10-gingerol induces oxidative stress through HTR1A in cumulus cells: in-vitro and in-silico studies
-
Kiptiyah Kiptiyah
, Widodo Widodo
, Gatot Ciptadi , Aulanni’am Aulanni’Am , Mohammad A. Widodo und Sutiman B. Sumitro
Abstract
Background
We investigated whether 10-gingerol is able to induce oxidative stress in cumulus cells.
Methods
For the in-vitro research, we used a cumulus cell culture in M199, containing 10-gingerol in various concentrations (0, 12, 16, and 20 µM), and detected oxidative stress through superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentrations, with incubation periods of 24, 48, 72, and 96 h. The obtained results were confirmed by in-silico studies.
Results
The in-vitro data revealed that SOD activity and MDA concentration increased with increasing incubation periods: SOD activity at 0 µM (1.39 ± 0.24i), 12 µM (16.42 ± 0.35ab), 16 µM (17.28 ± 0.55ab), 20 µM (17.81 ± 0.12a), with a contribution of 71.1%. MDA concentration at 0 µM (17.82 ± 1.39 l), 12 µM (72.99 ± 0.31c), 16 µM (79.77 ± 4.19b), 20 µM (85.07 ± 2.57a), with a contribution of 73.1%. Based on this, the in-silico data uncovered that 10˗gingerol induces oxidative stress in cumulus cells by inhibiting HTR1A functions and inactivating GSK3B and AKT˗1.
Conclusions
10-gingerol induces oxidative stress in cumulus cells through enhancing SOD activity and MDA concentration by inhibiting HTR1A functions and inactivating GSK3B and AKT˗1.
Abbreviations
- 10-G
10-gingerol
- CID
chem identity
- ELISA
enzyme-linked immunoabsorbent assay
- eNOS
endothelial nitric oxide synthase
- FOXO
forkhead box
- GSK3B
glycogen synthase kynase-3 β
- h
hour
- HTR1A
5-hydroxytryptamine receptor 1 A
- ILK
integrin-linked kinase
- M199
medium 199
- MDA
malondialdehyde
- MDM2
murine double minute clone 2
- mTOR
mammalian target of rapamycin
- NO
nitric oxide
- NOS
nitric oxide synthase
- NOS3
nitric oxide synthase 3
- PDB
protein data bank
- PI3K/AKT
phosphatidylinositol-3-OH kinase/AKT
- PTEN
phosphatase and tensin homologue delete on chromosome ten
- PUFA
polyunsaturated fatty acids
- RICTOR
rapamycin-insensitive companion of mTOR
- ROS
reactive oxygen species
- SOD
superoxide dismutase.
Acknowledgments
We would like to thank the laboratories in the Maulana Malik Ibrahim Islamic State University of Malang, State Polytechnic of Malang, Brawijaya University of Malang, the abattoir in Malang City, and CV. Gamma Scientific Biolab of Malang, who collaborated with us and National Educational Ministry of Indonesian Republic Government which supplied fund No. 708/H10.14/AK/2010. The authors declare that no conflict of interest would prejudice the impartiality of this scientific work.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: National Educational Ministry of Indonesian Republic Government, fund No. 708/H10.14/AK/2010.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
[1] Tatemoto H, Sakurai N, Muto N. Protection of porcine oocytes against apoptotic cell death caused by oxidative stress during in vitro maturation: role of cumulus cells1. Biol Reprod 2000;63:805–10.10.1095/biolreprod63.3.805Suche in Google Scholar
[2] Wang Q, Frolova AI, Purcell S, Adastra K, Schoeller E, Chi MM, et al. Mitochondrial dysfunction and apoptosis in cumulus cells of type I diabetic mice. PLoS One 2010;5:e15901.10.1371/journal.pone.0015901Suche in Google Scholar
[3] Aardema H, Vos PL, Gadella BM. Cumulus cells protect the oocyte against saturated free fatty acids. Anim Reprod 2018;15:737–50.10.21451/1984-3143-AR2018-0063Suche in Google Scholar
[4] Combelles CM, Gupta S, Agarwal A. Could oxidative stress influence the in-vitro maturation of oocytes? Reprod Biomed Online 2009;18:864–80.10.1016/S1472-6483(10)60038-7Suche in Google Scholar
[5] Lourenço B, Sousa AP, Almeida-Santos T, Ramalho-Santos J. Relation of cumulus cell status with single oocyte maturity, fertilization capability and patient age. J Reprod Infertil 2014;15:15–21.Suche in Google Scholar
[6] Gierisch JM, Coeytaux RR, Urrutia RP, Havrilesky LJ, Moorman PG, Lowery WJ, et al. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev 2013;22:1931–43.10.1158/1055-9965.EPI-13-0298Suche in Google Scholar PubMed
[7] Rodrigues FA, Prata MM, Oliveira IC, Alves NT, Freitas RE, Monteiro HS, et al. Gingerol fraction from Zingiber officinale protects against gentamicin-induced nephrotoxicity. Antimicrob Agents Chemother 2014;58:1872–8.10.1128/AAC.02431-13Suche in Google Scholar PubMed PubMed Central
[8] Swapna Sonale R, Kadimi US. Characterization of gingerol analogues in supercritical carbon dioxide (SC CO2) extract of ginger (Zingiber officinale, R.,). J Food Sci Technol 2014;51:3383–9.10.1007/s13197-012-0851-4Suche in Google Scholar PubMed PubMed Central
[9] Akimoto M, Iizuka M, Kanematsu R, Yoshida M, Takenaga K. Anticancer effect of ginger extract against pancreatic cancer cells mainly through reactive oxygen species-mediated autotic cell death. PLoS One 2015;10:e0126605.10.1371/journal.pone.0126605Suche in Google Scholar PubMed PubMed Central
[10] Lee D-H, Kim D-W, Jung C-H, Lee YJ, Park D. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells. Toxicol Appl Pharmacol 2014;279:253–65.10.1016/j.taap.2014.06.030Suche in Google Scholar PubMed PubMed Central
[11] Fu J, Chen H, Soroka DN, Warin RF, Sang S. Cysteine-conjugated metabolites of ginger components, shogaols, induce apoptosis through oxidative stress-mediated p53 pathway in human colon cancer cells. J Agric Food Chem 2014;62:4632–42.10.1021/jf501351rSuche in Google Scholar PubMed PubMed Central
[12] Ryu MJ, Chung HS. [10]-Gingerol induces mitochondrial apoptosis through activation of MAPK pathway in HCT116 human colon cancer cells. In Vitro Cell Dev Biol Anim 2015;51:92–101.10.1007/s11626-014-9806-6Suche in Google Scholar PubMed
[13] Han X, Zhang Y, Liang Y, Zhang J, Li M, Zhao Z, et al. 6-Gingerol, an active pungent component of ginger, inhibits L-type Ca2+ current, contractility, and Ca2+ transients in isolated rat ventricular myocytes. Food Sci Nutr 2019;7:1344–52.10.1002/fsn3.968Suche in Google Scholar PubMed PubMed Central
[14] Bernard MM, McConnery JR, Hoskin DW. [10]-Gingerol, a major phenolic constituent of ginger root, induces cell cycle arrest and apoptosis in triple-negative breast cancer cells. Exp Mol Pathol 2017;102:370–6.10.1016/j.yexmp.2017.03.006Suche in Google Scholar PubMed
[15] Nievergelt A, Huonker P, Schoop R, Altmann K-H, Gertsch J. Identification of serotonin 5-HT1A receptor partial agonists in ginger. Bioorg Med Chem 2010;18:3345–51.10.1016/j.bmc.2010.02.062Suche in Google Scholar PubMed
[16] Cowen DS, Johnson-Farley NN, Travkina T. 5-HT1A receptors couple to activation of Akt, but not extracellular-regulated kinase (ERK), in cultured hippocampal neurons. J Neurochem 2005;93:910–17.10.1111/j.1471-4159.2005.03107.xSuche in Google Scholar PubMed PubMed Central
[17] Hsiung S, Adlersberg M, Arango V, Mann JJ, Tamir H, Liu K. Attenuated 5-HT1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen-activated protein kinase. J Neurochem 2003;87:182–94.10.1046/j.1471-4159.2003.01987.xSuche in Google Scholar PubMed
[18] Henriksen R, Dizeyi N, Abrahamsson P-A. Expression of serotonin receptors 5-HT1A, 5-HT1B, 5-HT2B and 5-HT4 in ovary and in ovarian tumours. Anticancer Res 2012;32:1361–6.Suche in Google Scholar
[19] Kiptiyah K, Widodo W, Ciptadi G, Aulanni’am A, Widodo MA, Sumitro SB. 10-Gingerol as an inducer of apoptosis through HTR1A in cumulus cells: In-vitro and in-silico studies. J Taibah Univ Med Sci 2017;12:397–406.10.1016/j.jtumed.2017.05.012Suche in Google Scholar PubMed PubMed Central
[20] Runyon ST, Zhang Y, Appleton BA, Sazinsky SL, Wu P, Pan B, et al. Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3. Protein Sci 2007;16:2454–71.10.1110/ps.073049407Suche in Google Scholar PubMed PubMed Central
[21] Cao Q, Lu X, Feng Y-J. Glycogen synthase kinase-3beta positively regulates the proliferation of human ovarian cancer cells. Cell Res 2006;16:671–7.10.1038/sj.cr.7310078Suche in Google Scholar PubMed
[22] Joo J-H, Hong -S-S, Cho Y-R, Seo D-W. 10-Gingerol inhibits proliferation and invasion of MDA-MB-231 breast cancer cells through suppression of Akt and p38MAPK activity. Oncol Rep 2016;35:779–84.10.3892/or.2015.4405Suche in Google Scholar PubMed
[23] Li J, Su W, Zhang S, Hu Y, Liu J, Zhang X, et al. Epidermal growth factor receptor and AKT1 gene copy numbers by multi-gene fluorescence in situ hybridization impact on prognosis in breast cancer. Cancer Sci 2015;106:642–9.10.1111/cas.12637Suche in Google Scholar PubMed PubMed Central
[24] Beurel E, Jope RS. The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog Neurobiol 2006;79:173–89.10.1016/j.pneurobio.2006.07.006Suche in Google Scholar PubMed PubMed Central
[25] Uranga RM, Katz S, Salvador GA. Enhanced phosphatidylinositol 3-kinase (PI3K)/Akt signaling has pleiotropic targets in hippocampal neurons exposed to iron-induced oxidative stress. J Biol Chem 2013;288:19773–84.10.1074/jbc.M113.457622Suche in Google Scholar PubMed PubMed Central
[26] Klotz L-O, Sánchez-Ramos C, Prieto-Arroyo I, Urbánek P, Steinbrenner H, Monsalve M. Redox regulation of FoxO transcription factors. Redox Biol 2015;6:51–72.10.1016/j.redox.2015.06.019Suche in Google Scholar PubMed PubMed Central
[27] Raju I, Kannan K, Abraham EC. FoxO3a serves as a biomarker of oxidative stress in human lens epithelial cells under conditions of hyperglycemia. PLoS One 2013;8:e67126.10.1371/journal.pone.0067126Suche in Google Scholar PubMed PubMed Central
[28] Akasaki Y, Alvarez-Garcia O, Saito M, Caramés B, Iwamoto Y, Lotz MK. FOXO transcription factors support oxidative stress resistance in human chondrocytes. Arthritis Rheumatol 2014;66:3349–58.10.1002/art.38868Suche in Google Scholar PubMed PubMed Central
[29] Kandula V, Kosuru R, Li H, Yan D, Zhu Q, Lian Q, et al. Forkhead box transcription factor 1: role in the pathogenesis of diabetic cardiomyopathy. Cardiovasc Diabetol 2016;15:44.10.1186/s12933-016-0361-1Suche in Google Scholar PubMed PubMed Central
[30] Marinkovic D, Zhang X, Yalcin S, Luciano JP, Brugnara C, Huber T, et al. Foxo3 is required for the regulation of oxidative stress in erythropoiesis. J Clin Invest 2007;117:2133–44.10.1172/JCI31807Suche in Google Scholar PubMed PubMed Central
[31] Chang C-J, Mulholland DJ, Valamehr B, Mosessian S, Sellers WR, Wu H. PTEN nuclear localization is regulated by oxidative stress and mediates p53-dependent tumor suppression. Mol Cell Biol 2008;28:3281–9.10.1128/MCB.00310-08Suche in Google Scholar PubMed PubMed Central
[32] Kitagishi Y, Matsuda S. Redox regulation of tumor suppressor PTEN in cancer and aging (Review). Int J Mol Med 2013;31:511–15.10.3892/ijmm.2013.1235Suche in Google Scholar PubMed
[33] Nakanishi A, Wada Y, Kitagishi Y, Matsuda S. Link between PI3K/AKT/PTEN pathway and NOX proteinin diseases. Aging Dis 2014;5:203–11.10.14336/ad.2014.0500203Suche in Google Scholar PubMed PubMed Central
[34] Ferreira FR, Oliveira AM, Dinarte AR, Pinheiro DG, Greene LJ, Silva WA, et al. Changes in hippocampal gene expression by 7-nitroindazole in rats submitted to forced swimming stress. Genes Brain Behav 2012;11:303–13.10.1111/j.1601-183X.2011.00757.xSuche in Google Scholar PubMed
[35] Saito A, Hayashi T, Okuno S, Nishi T, Chan PH. Oxidative stress affects the integrin-linked kinase signaling pathway after transient focal cerebral ischemia. Stroke 2004;35:2560–5.10.1161/01.STR.0000144653.32853.edSuche in Google Scholar PubMed
[36] Hock AK, Vigneron AM, Carter S, Ludwig RL, Vousden KH. Regulation of p53 stability and function by the deubiquitinating enzyme USP42. Embo J 2011;30:4921–30.10.1038/emboj.2011.419Suche in Google Scholar PubMed PubMed Central
[37] Jung H, Kim MJ, Kim DO, Kim WS, Yoon S-J, Park Y-J, et al. TXNIP maintains the hematopoietic cell pool by switching the function of p53 under oxidative stress. Cell Metab 2013;18:75–85.10.1016/j.cmet.2013.06.002Suche in Google Scholar PubMed
[38] Chen L, Xu B, Liu L, Luo Y, Yin J, Zhou H, et al. Hydrogen peroxide inhibits mTOR signaling by activation of AMPKalpha leading to apoptosis of neuronal cells. Lab Invest 2010;90:762–73.10.1038/labinvest.2010.36Suche in Google Scholar PubMed PubMed Central
[39] Kennedy BK, Lamming DW. The mechanistic target of rapamycin: The grand conducTOR of metabolism and aging. Cell Metab 2016;23:990–1003.10.1016/j.cmet.2016.05.009Suche in Google Scholar PubMed PubMed Central
[40] Lai P, Song Q, Yang C, Li Z, Liu S, Liu B, et al. Loss of Rictor with aging in osteoblasts promotes age-related bone loss. Cell Death Dis 2016;7:e2408–e2408.10.1038/cddis.2016.249Suche in Google Scholar PubMed PubMed Central
[41] Hou Y-Q, Yao Y, Bao Y-L, Song Z-B, Yang C, Gao X-L, et al. Juglanthraquinone C induces intracellular ROS increase and apoptosis by activating the Akt/Foxo signal pathway in HCC cells. Oxid Med Cell Longev [Internet] 2016 [cited 2019 Oct 16];2016. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670685/.10.1155/2016/4941623Suche in Google Scholar PubMed PubMed Central
[42] Shah D, Mahajan N, Sah S, Nath SK, Paudyal B. Oxidative stress and its biomarkers in systemic lupus erythematosus. J Biomed Sci 2014;21:23.10.1186/1423-0127-21-23Suche in Google Scholar PubMed PubMed Central
[43] Ansari K. The effect of ginger (Zingiber officinale) on oxidative stress status in the small intestine of diabetic rats. In 2008.Suche in Google Scholar
[44] Filograna R, Godena VK, Sanchez-Martinez A, Ferrari E, Casella L, Beltramini M, et al. Superoxide dismutase (SOD)-mimetic M40403 is protective in cell and fly models of paraquat toxicity. J Biol Chem 2016;291:9257–67.10.1074/jbc.M115.708057Suche in Google Scholar PubMed PubMed Central
[45] Alem MM. Biological markers of oxidative stress and allopurinol therapy: a meta-analysis of randomized controlled trials. J Pharmacol Ther Res [Internet] 2018 [cited 2019 Oct 16];2. Available from: https://www.alliedacademies.org/abstract/biological-markers-of-oxidative-stress-and-allopurinol-therapy-a-metaanalysis-of-randomized-controlled-trials-9497.html.Suche in Google Scholar
[46] Noh S-J, Lee SH, Shin KY, Lee CK, Cho IH, Kim H-S, et al. SP-8203 reduces oxidative stress via SOD activity and behavioral deficit in cerebral ischemia. Pharmacol Biochem Behav 2011;98:150–4.10.1016/j.pbb.2010.12.014Suche in Google Scholar PubMed
[47] Deng R, Hua X, Li J, Chi W, Zhang Z, Lu F, et al. Oxidative stress markers induced by hyperosmolarity in primary human corneal epithelial cells. PLoS One 2015;10:e0126561.10.1371/journal.pone.0126561Suche in Google Scholar PubMed PubMed Central
[48] Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014;2014:360438.10.1155/2014/360438Suche in Google Scholar PubMed PubMed Central
[49] Gorshinova VK, Tsvirkun DV, Sukhanova IA, Tarasova NV, Volodina MA, Marey MV, et al. Cumulus cell mitochondrial activity in relation to body mass index in women undergoing assisted reproductive therapy. BBA Clin 2017;5:141–6.10.1016/j.bbacli.2017.03.005Suche in Google Scholar PubMed PubMed Central
[50] Khazaei M, Aghaz F. Reactive oxygen species generation and use of antioxidants during In vitro maturation of oocytes. Int J Fertil Steril 2017;11:63–70.Suche in Google Scholar
[51] Song Z-Q, Li X, Wang Y-K, Du Z-Q, Yang C-X. DMBA acts on cumulus cells to desynchronize nuclear and cytoplasmic maturation of pig oocytes. Sci Rep [Internet] 2017 [cited 2019 Oct 16];7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431913/.10.1038/s41598-017-01870-6Suche in Google Scholar PubMed PubMed Central
[52] Rastogi N, Duggal S, Singh SK, Porwal K, Srivastava VK, Maurya R, et al. Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-gingerol in cervical cancer cells. Oncotarget 2015;6:43310–25.10.18632/oncotarget.6383Suche in Google Scholar PubMed PubMed Central
[53] Luna-Dulcey L, Tomasin R, Naves MA, da Silva JA, Cominetti MR. Autophagy-dependent apoptosis is triggered by a semi-synthetic [6]-gingerol analogue in triple negative breast cancer cells. Oncotarget 2018;9:30787–804.10.18632/oncotarget.25704Suche in Google Scholar PubMed PubMed Central
[54] Impheng H, Richert L, Pekthong D, Scholfield CN, Pongcharoen S, Pungpetchara I, et al. [6]-Gingerol inhibits de novo fatty acid synthesis and carnitine palmitoyltransferase-1 activity which triggers apoptosis in HepG2. Am J Cancer Res 2015;5:1319–36.Suche in Google Scholar
[55] Lechner JF, Stoner GD. Gingers and their purified components as cancer chemopreventative agents. Molecules [Internet] 2019 [cited 2019 Oct 17];24. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719158/.10.3390/molecules24162859Suche in Google Scholar PubMed PubMed Central
[56] Nazim UM, Jeong J-K, Seol J-W, Hur J, Eo S-K, Lee J-H, et al. Inhibition of the autophagy flux by gingerol enhances TRAIL-induced tumor cell death. Oncol Rep 2015;33:2331–6.10.3892/or.2015.3869Suche in Google Scholar PubMed
[57] Mao -Q-Q, Xu X-Y, Cao S-Y, Gan R-Y, Corke H, Beta T, et al. Bioactive compounds and bioactivities of ginger (Zingiber officinale Roscoe). Foods [Internet] 2019 [cited 2019 Oct 17];8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616534/.10.3390/foods8060185Suche in Google Scholar PubMed PubMed Central
[58] Wallace DR Natural Products as a Source of Anti-Cancer Lead Compounds: Ginger and Breast Cancer. In 2016.10.19080/JPCR.2016.01.555564Suche in Google Scholar
[59] M K, Mr S, Pa N, T B. 6-Gingerol is the most potent anticancerous compound in ginger (Zingiber officinale Rosc.). J Dev Drugs [Internet] 2017 [cited 2019 Oct 17];06. Available from: https://www.omicsgroup.org/journals/6gingerol-is-the-most-potent-anticancerous-compound-in-ginger-zingiber-officinale-rosc-2329-6631-1000167.php?aid=85169.10.4172/2329-6631.1000167Suche in Google Scholar
[60] Lin C-B, Lin -C-C, Tsay GJ. 6-Gingerol inhibits growth of colon cancer cell LoVo via induction of G2/M arrest. Evid Based Complement Alternat Med 2012;2012:326096.10.1155/2012/326096Suche in Google Scholar PubMed PubMed Central
[61] Mughal MH 6-Gingerol and Shogaol; A Comprehensive Strategy Against Various Maladies.:5.Suche in Google Scholar
[62] Radhakrishnan EK, Bava SV, Narayanan SS, Nath LR, Thulasidasan AK, Soniya EV, et al. [6]-Gingerol induces caspase-dependent apoptosis and prevents PMA-induced proliferation in colon cancer cells by inhibiting MAPK/AP-1 signaling. PLoS One 2014;9:e104401.10.1371/journal.pone.0104401Suche in Google Scholar PubMed PubMed Central
[63] Zhu Y, Wang F, Zhao Y, Wang P, Sang S. Gastroprotective [6]-Gingerol aspirinate as a novel chemopreventive prodrug of aspirin for colon cancer. Sci Rep 2017;7:40119.10.1038/srep40119Suche in Google Scholar PubMed PubMed Central
[64] Prasad S, Tyagi AK. Ginger and its constituents: role in prevention and treatment of gastrointestinal cancer [Internet]. Gastroenterol Res Pract 2015 [cited 2019 Oct 17]. Available from: https://www.hindawi.com/journals/grp/2015/142979/,10.1155/2015/142979Suche in Google Scholar PubMed PubMed Central
[65] Manatunga DC, de Silva RM, KM DS, Wijeratne DT, Malavige GN, Williams G. Fabrication of 6-gingerol, doxorubicin and alginate hydroxyapatite into a bio-compatible formulation: enhanced anti-proliferative effect on breast and liver cancer cells. Chem Cent J 2018;12:119.10.1186/s13065-018-0482-6Suche in Google Scholar PubMed PubMed Central
[66] Zhang H, Wang Q, Sun C, Zhu Y, Yang Q, Wei Q, et al. Enhanced oral bioavailability, anti-tumor activity and hepatoprotective effect of 6-Shogaol loaded in a type of novel micelles of polyethylene glycol and linoleic acid conjugate. Pharmaceutics [Internet] 2019 [cited 2019 Oct 17];11. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470752/.10.3390/pharmaceutics11030107Suche in Google Scholar PubMed PubMed Central
[67] Li Z, Wang Y, Gao M, Cui W, Zeng M, Cheng Y, et al. Nine new gingerols from the Rhizoma of Zingiber officinale and their cytotoxic activities. Molecules 2018;23.10.3390/molecules23020315Suche in Google Scholar PubMed PubMed Central
[68] Martin AC, Fuzer AM, Becceneri AB, da Silva JA, Tomasin R, Denoyer D, et al. [10]-gingerol induces apoptosis and inhibits metastatic dissemination of triple negative breast cancer in vivo. Oncotarget 2017;8:72260–71.10.18632/oncotarget.20139Suche in Google Scholar PubMed PubMed Central
[69] Yusof KM, Makpol S, Jamal R, Harun R, Mokhtar N, Ngah WZ. γ-Tocotrienol and 6-Gingerol in combination synergistically induce cytotoxicity and apoptosis in HT-29 and SW837 human colorectal cancer cells. Molecules 2015;20:10280–97.10.3390/molecules200610280Suche in Google Scholar PubMed PubMed Central
[70] Yagihashi S, Miura Y, Yagasaki K. Inhibitory effect of gingerol on the proliferation and invasion of hepatoma cells in culture. Cytotechnology 2008;57:129–36.10.1007/s10616-008-9121-8Suche in Google Scholar PubMed PubMed Central
[71] Vergara M, Torres M, Müller A, Avello V, Acevedo C, Berrios J, et al. High glucose and low specific cell growth but not mild hypothermia improve specific r-protein productivity in chemostat culture of CHO cells. PLoS One 2018;13:e0202098.10.1371/journal.pone.0202098Suche in Google Scholar PubMed PubMed Central
[72] Hou Y-Q, Yao Y, Bao Y-L, Song Z-B, Yang C, Gao X-L, et al. Juglanthraquinone C induces intracellular ROS increase and apoptosis by activating the Akt/Foxo signal pathway in HCC cells. Oxid Med Cell Longev [Internet] 2016 [cited 2019 Oct 17]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670685/.10.1155/2016/4941623Suche in Google Scholar PubMed PubMed Central
[73] Deorosan B, Nauman EA. The role of glucose, serum, and three-dimensional cell culture on the metabolism of bone marrow-derived mesenchymal stem cells. Stem Cells Int 2011;2011:429187.10.4061/2011/429187Suche in Google Scholar PubMed PubMed Central
[74] Shen M, Lin F, Zhang J, Tang Y, Chen W-K, Liu H. Involvement of the up-regulated FoxO1 expression in follicular granulosa cell apoptosis induced by oxidative stress. J Biol Chem 2012;287:25727–40.10.1074/jbc.M112.349902Suche in Google Scholar PubMed PubMed Central
[75] Gandhi S, Abramov AY. Mechanism of oxidative stress in neurodegeneration. Oxid Med Cell Longev 2012;2012:428010.10.1155/2012/428010Suche in Google Scholar PubMed PubMed Central
[76] Jeong S-G, Oh YS, Joe I-S, Jeong SY, Cho HM, Lee JS, et al. Functional restoration of replicative senescent mesenchymal stem cells by the brown alga Undaria pinnatifida. Anim Cells Syst (Seoul) 2017;21:108–14.10.1080/19768354.2017.1292951Suche in Google Scholar PubMed PubMed Central
[77] Krzyściak W, Kózka M. Generation of reactive oxygen species by a sufficient, insufficient and varicose vein wall. Acta Biochim Pol 2011;58:89–94.10.18388/abp.2011_2290Suche in Google Scholar
[78] Ho E, Karimi Galougahi K, Liu -C-C, Bhindi R, Figtree GA. Biological markers of oxidative stress: applications to cardiovascular research and practice. Redox Biol 2013;1:483–91.10.1016/j.redox.2013.07.006Suche in Google Scholar PubMed PubMed Central
[79] Siddique YH, Ara G, Afzal M. Estimation of lipid peroxidation induced by hydrogen peroxide in cultured human lymphocytes. Dose Response 2012;10:1–10.10.2203/dose-response.10-002.SiddiqueSuche in Google Scholar PubMed PubMed Central
[80] Powers SK, Ji LL, Kavazis AN, Jackson MJ. Reactive oxygen species: impact on skeletal muscle. Compr Physiol 2011;1:941–69.10.1002/cphy.c100054Suche in Google Scholar PubMed PubMed Central
[81] Naudi A, Jove M, Ayala V, Cassanye A, Serrano J, Gonzalo H, et al. Cellular dysfunction in diabetes as maladaptive response to mitochondrial oxidative stress. Exp Diabetes Res 2012;2012:696215.10.1155/2012/696215Suche in Google Scholar PubMed PubMed Central
[82] Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol 2003;552:335–44.10.1113/jphysiol.2003.049478Suche in Google Scholar PubMed PubMed Central
[83] Moreno M-L, Mérida S, Bosch-Morell F, Miranda M, Villar VM. Autophagy dysfunction and oxidative stress, two related mechanisms implicated in retinitis pigmentosa. Front Physiol [Internet] 2018 [cited 2019 Oct 17];9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070619/.10.3389/fphys.2018.01008Suche in Google Scholar PubMed PubMed Central
[84] Wei S, Sun P, Guo Y, Chen J, Wang J, Song C, et al. Gene expression in the hippocampus in a rat model of premenstrual dysphoric disorder after treatment with baixiangdan capsules. Front Psychol [Internet] 2018 [cited 2019 Oct 17];9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242977/.10.3389/fpsyg.2018.02065Suche in Google Scholar PubMed PubMed Central
[85] Albert PR, François BL, Millar AM. Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness. Mol Brain 2011;4:21.10.1186/1756-6606-4-21Suche in Google Scholar PubMed PubMed Central
[86] Cai G, Wang J, Xin X, Ke Z, Luo J. Phosphorylation of glycogen synthase kinase-3 beta at serine 9 confers cisplatin resistance in ovarian cancer cells. Int J Oncol 2007;31:657–62.10.3892/ijo.31.3.657Suche in Google Scholar
[87] Martins R, Lithgow GJ, Link W. Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell 2016;15:196–207.10.1111/acel.12427Suche in Google Scholar PubMed PubMed Central
[88] Santo EE, Stroeken P, Sluis PV, Koster J, Versteeg R, Westerhout EM. FOXO3a is a major target of inactivation by PI3K/AKT signaling in aggressive neuroblastoma. Cancer Res 2013;73:2189–98.10.1158/0008-5472.CAN-12-3767Suche in Google Scholar PubMed
[89] Zhao Y, Wang Y, Zhu W-G. Applications of post-translational modifications of FoxO family proteins in biological functions. J Mol Cell Biol 2011;3:276–82.10.1093/jmcb/mjr013Suche in Google Scholar PubMed
[90] Das TP, Suman S, Alatassi H, Ankem MK, Damodaran C. Inhibition of AKT promotes FOXO3a-dependent apoptosis in prostate cancer. Cell Death Dis 2016;7:e2111.10.1038/cddis.2015.403Suche in Google Scholar PubMed PubMed Central
[91] Ambrogini E, Almeida M, Martin-Millan M, Paik J-H, Depinho RA, Han L, et al. FoxO-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice. Cell Metab 2010;11:136–46.10.1016/j.cmet.2009.12.009Suche in Google Scholar PubMed PubMed Central
[92] Makker A, Goel MM, Mahdi AA. PI3K/PTEN/Akt and TSC/mTOR signaling pathways, ovarian dysfunction, and infertility: an update. J Mol Endocrinol 2014;53:R103–118.10.1530/JME-14-0220Suche in Google Scholar PubMed
[93] Li C-J, Elsasser TH, Kahl S. AKT/eNOS signaling module functions as a potential feedback loop in the growth hormone signaling pathway. J Mol Signal 2009;4:1.10.1186/1750-2187-4-1Suche in Google Scholar PubMed PubMed Central
[94] Verim L, Toptas B, Ozkan NE, Cacina C, Turan S, Korkmaz G, et al. Possible relation between the NOS3 gene GLU298ASP polymorphism and bladder cancer in Turkey. Asian Pac J Cancer Prev 2013;14:665–8.10.7314/APJCP.2013.14.2.665Suche in Google Scholar
[95] Tiemann K, Schnekenburger J, Schick V, Demus U, Müller-Werdan U, Atiakshin D, et al. Oxidative stress and NO generation in cerulein-induced rat pancreatitis. BJSTR 2018;4:001–6.10.18499/2225-7357-2019-8-1-68-76Suche in Google Scholar
[96] Li Q, Li C, Zhang -Y-Y, Chen W, Lv J-L, Sun J, et al. Silencing of integrin-linked kinase suppresses in vivo tumorigenesis of human ovarian carcinoma cells. Mol Med Rep 2013;7:1050–4.10.3892/mmr.2013.1285Suche in Google Scholar PubMed
[97] McDonald PC, Fielding AB, Dedhar S. Integrin-linked kinase–essential roles in physiology and cancer biology. J Cell Sci 2008;121:3121–32.10.1242/jcs.017996Suche in Google Scholar PubMed
[98] Watzka SB, Setinek U, Huber M, Cantonati H, Lax F, Watson S, et al. Reactivity of integrin-linked kinase in human mesothelial cell proliferation. Interact Cardiovasc Thorac Surg 2008;7:107–10.10.1510/icvts.2007.160473Suche in Google Scholar PubMed
[99] Daniele S, Costa B, Zappelli E, Da Pozzo E, Sestito S, Nesi G, et al. Combined inhibition of AKT/mTOR and MDM2 enhances Glioblastoma Multiforme cell apoptosis and differentiation of cancer stem cells. Sci Rep 2015;5:9956.10.1038/srep09956Suche in Google Scholar PubMed PubMed Central
[100] Malonia SK, Dutta P, Santra MK, Green MR. F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress. Proc Natl Acad Sci USA 2015;112:8632–7.10.1073/pnas.1510929112Suche in Google Scholar PubMed PubMed Central
[101] Zhang C, Liu J, Wang X, Feng Z. The regulation of the p53/MDM2 feedback loop by microRNAs. RNA Dis 2015;2:e502.Suche in Google Scholar
[102] Tsai J-P, Lee C-H, Ying T-H, Lin C-L, Lin C-L, Hsueh J-T, et al. Licochalcone A induces autophagy through PI3K/Akt/mTOR inactivation and autophagy suppression enhances Licochalcone A-induced apoptosis of human cervical cancer cells. Oncotarget 2015;6:28851–66.10.18632/oncotarget.4767Suche in Google Scholar PubMed PubMed Central
[103] Julien L-A, Carriere A, Moreau J, Roux PP. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol 2010;30:908–21.10.1128/MCB.00601-09Suche in Google Scholar PubMed PubMed Central
[104] Mori S, Nada S, Kimura H, Tajima S, Takahashi Y, Kitamura A, et al. The mTOR pathway controls cell proliferation by regulating the FoxO3a transcription factor via SGK1 kinase. PLoS One 2014;9:e88891.10.1371/journal.pone.0088891Suche in Google Scholar PubMed PubMed Central
[105] Im-aram A, Farrand L, Bae S-M, Song G, Song YS, Han JY, et al. The mTORC2 component rictor contributes to cisplatin resistance in human ovarian cancer cells. PLoS One 2013;8:e75455.10.1371/journal.pone.0075455Suche in Google Scholar PubMed PubMed Central
[106] Hambright HG, Meng P, Kumar AP, Ghosh R. Inhibition of PI3K/AKT/mTOR axis disrupts oxidative stress-mediated survival of melanoma cells. Oncotarget 2015;6:7195–208.10.18632/oncotarget.3131Suche in Google Scholar PubMed PubMed Central
[107] Cai W, Andres DA. mTORC2 is required for rit-mediated oxidative stress resistance. PLoS One 2014;9:e115602.10.1371/journal.pone.0115602Suche in Google Scholar PubMed PubMed Central
[108] Heberle AM, Prentzell MT, van Eunen K, Bakker BM, Grellscheid SN, Thedieck K. Molecular mechanisms of mTOR regulation by stress. Mol Cell Oncol [Internet] 2014 [cited 2019 Oct 17];2. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904989/.10.4161/23723548.2014.970489Suche in Google Scholar PubMed PubMed Central
[109] Breuleux M, Klopfenstein M, Stephan C, Doughty CA, Barys L, Maira S-M, et al. Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther 2009;8:742–53.10.1158/1535-7163.MCT-08-0668Suche in Google Scholar PubMed PubMed Central
[110] Smrz D, Cruse G, Beaven MA, Kirshenbaum A, Metcalfe DD, Gilfillan AM. Rictor negatively regulates FcεRI-induced mast cell degranulation. J Immunol 2014;193:5924–32.10.4049/jimmunol.1303495Suche in Google Scholar PubMed PubMed Central
[111] Jebali A, Dumaz N. The role of RICTOR downstream of receptor tyrosine kinase in cancers. Mol Cancer 2018;17:39.10.1186/s12943-018-0794-0Suche in Google Scholar PubMed PubMed Central
© 2020 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Reviews
- Music in the workplace: A narrative literature review of intervention studies
- Vitamin C supplementation and C-reactive protein levels: Findings from a systematic review and meta-analysis of clinical trials
- An overview on red algae bioactive compounds and their pharmaceutical applications
- RA-Experimental
- Phenolic composition and antioxidant capacity of hawthorn (Crataegus oxyacantha L.) flowers and fruits grown in Algeria
- Identification of bioactive constituents in Coldenia procumbens L. and its antidiabetic activity against streptozotocin induced Wistar albino rats
- 10-gingerol induces oxidative stress through HTR1A in cumulus cells: in-vitro and in-silico studies
- Evaluation of subacute toxicity and herb–drug interaction potential of an herbal Arishta formulation
- Modulatory effect of Polyalthia longifolia leaves against cadmium-induced oxidative stress and hepatotoxicity in rats
- Can measurements be physically conditioned by thought? Further observations following a focused intention experiment
- The cytotoxic activity of Salvia officinalis L. and Rosmarinus officinalis L. Leaves extracts on human glioblastoma cell line and their antioxidant effect
- Curculigo pilosa mitigates against oxidative stress and structural derangements in pancreas and kidney of streptozotocin-induced diabetic rats
- Interspecific variability of 1,8-cineole content, phenolics and bioactivity among nine Eucalyptus taxa growing under the sub-humid bioclimate stage
- RA-Clinical
- Ethnobotanical survey of three members of family Lamiaceae among the inhabitants of Bejaia, Northern Algeria
- Effectiveness of video game on bio- physiological parameters during intravenous cannulation among preschool children
- Could Anise decrease the intensity of premenstrual syndrome symptoms in comparison to placebo? A double-blind randomized clinical trial
- Epigenetic study of global gene methylation in PON1, XRCC1 and GSTs different genotypes in rural and urban pesticide exposed workers
- Effect of yoga practices on general mental ability in urban residential school children
- Perceptions and utilization of traditional healing among Marshallese adults residing in Arkansas
- Effectiveness of neurobic exercise program on memory and depression among elderly residing at old age home
- Does soft tissue mobilization assist static stretching to improve hamstring flexibility? A randomized controlled trial
- Letter to the Editor
- Hot arm and foot bath on heart rate variability and blood pressure in healthy volunteers – needs to be verified with standard device?
Artikel in diesem Heft
- Reviews
- Music in the workplace: A narrative literature review of intervention studies
- Vitamin C supplementation and C-reactive protein levels: Findings from a systematic review and meta-analysis of clinical trials
- An overview on red algae bioactive compounds and their pharmaceutical applications
- RA-Experimental
- Phenolic composition and antioxidant capacity of hawthorn (Crataegus oxyacantha L.) flowers and fruits grown in Algeria
- Identification of bioactive constituents in Coldenia procumbens L. and its antidiabetic activity against streptozotocin induced Wistar albino rats
- 10-gingerol induces oxidative stress through HTR1A in cumulus cells: in-vitro and in-silico studies
- Evaluation of subacute toxicity and herb–drug interaction potential of an herbal Arishta formulation
- Modulatory effect of Polyalthia longifolia leaves against cadmium-induced oxidative stress and hepatotoxicity in rats
- Can measurements be physically conditioned by thought? Further observations following a focused intention experiment
- The cytotoxic activity of Salvia officinalis L. and Rosmarinus officinalis L. Leaves extracts on human glioblastoma cell line and their antioxidant effect
- Curculigo pilosa mitigates against oxidative stress and structural derangements in pancreas and kidney of streptozotocin-induced diabetic rats
- Interspecific variability of 1,8-cineole content, phenolics and bioactivity among nine Eucalyptus taxa growing under the sub-humid bioclimate stage
- RA-Clinical
- Ethnobotanical survey of three members of family Lamiaceae among the inhabitants of Bejaia, Northern Algeria
- Effectiveness of video game on bio- physiological parameters during intravenous cannulation among preschool children
- Could Anise decrease the intensity of premenstrual syndrome symptoms in comparison to placebo? A double-blind randomized clinical trial
- Epigenetic study of global gene methylation in PON1, XRCC1 and GSTs different genotypes in rural and urban pesticide exposed workers
- Effect of yoga practices on general mental ability in urban residential school children
- Perceptions and utilization of traditional healing among Marshallese adults residing in Arkansas
- Effectiveness of neurobic exercise program on memory and depression among elderly residing at old age home
- Does soft tissue mobilization assist static stretching to improve hamstring flexibility? A randomized controlled trial
- Letter to the Editor
- Hot arm and foot bath on heart rate variability and blood pressure in healthy volunteers – needs to be verified with standard device?