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Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder defined by progressive cognitive impairment, neuroinflammation, oxidative stress, amyloid-β (Aβ) accumulation, synaptic dysfunction, mitochondrial impairment, and tau hyperphosphorylation. The gut-brain axis (GBA) is a crucial regulatory signaling cascade that links intestinal microbiome composition with both neural health and disease through the vagus nerve. Gut dysbiosis has increasingly been implicated in AD pathogenesis by exacerbating systemic and neuroinflammatory signaling, disrupting intestinal and blood-brain barrier (BBB) structural stability, and promoting microglial activation, thereby facilitating Aβ aggregation and neurodegeneration. Preclinical studies indicate that symbiotic interventions restore microbial balance and improve gut-brain communication, contributing to neuroprotective effects. Additionally, it has been demonstrated that symbiotics can restore synaptic plasticity and cognitive resilience by suppressing pro-inflammatory cytokines, as exemplified by interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α), and by upregulating neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF). These effects are associated with normalised glial reactivity, attenuation of oxidative stress, and improved mitochondrial bioenergetics, together contributing to enhanced synaptic function, reduced neuroinflammation, and preservation of cognitive performance. This review highlights a critical assessment of the treatment potential of symbiotic interventions in modulating the GBA in AD, emphasising mechanistic insights into neurodegenerative pathways and evaluating their capacity to mitigate symptoms and delay disease progression, as supported by current preclinical evidence. Show less

The dental pulp is an immunologically active tissue that responds dynamically to cariogenic challenge. Peripheral pulp cells adjacent to dentine encounter bacterial stimuli earlier than cells located in the central pulp. To investigate signalling and immune interactions, this study profiled the transcriptomes of dentine-adherent cells (DACs) and central dental pulp cells (DPCs) cocultured with Streptococcus mutans. Primary cultures of both DACs and DPCs were obtained from healthy third molars of three female and three male donors aged 13-16. Cells were cocultured with viable S. mutans (2 × 10 RNA-Seq revealed a dynamic shift in the transcriptome of DACs and DPCs stimulated with S. mutans, while cells exposed to γ-inactivated or no bacteria did not. Although DACs and DPCs shared common DEGs (33 up, 8 down), several regulations were exclusive to DACs (22 up, 9 down) and DPCs (9 up, 25 down), highlighting a donor-independent functional specificity of the pulp subpopulations. Functional enrichment analysis revealed a strong and comparable activation of hypoxia-related pathways in both DPCs and DACs. However, DACs additionally showed enrichment in extracellular matrix organisation and cytokine signalling, while DPCs were characterised by intracellular stress responses and protein folding pathways. Additionally, protein-protein interaction analysis identified IL-6 as a key hub in DACs, while ANGPTL4 was central in DPCs. Following exposure to S. mutans, mechanically isolated DACs and DPCs displayed distinct transcriptomic profiles, indicating functional heterogeneity in the pulpal immune response. DACs engaged immunomodulatory pathways, while DPCs were marked by cellular stress responses, suggesting divergent contributions to tissue defence and homeostasis. Show less

Conventional biomarkers such as low-density lipoprotein (LDL) and high-density lipoprotein may fail to identify patients' risk for significant coronary artery disease (CAD). This study evaluates the associations between multiple biomarkers and different CAD phenotypes, exploring a machine-learning biomarker-based patient clustering. We included 787 patients on primary prevention from the prospective ACTION registry (January 2024 to June 2025). All patients underwent coronary CTA and simultaneous biomarker testing, including LDL, high-density lipoprotein, triglyceride, apolipoprotein A-1, apolipoprotein B, lipoprotein(a) [Lp(a)], glycated hemoglobin (HbA1c), and high-sensitivity C-reactive protein. Of 382 patients (48.5%) with coronary artery calcium = 0, 42 (11%) had coronary plaque. These patients showed higher Lp(a) vs those without plaque (16.5 vs 11.5, P = .030), despite comparable SCORE2 risk (3.5% vs 3.0%, P = .284). Three biomarker-defined groups were identified after a machine learning unsupervised clustering: Cluster 1 had a favorable lipid profile with the lowest prevalence of CAD-Reporting and Data System (RADS) ≥ 3 (9.9%). Cluster 2 and 3, despite their significant intercluster differences in terms of Lp(a), LDL, and HbA1c levels, both showed a significantly higher prevalence of CAD-RADS ≥ 3 compared to cluster 1 (respectively 21.8% and 17.9%; vs cluster 1, P = .001). High-risk biomarker signatures were significantly associated to the prevalence of CAD-RADS ≥ 3, independently from the baseline SCORE2 (adjusted odds ratio 2.25; 95% confidence interval 1.32-3.82). Distinct biomarker signatures associate with distinct CAD prevalence and severity that conventional lipid markers fail to distinguish. Lp(a) appears relevant for early plaque detection in coronary artery calcium = 0 patients. A comprehensive biomarker evaluation may help identifying high-risk subgroups overlooked by a conventional assessment. Show less

Chaihu Shugan San (CSS), a classical Traditional Chinese Medicine (TCM) formula, was first recorded in Jingyue Quanshu (1624 AD) for treating "liver qi stagnation" (Yu Syndrome), a TCM diagnostic pattern analogous to modern mood disorders. Although CSS has been prescribed for emotional distress, irritability, and depressive symptoms for centuries, the neurobiological mechanisms underlying its antidepressant efficacy, particularly in the context of gender-specific pathology, remain poorly revealed. The present study probed the antidepressant effects of CSS in female mice, while elucidating the underlying molecular mechanisms involving hippocampal neuroinflammation and neuroplasticity. We hypothesized that CSS reverses chronic stress-induced depressive phenotypes by suppressing interleukin-6 (IL-6), which in turn facilitates cAMP-CaMKII-BDNF signaling pathway in the hippocampus. Adult female C57BL/6J mice were subjected to a 5-week chronic unpredictable mild stress (CUMS) regimen to evoke depressive-like behaviors. During the final 2 weeks of the regimen, CSS was administered intragastrically at 0.5, 1.0, or 1.5 g/kg, with fluoxetine (10 mg/kg) as the positive control. Behavioral assessments included forced swimming test (FST), sucrose preference test (SPT), open field test (OFT), and tail suspension test (TST). Hippocampal IL-6, cAMP, CaMKII, and BDNF levels were quantified by ELISA. Mechanistic validation employed acute hippocampal microinjection of recombinant IL-6 (1 μg/site) and systemic administration of the CaMKII inhibitor KN-93 (6 mg/kg). Chemical constituents were identified by UHPLC-QTOF MS. CSS alleviated CUMS-induced depressive-like behaviors in a dose-dependent manner, cutting down immobility time in TST/FST and reinstating sucrose preference, similar to the action of fluoxetine. CSS significantly suppressed hippocampal IL-6 while upregulating cAMP, CaMKII activity, and BDNF expression. Acute IL-6 elevation completely abolished both the behavioral antidepressant effects and molecular actions of CSS. Pharmacological inhibition of CaMKII blocked CSS-induced behavioral improvement and its upregulation of cAMP-BDNF signaling, without affecting basal behaviors. CSS exhibited no anxiogenic or locomotor side effects. CSS exerts potent antidepressant effects in female mice through coordinated suppression of hippocampal IL-6 and activation of the cAMP-CaMKII-BDNF neuroplasticity-related pathway, with CaMKII playing a critical role in this process. These findings offer scientific evidence for the traditional use of CSS in addressing emotional disorders and highlight its therapeutic potential as a multi-targeted, anti-inflammatory botanical medicine for female-specific depression. Show less

Acute respiratory distress syndrome (ARDS) induced by sepsis is a clinical syndrome characterized by high morbidity and mortality rates. This study aims to clarify the effects of recombinant mouse IL-27 protein on macrophage ferritinophagy, macrophage polarization, and its interventional role in sepsis-induced ARDS. This study utilized wild-type (WT) and IL-27 receptor knockout (IL-27R This study investigates the role of IL-27 in exacerbating ferritinophagy and ferroptosis in macrophages and septic lung injury, and explores the therapeutic potential of the NCOA4 degrader CV3. We found that IL-27 synergizes with LPS to enhance NCOA4-mediated ferritinophagy, leading to increased degradation of FTH1, upregulation of LC3A/B, and promotion of ferroptosis. Ferritinophagy amplification drove M1 macrophage polarization and inflammatory cytokine release. CV3, a PROTAC-based NCOA4 degrader, effectively disrupted the NCOA4-FTH1 interaction, inhibited ferritinophagy, and mitigated ferroptosis and inflammation. In murine models of sepsis-induced ARDS, CV3 alleviated lung injury, restored antioxidant defenses, and reduced ferroptosis. Notably, IL-27R These findings reveal a potential mechanistic link between NCOA4-mediated ferritinophagy and sepsis-associated ARDS pathogenesis. Targeting this pathway with CV3 may offer a novel therapeutic strategy, which warrants further investigation. Show less

BackgroundAlzheimer's disease (AD) has been reported to be associated with changes in inflammatory levels, although further research is needed. This study focused on identifying specific inflammatory biomarkers in peripheral blood that could differentiate patients with AD from healthy control subjects.ObjectiveThe primary objective was to determine whether a selection of peripheral blood inflammatory biomarkers could serve as a diagnostic tool for AD.MethodsA multicenter study was conducted, comparing 39 patients with AD to 27 healthy controls. AD diagnosis was confirmed through a comprehensive evaluation, including the Mini-Mental State Examination and analysis of cerebrospinal fluid or positron emission tomography. Thirteen inflammatory markers were measured, and logistic regression analysis was used to assess their discriminatory potential. The relationship between the Show less

Alzheimer's disease features early a pathology in the locus coeruleus (LC), yet how sex and life experience shape LC vulnerability remains poorly understood. We expressed pseudophosphorylated human tau (htauE14) in LC neurons of TH-Cre rats and exposed both sexes to early- or late-life enrichment or stress. Behavioral, histological, protein, and hippocampal single-nucleus RNA sequencing (snRNA-seq) analyses were performed. LC-targeted htauE14 impaired learning and increased anxiety-like behavior. Early enrichment reduced htauE14 spread and LC microglia activation, elevated hippocampal brain-derived neurotrophic factor (BDNF), and improved olfactory learning in males. Late enrichment alleviated anxiety and enhanced spatial memory, whereas late stress exacerbated LC degeneration. Hippocampal snRNA-seq revealed sex- and cell type-specific transcriptional responses, with htauE14 preferentially engaging metabolic and synaptic pathways in females, effects amplified by early stress but stabilized by early enrichment. Late-life experiences primarily recruited homeostatic regulatory programs. Sex and developmental history critically shape early LC tau-related vulnerability. Show less

Sudden arrhythmic death syndrome (SADS) refers to sudden cardiac death with structurally normal hearts at autopsy, most frequently attributed to inherited arrhythmia syndromes or concealed cardiomyopathies. Postmortem genetic testing may help identify underlying genetic causes. We aimed to investigate the yield of postmortem genetic testing in SADS cases by determining the prevalence of pathogenic or likely pathogenic variants in channelopathy- and cardiomyopathy-associated genes in autopsy-negative SADS victims. This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in PROSPERO (REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420251067244). PubMed and Embase were searched on June 4, 2025, for observational studies including individuals aged 1 to 50 years with SADS and negative or nonspecific findings at autopsy. Eligible studies reported postmortem genetic testing for channelopathy and cardiomyopathy genes. Pathogenic or likely pathogenic variant classification followed American College of Medical Genetics and Genomics criteria and ClinGen gene-disease associations. Pooled prevalence was estimated using random-effects models. A total of 45 studies involving 2498 SADS cases were included. Among 1697 SADS victims tested for both channelopathy and cardiomyopathy genes (33 studies), the pooled prevalence of pathogenic or likely pathogenic variants was 11.1% (95% CI, 4.1%-26.6%, Postmortem genetic testing identifies pathogenic or likely pathogenic variants in a significant subset of SADS cases, supporting its utility in postmortem evaluation. Show less

Nitrogen metabolism plays a key role in maintaining normal physiological functions of the organism and cell proliferation and differentiation. Nitrogen metabolism in normal human body maintains a dynamic balance to meet the body's demand for synthesis of biological macromolecules such as proteins and nucleic acids. However, in the process of tumor development, the nitrogen metabolism of tumor cells is reprogrammed to meet the demand of rapid proliferation, showing significantly different metabolic characteristics from normal cells. Key enzymes in the tumor microenvironment affect nitrogen metabolism through multiple mechanisms, providing essential nitrogen sources and energy for tumor cells. In-depth exploration of the regulatory mechanisms of tumor nitrogen metabolism not only helps to reveal the molecular basis of tumor development, but also provides a theoretical basis for the development of new tumor therapeutic strategies. In this paper, the relationship between nitrogen metabolism and tumors is systematically elaborated from the characteristics of nitrogen metabolism in normal people, the reprogramming of nitrogen metabolism in tumor patients, the influence of key enzymes on nitrogen metabolism in the tumor microenvironment, as well as the mechanism of tumor nitrogen metabolism regulation, etc., so as to provide references for the related research. Show less

Decline in mitochondrial quality is a prominent pathological feature of Alzheimer's disease (AD), manifested by impaired energy metabolism, disrupted mitochondrial biogenesis, abnormal mitochondrial dynamics, and defective mitophagy. Increasing evidence indicates that mitochondrial dysfunction contributes to the exacerbation of amyloid-β (Aβ) deposition and tau protein hyperphosphorylation, thereby accelerating AD pathogenesis. Of particular interest, physical exercise has been shown to effectively enhance mitochondrial quality and help prevent or slow the progression of AD, largely through the activation of key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). However, regular physical activity may not be feasible for individuals in the prodromal or clinical stages of AD. In this context, exercise mimetics-compounds that pharmacologically simulate the molecular effects of exercise-have emerged as a promising alternative intervention. This review analyzes the mechanistic roles of exercise mimetics in improving mitochondrial quality under AD conditions, with a focus on their regulation of mitochondrial homeostasis via key signaling pathways. It further aims to provide theoretical insight for the development of mitochondria-targeted exercise mimetics and offer a potential strategy for addressing the growing global burden of AD. Show less

Neuroplasticity refers to the ability of the brain to modify synaptic connections and reorganize neural circuits, underpinning cognitive function, emotional regulation, and recovery from injury. Recent advances have redefined adult neuroplasticity as more dynamic and therapeutically accessible than previously thought, spurring investigation into pharmacological interventions that can augment these adaptive processes. This review dissects current evidence for drug strategies targeting synaptic modulators (NMDA, AMPA, and GABA receptors), neuropeptide systems (including BDNF, oxytocin, vasopressin), and psychedelic compounds (psilocybin, LSD, ketamine), integrating insights from cellular, preclinical, and clinical studies. We detail how these agents modulate molecular pathways governing synaptic transmission, dendritic remodeling, and gene expression linked to neuronal growth and resilience. Highlighted findings include the rapid-acting antidepressant effects of NMDA antagonists, the structural and functional reorganization induced by classic psychedelics via 5-HT2A receptor activation, and the neurorestorative roles of neuropeptides in synaptic and network adaptation. Alongside these advances, we critically address safety, ethical considerations, and the risk of maladaptive plasticity, underscoring the importance of dosing, patient selection, and controlled therapeutic environments. Non-hallucinogenic neuroplastogens and combinatorial approaches that are still emerging offer new avenues to fine-tune plasticity with an improved safety profile. The collective evidence positions neuroplasticity-targeting pharmacology as a promising and complex frontier for the treatment of neuropsychiatric and neurodegenerative disorders in adulthood. Show less

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

Chronic toxoplasmosis has been increasingly associated with behavior disorders, including depression-like behaviors, while the underlying mechanisms remain poorly understood. In this study, we demonstrated that chronic toxoplasmosis induced depression-like behaviors in mice, which were observed together with neuroinflammation, neuronal injury, and suppression of the BDNF-TrkB pathway. Treatment with the TrkB agonist 7,8-DHF alleviated these behavioral deficits by restoring BDNF-TrkB signaling, preserving neuronal function, and reducing neuroinflammation through inhibition of NF-κB and MAPK pathways. Additionally, 7,8-DHF also reduced astrocyte overactivation and protected blood-brain barrier structure integrity. These findings highlight that disruption of BDNF-TrkB signaling contributes to T. gondii-induced behavioral abnormalities and that targeting this pathway may represent a promising therapeutic strategy against neuroinflammation and neuronal damage associated with chronic infection. Show less

Diabetic foot ulcers (DFU) are a severe complication of diabetes. Although dysregulated M2 macrophage polarization is recognized as a key driver of chronic inflammation in DFU, the molecular checkpoints that can be therapeutically targeted to restore M2 bias remain poorly defined. Here, we aimed to determine whether the RNA-binding protein TAF15 acts as a post-transcriptional stabilizer of the M2-promoting CEBPB/APOE/PTX3 axis, thereby accelerating DFU healing. First, we confirmed that APOE positively regulates PTX3, which supports M2 polarization and the proliferation and migration of HDF. CEBPB transcriptionally activated APOE and promoted M2 macrophage polarization. TAF15 stabilized CEBPB mRNA and affected HDF cell proliferation and migration by promoting M2 macrophage polarization. Additionally, TAF15 overexpression partially counteracted the disruption of M2 macrophage polarization caused by APOE silencing and facilitated DFU wound healing. Collectively, our findings establish TAF15-driven stabilization of CEBPB mRNA as a target point that sequentially activates APOE/PTX3 signaling to enforce M2 polarization and accelerate DFU closure. This study provides a preclinical rationale for the development of TAF15-targeted oligonucleotides or small-molecule strategies to reprogram wound macrophages and improve DFU outcomes in patients with diabetes. Show less

Acute spinal cord injury (SCI) results in irreversible neurological deficits. We hypothesized that local transplantation of bone marrow mesenchymal stem cells (BMSCs) combined with erythropoietin (EPO) would inhibit glial scarring and accelerate functional recovery. To quantify the therapeutic efficacy and underlying mechanisms of BMSCs+EPO versus BMSCs alone in a rat model of acute SCI. Forty SD rats (T10 Allen 60 g·cm impact) were randomized to sham, SCI, SCI+BMSCs, or SCI+BMSCs+EPO ( At 4 weeks, BBB scores in the BMSCs+EPO group reached 12.7 ± 1.5, representing a 54% increase over the BMSCs-alone group (8.3 ± 0.7, BMSCs+EPO exerts synergistic neuroprotective effects, achieving superior locomotor recovery compared with BMSCs monotherapy, and represents a promising adjuvant strategy for acute SCI. Show less

'Small extracellular vesicles (sEVs) are nanosized, membrane-enclosed sacs released by diverse cell types. They play a critical role in cell-cell communication through their cargo, which includes a wide range of proteins, lipids, and nucleic acids. Physiologically, sEVs circulate in various body fluids such as blood, urine, and saliva, making them accessible for diagnostic via non-invasive isolation techniques. Recent advances in high-throughput proteomics have significantly enhanced our ability to characterize the protein content of sEVs. Importantly, multiple studies on human fluids have identified specific protein markers across different cancer types, encompassing molecules involved in inflammation, cellular adhesion, immunity, and lipoprotein regulation. Interestingly, some of these proteins are consistently detected across multiple cancer types and sample sources, suggesting the existence of a shared "oncogenic signature" that may be transferred via sEVs. Among body fluids, urine and saliva are particularly promising for easy, non-invasive diagnostics. However, these sample types remain underexplored as compared to the serum, leaving substantial opportunities for future research. Taken together, these findings position sEVs as a powerful tool with significant potential for advancing precision cancer care. SIGNIFICANCE: Living cells release nanosized membrane-enclosed vesicles called small extracellular vesicles (sEVs) into the extracellular environment. sEVs contain protein cargo molecules that critically take part in cell-cell communications. Quantitative proteomics identified potential sEV associated biomarkers for early cancer diagnosis and therapy. sEV Proteins associated with cell adhesion and inflammation, lipoproteins and immunoglobulins are potential molecules that were majorly identified. Interestingly, some of these proteins such as APOA4, SAA4, ITIH4, SERPINC1 and VWF were consistently identified across multiple cancer types and sample sources, highlighting their potential as future biomarkers. Show less

The origins of major depressive disorder (MDD) are complex, involving both environmental influences and a substantial genetic contribution. Genetic polymorphisms have been implicated in modulating susceptibility, disease course, and treatment response, yet findings are often modest, population-dependent, and sometimes inconsistent. This narrative review synthesizes current evidence on genetic variants associated with MDD, highlighting well-replicated results while distinguishing exploratory or emerging findings. Key systems reviewed include serotonergic ( Show less

This study, adopting a person-centered approach and using network analysis, explores latent subtypes of Junzi personality among college students and their links to Receptiveness to Opposing Views, offering empirical backing for the ancient Chinese idea of "Junzi harmonize yet remain distinct." Traditional variable-centered methods often fail to fully expose the underlying typological structure due to the possible heterogeneous combinations in Junzi personality dimensions. Thus, a person-centered latent profile analysis (LPA) was used to pinpoint typical personality trait patterns. With 1116 college students as participants, the study employed the Junzi Personality Questionnaire Based on Confucian Thought and the Receptiveness to Opposing Views Scale. LPA identified three personality types: The Moderate Type (50%), The Daring-Aggressive Type (15%), and The Virtuously-Accomplished Type (35%). Regression analysis showed significant correlations between gender, age, and personality type, with The Virtuously-Accomplished Type scoring notably higher in Receptiveness to Opposing Views. Network analysis further revealed distinct differences in the network structures of Receptiveness to Opposing Views among the three types: The Moderate Type centered on "derogation of opponents," "refraining from what should not be done," and "respectfulness and propriety"; The Daring-Aggressive Type focused on "conversancy with righteousness and cherishment of benign rule," "derogation of opponents," and "respectfulness and propriety"; while The Virtuously-Accomplished Type highlighted "negative emotions" and "wisdom, benevolence, and courage," with "taboo issues" at the periphery in all datasets. The findings uncover the heterogeneity of Junzi personality and its varied associations with Receptiveness to Opposing Views, providing insights for understanding harmonious interactions in diverse settings. Show less

Press needle therapy, may alleviate depressive-like behaviors. Male rats were randomly allocated into four groups ( Press-needle ameliorated depressive-like behaviors in CUMS-exposed rats, restored body weight gain and improved behavioral performance. The treatment upregulated the hippocampal BDNF/TrkB/CREB signaling pathway, increasing BDNF, TrkB, CREB, AKT, and PI3K in the hippocampus. The therapy modulated serotonergic neurotransmission by increasing hippocampal 5-HTT expression, while downregulating 5-HT1A and 5-HT2C receptors and PKA. Notably, press-needle exerted anti-neuroinflammatory effects, reducing hippocampal and serum levels of TNF-α and IL-6. Histopathological analysis confirmed its neuroprotective efficacy, demonstrating attenuated neuronal damage in hippocampal tissues. Show less

Metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), dyslipidaemia, and metabolic dysfunction-associated steatotic liver disease (MASLD) are increasingly recognised as chronic inflammatory conditions driven in part by innate immune dysregulation. Among the metabolic factors implicated in this process, branched-chain amino acids (BCAAs) have emerged as key regulators linking nutrient sensing to immune cell function. Circulating BCAA concentrations are consistently elevated in these metabolic diseases. However, experimental and clinical studies also show that BCAA supplementation can improve metabolic and immune outcomes in specific contexts, revealing a paradoxical relationship between BCAA metabolism and inflammation. This narrative review examines how dysregulated BCAA metabolism and accumulation of branched-chain keto acids (BCKAs) shape the functional programming of innate immune cells across these conditions, including monocytes/macrophages, granulocytes, dendritic cells, and natural killer cells. Evidence indicates that the immunometabolic effects of BCAAs depend not solely on circulating concentrations but on the efficiency of their intracellular catabolism. When BCAA oxidation is preserved, these amino acids support mitochondrial metabolism and immune competence. Conversely, impaired catabolism leads to the accumulation of branched chain ketoacids, which activate inflammatory pathways and contribute to metabolic dysfunction. Resolving this paradox requires the need of targeting catabolic flux restoration rather than simple BCAA restriction or supplementation, and requires stratifying patients by enzymatic capacity, BCAA/BCKA ratios, and disease stage. Pharmacological modulators, including BCKDK inhibitors and BCAT1-targeted agents, show promise in simultaneously addressing metabolic and immune dysregulation. Show less

Gastric cancer (GC) is a leading cause of cancer-related deaths and has high recurrence rate. Although fibronectin domain-containing protein 1 (FNDC1) is implicated in GC progression, its molecular mechanisms remain unclear. Multi-omics analyses (TCGA, GEO datasets) were used to assess FNDC1 expression and clinical correlation. In vitro (cell proliferation, invasion, EMT markers) and in vivo (xenograft) experiments, combined with molecular assays (Co-IP, WB, ChIP), explored FNDC1's function and mechanism. FNDC1 was significantly upregulated in GC, correlating with advanced clinicopathological features and poor prognosis. Knockdown of FNDC1 suppressed GC cell proliferation, invasion, and metastasis by inhibiting EMT and Wnt/β-catenin signaling. Mechanistically, FNDC1 competitively bound the WD5 domain (residues 224-254) of Gβ2, disrupting Gβγ-Dvl1 interaction. This prevented Dvl1 degradation, promoted Axin1 ubiquitination, and destabilized the β-catenin-destruction complex (GSK3 β-APC-Axin1), leading to β-catenin accumulation and Wnt pathway activation. FNDC1 drives GC malignancy by targeting the Gβ2-Dvl1 axis to activate Wnt/β-catenin signaling, suggesting FNDC1 as a novel prognostic biomarker and therapeutic target. Show less

The purposes of this study were to identify different psychological capital subtypes among college students through latent profile analysis (LPA) and to explore the associations of psychological capital subtypes, internet usage duration and physical exercise frequency with on both depression and anxiety. Cross-sectional study design was implemented. A cross-sectional survey was conducted using the "Questionnaire Star" platform. The questionnaires of Psychological Capital Scale, PHQ-9, and GAD-7 were administered to 1089 college students from a university in Zhengzhou, China. Latent profile analysis was applied to identify latent subtypes of psychological capital. Multivariate regression analysis was performed to investigate the associations of psychological capital subtypes with both depression and anxiety. Three psychological capital latent profiles were identified: low self-efficacy (11.7%), moderate (57.8%), and high psychological capital (30.5%) in Chinese college students. High psychological capital group showed significantly higher scores of self-efficacy, resilience, hope, and optimism than other two groups (P < 0.001). Internet usage time and physical exercise frequency exhibited positive associations with psychological capital subtypes. Compared with the low self-efficacy group, the moderate and high latent groups had significantly lower scores of both depression and anxiety. Older students had higher scores of both depression and anxiety than younger. Three latent profiles, low self-efficacy, moderate, and high psychological capital, were identified in Chinese college students. Self-efficacy is the key dimension distinguishing between the different subtypes. Adequate internet use and physical exercise frequency improved psychological capital profile. High psychological capital levels effectively reduced the scores of both depression and anxiety. Show less

Familial hypobetalipoproteinemia is a rare autosomal codominant disorder, often caused by a defect in apolipoprotein B (apoB) production required for lipoprotein formation and secretion. Characterization of the lipid profiles of 3 family members exhibiting very low circulating cholesterol levels. Plasma samples from the control sibling and the affected patients were analyzed. Fast protein liquid chromatography and high-performance liquid chromatography were used to characterize the lipid profiles, size, and distribution of lipoprotein particles. Exome sequencing of family members revealed a single-nucleotide deletion in APOB in the 3 affected individuals. The effect of the single-nucleotide deletion on the secretion of apoB was analyzed in Immortalized Human Hepatocyte (IHH) cells. Plasma lipid profiles revealed that the affected individuals have low levels of total cholesterol and low-density lipoprotein cholesterol, with no difference in lipoprotein particle size. DNA sequencing of APOB revealed a single heterozygote deletion of an adenosine in exon 3 at the nucleotide position 1268 in all affected members. This deletion introduces a reading frame shift at glutamine 380, resulting in a stop codon at position 397. The C-terminally truncated apoB, called apoB9, is a variant spanning ∼9% of the full-length protein. Upon expression of apoB9 in IHH cells, the protein did not exit the endoplasmic reticulum/cis-Golgi and, hence, was not secreted into the media. Molecular modeling revealed that apoB9 lacks the βA- and βB-sheets that are required for lipid particle formation, which can explain the absence of apoB9 secretion. Our data suggested that the affected family members have ∼50% to 60% lower apoB levels and are likely protected against the development of atherosclerosis and cardiovascular diseases. Show less

Therapeutic interventions effective in reestablishing redox homeostasis in preterm infants require further investigation because immature lungs are extremely vulnerable to high-oxygen-induced lung injury. Flavin adenine dinucleotide (FAD) facilitates glutathione reductase (GR) activity and increases the bioavailability of the antioxidant glutathione (GSH). As such, we hypothesize that intranasal delivery of FAD can attenuate hyperoxic lung injury by restoring redox homeostasis, thereby altering pro-inflammatory signal transduction pathways. The term C57Bl6/N mouse model exposed to 0.85 fraction of inspired oxygen (85% [Formula: see text]) was used to model high oxygen-induced oxidative stress and bronchopulmonary dysplasia (BPD). Our studies show that FAD protects neonatal lungs (males and females) from high oxygen-induced oxidative stress by improving GSH/oxidized glutathione (GSSG) redox potential ( Show less

This study investigated the expression of brain-derived neurotrophic factor (BDNF) signaling components (BDNF-TrkB-AKT1) and apoptosis-related factors (Bcl-2 and Bax) in yak brain regions at different altitudes. The cerebral cortex, cerebellum, hippocampus, thalamus, and medulla oblongata were collected from 3-year-old yaks living at low and high altitudes. The relative mRNA expression of BDNF, TrkB, AKT1, Bcl-2, and Bax was assessed by qRT-PCR. Protein abundance and cellular localization of BDNF, TrkB, AKT1, Bcl-2, and Bax were evaluated by Western blotting and immunohistochemistry, with immunoreactivity quantified by optical density analysis. Within each altitude group, BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and the corresponding protein levels (BDNF, TrkB, AKT1, and Bcl-2) were significantly higher in the cerebral cortex and hippocampus than in the cerebellum, thalamus, and medulla oblongata (P < 0.05). In contrast, Bax mRNA and Bax protein levels did not differ significantly among the five regions. Compared with low-altitude yaks, high-altitude yaks showed significantly higher BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and higher BDNF, TrkB, AKT1, and Bcl-2 protein levels in brain tissues (P < 0.05), whereas Bax protein expression did not differ between altitude groups. Immunohistochemistry revealed immunoreactivity for BDNF, TrkB, AKT1, Bcl-2, and Bax in both altitude groups, with prominent labeling in cortical pyramidal neurons and across the pyramidal cell layer in the hippocampal CA region. Immunoreactivity was also detected in large neurons of the thalamus and medulla oblongata. In the cerebellum, labeling was strongest in Purkinje cells, with weaker signals in the granule cell layer and molecular layer. BDNF-TrkB-AKT1 pathway components and Bcl-2 showed relatively higher expression in the cerebral cortex and hippocampus within each altitude group, whereas Bax expression did not vary across regions. These patterns are consistent with an association between BDNF-TrkB-AKT1 signaling and increased Bcl-2 expression without a corresponding increase in Bax, which may support neuronal adaptation in the cerebral cortex and hippocampus. Elevated expression of BDNF, TrkB, AKT1, and Bcl-2 at high altitude suggests enhanced adaptation to hypoxia in high-altitude yaks; the underlying mechanisms require further investigation. Show less

Inflammation has emerged as a prominent feature of bipolar disorder (BD) pathophysiology, drawing attention to brain barriers known to regulate immune-brain interactions. While perturbation of the blood-brain barrier has been reported in BD, the blood-cerebrospinal fluid (CSF) barrier formed largely by the choroid plexus (ChP) remains underexamined. To address this gap in knowledge, we used a multiplex array to measure cytokine protein abundance in postmortem ChP tissue from individuals with BD and unaffected controls, revealing elevated levels of CCL2 and SPP1, factors associated with monocyte and macrophage recruitment and activation. In contrast, expression of cytokines involved in tissue homeostasis, trophic support, and immune signaling, including OSM, IGF-1, CX3CL1, TGFB3, GDNF, LIF, BDNF, SCF, and FGFs, was reduced. Several cytokines, including CCL2 and PLGF, exhibited condition-specific divergent age trajectories. Bulk RNA sequencing of the same cohort revealed a modest set of differentially expressed genes, including transcripts associated with oxidative stress, mitochondrial function, and immune regulation that were upregulated in BD. Notably, the BD CSF biomarker NELL2 was downregulated in the ChP. Gene set enrichment analysis highlighted activation of inflammatory and cellular stress pathways, as well as reduced expression of junction-related gene programs. These findings suggest a shift in ChP function in BD characterized by increased pro-inflammatory signaling and reduced trophic and barrier-supportive activity. Together, these data identify the ChP as an active site of immune dysregulation in BD and support the broader notion of brain barrier dysfunction in mood disorder pathology. Show less

Researchers reported on the pathogenic role of hypercholesterolemia in thyroid orbitopathy (TO) and the use of statins in its prevention and treatment. To confirm these observations, we conducted a prospective study of patients with Graves' and Basedow's disease (GBD) to evaluate the relationship between the presence of TO and levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and apolipoproteins A1 and B (Apo A1, Apo B), along with the impact of immunosuppressive treatment on the lipid profile. Forty-seven patients with GBD diagnosed within the past 12 months were eligible for the study. In the GBD group, 31 patients were diagnosed with active TO and qualified for immunosuppressive treatment, while 16 patients did not have TO. TC, TG, HDL-C, and LDL-C levels were measured in serum using enzymatic methods, and Apo A-1 and Apo B levels were determined by immunoturbidimetric methods. The mean TC concentration in patients with active TO who qualified for immunosuppressive treatment was 207.7 ± 42.7 mg/dL, significantly higher than the values in GBD patients without TO symptoms (191.5 ± 47.8 mg/dL). After completing immunosuppressive treatment, the mean TC concentration increased to 214.3 ± 49.8 mg/dL, remaining significantly higher than before treatment. The mean LDL-C concentration in patients with active TO was 131.6 ± 40.4 mg/dL and was higher, though not significantly, compared to the GBD group without TO symptoms (122.6 ± 49.0 mg/dL). After immunosuppressive treatment, the mean LDL-C levels increased to 142.1 ± 54.5 mg/dL and were also significantly higher than before treatment. Additionally, the mean Apo B concentration in patients with active TO was significantly higher than in patients without TO. After immunosuppressive treatment, the mean Apo B concentration increased and remained significantly higher than before treatment. There was no significant difference in HDL-C, Apo A1, and TG concentrations between the groups with and without TO, nor their levels after immunosuppressive treatment. The use of statins as adjunctive therapy in GBD patients with active TO qualified for immunosuppressive treatment is reasonable due to the increase in TC, LDL-C, and Apo B levels during treatment, as well as for their pleiotropic effects, including their anti-inflammatory effects. Show less

Post-traumatic stress disorder (PTSD) is a chronic psychiatric condition linked with abnormal fear responses, oxidative imbalance, inflammation, and neuronal injury. The present work examined the protective effects of morin hydrate (MH), a natural flavonoid known for its antioxidant and neuroprotective properties, in a stress-re-stress (SRS) rat model of PTSD. Male Wistar rats were exposed to repeated stress cues and then treated with vehicle, paroxetine (10 mg/kg, p.o.), or MH (15 and 30 mg/kg, p.o.). Behavioral outcomes were assessed using fear conditioning, elevated plus maze, open field, Y-maze, novel object recognition, forced swim, and sucrose preference tests. Animals exposed to SRS developed pronounced fear retention, anxiety-like and depressive behaviors, and cognitive impairment. Treatment with MH, especially at 30 mg/kg, improved exploratory activity, reduced immobility, and enhanced memory performance. Biochemical studies showed reduced lipid peroxidation and restoration of glutathione, superoxide dismutase, and catalase. MH also lowered pro-inflammatory cytokines (TNF-α, IL-1β) and increased hippocampal brain-derived neurotrophic factor (BDNF). Histological analysis confirmed preservation of neuronal density in CA1 and CA2 regions of the hippocampus. In summary, MH produced behavioral, biochemical, and structural improvements in the SRS model, suggesting its value as a natural therapeutic candidate for PTSD. Show less

Resveratrol (RSV), a dietary polyphenol widely present in traditional medicinal plants and foods, exhibits antioxidant and anti-inflammatory properties that are relevant to ethnopharmacological strategies for protecting against environmental neurotoxicants. Given increasing real-world co-exposure to lead (Pb) and cadmium (Cd), elucidating RSV's capacity to preserve gut-brain axis (GBA) homeostasis has direct translational relevance for populations relying on phytochemical interventions. Sprague-Dawley rats were randomized into control, Pb-Cd model, and RSV treatment groups (10, 20, or 40 mg/kg). For 4 weeks, rats received Pb (300 mg/L) and Cd (50 mg/L) in drinking water with daily RSV. Cognitive function was assessed by Morris water maze; barrier integrity by Evans blue assay, histology, and Western blot for ZO-1/Occludin; synaptic ultrastructure by TEM; microbiota composition by 16S rRNA sequencing; and short-chain fatty acids (SCFAs) by GC-MS. Neurotransmitters (5-HT, GABA, SP, VIP) and cytokines (IL-6, IL-1β, TNF-α) were measured by ELISA. RSV improved spatial learning, reduced EB extravasation, preserved synaptic ultrastructure and proteins (BDNF, SYN, PSD-95), and restored intestinal architecture with increased ZO-1/Occludin. RSV attenuated cytokine release, normalized goblet cells, reversed dysbiosis by restoring Lactobacillaceae/Prevotellaceae, and increased acetate, propionate, and butyrate. It reinstated 5-HT and GABA while reducing SP and restoring VIP across serum, colon, and hippocampus. RSV attenuated Pb-Cd-associated neurotoxicity and was accompanied by improved intestinal and BBB-related readouts, partial normalization of gut microbiota features and SCFA levels, and preservation of synaptic and neurotransmitter-related markers, consistent with a link to gut-brain axis function. This study is among the first to test RSV in a Pb-Cd co-exposure model using a multi-dose regimen with integrated behavioral, barrier, microbial, and neurochemical endpoints. Show less