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1.
Aquat Toxicol ; 227: 105586, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32882451

RESUMO

Estrogenic effects triggered by androgens have been previously shown in a few studies. Aromatization and direct binding to estrogen receptors (ERs) are the most proposed mechanisms. For example, previously, a modulation of vitellogenin A (VtgA) by testosterone (T), an aromatizable androgen, was reported in brown trout primary hepatocytes. The effect was reversed by an ER antagonist. In this study, using the same model the disruption caused by T and by the non-aromatizable androgen - dihydrotestosterone (DHT), was assessed in selected estrogenic targets. Hepatocytes were exposed (96 h) to six concentrations of each androgen. The estrogenic targets were VtgA, ERα, ERß1 and two zona pellucida genes, ZP2.5 and ZP3a.2. The aromatase CYP19a1 gene and the androgen receptor (AR) were also included. Modulation of estrogenic targets was studied by quantitative real-time PCR and immunohistochemistry, using an HScore system. VtgA and ERα were up-regulated by DHT (1, 10, 100 µM) and T (10, 100 µM). In contrast, ERß1 was down-regulated by DHT (10, 100 µM), and T (100 µM). ZP2.5 mRNA levels were increased by DHT and T (1, 10, 100 µM), while ZP3a.2 was up-regulated by DHT (100 µM) and T (10, 100 µM). Positive correlations were found between VtgA and ERα mRNA levels and ZPs and ERα, after exposure to both androgens. The mRNA levels of CYP19a1 were not changed, while AR expression tended to increase after micromolar DHT exposures. HScores for Vtg and ZPs corroborated the molecular findings. Both androgens triggered estrogen signaling through direct binding to ERs, most probably ERα.


Assuntos
Androgênios/toxicidade , Di-Hidrotestosterona/toxicidade , Estrogênios/metabolismo , Hepatócitos/efeitos dos fármacos , Testosterona/toxicidade , Truta/metabolismo , Poluentes Químicos da Água/toxicidade , Androgênios/metabolismo , Animais , Células Cultivadas , Di-Hidrotestosterona/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Estrogênios/genética , Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Cultura Primária de Células , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Testosterona/metabolismo , Vitelogeninas/genética , Vitelogeninas/metabolismo , Poluentes Químicos da Água/metabolismo
2.
PLoS One ; 15(8): e0236669, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750092

RESUMO

This study examined the effect of a competitive season on salivary responses [cortisol (sC), testosterone (sT), Testosterone/Cortisol ratio (sT/C), Immunoglobulin A (sIgA), sIgA secretion rate (srIgA), alpha-amylase (sAA)] and upper respiratory symptoms (URS) occurrence in three teams of male soccer players (Under-15, Under-17 and Under-19 yrs.). Training and competition volumes, salivary biomarkers and URS were determined monthly. No differences were found for monthly training volume between teams. Incidence of URS was higher for the U15 (44.9% of the total cases). Higher sT and srIgA were observed for the U19, lower sC were found for the U17 and sAA showed higher values for the U15 throughout the season. In the U15, significant difference (p = .023) was found for sIgA concentration with higher concentration values in January compared to December (-42.7%; p = .008) and the sT showed seasonal variation (p < .001) with the highest value in January significantly different from October (-40.2%; p = .035), November (-38.5%; p = 0.022) and December (-51.6%; p = .008). The U19 presented an increase in sC in March compared to February (-66.1%, p = .018), sT/C were higher in February compared to March (-58.1%; p = .022) and sAA increased in March compared to September (-20.5%; p = .037). Negative correlations, controlled for age group, were found between URS occurrence and srIgA (r = -0.170, p = .001), sAA (r = -0.179, p = .001) and sT (r = -0.107, p = .047). Monitoring salivary biomarkers provides information on mucosal immunity with impact in URS occurrence. Coaches could manipulate training loads to attenuate the physical stressors imposed on athletes, especially at demanding and stressful periods.


Assuntos
Atletas , Imunidade nas Mucosas , Doenças Respiratórias/imunologia , Saliva/imunologia , Futebol , Adolescente , Biomarcadores/metabolismo , Humanos , Hidrocortisona/metabolismo , Imunoglobulina A Secretora/metabolismo , Masculino , Estações do Ano , Testosterona/metabolismo , alfa-Amilases/metabolismo
4.
Int J Nanomedicine ; 15: 3415-3431, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32523341

RESUMO

Purpose: Lanthanum oxide (La2O3) nanoparticles (NPs) have been widely used in catalytic and photoelectric applications, but the reproductive toxicity is still unclear. This study evaluated the reproductive toxicity of two different-sized La2O3 particles in the testes. Materials and Methods: Fifty Kunming mice were randomly divided into five groups. Mice were treated with La2O3 NPs by repeated intragastric administration for 90 days (control, nano-sized with 5, 10, 50 mg/kg BW and micro-sized with 50 mg/kg BW). Mice in the control group were treated with de-ionised water without La2O3 NPs. Sperm parameters, testicular histopathology, TEM assessment, hormone assay and nuclear factor erythroid 2-related factor 2 (Nrf-2) pathway were performed and evaluated. Results: The body weight of mice treated with La2O3 NPs or not had no difference; sperm parameters and histological assessment showed that La2O3 NPs could induce reproductive toxicity in the testicle. Serum testosterone and gonadotropin-releasing hormone (GnRH) in the NH (nano-sized with 50 mg/kg BW) group were markedly decreased relative to control group, and an increase of luteinizing hormone (LH) in NH group was detected . Additionally, transmission electron microscopy revealed that the ultrastructural abnormalities induced by La2O3 NPs were more severe than La2O3 MPs in the testes. Furthermore, La2O3 NPs treatment inhibited the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm into the nucleus as well as the expression of downstream genes NAD(P)H quinone oxidoreductase1 (NQO1), hemeoxygenase 1 (HO-1) and (glutathione peroxidase) GSH-Px, thus abrogating Nrf-2-mediated defense mechanisms against oxidative stress. Conclusions: The results of this study demonstrated that La2O3 NPs improved the spermatogenesis defects in mice. La2O3 NPs inhibited Nrf-2/ARE signaling pathway that resulted in apoptosis in the mice testes.


Assuntos
Elementos de Resposta Antioxidante/genética , Lantânio/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Nanopartículas/toxicidade , Óxidos/toxicidade , Reprodução/efeitos dos fármacos , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Inflamação/patologia , Lantânio/sangue , Masculino , Camundongos , Nanopartículas/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Óxidos/sangue , Transdução de Sinais/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Testículo/ultraestrutura , Testosterona/biossíntese , Testosterona/metabolismo
6.
Toxicology ; 441: 152528, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32565124

RESUMO

Cisplatin (Cis) is an effective chemotherapeutic intervention against many cancer types. However, the oxidative stress-related toxicities associated with cancer cell resistance-induced dose scaling has limited its long-term use. In the present study, we explored the benefits of the antioxidant, tert-butylhydroquinone (tBHQ; 50 mg/kg b.w./day, for 14 days) against Cis single dose injection (7 mg/kg b.w., i.p on Day 8), on testicular toxicity of male Wistar rats. Cis triggered testicular and epididymal oxidative stress, testicular inflammation (upregulated NF-κB, TNF-α and IL-1ß mRNA levels, and downregulated IL-10 mRNA level), increased testicular apoptosis (increased Bax/Bcl2 and caspase-3 mRNA levels) and decreased testicular germ cells proliferation. Further, Cis decreased testicular steroidogenesis (decreased expression of StAR, CYP11A1, 3ß-HSD and 17ß-HSD mRNA and proteins) and decreased follicle stimulating hormone, luteinizing hormone and testosterone levels. Cis also decreased sperm count, motility, viability, normal morphology and Johnsen score. However, intervention with tBHQ significantly decreased oxidative stress by upregulating Nrf2 gene, suppressed inflammation, apoptosis and increased testicular germ cells proliferation. tBHQ also increased steroidogenesis and improved sperm parameters. Taken together, tBHQ improves steroidogenesis and spermatogenesis in Cis-intoxicated rats by improving antioxidant status, dampening inflammation and apoptosis, thus improving the proliferative capacity of spermatogenic cells.


Assuntos
Apoptose/efeitos dos fármacos , Cisplatino/toxicidade , Hidroquinonas/farmacologia , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Cisplatino/antagonistas & inibidores , Hormônio Foliculoestimulante/metabolismo , Hormônio Luteinizante/metabolismo , Masculino , Ratos , Ratos Wistar , Testículo/metabolismo , Testosterona/metabolismo
7.
PLoS Genet ; 16(6): e1008810, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32497091

RESUMO

Urogenital tract abnormalities are among the most common congenital defects in humans. Male urogenital development requires Hedgehog-GLI signaling and testicular hormones, but how these pathways interact is unclear. We found that Gli3XtJ mutant mice exhibit cryptorchidism and hypospadias due to local effects of GLI3 loss and systemic effects of testicular hormone deficiency. Fetal Leydig cells, the sole source of these hormones in developing testis, were reduced in numbers in Gli3XtJ testes, and their functional identity diminished over time. Androgen supplementation partially rescued testicular descent but not hypospadias in Gli3XtJ mutants, decoupling local effects of GLI3 loss from systemic effects of androgen insufficiency. Reintroduction of GLI3 activator (GLI3A) into Gli3XtJ testes restored expression of Hedgehog pathway and steroidogenic genes. Together, our results show a novel function for the activated form of GLI3 that translates Hedgehog signals to reinforce fetal Leydig cell identity and stimulate timely INSL3 and testosterone synthesis in the developing testis. In turn, exquisite timing and concentrations of testosterone are required to work alongside local GLI3 activity to control development of a functionally integrated male urogenital tract.


Assuntos
Criptorquidismo/genética , Regulação da Expressão Gênica no Desenvolvimento , Células Intersticiais do Testículo/patologia , Proteínas do Tecido Nervoso/metabolismo , Diferenciação Sexual/genética , Proteína Gli3 com Dedos de Zinco/metabolismo , Animais , Criptorquidismo/patologia , Modelos Animais de Doenças , Proteínas Hedgehog/metabolismo , Humanos , Insulina/metabolismo , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas/metabolismo , Transdução de Sinais/genética , Testosterona/metabolismo , Proteína Gli3 com Dedos de Zinco/genética
8.
Life Sci ; 254: 117782, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407847

RESUMO

AIMS: This study assessed the prophylactic or therapeutic effects of taurine (TR) and/or hesperidin (HES) on carbon tetrachloride (CCl4) induced acute kidney and testicular injury in rats. MAIN METHODS: Rats were randomly divided into nine experimental groups including control; corn oil; CCl4; HES/CCl4; TR/CCl4; HES + TR/CCl4; CCl4/HES; CCl4/TR; and CCl4/HES + TR groups. CCl4 was intraperitoneally injected with a single dose of 2 ml /kg b.w. HES and TR were orally gavaged twice weekly 100 mg/kg b.w. for four weeks. Kidney function, inflammatory response, sexual hormones, and oxidative stress indicators were assessed. Histomorphological and immune-histochemical studies of the inflammatory marker nuclear factor kappa (NF-κB) in renal and testicular tissues were performed. KEY FINDINGS: The results showed that the TR and/or HES treatment significantly suppressed CCl4 induced rise of urea, uric acid, potassium, and follicle-stimulating hormone levels. However, significant restoration of sodium, testosterone, and luteinizing hormone was apparent in CCl4 exposed rats received HES and/or TR. Also, the HES and/or TR treatment significantly rescues CCl4 induced oxidative stress and inflammation. Moreover, the HES and/or TR dosing significantly repaired the CCl4 evoked altered renal and testicular architecture and suppressed NF-κB immunoexpression. Notably, alleviating CCl4 induced renal and testicular damage was more effective in the prophylactic groups than the therapeutic groups. Also, most of the estimated parameters of the HES + TR group did not significantly vary from those of single TR or HES. SIGNIFICANCE: In conclusion, HES or TR could efficiently guard against CCl4 nephro-and reprotoxic effects, but both bioactive combinations afford only a limited synergistic outcome.


Assuntos
Hesperidina/farmacologia , Inflamação/prevenção & controle , Rim/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Taurina/farmacologia , Testículo/metabolismo , Animais , Tetracloreto de Carbono , Sinergismo Farmacológico , Hormônio Foliculoestimulante/metabolismo , Rim/patologia , Hormônio Luteinizante/metabolismo , Masculino , NF-kappa B/metabolismo , Potássio/metabolismo , Ratos , Sódio/metabolismo , Testículo/patologia , Testosterona/metabolismo , Ureia/metabolismo , Ácido Úrico/metabolismo
9.
Int J Nanomedicine ; 15: 3087-3098, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431503

RESUMO

Purpose: Aldo-ketoreductase (AKR) 1C3 is crucial for testosterone synthesis. Abnormally high expression/activity of AKR1C3 can promote castration-resistant prostate cancer (CRPC). A mansonone derivative and AKR1C3 inhibitor, 6e, was combined with 4D5 (extracellular fragment of the monoclonal antibody of human epidermal growth factor receptor-2)-modified chitosan to achieve a nanodrug-delivery system (CS-4D5/6e) to treat CRPC. Materials and Methods: Morphologies/properties of CS-4D5/6e were characterized by atomic force microscopy, zeta-potential analysis, and Fourier transform-infrared spectroscopy. CS-4D5/6e uptake was measured by immunofluorescence under confocal laser scanning microscopy. Testosterone in LNCaP cells overexpressing human AKR1C3 (LNCaP-AKR1C3) and cell lysates was measured to reflect AKR1C3 activity. Androgen receptor (AR) and prostate-specific antigen (PSA) expression was measured by Western blotting. CS-4D5/6e-based inhibition of AKR1C3 was evaluated in tumor-xenografted mice. Results: CS-4D5/6e was oblate, with a particle size of 200-300 nm and thickness of 1-5 nm. Zeta potential was 1.39±0.248 mV. 6e content in CS-4D5/6e was 7.3±1.4% and was 18±3.6% for 4D5. 6e and CS-4D5/6e inhibited testosterone production significantly in a concentration-dependent manner in LNCaP-AKR1C3 cells, and a decrease in expression of AKR1C3, PSA, and AR was noted. Half-maximal inhibitory concentration of CS-4D5/6e on LNCaP-AKR1C3 cells was significantly lower than that in LNCaP cells (P<0.05). CS-4D5/6e significantly reduced growth of 22Rv1 tumor xenografts by 57.00% compared with that in the vehicle group (P<0.01). Conclusion: We demonstrated the antineoplastic activity of a potent AKR1C3 inhibitor (6e) and its nanodrug-delivery system (CS-4D5/6e). First, CS-4D5/6e targeted HER2-positive CRPC cells. Second, it transferred 6e (an AKR1C3 inhibitor) to achieve a reduction in intratumoral testosterone production. Compared with 6e, CS-4D5/6e showed lower systemic toxicity. CS-4D5/6e inhibited tumor growth effectively in mice implanted with tumor xenografts by downregulating testosterone production mediated by intratumoral AKR1C3. These results showed a promising strategy for treatment of the CRPC that develops invariably in prostate-cancer patients.


Assuntos
Membro C3 da Família 1 de alfa-Ceto Redutase/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Terapia de Alvo Molecular/métodos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Animais , Anticorpos Monoclonais/química , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Naftoquinonas/química , Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptor ErbB-2/imunologia , Receptores Androgênicos/metabolismo , Sesquiterpenos/química , Testosterona/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Gene ; 753: 144812, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32470507

RESUMO

Spermatogenesis is a complex and elaborate differentiation process and is critical for male fertility. The hypothalamic-pituitary-gonadal axis serves as a significant neuroendocrine system to regulate spermatogenesis. As a constitute of the hypothalamic-pituitary-gonadal axis, Sertoli cells promote spermatogenesis via protecting, nourishing, and supporting germ cells upon hormone determination. Here we clarified how the hormones in the hypothalamic-pituitary-gonadal axis, including FSH, testosterone and LH, regulate spermatogenesis via the androgen receptor, cAMP/PKA, PI3k/Akt signaling pathways in Sertoli cells. Other endogenous hormones in higher vertebrates, including ouabain, estradiol, leptin, MIS, PGD2, and thyroid hormone, also regulate spermatogenesis via the AR or cAMP/PKA signaling pathway. Among them, the dynamics of adherens junctions, gap junctions, and blood-testis barrier, glucose uptake, lactate supply and differentiation of Sertoli cells are regulated by more comprehensive hormones and signaling pathways in Sertoli cells. In infertile patients or patients with blocked spermatogenesis, the AR, cAMP/PKA and PI3k/Akt signaling pathways and related components exhibit abnormal activity or disordered content. The clinical specimens from patients with testicular cancer show similar mutated AR genes. According to the existing clinical evidence, it is valuable to study the deep mechanism of male infertility and testicular tumors from the perspective of hormones and signaling pathways in Sertoli cells.


Assuntos
Infertilidade Masculina/metabolismo , Células de Sertoli/metabolismo , Células de Sertoli/fisiologia , Animais , Hormônio Foliculoestimulante/metabolismo , Humanos , Hormônio Luteinizante/metabolismo , Masculino , Neoplasias Embrionárias de Células Germinativas/metabolismo , Receptores Androgênicos/genética , Transdução de Sinais/fisiologia , Espermatogênese/genética , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/fisiopatologia , Testículo/metabolismo , Testosterona/metabolismo
11.
Int J Behav Med ; 27(3): 262-266, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32405916

RESUMO

BACKGROUND: Accurate estimation in statistical models depends on sample size but also, critically, reliability of the measure. Physiometrics is the equivalent of psychometrics for measures such as sex hormones, catabolic hormones, and products of the immune system. METHOD: There are multiple ways to measure physiometrics, from simple correlation to complex generalizability theory designs. Depending on the design, these estimates can provide information about equivalency (e.g., the correlation between two measurements taken close together in time) or stability (e.g., the correlation between two measurements taken farther apart in time). RESULTS: The physiometrics of salivary measures including cortisol, α-amylase, testosterone, and cytokines range from highly stable, requiring only a single sample, to highly unstable, requiring multiple samples to achieve generalizability to longer periods of time. However, generalizability is relative to the study design, and only some designs call for stable and generalizable measures. CONCLUSION: Both dedicated physiometric studies and more reporting of physiometrics in psychoneuroendocrinology and psychoneuroimmunology will improve the quality of salivary bioscience study designs in the future.


Assuntos
Hidrocortisona/metabolismo , Saliva/metabolismo , Humanos , Reprodutibilidade dos Testes , Projetos de Pesquisa , Testosterona/metabolismo
12.
Gene ; 747: 144672, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32305634

RESUMO

Brain and muscle Arnt-like protein-1 (BMAL1) is a clock gene that plays an important role in hormone secretion and apoptosis, but its effect on Leydig cells is unidentified. Here the role of BMAL1 in apoptosis and testosterone secretion in TM3 Leydig cell line were investigated by inhibiting its expression using small interfering RNA (siRNA). Results showed that BMAL1 knockdown promoted the apoptosis of Leydig cells and expression of (BCL2 associated X) BAX mRNA and protein, and reduced the expression of (B-cell lymphoma-2) BCL-2 mRNA and protein. BMAL1 inhibition resulted in decreased testosterone secretion and reduced expression of key genes during hormone synthesis, specifically steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1), and 3ß-hydroxysteroid dehydrogenase (3ß-HSD). In addition, BMAL1 knockdown reduced the expression of phosphorylated p85 and AKT as confirmed by western blot. In conclusion, BMAL1 may affect testosterone secretion and apoptosis in mouse Leydig cells through regulation of the PI3K/AKT signaling pathway.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Apoptose , Técnicas de Silenciamento de Genes , Testosterona/metabolismo , Fatores de Transcrição ARNTL/genética , Animais , Apoptose/genética , Linhagem Celular , Regulação da Expressão Gênica , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Testosterona/biossíntese , Transcrição Genética
13.
Chem Biol Interact ; 324: 109093, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298659

RESUMO

Polycystic Ovary Syndrome (PCOS), as a common endocrine disorder is accompanied by hyperandrogenism, insulin resistance, ovulation problems, and infertility. Various types of off-label drugs like metformin have been used for the management of targeted problems caused by PCOS such as insulin resistance and hyperandrogenism. Nicotinamide (NAM) acts as a substrate of visfatin and Nicotinamide N-Methyltransferase (NNMT) leading to the generation of Nicotinamide Adenine Dinucleotide (NAD) and N1-Methylnicotinamide (MNAM), respectively. MNAM is known as an anti-inflammatory, anti-thrombosis, and anti-diabetic agent. In this study, the effects of NAM and MNAM on metabolic and endocrine abnormalities were evaluated in the adipose and ovarian tissues of a letrozole-induced rat model of PCOS. Our results showed that MNAM and NAM reversed abnormal estrous cycle and reduced the serum testosterone levels and CYP17A1 gene expression. Furthermore, all therapeutic factors improved HOMA-IR after treatment and NAM significantly increased the expression of GLUT4 and decreased the gene expression of visfatin. Also, MNAM diminished the gene expression of visfatin and resistin. It is noteworthy that all the therapeutic factors successfully activated the AMPK. In summary, this study is the first study reported beneficial effects of NAM and MNAM on the treatment of PCOS. Additionally, the alleviative effects of our therapeutic factors may be partially mediated by the AMPK-dependent manner due to the contribution of the AMPK in the expression of CYP17A1, visfatin, resistin, and GLUT4. Although more studies are required to unravel the exact mode of actions of MNAM and NAM in the PCOS, the findings of the current study shed light on an urgent need for discovering novel therapeutic pharmaceuticals regarding the treatment of PCOS.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Ovário/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Ciclo Estral/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Hiperandrogenismo/tratamento farmacológico , Hormônio Luteinizante/metabolismo , Metformina/uso terapêutico , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Ratos Wistar , Resistina/genética , Resistina/metabolismo , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Testosterona/metabolismo
14.
Nat Commun ; 11(1): 1613, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32235862

RESUMO

In men, the incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male. The immune system is known to play a key role in controlling the growth and spread of malignancies, but whether age- and sex-dependent changes in immune cell function account for this effect remains unknown. Here, we show that in castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. Replacement of testosterone effectively normalized the tumor burden in castrated male mice. Further, the aberrant neutrophil phenotype was also observed in prostate cancer patients receiving androgen deprivation therapy, highlighting the evolutionary conservation and clinical relevance of the phenotype. Taken together, these results provide a better understanding of the role of androgen signaling in neutrophil function and the impact of this biology on immune control of malignancies.


Assuntos
Antagonistas de Androgênios/farmacologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Testosterona/metabolismo , Antagonistas de Androgênios/uso terapêutico , Androgênios , Animais , Antineoplásicos/farmacologia , Medula Óssea/patologia , Transplante de Medula Óssea , Modelos Animais de Doenças , Feminino , Terapia de Reposição Hormonal/métodos , Pulmão/patologia , Masculino , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Testosterona/imunologia
15.
PLoS One ; 15(3): e0230838, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32231386

RESUMO

A growing body of evidence suggests that men may perceive women's bodily odour to be more attractive during the high-fertility ovulatory phase than during other phases in the menstrual cycle. In particular, women's bodily odour may influence important aspects of male mating behaviour, but the precise nature of this phenomena remains to be elucidated. Twenty-six men and five women participated in the study. Each woman wore a cotton T-shirt during the night for 3 days during the ovulatory phase, after which the regions of the T-shirt that had been in contact with the woman's chest, armpits, and back, were cut out of the garment. We evaluated the changes in testosterone and cortisol levels in the saliva of men who smelled these cloth pieces. The odour emitted from the backs of women in the ovulatory phase was found to increase testosterone secretion in men, whereas the odour emitted from the chests of women in the ovulatory phase reduced cortisol secretion in men. These results suggest that the odour of specific body parts of women modulate unconscious physiological reactions in men.


Assuntos
Hidrocortisona/metabolismo , Odorantes , Ovulação/metabolismo , Testosterona/metabolismo , Feminino , Humanos , Masculino , Ciclo Menstrual/metabolismo , Comportamento Sexual/efeitos dos fármacos , Comportamento Sexual/fisiologia , Adulto Jovem
16.
J Spec Oper Med ; 20(1): 94-100, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32203613

RESUMO

OBJECTIVE: Due to physical demands, Special Operations Forces (SOF) endure changes in body composition, work capacity, and endocrine function. These changes result in energy deficits and sleep deprivation, where sleep averaged 3 hours/ day, independently known to decrease testosterone levels. The use of exogenous testosterone shows increases in lean body mass (LBM) and muscle function in healthy males and reverses cachexia in diseased populations. Therefore, the review's primary purpose is to summarize and contrast literature in both SOF and nonmilitary personnel regarding the correlation between negative energy balance, sleep deprivation, and decreased testosterone. The secondary purpose summarizes the effects of exogenous testosterone therapy in healthy males as well as reversing the effects of muscle wasting diseases. METHODS: An online literary search from 1975 to 2015 identified 46 of 71 sources addressing both purposes, and data were summarized into tables providing mean observations. CONCLUSIONS: SOF training results in decreased testosterone (-6.3%), LBM (-4.6%), and strength (-11.7%), tied to energy deficits (-3,351 kcal/day) and sleep deprivation (3 hours/ day). Exogenous testosterone therapy increases LBM (6.2%), strength (7.9-14.8%), reverses cachexia (2.0%) and increases strength (12.7%) in those with chronic diseases. Therefore, testosterone supplementation in SOF may attenuate changes in body composition and muscle function during training and sustained Special Operations (SUSOPS).


Assuntos
Composição Corporal , Militares/educação , Força Muscular , Testosterona/metabolismo , Humanos , Masculino , Testosterona/uso terapêutico
17.
PLoS One ; 15(3): e0224052, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32168344

RESUMO

BACKGROUND: Codeine, a 3-methylmorphine, and other related opioids have been implicated in androgen suppression, although the associated mechanisms remain unclear. AIM: Therefore, the objective of the current study was to elucidate the in vivo molecular mechanisms underlying codeine-induced androgen suppression. METHODS: This study made use of twenty-one healthy male rabbits, distributed into three groups randomly, control and codeine-treated groups. The control had 1ml of normal saline daily p.o. The codeine-treated groups received either 4mg/kg b.w of codeine or 10mg/kg b.w of codeine p.o. for six weeks. Reproductive hormonal profile, testicular weight, testicular enzymes, oxidative and inflammatory parameters, testicular DNA fragmentation, histological examination and apoptosis marker were evaluated to examine the effects of codeine use. KEY FINDINGS: Oral administration of codeine resulted in testicular atrophy and alterations in testicular histomorphology, elevated testicular enzymes, and suppression of circulatory and intra-testicular testosterone. These changes were associated with a marked rise in oxidative markers and decline in the activities of testicular enzymatic antioxidants, as well as oxidative DNA damage, inflammatory response, testicular DNA fragmentation, and caspase-dependent apoptosis (p<0.05). SIGNIFICANCE: In conclusion, chronic codeine use resulted in testicular degeneration and testosterone suppression, which is attributable to TNF-α/nitric oxide-/oxidative stress-mediated caspase-dependent apoptotic testicular cell death and loss of testicular function.


Assuntos
Caspase 3/metabolismo , Codeína/toxicidade , Fragmentação do DNA/efeitos dos fármacos , Óxido Nítrico/metabolismo , Testículo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Administração Oral , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Codeína/administração & dosagem , Masculino , Estresse Oxidativo/efeitos dos fármacos , Coelhos , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Testículo/metabolismo , Testosterona/metabolismo
18.
Poult Sci ; 99(2): 708-718, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32029156

RESUMO

This study was conducted to evaluate the effects of dietary polyunsaturated fatty acids (PUFA) sources and rosemary leaves powder (RLP) on the semen quality, fatty acid analysis, and some reproductive hormones of senescent broiler breeder roosters. Thirty-five 45-wk-old Ross breeder roosters were randomly divided into 7 groups (5 birds/group), and received following treatments including control group (basal diet), fish oil (2%), corn oil (2%), an equal (50:50%) proportion of fish oil and corn oil (50:50%), fish oil (2%) with 5 g/kg capsulated RLP, corn oil (2%) with 5 g/kg capsulated RLP, and an equal (50:50) proportion of fish oil and corn oil (50:50%) with 5 g/kg capsulated RLP of diet for 60 D, during which time their seminal characteristics were evaluated every 20 D. At the end of the trial (on day 60), semen samples were tested for determination of sperm fatty acid analysis, lipid peroxidation, and some reproductive hormones. Results showed that feeding fish oil and fish/corn oil with RLP was associated with an increase in docosahexaenoic acid (C22:6n-3) and docosatetraenoic acid (C22:4n-6) in sperm. The fish oil diet increased the proportion of n-3 fatty acids in sperm, and as a consequence, the (n-6)/(n-3) ratio also decreased (P < 0.05). RLP (5 g/kg) to the fish and fish/corn-oil (50:50%)-based diet resulted in improvement in sperm concentration, total motility (%), sperm progressive motility (%), membrane integrity, and viability in terms 0 to 60 day trial (P < 0.05). Diets and age interacted to positively affect sperm concentration and sperm membrane integrity. Also this herbal antioxidant decreased the seminal content of malondialdehyde (MDA) significantly (P < 0.05). Testosterone and LH serum levels of reproductive hormones were significantly higher in fish and fish/corn-oil with RPL (50:50%)-based diet than other groups (P < 0.05). It can be concluded that RLP as an antioxidant could remarkably improve the effects of n-3 and n-3/n-6 PUFA on sperm characteristics, seminal MDA, and hormones levels in aged breeder roosters. The susceptibility of semen to lipid peroxidation was increased in chickens fed without RLP. Future studies are needed to disclose the causal mechanisms involved.


Assuntos
Galinhas/fisiologia , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Rosmarinus/química , Sêmen/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-6/administração & dosagem , Hormônio Luteinizante/efeitos dos fármacos , Hormônio Luteinizante/metabolismo , Masculino , Folhas de Planta/química , Pós/administração & dosagem , Distribuição Aleatória , Análise do Sêmen/veterinária , Testosterona/metabolismo
19.
Chemistry ; 26(28): 6214-6223, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32049373

RESUMO

The hydroxylation of nonreactive C-H bonds can be easily catalyzed by a variety of metalloenzymes, especially cytochrome P450s (P450s). The mechanism of P450 mediated hydroxylation has been intensively studied, both experimentally and theoretically. However, understanding the regio- and stereoselectivities of substrates hydroxylated by P450s remains a great challenge. Herein, we use a multi-scale modeling approach to investigate the selectivity of testosterone (TES) and dihydrotestosterone (DHT) hydroxylation catalyzed by two important P450s, CYP3A4 and CYP19A1. For CYP3A4, two distinct binding modes for TES/DHT were predicted by dockings and molecular dynamics simulations, in which the experimentally identified sites of metabolism of TES/DHT can access to the catalytic center. The regio- and stereoselectivities of TES/DHT hydroxylation were further evaluated by quantum mechanical and ONIOM calculations. For CYP19A1, we found that sites 1ß, 2ß and 19 can access the catalytic center, with the intrinsic reactivity 2ß>1ß>19. However, our ONIOM calculations indicate that the hydroxylation is favored at site 19 for both TES and DHT, which is consistent with the experiments and reflects the importance of the catalytic environment in determining the selectivity. Our study unravels the mechanism underlying the selectivity of TES/DHT hydroxylation mediated by CYP3A4 and CYP19A1 and is helpful for understanding the selectivity of other substrates that are hydroxylated by P450s.


Assuntos
Aromatase/metabolismo , Citocromo P-450 CYP3A/metabolismo , Di-Hidrotestosterona/química , Testosterona/metabolismo , Aromatase/química , Catálise , Citocromo P-450 CYP3A/química , Humanos , Hidroxilação , Cinética , Oxirredução , Testosterona/química
20.
BMC Complement Med Ther ; 20(1): 42, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046715

RESUMO

BACKGROUND: Qilin pills (QLPs), a classic Traditional Chinese Medicine (TCM) formula for treating male infertility, effectively improve semen quality in clinical trials. This study was designed to evaluate the effects of QLPs on spermatogenesis, reproductive hormones, oxidative stress, and the testis-specific serinekinase-2 (TSSK2) gene in a rat model of oligoasthenospermia. METHODS: Forty adult male Sprague-Dawley (SD) rats were randomly divided into four groups. The rat model with oligoasthenospermia was generated by intragastric administration of tripterygium glycosides (TGs) once daily for 4 weeks. Then, two treatment groups were given different doses (1.62 g/kg and 3.24 g/kg) of QLPs once daily for 60 days. Sperm parameters, testicular histology and reproductive hormone measurements, oxidative stress tests, and TSSK2 expression tests were carried out. RESULTS: QLPs effectively improved semen parameters and testicular histology; restored the levels of FSH, LH, PRL, fT, and SHBG; reduced the levels of oxidative stress products (ROS and MDA); increased testicular SOD activity; and restored the expression of spermatogenesis-related gene TSSK2. CONCLUSION: QLPs have a therapeutic effect on a rat model of oligoasthenospermia, and this effect is manifested as improvement of semen quality and testis histology, gonadal axis stability, decreased oxidative stress, and the regulation of testis-specific spermatogenesis-related gene TSSK2.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hormônios/metabolismo , Oligospermia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Espermatogênese/efeitos dos fármacos , Animais , China , Modelos Animais de Doenças , Gonadotropinas Hipofisárias/metabolismo , Masculino , Medicina Tradicional Chinesa , Prolactina/metabolismo , Ratos , Ratos Sprague-Dawley , Globulina de Ligação a Hormônio Sexual/metabolismo , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testosterona/metabolismo
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