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Tomisato, Wataru; Takahashi, Naoko; Komoto, Chiho; Rokutan, Kazuhito; Tsuchiya, Tomofusa; Mizushima, Tohru

doi:10.1023/a:1005597902470

Cited by 38 publications

(19 citation statements)

References 21 publications

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“…We have also shown previously that GGA and low concentrations of ethanol also protected gastric mucosal cells from necrotic cell death induced by NSAIDs. 7) Furthermore, these HSP-inducers inhibited gastric stressor-induced apoptosis in gastric mucosal cells in primary culture. 16) Thus, it seems that preinduction of HSPs in gastric mucosal cells protects the cells from both necrotic and apoptotic cell death due to all of gastric stressors.…”

Section: Discussionmentioning

confidence: 95%

“…5) Using gastric mucosal cells in primary culture, we previously showed that pre-induction of HSPs makes cells resistant to necrotic cell death induced by NSAIDs. 7) Pre-induction of HSPs also makes cells resistant to cell death induced by ethanol. 6) We therefore examined here the effect of pre-induction of HSPs on necrotic cell death due to these gastric stressors, using GGA, an anti-ulcer drug with the capability of inducing HSP-expression.…”

Section: Effect Of Gga and Low Concentrations Of Ethanol On Necrosis mentioning

confidence: 99%

“…6) We also showed that pre-induction of HSPs by GGA prevents subsequent necrosis by NSAIDs in guinea pig gastric mucosal cells in primary culture. 7) Thus, it is reasonable to predict that pre-induction of HSPs by GGA also prevents subsequent necrosis by gastric stressors other than NSAIDs. We show here that short-term treatment with various gastric stressors (ethanol, hydrogen peroxide and hydrochloric acid) induces necrosis in guinea pig gastric mucosal cells in primary culture.…”

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confidence: 99%

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Geranylgeranylacetone Protects Guinea Pig Gastric Mucosal Cells from Gastric Stressor-Induced Necrosis by Induction of Heat-Shock Proteins.

Tomisato

Tsutsumi

Tsuchiya

et al. 2001

Biological & Pharmaceutical Bulletin

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Section: Discussionmentioning

confidence: 95%

Section: Effect Of Gga and Low Concentrations Of Ethanol On Necrosis mentioning

confidence: 99%

mentioning

confidence: 99%

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Geranylgeranylacetone Protects Guinea Pig Gastric Mucosal Cells from Gastric Stressor-Induced Necrosis by Induction of Heat-Shock Proteins.

Tomisato

Tsutsumi

Tsuchiya

et al. 2001

Biological & Pharmaceutical Bulletin

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“…28,29) Isolated gastric mucosal cells were cultured for 12 h in RPMI 1640 containing 0.3% v/v FBS, 100 U/ml ampicillin and 100 mg/ml streptomycin in type-I collagen-coated plastic culture plates under the conditions of 5% CO 2 /95% air and 37°C. After removing non-adherent cells, cells attached to the plate were used.…”

Section: Methodsmentioning

confidence: 99%

Low Direct Cytotoxicity of Loxoprofen on Gastric Mucosal Cells

Yamakawa

Suemasu

Kimoto

et al. 2010

Biological & Pharmaceutical Bulletin

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Non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, are a useful family of therapeutics.1) An inhibitory effect of NSAIDs on cyclooxygenase (COX) activity is responsible for their anti-inflammatory actions because COX is an enzyme essential for the synthesis of prostaglandins (PGs), such as PGE 2 , which have a strong capacity to induce inflammation. On the other hand, NSAID use is associated with gastrointestinal complications. [2][3][4] In 1991, two subtypes of COX, COX-1 and COX-2, which are responsible for the majority of COX activity at the gastrointestinal mucosa and in tissues with inflammation, respectively, were identified. 5,6) Since PGE 2 has a strong protective effect on the gastrointestinal mucosa, it is reasonable to speculate that selective COX-2 inhibitors maintain anti-inflammatory activity without gastrointestinal side-effects. In fact, a greatly reduced incidence of gastroduodenal lesions has been reported for selective COX-2 inhibitors (such as celecoxib and rofecoxib).7-9) However, a recently raised issue concerning the use of selective COX-2 inhibitors is their potential risk for cardiovascular thrombotic events. 10,11) This may be due to the fact that prostacyclin, a potent antiaggregator of platelets and a vasodilator, is mainly produced by COX-2 in vascular endothelial cells, while thromboxane A 2 , a potent aggregator of platelets and a vasoconstrictor, is mainly produced by COX-1 in platelets. [12][13][14] Because of this concern, rofecoxib was withdrawn from the worldwide market. Therefore, NSAIDs exhibiting gastrointestinal safety, other than selective COX-2 inhibitors, are clinically important.The inhibition of COX by NSAIDs is not the sole explanation for the gastrointestinal side-effects of NSAIDs.15) We have recently demonstrated that NSAIDs induce necrosis and apoptosis in cultured gastric mucosal cells and at gastric mucosa in a manner independent of COX inhibition. [16][17][18][19][20] We clearly showed that the primary target of NSAIDs for induction of necrosis and apoptosis is cytoplasmic membranes. 16,18) As for the molecular mechanism governing this apoptosis, we have proposed the following pathway. Permeabilization of cytoplasmic membranes by NSAIDs stimulates Ca 2ϩ influx and increases intracellular Ca 2ϩ levels, which in turn induces the endoplasmic reticulum (ER) stress response. 16,21,22) In this response, an apoptosis-inducing transcription factor, CCAAT/enhancer-binding protein (C/EBP) homologous transcription factor (CHOP), is induced and CHOP induces expression of p53 up-regulated modulator of apoptosis (PUMA) and resulting translocation and activation of Bax, mitochondrial dysfunction, activation of caspases and apoptosis.17,23) Furthermore, we have suggested that both COX inhibition and gastric mucosal cell death are required for the formation of NSAID-induced gastric lesions in vivo. 20,24) Loxoprofen has been used clinically for a long time as a standard NSAID in Japan, and clinical studies have suggested that it is safer than other NSAIDs, s...

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“…2,3) We have also previously shown that endogenous factors that protect the gastric mucosa from such irritants (heat shock proteins (HSPs) and prostaglandins (PGs)) or anti-ulcer drugs suppress apoptosis and necrosis in this cell model. [4][5][6][7][8][9] This suggests that this in vitro system is useful for understanding the mechanisms underlying irritant-induced gastric lesions in vivo.…”

mentioning

confidence: 99%

Cytotoxic Synergy between Indomethacin and Hydrochloric Acid in Gastric Mucosal Cells

Tanaka

Tomisato

Tsutsumi

et al. 2004

Biological & Pharmaceutical Bulletin

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Orally ingested non-steroidal anti-inflammatory drugs (NSAIDs) and acid in gastric secretions are gastric irritants that co-exist at the surface of the gastric mucosa. Here, we examined the individual and combined effects of indomethacin, a typical NSAID, and hydrochloric acid on cell death in primary cultures of guinea pig gastric mucosal cells. Indomethacin alone (at concentrations less than 200 m mM) did not induce apoptosis; however, hydrochloric acid-induced apoptosis was stimulated in the presence of indomethacin (50-200 m mM). Isobologram analysis confirmed the presence of a cytotoxic synergy between indomethacin and hydrochloric acid. The synergistic response between the two gastric irritants was also observed for necrosis. Given that the IC 50 value of indomethacin for inhibition of prostaglandin synthesis is about 5 nM, the synergistic response between indomethacin and hydrochloric acid appears to be independent of the inhibition of cyclooxygenase activity by indomethacin.

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Cited by 38 publications

References 21 publications

Geranylgeranylacetone Protects Guinea Pig Gastric Mucosal Cells from Gastric Stressor-Induced Necrosis by Induction of Heat-Shock Proteins.

Geranylgeranylacetone Protects Guinea Pig Gastric Mucosal Cells from Gastric Stressor-Induced Necrosis by Induction of Heat-Shock Proteins.

Low Direct Cytotoxicity of Loxoprofen on Gastric Mucosal Cells

Cytotoxic Synergy between Indomethacin and Hydrochloric Acid in Gastric Mucosal Cells

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