Background Early-life stress, such as maternal deprivation (MD), is a stressor that can lead to cognitive deficits in adulthood. Among the neurochemical mechanisms involved in MD-induced pathophysiology are alterations in the dopaminergic and noradrenergic systems. We recently demonstrated that pharmacological stimulation of dopaminergic neurons in the ventral tegmental area (VTA) improves novel object recognition (NOR) memory in rats subjected to MD. Furthermore, projections from the locus coeruleus (LC) to the dorsal hippocampus (DH) are important for memory consolidation. Methods From postnatal day (PND) 1–PND10, male and female rats were either subjected to MD or left undisturbed. In adulthood, the animals underwent stereotaxic surgery for bilateral cannulation of the DH and LC. Following recovery and habituation, the animals were trained in the NOR task and immediately received vehicle or timolol in the DH, and either vehicle or NMDA in the LC. NOR memory was assessed at 24 h, as well as 7 and 14 d after training, to evaluate memory consolidation and persistence, respectively. Results MD impaired NOR memory in male rats, but not in females. Pharmacological stimulation of the LC with NMDA promoted NOR memory persistence in both non-MD and MD males and females. In males, LC stimulation also reversed the MD-associated memory impairment. These effects were maintained despite hippocampal β-adrenergic receptor blockade with timolol. Conclusion These findings suggest that LC-related pathways contribute to the processing of NOR memory persistence following early-life stress in a sex-dependent manner. This effect appears to be independent of hippocampal β-adrenergic signaling.
Background Abnormal intestinal morphology and dysbiosis contribute to metabolic disease development. Maternal obesity increases offspring susceptibility to gut dysfunction. The α7 nicotinic acetylcholine receptor (α7nAChR), encoded by Chrna7, is a key mediator of the cholinergic anti-inflammatory pathway and modulates intestinal immunity and cell proliferation. However, the role of cholinergic signaling in offspring intestinal development remains unclear. Methods 5-week-old female C57BL/6 mice were fed a control (SC, 10% fat) or a high-fat diet (HFD, 45% fat) before and during pregnancy and lactation. The small intestines of fetal (e20) offspring were analyzed for inflammatory markers and tight junctions (Claudin-1, Claudin-2, Occludin, Zonula occludens-1). Additional evaluations at weaning (d28) included histomorphometry, intestinal transit and permeability assays, and microbiota analysis. Chrna7⁻/⁻ mice were evaluated for histomorphometry and intestinal permeability. Results Maternal HFD disrupted the intestinal morphology and function of offspring, resulting in shorter villi, reduced mucosal thickness and goblet cell proportion, reduced α7nAChR expression, and increased permeability. While male HFD-O exhibited an increased Firmicutes/Bacteroidetes ratio, female HFD-O presented a significant reduction in Akkermansia and Verrucomicrobiota abundance, though they displayed an early adaptive response in tight junction expression at e20. Chrna7⁻/⁻ mice exhibited similar intestinal morphological alterations, recapitulating most features observed in offspring of HFD-fed dams. Conclusions Maternal HFD programs a vulnerable intestinal phenotype in offspring characterized by significant structural and moderate functional and microbiota reprogramming. The phenotypic similarities between HFD-O and Chrna7–/– suggest a potential involvement of this receptor in shaping offspring gut health, offering potential targets to prevent diet-induced intestinal dysfunctions.
Background During early pregnancy, the decidua supports embryo development and maternal adaptations to pregnancy. Maternal diabetes programs gestational diabetes mellitus (GDM) in offspring, and a pro-oxidant intrauterine environment has been implicated. Diets enriched with extra virgin olive oil (EVOO) can provide antioxidant effects. This study hypothesized that EVOO-enriched diets administered to pregestational diabetic pregnant rats (F0) would confer beneficial effects on the decidua of their early-pregnant offspring (F1), who are prone to developing GDM. Aims To evaluate signaling pathways and pro-oxidant state markers in the decidua of 9 d pregnant offspring of diabetic dams who either received or did not receive a 6% EVOO-enriched diet during the F0 pregnancy. Methods Rats with mild diabetes and controls were fed diets with or without 6% EVOO during F0 pregnancy, and their 9 d pregnant offspring were then evaluated. Markers of decidual function (prolactin, PPAR and mTOR pathways) and the pro-oxidant state were evaluated in the decidua. Results Despite normal maternal glycemia and progesterone levels, the decidua of 9 d pregnant offspring of diabetic dams exhibited reduced prolactin and mTOR pathway activity. PPAR levels decreased, while microRNAs that regulate their expression increased. These alterations were not prevented by the EVOO-enriched diet provided in the F0 generation. Levels of FABP4 (involved in decidualization and a marker of a pro-oxidant state) and lipoperoxidation were increased in the decidua of 9 d pregnant offspring of diabetic dams. The EVOO-enriched diet prevented these alterations. Conclusion Maternal diabetes programs impaired markers of decidualization and the pro-oxidant state in early-pregnancy offspring. These alterations were partially ameliorated by maternal diets enriched with EVOO.
Background Hypoglycemia in hospitalized adults without diabetes is often considered incidental, but acute infection may disrupt glucose homeostasis. Aims To determine the incidence of hypoglycemia in adults without diabetes hospitalized for acute infection and evaluate its association with clinical outcomes. Methods We conducted a retrospective cohort study of 64,871 adults without diabetes admitted for acute infection between 2010 and 2025 at a tertiary academic center. Patients with diabetes or prior glucose-lowering therapy were excluded. Mild hypoglycemia was defined as 55–69 mg/dL and severe hypoglycemia as < = 54 mg/dL. Outcomes included 30 and 90 d mortality, clinical deterioration, and ICU admission. Results Hypoglycemia occurred in 8,827 patients (13.6%): 5,684 (8.8%) had mild and 3,143 (4.8%) had severe hypoglycemia. Mortality increased by hypoglycemia severity. For 90 d mortality, adjusted odds ratios (aORs) were 1.30 (95% CI, 1.20–1.42; p <0.001) for mild and 1.73 (95% CI, 1.57–1.91; p <0.001) for severe hypoglycemia. For 30 d mortality, aORs were 1.19 (95% CI, 1.07–1.33; p <0.001) and 1.70 (95% CI, 1.51–1.91; p <0.001), respectively. Achievement of subsequent normoglycemia following hypoglycemia was associated with lower observed mortality, whereas transition to hyperglycemia was associated with worse outcomes. Conclusions In adults without diabetes hospitalized for acute infections, hypoglycemia is common and associated with mortality in a severity-dependent manner. Glycemic overshoot after correction may identify an additional high-risk state, supporting careful glucose monitoring and controlled correction during acute illness.
Background Bisphenol A (BPA) is an endocrine-disrupting chemical with estrogenic properties that affects various tissues. It has been linked to chronic and inflammatory diseases, such as diabetes and metabolic syndrome. Aim To investigate the obesogenic effects of a single neonatal administration of BPA on obesity and its underlying mechanisms in mice. Methods We established a neonatal BPA administration model in mice and measured various biochemical parameters. We also analyzed retroperitoneal, mesenteric, and gonadal fat depots using magnetic resonance imaging (MRI). In addition, to provide a translational context, we measured the serum BPA levels in male obese patients. Results Neonatal BPA administration in mice induced chronic dimorphic obesity and metabolic syndrome only in male mice. These findings were also reproducible in obese male patients, who exhibited higher concentrations of this endocrine-disrupting chemical than their non-obese counterparts. In addition, the results showed that the number of adult male mice was significantly higher in the BPA-treated group compared with the control and vehicle groups. Metabolic and biochemical parameters, such as adipose tissue, cholesterol, triglycerides, and glucose, were also significantly higher in mice that received BPA in the neonatal stage. Conclusion Single neonatal BPA administration could be used as a novel strategy in the study of obesity.
