Enhanced fatty acid oxidation through metformin and baicalin as therapy for COVID-19 and associated inflammatory states in lung and kidney
Verónica Miguel, Carlos Rey-Serra, Jessica Tituaña, Belén Sirera, Elena Alcalde-Estévez, J Ignacio Herrero, Irene Ranz, Laura Fernández, Carolina Castillo, Lucía Sevilla, James Nagai, Katharina C Reimer, Jitske Jansen, Rafael Kramann, Ivan G Costa, Ana Castro, David Sancho, José Miguel Rodríguez González-Moro, Santiago Lamas
Redox Biology, doi:10.1016/j.redox.2023.102957
Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. It is the final outcome of the acute respiratory distress syndrome (ARDS), characterized by an initial exacerbated inflammatory response, metabolic derangement and ultimate tissue scarring. A positive balance of cellular energy may result crucial for the recovery of clinical COVID-19. Hence, we asked if two key pathways involved in cellular energy generation, AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling and fatty acid oxidation (FAO) could be beneficial. We tested the drugs metformin (AMPK activator) and baicalin (CPT1A activator) in different experimental models mimicking COVID-19 associated inflammation in lung and kidney. We also studied two different cohorts of COVID-19 patients that had been previously treated with metformin. These drugs ameliorated lung damage in an ARDS animal model, while activation of AMPK/ ACC signaling increased mitochondrial function and decreased TGF-β-induced fibrosis, apoptosis and inflammation markers in lung epithelial cells. Similar results were observed with two indole derivatives, IND6 and IND8 with AMPK activating capacity. Consistently, a reduced time of hospitalization and need of intensive care was observed in COVID-19 patients previously exposed to metformin. Baicalin also mitigated the activation of pro-inflammatory bone marrow-derived macrophages (BMDMs) and reduced kidney fibrosis in two animal models of kidney injury, another key target of COVID-19. In human epithelial lung and kidney cells, both drugs improved mitochondrial function and prevented TGF-β-induced renal epithelial cell dedifferentiation. Our results support that favoring cellular energy production through enhanced FAO may prove useful in the prevention of COVID-19-induced lung and renal damage.
Author contributions SL conceived and directed research. VM designed, performed and analyzed the majority of experiments. CRS, JT, BS, EA, IR and LF performed experiments. JIH provided technical assistance for mouse experiments. CC performed histological evaluation. KCR, JJ, RK and DS provided intellectual insight and resources. LS and JMRGM collected information about COVID-19 patient cohorts. JN and IC performed bioinformatic studies. AC provided indol-based compounds. All authors helped with the discussion of the results and SL and VM wrote the manuscript.
Declaration of competing interest The authors have no conflicts of interest.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.redox.2023.102957.
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