Melatonin treatment enhances therapeutic effects of exosomes

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.

Sun CK, Chen CH, Chang CL, Chiang HJ, Sung PH, Chen KH, Chen YL, Chen SY, Kao GS, Chang HW, Lee MS, Yip HK. (2017) Melatonin treatment enhances therapeutic effects of exosomes against acute liver ischemia-reperfusion injury. Am J Transl Res 9(4):1543-1560. [article]

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