<i>N</i>‐Acetylcysteine protects epithelial cells against the oxidative imbalance due to <i>Clostridium difficile</i> toxins

Fiorentini, Carla; Falzano, Loredana; Rivabene, Roberto; Fabbri, Alessia; Malorni, Walter

doi:10.1016/s0014-5793(99)00706-1

Cited by 33 publications

(27 citation statements)

References 23 publications

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“…At this dose, the scavenger could counteract the toxin-raised ROS production (Fig. 2a), as described previously (17). NAC was also able to diminish CNF1-induced up-regulation of TNF-␣, IL-6, and IL-8 gene expression (Fig.…”

supporting

confidence: 79%

Cytotoxic Necrotizing Factor 1 Enhances Reactive Oxygen Species-Dependent Transcription and Secretion of Proinflammatory Cytokines in Human Uroepithelial Cells

Falzano¹,

Quaranta

Travaglione³

et al. 2003

Infect Immun

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Uropathogenic Escherichia coli strains frequently produce a Rho-activating protein toxin named cytotoxic necrotizing factor type 1 (CNF1). We herein report that CNF1 promotes transcription and release of tumor necrosis factor alpha, gamma interferon, interleukin-6 (IL-6), and IL-8 proinflammatory cytokines and increases the production of reactive oxygen species (ROS) in uroepithelial T24 cells. The antioxidant N-acetyl-l-cysteine counteracts these phenomena, a fact which suggests a role for ROS-mediated signaling in CNF1-induced proinflammatory cytokine production

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supporting

confidence: 79%

Cytotoxic Necrotizing Factor 1 Enhances Reactive Oxygen Species-Dependent Transcription and Secretion of Proinflammatory Cytokines in Human Uroepithelial Cells

Falzano¹,

Quaranta

Travaglione³

et al. 2003

Infect Immun

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“…Previous reports have noted oxidative stress pathways activated or up-regulated in response to C. difficile TcdA (26,27), and NAC is known to modify the oxidative imbalance in TcdBtreated cells (28). Although many of the previous studies of TcdA have suggested that the oxidative stress is due to mitochondrial ROS production, the dependence on Rac1 led us to speculate that the primary driver of oxidative stress in response to TcdB is NOX-mediated.…”

Section: Discussionmentioning

confidence: 88%

Clostridium difficile toxin B-induced necrosis is mediated by the host epithelial cell NADPH oxidase complex

Farrow

Chumbler²,

Lapierre³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

108

131

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Clostridium difficile infection (CDI) is a leading cause of health care-associated diarrhea and has increased in incidence and severity over the last decade. Pathogenesis is mediated by two toxins, TcdA and TcdB, which cause fluid secretion, inflammation, and necrosis of the colonic mucosa. TcdB is a potent cytotoxin capable of inducing enzyme-independent necrosis in both cells and tissue. In this study, we show that TcdB-induced cell death depends on assembly of the host epithelial cell NADPH oxidase (NOX) complex and the production of reactive oxygen species (ROS). Treating cells with siRNAs directed against key components of the NOX complex, chemical inhibitors of NOX function, or molecules that scavenge superoxide or ROS confers protection against toxin challenge. To test the hypothesis that chemical inhibition of TcdB-induced cytotoxicity can protect against TcdB-induced tissue damage, we treated colonic explants with diphenyleneiodonium (DPI), a flavoenzyme inhibitor, or N-acetylcysteine (NAC), an antioxidant. TcdB-induced ROS production in colonic tissue was inhibited with DPI, and both DPI and NAC conferred protection against TcdB-induced tissue damage. The efficacy of DPI and NAC provides proof of concept that chemical attenuation of ROS could serve as a viable strategy for protecting the colonic mucosa of patients with CDI.

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“…ROS (particularly intracellular H 2 O 2 ) generation is associated with TNF-␣-, Fas-, and angiotensin II-mediated apoptosis and various other stimuli (44 -46). In many cell types, including hepatocytes and fibroblasts, oxidative stress produces a severe F-actin reorganization (47)(48)(49)(50), whereas in human intestinal cell monolayers (Caco-2), H 2 O 2 enhances the chemical modification of actin and reorganizes F-actin (51,52). These findings suggest that a sustained increase in intracellular H 2 O 2 in GMF-␤-overexpressing cells may result in their vulnerability to apoptosis and F-actin reorganization.…”

Section: Discussionmentioning

confidence: 99%

Induction of Glia Maturation Factor-β in Proximal Tubular Cells Leads to Vulnerability to Oxidative Injury through the p38 Pathway and Changes in Antioxidant Enzyme Activities

Kaimori

Takenaka

Nakajima

et al. 2003

Journal of Biological Chemistry

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Proteinuria is an independent risk factor for progression of renal diseases. Glia maturation factor-␤ (GMF-␤), a 17-kDa brain-specific protein originally purified as a neurotrophic factor from brain, was induced in renal proximal tubular (PT) cells by proteinuria. To examine the role of GMF-␤ in PT cells, we constructed PT cell lines continuously expressing GMF-␤. The PT cells overexpressing GMF-␤ acquired susceptibility to cell death upon stimulation with tumor necrosis factor-␣ and angiotensin II, both of which are reported to cause oxidative stress. GMF-␤ overexpression also promoted oxidative insults by H 2 O 2 , leading to the reorganization of F-actin as well as apoptosis in non-brain cells (not only PT cells, but also NIH 3T3 cells). The measurement of intracellular reactive oxygen species in the GMF-␤-overexpressing cells showed a sustained increase in H 2 O 2 in response to tumor necrosis factor-␣, angiotensin II, and H 2 O 2 stimuli. The sustained increase in H 2 O 2 was caused by an increase in the activity of the H 2 O 2 -producing enzyme copper/zinc-superoxide dismutase, a decrease in the activities of the H 2 O 2 -reducing enzymes catalase and glutathione peroxidase, and a depletion of the content of the cellular glutathione peroxidase substrate GSH. The p38 pathway was significantly involved in the sustained oxidative stress to the cells. Taken together, the alteration of the antioxidant enzyme activities, in particular the peroxide-scavenging deficit, underlies the susceptibility to cell death in GMF-␤-overexpressing cells. In conclusion, we suggest that the proteinuria induction of GMF-␤ in renal PT cells may play a critical role in the progression of renal diseases by enhancing oxidative injuries.In chronic nephropathies, proteinuria is reportedly one of the best predictors, independent of mean arterial blood pressure, for disease progression toward end-stage renal failure (1, 2). Microalbuminuria, which features a small quantity of albumin only (30 -300 mg/24 h), is known as an important early sign of diabetic nephropathy (3, 4) and of progressive renal function loss in a non-diabetic population (5). In experimental models, proteinuria caused tubular insults accompanying infiltration of macrophages and T lymphocytes into the kidney (6). Interstitial inflammation can trigger fibroblast proliferation and accumulation of extracellular matrix proteins, which may facilitate tubulointerstitial fibrosis, which is a hallmark of progression of renal disease. In cultured proximal tubular (PT) 1 cells activated by administration of albumin, a number of genes encoding vasoactive and inflammatory molecules, which have potentially toxic effects on the kidney, were transactivated (7). These results strongly suggest that altering the disposition of PT cells by proteinuria must be involved in the process of renal damage. However, the mechanisms by which proteinuria accelerates renal disease progression remain largely unknown.We recently found that the brain-specific glia maturation factor-␤ (GMF-␤) gene is ind...

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N‐Acetylcysteine protects epithelial cells against the oxidative imbalance due to Clostridium difficile toxins

Cited by 33 publications

References 23 publications

Cytotoxic Necrotizing Factor 1 Enhances Reactive Oxygen Species-Dependent Transcription and Secretion of Proinflammatory Cytokines in Human Uroepithelial Cells

Cytotoxic Necrotizing Factor 1 Enhances Reactive Oxygen Species-Dependent Transcription and Secretion of Proinflammatory Cytokines in Human Uroepithelial Cells

Clostridium difficile toxin B-induced necrosis is mediated by the host epithelial cell NADPH oxidase complex

Induction of Glia Maturation Factor-β in Proximal Tubular Cells Leads to Vulnerability to Oxidative Injury through the p38 Pathway and Changes in Antioxidant Enzyme Activities

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