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Chronic psychological stress drives neuroimmune crosstalk and accelerates atherosclerosis progression. Physical exercise confers broad health benefits and is associated with reduced inflammation. However, the exercise-mediated factors and mechanisms that mitigate stress-induced vascular inflammation remain unclear. Chronic restraint stress (CRS) and voluntary exercise models were established to investigate the role of exercise in neuroimmune crosstalk. RNA sequencing identified kinesin family member 4 (Kif4) as a key gene associated with the attenuation of stress-induced inflammatory responses in peripheral blood monocytes following exercise. Combined co-immunoprecipitation-mass spectrometry and membrane proteomics identified T cell-interacting activating receptors on myeloid cell 1 (TARM1) as the Kif4 cargo. The function of TARM1 was validated using an immobilized TARM1-Fc fusion protein. Brain-derived neurotrophic factor (BDNF), a key effector during exercise and stress, regulated the Kif4-TARM1 axis using recombinant BDNF (rBDNF) and the TrkB inhibitor ANA-12. Finally, exercise-mediated effects and mechanisms were examined in atherosclerotic CRS-exposed mouse models and in patients with coronary artery disease (CAD) experiencing high psychological stress. Physical exercise alleviated stress-induced neuroimmune crosstalk, reduced the proinflammatory CD11b Physical exercise alleviates stress-induced neuroimmune crosstalk through the BDNF-Kif4-TARM1 axis, revealing a novel neuroimmune-mediated brain-heart axis that supports exercise-based therapeutic strategies for psychogenic CAD. Chronic psychological stress drives systemic inflammation through neuroimmune mechanisms, thereby accelerating the progression of coronary artery disease (CAD). Physical exercise alleviates stress-induced neuroimmune crosstalk, partly by suppressing proinflammatory responses in monocytes/macrophages. This study provides novel insights into exercise-regulated neuroimmune mechanisms involving the monocyte BDNF-Kif4-TARM1 axis. In both an atherosclerotic mouse model and patients with CAD, exercise mitigated stress-induced inflammation via the BDNF-Kif4-TARM1 axis. Show less

India's escalating burden of obesity and metabolic disease is characterized by a distinctive "thin-fat" phenotype, in which individuals with normal or near-normal body mass index exhibit disproportionate visceral adiposity, reduced skeletal muscle mass, and heightened susceptibility to insulin resistance. Conventional obesity models centered primarily on caloric imbalance fail to adequately explain this pattern, underscoring the need for a more integrative pathophysiological framework. Emerging evidence implicates gut microbiome dysbiosis, impaired fermentation of dietary fibers, reduced short-chain fatty acid (SCFA) signaling, altered bile acid metabolism, metabolic endotoxemia, and dysregulated adipose tissue crosstalk as key contributors to metabolic vulnerability in South Asian populations. This commentary synthesizes mechanistic insights into the gut-metabolic axis and examines their relevance to India's phenotype-specific challenges. Key pathways, including SCFA-mediated incretin secretion, Toll-like receptor 4 (TLR4)-driven inflammatory signaling, angiopoietin-like protein 4 (ANGPTL4)-mediated lipid partitioning, and microbiota-dependent bile acid biotransformation, are discussed as interconnected drivers of metabolic dysfunction. Emerging clinical evidence from randomized controlled trials evaluating synbiotic and prebiotic-botanical formulations is also discussed, highlighting their potential benefits as adjuncts to lifestyle modification. Given India's dietary patterns and widespread deficiency of fermentable fiber intake, synbiotics may represent a scalable and biologically coherent strategy to support metabolic health. However, heterogeneity of formulations, interindividual microbiome variability, and limited long-term outcome data necessitate cautious interpretation. Advancing precision microbiome-targeted interventions will require population-specific research, multi-omics integration, and rigorous clinical evaluation. Show less

Recent work by Mu et al. identifying irisin as a modulator of adipose tissue IL-33 and regulatory T cells introduces a new paradigm in immunometabolic biology, shifting attention from thermogenesis alone toward immune-stromal crosstalk as a determinant of metabolic health. By inducing IL-33 production in adipose mesenchymal stromal cells, irisin preserves ST2+ regulatory T cells (Tregs) in visceral adipose tissue, thereby restraining inflammation, improving insulin sensitivity, and promoting metabolic homeostasis. This mechanism expands the concept of exercise-induced metabolic protection by highlighting adipose tissue immune niches as critical targets of myokine action. In parallel, emerging evidence from preclinical models indicates that irisin-driven IL-33 signaling in subcutaneous adipose tissue contributes to thermogenic activation through mechanisms distinct from Treg-mediated immune regulation, highlighting depot-specific effects of this pathway. Beyond adipose tissue, irisin has emerged as a pleiotropic mediator with reported roles in glucose homeostasis, cardiovascular protection, and neurobiology. Importantly, accumulating evidence indicates that irisin may also exert neuroprotective effects, including the induction of brain-derived neurotrophic factor (BDNF), amyloid-β (Aβ) clearance, and α-synuclein degradation, thereby linking metabolic and neurodegenerative pathways. Although the findings of Mu et al. derive from preclinical models, they provide a conceptual model for therapeutic strategies aimed at reproducing selected benefits of exercise in obesity, metabolic and neurodegenerative disorders. Notably, these effects appear to depend on sustained irisin exposure in preclinical systems, supporting a role for irisin as a regulator of long-term immunometabolic homeostasis. Collectively, these observations position the irisin/IL-33/Treg axis as a promising link between exercise, adipose tissue immunity, and systemic metabolic regulation, suggesting that targeting immunometabolic circuits, rather than energy balance alone, may open new avenues for future therapeutic intervention. Show less

Dietary diversity plays a crucial role in maintaining physical function. This study explored the association and potential mechanisms between dietary diversity and gait characteristics measured by wearable devices in older adults. This cross-sectional study included 861 older adults aged 60 years or above. Dietary diversity score (DDS) was assessed using a standard food frequency questionnaire. A multi-sensor gait system was used to measure periodic, kinetic, and spatiotemporal gait parameters during a 12-meter walking test. The coefficient of variation (CV) was calculated for each parameter to assess gait stability. Multivariable linear regression models were conducted to examine the relationship between DDS and gait parameters, adjusting for demographics, lifestyle factors, cognitive function, and comorbidities. Participants had a mean age of 70.25 ± 6.19 years, with 58.30% being female. After adjusting for all covariates, each 1-SD increase in DDS was positively associated with Z-scores of landing control force (β = 0.072, SE = 0.033, P = 0.033), foot-off angle (β = 0.076, SE = 0.033, P = 0.021), gait speed (β = 0.086, SE = 0.033, P = 0.008), step length (β = 0.068, SE = 0.031, P = 0.032), and stride length (β = 0.078, SE = 0.033, P = 0.013). Furthermore, higher DDS was negatively associated with the CVs of initial limb support time, step time, stride time, ground reaction force, landing control force, foot-off angle, gait speed, and step length (all P < 0.05). We also identified biomarkers simultaneously related to both DDS and gait characteristics, including albumin, leptin, myostatin, brain-derived neurotrophic factor, insulin-like growth factor-1, high-sensitivity C-reactive protein, interleukin-6, and glutathione reductase. Higher DDS is associated with superior kinetic and spatiotemporal gait vigor performance and enhanced gait stability. Pathways involving nutritional status, energy metabolism, inflammatory regulation, antioxidant defense, and neural function may underpin this association. Show less

Neuroinflammation is a chronic inflammatory response that contributes to synaptic dysfunction and neuronal damage, it is a common feature among various neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD). Tocotrienol-rich fraction (TRF) is a form of vitamin E that is known for its anti-inflammatory, antioxidant and neuroprotective properties. Yet, it has not been adequately investigated in both cellular and animal neuroinflammation models. In this study, the potential therapeutic effects of TRF were investigated in-vitro using BV2 microglial cells and also in-vivo in a pilot study using Sprague Dawley rats. TRF at 5 and 10 µg/mL were found to reduce nitric oxide (NO) and reactive oxygen species (ROS) levels. Furthermore, in-vivo treatment with TRF significantly increases the recognition index implying improvement in cognition ability. Gene expression analysis showed downregulation of RelA, TNF-α and IL-6 while NFE2L2 and BDNF were upregulated. These findings suggests that TRF may help mitigates neuroinflammation and oxidative stress, indicating its potential as a candidature for further investigation in neurodegenerative diseases associated with chronic neuroinflammation. Show less

Research using latent profile analysis (LPA) has yielded inconsistent results regarding the number of personality profiles among athletes, the specific configuration of the Big Five traits, and their interpretation. This study seeks to explore personality types by excluding additional variables from the LPA model, aiming to assess how well personality profiles are universal (independent of gender and cultural context) and can predict academic achievement in student athletes. A cross-sectional study was conducted using a paper-and-pencil questionnaire among 424 student athletes from two universities in Poland and Ukraine. The average age of participants was 20 years old ( Show less

Depression is a prevalent mental disorder that profoundly affects patients' quality of life and work efficiency. The exploration of effective and safe treatment options remains a research focus for alleviating depression. This study aimed to assess the potential of We initially investigated the effects of GM12 on corticosterone (CORT)-induced injury in PC12 cells. Subsequently, the male Sprague-Dawley rats ( GM12 improved the viability of PC12 cells, reduced LDH release and apoptosis, thereby exerting protective effects against CORT-induced cell damage. GM12 administration significantly ameliorated depressive-like behaviors, restored 5-HT levels, normalized HPA axis hormone imbalances, reduced inflammatory response and upregulated of BDNF level and the BDNF/CREB protein expression in rats. The beneficial effects of GM12 may be mediated via multiple mechanisms, including regulation of gut microbiota composition and homeostasis, inhibition of inflammation and the modulation of the microbiota-gut-brain axis. This study can provide early evidence for the research of in-depth mechanism and development of this strain. Overall, GM12 shows promise as a potential treatment strategy or dietary supplement for depression, with significant potential for future application. Show less

Prenatal exposure to opioids such as morphine poses significant risks to fetal neurodevelopment, particularly in brain regions critical for cognition, such as the hippocampus. Despite the prescription and use of opioids during pregnancy, the molecular and histological consequences of such exposure remain insufficiently explored. To evaluate the effects of short-term prenatal morphine exposure on the expression of key neurodevelopmental genes and the structural integrity of the hippocampus in neonatal rats. Pregnant Sprague Dawley rats were administered intraperitoneal injections of morphine sulfate (10 mg/kg) on gestational days 15 and 16. On postnatal day 12, offspring (n = 6 per group) were euthanized, and their hippocampal tissues were collected. Quantitative real-time PCR was performed to assess the expression levels of neurodevelopmental genes, including MDH2, Neurog1, and BDNF. Histological evaluations were conducted using hematoxylin and eosin and cresyl violet staining to assess cellular architecture and neuronal viability. Immunohistochemical staining for GFAP, S100, and synaptophysin was used to evaluate astrocytic integrity and synaptic density. The morphine-exposed group showed significant up-reglation of MDH2, Neurog1, and BDNF ( Prenatal morphine exposure leads to marked molecular and histopathological changes in the developing hippocampus, suggesting long-term risks for neurocognitive dysfunction. These findings emphasize the importance of limiting opioid use during pregnancy and identifying molecular targets for future therapeutic interventions. Show less

Arsenic trioxide (ATO) remains vital in acute promyelocytic leukemia therapy, yet its clinical use is limited by cumulative organ toxicities, particularly neurotoxicity, which compromise tolerability and outcomes. Perindopril and L‑Arginine exert cytoprotective effects through antioxidant and anti‑inflammatory mechanisms. This study evaluated their neuroprotective efficacy against ATO‑induced neurotoxicity, emphasizing mechanistic pathways. Male rats were assigned to five groups: Control, ATO‑only (7.5 mg/kg, intraperitoneally, 14 days), Perindopril (2 mg/kg, orally), L‑Arginine (200 mg/kg, orally), and combined therapy. Interventions commenced seven days prior to the ATO challenge and continued for 21 days. Body weight was documented at baseline and endpoint; survival indices were monitored. Biochemical, histopathological, and molecular evaluations examined oxidative stress, inflammatory mediators, and apoptotic signaling. ATO exposure increased malondialdehyde (MDA) and nitric oxide derivatives (NOx), while reducing glutathione (GSH), superoxide dismutase (SOD), and catalase activities. It elevated tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β), and interleukin‑6 (IL‑6), while suppressing brain‑derived neurotrophic factor (BDNF) and nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1 (Nrf2/HO‑1) signaling. Upregulation of Kelch‑like ECH‑associated protein 1/Nuclear factor kappa‑light‑chain‑enhancer of activated B cells (Keap1/NF‑κB), cleaved caspase‑3, and caspase‑3, alongside downregulation of B cell lymphoma‑2 (Bcl‑2), was evident. Histopathological lesions substantiated neurotoxicity. Perindopril and L‑Arginine markedly reversed these perturbations, reinstating molecular and structural homeostasis. Their combination afforded superior neuroprotection compared with monotherapies. Both agents mitigate ATO‑induced neurotoxicity through antioxidant, anti‑inflammatory, and anti‑apoptotic mechanisms, with their co‑administration surpassing individual efficacy. The Keap‑1/Nrf2/HO‑1 axis emerges as a critical therapeutic node, underscoring the translational potential of combined intervention. Show less

Chronic stress induces detrimental effects on cognition, behavior, and hippocampal integrity. An enriched environment (EE) has been shown to enhance learning and memory; however, its role against chronic immobilization stress (CIS)-induced alterations and the underlying mechanisms remain insufficiently explored. This study aimed to investigate the protective effects of EE on CIS-induced behavioral, molecular, and structural changes in the hippocampus of adult male rats. Thirty-two adult male Wistar albino rats were assigned to four groups: control, control + EE, CIS, and CIS + EE. Rats were subjected to CIS (4 h/day) followed by EE exposure (2 h/day) for 28 days. Behavioral assessments were conducted. Serum corticosterone levels, hippocampal brain-derived neurotrophic factor (BDNF), and mRNA expression of aquaporin-4 (AQP4) and glutamate receptors (GluA1 and GluA2) were evaluated. Histopathological, ultrastructural, and immunohistochemical (LC3) examinations were performed. EE significantly ameliorated CIS-induced cognitive and behavioral impairments and restored hippocampal histological and ultrastructural integrity. These effects were associated with reduced serum corticosterone levels, increased hippocampal BDNF levels, and upregulated expression of AQP4, GluA1, and GluA2 mRNA. These findings suggest that EE is a promising non-pharmacological strategy for mitigating stress-induced hippocampal dysfunction and cognitive decline. Show less

Ischemic stroke is a leading cause of death and disability among youth, with sex-specific differences in risk and outcomes, including post-stroke cognitive impairment. However, the neurodevelopmental factors underlying these pathological states are unclear. This study examined hypoxia-inducible factor-1 alpha (HIF-1α) and brain-derived neurotrophic factor (BDNF) levels in bilateral common carotid artery occlusion/reperfusion (BCCAO/R)-induced ischemic stroke in rats. It focused on post-stroke cognitive decline in male and female adult offspring following BCCAO/R-induced ischemic stroke, after prenatal immune activation (PIA) and late-trimester intermittent maternal hypoxic stress (IMHS). PIA was induced by lipopolysaccharide (0.1 mg/kg, i.p.) injection at gestational day (GD) 15, followed by IMHS exposure from GDs 17 until delivery. Thereafter, offspring (n = 10, male and females) from sham control, LPS-exposed, hypoxia-exposed, and combined LPS + hypoxia group were exposed to BCCAO/R-induced ischemic stroke at postnatal day 90. Neurological deficits and post-stroke cognitive function were assessed using Y-maze and novel-object recognition tests at 1-day and 5-days post-surgery. The prefrontal cortex and striatum, where structural and functional alterations have primarily been described in stroke patients, were isolated for BDNF and HIF-1α ELISA quantification. In female rats, non-spatial working memory was acutely reduced after BCCAO/R-induced stroke following PIA-IMHS exposures, but males were unaffected. Rats co-exposed to LPS + hypoxia show decreased HIF-1α in the male striatum compared to sham or LPS/hypoxia groups. The two-hit factor increased striatal BDNF levels compared with LPS alone. In females' prefrontal cortex, LPS + hypoxia versus controls, but LPS + hypoxia reduces BDNF more than LPS alone, indicating a synergistic and sex-dependent role of PIA and IMHS in stroke vulnerability at adulthood. Show less

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited white matter disorder. Initially, a "classic" phenotype has been characterized, presenting early-onset macrocephaly, cerebellar ataxia, mild spasticity, and a distinctive neuroimaging pattern of diffuse white matter abnormalities with subcortical cysts. An "improving" phenotype has also been described, featuring milder or absent neurological signs and a remitting pattern on neuroimaging. Mutations in four genes, MLC1, HEPACAM, GPRC5B and AQP4 have been associated with MLC. We describe clinical and genetic features of a cohort of genetically confirmed Italian MLC patients, representing the largest Italian cohort reported to date. We conducted a retrospective, multicenter, observational study. Patients were included based on clinical and neuroimaging features consistent with MLC, along with a confirmed genetic diagnosis. Data were collected using a standardized database and included demographic, clinical, neuroimaging, neurophysiological, and genetic information. Thirty-three patients from eight Italian centers were enrolled. Twenty-seven harbored biallelic MLC1 variants (23 distinct mutations, including three novel variants), while six had three distinct heterozygous HEPACAM variants. All MLC1-mutated patients exhibited the "classic" phenotype, frequently accompanied by orthopedic, gastrointestinal, and respiratory comorbidities. HEPACAM-mutated patients were consistent with the "improving" phenotype. No patients harbored mutations in GPRC5B or AQP4. Our findings expand the mutational spectrum of MLC1, further characterize the disease phenotype, and provide valuable insights into its presence in Italy. They also underscore management needs of individuals with MLC, highlighting the importance of multidisciplinary care. Show less

Insufficient physical activity is prevalent among perinatal women, and digital health interventions offer a promising avenue to promote engagement in physical activity within this population. However, previous studies have relied heavily on self-reported data, lacking a systematic synthesis based on objective measurements. This study aims to systematically evaluate the effects of digital health interventions on objectively measured physical activity and sedentary behavior in perinatal women. A systematic search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library databases from inception to December 20, 2025. Fourteen randomized controlled trials (RCTs) involving 2,101 participants were included. The Risk of Bias 2.0 (RoB 2.0) tool was used to assess bias risk, random-effects models were employed to pool effect sizes, and the quality of evidence was evaluated using the GRADE system. The meta-analysis showed that, following the exclusion of outliers via sensitivity analysis, digital health interventions significantly increased daily step counts (MD = 0.68, Digital health interventions can effectively and robustly enhance daily baseline activity levels in perinatal women, with the observed increments potentially reaching the minimal effective dose for improving metabolic health. However, current intervention designs face challenges in driving high-intensity behavior change and disrupting sedentary habits. Future research should explore more targeted and personalized intervention strategies. This systematic review and meta-analysis has been registered in PROSPERO (www.crd.york.ac.uk/prospero), identifier CRD420261280936. Show less

Chronic stress is a risk factor for the development of anxiety, depression, and comorbid systemic conditions. Ayahuasca (AYA) has been used for hundreds of years and it elicits antidepressant and anxiolytic effects. However, it remains unknown whether AYA elicits a behavioral and biochemical protective effect in chronic stress. Therefore, we evaluated the therapeutic potential of AYA in reversing or attenuating the behavioral and biochemical alterations induced by an unpredictable chronic stress (UCS) paradigm in adult zebrafish. Zebrafish underwent an unpredictable chronic stress (UCS) protocol for 14 days or were left undisturbed in their tanks. On the 15th day, AYA was added to the tank at a dose of 0.5 or 1 mL/L for one hour. On day 16, fish underwent the sociability test and the novel tank test. The levels of whole-body cortisol and brain-derived neurotrophic factor (BDNF) were measured via ELISA. AYA restored stress-induced sociability impairments, anxiety-like behavior, and stress-induced hyperlocomotion and increased moving velocity in the novel tank test. Additionally, AYA reversed the stress-induced increase in whole-body cortisol and the stress-induced decrease in whole-brain BDNF. A single exposure of zebrafish to AYA restored the chronic stress-induced impairments in sociability, stress-induced anxiety-like behavior, and biochemical markers of stress and impaired neuroplasticity. These findings support the potential of AYA to reverse stress-induced behavioral and neuroendocrine alterations. Clinical studies are warranted to evaluate the translational relevance of these effects in individuals exposed to chronic stress. Show less

Neuritin 1 (NRN1) has emerged as a multifaceted regulator of synaptic plasticity, neuronal excitability and structural remodelling. This review synthesises knowledge of NRN1 function across the central and peripheral nervous systems, with a focus on its roles in sensory neurones and neuronal repair following injury. We discuss evidence that NRN1 interacts with classical neurotrophic pathways, including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), while engaging distinct cellular mechanisms that span activity-dependent trafficking, modulation of calcium and potassium channel function and regulated local axonal mRNA translation. Accumulating data indicate that NRN1 contributes to injury-induced plasticity and functional recovery through both cell-autonomous neuronal mechanisms and non-cell-autonomous signalling involving glial and stromal cells. In long-projecting sensory axons, regulated transport and local translation of Nrn1 mRNA position NRN1 as a spatially restricted effector of axonal growth, excitability and regeneration. Dysregulation of NRN1 expression and signalling has been implicated in pathological contexts including neurodegeneration, diabetic peripheral neuropathy and inflammatory pain, where restoration of NRN1 activity promotes axonal integrity, Schwann cell survival and neurotrophic support. Beyond neurons, NRN1 also modulates inflammatory and angiogenic pathways, including VEGF and CXCR4 signalling, linking neuronal plasticity to broader tissue and immune responses. Together, these findings support a model in which NRN1 acts as a molecular integrator of neurotrophic, metabolic and injury-associated signals, coordinating plasticity while also presenting potential routes to maladaptive sensitisation. We highlight key mechanistic and translational challenges that must be addressed to harness NRN1 biology therapeutically aimed at enhancing neuronal repair while limiting persistent sensory dysfunction. Show less

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare lung malignancy characterized by an aggressive clinical course and an unfavorable prognosis. Next-generation sequencing (NGS) has revealed that LCNECs exhibit molecular features resembling either small-cell lung carcinoma (SCLC-like LCNEC) or non-small cell lung carcinoma (NSCLC-like LCNEC). This study aimed to characterize the incidence of actionable gene variants in a retrospective cohort of LCNEC patients using a targeted NGS approach. Microscopic diagnosis was established according to the 2021 World Health Organization (WHO) classification using a standard immunohistochemical (IHC) panel. In total, 216 LCNEC tumor samples were analyzed for molecular variants in 17 genes using the RNA-based Archer FusionPlex Lung NGS assay (Integrated DNA Technologies, USA) and the MiSeq platform (Illumina, USA)-an algorithm utilized for routine NSCLC diagnosis. Overall, 46 variants were identified in 46/216 (21.3%) tumor samples, with 28/216 (13%) LCNECs harboring at least one actionable molecular variant potentially targetable by registered or investigational agents. Show less

TF (transcription factor) Prdm16 (positive regulatory domain-containing protein 16) regulates hematopoietic and neuronal stem cell homeostasis, adipose differentiation, and cardiac development. Its role in the circulatory system extends beyond the heart, as Prdm16 loss in arterial endothelial cells (ECs) impairs arterial reperfusion of ischemic mouse limbs due to endothelial dysfunction, and Zebrafish were used to analyze vascular development, arteriovenous endothelial specification, and the emergence of arteriovenous malformations in the absence or presence of Prdm16 or Notch signaling. Lentiviral-mediated Prdm16 overexpression in human endothelial (progenitor) cells was coupled to qRT-PCR (real-time quantitative polymerase chain reaction), Western blot, and transcriptional profiling to document Prdm16's importance for arterial lineage specification. Coimmunoprecipitation in HEK293 (human embryonic kidney 293) cells was performed to assess physical interaction between Prdm16 and the Notch pathway. Existing mouse and human data sets were reanalyzed to evaluate Prdm16 expression in mammalian arteriovenous malformations. Prdm16 actively promotes arterial EC identity while suppressing venous fate. Like in mice, Prdm16 is expressed by arterial ECs early during vascular development in zebrafish, where it synergistically coordinates arterial development together with canonical notch signaling, as their combined loss in zebrafish leads to arteriovenous malformations. PRDM16's arterializing effect on human ECs is dependent on canonical Notch activity, as it is blunted in the presence of canonical Notch inhibitors and potentiated in the presence of delta-like ligand 4. Mechanistically, Prdm16 does not increase the protein levels of the cleaved intracellular domain of Notch receptors (notch intracellular domain) but rather potentiates the effect of the latter via physical and functional interaction. Prdm16 further finetunes Notch signaling and arterial development by complexing with Hey2 (Hes-related family bHLH TF with YRPW motif 2), the basic helix-loop-helix TF acting downstream of canonical Notch during arterial lineage specification and development. Together, our data demonstrate an intricate interplay between Prdm16 and Notch in ECs and indicate that Prdm16 signaling may constitute a novel therapeutic target for arteriovenous malformations. Show less

A vital question in neuroscience is whether and how efficiently cellular models may be differentiated into functional neuronal cells in culture. Despite the frequent use of the human neuroblastoma cell line SH-SY5Y, differentiation protocols vary extensively, with the most common being differentiation via the addition of retinoic acid and brain-derived neurotrophic factor. However, due to the lack of a reliable evaluation method, their adequacy as synaptic models remains unclear. Here, we investigate whether SH-SY5Y cells constitute a functional model for synaptic studies by phenotypically and ultrastructurally analyzing synaptogenesis in SH-SY5Y cells subjected to different differentiation protocols. Electron microscopy (EM) techniques, including conventional EM, cryo-EM, and cryo-electron tomography, were systematically applied to characterize synaptogenesis in SH-SY5Y cells. Further characterization was performed using immunostaining and functional assays, such as live exocytosis assays and whole-cell patch-clamp electrophysiology. Despite exhibiting some presynaptic-like features, differentiated SH-SY5Y cells do not form morphologically or functionally complete synapses under the conditions tested. Immunostaining results were consistent with previous findings, showing synaptic markers. However, functional investigations did not detect synaptic activity. High-throughput EM analyses revealed an absence of synaptic structures in these cells. Additionally, an alternative differentiation approach incorporating additional neurotrophic factors promoted the formation of presynaptic-like compartments containing synaptic vesicle-like vesicles (SVLVs). In contrast to typical synaptic vesicles, these SVLVs exhibited a pleomorphic size distribution and lacked connectors. These findings underscore the need for cautious interpretation of results derived from SH-SY5Y cells when investigating molecular synaptic architecture or function, as well as neurodegenerative diseases. Show less

Alzheimer's disease (AD) involves progressive neurodegeneration, with abnormal receptor signaling and disrupted cell-cycle activity leading to neuronal loss. Here, we identify a previously unknown mechanism linking β-amyloid (Aβ) exposure to the nuclear translocation of the Insulin-like Growth Factor 1 Receptor (IGF1R) in differentiated SH-SY5Y neuronal cells. The differentiated cholinergic model induced by retinoic acid and BDNF expresses acetylcholinesterase (AChE) and indicates that under amyloidogenic stress, IGF1R may transition from homeostatic membrane and vesicular signaling to a nuclear-centric function. We show that prolonged Aβ treatment causes phosphorylation-dependent nuclear import of IGF1R, confirmed by confocal imaging and biochemical fractionation. IGF1R is conventionally located in the membrane and vesicular membranes; however, under amyloidogenic stress, we show here that it is imported to the nucleus and exerts transcriptional control. The buildup of nuclear IGF1R coincided with increased Cyclin D1 levels and redistribution of neurons into S and G₂ phases, indicating abnormal cell-cycle re-entry. Chromatin immunoprecipitation demonstrated increased IGF1R binding at the CCND1 and JUN promoters after Aβ exposure, suggesting a direct role in gene transcription. Pharmacological blockade of IGF1R phosphorylation by PPP or SUMOylation by Ginkgolic acid significantly reduced Cyclin D1 elevation, implying that both post-translational modifications are involved in receptor nuclear trafficking. Co-immunoprecipitation and confocal imaging identified Nucleophosmin (NPM1) as a putative IGF1R interacting partner, potentially contributing to its nuclear transport and stabilizing receptor-chromatin complexes. These results establish IGF1R as a signaling-transcription connector linking extracellular amyloid stress to nuclear gene regulation, providing a mechanistic explanation for faulty neuronal cell-cycle re-entry in AD. We suggest that abnormal IGF1R-NPM1 interactions contribute to receptor mislocalization and cell-cycle failure, highlighting new targets for therapeutic intervention aimed at receptor trafficking and neuroprotection in Alzheimer's disease. Show less

Aging is associated with disturbances in brain energy metabolism, mitochondrial dysfunction, and increased oxidative stress, all of which increase neuronal vulnerability and contribute to the development of neurodegenerative disorders. Growing evidence indicates that physical exercise exerts neuroprotective effects through the release of exerkines-exercise-induced signaling molecules that mediate communication between peripheral tissues and the brain. Among them, irisin, a proteolytic cleavage product of the membrane protein FNDC5, has emerged as an important mediator of the muscle-brain axis. This review summarizes current knowledge on the molecular mechanisms underlying irisin activity in the central nervous system, with particular emphasis on the AMPK-PGC-1α-FNDC5/BDNF signaling axis, rapid receptor-mediated pathways involving the cAMP/PKA/CREB and ERK/CREB cascades, and the regulation of mitochondrial homeostasis, including biogenesis, dynamics, autophagy, and mitophagy. Experimental studies suggest that irisin may improve neuroplasticity, neuronal survival, mitochondrial function, and reduce oxidative stress, thereby alleviating cognitive deficits in models of aging and neurodegeneration. Although the precise receptor mechanisms and intracellular signaling events remain incompletely understood, accumulating evidence identifies irisin as a promising therapeutic target linking metabolic adaptation with neuroprotection. Further investigation of irisin-dependent pathways may facilitate the development of novel strategies aimed at preserving brain function and delaying the progression of age-related neurodegenerative diseases. Show less

Housing conditions, particularly environmental enrichment (EE), can influence experimental outcomes and welfare. While EE is generally regarded as beneficial, a male bias exists in research supporting this. This study investigated whether sex differences exist in levels of BDNF in the brain and peripheral tissues in environmentally enriched mice. Expression of the catecholamine biosynthetic enzymes of the adrenal glands, key to the sympathoadrenal medullary system and stress response, was also investigated. We showed that female mice exposed to EE exhibited increased anxiety-like behaviors. EE in male mice did not induce anxiety-like behavior, and it was associated with increased hippocampal and pituitary BDNF expression, suggestive of enhanced neurotrophic support. In the adrenal gland, the levels of adrenal catecholamine biosynthetic enzymes, specifically total tyrosine hydroxylase and PNMT levels, were increased in females, but not in males. In conclusion, EE may serve as a mild stressor in female mice. In male mice, EE may have induced neurotrophic support of the hippocampus since hippocampal BDNF levels were increased with minimal changes to adrenal catecholamine synthetic enzymes. This study highlights the importance of considering sex as a biological variable in translational neuroscientific research. Show less

Age-related cognitive decline is a growing public health concern, yet early molecular indicators remain poorly defined. Since brain changes often precede behavioral symptoms, identifying early markers of vulnerability is critical. Here, we investigated whether dopamine regulation and synaptic or inflammatory signaling might provide early indicators of cognitive decline, prior to behavioral impairment. Method and Finding: Female hooded-Lister rats at 6 (young) and 12 (age-unimpaired) months of age were tested using the novel object recognition (NOR) task, with no observable cognitive deficits found in either group. Biochemical analyses revealed marked molecular differences in the prefrontal cortex (PFC) of aged-unimpaired rats. Synaptic proteins BDNF, PSD-95, and synaptophysin were significantly reduced, indicating synaptic destabilization. Concurrently, expression of COMT and NET, key regulators of dopamine catabolism and reuptake, was increased, suggesting reduced dopaminergic tone. Inflammatory signaling also shifted: Nfkb and Socs3 were increased at the transcriptional level in the PFC, while Il-6 and Cox2 remained stable. In contrast, the hippocampus showed relative resistance to these changes, with no significant alterations in most markers, although NF-κB activation was detected at the mRNA level, indicating posttranscriptional regulation. Our findings suggest that the PFC undergoes a latent vulnerability phase during midlife, marked by synaptic and dopaminergic dysregulation alongside low-grade inflammation, despite preserved cognitive performance. The hippocampus appears more resilient at this stage. Together, these early molecular changes may indicate later cognitive decline and offer a critical window for preventive intervention. Targeting these early shifts in the aging brain could hold transformative potential for delaying cognitive impairment. Show less

Neuropathic pain is a chronic condition initiated by nerve injury and frequently accompanied by affective disturbances, including anxiety and depression. Growing evidence suggests that maladaptive neuroplasticity in the anterior cingulate cortex (ACC) contributes to the persistence and affective dimension of neuropathic pain. To narratively review and critically synthesize current evidence on ACC-related neuroplasticity in neuropathic pain across molecular, circuit, glial, and translational domains. We narratively reviewed experimental and clinical studies addressing ACC-related molecular signaling, synaptic and circuit remodeling, glial and neuroimmune mechanisms, and interventional approaches relevant to neuropathic pain and its affective dimension. At the molecular level, abnormal ACC synaptic plasticity has been associated with long-term potentiation involving N-methyl-D-aspartate (NMDA) receptors-particularly GluN2B-dependent signaling-while the brain-derived neurotrophic factor (BDNF)-TrkB axis may further contribute to dendritic remodeling and maladaptive synaptic strengthening. At the circuit level, the ACC interacts with limbic regions including the insula and amygdala, within distributed networks that appear to contribute to aversive learning and pain-related affect. At the non-neuronal level, alterations in the ACC microenvironment include astrocyte-linked neuroinflammation and microglia-associated synaptic remodeling, which may shift excitation-inhibition balance. Therapeutically, ACC-targeted strategies are evolving from broad pharmacological modulation toward more spatially specific neuromodulation, although major translational challenges remain, including limited target specificity, cross-species differences, and uncertain causal inference in humans. ACC-related neuroplasticity appears to be an important component of neuropathic pain-affect pathophysiology. Future progress will depend on integrating mechanistic insights with network-level interpretation and improving the precision and clinical translatability of ACC-engaging interventions. Show less

Adult neurogenesis, the generation of new neurons in the adult brain, acts as a fundamental driver of neural plasticity within specialized microenvironments. The integrity of the hippocampal subgranular zone, essential for pattern separation and mood regulation, relies on a functional syncytium formed by the vasculature, glial cells, and neural stem cells (NSCs). This review delineates the architecture of this system, detailing how the vascular pillar provides angiocrine support via vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), while the glial pillar-comprising astrocytes and microglia-orchestrates metabolic homeostasis and immune surveillance. The dynamic regulation of this local ecosystem by systemic factors, including physical exercise and the gut-brain axis, is also explored. Furthermore, the breakdown of this alliance is examined as a pathological hub in aging, Alzheimer's disease (AD), and chronic stress. Crucially, the text addresses the significant translational gap between rodent models and human physiology. The ongoing controversy regarding the persistence of adult human neurogenesis is critically evaluated, attributing conflicting data to methodological variables such as postmortem interval (PMI) and fixation kinetics. Additionally, the risks of maladaptive plasticity, where aberrant neurogenesis contributes to conditions like epilepsy, are discussed. Finally, future directions involving high-resolution omics and imaging are highlighted, emphasizing that therapeutic strategies must navigate the complex biological risks of neural repair. Show less

University students exhibit high rates of mental health problems alongside a significant gap between their physical activity (PA) intentions and actual behavior. To understand the psychological heterogeneity within this intention-behavior gap (IBG) in high-pressure academic environments, a person-centered approach is essential. The present study aimed to identify distinct psychological profiles of students based on key self-regulatory constructs related to PA and to examine how these profiles longitudinally predict changes in mental health over an academic semester. A two-wave longitudinal survey was conducted with a cohort of 850 university students during the post-pandemic return to campus life, situated within a high-achieving Chinese higher education context. At baseline (T1), PA intention, action and coping planning, self-efficacy, maladaptive perfectionism, and procrastination were measured. At both T1 and the end of the semester (T2), PA behavior (IPAQ-SF) and mental health outcomes, including depression (PHQ-9), anxiety (GAD-7), and academic burnout (SBI) were assessed. Latent Profile Analysis (LPA) was employed to identify distinct profiles from the T1 psychological data. Longitudinal regression models were then used to test the predictive validity of these profiles on T2 mental health, controlling for T1 baseline mental health, demographic covariates, and critically, T1 baseline PA behavior. LPA revealed four distinct profiles: "Effective Planners" (25.0%), "Ambitious Procrastinators" (30.0%), "Cautious Doers" (24.9%), and "Indifferent & Sedentary" (20.1%). The "Ambitious Procrastinators" exhibited the largest intention-behavior gap. Even after controlling for baseline PA behavior, membership in this profile significantly predicted greater increases in depression ( The physical activity intention-behavior gap is not a monolithic phenomenon, and the "Ambitious Procrastinators" represent a particularly vulnerable subgroup. Findings suggest that university wellness programs should move beyond generic motivational campaigns and instead deliver tailored, skill-based interventions**, such as specific cognitive restructuring and behavioral activation, **targeting the specific self-regulatory deficits of these high-risk students. Show less

Hypertension is increasingly prevalent among middle-aged adults, but the impacts of physical activity and postures are not fully understood in middle-aged males and females, limiting targeted prevention. This study investigated associations between habitual physical activity and postures with hypertension, and whether they differ between sexes at the same age. 4416 participants (age: 46 years) in the 10th sweep of the 1970 British Cohort Study were used. Participants wore an activPAL to measure physical behaviors. Stage 2 hypertension was defined as >140/90 mmHg or antihypertensive medication use. Isotemporal substitution models assessed the theoretical effect of reallocating 30 min of one behavior with another. Males had higher mean body mass index (BMI: 28.5 ± 4.6 kg/m Show less

Persons with human immunodeficiency virus (HIV) well-treated on antiretrovirals have increased arterial inflammation, which can lead to development of atherosclerotic disease. We have previously shown that treatment with eplerenone can significantly reduce arterial inflammation, as measured by target-to-background ratio (TBR) on cardiac We performed a targeted discovery-based approach to identify a proteomics signature associated with eplerenone treatment that may provide a plausible mechanism for the reduction in arterial inflammation. In an exploratory study, we leveraged analyzable samples from participants who completed the 12-month, placebo-controlled, randomized controlled trial MIRABELLA HIV to evaluate 276 proteins (Olink Target 96 Cardiometabolic, Cardiovascular II, Cardiovascular III), with relevance to cardiovascular and cardiometabolic disease. We identified 11 proteins that differed in expression between treatment groups. Eight proteins (CDH1, CES1, ADM, IL-4RA, FGF-21, FS, FABP2, Gal-4) decreased and 2 proteins increased (CSTB, MPO) in expression with eplerenone compared to placebo. An increase in expression of IL-27 was prevented among eplerenone-treated versus placebo-treated groups. Changes in TBR of the most diseased segment of the index vessel correlated with changes in 3 of these proteins: CDH1 (ρ = 0.53, Through this proteomics approach, we discovered that 3 key proteins, CDH1, FGF-21, and Gal-4, are decreased in parallel with reductions in arterial inflammation after treatment with eplerenone. Eplerenone-induced reductions in these proteins, known to be related to inflammation, epithelial barrier disruption, vascular dysfunction, and metabolic dysregulation, provide mechanistic insight into pathways by which eplerenone may improve cardiovascular disease in HIV. NCT02740179. Show less

Hypertriglyceridemia is a widely prevalent disorder of lipid metabolism that increases the risk of cardiovascular disease and pancreatitis, and it often remains difficult to control even with standard treatments. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III (ApoC-III), offers a new and promising option for lowering triglyceride levels. A systematic search of PubMed, Scopus, Web of Science, and Cochrane was conducted through September 2025 to identify randomized controlled trials (RCTs) comparing olezarsen with placebo in adults with hypertriglyceridemia at high cardiovascular risk. Dichotomous outcomes were analysed as risk ratios (RRs) and continuous outcomes as percentage mean differences (MDs), both with 95% confidence intervals (CIs). Four RCTs (n = 1615 patients) were included. Olezarsen significantly reduced triglycerides (MD -47.71%, 95% CI -56.78 to -38.64, p < 0.0001), non-HDL-C (MD -22.11%, 95% CI -28.48 to -15.75, p < 0.0001), ApoC-III (MD -68.93%, 95% CI -77.54 to -60.31, p < 0.0001), VLDL-C (MD -48.52%, 95% CI -57.16 to -39.87, p < 0.0001), and ApoB (MD -10.67%, 95% CI -16.83 to -4.51, p = 0.0007), while increasing HDL-C (MD 35.13%, 95% CI -27.30 to -42.96, p < 0.0001). LDL-C showed no significant change. The risks of any or serious adverse events were comparable to placebo. Olezarsen was associated with fewer acute pancreatitis events (p = 0.035) but higher rates of liver enzyme elevations ≥ 3× ULN (p = 0.046). Olezarsen demonstrated consistent improvements in triglycerides and other atherogenic lipid parameters with an overall acceptable safety profile. These findings suggest that olezarsen may be a useful adjunct option for patients with persistent hypertriglyceridemia despite standard therapy. Further large-scale and long-term studies are needed to confirm its cardiovascular and safety outcomes. Show less