Obesogenic Diet in Mice Leads to Inflammation and Oxidative Stress in the Mother in Association with Sex-Specific Changes in Fetal Development, Inflammatory Markers and Placental Transcriptome.

BACKGROUND: Obesity during pregnancy is related to adverse maternal and neonatal outcomes. Factors involved in these outcomes may include increased maternal insulin resistance, inflammation, oxidative stress, and nutrient mishandling. The placenta is the primary determinant of fetal outcomes, and its function can be impacted by maternal obesity. The aim of this study on mice was to determine the effect of obesity on maternal lipid handling, inflammatory and redox state, and placental oxidative stress, inflammatory signaling, and gene expression relative to female and male fetal growth. METHODS: Female mice were fed control or obesogenic high-fat/high-sugar diet (HFHS) from 9 weeks prior to, and during, pregnancy. On day 18.5 of pregnancy, maternal plasma, and liver, placenta, and fetal serum were collected to examine the immune and redox states. The placental labyrinth zone (Lz) was dissected for RNA-sequencing analysis of gene expression changes. RESULTS: the HFHS diet induced, in the dams, hepatic steatosis, oxidative stress (reduced catalase, elevated protein oxidation) and the activation of pro-inflammatory pathways (p38-MAPK), along with imbalanced circulating cytokine concentrations (increased IL-6 and decreased IL-5 and IL-17A). HFHS fetuses were asymmetrically growth-restricted, showing sex-specific changes in circulating cytokines (GM-CSF, TNF-α, IL-6 and IFN-γ). The morphology of the placenta Lz was modified by an HFHS diet, in association with sex-specific alterations in the expression of genes and proteins implicated in oxidative stress, inflammation, and stress signaling. Placental gene expression changes were comparable to that seen in models of intrauterine inflammation and were related to a transcriptional network involving transcription factors, LYL1 and PLAG1. CONCLUSION: This study shows that fetal growth restriction with maternal obesity is related to elevated oxidative stress, inflammatory pathways, and sex-specific placental changes. Our data are important, given the marked consequences and the rising rates of obesity worldwide.

Placental inflammation, oxidative stress, and fetal outcomes in maternal obesity.

The obesity epidemic has led to a growing body of research investigating the consequences of maternal obesity on pregnancy and offspring health. The placenta, traditionally viewed as a passive intermediary between mother and fetus, is known to play a critical role in modulating the intrauterine environment and fetal development, and we now know that maternal obesity leads to increased inflammation, oxidative stress, and altered placental function. Here, we review recent research exploring the involvement of inflammation and oxidative stress as mechanisms impacting the placenta and fetus during obese pregnancy. Understanding them is crucial for informing strategies that can mitigate the adverse health effects of maternal obesity on offspring development and disease risk.

Next steps to advance general physical activity recommendations towards physical exercise prescription: a narrative review.

Physical inactivity is a major health concern, associated with the development of several non-communicable diseases and with an increased mortality rate. Therefore, promoting active lifestyles has become a crucial public health necessity for enhancing overall health and quality of life. The WHO guidelines for physical activity (PA) present valuable contributions in this respect; however, we believe that greater specificity should be added or complemented towards physical exercise (PE) testing, prescription and programming in future recommendations. In this review article, we suggest simple and practical tools accessible to the entire population to improve the specificity of this approach, highlighting aspects of PE programming used by trained subjects. By adopting these suggestions, exercise professionals, clinicians and physical trainers can optimise the current general PA recommendations towards PE prescription to improve fitness status and encourage PE adherence in the general population.

Chronic intermittent hypobaric hypoxia induces cardiovascular dysfunction in a high-altitude working shift model.

AIMS: Chronic intermittent hypobaric hypoxia (CIHH) exposure due to shift work occurs mainly in 4 × 4 or 7 × 7 days shifts in mining, astronomy, and customs activities, among other institutions. However, the long-lasting effects of CIHH on cardiovascular structure and function are not well characterized. We aimed to investigate the effects of CIHH on the cardiac and vascular response of adult rats simulating high-altitude (4600 m) x low-altitude (760 m) working shifts. MAIN METHODS: We analyzed in vivo cardiac function through echocardiography, ex vivo vascular reactivity by wire myography, and in vitro cardiac morphology by histology and protein expression and immunolocalization by molecular biology and immunohistochemistry techniques in 12 rats, 6 exposed to CIHH in the hypoxic chamber, and respective normobaric normoxic controls (n = 6). KEY FINDINGS: CIHH induced cardiac dysfunction with left and right ventricle remodeling, associated with an increased collagen content in the right ventricle. In addition, CIHH increased HIF-1α levels in both ventricles. These changes are associated with decreased antioxidant capacity in cardiac tissue. Conversely, CIHH decreased contractile capacity with a marked decreased in nitric oxide-dependent vasodilation in both, carotid and femoral arteries. SIGNIFICANCE: These data suggest that CIHH induces cardiac and vascular dysfunction by ventricular remodeling and impaired vascular vasodilator function. Our findings highlight the impact of CIHH in cardiovascular function and the importance of a periodic cardiovascular evaluation in high-altitude workers.

The Role of Omega-3 Polyunsaturated Fatty Acids and Their Lipid Mediators on Skeletal Muscle Regeneration: A Narrative Review.

Skeletal muscle is the largest tissue in the human body, comprising approximately 40% of body mass. After damage or injury, a healthy skeletal muscle is often fully regenerated; however, with aging and chronic diseases, the regeneration process is usually incomplete, resulting in the formation of fibrotic tissue, infiltration of intermuscular adipose tissue, and loss of muscle mass and strength, leading to a reduction in functional performance and quality of life. Accumulating evidence has shown that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and their lipid mediators (i.e., oxylipins and endocannabinoids) have the potential to enhance muscle regeneration by positively modulating the local and systemic inflammatory response to muscle injury. This review explores the process of muscle regeneration and how it is affected by acute and chronic inflammatory conditions, focusing on the potential role of n-3 PUFAs and their derivatives as positive modulators of skeletal muscle healing and regeneration.

Developmental Ultrasound Characteristics in Guinea Pigs: Similarities with Human Pregnancy.

BACKGROUND: Biometrical and blood flow examinations are fundamental for assessing fetoplacental development during pregnancy. Guinea pigs have been proposed as a good model to study fetal development and related gestational complications; however, longitudinal growth and blood flow changes in utero have not been properly described. This study aimed to describe fetal and placental growth and blood flow of the main intrauterine vascular beds across normal guinea pig pregnancy and to discuss the relevance of this data for human pregnancy. METHODS: Pregnant guinea pigs were studied from day 25 of pregnancy until term (day ~70) by ultrasound and Doppler assessment. The results were compared to human data from the literature. RESULTS: Measurements of biparietal diameter (BPD), cranial circumference (CC), abdominal circumference, and placental biometry, as well as pulsatility index determination of umbilical artery, middle cerebral artery (MCA), and cerebroplacental ratio (CPR), were feasible to determine across pregnancy, and they could be adjusted to linear or nonlinear functions. In addition, several of these parameters showed a high correlation coefficient and could be used to assess gestational age in guinea pigs. We further compared these data to ultrasound variables from human pregnancy with high similarities. CONCLUSIONS: BPD and CC are the most reliable measurements to assess fetal growth in guinea pigs. Furthermore, this is the first report in which the MCA pulsatility index and CPR are described across guinea pig gestation. The guinea pig is a valuable model to assess fetal growth and blood flow distribution, variables that are comparable with human pregnancy.

Role of specialized pro-resolving mediators on inflammation, cardiometabolic health, disease progression, and quality of life after omega-3 PUFA supplementation and aerobic exercise training in individuals with rheumatoid arthritis: a randomized 16-week, placebo-controlled interventional trial.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by autoantibody production and synovial membrane damage. It significantly impairs overall function and quality of life. Consumption of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and regular aerobic exercise (AEx) training are reported to have positive effects on the progression of RA. However, the mechanisms behind these benefits are still inconclusive. This study protocol will investigate the effects of n-3 PUFA supplementation and AEx training on disease progression, cardiometabolic health, and quality of life, and their association with the plasma and synovial fluid levels of specialized pro-resolving mediators (SPMs) in subjects with RA. Methods: The study consists of a 16-week intervention period, during which participants will be randomly assigned in a double-blinded manner to one of four groups: placebo control (PLA), PLA+AEx, n-3, or n-3+AEx. The PLA groups will be given a gelatin-filled capsule, while the n-3 groups will be given n-3 PUFAs equivalent to 2.5 g/d of docosahexaenoic acid and 0.5 g/d of eicosapentaenoic acid. The AEx groups will perform exercise three times per week on a stationary electronically braked cycle ergometer at 60-70% of their VO2peak for 50-60 minutes. Before and after the intervention, participants will undergo RA-specific and functional measurements, peak aerobic capacity test, and a dietary and physical activity assessment. Venous blood and synovial fluid from the knee joint will be collected. Changes in disease progression, cardiometabolic health, and quality of life, as well as erythrocyte membrane composition to assess n-3 incorporation, SPM levels, inflammatory markers, and gene expression from blood and synovial fluid will be analyzed. Conclusions: The study aims to elucidate the SPMs that regulate the inflammatory gene expression pathways and associate them with the improvements in disease progression, cardiometabolic health, and quality of life after n-3 PUFA supplementation and AEx training. Registration: ClinicalTrials.gov #NCT05945693.

Community strategies for health promotion and prevention of chronic non-communicable diseases with a focus on physical activity and nutrition: the URO/FOCOS study protocol.

Non-communicable diseases (NCDs) account for 71% of all annual deaths, totaling 41 million people worldwide. The development and progression of these diseases are highly related to the environment and lifestyle choices, among which physical inactivity and excess malnutrition stand out. Currently, in Chile, there is no evidence at the regional and local level on the impact of physical activity and healthy nutrition plans and interventions on health promotion, prevention, and timely treatment of NCDs. The following protocol delineates the URO/FOCOS (Universidad Regional de O'Higgins/FOrtaleciendo COmunidades Saludables- Regional University of O'Higgins/Strengthening Healthy Communities) study, which will assess pilot community intervention strategies using a participatory action research approach by identifying barriers and facilitators on the practice of physical activity and healthy eating habits. In this project, the community from the O'Higgins region will be involved throughout the entire research process to develop strategies that promote regular physical activity and healthy eating practices. We propose three interrelated strategies: (1) Participatory Action Research, (2) Community interventions for promoting physical activity and healthy nutrition practices, and (3) health education. The URO/FOCOS study offers a unique opportunity in the O'Higgins region to develop participatory strategies and interventions based on the community's needs and motivations with regard to physical activity and healthy eating habits. We believe these strategies will help to improve the community's overall health through effective changes in their decision and preferences toward a more active lifestyle and healthier nutrition practices.

Obesogenic diet in mice compromises maternal metabolic physiology and lactation ability leading to reductions in neonatal viability.

AIMS: Diets containing high-fat and high sugar (HFHS) lead to overweight/obesity. Overweight/obesity increases the risk of infertility, and of the pregnant mother and her child for developing metabolic conditions. Overweight/obesity has been recreated in mice, but most studies focus on the effects of chronic, long-term HFHS diet exposure. Here, we exposed mice to HFHS from 3 weeks prior to pregnancy with the aim of determining impacts on fertility, and gestational and neonatal outcomes. METHODS: Time-domain NMR scanning was used to assess adiposity, glucose, and insulin tolerance tests were employed to examine metabolic physiology, and morphological and proteomic analyses conducted to assess structure and nutrient levels of maternal organs and placenta. RESULTS: Fertility measures of HFHS dams were largely the same as controls. HFHS dams had increased adiposity pre-pregnancy, however, exhibited exacerbated lipolysis/hyper-mobilization of adipose stores in late pregnancy. While there were no differences in glucose or insulin tolerance, HFHS dams were hyperglycemic and hyperinsulinemic in pregnancy. HFHS dams had fatty livers and altered pancreatic islet morphology. Although fetuses were hyperglycemic and hyperinsulinemic, there was no change in fetal growth in HFHS dams. There were also reductions in placenta formation. Moreover, there was increased offspring loss during lactation, which was related to aberrant mammary gland development and milk protein composition in HFHS dams. CONCLUSIONS: These findings are relevant given current dietary habits and the development of maternal and offspring alterations in the absence of an increase in maternal weight and adiposity during pregnancy, which are the current clinical markers to determine risk across gestation.

Cardioprotective Antioxidant and Anti-Inflammatory Mechanisms Induced by Intermittent Hypobaric Hypoxia.

More than 80 million people live and work (in a chronic or intermittent form) above 2500 masl, and 35 million live in the Andean Mountains. Furthermore, in Chile, it is estimated that 100,000 people work in high-altitude shifts, where stays in the lowlands are interspersed with working visits in the highlands. Acute exposure to high altitude has been shown to induce oxidative stress in healthy human lowlanders due to increased free radical formation and decreased antioxidant capacity. However, intermittent hypoxia (IH) induces preconditioning in animal models, generating cardioprotection. Here, we aim to describe the responses of a cardiac function to four cycles of intermittent hypobaric hypoxia (IHH) in a rat model. The twelve adult Wistar rats were randomly divided into two equal groups, a four-cycle of IHH and a normobaric hypoxic control. Intermittent hypoxia was induced in a hypobaric chamber in four continuous cycles (1 cycle = 4 days of hypoxia + 4 days of normoxia), reaching a barometric pressure equivalent to 4600 m of altitude (428 Torr). At the end of the fourth cycle, cardiac structural and functional variables were also determined by echocardiography; furthermore, cardiac oxidative stress biomarkers (4-Hydroxynonenal, HNE; nitrotyrosine, NT), antioxidant enzymes, and NLRP3 inflammasome panel expression are also determined. Our results show a higher ejection and a shortening fraction of the left ventricle function by the end of the fourth cycle. Furthermore, cardiac tissue presented a decreased expression of antioxidant proteins. However, a decrease in IL-1ß, TNF-αn, and oxidative stress markers is observed in IHH compared to normobaric hypoxic controls. Non-significant differences were found in protein levels of NLRP3 and caspase-1. IHH exposure determines structural and functional heart changes. These findings suggest that initial states of IHH are beneficial for cardiovascular function and protection.

Utilidad de la ecografía Doppler en el diagnóstico, el pronóstico y el manejo de la restricción del crecimiento fetal: situación en Chile / Usefulness of Doppler ultrasound for the diagnosis, prognosis and management of fetal growth restriction: situation in Chile

INTRODUCCIÓN: La restricción del crecimiento fetal (RCF) se define como la disminución patológica de la tasa de crecimiento fetal, generalmente asociada a insuficiencia placentaria. Se diagnostica mediante ultrasonografía obstétrica y velocimetría Doppler, pero no existe un consenso global respecto a los parámetros referenciados. OBJETIVO: Brindar una revisión actualizada de la aproximación clínica de la RCF en Chile, enfocada en el uso de la ultrasonografía Doppler como herramienta fundamental para el diagnóstico, el pronóstico y el manejo de esta patología, y realizar una comparativa con respecto a otros países. MÉTODO: Se realizó una revisión con palabras clave en las bases de datos PubMed y SciELO. RESULTADOS: Se obtuvieron 89 referencias bibliográficas, logrando una revisión de datos actualizados del uso del Doppler en la RCF tanto en el mundo como en Chile. CONCLUSIONES: La Guía Perinatal 2015 publicada en Chile carece de actualización con los conocimientos y la evidencia científica más recientes. Sin embargo, concuerda en gran parte con los lineamientos y las pautas generales de manejo de la RCF de las diferentes guías clínicas analizadas. Las discrepancias entre las guías revisadas podrían explicarse por la gran variabilidad de la evidencia de los estudios científico-clínicos, los cuales es importante unificar a través de una guía que promueva una estandarización de la atención de la RCF en el país.

INTRODUCTION: Fetal growth restriction (FGR) is the pathological decrease in the fetal growth rate generally associated with placental insufficiency. Diagnosis is made by obstetric ultrasonography and Doppler velocimetry, assessing different biometric and hemodynamic parameters. However, there is no global consensus regarding the parameters to be referenced. OBJECTIVE: To provide an updated review of the FGR clinical approach in Chile, focused on the use of Doppler ultrasonography as a fundamental tool in the diagnosis, prognosis, and management of this pathology and to compare with other countries. METHOD: A literature search was conducted in the PubMed and SciELO databases, including relevant and updated articles. RESULTS: The search included 89 bibliographic references under which it was possible to make a review of the most current data on the use of Doppler in FGR both worldwide and in Chile. CONCLUSIONS: The 2015 Perinatal Guidelines published in Chile is not updated with the latest scientific evidence and knowledge. However, it largely agrees with international guidelines for FGR management. The discrepancies between the revised guidelines could be explained due to the variability of evidence from scientific-clinical studies, which are essential to unify for standardized care of FGR in the country.

Melatonin treatment during chronic hypoxic gestation improves neonatal cerebrovascular function.

BACKGROUND: Fetal chronic hypoxia is associated with blood flow redistribution and oxidative damage in the brain, leading to increased perinatal morbimortality. Melatonin reduces oxidative stress, improves vascular function, and has neuroprotective effects. OBJECTIVES: This study aimed to determine the effects of an oral melatonin treatment to pregnant ewes at high-altitude, on the cerebrovascular function of their neonates. STUDY DESIGN: Ten high-altitude pregnant sheep received either vehicle or melatonin (10 mg/d) during the last third of gestation until delivery. Postnatal daily hemodynamic measurements were recorded from lambs until 12 days old. In addition, lambs were submitted to a graded oxygenation protocol to assess cerebrovascular responses. Subsequently, lambs were euthanized, and middle cerebral arteries (MCA) were collected for vascular function, protein levels, and morphostructural analyses. RESULTS: Antenatal treatment doubled plasma levels of melatonin in pregnant ewes. Melatonin increased carotid flow and decreased carotid vascular resistance in the lambs by the end of the first week. Furthermore, melatonin increased MCA's maximal vasoconstrictor and vasodilator responses, associated with nitric oxide-dependent and independent mechanisms. CONCLUSIONS: An oral treatment with melatonin during pregnancy promotes postnatal cerebral perfusion in chronically hypoxic neonates. Melatonin is a potential treatment for cerebrovascular dysfunction due to perinatal chronic hypoxia.

The newborn sheep translational model for pulmonary arterial hypertension of the neonate at high altitude.

Chronic hypoxia during gestation induces greater occurrence of perinatal complications such as intrauterine growth restriction, fetal hypoxia, newborn asphyxia, and respiratory distress, among others. This condition may also cause a failure in the transition of the fetal to neonatal circulation, inducing pulmonary arterial hypertension of the neonate (PAHN), a syndrome that involves pulmonary vascular dysfunction, increased vasoconstrictor tone and pathological remodeling. As this syndrome has a relatively low prevalence in lowlands (~7 per 1000 live births) and very little is known about its prevalence and clinical evolution in highlands (above 2500 meters), our understanding is very limited. Therefore, studies on appropriate animal models have been crucial to comprehend the mechanisms underlying this pathology. Considering the strengths and weaknesses of any animal model of human disease is fundamental to achieve an effective and meaningful translation to clinical practice. The sheep model has been used to study the normal and abnormal cardiovascular development of the fetus and the neonate for almost a century. The aim of this review is to highlight the advances in our knowledge on the programming of cardiopulmonary function with the use of high-altitude newborn sheep as a translational model of PAHN.

Melatonin long-lasting beneficial effects on pulmonary vascular reactivity and redox balance in chronic hypoxic ovine neonates.

Pulmonary arterial hypertension of the neonate (PAHN) is a pathophysiological condition characterized by maladaptive pulmonary vascular remodeling and abnormal contractile reactivity. This is a multifactorial syndrome with chronic hypoxia and oxidative stress as main etiological drivers, and with limited effectiveness in therapeutic approaches. Melatonin is a neurohormone with antioxidant and vasodilator properties at the pulmonary level. Therefore, this study aims to test whether a postnatal treatment with melatonin during the neonatal period improves in a long-lasting manner the clinical condition of PAHN. Ten newborn lambs gestated and born at 3600 m were used in this study, five received vehicle and five received melatonin in daily doses of 1 mg kg-1 for the first 3 weeks of life. After 1 week of treatment completion, lung tissue and small pulmonary arteries (SPA) were collected for wire myography, molecular biology, and morphostructural analyses. Melatonin decreased pulmonary arterial pressure the first 4 days of treatment. At 1 month old, melatonin decreased the contractile response to the vasoconstrictors K+ , TX2 , and ET-1. Further, melatonin increased the endothelium-dependent and muscle-dependent vasodilation of SPA. Finally, the treatment decreased pulmonary oxidative stress by inducing antioxidant enzymes and diminishing pro-oxidant sources. In conclusion, melatonin improved vascular reactivity and oxidative stress at the pulmonary level in PAHN lambs gestated and born in chronic hypoxia.

Melatonin Decreases Pulmonary Vascular Remodeling and Oxygen Sensitivity in Pulmonary Hypertensive Newborn Lambs.

Background: Chronic hypoxia and oxidative stress during gestation lead to pulmonary hypertension of the neonate (PHN), a condition characterized by abnormal pulmonary arterial reactivity and remodeling. Melatonin has strong antioxidant properties and improves pulmonary vascular function. Here, we aimed to study the effects of melatonin on the function and structure of pulmonary arteries from PHN lambs. Methods: Twelve lambs (Ovis aries) gestated and born at highlands (3,600 m) were instrumented with systemic and pulmonary catheters. Six of them were assigned to the control group (CN, oral vehicle) and 6 were treated with melatonin (MN, 1 mg.kg-1.d-1) during 10 days. At the end of treatment, we performed a graded oxygenation protocol to assess cardiopulmonary responses to inspired oxygen variations. Further, we obtained lung and pulmonary trunk samples for histology, molecular biology, and immunohistochemistry determinations. Results: Melatonin reduced the in vivo pulmonary pressor response to oxygenation changes. In addition, melatonin decreased cellular density of the media and diminished the proliferation marker KI67 in resistance vessels and pulmonary trunk (p < 0.05). This was associated with a decreased in the remodeling markers α-actin (CN 1.28 ± 0.18 vs. MN 0.77 ± 0.04, p < 0.05) and smoothelin-B (CN 2.13 ± 0.31 vs. MN 0.88 ± 0.27, p < 0.05). Further, melatonin increased vascular density by 134% and vascular luminal surface by 173% (p < 0.05). Finally, melatonin decreased nitrotyrosine, an oxidative stress marker, in small pulmonary vessels (CN 5.12 ± 0.84 vs. MN 1.14 ± 0.34, p < 0.05). Conclusion: Postnatal administration of melatonin blunts the cardiopulmonary response to hypoxia, reduces the pathological vascular remodeling, and increases angiogenesis in pulmonary hypertensive neonatal lambs.These effects improve the pulmonary vascular structure and function in the neonatal period under chronic hypoxia.