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This report introduces a novel method, rabbit whole embryo culture (WEC) combined with toxicokinetics (TK), for toxicity testing. Rodent WEC has been extensively used for in vitro screening of developmental toxicity. To improve the reliability of in vitro data, it is important to consider TK and species specificity. To test the utility and effectiveness of this method, we investigated the toxic effect of thalidomide on rabbit embryos and its behavior in test systems both in vitro and in vivo under the same experimental condition. The data showed that thalidomide induced embryo malformations such as embryonic brain hypoplasia, short limb buds, and declined embryonic growth both in vitro and in vivo. The toxic effect increased with the increasing exposure of the embryo to thalidomide. In addition, we observed similar toxic effects and exposure-effect relationships in vivo and in vitro. Therefore, we preliminarily conclude that this new method can effectively predict and explain thalidomide toxicity. Furthermore, we investigated the behavior of test compounds in the WEC system for the first time, and this method is expected to be an important technique for in vitro toxicity study after extensive verification.
Assuntos
Embrião de Mamíferos/efeitos dos fármacos , Técnicas In Vitro/métodos , Teratogênicos/toxicidade , Testes de Toxicidade/métodos , Toxicocinética , Animais , Coelhos , Reprodutibilidade dos Testes , Testes de Toxicidade/instrumentaçãoRESUMO
This study investigates the inhibitory effect of astaxanthin (AST) on testosterone-induced benign prostatic hyperplasia (BPH) in rats. Except for the sham operation, BPH model rats were randomly assigned to five groups: the BPH model control rats, AST-treated BPH model rats (20 mg/kg, 40 mg/kg, and 80 mg/kg), and epristeride (EPR)-treated BPH model rats. After treatment, as compared with the BPH model control rats, the prostate and ventral prostate weights of the AST-treated rats decreased, while there was a marked decline in the 80 mg/kg AST-treated rats. The same effect was also observed in the prostate index and ventral prostate index. The proliferation characteristics of epithelia observed in the BPH model control group were gradually alleviated in the AST-treated rats. As compared with the BPH model control rats, lower epithelial thicknesses of prostates and fewer secretory granules in epithelia were observed in the AST-treated rats. The superoxide dismutase (SOD) activity of prostates increased in all the AST-treated rats with a significant increase in the 40 mg/kg and 80 mg/kg AST-treated rats. The testosterone (T) and dihydrotestosterone (DHT) levels of prostates in the AST-treated groups were lower than those in the BPH model control group, and a significant decline was found in the T level of prostates in the 40 g/kg and 80 mg/kg AST-treated rats and the DHT level of prostates in the 40 mg/kg AST-treated rats. These results indicate that AST might have an inhibitory effect on T-induced BPH in rats, possibly due to SOD activity regulation and T and DHT levels.
Assuntos
Peixes , Próstata/efeitos dos fármacos , Hiperplasia Prostática/prevenção & controle , Animais , Organismos Aquáticos , Modelos Animais de Doenças , Masculino , Hiperplasia Prostática/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Organismos Livres de Patógenos Específicos , Testosterona , Xantofilas/química , Xantofilas/farmacologiaRESUMO
BACKGROUND: The Qilin pill (QLP) is a traditional Chinese compound prescription comprising 15 herbs that has demonstrated significant therapeutic effects on premature ovarian insufficiency (POI) in recent years. However, a pharmacological evaluation of QLP on ovarian function remains to be conducted, and the key mechanism of QLP treatment on POI is unclear. METHODS: Premature ovarian insufficiency rats were established by bilateral partial ovariectomy. The model rats were administrated with low (QLP-L), medium (QLP-M) and high (QLP-H) doses of QLP for 4 weeks to evaluate the ovarian function in terms of estrous cycle, hormone level, and follicle count. The mechanism of QLP in the treatment of POI was systematically explored by network pharmacology, and expression levels of the MAPK and PI3K-AKT signaling pathways were verified by Western blotting and molecular docking. RESULTS: The rat model of resection-induced POI was successfully established, and QLP could significantly recover the estrous cycle, decrease serum FSH levels, and decelerate follicle depletion after 4 weeks of administration. The optimal dose of QLP in the experiment was preliminarily determined to be 0.9 g/kg. Based on the network pharmacology methods, we constructed the compound-target network and protein protein interaction (PPI) network of QLP for the treatment of POI. The experimental verification of the enrichment analysis showed that QLP inhibited the MAPK and PI3K-AKT signaling pathways, and the key compounds and key targets involved were verified by molecular docking. CONCLUSION: QLP exerted significant therapeutic effects on resection-induced POI rats, and this was achieved by the inhibition of the MAPK and PI3K-AKT signaling pathways. This study is the first to systematically investigate the effects and mechanism of QLP on POI rats, which will provide valuable guidance in clinic.
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Medicamentos de Ervas Chinesas/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Insuficiência Ovariana Primária/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Feminino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Ovariectomia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
This study aimed to identify prostaglandin synthases (PGS) that mediate bisphenol A (BPA)-induced prostatic hyperplasia and explore their underlying mechanisms. In an in vivo study, male adult Sprague-Dawley rats were treated with different concentrations of BPA (10, 30, 90, or 270 µg/kg, i.g., daily), or with vehicle for 4 weeks. Results revealed that low-dose BPA induced prostatic hyperplasia with increased PCNA/TUNEL ratio. It significantly upregulated the expression of cyclooxygenase-2 (COX-2) and NF-κB in the dorsolateral prostate (P < 0.05) and the expression of lipocalin-type prostaglandin D synthase (L-PGDS) in ventral prostate (P < 0.05). The level of estradiol (E2)/testosterone (T) and expression of androgen receptor (AR) and estrogen receptor α (ERα) were also altered. In vitro studies showed that low-dose BPA (0.1-10 nM) promoted the proliferation of human prostate fibroblasts and epithelial cells, and significantly upregulated the expression of COX-2 and L-PGDS in the cells. The two types of cell proliferation induced by BPA were inhibited by COX-2 inhibitor (NS398) and L-PGDS inhibitor (AT56), with increased apoptosis level. These findings suggested that COX-2 and L-PGDS could mediate low-dose BPA-induced prostatic hyperplasia through pathways involved in cell proliferation and apoptosis, which might be related to the functions of ERα and AR. The role of COX-2/NF-κB pathway in dorsolateral prostate requires further research.
Assuntos
Compostos Benzidrílicos/farmacologia , Ciclo-Oxigenase 2/metabolismo , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/metabolismo , Fenóis/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estradiol/sangue , Receptor alfa de Estrogênio/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Hiperplasia Prostática/sangue , Hiperplasia Prostática/patologia , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Testosterona/sangueRESUMO
The aim of the present study was to establish an animal model of prostatic hyperplasia to explore the mechanisms of this disease. Sulpiride, a specific type 2 dopamine receptor antagonist, causes prostate toxicity by stimulating prolactin (PRL) production. Male Brown-Norway (BN) rats were treated intragastrically (i.g.) with sulpiride (40 and 120 mg/kg daily) and vehicle (i.g., daily) for 4 weeks. The results demonstrated that sulpiride-treatment resulted in increased prostate size, prostate lobe weight, epithelial height and acinar luminal area. Furthermore, prostate lobe weight, epithelial height and acinar luminal area of lateral lobes (LP) significantly increased. These effects were dose dependent. Sulpiride treatment increased serum PRL, follicle-stimulating hormone and testosterone levels, while serum luteinizing hormone levels were reduced. Immunohistochemical analysis revealed that proliferating cell nuclear antigen and B-cell lymphoma-2 were significantly increased in certain sulpiride treated groups. Furthermore, estrogen receptor (ER)-α and androgen receptors were upregulated, while ERß was downregulated in LP. The expression of stromal cell biomarkers, including vimentin, fibronectin and α-smooth muscle actin were significantly increased in LP following 40 mg/kg sulpiride administration. These results suggest that sulpiride causes LP hyperplasia in BN rats by promoting proliferation and inhibiting prostate cell apoptosis via ERα and AR signaling.
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Prostate is sensitive to endocrine hormone level, and the synergetic effect of estrogen and androgen is critical in prostate growth. The change of signal pathways caused by the imbalance of estrogen and androgen might function in the occurrence of prostate diseases. As a well-known endocrine disruptor compound, bisphenol A (BPA) can disturb the normal function of endocrine hormone and affect prostate development. This study aims to investigate effects of BPA on the dorsolateral prostate (DLP) and the related gene expression of the tissue in adult Sprague-Dawley (SD) rats and to explore the mechanism for the effect of low-dose BPA on DLP hyperplasia. Three-month-old male SD rats were treated with BPA (10.0, 30.0, or 90.0 µg (kg.day)-1, gavage) or vehicle (gavage) for 4 weeks. BPA significantly increased the DLP weight, the DLP organ coefficient, and the prostate epithelium height (p < 0.01) of rats dose-dependently. Microarray analysis and quantitative real-time polymerase chain reaction showed that BPA significantly upregulated the transcriptional levels of some genes, including pituitary tumor transforming gene 1, epidermal growth factor, Sh3kbp1, and Pcna. Furthermore, the expression of PCNA (p < 0.01), androgen receptor (p < 0.01), and EGF receptor (EGFR) (p < 0.001) in DLP was increased significantly by BPA treatment, and the expression of estrogen receptor alpha was also upregulated. The findings evidenced that low-dose BPA could induce DLP hyperplasia in adult rats, and the upregulated EGF/EGFR pathway that was responsive to estrogen and androgen might play an essential role in the DLP hyperplasia induced by low-dose BPA.
Assuntos
Compostos Benzidrílicos/farmacologia , Disruptores Endócrinos/farmacologia , Receptores ErbB/biossíntese , Fenóis/farmacologia , Próstata/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Hiperplasia , Masculino , Ratos , Ratos Sprague-Dawley , Testosterona/metabolismo , Regulação para CimaRESUMO
Benign prostatic hyperplasia (BPH) develops more likely with increasing age and changing serum concentrations of circulating estradiol (E2) and/or testosterone (T). In this study, we explored the relationship between serum E2/T ratio and BPH risk in rats by fitting a mathematical model. A total of 176 rats were randomized to one of the following treatment groups: normal control, castrated control, and 20 more groups of castrated animals treated with increasing dose combinations of T and E2, once daily for 30 days. Serial blood samples were obtained to determine serum T and E2 levels by magnetic bead enzyme-linked immunosorbent assay. Prostate tissue was taken to measure prostate volume. MATLAB software was used to simulate the relationship between prostate/body weight ratio (PBR) and E2/T ratio with a mathematical equation. The values of PBR, E2 and T in the treatment groups were significantly higher than those in the control groups. Stepwise regression showed that PBR was a function of E2 and T. PBR = -0.1782 + 0.0081 E2 + 0.063 T - 0.6 × 10-5 E22 - 0.28 × 10-3 T2. E2/T ratio change may be one of the risk factors for PBR, which is associated with the development of BPH.
Assuntos
Estradiol/sangue , Modelos Teóricos , Hiperplasia Prostática/diagnóstico , Testosterona/sangue , Animais , Simulação por Computador , Modelos Animais de Doenças , Humanos , Masculino , Valor Preditivo dos Testes , Prognóstico , Hiperplasia Prostática/sangue , Hiperplasia Prostática/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Prostate cancer (PCa) is the second most frequently diagnosed cancer and the fifth leading cause of death from cancer in men worldwide. Increased understanding of the prostate cancer metastasis mechanisms will help identify more efficient intervention strategies to prevent or treat this deadly disease in the future. To identify the candidate proteins that contribute to metastasis of PCa, isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis was performed to explore differentially expressed proteins between two homologous human prostate cancer cell lines including highly-metastatic PC-3M-1E8 cell line and poorly-metastatic PC-3M-2B4 cell line. Here, a total of 58 proteins were identified to be significantly differentially expressed between PC-3M-1E8 and PC-3M-2B4 cells, which were further verified using real-time quantitative PCR and western blot analysis. The bioinformatic analysis suggested that the differentially expressed proteins, like MMP1 and FHL1, may contribute to the higher metastatic ability of PC-3M-1E8 cells than PC-3M-2B4 cells. In addition, functional analyses proved MMP1's positive effect on the higher metastatic ability of PC-3M-1E8 cells than PC-3M-2B4 cells. These findings provided a unique resource to specifically reveal the complex molecular regulatory mechanisms underlying the progression of prostate cancer from poorly-metastatic to highly-metastatic stage.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Proteínas Musculares/metabolismo , Neoplasias da Próstata/metabolismo , Proteômica/métodos , Linhagem Celular Tumoral , Movimento Celular , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Masculino , Metaloproteinase 1 da Matriz/genética , Proteínas Musculares/genética , Metástase Neoplásica , Neoplasias da Próstata/genética , Mapas de Interação de ProteínasRESUMO
To study the chronic hepatotoxicity of Chinese medicine Zishen Yutai pill (ZYP) prepared from Polygonum multiflorum with the recommended dosage in normal Beagle dogs. Low, middle and high doses of ZYP (1.5, 3.0, 6.0 g·kg⻹; i.e. 3×, 6× and 12× equivalent doses) were given orally to dogs for 39 consecutive weeks. At the same time, the same volume of deionized water was used as the solvent control group, one time a day. The general condition of the animals was observed every day during the period of administration, and the blood was collected before and 13, 26, 39, 43 weeks after administration to detect the biomarkers related to the hepatotoxicity of the dog serum. 2/7, 3/7 and 2/7 animals were dissected after 13, 39, and 43 weeks of administration to observe the pathological changes of the animal organs, weigh the mass of main organs and conduct pathological examination of the liver. As compared to the solvent control group, 11 liver hepatotoxicity traditional biomarkers such as ALT, AST were found no ZYP-related changes at month 3, 6, 9 of the administration and month 1 in recovery period; There was no significant difference in liver viscera index and liver pathology. Therefore, no obvious hepatotoxicity was shown by ZYP administered up to 6.0 g·kg⻹ for 9 months in normal dogs at doses of 1.5, 3.0, and 6.0 g·kg⻹.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas/toxicidade , Plantas Medicinais/toxicidade , Polygonum/toxicidade , Animais , Biomarcadores/sangue , Cães , Raízes de Plantas/toxicidadeRESUMO
Prostate-specific antigen (PSA) is a biomarker for the diagnosis and management of prostate cancer and involved in the development of prostate cancer and/or its progression from the localized to the metastatic stage. This review presents an overview of the roles of PSA in promoting the progression and metastasis of human prostate cancer and its underlying mechanisms, including its serine protease activity, interaction with the cellular membrane receptor, and suppression of specific immune responsiveness, and also points out some of the key problems to be solved.
Assuntos
Antígeno Prostático Específico/fisiologia , Neoplasias da Próstata/patologia , Progressão da Doença , Humanos , Masculino , Metástase NeoplásicaRESUMO
PURPOSE: Folic acid (FA) intake has increased to high levels in many countries for the prevention of neural tube defects. However, the impact of excess FA intake, particularly before and during pregnancy, requires further investigation. Our aim was to investigate the effect of maternal folic acid supplementation on prostatitis risk in the rat offspring. METHODS: Female SD rats were administrated with different doses of FA by oral gavage from 2 weeks prior to mating to GD14: 0 mg/kg (distilled water), 0.2 mg/kg FA and 2.0 mg/kg FA respectively. The male rat offspring from each maternal FA group were castrated on PND56 and injected different doses of 17ß-estradiol (E2) subcutaneously for 30 days to induce prostatitis: 0 mg/kg (corn oil) and 1.25 mg/kg E2 respectively. At necropsy, the prostates were collected for histopathological analysis. Fasting blood was collected for the determination of serum E2, T, DHT, and folic acid levels. The expression of TNF-α, COX-2, and ER-α was determined by immunohistochemistry. RESULTS: High-dose (2.0 mg/kg) maternal folic acid supplementation significantly increased the proportion of prostatitis in FA(2.0) + E2(1.25) group (87.5%) compared with FA(0) + E2(1.25) group (25%). The inflammation was focal and severe, and large amounts of inflammatory cells appeared in different regions of the prostate in FA(2.0) + E2(1.25) group. The serum T, DHT, and FA levels in FA(2.0) + E2(1.25) group were significantly higher than those in FA(0) + E2(1.25) group. The expression of TNF-α, COX-2, and ER-α in three 1.25 mg/kg E2 groups presented positive, and the number and distribution of positive cells increased as FA dosage increased. CONCLUSIONS: Our findings suggest that high-dose (2.0 mg/kg) maternal folic acid supplementation significantly increases the proportion of prostatitis and the prostatic inflammation is more obvious and severe in the rat offspring.
Assuntos
Suplementos Nutricionais/efeitos adversos , Ácido Fólico/efeitos adversos , Fenômenos Fisiológicos da Nutrição Pré-Natal , Prostatite/etiologia , Complexo Vitamínico B/efeitos adversos , Animais , Feminino , Masculino , Gravidez , Prostatite/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Cimetidine is widely used for the treatment of digestive tract ulcers, but it induces testis injury. To explore the mechanisms underlying cimetidine-induced toxicity towards the testis, the effects of oral cimetidine on the reproductive system of male rats were assessed. Cimetidine was orally administered to male rats at 20, 40 or 120 mg/kg/day for 9 weeks. The rats were then euthanized, and serum, testis, epididymis, prostate gland, seminal vesicle, preputial gland, levator ani muscle and sphincter ani samples were collected. Sperm parameters were obtained by computer-assisted sperm analysis. Serum hormone levels were measured by ELISA. Protein expression levels were detected by immunohistochemistry. Apoptosis was assessed with the DeadEnd™ Colorimetric Apoptosis Detection System. The results indicated that the sperm average path velocity, straight line velocity and curvilinear velocity were significantly decreased in the 120 mg/kg cimetidine group compared with the control group, while luteinizing hormone and testosterone levels were significantly higher compared with the control group. Testicular lesions were observed by histopathology in the 120 mg/kg cimetidine group. The amounts of cells positive for cyclooxygenase-2 (COX-2) and nuclear factor κB (NF-κB) were increased in the 120 mg/kg cimetidine group compared with the control group. The amounts of cells positive for iNOS were increased in all cimetidine treatment groups. In addition, apoptotic cells were significantly more abundant in the 120 mg/kg cimetidine group compared with the control group, as indicated by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling. Overall, 9 weeks of oral cimetidine induced pathological changes in the testicles and hormone secretion disorder in rats. COX-2, iNOS and NF-κB upregulation and induction of apoptosis may be associated with the reproductive toxicity caused by cimetidine.
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As an ubiquitous environmental endocrine disruptor, di(2-ethylhexyl) phthalate (DEHP) has been shown to interfere with the development of reproductive organs and induce pathological changes in prostate. Our previous finding showed that in utero and lactational (IUL) DEHP exposure could disrupt the balance of testosterone and estrogen and increase the susceptibility of prostate carcinogenesis. The purpose of this study is to investigate whether the early-life specific epigenetic modifications could mediate the effect of DEHP exposure on prostate carcinogenesis in rodents, for epigenetic modifications play important roles in regulating prostate carcinogenesis. The pregnant rats were treated with corn oil (negative control) or DEHP at 0.01, 0.1 and 1â¯mg/kg BW/day from GD7 to PND21. On PND21, the expression and DNA methylation change of six prostate carcinogenesis-related genes (ESR2/GSTP1/NKX3.1/PSCA/PTGS2/Rassf1a) were assessed through SYBR-Green real-time PCR combined with pyrosequencing assay in F1 male offspring. On PND196, the relationship b(STP1, PSCA and PTGS2 in a dose-dependent manner, which were positively correlated with PIN scores, Gleason scores, serum PSA concentrations and negatively correlated with prostate/body weight ratio on PND196. Meanwhile, 1â¯mg/kg BW/day DEHP markedly reduced DNA methylation level of PSCA in all studied CpG sites. Significant inverse correlations between methylation levels of the promoter CpG site and PSCA mRNA expression were observed. These results indicated that transcriptional changes of GSTP1, PSCA and PTGS2 induced by DEHP exposure might be contribute to the increasing susceptibility of prostate carcinogenesis in late life. Moreover, hypomethylation of PSCA could mediate the effect of DEHP on prostate carcinogenesis in rats.
Assuntos
Antígenos de Neoplasias/genética , Metilação de DNA/efeitos dos fármacos , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Proteínas Ligadas por GPI/genética , Lactação , Proteínas de Neoplasias/genética , Plastificantes/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Neoplasias da Próstata/induzido quimicamente , Fatores Etários , Animais , Animais Recém-Nascidos , Antígenos de Neoplasias/metabolismo , Ilhas de CpG , Relação Dose-Resposta a Droga , Feminino , Proteínas Ligadas por GPI/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Idade Gestacional , Masculino , Exposição Materna , Proteínas de Neoplasias/metabolismo , Gravidez , Regiões Promotoras Genéticas , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transcrição Gênica/efeitos dos fármacosRESUMO
Bisphenol A (BPA) is a well-known endocrine disruptor compound reported to have prostate toxicity. This study aimed to assess the effect of BPA on the proliferation of dorsolateral prostate (DLP) and the expression of epithelial-mesenchymal transition (EMT)-related genes in aged rats. Male aged SD rats were treated with BPA (10.0, 30.0, and 90.0 µg/kg i.g., daily) or vehicle (i.g., daily) for 3 months. Treatment with BPA resulted in increased the expression of PCNA, DLP weight and DLP epithelial height compared with the control group (P < 0.01); such effects were more obvious at higher BPA doses. 90 µg/kg BPA significantly increased the estrogen to androgen ratio (P < 0.05). The EMT chip showed the BPA induced upregulation of vimentin, Snail, Twist1, and transforming growth factor beta 1, as well as the downregulation of E-cadherin in the DLP. Immunohistochemical data showed that the expression of vimentin, estrogen receptor subtypes, and androgen receptor increased and the expression of E-cadherin decreased in 30 and 90 µg/kg BPA groups. It was concluded that environmental exposure to low doses of BPA might promote the proliferation of DLP in aged rats by increasing the estrogen to androgen ratio and inducing EMT.
Assuntos
Compostos Benzidrílicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fenóis/toxicidade , Animais , Caderinas/genética , Caderinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Testosterona/sangue , Regulação para Cima/efeitos dos fármacos , Vimentina/genética , Vimentina/metabolismoRESUMO
Cardiac fibrosis, denoted by the deposition of extracellular matrix, manifests with a variety of diseases such as hypertension, diabetes, and myocardial infarction. Underlying this pathological extracellular matrix secretion is an expansion of fibroblasts. The mouse is now a common experimental model system for the study of cardiovascular remodeling and elucidation of fibroblast responses to cardiac growth and stress is vital for understanding disease processes. Here, using diverse but fibroblast specific markers, we report murine fibroblast distribution and proliferation in early postnatal, adult, and injured hearts. We find that perinatal fibroblasts and endothelial cells proliferate at similar rates. Furthermore, regardless of the injury model, fibroblast proliferation peaks within the first week after injury, a time window similar to the period of the inflammatory phase. In addition, fibroblast densities remain high weeks after the initial insult. These results provide detailed information regarding fibroblast distribution and proliferation in experimental methods of heart injury.
Assuntos
Fibroblastos/patologia , Coração/crescimento & desenvolvimento , Remodelação Ventricular , Animais , Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Coração/efeitos dos fármacos , Isoproterenol/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/patologia , Pressão , Receptores Adrenérgicos beta/metabolismo , Remodelação Ventricular/efeitos dos fármacosRESUMO
Bisphenol A (BPA) is a well-known endocrine disruptor compound (EDC) that aggravates testosterone-induced benign prostate hyperplasia by increasing the relative weight of the ventral and dorsolateral prostate in rats. This phenomenon is primarily attributed to the exogenous estrogen effect of BPA. However, the direct effect of BPA on prostate cells has not been characterized. The present study investigated the proliferative effect and possible mechanisms of action of BPA on the prostatic epithelium of rats. The ventral prostate epithelial cells were cultured in vitro and the proliferation effects of BPA on cells were studied. The cells were identified as prostatic epithelial cells, and cell viability, cell apoptosis and the expressions of androgen receptors (AR) and estrogen receptors (ER), were detected. It was observed that 0.01-1 nM BPA promoted cell growth, with 1 nM BPA inducing the greatest increase in the rate of cell growth. However, BPA-treated cells exhibited no marked morphological changes compared with the control group. The cell apoptosis rate in each BPA-treated group was lower compared with the control group. The expression levels of ERα and ERß increased, but the expression of AR decreased. The present study demonstrated that environmental exposure to BPA directly promoted the proliferation of prostate cells in rats through increasing the expression of estrogen receptors, reducing the expression of androgen receptors of the cells and decreasing apoptosis-induced cell death.
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The purpose of this study is to identify the potential of a two-dimensional preantral follicle culture as an in vitro model of predicting premature ovarian failure. The two-dimensional preantral follicles culture method was established by cultivating preantral follicles collected from ICR F1 hybrids (aged 12-14days) for 12days. The preantral follicles were incubated with 0.54mg/ml cyclophosphamide, 0.5mg/ml busulfan, 0.12mg/ml cisplatin, 3.12mg/ml 4-vinylcyclohexene diepoxide, 5mg/ml D (+) galactose, and 0.5mg/ml hydrocortisone for 24h at culture days 2, 6 and 11. The diameter of follicles, the cumulus-oocyte complex number and the maturity of oocytes were recorded as the parameters to detect follicular maturation induced by the culture agents. The results indicated that, except for busulfan, D (+) galactose, and hydrocortisone, such test articles could significantly decrease follicular growth (p<0.05 or p<0.01), and induce oocyte degeneration and follicle atresia when the follicles were treated at day 2. With the exception of hydrocortisone, such agents also gradually decreased follicular development (p<0.05 or p<0.01) when the follicles were treated at day 6. All of the test articles but hydrocortisone can interfere with the ovulation, the cumulus-oocyte complex discharge and oocyte maturation of follicles when treated at days 2, 6 and 11. It is suggested that two-dimensional preantral follicle culture could be utilized as a potential in vitro system to mimic the POF model. It may also be employed in screening potential ovarian toxic agents, reducing laboratory animal use and promoting animal welfare.
Assuntos
Técnicas de Cultura de Células/métodos , Modelos Animais de Doenças , Folículo Ovariano/efeitos dos fármacos , Insuficiência Ovariana Primária , Animais , Feminino , Camundongos , Camundongos Endogâmicos ICRRESUMO
di(2-ethylhexyl) phthalate (DEHP) is one of the most commonly-used plasticizers and can exert estrogen-like effects and anti-androgen-like effects after entering the body. The critical windows for DEHP exposure are in utero and during lactation. There's substantial evidence that hormonally active environmental estrogen perturbations in early life are associated with prostate carcinogenesis susceptibility later in life. In order to explore the effects of in utero and lactational exposure to DEHP on the male offspring's susceptibility to prostate carcinogenesis, we established a rat model of developmental estrogenization: pregnant rats in three treatment groups were treated with DEHP at 0.01, 0.1 and 1mg/kg BW/day from GD7 to PND21, and the male pups in positive group were treated with EB at 25ug/pup on PND 1, 3, 5. In order to induce the prostate carcinogenesis, half of the male offspring were given implants packed with estradiol and testosterone, and the other half were given empty tubes on PND90. The prostate weight, concentration of PSA in serum and histopathological changes were measured in male offspring on PND196. Data was analyzed by one-way analysis of variance (ANOVA) and x2 using SPSS Statistics software. Results showed that in utero treatment of DEHP decreased the prostate weight, prostate/body weight ratio and increased PSA concentrations of male pups in a dose-dependent manner. Compared with non-T+E treatment groups, T+E treatment increased the prostate weight and ratio of prostate/body weight, as well as the concentration of PSA. The results of prostate carcinogenesis parameters including PIN scores/frequency and Gleason scores/frequency were consistent with PSA, which meant that in utero and lactational exposure of DEHP was a risk factor of prostate carcinogenesis, and the increased estrogen/testosterone (E/T) ratio in adult might exert synergistic effects in the process of prostate carcinogenesis formation.
Assuntos
Carcinogênese/efeitos dos fármacos , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Plastificantes/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Próstata/efeitos dos fármacos , Animais , Epididimo/efeitos dos fármacos , Epididimo/patologia , Estrogênios/farmacologia , Feminino , Lactação , Masculino , Troca Materno-Fetal , Gradação de Tumores , Gravidez , Próstata/patologia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Ratos , Ratos Sprague-Dawley , Fatores de Risco , Testículo/efeitos dos fármacos , Testículo/patologia , Testosterona/farmacologiaRESUMO
Prostaglandin synthase (PGS) can catalyze the production of various types of prostaglandins and regulate the expression levels of related substances. The regulation mechanisms of the PGS gene are closely related with the occurrence and development of prostate diseases. However, few studies are reported on the regulation mechanisms of PGS in prostatic diseases, such as benign prostatic hyperplasia (BPH) and prostate cancer (PCa), or on the relationship between PGS gene regulation and prostate diseases. This review aims to analyze their correlation and provide some ideas for the prevention and control of BPH and PCa by intervention of the prostaglandin synthase regulatory pathway.
Assuntos
Regulação da Expressão Gênica , Prostaglandina-Endoperóxido Sintases/genética , Hiperplasia Prostática/prevenção & controle , Neoplasias da Próstata/prevenção & controle , Humanos , Masculino , Prostaglandina-Endoperóxido Sintases/fisiologia , Hiperplasia Prostática/enzimologia , Hiperplasia Prostática/genética , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genéticaRESUMO
LHRH receptor, is over-expressed in a variety of human tumors and, is a potential binding site for targeted metastatic prostate cancer therapy. The objectives of our study were to synthesize a bioconjugate of the LHRH analog [DLys6]-LHRH and the anti-tumor agent methotrexate and test the hypothesis that [DLys6]-LHRH-MTX targets and inhibits prostate cancer cell growth in vitro and in vivo. The results of in vitro studies, showed that both [DLys6]-LHRH-MTX and MTX displayed superior cytotoxicity against prostate cancer cells in a concentration-dependent manners, with IC50 concentrations for PC-3 cells of, 1.02 ± 0.18 µmol/L and 6.34 ± 1.01 µmol/L; for DU-145 cells, 1.53 ± 0.27 µmol/L and 8.03 ± 1.29 µmol/L; and for LNCaP cells, 1.93 ± 0.19 µmol/L and 9.68 ± 1.24 µmol/L, respectively. The IC50 values of [DLys6]-LHRH-MTX and MTX were 110.77 ± 15.31 µmol/L and 42.33 ± 7.25 µmol/L, respectively. Finally, [DLys6]-LHRH-MTX significantly improved the anti-tumor activity of MTX in nude mice bearing PC-3 tumor xenografts. The inhibition ratios of tumor volume and tumor weight in the [DLys6]-LHRH-MTX treated group were significantly higher than those in the MTX-treated group. Tumor volume doubling time was also significantly extended from 6.13 days in control animals to 9.67 days in mice treated with [DLys6]-LHRH-MTX. In conclusion, [DLys6]-LHRH -MTX may be useful in treating prostate cancer.