Search Results (336)

Brain organoid technology has revolutionized in vitro modeling of human neurodevelopment and disease, providing unprecedented insights into cortical patterning, neural circuit assembly, and pathogenic mechanisms of neurological disorders. Critically, human brain organoids uniquely recapitulate human-specific developmental processes—such as the expansion of outer radial glia and neuromelanin—that are absent in rodent models, making them indispensable for studying human brain evolution and dysfunction. However, a major bottleneck persists: Extended culture periods (≥6 months) are empirically required to achieve late-stage maturation markers like synaptic refinement, functional network plasticity, and gliogenesis. Yet prolonged conventional 3D culture exacerbates metabolic stress, hypoxia-induced necrosis, and microenvironmental instability, leading to asynchronous tissue maturation—electrophysiologically active superficial layers juxtaposed with degenerating cores. This immaturity/heterogeneity severely limits their utility in modeling adult-onset disorders (e.g., Alzheimer’s disease) and high-fidelity drug screening, as organoids fail to recapitulate postnatal transcriptional signatures or neurovascular interactions without bioengineering interventions. We summarize emerging strategies to decouple maturation milestones from rigid temporal frameworks, emphasizing the synergistic integration of chronological optimization (e.g., vascularized co-cultures) and active bioengineering accelerators (e.g., electrical stimulation and microfluidics). By bridging biological timelines with scalable engineering, this review charts a roadmap to generate translationally relevant, functionally mature brain organoids. Full article

Background: Astrocytes are not only structural cells but also play a pivotal role in neurogenesis and neuroprotection by secreting a variety of neurotrophic factors that support neuronal survival, growth, and repair. This study investigates the time-dependent responses of primary rat cortical astrocytes to oxygen–glucose deprivation (OGD) and evaluates the neuroprotective potential of astrocyte-conditioned medium (ACM). Methods: Primary rat cortical astrocytes and neurons were obtained from postnatal Sprague Dawley rat pups (P1–3) and embryos (E17–18), respectively. Astrocytes exposed to 6, 24, and 48 h of OGD (0.3% O₂) were assessed for viability, metabolic function, hypoxia-inducible factor 1 and its downstream genes expression. Results: While 6 h OGD upregulated protective genes such as Vegf, Glut1, and Pfkfb3 without cell loss, prolonged OGD, e.g., 24 or 48 h, led to significant astrocyte death and stress responses, including elevated LDH release, reduced mitochondrial activity, and increased expression of pro-apoptotic marker Bnip3. ACM from 6 h OGD-treated astrocytes significantly enhanced neuronal survival following 6 h OGD and 24 h reperfusion, preserving dendritic architecture, improving mitochondrial function, and reducing cell death. This protective effect was not observed with ACM from 24 h OGD astrocytes. Furthermore, 6 h OGD-ACM induced autophagy in neurons, as indicated by elevated LC3b-II and decreased p62 levels, suggesting autophagy as a key mechanism in ACM-mediated neuroprotection. Conclusions: These findings demonstrate that astrocytes exhibit adaptive, time-sensitive responses to ischemic stress and secrete soluble factors that can confer neuroprotection. This study highlights the therapeutic potential of targeting astrocyte-mediated signalling pathways to enhance neuronal survival following ischemic stroke. Full article

Maternal obesity programs the fetus for increased risk of chronic disease development in early life and adulthood. We hypothesized that maternal nutrient excess leads to fetal inflammation and impairs offspring skeletal muscle mitochondrial biogenesis in non-human primates. At least 12 months before pregnancy, female baboons were fed a normal chow (CTR, 12% energy fat) or a maternal nutrient excess (MNE, 45% energy fat, and ad libitum fructose sodas) diet, with the latter to induce obesity. After 165 days of gestation (0.9 G), offspring baboons were delivered by cesarean section, and the soleus muscle was collected (CTR n = 16, MNE n = 5). At conception, MNE mothers presented increased body fat and weighed more than controls. The soleus muscle of MNE fetuses exhibited increased levels of stress signaling associated with inflammation (TLR4, TNFα, NF-kB p65, and p38), concomitant with reduced expression of key regulators of mitochondrial biogenesis, including PGC1α, both at the protein and transcript levels, as well as downregulation of PPARGC1B, PPARA, PPARB, CREB1, NOS3, SIRT1, SIRT3. Decreased transcript levels of NRF1 were observed alongside diminished mitochondrial DNA copy number, mitochondrial fusion elements (MFN1, MFN2), cytochrome C protein levels, and cytochrome C oxidase subunits I and II transcripts (cox1 and cox2). MNE coupled to MO-induced stress signaling in fetal baboon soleus muscle is associated with impaired mitochondrial biogenesis and lower mitochondrial content, resembling the changes observed in metabolic dysfunctions, such as diabetes. The observed fetal alterations may have important implications for postnatal development and metabolism, potentially increasing the risk of early-onset metabolic disorders and other non-communicable diseases. Full article

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, with increasing evidence suggesting that their origins may lie in prenatal life. Endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), have been implicated in the alteration of fetal programming mechanisms that cause a predisposition to long-term cardiovascular vulnerability. However, the impact of prenatal endocrine disruption on fetal heart development and its sex-specific nature remains incompletely understood. This study investigates the molecular and structural effects of low-dose prenatal BPA exposure on fetal rat hearts. Our results reveal that BPA disrupts estrogen receptor (ER) signaling in a sex-dependent manner, with distinct alterations in ERα, ERβ, and GPER expression. BPA exposure also triggers significant inflammation, oxidative stress, and ferroptosis; this is evidenced by elevated NF-κB, IL-1β, TNF-α, and NLRP3 inflammasome activation, as well as impaired antioxidant defenses (SOD1, SOD2, CAT, and SELENOT), increased lipid peroxidation (MDA) and protein oxidation, decreased GPX4, and increased ACSL4 levels. These alterations are accompanied by increased markers of cardiac distension (ANP, BNP), extracellular matrix remodeling mediators, and pro-fibrotic regulators (Col1A1, Col3A1, TGF-β, and CTGF), with a more pronounced response in males. Histological analyses corroborated these molecular findings, revealing structural alterations as well as glycogen depletion in male fetal hearts, consistent with altered cardiac morphogenesis and metabolic stress. These effects were milder in females, reinforcing the notion of sex-specific vulnerability. Moreover, prenatal BPA exposure affected myocardial fiber architecture and vascular remodeling in a sex-dependent manner, as evidenced by reduced expression of desmin alongside increased levels of CD34 and Ki67. Overall, our findings provide novel insights into the crucial role of prenatal endocrine disruption during fetal heart development and its contribution to the early origins of CVD, underscoring the urgent need for targeted preventive strategies and further research into the functional impact of BPA-induced alterations on postnatal cardiac function and long-term disease susceptibility. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted social communication and repetitive behaviors. Prenatal stress is critical in neurodevelopment and increases risk for ASD, particularly in those with greater genetic susceptibility to stress. Docosahexaenoic acid (DHA) is one of the most abundant ω-3 fatty acids in the membrane phospholipids of the mammalian brain, and dietary DHA plays an important role in brain development and maintenance of brain structure. In this study, we investigated whether peri-natal supplementation of DHA can alleviate autistic-like behaviors in a genetic risk/stress mouse model and how it alters lipid peroxidation activity and GABAergic system gene expression in the forebrain. Pregnant heterozygous serotonin transporter knockout (SERT-KO) and wild-type (WT) dams were placed in either non-stressed control conditions or chronic variable stress (CVS) conditions and fed either a control diet or a DHA-rich (1% by weight) diet. Offspring of each group were assessed for anxiety and autism-associated behavior at post-natal day 60 using an open field test, elevated plus maze test, repetitive behavior, and the 3-chamber social approach test. A liquid chromatography-mass spectrometry (LC-MS)-based method was used to follow changes in levels of lipid peroxidation products in the cerebral cortex. Male offspring of prenatally stressed SERT-het KO dams exhibited decreased social preference behaviors and increased repetitive grooming behaviors compared to WT control offspring. Moreover, DHA supplementation in male SERT-het mice decreased frequency of grooming behaviors albeit showing no associated effects on social behaviors. Regardless of stress conditions, supplementation of DHA to the WT mice did not result in alterations in grooming nor social interaction in the offspring. Furthermore, no apparent changes were observed in the lipid peroxidation products comparing the stressed and non-stressed brains. Gad2 was downregulated in the cortex of female offspring of prenatally stressed SERT-KO dams, and this change appeared to be rescued by DHA supplementation in offspring. Gad2 was upregulated in the striatum of male offspring of prenatally stressed SERT-KO dams, but DHA did not significantly alter the expression compared to the control diet condition. Full article

Perinatal depression is one of the most common mental illnesses in women. The aim of this study was to assess the association of life stressors, perceived stress, obstetric and neonatal complications, and depressive symptoms in the early postpartum period and to compare these variables in two groups of women (preterm and term deliveries). Methods: A case–control study was conducted among 300 women who gave birth in 2019 at the University of Szeged. Cases included women with preterm deliveries (<37 weeks, n = 100), and the controls included women with term deliveries (≥37 weeks, n = 200). Data were collected during postpartum hospital stays through a self-administered questionnaire (containing validated questionnaires: the Holmes–Rahe Life Stress Inventory, the Perceived Stress Scale (PSS-14), and the Edinburgh Postnatal Depression Scale (EPDS)) and the medical records of women and newborns. A descriptive statistical analysis and logistic regression were used to identify predictors of high EPDS scores (≥10). Results: Perceived stress levels were significantly higher among cases than controls (p < 0.001). Higher perceived stress was associated with a higher risk of depression in cases (OR: 1.31, 95% CI: 1.17–1.48, p < 0.001) and controls (OR: 1.33, 95% CI: 1.21–1.45, p < 0.001), too. Newborn complications were associated with an increased perinatal depression risk in the controls (OR: 2.48, 95% CI: 1.05–5.91; p = 0.039) but not in the cases (OR: 2.79, 95% CI: 0.79–9.85; p = 0.111). It is supposed that premature birth was stressful itself, and women with preterm babies were less sensitive to any complications occurring in their newborns compared to women with term newborns. Neither maternal age, education, nor obstetric complications predicted depressive symptoms. Conclusions: Our findings highlight the impact of maternal perceived stress and newborns’ health status on the risk of developing depression during the early postpartum period. These results emphasize the need for ongoing screening and follow-up measures, especially for women with higher EPDS scores. Full article

Salivary cortisol is widely used to assess stress and circadian rhythms, yet its control variables in neonates, particularly regarding postnatal age, remain poorly understood. To elucidate age-specific effects of clinical variables on cortisol levels, 91 neonates with a mean (standard deviation) gestational age of 34.2 (3.8) weeks and postnatal age of 38.3 (35.4) days were categorised into Early, Medium, and Late groups by quartiles (days 10 and 56). Interactions with postnatal age were evaluated by comparing Early-to-Medium or Early-to-Late differences in regression coefficients between independent variables and cortisol levels. In the whole cohort, maternal hypertensive disorders of pregnancy and morning sampling were associated with reduced cortisol levels (both p = 0.001). Mean regression coefficients (95% CI) between variables and cortisol levels were as follows: for postconceptional age, Early, −0.102 (−0.215, 0.010) and Late, 0.065 (−0.203, 0.332) (p = 0.035); for feeding duration, Early, 0.796 (−0.134, 1.727) and Late, −0.702 (−2.778, 1.376) (p = 0.010); for time elapsed since feeding, Early, −0.748 (−1.275, −0.221) and Late, −0.071 (−1.230, 1.088) (p = 0.036); and for blood lactate, Early, 0.086 (0.048 to 0.124), Medium, 0.022 (−0.063, 0.108), and Late, −0.018 (−0.106, 0.070) (p = 0.008 and <0.001 vs. Medium and Late, respectively). The influence of postconceptional age, oral feeding, and anaerobic metabolism on salivary cortisol levels was observed during the birth transition period but not beyond 10 days of life. Given the age-specific dependence of cortisol levels on clinical variables, including postconceptional age, feeding, and oxygen metabolism, caution is warranted when interpreting findings from studies on salivary cortisol in newborn infants. Full article

Prenatal hypoxia (PH) adversely affects the development of the fetal heart, contributing to persistent cardiovascular impairments in postnatal life. A key component in regulating cardiac physiology is the nitric oxide (NO) system, which influences vascular tone, myocardial contractility, and endothelial integrity during development. Exposure to PH disrupts NO-related signaling pathways, leading to endothelial dysfunction, mitochondrial damage, and an escalation of oxidative stress—all of which exacerbate cardiac injury and trigger cardiomyocyte apoptosis. The excessive generation of reactive nitrogen species drives nitrosative stress, thereby intensifying inflammatory processes and cellular injury. In addition, the interplay between NO and hypoxia-inducible factor (HIF) shapes adaptive responses to PH. NO also modulates the synthesis of heat shock protein 70 (HSP70), a critical factor in cellular defense against stress. This review emphasizes the involvement of NO in cardiovascular injury caused by PH and examines the cardioprotective potential of NO modulators—Angiolin, Thiotriazoline, Mildronate, and L-arginine—as prospective therapeutic agents. These agents reduce oxidative stress, enhance endothelial performance, and alleviate the detrimental effects of PH on the heart, offering potential new strategies to prevent cardiovascular disorders in offspring subjected to prenatal hypoxia. Full article

Gestational chronic hypoxia impacts prenatal development, leading to fetal growth restriction (FGR), defined as the fetus’s failure to reach its genetic growth potential. Postnatal hypoxia in the cerebral tissue can induce a redox imbalance and mitochondrial dysfunction, consequently increasing neuronal death. However, these data cannot necessarily be extrapolated to prenatal hypoxia. In this regard, this study aims to describe the effect of gestational hypoxia on redox balance and apoptosis cell death mechanisms in the prefrontal cortex of guinea pigs. Ten Guinea pig (Cavia porcellus) pregnant dams were utilized in this study; five gestated in normoxia (Nx; three newborn males, and two females) and five gestated under chronic hypobaric hypoxia (Hx; two newborn males, and three females). We monitored the pregnancies by ultrasound examinations from gestational days 20 to 65 (term ~ 70). At birth, pups were euthanized, and the fetal brain was collected for cellular redox measurement, mitochondrial enzyme expression, and apoptosis assay. Gestation under hypoxia induced an imbalance in the expression of anti- and pro-oxidant enzymes, resulting in increased oxidative stress. Additionally, a decrease in cytochrome I and III expression and neuronal density in the neonatal prefrontal cortex was observed. Finally, DNA fragmentation was increased by the TUNEL assay in the brain tissue of newborns gestated under chronic hypoxia. Our findings demonstrate the association of gestational hypoxia with oxidative stress and neuronal death in newborns, which may predispose to neuronal dysfunction in adulthood. Full article

Stressor stimuli induce oxidative stress and functional abnormalities in sperm, which are linked to a reduced sperm quality and male infertility. Furthermore, oxidative stress can trigger cell death. However, the impact of stressor stimulation on testicles and epididymal sperms and apoptosis has not been explored. This study analyzes the expression of extrinsic and intrinsic apoptotic markers in the testicle and epididymis of rats exposed to chronic variable stress (CVS). We used male Wistar rats divided into two groups: the control group was kept undisrupted, and the stress group was stressed daily using a CVS model for four weeks, except for the weekends (from postnatal days 51 to 81). After the last week, the rats were sacrificed, and complete testicles and epididymal sperm were used to measure oxidative stress and the total antioxidant status by colorimetric methods. The expressions of PPAR-γ, p53, Bax, and Bcl-2 markers at the mRNA level were determined by real-time PCR, and the p-Akt, AP-2α, PPAR-γ, C/EBP-β and FAS protein levels were detected by immunoblot. The results showed low levels of p-Akt and AP-2α proteins and high levels of FAS, PPAR-γ, and C/EBP-β in the testicle and epididymis of rats exposed to CVS. At the mRNA level, we observed the upregulation of PPAR-γ, p53, p21, HIF-α, and Bax expressions in the epididymis of rats exposed to CVS, consistent with the significant caspase-3 activity observed in both the epididymis and testicles in the CVS group. In conclusion, CVS damage triggers the induction of apoptosis markers by intrinsic (PPAR-γ, p53, p21, HIF-α, and Bax) and extrinsic (p-Akt, AP-2α, and FAS) caspase-3-dependent pathways in complete extracts of both the testicles and epididymis. This study supports the view that stressor stimuli could be involved in the infertility process. Full article

Background: The limited regenerative capacity of adult mammalian cardiomyocytes (CMs) poses a significant challenge for cardiac repair following myocardial infarction. In contrast to adult mammals, CMs in zebrafish and newt hearts retain a lifelong capacity for proliferation and cardiac regeneration. Likewise, neonatal mice exhibit a brief postnatal period, during which CMs retain the ability to proliferate and contribute to myocardial repair, which markedly diminishes within the first week of life. Emerging evidence indicates that adult CM cell cycle progression is critically influenced by oxidative stress. Adult mammalian CMs possess a high mitochondrial content to meet their substantial energy demands. However, this also leads to elevated reactive oxygen species (ROS) production, resulting in DNA damage and subsequent cell cycle arrest. We hypothesize that reducing the mitochondrial content in adult CMs will mitigate ROS production, thereby facilitating cell cycle progression. Methods: Adult CMs were isolated from adult rats (≥12 weeks old). To induce mitophagy, adult CMs were transfected with parkin-expressing plasmid and then treated with carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a mitochondrial protonophore, for 7 days. Post-treatment assessments included the quantification of adult CM proliferation, mitochondrial content, and ROS levels. Results: CCCP-treated adult CMs exhibited a significant increase in proliferation markers, including EdU incorporation, KI67, phospho-histone H3, and Aurora B. Furthermore, CCCP treatment significantly reduced the mitochondrial content, as evidenced by decreased MitoTracker, TMRM, and Tom20 staining compared to controls. This was accompanied by electron microscopy analysis, which showed a significant reduction in the mitochondrial number in the adult CM after CCCP treatment. Moreover, our results also demonstrate a marked reduction in oxidative stress, demonstrated by lower 123-dihydro-rhodamine (123-DHR), CellROX signals, and VDAC. Conclusions: Our findings demonstrate that CCCP-mediated mitochondrial depletion reduces oxidative stress and promotes cell cycle re-entry in adult CM. This study provides direct experimental evidence and substantiates the role of elevated mitochondria and ROS levels in adult CM cell cycle exit. Full article

Background: Exposure to early life stress significantly increases the risk of psychopathology later in life. However, the impact of early life stress on the gut microbiome and its potential role in mental health outcomes remains insufficiently understood. This narrative review examines the current knowledge on how early life stress and its associated consequences may affect the gut microbiome, with a particular focus on conditions such as anxiety, depression, and post-traumatic stress disorder. Method: A comprehensive literature search was conducted in the PubMed and Web of Science databases between January and February 2025, covering studies published between 2015 and 2025. Results: Early life stress can profoundly impact cognitive function and neurodevelopment, with maternal early-life nutrition playing a significant role in modulating the effects of prenatal and postnatal stress. Early life stress influences the gut microbiome, disrupting its composition and function by altering the synthesis of microbial metabolites, neurotransmitters, and the activation of key metabolic pathways. However, the precise role of the gut microbiome in modulating stress responses during childhood and adolescence has not yet been fully elucidated. Conclusions: Several studies have demonstrated an association between early life stress and the gut microbiome. However, causality has not yet been established due to the numerous intrinsic and extrinsic factors influencing the microbiome-gut–brain axis. In the coming years, research on key microbial regulators, such as short-chain fatty acids, amino acids, and psychobiotics, may represent a promising approach for addressing central nervous system alterations linked to early life stress. Thus, further studies will be necessary to evaluate their potential as therapeutic agents. Full article

The paraventricular nucleus of the hypothalamus (PVN) regulates, among others, the stress response, sexual behavior, and energy metabolism through its magnocellular and parvocellular neurosecretory cells. Within the PVN, ensemble coordination occurs through the many long-range synaptic afferents, whose activity in time relies on retrograde neuromodulation by, e.g., endocannabinoids. However, the nanoarchitecture of endocannabinoid signaling in the PVN, especially during neuronal development, remains undescribed. By using single-cell RNA sequencing, in situ hybridization, and immunohistochemistry during fetal and postnatal development in mice, we present a spatiotemporal map of both the 2-arachidonoylglycerol (2-AG) and anandamide (AEA) signaling cassettes, with a focus on receptors and metabolic enzymes, in both molecularly defined neurons and astrocytes. We find type 1 cannabinoid receptors (Cnr1), but neither Cnr2 nor Gpr55, expressed in neurons of the PVN. Dagla and Daglb, which encode the enzymes synthesizing 2-AG, were found in all neuronal subtypes of the PVN, with a developmental switch from Daglb to Dagla. Mgll, which encodes an enzyme degrading 2-AG, was only found sporadically. Napepld and Faah, encoding enzymes that synthesize and degrade AEA, respectively, were sparsely expressed in neurons throughout development. Notably, astrocytes expressed Mgll and both Dagl isoforms. In contrast, mRNA for any of the three major cannabinoid-receptor subtypes could not be detected. Immunohistochemistry validated mRNA expression and suggested that endocannabinoid signaling is configured to modulate the activity of afferent inputs, rather than local neurocircuits, in the PVN. Full article

The gut microbiota plays a central role in host energy metabolism and the development of metabolic disorders, partly through its influence on mitochondrial function. Probiotic supplementation, particularly with Lactobacillus rhamnosus GG, has been proposed as a strategy to modulate the microbiota and improve host metabolic health. Adolescent binge-like alcohol consumption is a critical public health issue known to induce neuroinflammation, oxidative stress, mitochondrial dysfunction, and intestinal dysbiosis, contributing to disorders such as alcoholic liver disease (ALD). This study aimed to evaluate the effects of L. rhamnosus GG supplementation on mitochondrial physiology in Sprague Dawley rats exposed to binge-like ethanol (BEP group) or saline (SP group) during adolescence (postnatal days 30–43). Starting on postnatal day 44, L. rhamnosus GG was administered orally for 28 days. Fecal colonization was confirmed by qPCR, and mitochondrial function was assessed in the liver, heart, and bone marrow through quantification of NADH, ATP, ADP/ATP ratio, total antioxidant capacity, and the expression of mitochondrial genes Higd2a, MnSOD1, and AMPKα1. L. rhamnosus GG supplementation induced tissue-specific mitochondrial adaptations. In the liver, it increased Higd2a expression and restored antioxidant and energy balance in ethanol-exposed rats. In the bone marrow, it reversed ethanol-induced metabolic stress and enhanced AMPKα1 expression. In contrast, in the heart, L. rhamnosus GG had minimal impact on mitochondrial energy markers but increased antioxidant capacity, indicating a more limited, redox-focused effect. These findings suggest that L. rhamnosus GG exerts context-dependent, tissue-specific benefits on mitochondrial physiology, primarily through the modulation of antioxidant defenses, activation of AMPKα1, and remodeling of respiratory complexes. This probiotic may represent a promising therapeutic strategy to mitigate mitochondrial dysfunction associated with early-life alcohol exposure. Full article

This study examined the mediating role of prenatal cortisol on the relationship between gestational weight or adiposity and postpartum depression (PPD), while considering the moderating roles of breastfeeding (BF) or socioeconomic resources. We hypothesized that women with a higher pre-pregnancy body mass index (PPBMI) or a larger abdominal circumference would have elevated diurnal cortisol levels in late pregnancy, which would predict more PPD symptoms. Additionally, we hypothesized that BF and access to more socioeconomic resources would buffer the positive relationship between prenatal diurnal cortisol and PPD symptoms. We used longitudinal data from the Infant Development and Health Outcomes in Mothers Study, in which women self-reported PPBMI, BF frequency at 6 months, familial education, occupation, and income and completed the Edinburgh Postnatal Depression Scale. The abdominal circumference, cortisol area under the curve with respect to ground (AUC_G), and cortisol awakening response (CAR) were measured. Higher breastfeeding frequency and greater socioeconomic resources were associated with fewer PPD symptoms. There were main and interactive associations of AUC_G with BF frequency with PPD. Notably, higher cortisol levels were linked to more PPD symptoms among women with less frequent BF. Thus, BF may mitigate the relationship between prenatal stress and PPD, highlighting the importance of BF support in PPD prevention. Full article