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Orthodontic tooth movement (OTM) is a biomechanically driven process governed by dynamic cellular and molecular signaling interactions between neural and skeletal systems. This review synthesizes current evidence on neuron-bone cell crosstalk and the coordinated involvement of immune and vascular components in regulating alveolar bone remodeling during OTM. Key neural contributors include sensory neurons (nociceptors), autonomic neurons, central nervous system (CNS) circuits, and Schwann cells, which communicate with osteoblasts, osteoclasts, and periodontal ligament cells to modulate their proliferation, differentiation, and functional activity. These interactions are mediated by defined signaling pathways, including neuropeptide signaling (CGRP-CLR, SP-NK1, NGF-TrkA, BDNF-TrkB), axon guidance signaling (Sema3A-PlexinA/Nrp1), adrenergic signaling (β2-AR-dependent pathways), and intracellular cascades such as Rac1-β-catenin, RhoA/ROCK2, and Notch3. Sensory nerves function as primary initiators by releasing neuropeptides that promote osteoclastogenesis in pressure zones and osteogenesis in tension zones, while simultaneously shaping local immune responses and vascular remodeling. The autonomic nervous system exerts context-dependent regulation, with sympathetic signaling favoring bone resorption and parasympathetic pathways emerging as modulators of osteogenesis and neurovascular homeostasis. CNS circuits integrate sensory and autonomic inputs to coordinate OTM kinetics and pain perception. Together, these neuro-osteogenic signaling networks define mechanistic targets for improving orthodontic outcomes and pain management via neuromodulation. Show less

High mobility group AT-hook 1 (HMGA1) is a chromatin regulator overexpressed in various cancers, often predicting poor outcomes. However, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. A hallmark of HNSCC is the rapid growth of its vasculature. Here, we identify an epigenetic mechanism whereby HMGA1 promotes tumor progression and angiogenesis via upregulation of fibroblast growth factor-binding protein 1 (FGFBP1). Show less

We assessed whether Tridax procumbens (TP) extracts could be used therapeutically against pancreatic cancer and remain nontoxic to normal cell types. The crude extract from TP (CETP) was fractionated using hexane, dichloromethane, and ethyl acetate to obtain fractions (NHF, DCMF, and EAF, respectively). The pancreatic ductal adenocarcinoma cell line (PANC-1) was cultured with (10, 20, 50, 100, and 250 μg/mL) dimethyl sulfoxide (DMSO) (control), CETP, and CETP-fractions for 24 or 48 h. As a normal cell type, we cultured E11.5d mouse pancreatic explants for five days before treating with the test samples (20 μg/mL) in DMSO for a further 48 h. Cytotoxicity assays (MTT and Live-Dead) were conducted, and the expression of cellular biomarkers, such as vimentin, Ki-67, p53, p21, and caspase-3, was evaluated. DCMF elicited PANC-1 cell death (IC Show less

Biomarkers that capture the dynamic transition from obesity to metabolic dysfunction and subsequent cardiorenal disease remain insufficient. This study evaluated stage-specific associations of lipid-inflammation indices across this continuum. We included 109,442 obese adults (UK Biobank) across four stages, obesity (Stage 1), metabolic disorders (Stage 2), cardiorenal disease (Stage 3), and death (Stage 4). Five baseline indices (ApoB/A1-CRP, RCII, NHR, lymphocyte-to-HDL-C, monocyte-to-HDL-C) were evaluated. Markov multistate models were used to estimate transition-specific risks, with Cox regression and restricted cubic spline (RCS) analyses as complementary approaches. During a median follow-up of 15.73 years, 11.14% of participants progressed from Stage 1 to 2, and 25.88% from Stage 2 to 3. In fully adjusted model, ApoB/A1-CRP (HR, 1.07, 95% CI, 1.00-1.14, P = 0.048) and RCII (HR, 1.08, 95% CI, 1.01-1.15, P = 0.017) were significantly associated with Stage 2 to 3 progression. Upon Stage 3 stratification, NHR was primarily associated with mortality following cardiorenal disease onset. RCS analyses indicated significant non-linear associations for ApoB/A1-CRP, RCII, and NHR. RCII demonstrates robustness in sensitivity analysis. RCII is independently associated with the progression from metabolic disorders to cardiorenal diseases in obesity. It may serve as a clinically biomarker for early risk stratification. Show less

Electrical stimulation (ES) is emerging as a non-pharmacological neuromodulation strategy, but its direct impact on human dopaminergic neurons and its relationship to rapid-acting antidepressant mechanisms remain unclear. This study aimed to investigate whether brief biphasic low-frequency low-intensity (LF-LI) ES can induce structural and molecular plasticity in human induced pluripotent stem cell (iPSC)-derived mesencephalic dopaminergic neurons, identify the underlying signaling mechanisms, and evaluate its potential to rescue cortisol-induced impairments as in-vitro endocrine model of depression. iPSC-derived dopaminergic neurons were exposed to LF-LI ES using a custom culture-compatible stimulator, and structural plasticity was quantified three days later by computer-assisted morphometry. Pharmacological blockers, quantitative PCR and Western blot analyses were employed to assess calcium influx, brain-derived neurotrophic factor (BDNF)-TrkB-extracellular signal-regulated kinase (ERK)-mTOR signaling, and dopamine D3 auto-receptor roles in mediating LF-LI ES effects. A single 1h LF-LI ES session at 4 mA induced robust increases in maximal dendrite length, primary dendrite number, and soma area, comparable to 1 μM ketamine. LF-LI ES rapidly enhanced ERK and p70-S6K phosphorylation and required L-type voltage-gated calcium channels, TrkB and mTOR, as their inhibition prevented structural remodeling. LF-LI ES increased dopamine D3 auto-receptors mRNA, and its antagonism attenuated LF-LI ES-induced plasticity. In cortisol-treated neurons, LF-LI ES fully reversed dendritic hypotrophy and soma shrinkage. In conclusion, brief LF-LI ES elicits long-lasting, ketamine-like structural and molecular plasticity in human dopaminergic neurons and rescues stress hormone-induced impairments, supporting LF-LI ES-based neuromodulation approaches targeting dopaminergic circuits in major depressive disorder and treatment-resistant depression. Show less

Multispecific therapeutics represent an increasingly important approach for enhancing the efficacy in complex diseases. Here, we report the design and optimization of novel antibody-peptide conjugates that combine glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonism with glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism for the treatment of obesity. A series of hybrid molecules was generated by conjugating synthetic GLP-1 peptides to IgG-based anti-GIPR antibodies, yielding markedly prolonged systemic exposure of the structurally intact GLP-1 peptide. In diet-induced obese mice and obese monkeys, once weekly administration of anti-GIPR-Ab/GLP-1 conjugates produced sustained body weight loss and improvements in metabolic parameters. This optimization effort culminated in the discovery of AMG 133, currently in phase III clinical trials with a profile that may support monthly dosing. Show less

Glycosyltransferases that biosynthesize glycans and their genes (glycogenes) play important roles in health and disease. In general, pathophysiological changes are defined by comparing knock-out (KO) or knock-in mice generated using CRISPR-Cas9 and other technologies to normal mice. Next, target molecules such as glycoproteins, glycolipids, and proteoglycans to which various biosynthetic glycans bind were identified. As a result, we found that N-glycan branches biosynthesized by glycosyltransferases are intrinsically involved in Alzheimer's disease, cancer metastasis, epithelial mesenchymal transition (EMT)/mesenchymal epithelial transition (MET), type 2 diabetes, chronic obstructive pulmonary disease (COPD), and ulcerative colitis. For example, the addition of core fucose biosynthesized by α1,6-fucosyltransferase (Fut8) leads to dysregulation of TGF-β receptors. Bisecting N-acetylglucosamine (GlcNAc) biosynthesized by β-1,4-GlcNAc transferase III (GnT-III) affects the subcellular localization of Beta-site Amyloid Precursor Protein Cleaving Enzyme 1 (β-secretase 1, referred to as BACE1). β1,6GlcNAc branching biosynthesized by GnT-V leads to the modification of matrix metalloproteinase (MMP). Identification and characterization of N-glycan structures on these proteins were performed using a glycoproteomic approach based on lectin blotting, western blotting, liquid chromatography-electron spray ionization mass spectrometry, and histochemical staining. Recently, studies concerning redox regulation of N-glycans, termed Glyco-Redox, have emerged as a promising approach. Functional and pathophysiological glycan studies are one of the main goals of glycobiology research. In this review, we describe the role of N-glycan branching glycosyltransferases and their biosynthesized glycans in relation to various diseases, such as cancer metastasis, COPD, Alzheimer's disease, and ulcerative colitis. Show less

Modifying nanomedicines with targeting ligands represents an encouraging strategy for active tumor targeting, but its clinical failure underscores ongoing challenges. Herein, a series of liposomes with different targeting ligands (e.g., PEGylation, folic acid, mannose, RGD peptide, and melittin) were rationally designed to investigate the principles and mechanisms governing tumor targeting and penetration profiles. In primary and lung metastatic breast cancer models, these liposomes exhibited a systematic tendency of intratumor distribution, with melittin-modified liposomes showing optimal tumor targeting and therapeutic performance. Further studies revealed that the ligand modifications in liposomes could modulate the composition of their protein corona, particularly the level of Apolipoprotein A4 (ApoA4), which, in turn, influenced tumor targeting and intratumor distribution, ultimately affecting the therapeutic outcome of tumor inhibition and survival prolongation. This research provided a distinct correlation between ligand modification of liposomes and their Show less

This study investigates the independent and interactive effects of apolipoprotein E (APOE) genotypes and white matter hyperintensities (WMH) on distinct neuropsychiatric symptom (NPS) phenotypes in patients with Alzheimer's disease (AD). We enrolled 325 AD patients consecutively diagnosed at a specialized memory clinic between May 2024 and May 2025. All participants underwent comprehensive clinical assessments-including the Chinese Mini-Mental State Examination (CMMSE), Activities of Daily Living (ADL) scale, and the Neuropsychiatric Inventory (NPI)-as well as 3T brain MRI for WMH quantification and APOE genotyping. First, we compared NPS profiles and cognitive/functional scores across APOE genotype groups (ϵ2/ϵ2-ϵ2/ϵ3, ϵ3/ϵ3, ϵ3/ϵ4, ϵ4/ϵ4) using analysis of variance (ANOVA) or Kruskal-Wallis tests, as appropriate. Second, we applied mediation analysis (PROCESS macro Model 4, 5,000 bootstrap samples) to examine whether WMH burden mediates the association between APOE genotype (X) and outcomes including CMMSE total score and domain-specific NPS subscores (delusions, agitation, irritability, euphoria). Significant differences emerged across APOE genotypes in both cognition (CMMSE, p < 0.05) and functional status (ADL, p < 0.05). At the symptom level, carriers of at least one ϵ4 allele exhibited higher agitation scores than non-carriers (p < 0.05); notably, the ϵ4/ϵ4 homozygotes showed significantly greater severity in delusions, agitation, irritability, and euphoria compared with all other genotype groups (all p < 0.05). Mediation analyses revealed no statistically significant indirect effect of APOE genotype on any outcome via WMH, indicating that WMH does not mediate these associations. Instead, APOE genotype exerted robust direct effects on both cognitive performance and specific NPS domains. APOE genotype-particularly the ϵ4/ϵ4 homozygous status-is associated with more pronounced cognitive decline and a distinct, severe NPS profile in AD, especially involving delusions, agitation, Euphoria, and irritability. These associations are independent of WMH burden, suggesting that APOE exerts direct neurobiological effects on neuropsychiatric manifestations. Thus, APOE genotyping holds dual clinical value: not only as a well-established biomarker for AD risk and diagnosis but also as a potential prognostic indicator for behavioral and psychological symptoms-offering actionable insights beyond conventional neuroimaging markers. Show less

Problematic mobile phone use (PMPU) has become a prominent public health concern among Chinese adolescents and emerging adults, yet prior research has largely relied on variable-centered approaches that overlook within-group heterogeneity and provide limited insight into multilevel mechanisms. To address these gaps, this study adopted an integrated analytic framework combining latent profile analysis (LPA), structural equation modeling (SEM), and psychological network analysis. A total of 2345 Chinese university students completed measures of alexithymia (TAS-20), social interaction anxiety (IAS), and PMPU (MPAI). LPA identified three distinct PMPU profiles: Low-risk (62.7%), moderate-risk (24.8%), and high-risk (12.5%). SEM results indicated that alexithymia was positively associated with PMPU in the overall sample, with social interaction anxiety partially mediating this association. Profile-specific analyses further showed that the indirect pathway was significant in the low-risk and moderate-risk profiles but not in the high-risk profile, in which only a direct effect emerged. Network analyses in the low- and moderate-risk groups revealed profile-specific central and bridge nodes, primarily IAS items, highlighting potential symptom targets linking alexithymia and PMPU. Overall, findings underscore meaningful heterogeneity in PMPU and support profile-tailored prevention and intervention strategies emphasizing emotion-processing skills and social anxiety reduction. Show less

Frailty is associated with increased risks of falls, disability, hospitalization, and mortality. The 24-h movement behaviors (24HMB) framework conceptualizes sleep, sedentary behavior (SB), light-intensity physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) as mutually constrained components of daily time use and may inform frailty prevention and management. This scoping review maps evidence on associations between 24HMB and frailty and identifies methodological gaps to inform future research and nursing practice. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and follows Joanna Briggs Institute (JBI) guidance. We searched PubMed, Embase, CINAHL, and Web of Science. We included observational studies of adults aged ≥18 years. Exposures were objectively measured or validated self-reported sleep, SB, LPA, and MVPA, including step counts, breaks in SB, isotemporal substitution models (ISM), and compositional data analysis (CoDA). Outcomes were frailty or prefrailty assessed using validated instruments. Quality was appraised with JBI tools. Thirty-three studies showed good methodological quality. Longer SB, particularly prolonged, uninterrupted bouts, was associated with higher frailty. Greater MVPA was consistently associated with lower frailty. Light-intensity physical activity was generally beneficial but often attenuated when MVPA or total activity volume was modeled. Sleep fragmentation and poor sleep quality were associated with frailty. Isotemporal substitution models and compositional data analysis indicated that reallocating sedentary time to MVPA would yield the largest theoretical benefit, followed by reallocating to LPA. Higher daily step counts and more frequent or higher-intensity breaks in SB were associated with lower frailty. Evidence supports a 24-h integrated movement-behavior approach centered on MVPA, combined with reducing prolonged SB and improving sleep quality, for the prevention and nursing management of frailty. The study design and analytical protocol were prospectively registered on the Open Science Framework (OSF). The unique identifier is S39Y4, and the publicly accessible URL is https://doi.org/10.17605/OSF.IO/S39Y4. Show less

Diabetic nephropathy (DN) is a chronic renal complication characterized by persistent proteinuria, glomerular hypertrophy, impaired filtration capacity, and progressive renal fibrosis, ultimately leading to a gradual decline in kidney function. DN remains one of the leading causes of end-stage renal disease worldwide, contributing substantially to morbidity and mortality. Although the precise etiology of DN is not fully elucidated, its development is closely linked to prolonged hyperglycemia, renal hyperfiltration, accumulation of advanced glycation end products (AGEs), activation of pro-inflammatory cytokines, and oxidative stress-mediated injury. These pathogenic events involve multiple diabetes-associated pathways, including protein kinase C activation and increased reactive oxygen species (ROS) generation. O-linked β-N-acetylglucosamine (O-GlcNAc) modification is a dynamic post-translational protein modification that is significantly upregulated in DN and plays a critical role in regulating cellular signaling pathways associated with disease initiation and progression. This review summarizes current evidence on the role of O-GlcNAcylation in modulating molecular mechanisms underlying DN. Furthermore, Angiopoietin-like 4 (ANGPTL4) has emerged as a key regulator of lipid metabolism through inhibition of lipoprotein lipase and interactions with integrins, influencing vascular permeability, oxidative stress, and tissue remodeling. Increasing evidence suggests that ANGPTL4 plays a pivotal role in DN onset and progression. Show less

Epidemiological analyses suggest that the Ɛ4 allele of apolipoprotein E (ApoE) genes may influence the effects of alcohol on cognitive and executive function and dementia risk compared to the Ɛ3 allele. Here, we investigated this question in female rats given that women are more vulnerable than men to the Ɛ4 genotype effects on various diseases. Experiment 1 examined the effects of alcohol drinking on performance in a Barnes maze and an operant strategy set-shifting (OSS) task during abstinence in wildtype (WT) and homozygous ApoE4 knock-in (E4) rats. Experiment 2 repeated the behavioral assessments to assess the effects of heavy alcohol exposure and explored seizure susceptibility in E4 and homozygous ApoE3 knock-in (E3) rats. The experiments revealed that E4 rats drank significantly higher doses of alcohol than did the WT and E3 rats. However, there was no genotype or alcohol effect on performance in the Barnes maze and the OSS task. Notably, E4 rats had a shorter latency to kainate-induced seizures and maintained worse seizures compared to age-matched E3 rats. These findings suggest that the Ɛ4 allele may confer a higher risk for increased alcohol drinking without significantly exacerbating alcohol-associated decline in cognitive and executive function in females. Given the scarcity and discrepant reports regarding the role of ApoE polymorphism on seizure disorders among human and rodent studies, results of this study also underscore the need for more rigorous clinical and preclinical studies to determine the role of ApoE in sporadic and alcohol withdrawal seizures. Show less

This study aimed to compare positron emission tomography (PET) and plasma-based temporal modeling of amyloid and tau biomarkers in Alzheimer's disease. Longitudinal amyloid PET (n = 1,097, mean age ± SD = 72.5 ± 7.38 year, 51.4% male), Plasma and PET models generated similar results for estimated amyloid and tau onset, with stronger model agreement for tau (r = 0.88[0.86, 0.89], t = 57.4, p < 0.001) than amyloid (r = 0.75[0.72, 0.77], t = 37.4, p < 0.001) onset. Accuracy of estimated onset compared to actual onset was high within modality (mean absolute error [MAE] ≤ 2.03) with slightly greater error (MAE 3.09-3.42) when comparing across modalities (ie, plasma to PET). For both plasma and PET, earlier tau onset was associated with younger amyloid onset, female sex, and ≥1 apolipoprotein (ApoE) ε4 allele. Earlier dementia onset after tau was associated with later tau onset for both plasma and PET, while male sex was associated with shorter tau to dementia gap in plasma models. Temporal modeling of plasma biomarkers provides comparable information to PET-based models, particularly for tau onset age, and can serve as a widely accessible tool for clinical assessment of biological disease severity. ANN NEUROL 2026. Show less

Resilience is a critical indicator of the personal recovery process for people with serious mental illness (SMI). However, little is known about resilience subtypes among this population. Grounded in Kumpfer's resilience model (KRM), the study aims to identify latent types of resilience among people with SMI using latent profile analysis (LPA). A cross-sectional survey design was used. A total of 297 individuals with self-reported SMI completed an online survey, including demographic variables and measures that resemble core components of the KRM. The LPA identified three resilience profiles: Maladaptive, Homeostatic and Resilient. One-way analyses of variance (ANOVA) revealed distinct patterns of the three resilience profiles on all factors in the KRM and the outcome variable-adaptation to psychiatric disability. ANOVA and Chi-square tests indicated several demographic variables predict profile membership, including age, marital status, highest educational attainment, employment status, average weekly work hours and primary SMI diagnosis. However, sex, race-ethnicity, annual income and years since SMI diagnosis do not predict profile membership. The study contributes to the understanding of resilience subtypes and associated protective and risk factors for resilience among people with SMI, suggesting early, tailored strength-based interventions to promote resilience and personal recovery. Show less

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor with an essential role in appetite suppression and energy homeostasis. Genetic mutations in the receptor and components of its signalling pathway that cause obesity in humans, dogs and rodent models have revealed important insights into how the receptor signals and what regulates its cell surface expression. Structural studies have identified calcium as a critical cofactor for agonist binding and receptor function, while several transmembrane proteins have been shown to modulate MC4R activity. Here, we describe recent developments in our understanding of how accessory proteins and cofactors, identified using genomic approaches and screens for protein interaction, modify MC4R trafficking and signalling. We discuss how signalling by G Show less

Bioinformatics is considered a powerful tool to investigate and deeply analyze large datasets. A significant quantity of data is generated by prostate cancer and dysregulation of microRNA (miRNA) in tissues and bodily fluids (serum, plasma, urine). Screening dysregulated miRNA is currently more accessible, more reliable, and more precise with the help of insilico approaches. Hence the objective of the study is to identify miRNAs and explore their mRNA interaction in prostate cancer development. Here in the present study, we analyzed the GEO dataset GSE112264 and performed GEO-2R analysis to segregate significantly upregulated and downregulated miRNAs. The targetome of each miRNA containing several target genes was analyzed and put in an interactive network form. Functional enrichment analysis using DAVID 6.8 and GSEA was carried out to get KEGG, Reactome, and GO-BP analysis. Our analysis revealed that out of 190 overlapped significant miRNAs, only 9 miRNAs (hsa-miRNA-185-5p, hsa-miRNA-211-5p, hsa-miRNA-330-3p, hsa-miRNA-342-3p, hsa-miRNA-3622b-5p, hsa-miRNA-486-5p, hsa-miRNA-520a-3p, hsa-miRNA-550a-3p, hsa-miRNA-574-3p) were found to target 20 unique target genes (AKT1, EP300, E2F1, KRAS, AR, CREB5, CCND1, CDKNA1, EGFR, ERBB2, FGFR1, FOXO1, IKBKG, IGF1R, MAPK1, PTEN, PIK3R1, and TP53) that were involved in Prostate cancer survival and proliferation. Out of 9 miRNAs, two miRNAs (miRNA-520a-3p and miRNA-550a-3p) are novel miRNAs that have yet to be explored in Prostate cancer pathogenesis. To conclude and for future research, 8 miRNAs are yet to be explored for non-invasive potential as diagnostic and prognostic biomarkers in Prostate cancer progression and development. The target genes of each miRNA could provide novel insights in developing therapeutics for better management of disease. Show less

Dyslipidemia is an established risk factor for atherosclerotic cardiovascular disease (ASCVD). Recaticimab is a novel humanized monoclonal antibody that specifically targets proprotein convertase subtilisin/kexin type 9 (PCSK9). It has shown promising results in reducing low-density lipoprotein cholesterol (LDL-C) levels. Here, we aim to further investigate the safety and efficacy of recaticimab in patients with dyslipidemia. We comprehensively searched PubMed, Scopus, Web of Science, and Cochrane Library databases to identify all randomized controlled trials (RCTs) comparing recaticimab with placebo. Eligible RCTs were selected, and their data were extracted and analyzed using the RevMan software. Four studies involving 1657 patients were included in this meta-analysis. In terms of efficacy outcomes, compared with the placebo group, recaticimab significantly decreased levels of LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), triglyceride (TG), and lipoprotein(a) [Lp(a)], with the following values, respectively: (mean difference (MD): -52.62, 95% confidence interval (CI) [-57.25, -47.99], p < 0.00001); (MD: -47.03, 95% CI [-48.96, -45.11], p < 0.00001); (MD: -44.33, 95% CI [-46.08, -42.58], p < 0.00001); (MD: -8.83, 95% CI [-13.03, -4.63], p < 0.0001); and (MD: -29.21, 95% CI [-32.10, -26.31], p < 0.00001). In terms of safety outcomes, there was no significant difference between recaticimab and placebo groups in the incidence of any adverse events (odds ratio (OR): 1.16, 95% CI [0.90, 1.51], p = 0.26), serious adverse events, upper respiratory tract infections, or elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), or gamma-glutamyl transferase (GGT). However, recaticimab was associated with higher odds of injection site reactions compared with placebo (OR: 2.65, 95% CI [1.24, 5.67], p = 0.01). Recaticimab significantly reduced LDL-C levels and was associated with a manageable safety profile, even with dosing intervals of up to 12 weeks. Further studies should be conducted globally in larger and more diverse patient populations. Show less

Lipoprotein(a) (Lp(a)) is increasingly recognised as an independent and causal risk factor for atherosclerotic cardiovascular disease. Although the underlying mechanisms remain incompletely defined, evidence supports a multifactorial role for Lp(a) in atherogenesis. Lp(a) contributes to endothelial dysfunction, promotes vascular inflammation and enhances lipid retention and oxidation within the arterial wall. These changes drive foam cell formation and smooth muscle cell activation, hallmarks of early plaque development. In addition, Lp(a) exerts prothrombotic effects through structural homology with plasminogen, interfering with fibrinolysis and promoting thrombosis, which may increase the risk of plaque rupture and acute events. Collectively, these overlapping mechanisms underscore the unique contribution of Lp(a) to both the development and progression of atherosclerosis. As novel targeting therapies emerge, a deeper understanding of Lp(a) biology will be essential for translating these insights into clinical benefit. Show less

Neurodegenerative and mental disorders impose significant global disease burdens and pose serious social and economic challenges. Physical exercise (PE) exerts beneficial effects on brain health, contributing to a reduction in the risk of Alzheimer's disease (AD), Parkinson's disease (PD), depression, anxiety, and post-traumatic stress disorder (PTSD). To understand these effects of PE, a variety of molecules released from various tissues in response to PE have been discovered, which are collectively called 'exerkines'. In particular, the skeletal muscle acts as an endocrine organ, secreting exerkines and is included in the category of myokines that facilitate direct or indirect crosstalk between the muscle and the brain. Although muscles actively interact with organs such as the liver, pancreas, and adipose tissue, the precise mechanisms of muscle-brain communication have yet to be fully elucidated. In the skeletal muscle, the types of exerkines secreted and their effects vary depending on the PE modality. Furthermore, these exerkines can cross the blood-brain barrier (BBB) to exert direct effects or act indirectly Show less

Obesity is a major global health crisis, yet the molecular mechanisms underlying adult-onset metabolic dysfunction remain incompletely understood. The tubby mouse is a foundational genetic model of maturity-onset obesity; however, the specific tissues and cell populations responsible for its metabolic phenotype have long remained elusive. Here, we demonstrate that the loss of tubby disrupts the coordinated regulation of energy intake and expenditure, leading to a sustained positive energy balance. Using cell-type-specific genetic tools, we identified MC4R-expressing and VGLUT2-expressing neurons as essential sites of tubby function. We found that tubby acts through the combined contribution of these neuronal populations, as selective deletion in either MC4R or VGLUT2 neurons is sufficient to phenocopy key features of the global Tub mutant. Together, these findings establish tubby as a central neuronal regulator of systemic energy homeostasis and define an excitatory MC4R-VGLUT2 circuit that governs feeding behavior and metabolic output. Show less

Nurses' voice behavior is critical for patient safety and organizational improvement. However, its manifestation is not uniform among nurses. This study aimed to identify latent profiles of nurses' voice behavior using Latent Profile Analysis (LPA) to understand this heterogeneity and explore its influencing factors, with a specific focus on differences across work motivation dimensions (rooted in Self-Determination Theory, SDT). A multicenter cross-sectional design was adopted. Data from 701 clinical nurses across six hospitals in Guangxi Province were analyzed: LPA identified four distinct profiles, and Multinomial Logistic Regression was used to examine predictors. Work motivation was measured by the Multidimensional Work Motivation Scale (MWMS), and voice behavior by the Voice Behavior Scale (VBS). LPA identified four distinct profiles (Conservative, 5.42%; Balanced Risk-Taker, 26.39%; Transitional, 34.38%; Challenging, 33.8%), and Multinomial Logistic Regression was used to examine predictors. Work motivation was measured by the Multidimensional Work Motivation Scale (MWMS), and voice behavior by the Voice Behavior Scale (VBS). Results showed autonomous motivation (e.g., intrinsic drive) strongly predicted active voice behavior, while amotivation predicted conservative profiles. Nurses exhibited high work motivation (MWMS: 93.02 ± 21.09) and moderately high voice behavior (VBS: 39.27 ± 8.736). The research found that nurses exhibited high work motivation and moderately high voice behavior, with autonomous motivation being a pivotal predictor. Differentiated strategies targeting intrinsic motivation enhancement are critical for fostering nursing innovation and improving care quality. Show less

Substance use disorder (SUD) is a complex neurobiological disorder characterized by the consolidation of maladaptive neuroplasticity affecting dopaminergic, glutamatergic, and neurotrophic systems, as well as cortical and subcortical networks critical for executive control, emotional regulation, and associative learning. This systematic review was conducted in accordance with PRISMA 2020 guidelines and integrated 57 studies published between 2020 and 2025 to analyze neuroplastic mechanisms involved in vulnerability to substance use disorder and brain recovery following chronic substance exposure. The findings revealed consistent alterations in synaptic density, BDNF/TrkB signaling, glutamatergic homeostasis, and epigenetic regulation, along with structural and functional neuroimaging changes in regions such as the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala. Four core therapeutic domains for neuroplastic restoration were identified: neuromodulation approaches (including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation), compounds that promote neuroplasticity via neurotrophic signaling, epigenetic and anti-inflammatory interventions, and psychological therapies based on memory reconsolidation processes. These strategies demonstrated the capacity to normalize prefrontal activity, modulate reward networks, strengthen emotional regulation, and reduce craving. Despite significant advances, important gaps remain, including methodological heterogeneity, scarcity of longitudinal studies, and limited clinical generalizability. Overall, the evidence suggests that recovery from substance use disorder requires multimodal interventions simultaneously targeting molecular, synaptic, and circuit-level plasticity, with growing emphasis on personalized approaches guided by neurobiological biomarkers. Show less

Lung cancer remains a leading cause of cancer-related mortality worldwide. Depression, highly prevalent in lung cancer patients, not only impairs quality of life but also adversely affects disease progression and treatment outcomes through complex biological pathways. Previously considered merely a psychological reaction, depression is now recognized as sharing bidirectional pathophysiological interactions with lung cancer. This narrative review comprehensively reviews current evidence on the molecular mechanisms linking depression to lung cancer progression, with a focus on dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), cytokine-mediated inflammation, and the lung-brain axis involving BDNF/TrkB signaling. We also discuss the potential therapeutic implications of antidepressants, including their effects on apoptosis, autophagy, and immune modulation. Key findings suggest that depression promotes tumor progression via chronic stress pathways, while antidepressants may counter these effects through multiple mechanisms. Understanding these pathways may inform integrated treatment strategies and improve prognosis in lung cancer with comorbid depression. Show less

Neurotrophins are a class of proteins that maintain the health and phenotype of neuronal cells under normal physiological conditions. Nerve growth factor was the first neurotrophin to be discovered, supporting the survival and cholinergic phenotype of basal forebrain cholinergic neurons, which are crucial in maintaining cognitive function in healthy individuals. Nerve growth factor metabolism is altered in Alzheimer's disease and, along with the degeneration of basal forebrain cholinergic neurons and loss of cholinergic pathways in the affected brain, contributes to cognitive problems. These findings initiated the application of nerve growth factor supplementation as a regenerative strategy against Alzheimer's disease in the late 20 th century. Later decades witnessed the development of drugs that support cholinergic activity, namely, cholinesterase inhibitors offering small but persisting cognitive benefits in Alzheimer's disease patients. Further developments in the Alzheimer's disease field have witnessed the rise of anti-amyloid immunotherapies that target the amyloid plaques in Alzheimer's disease brains in an attempt to reduce disease pathology. Over the years, several reports have appeared in support of or undermining the therapeutic claims of each strategy, while many other therapeutic approaches are being presently tested. In this narrative review, we present broader perspectives regarding cholinergic therapeutic strategies against Alzheimer's disease, highlighting aspects in the Alzheimer's disease field that need to be addressed, and propose future perspectives. We provide a special focus on neurotrophic molecules, especially on nerve growth factor, due to its close association with cognitive pathways and its relationship with cholinergic pathways, since cholinesterase inhibitors remain a widely used medication for Alzheimer's disease patients even after 30 years of research. Show less

Mutations in INTS11, the catalytic subunit of the Integrator complex essential for RNA processing and transcriptional termination, have been linked to neurodevelopmental disorders (NDDs), yet the underlying mechanisms remain poorly understood. To address this gap, we developed and characterized a novel ints11 loss-of-function zebrafish model using CRISPR/Cas9 and morpholino-based approaches, which recapitulates key phenotypic traits observed in human patients, including motor and behavioral deficits. ints11 deficiency led to marked impairments in locomotor activity and visual motor response, consistent with the neurological manifestations reported in INTS11-mutated patients. These behavioral abnormalities were paralleled by significant dysregulation of neurodevelopmental gene expression, including decreased expression of islet1, map2, gfap, and mag, and upregulation of the progenitor marker nestin, indicating defective neuronal differentiation and glial maturation. Interestingly, the observed phenotypes are rescued not only by mRNA-mediated re-expression of ints11, but also through pharmacological administration with brain-derived neurotrophic factor (BDNF) and the GM1 ganglioside-derived oligosaccharide (OligoGM1). These findings highlight neurotrophic signaling as a potential compensatory axis counteracting RNA-processing defects. In conclusion, our work establishes the first in vivo zebrafish model of INTS11-associated neurodevelopmental dysfunction, uncovering conserved molecular mechanisms that link Integrator complex activity, neurotrophic support, and neuronal maturation and providing a valuable platform for dissecting disease mechanisms and evaluating therapeutic strategies targeting RNA processing pathways and neurotrophic support in NDDs. Show less

Neurodegenerative diseases present a significant challenge in modern medicine, largely due to the interplay of oxidative stress, apoptosis, and neuroinflammation. The development of advanced materials capable of simultaneously regulating multiple pathological processes is a critical unmet need. Here, we introduce ionizable pH-responsive lyotropic liquid crystalline nanocarriers as a promising self-assembled materials-based solution for neuroregeneration. We engineered non-lamellar polyunsaturated (DLin-MC3-DMA)-based lipid nanoassemblies with a unique combination of antioxidant, anti-apoptotic, and neurotrophic functionalities. By incorporating a multi-targeted phytochemical blend (quercetin, ginkgolides B and C, and kaempferol), the lipid-based nanomedicines effectively suppress inflammatory mediators (IL-1β, NF-κB, and JNK1/2) and stimulate endogenous antioxidant defenses via NRF2/ARE activation. The mechanistic involvement of the mTOR/AKT/BDNF/GSK3β pathway was examined to assess the in vitro therapeutic potential of the antioxidant‑loaded lipid nanoparticles (LNPs). The designed assemblies activate pro‑survival (p‑AKT/mTOR) and neurotrophic (BDNF) signaling pathways while preserving mitochondrial integrity in a cellular neurodegeneration model. The ionizable nature of DLin‑MC3‑DMA imparts pH‑responsiveness to the LNPs, driving a progressive enrichment of the inverted hexagonal (H Show less

The utility of coronary artery calcium (CAC) scoring in individuals with elevated lipoprotein(a) [Lp(a)] for atherosclerotic cardiovascular disease (ASCVD) risk assessment is currently unclear given the propensity of Lp(a) toward noncalcified plaque. The authors aimed to evaluate the interaction between elevated Lp(a) (>50 mg/dL) and CAC score, and the association of Lp(a) with ASCVD risk across strata of CAC. A pooled cohort of participants without known ASCVD from 4 U.S.-based prospective cohort studies with baseline Lp(a) and CAC measurements was used. The association between elevated Lp(a) across CAC strata and incident ASCVD (myocardial infarction, stroke, coronary revascularization) was evaluated in multivariable Cox regression models. The study included 11,319 participants (mean age 56 years, 54% women) with 1,569 incident ASCVD events over 14.8 year mean follow-up. Lp(a) >50 mg/dL (HR: 1.24; 95% CI: 1.09-1.41) and CAC >0 (HR: 2.44; 95% CI: 2.14-2.77) were independently associated with ASCVD risk (P interaction = 0.80). Among individuals with CAC = 0, ASCVD incidence rates were low overall, but higher with Lp(a) >50 mg/dL vs ≤50 mg/dL (4.9 vs 3.8/1,000 person-years, HR: 1.28; 95% CI: 1.01-1.60). Among those with CAC >0, increased risk was again noted with elevated Lp(a) (21.2 vs 18.2/1,000 person-years, HR: 3.03; 95% CI: 2.52-3.64). Similar results were observed when examining further CAC strata with the greatest risk noted with both CAC ≥300 and Lp(a) >50 mg/dL (HR: 6.12; 95% CI: 4.80-7.81). Consistent results were noted by age and sex with greater absolute risk in general among individuals >50 years of age and men. Elevated Lp(a) is associated with higher relative risk across CAC strata, including CAC of 0. Among individuals with CAC of 0, absolute event rates remain low even when Lp(a) is elevated. CAC scoring remains a powerful tool for risk assessment among individuals with elevated Lp(a). Show less

Based on self-determination theory (SDT), this study aimed to identify latent profiles of health motivation characteristics among young and middle-aged individuals with prediabetes and to examine their associations with self-management behaviours and metabolic risk indicators. This cross-sectional study recruited individuals with prediabetes from January 2024 to January 2025 using a convenience sampling method, enrolling 309 participants. Health behaviour motivation, basic psychological needs, prediabetes-related disease knowledge and self-management were assessed using validated questionnaires. Latent profile analysis (LPA) was conducted to identify distinct subgroups. Multinomial logistic regression was used to examine demographic, lifestyle and clinical factors associated with profile membership. Three types of health motivation characteristics were identified: high psychological need satisfaction-autonomous motivation profile (24.0%), moderate psychological need satisfaction-externally controlled motivation dominant profile (15.0%) and low psychological need satisfaction-low motivation profile (61.0%). After adjustment, BMI, comorbidity history and occupation were significantly associated with profile membership, whereas distance to primary healthcare facilities showed a non-robust pattern. Significant heterogeneity exists in health motivation characteristics among young and middle-aged individuals with prediabetes, with the low psychological need satisfaction-low motivation profile representing the largest proportion. Incorporating motivation-oriented stratification into diabetes prevention strategies may provide a useful framework for delivering tailored interventions and supporting more sustainable self-management. Show less