Search Results (409)

In this study, we assessed the impact of repeated valproate administration on its anticonvulsant effects and side effects in mice. We measured the plasma and brain concentrations of valproate and examined changes in the expression of selected genes in the mouse hippocampus after both acute and chronic treatments. Electroconvulsions were induced using an alternating current (50 Hz, 25 mA, 0.2 s) through ear clip electrodes. Motor impairment and long-term memory deficits were assessed with the chimney test and passive avoidance task. Valproate concentrations in the brain and plasma were measured by a fluorescence polarization immunoassay. mRNA was isolated using a modified Chomczyński and Sacchi method, and RQ-PCR was performed with an Applied Biosystems 7900 using SDS and RQ Study software. The 50% effective dose (ED₅₀) of valproate in the 14 × 2 protocol was significantly lower than the control. Despite no observed memory deficits in chronic protocols, the 50% toxic dose (TD₅₀) for motor impairment was also significantly lower. Chronic valproate treatment did not alter the plasma and brain concentrations. However, the expression levels of three genes (CACNA1G, GAD1, SCN1A) were significantly higher in the chronic protocols with the higher dose of valproate compared to single protocols, suggesting a dose-dependent effect. The repeated administration of valproate resulted in both enhanced efficacy and increased toxicity in terms of motor impairment. The observed effect may be associated with transcriptional adaptations potentially mediated by epigenetic mechanisms rather than with pharmacokinetic events. To enhance the reliability of the results obtained in animal epilepsy models, antiepileptic drugs should be administered chronically. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by progressive memory impairment and cognitive decline. The APOE4 allele represents one of the most prominent genetic risk factors. In this study, we investigated the impact of APOE4 on the cholinergic neuronal development and on the neuronal inflammatory response to TNF-α stimulation. To address this, human induced pluripotent stem cells (hiPSCs) carrying a homozygous APOE4 genotype and an isogenic APOE3 control were differentiated into cholinergic-like induced neurons (iNs) by LHX8 overexpression. APOE4 was associated with accelerated early neuronal differentiation, as reflected by earlier downregulation of the progenitor marker Nestin. However, delayed expression of synaptophysin indicated impaired synaptic maturation. Functionally, APOE3 iNs exhibited a robust but temporally regulated response to TNF-α, whereas APOE4 iNs were characterized by a delayed yet sustained induction of inflammatory signaling. Moreover, APOE4 iNs displayed an enhanced stress-associated transcriptional response at early differentiation stages. Collectively, these findings suggest that APOE4 influences both neuronal development and the timing and persistence of inflammatory responses, potentially predisposing cholinergic neurons to later dysfunction in AD. Full article

The present investigation was designed to assess how perinatal contact with the pyrethroid insecticide cyfluthrin (CY) influences cognitive performance in developing rat progeny and to clarify the contributing cellular events through examination of neuroinflammatory processes alongside pyroptotic and apoptotic pathways. An experimental framework involving CY administration during gestation was implemented using Sprague–Dawley (SD) dams, with subsequent monitoring of placental parameters and neonatal outcomes. Once offspring reached postnatal day twenty-one, their behavior was characterized via a battery consisting of the open field paradigm, novel object recognition task, and the Morris water navigation test. Hippocampal tissue architecture and fine structural details were visualized by employing hematoxylin–eosin (HE) staining and Nissl substance labeling. Protein and transcript abundances for pro-inflammatory mediators (TNF-α, IL-6), synaptic constituents (postsynaptic density protein-95, PSD-95; synaptophysin, SYP), and pyroptotic machinery components (NLRP3, GSDMD, Caspase-1) within hippocampal homogenates were quantified through immunoblotting and real-time quantitative PCR procedures, and the spatial distribution of these molecules was validated via immunohistochemical detection. Neuronal apoptosis was assessed by TUNEL staining. The results demonstrated that gestational CY exposure led to reduced placental weight and diameter, decreased blood sinus area in the labyrinth zone, lower offspring birth weight, and impaired catch-up growth. Behavioral tests revealed that CY-exposed offspring exhibited diminished spontaneous locomotor activity, impaired novel object recognition memory, and significant deficits in spatial learning and memory. Pathological analysis showed disorganized neuronal arrangement and reduced Nissl bodies in the hippocampal CA1 region. Compared to the control group, CY exposure markedly upregulated the protein expression of TNF-α and IL-6, downregulated PSD-95 and SYP, activated the NLRP3/GSDMD/Caspase-1-mediated pyroptotic pathway, and increased the expression of the apoptotic protein Caspase-3, culminating in a significant increase in hippocampal neuronal apoptosis. In conclusion, early-life exposure to cyfluthrin impairs cognitive function in offspring, an effect closely associated with the induction of hippocampal neuroinflammation and the activation of pyroptotic and apoptotic pathways. These findings provide novel toxicological evidence for a more comprehensive assessment of the potential health risks posed by CY exposure in human populations. Full article

Volatility is a fundamental indicator for assessing the risk of financial assets. By integrating unstructured data, such as earnings call transcripts, the limitations of traditional time series data can be transcended, enabling collaborative forecasting from multiple data sources, enhancing the robustness of volatility prediction, and improving the efficiency of risk management. Although current research has effectively utilized earnings call data to predict asset volatility, price trends, and stock correlations, it often overlooks the inherent challenges of integrating textual and time series data, as well as the self-exciting and clustering characteristics of financial events. While conventional Long Short-Term Memory (LSTM) networks excel in processing fused data, they lack the structural capacity to explicitly model event-driven temporal decay, often failing to differentiate the varying influence of historical shocks over time. To surmount this limitation, we have significantly enhanced the predictive model by focusing on extracting salient information and integrating temporal dependency modeling with dynamic state adjustment mechanisms. The core innovation is introducing the Hawkes process to explicitly capture the self-exciting effect of financial events, which is the key to modeling volatility clustering around earnings releases. The proposed Hawkes LSTM model introduces a decay gating module and a textual information knowledge enhancement module. The decay gating module is specifically designed to more effectively capture the temporal dependencies between events within an event sequence. This allows the model to focus more on recent significant events, with the influence of an event on subsequent events typically diminishing as the temporal interval between them increases. By integrating temporal dependency modeling, the model is enabled to utilize historical data in a more flexible manner. The dynamic state adjustment mechanism further enhances its capacity to capture dynamically changing characteristics. Together, these features provide a more robust and precise solution for volatility prediction. Experimental results on two real-world earnings call datasets show that this approach significantly outperforms existing benchmark models on most prediction horizons, achieving competitive and superior performance and verifying its effectiveness and robustness. Full article

Attention deficit hyperactivity disorder (ADHD), a prevalent neurodevelopmental disorder characterized by inattention, impulsivity, and hyperactivity, is associated with monoaminergic dysfunction, neuronal damage, and gut microbiota disorders. Low molecular weight fucoidan (LMWF) is a sulfated polysaccharide extracted from Saccharina japonica (Phaeophyta), processes antioxidant, anti-inflammatory, and neuroprotective properties, suggesting its potential relevance for ADHD-related pathophysiology. This study investigated the therapeutic effects of LMWF on ADHD-like symptoms in spontaneously hypertensive rats (SHR). Behavioral tests revealed that LMWF reduced hyperactivity and anxiety-related behavior in the open field test, and improved spatial memory in the Morris water maze test. LMWF treatment significantly increased dopamine (DA), norepinephrine (NE), and 5-hydroxyindoleacetic acid (5-HIAA) levels in the prefrontal cortex (PFC). The transcript levels of tyrosine hydroxylase (Th) and synaptosome-associated protein-25 (Snap25) were upregulated, while dopamine transport (Dat) was downregulated in the PFC. TH protein expression was elevated in the striatum (STR), and neuronal integrity was preserved in the STR and cerebellum. LMWF also reshaped gut microbiota composition and enhanced microbial diversity, contributing to improved gut-brain axis homeostasis. These findings suggest that LMWF may serve as a promising dietary intervention for ADHD through neurochemical restoration and microbiota modulation. Full article

Both genetic and epigenetic factors influence the development and pathology of alcohol use disorder (AUD), which is further associated with changes in learning, memory, and synaptic plasticity. Histone acetylation is an epigenetic mechanism that changes the chromatin architecture, influencing gene transcription, which may further impact neuronal signaling, cognition, and addiction-related behaviors. In this review, we summarize the existing literature on how alcohol exposure impacts histone acetylation and the expression and activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Overall, alcohol appears to dynamically regulate histone acetylation and the expression and activity of HATs and HDACs in a brain region-, alcohol quantity-, exposure paradigm-, and sex-specific manner. While general patterns exist, more work is needed to elucidate the precise mechanisms through which alcohol changes histone marks across a variety of experimental and biological conditions, thus changing downstream gene expression. We suggest here that a more nuanced understanding of the relationship between histone acetylation and alcohol consumption is needed. Going forward, unbiased molecular techniques for profiling histone marks across the genome will allow for greater precision in determining the impact of alcohol on epigenetic regulation of transcription. However, these approaches must be performed with consideration to differences in mode and quantity of alcohol exposure, as well as withdrawal time and sex, in order for this research to uncover therapeutic targets for future treatment options. Overall, comprehensive, unbiased studies may yield novel insights into the regulatory role of alcohol-induced epigenetic modifications in the pathophysiology and neuropsychiatric correlates of AUD. Full article

Soil salinization is increasingly threatening global agricultural productivity and food security, currently affecting over 6% of the world’s land and one-third of irrigated areas. Tomato (Solanum lycopersicum L.), a major vegetable crop worldwide, exhibits moderate sensitivity to salinity, which limits both its yield and fruit quality. In recent years, epigenetic regulation has gained attention as a key mechanism enabling flexible and reversible control of gene expression without altering DNA sequences. This review synthesizes current knowledge on the epigenetic control of salt stress responses in tomato, focusing on three interconnected levels: DNA methylation dynamics, RNA-directed DNA methylation (RdDM), and histone modifications. We explore how DNA methyltransferases reshape the methylome under salinity, using examples such as PKE1 and SlGI to illustrate functional gene-body methylation. The RdDM pathway is discussed with emphasis on the unexpected role of SlAGO4A as a negative modulator of stress tolerance and the growing evidence for RdDM-mediated regulation of transcription factors. We also examine the balanced regulation of histone acetylation and deacetylation, highlighting the conserved role of GCN5 in maintaining cell wall integrity and the diverse functions of histone deacetylases, such as SlHDA1, SlHDA3, and SlHDA5, in stress adaptation. Additionally, insights from wild tomato species and grafting-induced epigenetic changes are presented, revealing new dimensions of stress memory. Collectively, these epigenetic mechanisms constitute a complex regulatory framework that integrates stress responses with growth and development, providing potential targets for epigenetic breeding of salt-tolerant tomatoes. Full article

Plants frequently encounter overlapping, sequential, and recurrent stresses, but the cellular mechanisms that organize responses to these complex conditions remain incompletely understood. Biomolecular condensates are membrane-less assemblies formed through phase separation and multivalent molecular interactions, and they can regulate RNA metabolism, protein sequestration, signaling specificity, transcriptional control, and stress recovery. This review evaluates the hypothesis that plant condensates may contribute to the organization of combined and recurrent stress responses by modulating molecular accessibility, transcript fate, proteostasis, and regulatory crosstalk. We synthesize current knowledge on stress granules, processing bodies, nuclear condensates, plastid-associated condensate-like assemblies, and other stress-responsive compartments, with emphasis on their possible roles in signal filtering, RNA triage, and recovery-associated reprogramming. We also distinguish established evidence from emerging hypotheses, particularly regarding condensate-mediated signal prioritization and stress memory. Current data support condensates as rapid stress-responsive organizers, but direct evidence for their persistence after recovery or their causal roles under simultaneous multi-stress conditions remains limited. By integrating phase separation biology with plant multi-stress physiology, this review proposes a testable conceptual framework and identifies methodological priorities for future studies in plant stress resilience and crop improvement. Full article

Somatic cell nuclear transfer (SCNT) in pigs has been a widely used technique for producing gene-edited pigs for biomedical research, yet its wide-spread application through serial cloning remains markedly limited. Unlike in mice, where the serial cloning can be sustained across numerous generations, in pigs it is usually limited to only a few rounds. Specifically, porcine serial cloning has not been reported beyond three consecutive generations in live-born offspring, with blastocyst development rates declining from approximately 4.4% in G1 to 1–5% in G2–G3, and live-birth cloning efficiency (offspring/recipient) dropping sharply with each successive round. Compelling evidence suggests that cumulative epigenetic instability, incomplete embryo genome activation, DNA methylation reprogramming, persistent donor-cell memory, and imprinting disruption collectively erode transcriptional integrity across generations. Although several manipulations, including epigenetic modifiers, transiently improved the early development, they failed to sustain the reprogramming across several generations. Here, we synthesize comparative advances in serial cloning across species and propose that species-specific differences in chromatin plasticity and cytoplasmic reprogramming capacity define a porcine “reprogramming ceiling”. Deciphering and overcoming this barrier will be critical for advancing sustainable livestock engineering, xenotransplantation and translational medicine biotechnology. Full article

The increasing frequency of high-temperature episodes associated with climate change poses challenges to crop productivity. Stress priming could help to mitigate these effects, with the capacity to enhance plant resilience through metabolic adjustments and memory mechanisms. We evaluated the efficacy of the Stress Memory Encoder biofertilizer (SME, TIMAC Agro) as a seed treatment to induce heat stress (HS) memory in soybean plants [Glycine max (L.) Merrill]. In Experiment 1, plants with SME (0, 2, and 4 mL kg⁻¹) were exposed to HS (35 °C for 48 h) at V3 and V6 vegetative stages. The 4 mL kg⁻¹ dose at V6 under HS consistently improved photosynthetic traits and reductions in reactive oxygen species and lipid peroxidation. Non-enzymatic antioxidants were detected to this dose at V3. Multivariate analysis revealed patterns consistent with dose-dependent physiological adjustments and potential memory acquisition. In Experiment 2, plants treated with SME were exposed to HS (34 °C for 48 h) consecutively (V3 + V6). The SME-primed plants had a higher expression of transcript factors and genes related to HS. Overall, the findings indicate that SME may act as a priming agent capable of inducing somatic memory and enhancing adaptive responses to HS in soybean. Full article

Obesity is characterized by chronic low-grade inflammation (meta-inflammation) and metabolic dysregulation. Adipose tissue acts as an immunometabolic organ, with macrophages playing a central role. This review examines inflammatory memory in adipose tissue, focusing on CD68+ macrophages and their role in cardiometabolic and cancer risk during weight cycling. (2) Narrative synthesis of evidence from immunology, obesitology, and oncology, with emphasis on macrophage polarization and signaling pathways. (3) Weight cycling induces persistent immune memory in adipose tissue, characterized by exaggerated macrophage responses upon weight regain. CD68+ macrophages contribute to extracellular matrix remodeling, tumor signaling, and metabolic dysfunction. Key mechanisms include PI3K/AKT/mTOR dysregulation, FOXO1/KLF10 axis impairment, and CREB-mediated transcription. This inflammatory memory promotes atherosclerosis progression, insulin resistance, and increased cancer risk, despite prior weight loss. (4) Macrophage-driven inflammatory memory represents a key mechanistic link between obesity, cardiometabolic disease, and cancer. Targeting meta-inflammation independent of body weight should be integral to future therapies. Full article

In recent years, plant stress biology has moved beyond single-pathway descriptions toward an integrated framework in which stress perception, hormonal control, and gene regulation are tightly interconnected. Early events such as membrane-associated sensing, calcium influx, reactive oxygen species (ROS) generation, and kinase activation converge with phytohormonal networks to shape context-dependent responses. Within this framework, abscisic acid, salicylic acid, jasmonates, ethylene, auxin, cytokinins, gibberellins, brassinosteroids, and strigolactones function not as isolated regulators but as components of a dynamic signaling matrix that balances survival, defense, growth restraint, and recovery. These hormonal signals are ultimately translated into adaptive outcomes through extensive transcriptional and post-transcriptional reprogramming mediated by transcription factors, RNA-based regulators, chromatin remodeling, and stress memory mechanisms. This review synthesizes current understanding of how plants integrate stress perception, phytohormonal crosstalk, and transcriptional regulation to establish stress tolerance. We first examine the molecular basis of stress sensing and early signaling. We then discuss the central functions of major phytohormones and the logic of hormone–hormone interaction networks in coordinating stress adaptation. Next, we analyze transcriptional, post-transcriptional, and epigenetic mechanisms that determine response specificity, intensity, and persistence. We further highlight points of convergence between abiotic and biotic stress responses and discuss how combined stresses challenge traditional single-stress models. Finally, we consider the roles of omics, systems biology, and translational technologies in decoding and engineering stress-resilient phenotypes. By integrating these perspectives, this review presents plant stress tolerance as a multilevel systems property and outlines key priorities for future research aimed at developing climate-resilient crops. Full article

Background: Long-term diabetes mellitus may precipitate severe complications, including cognitive dysfunction. Existing research has shown that diabetic cognitive impairment (DCI) in rats is characterized by memory deterioration and a disordered arrangement of hippocampal cells. The Shichangpu–Xiyangshen herb pair (SX) effectively improved the pathological changes induced by DCI. However, the role of SX in regulating the physiological and behavioral responses to DCI remains unclear. Methods: We sought to determine the small-molecule metabolites of cerebrospinal fluid (CSF) and delineate the pathways to elucidate the potential mechanism of the effect of SX in the treatment of DCI by metabolomics strategies, focusing on key mechanisms. Behavioral assessments were conducted on DCI rats and the rats treated with SX, as well as an evaluation of neuronal morphology in the hippocampal region. Metabolomics was used to analyze biomarkers in cerebrospinal fluid at different time points during the development of DCI, to uncover the underlying core mechanisms of DCI, and to investigate the regulatory effects of SX on these core mechanisms. The mechanisms of SX on DCI were investigated using quantitative reverse transcription polymerase chain reaction, immunohistochemistry, Western blot, and ELISA. Results: The Morris water maze (MWM) and social interaction test results revealed that SX administration effectively counteracted cognitive impairments in rats with DCI while simultaneously diminishing pathological damage in the CA1, CA3, and DG hippocampal regions. Further analysis showed that SX restored the significantly reduced levels of IL-8, ROX, and TNF-α, and reduced Aβ plaque formation (as indicated by APP and BACE1 protein expression). Simultaneously, SX markedly ameliorated arachidonic acid metabolic disorders in DCI, including significant reductions in arachidonic acid (AA), PGE2, and LTB4 and reduced expression of COX-2 (PTGS2) and 5-LOX (ALOX-5). Conclusions: Our findings indicate that SX effectively counteracted cognitive impairment in rats with DCI by inhibiting AA metabolism through both cyclooxygenase and lipoxygenase pathways, thereby minimizing neuronal damage. Full article

Despite prolonged viral inhibition with combination antiretroviral therapy (ART), HIV-1 survives as genetically intact, replication-capable proviruses within durable CD4+ T-cell fractions, involving central memory, transitional memory, and stem cell-like memory populations, as well as within tissue-resident compartments including lymphoid follicles and gut-associated lymphoid tissue. Reservoir stability is preserved via clonal growth of infected cells and epigenetic processes that impose proviral transcriptional silencing. As a result, current therapeutic approaches seek to either directly alter proviral survival or to improve immune-driven elimination of infected cells. At the molecular level, investigational strategies such as CRISPR–Cas9 and CRISPR–Cas12 gene-editing systems are intended to remove or induce inactivating mutations inside embedded proviral DNA, as well as alter host entrance co-receptors such as CCR5 to provide cellular resistance to infection. In addition, pharmacologic latency regulation is being studied via histone deacetylase inhibitors, protein kinase C agonists, and bromodomain inhibitors to reverse latency, along with Tat inhibitors and other transcriptional repressors aimed to persistently silence proviral expression. Moreover, immunological techniques aim to counteract inefficient endogenous antiviral defenses. Broadly neutralizing antibodies with tailored Fc-driven effector functions are under examination for both neutralization and antibody-dependent cellular cytotoxicity. Therapeutic vaccine approaches seek to elevate polyfunctional HIV-specific CD8+ T-cell responses, while adoptive cellular approaches, involving CAR-T cells aiming HIV envelope epitopes, remain in early clinical research. Immune checkpoint blockade is also being investigated to reverse T-cell depletion inside reservoir-rich tissues. Nevertheless, the key obstacles continue to be the diverse reservoir composition, restricted tissue penetration, viral escape, and safety limitations. The molecular and translational obstacles that characterize attempts toward an HIV cure must be addressed through ongoing multidisciplinary research. Full article

Polyamines are small, positively charged molecules essential for fundamental cellular processes, including transcription, translation, and membrane fluidity. In the central nervous system (CNS), these molecules serve as homeostatic gatekeepers by modulating neuroreceptors like NMDA and supporting autophagic clearance. While basal polyamine levels are necessary for proper neuronal differentiation and memory formation, their dysregulation is a hallmark of neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases. Neurotropic viruses, including poliovirus, Zika virus, and human cytomegalovirus are significant human pathogens that rely on cellular metabolites for their replication, including polyamines. These pathogens exploit polyamines at multiple stages of their life cycles, relying on them for virion stability, cellular attachment, and the stimulation of viral enzyme activity. Notably, diverse viral families share this dependence, making polyamine biosynthesis a prime target for broad-spectrum antiviral therapies. This review covers the current understanding of polyamine metabolism in virus infection and CNS health and disease, as well as considering antiviral therapies targeting host polyamines to limit neurotropic virus infection. Full article