Caffeic acid phenethyl ester protects against oxidative stress and dampens inflammation via heme oxygenase 1

Abstract

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.

Naturally Derived Heme-Oxygenase 1 Inducers and Their Therapeutic Application to Immune-Mediated Diseases

“…It has been described that CAPE inhibits cytokine production by stimulated DCs ( 180 ) and suppresses DNA synthesis of human peripheral blood mononuclear cells (PBMCs) in response to mitogens ( 181 ). Besides, CAPE has been identified as a potent HO-1 activator ( 12 ), which induces Nrf2 and in turn inhibits NFκB activation in macrophages ( Figure 1 ) ( 182 , 183 ). Caffeic acid phenethyl ester derivative compounds promote the switch of macrophage phenotypes from proinflammatory M1 to resolving M2.…”

Effect of Caffeic Acid Phenethyl Ester Provision on Fibroblast Growth Factor-2, Matrix Metalloproteinase-9 Expression, Osteoclast and Osteoblast Numbers during Experimental Tooth Movement in Wistar Rats (Rattus norvegicus)

“…CAPE has potential antioxidant activity and anti-inflammatory ability that can promote bone formation and inhibit bone resorption. 23,24 Based on our study result, CAPE provision may delay OTM rate due to inhibit the number of osteoclast and MMP-9 expression. The provision of CAPE, which is contained in propolis, may provide these healthy benefits and may become an adjuvant herbal-based therapy that suitable for relapse prevention after orthodontic treatment or OIRR prevention due to OTM excessive force.…”

Botanic Origin of Propolis Extract Powder Drives Contrasted Impact on Diabesity in High-Fat-Fed Mice

“…Such activation could be involved in the reported PPEP effect on obesity and associated disorders [ 40 ], since several Nrf2 agonists, including CDDO-lm [ 48 ], oltipraz [ 49 ], glycyrrhizin [ 50 ], or glucoraphanin [ 51 ], were able to blunt the HF-mediated obesity and insulin resistance in rodents. In addition, several bioactive molecules found in propolis are able to activate the Nrf2 signaling pathway [ 52 ], including CAPE [ 53 ], as suggested by cell culture experiments presented here. Nevertheless, the mechanisms by which Nrf2 activators restore energy homeostasis in a diet-induced obesity mice model remains elusive, and several hypotheses have been emitted, including induction of lipid oxidation and limitation of oxidative stress and inflammation, which display an important role in energy homeostasis and insulin sensitivity disruption [ 54 , 55 ].…”