The Enhancing Effect of the Antioxidant<i> N</i>-Acetylcysteine on Urinary Bladder Injury Induced by Dimethylarsinic Acid

Takahashi, Naofumi; Yoshida, Toshinori; Ohnuma, Aya; Horiuchi, Haruka; Ishitsuka, Katsumi; Kashimoto, Yukiko; Kuwahara, Maki; Nakashima, Nobuaki; Harada, Takanori

doi:10.1177/0192623311422076

Cited by 7 publications

(5 citation statements)

References 31 publications

(38 reference statements)

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“…The high dose of NAC resulted in dimethylarsinic acid-induced inflammation and cell proliferation, leading to papillary and nodular hyperplasia of the urothelium in the rat model by Takahashi et al . 34 NAC is presumed to enhance oxidative stress and to upregulate extracellular signal regulated kinase (ERK) 1/2 and cyclin D1. Upregulation of ERK signaling is consistent with an early change in urinary carcinogenesis in humans 35 .…”

Section: Discussionmentioning

confidence: 99%

N-acetylcysteine prevents bladder tissue fibrosis in a lipopolysaccharide-induced cystitis rat model

Ryu

Shin

et al. 2019

Sci Rep

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Therapeutic options for non-Hunner type interstitial cystitis (IC), which is histologically characterized by fibrosis and mast cell infiltration, are limited. We developed a rat model that replicates chronic inflammation and fibrosis and evaluated the therapeutic effect of N-acetylcysteine (NAC), a well-known anti-fibrotic agent, on the model. Intravesical instillation of lipopolysaccharide (LPS, 750 μg) after protamine sulfate (10 mg) was conducted twice per week for five consecutive weeks. One week after final instillation, 200 mg/kg NAC (n = 10, IC + NAC group) or phosphate-buffered saline (n = 10, IC group) was daily injected intraperitoneally once daily for 5 days. LPS instillation induced bladder fibrosis, mast cell infiltration, and apoptotic tissue damage. Functionally, LPS insult led to irregular micturition, decreased inter-contraction intervals, and decreased micturition volume. NAC significantly improved most of the voiding parameters and reversed histological damages including fibrosis. NAC inhibited the induction and nuclear localization of phospho-Smad2 protein in bladder tissues and the upregulation of genes related to fibrosis, such as Tgfb2 , Tgfb3 , Smad2 , Smad3 , Cxcl10 , and Card10 . This is the first study to demonstrate the beneficial effects on NAC in restoring voiding function, relieving tissue fibrosis and related bladder injuries, in the LPS-induced cystitis rat model.

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Section: Discussionmentioning

confidence: 99%

N-acetylcysteine prevents bladder tissue fibrosis in a lipopolysaccharide-induced cystitis rat model

Ryu

Shin

et al. 2019

Sci Rep

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“…The goal of this investigation was to gain additional mechanistic insight into the spatiotemporal characteristics of this cellular response during the early stages (first week) of regeneration. Specifically, we evaluated the proliferative cellular response during the first week following STC using fluorescent BrdU cell labeling, a label-retaining technique that has been utilized to investigate a variety of stem/progenitor cell niches including liver, kidney, intestine, and previous bladder injury models [26], [27], [28], [29], [30], [31], [32], [33]…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Early Proliferative Response of the Rodent Bladder to Subtotal Cystectomy: A Unique Model of Mammalian Organ Regeneration

et al. 2012

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Subtotal cystectomy (STC; surgical removal of ∼75% of the rat urinary bladder) elicits a robust proliferative response resulting in complete structural and functional bladder regeneration within 8-weeks. The goal of these studies was to characterize the early cellular response that mediates this regenerative phenomenon, which is unique among mammalian organ systems. STC was performed on eighteen 12-week-old female Fischer F344 rats. At 1, 3, 5 and 7-days post-STC, the bladder was harvested 2-hours after intraperitoneal injection of bromodeoxyuridine (BrdU). Fluorescent BrdU labeling was quantified in cells within the urothelium, lamina propria (LP), muscularis propria (MP) and serosa. Cell location was confirmed with fluorescently co-labeled cytokeratin, vimentin or smooth muscle actin (SMA), to identify urothelial, interstitial and smooth muscle cells, respectively. Expression of sonic hedgehog (Shh), Gli-1 and bone morphogenic factor-4 (BMP-4) were evaluated with immunochemistry. Three non-operated rats injected with BrdU served as controls. Less than 1% of cells in the bladder wall were labeled with BrdU in control bladders, but this percentage significantly increased by 5-8-fold at all time points post-STC. The spatiotemporal characteristics of the proliferative response were defined by a significantly higher percentage of BrdU-labeled cells within the urothelium at 1-day than in the MP and LP. A time-dependent shift at 3 and 5-days post-STC revealed significantly fewer BrdU-labeled cells in the MP than LP or urothelium. By 7-days the percentage of BrdU-labeled cells was similar among urothelium, LP and MP. STC also caused an increase in immunostaining for Shh, Gli-1 and BMP-4. In summary, the early stages of functional bladder regeneration are characterized by time-dependent changes in the location of the proliferating cell population, and expression of several evolutionarily conserved developmental signaling proteins. This report extends previous observations and further establishes the rodent bladder as an excellent model for studying novel aspects of mammalian organ regeneration.

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“… 21 39 In another study, NAC exacerbated the toxic effect of arsenic metabolites and this was attributed to the ability of NAC to act as pro-oxidant or to produce further reactive metabolites. 40 At 24-hour exposure time, the co-administration of 500 µM NAC with 50 µM As 2 O 3 resulted in a lower OD value compared with 50 µM As 2 O 3 alone, but this difference did not reach the level of significance. Some of the differences between the studies evaluating the protective effect of NAC on arsenic-induced toxicity can be attributed to variation in cell lineage, methodology, or concentration and type of reagents.…”

Section: Discussionmentioning

confidence: 89%

The Hormetic Effect of Arsenic Trioxide on Rat Pulpal Cells: An In Vitro Preliminary Study

et al. 2020

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Objectives Despite the agreement that there is no longer any indication for arsenic use in modern endodontics, some concerns are surfacing about the minute amount of arsenic trioxide (As2O3) released from Portland cement-based materials. The present study investigated the effect of different concentrations of As2O3 on rat pulpal cells and the efficacy of N-acetylcysteine (NAC) in preventing As2O3-mediated toxicity. Materials and Methods Cytotoxicities of 50, 10, or 5 µm As2O3 and the effect of cells co-treatment with 50 µm As2O3 and 5,000 µm NAC or 500 µm NAC were tested at 24 hours or 3 days. Cell viability was assessed by means of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and cellular morphological changes were observed under phase contrast microscope. Statistical Analysis Two-way analysis of variance with Tukey’s post-hoc test was used to evaluate differences between the groups (α = 0.05). Results At both exposure times, 50 µm As2O3 resulted in lower optical density (OD) values when compared with 10 or 5 µm As2O3. At 24 hours, 10 µm As2O3 resulted in a higher OD value compared with the control; however, at 3 days the difference was statistically insignificant. At each exposure time, the OD value of 5 µm As2O3 group was comparable to the control and 10 µm As2O3 group. There were no significant differences between 50 µm As2O3 group and 500 NAC+50 µm As2O3 group; however, these two groups had lower OD values when compared with 5,000 NAC + 50 µm As2O3 group at 24 hours and 3 days. The latter group showed significantly lower OD value in comparison with the control at 24 hours and 3 days. Control cells were polygonal-shaped while 50 µm As2O3-treated cells exhibited contracted and spherical morphology with increased intercellular spaces. At 24 hours, 10 μm and 5 µm As2O3-treated cells were slightly hypertrophic. Cells co-treated with NAC and As2O3 showed increased intercellular spaces and lower cellular density compared with the control. Conclusions As2O3 displayed a hormetic effect on pulpal cells; however, the proliferative effect induced by low As2O3 concentrations should be interpreted with caution. NAC did not prevent As2O3-mediated toxicity; however, it demonstrated potential for ameliorating this toxicity.

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The Enhancing Effect of the Antioxidant N-Acetylcysteine on Urinary Bladder Injury Induced by Dimethylarsinic Acid

Cited by 7 publications

References 31 publications

N-acetylcysteine prevents bladder tissue fibrosis in a lipopolysaccharide-induced cystitis rat model

N-acetylcysteine prevents bladder tissue fibrosis in a lipopolysaccharide-induced cystitis rat model

Characterization of the Early Proliferative Response of the Rodent Bladder to Subtotal Cystectomy: A Unique Model of Mammalian Organ Regeneration

The Hormetic Effect of Arsenic Trioxide on Rat Pulpal Cells: An In Vitro Preliminary Study

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