Nonalcoholic fatty liver disease (NAFLD) has emerged as a common public health problem in recent decades. However, the underlying mechanisms leading to the development of NAFLD are not fully understood. The endoplasmic reticulum (ER) stress response has recently been proposed to play a crucial role in both the development of steatosis and progression to nonalcoholic steatohepatitis. ER stress is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed due to the accumulation of unfolded or misfolded proteins. However, delayed or insufficient responses to ER stress may turn physiological mechanisms into pathological consequences, including fat accumulation, insulin resistance, inflammation, and apoptosis, all of which play important roles in the pathogenesis of NAFLD. Therefore, understanding the role of ER stress in the pathogenesis of NAFLD has become a topic of intense investigation. This review highlights the recent findings linking ER stress signaling pathways to the pathogenesis of NAFLD.
Background Magnifying endoscopy with narrow band imaging (M-NBI) has been applied to examine early gastric cancer by observing microvascular architecture and microsurface structure of gastric mucosal lesions. However, the diagnostic efficacy of non-experts in differentiating early gastric cancer from non-cancerous lesions by M-NBI remained far from satisfactory. In this study, we developed a new system based on convolutional neural network (CNN) to analyze gastric mucosal lesions observed by M-NBI. Methods A total of 386 images of non-cancerous lesions and 1702 images of early gastric cancer were collected to train and establish a CNN model (Inception-v3). Then a total of 341 endoscopic images (171 non-cancerous lesions and 170 early gastric cancer) were selected to evaluate the diagnostic capabilities of CNN and endoscopists. Primary outcome measures included diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. Results The sensitivity, specificity, and accuracy of CNN system in the diagnosis of early gastric cancer were 91.18%, 90.64%, and 90.91%, respectively. No significant difference was spotted in the specificity and accuracy of diagnosis between CNN and experts. However, the diagnostic sensitivity of CNN was significantly higher than that of the experts. Furthermore, the diagnostic sensitivity, specificity and accuracy of CNN were significantly higher than those of the non-experts. Conclusions Our CNN system showed high accuracy, sensitivity and specificity in the diagnosis of early gastric cancer. It is anticipated that more progress will be made in optimization of the CNN diagnostic system and further development of artificial intelligence in the medical field.
Nonalcoholic fatty liver disease (NAFLD) has emerged as a common public health problem that can progress to end-stage liver disease. A high-fat diet (HFD) may promote the development of NAFLD through a mechanism that is poorly understood. We adopted a proteomic approach to examine the effect of HFD on the liver proteome during the progression of NAFLD. Male Sprague-Dawley rats fed an HFD for 4, 12, and 24 weeks replicated the progression of human NAFLD: steatosis, nonspecific inflammation, and steatohepatitis. Using two-dimensional difference gel electrophoresis (DIGE) combined with matrix-assisted laser desorption ionization time of flight/time of flight analysis, 95 proteins exhibiting significant changes (ratio > 1.5 or <؊1.5, P < 0.05) during the development of NAFLD were identified. Biological functions for these proteins reflected phase-specific characteristics during the progression of the disease. The potential role of enoyl-coenzyme A hydratase (ECHS1), an enzyme that catalyzes the second step of mitochondrial fatty acid beta-oxidation, received further investigation. First, the reduced protein level of ECHS1 was validated both in rat models and in patients with biopsy-proven hepatic simple steatosis via immunoblotting or immunohistochemical analysis. Then the small interfering RNA (siRNA)-mediated knockdown of ECHS1 in the murine hepatocyte cell line alpha mouse liver 12 (AML12) demonstrated increased cellular lipid accumulation induced by free fatty acid (FFA) overload. Furthermore, using a hydradynamic transfection method, the in vivo silencing effect of siRNA duplexes targeting ECHS1 was further investigated in mice. Administering ECHS1 siRNA specifically reduced the expression of ECHS1 protein in mice liver, which significantly exacerbated the hepatic steatosis induced by an HFD. Conclusion: Our results revealed that ECHS1 down-regulation contributed to HFD-induced hepatic steatosis, which may help clarify the pathogenesis of NAFLD and point to potential targets for therapeutic interventions. (HEPATOLOGY 2010;51:1190-1199
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