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1.
Int J Mol Sci ; 25(13)2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-39000532

RESUMO

We hypothesized and investigated whether prenatal exposure to preeclampsia (PE) would simultaneously affect perinatal cardiovascular features and angiotensin system expressions. This prospective study was composed of mother-neonate dyads with (n = 49) and without maternal preeclampsia (n = 48) in a single tertiary medical center. The neonates exposed to PE had significantly larger relative sizes for the left and right coronary arteries and a higher cord plasma level of aminopeptidase-N, which positively correlated with the maternal diastolic blood pressures and determined the relative sizes of the left and right coronary arteries, whereas the encoding aminopeptidase-N (ANPEP) mRNA level in the PE cord blood leukocytes was significantly decreased, positively correlated with the neonatal systolic blood pressures (SBPs), and negatively correlated with the cord plasma-induced endothelial vascular cell adhesion molecule-1 mRNA levels. The PE cord plasma significantly induced higher endothelial mRNA levels of angiotensin II type 1 receptor (AT1R) and AT4R, whereas in the umbilical arteries, the protein expressions of AT2R and AT4R were significantly decreased in the PE group. The endothelial AT1R mRNA level positively determined the maternal SBPs, and the AT4R mRNA level positively determined the neonatal chamber size and cardiac output. In conclusion, PE may influence perinatal angiotensin system and cardiovascular manifestations of neonates across placentae. Intriguing correlations between these two warrant further mechanistic investigation.


Assuntos
Pré-Eclâmpsia , Humanos , Feminino , Gravidez , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/genética , Adulto , Recém-Nascido , Sangue Fetal/metabolismo , Pressão Sanguínea , Estudos Prospectivos , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Cardiovascular/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
2.
J Biochem Mol Toxicol ; 37(5): e23323, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36890697

RESUMO

With the improvement in children's acute lymphoblastic leukemia (ALL) care, the survival rate in children ALL has improved much. Methotrexate (MTX) plays an essential role in the success of children's ALL treatment. Since hepatotoxicity is commonly reported in individuals treated with intravenous or oral MTX, our study further examined the hepatic effect following intrathecal MTX treatment, which is an essential treatment for leukemia patients. Specifically, we examined the pathogenesis of MTX hepatotoxicity in young rats and explored the impact of melatonin treatment in protection against MTX hepatotoxicity. Successfully, we found that melatonin was able to protect against MTX hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Melatonina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Ratos , Animais , Metotrexato/toxicidade , Melatonina/farmacologia , Melatonina/uso terapêutico , Proteínas Proto-Oncogênicas c-akt , Fosfatidilinositol 3-Quinases , Serina-Treonina Quinases TOR , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle
3.
Int J Mol Sci ; 23(15)2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35955421

RESUMO

Hypertension is an important public health challenge, affecting up to 30-50% of adults worldwide. Several epidemiological studies indicate that high blood pressure originates in fetal life-the so-called programming effect or developmental origin of hypertension. Iron-deficiency anemia has become one of the most prevalent nutritional problems globally. Previous animal experiments have shown that prenatal iron-deficiency anemia adversely affects offspring hypertension. However, the underlying mechanism remains unclear. We used a maternal low-iron diet Sprague Dawley rat model to study changes in blood pressure, the renal renin-angiotensin system, oxidative stress, inflammation, and sodium transporters in adult male offspring. Our study revealed that 16-week-old male offspring born to mothers with low dietary iron throughout pregnancy and the lactation period had (1) higher blood pressure, (2) increased renal cortex angiotensin II receptor type 1 and angiotensin-converting enzyme abundance, (3) decreased renal cortex angiotensin II receptor type 2 and MAS abundance, and (4) increased renal 8-hydroxy-2'-deoxyguanosine and interleukin-6 abundance. Improving the iron status of pregnant mothers could influence the development of hypertension in their offspring.


Assuntos
Anemia Ferropriva , Hipertensão , Deficiências de Ferro , Efeitos Tardios da Exposição Pré-Natal , Anemia Ferropriva/metabolismo , Animais , Pressão Sanguínea , Feminino , Hipertensão/metabolismo , Ferro/metabolismo , Ferro da Dieta/metabolismo , Rim/metabolismo , Lactação , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Estresse Oxidativo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina
4.
Int J Mol Sci ; 23(22)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36430717

RESUMO

Maternal high-fat (HF) diet exposure in utero may affect fetal development and cause metabolic problems throughout life due to lipid dysmetabolism and oxidative damage. Metformin has been suggested as a potential treatment for body weight reduction and nonalcoholic fatty liver disease, but its reprogramming effect on offspring is undetermined. This study assesses the effects of maternal metformin treatment on hepatic steatosis in offspring caused by maternal HF diet. Female rats were fed either a control or an HF diet before conception, with or without metformin treatment during gestation, and placenta and fetal liver tissues were collected. In another experiment, the offspring were fed a control diet until 120 d (adult stage). Metformin treatment during pregnancy ameliorates placental oxidative stress and enhances placental glucose transporter 1 (GLUT1), GLUT3, and GLUT4 expression levels through 5' adenosine monophosphate-activated protein kinase (AMPK) activation. Maternal metformin treatment was shown to reprogram maternal HF diet-induced changes in offspring fatty liver with the effects observed in adulthood as well. Further validation is required to develop maternal metformin therapy for clinical applications.


Assuntos
Metformina , Hepatopatia Gordurosa não Alcoólica , Feminino , Ratos , Gravidez , Animais , Dieta Hiperlipídica/efeitos adversos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Placenta/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Metformina/metabolismo , Gorduras na Dieta/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo
5.
J Pediatr ; 228: 58-65.e3, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32712283

RESUMO

OBJECTIVES: To investigate the cardiovascular features and endothelium in neonates born to mothers with preeclampsia. STUDY DESIGN: In this combined observational cohort and case-control study, neonates born to mothers with normotension and mothers with preeclampsia were recruited at a neonatal intensive care unit of a tertiary medical center. Cardiovascular measurements by echocardiography and the clinical measures upon admission were analyzed. Vascular cell adhesion molecule-1 expression in umbilical arteries and in in vitro endothelial cell stimulation with plasma were examined. Continuous data were compared using nonparametric analysis, and their relationships were analyzed using linear regression. Binary logistic regression was performed in the model of adjustment of birth body weight and for multivariate analysis. RESULTS: In the cohort, almost all cardiovascular segments positively correlated to birth weight. Notably, neonates (n = 65) of mothers with preeclampsia had significantly larger coronary arteries at birth than neonates of mothers with normotension (n = 404) (median size of left main coronary artery 1.36 mm versus 1.08 mm, p <0.001; median size of right coronary artery, RCA 1.25 mm versus 1.0 mm, p <0.001). The size of the right coronary artery positively correlated to the maternal antepartum diastolic blood pressure (r = 0.298, P = .018) and was associated with in-hospital death (P < .001). Meanwhile, endothelial vascular cell adhesion molecule-1 expression was significantly increased in the umbilical arteries of the preeclamptic group and following preeclamptic cord-plasma stimulation. The latter also correlated with their relative coronary sizes. CONCLUSIONS: Neonates of mothers with preeclampsia had distinctive coronary dilatation at birth. Coronary size might be useful as a severity index of neonatal endothelial inflammation as a result of maternal preeclampsia.


Assuntos
Doença da Artéria Coronariana/etiologia , Vasos Coronários/fisiopatologia , Endotélio Vascular/fisiopatologia , Inflamação/diagnóstico , Pré-Eclâmpsia/diagnóstico , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/fisiopatologia , Dilatação Patológica/diagnóstico , Dilatação Patológica/etiologia , Dilatação Patológica/fisiopatologia , Endotélio Vascular/diagnóstico por imagem , Feminino , Seguimentos , Idade Gestacional , Humanos , Recém-Nascido , Inflamação/fisiopatologia , Masculino , Gravidez , Estudos Retrospectivos
6.
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.


Assuntos
Disbiose/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Metformina/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/tratamento farmacológico , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Água Potável/administração & dosagem , Disbiose/etiologia , Disbiose/metabolismo , Disbiose/patologia , Ácidos Graxos Voláteis/metabolismo , Feminino , Feto , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Inflamação , Intestinos/efeitos dos fármacos , Intestinos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Gravidez , Ratos , Ratos Sprague-Dawley , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo
7.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201550

RESUMO

With the improvement of the survival rate of acute lymphoblastic leukemia (ALL) in children, some children ALL survivors reveal inferior intellectual and cognition outcome. Methotrexate (MTX), while serving as an essential component in ALL treatment, has been reported to be related to various neurologic sequelae. Using combined intrathecal (IT) and intraperitoneal (IP) MTX model, we had demonstrated impaired spatial memory function in developing rats, which can be rescued by melatonin treatment. To elucidate the impact of MTX treatment on the epigenetic modifications of the myelination process, we examined the change of neurotrophin and myelination-related transcriptomes in the present study and found combined IT and IP MTX treatment resulted in altered epigenetic modification on the myelination process, mainly in the hippocampus. Further, melatonin can restore the MTX effect through alterations of the epigenetic pathways.


Assuntos
Encéfalo/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Metotrexato/toxicidade , Bainha de Mielina/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/toxicidade , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Ilhas de CpG , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Injeções Espinhais , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Bainha de Mielina/patologia , Síndromes Neurotóxicas/patologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/genética , Ratos Sprague-Dawley , Fatores de Transcrição SOXE/genética
8.
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
9.
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
10.
Int J Mol Sci ; 21(12)2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32604820

RESUMO

Hypertension and chronic kidney disease (CKD) can originate during early-life. Tryptophan metabolites generated by different pathways have both detrimental and beneficial effects. In CKD, uremic toxins from the tryptophan-generating metabolites are endogenous ligands of the aryl hydrocarbon receptor (AHR). The interplay between AHR, nitric oxide (NO), the renin-angiotensin system (RAS), and gut microbiota is involved in the development of hypertension. We examined whether tryptophan supplementation in pregnancy can prevent hypertension and kidney disease programmed by maternal CKD in adult offspring via the aforementioned mechanisms. Sprague-Dawley (SD) female rats received regular chow or chow supplemented with 0.5% adenine for 3 weeks to induce CKD before pregnancy. Pregnant controls or CKD rats received vehicle or tryptophan 200 mg/kg per day via oral gavage during pregnancy. Male offspring were divided into four groups (n = 8/group): control, CKD, tryptophan supplementation (Trp), and CKD plus tryptophan supplementation (CKDTrp). All rats were sacrificed at the age of 12 weeks. We found maternal CKD induced hypertension in adult offspring, which tryptophan supplementation prevented. Maternal CKD-induced hypertension is related to impaired NO bioavailability and non-classical RAS axis. Maternal CKD and tryptophan supplementation differentially shaped distinct gut microbiota profile in adult offspring. The protective effect of tryptophan supplementation against maternal CKD-induced programmed hypertension is relevant to alterations to several tryptophan-metabolizing microbes and AHR signaling pathway. Our findings support interplay among tryptophan-metabolizing microbiome, AHR, NO, and the RAS in hypertension of developmental origins. Furthermore, tryptophan supplementation in pregnancy could be a potential approach to prevent hypertension programmed by maternal CKD.


Assuntos
Microbioma Gastrointestinal , Hipertensão/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Receptores de Hidrocarboneto Arílico/metabolismo , Insuficiência Renal Crônica/complicações , Triptofano/administração & dosagem , Triptofano/metabolismo , Animais , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/metabolismo , Suplementos Nutricionais , Feminino , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Exposição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/metabolismo , Ratos , Ratos Sprague-Dawley
11.
Int J Mol Sci ; 21(10)2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32408716

RESUMO

To examine the effects of maternal resveratrol in rats borne to dams with gestational high-fat diet (HFD)/obesity with or without postnatal high-fat diet. We first tested the effects of maternal resveratrol intake on placenta and male fetus brain in rats borne to dams with gestational HFD/obesity. Then, we assessed the possible priming effect of a subsequent insult, male offspring were weaned onto either a rat chow or a HFD. Spatial learning and memory were assessed by Morris water maze test. Blood pressure and peripheral insulin resistance were examined. Maternal HFD/obesity decreased adiponectin, phosphorylation alpha serine/threonine-protein kinase (pAKT), sirtuin 1 (SIRT1), and brain-derived neurotrophic factor (BDNF) in rat placenta, male fetal brain, and adult male offspring dorsal hippocampus. Maternal resveratrol treatment restored adiponectin, pAKT, and BDNF in fetal brain. It also reduced body weight, peripheral insulin resistance, increased blood pressure, and alleviated cognitive impairment in adult male offspring with combined maternal HFD and postnatal HFD. Maternal resveratrol treatment restored hippocampal pAKT and BDNF in rats with combined maternal HFD and postnatal HFD in adult male offspring dorsal hippocampus. Maternal resveratrol intake protects the fetal brain in the context of maternal HFD/obesity. It effectively reduced the synergistic effects of maternal HFD/obesity and postnatal HFD on metabolic disturbances and cognitive impairment in adult male offspring. Our data suggest that maternal resveratrol intake may serve as an effective therapeutic strategy in the context of maternal HFD/obesity.


Assuntos
Resistência à Insulina/fisiologia , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Obesidade/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Resveratrol/administração & dosagem , Adiponectina/metabolismo , Animais , Antioxidantes/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Obesidade/metabolismo , Placenta/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos Sprague-Dawley , Desmame
12.
Molecules ; 25(18)2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32937766

RESUMO

To facilitate broad applications and enhance bioactivity, resveratrol was esterified to resveratrol butyrate esters (RBE). Esterification with butyric acid was conducted by the Steglich esterification method at room temperature with N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide (EDC) and 4-dimethyl aminopyridine (DMAP). Our experiments demonstrated the synthesis of RBE through EDC- and DMAP-facilitated esterification was successful and that the FTIR spectra of RBE revealed absorption (1751 cm-1) in the ester region. 13C-NMR spectrum of RBE showed a peak at 171 ppm corresponding to the ester group and peaks between 1700 and 1600 cm-1 in the FTIR spectra. RBE treatment (25 or 50 µM) decreased oleic acid-induced lipid accumulation in HepG2 cells. This effect was stronger than that of resveratrol and mediated through the downregulation of p-ACC and SREBP-2 expression. This is the first study demonstrating RBE could be synthesized by the Steglich method and that resulting RBE could inhibit lipid accumulation in HepG2 cells. These results suggest that RBE could potentially serve as functional food ingredients and supplements for health promotion.


Assuntos
Ácido Butírico/síntese química , Ésteres/síntese química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Resveratrol/síntese química , Resveratrol/farmacologia , Acetil-CoA Carboxilase/metabolismo , Carbodi-Imidas/química , Técnicas de Cultura de Células , Regulação para Baixo , Esterificação , Células Hep G2 , Humanos , Lipídeos/química , Espectroscopia de Ressonância Magnética , Piridinas/química , Espectroscopia de Infravermelho com Transformada de Fourier , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Termogravimetria
13.
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
14.
Int J Mol Sci ; 20(22)2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31766163

RESUMO

Cardiovascular and neurological diseases can originate in early life. Melatonin, a biologically active substance, acts as a pleiotropic hormone essential for pregnancy and fetal development. Maternal melatonin can easily pass the placenta and provide photoperiodic signals to the fetus. Though melatonin uses in pregnant or lactating women have not yet been recommended, there is a growing body of evidence from animal studies in support of melatonin as a reprogramming strategy to prevent the developmental programming of cardiovascular and neurological diseases. Here, we review several key themes in melatonin use in pregnancy and lactation within offspring health and disease. We have particularly focused on the following areas: the pathophysiological roles of melatonin in pregnancy, lactation, and fetal development; clinical uses of melatonin in fetal and neonatal diseases; experimental evidence supporting melatonin as a reprogramming therapy to prevent cardiovascular and neurological diseases; and reprogramming mechanisms of melatonin within developmental programming. The targeting of melatonin uses in pregnancy and lactation will be valuable in the prevention of various adult chronic diseases in later life, and especially cardiovascular and neurological diseases.


Assuntos
Antioxidantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Doenças Fetais/prevenção & controle , Doenças do Recém-Nascido/prevenção & controle , Melatonina/uso terapêutico , Doenças do Sistema Nervoso/prevenção & controle , Animais , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Humanos , Recém-Nascido , Lactação/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Gravidez
15.
Int J Mol Sci ; 20(3)2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30695995

RESUMO

Resveratrol, also known as 3,5,4'-trihydroxystilbene, is a natural polyphenol that occurs as a phytoalexin. It is produced by plant sources such as grapes, apples, blueberries, plums, peanuts, and other oilseeds. This compound has a variety of effects on human health and diseases. This review summarizes the mounting evidence that resveratrol is helpful in treating metabolic syndrome and related disorders. Resveratrol can be provided either early as a reprogramming agent or later as part of treatment. A few of the main mechanisms underlying the beneficial effects of resveratrol on metabolic syndrome are outlined. This review also discusses the potential of resveratrol derivatives as a complementary or alternative medicine. In conclusion, resveratrol could be a useful regimen for the prevention and treatment of metabolic syndrome and its related conditions.


Assuntos
Síndrome Metabólica/tratamento farmacológico , Resveratrol/uso terapêutico , Animais , Modelos Animais de Doenças , Humanos , Resveratrol/síntese química , Resveratrol/química , Resveratrol/farmacologia
16.
Int J Mol Sci ; 20(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416234

RESUMO

Hypertension can originate from early-life exposure to oxidative stress. As reported, dimethyl fumarate (DMF) activates nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and protects against oxidative stress damage. We examined whether maternal DMF therapy protects adult offspring against hypertension programmed by prenatal dexamethasone (DEX) and postnatal high-fat (HF) diet exposure. We examined male Sprague Dawley rat offspring at 4 months of age from five groups (n = 11-13/group): control, DEX (0.1mg/kg i.p. from gestational day 16 to 22), HF (D12331 diet from weaning to 16 weeks of age), DEX+HF, and DEX+HF+DMF (50mg/kg/day via gastric gavage for 3 weeks during pregnancy). Maternal DMF therapy prevented male offspring against hypertension programmed by combined DEX and HF exposures. The protective effects of maternal DMF include reduced oxidative stress, decreased plasma asymmetric dimethylarginine (ADMA) levels, downregulated the renin-angiotensin system (i.e. Ren, Agt, Ace, and Agtr1a), increased renal protein levels of certain nutrient-sensing signals, and promoted autophagy. In conclusion, maternal Nrf2 activation by DMF protects male adult offspring against hypertension programmed by combined DEX and HF exposures. Our results cast a new light on the therapeutic potential of targeting Nrf2 signaling pathway as reprogramming strategies to prevent programmed hypertension in children exposed to antenatal corticosteroids and postnatally excessive consumption of fat.


Assuntos
Dexametasona/administração & dosagem , Dieta Hiperlipídica , Fumarato de Dimetilo/administração & dosagem , Hipertensão/etiologia , Hipertensão/prevenção & controle , Exposição Materna , Fator 2 Relacionado a NF-E2/agonistas , Efeitos Tardios da Exposição Pré-Natal , Animais , Biomarcadores , Feminino , Expressão Gênica , Humanos , Hipertensão/diagnóstico , Hipertensão/metabolismo , Recém-Nascido , Masculino , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Fosforilação , Gravidez , Ratos
17.
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 , Proto-Oncogene Mas , 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
18.
Lipids Health Dis ; 17(1): 50, 2018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-29540174

RESUMO

BACKGROUND: Hypertension may result from high-fat (HF) diet induced-obesity and overexposure to glucocorticoids in utero. Recent studies demonstrated the potent contribution of adipose tissue's renin-angiotensin system (RAS) to systemic RAS, which plays a key role in regulating blood pressure (BP). In this study, we investigated the effects of prenatal dexamethasone (DEX) exposure and postnatal HF diet on RAS of adipose tissue. METHODS: RAS and BP of 6-month old rats exposed to prenatal DEX and/or postnatal HF diet were examined. RESULTS: Prenatal DEX plus postnatal HF exerted a synergistic effect on systolic BP. Prenatal DEX exposure suppressed plasma angiotensin (ANG) I and ANG II, whereas postnatal HF suppressed plasma ANG-(1-7) level. Prenatal DEX increased prorenin receptor and renin levels, but suppressed angiotensinogen (AGT) and angiotensin-converting-enzyme 1 (ACE1) mRNA expressions in adipose tissue. Postnatal HF increased AGT mRNA expression, but suppressed prorenin receptor, renin, ACE2, ANG II type 2 receptor (AT2R), and Mas receptor (MasR) mRNA expression levels. CONCLUSIONS: Prenatal GC exposure altered the ACE1/ANG II/ANG II type 1 receptor (AT1R) axis, whereas postnatal HF negatively impacted the ACE2/ANG-(1-7)/MasR axis. Prenatal DEX exposure and postnatal HF synergistically elevated BP through a distinct programming mechanism of systemic and adipose RAS. Adipose RAS might be a target for precise hypertension treatment.


Assuntos
Dexametasona/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Hipertensão/genética , Sistema Renina-Angiotensina/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Angiotensinogênio/genética , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/patologia , Peptidil Dipeptidase A/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/patologia , Proto-Oncogene Mas , Ratos , Receptores de Superfície Celular/genética , Renina/genética , Sistema Renina-Angiotensina/genética , ATPases Vacuolares Próton-Translocadoras/genética
19.
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
20.
Tohoku J Exp Med ; 241(3): 225-237, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28344212

RESUMO

Prenatal glucocorticoid therapy is indicated in preterm delivery to prevent respiratory distress. This study was designed to evaluate the age-dependent effects of prenatal dexamethasone (DEX) therapy on the immune system using a rat model. Pregnant Sprague-Dawley rats received an intraperitoneal injection of DEX (0.1 mg/kg/day) or saline (VEH) over gestational days 14-20. Male offspring were sacrificed at postnatal day 7 (D7; infant stage), D120 (young adult stage), and D180 (adult stage) for evaluation of leukocyte subsets and isolation of splenocytes. The production of innate and adaptive immune cytokines was assessed from the culture supernatants of splenocytes, stimulated with lipopolysaccharide and concanavalin A, respectively. For innate cytokines, the levels of interferon gamma inducible protein 10 were significantly higher, but those of tumor necrosis factor-α were significantly lower, in the culture medium of splenocytes prepared from the DEX group at D120 than those in the VEH group. For adaptive cytokines, the levels of interleukin-4 (IL-4) were significantly higher at D7 and those of IL-10 were significantly higher at D120 after prenatal exposure to DEX. We also showed that the expression level of IL-4 mRNA was significantly higher in splenocytes prepared from the DEX group at D7, compared with the VEH group. Importantly, the mRNA expression level of T-bet, a key transcription factor for immune cells, was greatly decreased in the spleen of the DEX group at D7, compared with the VEH group. In conclusion, prenatal dexamethasone exposure shows the greater impact on immune responses of their male offspring in early life.


Assuntos
Envelhecimento/efeitos dos fármacos , Dexametasona/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Feminino , Histonas/metabolismo , Imunidade Inata/efeitos dos fármacos , Imunoglobulina A/sangue , Imunoglobulina M/sangue , Interleucina-10/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Leucócitos/metabolismo , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
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