Garcia 2015 FASEB J: Difference between revisions
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{{Publication | {{Publication | ||
|title=García JA, Volt H, Venegas C, Doerrier C, Escames G, López LC, Acuña-Castroviejo D (2015) Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. FASEB J | |title=García JA, Volt H, Venegas C, Doerrier C, Escames G, López LC, Acuña-Castroviejo D (2015) Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. FASEB J 29:3863-75. | ||
|info=[http://www.ncbi.nlm.nih.gov/pubmed/26045547 PMID: 26045547] | |info=[http://www.ncbi.nlm.nih.gov/pubmed/26045547 PMID: 26045547] | ||
|authors=Garcia JA, Volt H, Venegas C, Doerrier C, Escames G, Lopez LC, Acuna-Castroviejo D | |authors=Garcia JA, Volt H, Venegas C, Doerrier C, Escames G, Lopez LC, Acuna-Castroviejo D | ||
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|abstract=We determined the NF-κB- and NOD-like receptor (NLR)P3-dependent molecular mechanisms involved in sepsis and evaluated the role of retinoid-related orphan receptor (ROR)-α in melatonin's anti-inflammatory actions. Western blot, RT-PCR, ELISA, and spectrophotometric analysis revealed that NF-κB and NLRP3 closely interact, leading to proinflammatory and pro-oxidant status in heart tissue of septic C57BL/6J mice. Moreover, mitochondrial oxygen consumption was reduced by 80% in septic mice. ''In vivo'' and ''in vitro'' analysis showed that melatonin administration blunts NF-κB transcriptional activity through a sirtuin1-dependent NF-κB deacetylation in septic mice. Melatonin also decreased NF-κB-dependent proinflammatory response and restored redox balance and mitochondrial homeostasis, thus inhibiting the NLRP3 inflammasome. In an important finding, the inhibition of NF-κB by melatonin, but not that of NLRP3, was blunted in RORα<sup>sg/sg</sup> mice, indicating that functional RORα transcription factor is necessary for the initiation of the innate immune response against inflammation. Our results are evidence of the NF-κB/NLRP3 connection during sepsis and identify NLRP3 as a novel molecular target for melatonin. The multiple molecular targets of melatonin in this study explain its potent anti-inflammatory efficacy against systemic innate immune activation and herald a promising therapeutic application for melatonin in the treatment of sepsis. | |abstract=We determined the NF-κB- and NOD-like receptor (NLR)P3-dependent molecular mechanisms involved in sepsis and evaluated the role of retinoid-related orphan receptor (ROR)-α in melatonin's anti-inflammatory actions. Western blot, RT-PCR, ELISA, and spectrophotometric analysis revealed that NF-κB and NLRP3 closely interact, leading to proinflammatory and pro-oxidant status in heart tissue of septic C57BL/6J mice. Moreover, mitochondrial oxygen consumption was reduced by 80% in septic mice. ''In vivo'' and ''in vitro'' analysis showed that melatonin administration blunts NF-κB transcriptional activity through a sirtuin1-dependent NF-κB deacetylation in septic mice. Melatonin also decreased NF-κB-dependent proinflammatory response and restored redox balance and mitochondrial homeostasis, thus inhibiting the NLRP3 inflammasome. In an important finding, the inhibition of NF-κB by melatonin, but not that of NLRP3, was blunted in RORα<sup>sg/sg</sup> mice, indicating that functional RORα transcription factor is necessary for the initiation of the innate immune response against inflammation. Our results are evidence of the NF-κB/NLRP3 connection during sepsis and identify NLRP3 as a novel molecular target for melatonin. The multiple molecular targets of melatonin in this study explain its potent anti-inflammatory efficacy against systemic innate immune activation and herald a promising therapeutic application for melatonin in the treatment of sepsis. | ||
|keywords=Bmal1, Inflammasome, Innate immunity, Oxidative stress, Sirtuin-1 | |keywords=Bmal1, Inflammasome, Innate immunity, Oxidative stress, Sirtuin-1 | ||
|mipnetlab= | |mipnetlab=ES Granada Acuna-Castroviejo D | ||
}} | }} | ||
{{Labeling | {{Labeling | ||
|area=Respiration, mtDNA;mt-genetics, Pharmacology;toxicology | |area=Respiration, mtDNA;mt-genetics, Pharmacology;toxicology | ||
|diseases=Sepsis | |||
|organism=Mouse | |organism=Mouse | ||
|tissues=Heart | |tissues=Heart | ||
|preparations=Permeabilized tissue | |preparations=Permeabilized tissue | ||
|couplingstates=OXPHOS | |couplingstates=OXPHOS | ||
| | |pathways=NS, ROX | ||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional= | |additional=Melatonin, | ||
}} | }} | ||
Latest revision as of 00:50, 10 February 2020
| García JA, Volt H, Venegas C, Doerrier C, Escames G, López LC, Acuña-Castroviejo D (2015) Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. FASEB J 29:3863-75. |
Garcia JA, Volt H, Venegas C, Doerrier C, Escames G, Lopez LC, Acuna-Castroviejo D (2015) FASEB J
Abstract: We determined the NF-κB- and NOD-like receptor (NLR)P3-dependent molecular mechanisms involved in sepsis and evaluated the role of retinoid-related orphan receptor (ROR)-α in melatonin's anti-inflammatory actions. Western blot, RT-PCR, ELISA, and spectrophotometric analysis revealed that NF-κB and NLRP3 closely interact, leading to proinflammatory and pro-oxidant status in heart tissue of septic C57BL/6J mice. Moreover, mitochondrial oxygen consumption was reduced by 80% in septic mice. In vivo and in vitro analysis showed that melatonin administration blunts NF-κB transcriptional activity through a sirtuin1-dependent NF-κB deacetylation in septic mice. Melatonin also decreased NF-κB-dependent proinflammatory response and restored redox balance and mitochondrial homeostasis, thus inhibiting the NLRP3 inflammasome. In an important finding, the inhibition of NF-κB by melatonin, but not that of NLRP3, was blunted in RORαsg/sg mice, indicating that functional RORα transcription factor is necessary for the initiation of the innate immune response against inflammation. Our results are evidence of the NF-κB/NLRP3 connection during sepsis and identify NLRP3 as a novel molecular target for melatonin. The multiple molecular targets of melatonin in this study explain its potent anti-inflammatory efficacy against systemic innate immune activation and herald a promising therapeutic application for melatonin in the treatment of sepsis. • Keywords: Bmal1, Inflammasome, Innate immunity, Oxidative stress, Sirtuin-1
• O2k-Network Lab: ES Granada Acuna-Castroviejo D
Labels: MiParea: Respiration, mtDNA;mt-genetics, Pharmacology;toxicology
Pathology: Sepsis
Organism: Mouse Tissue;cell: Heart Preparation: Permeabilized tissue
Coupling state: OXPHOS
Pathway: NS, ROX
HRR: Oxygraph-2k
Melatonin
