Scutellarein alleviates chronic obstructive pulmonary disease through inhibition of ferroptosis by chelating iron and interacting with arachidonate 15-lipoxygenase.
ALOX15
HO-1
chronic obstructive pulmonary disease
ferroptosis
iron chelation
scutellarein
Journal
Phytotherapy research : PTR
ISSN: 1099-1573
Titre abrégé: Phytother Res
Pays: England
ID NLM: 8904486
Informations de publication
Date de publication:
Oct 2023
Oct 2023
Historique:
revised:
16
05
2023
received:
18
01
2023
accepted:
12
06
2023
pubmed:
24
6
2023
medline:
24
6
2023
entrez:
24
6
2023
Statut:
ppublish
Résumé
Ferroptosis, an iron-dependent cell death characterized by lethal lipid peroxidation, is involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Therefore, ferroptosis inhibition represents an attractive strategy for COPD therapy. Herein, we identified natural flavonoid scutellarein as a potent ferroptosis inhibitor for the first time, and characterized its underlying mechanisms for inhibition of ferroptosis and COPD. In vitro, the anti-ferroptotic activity of scutellarein was investigated through CCK8, real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting, flow cytometry, and transmission electron microscope (TEM). In vivo, COPD was induced by lipopolysaccharide (LPS)/cigarette smoke (CS) and assessed by changes in histopathological, inflammatory, and ferroptotic markers. The mechanisms were investigated by RNA-sequencing (RNA-seq), electrospray ionization mass spectra (ESI-MS), local surface plasmon resonance (LSPR), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and molecular dynamics. Our results showed that scutellarein significantly inhibited Ras-selective lethal small molecule (RSL)-3-induced ferroptosis and mitochondria injury in BEAS-2B cells, and ameliorated LPS/CS-induced COPD in mice. Furthermore, scutellarein also repressed RSL-3- or LPS/CS-induced lipid peroxidation, GPX4 down-regulation, and overactivation of Nrf2/HO-1 and JNK/p38 pathways. Mechanistically, scutellarein inhibited RSL-3- or LPS/CS-induced Fe
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4587-4606Subventions
Organisme : National Natural Science Foundation of China
ID : 82004065
Informations de copyright
© 2023 John Wiley & Sons Ltd.
Références
Agusti, A., Fabbri, L. M., Singh, D., Vestbo, J., Celli, B., Franssen, F. M. E., Rabe, K. F., & Papi, A. (2018). Inhaled corticosteroids in COPD: Friend or foe? The European Respiratory Journal, 52, 1801219.
Anand, U., Jacobo-Herrera, N., Altemimi, A., & Lakhssassi, N. (2019). A comprehensive review on medicinal plants as antimicrobial therapeutics: Potential avenues of biocompatible drug discovery. Metabolites, 9, 258.
Anand, U., Tudu, C. K., Nandy, S., Sunita, K., Tripathi, V., Loake, G. J., Dey, A., & Proćków, J. (2022). Ethnodermatological use of medicinal plants in India: From ayurvedic formulations to clinical perspectives-A review. Journal of Ethnopharmacology, 284, 114744.
Barnes, P. J. (2020). Oxidative stress-based therapeutics in COPD. Redox Biology, 33, 101544.
Campbell, N. K., Fitzgerald, H. K., & Dunne, A. (2021). Regulation of inflammation by the antioxidant haem oxygenase 1. Nature Reviews. Immunology, 21, 411-425.
Chang, L. C., Chiang, S. K., Chen, S. E., Yu, Y. L., Chou, R. H., & Chang, W. C. (2018). Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis. Cancer Letters, 416, 124-137.
Chen, H., Wang, L., Gong, T., Yu, Y., Zhu, C., Li, F., Wang, L., & Li, C. (2010). EGR-1 regulates Ho-1 expression induced by cigarette smoke. Biochemical and Biophysical Research Communications, 396, 388-393.
Chen, Q. M. (2022). Nrf 2 for protection against oxidant generation and mitochondrial damage in cardiac injury. Free Radical Biology & Medicine, 179, 133-143.
Chen, Y., Fang, Z. M., Yi, X., Wei, X., & Jiang, D. S. (2023). The interaction between ferroptosis and inflammatory signaling pathways. Cell Death & Disease, 14, 205.
Chillappagari, S., Belapurkar, R., Moller, A., Molenda, N., Kracht, M., Rohrbach, S., & Schmitz, M. L. (2020). SIAH2-mediated and organ-specific restriction of HO-1 expression by a dual mechanism. Scientific Reports, 10, 2268.
Cloonan, S. M., Glass, K., Laucho-Contreras, M. E., Bhashyam, A. R., Cervo, M., Pabón, M. A., Konrad, C., Polverino, F., Siempos, I. I., Perez, E., Mizumura, K., Ghosh, M. C., Parameswaran, H., Williams, N. C., Rooney, K. T., Chen, Z. H., Goldklang, M. P., Yuan, G. C., Moore, S. C., … Choi, A. M. (2016). Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nature Medicine, 22, 163-174.
Deng, M., Sun, J., Peng, L., Huang, Y., Jiang, W., Wu, S., Zhou, L., Chung, S. K., & Cheng, X. (2022). Scutellarin acts on the AR-NOX axis to remediate oxidative stress injury in a mouse model of cerebral ischemia/reperfusion injury. Phytomedicine, 103, 154214.
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., Morrison, B., & Stockwell, B. R. (2012). Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 149, 1060-1072.
Dixon, S. J., & Stockwell, B. R. (2019). The hallmarks of ferroptosis. Annual Review of Cancer Biology, 3, 35-54.
Dodson, M., Castro-Portuguez, R., & Zhang, D. D. (2019). NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biology, 23, 101107.
Eleftheriadis, N., Thee, S. A., Zwinderman, M. R. H., Leus, N. G. J., & Dekker, F. J. (2016). Activity-based probes for 15-lipoxygenase-1. Angewandte Chemie (International Ed. in English), 55, 12300-12305.
Fang, X., Wang, H., Han, D., Xie, E., Yang, X., Wei, J., Gu, S., Gao, F., Zhu, N., Yin, X., Cheng, Q., Zhang, P., Dai, W., Chen, J., Yang, F., Yang, H. T., Linkermann, A., Gu, W., Min, J., & Wang, F. (2019). Ferroptosis as a target for protection against cardiomyopathy. Proceedings of the National Academy of Sciences, 116, 2672-2680.
Fu, Y. S., Kang, N., Yu, Y., Mi, Y., Guo, J., Wu, J., & Weng, C. F. (2022). Polyphenols, flavonoids and inflammasomes: The role of cigarette smoke in COPD. European Respiratory Review, 31, 220028.
Garcia, S. C., Grotto, D., Bulcao, R. P., Moro, A. M., Roehrs, M., Valentini, J., de Freitas, F. A., Paniz, C., Bubols, G. B., & Charão, M. F. (2013). Evaluation of lipid damage related to pathological and physiological conditions. Drug and Chemical Toxicology, 36, 306-312.
Halder, S., Anand, U., Nandy, S., Oleksak, P., Qusti, S., Alshammari, E. M., El-Saber Batiha, G., Koshy, E. P., & Dey, A. (2021). Herbal drugs and natural bioactive products as potential therapeutics: A review on pro-cognitives and brain boosters perspectives. Saudi Pharmaceutical Journal, 29, 879-907.
Hassannia, B., Wiernicki, B., Ingold, I., Qu, F., van Herck, S., Tyurina, Y. Y., Bayır, H., Abhari, B. A., Angeli, J. P. F., Choi, S. M., Meul, E., Heyninck, K., Declerck, K., Chirumamilla, C. S., Lahtela-Kakkonen, M., van Camp, G., Krysko, D. V., Ekert, P. G., Fulda, S., … vanden Berghe, T. (2018). Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. The Journal of Clinical Investigation, 128, 3341-3355.
He, S., Tian, R., Zhang, X., Yao, Q., Chen, Q., Liu, B., Liao, L., Gong, Y., Yang, H., & Wang, D. (2023). PPARγ inhibits small airway remodeling through mediating the polarization homeostasis of alveolar macrophages in COPD. Clinical Immunology, 250, 109293.
Hoffmann, R. F., Zarrintan, S., Brandenburg, S. M., Kol, A., de Bruin, H. G., Jafari, S., Dijk, F., Kalicharan, D., Kelders, M., Gosker, H. R., Ten Hacken, N. H., van der Want, J. J., van Oosterhout, A. J., & Heijink, I. H. (2013). Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells. Respiratory Research, 14, 97.
Ivanov, I., Kuhn, H., & Heydeck, D. (2015). Structural and functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15). Gene, 573, 1-32.
Jensen, E. C. (2013). Quantitative analysis of histological staining and fluorescence using imageJ. The Anatomical Record (Hoboken), 296, 378-381.
Jiang, D. P., Li, Q., Yang, J., Perelman, J. M., Kolosov, V. P., & Zhou, X. D. (2011). Scutellarin attenuates human-neutrophil-elastase-induced mucus production by inhibiting the PKC-ERK signaling pathway in vitro and in vivo. The American Journal of Chinese Medicine, 39, 1193-1206.
Kopacz, A., Kloska, D., Forman, H. J., Jozkowicz, A., & Grochot-Przeczek, A. (2020). Beyond repression of Nrf 2: An update on Keap 1. Free Radical Biology & Medicine, 157, 63-74.
Latunde-Dada, G. O. (2017). Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy. Biochimica et Biophysica Acta - General Subjects, 1861, 1893-1900.
Lei, P., Bai, T., & Sun, Y. (2019). Mechanisms of ferroptosis and relations with regulated cell death: A review. Frontiers in Physiology, 10, 139.
Li, J., Cao, F., Yin, H. L., Huang, Z. J., Lin, Z. T., Mao, N., Sun, B., & Wang, G. (2020). Ferroptosis: Past, present and future. Cell Death & Disease, 11, 88.
Li, Y., Xia, J., Shao, F., Zhou, Y., Yu, J., Wu, H., Du, J., & Ren, X. (2021). Sorafenib induces mitochondrial dysfunction and exhibits synergistic effect with cysteine depletion by promoting HCC cells ferroptosis. Biochemical and Biophysical Research Communications, 534, 877-884.
Li, Y., Yang, Y., & Yang, Y. (2022). Multifaceted roles of ferroptosis in lung diseases. Frontiers in Molecular Biosciences, 9, 919187.
Lian, N., Zhang, Q., Chen, J., Chen, M., Huang, J., & Lin, Q. (2021). The role of ferroptosis in bronchoalveolar epithelial cell injury induced by cigarette smoke extract. Frontiers in Physiology, 12, 751206.
Lin, Z., Liu, J., Kang, R., Yang, M., & Tang, D. (2021). Lipid metabolism in ferroptosis. Advanced Biology (Weinh), 5, e2100396.
Liu, X., Ma, Y., Luo, L., Zong, D., Li, H., Zeng, Z., Cui, Y., Meng, W., & Chen, Y. (2022). Dihydroquercetin suppresses cigarette smoke induced ferroptosis in the pathogenesis of chronic obstructive pulmonary disease by activating Nrf 2-mediated pathway. Phytomedicine, 96, 153894.
Lu, B., Chen, X. B., Hong, Y. C., Zhu, H., He, Q. J., Yang, B., Ying, M. D., & Cao, J. (2019). Identification of PRDX6 as a regulator of ferroptosis. Acta Pharmacologica Sinica, 40, 1334-1342.
Lyu, J., Xie, Y., Sun, M., & Zhang, L. (2020). Clinical evidence and GRADE assessment for breviscapine injection (Deng Zhan HuaSu) in patients with acute cerebral infarction. Journal of Ethnopharmacology, 262, 113137.
McCubrey, J. A., Lahair, M. M., & Franklin, R. A. (2006). Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxidants & Redox Signaling, 8, 1775-1789.
Meng, H., Dai, Z., Zhang, W., Liu, Y., & Lai, L. (2018). Molecular mechanism of 15-lipoxygenase allosteric activation and inhibition. Physical Chemistry Chemical Physics, 20, 14785-14795.
Minagawa, S., Yoshida, M., Araya, J., Hara, H., Imai, H., & Kuwano, K. (2020). Regulated necrosis in pulmonary disease. A focus on necroptosis and ferroptosis. American Journal of Respiratory Cell and Molecular Biology, 62, 554-562.
Mirza, S., Clay, R. D., Koslow, M. A., & Scanlon, P. D. (2018). COPD guidelines: A review of the 2018 GOLD report. Mayo Clinic Proceedings, 93, 1488-1502.
Mitra, S., Anand, U., Ghorai, M., Vellingiri, B., Jha, N. K., Behl, T., Kumar, M., Shekhawat, M. S., Proćków, J., & Dey, A. (2022). Unravelling the therapeutic potential of botanicals against chronic obstructive pulmonary disease (COPD): Molecular insights and future perspectives. Frontiers in Pharmacology, 13, 824132.
Mladěnka, P., Macáková, K., Filipský, T., Zatloukalová, L., Jahodář, L., Bovicelli, P., Silvestri, I. P., Hrdina, R., & Saso, L. (2011). In vitro analysis of iron chelating activity of flavonoids. Journal of Inorganic Biochemistry, 105, 693-701.
Nakamura, T., Naguro, I., & Ichijo, H. (2019). Iron homeostasis and iron-regulated ROS in cell death, senescence and human diseases. Biochimica et Biophysica Acta - General Subjects, 1863, 1398-1409.
Newman, D. J., & Cragg, G. M. (2020). Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. Journal of Natural Products, 83, 770-803.
Ren, Q., Li, X., Li, Q., Yang, H., Wang, H., Zhang, H., Zhao, L., Jiang-Yong, S. L., Meng, X., Zhang, Y., & Shen, X. (2019). Total flavonoids from sea buckthorn ameliorates lipopolysaccharide/cigarette smoke-induced airway inflammation. Phytotherapy Research, 33, 2102-2117.
Seiler, A., Schneider, M., Förster, H., Roth, S., Wirth, E. K., Culmsee, C., Plesnila, N., Kremmer, E., Rådmark, O., Wurst, W., Bornkamm, G. W., Schweizer, U., & Conrad, M. (2008). Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metabolism, 8, 237-248.
Shintoku, R., Takigawa, Y., Yamada, K., Kubota, C., Yoshimoto, Y., Takeuchi, T., Koshiishi, I., & Torii, S. (2017). Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3. Cancer Science, 108, 2187-2194.
Sihvola, V., & Levonen, A. L. (2017). Keap 1 as the redox sensor of the antioxidant response. Archives of Biochemistry and Biophysics, 617, 94-100.
Stoyanovsky, D. A., Tyurina, Y. Y., Shrivastava, I., Bahar, I., Tyurin, V. A., Protchenko, O., Jadhav, S., Bolevich, S. B., Kozlov, A. V., Vladimirov, Y. A., Shvedova, A. A., Philpott, C. C., Bayir, H., & Kagan, V. E. (2019). Iron catalysis of lipid peroxidation in ferroptosis: Regulated enzymatic or random free radical reaction? Free Radical Biology & Medicine, 133, 153-161.
Sun, Y., Chen, P., Zhai, B., Zhang, M., Xiang, Y., Fang, J., Xu, S., Gao, Y., Chen, X., Sui, X., & Li, G. (2020). The emerging role of ferroptosis in inflammation. Biomedicine & Pharmacotherapy, 127, 110108.
Tang, H., Tang, Y., Li, N., Shi, Q., Guo, J., Shang, E., & Duan, J. A. (2014). Neuroprotective effects of scutellarin and scutellarein on repeatedly cerebral ischemia-reperfusion in rats. Pharmacology, Biochemistry, and Behavior, 118, 51-59.
Tang, Z., Ju, Y., Dai, X., Ni, N., Liu, Y., Zhang, D., Gao, H., Sun, H., Zhang, J., & Gu, P. (2021). HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration. Redox Biology, 43, 101971.
Wang, C., Zhou, J., Wang, J., Li, S., Fukunaga, A., Yodoi, J., & Tian, H. (2020). Progress in the mechanism and targeted drug therapy for COPD. Signal Transduction and Targeted Therapy, 5, 248.
Wang, H., Liu, C., Zhao, Y., & Gao, G. (2020). Mitochondria regulation in ferroptosis. European Journal of Cell Biology, 99, 151058.
Wang, L., & Ma, Q. (2018). Clinical benefits and pharmacology of scutellarin: A comprehensive review. Pharmacology & Therapeutics, 190, 105-127.
Wang, L., Zhang, Y., Johnpaul, I. A., Hong, K., Song, Y., Yang, X., Lv, C., & Ma, C. (2022). Exploring two types of prenylated bitter compounds from hop plant (Humulus lupulus L.) against α-glucosidase in vitro and in silico. Food Chemistry, 370, 130979.
Wang, Y., Liao, S., Pan, Z., Jiang, S., Fan, J., Yu, S., Xue, L., Yang, J., Ma, S., Liu, T., Zhang, J., & Chen, Y. (2022). Hydrogen sulfide alleviates particulate matter-induced emphysema and airway inflammation by suppressing ferroptosis. Free Radical Biology & Medicine, 186, 1-16.
Wang, Z., Yu, J., Wu, J., Qi, F., Wang, H., Wang, Z., & Xu, Z. (2016). Scutellarin protects cardiomyocyte ischemia-reperfusion injury by reducing apoptosis and oxidative stress. Life Sciences, 157, 200-207.
Xu, X., Li, J., Zhang, Y., & Zhang, L. (2021). Arachidonic acid 15-lipoxygenase: Effects of its expression, metabolites, and genetic and epigenetic variations on airway inflammation. Allergy, Asthma & Immunology Research, 13, 684-696.
Yan, H. F., Tuo, Q. Z., Yin, Q. Z., & Lei, P. (2020). The pathological role of ferroptosis in ischemia/reperfusion-related injury. Zoological Research, 41, 220-230.
Yan, H. F., Zou, T., Tuo, Q. Z., Xu, S., Li, H., Belaidi, A. A., & Lei, P. (2021). Ferroptosis: Mechanisms and links with diseases. Signal Transduction and Targeted Therapy, 6, 49.
Yang, L., Cao, L. M., Zhang, X. J., & Chu, B. (2022). Targeting ferroptosis as a vulnerability in pulmonary diseases. Cell Death & Disease, 13, 649.
Yang, W. S., Kim, K. J., Gaschler, M. M., Patel, M., Shchepinov, M. S., & Stockwell, B. R. (2016). Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proceedings of the National Academy of Sciences, 113, E4966-E4975.
Yang, W. S., Ramaratnam, R., Welsch, M. E., Shimada, K., Skouta, R., Viswanathan, V. S., Cheah, J. H., Clemons, P. A., Shamji, A. F., Clish, C. B., Brown, L. M., Girotti, A. W., Cornish, V. W., Schreiber, S. L., & Stockwell, B. R. (2014). Regulation of ferroptotic cancer cell death by GPX4. Cell, 156, 317-331.
Yoshida, M., Minagawa, S., Araya, J., Sakamoto, T., Hara, H., Tsubouchi, K., Hosaka, Y., Ichikawa, A., Saito, N., Kadota, T., Sato, N., Kurita, Y., Kobayashi, K., Ito, S., Utsumi, H., Wakui, H., Numata, T., Kaneko, Y., Mori, S., … Kuwano, K. (2019). Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis. Nature Communications, 10, 3145.
Zhang, W. Z., Butler, J. J., & Cloonan, S. M. (2019). Smoking-induced iron dysregulation in the lung. Free Radical Biology & Medicine, 133, 238-247.
Zheng, K., Dong, Y., Yang, R., Liang, Y., Wu, H., & He, Z. (2021). Regulation of ferroptosis by bioactive phytochemicals: Implications for medical nutritional therapy. Pharmacological Research, 168, 105580.