Apocynin increases glutathione synthesis and activates AP‐1 in alveolar epithelial cells

Lapperre, Thérèse S.; Jiménez, Luis A.; Antonicelli, Frank; Drost, Ellen; Hiemstra, Pieter S.; Stolk, Jan; MacNee, William; Rahman, Irfan

doi:10.1016/s0014-5793(98)01723-2

Cited by 74 publications

(43 citation statements)

References 30 publications

(41 reference statements)

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“…Finally, our studies also provide preliminary evidence that NADPH oxidase may be involved in an oxygen radical-dependent killing mechanism during P. falciparum infection (47). Previous studies have shown that apocynin targets NADPH oxidase and that the antioxidant property of apocynin results from an increase in GSH biosynthesis (48). Even though apocynin has been shown to specifically target NADPH oxidase, the higher concentrations required may also indicate other unknown, "off-target" effects.…”

Section: Discussionsupporting

confidence: 51%

Antimalarial Action of Artesunate Involves DNA Damage Mediated by Reactive Oxygen Species

Gopalakrishnan

Kumar

2015

Antimicrob Agents Chemother

136

138

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Artemisinin-based combination therapy (ACT) is the recommended first-line treatment for Plasmodium falciparum malaria. It has been suggested that the cytotoxic effect of artemisinin is mediated by free radicals followed by the alkylation of P. falciparum proteins. The endoperoxide bridge, the active moiety of artemisinin derivatives, is cleaved in the presence of ferrous iron, generating reactive oxygen species (ROS) and other free radicals. However, the emergence of resistance to artemisinin in P. falciparum underscores the need for new insights into the molecular mechanisms of antimalarial activity of artemisinin. Here we show that artesunate (ART) induces DNA double-strand breaks in P. falciparum in a physiologically relevant dose-and time-dependent manner. DNA damage induced by ART was accompanied by an increase in the intracellular ROS level in the parasites. Mannitol, a ROS scavenger, reversed the cytotoxic effect of ART and reduced DNA damage, and modulation of glutathione (GSH) levels was found to impact ROS and DNA damage induced by ART. Accumulation of ROS, increased DNA damage, and the resulting antiparasite effect suggest a causal relationship between ROS, DNA damage, and parasite death. Finally, we also show that ARTinduced ROS production involves a potential role for NADPH oxidase, an enzyme involved in the production of superoxide anions. Our results with P. falciparum provide novel insights into previously unknown molecular mechanisms underlying the antimalarial activity of artemisinin derivatives and may help in the design of next-generation antimalarial drugs against the most virulent Plasmodium species.

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Section: Discussionsupporting

confidence: 51%

Antimalarial Action of Artesunate Involves DNA Damage Mediated by Reactive Oxygen Species

Gopalakrishnan

Kumar

2015

Antimicrob Agents Chemother

136

138

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“…Conversely, some compounds such as 4′-HC, curcumin, and 2-HE elevated intracellular GSH levels in HL-60 and PC-3 cells. This accumulation is likely due to stimulation of GSH synthesis, as has been shown with apocynin and curcumin in A549 cells [51,52]. Interestingly, curcumin, 4′-HC and apocynin have in common the presence of a hydroxyl group in position 4 of a phenolic moiety.…”

Section: Discussionmentioning

confidence: 67%

Flavonoid-induced glutathione depletion: Potential implications for cancer treatment

Kachadourian

Day

2006

Free Radical Biology and Medicine

122

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The ability of a number of flavonoids to induce glutathione (GSH) depletion was measured in lung (A549), myeloid (HL-60), and prostate (PC-3) human tumor cells. The hydroxychalcone (2′-HC) and the dihydroxychalcones (2′,2-, 2′,3-, 2′,4-, and 2′,5′-DHC) were the most effective in A549 and HL-60 cells, depleting more than 50% of intracellular GSH within 4 h of exposure at 25 µM. In contrast, the flavones chrysin and apigenin were the most effective in PC-3 cells, depleting 50-70% of intracellular GSH within 24 h of exposure at 25 µM. In general, these flavonoids were more effective than three classical substrates of multidrug resistance protein 1 (MK-571, indomethacin, and verapamil). Prototypic flavonoids (2′,5′-DHC and chrysin) were subsequently tested for their abilities to potentiate the toxicities of prooxidants (etoposide, rotenone, 2-methoxyestradiol, and curcumin). In A549 cells, 2′,5′-DHC potentiated the cytotoxicities of rotenone, 2-methoxyestradiol, and curcumin, but not etoposide. In HL-60 and PC-3 cells, chrysin potentiated the cytotoxicity of curcumin, cytotoxicity that was attenuated by the catalytic antioxidant manganese(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP). Assessments of mitochondrial GSH levels mitochondrial membrane potential and cytochrome c release showed that the potentiation effects induced by 2′,5′-DHC and chrysin involve mitochondrial dysfunction.

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“…The plant-derived phenolic antioxidant apocynin (4-hydroxy-3-methoxyacetophenone) also induces GSH synthesis in human alveolar epithelial cells [79]. These effects of phenolic antioxidants are associated with AP-1 transactivation [57,60,102].…”

Section: At Transcriptional Levelmentioning

confidence: 99%

Oxidative stress and regulation of glutathione in lung inflammation

Rahman¹,

MacNee²

2000

Eur Respir J

807

555

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Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance, a major cause of cell damage. The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox‐sensitive transcription factors such as nuclear factor‐κB, and activator protein‐1 (AP‐1), which regulate the genes for pro‐inflammatory mediators and protective antioxidant genes. Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra‐ and extracellular protective antioxidant against oxidative/nitrosative stresses, which plays a key role in the control of pro‐inflammatory processes in the lungs. Recent findings have suggested that GSH is important in immune modulation, remodelling of the extracellular matrix, apoptosis and mitochondrial respiration. The rate‐limiting enzyme in GSH synthesis is γ‐glutamylcysteine synthetase (γ‐GCS). The human γ‐GCS heavy and light subunits are regulated by AP‐1 and antioxidant response elements and are modulated by oxidants, phenolic antioxidants, growth factors, and inflammatory and anti‐inflammatory agents in lung cells. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma. The imbalance and/or genetic variation in antioxidant γ‐GCS and pro‐inflammatory versus antioxidant genes in response to oxidative stress and inflammation in some individuals may render them more susceptible to lung inflammation. Knowledge of the mechanisms of GSH regulation and balance between the release and expression of pro‐ and anti‐inflammatory mediators could lead to the development of novel therapies based on the pharmacological manipulation of the production as well as gene transfer of this important antioxidant in lung inflammation and injury. This review describes the redox control and involvement of nuclear factor‐κB and activator protein‐1 in the regulation of cellular glutathione and γ‐glutamylcysteine synthetase under conditions of oxidative stress and inflammation, the role of glutathione in oxidant‐mediated susceptibility/tolerance, γ‐glutamylcysteine synthetase genetic susceptibility and the potential therapeutic role of glutathione and its precursors in protecting against lung oxidant stress, inflammation and injury.

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Apocynin increases glutathione synthesis and activates AP‐1 in alveolar epithelial cells

Cited by 74 publications

References 30 publications

Antimalarial Action of Artesunate Involves DNA Damage Mediated by Reactive Oxygen Species

Antimalarial Action of Artesunate Involves DNA Damage Mediated by Reactive Oxygen Species

Flavonoid-induced glutathione depletion: Potential implications for cancer treatment

Oxidative stress and regulation of glutathione in lung inflammation

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