Rebamipide Significantly Inhibits Indomethacin-Induced Mitochondrial Damage, Lipid Peroxidation, and Apoptosis in Gastric Epithelial RGM-1 Cells

Nagano, Yumiko; Matsui, Hirofumi; Muramatsu, Mutsumi; Shimokawa, Osamu; Shibahara, Takeshi; Yanaka, Akinori; Nakahara, Akira; Matsuzaki, Yasushi; Tanaka, Naomi; Nakamura, Yukio

doi:10.1007/s10620-005-2810-7

Cited by 80 publications

(70 citation statements)

References 24 publications

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“…Furthermore, in vitro studies using intestinal epithelial cell lines also have indicated that indomethacin induced apoptosis of the intestinal epithelial cells accompanied by an increased production of reactive oxygen species (ROS) (26,27). Omatsu et al (28) have reported that indomethacin induced small intestinal epithelial apoptosis through ROS production and subsequent release of cytochrome c and smac/DIABLO and the activation of caspase-3 in vitro.…”

Section: Discussionmentioning

confidence: 99%

Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice

Fukumoto

Naito

Takagi³

et al. 2011

Int J Mol Med

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Abstract. The pathogenesis of small intestinal damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin is still unclear. For this reason, there is currently no therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF)-α exert beneficial effects on intestinal lesions in patients with inflammatory bowel disease (IBD). To clarify the participation of TNF-α in NSAID-induced small intestinal damage, we investigated the effects of indomethacin administration in mice with targeted deletion of the TNF-α gene. Indomethacin (10 mg/kg) was administered subcutaneously to male C57BL/6 (wild-type: WT) mice and TNF-α-deficient (TNF-α -/-) mice to induce small intestinal damage. The ulcer score, the tissue-associated myeloperoxidase (MPO) activity as an index of neutrophil infiltration, and the expression of keratinocyte chemoattractant (KC) mRNA in the small intestinal mucosa were measured. In addition, we performed a TUNEL assay to evaluate indomethacininduced apoptosis of intestinal epithelial cells and measured the expression of caspase-3 protein and Bcl-2 mRNA. The ulcer score, MPO activity, and expression of KC mRNA were significantly increased after indomethacin administration. These increases were significantly inhibited in TNF-α -/-mice compared with WT mice. Apoptotic cells were observed by the TUNEL assay in the area of the ulcerative lesion, and they were significantly fewer in TNF-α -/-mice compared with WT mice. The expression of cleaved caspase-3 protein was induced by indomethacin administration, and significantly inhibited in TNF-α -/-mice compared with that of WT mice. The expression level of Bcl-2 mRNA in indomethacin-treated TNF-α -/-mice was significantly higher than that in WT mice. TNF-α plays an important role in the pathogenesis of indomethacin-induced small intestinal damage. These results suggest that TNF-α could become a new therapeutic target for NSAID-induced small intestinal damage.

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Section: Discussionmentioning

confidence: 99%

Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice

Fukumoto

Naito

Takagi³

et al. 2011

Int J Mol Med

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“…Hoechst 33258 was used for examination of chromatin DNA. We observed the fluorescent nuclei showing apoptotic changes, mainly due to chromatin condensation at 200 × and 1,000 × magnification [17]. Further, at 18, 24, 30 hr after inoculation, we counted 10 microscopic fields at 400 × magnification the number fluorescent cells infected with M. hyorhinis showing apoptotic changes, AsA+ or AsA-.…”

Section: Cell Culturesmentioning

confidence: 99%

“…Mitochondrial activity was examined by microscopic observation of the AZ-521 cells stained with MitoRed [17]. Hoechst 33258 was used for examination of chromatin DNA.…”

Section: Cell Culturesmentioning

confidence: 99%

L-Ascorbic Acid Enhances Apoptosis in Human Gastric Carcinoma Cell Line AZ-521 Cells Infected with Mycoplasma hyorhinis

Obara

Harasawa

2008

The Journal of Veterinary Medical Science

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ABSTRACT. Mycoplasma hyorhinis (M. hyorhinis) exerts multiple effects on cell metabolisms including apoptosis mediated by their endonucleases and nitric oxide production in vitro. Although AsA is preferable to health in general because of its reactive oxygen species scavenging activity, we found that in a human carcinoma cell line AZ-521 infected with M. hyorhinis, apoptosis was enhanced by addition of L-ascorbic acid (AsA) to the cell cultures. No significant differences were evident between the AZ-521 cells with and without AsA (AsA-) after 24 hr of incubation in the mitochondrial fluorescence. M. hyorhinis-infected AZ-521 cells treated with AsA (AsA +) have developed distinct DNA ladders as compared to the control cells AsA-after 24 hr of incubation. Marked cytopathic effects were rather apparent in AsA-treated cells than in control cells AsA-after 24 hr. Our data demonstrate that AsA addition to cell cultures enhances apoptosis induced by M. hyorhinis infection. We suggest that the presence of another external apoptotic pathway by M. hyorhinis infection. While most mycoplasmas are not primarily pathogenic to humans and animals, a few specific maycoplasma species are responsible for chronic and degenerative diseases [26]. Mycoplasma hyorhinis (M. hyorhinis) is causative of polyserositis [3], otitis media [16], arthritis [6], and mycoplasmal pneumonia [11] in piglets, and may lead the swine production to serious situation [30].M. hyorhinis is also a common contaminant in cell cultures [1]. Infection with M. hyorhinis leads the culture cells to apoptosis, which is mediated by their endonucleases [20,21]. We examined the effect of L-ascorbic acid (AsA) to the apoptosis in cultured cells infected by M. hyorhinis, since it has been known that AsA has reactive oxygen species (ROS) scavenging activity by protecting the membrane phospholipids against the peroxidative damage by ROS, and by suppressing ROS production [2,8]. However, dietary taken AsA exhibits a pro-oxidant, which attributes to DNA damage, in healthy humans so it is possible that AsA may play a role in diseases such as cancer, rheumatoid arthritis and atherosclerosis [24].In contrast to our initial assumption that AsA may prevent apoptosis of the cells infected with M. hyorhinis, in the process of the experiments, we found excess AsA addition enhanced apoptosis of the cells infected with M. hyorhinis rather than preventative.In the present study, we demonstrated that a human carcinoma cell line AZ-521 cells infected with M. hyorhinis lead to apoptosis enhanced by addition of AsA, revealed by fluorescence DNA staining and DNA ladder formation, but no significant differences in the mitochondrial fluorescence as compared to the controls. These suggest the presence of another external apoptotic pathway by M. hyorhinis infection. MATERIALS AND METHODS Cell cultures:Human gastric cancer cell line AZ-521 was obtained from the Health Science Research Resources Bank (Osaka). The cell culture was maintained as previously described [31]. To minimize the pH decreas...

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“…NSAIDs cause mitochondrial injury by dissipating the mitochondrial transmembrane potential and inducing mitochondrial permeability transition pore, which liberates cytochrome C. This enzyme generates reactive oxygen species which trigger the cellular lipid peroxidation, resulting in cellular apoptosis 17 . Earlier findings have also suggested that NSAIDs raise the MDA level with respect to the control value representing their significant lipid peroxidation activity 18 .…”

Section: S Of Anterior Latissimus Dorsi Muscle Of Diclofenac Treatedmentioning

confidence: 99%

Effects of Intramuscular Diclofenac Use on Lipid Peroxidation and Skeletal Muscle Histology in Balb-C Mice

Sharma¹,

Thakur²

2017

Int. Res. J. Pharm.

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Diclofenac is a nonsteroidal anti-inflammatory drug that is widely used for the treatment of musculoskeletal complaints, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and acute muscle pain conditions. There is considerable interest in the toxicity of diclofenac because of its clinical uses. In the present study, the sub-chronic administration of diclofenac (10 mg/kg body weight; 30 days) resulted in various changes in activity of SOD enzyme (a marker of oxidative stress) and lipid peroxidation levels of mice. Changes in the activity of enzyme represent adaptive responses in muscle after diclofenac treatment. Results show that diclofenac is a strong inducer of oxidative stress. Increase in the formation of thiobarbituric acid reactive species (TBARS) and SOD activity is observed which indicates a link between oxidative stress and muscular toxicity. Maximum increase is seen in drug treated mice at 30 days' stage of investigation.

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Rebamipide Significantly Inhibits Indomethacin-Induced Mitochondrial Damage, Lipid Peroxidation, and Apoptosis in Gastric Epithelial RGM-1 Cells

Cited by 80 publications

References 24 publications

Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice

Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice

L-Ascorbic Acid Enhances Apoptosis in Human Gastric Carcinoma Cell Line AZ-521 Cells Infected with Mycoplasma hyorhinis

Effects of Intramuscular Diclofenac Use on Lipid Peroxidation and Skeletal Muscle Histology in Balb-C Mice

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