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Renal ischaemia and reperfusion (I/R) is caused by a sudden temporary impairment of the blood flow. I/R is a prevalent cause of acute kidney injury. As nitric oxide generated by inducible nitric oxide synthase (iNOS) has detrimental effects during I/R, the pharmacological blockade of iNOS has been proposed as a potential strategy to prevent I/R injury. The aim of this study was to improve the understanding of 1400W (an iNOS inhibitor) on renal I/R as a pharmacological strategy against kidney disease. BALB/c mice received 30 min of bilateral ischaemia, followed by 48 h or 28 days of reperfusion. Vehicle or 1400W (10 mg/kg) was administered 30 min before inducing ischaemia. We found that after 48 h of reperfusion 1400W decreased the serum creatinine, blood urea nitrogen, neutrophil gelatinase-associated lipocalin and proliferating cell nuclear antigen 3 in the I/R animals. Unexpectedly, we observed mRNA upregulation of genes involved in kidney injury, cell-cycle arrest, inflammation, mesenchymal transition and endothelial activation in the renal medulla of sham animals treated with 1400W. We also explored if 1400W promoted chronic kidney dysfunction 28 days after I/R and did not find significant alterations in renal function, fibrosis, blood pressure or mortality. The results provide evidence that 1400W may have adverse effects in the renal medulla. Importantly, our data point to 1400W-induced endothelial dysfunction, establishing therapeutic limitations for its use. KEY POINTS: Acute kidney injury is a global health problem associated with high morbidity and mortality. The pharmacological blockade of inducible nitric oxide synthase (iNOS) has been proposed as a potential strategy to prevent AKI induced by ischaemia and reperfusion (I/R). Our main finding is that 1400W, a selective and irreversible iNOS inhibitor with low toxicity that is proposed as a therapeutic strategy to prevent kidney I/R injury, produces aberrant gene expression in the medulla associated to tissue injury, cell cycle arrest, inflammation, mesenchymal transition and endothelial activation. The negative effect of 1400W observed in the renal medulla at 48 h from drug administration, is transient as it did not translate into a chronic kidney disease condition.
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OBJECTIVES: To evaluate the relationship between obesity and periodontitis staging compared with periodontal healthy or gingivitis in pregnant women. MATERIALS AND METHODS: An analytical cross-sectional study was conducted on pregnant women between 11 and 14 weeks of pregnancy. Sociodemographic, clinical, obstetric, and periodontal variables were studied. The exposure variable was obesity (body mass index [BMI] ≥ 30), and the primary outcome was periodontitis staging versus periodontal healthy/gingivitis. Data were analysed and estimated by multinomial logistic regression models. RESULTS: The present study screened 1086 pregnancies and analysed 972 women with a median age of 29 years; 36.8% were diagnosed as obese. 26.9% of patients were diagnosed as periodontal healthy or gingivitis, 5.5% with stage I periodontitis, 38.6% with stage II periodontitis, 24% with stage III periodontitis, and 5.1% with stage IV periodontitis. After identifying and adjusting for confounding variables (educational level and plaque index), obesity had a relative risk ratio (RRR) of 1.66 (95% CI: 1.05-2.64; p = 0.03) and 1.57 (95% CI: 1.09-2.27; p = 0.015) for stage III periodontitis compared to periodontal healthy/gingivitis and stage II periodontitis, respectively. CONCLUSION: Besides the already known risk indicators for periodontitis (age, smoking, and educational level), our study suggests a relationship between obesity and periodontitis staging in pregnancy. CLINICAL RELEVANCE: Obesity can alter host immune responses, leading to increased susceptibility to infections and overactive host immunity, which could influence the prevalence and severity of maternal periodontitis in pregnancy.
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Gengivite , Periodontite , Feminino , Humanos , Gravidez , Adulto , Estudos Transversais , Periodontite/complicações , Periodontite/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Fatores de Risco , Gengivite/epidemiologiaRESUMO
OBJECTIVE: To analyse serum folate levels in women of childbearing age in the Metropolitan Region (MR) of Chile. DESIGN: Cross-sectional design as part of the 2016-2017 National Health Survey (Encuesta Nacional de Salud, ENS 2016-2017), using a household-based multistage stratified random sample. Serum folate levels measured by electrochemiluminescence immunoassay in fasting venous blood samples were classified as deficient (<4·4 ng/ml), normal (4·4-20 ng/ml) or supraphysiological (>20 ng/ml). SETTING: The MR of Chile. PARTICIPANTS: Women of reproductive age (15-49 years, n 222) from the MR participated in the ENS 2016-2017. RESULTS: The mean, median and range of serum folate were 14·2 (se 0·4), 13·9 and 2·1-32·2 ng/ml, respectively. Folate deficiency was detected in 0·9 % of women, while 7·0 % had supraphysiological levels of the vitamin. No significant effects of age, educational level, marital status, parity, smoking status or nutritional status on serum folate levels were detected by univariate or multivariate analyses. Intake of folic acid supplements showed a significant association with serum folate levels, but only 1·2 % of women used supplements. CONCLUSIONS: Folate deficiency in women of reproductive age living in the MR of Chile is almost inexistent according to the ENS 2016-2017, suggesting that the current population-wide mandatory folic acid fortification of flour is an effective and equitable measure to prevent folate deficiency. These results support the option of maintaining current folic acid fortification in Chile, particularly based on the low adherence to supplementation regimes evidenced in other populations.
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Ácido Fólico , Defeitos do Tubo Neural , Adolescente , Adulto , Chile , Estudos Transversais , Suplementos Nutricionais , Feminino , Ácido Fólico/administração & dosagem , Ácido Fólico/sangue , Alimentos Fortificados , Inquéritos Epidemiológicos , Humanos , Pessoa de Meia-Idade , Defeitos do Tubo Neural/prevenção & controle , Gravidez , Adulto JovemRESUMO
Periodontitis is a chronic inflammatory immune disease associated with a dysbiotic state, influenced by keystone bacterial species responsible for disrupting the periodontal tissue homeostasis. Furthermore, the severity of periodontitis is determined by the interaction between the immune cell response in front of periodontitis-associated species, which leads to the destruction of supporting periodontal tissues and tooth loss in a susceptible host. The persistent bacterial challenge induces modifications in the permeability and ulceration of the sulcular epithelium, which facilitates the systemic translocation of periodontitis-associated bacteria into distant tissues and organs. This stimulates the secretion of pro-inflammatory molecules and a chronic activation of immune cells, contributing to a systemic pro-inflammatory status that has been linked with a higher risk of several systemic diseases, such as type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM). Although periodontitis and GDM share the common feature of systemic inflammation, the molecular mechanistic link of this association has not been completely clarified. This review aims to examine the potential biological mechanisms involved in the association between periodontitis and GDM, highlighting the contribution of both diseases to systemic inflammation and the role of new molecular participants, such as extracellular vesicles and non-coding RNAs, which could act as novel molecular intercellular linkers between periodontal and placental tissues.
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Diabetes Gestacional , Periodontite , Periodonto , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Gestacional/metabolismo , Diabetes Gestacional/microbiologia , Feminino , Humanos , Periodontite/etiologia , Periodontite/metabolismo , Periodontite/microbiologia , Periodonto/metabolismo , Periodonto/microbiologia , GravidezRESUMO
High density lipoproteins (HDL) take up cholesterol from peripheral tissues via ABC transporters and deliver it to the liver via scavenger receptor class B type I (SR-B1). HDL are the main lipoproteins present in follicular fluid (FF). They are thought to derive from plasma, but their origin is still controversial. SR-B1 knock-out (KO) mice have provided important evidence linking HDL metabolism and female fertility. These mice have cholesterol-rich circulating HDL and female infertility that can be restored by treating mice with the cholesterol-lowering drug probucol. Ovulated oocytes from SR-B1 KO females are dysfunctional and show excess cholesterol. The mechanisms explaining the contribution of FF HDL to oocyte cholesterol homeostasis are unknown. Here, using quantitation of filipin fluorescence we show that in SR-B1 KO ovaries, cholesterol excess is first observed in immature oocytes in antral follicles. By performing cross-transplant experiments between WT and apolipoprotein A-I deficient (ApoA-I KO) mice, which lack the main protein component of HDL, we provide evidence supporting the plasmatic origin of FF HDL. Also, we demonstrate that probucol treatment in SR-B1 KO females results in lowering of cholesterol content in their oocytes. Incubation of oocytes from SR-B1 KO mice with purified WT HDL reduces their cholesterol content, suggesting that HDL promote efflux of excess cholesterol from oocytes. In agreement with this hypothesis, we identified ABC transporters in oocytes and observed that ABCA1 KO oocytes have excess cholesterol and lower viability than WT oocytes.
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Transportadores de Cassetes de Ligação de ATP/metabolismo , HDL-Colesterol/metabolismo , Colesterol/metabolismo , Líquido Folicular/metabolismo , Oócitos/metabolismo , Ovário/metabolismo , Animais , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Transporte Biológico , Feminino , Fígado/metabolismo , Camundongos , Camundongos Knockout , Folículo Ovariano/metabolismo , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismoRESUMO
BACKGROUND: The high-density lipoprotein receptor SR-B1 mediates cellular uptake of several lipid species, including cholesterol and vitamin E. During early mouse development, SR-B1 is located in the maternal-fetal interface, where it facilitates vitamin E transport towards the embryo. Consequently, mouse embryos lacking SR-B1 are vitamin E-deficient, and around half of them fail to close the neural tube and show cephalic neural tube defects (NTD). Here, we used transcriptomic profiling to identify the molecular determinants of this phenotypic difference between SR-B1 deficient embryos with normal morphology or with NTD. RESULTS: We used RNA-Seq to compare the transcriptomic profile of three groups of embryos retrieved from SR-B1 heterozygous intercrosses: wild-type E9.5 embryos (WT), embryos lacking SR-B1 that are morphologically normal, without NTD (KO-N) and SR-B1 deficient embryos with this defect (KO-NTD). We identified over 1000 differentially expressed genes: down-regulated genes in KO-NTD embryos were enriched for functions associated to neural development, while up-regulated genes in KO-NTD embryos were enriched for functions related to lipid metabolism. Feeding pregnant dams a vitamin E-enriched diet, which prevents NTD in SR-B1 KO embryos, resulted in mRNA levels for those differentially expressed genes that were more similar to KO-N than to KO-NTD embryos. We used gene regulatory network analysis to identify putative transcriptional regulators driving the different embryonic expression profiles, and identified a regulatory circuit controlled by the androgen receptor that may contribute to this dichotomous expression profile in SR-B1 embryos. Supporting this possibility, the expression level of the androgen receptor correlated strongly with the expression of several genes involved in neural development and lipid metabolism. CONCLUSIONS: Our analysis shows that normal and defective embryos lacking SR-B1 have divergent expression profiles, explained by a defined set of transcription factors that may explain their divergent phenotype. We propose that distinct expression profiles may be relevant during early development to support embryonic nutrition and neural tube closure.
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Antígenos CD36/deficiência , Antígenos CD36/genética , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Redes Reguladoras de Genes , Tubo Neural/embriologia , Transcrição Gênica , Animais , Humanos , Camundongos , Tubo Neural/metabolismo , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Fenótipo , DesmameRESUMO
Scavenger receptor class B type 1 (SR-B1) plays an essential role in high density lipoprotein (HDL) metabolism. SR-B1 deficient (SR-B1 KO) mice are prone to atherosclerosis and exhibit abnormally large, cholesterol-rich, dysfunctional HDL. In a recent issue of J Transl Med, Cao et al. described results of proteomics analyses of HDL isolated from wild-type (WT) and SR-B1 KO mice using precipitation of large lipoproteins with polyethylene glycol (PEG). They report abnormalities in SR-B1 KO HDL protein components that correlate with HDL function. In this commentary, we describe and discuss the differences in the results published by Cao et al. and those obtained in a recent study from our laboratory using shotgun proteomics of HDL of SR-B1 KO mice isolated by ultracentrifugation. We propose that different HDL purification procedures used may account for the discrepancies observed. We show that SR-B1 KO HDL purification using either PEG or dextran sulfate precipitation results in enrichment of small HDL subclasses, and may therefore underestimate alterations in lipoprotein composition or function. Compared to HDL obtained by ultracentrifugation, HDL isolated by PEG precipitation show a lower ApoE/ApoA-I proportion and reduced cholesterol content. HDL protein components described by Cao et al. or our laboratory are mostly inconsistent: only 33 HDL proteins were detected in both datasets, whereas a significant number of proteins were only identified by Cao et al. (n = 43) or Contreras-Duarte et al. (n = 26) datasets. The relative abundance of HDL-associated peptide and protein levels in WT vs SR-B1 HDL were also highly different in both datasets. This study indicates that caution must be taken when interpreting results from HDL isolated by chemical precipitation.
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HDL-Colesterol/metabolismo , Proteoma/metabolismo , Receptores Depuradores Classe B/deficiência , Animais , Precipitação Química , HDL-Colesterol/sangue , Camundongos Knockout , Proteômica , Receptores Depuradores Classe B/metabolismoRESUMO
The HDL receptor scavenger receptor, class B type I (SR-BI) controls the structure and fate of plasma HDL. Female SR-BI KO mice are infertile, apparently because of their abnormal cholesterol-enriched HDL particles. We examined the growth and meiotic progression of SR-BI KO oocytes and found that they underwent normal germinal vesicle breakdown; however, SR-BI KO eggs, which had accumulated excess cholesterol in vivo, spontaneously activated, and they escaped metaphase II (MII) arrest and progressed to pronuclear, MIII, and anaphase/telophase III stages. Eggs from fertile WT mice were activated when loaded in vitro with excess cholesterol by a cholesterol/methyl-ß-cyclodextrin complex, phenocopying SR-BI KO oocytes. In vitro cholesterol loading of eggs induced reduction in maturation promoting factor and MAPK activities, elevation of intracellular calcium, extrusion of a second polar body, and progression to meiotic stages beyond MII. These results suggest that the infertility of SR-BI KO females is caused, at least in part, by excess cholesterol in eggs inducing premature activation and that cholesterol can activate WT mouse eggs to escape from MII arrest. Analysis of SR-BI KO female infertility raises the possibility that abnormalities in cholesterol metabolism might underlie some cases of human female infertility of unknown etiology.
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HDL-Colesterol/metabolismo , Colesterol/toxicidade , Infertilidade Feminina/etiologia , Meiose/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Receptores Depuradores Classe B/deficiência , Animais , Sobrevivência Celular , Ácido Egtázico/farmacologia , Feminino , Sistema de Sinalização das MAP Quinases , Meiose/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oócitos/citologia , Corpos Polares , Receptores Depuradores Classe B/fisiologia , Estrôncio/farmacologia , beta-Ciclodextrinas/farmacologiaRESUMO
The srbi gene encodes a lipoprotein receptor with high affinity for high density lipoprotein that is mainly expressed in the liver and in steroidogenic tissues. Disruption of this gene in mice and mutations in humans lead to alterations in lipoprotein metabolism and/or fertility. During murine development, scavenger receptor class B member I (SR-BI) is present in the yolk sac and the placenta and is only expressed in the embryo itself late in gestation. In humans, it has been detected in trophoblast cells and placenta. Although the proportion of mice carrying a null mutation in SR-BI obtained from heterozygous intercrosses is lower than the expected by the Mendelian ratio, suggesting the involvement of this receptor in intrauterine development, the cause of this demise has remained unknown. In this work, we show that embryos lacking SR-BI exhibit a high prevalence of exencephaly with a sex bias toward females. Immunolocalization studies confirmed that SR-BI is not expressed in the embryo at early stages of development and allowed a more detailed description of its localization in the cells that mediate maternal-fetal transport of nutrients. SR-BI-null embryos contain less cholesterol than their wild-type littermates, suggesting the involvement of SR-BI in materno-fetal cholesterol transport. Newborn SR-BI-deficient pups exhibit intrauterine growth restriction, suggesting that this receptor is also important for fetal growth. Altogether, the results of our work suggest that the presence of SR-BI in extraembryonic tissues is involved in the maternal-fetal transport of cholesterol and/or other lipids with a role during neural tube closure and fetal growth.
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Lipoproteínas HDL/deficiência , Receptores de Lipoproteínas/deficiência , Receptores Depuradores Classe B/deficiência , Síndrome de Smith-Lemli-Opitz/embriologia , Síndrome de Smith-Lemli-Opitz/metabolismo , Animais , Colesterol/metabolismo , Modelos Animais de Doenças , Feminino , Feto/anormalidades , Feto/embriologia , Feto/metabolismo , Humanos , Metabolismo dos Lipídeos , Lipoproteínas HDL/genética , Masculino , Troca Materno-Fetal , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez , Receptores de Lipoproteínas/genética , Receptores Depuradores Classe B/genética , Síndrome de Smith-Lemli-Opitz/genéticaRESUMO
To measure the impact of a "Preventive Letter" designed to encourage the return of gestational diabetes mellitus (GDM) mothers to follow up visit after delivery, in the context of a worldwide concern about low return rates after delivery of these patients. Mothers with GDM require medical evaluation and an oral glucose tolerance test (OGTT) 6 weeks after delivery, in order to: [a] confirm remission of GDM and [b] provide advice on the prevention of type 2 diabetes. In the year 2003 we developed a "Preventive Letter", containing three aspects: [a] current treatment, [b] suggested management during labor, and [c] a stapled laboratory order for OGTT to be performed 6 weeks after delivery. The return rate after delivery was assessed in two groups of GDM mothers: [a] "Without Preventive Letter" (n = 253), and "With Preventive Letter" (n = 215). Both groups, similar with respect to age (33.0 ± 5.4 and 32.3 ± 4.9 years respectively, p = 0.166) and education time (14.9 ± 1.8 and 15.0 ± 1.8 years respectively, p = 0.494), showed a significant difference in the 1-year return rate after delivery, as assessed by the Kaplan-Meier test: 32.0 % for the group "Without Preventive Letter", and 76.0 % for the group "With Preventive Letter" (p < 0.001). The 1-year return rate after delivery of GDM mothers was 2.4 times higher in the group "With Preventive Letter" than in the group without it. We believe that this low-cost approach could be useful in other institutions caring for pregnant women with diabetes.
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Correspondência como Assunto , Diabetes Mellitus Tipo 2/prevenção & controle , Promoção da Saúde/métodos , Promoção da Saúde/estatística & dados numéricos , Cooperação do Paciente/estatística & dados numéricos , Adulto , Aminoácidos , Peptídeo C/sangue , Chile , Cromo , Diabetes Gestacional/sangue , Diabetes Gestacional/terapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Ácidos Nicotínicos , Cuidado Pós-Natal/métodos , Gravidez , Faculdades de MedicinaRESUMO
The cholesterol content of the sperm membrane is regulated during both maturation in the epididymis and capacitation in the female tract, two processes required for the spermatozoa to acquire their fertilising ability. Because Niemann-Pick disease, type C2 (NPC2) protein is one of the most abundant components of the epididymal fluid and contains a functional cholesterol-binding site that can transfer cholesterol between membranes, it has been suggested for years that NPC2 could be involved in the regulation of cholesterol levels in spermatozoa during epididymal maturation. In the present study, western blot and immunohistochemistry analyses demonstrated significant levels of NPC2 in the mouse epididymal epithelium. Epididymal spermatozoa obtained from NPC2(-/-) mice were morphologically normal and had normal motility parameters, but had a reduced cholesterol content compared with that of wild-type (WT) spermatozoa, as determined by both biochemical and by flow cytometry analyses. These results suggest that NPC2 could be involved in regulating cholesterol levels in spermatozoa during epididymal maturation. To understand the relevance of epididymal NPC2 for sperm function, the ability of spermatozoa to undergo events influenced by epididymal maturation, such as capacitation and fertilisation, were compared between WT and NPC2(-/-) mice. Capacitated NPC2(-/-) spermatozoa exhibited defective tyrosine phosphorylation patterns and a reduced ability to fertilise cumulus-oocyte complexes compared with WT spermatozoa, supporting the relevance of mouse epididymal NPC2 for male fertility.
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Colesterol/metabolismo , Epididimo/metabolismo , Fertilização in vitro , Espermatozoides/metabolismo , Proteínas de Transporte Vesicular/deficiência , Animais , Epididimo/patologia , Feminino , Fertilidade , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Capacitação Espermática , Interações Espermatozoide-Óvulo , Espermatozoides/patologia , Fatores de Tempo , Tirosina , Proteínas de Transporte Vesicular/genéticaRESUMO
High density lipoproteins (HDL) are responsible of reverse cholesterol transport and play an important antiatherogenic role. In recent years, several studies suggest that HDL have additional functions, including a possible anti-inflammatory activity in infectious conditions. Furthermore, available evidence indicates that the presence of lipopolysaccharide (LPS) within the circulation during infectious states induced by gram-negative bacteria may be involved in the decrease in HDL cholesterol levels and changes in lipoprotein composition, which have been associated with a higher mortality due to sepsis in animal models and in humans. In this article, we review this subject and also discuss possible mechanisms that explain the positive impact achieved by native HDL, reconstituted HDL, or HDL apolipoprotein peptides on the inflammatory response and mortality in models of endotoxemia. In this regard, it has been proposed that one of the mechanisms by which HDL protect against sepsis may be mediated by its binding ability and/or neutralizing capacity on LPS, avoiding an excessive response of the immune system. Thus, increasing blood levels of HDL and/or parenteral HDL administration may represent a new anti-inflammatory tool for managing septic states in humans.
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Aterosclerose/prevenção & controle , Endotoxemia/imunologia , Lipoproteínas HDL/fisiologia , Estresse Oxidativo/fisiologia , Sepse/imunologia , Animais , Anti-Inflamatórios/farmacologia , Apolipoproteína A-I/análise , Colesterol/sangue , Modelos Animais de Doenças , Endotoxemia/sangue , Humanos , Inflamação/sangue , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/sangue , Lipoproteínas HDL/sangue , Lipoproteínas HDL/efeitos dos fármacos , Camundongos , Sepse/sangue , Trombose/sangueRESUMO
Since 1964, the hypothesis of Pedersen has been used to explain fetal macrosomia observed in gestational diabetes mellitus (GDM), by a mechanism involving maternal hyperglycemia--fetal hyperglycemia--fetal hyperinsulinemia. However, since the 1980-89 decade, it is known that pregnant women with pre-gestational overweight not suffering from GDM still have a higher frequency of fetal macrosomia. Furthermore, pregnant women with GDM, despite being subjected to optimal glycemic control, still show unacceptably high frequencies of fetal macrosomia, a phenomenon that is concentrated in pregnancies with overweight or obesity prior to pregnancy. If glucose is not the single nutrient responsible for fetal macrosomia in pregnant women with gestational diabetes that undergo strict glycemic control, other nutrients may cause excessive fetal growth in pre-pregnancy overweight mothers. In this review, we propose that triglycerides (TG) could be responsible for this accelerated fetal growth. If this hypothesis is validated in animal models and clinical studies, then normal and pathological ranges of TG should be defined, and monitoring of triglyceride levels during pregnancy should be advised as a possible new alternative, besides a good glycemic control, for the management of fetal macrosomia in GDM women with overweight prior to pregnancy.
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Diabetes Gestacional/sangue , Macrossomia Fetal/etiologia , Hiperglicemia/complicações , Hipertrigliceridemia/complicações , Triglicerídeos/sangue , Glicemia/fisiologia , Feminino , Idade Gestacional , Teste de Tolerância a Glucose , Humanos , Hipertrigliceridemia/sangue , Recém-Nascido , Obesidade/complicações , Sobrepeso/etiologia , GravidezRESUMO
SCOPE: Quinoa intake exerts hypoglycemic and hypolipidemic effects in animals and humans. Although peptides from quinoa inhibit key enzymes involved in glucose homeostasis in vitro, their in vivo antidiabetic properties have not been investigated. METHODS AND RESULTS: This study evaluated the effect of oral administration of a quinoa protein hydrolysate (QH) produced through enzymatic hydrolysis and fractionation by electrodialysis with ultrafiltration membrane (EDUF) (FQH) on the metabolic and pregnancy outcomes of Lepdb/+ pregnant mice, a preclinical model of gestational diabetes mellitus. The 4-week pregestational consumption of 2.5 mg mL-1 of QH in water prevented glucose intolerance and improves hepatic insulin signaling in dams, also reducing fetal weights. Sequencing and bioinformatic analyses of the defatted FQH (FQHD) identified 11 peptides 6-10 amino acids long that aligned with the quinoa proteome and exhibited putative anti-dipeptidyl peptidase-4 (DPP-IV) activity, confirmed in vitro in QH, FQH, and FDQH fractions. Peptides homologous to mouse and human proteins enriched for biological processes related to glucose metabolism are also identified. CONCLUSION: Processing of quinoa protein may be used to develop a safe and effective nutritional intervention to control glucose intolerance during pregnancy. Further studies are required to confirm if this nutritional intervention is applicable to pregnant women.
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Chenopodium quinoa , Diabetes Gestacional , Intolerância à Glucose , Humanos , Camundongos , Feminino , Animais , Gravidez , Diabetes Gestacional/terapia , Hidrolisados de Proteína/química , Ultrafiltração , Hipoglicemiantes , Peptídeos/químicaRESUMO
Cholesterol is an essential component of animal cells. Different regulatory mechanisms converge to maintain adequate levels of this lipid because both its deficiency and excess are unfavorable. Low cell cholesterol content promotes its synthesis and uptake from circulating lipoproteins. In contrast, its excess induces the efflux to high-density lipoproteins (HDL) and their transport to the liver for excretion, a process known as reverse cholesterol transport. Different studies suggest that an abnormal HDL metabolism hinders female fertility. HDL are the only lipoproteins detected in substantial amounts in follicular fluid (FF), and their size and composition correlate with embryo quality. Oocytes obtain cholesterol from cumulus cells via gap junctions because they cannot synthesize cholesterol de novo and lack HDL receptors. Recent evidence has supported the possibility that FF HDL play a major role in taking up excess unesterified cholesterol (UC) from the oocyte. Indeed, genetically modified mouse models with disruptions in reverse cholesterol transport, some of which show excessive circulating UC levels, exhibit female infertility. Cholesterol accumulation can affect the egg´s viability, as reported in other cell types, and activate the plasma membrane structure and activity of membrane proteins. Indeed, in mice deficient for the HDL receptor Scavenger Class B Type I (SR-B1), excess circulating HDL cholesterol and UC accumulation in oocytes impairs meiosis arrest and hinders the developmental capacity of the egg. In other cells, the addition of cholesterol activates calcium channels and dysregulates cell death/survival signaling pathways, suggesting that these mechanisms may link altered HDL cholesterol metabolism and infertility. Although cholesterol, and lipids in general, are usually not evaluated in infertile patients, one study reported high circulating UC levels in women showing longer time to pregnancy as an outcome of fertility. Based on the evidence described above, we propose the existence of a well-regulated and largely unexplored system of cholesterol homeostasis controlling traffic between FF HDL and oocytes, with significant implications for female fertility.
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BACKGROUND/AIMS: Apolipoprotein A-I (apo A-I) is the main protein component of plasma high-density lipoproteins (HDL) and a key determinant of HDL cholesterol levels and metabolism. The relevance of HDL in controlling the traffic of cholesterol from plasma into bile has been partially addressed. The aim of this study was to evaluate the role of apo A-I expression in controlling the secretion of biliary lipids as well as the risk of gallstone disease in vivo. METHODS: We evaluated biliary lipid secretion and bile acid homeostasis in mice deficient for apo A-I compared with wild-type animals when fed with low- or high-cholesterol diets. In addition, we assessed the importance of murine apoA-I expression for gallstone formation after feeding a lithogenic diet. RESULTS: Bile acid pool size and faecal excretion were within the normal range in chow- and cholesterol-fed apo A-I knockout (KO) mice. Basal biliary cholesterol secretion was comparable and increased similarly in both murine strains after cholesterol feeding. Lithogenic diet-fed apo A-I KO mice exhibited an impaired hypercholesterolaemic response owing to a lower increase in cholesterol levels transported in large lipoproteins. However, the lack of apo A-I expression did not affect biliary cholesterol precipitation or gallstone formation in lithogenic diet-fed mice. CONCLUSIONS: These findings indicate that biliary lipid secretion, bile acid metabolism and gallstone formation are independent of apo A-I expression and plasma HDL cholesterol levels in mice.
Assuntos
Apolipoproteína A-I/deficiência , Ácidos e Sais Biliares/metabolismo , HDL-Colesterol/sangue , Cálculos Biliares/fisiopatologia , Animais , Apolipoproteína A-I/genética , Dieta Aterogênica , Fezes/química , Camundongos , Camundongos Knockout , RNA Mensageiro/isolamento & purificaçãoRESUMO
Vitamin E was identified as a lipophilic compound essential to maintain rat pregnancy. Low vitamin E intake during early pregnancy associates with congenital malformations and embryonic loss in animals and with miscarriage and intrauterine growth restriction in humans. Vitamin E protects cell membranes from lipoperoxidation and exerts non-antioxidant activities. Its function can be restored by vitamin C; thus, intake and circulating levels of both micronutrients are frequently analyzed together. Although substantial vitamin E inadequacy was reported worldwide, its consumption in Latin America (LatAm) is mostly unknown. Using data from the Latin American Study of Nutrition and Health (Estudio Latinoamericano de Nutrición y Salud, ELANS), we evaluated vitamin E and C intake in women of reproductive age (WRA) from eight LatAm countries and identified their main food sources. Two non-consecutive 24-h dietary recalls in 3704 women aged from 15 to 49 years and living in urban locations showed low average intake of vitamin E (7.9 mg/day vs. estimated average requirement (EAR) of 12 mg/day) and adequate overall vitamin C consumption (95.5 mg/day vs. EAR of 60 mg/day). The mean regional inadequacy was 89.6% for vitamin E and 36.3% for vitamin C. The primary food sources of vitamin E were fats and oils, as well as vegetables. Vitamin C intake was explained mainly by the consumption of fruit juices, fruits, and vegetables. Combined deficient intake of both vitamins was observed in 33.7% of LatAm women. Although the implications of low antioxidant vitamins' consumption in WRA are still unclear, the combined deficient intake of both vitamins observed in one-third of ELANS participants underscores the need for further research on this topic.
Assuntos
Ácido Ascórbico/farmacologia , Saúde , Estado Nutricional , Reprodução , Vitamina E/farmacologia , Adolescente , Adulto , Fatores Etários , Comportamento Alimentar , Feminino , Alimentos , Humanos , América Latina , Pessoa de Meia-Idade , Adulto JovemRESUMO
Scavenger receptor class B type 1 (SR-B1) is a membrane lipoprotein receptor/lipid transporter involved in the pathogenesis of atherosclerosis, but its role in obesity and fatty liver development is unclear. Here, we determined the effects of SR-B1 deficiency on plasma metabolic and inflammatory parameters as well as fat deposition in adipose tissue and liver during obesity. To induce obesity, we performed high-fat diet (HFD) exposure for 12 weeks in male SR-B1 knock-out (SR-B1-/-, n = 14) and wild-type (WT, n = 12) mice. Compared to HFD-fed WT mice, plasma from HFD-fed SR-B1-/- animals exhibited increased total cholesterol, triglycerides (TG) and tumor necrosis factor-α (TNF-α) levels. In addition, hypertrophied adipocytes and macrophage-containing crown-like structures (CLS) were observed in adipose tissue from HFD-fed SR-B1 deficient mice. Remarkably, liver from obese SR-B1-/- mice showed attenuated TG content, dysregulation in hepatic peroxisome proliferator-activated receptors (PPARs) expression, increased hepatic TG secretion, and altered hepatic fatty acid (FA) composition. In conclusion, we show that SR-B1 deficiency alters the metabolic environment of obese mice through modulation of liver and adipose tissue lipid accumulation. Our findings provide the basis for further elucidation of SR-B1's role in obesity and fatty liver, two major public health issues that increase the risk of advanced chronic diseases and overall mortality.
Assuntos
Tecido Adiposo/patologia , Antígenos CD36/deficiência , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/complicações , Fígado Gorduroso/metabolismo , Obesidade/complicações , Obesidade/etiologia , Animais , Suscetibilidade a Doenças , Ácidos Graxos/metabolismo , Fígado Gorduroso/patologia , Inflamação/complicações , Fígado/metabolismo , Masculino , Camundongos , Triglicerídeos/metabolismoRESUMO
Mammalian fertilization is a complex multi-step process mediated by different molecules present on both gametes. CRISP1 (cysteine-rich secretory protein 1) is an epididymal protein thought to participate in gamete fusion through its binding to egg-complementary sites. Structure-function studies using recombinant fragments of CRISP1 as well as synthetic peptides reveal that its egg-binding ability resides in a 12 amino acid region corresponding to an evolutionary conserved motif of the CRISP family, named Signature 2 (S2). Further experiments analyzing both the ability of other CRISP proteins to bind to the rat egg and the amino acid sequence of their S2 regions show that the amino acid sequence of the S2 is needed for CRISP1 to interact with the egg. CRISP1 appears to be involved in the first step of sperm binding to the zona pellucida, identifying a novel role for this protein in fertilization. The observation that sperm testicular CRISP2 is also able to bind to the egg surface suggests a role for this protein in gamete fusion. Subsequent experiments confirmed the participation of CRISP2 in this step of fertilization and revealed that CRISP1 and CRISP2 interact with common egg surface binding sites. Together, these results suggest a functional cooperation between CRISP1 and CRISP2 to ensure the success of fertilization. These observations contribute to a better understanding of the molecular mechanisms underlying mammalian fertilization.