📋 Browse Articles

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

Study DesignRetrospective Single-center propensity score-matched cohort study.ObjectiveAdjacent segment disease remains a major cause of revision surgery after multilevel lumbosacral fusion, and muscle-preserving approaches may help reduce this risk. This study compared clinical and radiographic outcomes between a muscle-preserving fusion combining standalone anterior plus lateral lumbar interbody fusion (A + LLIF) vs circumferential lateral plus posterior lumbar interbody fusion (L + PLIF).MethodsPatients who underwent multilevel lumbosacral fusion (2016-2023) with either A + LLIF or L + PLIF were included. L + PLIF patients with contraindications to standalone A + LLIF were excluded. Propensity score matching, based on age, BMI, PI-LL mismatch and stenosis severity, yielded 90 1:1-matched patients. The primary outcome was revision surgery. Secondary outcomes included spinopelvic alignment, cage subsidence, and perioperative metrics.ResultsBaseline characteristics were comparable between groups (mean age 57 ± 10 years; median fusion levels: 2 [range 2-4]). The 5-year cumulative incidence of revision surgery was significantly lower with A + LLIF (1/45 events; 2.2%) than with L + PLIF (14/45 events; 31.1%; Show less

Atherosclerotic cardiovascular diseases (ASCVDs) remain the primary cause of morbidity and mortality. Macrophages are involved in the progression and regression of atherosclerosis, and macrophage amino acid metabolism is important during this process. Here, we identified that the expression of cystine/glutamate antiporter Slc7a11 was upregulated by oxidized low-density lipoprotein, and specifically enhanced in the macrophages of atherosclerotic plaques. Macrophage-specific Show less

Coronary heart disease (CHD) is driven by endothelial dysfunction and chronic vascular inflammation. hsa-miR-2110 (miR-2110) has been associated with adverse cardiovascular outcomes, but its mechanistic role in CHD remains unclear. In this study, miR-2110 expression was quantified in peripheral blood from CHD patients and healthy controls. Functional effects were assessed in EA.hy926 endothelial cells following lentiviral overexpression of miR-2110. The target gene Show less

Non-suicidal self-injury (NSSI) is highly prevalent among adolescents with depression, yet the heterogeneity of underlying temperamental risk factors remains poorly understood. Traditional variable-centered approaches fail to capture how distinct affective temperaments co-occur within individuals. This study aimed to identify latent profiles of affective temperaments and examine their association with NSSI, exploring the statistical mediating role of cognitive emotion regulation (CER). A cross-sectional study was conducted from February 2025 to September 2025 at the First Hospital of Hebei Medical University. A total of 290 adolescents (aged 10–19) diagnosed with Major Depressive Disorder were recruited, with 282 valid responses included in the final analysis. Participants completed the TEMPS-A, CERQ, and ASHS. Latent Profile Analysis (LPA) was utilized to identify temperament subgroups. Mediation analysis with bootstrapping was performed to test the indirect effects of CER strategies. LPA identified three distinct profiles: Resilient/Low-risk (Class 1, 32.6%), Anxious-Depressive (Class 2, 46.1%), and Mixed-Dysregulated (Class 3, 21.3%). The Mixed-Dysregulated group, characterized by simultaneous elevations in depressive, anxious, irritable, and cyclothymic temperaments, exhibited the highest frequency (45.2 ± 21.3 times/year) and prevalence (98.8%) of NSSI compared to other groups ( The findings delineate a specific “Mixed-Dysregulated” risk phenotype within adolescent depression that is associated with severe NSSI. Interventions should move beyond standard depression care to target cognitive flexibility and emotional regulation skills. Statistical mediation analysis suggests that this risk is mediated by maladaptive cognitive emotion regulation strategies. Not applicable. Show less

Recent years have seen a marked increase in the number of patients diagnosed with spinal disorders, including chronic cervical myofascial pain syndrome (CMPS). This article aims to explore the potential of inflammatory process biomarkers in the blood and brain-derived neurotrophic factor (BDNF) as a means to assess the efficacy of collagen mesotherapy in the management of chronic CMPS. The second objective of this article is to evaluate the safety of collagen mesotherapy in chronic CMPS. The study comprised 23 subjects, who were randomly assigned either to the collagen mesotherapy group (n = 11) or the lignocaine mesotherapy group (n = 12). Blood was collected from each patient, and also the subjects were evaluated with the numerical rating scale (NRS) and the neck disability index (NDI). Results Both collagen and lignocaine mesotherapy have been observed to cause a significant reduction in pain intensity (NRS) and disability (NDI) over time, with no significant differences seen between the two interventions. However, the fluctuations in the levels of inflammatory biomarkers (TNFα, IL-1β, IL-6) and BDNF did not correspond with the clinical improvement noted. No adverse events related to the intervention were also observed. The potential of inflammatory biomarkers and BDNF, when assessed in blood serum, to serve as a basis for evaluating the efficacy of collagen mesotherapy in chronic CMPS; remains to be elucidated. Nevertheless, collagen mesotherapy appears to be an effective and safe treatment for chronic CMPS. However, further research in this area is required. Trial registration: NCT06807177. https//clinicaltrials.gov/study/NCT06807177. Show less

B-cell maturation antigen (BCMA) is the main target for chimeric antigen receptor (CAR)-T cells in multiple myeloma (MM), demonstrating promising outcomes. However, unlike what happens with CART19 in lymphoblastic leukemia and non-Hodgkin's lymphoma, a high proportion of patients will relapse after CAR-T BCMA therapy due to insufficient antigen expression, low CAR-T cell persistence and/or T-cell exhaustion. In other B cell malignancies, second-generation anti-CD19 4-1BB CARs with CD28-transmembrane domain (TMD) have shown high efficacy and a favorable toxicity profile. We have developed a second-generation CD8α-TM BCMA-4-1BBζ CAR-T product, ARI0002h (Cesnicabtagene-autoleucel) for patients with relapsed/refractory MM. We hypothesized that replacing the TMD of ARI0002h with a CD28-TMD could increase efficacy and reduce tumor escape while maintaining a tolerable toxicity profile. We generated CAR-T cells using T-cells isolated from buffy coats and evaluated the efficacy and fitness of CAR-Ts at day 8-10 of expansion against several MM cell lines. In vitro analyses included cytotoxicity, proliferation, cytokine secretion, T-cell subset markers, activation and exhaustion profiling, metabolomic assays, and RNA-seq after multiple tumor challenges. In in vivo xenograft studies using NSG mice, with tumor cells expressing GFP-ffLuc, disease progression was monitored weekly via bioluminescence imaging. Despite showing similar in vitro performance regarding cytotoxicity, proliferation and cytokine production, ARI2h-TM28 outperforms ARI0002h in a low BCMA expression setting and achieves superior in vivo tumor control and survival in relapse models with antigen downregulation. Furthermore, ARI2h-TM28 showed an optimized metabolic profile, more oxidative and energetic compared with ARI0002h, with downregulation of proinflammatory genes in CD8 T cells, contributing altogether both to reduced exhaustion and increased persistence of the CARs, improving their efficacy in preclinical models. Incorporating a CD28-TMD into the ARI0002h CAR enhances tumor control even in relapse models with downregulation of the target antigen, offering improved long-term disease management. This modification increases potency against MM tumor cell lines with both normal and reduced BCMA expression, demonstrating superior metabolic endurance and in vivo activity. Show less

Hypoxic-ischemic brain damage (HIBD) represents a major cause of neonatal morbidity and mortality, resulting from perinatal oxygen deprivation and impaired cerebral blood flow. This study aims to investigate the neuroprotective effects of Arctiin, a bioactive lignan derived from Neonatal rats at postnatal day 8 were randomly assigned to four groups: Sham-operated (SHAM), Hypoxia-Ischemia (HI), Hypoxia-Ischmia with Solvent control (HI/SO), and Hypoxia-Ischemia treated with Arctiin (HI/Arc). HIBD was induced via unilateral carotid artery ligation followed by exposure to hypoxia. The HI/Arc group was administered Arctiin orally at a dosage of 60 mg/kg daily for seven consecutive days. Behavioral performance, biochemical parameters, histological integrity, and gene expression profiles were assessed to evaluate the neuroprotective efficacy of Arctiin. Arctiin administration resulted in a significant reduction in C-reactive protein (CRP), and total oxidant capacity (TOC). Simultaneously, it enhanced total antioxidant capacity (TAC) and brain-derived neurotrophic factor (BDNF) levels. Histological analysis showed diminished infarct volume in the Arctiin-treated group. Moreover, gene expression studies revealed significant restoration of Neuregulin-1 (NRG-1) in group treated by arctiin. Neurobehavioral assessments further confirmed significant improvements in sensorimotor function in the Arctiin-treated group. Our study provides evidence indicating that Arctiin mitigates hypoxic-ischemic brain damage in rat pups through a synergistic mechanism involving the suppression of inflammation and oxidative stress, coupled with the upregulation of critical neuroprotective genes and proteins, specifically NRG-1 gene expression and BDNF protein levels. Future studies should investigate the precise molecular pathways downstream of NRG-1 that mediate Arctiin's neuroprotective effects. Show less

Identifying high-performing advanced practice nursing roles and understanding the factors that contribute to their effectiveness are critical for advancing professional development, optimizing workforce deployment, and ensuring long-term sustainability in nursing. This study aimed to (1) identify distinct latent profiles of advanced practice nursing among specialist nurses in mainland China, (2) quantitatively examine the individual and contextual factors associated with high performance, as characterized by these profiles, and (3) qualitatively confirm the significant factors using explanatory semistructured interviews in the high-performance groups. A mixed-methods sequential explanatory design was used, in which quantitative data were collected first and subsequently explained through qualitative interviews. Certified specialist nurses from 16 hospitals across urban and rural areas of Shanghai were included. Latent profile analysis (LPA) was conducted using the five domains from the Advanced Practice Role Delineation tool as manifest indicators to classify nurses into distinct performance profiles. Multinomial logistic regression was used to examine potential determinants (e.g., job position) of group membership. Additionally, a backpropagation neural network (BPNN) was developed to rank the importance of contributing factors. Specialist nurses identified as high performers in the quantitative phase were purposively sampled for explanatory semistructured qualitative interviews. Three latent profiles emerged: high performance (26.1%), moderate performance (46.3%), and low performance (27.6%). Compared to APNs, staff nurses had significantly lower odds of belonging to the high-performance group ( Identifying the profiles of advanced practice nursing roles provides valuable insights for optimizing APN performance and informing targeted management and policy strategies. High-performing specialist nurses are positioned at the nexus of individual capability, interdisciplinary collaboration, and institutional support. Show less

Huntington’s disease (HD) pathogenesis involves diverse cellular mechanisms, yet the contributions of pyroptosis and ferroptosis remain elusive. Roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor, has shown neuroprotective effects, but its precise mechanisms are yet to be elucidated. We evaluated the potential neuroprotective and therapeutic effects of roflumilast in 3-nitropropionic acid (3-NP)-induced HD-like neurodegeneration, focusing on pyroptotic and ferroptotic cell death signaling. Adult male Wistar rats were assigned to five groups: normal control (saline + 0.5% carboxymethyl cellulose), roflumilast-control (1 mg/kg/day, p.o. for 21 days), 3-NP (20 mg/kg/day, i.p. for seven days), roflumilast-prophylactic (1 mg/kg/day, p.o. for 21 days prior to 3-NP), and roflumilast-treatment (1 mg/kg/day, p.o. for 21 days post-3-NP). Behavioral outcomes of the open-field, rotarod, and grip strength tests were assessed. Striatal PDE-4, total and p-CREB, BDNF, interleukin-1β, and markers of pyroptosis (NLRP3, caspase-1, and gasdermin D) and ferroptosis (iron, GPx4, GSH, and malondialdehyde) were measured alongside histopathological alterations and GFAP and Iba-1 immunohistochemical staining. Bioinformatics was used to visualize the target genes’ protein-protein interaction network. Behavioral assessments revealed impaired locomotion, motor coordination, and muscle strength in the 3-NP-injected rats. Biochemical analysis showed increased striatal PDE-4 expression and decreased p-CREB/BDNF axis alongside NLRP3 inflammasome/caspase-1/gasdermin D activation and elevated interleukin-1β. In parallel, ferroptosis was evidenced by increased striatal iron and malondialdehyde levels, along with reduced GPx4 and GSH. Histopathological examination revealed pronounced striatal neurodegeneration, accompanied by enhanced GFAP and Iba-1 immunostaining, indicating astrogliosis and microglial activation. Roflumilast, administered prophylactically or therapeutically, significantly improved functional and behavioral abnormalities while ameliorating biochemical, histopathological, and immunohistochemical derangements induced by 3-NP. The therapeutic regimen exhibited superior efficacy relative to prophylaxis. Conclusively, roflumilast exerts therapeutic and neuroprotective effects in HD-like neurodegeneration by mitigating pyroptosis and ferroptosis, attenuating astrogliosis, microglial activation, and neuroinflammation, and restoring synaptic plasticity. A graphical abstract illustrating the proposed mechanistic pathway underlying the neuroprotection of the PDE-4 inhibitor roflumilast through reducing striatal pyroptosis, ferroptosis, microglial and astrocyte activation, and neuroinflammation, while restoring synaptic plasticity in experimental Huntington’s disease-like neurodegeneration induced by 3-NP. [Image: see text] Show less

The approach to physical activity in patients with epilepsy has substantially changed over the last decade. Despite multiple positive effects of physical activity on general health and well-being, patients with epilepsy have long been advised not to engage in sports activities. Recent studies have led physicians to formulate updated recommendations and to encourage patients to remain active. It has been demonstrated that sport does not increase seizure prevalence, and the rate of sport-induced injuries in people with epilepsy is comparable to that of the general population. Additionally, physical activity modulates brain plasticity through a number of mechanisms, including the effect of brain-derived neurotrophic factor (BDNF), gamma-aminobutyric acid (GABA)/glutamate balance, and maintaining long-term potentiation states in synapses. The International League Against Epilepsy (ILAE) classifies sports into three categories according to the potential risk of injury in the event of a seizure. While most activities fall into low- or moderate-risk groups, high-risk sports include aviation, climbing, diving, horse racing, motor sports, parachuting, rodeo, scuba diving, ski jumping, solitary sailing, surfing, and windsurfing. Qualification for sports participation requires individual assessments of predispositions, seizure type and frequency, reaction to specific sports disciplines, respiratory function, and adjustment of hydration and nutrition. The intensity of training should be increased gradually to avoid triggering factors, such as hyperventilation, alkalosis, and hyperthermia. Seizure occurrence differs between aerobic and anaerobic sports, which is another aspect that needs to be included. Exercise electroencephalographic (EEG) and ambulatory EEG monitoring should be taken into account in patients with exercise-induced seizures to optimize their training plan. Despite the evolving recommendations, it is difficult to formulate universal recommendations for everyone. Each patient with epilepsy should undergo an individual qualification process and be appropriately monitored. Show less

Malignant phosphaturic mesenchymal tumors (MPMT) are rarely seen soft tissue tumors. They can result in tumor-induced osteomalacia with hypophosphatemia. These tumors show FN1::FGFR1/FGF1 gene fusions. We present a 59-year-old male patient with a swelling in his right knee. Magnetic resonance imaging examination revealed a soft tissue mass with a maximum diameter of 2 cm in his distal right thigh. Histopathologically, the tumor was composed of atypical spindle cells. Coagulative tumor cell necrosis, extensive osteoid-like matrix, calcifications, and aneurysmal bone cyst-like areas were present. Mitotic index was 16/mm Show less

This study investigated longitudinal plasma serotonin dynamics across the Alzheimer's disease (AD) continuum (cognitively normal [CN], mild cognitive impairment [MCI], and AD) to determine whether baseline serotonin and its 24-month change are associated with CSF amyloid-β (Aβ42), tau biomarkers, amyloid PET burden, structural brain integrity, and cognitive decline. Data from 959 ADNI participants (CN = 306, MCI = 421, AD = 232) with baseline and 24-month follow-up were analyzed. Measures included plasma serotonin, CSF biomarkers (Aβ42, total tau, p-tau181), florbetapir PET, MRI (hippocampal volume, cortical thickness), and cognitive tests (MMSE, ADAS-Cog 11, CDR-SB). Group differences were tested using ANOVA or Kruskal-Wallis, and associations were examined via partial correlations and mixed-effects models adjusted for age, sex, education, and APOE ε4, with FDR correction. The results revealed that baseline plasma serotonin levels showed a stepwise decline across the clinical continuum (CN > MCI > AD; p ≤ 0.05), consistent with progressive serotonergic dysregulation. In AD participants, higher baseline serotonin was significantly associated with less amyloid pathology and preserved brain structure, including higher CSF Aβ42 (β = 0.28, FDR p = 0.01), lower florbetapir PET SUVR (β = -0.31, FDR p = 0.02), and larger hippocampal volume (β = 0.33, FDR p = 0.02). Higher serotonin was also linked to better cognitive performance (MMSE: β = 0.22, FDR p = 0.02; ADAS-Cog 11: β = -0.24, FDR p = 0.02). Longitudinally, decreases in serotonin over 24 months in AD were associated with worsening amyloid burden (ΔPET SUVR: β = -0.29, FDR p = 0.02) and accelerated hippocampal atrophy (β = 0.32, FDR p = 0.01). Baseline serotonin predicted smaller 24-month declines in CSF Aβ42 (β = 0.28, FDR p = 0.01) and reduced hippocampal volume loss (β = 0.31, FDR p = 0.01). In CN and MCI groups, associations between serotonin and AD biomarkers or cognitive outcomes were not significant after FDR correction. On the whole, lower plasma serotonin levels are linked to amyloid pathology, hippocampal neurodegeneration, and cognitive decline in AD, supporting serotonin's potential as a stage-specific biomarker and mechanistic contributor to disease progression. Integrative longitudinal studies are needed to clarify causality and evaluate serotonergic pathways as therapeutic targets. Show less

Circulating lipoprotein(a) [Lp(a)] levels are highly heritable and linked to atherosclerotic cardiovascular disease, yet clinical measurement rates remain low (<1%) in the United States. The high heritability of Lp(a) across populations makes genetic prediction an attractive approach for closing this testing gap, but existing polygenic scores transfer poorly across populations. Haplotype-based prediction models, which use standard genome-wide genotype data to capture common-, rare-, and structural-variation at the LPA locus, could bridge this gap, enabling opportunistic identification of individuals with elevated Lp(a) levels across diverse populations within existing large, genotyped cohorts. This study sought to develop and validate a haplotype-based prediction model using genome-wide genotype data to identify individuals with elevated Lp(a) levels across diverse populations. We developed an Among PMBB (n = 1856), MGBB (n = 1401), and BioMe (n = 1686) participants with available genotype and Lp(a) measurements, average age was 60 years, and 51% were female. Overall r A haplotype-based genetic model effectively identified individuals with elevated Lp(a) levels across diverse populations, with potential utility for opportunistic screening among cohorts where genotype data is available, but Lp(a) testing rates are low. Show less

A high-fat diet (HFD) induces oxidative stress and reduces hippocampal neurotrophic factors, contributing to cognitive impairment. Hydrogen sulfide (H₂S) is an endogenous gaseous signaling molecule with recognized neuroprotective and antioxidant properties. This study investigated the effects of sodium hydrosulfide (NaHS), an H₂S donor, on hippocampal brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and oxidative stress in rats fed an HFD. Forty-two adult male Wistar rats were assigned to control or HFD groups, with or without daily NaHS administration (3 or 5 mg/kg) for 11 weeks. HFD feeding significantly decreased hippocampal BDNF and IGF-1 protein levels and reduced the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GSR). NaHS treatment, particularly at 5 mg/kg, restored neurotrophic protein levels and normalized antioxidant enzyme activities. These effects occurred without consistent changes in mRNA expression, suggesting post-transcriptional regulation. Collectively, these findings demonstrate that H₂S mitigates HFD-induced neurotrophic and oxidative deficits, supporting its potential as a therapeutic strategy for obesity-related hippocampal dysfunction. Show less

Background With the prevalence of coronary artery diseases (CAD) on the rise, especially in the younger population, characterization of non-conventional risk factors remains essential, especially in the inherently predisposed Southeast Asian population. This study aimed at clinical and biochemical profiling in angiographically proven CAD in young Gujarati Indians without conventional risk factors such as tobacco/alcohol consumption. Methodology This single-center, descriptive, cross-sectional case series included consecutive Gujarati patients aged ≤45 years presenting with symptomatic, angiographically significant CAD over a 15-month period. Patients with tobacco or alcohol exposure and those with concomitant pre-existing diabetes mellitus and hypertension were excluded. Clinical characteristics, biochemical parameters (glycated hemoglobin, lipid profile, lipoprotein A (LpA), homocysteine, apolipoproteins), and coronary angiographic findings were recorded. Analyses were primarily descriptive, with limited exploratory comparisons. Results Overall, 2/4 obese patients (50%) and 3/4 obese patients (75%) were newly diagnosed with dysglycemia and dyslipidemia, respectively. Among patients with single-vessel disease (SVD; n = 16), eight (50%) patients presented with ST-segment elevation myocardial infarction, whereas among those with multi-vessel disease (MVD; n = 6), three (50%) patients presented with non-ST-segment elevation myocardial infarction. Elevated low-density lipoprotein cholesterol levels were observed in 8/16 (50%) patients with SVD and 3/6 (50%) patients with MVD. More than 5/6 (83.3%) patients with elevated LpA had SVD. Conclusions The study showed that non-conventional risk factors, such as obesity and family history of CAD, when combined with LpA and lipid profiles, can help in earlier identification of a predisposed individual in a high-risk population. Show less

Programmed Cell Death 4 (PDCD4) is a multifunctional regulator with critically divergent, context-dependent roles: it acts as a tumor suppressor in neuro-oncology but a pathogenic driver in neuroinflammatory and degenerative conditions. Elucidating this functional duality is clinically relevant because PDCD4 dysregulation directly contributes to disease progression in both contexts. Its dual role is governed by disease-specific molecular environments, differential downstream mRNA targeting, and dynamic regulation of its expression and interactions. In gliomas, PDCD4 is frequently downregulated via promoter methylation, non-coding RNA inhibition (e.g., miR-21), and signaling pathway dysregulation (e.g., FAT1-STAT1 axis)-compromising key anti-tumor functions including cell cycle arrest, apoptosis induction, negative regulation of autophagy-lysosomal activity, and reversal of therapy resistance. Conversely, in conditions such as neural injury, neurodegenerative diseases, and mood disorders, PDCD4 is pathologically upregulated. Here, it exacerbates damage by driving the activation of pro-inflammatory pathways (e.g., MAPK/NF-κB, NLRP3 inflammasome), inducing neuronal death (apoptosis/ferroptosis), and impairing repair processes such as axonal growth by suppressing neurotrophic factors like brain-derived neurotrophic factor (BDNF). A multilayered regulatory network centered on miRNA-mediated control (notably miR-21), and expanded by epigenetic modifications and competitive endogenous RNA mechanisms, orchestrates its context-specific expression and activity. Current research gaps include an incomplete understanding of regulatory synergies, cell-type-specific functions, and key molecular interactions. Future studies employing multi-omics and cell-specific tools are needed to decipher these mechanisms and develop targeted therapeutic strategies. Show less

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder that complicates the identification of effective therapeutic targets. The potential of stem cells and neurotrophins as promising candidates has become increasingly evident, owing to their neuroprotective and anti-inflammatory properties. In this study, a preclinical evaluation of the safety and biodistribution of mesenchymal stromal/stem cells (MSCs) combined with neurotrophin-releasing polyelectrolyte nanoparticles (NTs) was conducted in a porcine intrathecal delivery model relevant to ALS therapy development. Four groups of male pigs were administered saline with NTs, adipose-derived stem cells (ASCs) with NTs, Wharton's jelly-derived MSCs (WJ-MSCs) with NTs, or spinal puncture only. The safety of the treatment was assessed using magnetic resonance imaging (MRI), haematological and biochemical analyses, cerebrospinal fluid profiling, and histology. No adverse effects or significant systemic alterations were observed. It is noteworthy that C-reactive protein levels diminished following NT and NT-MSC administration, suggesting a systemic anti-inflammatory effect. The migration of MSCs was facilitated by cerebrospinal fluid, leading to their accumulation around the spinal cord and brain parenchyma. The present findings demonstrate short-term safety and biodistribution patterns following intrathecal administration of MSCs combined with neurotrophin-releasing nanoparticles in a large-animal model. These preliminary observations provide a pilot framework for future efficacy studies in disease-specific ALS models. This work establishes a translational platform for the development of future ALS therapies, with subsequent studies focused on efficacy testing in disease-specific models that more accurately reflect the slow, heterogeneous, multisystem nature of human ALS. Show less

Melanocortin-2 receptor accessory protein-2 (MRAP2) modulates the activity of hypothalamic melanocortin-4 (MC4R) and growth hormone-secretagogue (GHSR) receptors, which suppress and promote appetite, respectively. We investigate whether obesity-associated variants of MRAP2 alter their ability to modulate MC4R and GHSR signalling as a possible mechanistic link to the development of obesity. Functional effects of five obesity-associated MRAP2 variants were analysed in HEK293 cells by co-expressing wild-type or variant MRAP2 with MC4R or GHSR. Endpoints included cell-surface and total expression, and ligand-induced second-messenger responses, β-arrestin-2 recruitment, and alternative G-protein activation. MRAP2 decreased basal MC4R cell-surface expression while GHSR cell-surface expression was not affected. In MC4R/MRAP2 expressing cells, maximal α-MSH-induced cAMP and β-arrestin-2 recruitment responses were increased. Similarly, ghrelin-induced Ca2+-mobilization in GHSR/MRAP2 expressing cells was increased, but β-arrestin-2 recruitment was suppressed. MRAP2 did not bias G-protein activation by either receptor, although previous reports show MRAP2 biases MC4R signalling towards Gαq/11. The variants did not significantly affect the ability of MRAP2 to modulate MC4R and GHSR signalling. Our results indicate that MRAP2 potentiates the ligand responsiveness of MC4R and GHSR, but has differential effects on β-arrestin-2 recruitment. The MRAP2 variants had no significant effects on the signalling endpoints tested. This suggests that, despite their association with obesity, the variants may be functionally benign, or that the absence of effects reflects limitations inherent to our cellular model. In addition, since MRAP2 can modulate multiple receptors and differentially modulate their signalling, we cannot rule out their influence on body weight regulation via other mechanisms. Show less

Stress is defined as a disruption of homeostasis that elicits adaptive responses aimed at restoring physiological balance. However, when stress becomes chronic or overwhelming, maladaptive changes may occur, contributing to endocrine, behavioral, and neuropsychiatric dysfunctions. Beyond the classical neuroendocrine axes, such as the sympatho-adrenomedullary and hypothalamic-pituitary-adrenal (HPA) axes, the renin-angiotensin system has also being implicated in stress modulation. Previous studies have shown that angiotensin-(1-7), acting through its receptor Mas, exerts a modulatory effect on the stress response, attenuating anxiety- and depression-like behaviors induced by various stressors. Here we investigated the impact of genetic deletion of Mas on the consequences of chronic unpredictable stress (CUS) exposure. Over 21 consecutive days, mice were subjected to random stressors, after which endocrine, behavioral and neurochemical assessments were performed. Mas knockout (KO) mice exposed to CUS exhibited significantly elevated corticosterone and blood glucose levels compared to stressed wild-type mice. In behavioral tests, stressed Mas KO mice displayed the highest immobility times in the forced swimming test, indicating enhanced depressive-like behavior. Anxiety-like behavior was also heightened in Mas KO mice, as evidenced by a significant reduction in the percentage of time spent in the open arms of the elevated plus maze test. Neurochemical analysis revealed a marked reduction in brain-derived neurotrophic factor (BDNF) levels in key brain regions of stressed Mas KO animals. Together, these findings suggest that Mas plays a critical role in the neurobiology of stress, since its absence exacerbates HPA axis hyperactivity, depression- and anxiety-like behaviors, as well as BDNF reduction. Overall, these results highlight the potential neuroprotective role of Mas in stress-related disorders. Show less

Both brain-derived neurotrophic factor (BDNF) and ovarian hormones are powerful neuromodulators, yet evidence of their impact on human cognition remains mixed. As prior work has studied them in isolation, examining their interacting effects presents a key empirical opportunity for explicating their effects on cognition. We genotyped participants for the BDNF Val66Met single nucleotide polymorphism, which is associated with less efficient activity-dependent BDNF secretion and altered hippocampal function, and examined their performance on a complex learning task at two points in the menstrual cycle: early follicular (characterized by low levels of ovarian hormones) and late follicular (characterized by high estradiol). While met carriers showed advantages during the early follicular timepoint, val homozygotes outperformed them at the late follicular timepoint. Furthermore, effects in met carriers were largely driven by increased sensitivity to both absolute levels and changes in levels of estradiol. The current findings provide the first evidence of BDNF Val66Met interacting with the menstrual cycle to predict cognition, demonstrate nuanced genotype- and hormone-specific outcomes, and underscore the importance of studying effects of interacting biological systems on human cognition. Show less

In recent years, young adults have navigated multiple, simultaneous crises - COVID-19, war in Ukraine, economic turbulence, climate change, and rapid AI growth - which pose complex mental-health risks. Drawing on multisystemic resilience models and the dual-factor model of mental health, we examine how individual (emotion-regulation difficulties), relational (attachment, social support), and contextual resources (social engagement, place attachment, socioeconomic status) relate to distinct emotional-response profiles and their change across three waves (July 2023, February 2024, September 2024) in a representative Polish sample ( The online version contains supplementary material available at 10.1186/s12992-026-01199-8. Show less

Global studies have shown a bidirectional association of gestational diabetes mellitus (GDM) with postpartum depression (PPD). Despite high GDM prevalence in Pakistan (3.3%-17.8%), no prior studies have explored its link with PPD. In this study, association between GDM and risk of developing PPD was investigated and risk factors for PPD were identified using the gold-standard Edinburgh Postnatal Depression Scale (EPDS). Evidence suggests that PPD has strong genetic basis. The BDNF gene is a known candidate for PPD pathogenesis, while the orexin system is linked to arousal, energy metabolism, with emerging role in neuropsychiatric disorders. This study is the first study to explore association of orexin SNP ORX1 10914456 with PPD together with the BDNF SNP rs6265 (Val/Met66), among participants with and without GDM diagnosis. Among 1,000 women approached in hospitals of Islamabad, Rawalpindi, 800 met inclusion criteria (400 GDM, 400 non-GDM controls) and were genotyped for BDNF and orexin SNPs. Participants completed the EPDS 1 week postpartum. Using a cutoff of ≥13, 84.9% of GDM patients and 18% of non-GDM controls scored ≥13 on EPDS (χ2 = 78.337, p < 0.00001). Multivariate logistic regression revealed GDM diagnosis, BMI >25, fasting plasma glucose >126 mg/dL, 31-39-week gestation, <12 years of education, and urban locality as significant risk factors for PPD. GDM diagnosis increased odds of PPD by 2.5-fold (OR = 2.5, 95% CI: 21.48-4.31, p < 0.0001). The orexin SNP Orx1 10914456, CC genotype and BDNF SNP rs6265, AA genotype increased the odds of having higher EPDS scores in GDM patients by 3.11 (OR = 3.11, 95% CI: 1.29-7.47, p < 0.001) and 3.3 (OR = 3.3, 95% CI: 1.31-8.13, p = 0.04, p < 0.05), respectively, in comparison to other genotypic variants. Our study supports orexin and BDNF system-targeted therapies for PPD. Show less

Dementia comprises a spectrum of neurodegenerative disorders marked by progressive cognitive and behavioural decline, with Alzheimer’s disease (AD) being the most prevalent form. While several genetic factors have been implicated in AD pathogenesis, a significant portion of heritability remains unexplained. One potential contributor to this “missing heritability” is structural variation within non-coding regions, such as variable-number tandem repeats (VNTRs). This study investigated the 40-bp VNTR located in the 3’ untranslated region of the A cohort of 799 elderly individuals from Central Italy, including AD, mild cognitive impairment (MCI), mixed dementia, and control subjects, was genotyped for the No significant association was observed between These findings suggest that while the The online version contains supplementary material available at 10.1186/s12920-026-02341-6. Show less

Esophageal cancer is a formidable malignancy, presenting a significant health challenge due to its widespread prevalence and associated high mortality rates. Epithelial cell adhesion molecule (EpCAM), a pro-oncogenic glycoprotein, has been identified as an upregulated protein in esophageal adenocarcinoma (ESCA) through multi-OMICS platforms. However, its functional role in ESCA remains relatively understudied. Here, we investigated the contribution of EpCAM to ESCA pathogenesis using an EpCAM-null ESCA cell line, FLO-1, as a gain-of-function model. Introduction of a recombinant EpCAM-GFP fusion construct into FLO-1 cells resulted in enhanced cell migration, adhesion, clonogenic survival, and invasive capacity, supporting a pro-tumorigenic role for EpCAM. To define EpCAM-associated regulatory networks, RNA sequencing was performed on EpCAM-overexpressing cells, revealing 797 differentially expressed genes. Functional enrichment analyses indicated significant involvement of pathways related to cell adhesion, cell motility, transmembrane activity, and neuronal-associated processes, with enrichment in plasma membrane, focal adhesion, and neuron projection terminus compartments. Protein-protein interaction network analysis identified key hub genes, including SOX2, COL1A1, LOX, COL3A1, LUM, PXDN, BDNF, NCAM1, TLR2, and CCL5, linking EpCAM signaling to PI3K-Akt, ECM-receptor interaction, and focal adhesion pathways. Importantly, quantitative polymerase chain reaction (qPCR) validation of selected hub genes confirmed significant upregulation of the extracellular matrix components COL1A1 and PXDN in EpCAM-overexpressing FLO-1 cells, supporting the transcriptomic predictions and implicating ECM remodeling as a downstream consequence of EpCAM signaling. Collectively, these findings demonstrate that EpCAM promotes aggressive cellular phenotypes in ESCA and drives transcriptional programs associated with adhesion, invasion, and extracellular matrix regulation, highlighting potential therapeutic vulnerabilities in EpCAM-driven ESCA. Show less

Intramuscular fat (IMF) is a key determinant of meat quality, influencing tenderness, juiciness, and flavor. Previous studies have reported that the deposition of IMF is controlled by various factors. However, there is a shortage of research exploring the variations in IMF deposition across age groups from a microbial perspective. This study evaluated the differences in IMF deposition between yearling (1-year-old) and mature (4-year-old) Longdong Cashmere goats and analyzed its association with gut microbiota. The results revealed that the IMF content in shoulder meat and blood lipid levels increased with age (p < 0.05). Conversely, the contents of lipoprotein lipase (LPL) in the liver and duodenum significantly decreased with age. Microbial diversity differed between the two age groups, with specific microbiota identified from the gut of goats involved in the lipid metabolism pathway. The concentrations of valeric and isovaleric acids in the rumen, as well as acetic, propionic and isovaleric acids in the colon, were higher in yearling goats than in mature goats (p < 0.05). Spearman correlation analysis of IMF deposition indicators with gut microbiota revealed that, within the rumen, the abundances of CAG-791 and Sodaliphilus were positively correlated with IMF content in shoulder meat and TG levels, while exhibiting a negative correlation with the contents of valeric acids. Furthermore, the abundance of Clostridium_R showed a positive association with IMF content in shoulder meat and with the abundances of CAG-791and Sodaliphilus. In contrast, the abundance of Bact₁₁ was negatively correlated with IMF content in shoulder meat, TG levels, and the abundances of CAG-791, Sodaliphilus and Clostridium_R. Within the abomasum, the abundances of UMGS and Hylemonella₅₈₂₃₀₈ were correlated with IMF content in the shoulder meat, as well as serum LDL and VLDL levels. This study provides significant insights into the age-dependent gut microbiota associated with intramuscular fat deposition in goats and identifies several potential gut microbiota for further research on their impacts on IMF deposition. Show less

Osteoporosis has emerged as a growing public health concern due to its high prevalence and substantial economic burden on both individuals and society. Recent studies have identified the serum uric acid to high-density lipoprotein cholesterol ratio (UHR) as a novel predictive biomarker for various diseases. However, its association with bone mineral density (BMD) remains unclear. This study evaluated the association of the UHR and forearm BMD (FR-BMD) in a middle-aged and elderly cohort. We also assessed the interaction effects of age, sex, and body mass index (BMI). A total of 4,958 adults aged ≥50 years were enrolled from health examinees at Heze Municipal Hospital (2022-2025). We collected demographic data, serum lipids, and uric acid levels. Measurements of FR-BMD were performed on the left distal radius (1/3 site) utilizing dual-energy X-ray absorptiometry. Multivariate linear regression analyses evaluated the UHR-BMD relationship, supplemented by subgroup analyses and interaction tests. Nonlinear associations were assessed using generalized additive models with smoothing curves. After adjusting for age, sex, BMI, Alb, ALP, ALT, BUN, TP, Scr, Lp(a), TC, GGT and hypertension, a higher UHR was significantly associated with lower FR-BMD [β=-0.076, 95%CI(-0.138~-0.015), P = 0.015]. Significant interaction effects were observed for age and sex ( The association of UHR with FR-BMD is significantly modified by age and sex in middle-aged and elderly populations. Nonlinear relationships exist in males <60 years, females ≥60 years and non-overweight individuals. The potential of UHR as a novel indicator for bone health assessment in select populations is highlighted by our results. Show less

Brain-derived neurotrophic factor (BDNF) crosses the blood-brain barrier and may serve as a marker of neuroplasticity. This study evaluated whether serum levels of mature BDNF, proBDNF, and matrix metalloproteinase-9 (MMP-9) can predict functional recovery after stroke. In this prospective observational study, 93 patients with unilateral stroke and motor impairment were recruited. Clinical, and demographic data, as well as serum levels of mature BDNF, proBDNF, and MMP-9 were collected. Functional assessments measuring stroke severity, cognition, motor function, balance, and mood were conducted at three timepoints: after acute care (T0), 2 weeks post-rehabilitation (T1), and 3 months post-onset (T2). Mature BDNF significantly decreased from T0 to T2 (p = 0.003), while proBDNF remained stable. MMP-9 declined consistently across timepoints (p < 0.001). MMP-9 levels at baseline differed by BDNF genotype (p < 0.05). However, none of the biomarkers independently predicted functional recovery. Functional outcomes improved significantly over time (p < 0.001), with baseline functional scores being the strongest predictors at T1 and T2. Although these biomarkers were not independent predictors of recovery, their longitudinal trajectories may reflect underlying neurobiological recovery mechanisms during rehabilitation, although their prognostic utility remains inconclusive. Show less

Clarifying relationships between amyloid, tau, and cognition is crucial to understanding dementia risk, but has been mainly performed in non-Hispanic White (NHW) participants. It is unknown whether findings are generalizable to other ethnoracial groups. We evaluated relationships between amyloid-β (Aβ) positivity, apolipoprotein E allele (APOE) ε4, tau-positron emission tomography (PET) Black (β = 0.28, p < 0.001) and Hispanic (β = 0.34, p < 0.001) participants had higher medial temporal lobe (MTL) tau than NHW participants; however, findings were attenuated when accounting for choroid plexus off-target binding. Hispanic participants showed higher tau in lateral temporal regions compared to NHW and Black participants; however, reducing meningeal off-target binding through erosion demonstrated similar lateral temporal tau across groups. Factors other than amyloid and tau may impact cognition in Black participants. PI2620 off-target ethnoracial differences should be investigated. Show less