Concomitant Nrf2- and ATF4-Activation by Carnosic Acid Cooperatively Induces Expression of Cytoprotective Genes
Abstract
:1. Introduction
2. Results
2.1. Dose-Dependent Induction of NGF and AKR1B10 by CA
2.2. High-Dose CA Activates the ATF4 Pathway
2.3. Nrf2 and ATF4 Cooperatively Contribute to CA-Inducible NGF Gene Expression and Other Antioxidant Genes
2.4. CA Activates ATF4 through the ISR Pathway
2.5. CA Activates ISR in An HRI-Dependent Manner
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Cell Culture and Treatment
4.3. Microarray Analysis
4.4. Quantitative Reverse Transcription PCR (RT-qPCR)
4.5. Preparation of Cell Lysate
4.6. Immunoblot
4.7. RNA Interference
4.8. Transient Transfection and Luciferase Assay
4.9. ChIP Assay
4.10. Metabolic Labeling
4.11. Pull-Down Assay
4.12. Statistical and Quantitative Analysis
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AARE | amino acid response element |
ARE | antioxidant response element |
ASNS | asparagine synthetase |
ATF4 | activating transcription factor 4 |
bZip | basic leucine zipper |
CA | carnosic acid |
ChIP | chromatin immunoprecipitation |
CNC | cap‘n’collar |
eIF2α | eukaryotic initiation factor 2 alpha |
ER stress | endoplasmic reticulum stress |
HO-1 | heme oxygenase-1 |
HRI | heme-regulated inhibitor kinase |
ISR | integrated stress response |
Keap1 | Kelch-like ECH-associated protein 1 |
NGF | nerve growth factor |
Nrf2 | NF-E2-related factor 2 |
tBHQ | tert-butylhydroquinone |
Trib3 | tribbles homolog 3 |
TXNRD1 | thioredoxin reductase 1 |
References
- Hayes, J.D.; Dinkova-Kostova, A.T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 2014, 39, 199–218. [Google Scholar] [CrossRef] [PubMed]
- Hirotsu, Y.; Katsuoka, F.; Funayama, R.; Nagashima, T.; Nishida, Y.; Nakayama, K.; Engel, J.D.; Yamamoto, M. Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res. 2012, 40, 10228–10239. [Google Scholar] [CrossRef] [PubMed]
- Suzuki, T.; Motohashi, H.; Yamamoto, M. Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol. Sci. 2013, 34, 340–346. [Google Scholar] [CrossRef] [PubMed]
- Birtić, S.; Dussort, P.; Pierre, F.-X.; Bily, A.C.; Roller, M. Carnosic acid. Phytochemistry 2015, 115, 9–19. [Google Scholar] [CrossRef] [PubMed]
- Moreno, S.; Scheyer, T.; Romano, C.S.; Vojnov, A.A. Antioxidant and antimicrobial activities of rosemary extracts linked to their polyphenol composition. Free Radic. Res. 2006, 40, 223–231. [Google Scholar] [CrossRef] [PubMed]
- Mimura, J.; Kosaka, K.; Maruyama, A.; Satoh, T.; Harada, N.; Yoshida, H.; Satoh, K.; Yamamoto, M.; Itoh, K. Nrf2 regulates NGF mRNA induction by carnosic acid in T98G glioblastoma cells and normal human astrocytes. J. Biochem. (Tokyo) 2011, 150, 209–217. [Google Scholar] [CrossRef] [PubMed]
- Yoshida, H.; Mimura, J.; Imaizumi, T.; Matsumiya, T.; Ishikawa, A.; Metoki, N.; Tanji, K.; Ota, K.; Hayakari, R.; Kosaka, K.; et al. Edaravone and carnosic acid synergistically enhance the expression of nerve growth factor in human astrocytes under hypoxia/reoxygenation. Neurosci. Res. 2011, 69, 291–298. [Google Scholar] [CrossRef] [PubMed]
- Kosaka, K.; Mimura, J.; Itoh, K.; Satoh, T.; Shimojo, Y.; Kitajima, C.; Maruyama, A.; Yamamoto, M.; Shirasawa, T. Role of Nrf2 and p62/ZIP in the neurite outgrowth by carnosic acid in PC12h cells. J. Biochem. (Tokyo) 2010, 147, 73–81. [Google Scholar] [CrossRef] [PubMed]
- Satoh, T.; Kosaka, K.; Itoh, K.; Kobayashi, A.; Yamamoto, M.; Shimojo, Y.; Kitajima, C.; Cui, J.; Kamins, J.; Okamoto, S.; et al. Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1. J. Neurochem. 2008, 104, 1116–1131. [Google Scholar] [CrossRef] [PubMed]
- Lipton, S.A.; Rezaie, T.; Nutter, A.; Lopez, K.M.; Parker, J.; Kosaka, K.; Satoh, T.; McKercher, S.R.; Masliah, E.; Nakanishi, N. Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer’s disease models. Cell Death Dis. 2016, 7, e2499. [Google Scholar] [CrossRef]
- Johnson, J.A.; Johnson, D.A.; Kraft, A.D.; Calkins, M.J.; Jakel, R.J.; Vargas, M.R.; Chen, P.-C. The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Ann. N. Y. Acad. Sci. 2008, 1147, 61–69. [Google Scholar] [CrossRef] [PubMed]
- Lange, P.S.; Chavez, J.C.; Pinto, J.T.; Coppola, G.; Sun, C.-W.; Townes, T.M.; Geschwind, D.H.; Ratan, R.R. ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo. J. Exp. Med. 2008, 205, 1227–1242. [Google Scholar] [CrossRef]
- Espinosa-Diez, C.; Miguel, V.; Mennerich, D.; Kietzmann, T.; Sánchez-Pérez, P.; Cadenas, S.; Lamas, S. Antioxidant responses and cellular adjustments to oxidative stress. Redox Biol. 2015, 6, 183–197. [Google Scholar] [CrossRef] [PubMed]
- Jeyapaul, J.; Jaiswal, A.K. Nrf2 and c-Jun regulation of antioxidant response element (ARE)-mediated expression and induction of gamma-glutamylcysteine synthetase heavy subunit gene. Biochem. Pharmacol. 2000, 59, 1433–1439. [Google Scholar] [CrossRef]
- He, C.H.; Gong, P.; Hu, B.; Stewart, D.; Choi, M.E.; Choi, A.M.; Alam, J. Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J. Biol. Chem. 2001, 276, 20858–20865. [Google Scholar] [CrossRef] [PubMed]
- Ameri, K.; Harris, A.L. Activating transcription factor 4. Int. J. Biochem. Cell Biol. 2008, 40, 14–21. [Google Scholar] [CrossRef] [PubMed]
- Han, J.; Back, S.H.; Hur, J.; Lin, Y.-H.; Gildersleeve, R.; Shan, J.; Yuan, C.L.; Krokowski, D.; Wang, S.; Hatzoglou, M.; et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 2013, 15, 481–490. [Google Scholar] [CrossRef]
- Pakos-Zebrucka, K.; Koryga, I.; Mnich, K.; Ljujic, M.; Samali, A.; Gorman, A.M. The integrated stress response. EMBO Rep. 2016, 17, 1374–1395. [Google Scholar] [CrossRef]
- Ye, P.; Mimura, J.; Okada, T.; Sato, H.; Liu, T.; Maruyama, A.; Ohyama, C.; Itoh, K. Nrf2- and ATF4-dependent upregulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition. Mol. Cell. Biol. 2014, 34, 3421–3434. [Google Scholar] [CrossRef]
- Kosaka, K.; Yokoi, T. Carnosic acid, a component of rosemary (Rosmarinus officinalis L.), promotes synthesis of nerve growth factor in T98G human glioblastoma cells. Biol. Pharm. Bull. 2003, 26, 1620–1622. [Google Scholar] [CrossRef] [PubMed]
- Rau, O.; Wurglics, M.; Paulke, A.; Zitzkowski, J.; Meindl, N.; Bock, A.; Dingermann, T.; Abdel-Tawab, M.; Schubert-Zsilavecz, M. Carnosic acid and carnosol, phenolic diterpene compounds of the labiate herbs rosemary and sage, are activators of the human peroxisome proliferator-activated receptor gamma. Planta Med. 2006, 72, 881–887. [Google Scholar] [CrossRef] [PubMed]
- Cullinan, S.B.; Zhang, D.; Hannink, M.; Arvisais, E.; Kaufman, R.J.; Diehl, J.A. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol. Cell. Biol. 2003, 23, 7198–7209. [Google Scholar] [CrossRef] [PubMed]
- Sidrauski, C.; Tsai, J.C.; Kampmann, M.; Hearn, B.R.; Vedantham, P.; Jaishankar, P.; Sokabe, M.; Mendez, A.S.; Newton, B.W.; Tang, E.L.; et al. Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. eLife 2015, 4, e07314. [Google Scholar] [CrossRef] [PubMed]
- Scheuner, D.; Song, B.; McEwen, E.; Liu, C.; Laybutt, R.; Gillespie, P.; Saunders, T.; Bonner-Weir, S.; Kaufman, R.J. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell 2001, 7, 1165–1176. [Google Scholar] [CrossRef]
- Donnelly, N.; Gorman, A.M.; Gupta, S.; Samali, A. The eIF2α kinases: their structures and functions. Cell. Mol. Life Sci. CMLS 2013, 70, 3493–3511. [Google Scholar] [CrossRef] [PubMed]
- Min, K.-J.; Jung, K.-J.; Kwon, T.K. Carnosic Acid Induces Apoptosis Through Reactive Oxygen Species-mediated Endoplasmic Reticulum Stress Induction in Human Renal Carcinoma Caki Cells. J. Cancer Prev. 2014, 19, 170–178. [Google Scholar] [CrossRef] [PubMed]
- Pirola, L.; Fröjdö, S. Resveratrol: one molecule, many targets. IUBMB Life 2008, 60, 323–332. [Google Scholar] [CrossRef]
- Yu, Y.-M.; Lin, C.-H.; Chan, H.-C.; Tsai, H.-D. Carnosic acid reduces cytokine-induced adhesion molecules expression and monocyte adhesion to endothelial cells. Eur. J. Nutr. 2009, 48, 101–106. [Google Scholar] [CrossRef]
- López-Jiménez, A.; García-Caballero, M.; Medina, M.Á.; Quesada, A.R. Anti-angiogenic properties of carnosol and carnosic acid, two major dietary compounds from rosemary. Eur. J. Nutr. 2013, 52, 85–95. [Google Scholar] [CrossRef]
- Hai, T.; Hartman, M.G. The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: Activating transcription factor proteins and homeostasis. Gene 2001, 273, 1–11. [Google Scholar] [CrossRef]
- Huggins, C.J.; Mayekar, M.K.; Martin, N.; Saylor, K.L.; Gonit, M.; Jailwala, P.; Kasoji, M.; Haines, D.C.; Quiñones, O.A.; Johnson, P.F. C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4. Mol. Cell. Biol. 2015, 36, 693–713. [Google Scholar] [CrossRef]
- Quirós, P.M.; Prado, M.A.; Zamboni, N.; D’Amico, D.; Williams, R.W.; Finley, D.; Gygi, S.P.; Auwerx, J. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J. Cell Biol. 2017, 216, 2027–2045. [Google Scholar] [CrossRef] [PubMed]
- B’chir, W.; Maurin, A.-C.; Carraro, V.; Averous, J.; Jousse, C.; Muranishi, Y.; Parry, L.; Stepien, G.; Fafournoux, P.; Bruhat, A. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 2013, 41, 7683–7699. [Google Scholar] [CrossRef] [PubMed]
- Jain, A.; Lamark, T.; Sjøttem, E.; Larsen, K.B.; Awuh, J.A.; Øvervatn, A.; McMahon, M.; Hayes, J.D.; Johansen, T. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J. Biol. Chem. 2010, 285, 22576–22591. [Google Scholar] [CrossRef] [PubMed]
- Sasaki, H.; Sato, H.; Kuriyama-Matsumura, K.; Sato, K.; Maebara, K.; Wang, H.; Tamba, M.; Itoh, K.; Yamamoto, M.; Bannai, S. Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. J. Biol. Chem. 2002, 277, 44765–44771. [Google Scholar] [CrossRef] [PubMed]
- Sato, H.; Nomura, S.; Maebara, K.; Sato, K.; Tamba, M.; Bannai, S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. Biochem. Biophys. Res. Commun. 2004, 325, 109–116. [Google Scholar] [CrossRef]
- Lee, J.-I.; Dominy, J.E.; Sikalidis, A.K.; Hirschberger, L.L.; Wang, W.; Stipanuk, M.H. HepG2/C3A cells respond to cysteine deprivation by induction of the amino acid deprivation/integrated stress response pathway. Physiol. Genom. 2008, 33, 218–229. [Google Scholar] [CrossRef] [PubMed]
- Rössler, O.G.; Thiel, G. Specificity of Stress-Responsive Transcription Factors Nrf2, ATF4, and AP-1. J. Cell. Biochem. 2017, 118, 127–140. [Google Scholar] [CrossRef] [PubMed]
- Dey, S.; Sayers, C.M.; Verginadis, I.I.; Lehman, S.L.; Cheng, Y.; Cerniglia, G.J.; Tuttle, S.W.; Feldman, M.D.; Zhang, P.J.L.; Fuchs, S.Y.; et al. ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. J. Clin. Investig. 2015, 125, 2592–2608. [Google Scholar] [CrossRef] [PubMed]
- Komatsu, M.; Kurokawa, H.; Waguri, S.; Taguchi, K.; Kobayashi, A.; Ichimura, Y.; Sou, Y.-S.; Ueno, I.; Sakamoto, A.; Tong, K.I.; et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 2010, 12, 213–223. [Google Scholar] [CrossRef]
- Afonyushkin, T.; Oskolkova, O.V.; Philippova, M.; Resink, T.J.; Erne, P.; Binder, B.R.; Bochkov, V.N. Oxidized phospholipids regulate expression of ATF4 and VEGF in endothelial cells via NRF2-dependent mechanism: novel point of convergence between electrophilic and unfolded protein stress pathways. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 1007–1013. [Google Scholar] [CrossRef] [PubMed]
- Miyamoto, N.; Izumi, H.; Miyamoto, R.; Bin, H.; Kondo, H.; Tawara, A.; Sasaguri, Y.; Kohno, K. Transcriptional regulation of activating transcription factor 4 under oxidative stress in retinal pigment epithelial ARPE-19/HPV-16 cells. Investig. Ophthalmol. Vis. Sci. 2011, 52, 1226–1234. [Google Scholar] [CrossRef] [PubMed]
- Ehren, J.L.; Maher, P. Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. Biochem. Pharmacol. 2013, 85, 1816–1826. [Google Scholar] [CrossRef]
- Crawford, R.R.; Prescott, E.T.; Sylvester, C.F.; Higdon, A.N.; Shan, J.; Kilberg, M.S.; Mungrue, I.N. Human CHAC1 Protein Degrades Glutathione, and mRNA Induction Is Regulated by the Transcription Factors ATF4 and ATF3 and a Bipartite ATF/CRE Regulatory Element. J. Biol. Chem. 2015, 290, 15878–15891. [Google Scholar] [CrossRef] [PubMed]
- Inoue, Y.; Hara, H.; Mitsugi, Y.; Yamaguchi, E.; Kamiya, T.; Itoh, A.; Adachi, T. 4-Hydroperoxy-2-decenoic acid ethyl ester protects against 6-hydroxydopamine-induced cell death via activation of Nrf2-ARE and eIF2α-ATF4 pathways. Neurochem. Int. 2018, 112, 288–296. [Google Scholar] [CrossRef]
- Taniuchi, S.; Miyake, M.; Tsugawa, K.; Oyadomari, M.; Oyadomari, S. Integrated stress response of vertebrates is regulated by four eIF2α kinases. Sci. Rep. 2016, 6, 32886. [Google Scholar] [CrossRef] [PubMed]
- Bauer, B.N.; Rafie-Kolpin, M.; Lu, L.; Han, A.; Chen, J.J. Multiple autophosphorylation is essential for the formation of the active and stable homodimer of heme-regulated eIF2alpha kinase. Biochemistry 2001, 40, 11543–11551. [Google Scholar] [CrossRef]
- Lu, L.; Han, A.P.; Chen, J.J. Translation initiation control by heme-regulated eukaryotic initiation factor 2alpha kinase in erythroid cells under cytoplasmic stresses. Mol. Cell. Biol. 2001, 21, 7971–7980. [Google Scholar] [CrossRef]
- McEwen, E.; Kedersha, N.; Song, B.; Scheuner, D.; Gilks, N.; Han, A.; Chen, J.-J.; Anderson, P.; Kaufman, R.J. Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure. J. Biol. Chem. 2005, 280, 16925–16933. [Google Scholar] [CrossRef]
- Suragani, R.N.V.S.; Zachariah, R.S.; Velazquez, J.G.; Liu, S.; Sun, C.-W.; Townes, T.M.; Chen, J.-J. Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis. Blood 2012, 119, 5276–5284. [Google Scholar] [CrossRef]
- Wang, L.; Wang, X.; Zhang, S.; Qu, G.; Liu, S. A protective role of heme-regulated eIF2α kinase in cadmium-induced toxicity in erythroid cells. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2013, 62, 880–891. [Google Scholar] [CrossRef] [PubMed]
- Hirai, K.; Martinkova, M.; Igarashi, J.; Saiful, I.; Yamauchi, S.; El-Mashtoly, S.; Kitagawa, T.; Shimizu, T. Identification of Cys385 in the isolated kinase insertion domain of heme-regulated eIF2 alpha kinase (HRI) as the heme axial ligand by site-directed mutagenesis and spectral characterization. J. Inorg. Biochem. 2007, 101, 1172–1179. [Google Scholar] [CrossRef] [PubMed]
- Igarashi, J.; Murase, M.; Iizuka, A.; Pichierri, F.; Martinkova, M.; Shimizu, T. Elucidation of the heme binding site of heme-regulated eukaryotic initiation factor 2alpha kinase and the role of the regulatory motif in heme sensing by spectroscopic and catalytic studies of mutant proteins. J. Biol. Chem. 2008, 283, 18782–18791. [Google Scholar] [CrossRef] [PubMed]
- Thulasiraman, V.; Xu, Z.; Uma, S.; Gu, Y.; Chen, J.J.; Matts, R.L. Evidence that Hsc70 negatively modulates the activation of the heme-regulated eIF-2alpha kinase in rabbit reticulocyte lysate. Eur. J. Biochem. 1998, 255, 552–562. [Google Scholar] [CrossRef] [PubMed]
- Wehner, K.A.; Schütz, S.; Sarnow, P. OGFOD1, a novel modulator of eukaryotic translation initiation factor 2alpha phosphorylation and the cellular response to stress. Mol. Cell. Biol. 2010, 30, 2006–2016. [Google Scholar] [CrossRef]
- Ben-Sahra, I.; Hoxhaj, G.; Ricoult, S.J.H.; Asara, J.M.; Manning, B.D. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 2016, 351, 728–733. [Google Scholar] [CrossRef] [PubMed]
- Cho, H.; Wu, M.; Zhang, L.; Thompson, R.; Nath, A.; Chan, C. Signaling dynamics of palmitate-induced ER stress responses mediated by ATF4 in HepG2 cells. BMC Syst. Biol. 2013, 7, 9. [Google Scholar] [CrossRef]
- Jin, H.-O.; Seo, S.-K.; Woo, S.-H.; Choe, T.-B.; Hong, S.-I.; Kim, J.-I.; Park, I.-C. Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4. IUBMB Life 2009, 61, 1153–1158. [Google Scholar] [CrossRef]
- Kasai, S.; Yamazaki, H.; Tanji, K.; Engler, M.J.; Matsumiya, T.; Itoh, K. Role of the ISR-ATF4 pathway and its cross talk with Nrf2 in mitochondrial quality control. J. Clin. Biochem. Nutr. 2019, 64, 1–12. [Google Scholar] [CrossRef]
- Cattaneo, A.; Calissano, P. Nerve growth factor and Alzheimer’s disease: new facts for an old hypothesis. Mol. Neurobiol. 2012, 46, 588–604. [Google Scholar] [CrossRef]
- Zong, Z.-H.; Du, Z.-X.; Li, N.; Li, C.; Zhang, Q.; Liu, B.-Q.; Guan, Y.; Wang, H.-Q. Implication of Nrf2 and ATF4 in differential induction of CHOP by proteasome inhibition in thyroid cancer cells. Biochim. Biophys. Acta 2012, 1823, 1395–1404. [Google Scholar] [CrossRef] [PubMed]
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Mimura, J.; Inose-Maruyama, A.; Taniuchi, S.; Kosaka, K.; Yoshida, H.; Yamazaki, H.; Kasai, S.; Harada, N.; Kaufman, R.J.; Oyadomari, S.; et al. Concomitant Nrf2- and ATF4-Activation by Carnosic Acid Cooperatively Induces Expression of Cytoprotective Genes. Int. J. Mol. Sci. 2019, 20, 1706. https://doi.org/10.3390/ijms20071706
Mimura J, Inose-Maruyama A, Taniuchi S, Kosaka K, Yoshida H, Yamazaki H, Kasai S, Harada N, Kaufman RJ, Oyadomari S, et al. Concomitant Nrf2- and ATF4-Activation by Carnosic Acid Cooperatively Induces Expression of Cytoprotective Genes. International Journal of Molecular Sciences. 2019; 20(7):1706. https://doi.org/10.3390/ijms20071706
Chicago/Turabian StyleMimura, Junsei, Atsushi Inose-Maruyama, Shusuke Taniuchi, Kunio Kosaka, Hidemi Yoshida, Hiromi Yamazaki, Shuya Kasai, Nobuhiko Harada, Randal J. Kaufman, Seiichi Oyadomari, and et al. 2019. "Concomitant Nrf2- and ATF4-Activation by Carnosic Acid Cooperatively Induces Expression of Cytoprotective Genes" International Journal of Molecular Sciences 20, no. 7: 1706. https://doi.org/10.3390/ijms20071706