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Latino persons with chronic spine pain (CSP) face challenges engaging in physical activity (PA) and minimizing sedentary behavior (SB). This study aimed to objectively characterize PA and identify correlates of PA and SB in Latino persons with CSP. Cross-sectional baseline data from Latino participants who were enrolled in a clinical trial for CSP near the U.S.-Mexico border were utilized. Blockwise regression assessed the association between sociodemographic, clinical, interpersonal, and environmental factors with light PA (LPA), moderate-to-vigorous PA (MVPA), and SB. Participants (N = 154, Mage = 47.5 ± 12.1 years) spent 342.8 ± 111.6 min/day in LPA, 56.1 ± 71.1 min/day in MVPA, and 550.3 ± 140.9 min/day in SB. Seventy-five percent of participants met national PA guidelines. Lower income and higher pain interference were associated with lower LPA (R2 = 9%, p < .05). Younger age and lower income were associated with higher MVPA (R2 = 13%, p < .05). Lower income was associated with lower SB (R2 = 5%, p < .05). Younger age (OR 95% confidence interval [CI] [0.87, 0.98]) and higher exercise self-efficacy (OR 95% CI [1.06, 8.09]) increased the odds of meeting PA guidelines. Participants with CSP exhibited greater levels of LPA, MVPA, and SB compared with prior studies of Latino persons without pain. Sociodemographic variables including age and income were most consistently associated with PA and SB outcomes. Future research is needed to identify other relevant intrapersonal, interpersonal, and environmental determinants of PA and SB in this clinical population. (PsycInfo Database Record (c) 2025 APA, all rights reserved). Show less

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a key treatment for type 2 diabetes mellitus (T2DM), with cardiorenal effects that extend beyond glycemic management. One important mechanism underpinning these pleiotropic effects is their interaction with AMP-activated protein kinase (AMPK), a crucial regulator of cellular energy balance. This review summarizes the strong evidence that SGLT2 inhibitors activate AMPK via both shared and drug-specific mechanisms. Empagliflozin induces on-target energetic stress, dapagliflozin activates the FGFR1-LKB1 axis, and canagliflozin inhibits mitochondrial complex I off-target. We describe how AMPK activation coordinates a protective network that includes PGC-1α-mediated mitochondrial biogenesis, ULK1-driven autophagy, Nrf2-antioxidant responses, and mTOR/NF-κB signaling inhibition. This interaction leads to enhanced insulin sensitivity, decreased oxidative stress, and sustained heart, kidney, and liver function. Furthermore, we conduct a comparative investigation of the distinct AMPK-modulatory profiles of prominent SGLT2 inhibitors and explore the practical applicability of these processes, including possible drawbacks such as the theoretical risk of muscle atrophy associated with persistent AMPK activation. By thoroughly describing the SGLT2-AMPK axis, this review emphasizes its importance as a therapeutic target and offers a framework for understanding the entire range of SGLT2 inhibitor activity in diabetes and associated consequences. Show less

While the epithelial-mesenchymal transition (EMT) is known to promote cancer stemness and metastasis, a hybrid partial EMT (p-EMT) state has recently been identified. This study examined the influence of HCT 116 cells were infected with Show less

Plin4 is transcriptionally regulated by peroxisome proliferator-activated receptor gamma and is primarily expressed in white adipose tissue (WAT). We found that expression of Plin4 is elevated in the liver upon prolonged feeding with an obesogenic diet containing saturated fat, fructose, and cholesterol (Western diet). To investigate the functional role of Plin4 in energy metabolism, we generated Plin4 Show less

This pilot study investigated the protective effect of transfecting brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (bcl-2) genes in retinal ganglion cells (RGCs) using in vivo electroporation in an adult rat optic nerve transection model. Sprague-Dawley rats were randomly divided into five groups: BDNF(+)/bcl-2(+), BDNF(+), bcl-2(+), empty plasmid (EP), and no surgery (NS). The plasmids were intravitreally injected and electroporated into the left eye. Seven days later, optic nerve transection was performed in all groups except the NS group. Protein expression was examined using Western blotting, RGC survival was quantified using 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) retrograde labeling, and apoptosis was assessed using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) at multiple time points (7, 14, and 28 d after transfection). A significantly higher number of DiI (+) RGCs and lower number of apoptotic cells were observed in the BDNF(+)/bcl-2(+), BDNF(+), and bcl-2(+) groups compared to those in the EP group at all time points. The number of DiI (+) RGCs in the three treatment groups was significantly lower than that in the NS group. However, there were no significant differences among the three treatment groups. The protective effects of gene transfection tended to be strongest in the BDNF(+)/bcl-2(+) group, followed by the BDNF(+) group and then the bcl-2(+) group. Thus, all gene transfection treatments had a protective effect against the loss of DiI(+) RGCs induced by optic nerve transection but did not result in full recovery. This study also confirmed the value of in vivo electroporation. The findings of this pilot study provide a working base for the development of gene therapy for blinding optic nerve disorders. Show less

Internalisation of G protein-coupled receptors (GPCRs) can contribute to altered cellular responses by directing signalling from non-canonical locations, such as endosomes. If signalling processes are locally constrained, active receptors in different subcellular locations could produce different downstream effects. This phenomenon may be relevant to the optimal targeting of the glucagon-like peptide-1 receptor (GLP-1R), a type 2 diabetes and obesity target GPCR for which several ligands with varying internalisation tendency have been discovered. To investigate, we compared the signalling localisation effects of two prototypical GLP-1RAs with opposite signal bias and effects on GLP-1R trafficking: exendin-asp3 (ExD3), a full agonist that drives rapid internalisation, and exendin-phe1 (ExF1), which shows much slower internalisation. After using bioorthogonal labelling and fluorescent agonist conjugates to verify the divergent trafficking patterns of ExF1 and ExD3 in β-cell lines and primary pancreatic islets, we used live cell biosensors to monitor signalling at different subcellular locations. This revealed that cAMP/PKA/ERK signalling in β-cells is in fact distributed widely across the cell over short- (<5 min) and medium-term (up to 60 min) stimulation at pharmacological (>10 pM) concentrations, with no major differences in signal localisation that could be linked to internalised versus cell surface-bound GLP-1R. Moreover, washout experiments highlighted that, whilst fast-internalising ExD3 shows much greater accumulation and binding to GLP-1R in endosomes than slow-internalising ExF1, it is a rather inefficient driver of both cAMP production in β-cells and insulin secretion from perfused rat pancreata. These data provide a greater understanding of the cellular effects of biased GLP-1R agonism. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen-cholinergic-NGF axis: E Show less

Atherosclerosis is a chronic immunometabolic disease driven by lipid accumulation and immune cell infiltration. Macrophages and T cells play key roles throughout plaque development. Galectin-1 (Gal-1), a glycan-binding protein, modulates immune functions in these cells and has been reported to attenuate atherosclerosis, though its mechanisms remain incompletely understood. Here, we investigated the effects of Gal-1 on macrophages and T cells during plaque formation. Effects of Gal-1 on atherosclerosis, macrophages and T cells during lesion formation were studied in Apoe Gal-1 treatment reduced lesion size and increased circulating IL-10 levels, inversely correlating with plaque burden. Unexpectedly, IL-10 neutralization also mitigated atherosclerosis, indicating that its action is at least partially IL-10-independent. In plaques, Gal-1 promoted anti-inflammatory macrophage phenotypes, mirrored by a quiescent metabolic and anti-inflammatory profile in foamy macrophages ex vivo. The use of the Gal-1 Gal-1 protects against atherosclerosis associated with reprogramming macrophages and tuning T cell immunity through glycan-dependent and -independent pathways. Show less

Pregnancy constitutes a critical window of vulnerability during which maternal and environmental exposures may shape fetal development through epigenetic mechanisms. While prenatal maternal anxiety and exposure to green spaces have been independently associated with child neurodevelopment, their potential interactive effects on neonatal epigenetic profiles remain largely unexplored. This study examined the independent and interactive effects of maternal trait anxiety and residential green space exposure during pregnancy on neonatal DNA methylation (DNAm) of the brain-derived neurotrophic factor (BDNF) gene. A sample of 110 mother-infant dyads was enrolled at delivery. Maternal trait anxiety was assessed using the Stait-Trait Anxiety Inventory (STAI-Y) and infants' BDNF DNAm at birth was assessed in 11 CpG sites in buccal cells. Prenatal residential addresses were geocoded and green space availability within 300, 500, and 1000 m buffers was calculated using the CLCplus Backbone 2021 land cover dataset. Hierarchical linear regression models were adjusted for infant sex and prenatal exposure to PM2.5. Results indicated that higher maternal trait anxiety was associated with increased BDNF DNAm at four CpG sites only among infants with lower exposure to green space within a 300 m buffer. This association was not significant at higher levels of greenness, suggesting a neuroprotective effect of natural environments during gestation. Findings provide novel evidence that urban green space may buffer the biological impact of maternal anxiety on neonatal BDNF methylation. This highlights the importance of integrating psychological and environmental-level exposures to elucidate early-life determinants of neurodevelopment. Show less

Fibroblast growth factor 21 (FGF21) analogs are in development for metabolic dysfunction-associated steatotic liver disease (MASLD), but their impact on problematic alcohol use (PAU), alcohol use disorder, binge drinking, and alcohol-related liver disease (ALD) is unknown. We leveraged genome-wide association study data from the UK Biobank, FinnGen, Million Veterans Program, and GenomALC for PAU, alcohol use disorder, binge drinking, weekly drinks, and ALD. Our four-tier evaluation included: (1) multivariable Mendelian randomization (MR) and mediation with circulating FGF21 levels; (2) comparative MR of MASLD and ALD targets (PNPLA3, TM6SF2, HSD17B13) using liver fat and expression instruments; (3) receptor-focused MR of β-Klotho (KLB) and FGFR1/2/3 incorporating brain-region expression; and (4) a phenome-wide MR across 1,022 traits to assess safety. Genetically higher FGF21 protein levels were associated with lower PAU (β = -0.097, 95% CI -0.135 to -0.059, p = 6.13 × 10 Human genetic evidence indicates that FGF21 analogs mitigate hazardous drinking and ALD via both behavioral and metabolic pathways. These findings distinguish FGF21 from other MASLD targets and highlight its potential for precision treatment of alcohol-related disorders. This study leverages human genetic evidence to validate FGF21 - a liver-derived hormone currently in clinical trials for fatty liver disease - as a dual-action therapeutic that both curbs harmful drinking behaviors and protects against alcohol-related liver injury, addressing a critical therapeutic gap with limited existing pharmacotherapies. The results are important for clinicians and researchers seeking precision medicine strategies for alcohol use disorder and liver disease, as well as for patients who currently face limited treatment options. By pinpointing FGF21's behavioral and metabolic pathways and demonstrating a favorable safety profile, our findings support the repurposing of FGF21 analogs in clinical trials of alcohol use disorder and alcohol-related liver disease and suggest that genetic stratification could optimize patient selection for therapy. While these conclusions rely on European-ancestry genetic data and Mendelian randomization assumptions, they help inform future clinical studies, biomarker development, and policy efforts aimed at expanding treatment options for alcohol-related conditions. Show less

Epidemiological evidence suggests that atherosclerosis (AS) may precede or coexist with type 2 diabetes mellitus (T2DM); however, whether anti-atherosclerotic interventions can reduce T2DM risk remains unclear. Chensinin-1b (C-1b), an antimicrobial peptide derived from the skin secretions of Rana chensinensis, has previously demonstrated anti-atherosclerotic activity, suggesting a potential therapeutic effect against T2DM in the context of AS. In an apolipoprotein E-knockout (ApoE In the early and middle stages of AS (6-10 weeks), mice fasting blood glucose (FBG) did not change, but atherosclerotic symptoms were significantly exhibited, such as the increased pro-inflammatory factors levels, aortic plaque and blood lipid levels. During the late stage of AS (14 weeks), it was found that the FBG of ApoE In ApoE Show less

Perioperative neurocognitive disorder (PND) is one of the most prevalent neurological complications in elderly surgical patients. Dysregulated lipid metabolism is a hallmark of aging and is strongly associated with cognitive dysfunction. This study aimed to investigate whether ω-6 polyunsaturated fatty acid (PUFA) metabolism contribute to PND and examined whether fatty acid desaturase 1 (FADS1) represents a key regulatory link between fatty acid metabolism and PND in aged mice. An anesthesia/surgery-induced cognitive dysfunction model was established Anesthesia/surgery significantly upregulated hippocampal FADS1 expression (1.91-fold [0.37] vs. 1.00-fold [0.43]; These findings highlight anesthesia/surgery could disrupt ω-6 PUFA metabolism, notably activating the PGD The online version contains supplementary material available at 10.1186/s12974-025-03678-y. Show less

Several studies show that neurosteroids currently play a significant role in autism spectrum disorders (ASD). However, the pathway of neurosteroid synthesis involved in ASD remains unclear. This study aimed to investigate the crosstalk between autism and neurosteroids, focusing on the mechanism of allopregnanolone production. We used the BTBR T+ tf/J (BTBR) mouse, a well-established animal model of ASD that exhibits typical autism-like behaviors along with neuroinflammation. In the hippocampus of BTBR mice, we observed a marked overexpression of pregnenolone and a related reduction in allopregnanolone levels. This neurosteroid imbalance also appears to be associated with an inflammatory pattern and the manifestation of repetitive and asocial behaviors. The combination of low doses of ultramicronized palmitoylethanolamide (PEA-um) and docosahexaenoic acid (DHA) restores allopregnanolone production modulating neurosteroidogenesis. In association with neurosteroid modulation, this restoration reduces repetitive behaviors and improves social interactions in BTBR mice, also modulating the inflammatory profile with a significant reduction in proinflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in the hippocampus. These effects demonstrate an important role of the peroxisome proliferator-activated receptor alpha (PPAR-α), whose expression is particularly reduced in BTBR mice. In addition, the pivotal involvement of PPAR-α was further supported by administering a specific antagonist that abolished the advantageous effects of PEA-um ​+ ​DHA. Overall, our findings demonstrate the potential synergistic effect of the low-dose combination of PEA-um and DHA, confirming their therapeutic effect in ASD and the involvement of neurosteroids in their mechanism of action. Show less

The aim of the current study was to assess the potential neuroprotective effects of lithium chloride (LiCl) against retinal degeneration (RD) induced by N-methyl-N-nitrosourea (MNU) in the rats. 108 rats were assigned to 6 groups: Control, MNU (80 mg/kg), MNU + 30 mg/kg LiCI, MNU + 60 mg/kg LiCI, 30 mg/kg LiCI, and 60 mg/kg LiCI. The experimental groups comprised 18 rats each and the animals were euthanised on the 2nd, 7th and 14th days following the administration of MNU. Compared with the MNU group, both doses of LiCl significantly reduced retinal cell apoptosis and increased retinal thickness (P < 0.05). MNU group had a higher apoptotic index than the treatment groups, as evidenced by increased immunoreactivities of caspase-3, caspase-6, Bax, and 8-OHdG and decreased immunoreactivities of Bcl-2 at day 2. The outer nuclear layer (ONL) of the retina in rats treated with MNU exhibited a significant reduction in comparison the control group on both days 7 and 14 (P < 0.05). In contrast to the MNU-treated figgroup, the LiCl-injected rats exhibited a notable elevation in the expression levels of BDNF and Bcl-2 (P < 0.05). Conversely, the MNU-treated group exhibited markedly increased expression of GSK-3β, Bax, 8-OHdG, caspase-3, and caspase 6 (P < 0.05). In conclusion, LiCl demonstrated dose-dependent neuroprotective effects against MNU-induced RD in rats. These effects included a reduction in retinal cell apoptosis, an improvement in retinal thickness, and the potential involvement of anti-apoptotic mechanisms, glial activation inhibition, and neurotrophic factor modulation. Show less

Apolipoprotein E (apoE), a major protein for lipid transport in circulation and the brain, has three common isoforms, apoE2, apoE3 and apoE4. APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Recently identified rare apoE variants, the apoE3(R136S)-Christchurch, apoE3(V236E)-Jacksonville and apoE4(R251G), appear to exert protective functions against AD and reduce the disease risk, but the molecular basis behind these effects is unknown. ApoE is a structurally dynamic protein, undergoing significant rearrangements that are important for its biological function. To examine the structural basis behind the properties of the protective apoE variants, we analyzed their structural and thermodynamic integrity both in APOE3 and APOE4 allelic backgrounds compared to their wild-type counterparts. Circular dichroism spectroscopy showed that only the V236E variation significantly alters the secondary structure of apoE3 and apoE4 in lipid-free form. This variant was also less prone to oligomerization. Chemical denaturation analysis indicated changes in the unfolding profile of V236E and R251G apoE variants in lipid-free form. Thermal unfolding analysis revealed small thermodynamic alterations in each variant compared to their wild-type apoE counterparts in lipid-free form, but a thermodynamic stabilization in lipoprotein-associated form. Additionally, following lipidation, all protective apoE variants were found to enhance the viability of SK-N-SH neuroblastoma cells and reduce the production of TNFα from BV2 microglia cells. Overall, these findings suggest that the specific amino acid substitutions found in AD-protective apoE variants can induce changes in the molecule's stability and conformation that may underlie common functional consequences, which are independent of the apoE background. Show less

Alterations in the gut microbiome and a "leaky" gut are associated with Parkinson's disease (PD), which implies the prospect of rebalancing via dietary intervention. Here, we investigate the impact of a diet rich in resistant starch on the gut microbiome through a multi-omics approach. We conducted a randomized, controlled trial with short-term and long-term phases involving 74 PD patients of three groups: conventional diet, supplementation with resistant starch, and high-fibre diet. Our findings reveal associations between dietary patterns and changes in the gut microbiome's taxonomic composition, functional potential, metabolic activity, and host inflammatory proteome response. Resistant starch supplementation led to an increase in Faecalibacterium species and short-chain fatty acids alongside a reduction in opportunistic pathogens. Long-term supplementation also increased blood APOA4 and HSPA5 and reduced symptoms of PD. Our study highlights the potential of dietary interventions to modulate the gut microbiome and improve the quality of life for PD patients. Show less

Depression is a major mental illness, and its underlying mechanisms remain unclear. Emerging evidence suggests that astrocytes, which play a crucial role in brain function, may be involved in the pathophysiology of depression. We previously showed that downregulation of astrocytic connexin43 (Cx43) enhances the antidepressant effect of amitriptyline. However, the precise molecular mechanisms underlying this phenomenon remain unknown. In the present study, we investigated the signaling pathways involved in the antidepressant action of amitriptyline using an in vitro model involving Cx43-knockdown astrocytes. We found that amitriptyline potentiated the expression of brain-derived neurotrophic factor (BDNF), a key neurotrophic factor, in Cx43-knockdown astrocytes. This potentiation was mediated by the activation of Gq protein-coupled lysophosphatidic acid (LPA) receptors, a pathway that was sensitized by Cx43 downregulation. We further demonstrated that this signaling cascade involved the activation of Protein Kinase C (PKC) δ and transcription factor NF-κB, but not the conventional BDNF transcription factor CREB. We propose that Cx43 downregulation enhances the antidepressant effect of amitriptyline by specifically engaging the Gq-PKCδ-NF-κB pathway. These findings suggest that Cx43 downregulation in astrocytes, which has been considered a pathological feature of depression, may paradoxically contribute to the therapeutic efficacy of antidepressants by sensitizing a specific signaling pathway. Our study provides new insights into the molecular mechanism of antidepressant action and highlights the potential role of astrocytic Cx43 in modulating therapeutic responses. Show less

Pro-inflammatory macrophage function is linked to an increase in mitochondrial fission. Melatonin has a positive impact on atherosclerosis and has a significant effect on the control of mitochondrial fission and fusion. Nevertheless, it is still unclear how melatonin contributes to slowing the advancement of atherosclerosis. The ApoE The study found that melatonin treatment decreased the area of atherosclerotic plaque, decreased lipid deposition, suppressed inflammatory cytokine levels, inhibited macrophage pro-inflammatory differentiation, inhibited mitochondrial fragmentation, increased the level of Sirt3, and decreased Drp1 expression in atherosclerosis (AS) mice. However, Sirt3 inhibition abolished the protective affects of melatonin in AS mice. Melatonin therapy upregulated Sirt3 expression in RAW264.7 cells subjected to ox-LDL, blocked Drp1-mediated mitochondrial fission, and reduced inflammatory cytokine levels. On the other hand, melatonin's inhibitory effects on Drp1 expression and mitochondrial fission were lessened by Sirt3 inhibition. Additionally, DRP1 siRNA knockdown inhibited mitochondrial fission and pro-inflammatory differentiation of macrophages induced by ox-LDL. Melatonin inhibits the growth of atherosclerosis and the pro-inflammatory differentiation of macrophages by blocking the Sirt3-Drp1 pathway, which prevents mitochondria from fission. Melatonin's suppression of mitochondrial fission may be a viable strategy for postponing cardiovascular problems in atherosclerosis patients. Show less

The gut microbiota plays a pivotal role in maintaining host health and has increasingly been linked to the pathogenesis of neurodegenerative diseases through the microbiota-gut-brain axis. Parkinson's disease (PD), characterized by dopaminergic dysfunction, neuro inflammation, and pathological alpha-synuclein (α-synuclein) aggregation, is frequently accompanied by gut microbial dysbiosis. Probiotics isolated from human infants could offer distinct neuroprotective and immunomodulatory benefits, yet their effects on integrated gut-brain axis models remain underexplored. In this study, we investigated the therapeutic potential of Lactobacillus acidophilus SLAM_LAA02 (L. acidophilus SLAM_LAA02), a novel infant-derived strain, in modulating PD-related behavioral and neuropathological features via modulation of the gut-brain axis. Following comprehensive safety and functional assessments, we first assessed L. acidophilus SLAM_LAA02 in Caenorhabditis elegans, where supplementation extended lifespan, enhanced antimicrobial defense, improved behavioral responses, and reduced α-synuclein expression in transgenic worms. We then evaluated its effects in a rotenone-induced mouse model that reflects early-stage PD-like features. L. acidophilus SLAM_LAA02 administration ameliorated motor dysfunction, modulated neuroinflammatory signaling, restored gut microbial diversity, and improved intestinal barrier-associated outcomes. These changes were accompanied by a notable reduction in α-synuclein expression and upregulated neuroprotective gene expression, including brain-derived neurotrophic factor (BDNF). Together, these findings suggest that L. acidophilus SLAM_LAA02 exhibits neuroprotective and gut-modulating properties across complementary model systems, supporting its potential as a promising probiotic candidate for alleviating early PD-related dysfunctions through the gut-brain axis. Show less

Neurodegenerative and psychiatric disorders share overlapping molecular mechanisms, including neuroinflammation, oxidative stress, and neurotransmitter dysregulation. Essential oils from Lavandula angustifolia (TLEO) and Rosa rugosa (PREO) contain neuroactive compounds with therapeutic potential, but their mechanisms remain poorly defined. This study aimed to elucidate the shared and distinct molecular targets and pathways of TLEO and PREO using a multi-scale computational strategy. Compounds identified by GC-MS were evaluated through ADMET profiling, target prediction, and disease-target intersection analysis. Enrichment, network, docking, and dynamics analyses were performed on shared protein-coding targets between essential oils and twelve brain disorders, including seven neurodegenerative conditions (Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, spinal muscular atrophy) and five psychiatric disorders (autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia). A total of 110 compounds yielded 252 common targets, with CHRM2 (GPCR) and NR1H3 (non-GPCR) identified as key hubs. Docking suggested strong binding affinities for caryophyllene oxide at CHRM2 (-7.3 kcal/mol) and α-himachalene at NR1H3 (-8.5 kcal/mol). Molecular dynamics simulations confirmed stable, compact complexes with low RMSD and SASA values. MM/PBSA free energy calculations quantitatively validated these interactions, revealing favorable binding energetics driven predominantly by van der Waals and hydrophobic contributions, consistent with the terpenoid chemical profiles. Functional enrichment highlighted involvement in cholinergic signaling, lipid metabolism, and inflammatory regulation. This study demonstrates that PREO and TLEO can modulate multiple targets relevant to brain disorders through both GPCR and non-GPCR mechanisms. These findings provide a computationally inferred mechanistic framework for the potential neuroprotective synergy of these oils and highlight essential oil-derived compounds as promising leads for further experimental investigation. Show less

Sensory neurotoxicity involves damage to the sensory nerves, often resulting from exposure to chemicals, medications, toxins, infections, or neurological disorders. Benzalkonium chloride (BKC) is a widely used quaternary ammonium compound with antiseptic properties, commonly present in pharmaceuticals, household products, and cosmetics. While the potential neurotoxicity of BKC has been previously explored in ocular and nasal epithelia, its impact on other sensory systems and the underlying mechanisms remain largely unclear. In this study, we used zebrafish (Danio rerio) embryos to assess the developmental neurotoxicity of BKC. Embryonic exposure to 0.72, 1.28, and 2.24 mg/L BKC led to dose-dependent impairments in mechanosensory hair cells, reduced startle responses, and heightened nociceptive sensitivity upon noxious stimulation. BKC exposure induced pronounced oxidative stress, evidenced by increased reactive oxygen species levels, reduced antioxidant enzyme activity, and altered expression of redox-regulating genes. Moreover, BKC significantly upregulated inflammatory and pain-associated genes, including tnfa, il1b, cox2, bdnf, and trpa1b. Expression profiling of hair cell differentiation markers revealed increased pou4f3 and decreased tmc2a/tmc2b, suggesting that BKC disrupts both terminal differentiation and mechanotransduction processes in sensory hair cells. Collectively, these findings uncover a novel mechanistic link between oxidative stress, impaired hair-cell maturation, and sensory dysfunction, offering new insights into the mechanisms underlying BKC-induced sensory neurotoxicity. This study emphasizes the ecological and toxicological relevance of quaternary ammonium compounds in aquatic environments. Show less

Cognitive impairment is a significant health concern in aging populations, but the interplay between biological aging, lifestyle factors, and genetic susceptibility remains unclear. This study examined whether accelerated biological aging is associated with cognitive impairment, whether lifestyle modifies this association, and how genetic background influences these relationships in Chinese older adults. In this cross-sectional study (2022-2023), 7033 participants from southwestern China were included. Accelerated biological aging was calculated as the residual difference between biological age (based on 10 biomarkers) and chronological age. Lifestyle was assessed via a composite index (smoking, alcohol, physical activity, diet, sleep). Cognitive function was measured using the Chinese Mini-Mental State Examination (C-MMSE), and genetic risk was evaluated through polygenic scores and APOE ε4 status. Linear and logistic regression models assessed associations between accelerated aging and cognition. Accelerated biological aging was associated with lower MMSE scores ( β = -0.243, 95% CI: -0.354, -0.133) and higher cognitive impairment prevalence (OR = 1.098, 95% CI: 1.040, 1.158). An unhealthy lifestyle exacerbated cognitive impairment in biologically older individuals (RERI = 0.25). Those with both accelerated aging and unhealthy lifestyle had the lowest MMSE scores ( β = -1.424, 95% CI: -1.846, -1.003) and highest odds of cognitive impairment (OR = 1.467, 95% CI: 1.194, 1.803). These effects were consistent across all genetic background subgroups. Accelerated aging was associated with lower cognitive function, especially in individuals with unhealthy lifestyles, regardless of genetic susceptibility. This highlights lifestyle modification as a potential intervention target for aging-related cognitive impairment. Show less

Hereditary Multiple Osteochondromas (HMO) is a rare, pediatric skeletal disorder characterized by osteochondromas that form along the growth plates. These benign tumors can cause skeletal deformities, joint dysfunction, chronic pain and other health problems. Most HMO patients are born with a heterozygous mutation in EXT1 or EXT2 that encode Golgi enzymes responsible for heparan sulfate synthesis. However, prior studies have established that these mutations alone are insufficient to trigger osteochondroma formation, but additional genetic changes are needed. Loss-of-heterozygosity (LOH) has been invoked in some cases, but the full genomic landscape of osteochondromas remains unclear. Here, we carried out a proof-of-principle study and asked whether gene variants occur in osteochondromas in addition to EXT mutations, whether the variants are shared by osteochondromas in same or different patients and what putative pathogenic roles they may have. A total of 8 tumors from 4 patients were subjected to whole exome sequencing (WES) along with saliva DNA from the 4 patients and 3 parents that was used as specific reference. WES identified over 1,600 somatic single nucleotide variants or insertion/deletions that were only partially shared amongst the tumors and were absent in the saliva DNA. Six genes were commonly mutated, including PABC1, TDG and ANKRD36. These genes exert action which could directly or indirectly influence chondrogenesis, the first differentiation step in osteochondroma formation. The study reveals that osteochondromas do possess gene variants distinguishing them in the same or different patients. These traits could modulate their tumorigenic character and add complexity to HMO pathogenesis. Clinical Significance: This study provides insights into the genomic landscape of osteochondromas, potentially leading to development of disease diagnostic and prognostic tools. Show less

Previous Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD), whereas their associations with mild cognitive impairment (MCI) remain unclear. To evaluate the associations between 100 representative AD-associated SNPs and susceptibility to MCI in the Chinese population. We recruited 200 MCI patients and 200 cognitively-healthy controls from the community, matched for age and sex. Associations between SNPs and MCI risk were estimated using lasso regression, adjusted for APOE status, using different genetic models. Fifteen SNPs in nine genes (including CLU, SORL1, PICALM, BDNF, NOS3, MTHFR, TOMM40, BIN1, and PVRL2) were associated with MCI in single-SNP analysis. In the multi-SNP association test, rs1801133 and rs9331888 of CLU were consistently associated with MCI risk in the dominant model. TOMM40 rs2075650 (G) was associated with MCI risk in the dominant model by age and education (OR = 2.41, 95%CI = 1.27-4.59), but disappeared when further adjusted for APOEε4 status. PICALM rs561655 (G) (OR = 0.52, 95%CI = 0.30-0.92) and NOS3 rs1549758 (T) (OR = 0.53, 95%CI = 0.30-0.94) were identified as protective genetic factors of MCI for the first time in dominant model combined with the APOEε4 allele. Moreover, MTHFR rs1801133 (A) and CLU rs9331888 (G) showed more susceptibility to MCI in the additive model. SORL1 rs641120(G) showed a protective effect, whereas BIN1 rs5733839 consistently showed a risk effect for MCI in the overdominant model, regardless of APOEε4 status. This study suggests that some AD-associated SNPs are associated with cognitive decline and may have important implications for future studies. Show less

Alzheimer's disease (AD) is the leading cause of dementia, with an increasing incidence due to population aging. Approximately two-thirds of the people affected are women, possibly due to biological and hormonal factors. Also, lipids could play an important role in AD and show associations with cognitive impairment. Apolipoprotein E allele 4 (ApoE ε4) genotype and cardiovascular (CV) risk lipid ratios could be relevant in lipidomic studies. This work aims to identify specific alterations in plasma lipid profiles associated with AD in women and to explore these alterations related to ApoE and 2 CV risk lipid ratios. A lipidomic mass spectrometry-based method was applied to plasma samples from a clinical cohort of women. The patients were accurately classified into AD (n = 76) and non-AD (n = 74) groups by cerebrospinal fluid amyloid beta (Aβ)42/Aβ40 levels. The identified lipid species were evaluated and grouped into families and subfamilies. The lipids with significant differences between groups were examined in relation to ApoE genotype and 2 CV risk ratios (total cholesterol/high-density lipoprotein [HDL], triglycerides/HDL). Fatty acyls and monoacylglycerols showed higher levels in AD compared with non-AD, while diacylglycerols showed lower levels in AD. Also, specific subfamilies correlated with aging, CV risk, AD biomarkers, and cognitive status. Of the 627 lipid species detected, 45 showed statistically significant differences between groups, and some of them [lysophosphatidylcholine (24:1), diacylglycerol (18:0/18:1), and triacylglycerol (50:3)] showed significant associations with ApoE genotype and CV risk. This study identified associations between lipid profiles in women and AD pathology, ApoE ε4 genotype, and high CV risk ratios. Show less

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with limited effective treatments. This study explores the anti-GBM potential of an α-conopeptide isolated from the venom of Conus planorbis, a marine cone snail from Rameswaram, India. Peptide extraction and BCA assay quantified an average concentration of 473.34 ± 70.07 µg/mL. Structural analysis via Show less

Multiple sclerosis (MS) is a chronic neurodegenerative disorder for which dysregulated ferroptosis and necroptosis have demonstrated pathological associations but these lack causal validation in disease susceptibility. This study employed proteome-wide Mendelian randomization (MR) to investigate causal links between ferroptosis/necroptosis pathways, their upstream regulators, immune interactions, and MS risk. Transcriptomic validation utilized bulk RNA-seq and single-cell RNA-seq data. MR identified IFNA4 (OR = 0.24) and TNFAIP3 (OR = 2.0) as key causal ferroptosis/necroptosis-related proteins for MS risk. Analysis revealed 15 upstream regulators significantly associated with MS (FDR < 0.05; e.g., GZMA, CXCL3, APOE, CFB, CA6, KIR2DL2/3). Transcriptomic validation consistently identified ceruloplasmin (CP) as upregulated in MS microglia and lesions. Mediation analyses established two complete causal pathways: an IFNA4-mediated pathway wherein five upstream immune regulators (KIR2DL2, KIR2DL3, CFB, GZMA, and CA6) influence MS susceptibility through IFNA4 regulation, with all component effects statistically significant; and an APOE-driven pathway operating via TNFAIP3, demonstrating significant total effects and near-significant mediator-outcome effects on MS risk. While 59 immune traits were MS-associated, only TNFAIP3 showed a suggestive association with CD27⁺ memory B cells. This study establishes ferroptosis/necroptosis pathways as causal drivers of MS susceptibility, highlighting TNFAIP3, IFNA4, CP, and APOE as therapeutically actionable targets. Show less