Molecular and Cellular Biochemistry最新文献

Spindle and kinetochore-associated complex subunit 3 (SKA3) contributes to tumor growth and metastasis, but its specific roles have not been clearly elucidated. In this study, we found that SKA3 contributed to lung adenocarcinoma (LUAD) progression by interacting with integrin β1. The expression characteristics of SKA3 in LUAD patients were analyzed by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets and validated in 33 paired LUAD tissues by immunohistochemistry. Our data confirmed that SKA3 was a crucial regulator of LUAD progression and was associated with worse patient survival. In vitro and in vivo studies showed that SKA3 increased cell migration and invasion. Mechanistically, it was demonstrated that SKA3 could bind to integrin β1 and promote its activation, which further promoted the activation of EGFR. As a positive feedback loop, the activation of EGFR in turn promoted the expression of SKA3 via E2F1-mediated transcriptional regulation. Inhibition of EGFR with AZD9291 blocked SKA3 signaling induced by E2F1. These results indicated that SKA3 was crucial for the activation of EGFR and its downstream signaling pathway. Our findings uncovered the oncogenic role of SKA3 in LUAD progression and elucidated a novel EGFR/E2F1/SKA3/integrin β1 signaling loop, providing a potential SKA3-directed therapeutic strategy for LUAD patients.

The increasing prevalence of early onset coronary artery disease (CAD) in individuals under 50 presents a significant public health challenge, with substantial impacts on quality of life and escalating healthcare costs. Human papillomavirus (HPV), a pervasive sexually transmitted infection, has emerged as a potential contributor to atherosclerotic lesion development. This article explores the complex inflammatory pathways HPV infection activates that could contribute to atherogenesis. HPV may contribute to CAD by influencing components of metabolic syndrome. Investigating these interactions could provide new insights into disease mechanisms. The virus's capacity to cause cellular immortalization, leading to uncontrolled growth and proliferation, may also play a role in the advancement of atherosclerotic lesions in CAD patients. HPV may represent a novel risk factor for CAD, warranting further research into preventive strategies, including vaccination. This understanding opens new opportunities for effective research and intervention to address this significant public health issue. The significant association between HPV and CAD emphasizes the need for further investigation to develop preventive measures and treatment strategies, especially important for reducing the increasing incidence of CAD in younger populations.

Macrophages polarization play crucial roles in regulating inflammation and functional recovery after spinal cord injury (SCI). This study aimed to investigate the key macrophage polarization-related genes (MPRGs) for the treatment of SCI. Our research involved identifying differentially expressed genes (DEGs), using immune infiltration analysis, weighted gene co-expression network analysis (WGCNA) and machine learning to screening out key MPRGs in the GSE5296. The discriminative potential of MPRGs were validated using expression analysis and receiver operating characteristic (ROC) curves in the GSE45376, while the distribution of hub MPRGs in different cell subtypes were visualized in the single-cell dataset GSE189070. The relationship between the MPRGs and immune infiltration was investigated through correlation analysis. Finally, we detected the effect of blocking sterol O-acyltransferase 1 (SOAT1) on macrophage polarization and functional recovery of SCI. A total of 52 MPRGs were identified. Elevated immune infiltration levels and activation of macrophage-associated biological pathways were noted after SCI. Machine learning determined SOAT1, LGALS3, HAVCR2, IRF8 and PTPRC as the hub MPRGs. External validation confirmed their expression, robust predictive value and distribution patterns. Immune infiltration analysis highlighted the strong correlation between SOAT1 and macrophages. Further, inhibiting of SOAT1 could enhance M2 macrophage polarization, improve inflammatory environment and promote functional recovery of SCI. Our study enhances the understanding of macrophage polarization-related genes in the inflammatory responses of SCI. Targeting SOAT1 emerges as a promising therapeutic strategy for SCI repair.

Non-small cell lung cancer (NSCLC) is a highly prevalent and aggressive malignancy, where early diagnosis and therapeutic intervention are pivotal for enhancing patient prognosis. Nonetheless, the lack of reliable biomarkers remains a substantial hurdle in clinical practice. In this study, we identified dysregulated microRNAs (miRNAs) in NSCLC, revealing a significant downregulation of miR-3202 and an upregulation of miR-3182. We demonstrate that both miR-3202 and miR-3182 play critical roles in modulating NSCLC cell proliferation and motility. Notably, we identify DTL as a direct target of miR-3202, with sustained expression of DTL reversing the effects of miR-3202 on cell growth and migration. Mechanistically, we show that miR-3202 regulates the ubiquitination and proteasomal degradation of p21 through DTL. These findings provide novel insights into the miRNA landscape in NSCLC and underscore the functional significance of the miR-3202-DTL-p21 axis. Our results position miR-3202 as a potential biomarker for NSCLC, thereby offering a foundation for the development of targeted diagnostic and therapeutic strategies.

Emerging evidence indicates that chloride channels (ClCs) significantly affect the pathogenesis of inflammatory bowel disease (IBD) through their regulatory roles in mast cell function and epithelial integrity. IBD, encompassing conditions such as Crohn's disease and ulcerative colitis, involves chronic inflammation of the gastrointestinal tract, where channels influence immune responses, fluid balance, and cellular signalling pathways essential for maintaining mucosal homeostasis. This review examines the specific roles of ClC in mast cells, focussing on the regulation of mast cell activation, degranulation, cytokine release, and immune cell recruitment in inflamed tissues. Key channels, including Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and ClC-2, are discussed in detail because of their involvement in maintaining intestinal epithelial barrier function, a critical factor disrupted in IBD. For example, CFTR facilitates chloride ion transport across epithelial cells, which is essential for mucosal hydration and maintenance of the intestinal barrier. Reduced CFTR function can compromise this barrier, permitting microbial antigens to penetrate the underlying tissues and triggering excessive immune responses. ClC-2, another chloride channel expressed in mast cells and epithelial cells, supports tight junction integrity, contributes to barrier function, and reduces intestinal permeability. Dysregulation of these channels is linked to altered mast cell activity and excessive release of pro-inflammatory mediators, exacerbating IBD symptoms, such as diarrhoea, abdominal pain, and tissue damage. Here, we review recent pharmacological strategies targeting ClC, including CFTR potentiators and ClC-2 activators, which show the potential to mitigate inflammatory responses. Additionally, experimental approaches for selective modulation of chloride channels in mast cells have been explored. Although targeting ClC offers promising therapeutic avenues, challenges remain in achieving specificity and minimizing side effects. This review highlights the therapeutic potential of Cl channel modulation in mast cells as a novel approach for IBD treatment, aiming to reduce inflammation and restore intestinal homeostasis in affected patients.

Hepatocellular carcinoma (HCC) is one of the most common cancers, and diabetes is a risk factor for hepatocarcinogenesis. N6-methyladenosine (m6A) methyltransferase WT1-associated protein (WTAP) is highly expressed in HCC and contributes to tumor progression. However, its role in high glucose-driven HCC progression remains unclear. The m6A quantitative assay was used to detect the m6A modification level. The levels of mRNAs and proteins were detected by qPCR, Western blot, and immunohistochemistry. CCK-8, colony formation, EdU, and transwell assays were used to detect HCC cell proliferation, invasion, and migration. Immunoprecipitation and CHX assays were used to reveal the regulatory effect of high glucose on WTAP. An RNA degradation experiment was used to explore WTAP's regulation of HK2 mRNA. To demonstrate the effect of high glucose on HCC growth in vivo, a diabetic mouse model was constructed, and HCC cells were subcutaneously injected. High glucose prominently increased the global level of m6A in HCC cells. Interestingly, high glucose upregulated WTAP protein rather than mRNA expression. We found that WTAP expression was significantly upregulated in HCC tissues, especially in tumor tissues of diabetic patients. WTAP knockdown markedly attenuated high glucose-induced abilities of HCC cell proliferation, colony formation, migration, and invasion. Meanwhile, WTAP overexpression significantly enhanced the malignant behaviors of HCC cells under low glucose conditions. High glucose reduced the ubiquitination of WTAP, thereby inhibiting its proteasomal and lysosomal degradation. Phosphorylated ERK (p-ERK) was required for high glucose-mediated WTAP stability. WTAP knockdown prominently abrogated high glucose-induced global m6A levels and HK2 expression in HCC cells. WTAP positively regulated HK2 expression by increasing mRNA stability. HK2 overexpression remarkably reversed the suppressive effects of WTAP knockdown on HCC cells. HK2 knockdown prominently abolished the promoting role of WTAP in HCC cells. Importantly, the growth of HCC cells in diabetic mice was significantly faster than that in control mice, which was prominently attenuated by WTAP knockdown. Our study demonstrated that high glucose decreased WTAP degradation and maintained its protein level by activating ERK phosphorylation. WTAP promoted HCC cell proliferation, colony formation, migration, and invasion by stabilizing HK2 mRNA.

Polycythemia vera (PV) is the most common chronic myeloproliferative neoplasm (MPN) in adults. Pegylated interferon-α2 (IFN-α2) is an effective and safe drug for the treatment of PV. However, the mechanisms of its action in PV are still not fully understood. Using the WGCNA and Limma algorithm, we found a subset of IFN-α2 sensitive genes and four gene co-expression modules. Meanwhile, we also found 820 genes were differentially expressed in PV compared with healthy controls. By integrating the above results, several differentially expressed genes (DEGs) that were up- or down-regulated in PV but showed opposite alterations in the IFN-α2-treated group were found. These genes were mainly related to three types of biological processes (metal ion homeostasis, metabolic/catabolic process, and Jak-STAT signaling pathway), the dysfunctions of which were prevalent in PV. Moreover, we applied another threshold-free analysis method to compare global gene expression between IFN-α2 treated PV, PV, and control groups. Results showed the transcriptome changes of PV versus controls were negatively correlated with that of IFN-α2 treated versus untreated PV, indicating IFN-α2 treatment could partially reverse the dysregulated gene expression profile due to PV pathology. In summary, interferon may alleviate the progression of PV through multiple pathways. The findings may be of assistance in understanding the molecular basis underlying this treatment.

Diabetes is a well-known risk factor for atherosclerosis (AS), but the underlying molecular mechanism remains unknown. The dysregulated immune response is an important reason. High glucose is proven to induce foam cell formation under lipidemia situations in clinical patients. Exploring the potential regulatory programs of accelerated foam cell formation stimulated by high glucose is meaningful. Macrophage-derived foam cells were induced in vitro, and high-throughput sequencing was performed. Coexpression gene modules were constructed using weighted gene co-expression network analysis (WGCNA). Highly related modules were identified. Hub genes were identified by multiple integrative strategies. The potential roles of selected genes were further validated in bulk-RNA and scRNA datasets of human plaques. By transfection of the siRNA, the role of the screened gene during foam cell formation was further explored. Two modules were found to be both positively related to high glucose and ox-LDL. Further enrichment analyses confirmed the association between the brown module and AS. The high correlation between the brown module and macrophages was identified and 4 hub genes (Aldoa, Creg1, Lgmn, and Pkm) were screened. Further validation in external bulk-RNA and scRNA revealed the potential diagnostic and therapeutic value of selected genes. In addition, the survival analysis confirmed the prognostic value of Aldoa while knocking down Aldoa expression alleviated the foam cell formation in vitro. We systematically investigated the synergetic effects of high glucose and ox-LDL during macrophage-derived foam cell formation and identified that ALDOA might be an important diagnostic, prognostic, and therapeutic target in these patients.

Partial least squares structural equation modeling is a simple approach that may be used to determine the factors associated with diseases. In the current study, we aimed to explore the most associated high-sensitivity C-reactive protein (hs-CRP) as well as hematologic-inflammatory indices for the risk of cardiovascular disease (CVD). A total of 7362 healthy (non-CVD) participants aged 35-65 years old from baseline investigation were evaluated in the Phase 2 follow-up. Of these, 1022 individuals were found to have CVDs in the second phase (10-year follow-up) of the Mashhad Stroke and Heart Atherosclerotic Disorder (MASHAD) cohort study. We used partial least squares structural equation modeling to develop a prediction model for association of CVD risk factors and hs-CRP as well as hematologic-inflammatory indices in the study population. According to the study, age had the most significant impact on the presence of CVD. Increasing in age by one unit raises the risk of CVD by 0.166. Also, serum hs-CRP was found to have the second-highest impact on CVD; increasing in age by one unit raises the risk of CVD by 0.042. The study also discovered a strong and significant correlation between red cell distribution width (RDW) and CVD. Moreover, the study found that several factors such as hemoglobin (HGB), neutrophil (NEUT), neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and platelet-to-lymphocyte ratio (PLR) have indirect effects on CVD that are mediated by hs-CRP while controlling for age, sex and social-economic factors. Generally, the results showed that age, hs-CRP, and RDW were the most important risk factors on CVD.

Cardiovascular disease is one of the leading causes of mortality worldwide, primarily driven by atherosclerosis, a chronic inflammatory condition contributing significantly to fatalities. Various biological determinants affecting cardiovascular health across different age and sex groups have been identified. In this context, recent attention has focused on the potential therapeutic and preventive role of increasing circulating levels of heat shock protein 27 (plasma HSP27) in combating atherosclerosis. Plasma HSP27 is recognized for its protective function in inflammatory atherogenesis, offering promising avenues for intervention and management strategies against this prevalent cardiovascular ailment. Exercise has emerged as a pivotal strategy in preventing and managing cardiovascular disease, with literature indicating an increase in plasma HSP27 levels post-exercise. However, there is limited understanding of the impact of exercise on the release of HSP27 into circulation. Clarifying these aspects is crucial for understanding the role of exercise in modulating plasma HSP27 levels and its potential implications for cardiovascular health across diverse populations. Therefore, this review aims to establish a more comprehensive understanding of the relationship between plasma HSP27 and exercise.