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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Targeting Mammalian Target of Rapamycin: Prospects for the Treatment of Inflammatory Bowel Diseases

Author(s): Naser-Aldin Lashgari, Nazanin Momeni Roudsari, Saeideh Momtaz, Negar Ghanaatian, Parichehr Kohansal, Mohammad Hosein Farzaei, Khashayar Afshari, Amirhossein Sahebkar* and Amir Hossein Abdolghaffari*

Volume 28, Issue 8, 2021

Published on: 04 May, 2020

Page: [1605 - 1624] Pages: 20

DOI: 10.2174/0929867327666200504081503

Price: $65

Abstract

Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview of plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

Keywords: Gastroenterology, inflammatory bowel disease, ulcerative colitis, crohn’s disease, mammalian target of rapamycin, natural products.

[1]
Deng, L.; Zhou, J-F.; Sellers, R.S.; Li, J-F.; Nguyen, A.V.; Wang, Y.; Orlofsky, A.; Liu, Q.; Hume, D.A.; Pollard, J.W.; Augenlicht, L.; Lin, E.Y. A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. Am. J. Pathol., 2010, 176(2), 952-967.
[http://dx.doi.org/10.2353/ajpath.2010.090622] [PMID: 20042677]
[2]
Anbazhagan, A.N.; Priyamvada, S.; Alrefai, W.A.; Dudeja, P.K. Pathophysiology of IBD associated diarrhea. Tissue Barriers, 2018, 6(2)e1463897
[http://dx.doi.org/10.1080/21688370.2018.1463897] [PMID: 29737913]
[3]
Benchimol, E.I.; Fortinsky, K.J.; Gozdyra, P.; Van den Heuvel, M.; Van Limbergen, J.; Griffiths, A.M. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm. Bowel Dis., 2011, 17(1), 423-439.
[http://dx.doi.org/10.1002/ibd.21349] [PMID: 20564651]
[4]
Van Limbergen, J.; Radford-Smith, G.; Satsangi, J. Advances in IBD genetics. Nat. Rev. Gastroenterol. Hepatol., 2014, 11(6), 372-385.
[http://dx.doi.org/10.1038/nrgastro.2014.27] [PMID: 24614343]
[5]
Graff, L.A.; Walker, J.R.; Bernstein, C.N. Depression and anxiety in inflammatory bowel disease: a review of comorbidity and management. Inflamm. Bowel Dis., 2009, 15(7), 1105-1118.
[http://dx.doi.org/10.1002/ibd.20873] [PMID: 19161177]
[6]
Gamallat, Y.; Ren, X.; Walana, W.; Meyiah, A.; Xinxiu, R.; Zhu, Y.; Li, M.; Song, S.; Xie, L.; Jamalat, Y. Probiotic Lactobacillus rhamnosus modulates the gut microbiome composition attenuates preneoplastic colorectal Aberrant crypt foci. J. Funct. Foods, 2019, 53, 146-156.
[http://dx.doi.org/10.1016/j.jff.2018.12.018]
[7]
Guan, Q.; Zhang, J. Recent advances: the imbalance of cytokines in the pathogenesis of inflammatory bowel disease. Mediators Inflamm., 2017, 20174810258
[http://dx.doi.org/10.1155/2017/4810258] [PMID: 28420941]
[8]
Wilhelm, S.M.; Love, B.L. Management of patients with inflammatory bowel disease: current and future treatments. Clin. Pharm., 2019, 9(3), 83-92.
[http://dx.doi.org/10.1211/CP.2017.20202316 ]
[9]
Farzaei, M.H.; Bahramsoltani, R.; Abdolghaffari, A.H.; Sodagari, H.R.; Esfahani, S.A.; Rezaei, N. A mechanistic review on plant-derived natural compounds as dietary supplements for prevention of inflammatory bowel disease. Expert Rev. Gastroenterol. Hepatol., 2016, 10(6), 745-758.
[http://dx.doi.org/10.1586/17474124.2016.1145546] [PMID: 26799847]
[10]
Farzaei, M.H.; El-Senduny, F.F.; Momtaz, S.; Parvizi, F.; Iranpanah, A.; Tewari, D.; Naseri, R.; Abdolghaffari, A.H.; Rezaei, N. An update on dietary consideration in inflammatory bowel disease: anthocyanins and more. Expert Rev. Gastroenterol. Hepatol., 2018, 12(10), 1007-1024.
[http://dx.doi.org/10.1080/17474124.2018.1513322] [PMID: 30136591]
[11]
Sarkar, S. Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochem. Soc. Trans., 2013, 41(5), 1103-1130.
[http://dx.doi.org/10.1042/BST20130134] [PMID: 24059496]
[12]
Volkart, P.A.; Bitencourt-Ferreira, G.; Souto, A.A.; de Azevedo, W.F. Cyclin-dependent kinase 2 in cellular senescence and cancer. a structural and functional review. Curr. Drug Targets, 2019, 20(7), 716-726.
[http://dx.doi.org/10.2174/1389450120666181204165344] [PMID: 30516105]
[13]
Levin, N.M.B.; Pintro, V.O.; de Avila, M.B.; de Mattos, B.B.; De Azevedo, W.F. Jr. Understanding the structural basis for inhibition of cyclin-dependent kinases. new pieces in the molecular puzzle. Curr. Drug Targets, 2017, 18(9), 1104-1111.
[http://dx.doi.org/10.2174/1389450118666161116130155] [PMID: 27848884]
[14]
de Ávila, M.B.; Xavier, M.M.; Pintro, V.O.; de Azevedo, W.F. Jr. Supervised machine learning techniques to predict binding affinity. A study for cyclin-dependent kinase 2. Biochem. Biophys. Res. Commun., 2017, 494(1-2), 305-310.
[http://dx.doi.org/10.1016/j.bbrc.2017.10.035] [PMID: 29017921]
[15]
Levin, N.M.B.; Pintro, V.O.; Bitencourt-Ferreira, G.; de Mattos, B.B.; de Castro Silvério, A.; de Azevedo, W.F. Jr Development of CDK-targeted scoring functions for prediction of binding affinity. Biophys. Chem., 2018, 235, 1-8.
[http://dx.doi.org/10.1016/j.bpc.2018.01.004] [PMID: 29407904]
[16]
Bitencourt-Ferreira, G.; da Silva, A.D.; de Azevedo, W.F. Jr. Application of machine learning techniques to predict binding affinity for drug targets. a study of cyclin-dependent kinase 2. Curr. Med. Chem., 2021, 28(2), 253-265.
[http://dx.doi.org/10.2174/2213275912666191102162959] [PMID: 31729287]
[17]
Dos Santos Paparidis, N.F.; Canduri, F. The emerging picture of CDK11: genetic, functional and medicinal aspects. Curr. Med. Chem., 2018, 25(8), 880-888.
[http://dx.doi.org/10.2174/0929867324666170815102036] [PMID: 28814241]
[18]
Saxton, R.A.; Sabatini, D.M. mTOR signaling in growth, metabolism, and disease. Cell, 2017, 168(6), 960-976.
[http://dx.doi.org/10.1016/j.cell.2017.02.004] [PMID: 28283069]
[19]
Yu, K.; Toral-Barza, L.; Discafani, C.; Zhang, W.G.; Skotnicki, J.; Frost, P.; Gibbons, J.J. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr. Relat. Cancer, 2001, 8(3), 249-258.
[http://dx.doi.org/10.1677/erc.0.0080249] [PMID: 11566616]
[20]
Chen, J.; Zhao, K-N.; Li, R.; Shao, R.; Chen, C. Activation of PI3K/Akt/mTOR pathway and dual inhibitors of PI3K and mTOR in endometrial cancer. Curr. Med. Chem., 2014, 21(26), 3070-3080.
[http://dx.doi.org/10.2174/0929867321666140414095605] [PMID: 24735369]
[21]
Ebrahimi, S.; Hosseini, M.; Shahidsales, S.; Maftouh, M.; Ferns, G.A.; Ghayour-Mobarhan, M.; Hassanian, S.M.; Avan, A. A Ferns G, Ghayour-Mobarhan M, Mahdi Hassanian S, Avan A. Targeting the Akt/PI3K signaling pathway as a potential therapeutic strategy for the treatment of pancreatic cancer. Curr. Med. Chem., 2017, 24(13), 1321-1331.
[http://dx.doi.org/10.2174/0929867324666170206142658] [PMID: 28176634]
[22]
Leibowitz, G.; Cerasi, E.; Ketzinel-Gilad, M. The role of mTOR in the adaptation and failure of β-cells in type 2 diabetes. Diabetes Obes. Metab., 2008, 10(Suppl. 4), 157-169.
[http://dx.doi.org/10.1111/j.1463-1326.2008.00952.x] [PMID: 18834443]
[23]
Sciarretta, S.; Volpe, M.; Sadoshima, J. Mammalian target of rapamycin signaling in cardiac physiology and disease. Circ. Res., 2014, 114(3), 549-564.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.302022] [PMID: 24481845]
[24]
Wong, M. Mammalian target of rapamycin (mTOR) pathways in neurological diseases. Biomed. J., 2013, 36(2), 40-50.
[http://dx.doi.org/10.4103/2319-4170.110365] [PMID: 23644232]
[25]
Hu, S.; Chen, M.; Wang, Y.; Wang, Z.; Pei, Y.; Fan, R.; Liu, X.; Wang, L.; Zhou, J.; Zheng, S.; Zhang, T.; Lin, Y.; Zhang, M.; Tao, R.; Zhong, J. mTOR inhibition attenuates dextran sulfate sodium-induced colitis by suppressing T cell proliferation and balancing TH1/TH17/Treg profile. PLoS One, 2016, 11(4)e0154564
[http://dx.doi.org/10.1371/journal.pone.0154564] [PMID: 27128484]
[26]
Larussa, T.; Imeneo, M.; Luzza, F. Potential role of nutraceutical compounds in inflammatory bowel disease. World J. Gastroenterol., 2017, 23(14), 2483-2492.
[http://dx.doi.org/10.3748/wjg.v23.i14.2483] [PMID: 28465632]
[27]
Loewith, R.; Hall, M.N. Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics, 2011, 189(4), 1177-1201.
[http://dx.doi.org/10.1534/genetics.111.133363] [PMID: 22174183]
[28]
Hay, N.; Sonenberg, N. Upstream and downstream of mTOR. Genes Dev., 2004, 18(16), 1926-1945.
[http://dx.doi.org/10.1101/gad.1212704] [PMID: 15314020]
[29]
Laplante, M Sabatini, DM mTOR signaling in growth control and disease cell, 2012, 149, 274-293.
[30]
Feng, J.; Liao, Y.; Xu, X.; Yi, Q.; He, L.; Tang, L. hnRNP A1 promotes keratinocyte cell survival post UVB radiation through PI3K/Akt/mTOR pathway. Exp. Cell Res., 2018, 362(2), 394-399.
[http://dx.doi.org/10.1016/j.yexcr.2017.12.002] [PMID: 29229447]
[31]
Giguère, V. Canonical signaling and nuclear activity of mTOR-a teamwork effort to regulate metabolism and cell growth. FEBS J., 2018, 285(9), 1572-1588.
[http://dx.doi.org/10.1111/febs.14384] [PMID: 29337437]
[32]
Huang, J.; Manning, B.D. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J., 2008, 412(2), 179-190.
[http://dx.doi.org/10.1042/BJ20080281] [PMID: 18466115]
[33]
Zinzalla, V.; Stracka, D.; Oppliger, W.; Hall, M.N. Activation of mTORC2 by association with the ribosome. Cell, 2011, 144(5), 757-768.
[http://dx.doi.org/10.1016/j.cell.2011.02.014] [PMID: 21376236]
[34]
Garami, A.; Zwartkruis, F.J.; Nobukuni, T.; Joaquin, M.; Roccio, M.; Stocker, H.; Kozma, S.C.; Hafen, E.; Bos, J.L.; Thomas, G. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell, 2003, 11(6), 1457-1466.
[http://dx.doi.org/10.1016/S1097-2765(03)00220-X] [PMID: 12820960]
[35]
Huang, Z.; Wu, Y.; Zhou, X.; Qian, J.; Zhu, W.; Shu, Y.; Liu, P. Clinical efficacy of mTOR inhibitors in solid tumors: a systematic review. Future Oncol., 2015, 11(11), 1687-1699.
[http://dx.doi.org/10.2217/fon.15.70] [PMID: 26043220]
[36]
Bar-Peled, L.; Sabatini, D.M. Regulation of mTORC1 by amino acids. Trends Cell Biol., 2014, 24(7), 400-406.
[http://dx.doi.org/10.1016/j.tcb.2014.03.003] [PMID: 24698685]
[37]
Takahara, T.; Maeda, T. Evolutionarily conserved regulation of TOR signalling. J. Biochem., 2013, 154(1), 1-10.
[http://dx.doi.org/10.1093/jb/mvt047] [PMID: 23698095]
[38]
Albert, V.; Hall, M.N. mTOR signaling in cellular and organismal energetics. Curr. Opin. Cell Biol., 2015, 33, 55-66.
[http://dx.doi.org/10.1016/j.ceb.2014.12.001] [PMID: 25554914]
[39]
Betz, C.; Hall, M.N. Where is mTOR and what is it doing there? J. Cell Biol., 2013, 203(4), 563-574.
[http://dx.doi.org/10.1083/jcb.201306041] [PMID: 24385483]
[40]
Walker, N.M.; Belloli, E.A.; Stuckey, L.; Chan, K.M.; Lin, J.; Lynch, W.; Chang, A.; Mazzoni, S.M.; Fingar, D.C.; Lama, V.N. Mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 as key signaling intermediates in mesenchymal cell activation. J. Biol. Chem., 2016, 291(12), 6262-6271.
[http://dx.doi.org/10.1074/jbc.M115.672170] [PMID: 26755732]
[41]
Bhonde, M.R.; Gupte, R.D.; Dadarkar, S.D.; Jadhav, M.G.; Tannu, A.A.; Bhatt, P.; Bhatia, D.R.; Desai, N.K.; Deore, V.; Yewalkar, N.; Vishwakarma, R.A.; Sharma, S.; Kumar, S.; Dagia, N.M. A novel mTOR inhibitor is efficacious in a murine model of colitis. Am. J. Physiol. Gastrointest. Liver Physiol., 2008, 295(6), G1237-G1245.
[http://dx.doi.org/10.1152/ajpgi.90537.2008] [PMID: 18927209]
[42]
Yang, H.; Rudge, D.G.; Koos, J.D.; Vaidialingam, B.; Yang, H.J.; Pavletich, N.P. mTOR kinase structure, mechanism and regulation. Nature, 2013, 497(7448), 217-223.
[http://dx.doi.org/10.1038/nature12122] [PMID: 23636326]
[43]
Peterson, T.R.; Laplante, M.; Thoreen, C.C.; Sancak, Y.; Kang, S.A.; Kuehl, W.M.; Gray, N.S.; Sabatini, D.M. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell, 2009, 137(5), 873-886.
[http://dx.doi.org/10.1016/j.cell.2009.03.046] [PMID: 19446321]
[44]
Lawrence, J.; Nho, R. The role of the mammalian target of rapamycin (mTOR) in pulmonary fibrosis. Int. J. Mol. Sci., 2018, 19(3), 778.
[http://dx.doi.org/10.3390/ijms19030778] [PMID: 29518028]
[45]
Chen, X.; Liu, M.; Tian, Y.; Li, J.; Qi, Y.; Zhao, D.; Wu, Z.; Huang, M.; Wong, C.C.L.; Wang, H-W.; Wang, J.; Yang, H.; Xu, Y. Cryo-EM structure of human mTOR complex 2. Cell Res., 2018, 28(5), 518-528.
[http://dx.doi.org/10.1038/s41422-018-0029-3] [PMID: 29567957]
[46]
Murray, E.R.; Cameron, A.J.M. Towards specific inhibition of mTORC2. Aging (Albany NY), 2017, 9(12), 2461-2462.
[http://dx.doi.org/10.18632/aging.101346] [PMID: 29232655]
[47]
Oh, W.J.; Jacinto, E. mTOR complex 2 signaling and functions. Cell Cycle, 2011, 10(14), 2305-2316.
[http://dx.doi.org/10.4161/cc.10.14.16586] [PMID: 21670596]
[48]
Hsu, P.P.; Kang, S.A.; Rameseder, J.; Zhang, Y.; Ottina, K.A.; Lim, D.; Peterson, T.R.; Choi, Y.; Gray, N.S.; Yaffe, M.B.; Marto, J.A.; Sabatini, D.M. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science, 2011, 332(6035), 1317-1322.
[http://dx.doi.org/10.1126/science.1199498] [PMID: 21659604]
[49]
Rahimi, R.A.; Andrianifahanana, M.; Wilkes, M.C.; Edens, M.; Kottom, T.J.; Blenis, J.; Leof, E.B. Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-β. Cancer Res., 2009, 69(1), 84-93.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-2146] [PMID: 19117990]
[50]
Wang, R-H.; Kim, H-S.; Xiao, C.; Xu, X.; Gavrilova, O.; Deng, C-X. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J. Clin. Invest., 2011, 121(11), 4477-4490.
[http://dx.doi.org/10.1172/JCI46243] [PMID: 21965330]
[51]
Inoki, K.; Ouyang, H.; Zhu, T.; Lindvall, C.; Wang, Y.; Zhang, X.; Yang, Q.; Bennett, C.; Harada, Y.; Stankunas, K.; Wang, C.Y.; He, X.; MacDougald, O.A.; You, M.; Williams, B.O.; Guan, K.L. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell, 2006, 126(5), 955-968.
[http://dx.doi.org/10.1016/j.cell.2006.06.055] [PMID: 16959574]
[52]
Sancak, Y.; Thoreen, C.C.; Peterson, T.R.; Lindquist, R.A.; Kang, S.A.; Spooner, E.; Carr, S.A.; Sabatini, D.M. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell, 2007, 25(6), 903-915.
[http://dx.doi.org/10.1016/j.molcel.2007.03.003] [PMID: 17386266]
[53]
White, M.F. IRS proteins and the common path to diabetes. Am. J. Physiol. Endocrinol. Metab., 2002, 283(3), E413-E422.
[http://dx.doi.org/10.1152/ajpendo.00514.2001] [PMID: 12169433]
[54]
Tzatsos, A.; Kandror, K.V. Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol. Cell. Biol., 2006, 26(1), 63-76.
[http://dx.doi.org/10.1128/MCB.26.1.63-76.2006] [PMID: 16354680]
[55]
Hardie, D.G.; Schaffer, B.E.; Brunet, A. AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol., 2016, 26(3), 190-201.
[http://dx.doi.org/10.1016/j.tcb.2015.10.013] [PMID: 26616193]
[56]
Gwinn, D.M.; Shackelford, D.B.; Egan, D.F.; Mihaylova, M.M.; Mery, A.; Vasquez, D.S.; Turk, B.E.; Shaw, R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell, 2008, 30(2), 214-226.
[http://dx.doi.org/10.1016/j.molcel.2008.03.003] [PMID: 18439900]
[57]
Brugarolas, J.; Lei, K.; Hurley, R.L.; Manning, B.D.; Reiling, J.H.; Hafen, E.; Witters, L.A.; Ellisen, L.W.; Kaelin, W.G. Jr Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev., 2004, 18(23), 2893-2904.
[http://dx.doi.org/10.1101/gad.1256804] [PMID: 15545625]
[58]
Feng, Z.; Hu, W.; de Stanchina, E.; Teresky, A.K.; Jin, S.; Lowe, S.; Levine, A.J. The regulation of AMPK β1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res., 2007, 67(7), 3043-3053.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4149] [PMID: 17409411]
[59]
Clevers, H. The intestinal crypt, a prototype stem cell compartment. Cell, 2013, 154(2), 274-284.
[http://dx.doi.org/10.1016/j.cell.2013.07.004] [PMID: 23870119]
[60]
Yilmaz, Ö.H.; Katajisto, P.; Lamming, D.W.; Gültekin, Y.; Bauer-Rowe, K.E.; Sengupta, S.; Birsoy, K.; Dursun, A.; Yilmaz, V.O.; Selig, M.; Nielsen, G.P.; Mino-Kenudson, M.; Zukerberg, L.R.; Bhan, A.K.; Deshpande, V.; Sabatini, D.M. mTORC1 in the paneth cell niche couples intestinal stem-cell function to calorie intake. Nature, 2012, 486(7404), 490-495.
[http://dx.doi.org/10.1038/nature11163] [PMID: 22722868]
[61]
Hong, S.; Zhao, B.; Lombard, D.B.; Fingar, D.C.; Inoki, K. Cross-talk between sirtuin and mammalian target of rapamycin complex 1 (mTORC1) signaling in the regulation of S6 kinase 1 (S6K1) phosphorylation. J. Biol. Chem., 2014, 289(19), 13132-13141.
[http://dx.doi.org/10.1074/jbc.M113.520734] [PMID: 24652283]
[62]
Igarashi, M.; Guarente, L. mTORC1 and SIRT1 cooperate to foster expansion of gut adult stem cells during calorie restriction. Cell, 2016, 166(2), 436-450.
[http://dx.doi.org/10.1016/j.cell.2016.05.044] [PMID: 27345368]
[63]
Zhou, Y.; Rychahou, P.; Wang, Q.; Weiss, H.L.; Evers, B.M. TSC2/mTORC1 signaling controls paneth and goblet cell differentiation in the intestinal epithelium. Cell Death Dis., 2015, 6e1631
[http://dx.doi.org/10.1038/cddis.2014.588] [PMID: 25654764]
[64]
Richmond, C.A.; Shah, M.S.; Deary, L.T.; Trotier, D.C.; Thomas, H.; Ambruzs, D.M.; Jiang, L.; Whiles, B.B.; Rickner, H.D.; Montgomery, R.K.; Tovaglieri, A.; Carlone, D.L.; Breault, D.T. Dormant intestinal stem cells are regulated by PTEN and nutritional status. Cell Rep., 2015, 13(11), 2403-2411.
[http://dx.doi.org/10.1016/j.celrep.2015.11.035] [PMID: 26686631]
[65]
Maya-Monteiro, C.M.; Bozza, P.T. Leptin and mTOR: partners in metabolism and inflammation. Cell Cycle, 2008, 7(12), 1713-1717.
[http://dx.doi.org/10.4161/cc.7.12.6157] [PMID: 18583936]
[66]
Cosin-Roger, J.; Simmen, S.; Melhem, H.; Atrott, K.; Frey-Wagner, I.; Hausmann, M.; de Vallière, C.; Spalinger, M.R.; Spielmann, P.; Wenger, R.H.; Zeitz, J.; Vavricka, S.R.; Rogler, G.; Ruiz, P.A. Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation. Nat. Commun., 2017, 8(1), 98.
[http://dx.doi.org/10.1038/s41467-017-00213-3] [PMID: 28740109]
[67]
Haq, S.; Grondin, J.; Banskota, S.; Khan, W.I. Autophagy: roles in intestinal mucosal homeostasis and inflammation. J. Biomed. Sci., 2019, 26(1), 19.
[http://dx.doi.org/10.1186/s12929-019-0512-2] [PMID: 30764829]
[68]
Kim, Y.C.; Guan, K-L. mTOR: a pharmacologic target for autophagy regulation. J. Clin. Invest., 2015, 125(1), 25-32.
[http://dx.doi.org/10.1172/JCI73939] [PMID: 25654547]
[69]
Zhou, M.; Xu, W.; Wang, J.; Yan, J.; Shi, Y.; Zhang, C.; Ge, W.; Wu, J.; Du, P.; Chen, Y. Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-κB pathway quenches intestinal inflammation and oxidative stress injury. EBioMedicine, 2018, 35, 345-360.
[http://dx.doi.org/10.1016/j.ebiom.2018.08.035] [PMID: 30170968]
[70]
Williams, J.P.; Johnston, C.J.; Finkelstein, J.N. Treatment for radiation-induced pulmonary late effects: spoiled for choice or looking in the wrong direction? Curr. Drug Targets, 2010, 11(11), 1386-1394.
[http://dx.doi.org/10.2174/1389450111009011386] [PMID: 20583979]
[71]
Ji, Y-X.; Zhang, P.; Zhang, X-J.; Zhao, Y-C.; Deng, K-Q.; Jiang, X.; Wang, P-X.; Huang, Z.; Li, H. The ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling. Nat. Commun., 2016, 7, 11267.
[http://dx.doi.org/10.1038/ncomms11267] [PMID: 27249171]
[72]
Citrin, D.E.; Mitchell, J.B. Mechanisms of normal tissue injury from irradiation. Semin. Radiat. Oncol., 2017, 27(4), 316-324.
[http://dx.doi.org/10.1016/j.semradonc.2017.04.001] [PMID: 28865514]
[73]
Citrin, D.E.; Prasanna, P.G.S.; Walker, A.J.; Freeman, M.L.; Eke, I.; Barcellos-Hoff, M.H.; Arankalayil, M.J.; Cohen, E.P.; Wilkins, R.C.; Ahmed, M.M.; Anscher, M.S.; Movsas, B.; Buchsbaum, J.C.; Mendonca, M.S.; Wynn, T.A.; Coleman, C.N. Radiation-induced fibrosis: mechanisms and opportunities to mitigate. Report of an NCI workshop, September 19, 2016. Radiat. Res., 2017, 188(1), 1-20.
[http://dx.doi.org/10.1667/RR14784.1] [PMID: 28489488]
[74]
Neuzillet, C.; Tijeras-Raballand, A.; Cohen, R.; Cros, J.; Faivre, S.; Raymond, E.; de Gramont, A. Targeting the TGFβ pathway for cancer therapy. Pharmacol. Ther., 2015, 147, 22-31.
[http://dx.doi.org/10.1016/j.pharmthera.2014.11.001] [PMID: 25444759]
[75]
Weichhart, T.; Hengstschläger, M.; Linke, M. Regulation of innate immune cell function by mTOR. Nat. Rev. Immunol., 2015, 15(10), 599-614.
[http://dx.doi.org/10.1038/nri3901] [PMID: 26403194]
[76]
Bai, D.; Zhao, Y.; Zhu, Q.; Zhou, Y.; Zhao, Y.; Zhang, T.; Guo, Q.; Lu, N. LZ205, a newly synthesized flavonoid compound, exerts anti-inflammatory effect by inhibiting M1 macrophage polarization through regulating PI3K/AKT/mTOR signaling pathway. Exp. Cell Res., 2018, 364(1), 84-94.
[http://dx.doi.org/10.1016/j.yexcr.2018.01.033] [PMID: 29391152]
[77]
Noda, T.; Ohsumi, Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J. Biol. Chem., 1998, 273(7), 3963-3966.
[http://dx.doi.org/10.1074/jbc.273.7.3963] [PMID: 9461583]
[78]
Liu, D.; Xu, J.; Qian, G.; Hamid, M.; Gan, F.; Chen, X.; Huang, K. Selenizing astragalus polysaccharide attenuates PCV2 replication promotion caused by oxidative stress through autophagy inhibition via PI3K/AKT activation. Int. J. Biol. Macromol., 2018, 108, 350-359.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.12.010] [PMID: 29217185]
[79]
Lu, Z-J.; Wu, J-J.; Jiang, W-L.; Xiao, J-H.; Tao, K-Z.; Ma, L.; Zheng, P.; Wan, R.; Wang, X-P. MicroRNA-155 promotes the pathogenesis of experimental colitis by repressing SHIP-1 expression. World J. Gastroenterol., 2017, 23(6), 976-985.
[http://dx.doi.org/10.3748/wjg.v23.i6.976] [PMID: 28246471]
[80]
Yang, X.; Cheng, Y.; Li, P.; Tao, J.; Deng, X.; Zhang, X.; Gu, M.; Lu, Q.; Yin, C. A lentiviral sponge for miRNA-21 diminishes aerobic glycolysis in bladder cancer T24 cells via the PTEN/PI3K/AKT/mTOR axis. Tumour Biol., 2015, 36(1), 383-391.
[http://dx.doi.org/10.1007/s13277-014-2617-2] [PMID: 25266796]
[81]
Wang, W-J.; Yang, W.; Ouyang, Z-H.; Xue, J-B.; Li, X-L.; Zhang, J.; He, W-S.; Chen, W-K.; Yan, Y-G.; Wang, C. MiR-21 promotes ECM degradation through inhibiting autophagy via the PTEN/akt/mTOR signaling pathway in human degenerated NP cells. Biomed. Pharmacother., 2018, 99, 725-734.
[http://dx.doi.org/10.1016/j.biopha.2018.01.154] [PMID: 29710470]
[82]
Li, N.; Miao, Y.; Shan, Y.; Liu, B.; Li, Y.; Zhao, L.; Jia, L. MiR-106b and miR-93 regulate cell progression by suppression of PTEN via PI3K/Akt pathway in breast cancer. Cell Death Dis., 2017, 8(5)e2796
[http://dx.doi.org/10.1038/cddis.2017.119] [PMID: 28518139]
[83]
Huang, X.; Shen, Y.; Liu, M.; Bi, C.; Jiang, C.; Iqbal, J.; McKeithan, T.W.; Chan, W.C.; Ding, S-J.; Fu, K. Quantitative proteomics reveals that miR-155 regulates the PI3K-AKT pathway in diffuse large B-cell lymphoma. Am. J. Pathol., 2012, 181(1), 26-33.
[http://dx.doi.org/10.1016/j.ajpath.2012.03.013] [PMID: 22609116]
[84]
Guertin, D.A.; Sabatini, D.M. Defining the role of mTOR in cancer. Cancer Cell, 2007, 12(1), 9-22.
[http://dx.doi.org/10.1016/j.ccr.2007.05.008] [PMID: 17613433]
[85]
Gerster, R.; Eloranta, J.J.; Hausmann, M.; Ruiz, P.A.; Cosin-Roger, J.; Terhalle, A.; Ziegler, U.; Kullak-Ublick, G.A.; von Eckardstein, A.; Rogler, G. Anti-inflammatory function of high-density lipoproteins via autophagy of IκB kinase. Cell. Mol. Gastroenterol. Hepatol, 2015, 1(2), 171-187. e1.
[http://dx.doi.org/10.1016/j.jcmgh.2014.12.006] [PMID: 28247863]
[86]
Guo, W.; Sun, Y.; Liu, W.; Wu, X.; Guo, L.; Cai, P.; Wu, X.; Wu, X.; Shen, Y.; Shu, Y.; Gu, Y.; Xu, Q. Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer. Autophagy, 2014, 10(6), 972-985.
[http://dx.doi.org/10.4161/auto.28374] [PMID: 24879148]
[87]
Hedl, M.; Abraham, C. Secretory mediators regulate Nod2-induced tolerance in human macrophages. Gastroenterology, 2011, 140(1), 231-241.
[http://dx.doi.org/10.1053/j.gastro.2010.09.009] [PMID: 20854823]
[88]
Fantini, M.C.; Pallone, F. Cytokines: from gut inflammation to colorectal cancer. Curr. Drug Targets, 2008, 9(5), 375-380.
[http://dx.doi.org/10.2174/138945008784221206] [PMID: 18473765]
[89]
Ghanaatian, N.; Lashgari, N.A.; Abdolghaffari, A.H.; Rajaee, S.M.; Panahi, Y.; Barreto, G.E.; Butler, A.E.; Sahebkar, A. Curcumin as a therapeutic candidate for multiple sclerosis: Molecular mechanisms and targets. J. Cell. Physiol., 2019, 234(8), 12237-12248.
[http://dx.doi.org/10.1002/jcp.27965] [PMID: 30536381]
[90]
Kordjazy, N.; Haj-Mirzaian, A.; Haj-Mirzaian, A.; Rohani, M.M.; Gelfand, E.W.; Rezaei, N.; Abdolghaffari, A.H. Role of toll-like receptors in inflammatory bowel disease. Pharmacol. Res., 2018, 129, 204-215.
[http://dx.doi.org/10.1016/j.phrs.2017.11.017] [PMID: 29155256]
[91]
Ke, P.; Shao, B-Z.; Xu, Z-Q.; Wei, W.; Han, B-Z.; Chen, X-W.; Su, D-F.; Liu, C. Activation of cannabinoid receptor 2 ameliorates DSS-induced colitis through inhibiting NLRP3 inflammasome in macrophages. PLoS One, 2016, 11(9)e0155076
[http://dx.doi.org/10.1371/journal.pone.0155076] [PMID: 27611972]
[92]
Sánchez-Muñoz, F.; Fonseca-Camarillo, G.C.; Villeda-Ramirez, M.A.; Barreto-Zuniga, R.; Bojalil, R.; Domínguez-Lopez, A.; Uribe, M.; Yamamoto-Furusho, J.K. TLR9 mRNA expression is upregulated in patients with active ulcerative colitis. Inflamm. Bowel Dis., 2010, 16(8), 1267-1268.
[http://dx.doi.org/10.1002/ibd.21155] [PMID: 19902548]
[93]
Qi, J.; Chen, C.; Meng, Q-X.; Wu, Y.; Wu, H.; Zhao, T-B. Crosstalk between activated microglia and neurons in the spinal dorsal horn contributes to stress-induced hyperalgesia. Sci. Rep., 2016, 6, 39442.
[http://dx.doi.org/10.1038/srep39442] [PMID: 27995982]
[94]
Sarbassov, D.D.; Ali, S.M.; Sengupta, S.; Sheen, J-H.; Hsu, P.P.; Bagley, A.F.; Markhard, A.L.; Sabatini, D.M. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell, 2006, 22(2), 159-168.
[http://dx.doi.org/10.1016/j.molcel.2006.03.029] [PMID: 16603397]
[95]
Kim, H.; Banerjee, N.; Ivanov, I.; Pfent, C.M.; Prudhomme, K.R.; Bisson, W.H.; Dashwood, R.H.; Talcott, S.T.; Mertens-Talcott, S.U. Comparison of anti-inflammatory mechanisms of mango (Mangifera Indica L.) and pomegranate (Punica granatum L.) in a preclinical model of colitis. Mol. Nutr. Food Res., 2016, 60(9), 1912-1923.
[http://dx.doi.org/10.1002/mnfr.201501008] [PMID: 27028006]
[96]
Kim, H.; Banerjee, N.; Barnes, R.C.; Pfent, C.M.; Talcott, S.T.; Dashwood, R.H.; Mertens-Talcott, S.U. Mango polyphenolics reduce inflammation in intestinal colitis-involvement of the miR-126/PI3K/AKT/mTOR axis in vitro and in vivo. Mol. Carcinog., 2017, 56(1), 197-207.
[http://dx.doi.org/10.1002/mc.22484] [PMID: 27061150]
[97]
Lee, S-Y.; Tsai, W-C.; Lin, J-C.; Ahmetaj-Shala, B.; Huang, S-F.; Chang, W-L.; Chang, T-C. Astragaloside II promotes intestinal epithelial repair by enhancing L-arginine uptake and activating the mTOR pathway. Sci. Rep., 2017, 7(1), 12302.
[http://dx.doi.org/10.1038/s41598-017-12435-y] [PMID: 28951595]
[98]
Li, L.; Wan, G.; Han, B.; Zhang, Z. Echinacoside alleviated LPS-induced cell apoptosis and inflammation in rat intestine epithelial cells by inhibiting the mTOR/STAT3 pathway. Biomed. Pharmacother., 2018, 104, 622-628.
[http://dx.doi.org/10.1016/j.biopha.2018.05.072] [PMID: 29803175]
[99]
Roudsari, N.M.; Lashgari, N-A.; Momtaz, S.; Farzaei, M.H.; Marques, A.M.; Abdolghaffari, A.H. Natural polyphenols for the prevention of irritable bowel syndrome: molecular mechanisms and targets; a comprehensive review. Daru, 2019, 27(2), 755-780.
[http://dx.doi.org/10.1007/s40199-019-00284-1] [PMID: 31273572]
[100]
Yao, J.; Wei, C.; Wang, J-Y.; Zhang, R.; Li, Y-X.; Wang, L-S. Effect of resveratrol on Treg/Th17 signaling and ulcerative colitis treatment in mice. World J. Gastroenterol., 2015, 21(21), 6572-6581.
[http://dx.doi.org/10.3748/wjg.v21.i21.6572] [PMID: 26074695]
[101]
Fu, X.; Sun, F.; Wang, F.; Zhang, J.; Zheng, B.; Zhong, J.; Yue, T; Zheng, X.; Xu, J-F.; Wang, C-Y. Aloperine protects mice against DSS-induced colitis by PP2A-mediated PI3K/Akt/mTOR signaling suppression. Mediators Inflamm., 2017, 20175706152
[http://dx.doi.org/10.1155/2017/5706152] [PMID: 29056830 ]
[102]
Lyons, J.; Ghazi, P.C.; Starchenko, A.; Tovaglieri, A.; Baldwin, K.R.; Poulin, E.J.; Gierut, J.J.; Genetti, C.; Yajnik, V.; Breault, D.T.; Lauffenburger, D.A.; Haigis, K.M. The colonic epithelium plays an active role in promoting colitis by shaping the tissue cytokine profile. PLoS Biol., 2018, 16(3)e2002417
[http://dx.doi.org/10.1371/journal.pbio.2002417] [PMID: 29596476]
[103]
Figueroa-González, G.; García-Castillo, V.; Coronel-Hernández, J.; López-Urrutia, E.; León-Cabrera, S.; Arias-Romero, L.E.; Terrazas, L.I.; Rodríguez-Sosa, M.; Campos-Parra, A.D.; Zúñiga-Calzada, E.; Lopez-Camarillo, C.; Morales-González, F.; Jacobo-Herrera, N.J.; Pérez-Plasencia, C. Anti-inflammatory and antitumor activity of a triple therapy for a colitis-related colorectal cancer. J. Cancer, 2016, 7(12), 1632-1644.
[http://dx.doi.org/10.7150/jca.13123] [PMID: 27698900]
[104]
Guan, Y.; Zhang, L.; Li, X.; Zhang, X.; Liu, S.; Gao, N.; Li, L.; Gao, G.; Wei, G.; Chen, Z.; Zheng, Y.; Ma, X.; Siwko, S.; Chen, J.L.; Liu, M.; Li, D. Repression of mammalian target of rapamycin complex 1 inhibits intestinal regeneration in acute inflammatory bowel disease models. J. Immunol., 2015, 195(1), 339-346.
[http://dx.doi.org/10.4049/jimmunol.1303356] [PMID: 26026060]

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