miR-18a-5p Is Involved in the Developmental Origin of Prostate Cancer in Maternally Malnourished Offspring Rats: A DOHaD Approach.

The Developmental Origins of Health and Disease (DOHaD) concept correlates early life exposure to stressor conditions with the increased incidence of non-communicable chronic diseases, including prostate cancer (PCa), throughout the life span. However, the molecular mechanisms involved in this process remain poorly understood. In this study, the deregulation of two miRNAs (rno-miR-18a-5p and rno-miR-345-3p) was described in the ventral prostate VP of old rats born to dams fed with a low protein diet (LPD) (6% protein in the diet) during gestational and lactational periods. Integrative analysis of the (VP) transcriptomic and proteomic data revealed changes in the expression profile of 14 identified predicted targets of these two DE miRNAs, which enriched terms related to post-translational protein modification, metabolism of proteins, protein processing in endoplasmic reticulum, phosphonate and phosphinate metabolism, the calnexin/calreticulin cycle, metabolic pathways, N-glycan trimming in the ER and the calnexin/calreticulin cycle, hedgehog ligand biogenesis, the ER-phagosome pathway, detoxification of reactive oxygen species, antigenprocessing-cross presentation, RAB geranylgeranylation, collagen formation, glutathione metabolism, the metabolism of xenobiotics by cytochrome P450, and platinum drug resistance. RT-qPCR validated the deregulation of the miR-18a-5p/P4HB (prolyl 4-hydroxylase subunit beta) network in the VP of older offspring as well as in the PNT-2 cells transfected with mimic miR-18a-5p. Functional in vitro studies revealed a potential modulation of estrogen receptor α (ESR1) by miR-18a-5p in PNT-2 cells, which was also confirmed in the VP of older offspring. An imbalance of the testosterone/estrogen ratio was also observed in the offspring rats born to dams fed with an LPD. In conclusion, deregulation of the miR-18a-5p/P4HB network can contribute to the developmental origins of prostate cancer in maternally malnourished offspring, highlighting the need for improving maternal healthcare during critical windows of vulnerability early in life.

Sex-differential RXRα gene methylation effects on mRNA and protein expression in umbilical cord of the offspring rat exposed to maternal obesity.

Maternal obesity (MO) induces negative consequences in the offspring development. Adiposity phenotype is associated with maternal diet at early pregnancy and DNA methylation marks in the RXRα promotor at birth. Glucocorticoids play an important role in the regulation of metabolism through the activation of nuclear hormone receptors such as the RXRα protein. The aim of the study was to analyze steroid hormone changes at the end of pregnancy in the obese mother and RXRα gene methylation in the umbilical cord. For this purpose, in a well-established MO model, female Wistar rats were fed either standard chow (controls: C) or high-fat obesogenic diet (MO) before and during pregnancy to evaluate at 19 days of gestation (19 dG): 1) maternal concentration of circulating steroid hormones in MO and C groups, 2) maternal and fetal weights, 3) analysis of correlation between hormones concentration and maternal and fetal weights, 4) DNA methylation status of a single locus of RXRα gene near the early growth response (EGR-1) protein DNA binding site, and 5) RXRα mRNA and protein expressions in umbilical cords. Our results demonstrate that at 19 dG, MO body weight before and during pregnancy was higher than C; MO progesterone and corticosterone serum concentrations were higher and estradiol lower than C. There were not differences in fetal weight between male and female per group, therefore averaged data was used; MO fetal weight was lower than C. Positive correlations were found between progesterone and corticosterone with maternal weight, and estradiol with fetal weight, while negative correlation was observed between corticosterone and fetal weight. Additionally, male umbilical cords from MO were hypermethylated in RXRα gene compared to male C group, without differences in the female groups; mRNA and protein expression of RXRα were decreased in F1 male but not in female MO compared to C. In conclusion, MO results in dysregulation of circulating steroid hormones of the obese mothers and low fetal weight in the F1, modifying DNA methylation of RXRα gene as well as RXRα mRNA and protein expression in the umbilical cord in a sex-dependent manner.

Ethical considerations in animal research: the principle of 3r's

In the last century, progress in the knowledge of human diseases, their diagnosis and treatment have grown exponentially, due in large part to the introduction and use of laboratory animals. Along with this important progress, the need to provide training and guidance to the scientific community in all aspects related to the proper use of experimental animals has been indispensable. Animal research committees play a primary role in evaluating experimental research protocols, from their feasibility to the rational use of animals, but above all in seeking animal welfare. The Institutional Committee for the Care and Use of Animals (IACUC) has endeavored to share several relevant aspects in conducting research with laboratory animals. Here, we present and discuss the topics that we consider of utmost importance to take in the account during the design of any experimental research protocol, so we invite researchers, technicians, and undergraduate and graduate students to dive into the fascinating subject of proper animal care and use for experimentation. The main intention of these contributions is to sensitize users of laboratory animals for the proper and rational use of them in experimental research, as well as to disseminate the permitted and unpermitted procedures in laboratory animals. In the first part, the significance of experimental research, the main functions of IACUC, and the principle of the three R's (replacement, reduction, and refinement) are addressed.

Increased oxidative stress and cancer biomarkers in the ventral prostate of older rats submitted to maternal malnutrition.

The concept of Developmental Origins of Health and Disease (DOHaD) states that exposure to malnutrition early in life increase the incidence of non-communicable chronic diseases throughout the lifespan. In this study, a reduction in serum testosterone and an increase in estrogen levels were shown in older rats born to protein malnourished dams (6% protein in the diet) during gestation and lactation. Intraprostatic levels of reduced glutathione were decreased, while tissue expression of glutathione S-transferase pi and sulfiredoxin-1 were increased in these animals. Strong immunostaining for alfametilacil CoA racemase (AMACR), vascular endothelial growth factor-A (VEGF-A), and aquaporin-1 (AQP1) was also observed. In silico analysis confirmed commonly deregulated proteins in the ventral prostate of old rats and patients with prostate cancer. In conclusion, the increase in oxidative stress associated with an imbalance of sex hormones may contribute to prostate carcinogenesis in offspring, highlighting early-life malnutrition as a key risk factor for this malignance.

Leuconostoc mesenteroides subsp. mesenteroides SD23 Prevents Metabolic Dysfunction Associated with High-Fat Diet-Induced Obesity in Male Mice.

High-fat diet (HFD) consumption induces obesity and increases blood glucose, insulin resistance, and metabolic disorders. Recent studies suggest that probiotics might be a novel approach to counteract these effects in the treatment of obesity. Here, we evaluated the effect of Leuconostoc mesenteroides subsp. mesenteroides SD23 on obesity-related metabolic dysfunction. In the present study, mice were randomly divided into four dietary groups: standard diet (C), HFD (OB), standard diet with L. mesenteroides SD23 (CP), and HFD with L. mesenteroides SD23 (OBP). Diets were maintained for 14 weeks. Animal weight was monitored and biochemical and histological analyses were performed after intervention. OB showed metabolic dysfunction, and increased the number of larger adipocytes compared to C. OB induced liver tumor necrosis factor-α (TNF-α) expression, increased cholesterol, leptin, and glucose levels compared to C. OBP reduced body weight, glucose, cholesterol, and leptin levels and improved glucose tolerance compared to OB. OBP also reduced liver steatosis, the number of larger adipocytes in adipose tissue, and reduced the villus height in the small intestine. OBP decreased expression of TNF-α and increased expression of IL-10 in liver. The parameters evaluated in the CP were similar to the C. This study provides novel evidence that dietary intervention with L. mesenteroides SD23 improves metabolic dysfunction related to obesity in HFD-fed mice.

Resilience to acute kidney injury in offspring of maternal protein restriction.

Protein restriction (PR) during pregnancy induces morphofunctional alterations related to deficient nephrogenesis. We studied the renal functional and morphological significance of PR during pregnancy and/or lactation in adult male rat offspring and the repercussions on acute kidney injury (AKI) severity. Female rats were randomly assigned to the following groups: control diet during pregnancy and lactation (CC), control diet during pregnancy and PR diet during lactation (CR), PR during pregnancy and control diet during lactation (RC), and PR during pregnancy and lactation (RR). Three months after birth, at least 12 male offspring of each group randomly underwent either bilateral renal ischemia for 45 min [ischemia-reperfusion (IR)] or sham surgery. Thus, eight groups were studied 24 h after reperfusion: CC, CC + IR, CR, CR + IR, RC, RC + IR, RR, and RR + IR. Under basal conditions, the CR, RC, and RR groups exhibited a significant reduction in nephron number that was associated with a reduction in renal blood flow. Glomerular hyperfiltration was present as a compensatory mechanism to maintain normal renal function. mRNA levels of several vasoactive, antioxidant, and anti-inflammatory molecules were decreased. After IR, renal function was similarly reduced in all of the studied groups. Although all of the offspring from maternal PR exhibited renal injury, the magnitude was lower in the RC and RR groups, which were associated with faster renal blood flow recovery, differential vasoactive factors, and hypoxia-inducible factor-1α signaling. Our results show that the offspring from maternal PR are resilient to AKI induced by IR that was associated with reduced tubular injury and a differential hemodynamic response.

Indicadores socioeconómicos de obesidad materna. El estudio de una cohorte en Morelos, México / Socioeconomic indicators of maternal obesity. Study of a cohort in Morelos, México / Indicadores socioeconómicos da obesidade materna. Estudo de uma coorte no Morelos, México / Indicateurs socio-économiques de l'obésité maternelle. Étude d'une cohorte au Morelos, Mexique

Resumen: Objetivo: Identificar y analizar desde una perspectiva cuanti/cualitativita los indicadores socioeconómicos de la obesidad materna en México. Material y métodos: Investigación evaluativa basada en un diseño de cohorte de tipo prospectivo/descriptivo. El tamaño de la muestra se conformó por todas las mujeres que llegaron a consulta prenatal a partir de la semana 24 de gestación en un hospital de referencia estatal. El tamaño de la muestra se estimó con un 80% de poder y 95% de confianza y significancia. Los indicadores de interés fueron aspectos socioeconómicos, alimentación, antropometría, dieta, seguridad alimentaria y actividad física. El análisis cuantitativo se realizó utilizando el software Stata versión 14 y el análisis cualitativo con Atlas-ti versión 8.0. Resultados: La cohorte estuvo conformada por 402 mujeres embarazadas en 2017. De los resultados principales encontramos que el 55% de las mujeres se encontraba en el rango de edad de 18-24 años; el 15% de las mujeres refirió contar con un empleo remunerado; el 42% de la población tenía secundaria completa; el 32.1% presentó un grado de inseguridad alimentaria; la media de IMC fue de 27.8±4.8, el 48% de las mujeres presentaron sobrepeso y obesidad. Conclusiones: Los resultados cuantitativos sugieren que poblaciones con mayor vulnerabilidad socio-económica, inseguridad alimentaria y escasa actividad física, son más propensas a la obesidad materna. Los resultados cualitativos, además de complementar y reforzar los resultados cuantitativos, plantean evidencias para identificar a mayor detalle las barreras y facilitadores para fortalecer programas de intervención en la prevención de la obesidad materna.

Abstract; Objective: To identify and analyze from a quantitative / qualitative perspective the socioeconomic indicators of maternal obesity in Mexico. Methods and material: Evaluative research based on a prospective / analytical cohort design. The sample size was established by all the women who came to the antenatal clinic from the 24th week of gestation in a state referral hospital. The sample size was estimated with 80% power and 95% confidence and significance. The indicators of interest were socioeconomic aspects, nutrition, anthropometry, diet, food safety and physical activity. The quantitative analysis was performed using the Stata version 14 software and the qualitative analysis with Atlas-ti version 8.0. Results: The cohort was comprised of 402 pregnant women in 2017. From the main results we found that 55% of the women were in the age range of 18-24 years; 15% of women reported having a paid job; 42% of the population had full secondary education; 32.1% presented a degree of food insecurity; the mean BMI was 27.8 ± 4.8, 48% of the women were overweight and obese. Conclusions: Quantitative results suggest that populations with greater socio-economic vulnerability, food insecurity and low physical activity are more prone to maternal obesity. The qualitative results, besides complementing and reinforcing the quantitative results, present evidence to identify in greater detail the barriers and facilitators to strengthen intervention programs in the prevention of maternal obesity.

Resumo: Objetivo: Identificar e analisar, de uma perspectiva quantitativa / qualitativa, os indicadores socioeconômicos da obesidade materna no México. Materiais e métodos: Pesquisa avaliativa baseada em um desenho de coorte prospectivo / analítico. O tamanho da amostra foi estabelecido por todas as mulheres que chegaram à clínica pré-natal a partir da 24a semana de gestação em um hospital estadual de referência. O tamanho da amostra foi estimado com 80% de poder e 95% de confiança e significância. Os indicadores de interesse foram aspectos socioeconómicos, nutrição, antropometria, dieta, segurança alimentar e atividade física. A análise quantitativa foi realizada utilizando o software Stata versão 14 e a análise qualitativa com Atlas-ti versão 8.0. Resultados: A coorte foi composta por 402 gestantes em 2017. Dos principais resultados, constatou-se que 55% das mulheres encontravam- se na faixa etária de 18 a 24 anos; 15% das mulheres relataram ter um emprego remunerado; 42% da população tinha ensino secundário completo; 32,1% apresentaram grau de insegurança alimentar; a média do IMC foi de 27,8 ± 4,8, 48% das mulheres estavam acima do peso e obesas. Conclusões: Os resultados quantitativos sugerem que populações com maior vulnerabilidade socioeconómica, insegurança alimentar e baixa atividade física são mais propensas à obesidade materna. Os resultados qualitativos, além de complementar e reforjar os resultados quantitativos, apresentam evidencias para identificar em maior detalhe as barreiras e facilitadores para fortalecer os programas de intervenção na prevenção da obesidade materna.

Résumé: Objectif: Identifier et analyser d'un point de vue quantitatif / qualitatif les indicateurs socio-économiques de l'obésité maternelle au Mexique. Matériel et méthodes: Recherche évaluative basée sur une conception de cohorte prospective / analytique. La taille de l'échantillon a été établie par toutes les femmes qui sont venues á la clinique prénatale á partir de la 24e semaine de gestation dans un hópital de référence. La taille de l'échantillon a été estimée avec 80% de puissance et 95% de confiance et de signification. Les indicateurs d'intéret étaient les aspects socio-économiques, la nutrition, l'anthropométrie, l'alimentation, la sécurité alimentaire et l'activité physique. L'analyse quantitative a été réalisée á l'aide du logiciel Stata version 14 et de l'analyse qualitative avec Atlas-ti version 8.0. Résultats: La cohorte était composée de 402 femmes enceintes en 2017. D'aprés les principaux résultats, nous avons constaté que 55% des femmes étaient agées de 18 á 24 ans; 15% des femmes ont déclaré avoir un travail rémunéré; 42% de la population ont fait des études secondaires complétes; 32,1% présentaient un degré d'insécurité alimentaire; l'IMC moyen était de 27,8 ± 4,8, 48% des femmes étaient en surpoids et obéses. Conclusions: Les résultats quantitatifs suggérent que les populations ayant une plus grande vulnérabilité socio-économique, l'insécurité alimentaire et une faible activité physique sont plus sujettes á l'obésité maternelle. Les résultats qualitatifs, en plus de compléter et de renforcer les résultats quantitatifs, présentent des preuves pour identifier plus en détail les obstacles et les facilitateurs pour renforcer les programmes d'intervention dans la prévention de l'obésité maternelle.

I. The role of research ethics committees in observational studies: epidemiological registries, case reports, interviews, and retrospective studies

Abstract It is often unclear to the clinical investigator whether observational studies should be submitted to a research ethics committee (REC), mostly because, in general, no active or additional interventions are performed. Moreover, obtaining an informed consent under these circumstances may be challenging, either because these are very large epidemiological registries, or the subject may no longer be alive, is too ill to consent, or is impossible to contact after being discharged. Although observational studies do not involve interventions, they entail ethical concerns, including threats such as breaches in confidentiality and autonomy, and respect for basic rights of the research subjects according to the good clinical practices. In this context, in addition to their main function as evaluators from an ethical, methodological, and regulatory point of view, the RECs serve as mediators between the research subjects, looking after their basic rights, and the investigator or institution, safeguarding them from both legal and unethical perils that the investigation could engage, by ensuring that all procedures are performed following the international standards of care for research. The aim of this manuscript is to provide information on each type of study and its risks, along with actions to prevent such risks, and the function of RECs in each type of study.

Socio-economic indicators, dietary patterns, and physical activity as determinants of maternal obesity in middle-income countries: Evidences from a cohort study in Mexico.

Maternal obesity is one of the main public health problems at a world level. It is a multifactorial disease with multiple causes, and few studies exist on its dietary patterns, physical activity and social determinants. This work aims to identify determinants of maternal obesity in a middle income country. Research is based on a prospective cohort design. Data were collected using questionnaires applied to pregnant women. Three dietary patterns were identified, and only half of the women carry out physical activity. The regression analysis showed an association between overweight/obesity and the following variables: age 25 to 29 years old (3.8; CI 1.6-9.0), 30 to 34 years old (3.7; CI 1.2-11.6); health problems during pregnancy (2.1; CI 1.0-4.1); socio-economic income (1.73; CI 1.54-2.05); hypertension (2.7; CI 1.4-4.5); mild food insecurity (1.9; CI 1.0-3.8); moderate insecurity (3.7; CI 0.92-15.4); refined food dietary pattern (.76; CI.61-.95). The risk of increasing BMI during pregnancy mainly depends on socioeconomic and demographic variables such as age, educational level, income, food insecurity, and dietary pattern. This study's results could be used as evidences for the revision, planning, and adjustment of interventions for the prevention and management of maternal obesity, as a part of the national strategies against overweight and obesity.

[Socioeconomic determinants of maternal obesity in Mexico and France. Comparative analysis of two cohorts]. / Indicadores socioeconómicos de la obesidad materna en México y Francia. Análisis comparado de dos cohortes.

OBJECTIVE: To identify and analyze the socioeconomic indicators of maternal obesity in Mexico and France. MATERIAL AND METHODS: Comparative study of two cohorts: EDEN (France) and NUTTSEA (Mexico). The study population consisted of women who requested prenatal consultation at week 24 of pregnancy. Data were collected using questionnaires and semi-structured interviews. The variables of interest were socioeconomic aspects, nutrition, anthropometry and food security. The quantitative analysis was performed using Stata and the qualitative analysis with Atlas-ti. RESULTS: In the EDEN cohort, 68.6% were aged 25-34 years, 73% had paid employment and 53% completed high school. In addition, 6.6% reported having difficulty accessing food and the mean gestational BMI was 23.23 ± 4.6. In the NUTTSEA cohort, 55% were in the age range 18-24 years, 15% reported having paid employment, 42% had completed secondary education, 32.1% presented a degree of food insecurity, and the mean BMI was 27.8 ± 4.8. CONCLUSIONS: The qualitative and quantitative results of both cohorts suggest that populations with greater socio-economic vulnerability are more prone to maternal obesity, which leads to determine guidelines on barriers and facilitators to strengthen programs to prevent it maternal obesity.

OBJETIVO: Identificar y analizar los indicadores socioeconómicos de obesidad materna en México y Francia. METODOLOGÍA: Estudio comparativo de dos cohortes EDEN sus siglas en francés (Etude des déterminants pré et post natals précoces de la santé et de développement de l'enfant) (Francia) y NUTTSEA (México). La población de estudio se conformó por mujeres que solicitaron consulta prenatal en semana 24 de gestación. Los datos fueron recolectados con cuestionarios y entrevistas semi-estructuradas. Las variables de interés fueron aspectos socioeconómicos, alimentación, antropometría y seguridad alimentaria. El análisis cuantitativo se realizó utilizando Stata y el análisis cualitativo con Atlas-ti. RESULTADOS: En cohorte EDEN el 68.6% resultó con edad de 25-34 años, el 73% tenían un empleo remunerado, el 53% preparatoria completa; el 6.6% refirió tener dificultad para acceder a los alimentos; la media del IMC gestacional fue de 23.23±4.6. En la cohorte NUTTSEA el 55% se encontraba en el rango de edad de 18-24 años; el 15% refirió contar con un empleo remunerado; el 42% de la población tenía secundaria completa; el 32.1% presentó un grado de inseguridad alimentaria; la media de IMC fue de 27.8±4.8. CONCLUSIONES: Los resultados cuali-cuantitativos de ambas cohortes sugieren que poblaciones con mayor vulnerabilidad socio-económica son más propensas a la obesidad materna, determinando directrices sobre barreras y facilitadores para fortalecer programas de prevención de la obesidad materna.

Macrophage Populations in Visceral Adipose Tissue from Pregnant Women: Potential Role of Obesity in Maternal Inflammation.

Obesity is associated with inflammatory changes and accumulation and phenotype polarization of adipose tissue macrophages (ATMs). Obese pregnant women have alterations in adipose tissue composition, but a detailed description of macrophage population is not available. In this study, we characterized macrophage populations in visceral adipose tissue (VAT) from pregnant women with normal, overweight, and obese pregestational weight. Immunophenotyping of macrophages from VAT biopsies was performed by flow cytometry using CD45 and CD14 as markers of hematopoietic and monocyte linage, respectively, while HLA-DR, CD11c, CD163, and CD206 were used as pro- and anti-inflammatory markers. Adipocyte number and size were evaluated by light microscopy. The results show that pregnant women that were overweight and obese during the pregestational period had adipocyte hypertrophy. Two different macrophage populations in VAT were identified: recruited macrophages (CD45⁺CD14⁺), and a novel population lacking CD45, which was considered to be a resident macrophages subset (CD45−CD14⁺). The number of resident HLA−DRlow/− macrophages showed a negative correlation with body mass index (BMI). Both resident and recruited macrophages from obese women expressed higher CD206 levels. CD11c expression was higher in resident HLA-DR⁺ macrophages from obese women. A strong correlation between CD206 and CD11c markers and BMI was observed. Our findings show that being overweight and obese in the pregestational period is associated with adipocyte hypertrophy and specific ATMs populations in VAT.

Indicadores socioeconómicos de la obesidad materna en México y Francia: análisis comparado de dos cohortes / Socioeconomic determinants of maternal obesity in Mexico and France: comparative analysis of two cohorts

RESUMEN Objetivo Identificar y analizar los indicadores socioeconómicos de obesidad materna en México y Francia. Metodología Estudio comparativo de dos cohortes EDEN sus siglas en francés (Etude des déterminants pré et post natals précoces de la santé et de développement de l'enfant) (Francia) y NUTTSEA (México). La población de estudio se conformó por mujeres que solicitaron consulta prenatal en semana 24 de gestación. Los datos fueron recolectados con cuestionarios y entrevistas semi-estructuradas. Las variables de interés fueron aspectos socioeconómicos, alimentación, antropometría y seguridad alimentaria. El análisis cuantitativo se realizó utilizando Stata y el análisis cualitativo con Atlas-ti. Resultados En cohorte EDEN el 68.6% resultó con edad de 25-34 años, el 73% tenían un empleo remunerado, el 53% preparatoria completa; el 6.6% refirió tener dificultad para acceder a los alimentos; la media del IMC gestacional fue de 23.23±4.6. En la cohorte NUTTSEA el 55% se encontraba en el rango de edad de 18-24 años; el 15% refirió contar con un empleo remunerado; el 42% de la población tenía secundaria completa; el 32.1% presentó un grado de inseguridad alimentaria; la media de IMC fue de 27.8±4.8. Conclusiones Los resultados cuali-cuantitativos de ambas cohortes sugieren que poblaciones con mayor vulnerabilidad socio-económica son más propensas a la obesidad materna, determinando directrices sobre barreras y facilitadores para fortalecer programas de prevención de la obesidad materna.(AU)

ABSTRACT Objective To identify and analyze the socioeconomic indicators of maternal obesity in Mexico and France. Material and Methods Comparative study of two cohorts: EDEN (France) and NUTTSEA (Mexico). The study population consisted of women who requested prenatal consultation at week 24 of pregnancy. Data were collected using questionnaires and semi-structured interviews. The variables of interest were socioeconomic aspects, nutrition, anthropometry and food security. The quantitative analysis was performed using Stata and the qualitative analysis with Atlas-ti. Results In the EDEN cohort, 68.6% were aged 25-34 years, 73% had paid employment and 53% completed high school. In addition, 6.6% reported having difficulty accessing food and the mean gestational BMI was 23.23 ± 4.6. In the NUTTSEA cohort, 55% were in the age range 18-24 years, 15% reported having paid employment, 42% had completed secondary education, 32.1% presented a degree of food insecurity, and the mean BMI was 27.8 ± 4.8. Conclusions The qualitative and quantitative results of both cohorts suggest that populations with greater socio-economic vulnerability are more prone to maternal obesity, which leads to determine guidelines on barriers and facilitators to strengthen programs to prevent it maternal obesity.(AU)

Gender Differences in the Acute Kidney Injury to Chronic Kidney Disease Transition.

This study evaluated if there is a sexual dimorphism in the acute kidney injury (AKI) to chronic kidney disease (CKD) transition and the time-course of the potential mechanisms involved in the dimorphic response. Female and male rats were divided into sham-operated or underwent 45-min renal ischemia (F + IR, and M + IR). All groups were studied at 24-h and 1, 2, 3, or 4-months post-ischemia. Additionally, oophorectomized rats were divided into sham or IR groups. After 24-h, AKI extent was simllar in females and males, but female rats exhibited less oxidative stress and increased renal GSH content. After 4-months and despite similar AKI, the M + IR group developed CKD characterized by proteinuria, tubulointerstitial fibrosis, glomerular hypertrophy, increased oxidative stress and a reduction in HIF1α and VEGF from the 1st-month and persisting throughout the time-course studied. Interestingly, the F + IR group did not develop CKD due to lesser oxidative stress and increased eNOS, TGFß and HIF1α mRNA levels from the 1st-month after IR. Whereas, oophorectomized rats did develop CKD. We found a sexual dimorphic response in the AKI to CKD transition. Early antioxidant defense and higher TGFß, HIF1α and eNOS were among the renoprotective mechanisms that the F + IR group demonstrated.

Comparative analysis of two different models of swimming applied to pregnant rats born small for pregnant age

ABSTRACT The aim of this study was to compare two models of swimming applied to pregnant rats born small for pregnancy age (SPA). Diabetes was chemically induced in adult female rats to develop an inadequate intrauterine environment, leading to birth of a SPA offspring. In adulthood, the female SPA rats were mated and submitted to different swimming programs. The exercise program 1 (Ex1) consisted of swimming for 15 minutes, followed by 15 minutes of rest and another 15 minutes of swimming, 3 days a week before and during pregnancy. Another program (Ex2) was applied during 60 minutes uninterrupted a day, 6 days/week during pregnancy. The pregnant rats presented no interference on body weight and glycemia. The rats submitted to Ex2 model showed decreased insulin and blood glucose levels by oral glucose tolerance test, and reduction in area under curve values. The offspring from dams submitted to both exercise protocols presented an increased rate of newborns SPA. However, the offspring from Ex2 dams showed percentage twice higher of newborns SPA than Ex1 offspring. Our data suggests that continuous exercise of 60 min/day ameliorated the enhanced peripheral insulin sensitivity in growth-restricted females. However, this protocol employed at pregnancy leads to intrauterine growth restriction.

Maternal obesity in the rat impairs male offspring aging of the testicular antioxidant defence system.

A high-fat diet during intrauterine development predisposes offspring (F1) to phenotypic alterations, such as lipid synthesis imbalance and increased oxidative stress, causing changes in male fertility. The objective of this study was to evaluate the effects of maternal obesity during pregnancy and lactation on antioxidant enzymes in the F1 testes. Female Wistar rats (F0) were fed either a control (C, 5% fat) or an obesogenic (MO, maternal obesity, 25% fat) diet from weaning and throughout subsequent pregnancy and lactation. F1 offspring were weaned to the control diet. Testes were retrieved at 110, 450 and 650 postnatal days (PND) for real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC) antioxidant enzyme analyses. Catalase was similar between groups by RT-qPCR, whereas by IHC it was higher in the MO group at all ages than in the C group. Superoxide dismutase 1 (SOD1) had lower expression at PND 110 in MO than in C by both techniques; at PND 450 and 650 by immunoanalysis SOD1 was higher in MO than in C. Glutathione peroxidase 1 (GPX1), GPX2 and GPX4 by RT-qPCR were similar between groups and ages; by IHC GPX1/2 was higher in MO than in C, whereas GPX4 showed the opposite result at PND 110 and 450. In conclusion, antioxidant enzymes in the rat testes are modified with age. Maternal obesity negatively affects the F1 testicular antioxidant defence system, which, in turn, can explain the decrease in reproductive capacity.

Ovarian hormones and prolactin increase renal NaCl cotransporter phosphorylation.

Unique situations in female physiology require volume retention. Accordingly, a dimorphic regulation of the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) has been reported, with a higher activity in females than in males. However, little is known about the hormones and mechanisms involved. Here, we present evidence that estrogens, progesterone, and prolactin stimulate NCC expression and phosphorylation. The sex difference in NCC abundance, however, is species dependent. In rats, NCC phosphorylation is higher in females than in males, while in mice both NCC expression and phosphorylation is higher in females, and this is associated with increased expression and phosphorylation of full-length STE-20 proline-alanine-rich kinase (SPAK). Higher expression/phosphorylation of NCC was corroborated in humans by urinary exosome analysis. Ovariectomy in rats resulted in decreased expression and phosphorylation of the cotransporter and promoted the shift of SPAK isoforms toward the short inhibitory variant SPAK2. Conversely, estradiol or progesterone administration to ovariectomized rats restored NCC phosphorylation levels and shifted SPAK expression and phosphorylation towards the full-length isoform. Estradiol administration to male rats induced a significant increase in NCC phosphorylation. NCC is also modulated by prolactin. Administration of this peptide hormone to male rats induced increased phosphorylation of NCC, an effect that was observed even using the ex vivo kidney perfusion strategy. Our results indicate that estradiol, progesterone, and prolactin, the hormones that are involved in sexual cycle, pregnancy and lactation, upregulate the activity of NCC.

Adult exercise effects on oxidative stress and reproductive programming in male offspring of obese rats.

Exercise improves health but few data are available regarding benefits of exercise in offspring exposed to developmental programming. There is currently a worldwide epidemic of obesity. Obesity in pregnant women predisposes offspring to obesity. Maternal obesity has well documented effects on offspring reproduction. Few studies address ability of offspring exercise to reduce adverse outcomes. We observed increased oxidative stress and impaired sperm function in rat offspring of obese mothers. We hypothesized that regular offspring exercise reverses adverse effects of maternal obesity on offspring sperm quality and fertility. Female Wistar rats ate chow (C) or high-energy, obesogenic diet (MO) from weaning through lactation, bred at postnatal day (PND) 120, and ate their pregnancy diet until weaning. All offspring ate C diet from weaning. Five male offspring (different litters) ran on a wheel for 15 min, 5 times/week from PND 330 to 450 and were euthanized at PND 450. Average distance run per session was lower in MO offspring who had higher body weight, adiposity index, and gonadal fat and showed increases in testicular oxidative stress biomarkers. Sperm from MO offspring had reduced antioxidant enzyme activity, lower sperm quality, and fertility. Exercise in MO offspring decreased testicular oxidative stress, increased sperm antioxidant activity and sperm quality, and improved fertility. Exercise intervention has beneficial effects on adiposity index, gonadal fat, oxidative stress markers, sperm quality, and fertility. Thus regular physical exercise in male MO offspring recuperates key male reproductive functions even at advanced age: it's never too late.

Maternal protein restriction during pregnancy and/or lactation negatively affects follicular ovarian development and steroidogenesis in the prepubertal rat offspring.

BACKGROUND AND AIMS: Maternal protein restriction during rat pregnancy and lactation is associated with alterations in reproductive function of female offspring including delayed onset of puberty, decreased fertility and premature reproductive aging. These alterations may be related to ovarian prepubertal development, distribution of follicle populations and their steroidogenic capacities. We undertook this study to evaluate the ovarian function of prepubertal female offspring exposed to maternal protein restriction during pregnancy and/or lactation. METHODS: Adult female Wistar rats were fed a control (C-20% casein diet) or restricted isocaloric diet (R-10% casein) during pregnancy--first letter--and lactation--second letter, to form four groups, CC, RR, CR, RC. Ovaries were collected from 21-day-old female offspring. Preantral and antral follicles were quantified and mRNA expression of key genes involved in follicular development and steroidogenesis (gonadotropin receptors, StAR, P450scc and P450 aromatase) was evaluated. Serum gonadotropin levels were measured. RESULTS: Significantly decreased numbers of preantral and antral follicles were observed in CR and RC ovaries compared with CC. LH levels were lower and FSH higher in CR pups. mRNA expression of LH receptor (LH-R) was decreased in RR in comparison with the other groups. CR and RC expressed higher StAR, RC increased and RR decreased P450scc, whereas RR and CR decreased aromatase expression in comparison with CC. CONCLUSIONS: Maternal protein restriction influences prepubertal ovarian follicular number and steroidogenic function in the rat offspring, although RR and CR nutritional schemes have similar outcomes, the mechanisms affecting ovarian function are at different levels of the hypothalamic-pituitary-ovarian axis.

Fetal programming of sexual development and reproductive function.

The recent growth of interest in developmental programming of physiological systems has generally focused on the cardiovascular system (especially hypertension) and predisposition to metabolic dysfunction (mainly obesity and diabetes). However, it is now clear that the full range of altered offspring phenotypes includes impaired reproductive function. In rats, sheep and nonhuman primates, reproductive capacity is altered by challenges experienced during critical periods of development. This review will examine available experimental evidence across commonly studied experimental species for developmental programming of female and male reproductive function throughout an individual's life-course. It is necessary to consider events that occur during fetal development, early neonatal life and prior to and during puberty, during active reproductive life and aging as reproductive performance declines.

Fascioliasis coledociana por Fasciola hepatica en cirugía de colecistitis crónica calculosa / Choledocal fasciolasis by Fasciola hepatica in surgery of chronic calculous cholecistitis

Se reporta un caso de Fasciola hepatica en una mujer de 50 años de edad, natural de Huaral, procedente de un asentamiento humano del distrito de Ate en Lima, con un tiempo de enfermedad de siete días caracterizado al inicio por dolor abdominal tipo cólico de curso progresivo en el epigastrio, dolor que se irradia a hipocondrio derecho. Luego presentó luego náuseas y vómitos en cuatro oportunidades, de contenido alimenticio y bilioso, por lo que se decide su hospitalización previa atención por emergencia. Al examen físico se encontró conjuntivas oculares levemente ictéricas, abdomen balonado, blando, depresible, no visceromegalia, Murphy positivo, ruidos hidroaéreos presentes, tórax y pulmones sin alteraciones. Posteriormente a los exámenes auxiliares, se diagnosticó colecistitis calculosa aguda y fascioliasis coledociana. En el acto quirúrgico se extrajo tres especímenes identificados como Fasciola hepatica. La paciente después de recibir el triclabendazol, concurrió al Hospital para la evaluación y control, habiendo logrado mejoría y bienestar.

We report a case of Fasciola hepatica in a 50 year-old woman born in Huaral, Lima, and living in Ate Vitarte, district of Lima, Peru, who was admitted because of seven days of disease characterized by progressive abdominal pain. She visited AteÆs Hospital because of right hipocondrial and epigastric cramping abdominal pain in the morning accompanied by nausea and vomiting in four opportunities. Conjunctives were slightly icteric, abdomen was distended and depressible, there was no visceromegaly, MurphyÆs sign was positive, and thorax and lungs showed no alterations. At cholecistectomy three specimens identified as Fasciola hepatica were extracted. Following treatment with triclabendazole, clinical course was uneventful.