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Peripheral nerve injuries often lead to significant functional impairment. While autografts remain the gold standard for repairing critical-sized nerve defects, donor site morbidity and limited graft availability have prompted the exploration of alternative strategies. Although studies investigating nerve regeneration using nerve conduits and biological agents are present in the literature, research investigating the effect of neurotrophic factors enriched secretome with biocompatible 3D conduits combination is insufficient. The aim of this study is to evaluate the regenerative potential of 3D biodegradable chitosan-PCL nerve conduit combined with BDNF-enriched secretome in peripheral nerve defects. In this study, biodegradable three-dimensional (3D) nerve conduits composed of polycaprolactone (PCL) and chitosan (75:25 wt/wt) were fabricated and used to bridge 10 mm sciatic nerve defects in rats. The conduits were evaluated alone or in combination with the secretome derived from Wharton's Jelly mesenchymal stem cells (WJ-MSC), either in the native form or enriched with brain-derived neurotrophic factor (BDNF). Thirty-two adult male Wistar Albino rats (mean weight 300-400 g) were randomized into four groups: Autograft (Group 1), conduit only (Group 2), conduit and WJ-MSC derived secretome (Group 3), and conduit combined with BDNF-enriched WJ-MSC derived secretome (Group 4). Functional recovery was assessed using the sciatic functional index (SFI), electromyography (EMG), and gastrocnemius muscle wet weight. Morphological and histological evaluations were performed at 12 weeks postoperatively. At the end of 12 weeks, Group 4 (-49.48 ± 2.82) exhibited significantly improved SFI values compared to Group 2 (-66.62 ± 5.31) and Group 3 (-60.60 ± 5.34) (p < 0.05). Electromyographic analysis revealed higher compound muscle action potential amplitutes in Group 4 (19.72 ± 3.62 mV) than Group 2 and Group 3 (p < 0.05), with values compared to the autograft group. Gasrtrocnemius muscle wet weight ratios were also significantly higher in Group 4 (69.09% ± 9.88%) than in Groups 2 and 3. Histological analyses showed enhanced axonal regeneration, reduced inflammation, and better myelination in Group 4. Scanning electron microscopy confirmed the conduit structural integrity and stability over the 12-week period. The combination of a 3D biodegradable chitosan-PCL conduit with BDNF-enriched WJ-MSC-derived secretome significantly enhanced peripheral nerve regeneration in a rat model. This strategy shows strong potential as an alternative to autografts for treating critical-sized nerve defects. Show less

This study aimed to investigate the effects of L-borneol on the molecular, biochemical, and histological damage caused by acrylamide (ACR) in the hippocampus of adult male Wistar rats. It also examined the impact of L-borneol on spatial memory and anxiety-like behaviors in these animals. Animals were divided into four groups: control, L-borneol, ACR, and ACR + L-borneol. ACR (25 mg/kg) and L-borneol (50 mg/kg) were administered orally for 21 consecutive days. L-borneol reduced levels of malondialdehyde and nitric oxide, increased glutathione content, and enhanced superoxide dismutase activity in the hippocampus of rats treated with ACR. In addition, L-borneol lowered the expression of pro-inflammatory markers, nuclear factor-κB, and inducible nitric oxide synthase in the hippocampus. It effectively prevented changes in the expression of apoptosis-related genes, which are associated with decreased neuronal death in the cornus ammonis 1 and dentate gyrus regions. Moreover, L-borneol increased the expression of sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), brain-derived neurotrophic factor, and alpha 7-nicotinic acetylcholine receptors, while reducing the expression and activity of acetylcholinesterase. Finally, L-borneol improved spatial memory and reduced anxiety-like behaviors. In conclusion, L-borneol enhances behavioral performance in ACR-exposed animals by decreasing oxidative and nitrosative stress, as well as inhibiting inflammation and apoptosis. It appears that the upregulation of the SIRT1/Nrf2/HO-1 signaling pathway and the stimulation of acetylcholine signaling are crucial for mitigating ACR-induced neurotoxicity. Show less

Memantine (Mem), an uncompetitive antagonist of the N-methyl-D-aspartate receptor (NMDAr), has demonstrated neuroprotective effects in preclinical stroke models by reducing excitotoxic damage. However, the efficacy of low acute doses administered during the immediate post-ischemic phase remains insufficiently characterized. Male rats underwent permanent middle cerebral artery occlusion (pMCAO) and received a single intraperitoneal dose of Mem (5 mg/kg) two hours post-occlusion. Neurological deficits were assessed using the modified Neurological Severity Score (mNSS). Infarct area and neuronal preservation were quantified using MAP2 immunohistochemistry. BDNF and PSD95 protein levels were measured by ELISA, and their gene expression was evaluated via RT-PCR. Mem treatment significantly reduced infarct area (p = 0.000029) and attenuated neurological deficits (p < 0.0001). MAP2 immunoreactivity was higher in the Mem-treated group (p = 0.000003), indicating preservation of neuronal structure. BDNF protein levels did not differ between the pMCAO and pMCAO+Mem groups; PSD95 protein and its corresponding DLG4 mRNA were increased in the pMCAO group compared with Sham. In the other groups, levels remained unchanged. Early administration of low-dose memantine confers acute neuroprotection after stroke by reducing tissue damage and preserving neuronal integrity, without affecting ischemia-induced BDNF and PSD95 protein and gene expression. These findings suggest a selective early neuroprotective mechanism and highlight the need for long-term and sex-inclusive studies to further evaluate memantine's therapeutic potential. Show less

Neuroinflammation driven by dysfunctional microglial responses represents a critical early pathogenic process, particularly in the context of Alzheimer's disease (AD). The natural flavonoid fisetin possesses anti-inflammatory characteristics; however, the exact mechanisms via which it mitigates microglial dysfunction in AD are not fully elucidated. This work employed a combination of in vivo and in vitro approaches, utilizing male APP/PS1 mice and ADDL-stimulated primary microglia. Behavioral tests, immunohistochemistry, molecular profiling, and mitochondrial function assays were conducted. This research combines network pharmacology, molecular docking, and cellular thermal shift assays (CETSA) to offer predictive insights. Fisetin treatment improved cognitive performance in APP/PS1 mice, concurrently reducing amyloid pathology and plaque-associated microglial clustering. In primary microglia, fisetin potently inhibited ADDL-induced pro-inflammatory activation, mitochondrial ROS overproduction, and membrane depolarization. PI3K was identified as a signaling node potentially involved in fisetin-mediated regulation of microglial inflammatory responses. Accordingly, fisetin constrained microglial inflammatory signaling, at least in part through modulation of the PI3K-Akt-NF-κB axis, thereby limiting NF-κB nuclear translocation and pro-inflammatory cytokine release in both the mouse hippocampus and cultured primary microglia. Furthermore, conditioned medium from fisetin-treated microglia alleviated neuronal damage and restored the expression of BDNF and PSD95 in primary neurons. The collective findings, along with experimental studies utilizing the PI3K inhibitor (LY294002), indicate that PI3K may act as a molecular target of fisetin, underscoring its potential therapeutic significance in regulating early inflammatory processes in AD. Show less

Lithium deficiency may contribute to Alzheimer disease pathogenesis. No randomized clinical trial has examined lithium's effects on cognition, neuroimaging, and plasma biomarkers in mild cognitive impairment (MCI). To examine the feasibility, safety, and preliminary efficacy of lithium carbonate for delaying cognitive decline in older adults with MCI. This single-site, randomized, double-blind, placebo-controlled pilot feasibility clinical trial was conducted at the University of Pittsburgh School of Medicine from February 2018 to August 2024, with 2-year follow-up. Analyses used linear mixed-effects models in the intention-to-treat population. Adults aged 60 years or older with MCI who were free of major psychiatric or neurologic illness and contraindications to lithium were included. Of 170 individuals assessed, 83 were randomized (41 lithium vs 42 placebo), with 80 starting treatment (41 lithium vs 39 placebo). Data were analyzed from August 2024 to December 2025. Daily low-dose lithium carbonate or placebo for 2 years. Six prespecified coprimary outcomes included cognitive performance (California Verbal Learning Test-II [CVLT-II] delayed recall, Brief Visuospatial Memory Test-Revised, preclinical Alzheimer cognitive composite), hippocampal volume, cortical gray matter volume, and brain-derived neurotrophic factor. Among 80 participants (mean [SD] age, lithium: 72.93 [8.77] years; placebo: 71.22 [6.47] years; 56% female), none of the 6 coprimary outcomes met the prespecified significance threshold. Mean (SD) CVLT-II baseline scores were 7.95 (3.4) for lithium and 7.90 (3.9) for placebo; scores declined 1.42 points annually in the placebo group vs 0.73 points in the lithium group (difference, 0.69 points per year; 95% CI, 0.01-1.37; P = .05). Hippocampal and cortical volumes showed a decline over time in both groups, but no significant treatment × time interactions. Serious adverse events occurred in 12 of 41 (29%) receiving lithium vs 9 of 39 (23%) receiving placebo; none were definitely treatment related. One death occurred in the placebo group. Common adverse events included increased creatinine levels (12 of 41 [29%] with lithium vs 12 of 39 [31%] with placebo), diarrhea (12 of 41 [29%] vs 6 of 39 [15%]), tiredness (12 of 41 [29%] vs 6 of 39 [15%]), and tremor occurrence (10 of 41 [24%] vs 6 of 39 [15%]). This pilot randomized clinical trial established feasibility, confirmed safety and tolerability, and generated effect size estimates for future trials of low-dose lithium in MCI. None of the coprimary outcomes met the prespecified significance threshold. ClinicalTrials.gov Identifier: NCT03185208. Show less

Recent years have seen a marked increase in the number of patients diagnosed with spinal disorders, including chronic cervical myofascial pain syndrome (CMPS). This article aims to explore the potential of inflammatory process biomarkers in the blood and brain-derived neurotrophic factor (BDNF) as a means to assess the efficacy of collagen mesotherapy in the management of chronic CMPS. The second objective of this article is to evaluate the safety of collagen mesotherapy in chronic CMPS. The study comprised 23 subjects, who were randomly assigned either to the collagen mesotherapy group (n = 11) or the lignocaine mesotherapy group (n = 12). Blood was collected from each patient, and also the subjects were evaluated with the numerical rating scale (NRS) and the neck disability index (NDI). Results Both collagen and lignocaine mesotherapy have been observed to cause a significant reduction in pain intensity (NRS) and disability (NDI) over time, with no significant differences seen between the two interventions. However, the fluctuations in the levels of inflammatory biomarkers (TNFα, IL-1β, IL-6) and BDNF did not correspond with the clinical improvement noted. No adverse events related to the intervention were also observed. The potential of inflammatory biomarkers and BDNF, when assessed in blood serum, to serve as a basis for evaluating the efficacy of collagen mesotherapy in chronic CMPS; remains to be elucidated. Nevertheless, collagen mesotherapy appears to be an effective and safe treatment for chronic CMPS. However, further research in this area is required. Trial registration: NCT06807177. https//clinicaltrials.gov/study/NCT06807177. Show less

The approach to physical activity in patients with epilepsy has substantially changed over the last decade. Despite multiple positive effects of physical activity on general health and well-being, patients with epilepsy have long been advised not to engage in sports activities. Recent studies have led physicians to formulate updated recommendations and to encourage patients to remain active. It has been demonstrated that sport does not increase seizure prevalence, and the rate of sport-induced injuries in people with epilepsy is comparable to that of the general population. Additionally, physical activity modulates brain plasticity through a number of mechanisms, including the effect of brain-derived neurotrophic factor (BDNF), gamma-aminobutyric acid (GABA)/glutamate balance, and maintaining long-term potentiation states in synapses. The International League Against Epilepsy (ILAE) classifies sports into three categories according to the potential risk of injury in the event of a seizure. While most activities fall into low- or moderate-risk groups, high-risk sports include aviation, climbing, diving, horse racing, motor sports, parachuting, rodeo, scuba diving, ski jumping, solitary sailing, surfing, and windsurfing. Qualification for sports participation requires individual assessments of predispositions, seizure type and frequency, reaction to specific sports disciplines, respiratory function, and adjustment of hydration and nutrition. The intensity of training should be increased gradually to avoid triggering factors, such as hyperventilation, alkalosis, and hyperthermia. Seizure occurrence differs between aerobic and anaerobic sports, which is another aspect that needs to be included. Exercise electroencephalographic (EEG) and ambulatory EEG monitoring should be taken into account in patients with exercise-induced seizures to optimize their training plan. Despite the evolving recommendations, it is difficult to formulate universal recommendations for everyone. Each patient with epilepsy should undergo an individual qualification process and be appropriately monitored. Show less

Esophageal cancer is a formidable malignancy, presenting a significant health challenge due to its widespread prevalence and associated high mortality rates. Epithelial cell adhesion molecule (EpCAM), a pro-oncogenic glycoprotein, has been identified as an upregulated protein in esophageal adenocarcinoma (ESCA) through multi-OMICS platforms. However, its functional role in ESCA remains relatively understudied. Here, we investigated the contribution of EpCAM to ESCA pathogenesis using an EpCAM-null ESCA cell line, FLO-1, as a gain-of-function model. Introduction of a recombinant EpCAM-GFP fusion construct into FLO-1 cells resulted in enhanced cell migration, adhesion, clonogenic survival, and invasive capacity, supporting a pro-tumorigenic role for EpCAM. To define EpCAM-associated regulatory networks, RNA sequencing was performed on EpCAM-overexpressing cells, revealing 797 differentially expressed genes. Functional enrichment analyses indicated significant involvement of pathways related to cell adhesion, cell motility, transmembrane activity, and neuronal-associated processes, with enrichment in plasma membrane, focal adhesion, and neuron projection terminus compartments. Protein-protein interaction network analysis identified key hub genes, including SOX2, COL1A1, LOX, COL3A1, LUM, PXDN, BDNF, NCAM1, TLR2, and CCL5, linking EpCAM signaling to PI3K-Akt, ECM-receptor interaction, and focal adhesion pathways. Importantly, quantitative polymerase chain reaction (qPCR) validation of selected hub genes confirmed significant upregulation of the extracellular matrix components COL1A1 and PXDN in EpCAM-overexpressing FLO-1 cells, supporting the transcriptomic predictions and implicating ECM remodeling as a downstream consequence of EpCAM signaling. Collectively, these findings demonstrate that EpCAM promotes aggressive cellular phenotypes in ESCA and drives transcriptional programs associated with adhesion, invasion, and extracellular matrix regulation, highlighting potential therapeutic vulnerabilities in EpCAM-driven ESCA. Show less

Hypoxic-ischemic brain damage (HIBD) represents a major cause of neonatal morbidity and mortality, resulting from perinatal oxygen deprivation and impaired cerebral blood flow. This study aims to investigate the neuroprotective effects of Arctiin, a bioactive lignan derived from Neonatal rats at postnatal day 8 were randomly assigned to four groups: Sham-operated (SHAM), Hypoxia-Ischemia (HI), Hypoxia-Ischmia with Solvent control (HI/SO), and Hypoxia-Ischemia treated with Arctiin (HI/Arc). HIBD was induced via unilateral carotid artery ligation followed by exposure to hypoxia. The HI/Arc group was administered Arctiin orally at a dosage of 60 mg/kg daily for seven consecutive days. Behavioral performance, biochemical parameters, histological integrity, and gene expression profiles were assessed to evaluate the neuroprotective efficacy of Arctiin. Arctiin administration resulted in a significant reduction in C-reactive protein (CRP), and total oxidant capacity (TOC). Simultaneously, it enhanced total antioxidant capacity (TAC) and brain-derived neurotrophic factor (BDNF) levels. Histological analysis showed diminished infarct volume in the Arctiin-treated group. Moreover, gene expression studies revealed significant restoration of Neuregulin-1 (NRG-1) in group treated by arctiin. Neurobehavioral assessments further confirmed significant improvements in sensorimotor function in the Arctiin-treated group. Our study provides evidence indicating that Arctiin mitigates hypoxic-ischemic brain damage in rat pups through a synergistic mechanism involving the suppression of inflammation and oxidative stress, coupled with the upregulation of critical neuroprotective genes and proteins, specifically NRG-1 gene expression and BDNF protein levels. Future studies should investigate the precise molecular pathways downstream of NRG-1 that mediate Arctiin's neuroprotective effects. Show less

This study aimed to evaluate the therapeutic potential of stem cells from human exfoliated deciduous teeth (SHED) against depression and to elucidate the underlying mechanisms involving neuroinflammation and synaptic plasticity in a rat model of chronic unpredictable mild stress (CUMS). A robust rat model of depression was established using chronic unpredictable mild stress (CUMS) paradigm. CUMS-exposed rats received intracerebroventricular transplantation of SHED at three doses (0.5×10 SHED transplantation rapidly ameliorated CUMS-induced behavioral deficits, showing efficacy comparable to fluoxetine but with a notably faster onset. Mechanistically, SHED potently attenuated neuroinflammation by reducing hippocampal and cortical levels of pro inflammatory cytokines and by promoting a phenotypic shift in microglia from the M1 to the M2 state, as evidenced by morphology and marker expression. Transcriptomic analysis revealed that SHED treatment upregulated gene sets related to postsynaptic density, while downregulating the NOD like receptor (NLRP3 inflammasome) signaling pathway. At the molecular level, SHED enhanced the expression of key synaptic protein (PSD95) and restored the impaired BDNF/TrkB signaling axis in stress-vulnerable brain regions. SHED exerts rapid and potent antidepressant effects in the CUMS model through a convergent dual mechanism: suppressing neuroinflammation via microglial reprogramming and inflammasome inhibition, and enhancing structural and functional synaptic plasticity. These robust preclinical findings strongly support SHED as a novel, mechanism-based, cell therapeutic strategy for major depressive disorder. Show less

Both brain-derived neurotrophic factor (BDNF) and ovarian hormones are powerful neuromodulators, yet evidence of their impact on human cognition remains mixed. As prior work has studied them in isolation, examining their interacting effects presents a key empirical opportunity for explicating their effects on cognition. We genotyped participants for the BDNF Val66Met single nucleotide polymorphism, which is associated with less efficient activity-dependent BDNF secretion and altered hippocampal function, and examined their performance on a complex learning task at two points in the menstrual cycle: early follicular (characterized by low levels of ovarian hormones) and late follicular (characterized by high estradiol). While met carriers showed advantages during the early follicular timepoint, val homozygotes outperformed them at the late follicular timepoint. Furthermore, effects in met carriers were largely driven by increased sensitivity to both absolute levels and changes in levels of estradiol. The current findings provide the first evidence of BDNF Val66Met interacting with the menstrual cycle to predict cognition, demonstrate nuanced genotype- and hormone-specific outcomes, and underscore the importance of studying effects of interacting biological systems on human cognition. Show less

Adverse childhood experiences (ACEs) increase susceptibility to depression and anxiety disorders in adulthood. This study investigated the potential mechanisms through which ACEs enhance vulnerability to depression and anxiety in adulthood, using a novel "two-hit" mouse model by combining maternal separation (MS) with 14 or 21 days of restraint stress (RS). Behavioral assessments (sucrose preference test, tail suspension test, open field test, elevated zero maze) confirmed depressive- and anxiety-like behaviors in the MS + RS 21d group mice. Neurobiological analyses revealed hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis (elevated serum corticosterone [CORT] and adrenocorticotropic hormone [ACTH]) and dysregulation, characterized by reduced levels of monoamine neurotransmitters (5-hydroxytryptamine [5-HT], 5-hydroxyindoleacetic acid, dopamine, norepinephrine), altered mRNA expression of key genes (e.g., increased ACTH, CRH, SERT; decreased GR, brain-derived neurotrophic factor [BDNF]), and corresponding protein-level changes (e.g., increased 5-HT1AR, CRHRs; decreased BDNF, TrkB). Our findings indicate that the two-hit mouse model, combining MS with a 21-day RS, stably induces depressive- and anxiety-like behaviors in mice. The underlying mechanism may be associated with HPA axis dysfunction, serotonergic system dysregulation, and aberrant BDNF signaling within the prefrontal cortex-amygdala-hypothalamus circuit. Show less

This research investigated the potential therapeutic role of α-(phenylselanyl) acetophenone (PSAP) in the comorbidity of chronic pain and depression triggered by partial sciatic nerve ligation (PSNL). Male Swiss mice underwent PSNL surgery, and after a four-week period, they received either PSAP (1-50 mg/kg, administered intragastrically) or imipramine (IMI) (50 mg/kg) 30 min prior to behavioral assessments. Both PSAP and IMI effectively alleviated PSNL-induced hypersensitivity to pain and depressive-like symptoms, as demonstrated in forced swim and allodynia tests. Additionally, PSAP counteracted the elevated levels of lipid peroxidation and reactive oxygen species observed in the cortex and hippocampus following PSNL. These neuroprotective effects appear to be linked to PSAP's anti-inflammatory properties, as it downregulated the expression of pro-inflammatory markers such as NF-κB p65, TNF-α, and IDO mRNA in the affected brain regions. Furthermore, PSAP restored hippocampal BDNF mRNA levels, which had been diminished by nerve injury. Since inflammation is a common pathway in both chronic pain and depression, the findings indicate that PSAP holds promise as a treatment for this comorbid condition. Show less

Retigabine (RTG) shows notable neuroprotective efficacy in multiple brain injury models; however, its interplay with endoplasmic reticulum stress (ERS) is poorly understood. This study was designed to explore the therapeutic potential of RTG against CRS-induced depression-like behaviors and cognitive deficits in mice and to uncover the associated molecular mechanisms. A depression-like and cognitive impairment model was established in C57BL/6 male mice using chronic restraint stress (CRS). Six-week-old C57BL/6 male mice were randomly assigned to the following groups: control (Con), model (CRS), RTG (10 mg/kg), XE-991 (2 mg/kg) or tunicamycin (Tm, 2 mg/kg). Behavioral tests were conducted to assess depression-like behaviors and cognitive function. Hippocampal neuronal morphology was examined by H&E and immunofluorescence staining, while changes in endoplasmic reticulum stress (ERS)-related signaling pathways were analyzed by Western blot. Retigabine treatment reduced hippocampal neuronal damage and the expression of ERS-related factors (GRP78, CHOP) and the pro-apoptotic factor BAX in CRS-induced mice, while it increased the levels of BDNF. These effects were antagonized by XE-991 and the ERS agonist tunicamycin (Tm). Retigabine may alleviate CRS-induced depressive-like behaviors and cognitive impairment by inhibiting ERS-mediated apoptosis, suggesting its potential as a novel therapeutic strategy for depression. Show less

Neuroplasticity refers to the ability of the brain to modify synaptic connections and reorganize neural circuits, underpinning cognitive function, emotional regulation, and recovery from injury. Recent advances have redefined adult neuroplasticity as more dynamic and therapeutically accessible than previously thought, spurring investigation into pharmacological interventions that can augment these adaptive processes. This review dissects current evidence for drug strategies targeting synaptic modulators (NMDA, AMPA, and GABA receptors), neuropeptide systems (including BDNF, oxytocin, vasopressin), and psychedelic compounds (psilocybin, LSD, ketamine), integrating insights from cellular, preclinical, and clinical studies. We detail how these agents modulate molecular pathways governing synaptic transmission, dendritic remodeling, and gene expression linked to neuronal growth and resilience. Highlighted findings include the rapid-acting antidepressant effects of NMDA antagonists, the structural and functional reorganization induced by classic psychedelics via 5-HT2A receptor activation, and the neurorestorative roles of neuropeptides in synaptic and network adaptation. Alongside these advances, we critically address safety, ethical considerations, and the risk of maladaptive plasticity, underscoring the importance of dosing, patient selection, and controlled therapeutic environments. Non-hallucinogenic neuroplastogens and combinatorial approaches that are still emerging offer new avenues to fine-tune plasticity with an improved safety profile. The collective evidence positions neuroplasticity-targeting pharmacology as a promising and complex frontier for the treatment of neuropsychiatric and neurodegenerative disorders in adulthood. Show less

Paternal environmental factors before conception and during sperm development may influence the offspring's health later in life. This study aimed to investigate whether paternal exposure to anabolic-androgenic steroids (AAS) before conception predisposes mouse offspring to autism spectrum disorder (ASD)-like behavior. For this purpose, male Swiss mice were randomly divided into two groups: the control group received peanut oil, while the treated group was administered testosterone propionate (7.5 mg/kg, s.c.) twice a week for five weeks. After this period, these males were mated, and their offspring underwent a behavioral test battery at 70 days of age, including the open field test, object recognition task, three-chamber social approach test, and light-dark box test. At the end of the experiment, the hippocampus was dissected for RNA analysis. Our results indicate that paternal AAS treatment induces long-lasting behavioral alterations in both female and male offspring, including increased anxiety-like behavior, impaired memory, and deficits in social interaction. Additionally, a strong effect of paternal AAS treatment during preconception period was verified in Gad1, Gabra2 and Bdnf expression. These findings suggest that paternal AAS exposure may program neurodevelopmental vulnerabilities in offspring, contributing to ASD-like phenotypes. Show less

Programmed Cell Death 4 (PDCD4) is a multifunctional regulator with critically divergent, context-dependent roles: it acts as a tumor suppressor in neuro-oncology but a pathogenic driver in neuroinflammatory and degenerative conditions. Elucidating this functional duality is clinically relevant because PDCD4 dysregulation directly contributes to disease progression in both contexts. Its dual role is governed by disease-specific molecular environments, differential downstream mRNA targeting, and dynamic regulation of its expression and interactions. In gliomas, PDCD4 is frequently downregulated via promoter methylation, non-coding RNA inhibition (e.g., miR-21), and signaling pathway dysregulation (e.g., FAT1-STAT1 axis)-compromising key anti-tumor functions including cell cycle arrest, apoptosis induction, negative regulation of autophagy-lysosomal activity, and reversal of therapy resistance. Conversely, in conditions such as neural injury, neurodegenerative diseases, and mood disorders, PDCD4 is pathologically upregulated. Here, it exacerbates damage by driving the activation of pro-inflammatory pathways (e.g., MAPK/NF-κB, NLRP3 inflammasome), inducing neuronal death (apoptosis/ferroptosis), and impairing repair processes such as axonal growth by suppressing neurotrophic factors like brain-derived neurotrophic factor (BDNF). A multilayered regulatory network centered on miRNA-mediated control (notably miR-21), and expanded by epigenetic modifications and competitive endogenous RNA mechanisms, orchestrates its context-specific expression and activity. Current research gaps include an incomplete understanding of regulatory synergies, cell-type-specific functions, and key molecular interactions. Future studies employing multi-omics and cell-specific tools are needed to decipher these mechanisms and develop targeted therapeutic strategies. Show less

Huntington’s disease (HD) pathogenesis involves diverse cellular mechanisms, yet the contributions of pyroptosis and ferroptosis remain elusive. Roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor, has shown neuroprotective effects, but its precise mechanisms are yet to be elucidated. We evaluated the potential neuroprotective and therapeutic effects of roflumilast in 3-nitropropionic acid (3-NP)-induced HD-like neurodegeneration, focusing on pyroptotic and ferroptotic cell death signaling. Adult male Wistar rats were assigned to five groups: normal control (saline + 0.5% carboxymethyl cellulose), roflumilast-control (1 mg/kg/day, p.o. for 21 days), 3-NP (20 mg/kg/day, i.p. for seven days), roflumilast-prophylactic (1 mg/kg/day, p.o. for 21 days prior to 3-NP), and roflumilast-treatment (1 mg/kg/day, p.o. for 21 days post-3-NP). Behavioral outcomes of the open-field, rotarod, and grip strength tests were assessed. Striatal PDE-4, total and p-CREB, BDNF, interleukin-1β, and markers of pyroptosis (NLRP3, caspase-1, and gasdermin D) and ferroptosis (iron, GPx4, GSH, and malondialdehyde) were measured alongside histopathological alterations and GFAP and Iba-1 immunohistochemical staining. Bioinformatics was used to visualize the target genes’ protein-protein interaction network. Behavioral assessments revealed impaired locomotion, motor coordination, and muscle strength in the 3-NP-injected rats. Biochemical analysis showed increased striatal PDE-4 expression and decreased p-CREB/BDNF axis alongside NLRP3 inflammasome/caspase-1/gasdermin D activation and elevated interleukin-1β. In parallel, ferroptosis was evidenced by increased striatal iron and malondialdehyde levels, along with reduced GPx4 and GSH. Histopathological examination revealed pronounced striatal neurodegeneration, accompanied by enhanced GFAP and Iba-1 immunostaining, indicating astrogliosis and microglial activation. Roflumilast, administered prophylactically or therapeutically, significantly improved functional and behavioral abnormalities while ameliorating biochemical, histopathological, and immunohistochemical derangements induced by 3-NP. The therapeutic regimen exhibited superior efficacy relative to prophylaxis. Conclusively, roflumilast exerts therapeutic and neuroprotective effects in HD-like neurodegeneration by mitigating pyroptosis and ferroptosis, attenuating astrogliosis, microglial activation, and neuroinflammation, and restoring synaptic plasticity. A graphical abstract illustrating the proposed mechanistic pathway underlying the neuroprotection of the PDE-4 inhibitor roflumilast through reducing striatal pyroptosis, ferroptosis, microglial and astrocyte activation, and neuroinflammation, while restoring synaptic plasticity in experimental Huntington’s disease-like neurodegeneration induced by 3-NP. [Image: see text] Show less

The global rise in mental health conditions has prompted interest in interventions that act beyond conventional psychopharmacology. Psychobiotics, broadly understood as live microorganisms or microbe-derived products that interact with the microbiota-gut-brain axis, have been suggested to exert neuroactive effects through neural, immune, endocrine and metabolic routes. This narrative review synthesizes recent preclinical, mechanistic and early clinical observations. Experimental studies show that selected strains can modulate cytokine signalling, influence stress-responsive systems such as the hypothalamic-pituitary-adrenal axis, and support synaptic plasticity via factors such as brain-derived neurotrophic factor. A limited number of human trials using well-characterized Lactobacillus and Bifidobacterium strains have reported improvements in affective and stress-related outcomes, but these effects are generally small to moderate, more apparent in adjunctive than stand-alone use, and dependent on strain, dose, population and intervention length (typically 4-12 weeks). Evidence on neurodevelopmental conditions (e.g., autism spectrum disorder, attention-deficit/hyperactivity disorder) remains preliminary, based on small and heterogeneous samples. Across studies, key constraints include methodological heterogeneity, incomplete strain-level reporting, and gaps in mechanistic resolution that make it difficult to link microbial shifts to psychiatric benefit. Emerging microbiome- and metabolomics-informed approaches may help identify likely responders and improve translational precision, but they are not yet ready for routine clinical application. Overall, psychobiotics should currently be viewed as a promising adjunct within integrative mental health care, warranting larger, standardized trials with clearly defined strains, doses and mechanistic endpoints. Show less

Neuropathic pain (NP) is a debilitating condition with limited treatment options. The ethanolic extract of Bauhinia brachycarpa Benth (EEBb) has demonstrated antinociceptive effects in NP, but its active components and underlying mechanisms of action remain largely unexplored. Bauhinia brachycarpa Benth (BBB), an ethnic medicine in China, has antinociceptive effect on neuropathic pain (NP). In this study, an effective portion from BBB was screened and its antinociceptive mechanism was investigated. After the preparation of ethanolic extract from BBB (EEBb) and different soluble portion from EEBb (peEEBb, eaEEBb, nbEEBb), the total content of flavonoids and phenolic acids were measured. A partial sciatic nerve ligation (PSNL) model in vivo was applied to evaluate the antinociceptive effect and the influence on microglia function of these samples. The possible acting target of BBB was predicted by network pharmacology. And the mechanism of nbEEBb, the most effective antinociceptive portion, were studied by PSNL model in vivo and ATP-induced activation of BV2 model in vitro. nbEEBb had the strongest ability of alleviating NP as well as the obvious effect on microglia polarization. The action of nbEEBb was positively correlated to the total content of flavonoids or phenolic acids. nbEEBb inhibited the protein and gene expressions of most key components in P2X4-BDNF-TrkB signaling pathway. nbEEBb is the most effective portion from BBB on NP, and its mechanism refers to the inhibition of P2X4-BDNF-TrkB signaling pathway, which involved in neuron-microglia interaction. Show less

Parkinson's disease (PD) is a common neurodegenerative disorder involving multiple pathological processes. Bergapten (BeG) exhibits various pharmacological activities, including anti-inflammatory, antioxidant and neuroprotective effects, but its mechanism of action in PD remains unclear. This study aimed to investigate the neuroprotective effects and underlying mechanisms of BeG in PD models. An in vitro neuroinflammation model was established using LPS-treated astrocytes. In-vitro studies demonstrated that BeG counteracted LPS-induced astrocyte activation by reducing the expressions of GFAP, inflammatory mediators (IL-6, TNF-α, IL-1β), and A1 polarization markers. It alleviated ERS (as indicated by reduced levels of GRP78, CHOP) and apoptosis (as shown by changes in Bax, caspase-3) while enhancing Bcl-2. Mechanistically, BeG suppressed LCN2 expression and JAK2/STAT3 phosphorylation, with LCN2 overexpression attenuating its protective effects. In MPTP-treated mice, BeG improved motor function, preserved dopaminergic neurons, and reduced astrocyte activation and A1 polarization. It increased neurotrophic factors (BDNF, GDNF) while decreasing inflammation, ER stress and apoptotic markers. The inhibition of the LCN2/JAK2/STAT3 pathway was consistently observed in both models, suggesting its central role in BeG's neuroprotective mechanism. These findings suggest that BeG exerts neuroprotective effects in PD by inhibiting the LCN2/JAK2/STAT3 signaling pathway, thereby effectively inhibiting astrocyte activation-mediated neuroinflammation and ERS. Show less

Stress is defined as a disruption of homeostasis that elicits adaptive responses aimed at restoring physiological balance. However, when stress becomes chronic or overwhelming, maladaptive changes may occur, contributing to endocrine, behavioral, and neuropsychiatric dysfunctions. Beyond the classical neuroendocrine axes, such as the sympatho-adrenomedullary and hypothalamic-pituitary-adrenal (HPA) axes, the renin-angiotensin system has also being implicated in stress modulation. Previous studies have shown that angiotensin-(1-7), acting through its receptor Mas, exerts a modulatory effect on the stress response, attenuating anxiety- and depression-like behaviors induced by various stressors. Here we investigated the impact of genetic deletion of Mas on the consequences of chronic unpredictable stress (CUS) exposure. Over 21 consecutive days, mice were subjected to random stressors, after which endocrine, behavioral and neurochemical assessments were performed. Mas knockout (KO) mice exposed to CUS exhibited significantly elevated corticosterone and blood glucose levels compared to stressed wild-type mice. In behavioral tests, stressed Mas KO mice displayed the highest immobility times in the forced swimming test, indicating enhanced depressive-like behavior. Anxiety-like behavior was also heightened in Mas KO mice, as evidenced by a significant reduction in the percentage of time spent in the open arms of the elevated plus maze test. Neurochemical analysis revealed a marked reduction in brain-derived neurotrophic factor (BDNF) levels in key brain regions of stressed Mas KO animals. Together, these findings suggest that Mas plays a critical role in the neurobiology of stress, since its absence exacerbates HPA axis hyperactivity, depression- and anxiety-like behaviors, as well as BDNF reduction. Overall, these results highlight the potential neuroprotective role of Mas in stress-related disorders. Show less

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder that complicates the identification of effective therapeutic targets. The potential of stem cells and neurotrophins as promising candidates has become increasingly evident, owing to their neuroprotective and anti-inflammatory properties. In this study, a preclinical evaluation of the safety and biodistribution of mesenchymal stromal/stem cells (MSCs) combined with neurotrophin-releasing polyelectrolyte nanoparticles (NTs) was conducted in a porcine intrathecal delivery model relevant to ALS therapy development. Four groups of male pigs were administered saline with NTs, adipose-derived stem cells (ASCs) with NTs, Wharton's jelly-derived MSCs (WJ-MSCs) with NTs, or spinal puncture only. The safety of the treatment was assessed using magnetic resonance imaging (MRI), haematological and biochemical analyses, cerebrospinal fluid profiling, and histology. No adverse effects or significant systemic alterations were observed. It is noteworthy that C-reactive protein levels diminished following NT and NT-MSC administration, suggesting a systemic anti-inflammatory effect. The migration of MSCs was facilitated by cerebrospinal fluid, leading to their accumulation around the spinal cord and brain parenchyma. The present findings demonstrate short-term safety and biodistribution patterns following intrathecal administration of MSCs combined with neurotrophin-releasing nanoparticles in a large-animal model. These preliminary observations provide a pilot framework for future efficacy studies in disease-specific ALS models. This work establishes a translational platform for the development of future ALS therapies, with subsequent studies focused on efficacy testing in disease-specific models that more accurately reflect the slow, heterogeneous, multisystem nature of human ALS. Show less

Brain-derived neurotrophic factor (BDNF) is a neurotrophin with crucial roles in the developing and adult nervous system, contributing to neuronal survival, differentiation, and synaptic plasticity. The pleiotropic functions of BDNF require stringent spatiotemporal control of its expression, making BDNF one of the most thoroughly studied activity-regulated genes. Over the years, substantial evidence has accumulated, providing insights into BDNF gene structure, numerous mRNA variants, their different localization patterns and translational efficiencies, as well as the functions of the BDNF protein in different tissues. This review aims to summarize the current understanding of the mechanisms governing BDNF expression at transcriptional, posttranscriptional, and translational levels, offering an integrated perspective of BDNF regulation. Show less

Repetitive magnetic stimulation (rMS) is used to treat neurological conditions. Understanding its modulatory effects requires investigating cellular processes and molecular pathways Active (75-, 150-, and 300-sec exposure) or sham rMS was administered daily (4 days/300mT-1Hz) to two neuronal [SK-N-BE(2) and SH-SY5Y] and one non-neuronal (HOS) tumor line. Cell viability, cell death, and gene expression of Both neuroblastoma cell lines, SH-SY5Y (150-sec) and SK-N-BE(2) (75-sec), exhibited increased viability compared to the 300-sec group immediately after treatment; however, none of the stimulated groups was different from sham. rMS increased rMS did not affect cell viability or death in these Show less

Substance use disorders (SUDs) present a global health challenge with high relapse rates. Emerging evidence implicates gut microbiota dysbiosis in SUD pathophysiology via the gut-brain axis. This 24-week randomized controlled trial investigated whether precision exercise interventions could modulate the gut microbiota-emotion axis to improve psychological outcomes in individuals undergoing compulsory drug rehabilitation. Thirty male participants were randomized to a precision exercise group (n = 15; individualized aerobic + resistance training, 4-5 sessions/week) or control group (n = 15; standard rehabilitation activities). Multi-dimensional assessments included weekly fecal (16S rRNA sequencing), urine (SCFAs via GC-MS), and saliva samples (cortisol, serotonin, BDNF via ELISA), alongside psychological evaluations (SCL-90-R, POMS) and physiological measures. The exercise group exhibited significant increases in gut microbial diversity (Shannon index: +18.2%, p < 0.001; Cohen's d = 2.14) and enrichment of beneficial taxa (e.g., Faecalibacterium, Bifidobacterium; LDA >3.5). Urinary SCFAs increased markedly (butyrate: 3.12-fold, p < 0.001), correlating with elevated salivary BDNF (+82%, p < 0.001) and reduced cortisol (-41.1%, p < 0.001). Psychological outcomes improved substantially: SCL-90-R Global Severity Index decreased by 43.3% (p < 0.001), and 78.6% of exercise participants achieved clinically meaningful improvement. Machine learning models predicted treatment response (AUC = 0.91) using baseline microbiome features. Precision exercise restores gut microbiota homeostasis, enhances neuroactive metabolite production, and improves emotional regulation in SUD recovery. The gut microbiota-emotion axis represents a viable target for non-pharmacological interventions, with microbiome profiles enabling personalized treatment strategies. Show less

Brain-derived neurotrophic factor (BDNF) crosses the blood-brain barrier and may serve as a marker of neuroplasticity. This study evaluated whether serum levels of mature BDNF, proBDNF, and matrix metalloproteinase-9 (MMP-9) can predict functional recovery after stroke. In this prospective observational study, 93 patients with unilateral stroke and motor impairment were recruited. Clinical, and demographic data, as well as serum levels of mature BDNF, proBDNF, and MMP-9 were collected. Functional assessments measuring stroke severity, cognition, motor function, balance, and mood were conducted at three timepoints: after acute care (T0), 2 weeks post-rehabilitation (T1), and 3 months post-onset (T2). Mature BDNF significantly decreased from T0 to T2 (p = 0.003), while proBDNF remained stable. MMP-9 declined consistently across timepoints (p < 0.001). MMP-9 levels at baseline differed by BDNF genotype (p < 0.05). However, none of the biomarkers independently predicted functional recovery. Functional outcomes improved significantly over time (p < 0.001), with baseline functional scores being the strongest predictors at T1 and T2. Although these biomarkers were not independent predictors of recovery, their longitudinal trajectories may reflect underlying neurobiological recovery mechanisms during rehabilitation, although their prognostic utility remains inconclusive. Show less

Global studies have shown a bidirectional association of gestational diabetes mellitus (GDM) with postpartum depression (PPD). Despite high GDM prevalence in Pakistan (3.3%-17.8%), no prior studies have explored its link with PPD. In this study, association between GDM and risk of developing PPD was investigated and risk factors for PPD were identified using the gold-standard Edinburgh Postnatal Depression Scale (EPDS). Evidence suggests that PPD has strong genetic basis. The BDNF gene is a known candidate for PPD pathogenesis, while the orexin system is linked to arousal, energy metabolism, with emerging role in neuropsychiatric disorders. This study is the first study to explore association of orexin SNP ORX1 10914456 with PPD together with the BDNF SNP rs6265 (Val/Met66), among participants with and without GDM diagnosis. Among 1,000 women approached in hospitals of Islamabad, Rawalpindi, 800 met inclusion criteria (400 GDM, 400 non-GDM controls) and were genotyped for BDNF and orexin SNPs. Participants completed the EPDS 1 week postpartum. Using a cutoff of ≥13, 84.9% of GDM patients and 18% of non-GDM controls scored ≥13 on EPDS (χ2 = 78.337, p < 0.00001). Multivariate logistic regression revealed GDM diagnosis, BMI >25, fasting plasma glucose >126 mg/dL, 31-39-week gestation, <12 years of education, and urban locality as significant risk factors for PPD. GDM diagnosis increased odds of PPD by 2.5-fold (OR = 2.5, 95% CI: 21.48-4.31, p < 0.0001). The orexin SNP Orx1 10914456, CC genotype and BDNF SNP rs6265, AA genotype increased the odds of having higher EPDS scores in GDM patients by 3.11 (OR = 3.11, 95% CI: 1.29-7.47, p < 0.001) and 3.3 (OR = 3.3, 95% CI: 1.31-8.13, p = 0.04, p < 0.05), respectively, in comparison to other genotypic variants. Our study supports orexin and BDNF system-targeted therapies for PPD. Show less

The origins of major depressive disorder (MDD) are complex, involving both environmental influences and a substantial genetic contribution. Genetic polymorphisms have been implicated in modulating susceptibility, disease course, and treatment response, yet findings are often modest, population-dependent, and sometimes inconsistent. This narrative review synthesizes current evidence on genetic variants associated with MDD, highlighting well-replicated results while distinguishing exploratory or emerging findings. Key systems reviewed include serotonergic ( Show less