A team led by researchers at I-Shou University School of Medicine tested the hypothesis that combined melatonin and exogenic adipose mesenchymal stem cell (ADMSC)-derived exosome treatment offers superior protection against liver ischemia-reperfusion (LIR) injury compared to either alone. In vitro studies utilized a macrophage cell line (RAW) pretreated with lipopolysaccharide and hepatocytes pretreated with melatonin or exosomes before hypoxia treatment, while in vitro experiments involved analyses of liver specimens from male adult Sprague-Dawley rats (n = 50) equally categorized into sham controls (SC), LIR only, LIR-exosome (100 µg, 30 minute post-LIR), LIR-melatonin (20 mg/kg, 30 minute post-LIR and 50 mg/kg at 6 and 18 hours post-LIR), and LIR-exosome-melatonin groups. In vitro studies showed suppression of inflammation (MIF, MMP-9, IL-1β, TNF-α, COX-2) and oxidative stress (NOX-1, NOX-2, oxidized protein)/apoptosis (cleaved caspase 3 and PARP) by exosome and exosome/melatonin treatment, respectively (all P<0.001). In vivo data demonstrated lowest liver injury score and plasma AST concentrations in LIR-exosome-melatonin group compared with other groups (P<0.001).
Proposed mechanisms underlying protective effects of exosome-melatonin treatment against liver ischemia-reperfusion injury based on findings of this study
A: Suppression of inflammatory responses (i.e., upregulated expressions of pro-inflammatory biomarkers) in macrophage in vitro by exosomes after lipopolysaccharide (LPS) pre-treatment. B: In vitro alleviation of oxidative stress and apoptosis in hepatocytes after exosome/melatonin treatment before hypoxic stimulation. C: In vivo impacts of exosome/melatonin treatment on inflammation, oxidative stress, DNA damage, mitochondrial damage, apoptosis, and immune reactions that contribute to impaired hepatocyte and histological integrity.
In conclusion, combined exosome-melatonin regimen was superior to either alone in protecting the liver against ischemia-reperfusion injury.