ABSTRACT
OBJECTIVE: Previous studies reported that pirfenidone (PFD) is associated with liver disease. However, the effects of pirfenidone on energy metabolism and hepatic lipid accumulation are still poorly understood. METHODS: In this study, C57BL/6J mice were randomly divided into two groups, and fed a normal chow diet (NCD) or a high-fat diet (HFD) for 16 weeks. At the end of the eighth week, half of the mice fed on both diets were treated with PFD. Biochemical and lipid metabolism-related indices were analyzed. Furthermore, Hepa 1-6 cells and mouse primary hepatocytes (MPHs) were incubated with PFD with or without free fatty acid (FFA) treatment. Then, stattic (a p-STAT3 inhibitor) or Ad-shSTAT3 was used to further elucidate the effects of Signal Transducer and Activator of Transcription 3 (STAT3) signaling on PFD regulation of hepatic steatosis. RESULTS: PFD ameliorated obesity and hepatic lipid deposition in HFD mice by decreasing stearoyl-CoA desaturase 1 (SCD1) expression and upregulating p-STAT3 in the liver. In Hepa 1-6 cells and MPHs, PFD also down-regulated the expression of SCD1. STAT3 inhibition treatment eliminated the benefits of PFD on both SCD1 and hepatic steatosis. CONCLUSION: In summary, our data reveal that PFD may play an important role in mitigating hepatic steatosis in a STAT3-SCD1-dependent manner.
Subject(s)
Fatty Liver , STAT3 Transcription Factor , Mice , Animals , STAT3 Transcription Factor/metabolism , Mice, Inbred C57BL , Fatty Liver/drug therapy , Fatty Liver/metabolism , Liver/metabolism , Diet, High-Fat , LipidsABSTRACT
Pulmonary vascular endothelial dysfunction is a key pathogenic mechanism in acute respiratory distress syndrome (ARDS), resulting in fibrosis in lung tissues, including in the context of COVID-19. Pirfenidone (PFD) has become a novel therapeutic agent for treating idiopathic pulmonary fibrosis (IPF) and can improve lung function, inhibit fibrosis and inhibit inflammation. Recently, endothelial-to-mesenchymal transition (EndMT) was shown to play a crucial role in various respiratory diseases. However, the role of PFD in the course of EndMT in LPS-induced ARDS remains poorly understood. The purpose of this study was to explore the anti-EndMT effects of PFD on pulmonary fibrosis after LPS-induced ARDS. First, we determined that PFD significantly reduced LPS-induced ARDS, as shown by significant pathological alterations, and alleviated the oxidative stress and inflammatory response in vitro and in vivo. Furthermore, PFD decreased pulmonary fibrosis in LPS-induced ARDS by inhibiting EndMT and reduced the expression levels of Hedgehog (HH) pathway target genes, such as Gli1 and α-SMA, after LPS induction. In summary, this study confirmed that inhibiting the HH pathway by PFD could decrease pulmonary fibrosis by downregulating EndMT in LPS-induced ARDS. In conclusion, we demonstrate that PFD is a promising agent to attenuate pulmonary fibrosis following ARDS in the future.
Subject(s)
Hedgehog Proteins , Pulmonary Fibrosis , Pyridones , Respiratory Distress Syndrome , Animals , Hedgehog Proteins/metabolism , Lipopolysaccharides , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pyridones/pharmacology , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/drug therapy , Signal TransductionABSTRACT
ABSTRACT: The effects of ferroptosis, an iron-dependent cell death, on acute respiratory distress syndrome (ARDS) remain largely elusive. Hepcidin, encoded by the HAMP gene, affects inflammation, and iron homeostasis. The present study aimed to investigate whether hepcidin protects against ferroptosis in lipopolysaccharide (LPS)-induced ARDS. Our results confirmed that ferroptosis aggravated lung inflammation and damage in LPS-induced ARDS. Hepcidin defended against ferroptosis, with results similar to those of the ferroptosis inhibitor ferrostatin-1 (Fer-1). Moreover, hepcidin decreased iron uptake, as determined by Transferrin Receptor 1 (TfR1) expression levels, and increased iron storage, based on ferritin heavy chain (FTH) expression. The effects of hepcidin on the A549 cell line were in line with the in vivo results. In addition, we used si-FTH to knock down FTH expression and found that this suppressed the ability of hepcidin to protect against ferroptosis. Collectively, our data suggest that hepcidin inhibits ferroptosis by increasing FTH expression in LPS-induced ARDS; thus, hepcidin may represent a possible treatment targeting ferroptosis.
Subject(s)
Ferritins , Ferroptosis , Hepcidins , Lipopolysaccharides , Respiratory Distress Syndrome , Hepcidins/metabolism , Humans , Iron/metabolism , Lipopolysaccharides/toxicity , Oxidoreductases , Respiratory Distress Syndrome/chemically inducedABSTRACT
Background: Coronavirus disease 2019 (COVID-19) is spreading throughout the world. Limited data are available for recurrence of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in patients with long duration of COVID-19. Methods: We reported four cases recovered from COVID-19 with recurrence of positive SARS-CoV-2 results during the long-term follow-up. Results: The four patients recovered from COVID-19 showed recurrence of positive SARS-CoV-2 results for more than 120 days with no symptoms and normal chest CT scan. Conclusions: The dynamic surveillance of SARS-CoV-2 by nucleic acid detection and serological assays is important for asymptomatic patients who might be potentially infectious.
