PMID- 37977043
OWN - NLM
STAT- MEDLINE
DCOM- 20231206
LR  - 20231217
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 68
DP  - 2023 Dec
TI  - Enhanced fatty acid oxidation through metformin and baicalin as therapy for 
      COVID-19 and associated inflammatory states in lung and kidney.
PG  - 102957
LID - S2213-2317(23)00358-0 [pii]
LID - 10.1016/j.redox.2023.102957 [doi]
LID - 102957
AB  - 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-beta-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-beta-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.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Miguel, Veronica
AU  - Miguel V
AD  - Program of Physiological and Pathological Processes, Centro de Biologia Molecular 
      "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain; Centro Nacional de 
      Investigaciones Cardiovasculares Carlos III (CNIC), 28029, Madrid, Spain. 
      Electronic address: veronica.miguel@cnic.es.
FAU - Rey-Serra, Carlos
AU  - Rey-Serra C
AD  - Program of Physiological and Pathological Processes, Centro de Biologia Molecular 
      "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain.
FAU - Tituana, Jessica
AU  - Tituana J
AD  - Program of Physiological and Pathological Processes, Centro de Biologia Molecular 
      "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain.
FAU - Sirera, Belen
AU  - Sirera B
AD  - Program of Physiological and Pathological Processes, Centro de Biologia Molecular 
      "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain.
FAU - Alcalde-Estevez, Elena
AU  - Alcalde-Estevez E
AD  - Program of Physiological and Pathological Processes, Centro de Biologia Molecular 
      "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain.
FAU - Herrero, J Ignacio
AU  - Herrero JI
AD  - Program of Physiological and Pathological Processes, Centro de Biologia Molecular 
      "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain.
FAU - Ranz, Irene
AU  - Ranz I
AD  - Program of Physiological and Pathological Processes, Centro de Biologia Molecular 
      "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain.
FAU - Fernandez, Laura
AU  - Fernandez L
AD  - Program of Physiological and Pathological Processes, Centro de Biologia Molecular 
      "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain.
FAU - Castillo, Carolina
AU  - Castillo C
AD  - Department of Pathology. University Hospital "Principe de Asturias", Alcala de 
      Henares, Madrid, Spain.
FAU - Sevilla, Lucia
AU  - Sevilla L
AD  - Department of Pneumology, University Hospital "Principe de Asturias", Alcala de 
      Henares, Madrid, Spain.
FAU - Nagai, James
AU  - Nagai J
AD  - Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, 
      Germany; Joint Research Center for Computational Biomedicine, RWTH Aachen 
      University Hospital, Aachen, Germany.
FAU - Reimer, Katharina C
AU  - Reimer KC
AD  - Department of Medicine 2, Nephrology, Rheumatology and Immunology, RWTH Aachen 
      University, Medical Faculty, Aachen, Germany; Institute for Biomedical 
      Technologies, Department of Cell Biology, RWTH Aachen University, Aachen, 
      Germany.
FAU - Jansen, Jitske
AU  - Jansen J
AD  - Department of Medicine 2, Nephrology, Rheumatology and Immunology, RWTH Aachen 
      University, Medical Faculty, Aachen, Germany; Department of Pathology, Radboud 
      Institute for Molecular Life Sciences, Radboud University Medical Center, 
      Nijmegen, the Netherlands.
FAU - Kramann, Rafael
AU  - Kramann R
AD  - Department of Medicine 2, Nephrology, Rheumatology and Immunology, RWTH Aachen 
      University, Medical Faculty, Aachen, Germany.
FAU - Costa, Ivan G
AU  - Costa IG
AD  - Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, 
      Germany; Joint Research Center for Computational Biomedicine, RWTH Aachen 
      University Hospital, Aachen, Germany.
FAU - Castro, Ana
AU  - Castro A
AD  - Instituto de Quimica Medica (IQM-CSIC), Juan de la Cierva 3, 28006, Madrid, 
      Spain.
FAU - Sancho, David
AU  - Sancho D
AD  - Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029, 
      Madrid, Spain.
FAU - Rodriguez Gonzalez-Moro, Jose Miguel
AU  - Rodriguez Gonzalez-Moro JM
AD  - Department of Pneumology, University Hospital "Principe de Asturias", Alcala de 
      Henares, Madrid, Spain.
FAU - Lamas, Santiago
AU  - Lamas S
AD  - Program of Physiological and Pathological Processes, Centro de Biologia Molecular 
      "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain. Electronic address: 
      slamas@cbm.csic.es.
LA  - eng
PT  - Journal Article
DEP - 20231103
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - 347Q89U4M5 (baicalin)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Fatty Acids)
SB  - IM
MH  - Animals
MH  - Humans
MH  - *Metformin/pharmacology/therapeutic use
MH  - AMP-Activated Protein Kinases/metabolism
MH  - *COVID-19
MH  - Kidney/metabolism
MH  - Lung/metabolism
MH  - Inflammation/drug therapy
MH  - Transforming Growth Factor beta
MH  - *Respiratory Distress Syndrome
MH  - Fibrosis
MH  - Fatty Acids
PMC - PMC10682832
OTO - NOTNLM
OT  - COVID-19
OT  - Fibrosis
OT  - Inflammation
OT  - Metabolism
OT  - Mitochondria
COIS- Declaration of competing interest The authors have no conflicts of interest.
EDAT- 2023/11/18 11:42
MHDA- 2023/12/06 06:42
PMCR- 2023/11/03
CRDT- 2023/11/17 18:17
PHST- 2023/09/25 00:00 [received]
PHST- 2023/11/01 00:00 [revised]
PHST- 2023/11/01 00:00 [accepted]
PHST- 2023/12/06 06:42 [medline]
PHST- 2023/11/18 11:42 [pubmed]
PHST- 2023/11/17 18:17 [entrez]
PHST- 2023/11/03 00:00 [pmc-release]
AID - S2213-2317(23)00358-0 [pii]
AID - 102957 [pii]
AID - 10.1016/j.redox.2023.102957 [doi]
PST - ppublish
SO  - Redox Biol. 2023 Dec;68:102957. doi: 10.1016/j.redox.2023.102957. Epub 2023 Nov 
      3.