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1.
Cell Prolif ; 53(2): e12756, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31943490

RESUMO

OBJECTIVES: To evaluate the rapid repair potential of adipose-derived stem cells (ADSCs) co-overexpressing VEGF and GDNF on bilateral cavernous nerve injury (BCNI) in rat models. Progressive fibrosis of the penis that occurs shortly after BCNI is a key cause of clinical treatment difficulty of erectile dysfunction (ED). Traditional medications are ineffective for ED caused by BCNI. ADSCs have shown therapeutic effects in animal models, but disappointing in clinical treatment suggests that we should explore optimal treatment of it. MATERIALS AND METHODS: We extracted ADSCs from rat epididymis. Lentiviral transfection was verified by western blot and immunofluorescence. Thirty-six SD rats (10 weeks old) were randomly divided into six groups (n = 6 per group): sham surgery, and remaining five BCNI groups transplanted PBS or ADSCs which were genetically modified by vehicle, VEGF (ADSC-V), GDNF (ADSC-G), or VEGF&GDNF (ADSC-G&V) around major pelvic ganglion (MPG). We investigated the therapeutic effects of BCNI rat model which is characterized by ED, penile tissue fibrosis and hypoxia, and lack of nitrogen nerves or vascular atrophy. RESULTS: Erectile function was almost recovered after 2 weeks of transplantation of ADSC-G&V, promoted cavernous nerve repair, prevented penile fibrosis and preserving the vascular endothelium, which was significant differences amongst ADSC-V or ADSC-G. Moreover, GM-ADSCs were detected in MPG and penis, indicating that their participation in repair of target organs and transverse nerves. CONCLUSIONS: These promising data indicate that ADSCs co-overexpressed VEGF and GDNF-induced synergistic effects, make it a potential tool for recovering of erectile function speedily after BCNI.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Disfunção Erétil/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Neurogênese/fisiologia , Células-Tronco/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Masculino , Ereção Peniana/fisiologia , Pênis/metabolismo , Ratos , Ratos Sprague-Dawley , Transplante de Células-Tronco
3.
Andrologia ; 51(9): e13344, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31206753

RESUMO

To investigate whether low androgen status affects erectile function by regulating the expression of adenosine A2A and A2B receptors in rat penile corpus cavernosum. Thirty-six 8-week-old male Sprague-Dawley rats were randomly divided into six groups: sham-operated group (4w-sham, 8w-sham), castration group (4w-cast, 8w-cast) and androgen replacement group (4w-cast+T, 8w-cast+T). The rats in the androgen replacement groups were subcutaneously injected with testosterone propionate (3 mg/kg) every other day after castration. The maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP), the expression of A2A , A2B , AKT and eNOS and the concentrations of cAMP and cGMP in the corpus cavernosum were detected at the 4th and 8th weeks after the operation. The serum testosterone level and the ratio of ICPmax/MAP decreased significantly in the castration group as compared to other groups (p < 0.01). There was no significant difference in the expression of A2A receptor among groups, while the expression of A2B , AKT and eNOS and the concentrations of cAMP and cGMP in the castration group were significantly lower than in other groups (p < 0.01). Low androgen status inhibits the AKT/eNOS/cGMP signalling pathways and the production of cAMP in the corpus cavernosum of castrated rats by down-regulating the expression of A2B receptor, and results in decreased of ICPmax/MAP.


Assuntos
Androgênios/metabolismo , Disfunção Erétil/fisiopatologia , Pênis/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptor A2B de Adenosina/metabolismo , Androgênios/sangue , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/etiologia , Terapia de Reposição Hormonal/métodos , Humanos , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Orquiectomia/efeitos adversos , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/fisiologia , Pênis/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Propionato de Testosterona/administração & dosagem
4.
Eur J Pharmacol ; 858: 172447, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31228454

RESUMO

Mirabegron is the first ß3-adrenoceptor agonist approved on the market and may offer beneficial pharmacological action in patients with overactive bladder and erectile dysfunction. Here, we further investigate the mechanisms by which mirabegron induces rat corpus cavernosum (CC) relaxation. Adult male Wistar rats were used. The CC were isolated for in vitro functional assays and ß-adrenoceptors subtypes mRNA expression evaluation. Animals were treated orally with mirabegron (30 mg/kg, 3 h), tadalafil (10 mg/kg, 3 h) or both for intracavernous pressure (ICP). Intracellular levels of cAMP and cGMP were also determined. The ß1-, ß2- and ß3-adrenoceptors subtypes were expressed in rat CC. Mirabegron produced concentration-dependent CC relaxations that were unaffected by the ß1-, ß2- or ß3-adrenoceptor antagonists atenolol (1 µM), ICI-118,551 (1 µM) and L748,337 (10 µM), respectively. Mirabegron-induced relaxations were not affected by the phosphodiesterase type 4 inhibitor, rolipram, or the adenylyl cyclase selective inhibitor, SQ 22,536. Potassium channel- or calcium influx-blockade are not involved in mirabegron-induced relaxations. In contrast, mirabegron produced rightward shifts in the contractile response induced by the α1-adrenoceptor agonist, phenylephrine. Finally, cavernous nerve stimulation caused frequency-dependent ICP increases, which were significantly increased in rats treated with mirabegron in a similar degree of tadalafil-treated rat, without promoting a significant cAMP or cGMP accumulation. Together, our results demonstrate that mirabegron induced CC relaxation through α1-adrenoceptor blockade. Care should be taken to translate the effect of mirabegron into the clinic, especially when using rat as an animal model of erectile dysfunction.


Assuntos
Acetanilidas/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Ereção Peniana/efeitos dos fármacos , Pênis/efeitos dos fármacos , Pênis/fisiologia , Tiazóis/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Masculino , Contração Muscular/efeitos dos fármacos , Pênis/citologia , Pênis/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/genética
5.
Biomed Pharmacother ; 111: 1029-1035, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841416

RESUMO

Sexual dysfunction is a side effect of the antidepressant drug paroxetine. Anogeissus leiocarpus is a medicinal plant with a wide range of biological activities which include antioxidant and antiulcer properties. With these in mind, we investigated the effect of Anogeissus leiocarpus stem bark extract on paroxetine-induced sexual dysfunction in male Wistar rats. Forty-two adult male Wistar rats were divided into seven experimental groups: normal control, PAR (10 mg/kg), PAR + sildenafil (5 mg/kg), ALE (50 and 100 mg/kg) and PAR + ALE (50 and 100 mg/kg). The experiment lasted for 21 days, after which the rats were subjected to sexual behavioral test. Various biochemical assays (phosphodiesterase-5, arginase, acetylcholinesterase, nitric oxide and MDA) were carried out on the penile tissue homogenate. From our findings, paroxetine significantly altered sexual behavior in male rats and increased phosphodiesterase-5, arginase and acetylcholinesterase activities with a concomitant decrease in nitric oxide level. Furthermore, paroxetine altered antioxidant status which revealed by increased MDA level and reduced thiol level. However, treatment with Anogeissus leiocarpus stem bark extract reversed the altered sexual behavior in male rats and boosted antioxidant status. In addition, administration of Anogeissus leiocarpus stem bark extract resulted in a significant attenuation of phosphodiesterase-5, arginase and acetylcholinesterase activities in paroxetine-induced rats. In view of the aforementioned findings, Anogeissus leiocarpus could be considered a promising natural agent in erectile dysfunction management.


Assuntos
Antioxidantes/metabolismo , Óxido Nítrico/metabolismo , Paroxetina/farmacologia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Comportamento Sexual/efeitos dos fármacos , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Animais , Arginase/metabolismo , Combretaceae/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/metabolismo , Masculino , Malondialdeído/metabolismo , Pênis/efeitos dos fármacos , Pênis/metabolismo , Ratos , Ratos Wistar , Disfunções Sexuais Fisiológicas/metabolismo , Citrato de Sildenafila/farmacologia
6.
Biomed Pharmacother ; 111: 1458-1466, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841461

RESUMO

INTRODUCTION: Prostaglandins (PGs) play an important role in corpus cavernosum relaxation, as evidenced by alprostadil being used as a drug for erectile dysfunction. Reports about the effect of cyclooxygenase (COX) inhibitors on erectile function are highly contradictory. AIM: To compare the potential effects of some COX inhibitors with varying COX-1/COX-2 selectivities (indomethacin, ketoprofen and diclofenac) with that of the selective COX-2 inhibitor (DFU) on corpus cavernosal tone in-vitro. The role played by PGE1, PGI2-analogue and PGE4 receptor (EP4)-agonist in controlling corpus cavernosum function and the modulation of their action by sildenafil is also studied. METHODS: Organ bath experiments were performed using isolated rat corpus cavernosum. Direct relaxations and changes to electric field stimulation (EFS, 2-16 Hz, 60 V, 0.8 ms, 10 s train)-induced relaxation by the effect of the selected drugs were studied. Strips were precontracted using phenylephrine (PE, 10-5 M). Results are expressed as mean ± SEM of 5-9 rats. RESULTS: Alprostadil, iloprost and L902688 (selective EP4 agonist) induced direct relaxation where L902688 showed greater relaxant effect. Sildenafil potentiated the Emax of alprostadil and iloprost but not L902688. EFS and acetylcholine (ACh)-induced relaxations were significantly potentiated in presence of indomethacin, ketoprofen and diclofenac (20, 100 µM) but not in presence of selective COX-2 inhibitor (DFU, 1 µM). GR32191B (Thromboxane A2 receptor antagonist, 10-6 M) significantly reduced the potentiatory effect of indomethacin. Only diclofenac succeeded to potentiate sodium nitroprusside (SNP)-induced relaxation. CONCLUSIONS: EP4 receptors may play an important nitric oxide (NO)/cGMP-independent role in corpus cavernosal relaxation. Nonselective COX inhibitors seem of no harm concerning cavernosal tissue relaxation, possibly because they inhibit the synthesis of the highly contracting mediator thromboxane A2.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Pênis/efeitos dos fármacos , Prostaglandinas/metabolismo , Alprostadil/farmacologia , Animais , GMP Cíclico/metabolismo , Diclofenaco/farmacologia , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/metabolismo , Iloprosta/farmacologia , Indometacina/farmacologia , Cetoprofeno/farmacologia , Masculino , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Ereção Peniana/efeitos dos fármacos , Pênis/metabolismo , Piperazinas/farmacologia , Ratos , Citrato de Sildenafila/farmacologia , Sulfonas/farmacologia
7.
Andrologia ; 51(5): e13240, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30706510

RESUMO

Men with hypertension often develop erectile dysfunction (ED). The present study aimed to examine the effects of sodium hydrosulphide (NaHS), a hydrogen (H2 S) donor, treatment on ED in nitric oxide synthase (NOS) inhibitor (L-NAME)-induced hypertensive rats. Forty adult Sprague-Dawley rats were divided into four groups: control, NaHS (0.037 mg kg day-1 )-treated control, L-NAME-induced hypertension (40 mg kg day-1 ) and NaHS-treated L-NAME-induced hypertension. The ratio of intracavernosal pressure to mean arterial pressure and isometric tension of corpus cavernosum (CC) were measured. The penile expression of endothelial and neuronal NOS (eNOS and nNOS), inflammation markers [nuclear factor kappa B (NF-κB) and inhibitor kappa B alpha (IκBα)], H2 S-producing enzymes[cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE)], the smooth muscle/collagen ratio and H2 S concentrations were determined. The blood pressure was significantly increased in the hypertensive group, but not reversed by NaHS. The erectile response in hypertensive rats was partially prevented by NaHS. The relaxation response to electrical field stimulation was increased in CC from NaHS-treated hypertensive rats. NaHS treatment restored decreased protein expression of eNOS, nNOS and CSE as well as smooth muscle/collagen ratio and H2 S levels and increased NF-κB and IκBα protein expression in the penile tissue of hypertensive rats. NaHS promoted the recovery of erectile responses in hypertensive rats by improvement of neuronal function and downregulation of fibrosis and NF-κB signalling.


Assuntos
Disfunção Erétil/tratamento farmacológico , Hipertensão/complicações , Ereção Peniana/efeitos dos fármacos , Pênis/efeitos dos fármacos , Sulfetos/farmacologia , Animais , Cistationina gama-Liase/metabolismo , Modelos Animais de Doenças , Disfunção Erétil/etiologia , Fibrose/tratamento farmacológico , Fibrose/patologia , Humanos , Sulfeto de Hidrogênio/farmacologia , Hipertensão/induzido quimicamente , Masculino , NG-Nitroarginina Metil Éster/toxicidade , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Pênis/metabolismo , Pênis/patologia , Ratos , Ratos Sprague-Dawley , Sulfetos/uso terapêutico , Resultado do Tratamento
8.
Endocr J ; 66(4): 387-393, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30787207

RESUMO

Endogenous and exogenous androgens induce masculinization of external genitalia through binding to the androgen receptor (AR). The target genes of androgens in external genitalia remain to be determined, although previous studies have shown that the apolipoprotein D gene (APOD) was significantly upregulated by dihydrotestosterone (DHT), the most potent androgen in humans. In the present study, we performed microarray analysis for genital skin fibroblasts obtained from four boys with buried penis (the control individuals) and a patient with partial androgen insensitivity syndrome (PAIS) due to a hypomorphic mutation in AR (the PAIS patient). We identified 24 transcripts that were upregulated or downregulated by DHT in all samples of control individuals and, to a lesser extent, in the sample of the PAIS patient. Differences between DHT-treated and -untreated samples were small; the results of 24 transcripts did not reach statistical significance. The 24 transcripts included CYP1B1, a gene possibly involved in the development of genital tubercle in mice, and APOD, as well as several genes that have been reported as androgen targets in prostate or other tissues. The results of this study indicate that androgen-mediated masculinization of external genitalia is unlikely to depend on massive transcriptional changes in specific AR target genes. Rather, minor transcriptional changes of several genes, and/or a complex molecular network may play a major role in penile development. Importantly, our data suggest the possible involvement of CYP1B1 in human genital development and confirm the clinical importance of APOD as a biomarker for AR function.


Assuntos
Androgênios/farmacologia , Di-Hidrotestosterona/farmacologia , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Pênis/efeitos dos fármacos , Síndrome de Resistência a Andrógenos/genética , Síndrome de Resistência a Andrógenos/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Lactente , Masculino , Pênis/citologia , Pênis/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Análise Serial de Tecidos
9.
Andrologia ; 51(3): e13200, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30467872

RESUMO

We explored whether platelet-derived growth factor (PDGF)-BB regulates corpus cavernosum smooth muscle cell gap junctions and can ameliorate erectile dysfunction and how it modulates connexin43 (CX43) after bilateral cavernous neurectomy. Primary cultured rat corpus cavernosum smooth muscle cells were treated with PDGF-BB with or without a PDGFR inhibitor, Akt siRNA or the depletion or promotion of ß-catenin. PDGF-BB improved CCSMCs gap junction coupling and increased CX43 and PDGFRß expression; inhibition of PDGFR activity down-regulated CX43 and decreased Akt and nuclear ß-catenin. Knockdown or promotion of ß-catenin down-regulated and up-regulated CX43 expression respectively. Moreover, ß-catenin activation induced CX43 nuclear accumulation, which impeded CX43 down-regulation induced by PDGFR inhibition, suggesting that CX43 expression is positively correlated with nuclear ß-catenin expression. Furthermore, CX43 promoter luciferase and chromatin immunoprecipitation assays indicated that ß-catenin regulates CX43 transcription by directly interacting with its promoter. Male rats underwent bilateral cavernous neurectomy. After 12 weeks, they were injected with PDGF-BB, CX43 and PDGFRß expression was significantly lower than in the control group, which was reversed by PDGF-BB injection. These results suggested that PDGF-BB contributed to the improvement of gap junction intracellular communication among corpus cavernosum smooth muscle cells, increased CX43 through PDGFRß/Akt/nuclear ß-catenin signalling, and ameliorated cavernous nerve injury-induced erectile dysfunction.


Assuntos
Becaplermina/farmacologia , Conexina 43/metabolismo , Junções Comunicantes/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Pênis/irrigação sanguínea , Animais , Células Cultivadas , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Pênis/efeitos dos fármacos , Pênis/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno , Ratos , Transdução de Sinais/efeitos dos fármacos , beta Catenina/genética , beta Catenina/metabolismo
10.
Endocrine ; 63(3): 615-631, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30460485

RESUMO

PURPOSE: Diabetic mellitus-induced erectile dysfunction (DMED) represents a significant complication associated with diabetes mellitus (DM) that greatly affects human life quality. Various reports have highlighted the involvement of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in the regulation of mitochondrial fatty acid oxidation, which has also been linked with DM. Through bioinformatics analysis, HMGCS2 was determined to be a novel target among DM patients suffering from erectile dysfunction (ED), and enriched in the Ras/ERK/PPAR signaling axis. Owing to the fact that the key mechanism HMGCS2 involved in DM remains largely unknown, we set out to investigate the role of the Ras/MAPK/PPARγ signaling axis and HMGCS2 in the corpus cavernosal endothelial cells (CCECs) of rats with DMED. METHODS: Firstly, bioinformatics analysis was used to screen out differentially expressed genes in DMED. Then, to investigate the influence of the Ras/MAPK/PPARγ signaling axis and HMGCS2 on DMED, a rat model of DMED was established and injected with Simvastatin and si-Hmgcs2. The individual expression patterns of Ras, MAPK, PPARγ and HMGCS2 were determined by RT-qPCR, immunohistochemistry and western blot analysis methods. Afterwards, to investigate the mechanism of Ras/MAPK/PPARγ signaling axis and HMGCS2, CCECs were isolated from DMED rats and transfected with agonists and inhibitors of the Ras/MAPK/PPARγ signaling axis and siRNA of HMGCS2, with their respective functions in apoptosis and impairment of CCECs evaluated using TUNEL staining and flow cytometry. RESULTS: Microarray analysis and KEGG pathway enrichment analysis revealed that Ras/ERK/PPAR signaling axis mediated HMGCS2 in DMED. Among the DMED rats, the Ras/MAPK/PPAR signaling axis was also activated while the expression of HMGCS2 was upregulated. The activation of Ras was determined to be capable of upregulating ERK expression which resulted in the inhibition of the transcription of PPARγ and subsequent upregulation of HMGCS2 expression. The inhibited activation of the Ras/ERK/PPAR signaling axis and silencing HMGCS2 were observed to provide an alleviatory effect on the injury of DMED while acting to inhibit the apoptosis of CCECs. CONCLUSION: Collectively, the key findings suggested that suppression of the Ras/MAPK/PPARγ signaling axis could downregulate expression of HMGCS2, so as to alleviate DMED. This study defines the potential treatment for DMED through inhibition of the Ras/MAPK/PPARγ signaling axis and silencing HMGCS2.


Assuntos
Diabetes Mellitus Experimental/complicações , Disfunção Erétil/tratamento farmacológico , Hidroximetilglutaril-CoA Sintase/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases , Sinvastatina/uso terapêutico , Animais , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais/metabolismo , Disfunção Erétil/enzimologia , Disfunção Erétil/etiologia , Hidroximetilglutaril-CoA Sintase/metabolismo , Masculino , PPAR gama/metabolismo , Pênis/metabolismo , RNA Interferente Pequeno/uso terapêutico , Ratos Sprague-Dawley , Sinvastatina/farmacologia , Proteínas ras/metabolismo
11.
Andrologia ; 51(1): e13173, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30311248

RESUMO

The aim of the study was to investigate how testosterone regulating endothelial function in the corpus cavernosum of rats. A total of 32 male Sprague-Dawley (SD) rats, 10-weeks-old, were divided randomly into four groups: normal control group (Control); castration group (Castration); the other 16 rats were castrated followed by testosterone supplementation (orally) every day for 8 weeks: castration +10 mg/kg (lower dose) testosterone group (Castration +LT) and castration +20 mg/kg (high dose) testosterone group (Castration +HT). The data showed that androgen deficiency in the Castration group could induce oxidative stress to attenuate endothelial function, manifested by the impairment of endothelial intercellular junction and endothelial content. This was in parallel with a significant decrease in Akt, Akt target and FOXO3a phosphorylation. Testosterone supplementation in the Castration +LT and Castration +HT groups could greatly preserve testosterone serum levels, endothelial function and erectile function through activation of sphingosine-1-phosphate receptor 1 (S1P1)/Akt/FOXO3a pathway. Together, this study suggested that S1P1/Akt/FOXO3a pathway was involved in endothelial dysfunction in the context of androgen deficiency and oxidative stress, which might further explain the mechanism of androgen deficiency inducing ED.


Assuntos
Endotélio Vascular/metabolismo , Pênis/metabolismo , Transdução de Sinais/fisiologia , Testosterona/metabolismo , Animais , Castração , Endotélio Vascular/efeitos dos fármacos , Proteína Forkhead Box O3/metabolismo , Masculino , Pênis/efeitos dos fármacos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Testosterona/farmacologia
12.
Andrologia ; 51(1): e13167, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30295340

RESUMO

The aim of this study was to investigate the relationship between sulphur dioxide (SO2 ) signalling pathway and the changes in erectile function under low androgen levels. Thirty-six healthy male Sprague Dawley (SD) rats aged eight weeks were randomly divided into androgen replacement group, castration group and sham group. Rats in the androgen replacement group were subcutaneously injected with testosterone propionate at 3 mg/kg every other day postcastration. The maximum intracavernous pressure/mean arterial pressure (ICPmax /MAP) and the relative content of SO2 in the penile corpus cavernosum were measured. The mRNA and protein expressions of aspartate aminotransferase (AAT1 and AAT2), cysteine oxidase (CDO), endothelial nitric oxide synthase (eNOS) and phosphorylation of endothelial nitric oxide synthase (P-eNOS) were detected. ICPmax /MAP, P-eNOS/eNOS and the level of SO2 decreased significantly in the castration group compared to the other groups (p < 0.05). The expressions of mRNA and protein decreased significantly in the castration group compared to the androgen replacement group and the sham group (p < 0.05), while there was no significant difference between the androgen replacement group and sham group. Low androgen levels can inhibit erectile function by downregulating the SO2 signalling pathway.


Assuntos
Androgênios/sangue , Ereção Peniana/fisiologia , Pênis/metabolismo , Transdução de Sinais/fisiologia , Dióxido de Enxofre/metabolismo , Propionato de Testosterona/farmacologia , Androgênios/farmacologia , Animais , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Ereção Peniana/efeitos dos fármacos , Pênis/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
13.
Urol Int ; 102(2): 218-223, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30317233

RESUMO

PURPOSE: The objective of this study was to evaluate the effects of intratunical injection of platelet rich plasma (PRP) for the treatment of Peyronie's disease (PD) in a rat model. MATERIALS AND METHODS: Twenty male Sprague-Dawley rats (300-350 g) were randomly divided into 4 groups: sham, PD, PD + PRP, and PRP. The PD + PRP groups received intratunical injections with 0.1 mL PRP on day 15 (treatment) or day 0 (PRP effect). Forty-five days following transforming growth factor-beta 1 injection, rats underwent pathological examination. Tissues were evaluated histologically for fibrosis grade (Haematoxylin & Eosin staining), collagen/smooth muscle ratio (Masson Trichrome staining) and type III/type I collagen ratio (Picro-sirius red staining). Statistical analysis was performed by Kruskal-Wallis and chi-square followed by the Mann-Whitney U test for post hoc comparisons. RESULTS: Significant changes were found in all 3 groups compared to the sham group (p < 0.0001 for fibrosis, p = 0.001 for collagen/smooth muscle ratio and p = 0.003 for type III/type I collagen ratio). The values in the PRP group and the findings in the PD group are similar (p = 0.122 for fibrosis, p = 0.221 for collagen/smooth muscle ratio and p = 1.0 for type III/type I collagen ratio). CONCLUSION: This is the first study of PRP on PD. As a result of pathological examinations, PRP shows PD-like effects in rats. PRP may be a cheap, easily accessible, and an effective disease model for PD treatment research.


Assuntos
Músculo Liso/patologia , Induração Peniana/etiologia , Pênis/patologia , Plasma Rico em Plaquetas , Animais , Modelos Animais de Doenças , Colágenos Fibrilares/metabolismo , Fibrose , Injeções , Masculino , Músculo Liso/metabolismo , Induração Peniana/sangue , Induração Peniana/patologia , Induração Peniana/terapia , Pênis/metabolismo , Plasma Rico em Plaquetas/metabolismo , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1
14.
Int J Impot Res ; 31(1): 31-38, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30127396

RESUMO

Neuronal and endothelial nitric oxide synthases (nNOS and eNOS respectively) play major roles in generating the nitric oxide bioactivity necessary for erectile function. S-nitrosylation has been shown to regulate NOS activity. The presence of S-nitrosylated NOS in the penis and the impact of NOS S-nitrosylation/denitrosylation on erectile function were examined. S-nitrosylated forms of NOS were identified by biotin-switch assay followed by western blot analysis. Erectile function in S-nitrosoglutathione reductase deficient (GSNO+/-) and null (GSNO-/-) mice were assessed by continuous cavernous nerve electrical stimulation (CCNES). Glutathione ethyl ester (GSHee) was used to manipulate S-nitrosylated NOS levels. Immunohistological and immunofluorescence analyses were used to identify the location of eNOS and GSNO-R in corporal tissue. eNOS and nNOS were S-nitrosylated in unstimulated penises of the mice. CCNES resulted in a time-dependent increase in eNOS S-nitrosylation with peak eNOS S-nitrosylation observed during detumescence. S-nitrosylated nNOS levels were unchanged. Intracorporal injection of GSHee reduced S-nitrosylated eNOS levels, enhancing time to maximum intracorporal pressure (ICP). eNOS and GSNO-R co-localize to the endothelium of the corpus cavernosum in the mouse and the human. ICP measurements obtained during CCNES demonstrate GSNO-R+/- and GSNO-R-/- animals cannot maintain an elevated ICP. Results suggest eNOS S-nitrosylation/denitrosylation is an important mechanism regulating eNOS activity during erectile function. GSNO-R is a key enzyme involved in the eNOS denitrosylation. The increase in eNOS S-nitrosylation (inactivation) observed with tumescence may begin a cycle leading to detumescence. Clinically this may indicate that alterations in the balance of S-nitrosylation/denitrosylation either directly or indirectly contribute to erectile dysfunction.


Assuntos
Aldeído Oxirredutases/metabolismo , Disfunção Erétil/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ereção Peniana/fisiologia , Aldeído Oxirredutases/genética , Animais , Endotélio Vascular/metabolismo , Disfunção Erétil/genética , Masculino , Camundongos , Camundongos Knockout , Pênis/metabolismo
15.
Int Urol Nephrol ; 51(2): 231-238, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30515737

RESUMO

PURPOSE: This study aimed to demonstrate the effects of oxytocin on penile tissues in ischemia-reperfusion injury developed after priapism. METHODS: Forty Wistar Albino strain male rats were divided into four groups. The control group (n = 10) was not intervened. In Group 2, a rat model of priapism was constructed and maintained for 1 h. In Group 3, reperfusion was ensured for 30 min following priapism. Rats in Group 4 rats were given oxytocin 30 min before the induction of reperfusion following priapism. All rats were penectomized, and adequate amounts of blood sample were drawn. Inflammation, vasocongestion, desquamation, and edema in penile tissue were scored between 0 and 3 points (0: normal, 1: mild, 2: moderate, 3: severe) to evaluate the severity of tissue damage. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the levels of malondialdehyde (MDA), and nitric oxide (NO) in blood samples were determined spectrophotometrically. RESULTS: In histopathological examination, statistically significant positive changes were detected in vasocongestion, inflammation, desquamation, and edema scores in Group 4 than in Group 2 and Group 3 (p < 0.001). Biochemical test results revealed that NO levels were significantly lower in Group 4 than in Group 3 (p < 0.001). Serum GSH-Px activities in Group 4 significantly increased when compared with the other groups 2 and 3 (p = 0.002, p = 0.001, respectively). There was no statistical difference among the groups regarding SOD activities and MDA levels (p > 0.05). CONCLUSIONS: Oxytocin protected against priapism-induced ischemia-reperfusion injury developed in cavernosal tissue as observed based on histopathological and biochemical evidence. Although this is an experimental study, oxytocin can be thought as an alternative drug in the treatment of priapism.


Assuntos
Ocitocina/metabolismo , Pênis , Priapismo/complicações , Traumatismo por Reperfusão/metabolismo , Animais , Modelos Animais de Doenças , Glutationa Peroxidase/sangue , Masculino , Malondialdeído/sangue , Óxido Nítrico/sangue , Pênis/irrigação sanguínea , Pênis/metabolismo , Pênis/patologia , Fatores de Proteção , Ratos , Ratos Wistar , Traumatismo por Reperfusão/etiologia , Índice de Gravidade de Doença , Superóxido Dismutase/sangue , Fatores de Tempo
16.
Zhonghua Nan Ke Xue ; 25(12): 1066-1076, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-32251556

RESUMO

Objective: To search for specific protein makers and target proteins for intervention with Yimusake Tablets (YT) in the penile tissue of rats with ED induced by compound cold stress and explore the molecular mechanisms underlying the development and progression of ED. METHODS: Eighty adult male rats were screened and divided into three groups, normal control (n = 10), ED model control (n = 15) and YT intervention (n = 15). The model of compound cold stress-induced ED was established in the latter two groups, and meanwhile the animals in the YT intervention group were treated with oral YT for 2 weeks. After that, proteins were extracted from the penile tissues of the rats for screening and identification by iTRAQ labeling combined with LC-MS-MS proteomics, and the IPA bioinformatics software was used for analysis of differentially expressed proteins. RESULTS: A total of 48 differentially expressed proteins were identified from the penile tissue of the ED model controls, of which 18 were associated with endothelial function, 5 with smooth muscle activity and 4 with inflammation, involving the biological processes of glucose metabolism and alcohol catabolism and the signaling pathways of glucose metabolism, calcium and RXR activation. In comparison, 29 differentially expressed proteins were identified from the rats in the YT intervention group, of which 5 were associated with endothelial function, 1 with smooth muscle activity and 4 with inflammation, involving the biological processes of glucose metabolism, vasodilation and acute-phase response and the signaling pathways glucose metabolism, RXR activation and acute-phase response. Seven ED-associated candidate biomarkers were obtained from the differentially expressed proteins in the ED model control and YT intervention group, including Collagen alpha-1(III) chain(COL3α1), Collagen alpha-1(I) chain(COL1α1), Collagen alpha-2(I) chain(COL1α2), Glyceraldehyde-3-phosphate dehydrogenase(GAPDH), T-kininogen 1(MAP1),Biglycan(BGN), and Myosin-11(MYH11). CONCLUSIONS: Changes of vascular endothelial and smooth muscle functions in the penile tissue are likely to be the key mechanisms underlying the development and progression of compound stress-induced ED, which is also associated with inflammation as well as the interaction of the identified differentially expressed proteins and their participation in the relevant signaling pathways. The 7 proteins obtained can be used as the markers of compound stress-induced ED in the rat penile tissue, of which MAP1, GAPDH, BGN and MYH11 may serve as target proteins for YT intervention.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Disfunção Erétil/tratamento farmacológico , Pênis/efeitos dos fármacos , Proteoma/metabolismo , Animais , Biologia Computacional , Endotélio Vascular , Disfunção Erétil/metabolismo , Masculino , Músculo Liso , Pênis/metabolismo , Ratos , Estresse Fisiológico , Comprimidos
17.
BMC Complement Altern Med ; 18(1): 343, 2018 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-30587186

RESUMO

BACKGROUND: Erectile dysfunction (ED) is a common complication of diabetes. This study aimed to explore the beneficial effect of Danshen injection on ED in a streptozotocin (STZ)-induced diabetic rat model and the underlying mechanism. METHODS: The diabetic rat model was established by an intraperitoneal injection of 60 mg/kg STZ in male Sprague-Dawley rats. The diabetic rats were intraperitoneally injected with Danshen solution (0.5 or 1 mL/kg/day) or the same volume of saline for 6 weeks. Age-matched rats served as controls. After 6 weeks, erectile function and histological morphology of the corpora cavernosum were assessed. Oxidative stress indicators, including superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and reactive oxygen species (ROS) levels, were measured in penile tissues. The expression levels of glucose-regulated protein 78 (Grp78), growth arrest and DNA damage-inducible gene 153 (GADD153/CHOP) were determined by immunohistochemistry, immunoblotting, and RT-PCR. Apoptosis was detected by a TUNEL assay. RESULTS: The erection times of diabetic rats were significantly less than those of control rats. Danshen injection could improve erectile function via increased erection times. Danshen injection was also found to ameliorate the morphological abnormalities of the corpora cavernosum, to reduce the number of apoptotic cells, and to suppress caspase-3 activation in penile tissue, accompanied by downregulation of the endoplasmic reticulum stress biomarkers Grp78 and CHOP. Danshen injection could increase SOD activity as well as reduce ROS and MDA levels in diabetic rats, indicating suppression of oxidative stress. CONCLUSION: Danshen injection could rescue diabetes-associated ED, possibly via suppressing the oxidative stress and endoplasmic reticulum (ER) stress-induced apoptosis pathways.


Assuntos
Complicações do Diabetes/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Disfunção Erétil/tratamento farmacológico , Salvia miltiorrhiza/química , Animais , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Disfunção Erétil/metabolismo , Disfunção Erétil/fisiopatologia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/fisiologia , Humanos , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pênis/efeitos dos fármacos , Pênis/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
18.
Differentiation ; 103: 100-119, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30287094

RESUMO

We have studied the ontogeny of the developing human male and female urogenital tracts from 9 weeks (indifferent stage) to 16 weeks (advanced sex differentiation) of gestation by immunohistochemistry on mid-sagittal sections. Sixteen human fetal pelvises were serial sectioned in the sagittal plane and stained with antibodies to epithelial, muscle, nerve, proliferation and hormone receptor markers. Key findings are: (1) The corpus cavernosum in males and females extends into the glans penis and clitoris, respectively, during the ambisexual stage (9 weeks) and thus appears to be an androgen-independent event. (2) The entire human male (and female) urethra is endodermal in origin based on the presence of FOXA1, KRT 7, uroplakin, and the absence of KRT10 staining. The endoderm of the urethra interfaces with ectodermal epidermis at the site of the urethral meatus. (3) The surface epithelium of the verumontanum is endodermal in origin (FOXA1-positive) with a possible contribution of Pax2-positive epithelial cells implying additional input from the Wolffian duct epithelium. (4) Prostatic ducts arise from the endodermal (FOXA1-positive) urogenital sinus epithelium near the verumontanum. (5) Immunohistochemical staining of mid-sagittal and para-sagittal sections revealed the external anal sphincter, levator ani, bulbospongiosus muscle and the anatomic relationships between these developing skeletal muscles and organs of the male and female reproductive tracts. Future studies of normal human developmental anatomy will lay the foundation for understanding congenital anomalies of the lower urogenital tract.


Assuntos
Desenvolvimento Fetal/genética , Imuno-Histoquímica , Uretra/crescimento & desenvolvimento , Sistema Urogenital/crescimento & desenvolvimento , Clitóris/crescimento & desenvolvimento , Clitóris/metabolismo , Epitélio/crescimento & desenvolvimento , Epitélio/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genitália Feminina/crescimento & desenvolvimento , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Queratina-10/genética , Masculino , Fator de Transcrição PAX2/genética , Pênis/crescimento & desenvolvimento , Pênis/metabolismo , Uretra/metabolismo , Sistema Urogenital/metabolismo , Vagina/crescimento & desenvolvimento , Vagina/metabolismo
19.
Biosci Rep ; 38(6)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30333254

RESUMO

Background: Stem-cell-based therapies have recently been explored in the field of erectile dysfunction (ED). However, the cellular and molecular phenotype of adipose derived stem cells (ADSCs) stromal vascular fraction (SVF) from ED patients remains largely unknown. Herein we compared the global gene expression profile in the SVF from ED patients and healthy individuals and identified altered signaling pathways between the two groups.Methods: Samples (2-5 g) of abdominal adipose tissue from ED patients (n = 6) and healthy individual controls (n = 3) undergoing elective cosmetic liposuction were collected. Immediately after removal, SVF was separated using Collagenase type I and type IV protocol. RNA was isolated and microarray experiments were conducted using the Agilent platform. Data were normalized and pathway analyses were performed using GeneSpring software.Results: Our data revealed multiple differentially expressed genes between the ED and control group. Hierarchical clustering based on differentially expressed mRNAs revealed clear separation of the two groups. The distribution of the top enriched pathways for the up-regulated genes indicated enrichment in inflammatory response and T-cell receptor signaling, while pathway analysis performed on the down-regulated genes revealed enrichment in mitogen-activated protein kinase, TGF-ß, senescence, FAK, adipogenesis, androgen receptor, and EGF-EGFR signaling pathways in SVF from ED patient.Conclusion: Our data revealed the existence of multiple altered signaling pathways in the SVF from ED patients, which could potentially play a role in the etiology of this disease. Therefore, therapeutic strategies targeting these pathways might provide novel therapeutic opportunity for ED patients.


Assuntos
Tecido Adiposo/metabolismo , Disfunção Erétil/genética , Células-Tronco Mesenquimais/metabolismo , RNA Mensageiro/genética , Células Estromais/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/crescimento & desenvolvimento , Adulto , Idoso , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Diferenciação Celular/genética , Senescência Celular , Fator de Crescimento Epidérmico/genética , Receptores ErbB/genética , Disfunção Erétil/patologia , Disfunção Erétil/terapia , Regulação da Expressão Gênica no Desenvolvimento/genética , Genoma Humano/genética , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Pessoa de Meia-Idade , Pênis/irrigação sanguínea , Pênis/crescimento & desenvolvimento , Pênis/metabolismo , Pênis/patologia , Receptores Androgênicos/genética , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais , Células Estromais/patologia , Análise Serial de Tecidos , Fator de Crescimento Transformador beta/genética
20.
Clin Sci (Lond) ; 132(20): 2175-2188, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30232174

RESUMO

Increased production of reactive oxygen species (ROS) and inflammation are major contributors to the development and progression of diabetes-associated erectile dysfunction (DMED). As an endogenous antioxidant and anti-inflammatory factor, the potential implication of pigment epithelium-derived factor (PEDF) in DMED has not been revealed. To assess the potential antioxidant and anti-inflammatory functions of PEDF in DMED, we first demonstrated that PEDF was significantly decreased at the levels of the mRNA and protein in the penis of diabetic rats compared with normal controls. To test the hypothesis that decreased the penile levels of PEDF are associated with oxidative stress and inflammation in DMED, an adenovirus expressing PEDF (Ad-PEDF) or the same titer of control virus (Ad-GFP) was intracavernously administered at 2 weeks after diabetic onset. After 6 weeks of treatment, we found that administration of Ad-PEDF could significantly increase erectile response to cavernosal nerve stimulation in the diabetic rats by restoring the endothelial NO synthase (eNOS), P-eNOS, and neuronal NO synthase (nNOS) protein levels to the standard levels represented in normal rats and by suppressing the levels of tumor necrosis factor-α (TNF-α) and oxidative stress. In conclusion, the present data indicated that the antioxidant and anti-inflammatory potential of PEDF plays important role in restoring erectile function by the inhibition of oxidative stress and TNF-α production.


Assuntos
Diabetes Mellitus Experimental/genética , Proteínas do Olho/genética , Fatores de Crescimento Neural/genética , Ereção Peniana/genética , Pênis/metabolismo , Serpinas/genética , Animais , Diabetes Mellitus Experimental/metabolismo , Regulação para Baixo , Proteínas do Olho/metabolismo , Regulação da Expressão Gênica , Masculino , Fatores de Crescimento Neural/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Serpinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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