male fertility.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)CNPqSao Paulo Research Foundation (FAPESP)Pro-Reitoria de Pesquisa/UNESPUniv Fed Sao Paulo, Escola Paulista Med, Sect Expt Endocrinol, Dept Pharmacol, BR-04044020 Sao Paulo, SP, BrazilUniv Estadual Paulista, Dept Pharmacol, Inst Biosci Botucatu, Botucatu, SP, BrazilSci & Innovat Ctr Androl, Androsci, BR-03178200 Sao Paulo, SP, BrazilUniv Sao Paulo, Med Sch, Hosp Clin, Reprod Toxicol Unity,Dept Pathol, BR-01246903 Sao Paulo, SP, BrazilUniv Sao Paulo, Med Sch, Hosp Clin, Div Urol, BR-01246903 Sao Paulo, SP, BrazilState Univ Centro Oeste, Dept Pharm, BR-85040080 Guarapuava, PR, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Sect Expt Endocrinol, Dept Pharmacol, BR-04044020 Sao Paulo, SP, Brazil(CNPq)/CSF/BJT: 401718/2012-3CNPq: 479546/2013-4, 455450/2014-5, 308349/2010-5FAPESP: 2010/52711-0, 2015/08227-0Pro-Reitoria de Pesquisa/UNESP: 557Web of Scienc

Factors of staff turnover in textile businesses in Colombia

The Colombian textile sector, which represents 3% of the gross domestic product, has staff turnover problems. When a worker quits, an immediate replacement is needed in order to not affect productivity. Companies often recruit people without training or even experience. In this paper is analyses job turnover of businesses in the textile sector in Barranquilla (Colombia) through internal, external and contextual factors with their respective indicators. The investigation is quantitative with a correlational scope and a cross-sectional design. The methodology consisted of reliability testing (Cronbach’s alpha and McDonald’s omega) and construct validity (exploratory factor analysis) for the measurement instrument. This was followed by a descriptive analysis, with measures in relation to central tendency and dispersion for each factor indicator, concluding a confirmatory factor analysis with maximum likelihood estimates to observe causality, covariation and incidence relationships. The results established that the relevant indicators are commitment and satisfaction, sickness and company flexibility. The strongest covariance is between internal and contextual factors. Consistent with the theory, it was possible to statistically validate the theoretical model applied and a tool to measure job turnover

Dissecting EPPIN protease inhibitor domains in sperm motility and fertilizing ability: Repercussions for male contraceptive development

EPPIN (epididymal protease inhibitor) is a mammalian conserved sperm-binding protein displaying an N-terminal WFDC (whey-acidic protein four-disulfide core) and a C-terminal Kunitz protease inhibitor domains. EPPIN plays a key role in regulating sperm motility after ejaculation via interaction with the seminal plasma protein SEMG1 (semenogelin-1). EPPIN ligands targeting the SEMG1 binding site in the Kunitz domain are under development as male contraceptive drugs. Nevertheless, the relative contributions of EPPIN WFDC and Kunitz domains to sperm function remain obscure. Here, we evaluated the effects of antibodies targeting specific epitopes in EPPIN's WFDC (Q20E antibody, Gln20-Glu39 epitope) and Kunitz (S21C and F21C antibodies, Ser103-Cys123 and Phe90-C110 epitopes, respectively) domains on mouse sperm motility and fertilizing ability. Computer-assisted sperm analysis showed that sperm co-incubation with S21C antibody (but not F21C antibody) lowered progressive and hyperactivated motilities and impaired kinematic parameters describing progressive (straight-line velocity; VSL, average path velocity; VAP and straightness; STR) and vigorous sperm movements (curvilinear velocity; VCL, amplitude of lateral head movement; ALH, and linearity; LIN) compared with control. Conversely, Q20E antibody-induced milder inhibition of progressive motility and kinematic parameters (VAP, VCL and ALH). Sperm co-incubation with S21C or Q20E antibodies affected in vitro fertilization as revealed by reduced cleavage rates, albeit without changes in capacitation-induced tyrosine phosphorylation. In conclusion, we show that targeting specific epitopes in EPPIN Kunitz and WFDC domains inhibits sperm motility and capacitation-associated events, which decrease their fertilizing ability; nevertheless, similar observations in vivo remain to be demonstrated. Simultaneously targeting residues in S21C and Q20E epitopes is a promising approach for the rational design of EPPIN-based ligands with spermostatic activity.Fil: Silva, Alan A. S.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Raimundo, Tamiris R. F.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Mariani, Noemia A. P.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Kushima, Hélio. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Avellar, Maria Christina W.. Universidade Federal de Sao Paulo; BrasilFil: Buffone, Mariano Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Paula Lopes, Fabíola F.. Universidade Federal de Sao Paulo; BrasilFil: Moura, Marcelo T.. Universidade Federal de Sao Paulo; BrasilFil: Silva, Erick J. R.. Universidade Estadual Paulista Julio de Mesquita Filho; Brasi

Relationship between Field Measurements in Three \u3cem\u3eBrachiaria\u3c/em\u3e Species with Leaf Area Index and Light Interception by Indirect Methods

Brachiaria species play a strategic role in ruminant production systems in Brazil, covering an estimated pasture area of approximately 90 million hectares (Karia et al., 2006), however, these pastures are subject to different degrees of degradation due to inadequate management. In pasture management, field measurements such as canopy height, for example, are used by managers as a tool to establish parameters for the optimal point to cut the forage and for the post-grazing residue, in order to maximize production by harvesting at maximum of herbage mass accumulation, and to avoid problems associated to overgrazing, by setting ideal post-grazing height for forage regrowth. The use of the variables light interception (LI) and leaf area index (LAI) has been recommended as a tool for pasture management, based on the theory that, when the canopy reaches a light interception of 95%, the forage is near its maximum growth rate, which is called critical LAI (Brougham, 1956). The residual LAI refers to the leaf area of the post-grazed stubble. Residual LAI is used to establish the minimum leaf area necessary to ensure an efficient pasture regrowth (Lemos et al., 2014). Light interception and the LAI are difficult to measure at the farm level, due to the high cost of the equipment and technical feasibility of the process. The objective of this study was to evaluate the relationship between LI and LAI measured by two different equipment, with canopy height and soil cover in three species of Brachiaria

Implications of the polymorphism of HLA-G on its function, regulation, evolution and disease association

The HLA-G gene displays several peculiarities that are distinct from those of classical HLA class I genes. The unique structure of the HLA-G molecule permits a restricted peptide presentation and allows the modulation of the cells of the immune system. Although polymorphic sites may potentially influence all biological functions of HLA-G, those present at the promoter and 3′ untranslated regions have been particularly studied in experimental and pathological conditions. The relatively low polymorphism observed in the MHC-G coding region both in humans and apes may represent a strong selective pressure for invariance, whereas, in regulatory regions several lines of evidence support the role of balancing selection. Since HLA-G has immunomodulatory properties, the understanding of gene regulation and the role of polymorphic sites on gene function may permit an individualized approach for the future use of HLA-G for therapeutic purposes

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies : an international multicenter retrospective study

Background: Immunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n 5 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term.disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen