The pathogenesis of non-alcoholic steatohepatitis (NASH) involves the simultaneous interaction of multiple factors such as lipid accumulation, oxidative stress, and inflammatory response. Here, the effect of human serum albumin (HSA) fused to thioredoxin (Trx) on NASH was investigated. Trx is known to have anti-oxidative, anti-inflammatory, and anti-apoptotic effects. However, Trx is a low molecular weight protein and is rapidly eliminated from the blood. To overcome the low availability of Trx, HSA-Trx fusion protein was produced and evaluated the therapeutic effect on high-fat diet (HFD)-induced NASH model mice. HSA-Trx administered before the formation of NASH pathology showed it to have a preventive effect. Specifically, HSA-Trx was found to prevent the pathological progression to NASH by suppressing lipid accumulation, liver injury markers, and liver fibrosis. When HSA-Trx was administered during the early stage of NASH there was a marked reduction in lipid accumulation, inflammation, and fibrosis in the liver, indicating that HSA-Trx ameliorates NASH pathology. The findings indicate that HSA-Trx influences multiple pathological factors, such as oxidative stress, inflammation, and apoptosis, to elicit a therapeutic benefit. HSA-Trx also inhibited palmitic acid-induced lipotoxicity in HepG2 cells. Taken together, these results indicate that HSA-Trx has potential as a therapeutic agent for NASH pathology.
Cisplatin-induced acute kidney injury (AKI) is an important factor that limits the clinical use of this drug for the treatment of malignancies. Oxidative stress and inflammation are considered to be the main causes of not only cisplatin-induced death of cancer cells but also cisplatin-induced AKI. Therefore, developing agents that exert antioxidant and anti-inflammatory effects without weakening the anti-tumor effects of cisplatin is highly desirable. Carbon monoxide (CO) has recently attracted interest due to its antioxidant, anti-inflammatory, and anti-tumor properties. Herein, we report that CO-loaded red blood cell (CO-RBC) exerts renoprotective effects on cisplatin-induced AKI. Cisplatin treatment was found to reduce cell viability in proximal tubular cells via oxidative stress and inflammation. Cisplatin-induced cytotoxicity, however, was suppressed by the CO-RBC treatment. The intraperitoneal administration of cisplatin caused an elevation in the blood urea nitrogen and serum creatinine levels. The administration of CO-RBC significantly suppressed these elevations. Furthermore, the administration of CO-RBC also reduced the deterioration of renal histology and tubular cell injury through its antioxidant and anti-inflammatory effects in cisplatin-induced AKI mice. Thus, our data suggest that CO-RBC has the potential to substantially prevent the onset of cisplatin-induced AKI, which, in turn, may improve the usefulness of cisplatin-based chemotherapy.
