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Huangqi Guizhi Wuwu Decoction (HGWD) is a classic formula recorded in the Jin Gui Yao Lue. It is primarily used to treat symptoms of "blood stasis", such as numbness in the limbs and poor circulation, and has been widely applied clinically in the treatment of stroke. Its traditional efficacy suggests potential for promoting neurological function recovery and regulating the microenvironment. However, its mechanism in neuroprotection and functional recovery after ischemic stroke (IS) remains unclear. This study aims to elucidate the molecular mechanism by which HGWD exerts neuroprotective effects and promotes neurological recovery following IS by inducing M2 polarization of microglia through activation of the PI3K/Akt/mTOR signaling pathway. The chemical constituents of HGWD were identified using Ultra Performance Liquid Chromatography-Mass Spectrometry (UHPLC-MS). Network pharmacology was employed to predict the active components of HGWD and targets, along with potential signaling pathways. A middle cerebral artery occlusion (MCAO) in vivo model was established using Sprague-Dawley (SD) rats, whilst primary microglia were isolated to construct an oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro model. TTC staining was used to assess the volume of cerebral infarction, and neurological function was evaluated using mNSS and the rotarod test. RT-qPCR, Western blot, immunofluorescence, or flow cytometry were used to detect axonal remodeling, the PI3K/Akt/mTOR signaling pathway, and microglial polarization markers, while ELISA was used to detect inflammatory cytokines. The in vivo dosage of HGWD was 2.5 g/kg i.g. and 5 g/kg i.g., and the in vitro concentrations were 50 μg/mL and 100 μg/mL. Using LY294002 and Rapamycin as PI3K and mTOR inhibitors, we verified that HGWD promotes the recovery of neurological function after IS by activating the PI3K/Akt/mTOR signaling pathway. Network pharmacology revealed that the core components of HGWD overlap with the PI3K/Akt/mTOR signaling pathway and microglial polarization targets. HGWD significantly improved neurological function in MCAO rats, reduced cerebral infarction area, and increased neuronal survival. This formula increased the expression of GAP-43, PSD95, and BDNF, while promoting axonal remodeling and synaptic repair. HGWD inhibited the expression of M1-type markers (CD86, iNOS) and increased the expression of M2-type markers (CD206, ARG1), while ELISA showed a shift of inflammatory cytokines towards anti-inflammatory effects. In microglia, HGWD restored OGD/R-induced cell viability and promoted M2 polarization via the PI3K/Akt/mTOR signaling pathway. Both in vivo and in vitro experiments showed that HGWD significantly increased the phosphorylation levels of PI3K, Akt, and mTOR. LY294002 and rapamycin partially blocked these results, while rescue experiments using the Akt activator SC79 combined with analysis of downstream STAT3 and P65 further illustrate that this process is Akt pathway dependent. The results suggest that HGWD can exert a neuroprotective effect by activating the PI3K/Akt/mTOR signaling pathway, thereby promoting neurological function recovery. HGWD may activate the PI3K/Akt/mTOR signaling pathway, drive microglia to M2 polarization, regulate neuroinflammation, and promote neuroplasticity, thereby achieving neuroprotection and functional recovery after IS. Show less

Elevated lipoprotein(a) [Lp(a)] is an inherited, causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Despite guideline endorsement, its measurement is inconsistently adopted within the UK healthcare setting. Understanding whether identifying raised Lp(a) alters real-world management and lipid outcomes is key to guiding policy. To evaluate the distribution of Lp(a) levels in a UK lipid clinic, quantify management changes across clinically relevant thresholds and explore the relationship between Lp(a) and final non-HDL-cholesterol (non-HDL-C) attainment. This retrospective observational study included 337 patients attending a specialist lipid clinic. Demographics, atherosclerotic cardiovascular (ASCVD) disease status, HEART UK Lp(a) testing criteria, management actions, and final non-HDL-C values were analyzed. Lp(a) concentrations were initially grouped into five descriptive categories (<30, 30-49, 50-89, 90-179, and ≥180 mg/dL) for baseline characterization. For management-change analyses, categories <50 mg/dL were combined to reflect the ESC/EAS-defined threshold for elevated Lp(a), which served as the clinical reference point for assessing management impact. Management changes were observed in 3.5% of patients with Lp(a) < 50 mg/dL, 56% with 50-89 mg/dL, and 79% and 83% of those with 90-179 mg/dL and ≥180 mg/dL, respectively. Interventions involved medication up-titration, reinforcement of lifestyle measures, or strengthened clinical emphasis on the importance of lifelong lipid-lowering therapy. Family cascade screening was initiated exclusively among patients with Lp(a) ≥ 90 mg/dL, representing around one-third of this subgroup. Mean final non-HDL-C increased with Lp(a) category, while target attainment (<2.5 mmol/L) declined, likely reflecting the biochemical contribution of Lp(a)-cholesterol to the non-HDL-C fraction rather than suboptimal management. Routine Lp(a) testing meaningfully alters management and reveals a form of residual dyslipidaemia resistant to standard therapy. These findings, combined with recent cost-effectiveness modelling showing NHS and societal savings from one-time testing, support incorporation of Lp(a) measurement into universal cardiovascular risk assessment. Show less

Scavenger receptor B3/differentiation cluster 36 (SCARB3/CD36) has been established as a fatty acid transporter and genetic deficiency of CD36 in mice models shows decreased uptake of oxidized low-density lipoprotein (oxLDL) and reduced atherosclerosis. The present study proposes CD36 as a drug target inhibited by leonurine to alleviate inflammation and prohibit unstable atherosclerotic plaques. We showed that the anti-atherosclerotic effects of leonurine were dependent on CD36 in a mice model of arterial atherosclerosis induced by tandem stenosis surgery fed with Western diet (TS + WD) established in both wild type (WT) and Cd36 Show less

This study aims to evaluate the association between multiple lipid indices and coronary collateral circulation (CCC) in patients diagnosed with acute ST-segment elevation myocardial infarction (STEMI). This was a cross-sectional retrospective study involving 421 patients with STEMI who underwent coronary angiography between January 2022 and December 2024. Participants were categorized into a poor CCC group (Rentrop grade 0-1) and a good CCC group (Rentrop grade 2-3) according to Rentrop grading criteria. The following lipid parameters were evaluated as both continuous and categorical variables: total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) [Lp(a)], apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I), non-HDL-C/HDL-C, ApoB/ApoA-I, atherogenic index of plasma (AIP), and lipoprotein composite index (LCI). The associations between these lipid indices and CCC status were assessed using multivariate logistic regression and receiver operating characteristic (ROC) curve analysis. Multivariate logistic regression analysis revealed that higher HDL-C quartiles were significantly associated with reduced odds of poor CCC (odds ratio [OR]: 0.544, 95% confidence interval [CI]: 0.351-0.771, P < 0.05), whereas elevated LDL-C (OR: 29.299, 95% CI: 3.562-240.976, P < 0.05), non-HDL-C (OR: 50.140, 95% CI: 5.408-464.834, P < 0.01), and non-HDL-C/HDL-C (OR: 4.510, 95% CI: 1.186-25.368, P < 0.05) quartiles were significantly associated with increased odds of poor CCC. Receiver operating characteristic (ROC) curve analysis demonstrated that LDL-C (cutoff: 3.265, AUC: 0.647, 95% CI: 0.573-0.721, P < 0.001), non-HDL-C (cutoff: 2.735, AUC: 0.752, 95% CI: 0.688-0.816, P < 0.001), and non-HDL-C/HDL-C (cutoff: 2.393, AUC: 0.686, 95% CI: 0.611-0.761, P < 0.001) exhibited favorable predictive performance for poor CCC. Stratification analysis showed that the highest prevalence of poor CCC was observed in patients with concurrently elevated levels of LDL-C, non-HDL-C, and non-HDL-C/HDL-C. Several lipid indices-including LDL-C, non-HDL-C, and the non-HDL-C/HDL-C ratio-are significantly associated with impaired CCC in patients with STEMI. Notably, non-HDL-C exhibits the strongest association with CCC dyscrasia and therefore warrants early clinical attention. Show less

Semaglutide (SEM) is a glucagon-like peptide-1 (GLP-1) receptor agonist formulated for oral delivery with the absorption enhancer salcaprozate sodium (SNAC). Although oral SEM achieves 0.4-1% bioavailability through gastric epithelial uptake, gastrointestinal (GI) adverse events remain a major cause of therapy discontinuation. This study examined the effects of SEM (0.74 mg/kg/day), SNAC (22 mg/kg/day), and combined SEM-SNAC (1:33 w/w) treatments on microbiota and metabolic function, in healthy Sprague Dawley rats over 21 days. Whilst microbial α-diversity remained stable, SNAC significantly altered β-diversity (PERMANOVA, p < 0.05) and depleted primary fermenters in Muribaculaceae (-62%) and Bacteroidaceae (-77%) compared to the control group. These compositional changes correlated with reduced predicted saccharolytic enzyme abundance and fecal butyrate concentrations (-77% SNAC, -75% SEM-SNAC). Plasma cytokine analysis showed elevated tumor necrosis factor-α (TNF-α, 70%) and suppressed brain-derived neurotrophic factor (BDNF, 85%), consistent with changes in circulating inflammatory and neurotrophic markers from SNAC monotherapy. SNAC-treated animals also exhibited increased liver weight and reduced caecum mass, occurring alongside microbiota compositional changes and altered fermentation-associated markers. Spearman correlations linked Muribaculaceae and Bacteroidaceae loss with decreased saccharolytic enzyme abundance, lower SCFA levels, and increased TNF-α. While these findings are associative and require mechanistic validation, they indicate that chronic SNAC exposure is linked to concurrent microbial, metabolic, and inflammatory marker changes in healthy rats, highlighting the potential need for alternative, microbiota-safe strategies for oral peptide delivery. Show less

Electroconvulsive therapy (ECT) proves to be an effective intervention in severe cases of major depressive disorder (MDD), especially when there is resistance to pharmacological treatment. The neurotrophic hypothesis proposes that an increase in brain-derived neurotrophic factor (BDNF) is one of the mechanisms responsible for the therapeutic response. The aim of this study is to investigate the effects of ECT on peripheral levels of BDNF, measured in serum and plasma, and analyze clinical outcomes associated with this intervention, as well as identify methodological variables that may influence findings. A systematic review and meta-analysis of studies published between 1995 and 2025 on the PubMed, Scopus and Web of Science databases were conducted, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Studies of BDNF in serum (14) and plasma (6) were performed separately. Clinical effectiveness was evaluated according to average standardized differences in depression scores. Meta-regressions in the R software identified the impact of four moderators: type of ECT, number of sessions, type of anesthetic and the time blood sample was taken. ECT was associated with an increase in BDNF levels in both biological matrices, especially in studies with plasma (I Show less

Lumbrokinase belongs to a group of fibrinolytic enzymes, particularly tissue plasminogen activator (tPA), which can facilitate the proteolytic maturation of brain-derived neurotrophic factor (BDNF). Drugs administered via oral or intravenous routes are often metabolized in the liver or kidneys, and these delivery methods for brain-targeted therapies must overcome the natural barriers of the central nervous system (CNS). Intranasal drug delivery via the nose-to-brain route has emerged as a promising approach to bypass these barriers, enhance drug penetration into the brain, and minimize exposure to peripheral organs. In this study, we demonstrate that intranasally administered lumbrokinase successfully reached the brain. Behaviorally, lumbrokinase significantly improved chronic social defeat stress (CSDS)-induced social avoidance and cognitive impairments. At the molecular level, CSDS increased hippocampal precursor BDNF (proBDNF) expression and reduced mature BDNF (mBDNF) compared with control mice. Importantly, lumbrokinase treatment promoted the expression of tPA and plasmin, thereby restoring the proBDNF/mBDNF balance in the hippocampus and reversing stress-induced maladaptive behaviors. Additionally, lumbrokinase increased TrkB, PSD95, and enhanced phosphorylation of PI3K, AKT, and mTOR in the hippocampus, indicating improved synaptic signaling and plasticity. In conclusion, this study demonstrates that intranasal delivery enables lumbrokinase to reach the brain effectively, providing robust therapeutic benefits against CSDS-induced behavioral and cognitive deficits. Enhancing plasmin-mediated BDNF maturation through non-invasive intranasal enzyme delivery may represent a promising approach for treating stress-related mood disorders. Show less

To evaluate the effect of inclisiran therapy on the blood lipid profile 90 days post-injection and to describe the baseline structural and ultrasound characteristics of carotid and femoral plaques in high- and very high-risk patients who failed to achieve low-density lipoprotein cholesterol goals despite ongoing lipid-lowering treatment. This prospective observational single-center study included 22 patients (mean age 50.9±8.6 years, 50% men) with dyslipidemia and atherosclerotic plaques in peripheral arteries narrowing the lumen by 25-49%. Familial hypercholesterolemia was diagnosed in 59% of patients, and statin intolerance in 36%. Duplex scanning of the carotid and femoral arteries was performed. The gray-scale median (GSM) method is currently used for the quantitative assessment of carotid artery (CA) plaque echogenicity. Inclisiran was administered on day 1, day 90, and then every six months. Blood lipid profiles, including low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides, and lipoprotein (a) [Lp(a)], were assessed. At baseline, median concentrations were 3.7 [2.5; 5.4] mmol/l for LDL-C, 5.4 [4.4; 6.8] mmol/l for TC, and 22.0 [5.0; 108.0] mg/dl for Lp(a). Carotid artery evaluation showed a median of 4.0 [2.0; 4.0] plaques, total stenosis of 110% [63.8; 118.8], and a GSM of 38.6 [28.6; 52.4], with a predominance of heterogeneous plaques (59%). Femoral artery assessment revealed a median of 2.0 [2.0; 3.0] plaques, 75% [42.5; 111.3] total stenosis, and a minimum echogenicity of 41.5 [33.4; 57.4] gray-scale units, with 65% heterogeneous plaques. Ninety days post-initiation of inclisiran, LDL-C was reduced by 65% (to 1.3 [1.2; 2.9] mmol/L, p<0.01), TC by 30% (p<0.01), triglycerides by 35%, and Lp(a) by 33%. Inclisiran demonstrated high efficacy in reducing LDL-C levels in patients at high and very high risk of cardiovascular disease who failed to reach targets with standard therapy. The identified plaque characteristics indicate a high risk of atherothrombosis in this cohort. The dynamics of these structural plaque changes will be assessed after completing the one-year follow-up. Show less

Insulin resistance (IR) and lipoprotein(a), Lp(a), are established contributors to cardiovascular disease (CVD) risk. Whether IR modifies the association between Lp(a) and CVD in primary prevention remains uncertain. This prospective cohort study included UK Biobank participants without baseline CVD. IR at enrollment was assessed using the triglyceride-glucose index (TyG). The primary outcome was first major adverse cardiovascular event, defined as peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, or cardiovascular death. Cox models estimated adjusted hazard ratios (aHRs) with 95% CIs for log-transformed Lp(a) and TyG, adjusting for each other. Lp(a) was categorized as <125 or ≥125 nmol/L; high IR was TyG ≥75th cohort percentile. Participants were stratified into 4 joint Lp(a)/IR groups using low Lp(a)/low IR as reference. Among 328 031 participants (mean age 56.4 years; 54.7% women), 26 865 CVD events occurred over 14.6 years median follow-up (interquartile range 13.7-15.4). Per 1-SD increase, aHRs were 1.08 (95% CI, 1.06-1.09) for log-Lp(a) and 1.06 (95% CI, 1.04-1.07) for TyG, each adjusted for the other. The Lp(a) and IR each independently contribute to cardiovascular risk, with a combination offering improved risk stratification. This suggests that accounting for IR may enhance the assessment of Lp(a)-associated risk in the context of primary CVD prevention setting. Show less

Toxoplasmosis is one of the most important parasitic factors causing miscarriage in pregnant women. This cross-sectional study was conducted to evaluate some hematological parameters and cytokine levels (IL-6 and IL-27) in women who had first-trimester miscarriage due to toxoplasmosis compared to the control group. From January to December 2023, 65 women in Al-Shamiya District, Diwaniyah Governorate, central Iraq, who had previously been diagnosed with toxoplasmosis through serological testing and experienced a first-trimester miscarriage, were the subject of the current study. As controls, there were twenty healthy, non-pregnant women. Laboratory tests were performed on venous blood samples in order to evaluate hematological parameters. The slide agglutination test was also used to identify blood types, and the ELISA test was used to measure the levels of the immunological markers interleukin-6 and interleukin-27. According to the current findings, a statistically significant association was found between blood type and toxoplasmosis incidence (χ² = 12.39, df = 3, P = 0.006). This indicates a genuine association between the two variables, particularly the higher incidence among individuals with blood type B. Laboratory tests confirmed statistically significant differences between the infected women and the control group in most of the analyzed blood parameters. A marked increase in total white blood cell count was observed, while the red blood cell count decreased. The effect size and 95% confidence intervals further support the statistical reliability of the pooled data. The results confirmed a statistically significant difference (p < 0.001) in interleukin-27 levels between the two study groups. However, the mean of 88 pg/mL in the abortion group and 73 pg/mL in the control group indicated a slight increase in serum interleukin-6 levels in the women who had abortions. No statistically significant differences were observed between the two groups (p ≈ 0.16) according to the Mann-Whitney U test used, due to the large variability in the results shown by the aborted animals. The present findings represent preliminary evidence that warrants further research in order to understand the molecular or immunological mechanisms underlying the relationship between toxoplasmosis infection and hematologic parameters and immune markers among women with history of abortion. This will to help stratify the most at-risk people and establish better prevention and early detection in the future. Show less

Peripheral metabolic disorders, which drive brain insulin resistance, increase the risk of cognitive impairment, a key contributor to Alzheimer's disease. Conditioned media derived from human mesenchymal stem cells (CM-hMSCs) have shown potential for modulating neurological pathways. Male and female offspring exposed to maternal and post-weaning high-fat diet (HFD) were treated with CM-hMSCs. Spatial memory and anxiety-like behaviors were assessed along with hippocampal markers of glucose metabolism, inflammation, and Alzheimer's disease-related pathways. In male offspring, CM-hMSCs partially improved molecular pathways involved in brain glucose metabolism, as indicated by increased hippocampal mRNA expression of Glut1, Glut4, and IDE, and elevated BDNF levels. CM-hMSC treatment also modulated the inflammatory profile, with increased IL-10 and reduced IL-1β in the hippocampus. However, CM-hMSCs did not produce significant improvements in behavioral outcomes. CM-hMSCs exert early, region-specific molecular effects on hippocampal glucose metabolism and inflammatory responses in HFD-exposed male offspring. Show less

Cognitive impairment and mood disturbances are increasingly linked to underlying mechanisms such as oxidative stress, neurotransmitter dysregulation, and reduced neurotrophic support. As conventional pharmacological treatments often provide limited efficacy or are associated with tolerability concerns, there is growing scientific interest in botanical supporting strategies that may modulate the above pathways and provide complementary support for cognitive function and emotional well-being. This study aimed to investigate the mechanistic basis of a botanical association consisting of a standardized Show less

Premature coronary artery disease (CAD) poses diagnostic challenges, particularly in patients with minimal traditional risk factors. High lipoprotein(a) [Lp(a)] is an independent, genetically determined risk factor for atherosclerotic cardiovascular disease, and it contributes to early and progressive CAD. We report the case of a 35-year-old African American woman with recurrent chest pain who was diagnosed with severe multivessel CAD despite minimal traditional cardiovascular risk factors. Further evaluation revealed markedly high Lp(a) levels. She underwent successful percutaneous coronary intervention and achieved optimal low-density lipoprotein cholesterol (LDL-C) control with high-intensity statin therapy and a PCSK9 inhibitor. Despite aggressive lipid-lowering therapy, she developed recurrent angina within 6 months, and repeat coronary angiography demonstrated disease progression. This case highlights the role of high Lp(a) in driving premature and progressive CAD independent of LDL-C levels. Early identification of high Lp(a) may improve risk stratification and inform management strategies. High Lp(a) may contribute to premature and progressive CAD even with optimal LDL-C control, supporting consideration of Lp(a) testing in young patients with unexplained or familial CAD. Show less

Ischemic stroke is a leading cause of mortality and disability worldwide, and there is an urgent need for safe dietary agents with neuroprotective potential. Water-soluble tomato concentrate (WSTC), a tomato-derived functional ingredient approved in Europe for cardiovascular health, was evaluated for its protective effects against cerebral ischemia-reperfusion injury. Using a middle cerebral artery occlusion/reperfusion rat model and oxygen-glucose deprivation/reoxygenation neuronal model, we demonstrated that WSTC improved cerebral perfusion, reduced infarct volume, alleviated histopathological damage, and enhanced neurological recovery. Mechanistic studies integrating transcriptomics, network pharmacology, and molecular assays revealed that WSTC inhibited oxidative stress and neuronal apoptosis while activating the ERK/CREB/BDNF signaling pathway. These findings provide the first comprehensive evidence that WSTC confers multi-target neuroprotection and highlight its translational potential as a safe, plant-based functional food ingredient for promoting brain health and reducing ischemic injury. Show less

To identify latent family resilience profiles among families of patients with first-episode stroke in the intensive care unit (ICU) and examine factors associated with resilience heterogeneity, with the aim of informing targeted family-support interventions. A cross-sectional study was conducted among 335 ICU patients with first-episode stroke and their primary caregivers. Family resilience was assessed using the Chinese version of the Family Resilience Assessment Scale (FRAS-C). Latent profile analysis (LPA) was used to identify subgroups of family resilience, while LASSO regression and multiple binary logistic regression were applied to determine influencing factors. Two distinct resilience profiles were identified: Developing Families, characterized by lower levels of communication, resource utilization, and positive outlook; and Optimized Families, characterized by higher resilience across all dimensions. ICU admission count (OR = 2.299, 95% CI: 1.066-4.960), frequency of care and support from relatives or friends (OR = 1.851, 95% CI: 1.068-3.206), and number of additional organ system dysfunctions (OR = 0.233, 95% CI: 0.122-0.445) were significantly associated with family resilience profiles (all Family resilience among ICU first-episode stroke patients shows notable heterogeneity, with two typical resilience patterns. Early identification of high-risk families-particularly those with limited social support or higher disease complexity-can guide clinicians in delivering targeted communication support, psychological counseling, and resource linkage interventions. Tailored resilience-enhancing strategies may contribute to better patient recovery and improved family adaptation during critical care. Show less

Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we developed a clinically relevant, immunocompetent serous-like mouse model incorporating oncogenic Show less

Breast cancer patients frequently experience debilitating cancer-related fatigue (CRF) during chemotherapy. Emerging evidence implicates the gut microbiota (GM) and the gut-brain axis in CRF pathogenesis, yet whether pre-chemotherapy GM profiles can predict CRF remains unclear. This prospective cohort study enrolled 100 breast cancer patients initiating chemotherapy. GM profiling and fatigue assessment (Visual Analogue Fatigue Scale, Cancer Fatigue Scale) were performed at baseline and the third chemotherapy cycle. Serum levels of neuroimmune-endocrine markers were also measured. Multivariate logistic regression was used to build a predictive model for moderate-to-severe CRF. Patients experiencing moderate-to-severe CRF at the third chemotherapy cycle demonstrated higher baseline Baseline GM characteristics predict the risk and severity of chemotherapy-induced CRF, potentially through modulation of neuroimmune-endocrine pathways via gut-brain axis. These findings underscore the potential role of GM as a predictive biomarker and a therapeutic target for chemotherapy-induced CRF. Show less

This study aimed to identify latent classes of adherence for serum phosphorus control and their influencing factors among patients receiving Peritoneal Dialysis with hyperphosphatemia. This cross-sectional study using convenience sampling was conducted among patients receiving peritoneal dialysis with hyperphosphatemia between December 2024 and May 2025. Participants were assessed using the Phosphate Control Adherence Scale, Self-Efficacy Scale, and Family Care and Social Support Scale. Demographic and clinical data were also collected. Latent profile analysis (LPA) was used to identify adherence subgroups. Univariate analysis and multicollinearity diagnostics were performed, followed by binary logistic regression to determine predictors of adherence. Blood phosphorus control adherence can be classified into two categories: the low-level medical adherence group, characterized by poor dietary self-control (19.93%), and the high-level medical adherence group, marked by effective medication adherence (80.07%). The results indicated that residence conditions, types of medication, and self-efficacy significantly influenced blood phosphorus control adherence among patients with various forms of PD hyperphosphatemia (all p < 0.05). Patients with hyperphosphatemia undergoing peritoneal dialysis exhibit heterogeneity in adherence to serum phosphorus control. This indicates that healthcare providers should identify the adherence characteristics of different patient groups at an early stage and implement targeted intervention strategies to enhance patients' adherence to serum phosphorus management. Show less

Obesity results from the interaction of polygenic susceptibility and environmental factors. Given this complex etiology, physical activity (PA) remains a cornerstone of cost-effective intervention strategies. This longitudinal natural experiment investigated how PA modifies the effects of genetic predisposition on obesity in Chinese youth. We conducted a 4-year natural experiment leveraging curriculum-driven PA disparities in a specialized arts school (n = 591), creating distinct high-PA (HPA) and low-PA (LPA) exposure groups. Weighted genetic risk scores (WGRSs) were calculated from 13 Asian-derived obesity-related single-nucleotide polymorphisms. Annual anthropometric, metabolic, and lifestyle data were analyzed using generalized linear mixed models to assess gene-PA interactions on obesity. The WGRS predicted baseline obesity measures, with each unit increase associated with a 0.21-kg/m² higher BMI. Over the natural experiment period, BMI increases in the HPA group were smaller than in the LPA group. After adjusting for age, sex, ethnicity, and dietary factors, significant WGRS-PA interactions were observed for BMI trajectories. Participants with higher genetic risk for obesity experienced greater BMI and weight reduction benefits from sustained long-term PA. In summary, the present study identified a significant interaction effect between PA levels and WGRS in modifying BMI trajectories. Genetic susceptibility significantly modifies the protective effects of long-term PA on BMI progression in this cohort of Chinese youth. Show less

Sleep deprivation (SD) is a critical risk factor for cognitive decline and is closely linked to psychiatric disorders. The hippocampal CA2 region is critically involved in encoding social memory and regulating emotional behavior, and it has been implicated in various neuropsychiatric conditions. However, how SD affects CA2-dependent synaptic plasticity and related behaviors remains poorly understood. Here, we subjected mice to 5 h of SD via gentle handling and examined synaptic plasticity, molecular signaling, and social recognition memory. Electrophysiological recordings revealed that SD markedly impaired long-term potentiation (LTP) in CA2 and disrupted social recognition memory, as evidenced by failure to distinguish novel from familiar conspecifics. These deficits were accompanied by upregulation of adenosine A1 receptors and PDE4A5, along with reduced expression of plasticity-related proteins including PKMζ, ERK, and BDNF. Moreover, caffeine-induced synaptic potentiation was diminished in SD mice, whereas caffeine supplementation reversed both synaptic and behavioral impairments. Together, these findings demonstrate that SD compromises CA2-dependent plasticity and social cognition through adenosine receptor signaling and identify CA2 as a vulnerable, therapeutically relevant region. Targeting adenosine pathways may represent a novel strategy to mitigate sleep loss-related cognitive dysfunction in neuropsychiatric disorders. Show less

Brain derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) play crucial roles in neuronal development, synaptic transmission, and neuroplasticity. Deficits in BDNF/TrkB signalling and trafficking have been identified in several neurodegenerative diseases, including Alzheimer's disease (AD). Individuals with Down syndrome (DS) are at an increased risk of developing AD compared to the general population. Basal forebrain neurons (BFNs) are among the first to degenerate in AD and DS, but the mechanisms underlying their vulnerability remain unclear. Using BFNs derived from the Dp1Tyb mouse model of DS, we investigated neurotrophic signalling and trafficking deficits in AD-DS. We found enlarged early endosomes and elevated levels of active Rab5, a GTPase critical for early endosome formation, in Dp1Tyb BFNs. These abnormalities were associated with impaired transport of internalised TrkB from axon terminals to the soma. Using microfluidic devices, we demonstrated that axonal BDNF stimulation enhanced signalling endosome dynamics in wild-type but not Dp1Tyb BFNs, which is likely due to impaired axonal ERK1/2 signalling. Our findings establish a link between Rab5 hyperactivation, endosomal dysfunction, and impaired ERK1/2 signalling, highlighting the interplay between trafficking and neurotrophic signalling, and underscore the importance of targeting endolysosomal and signalling pathways to mitigate neuronal dysfunction in AD-DS. Show less

Organ-specific proteomic clocks are promising tools for quantifying heterogeneity in biological aging, but their longitudinal behavior remains largely unexplored. Here, we analyzed paired plasma proteomic profiles with 10-year follow-up in middle-aged adults ( Show less

To evaluate the safety, tolerability, and potential functional signals associated with cord blood serum (CBS) eye drops as adjunctive treatment in patients with open-angle glaucoma (OAG) already under intraocular pressure (IOP)-lowering therapy. In this monocentric prospective pilot study, 20 OAG patients (37 eyes) received topical CBS eye drops 8 times daily for 60 days, in addition to their standard hypotensive therapy. Ophthalmic evaluations were performed at baseline (V1), end of treatment (V4), and 60 days after discontinuation (V5), and included best-corrected visual acuity (BCVA), IOP, visual field (VF), pattern electroretinography (PERG), and retinal nerve fiber layer (RNFL) thickness. Statistical analyses assessed changes in functional and structural parameters. The treatment was well tolerated, with no adverse events and no significant changes in IOP or BCVA. Visual field mean deviation (MD), PERG parameters, and RNFL thickness showed non-significant variations across visits. A statistically significant RNFL thinning was observed in the infero-temporal sector between V1 and V4, although likely due to outlier effects. Linear mixed model analysis showed a significant increase in N95 amplitude at V5 compared to V4 when baseline MD was considered as a covariate. CBS eye drops were safe and well tolerated in this glaucoma population. Although no statistically significant functional or structural improvement was observed, some exploratory signals suggest potential neuroretinal involvement that warrants further investigation in larger, controlled studies. Show less

While the carcinogenicity of Benzo[a]pyrene (BaP) in lung adenocarcinoma (LUAD) is well-documented, the molecular mechanisms underlying BaP-driven tumorigenesis remain not fully clear. We first identified BaP-related prognostic genes for LUAD by analyzing online data and constructed prognostic models. Then diagnostic genes were screened from the aforementioned genes, and machine learning algorithms were employed to develop diagnostic models. Subsequently, single-cell and spatial transcriptomics were applied to characterize the cellular and spatial distribution of target genes, along with their gene co-localization. Molecular docking and dynamics were conducted to assess the binding affinities and stability between BaP and target proteins. In addition, we conducted some other analyses such as the correlation analysis between the expression of target genes (as well as the key genes of some pathways) and the patients' smoking status. During the construction of prognostic and diagnostic models, we identified five genes (SOD1, HK2, ACSS1, ANGPTL4, and CTBP2) that serve as core targets for BaP in the occurrence and progression of LUAD. Single-cell RNA sequencing and spatial transcriptomic analysis further validated these targets, and explained possible pathways how BaP causes LUAD, such as immunity and metabolism together with other analyses. Molecular docking and dynamics collectively revealed strong binding affinities and dynamic interactions between BaP and these targets, while the correlation analysis has also shown good results. Drug enrichment analysis highlighted tiopronin as promising therapeutic candidate for BaP-exposed populations. This study bridges BaP carcinogenesis and LUAD pathogenesis, offering translational insights for risk assessment, early diagnosis, and targeted therapy of BaP-related LUAD. Show less

White adipose tissue (WAT) expansion occurs through generation of new adipocytes from adipose progenitor cells (APC). The objective of this study was to characterize and validate a new transcriptional profile of APC. Single-cell (sc)/nuclei (sn) RNA-Seq was performed on nuclei from whole WAT (n = 20), cells from WAT stromal vascular fraction (n = 5), and cultured APC in vitro (n = 8) using ICELL8 smart-Seq technology. Additional snRNA-Seq was performed on WAT using 10x genomic platform. Pseudotime analyses and differentiation of hiPSCs was used to track the temporal patterns of novel gene signatures. Immunohistochemistry was performed to validate a new marker. A pre-adipocyte population was found across the four independent datasets that expressed known pre-adipocyte markers (ZNF423 and DLK1) in addition to genes typically associated with neurogenes (DPP10, PTRPT, CTNNA2, NRXN3, CTNNA2, PTPRD, CNTNAP2 and RBFOX1). The expression of these genes were temporally regulated with adipocyte differentiation. Immunohistochemistry analyses confirmed these pre-adipocytes are located in the neurovascular niche of WAT but are not neurons or endothelial cells. This work has defined a new transcriptional signature of pre-adipocytes in human subcutaneuous WAT that are distinct from mesencyhmal stem cell populations and represent novel targets for WAT expansion. Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by extreme hypertriglyceridemia (>1000 mg/dL), recurrent pancreatitis, and lipoprotein lipase (LPL) deficiency. FCS is caused by biallelic loss-of-function variants in LPL or in 4 other genes encoding its cofactors and regulators, including LMF1 (lipase maturation factor 1). Variants in LMF1 are rare and present only in 1% to 2% of the FCS cases. To assess in 3 patients with severe hypertriglyceridemia and recurrent pancreatitis and in whom a homozygous LMF1 duplication, initially classified as a variant of uncertain significance (VUS) was identified, post-heparin LPL activity. We collected demographics, fasting lipid profiles, and body mass index, and performed next-generation sequencing using a targeted panel that included canonical FCS genes. A homozygous in-frame duplication in LMF1 (c.914₉₂₈dup; p.Ser309_Phe310dup) was identified. Variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines and cross-referenced with public archive of reports of the relationships among human variations and phenotypes (ClinVar), The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff (HGMD), Leiden Open Variation Database (LOVD), The Single Nucleotide Polymorphism database (dbSNP), The Genome Aggregation Database (gnomAD), and in-house databases. LPL activity was assessed in post-heparin plasma using a radiometric assay. All 3 patients were homozygous for c.914₉₂₈dup (this variant was classified as a VUS) and exhibited markedly reduced LPL activity (<20% of normal). Clinical manifestations were consistent with FCS, including extreme triglyceride elevations and recurrent pancreatitis. One patient died from fulminant pancreatitis. The combined clinical, biochemical, and genetic evidence supports the reclassification of LMF1 c.914₉₂₈dup (p.Ser309_Phe310dup) as likely pathogenic according to ACMG/AMP guidelines and indicates its association with severe pancreatitis. Show less

Species from octopi to humans engage in play. This review examines how epigenetic mechanisms, such as DNA methylation, may regulate play behaviour across taxa. We frame play through historical definitions, categorizing it into object, locomotor, and social forms, and examine how each may be linked to epigenetic shifts, for example in brain-derived neurotrophic factor (BDNF) expression. We then explore the role of domestication in enhancing play via methylation of stress and sociality genes, comparing domesticated chickens, dogs, and foxes to their wild kin. We link the neurobiology of play, spanning the hypothalamic-pituitary-adrenal (HPA) axis and reward circuits, to epigenetic modulation. Assessing the evolutionary fitness advantages of play, we compare adaptive benefits against the surplus resource theory. Despite its presence in many taxa, there remains limited direct evidence for a role of epigenetic mechanisms in play, and we urge research into the developmental and adaptive roles of play across a wider range of species. Show less

Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition in Saudi Arabia, with genetic susceptibility remaining incompletely characterized. Reduced brain-derived neurotrophic factor (BDNF) activity has been implicated in MDD. The Val66Met polymorphism (rs6265), involving the substitution of valine (Val, G allele) with methionine (Met, A allele), impairs activity-dependent BDNF secretion. This study examined the frequency of Val66Met and its association with MDD in a Saudi cohort. A case-control study was conducted, including 87 patients with MDD (44 males, 43 females; mean age 44.2 ± 11.5 years) and 87 healthy controls (39 males, 48 females; mean age 28.7 ± 8.4 years). Genotyping was performed using tetra-primer amplification refractory mutation system-polymerase chain reaction. Unadjusted and age- and sex-adjusted logistic regression analyses were applied under genotype-specific, dominant, recessive, and allelic models. The Val/Val (GG) genotype was more frequent in controls than patients (54.0% vs. 34.5%), whereas the Met/Met (AA) genotype was detected exclusively in patients (21.8% vs. 0%; χ The BDNF Val66Met polymorphism is associated with MDD susceptibility in Saudis. The Met (A) allele, particularly in homozygosity, confers increased risk, while the Val/Val genotype appears protective, supporting population-specific genetic contributions to depression. Show less

Lipoprotein(a), Lp(a), is a genetically determined, lifelong risk factor for atherosclerotic cardiovascular disease (ASCVD). Despite broad guideline support for universal one-time testing, Lp(a) measurement remains rare in clinical practice. This review summarizes recent advances in machine learning-based strategies that can enhance the efficiency, yield, and equity of Lp(a) screening. To date, three studies have developed and validated machine learning models to identify individuals with elevated Lp(a) using routinely available clinical variables. The ARISE framework, derived from the UK Biobank and validated across multiple US cohorts, reduced the number needed to test by more than 50% while maintaining consistent discrimination across demographic subgroups. Additional studies have confirmed the feasibility of decision-tree and neural network models to improve case finding for elevated Lp(a) in both clinical and population-based settings. Machine learning-based strategies provide a scalable means of operationalizing universal Lp(a) testing recommendations within health systems. When developed using unbiased data, externally validated, and assessed for fairness and interpretability, these models can support systematic identification of individuals with elevated Lp(a) and integration of Lp(a) measurement into routine cardiovascular risk assessment. Show less