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1.
PLoS One ; 15(8): e0236879, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790676

RESUMO

Benign prostatic hyperplasia (BPH) is a progressive pathological condition associated with proliferation of prostatic tissues, prostate enlargement, and lower-urinary tract symptoms. However, the mechanism underlying the pathogenesis of BPH is unclear. The aim of this study was to investigate the protective effects of a combination of Stauntonia hexaphylla and Cornus officinalis (SC extract) on a testosterone propionate (TP)-induced BPH model. The effect of SC extract was examined in a TP-induced human prostate adenocarcinoma cell line. Male Sprague-Dawley rats were randomly divided into 5 groups (n = 6) for in vivo experiments. To induce BPH, all rats, except those in the control group, were administered daily with subcutaneous injections of TP (5 mg/kg) and orally treated with appropriate phosphate buffered saline/drugs (finasteride/saw palmetto/SC extract) for 4 consecutive weeks. SC extract significantly downregulated the androgen receptor (AR), prostate specific antigen (PSA), and 5α-reductase type 2 in TP-induced BPH in vitro. In in vivo experiments, SC extract significantly reduced prostate weight, size, serum testosterone, and dihydrotestosterone (DHT) levels. Histologically, SC extract markedly recovered TP-induced abnormalities and reduced prostatic hyperplasia, thereby improving the histo-architecture of TP-induced BPH rats. SC extract also significantly downregulated AR and PSA expression, as assayed using immunoblotting. Immunostaining revealed that SC extract markedly reduced the 5α-reductase type 2 and significantly downregulated the expression of proliferating cell nuclear antigen. In addition, immunoblotting of B-cell lymphoma 2 (Bcl-2) family proteins indicated that SC extract significantly downregulated anti-apoptotic Bcl-2 and markedly upregulated pro-apoptotic B cell lymphoma-associated X (Bax) expression. Furthermore, SC treatment significantly decreased the Bcl-2/Bax ratio, indicating induced prostate cell apoptosis in TP-induced BPH rats. Thus, our findings demonstrated that SC extract protects against BPH by inhibiting 5α-reductase type 2 and inducing prostate cell apoptosis. Therefore, SC extract might be useful in the clinical treatment of BPH.


Assuntos
Apoptose/efeitos dos fármacos , Colestenona 5 alfa-Redutase/química , Extratos Vegetais/farmacologia , Hiperplasia Prostática/prevenção & controle , Substâncias Protetoras/uso terapêutico , Inibidores de 5-alfa Redutase/química , Inibidores de 5-alfa Redutase/farmacologia , Inibidores de 5-alfa Redutase/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Cornus/química , Cornus/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Folhas de Planta/metabolismo , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/etiologia , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ranunculales/química , Ranunculales/metabolismo , Ratos , Ratos Sprague-Dawley , Propionato de Testosterona/efeitos adversos
2.
J Ethnopharmacol ; 250: 112446, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-31812646

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Stauntonia hexaphylla (Lardizabalaceae, S. hexaphylla) is traditionally used as a folk remedy for alleviating fever and for its anti- inflammatory and analgesic properties. In Korea and China, S. hexaphylla has been used as a traditional medicine that acts as diuretic and analgesic. S. hexaphylla has also been reported to inhibit osteoporosis and aldose reductase activity. AIM OF THE STUDY: The study aimed to evaluate the therapeutic effects of an extract of S. hexaphylla on testosterone induced benign prostate hyperplasia (BPH) models and to observe its mechanism of action. MATERIALS AND METHODS: To induce a BPH model in vitro and in vivo, a testosterone-treated LNCaP cell line and Sprague Dawley (SD) rats were used, respectively. Androgen receptors (ARs) and prostate-specific antigens (PSA), which are typical BPH-related proteins, were evaluated using western blotting. Prostate weights and dihydrotestosterone (DHT) levels were measured in vivo, and histopathology of the prostate examined using hematoxylin and eosin staining. Proliferating cell nuclear antigen (PCNA) and 5α-reductase type 2 were also evaluated via immunohistochemistry (IHC). In addition, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining and LC3 staining of IHC were performed to evaluate apoptosis and autophagy. RESULTS: S. hexaphylla reduced prostates weights and the thickness of prostate epithelial cells. In vivo and in vitro, PSA and ARs were downregulated following S. hexaphylla treatment. The S. hexaphylla extracts also reduced DHT and 5α-reductase type 2 expression. In addition, the expression of PCNA was reduced, and in the TUNEL staining and IHC of LC3, the number of positive cells was increased in the groups treated with S. hexaphylla. CONCLUSIONS: It was observed that extracts of S. hexaphylla inhibited both 5α -reductase type 2 and ARs. The results indicate that the use of S. hexaphylla extract in BPH is probably beneficial through 5α-reductase inhibition and α-adrenergic receptor blockade. In addition, apoptosis and autophagy were induced, and PCNA was downregulated after S. hexaphylla treatment. Therefore, it can be concluded that S. hexaphylla has a therapeutic effect on BPH.


Assuntos
Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Ranunculales , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Di-Hidrotestosterona/metabolismo , Humanos , Masculino , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo
3.
Sci Rep ; 9(1): 19703, 2019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31873149

RESUMO

Benign prostatic hyperplasia (BPH) is one of the most common diseases in the urinary system of elderly men. Pao extract is an herbal preparation of the bark of the Amazon rainforest tree Pao Pereira (Geissospermum vellosii), which was reported to inhibit prostate cancer cell proliferation. Herein we investigated the therapeutic potential of Pao extract against BPH development in a testosterone-induced BPH rat model. The administration of testosterone induced the prostate enlargement, compared with the sham operated group with vehicle treatment. The BPH/Pao group showed reduced prostate weight comparable with BPH/finasteride group. Notably, Pao treatment did not significantly reduce body weights and sperm number of rats, compared with the control group. Furthermore, Pao extract treatment reduced the proliferative index in prostate glands and testosterone-induced expression levels of AR, as well as androgen-associated proteins such as SRD5A1 and PSA. Moreover, Pao extract and its active component, flavopereirine, induced cytotoxicity on human prostate epithelial RWPE-1 cells in a dose- and time- dependent manner with G2/M arrest. Consistently, Pao extract and flavopereirine suppressed the expression levels of SRD5A1, AR and PSA, respectively. Together, these data demonstrated that Pao extract suppresses testosterone-induced BPH development through inhibiting AR activity and expression, and suggested that Pao extract may be a promising and relative safe agent for BPH.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Apocynaceae/química , Colestenona 5 alfa-Redutase/metabolismo , Extratos Vegetais/farmacologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Animais , Carbolinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Masculino , Extratos Vegetais/uso terapêutico , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Antígeno Prostático Específico/metabolismo , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Testosterona
4.
Sci Rep ; 9(1): 16439, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712739

RESUMO

In vertebrates, the steroidogenesis enzyme 5α-reductase converts testosterone to the more potent androgen 5α-dihydrotestosterone. Homologues of 5α-reductase genes have been identified in molluscs. However, recent findings suggest that vertebrate-type steroid androgens are not utilised in molluscan reproductive development. Genomic searches have revealed that molluscs do not possess many of the steroidogenic enzymes required to make testosterone, nor a nuclear androgen receptor. Consequently, the role of 5α-reductase in molluscs presents a mystery. Here, developmental exposures of Biomphalaria glabrata to selective pharmaceutical 5α-reductase inhibitors elicited a strong, highly reproducible phenotypic response characterised by the development of elongated "banana-shaped" shell morphology. In comparison to untreated snails, the shells are open-coiled and the whorls are unattached. Dutasteride (5α-reductase inhibitor) is approximately 10-times more potent at provoking the banana-shaped shell phenotype than finasteride, paralleling the pharmaceuticals' efficacy in humans. Other enzyme inhibitors with different modes of action were tested to investigate the specificity of the phenotype. However, only the pharmaceutical 5α-reductase inhibitors provoked the response. Dutasteride elicited the same phenotype in a second gastropod, Physella acuta. In the absence of evidence for de novo androgen steroidogenesis in molluscs, these findings suggest that novel substrates for 5α-reductase exist in gastropods, lending support to the contention that molluscan endocrinology differs from the well-characterised vertebrate endocrine system.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Exoesqueleto/anatomia & histologia , Colestenona 5 alfa-Redutase/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Gastrópodes/anatomia & histologia , Gastrópodes/efeitos dos fármacos , Exoesqueleto/embriologia , Animais , Água Doce , Gastrópodes/embriologia , Gastrópodes/enzimologia , Humanos
5.
Molecules ; 24(21)2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31689885

RESUMO

The effect of Rhodiola sachalinensis Boriss extract irradiated with 50 kGy gamma rays (HKC) on benign prostatic hyperplasia (BPH) was investigated. Seven-week-old male SD rats received a subcutaneous injection of 20 mg/kg of testosterone propionate (TP) to induce BPH. Then, the testosterone only group received testosterone, the testosterone + finasteride group received testosterone and finasteride (5 mg/kg), the testosterone + HKC group received testosterone and HKC extract (500 mg/kg). Prostate weight and the dihydrotestosterone (DHT) levels in serum or prostate tissue were determined. The mRNA expressions of 5-alpha reductase (AR) in prostate tissue were also measured. Compared to the control group, prostate weight was significantly improved in the TP group and decreased in the HKC and finasteride-treated groups. Furthermore, the mRNA expression of 5-AR in the prostate was significantly reduced in the HKC and finasteride-treated groups. Similarly, the expression levels of α-smooth muscle actin (α-SMA) and cytokeratin, which are associated with prostatic enlargement in the HKC and finasteride groups, were much lower than in the TP group. HKC treatment showed similar efficacy to finasteride treatment on rats with testosterone-induced BPH. HKC may be explored as a potential new drug for BPH treatment.


Assuntos
Colestenona 5 alfa-Redutase/metabolismo , Raios gama , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Rhodiola/química , Testosterona/metabolismo , Testosterona/toxicidade , Animais , Colestenona 5 alfa-Redutase/genética , Masculino , Hiperplasia Prostática/sangue , Ratos , Ratos Sprague-Dawley , Testosterona/sangue
6.
J Food Biochem ; 43(9): e12987, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31489669

RESUMO

The preventive effects of purple rice crude ethanolic extract (PRE) were firstly investigated on testosterone-induced benign prostatic hyperplasia (BPH) in castrated rats. As compared to vehicle-treated rats, lower prostate weights were found in the BPH rats that received PRE 1 g/kg bw. In addition, the PRE treatment down-regulated the androgen receptor (AR) expression in the dorsolateral prostate of those rats. In human prostate cancer cell line, LNCaP, PRE could reduce the cell growth, down-regulate the expression of AR and suppress prostate-specific antigen (PSA) secretion. Moreover, PRE also inhibited an activity of 5α-reductase from rat liver microsomes and the mutagenicity of Salmonella Typhimurium induced by standard mutagen. These results demonstrate that PRE altered testosterone-induced BPH in rats and retarded prostate cancer cell growth by modulating AR expression. It is therefore recommended that further investigation is undertaken into the chemopreventive potential of PRE in androgen-AR mediated diseases. PRACTICAL APPLICATIONS: This study revealed the mechanisms of purple rice extract on testosterone-induced rat benign prostatic hyperplasia. Such information, purple rice components show promise as an effective chemopreventive agent for prostatic hyperplasia prevention by alternating the influence of testosterone through its receptor. Thus, purple rice might be developed as food supplement for reduction of prostatic hyperplasia or cancer in elder men.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Oryza/química , Extratos Vegetais/farmacologia , Hiperplasia Prostática/induzido quimicamente , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Testosterona/toxicidade , Antagonistas de Receptores de Andrógenos/química , Animais , Colestenona 5 alfa-Redutase/metabolismo , Relação Dose-Resposta a Droga , Humanos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Extratos Vegetais/química , Hiperplasia Prostática/tratamento farmacológico , Ratos Wistar
7.
J Steroid Biochem Mol Biol ; 194: 105433, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31376460

RESUMO

The steroid hormones not only exert various endocrine functions but also act as the autocrine or paracrine factors in different tissues of mammals. In the present study, the seasonal expressions of androgen receptor (AR), estrogen receptors alpha and beta (ERα and ERß), aromatase cytochrome P450 (P450arom) and 5α-reductase 1, 2 were investigated in the epididymis of the muskrat. HE staining showed enlarged lumen and abundant sperm in the breeding season while reduced lumen with no sperm in the non-breeding season. The staining of AR was presented in nuclei of epithelial cells of the epididymis in both seasons. The immunostaining of ERα was localized in both nuclei and cytoplasm of epithelial cells of the epididymis during the breeding season, while the weak staining of ERα was only in the nuclei of epithelial cells during the non-breeding season. In contrast, ERß signal was negative in the epididymis of the muskrat in both seasons. The positive signals for P450arom and 5α-reductase 1, 2 were found in the cytoplasm of epithelial and smooth muscle cells during both seasons. Moreover, the protein and mRNA expression levels of AR, ERα, P450arom and 5α-reductase 1, 2 were significantly higher in the epididymis during the breeding season than those of the non-breeding season, and the expression level of 5α-reductase 1 was higher when compared with 5α-reductase 2. In addition, the levels of testosterone (T) and dihydrotestosterone (DHT) in the epididymis and serum were remarkably higher during the breeding season. Taken together, these findings suggested androgen and estrogen might play an important endocrine or autocrine/paracrine role to regulate the epididymal functions of the muskrat.


Assuntos
Aromatase/metabolismo , Colestenona 5 alfa-Redutase/metabolismo , Epididimo/metabolismo , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/metabolismo , Animais , Aromatase/genética , Arvicolinae , Colestenona 5 alfa-Redutase/genética , Masculino , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Receptores Estrogênicos/genética , Reprodução , Estações do Ano
8.
J Enzyme Inhib Med Chem ; 34(1): 1597-1606, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31469015

RESUMO

Prostate cancer (PCa) is the second leading cause of death in men. Apart from androgen receptor, 5α-reductase has also been recognized as a potential target. In this study, a series of androst-17ß-amide compounds have been designed and synthesized targeting both AR and 5α-reductase. Their anti-proliferation activities were evaluated in AR + cell line 22RV1 and AR - cell line PC-3. The results indicated that most of the synthesized compounds inhibited the testosterone-stimulated cell proliferation with good selectivity and safety. Among all the compounds, androst[3,2-c]pyrazole derivatives (9a-9d) displayed the best inhibition activity comparable with flutamide. Moreover, most of the synthesized compounds displayed good 5α-reductase inhibitory activities with IC50 lower than 1 µM. The docking result of 9d-AR indicated that AR was forced to expands its binding cavity and maintain an antagonistic conformation since the steric hindrance of 9d impeded H12 transposition. Overall, compound 9d can be identified as a potential dual 5α-reductase inhibitor and AR antagonist, which might be of therapeutic importance for PCa treatment.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Antagonistas de Receptores de Andrógenos/farmacologia , Androstenos/farmacologia , Colestenona 5 alfa-Redutase/metabolismo , Desenho de Fármacos , Receptores Androgênicos/metabolismo , Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/química , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Androstenos/síntese química , Androstenos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Células PC-3 , Relação Estrutura-Atividade , Células Tumorais Cultivadas
9.
J Neuroendocrinol ; 31(6): e12736, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31102564

RESUMO

The brain is a steroidogenic tissue. It expresses key molecules involved in the synthesis and metabolism of neuroactive steroids, such as steroidogenic acute regulatory protein (StAR), translocator protein 18 kDa (TSPO), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), 3ß-hydroxysteroid dehydrogenases (3ß-HSD), 5α-reductases (5α-R) and 3α-hydroxysteroid oxidoreductases (3α-HSOR). Previous studies have shown that the levels of brain steroids are different in male and female rats under basal conditions and after gonadectomy. In the present study, we assessed gene expression of key neurosteroidogenic molecules in the cerebral cortex and cerebellum of gonadally intact and gonadectomised adult male and female rats. In the cerebellum, the basal mRNA levels of StAR and 3α-HSOR were significantly higher in females than in males. By contrast, the mRNA levels of TSPO and 5α-R were significantly higher in males. In the cerebral cortex, all neurosteroidogenic molecules analysed showed similar mRNA levels in males and females. Gonadectomy increased the expression of 5α-R in the brain of both sexes, although it affected the brain expression of StAR, TSPO, P450scc and 3α-HSOR in females only and with regional differences. Although protein levels were not investigated in the present study, our findings indicate that mRNA expression of steroidogenic molecules in the adult rat brain is sexually dimorphic and presents regional specificity, both under basal conditions and after gonadectomy. Thus, local steroidogenesis may contribute to the reported sex and regional differences in the levels of brain neuroactive steroids and may be involved in the generation of sex differences in the adult brain function.


Assuntos
Cerebelo/metabolismo , Córtex Cerebral/metabolismo , Expressão Gênica , Oxirredutases/metabolismo , Caracteres Sexuais , Esteroides/metabolismo , 3-alfa-Hidroxiesteroide Desidrogenase (B-Específica)/metabolismo , Animais , Proteínas de Transporte/metabolismo , Castração , Cerebelo/enzimologia , Córtex Cerebral/enzimologia , Colestenona 5 alfa-Redutase/metabolismo , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Feminino , Masculino , Fosfoproteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo
10.
J Appl Toxicol ; 39(7): 1066-1078, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30847954

RESUMO

The impact of the perfluoro-chemical, perfluorooctanesulfonate (PFOS), on gonadal steroidogenesis during sexual differentiation in Silurana tropicalis was examined because of its ubiquity in the environment, bioaccumulative nature and potential to disturb endocrine activity. A partial life cycle study exposing S. tropicalis to varying concentrations of PFOS 0.06, 0.13, 0.25, 0.50 and 1.0 mg PFOS/L [nominal]) was conducted. Gonad and plasma samples were collected from juvenile control specimens and organisms exposed to PFOS from early embryo through 150 days post-metamorphosis. Gonad CYP17, aromatase and 5α-reductase activities were measured. Plasma estradiol, testosterone, dihydrotestosterone (DHT) and gonadal testosterone were measured in both males and females. Increased plasma DHT and gonadal testosterone were found in PFOS-treated juvenile male S. tropicalis compared to controls. Decreased plasma estradiol, but not testosterone, was detected in PFOS-treated female S. tropicalis compared to controls. Plasma DHT was not detected and an increase in gonadal testosterone was detected in PFOS-treated female frogs. Female S. tropicalis exposed to PFOS exhibited a concentration-related decrease in the mean aromatase activity, but not 5α-reductase. PFOS exposure in male frogs induced a concentration-related increase in 5α-reductase activity, but did not alter aromatase activity compared to control frogs. A concentration-related increase in CYP 17,20-lyase activity, but not 17-hydroxylase activity, was found in both female and male S. tropicalis exposed to PFOS.


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Aromatase/metabolismo , Colestenona 5 alfa-Redutase/metabolismo , Disruptores Endócrinos/toxicidade , Fluorcarbonetos/toxicidade , Hormônios Esteroides Gonadais/sangue , Gônadas/efeitos dos fármacos , Animais , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Feminino , Gônadas/enzimologia , Gônadas/crescimento & desenvolvimento , Masculino , Metamorfose Biológica/efeitos dos fármacos , Diferenciação Sexual/efeitos dos fármacos , Xenopus
11.
J Cosmet Dermatol ; 18(1): 414-421, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29808617

RESUMO

BACKGROUND: Costunolide (COS), a naturally occurring sesquiterpene lactone, is known to exert anti-inflammatory, antioxidant, and anticancer effects. This study was undertaken to investigate the effects of costunolide on the promotion of hair growth. METHODS: Real-time cell analyzer (RTCA), measurement of 5α-reductase activity, mRNA expression, and Western blotting were adopted to address whether COS can stimulate the proliferation of human hair follicle dermal papilla cells (hHFDPCs). The effect of COS on in vivo hair growth was examined by reconstitution assay and shaven dorsal skin in C57BL/6 mice. RESULTS: Costunolide significantly promoted the proliferation of hHFDPCs, which is comparable to that of tofacitinib. COS also inhibited the 5α-reductase activity in hHFDPCs. While COS increased the level of ß-catenin and Gli1 mRNA and proteins, it suppressed transforming growth factor (TGF)-ß1-induced phosphorylation of Smad-1/5 in hHFDPCs. COS increased the number of cultured hHFDPCs to induce hair follicles from mouse epidermal cells in Spheres formation of reconstitution assay. Topical application of COS on the shaven back of C57BL/6 mice significantly improved the hair growth. CONCLUSIONS: Our results illustrate that COS promotes hair growth in vitro and in vivo by regulating the amount of growth factors and/or the activity of cellular responses through coordination of the WNT-ß-catenin, hedgehog-Gli, and TGF-ß1-Smad pathways.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Proliferação de Células/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Sesquiterpenos/farmacologia , Inibidores de 5-alfa Redutase/administração & dosagem , Administração Cutânea , Animais , Células Cultivadas , Colestenona 5 alfa-Redutase/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Folículo Piloso/citologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Distribuição Aleatória , Sesquiterpenos/administração & dosagem , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
12.
Psychoneuroendocrinology ; 99: 206-215, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30265917

RESUMO

Persistent alteration of plasma neuroactive steroid levels associated with major depression has been recently reported in men after the suspension of the treatment for androgenetic alopecia with finasteride, an inhibitor of the enzyme 5alpha-reductase. Observations in male rats confirmed persistent alterations in neuroactive steroid levels also in the brain. In the present study, we have ascertained possible effects on depressive-like behavior, neurogenesis, gliosis, neuroinflammation and gut microbiota in male rats after subchronic treatment for 20 days with finasteride and after one month of its withdrawal. At the end of treatment there was an increase in the number of pH3 immunoreactive cells in the subgranular zone of the dentate gyrus together with an increase in the mRNA levels of TNF-α in the hippocampus. By one month after the end of finasteride treatment, rats showed depressive-like behavior coupled with a decrease in the number of pH3 immunoreactive cells in the subgranular zone of the dentate gyrus, a decrease in granule cell density in the granule cell layer and an increase in the number of GFAP immunoreactive astrocytes in the dentate gyrus. Finally, alteration of gut microbiota (i.e., an increase in Bacteroidetes phylum and in Prevotellaceae family at the end of the treatment and a decrease in Ruminococcaceae family, Oscillospira and Lachnospira genus at the end of the withdrawal period) was detected. In conclusion, finasteride treatment in male rats has long term effects on depressive-like behavior, hippocampal neurogenesis and neuroinflammation and gut microbiota composition.


Assuntos
Depressão/tratamento farmacológico , Finasterida/farmacologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Inibidores de 5-alfa Redutase/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Giro Denteado/efeitos dos fármacos , Finasterida/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Neurogênese/efeitos dos fármacos , Neuroimunomodulação/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Esteroides/sangue
13.
Gen Comp Endocrinol ; 270: 26-34, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30291863

RESUMO

Testosterone (T) is a sex steroid hormone that often varies seasonally and mediates trade-offs between territorial aggression and parental care. Prior work has provided key insights into the 'top-down' hypothalamic control of this seasonal plasticity in T, yet mechanisms acting outside of the brain may also influence circulating T levels. We hypothesized that peripheral mechanisms may be especially critical for females, because peripheral regulation may mitigate the costs of systemically elevated T. Here, we begin to test this hypothesis using a seasonal comparative approach, measuring gene expression in peripheral tissues in tree swallows (Tachycineta bicolor), a songbird with intense female-female competition and T-mediated aggression. We focused on the gonad and liver for their role in T production and metabolism, respectively, and we contrasted females captured during territory establishment versus incubation. During territory establishment, when T levels are highest, we found elevated gene expression of the hepatic steroid metabolizing enzyme CYP2C19 along with several ovarian steroidogenic enzymes, including the androgenic 5α-reductase. Despite these seasonal changes in gene expression along the steroidogenic pathway, we did not observe seasonal changes in sensitivity to upstream signals, measured as ovarian mRNA abundance of luteinizing hormone receptor. Together, these data suggest that differential regulation of steroidogenic gene expression in the ovary is a potentially major contributor to seasonal changes in T levels in females. Furthermore, these data provide a unique and organismal glimpse into tissue-specific gene regulation and its potential role in hormonal plasticity in females.


Assuntos
Colestenona 5 alfa-Redutase/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Testosterona/metabolismo , Animais , Feminino
14.
J Neuroendocrinol ; 30(11): e12649, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30303567

RESUMO

Changes of neurosteroids may be involved in the pathophysiology of multiple sclerosis (MS). The present study investigated whether changes of neurosteroidogenesis also occurred in the grey and white matter regions of the brain in mice subjected to cuprizone-induced demyelination. Accordingly, we compared the expression of neurosteroidogenic proteins, including steroidogenic acute regulatory protein (StAR), voltage-dependent anion channel (VDAC) and 18 kDa translocator protein (TSPO), as well as neurosteroidogenic enzymes, including the side chain cleavage enzyme (P450scc), 3ß-hydroxysteroid dehydrogenase/isomerase and 5α-reductase (5α-R), during the demyelination and remyelination periods. Using immunohistochemistry and a quantitative polymerase chain reaction, we demonstrated a decreased expression of StAR, P450scc and 5α-R with respect to an increase astrocytic and microglial reaction and elevated levels of tumor necrosis factor (TNF)α during the cuprizone demyelination period in the hippocampus, cortex and corpus callosum. These parameters, as well as the glial reaction, were normalised after 2 weeks of spontaneous remyelination in regions containing grey matter. Conversely, persistent elevated levels of TNFα and low levels of StAR and P450scc were observed during remyelination in corpus callosum white matter. We conclude that neurosteroidogenesis/myelination status and glial reactivity are inversely related in the hippocampus and neocortex. Establishing a cause and effect relationship for the measured variables remains a future challenge for understanding the pathophysiology of MS.


Assuntos
Encéfalo/enzimologia , Encéfalo/metabolismo , Bainha de Mielina/enzimologia , Bainha de Mielina/metabolismo , Remielinização , 3-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Cuprizona/administração & dosagem , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos C57BL , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/enzimologia , Esclerose Múltipla/metabolismo , Bainha de Mielina/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neuroglia/enzimologia , Neuroglia/metabolismo , Fosfoproteínas/metabolismo , Receptores de GABA/metabolismo , Remielinização/efeitos dos fármacos , Canal de Ânion 1 Dependente de Voltagem/metabolismo
15.
Arch Ital Urol Androl ; 90(3): 199-202, 2018 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-30362688

RESUMO

OBJECTIVES: Benign Prostatic Hyperplasia (BPH) is a form of benign tumor that occurs in humans mainly with ageing. It affects more than 50% of over 50 years old males and it is characterized by an increased synthesis of dihydrotestosterone (DHT), due to the 5α-reductase activity. The BPH therapeutic approach mainly uses 5α-reductase inhibitors, such as the active compounds present in the extracts deriving from species Serenoa repens. Many lipidosterolic extracts are available on the market, which are obtained with different solvents, among them ethanol is recognized as non-toxic and has less handling risks than hexane. The purpose of the present experimental study was to investigate in-vitro the potency of an ethanol extract of S. repens comparing it with an n-hexane one. MATERIALS AND METHODS: Two different lipido-sterolic extracts of S. repens have been tested: ethanol extract and n-hexane extract, two batches for each one. The inhibitory action of the extract was evaluated estimating in-vitro the activity of enzyme 5α-reductase type I (5α-RI), which was mainly active under the experimental condition of pH 7.5. DHT amount, synthesized from testosterone (1 µM), was evaluated in a co-culture model of epithelial cells and fibroblasts resulting from prostatic biopsy of a patient with BPH. RESULTS: The analysis of the resulting dose-response curves showed that the entire S. repens extracts inhibited the 5α-RI showing no difference between the two kinds of extract or between the batches. The resulting IC50 values were the following: 8.809 (95% CI = 5.133-15.56) and 9.464 (95% CI = 5.094- 18.27) for ethanol extracts; 11.08 (95% CI = 6.389-19.98) and 12.72 (95% CI = 7.758-21.53) for n-hexane extracts. CONCLUSIONS: The potency of ethanol extracts of S. repens was comparable with the one of n-hexane extracts.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Colestenona 5 alfa-Redutase/efeitos dos fármacos , Extratos Vegetais/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Inibidores de 5-alfa Redutase/administração & dosagem , Células Cultivadas , Colestenona 5 alfa-Redutase/metabolismo , Técnicas de Cocultura , Di-Hidrotestosterona/metabolismo , Relação Dose-Resposta a Droga , Células Epiteliais/metabolismo , Etanol/química , Fibroblastos/metabolismo , Hexanos/química , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Masculino , Extratos Vegetais/administração & dosagem , Hiperplasia Prostática/enzimologia , Hiperplasia Prostática/patologia , Solventes/química
16.
Biosci Biotechnol Biochem ; 82(12): 2101-2108, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30124113

RESUMO

Benign prostatic hyperplasia (BPH) is commonly observed in men > 50 years worldwide. Phytotherapy is one of the many treatment options. Sorghum (Sorghum bicolor L.) contains various health-improving phytochemicals with antioxidant and inhibitory activities on cell proliferation, both in vitro and in vivo. To confirm the effects of Donganme sorghum ethyl-acetate extract (DSEE) on BPH, we induced BPH in Spragye-Dawley rats using exogenous testosterone. We measured prostate weight, examined prostrates histopathologically, and analyzed mRNAs associated with male hormones and proteins associated with cell proliferation in the prostate. DSEE inhibited weight gain of the prostate; decreased mRNA expressions of androgen receptor and 5α-reductase II; and improved histopathological symptoms, the protein-expressed ratio of Bax/Bcl-2, and the oxidative status of BPH induced by testosterone in SD rats. Therefore, DSEE may have potential as a preventive or therapeutic agent against BPH.


Assuntos
Acetatos/química , Extratos Vegetais/farmacologia , Hiperplasia Prostática/prevenção & controle , Sorghum/química , Animais , Proliferação de Células/efeitos dos fármacos , Colestenona 5 alfa-Redutase/genética , Colestenona 5 alfa-Redutase/metabolismo , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/genética , Testosterona
17.
Bioorg Med Chem ; 26(14): 4058-4064, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30007568

RESUMO

It is known that the growth of prostate metastatic bone tumor depends on androgens, and tumor formation can start from migratory malignant cells produced in that organ. These cells exhibit grater type 1 5α-reductase (5α-R1) activity than type 2 5α-reductase. Noteworthy, both isozymes convert testosterone (T) to the more active androgen dihydrotestosterone (DHT) in the target tissues. Thus, in order to potentially improve the prognosis of this disease, in this work, seven derivatives of 17-(1H-benzimidazol-1-yl)-16-formillandrosta-5,16-dien-3ß-yl benzoate (4a-f) and 17-(1H-benzimidazol-1-yl)-3-hydroxy-16-formylandrost-5,16-diene (4) were synthesized, characterized and identified as inhibitors of type 1 5α-reductase (5αR1). These derivatives having the advantage of improved plasma half-life. The inhibitory activity of the compounds towards 5α-R1 isoenzyme was determined by conversion of T into DHT in the presence or absence of compounds 4, 4a-f. Further, in vivo experiments were also carried out, treating gonadectomized hamsters with T and/or 4, 4a-f and evaluating their effect on the diameter of hamster flank organs and on the weight of the prostatic and seminal vesicles. Results indicated that compounds 4, 4b, 4c, served as in vitro inhibitors of the enzyme 5α-R1 and pharmacological experiments showed that 4 and derivatives 4a-f decreased the diameter of the flank glands, the weight of the prostate and seminal vesicles of treated hamsters without any appreciable toxicity during observation. Noteworthy the fact that compound 4 is the product, in all cases, of the hydrolysis of the series of esters 4a-f, thus they can serve as precursors (prodrugs) of the active form 4.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Benzoatos/farmacologia , Colestenona 5 alfa-Redutase/metabolismo , Inibidores de 5-alfa Redutase/administração & dosagem , Inibidores de 5-alfa Redutase/química , Animais , Benzoatos/administração & dosagem , Benzoatos/química , Cricetinae , Relação Dose-Resposta a Droga , Injeções Subcutâneas , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Conformação Molecular , Ratos , Solubilidade , Relação Estrutura-Atividade
18.
Inflamm Res ; 67(7): 617-626, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29679313

RESUMO

OBJECTIVE AND DESIGN: To characterize the impact of inflammatory process and oxidative stress in the degree of benign prostatic hyperplasia (BPH), a common condition in which chronic inflammation plays a crucial role, we investigated the effect of different plant extract preparations in an in vivo model of BPH as new therapeutic target. MATERIAL: BPH was made in rats with daily administration of testosterone propionate (3 mg/kg) for 14 days. TREATMENT: Rats were randomized into different groups to receive oral administration of plant extract preparations: Serenoa repens with selenium (SeR 28.5 mg/kg associated with Se 0.005 mg/kg), Teoside (2 mg/kg), and Puryprost (14 mg/kg containing Teoside 50% 2 mg/kg and Epilobium 12 mg/kg). METHODS: After 14 days, rats were killed and histological changes, prostate weight and apoptotic pathways were assayed. RESULTS: The results obtained demonstrated that the association of treatments reduced prostate weight and hyperplasia, while treatment with Puryprost demonstrated a greater trend of protection compared to the other treatments. CONCLUSION: Thus, our results indicate that plant extract could be considered as new useful therapy in the treatment of BPH with particular attention on Puryprost that represents a rational approach to reduce BPH through modulation of inflammatory process and anti-oxidant process.


Assuntos
Ajuga , Epilobium , Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Selênio/uso terapêutico , Serenoa , Animais , Apoptose/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Ciclo-Oxigenase 2/metabolismo , Di-Hidrotestosterona/sangue , Dinoprostona/metabolismo , Modelos Animais de Doenças , Masculino , Malondialdeído/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/patologia , Ratos Sprague-Dawley , Selênio/farmacologia , Propionato de Testosterona
19.
Food Chem Toxicol ; 115: 20-25, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29501275

RESUMO

The impact of bisphenol A (BPA) on the prostate gland has taken center stage, with a special focus placed on understanding how BPA affects prostate physiopathology. In this study, we evaluated the ability of lower doses of BPA to induce alterations in 5α-R isozymes and aromatase, in the prostate of juvenile rats exposed during developmental stage. Gestating Wistar rats were treated s.c with either vehicle or BPA (2.4 and 10 µg/kg b.w./day) from gestational day 12 to parturition. Then, male pups were s.c treated from postnatal day 1 through day 21, when they were euthanized and qRT-PCR, western blot and hormone levels determination were performed. We found that BPA at dose of 2.4 and 10 µg/kg b.w./day significantly decreased the mRNA and protein levels of 5α-R2. However, neither 5α-R1 nor 5α-R3 was affected by this exposure. BPA at dose of 10 µg/kg b.w./day significantly increased the mRNA and protein levels of aromatase. BPA also decreased plasma levels of both testosterone and dihydrotestosterone and increased estradiol. These data lend support that low-dose BPA during fetal and neonatal prostate development interfere with in situ estrogen and androgen production in the prostate gland of juvenile rats through the enzymes aromatase and 5α-Reductase.


Assuntos
Aromatase/metabolismo , Compostos Benzidrílicos/toxicidade , Colestenona 5 alfa-Redutase/metabolismo , Fenóis/toxicidade , Próstata/efeitos dos fármacos , Próstata/enzimologia , Androgênios/metabolismo , Animais , Aromatase/genética , Colestenona 5 alfa-Redutase/genética , Feminino , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Exposição Materna/efeitos adversos , Próstata/crescimento & desenvolvimento , Ratos , Ratos Wistar , Testosterona/metabolismo
20.
Curr Top Med Chem ; 18(32): 2816-2834, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30659542

RESUMO

BACKGROUND: 5α-Reductase (5AR), an NADPH dependent enzyme, is expressed in most of the prostate epithelial cells. By converting testosterone (T) into more potent androgen dihydrotestosterone (DHT), it plays an important role in men physiology and represents an efficient therapeutic target for androgen-dependent diseases. Over the last few years, significant efforts have been made in order to develop 5AR inhibitors (5ARI) to treat Benign Prostatic Hyperplasia because of excessive production of DHT. METHODS: In the present study, 2D and 3D QSAR pharmacophore models have been generated for 5ARI based on known IC50 values with extensive validations. The four featured 2D pharmacophore based PLS model correlated the topological interactions (SsOHE-index); semi empirical (Quadrupole2) and physicochemical descriptors (Mol. Wt, Bromines Count, Chlorines Count) with 5AR inhibitory activity, and has the highest correlation coefficient (r2 = 0.98, q2 =0.84; F = 57.87, pred r2 = 0.88). Internal and external validation was carried out using test and proposed set of compounds. The contribution plot of electrostatic field effects and steric interactions generated by 3D-QSAR showed interesting results in terms of internal and external predictability. The well-validated 2D PLS, and 3D kNN models were used to search novel 5AR inhibitors with different chemical scaffold. The compounds were further sorted by applying ADMET properties and in vitro cytotoxicity studies against prostate cancer cell lines PC-3. Molecular docking studies have also been employed to investigate the binding interactions and to study the stability of docked conformation in detail. RESULTS: Several important hydrophobic and hydrogen bond interactions with 5AR lead to the identification of active binding sites of 4AT0 protein in the docked complex, which include the gatekeeper residues ALA 63A (Chain A: ALA63), THR 60 A (Chain A: THR60), and ARG 456 A (Chain A: ARG456), at the hinge region. CONCLUSION: Overall, this study suggests that the proposed compounds have the potential as effective inhibitors for 5AR.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Colestenona 5 alfa-Redutase/metabolismo , Simulação de Acoplamento Molecular , Hiperplasia Prostática/tratamento farmacológico , Relação Quantitativa Estrutura-Atividade , Inibidores de 5-alfa Redutase/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Estrutura Molecular , Hiperplasia Prostática/enzimologia , Hiperplasia Prostática/patologia , Software
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