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1.
Zhongguo Zhen Jiu ; 44(6): 676-84, 2024 Jun 12.
Artigo em Chinês | MEDLINE | ID: mdl-38867630

RESUMO

OBJECTIVE: To observe the effects of electroacupuncture (EA) on the autophagy of ovarian granulosa cells in rats with premature ovarian insufficiency (POI), and explore the mechanism of EA in improving POI. METHODS: Thirty-two female SD rats were randomly divided into a blank group (n=8) and a model making group (n=24). The rats in the model making group were injected intraperitoneally with cyclophosphamide for 15 days to establish the POI model (the dosage on the 1st day was 50 mg/kg, and 8 mg/kg from the 2nd day to 15th day). The successfully modeled rats were then randomly divided into a model group, an EA group, and an estradiol (E2) group, with 8 rats in each group. Rats in the EA group received EA at bilateral "Gongsun" (SP 4) with continuous wave, frequency of 2 Hz, and current intensity of 0.1 to 1 mA, 20 min per treatment, once daily for 14 days. Rats in the E2 group were administered with E2 (0.01 mg/mL) by gavage (10 mL/kg), once daily for 14 days. The changes in estrous cycle were observed by rapid Giemsa staining before and after modeling. After intervention, ovarian tissue morphology was observed by HE staining; serum levels of follicle-stimulating hormone (FSH), E2, anti-Mullerian hormone (AMH), and inhibin B (INHB) were detected by ELISA; immunofluorescence staining was used to observe the expression of p62 in ovarian granulosa cells; the ultrastructure of ovarian granulosa cells was observed by transmission electron microscopy, and the number of autophagosomes and autolysosomes was compared; Western blot and real-time fluorescence quantitative PCR were used to detect the protein and mRNA expression of p62, Beclin-1, and microtubule-associated protein 1A/1B-light chain 3 (LC3) in ovarian tissue. RESULTS: The results of vaginal smears in the blank group showed regular cyclical changes; the rats in the model group showed prolonged estrous cycle or cycle arrest, mostly in proestrus or metestrus, with overall ovarian atrophy, disordered structure, and decreased granulosa cells. Compared with the blank group, rats in the model group showed increased serum FSH level (P<0.01), decreased serum levels of E2, AMH, and INHB (P<0.01), decreased positive expression of p62 in ovarian granulosa cells (P<0.01), with obvious swelling of ovarian granulosa cells, mild to moderate swelling of mitochondria, slight expansion of rough endoplasmic reticulum, and hypertrophy of Golgi apparatus; the number of autophagosomes and autolysosomes in the ovaries was increased (P<0.01), the expression of p62 protein and mRNA was decreased (P<0.01), and the expression of Beclin-1 and LC3 protein and mRNA in ovarian tissue was increased (P<0.01). Compared with the model group, rats in the EA group and the E2 group showed decreased serum FSH levels (P<0.01), increased levels of E2, AMH, and INHB (P<0.01), increased positive expression of p62 in ovarian granulosa cells (P<0.01), alleviated degree of ovarian granulosa cell damage, with relatively intact organelle morphology, and decreased number of autophagosomes and autolysosomes in the ovaries (P<0.01); the rats also showed increased expression of p62 protein and mRNA (P<0.01), and decreased expression of Beclin-1 and LC3 protein and mRNA (P<0.01) in ovarian tissue. CONCLUSION: EA at "Gongsun" (SP 4) could improve ovarian reserve function in POI rats by reducing the number of autophagosomes and autolysosomes, up-regulating p62 expression, and down-regulating Beclin-1 and LC3 expression, thus inhibiting autophagy of ovarian granulosa cells, and regulating the serum levels of FSH, E2, AMH, and INHB.


Assuntos
Autofagia , Eletroacupuntura , Células da Granulosa , Insuficiência Ovariana Primária , Ratos Sprague-Dawley , Animais , Feminino , Insuficiência Ovariana Primária/terapia , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/fisiopatologia , Ratos , Humanos , Células da Granulosa/metabolismo , Modelos Animais de Doenças
2.
J Ovarian Res ; 17(1): 103, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760837

RESUMO

BACKGROUND: Fragile X-associated primary ovarian insufficiency (FXPOI), characterized by amenorrhea before age 40 years, occurs in 20% of female FMR1 premutation carriers. Presently, there are no molecular or biomarkers that can help predicting which FMR1 premutation women will develop FXPOI. We previously demonstrated that high FMR4 levels can discriminate between FMR1 premutation carriers with and without FXPOI. In the present study the relationship between the expression levels of FMR4 and the ovarian reserve markers was assessed in female FMR1 premutation carriers under age of 35 years. METHODS: We examined the association between FMR4 transcript levels and the measures of total antral follicle count (AFC) and serum anti-müllerian hormone (AMH) levels as markers of ovarian follicle reserve. RESULTS: Results revealed a negative association between FMR4 levels and AMH (r = 0.45) and AFC (r = 0.64). Statistically significant higher FMR4 transcript levels were found among those FMR1 premutation women with both, low AFCs and AMH levels. CONCLUSIONS: These findings reinforce previous studies supporting the association between high levels of FMR4 and the risk of developing FXPOI in FMR1 premutation carriers.


Assuntos
Hormônio Antimülleriano , Biomarcadores , Proteína do X Frágil da Deficiência Intelectual , Reserva Ovariana , Insuficiência Ovariana Primária , Humanos , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Reserva Ovariana/genética , Adulto , Biomarcadores/sangue , Hormônio Antimülleriano/sangue , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/sangue , Heterozigoto , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/sangue , Mutação , Folículo Ovariano/metabolismo , Adulto Jovem
3.
Gynecol Endocrinol ; 40(1): 2360085, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38813955

RESUMO

Premature ovarian insufficiency (POI) is a common gynecological endocrine disease, which seriously affects women's physical and mental health and fertility, and its incidence is increasing year by year. With the development of social economy and technology, psychological stressors such as anxiety and depression caused by social, life and environmental factors may be one of the risk factors for POI. We used PubMed to search peer-reviewed original English manuscripts published over the last 10 years to identify established and experimental studies on the relationship between various types of stress and decreased ovarian function. Oxidative stress, follicular atresia, and excessive activation of oocytes, caused by Stress-associated factors may be the main causes of ovarian function damage. This article reviews the relationship between psychological stressors and hypoovarian function and the possible early intervention measures in order to provide new ideas for future clinical treatment and intervention.


Assuntos
Insuficiência Ovariana Primária , Estresse Psicológico , Humanos , Insuficiência Ovariana Primária/psicologia , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/terapia , Feminino , Estresse Psicológico/complicações , Estresse Oxidativo/fisiologia , Fatores de Risco , Depressão/etiologia
4.
Front Endocrinol (Lausanne) ; 15: 1340993, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38818501

RESUMO

Background: The causal relationship between juvenile idiopathic arthritis (JIA) and primary ovarian failure (POF) remains uncertain. To elucidate this relationship, we employed a two-sample Mendelian randomization analysis. Methods: The single nucleotide polymorphisms (SNPs) associated with JIA were obtained from a previously published genome-wide association study (GWAS), while the pooled data for POF originated from the FinnGen consortium. The study populations consisted exclusively of individuals of European descent. In our Mendelian randomization analysis, we performed inverse-variance weighted analysis, weighted-median analysis, weighted-mode analysis and Mendelian randomization-Egger regression analysis, supplemented by sensitivity analyses to validate the accuracy and robustness of the findings. Results: The IVW (OR = 1.23, 95% CI 1.06-1.43; P = 0.007) and weighted median (OR = 1.25, 95% CI 1.06-1.47; P = 0.009), along with sensitivity analysis validation, provide compelling evidence of a significant causal association between JIA and POF. Conclusion: The study revealed a significant causal association between genetically predicted JIA and POF, indicating that JIA significantly elevates the risk of developing POF. Therefore, it is recommended to implement screening for premature ovarian failure in women diagnosed with JIA.


Assuntos
Artrite Juvenil , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Insuficiência Ovariana Primária , Humanos , Análise da Randomização Mendeliana/métodos , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/epidemiologia , Feminino , Artrite Juvenil/genética , Artrite Juvenil/epidemiologia , Estudos de Coortes , Masculino , Predisposição Genética para Doença
5.
Cell Mol Biol (Noisy-le-grand) ; 70(5): 226-232, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38814209

RESUMO

This study aims to analyze the active components and mechanism of Bushen Huoxue (BSHX) formula on the autoimmune premature ovarian insufficiency (POI) by combining network pharmacology and Transcriptomics. The active components and targets of BSHXF were screened through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). POI-related targets were identified through Therapeutic Targets Database (TTD), DisGeNET and drugbank database. The Veen diagram was performed to obtain the action targets. The active compound-target network and Protein-Protein Interaction (PPI) network were built by using STRING database and Cytoscape software. Key targets and active compounds were further identified by topological analysis. Molecular docking shows that Kaempferol, Isorhamnetin and Anhydroicaritin have strong binding to AKT. Finally, a zp3-induced autoimmune ovarian function deficiency mouse model was used to explore the potential mechanism of POI. The potential pathways of BSHXF for the treatment of POI were identified by Transcriptomic analysis. PI3K-AKT and NF-kb pathways were the common pathways between network pharmacology and transcriptomics. Our results revealed that BSHXF could reduce the FSH expression levels and raise the E2, and AMH levels in the serum. Western bloting demonstrates that BSHXF could upregulate the expression of p-PI3K and p-AKT.


Assuntos
Medicamentos de Ervas Chinesas , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fosfatidilinositol 3-Quinases , Insuficiência Ovariana Primária , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/metabolismo , Feminino , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Camundongos , Perfilação da Expressão Gênica , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Modelos Animais de Doenças , Humanos
6.
Reprod Toxicol ; 126: 108608, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38735593

RESUMO

Tripterygium wilfordii (TW) preparations have been utilized in China for treating rheumatoid arthritis and autoimmune diseases. However, their clinical use is limited due to reproductive toxicity, notably premature ovarian failure (POF). Our study aimed to investigate the effect and mechanism of bergenin in attenuating POF induced by triptolide in mice. POF was induced in female ICR mice via oral triptolide administration (50 µg/kg) for 60 days. Mice received bergenin (25, 50, 100 mg/kg, i.g.) or estradiol valerate (EV) (0.1 mg/kg, i.g.) daily, 1 h before triptolide treatment. In vitro, ovarian granulosa cells (OGCs) were exposed to triptolide (100 nM) and bergenin (1, 3, 10 µM). Antioxidant enzyme activity, protein expression, apoptosis rate, and reactive oxygen species (ROS) levels were assessed. The results showed that triptolide-treated mice exhibited evident atrophy, along with an increase in atretic follicles. Bergenin (50, 100 mg/kg) and EV (0.1 mg/kg), orally administered, exerted significant anti-POF effect. Bergenin and EV also decreased apoptosis in mouse ovaries. In vitro, bergenin (1, 3, 10 µM) attenuated triptolide-induced OGCs apoptosis by reducing levels of apoptosis-related proteins. Additionally, bergenin reduced oxidative stress through downregulation of antioxidant enzymes activity and overall ROS levels. Moreover, the combined use with Sh-Nrf2 resulted in a reduced protection of bergenin against triptolide-induced apoptosis of OGCs. Together, bergenin counteracts triptolide-caused POF in mice by inhibiting Nrf2-mediated oxidative stress and preventing OGC apoptosis. Combining bergenin with TW preparations may effectively reduce the risk of POF.


Assuntos
Antioxidantes , Apoptose , Benzopiranos , Diterpenos , Compostos de Epóxi , Células da Granulosa , Camundongos Endogâmicos ICR , Fenantrenos , Insuficiência Ovariana Primária , Espécies Reativas de Oxigênio , Animais , Feminino , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/prevenção & controle , Diterpenos/farmacologia , Fenantrenos/toxicidade , Fenantrenos/farmacologia , Compostos de Epóxi/toxicidade , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Benzopiranos/farmacologia , Benzopiranos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Camundongos , Células Cultivadas
7.
Transpl Immunol ; 84: 102051, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38744348

RESUMO

BACKGROUND: Premature ovarian failure (POF), also known as primary ovarian insufficiency, is a common endocrine disease in young women. The emergence of regenerative medicine using stem cells may improve ovarian function and structure, and represents a promising prospect for POF treatment. In his study, we explored the therapeutic effects of human umbilical cord mesenchymal stem cell (HUCMSC) transplantation in a Tibetan miniature pig model of cyclophosphamide (CTX)-induced POF. METHODS: We cultured and identified HUCMSCs, labeled them with DiR iodide red dye, and implanted them into a CTX-induced model of POF in Tibetan miniature pigs. The daily weight changes were recorded, and the levels of estradiol (E2) and follicle-stimulating hormone (FSH) were measured on days 0, 7, and 14. At the end of the 21-day observation period, in vivo imaging of the bilateral ovaries was performed, and the ovarian index was measured. Ovarian tissue morphology and follicles were examined by hematoxylin-eosin staining. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay was employed to assess cell apoptosis, and immunohistochemistry was used to determine the levels of p-AKT, p-ERK1/2, BAX, and BCL2 expression. RESULTS: Our analysis indicated successful delivery of HUCMSCs to the ovaries of the POF pig model. Significant increases were observed in body weight, E2 levels, ovarian index, and number of normal follicles (all p < 0.05). Moreover, FSH levels reduced and ovarian tissue morphology improved following HUCMSCs transplantation (all p < 0.05). Importantly, upregulated p-AKT, p-ERK1/2, and BCL2 expression were observed, whereas the expression of BAX was suppressed (all p < 0.05), suggesting the inhibition of ovarian cell apoptosis. CONCLUSION: Our study highlights the significant therapeutic effects of HUCMSC transplantation on CTX-induced POF in a Tibetan miniature pig model.


Assuntos
Apoptose , Ciclofosfamida , Modelos Animais de Doenças , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Insuficiência Ovariana Primária , Porco Miniatura , Animais , Feminino , Insuficiência Ovariana Primária/terapia , Insuficiência Ovariana Primária/induzido quimicamente , Suínos , Transplante de Células-Tronco Mesenquimais/métodos , Humanos , Apoptose/efeitos dos fármacos , Cordão Umbilical/citologia , Células Cultivadas , Estradiol/sangue , Ovário/patologia
8.
Cancer Treat Rev ; 128: 102769, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38810574

RESUMO

The therapeutic landscape for early breast cancer (eBC) has expanded by introducing novel anticancer agents into clinical practice. During their reproductive years, women with eBC should be informed of the potential risk of premature ovarian insufficiency (POI) and infertility with the proposed systemic therapy. Although the topic of female fertility is becoming increasingly relevant in patients with cancer, limited information is available on the gonadotoxicity of new agents available for eBC treatment. Analyses from clinical trials and prospective data on ovarian function biomarkers are lacking. The purpose of this systematic review is to report the available preclinical and clinical data on female fertility risk with the use of the new agents that are part of clinical practice use or under development for eBC management. This review highlights the clear need to perform additional research efforts to improve our understanding on the gonoadtoxicity of new anticancer agents.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fertilidade/efeitos dos fármacos , Infertilidade Feminina/induzido quimicamente , Infertilidade Feminina/etiologia , Insuficiência Ovariana Primária/induzido quimicamente , Medição de Risco
9.
Front Endocrinol (Lausanne) ; 15: 1307944, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38737546

RESUMO

Background: Primary ovarian insufficiency (POI) is a common clinical endocrine disorder with a high heterogeneity in both endocrine hormones and etiological phenotypes. However, the etiology of POI remains unclear. Herein, we unraveled the causality of genetically determined metabolites (GDMs) on POI through Mendelian randomization (MR) study with the overarching goal of disclosing underlying mechanisms. Methods: Genetic links with 486 metabolites were retrieved from GWAS data of 7824 European participants as exposures, while GWAS data concerning POI were utilized as the outcome. Via MR analysis, we selected inverse-variance weighted (IVW) method for primary analysis and several additional MR methods (MR-Egger, weighted median, and MR-PRESSO) for sensitivity analyses. MR-Egger intercept and Cochran's Q statistical analysis were conducted to assess potential heterogeneity and pleiotropy. In addition, genetic variations in the key target metabolite were scrutinized further. We conducted replication, meta-analysis, and linkage disequilibrium score regression (LDSC) to reinforce our findings. The MR Steiger test and reverse MR analysis were utilized to assess the robustness of genetic directionality. Furthermore, to deeply explore causality, we performed colocalization analysis and metabolic pathway analysis. Results: Via IVW methods, our study identified 33 metabolites that might exert a causal effect on POI development. X-11437 showed a robustly significant relationship with POI in four MR analysis methods (P IVW=0.0119; P weighted-median =0.0145; PMR-Egger =0.0499; PMR-PRESSO =0.0248). Among the identified metabolites, N-acetylalanine emerged as the most significant in the primary MR analysis using IVW method, reinforcing its pivotal status as a serum biomarker indicative of an elevated POI risk with the most notable P-value (P IVW=0.0007; PMR-PRESSO =0.0022). Multiple analyses were implemented to further demonstrate the reliability and stability of our deduction of causality. Reverse MR analysis did not provide evidence for the causal effects of POI on 33 metabolites. Colocalization analysis revealed that some causal associations between metabolites and POI might be driven by shared genetic variants. Conclusion: By incorporating genomics with metabolomics, this study sought to offer a comprehensive analysis in causal impact of serum metabolome phenotypes on risks of POI with implications for underlying mechanisms, disease screening and prevention.


Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Metabolômica , Insuficiência Ovariana Primária , Humanos , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/metabolismo , Feminino , Metabolômica/métodos , Polimorfismo de Nucleotídeo Único , Metaboloma , Biomarcadores/sangue
10.
Cell Biol Toxicol ; 40(1): 29, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38700571

RESUMO

Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. Mesenchymal stem cells-derived small extracellular vesicles (MSCs-sEVs) are attractive candidates for ovarian function restoration and folliculogenesis for POF due to their safety and efficacy, however, the key mediator in MSCs-sEVs that modulates this response and underlying mechanisms remains elusive. Herein, we reported that YB-1 protein was markedly downregulated in vitro and in vivo models of POF induced with H2O2 and CTX respectively, accompanied by granulosa cells (GCs) senescence phenotype. Notably, BMSCs-sEVs transplantation upregulated YB-1, attenuated oxidative damage-induced cellular senescence in GCs, and significantly improved the ovarian function of POF rats, but that was reversed by YB-1 depletion. Moreover, YB-1 showed an obvious decline in serum and GCs in POF patients. Mechanistically, YB-1 as an RNA-binding protein (RBP) physically interacted with a long non-coding RNA, MALAT1, and increased its stability, further, MALAT1 acted as a competing endogenous RNA (ceRNA) to elevate FOXO3 levels by sequestering miR-211-5p to prevent its degradation, leading to repair of ovarian function. In summary, we demonstrated that BMSCs-sEVs improve ovarian function by releasing YB-1, which mediates MALAT1/miR-211-5p/FOXO3 axis regulation, providing a possible therapeutic target for patients with POF.


Assuntos
Exossomos , Proteína Forkhead Box O3 , Células da Granulosa , Células-Tronco Mesenquimais , MicroRNAs , Insuficiência Ovariana Primária , RNA Longo não Codificante , Proteína 1 de Ligação a Y-Box , Animais , Feminino , Humanos , Ratos , Senescência Celular , Exossomos/metabolismo , Proteína Forkhead Box O3/metabolismo , Proteína Forkhead Box O3/genética , Células da Granulosa/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Ovário/metabolismo , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/genética , Ratos Sprague-Dawley , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Proteína 1 de Ligação a Y-Box/genética
11.
Front Endocrinol (Lausanne) ; 15: 1343803, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38745952

RESUMO

Purpose: This study aims to retrospectively estimate cumulative reproductive outcomes in women with primary ovarian insufficiency (POI) in assisted reproductive technology (ART) therapy. Methods: A total of 139 patients diagnosed with POI were reviewed in this study. Firstly, they were divided into two groups according to oocyte origin: using their own oocytes (OG group) or accepting oocyte donations (OD I group). Secondly, the patients were split depending on the pregnancy outcome. In the OG group, nine patients decided to use others' oocytes after a failure of attempting to use their own, and this population was the oocyte donation II group (OD II group). Results: There were 88 patients who used their own oocytes, while 51 patients accepted oocyte donations. In the OG group, there are only 10 (7.2%) patients who got pregnant, and patients in the OD group had worse hormone levels (FSH 71.37 ± 4.18 vs. 43.98 ± 2.53, AMH 0.06 ± 0.04 vs. 1.15 ± 0.15, and AFC 0.10 ± 0.06 vs. 1.15 ± 0.15) and more years of infertility (5.04 ± 0.48 vs. 3.82 ± 0.30), which explained why they choose oocyte donation. In all the three groups, baseline characteristics were comparable between pregnant women and non-pregnant women. Of the 10 pregnant patients in the OG group, four of them used luteal-phase short-acting long protocol and had pregnancies successfully in their first cycles. Conclusion: Ovarian stimulation in POI women requires more cost and time. For those with a stronger desire to have genetic offspring, luteal-phase short-acting long protocol may help them obtain pregnancy rapidly.


Assuntos
Doação de Oócitos , Resultado da Gravidez , Insuficiência Ovariana Primária , Técnicas de Reprodução Assistida , Humanos , Feminino , Gravidez , Estudos Retrospectivos , Insuficiência Ovariana Primária/terapia , Adulto , Taxa de Gravidez , Indução da Ovulação/métodos , Infertilidade Feminina/terapia
12.
Reprod Biol ; 24(2): 100889, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38733657

RESUMO

Mitophagy, the cellular process that removes damaged mitochondria, plays a crucial role in maintaining normal cell functions. It is deeply involved in the entire process of follicle development and is associated with various ovarian diseases. This review aims to provide a comprehensive overview of mitophagy regulation, emphasizing its role at different stages of follicular development. Additionally, the study illuminates the relationship between mitophagy and ovarian diseases, including ovary aging (OA), primary ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS). A detailed understanding of mitophagy could reveal valuable insights and novel strategies for managing female ovarian reproductive health.


Assuntos
Mitofagia , Folículo Ovariano , Mitofagia/fisiologia , Feminino , Folículo Ovariano/fisiologia , Humanos , Animais , Mitocôndrias/fisiologia , Mitocôndrias/metabolismo , Insuficiência Ovariana Primária
13.
J Ovarian Res ; 17(1): 75, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38575997

RESUMO

Umbilical cord-derived mesenchymal stem cell (UCMSC) transplantation has been deeply explored for premature ovarian insufficiency (POI) disease. However, the associated mechanism remains to be researched. To explore whether and how the microRNA 21 (miR-21) functions in POI mice with UCMSCs transplantation, the autoimmune-induced POI mice model was built up, transplanted with or without UCMSCs transfect with the LV-hsa-miR-21-5p/LV-hsa-miR-21-5p-inhibition, with the transfection efficiency analyzed by QRT-PCR. Mice hormone secretion and the anti-Zona pellucida antibody (AZPAb) levels were analyzed, the ovarian morphological changes and folliculogenesis were observed, and the ovarian apoptosis cells were detected to evaluate ovarian function. The expression and localization of the PTEN/Akt/FOXO3a signal pathway-related cytokines were analyzed in mice ovaries.Additionally, the spleen levels of CD8 + CD28-T cells were tested and qualified with its significant secretory factor, interleukin 10 (IL-10). We found that with the LV-hsa-miR-21-5p-inhibition-UCMSCs transplantation, the mice ovarian function can be hardly recovered than mice with LV-NC-UCMSCs transplantation, and the PTEN/Akt/FOXO3a signal pathway was activated. The expression levels of the CD8 + CD28-T cells were decreased, with the decreased levels of the IL-10 expression. In contrast, in mice with the LV-hsa-miR-21-5p-UCMSCs transplantation, the injured ovarian function can be reversed, and the PTEN/AKT/FOXO3a signal pathway was detected activated, with the increased levels of the CD8 + CD28-T cells, and the increased serum levels of IL-10. In conclusion, miR-21 improves the ovarian function recovery of POI mice with UCMSCs transplantation, and the mechanisms may be through suppressing the PTEN/AKT/FOXO3a signal pathway and up-regulating the circulating of the CD8 + CD28-T cells.


Assuntos
Menopausa Precoce , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , MicroRNAs , Insuficiência Ovariana Primária , Animais , Feminino , Camundongos , Antígenos CD28 , Interleucina-10/genética , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/terapia , Insuficiência Ovariana Primária/induzido quimicamente , Proteínas Proto-Oncogênicas c-akt
14.
Stem Cell Res Ther ; 15(1): 102, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38589967

RESUMO

BACKGROUND: Premature ovarian insufficiency (POI) is a major cause of infertility. In this study, we aimed to investigate the effects of the combination of bone marrow mesenchymal stem cells (BMSCs) and moxibustion (BMSCs-MOX) on POI and evaluate the underlying mechanisms. METHODS: A POI rat model was established by injecting different doses of cyclophosphamide (Cy). The modeling of POI and the effects of the treatments were assessed by evaluating estrous cycle, serum hormone levels, ovarian weight, ovarian index, and ovarian histopathological analysis. The effects of moxibustion on BMSCs migration were evaluated by tracking DiR-labeled BMSCs and analyzing the expression of chemokines stromal cell-derived factor 1 (Sdf1) and chemokine receptor type 4 (Cxcr4). Mitochondrial function and mitophagy were assessed by measuring the levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ATP, and the mitophagy markers (Drp1, Pink1, and Parkin). Furthermore, the mitophagy inhibitor Mdivi-1 and the mitophagy activator CCCP were used to confirm the role of mitophagy in Cy-induced ovarian injury and the underlying mechanism of combination therapy. RESULTS: A suitable rat model of POI was established using Cy injection. Compared to moxibustion or BMSCs transplantation alone, BMSCs-MOX showed improved outcomes, such as reduced estrous cycle disorders, improved ovarian weight and index, normalized serum hormone levels, increased ovarian reserve, and reduced follicle atresia. Moxibustion enhanced Sdf1 and Cxcr4 expression, promoting BMSCs migration. BMSCs-MOX reduced ROS levels; upregulated MMP and ATP levels in ovarian granulosa cells (GCs); and downregulated Drp1, Pink1, and Parkin expression in ovarian tissues. Mdivi-1 significantly mitigated mitochondrial dysfunction in ovarian GCs and improved ovarian function. CCCP inhibited the ability of BMSCs-MOX treatment to regulate mitophagy and ameliorate Cy-induced ovarian injury. CONCLUSIONS: Moxibustion enhanced the migration and homing of BMSCs following transplantation and improves their ability to repair ovarian damage. The combination of BMSCs and moxibustion effectively reduced the excessive activation of mitophagy, which helped prevent mitochondrial damage, ultimately improving ovarian function. These findings provide a novel approach for the treatment of pathological ovarian aging and offer new insights into enhancing the efficacy of stem cell therapy for POI patients.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Moxibustão , Insuficiência Ovariana Primária , Humanos , Feminino , Ratos , Animais , Mitofagia , Espécies Reativas de Oxigênio/metabolismo , Carbonil Cianeto m-Clorofenil Hidrazona/efeitos adversos , Carbonil Cianeto m-Clorofenil Hidrazona/metabolismo , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/terapia , Insuficiência Ovariana Primária/patologia , Ciclofosfamida/efeitos adversos , Células-Tronco Mesenquimais/metabolismo , Mitocôndrias/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Quinases/metabolismo , Hormônios/efeitos adversos , Hormônios/metabolismo , Trifosfato de Adenosina/metabolismo
15.
Stem Cell Res Ther ; 15(1): 97, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38581065

RESUMO

BACKGROUND: DNA damage and oxidative stress induced by chemotherapy are important factors in the onset of premature ovarian insufficiency (POI). Studies have shown that mitochondria derived from mesenchymal stem cells (MSC-Mito) are beneficial for age-related diseases, but their efficacy alone is limited. Pyrroloquinoline quinone (PQQ) is a potent antioxidant with significant antiaging and fertility enhancement effects. This study aimed to investigate the therapeutic effect of MSC-Mito in combination with PQQ on POI and the underlying mechanisms involved. METHODS: A POI animal model was established in C57BL/6J mice by cyclophosphamide and busulfan. The effects of MSC-Mito and PQQ administration on the estrous cycle, ovarian pathological damage, sex hormone secretion, and oxidative stress in mice were evaluated using methods such as vaginal smears and ELISAs. Western blotting and immunohistochemistry were used to assess the expression of SIRT1, PGC-1α, and ATM/p53 pathway proteins in ovarian tissues. A cell model was constructed using KGN cells treated with phosphoramide mustard to investigate DNA damage and apoptosis through comet assays and flow cytometry. SIRT1 siRNA was transfected into KGN cells to further explore the role of the SIRT1/ATM/p53 pathway in combination therapy with MSC-Mito and PQQ for POI. RESULTS: The combined treatment of MSC-Mito and PQQ significantly restored ovarian function and antioxidant capacity in mice with POI. This treatment also reduced the loss of follicles at various stages, improving the disrupted estrous cycle. In vitro experiments demonstrated that PQQ facilitated the proliferation of MitoTracker-labelled MSC-Mito, synergistically restoring mitochondrial function and inhibiting oxidative stress in combination with MSC-Mito. Both in vivo and in vitro, the combination of MSC-Mito and PQQ increased mitochondrial biogenesis mediated by SIRT1 and PGC-1α while inhibiting the activation of ATM and p53, consequently reducing DNA damage-mediated cell apoptosis. Furthermore, pretreatment of KGN cells with SIRT1 siRNA reversed nearly all the aforementioned changes induced by the combined treatment. CONCLUSIONS: Our research findings indicate that PQQ facilitates MSC-Mito proliferation and, in combination with MSC-Mito, ameliorates chemotherapy-induced POI through the SIRT1/ATM/p53 signaling pathway.


Assuntos
Células-Tronco Mesenquimais , Insuficiência Ovariana Primária , Animais , Feminino , Humanos , Camundongos , Antioxidantes/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Cofator PQQ/farmacologia , Insuficiência Ovariana Primária/patologia , RNA Interferente Pequeno/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
16.
J Ovarian Res ; 17(1): 80, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622725

RESUMO

BACKGROUND: Chemotherapy exposure has become a main cause of premature ovarian insufficiency (POI). This study aimed to evaluate the role and molecular mechanism of human umbilical cord mesenchymal stem cell-derived exosomes (hUMSC-Exos) in ovarian function protection after chemotherapy. METHODS: hUMSC-Exos were applied to cyclophosphamide-induced premature ovarian insufficiency mice and human ovarian granulosa tumor cells (KGN) to determine their effects on follicular development and granulosa cell apoptosis. Evaluation was done for iron ion and reactive oxygen species (ROS) production, lipid peroxidation levels, and changes in iron death-related molecules (nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Glutathione Peroxidase enzyme 4 (GPX4), and Solute carrier family 7 member 11 cystine glutamate transporter (SLC7A11; xCT)). Furthermore, rescue experiments using an Nrf2 inhibitor were performed to assess the therapeutic effects of hUMSC-Exos on granulosa cells. RESULTS: hUMSC-Exos promoted ovarian hormone levels and primary follicle development in POI mice and reduced granulosa cell apoptosis. After hUMSC-Exos treatment, the ROS production, free iron ions and lipid peroxidation levels of granulosa cells decreased, and the iron death marker proteins Nrf2, xCT and GPX4 also decreased. Furthermore, the Nrf2 inhibitor ML385 significantly attenuated the effects of hUMSC-Exos on granulosa cells. CONCLUSION: hUMSC-Exos inhibit ferroptosis and protect against CTX-induced ovarian damage and granulosa cell apoptosis through the Nrf2/GPX4 signaling pathway, revealing a novel mechanism of hUMSC-Exos in POI therapy.


Assuntos
Antineoplásicos , Exossomos , Ferroptose , Menopausa Precoce , Células-Tronco Mesenquimais , Insuficiência Ovariana Primária , Feminino , Humanos , Animais , Camundongos , Fator 2 Relacionado a NF-E2 , Espécies Reativas de Oxigênio , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/terapia , Ferro
17.
PeerJ ; 12: e17251, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38646488

RESUMO

The occupational chemical 4-Vinylcyclohexene diepoxide (VCD) is a reproductively toxic environmental pollutant that causes follicular failure, leading to premature ovarian insufficiency (POI), which significantly impacts a woman's physical health and fertility. Investigating VCD's pathogenic mechanisms can offer insights for the prevention of ovarian impairment and the treatment of POI. This study established a mouse model of POI through intraperitoneal injection of VCD into female C57BL/6 mice for 15 days. The results were then compared with those of the control group, including a comparison of phenotypic characteristics and transcriptome differences, at two time points: day 15 and day 30. Through a comprehensive analysis of differentially expressed genes (DEGs), key genes were identified and validated some using RT-PCR. The results revealed significant impacts on sex hormone levels, follicle number, and the estrous cycle in VCD-induced POI mice on both day 15 and day 30. The DEGs and enrichment results obtained on day 15 were not as significant as those obtained on day 30. The results of this study provide a preliminary indication that steroid hormone synthesis, DNA damage repair, and impaired oocyte mitosis are pivotal in VCD-mediated ovarian dysfunction. This dysfunction may have been caused by VCD damage to the primordial follicular pool, impairing follicular development and aggravating ovarian damage over time, making it gradually difficult for the ovaries to perform their normal functions.


Assuntos
Cicloexenos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Camundongos Endogâmicos C57BL , Insuficiência Ovariana Primária , Compostos de Vinila , Animais , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/patologia , Feminino , Compostos de Vinila/toxicidade , Camundongos , Transcriptoma/efeitos dos fármacos , Ciclo Estral/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Ovário/efeitos dos fármacos , Ovário/patologia , Ovário/metabolismo
18.
J Ovarian Res ; 17(1): 74, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570862

RESUMO

OBJECTIVE: To comprehensively evaluate the effect of low birth weight on premature ovarian insufficiency. METHODS: We performed a systematic review of the literature by searching MEDLINE, EMBASE, Web of Science, Scopus, Wanfang and CNKI up to August 2023. All cohort and case-control studies that included birth weight as an exposure and premature ovarian insufficiency as an outcome were included in the analysis. Data were combined using inverse-variance weighted meta-analysis with fixed and random effects models and between-study heterogeneity evaluated. We evaluated risk of bias using the Newcastle Ottawa Scale and using Egger's method to test publication bias. All statistical analyses were performed with the use of R software. RESULTS: Five articles were included in the review. A total of 2,248,594 women were included, including 21,813 (1%) cases of premature ovarian insufficiency, 150,743 cases of low birth weight, and 220,703 cases of macrosomia. We found strong evidence that changed the results of the previous review that low birth weight is associated with an increased risk of premature ovarian insufficiency (OR = 1.15, 95%CI 1.09-1.22) in adulthood compared with normal birth weight. No effect of macrosomia on premature ovarian insufficiency was found. CONCLUSIONS: Our meta-analysis showed strong evidence of an association between low birth weight and premature ovarian insufficiency. We should reduce the occurrence of low birth weight by various methods to avoid the occurrence of premature ovarian insufficiency.


Assuntos
Menopausa Precoce , Insuficiência Ovariana Primária , Recém-Nascido , Feminino , Humanos , Peso ao Nascer , Macrossomia Fetal , Recém-Nascido de Baixo Peso
19.
Sci Rep ; 14(1): 9413, 2024 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-38658584

RESUMO

Previous studies investigating the relationship between systemic lupus erythematosus (SLE) and primary ovarian failure (POF) generated conflicting results. To data, no mendelian randomization study has been applied to examine this association. In this study, genetic instruments for exposure (SLE) were selected from a GWAS study with 5201 cases and 9066 noncases. Outcome data for POF and three reproductive traits (age at menarche, age at menopause, and age at first live birth) were obtained from other eligible GWASs. To estimate causal association, the inverse-variance weighted (IVW) method (the main analyse), MR Egger test, weighted median, simple mode, and weighted mode were applied. Moreover, sensitivity analyses were conducted to ensure the robustness of the results. Estimated by the IVW method, SLE was suggested to be causally related to the risk of POF (OR = 1.166, 95% CI 1.055-1.289, P = 0.003) and delayed age at first live birth (OR = 1.006, 95% CI 1.002-1.010, P = 0.007), with no evidence of a causal association between SLE and age at menopause or menarche. The estimates were robust according to sensitivity analysis. In conclusion, the two-sample MR study supported a causal association between SLE and POF from a genetic aspect.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Insuficiência Ovariana Primária , Humanos , Lúpus Eritematoso Sistêmico/genética , Insuficiência Ovariana Primária/genética , Feminino , Menarca/genética , Fatores de Risco , Menopausa/genética , Adulto
20.
J Pediatr Endocrinol Metab ; 37(5): 482-485, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38618883

RESUMO

OBJECTIVES: Childhood cancer survivors are at risk for premature ovarian insufficiency, especially after treatment with alkylating agents. The objective of this report is to highlight a case in which this phenomenon caused a false-positive pregnancy test. CASE PRESENTATION: A workup was performed in a 14-year-old girl with a positive pregnancy test. She was diagnosed with stage IV neuroblastoma of the left adrenal gland at the age of 4 years. She received extensive treatment, including alkylating agents, and had been diagnosed with premature ovarian insufficiency. An LH/hCG suppression test was performed using high dose 17 bèta-estradiol: hCG levels normalized. CONCLUSIONS: The pregnancy test was false-positive due to production of low amounts of hCG by the pituitary gland as a result of high LH concentrations following premature ovarian insufficiency. It may be helpful to perform the LH/hCG suppression test to prove pituitary origin of the hCG overproduction.


Assuntos
Insuficiência Ovariana Primária , Humanos , Feminino , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/patologia , Adolescente , Gravidez , Testes de Gravidez , Neuroblastoma/complicações , Neuroblastoma/patologia , Neuroblastoma/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Reações Falso-Positivas , Hormônio Luteinizante/sangue , Prognóstico
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