Melatonin pretreatment enhances the therapeutic effects of exogenous mitochondria against hepatic ischemia–reperfusion injury in rats through suppression of mitochondrial permeability transition |
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| Authors: | Hong‐Hwa Chen Yen‐Ta Chen Chih‐Chao Yang Kuan‐Hung Chen Pei‐Hsun Sung Hsin‐Ju Chiang Chih‐Hung Chen Sarah Chua Sheng‐Ying Chung Yi‐Ling Chen Tien‐Hung Huang Gour‐Shenq Kao Sheng‐Yi Chen Mel S. Lee Hon‐Kan Yip |
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| Affiliation: | 1. Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;2. Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;3. Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;4. Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;5. Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;6. Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;7. Divisions of General Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;8. Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;9. Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan;10. Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan;11. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan;12. Department of Nursing, Asia University, Taichung, Taiwan |
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| Abstract: | We tested the hypothesis that melatonin (Mel) enhances exogenous mitochondria (Mito) treatment against rodent hepatic ischemia–reperfusion (IR) injury. In vitro study utilized three groups of hepatocytes (i.e. nontreatment, menadione, and menadione–melatonin treatment, 4.0 × 105 each), while in vivo study used adult male Sprague Dawley rats (n = 40) equally divided into sham‐control (SC), IR (60‐min left‐lobe ischemia + 72‐hr reperfusion), IR‐Mel (melatonin at 30 min/6/8 hr after reperfusion), IR‐Mito (mitochondria 15,000 μg/rat 30 min after reperfusion), and IR‐Mel‐Mito. Following menadione treatment in vitro, oxidative stress (NOX‐1/NOX‐2/oxidized protein), apoptotic (cleaved caspase‐3/PARP), DNA damage (γ‐H2AX/CD90/XRCC1), mitochondria damage (cytosolic cytochrome c) biomarkers, and mitochondrial permeability transition were found to be lower, whereas mitochondrial cytochrome c were found to be higher in hepatocytes with melatonin treatment compared to those without (all P < 0.001). In vivo study demonstrated highest liver injury score and serum AST in IR group, but lowest in SC group and higher in IR‐Mito group than that in groups IR‐Mel and IR‐Mel‐Mito, and higher in IR‐Mel group than that in IR‐Mel‐Mito group after 72‐hr reperfusion (all P < 0.003). Protein expressions of inflammatory (TNF‐α/NF‐κB/IL‐1β/MMP‐9), oxidative stress (NOX‐1/NOX‐2/oxidized protein), apoptotic (caspase‐3/PARP/Bax), and mitochondria damage (cytosolic cytochrome c) biomarkers displayed an identical pattern, whereas mitochondria integrity marker (mitochondrial cytochrome c) showed an opposite pattern compared to that of liver injury score (all P < 0.001) among five groups. Microscopically, expressions of apoptotic nuclei, inflammatory (MPO + /CD68 + /CD14 + cells), and DNA damage (γ‐H2AX + cells) biomarkers exhibited an identical pattern compared to that of liver injury score (all P < 0.001) among five groups. Melatonin‐supported mitochondria treatment offered an additional benefit of alleviating hepatic IR injury. |
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| Keywords: | DNA and mitochondrial damage inflammation liver ischemia– reperfusion injury melatonin mitochondria oxidative stress |
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