Melatonin attenuates renal fibrosis in diabetic mice by activating the AMPK/PGC1α signaling pathway and rescuing mitochondrial function

Li,Jian; Li,Nan; Yan,Shuangtong; Lu,Yanhui; Miao,Xinyu; Gu,Zhaoyan; Shao,Yinghong

doi:10.3892/mmr.2018.9708

Melatonin attenuates renal fibrosis in diabetic mice by activating the AMPK/PGC1α signaling pathway and rescuing mitochondrial function

Authors:
- Jian Li
- Nan Li
- Shuangtong Yan
- Yanhui Lu
- Xinyu Miao
- Zhaoyan Gu
- Yinghong Shao
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Affiliations: Department of Geriatric Endocrinology, Chinese PLA General Hospital, National Clinical Center of Geriatric Medicine, Beijing 100853, P.R. China, Outpatient Department, Chinese PLA General Hospital, Beijing 100853, P.R. China
Published online on: November 29, 2018 https://doi.org/10.3892/mmr.2018.9708
Pages: 1318-1330

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Abstract

Mitochondrial homeostasis is a highly regulated process that serves a critical role in the maintenance of renal structure and function. The growing interest in the field of mitochondrial homeostasis promises to provide more information regarding the mechanisms involved in diabetic renal fibrosis, and aid in the development of novel strategies to combat the disease. In the present study, the effects of melatonin on renal damage in mice with diabetes were evaluated and the underlying mechanisms were investigated. Cellular apoptosis was determined using TUNEL assay and western blotting. Mitochondrial function was measured using fluorescence assay and western blotting. The results indicated that diabetic renal fibrosis was associated with 5'adenosine monophosphate‑activated protein kinase (AMPK) downregulation. However, melatonin administration rescued AMPK activity, reduced diabetic renal fibrosis, alleviated glomerular apoptosis and preserved kidney function. The functional experiments demonstrated that melatonin‑induced AMPK activation enhanced peroxisome proliferator‑activated receptor γ coactivator 1‑α (PGC1α) expression, sustained mitochondrial function and blocked mitochondrial apoptosis, leading to protection of the glomerulus against glucotoxicity. However, loss of AMPK and PGC1α negated the protective effects of melatonin on mitochondrial homeostasis, glomerular survival and diabetic renal fibrosis. In summary, the present study revealed that melatonin rescued impaired mitochondrial function and reduced glomerular apoptosis in the context of diabetic renal fibrosis by activating the AMPK/PGC1α pathway.

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1	Hung YC, Lin YC, Hsieh HM, Huang CJ and Chiu HC: Impact of non-apnea sleep disorders on diabetic control and metabolic outcome-A population-based cohort study. Gen Hosp Psychiatry. 52:1–7. 2018. View Article : Google Scholar : PubMed/NCBI
2	Zaman SB, Karim MA, Hossain N, Al Kibria GM and Islam SMS: Plasma triglycerides as a risk factor for chronic kidney disease in type 2 diabetes mellitus: Evidence from the northeastern of Thailand. Diabetes Res Clin Pract. 138:238–245. 2018. View Article : Google Scholar : PubMed/NCBI
3	Hu S, Gao Y, Zhou H, Kong F, Xiao F, Zhou P and Chen Y: New insight into mitochondrial changes in vascular endothelial cells irradiated by gamma ray. Int J Radiat Biol. 93:470–476. 2017. View Article : Google Scholar : PubMed/NCBI
4	Li R, Xin T, Li D, Wang C, Zhu H and Zhou H: Therapeutic effect of Sirtuin 3 on ameliorating nonalcoholic fatty liver disease: The role of the ERK-CREB pathway and Bnip3-mediated mitophagy. Redox Biol. 18:229–243. 2018. View Article : Google Scholar : PubMed/NCBI
5	Zhou H, Wang J, Zhu P, Hu S and Ren J: Ripk3 regulates cardiac microvascular reperfusion injury: The role of IP3R-dependent calcium overload, XO-mediated oxidative stress and F-action/filopodia-based cellular migration. Cell Signal. 45:12–22. 2018. View Article : Google Scholar : PubMed/NCBI
6	Zhou H, Yang J, Xin T, Li D, Guo J, Hu S, Zhou S, Zhang T, Zhang Y, Han T and Chen Y: Exendin-4 protects adipose-derived mesenchymal stem cells from apoptosis induced by hydrogen peroxide through the PI3K/Akt-Sfrp2 pathways. Free Radic Biol Med. 77:363–375. 2014. View Article : Google Scholar : PubMed/NCBI
7	Zhang Y, Zhou H, Wu W, Shi C, Hu S, Yin T, Ma Q, Han T, Zhang Y, Tian F and Chen Y: Liraglutide protects cardiac microvascular endothelial cells against hypoxia/reoxygenation injury through the suppression of the SR-Ca(2+)-XO-ROS axis via activation of the GLP-1R/PI3K/Akt/survivin pathways. Free Radic Biol Med. 95:278–292. 2016. View Article : Google Scholar : PubMed/NCBI
8	Zhou H, Li D, Shi C, Xin T, Yang J, Zhou Y, Hu S, Tian F, Wang J and Chen Y: Effects of Exendin-4 on bone marrow mesenchymal stem cell proliferation, migration and apoptosis in vitro. Sci Rep. 5:128982015. View Article : Google Scholar : PubMed/NCBI
9	Zhou H, Wang J, Zhu P, Zhu H, Toan S, Hu S, Ren J and Chen Y: NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2α. Basic Res Cardiol. 113:232018. View Article : Google Scholar : PubMed/NCBI
10	Randriamboavonjy V, Kyselova A, Elgheznawy A, Zukunft S, Wittig I and Fleming I: Calpain 1 cleaves and inactivates prostacyclin synthase in mesenteric arteries from diabetic mice. Basic Res Cardiol. 112:102017. View Article : Google Scholar : PubMed/NCBI
11	Ronchi C, Torre E, Rizzetto R, Bernardi J, Rocchetti M and Zaza A: Late sodium current and intracellular ionic homeostasis in acute ischemia. Basic Res Cardiol. 112:122017. View Article : Google Scholar : PubMed/NCBI
12	Zhou H, Ma Q, Zhu P, Ren J, Reiter RJ and Chen Y: Protective role of melatonin in cardiac ischemia-reperfusion injury: From pathogenesis to targeted therapy. J Pineal Res. 64:2018.doi: 10.1111/jpi.12471. View Article : Google Scholar
13	Motawi TK, Ahmed SA, A Hamed M, El-Maraghy SA and M Aziz W: Melatonin and/or rowatinex attenuate streptozotocin-induced diabetic renal injury in rats. J Biomed Res. Nov 1–2017.(Epub ahead of print). PubMed/NCBI
14	Hrenak J, Paulis L, Repova K, Aziriova S, Nagtegaal EJ, Reiter RJ and Simko F: Melatonin and renal protection: Novel perspectives from animal experiments and human studies (review). Curr Pharm Des. 21:936–949. 2015. View Article : Google Scholar : PubMed/NCBI
15	Garcia-Nino WR, Correa F, Rodriguez-Barrena JI, León-Contreras JC, Buelna-Chontal M, Soria-Castro E, Hernández-Pando R, Pedraza-Chaverri J and Zazueta C: Cardioprotective kinase signaling to subsarcolemmal and interfibrillar mitochondria is mediated by caveolar structures. Basic Res Cardiol. 112:152017. View Article : Google Scholar : PubMed/NCBI
16	Li Y, Wu H, Liu N, Cao X, Yang Z, Lu B, Hu R, Wang X and Wen J: Melatonin exerts an inhibitory effect on insulin gene transcription via MTNR1B and the downstream Raf1/ERK signaling pathway. Int J Mol Med. 41:955–961. 2018.PubMed/NCBI
17	Yu LM, Di WC, Dong X, Li Z, Zhang Y, Xue XD, Xu YL, Zhang J, Xiao X, Han JS, et al: Melatonin protects diabetic heart against ischemia-reperfusion injury, role of membrane receptor-dependent cGMP-PKG activation. Biochim Biophys Acta. 1864:563–578. 2018. View Article : Google Scholar
18	Zhou H, Du W, Li Y, Shi C, Hu N, Ma S, Wang W and Ren J: Effects of melatonin on fatty liver disease: The role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy. J Pineal Res. 64:2018.doi: 10.1111/jpi.12450. View Article : Google Scholar
19	Zhu H, Jin Q, Li Y, Ma Q, Wang J, Li D, Zhou H and Chen Y: Melatonin protected cardiac microvascular endothelial cells against oxidative stress injury via suppression of IP3R-[Ca²⁺]c/VDAC-[Ca²⁺]m axis by activation of MAPK/ERK signaling pathway. Cell Stress Chaperones. 23:101–113. 2018. View Article : Google Scholar : PubMed/NCBI
20	Zhou H, Wang S, Zhu P, Hu S, Chen Y and Ren J: Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol. 15:335–346. 2018. View Article : Google Scholar : PubMed/NCBI
21	Torres-Quesada O, Mayrhofer JE and Stefan E: The many faces of compartmentalized PKA signalosomes. Cell Signal. 37:1–11. 2017. View Article : Google Scholar : PubMed/NCBI
22	Jovancevic N, Dendorfer A, Matzkies M, Kovarova M, Heckmann JC, Osterloh M, Boehm M, Weber L, Nguemo F, Semmler J, et al: Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor. Basic Res Cardiol. 112:132017. View Article : Google Scholar : PubMed/NCBI
23	Alghanem AF, Wilkinson EL, Emmett MS, Aljasir MA, Holmes K, Rothermel BA, Simms VA, Heath VL and Cross MJ: RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells. Angiogenesis. 20:341–358. 2017. View Article : Google Scholar : PubMed/NCBI
24	Zhou H, Zhu P, Wang J, Zhu H, Ren J and Chen Y: Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2α-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy. Cell Death Differ. 25:1080–1093. 2018. View Article : Google Scholar : PubMed/NCBI
25	Zhou H, Zhang Y, Hu S, Shi C, Zhu P, Ma Q, Jin Q, Cao F, Tian F and Chen Y: Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis. J Pineal Res. 63:2017.doi: 10.1111/jpi.12413. View Article : Google Scholar :
26	Zhou H, Li D, Zhu P, Hu S, Hu N, Ma S, Zhang Y, Han T, Ren J, Cao F and Chen Y: Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways. J Pineal Res. 63:2017.doi: 10.1111/jpi.12438. View Article : Google Scholar :
27	Oanh NTK, Park YY and Cho H: Mitochondria elongation is mediated through SIRT1-mediated MFN1 stabilization. Cell Signal. 38:67–75. 2017. View Article : Google Scholar : PubMed/NCBI
28	Fuhrmann DC and Brüne B: Mitochondrial composition and function under the control of hypoxia. Redox Biol. 12:208–215. 2017. View Article : Google Scholar : PubMed/NCBI
29	Zhai M, Li B, Duan W, Jing L, Zhang B, Zhang M, Yu L, Liu Z, Yu B, Ren K, et al: Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis. J Pineal Res. 63:2017.doi: 10.1111/jpi.12419. View Article : Google Scholar
30	Zhang R and Sun Y, Liu Z, Jin W and Sun Y: Effects of melatonin on seedling growth, mineral nutrition, and nitrogen metabolism in cucumber under nitrate stress. J Pineal Res. 62:2017.doi: 10.1111/jpi.12403. View Article : Google Scholar
31	Couto JA, Ayturk UM, Konczyk DJ, Goss JA, Huang AY, Hann S, Reeve JL, Liang MG, Bischoff J, Warman ML and Greene AK: A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth. Angiogenesis. 20:303–306. 2017. View Article : Google Scholar : PubMed/NCBI
32	Griffiths HR, Gao D and Pararasa C: Redox regulation in metabolic programming and inflammation. Redox Biol. 12:50–57. 2017. View Article : Google Scholar : PubMed/NCBI
33	Tallman KA, Kim HH, Korade Z, Genaro-Mattos TC, Wages PA, Liu W and Porter NA: Probes for protein adduction in cholesterol biosynthesis disorders: Alkynyl lanosterol as a viable sterol precursor. Redox Biol. 12:182–190. 2017. View Article : Google Scholar : PubMed/NCBI
34	Shi C, Cai Y, Li Y, Li Y, Hu N, Ma S, Hu S, Zhu P, Wang W and Zhou H: Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways. Redox Biol. 14:59–71. 2018. View Article : Google Scholar : PubMed/NCBI
35	Zhou H, Yang J, Xin T, Zhang T, Hu S, Zhou S, Chen G and Chen Y: Exendin-4 enhances the migration of adipose-derived stem cells to neonatal rat ventricular cardiomyocyte-derived conditioned medium via the phosphoinositide 3-kinase/Akt-stromal cell-derived factor-1α/CXC chemokine receptor 4 pathway. Mol Med Rep. 11:4063–4072. 2015. View Article : Google Scholar : PubMed/NCBI
36	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
37	Salminen A, Kaarniranta K and Kauppinen A: Integrated stress response stimulates FGF21 expression: Systemic enhancer of longevity. Cell Signal. 40:10–21. 2017. View Article : Google Scholar : PubMed/NCBI
38	Sigala F, Efentakis P, Karageorgiadi D, Filis K, Zampas P, Iliodromitis EK, Zografos G, Papapetropoulos A and Andreadou I: Reciprocal regulation of eNOS, H₂S and CO-synthesizing enzymes in human atheroma: Correlation with plaque stability and effects of simvastatin. Redox Biol. 12:70–81. 2017. View Article : Google Scholar : PubMed/NCBI
39	Jin Q, Li R, Hu N, Xin T, Zhu P, Hu S, Ma S, Zhu H, Ren J and Zhou H: DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. Redox Biol. 14:576–587. 2018. View Article : Google Scholar : PubMed/NCBI
40	Zhou H, Zhu P, Guo J, Hu N, Wang S, Li D, Hu S, Ren J, Cao F and Chen Y: Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury. Redox Biol. 13:498–507. 2017. View Article : Google Scholar : PubMed/NCBI
41	Yu S, Wang X, Geng P, Tang X, Xiang L, Lu X, Li J, Ruan Z, Chen J, Xie G, et al: Melatonin regulates PARP1 to control the senescence-associated secretory phenotype (SASP) in human fetal lung fibroblast cells. J Pineal Res. 63:2017.doi: 10.1111/jpi.12405. View Article : Google Scholar
42	Lee K and Back K: Overexpression of rice serotonin N-acetyltransferase 1 in transgenic rice plants confers resistance to cadmium and senescence and increases grain yield. J Pineal Res. 62:2017.doi: 10.1111/jpi.12392. View Article : Google Scholar
43	Fukumoto M, Kondo K, Uni K, Ishiguro T, Hayashi M, Ueda S, Mori I, Niimi K, Tashiro F, Miyazaki S, et al: Tip-cell behavior is regulated by transcription factor FoxO1 under hypoxic conditions in developing mouse retinas. Angiogenesis. 21:203–214. 2018. View Article : Google Scholar : PubMed/NCBI
44	Lee HJ, Jung YH, Choi GE, Ko SH, Lee SJ, Lee SH and Han HJ: BNIP3 induction by hypoxia stimulates FASN-dependent free fatty acid production enhancing therapeutic potential of umbilical cord blood-derived human mesenchymal stem cells. Redox Biol. 13:426–443. 2017. View Article : Google Scholar : PubMed/NCBI
45	Liu Z, Gan L, Luo D and Sun C: Melatonin promotes circadian rhythm-induced proliferation through Clock/histone deacetylase 3/c-Myc interaction in mouse adipose tissue. J Pineal Res. 62:2017.doi: 10.1111/jpi.12383. View Article : Google Scholar
46	Le Cras TD, Mobberley-Schuman PS, Broering M, Fei L, Trenor CC III and Adams DM: Angiopoietins as serum biomarkers for lymphatic anomalies. Angiogenesis. 20:163–173. 2017. View Article : Google Scholar : PubMed/NCBI
47	Vargas LA, Velasquez FC and Alvarez BV: Compensatory role of the NBCn1 sodium/bicarbonate cotransporter on Ca²⁺-induced mitochondrial swelling in hypertrophic hearts. Basic Res Cardiol. 112:142017. View Article : Google Scholar : PubMed/NCBI
48	Pickard JM, Burke N, Davidson SM and Yellon DM: Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning. Basic Res Cardiol. 112:112017. View Article : Google Scholar : PubMed/NCBI
49	Brasacchio D, Alsop AE, Noori T, Lufti M, Iyer S, Simpson KJ, Bird PI, Kluck RM, Johnstone RW and Trapani JA: Epigenetic control of mitochondrial cell death through PACS1-mediated regulation of BAX/BAK oligomerization. Cell Death Differ. 24:961–970. 2017. View Article : Google Scholar : PubMed/NCBI
50	Kim EJ, Kim SH, Jin X, Jin X and Kim H: KCTD2, an adaptor of Cullin3 E3 ubiquitin ligase, suppresses gliomagenesis by destabilizing c-Myc. Cell Death Differ. 24:649–659. 2017. View Article : Google Scholar : PubMed/NCBI
51	Zhou H, Hu S, Jin Q, Shi C, Zhang Y, Zhu P, Ma Q, Tian F and Chen Y: Mff-dependent mitochondrial fission contributes to the pathogenesis of cardiac microvasculature Ischemia/reperfusion injury via induction of mROS-mediated cardiolipin oxidation and HK2/VDAC1 Disassociation-involved mPTP opening. J Am Heart Assoc. 6(pii): e0053282017.PubMed/NCBI
52	Solomon H, Brauning B, Fainer I, Ben-Nissan G, Rabani S, Goldfinger N, Moscovitz O, Shakked Z, Rotter V and Sharon M: Post-translational regulation of p53 function through 20S proteasome-mediated cleavage. Cell Death Differ. 24:2187–2198. 2017. View Article : Google Scholar : PubMed/NCBI
53	Morozzi G, Beccafico S, Bianchi R, Riuzzi F, Bellezza I, Giambanco I, Arcuri C, Minelli A and Donato R: Oxidative stress-induced S100B accumulation converts myoblasts into brown adipocytes via an NF-κB/YY1/miR-133 axis and NF-κB/YY1/BMP-7 axis. Cell Death Differ. 24:2077–2088. 2017. View Article : Google Scholar : PubMed/NCBI
54	Zhou H, Li D, Zhu P, Ma Q, Toan S, Wang J, Hu S, Chen Y and Zhang Y: Inhibitory effect of melatonin on necroptosis via repressing the Ripk3-PGAM5-CypD-mPTP pathway attenuates cardiac microvascular ischemia-reperfusion injury. J Pineal Res. May 16;e125032018.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
55	Zhou H, Wang S, Hu S, Chen Y and Ren J: ER-mitochondria microdomains in cardiac Ischemia-reperfusion injury: A fresh perspective. Front Physiol. 9:7552018. View Article : Google Scholar : PubMed/NCBI
56	Zhang W, Tao A, Lan T, Cepinskas G, Kao R, Martin CM and Rui T: Carbon monoxide releasing molecule-3 improves myocardial function in mice with sepsis by inhibiting NLRP3 inflammasome activation in cardiac fibroblasts. Basic Res Cardiol. 112:162017. View Article : Google Scholar : PubMed/NCBI
57	Banerjee K, Keasey MP, Razskazovskiy V, Visavadiya NP, Jia C and Hagg T: Reduced FAK-STAT3 signaling contributes to ER stress-induced mitochondrial dysfunction and death in endothelial cells. Cell Signal. 36:154–162. 2017. View Article : Google Scholar : PubMed/NCBI
58	Rovira-Llopis S, Apostolova N, Bañuls C, Muntané J, Rocha M and Victor VM: Mitochondria, the NLRP3 inflammasome, and sirtuins in type 2 diabetes: New therapeutic targets. Antioxid Redox Signal. 29:749–791. 2018. View Article : Google Scholar : PubMed/NCBI
59	Pierelli G, Stanzione R, Forte M, Migliarino S, Perelli M, Volpe M and Rubattu S: Uncoupling protein 2: A key player and a potential therapeutic target in vascular diseases. Oxid Med Cell Longev. 2017:73483722017. View Article : Google Scholar : PubMed/NCBI
60	Rauckhorst AJ, Gray LR, Sheldon RD, Fu X, Pewa AD, Feddersen CR, Dupuy AJ, Gibson-Corley KN, Cox JE, Burgess SC and Taylor EB: The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity. Mol Metab. 6:1468–1479. 2017. View Article : Google Scholar : PubMed/NCBI
61	Dufour F, Rattier T, Shirley S, Picarda G, Constantinescu AA, Morlé A, Zakaria AB, Marcion G, Causse S, Szegezdi E, et al: N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death. Cell Death Differ. 24:500–510. 2017. View Article : Google Scholar : PubMed/NCBI
62	Gao Y, Xiao X, Zhang C, Yu W, Guo W, Zhang Z, Li Z, Feng X, Hao J, Zhang K, et al: Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-kB/iNOS signaling pathways. J Pineal Res. 62:2017.doi: 10.1111/jpi.12380. View Article : Google Scholar
63	Daiber A, Oelze M, Steven S, Kroller-Schon S and Münzel T: Taking up the cudgels for the traditional reactive oxygen and nitrogen species detection assays and their use in the cardiovascular system. Redox Biol. 12:35–49. 2017. View Article : Google Scholar : PubMed/NCBI
64	Zhou H, Shi C, Hu S, Zhu H, Ren J and Chen Y: BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways. Angiogenesis. 21:599–615. 2018. View Article : Google Scholar : PubMed/NCBI
65	Zhou H, Yue Y, Wang J, Ma Q and Chen Y: Melatonin therapy for diabetic cardiomyopathy: A mechanism involving Syk-mitochondrial complex I-SERCA pathway. Cell Signal. 47:88–100. 2018. View Article : Google Scholar : PubMed/NCBI
66	Mayo JC, Sainz RM, Gonzalez Menendez P, Cepas V, Tan DX and Reiter RJ: Melatonin and sirtuins: A ‘not-so unexpected’ relationship. J Pineal Res. 62:2017.doi: 10.1111/jpi.12391. View Article : Google Scholar
67	Lee JH, Han YS and Lee SH: Potentiation of biological effects of mesenchymal stem cells in ischemic conditions by melatonin via upregulation of cellular prion protein expression. J Pineal Res. 62:2017.doi: 10.1111/jpi.12385. View Article : Google Scholar
68	Lee HY and Back K: Melatonin is required for H₂ O₂- and NO-mediated defense signaling through MAPKKK3 and OXI1 in Arabidopsis thaliana. J Pineal Res. 62:2017.doi: 10.1111/jpi.12379. View Article : Google Scholar
69	Lee MS, Yin TC, Sung PH, Chiang JY, Sun CK and Yip HK: Melatonin enhances survival and preserves functional integrity of stem cells: A review. J Pineal Res. 62:2017.doi: 10.1111/jpi.12372. View Article : Google Scholar
70	Tamura H, Kawamoto M, Sato S, Tamura I, Maekawa R, Taketani T, Aasada H, Takaki E, Nakai A, Reiter RJ and Sugino N: Long-term melatonin treatment delays ovarian aging. J Pineal Res. 62:2017.doi: 10.1111/jpi.12381. View Article : Google Scholar : PubMed/NCBI
71	Ligeza J, Marona P, Gach N, Lipert B, Miekus K, Wilk W, Jaszczynski J, Stelmach A, Loboda A, Dulak J, et al: MCPIP1 contributes to clear cell renal cell carcinomas development. Angiogenesis. 20:325–340. 2017. View Article : Google Scholar : PubMed/NCBI