📋 Browse Articles

To investigate the therapeutic mechanisms of miR-9-5p-overexpressing human umbilical cord mesenchymal stromal cells (hUC-MSCs) in neonatal rat models of hypoxic-ischemic brain damage (HIBD). Fresh neonatal umbilical cords were collected to isolate and culture human umbilical cord mesenchymal stromal cells (hUC-MSCs). Recombinant adenovirus was used to amplify miR-9-5p and transduce hUC-MSCs, generating miR-9-5p-overexpressing cells. Functional assessments included: ELISA to evaluate secretory function (e.g., neurotrophic and anti-inflammatory factors), real-time cell analysis to measure proliferation capacity, Transwell and Dunn chamber assays to assess chemotactic migration ability. Healthy 7-day-old Sprague-Dawley (SD) rats of both sexes were randomly allocated into four groups (n = 12/group, with 4 rats per group assigned to TTC staining, Western blot, or Morris water maze assay, respectively): Sham-operated control group (mock surgery), Hypoxic-ischemic brain damage (HIBD) model group, miR-9-5p-hUC-MSCs treatment group, and Adenovirus-transduced hUC-MSCs (Ad-hUC-MSCs) treatment group. The HIBD model was induced in groups 2-4. At 24 h post-modeling, 1×10 Spindle-shaped and polygonal adherent cells emerged within 3-5 days following umbilical cord tissue block inoculation, with flow cytometric analysis confirming their identity as mesenchymal stromal cells (MSCs). Compared to the Ad-hUC-MSCs treatment group, miR-9-5p enhanced the secretion of neuroreparative and anti-inflammatory factors (e.g., NGF, BDNF, IL-6) in hUC-MSCs while suppressing pro-inflammatory cytokines (e.g., IL-1, IL-2) (p < 0.05). Furthermore, miR-9-5p significantly promoted hUC-MSCs proliferation and augmented the chemotactic migratory capacity of miR-9-5p-hUC-MSCs. At 48 h post-transplantation in the miR-9-5p-hUC-MSCs group, the sham-operated controls showed no detectable cerebral infarction, whereas the model group exhibited distinct pale infarct foci occupying 33.15% ± 4.38% of total brain volume (vs. controls, p < 0.05), indicating severe cerebral injury. Both miR-9-5p-hUC-MSCs and Ad-hUC-MSCs treatments markedly reduced infarct volumes to 14.85% ± 2.79% and 19.11% ± 4.57%, respectively, with the miR-9-5p-hUC-MSCs group demonstrating a statistically superior therapeutic effect compared to Ad-hUC-MSCs (p < 0.05). Transplantation of either Ad-hUC-MSCs or miR-9-5p-hUC-MSCs significantly improved short- and long-term neurobehavioral outcomes in hypoxic-ischemic brain damage (HIBD) rats. At 48 h post-HIBD induction, upregulated expression of Beclin-2 and Caspase-3 proteins was observed in brain tissue. Notably, these elevated protein levels were attenuated following treatment with miR-9-5p-hUC-MSCs or Ad-hUC-MSCs. MiR-9-5p enhances the secretion of immunomodulatory factors and improves the migratory and proliferative capacities of hUC-MSCs. Overexpression of miR-9-5p promotes in vivo homing of hUC-MSCs, which mitigate cerebral injury and exert neuroprotective and reparative effects through dual mechanisms: modulating immune responses and providing neurotrophic support. Furthermore, hUC-MSCs significantly reduce cerebral infarct volume in hypoxic-ischemic brain damage (HIBD) rats and downregulate levels of apoptotic proteins (Beclin-2 and Caspase-3) in brain tissue, demonstrating potent cerebroprotective effects. Show less

The mechanisms of neuropathic pain after spinal cord injury (SCI) are not fully understood, although spinal and peripheral processes are involved. Maladaptive tropomyosin receptor kinase-B (TrkB) signaling has been implicated in pain hypersensitivity after SCI. A-delta-low threshold mechanoreceptors (Aδ-LTMRs) innervate the hairy skin and normally signal directional touch and are identified by their preferential TrkB expression. This study investigated whether Aδ-LTMRs play a role in at-level pain after thoracic contusion SCI. Using a modified light-dark chamber conditioned place aversion (CPA) paradigm, we assessed chamber preferences and transitions between chambers in response to mechanical stimulation, and optogenetic stimulation of Aδ-LTMRs in the trunk skin of adult TrkB Show less

The increasing prevalence of dementia and age-related decline in cognitive function poses significant public health challenges. Brain Gym exercises and mind-body practices (MBPs), which are nonpharmacological interventions, enhance cognitive reserve and neuroplasticity through integrated breathing, meditative, and physical elements; however, in older adults with cognitive impairment, the evidence remains fragmented. Hence, this scoping review maps the evidence in older adults regarding the effectiveness of Brain Gym and MBPs for improving cognitive function, compares outcomes with conventional or no interventions, assesses feasibility and safety, and identifies research gaps while outlining recommendations. A comprehensive search of PubMed and ScienceDirect (January 2020 to December 2025) identified English-language, full-text original research on MBPs versus comparators in community-dwelling or institutionalized adults. Five reviewers screened records, extracted data on study characteristics, interventions, and findings, and appraised quality using the Mixed Methods Appraisal Tool. A narrative synthesis approach was utilized to present the results. Eleven high-quality studies (n = 19-585; 2020-2025), primarily randomized controlled trials (RCTs) conducted in community settings across Asia, the US, Mexico, and Indonesia, were included. MBPs improved global cognition, memory quotients, executive function, and attention compared with usual care, with mixed superiority over aerobic comparators; Brain Gym enhanced brain-derived neurotrophic factor (BDNF) levels and domain-specific scores. Feasibility was high (81%-100% adherence, 89%-97% retention, no serious adverse events). Neuroimaging revealed gray matter increases in temporal and frontal regions and reduced inflammation. Gaps included short follow-up periods, limited virtual delivery, underrepresentation of frail subgroups, and limited mechanistic depth. Thus, MBPs and Brain Gym demonstrate accessible and promising cognitive benefits via neuroplastic mechanisms, outperforming controls in feasibility and domain-specific gains. Multicenter, long-term studies with diverse, high-risk cohorts and hybrid modalities are essential to refine protocols, address equity, and support integration into geriatric care for dementia prevention. Show less

Peripheral nerve injuries often lead to painful neuroma formation and chronic neuropathic pain, and the optimal surgical strategy for prevention remains debated. Targeted muscle reinnervation (TMR), regenerative peripheral nerve interfaces (RPNI), and nerve-in-muscle implantation (NIM) are surgical techniques developed to mitigate neuroma-related pain, but their relative efficacy has not been compared systematically. This preclinical study compared TMR, NIM, and two RPNI variants in a rat tibial nerve transection model to identify which approach best reduces neuroma formation and pain. Sprague-Dawley rats underwent right tibial nerve transection and were randomized into five groups: control (no repair), NIM, W-RPNI (wrapped RPNI), E-RPNI (embedded RPNI), or TMR. Behavioral outcomes including gait analysis (CatWalk), mechanical hypersensitivity (von Frey test), thermal hyperalgesia (Hargreaves test), and neuroma tenderness were assessed over 12 weeks. At week 12, distal nerve stumps and L4-L5 dorsal root ganglia (DRG) were harvested for histological evaluation, immunohistochemistry/immunofluorescence, and molecular analyses (qRT-PCR and Western blot) targeting pain- and inflammation-related biomarkers. By 12 weeks, TMR-treated rats showed the most robust improvements, including significantly longer stance duration, larger paw contact area, near-baseline withdrawal thresholds, and minimal neuroma tenderness, whereas untreated controls developed gross neuromas and persistent hypersensitivity. TMR also preserved organized nerve architecture with orderly axonal regeneration and minimal collagen I/III fibrosis at the stump. Molecular assays confirmed that TMR markedly attenuated nociceptive and inflammatory signaling, with TMR rats exhibiting the lowest expression of pain-related mediators (c-Fos, TRPA1, TRPV1, CGRP, NPY, BDNF) and pro-inflammatory/fibrotic markers (galectin, α-SMA, IL-1β, TNF-α, TGF-β) in nerve and DRG tissues. Conversely, the anti-inflammatory cytokine IL-10 and axonal ion pump subunits ATP1A2/ATP2B1 were significantly upregulated with TMR. Outcomes for the two RPNI groups were similar to each other and generally intermediate between TMR and control. TMR was superior to RPNI variants and NIM in preventing neuroma formation and alleviating neuropathic pain in this animal model. These findings support TMR as a promising surgical strategy to mitigate post-amputation neuroma pain. Show less

Nicotine withdrawal during adolescence induces severe neurobehavioral disturbances and neurochemical alterations, including anxiety, depression, affective dysregulation, oxidative stress, and neuroinflammation. Current therapeutic options for managing nicotine dependence remain suboptimal. This study investigated the neuroprotective potential of naringenin (NG) in alleviating behavioral and biochemical sequelae of nicotine withdrawal in adolescent rats. Male adolescent Wistar rats were allocated into eight groups and subjected to nicotine exposure (1 mg/kg) and NG treatment (50 or 100 mg/kg) across nicotine exposure and withdrawal phases. Behavioral assays (OFT, EPM, FST) were employed to evaluate anxiety- and depression-like behaviors. Neurochemical assessments of dopamine, serotonin, their metabolites (DOPAC, 5-HIAA), MAO-A activity, oxidative stress markers (MDA, Nit), antioxidant enzymes (SOD, CAT, TT), and neuroinflammatory/neurodegenerative biomarkers (GFAP, IL-10, BDNF, NSE) were conducted in prefrontal cortex (PFC) homogenates. Nicotine withdrawal significantly induced anxiety- and depression-like behaviors, disrupted monoaminergic balance, elevated MAO-A activity, and triggered oxidative and neuroinflammatory responses in the PFC. NG administration, particularly at 100 mg/kg across both phases, significantly ameliorated behavioral impairments, restored neurotransmitter homeostasis, inhibited MAO-A, suppressed lipid peroxidation and nitrosative stress, enhanced antioxidant defenses, reduced GFAP and NSE expression, and restored IL-10 and BDNF levels. NG exerts anxiolytic, antidepressant, antioxidant, and anti-inflammatory effects, likely via modulation of monoaminergic pathways and suppression of neuroinflammation and oxidative stress. These findings underscore the potential of NG as a promising candidate for mitigating neuropathological effects associated with nicotine withdrawal-induced neuropathology, particularly during adolescence. Show less

Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of Show less

Single Particle Tracking (SPT) is a powerful technique for elucidating the dynamic behaviours of macromolecules within live cells. However, SPT's application to subcellular environments is hampered by the error-proneness of tracking at high particle velocities and densities and the lack of tools to assess trajectory reliability. Here, we introduce FidlTrack, a methodology that benchmarks and improves SPT fidelity. It contains three modules: a parameter optimiser that uses synthetic ground truth SPT data to determine the fidelity-maximising experimental and tracking settings; Structure-aware tracking, that exploits the information provided by organelle structures to constrain particle tracking algorithms; And a tracking quality evaluator that detects, quantifies and removes error-prone ambiguous track segments. Together these tools allow the rational design of SPT experiments, resolving the motion in tight and convoluted organelles, and provide up to 2-fold enrichment in accurate data. We showcase FidlTrack's utility for reliably tracking proteins in the cytosol, mitochondria and endoplasmic reticulum (ER). Further, we demonstrate its efficacy by analysing ER protein dynamics at exit sites, resolving BACE1 amyloidogenic cleavage of the amyloid precursor protein and characterising the spatiotemporal binding dynamics of an ER-targeted intrabody. FidlTrack is provided as a universal open-access platform that can be incorporated into any SPT pipeline. Show less

Clozapine (CLZ) is an atypical antipsychotic mainly prescribed for treatment-resistant schizophrenia. Beyond psychotic symptoms, patients often exhibit persistent cognitive impairments across domains such as attention, learning, and memory. The mechanisms by which CLZ may influence cognition and provide neuroprotection are not fully elucidated. Accordingly, this study examined how CLZ modulates lipopolysaccharide (LPS)-induced neurotoxicity in rats. Rats were administered LPS to induce cognitive impairment and subsequently treated with CLZ. Behavioral assessments were performed using maze tests (elevated plus-maze (EPM), novel object recognition (NOR), and Y-maze). Biochemical analyses included cholinergic function (acetylcholine (ACh)), neurodegeneration-associated enzymes (glycogen synthase kinase-3 beta (GSK-3β), β-site amyloid precursor protein cleaving enzyme-1 (BACE-1), and dipeptidyl peptidase-4 (DPP-4)), oxidative stress markers (lipid Peroxidation (LPO), catalase, and reduced glutathione (GSH)), and apoptotic proteins (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved Caspase-3 (c-Caspase-3)). CLZ treatment markedly improved performance in EPM, NOR, and Y-maze tasks, indicating recovery of cognitive function in LPS-exposed rats. At the molecular level, CLZ enhanced ACh levels, upregulated the anti-apoptotic protein Bcl-2, and restored antioxidant defenses (catalase and GSH). Conversely, CLZ reduced LPS-induced neurotoxicity by lowering GSK-3β activity, LPO, and pro-apoptotic markers (Bax and c-Caspase-3). The findings demonstrate that CLZ exerts neuroprotective effects in an LPS-induced rat model, improving cognition through modulation of cholinergic transmission, oxidative stress, and apoptosis pathways. These results clarify key mechanistic pathways through which CLZ may exert cognitive benefits and highlight its potential relevance for improving schizophrenia-related cognitive dysfunction. Further molecular studies are warranted to confirm and extend these observations toward clinical translation. Show less

Atherosclerosis is considered as a major contributor for cardiovascular disease with high morbidity and mortality globally. However, the cross-talk between efferocytosis and inflammation in atherosclerosis remains elusive. ApoE (apolipoprotein E) YY1 and NEDD4L were upregulated, but MerTK was downregulated in the arteries of ApoE Our findings demonstrated that YY1 positively regulated NEDD4L to modulate MerTK-mediated efferocytosis and activate NLRP3-mediated inflammation and pyroptosis, thus exacerbating atherosclerosis. Show less

Neuroinflammation is a key pathogenic process in multiple central nervous system (CNS) disorders. It can lead to neuronal injury and cognitive decline through excessive glial activation and aberrant engagement of the programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint axis. To address these pathologies, we engineered a PD-1-enriched macrophage-membrane, lactoferrin-modified, PEGylated, glycyrrhizic-acid-loaded biomimetic hybrid liposome (PMLpGL) for dual, precise modulation of the neuroinflammatory microenvironment. PMLpGL alleviates neuronal inhibitory signaling by reversibly sequestering excess PD-L1 via membrane-anchored PD-1, while its cargo GA suppresses high-mobility group box-1 (HMGB1)-driven inflammatory cascades, thereby returning inducible PD-1/PD-L1 expression and glial activation toward homeostasis. Physicochemical characterization showed a hydrodynamic diameter of 165 ± 3 nm and a zeta potential of -10.2 ± 0.2 mV. Engineered macrophage membranes displayed marked PD-1 overexpression, and ligand-depletion saturation assays demonstrated specific, saturable PD-1/PD-L1 binding. In a Transwell blood-brain barrier (BBB) model, PMLpGL achieved a 24-h permeability of 22.86 ± 0.14 %, indicating robust in-vitro BBB traversal. In vivo fluorescence imaging showed peak brain accumulation at 24 h with retention to 48 h; liquid chromatography-tandem mass spectrometry further confirmed brain targeting and persistence-at 12 h, brain GA with PMLpGL was ∼48-fold higher than free drug and remained quantifiable at 48 h. Pharmacodynamic evaluations in cells and mice demonstrated that PMLpGL suppresses glial activation and normalizes inducible checkpoint expression; reshapes the cytokine milieu by lowering IL-6, IL-1β, TNF-α, and HMGB1 while increasing IL-10, TGF-β, and brain-derived neurotrophic factor; and restores the synaptic protein synapsin-1. Correspondingly, PMLpGL significantly improved cognition in open-field, novel object recognition, and Morris water maze tests. Collectively, PMLpGL combines PD-1 decoy sequestration with GA-mediated upstream immunomodulation to attenuate neuroinflammatory cascades, protect neurons, and reverse cognitive deficits. By pairing BBB compatibility with microenvironment-precise regulation, this platform offers a promising therapeutic strategy for CNS diseases associated with cognitive decline. 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

X-linked adrenoleukodystrophy (X-ALD) is a congenital metabolic disorder characterized mainly by inflammatory demyelination and adrenal insufficiency. Newborn screening using hexacosanoyl lysophosphatidylcholine (C26:0-LPC) in dried blood spots as a diagnostic marker can successfully identify potential patients with X-ALD and prevent disease onset. C26:0-LPC accumulates in patients with X-ALD, although the machinery synthesizing it has remained unclear. In this study, we focused on phosphatidylcholine (PC) with C26:0 moiety as a precursor of C26:0-LPC. We identified that lysophospholipid (LPL) acyltransferase 10 (LPLAT10)/LPCAT4/LPEAT2/AGPAT7 (1-acylglycerol-3-phosphate O-acyltransferase 7) is the responsible LPL acyltransferase that produces PC with C26:0 moiety by transferring C26:0-CoA into 2-acyl-LPC. We also found that LPLAT10 deficiency decreased the amount of C26:0-LPC in fibroblasts from X-ALD patients. Mechanistically, LPLAT10 introduced saturated fatty acid-CoA of various chain lengths as substrates into the sn-1 position of LPC but did not transfer C26:0-CoA to other LPL classes, such as lysophosphatidylethanolamine. Structural analysis revealed that a trimethylamine group of PC was placed between two tryptophan residues (W242 and W244), forming a W-X-W motif, possibly through cation-π interaction. Finally, it was shown that exogenously administered C26:0 FFA-d Show less

Abdominal aortic aneurysm (AAA) is a serious disease with no effective pharmacological therapy. Although inflammation is recognized as a key regulator of AAA, targeting inflammatory pathways once the disease is established does not improve outcomes. Understanding the earliest molecular indicators could clarify precise biological targets and prognostic markers for AAA. Using ApoE-deficient mice, we performed RNA-Seq on suprarenal abdominal aortas (SRAs) from Ang II- and saline-treated mice 24 h after infusion. We further developed a unique model of hyperlipidemic mice in which the expression of the inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ) can be conditionally suppressed in vascular smooth muscle cells (VSMCs). RNA-Seq data revealed early IKKβ-dependent cellular anabolic processes in SRAs, including activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, deletion of the Show less

Alzheimer's disease (AD) is characterized by the gradual deterioration of cognitive functions, speech impairment, and memory loss. It can potentially be treated by targeting the beta-site amyloid precursor protein cleavage enzyme 1 (BACE1), which plays a key role in amyloid plaque formation, neurofibrillary tangles, and hyperphosphorylated tau protein. Current drugs have limitations in terms of safety, efficacy, and blood-brain barrier permeability. In view of this, this study was designed to determine the potential inhibitors of the BACE1 enzyme by virtual screening using a curated library of 415 natural products including terpenoids, phenolic compounds, and alkaloids from different medicinal plants. Based on the docking score and interaction analysis, 50 compounds were selected for the downstream analysis, such as ligand binding interactions, pharmacokinetics, druglikness and physicochemical parameters. Among the lead compounds, Palmatine (compound 45) and Berberine (compound 49), demonstrated optimal drug-likeness and blood-brain barrier permeability among the top compounds. 2-[(9Z,12Z)-heptadeca-9,12-dienyl]-6-hydroxybenzoic acid (compound 4) was inactive in most toxicity parameters. Pharmacophore analysis revealed that Palmatine and Berberine share similar features with the standard, highlighting their potential as effective compounds. Furthermore, structural chemistry analysis provided insights on their shared isoquinoline alkaloid framework, illustrating their structural similarities. Molecular dynamics simulations confirmed the stability of the Palmatine-BACE1 and Berberine-BACE1 complexes during a 50 ns production run. Overall, these findings highlighted the potential of Palmatine and Berberine as promising candidates for the experimental validation and the development of the drugs for the treatment of AD. Show less

This review comprehensively summarizes the interaction mechanisms between Megalin and several key ligands, including calcium ions, gentamicin, ApoE, ANKRA2, FVIII, TTR, STC1, RAP, and MMP-9, focusing on the specific amino acid binding sites involved. The analysis highlights the structural basis of these interactions and their clinical relevance, particularly concerning diseases such as nephrotoxicity, Alzheimer's disease, metabolic disorders, and renal pathologies. This review comprehensively summarizes the specific binding sites of Megalin with its ligands and explores the mechanisms, including protein reabsorption, blood coagulation, and neuroprotection, by integrating the results of animal studies and human clinical studies. This review proposes a theoretical framework for designing therapeutic strategies that target the binding sites of Megalin with its ligands. Gene editing technology and monoclonal antibody therapy aim to regulate Megalin receptor-ligand interactions to achieve therapeutic effects on related diseases. Show less

Fibromyalgia (FM) is a multifactorial syndrome involving chronic pain and psychological distress. Psychological traits such as anxiety, depression, and catastrophising are linked to symptom severity. Genetic variability may contribute to these dimensions through mechanisms related to pain modulation and stress response. To examine associations between selected genetic polymorphisms and psychological variables in women with FM. A cross-sectional study was conducted in 67 women diagnosed with FM. Pain intensity, FM impact and psychological variables-anxiety, depression and catastrophising-were assessed using validated questionnaires. Saliva samples were collected and 10 SNPs were genotyped (COMT rs4680, DRD3 rs6280, OPRM1 rs1799971, BDNF rs6265, MAOA rs1137070, FKBP5 rs1360780, IL6 rs1800796, TNF rs1800629, IL10 rs1800896, IFITM3 rs12252). Correlations were assessed using Pearson or Spearman coefficients, and associations were examined using ANOVA or Kruskal-Wallis with Tukey or Mann-Whitney post hoc tests. Pain intensity correlated with depression (r = 0.476, p < 0.001), catastrophising (r = 0.414, p < 0.001), and anxiety (r = 0.314, p = 0.009). Catastrophising was related to depression (r = 0.615, p < 0.001), anxiety (r = 0.453, p < 0.001), and kinesiophobia (r = 0.445, p < 0.001). BDNF rs6265 was associated with catastrophising (p = 0.044), OPRM1 rs1799971 with anxiety (p = 0.030), and MAOA rs1137070 with depression (p = 0.020). Psychological variables in FM are interrelated and linked to pain perception. BDNF, OPRM1 and MAOA polymorphisms are associated with indices of psychological vulnerability, underscoring the importance of integrating genetic and psychological perspectives to understand variability in FM. Genetic variability influences psychological vulnerability in fibromyalgia. Specific variants were associated with key psychological traits: BDNF rs6265 with pain catastrophising, OPRM1 rs1799971 with anxiety, and MAOA rs1137070 with depressive symptoms. These findings reveal an interplay between genetic and psychological factors that may guide more personalised strategies for managing fibromyalgia. Show less

The inhibition of β-site amyloid precursor protein-cleaving enzyme 1 presents a promising therapeutic strategy for treating Alzheimer's disease by reducing amyloid-β (Aβ) production. This paper employed a computational approach that combined machine learning (ML) and atomistic simulations to accelerate the discovery of potential BACE1 inhibitors. Our ML models, trained on a set of ligands with experimental binding affinity, showed high accuracy when tested on a holdout test set. The best model was used to screen more than two million compounds in the CHEMBL33 chemical library to obtain a short list of top-hit compounds, which were further analyzed using molecular docking and fast pulling of ligand (FPL) simulations. The insights into structure and binding energetics obtained from FPL simulations elucidate the stability and interaction mechanisms of the BACE1-ligand bound state, providing data useful for the rational design of novel AD therapeutics. Show less

Primary dysmenorrhea (PDM) involves recurrent pelvic pain (RPP), alongside menstruation and psychological comorbidity, yet existing models inadequately capture its recurrent nature. In this study, we established a pharmacologically induced rat model of RPP, using estradiol benzoate and oxytocin over six 4-day cycles. The RPP model produced robust and sustained writhing responses, with writhing latency dropping from 30 to 4 min ( Show less

Alcohol use disorder (AUD) remains a major public health problem, with few effective medications currently available. However, peptides of the gut-brain axis appear to offer promising therapeutic targets for AUD as they influence the mesolimbic reward circuitry. Here, we examined the effects of tirzepatide, a long-acting dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist approved for diabetes and obesity, using behavioural assays (locomotor activity and conditioned place preference), alcohol intake paradigms (intermittent access two-bottle choice, drinking in the dark and the alcohol deprivation effect), and molecular analyses (microdialysis, electrophysiology and proteomics) in rodents. First, tirzepatide effectively attenuated the rewarding properties of alcohol, measured through locomotor stimulation, conditioned place preference, and accumbal dopamine release (P < 0.001). Subsequently, this GLP-1R/GIPR agonist dose-dependently reduced voluntary alcohol consumption (P < 0.001), prevented binge (P < 0.01) and relapse-like drinking (P < 0.001), and maintained efficacy during repeated administration (P < 0.001). Finally, tirzepatide induced sustained synaptic depression in the lateral septum (P < 0.05) and further altered histone regulatory proteins in this region (P < 0.05), suggesting a potential neural substrate for its effects. Moreover, the GLP-1R/GIPR agonist affected metabolic parameters including body weight (P < 0.001), adipose tissue mass (P < 0.01), hepatic triglycerides (P < 0.01) and circulating pro-inflammatory cytokines (P < 0.05). Together, our findings suggest tirzepatide modulates alcohol-related behaviours through reward-related mechanisms while also affecting physiological consequences associated with long-term alcohol use. Given tirzepatide's established clinical use and the consistency of effects observed here, these results support further investigation for treating AUD and associated complications. The study is supported by grants from the Swedish Research Council (2023-2600, 2020-00559, 2020-01463, 2024-03054), LUA/ALF (723941 & 1005347) from the Sahlgrenska University Hospital, Alcohol Research Council of the Swedish Alcohol Retailing Monopoly (FO2024-0048), National Institutes of Health (NIH) (P50 AA010761 & U01 AA014095), U.S. Department of Veterans Affairs Office of Research and Development (BLR&D I01BX000813 & IK6BX006299), Herbert & Karin Jacobssons Foundation (2024-Forskning-225), Adlerbertska Research Foundation (2024-791), Wilhelm & Martina Lundgren's Research Foundation (2024-SA-4698), Åke Wibergs Foundation (M24-0216), Swedish Diabetes Foundation (DIA 2024-898) and Mary von Sydow Foundation (2024-36 & 2024-185). Thaynnam A Emous held an international internship scholarship from the São Paulo Research Foundation (FAPESP), Process Number #2023/18470-5, while conducting research at the University of Gothenburg. Show less

Alzheimer's disease (AD) is characterized by progressive cognitive decline associated with the accumulation of amyloid-β (Aβ) peptides and dysregulation of β-site amyloid precursor protein-cleaving enzyme (BACE1) and its phosphorylation at T252 (P-BACE1-T252) as well to the kinase's expression and activity. In this study, the effects of chronic scopolamine administration on Aβ Show less

Beta-site APP-cleaving enzyme 1 (BACE1), a critical rate-limiting enzyme that synthesizes β-amyloid peptide (Aβ), is an important marker of early pathological changes in Alzheimer's disease (AD). Early small plaques cannot be accurately detected using traditional Magnetic resonance imaging (MRI) probes. Therefore, magnetic resonance tuning (MRET) and susceptibility weighted imaging (SWI)-based smart responsive MR nanoprobes are designed to achieve the sensitive detection of BACE1 and Aβ plaques. This probe is modified with a blood-brain barrier-penetrating targeting peptide that enables its reach to the AD microenvironment. The enhancement of T1WI signals owing to the MRET effect caused by the separation of probes in response to BACE1 is used to reflect real-time BACE1 changes. When Aβ plaques are present, the remaining probes that bound around Aβ plaques underwent in situ thiol cross-linking under the action of peroxynitrite (ONOO Show less

Cognitive outcomes following brain insult are shaped by a range of factors, including genetic predispositions. Emerging evidence indicates that specific genetic variants may affect the susceptibility to cognitive impairment in individual patients. In this systematic review we summarize the evidence for genetic variants on cognitive outcomes following brain insults. A systematic search was conducted in PubMed, Embase, PsycINFO, bioRxiv, medRxiv, reference lists, and ClinicalTrials.gov to identify studies published before June 14, 2023, reporting associations between genetic variants and cognitive outcomes following brain insults. Only studies conducted in humans and published in English were included. A broad definition of brain insults was applied, with a primary focus on stroke, traumatic brain injury (TBI), and brain tumors. All articles underwent bias assessment using the JBI critical appraisal tools. Of the 121 studies included, 80 (66%) were rated as low risk of bias. The APOE gene was investigated in 56% of TBI studies, 52% of stroke studies, and 43% of studies on other brain injuries. Of the 74 studies on APOE, 50 (68%) focused on the ε4 allele, with 39 studies (87%) reporting associations between the ε4 allele and worse cognitive outcomes. The BDNF rs6265 polymorphism was examined in 18 studies, 15 of which reported significant effects on cognitive outcomes. However, the direction of these effects was inconsistent, with seven studies linking the G allele and seven the A allele to worse cognitive outcomes. For the COMT rs4680 polymorphism, nine out of 12 studies reported worsened cognitive outcomes linked to the G allele, while several reported a protective association for the A allele. Injury- and population-specific patterns were not consistent. This systematic review suggests that APOE-ε4 and potentially the G allele of COMT rs4680 are associated with poor cognitive outcomes following brain insults. The type of brain injury does not appear to influence whether genetic variants predispose to favorable or unfavorable cognitive outcomes. Future research may benefit from focusing on these markers, particularly in larger datasets, to validate these findings. Show less

The hallmark lesions of the Alzheimer's disease (AD) brain are amyloid plaques consisting of the β-amyloid protein and neurofibrillary tangles comprised of hyperphosphorylated, aggregated tau protein, which both cause neuronal dysfunction and loss. One goal of neuroprotective therapies is to maintain normal neuronal function and survival in the presence of toxic pathologies such as plaques and tangles. A potential neuroprotective target is nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, which regulates the expression of many antioxidant and detoxification genes. Nrf2 mRNA is decreased in AD brains, and deletion of the Nrf2 gene causes increased BACE1 and Aβ production and worsened cognitive deficits in amyloid pathology mouse models. Overexpression of Nrf2 in astrocytes has been shown to be protective against neurodegeneration, but the role of Nrf2 is neurons is unclear. We overexpressed Nrf2 from birth in neurons of 5XFAD amyloid pathology model mice using AAV8, hypothesizing that neuronal Nrf2 overexpression decreases cortical neuron loss and reduces plaque load by decreasing BACE1 levels. We quantified protein levels by immunoblot and neuropathology by immunofluorescent staining, using two-way ANOVA to measure differences between genotypes and AAV treatments. To assess genetic changes, we performed bulk mRNA seq. While neuronal overexpression of Nrf2 in 5XFAD mice did not prevent neuronal loss as measured by NeuN labeling, decrease neuroinflammation by Iba1 or GFAP labeling, or reduce amyloid load by Aβ antibody or methoxy-XO4 staining, we show that increased Nrf2 expression reduces BACE1 protein levels, especially in swollen axonal dystrophic neurites around amyloid plaques. Other proteins that accumulate in dystrophic neurites were also reduced, indicating decreased dystrophic neurites overall. Immunoblot analysis suggested increased autophagy was unlikely to play a role, while bulk mRNA sequencing indicated changes in lipid metabolism and microtubule stability may have contributed to reduced dystrophic neurite formation. Dystrophic neurites impair action potential conductance and contribute to tau seeding and spreading. Their reduction by neuronal Nrf2 overexpression may protect neurons against these pathologic changes. Further study of the mechanisms by which Nrf2 reduces dystrophic neurites may lead to therapeutic strategies that can limit neuritic damage caused by cerebral amyloid accumulation. Show less

A series of novel granatane-triazole hybrid molecules was designed, synthesized, and evaluated as dual acetylcholinesterase (AChE) and β-secretase 1 (BACE1) inhibitors. The compounds were obtained through a convergent synthetic route involving azide formation, triazole construction via dipolar cycloaddition, and final coupling with a granatane scaffold to give a pseudopelletierine (3-granatanone) analogue. In vitro assays demonstrated that all target compounds inhibited both AChE and BACE1. Molecular docking and molecular dynamics simulations revealed stable interactions with key catalytic residues, suggesting distinct binding modes compared to reference ligands. QSAR-based pharmacokinetic predictions indicated favorable blood-brain barrier permeability and compliance with key drug-likeness filters. These findings identify granatane-triazole hybrids as promising multi-target directed ligand (MTDL) candidates with potential for further optimization in the search for new anti-Alzheimer therapeutics. Show less

Accumulation of amyloid β (Aβ) peptide in the brain is a characteristic pathological feature of Alzheimer's disease that occurs several decades before the onset of symptoms. Aβ is produced from the membrane-bound amyloid β precursor protein (APP) by β-secretase 1 (BACE1) and γ-secretase-mediated proteolytic cleavage. Alternatively, ADAM10/17 α-secretase and γ-secretase cleavage does not generate Aβ. Accumulating evidence indicates that intracellular trafficking of APP to each secretase determines the level of Aβ production. In this chapter, we summarize how glycosylation affects the Aβ production, possibly by modulating the intracellular localization of APP and its secretases. Show less

Retinal neurodegenerative diseases such as Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa cause irreversible vision loss due to the limited regenerative capacity of the mammalian retina. Cerium oxide nanoparticles (nanoceria) are emerging therapeutics against oxidative stress and inflammation, major drivers of photoreceptor degeneration, and have demonstrated morphological and functional neuroprotection in preclinical models. However, the genome-wide transcriptional mechanisms underlying these effects remain incompletely characterized. We performed retinal transcriptomic analysis in a rat AMD model induced by intense light and treated intravitreally with nanoceria. Six groups were analyzed: control, light damage, vehicle, nanoceria, vehicle + light damage, and nanoceria + light damage. Light damage activated inflammatory and apoptotic programs, with upregulation of cytokines (Tnf, Il6, Il1b, Ccl2) and downregulation of photoreceptor genes (Rho, Pde6a/b, Gnat1). Nanoceria treatment counteracted these effects, suppressing pro-inflammatory mediators, restoring antioxidative genes (Nfe2l2, Gclc, Sod2), and enhancing neuroprotective factors (Bdnf, Cntf, Ngf). Pathway analyses revealed inhibition of TNF/NF-κB/IL-17 signaling and activation of PI3K-Akt, JAK-STAT, and neurotrophin pathways. Unexpectedly, nanoceria also modulated amino acid and insulin metabolism (Ass1, Cps1, Insr, Irs1, Slc2a4) and reactivated transcription factors (Ascl1, Sox2, Notch1) typically silent in adult retina. Our findings highlight nanoceria as a multifunctional therapeutic that mitigates retinal degeneration by coordinating oxidative, inflammatory, and regenerative responses. Together with prior morphological and functional validations, these results support the translational potential of nanoceria for treating retinal neurodegenerative diseases. Show less