Mechanical Characterization of the Erythrocyte Membrane Using a Capacitor-Based Technique.

Pathological processes often change the mechanical properties of cells. Increased rigidity could be a marker of cellular malfunction. Erythrocytes are a type of cell that deforms to squeeze through tiny capillaries; changes in their rigidity can dramatically affect their functionality. Furthermore, differences in the homeostatic elasticity of the cell can be used as a tool for diagnosis and even for choosing the adequate treatment for some illnesses. More accurate types of equipment needed to study biomechanical phenomena at the single-cell level are very costly and thus out of reach for many laboratories around the world. This study presents a simple and low-cost technique to study the rigidity of red blood cells (RBCs) through the application of electric fields in a hand-made microfluidic chamber that uses a capacitor principle. As RBCs are deformed with the application of voltage, cells are observed under a light microscope. From mechanical force vs. deformation data, the elastic constant of the cells is determined. The results obtained with the capacitor-based method were compared with those obtained using optical tweezers, finding good agreement. In addition, P. falciparum-infected erythrocytes were tested with the electric field applicator. Our technique provides a simple means of testing the mechanical properties of individual cells.

On knowing a gene: A distributional hypothesis of gene function.

As words can have multiple meanings that depend on sentence context, genes can have various functions that depend on the surrounding biological system. This pleiotropic nature of gene function is limited by ontologies, which annotate gene functions without considering biological contexts. We contend that the gene function problem in genetics may be informed by recent technological leaps in natural language processing, in which representations of word semantics can be automatically learned from diverse language contexts. In contrast to efforts to model semantics as "is-a" relationships in the 1990s, modern distributional semantics represents words as vectors in a learned semantic space and fuels current advances in transformer-based models such as large language models and generative pre-trained transformers. A similar shift in thinking of gene functions as distributions over cellular contexts may enable a similar breakthrough in data-driven learning from large biological datasets to inform gene function.

Impaired Ischemia-Reperfusion Responses in the Hearts of Aged Male and Female Offspring of Obese Rats.

Maternal obesity predisposes offspring (F1) to cardiovascular disease. To evaluate basal heart function and ischemia-reperfusion (IR) responses in F1 males and females of obese mothers, female Wistar rats (F0) were fed chow or an obesogenic (MO) diet from weaning through pregnancy and lactation. Non-sibling F1 males and females were weaned to chow at postnatal day (PND) 21 and euthanized at PND 550. Offspring of MO mothers (MOF1) rarely survive beyond PND 650. Hearts were immediately isolated from euthanized F1s and subjected to 30 min ischemia with 20 min reperfusion. Retroperitoneal fat, serum triglycerides, glucose, insulin, and insulin resistance were measured. Baseline left ventricular developed pressure (LVDP) was lower in male and female MOF1 than in controls. After global ischemia, LVDP in control (C) male and female F1 recovered 78 and 83%, respectively, while recovery in MO male and female F1 was significantly lower at 28 and 52%, respectively. Following the IR challenge, MO hearts showed a higher functional susceptibility to reperfusion injury, resulting in lower cardiac reserve than controls in both sexes. Female hearts were more resistant to IR. Retroperitoneal fat was increased in male MOF1 vs. CF1. Circulating triglycerides and insulin resistance were increased in male and female MOF1 vs. CF1. These data show that MO programming reduces F1 cardiac reserve associated with age-related insulin resistance in a sex-specific manner.

Combinatorial prediction of therapeutic perturbations using causally-inspired neural networks.

As an alternative to target-driven drug discovery, phenotype-driven approaches identify compounds that counteract the overall disease effects by analyzing phenotypic signatures. Our study introduces a novel approach to this field, aiming to expand the search space for new therapeutic agents. We introduce PDGrapher, a causally-inspired graph neural network model designed to predict arbitrary perturbagens - sets of therapeutic targets - capable of reversing disease effects. Unlike existing methods that learn responses to perturbations, PDGrapher solves the inverse problem, which is to infer the perturbagens necessary to achieve a specific response - i.e., directly predicting perturbagens by learning which perturbations elicit a desired response. Experiments across eight datasets of genetic and chemical perturbations show that PDGrapher successfully predicted effective perturbagens in up to 9% additional test samples and ranked therapeutic targets up to 35% higher than competing methods. A key innovation of PDGrapher is its direct prediction capability, which contrasts with the indirect, computationally intensive models traditionally used in phenotypedriven drug discovery that only predict changes in phenotypes due to perturbations. The direct approach enables PDGrapher to train up to 30 times faster, representing a significant leap in efficiency. Our results suggest that PDGrapher can advance phenotype-driven drug discovery, offering a fast and comprehensive approach to identifying therapeutically useful perturbations.

¿Cómo construir un Cuerpo Académico... y tener éxito? / How to integrate an Academic Group... and be successful?

Introducción: para las universidades públicas, uno de los indicadores fundamentales es consolidar los grupos de investigación en Cuerpos Académicos (CA). Sin embargo, no existe una guía que apoye la transición. El propósito es exponer algunas recomendaciones para conformar un CA con éxito, con base en las experiencias de trabajo del Cuerpo Académico Intervenciones para el Cuidado de la Salud. Desarrollo: los CA están conformados por docentes-investigadores de tiempo completo que comparten y desarrollan una línea de investigación en temas disciplinares o multidisciplinares, enfocados en objetivos académicos comunes. La reflexión que plantea este manuscrito contribuye a identificar las fortalezas y áreas de oportunidad de los grupos de investigación, así mismo se describen algunas estrategias para transitar y consolidar un CA: 1. Selección de los integrantes, 2. Línea de investigación, 3. Proyectos, 4. Servicio a la sociedad, 5. Trabajo colegiado, 6. Redes de investigación, 7. Integración de estudiantes y 8. Liderazgo transformacional. Conclusión: la creación de CA es fundamental en el desarrollo de las instituciones de educación superior en México, para alcanzar este reto es necesario integrar estrategias innovador... (AU)

Abstract Introduction: For public universities, a fundamental indicator is to consolidate research groups in Academic Bodies (AB). However, there is no guide to support the transition. Purpose: to present some recommendations to form AB successfully based on the work experiences of the Academic Body Interventions for Health Care. Development: The academic bodies are made up of full-time professors-researchers who share and develop a line of research on disciplinary or multidisciplinary topics and which entail a set of common academic objectives and goals. The reflection proposed by this manuscript contributes to identifying the strengths and areas of opportunity of the research groups, as well as describing some strategies to consolidate as an academic body: 1. The selection of the members, 2. The line of research, 3. Projects, 4. Service to society, 5. Collegiate work, 6. Research networks, 7. Integration of students and 8. Transformational leadership. Conclusion: Creating Academic Bodies is essential in the development of higher education institutions in Mexico, to meet this challenge it is necessary to integrate innovative strategies to generate and disseminate knowledge and the disposition of the members for collegiate work.

Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells.

Mesothelioma is an aggressive cancer of the mesothelial layer associated with an extensive fibrotic response. The latter is in large part mediated by cancer-associated fibroblasts which mediate tumour progression and poor prognosis. However, understanding of the crosstalk between cancer cells and fibroblasts in this disease is mostly lacking. Here, using co-cultures of patient-derived mesothelioma cell lines and lung fibroblasts, we demonstrate that fibroblast activation is a self-propagated process producing a fibrotic extracellular matrix (ECM) and triggering drug resistance in mesothelioma cells. Following characterisation of mesothelioma cells/fibroblasts signalling crosstalk, we identify several FDA-approved targeted therapies as far more potent than standard-of-care Cisplatin/Pemetrexed in ECM-embedded co-culture spheroid models. In particular, the SRC family kinase inhibitor, Saracatinib, extends overall survival well beyond standard-of-care in a mesothelioma genetically-engineered mouse model. In short, we lay the foundation for the rational design of novel therapeutic strategies targeting mesothelioma/fibroblast communication for the treatment of mesothelioma patients.

Genomic-driven nutritional interventions for radiotherapy-resistant rectal cancer patient.

Radiotherapy response of rectal cancer patients is dependent on a myriad of molecular mechanisms including response to stress, cell death, and cell metabolism. Modulation of lipid metabolism emerges as a unique strategy to improve radiotherapy outcomes due to its accessibility by bioactive molecules within foods. Even though a few radioresponse modulators have been identified using experimental techniques, trying to experimentally identify all potential modulators is intractable. Here we introduce a machine learning (ML) approach to interrogate the space of bioactive molecules within food for potential modulators of radiotherapy response and provide phytochemically-enriched recipes that encapsulate the benefits of discovered radiotherapy modulators. Potential radioresponse modulators were identified using a genomic-driven network ML approach, metric learning and domain knowledge. Then, recipes from the Recipe1M database were optimized to provide ingredient substitutions maximizing the number of predicted modulators whilst preserving the recipe's culinary attributes. This work provides a pipeline for the design of genomic-driven nutritional interventions to improve outcomes of rectal cancer patients undergoing radiotherapy.

Acute exposure to fluoxetine leads to oxidative stress and hematological disorder in Danio rerio adults.

Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI), is consistently introduced into the environment due to its ongoing consumption and inadequate removal by wastewater treatment plants. As a result, the scientific community has displayed a keen interest in investigating the potential toxicological effects associated with this medication. Nevertheless, there is a scarcity of available data regarding the impact of FLX on blood parameters. With this in mind, this study aimed to evaluate the potential toxicological consequences of FLX at environmentally significant concentrations (5, 16, and 40 ng/L) following a 96-hour acute exposure blood parameters in Danio rerio fish. Moreover, the investigation encompassed an assessment of oxidative stress parameters to determine whether the drug could induce disruptions in the REDOX status of the fish. The findings unveiled that FLX prompted the induction of oxidative stress in various organs of the fish, encompassing the liver, gut, brain, and gills. Notably, the gills and brain exhibited heightened susceptibility to the drug's effects compared to other organs. Furthermore, following acute exposure to FLX, there was an upregulation of antioxidant-related genes (sod, cat, gpx, nrf1, and nrf2), thereby providing additional evidence supporting the induction of oxidative stress in the organs of the fish. Lastly, FLX significantly impacted the customary values of various blood parameters, including glucose, blood urea nitrogen, alanine aminotransferase, alkaline phosphatase, red blood cell count, hemoglobin, and hematocrit. Thus, it can be inferred that FLX harmed the overall health status of the fish, resulting in the development of liver disease, anemia, and other associated illnesses.

Maternal Obesity Programs the Premature Aging of Rat Offspring Liver Mitochondrial Electron Transport Chain Genes in a Sex-Dependent Manner.

We investigated whether maternal obesity affects the hepatic mitochondrial electron transport chain (ETC), sirtuins, and antioxidant enzymes in young (110 postnatal days (PND)) and old (650PND) male and female offspring in a sex- and age-related manner. Female Wistar rats ate a control (C) or high-fat (MO) diet from weaning, through pregnancy and lactation. After weaning, the offspring ate the C diet and were euthanized at 110 and 650PND. The livers were collected for RNA-seq and immunohistochemistry. Male offspring livers had more differentially expressed genes (DEGs) down-regulated by both MO and natural aging than females. C-650PND vs. C-110PND and MO-110PND vs. C-110PND comparisons revealed 1477 DEGs in common for males (premature aging by MO) and 35 DEGs for females. Analysis to identify KEGG pathways enriched from genes in common showed changes in 511 and 3 KEGG pathways in the male and female livers, respectively. Mitochondrial function pathways showed ETC-related gene down-regulation. All ETC complexes, sirtuin2, sirtuin3, sod-1, and catalase, exhibited gene down-regulation and decreased protein expression at young and old ages in MO males vs. C males; meanwhile, MO females down-regulated only at 650PND. Conclusions: MO accelerates the age-associated down-regulation of ETC pathway gene expression in male offspring livers, thereby causing sex-dependent oxidative stress, premature aging, and metabolic dysfunction.

Renal Glucose Release after Unilateral Renal Denervation during a Hypoglycemic Clamp in Pigs with an Altered Hypothalamic Pituitary Adrenal Axis after Late-Gestational Dexamethasone Injection.

Previously, we demonstrated in pigs that renal denervation halves glucose release during hypoglycaemia and that a prenatal dexamethasone injection caused increased ACTH and cortisol concentrations as markers of a heightened hypothalamic pituitary adrenal axis (HPAA) during hypoglycaemia. In this study, we investigated the influence of an altered HPAA on renal glucose release during hypoglycaemia. Pigs whose mothers had received two late-gestational dexamethasone injections were subjected to a 75 min hyperinsulinaemic-hypoglycaemic clamp (<3 mmol/L) after unilateral surgical denervation. Para-aminohippurate (PAH) clearance, inulin, sodium excretion and arterio-venous blood glucose difference were measured every fifteen minutes. The statistical analysis was performed with a Wilcoxon signed-rank test. PAH, inulin, the calculated glomerular filtration rate and plasma flow did not change through renal denervation. Urinary sodium excretion increased significantly (p = 0.019). Side-dependent renal net glucose release (SGN) decreased by 25 ± 23% (p = 0.004). At 25 percent, the SGN decrease was only half of that observed in non-HPAA-altered animals in our prior investigation. The current findings may suggest that specimens with an elevated HPAA undergo long-term adaptations to maintain glucose homeostasis. Nonetheless, the decrease in SGN warrants further investigations and potentially caution in performing renal denervation in certain patient groups, such as diabetics at risk of hypoglycaemia.

Alzheimer's disease: using gene/protein network machine learning for molecule discovery in olive oil.

Alzheimer's disease (AD) poses a profound human, social, and economic burden. Previous studies suggest that extra virgin olive oil (EVOO) may be helpful in preventing cognitive decline. Here, we present a network machine learning method for identifying bioactive phytochemicals in EVOO with the highest potential to impact the protein network linked to the development and progression of the AD. A balanced classification accuracy of 70.3 ± 2.6% was achieved in fivefold cross-validation settings for predicting late-stage experimental drugs targeting AD from other clinically approved drugs. The calibrated machine learning algorithm was then used to predict the likelihood of existing drugs and known EVOO phytochemicals to be similar in action to the drugs impacting AD protein networks. These analyses identified the following ten EVOO phytochemicals with the highest likelihood of being active against AD: quercetin, genistein, luteolin, palmitoleate, stearic acid, apigenin, epicatechin, kaempferol, squalene, and daidzein (in the order from the highest to the lowest likelihood). This in silico study presents a framework that brings together artificial intelligence, analytical chemistry, and omics studies to identify unique therapeutic agents. It provides new insights into how EVOO constituents may help treat or prevent AD and potentially provide a basis for consideration in future clinical studies.

Programming Mechanism of Adipose Tissue Expansion in the Rat Offspring of Obese Mothers Occurs in a Sex-Specific Manner.

We investigated whether excessive retroperitoneal adipose tissue (AT) expansion programmed by maternal obesity (MO) affects adipocyte size distribution and gene expression in relation to adipocyte proliferation and differentiation in male and female offspring (F1) from control (F1C) and obese (F1MO) mothers. Female Wistar rats (F0) ate a control or high-fat diet from weaning through pregnancy and lactation. F1 were weaned onto a control diet and euthanized at 110 postnatal days. Fat depots were weighed to estimate the total AT. Serum glucose, triglyceride, leptin, insulin, and the insulin resistance index (HOMA-IR) were determined. Adipocyte size and adipogenic gene expression were examined in retroperitoneal fat. Body weight, retroperitoneal AT and adipogenesis differed between male and female F1Cs. Retroperitoneal AT, glucose, triglyceride, insulin, HOMA-IR and leptin were higher in male and female F1MO vs. F1C. Small adipocytes were reduced in F1MO females and absent in F1MO males; large adipocytes were increased in F1MO males and females vs. F1C. Wnt, PI3K-Akt, and insulin signaling pathways in F1MO males and Egr2 in F1MO females were downregulated vs. F1C. MO induced metabolic dysfunction in F1 through different sex dimorphism mechanisms, including the decreased expression of pro-adipogenic genes and reduced insulin signaling in males and lipid mobilization-related genes in females.

Developmental Programming-Aging Interactions Have Sex-Specific and Developmental Stage of Exposure Outcomes on Life Course Circulating Corticosterone and Dehydroepiandrosterone (DHEA) Concentrations in Rats Exposed to Maternal Protein-Restricted Diets.

The steroids corticosterone and dehydroepiandrosterone (DHEA) perform multiple life course functions. Rodent life-course circulating corticosterone and DHEA trajectories are unknown. We studied life course basal corticosterone and DHEA in offspring of rats fed protein-restricted (10% protein, R) or control (20% protein, C), pregnancy diet first letter, and/or lactation second letter, producing four offspring groups-CC, RR, CR, and RC. We hypothesize that 1. maternal diet programs are sexually dimorphic, offspring life course steroid concentrations, and 2. an aging-related steroid will fall. Both changes differ with the plastic developmental period offspring experienced R, fetal life or postnatally, pre-weaning. Corticosterone was measured by radioimmunoassay and DHEA by ELISA. Steroid trajectories were evaluated by quadratic analysis. Female corticosterone was higher than male in all groups. Male and female corticosterone were highest in RR, peaked at 450 days, and fell thereafter. DHEA declined with aging in all-male groups. DHEA: corticosterone fell in three male groups but increased in all-female groups with age. In conclusion, life course and sexually dimorphic steroid developmental programming-aging interactions may explain differences in steroid studies at different life stages and between colonies experiencing different early-life programming. These data support our hypotheses of sex and programming influences and aging-related fall in rat life course serum steroids. Life course studies should address developmental programming-aging interactions.

Microwaves can kill malaria parasites non-thermally.

Malaria, which infected more than 240 million people and killed around six hundred thousand only in 2021, has reclaimed territory after the SARS-CoV-2 pandemic. Together with parasite resistance and a not-yet-optimal vaccine, the need for new approaches has become critical. While earlier, limited, studies have suggested that malaria parasites are affected by electromagnetic energy, the outcomes of this affectation vary and there has not been a study that looks into the mechanism of action behind these responses. In this study, through development and implementation of custom applicators for in vitro experimentation, conditions were generated in which microwave energy (MW) killed more than 90% of the parasites, not by a thermal effect but via a MW energy-induced programmed cell death that does not seem to affect mammalian cell lines. Transmission electron microscopy points to the involvement of the haemozoin-containing food vacuole, which becomes destroyed; while several other experimental approaches demonstrate the involvement of calcium signaling pathways in the resulting effects of exposure to MW. Furthermore, parasites were protected from the effects of MW by calcium channel blockers calmodulin and phosphoinositol. The findings presented here offer a molecular insight into the elusive interactions of oscillating electromagnetic fields with P. falciparum, prove that they are not related to temperature, and present an alternative technology to combat this devastating disease.

High-fat diet consumption by male rat offspring of obese mothers exacerbates adipose tissue hypertrophy and metabolic alterations in adult life.

Obese mothers' offspring develop obesity and metabolic alterations in adulthood. Poor postnatal dietary patterns also contribute to obesity and its comorbidities. We aimed to determine whether in obese mothers' offspring an adverse postnatal environment, such as high-fat diet (HFD) consumption (second hit) exacerbates body fat accumulation, metabolic alterations and adipocyte size distribution. Female Wistar rats ate chow (C-5 %-fat) or HFD (maternal obesity (MO)-25 %-fat) from weaning until the end of lactation. Male offspring were weaned on either control (C/C and MO/C, maternal diet/offspring diet) or HFD (C/HF and MO/HF) diet. At 110 postnatal days, offspring were killed. Fat depots were excised to estimate adiposity index (AI). Serum glucose, triglyceride, leptin, insulin, insulin resistance index (HOMA-IR), corticosterone and dehydroepiandrosterone (DHEA) were determined. Adipocyte size distribution was evaluated in retroperitoneal fat. Body weight was similar in C/C and MO/C but higher in C/HF and MO/HF. AI, leptin, insulin and HOMA-IR were higher in MO/C and C/HF v. C/C but lower than MO/HF. Glucose increased in MO/HF v. MO/C. C/HF and MO/C had higher triglyceride and corticosterone than C/C, but lower corticosterone than MO/HF. DHEA and the DHEA/corticosterone ratio were lower in C/HF and MO/C v. C/C, but higher than MO/HF. Small adipocyte proportion decreased while large adipocyte proportions increased in MO/C and C/HF v. C/C and exacerbated in MO/HF v. C/HF. Postnatal consumption of a HFD by the offspring of obese mothers exacerbates body fat accumulation as well as the decrease of small and the increase of large adipocytes, which leads to larger metabolic abnormalities.

Antiviral activity of two Acanthospermum species against herpes simplex virus 1.

ETHNOPHARMACOLOGICAL RELEVANCE: Acanthospermum species are used in traditional medicine for treating various pathologies, including bacterial and viral infections. In a screening study, we identified the activity of the ethanolic extracts of Acanthospermum australe and Acanthospermum hispidum against herpes simplex virus 1 (HSV-1). AIM OF THE STUDY: In this work, we analyzed the phytochemical profile and antiviral activity of the chemical fractionation products of Acanthospermum australe and Acanthospermum hispidum. Additionally, we identified the effect of these fractions on different steps of the viral cycle. MATERIALS AND METHODS: Acanthospermum samples were extracted with methanol and further partitioned with solvents of increasing polarities: hexane, chloroform, ethyl acetate, and butanol. Cytotoxicity and antiviral activity were analyzed for each fraction. The active fractions were tested to identify the virucidal effect and the inhibition of virus-cell binding. Further, the effect of these fractions on the replication and viral gene was quantitated by qPCR, and the expression of gD protein was evaluated by Western blot. RESULTS: The chloroform and hexane fractions of Acanthospermum hispidum and Acanthospermum australe showed dose-dependent antiviral activity. The chloroform fraction inhibited the virus-cell binding and virus cycle in a post-entry mechanism by decreasing replication and the expression of early and late viral genes. The hexane fraction did not inhibit virus binding; however, it showed antiviral activity in post-entry events by inhibiting the immediate-early, early, and late genes. We identified in both species the presence of 3.6-dimetoxiapigenin, axillarin, and penduletin in the chloroform fraction and methyl-(Z,Z)-9,12-octadecadienoate and phytol in the hexane fraction. CONCLUSIONS: Acanthospermum hispidum and Acanthospermum australe possess antiviral activity against HSV-1 and affect different steps of the viral cycle. These characteristics make them good candidates for developing phytotherapeutic products against HSV-1.

Screening of medicinal plants from El Salvador for anti-viral activity against Herpes simplex 1.

Herpes simplex virus 1 is one of the most prevalent pathogens worldwide. Resistant strains to current anti-viral treatment have been reported, requiring the search for novel anti-virals. Using a qPCR method to assess anti-herpetic activity from natural products, we analyzed 72 plant extracts from El Salvador and identified eighteen methanolic extracts with anti-viral activity of ≥ 75%. Anti-herpetic activity has not been previously reported in fourteen of the plants (Euphorbia lancifolia, Piper tuberculatum, Cordia alliodora, Tecoma stans, Taraxacum officinale, Hamelia patens, Witheringia solanacea, Emilia fosbergii, Gnaphalium viscosum, Citrus aurantium, Ambrosia peruviana, Carica papaya, Solanum hazenii and Melothria pendula). Four extracts were from species with previously reported anti-herpetic activity (Plantago major, Psidium guajava, Sida acuta and Bursera simaruba). These extracts effective anti-viral concentrations (EC50) were between 203 and 6.31 µg/mL, while the selectivity indexes (SI) were between 55.91 and 2.57. Euphorbia lancifolia showed the most effective anti-viral activity (EC50 = 6.31 µg/mL, SI = 51.82).

Resveratrol Supplementation in Obese Pregnant Rats Improves Maternal Metabolism and Prevents Increased Placental Oxidative Stress.

Maternal obesity (MO) causes maternal and fetal oxidative stress (OS) and metabolic dysfunction. We investigated whether supplementing obese mothers with resveratrol improves maternal metabolic alterations and reduces OS in the placenta and maternal and fetal liver. From weaning through pregnancy female Wistar rats ate chow (C) or a high-fat diet (MO). One month before mating until 19 days' gestation (dG), half the rats received 20 mg resveratrol/kg/d orally (Cres and MOres). At 19dG, maternal body weight, retroperitoneal fat adipocyte size, metabolic parameters, and OS biomarkers in the placenta and liver were determined. MO mothers showed higher body weight, triglycerides and leptin serum concentrations, insulin resistance (IR), decreased small and increased large adipocytes, liver fat accumulation, and hepatic upregulation of genes related to IR and inflammatory processes. Placenta, maternal and fetal liver OS biomarkers were augmented in MO. MOres mothers showed more small and fewer large adipocytes, lower triglycerides serum concentrations, IR and liver fat accumulation, downregulation of genes related to IR and inflammatory processes, and lowered OS in mothers, placentas, and female fetal liver. Maternal resveratrol supplementation in obese rats improves maternal metabolism and reduces placental and liver OS of mothers and fetuses in a sex-dependent manner.

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.

Neonatal Antibiotic Treatment Can Affect Stool Pattern and Oral Tolerance in Preterm Infants.

Preterm neonates are at high risk of infectious and inflammatory diseases which require antibiotic treatment. Antibiotics influence neonatal gut microbiome development, and intestinal dysbiosis has been associated with delayed gastrointestinal transit. Neonates who take less time to pass meconium have a better tolerance to enteral feeding. We analyzed the effect of neonatal antibiotic treatment on the stool pattern and oral tolerance in 106 preterm infants < 33 weeks gestational age. Neonates were classified in 3 groups according to neonatal antibiotic (ABT) treatment days: no antibiotics, 3−7 d ABT, and ≥8 d ABT. Preterm infants from the ≥8 d ABT group took longer to pass meconium and to start green and yellow stools, took longer to reach 100 and 150 mL/kg/day, and reached reduced volumes in enteral feeds at day of life 14 and 28 than infants from no ABT and 3−7 d ABT groups. Multiple linear regression models showed that neonatal antibiotic treatment, birth weight, invasive mechanical ventilation, surfactant, enteral feeding start day, neonatal parenteral nutrition, and neonatal fasting days are associated with the stool pattern and oral tolerance in preterm infants.