title: Pinocembrin Provides Mitochondrial Protection by the Activation of the Erk1/2-Nrf2 Signaling Pathway in SH-SY5Y Neuroblastoma Cells Exposed to Paraquat.
abstract: Pinocembrin (PB; 5,7-dihydroxyflavanone; C15H12O4) is a flavonoid found in propolis and exerts antioxidant, anti-inflammatory, and antimicrobial effects. Furthermore, PB has been studied as a neuroprotective agent. However, it remains to be understood whether and how PB would induce mitochondrial protection in mammalian cells. Therefore, we investigated here the mechanism involved in the protective effects elicited by PB in paraquat (PQ; 100 μM)-treated SH-SY5Y neuroblastoma cells. PB (25 μM) pretreatment (for 4 h) downregulated the levels of Bcl-2-associated X protein (Bax), blocked the release of cytochrome c to the cytosol, and inhibited the PQ-induced activation of caspase-9 and caspase-3. Besides, PB prevented mitochondrial dysfunction by suppressing the PQ-elicited inhibition of complexes I and V. Moreover, PB abrogated the loss of mitochondrial membrane potential (MMP) and the decline in ATP levels in the cells exposed to PQ. PB exerted antioxidant effects on mitochondria by decreasing the levels of redox impairment markers in mitochondrial membranes. Importantly, PB enhanced the levels of mitochondrial reduced glutathione (GSH). Upregulation of enzymes involved in the synthesis of GSH was seen in the cells exposed to PB. PB afforded mitochondrial protection by activating the extracellular signal-regulated kinase/nuclear factor erythroid 2-related factor 2 (Erk1/2-Nrf2) axis, since inhibition of Erk1/2 or silencing of Nrf2 abrogated these effects. Therefore, PB exerted mitochondrial and cellular protection by an Erk1/2-Nrf2-dependent mechanism.
authors.affiliation: Department of Chemistry/ICET, Federal University of Mato Grosso (UFMT), Av. Fernando Corrêa da Costa, 2367, Cuiaba, MT, 78060-900, Brazil. mrobioq@gmail.com.
authors.forename: Marcos Roberto
authors.initials: MR
authors.lastname: de Oliveira
authors.affiliation: Health Basic Sciences Department, Federal University of Health Sciences of Porto Alegre, Porto Alegre, RS, Brazil.|Centro de Pesquisa da Pós-Graduação, Centro Universitário Metodista IPA, Porto Alegre, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Peres
authors.affiliation: Laboratório de Psiquiatria Molecular, Instituto Nacional de Ciência e Tecnologia-Medicina Translacional (INCT-TM), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.|Programa de Pós-Graduação em Medicina: Psiquiatria, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Clarissa Severino
authors.initials: CS
authors.lastname: Gama
authors.affiliation: Federal University of Health Sciences of Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Simone Morelo Dal
authors.initials: SMD
authors.lastname: Bosco
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D044950:Flavanones / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010269:Paraquat / Q000494:pharmacology*
chemical_list: D044950:Flavanones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D018696:Neuroprotective Agents; C016063:pinocembrin; D045304:Cytochromes c; D010269:Paraquat
keywords: Antioxidant; Mitochondria; Nrf2; Paraquat; Pinocembrin