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Recent research has identified metabolic pathways which play key roles in the differentiation and function of osteoblasts and osteoclasts. However, the mechanisms by which osteocytes, the most numerous cells in bone, meet their energetic demands are still unknown. To address this, we used the IDG-SW3 osteocyte cell line to examine changes in metabolism during differentiation from late osteoblasts to mature osteocytes. There was a significant increase in the expression of glycolysis genes (including Pkm and Ldha), glucose consumption and lactate production during late differentiation of these cells. This was concurrent with the onset of the expression of mature osteocyte markers. Inhibition of glucose metabolism using the glucose analogue 2-deoxy-d-glucose (2-DG) inhibited IDG-SW3 cell mineralization and differentiation into osteocytes. To examine the effect of glucose metabolism inhibition on mature osteocytes, we treated differentiated IDG-SW3 cells and long bone osteocytes with 2-DG, which resulted in decreased expression of the bone formation inhibitor Sost and mineralization inhibitor Fgf23. Concurrently, there was an increase in genes associated with lipolysis (Lpl) fatty acid β-oxidation (Pparδ and Cpt1a). Treatment of differentiated IDG-SW3 cells with the unsaturated fatty acid oleic acid increased Cpt1a expression and downregulated Sost and Fgf23. Application of mechanical stress to IDG-SW3 cells resulted in upregulation of oxidative metabolism, Pparδ and Cpt1a expression. Long and short chain acylcarnitines were increased in the cortical bone of axially loaded tibiae compared to non-loaded controls, indicative of increased β-oxidation. Overall, our data suggests that while glucose metabolism is essential for osteocyte differentiation, mature osteocytes are metabolically flexible. Furthermore, β-oxidation may play an important role in the osteocyte response to mechanical stress. Show less

Elevated levels of lipoprotein(a) (Lp[a]) are a causal risk factor for atherosclerotic cardiovascular disease. Similarities between the apolipoprotein(a) (apo[a]) component of Lp(a) and plasminogen suggest that antifibrinolytic properties may account for the pathological effects of Lp(a). However, the antifibrinolytic effects of apo(a) do not appear to be retained by the complete Lp(a) particle. We evaluated the effects of Lp(a), apo(a), and various apo(a) variants on clot formation and lysis times, thrombin generation, plasminogen activation, and fibrin architectures in ex vivo plasma clots. We also constructed predictive protein models to gain insight into the apo(a)-plasminogen interaction. Apo(a) strongly inhibited fibrinolysis, an effect dependent on the presence of the apo(a) protease domain and mediated by Lys216 in this domain. Modeling of apo(a) suggests that Lys216 is blocked from binding to plasminogen in the Lp(a) particle by the presence of the apoB-containing lipoprotein. Lp(a) and apo(a) shortened plasma clot formation times, and accounting for this revealed a small but significant prolongation of fibrinolysis by Lp(a). The procoagulant effects involved the development of lysis-resistant clot architectures and were mediated through the strong lysine-binding site in apo(a) kringle IV type 10. In addition, Lp(a) (but not apo[a]) accelerated thrombin generation. The strong antifibrinolytic effects of apo(a) do not appear to be retained in the complete Lp(a) particle. However, Lp(a) and apo(a) displayed procoagulant effects, in part dependent on the kringle 4-like lysine-binding site. Further analysis is required to determine whether these reported procoagulant effects of Lp(a) impact thrombosis in vivo. Show less

Although the specific reasons for exercise motivation and the emotions felt during it are both important for physical activity (PA), little is known about how they combine to form distinct psychological profiles. This study used a person-centered approach to identify these latent profiles based on specific exercise motives and exercise-induced emotions among Chinese college students, and examined their associations with gender and PA. We recruited 1,586 undergraduates from a university in southern China ( Show less

Calcific aortic valve disease (CAVD) involves pathological mineralization, but the roles of chemokine signaling and ferroptosis remain unclear. This study investigated the regulatory function of C-C motif chemokine ligand 5 (CCL5) in CAVD progression via the chemokine pathway and ferroptosis. Bioinformatics analysis and single-cell RNA sequencing analysis were performed to identify hub genes and potential cell types. Human aortic valve interstitial cells (VICs) were treated with osteogenic medium (OM) to induce calcification. Apoe CCL5 was identified as a key hub gene in CAVD. Knockdown of CCL5 significantly attenuated OM-induced VICs calcification, osteogenic differentiation, oxidative stress, and ferroptosis. Similar protective effects were observed in vivo, with reduced valve thickening and calcification in Apoe CCL5 promoted CAVD progression by activating the chemokine signaling pathway to induce ferroptosis. Targeting CCL5 may offer a novel therapeutic strategy for CAVD. Show less

Intrinsic Capacity (IC) is defined as the composite of physical and mental abilities an individual possesses, encompassing five domains: cognition, psychological health, sensory function, vitality, and locomotion. This construct is central to the World Health Organization's framework for assessing functional ability in older adults. Growing evidence highlights the critical role of the musculoskeletal system in maintaining these domains, while conditions such as sarcopenia, osteoporosis, and their coexistence as osteosarcopenia (OS) are increasingly associated with IC decline. This narrative review compiles current evidence on the modulatory role of muscles and bones in IC and the impacts of sarcopenia, osteoporosis, and OS. Most findings suggest that musculoskeletal tissues influence IC not only through biomechanical functions but also as secretory organs, releasing myokines and osteokines with endocrine, paracrine, and autocrine effects. Among the most studied are brain-derived neurotrophic factor, irisin, osteocalcin, and interleukin-6. Dysregulation of these pathways, along with biomechanical dysfunction and systemic inflammation, links sarcopenia, osteoporosis, and OS to IC impairment. Further research is needed to clarify the specific mechanisms involved, particularly in the sensory and vitality domains, to inform targeted interventions that promote healthy aging. Show less

Although recommended for cardiovascular (CV) risk stratification in adults, the role of lipoprotein(a) [Lp(a)] in hypertension is not fully established. To evaluate Lp(a) levels in adult outpatients with essential arterial hypertension. A retrospective, observational study was conducted in outpatients of both sexes, aged ≥ 18 years, with treated or untreated essential hypertension, who were consecutively evaluated at the Hypertension Unit, Excellence Hypertension Center, Sant'Andrea Hospital, Rome, Italy. Participants underwent office and out-of-office blood pressure (BP) measurements, as well as assessment of hypertension-mediated organ damage (HMOD). BP measurements were performed, and hypertension phenotypes were classified according to 2023 European hypertension guidelines. Lp(a) levels were measured, and the study population was stratified according to a Lp(a) cut-off value of ≥50 mg/dl. Due to the non-uniform distribution, absolute Lp(a) values were logarithmically transformed. A total of 230 patients with available Lp(a) values were included (42.6% women, mean age 66.3 ± 11.5 years, BMI 27.1 ± 4.5 kg/m2, office BP 137.1 ± 18.1/83.7 ± 11.0 mmHg, 24-hour BP 129.8 ± 14.5/79.6 ± 9.8 mmHg, Lp(a) 51.4 ± 65.3 mg/dL), among whom 32.2% had Lp(a) ≥50 mg/dl. There were significantly higher proportions of men (74.3% vs. 49.4%; P < 0.001), dyslipidaemia (97.3% vs. 75.0%; P < 0.001) and comorbidities (55.4% vs. 30.8%; P < 0.001) in patients with high Lp(a) than in those with normal Lp(a), who also received more frequently lipid lowering therapies (P < 0.001) and aspirin (P = 0.003). However, lower office systolic BP values (133.5±18.8 vs. 138.8±17.6 mmHg: P = 0.036) were observed in patients with Lp(a) ≥50 mg/dL than in those with < 50 mg/dl. Also, no significant differences for Lp(a) levels were observed among various hypertension phenotypes, as defined by office (P = 0.156) or out-of-office BP values (P = 0.065). No significant correlations were found between Lp(a) and office or out-of-office BP levels, both in treated and untreated hypertensive outpatients. In our population, Lp(a) levels were not associated with either office or out-of-office BP values, irrespective of antihypertensive treatment status. The role of Lp(a) in hypertension warrants further investigation. Show less

Atherosclerotic cardiovascular disease (ASCVD) continues to be a major global health burden, with substantial residual cardiovascular risk remaining. Growing evidence highlights the liver’s pivotal role in the onset and development of ASCVD through multiple interconnected pathways. As the metabolic center of the body, the liver regulates the synthesis, secretion, and clearance of several atherogenic lipoproteins while simultaneously serving as a systemic inflammation amplifier, producing cytokines, acute-phase proteins, and coagulation factors. Traditional liver-targeted therapies, such as statins, have demonstrated that regulating liver metabolism can confer significant cardiovascular benefits. Subsequently, advances in nucleic acid-based drugs and in vivo gene-editing tools have broadened this strategy, enabling accurate and durable modulation of hepatic gene expression. However, recent clinical trials suggest that improvements in laboratory biomarkers do not always translate into proportional reductions in major adverse cardiovascular events. Moreover, the long-term safety and durability of lipid nanoparticles and gene-editing platforms remain ongoing concerns. Future research should focus on the classification of patients based on multiple omics data, and distinguish those whose main problem is metabolic disorder from those who are mainly at high risk of inflammation, thereby facilitating personalized therapeutic targeting. Overall, current evidence indicates that the liver represents a convergent therapeutic target for modulating both lipid metabolism and inflammation, offering a promising opportunity for deeper and more durable cardiovascular risk reduction. Show less

The pathogenesis of Alzheimer's disease (AD) is complex, involving multiple interrelated pathways. Consequently, developing multi-target-directed ligands may represent an effective therapeutic strategy. This study investigates the anti-Alzheimer potential of two biflavonoids isolated from Allanblackia floribunda against monoamine oxidase A (MAO-A), β-secretase (BACE-1), and glycogen synthase kinase-3β (GSK-3β), three key enzymes implicated in AD progression. The biflavonoids, (2S,3S)-volkensiflavone-7-O-β-glucopyranoside (1) and (2R,3S)-volkensiflavone-7-O-β-D-acetylglucopyranoside (2), were purified and structurally identified using spectroscopic methods. Enzymatic fluorimetric assays were conducted to assess their inhibition of MAO-A, BACE-1, and GSK-3β. The mode and reversibility of inhibition were characterized for both compounds, confirming them as potent MAO-A inhibitors. In silico simulations were performed on the three enzymes to gain insights into their interactions and modes of action. Compounds 1 and 2 were found to be reversible and moderately selective MAO-A inhibitors with IC Show less

Most newly discovered membranous nephropathy (MN) antigens have been mutually exclusive, but there are rare cases of dual antigen MN based on immunohistochemistry (IHC)/immunofluorescence (IF) or serologic testing. Here, we searched for cases of dual antigen MN at Mayo Clinic and Arkana Laboratories with the diagnosis established by light/electron microscopy and IF. At Mayo Clinic, we performed laser capture microdissection of glomeruli followed by liquid chromatography tandem mass spectrometry (LC MS/MS) on paraffin-embedded kidney biopsy tissue to detect 12 MN antigens. Nine cases of dual antigen MN (four at Mayo Clinic, five at Arkana Laboratories) were confirmed by both LC MS/MS and IHC/IF. The detected antigens were NELL1 + CNTN1 (two cases), NCAM1 + EXT1/2 (two cases), and one case each NDNF + NELL1, NELL1 + PLA2R1, THSD7A + PLA2R1, PCDH7 + PLA2R1, and CNTN1 + PCDH7. Median age at diagnosis was 68 years (range 23-84). Eight patients presented with nephrotic syndrome and microscopic hematuria. Median serum creatinine at diagnosis was 1 mg/dL. The underlying conditions, when present, and serological characteristics, correlated with the involved antigens. The frequency at Mayo Clinic was 2.6% of PLA2R1-negative MN cases. Given that IHC/IF and LC MS/MS for MN antigen detection are typically not pursued in PLA2R1-associated MN, dual-antigen MN is likely underdiagnosed. Dual-antigen MN can involve a variety of MN antigens, including those that are podocyte-expressed, transmembrane, or secreted. Most patients with MN present with nephrotic syndrome and microscopic hematuria. Further studies are needed to understand the pathophysiology of dual-antigen MN and determine their role both in the therapeutic approach and clinical outcomes. Our findings suggest that LC MS/MS is a valuable methodology for detection of dual antigen MN. Show less

The mutual effects of different activity intensities in daily life, such as sedentary behavior (SB) and physical activity (PA), on dementia onset are not yet fully understood. The purpose of this study was to examine the association between replacing SB with PA and the risk of dementia in older adults by using the isotemporal substitution (IS) model. Prospective cohort study. Community-dwelling older adults living without dementia in Takahama, were enrolled, interviewed, and physically examined. Follow-up data were collected from the Japanese Public Health Insurance and/or Long-Term Care Insurance system databases during follow-up. SB and PA data [light-intensity PA (LPA) and moderate-to-vigorous PA (MVPA)] were measured using a triaxial accelerometer for 14 days, and the average daily time for SB and PA was calculated in 10-minute increments. Participants were followed up monthly for new-onset dementia over 5 years. Cox proportional-hazards regression analysis was performed by using IS to estimate the effect of replacing one activity with another on the dementia onset. We included 1664 participants (mean ± standard deviation age, 73.1 ± 5.9 years) in this study. Over 5 years, 128 of 1664 participants developed dementia. Replacing 10 min/d of SB with LPA (hazard ratio, 0.86; 95% CI, 0.75-0.99) or MVPA (0.84; 0.74-0.96) was associated with a lower risk of dementia. Replacing 10 minutes of SB with LPA or MVPA was associated with a lower risk of dementia. Feasible behavioral changes in daily life may lead to a healthy life expectancy. Show less

To develop and evaluate an automated clinical decision support system (CDSS) capable of computing both categorical and exact-percentage cardiovascular risk (CVR) in routine clinical practice. We developed and implemented an automated CDSS (AlinIQ®) for CVR assessment within the Clinical Laboratory Department of Hospital Universitari i Politècnic La Fe (València, Spain), applied to patients referred from Primary Care. The analytical profile-requested either via automatic trigger or proactive clinician order-included total cholesterol, HDL-C, LDL-C, non-HDL-C, triglycerides, lipoprotein(a) [Lp(a)], serum creatinine, and estimated glomerular filtration rate. Additional required inputs were smoking status, systolic blood pressure, country of origin, and age at diabetes onset. The CDSS automatically computed SCORE2, SCORE2-OP, SCORE2-Diabetes, and SCORE2 Asia-Pacific, generating both categorical strata and exact-percentage CVR. Lp(a)-adjusted CVR was derived using coefficients from the Spanish Atherosclerosis Society. Following the ESC 2025 Focused Update, patients meeting predefined clinical criteria for moderate, high, or very high CVR were directly assigned to the corresponding category without SCORE calculation. The system also incorporated modifying risk factors, generating standardized interpretive comments and personalized lipid targets. Over one month, 2289 screenings were requested; 189 (8.3%) were excluded. A total of 171 patients (7.5%) were classified as high risk based on score-based calculation (164 [95.9%] triggered automatically), and 29 (1.6%) as very high risk (23 [79.3%] triggered automatically). 119 individuals (6.8%) were reclassified to a higher risk category after Lp(a)-based adjustment. This CDSS provides a scalable and reproducible framework for laboratory-driven cardiovascular prevention. Show less

Preclinical atherosclerosis and prediabetes are key targets of preventive medicine as their prevalence rises. Therefore, it is crucial to identify early processes and limit confounders such as lipid-lowering or antidiabetic therapy and advanced atherosclerosis. Proteomics enables the identification of biomarkers and molecular pathways related to atherogenesis in prediabetes. To investigate the relationship between prediabetes and preclinical atherosclerosis in apparently healthy individuals using a comprehensive proteomic approach. This cross-sectional, population-based study included 389 participants (mean age 49 ± 10 years; 47% males) from the Białystok PLUS cohort in Poland. Individuals with known diabetes, major cardiovascular, inflammatory, or malignant diseases, or those receiving steroidal or lipid-lowering therapy were excluded. Carotid ultrasound was used to assess preclinical atherosclerosis, and prediabetes was defined as impaired fasting glucose, impaired glucose tolerance, or HbA1c 5.7–6.4%. Proteomic profiling was performed using the Olink® Reveal platform, enabling deep profiling of 1050 proteins with the Proximity Extension Assay and next-generation sequencing readout, yielding log2-scaled NPX (Normalized Protein eXpression) values. In preliminary analyses, we identified proteins associated with prediabetes and then linked them to early atherosclerotic lesions. A block-sPLS-DA model integrating clinical and proteomic data revealed clear separation between participants with and without prediabetes. The clinical block comprised eight variables reflecting cardiometabolic status, whereas the proteomic block retained 45 proteins across two components. The heatmap shows pairwise Pearson correlations between selected serum proteins and clinical variables (Fig. 1). Vascular and age measures cluster together and share correlation patterns distinct from those of BMI and glycaemic parameters. A protein module including the ectodysplasin A2 receptor (EDA2R) and leiomodin 1 (LMOD1) correlates positively with age and vascular parameters, and inversely with GFR and HDL-C. Multivariable linear regression analyses were performed with selected vascular parameters as dependent variables and clinical covariates, together with proteins identified in Component 2, which are weakly related to clinical parameters and thus may represent novel biomarkers associated with prediabetes (Fig. 2). Expression of EDA2R (B = 0.05; An integrative block-sPLS-DA approach separated individuals with prediabetes from those without and revealed a proteomic signature independent of clinical covariates. Within this signature, the expression of LMOD1, EDA2R, and C16orf89 showed robust associations with atherosclerosis-related vascular traits. Enrichment analyses highlighted proteins involved in neuronal processes as candidate pathways linking early glucose disturbances with preclinical atherosclerosis. The online version contains supplementary material available at 10.1186/s12933-026-03128-w. Show less

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4d-UT) is an uncommon, aggressive lung neoplasm associated with smoking and characterized by loss of SMARCA4 (BRG-1) expression. Although originally considered to be a primary sarcoma, there is growing evidence that these lesions may represent transformation of conventional non-small cell carcinoma. In this study, we probe this relationship based on the clinical, histologic and molecular findings of 18 SMARCA4-deficient malignancies of the lung. Cases diagnosed as SMARCA4d-UT and SMARCA4-deficient carcinoma were retrospectively reviewed, including histologic and immunophenotypic features, and next generation sequencing studies. Of the 18 tumors, 5 were considered to represent undifferentiated SMARCA4d-UT, and 13 SMARCA4-deficient carcinomas, including 11 adenocarcinomas, 1 squamous cell carcinoma, and 1 poorly differentiated non-small cell carcinoma. All 13 carcinomas had a morphologically identifiable undifferentiated component. Survival outcomes were similar in both SMARCA4d-UT and carcinomas. Genetic alterations often seen in lung cancer were identified in 8 cases, including mutations in EGFR (in 2 SMARCA4-deficient adenocarcinomas), KRAS (1 SMARCA4d-UT and 1 SMARCA4-deficient adenocarcinoma), MAP2K1 (1 SMARCA4-deficient adenocarcinoma), and a gene fusion involving EML4::ALK (1 SMARCA4d-UT). The patient with EML4::ALK fusion was treated with alectinib with partial response. Fusions involving BRAF::CHCHD3 and FGFR1::FILIP1 were identified in 2 SMARCA4-deficient adenocarcinomas. High expression of PD-L1 (TPS >50 %) was seen in 12 cases (67 %). These finding further suggest that SMARCA4d-UT and carcinomas with SMARCA4 loss may be on the same spectrum of disease, and accurate histologic distinction between these lesions may be challenging. A unified terminology may be beneficial for appropriate diagnosis and treatment. Show less

Chia (Salvia hispanica L.) is a functional food that can help control the metabolic changes caused by unbalanced diets. The aim of this study was to investigate the effects of chia flour (CF) and chia oil (CO) on satiety, inflammation, and antioxidant potential in the brain of rats fed a high-fat high-fructose diet (HFHF). Male Wistar rats were divided into two groups: AIN-93M (n = 8) and HFHF (n = 24) for 8 wk. Subsequently, HFHF-fed animals were subdivided (n = 8) into: HFHF, HFHF+CF, and HFHF+CO for 10 wk. Gene expression of satiety and inflammation-related proteins was analyzed by RT-qPCR; leptin and adiponectin levels were quantified by ELISA; and antioxidant potential was assessed via SOD and CAT activity. In silico analysis was performed using molecular docking, and the correlations were evaluated via Pearson's analyses. The HFHF+CO group showed higher POMC/CART gene expression, as well as reduced leptin levels compared to the HFHF+CF and AIN-93M groups. Both chia flour and oil reduced NPY, LEP-r, and NF-κB gene expressions compared to the HFHF group. The HFHF+CF group showed increased Nrf2 gene expression compared to the HFHF group. All main phenolic acids found in chia flour showed good interactions with the analyzed markers LEP-r, MC4R, and NPY-Y1. Main positive correlations were observed beteween adiponectin and SOD, phenolics consumption and ALA, MC4R and NPY, NPY and AgRP, and AgRP and MC4R. Thus, this study highlights chia flour and oil as potential modulators of satiety and inflammatory response in the brain, in addition to reinforcing the antioxidant effect of flour. Show less

Ambient air pollution aggravates cardiovascular-kidney-metabolic (CKM) disorders and sarcopenia, yet the shared genetic and epigenetic mechanisms that underlie their frequent co-occurrence remain poorly understood. We integrated genome-wide association study (GWAS) data for CKM components (cardiovascular disease [CVD], chronic kidney disease [CKD], metabolic syndrome), CKM-related cardiovascular events, and sarcopenia diagnostic criteria from European-ancestry cohorts, and conducted meta-analyses harmonizing each phenotype across at least three studies. We employed Mendelian Randomization (MR) to assess potential causal links and genetic correlation analyses (global and local) to quantify shared heritability. Multi-omics analyses included two sequential phases: Phase 1 identified and validated novel shared CKM-sarcopenia genes through integrated methylation (n = 1980) and expression (n = 31,684) analyses, followed by cross-validation using two complementary transcriptome-wide association studies (TWAS). Phase 2 prioritized druggable targets through proteomic analysis across five independent cohorts (deCODE, n = 35,559; UK Biobank Pharma Proteomics Project (UKB-PPP), n = 54,219; Fenland, n = 10,708; FinnGen Olink, n = 619; FinnGen Somascan, n = 828) and integrated colocalization. MR suggested genetically predicted associations between sarcopenia and CKM; genetically slower walking pace was associated with higher CVD risk (OR = 0.85, P = 9.56 × 10 Ambient air pollution likely promotes CKM-sarcopenia comorbidity chiefly via inflammatory signaling and epigenetic modifications. Our multi-omics integration reveals convergent pathways, candidate driver genes, and differential methylation sites that link these conditions. We propose these targets for environmental mitigation and molecular intervention, which require validation in diverse populations. Show less

Exosomes are crucial mediators of intercellular communication. As a key component of milk, milk-derived exosomes are abundant in genetic cargo, particularly microRNAs (miRNAs), indicating their potential role in regulating mammary gland physiology. Therefore, this study aimed to investigate the specificity of miRNAs in milk-derived exosomes and their regulatory roles in lipid synthesis in bovine mammary epithelial cells (BMECs). Based on 17,838 DHI records showing a significantly higher milk fat percentage (MFP) in late lactation (4.24% ± 1.07%), 10 high- (5.96% ± 0.26%, HMF) and 10 low-MFP (1.68% ± 0.23%, LMF) cows were selected during this stage for milk-derived exosome isolation and miRNA profiling. Exosomes isolated via differential ultracentrifugation were verified as 50-150 nm vesicles expressing CD9, CD81, and TSG101. miRNA sequencing identified 1,320 differentially expressed miRNAs (496 upregulated and 824 downregulated) between the HMF_EXO and LMF_EXO groups. Uptake assays confirmed that BMECs internalized these exosomes, and qRT-PCR validation showed that miR-423-5p and miR-125b were significantly upregulated and downregulated in HMF_EXO- and LMF_EXO-treated BMECs, respectively. Functionally, exosomal miR-423-5p promoted intracellular lipid accumulation and TG synthesis in BMECs by targeting APOA5, whereas miR-125b inhibited lipolysis and fatty acid oxidation by repressing SLC27A1. This study demonstrates that milk-derived exosomal miRNAs represent a novel mechanism for regulating milk fat synthesis. Specifically, miR-423-5p and miR-125b directly modulated lipid metabolism in BMECs via the miR-423-5p/APOA5 and miR-125b/SLC27A1 pathways. These findings provide new insights into the molecular regulation of milk fat synthesis and highlight the importance of exosome-mediated intercellular communication in the lactating mammary gland. Show less

Apolipoprotein B (APOB), a structural component of low-density lipoproteins (LDL), has historically been associated with peripheral lipid transport and cardiovascular disease. Recent studies have revealed a link between APOB and Alzheimer's disease (AD), with increased cerebrospinal fluid (CSF) APOB levels correlating with tau pathology. Although APOB is known to be locally expressed in the brain, albeit at very low levels, its function in the central nervous system and contribution to neurodegenerative processes remains poorly understood. To investigate the effects of chronic APOB overexpression on brain molecular homeostasis, we used a transgenic mouse model expressing human APOB-100 and integrated findings with human cohort data to assess its functional relevance to AD pathology. Human APOB transgenic (hAPOB) and wild-type mice were aged to 6 and 12 months. Frontal cortices were analyzed using RNA sequencing and mass spectrometry-based proteomics. Differentially expressed genes and proteins were analyzed via pathway enrichment and cell type deconvolution. Findings were contrasted to post-mortem proteomic alterations observed in brain tissue (ROSMAP) and in the CSF (ADNI). hAPOB overexpression in mice induced a robust and persistent upregulation of innate immune genes, particularly those associated with type I interferon responses (Irf7, Ifit1, Oas2), in both young and old transgenic mice. Reduced microglial and endothelial cell signatures were observed through cell type deconvolution, which suggests immune activation without proliferation and possible blood-brain barrier damage. Proteomic analyses showed differentially expressed proteins associated with oxidative stress and dendritic remodeling. Proteins dysregulated in mice-such as CTSD, CRK, and SULT4A1-also showed altered expression in AD human brain and CSF. Remarkably, these proteins are dysregulated in the opposite direction in humans than in mice, unveiling a complex downstream regulation of APOB overexpression. Chronic hAPOB overexpression drives sustained neuroinflammatory and oxidative responses, potentially mimicking viral-like immune activation in the brain. The proteins dysregulated in hAPOB transgenic mice brains were also dysregulated in humans on opposite side of the APOB level spectrum. Nevertheless, this result shows a consistency across species on hAPOB-driven downstream effects. Some of these proteins were also shown to associate with key features of AD pathology, namely Aβ, Tau and pTau. Our findings support a novel role for APOB in modulating brain immune homeostasis and neurodegenerative processes, offering a mechanistic link between vascular risk and Alzheimer's disease. Show less

Rising global temperatures lead to a continuous increase in the frequency and intensity of extreme weather events, such as droughts and floods, posing serious threats to terrestrial homeotherms. However, adaptive changes in respiratory metabolism and molecular mechanisms in lung tissues of small mammals under extreme water shortage conditions remain unclear. This study hypothesized that small desert mammals can adapt to extreme water shortage environments by regulating the plasticity of lung tissue gene expression and respiratory metabolism. Using 29 wild-caught Siberian jerboas ( Show less

Elevated lipoprotein(a) [Lp(a)] is an important genetic risk factor for cardiovascular diseases (CVDs). Because Lp(a)-lowering therapies are limited, prevention focuses on identifying individuals with elevated Lp(a) and optimizing other modifiable risk factors. We aimed to assess the distribution of Lp(a) levels in Finnish adults and examine its association with other CVD risk factors, as well as the awareness, treatment, and control of dyslipidemia. Data were derived from the Healthy Finland health examination survey conducted in 2023, comprising a nationally representative sample of 5,484 adults. Lp(a) levels were categorized using a cut-point at 125 nmol/L. Other CVD risk factors included were dyslipidemia, abnormal glucose metabolism, hypertension, and obesity. Analyses were weighted taking into account the sampling design and non-participation to provide nationally representative results. Mean Lp(a) levels were 41.7 nmol/L (95% CI 39.0-44.3) in men (M) and 41.9 nmol/L (39.7-44.1) in women (W). Elevated Lp(a) was observed in 11.0% of men and 10.4% of women. Dyslipidemia was more prevalent among individuals with elevated Lp(a) (M: 88.1% vs. 78.4% p = 0.003, W: 79.2% vs. 73.2% p = 0.030) but this association reversed after correcting cholesterol for Lp(a). No associations were found between Lp(a) and other cardiometabolic risk factors. Individuals with elevated Lp(a) had slightly lower unawareness (M: 42.3% vs. 47.5%, p = 0.180, W: 38.8% vs.48.4%, p = 0.042) and better treatment (M: 38.1% vs. 31.7%, p = 0.010, W: 29.2% vs. 24.7%, p = 0.090) of dyslipidemia than those with lower levels while no association was found between Lp(a) and dyslipidemia control (M: 81.4% vs. 84.1%, p = 0.520, W: 74.6% vs. 73.0%, p = 0.740). Approximately one in ten Finnish adults had elevated Lp(a), a lower prevalence than in many other European populations but still affecting a substantial share of the population. Elevated Lp(a) was associated with higher prevalence of dyslipidemia prior to Lp(a) correction, but not with other CVD risk factors, and these individuals also showed slightly greater awareness and treatment of dyslipidemia. These findings emphasize the need for comprehensive management of modifiable CVD risk factors to reduce the overall burden of CVDs. Show less

Dysregulated extracellular matrix (ECM) deposition and epithelial-mesenchymal transition (EMT) in the trabecular meshwork (TM) contribute to glaucoma-associated fibrotic remodeling, and lysophosphatidic acid (LPA) potently induces these profibrotic responses in human trabecular meshwork (HTM) cells. We investigated whether an ethanolic extract of Show less

Atherosclerotic plaque destabilization during acute infections such as pneumonia represents a critical clinical challenge, yet the underlying molecular dynamics remain poorly characterized. This study introduces a furin-responsive photoacoustic/fluorescence dual-modal probe (FRP) to investigate intraplaque furin activity in ApoE Show less

Digital technology is frequently regarded as a tool to alleviate loneliness and enhance mental health among older adults, yet its effectiveness remains contested. This study explores whether digital exclusion moderates the association between loneliness and depressive, and examines symptom structure and depressive subtypes. Drawing on data form the 2018 and 2020 waves of the CHARLS (N = 13,719), we employed fixed-effect and mixed-effect models to assess the effect of loneliness on depressive and the moderating role of digital exclusion. Latent profile analysis (LPA) was used to identify symptoms subtypes, while symptom network analysis assessed centrality and network stability. Loneliness significantly predicted depressive symptoms across multiple models, demonstrating robust effects. Digital exclusion was positively associated with depressive symptoms but did not exhibit a statistically significant moderating effect on the loneliness-depression relationship (p > 0.05, Δβ ≈ 0.011). LPA identified six psychologically meaningful subtypes of depression. Symptom network analysis revealed that emotional and motivational symptoms occupied central positions within the network structure, whereas loneliness, despite its strong connections, exhibited relatively low centrality. The overall network structure remained stable over two years, with the digital access group exhibiting stronger network connectivity. This study emphasizes that digital access alone is not a universal remedy for alleviating loneliness. The psychological benefits of digital technology depend on the alignment between individual motivations, usage patterns, and broader social contexts. Future research should focus on digital usage quality and contextual adaptability of interventions, promoting a shift from customization in digital mental health intervention strategies. Show less

Moutan Cortex, a traditional Chinese medicine, has been used to treat cardiovascular diseases. Paeonol (Pae), a key bioactive compound, is responsible for its anti-atherosclerotic effects. Although CD8 We investigated whether Pae inhibits atherosclerosis by targeting the spleen tyrosine kinase (SYK)/nuclear factor of activated T-cells c1 (NFATc1) pathway, thereby reducing CD8 High-fat diet-fed apolipoprotein E-deficient (ApoE Pae attenuated plaque formation and T-cell activation in ApoE SYK in CD8 Show less

Recent evidence has shown that bone marrow mesenchymal stem cells (BMSCs) have multiple biological applications and play an important role in improving cognitive dysfunction. However, it is still unclear whether BMSCs play a role in cognitive impairment induced by chronic pain. This study aimed to evaluate the therapeutic effect of BMSCs on neuropathic pain-induced cognitive dysfunction and explore its potential mechanisms. A mouse chronic constriction injury (CCI) model was established, and the new object recognition task and fear conditioning were used to detect cognitive function; the expression of CXCL12/CXCR4 in blood and hippocampus was detected. After intravenous injection of BMSCs, changes in cognitive function and expression of the CXCL12/CXCR4 pathway, dentate gyrus neurogenesis, and excitability of hippocampal neurons were detected. In addition, induction of cognitive impairment in normal mice by CXCL12 recombinant protein was used to clarify whether the CXCL12/CXCR4 pathway mediates the cognitive function improvement effect of BMSCs. Our results found CCI mice showed significant cognitive impairment 21 days after surgery, with significantly increased expression of CXCL12/CXCR4 in blood and hippocampus. Intravenous injection of BMSCs significantly improved cognitive function, inhibited expression of CXCL12/CXCR4 in blood and hippocampus, promoted neurogenesis in dentate gyrus of CCI mice, and increased expression of BDNF and c-Fos in the hippocampus. In addition, BMSCs alleviate cognitive impairment induced by intravenous injection of CXCL12 recombinant protein in mice. In summary, BMSCs improve chronic neuropathic pain-induced cognitive dysfunction through peripheral blood CXCL12/CXCR4, and BMSCs may develop into therapeutic targets for chronic pain induced cognitive impairment. Show less

Hereditary Multiple Osteochondromas (HMO) is a rare autosomal dominant skeletal disorder caused by heterozygous loss-of-function mutations in EXT1 or EXT2, which encode glycosyltransferases essential for heparan sulfate (HS) biosynthesis. Whether haploinsufficiency alone suffices or biallelic inactivation is required for osteochondroma formation remains a central unresolved question. In this study, we employed CRISPR/Cas9 combined with PiggyBac transposon technology to introduce a second pathogenic mutation (c.1883+1G>T) into patient-derived induced pluripotent stem cells (iPSCs) carrying a heterozygous EXT1 c.1126C>T mutation. This approach enabled the generation of isogenic iPSC lines: wild-type (WT), single-mutant (SM), and double-mutant (DM). These iPSCs were differentiated through induced mesenchymal stem cells (iMSCs) into chondrocytes. Biallelic EXT1 mutation in DM cells led to significant upregulation of SOX9, COL2A1, and ACAN, elevated glycosaminoglycan (GAG) levels, and markedly reduced HS, whereas SM cells remained indistinguishable from WT. Three-dimensional (3D) chondrogenic organoid cultures revealed that DM organoids were enlarged and structurally disorganized, partially recapitulating key histopathological features of osteochondromas. Transcriptomic analysis identified the Wnt signaling pathway as the most significantly enriched pathway among differentially expressed genes following EXT1 loss. Collectively, these findings provide direct human cellular evidence that complete EXT1 inactivation-not haploinsufficiency-drives aberrant chondrogenesis, likely through impaired sequestration of morphogen ligands, thereby supporting the Two-hit pathogenic model. Show less

Lipoprotein (a) [Lp(a)] is a lipoprotein similar to low-density lipoprotein (LDL), which binds to a characteristic component: apolipoprotein (a). The plasma Lp(a) level is mainly determined by genetic factors, with variations across ethnic groups. In adults, various epidemiological and genetic studies have shown that elevated Lp(a) levels are an independent risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis, associated with inflammatory, atherogenic, and thrombotic mechanisms. Given that the distribution, variability, and prognostic value of this marker in the pediatric population have been less investigated, the objective of this review is to analyze the available evidence on the behavior of Lp(a) as a risk marker in children and adolescents, current recommendations for its measurement in pediatrics, and treatment prospects. Show less

The maternal environment during gestation influences fetal development, with long-lasting effects on postnatal health and productivity. This study evaluated the effect of prenatal heat stress (PNHS) on blood DNA methylation of dairy calves immediately after birth and whether such modifications persist into early life. Holstein calves were born to dams exposed to either PNHS (n = 36, temperature-humidity index >68, access to shade of a freestall barn) or prenatal cooling (PNTN; n = 37, access to shade and evaporative cooling) during the last 54 ± 5 d of gestation. Whole-genome enzymatic DNA methyl sequencing was performed on blood samples collected at birth (d 0; n = 3 PNHS, n = 5 PNTN) and 1 wk post-weaning (d 63 of age; n = 8 PNHS, n = 8 PNTN). From birth onward, all calves were actively cooled and managed under the same conditions. At birth, 682,898 differentially methylated cytosines (DMC) were identified genome-wide. Principal component analysis using 55,304 DMC located in genes expressed in blood cells revealed a clear clustering by prenatal treatment. However, at weaning, clear clustering by treatment was no longer observed using 23,977 treatment-associated DMC in blood-expressed genes, despite 97,289 DMC persisting genome-wide from birth to weaning. Immune cell deconvolution showed only minor differences in granulocytes (d 0) and CD4/CD8 Show less

Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found that TMEM41B is significantly upregulated in VSMCs of both human atherosclerotic (AS) lesions and murine models. Silencing TMEM41B in VSMCs of apolipoprotein E-deficient (ApoE Show less

Neuroinflammation appears in a variety of neurological disorders, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis. The adenosine A₂A receptor (A₂AR), a Gs protein-coupled receptor that affects cAMP signaling and downstream kinases like PKA, CREB, and NF-κB, is one of the primary regulators of this process. Context-dependent effects of A₂AR activation include lowering acute inflammation and promoting neuronal survival when stimulated moderately, but increasing glial activation and cytokine production when overexpressed over an extended period of time. In microglia and astrocytes, A₂AR signaling regulates inflammatory pathways mediated by NF-κB and MAPK, affecting oxidative stress, blood-brain barrier (BBB) stability, and excitotoxicity. Acute or transient (short-term) A₂AR activation, on the other hand, increases the production of anti-inflammatory cytokines like IL-10 and enhances neurotrophic support through BDNF. A₂AR antagonists, including istradefylline and SCH58261, may reduce microglial triggering and have neuroprotective benefits, according to clinical and experimental data. The context-dependent activity of the receptor is shown by the fact that total receptor blockage interferes with adaptive immune control. Therefore, the therapeutic challenge is to carefully modify A₂AR signaling in particular cell populations, specifically targeting astrocytic or microglial receptors while maintaining the peripheral immunoregulatory activities. The dual regulatory role of A₂AR in neuroinflammation is summarized in this review along with its molecular mechanisms, disease-specific actions, and therapeutic significance. Developing next-generation neuroprotective strategies that reduce A₂AR signaling's pro-inflammatory and neurotoxic effects while preserving its beneficial homeostatic effects will require an understanding of the temporal and cell-specific dynamics of this signaling. Show less

Tc17 cells (IL-17 The percentage of Tc17 cells, monocytes and IL-1β Higher populations of Tc17 cells, IL-1β The present results show that suppressing IL-1β expression by preventing CD80 [Figure: see text] The online version contains supplementary material available at 10.1186/s12964-026-02785-4. Show less