Our aim was to explore the IL-27 effect in sepsis (SP)-related acute hepatic injury (AHI) as well as its possible mechanism. Herein, we utilized both wild-type (WT) and IL-27 receptor (WSX-1)-deficien Show more
Our aim was to explore the IL-27 effect in sepsis (SP)-related acute hepatic injury (AHI) as well as its possible mechanism. Herein, we utilized both wild-type (WT) and IL-27 receptor (WSX-1)-deficient (IL-27R The results revealed that IL-27 exacerbated systemic inflammation and liver damage in AHI mice by promoting M1 macrophage polarization, thereby increasing pro-inflammatory phenotype macrophages (M1). This further exacerbated the inflammatory response and pyroptosis in vivo and in vitro. Additionally, IL-27 down-regulated p-AMPK and SIRT1 protein expression while overexpressing macrophage inflammatory mediators including IL-1β/6 and TNFα. Furthermore, IL-27 promoted increased RAGE and caspase-11 protein expression, aggravating macrophage pyroptosis. Employing CC to block the AMPK pathway further aggravated M1 macrophage polarization and pyroptosis in vitro and in vivo, ultimately worsening liver injury. Here, IL-27 aggravates AHI by promoting macrophage M1 polarization to induce caspase-11-mediated pyroptosis in vitro and in vivo, which may be linked to the AMPK/SIRT1 signaling pathway. Show less
The objective was to assess the clinical efficacy of long non-coding RNA (lncRNA) alpha-2-macroglobulin-antisense 1 (A2M-AS1) in acute myocardial infarction (AMI). One hundred patients with AMI and ei Show more
The objective was to assess the clinical efficacy of long non-coding RNA (lncRNA) alpha-2-macroglobulin-antisense 1 (A2M-AS1) in acute myocardial infarction (AMI). One hundred patients with AMI and eighty patients with chest pain were recruited in the case-control study. A2M-AS1 expression was examined by quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was utilized for evaluating the diagnostic value. Pearson's correlation analysis was used to analyze the correlation between A2M-AS1 and conventional AMI biomarkers. AMI-associated risk indicators were identified using logistic regression analysis. A significant reduction of serum A2M-AS1 was measured in AMI patients relative to chest pain patients. A2M-AS1 had an area under the curve (AUC) of 0.927 to distinguish AMI patients from those with chest pain. Pearson's correlation analysis showed that A2M-AS1 was adversely correlated with white blood cell (WBC) (r=-0.6682, P < 0.001), low density lipoprotein cholesterol (LDL-C) (r=-0.5795, P < 0.001), creatine kinase MB (CK-MB) (r=-0.6022, P < 0.001) and cTnl (r=-0.5473; P < 0.001), while positively correlated with high density lipoprotein cholesterol (HDL-C) (r = 0.6445, P < 0.001). Relative to non-Major Adverse Cardiovascular Events (non-MACE) group, serum A2M-AS1 was obviously declined in the MACE group of AMI patients with high capacity to distinguish the MACE group from the non-MACE patients (AUC = 0.802). Additionally, A2M-AS1 (P = 0.013; OR = 0.268; 95%CI = 0.095-0.760) was a risk indicator for predicting MACE with AMI patients, as well as age (P = 0.014; OR = 3.478; 95%CI = 1.285-9.414). A reduction in A2M-AS1 expression was observed in AMI patients, suggesting its potential as an underlying indicator for AMI diagnosis. Show less
The embryos of lotus (Nelumbo nucifera Gaertn.) is a famous traditional Chinese medicine used to treat insomnia, memory decline, and dementia for a long time. However, the underlying material basis an Show more
The embryos of lotus (Nelumbo nucifera Gaertn.) is a famous traditional Chinese medicine used to treat insomnia, memory decline, and dementia for a long time. However, the underlying material basis and mechanisms of this medicine are still unclear. Isoliensinine (IL) is a major alkaloid derived from lotus embryos. Our previous research has demonstrated that IL can exert strong anti-inflammatory and neuroprotective effects in vitro. To reveal the underlying therapeutic effect and mechanism of IL on Alzheimer's disease (AD)-like mice induced by AlCl The AD-like mice were modeled by intragastric injection (i.g.) of AlCl IL (1, 3, and 10 mg/kg) treatment effectively ameliorated cognitive impairment in AD-like model mice. IL inhibited the decrease of brain index and body weight in AD-like mice and alleviated neuronal damage in the cortex and hippocampus (DG, CA1, and CA3). IL decreased the levels of Ca IL has a significant therapeutic effect on pathological alterations and cognitive impairment in AlCl Show less
Health literacy plays an important role in disease prevention and control. The aim of this study is to explore the health literacy patterns and associated factors among residents in Zhejiang Province. Show more
Health literacy plays an important role in disease prevention and control. The aim of this study is to explore the health literacy patterns and associated factors among residents in Zhejiang Province. This study included 56,863 residents aged 15-69 years from the 2024 Zhejiang Province Health Literacy Survey. Latent Profile Analysis (LPA) was used to investigate health literacy patterns, and multinomial logistic regression analysis was employed to identify associated factors. Dominance analysis was performed to compare the relative contribution of the main variables associated with health literacy. The analysis identified three distinct health literacy profiles: low literacy (15.13%), moderate literacy (32.24%), and relatively high literacy (52.63%). The low literacy group was characterized by an older demographic (with an average age of 58.71 years), lower educational attainment (20.72% had no formal education), a higher proportion of farmers (52.93%), and a significant share of low-income individuals (40.98%). Multinomial logistic regression and dominance analysis revealed that education level, age, and occupation were the most important associated factors of health literacy. The study findings highlighted the heterogeneity in health literacy among various population groups and emphasized the need for targeted interventions. This study provides empirical evidence to inform precision health promotion strategies in developed regions of China. Show less
Age increases of brain amyloid plaques may be mediated by prior increase of soluble Aβ42. Here, we show that frontal cortex samples from brains of cognitively normal aging humans had progressively inc Show more
Age increases of brain amyloid plaques may be mediated by prior increase of soluble Aβ42. Here, we show that frontal cortex samples from brains of cognitively normal aging humans had progressively increased levels of soluble amyloid peptide Aβ40 throughout the lifespan. Aggregated amyloid fraction was subsequently obtained by formic acid, where Aβ42 showed increases only in humans over 90 years old when compared to those younger than 50. Similarly, aging wild-type mice without amyloid plaques had increases of both soluble Aβ40 and Aβ42, as previously shown in normal aging rats. Aging also alters secretase enzymes and processing of amyloid precursor protein (APP). Here, we isolate membrane domains known as lipid rafts, a site of APP cleavage. We found that lipid rafts isolated from mouse and human cerebral cortex showed age increases of β-secretase enzyme activity, while amyloidogenic secretase proteins levels BACE1 and PS1 decreased with age in mouse. Lipid rafts merit further study in aging and neurodegeneration. Show less
Clustered regularly interspaced short palindromic repeats-Cas13 effectors are used for RNA editing but the adeno-associated virus (AAV) packaging limitations because of their big sizes hinder their th Show more
Clustered regularly interspaced short palindromic repeats-Cas13 effectors are used for RNA editing but the adeno-associated virus (AAV) packaging limitations because of their big sizes hinder their therapeutic application. Here we report the identification of the Cas13j family, with LepCas13j (529 aa) and ChiCas13j (424 aa) being the smallest and most highly efficient variants for RNA interference. The miniaturized Cas13j proteins enable the development of compact RNA base editors. Chi-RESCUE-S, by fusing dChiCas13j with hADAR2dd, demonstrates high efficiency and specificity in A-to-G and C-to-U conversions. Importantly, this system is compatible with single-AAV packaging without the need for protein sequence truncation. It successfully corrected pathogenic mutations, such as APOC3 Show less
Qingyu Zhang, Zongliang Yu · 2025 · International journal of general medicine · added 2026-04-24
Heart failure with preserved ejection fraction (HFpEF) is becoming increasingly prevalent, yet clinical practice lacks specific biomarkers, early diagnostic tools, and reliable risk assessment methods Show more
Heart failure with preserved ejection fraction (HFpEF) is becoming increasingly prevalent, yet clinical practice lacks specific biomarkers, early diagnostic tools, and reliable risk assessment methods. Given the growing burden of HFpEF, identifying novel diagnostic markers is crucial. This study investigates the diagnostic potential of apolipoprotein C3 (ApoC3) in HFpEF and its correlation with ventricular structure. We analyzed data from HFpEF patients admitted to the Kunshan Branch of Gusu College of Nanjing Medical University and the First People's Hospital of Kunshan (March-December 2023). Controls included HFrEF+HFmrEF patients and healthy individuals. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentration of ApoC3 in all collected cases. The receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic performance of ApoC3 alone and combined with the fibrinogen-to-albumin ratio (FAR) in plasma, and the relative wall thickness (RWT) in echocardiography for HFpEF. After exclusions, 80 HFpEF patients (39 male, 41 female), 41 HFrEF+HFmrEF patients (27 male, 14 female), and 79 healthy controls (53 male, 26 female) were included. ApoC3 levels were significantly higher in HFpEF (63136.03±12,113.07 ng/mL) than in HFrEF+HFmrEF (55580.84±13,685.35 ng/mL) and controls (53090.31±5893.25 ng/mL, P<0.001). ROC analysis demonstrated that ApoC3 alone (AUC=0.836) and the combined index (ApoC3+FAR+RWT, AUC=0.891) effectively distinguished HFpEF. Both also aided in differentiating HFpEF from HFrEF+HFmrEF (AUC=0.702 vs 0.823). ApoC3 is a promising biomarker for HFpEF diagnosis, and the combined index (ApoC3+FAR+RWT) enhances diagnostic accuracy. These findings may improve early detection and clinical management of HFpEF. Show less
The development of unconventional oil and gas resources is increasingly shifting toward heterogeneous reservoirs with complex permeability distributions, making the effective control of hydraulic frac Show more
The development of unconventional oil and gas resources is increasingly shifting toward heterogeneous reservoirs with complex permeability distributions, making the effective control of hydraulic fracture propagation patterns critical for optimizing production. To this end, this study establishes a 3D multilayered heterogeneous reservoir model using the finite element method to analyze fracture mechanisms. The impacts of permeability heterogeneous, injection rate, and fracturing fluid viscosity on fracture morphology are systematically investigated, and the elasticity coefficient method was used to evaluate the influence weights of each parameter.The main conclusions are as follows: (1) Permeability distribution is the core factor controlling the fracture propagation direction, with HPL dominating the extension path while MPL and LPL show limited efficiency. (2) An increase in the number of permeability layers inhibits the overall expansion of cracks, and the shape of the cracks gradually changes to rectangular. (3) Higher injection rates significantly expand fracture area, whereas fracturing fluid viscosity ≥50 mPa·s stabilizes fracture morphology. (4) The elastic coefficient method identifies injection rate, permeability heterogeneous, and fracturing fluid viscosity as the key control parameters in order. This work provides theoretical guidance for optimizing hydraulic fracturing parameters in complex geological settings. Show less
The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-γ production. The mechanisms underlying this functional bias remain elusive. Previous studies Show more
The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-γ production. The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4 Show less
Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from Show more
Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival (P = 0.025) and overall survival (P = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3-FGFR1. Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies. Show less
Hepatoid carcinoma of the ovary (HCO) is a highly uncommon and aggressive neoplasm originating from the surface epithelial cells of the ovary, characterized by hepatocyte-like differentiation. To date Show more
Hepatoid carcinoma of the ovary (HCO) is a highly uncommon and aggressive neoplasm originating from the surface epithelial cells of the ovary, characterized by hepatocyte-like differentiation. To date, most information on HCO is derived from case reports, with fewer than 50 documented cases globally. In this case report, we present a detailed account of the diagnosis, treatment, and prognosis of a patient diagnosed as having bilateral HCO, which is even rarer. Targeted next-generation sequencing revealed somatic mutations in PIK3C3 and TP53, with no BRCA1/2 alterations, and a molecular profile consistent with microsatellite stability and low tumor mutational burden. We also review the current literature to situate our findings within the broader context of existing knowledge. Given the rarity of bilateral HCO, our objective is to contribute to the existing body of knowledge by providing a comprehensive description of its clinical features, molecular characteristics, and treatment strategies. This effort may enhance understanding of this rare malignancy and offer insights to improve patient outcomes in clinical practice. Show less
Integration of human genomics and other omics across different ancestries provides novel, affordable, and systematic approach for target identification. We used Mendelian randomization approaches to u Show more
Integration of human genomics and other omics across different ancestries provides novel, affordable, and systematic approach for target identification. We used Mendelian randomization approaches to unravel causal associations between 2,940 circulating proteins and 19 CVD. We found 218 proteins that impacted risk of one or more CVDs through forward MR (106 and 182 using cis-pQTLs only and cis- + trans-pQTLs, respectively), among which 107 were previously reported as associated with CVD or CVD-related traits. There were 102 proteins replicated (FDR < 5%, 53 with cis-pQTLs only and 88 with cis- + trans-pQTLs) using the FinnGen Olink data. BTN3A2 was highlighted as a novel candidate gene for ischemic stroke, suggesting a crosstalk between immune modulation and stroke pathogenesis. Single cell integration prioritized PAM for stable angina pectoris and ventricular arrhythmia and LPL for peripheral artery disease, whose transcriptional expressions were enriched in cardiomyocytes. Forward and reverse MR found largely non-overlapping proteins (only 2 overlapped: LGALS4 and MMP12), suggesting distinct proteomic causes and consequences of CVD. Our study provides human genetics-based evidence of novel candidate genes, a foundational step towards full-scale causal human biology-based drug discovery for CVD. Show less
The pyroptosis of retinal Müller cells is intricately linked to the pathogenesis of diabetic retinopathy (DR). Ubiquitin-fold modifier 1 (UFM1)-mediated UFMylation plays an important role in insulin a Show more
The pyroptosis of retinal Müller cells is intricately linked to the pathogenesis of diabetic retinopathy (DR). Ubiquitin-fold modifier 1 (UFM1)-mediated UFMylation plays an important role in insulin and diabetes mellitus metabolism and regulates cell death such as apoptosis and pyroptosis. UFM1-specific protease 2 (UFSP2) mediates the maturation of the UFM1 precursor and thus affects UFMylation reaction. However, its role in DR remains unknown. The aim of our study was to determine the mechanism and upstream regulation of UFSP2 on the pyroptosis of rat retinal Müller cells. Pathological changes, UFSP2 expression and succinate accumulation were determined in retinal tissues of db/db diabetic mice via Hematoxylin and eosin and immunofluorescence staining and biochemical analysis. High glucose (HG) was used to construct a DR cell model using rat retinal Müller cells (rMC-1). Ufsp2 RNA interference and overexpression plasmids were constructed to determine the effects of UFSP2. Pyroptosis and reactive oxygen species (ROS) levels were assessed via flow cytometry. Inflammatory cytokine (IL-1β and IL-18) levels and key molecular markers related to pyroptosis (NLRP3, ASC, Caspase-1p20, GSDMD-N) were measured by enzyme linked immunosorbent assay and Western blot, respectively. Succinate-mediated H3K3me3 enrichment in Ufsp2 promoter region was measured by chromatin immunoprecipitation. In vivo experiments revealed that the UFSP2 expression and succinate levels were increased in retinal tissues of db/db diabetic mice with thinning of retinal thickness. Moreover, in vitro experiments showed that The mRNA and protein levels of Ufsp2 exhibited a time-dependent increase under HG conditions. Upon Ufsp2 knockdown, the elevated oxidative stress, inflammatory responses, and pyroptosis stimulated by HG were significantly suppressed. The effect of Ufsp2 overexpression on pyroptosis and inflammatory responses was consistent with the HG stimulation, whereas the UFSP2-induced heightened levels of pyroptosis as well as the inflammatory state were significantly reversed when co-administered with NLRP3 inhibitor or ROS inhibitor. Further activating NLRP3 inflammasome using LPS + ATP stimulation revealed that the knockdown of Ufsp2 resulted in inhibited pyroptosis levels and inflammatory responses, while the Ufsp2 overexpression markedly increased pyroptosis and inflammatory responses. Lastly, succinate was demonstrated to influence Ufsp2 transcription, as well as the expression of H3K3me3 and its enrichment in the Ufsp2 promoter region, ultimately affecting pyroptosis and inflammatory responses. Succinate-mediated Ufsp2 transcription promotes pyroptosis in rMC-1 cells by activating NLRP3 inflammasome and oxidative stress. Show less
Fatty acids serve as a crucial energy source for tumor cells during the progression of chronic lymphocytic leukemia (CLL). The present study aims to elucidate the characteristics of fatty acid metabol Show more
Fatty acids serve as a crucial energy source for tumor cells during the progression of chronic lymphocytic leukemia (CLL). The present study aims to elucidate the characteristics of fatty acid metabolism (FAM) in CLL, construct a related prognostic score, and investigate the regulatory role and mechanisms of FAM in CLL development. Bulk RNA sequencing data from CLL patients and healthy controls were analyzed to identify differentially expressed fatty acid metabolic genes. FAM-score was constructed using Cox-LASSO regression and validated. Single-cell RNA sequencing was used to analyze the expression of key FAM genes in CLL immune cell subsets and investigate cellular communication. Functional assays, including cell viability, drug sensitivity, and oxygen consumption assays, were performed to assess the impact of fatty acid oxidation (FAO) inhibition on CLL cells. Three FAM-related genes (LPL, SOCS3, CNR1) were identified with independent prognostic significance to construct the risk score. The FAM-score demonstrated superior prognostic performance compared to the Binet stage and was associated with established clinical prognostic markers. Single-cell analysis revealed distinct expression patterns of LPL, SOCS3, and CNR1 across CLL immune cell subsets. Cellular communication analysis highlighted the regulatory role of distinct B cell and Treg subsets in the CLL microenvironment. CLL patients with high FAM-score displayed distinct immune infiltration patterns, with increased FAO pathway activity. Inhibition of FAO reduced CLL cell viability, synergistically enhanced the efficacy of the PI3K inhibitor idelalisib. The present study constructed a prognostic risk score based on FAM gene expression, revealing related immune phenotypic differences and exploring the regulatory role of FAO in CLL development. Targeting fatty acid metabolism potentially modulates the CLL immune microenvironment and synergistically enhances the efficacy of PI3K inhibitors. Show less
Lung adenocarcinoma (LUAD) is one of the leading causes of death worldwide, and thus, more biomarker and therapeutic targets need to be explored. Herein, we aimed to explore new biomarkers of LUAD by Show more
Lung adenocarcinoma (LUAD) is one of the leading causes of death worldwide, and thus, more biomarker and therapeutic targets need to be explored. Herein, we aimed to explore new biomarkers of LUAD by integrating bioinformatics analysis with cell experiments. We firstly identified 266 druggable genes that were significantly differentially expressed between LUAD tissues and adjacent normal lung tissues. Among these genes, SMR analysis with Show less
Colorectal cancer (CRC) is a leading cause of cancer mortality while diabetes is a recognized risk factor for CRC. Here we report that tirzepatide (TZP), a novel polypeptide/glucagon-like peptide 1 re Show more
Colorectal cancer (CRC) is a leading cause of cancer mortality while diabetes is a recognized risk factor for CRC. Here we report that tirzepatide (TZP), a novel polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist for the treatment of diabetes, has a role in attenuating CRC growth. TZP significantly inhibited colon cancer cell proliferation promoted apoptosis in vitro and induced durable tumor regression in vivo under hyperglycemic and nonhyperglycemic conditions across multiple murine cancer models. As glucose metabolism is known to critically regulate colon cancer progression, spatial metabolomics results revealed that glucose metabolites are robustly reduced in the colon cancer regions of the TZP-treated mice. TZP inhibited glucose uptake and destabilized hypoxia-inducible factor-1 alpha (HIF-1α) with reduced expression and activity of the rate-limiting enzymes 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK-1). These effects contributed to the downregulation of glycolysis and the tricarboxylic acid (TCA) cycle. TZP also delayed tumor development in a patient-derived xenograft (PDX) mouse model accompanied by HIF-1α mediated PFKFB3-PFK-1 inhibition. Therefore, the study provides strong evidence that glycolysis-blocking TZP, besides its application in treating type 2 diabetes, has the potential for preclinical studies as a therapy for colorectal cancer used either as monotherapy or in combination with other anticancer therapies. Show less
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. Show more
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
Conjugated linoleic acid (CLA) isomers have been reported to reduce body weight and promote glycolipid metabolism in animals. In a preliminary study, we revealed that trans-10, cis-12-CLA (10,12-CLA) Show more
Conjugated linoleic acid (CLA) isomers have been reported to reduce body weight and promote glycolipid metabolism in animals. In a preliminary study, we revealed that trans-10, cis-12-CLA (10,12-CLA) plays an important role in modulating lipid metabolism in chickens. However, the underlying mechanism remains unclear. In this study, we constructed an isolated in vitro model with primary chicken hepatocytes to investigate the effect of 10,12-CLA on lipid metabolism. 10,12-CLA inhibited lipid accumulation by decreasing the mRNA expression of sterol regulatory element-binding protein-1c (SREBP-1c), SREBP2, 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR), fatty acid synthase (FAS), adipose triacylglyceride lipase (ACC), and lipoprotein lipase (LPL) and increasing the mRNA expression of peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1 (CPT1) and adipose triacylglyceride lipase (ATGL). Furthermore, 10,12-CLA treatment activated the protein expression of extracellular signal-regulated kinase 1/2 (ERK1/2) and AMP-activated protein kinase (AMPK), whereas treatment with the ERK1/2 inhibitor U0126 reversed the inhibitory effects of 10,12-CLA on lipid accumulation by blocking the ERK1/2-AMPK pathway, leading to increased lipid accumulation and triglyceride content in primary chicken hepatocytes. These findings suggest that in chicken hepatocytes, 10,12-CLA alleviates hepatocyte lipid deposition by activating the ERK1/2-AMPK pathway, promoting fatty acid oxidation and reducing lipid synthesis, revealing the potential mechanism through which 10,12-CLA regulates hepatic lipid metabolism in chickens. Show less
Vaccinia-related kinase 1 (VRK1) is involved in numerous cellular processes, including DNA repair, cell cycle and cell proliferation. However, its roles and molecular mechanism underlying the progress Show more
Vaccinia-related kinase 1 (VRK1) is involved in numerous cellular processes, including DNA repair, cell cycle and cell proliferation. However, its roles and molecular mechanism underlying the progression of hepatocellular carcinoma (HCC) are yet largely unexplored. Here, we demonstrated that VRK1 expression is elevated in HCC tumor tissues, which is associated with high tumor stage and poor prognosis in HCC patients. In vitro and in vivo experiments manifested that VRK1 overexpression significantly promotes cell proliferation, colony formation, migration and tumor growth of HCC by inducing epithelial-mesenchymal transition (EMT) program. Mechanistically, immunoprecipitation combined with mass spectrometry analysis determined that VRK1 interacts with CHD1L, which mediates the phosphorylation of CHD1L at serine 122 site. RNA-seq revealed that one of the key downstream target genes of VRK1 is SNAI1, by which VRK1 promotes EMT process and HCC progression. Furthermore, VRK1 upregulates SNAI1 expression through phosphorylating CHD1L. In conclusion, these findings suggested that VRK1/CHD1L/SNAI1 axis acts as a cancer-driving pathway to promote the proliferation and EMT of HCC, indicating that targeting VRK1 may be an attractive therapeutic strategy of HCC. Show less
Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease (CVD). Related mutations contributing to hypercontractility and poor relaxation in HCM are not completely u Show more
Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease (CVD). Related mutations contributing to hypercontractility and poor relaxation in HCM are not completely understood. This study aimed to explore and verify a novel variant of cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3) in an HCM family. Clinical information and cardiac parameters were collected in the pedigree. Genomic DNA was extracted from peripheral blood and second-generation sequencing technology was used to investigate the proband and his family members. Subsequent sequence analysis was performed with DNAMAN software. The cardiac expression levels of MYBPC3 mRNA and cMyBP-C protein were assessed using RT-qPCR and Western blot analysis, respectively. Typical interventricular septal thickening was detected in all four HCM patients without left ventricular outflow tract obstruction. The c.1042₁₀₄₃insCGGCA mutation in MYBPC3 was verified in the proband and family members. In silico analysis of the mutation revealed that c.1042₁₀₄₃insCGGCA led to a shift in the sequence of nucleotides, creating a premature stop codon at the new reading frame. RT-qPCR analysis of MYBPC3 mRNA revealed a marked reduction in HCM heart compared to the normal controls (P < 0.05). Consistently, Western blot analysis showed significantly reduced expression of cMyBP-C in the pedigree in comparison with the controls (P < 0.05). The novel c.1042₁₀₄₃insCGGCA MYBPC3 mutation is a genetic basis for HCM due to c-MyBP-C haploinsufficiency. Show less
Fibroblast growth factor receptors (FGFRs) are well-established oncology targets, with aberrant FGFR2 and FGFR3 activation implicated in multiple tumor types, including cholangiocarcinoma and urotheli Show more
Fibroblast growth factor receptors (FGFRs) are well-established oncology targets, with aberrant FGFR2 and FGFR3 activation implicated in multiple tumor types, including cholangiocarcinoma and urothelial carcinoma. Currently approved FGFR2/3-targeted therapies rely on pan-FGFR small-molecule kinase inhibitors, which often lead to off-target toxicities due to unintended inhibition of FGFR1 and FGFR4, as well as acquired resistance driven by gatekeeper mutations. Herein, we report the discovery of INCB126503, a highly potent, orally bioavailable FGFR2/3 inhibitor with excellent isoform selectivity and equipotent activity against gatekeeper mutants. INCB126503 effectively suppresses FGFR signaling in vivo without inducing hyperphosphatemia and demonstrates significant antitumor efficacy in xenograft models harboring FGFR3 genetic alterations. Show less
The functional and pharmacological significance of dopamine receptor D4 (DRD4) in psychiatric and neurological disorders is well elucidated. However, the roles of DRD4 in colorectal cancer (CRC) remai Show more
The functional and pharmacological significance of dopamine receptor D4 (DRD4) in psychiatric and neurological disorders is well elucidated. However, the roles of DRD4 in colorectal cancer (CRC) remain unclear. This study observes a significant upregulation of DRD4 expression in clinical samples, which is negatively correlated with patient prognosis. In vitro, overexpression of DRD4 causes a constitutive activation of β-Arrestin2/PP2A/AKT independent of dopamine. Interestingly, this classical signaling pathway is not associated with the phenotype of DRD4-promoted migration and invasion in CRC cells. Instead, DRD4 interacts with transforming growth factor beta receptors (TGFBR1 and TGFBR2) to activate Smad2 phosphorylation and promote Smad2/Smad4 complex nucleus translocation. Then, SNAI1 and JAG1 are transcriptionally activated to induce epithelial-mesenchymal transition and enhance the metastatic potential of CRC. Notably, the COOH-terminal domain is identified as the key intracellular region for the pro-metastatic roles of DRD4. Furthermore, treatment with a TGFBR1 inhibitor combined with a BMP inhibitor effectively counteracts the pro-metastatic effects induced by DRD4 both in vitro and in vivo. In conclusion, these findings uncover an unconventional role for DRD4 beyond its classic function as a neurotransmitter receptor. The intracellular signaling of DRD4 interacting with TGFBR1 can be targeted pharmacologically for CRC therapy. Show less
Cardiovascular disease (CVD) is the leading cause of mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), yet traditional risk predictors remain limited in clin Show more
Cardiovascular disease (CVD) is the leading cause of mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), yet traditional risk predictors remain limited in clinical practice. To develop machine learning (ML) models for classifying prevalent atherosclerotic cardiovascular disease (ASCVD) risk in MASLD patients, and to enhance model interpretability using SHapley Additive exPlanations (SHAP). Methods: This retrospective study included 590 MASLD patients diagnosed at the Affiliated Hospital of Qingdao University between December 2019 and December 2024. Patients were randomly divided into a training set (n=413) and a validation set (n=177), and further stratified based on ASCVD status. Least absolute shrinkage and selection operator (LASSO) regression was used for feature selection. Six ML models were developed and evaluated using sensitivity, specificity, accuracy, area under the receiver operating characteristic curve (AUC), and F1 score. SHAP analysis was performed to interpret feature contributions. ASCVD was present in 434 of 590 patients (73.6%). The Gradient Boosting (GB) model achieved the best performance, with AUCs of 0.918 (95% CI: 0.890-0.944) in the training set and 0.817 (95% CI: 0.739-0.883) in the validation set. SHAP analysis identified the top predictors as the Cholesterol-HDL-Glucose (CHG) index, Castelli Risk Index II (CRI-II), lipoprotein(a) [Lp(a)], serum creatinine (Scr), and uric acid (UA). The GB model demonstrated strong high accuracy in identifying existing ASCVD in MASLD patients and may serve as a useful tool for early risk stratification in clinical settings. Show less
Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly individuals. Retinal pigment epithelium (RPE) ferroptosis is a significant pathogenetic component in AMD. T Show more
Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly individuals. Retinal pigment epithelium (RPE) ferroptosis is a significant pathogenetic component in AMD. This study aims to elucidate the role and mechanisms of fatty acid desaturase 1 (FADS1) in ferroptosis as well as AMD progression. An integrated bioinformatics analysis based on the array of data from the GEO database was conducted to identify candidates involved in ferroptosis during AMD. Subsequently, cellular and mouse models of AMD were developed using sodium iodate (NaIO FADS1 expression was upregulated in AMD patients and in vitro and in vivo models of AMD. Its pharmacological inhibition had decreased mitochondrial ROS formation, lipid peroxidation, and ferroptosis as well as increased RPE cell function in ARPE-19 cells and C57BL/6J mouse models of AMD. Mechanistically, Sp1 was identified as a key transcription factor of FADS1. Moreover, Sp1 inhibition downregulated FADS1 expression consequently attenuating FADS1-mediated ferroptosis as well as AMD phenotypes. For the first time, we demonstrated that Sp1 regulates FADS1-mediated ferroptosis in RPE cells. Our findings provide novel insights into the progression and treatment of AMD. Show less
Lipoproteins are essential for lipid transport in all bilaterians. A single Apolipoprotein B (ApoB) molecule is the inseparable structural scaffold of each ApoB-containing lipoprotein (B-lps), which a Show more
Lipoproteins are essential for lipid transport in all bilaterians. A single Apolipoprotein B (ApoB) molecule is the inseparable structural scaffold of each ApoB-containing lipoprotein (B-lps), which are responsible for transporting lipids to peripheral tissues. The cellular mechanisms that regulate ApoB and B-lp production, secretion, transport, and degradation remain to be fully defined. In humans, elevated levels of vascular B-lps play a causative role in cardiovascular disease. Previously, we have detailed that human B-lp biology is remarkably conserved in the zebrafish using an Show less
Myeloid/lymphoid neoplasms with tyrosine kinase gene fusions (MLN-TK) are rare hematologic malignancies characterized by recurrent kinase rearrangements, including