Ketone Analog of Caffeic Acid Phenethyl Ester Exhibits Antioxidant Activity via Activation of ERK-Dependent Nrf2 Pathway
Due to their robust antioxidant properties, phenolic acids and their analogs are extensively studied for their ability to activate cellular antioxidant pathways, including nuclear factor (erythroid-derived-2)-like 2 (Nrf2)-antioxidant response element (ARE) pathway. Caffeic, ferulic, and gallic acid...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-03-01
|
| Series: | Applied Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3417/12/6/3062 |
| _version_ | 1797473017889030144 |
|---|---|
| author | Khushwant S. Bhullar Manal A. Nael Khaled M. Elokely Jérémie A. Doiron Luc M. LeBlanc Grégoire Lassalle-Claux Mohamed Salla Fahad S. Aldawsari Mohamed Touaibia H. P. Vasantha Rupasinghe |
| author_facet | Khushwant S. Bhullar Manal A. Nael Khaled M. Elokely Jérémie A. Doiron Luc M. LeBlanc Grégoire Lassalle-Claux Mohamed Salla Fahad S. Aldawsari Mohamed Touaibia H. P. Vasantha Rupasinghe |
| author_sort | Khushwant S. Bhullar |
| collection | DOAJ |
| description | Due to their robust antioxidant properties, phenolic acids and their analogs are extensively studied for their ability to activate cellular antioxidant pathways, including nuclear factor (erythroid-derived-2)-like 2 (Nrf2)-antioxidant response element (ARE) pathway. Caffeic, ferulic, and gallic acid are well-studied members of phenolic acids. Constant efforts are made to improve the pharmacological effects and bioavailability of phenolic acids by synthesizing their chemical derivatives. This study determines how modifications of the chemical structure of these phenolic acids affect their antioxidant and cytoprotective activities. We have selected six superior antioxidant compounds (<b>12</b>, <b>16</b>, <b>26</b>, <b>35</b>, <b>42</b>, and <b>44</b>) of the 48 caffeic acid phenethyl ester (CAPE) analogs based on their ability to scavenge free radicals in vitro using standard antioxidant assays. These compounds exhibited minimal toxicity as indicated by cell cycle and cytochrome C release assays. Among these compounds, <b>44</b>, the ketone analog of CAPE, exhibited the ability to increase p-Nrf2 (Ser40) levels in 293T cells (<i>p</i> < 0.05). Further, <b>44</b>, exhibited its antioxidant effect in <i>Drosophila Melanogaster</i> as indicated by an increase in mRNA levels of Nrf2 and GPx (<i>p</i> < 0.05). Finally, the ability of <b>44</b> to activate the antioxidant pathway was abolished in the presence of extracellular signal-regulated kinase (ERK) inhibitor in 293T cells. Thus, we identify <b>44</b>, the ketone analog of CAPE, as a unique antioxidant molecule with the function of ERK-mediated Nrf2 activation. |
| first_indexed | 2024-03-09T20:09:12Z |
| format | Article |
| id | doaj.art-e99825905771403dbedf112cdbd9e2ea |
| institution | Directory Open Access Journal |
| issn | 2076-3417 |
| language | English |
| last_indexed | 2024-03-09T20:09:12Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Applied Sciences |
| spelling | doaj.art-e99825905771403dbedf112cdbd9e2ea2023-11-24T00:23:09ZengMDPI AGApplied Sciences2076-34172022-03-01126306210.3390/app12063062Ketone Analog of Caffeic Acid Phenethyl Ester Exhibits Antioxidant Activity via Activation of ERK-Dependent Nrf2 PathwayKhushwant S. Bhullar0Manal A. Nael1Khaled M. Elokely2Jérémie A. Doiron3Luc M. LeBlanc4Grégoire Lassalle-Claux5Mohamed Salla6Fahad S. Aldawsari7Mohamed Touaibia8H. P. Vasantha Rupasinghe9Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS B2N 5E3, CanadaInstitute for Computational Molecular Science and Department of Chemistry, Temple University, Philadelphia, PA 19122, USAInstitute for Computational Molecular Science and Department of Chemistry, Temple University, Philadelphia, PA 19122, USADepartment of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, CanadaDepartment of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, CanadaDepartment of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, CanadaDepartment of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, CanadaReference Laboratory for Medicines and Cosmetics, Saudi Food and Drug Authority, Riyadh 2411, Saudi ArabiaDepartment of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, CanadaDepartment of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS B2N 5E3, CanadaDue to their robust antioxidant properties, phenolic acids and their analogs are extensively studied for their ability to activate cellular antioxidant pathways, including nuclear factor (erythroid-derived-2)-like 2 (Nrf2)-antioxidant response element (ARE) pathway. Caffeic, ferulic, and gallic acid are well-studied members of phenolic acids. Constant efforts are made to improve the pharmacological effects and bioavailability of phenolic acids by synthesizing their chemical derivatives. This study determines how modifications of the chemical structure of these phenolic acids affect their antioxidant and cytoprotective activities. We have selected six superior antioxidant compounds (<b>12</b>, <b>16</b>, <b>26</b>, <b>35</b>, <b>42</b>, and <b>44</b>) of the 48 caffeic acid phenethyl ester (CAPE) analogs based on their ability to scavenge free radicals in vitro using standard antioxidant assays. These compounds exhibited minimal toxicity as indicated by cell cycle and cytochrome C release assays. Among these compounds, <b>44</b>, the ketone analog of CAPE, exhibited the ability to increase p-Nrf2 (Ser40) levels in 293T cells (<i>p</i> < 0.05). Further, <b>44</b>, exhibited its antioxidant effect in <i>Drosophila Melanogaster</i> as indicated by an increase in mRNA levels of Nrf2 and GPx (<i>p</i> < 0.05). Finally, the ability of <b>44</b> to activate the antioxidant pathway was abolished in the presence of extracellular signal-regulated kinase (ERK) inhibitor in 293T cells. Thus, we identify <b>44</b>, the ketone analog of CAPE, as a unique antioxidant molecule with the function of ERK-mediated Nrf2 activation.https://www.mdpi.com/2076-3417/12/6/3062caffeic acidphenolic acidantioxidantoxidative stresscell signaling |
| spellingShingle | Khushwant S. Bhullar Manal A. Nael Khaled M. Elokely Jérémie A. Doiron Luc M. LeBlanc Grégoire Lassalle-Claux Mohamed Salla Fahad S. Aldawsari Mohamed Touaibia H. P. Vasantha Rupasinghe Ketone Analog of Caffeic Acid Phenethyl Ester Exhibits Antioxidant Activity via Activation of ERK-Dependent Nrf2 Pathway Applied Sciences caffeic acid phenolic acid antioxidant oxidative stress cell signaling |
| title | Ketone Analog of Caffeic Acid Phenethyl Ester Exhibits Antioxidant Activity via Activation of ERK-Dependent Nrf2 Pathway |
| title_full | Ketone Analog of Caffeic Acid Phenethyl Ester Exhibits Antioxidant Activity via Activation of ERK-Dependent Nrf2 Pathway |
| title_fullStr | Ketone Analog of Caffeic Acid Phenethyl Ester Exhibits Antioxidant Activity via Activation of ERK-Dependent Nrf2 Pathway |
| title_full_unstemmed | Ketone Analog of Caffeic Acid Phenethyl Ester Exhibits Antioxidant Activity via Activation of ERK-Dependent Nrf2 Pathway |
| title_short | Ketone Analog of Caffeic Acid Phenethyl Ester Exhibits Antioxidant Activity via Activation of ERK-Dependent Nrf2 Pathway |
| title_sort | ketone analog of caffeic acid phenethyl ester exhibits antioxidant activity via activation of erk dependent nrf2 pathway |
| topic | caffeic acid phenolic acid antioxidant oxidative stress cell signaling |
| url | https://www.mdpi.com/2076-3417/12/6/3062 |
| work_keys_str_mv | AT khushwantsbhullar ketoneanalogofcaffeicacidphenethylesterexhibitsantioxidantactivityviaactivationoferkdependentnrf2pathway AT manalanael ketoneanalogofcaffeicacidphenethylesterexhibitsantioxidantactivityviaactivationoferkdependentnrf2pathway AT khaledmelokely ketoneanalogofcaffeicacidphenethylesterexhibitsantioxidantactivityviaactivationoferkdependentnrf2pathway AT jeremieadoiron ketoneanalogofcaffeicacidphenethylesterexhibitsantioxidantactivityviaactivationoferkdependentnrf2pathway AT lucmleblanc ketoneanalogofcaffeicacidphenethylesterexhibitsantioxidantactivityviaactivationoferkdependentnrf2pathway AT gregoirelassalleclaux ketoneanalogofcaffeicacidphenethylesterexhibitsantioxidantactivityviaactivationoferkdependentnrf2pathway AT mohamedsalla ketoneanalogofcaffeicacidphenethylesterexhibitsantioxidantactivityviaactivationoferkdependentnrf2pathway AT fahadsaldawsari ketoneanalogofcaffeicacidphenethylesterexhibitsantioxidantactivityviaactivationoferkdependentnrf2pathway AT mohamedtouaibia ketoneanalogofcaffeicacidphenethylesterexhibitsantioxidantactivityviaactivationoferkdependentnrf2pathway AT hpvasantharupasinghe ketoneanalogofcaffeicacidphenethylesterexhibitsantioxidantactivityviaactivationoferkdependentnrf2pathway |