RESUMEN

The renin-angiotensin system (RAS) is composed of a series of peptides, receptors, and enzymes that play a pivotal role in maintaining cardiovascular homeostasis. Among the most important players in this system are the angiotensin-II and angiotensin-(1-7) peptides. Our group has recently demonstrated that alamandine (ALA), a peptide with structural and functional similarities to angiotensin-(1-7), interacts with cardiomyocytes, enhancing contractility via the Mas-related G protein-coupled receptor member D (MrgD). It is currently unknown whether this modulation varies along the distinct phases of the day. To address this issue, we assessed the ALA-induced contractility response of cardiomyocytes from mice at four Zeitgeber times (ZTs). At ZT2 (light phase), ALA enhanced cardiomyocyte shortening in an MrgD receptor-dependent manner, which was associated with nitric oxide (NO) production. At ZT14 (dark phase), ALA induced a negative modulation on the cardiomyocyte contraction. ß-Alanine, an MrgD agonist, reproduced the time-of-day effects of ALA on myocyte shortening. NG-nitro-l-arginine methyl ester, an NO synthase inhibitor, blocked the increase in fractional shortening induced by ALA at ZT2. No effect of ALA on myocyte shortening was observed at ZT8 and ZT20. Our results show that ALA/MrgD signaling in cardiomyocytes is subject to temporal modulation. This finding has significant implications for pharmacological approaches that combine chronotherapy for cardiac conditions triggered by disruption of circadian rhythms and hormonal signaling.NEW & NOTEWORTHY Alamandine, a member of the renin-angiotensin system, serves critical roles in cardioprotection, including the modulation of cardiomyocyte contractility. Whether this effect varies along the day is unknown. Our results provide evidence that alamandine via receptor MrgD exerts opposing actions on cardiomyocyte shortening, enhancing, or reducing contraction depending on the time of day. These findings may have significant implications for the development and effectiveness of future cardiac therapies.

Asunto(s)

Contracción Miocárdica , Miocitos Cardíacos , Óxido Nítrico , Oligopéptidos , Receptores Acoplados a Proteínas G , Animales , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Contracción Miocárdica/fisiología , Ratones , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Óxido Nítrico/metabolismo , Oligopéptidos/farmacología , Ratones Endogámicos C57BL , Ritmo Circadiano/fisiología , Ritmo Circadiano/efectos de los fármacos , Receptores de Neuropéptido/metabolismo , Receptores de Neuropéptido/agonistas , Receptores de Neuropéptido/antagonistas & inhibidores , Masculino , Células Cultivadas , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología

RESUMEN

Cardiac maturation represents the last phase of heart development and is characterized by morphofunctional alterations that optimize the heart for efficient pumping. Its understanding provides important insights into cardiac regeneration therapies. Recent evidence implies that adrenergic signals are involved in the regulation of cardiac maturation, but the mechanistic underpinnings involved in this process are poorly understood. Herein, we explored the role of ß-adrenergic receptor (ß-AR) activation in determining structural and functional components of cardiomyocyte maturation. Temporal characterization of tyrosine hydroxylase and norepinephrine levels in the mouse heart revealed that sympathetic innervation develops during the first 3 wk of life, concurrent with the rise in ß-AR expression. To assess the impact of adrenergic inhibition on maturation, we treated mice with propranolol, isolated cardiomyocytes, and evaluated morphofunctional parameters. Propranolol treatment reduced heart weight, cardiomyocyte size, and cellular shortening, while it increased the pool of mononucleated myocytes, resulting in impaired maturation. No changes in t-tubules were observed in cells from propranolol mice. To establish a causal link between ß-AR signaling and cardiomyocyte maturation, mice were subjected to sympathectomy, followed or not by restoration with isoproterenol treatment. Cardiomyocytes from sympathectomyzed mice recapitulated the salient immaturity features of propranolol-treated mice, with the additional loss of t-tubules. Isoproterenol rescued the maturation deficits induced by sympathectomy, except for the t-tubule alterations. Our study identifies the ß-AR stimuli as a maturation promoting signal and implies that this pathway can be modulated to improve cardiac regeneration therapies.NEW & NOTEWORTHY Maturation involves a series of morphofunctional alterations vital to heart development. Its regulatory mechanisms are only now being unveiled. Evidence implies that adrenergic signaling regulates cardiac maturation, but the mechanisms are poorly understood. To address this point, we blocked ß-ARs or performed sympathectomy followed by rescue experiments with isoproterenol in neonatal mice. Our study identifies the ß-AR stimuli as a maturation signal for cardiomyocytes and highlights the importance of this pathway in cardiac regeneration therapies.

Asunto(s)

Miocitos Cardíacos , Propranolol , Transducción de Señal , Animales , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Ratones , Propranolol/farmacología , Receptores Adrenérgicos beta/metabolismo , Ratones Endogámicos C57BL , Isoproterenol/farmacología , Masculino , Corazón/efectos de los fármacos , Células Cultivadas , Agonistas Adrenérgicos beta/farmacología , Norepinefrina/metabolismo , Norepinefrina/farmacología , Antagonistas Adrenérgicos beta/farmacología

RESUMEN

Telocytes (TCs) are CD34-positive interstitial cells that have long cytoplasmic projections, called telopodes; they have been identified in several organs and in various species. These cells establish a complex communication network between different stromal and epithelial cell types, and there is growing evidence that they play a key role in physiology and pathology. In many tissues, TC network impairment has been implicated in the onset and progression of pathological conditions, which makes the study of TCs of great interest for the development of novel therapies. In this review, we summarise the main methods involved in the characterisation of these cells as well as their inherent difficulties and then discuss the functional assays that are used to uncover the role of TCs in normal and pathological conditions, from the most traditional to the most recent. Furthermore, we provide future perspectives in the study of TCs, especially regarding the establishment of more precise markers, commercial lineages and means for drug delivery and genetic editing that directly target TCs.

Asunto(s)

Telocitos , Telocitos/citología , Telocitos/metabolismo , Humanos , Animales

RESUMEN

OBJECTIVE: Pressure overload can result in significant changes to the structure of blood vessels, a process known as vascular remodeling. High levels of tension can cause vascular inflammation, fibrosis, and structural alterations to the vascular wall. Prior research from our team has demonstrated that the oral administration of alamandine can promote vasculoprotective effects in mice aorta that have undergone transverse aortic constriction (TAC). Furthermore, changes in local hemodynamics can affect the right and left carotid arteries differently after TAC. Thus, in this study, we aimed to assess the effects of alamandine treatment on right carotid remodeling and the expression of oxidative stress-related substances induced by TAC. METHODS AND RESULTS: Male C57BL/6 mice were categorized into three groups: Sham, TAC, and TAC treated with alamandine (TAC+ALA). Alamandine treatment was administered orally by gavage (30 µg/kg/day), starting three days before the surgery, and continuing for a period of fourteen days. Morphometric analysis of hematoxylin and eosin-stained sections revealed that TAC induced hypertrophic and positive remodeling in the right carotid artery. Picrosirius Red staining also demonstrated an increase in total collagen deposition in the right carotid artery due to TAC-induced vascular changes. Alamandine treatment effectively prevented the increase in reactive oxygen species production and depletion of nitric oxide levels, which were induced by TAC. Finally, alamandine treatment was also shown to prevent the increased expression of nuclear factor erythroid 2-related factor 2 and 3-nitrotyrosine that were induced by TAC. CONCLUSION: Our results suggest that alamandine can effectively attenuate pathophysiological stress in the right carotid artery of animals subjected to TAC.

Asunto(s)

Arterias Carótidas , Estrés Oxidativo , Masculino , Ratones , Animales , Constricción , Ratones Endogámicos C57BL , Arterias Carótidas/cirugía , Remodelación Ventricular , Modelos Animales de Enfermedad

RESUMEN

Telocytes are interstitial cells that are present in various tissues, have long cytoplasmic projections known as telopodes, and are classified as CD34+ cells. Telopodes form extensive networks that permeate the stroma, and there is evidence that these networks connect several stromal cell types, giving them an important role in intercellular communication and the maintenance of tissue organisation. Data have also shown that these networks can be impaired and the number of telocytes reduced in association with many pathological conditions such as cancer and fibrosis. Thus, techniques that promote telocyte proliferation have become an important therapeutic target. In this study, ex vivo and in vitro assays were conducted to evaluate the impact on prostatic telocytes of SDF-1, a factor involved in the proliferation and migration of CD34+ cells. SDF-1 caused an increase in the number of telocytes in explants, as well as morphological changes that were possibly related to the proliferation of these cells. These changes involved the fusion of telopode segments, linked to an increase in cell body volume. In vitro assays also showed that SDF-1 enriched prostate stromal cells with telocytes. Altogether, the data indicate that SDF-1 may offer promising uses in therapies that aim to increase the number of telocytes. However, further studies are needed to confirm the efficiency of this factor in different tissues/pathological conditions.

Asunto(s)

Quimiocina CXCL12 , Telocitos , Masculino , Humanos , Quimiocina CXCL12/metabolismo , Telocitos/metabolismo , Telopodos/metabolismo , Células del Estroma , Citoplasma

RESUMEN

The prostate is not an organ exclusive to the male. It is also found in females of several species, including humans, in which part of the Skene gland is homologous to the male prostate. Evidence is accumulating that changes in the stroma are central to tumorigenesis. Equally, telocytes, a recently discovered type of interstitial cell, are essential for the maintenance of stromal organization. However, it is still uncertain whether there are telocytes in the female prostate and if they play a role in tumorigenesis. The present study used ultrastructural and immunofluorescence techniques to investigate the presence of telocytes in the prostate of Mongolian gerbil females, a rodent model that often has a functional prostate in females, as well as to assess the impact of a combination of N-ethyl-N-nitrosourea, testosterone, and estradiol on telocytes. The results point to the presence of telocytes in the female prostate in the perialveolar and interalveolar regions, and reveal that these cells are absent in regions of benign and premalignant lesions in the gland, in which the perialveolar smooth muscle is altered. Additionally, telocytes are also closely associated with infiltrated immune cells in the stroma. Our data suggest that telocytes are important for both the maintenance of smooth muscle and prostatic epithelium integrity, which indicates a protective role against the advancement of tumorigenesis. But telocytes are also associated with immune cells and a proinflammatory/proangiogenic role for these cells cannot be ruled out, implying that telocytes have a complex role in prostatic tumorigenesis in females.

Asunto(s)

Próstata , Telocitos , Animales , Antígenos CD34/metabolismo , Carcinogénesis/metabolismo , Femenino , Gerbillinae/metabolismo , Humanos , Masculino , Próstata/metabolismo , Telocitos/metabolismo

RESUMEN

The presence of the prostate in female mammals has long been known. However, pieces of information related to its development are still lacking. The aim of this study was to explore the budding dynamic during the initial prostate development in female gerbils. Pregnant females were timed, the fetuses were euthanized, and the urogenital sinus was dissected out between the embryonic days 20 and 24 (E20-E24 groups). Newborn pups (1-day-old; P1 group) underwent the same procedures. The female prostate development was based on epithelial buds which arose far from the paraurethral mesenchyme (PAM). The epithelial buds reached the PAM at prenatal day 24, crossing a small gap in the smooth muscle layer between the periurethral mesenchyme (PEM) and the PAM. Steroid nuclear receptors such as the androgen receptor and estrogen receptor alpha were localized in the PEM through the urethral wall, although some epithelial labeling was also present in the urogenital sinus epithelium (UGE). P63-positive cells were found only in the UGE, becoming restricted to the basal compartment after the 23rd prenatal day. The results showed that the gerbil female prostate exhibits a distinct budding pattern as compared to the male prostate development.

Asunto(s)

Próstata , Sistema Urogenital , Animales , Epitelio , Femenino , Gerbillinae , Humanos , Recién Nacido , Masculino , Mesodermo , Embarazo

RESUMEN

Advances in prostatic stroma studies over the past few decades have demonstrated that the stroma not only supports and nourishes the gland's secretory epithelium but also participates in key aspects of morphogenesis, in the prostate's hormonal metabolism, and in the functionality of the secretory epithelium. Furthermore, the stroma is implicated in the onset and progression of prostate cancer through the formation of the so-called reactive stroma, which corresponds to a tumorigenesis-permissive microenvironment. Prostatic stromal cells are interconnected and exchange paracrine signals among themselves in a gland that is highly sensitive to endocrine hormones. There is a growing body of evidence that telocytes, recently detected interstitial cells that are also present in the prostate, are involved in stromal organization, so that their processes form a network of interconnections with both the epithelium and the other stromal cells. The present review provides an update on the different types of prostate stromal cells, their interrelationships and implications for prostate development, physiology and pathological conditions.

Asunto(s)

Próstata/patología , Células del Estroma/patología , Animales , Humanos , Masculino , Comunicación Paracrina/fisiología , Neoplasias de la Próstata/patología

RESUMEN

The male urogenital system is composed of the reproductive system and the urinary tract; they have an interconnected embryonic development and share one of their anatomical components, the urethra. This system has a highly complex physiology deeply interconnected with the circulatory and nervous systems, as well as being capable of adapting to environmental variations; it also undergoes changes with aging and, in the case of the reproductive system, with seasonality. The stroma is an essential component in this physiological plasticity and its complexity has increased with the description in the last decade of a new cell type, the telocyte. Several studies have demonstrated the presence of telocytes in the organs of the male urogenital system and other systems; however, their exact function is not yet known. The present review addresses current knowledge about telocytes in the urogenital system in terms of their locations, interrelationships, possible functions and pathological implications. It has been found that telocytes in the urogenital system possibly have a leading role in stromal tissue organization/maintenance, in addition to participation in stem cell niches and an association with the immune system, as well as specific functions in the urogenital system, lipid synthesis in the testes, erythropoiesis in the kidneys and the micturition reflex in the bladder. There is also evidence that telocytes are involved in pathologies in the kidneys, urethra, bladder, prostate, and testes.

Asunto(s)

Telocitos/patología , Telocitos/fisiología , Sistema Urogenital/patología , Sistema Urogenital/fisiología , Animales , Enfermedades de los Genitales Masculinos/patología , Enfermedades de los Genitales Masculinos/fisiopatología , Humanos , Metabolismo de los Lípidos/fisiología , Masculino , Próstata/citología , Próstata/patología , Próstata/fisiología , Células Madre/patología , Células Madre/fisiología , Testículo/citología , Testículo/patología , Testículo/fisiología , Vejiga Urinaria/citología , Vejiga Urinaria/patología , Vejiga Urinaria/fisiología , Sistema Urogenital/citología

RESUMEN

Alamandine is the newest identified peptide of the renin-angiotensin system (RAS) and has protective effects in the cardiovascular system. Although the involvement of classical RAS components in the genesis and progression of cardiac remodeling is well known, less is known about the effects of alamandine. Therefore, in the present study we investigated the effects of alamandine on cardiac remodeling induced by transverse aortic constriction (TAC) in mice. Male mice (C57BL/6), 10-12 wk of age, were divided into three groups: sham operated, TAC, and TAC + ALA (30 µg/kg/day alamandine for 14 days). The TAC surgery was performed under ketamine and xylazine anesthesia. At the end of treatment, the animals were submitted to echocardiographic examination and subsequently euthanized for tissue collection. TAC induced myocyte hypertrophy, collagen deposition, and the expression of matrix metalloproteinase (MMP)-2 and transforming growth factor (TGF)-ß in the left ventricle. These markers of cardiac remodeling were reduced by oral treatment with alamandine. Western blotting analysis showed that alamandine prevents the increase in ERK1/2 phosphorylation and reverts the decrease in 5'-adenosine monophosphate-activated protein kinase (AMPK)α phosphorylation induced by TAC. Although both TAC and TAC + ALA increased SERCA2 expression, the phosphorylation of phospholamban in the Thr17 residue was increased solely in the alamandine-treated group. The echocardiographic data showed that there are no functional or morphological alterations after 2 wk of TAC. Alamandine treatment prevents myocyte hypertrophy and cardiac fibrosis induced by TAC. Our results reinforce the cardioprotective role of alamandine and highlight its therapeutic potential for treating heart diseases related to pressure overload conditions.NEW & NOTEWORTHY Alamandine is the newest identified component of the renin-angiotensin system protective arm. Considering the beneficial effects already described so far, alamandine is a promising target for cardiovascular disease treatment. We demonstrated for the first time that alamandine improves many aspects of cardiac remodeling induced by pressure overload, including cell hypertrophy, fibrosis, and oxidative stress markers.

Asunto(s)

Fármacos Cardiovasculares/farmacología , Ventrículos Cardíacos/efectos de los fármacos , Hipertrofia Ventricular Izquierda/prevención & control , Oligopéptidos/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Aorta/fisiopatología , Aorta/cirugía , Proteínas de Unión al Calcio/metabolismo , Colágeno/metabolismo , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Ligadura , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Fosforilación , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo

RESUMEN

NEW FINDINGS: What is the central question of this study? How does swimming exercise training impact hydro-electrolytic balance, renal function, sympathetic contribution to resting blood pressure and cerebrospinal fluid (CSF) [Na+ ] in rats fed a high-sodium diet from weaning? What is the main finding and its importance? An exercise-dependent reduction in blood pressure was associated with decreased CSF [Na+ ], sympathetically driven vasomotor tonus and renal fibrosis indicating that the anti-hypertensive effects of swimming training in rats fed a high-sodium diet might involve neurogenic mechanisms regulated by sodium levels in the CSF rather than changes in blood volume. ABSTRACT: High sodium intake is an important factor associated with hypertension. High-sodium intake with exercise training can modify homeostatic hydro-electrolytic balance, but the effects of this association are mostly unknown. In this study, we sought to investigate the effects of swimming training (ST) on cerebrospinal fluid (CSF) Na+ concentration, sympathetic drive, blood pressure (BP) and renal function of rats fed a 0.9% Na+ (equivalent to 2% NaCl) diet with free access to water for 22 weeks after weaning. Male Wistar rats were assigned to two cohorts: (1) fed standard diet (SD) and (2) fed high-sodium (HS) diet. Each cohort was further divided into trained and sedentary groups. ST normalised BP levels of HS rats as well as the higher sympathetically related pressor activity assessed by pharmacological blockade of ganglionic transmission (hexamethonium). ST preserved the renal function and attenuated the glomerular shrinkage elicited by HS. No change in blood volume was found among the groups. CSF [Na+ ] levels were higher in sedentary HS rats but were reduced by ST. Our findings showed that ST effectively normalised BP of HS rats, independent of its effects on hydro-electrolytic balance, which might involve neurogenic mechanisms regulated by Na+ levels in the CSF as well as renal protection.

Asunto(s)

Sistema Nervioso Autónomo/fisiopatología , Presión Sanguínea/fisiología , Hipertensión/fisiopatología , Riñón/fisiopatología , Sodio en la Dieta , Animales , Sistema Nervioso Autónomo/patología , Dieta , Frecuencia Cardíaca/fisiología , Hipertensión/patología , Riñón/patología , Masculino , Condicionamiento Físico Animal , Ratas , Ratas Wistar , Natación , Equilibrio Hidroelectrolítico

RESUMEN

Telocytes are interstitial cells present in the stroma of several organs, including the prostate. There is evidence that these cells are present during prostate alveologenesis, in which these cells play a relevant role, but there is no information about the presence of and possible changes in telocytes during prostate aging. Throughout aging, the prostate undergoes several spontaneous changes in the stroma that are pro-pathogenic. Our study used histochemistry, 3D reconstructions, ultrastructure and immunofluorescence to compare the adult prostate with the senile prostate of the Mongolian gerbil, in order to investigate possible changes in telocytes with senescence and a possible role for these cells in the age-associated alterations. It was found that the layers of perialveolar smooth muscle become thinner as the prostatic alveoli become more dilated during aging, and that telocytes form a network that involves smooth muscle cells, which could possibly indicate a role for telocytes in maintaining the integrity of perialveolar smooth muscles. On the other hand, with senescence, VEGF+ telocytes are seen in stroma possibly contributing to angiogenesis, together with TNFR1+ telocytes, which are associated with a pro-inflammatory microenvironment in the prostate. Together, these data indicate that telocytes are important both in understanding the aging-related changes that are seen in the prostate and also in the search for new therapeutic targets for pathologies whose frequency increases with age.

Asunto(s)

Próstata/citología , Próstata/metabolismo , Telocitos/citología , Telocitos/metabolismo , Animales , Tejido Conectivo/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Técnicas In Vitro , Masculino , Microscopía Electrónica de Transmisión , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo

RESUMEN

The postlactational involution of the mammary gland is a complex process. It involves the collapse of the alveoli and the remodeling of the extracellular matrix, which in turn implies a complex set of interrelations between the epithelial, stromal, and extracellular matrix elements. The telocytes, a new type of CD34-positive stromal cell that differs from fibroblasts in morphological terms and gene expression, were detected in the stroma of several tissues, including the mammary gland; however, their function remains elusive. The present study employed three-dimensional reconstructions and immunohistochemical, ultrastructural, and immunofluorescence techniques in histological sections of the mammary gland of the Mongolian gerbil during lactation and postlactational involution to evaluate the presence of telocytes and to investigate a possible function for these cells. By means of immunofluorescence assays for CD34 and c-kit, major markers of telocytes, and also through morphological and ultrastructural evidences, telocytes were observed to surround the mammary ducts and collapsing alveoli. It was also found that these cells are associated with matrix metalloproteinase 9, which indicates that telocytes can play a role in extracellular matrix digestion, as well as vascular endothelial growth factor, a factor that promotes angiogenesis. Together, these data indicate that telocytes are a distinct cell type in the mammary gland and, for the first time, show that these cells possibly play a role in tissue remodeling and angiogenesis during the postlactional involution of the mammary gland.

Asunto(s)

Lactancia/metabolismo , Glándulas Mamarias Animales/fisiología , Telocitos/metabolismo , Animales , Antígenos CD34/metabolismo , Matriz Extracelular/metabolismo , Femenino , Expresión Génica/genética , Gerbillinae/metabolismo , Glándulas Mamarias Animales/metabolismo , Neovascularización Patológica/metabolismo , Células del Estroma/metabolismo , Telocitos/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

Telocytes are cells present in the stroma of various tissues including the prostate. The detection of telocytes is still very much dependent on obtaining ultrastructural data that show the presence of telopodes, which are cytoplasmic projections that alternate between dilated regions, the podoms, and thin segments, the podomers. These structures are the distinctive characteristics of the telocytes. Thus, in vitro assays are important for the study of telocytes, which are more easily identified in culture, which also enables the experimental manipulation of these cells. The isolation of telocytes per se does not allow the analysis of the behavior of these cells in relation to other cell types in a given organ. In this sense, in the prostate, explants could be a useful tool for the study of telocytes. The present study obtained prostatic explants and evaluated the influence of recombinant proteins, scattering factor (SCF) and stromal-derived factor 1 (SDF-1), which could impact on the migration of CD34-positive cells. Telocytes migrate out of explants and SDF-1 stimulates the proliferation and formation of telocyte networks in vitro. Telocytes are not smooth muscle cell progenitors in the prostate; on the contrary, they are CD90- and CD44-negative cells and, hence, have limited progenitor capacity. The present study demonstrated that explants are useful tools to elucidate the nature of telocytes and their functions.

Asunto(s)

Quimiocina CXCL12/metabolismo , Factor de Crecimiento de Hepatocito/metabolismo , Telocitos/metabolismo , Animales , Antígenos CD34/metabolismo , Técnicas de Cultivo de Célula/métodos , Gerbillinae , Masculino , Próstata/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Telocitos/fisiología

RESUMEN

The development and maintenance of prostate function depend on a fine balance between oestrogen and androgen levels. Finasteride inhibits 5α-reductase, which is responsible for the conversion of testosterone into its most active form, dihydrotestosterone. Enzymes that metabolize these hormones have a highly relevant role in both the normal prostate metabolism and in the occurrence of pathological conditions. There are few studies on the impact of finasteride on male prostate development and fewer studies on the female prostate and possible intersexual differences. Therefore, we treated male and female gerbils from 7 to 14 days in postnatal life with a high dose of finasteride (500 µg/kg/day); the prostate complexes were then removed and submitted to immunohistochemistry, immunofluorescence and three-dimensional reconstruction. In addition, hormonal serum dosages were administered. Treatment with finasteride resulted in an increased thickness of the periductal smooth musculature in the prostate of both male and female gerbils, such as well as a reduction in the thickness of developing prostate alveoli in both sexes. In addition, intersexual differences were observed as increased epithelial proliferation and decreases in the number of developing alveoli in females. Together, the data indicate that postnatal exposure to finasteride causes greater changes in the female gerbil prostate than in the male.

Asunto(s)

Finasterida/toxicidad , Gerbillinae/crecimiento & desarrollo , Próstata , Animales , Femenino , Masculino , Próstata/efectos de los fármacos , Próstata/crecimiento & desarrollo , Receptores Androgénicos/metabolismo , Testosterona/sangre

RESUMEN

The prostate is a gland that is not exclusively present in males, being also found in females of several mammalian species, including humans. There is evidence that the prostate in both sexes is affected by the same pathologies such as prostatitis, benign alterations and even cancer. In view of the difficulties of manipulating the prostate gland, the Mongolian gerbil (Meriones unguiculatus), a rodent species with high incidence of functional prostates in females, is widely used in studies of the female prostate. However, despite knowing much about the similarities between the female and male prostate, little emphasis has been placed on the differences between them. This review investigates the intersex differences in prostate development, physiology and pathogenesis. The female prostate develops earlier than in males and studies indicate that it is more sensitive to oestrogens than the male prostate, as well as being more sensitive to exposure to xenoestrogens, such as Bisphenol A and methylparaben, with a higher susceptibility to benign lesions in the adult and senile prostate than in males. In addition, the female prostate is impacted by pregnancy and the oestrous cycle, and is also dependent on progesterone. The peculiarities of the female prostate raise concerns about the risk of it undergoing neglected changes as a result of environmental chemicals, since safe dosages are established exclusively for the male prostate.

RESUMEN

The prostate is an accessory reproductive gland that is sensitive to the action of exogenous compounds known as endocrine disrupters that alter normal hormonal function. Finasteride is a widely used chemical that acts to inhibit the conversion of testosterone in its most active form, dihydrotestosterone. It is known that intrauterine exposure to finasteride causes changes in the male prostate even at low dosages; however, it is not known whether these dosages are capable of causing changes in the female prostate, which is present in a large number of mammalian species, including humans. In the present study, histochemistry, immunohistochemistry, immunofluorescence, serological dosages, and three-dimensional reconstruction techniques were employed to evaluate the effects of intrauterine exposure to a low dose of finasteride (100 µg.BW/d) on postnatal prostate development in male and female Mongolian gerbils. The results indicate that the gerbil female prostate also undergoes alterations following intrauterine exposure to finasteride, exhibiting a thickening of periductal smooth muscle and increased stromal proliferation. There are also intersex differences in the impact of exposure on the expression of the androgen receptor, which was increased in males, and of the estrogen-α receptor, which was decreased in the male prostate but unchanged in females. Altogether, this study indicates there are sex differences in the effects of finasteride exposure even at low dosages.

Asunto(s)

Desarrollo Embrionario/efectos de los fármacos , Disruptores Endocrinos/toxicidad , Finasterida/toxicidad , Genitales Femeninos/efectos de los fármacos , Gerbillinae/embriología , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Próstata/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Femenino , Genitales Femeninos/embriología , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Próstata/embriología , Receptores Androgénicos/metabolismo , Reproducción/efectos de los fármacos , Testosterona/metabolismo

RESUMEN

Finasteride is a drug that is widely used in the treatment of benign prostatic hyperplasia, hair loss and even as a chemotherapeutic agent in the treatment of prostatic adenocarcinoma. However, its use is known to cause several side effects in adults and it can also cause changes in the embryonic development of the male prostate, which is a cause for concern given the possibility of the accumulation of finasteride in the environment. Nevertheless, no studies have investigated the effects of finasteride on the development of the prostate in females, which occurs in several species of mammals. To evaluate the effects of intrauterine exposure to finasteride (500µgkg-1 day-1) on postnatal prostate development in the Mongolian gerbil in the present study, we used immunohistochemistry, immunofluorescence, serological analysis and three-dimensional reconstruction techniques. Differences were observed in the effects of finasteride on periductal smooth muscle and cell proliferation between the sexes, as well as intersex differences in the presence of the androgen receptor, which was elevated in males, and the oestrogen receptor ERα, which was increased in females. Together, the data indicate that the female prostate has its own hormone dynamics and that there are sex-specific differences in the way in which the female prostate reacts to prenatal exposure to finasteride.

Asunto(s)

Finasterida/farmacología , Gerbillinae/crecimiento & desarrollo , Efectos Tardíos de la Exposición Prenatal , Próstata/efectos de los fármacos , Próstata/crecimiento & desarrollo , Animales , Femenino , Inmunohistoquímica , Masculino , Organogénesis/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Efectos Tardíos de la Exposición Prenatal/veterinaria , Próstata/metabolismo , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Caracteres Sexuales

RESUMEN

Telocytes are CD34-positive cells with a fusiform cell body and long, thin cytoplasmic projections called telopodes. These cells were detected in the stroma of various organs, including the prostate. The prostate is a complex gland capable of undergoing involution due to low testosterone levels; and this condition can be reversed with testosterone replacement. Telocyte function in the mature prostate remains to be dermined, and it is not known whether telocytes can take place in tissue remodeling during prostate involution and regrowth. The present study employed structural, ultrastructural and immunohistochemical methods to investigate the telocyte's phenotypes in the ventral prostate (VP) from control (CT), castrated (CS) and testosterone replacement (TR) groups of adult male Wistar rats. Telocytes were found in the subepithelial, perimuscular and interstitical regions around glandular acini. Telocytes from CT animals have condensed chromatin and long and thin telopodes. In CS group, telocytes appeared quiescent and exhibited layers of folded up telopodes. After TR, telocytes presented loose chromatin, abundant rough endoplasmic reticulum and enlarged telopodes, closely associated with bundles of collagen fibrils. We called these cells "telocytes with a synthetic phenotype". As testosterone levels and glandular morphology returned toward to the CT group parameters, after 10 days of TR, these telocytes progressively switched to the normal phenotype. Our results demonstrate that telocytes exhibit phenotypic plasticity upon androgen manipulation and interact with fibroblast and smooth muscle cells to maintain glandular architecture in control animals and during tissue remodeling after hormonal manipulation.

Asunto(s)

Próstata/citología , Telocitos/citología , Propionato de Testosterona/administración & dosificación , Animales , Antígenos CD34/metabolismo , Masculino , Orquiectomía , Próstata/efectos de los fármacos , Próstata/crecimiento & desarrollo , Próstata/metabolismo , Ratas , Ratas Wistar , Telocitos/efectos de los fármacos , Telocitos/metabolismo , Testosterona/sangre , Propionato de Testosterona/farmacología

RESUMEN

The number of embryos produced by in vitro fertilization (IVF) has grown exponentially in recent years. Recently, for the first time, the number of embryos produced and transferred in vitro was significantly higher than the number developed in vivo worldwide. In this context, a particular boost occurred with ovum pick-up (OPU) and in vitro embryos produced in North America, and this technology is becoming more prominent for commercial dairy farms. However, despite many advances in recent decades, laboratories and companies are looking for methods and alternatives that can be used in collaboration with the existing process to improve it. Among the strategies used to improve the dairy industry are the use of genomic analysis for the selection of animals with desired traits or as an evaluation tool of oocyte and embryo quality, the optimization of the collection and use of gametes from prepubertal females and males, the effective use of sexed semen, and improvements in culture media and methods of embryo cryopreservation. Thus, this review aims to discuss the highlights of the commercial use of IVF and some strategies to increase the application of this technique in large-scale dairy programs.