RESUMEN
Considering the properties of myo-inositol (MI) and D-chiro-inositol (DCI), which are well known in polycystic ovary syndrome therapy, and the limitations of adult granulosa cell tumor (AGCT) treatment, especially for androgen-secreting tumors, we studied the role of MI and DCI in the androgen-rich environment of AGCTs. For this purpose, we analyzed the mRNA expression of steroidogenic genes and the secretion of progesterone (P4) and 17ß-estradiol (E2) in an unstimulated and/or dihydrotestosterone (DHT)-stimulated environment under MI and DCI influence. Thus, we used the HGrC1 and KGN cell lines as in vitro models of healthy and cancerous granulosa cells. We found that DHT, the most potent androgen, increased E2 secretion and steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage gene (CYP11A1) mRNA expression without affecting 450 aromatase (CYP19A1) in AGCTs. However, after the MI and DCI treatment of KGN cells, both compounds strongly reduced StAR and CYP11A1 expression. Interestingly, in DHT-stimulated KGN cells, only DCI alone and its cotreatment with MI reduced both CYP11A1 mRNA and E2 secretion. These findings suggest that CYP11A1 is responsible for the antiestrogenic effect of DCI in the androgen-rich environment of AGCTs. Therefore, MI and DCI could be used as effective agents in the adjuvant treatment of AGCT, but further detailed studies are needed.
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Dihidrotestosterona , Estradiol , Tumor de Células de la Granulosa , Inositol , Femenino , Humanos , Tumor de Células de la Granulosa/metabolismo , Tumor de Células de la Granulosa/genética , Dihidrotestosterona/farmacología , Dihidrotestosterona/metabolismo , Inositol/farmacología , Línea Celular Tumoral , Estradiol/farmacología , Estradiol/metabolismo , Aromatasa/metabolismo , Aromatasa/genética , Progesterona/metabolismo , Progesterona/farmacología , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/metabolismo , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Adulto , Andrógenos/metabolismo , Andrógenos/farmacología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células de la Granulosa/metabolismo , Células de la Granulosa/efectos de los fármacosRESUMEN
Aging is one of the main factors associated with cardiovascular diseases. Androgens exert beneficial effects on the cardiovascular system and testosterone (TES) replacement therapy improves cardiometabolic risk factors. However, TES is contraindicated in patients with prostate cancer due to its proliferative effects on prostatic tumor cells. Additionally, TES and its reduced metabolites 5α- and 5ß-dihydrotestosterone (5α-DHT and 5ß-DHT) exert vasodilatory effects. Since androgen levels decrease during aging and 5ß-DHT lacks genomic effects, this study is focused on analyzing its effect on vasodilator function and the proliferation rate of prostatic tumor and vascular smooth muscle cells. To study the vascular function, mesenteric arteries from aged-orchidectomized Sprague-Dawley rats were used. Mesenteric segments were divided into one control (without treatment) and three groups with the androgens (10 nM, 30 min) to analyze: acetylcholine- and sodium nitroprusside-induced responses and nitric oxide and superoxide anion production. To analyze cell proliferation, the effect of androgens on cell viability was determined. The results showed that 5ß-DHT improves vasodilator function in arteries from aged-orchidectomized rats and induces antioxidant action, while the proliferation rate of the androgen-dependent prostatic tumor cells remains unaltered. These results make 5ß-DHT a promising therapeutic agent for the treatment of cardiovascular pathologies.
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Proliferación Celular , Dihidrotestosterona , Ratas Sprague-Dawley , Vasodilatación , Animales , Proliferación Celular/efectos de los fármacos , Masculino , Ratas , Dihidrotestosterona/farmacología , Vasodilatación/efectos de los fármacos , Humanos , Vasodilatadores/farmacología , Óxido Nítrico/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Arterias Mesentéricas/efectos de los fármacos , Superóxidos/metabolismo , Nitroprusiato/farmacología , Acetilcolina/farmacología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Andrógenos/farmacologíaRESUMEN
Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is closely associated with chronic low-grade inflammation and insulin resistance. To clarify the contribution of prepubertal weight gain to the development of insulin resistance in PCOS, we investigated the effects of early postnatal overfeeding on inflammatory and energy-sensing pathways as well as on markers of insulin signaling in the liver of the PCOS rat model. Methods: Obesity induced by overfeeding was achieved by reducing litter size, while the PCOS-like condition was developed by treatment with 5α-dihydrotestosterone (DHT). Western blot and qPCR were used to analyze the expression of pro-inflammatory transcription factors and cytokines, as well as markers of the energy sensing and insulin signaling pathways. Results: The results showed that hepatic insulin sensitivity was impaired only in DHT-treated rats raised in small litters, as evidenced by increased phosphorylation of IRS1 on Ser307 and decreased expression of total IRS1. Postnatal overfeeding stimulated JNK1 activation independent of hyperandrogenemia; nevertheless, the synergistic effect of both factors triggered NLRP3 activation and increased IL1ß expression in the small litter DHT-treated group. This pro-inflammatory state was accompanied by decreased activatory phosphorylation of AMPK and reduced levels of its protein targets. Conclusions: Overfeeding in the early postnatal period leads to a decrease in hepatic insulin sensitivity in the rat model of PCOS, which is associated with decreased activation of AMPK and stimulation of the hepatic NLRP3-IL1ß signaling pathway. Accordingly, the inhibition of NLRP3 activation could provide a basis for the development of new therapeutic strategies for the treatment of insulin resistance in women with PCOS.
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Dihidrotestosterona , Modelos Animales de Enfermedad , Inflamación , Resistencia a la Insulina , Hígado , Hipernutrición , Síndrome del Ovario Poliquístico , Animales , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/patología , Femenino , Ratas , Dihidrotestosterona/farmacología , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Inflamación/metabolismo , Inflamación/patología , Hipernutrición/metabolismo , Hipernutrición/complicaciones , Ratas Wistar , Obesidad/metabolismo , Animales Recién Nacidos , Transducción de Señal/efectos de los fármacos , Proteínas Sustrato del Receptor de Insulina/metabolismoRESUMEN
AIMS: Microglial cells are integral to the pathogenesis of Alzheimer's disease (AD). The observed sex disparity in AD prevalence, with a notable predominance in women, implies a potential influence of sex hormones, such as androgens, on disease mechanisms. Despite this, the specific effects of androgens on microglia remain unclear. This study is designed to delineate the interplay between androgens and the survival and inflammatory profile of microglial cells, as well as to explore their contribution to the progression of AD. METHODS AND KEY FINDINGS: To create a chronic androgen deficiency model, 3-month-old wild-type (WT) mice and APP/PS1 mice underwent bilateral orchiectomy (ORX), with age-matched sham-operated controls. Cognitive and memory were evaluated at 5 and 12 months, paralleled by assessments of amyloid-beta (Aß) and microglial morphology in hippocampal and cortical areas. The ORX treatment in mice resulted in diminished microglial populations and morphological alterations, alongside an increase in Aß plaques and a concomitant decline in cognitive performance that exacerbated over time. In vitro, dihydrotestosterone (DHT) was found to stimulate microglial proliferation and ameliorate Aß1-42-induced apoptosis. SIGNIFICANCE: These findings suggested that androgens may exert a protective role, maintaining the normal proliferation and functionality of microglial cells. This preservation could potentially slow the progression of AD. As a result, our study provided a conceptual framework for the development of novel therapeutic strategies for AD.
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Enfermedad de Alzheimer , Andrógenos , Ratones Transgénicos , Microglía , Animales , Microglía/patología , Microglía/metabolismo , Microglía/efectos de los fármacos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Masculino , Ratones , Andrógenos/farmacología , Andrógenos/metabolismo , Andrógenos/deficiencia , Orquiectomía , Péptidos beta-Amiloides/metabolismo , Ratones Endogámicos C57BL , Dihidrotestosterona/farmacología , Modelos Animales de Enfermedad , Hipocampo/patología , Hipocampo/metabolismo , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Factores de Edad , Placa Amiloide/patología , Placa Amiloide/metabolismoRESUMEN
BACKGROUND: Endocrine therapy is the most important treatment modality of breast cancer patients whose tumors express the estrogen receptor α (ERα). The androgen receptor (AR) is also expressed in the vast majority (80-90%) of ERα-positive tumors. AR-targeting drugs are not used in clinical practice, but have been evaluated in multiple trials and preclinical studies. METHODS: We performed a genome-wide study to identify hormone/drug-induced single nucleotide polymorphism (SNP) genotype - dependent gene-expression, known as PGx-eQTL, mediated by either an AR agonist (dihydrotestosterone) or a partial antagonist (enzalutamide), utilizing a previously well characterized lymphoblastic cell line panel. The association of the identified SNPs-gene pairs with breast cancer phenotypes were then examined using three genome-wide association (GWAS) studies that we have published and other studies from the GWAS catalog. RESULTS: We identified 13 DHT-mediated PGx-eQTL loci and 23 Enz-mediated PGx-eQTL loci that were associated with breast cancer outcomes post ER antagonist or aromatase inhibitors (AI) treatment, or with pharmacodynamic (PD) effects of AIs. An additional 30 loci were found to be associated with cancer risk and sex-hormone binding globulin levels. The top loci involved the genes IDH2 and TMEM9, the expression of which were suppressed by DHT in a PGx-eQTL SNP genotype-dependent manner. Both of these genes were overexpressed in breast cancer and were associated with a poorer prognosis. Therefore, suppression of these genes by AR agonists may benefit patients with minor allele genotypes for these SNPs. CONCLUSIONS: We identified AR-related PGx-eQTL SNP-gene pairs that were associated with risks, outcomes and PD effects of endocrine therapy that may provide potential biomarkers for individualized treatment of breast cancer.
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Neoplasias de la Mama , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Receptores Androgénicos , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Femenino , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Dihidrotestosterona/farmacología , Feniltiohidantoína/farmacología , Feniltiohidantoína/uso terapéutico , Nitrilos/uso terapéutico , Genotipo , Farmacogenética/métodos , Variantes Farmacogenómicas , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Hormonales/farmacología , BenzamidasRESUMEN
Prostaglandin E2 (PGE2) is known to be effective in regenerating tissues, and bimatoprost, an analog of PGF2α, has been approved by the FDA as an eyelash growth promoter and has been proven effective in human hair follicles. Thus, to enhance PGE2 levels while improving hair loss, we found dihydroisoquinolinone piperidinylcarboxy pyrazolopyridine (DPP), an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using DeepZema®, an AI-based drug development program. Here, we investigated whether DPP improved hair loss in human follicle dermal papilla cells (HFDPCs) damaged by dihydrotestosterone (DHT), which causes hair loss. We found that DPP enhanced wound healing and the expression level of alkaline phosphatase in DHT-damaged HFDPCs. We observed that DPP significantly down-regulated the generation of reactive oxygen species caused by DHT. DPP recovered the mitochondrial membrane potential in DHT-damaged HFDPCs. We demonstrated that DPP significantly increased the phosphorylation levels of the AKT/ERK and activated Wnt signaling pathways in DHT-damaged HFDPCs. We also revealed that DPP significantly enhanced the size of the three-dimensional spheroid in DHT-damaged HFDPCs and increased hair growth in ex vivo human hair follicle organ culture. These data suggest that DPP exhibits beneficial effects on DHT-damaged HFDPCs and can be utilized as a promising agent for improving hair loss.
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Folículo Piloso , Hidroxiprostaglandina Deshidrogenasas , Humanos , Folículo Piloso/efectos de los fármacos , Folículo Piloso/metabolismo , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Hidroxiprostaglandina Deshidrogenasas/antagonistas & inhibidores , Dihidrotestosterona/farmacología , Dihidrotestosterona/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Dermis/metabolismo , Dermis/citología , Dermis/efectos de los fármacos , Células Cultivadas , Vía de Señalización Wnt/efectos de los fármacos , Alopecia/tratamiento farmacológico , Alopecia/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Cabello/efectos de los fármacos , Cabello/crecimiento & desarrollo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Inhibidores Enzimáticos/farmacologíaRESUMEN
BACKGROUND: Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with increased obesity, hyperandrogenism, and altered brown adipose tissue (BAT) thermogenesis. MicroRNAs play critical functions in brown adipocyte differentiation and maintenance. We aim to study the role of microRNA-21 (miR-21) in altered energy homeostasis and BAT thermogenesis in a PCOS mouse model of peripubertal androgen exposure. METHODS: Three-week-old miR-21 knockout (miR21KO) or wild-type (WT) female mice were treated with dihydrotestosterone (DHT) or vehicle for 90 days. Body composition was determined by EchoMRI. Energy expenditure (EE), oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory exchange ratio (RER) were measured by indirect calorimetry. Androgen receptor (AR), and markers of adipogenesis, de novo lipogenesis, angiogenesis, extracellular matrix remodeling, and thermogenesis were quantified by RT-qPCR and/or Western-blot. RESULTS: MiR-21 ablation attenuated DHT-mediated increase in body weight while having no effect on fat or BAT mass. MiR-21 ablation attenuated DHT-mediated BAT AR upregulation. MiR-21 ablation did not alter EE; however, miR21KO DHT-treated mice have reduced VO2, VCO2, and RER. MiR-21 ablation reversed DHT-mediated decrease in food intake and increase in sleep time. MiR-21 ablation decreased some adipogenesis (Adipoq, Pparγ, and Cebpß) and extracellular matrix remodeling (Mmp-9 and Timp-1) markers expression in DHT-treated mice. MiR-21 ablation abolished DHT-mediated increases in thermogenesis markers Cpt1a and Cpt1b, while decreasing CIDE-A expression. CONCLUSIONS: Our findings suggest that BAT miR-21 may play a role in regulating DHT-mediated thermogenic dysfunction in PCOS. Modulation of BAT miR-21 levels could be a novel therapeutic approach for the treatment of PCOS-associated metabolic derangements.
Polycystic ovary syndrome (PCOS) is a common hormone disorder in premenopausal women, often linked to obesity and abnormal brown fat tissue activity. Women with PCOS have elevated male hormones, which are responsible for many metabolic problems. Our study focuses on understanding the role of microRNA-21 (miR-21) in the energy balance and brown fat tissue activity in a PCOS mouse model. We studied female mice with and without miR-21, treating them with a male hormone. We measured body composition and energy expenditure. We also analyzed the levels of specific genes and proteins related to fat tissue and energy production. Our findings showed that mice lacking miR-21 had less weight gain in response to male hormones, without fat or brown fat tissue mass changes. They also had reduced energy production, changed eating habits, and altered expression of genes related to fat tissue and energy production. In conclusion, our study suggests that miR-21 in brown fat tissue may regulate the energy imbalance caused by male hormones in PCOS. Adjusting miR-21 levels in brown fat tissue could be a new way to address the metabolic issues associated with PCOS.
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Adipogénesis , Tejido Adiposo Pardo , Modelos Animales de Enfermedad , Ratones Noqueados , MicroARNs , Síndrome del Ovario Poliquístico , Termogénesis , Animales , Síndrome del Ovario Poliquístico/metabolismo , Femenino , MicroARNs/metabolismo , MicroARNs/genética , Tejido Adiposo Pardo/metabolismo , Dihidrotestosterona/farmacología , Ratones , Ratones Endogámicos C57BL , Receptores Androgénicos/metabolismoRESUMEN
BACKGROUND: Alopecia affects patients' appearance and psychology. Mixed-lineage kinase domain-like pseudokinase (MLKL)-mediated necroptosis plays a role in various skin diseases, but its effect on hair growth is unclear. OBJECTIVE: To investigate the effects of MLKL on hair growth and its regulatory mechanisms and to determine the potential clinical value of Necrosulfonamide (NSA, a MLKL-targeting inhibitor) in promoting hair growth and counteracting dihydrotestosterone (DHT) inhibition of hair growth. METHODS: The expression level of MLKL was detected in the scalp of androgenetic alopecia (AGA) patients and the skin tissues of mice. Knock down MLKL expression or use NSA to observe hair growth in vivo and in vitro. RESULTS: In AGA patients, MLKL expression is elevated in the alopecia areas. In mice, MLKL is significantly expressed in the outer root sheath (ORS) cells of hair follicles, peaking during the catagen phase. Knockdown expression of MLKL in mice skin promoted hair growth. NSA enhanced hair growth and prevented hair follicle regression via the Wnt signaling. Reduced MLKL boosts ORS cell proliferation without directly impacting DPCs' growth. Interestingly, NSA boosts DPCs' proliferation and induction when co-cultured with ORS cells. Besides, NSA alleviated the inhibition of DHT on hair growth in vivo and vitro. CONCLUSION: NSA inhibited the activation of MLKL in ORS cells, promoted the activation of Wnt signal in DPC cells, and improved the inhibition of hair growth by DHT, illuminating a new alopecia mechanism and aiding anti-alopecia drug development.
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Alopecia , Proliferación Celular , Dihidrotestosterona , Folículo Piloso , Proteínas Quinasas , Sulfonamidas , Animales , Alopecia/tratamiento farmacológico , Alopecia/patología , Ratones , Folículo Piloso/efectos de los fármacos , Folículo Piloso/crecimiento & desarrollo , Folículo Piloso/metabolismo , Humanos , Dihidrotestosterona/farmacología , Sulfonamidas/farmacología , Masculino , Proliferación Celular/efectos de los fármacos , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Cabello/crecimiento & desarrollo , Cabello/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Adulto , Cuero Cabelludo/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Although low estrogen is considered to suppress uterine endometrial carcinoma, the most cases occur in the postmenopausal stage. After menopause, the production of androgen level also declines. Therefore, to resolve the above enigma, we hypothesize that the postmenopausal decline of androgen is a trigger of its progression. In the present study, to validate this hypothesis, we examine the pathological roles of androgen/AR by analyzing clinical data, culturing endometrioid cancer cell lines, and using murine models. Clinical data show that androgen receptor (AR) expression and serum dihydrotestosterone (DHT) are associated with lower disease-free survival (DFS). DHT suppresses malignant behaviors in AR-transfected human endometrial cancer cells (ECC). In ovariectomized Ptenff/PRcre/+ mice, DHT decreases the proliferation of spontaneously developed murine ECC. In AR-transfected human ECC and Ptenff/PRcre/+ mice, DHT suppresses FOXP4 expression. FOXP4-overexpressed human ECC increases, while FOXP4-knocked-down ECC shows decreased malignant behaviors. DHT/AR-mediated ECC suppression is restored by FOXP4 overexpression. The high FOXP4 expression is significantly correlated with low postoperative DFS. These findings indicate that the androgen/AR system suppresses the malignant activity of endometrial carcinoma and that downstream FOXP4 is another target molecule. These findings will also impact developments in clinical approaches to elderly health.
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Andrógenos , Neoplasias Endometriales , Factores de Transcripción Forkhead , Receptores Androgénicos , Femenino , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/genética , Humanos , Animales , Ratones , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genética , Andrógenos/metabolismo , Línea Celular Tumoral , Dihidrotestosterona/metabolismo , Dihidrotestosterona/farmacología , Regulación Neoplásica de la Expresión Génica , Persona de Mediana Edad , Proliferación CelularRESUMEN
Endothelial progenitor cells (EPCs) play a critical role in cardiovascular regeneration. Enhancement of their native properties would be highly beneficial to ensuring the proper functioning of the cardiovascular system. As androgens have a positive effect on the cardiovascular system, we hypothesized that dihydrotestosterone (DHT) could also influence EPC-mediated repair processes. To evaluate this hypothesis, we investigated the effects of DHT on cultured human EPCs' proliferation, viability, morphology, migration, angiogenesis, gene and protein expression, and ability to integrate into cardiac tissue. The results showed that DHT at different concentrations had no cytotoxic effect on EPCs, significantly enhanced the cell proliferation and viability and induces fast, androgen-receptor-dependent formation of capillary-like structures. DHT treatment of EPCs regulated gene expression of androgen receptors and the genes and proteins involved in cell migration and angiogenesis. Importantly, DHT stimulation promoted EPC migration and the cells' ability to adhere and integrate into murine cardiac slices, suggesting it has a role in promoting tissue regeneration. Mass spectrometry analysis further highlighted the impact of DHT on EPCs' functioning. In conclusion, DHT increases the proliferation, migration, and androgen-receptor-dependent angiogenesis of EPCs; enhances the cells' secretion of key factors involved in angiogenesis; and significantly potentiates cellular integration into heart tissue. The data offer support for potential therapeutic applications of DHT in cardiovascular regeneration and repair processes.
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Movimiento Celular , Dihidrotestosterona , Células Progenitoras Endoteliales , Sangre Fetal , Receptores Androgénicos , Sangre Fetal/citología , Dihidrotestosterona/farmacología , Humanos , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Células Progenitoras Endoteliales/citología , Células Progenitoras Endoteliales/metabolismo , Proliferación Celular , Supervivencia Celular , Expresión Génica , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Proteínas de la Membrana/genética , Metaloproteinasa 9 de la Matriz/genética , Basigina/genética , Animales , Ratones , Ventrículos Cardíacos/citología , Movimiento Celular/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Androgenic alopecia (AGA) is the most prevalent form of hair loss in clinical practice and affects the physical and psychological well-being of adolescents. Paeonia lactiflora Pallas (PL), which is widely used in traditional Chinese medicine, enhances blood function and promotes hair growth, and ellagic acid (EA), a polyphenol in PL extract, shows strong antioxidant, anti-aging, and anti-inflammatory properties and also plays a role in the treatment of various skin conditions. However, its role and mechanism of action in AGA remain unclear. AIM OF THE STUDY: To determine whether EA can rescue slow hair regeneration by regulating dihydrotestosterone (DHT)-induced ferroptosis in AGA mice and clarify the effect of EA on DHT-induced ferroptosis in dermal papilla cells (DPCs). MATERIALS AND METHODS: Male C57BL/6 mice were used to establish a DHT-induced AGA mouse model, whereas DPCs were used to establish a DHT-induced cellular model. Thereafter, we investigated the therapeutic mechanism of action of EA via immunofluorescence, western blot analysis, immunohistochemistry, electron microscopy, and molecular docking. RESULTS: EA stimulated hair regeneration in mice and reversed DHT-induced increases in iron content, lipid peroxidation, and DHT-induced mitochondrial dysfunction by activating the Wnt/ß-catenin signaling pathway. Further, ß-catenin knockdown suppressed the inhibitory effect of EA on DHT-induced ferroptosis in DPCs. CONCLUSION: EA inhibits DHT-induced ferroptosis and promotes hair regrowth in mice by activating the Wnt/ß-catenin signaling pathway. Thus, it has potential for use as a treatment option for AGA.
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Alopecia , Dihidrotestosterona , Ácido Elágico , Cabello , Regeneración , Vía de Señalización Wnt , Animales , Masculino , Ratones , Alopecia/tratamiento farmacológico , Alopecia/inducido químicamente , beta Catenina/metabolismo , Dihidrotestosterona/farmacología , Ácido Elágico/farmacología , Ferroptosis/efectos de los fármacos , Cabello/efectos de los fármacos , Cabello/crecimiento & desarrollo , Ratones Endogámicos C57BL , Regeneración/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular degenerative disease caused by a polyglutamine expansion in the androgen receptor (AR). This mutation causes AR to misfold and aggregate, contributing to toxicity in and degeneration of motor neurons and skeletal muscle. There is currently no effective treatment or cure for this disease. The role of an interdomain interaction between the amino- and carboxyl-termini of AR, termed the N/C interaction, has been previously identified as a component of androgen receptor-induced toxicity in cell and mouse models of SBMA. However, the mechanism by which this interaction contributes to disease pathology is unclear. This work seeks to investigate this mechanism by interrogating the role of AR homodimerization- a unique form of the N/C-interaction- in SBMA. We show that, although the AR N/C-interaction is reduced by polyglutamine-expansion, homodimers of 5α-dihydrotestosterone (DHT)-bound AR are increased. Additionally, blocking homodimerization results in decreased AR aggregation and toxicity in cell models. Blocking homodimerization results in the increased degradation of AR, which likely plays a role in the protective effects of this mutation. Overall, this work identifies a novel mechanism in SBMA pathology that may represent a novel target for the development of therapeutics for this disease.
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Dihidrotestosterona , Péptidos , Multimerización de Proteína , Receptores Androgénicos , Animales , Humanos , Ratones , Atrofia Bulboespinal Ligada al X/metabolismo , Atrofia Bulboespinal Ligada al X/genética , Atrofia Bulboespinal Ligada al X/patología , Dihidrotestosterona/farmacología , Dihidrotestosterona/metabolismo , Péptidos/metabolismo , Péptidos/genética , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genética , Ratas , Línea CelularRESUMEN
Bisphenol A (BPA) and its various forms used as BPA alternatives in industries are recognized toxic compounds and antiandrogenic endocrine disruptors. These chemicals are widespread in the environment and frequently detected in biological samples. Concerns exist about their impact on hormones, disrupting natural biological processes in humans, together with their negative impacts on the environment and biotic life. This study aims to characterize the interaction between BPA analogs and the androgen receptor (AR) and the effect on the receptor's normal activity. To achieve this goal, molecular docking was conducted with BPA and its analogs and dihydrotestosterone (DHT) as a reference ligand. Four BPA analogs exhibited higher affinity (-10.2 to -8.7 kcal/mol) for AR compared to BPA (-8.6 kcal/mol), displaying distinct interaction patterns. Interestingly, DHT (-11.0 kcal/mol) shared a binding pattern with BPA. ADMET analysis of the top 10 compounds, followed by molecular dynamics simulations, revealed toxicity and dynamic behavior. Experimental studies demonstrated that only BPA disrupts DHT-induced AR dimerization, thereby affecting AR's function due to its binding nature. This similarity to DHT was observed during computational analysis. These findings emphasize the importance of targeted strategies to mitigate BPA toxicity, offering crucial insights for interventions in human health and environmental well-being.
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Disruptores Endocrinos , Receptores Androgénicos , Humanos , Receptores Androgénicos/metabolismo , Disruptores Endocrinos/metabolismo , Simulación del Acoplamiento Molecular , Fenoles/metabolismo , Dihidrotestosterona/farmacología , Compuestos de Bencidrilo/toxicidad , Compuestos de Bencidrilo/metabolismoRESUMEN
PURPOSE: Prostatitis is a highly prevalent condition that seriously affects men's physical and mental health. Although epidemiological investigations have provided evidence of a correlation between insufficient sleep and prostatitis, the pathogenesis of prostatitis remains unclear. We sought to identify the underlying mechanism involved and identify a promising therapeutic target. METHODS: Sleep deprivation (SD) was utilized to establish a mouse model of insufficient sleep in a special device. Prostatitis was observed at different time points post-SD. The degree of prostatitis was evaluated by pathological section and behavioural tests. Using immunofluorescence, western blot, and proteomic analyses, the underlying mechanism of SD-related prostatitis was investigated, and the development and therapeutic target of prostatitis were elucidated. RESULTS: SD, as an initial pathological trigger, resulted in a reduction in dihydrotestosterone and melatonin levels. Proteomic analysis revealed that the cGAS-STING pathway may play a significant role in inducing prostatitis. The subsequent results illustrated that the dual reduction in dihydrotestosterone and melatonin led to an accumulation of reactive oxygen species and the release of mitochondrial DNA (mt-DNA). The accumulation of mt-DNA activated the cGAS-STING pathway, which recruited inflammatory cells into the prostatic stroma through the secretion of interferon-ß. Consequently, an inflammatory microenvironment was formed, ultimately promoting the development of prostatitis. Notably, mice with SD-induced prostatitis gradually recovered to a normal state within 7 days of recovery sleep. However, after being subjected to SD again, these mice tended to have a more pronounced manifestation of prostatitis within a shorter timeframe, which suggested that prostatitis is prone to relapse. CONCLUSIONS: The cGAS-STING pathway activated by dual deficiency of dihydrotestosterone and melatonin plays a comprehensive inflammatory role in SD-related prostatitis. This research provides valuable insights into the pathogenesis, therapeutic targets, and prevention strategies of prostatitis.
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Melatonina , Prostatitis , Humanos , Masculino , Animales , Ratones , Privación de Sueño/complicaciones , Dihidrotestosterona/farmacología , Proteómica , Sueño , ADN Mitocondrial , NucleotidiltransferasasRESUMEN
Excess levels of circulating androgens during prenatal or peripubertal development are an important cause of polycystic ovary syndrome (PCOS), with the brain being a key target. Approximately half of the women diagnosed with PCOS also experience metabolic syndrome; common features including obesity, insulin resistance and hyperinsulinemia. Although a large amount of clinical and preclinical evidence has confirmed this relationship between androgens and the reproductive and metabolic features of PCOS, the mechanisms by which androgens cause this dysregulation are unknown. Neuron-specific androgen receptor knockout alleviates some PCOS-like features in a peripubertal dihydrotestosterone (DHT) mouse model, but the specific neuronal populations mediating these effects are undefined. A candidate population is the agouti-related peptide (AgRP)-expressing neurons, which are important for both reproductive and metabolic function. We used a well-characterised peripubertal androgenized mouse model and Cre-loxP transgenics to investigate whether deleting androgen receptors specifically from AgRP neurons can alleviate the induced reproductive and metabolic dysregulation. Androgen receptors were co-expressed in 66% of AgRP neurons in control mice, but only in <2% of AgRP neurons in knockout mice. The number of AgRP neurons was not altered by the treatments. Only 20% of androgen receptor knockout mice showed rescue of DHT-induced androgen-induced anovulation and acyclicity. Furthermore, androgen receptor knockout did not rescue metabolic dysfunction (body weight, adiposity or glucose and insulin tolerance). While we cannot rule out developmental compensation in our model, these results suggest peripubertal androgen excess does not markedly influence Agrp expression and does not dysregulate reproductive and metabolic function through direct actions of androgens onto AgRP neurons.
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Andrógenos , Síndrome del Ovario Poliquístico , Animales , Femenino , Humanos , Ratones , Embarazo , Proteína Relacionada con Agouti/metabolismo , Andrógenos/metabolismo , Dihidrotestosterona/farmacología , Ratones Noqueados , Neuronas/metabolismo , Obesidad/metabolismo , Péptidos/farmacología , Receptores Androgénicos/metabolismo , Virilismo/metabolismoRESUMEN
Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex and increased AAS levels are associated with earlier and more severe manifestation of common cardiac conditions, such as atrial fibrillation, and rare ones, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical observations suggest a potential atrial involvement in ARVC. Arrhythmogenic right ventricular cardiomyopathy is caused by desmosomal gene defects, including reduced plakoglobin expression. Here, we analysed clinical records from 146 ARVC patients to identify that ARVC is more common in males than females. Patients with ARVC also had an increased incidence of atrial arrhythmias and P wave changes. To study desmosomal vulnerability and the effects of AAS on the atria, young adult male mice, heterozygously deficient for plakoglobin (Plako+/-), and wild type (WT) littermates were chronically exposed to 5α-dihydrotestosterone (DHT) or placebo. The DHT increased atrial expression of pro-hypertrophic, fibrotic and inflammatory transcripts. In mice with reduced plakoglobin, DHT exaggerated P wave abnormalities, atrial conduction slowing, sodium current depletion, action potential amplitude reduction and the fall in action potential depolarization rate. Super-resolution microscopy revealed a decrease in NaV1.5 membrane clustering in Plako+/- atrial cardiomyocytes after DHT exposure. In summary, AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. Male sex is likely to increase the risk of atrial arrhythmia, particularly in those with desmosomal gene variants. This risk is likely to be exaggerated further by AAS use. KEY POINTS: Androgenic male sex hormones, such as testosterone, might increase the risk of atrial fibrillation in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), which is often caused by desmosomal gene defects (e.g. reduced plakoglobin expression). In this study, we observed a significantly higher proportion of males who had ARVC compared with females, and atrial arrhythmias and P wave changes represented a common observation in advanced ARVC stages. In mice with reduced plakoglobin expression, chronic administration of 5α-dihydrotestosterone led to P wave abnormalities, atrial conduction slowing, sodium current depletion and a decrease in membrane-localized NaV1.5 clusters. 5α-Dihydrotestosterone, therefore, represents a stimulus aggravating the pro-arrhythmic phenotype in carriers of desmosomal mutations and can affect atrial electrical function.
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gamma Catenina , Animales , Masculino , Femenino , Ratones , Humanos , gamma Catenina/genética , gamma Catenina/metabolismo , Adulto , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/metabolismo , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Displasia Ventricular Derecha Arritmogénica/metabolismo , Dihidrotestosterona/farmacología , Andrógenos/farmacología , Potenciales de Acción/efectos de los fármacos , Ratones Endogámicos C57BL , Adulto Joven , Anabolizantes/farmacología , Esteroides Anabólicos AndrogénicosRESUMEN
Objective: To explore the optimal ratio of dihydrotestosterone and hydroxyflutamide (hereinafter referred to as DH), construct a dual release system of androgen and its antagonist, and analyze the application effect of this system in the repair of full-thickness burn wounds in mice. Methods: This study was an experimental study. The HaCaT cells were divided into blank group (without drug culture), low baseline group, medium baseline group, and high baseline group according to the random number table (the same grouping method below), and the last three groups of cells were cultured by adding three different ratios of DH. Under a medium ratio, the mass of dihydrotestosterone in the three baseline groups from low to high was 1.4, 2.8, and 4.0 µg, respectively, and the mass of hydroxyflutamide was 1.2, 1.6, and 2.0 µg, respectively. On this basis, under a small ratio, the mass of dihydrotestosterone was reduced by half and the mass of hydroxyflutamide was increased by half; under a large ratio, the mass of dihydrotestosterone was increased by half and the mass of hydroxyflutamide was reduced by half. After culture of 2 days, the cell proliferation level was detected by cell counting kit 8 (n=4). Sixteen 6-8-week-old male BALB/c mice were used to establish a full-thickness burn wound on the back and divided into blank group, small ratio group, medium ratio group, and large ratio group, with 4 mice in each group. On post injury day (PID) 7, normal saline containing different ratios of DH was locally dropped to the wounds of mice in the last three groups of mice (the total mass of DH in the three ratio groups from small to large was 127.5, 165.0, and 202.5 µg, respectively, and the mass ratios of dihydrotestosterone to hydroxyflutamide (hereinafter referred to as drug mass ratio) were 8â¶9, 8â¶3, and 8â¶1, respectively), afterwards, the administration was repeated every 48 hours until PID 27; normal saline was dropped to the wound of mice in blank group at the aforementioned time points. The wound healing status on PID 0 (immediately), 7, 14, 21, and 28 was observed, and the wound healing rates on PID 7, 14, 21, and 28 were calculated (n=4). On PID 28, the wound tissue was taken, which was stained with hematoxylin and eosin for observing re-epithelialization and with Masson for observing collagen fibers, and the proportion of collagen fibers was analyzed (n=3). Twenty 6-8-week-old male BALB/c mice were used to establish a full-thickness burn wound on the back and divided into ordinary scaffold group, small proportion scaffold group, medium proportion scaffold group, and large proportion scaffold group (with 5 mice in each group). On PID 7, the wound was continuously dressed with a polycaprolactone scaffold without drug and a polycaprolactone scaffold containing DH with a drug mass ratio of 1â¶3, 1â¶1, or 3â¶1 (i.e. the dual release system of androgen and its antagonist, with total mass of DH being about 1.7 mg) prepared by using electrospinning technology until the end of the experiment. Histopathological analyses of tissue (n=3) at the same time points as those in the previous animal experiment were performed. On PID 7 and 14, the wound exudates were collected and the relative abundance of bacterial communities was analyzed using 16S ribosomal RNA high-throughput sequencing (n=3). Results: After culture of 2 days, under a small ratio, the proliferation levels of HaCaT cells in low baseline group and high baseline group were significantly higher than the level in blank group (P<0.05). As the time after injury prolonged, the wounds of all four groups of mice continued to shrink. On PID 14, the wound healing rate of mice in large ratio group was 72.5% (61.7%, 75.1%), which was close to 53.3% (49.5%, 64.4%) in blank group (P>0.05); the wound healing rates of mice in small and medium ratio groups were 74.2% (71.0%, 84.2%) and 70.4% (65.1%, 74.4%), respectively, which were significantly higher than the rate in blank group (with both Z values being -2.31, P<0.05). On PID 21, the wound healing rate of mice in small ratio group was significantly higher than that in blank group (Z=-2.31, P<0.05). On PID 28, the wounds of mice in the three ratio groups were completely re-epithelialized and the epidermis was thicker than that in blank group; compared with that in blank group, the collagen fiber content in the wound tissue of mice in the three ratio groups was higher and arranged more orderly, and the proportions of collagen fibers in the wound tissue of mice in small and large ratio groups were significantly increased (P<0.05). On PID 28, the wounds of mice in ordinary scaffold group were partially epithelialized, while the wounds of mice in the three proportion scaffold groups were almost completely epithelialized. Among them, the wounds of mice in small proportion scaffold group had the thickest epidermis. The proportion of collagen fibers in the wound tissue of mice in small proportion scaffold group was significantly increased compared with that in ordinary scaffold group (P<0.05). On PID 7, the bacterial communities with high relative abundance in the wound exudation of mice in the four groups included bacteria of Corynebacterium, Staphylococcus, and Rhodococcus. On PID 14, the bacterial communities with high relative abundance in the wound exudation of mice in the four groups included bacteria of Stenotrophomonas, Rhodococcus, and Staphylococcus, and the number of bacterial species in the wound exudation of mice in the three proportion scaffold groups was more than that in ordinary scaffold group. Conclusions: When the drug mass ratio is relatively small, DH has the effect of promoting the proliferation of HaCaT cells. The ratio of 8â¶9 is the optimal mass ratio of dihydrotestosterone to hydroxyflutamide, and DH with this mass ratio can promote re-epithelialization and collagen deposition of full-thickness burn wounds in mice, and promote wound healing. The constructed dual release system of androgen and its antagonist with DH in a 1â¶3 drug mass ratio contributes to the re-epithelialization and collagen deposition of the full-thickness burn wounds in mice, and can improve the diversity of wound microbiota.
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Quemaduras , Flutamida/análogos & derivados , Traumatismos de los Tejidos Blandos , Ratones , Masculino , Animales , Cicatrización de Heridas , Andrógenos/farmacología , Dihidrotestosterona/farmacología , Solución Salina , Colágeno , Quemaduras/tratamiento farmacológicoRESUMEN
Neuroinflammation induced by microglia following spinal cord injury (SCI) leads to secondary neurologic injury. Androgens including testosterone and dihydrotestosterone (DHT) show as endogenous neuroprotective factors against multiple neurologic diseases, while their therapeutic role in SCI-induced neuroinflammation and underlying mechanism remains elusive. In the study, we aimed to investigate the role of DHT against microglia-induced neuroinflammation in SCI and evaluate its protective treatment. BV2 cells were activated by neuroinflammation via LPS in vitro. Adult male C57BL/6 mice were used to establish the SCI model. BV2 cells and SCI mice were administrated DHT. Microglia activation, pro-inflammatory factors, p38 and p65 phosphorylation, glial scar, fibrotic scar, histology, and locomotor function recovery were measured, respectively. We demonstrated that DHT administration attenuates neuroinflammation in microglia through inhibition of p38 and p65 pathways. Moreover, DHT reduces microglia and astrocyte accumulation, cord fibrosis and histologic damage. Besides, DHT ameliorates locomotor functional recovery after SCI. DHT is verified to play a neuroprotective role in SCI, which fights against neuroinflammation by inhibition of p38 and p65 pathways. Therefore, Mel is defined as a promising factor in protecting neural tissue after SCI.
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FN-kappa B , Traumatismos de la Médula Espinal , Animales , Masculino , Ratones , Dihidrotestosterona/farmacología , Dihidrotestosterona/uso terapéutico , Inflamación/metabolismo , Ratones Endogámicos C57BL , Microglía/metabolismo , Enfermedades Neuroinflamatorias , FN-kappa B/metabolismo , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/tratamiento farmacológicoRESUMEN
Androgen binding to the androgen receptor (AR) in the cytoplasm induces the AR to translocate to the nucleus, where it regulates the expression of target genes. Here, we found that androgens rapidly activated a plasma membrane-associated signaling node that enhanced nuclear AR functions. In murine primary osteoblasts, dihydrotestosterone (DHT) binding to a membrane-associated form of AR stimulated plasma membrane-associated protein kinase G type 2 (PKG2), leading to the activation of multiple kinases, including ERK. Phosphorylation of AR at Ser515 by ERK increased the nuclear accumulation and binding of AR to the promoter of Ctnnb1, which encodes the transcription factor ß-catenin. In male mouse osteoblasts and human prostate cancer cells, DHT induced the expression of Ctnnb1 and CTNN1B, respectively, as well as ß-catenin target genes, stimulating the proliferation, survival, and differentiation of osteoblasts and the proliferation of prostate cancer cells in a PKG2-dependent fashion. Because ß-catenin is a master regulator of skeletal homeostasis, these results explain the reported male-specific osteoporotic phenotype of mice lacking PKG2 in osteoblasts and imply that PKG2-dependent AR signaling is essential for maintaining bone mass in vivo. Our results suggest that widely used pharmacological PKG activators, such as sildenafil, could be beneficial for male and estrogen-deficient female patients with osteoporosis but detrimental in patients with prostate cancer.
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Andrógenos , Neoplasias de la Próstata , Animales , Humanos , Masculino , Ratones , Andrógenos/farmacología , Andrógenos/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Línea Celular Tumoral , Membrana Celular/metabolismo , Dihidrotestosterona/farmacología , Dihidrotestosterona/metabolismo , Osteoblastos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismoRESUMEN
Finasteride is commonly used for androgenetic alopecia (AGA) treatment. The aim of this study was to assess the therapeutic maintenance effect of a finasteride every other month (EOM) regimen and analyze clinical and laboratory differences in patients with AGA according to their treatment response. One hundred males with AGA who received finasteride 1 mg daily treatment for a year were enrolled in the study. At 1 year follow-up, treatment responses of patients who completed the visit schedule were assessed using five scales. The patients were assigned to good or bad response groups according to their assessment. Further, they were randomly divided into two groups (daily vs. EOM) and treated with finasteride (1 mg) for 1 more year. At 2 years follow-up, treatment efficacy was assessed. At 1-year follow-up, 36 patients completed the schedule, including eight and three patients in the good and bad response groups, respectively. At the 2-year follow-up, 23 patients completed the schedule, with nine in the daily group and 14 in the EOM group. Changes in global photographic assessment in the second year were 1.33 and 1.29 for the daily and EOM groups, respectively. The daily group showed an elevated hair density and lower concentration of dihydrotestosterone (DHT) and the DHT to testosterone ratio (DHT/T). However, the EOM group showed decreased hair density and elevated DHT and DHT/T. Following treatment response assessment after 1 year of treatment, the good response group showed early onset which was associated with maternal AGA. Analysis of serum androgen hormone magnitude of DHT reduction was much greater (54.4% vs. 44.4%). DHT/T was higher in the bad response group (1.98 vs. 2.33). We concluded that the finasteride EOM regimen showed similar maintenance effects to the daily regimen.