Free radical biology & medicine
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Free Radic. Biol. Med. · Nov 2020
PINK1-mediated mitophagy protects against hepatic ischemia/reperfusion injury by restraining NLRP3 inflammasome activation.
Activation of nucleotide-binding domain leucine-rich repeat containing family pyrin domain containing 3 (NLRP3) inflammasome in Kupffer cells (KCs) contributes significantly to hepatic ischemia/reperfusion (I/R) injury, while the mechanism of how NLRP3 inflammasome is regulated remains less well defined. Recent evidence has showed that mitophagy acts as a central player for maintaining mitochondrial homeostatis through elimination of damaged mitochondria, leading to the prevention of hyperinflammation triggered by NLRP3 activation. In this study, we aimed at investigating the potential role of PTEN-induced kinase 1 (PINK1)-mediated mitophagy in hepatic I/R injury. ⋯ Blocking of mitophagy/autophagy by silencing of PINK1/Parkin, ATG5, NDP52 or OPTN showed the totally opposite effects, respectively. Treatment with different autophagic inhibitors also consistently reversed the PINK1-mediated effects, suggesting that an intact PINK1-mediated mitophagy signaling was crucial for ablation of NLRP3 signaling in the presence of A/R. Together, these results support a critical role of PINK1-mediated mitophagy in mitochondrial quality control for KC activation and function in hepatic I/R.
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Free Radic. Biol. Med. · Jul 2020
Retraction Of PublicationTEMPORARY REMOVAL: Selenium - associated gene signatures within the SARS-CoV-2 - host genomic interaction interface.
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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Free Radic. Biol. Med. · May 2020
Erythromycin reverses cigarette smoke extract-induced corticosteroid insensitivity by inhibition of the JNK/c-Jun pathway.
Corticosteroid insensitivity is a feature of airway inflammation in chronic obstructive pulmonary disease (COPD). Erythromycin exhibits anti-inflammatory activity in COPD, but the concrete mechanism is still unclear. This study aimed to investigate the effects of erythromycin on corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) and U937 cells (a human monocytic cell line). ⋯ This study provides evidence that erythromycin restores corticosteroid sensitivity in PBMCs and U937 cells. JNK inhibition by erythromycin restores corticosteroid sensitivity via the inhibition of c-Jun expression. Thus, JNK/c-Jun is a potential novel therapeutic target for COPD.
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Free Radic. Biol. Med. · Jan 2020
An unexpected new pathway for nitroxide radical production via more reactve nitrogen-centered amidyl radical intermediate during detoxification of the carcinogenic halogenated quinones by N-alkyl hydroxamic acids.
We found previously that nitroxide radical of desferrioxamine (DFO•) could be produced from the interaction between the classic iron chelating agent desferrioxamine (DFO, an N-alkyl trihydroxamic acid) and tetrachlorohydroquinone (TCHQ), one of the carconogenic quinoind metabolites of the widely used wood preservative pentachlorophenol. However, the underlying molecular mechanism remains unclear. Here N-methylacetohydroxamic acid (N-MeAHA) was synthesized and used as a simple model compound of DFO for further mechanistic study. ⋯ Analogous radical homolysis mechanism was observed with other halogenated quinoid compounds and N-alkyl hydroxamic acids including DFO. Interestingly, amidyl radicals were found to induce both DNA strand breaks and DNA adduct formation, suggesting that N-alkyl hydroxamic acids may exert their potential side-toxic effects via forming the reactive amidyl radical species. This study represents the first report of an unexpected new pathway for nitroxide radical production via hydrogen abstration reaction of a more reactive amidyl radical intermediate during the detoxification of the carcinogenic polyhalogenated quinones by N-alkyl hydroxamic acids, which provides more direct experimental evidence to better explain not only our previous finding that excess DFO can provide effective but only partial protection against TCHQ (or TCBQ)-induced biological damage, and also the potential side-toxic effects induced by DFO and other N-alkyl hydroxamic acid drugs.
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Free Radic. Biol. Med. · May 2019
Mito-TEMPO, a mitochondria-targeted antioxidant, prevents N-nitrosodiethylamine-induced hepatocarcinogenesis in mice.
Oxidative stress and mitochondrial dysfunction play a significant role in hepatocarcinogenesis. Mitochondria are source organelle as well as target for free radicals. The oxidative damage to mitochondria can be prevented by mitochondria-targeted antioxidant, mito-TEMPO. However, its efficacy in prevention of hepatocellular carcinoma has not been investigated so far. ⋯ Mito-TEMPO was effective in combating hepatocarcinogenesis.