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1.
Lipids Health Dis ; 20(1): 100, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496884

RESUMO

BACKGROUND: The deleterious effect of maternal high-fat diet (HFD) on the fetal rat liver may cause later development of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the effect of maternal HFD-induced maternal hepatic steatosis and dysbiosis on the fetal liver and intestines, and the effect of prenatal metformin in a rat model. METHODS: Sprague-Dawley rats were assigned to three groups (N = 6 in each group). Before mating, the rats were randomly assigned to HFD or normal-chow diet (NCD) group for 7 weeks. After mating, the HFD group rats were continued with high-fat diet during pregnancy and some of the HFD group rats were co-treated with metformin (HFMf) via drinking water during pregnancy. All maternal rats and their fetuses were sacrificed on gestational day 21. The liver and intestinal tissues of both maternal and fetal rats were analyzed. In addition, microbial deoxyribonucleic acid extracted from the maternal fecal samples was analyzed. RESULTS: HFD resulted in maternal weight gain during pregnancy, intrahepatic lipid accumulation, and change in the serum short-chain fatty acid profile, intestinal tight junctions, and dysbiosis in maternal rats. The effect of HFD on maternal rats was alleviated by prenatal metformin, which also ameliorated inflammation and apoptosis in the fetal liver and intestines. CONCLUSIONS: This study demonstrated the beneficial effects of prenatal metformin on maternal liver steatosis, focusing on the gut-liver axis. In addition, the present study indicates that prenatal metformin could ameliorate maternal HFD-induced inflammation and apoptosis in the fetal liver and intestines. This beneficial effect of in-utero exposure of metformin on fetal liver and intestines has not been reported. This study supports the use of prenatal metformin for pregnant obese women.

2.
Cancer Biomark ; 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397404

RESUMO

BACKGROUND: CA125 level normalization at different chemotherapy cycles has been reported to be a prognosticator in advanced epithelial ovarian cancer. OBJECTIVE: In the present study, we investigated whether the time (in days) to CA125 normalization or nadir during treatment could be used as markers to predict survival. METHODS: Patients with FIGO stage III-IV epithelial ovarian cancer treated with cytoreductive surgery followed by adjuvant chemotherapy between 2008 and 2016 were enrolled in this retrospective study. Clinicopathological characteristics, changes in CA125 level during treatment, and survival outcomes were analyzed. Time-dependent receiver operating characteristic curve analysis was used to determine the optimal cut-off values of the time to normalization and time to nadir of CA125 levels to predict survival. Univariate and multivariate Cox regression analysis were used to examine the impact of each variable on survival. RESULTS: A total of 106 patients were included in the analysis. The optimal cut-off values for the time to normalization and nadir for predicting survival were 60 and 194 days, respectively. In Kaplan-Meier survival analysis, CA125 level normalization ⩽ 60 days and CA125 ⩽ 35 u/mL after the third cycle, and CA125 level ⩽ 10 u/mL after the sixth cycle of chemotherapy were associated with significantly better 5-year progression-free survival (PFS) and overall survival (OS). In multivariate analysis, only CA125 level normalization > 60 days was significantly associated with poor survival outcomes (PFS, HR 2.62 [95% CI: 1.54, 4.45], p= 0.004; OS, HR 2.40 [95% CI: 1.19, 4.81], p= 0.014). CONCLUSIONS: Normalization of CA125 level within 60 days after cytoreductive surgery followed by adjuvant chemotherapy in patients with advanced ovarian epithelial cancer could be used as a marker to predict survival.

3.
Int J Gynecol Pathol ; 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34347667

RESUMO

Screening for mismatch repair (MMR) deficiency in unselected patients with endometrial carcinoma (EC) and the clinicopathologic descriptions of ECs with MMR deficiency have been well demonstrated in Western populations, but studies on Asian populations are relatively scarce. In this study, we described the clinicopathologic features of ECs according to MMR status in unselected Taiwanese patients. We also conducted subgroup analysis of MMR-deficient (dMMR) cases according to the presence or absence of MLH1. Patients diagnosed with ECs between January 2017 and February 2020 at our institution were included. Immunohistochemistry analysis of MLH1, PMS2, MSH2, and MSH6 proteins on endometrial primary tumors and clinicopathologic variables were assessed retrospectively. A total of 231 EC patients were enrolled, of whom 50 (21.6%) had dMMR tumors. Of these 50 cases, 39 had tumors that lacked MLH1 expression and 11 were positive for MLH1. The overall dMMR group was significantly related to older age, parity, and high histologic grade compared with the MMR-proficient (pMMR) group. ECs with MLH1 deficiency were obviously associated with several poor pathologic features, including high histologic grade, lymph node metastasis, and lymphovascular space invasion. Moreover, we first reported that parity and the late age at menopause are strongly correlated with MLH1-related dMMR EC group compared with pMMR group. In conclusion, triaging EC patients into pMMR, MLH1-related dMMR and non-MLH1-related dMMR groups by immunohistochemistry analysis may help clinicians to predict disease behavior and guide further management. The strong association between parity and MLH1-related dMMR ECs warrants further investigation on the underlying mechanism.

4.
J Obstet Gynaecol Res ; 47(8): 2729-2736, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34028127

RESUMO

AIM: The predictive accuracy of frozen sections for borderline ovarian tumors (BOTs) is suboptimal. The aim of this study was to determine the diagnostic accuracy of BOTs and factors associated with an upgrade to a permanent pathological diagnosis of invasive carcinoma in patients diagnosed with BOTs by frozen section. METHODS: We conducted a retrospective study between 2011 and 2018 at Kaohsiung Chang Gung Memorial Hospital (KCGMH). Two hundred and twenty-five records of eligible patients with a diagnosis of BOT by frozen section or permanent diagnosis were reviewed. Positive predictive value and the diagnostic accuracy of frozen sections were calculated. Univariate and multivariate analyses were used to determine the clinicopathological factors associated with an upgrade of the diagnosis from a borderline tumor to malignancy. RESULTS: The agreement between frozen section and permanent pathological diagnoses was 63.1%, and the positive predictive value was 72.1%. The multivariate analysis revealed that CA-125 level > 136 U/mL (odds ratio [OR] = 2.96, 95% confidence interval [CI] = 1.3-6.9; p = 0.012), and tumor histologic type (clear cell/endometrioid vs. mucinous; OR:32.8, 95% CI = 6.9-154.8, p < 0.001; clear cell/endometrioid vs. serous: OR 48.1, 95% CI = 8.8-261.8, p < 0.001) were independent risk factors for an upgrade of the permanent diagnosis from a BOT to ovarian carcinoma. CONCLUSION: An elevated CA-125 level (over 136 U/mL) and tumor histologic type (clear cell and endometrioid subtypes) were associated with an upgrade in the diagnosis of ovarian tumor from a BOT on frozen section to a permanent diagnosis of malignancy.


Assuntos
Secções Congeladas , Neoplasias Ovarianas , Antígeno Ca-125 , Feminino , Humanos , Neoplasias Ovarianas/diagnóstico , Valor Preditivo dos Testes , Estudos Retrospectivos
5.
J Clin Endocrinol Metab ; 106(5): 1516-1529, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33507273

RESUMO

CONTEXT: Small extracellular vesicles (sEVs) have emerged as modulators of the disease microenvironment, thereby supporting disease progression. However, the potential role of EVs and their content to the pathophysiology of endometriosis remain unclear. OBJECTIVE: This work aimed to investigate whether the EVs from eutopic (Eu) and ectopic (Ec) endometrial stromal cells (ESCs) differ with respect to protein composition and role in endometriosis. METHODS: Human Eu and Ec endometrium-derived ESCs were isolated from samples of the same patients (n = 3). sEVs were isolated from ESCs via ultracentrifugation; these sEVs were characterized by Western blotting, transmission electron microscopy, and nanoparticle tracking analysis and analyzed using mass spectrometry. The potential role of EcESCs-derived sEVs (EcESCs-sEVs) in endometriosis was explored by assaying their effects on cell viability/proliferation, migration, and angiogenesis. RESULTS: In total, 105 ESCs-sEV-associated proteins were identified from EcESCs-sEVs and EuESCs-sEVs by mass spectrometry analysis. The protein content differed between EcESCs-sEVs and EuESCs-sEVs, with annexin A2 (ANXA2) being the most prominent difference-present in EcESCs-sEVs but not EuESCs-sEVs. We also found that sEVs-ANXA2 regulates the motility, proliferation, and angiogenesis of ESCs via the extracellularly regulated kinase (ERK)/STAT3 pathway. Notably, treatment of ESCs with sEVs-ANXA2 resulted in increased proliferation and motility, suggesting that sEVs-ANXA2 may be involved in regulating endometriosis. Our data suggest that EcESCs-sEVs-ANXA2 regulates the motility and the angiogenic potential of ESCs, implying a role for sEVs-ANXA2 in the pathogenesis of endometriosis. CONCLUSION: The study of sEVs-ANXA2 from Ec endometriotic cells uncovers a new mechanism of endometriosis progression and will inform the development of novel therapeutic strategies.


Assuntos
Endométrio/metabolismo , Vesículas Extracelulares/metabolismo , Células Estromais/metabolismo , Anexina A2/metabolismo , Anexina A2/fisiologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Micropartículas Derivadas de Células/metabolismo , Células Cultivadas , Endometriose/metabolismo , Endometriose/patologia , Endométrio/irrigação sanguínea , Endométrio/citologia , Vesículas Extracelulares/patologia , Feminino , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Doenças Peritoneais/metabolismo , Doenças Peritoneais/patologia , Proteômica , Células Estromais/citologia
6.
Lipids Health Dis ; 19(1): 174, 2020 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-32711539

RESUMO

BACKGROUND: Maternal obesity is an emerging problem in the modern world. Growing evidence suggests that intrauterine high-fat (HF) exposure may predispose progeny to subsequent metabolic challenges. Progeny born to mothers who ate an HF diet also tends to eat an HF diet when growing and aggravate metabolic issues. Thus, the generational transmission of obesity is cyclical. Developing a strategy to prevent the occurrence of metabolic syndrome related to prenatal and/or postnatal HF diet is important. In this study, the reprogramming effects of maternal resveratrol treatment for the progeny with maternal HF/postnatal HF diets were investigated. METHODS: Sprague-Dawley dams were fed either a control or a high-fat/high sucrose diet (HFHS) from mating to lactation. After weaning, the progeny was fed chow or an HF diet. Four experimental groups were yielded: CC (maternal/postnatal control diet), HC (maternal HF/postnatal control diet), CH (maternal control/postnatal HFHS diet), and HH (maternal/postnatal HFHS diet). A fifth group (HRH) received a maternal HFHS diet plus maternal resveratrol treatment and a postnatal chow diet to study the effects of maternal resveratrol therapy. RESULTS: Maternal resveratrol treatment lessened the weight and adiposity of progeny that were programmed by combined prenatal and postnatal HFHS diets. Maternal resveratrol therapy ameliorated the decreased abundance of the sirtuin 1 (SIRT1) enzyme in retroperitoneal tissue and the altered leptin/soluble leptin receptor ratio of progeny. Maternal resveratrol therapy also decreased lipogenesis and increased lipolysis for progeny. CONCLUSIONS: Maternal resveratrol intervention can prevent adiposity programmed by maternal and postnatal HFHS diets by inducing lipid metabolic modulation. This study offers a novel reprogramming role for the effect of maternal resveratrol supplements against obesity.


Assuntos
Adiposidade/efeitos dos fármacos , Resveratrol/farmacologia , Análise de Variância , Animais , Western Blotting , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Lactação/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Masculino , Obesidade/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sirtuína 1/metabolismo
7.
Lipids Health Dis ; 19(1): 105, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32450865

RESUMO

BACKGROUND: Fat accumulation in the liver contributes to the development of non-alcoholic fatty liver disease (NAFLD). N-acetylcysteine (NAC) is an antioxidant, acting both directly and indirectly via upregulation of cellular antioxidants. We examined the mechanisms of liver steatosis after 12 months high fat (HF) diet and tested the ability of NAC to rescue liver steatosis. METHODS: Seven-week-old C57BL/6 (B6) male mice were administered HF diet for 12 months (HF group). Two other groups received HF diet for 12 months accompanied by NAC for 12 months (HFD + NAC(1-12)) or 6 months (HFD + NAC(1-6)). The control group was fed regular diet for 12 months (CD group). RESULTS: Liver steatosis was more pronounced in the HF group than in the CD group after 12 month feeding. NAC intake for 6 or 12 months decreased liver steatosis in comparison with HF diet (p < 0.05). Furthermore, NAC treatment also reduced cellular apoptosis and caspase-3 expression. In the unfolded protein response (UPR) pathway, the expression of ECHS1, HSP60, and HSP70 was decreased in the HFD group (p < 0.05) and rescued by NAC therapy. With regards to the endoplasmic reticulum (ER) stress, Phospho-PERK (p-PERK) and ATF4 expression was decreased in the HF group, and only the HFD + NAC(1-12), but not HFD + NAC(1-6) group, showed significant improvement. CONCLUSION: HF diet for 12 months induces significant liver steatosis via altered ER stress and UPR pathway activity, as well as liver apoptosis. NAC treatment rescues the liver steatosis and apoptosis induced by HF diet.


Assuntos
Acetilcisteína/uso terapêutico , Dieta Hiperlipídica , Estresse do Retículo Endoplasmático , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Resposta a Proteínas não Dobradas , Acetilcisteína/farmacologia , Fator 4 Ativador da Transcrição/genética , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose , Chaperonina 60/genética , Enoil-CoA Hidratase/genética , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Regulação da Expressão Gênica , Proteínas de Choque Térmico HSP70/genética , Fígado/metabolismo , Fígado/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia
8.
Artigo em Inglês | MEDLINE | ID: mdl-32316577

RESUMO

Obesity during pregnancy increases the risk of cardiovascular problems, diabetes, asthma, and cognitive impairments, affecting the offspring. It is important to reduce the negative effects of obesity and high-fat (HF) diet during pregnancy. We employed a rat model of maternal HF diet to evaluate the possible de-programming effects of resveratrol in rodent male offspring with maternal HF diet/obesity. Male rat offspring were randomized into four groups: maternal control diet/postnatal control diet, maternal HF diet/postnatal control diet, maternal control diet plus maternal resveratrol treatment/postnatal control diet, and maternal HF diet plus maternal resveratrol treatment/postnatal control diet. Maternal HF diet during pregnancy plus lactation resulted in retroperitoneal adiposity in the male offspring. Maternal resveratrol treatment re-programmed maternal HF exposure-induced visceral adiposity. Offspring that received prenatal HF diet showed higher leptin/soluble leptin receptor (sOB-R) ratio than offspring that received prenatal control diet. Maternal resveratrol treatment ameliorated maternal HF exposure-induced increase in leptin/sOB-R ratio and altered the expression of genes for crucial fatty acid synthesis enzymes in the offspring. Thus, maternal resveratrol administration reduces retroperitoneal adiposity in rat offspring exposed to prenatal HF diet/obesity and could be used to ameliorate negative effects of maternal HF diet in the offspring.


Assuntos
Adiposidade , Dieta Hiperlipídica , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal , Resveratrol/administração & dosagem , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Masculino , Gravidez , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
9.
J Nutr Biochem ; 75: 108260, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31707285

RESUMO

A maternal high-fat (HF) diet sensitizes offspring to the adverse effects of postnatal HF intake and can lead to metabolic dysregulation. Resveratrol, a natural polyphenolic compound found in grapes and red wine, could help to relieve metabolic syndrome dysregulation. Since the gut microbiota is known to be closely related to metabolic homeostasis, this study aimed to investigate the impact of a combination of maternal and postweaning HF diets on the gut microbiota and whether resveratrol could relieve the gut dysbiosis associated with metabolic dysregulation. Sprague-Dawley dams were sustained on either a chow or HF diet before mating, during pregnancy and during lactation. Their offspring were randomly fed chow or a HF diet after weaning. Four experimental groups were generated: CC (maternal/postnatal chow diet), HC (maternal HF/postnatal chow diet), CH (maternal chow/postnatal high-fat diet) and HH (maternal/postnatal HF diet). A fifth group consisted of HH with resveratrol treatment. We found that both maternal and postnatal HF exposure has a distinct effect on the gut microbiota metagenome of offspring. Maternal HF diet exposure decreased plasma acetate, propionate and butyrate level, while postnatal HF diet exposure decreased plasma acetate level in adult life. The metabolic dysregulation programed by the maternal and postnatal HF diets was related to the relevant gut microbiota. Resveratrol treatment ameliorated the altered plasma propionate level related to maternal HF and postnatal HF diet treatment. Resveratrol treatment also improved most of the altered metabolic dysregulation and related dysbiosis programmed by maternal and postnatal HF diet exposure.


Assuntos
Dieta Hiperlipídica , Disbiose/terapia , Intestinos/efeitos dos fármacos , Resveratrol/farmacologia , Animais , Pressão Sanguínea , Peso Corporal , Ácidos Graxos Voláteis/metabolismo , Feminino , Microbioma Gastrointestinal , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Metabolismo dos Lipídeos , Fenômenos Fisiológicos da Nutrição Materna/genética , Metagenoma , Polifenóis/química , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos , Ratos Sprague-Dawley
10.
BMC Womens Health ; 19(1): 103, 2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340789

RESUMO

BACKGROUND: Probiotics has been shown to be effective in reducing vaginal colonization of pathogenic organisms. The aim of this study was to investigate the influence of probiotic strains Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 on genital high-risk human papilloma virus (HR-HPV) clearance and quality of cervical smear. METHODS: This was a randomized, double-blinded, placebo-controlled trial. Women with genital HR-HPV infection were randomized into study and control groups. A probiotic or placebo preparation was administered orally (one capsule daily) until negative HR-HPV testing. A cervical smear and HR-HPV tests were performed at the beginning of the study and every 3 months thereafter until a negative result was obtained. RESULTS: A total of 121 women with genital HR-HPV infection were enrolled (62 in the study group and 59 in the control group). There was no significant difference in HR-HPV clearance rate between the two groups (58.1% vs. 54.2%). The only factor predicting HR-HPV clearance was a lower initial viral load (HR 3.214; 95% CI: 1.398, 7.392; p = 0.006). Twenty-two women had a mildly abnormal initial cervical smear and nine had an unsatisfactory smear. At 6 months follow-up, both mildly abnormal cervical smear and unsatisfactory smear rates had decreased significantly in the study group compared to the control group (p = 0.017 and 0.027). CONCLUSIONS: The application of probiotic strains Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 did not influence genital HR-HPV clearance, but may have decreased the rates of mildly abnormal and unsatisfactory cervical smears. TRIAL REGISTRATION: Clinicaltrials.gov NCT01599416 , May, 2012. Retrospectively registered.


Assuntos
Colo do Útero/patologia , Colo do Útero/virologia , Papillomaviridae , Infecções por Papillomavirus/terapia , Probióticos/uso terapêutico , Vagina/virologia , Adulto , Método Duplo-Cego , Feminino , Genótipo , Humanos , Lactobacillus reuteri , Lactobacillus rhamnosus , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/virologia , Estudos Retrospectivos , Esfregaço Vaginal , Carga Viral
11.
J Nutr Biochem ; 70: 28-37, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31108332

RESUMO

Oxidative stress, nutrient-sensing signals, high-fat (HF) intake and dysbiosis of gut microbiota are involved in the development of hypertension, a disorder that can originate in early life. We examined whether postnatal HF diet can aggravate maternal NG-nitro-L-arginine-methyl ester (L-NAME) treatment-induced programmed hypertension and whether resveratrol therapy can prevent it. Pregnant Sprague-Dawley rats received L-NAME administration at 60 mg/kg/day subcutaneously during pregnancy alone, or with additional resveratrol (R) 50 mg/L in drinking water during the pregnancy and lactation. The offspring were onto either regular chow or HF diet (D12331) from weaning to 16 weeks of age. Male offspring rats were assigned to five groups (N=8/group): control, L-NAME, HF, L-NAME+HF and L-NAME+HF + R at weaning at 3 weeks of age. Rats were sacrificed at 16 weeks of age. We observed that postnatal HF diet exacerbates maternal L-NAME treatment-induced programmed hypertension in male adult offspring, which resveratrol attenuated. Combined L-LAME and HF diet-induced hypertension is related to increased oxidative stress, inhibiting AMP-activated protein kinase (AMPK)/ peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) pathway and altered gut microbiota compositions. L-NAME+HF caused an increase of the Firmicutes to Bacteroidetes ratio, which resveratrol therapy prevented. Additionally, the abundances of phylum Verrucomicrobia and genus Akkermansia were amplified by resveratrol therapy. Conclusively, our data highlighted the interactions between maternal NO deficiency, HF diet, AMPK/PGC-1α pathway and gut microbiota in which the blood pressure of adult offspring can be modified by resveratrol. Resveratrol might be a useful reprogramming strategy to prevent L-NAME and HF diet-induced hypertension of developmental origin.


Assuntos
Microbioma Gastrointestinal , Hipertensão/prevenção & controle , NG-Nitroarginina Metil Éster/administração & dosagem , Estresse Oxidativo , Resveratrol/administração & dosagem , Animais , Dieta Hiperlipídica , Análise Discriminante , Inibidores Enzimáticos/administração & dosagem , Feminino , Exposição Materna , Óxido Nítrico/metabolismo , Nutrientes , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos , Ratos Sprague-Dawley
12.
Mol Nutr Food Res ; : e1801385, 2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31004461

RESUMO

SCOPE: Prenatal high-fat (HF) and postnatal HF diet are both associated with obesity and metabolic disturbances in adults. Leptin resistance induced by obesity limits its biological effects. The anti-obesity mechanism of resveratrol in visceral adiposity is investigated here. METHODS AND RESULTS: During mating and lactation, Sprague-Dawley dams are fed either control or a HF diet. Subsequently, the offspring are fed chow or an HF diet. A fifth group that received maternal/postnatal HF diet and resveratrol after weaning (HHR) is used to study the effects of resveratrol treatment. Resveratrol treatment alleviates adiposity programed by maternal and postnatal HF diet by decreasing feed intake or inducing metabolic changes. Resveratrol treatment is also found to ameliorate the decrease in SIRT1 abundance observed in retroperitoneal adipose tissue, programed by maternal and postnatal HF diet. Moreover, resveratrol therapy decreases plasma leptin level and increases leptin receptor expression in retroperitoneal adipose tissue through DNA methylation modification. CONCLUSION: These results suggest that resveratrol can alleviate peripheral leptin resistance programed by the combined effect of prenatal and postnatal HF diet through epigenetic regulation of genes coding leptin and its receptor. It provides insights into a novel mechanism explaining the beneficial effects of resveratrol in obesity management.

13.
Placenta ; 78: 44-53, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30955710

RESUMO

INTRODUCTION: Maternal nutrition is an extremely important health issue. We evaluated the impact of maternal high fat diet (HFD) on pregnancy outcomes, elucidated how the rat placenta and fetus respond to diet manipulation based on fetal sex, and identified candidate genes and pathways. METHODS: Rats were fed a normal or HFD diet for 10 weeks before conception and during gestation. The placenta was collected on gestational day 21 and sexed. Placental histology was analyzed and placental candidate genes and pathways were identified using whole-genome RNA next-generation sequencing. RESULTS: Pup weights in both sexes from HFD dams were reduced. The weight of the placenta from the HFD group was also decreased in both sexes, but changes in placental layer distributions were only significant for female fetuses. Maternal HFD altered the placental transcriptome in a sex-specific manner. Activation of the placental renin-angiotensin system (RAS) by maternal HFD was associated with fetal growth restriction in both fetal sexes. CONCLUSIONS: The placenta reacts to maternal HFD by altering the placental layer distribution and gene expression in a sex-specific manner. The male placenta in late gestation is thought to exhibit greater plasticity relative to the female placenta; however, fetuses of both sexes exhibited similar growth restriction. Our data reveal an association between the placental RAS and HFD-induced fetal growth restriction.


Assuntos
Dieta Hiperlipídica , Gorduras na Dieta/farmacologia , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Placenta/efeitos dos fármacos , Placenta/metabolismo , Caracteres Sexuais , Transcriptoma/efeitos dos fármacos , Animais , Feminino , Perfilação da Expressão Gênica/métodos , Intolerância à Glucose/complicações , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Insulinas/genética , Insulinas/metabolismo , Masculino , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Placenta/patologia , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/metabolismo , Ratos , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/genética
14.
Cancers (Basel) ; 11(3)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875953

RESUMO

Ectopic expression of codon-modified granulocyte-macrophage colony-stimulating factor (cGM-CSF) in TC-1 cells (TC-1/cGM-CSF), a model cell line for human papillomavirus (HPV)-infected cervical cancer cells, increased the expression level of GM-CSF and improved the efficacy of tumor cell-based vaccines in a cervical cancer mouse model. The number of vaccine doses required to induce a long-term immune response in a cervical cancer mouse model is poorly understood. Here, we investigated one, three, and five doses of the irradiated TC-1/cGM-CSF vaccine to determine which dose was effective in inducing a greater immune response and the suppression of tumors. Our findings showed that three doses of irradiated TC-1/cGM-CSF vaccine elicited slower tumor growth rates and enhanced survival rates compared with one dose or five doses of irradiated TC-1/cGM-CSF vaccine. Consistently, mice vaccinated with three doses of irradiated TC-1/cGM-CSF vaccine exhibited stronger interferon gamma (IFN-γ) production in HPV E7-specific CD8⁺ T cells and CD4⁺ T cells. A higher percentage of natural killer cells and interferon-producing killer dendritic cells (IKDCs) appeared in the splenocytes of the mice vaccinated with three doses of irradiated TC-1/cGM-CSF vaccine compared with those of the mice vaccinated with one dose or five doses of irradiated TC-1/cGM-CSF vaccine. Our findings demonstrate that single or multiple vaccinations, such as five doses, with irradiated TC-1/cGM-CSF vaccine suppressed the immune response, whereas three doses of irradiated TC-1/cGM-CSF vaccine elicited a greater immune response and subsequent tumor suppression.

15.
Lipids Health Dis ; 18(1): 19, 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30658634

RESUMO

BACKGROUND: Prenatal dexamethasone treatment has been shown to enhance the susceptibility of offspring to postnatal high-fat (HF) diet-induced programmed obesity. We investigated the metabolic phenotypes, nutrient-sensing signal and circadian-clock genes in adipose tissue that are programmed by prenatal dexamethasone exposure and postnatal HF diet. METHODS: Male offspring of Sprague-Dawley rats were divided into four experimental groups: normal diet, prenatal dexamethasone exposure, postnatal HF diet, and prenatal dexamethasone plus postnatal HF diet. Postnatal HF diet was prescribed from weaning to 6 months of age. RESULTS: Prenatal dexamethasone and postnatal HF diet exerted synergistic effects on body weight and visceral adiposity, whereas prenatal dexamethasone and postnatal HF diet altered the metabolic profile and caused leptin dysregulation. Prenatal dexamethasone and postnatal HF diet distinctly influenced nutrient-sensing molecules and circadian-clock genes in adipose tissue. The mRNA expression of mTOR, AMPK-α2, PPAR-α, and PPAR-γ was suppressed by prenatal dexamethasone but enhanced by postnatal HF diet. CONCLUSION: Prenatal dexamethasone and postnatal HF treatment cause dysregulation of nutrient-sensing molecules and circadian-clock genes in visceral adipose tissue. Characterizing altered nutrient-sensing molecules and circadian-clock genes has potential therapeutic relevance with respect to the pathogenesis and treatment of prenatal stress and postnatal HF diet-related metabolic disorders.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal/genética , Relógios Circadianos/genética , Dexametasona/efeitos adversos , Dieta Hiperlipídica , Gordura Intra-Abdominal/patologia , Obesidade/etiologia , Obesidade/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Biomarcadores/metabolismo , Glicemia/metabolismo , Peso Corporal , Feminino , Inflamação/genética , Inflamação/patologia , Gordura Intra-Abdominal/metabolismo , Leptina/metabolismo , Tamanho do Órgão , Gravidez , Ratos Sprague-Dawley , Sirtuína 1/metabolismo
16.
Oncol Rep ; 40(6): 3734-3742, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30542723

RESUMO

Ovarian cancer is the one of the most lethal gynecological cancer types. MicroRNAs (miRs) are noncoding RNAs that modulate the translation of their target mRNAs via binding to a complementary sequence in the target 3' untranslated region, and the dysregulation of certain miRs has been demonstrated to contribute to cancer progression. In this regard, the current study extended our previous work and used next­generation sequencing data to search for upstream regulators of genetic alterations that are common in ovarian cancer, as well as the miRs that are involved in controlling the expression of these regulators. An miR prediction program was used to identify miR­381 as an upstream regulator of phosphatidylinositol 3­kinase catalytic subunit α (PIK3CA) in the context of ovarian cancer. Levels of miR­381 were decreased in clear cell and endometrioid carcinoma ovarian cancer. Experimentally induced upregulation of miR­381 led to a decrease in the level of PIK3CA in ovarian cancer cells. Furthermore, experimentally induced upregulation of miR­381 inhibited the proliferation of ovarian cancer cells in vitro and their ability to form colonies and migrate. The observed decrease in miR­381 in ovarian cancer could be reversed upon overexpression of the gene encoding the tumor suppressor homeobox D10. The current results highlight the role of miR­381­mediated regulation of PIK3CA in the development and progression of ovarian cancer and suggest that restoration of miR­381 to normal levels in ovarian cancer cells may constitute a therapeutic strategy for patients.


Assuntos
Adenocarcinoma de Células Claras/genética , Carcinoma Endometrioide/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Endometriose/patologia , MicroRNAs/metabolismo , Neoplasias Ovarianas/genética , Adenocarcinoma de Células Claras/patologia , Adulto , Carcinoma Endometrioide/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Progressão da Doença , Endometriose/genética , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , MicroRNAs/antagonistas & inibidores , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Adulto Jovem
17.
Int J Mol Sci ; 19(11)2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30424542

RESUMO

We examined the mechanisms of chronic liver steatosis after prenatal dexamethasone exposure and whether melatonin rescues adult offspring with liver steatosis. Melatonin rescued prenatal dexamethasone-exposed livers with steatosis in young rats. Sprague-Dawley rats pregnant at gestational day 14⁻21 were administered with intraperitoneal dexamethasone (DEX) or prenatal dexamethasone and melatonin between gestational day 14 and postnatal day ~120 (DEX+MEL). Chronic programming effects in the liver were assessed at day ~120. Liver steatosis increased in the DEX compared with that in the vehicle group and decreased in the DEX+MEL group (p < 0.05), with no changes in cellular apoptosis. Expression of leptin and its receptor decreased in the DEX (p < 0.05) and increased in the DEX+MEL group (p < 0.05), as revealed by RT-PCR and Western blotting. Tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 expression increased in the DEX group compared with that in the vehicle group and decreased in the DEX+MEL group (p < 0.05). Liver DNA methyltransferase activity and leptin methylation increased in the DEX group (p < 0.05) and decreased in the DEX+MEL group (p < 0.05), with no changes in HDAC activity. Thus, prenatal dexamethasone induces liver steatosis at ~120 days via altered leptin expression and liver inflammation without leptin resistance. Melatonin reverses leptin methylation and expression and decreases inflammation and chronic liver steatosis not via apoptosis or histone deacetylation (HDAC).


Assuntos
Apoptose , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Leptina/metabolismo , Acetilação , Animais , Peso Corporal , DNA (Citosina-5-)-Metiltransferases/metabolismo , Histonas/metabolismo , Inflamação/patologia , Fígado/enzimologia , Fígado/patologia , Metilação , Tamanho do Órgão , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
18.
Cancers (Basel) ; 10(12)2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30469497

RESUMO

Increased number of tumor-infiltrating CD8+ lymphocytes is associated with improved survival in patients with advanced stage high grade serous ovarian cancer (HGSOC) but the underlying molecular mechanism has not been thoroughly explored. Using transcriptome profiling of microdissected HGSOC tissue with high and low CD8+ lymphocyte count and subsequent validation studies, we demonstrated that significantly increased ISG15 (Interferon-stimulated gene 15) expression in HGSOC was associated with high CD8+ lymphocyte count and with the improvement in median overall survival in both univariate and multivariate analyses. Further functional studies showed that endogenous and exogenous ISG15 suppressed ovarian cancer progression through ISGylation of ERK in HGSOC, and activation of NK cells and CD8+ T lymphocytes. These data suggest that the development of treatment strategies based on up-regulating ISG15 in ovarian cancer cells or increased circulating ISG15 in ovarian cancer patients is warranted.

19.
Exp Ther Med ; 16(2): 917-924, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30112044

RESUMO

Prenatal exposure to glucocorticoids is associated with negative health consequences for the offspring that persist into adulthood, including liver steatosis. Melatonin has previously been demonstrated to suppress liver steatosis and oxidative stress in humans with non-alcoholic fatty liver disease and in animal models of obesity. The present study aimed to determine whether melatonin protects against liver steatosis induced by prenatal dexamethasone exposure followed by postnatal high-fat diet. Pregnant Sprague-Dawley rats at gestational days 14-21 were administered dexamethasone (0.1 mg/kg/day) or saline via intraperitoneal injection. The offspring were then divided into five groups, as follows: Vehicle, postnatal high-fat diet (VHF), prenatal dexamethasone exposure (DEX), prenatal dexamethasone exposure + postnatal high-fat diet (DHF), and prenatal dexamethasone exposure + postnatal high-fat diet + melatonin (DHFM) group. Following vehicle or dexamethasone exposure of the maternal rats, the offspring rats in the VHF, DHF and DHFM groups received a high-fat diet (58% fat) between weaning and 6 months of age. In the DHFM group, melatonin was administered to the mothers from gestational days 14-21 until weaning. The offspring continued to receive melatonin until they were sacrificed at 6 months old. Oil Red O staining demonstrated stronger intensity in the DHF group compared with that in the other four groups. Western blot analysis also revealed higher levels of cleaved caspase-3, tumor necrosis factor-α (TNF-α), suppressor of cytokine signaling 3 (SOCS3) and malondialdehyde (MDA), as well as reduced expression of manganese superoxide dismutase (MnSOD) and phosphoinositide 3-kinase (PI3K) in the DHF group compared with the vehicle and DHFM groups. In addition, melatonin reduced the Oil Red O staining intensity and the levels of cleaved caspase-3, TNF-α, SOCS3 and MDA, while it increased the MnSOD and PI3K levels, in the DHFM group compared with the DHF group. In conclusion, postnatal high-fat diet aggravated the prenatal dexamethasone-induced liver steatosis in adult rat offspring via inflammation, oxidative stress and cellular apoptosis, which may be ameliorated by prenatal melatonin therapy.

20.
Lipids Health Dis ; 17(1): 178, 2018 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-30055626

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) can develop in prenatal stages and can be exacerbated by exposure to a postnatal high-fat (HF) diet. We investigated the protective effects of resveratrol on prenatal and postnatal HF diet-induced NAFLD. METHODS: Male Sprague-Dawley rat offspring were placed in five experimental groups (n = 10-12 per group): normal diet (VNF), maternal HF diet (ONF), postnatal HF diet (VHF), and maternal HF diet/postnatal HF diet (OHF). A therapeutic group with resveratrol for maternal HF diet/postnatal HF diet (OHFR) was used for comparison. Resveratrol (50 mg/kg/day) was dissolved in drinking water for offspring from post-weaning to postnatal day (PND) 120. RESULTS: We found that HF/HF-induced NAFLD was prevented in adult offspring by the administration of resveratrol. Resveratrol administration mediated a protective effect on rats on HF/HF by regulating lipid metabolism, reducing oxidative stress and apoptosis, restoring nutrient-sensing pathways by increasing Sirt1 and leptin expression, and mediating the renin-angiotensin system (RAS) to decrease angiotensinogen, renin, ACE1, and AT1R levels and increased ACE2, AT2R and MAS1 levels compared to those in the OHF group. CONCLUSION: Our results suggest that a maternal and post-weaning HF diet increases liver steatosis and apoptosis via the RAS. Resveratrol might serve as a therapeutic target by mediating protective actions against NAFLD in offspring exposed to a combination of maternal and postnatal HF diet.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hipolipemiantes/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Estilbenos/farmacologia , Enzima de Conversão de Angiotensina 2 , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Animais , Animais Recém-Nascidos , Dieta Hiperlipídica/efeitos adversos , Feminino , Leptina/genética , Leptina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Renina/genética , Renina/metabolismo , Resveratrol , Sirtuína 1/genética , Sirtuína 1/metabolismo , Desmame
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