Towards natural mimetics of metformin and rapamycin

Aging

Volumn 9, Issue 11, 2017, Pages 2245-2268

  Aliper, Alexander ^a   Jellen, Leslie ^a   Cortese, Franco ^b,c   Artemov, Artem ^a   Karpinsky Semper, Darla ^d   Moskalev, Alexey ^e   Swick, Andrew G ^d   Zhavoronkov, Alex ^a,b  

^a Insilico Medicine Inc   (United States)

^b The Biogerontology Research Foundation   (United Kingdom)

^c QUEEN S UNIVERSITY   (Canada)

^d Scientific Affairs and Medical Development Life Extension Inc   (United States)

^e INSTITUTE OF BIOLOGY   (Russian Federation)

Author keywords

Compound screening; Deep learning; Geroprotector; Metformin; Natural; Nutraceutical; Rapamycin

Indexed keywords

METFORMIN; PROTEIN KINASE INHIBITOR; RAPAMYCIN; TARGET OF RAPAMYCIN KINASE;

ANTAGONISTS AND INHIBITORS; ARTIFICIAL NEURAL NETWORK; BIOLOGY; CHEMICAL STRUCTURE; CHEMISTRY; CLASSIFICATION; DIETARY SUPPLEMENT; DRUG DEVELOPMENT; DRUG EFFECTS; GENE REGULATORY NETWORK; GENETIC DATABASE; HIGH THROUGHPUT SCREENING; HUMAN; MACHINE LEARNING; MOLECULAR MIMICRY; MOLECULARLY TARGETED THERAPY; PROCEDURES; PROTEIN PROTEIN INTERACTION; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION;

COMPUTATIONAL BIOLOGY; DATABASES, GENETIC; DIETARY SUPPLEMENTS; DRUG DISCOVERY; GENE REGULATORY NETWORKS; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; MACHINE LEARNING; METFORMIN; MOLECULAR MIMICRY; MOLECULAR STRUCTURE; MOLECULAR TARGETED THERAPY; NEURAL NETWORKS (COMPUTER); PROTEIN INTERACTION MAPS; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION; SIROLIMUS; STRUCTURE-ACTIVITY RELATIONSHIP; TOR SERINE-THREONINE KINASES;

EID: 85035767903     PISSN: 19454589     EISSN: None     Source Type: Journal    
DOI: 10.18632/aging.101319     Document Type: Article

References (194)

1. Colby SL, Ortman JM. Projections of the size and composition of the US population: 2014 to 2060. US Census Bureau. 2015; 9
2. Niccoli T, Partridge L. Ageing as a risk factor for disease. Curr Biol. 2012; 22:R741-52. https://doi.org/10.1016/j.cub.2012.07.024
3. Moskalev A, Zhikrivetskaya S, Shaposhnikov M, Dobrovolskaya E, Gurinovich R, Kuryan O, Pashuk A, Jellen LC, Aliper A, Peregudov A, Zhavoronkov A. Aging Chart: a community resource for rapid exploratory pathway analysis of age-related processes. Nucleic Acids Res. 2016; 44:D894-99. https://doi.org/10.1093/nar/gkv1287
4. Barardo D, Thornton D, Thoppil H, Walsh M, Sharifi S, Ferreira S, Anžic A, Fernandes M, Monteiro P, Grum T, Cordeiro R, De-Souza EA, Budovsky A, et al. The DrugAge database of aging-related drugs. Aging Cell. 2017; 16:594-97. https://doi.org/10.1111/acel.12585
5. Moskalev A, Chernyagina E, de Magalhães JP, Barardo D, Thoppil H, Shaposhnikov M, Budovsky A, Fraifeld VE, Garazha A, Tsvetkov V, Bronovitsky E, Bogomolov V, Scerbacov A, et al. Geroprotectors.org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease. Aging (Albany NY). 2015; 7:616-28. https://doi.org/10.18632/aging.100799
6. Blagosklonny MV. Validation of anti-aging drugs by treating age-related diseases. Aging (Albany NY). 2009; 1:281-88. https://doi.org/10.18632/aging.100034
7. Zhavoronkov A, Buzdin AA, Garazha AV, Borisov NM, Moskalev AA. Signaling pathway cloud regulation for in silico screening and ranking of the potential geroprotective drugs. Front Genet. 2014; 5:49. https://doi.org/10.3389/fgene.2014.00049
8. Moskalev A, Anisimov V, Aliper A, Artemov A, Asadullah K, Belsky D, Baranova A, de Grey A, Dixit VD, Debonneuil E, Dobrovolskaya E, Fedichev P, Fedintsev A, et al. A review of the biomedical innovations for healthy longevity. Aging (Albany NY). 2017; 9:7-25. https://doi.org/10.18632/aging.101163
9. Moskalev A, Chernyagina E, Tsvetkov V, Fedintsev A, Shaposhnikov M, Krut'ko V, Zhavoronkov A, Kennedy BK. Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Aging Cell. 2016; 15:407-15. https://doi.org/10.1111/acel.12463
10. Pryor R, Cabreiro F. Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem J. 2015; 471:307-22. https://doi.org/10.1042/BJ20150497
11. Cardone L. Biocomputing drug repurposing toward targeted therapies. Aging (Albany NY). 2016; 8:2609-10 https://doi.org/10.18632/aging.101135
12. Ingram DK, Anson RM, de Cabo R, Mamczarz J, Zhu M, Mattison J, Lane MA, Roth GS. Development of calorie restriction mimetics as a prolongevity strategy. Ann N Y Acad Sci. 2004; 1019:412-23. https://doi.org/10.1196/annals.1297.074
13. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. 2017; 8:14063. https://doi.org/10.1038/ncomms14063
14. Phelan JP, Rose MR. Why dietary restriction substantially increases longevity in animal models but won't in humans. Ageing Res Rev. 2005; 4:339-50. https://doi.org/10.1016/j.arr.2005.06.001
15. Zhavoronkov A. Inhibitors of mTOR in aging and cancer. Oncotarget. 2015; 6:45010-11. https://doi.org/10.18632/oncotarget.6878
16. Blagosklonny MV. Rejuvenating immunity: "anti-aging drug today" eight years later. Oncotarget. 2015; 6:19405-12. https://doi.org/10.18632/oncotarget.3740
17. Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD. Regulation of longevity and stress resistance by Sch9 in yeast. Science. 2001; 292:288-90. https://doi.org/10.1126/science.1059497
18. Jia K, Chen D, Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development. 2004; 131:3897-906. https://doi.org/10.1242/dev.01255
19. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature. 2003; 426:620-620. https://doi.org/10.1038/426620a
20. Wu JJ, Liu J, Chen EB, Wang JJ, Cao L, Narayan N, Fergusson MM, Rovira II, Allen M, Springer DA, Lago CU, Zhang S, DuBois W, et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Reports. 2013; 4:913-20. https://doi.org/10.1016/j.celrep.2013.07.030
21. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science. 2009; 326:140-44. https://doi.org/10.1126/science.1177221
22. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009; 460:392-95. https://doi.org/10.1038/nature08221
23. Roth GS, Ingram DK. Manipulation of health span and function by dietary caloric restriction mimetics. Ann N Y Acad Sci. 2016; 1363:5-10. https://doi.org/10.1111/nyas.12834
24. Alvers AL, Wood MS, Hu D, Kaywell AC, Dunn WA Jr, Aris JP. Autophagy is required for extension of yeast chronological life span by rapamycin. Autophagy. 2009; 5:847-49. https://doi.org/10.4161/auto.8824
25. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010; 11:35-46. https://doi.org/10.1016/j.cmet.2009.11.010
26. Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice. J Gerontol A Biol Sci Med Sci. 2016; 71:876-81. https://doi.org/10.1093/gerona/glw064
27. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2011; 66:191-201 https://doi.org/10.1093/gerona/glq178
28. Swindell WR. Meta-Analysis of 29 Experiments Evaluating the Effects of Rapamycin on Life Span in the Laboratory Mouse. J Gerontol A Biol Sci Med Sci. 2017; 72:1024-32. https://doi.org/10.1093/gerona/glw153
29. Yakupoglu YK, Buell JF, Woodle S, Kahan BD. Individualization of immunosuppressive therapy. III. Sirolimus associated with a reduced incidence of malignancy. Transplant Proc. 2006; 38:358-61. https://doi.org/10.1016/j.transproceed.2006.01.019
30. Campistol JM, Eris J, Oberbauer R, Friend P, Hutchison B, Morales JM, Claesson K, Stallone G, Russ G, Rostaing L, Kreis H, Burke JT, Brault Y, et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol. 2006; 17:581-89. https://doi.org/10.1681/ASN.2005090993
31. Garrick R. Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation. Year Book Med. 2007; 2007:226-27. https://doi.org/10.1016/S0084-3873(08)70153-6
32. Campistol JM, Eris J, Oberbauer R, Friend P, Hutchison B, Morales JM, Claesson K, Stallone G, Russ G, Rostaing L, Kreis H, Burke JT, Brault Y, et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol. 2006; 17:581-89. https://doi.org/10.1681/ASN.2005090993
33. Zmonarski SC, Boratynska M, Bernat B, Kaminska D, Rabczynski J, Klinger M. Regression of Kaposis's sarcoma in renal graft recirients after conversion to Sirolimus treatment. Transplantation. 2004; 78:500. https://doi.org/10.1097/00007890-200407271-01348
34. Cullis B, D'Souza R, McCullagh P, Harries S, Nicholls A, Lee R, Bingham C. Sirolimus-induced remission of posttransplantation lymphoproliferative disorder. Am J Kidney Dis. 2006; 47:e67-72. https://doi.org/10.1053/j.ajkd.2006.01.029
35. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Rosenfeld SV, Blagosklonny MV. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle. 2011; 10:4230-36. https://doi.org/10.4161/cc.10.24.18486
36. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Antoch MP, Blagosklonny MV. Rapamycin extends maximal lifespan in cancer-prone mice. Am J Pathol. 2010; 176:2092-97. https://doi.org/10.2353/ajpath.2010.091050
37. Danilov A, Shaposhnikov M, Plyusnina E, Kogan V, Fedichev P, Moskalev A. Selective anticancer agents suppress aging in Drosophila. Oncotarget. 2013; 4:1507-26. https://doi.org/10.18632/oncotarget.1272
38. Leontieva OV, Demidenko ZN, Blagosklonny MV. Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program). Oncotarget. 2015; 6:23238-48. https://doi.org/10.18632/oncotarget.4836
39. Blagosklonny MV. Prevention of cancer by inhibiting aging. Cancer Biol Ther. 2008; 7:1520-24. https://doi.org/10.4161/cbt.7.10.6663
40. Blagosklonny MV. From rapalogs to anti-aging formula. Oncotarget. 2017; 8:35492-507. https://doi.org/10.18632/oncotarget.18033
41. Apontes P, Leontieva OV, Demidenko ZN, Li F, Blagosklonny MV. Exploring long-term protection of normal human fibroblasts and epithelial cells from chemotherapy in cell culture. Oncotarget. 2011; 2:222-33. https://doi.org/10.18632/oncotarget.248
42. Castillo-Quan JI, Blackwell TK. Metformin: Restraining Nucleocytoplasmic Shuttling to Fight Cancer and Aging. Cell. 2016; 167:1670-71. https://doi.org/10.1016/j.cell.2016.11.058
43. Nair V, Sreevalsan S, Basha R, Abdelrahim M, Abudayyeh A, Rodrigues Hoffman A, Safe S. Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors. J Biol Chem. 2014; 289:27692-701. https://doi.org/10.1074/jbc.M114.592576
44. Pérez-Revuelta BI, Hettich MM, Ciociaro A, Rotermund C, Kahle PJ, Krauss S, Di Monte DA. Metformin lowers Ser-129 phosphorylated α-synuclein levels via mTOR-dependent protein phosphatase 2A activation. Cell Death Dis. 2014; 5:e1209. https://doi.org/10.1038/cddis.2014.175
45. Kickstein E, Krauss S, Thornhill P, Rutschow D, Zeller R, Sharkey J, Williamson R, Fuchs M, Köhler A, Glossmann H, Schneider R, Sutherland C, Schweiger S. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc Natl Acad Sci USA. 2010; 107:21830-35. https://doi.org/10.1073/pnas.0912793107
46. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005; 330:1304-05. https://doi.org/10.1136/bmj.38415.708634.F7
47. Anisimov VN. Metformin for aging and cancer prevention. Aging (Albany NY). 2010; 2:760-74. https://doi.org/10.18632/aging.100230
48. Zhao P, Sui BD, Liu N, Lv YJ, Zheng CX, Lu YB, Huang WT, Zhou CH, Chen J, Pang DL, Fei DD, Xuan K, Hu CH, Jin Y. Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application. Aging Cell. 2017; 16:1083-93. https://doi.org/10.1111/acel.12635
49. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013; 4:2192. https://doi.org/10.1038/ncomms3192
50. Slack C, Foley A, Partridge L. Activation of AMPK by the putative dietary restriction mimetic metformin is insufficient to extend lifespan in Drosophila. PLoS One. 2012; 7:e47699. https://doi.org/10.1371/journal.pone.0047699
51. Onken B, Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS One. 2010; 5:e8758. https://doi.org/10.1371/journal.pone.0008758
52. Anisimov VN, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Egormin PA, Yurova MV, Rosenfeld SV, Semenchenko AV, Kovalenko IG, Poroshina TE, Berstein LM. Gender differences in metformin effect on aging, life span and spontaneous tumorigenesis in 129/Sv mice. Aging (Albany NY). 2010; 2:945-58. https://doi.org/10.18632/aging.100245
53. Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Kovalenko IG, Poroshina TE. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY). 2011; 3:148-57. https://doi.org/10.18632/aging.100273
54. Batandier C, Guigas B, Detaille D, El-Mir MY, Fontaine E, Rigoulet M, Leverve XM. The ROS production induced by a reverse-electron flux at respiratorychain complex 1 is hampered by metformin. J Bioenerg Biomembr. 2006; 38:33-42. https://doi.org/10.1007/s10863-006-9003-8
55. Hirsch A, Hahn D, Kempná P, Hofer G, Nuoffer JM, Mullis PE, Flück CE. Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain. Endocrinology. 2012; 153:4354-66. https://doi.org/10.1210/en.2012-1145
56. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000; 348:607-14. https://doi.org/10.1042/bj3480607
57. Fontaine E. Metformin and respiratory chain complex I: the last piece of the puzzle? Biochem J. 2014; 463:e3-5. https://doi.org/10.1042/BJ20141020
58. Bridges HR, Jones AJ, Pollak MN, Hirst J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J. 2014; 462:475-87. https://doi.org/10.1042/BJ20140620
59. Zheng Z, Chen H, Li J, Li T, Zheng B, Zheng Y, Jin H, He Y, Gu Q, Xu X. Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes. 2012; 61:217-28. https://doi.org/10.2337/db11-0416
60. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000; 348:607-14. https://doi.org/10.1042/bj3480607
61. El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000; 275:223-28. https://doi.org/10.1074/jbc.275.1.223
62. Stephenne X, Foretz M, Taleux N, van der Zon GC, Sokal E, Hue L, Viollet B, Guigas B. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia. 2011; 54:3101-10. https://doi.org/10.1007/s00125-011-2311-5
63. Lien F, Berthier A, Bouchaert E, Gheeraert C, Alexandre J, Porez G, Prawitt J, Dehondt H, Ploton M, Colin S, Lucas A, Patrice A, Pattou F, et al. Metformin interferes with bile acid homeostasis through AMPKFXR crosstalk. J Clin Invest. 2014; 124:1037-51. https://doi.org/10.1172/JCI68815
64. Lu J, Shi J, Li M, Gui B, Fu R, Yao G, Duan Z, Lv Z, Yang Y, Chen Z, Jia L, Tian L. Activation of AMPK by metformin inhibits TGF-β-induced collagen production in mouse renal fibroblasts. Life Sci. 2015; 127:59-65. https://doi.org/10.1016/j.lfs.2015.01.042
65. Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010; 120:2355-69. https://doi.org/10.1172/JCI40671
66. Cho K, Chung JY, Cho SK, Shin HW, Jang IJ, Park JW, Yu KS, Cho JY. Antihyperglycemic mechanism of metformin occurs via the AMPK/LXRa/POMC pathway. Sci Rep. 2015; 5:8145. https://doi.org/10.1038/srep08145
67. Hardie DG. AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obes. 2008 (Suppl 4); 32:S7-12. https://doi.org/10.1038/ijo.2008.116
68. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMPactivated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108:1167-74. https://doi.org/10.1172/JCI13505
69. Liu B, Fan Z, Edgerton SM, Yang X, Lind SE, Thor AD. Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions. Cell Cycle. 2011; 10:2959-66. https://doi.org/10.4161/cc.10.17.16359
70. Zhang E, Guo Q, Gao H, Xu R, Teng S, Wu Y. Metformin and Resveratrol Inhibited High Glucose-Induced Metabolic Memory of Endothelial Senescence through SIRT1/p300/p53/p21 Pathway. PLoS One. 2015; 10:e0143814. https://doi.org/10.1371/journal.pone.0143814
71. Arunachalam G, Samuel SM, Marei I, Ding H, Triggle CR. Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1. Br J Pharmacol. 2014; 171:523-35. https://doi.org/10.1111/bph.12496
72. Bashmakov YK, Petyaev IM. Old Drug Acquires New Target: metformin and Sirt1. J Diabetes Metab. 2011; 2:107e. https://doi.org/10.4172/2155-6156.1000107e
73. Chen Q, Yang X, Zhang H, Kong X, Yao L, Cui X, Zou Y, Fang F, Yang J, Chang Y. Metformin impairs systemic bile acid homeostasis through regulating SIRT1 protein levels. Biochim Biophys Acta. 2017; 1864:101-12. https://doi.org/10.1016/j.bbamcr.2016.10.020
74. Howell JJ, Hellberg K, Turner M, Talbott G, Kolar MJ, Ross DS, Hoxhaj G, Saghatelian A, Shaw RJ, Manning BD. Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex. Cell Metab. 2017; 25:463-71. https://doi.org/10.1016/j.cmet.2016.12.009
75. Chen B, Ma L, Paik H, Sirota M, Wei W, Chua MS, So S, Butte AJ. Reversal of cancer gene expression correlates with drug efficacy and reveals therapeutic targets. Nat Commun. 2017; 8:16022. https://doi.org/10.1038/ncomms16022
76. High KP. The antimicrobial activities of cyclosporine, FK506, and rapamycin. Transplantation. 1994; 57:1689-700. https://doi.org/10.1097/00007890-199457120-00001
77. Büchler M, Caillard S, Barbier S, Thervet E, Toupance O, Mazouz H, Hurault de Ligny B, Le Meur Y, Thierry A, Villemain F, Heng AE, Moulin B, Morin MP, et al, and SPIESSER Group. Sirolimus versus cyclosporine in kidney recipients receiving thymoglobulin, mycophenolate mofetil and a 6-month course of steroids. Am J Transplant. 2007; 7:2522-31. https://doi.org/10.1111/j.1600-6143.2007.01976.x
78. Houde VP, Brûlé S, Festuccia WT, Blanchard PG, Bellmann K, Deshaies Y, Marette A. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes. 2010; 59:1338-48. https://doi.org/10.2337/db09-1324
79. Chang GR, Wu YY, Chiu YS, Chen WY, Liao JW, Hsu HM, Chao TH, Hung SW, Mao FC. Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice. Basic Clin Pharmacol Toxicol. 2009; 105:188-98. https://doi.org/10.1111/j.1742-7843.2009.00427.x
80. Schindler CE, Partap U, Patchen BK, Swoap SJ. Chronic rapamycin treatment causes diabetes in male mice. Am J Physiol Regul Integr Comp Physiol. 2014; 307:R434-43. https://doi.org/10.1152/ajpregu.00123.2014
81. Blagosklonny MV. Rapamycin-induced glucose intolerance: hunger or starvation diabetes. Cell Cycle. 2011; 10:4217-24. https://doi.org/10.4161/cc.10.24.18595
82. Dujic T, Causevic A, Bego T, Malenica M, Velija-Asimi Z, Pearson ER, Semiz S. Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with Type 2 diabetes. Diabet Med. 2016; 33:511-14. https://doi.org/10.1111/dme.13040
83. Blonde L, Dailey GE, Jabbour SA, Reasner CA, Mills DJ. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin. 2004; 20:565-72. https://doi.org/10.1185/030079904125003278
84. Lalau JD. Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf. 2010; 33:727-40. https://doi.org/10.2165/11536790-000000000-00000
85. Kim MJ, Han JY, Shin JY, Kim SI, Lee JM, Hong S, Kim SH, Nam MS, Kim YS. Metformin-associated lactic acidosis: predisposing factors and outcome. Endocrinol Metab (Seoul). 2015; 30:78-83. https://doi.org/10.3803/EnM.2015.30.1.78
86. Biradar V, Moran JL, Peake SL, Peter JV. Metforminassociated lactic acidosis (MALA): clinical profile and outcomes in patients admitted to the intensive care unit. Crit Care Resusc. 2010; 12:191-95
87. Leontieva OV, Blagosklonny MV. M(o)TOR of pseudohypoxic state in aging: rapamycin to the rescue. Cell Cycle. 2014; 13:509-15. https://doi.org/10.4161/cc.27973
88. Nasri H, Baradaran A, Shirzad H, Rafieian-Kopaei M. New concepts in nutraceuticals as alternative for pharmaceuticals. Int J Prev Med. 2014; 5:1487-99
89. Zhu Q, Izumchenko E, Aliper AM, Makarev E, Paz K, Buzdin AA, Zhavoronkov AA, Sidransky D. Pathway activation strength is a novel independent prognostic biomarker for cetuximab sensitivity in colorectal cancer patients. Hum Genome Var. 2015; 2:15009. https://doi.org/10.1038/hgv.2015.9
90. Borisov NM, Terekhanova NV, Aliper AM, Venkova LS, Smirnov PY, Roumiantsev S, Korzinkin MB, Zhavoronkov AA, Buzdin AA. Signaling pathways activation profiles make better markers of cancer than expression of individual genes. Oncotarget. 2014; 5:10198-205. https://doi.org/10.18632/oncotarget.2548
91. Lezhnina K, Kovalchuk O, Zhavoronkov AA, Korzinkin MB, Zabolotneva AA, Shegay PV, Sokov DG, Gaifullin NM, Rusakov IG, Aliper AM, Roumiantsev SA, Alekseev BY, Borisov NM, Buzdin AA. Novel robust biomarkers for human bladder cancer based on activation of intracellular signaling pathways. Oncotarget. 2014; 5:9022-32. https://doi.org/10.18632/oncotarget.2493
92. Artemov A, Aliper A, Korzinkin M, Lezhnina K, Jellen L, Zhukov N, Roumiantsev S, Gaifullin N, Zhavoronkov A, Borisov N, Buzdin A. A method for predicting target drug efficiency in cancer based on the analysis of signaling pathway activation. Oncotarget. 2015; 6:29347-56. https://doi.org/10.18632/oncotarget.5119
93. Aliper A, Belikov AV, Garazha A, Jellen L, Artemov A, Suntsova M, Ivanova A, Venkova L, Borisov N, Buzdin A, Mamoshina P, Putin E, Swick AG, et al. In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state. Aging (Albany NY). 2016; 8:2127-52. https://doi.org/10.18632/aging.101047
94. Wei T, Li S. Development of Genomics-Based Gene Expression Signature Biomarkers in Oncology and Toxicology to Facilitate Drug Discovery and Translational Medicine. Curr Bioinform. 2010; 5:109-17 https://doi.org/10.2174/157489310791268423
95. Sithara S, Crowley TM, Walder K, Aston-Mourney K. Gene expression signature: a powerful approach for drug discovery in diabetes. J Endocrinol. 2017; 232:R131-39. https://doi.org/10.1530/JOE-16-0515
96. Luizon MR, Eckalbar WL, Wang Y, Jones SL, Smith RP, Laurance M, Lin L, Gallins PJ, Etheridge AS, Wright F, Zhou Y, Molony C, Innocenti F, et al. Genomic Characterization of Metformin Hepatic Response. PLoS Genet. 2016; 12:e1006449. https://doi.org/10.1371/journal.pgen.1006449
97. Leff T. AMP-activated protein kinase regulates gene expression by direct phosphorylation of nuclear proteins. Biochem Soc Trans. 2003; 31:224-27. https://doi.org/10.1042/bst0310224
98. Spindler SR. Use of microarray biomarkers to identify longevity therapeutics. Aging Cell. 2006; 5:39-50. https://doi.org/10.1111/j.1474-9726.2006.00194.x
99. Dhahbi JM, Mote PL, Fahy GM, Spindler SR. Identification of potential caloric restriction mimetics by microarray profiling. Physiol Genomics. 2005; 23:343-50. https://doi.org/10.1152/physiolgenomics.00069.2005
100. Cao SX, Dhahbi JM, Mote PL, Spindler SR. Genomic profiling of short-and long-term caloric restriction effects in the liver of aging mice. Proc Natl Acad Sci USA. 2001; 98:10630-35. https://doi.org/10.1073/pnas.191313598
101. Spindler SR. Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction. Mech Ageing Dev. 2005; 126:960-66. https://doi.org/10.1016/j.mad.2005.03.016
102. Aliper A, Plis S, Artemov A, Ulloa A, Mamoshina P, Zhavoronkov A. Deep Learning Applications for Predicting Pharmacological Properties of Drugs and Drug Repurposing Using Transcriptomic Data. Mol Pharm. 2016; 13:2524-30. https://doi.org/10.1021/acs.molpharmaceut.6b00248
103. Buzdin AA, Zhavoronkov AA, Korzinkin MB, Venkova LS, Zenin AA, Smirnov PY, Borisov NM. Oncofinder, a new method for the analysis of intracellular signaling pathway activation using transcriptomic data. Front Genet. 2014; 5:55. https://doi.org/10.3389/fgene.2014.00055
104. Ozerov IV, Lezhnina KV, Izumchenko E, Artemov AV, Medintsev S, Vanhaelen Q, Aliper A, Vijg J, Osipov AN, Labat I, West MD, Buzdin A, Cantor CR, et al. In silico Pathway Activation Network Decomposition Analysis (iPANDA) as a method for biomarker development. Nat Commun. 2016; 7:13427. https://doi.org/10.1038/ncomms13427
105. Gu J, Gui Y, Chen L, Yuan G, Lu HZ, Xu X. Use of natural products as chemical library for drug discovery and network pharmacology. PLoS One. 2013; 8:e62839. https://doi.org/10.1371/journal.pone.0062839
106. Kanehisa M, Sato Y, Kawashima M, Furumichi M, Tanabe M. KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res. 2016; 44:D457-62. https://doi.org/10.1093/nar/gkv1070
107. Lin KC, Yeh LR, Chen LJ, Wen YJ, Cheng KC, Cheng JT. Plasma glucose-lowering action of allantoin is induced by activation of imidazoline I-2 receptors in streptozotocin-induced diabetic rats. Horm Metab Res. 2012; 44:41-46. https://doi.org/10.1055/s-0031-1295439
108. Niu CS, Chen W, Wu HT, Cheng KC, Wen YJ, Lin KC, Cheng JT. Decrease of plasma glucose by allantoin, an active principle of yam ( Dioscorea spp.), in streptozotocin-induced diabetic rats. J Agric Food Chem. 2010; 58:12031-35. https://doi.org/10.1021/jf103234d
109. Vogels GD, Van der Drift C. Degradation of purines and pyrimidines by microorganisms. Bacteriol Rev. 1976; 40:403-68
110. Kahn K, Serfozo P, Tipton PA. Identification of the True Product of the Urate Oxidase Reaction. J Am Chem Soc. 1997; 119:5435-42. https://doi.org/10.1021/ja970375t
111. Malir F, Ostry V, Pfohl-Leszkowicz A, Malir J, Toman J. Ochratoxin A: 50 Years of Research. Toxins (Basel). 2016; 8:191. https://doi.org/10.3390/toxins8070191
112. Zeng C, Wei J, Li H, Wang YL, Xie DX, Yang T, Gao SG, Li YS, Luo W, Lei GH. Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee. Sci Rep. 2015; 5:16827. https://doi.org/10.1038/srep16827
113. Yadav VR, Prasad S, Sung B, Aggarwal BB. The role of chalcones in suppression of NF-?B-mediated inflammation and cancer. Int Immunopharmacol. 2011; 11:295-309. https://doi.org/10.1016/j.intimp.2010.12.006
114. Niu PG, Zhang YX, Shi DH, Liu Y, Chen YY, Deng J. Cardamonin Inhibits Metastasis of Lewis Lung Carcinoma Cells by Decreasing mTOR Activity. PLoS One. 2015; 10:e0127778. https://doi.org/10.1371/journal.pone.0127778
115. Ohji G, Hidayat S, Nakashima A, Tokunaga C, Oshiro N, Yoshino K, Yokono K, Kikkawa U, Yonezawa K. Suppression of the mTOR-raptor signaling pathway by the inhibitor of heat shock protein 90 geldanamycin. J Biochem. 2006; 139:129-35. https://doi.org/10.1093/jb/mvj008
116. Gianni L, Norton L, Wolmark N, Suter TM, Bonadonna G, Hortobagyi GN. Role of anthracyclines in the treatment of early breast cancer. J Clin Oncol. 2009; 27:4798-808. https://doi.org/10.1200/JCO.2008.21.4791
117. Flavin R, Peluso S, Nguyen PL, Loda M. Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 2010; 6:551-62. https://doi.org/10.2217/fon.10.11
118. Cherblanc FL, Chapman KL, Brown R, Fuchter MJ. Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases. Nat Chem Biol. 2013; 9:136-37. https://doi.org/10.1038/nchembio.1187
119. Lee YM, Lim JH, Yoon H, Chun YS, Park JW. Antihepatoma activity of chaetocin due to deregulated splicing of hypoxia-inducible factor 1a pre-mRNA in mice and in vitro. Hepatology. 2011; 53:171-80. https://doi.org/10.1002/hep.24010
120. Min J, Huang K, Tang H, Ding X, Qi C, Qin X, Xu Z. Phloretin induces apoptosis of non-small cell lung carcinoma A549 cells via JNK1/2 and p38 MAPK pathways. Oncol Rep. 2015; 34:2871-79. https://doi.org/10.3892/or.2015.4325
121. Lee IC, Choi BY. Withaferin-A-A Natural Anticancer Agent with Pleitropic Mechanisms of Action. Int J Mol Sci. 2016; 17:290. https://doi.org/10.3390/ijms17030290
122. Mazimba O. Umbelliferone: Sources, chemistry and bioactivities review. Bulletin of Faculty of Pharmacy, Cairo University. 2017. https://doi.org/10.1016/j.bfopcu.2017.05.001
123. Amalan V, Vijayakumar N, Indumathi D, Ramakrishnan A. Antidiabetic and antihyperlipidemic activity of p-coumaric acid in diabetic rats, role of pancreatic GLUT 2: in vivo approach. Biomed Pharmacother. 2016; 84:230-36. https://doi.org/10.1016/j.biopha.2016.09.039
124. Pragasam SJ, Venkatesan V, Rasool M. Immunomodulatory and anti-inflammatory effect of pcoumaric acid, a common dietary polyphenol on experimental inflammation in rats. Inflammation. 2013; 36:169-76. https://doi.org/10.1007/s10753-012-9532-8
125. Park BS, Abdel-Azeem AZ, Al-Sanea MM, Yoo KH, Tae JS, Lee SH. Staurosporine analogues from microbial and synthetic sources and their biological activities. Curr Med Chem. 2013; 20:3872-902. https://doi.org/10.2174/09298673113209990176
126. Phelan JP, Reen FJ, Dunphy N, O'Connor R, O'Gara F. Bile acids destabilise HIF-1a and promote antitumour phenotypes in cancer cell models. BMC Cancer. 2016; 16:476. https://doi.org/10.1186/s12885-016-2528-2
127. Garbett NC, Graves DE. Extending nature's leads: the anticancer agent ellipticine. Curr Med Chem Anticancer Agents. 2004; 4:149-72. https://doi.org/10.2174/1568011043482070
128. Nagle DG, Ferreira D, Zhou YD. Epigallocatechin-3-gallate (EGCG): chemical and biomedical perspectives. Phytochemistry. 2006; 67:1849-55. https://doi.org/10.1016/j.phytochem.2006.06.020
129. Chew WS, Wang W, Herr DR. To fingolimod and beyond: the rich pipeline of drug candidates that target S1P signaling. Pharmacol Res. 2016; 113:521-32 https://doi.org/10.1016/j.phrs.2016.09.025
130. Peng F, Du Q, Peng C, Wang N, Tang H, Xie X, Shen J, Chen J. A Review: The Pharmacology of Isoliquiritigenin. Phytother Res. 2015; 29:969-77. https://doi.org/10.1002/ptr.5348
131. Pajak B. Antiapoptotic proteins as targets for bioactive compounds. Pol J Vet Sci. 2007; 10:127-30
132. Peggy Hsu P. Natural Medicines Comprehensive Database, J Med Libr Assoc. Medical Library Association. 2002; 90:114
133. Lehár J, Krueger AS, Avery W, Heilbut AM, Johansen LM, Price ER, Rickles RJ, Short GF 3rd, Staunton JE, Jin X, Lee MS, Zimmermann GR, Borisy AA. Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat Biotechnol. 2009; 27:659-66. https://doi.org/10.1038/nbt.1549
134. Tan X, Hu L, Luquette LJ 3rd, Gao G, Liu Y, Qu H, Xi R, Lu ZJ, Park PJ, Elledge SJ. Systematic identification of synergistic drug pairs targeting HIV. Nat Biotechnol. 2012; 30:1125-30. https://doi.org/10.1038/nbt.2391
135. Katouli AA, Komarova NL. Optimizing combination therapies with existing and future CML drugs. PLoS One. 2010; 5:e12300. https://doi.org/10.1371/journal.pone.0012300
136. Liu L, Li H, Guo Z, Ma X, Cao N, Zheng Y, Geng S, Duan Y, Han G, Du G. The Combination of Three Natural Compounds Effectively Prevented Lung Carcinogenesis by Optimal Wound Healing. PLoS One. 2015; 10:e0143438. https://doi.org/10.1371/journal.pone.0143438
137. Bulusu KC, Guha R, Mason DJ, Lewis RP, Muratov E, Kalantar Motamedi Y, Cokol M, Bender A. Modelling of compound combination effects and applications to efficacy and toxicity: state-of-the-art, challenges and perspectives. Drug Discov Today. 2016; 21:225-38. https://doi.org/10.1016/j.drudis.2015.09.003
138. Dessale T, Batchu KC, Barardo D, Ng LF, Lam VY, Xiao L, Wenk MR, Tolwinski NS, Gruber J. Doubling healthy lifespan using drug synergies. bioRxiv. 2017; 153205. https://doi.org/10.1101/153205
139. Zanetti A, Affatato R, Centritto F, Fratelli M, Kurosaki M, Barzago MM, Bolis M, Terao M, Garattini E, Paroni G. All-trans-retinoic Acid Modulates the Plasticity and Inhibits the Motility of Breast Cancer Cells: ROLE OF NOTCH1 AND TRANSFORMING GROWTH FACTOR (TGFβ). J Biol Chem. 2015; 290:17690-709. https://doi.org/10.1074/jbc.M115.638510
140. Lee J, Liu J, Feng X, Salazar Hernández MA, Mucka P, Ibi D, Choi JW, Ozcan U. Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. Nat Med. 2016; 22:1023-32. https://doi.org/10.1038/nm.4145
141. Hahm ER, Lee J, Kim SH, Sehrawat A, Arlotti JA, Shiva SS, Bhargava R, Singh SV. Metabolic alterations in mammary cancer prevention by withaferin A in a clinically relevant mouse model. J Natl Cancer Inst. 2013; 105:1111-22. https://doi.org/10.1093/jnci/djt153
142. Mohan R, Hammers HJ, Bargagna-Mohan P, Zhan XH, Herbstritt CJ, Ruiz A, Zhang L, Hanson AD, Conner BP, Rougas J, Pribluda VS. Withaferin A is a potent inhibitor of angiogenesis. Angiogenesis. 2004; 7:115-22 https://doi.org/10.1007/s10456-004-1026-3
143. Nishikawa Y, Okuzaki D, Fukushima K, Mukai S, Ohno S, Ozaki Y, Yabuta N, Nojima H, Withaferin A. Withaferin A Induces Cell Death Selectively in Androgen-Independent Prostate Cancer Cells but Not in Normal Fibroblast Cells. PLoS One. 2015; 10:e0134137. https://doi.org/10.1371/journal.pone.0134137
144. Issa ME, Cuendet M. Withaferin A induces cell death and differentiation in multiple myeloma cancer stem cells. MedChemComm. 2017; 8:112-21. https://doi.org/10.1039/C6MD00410E
145. Koduru S, Kumar R, Srinivasan S, Evers MB, Damodaran C. Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis. Mol Cancer Ther. 2010; 9:202-10. https://doi.org/10.1158/1535-7163.MCT-09-0771
146. Khazal KF, Samuel T, Hill DL, Grubbs CJ. Effect of an extract of Withania somnifera root on estrogen receptor-positive mammary carcinomas. Anticancer Res. 2013; 33:1519-23
147. Choi BY, Kim BW. Withaferin-A Inhibits Colon Cancer Cell Growth by Blocking STAT3 Transcriptional Activity. J Cancer Prev. 2015; 20:185-92. https://doi.org/10.15430/JCP.2015.20.3.185
148. Tahara T, Streit U, Pelish HE, Shair MD. STAT3 Inhibitory Activity of Structurally Simplified Withaferin A Analogues. Org Lett. 2017; 19:1538-41. https://doi.org/10.1021/acs.orglett.7b00332
149. Lee HE, Shin JA, Jeong JH, Jeon JG, Lee MH, Cho SD. Anticancer activity of Ashwagandha against human head and neck cancer cell lines. J Oral Pathol Med. 2016; 45:193-201. https://doi.org/10.1111/jop.12353
150. Um HJ, Min KJ, Kim DE, Kwon TK. Withaferin A inhibits JAK/STAT3 signaling and induces apoptosis of human renal carcinoma Caki cells. Biochem Biophys Res Commun. 2012; 427:24-29. https://doi.org/10.1016/j.bbrc.2012.08.133
151. Yu Y, Hamza A, Zhang T, Gu M, Zou P, Newman B, Li Y, Gunatilaka AA, Zhan CG, Sun D. Withaferin A targets heat shock protein 90 in pancreatic cancer cells. Biochem Pharmacol. 2010; 79:542-51. https://doi.org/10.1016/j.bcp.2009.09.017
152. Yan X, Huang G, Liu Q, Zheng J, Chen H, Huang Q, Chen J, Huang H. Withaferin A protects against spinal cord injury by inhibiting apoptosis and inflammation in mice. Pharm Biol. 2017; 55:1171-76. https://doi.org/10.1080/13880209.2017.1288262
153. Christensen LP. Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Adv Food Nutr Res. 2009; 55:1-99
154. Lim SW, Doh KC, Jin L, Jin J, Piao SG, Heo SB, Chung BH, Yang CW. Ginseng treatment attenuates autophagic cell death in chronic cyclosporine nephropathy. Nephrology (Carlton). 2014; 19:490-99. https://doi.org/10.1111/nep.12273
155. Yoo HS, Kim JM, Jo E, Cho CK, Lee SY, Kang HS, Lee MG, Yang PY, Jang IS. Modified Panax ginseng extract regulates autophagy by AMPK signaling in A549 human lung cancer cells. Oncol Rep. 2017; 37:3287-96 https://doi.org/10.3892/or.2017.5590
156. Kim MJ, Yun H, Kim DH, Kang I, Choe W, Kim SS, Ha J. AMP-activated protein kinase determines apoptotic sensitivity of cancer cells to ginsenoside-Rh2. J Ginseng Res. 2014; 38:16-21. https://doi.org/10.1016/j.jgr.2013.11.010
157. Chen G, Li H, Gao Y, Zhang L, Zhao Y. Flavored black ginseng exhibited antitumor activity via improving immune function and inducing apoptosis. Food Funct. 2017; 8:1880-89. https://doi.org/10.1039/C6FO01870J
158. Immunomodulatory Effects of Non-saponin Red Ginseng Components on Innate Immune Cells. Immunomodulatory Effects of Non-saponin Red Ginseng Components on Innate Immune Cells. J Ginseng Res. 2008; 32:67-72. https://doi.org/10.5142/JGR.2008.32.1.067
159. Kang S, Min H. Ginseng, the 'Immunity Boost': The Effects of Panax ginseng on Immune System. J Ginseng Res. 2012; 36:354-68. https://doi.org/10.5142/jgr.2012.36.4.354
160. Larsen MW, Moser C, Høiby N, Song Z, Kharazmi A. Ginseng modulates the immune response by induction of interleukin-12 production. APMIS. 2004; 112:369-73. https://doi.org/10.1111/j.1600-0463.2004.apm1120607.x
161. Hafez MM, Hamed SS, El-Khadragy MF, Hassan ZK, Al Rejaie SS, Sayed-Ahmed MM, Al-Harbi NO, Al-Hosaini KA, Al-Harbi MM, Alhoshani AR, Al-Shabanah OA, Alsharari SD. Effect of ginseng extract on the TGF-β1 signaling pathway in CCl4-induced liver fibrosis in rats. BMC Complement Altern Med. 2017; 17:45. https://doi.org/10.1186/s12906-016-1507-0
162. Lee YY, Park JS, Lee EJ, Lee SY, Kim DH, Kang JL, Kim HS. Anti-inflammatory mechanism of ginseng saponin metabolite Rh3 in lipopolysaccharide-stimulated microglia: critical role of 5'-adenosine monophosphate-activated protein kinase signaling pathway. J Agric Food Chem. 2015; 63:3472-80. https://doi.org/10.1021/jf506110y
163. Inoue K. Korean red ginseng for allergic rhinitis. Immunopharmacol Immunotoxicol. 2013; 35:693. https://doi.org/10.3109/08923973.2013.838254
164. Lee EJ, Song MJ, Kwon HS, Ji GE, Sung MK. Oral administration of fermented red ginseng suppressed ovalbumin-induced allergic responses in female BALB/c mice. Phytomedicine. 2012; 19:896-903. https://doi.org/10.1016/j.phymed.2012.04.008
165. Li LC, Piao HM, Zheng MY, Lin ZH, Choi YH, Yan GH. Ginsenoside Rh2 attenuates allergic airway inflammation by modulating nuclear factor-?B activation in a murine model of asthma. Mol Med Rep. 2015; 12:6946-54. https://doi.org/10.3892/mmr.2015.4272
166. Chan GH, Law BY, Chu JM, Yue KK, Jiang ZH, Lau CW, Huang Y, Chan SW, Ying-Kit Yue P, Wong RN. Ginseng extracts restore high-glucose induced vascular dysfunctions by altering triglyceride metabolism and downregulation of atherosclerosis-related genes. Evid Based Complement Alternat Med. 2013; 2013:797310. https://doi.org/10.1155/2013/797310
167. Hong SY, Kim JY, Ahn HY, Shin JH, Kwon O. Panax ginseng extract rich in ginsenoside protopanaxatriol attenuates blood pressure elevation in spontaneously hypertensive rats by affecting the Akt-dependent phosphorylation of endothelial nitric oxide synthase. J Agric Food Chem. 2012; 60:3086-91. https://doi.org/10.1021/jf204447y
168. Wang Y, Dong J, Liu P, Lau CW, Gao Z, Zhou D, Tang J, Ng CF, Huang Y. Ginsenoside Rb3 attenuates oxidative stress and preserves endothelial function in renal arteries from hypertensive rats. Br J Pharmacol. 2014; 171:3171-81. https://doi.org/10.1111/bph.12660
169. Seo YS, Shon MY, Kong R, Kang OH, Zhou T, Kim DY, Kwon DY. Black ginseng extract exerts antihyperglycemic effect via modulation of glucose metabolism in liver and muscle. J Ethnopharmacol. 2016; 190:231-40. https://doi.org/10.1016/j.jep.2016.05.060
170. Lee B, Sur B, Cho SG, Yeom M, Shim I, Lee H, Hahm DH. Ginsenoside Rb1 rescues anxiety-like responses in a rat model of post-traumatic stress disorder. J Nat Med. 2016; 70:133-44. https://doi.org/10.1007/s11418-015-0943-3
171. Cha HY, Park JH, Hong JT, Yoo HS, Song S, Hwang BY, Eun JS, Oh KW. Anxiolytic-like effects of ginsenosides on the elevated plus-maze model in mice. Biol Pharm Bull. 2005; 28:1621-25. https://doi.org/10.1248/bpb.28.1621
172. Kim NH, Kim KY, Jeong HJ, Kim HM. Antidepressantlike effect of altered Korean red ginseng in mice. Behav Med. 2011; 37:42-46. https://doi.org/10.1080/08964289.2011.566591
173. Jeong KJ, Kim GW, Chung SH. AMP-activated protein kinase: an emerging target for ginseng. J Ginseng Res. 2014; 38:83-88. https://doi.org/10.1016/j.jgr.2013.11.014
174. Han JY, Lee S, Yang JH, Kim S, Sim J, Kim MG, Jeong TC, Ku SK, Cho IJ, Ki SH. Korean Red Ginseng attenuates ethanol-induced steatosis and oxidative stress via AMPK/Sirt1 activation. J Ginseng Res. 2015; 39:105-15. https://doi.org/10.1016/j.jgr.2014.09.001
175. Go HK, Rahman MM, Kim GB, Na CS, Song CH, Kim JS, Kim SJ, Kang HS. Antidiabetic Effects of Yam (Dioscorea batatas) and Its Active Constituent, Allantoin, in a Rat Model of Streptozotocin-Induced Diabetes. Nutrients. 2015; 7:8532-44. https://doi.org/10.3390/nu7105411
176. Hsu JH, Wu YC, Liu IM, Cheng JT. Dioscorea as the principal herb of Die-Huang-Wan, a widely used herbal mixture in China, for improvement of insulin resistance in fructose-rich chow-fed rats. J Ethnopharmacol. 2007; 112:577-84. https://doi.org/10.1016/j.jep.2007.05.013
177. Liu Y, Li H, Fan Y, Man S, Liu Z, Gao W, Wang T. Antioxidant and Antitumor Activities of the Extracts from Chinese Yam (Dioscorea opposite Thunb.) Flesh and Peel and the Effective Compounds. J Food Sci. 2016; 81:H1553-64. https://doi.org/10.1111/1750-3841.13322
178. Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM. Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA. 1994; 91:8324-28. https://doi.org/10.1073/pnas.91.18.8324
179. Fukuyo Y, Hunt CR, Horikoshi N. Geldanamycin and its anti-cancer activities. Cancer Lett. 2010; 290:24-35. https://doi.org/10.1016/j.canlet.2009.07.010
180. Miyata Y. Hsp90 inhibitor geldanamycin and its derivatives as novel cancer chemotherapeutic agents. Curr Pharm Des. 2005; 11:1131-38. https://doi.org/10.2174/1381612053507585
181. Jurczyszyn A, Zebzda A, Czepiel J, Perucki W, Bazan-Socha S, Cibor D, Owczarek D, Majka M. Geldanamycin and Its Derivatives Inhibit the Growth of Myeloma Cells and Reduce the Expression of the MET Receptor. J Cancer. 2014; 5:480-90. https://doi.org/10.7150/jca.8731
182. Kitson RR, Chang CH, Xiong R, Williams HE, Davis AL, Lewis W, Dehn DL, Siegel D, Roe SM, Prodromou C, Ross D, Moody CJ. Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90. Nat Chem. 2013; 5:307-14. https://doi.org/10.1038/nchem.1596
183. Khandelwal A, Crowley VM, Blagg BS. Natural Product Inspired N-Terminal Hsp90 Inhibitors: From Bench to Bedside? Med Res Rev. 2016; 36:92-118. https://doi.org/10.1002/med.21351
184. Yin Z, Henry EC, Gasiewicz TA. (-)-Epigallocatechin-3-gallate is a novel Hsp90 inhibitor. Biochemistry. 2009; 48:336-45. https://doi.org/10.1021/bi801637q
185. Zhang Z, Li HM, Zhou C, Li Q, Ma L, Zhang Z, Sun Y, Wang L, Zhang X, Zhu B, Hong YS, Wu CZ, Liu H. Nonbenzoquinone geldanamycin analogs trigger various forms of death in human breast cancer cells. J Exp Clin Cancer Res. 2016; 35:149. https://doi.org/10.1186/s13046-016-0428-6
186. Kinzel L, Ernst A, Orth M, Albrecht V, Hennel R, Brix N, Frey B, Gaipl US, Zuchtriegel G, Reichel CA, Blutke A, Schilling D, Multhoff G, et al. A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer. Oncotarget. 2016; 7:43199-219. https://doi.org/10.18632/oncotarget.9774
187. Liu Y, Fan C, Pu L, Wei C, Jin H, Teng Y, Zhao M, Yu AC, Jiang F, Shu J, Li F, Peng Q, Kong J, et al. Phloretin induces cell cycle arrest and apoptosis of human glioblastoma cells through the generation of reactive oxygen species. J Neurooncol. 2016; 128:217-23. https://doi.org/10.1007/s11060-016-2107-z
188. Chen G, Hu X, Zhang W, Xu N, Wang FQ, Jia J, Zhang WF, Sun ZJ, Zhao YF. Mammalian target of rapamycin regulates isoliquiritigenin-induced autophagic and apoptotic cell death in adenoid cystic carcinoma cells. Apoptosis. 2012; 17:90-101. https://doi.org/10.1007/s10495-011-0658-1
189. Espín JC, García-Conesa MT, Tomás-Barberán FA. Nutraceuticals: facts and fiction. Phytochemistry. 2007; 68:2986-3008. https://doi.org/10.1016/j.phytochem.2007.09.014
190. Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, Ståhlman M, Olsson LM, Serino M, Planas-Fèlix M, Xifra G, Mercader JM, Torrents D, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017; 23:850-58. https://doi.org/10.1038/nm.4345
191. Iorio F, Rittman T, Ge H, Menden M, Saez-Rodriguez J. Transcriptional data: a new gateway to drug repositioning? Drug Discov Today. 2013; 18:350-57. https://doi.org/10.1016/j.drudis.2012.07.014
192. Nair V, Hinton GE. Rectified linear units improve restricted boltzmann machines. Proceedings of the 27th international conference on machine learning (ICML-10). 2010;807-14
193. Kingma D, Ba J. Adam: A method for stochastic optimization. arXiv preprint. 2014; arXiv:14126980
194. Srivastava N, Hinton GE, Krizhevsky A, Sutskever I, Salakhutdinov R. Dropout: a simple way to prevent neural networks from overfitting. J Mach Learn Res. 2014; 15:1929-58