👤 Ying Cui

Vascular calcification (VC) significantly increases the incidence and mortality of many diseases. The causal relationships of dyslipidaemia and lipid-lowering drug use with VC severity remain unclear. This study explores the genetic causal associations of different circulating lipids and lipid-lowering drug targets with coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC). We obtained single-nucleotide polymorphisms (SNPs) and expression quantitative trait loci (eQTLs) associated with seven circulating lipids and 13 lipid-lowering drug targets from publicly available genome-wide association studies and eQTL databases. Causal associations were investigated by univariable, multivariable, drug-target, and summary data-based Mendelian randomization (MR) analyses. Potential mediation effects of metabolic risk factors were evaluated. MR analysis revealed that genetic proxies for low-density lipoprotein cholesterol (LDL-C), triglycerides (TC) and Lipoprotein (a) (Lp(a)) were causally associated with CAC severity, and apolipoprotein B (apoB) level was causally associated with AAC severity. A significant association was detected between hepatic Lipoprotein(A) (LPA) gene expression and CAC severity. Colocalisation analysis supported the hypothesis that the association between LPA expression and CAC quantity is driven by different causal variant sites within the ±1 Mb flanking region of LPA. Serum calcium and phosphorus had causal associations with CAC severity. Inhibitors targeting LPA might represent CAC drug candidates. Moreover, T2DM, hypercalcemia, and hyperphosphatemia are positively causally associated with CAC severity, while chronic kidney disease and estimated glomerular filtration rate are not. Show less

Growing evidence suggests that lipid metabolism may play a crucial role in mood disorder pathophysiology, and the correlation between blood lipids and mood disorder remains further clarified. This prospective, population-based cohort study utilized data from the UK Biobank. The study included 268,098 and 292,121 participants who had never been diagnosed with depression or bipolar disorder and who had complete data at both the baseline and follow-up points. A principal component analysis (PCA) was conducted on seven blood lipids, and the first three principal components (PCs) were derived. Cox regression analysis was employed to examine the correlation between the risk of mood disorders and the PCs. Multiplicative interaction and sensitivity analyses were also conducted. The relationship between blood lipids and neurological biomarkers was explored using Spearman's analysis. PC1, primarily reflecting levels of Apolipoprotein B (ApoB), cholesterol, and low-density lipoprotein cholesterol (LDL-C), showed a protective effect against depression, with HRs of 0.98 (95 % CI: 0.96,1.00) in the fully adjusted Cox regression model. In contrast, PC2, characterized by opposite loadings for triglycerides and high-density lipoprotein cholesterol (HDLC), was positively associated with the risk of depression and bipolar disorder.(HR = 1.03,95 % CI: 1.01,1.06; HR = 1.11, 95 % CI: 1.01,1.23). Increased PC2 level was related to a significant increase in bipolar disorder risk among participants with high genetic risk (genetic risk score > 90 %, HR = 1.22, 95 % CI: 1.02,1.46). Complicated correlations between blood lipids and serum neuroproteins were detected. These findings suggest complex associations between blood lipid profiles and the risk of depression and bipolar disorder. Show less

To investigate the causal relationship between various lipid-modifying drugs and new-onset diabetes, as well as the mediators contributing to this relationship. Mediation Mendelian randomization was performed to investigate the causal effect of lipid-modifying drug targets on type 2 diabetes (T2D) outcomes and the proportion of this association that is mediated through ectopic fat accumulation traits. Specific sets of variants in or near genes that encode 11 lipid-modifying drug targets (LDLR, HMGCR, NPC1L1, PCSK9, APOB, ABCG5/ABCG8, LPL, PPARA, ANGPTL3, APOC3, and CETP; for expansion of gene symbols, use search tool at www.genenames.org) were extracted. Random effects inverse variance weighted were performed to evaluate the causal effects among outcomes. Mediation analyses were performed to identify the mediators of the association between lipid-modifying drugs and T2D. The study was conducted from November 10, 2023, to April 2, 2024 RESULTS: The genetic mimicry of HMGCR and APOB inhibition was associated with an increased T2D risk, whereas the genetic mimicry of LPL enhancement was linked to a lower T2D risk. Gluteofemoral adipose tissue volume was a mediator for explaining 9.52% (P=.002), 16.90% (P=.03), and 10.50% (P=.003) of the total effect of HMGCR, APOB, and LPL on T2D susceptibility, respectively. Liver fat was a mediator for explaining 21.12% (P=.005), 12.28% (P=.03), and 9.84% (P=.005) of the total effect of HMGCR, APOB, and LPL on T2D susceptibility, respectively. Our findings support the hypothesis that liver fat and gluteofemoral adipose tissue play a mediating role in the prodiabetic effects of HMGCR and APOB inhibition, as well as in the antidiabetic effects of LPL enhancement. Show less

Studies using machine learning to identify the target characteristics and develop predictive models for coronary artery disease severity in patients with premature myocardial infarction (PMI) are limited. In this observational study, 1111 PMI patients (≤55 years) at Tianjin Chest Hospital from 2017 to 2022 were selected and divided according to their SYNTAX scores into a low-risk group (≤22) and medium-high-risk group (>22). These groups were further randomly assigned to a training or test set in a ratio of 7:3. Lasso-logistic was initially used to screen out target factors. Subsequently, Lasso-logistic, random forest (RF), k-nearest neighbor (KNN), support vector machine (SVM), and eXtreme Gradient Boosting (XGBoost) were used to establish prediction models based on the training set. After comparing prediction performance, the best model was chosen to build a prediction system for coronary artery severity in PMI patients. Glycosylated hemoglobin (HbA1c), angina, apolipoprotein B (ApoB), total bile acid (TBA), B-type natriuretic peptide (BNP), D-dimer, and fibrinogen (Fg) were associated with the severity of lesions. In the test set, the area under the curve (AUC) of Lasso-logistic, RF, KNN, SVM, and XGBoost were 0.792, 0.775, 0.739, 0.656, and 0.800, respectively. XGBoost showed the best prediction performance according to the AUC, accuracy, F1 score, and Brier score. In addition, we used decision curve analysis (DCA) to assess the clinical validity of the XGBoost prediction model. Finally, an online calculator based on the XGBoost was established to measure the severity of coronary artery lesions in PMI patients. In summary, we established a novel and convenient prediction system for the severity of lesions in PMI patients. This system can swiftly identify PMI patients who also have severe coronary artery lesions before the coronary intervention, thus offering valuable guidance for clinical decision-making. Show less

Cardiovascular diseases caused by atherosclerosis (AS) are the leading causes of disability and death worldwide. Apolipoprotein B (ApoB), the core protein of low-density lipoproteins, is a major contributor to cardiovascular disease-related morbidity and mortality, with apolipoprotein B (ApoB) playing a critical role in its pathogenesis. However, no bibliometric studies on the involvement of ApoB in AS have been published. This study aimed to conduct a comprehensive bibliometric analysis to explore the current and future trends regarding the role of ApoB in AS. Utilizing the Web of Science Core Collection, a thorough search was conducted for ApoB in AS-related papers related to research on ApoB in the field of AS during 1991-2023. The analysis focused on annual publication trends, leading countries/regions and institutions, influential authors, journal and key journals. CiteSpace and VOSviewer were employed to visualize reference co-citations, and keyword co-occurrences, offering insights into the research landscape and emerging trends. This bibliometric analysis employed network diagrams for cluster analysis of a total of 2105 articles and reviews, evidencing a discernible upward trend in annual publication volume. This corpus of research emanates from 76 countries/regions and 2343 organizations, illustrating the widespread international engagement in ApoB-related AS studies. Notably, the United States and the University of California emerge as the most prolific contributors, which underscores their pivotal roles in advancing this research domain. The thematic investigation has increasingly focused on elucidating the mechanistic involvement of ApoB in atherosclerosis, its potential as a diagnostic biomarker, and its implications for therapeutic strategies. This bibliometric analysis provides the first comprehensive perspective on the evolving promise of ApoB in AS-related research, emphasizing the importance of this molecule in opening up new diagnostic and therapeutic avenues. This study emphasizes the need for continued research and interdisciplinary efforts to strengthen the fight against AS. Furthermore, it emphasizes the critical role of international collaboration and interdisciplinary exploration in leveraging new insights to achieve clinical breakthroughs, thereby addressing the complexities of AS by focusing on ApoB. Show less

Atherosclerosis (AS) is a chronic inflammatory disorder driven by dysregulated lipid metabolism and remains a leading cause of cardiovascular morbidity. The Shen-Hong-Tong-Luo (SHTL) preparation has demonstrated clinical benefit in stabilizing atherosclerotic plaques, yet its molecular mechanisms are not fully defined. This research sought to elucidate the protective effects exerted by SHTL on AS progression. To investigate the impact of SHTL on macrophage function and plaque stability, we utilized ApoE SHTL markedly attenuated the progression of AS, demonstrated by reduced plaque formation within both the aortic root and aorta, diminished plasma lipid concentrations, and suppressed inflammatory responses. SHTL demonstrates significant anti-inflammatory and lipid-regulatory effects, attenuating AS progression through the PPARγ/Mfge8 pathway, thereby enhancing macrophage efferocytosis. These findings highlight a novel mechanism by which SHTL may contribute to preventing and treating atherosclerotic diseases. Show less

Extensive research has demonstrated that gut microbiota and its metabolites-including short-chain fatty acids, trimethylamine N-oxide (TMAO), and bile acids-play a crucial role in the pathophysiology of coronary artery disease (CAD).The bidirectional interaction between the gut microbiota and the cardiovascular system significantly influences host metabolic and inflammatory homeostasis. As a result, targeted modulation of the gut microbiota emerges as a promising adjunctive therapeutic strategy for CAD, offering potential benefits with minimal side effects. This study aims to elucidate the therapeutic mechanisms of the clinically validated Chinese medicine formula HJ11 in mitigating coronary heart disease (CHD), with a particular focus on its regulation of the heart-gut axis and associated atherosclerotic processes. This study established an ApoE-/- mouse model of atherosclerosis and treated with HJ11 via gavage.We investigated the effects of HJ11 on the gut microenvironment in these atherosclerotic mice. Gut microbial composition and faecal metabolite profiles were analyzed using 16S rDNA sequencing and metabolomics. Additionally, an in vitro model of atherosclerosis was used to examine whether HJ11 exerts anti-inflammatory effects by modulating the TLR4/MYD88/IκB-α signaling pathway. HJ11 exerted protective effects on coronary atherosclerosis by reducing systemic serum lipid levels and inhibiting plaque formation, vascular inflammation, and collagen deposition, while also alleviating aortic injury. It suppressed endothelial inflammation and inhibited the proliferation of vascular smooth muscle cells. In the gut, HJ11 alleviated intestinal structural damage and enhanced barrier integrity. Notably, it promoted the function of Akkermansia, a beneficial bacterium known to influence TLR4 expression. Finally, in an in vitro atherosclerosis model, HJ11 decoction inhibited cell proliferation and migration by inactivating the TLR4/MYD88/IκB-α signaling pathway-an effect that was abolished by TLR4 overexpression. Show less

This study aims to identify oxidative stress-related genes (OSGs) in papillary thyroid carcinoma (PTC) and their common targets with resveratrol. Oxidative stress-related differentially expressed genes (OS-DEGs) were identified by intersecting datasets. The screened core genes were utilized to construct a prognostic model, and their prognostic value, along with their associations with clinical pathological characteristics and immune infiltration, was assessed. Subsequently, the core targets at the intersection of resveratrol and oxidative stress (OS) in PTC were screened, and their binding properties with resveratrol were analyzed. By conducting cross-database analysis, 38 OS-DEGs were identified, and 3 core genes APOE、CDKN2A、APOD were determined. The prognostic model based on core genes exhibited robust prognostic capabilities. The core genes displayed significant correlations with various clinical pathological parameters and a range of immune cells. Additionally, 13 targets of resveratrol for antioxidative stress were screened from databases. 6 high-performing targets, JUN, TGFB1, BCL2, CDKN1A, FOS, ICAM1, were revealed by topological analysis, all exhibiting binding energies lower than - 5.0 kcal/mol. Our study is the pioneering research to provide new insights into the diagnosis, prognosis, and treatment of PTC through the analysis of OSGs, presenting potential clinical implications. Furthermore, this research reveals the molecular functions associated with resveratrol and its pharmacological targets regulating OS in PTC for the first time. Show less

Abnormal glymphatic system may play a critical role in amyloid-β (Aβ) accumulation in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) patients. This study aims to use diffusion tensor image analysis along the perivascular space (DTI-ALPS) and perivascular space volume fraction (PVSVF) to investigate the aberrant glymphatic functions and the association between Aβ deposition and clinical symptoms in AD spectrum. The ALPS index was significantly lower in AD patients compared to MCI and normal controls (NC) groups. Additionally, the AD group showed a significantly higher PVSVF in hippocampus (HP) compared to NC group. No notable variations were observed in the ALPS index or PVSVF across various regions when comparing the MCI group to the NC group. Apolloprotein E (APOE) ε4 + group showed significantly higher PVSVF-HP and PVSVF in basal ganglia compared to APOE ε4 − group. All participants’ HP volume, lower cognitive scores, and higher Our findings demonstrate that glymphatic dysfunction is associated with cognitive decline, underscoring the critical roles of Aβ pathology and the APOE genotype in mediating this relationship. Further exploration of glymphatic function holds significantly promise for advancing research on AD pathogenesis. The online version contains supplementary material available at 10.1186/s13550-025-01339-y. Show less

The Wnt/β-catenin signaling pathway is a classical pathway that regulates bone metabolism. The G protein inhibitory α subunits 1 and 3 (Gαi1/3) can couple with multiple growth factor/cytokine receptors and act as universal adaptor proteins to mediate the activation of key downstream signaling pathways. However, it remains unclear whether and how Gαi1/3 proteins mediate Wnt/β-catenin signal transduction. In this study, we utilized single-cell sequencing analysis and employed viral transfection and gene editing techniques to alter the expression of Gαi1/3 in mouse embryonic osteoblast precursor cells. We examined the relationship between Gαi1/3 expression and the Wnt/β-catenin signaling pathway. Immunoprecipitation and confocal experiments were conducted to further explore the mechanisms by which Gαi1/3 exerts its functions. Osteogenic-related protein levels were detected by Western blotting, and the effects of Gαi1/3 proteins on osteogenic function were examined through alkaline phosphatase and Alizarin red staining. Additionally, micro-CT was used to compare bone mass in mice with different levels of Gαi1/3 expression, showing the relationship between Gαi1/3 and bone formation. Our findings indicate that Gαi1/3 proteins are significantly inversely correlated with age. Gαi1/3, rather than Gαi2, mediates the Wnt/β-catenin signaling pathway and promotes osteogenesis. Mechanistically, Gαi1/3 interacts with Axin1 and recruits it to the cell membrane, leading to inactivation of the β-catenin degradation complex. This results in β-catenin accumulation and nuclear translocation, where it activates the transcription of osteogenic genes. In vivo experiments further confirm that knockdown of Gαi1/3 significantly inhibits bone formation in mice. Our study identified Gαi1/3 as key regulatory proteins in Wnt/β-catenin signaling-mediated osteogenesis, and further elucidated its molecular mechanism in bone formation, which may provide a new therapeutic target for osteoporosis. Show less

Cervical cancer (CC) remains a major global health challenge, with radiotherapy resistance (RR) representing a critical impediment to treatment efficacy. This study investigated the underlying mechanisms of replication stress (RS) in RR and identified potential therapeutic targets for CC. A comprehensive bioinformatics workflow was applied to analyze the expression profiles and prognostic significance of RS-related differentially expressed genes (RSRDs) in patients with RR. The prognostic utility of an RS-based risk score model was subsequently evaluated in the context of the tumor microenvironment, somatic mutation landscape, etc. The clinical relevance of the identified hub RSRDs was validated through immunohistochemistry, univariate and multivariate Cox regression analyses, and a prognostic nomogram using data from a real-world patient cohort. Functional assays conducted both in vitro and in vivo further confirmed the role of the key RSRD. Thus, enrichment analysis of the 124 common differentially expressed genes showed RS-related biological processes were enriched. The RS risk score model, constructed using 2 hub RSRDs (AXIN1 and C-terminal binding protein 1) identified through Least Absolute Shrinkage and Selection Operator (LASSO) regression, showed strong diagnostic and prognostic performance. Enrichment analysis showed the risk score model influenced CC prognosis by tumor microenvironment and mutation, etc. Immunohistochemistry analysis of tissue microarrays explored a significant downregulation of AXIN1 in RR samples. AXIN1 was also an independent prognosis biomarker for CC patients, particularly among patients receiving radiotherapy. Knockdown of AXIN1 significantly inhibited the radiosensitivity in CC cell lines, and in vivo experiments showed AXIN1 knockdown led to increased tumor volume following radiotherapy. Molecular docking analysis illustrated JQ1 may promote AXIN1 expression. This study is the first to identify AXIN1 as a replication stress-associated gene with prognostic value in CC, specifically in the context of radiotherapy. These findings may support personalized treatment strategies and provide a foundation for future investigations into RS-targeted therapies in CC. Show less

Age-related retinal degeneration, such as diabetic retinopathy and age-related macular degeneration, are major causes of blindness in modern society. Recent studies suggest that dysbiosis and intraocular translocation of bacteria from the blood circulation are critically involved in retinal degeneration. We hypothesise that the blood-retinal barrier (BRB) cells can protect the neuroretina from blood-borne pathogens by producing antimicrobial peptides (AMPs). The antimicrobial activity may decline during ageing, putting the retina at risk of low-degree chronic inflammation and degeneration. Here, we found that the retinal pigment epithelial (RPE) cells, which form the outer BRB, express a variety of AMPs/AMP precursors, including APP, RARRES2, FAM3A, HAMP, CAMP, GNLY, and PI3. Senescent RPE cells expressed lower levels of APP and RARRES2 mRNA, accompanied by increased intracellular retention of E. coli in a bactericidal assay. Silencing APP, not RARRES2, with shRNA reduced the antibacterial activity of RPE cells. Senescent RPE cells had lower levels of α-secretase and higher levels of β-secretase (BACE1) and γ-secretase (PS1), accompanied by reduced soluble APPα and increased amyloid beta (Aβ) production, particularly the Aβ42 isoform. Eyes from aged donors showed a higher Aβ accumulation within RPE cells. Our results suggest that while RPE cells possess antimicrobial activity, this ability declines with age and is impaired in senescent cells. The impaired antimicrobial activity and augmented Aβ deposition in senescent RPE cells may contribute to age-related retinal para-inflammation and neurodegeneration. Show less

Alzheimer's disease (AD), the most common neurodegenerative disease in humans, has been a major medical challenge. Lactoferrin (Ltf) in salivary glands might be identified as a potential detectable biomarker in AD and a therapeutic target for AD. Pharmaceutical studies directly addressing this biomarker, though, are scarce. Using a computational strategy for drug repurposing, we explored the proximal neighborhood of Ltf by exploring its interactome and regulatory constellations. We aimed to focus on the discovery of potential therapeutic agents for AD. Based on extensive analytical evaluation comprising structural congruence scales, profiling disease clusters, pathway enrichment analyses as well as molecular docking, SPR, in vivo studies, and immunofluorescence assays, our research identified three candidate repurposed drugs: Lovastatin, SU-11652, and SB-239063. Taken together, these results highlight strong binding affinities of the drug candidates to Ltf. In vitro studies showed that such compounds decrease β-amyloid (Aβ) production by increasing the fluorescence signal emitted by Ltf in N2a-sw cells, and that they act by modulating the expression of amyloidogenic pathway-associated enzymes (BACE1 and APH1α). In addition, in vivo studies showed a concomitant reduction in the expression levels of amyloidogenic pathway-related enzymes (BACE1 or APH1α). Thus, computational studies have focused on Ltf interactions that may recommend drug repurposing strategies and options for AD. Show less

Oxysterols, gut metabolites, and N6-methyladenosine (m6A) are extensively implicated in the pathogenesis of cognitive dysfunction, while their alterations in different stages of mild cognitive impairment (MCI) have not been elucidated. Therefore, this study was conducted to explore the associations of oxysterols, gut metabolites, and m6A methylation profiles in early MCI (EMCI) and late MCI (LMCI) individuals. Liquid chromatography-mass spectrometry, untargeted metabolomic analysis, and m6A mRNA Epitranscriptomic Microarray were used to detect the characteristics of serum oxysterols (n = 35/group), fecal gut metabolites (n = 30/group), and m6A in whole blood (n = 4/group) respectively. The concentration of serum β-amyloid (Aβ) was detected with ELISA (n = 25/group). The gene expression of amyloid precursor protein (APP) and its key enzyme β-secretase (BACE1) in whole blood were measured by quantitative real-time PCR (n = 25/group). EMCIs and LMCIs, especially LMCIs, exhibited poorer performance in almost all global and multidimensional cognitive tests. Serum 27-hydroxycholesterol (27-OHC) and 24S-hydroxycholesterol (24S-OHC) were elevated in EMCI and LMCI groups. Changes in gut metabolites occurred mainly in the EMCI group, in which several gut metabolites, including Procyanidin dimer B7 and Phorbol myristate, were significantly decreased. The m6A methylation landscape of EMCIs and LMCIs obviously differed from Controls. Hypomethylated mRNAs accounted for the majority and were mainly accompanied by downregulated mRNAs, which was consistent with the downregulated expression of the m6A writer methyltransferase-like 4 (METTL4). 27-OHC and 24S-OHC combined with various gut metabolites significantly distinguished between MCI subgroups from healthy controls (EMCI/Control: AUC = 0.877; LMCI/Control: AUC = 0.952). Heatmap revealed the correlation between Phorbol myristate and differentially m6A-methylated mRNAs. Differentially expressed gut metabolites and methylated mRNAs were commonly enriched in 34 KEGG metabolic pathways, including cholesterol metabolism and neurodegenerative disease-related pathways. Our study explored the altered oxysterols, gut metabolites, and m6A methylation and their associations in different stages of MCI. The potential function of aberrant gut metabolites in oxysterols and m6A methylation driving MCI progression warrants further mechanistic investigation. Show less

Lead (Pb) exposure poses significant health risks, particularly in neurodegenerative diseases such as Alzheimer's disease (AD). This study investigates the neuroprotective effects of pea peptide (PP4) on PC12 cells exposed to Pb. Using Cell Counting Kit-8 (CCK-8), pretreatment with PP4 at 50 and 200 µM concentrations significantly improved cell viability compared to Pb-only treated cells (P < 0.05), indicating a protective effect. Moreover, Pb exposure led to increased Amyloid Precursor Protein (APP) expression at 10 and 20 µM after 24 h (P < 0.05), while β-site amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) levels were elevated across all concentrations tested (P < 0.05). We established that PP4 can mitigate Pb-induced cytotoxicity and reduce the expression of APP and BACE1 by activating the Phosphoinositide 3-kinase / Protein Kinase (PI3K/AKT) signaling pathway. This study highlights the potential of PP4 as a therapeutic agent in preventing neurotoxic damage associated with lead exposure, suggesting a novel approach for the management of AD. Show less

Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining heart health by draining fluids and immune cells. However, their involvement in HFpEF remains largely unexplored. We examined cardiac lymphatic alterations in mice with HFpEF with comorbid obesity and hypertension, and in heart tissues from patients with HFpEF. Using genetically engineered mouse models and various cellular and molecular techniques, we investigated the role of cardiac lymphatics in HFpEF and the underlying mechanisms. In mice with HFpEF, cardiac lymphatics displayed substantial structural and functional anomalies, including decreased lymphatic endothelial cell (LEC) density, vessel fragmentation, reduced branch connections, and impaired capacity to drain fluids and immune cells. LEC numbers and marker expression levels were also decreased in heart tissues from patients with HFpEF. Stimulating lymphangiogenesis with an adeno-associated virus expressing an engineered variant of vascular endothelial growth factor C (VEGFC Our study provides evidence that cardiac lymphatic disruption, driven by impaired BCAA catabolism in LECs, is a key factor contributing to HFpEF. These findings unravel the crucial role of BCAA catabolism in modulating lymphatic biology, and suggest that preserving cardiac lymphatic integrity may present a novel therapeutic strategy for HFpEF. Show less

Lung adenocarcinoma (LUAD) is a leading cause of cancer deaths. Given that traditional pathologic features to diagnose LUAD do not fully reflect the biological differences in patients, the search for novel biomarkers is necessary. In this study, we obtained immune-related genes (IRGs) from ImmPort and performed cluster analysis on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to mine LUAD subtypes with different immune characteristics. Quantitative analysis of IRGs was performed by single-sample gene set enrichment analysis (ssGSEA). Based on the univariate cox and LASSO regression methods, we screened the characteristic genes that significantly affected LUAD and built the model based on the RiskScore coefficients. The relative expressions of characteristic genes in LUAD were determined using qRT-PCR. Transwell and wound healing assays were utilized to verify the practical regulation of these genes on the migration and invasion levels of LUAD. Correlations were established between RiskScore and LUAD drug sensitivity by oncoPredict. We acquired three LUAD subtypes and demonstrated heterogeneous IRGs scores and clinical features. The molecular subtypes were differentially enriched in bile acid metabolism, fatty acid metabolism, and ECM-receptor interaction. This study identified seven genes (MS4A1, EXO1, CPS1, ZNF750, S100P, NT5E, KCNN4) as a signature affecting prognosis, from the differentially expressed genes (DEGs) among the molecular subtypes, and constructed a RiskScore for the prognosis of LUAD. Cellular experiments verified that 6 of 7 characteristic genes were expression dysregulation in LUAD cell line. Silencing of EXO1 significantly suppressed the migration and invasion of LUAD cell lines. RiskScore and immune checkpoints such as CD276, TNFSF4, and TNFSF9 showed a positive correlation. This study identified three LUAD subtypes with distinct immune characteristics and constructed a seven-gene prognostic model. This model correlates with immune checkpoint and chemotherapy sensitivity, providing new targets and strategies for clinical diagnosis and treatment. Show less

This study isolated a high-molecular-weight Morchella esculenta polysaccharide (MEP-1), mainly composed of glucose with a triple-helix structure. MEP-1 alleviated high-fat diet (HFD)-induced hepatic lipid metabolic disorders and inflammation by significantly reducing the levels of TC, TG, LDL-C, TNF-α, IL-6, and IL-1β, especially at the high dose. Transcriptomic analysis revealed that arginine biosynthesis was the most significantly enriched pathway after MEP-1 intervention. Specifically, MEP-1 upregulated Ass1 and Cps1 expression to promote L-arginine biosynthesis, which subsequently activated the AMPK/Sirt1/PGC-1α signaling axis, thereby enhancing fatty acid oxidation (FAO) and ameliorating lipid metabolism disorders. This study further delineates a novel protective mechanism for MEP-1 ameliorating HFD-induced lipid metabolism disorders and providing a theoretical foundation for its application in functional food. Show less

Porcine circovirus type 3 (PCV3) is an emerging pathogen that causes porcine dermatitis, and reproductive failure. PCV3 Cap interacts with DExD/H-box helicase 36 (DHX36), a protein that functions primarily through regulating interferon (IFN)-β production. However, how the interaction between DHX36 and PCV3 Cap regulates viral replication remains unknown. Herein, we observed impaired PCV3 proliferation after DHX36 overexpression as indicated by decreased Rep protein expression and virus production. In contrast, PCV3 replication increased upon small interfering RNA-mediated DHX36 depletion. Furthermore, DHX36 positively regulated IFN-β production and interferon-stimulated genes (ISGs) expression. Mechanistically, PCV3 Cap interacted with DHX36, and the PCV3 Cap-NLS and DHX36-NTD were essential for the interaction. Furthermore, DHX36 may get degraded because its binding cellular partners became ubiquitinated and then reduced, and PCV3 Cap-(35-100aa) also promoted the degradation of DHX36 through the K48-linked ubiquitination. Taken together, these results show that DHX36 antagonizes PCV3 replication by interacting with PCV3 Cap and activating IFN-β response, which provides important insight on the prevention and controlling of PCV3 infection. IMPORTANCE: Porcine circovirus type 3 (PCV3) is a newly discovered pathogen associated with multiple clinicopathological signs. Clarifying the mechanisms that host factors modulate PCV3 replication helps understanding of the viral pathogenesis. The PCV3 capsid (Cap) protein has been shown to interact with DExD/H-box helicase 36 (DHX36) (Zhou et al., 2022b), a crucial protein that regulates virus replication. Herein, we further demonstrated that DHX36 protein is degraded in PCV3-infected cells and antagonizes the replication of PCV3 and that DHX36 increases interferon-β and interferon-stimulated gene levels by binding to PCV3 Cap. In addition, PCV3 infection could decrease DHX36 expression levels to antagonize its antiviral activity. These results reveal a molecular mechanism by which DHX36 antagonizes PCV3 replication by binding to PCV3 Cap protein and activating IFN signals, thereby providing important targets for preventing and controlling PCV3 infection. Show less

This study identified fibroblast-specific genes to develop a RiskScore model to improve prognostic accuracy and guide personalized treatment in glioblastoma (GBM). We analyzed fibroblast-specific signatures in the GSE273274 cohort using "Seurat" R package for scRNA-seq data processing. Fibroblast-related gene modules were identified via WGCNA, and functional enrichment was assessed with "clusterProfiler" package. A RiskScore model was established using univariate, Lasso Cox regression analysis, and "survival" package, validated by "timeROC" for receiver operator characteristic (ROC) curve. Finally, immune infiltration and drug sensitivity was evaluated applying "ESTIMATE," "TIMER," "MCPcounter," and "pRRophetic" packages. Experimental validation included qPCR for gene expression detection, and CCK-8, wound healing, and Transwell assays for functional measurement. The scRNA-seq analysis identified nine cell types of cells, with fibroblasts elevated in the GBM group. Fibroblast signatures were linked to tumorigenesis, cytoskeleton remodeling, and regulation of neuronal development process that affected GBM invasion. A 6-gene RiskScore divided GBM patients into high- and low-risk groups in training and validation sets, with high-risk patients exhibiting poorer survival, elevated StromalScore, and negative correlations with the infiltration of neutrophils and B_cells. Moreover, high-risk patients demonstrated heightened sensitivity to Cisplatin, MG-132, AZ628, Dasatinib, CGP-60474, A-770041, TGX221, and Bortezomib. Finally, qPCR showed that the VWA1 was upregulated in GBM cells, while knock-down of VWA1 inhibited the cell proliferation, migration, and invasion activity. We constructed a RiskScore model for predicting the survival outcomes based on fibroblasts-related genes. These findings highlighted the role of fibroblasts in GBM development and offered six potential therapeutic targets (VWA1, DUSP6, LOXL1, IGFBP4, CYGB, and ZIC3) for GBM treatment. Additionally, immune infiltration analysis and drug sensitivity prediction further supported the model's utility in guiding personalized treatment of GBM. Show less

Cervical cancer remains one of the leading causes of cancer-related deaths among women globally, and there is still a need to research molecular targets that can be used for prognosis assessment and personalized molecular therapies. Here, we investigate the role of potential molecular target ribosomal L22-like 1 (RPL22L1) on cervical cancer, identify its potential mechanisms, and explore its related applications in prognosis and molecular therapies. Multiple cervical cancer cohorts online, tissue microarrays and clinical tissue specimens were analyzed for the association between RPL22L1 expression and patient outcomes. Functional and molecular biology studies of cell and mice models were used to clarify the effects and potential mechanisms of RPL22L1 on cervical cancer. RPL22L1 is highly expressed in both cervical adenocarcinoma and squamous cell carcinoma, and its expression is significantly associated with histology grade, clinical stage, recurrence, vascular space involvement, tumor sizes and poor prognosis. In vitro and in vivo experiment revealed that RPL22L1 overexpression significantly promoted cervical cancer cell proliferation, migration, invasion, tumorigenicity and Sorafenib resistance, which were attenuated by RPL22L1 knockdown. Mechanistically, RPL22L1 competitively binds to ERK phosphatase DUSP6, leading to excessive activation of ERK. The combined application of ERK inhibitors can effectively inhibit RPL22L1 overexpressing cervical cancer cells both in vivo and in vitro. RPL22L1 promotes malignant biological behavior of cervical cancer cells by competitively binding with DUSP6, thereby activating the ERK pathway. The combined use of Sorafenib and an ERK inhibitor is a potentially effective molecular targeted therapy for RPL22L1-high cervical cancer. Show less

Obesity in women of childbearing age disrupts lipid metabolism in pregnancy. This study aims to evaluate the impact of prepregnancy glucagon-like peptide-1 receptor agonist (GLP-1RA) use on lipid metabolism during pregnancy. A retrospective case-control study with 42 participants was employed to analyze the impact of prepregnancy GLP-1RA use on lipid metabolism during pregnancy in women with obesity. An animal study involved 60 virgin female Sprague Dawley rats fed a normal diet or a high-fat diet (HFD) for 8 weeks, with the latter diet divided into HFD + saline, HFD + liraglutide, and HFD + semaglutide for 4 weeks. Rats were mated and then sacrificed on gestational day 21. Clinically, prepregnancy GLP-1RA use reduced prepregnancy BMI, gestational weight gain, ratio with first-trimester metabolic dysfunction-associated steatotic liver disease, and triglyceride levels during pregnancy. In animals, GLP-1RA improved plasma fibroblast growth factor 21 (FGF21), adiponectin, triglyceride levels, and leptin in midgestation. During late gestation, compared with the HFD group, the GLP-1RA groups exhibited improved liver lipid deposition, increased fatty acid oxidation and lipolysis genes, decreased lipogenesis genes, and increased extracellular signal-regulated kinase (ERK)/peroxisome proliferator-activated receptor γ (PPAR-γ) and AMP-activated protein kinase (AMPK)/NAD-dependent protein deacetylase sirtuin-1 (SIRT1) pathways in liver; in the visceral adipose, the GLP-1RA groups showed increased lipolysis genes, decreased lipogenesis genes, and increased phosphorylated to total fibroblast growth factor receptor 1 (FGFR1) with activated ERK/PPAR-γ pathways. Prepregnancy GLP-1RA use improves maternal lipid metabolism during pregnancy, potentially involving elevated liver-secreted FGF21. This study offers a new strategy for treating lipid metabolic disorders in pregnancy. Show less

The selective inhibition of fibroblast growth factor receptors (FGFR) presents a significant challenge due to the high degree of sequence and the close structural similarity of the subtypes. Herein, we designed selective dual FGFR2/3 inhibitors based on the in-depth understanding of protein-ligand interaction contributions. We efficiently identified ISM7594 ( Show less

Liver diseases, ranging from chronic liver disease (CLD) to acute liver injury (ALI), pose significant global health challenges. Metabolic dysfunction and inflammatory disorders are key to the progression of both CLD and ALI, suggesting that dual-targeting of metabolism and immune response may lead to better clinical performance for patients with liver disease. Interleukin-27 (IL-27) is a classic cytokine known for its immune-modulating role, with many ongoing clinical trials in the context of anti-tumoral therapy and inflammatory bowel disease. Our previous studies have revealed an unexpected role of IL-27 in promoting adipocyte thermogenesis and ameliorating role in systemic metabolism. This review outlines the involvement of the IL-27/IL-27R signaling pathway in hepatic metabolism and immunity, highlighting its potential as a therapeutic target for both CLD and ALI. Meanwhile, when serum IL-27 displays a disease-specific change in dynamic liver diseases, a summary and elaboration on its diagnostic potential are also carried out. Show less

In the non-obese diabetic (NOD) mouse model of autoimmune diabetes, interleukin (IL)-27 stimulates interferon γ (IFNγ) production by CD4 and CD8 T cells and is essential for disease development. Here, we tested the role of IL-27 in cellular communication. Single-cell RNA sequencing and T cell adoptive transfer showed that IL-27 intrinsically controlled the differentiation of islet-infiltrating CD4 T cells by driving them toward an IL-21 Show less

In recent years, the discovery of IL-12 family cytokines, which includes IL-12, IL-23, IL-27, IL-35, and IL-39, whose biological functions directly or indirectly affect various autoimmune diseases. In autoimmune diseases, IL-12 family cytokines are aberrantly expressed to varying degrees. These cytokines utilize shared subunits to influence T-cell activation and differentiation, thereby regulating the balance of T-cell subsets, which profoundly impacts the onset and progression of autoimmune diseases. In such conditions, IL-12 family members are aberrantly expressed to varying degrees. By exploring their immunomodulatory functions, researchers have identified varying therapeutic potentials for each member. This review examines the physiological functions of the major IL-12 family members and their interactions, discusses their roles in several autoimmune diseases, and summarizes the progress of clinical studies involving monoclonal antibodies targeting IL-12 and IL-23 subunits currently available for treatment. Show less

Epidemiological studies have suggested that dried fruit intake may be associated with a lower risk of breast cancer (BC), yet the genetic mechanisms underlying this association remain unclear. This study aimed to explore the potential genetic relationship between dried fruit intake and BC susceptibility. We conducted a comprehensive genetic analysis using genome-wide association study (GWAS) data for dried fruit intake and BC, focusing on individuals of European ancestry. We assessed genome-wide and region-specific genetic correlations using several complementary methods, including linkage disequilibrium score regression and regional genetic mapping. To identify shared genetic regions, we applied statistical approaches that integrate information across traits and improve the detection of common genetic signals. Modest but statistically significant negative genetic correlations were observed between dried fruit intake and BC, including its subtypes. Regional analysis revealed shared signals across multiple chromosomal regions. Five candidate loci were consistently identified as shared between the traits, including BCL11A, MAD1L1, MLLT10, JMJD1C, and RP11-795H16.2. This study provides evidence for a genome-wide genetic link between dried fruit intake and BC risk, identifying several loci that may be shared between the traits. These findings may help improve our understanding of BC development and offer preliminary leads for future dietary prevention and personalized interventions, pending further experimental validation. Show less

Lung cancer imposes a significant financial burden, including psychological financial hardship (PFH). This study aims to identify latent profiles of PFH in lung cancer patients and determine associated patient and caregiver factors. A cross-sectional analysis was conducted with 305 lung cancer patient-caregiver dyads. PFH was measured using the Comprehensive Score for Financial Toxicity (COST), while quality of life (QoL) and distress were also assessed. Latent Profile Analysis (LPA) identified PFH profiles, and one-way ANOVA examined their associations with QoL and distress. Multinomial logistic regression examined correlates of PFH profiles. Three PFH profiles were identified: high-level (COST 0-13), low-level (COST 14-29), and no PFH (COST 30-44). These profiles had medium effects on mental QoL (η Distinct PFH profiles and correlates were identified, highlighting the role of both patient and caregiver factors. Findings underscore the importance of early screening and family-centred interventions to mitigate financial hardship and support well-being in cancer care. Show less

This study aimed to identify and characterize the sedentary behavior (SED) and breaks accumulation patterns of children and adolescents and investigate the associations of these derived patterns with adiposity indicators. A total of 348 children and 562 adolescents from China participated in this study. Accelerometers were used to measure the bouts of SED and breaks. Adiposity indicators included body mass index (BMI) z-score, fat mass percentage (FM%), and fat mass index (FMI). Latent profile analysis was used to identify the SED and breaks accumulation patterns on the basis of 11 compositions of SED bouts and breaks. Mixed-effects multivariable linear regression models were used to analyze the associations of accumulation patterns with adiposity indicators. Four accumulation patterns were identified in children: "prolonged sitters" (N = 77, 22.1%), "shortened sitters" (N = 90, 25.9%), "LPA breakers" (N = 69, 19.8%), and "MVPA breakers"(N = 112, 32.2%). "MVPA breakers" had significantly lower BMI z-score, FM%, and FMI than "prolonged sitters." No significant differences in adiposity indicators were observed among the other three patterns. In adolescents, "prolonged sitters" (N = 250, 44.5%), "moderate sitters" (N = 211, 37.5%), and "breakers" (N = 101, 18.0%) were identified. "Breakers" had the lowest BMI z-score, FM%, and FMI among the three groups, followed by "moderate sitters" and "prolonged sitters." Different accumulation patterns of SED and breaks were identified for children and adolescents in China. Among them, "MVPA breakers" and "Breakers" are most beneficial to maintain a normal weight status. Health promotion efforts could consider increasing MVPA and decreasing SED time for children and restricting SED to at least 30 min for adolescents to improve their adiposity indicators. Show less

Cholesterol, an indispensable structural and signaling lipid, is fundamental to cellular membrane integrity, steroidogenesis, and developmental morphogen pathways. Its homeostasis hinges on the precise coordination of four interdependent metabolic modules: de novo biosynthesis, intestinal absorption, enzymatic conversion, and systemic clearance. This review delineates the molecular machinery governing these processes-from the Bloch/Kandutsch-Russell synthesis pathways and niemann-pick C1-like 1 (NPC1L1)-mediated cholesterol uptake to cholesterol 7α-hydroxylase (CYP7A1)-driven bile acid synthesis and HDL-dependent reverse transport. We further elucidate cholesterol's multifaceted roles in lipid raft assembly, Hedgehog signal transduction, and vitamin D/hormone production. Critically, dysregulation of cholesterol flux underpins pathogenesis in atherosclerosis, metabolic dysfunction-associated fatty liver disease (MAFLD), neurodegenerative disorders, and oncogenesis, with disrupted synthesis, efflux, or esterification cascades serving as key drivers. Emerging therapeutic strategies extend beyond conventional statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to include transformative modalities: CRISPR-based in vivo gene editing (e.g., VERVE-101 targeting PCSK9), small interfering RNA (siRNA) therapeutics (inclisiran), and microbiota-directed interventions. Pioneering approaches against targets Such as angiopoietin-like 3 (ANGPTL3), lipoprotein(a) [Lp(a)], and asialoglycoprotein receptor 1 (ASGR1)-alongside repurposed natural agents (berberine, probiotics)-offer promise for mitigating residual cardiovascular risk and advancing precision cardiometabolic medicine. By integrating mechanistic insights with clinical advancements, this review underscores the transition from broad-spectrum therapies to personalized, multi-target regimens, offering a roadmap for mitigating cholesterol-related diseases in the era of genomic and metabolic medicine. Show less