N-Acetyl-cysteine modulates inducible nitric oxide synthase gene expression in human hepatocytes

Majano, Pedro L.; Medina, Jesús; Zubia, I Aguirre; Sunyer, Lourdes; Lara‐Pezzi, Enrique; Maldonado-Rodríguez, Alejandra; López–Cabrera, Manuel; Moreno–Otero, Ricardo

doi:10.1016/j.jhep.2003.12.009

Cited by 58 publications

(29 citation statements)

References 38 publications

(35 reference statements)

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“…Some studies have demonstrated the beneficial effect of antioxidant substances such as NAC in the pathogenesis of some illnesses, including ischemic and nephrotoxic ARF (12)(13)(14)(15). In addition to being the precursor of the L-cysteine and glutathione reductase, NAC acts as a superoxide scavenger, capable of tripling endothelial NOS expression as well as increasing NO bioavailability (27,28). It has also been shown to inhibit the activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and the transcriptional factor NF-B, as well as preventing apoptosis and limiting the activity of some proteins (29,30).…”

Section: Discussionmentioning

confidence: 99%

Magnesium Supplementation Combined with N-Acetylcysteine Protects against Postischemic Acute Renal Failure

Araújo¹,

Andrade²,

Coimbra³

et al. 2005

Journal of the American Society of Nephrology

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Magnesium is a potent vasodilator whose effects have not been evaluated in renal ischemia. The antioxidant properties of N-acetylcysteine (NAC) partially protect animals from ischemic/reperfusion injury. This study was designed to evaluate magnesium supplementation, alone or combined with NAC, on ischemic acute renal failure. Rats were maintained on normal diets, supplemented or not with MgCl 2 ⅐6H 2 O (1% in drinking water) for 23 d, and some rats received NAC (440 mg/kg body wt) on days 20 to 23. On day 21, ischemia was induced by clamping both renal arteries for 30 min. Five groups were studied: Normal, ischemia, ischemia؉magnesium, ischemia؉NAC, and ischemia؉magnesium؉NAC. GFR (inulin clearance), renal blood flow (RBF), FEH 2 O, and FENa were determined. Serum magnesium was decreased in ischemia-only rats. Magnesium prevented postischemia GFR and RBF decreases but did not protect against tubular damage. However, NAC completely restored the tubular damage induced by ischemia/reperfusion. Semiquantitative immunoblotting showed that NAC prevented the decreased expression of Na-K-2Cl co-transporter and aquaporin 2 after renal ischemia/reperfusion. Untreated rats with acute renal failure demonstrated markedly decreased endothelial nitric oxide synthase expression. Significantly, treatment with NAC, magnesium, or both completely inhibited downregulation of endothelial nitric oxide synthase. The tubular necrosis scores were lower in rats that were treated with NAC alone or with the magnesium-NAC combination. Magnesium prevented postischemia GFR and RBF decreases but did not protect against tubular damage. The NAC protected tubules from ischemia, decreased infiltrating macrophages/lymphocytes, and had a mild protective effect on GFR. In ischemic/reperfusion injury, renal function benefits more from the magnesium-NAC combination than from magnesium alone.

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Section: Discussionmentioning

confidence: 99%

Magnesium Supplementation Combined with N-Acetylcysteine Protects against Postischemic Acute Renal Failure

Araújo¹,

Andrade²,

Coimbra³

et al. 2005

Journal of the American Society of Nephrology

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“…It is well known that in different liver cells H 2 O 2 exerts a genotoxic action whereas pharmacological actions of NAC include antioxidant and -inflammatory effects (27). However, poor data demonstrate the ability of H 2 O 2 and NAC to exert their pro-and anti-oxidant action in hepatoma cell lines.…”

Section: Proliferative and Apoptotic Response Was Dose-related In Hepmentioning

confidence: 99%

Glutathionylation of p65NF-κB correlates with proliferating/apoptotic hepatoma cells exposed to pro- and anti-oxidants

Alisi

Piemonte²,

Pastore³

et al. 2009

Int J Mol Med

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Abstract.Oxidative stress influences a variety of regulatory proteins, including nuclear factor-κB (NF-κB). NF-κB is critical for maintaining the proliferation/apoptosis balance in hepatocytes. In this study we investigated the causal links between glutathione, NF-κB and hepatocyte damage. HepG2 and 3B cells were exposed to different doses of H 2 O 2 or N-acetylcysteine (NAC) and the proliferation/apoptosis rate, glutathione forms, and p65NF-κB glutathionylation and activity were analysed. Our results demonstrate that H 2 O 2 stopped proliferative response at low doses, but induced apoptosis only at high doses. In contrast, NAC exerted, proportionally to its concentration, a dual role simultaneously increasing both proliferation and apoptosis. Interestingly, the levels of proteinbound glutathione were increased by H 2 O 2 and decreased by NAC. Moreover, the antibody recognizing the glutathionylated proteins co-precipitated and -localized with the cytoplasmic inactive form of p65NF-κB in H 2 O 2 -and NAC-treated cells, even when, in 1 mM NAC-treated cells, a part of p65 was glutathione-free and localized into the nucleus. Apoptotic cells were characterised principally by a cytoskeletal staining of glutathionylation and retention of NF-κB in the cytoplasmic region; whereas in proliferating cells, glutathionylated proteins were concentrated into the perinuclear region and p65NF-κB was traslocated into the nucleus. While cytoplasmic NF-κB retention correlated well with an increased apoptotic rate, a greater expression of this protein was observed in association with the NAC-dependent. In conclusion, our findings suggest that glutathionylation inhibits NF-κB activity causing reduced hepatocyte survival, which is common in several liver diseases.

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“…Thus, in models of sepsis, hepatitis, and liver regeneration, NO was found to protect against apoptotic cell death. By contrast, in warm ischemia reperfusion and hemorrhagic-shock models, it enhanced the hepatic oxidative injury (5,9,19).…”

mentioning

confidence: 94%

Effect of Rifampin on Production of Inflammatory Mediators in HepG2 Liver Epithelial Cells

Yuhas

Berent

Ashkenazi

2011

Antimicrob Agents Chemother

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Rifampin, a potent antibacterial agent, is one of the main drugs used in the treatment of mycobacterial infections. Hepatotoxicity is a well-documented adverse event. The aim of this study was to investigate the effect of rifampin on the production of inflammatory mediators in human epithelial HepG2 liver cells in the absence or presence of proinflammatory cytokines. Incubation of HepG2 cells with a cytokine mix plus rifampin was associated with a significant dose-dependent increase in the production of nitric oxide compared to incubation with the cytokine mix alone (P < 0.05) as well as with an increase in inducible nitric oxide synthase protein and mRNA expression. Rifampin significantly increased the secretion of interleukin 8 (IL-8) in both untreated cells (P < 0.001) and cytokine-treated cells (P < 0.006). An array screening assay revealed that rifampin stimulated the production of IL-1␤ and gamma interferon-induced protein-10 (IP-10) in untreated cells and increased the secretion of RANTES in cytokine-treated cells. Together, these results indicate that rifampin may exert proinflammatory effects on liver cells.

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N-Acetyl-cysteine modulates inducible nitric oxide synthase gene expression in human hepatocytes

Cited by 58 publications

References 38 publications

Magnesium Supplementation Combined with N-Acetylcysteine Protects against Postischemic Acute Renal Failure

Magnesium Supplementation Combined with N-Acetylcysteine Protects against Postischemic Acute Renal Failure

Glutathionylation of p65NF-κB correlates with proliferating/apoptotic hepatoma cells exposed to pro- and anti-oxidants

Effect of Rifampin on Production of Inflammatory Mediators in HepG2 Liver Epithelial Cells

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