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1.
Food Chem Toxicol ; 135: 110982, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31747621

RESUMO

With epidemic of obesity, it affects aspects of female reproduction. Genistein could ameliorate obesity in people and animals, but might exert adverse effects on the female reproductive system. To evaluate the effects of fetal and neonatal genistein exposure on the ovarian health of F1 obese female mice with obesity induced by high-fat diet after weaning, we simulated a diet-induced obesity model to observe and determine biological effects of genistein exposure on the ovarian follicle of overfed female mice. Results showed that F1 female mice with obesity induced by high-fat diet significantly prolonged the estrus cycle, disrupted sex hormonal balance and ovarian follicle development after they were exposed to 25 mg/kg b.w./day of genistein during the fetal and neonatal stages. Genistein significantly up-regulated the ovarian mRNA expression of estrogen receptor beta in F1 obese female mice, and high-fat diet influenced the ovarian mRNA expression of estrogen receptor alpha, luteinizing hormone receptor and follicle-stimulating hormone receptor. Hence, genistein exposure from the fetal stage might increase the risk of reproductive diseases in obese females in later life. Thus, the long-term risks of genistein to obese females should be thoroughly assessed.


Assuntos
Dieta Hiperlipídica , Genisteína/efeitos adversos , Obesidade/tratamento farmacológico , Folículo Ovariano/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Estradiol/metabolismo , Receptor beta de Estrogênio/genética , Ciclo Estral/efeitos dos fármacos , Feminino , Feto/efeitos dos fármacos , Hormônio Foliculoestimulante/metabolismo , Expressão Gênica/efeitos dos fármacos , Hormônio Luteinizante/metabolismo , Camundongos Endogâmicos ICR , Obesidade/metabolismo , Folículo Ovariano/embriologia , Folículo Ovariano/patologia , Gravidez , RNA Mensageiro/metabolismo
2.
Toxicol Lett ; 319: 175-186, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31733319

RESUMO

Information on the effects of gibberellic acid (gibberellin A3, GA3) on ovarian follicle development is limited. In our present study, 21-day-old female Wistar rats were exposed to GA3 by gavage (25, 50, and 100 mg/kg body weight, once per day) for eight weeks to evaluate the influence of GA3 on ovarian follicle development. After treatment, significant (P < 0.05) increases (to 40.17 % and 44.5 %, respectively) in atretic follicle proportions and significant decreases (to 19.49 % and 17.86 %, respectively) in corpus luteum proportions were observed in the 50 and 100 mg/kg treatment groups compared to the control group. Significant (P < 0.05) increases (to 31.3 % and 42.0 %, respectively) in follicle apoptosis were observed in the 50 and 100 mg/kg treatment groups by transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Significantly increased expression of caspase-3, caspase-8, caspase-9 and Fas was observed by real-time PCR and Western blotting. Bisulfite sequencing PCR (BSP) revealed obviously decreased total methylation percentages of the caspase-3 promoter region in the two treatment groups. Real-time quantitative PCR also showed significantly decreased mRNA expression of DNA methyltransferase (Dnmt) 3a and Dnmt3b. Further in vitro studies showed that a DNA methylation inhibitor could enhance the GA3-induced increase in the mRNA expression of caspase-3. Overall, our present study indicates that GA3 administration from weaning until sexual maturity can affect ovarian follicle development by inducing apoptosis and suggests that signaling through the Fas-mediated apoptotic pathway may be an important underlying mechanism of this apoptosis. In addition, GA3-induced aberrant DNA methylation patterns might be partly responsible for upregulation of caspase-3 gene expression.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Proteína de Domínio de Morte Associada a Fas/biossíntese , Giberelinas/toxicidade , Células da Granulosa/efeitos dos fármacos , Ovário/citologia , Transdução de Sinais/efeitos dos fármacos , Animais , DNA (Citosina-5-)-Metiltransferases/biossíntese , DNA (Citosina-5-)-Metiltransferases/genética , Proteína de Domínio de Morte Associada a Fas/efeitos dos fármacos , Feminino , Folículo Ovariano/efeitos dos fármacos , Ovário/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , Ratos , Ratos Wistar , Superovulação/efeitos dos fármacos
3.
J Sci Food Agric ; 100(1): 92-101, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31435952

RESUMO

BACKGROUND: Oyster polypeptides have various biofunctions, such as anti-cancer and anti-oxidative stress, but whether it has the protective effects to primary ovarian failure (POF) remains poorly understand. To address this issue, daily gavage of oyster polypeptides was performed to investigate their protective effect, basing on d-galactose-induced POF model in C57BL/6 female mice. RESULTS: Oyster polypeptides restored the irregular estrous cycles and the abnormal serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and progesterone (P) levels as well as the decreased mRNA expression level of Amh that were induced by d-galactose. The follicle development of POF mice was improved by increasing the primordial follicle ratio and decreasing the atretic follicle number after oral administration of oyster polypeptides. Moreover, in the oyster polypeptides treated mice, the total superoxide dismutase (T-SOD) activity was significantly increased, while the malondialdehyde levels were significantly decreased. The mRNA expression levels of stress-related genes (SOD2, SIRT1 and FOXO3a) were remarkably up-regulated after d-galactose induction, but the up-regulation was weakened or disappeared by the gavage of oyster polypeptides. In addition, oyster polypeptides treatment also reduced the apoptosis of the ovarian granulosa cells and down-regulated the mRNA expression levels of apoptosis-related genes (p53 and Bad but not Bcl-2). CONCLUSION: This study reveals that oyster polypeptides may protect ovary against d-galactose-induced POF by their anti-oxidative stress activity to rescue d-galactose-induced ovarian oxidative damage and therefore to prevent ovarian cells apoptosis, thereby tipping the abnormality trigged by POF to get close to the normal levels. © 2019 Society of Chemical Industry.


Assuntos
Ostreidae/química , Peptídeos/administração & dosagem , Insuficiência Ovariana Primária/tratamento farmacológico , Substâncias Protetoras/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Feminino , Galactose/efeitos adversos , Humanos , Hormônio Luteinizante/metabolismo , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/metabolismo , Progesterona/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
4.
Life Sci ; 239: 116999, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31654746

RESUMO

AIMS: The present study aimed to investigate the effects of cyclophosphamide (Cytoxan, CTX) on premature ovarian failure (POF) in mice and its regulatory mechanisms by transcriptome analysis. MAIN METHODS: Female C57BL/6 mice were treated with a single intraperitoneal injection of 70 mg/kg CTX. Serum levels of estradiol (E2) and follicle stimulating hormone (FSH) were measured by enzyme-linked immunosorbent assay (ELISA), and follicular structure differences were observed by hematoxylin and eosin (H&E) staining. The main mechanism of POF was investigated by RNA-seq data, protein-protein interaction (PPI) networks and qPCR analysis. KEY FINDINGS: The serum levels of E2 were significantly decreased and those of FSH were significantly increased compared to the control group. The ovarian weights of the mice in the CTX group were reduced, and abnormal follicular structures were also observed in the CTX group. The RNA-seq data show that the downregulated genes were related to the cholesterol biosynthesis pathway. The PPI network and qPCR analyses further confirm that the PPAR signaling pathway and the ovarian infertility genes were also involved in blocking the cholesterol biosynthesis pathway. The differences were statistically significant. SIGNIFICANCE: Our results indicate that CTX may exert its anti-tumor effects by inactivating the cholesterol biosynthesis pathway, and simultaneously reducing the supply of estrogen precursor materials, ultimately leading to the occurrence of POF. Our data provided a preliminary theoretical basis for resolving the clinical toxicity and side effects of CTX.


Assuntos
Antineoplásicos Alquilantes/toxicidade , Colesterol/biossíntese , Ciclofosfamida/toxicidade , Perfilação da Expressão Gênica , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/metabolismo , Animais , Regulação para Baixo/efeitos dos fármacos , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/biossíntese , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Receptores Ativados por Proliferador de Peroxissomo/genética , Insuficiência Ovariana Primária/genética , Mapas de Interação de Proteínas
5.
Rev Assoc Med Bras (1992) ; 65(9): 1144-1150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618328

RESUMO

OBJECTIVE: In view of the high incidence of polycystic ovary syndrome (PCOS) and the unsatisfactory therapeutic effects of dimethyldiguanide or clomifene citrate alone, our study aimed to investigate the therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of PCOS. METHODS: A total of 79 patients with POCS and 35 healthy females were included, and endometrial biopsies were obtained. The sterol regulatory element-binding protein-1 (SREBP1) expression in endometrial tissues was detected by qRT-PCR. POC patients were randomly divided into group A (n=40) and group B (n=39). Patients in group A were treated with dimethyldiguanide combined with clomifene citrate, while patients in group B were treated with clomifene citrate alone. The number of mature follicles and cervical mucus score, follicular development rate and single follicle ovulation rate, cycle pregnancy rate, early miscarriage rate, ovulation rate, endometrial thickness, positive rate of three lines sign, follicle stimulating hormone level and luteinizing hormone level were compared between the two groups. RESULTS: The expression level of SREBP1 was higher in PCOS patients than that in the healthy control. SREBP1 expression was inhibited after treatment, while the inhibitory effects of combined treatment were stronger than those of clomifene citrate alone. Compared with clomifene citrate alone, the combined treatment improved cervical mucus score, follicle development rate, single follicle ovulation rate, endometrial thickness, positive rate of three lines sign, and follicle-stimulating hormone level. CONCLUSION: The therapeutic effect of combined treatment is better than clomifene citrate alone in the treatment of PCOS.


Assuntos
Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Muco do Colo Uterino/efeitos dos fármacos , Clomifeno/farmacologia , Quimioterapia Combinada , Endométrio/fisiopatologia , Feminino , Fármacos para a Fertilidade Feminina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Folículo Ovariano/efeitos dos fármacos , Indução da Ovulação , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adulto Jovem
6.
Arq. bras. med. vet. zootec. (Online) ; 71(5): 1445-1452, set.-out. 2019. tab, graf
Artigo em Inglês | VETINDEX, LILACS | ID: biblio-1038672

RESUMO

The aim of this study was to evaluate the effect of Recombinant bovine somatotropin (rbST) on survival and diameter of bovine preantral ovarian follicles (PAOF) cultured in vitro. Ovaries were collected from adult cows and fragments of ovarian cortex were immediately fixed (non-cultured control) or cultured in vitro in α-MEM+ alone or containing 10, 50, 100 or 1,000ng/mL rbST. The fragments were processed for Classical Histology and Transmission Electron Microscopy. After one and seven days of culture, the percentage of normal follicles in the non-cultured control was superior (P< 0.05) to the follicles cultured in α-MEM+ alone or with different rbST concentrations. The oocyte and follicular mean diameter did not increase during the culture for one and seven days, both in media containing rbST and in the medium without this hormone. The only medium in which there was no reduction in follicular diameter with the time of culture was the medium without rbST. Ultrastructural damage in PAOF cultured in vitro was found. It is concluded that the use of rbST at different concentrations in in situ culture of bovine preantral follicles has no beneficial effects on survival and growth of bovine PAOF.(AU)


O objetivo deste trabalho foi avaliar o efeito da somatotropina recombinante bovina (rbST) sobre a sobrevivência e o diâmetro de folículos ovarianos pré-antrais (FOPA) bovinos cultivados in vitro. Ovários foram coletados de vacas adultas e fragmentos do córtex ovariano foram imediatamente fixados (controle não cultivado) ou cultivados in vitro em α-MEM + sozinho ou contendo 10, 50, 100 ou 1.000ng/mL de rbST. Os fragmentos foram processados para histologia clássica e microscopia eletrônica de transmissão. Após um e sete dias de cultivo, o percentual de folículos normais no controle não cultivado foi superior (P<0,05) aos cultivados em α-MEM + sozinho ou acrescido de diferentes concentrações de rbST. Os diâmetros médios oocitário e folicular não aumentaram durante o cultivo por um e sete dias, tanto nos meios contendo rbST, como no meio sem esse hormônio (α-MEM + ). O único meio em que não houve redução no diâmetro folicular com o tempo de cultivo foi o sem rbST. Verificaram-se ainda danos ultraestruturais em FOPA cultivados in vitro. Conclui-se que o uso de rbST em diferentes concentrações no cultivo in situ de folículos pré-antrais bovinos não tem efeitos benéficos na sobrevivência e no crescimento de FOPA bovinos.(AU)


Assuntos
Animais , Feminino , Bovinos/embriologia , Hormônio do Crescimento , Folículo Ovariano/anatomia & histologia , Folículo Ovariano/efeitos dos fármacos , Técnicas In Vitro/veterinária
7.
Rev Assoc Med Bras (1992) ; 65(8): 1122-1127, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31531613

RESUMO

Melatonin is known for its effects on both the sleep and reproductive system of mammals. The latter has melatonin receptors type 1 and 2, which act to regulate, among other things, cyclic AMP. Notwithstanding all the literature data, there is still no sound knowledge or a clear understanding of the hormone's action on the physiology of ovarian follicular cells. OBJECTIVE To review and evaluate studies about melatonin action on the ovarian granulosa/theca interna cells from the literature. METHODS The systematic review was carried out according to the PRISMA recommendations. The MEDLINE and Cochrane primary databases were consulted with the use of specific terms. There was no limitation on language or publication year. RESULTS Seven papers about melatonin action on granulosa cells were selected. The following can be attributed to the hormone's effects: a) progesterone increase in culture medium; b) increased estrogen production; c) antagonistic action on estrogen; d) improvement in cell quality resulting in improved embryo and higher pregnancy rates; e) improved cell proliferation via MAPK; f) reduction of free radicals. Nevertheless, there are contrarian papers reporting a reduction in progesterone production. Melatonin interferes in sex steroid production, boosting progesterone output. Such action may help improve oocyte quality.


Assuntos
Melatonina/farmacologia , Oócitos/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Células Cultivadas , Feminino , Células da Granulosa/efeitos dos fármacos , Humanos , Oócitos/crescimento & desenvolvimento , Gravidez , Progesterona/antagonistas & inibidores , Células Tecais/efeitos dos fármacos
8.
Ecotoxicol Environ Saf ; 183: 109544, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31400720

RESUMO

Cigarette smoke can affect female reproductive health by causing follicle destruction and oocyte dysfunction. Third-hand smoke has received increasing attention as a public health issue. However, the effects of third-hand smoke on the female reproductive system, particularly the ovaries, remain unclear. 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal (NNA) can be used as a biomarker of third-hand smoke. We studied the in vivo toxic effects of NNA on mice ovaries and offspring development. Three-week-old premature female mice were exposed to NNA at two different concentrations (0.075 µg/kg and 0.15 µg/kg body weight) and tap water (blank control) and diluted dimethylsulfoxide (solvent control) for 30 days. We found that oral administration of NNA (0.075 µg/kg and 0.15 µg/kg) significantly reduced ovary weight (the 0.15 µg/kg group was reduced to 18.69% ±â€¯0.89%) and ovarian follicle number (reduced by about 30%) (p < 0.05). Consumption of 0.15 µg/kg NNA reduced the survival rate of superovulated oocytes from 91.36% to 60.55% (p < 0.05). In addition, treated female mice in each group were mated with normal male mice to observe the effects of NNA on the F1 offspring, and during mating and lactation, all groups were given tap water. Two different concentrations of NNA exposure also significantly reduced body weight and impaired ear opening, tooth eruption and eye opening in F1 offspring, especially those exposed to 0.15 µg/kg NNA (p < 0.05). Our study suggested that NNA exposure had toxic effects on the reproductive health of female mice and their offspring. The results obtained may help evaluate the risks of third-hand smoke to women's reproductive health and to the health of their offspring.


Assuntos
Aldeídos/toxicidade , Ovário/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Piridinas/toxicidade , Reprodução/efeitos dos fármacos , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Lactação , Masculino , Camundongos , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/crescimento & desenvolvimento , Ovário/crescimento & desenvolvimento , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Tabaco/química
9.
Endocrinology ; 160(10): 2471-2484, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398247

RESUMO

Prenatal testosterone (T)-treated sheep, similar to women with polycystic ovary syndrome (PCOS), manifest oligo-/anovulation, hyperandrogenism, and polyfollicular ovary. The polyfollicular ovarian morphology, a result of persistence of antral follicles, arises, in part, by transcriptional changes in key mediators of follicular development that, in turn, are driven by epigenetic mechanisms. We hypothesized that prenatal T excess induces, in a cell-specific manner, transcriptional changes in key mediators of follicular development associated with relevant changes in epigenetic machinery. Expression levels of key mediators of follicular development, DNA methyltransferases (DNMTs), and histone de-/methylases and de-/acetylases were determined in laser-capture microdissection-isolated antral follicular granulosa and theca and ovarian stromal cells from 21 months of age control and prenatal T-treated sheep (100 mg IM twice weekly from gestational day 30 to 90; term: 147 days). Changes in histone methylation were determined by immunofluorescence. Prenatal T treatment induced the following: (i) cell-specific changes in gene expression of key mediators of follicular development and steroidogenesis; (ii) granulosa, theca, and stromal cell-specific changes in DNMTs and histone de-/methylases and deacetylases, and (iii) increases in histone 3 trimethylation at lysine 9 in granulosa and histone 3 dimethylation at lysine 4 in theca cells. The pattern of histone methylation was consistent with the expression profile of histone de-/methylases in the respective cells. These findings suggest that changes in expression of key genes involved in the development of the polyfollicular phenotype in prenatal T-treated sheep are mediated, at least in part, by cell-specific changes in epigenetic-modifying enzymes.


Assuntos
Epigênese Genética/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Síndrome do Ovário Policístico/veterinária , Doenças dos Ovinos/induzido quimicamente , Propionato de Testosterona/toxicidade , Animais , Feminino , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ovinos , Doenças dos Ovinos/metabolismo
10.
Adv Exp Med Biol ; 1155: 197-203, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468398

RESUMO

It is well known that a large quantity of taurine is present in mammalian ovaries. Taurine reportedly promotes the secretion of female reproductive hormones by stimulating hypothalamus-pituitary-gonadal axis function. Therefore, we speculated that taurine may have beneficial effects on follicle growth, oocyte maturation, fertilization and cleavage. Here, we cultured rat follicles, immature oocytes and sperms in vitro and treated with taurine to observe the changes in follicle diameter, estradiol concentration as well as the rate of oocytes maturation, fertilization and cleavage using an inverted microscope. The results showed that taurine can elevate ovarian follicles growth and oocyte maturation, fertilization, and cleavage rates in vitro, which may be attributed to its osmoregulation and stimulation on the estradiol secretion. Our results provide important insights into taurine application in female production, although the underlying mechanism need to be further addressed.


Assuntos
Oócitos/citologia , Folículo Ovariano/efeitos dos fármacos , Taurina/farmacologia , Animais , Células Cultivadas , Estradiol , Feminino , Ratos
11.
In Vivo ; 33(4): 1095-1102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31280197

RESUMO

BACKGROUND/AIM: Perinatal diethylstilbestrol (DES) treatment induces the polyovular follicle containing two or more oocytes in a follicle of mouse ovary through estrogen receptor (ER) ß. The aim of the study was to investigate the direct effects of DES on the neonatal mouse ovary and the gene expression of activins. MATERIALS AND METHODS: Ovaries from neonatal wild-type (WT) or ERß- knockout (ERßKO) mice were organ-cultured in a serum-free medium with or without DES, and polyovular follicle induction and expression of activin signaling related genes were examined. RESULTS: The polyovular follicle and cyst incidence in DES-treated organ-cultured ovaries from WT mice, but not from ERßKO mice, was significantly higher than that of control non-treated cultures. DES altered inhibin (Inh) a, Inhba and Inhbb expression in organ-cultured ovaries from C57BL/6J mice, while no change in Inha and an increase of Inhbb were observed by DES, in both WT and ERßKO mice. CONCLUSION: Alterations in activin signaling are involved in the polyovular follicle induction by DES.


Assuntos
Ativinas/genética , Dietilestilbestrol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ativinas/metabolismo , Animais , Animais Recém-Nascidos , Biomarcadores , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Inibinas/genética , Inibinas/metabolismo , Camundongos , Camundongos Knockout , Folículo Ovariano/citologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , RNA Mensageiro/genética
12.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340581

RESUMO

This study was designed to investigate the protective effect of resveratrol (RES) on premature ovarian failure (POF) and the proliferation of female germline stem cells (FGSCs) at the tissue and cell levels. POF mice were lavaged with RES, and POF ovaries were co-cultured with RES and/or GANT61 in vitro. FGSCs were pretreated with Busulfan and RES and/or GANT61 and co-cultured with M1 macrophages, which were pretreated with RES. The weights of mice and their ovaries, as well as their follicle number, were measured. Ovarian function, antioxidative stress, inflammation, and FGSCs survival were evaluated. RES significantly increased the weights of POF mice and their ovaries as well as the number of follicles, while it decreased the atresia rate of follicles. Higher levels of Mvh, Oct4, SOD2, GPx, and CAT were detected after treatment with RES in vivo and in vitro. RES treatment resulted in significantly lower TNF-α and IL-6 concentrations and an obviously higher IL-10 concentration in the ovaries. In FGSCs, higher Mvh, Oct4, and SOD2 concentrations and lower TNF-α, IL-6, and MDA concentrations were measured in the RES group. Blockage of the Hh signaling pathway reversed the protective effect of RES on FGSCs. In conclusion, RES effectively improved the ovarian function of the POF model and the productive capacity of FGSCs via relieving oxidative stress and inflammation and a mechanism involving the Hh signaling pathway, suggesting that RES is a potential agent against POF and can aid in the survival of FGSCs.


Assuntos
Antioxidantes/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células-Tronco de Oogônios/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Insuficiência Ovariana Primária/tratamento farmacológico , Resveratrol/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Bussulfano/toxicidade , Catalase/genética , Catalase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Feminino , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Células-Tronco de Oogônios/metabolismo , Células-Tronco de Oogônios/patologia , Tamanho do Órgão/efeitos dos fármacos , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Cultura Primária de Células , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/patologia , Piridinas/antagonistas & inibidores , Piridinas/farmacologia , Pirimidinas/antagonistas & inibidores , Pirimidinas/farmacologia , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
13.
Biomed Pharmacother ; 116: 109008, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152926

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Huyang Yangkun Formula (HYF) has been prescribed for premature ovarian insufficiency (POI) for decades in the clinical setting. Little is known regarding its underlying molecular mechanism. This study was conducted to elucidate the possible mechanism of the protective potential of HYF against POI induced by the industrial chemical 4-vinylcyclohexene diepoxide (VCD) in rats. AIM OF THE STUDY: Quality control of HYF was conducted via HPLC and UPLC-MS. Female rats were injected with VCD (160 mg/kg) daily for 15 days. Then, 1.35 g/kg (low dose) or 0.235 g/kg (high dose) HYF was administered once/day for 25 days. Serum AMH, FSH, E2, ALT, AST, BUN and Cr levels were detected through ELISA and HE-stained follicles were counted in ovarian sections. Additionally, RNA-seq profiling analysis and functional assays were used to screen for differentially expressed genes and key regulators with potentially important roles associated with HYF. RESULTS: The ovaries of POI rats contained fewer antral and maturing follicles (p < 0.05) than those of control rats, whereas atretic follicles were increased significantly (p < 0.05), and AMH levels were significantly lower in the VCD group than in the control group (p < 0.05). These conditions showed some improvement after low- and high-dose HYF treatment. Low- and high-dose HYF increased AMH levels by 42.4% and 25.9% and decreased FSH levels by 17.5% and 24.1%, respectively, in comparison to the VCD group. The two HYF dosage groups showed significantly increased numbers of antral and maturing follicles but a reduced number of atretic follicles (p < 0.05). HYF down-regulation of JAK, Lats2 and YAP mRNA expression gene expression (p < 0.05) compared with the VCD group. HYF resulted in a strongly attenuated VCD-induced phosphorylation of JAK2 and STAT3 (p < 0.01) and YAP (p < 0.001), but induced an increase in protein levels of LATS2 (p < 0.05). CONCLUSION: Our findings demonstrated the treatment efficacy of HYF in POI rats and showed that HYF repairs the dysfunction and enhances the ovarian function of POI rats through the Hippo-JAK2/STAT3 signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Janus Quinase 2/metabolismo , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Animais , Hormônio Antimülleriano/sangue , Análise por Conglomerados , Cicloexenos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Ontologia Genética , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Modelos Biológicos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/genética , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Padrões de Referência , Compostos de Vinila
14.
J Assist Reprod Genet ; 36(7): 1497-1511, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31187329

RESUMO

PURPOSE: To investigate the impact of chronically elevated androgens in the presence and absence of an obesogenic diet on oocyte quality in the naturally selected primate periovulatory follicle. METHODS: Rhesus macaques were treated using a 2-by-2 factorial design (n = 10/treatment) near the onset of menarche with implants containing either cholesterol (C) or testosterone (T, 4-5-fold increase above C) and a standard or "Western-style" diet alone (WSD) or in combination (T+WSD). Following ~ 3.5 years of treatment, females underwent controlled ovulation (COv, n = 7-10/treatment) cycles, and contents of the naturally selected periovulatory follicle were aspirated. Follicular fluid (FF) was analyzed for cytokines, chemokines, growth factors, and steroids. RNA was extracted from luteinizing granulosa cells (LGCs) and assessed by RNA-seq. RESULTS: Only healthy, metaphase (M) I/II-stage oocytes (100%) were retrieved in the C group, whereas several degenerated oocytes were recovered in other groups (33-43% of T, WSD, and T+WSD samples). Levels of two chemokines and one growth factor were reduced (p < 0.04) in FF of follicles with a MI/MII oocyte in WSD+T (CCL11) or T and WSD+T groups (CCL2 and FGF2) compared to C and/or WSD. Intrafollicular cortisol was elevated in T compared to C follicles (p < 0.02). Changes in the expression pattern of 640+ gene products were detected in LGC samples from follicles with degenerated versus MI/MII-stage oocytes. Pathway analysis on RNAs altered by T and/or WSD found enrichment of genes mapping to steroidogenic and immune cell pathways. CONCLUSIONS: Female primates experiencing hyperandrogenemia and/or consuming a WSD exhibit an altered intrafollicular microenvironment and reduced oocyte quality/competency, despite displaying menstrual cyclicity.


Assuntos
Androgênios/metabolismo , Células da Granulosa/metabolismo , Oócitos/metabolismo , Folículo Ovariano/metabolismo , Animais , Quimiocinas/metabolismo , Citocinas/metabolismo , Dieta Ocidental/efeitos adversos , Feminino , Líquido Folicular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Células da Granulosa/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Modelos Animais , Recuperação de Oócitos , Oócitos/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Primatas/metabolismo , Esteroides/metabolismo
15.
Chin Med J (Engl) ; 132(12): 1448-1453, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31205103

RESUMO

BACKGROUND: There is no absolute consensus for the best time for triggering. The aim of this study was to investigate the effect of different proportion of dominant follicles (PDF) on the human chorionic gonadotropin (HCG) day for the clinical outcomes in patients with polycystic ovary syndrome (PCOS) of different ovarian stimulation protocols. METHODS: A total of 371 cycles of the gonadotropin-releasing hormone (GnRH) agonist long protocol and 347 cycles of GnRH antagonist protocol from January 2014 to December 2016 were included in this retrospective study. Based on the PDF on the day of the HCG administration, the included patients were divided into three groups: Group A (low PDF), PDF <20%; Group B (medium PDF), 20%≤ PDF ≤40%; Group C (high PDF), PDF >40%. The measurements regarding ovarian stimulation characteristics, fertilization rate, top quality embryo rate, clinical pregnancy rate, and ovarian hyperstimualtion syndrome (OHSS) rate were compared in different PDF groups with different protocols. RESULTS: In both the GnRH antagonist protocol and GnRH agonist long protocol, the characteristics such as mean age, anti-Mullerian hormone, antral follicle count (AFC), and body mass index were comparable between groups. The number of oocytes retrieved decreased statistically significantly as the PDF and rate of matured oocytes increased. In the GnRH agonist long protocol, the rate of normally fertilized oocytes was highest in Group A (59.74 ±â€Š31.21 vs. 49.70 ±â€Š37.95, 49.67 ±â€Š36.62; F = 3.743, P = 0.025). There were no significant differences in the rate of top-quality embryos and the clinical pregnancy rate between the groups. The clinical pregnancy rate was similar in the three groups (63.6%, 62.5%, 67.5%, respectively, χ = 0.989, P = 0.911). The moderate and severe OHSS rate increased statistically significantly when the PDF increased, which was highest in group C (1.4%, 3.1%, 6.7%, respectively, χ = 12.014, P = 0.017). In the GnRH antagonist protocol, there were no significant differences in the rate of top-quality embryos, the rate of normally fertilized oocytes, the clinical pregnancy rate, and the moderate and severe OHSS rate between the groups. The clinical pregnancy rate in Group C was higher than that in Group A (57.9% vs. 46.6%, χ = 10.850, P = 0.093). CONCLUSIONS: In the GnRH antagonist protocol, PDF on the HCG day of less than 20% may be unfavorable to the clinical pregnancy rate in PCOS. In the GnRH agonist long protocol, delaying the HCG trigger timing has no good effect on clinical pregnancy and the risk of OHSS might increase in patients with PCOS.


Assuntos
Transferência Embrionária/métodos , Fertilização In Vitro/métodos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/fisiopatologia , Adulto , Gonadotropina Coriônica/uso terapêutico , Feminino , Hormônio Liberador de Gonadotropina/agonistas , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/uso terapêutico , Antagonistas de Hormônios/uso terapêutico , Humanos , Gravidez , Taxa de Gravidez , Estudos Retrospectivos
16.
J Dairy Sci ; 102(8): 7509-7521, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31155251

RESUMO

Our objective was to evaluate the effect of manipulating progesterone (P4) concentrations before timed artificial insemination (TAI) on reproductive and endocrine outcomes in high-producing Holstein cows. Multiparous lactating Holstein cows (n = 80) were synchronized for first TAI using a Double-Ovsynch protocol and were randomly assigned to receive 25 mg of PGF2α 1 d after the first GnRH treatment of the Breeding-Ovsynch protocol that included a once-used P4 insert (low-P4 group) or to receive 2 new P4 inserts during the Breeding-Ovsynch protocol (high-P4 group). Blood samples were collected thrice weekly from -10 to 32 d relative to TAI for all cows and from 32 to 67 d after TAI for pregnant cows and were analyzed for P4 and pregnancy-specific protein B (PSPB) concentrations. Expression of IFNτ-stimulated gene 15 (ISG15) was assessed in blood leukocytes 18 and 20 d after TAI. As expected, P4 concentrations were greater for high-P4 cows than for low-P4 cows from 3 to 8 d before TAI. Incidence of double ovulation was 3-fold greater for low-P4 cows than for high-P4 cows (33 vs. 10%), which resulted in more twin pregnancies 32 d after TAI for low-P4 cows than for high-P4 cows (29 vs. 0%). Low-P4 cows had larger preovulatory follicles at the last GnRH treatment of the Double-Ovsynch protocol and greater P4 concentrations than high-P4 cows after TAI. Relative expression of ISG15 mRNA 18 and 20 d after TAI was greater for low-P4 cows than for high-P4 cows and for pregnant cows than for nonpregnant cows. Overall, PSPB concentrations tended to be greater for low-P4 cows than for high-P4 cows, and pregnant cows had greater P4 concentrations than nonpregnant cows. In summary, cows with low P4 before TAI had increased preovulatory follicle diameter, PSPB concentrations, relative expression of ISG15 mRNA 18 and 20 d after TAI, double ovulations, and twinning compared with cows with high P4 before TAI. Increasing P4 before TAI may effectively decrease double ovulation and twinning in high-producing multiparous Holstein cows.


Assuntos
Bovinos/fisiologia , Progesterona/administração & dosagem , Animais , Cruzamento , Dinoprosta/administração & dosagem , Sincronização do Estro , Feminino , Hormônio Liberador de Gonadotropina/administração & dosagem , Inseminação Artificial/veterinária , Lactação , Masculino , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia , Ovulação/efeitos dos fármacos , Paridade , Gravidez , Progesterona/sangue , Reprodução/efeitos dos fármacos
17.
Reprod Domest Anim ; 54(8): 1139-1144, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152613

RESUMO

Oxygen concentration has been shown to influence in vitro viability and growth of ovarian follicles. The present study examined the effect of oxygen tension on in vitro development of dog follicles enclosed within the ovarian cortex. Ovaries were obtained from domestic dogs (age, 8 months to 2 years), and cortical fragments were recovered. The cortices were then incubated on 1.5% (w/v) agarose gel blocks within a 4-well culture plate containing Eagle Minimum Essential Medium (MEM). Ovarian follicles within the tissues were processed for histology and assessed for follicle density, viability and diameter immediately after collection (Control) or after 2 or 5 days of in vitro incubation. Apoptotic cells were assessed using TUNEL assay. Comparisons of follicular viability and diameter were performed using analysis of variance followed by Tukey's test (p < 0.05). Comparisons of follicle density and apoptosis among treatments were conducted using Non-parametric Kruskal-Wallis test followed by Friedman's test (p < 0.05). No difference (p > 0.05) in follicle density was observed among groups at Day 2 of in vitro culture. However, the density of follicles within cortices cultured in 20% oxygen for 5 days significantly reduced compared to the Control and those incubated in 5% concentration. The viability of cultured follicles in all treatments decreased (p < 0.05) compared to the Control after 2 days incubation, and this value further reduced (p < 0.05) in 20% oxygen group at Day 5. There were no differences in the percentages of apoptotic follicles between the two treatment groups (p > 0.05). Nevertheless, after 5 days of culture, the percentage of TUNEL-positive follicles increased significantly (p < 0.05) in cortices incubated in 20% oxygen environment. In conclusion, our findings demonstrated that 5% oxygen level was superior to 20% concentration in sustaining in vitro viability of dog follicles enclosed within the ovarian cortex.


Assuntos
Cães , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia , Oxigênio/administração & dosagem , Oxigênio/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Técnicas de Maturação in Vitro de Oócitos/veterinária , Técnicas de Cultura de Tecidos/veterinária
18.
Gen Comp Endocrinol ; 281: 83-90, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31170402

RESUMO

The function of insulin-like growth factor (Igf) system in ovary has attracted much attention, but the role of Igf binding proteins (Igfbps) in ovary is still largely unknown. In this study, the role of Igfbps in oocyte maturation was investigated in zebrafish. The expression of all eight identified Igfbps except Igfbp6b could be detected in the adult ovary and exhibited differential expression profiles during folliculogenesis. The expression of several Igfbps is dynamically changed during oocyte maturation induced by human chorionic gonadotropin (hCG). By treatment of an Igfbps inhibitor NBI-31772 in vitro, the oocyte maturation could be stimulated in a clear dose-, time- and stage-dependent manner. Such effects were also observed by administration of NBI-31772 in vivo. Igfbps are differentially expressed in both follicular cells and oocytes, but the effect of NBI-31772 could only be found in intact follicles and not in the denuded oocytes. Previous studies have demonstrated that Igf3 is the major Igf member in regulating oocyte maturation of zebrafish. Interestingly, NBI-31772 could increase the effect of Igf3 on oocyte maturation. Furthermore, we found the effect of NBI-31772 on oocyte maturation could be blocked by an Igf type 1 receptor inhibitor BMS-536924 in vitro, suggesting the Igfbps can inhibit the oocyte maturation via Igf/Igf1r pathway. Together, we provided the first evidence in fish that Igfbps inhibit oocyte maturation of zebrafish.


Assuntos
Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Oócitos/fisiologia , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Catecóis/farmacologia , Gonadotropina Coriônica/farmacologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Fator de Crescimento Insulin-Like I/metabolismo , Isoquinolinas/farmacologia , Oócitos/metabolismo , Oogênese/efeitos dos fármacos , Folículo Ovariano/citologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Theriogenology ; 136: 1-6, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229779

RESUMO

The objective of this study was to test the hypothesis that Leptin induced in vitro growth in preantral follicles in sheep involves modulation of P450 aromatase expression and steroidogenesis. Accordingly, the expression of P450 aromatase gene was studied in the cumulus cells and oocytes isolated from different stages of preantral follicles (PFs') grown in vivo, cultured in TCM 199B, TCM 199B + Leptin (10 ng/ml) (TCM199BL) or a standard PF culture medium supplemented with Leptin (10 ng/ml) (SML). Ovarian follicles grown in vivo or in SML expressed P450 aromatase both in cumulus cells and oocytes at all the development stages. In the oocytes from PFs' grown in vitro, P450 expression was consistently lower than in those from in vivo grown follicles at all except the preantral stage. The patterns of expression of aromatase gene in the cumulus cells from in vivo grown and the PFs' cultured in TCM 199BL were similar. Significantly higher levels of progesterone production were supported by SML at all the development stages than the other two media. Oestradiol concentration in the spent TCM 199B and SML showed a significant increase as the development progressed from preantral to large antral stage. However, such increase was not sustained beyond early antral stage in the PFs' cultured in TCM199BL. It is concluded that Leptin modulates the expression P450 aromatase while supporting the in vitro development of the ovarian follicles in sheep.


Assuntos
Aromatase/metabolismo , Estrogênios/biossíntese , Leptina/farmacologia , Folículo Ovariano/efeitos dos fármacos , Progesterona/biossíntese , Ovinos , Animais , Aromatase/genética , Meios de Cultura , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Técnicas de Cultura de Tecidos/veterinária
20.
Theriogenology ; 136: 86-94, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31254726

RESUMO

This study evaluated the effect of addition of kaempferol alone or combined with other antioxidants (transferrin, selenium and ascorbic acid) on in vitro culture of sheep isolated secondary follicles and if PI3K pathway is involved in kaempferol action. Secondary follicles were isolated and cultured for 12 days in α-Minimal Essential Medium (α-MEM) supplemented with BSA, insulin, glutamine and hypoxanthine (α-MEM: antioxidant free-medium) or in this medium also added by transferrin, selenium and ascorbic acid (AO: base medium with antioxidants). Moreover, different concentrations of kaempferol (0.1; 1 or 10 µM) were added to the different base media (α-MEM or AO). After culture, glutathione (GSH) levels, mitochondrial activity and meiotic resumption were evaluated. In addition, inhibition of PI3K activity was performed through pretreatment in medium supplemented with LY294002. After 12 days, the percentage of normal follicles was higher (P < 0.05) in AO base medium than the other treatments and similar (P > 0.05) to α-MEM supplemented with 1 or 10 µM kaempferol Moreover, α-MEM plus 1 or 10 µM kaempferol and AO medium showed similar (P > 0.05) follicular diameter, fully-grown oocytes, and GSH levels. However, at the end of the culture, antrum formation was higher (P < 0.05) in α-MEM + 1 µM kaempferol than in AO, and similar (P > 0.05) to α-MEM + 10 µM kaempferol. In addition, oocytes cultured in α-MEM supplemented with 1 µM kaempferol showed greater (P < 0.05) levels of active mitochondria than α-MEM + 10 µM kaempferol and AO medium. The rates of meiotic resumption were similar (P > 0.05) among α-MEM + 1 µM kaempferol and AO medium. LY294002 significantly inhibited antrum formation, follicular diameter and the percentage of fully grown oocytes stimulated by 1 µM kaempferol. In conclusion, 1 µM kaempferol can be used as the single antioxidant present in the base medium, replacing the addition of transferrin, selenium and ascorbic acid during in vitro culture of ovine secondary follicles, maintaining follicular survival, increasing active mitochondria levels, and promoting the oocyte meiotic resumption. Moreover, the development of the ovine secondary follicle stimulated by kaempferol is mediated by PI3K pathway.


Assuntos
Antioxidantes/farmacologia , Quempferóis/farmacologia , Folículo Ovariano/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Meios de Cultura , Feminino , Técnicas de Maturação in Vitro de Oócitos/veterinária , Ovinos , Técnicas de Cultura de Tecidos
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