Biomolecules & Therapeutics  
Melatonin Rescues Mesenchymal Stem Cells from Senescence Induced by the Uremic Toxin p-Cresol via Inhibiting mTOR-Dependent Autophagy
Seung Pil Yun1, Yong-Seok Han2, Jun Hee Lee3, Sang Min Kim1 and Sang Hun Lee2,*
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, 2Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Republic of Korea, 3Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA
E-mail: ykckss1114@nate.com, jhlee0407@sch.ac.kr
Tel: +82-2-709-9029, Fax: +82-2-792-5812
Received: March 21, 2017; Revised: April 22, 2017; Accepted: April 26, 2017; Published online: June 27, 2017.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
p-Cresol, found at high concentrations in the serum of chronic kidney failure patients, is known to cause cell senescence and other complications in different parts of the body. p-Cresol is thought to mediate cytotoxic effects through the induction of autophagy response. However, toxic effects of p-cresol on mesenchymal stem cells have not been elucidated. Thus, we aimed to investigate whether p-cresol induces senescence of mesenchymal stem cells, and whether melatonin can ameliorate abnormal autophagy response caused by p-cresol. We found that p-cresol concentration-dependently reduced proliferation of mesenchymal stem cells. Pretreatment with melatonin prevented pro-senescence effects of p-cresol on mesenchymal stem cells. We found that by inducing phosphorylation of Akt and activating the Akt signaling pathway, melatonin enhanced catalase activity and thereby inhibited the accumulation of reactive oxygen species induced by p-cresol in mesenchymal stem cells, ultimately preventing abnormal activation of autophagy. Furthermore, preincubation with melatonin counteracted other pro-senescence changes caused by p-cresol, such as the increase in total 5′-AMP-activated protein kinase expression and decrease in the level of phosphorylated mechanistic target of rapamycin. Ultimately, we discovered that melatonin restored the expression of senescence marker protein 30, which is normally suppressed because of the induction of the autophagy pathway in chronic kidney failure patients by p-cresol. Our findings suggest that stem cell senescence in patients with chronic kidney failure could be potentially rescued by the administration of melatonin, which grants this hormone a novel therapeutic role.
Keywords: Chronic kidney disease, p-Cresol, Melatonin, Senescence, Autophagy


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