未经证实:驱动从早期慢性肝病(CLD)进展为肝硬化的分子机制,最后,慢性急性肝衰竭(ACLF)在很大程度上是未知的.我们的目标是开发一种基于蛋白质网络的方法来研究驱动从早期CLD到ACLF进展的分子途径。
UNASSIGNED:对不同肝病阶段患者的肝活检进行转录组分析,包括纤维化,代偿性肝硬化,失代偿期肝硬化和ACLF,控制健康的肝脏。我们创建了9个肝脏特异性疾病相关的蛋白质-蛋白质相互作用网络,捕获潜在与CLD相关的关键病理生理过程。我们使用这些网络作为框架,并进行基因集富集分析(GSEA)以鉴定疾病进展的动态基因谱。
未经评估:主成分分析显示,样本根据疾病分期进行聚类。确定过程的GSEA显示炎症的上调,整个疾病进展过程中的纤维化和凋亡网络。有趣的是,我们没有发现补偿和失代偿期肝硬化之间的显著基因表达差异,而ACLF在所有定义的肝病相关网络中均显示出急性表达变化。疾病进展模式的分析确定了与ACLF发作相关的上升和下降表达谱。功能分析显示,上升的轮廓与炎症有关,纤维化,凋亡,衰老和致癌作用网络,而下降谱主要与氧化应激和遗传因素有关。我们通过qPCR确认了上升谱基因的上调,并在独立的患者队列中验证了我们的发现。
UNASSIGNED:ACLF的特征是与炎症相关的特定肝基因表达模式,纤维化,凋亡,衰老和致癌作用。此外,观察到的情况与代偿和失代偿期肝硬化的情况明显不同,支持ACLF应被视为一个独特实体的假设。
UNASSIGNED:通过使用从慢性肝病不同阶段患者获得的经颈静脉活检,我们揭示了慢性肝病进展为肝硬化和慢性急性肝衰竭的分子致病机制。这项研究中最相关的发现是,慢性急性肝衰竭患者呈现出与早期疾病阶段患者不同的特定肝基因表达模式。这种基因表达模式主要与炎症有关,纤维化,血管生成,以及肝脏中的衰老和凋亡途径。
UNASSIGNED: The molecular mechanisms driving the progression from early-chronic liver disease (CLD) to cirrhosis and, finally, acute-on-chronic liver failure (ACLF) are largely unknown. Our aim was to develop a protein network-based approach to investigate molecular pathways driving progression from early-CLD to ACLF.
UNASSIGNED: Transcriptome analysis was performed on liver biopsies from patients at different liver disease stages, including fibrosis, compensated cirrhosis, decompensated cirrhosis and ACLF, and control healthy livers. We created 9 liver-specific disease-related protein-protein interaction networks capturing key pathophysiological processes potentially related to CLD. We used these networks as a framework and performed gene set-enrichment analysis (GSEA) to identify dynamic gene profiles of disease progression.
UNASSIGNED: Principal component analyses revealed that samples clustered according to the disease stage. GSEA of the defined processes showed an upregulation of inflammation, fibrosis and apoptosis networks throughout disease progression. Interestingly, we did not find significant gene expression differences between compensated and decompensated cirrhosis, while ACLF showed acute expression changes in all the defined liver disease-related networks. The analyses of disease progression patterns identified ascending and descending expression profiles associated with ACLF onset. Functional analyses showed that ascending profiles were associated with inflammation, fibrosis, apoptosis, senescence and carcinogenesis networks, while descending profiles were mainly related to oxidative stress and genetic factors. We confirmed by qPCR the upregulation of genes of the ascending profile and validated our findings in an independent patient cohort.
UNASSIGNED: ACLF is characterized by a specific hepatic gene expression pattern related to inflammation, fibrosis, apoptosis, senescence and carcinogenesis. Moreover, the observed profile is significantly different from that of compensated and decompensated cirrhosis, supporting the hypothesis that ACLF should be considered a distinct entity.
UNASSIGNED: By using transjugular biopsies obtained from patients at different stages of chronic liver disease, we unveil the molecular pathogenic mechanisms implicated in the progression of chronic liver disease to cirrhosis and acute-on-chronic liver failure. The most relevant finding in this study is that patients with acute-on-chronic liver failure present a specific hepatic gene expression pattern distinct from that of patients at earlier disease stages. This gene expression pattern is mostly related to inflammation, fibrosis, angiogenesis, and senescence and apoptosis pathways in the liver.