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1.
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
2.
Hum Exp Toxicol ; 38(11): 1283-1295, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31370695

RESUMO

BACKGROUND: Cyclophosphamide (CP) causes premature ovarian failure (POF) due to ovarian toxicity. The toxicity mechanism is attributed to oxidative stress, inflammation, and apoptosis. We assessed whether quercetin and rosuvastatin could promote ovarian protection against CP ovotoxicity. METHODS: A total of 80 female BALB/c mice were randomly assigned; 10 mice into each of eight groups. Group 1 (control), group 2 (EH), group 3 (CP), group 4 (QH), group 5 (QL), group 6 (RH), group 7 (RL), and group 8 (COM). RESULTS: Quercetin and rosuvastatin groups (4:8) showed signs of restored ovarian function in the form of a significant, dose-dependent increase in primordial follicles number, serum anti-Mullerian hormone level, and ovarian tissue glutathione level (p < 0.05) versus group 3, and a significant, dose-dependent decrease in atretic follicles number and ovarian tissue level of malondialdehyde (p < 0.05) versus group 3. Immunohistochemistry analysis demonstrated a lower expression of caspase and nuclear factor-kappa B of groups (4:8) versus group 3, although quercetin and rosuvastatin showed a nonsignificant reduction in tumor volume. CONCLUSIONS: We demonstrated the protective effect of quercetin and rosuvastatin against ovarian toxicity and POF induced by CP without compromising its antitumor effect.


Assuntos
Antineoplásicos , Carcinoma de Ehrlich/tratamento farmacológico , Ciclofosfamida , Insuficiência Ovariana Primária/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Quercetina/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico , Animais , Hormônio Antimülleriano/sangue , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma de Ehrlich/sangue , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patologia , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Feminino , Glutationa/metabolismo , Camundongos Endogâmicos BALB C , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/patologia
3.
Zhongguo Zhong Yao Za Zhi ; 44(9): 1895-1903, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31342719

RESUMO

To establish a mouse model of premature ovarian insufficiency( POI) with kidney deficiency and blood stasis pattern by Tripterygium wilfordii polyglycoside( TWP) gavage,and to evaluate the ovarian function and fertility of the model,in order to find Bushen Culuan Decoction therapeutic mechanism. 60 SPF level Blab/c female mice with normal estrous cycle were randomly divided into 6 groups of 10 each: blank group 1( BG1),blank group 2( BG2),blank fertility group( BFG),model group( MG),model recovery group( MRG) and model fertility group( MFG). The mice in three model groups were treated by gastric gavage with TWP suspension 40 mg·kg-1 twice a day for 14 days,while the mice in three blank groups were treated by gastric gavage with same volume normal saline for 14 days. The mice in BG1 and MG were sacrificed and dissected on day 15. The mice in BG2,BFG,MRG and MFG were returned normal feeding from day 15 and were sacrificed and dissected on day 29. The mice in BFG and MFG were cohabited with male mice with a ratio of 2 ∶1( female ∶male) from day 15. The general situation and estrous cycles of all mice were observed every day. Serum sex hormone levels,ovarian index,uterine index,ovarian morphology,follicle count,ovarian VEGF and ES index were observed within the mice in BG1,BG2,MG and MRG. Pregnancy rate,litter size,survival number of newborn mice and male-female proportion were reported within the mice in BFG and MFG. In model establishing stage,the body weight of mice significantly decreased( P <0. 05) in MG and MFG. Compared with BG1,the mice in model group had irregular estrous cycle,decreased ovarian and uterine indexes,less primordial and developing follicles,more atretic follicles,increased VEGF expression and decreased ES expression( P <0. 05). Compared with blank group 2,the mice in model recovery group had irregular estrous cycle,increased FSH level,decreased ovarian indexes,less primordial and developing follicles,more atretic follicles,increased VEGF expression( P<0. 05). Compared with blank fertility group,the mice in model fertility group had smaller litter size and newborn mice survival count( P<0. 05). Gastric gavage with TWP 40 mg·kg-1 twice a day for 14 days is a feasible way to establish a POI kidney deficiency and blood stasis pattern mouse model. The mice ovarian functions didn't recovery on day 14 after stopping TWP intervening,which could suggest the effectiveness of subsequent therapeutic intervention.


Assuntos
Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Insuficiência Ovariana Primária/tratamento farmacológico , Tripterygium/efeitos adversos , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Gravidez , Insuficiência Ovariana Primária/induzido quimicamente , Distribuição Aleatória
4.
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
5.
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
6.
J Ethnopharmacol ; 239: 111885, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31009706

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Kuntai capsule (KTC), a type of herb formulas, was first described in the book of Shang Han Za Bing Lun in the third century. KTC has been widely used for the clinical treatment of menopausal syndrome. Considering that premature ovarian failure is also known as premature menopause, this study was designed to investigate the effects and mechanisms of KTC on a mouse model of premature ovarian failure. MATERIALS AND METHODS: Forty-five female C57BL/6 mice were chosen for this study. Fifteen of the mice were separated into the Control group. The remaining thirty were used to establish the premature ovarian failure model by injecting intraperitoneally with 75 mg/kg cyclophosphamide and then by randomly dividing the mice into two groups. One group was considered the Model group, the other group treated with the Kuntai capsule intragastrically every day for one week called the KTC group. After treatment, mice were sacrificed for sampling. The ovaries morphology of mice was observed by hematoxylin and eosin (HE) staining, and all follicles were counted under microscope. Western blotting was used to detect the PI3K/AKT/mTOR pathway activation. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and anti-mullerian hormone (AMH)levels were measured by enzyme-linked immunosorbent assay (ELISA). The fertility was observed by giving treated mice 8 weeks for breeding. RESULTS: We found that primordial follicle counts were increased in the KTC group compared to the Model group. The phosphorylation of PI3K, AKT, mTOR, 4E-BP1 and S6K in the KTC group significantly reduced compared to Model group. Serum FSH and LH levels in the KTC group were decreased compared to the Model group, while, serum E2 and AMH levels in the KTC group were increased compared with the Model group. The litter size in the KTC group was improved compared to Model group. CONCLUSIONS: The KTC showed protective potentials of ovarian reserve and fertility to attenuate premature ovarian failure, which was relatively associated with activation of the PI3K/AKT/mTOR signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Feminino , Fertilidade/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
J Ethnopharmacol ; 238: 111855, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30953821

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Zuogui Pills (ZGP), which is a classical prescription of Traditional Chinese Medicine (TCM), has been reported to be widely used in the treatment of premature ovarian failure (POF). AIM OF THE STUDY: To investigate the therapeutic effects of ZGP on the treatment of POF induced by chemotherapy, and elucidate the potential molecular mechanism. MATERIALS AND METHODS: Female 8-week-old Sprague-Dawley rats (N = 54) were randomized to six groups, containing the Control group, Model group, three ZGP groups and Triptorelin group which was served as a positive control. The Triptorelin group received triptorelin injection ten days before model establishment by cyclophosphamide. The three ZGP groups (high dose group, medium dose group and low dose group) were given a daily intragastric administration of ZGP at doses of 3.2, 1.6 and 0.8 g/kg for sixty days. We observed the general growth of rats and examed the estrous cycle and the rate of pregnancy, ovarian ultrastructures, follicles and corpora lutea numbers. The serum hormone concentrations were measured by Enzyme-linked immunosorbent assay (ELISA). To explore the molecular mechanism of the effect, gene and protein expression levels of Bax, Bcl-2 and Cyt-c related to apoptosis were determined by quantitative PCR (qPCR), Western Blot and Immunohistochemistry analysis, respectively. RESULTS: After treating with ZGP, though the rate of pregnancy showed no significant difference, the estrous cycle, ovarian ultrastructures, numbers of follicles and corpora lutea were improved significantly. And ZGP led to a significant lower concentration of follicle stimulating hormone (FSH) in the serum, and the concentration of oestradiol (E2) was increased. Furthermore, a significant downregulation of Bax, cytochrome c (Cyt-c), and upregulation of B cell lymphoma/leukemia-2 (Bcl-2) both on gene and protein levels were observed after the administration with ZGP. And effects showed a positive correlation with the dosages. CONCLUSIONS: Our study suggested that ZGP exerted significant effect on POF, which was meditated by inhibiting mitochondria-dependent apoptosis in the follicles.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Insuficiência Ovariana Primária/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Ciclofosfamida/farmacologia , Modelos Animais de Doenças , Estradiol/sangue , Ciclo Estral/efeitos dos fármacos , Feminino , Hormônio Foliculoestimulante/sangue , Masculino , Medicina Tradicional Chinesa , Folículo Ovariano/patologia , Insuficiência Ovariana Primária/patologia , Ratos Sprague-Dawley , Comprimidos
8.
Ann Clin Lab Sci ; 49(1): 16-22, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30814073

RESUMO

OBJECTIVE: This study aims to investigate the role of X-linked inhibitor of apoptosis protein (XIAP) in the pathogenesis of premature ovarian failure (POF) and the effects of the Modified Bazhen Decoction (MBD) in the treatment of POF. MATERIALS AND METHODS: Twenty-four eight-week-old Sprague Dawley (SD) rats were randomly divided into four groups: control group, POF group, MBD treatment group, and Fufang Ejiao Syrup (FES) treatment group. After adaptive feeding for one week, 18 SD rats in the POF, MBD and FES groups were subcutaneously injected with D-galactose (dissolved in saline) at the back of neck for eight weeks (150 mg/kg/day) to establish the POF model. Six SD rats in the control group received equal volumes of subcutaneous injection of saline. Tail blood was collected, and the concentration of follicle stimulating hormones (FSHs) and estradiol (E2) was measured, in order to evaluate the success of the POF model. SD rats in the MBD and FES treatment groups were intragastrically administered with MBD (10 ml/kg/day) and FES (10 ml/kg/day), respectively. Rats in the control and POF groups were intragastrically administered with saline (10 ml/kg/day). After four weeks of intragastrical administration with different medicines and saline, ovarian tissues were collected; and the expression level of XIAP, miR-23a and miR-27a were measured and compared among different groups. RESULTS: Compared with the control group, XIAP expression was significantly lower, and miR-23a and miR-27a expression significantly higher in the POF group. Furthermore, XIAP expression was significantly higher, and miR-23a and miR-27a expression was significantly lower in the MBD group. CONCLUSION: XIAP is involved in the regulation of oocyte and granulosa cells via the cysteinyl aspartate specific proteinase (caspase) pathway, and plays an important role in POF. MBD can dramatically activate XIAP, but inhibit the expression of miR-23a and miR-27a; preventing the apoptosis of oocyte and granulosa cells. Our study suggests that MBD may be a useful traditional Chinese medicine for the treatment of POF.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Células da Granulosa/efeitos dos fármacos , Fitoterapia , Insuficiência Ovariana Primária/tratamento farmacológico , Animais , Feminino , Células da Granulosa/metabolismo , Células da Granulosa/patologia , Proteínas Inibidoras de Apoptose/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/patologia , Ratos , Ratos Sprague-Dawley
10.
Biomed Pharmacother ; 109: 293-303, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30396087

RESUMO

Radiotherapy is one of the most relevant treatment modalities for various types of malignancies. However, it causes premature ovarian failure (POF) and subsequent infertility in women of reproductive age; hence urging the development of effective radioprotective agents. Chrysin, a natural flavone, possesses several pharmacological activities owing to its antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, the aim of this study was to investigate the efficacy of chrysin in limiting γ-radiation-mediated POF and to elucidate the underlying molecular mechanisms. Immature female Sprague-Dawley rats were subjected to a single dose of γ-radiation (3.2 Gy) and/or treated with chrysin (50 mg/kg) once daily for two weeks before and three days post-irradiation. Chrysin prevented the radiation-induced ovarian dysfunction by restoring estradiol levels, preserving the normal ovarian histoarchitecture and combating the follicular loss. Eelectron microscopic analysis showed that the disruption of ultrastructure components due to radiation exposure was hampered by chrysin administration. Mechanistically, chrsyin was able to reduce the levels of the inflammatory markers NF-κB, TNF-α, iNOS and COX-2 in radiation-induced ovarian damage. Chrysin also exhibited potent anti-apoptotic effects against radiation-induced cell death by downregulating the expression of cytochrome c and caspase 3. Radiation obviously induced upregulation of TGF-ß protein with subsequent phospholyration and hence activation of downstream mitogen-activated protein kinases (MAPKs); p38 and JNK. Notably, administration of chrysin successfully counteracted these effects. These findings revealed that chrysin may be beneficial in ameliorating radiation-induced POF, predominantly via downregulating TGF-ß/MAPK signaling pathways leading subsequently to hindering inflammatory and apoptotic signal transduction pathways implicated in POF.


Assuntos
Apoptose/efeitos dos fármacos , Flavonoides/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Insuficiência Ovariana Primária/tratamento farmacológico , Lesões Experimentais por Radiação/tratamento farmacológico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Apoptose/fisiologia , Citoproteção/efeitos dos fármacos , Citoproteção/fisiologia , Feminino , Flavonoides/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/patologia , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
13.
Cell Physiol Biochem ; 50(6): 2060-2070, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30415247

RESUMO

BACKGROUND/AIMS: Over 99% of mouse and human ovarian follicles will undergo specialized cell death including atresia and apoptosis. Reduction of apoptosis may help reduce infertility and maintain the reproductive ability in women. METHODS: 3-day B6D2F1 mice were used to culture small follicle and ovary tissue with niacin and 18-day mice were intraperitoneal injected with niacin to determine its effect on follicle development. Then establish 8-weeks POF animal model with cytoxan (CTX) or radiation. Treatment group was given 0.1 mL of 100 mM niacin by an intraperitoneal injection twice before ovulation. The ovaries were collected and the follicles were counted and categorized, and ovarian histologic sections were stained for TUNEL. Ovarian function was then evaluated by monitoring ovulation. Microarray analyses, Western blot, immunofluorescence and real-time quantitative PCR were used to assess the mechanism of ovarian injury and repair. RESULTS: We found that niacin promotes follicle growth in the immature oocyte and it increased the levels of a germ-line cell marker DDX4, and a cell proliferation marker PCNA in the ovary. Addition of niacin to the cell culture reduced oocyte apoptosis in vitro. Administration of niacin to treat premature ovarian failure (POF) in mouse models showed inhibition of follicular apoptosis under harmful conditions, such as radiation and chemotherapy damage, by markedly reducing cumulus cell apoptosis. Additionally, the number of developing follicles increased after administration of niacin. CONCLUSION: Niacin may have an important function in treating POF by reducing apoptosis in clinical applications.


Assuntos
Apoptose/efeitos dos fármacos , Niacina/farmacologia , Insuficiência Ovariana Primária/patologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ciclofosfamida/toxicidade , RNA Helicases DEAD-box/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Células da Granulosa/citologia , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Isocitrato Desidrogenase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Niacina/uso terapêutico , Folículo Ovariano/citologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/crescimento & desenvolvimento , Ovário/efeitos dos fármacos , Ovário/patologia , Ovário/efeitos da radiação , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/tratamento farmacológico , Antígeno Nuclear de Célula em Proliferação/metabolismo , Radiação Ionizante , Canais de Cátion TRPP/metabolismo
14.
Cell Death Dis ; 9(10): 943, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30237472

RESUMO

There is a controversy in literature as to whether c-Abl is crucial for the induction of TAp63-mediated apoptosis and whether that inhibition of c-Abl with imatinib, which was designed to inhibit the oncogenic kinase BCR-ABL and c-kit, protects oocytes from chemotherapy-induced apoptosis in mice. No human data are available on this issue. We therefore aimed to explore whether genomic damage induced by chemotherapy drug cisplatin activates c-Abl along with TAp63 and the inhibition of c-Abl with imatinib prevents cisplatin-induced oocyte death and follicle loss in human ovary. Exposure to cisplatin induced DNA damage, activated TAp63 and SAPK/JNK pathway, and triggered apoptosis in the oocytes and granulosa cells. However, TAp63 activation after cisplatin was not associated with any increase in the expression of c-Abl. Imatinib did not prevent cisplatin-induced apoptosis of the granulosa cells or oocytes. Moreover, treatment with this drug resulted in the formation of bizarre shaped follicles lacking oocytes and increased follicular atresia by inducing apoptosis of granulosa cells and oocytes. Similar toxic effects were observed when ovarian tissue samples were incubated with a c-kit antagonist drug anti-CD117, but not with another c-Abl tyrosine kinase inhibitor GNF-2, which lacks an inhibitory action on c-kit. Intraperitoneal administration of imatinib to the xenografted animals produced similar histomorphological abnormalities in the follicles in human ovarian grafts and did not prevent cisplatin-induced follicle loss when co-administered with cisplatin. Our findings provide, for the first time, a molecular evidence for ovarian toxicity of this drug in human. Furthermore, this study together with two previous case reports of a severely compromised ovarian response to gonadotropin stimulation and premature ovarian failure in patients, while receiving imatinib, further heighten the concerns about its potential gonadotoxicity on human ovary and urge caution in its use in young female patients.


Assuntos
Dano ao DNA/genética , Genes abl/fisiologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Feminino , Genes abl/genética , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Humanos , Mesilato de Imatinib/uso terapêutico , Immunoblotting , Injeções Intraperitoneais , Camundongos , Camundongos Nus , Oócitos/citologia , Oócitos/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/metabolismo , Técnicas de Cultura de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Natl Compr Canc Netw ; 16(9): 1137-1149, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30181423

RESUMO

Cancer treatments can damage the ovaries, causing primary ovarian insufficiency (POI), a condition associated with numerous sequelae that impact long-term quality of life. This article systematically reviews the literature on the prevalence, surveillance, and treatment of POI in survivors of pediatric and adolescent and young adult (AYA) cancers. A systematic review of the literature was conducted in January 2018 through a search of Medline, Embase, Web of Science, and SCOPUS, alongside the screening of relevant reference lists. An initial search identified 746 potentially relevant studies. A total of 36 studies were included in the final review. Studies were categorized into one of the following categories: incidence/prevalence of POI, measurement of ovarian reserve, and other. Depending on patient characteristics, cancer diagnosis, and treatment, the prevalence of POI ranged from 2.1% to 82.2%. Risk factors for POI included exposure to alkylating agents and abdominal/pelvic radiation. POI may be associated with a number of complications, including low bone mineral density and poor cardiovascular health. Radiotherapy and chemotherapy are known to cause gonadal damage in female survivors of pediatric and AYA cancers. Acute or chronic effects depend on the dose of treatment, age of the individual, radiotherapy field, and ovarian reserve of the individual. Some women experience short-term loss of reproductive function and then may resume menstrual cycles, months or even years later. Although protecting fertility through banking of mature eggs, embryos, and tissue samples has become standard of care, additional steps need to be taken to ensure that patients have adequate hormone levels to maintain whole-body health, including life expectancy, bone health, cardiovascular health, quality of life, sexual and genitourinary function, and neurologic function. Surveillance and management of each of these comorbidities is critically important to survivor health.


Assuntos
Terapia Comportamental/métodos , Sobreviventes de Câncer , Terapia de Reposição de Estrogênios/métodos , Neoplasias/terapia , Insuficiência Ovariana Primária/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Terapia de Reposição de Estrogênios/efeitos adversos , Feminino , Fertilidade/efeitos dos fármacos , Fertilidade/fisiologia , Fertilidade/efeitos da radiação , Preservação da Fertilidade/métodos , Humanos , Incidência , Lactente , Recém-Nascido , Neoplasias/complicações , Ovário/efeitos dos fármacos , Ovário/fisiopatologia , Ovário/efeitos da radiação , Prevalência , Insuficiência Ovariana Primária/epidemiologia , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/psicologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
16.
Gynecol Endocrinol ; 34(12): 1011-1015, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30044147

RESUMO

More empathized approach is required and is obligatory to women with premature ovarian insufficiency (POI) interested for pregnancy. In order to improve fertility rate in POI patients our suggestions would be: (1) To decrease FSH value to 10-15 IU/L by increasing estrogen. Oocyte donation can be suggested after a minimum of six month interval from FSH between 10-15 IU/L and when no dominant follicles are found. (2) To perform oral glucose tolerance test (OGTT). Insulin sensitizing agents has to be included, when indicated, 3-6 month before pregnancy. (3) TSH has to be 1-2.5 mM/L during 3-6 months before pregnancy. (4) Tests for thrombophyllia (Leiden V, FII, MTHFR, PAI) have to be obligatory. They are less expensive than those repeated in vitro fertilizations. Therapy has to be included according to the indications. (5) In order to regulate disturbed immune response in POI patients with endometriosis oral contraceptive therapy is needed for atleast six months prior to the pregnancy. (5) Encourage the patients and advice them about healthy life style and eating habits. (6) Add other drugs, when they are indicated. Complex interplay between endocrine, immunological, haematological, and psychological factors are very often underdetected in POI patients. It is very important to find out the real time for oocyte donation after correcting all the disturbances, improving endometrium receptivity and reaching women's acceptable psychological status. Untreated disturbances induce cardiovascular diseases, diabetes mellitus, thyroid diseases, coagulopathioes etc.


Assuntos
Endométrio/fisiopatologia , Estradiol/uso terapêutico , Infertilidade Feminina/etiologia , Insuficiência Ovariana Primária/complicações , Endometriose/complicações , Estradiol/deficiência , Feminino , Humanos , Resistência à Insulina , Doação de Oócitos , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/imunologia , Insuficiência Ovariana Primária/fisiopatologia , Trombofilia/complicações
17.
J Obstet Gynaecol Res ; 44(8): 1431-1438, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29851197

RESUMO

AIM: To investigate the mechanism of resveratrol treatment in chemically induced premature ovarian insufficiency (POI) in rats. METHODS: Five-week-old specific pathogen-free healthy Sprague-Dawley female rats (n = 90) were randomly divided into five groups (n = 18): low-dose resveratrol (group A), moderate-dose resveratrol (group B), high-dose resveratrol (group C), model control group (group D) and blank control group (group E). POI was induced in rats from the resveratrol-treated groups and the model control group according to observed indexes using a previously established model (oral administration of tripterygium wilfordii polyglycoside tablet 50 mg/kg/day for 14 days). Western blot analysis was performed to compare levels of PI3K, p-PI3K, Akt, p-Akt, mTOR, p-mTOR, Bax, Bcl-2 and Caspase-3 in ovarian tissues of each group, and expression of p-Akt, p-mTOR, Bax, Bcl-2 and Caspase-3 was also evaluated by immunohistochemistry. Serum levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined using enzyme-linked immunosorbent assay. RESULTS: Compared with controls, we found that serum MDA decreased and SOD increased in resveratrol-treated groups. In addition, we found increased expression of p-PI3K, p-Akt, p-mTOR and Bcl-2, and decreased expression of Bax and Caspase-3 were observed in ovarian tissues of treated rats with POI. There was reduced ovarian function in POI rats compared with rats from the blank control group. CONCLUSION: Resveratrol reduced oxidative stress and inhibited apoptosis in granulosa cells by activating the PI3K/Akt/mTOR signaling pathway in a rat model of POI.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Células da Granulosa/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/metabolismo , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Modelos Animais de Doenças , Feminino , Gravidez , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Resveratrol/administração & dosagem
18.
J Pediatr Adolesc Gynecol ; 31(6): 648-650, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29857112

RESUMO

BACKGROUND: The long-term morbidity of childhood cancer survivors is an emerging field as more patients are now expected to live through adulthood. CASE: We describe 2 adolescent patients with permanent premature ovarian failure and failure of endometrium to respond to estrogen after they received a combination of chemotherapy and pelvic radiation for metastatic Ewing sarcoma. Both girls were prepubertal at diagnosis of Ewing sarcoma. Puberty was induced with high-dose estrogen and progesterone; however, none of the patients had withdrawal bleeding. SUMMARY AND CONCLUSION: It is critical to counsel these patients that menstruation might not be possible even with hormone replacement therapy.


Assuntos
Amenorreia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Insuficiência Ovariana Primária/induzido quimicamente , Sarcoma de Ewing/tratamento farmacológico , Amenorreia/tratamento farmacológico , Criança , Endométrio/efeitos dos fármacos , Estrogênios/uso terapêutico , Feminino , Humanos , Insuficiência Ovariana Primária/tratamento farmacológico , Progesterona/uso terapêutico , Puberdade/efeitos dos fármacos
19.
Fertil Steril ; 109(4): 594-600.e1, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29605405

RESUMO

OBJECTIVE: To evaluate the association between estrogen (E) exposure and deficiency and cardiovascular disease (CVD) risk among women with primary ovarian insufficiency (POI). DESIGN: Cross-sectional study conducted between 1996 and 2016. SETTING: Tertiary referral centers. PATIENT(S): A total of 385 women with POI, defined by amenorrhea and FSH levels ≥40 IU/L before 40 years of age, were recruited. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Women underwent a standardized intake questionnaire including data on menstrual cyclicity. Lifetime E exposure and E-free period were assessed. Serum was analyzed for endocrine and CVD profiles. The Framingham 30-year risk of CVD was calculated. RESULT(S): Lifetime E exposure (mean ± SD) was 19.3 ± 7.0 years, E-free period was 3.1 ± 4.1 years, and age at screening was 34.8 ± 7.4 years. In multivariate models E-free interval associated positively with estimated risk of hard and general CVD events (ß 0.18 [95% confidence interval 0.08, 0.29]; 0.20 [0.05, 0.35], respectively), and lifetime E exposure associated negatively with estimated risk of hard and general CVD events (-0.15 [-0.24, -0.05]; -0.16 [-0.29, -0.03], respectively), as well as low density lipoprotein cholesterol (-0.03 [-0.06, 0.00]) and non-high density lipoprotein cholesterol (-0.04 [-0.07, 0.00]). CONCLUSION(S): Prolonged E deprivation is associated with an increased estimated risk of CVD, whereas prolonged E exposure is associated with a reduced estimated risk. These results support the policy of early and continued use of E replacement therapy in women with POI. CLINICAL TRIAL REGISTRATION NUMBER: NCT0230904.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Estradiol/deficiência , Terapia de Reposição de Estrogênios , Insuficiência Ovariana Primária/tratamento farmacológico , Adulto , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Estradiol/sangue , Terapia de Reposição de Estrogênios/efeitos adversos , Feminino , Humanos , Países Baixos/epidemiologia , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/epidemiologia , Prognóstico , Fatores de Proteção , Medição de Risco , Fatores de Risco , Fatores de Tempo
20.
Sci Rep ; 8(1): 6516, 2018 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-29695822

RESUMO

Dacarbazine is commonly administered for the treatment of cancers prevalent in reproductive age females. However, investigations of off-target effects of dacarbazine on the ovary are limited. We assessed the impact of dacarbazine on the ovarian reserve of primordial follicles, essential for fertility. Eight week and 6 month old C57BL/6 J mice were administered with dacarbazine or saline on day (d)0 and d7, then sacrificed after 12 hours (h), or 14d (n = 4-5/group). Follicle numbers, follicle density, serum AMH and corpora lutea were quantified and estrous cyclicity monitored. In reproductively young mice, dacarbazine did not affect primordial follicle numbers at 12 h, but resulted in a 36% reduction at 14d (p < 0.05). Dacarbazine-mediated primordial follicle depletion was accelerated with age, with a 24% (p < 0.05) and 36% (p < 0.01) reduction at 12 h and 14d. Follicle density remained unchanged between treatment groups at either age. Dacarbazine depleted antral follicles at 14d (p < 0.05), at both ages. Despite partial reduction of antral follicles, serum AMH, estrous cyclicity and corpora lutea (indicative of ovulation) remained unchanged between treatment groups, at both ages. Importantly, diminished ovarian reserve can result in premature ovarian insufficiency and infertility, thus, fertility preservation options should be considered for young female patients prior to dacarbazine treatment.


Assuntos
Corpo Lúteo/efeitos dos fármacos , Dacarbazina/farmacologia , Folículo Ovariano/efeitos dos fármacos , Reserva Ovariana/efeitos dos fármacos , Animais , Ciclo Estral/efeitos dos fármacos , Feminino , Fertilidade/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ovulação/efeitos dos fármacos , Insuficiência Ovariana Primária/tratamento farmacológico , Reprodução/efeitos dos fármacos
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