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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

Buchanania lanzan Spreng. (Anacardiaceae) seeds (BLHA) are the cheaper alternative to almonds used in the confectionery industry. The flour powder of seeds is used as a thickening agent to prepare sauces and flavourings for a batter. The socioeconomic importance of this species lies in its medicinal properties for curing diabetes. The study explored the multifaceted neuroprotective role of BLHA (500 mg/kg) in hyperlipidic high-fat diet streptozotocin (HFD/STZ)-induced type2 diabetic neuropathy (T2DN) rats via glucose metabolism, insulin resistance, and inflammation to mitigate nerve damage. Molecular docking analysis was performed to identify specific molecular targets of bioactive compounds in T2DN pathogenesis. Serum diabetic parameters, such as serum glucose (SG), insulin (SI), total protein (TP), triglycerides (TG), blood urea nitrogen (BUN), creatinine (Cr), HDL-C, and LDL-C, were studied. A strong correlation between HbA1C and insulin resistance assessed by HOMA-IR. Oxidative stress triggers the production of free radicals, so the antioxidant indicators in serum, tissues, and proinflammatory cytokines in the liver, brain, and pancreas were measured in T2DN rats. Effects on neurochemicals, BACE1, Aβ BLHA at 500 mg/kg significantly improved hyperglycemic (SG, SI, HOMA-IR, HbA1C), hepatic (AST, ALT, ALP, TP, TB), dyslipidemic (TC, TG, HDL-C, LDL-C), and kidney function markers (creatinine, BUN) in T2DN rats. BLHA restored oxidative (CAT, GSH, SOD, MDA) and cytokine markers (TNF-α, IL6) in the liver, pancreas, and brain cortex. Oxidative stress-impaired neurotransmitters were alleviated by enhancing cholinesterase (AChE, BChE) and BACE1 activities, and by ameliorating Aβ The multifaceted actions of dietary polyphenols, antioxidants, and antidiabetic compounds (Catechol, 2-Hydroxy-5-methylbenzaldehyde, 8-Octadecenoic acid methyl ester, n-Hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl)ethyl ester, β-Sitosterol, Hexadecenoic acid methyl ester) in BLHA modulated glucose metabolism, restored HOMA-IR, and reduced inflammation by protecting against oxidative stress, as a result, it improved neurotransmission and reduced neuropeptide aggregation in T2DN rats. The dock score of β-sitosterol (AChE: -12.7; BChE: -14.8; IL6: -9.8; and Atp1a3: -13.3 kcal/mol) correlated with the experimental evidence. Show less

Diagnosis of affective disorders among adolescent population links with the high risk of suicide attempt. The use of clinical psychological scales and biological markers may help to understand the background of suicidal process. Here we present the exploratory data study on retrospective suicide attempt risk factors and classification model of diagnosis conversion from major depressive disorder to bipolar disorder among adolescent population. This retrospective classification study was conducted on 45 adolescent/early-adulthood patients with the diagnosis of major depressive disorders. The psychological profile of patients was assessed with the use of standard clinical scales, like: Defence Style Questionnaire, Barrat Impulsiveness Scale, Beck Depression Inventory, Family APGAR, Emotional Intelligence Questionnaire and Temperament and Character Inventory. We assessed also the baseline concentration of blood-serum proteins: brain-derived neurotrophic factor, proBDNF, epidermal growth factor, macrophage migration inhibitory protein, and Stem Cell Factor. Suicide attempt history was determined at baseline (lifetime occurrence). The machine learning were used to assess the classification of the risk of suicidal attempt as well as diagnosis conversion from major depression to bipolar disorder. The winning models of machine learning were logistic regression and random forest. Regarding the suicidal attempt risk classification, significant coefficient were found mainly in Hamilton Depression Rating Scale (both factor and item assessment) and Temperament and Character Inventory (AUC = 0.74 (95% CI: 0.53-0.91), permutation p = 0.003). Serum biomarkers showed no discriminative ability (AUC = 0.35-0.40, p > 0.5) for suicide attempts in the past. We found not reliable clinical and biological data on the diagnosis conversion prediction. Clinical psychological scales, not peripheral biomarkers, distinguished suicide attempters in this exploratory analysis. Show less

Upwards of 50% of people do not respond to the primary treatment modalities for major depressive disorder (MDD), which has led to increased attention and use of alternative methods, including exercise and psychedelics. While interventions using either exercise or psychedelics have demonstrated largely positive results in isolation, their synergistic potential has yet to be explored. As such, this commentary provides an overview of exercise/psychedelics as a treatment for depression and their potential synergy and/or complementarity. From a biological perspective, psychedelics acutely enhance brain-derived neurotrophic factor (BDNF) signalling, while exercise provides sustained BDNF elevation; psychedelics enhance neuroplasticity largely in the cortex (with only modest effects in the hippocampus), while exercise boosts hippocampal neurogenesis; psychedelics increase glutamate release via stimulation of 5-HT Show less

Transcriptomics provides mechanistic insights into chemical toxicity and serves as a hypothesis-generating tool for prioritizing potential adverse outcomes. Here, we introduced a transcriptomics-guided outcome prediction (T-GOP) framework, a hypothesis-informed approach that uses transcriptomic enrichment to prioritize end points for targeted experimental validation. As a case study, the ecotoxicological effects of the PFOS alternative, sodium Show less

Exposure to a Western diet during gestation and lactation adversely impacts offspring mood, learning, and memory. We determined if high dose maternal methyl donor nutrient (MDN) supplementation ameliorated the effects of a high fat/high sucrose (HFS) diet during gestation and lactation on the behavior of young, adult offspring. Rat dams consumed the following diets through gestation and lactation: [1] AIN93G control (CON) diet, [2] 45% fat diet with sucrose (HFS), [3] CON diet supplemented with folic acid, B MDN supplementation increased depression-related behavior regardless of maternal base diet (P = 0.003). Learning under stress was reduced in offspring of MDN supplemented dams evidenced by fewer SBET escapes (P = 0.042) and increased escape latency in FR1 trials (P = 0.037). MDNs did not alter novelty reactivity, anxiety-related behavior, or working memory but improved reference memory (P = 0.023). MDNs did not affect corticosterone, reduced BDNF when dams consumed the HFS diet (P = 0.025), and tended to increase DNA methylation (P = 0.065). Maternal MDN supplementation increased depression-related behavior and decreased learning under stress, indicating high dose MDN supplementation may not be warranted. Show less

Prior studies indicate sex-specific obesity-frailty interactions, with postmenopausal estrogen decline increasing sarcopenic obesity risk and inflammation in women. This study evaluated circulating cytokines (IL-6, TNF-α), adipokines (adiponectin, resistin), myokines (GDF-15, BDNF, myostatin), health-related biomarkers (IGF-1, IGFBP-3), and physical performance (five-times chair stand, grip strength) in pre-frail and frail older adult women classified as having low appendicular lean mass (LALM), obesity, or obesity plus LALM. In this cross-sectional study, community-dwelling women aged ≥65 years from São Paulo, Brazil were screened (July 2022-September 2023); among 280 eligible, 88 met Fried frailty criteria. Body composition was assessed by DXA and participants were categorized as LALM (<20th percentile of residuals, -1.45), obesity (body mass index, BMI ≥30 kg/m Among 88 frail women (72.7% pre-frail and 27.3% frail), obesity plus LALM showed lower IGFBP-3 and higher GDF-15 vs. LALM (P Among pre-frail and frail older adult women, obesity-with or without low lean mass-was associated with adverse metabolic/inflammatory profiles (higher resistin, GDF-15, insulin; lower IGFBP-3) in full and frail-only analyses, alongside a trend toward slower chair-stand performance. These cross-sectional findings highlight obesity-frailty interactions, warranting prospective validation. Show less

Poststroke epilepsy (PSE) is a common complication following stroke and is associated with increased mortality and worse functional outcomes. There is no biomarker sufficiently to predict PSE, and antiseizure medications are initiated after the first unprovoked seizure. Early identification of patients at high risk for PSE is needed to consider preventive measures and improve management strategies. Illumina miRNA sequencing was performed on serum collected at follow-ups of patients with PSE and compared to ischemic stroke patients without epilepsy and patients with epilepsy without stroke ( miRNA profiling revealed significant differences among the groups, with miR-10b-5p expression reduced in PSE patients compared to those with stroke alone. miR-486-5p was significantly reduced in PSE patients compared to epilepsy patients. qPCR validation confirmed miR-10b-5p as a potential biomarker candidate to distinguish PSE patients from stroke patients without PSE. BDNF, a key regulator of post-stroke recovery and epileptogenesis, was identified as a primary target of miR-10b-5p. While no group-level differences in serum BDNF concentrations were observed, BDNF levels correlated with disease duration and seizure latency exclusively in the PSE group. Importantly, as samples were obtained during follow-up rather than the acute post-stroke phase, our results indicate an involvement of the miR-10b-5p/BDNF axis in long-term post-stroke remodeling or general PSE susceptibility rather than a predictive biomarker. However, the miR-10b-5p/BDNF axis may represent a biologically plausible pathway associated with post-stroke epileptogenesis and impaired post-ischemic recovery. Prospective longitudinal studies with early post-stroke sampling are required to determine its predictive value. Show less

Cerebrovascular diseases, including ischemic stroke and vascular cognitive impairment, represent a significant global health challenge due to the paucity of effective treatment options. Quercetin, a dietary flavonol, has emerged as a promising multi-target neuroprotective compound. This review elucidates the core mechanisms by which quercetin achieves vascular repair and neuroprotection in cerebrovascular diseases through synergistic regulation of multiple signaling pathways and explores strategies to bridge the gap between dietary intake and clinical application. At the vascular level, quercetin enhances antioxidant defense by activating the nuclear factor E2-related factor 2/heme oxygenase-1 axis, inhibits the Toll-like receptor 4/nuclear factor-κB pathway and NOD-like receptor protein 3 inflammasome, and maintains blood-brain barrier integrity by inhibiting matrix metalloproteinase-9 and upregulating tight junction proteins via the Wnt/ Show less

Cognitive impairment and mood disturbances are increasingly linked to underlying mechanisms such as oxidative stress, neurotransmitter dysregulation, and reduced neurotrophic support. As conventional pharmacological treatments often provide limited efficacy or are associated with tolerability concerns, there is growing scientific interest in botanical supporting strategies that may modulate the above pathways and provide complementary support for cognitive function and emotional well-being. This study aimed to investigate the mechanistic basis of a botanical association consisting of a standardized Show less

Evidence proved that electroacupuncture (EA) combined with antidepressants can improve the antidepressant effectiveness for depressed patients. However, the clinical mechanisms of EA remain unclear. This study aimed to observe the mechanism of EA as an adjunct therapy to escitalopram oxalate (EO) on depressed patients. This study was designed as a single-blinded, double-dummy randomized controlled trial. 61 participants were diagnosed with mild-to-moderate depression according to the International Classification of Diseases 10th Edition (ICD-10, F32) were randomly allocated to receive EA + EO placebo, EO + sham EA, or EA + EO for six weeks treatment. The clinical assessment including depression severity, quality of life (QOL) and clinical safety. Biological indicators of immune-inflammation, the brain-derived neurotrophic factor and glucocorticoid inducible genes in peripheral blood of participants were measured by using enzyme linked immunosorbent assay and real-time polymerase chain reaction respectively before and after treatment. Three interventions improved the depression severity and QOL (P < 0.05), and no inter-group difference was found in the 6th week (P > 0.05). Anxiety psychic and somatic general symptoms in the EA + EO group were improved significantly than those of the other two groups (P < 0.05). After six-week treatment of EA + EO, blood SGK1 mRNA, GILZ mRNA, and BDNF levels were increased significantly ( Show less

Schizophrenia primarily depends on pharmacotherapy, which has demonstrated limited efficacy in enhancing cognitive impairments. High-definition transcranial direct current stimulation (HD-tDCS) and computerized cognitive remediation therapy (CCRT) hold potential for improving cognitive impairments. This study aims to investigate the effects of combining HD-tDCS with CCRT on cognition and to explore the mechanisms of this approach in schizophrenia. This is the protocol of a randomized controlled trial. Schizophrenia patients will be randomly assigned to one of 4 groups: HD-tDCS + CCRT group (Group 1), HD-tDCS group (Group 2), CCRT group (Group 3), and a control group (Group 4). The central electrode will be personalized using magnetic resonance imaging (MRI)-guided localization in the medial prefrontal cortex (mPFC). CCRT includes 6 therapeutic modules and 10 distinct tasks. Both HD-tDCS and CCRT will be administered once daily, 5 days per week, for 4 consecutive weeks, culminating in a total of 20 sessions. Assessments will occur at baseline (T0), after 10 sessions (T1), after 20 sessions (T2), and after 6 months of follow-up (T3). The primary outcome measure is the change in cognition. We will employ multimodal MRI, serum concentrations of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) to explore the underlying mechanisms. An involvement of mPFC and synaptic plasticity in response to HD-tDCS and CCRT is hypothesized. The study will provide empirical evidence for the effectiveness of combined therapy at an individual level, explore its mechanisms, and may ultimately result in personalized medicine. ChiCTR2500102731, https://www.chictr.org.cn/hvshowprojectEN.html?id=276964&v=1.0. Show less

Major depression (MD) has been linked to both neuroinflammation and impaired synaptic plasticity. Furthermore, epigenetic mechanisms involving certain histone deacetylases (HDACs) may initiate these changes. Specifically, altered expression of particular HDACs, including HDAC5, HDAC2, SIRT1, and SIRT2, has been associated with depressive-like behavior, suppressed levels of brain-derived neurotrophic factor (BDNF), and the promotion of neuroinflammation. Additionally, changes in these HDACs within peripheral blood mononuclear cells might contribute to peripheral low-grade inflammation. Here, we investigated the influence of MD on the regulation of specific epigenetic targets, alongside the expression of genes involved in neuroplasticity and inflammation. We analyzed fluorescence-activated cell sorting (FACS)-isolated monocytes (classic, intermediate, and non-classic) and T-cells (CD3+) from fifty-six patients with moderate-to-severe MD and age- and sex-matched healthy controls. Decreased HDAC5 cytoplasm/nucleus ratio in MD monocytes were observed. Moreover, decreased HDAC5 cytoplasm/nucleus ratio negatively correlated with illness severity in MD monocyte subsets and T-cells. In addition, decreased SIRT2 cytoplasm/nucleus ratio in monocytes and T-cells were observed. Gene expression studies showed an increase in HDAC5 mRNA both in intermediate monocytes and T-cells as well as an increase of SIRT2 in intermediate monocytes. Moreover, decreased expression of the neuroplasticity biomarker BDNF, known to be regulated by these two epigenetic enzymes was observed in intermediate monocytes and T-cells. Moreover, an increase of ADRB2 mRNA, encoding the β2 adrenoceptor was observed in classic monocytes. Furthermore, in these cells, both ADRB2 and IL-6 mRNA showed a negative correlation with the HDAC5 cytoplasm/nucleus ratio. Importantly, logistic regression analysis revealed that changes observed with ADRB2 in classic monocytes, SIRT2 in intermediate monocytes and HDAC5 in T-cells were associated to MD with a moderate discriminatory accuracy. These studies suggest that MD promotes nuclear enrichment of the epigenetic enzymes HDAC5 and SIRT2 in monocytes and T-cells of MD patients. These epigenetic changes could potentially contribute to the observed adrenergic and neuroplasticity markers alterations in monocytes and T-cells respectively. Further, some of the targets studied were associated to MD with an acceptable diagnostic value, suggesting the need to enlarge the cohort in order to identify whether they are biomarkers for MD. The online version contains supplementary material available at 10.1038/s41598-026-36954-9. Show less

Acetylation, a key post-translational modification, is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among HDACs, HDAC6-a class II deacetylase with predominant cytoplasmic localization-plays a unique role in cellular processes that extend beyond histone modification. It is ubiquitously expressed throughout the central and peripheral nervous systems and is integral to key physiological functions including protein quality control, autophagy, mitochondrial transport, and oxidative stress responses. Notably, under pathological conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and peripheral nerve injury, HDAC6 undergoes nuclear translocation and contributes to epigenetic dysregulation by modulating the transcription of genes such as brain-derived neurotrophic factor, thereby impairing synaptic integrity and function. This dual role-cytoplasmic in protein homeostasis and nuclear in transcriptional regulation-highlights the HDAC6 paradox in neurological disorders. This review summarizes recent understanding of HDAC6's structure, expression, and functions within the nervous system, and discuss how targeting HDAC6 with selective inhibitors offers a promising therapeutic strategy for mitigating neurological disease pathogenesis. The goal is to provide insights that bridge HDAC6's roles in protein quality control and epigenetic regulation, fostering further exploration of HDAC6 inhibition in neurologic therapeutics. Show less

Depression and anxiety disorders are highly comorbid, yet their complex pathogenesis often limits the efficacy of monotherapy. Growing evidence implicates neuroinflammation in their pathogenesis. Co-drugs that linked two active molecules into a single compound and released the drugs after administration, which offering improved efficacy and tolerability than individual drug mixtures or monotherapy. In this work, five new co-drugs ODV-NSAIDs were synthesized from O-desmethylvenlafaxine (ODV) with non-steroidal anti-inflammatory drugs (NSAIDs) to achieve synergistic antidepression and anxiolytic effects. In vitro stability studies exhibited that these co-drugs can be metabolized into two single drugs within 60 min in simulated intestinal fluid. In both acute and chronic LPS-induced models, co-drug ODV-NAP significantly ameliorated depressive-like behaviors, evidenced by increased sucrose preference, reduced immobility in the tail suspension test (TST) and forced swim test (FST), and enhanced locomotion in the open field test (OFT). Furthermore, ODV-NAP decreased brain levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and malondialdehyde (MDA), while elevating serotonin (5-HT), norepinephrine (NE), and superoxide dismutase (SOD) activity. Nissl staining confirmed ODV-NAP significantly attenuated hippocampal neuronal damage. Moreover, western blotting revealed ODV-NAP inhibited the TLR4/NF-κB signaling pathway and upregulated BDNF and p-TrkB protein expression. ODV-NAP also inhibited LPS-induced p65 nuclear translocation in BV-2 microglia in vitro, and caused no toxicity in histology. Thus, co-drug ODV-NAP represented a promising novel candidate for treating depression and anxiety. Show less

BackgroundHigh intensity interval training (HIIT) involves vigorous intensity exercise bouts interspersed with low intensity bouts. Despite growing interest, the optimal dosage and clinical adaptability of HIIT in Parkinson's disease (PD) remain unclear. This scoping review synthesized the literature on systemic adaptations underlying HIIT in PD and developed a clinical framework while considering chronotropic incompetence, orthostatic hypotension, and disease progression.MethodsThree databases were searched for studies that incorporated HIIT interventions in PD. The Template for Intervention Description and Replication checklist was used to characterize the quality of intervention reporting.ResultsA total of 285 studies were screened, of which 10 studies were included. HIIT was administered 2-3 times/week for 30-60 min/session over 8-12 weeks. Seven studies used moderate-volume HIIT and three studies used high-volume HIIT protocols. The quality of intervention reporting was fair to good. HIIT improved cardiorespiratory fitness, motor severity, and functional mobility in PD, however, improvements were comparable to moderate intensity continuous training (MICT). HIIT may facilitate neuroplasticity by increasing brain-derived neurotrophic factor levels and dopamine transporter uptake. We recommend that HIIT programs for individuals with autonomic dysfunction use individualized heart rate targets, and perceived exertion for determining exercise intensity, and incorporate longer duration programs (>12 weeks).ConclusionHIIT is a well-tolerated intervention that may improve cardiorespiratory fitness, disease severity, and certain neurobiological markers in mild-moderate PD, with benefits similar to MICT. Larger trials comparing different HIIT volumes are needed to identify optimal exercise volume to inform individualized exercise prescription. Show less

Peripheral nerve injury (PNI) is a significant health concern, affecting millions worldwide. Key neurotrophic factors, including nerve growth factor, brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor, have shown promise in facilitating neural regeneration. The effects of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids have been extensively studied, emphasizing the importance of appropriate timing and duration of administration. Antioxidants such as vitamin E and melatonin have exhibited neuroprotective effects in animal models, but further research is necessary to determine their efficacy, optimal dosage, and administration in humans. Immunosuppressive agents like tacrolimus (FK506) and cyclosporin A have demonstrated substantial potential in enhancing peripheral nerve recovery. Supportive strategies, including physical therapy and neuromodulation techniques such as electrical and transcranial stimulation, have shown effectiveness in promoting nerve regeneration. Advances in bioengineering, including nerve conduits and stem cell transplantation, which mimic natural nerve repair mechanisms, hold considerable promise for improving PNI treatments. In conclusion, PNI therapy is progressing towards an integrative approach, combining surgical techniques with pharmacological interventions, bioengineering, and regenerative medicine to enhance outcomes while minimizing adverse effects. This review explores recent advancements in peripheral nerve regeneration using both natural and synthetic agents, highlighting the shift toward more comprehensive treatment strategies. Show less

Type 2 diabetes mellitus (T2DM) represents a systemic disease that extends beyond metabolic dysfunction to include accelerated neurocognitive decline driven by oxidative stress, inflammation, and insulin resistance. Emerging evidence suggests that essential micronutrients may interact synergistically or antagonistically with biguanides, particularly metformin, to influence neurocognitive function. This systematic review synthesized preclinical and clinical evidence on the interactions between essential micronutrients and biguanides (notably metformin) in modulating neurocognitive outcomes in T2DM. Following PRISMA 2020 guidelines, we systematically searched PubMed, Web of Science, and Scopus for studies published between 2010 and 2025. After screening 226 records in Rayyan, 40 studies met the inclusion criteria. Both preclinical and clinical studies were analyzed descriptively to identify patterns of mechanistic and functional outcomes. Extracted data covered intervention types, doses, duration, biomarkers, and cognitive outcomes. Of the 40 studies, 27 (67.5%) were preclinical and 13 (32.5%) were clinical, spanning 14 countries. Most interventions involved vitamin D, zinc, magnesium, vitamin E, or polyphenols, either alone or combined with metformin. Synergistic effects were observed in 77.5% of studies, with significant improvements in fasting plasma glucose, HbA1c, insulin sensitivity, and oxidative balance. Key molecular pathways involved AMPK, PI3K/Akt, GSK3β, and Nrf2-CREB, which mediated enhanced glucose utilization, mitochondrial function, and synaptic plasticity. Antagonistic effects (10%) were mainly linked to metformin-induced vitamin B12 depletion, which impaired neurotrophic signaling and elevated homocysteine levels. Across studies, neuroprotective benefits correlated with increased BDNF, PSD-95, and SIRT1 expression, and reduced IL-6, TNF-α, and MDA levels. Most (75%) of the studies showed a synergistic interaction between biguanides (metformin) and micronutrients save a few that showed antagonistic interaction. Integrating micronutrient supplementation particularly vitamin D, zinc, and antioxidant compounds into T2DM management enhances both metabolic control and cognitive function. These findings support a paradigm shift toward combined nutraceutical-pharmacologic therapy within clinical and public health frameworks. Future research should focus on dose optimization, mechanistic validation, and long-term clinical evaluation to develop evidence-based, nutrition-sensitive diabetes care models. 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

Chronic pain (CP) is increasingly recognized not only as a sensory and emotional condition but also as a significant contributor to cognitive dysfunction. Growing evidence indicates that CP-induced cognitive dysfunction arises from a cascade of neurobiological processes, including persistent neuroinflammation, neurotransmitter dysregulation, and impaired synaptic plasticity. These mechanisms particularly affect the hippocampus and medial prefrontal cortex (mPFC)-regions essential for memory, attention, and executive function. Neuroimaging studies have documented structural atrophy and disrupted network connectivity in these brain areas in CP patients. At the molecular level, pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) impair glutamatergic and GABAergic signaling, disrupt long-term potentiation (LTP), and inhibit neurogenesis. Additionally, dysregulation of brain-derived neurotrophic factor (BDNF) signaling exacerbates synaptic vulnerability, contributing to cognitive decline. These mechanistic overlaps are particularly relevant in aging populations and in Alzheimer's disease (AD), where CP may act as a risk factor. This review integrates clinical and preclinical findings on CP-related cognitive dysfunction, outlines key molecular mechanisms, and explores emerging therapeutic strategies targeting inflammation, neurotransmitter systems, and synaptic repair. Understanding the interaction between chronic pain and cognition is critical for developing precision treatments that address both nociceptive and neurodegenerative pathways. 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

The Angelica sinensis and Ligusticum chuanxiong Herb Pair (DC) serves as a core pairing in Traditional Chinese Medicine for treating blood stasis and blood deficiency syndromes, which are frequently associated with depressive-like symptoms in clinical practice. The antidepressant potential of this combination aligns with its traditional functions of promoting qi circulation, activating blood flow, and alleviating depression. This study aims to investigate the antidepressant effects of DC and its potential mechanisms through a combination of network pharmacology prediction and in vitro and in vivo experimental validation. Network pharmacology screening identified active components and target molecules in DC, constructing a component-target network and validating binding activity through molecular docking. A CUMS-induced rat model of depression was established, with drug efficacy evaluated via behavioral tests (forced swim, sucrose preference, and open field tests) and blood rheology parameters measured. ELISA assay of neurotransmitter and inflammatory factor levels in serum and hippocampal tissue, Observation of histopathological changes in hippocampal tissue using HE and Nissl staining, Western blot and immunofluorescence assays were performed to detect the expression of proteins in the PI3K/AKT pathway. An in vitro inflammatory model was established by inducing BV-2 cells with LPS. The MTT assay was used to screen for the safe concentration of drug-containing serum and observe cell morphology, the Gries method for detecting NO release, ELISA for detecting inflammatory cytokines, Western blot analysis of PI3K/AKT pathway proteins was performed, and pathway inhibition was validated using LY294002. Through network pharmacology analysis, seven major active components of DC and 197 related functional targets for depression treatment were identified, with the majority enriched in the PI3K/AKT signaling pathway. Behavioral studies and in vivo experiments indicate that DC significantly ameliorates depressive-like behaviors in CUMS rats, reduces blood viscosity, increases hippocampal tissue levels of 5-HT, NE, and DA, decreases IL-1β, IL-6, and TNF-α content, and mitigates hippocampal neuronal damage. Western blot and immunofluorescence results indicate that DC can activate the PI3K/AKT pathway, upregulating p-AKT and BDNF expression. In vitro experiments further confirmed that the drug-containing serum could suppress LPS-induced inflammatory responses in BV-2 cells, reducing the release of factors such as NO and IL-1β. This effect was reversible upon treatment with the PI3K inhibitor LY294002. DC exhibits potent antidepressant effects by modulating the PI3K/AKT pathway to enhance neurotransmitter release and reduce inflammatory factor levels. This mechanism protects neurons and alleviates neuroinflammation, thereby exerting antidepressant effects. 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

Chronic stress induces sensorimotor, cognitive, and neuroendocrine alterations, particularly in females who exhibit heightened vulnerability to stress-related disorders. This study tested the hypothesis that chronic quetiapine administration during ongoing unpredictable chronic mild stress (UCMS) would attenuate stress-induced impairments in sensorimotor gating, recognition memory, and HPA-axis–related biochemical markers in female rats. Adult female Wistar rats were exposed to a 9-week UCMS paradigm, with quetiapine (10 mg/kg/day, i.p.) administered during the final 3 weeks. Behavioral outcomes were assessed using prepulse inhibition (PPI), startle reactivity, and the Novel Object Recognition (NOR) test. Serum and hippocampal corticosterone and BDNF levels were quantified by ELISA. Chronic stress significantly reduced PPI and recognition memory performance and increased serum and hippocampal corticosterone levels. Quetiapine treatment improved PPI and startle responsiveness, restored NOR discrimination index values, and partially attenuated stress-induced corticosterone elevations. Hippocampal BDNF levels were elevated in stressed animals and were modulated toward intermediate levels following quetiapine treatment. These findings indicate that chronic quetiapine administration mitigates behavioral and neuroendocrine alterations induced by prolonged stress in female rats. [Image: see text] The online version contains supplementary material available at 10.1007/s11011-026-01834-8. Show less

The neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a key regulator of synaptic plasticity in hippocampus and cortex of mammalian brains. In the lateral nucleus of the amygdala (LA), BDNF is involved in the control of long-term potentiation (LTP). Here, we show that BDNF is involved in spike-timing dependent potentiation (STDP) of thalamic inputs onto LA projection neurons. Inhibition of BDNF/TrkB signaling with the TrkB scavenger TrkB/FC completely blocked this timing-dependent form of LTP (t-LTP). Disruption of lipid-rafts by depletion of cholesterol from synaptic microdomains with Methyl-β-cyclodextrin (MCD) also prevented induction and expression of t-LTP. These data suggest that BDNF-induced TrkB translocation into synaptic lipid-rafts is required for induction of t-LTP at thalamo-amygdala synapses. Since cholesterol-dependent modulation is not unique for TrkB receptor signaling but has been described for other receptors and ion channels involved in synaptic plasticity, additional studies are required to obtain a more complete picture regarding their role in t-LTP at thalamo-amygdala afferents. Show less

Anxiety and depression are growing global burdens with limited drug options. Traditional Chinese medicine (TCM) offers unique advantages, including Roudoukou-Suanzaoren (RS), an ancient TCM-derived beverage with the potential for treating these conditions. This study aims to explore whether this combination improves the outcomes. The results show that the main constituents of RS include flavonoids, terpenoids, alkaloids, and phenylpropanoids. Behavioral and histopathological analyses demonstrate that RS alleviates chronic restraint stress (CRS)-induced anxiety- and depression-like behaviors and attenuates neuropathological damage in relevant brain regions; the underlying mechanism is likely mediated by the CREB/BDNF/TrkB signaling pathway. Meanwhile, RS reduces proinflammatory cytokines in tissues, decreases hippocampal microglial numbers, and increases astrocytes. Additionally, RS attenuates colonic injury, restores intestinal permeability, upregulates tight-junction proteins, and improves gut microbiota dysbiosis. This study highlights that RS exerts antianxiety and antidepression effects by modulating the gut microbiota, controlling inflammatory responses, and increasing BDNF levels through the "gut-brain axis" pathway. Show less

Post-stroke depression (PSD) affects 29-52% of stroke survivors, with inflammation as a key pathophysiological mechanism. Hyperbaric oxygen therapy (HBOT) may modulate neurorestoration, but clinical evidence is limited. While meta-analytic evidence suggests HBOT may benefit PSD symptoms, high-quality randomized controlled trials employing rigorous sham-control and concurrently investigating neurotrophic mechanisms remain scarce. In this randomized, double-blind, sham-controlled trial, 61 PSD patients were allocated to HBOT (n=29) or Sham-HBOT (n=32) groups, respectively. HAMD, NIHSS and MBI scores and serum Brain-Derived Neurotrophic Factor (BDNF), and beta-Nerve Growth Factor (beta-NGF), were evaluated at baseline as well as 2 and 4 weeks after HBOT intervention. The primary outcome was the change in the 17-item Hamilton Depression Rating Scale (HAMD-17) score from baseline to week 4, analyzed in the modified intention-to-treat population. The trial was registered (ChiCTR2100053522). HAMD scores decreased significantly in the HBOT group vs sham-group at weeks 2 (p=0.017) and 4 (p<0.01). Serum BDNF and beta-NGF, levels were significantly elevated in the HBOT group (all p<0.01). Reductions in HAMD scores correlated with increases in BDNF (r = 0.66, p < 0.05) and beta-NGF (r = 0.47, p =0.01). HAMD scores decreased significantly in the HBOT group compared to the sham-group, with the between-group difference reaching significance at week 2 (p=0.017) and week 4 (p<0.001). Exploratory subgroup analyses by stroke type (ischemic vs hemorrhagic) and age (dichotomized at the median of 65 years) were conducted and these analyses revealed no significant interaction between treatment group and either stroke subtype or age subgroup on the change in HAMD-17 scores (all p > 0.05), suggesting a consistent trend of HBOT effect across these subgroups within this limited sample. This preliminary trial suggests that a 4-week course of HBOT may alleviate depressive symptoms in PSD patients, an effect associated with increased serum BDNF and β-NGF levels. Given the limited sample size and short follow-up, its long-term efficacy and clinical positioning require validation in larger trials with extended follow-up. Show less

Depression is one of the most prevalent and disabling non-motor symptoms in Parkinson's disease (PD), forming a bidirectional relationship with motor dysfunction that worsens quality of life. Pharmacological treatments exhibit limited and inconsistent efficacy, and may lead to adverse interactions. Acupuncture may improve both depressive and motor symptoms by regulating the neuro-immune-endocrine network, but high-quality evidence remains insufficient. This study aims to evaluate the efficacy and safety of acupuncture as an adjunctive therapy for depression in PD and to explore potential biological correlates of clinical changes using predefined serum biomarkers. In this single-center, evaluator-blinded, randomized controlled trial, 88 patients with PD and comorbid depression will be randomly assigned to an acupuncture group or a waitlist control group. The primary outcome is the change in the Montgomery-Asberg Depression Rating Scale (MADRS) score. Secondary outcomes include motor function, anxiety, sleep quality, and overall quality of life. Exploratory analyses will assess serum inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and kynurenine/tryptophan (KYN/TRP) ratio. We hypothesize that adjunctive acupuncture may improve depressive and motor symptoms compared with the control. Exploratory analyses will examine whether clinical changes are associated with changes in relevant biomarkers. This study will provide rigorous evidence for acupuncture as an adjunctive therapy, offering a non-pharmacological strategy to optimize the comprehensive management of PD and disrupt the bidirectional emotion-motor interplay. https://www.chictr.org.cn/, identifier ChiCTR2500113443. Show less

Valproic acid (VPA) is recognized for its neurotrophic properties and is widely used in psychiatric and peripheral disorders, while dextromethorphan (DM) has demonstrated anti-inflammatory and neuroprotective effects. This study examined whether adjunctive DM provides additional benefits on cognitive or immunomodulatory beyond standard VPA treatment in bipolar disorder (BD). BD aged 20-65 received open-label VPA (500-2500 mg/day; target blood level 50-100 μg/dl) for one week and were then randomized to VPA plus placebo (BDVPA) or VPA plus extended-release DM (BDVPA + DM; 30 or 60 mg/day) for twelve weeks. Neuropsychological measures (Continuous Performance Test, CPT; Wechsler Memory Scale-Revised, WMS-R), symptom severity, cytokines, and BDNF were assessed at baseline and post-treatment. A total of 109 participants (mean age 31.04 years, SD = 10.04) were enrolled; 96 completed cognitive testing and blood sampling (66 BD 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