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N. Aladdin and S. A. Ghareib, "Vitamin D3 Exerts a Neuroprotective Effect in Metabolic Syndrome Rats: Role of BDNF/TRKB/Akt/GS3Kβ Pathway," Journal of Biochemical and Molecular Toxicology 38, no. 12 (2024): e70082, https://doi.org/10.1002/jbt.70082. The above article, published online on 09 December 2024 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Hari K. Bhat; and Wiley Periodicals, LLC. The retraction has been agreed upon following concerns raised by a third party regarding data reuse between this article and two other articles previously published elsewhere by the same authors. An investigation confirmed that there are substantial overlaps among the three papers. The authors provided some supporting data and explained that the three studies were related, and that data from a limited number of animals were shared to confirm the disease model. However, analysis of the data showed that the overlaps were not restricted to disease model validation. The editors have therefore lost confidence in the results presented in this article and consider the conclusions to be invalid. The authors disagree with the retraction. Show less

The accumulation and deposition of amyloid-beta (Aß) peptides is detrimental to neuronal networks and is driven by the cleavage of amyloid precursor protein (APP) by beta-secretase 1 (BACE1). The proteolytic processing of APP is tightly regulated by the opposing activities of BACE1 and ADAM10, with the latter producing a truncated, non-amyloidogenic fragment. Maintaining this balance is critical for normal physiological function, as complete inhibition of BACE1 has proven detrimental owing to the important physiological roles of its many substrates. Brain-derived neurotrophic factor (BDNF), an important mediator of neuronal function and survival, has recently been shown to reduce BACE1 activity in neural tissue, but the mechanism for this remains unknown. Previous research suggests that BACE1 cleavage of APP is favoured at acidic intracellular compartments, whereas non-amyloidogenic processing preferentially occurs at the plasma membrane. Hence, we hypothesized that BDNF alters the subcellular distribution of BACE1, reducing ß-cleavage of APP. Here, we show that acute BDNF treatment of differentiated neural cells (SH-SY5Y) reduced levels of sAPPß, a product of BACE1 cleavage of APP. Using confocal microscopy and quantitative image analysis, we found that this reduction in sAPPß levels is coincident with increased BACE1 localization to the plasma membrane, and a concomitant reduction of BACE1 localization to early endosomes. This effect appears to be independent of clathrin-mediated endocytosis (CME), as inhibition of CME by PitStop2 treatment increased a-cleavage of APP but did not reduce ß-cleavage independent of BDNF treatment. Hence, BDNF may reduce production of Aß by altering BACE1 distribution and decreasing upstream ß-cleavage. Show less

We investigated the association between maternal overactive bladder (OAB) and voiding dysfunction (VD) in their children, and evaluated urinary nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels as potential biomarkers for early identification of VD. This prospective cross-sectional study included 196 participants: mothers with OAB (n = 39), their children with VD (n = 36), their children without VD (n = 41), healthy mothers (n = 40), and healthy children of healthy mothers (n = 40). Maternal OAB was diagnosed using the OAB-V8 questionnaire, while VD in children was assessed using the Dysfunctional Voiding Symptom Score (DVSS). Urinary NGF and BDNF levels were measured via ELISA. Receiver operating characteristic (ROC) analyses were performed to assess the diagnostic accuracy of these biomarkers. NGF and BDNF levels were significantly higher in mothers with OAB compared to controls (p < 0.001 for both). Children of OAB mothers with VD demonstrated markedly elevated DVSS scores, NGF, and BDNF levels compared to both healthy children of OAB mothers and children of healthy mothers (all p < 0.001). ROC analysis showed strong diagnostic performance for NGF (AUC = 0.828, cut-off 267.7 pg/ml, 75 % sensitivity, 99 % specificity) and acceptable performance for BDNF (AUC = 0.754, cut-off 3.06 ng/ml, 64 % sensitivity, 93 % specificity). Urinary NGF and BDNF levels were significantly elevated in mothers with OAB and their affected children. NGF demonstrated superior diagnostic accuracy for identifying VD in children, while BDNF may provide complementary value. These findings support the role of neurotrophin-related mechanisms in intergenerational transmission of lower urinary tract dysfunction. Show less

Schizophrenia is a severe mental disorder whose molecular mechanisms remain poorly understood. Investigating brain-derived neurotrophic factor (BDNF)-dependent signaling pathways and their contribution to schizophrenia pathogenesis is a promising research direction in schizophrenia research. BDNF activates multiple intracellular cascades, among which the MAPK/ERK pathway plays a central role. In this study, expression levels of key regulatory proteins of the MAPK/ERK signaling pathway (ERK1/2, STAT3, STAT5, NF-κB, IGF1R, IRS1, IR, TSC2, and CREB1) were examined in lysates of peripheral blood mononuclear cells (PBMCs) from schizophrenia patients using multiplex analysis. The study group included 58 patients diagnosed with schizophrenia (F20); the control group included 60 healthy individuals. The results revealed significantly increased expression of ERK1/2 and STAT3, along with decreased NF-κB levels, in PBMCs from schizophrenia patients compared to controls. Moreover, patients with leading positive symptoms exhibited elevated expression of CREB1 and ERK1/2. These findings suggest that dysregulation of the MAPK/ERK signaling may play a significant role in the pathogenesis schizophrenia. BDNF-dependent signaling pathways may therefore represent promising targets for diagnostics and therapy of this disorder. Show less

Recent evidence suggests that reduced peripheral levels of brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of bipolar disorder (BD), although its relevance in young populations remains uncertain. This systematic review synthesized studies that evaluated serum BDNF levels in children and adolescents with BD, examining its potential as a risk marker. Following PRISMA 2020 guidelines and a protocol registered in PROSPERO, searches were conducted in the Cochrane, MEDLINE, SciELO, and Scopus databases. Studies including participants aged 0-19 years diagnosed with BD according to DSM criteria were included. Studies with mixed samples (adults, children and adolescents) without separate age-group analyses were excluded. After screening and eligibility assessment, seven studies were included. Five of them included a control group, from which a meta-analysis was performed. Moderate methodological heterogeneity was observed and corrected after sensitivity analysis, reinforcing the robustness of the findings, although no statistically significant difference in serum BDNF levels was found between patients with bipolar disorder and controls. Current evidence does not support BDNF as a diagnostic biomarker for pediatric BD. Future studies with greater sample power and methodological standardization are needed to clarify its role in the risk and course of early-onset bipolar disorder. Show less

Huntington's Disease (HD) is a neurodegenerative ailment characterized by progressive motor, cognitive, and psychiatric decline, linked with mitochondrial dysfunction, oxidative stress, and neuroinflammation. Few effective treatments are available for Huntington's. Additionally, the therapeutic effects of natural polysaccharides against neurodegenerative disorders have not yet been fully explored. This study aimed to investigate the neuroprotective potential of Aloe Polysaccharides (APs) against 3-Nitropropionic Acid (3- NPA)-initiated HD-like symptoms in rats. Adult male rats were allocated to control, 3-NPA-treated, and APs-treated groups (100 and 200 mg/kg orally) following 3-NPA administration. Behavioral assessments (rotarod, open field, narrow beam walking) and biochemical analyses, including neurotransmitters [Acetylcholinesterase (AChE), Acetylcholine (ACh), Dopamine (DA), Norepinephrine (NE), Serotonin (5-HT), Gamma-Aminobutyric Acid (GABA), Glutamate (Glu)], oxidative/nitrative stress markers [Malondialdehyde (MDA, Nitric Oxide (NO)], antioxidant enzymes [Superoxide Dismutase (SOD), Catalase (CAT), Glutathione (GSH)], mitochondrial enzyme [Succinate Dehydrogenase (SDH)], inflammatory mediators [Nuclear Factor Kappa B (NF-κB), Tumor Necrosis Factor Alpha (TNF-α), Interleukin- 1 Beta (IL-1β), Cyclooxygenase-2 (COX-2)], neurotrophic factor [Brain-Derived Neurotrophic Factor (BDNF)], and apoptotic markers (caspase-3, caspase-9, B-Cell Lymphoma 2 (Bcl-2), Bcl-2-Associated X Protein (Bax)] were performed. Additionally, the impact of APs on regulators of mitochondrial biogenesis and antioxidant response [Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), Sirtuin 1 (Sirt1), Heme Oxygenase-1 (HO-1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PGC-1α), Adenosine Monophosphate-Activated Protein Kinase (AMPK), Uncoupling Protein 1 (UCP1), Uncoupling Protein 2 (UCP2)] was evaluated. Histopathological examination of the striatum was conducted. Statistical analysis was performed using one-way ANOVA followed by Tukey's post hoc test. 3-NPA administration induced significant motor deficits, neurotransmitter imbalance, elevated oxidative stress, inflammation, mitochondrial impairment, BDNF depletion, apoptosis, and striatal degeneration (P < 0.01). APs treatment significantly (P < 0.01; P < 0.001) reversed 3-NPA effects and improved behavioral performance (rotarod latency, OFT exploratory activity, and beam walk score); restored neurotransmitter balance; improved antioxidant enzymes (SOD, CAT, and GSH); mitigated MDA and NO effects; suppressed NF-κB, TNF-α, IL-1β, and COX-2; elevated BDNF and SDH activities; mitigated apoptosis (caspase-3 and 9, BAX, and BCl-2); and preserved striatal structure. APs showed neuroprotective potential in 3-NPA-induced HD rats by modulating the BDNF/NF-κB/Nrf2 pathway, controlling oxidative stress and neuroinflammation, restoring neurotransmitter function, and arresting striatal damage. Treatment with Aps markedly upregulated the levels of mitochondrial biogenesis-related proteins (Sirt1, PGC-1α, AMPK, UCP1, and UCP2) and antioxidant defense mediators (HO-1 and NQO1). In addition to behavioral and biochemical improvements, this study uniquely demonstrates that APs upregulate genes central to the mitochondrial biogenesis pathway, suggesting a new mechanistic basis for their neuroprotective effects in 3-NPA-induced HD. The study results showed that Applied Physiology Solution (APS) enhanced behavioural characteristics and neurotransmission function while simultaneously reducing the inflammatory response and cell stress and preserving striatal tissue structure. These findings reveal that APs promote neuroprotection not only by modulating oxidative stress, neuroinflammation, neurotransmission, and apoptosis, but also by specifically upregulating genes in the mitochondrial biogenesis pathway, highlighting their potential as a natural therapeutic candidate for HD management. Show less

Major depressive disorder (MDD) is a debilitating neuropsychiatric condition characterized by persistent low mood, affecting approximately 322 million individuals worldwide. With a staggering 15% mortality rate due to suicide among patients, MDD represents a critical global health challenge. Emerging evidence implicates microRNAs (miRNAs) in the pathogenesis of neuropsychiatric disorders; however, the role of miR-146a-3p in MDD-particularly its mechanistic involvement and potential as a diagnostic biomarker-remains unexplored. In this study, we integrated multi-database bioinformatics analyses with experimental validation to identify miR-146a-3p as a key regulator of MDD progression. Our computational screening revealed miR-146a-3p as a putative risk-associated non-coding RNA, alongside brain-derived neurotrophic factor (BDNF), a well-established MDD susceptibility gene. In vivo studies demonstrated a significant upregulation of miR-146a-3p and concurrent downregulation of BDNF in MDD model mice. Further bioinformatic predictions and dual-luciferase reporter assays confirmed a direct interaction between miR-146a-3p and BDNF mRNA, leading to post-transcriptional suppression of BDNF expression. Mechanistically, miR-146a-3p overexpression impaired synaptic plasticity, as evidenced by reduced levels of key synaptic proteins such as postsynaptic density protein 95 (PSD95) and synapsin (SYN-1), while in vitro transfection experiments validated its negative regulation of BDNF. Critically, intranasal delivery of a miR-146a-3p antagomir or exogenous BDNF protein rescued depressive-like behaviors in murine models, as assessed by open-field, forced swim, and tail suspension tests. These interventions restored synaptic protein expression and ameliorated behavioral deficits, suggesting a therapeutic avenue for MDD. Our findings establish miR-146a-3p as a pivotal epigenetic modulator of MDD pathogenesis, acting through direct suppression of BDNF-dependent synaptic plasticity. The reversibility of this pathway via antagomir inhibition highlights miR-146a-3p's dual potential as both a diagnostic biomarker and a therapeutic target. This study provides foundational insights for developing miRNA-based interventions in mood disorders. Show less

Brain-derived neurotrophic factor (BDNF) is a key regulator of neuroplasticity, synaptic integrity and cognitive function and its dysregulation has been implicated across major psychiatric disorders. However, its transdiagnostic association with cognitive performance remains incompletely understood. In this cross-sectional study, 160 participants were examined, including individuals with schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD) and healthy controls (HC) (n = 40 per group). Serum BDNF concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA), Trail Making Tests (TMT-A/B) and Digit Span (Forward/Backward). Significant group differences were observed for both serum BDNF levels and cognitive performance. Serum BDNF concentrations were lowest in SCZ (18.2 ± 4.6 ng/mL) and MDD (19.5 ± 5.1 ng/mL), intermediate in BD (23.7 ± 5.9 ng/mL) and highest in HC (26.3 ± 6.2 ng/mL) (F(3156) = 15.47, p < 0.001). Cognitive impairment followed a parallel gradient, with SCZ exhibiting the most severe deficits (p < 0.001). Across the full cohort, serum BDNF showed moderate positive associations with global cognition (MoCA: r = 0.42, p < 0.001) and working memory (Digit Span Backward: r = 0.38, p < 0.001) and a negative association with executive dysfunction as indexed by TMT-B completion time (r = -0.46, p < 0.001). These findings indicate that serum BDNF is modestly but consistently associated with cognitive performance across major psychiatric disorders, supporting its role as a transdiagnostic neurobiological correlate of impaired neuroplasticity rather than a disorder-specific or deterministic biomarker. Show less

The formulation of therapeutic proteins such as Brain-Derived Neurotrophic Factor (BDNF) remains difficult because of their inherent instability and limited bioavailability, especially in central nervous system delivery. In this study, we propose an integrated computational-experimental workflow for the rational selection of excipients to optimize BDNF-loaded cubosomal formulations. Structure-based computational analyses-including SiteMap evaluation, molecular docking, and molecular dynamics (MD) simulations-were used to characterize potential binding sites, and assess the molecular compatibility of lipids, stabilizers, and hydrotropes with BDNF. Among the screened excipients, phytantriol showed the most favorable polar and hydrophobic interactions with the protein, while Tween 80 and PEG 200 were identified as the preferred stabilizer and hydrotrope, respectively. The MD trajectories revealed that protein-excipient contacts were transient yet overall stabilizing, helping the protein maintain its conformational integrity under simulated conditions. Experimental confirmation using Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy supported these observations by demonstrating that BDNF's secondary structure was preserved in the presence of the selected excipients. This study provides molecular-level insight into excipient-protein interactions and demonstrates a predictive strategy for guiding the design of stable neurotrophin formulations. Show less

Brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal development and synaptic plasticity across various maturation stages. However, the extent to which BDNF modulates the neuronal transcriptome to mediate these effects, and the gene clusters most responsive at each culture stage, remain poorly understood. To address this, we investigated the time-dependent effects of BDNF on the transcriptomes of cultured cortical neurons at different culture durations. We found that the magnitude of the transcriptomic response to a 6-h BDNF treatment, relative to untreated controls, increased with longer culture duration. Furthermore, a BDNF-induced shift towards a more mature-like transcriptional state was observed specifically in neurons cultured for shorter durations, suggesting a response dependent on the length of time in culture. Specifically, matrix metalloproteinase 3 (MMP3) was robustly induced by BDNF. Single-nucleus RNA sequencing (snRNA-seq) revealed that this induction was primarily localized to Lhx6-positive inhibitory neurons. Additionally, BDNF regulated the expression of various ligand and receptor genes through a combination of cell type-specific and non-specific mechanisms. These findings provide a comprehensive view of BDNF-mediated transcriptional regulation over the course of cortical neuron culture. Show less

Acute exercise modulates circulating exerkines and affective states, yet it remains unclear whether mind-body exercise modalities, such as yoga, elicit responses observed in aerobic exercise. This study examined the acute effects of yoga, stretching, moderate-intensity aerobic exercise, and low-intensity aerobic exercise on exerkines and affect. Eighty-eight adults (52% female; mean age = 23.3 ± 5.79 years) were randomized to one of two study arms: aerobic exercise (moderate-intensity = 70-75% heart rate max and low-intensity = 40-50% heart rate max) or mind-body exercise (yoga and stretching). At two laboratory visits, participants completed 30-minutes of each condition within their assigned arm in a counterbalanced order. Venous blood collected immediately before and after exercise was analyzed for brain-derived neurotrophic factor (BDNF) and endocannabinoids (N-arachidonoylethanolamine [AEA], 2-arachidonoylglycerol [2-AG]). State anxiety and positive and negative affect were assessed pre- and post-exercise. Linear mixed-effects models tested pre-to-post changes and condition interactions. Moderate-intensity aerobic exercise increased circulating concentrations of AEA (b = 0.10, p = .005), while 2-AG and BDNF concentrations were unchanged across conditions. All four exercise conditions decreased state anxiety and negative affect, whereas only yoga, stretching, and moderate-intensity aerobic exercise increased positive affect. Pre-to-post AEA increases were correlated with changes in positive affect (b = 0.18, p = .041). In this randomized study-arm design, moderate-intensity aerobic exercise uniquely increased AEA, whereas affective improvements were observed across modalities. These findings implicate cardiovascular intensity in the endocannabinoid response to exercise, while diverse forms of acute exercise are associated with short-term affective benefits. Show less

Press needle therapy, may alleviate depressive-like behaviors. Male rats were randomly allocated into four groups ( Press-needle ameliorated depressive-like behaviors in CUMS-exposed rats, restored body weight gain and improved behavioral performance. The treatment upregulated the hippocampal BDNF/TrkB/CREB signaling pathway, increasing BDNF, TrkB, CREB, AKT, and PI3K in the hippocampus. The therapy modulated serotonergic neurotransmission by increasing hippocampal 5-HTT expression, while downregulating 5-HT1A and 5-HT2C receptors and PKA. Notably, press-needle exerted anti-neuroinflammatory effects, reducing hippocampal and serum levels of TNF-α and IL-6. Histopathological analysis confirmed its neuroprotective efficacy, demonstrating attenuated neuronal damage in hippocampal tissues. Show less

This study investigated the expression of brain-derived neurotrophic factor (BDNF) signaling components (BDNF-TrkB-AKT1) and apoptosis-related factors (Bcl-2 and Bax) in yak brain regions at different altitudes. The cerebral cortex, cerebellum, hippocampus, thalamus, and medulla oblongata were collected from 3-year-old yaks living at low and high altitudes. The relative mRNA expression of BDNF, TrkB, AKT1, Bcl-2, and Bax was assessed by qRT-PCR. Protein abundance and cellular localization of BDNF, TrkB, AKT1, Bcl-2, and Bax were evaluated by Western blotting and immunohistochemistry, with immunoreactivity quantified by optical density analysis. Within each altitude group, BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and the corresponding protein levels (BDNF, TrkB, AKT1, and Bcl-2) were significantly higher in the cerebral cortex and hippocampus than in the cerebellum, thalamus, and medulla oblongata (P < 0.05). In contrast, Bax mRNA and Bax protein levels did not differ significantly among the five regions. Compared with low-altitude yaks, high-altitude yaks showed significantly higher BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and higher BDNF, TrkB, AKT1, and Bcl-2 protein levels in brain tissues (P < 0.05), whereas Bax protein expression did not differ between altitude groups. Immunohistochemistry revealed immunoreactivity for BDNF, TrkB, AKT1, Bcl-2, and Bax in both altitude groups, with prominent labeling in cortical pyramidal neurons and across the pyramidal cell layer in the hippocampal CA region. Immunoreactivity was also detected in large neurons of the thalamus and medulla oblongata. In the cerebellum, labeling was strongest in Purkinje cells, with weaker signals in the granule cell layer and molecular layer. BDNF-TrkB-AKT1 pathway components and Bcl-2 showed relatively higher expression in the cerebral cortex and hippocampus within each altitude group, whereas Bax expression did not vary across regions. These patterns are consistent with an association between BDNF-TrkB-AKT1 signaling and increased Bcl-2 expression without a corresponding increase in Bax, which may support neuronal adaptation in the cerebral cortex and hippocampus. Elevated expression of BDNF, TrkB, AKT1, and Bcl-2 at high altitude suggests enhanced adaptation to hypoxia in high-altitude yaks; the underlying mechanisms require further investigation. Show less

Chaihu Shugan San (CSS), a classical Traditional Chinese Medicine (TCM) formula, was first recorded in Jingyue Quanshu (1624 AD) for treating "liver qi stagnation" (Yu Syndrome), a TCM diagnostic pattern analogous to modern mood disorders. Although CSS has been prescribed for emotional distress, irritability, and depressive symptoms for centuries, the neurobiological mechanisms underlying its antidepressant efficacy, particularly in the context of gender-specific pathology, remain poorly revealed. The present study probed the antidepressant effects of CSS in female mice, while elucidating the underlying molecular mechanisms involving hippocampal neuroinflammation and neuroplasticity. We hypothesized that CSS reverses chronic stress-induced depressive phenotypes by suppressing interleukin-6 (IL-6), which in turn facilitates cAMP-CaMKII-BDNF signaling pathway in the hippocampus. Adult female C57BL/6J mice were subjected to a 5-week chronic unpredictable mild stress (CUMS) regimen to evoke depressive-like behaviors. During the final 2 weeks of the regimen, CSS was administered intragastrically at 0.5, 1.0, or 1.5 g/kg, with fluoxetine (10 mg/kg) as the positive control. Behavioral assessments included forced swimming test (FST), sucrose preference test (SPT), open field test (OFT), and tail suspension test (TST). Hippocampal IL-6, cAMP, CaMKII, and BDNF levels were quantified by ELISA. Mechanistic validation employed acute hippocampal microinjection of recombinant IL-6 (1 μg/site) and systemic administration of the CaMKII inhibitor KN-93 (6 mg/kg). Chemical constituents were identified by UHPLC-QTOF MS. CSS alleviated CUMS-induced depressive-like behaviors in a dose-dependent manner, cutting down immobility time in TST/FST and reinstating sucrose preference, similar to the action of fluoxetine. CSS significantly suppressed hippocampal IL-6 while upregulating cAMP, CaMKII activity, and BDNF expression. Acute IL-6 elevation completely abolished both the behavioral antidepressant effects and molecular actions of CSS. Pharmacological inhibition of CaMKII blocked CSS-induced behavioral improvement and its upregulation of cAMP-BDNF signaling, without affecting basal behaviors. CSS exhibited no anxiogenic or locomotor side effects. CSS exerts potent antidepressant effects in female mice through coordinated suppression of hippocampal IL-6 and activation of the cAMP-CaMKII-BDNF neuroplasticity-related pathway, with CaMKII playing a critical role in this process. These findings offer scientific evidence for the traditional use of CSS in addressing emotional disorders and highlight its therapeutic potential as a multi-targeted, anti-inflammatory botanical medicine for female-specific depression. Show less

A single nucleotide polymorphism in the brain derived neurotrophic factor (BDNF)-encoding gene leads to diminished BDNF signaling resulting from Val66Met and has been linked to obesity. Previous imaging studies regarding the impact of BDNF Val66Met on the central serotonin system, which is involved in behavior, cognition and control of satiety, have not focused on body weight or food-intake related behavior. We revisited a cohort of thirty non-depressed individuals with obesity and 15 normal-weight controls. 29 obese and 13 controls underwent [ Show less

Premature ejaculation (PE) is one of the most common forms of male sexual dysfunction, yet its underlying neurobiological mechanisms remain unclear. This study aims to explore the role of S100 calcium-binding protein B (S100B) in PE and its regulatory relationship with brain-derived neurotrophic factor (BDNF) and serotonin (5-HT) signaling. A rat model of PE was established using behavioral screening criteria. Sexual behavior parameters were recorded, and the expression levels of S100B, BDNF, and 5-HT in brain tissues were measured using enzyme-linked immunosorbent assay, quantitative real-time PCR, Western blotting, immunohistochemistry, and immunofluorescence. The impact of S100B knockdown on PE-related behaviors and molecular expression was evaluated. The primary outcome was the effect of S100B regulation on PE-related behaviors and its interaction with the BDNF/5-HT signaling pathway. PE rats exhibited classical behavioral features, including shortened ejaculation latency and increased ejaculation frequency. Transcriptomic and protein analyses showed that S100B expression was significantly upregulated, while BDNF and 5-HT levels were markedly reduced in PE rats. S100B expression increased across several brain regions. Knockdown of S100B restored 5-HT and BDNF levels, prolonged ejaculation latency, and alleviated PE behaviors. BDNF overexpression elevated 5-HT levels and improved sexual behavior. Importantly, BDNF silencing reversed the beneficial effects of S100B knockdown, suggesting that S100B regulates ejaculation via the BDNF/5-HT pathway. Targeting S100B and its regulation of the BDNF/5-HT pathway may provide potential therapeutic strategies for managing premature ejaculation. Strengths include comprehensive molecular and behavioral analyses in a rat model provide insights into PE pathophysiology. Although this effect has been demonstrated in animal models, these models may not fully recapitulate the pathophysiological processes of human PE, and further clinical validation is required. Our findings indicate that S100B is upregulated in PE and may contribute to the pathophysiology of PE by modulating the BDNF/5-HT signaling pathway. This study provides a molecular basis for the development of therapeutic strategies targeting PE. Show less

The underlying mechanisms for exacerbated brain injury and poor recovery observed in patients with diabetes and ischemic stroke (IS) remain undetermined. We explored the role of microRNA-34a (miR-34a) in diabetic IS (DMIS) and ischemic postconditioning (IPOC)'s neuroprotective effects in tree shrews. We established a tree shrew DMIS model and exposed it to interventions, including miR-34a inhibition (antagomir), IPOC, and miR-34a overexpression (agomir). Infarct size and pathology were assessed via staining. Cellular/molecular changes (astrocytes, neurons, brain-derived neurotrophic factor [BDNF], Sine oculis homeobox 3 [SIX3], proliferation, apoptosis, axon formation) were analyzed using immunofluorescence, polymerase chain reaction (PCR), and Western blotting. In vitro, miR-34a's targeting of BDNF/SIX3 was validated, with rescue experiments testing regulation via these factors. Infarct size and neuronal damage were greater in the DMIS group than in the nondiabetic IS group. miR-34a inhibition or IPOC reduced infarcts, alleviated injury, improved cell survival, upregulated BDNF/SIX3, enhanced proliferation/axon formation, and reduced apoptosis. miR-34a overexpression reversed IPOC's benefits. In vitro, miR-34a directly targeted BDNF/SIX3, suppressing their expression; exogenous BDNF/SIX3 rescued neurotoxicity and restored function. IPOC exerts partial neuroprotection through miR-34a downregulation, highlighting miR-34a as a potential therapeutic target. Show less

Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder that occurs most frequently in early childhood, affecting approximately 1% of the global population. Currently, the elusive nature of the pathological mechanisms underlying ASD precludes the existence of a definitive, effective treatment approach. In this study, we have successfully generated a novel ASD rat model utilizing CRISPR/Cas9 technology, offering a promising platform for further investigation and potential therapeutic interventions. The model is characterized by two crucial point mutations occurring at key enzyme cleavage sites of brain-derived neurotrophic factor (BDNF), thereby causing disruptions in enzyme cleavage processes. The phenotypes of this rat model faithfully recapitulate the salient deficits frequently encountered in ASD patients, exhibiting impairments in social behavior, cognition, and anxiety, along with neuronal abnormalities with key brain regions, notably the hippocampus (HPC) and medial prefrontal cortex (mPFC). Through preliminary RNA-seq analysis, we found changes in gene expression patterns related to synapses and neuronal excitability in these areas, providing new insights into the pathogenesis of ASD. Furthermore, our utilization of 7,8-dihydroxyflavone (7,8-DHF), a robust enhancer for the upregulation of both BDNF and TrkB mRNA and simultaneously activates the BDNF-TrkB signaling pathway, appears to strengthen the BDNF-TrkB signaling cascade. This intervention modifies firing patterns of neuronal spikes and synaptic transmission, which may contribute to the amelioration of ASD-like social interaction behavior exhibited in BDNF Show less

Exercise has been shown to support brain health, cognitive function, and increase levels of brain-derived neurotrophic factor (BDNF). While BDNF is known to support the central nervous system through improved brain metabolism, vasculature, neurotransmission and synaptic plasticity, the association between exercise-induced changes in BDNF concentrations and exercise-related cognitive improvements is still unclear. This study investigated the relationship between exercise-induced changes in plasma BDNF (pBDNF) and serum BDNF (sBDNF), and haemodynamic indicators of prefrontal cortex function in sedentary adults. Participants (n = 23, female = 7) were randomized into intervention (12-week cycling programme) and control groups (no intervention). Participants completed V̇O Show less

To compare the effects of Mexidol, Cerebrolysin, and Cortexin on the levels of brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF The study was performed on male Wistar rats. Right MCA occlusion-reperfusion was modeled using the method of J. Koizumi (1986). The occlusion duration was 60 minutes (1 hour). At the onset of reperfusion, animals were administered a single intravenous injection of either saline (control), or Mexidol (ethylmethylhydroxypyridine succinate) intravenously at a dose of 50 mg/kg, or Cerebrolysin intraperitoneally at a dose of 215 mg/kg, or Cortexin intraperitoneally at a dose of 1 mg/kg. Twenty-four hours after the start of reperfusion, the brain lesion volume was analyzed after staining with a 1% solution of 2.3,5-triphenyltetrazolium chloride. Western blotting was used to assess the levels of BDNF, TNF In the MCA occlusion-reperfusion model, the necrosis volume in the affected hemisphere of control animals was 38.16±5.98%. Mexidol reduced the necrosis volume to 20.48±2.33% ( Thus, when administered at the onset of reperfusion following MCA occlusion, Mexidol exerts the most pronounced cerebroprotective effect, stimulating neurogenesis and suppressing the development of neuroinflammation and apoptosis. Show less

This study examines neuroanatomical and molecular changes that may be responsible for cognitive impairment in the BTBR mouse model of autism. Compared to control C57Bl/6 mice, BTBR mice exhibited cognitive inflexibility, impaired in an operant learning task. MRI revealed significant brain abnormalities, including reduced cortical volume, smaller ventricles, and asymmetry in the dorsal hippocampus, accompanied by neuronal loss. BTBR mice also showed impaired cerebrospinal fluid dynamics, with reduced production and outflow. Molecular analysis revealed brain region-specific reduction in the expression of Bdnf exons 1, 2, 3, and 4 in untrained BTBR mice. Furthermore, learning induced changes in transcription of Bdnf exons exclusively in BTBR. Elevated proBDNF levels and an increased proBDNF/mature BDNF ratio in the frontal cortex and striatum indicated aberrant BDNF processing. These findings suggest that ASD-related cognitive impairments are linked to a complex of neurodevelopmental abnormalities, potentially connected to disrupted transcription, processing, and signaling of BDNF. Show less

We examined whether seven consecutive days of warm-water immersion could elevate resting and exercise-induced levels of brain-derived neurotrophic factor (BDNF), irisin and klotho in older adults. These biomarkers support cognitive and metabolic health, but their levels decline with age. Passive heat exposure, like warm-water immersion, may offer a promising alternative to exercise for enhancing cellular-level physiological resilience in populations where exercise is limited. Twelve habitually active older men (median [IQR] age: 68 [64-73] years; Show less

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

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

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

The vital role of brain-derived neurotrophic factor (BDNF) in neuronal development, synaptic plasticity, and neuroprotection has been explored for decades. Therefore, the expression, processing, and signalling activities of this neurotrophin, which is reliant upon TrkB and p75NTR receptors, have been well characterised in both health and disease. This review summarises the latest findings on BDNF dysregulation in neuropathologies. Indeed, across diseases of both the central and peripheral nervous systems, BDNF signalling is frequently disrupted, contributing to neuronal dysfunction and degeneration. Consequently, through direct or indirect enhancement of its expression and/or function, BDNF has proved to be a promising therapeutic target across many neurological conditions. However, the complexity of its regulation and interaction with several different receptors underpins the need for further research to deepen our understanding of BDNF disruption in neuropathologies and to achieve its therapeutic potential. Show less

The laminins are a family of extracellular matrix proteins that regulate numerous cellular processes, including adhesion, neurite outgrowth, and axon guidance. However, it remains unclear whether laminin regulates axon guidance through local translation. Here, we show that laminin is necessary for local translation in axonal growth cones. Local translation is significantly increased in growth cones of embryonic day 17 mouse cortical neurons, either cultured on or acutely stimulated with soluble laminin 111, in the presence of BDNF. When cultured on laminin isoforms 211 or 221 in the presence of BDNF, there was a remarkable decrease in local translation in growth cones. Using a puromycin-proximity ligation assay to examine newly synthesized β-actin specifically, we find a significant increase in growth cones of neurons cultured on laminin 111 in the presence of BDNF. However, soluble laminin 111 alone results in a significant reduction in nascent β-actin protein synthesis. These results indicate that laminin isoforms can act in multiple ways, including synergistically with guidance cues and independently, to modulate local mRNA translation, thereby differentially influencing axon growth and guidance during development. Local translation in axons is critical for axon guidance. Laminin, a key component of the extracellular matrix, is necessary to induce local translation and thus mediate axon growth and guidance. Show less

We aim to verify clinical (depressive symptoms, rates of psychiatric admissions, and suicide attempts) and neurobiological (Brain-Derived Neurotrophic Factor - BDNF) changes in outpatients with depression undergoing evidence-based psychotherapies (EBP) over a 6-month follow-up. Longitudinal, naturalistic, prospective study, with 47 outpatients undergoing EBP, and 48 healthy controls (HC) for the BDNF levels comparisons. Data were collected at baseline and 6-month follow-up. Statistical analysis was performed using a paired t-test and a multiple linear regression model. BDI scores did not differ between baseline and 6-month follow-up (p = 0.253), and the rates of hospitalizations and suicide attempts at 6-month follow-up were 4.2% (2 cases reported). All patients were using psychotropics. BDNF levels at baseline and after 6-month follow-up did not vary significantly in the patient group (p = 0.314). There was no difference between patients' BDNF levels at baseline and HC BDNF levels (p = 0.211) and between patients' BDNF levels at 6-month follow-up and HC BDNF levels (p = 0.772). Using a mood stabilizer increased the BDNF levels. BDNF levels remained stable. Adding psychotherapy to medication may be associated with low rates of suicide attempts and psychiatric admissions in our sample. Our findings reinforce the importance of combined treatment in preventing adverse outcomes in naturalistic settings. Evidence supports the clinical effectiveness and economic efficiency of psychotherapy for patients with mental disorders, suggesting that outpatient psychotherapy can benefit healthcare systems and patients. Our findings corroborate the literature and reinforce the importance of psychotherapy associated with pharmacotherapy (combined treatment) to prevent outcomes such as further hospitalizations and suicide attempts, even in individuals with a history of severe psychiatric conditions. Research on how psychotherapy works, in terms of psychological mechanisms and its underlying effects on biological processes, is crucial. Scientific evidence makes it possible to include psychotherapies in public health policies worldwide, benefiting individuals suffering from mental disorders. Evidence from naturalistic designs is scarce in the literature. Show less