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1.
Nat Commun ; 12(1): 449, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33469028

RESUMO

Steroid hormones are essential in stress response, immune system regulation, and reproduction in mammals. Steroids with 3-oxo-Δ4 structure, such as testosterone or progesterone, are catalyzed by steroid 5α-reductases (SRD5As) to generate their corresponding 3-oxo-5α steroids, which are essential for multiple physiological and pathological processes. SRD5A2 is already a target of clinically relevant drugs. However, the detailed mechanism of SRD5A-mediated reduction remains elusive. Here we report the crystal structure of PbSRD5A from Proteobacteria bacterium, a homolog of both SRD5A1 and SRD5A2, in complex with the cofactor NADPH at 2.0 Å resolution. PbSRD5A exists as a monomer comprised of seven transmembrane segments (TMs). The TM1-4 enclose a hydrophobic substrate binding cavity, whereas TM5-7 coordinate cofactor NADPH through extensive hydrogen bonds network. Homology-based structural models of HsSRD5A1 and -2, together with biochemical characterization, define the substrate binding pocket of SRD5As, explain the properties of disease-related mutants and provide an important framework for further understanding of the mechanism of NADPH mediated steroids 3-oxo-Δ4 reduction. Based on these analyses, the design of therapeutic molecules targeting SRD5As with improved specificity and therapeutic efficacy would be possible.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/ultraestrutura , Proteínas de Bactérias/ultraestrutura , Esteroides/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/química , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Inibidores de 5-alfa Redutase/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Coenzimas/química , Coenzimas/metabolismo , Coenzimas/ultraestrutura , Cristalografia por Raios X , Desenho de Fármacos , Ligação de Hidrogênio , NADP/química , NADP/metabolismo , NADP/ultraestrutura , Oxirredução , Proteobactérias/enzimologia , Relação Estrutura-Atividade
2.
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
3.
J Pharmacol Sci ; 143(3): 234-237, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32249061

RESUMO

We investigated whether benzothiazepines could produce anxiolytic effects via allopregnanolone (ALLO) biosynthesis in mice. We compared the behavioral effects caused by benzothiazepines to those caused by carbamazepine and sodium valproate. We found that a pretreatment with finasteride (a 5 alpha-reductase inhibitor) suppressed carbamazepine-induced anxiolytic effects but not the effects of sodium valproate. Similar to carbamazepine, diltiazem and JTV-519 displayed anxiolytic effects that were suppressed by a pretreatment with finasteride. We clearly demonstrate that the benzothiazepines, diltiazem and JTV-519, exert an anxiolytic-like effect via ALLO biosynthesis in mice.


Assuntos
Ansiolíticos , Comportamento Animal/efeitos dos fármacos , Diltiazem/farmacologia , Pregnanolona/biossíntese , Tiazepinas/farmacologia , Inibidores de 5-alfa Redutase/farmacologia , Animais , Carbamazepina/antagonistas & inibidores , Carbamazepina/farmacologia , Diltiazem/antagonistas & inibidores , Relação Dose-Resposta a Droga , Finasterida/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Neuroesteroides , Tiazepinas/antagonistas & inibidores , Ácido Valproico/farmacologia
4.
Molecules ; 25(3)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033281

RESUMO

This work describes the utility of pyrazole-4-carbaldehyde 1 as starting material for the synthesis of a novel potent series of 5α-reductase and aromatase inhibitors derived from 1,2,3-triazole derivative. Condensation of 1 with active methylene and different amino pyrazoles produced the respective Schiff bases 2-4, 8 and 9. On the other hand, 1 was reacted with ethyl cyanoacetate and thiourea in one-pot reaction to afford the pyrazolo-6- thioxopyridin-2-[3H]-one (10). Moreover, α-ß unsaturated chalcone derivative 11 was prepared via the reaction of compound 1 with P-methoxy acetophenone, which in turn reacted with each of ethyl cyanoacetate, malononitrile, hydrazine hydrate, and thiosemicarbazide to afford the corresponding pyridine and pyrazole derivatives 13, 14, 17, and 20. The structure of newly synthesized compounds was characterized by analytical and spectroscopic data (IR, MS and NMR). All new compounds were evaluated against 5α-reductase and aromatase inhibitors and the results showed that many of these compounds inhibit 5α-reductase and aromatase activity; compound 13 was found to be the highest potency among the tested samples comparing with the reference drugs.


Assuntos
Inibidores de 5-alfa Redutase/síntese química , Inibidores de 5-alfa Redutase/farmacologia , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/farmacologia , Triazóis/química , Inibidores de 5-alfa Redutase/química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antivirais/síntese química , Antivirais/química , Aromatase/efeitos dos fármacos , Inibidores da Aromatase/química , Colestenona 5 alfa-Redutase/efeitos dos fármacos , Di-Hidrotestosterona/sangue , Letrozol/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Testosterona/sangue
5.
Andrologia ; 52(3): e13516, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31989657

RESUMO

Benign prostatic hyperplasia (BPH) is a pathology characterised by an increase in prostate size associated with low urinary tract symptoms. Finasteride (F), a 5a-reductase inhibitor, is the standard treatment for BPH reducing prostate weight but also sexual desire. The Peruvian plant known as Red Maca (RM) (Lepidium meyenii) inhibits BPH in rats and mice. The aim of the study was to assess the inflammatory effect of RM and finasteride in rats with testosterone enanthate (TE)-induced BPH. Thirty rats were divided into 5 groups: Control, TE (50 mg/rat), TE + F (0.6 mg/kg), and two groups of TE + RM 40/80 (40 or 80 mg). After treatments, tumour necrosis factor alpha (TNFa), interleukin 4 (IL4) and interferon gamma (INFg) as well as testosterone and oestradiol were evaluated and inflammatory cells (neutrophils, mast cells and lymphocytes) in prostate were quantified. Red Maca and finasteride treatments decreased inflammatory cells counts in prostate, inhibiting TNFa by different pathways. Finasteride increased IL4 whereas Red Maca increased INFg. In conclusion, data suggest that finasteride acts on Th2 response by increasing IL4 in prostate, while Red Maca acts on Th1 response mediated by INFg.


Assuntos
Lepidium/química , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Inibidores de 5-alfa Redutase/farmacologia , Inibidores de 5-alfa Redutase/uso terapêutico , Animais , Modelos Animais de Doenças , Finasterida/farmacologia , Finasterida/uso terapêutico , Humanos , Interferon gama/metabolismo , Interleucina-4/metabolismo , Masculino , Extratos Vegetais/uso terapêutico , Próstata/citologia , Próstata/imunologia , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/imunologia , Hiperplasia Prostática/patologia , Ratos , Transdução de Sinais/imunologia , Testosterona/análogos & derivados , Testosterona/toxicidade , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
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
7.
J Control Release ; 316: 1-11, 2019 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-31689460

RESUMO

Androgenetic alopecia is a common form of scalp hair loss that affects men in their mid-twenties and increases with age. Finasteride (FNS) has been approved and used orally to treat androgenetic alopecia; however, systemic effects on other androgen-dependent tissues cause severe side-effects. To overcome these systemic effects and target hair follicles in the scalp only, numerous topical formulations of FNS have been developed and further combined with the solid microneedle (SMN) technique to create micro-channels in the skin, thus overcoming the skin barrier properties. However, low delivery efficiency and concerns over patient safety of SMNs remain major limitations of the treatment. In the present study, we developed a novel FNS delivery system comprising powder-carrying microneedles (PCMs), which is a patch-less and self-administered powder delivery technique that simultaneously overcomes the safety issues. This system could directly implant FNS inside the skin by encapsulating the FNS powder in the center of the PCMs. In addition, we introduced the concept of a diffusion enhancer for this system, which facilitated the dissolution and release of the implanted FNS powder to achieve its successful intradermal delivery. Using implanted FNS powder as a reservoir inside the skin, this novel system permitted sustained release of the implanted FNS powder for 3 days with only one application of FNS-PCMs. In addition, compared with the topical FNS-gel, the developed system showed a higher efficacy in promoting hair growth and increased the amount and density of hair while addressing the safety concerns. This approach has the potential to advance the field of transdermal drug delivery for any type of powdered drug in a wide variety of biomedical applications.


Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Alopecia/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Finasterida/administração & dosagem , Inibidores de 5-alfa Redutase/farmacologia , Administração Tópica , Animais , Difusão , Finasterida/farmacologia , Cabelo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Agulhas , Pós , Pele/metabolismo , Suínos
8.
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
9.
Biomolecules ; 9(11)2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752360

RESUMO

Finasteride (FIN) is the prototypical inhibitor of steroid 5α-reductase (5αR), the enzyme that catalyzes the rate-limiting step of the conversion of progesterone and testosterone into their main neuroactive metabolites. FIN is clinically approved for the treatment of benign prostatic hyperplasia and male baldness; while often well-tolerated, FIN has also been shown to cause or exacerbate psychological problems in vulnerable subjects. Evidence on the psychological effects of FIN, however, remains controversial, in view of inconsistent clinical reports. Here, we tested the effects of FIN in a battery of tests aimed at capturing complementary aspects of mood regulation and stress reactivity in rats. FIN reduced exploratory, incentive, prosocial, and risk-taking behavior; furthermore, it decreased stress coping, as revealed by increased immobility in the forced-swim test (FST). This last effect was also observed in female and orchiectomized male rats, suggesting that the mechanism of action of FIN does not primarily reflect changes in gonadal steroids. The effects of FIN on FST responses were associated with a dramatic decrease in corticotropin release hormone (CRH) mRNA and adrenocorticotropic hormone (ACTH) levels. These results suggest that FIN impairs stress reactivity and reduces behavioral activation and impulsive behavior by altering the function of the hypothalamus-pituitary-adrenal (HPA) axis.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Hormônio Adrenocorticotrópico/metabolismo , Comportamento Animal/efeitos dos fármacos , Hormônio Liberador da Corticotropina/metabolismo , Finasterida/farmacologia , Estresse Psicológico , Afeto/efeitos dos fármacos , Animais , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Ratos , Ratos Long-Evans , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia
10.
BMC Complement Altern Med ; 19(1): 323, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752827

RESUMO

BACKGROUND: Carpinus tschonoskii (CT) has been previously studied for various activities in the improvement of skin diseases. In the present study, we examined the in vitro anti-acne vulgaris (AV) effect of CT leaves (CTL) and tellimagrandin I (TI), one of the main ellagitannins from CT, including skin barrier improvement and 5α-reductase inhibitory activity. METHODS: To test the anti-AV activities of CTL and TI, firstly, anti-oxidative and anti-inflammatory activities including DPPH radical scavenging activity, nitric oxide (NO) inhibitory activity, and cytokines [interleukin (IL)-6 and IL-8] were tested. Skin barrier improvement experiments were tested using developing cornified envelope (CE) formation, and filaggrin mRNA expression level was determined by RT-PCR. The 5α-reductase inhibitory activity was determined by measuring the testosterone levels in rat liver microsomes. RESULTS: CTL and TI showed potent anti-oxidative activity and anti-inflammatory activities. Especially, the cytokine production inhibitory activities of TI were found to be similar to the positive control, epigallocatechin gallate (EGCG). CTL and TI enhanced the CE formation and filaggrin mRNA expression levels and showed potent activities compared to that in the positive control, 1.5 mM Ca2+. In additionally, CTL and TI showed 5α-reductase inhibitory activities in a dose-dependent manner. CONCLUSION: The results showed that CTL and TI inhibit AV endogenous factors such as 5α-reductase and inflammatory cytokines and affect exogenous factors such as developing skin barrier function (CE and filaggrin levels). Therefore, CTL and TI may be plant-derived agent, promising in the treatment of acne vulgaris.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Betulaceae , Ácido Gálico/análogos & derivados , Glucosídeos/farmacologia , Extratos Vegetais/farmacologia , Acne Vulgar , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Ácido Gálico/farmacologia , Humanos , Camundongos , Extratos Vegetais/química , Folhas de Planta/química , Células RAW 264.7
11.
J Neurophysiol ; 122(5): 2130-2141, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31596653

RESUMO

The dorsal motor nucleus of the vagus (DMV) contains the preganglionic motor neurons important in the regulation of glucose homeostasis and gastrointestinal function. Despite the role of sex in the regulation of these processes, few studies examine the role of sex and/or ovarian cycle in the regulation of synaptic neurotransmission to the DMV. Since GABAergic neurotransmission is critical to normal DMV function, the present study used in vitro whole cell patch-clamping to investigate whether sex differences exist in GABAergic neurotransmission to DMV neurons. It additionally investigated whether the ovarian cycle plays a role in those sex differences. The frequency of phasic GABAA receptor-mediated inhibitory postsynaptic currents in DMV neurons from females was lower compared with males, and this effect was TTX sensitive and abolished by ovariectomy (OVX). Amplitudes of GABAergic currents (both phasic and tonic) were not different. However, females demonstrated significantly more variability in the amplitude of both phasic and tonic GABAA receptor currents. This difference was eliminated by OVX in females, suggesting that these differences were related to reproductive hormone levels. This was confirmed for GABAergic tonic currents by comparing females in two ovarian stages, estrus versus diestrus. Female mice in diestrus had larger tonic current amplitudes compared with those in estrus, and this increase was abolished after administration of a 5α-reductase inhibitor but not modulation of estrogen. Taken together, these findings demonstrate that DMV neurons undergo GABAA receptor activity plasticity as a function of sex and/or sex steroids.NEW & NOTEWORTHY Results show that GABAergic signaling in dorsal vagal motor neurons (DMV) demonstrates sex differences and fluctuates across the ovarian cycle in females. These findings are the first to demonstrate that female GABAA receptor activity in this brain region is modulated by 5α-reductase-dependent hormones. Since DMV activity is critical to both glucose and gastrointestinal homeostasis, these results suggest that sex hormones, including those synthesized by 5α-reductase, contribute to visceral, autonomic function related to these physiological processes.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Estrogênios/metabolismo , Potenciais Pós-Sinápticos Inibidores/fisiologia , Ciclo Menstrual/metabolismo , Neurônios Motores/fisiologia , Plasticidade Neuronal/fisiologia , Receptores de GABA-A/metabolismo , Caracteres Sexuais , Nervo Vago/fisiologia , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/efeitos dos fármacos , Inibidores de 5-alfa Redutase/farmacologia , Animais , Feminino , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Masculino , Camundongos , Neurônios Motores/metabolismo , Ovariectomia , Técnicas de Patch-Clamp , Nervo Vago/metabolismo , Ácido gama-Aminobutírico
12.
Am J Physiol Renal Physiol ; 317(4): F996-F1009, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390231

RESUMO

Laboratory mice are used to identify causes of urinary dysfunction including prostate-related mechanisms of lower urinary tract symptoms. Effective use of mice for this purpose requires a clear understanding of molecular, cellular, anatomic, and endocrine contributions to voiding function. Whether the prostate influences baseline voiding function has not been specifically evaluated, in part because most methods that alter prostate mass also change circulating testosterone concentrations. We performed void spot assay and cystometry to establish a multiparameter "baseline" of voiding function in intact male and female 9-wk-old (adult) C57BL/6J mice. We then compared voiding function in intact male mice to that of castrated male mice, male (and female) mice treated with the steroid 5α-reductase inhibitor finasteride, or male mice harboring alleles (Pbsn4cre/+; R26RDta/+) that significantly reduce prostate lobe mass by depleting prostatic luminal epithelial cells. We evaluated aging-related changes in male urinary voiding. We also treated intact male, castrate male, and female mice with exogenous testosterone to determine the influence of androgen on voiding function. The three methods used to reduce prostate mass (castration, finasteride, and Pbsn4cre/+; R26RDta/+) changed voiding function from baseline but in a nonuniform manner. Castration feminized some aspects of male urinary physiology (making them more like intact female mice) while exogenous testosterone masculinized some aspects of female urinary physiology (making them more like intact male mice). Our results provide evidence that circulating testosterone is responsible in part for baseline sex differences in C57BL/6J mouse voiding function while prostate lobe mass in young, healthy adult mice has a lesser influence.


Assuntos
Androgênios/fisiologia , Próstata/anatomia & histologia , Próstata/fisiologia , Fenômenos Fisiológicos do Sistema Urinário , Inibidores de 5-alfa Redutase/farmacologia , Envelhecimento , Animais , Células Epiteliais/fisiologia , Feminino , Finasterida/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Orquiectomia , Próstata/citologia , Caracteres Sexuais , Testosterona/farmacologia , Fenômenos Fisiológicos do Sistema Urinário/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Urinário/genética , Urodinâmica
13.
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
14.
Prostate ; 79(12): 1450-1456, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31233227

RESUMO

BACKGROUND: Prostate-specific membrane antigen (PSMA)-based imaging and therapy are increasingly used in the management of prostate cancer. However, low PSMA surface expression in certain patients is a limitation for PSMA-based technologies. We have previously shown that high doses of dutasteride, a 5α-reductase inhibitor generally used for the treatment of benign prostatic enlargement, increase the PSMA expression in vitro. We now further analyzed the concentration- and time-dependent effects of dutasteride in LNCaP cells. METHODS: Androgen receptor (AR) expressing prostate cancer cells (LNCaP) were treated for 7 to 14 days with vehicle control (0.1% dimethyl sulfoxide) or different concentrations of dutasteride (0.25 , 0.5 , 1 , and 5 µM). In addition to cell proliferation, PSMA surface expression was assessed using flow cytometry (FACS) and immunocytochemistry. Total PSMA and AR expression was analyzed by capillary western immunoassay (WES). In addition, tumor cell uptake and internalization assays of 177 Lu-PSMA-617 were performed. RESULTS: Dutasteride treatment resulted in a significant upregulation of PSMA surface expression compared to vehicle control after 7 days in all tested concentrations. After 14 days a further, concentration-dependent increase of PSMA surface expression was detectable. Total PSMA protein expression significantly increased after treatment of cells with high concentrations of dutasteride using 5 µM for 7 or 14 days. However, when lower concentrations were used total PSMA expression was not significantly altered compared to vehicle control. Further testing revealed a dose-dependent increase in uptake and internalization of 177Lu -PSMA-617 after 7 and 14 days. Though, a significantly increased uptake was only observed using a 5 µM dutasteride concentration for 7 days as well as 1 and 5 µM for 14 days. CONCLUSION: Our investigations revealed a concentration- and time-dependent effect of dutasteride on PSMA expression and uptake of 177Lu -PSMA-617 in LNCaP cells. A short-term treatment of patients with high doses of dutasteride might increase the detection rate of PSMA-based imaging and increase the effect of 177Lu -PSMA-617 therapy via upregulation of PSMA expression.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Antígenos de Superfície/biossíntese , Dutasterida/farmacologia , Glutamato Carboxipeptidase II/biossíntese , Próstata/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Linhagem Celular Tumoral , Dipeptídeos/metabolismo , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 1 Anel/metabolismo , Humanos , Lutécio/metabolismo , Masculino , Próstata/metabolismo , Radioisótopos/metabolismo , Receptores Androgênicos/biossíntese , Regulação para Cima
15.
Sci Rep ; 9(1): 7728, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118452

RESUMO

Pregnant women with MS experience fewer relapses, especially during the third trimester. In this study, we explore the cellular and molecular events that bring about the protective effect of late pregnancy on the course of de/remyelination in rats. Using cellular, molecular, and ultrastructural methods, we explored remyelination in response to a focal demyelination in the corpus callosum of late pregnant, virgin, and postpartum rats. We further explored the role of GABAA receptor (GABAAR) in the promyelinating effect observed during late pregnancy. Remyelination in response to a gliotoxin-induced demyelination in the corpus callosum was enhanced in late pregnant rats when compared to that seen in virgin and postpartum rats. This pregnancy-associated promyelinating effect was lost when either the GABAAR was blocked or when 5α-reductase, the rate limiting enzyme for the endogenous GABAAR activator allopregnanolone, was inhibited. Taken together, these data suggest that the pregnancy-associated pro-myelination operates, at least in part, through a GABAergic activated system.


Assuntos
Doenças Desmielinizantes/fisiopatologia , Proteínas do Tecido Nervoso/fisiologia , Complicações na Gravidez/fisiopatologia , Receptores de GABA-A/fisiologia , Remielinização , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/fisiologia , Inibidores de 5-alfa Redutase/farmacologia , Animais , Bicuculina/farmacologia , Corpo Caloso/patologia , Doenças Desmielinizantes/induzido quimicamente , Modelos Animais de Doenças , Feminino , Finasterida/farmacologia , Antagonistas GABAérgicos/farmacologia , Lisofosfatidilcolinas/toxicidade , Masculino , Microglia/fisiologia , Esclerose Múltipla , Proteínas da Mielina/biossíntese , Proteínas da Mielina/genética , Bainha de Mielina/patologia , Proteínas do Tecido Nervoso/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/patologia , Oligodendroglia/patologia , Gravidez , Pregnanolona/farmacologia , Transtornos Puerperais/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacos
16.
Artigo em Inglês | MEDLINE | ID: mdl-31100850

RESUMO

In the pharmacological treatment of prostate cancer, benign prostatic hyperplasia and androgenetic alopecia finasteride is commonly used. This drug inhibits 5α-reductase type 2, which is why finasteride affects androgen homeostasis, since testosterone (T) cannot be reduced to dihydrotestosterone (DHT). As studies on sex-related renal injuries suggest a high probability of androgen-induced renal dysfunction, the aim of this study was to determine the potential harmful effects of finasteride on the kidneys of rats. The study was performed on sexually mature male Wistar rats given finasteride. Histological sections of the kidneys were used for immunohistochemical visualization of the androgen receptor (AR), junctional proteins (occluding (Occ); E-cad, N-cad, E-/N-cadherin; ß-cat, ß-catenin; connexin 43 (Cx43)), proliferating cell nuclear antigen (PCNA), IL-6, and lymphocyte markers (CD3 for T cell, CD19 for B cell). The TUNEL method was used for cell apoptosis identification, and picro sirius red staining was used to assess collagen fibers thickness. The levels of T, DHT and estradiol (E2) were determined in blood serum. It was shown that finasteride treatment affected steroid hormone homeostasis, altered the expression of AR and intracellular junction proteins, changed the ratio between cell apoptosis and proliferation, and caused lymphocyte infiltration and an increase of IL-6. The thickening of collagen fibers was observed as tubular fibrosis and glomerulosclerosis. Summarizing, finasteride-induced hormonal imbalance impaired the morphology (i.e., dysplastic glomeruli, swollen proximal convoluted tubules) and physiology (changed level of detected proteins/markers expression) of the kidneys. Therefore, it is suggested that patients with renal dysfunction or following renal transplantation, with androgen or antiandrogen supplementation, should be under special control and covered by extended diagnostics, because the adverse negative effect of DHT deficiency on the progression of kidney disease cannot be ignored.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Finasterida/farmacologia , Rim/efeitos dos fármacos , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Animais , Pré-Escolar , Humanos , Rim/patologia , Masculino , Ratos , Ratos Wistar
17.
J Cosmet Dermatol ; 18(4): 966-975, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30980598

RESUMO

The second most common alopecia-Androgenetic alopecia (AGA)-occurs due to hormonal imbalance. Dihydrotestosterone (DHT) an androgenic hormone is a sex steroid, produced in the gonads. The target sites of DHT are similar to that of testosterone, and it attaches easily remaining bound for 53 minutes as compared to 35 minutes of testosterone. Excess of DHT causes miniaturization of hair reducing the anagen phase and increasing the telogen phase leading to hair loss. Normally up to ten percent of testosterone in the body irreversibly gets converted into DHT by the action of enzyme 5-alpha-reductase. Inadequate blood flow to the scalp can also be another reason for hair loss encountered due to lower oxygen and nutrients reaching it. AGA affects both sexes; however in males, it leads to major hair loss. Conventional drugs such as minoxidil and finasteride are widely used for the treatment. However, several drawbacks such as allergic contact dermatitis, burning, ejaculation disorder, and decreased libido are reported. Available literature suggests the role of herbal drugs to have the action against 5-alpha-reductase enzyme inhibiting it and reducing the hair loss. This can be further potentiated since they exhibit lesser side effects. Recent advancements observed in the medicinal, cosmetic, and engineering fields can prove to be an asset. This article focuses on herbs which can be used in AGA. A review of Saw palmetto (Serenoa repens), Green tea (Camellia sinensis), Pumpkin seed (Curcurbita pepo), Rosemary (Rosmarinus officinalis), Grape seed (Vitis vinifera), and Licorice (Glycyrrhiza glabra) is attempted.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Alopecia/tratamento farmacológico , Di-Hidrotestosterona/antagonistas & inibidores , Extratos Vegetais/uso terapêutico , Inibidores de 5-alfa Redutase/farmacologia , Alopecia/etiologia , Camellia sinensis/química , Cucurbita/química , Di-Hidrotestosterona/metabolismo , Glycyrrhiza/química , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Humanos , Extratos Vegetais/farmacologia , Serenoa/química , Vitis/química
18.
Behav Brain Res ; 365: 185-189, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-30836157

RESUMO

The enzyme 5α-Reductase (5α-R) catalyzes the formation of dihydrotestosterone, which is involved in male pattern hair loss and benign prostatic hyperplasia. Finasteride inhibits 5α-R and is used to treat both these conditions. Several clinical studies show that chronic finasteride treatment induces persistent depression, suicidal thoughts, and cognitive impairment. The neural mechanisms underlying these effects of finasteride are not known and it is imperative that an animal model that mimics the clinical neuropsychiatric effects of finasteride is developed. Accordingly, we evaluated the behavioral effects of acute and repeated finasteride administration. Two months old male Wistar rats were administered with either vehicle (hydroxypropyl-ß-cyclodextrin) or different doses of finasteride, subcutaneously, either acutely (30 min or 2 h) or for 1, 3, and 6 days (one dose per day). Behavioral despair and motivational behavior were evaluated in the forced swim test (FST) and splash test, respectively. FST and splash test were video-recorded and analyzed offline. Finasteride did not show any effects in the acute, one day or three days studies in the FST. However, repeated finasteride administration for 6 days significantly increased the immobility time. In the splash test, finasteride (100 mg/kg) administration increased the latency to groom and decreased the grooming duration implying lack of motivation in the three-day study. In the six-day study, latency to groom was significantly increased by the 100 mg/Kg dose. Further, a significant dose dependent decrease in the grooming duration was observed. In summary, our results indicate that repeated finasteride administration induces depression-like behavior in rats. This study provides the evidence that an animal model of finasteride-induced depression is feasible to investigate the cellular and molecular mechanisms, and the pharmacology underlying the neuropsychiatric effects of finasteride. Further, these results provide insights into the potential involvement of neurosteroids in depression and will lead to the development of novel therapeutics for its treatment.


Assuntos
Depressão/metabolismo , Finasterida/efeitos adversos , Finasterida/farmacologia , Inibidores de 5-alfa Redutase/efeitos adversos , Inibidores de 5-alfa Redutase/farmacologia , Animais , Depressão/induzido quimicamente , Transtorno Depressivo/induzido quimicamente , Transtorno Depressivo/metabolismo , Inibidores Enzimáticos/farmacologia , Finasterida/metabolismo , Asseio Animal/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Natação
19.
Cell Prolif ; 52(3): e12590, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30883989

RESUMO

OBJECTIVES: 5α-reductase inhibitor (5-ARI) is a commonly used medicine in the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Our study mainly focuses on the mechanism of BPH development after 5ARI treatment. MATERIALS AND METHODS: Prostate specimens from patients were collected. Insulin-like growth factor 1 (IGF-1), Beclin-1, LC3 levels, was analysed by immunohistochemistry. The role IGF-1 on autophagic flux in prostate epithelial cells was studied. Additionally, effect of autophagy on recombinant grafts consisting of prostate stromal and epithelial cells in nude mice was investigated. RESULTS: We demonstrated that IGF-1 expression is down-regulated in prostate fibroblasts after long-term 5-ARI application. A decrease in IGF-1 levels was found to activate autophagic flux through the mTOR pathway in prostate epithelial cells, while the inhibition of IGF-1 receptor function induced autophagy in prostate epithelial cells. In addition, we revealed that blocking autophagic flux initiation can reduce the volume of recombinant grafts in vivo. Finally, our findings suggest that long-term 5-ARI application reduces IGF-1 secretion by prostatic stromal cells, thereby inducing autophagy of prostatic epithelial cells, which is one of the mechanisms underlying BPH pathogenesis and progression. CONCLUSIONS: Focusing on the autophagy induced by low levels of IGF-1 in prostatic epithelial cells, after elucidating AR signalling impairment of prostate stromal cells, might provide a novel strategy for the treatment and prevention of BPH development.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Próstata/citologia , Próstata/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Próstata/metabolismo , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Receptores Androgênicos/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
20.
J Ethnopharmacol ; 235: 481-488, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30708034

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese Skullcap (Scutellaria baicalensis Georgi), which is part of the 50 fundamental herbs of Traditional Chinese Medicine, has been extensively used in the several East Asian countries to treat pyrexia, micturition disorder and inflammation. Although skullcap has effective properties on various diseases, the effects and molecular mechanism of Chinese Skullcap on BPH are still needed for better understanding. AIM OF THE STUDY: In present study, we aimed to demonstrate the efficacy of Chinese Skullcap root extract (SRE) in testosterone-induced BPH rats and investigate the exact regulatory mechanism involved. MATERIALS AND METHODS: We followed a protocol of testosterone-induced BPH. Rats were allocated into five groups: Group 1, control; Group 2, BPH-induced rats; Group 3, BPH-induced rats administrated with finasteride; Group 4, BPH-induced rats administrated with SRE 100 mg/kg/day; Group 5 - BPH-induced rats administrated with SRE 200 mg/kg/day. We measured the weight of prostate, and thickness of prostate using H&E staining. Western blotting, immunostaining and real-time PCR were used to measure proliferation- and inflammation-relative markers. To confirm the effects of SRE on apoptotic events in BPH-induced tissues, we performed the TUNEL assay. RESULTS: Compared with the untreated group, the SRE administration group suppressed pathological alterations, such as prostate growth and increase in serum DHT and 5α-reductase levels. Furthermore, SRE significantly obliterated the expression of AR and PCNA. SRE also restored Bax/Bcl-2 balance, inducing apoptosis in rats with BPH. These effect of SRE was more prevalent than commercial 5α-reductase inhibitor, finasteride. CONCLUSIONS: Taken together, we propose that SRE suppresses abnormal androgen events in prostate tissue and inhibits the development of BPH by targeting inflammation- and apoptosis-related markers. These finding strengthens that SRE could be used as plant-based 5α-reductase inhibitory alternative.


Assuntos
Apoptose/efeitos dos fármacos , Inflamação/tratamento farmacológico , Extratos Vegetais/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Inibidores de 5-alfa Redutase/farmacologia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Finasterida/farmacologia , Inflamação/patologia , Masculino , Medicina Tradicional Chinesa/métodos , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/patologia , Ratos , Ratos Sprague-Dawley , Testosterona/administração & dosagem
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