| BMC Complementary and Alternative Medicine | |
| 3,4-Dihydroxytoluene, a metabolite of rutin, inhibits inflammatory responses in lipopolysaccharide-activated macrophages by reducing the activation of NF-κB signaling | |
| Yi-Lin Sophia Chen1  Kuo-Feng Hua1  Ya-Ping Chen1  Chao Yuan Yu1  Kang-Yi Su2  | |
| [1] Department of Biotechnology and Animal Science, National Ilan University, Shen-Lung Road, Ilan 260, Taiwan;Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan | |
| 关键词: Inducible nitric oxide synthase; Cyclooxygenase-2 (COX-2); Anti-inflammation; Flavonoid; Saussurea involucrata; | |
| Others : 1220340 DOI : 10.1186/1472-6882-14-21 |
|
| received in 2013-06-22, accepted in 2014-01-10, 发布年份 2014 | |
PDF
|
|
【 摘 要 】
Background
Saussurea involucrata (Kar. et Kir.) (S. involucrate), is a rare traditional Chinese medicinal herb. Rutin and hispidulin as well as their metabolites are flavonoids of the flavonol type that abound in S. involucrata, which has been reported to inhibit nonoxidative advanced glycation end products which was involved in physiological inflammation. This study aims to investigate the role of 3,4-dihydroxytoluene (DHT), a metabolite of rutin, in inflammatory inhibition and its involved mechanism.
Methods
This study utilized lipopolysaccharide (LPS) stimulated murine macrophage cell line RAW 264.7 as inflammatory model. The inhibitory effects of DHT were evaluated by the expression level of several inflammation markers such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 after LPS treatment. In addition, underlying mechanisms, the activation of mitogen-activated protein kinases (MAPKs) and NF-κB, were also investigated.
Results
Our results showed that DHT significantly suppressed the LPS-induced production of nitric oxide (NO), iNOS, and COX-2 in a dose-dependent manner without cytotoxicity. DHT also reduced the generation of proinflammatory cytokines majorly in tumor necrosis factor (TNF)-α and minor in interleukin (IL)-1β and IL-6. In addition, LPS-stimulated I-κBα phosphorylation and degradation followed by translocation of the nuclear factor κB (NF-kB)-p65 from the cytoplasm to the nucleus were attenuated after DHT treatment.
Conclusions
Combined, the results suggest that DHT might exert anti-inflammatory effects in vitro in LPS stimulated RAW 264.7 macrophages and is potential in adjuvant treatment in inflammation disease.
【 授权许可】
2014 Su et al.; licensee BioMed Central Ltd.
【 预 览 】
| Files | Size | Format | View |
|---|---|---|---|
| 20150722030444992.pdf | 1855KB | ||
| Figure 6. | 68KB | Image | |
| Figure 5. | 65KB | Image | |
| Figure 4. | 33KB | Image | |
| Figure 3. | 67KB | Image | |
| Figure 2. | 69KB | Image | |
| Figure 1. | 55KB | Image |
【 图 表 】
Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
Figure 6.
【 参考文献 】
- [1]Fu LK: China plant Red data book: rare and endangered plants: vol 001. Science Pr 1992.
- [2]Way TD, Lee JC, Kuo DH, Fan LL, Huang CH, Lin HY, Shieh PC, Kuo PT, Liao CF, Liu H, et al.: Inhibition of epidermal growth factor receptor signaling by Saussurea involucrata, a rare traditional Chinese medicinal herb, in human hormone-resistant prostate cancer PC-3 cells. J Agric Food Chem 2010, 58(6):3356-3365.
- [3]Liu JH, Ho SC, Lai TH, Liu TH, Chi PY, Wu RY: Protective effects of Chinese herbs on D-galactose-induced oxidative damage. Methods Find Exp Clin Pharmacol 2003, 25(6):447-452.
- [4]Chen YL, Lin SZ, Chang JY, Cheng YL, Tsai NM, Chen SP, Chang WL, Harn HJ: In vitro and in vivo studies of a novel potential anticancer agent of isochaihulactone on human lung cancer A549 cells. Biochem Pharmacol 2006, 72(3):308-319.
- [5]La Casa C, Villegas I, Alarcon de la Lastra C, Motilva V, Martin Calero MJ: Evidence for protective and antioxidant properties of rutin, a natural flavone, against ethanol induced gastric lesions. J Ethnopharmacol 2000, 71(1–2):45-53.
- [6]Janbaz KH, Saeed SA, Gilani AH: Protective effect of rutin on paracetamol- and CCl4-induced hepatotoxicity in rodents. Fitoterapia 2002, 73(7–8):557-563.
- [7]Schwedhelm E, Maas R, Troost R, Boger RH: Clinical pharmacokinetics of antioxidants and their impact on systemic oxidative stress. Clin Pharmacokinet 2003, 42(5):437-459.
- [8]Sheu JR, Hsiao G, Chou PH, Shen MY, Chou DS: Mechanisms involved in the antiplatelet activity of rutin, a glycoside of the flavonol quercetin, in human platelets. J Agric Food Chem 2004, 52(14):4414-4418.
- [9]Mellou F, Loutrari H, Stamatis H, Roussos C, Kolisis FN: Enzymatic esterification of flavonoids with unsaturated fatty acids: effect of the novel esters on vascular endothelial growth factor release from K562 cells. Process Biochem 2006, 41(9):2029-2034.
- [10]Trumbeckaite S, Bernatoniene J, Majiene D, Jakštas V, Savickas A, Toleikis A: The effect of flavonoids on rat heart mitochondrial function. Biomed Pharmacother 2006, 60(5):245-248.
- [11]Katsube T, Imawaka N, Kawano Y, Yamazaki Y, Shiwaku K, Yamane Y: Antioxidant flavonol glycosides in mulberry (Morus alba L.) leaves isolated based on LDL antioxidant activity. Food Chem 2006, 97(1):25-31.
- [12]Nassiri-Asl M, Shariati-Rad S, Zamansoltani F: Anticonvulsive effects of intracerebroventricular administration of rutin in rats. Progr Neuro Psychopharmacol Biol Psychiatr 2008, 32(4):989-993.
- [13]Gupta R, Singh M, Sharma A: Neuroprotective effect of antioxidants on ischaemia and reperfusion-induced cerebral injury. Pharmacol Res 2003, 48(2):209-215.
- [14]Kuo SM: Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. Cancer Lett 1996, 110(1–2):41-48.
- [15]Middleton E Jr: Effect of plant flavonoids on immune and inflammatory cell function. Adv Exp Med Biol 1998, 439:175-182.
- [16]Deschner EE, Ruperto J, Wong G, Newmark HL: Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. Carcinogenesis 1991, 12(7):1193-1196.
- [17]Kwon KH, Murakami A, Ohigashi H: Suppressive effects of natural and synthetic agents on dextran sulfate sodium-induced interleukin-1beta release from murine peritoneal macrophages. Biosci Biotechnol Biochem 2004, 68(2):436-439.
- [18]Braune A, Gutschow M, Engst W, Blaut M: Degradation of quercetin and luteolin by Eubacterium ramulus. Appl Environ Microbiol 2001, 67(12):5558-5567.
- [19]Griffiths LA, Barrow A: Metabolism of flavonoid compounds in germ-free rats. Biochem J 1972, 130(4):1161-1162.
- [20]Schneider H, Simmering R, Hartmann L, Pforte H, Blaut M: Degradation of quercetin-3-glucoside in gnotobiotic rats associated with human intestinal bacteria. J Appl Microbiol 2000, 89(6):1027-1037.
- [21]Pashikanti S, de Alba DR, Boissonneault GA, Cervantes-Laurean D: Rutin metabolites: novel inhibitors of nonoxidative advanced glycation end products. Free Radic Biol Med 2010, 48(5):656-663.
- [22]Anderson MM, Hazen SL, Hsu FF, Heinecke JW: Human neutrophils employ the myeloperoxidase-hydrogen peroxide-chloride system to convert hydroxy-amino acids into glycolaldehyde, 2-hydroxypropanal, and acrolein. A mechanism for the generation of highly reactive alpha-hydroxy and alpha,beta-unsaturated aldehydes by phagocytes at sites of inflammation. J Clin Invest 1997, 99(3):424-432.
- [23]Lee W, Ku S-K, Bae J-S: Barrier protective effects of rutin in LPS-induced inflammation in vitro and in vivo. Food Chem Toxicol 2012, 50(9):3048-3055.
- [24]Olthof MR, Hollman PC, Buijsman MN, van Amelsvoort JM, Katan MB: Chlorogenic acid, quercetin-3-rutinoside and black tea phenols are extensively metabolized in humans. J Nutr 2003, 133(6):1806-1814.
- [25]Winter J, Moore LH, Dowell VR, Bokkenheuser VD: C-ring cleavage of flavonoids by human intestinal bacteria. Appl Environ Microbiol 1989, 55(5):1203-1208.
- [26]Kaisho T, Akira S: Critical roles of Toll-like receptors in host defense. Crit Rev Immunol 2000, 20(5):393-405.
- [27]Sweet MJ, Hume DA: Endotoxin signal transduction in macrophages. J Leukoc Biol 1996, 60(1):8-26.
- [28]Doyle SL, O’Neill LAJ: Toll-like receptors: from the discovery of NFκB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol 2006, 72(9):1102-1113.
- [29]Takeda K, Kaisho T, Akira S: Toll-like receptors. Annu Rev Immunol 2003, 21:335-376.
- [30]Liao P-C, Chien S-C, Ho C-L, Wang EIC, Lee S-C, Kuo Y-H, Jeyashoke N, Chen J, Dong W-C, Chao LK, et al.: Osthole regulates inflammatory mediator expression through modulating NF-κB, mitogen-activated protein kinases, protein kinase C, and reactive oxygen species. J Agric Food Chem 2010, 58(19):10445-10451.
- [31]Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD: The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 2011, 17(2):179-188.
- [32]Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z, et al.: Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 2010, 11(10):897-904.
- [33]Schroder K, Zhou R, Tschopp J: The NLRP3 inflammasome: a sensor for metabolic danger? Science 2010, 327(5963):296-300.
- [34]Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP: Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 2011, 12(5):408-415.
- [35]Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, et al.: NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010, 464(7293):1357-1361.
- [36]De Nardo D, Latz E: NLRP3 inflammasomes link inflammation and metabolic disease. Trends Immunol 2011, 32(8):373-379.
- [37]Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E: Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 2008, 9(8):847-856.
- [38]Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT: The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 2008, 9(8):857-865.
- [39]Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006, 440(7081):237-241.
- [40]Anders H-J, Muruve DA: The inflammasomes in kidney disease. J Am Soc Nephrol 2011, 22(6):1007-1018.
- [41]Tsai P-Y, Ka S-M, Chang J-M, Chen H-C, Shui H-A, Li C-Y, Hua K-F, Chang W-L, Huang J-J, Yang S-S, et al.: Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation. Free Radic Biol Med 2011, 51(3):744-754.
- [42]Spranger J, Kroke A, Möhlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AFH: Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based european prospective investigation into cancer and nutrition (EPIC)-potsdam study. Diabetes 2003, 52(3):812-817.
- [43]Yehuda H, Szuchman-Sapir A, Khatib S, Musa R, Tamir S: Human atherosclerotic plaque lipid extract promotes expression of proinflammatory factors in human monocytes and macrophage-like cells. Atherosclerosis 2011, 218(2):339-343.
- [44]Janabi M, Yamashita S, Hirano K-i, Sakai N, Hiraoka H, Matsumoto K, Zhang Z, Nozaki S, Matsuzawa Y: Oxidized LDL–induced NF-κB activation and subsequent expression of proinflammatory genes are defective in monocyte-derived macrophages from CD36-deficient patients. Arterioscler Thromb Vasc Biol 2000, 20(8):1953-1960.
- [45]Kleemann R, Zadelaar S, Kooistra T: Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 2008, 79(3):360-376.
- [46]Lee RP, Subeq YM, Lee CJ, Hsu BG, Peng TC: Freshwater clam extract decreased hemorrhagic shock-induced liver injury by attenuating TNF-alpha production. Biol Res Nurs 2012, 14(3):286-293.
- [47]Baeuerle PA: IκB–NF-κB structures: at the interface of inflammation control. Cell 1998, 95(6):729-731.
PDF