To assess the predictive value of serum lipoprotein(a) [Lp(a)] for contrast-induced nephropathy in patients with type 2 diabetes mellitus (T2DM). Consecutive T2DM patients who underwent coronary angio Show more
To assess the predictive value of serum lipoprotein(a) [Lp(a)] for contrast-induced nephropathy in patients with type 2 diabetes mellitus (T2DM). Consecutive T2DM patients who underwent coronary angiography (CAG) or percutaneous coronary intervention (PCI) between January 2019 and December 2021 were enrolled. Baseline Lp(a) was measured before the operation. CIN was defined as an increase in serum creatinine of more than 25% or 44 μmol within 72 h of contrast administration. The relationship between Lp(a) and CIN risk was analyzed. A total of 928 T2DM patients were included. CIN developed in 11.1% (103/928) of patients. The Lp(a) level was significantly higher in patients with CIN than in non-CIN patients (311.12 ± 278.66 vs. 254.19 ± 274.56 mg/L, A higher serum Lp(a) level indicates an increased risk of CIN in T2DM patients undergoing CAG or PCI and can serve as an independent predictor of CIN in this population. This study's findings will aid in the clinical prevention and treatment of contrast agent-induced kidney disease. Show less
To examine the causal association between obesity and osteoarthritis (OA) using an improved definition of obesity, and to identify mediating genes that may link obesity to OA pathogenesis. We analyzed Show more
To examine the causal association between obesity and osteoarthritis (OA) using an improved definition of obesity, and to identify mediating genes that may link obesity to OA pathogenesis. We analyzed data from the U.S. National Health and Nutrition Examination Survey (NHANES, 2011-2018; n = 8981). Obesity was defined using body mass index (BMI ≥ 30 kg/m²) combined with body fat percentage (BFP ≥ 25 % in men and ≥ 32 % in women). Logistic regression and subgroup analyses were conducted to evaluate associations with OA. Genetic correlation between obesity and OA was estimated using linkage disequilibrium score regression (LDSC). Two-sample Mendelian randomization (MR) was applied to assess causal effects using genome-wide association study (GWAS) summary statistics for BFP and OA. Transcriptome-wide association studies (TWAS) and colocalization analyses were performed to identify candidate genes. Mediation MR was conducted to verify their mediating roles. Obesity defined by BMI combined with BFP was significantly associated with OA (OR = 1.421, 95 %CI: 1.048-1.925, P = 0.025), and was independent of age, race, and various comorbidities. MR analysis confirmed a unidirectional causal effect of obesity on OA (IVW OR = 2.349, 95 %CI: 2.012-2.743, P < 0.001), with no reverse causality detected. TWAS and colocalization identified MAPK3, RBM6, and PRMT6 as potential mediators. Mediation MR confirmed significant effects of MAPK3 (β = 0.991, P = 0.015) and RBM6 (β = 2.740, P < 0.001) in the obesity-OA pathway. Obesity exerts a causal effect on OA, partially mediated by the downregulation of MAPK3 and RBM6. These genes represent potential targets for the prevention and treatment of obesity-related OA. Show less
The international consensus classification or the World Health Organization classifications underrepresented driver alterations enriched in pediatric acute myeloid leukemia (AML). To address this, we Show more
The international consensus classification or the World Health Organization classifications underrepresented driver alterations enriched in pediatric acute myeloid leukemia (AML). To address this, we retrospectively characterized the genomic landscape of 105 pediatric patients with AML of East Asian ancestry using transcriptome and whole-exome sequencing (WES). In addition to the common recurrent fusions such as RUNX1::RUNX1T1 and CBFB::MYH11, we identified rearrangements involving KMT2A, NUP98, GLIS, as well as FLT3 and UBTF tandem duplications. The median somatic mutation rate in AML was 0.97 per megabase, as estimated by WES. Frequently mutated pathways included signaling: 68.6% (72/105), transcription: 37.1% (39/105), epigenetic regulation: 26.7% (28/105), cohesin: 7.6% (8/105), RNA binding: 3.8% (4/105), and protein modification: 5.7% (6/105). When analyzed together, high-risk genetic subtypes including GLISr, UBTF tandem duplications, PICALM::MLLT10, and HOXr were significantly associated with poorer 5 year overall survival (OS) in multivariable analysis (p-value = 0.037). Although FLT3 internal tandem duplications were significantly associated with inferior 5 year OS in univariable analysis, this effect was not significant in multivariable analysis (p-value = 0.382). Patients with RUNX1 mutations had inferior 5 year OS in multivariable analysis (p-value = 0.009). These findings suggest specific genomic alterations that may refine risk stratification and guide future therapeutic protocols in Taiwanese pediatric patients with AML. Show less
Alzheimer's disease (AD) is a common neurodegenerative disorder wherein reactive oxygen species (ROS) and Amyloid-β-protein (Aβ) play critical roles. Inspired by traditional Chinese charcoal drug and Show more
Alzheimer's disease (AD) is a common neurodegenerative disorder wherein reactive oxygen species (ROS) and Amyloid-β-protein (Aβ) play critical roles. Inspired by traditional Chinese charcoal drug and the anti-inflammatory properties of some carbon dots, we developed Radix Isatidis derived carbon dots (RI-CDs) via a hydrothermal method. The RI-CDs can cross the blood-brain barrier (BBB) and were thus evaluated for AD therapy. In vitro, RI-CDs scavenged ROS, inhibited Aβ Show less
Internalisation of G protein-coupled receptors (GPCRs) can contribute to altered cellular responses by directing signalling from non-canonical locations, such as endosomes. If signalling processes are Show more
Internalisation of G protein-coupled receptors (GPCRs) can contribute to altered cellular responses by directing signalling from non-canonical locations, such as endosomes. If signalling processes are locally constrained, active receptors in different subcellular locations could produce different downstream effects. This phenomenon may be relevant to the optimal targeting of the glucagon-like peptide-1 receptor (GLP-1R), a type 2 diabetes and obesity target GPCR for which several ligands with varying internalisation tendency have been discovered. To investigate, we compared the signalling localisation effects of two prototypical GLP-1RAs with opposite signal bias and effects on GLP-1R trafficking: exendin-asp3 (ExD3), a full agonist that drives rapid internalisation, and exendin-phe1 (ExF1), which shows much slower internalisation. After using bioorthogonal labelling and fluorescent agonist conjugates to verify the divergent trafficking patterns of ExF1 and ExD3 in β-cell lines and primary pancreatic islets, we used live cell biosensors to monitor signalling at different subcellular locations. This revealed that cAMP/PKA/ERK signalling in β-cells is in fact distributed widely across the cell over short- (<5 min) and medium-term (up to 60 min) stimulation at pharmacological (>10 pM) concentrations, with no major differences in signal localisation that could be linked to internalised versus cell surface-bound GLP-1R. Moreover, washout experiments highlighted that, whilst fast-internalising ExD3 shows much greater accumulation and binding to GLP-1R in endosomes than slow-internalising ExF1, it is a rather inefficient driver of both cAMP production in β-cells and insulin secretion from perfused rat pancreata. These data provide a greater understanding of the cellular effects of biased GLP-1R agonism. Show less
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable s Show more
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable strategies for Show less
Glycolysis-derived lactate serves as a substrate for lysine lactylation, an epigenetic modification playing critical transcriptional regulatory roles in inflammatory diseases. Endothelial inflammation Show more
Glycolysis-derived lactate serves as a substrate for lysine lactylation, an epigenetic modification playing critical transcriptional regulatory roles in inflammatory diseases. Endothelial inflammation, characterized by upregulated glycolysis, initiates atherosclerosis, yet the contribution of histone lactylation remains undefined. Although narciclasine exhibits anti-inflammatory and antioxidant properties, its impact on endothelial inflammation in atherosclerosis is unknown. Connectivity Map (CMap) analysis predicted narciclasine as an inhibitor of oscillatory shear stress and TNF-α-induced endothelial inflammation. In vitro, treatment of human umbilical vein endothelial cells (HUVECs) with 20 nM narciclasine significantly suppressed ox-LDL-induced expression of VCAM1, ICAM1, SELE, and CCL2, reduced reactive oxygen species (ROS) production, and inhibited monocyte adhesion and migration. In vivo, administration of narciclasine (0.02 mg/kg) attenuated carotid artery endothelial inflammation and macrophage infiltration, consequently reducing early atherogenesis in partial carotid ligation model in ApoE Show less
Enzyme immobilization is critical for enhancing enzyme stability and reusability. Catalytically active inclusion bodies (CatIBs) have emerged as a promising immobilization strategy due to their straig Show more
Enzyme immobilization is critical for enhancing enzyme stability and reusability. Catalytically active inclusion bodies (CatIBs) have emerged as a promising immobilization strategy due to their straightforward production, ease of separation, and high purity. Unlike traditional cross-linked enzyme aggregates (CLEAs) that require a precipitation step, CatIBs form through carrier-free self-aggregation during expression. To overcome the limitations of conventional methods, a novel technique has been developed in this study, focusing on L-phenylserine aldolase (LPA) as the model enzyme. A hybrid tag (HLHLHL) was fused to the N-terminus of LPA to generate 3HL-LPA, which promotes the formation of active inclusion bodies. Based on structural prediction and surface properties, the active aggregation process of 3HL tags through electrostatic interactions and hydrophobic interactions was analyzed. Innovatively, we combined CatIBs and CLEAs technologies to develop novel CatIBs-CLEAs. For comparison, a control was prepared by fusing a hexahistidine tag (HHHHHH) to LPA's N-terminus (6H-LPA) to enhance soluble expression, followed by conventional CLEAs preparation. Results showed that CatIBs-CLEAs achieved an activity recovery of 69.87% after glutaraldehyde crosslinking, significantly higher than the 48.1% for conventional CLEAs. CatIBs-CLEAs also exhibited superior thermal stability across temperatures, high stability between pH 5-9, and retained over 70% activity after seven batch cycles. The integrated CatIBs-CLEAs technology combines the production advantages of CatIBs with the stability benefits of CLEAs, offering a promising strategy for designing efficient, robust industrial biocatalysts with broad application potential. Show less
Facial nerve injury (FNI) is a common peripheral neuropathy that severely impairs facial function and quality of life. Qianzheng Powder (QZP) is a traditional Chinese herbal formula used to treat faci Show more
Facial nerve injury (FNI) is a common peripheral neuropathy that severely impairs facial function and quality of life. Qianzheng Powder (QZP) is a traditional Chinese herbal formula used to treat facial paralysis clinically, yet its neuroprotective mechanisms remain unclear. This study aims to evaluate the therapeutic effects of QZP on FNI and potential underlying mechanisms. A FNI model was established in male C57BL/6 mice by performing facial nerve crush surgery. QZP (3.51 g/kg) was administered orally once daily for 14 days post-surgery. Facial function was assessed behaviorally. Tissue samples were collected on day 21 for histological evaluation, qPCR and Western blotting. Liver and kidney safety were also assessed via H&E staining and serum biochemical markers. QZP significantly improved facial motor function from day 7 post-injury. Additionally, QZP treatment mitigated neuronal loss in the facial motor nucleus, attenuated buccinator muscle atrophy, and enhanced myelin regeneration, as evidenced by increased MPZ and MBP expression. These were consistent with the increace of the BDNF, TrkB, and QZP promotes structural and functional recovery of facial nerve following injury, likely through activation of the BDNF/TrkB/CREB axis, and demonstrates a favorable safety profile. These findings support its potential as a therapeutic adjunct in peripheral nerve repair. Show less
Prior studies indicate that allyl isothiocyanate (AITC) alleviates metabolic dysfunction-associated steatotic liver disease (MASLD). The vitamin D receptor (VDR) is known to exert protective effects i Show more
Prior studies indicate that allyl isothiocyanate (AITC) alleviates metabolic dysfunction-associated steatotic liver disease (MASLD). The vitamin D receptor (VDR) is known to exert protective effects in MASLD; however, whether AITC alleviates MASLD through VDR remains unclear. To clarify the function and underlying mechanisms of AITC in MASLD AML-12 cells were exposed to 300 μM palmitate acid (PA) for 24 hours to establish an To establish an AITC provides a robust molecular basis for improving MASLD by activating hepatic VDR and driving the downstream HNF-4α/MTTP/ApoB signaling pathway. This pathway reduces hepatic lipid accumulation, promotes FA β-oxidation, and improves insulin resistance, establishing AITC as a promising treatment for MASLD. Show less
To investigate the connection betweenischemic stroke (IS) patients' risk of dying after being discharged and their residual cholesterol (RC) levels uponadmission. 2021 IS patients between the ages of Show more
To investigate the connection betweenischemic stroke (IS) patients' risk of dying after being discharged and their residual cholesterol (RC) levels uponadmission. 2021 IS patients between the ages of 35 and 80were chosen as the study's subjects, and data on deathendpoints following discharge were gathered. The doseresponse association between the risk of death and the RCat admission was examined using restricted cubic spline(RCS) regression. The hazard ratio (HR) and 95% CI werecalculated via Cox regression to analyse the associationbetween the RC level at admission and the risk of deathafter discharge in patients with IS. According to the RCS model, RC levels were nonlinearly associated with deaths from IS and other causes(P<0.001). With the median RC level as the cutoff value,the subjects were divided into two groups: a low RC group(RC<0.72 mmol/L) and a high RC group (RC≥0.72mmol/L). Compared with those in the high RC group, theage and male ratio in the low RC group were significantlygreater. The fasting blood glucose (GLU), total cholesterol(TC), triglyceride (TG), low-density lipoprotein cholesterol(LDL-C), non-high-density lipoprotein cholesterol (nonHDL-C), apolipoprotein A-1 (ApoA-1), and apolipoproteinB (ApoB) levels, as well as diabetes rates, were lower (P=0.01). Cox regression analysis revealed that withoutadjusting for covariates, the high-level RC group presenteda lower risk of all-cause death than the low-level RC group(HR=0.765, 95% CI: 0.619~0.946, P=0.013) and alower risk of death from IS (HR = 0.638, 95% CI:0.435~0.936, P=0.022). After adjusting for sex, age,smoking status, drinking status, hypertension status, anddiabetes status, the high-level group still had a lower risk ofall-cause death (HR = 760, 95% CI: 0.614~0.941,P=0.012) and a lower risk of death from IS (HR=0.653,95% CI: 0.444-0.961, P=0.031). Male sex (HR=0.753,95% CI: 0.572~0.990, P=0.042). Age ≥65 years (HR=0.598, 95% CI: 0.391~0.916, P=0.018), nonsmokingstatus (HR=0.628, 95% CI: 0.408~0.967, P=0.035),nonalcoholic status (HR=0.656, 95% CI: 0.439~0.979,P=0.039), not complicated with hypertension (HR=0.321, 95% CI: 0.108~0.957, P=0.041), no diabetesmellitus (HR=0.607, 95% CI: 0.389~0.947, P=0.028).Compared with those in the high RC group, the IS patientsin the low RC group had a lower incidence of all-causedeath, IS death and other causes of death and a higher survival rate. An RC<0.72 mmol/L at admission is associated with an increased risk of all-cause death and longterm IS death after discharge. Show less
Tumor-related metabolites in the tumor microenvironment may induce immune dysfunction, leading to malignant progression and metastasis of tumors. Here, it is demonstrated that tumoral PLA2G16, a phosp Show more
Tumor-related metabolites in the tumor microenvironment may induce immune dysfunction, leading to malignant progression and metastasis of tumors. Here, it is demonstrated that tumoral PLA2G16, a phospholipase catalyzes phospholipids to generate free fatty acid (FFA) or lysophosphatidic acid (LPA), is an important contributor to triple-negative breast cancer (TNBC) lung metastasis in an immune-dependent pattern by improving tetracosatetraenoic acid (C24:4 (n-6)) accumulation in the early metastatic niche of lung and impairing immune function of pulmonary CD8 Show less
Improving the patency rate of small-diameter vascular grafts in a pathological environment is the key to achieving their clinical translation and application. The current approach to in vivo implantat Show more
Improving the patency rate of small-diameter vascular grafts in a pathological environment is the key to achieving their clinical translation and application. The current approach to in vivo implantation evaluations of small-diameter vascular grafts is predominantly based on healthy animal models. However, the majority of patients who undergo vascular transplantation are afflicted with vascular diseases, such as hyperlipidaemia or atherosclerosis. In this study, we constructed an ApoE gene knockout atherosclerotic mouse model and investigated the patency and regenerative performance of small-diameter vascular grafts in a diseased environment. We prepared heparinized Poly (ε-caprolactone) (PCL) vascular grafts (PCL-Hep) using electrospinning technology. By taking advantage of the physical adsorption of heparin, rapamycin (RM) was loaded onto the surface of grafts to obtain PCL-Hep-RM vascular grafts, which exhibited exceptional mechanical properties and drug sustained-release characteristics. Subsequently, the PCL-Hep-RM vascular grafts were implanted into the carotid arteries of atherosclerotic mice. The results demonstrated that PCL-Hep-RM significantly enhanced the patency rate and suppressed intimal hyperplasia in comparison with the PCL control group. This study offers novel concepts and methodologies for addressing challenges such as the low long-term patency rate and luminal stenosis of vascular grafts in a diseased environment, thereby promoting the translational medicine research of small-diameter vascular grafts. Show less
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and Show more
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and genotype and allele frequencies were compared between groups. Multivariate logistic regression analyzed the link between ApoE polymorphisms and CAD risk in populations at middle and high altitudes. The data revealed significant differences in These findings validated that the Show less
Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progr Show more
Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progression, and is critically important for preventing cerebrovascular events (such as stroke, transient ischemic attack (TIA), and similar events). Mechanisms influencing plaque stability are still unclear. In this study, stable plaques (n = 5) and unstable plaques (n = 5) were collected from patients and analyzed using RNA-sequencing. 594 differently expressed genes were found by RNA-seq. Pathways enriched by KEGG analysis of differentially expressed genes included inflammation related pathway, cell adhesion related pathway and TGFβ signaling pathway. Especially, we found AMIGO1 was significantly upregulated in stable plaques. Functional assays including cell adhesion, and inflammation-related factor detection revealed that AMIGO1 significantly promotes endothelial cell adhesion while downregulating inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) production, thereby mitigating inflammatory responses. Co-immunoprecipitation (Co-IP) experiments further found that AMIGO1 interacts with transforming growth factor beta receptor II (TGFRII), stabilizing TGFRII protein levels and subsequently activating the TGFβ signaling pathway. AMIGO1 overexpression with AAV9 virus tail vein injection markedly stabilized plaques in ApoE Show less
Microglia-mediated neuroinflammation, considered one of the most plausible pathogenic hypotheses underlying Alzheimer’s disease (AD), plays a pivotal role in the initiation and progression of this dev Show more
Microglia-mediated neuroinflammation, considered one of the most plausible pathogenic hypotheses underlying Alzheimer’s disease (AD), plays a pivotal role in the initiation and progression of this devastating condition. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated promising neuroprotective effects in both preclinical and clinical studies. Previously, we developed an orally-administered GLP-1RA peptide called OHP2, which is capable of crossing the blood-brain barrier for the treatment of AD. OHP2 has been shown to effectively reduce brain inflammation in AD mouse models. In this study, we discovered that OHP2 treatment induced IL-27 secretion from astrocytes and modulated microglial reprogramming from the neurotoxic M1 phenotype to the neuroprotective M2 phenotype through glycolysis/cGAS lactylation clock/mTOR pathway, thereby alleviating excessive neuroinflammation. These findings provide a rationale for further pharmacological investigations into OHP2 and suggest that IL-27 may hold significant implications for AD therapy as a metabolic regulator. [Image: see text] The online version contains supplementary material available at 10.1186/s12974-025-03683-1. Show less
This study aims to investigate the role of DUSP6 in thyroid cancer metastasis and elucidate its underlying molecular mechanisms. Immunohistochemistry were performed to explore the expression of DUSP6, Show more
This study aims to investigate the role of DUSP6 in thyroid cancer metastasis and elucidate its underlying molecular mechanisms. Immunohistochemistry were performed to explore the expression of DUSP6, IL-8 and PAD4 in papillary thyroid carcinoma (PTC) tissues and adjacent non-cancerous thyroid tissues. Effects of DUSP6 on the proliferation, apoptosis, migration, and invasion of thyroid cancer cell lines TPC-1 and IHH4 were performed through in vitro experiments. A rescue experiment was performed to verified DUSP6 regulated the migration and invasion of thyroid cancer cells TPC-1 and IHH4 through IL-8 and neutrophil extracellular traps (NETs) formation. In addition, in vitro cell experiments were conducted to analyze the regulation of NETs formation by DUSP6 through IL-8. Finally, the effect of sh-DUSP6 on the growth of thyroid cancer tumors in mice were conducted through in vivo experiments. DUSP6 expression was significantly upregulated in PTC tissues. Moreover, the expression of DUSP6 in tumor tissues of TPC patients is positively correlated with the expression of IL-8 and PAD4. Overexpression of DUSP6 promotes the proliferation, migration, and invasion of thyroid cancer cells (TPC-1 and IHH4) while inhibiting apoptosis. Conversely, silencing DUSP6 exerts opposing effects. Knockdown of IL-8 reverses the enhanced migratory and invasive capabilities induced by DUSP6 overexpression in these cell lines. NETs treatment enhances the migration and invasion of TPC-1 and IHH4 cells, whereas the application of sh-DUSP6 or sh-IL-8 counteracts this NETs-mediated promotion. Furthermore, DUSP6 overexpression facilitates NETs formation by upregulating IL-8 expression. In vivo experiments demonstrate that sh-DUSP6 suppresses thyroid cancer tumor growth in mouse models. Conclusion: DUSP6 promotes the metastasis of thyroid cancer by facilitating the formation of neutrophil extracellular traps via IL-8. Show less
Coronary artery calcification (CAC) signifies advanced atherosclerosis and portends increased cardiovascular risk. Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerosis; however, its asso Show more
Coronary artery calcification (CAC) signifies advanced atherosclerosis and portends increased cardiovascular risk. Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerosis; however, its association with in vivo lesion morphology and clinical outcomes in patients with symptomatic, advanced CAC remains incompletely characterized. This study aimed to investigate the association between elevated Lp(a) levels and both in vivo lesion morphology and clinical outcomes in this high-risk population. In this retrospective cohort, 292 patients with intravascular ultrasound(IVUS)-confirmed CAC were stratified into elevated (≥50 mg/dL,n = 77) or low (<50 mg/dL,n = 215) Lp(a) groups. The primary endpoint was major adverse cardiovascular events (MACEs). Associations were assessed via multivariable Cox models adjusted for clinical covariates. Patients in the elevated Lp(a) group presented a greater incidence of aortic valve calcification (p < 0.001). IVUS revealed constrictive remodeling with a smaller lumen and vessel dimensions. During a median follow-up of 17.2 months, the elevated Lp(a) cohort had a significantly higher MACE rate (37.7% vs. 15.8%; adjusted hazard ratio [aHR] 2.60, 95% CI 1.55-4.35, p < 0.001). Elevated Lp(a) independently predicted increased risks of ischemic stroke (aHR 7.14) and in-stent restenosis (aHR 2.78). In symptomatic patients with IVUS-confirmed CAC, elevated Lp(a) identifies a high-risk phenotype characterized by constrictive vascular remodeling and a markedly increased risk of MACEs, driven particularly by ischemic stroke and in-stent restenosis. These findings support the integration of routine Lp(a) testing into the risk stratification of patients with severe CAC, thereby identifying a precise high-risk phenotype that warrants intensified monitoring and represents an ideal target for emerging Lp(a)-lowering therapies. Show less
Breast cancer is the most frequently diagnosed cancer, with metastasis accounting for the majority of cancer-related deaths. The mechanisms of early-stage breast cancer metastasis to regional immune s Show more
Breast cancer is the most frequently diagnosed cancer, with metastasis accounting for the majority of cancer-related deaths. The mechanisms of early-stage breast cancer metastasis to regional immune sites like lymph nodes remain elusive. Here, we performed an in-depth proteomic and phosphoproteomic analysis of a substantial series of breast cancer samples, alongside genomic and transcriptomic evaluations. This cohort encompasses 195 specimens: 65 primary breast tumors, their corresponding normal tissues, and metastatic axillary lymph nodes. We offer an overview of the molecular alterations at the transcriptomic, proteomic, and phosphoproteomic levels during lymph node metastasis. Notably, the findings indicate that regional lymph node metastasis is primarily influenced by proteomic and phosphoproteomic alterations, rather than genomic or transcriptomic changes. We found the ANGPTL4 and HMGB1 could serve as the biomarker of lymph node metastasis. Data analysis and cell experiments involving silencing of the alternative splicing factor HNRNPU demonstrated that alternative splicing plays a significant role in modulating protein expression, phosphorylation profiles and cell proliferation. The key phosphorylation sites, including MARCKSL1-S104 and FKBP15-S320, as well as the upstream kinase PRKCB, were identified as playing crucial roles in breast cancer lymph node metastasis. Targeted intervention of the kinase PRKCB resulted in effectively suppressing the proliferation and metastasis of breast cancer tumor cells. Immune profiling analysis and experimental validation of breast cancer cell cocultured with CD8+ T cell reveals correlations between phosphorylation of MARCKSL1-S104 and FKBP15-S320 with immune checkpoint PD-L1 expression, and their impact on tumor cell apoptosis, suggesting a potential mechanism of immune evasion in metastasis. This study systematically characterizes the molecular landscape and features of primary breast tumors and their matched metastatic lymph nodes. These insights enhance our understanding of early-stage breast cancer metastasis and may pave the way for improved diagnostic tools and targeted therapeutic strategies. Show less
To evaluate the apolipoprotein B (ApoB) to apolipoprotein A-I (ApoA-I) ratio as a biomarker for coronary heart disease (CHD) and its clinical phenotypes, beyond traditional lipid parameters. This sing Show more
To evaluate the apolipoprotein B (ApoB) to apolipoprotein A-I (ApoA-I) ratio as a biomarker for coronary heart disease (CHD) and its clinical phenotypes, beyond traditional lipid parameters. This single-center, case-control study analyzed 7,277 patients undergoing coronary angiography. Multivariable logistic regression assessed the independent association of the ApoB/ApoA-I ratio with CHD, acute myocardial infarction (AMI), multivessel disease (MVD), and percutaneous coronary intervention (PCI). Predictive performance was evaluated via ROC curve analysis, with prespecified subgroup analyses. The ApoB/ApoA-I ratio was the strongest independent lipid predictor of CHD (adjusted OR 4.49, 95% CI 1.98-10.19). It significantly predicted severe clinical phenotypes: AMI (OR 1.94, 95% CI 1.44-2.62), MVD (OR 1.67, 95% CI 1.24-2.26), and PCI requirement (OR 1.95, 95% CI 1.43-2.66). The ratio showed significant discriminatory power for all endpoints (AUCs 0.569-0.608). Subgroup analyses revealed markedly stronger associations in males, older adults (≥60 years), and hypertensive patients, but substantially attenuated predictive value in diabetic patients. The ApoB/ApoA-I ratio is a superior biomarker for CHD risk stratification, particularly for identifying severe disease manifestations and guiding revascularization decisions in specific patient subgroups. Its integration into clinical practice could enable more precise cardiovascular risk management. Show less
Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. T Show more
Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence. Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry. Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6 INTS6 The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival. Show less
Hepatotoxicity induced by environmental pollutants can be regulated at the transcriptional, translational, and post-translational levels. However, few studies have investigated the changes in liver ac Show more
Hepatotoxicity induced by environmental pollutants can be regulated at the transcriptional, translational, and post-translational levels. However, few studies have investigated the changes in liver acetylomics caused by pollutant exposure. In the present study, we demonstrated that perfluorooctanoate (PFOA) and its potential alternative, perfluoro-(3,5,7,9-tetraoxadecanoic) acid (PFO4DA), modified the liver acetylation profile in male mice exposed to 10 mg/kg/d PFOA or PFO4DA for 28 days. Relative to the control group, liver proteins in the exposed mice exhibited altered acetylation patterns, with 1508 and 498 differentially acetylated sites identified in the PFOA- and PFO4DA-exposed groups, respectively. These modifications were not confined to lipid metabolism, but also extended to the urea cycle and hyperammonemia. Furthermore, in vitro and in silico experiments revealed that mutation of CPS1-1168K to CPS1-1168R restored enzymatic activity under PFOA/PFO4DA exposure, while mutation to CPS1-1168Kac reduced the adenosine triphosphate (ATP) binding capacity, suggesting that CPS1-1168K may be a key acetylation site for PFOA and PFO4DA disruption of the urea cycle. Additionally, both chemicals exhibited the potential to compete with ATP for the ATP-binding site, which is essential for CPS1 activity. These findings contribute to understanding the mechanisms underlying PFAS toxicity and support the establishment of an adverse outcome pathway framework. Show less
This study explores the influence of congruence and incongruence in father-mother co-parenting on adolescent depression, as well as the mediating effect of self-esteem. A total of 1389 adolescents com Show more
This study explores the influence of congruence and incongruence in father-mother co-parenting on adolescent depression, as well as the mediating effect of self-esteem. A total of 1389 adolescents completed questionnaires assessing their levels of depression and self-esteem, while their fathers and mothers correspondingly reported on their own co-parenting behaviors using the Parental Co-parenting Scale in this cross-sectional study. Dates were analyzed using LPA, RSA, and mediation consecutively. The results show that: (1) We identified three distinct co-parenting profiles: positive parental co-parenting, negative parental co-parenting, and mixed parental co-parenting. (2) In cases of congruent parental co-parenting, high positive parental co-parenting was associated with lower adolescent depression, whereas high negative parental co-parenting was linked to higher depression, and the difference manifests in different forms among boys and girls. Girls showed nonlinear changes in depression while boys exhibited linear trends. (3) In cases of incongruence in parental co-parenting, mothers' co-parenting exerted a stronger influence on boys' depression, while girls were not affected by mothers' and fathers' discrepancies. (4) Self-esteem mediated the relationship between parental co-parenting (in)congruence and depression across both genders. This study provides evidence for the mechanism through which parental coparenting influences adolescent depression and offers a basis for future interventions targeting adolescent depression. Show less
C1q/TNF-related proteins (CTRPs) belong to the adipokine family. Here, we aimed to assess the relation of CTRP4 levels in serum and perivascular adipose tissue (PVAT) with coronary artery disease (CAD Show more
C1q/TNF-related proteins (CTRPs) belong to the adipokine family. Here, we aimed to assess the relation of CTRP4 levels in serum and perivascular adipose tissue (PVAT) with coronary artery disease (CAD), and investigate the effect of CTRP4 on atherosclerosis and the underlying mechanisms. CTRP4 levels were examined in serum and epicardial adipose tissue (a major PVAT) from patients with CAD. Atherosclerotic lesions were analysed in CTRP4 CTRP4 levels were lower in serum and epicardial adipose tissue of patients with CAD compared to non-CAD controls. CTRP4 knockout promoted atherosclerosis in ApoE Decreased CTRP4 levels in serum and epicardial adipose tissue are associated with CAD in patients. CTRP4 deficiency promotes the development of atherosclerosis in ApoE Show less
Neuropathic pain (NP) frequently co-occurs with depression (DP), exhibiting complex pathogenesis and limited clinical treatment options. This study aims to investigate the efficacy of Eupalinolide B ( Show more
Neuropathic pain (NP) frequently co-occurs with depression (DP), exhibiting complex pathogenesis and limited clinical treatment options. This study aims to investigate the efficacy of Eupalinolide B (EB) in alleviating NP co-occurring with DP and its potential molecular mechanisms. Combining network pharmacology, molecular docking, and molecular dynamics simulations to screen potential targets for EB, validated through transcriptomic data. Using a sciatic nerve branch-preserving injury (SNI) mouse model, we assessed pain and depression-like behaviors through von Frey testing, hot plate testing, tail suspension testing, forced swimming testing, and open field testing. Concurrently, Western blotting, immunofluorescence, and Nissl staining were employed to analyze relevant molecules and neuropathological alterations. Network pharmacology and bioinformatics analysis identified EGFR, PTGS2, and JUN as the key targets for EB in treating NP combined with DP. Behavioral studies showed that 20 mg/kg of EB significantly alleviated pain in SNI mice and improved depressive-like behaviors. Mechanism research indicated that EB downregulated the expression of EGFR and PTGS2, inhibited the activation of microglia and astrocytes, and reduced neuronal damage. Additionally, EB could upregulate the expression of synaptic proteins (PSD95, SYN1, and BDNF) in the hippocampus. EB alleviates neuroinflammation by reducing EGFR and PTGS2 protein expression, modulates synaptic plasticity, and improves pain-depression comorbidity. EB may represent a promising therapeutic approach for pain-related depression. Show less
To evaluate the current status and latent profiles of caregiver self-care contributions for patients with chronic obstructive pulmonary disease (COPD) and examine the associations between demographic Show more
To evaluate the current status and latent profiles of caregiver self-care contributions for patients with chronic obstructive pulmonary disease (COPD) and examine the associations between demographic characteristics, health literacy, confidence in self-care contributions, family intimacy, and profile membership. We recruited 275 dyads of patients with COPD and their family caregivers from five tertiary hospitals between May and November 2022 using convenience sampling. Latent profile analysis (LPA) was used to identify distinct profiles of caregiver self-care contributions. Univariate analysis and multinomial logistic regression were subsequently conducted to examine associations between participant characteristics and profile membership. LPA identified four distinct profiles of caregiver self-care contributions: low-contributing, under-monitored, maintenance-prioritized, and high-contributing. Significant differences were observed across these profiles in terms of patients' symptom severity, exacerbation frequency, number of hospitalizations, caregivers' education levels, caregiving duration, health literacy, confidence in self-management contributions, and family intimacy using univariate analysis. Multinomial logistic regression analysis revealed that caregivers' education levels, caregiving duration, confidence in self-management contributions, and health literacy were significant predictors of profile membership. Caregiver self-care contributions for patients with COPD can be characterized by four distinct profiles, with caregivers' educational level, health literacy, and confidence in self-management identified as key factors associated with profile membership. Show less
Human embryonic stem cell (hESC)-derived hepatocytes (hEHs) display functional deficits, particularly impaired albumin secretion and ammonia metabolism, compared to primary human hepatocytes (PHHs). H Show more
Human embryonic stem cell (hESC)-derived hepatocytes (hEHs) display functional deficits, particularly impaired albumin secretion and ammonia metabolism, compared to primary human hepatocytes (PHHs). Here, we investigated the regulatory role of CCAAT/enhancer-binding protein beta (C/EBPβ) in hepatocyte maturation. Forced C/EBPβ expression enhanced hepatocyte functionality and upregulated hepatocyte-specific genes, while suppressing epithelial-mesenchymal transition (EMT) via downregulating canonical EMT markers. Mechanistically, CUT&Tag and luciferase reporter assays confirmed C/EBPβ directly binds to the promoter regions of CDH1 (E-cadherin) and CPS1 (carbamoyl phosphate synthetase 1). Co-immunoprecipitation identified an interaction between C/EBPβ and the MAPK pathway. RNA interference combined with Western blot analysis revealed that MAPK1-mediated phosphorylation of C/EBPβ at Thr-235 augmented its transactivation activity, accelerating hepatocyte maturation. Our findings establish C/EBPβ as a master regulator that coordinates transcriptional networks and post-translational modifications during hEHs maturation, providing novel insights for generating mature hepatocytes for disease modeling and regenerative medicine applications. The transcriptional activity of C/EBPβ is regulated by MAPK1 protein within the ERK/MAPK signaling pathway. MAPK1 moves from the cytoplasm into the nucleus and transfers phosphate groups to C/EBPβ. This process reverses the "self-inhibition" state of C/EBPβ and enhances its transcriptional activity on downstream target genes. Show less
FURIN cleaves a subset of proproteins into functional mature fragments. Evidence suggests that FURIN is involved in brain development and the associated diseases, whereas the potential mechanisms rema Show more
FURIN cleaves a subset of proproteins into functional mature fragments. Evidence suggests that FURIN is involved in brain development and the associated diseases, whereas the potential mechanisms remain incompletely understood. Here, we report that cerebral FURIN-deficient mice exhibit cognitive decline and neurodegeneration. Lipid droplets (LDs) that are preferentially accumulated in astrocytes correlate with an increase of the LD markers PLIN2 and PLIN3, and conversely a decreased level of autophagic proteins including ATG5, BECN1 and MAP1LC3/LC3 as well as LAMP1. Accordingly, silencing of Show less
To explore the association between apolipoprotein E (APOE) gene polymorphisms and the risk of premature (age of onset: men ≤ 55 years old, women ≤ 65 years old) myocardial infarction (PMI). This study Show more
To explore the association between apolipoprotein E (APOE) gene polymorphisms and the risk of premature (age of onset: men ≤ 55 years old, women ≤ 65 years old) myocardial infarction (PMI). This study retrospectively collected the medical records (age, gender, hypertension, diabetes mellitus, smoking, drinking, and serum lipid) of 379 PMI patients and 628 age-matched non-AMI individuals (controls), from December 2018 to March 2024. The relationship between APOE polymorphisms and PMI was analyzed. 15(1.5%) individuals carried ɛ2/ɛ2, 147(14.6%) had ɛ2/ɛ3, 16(1.6%) presented with ɛ2/ɛ4, 670(66.5%) were ɛ3/ɛ3 carriers, 149(14.8%) had ɛ3/ɛ4, and 10 (1.0%) carried ɛ4/ɛ4. The proportion of ɛ2/ɛ3 genotype was significantly lower in the PMI group than in controls (7.7% vs. 18.8%, p < 0.001), whereas the prevalence of ɛ3/ɛ4 genotype was substantially higher in the PMI group (20.6% vs. 11.3%, p < 0.001). Logistic regression analysis identified some associated factors: smoking (odds ratio [OR]: 3.057, 95% confidence interval [CI]: 2.098-4.455, p < 0.001), hypertension (OR: 4.474, 95% CI: 3.273-6.117, p < 0.001), and dyslipidemia (OR: 1.805, 95% CI: 1.333-2.443, p < 0.001). Additionally, genetic factors were associated with PMI: the APOE ɛ3/ɛ4 genotype (vs. ɛ3/ɛ3, OR: 1.548, 95% CI: 1.038-2.309, p = 0.032) and the presence of ɛ4 allele (vs. ɛ3, OR: 1.521, 95% CI: 1.033-2.241, p = 0.034) were confirmed as independent associated factors. APOE ε3/ε4 genotype was significantly associated with PMI, suggesting that this genotype could serve as a potential genetic marker for PMI risk assessment. Show less
Influenza vaccination coverage among older adults in China is low. We sought to identify latent vaccine-hesitancy profiles and their correlates. This community-based cross-sectional survey from May to Show more
Influenza vaccination coverage among older adults in China is low. We sought to identify latent vaccine-hesitancy profiles and their correlates. This community-based cross-sectional survey from May to July 2025 involved 1773 older adults from various areas in Jiangsu province. Data were collected via Wenjuanxing and included demographics, the Influenza Vaccine Hesitancy Scale, and the vaccine literacy scale. Group differences were examined using chi-square tests and one-way ANOVA; latent profile analysis (LPA) identified vaccine hesitancy subgroups, and multinomial logistic regression estimated correlates of profile membership. Three profiles emerged: Low Hesitancy (23.0%), Moderate Hesitancy (35.0%), and High Hesitancy (42.0%). Rural residence predicted Moderate (OR = 2.030) and High (OR = 2.993) hesitancy. Lower household income and chronic disease were associated with the Moderate Hesitancy profile, whereas male sex was associated with the High Hesitancy profile. Higher interactive (OR = 0.686) and critical (OR = 0.599) vaccine literacy were inversely associated with High hesitancy.Concerns about vaccine quality predicted both Moderate (OR = 1.433) and High (OR = 1.376) groups; knowledge gaps and fear of adverse reactions concentrated in the High group. Older adults show heterogeneous vaccine hesitancy phenotypes. Uptake efforts should move beyond one-size-fits-all messaging toward segmented strategies. These strategies should integrate cost-related measures with literacy-sensitive, trust-oriented communication, prioritizing rural residents, older men, and those with chronic conditions. The reported proportions of hesitancy profiles reflect our sample only and should not be viewed as nationally representative. Show less