Amiodarone is a widely used antiarrhythmic drug that can cause the development of steatohepatitis as well as liver fibrosis and cirrhosis. The molecular mechanisms of amiodarone-mediated liver injury remain largely unknown. We therefore analyzed amiodarone-mediated hepatocellular injury in patients with chronic heart failure, in primary hepatocytes and HepG2 cells. We found that amiodarone-treated patients with chronic heart failure revealed significantly higher serum levels of caspase-cleaved keratin-18, an apoptosis biomarker, compared to healthy individuals or patients not receiving amiodarone. Furthermore, amiodarone treatment of hepatocytes resulted in apoptosis associated with lipid accumulation and ER-stress induction. Liver cell steatosis was accompanied by enhanced de novo lipogenesis which, after reaching peak levels, declined together with decreased activation of ER stress. The decline of amiodarone-mediated lipotoxicity was associated with protective autophagy induction. In contrast, in hepatocytes treated with the autophagy inhibitor chloroquine as well as in autophagy gene (ATG5 or ATG7)-deficient hepatocytes, amiodarone-triggered toxicity was increased. In conclusion, we demonstrate that amiodarone induces lipid accumulation associated with ER stress and apoptosis in hepatocytes, which is mirrored by increased keratin-18 fragment serum levels in amiodarone-treated patients. Autophagy reduces amiodarone-mediated lipotoxicity and could provide a therapeutic strategy for protection from drug-induced liver injury.
Introduction Finding new markers to assess prognosis of melanoma without the necessity to perform a surgical interventions is an important goal in melanoma research. The current study aimed to assess the correlation of clinical course and prognosis of primary and metastatic melanoma with expression of VEGF family and their receptors. Methods A ngTMA block was made from the randomly selected paraffin tissue blocks of the patients with melanocytic nevi, primary and metastatic melanoma. Then sections cut from ngTMA-block were immunohistochemically stained with proper antibodies. Expression of these proteins was investigated using automated image analysis and compared among the study groups. Results We analyzed the tissue of 238 patients with following diagnoses: 101 (42.4%) with a diagnosis of nevus, 86 (36.1%) Malignant melanoma and 51 (21.4%) metastasis. Median follow-up time for the malignant lesions was 5.71 years. Among the tested antigen, VEGF-C (p = 0.016), VEGF-R2 (p<0.001) and VEGF-R3 (p = 0.002) were significantly higher expressed in the metastatic tissues. When these scores were assessed in multiple regression models, the only independent factor linked to patient's diagnosis was VEGF-R2 (p<0.001). In addition, groups of highly correlated variables (VEGF-C and VEGF-R3, VEGF-A and VEGF-R1) were found to form separate sub-clusters. On the other side, high values of VEGF-C were associated with both overall and disease-free survival with a statically significant HR of 2.76 (95% CI: 1.27, 5.98; p = 0.01) and 2.82 (95%CI: 1.62, 4.91; p<0.001), respectively. Conclusions This study shows that VEGF-C and VEGF-R2 might represent new prognostic marker in MM. However, further prospective studies are warranted to test their real efficacy as a prognostic marker.
Liu et al. find a non-canonical role for an autophagy-related protein, ATG12, in regulating mitochondrial biogenesis and cellular bioenergetics. Cells deficient in ATG12 show distinct global metabolic features, decreasing β-oxidation (FAO), glycolysis, Krebs cycle (TCA cycle) activity, mitochondrial respiration and mitochondrial biogenesis as compared to control cells, leading in consequence to an insufficient energy supply and finally oncotic cell death, which does not occur in ATG12-deficient fibroblasts. ATG12, that we could detect partly at a mitochondrial localization, was upregulated in diverse types of solid tumors compared to the normal tissues in a multi-organ tissue microarray (TMA), thus suggesting a potential role for ATG12 in regulating cancer cell metabolism. Inducing oncosis by imposing an ATG12 deficiency in solid tumors might represent an anti-cancer therapy preferable to conventional caspase-dependent apoptosis that often shows undesirable consequences, such as incomplete cancer cell killing and silencing of the host immune system.
