Caffeic acid phenethyl ester protects against oxidative stress and dampens inflammation via heme oxygenase 1
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摘要
Periodontal disease is associated with chronic oxidative stress and inflammation. Caffeic acid phenethyl ester(CAPE), which is a potent inducer of heme oxygenase 1(HO1), is a central active component of propolis, and the application of propolis improves periodontal status in diabetic patients. Here, primary murine macrophages were exposed to CAPE. Target gene expression was assessed by whole-genome microarray, RT-PCR and Western blotting. The antioxidative and anti-inflammatory activities of CAPE were examined by exposure of the cells to hydrogen peroxide, saliva and periodontal pathogens. The involvement of HO1 was investigated with the HO1 inhibitor tin protoporphyrin(SnPP) and knockout mice for Nrf2, which is a transcription factor for detoxifying enzymes. CAPE increased HO1 and other heat shock proteins in murine macrophages. A p38 MAPK inhibitor and Nrf2 knockout attenuated CAPE-induced HO1 expression in macrophages. CAPE exerted strong antioxidative activity. Additionally, CAPE reduced the inflammatory response to saliva and periodontal pathogens. Blocking HO1 decreased the antioxidative activity and attenuated the anti-inflammatory activity of CAPE. In conclusion, CAPE exerted its antioxidative effects through the Nrf2-mediated HO1 pathway and its anti-inflammatory effects through NF-κB inhibition. However, preclinical models evaluating the use of CAPE in periodontal inflammation are necessary in future studies.
Periodontal disease is associated with chronic oxidative stress and inflammation. Caffeic acid phenethyl ester(CAPE), which is a potent inducer of heme oxygenase 1(HO1), is a central active component of propolis, and the application of propolis improves periodontal status in diabetic patients. Here, primary murine macrophages were exposed to CAPE. Target gene expression was assessed by whole-genome microarray, RT-PCR and Western blotting. The antioxidative and anti-inflammatory activities of CAPE were examined by exposure of the cells to hydrogen peroxide, saliva and periodontal pathogens. The involvement of HO1 was investigated with the HO1 inhibitor tin protoporphyrin(SnPP) and knockout mice for Nrf2, which is a transcription factor for detoxifying enzymes. CAPE increased HO1 and other heat shock proteins in murine macrophages. A p38 MAPK inhibitor and Nrf2 knockout attenuated CAPE-induced HO1 expression in macrophages. CAPE exerted strong antioxidative activity. Additionally, CAPE reduced the inflammatory response to saliva and periodontal pathogens. Blocking HO1 decreased the antioxidative activity and attenuated the anti-inflammatory activity of CAPE. In conclusion, CAPE exerted its antioxidative effects through the Nrf2-mediated HO1 pathway and its anti-inflammatory effects through NF-κB inhibition. However, preclinical models evaluating the use of CAPE in periodontal inflammation are necessary in future studies.
Periodontal disease is associated with chronic oxidative stress and inflammation. Caffeic acid phenethyl ester(CAPE), which is a potent inducer of heme oxygenase 1(HO1), is a central active component of propolis, and the application of propolis improves periodontal status in diabetic patients. Here, primary murine macrophages were exposed to CAPE. Target gene expression was assessed by whole-genome microarray, RT-PCR and Western blotting. The antioxidative and anti-inflammatory activities of CAPE were examined by exposure of the cells to hydrogen peroxide, saliva and periodontal pathogens. The involvement of HO1 was investigated with the HO1 inhibitor tin protoporphyrin(SnPP) and knockout mice for Nrf2, which is a transcription factor for detoxifying enzymes. CAPE increased HO1 and other heat shock proteins in murine macrophages. A p38 MAPK inhibitor and Nrf2 knockout attenuated CAPE-induced HO1 expression in macrophages. CAPE exerted strong antioxidative activity. Additionally, CAPE reduced the inflammatory response to saliva and periodontal pathogens. Blocking HO1 decreased the antioxidative activity and attenuated the anti-inflammatory activity of CAPE. In conclusion, CAPE exerted its antioxidative effects through the Nrf2-mediated HO1 pathway and its anti-inflammatory effects through NF-κB inhibition. However, preclinical models evaluating the use of CAPE in periodontal inflammation are necessary in future studies.
引文
1.El-Sharkawy,H.M.,Anees,M.M.&Van Dyke,T.E.Propolis improves periodontal status and glycemic control in patients with type 2 diabetes mellitus and chronic periodontitis:a randomized clinical trial.J.Periodontol.87,1418-1426(2016).
2.Ercan,N.,Erdemir,E.O.,Ozkan,S.Y.&Hendek,M.K.The comparative effect of propolis in two different vehicles;mouthwash and chewing-gum on plaque accumulation and gingival inflammation.Eur.J.Dent.9,272-276(2015).
3.AkhavanKarbassi,M.H.,Yazdi,M.F.,Ahadian,H.&SadrAbad,M.J.Randomized double-blind placebo-controlled trial of propolis for oral mucositis in patients receiving chemotherapy for head and neck cancer.Asian Pac.J.Cancer Prev.17,3611-3614(2016).
4.Yigit,U.,Kirzioglu,F.Y.,Uguz,A.C.,Naziroglu,M.&Ozmen,O.Is caffeic acid phenethyl ester more protective than doxycycline in experimental periodontitis?Arch.Oral Biol.81,61-68(2017).
5.Tolba,M.F.,El-Serafi,A.T.&Omar,H.A.Caffeic acid phenethyl ester protects against glucocorticoid-induced osteoporosis in vivo:impact on oxidative stress and RANKL/OPG signals.Toxicol.Appl.Pharmacol.324,26-35(2017).
6.Ucan,M.C.et al.Influence of caffeic acid phenethyl ester on bone healing in a rat model.J.Int.Med.Res.41,1648-1654(2013).
7.Li,L.,Sun,W.,Wu,T.,Lu,R.&Shi,B.Caffeic acid phenethyl ester attenuates lipopolysaccharide-stimulated proinflammatory responses in human gingival fibroblasts via NF-kappaB and PI3K/Akt signaling pathway.Eur.J.Pharmacol.794,61-68(2017).
8.Choi,E.Y.et al.Effect of caffeic acid phenethyl ester on Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages.J.Periodontal Res.50,737-747(2015).
9.Van Dyke,T.E.&Serhan,C.N.Resolution of inflammation:a new paradigm for the pathogenesis of periodontal diseases.J.Dent.Res.82,82-90(2003).
10.Kataoka,K.et al.Visualization of oxidative stress induced by experimental periodontitis in keap1-dependent oxidative stress detector-luciferase mice.Int.J.Mol.Sci.17,1907(2016).
11.Muniz,F.W.et al.The impact of antioxidant agents complimentary to periodontal therapy on oxidative stress and periodontal outcomes:a systematic review.Arch.Oral Biol.60,1203-1214(2015).
12.Shi,H.,Xie,D.,Yang,R.&Cheng,Y.Synthesis of caffeic acid phenethyl ester derivatives,and their cytoprotective and neuritogenic activities in PC12 cells.J.Agric.Food Chem.62,5046-5053(2014).
13.Chen,H.,Tran,J.T.,Anderson,R.E.&Mandal,M.N.Caffeic acid phenethyl ester protects 661W cells from H2O2-mediated cell death and enhances electroretinography response in dim-reared albino rats.Mol.Vis.18,1325-1338(2012).
14.Yang,J.et al.Synthesis of a series of caffeic acid phenethyl amide(CAPA)fluorinated derivatives:comparison of cytoprotective effects to caffeic acid phenethyl ester(CAPE).Bioorg.Med.Chem.18,5032-5038(2010).
15.Balogun,E.et al.Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element.Biochem.J.371,887-895(2003).
16.Zhang,M.et al.Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection.Prog.Neurobiol.100,30-47(2013).
17.Suttorp,C.M.et al.Orthodontic forces induce the cytoprotective enzyme heme oxygenase-1 in rats.Front.Physiol.7,283(2016).
18.Fan,W.et al.The heme oxygenase system and oral diseases.Oral Dis.17,252-257(2011).
19.Turkseven,S.et al.Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes.Am.J.Physiol.Heart Circ.Physiol.289,H701-H707(2005).
20.Keum,Y.S.Regulation of Nrf2-mediated phase II detoxification and anti-oxidant genes.Biomol.Ther.(Seoul)20,144-151(2012).
21.Park,E.Y.&Rho,H.M.The transcriptional activation of the human copper/zinc superoxide dismutase gene by 2,3,7,8-tetrachlorodibenzo-p-dioxin through two different regulator sites,the antioxidant responsive element and xenobiotic responsive element.Mol.Cell.Biochem.240,47-55(2002).
22.Ding,Y.et al.Heme oxygenase-1 dependant pathway contributes to protection by tetramethylpyrazine against chronic hypoxic injury on medulla oblongata in rats.J.Neurol.Sci.361,101-111(2016).
23.Miao,L.&St Clair,D.K.Regulation of superoxide dismutase genes:implications in disease.Free Radic.Biol.Med.47,344-356(2009).
24.Lin,H.Y.,Shen,S.C.&Chen,Y.C.Anti-inflammatory effect of heme oxygenase 1:glycosylation and nitric oxide inhibition in macrophages.J.Cell.Physiol.202,579-590(2005).
25.Jeong,G.S.et al.Effects of sappanchalcone on the cytoprotection and antiinflammation via heme oxygenase-1 in human pulp and periodontal ligament cells.Eur.J.Pharmacol.644,230-237(2010).
26.Lee,Y.et al.Caffeic acid phenethyl ester-mediated Nrf2 activation and IkappaBkinase inhibition are involved in NFkappaB inhibitory effect:structural analysis for NFkappaB inhibition.Eur.J.Pharmacol.643,21-28(2010).
27.Mapesa,J.O.et al.Catechols in caffeic acid phenethyl ester are essential for inhibition of TNF-mediated IP-10 expression through NF-kappaB-dependent but HO-1-and p38-independent mechanisms in mouse intestinal epithelial cells.Mol.Nutr.Food Res.55,1850-1861(2011).
28.Kurauchi,Y.,Hisatsune,A.,Isohama,Y.,Mishima,S.&Katsuki,H.Caffeic acid phenethyl ester protects nigral dopaminergic neurons via dual mechanisms involving haem oxygenase-1 and brain-derived neurotrophic factor.Br.J.Pharmacol.166,1151-1168(2012).
29.Chen,H.et al.A ROS-mediated mitochondrial pathway and Nrf2 pathway activation are involved in BDE-47 induced apoptosis in Neuro-2a cells.Chemosphere184,679-686(2017).
30.Roubalova,L.et al.Semisynthetic flavonoid 7-O-galloylquercetin activates Nrf2and induces Nrf2-dependent gene expression in RAW264.7 and Hepa1c1c7 cells.Chem.Biol.Interact.260,58-66(2016).
31.Nguyen,H.D.et al.7-Methoxy-(9H-beta-carbolin-1-il)-(E)-1-propenoic acid,a beta-carboline alkaloid from Eurycoma longifolia,exhibits anti-inflammatory effects by activating the Nrf2/heme oxygenase-1 pathway.J.Cell.Biochem.117,659-670(2016).
32.Kim,Y.M.,Kim,H.J.&Chang,K.C.Glycyrrhizin reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and endotoxemic mice by p38/Nrf2-dependent induction of HO-1.Int.Immunopharmacol.26,112-118(2015).
33.Tamura,R.E.et al.GADD45 proteins:central players in tumorigenesis.Curr.Mol.Med.12,634-651(2012).
34.Hinson,J.P.,Kapas,S.&Smith,D.M.Adrenomedullin,a multifunctional regulatory peptide.Endocr.Rev.21,138-167(2000).
35.Xin,L.,Wang,J.,Wu,Y.,Guo,S.&Tong,J.Increased oxidative stress and activated heat shock proteins in human cell lines by silver nanoparticles.Hum.Exp.Toxicol.34,315-323(2015).
36.Sardana,M.K.&Kappas,A.Dual control mechanism for heme oxygenase:tin(IV)-protoporphyrin potently inhibits enzyme activity while markedly increasing content of enzyme protein in liver.Proc.Natl Acad.Sci.USA 84,2464-2468(1987).
37.Pourgonabadi,S.,Muller,H.D.,Mendes,J.R.&Gruber,R.Saliva initiates the formation of pro-inflammatory macrophages in vitro.Arch.Oral Biol.73,295-301(2017).
38.Natarajan,K.et al.Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B.Proc.Natl Acad.Sci.USA 93,9090-9095(1996).
39.Kanzaki,H.et al.Pathways that regulate ROS scavenging enzymes,and their role in defense against tissue destruction in periodontitis.Front.Physiol.8,351(2017).
40.Akalin,F.A.,Toklu,E.&Renda,N.Analysis of superoxide dismutase activity levels in gingiva and gingival crevicular fluid in patients with chronic periodontitis and periodontally healthy controls.J.Clin.Periodontol.32,238-243(2005).
41.Fitzpatrick,L.R.,Wang,J.&Le,T.Caffeic acid phenethyl ester,an inhibitor of nuclear factor-kappaB,attenuates bacterial peptidoglycan polysaccharideinduced colitis in rats.J.Pharmacol.Exp.Ther.299,915-920(2001).
42.Mahmoud,A.M.&Abd El-Twab,S.M.Caffeic acid phenethyl ester protects the brain against hexavalent chromium toxicity by enhancing endogenous antioxidants and modulating the JAK/STAT signaling pathway.Biomed.Pharmacother.91,303-311(2017).
43.Taylan,M.et al.The protective effects of caffeic acid phenethyl ester on acetylsalicylic acid-induced lung injury in rats.J.Invest.Surg.29,328-334(2016).
44.Gokce,A.et al.Protective effect of caffeic acid phenethyl ester on cyclosporine A-induced nephrotoxicity in rats.Ren.Fail.31,843-847(2009).
45.Buyukberber,M.et al.Therapeutic effect of caffeic acid phenethyl ester on ceruleininduced acute pancreatitis.World J.Gastroenterol.15,5181-5185(2009).
46.Coban,S.et al.The effect of caffeic acid phenethyl ester(CAPE)against cholestatic liver injury in rats.J.Surg.Res.159,674-679(2010).
47.Tan,J.et al.Caffeic acid phenethyl ester possesses potent cardioprotective effects in a rabbit model of acute myocardial ischemia-reperfusion injury.Am.J.Physiol.Heart Circ.Physiol.289,H2265-H2271(2005).
48.Tomiyama,R.et al.3,4-dihydroxybenzalacetone and caffeic acid phenethyl ester induce preconditioning ER stress and autophagy in SH-SY5Y cells.J.Cell.Physiol.233,1671-1684(2018).
49.Wang,X.,Bynum,J.A.,Stavchansky,S.&Bowman,P.D.Cytoprotection of human endothelial cells against oxidative stress by 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole(CDDO-Im):application of systems biology to understand the mechanism of action.Eur.J.Pharmacol.734,122-131(2014).
50.Arai,C.et al.HSPA1A is upregulated in periodontal ligament at early stage of tooth movement in rats.Histochem.Cell Biol.134,337-343(2010).
51.Calenic,B.et al.p53-Pathway activity and apoptosis in hydrogen sulfide-exposed stem cells separated from human gingival epithelium.J.Periodontal Res.48,322-330(2013).
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2.Ercan,N.,Erdemir,E.O.,Ozkan,S.Y.&Hendek,M.K.The comparative effect of propolis in two different vehicles;mouthwash and chewing-gum on plaque accumulation and gingival inflammation.Eur.J.Dent.9,272-276(2015).
3.AkhavanKarbassi,M.H.,Yazdi,M.F.,Ahadian,H.&SadrAbad,M.J.Randomized double-blind placebo-controlled trial of propolis for oral mucositis in patients receiving chemotherapy for head and neck cancer.Asian Pac.J.Cancer Prev.17,3611-3614(2016).
4.Yigit,U.,Kirzioglu,F.Y.,Uguz,A.C.,Naziroglu,M.&Ozmen,O.Is caffeic acid phenethyl ester more protective than doxycycline in experimental periodontitis?Arch.Oral Biol.81,61-68(2017).
5.Tolba,M.F.,El-Serafi,A.T.&Omar,H.A.Caffeic acid phenethyl ester protects against glucocorticoid-induced osteoporosis in vivo:impact on oxidative stress and RANKL/OPG signals.Toxicol.Appl.Pharmacol.324,26-35(2017).
6.Ucan,M.C.et al.Influence of caffeic acid phenethyl ester on bone healing in a rat model.J.Int.Med.Res.41,1648-1654(2013).
7.Li,L.,Sun,W.,Wu,T.,Lu,R.&Shi,B.Caffeic acid phenethyl ester attenuates lipopolysaccharide-stimulated proinflammatory responses in human gingival fibroblasts via NF-kappaB and PI3K/Akt signaling pathway.Eur.J.Pharmacol.794,61-68(2017).
8.Choi,E.Y.et al.Effect of caffeic acid phenethyl ester on Prevotella intermedia lipopolysaccharide-induced production of proinflammatory mediators in murine macrophages.J.Periodontal Res.50,737-747(2015).
9.Van Dyke,T.E.&Serhan,C.N.Resolution of inflammation:a new paradigm for the pathogenesis of periodontal diseases.J.Dent.Res.82,82-90(2003).
10.Kataoka,K.et al.Visualization of oxidative stress induced by experimental periodontitis in keap1-dependent oxidative stress detector-luciferase mice.Int.J.Mol.Sci.17,1907(2016).
11.Muniz,F.W.et al.The impact of antioxidant agents complimentary to periodontal therapy on oxidative stress and periodontal outcomes:a systematic review.Arch.Oral Biol.60,1203-1214(2015).
12.Shi,H.,Xie,D.,Yang,R.&Cheng,Y.Synthesis of caffeic acid phenethyl ester derivatives,and their cytoprotective and neuritogenic activities in PC12 cells.J.Agric.Food Chem.62,5046-5053(2014).
13.Chen,H.,Tran,J.T.,Anderson,R.E.&Mandal,M.N.Caffeic acid phenethyl ester protects 661W cells from H2O2-mediated cell death and enhances electroretinography response in dim-reared albino rats.Mol.Vis.18,1325-1338(2012).
14.Yang,J.et al.Synthesis of a series of caffeic acid phenethyl amide(CAPA)fluorinated derivatives:comparison of cytoprotective effects to caffeic acid phenethyl ester(CAPE).Bioorg.Med.Chem.18,5032-5038(2010).
15.Balogun,E.et al.Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element.Biochem.J.371,887-895(2003).
16.Zhang,M.et al.Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection.Prog.Neurobiol.100,30-47(2013).
17.Suttorp,C.M.et al.Orthodontic forces induce the cytoprotective enzyme heme oxygenase-1 in rats.Front.Physiol.7,283(2016).
18.Fan,W.et al.The heme oxygenase system and oral diseases.Oral Dis.17,252-257(2011).
19.Turkseven,S.et al.Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes.Am.J.Physiol.Heart Circ.Physiol.289,H701-H707(2005).
20.Keum,Y.S.Regulation of Nrf2-mediated phase II detoxification and anti-oxidant genes.Biomol.Ther.(Seoul)20,144-151(2012).
21.Park,E.Y.&Rho,H.M.The transcriptional activation of the human copper/zinc superoxide dismutase gene by 2,3,7,8-tetrachlorodibenzo-p-dioxin through two different regulator sites,the antioxidant responsive element and xenobiotic responsive element.Mol.Cell.Biochem.240,47-55(2002).
22.Ding,Y.et al.Heme oxygenase-1 dependant pathway contributes to protection by tetramethylpyrazine against chronic hypoxic injury on medulla oblongata in rats.J.Neurol.Sci.361,101-111(2016).
23.Miao,L.&St Clair,D.K.Regulation of superoxide dismutase genes:implications in disease.Free Radic.Biol.Med.47,344-356(2009).
24.Lin,H.Y.,Shen,S.C.&Chen,Y.C.Anti-inflammatory effect of heme oxygenase 1:glycosylation and nitric oxide inhibition in macrophages.J.Cell.Physiol.202,579-590(2005).
25.Jeong,G.S.et al.Effects of sappanchalcone on the cytoprotection and antiinflammation via heme oxygenase-1 in human pulp and periodontal ligament cells.Eur.J.Pharmacol.644,230-237(2010).
26.Lee,Y.et al.Caffeic acid phenethyl ester-mediated Nrf2 activation and IkappaBkinase inhibition are involved in NFkappaB inhibitory effect:structural analysis for NFkappaB inhibition.Eur.J.Pharmacol.643,21-28(2010).
27.Mapesa,J.O.et al.Catechols in caffeic acid phenethyl ester are essential for inhibition of TNF-mediated IP-10 expression through NF-kappaB-dependent but HO-1-and p38-independent mechanisms in mouse intestinal epithelial cells.Mol.Nutr.Food Res.55,1850-1861(2011).
28.Kurauchi,Y.,Hisatsune,A.,Isohama,Y.,Mishima,S.&Katsuki,H.Caffeic acid phenethyl ester protects nigral dopaminergic neurons via dual mechanisms involving haem oxygenase-1 and brain-derived neurotrophic factor.Br.J.Pharmacol.166,1151-1168(2012).
29.Chen,H.et al.A ROS-mediated mitochondrial pathway and Nrf2 pathway activation are involved in BDE-47 induced apoptosis in Neuro-2a cells.Chemosphere184,679-686(2017).
30.Roubalova,L.et al.Semisynthetic flavonoid 7-O-galloylquercetin activates Nrf2and induces Nrf2-dependent gene expression in RAW264.7 and Hepa1c1c7 cells.Chem.Biol.Interact.260,58-66(2016).
31.Nguyen,H.D.et al.7-Methoxy-(9H-beta-carbolin-1-il)-(E)-1-propenoic acid,a beta-carboline alkaloid from Eurycoma longifolia,exhibits anti-inflammatory effects by activating the Nrf2/heme oxygenase-1 pathway.J.Cell.Biochem.117,659-670(2016).
32.Kim,Y.M.,Kim,H.J.&Chang,K.C.Glycyrrhizin reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and endotoxemic mice by p38/Nrf2-dependent induction of HO-1.Int.Immunopharmacol.26,112-118(2015).
33.Tamura,R.E.et al.GADD45 proteins:central players in tumorigenesis.Curr.Mol.Med.12,634-651(2012).
34.Hinson,J.P.,Kapas,S.&Smith,D.M.Adrenomedullin,a multifunctional regulatory peptide.Endocr.Rev.21,138-167(2000).
35.Xin,L.,Wang,J.,Wu,Y.,Guo,S.&Tong,J.Increased oxidative stress and activated heat shock proteins in human cell lines by silver nanoparticles.Hum.Exp.Toxicol.34,315-323(2015).
36.Sardana,M.K.&Kappas,A.Dual control mechanism for heme oxygenase:tin(IV)-protoporphyrin potently inhibits enzyme activity while markedly increasing content of enzyme protein in liver.Proc.Natl Acad.Sci.USA 84,2464-2468(1987).
37.Pourgonabadi,S.,Muller,H.D.,Mendes,J.R.&Gruber,R.Saliva initiates the formation of pro-inflammatory macrophages in vitro.Arch.Oral Biol.73,295-301(2017).
38.Natarajan,K.et al.Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B.Proc.Natl Acad.Sci.USA 93,9090-9095(1996).
39.Kanzaki,H.et al.Pathways that regulate ROS scavenging enzymes,and their role in defense against tissue destruction in periodontitis.Front.Physiol.8,351(2017).
40.Akalin,F.A.,Toklu,E.&Renda,N.Analysis of superoxide dismutase activity levels in gingiva and gingival crevicular fluid in patients with chronic periodontitis and periodontally healthy controls.J.Clin.Periodontol.32,238-243(2005).
41.Fitzpatrick,L.R.,Wang,J.&Le,T.Caffeic acid phenethyl ester,an inhibitor of nuclear factor-kappaB,attenuates bacterial peptidoglycan polysaccharideinduced colitis in rats.J.Pharmacol.Exp.Ther.299,915-920(2001).
42.Mahmoud,A.M.&Abd El-Twab,S.M.Caffeic acid phenethyl ester protects the brain against hexavalent chromium toxicity by enhancing endogenous antioxidants and modulating the JAK/STAT signaling pathway.Biomed.Pharmacother.91,303-311(2017).
43.Taylan,M.et al.The protective effects of caffeic acid phenethyl ester on acetylsalicylic acid-induced lung injury in rats.J.Invest.Surg.29,328-334(2016).
44.Gokce,A.et al.Protective effect of caffeic acid phenethyl ester on cyclosporine A-induced nephrotoxicity in rats.Ren.Fail.31,843-847(2009).
45.Buyukberber,M.et al.Therapeutic effect of caffeic acid phenethyl ester on ceruleininduced acute pancreatitis.World J.Gastroenterol.15,5181-5185(2009).
46.Coban,S.et al.The effect of caffeic acid phenethyl ester(CAPE)against cholestatic liver injury in rats.J.Surg.Res.159,674-679(2010).
47.Tan,J.et al.Caffeic acid phenethyl ester possesses potent cardioprotective effects in a rabbit model of acute myocardial ischemia-reperfusion injury.Am.J.Physiol.Heart Circ.Physiol.289,H2265-H2271(2005).
48.Tomiyama,R.et al.3,4-dihydroxybenzalacetone and caffeic acid phenethyl ester induce preconditioning ER stress and autophagy in SH-SY5Y cells.J.Cell.Physiol.233,1671-1684(2018).
49.Wang,X.,Bynum,J.A.,Stavchansky,S.&Bowman,P.D.Cytoprotection of human endothelial cells against oxidative stress by 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole(CDDO-Im):application of systems biology to understand the mechanism of action.Eur.J.Pharmacol.734,122-131(2014).
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