Cell Biochemistry and Function最新文献

The study was to evaluate the diagnostic significance of serum miR-125a in individuals with carotid artery stenosis (CAS) and its predictive capacity for cerebral ischemic events (CIEs). This study enrolled 116 healthy controls and 122 CAS patients. Serum miR-125a levels were quantified via RT-qPCR. Receiver operating characteristic (ROC) curve was utilized to evaluate the diagnostic value of miR-125a in differentiating CAS patients from healthy subjects. Logistic regression analysis was performed to explore the association between miR-125a levels and the severity of CAS. Kaplan-Meier (K-M) survival analysis and Cox regression were employed to evaluate the predictive value of miR-125a for the incidence of CIEs throughout the follow-up period. Serum miR-125a level was upregulated in CAS patients compared with controls. ROC curve analysis showed AUC of 0.931 for miR-125a in distinguishing CAS patients. Logistic regression identified miR-125a and low HDL levels as independent risk factors for severe stenosis. Cox regression analysis showed that high miR-125a expression was an independent predictor of CIEs, along with severe stenosis and low HDL. Serum miR-125a serves as a highly specific biomarker for early CAS diagnosis and predicts the risk of CIEs, providing a novel molecular target for CAS risk stratification and clinical intervention.

The extracellular matrix protein (ECM) Agrin could facilitate cardiac regeneration and repair after myocardial infarction (MI), but its specific impacts on epicardial cells (EpiCs) remains unexplored. To investigate Agrin′s influence on the activation and proliferation of EpiCs, we observed dynamic changes of Agrin in the heart of mice during developmental and injury periods. We also evaluated the effects of intramyocardial administration of Agrin post MI. We found that Agrin exhibited high expression in embryonic and neonatal myocardium and gradually decreased postnatally. Agrin treatment could stimulate EpiCs activation, proliferation, and migration post MI in mice. Agrin facilitated EpiCs' proliferation primarily by binding to the membrane receptor α-dystroglycan (α-DAG), with Yes-associated protein (YAP) acting as the intracellular transcriptional factor. Inhibiting the binding of Agrin to α-DAG resulted in reduced EpiCs proliferation and decreased YAP expression. Blocking YAP-TEAD activation also reduced the effects of Agrin on EpiCs proliferation. In addition, we also demonstrated that Agrin increased the survival rate of mice and improved heart function post MI. In conclusion, Agrin has the potential to promote EpiCs activation and proliferation, making it a promising candidate for heart repair post MI. The α-DAG-YAP axis is a crucial signaling pathway in Agrin-mediated EpiCs' activation, migration, and proliferation.

Advances in therapy have yet to substantially improve the 5-year survival metrics for non-small cell lung cancer (NSCLC) patients, underscoring a significant gap that necessitates novel and efficacious treatment solutions. In this study, we demonstrated that tanshinol significantly diminished A549 cell viability and disrupted their proliferative and metastatic capabilities, while simultaneously promoting apoptosis. These cellular responses were linked to suppression of the PI3K/AKT signaling pathway. Moreover, tanshinol contributed to the reduction of intracellular reactive oxygen species via modulation of the Nrf2/HO-1 antioxidative pathway. Simultaneously, it diminished the secretion of pro-inflammatory cytokines by inhibiting the NF-κB signaling pathway. Taken together, our findings indicate that tanshinol combats NSCLC by promoting apoptotic cell death via suppression of the PI3K/AKT pathway, alongside alleviating oxidative damage and inflammatory responses. Our findings lay the groundwork for subsequent in vivo research aimed at validating tanshinol as a promising agent for NSCLC therapy.

Tissue biopsies are routinely used for identifying driver mutations in tumors but limitations such as tumor heterogeneity have encouraged the use of liquid biopsies for the identification of new biomarkers. ATP-citrate lyase (ACLY) has been recognized as a potential target for tumor inhibition due to its overexpression in several cancers. However, the clinical significance of this enzyme remains unknown in liquid biopsies. In this study, 31 pleural effusion fluid samples were collected from patients suspected of malignancy for analyzing the gene expression of ACLY and associated metabolic enzymes. Gene expression profiling by RT-PCR revealed significantly increased ACLY mRNA levels along with other metabolic enzymes (FASN, ACC, CS, and ICD1) in malignant lung adenocarcinoma pleural fluid samples indicating that ACLY plays a critical role in the progression of lung adenocarcinoma. This study identified the potential of using metabolic enzymes as biomarkers in identification of lung adenocarcinoma patients. The observations highlighted the significance of lipogenic enzymes mainly ACLY and fatty acid synthase as diagnostic markers in lung adenocarcinoma liquid biopsies.

Reactive oxygen species (ROS) cause oxidative stress and contribute to cancer genesis and progression. Metastasis-associated in colon cancer 1 (MACC1) is a key metastasis-mediating transcription factor in colorectal cancer (CRC). Whether ROS epigenetically regulated MACC1 expression and increased tumor progression in CRC have not been elucidated so far. We applied oxidative stress in two CRC cell lines with differential MACC1 expression (HCT116 and SW480) and analyzed the distribution of the histone marks H3K4me3 (active) and H4K20me3 (repressive), as well as the expression of MACC1. Alteration in cell motility by ROS was assayed with Boyden chambers. Abundance of H4K20me3 on the MACC1 promoter was determined by ChIP-seq. Induced oxidative stress in SW480 and HCT116 cells increased MACC1 mRNA and protein expression and enhanced cell migration. In the low MACC1 expression SW480 cells, oxidative stress resulted in a higher abundance of the active histone mark H3K4me3, and a lower abundance of repressive mark H4K20me3, both overall and specifically on the MACC1 promoter, compared with the medium MACC1 expression HCT116 cells. Analysis of histological abundances of H3K4me3 and H4K20me3 marks in a small panel of human CRC tumors showed an inverse correlation of H4K20me3 with MACC1. Experimentally, inhibition of H4K20me3 formation caused increased MACC1 mRNA expression in HCT116 cells. Conclusions, we reported a potential ROS-mediated epigenetic regulation of MACC1 expression in CRC through altered histone methylation, as our data suggested an initial epigenetic silencing of MACC1, which was later partially reactivated under oxidative stress.

Osteoking (OK) exerts bone formation-promoting effects on menopausal osteoporosis and osteoporotic fractures. However, it remains to be determined whether OK ameliorates type 2 diabetic osteoporosis (T2DOP) via PI3K/AKT/GSK-3β pathway activation. Thus, the T2DOP animal model was established in db/db mice in this study. Microcomputed tomography (micro-CT) analysis revealed that OK significantly increased bone strength, improved bone metabolism, and promoted bone formation. GS and p-GSK-3β expression levels were increased in OK group as compared with db/db group by western blot analysis. IL-6, IL-17A, IFN-γ, TNF-α, and IL-1β were lower levels in the OK group compared to the db/db group, nevertheless, the IL-10 level was significantly higher. Furthermore, an in vitro cells model was constructed by stimulating with high glucose (HG, 30 mM). ALP protein was significantly elevated in the OK treatment group. Administration of OK at 0.288 mg/mL significantly increased p-AKT/AKT expression, while, combined with LY294002, an inhibitor of PI3K, OK significantly reduced the expression levels of p-PI3K/PI3K, p-AKT/AKT, and p-GSK-3β/GSK-3β. In conclusion, this study reveals OK exhibits efficacy against T2DOP in db/db mice by promoting osteogenesis of preosteoblast MC3T3-E1 cells through PI3K/AKT/GSK-3β pathway regulation.

Individuals with type 1 diabetes mellitus (T1DM) experience an increased risk of cardiovascular disease (CVD). To improve early detection and prevention strategies, a better understanding of early vascular changes is needed. Although coronary artery (CA) damage is a known T1DM complication, its underlying proteomic basis remains unclear. This study used a proteomic approach to identify differentially expressed proteins in the CAs of T1DM rat models, with the goal of identifying novel proteins and pathways associated with early diagnosis and prevention of CA complications. We established a streptozotocin-induced T1DM model in male Sprague–Dawley rats and conducted tandem mass tag-based quantitative proteomics and bioinformatics analyses to investigate protein expression profiles in CAs. The analyses identified 443 differentially expressed proteins, with 229 upregulated and 214 downregulated proteins. Functional annotation and pathway enrichment analyses revealed that these proteins primarily participate in lipid metabolism, the peroxisome proliferator-activated receptor (PPAR) signaling pathway, peroxisome function, and butanoate metabolism. Validation experiments using Western blotting analysis and quantitative real-time PCR confirmed significant upregulation of 3-hydroxy-3-methylglutaryl coenzyme A synthase 2 (HMGCS2), fatty acid-binding protein 4 (FABP4), and platelet glycoprotein 4 (CD36) at the protein and mRNA levels in diabetic rat CAs, consistent with the proteomic results. Our findings indicate that HMGCS2, FABP4, and CD36 may serve as important molecular markers for the early diagnosis or therapeutic targeting of CA damage in T1DM. The observed molecular changes appear to be linked to the PPAR signaling pathway.

Clinical trial registration. Not applicable.