Chronic hypoxia, whether continuous (CCH) or intermittent (CIH), occurs in many neonatal pathological conditions, such as bronchopulmonary dysplasia and obstructive sleep apnea. In this study, we explored the effect of CCH and CIH on cerebral capillary density and myelination. We subjected CD-1 mice starting at postnatal day 2 to either CCH 11% oxygen (O₂), or CIH 11% O₂(4-min cycles), for periods of 2 and 4 wk followed by reoxygenation for 4 wk. Mice were deeply anesthetized and perfused. Brains were removed to fixative for 24 h, then paraffin-embedded. Coronal brain sections were taken for analysis. Immunocytochemistry for glucose transporter 1 was used to assess angiogenesis, and Luxol fast blue and fluoromyelin stains were used to assess myelination. Capillary density increased after 2-wk exposure to CIH and CCH. By 4 wk, capillary density increased in both CIH and CCH by 25% and 47%, respectively, in cortex and by 29% and 44%, respectively, in hippocampus ( P < 0.05). There was a decrease in myelination in the corpus callosum of mice exposed to CIH (75% of control) and CCH (50% of control) ( P < 0.05). Reoxygenation reversed the increased capillary density seen in CCH to normoxic values. However, dysmyelination that occurred in CCH-exposed mice did not show any improvement upon reoxygenation. We conclude that neonatal chronic hypoxia 1) induces brain angiogenesis, which is reversible with reoxygenation, and 2) irreversibly reduces the extent of myelination in the corpus callosum. This potential irreversible effect on myelination in early life can, therefore, have long-term and devastating effects.

Breathing-disordered states, such as in obstructive sleep apnea, which are cyclical in nature, have been postulated to induce neurocognitive morbidity in both pediatric and adult populations. The oscillatory nature of intermittent hypoxia, especially when chronic, may mimic the paradigm of ischemia-reperfusion in that tissues and cells are exposed to episodes of low and high O₂ and this may lead to oxidant stress. Therefore, we decided to explore the potential contribution of oxidant stress in our intermittent hypoxia/hypercapnia animal model and the role that mitochondria might play in this stress. Neonatal mice were exposed to intermittent hypoxia/hypercapnia for 10 days and 2 wk. Combined intermittent hypoxia/hypercapnia led to a marked increase in apoptotic cell death in the cerebral cortex. Oxygen consumption studies in isolated mitochondria from intermittent hypoxia/hypercapnia-exposed brains demonstrated significant reductions in both state 4 and state 3 respiratory activities by ∼60% and 75%, respectively. Electron paramagnetic resonance spectroscopy registered a significant increase in superoxide production during nonphosphorylating state 4 by 37%, although superoxide leakage during state 3 did not increase upon treatment. Neuronal superoxide-specific dihydroethidium oxidation was also greater in exposed animals. These studies indicate that intermittent hypoxia/hypercapnia leads to oxidative stress due to mitochondrial response within the mouse central nervous system.

Exposure to chronic constant or intermittent hypoxia (CCH or CIH) may have different effects on growth and development in early life. In this work, we exposed postnatal day 2 (P2) CD1 mice to CCH or CIH (11% O₂) for 4 weeks and examined the effect of hypoxia on body and organ growth until P30. Regression analysis showed that weight increased in control, CCH and CIH cohorts with age with r² values of 0.99, 0.97, and 0.94, respectively. Between days 2 and 30, slopes were 0.93 ± 0.057, 0.76 ± 0.108, and 0.63 ± 0.061 (g/day, means ± SEM) for control, CIH, and CCH, respectively and significantly different from each other (P < 0.001). The slopes between P2 and P16 were 0.78 ± 0.012, 0.46 ± 0.002, and 0.47 ± 0.019 for control, CCH and CIH, respectively. From P16 to 30, slopes were 1.12 ± 0.033, 1.09 ± 0.143, and 0.82 ± 0.08 for control, CIH, and CCH, respectively with no significant difference from each other, suggesting a catch‐up growth in the latter part of the hypoxic period. Slower weight gain resulted in a 12% and 23% lower body weight in CIH and CCH mice (P < 0.001) by P30. Lung/body ratios were 0.010, 0.015, 0.015 for control, CIH, and CCH at P30, respectively. The decrease in liver, kidney, and brain weight were greater in CCH than CIH. Smaller liver weight was shown to be due to a reduction in cell size and cell number. Liver in CIH and CCH mice showed a 5% and 10% reduction in cell size (P < 0.05) and a reduction of 28% in cell number (P < 0.001) at P30. In contrast, CCH and CIH heart weight was 13% and 33% greater than control at P30 (P < 0.05), respectively. This increase in the heart weight was due to an increase in the size of cardiomyocytes which showed an increase of 12% and 14% (P < 0.001) for CIH and CCH, respectively as compared to control. Brain weight was 0.48 and 0.46 g for CIH and CCH, respectively (95% and 92% of normal). We concluded that (a) CIH and CCH follow different body and organ growth patterns; (b) mostly with CCH, the liver and kidneys are reduced in size in a proportionate way to body size but heart, lung, and brain are either spared or increased in size compared to body weight; and (c) the decrease in liver is secondary mostly to a decrease in cell number. Pediatr Pulmonol. 2008; 43:20–28.

Background: Gestational diabetes mellitus (GDM), characterized by gestational hyperglycemia due to insufficient insulin response, poses significant risks to both maternal and offspring health. Fetal exposure to maternal hyperglycemia leads to short-term complications such as macrosomia and neonatal hypoglycemia and long-term risks including obesity, metabolic syndrome, cardiovascular dysfunction, and type 2 diabetes. The Developmental Origins of Health and Disease (DOHaD) theory explains how maternal hyperglycemia alters fetal programming, increasing susceptibility to metabolic disorders later in life. Objective: This review explores the intergenerational impact of GDM, linking maternal hyperglycemia to lifelong metabolic, cardiovascular, and neurodevelopmental risks via epigenetic and microbiome alterations. It integrates the most recent findings, contrasts diagnostic methods, and offers clinical strategies for early intervention and prevention. Methods: A comprehensive literature search was conducted in PubMed, Scopus, and ScienceDirect to identify relevant studies published between 1 January 2000 and 31 December 2024. The search included studies focusing on the metabolic and developmental consequences of GDM exposure in offspring, as well as potential mechanisms such as epigenetic alterations and gut microbiota dysbiosis. Studies examining preventive strategies and management approaches were also included. Key Findings: Maternal hyperglycemia leads to long-term metabolic changes in offspring, with epigenetic modifications and gut microbiota alterations playing key roles. GDM-exposed children face increased risks of obesity, glucose intolerance, and cardiovascular diseases. Early screening and monitoring are crucial for risk reduction. Practical Implications: Understanding the intergenerational effects of GDM has important clinical implications for prenatal and postnatal care. Early detection, lifestyle interventions, and targeted postnatal surveillance are essential for reducing long-term health risks in offspring. These findings emphasize the importance of comprehensive maternal healthcare strategies to improve long-term outcomes for both mothers and their children.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have emerged as a promising therapeutic option beyond their established role in managing type 2 diabetes mellitus (T2DM) and obesity. Recent research has highlighted their beneficial effects on liver, kidney, and cardiovascular health, mediated by both direct and indirect mechanisms. In the liver, GLP-1 RAs contribute to the improvement of metabolic dysfunction-associated steatotic liver disease (MASLD) by reducing hepatic fat accumulation, inflammation, and oxidative stress. Additionally, they enhance insulin sensitivity and lipid metabolism. Similarly, in diabetic kidney disease (DKD), GLP-1 RAs exhibit renoprotective properties by mitigating inflammation, oxidative stress, and glomerular hypertension. Furthermore, they promote natriuresis and stabilize renal function. Moreover, GLP-1 RAs present significant cardiovascular benefits, including improved myocardial function, reduced atherosclerosis progression, enhanced endothelial health, and decreased major adverse cardiovascular events (MACEs). Additionally, emerging evidence suggests GLP-1 RAs may exert substantial neuropsychiatric benefits, including reductions in depressive symptoms, anxiety, substance use behaviors, and lowering the risk of Alzheimer’s disease, Parkinson’s disease, and other dementias likely mediated by the modulation of neurotransmitter systems and neuroinflammation. Genetic polymorphisms in the GLP1R gene also impact the therapeutic response, highlighting the importance of personalized medicine in optimizing GLP-1 RA efficacy. This review synthesizes preclinical and clinical evidence supporting the multifaceted effects of GLP-1 RAs across multiple organ systems, highlighting their therapeutic potential beyond glycemic control. As research advances, further exploration of their mechanisms of action and long-term clinical outcomes, safety and effectiveness across diverse patient populations will be essential in optimizing their use in treating metabolic and neuropsychiatric conditions.

Glioblastoma multiforme (GBM) is one of the most common and deadliest cancers of the central nervous system (CNS). GBMs high ability to infiltrate healthy brain tissues makes it difficult to remove surgically and account for its fatal outcomes. To improve the chances of survival, it is critical to screen for GBM-targeted anticancer agents with anti-invasive and antimigratory potential. Metformin, a commonly used drug for the treatment of diabetes, has recently emerged as a promising anticancer molecule. This prompted us, to investigate the anticancer potential of metformin against GBMs, specifically its effects on cell motility and invasion. The results show a significant decrease in the survival of SF268 cancer cells in response to treatment with metformin. Furthermore, metformin’s efficiency in inhibiting 2D cell motility and cell invasion in addition to increasing cellular adhesion was also demonstrated in SF268 and U87 cells. Finally, AKT inactivation by downregulation of the phosphorylation level upon metformin treatment was also evidenced. In conclusion, this study provides insights into the anti-invasive antimetastatic potential of metformin as well as its underlying mechanism of action.