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1.
PLoS One ; 15(1): e0219105, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31918436

RESUMO

Infertility has been a common postoperative problem caused by peritoneal adhesions. Since several prophylactic agents have recently shown promising preliminary results, more complete studies comparing their real efficacy and safety are needed urgently. The aim of this study was to investigate and describe practical considerations of a porcine model that can be used to assess such prophylactic agents. First, 10 healthy 5½ months old female pigs (24.3-31.3 Kg) underwent a standardized laparoscopy to provoke peritubal adhesion formation without prophylactic agents. After 30 days, a second-look laparoscopy was performed to evaluate adhesions and perform adnexectomy for histopathological evaluation. Adhesions at different sites were classified by grade, for which the scores range from 0 (no adhesion) to 3 (very strong vascularized adhesions), and also by area, with scores ranging from 0 (no adhesion) to 4 (>75% of the injured area). The histopathological evaluation of the distal uterine horns, oviducts and ovaries were compared withthose from a control group of six healthy pigs with no previous surgery. Biological samples were collected to assess vitality, inflammation and renal, hepatic and hematopoietic systems. There were small (but significant) changes in serum albumin (P = 0.07), globulin (P = 0.07), C-reactive protein (P = 0.011), fibrinogen (P = 0.023) and bilirubin (P<0.01) after 30 days, but all values were within the normal range. No inflammation or abscess formation was observed, but different degrees of adhesion were identified. The estimated occurrence of adhesion (scores >0) and of strong / very strong adhesion (scores >1) was 75% (95% CI: 55-94.9) and 65% (95% CI: 45-85), respectively. The porcine model represents a useful animal platform that can be used to test the efficacy and safety of candidate prophylactic agents intended to prevent postoperative peritubal adhesions formation. We present several practical considerations and measures that can help to minimize animal suffering and avoid problems during such experiments.


Assuntos
Tubas Uterinas/patologia , Laparoscopia/efeitos adversos , Ovário/patologia , Complicações Pós-Operatórias/patologia , Aderências Teciduais/patologia , Animais , Bilirrubina/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Modelos Animais de Doenças , Tubas Uterinas/metabolismo , Feminino , Fibrinogênio/metabolismo , Humanos , Ovário/metabolismo , Complicações Pós-Operatórias/sangue , Albumina Sérica/metabolismo , Índice de Gravidade de Doença , Suínos , Aderências Teciduais/sangue , Aderências Teciduais/etiologia
2.
Cancer Immunol Immunother ; 69(1): 115-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31802182

RESUMO

Pro-inflammatory cytokines are crucial mediators of cancer development, representing potential targets for cancer therapy. The molecular mechanism of a vital pro-inflammatory cytokine, IL-17A, in cancer progression and its potential use in therapy through influencing fatty acid (FA) metabolism, especially FA uptake of cancer cells, remains unknown. In the present study, we used IL-17A and ovarian cancer (OvCa), a representative of both obesity-related and inflammation-related cancers, to explore the interactions among IL-17A, cancer cells and adipocytes (which can provide FAs). We found that in the presence of palmitic acid (PA), IL-17A could directly increase the cellular uptake of PA, leading to the proliferation of OvCa cells via the IL-17A/IL-17RA/p-STAT3/FABP4 axis rather than via CD36. Moreover, in vivo experiments using an orthotopic implantation model in IL-17A-deficient mice demonstrated that endogenous IL-17A could fuel OvCa growth and metastasis with increased expression of FABP4 and p-STAT3. Furthermore, analysis of clinical specimens supported the above findings. Our data not only provide useful insights into the clinical intervention of the growth and metastasis of the tumors (such as OvCa) that are prone to growth and metastasis in an adipocyte-rich microenvironment (ARM) but also provides new insights into the roles of IL-17A in tumor progression and immunomodulatory therapy of OvCa.


Assuntos
Adipócitos/imunologia , Interleucina-17/metabolismo , Neoplasias Ovarianas/imunologia , Ácido Palmítico/metabolismo , Adipócitos/metabolismo , Animais , Antígenos CD36/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Ovário/patologia , Fosforilação , Receptores de Interleucina-17/metabolismo , Proteínas Recombinantes/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Microambiente Tumoral/imunologia
3.
Int J Cancer ; 146(7): 1851-1861, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31603993

RESUMO

The goal of our study was to demonstrate the spectrum of genomic alterations present in the residual disease of patients with advanced high-grade serous ovarian cancer (HGSOC) after neoadjuvant chemotherapy (NAC), including matched pretreatment biopsies. During the study period between 2006 and 2017, we collected pre-NAC and post-NAC tumor tissue samples from patients with advanced HGSOC. We performed combined next-generation sequencing and immunohistochemistry to identify actionable targets and pathway activation in post-NAC residual tumors. We also examined whether post-NAC profiling of residual HGSOC identified targetable molecular lesions in the chemotherapy-resistant component of tumors. Among 102 post-NAC samples, 41 (40%) of patients had mutations in homologous recombination repair (HRR) genes (HRR deficiency). Patients with HRR mutations had higher tumor mutation burdens (p < 0.001) and higher alterations in the PI3K-AKT-mTOR pathway (p = 0.004) than patients without these HRR mutations. Nevertheless, we found no significant differences in progression-free survival (p = 0.662) and overall survival (OS; p = 0.828) between the two groups. Most patients (91%) had alterations in at least one of the targetable pathways, and those patients with cell cycle (p = 0.004) and PI3K-AKT-mTOR signaling (p = 0.005) pathway alterations had poorer OS (Bonferroni-corrected threshold = 0.0083, 0.05/6). We showed the genomic landscape of tumor cells remaining in advanced HGSOC after NAC. Once validated, these data can help inform biomarker-driven adjuvant studies in targeting residual tumors to improve the outcomes of patients with advanced HGSOC after NAC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cistadenocarcinoma Seroso/genética , Neoplasias Ovarianas/genética , Ovário/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Ciclo Celular/genética , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/terapia , Procedimentos Cirúrgicos de Citorredução/métodos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Genômica , Humanos , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Terapia Neoadjuvante/métodos , Neoplasia Residual , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/terapia , Ovariectomia/métodos , Ovário/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estudos Retrospectivos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de Sobrevida , Serina-Treonina Quinases TOR/metabolismo
5.
Cancer Immunol Immunother ; 69(1): 33-42, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31781843

RESUMO

Blockading programmed death ligand 1 (PD-L1) shows promising results in patients with some cancers, but not in those with ovarian cancer. V-domain Ig suppressor of T cell activation (VISTA) is a recently discovered immune checkpoint protein that suppresses T cell activation. This study aimed to investigate the expression and clinical significance of VISTA in ovarian cancer as well as its relationship with PD-L1. VISTA and PD-L1 levels in 146 ovarian cancer samples were assessed using immunohistochemistry. We investigated the association between VISTA and other clinicopathological variables, including survival. The associations between the VISTA-encoding C10orf54 gene, other immune checkpoints, and survival were analyzed. VISTA was detected in 51.4% of all samples and 46.6% of PD-L1-negative samples; it was expressed in 28.8%, 35.6%, and 4.1% of tumor cells (TCs), immune cells (ICs), and endothelial cells, respectively. Furthermore, VISTA expression was associated with pathologic type and PD-L1 expression. Moreover, VISTA expression in TCs, but not in ICs, was associated with prolonged progression-free and overall survival in patients with high-grade serous ovarian cancer. The expression of C10orf54 mRNA was associated with prolonged overall survival and immune escape-modulating genes. These results showed that VISTA expression in ovarian tumor cells was associated with a favorable prognosis in patients with high-grade serous ovarian cancer; however, additional studies are required to better understand the expression and role of VISTA in ovarian cancer.


Assuntos
Antígenos B7/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Epitelial do Ovário/mortalidade , Cistadenocarcinoma/mortalidade , Neoplasias Ovarianas/mortalidade , Adulto , Idoso , Antígenos B7/imunologia , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/imunologia , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma/imunologia , Cistadenocarcinoma/patologia , Procedimentos Cirúrgicos de Citorredução , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Ovariectomia , Ovário/patologia , Ovário/cirurgia , Prognóstico , Intervalo Livre de Progressão , Evasão Tumoral/imunologia , Adulto Jovem
6.
Int J Cancer ; 146(2): 439-448, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31381147

RESUMO

AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB-IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2 ) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2-21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83-1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75-0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Indóis/administração & dosagem , Neoplasias Ovarianas/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Procedimentos Cirúrgicos de Citorredução , Feminino , Seguimentos , Humanos , Indóis/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/patologia , Ovário/cirurgia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Placebos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Adulto Jovem
7.
Medicine (Baltimore) ; 98(51): e18407, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31861005

RESUMO

Ovarian cancer (OC) is one of the most common malignant tumors in female reproductive system and most OC cases are diagnosed at an advanced stage with the overall 5-year survival rate below 40%. The function of CD247 enhances T-cell antigen receptor (TCR) signaling cascade and it is necessary for assembling of the TCR/CD3 complex on the surface of T lymphocytes. It is well established that defective CD247 function leads to impaired activation of T cells upon engagement of the TCR.Flow cytometry was used to examine the difference of CD247 T lymphocyte between the OC and ovarian cyst, immunohistochemistry analysis was used to investigate the correlation between CD247 expression and clinicopathologic features of epithelial OC patients.Our study showed that the expression of CD247 in peripheral blood lymphocytes from patients with OC is decreased compared with ovarian cyst patients and the expression of CD247 in tumor infiltrating lymphocytes with cancer tissue is decreased compared with adjacent tissues. We showed that abnormal expression of CD247 was related with differentiation and classification in OC.Our findings suggested that CD247-targeted treatment could be used as a potential therapeutic strategy for OC.


Assuntos
Complexo CD3/metabolismo , Carcinoma/metabolismo , Neoplasias Ovarianas/metabolismo , Carcinoma/classificação , Carcinoma/patologia , Feminino , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/patologia , Ovário/patologia
8.
Medicine (Baltimore) ; 98(48): e18009, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770214

RESUMO

RATIONALE: Strumal carcinoid tumor of the ovary (SCTO) is a very rare kind of ovarian tumor. The symptoms of SCTO are often nonspecific and misleading. Therefore, a full understanding of the characteristics, diagnosis, and treatment methods of SCTO is important. PATIENT CONCERNS: In this study, we report a 63-year-old woman with SCTO whose most obvious symptoms were abdominal distention and weight loss of 5 kg for about 1 month. DIAGNOSIS: Her carbohydrate antigen 125 (CA125) levels were higher than normal. Gynecologic sonography showed an 8.8 × 7.5 cm mass with mixed density and an irregular shape behind the uterus. Pathologic and immunohistologic examinations confirmed SCTO of the right ovary. INTERVENTIONS: The patient underwent complete surgical resection of the whole uterus, bilateral ovaries, and fallopian tubes. OUTCOMES: The patient recovered well with no obvious complications and was discharged on the 10th day postsurgery. LESSONS: Complete surgical resection is vital to treat SCTO. Postsurgical pathologic and immunohistologic examinations can confirm a diagnosis of SCTO.


Assuntos
Tumor Carcinoide/patologia , Neoplasias Ovarianas/patologia , Estruma Ovariano/patologia , Antígeno Ca-125/sangue , Tumor Carcinoide/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Ovário/patologia
9.
Nat Commun ; 10(1): 4626, 2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604923

RESUMO

Infertility in men and women is a complex genetic trait with shared biological bases between the sexes. Here, we perform a series of rare variant analyses across 73,185 women and men to identify genes that contribute to primary gonadal dysfunction. We report CSMD1, a complement regulatory protein on chromosome 8p23, as a strong candidate locus in both sexes. We show that CSMD1 is enriched at the germ-cell/somatic-cell interface in both male and female gonads. Csmd1-knockout males show increased rates of infertility with significantly increased complement C3 protein deposition in the testes, accompanied by severe histological degeneration. Knockout females show significant reduction in ovarian quality and breeding success, as well as mammary branching impairment. Double knockout of Csmd1 and C3 causes non-additive reduction in breeding success, suggesting that CSMD1 and the complement pathway play an important role in the normal postnatal development of the gonads in both sexes.


Assuntos
Infertilidade/genética , Proteínas de Membrana/genética , Proteínas Supressoras de Tumor/genética , Fatores Etários , Animais , Complemento C3/metabolismo , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/patologia , Menopausa/genética , Camundongos Knockout , Mutação , Ovário/patologia , Maturidade Sexual , Testículo/metabolismo
10.
J Ovarian Res ; 12(1): 95, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615543

RESUMO

BACKGROUND: Large cell neuroendocrine carcinoma is a very rare ovarian neoplasm that has a poor clinical outcome even in the early stage, and there is as yet no established treatment. Diagnostic laparoscopy has been used to determine the possibility of primary optimal cytoreductive surgery or neoadjuvant chemotherapy in patients with advanced epithelial ovarian cancer. However, the role of diagnostic laparoscopy is still unclear in large cell neuroendocrine carcinoma due to its rarity. CASE PRESENTATION: A 31-year-old woman with abdominal distention was referred to our hospital. She was strongly suspected of having advanced ovarian cancer because of a huge pelvic mass, massive ascites, and their appearance on medical imaging. However, cytological examinations from ascitic fluid by abdominal paracentesis did not show any malignant cells. She underwent diagnostic laparoscopy to evaluate the possibility of primary optimal cytoreductive surgery, and only tissue sampling was performed for pathological diagnosis because of the countless disseminated lesions of various sizes in the intraperitoneal organs. The patient had no postoperative complications, leading to the early start of postoperative chemotherapy. CONCLUSIONS: To date, there have been no systematic reviews that focused on determining the treatment strategy using laparoscopy. Diagnostic laparoscopy can be helpful to determine the optimal treatment, including primary debulking surgery, neoadjuvant chemotherapy, or best supportive care, assisting in decision-making particularly for patients with advanced large cell neuroendocrine carcinoma with carcinomatous peritonitis.


Assuntos
Abdome/patologia , Carcinoma de Células Grandes/diagnóstico , Carcinoma Neuroendócrino/diagnóstico , Ovário/patologia , Adulto , Líquido Ascítico/patologia , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/cirurgia , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Ovário/diagnóstico por imagem , Paracentese/métodos , Peritonite/diagnóstico , Peritonite/patologia
11.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597292

RESUMO

It is well known that chemotherapeutic agents may lead to premature ovarian failure and infertility. Therefore, fertility preservation is highly recommended for female cancer survivors. Despite the currently available techniques, new, non-invasive methods need to be developed to protect the ovarian follicles during oncological treatments. MicroRNAs can be effective tools in this field, as they alter their expression during chemotherapy exposure, and hence they can be useful to minimize the off-target toxicity. Previously, we identified several miRNAs with an important role in newborn mouse ovaries exposed to chemotherapy; among them, the miR-10a was one of the most downregulated miRNAs. Given the controversial role of miR-10a in the ovarian function, we decided to investigate its implication in chemotherapy-induced gonadotoxicity. The downregulated levels of miR-10a were restored by a liposome system conjugated with a mimic miR-10a, and the overexpressed miR-10a prevented the upregulation of the targeted gene, phosphatase and tensin homolog (Pten). The apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) Assay and Bax expression quantification, while histological studies were also performed to evaluate the follicle count and development. Our results showed that the miR-10a replacement could not protect the ovaries from chemotherapy-induced apoptosis, whereas the targeting of Pten may affect the follicle activation via the phosphoinositide 3-kinase (PI3K)/PTEN/protein kinase B (AKT) pathway. Consequently, the application of miR-10a in fertility preservation is not recommended, and the role of miR-10a needs to be further elucidated.


Assuntos
Antineoplásicos/efeitos adversos , MicroRNAs/genética , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/prevenção & controle , Terapêutica com RNAi , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Expressão Gênica , Lipossomos , Camundongos , MicroRNAs/administração & dosagem , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Insuficiência Ovariana Primária/patologia , Terapêutica com RNAi/métodos , Transdução de Sinais/efeitos dos fármacos , Transfecção , Resultado do Tratamento
12.
Endocr Regul ; 53(3): 146-153, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517633

RESUMO

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common and multifactorial disease associated with female factor infertility. Ulmus minor bark (UMB) is one of the medicinal plants used in Persian folklore as a fertility enhancer. In the current study, we aimed to elucidate the effect of UMB hydro-alcoholic extract on histological parameters and testosterone condition in an experimental model of PCOS rats. METHODS: Thirty female rats were randomly divided into five groups: (1) control, (2) vehicle, (3) PCOS/50 mg [6 mg/kg dehydroepiandrosterone (DHEA) + 50 mg/kg UMB hydro-alcoholic extract], (4) PCOS/150 mg (6 mg/kg DHEA + 150 mg/kg UMB hydro-alcoholic extract), and (5) PCOS (6 mg/kg DHEA). All interventions were performed for 21 days. Afterwards, stereological analysis was done for determination of ovarian volume and follicle number. The serum level of testosterone was measured by ELISA kit. RESULTS: UMB hydro-alcoholic extract improved the total number of the corpus luteum in the treatment groups when compared to the PCOS group (p<0.05). PCOS/150 mg and PCOS/50 mg groups showed significantly lower total number of the primordial, primary, and secondary follicles as well as testosterone level compared to the PCOS group (p<0.05). The total number of antral follicles and volume of ovary did not differ significantly between groups. CONCLUSION: UMB extract may be an effective and good alternative in improving PCOS histo-logical and testosterone disturbances although further studies are warranted to confirm the safety of UMB plant in human.


Assuntos
Ovário/efeitos dos fármacos , Casca de Planta/química , Extratos Vegetais/farmacologia , Síndrome do Ovário Policístico/patologia , Testosterona/sangue , Ulmus/química , Animais , Modelos Animais de Doenças , Etanol/química , Feminino , Fármacos para a Fertilidade Feminina/farmacologia , Infertilidade Feminina/sangue , Infertilidade Feminina/patologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Ovário/patologia , Fitoterapia , Síndrome do Ovário Policístico/sangue , Ratos , Água/química
13.
Aquat Toxicol ; 216: 105290, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31518775

RESUMO

Phthalate esters (PAEs), which are notable plasticizers, can be prolific contaminants in aquatic environments, and have been shown to induce reproductive toxicity. However, the studies concerning their toxicity towards aquatic species are based on individual chemicals, and the combined toxicity of PAEs to aquatic organisms remains unclear. The aim of this study was to explore the potential toxicity mechanisms associated with combined exposure to dibutyl phthalate (DBP) and diisobutyl phthalate (DiBP) in adult female zebrafish ovaries. Zebrafish were exposed to DBP, DiBP and their mixtures for 30 days, and their effects on ovarian histology, plasma sex hormones and ovarian transcriptomics were investigated. Plasma estradiol (E2) levels were significantly decreased by 38.9% in the DBP-1133 exposure group and 41.0% in the DiBP-1038 exposure group. The percentage of late/mature oocytes was also significantly decreased by 17.3% under DBP-1133 exposure and 16.2% under DiBP-1038 exposure, while that under combined exposure was not significantly affected. Nevertheless, transcriptome sequencing revealed 2564 differentially expressed genes (DEGs) in zebrafish ovaries after exposure to the mixtures. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the DEGs were involved in the neuroactive ligand-receptor interaction, GnRH, progesterone-mediated oocyte maturation, oocyte meiosis and steroid hormone biosynthesis signaling pathways. These results revealed that combined exposure exerts potential reproductive toxicity at the molecular level.


Assuntos
Dibutilftalato/análogos & derivados , Dibutilftalato/toxicidade , Exposição Ambiental , Perfilação da Expressão Gênica , Ovário/metabolismo , Transcriptoma/genética , Peixe-Zebra/genética , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Hormônios Esteroides Gonadais/sangue , Ovário/efeitos dos fármacos , Ovário/patologia , Reprodutibilidade dos Testes , Reprodução/efeitos dos fármacos , Reprodução/genética , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/sangue
14.
Toxicol Lett ; 316: 60-72, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520699

RESUMO

Cholestasis is a significant decrease in bile flow. The liver is the primary organ affected by cholestasis. Chronic cholestasis could entail to tissue fibrotic changes and liver cirrhosis. Other organs, including heart, kidneys, nervous system, skeletal muscles, as well as the reproductive system, might also be affected during cholestasis. Although the cholestasis-associated pathological and biochemical alterations in organs such as liver have been widely investigated, there is little information about complications such as cholestasis-induced reproductive toxicity. The current study aimed to evaluate the pathologic effects of cholestasis on reproductive organs in both male and female animals. Rats underwent bile duct ligation (BDL) surgery. Markers of reproductive toxicity, including serum hormonal changes, tissue histopathological alterations, biomarkers of oxidative stress, and markers of mitochondrial impairment, were evaluated. Increased serum markers of liver injury and elevated level of cytotoxic molecules such as bile acids and bilirubin were evident in BDL animals. On the other hand, the serum level of hormones such as testosterone was suppressed in BDL rats. Significant histopathological alterations were also evident in the testis and ovary of BDL animals. A significant increase in oxidative stress markers, including ROS formation, lipid peroxidation, protein carbonylation, and depleted glutathione and antioxidant reservoirs were also detected in BDL rats. Moreover, mitochondrial depolarization decreased dehydrogenases activity, and depleted ATP content was detected in sperm isolated from the BDL group. These data indicate that cholestasis-associated reproductive toxicity in male and female rats is restrictedly coupled with severe oxidative stress and mitochondrial impairment.


Assuntos
Colestase/metabolismo , Mitocôndrias/metabolismo , Ovário/metabolismo , Estresse Oxidativo , Reprodução , Espermatozoides/metabolismo , Testículo/metabolismo , Animais , Colestase/etiologia , Colestase/fisiopatologia , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Feminino , Ligadura , Peroxidação de Lipídeos , Masculino , Mitocôndrias/patologia , Ovário/patologia , Ovário/fisiopatologia , Carbonilação Proteica , Ratos Sprague-Dawley , Medição de Risco , Testículo/patologia , Testículo/fisiopatologia
15.
J Biochem Mol Toxicol ; 33(11): e22398, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31557371

RESUMO

Cyclophosphamide (CTX) has been broadly used in the clinic for the treatment of autoimmune disorders and ovarian cancer. The process of chemotherapy has significant toxicity in the reproductive system as it has detrimental effects on folliculogenesis, which leads to an irreversible premature ovarian failure (POF). Coenzyme Q10 (CoQ10) has positive impacts on the reproductive system due to its antioxidant properties, protecting the cells from free-radical oxidative damage and apoptosis. However, little is known about the possible synergistic effect of CTX and CoQ10 on the expression of genes involved in folliculogenesis, such as proliferation cell nuclear antigen (PCNA) and follicle-stimulating hormone receptor (FSHR). A total of 32 NMRI mice were applied and divided into four groups, including healthy control, CTX, CTX + CoQ10, and CoQ10 groups. The effects of CoQ10 on CTX-induced ovarian injury and folliculogenesis were examined by histopathological and real-time quantitative reverse transcription-polymerase chain reaction analyses. The rates of fertilization (in vitro fertilization), embryo development, as well as the level of reactive oxygen species (ROS) in metaphase II (MII) mouse oocytes after PMSG/HCC treatment were also assessed. Results showed that the treatment with CTX decreased the mRNA expression of PCNA and FSHR, IVF rate, and embryo development whereas the application of CoQ10 successfully reversed those factors. CoQ10 administration significantly enhanced histological morphology and decreased ROS levels and the number of atretic follicles in the ovary of CTX-treated mice. In conclusion, it seems that the protective effect of CoQ10 is exerted via the antioxidant and proliferative properties of this substance on CTX-induced ovarian damage.


Assuntos
Antioxidantes/farmacologia , Ciclofosfamida/farmacologia , Insuficiência Ovariana Primária/induzido quimicamente , Antígeno Nuclear de Célula em Proliferação/genética , Receptores do FSH/genética , Ubiquinona/análogos & derivados , Regulação para Cima/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Ciclofosfamida/administração & dosagem , Sinergismo Farmacológico , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Fertilização In Vitro/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Modelos Animais , Oócitos/metabolismo , Ovário/efeitos dos fármacos , Ovário/patologia , Indução da Ovulação , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ubiquinona/administração & dosagem , Ubiquinona/farmacologia
16.
Chem Biol Interact ; 312: 108792, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31491373

RESUMO

Cadmium (Cd) is an important toxic chemical due to its increasing levels in the environment and bioaccumulation in humans and animals. The present study was performed to evaluate the effects of long-term exposure to 1, 10, or 100 µg/L Cd in drinking water on the development, reproduction and neurotoxicity of offspring when administered to mice from parental puberty to postnatal 10 weeks in offspring. The development parameters measured in offspring included physical development, reflex ontogeny, body weight and body size. The reproductive indices measured consisted of anogenital distances (AGDs), estrous cycle, sperm quality, specific gene expression in Leydig or Sertoli cells, seminiferous epithelium cycle, sex hormone levels, histological morphology and apoptosis in testis or ovary, and the levels of oxidative stress. The determination of neurotoxicity included learning and memory ability, anxiety, and related serum indicators. In addition, blood lipid level, liver and kidney function were also determined by serum biochemical assays. The results showed that exposure to Cd in the present model had no adverse effects on development, but had some reproductive toxicity and neurotoxicity, including alteration of spermatogenic epithelial staging in testis and inducing anxiety in offspring. Furthermore, the levels of total protein, globulins, total bile acid and direct bilirubin were also significantly altered, especially in female offspring. The present study suggested that long-term exposure to low doses of Cd had adverse effects on the health of the next generation, and some harmful effects showed gender differences in offspring. The present study demonstrated that attention should be paid to Cd pollution in the environment, especially before pregnancy.


Assuntos
Cádmio/toxicidade , Reprodução/efeitos dos fármacos , Animais , Análise Química do Sangue , Feminino , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia
17.
Int J Mol Sci ; 20(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491902

RESUMO

This study aimed to investigate the effect of gonadotropin-releasing hormone agonist (GnRHa) treatment on the expression of neuritin 1 (NRN1) in women with ovarian endometriosis. We collected tissues and serum from women with endometriosis treated with (n = 45) or without (n = 37) GnRHa. NRN1 mRNA and protein levels were measured using qPCR and Western blot. Immunolocalization of NRN1 in endometriotic tissues was examined using immunohistochemistry. In addition, a follow-up study was carried out to monitor the serum level of NRN1 in patients before and after GnRHa treatment. Both mRNA (p = 0.046) and protein (p = 0.0155) levels of NRN1 were significantly lower in endometriotic tissues from patients receiving GnRHa treatment compared to the untreated group. Both epithelial and stromal cells of endometriotic tissues from untreated women with endometriosis exhibited stronger staining of NRN1 but not in those who were treated with GnRHa. The follow-up study showed that the serum level of the NRN1 concentration decreased significantly from 1149 ± 192.3 to 379.2 ± 80.16 pg/mL after GnRHa treatment (p = 0.0098). The expression of NRN1 was significantly lower in women with ovarian endometriosis treated with GnRHa. These results suggest that NRN1 may be a biomarker response to the effect of GnRHa treatment for patients with ovarian endometriosis.


Assuntos
Endometriose/etiologia , Endometriose/metabolismo , Hormônio Liberador de Gonadotropina/agonistas , Neuropeptídeos/genética , Ovário/patologia , Adulto , Biomarcadores , Biópsia , Endometriose/tratamento farmacológico , Endometriose/patologia , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Pessoa de Meia-Idade , Neuropeptídeos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto Jovem
18.
Gynecol Oncol ; 155(2): 280-282, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31522838

RESUMO

BACKGROUND: Prophylactic salpingectomy has been heavily promoted based on the theory that serous tubal intraepithelial carcinoma is a precursor lesion for serous ovarian carcinoma. However, the validity of prophylactic salpingectomy has yet to be proven through adequate research. The purpose of this study is to evaluate the completeness of salpingectomy intended for ovarian cancer risk reduction. MATERIALS AND METHODS: Women without a history of ovarian cancer who were undergoing salpingoophorectomy at a single institution in Honolulu, Hawaii were enrolled in this study. Salpingectomy was performed prior to oophorectomy. A blinded pathologist then examined the ovaries for the presence of residual salpingeal tissue. Data collected included type of surgery (minimally invasive or laparotomy) and level of surgeon (attending or resident). Data were analyzed using Fisher's exact test. RESULTS: A total of 107 ovaries were examined. Following salpingectomy, 5.6% (n = 6/107) of ovaries had residual salpingeal tissue present and 94.4% (n = 101/107) of ovaries were absent of salpingeal tissue. Of the ovaries with residual salpingeal tissue, there was no difference in level of surgeon (attending n = 3/107, resident n = 3/107, p = 1.0) or type of surgery (minimally invasive n = 5/107, laparotomy n = 1/107, p = 0.42). DISCUSSION: This is the largest blinded study ever conducted to examine ovaries for residual salpingeal tissue after salpingectomy. In addition, this is the only study to compare learner versus attending outcomes in this setting. This study found that over 94% of salpingectomies resulted in complete removal of salpingeal tissue. Of the ovaries with residual salpingeal tissue, there wasn't a difference among surgeon level and surgery type, but the study was not powered to detect this. This study supports the continued clinical practice of prophylactic salpingectomy for ovarian cancer risk reduction.


Assuntos
Neoplasias Ovarianas/prevenção & controle , Salpingectomia/métodos , Feminino , Humanos , Laparoscopia/métodos , Neoplasia Residual/patologia , Neoplasias Ovarianas/patologia , Ovário/patologia , Estudos Retrospectivos , Comportamento de Redução do Risco , Salpingectomia/estatística & dados numéricos , Salpingo-Ooforectomia/métodos , Salpingo-Ooforectomia/estatística & dados numéricos
19.
J Ovarian Res ; 12(1): 89, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547830

RESUMO

BACKGROUND: Gonadoblastoma (GB) is a rare mixed germ cell-sex cord-stromal tumour, first described in humans, commonly found in dysgenetic gonads of intersex patients that have a Y chromosome. However, this entity in not recognized in the WHO classification of tumours of genital system of domestic animals. Herein, we describe a case of ovarian gonadoblastoma with proliferation of dysgerminoma and sex cord-stromal tumour components, in a phenotypically and cytogenetically normal bitch. CASE PRESENTATION: A 17-year-old cross-breed bitch had a firm, grey-white multinodular mass in the left ovary. The tumour was submitted to histopathological examination and Y chromosome detected through karyotype analysis and PCR studies. Microscopically, the ovary was almost replaced by an irregular neoplasm composed of three distinct, intermixed elements: dysgerminoma, mixed germ cell-sex cord-stromal tumour resembling human GB and a proliferative sex cord-stromal tumour component. The germ cells of gonadoblastoma and dysgerminoma components were immunoreactive for c-KIT. Sex cord-stromal cells of gonadoblastoma were immunoreactive for α-inhibin. The sex cord-stromal tumour was immunoreactive for AE1/AE3, occasionally for α-inhibin and negative for epithelial membrane antigen (EMA). The karyotype was 78, XX and PCR analysis confirmed the absence of the Y chromosome. CONCLUSION: Based on these findings, a diagnosis of gonadoblastoma with proliferation of dysgerminoma and sex cord-stromal tumour was made. This is the first case of ovarian gonadoblastoma in a female dog.


Assuntos
Disgerminoma/diagnóstico , Gonadoblastoma/diagnóstico , Neoplasias Ovarianas/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico , Adulto , Animais , Proliferação de Células/genética , Doenças do Cão/diagnóstico , Doenças do Cão/patologia , Cães , Disgerminoma/complicações , Disgerminoma/patologia , Disgerminoma/veterinária , Feminino , Gonadoblastoma/complicações , Gonadoblastoma/patologia , Gonadoblastoma/veterinária , Humanos , Cariótipo , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/veterinária , Ovário/patologia , Fenótipo , Proteínas Proto-Oncogênicas c-kit/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/complicações , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/veterinária , Células Estromais/patologia , Cromossomo Y/genética
20.
Artigo em Inglês | MEDLINE | ID: mdl-31394255

RESUMO

In the present study, we investigated plasma biochemical and steroid hormone responses, together with gonado-histopathological alterations in Clarias gariepinus exposed to sublethal concentrations of two synthetic pyrethroids (cypermethrin and deltamethrin). Fish were exposed to environmentally-relevant concentrations of cypermethrin at 0 (ethanol solvent control), 0.07, 0.014, 0.028, 0.056) and deltamethrin at 0.22, 0.44, 0.88 and 1.76 µg/L, for 7, 14, 21 and 28 days. Plasma enzyme (aspartate transaminase: AST, alanine transaminase: ALT and alkaline phosphatase: ALP) and steroid hormones (estradiol-17ß: E2, testosterone: T) levels were analyzed. Gonado-histopathological evaluation shows the presence of ovo-testis (intersex), oocytes atresia, cytoplasmic degeneration and clumping of vitellogenic oocytes in females, while male fish displayed enlargement and degeneration of testicular seminiferous tubules after 28 days exposure to cypermethrin and deltamethrin. Plasma biochemical analysis in pesticides exposed fish revealed that AST, ALT and ALP were significantly increased in a concentration-dependent manner. In addition, we observed respective and apparent concentration- and time-dependent increase and decrease of plasma E2 and T levels, compared to control. Interestingly, the significant increase in E2 levels paralleled gonadal ovo-testis (intersex) condition in exposed fish, indicating endocrine disruptive effects of cypermethrin and deltamethrin that favor the estrogenic pathway, in addition to overt negative consequences on reproductive, biochemical and physiological health of the exposed fish.


Assuntos
Peixes-Gato/metabolismo , Disruptores Endócrinos/sangue , Nitrilos/toxicidade , Ovário/metabolismo , Piretrinas/toxicidade , Testículo/metabolismo , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Aspartato Aminotransferases/sangue , Estradiol/sangue , Feminino , Masculino , Ovário/patologia , Reprodução , Testículo/patologia , Testosterona/sangue , Poluentes Químicos da Água/toxicidade
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