Reactive oxygen species-quenching and anti-apoptotic effect of polaprezinc on indomethacin-induced small intestinal epithelial cell injury

Omatsu, Tatsushi; Naito, Yuji; Handa, Osamu; Mizushima, Katsura; Hayashi, Nakanobu; Qin, Ying; Harusato, Akihito; Hirata, Ikuhiro; Kishimoto, Etsuko; Okada, Hitomi; Uchiyama, Kazuhiko; Ishikawa, Takeshi; Takagi, Tomohisa; Yagi, Nobuaki; Kokura, Satoshi; Ichikawa, Hiroshi; Yoshikawa, Toshikazu

doi:10.1007/s00535-010-0213-9

Cited by 62 publications

(49 citation statements)

References 52 publications

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“…Cerebrovascular dysfunction is caused by ROS directly and via tight junction modification and matrix metalloproteinase activation (39). Intracellular ROS accumulates secondary to mitochondrial dysfunction (30,36). We show that DKA-P, but not DKA-CM, elevated intracellular oxidative stress in hCMEC/D3, indicating that DKA-P contains mitochondrial toxic substances exclusive of alterations in the cytokines/chemokines we investigated.…”

Section: Discussionmentioning

confidence: 75%

CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro

Omatsu

Cepinskas

Clarson

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Diabetic ketoacidosis (DKA) in children is associated with intracranial vascular complications, possibly due to leukocyte-endothelial interactions. Our aim was to determine whether DKA-induced inflammation promoted leukocyte adhesion to activated human cerebrovascular endothelium. Plasma was obtained from children with type 1 diabetes either in acute DKA or in an insulin-controlled state (CON). Plasma concentrations of 21 inflammatory analytes were compared between groups. DKA was associated with altered circulating levels of ↑CXCL1 (GROα), ↑CXCL8 (IL-8), ↑IL-6, ↑IFNα2, and ↓CXCL10 (IP-10) compared with CON. These plasma analyte measurements were then used to create physiologically relevant cytokine mixtures (CM). Human cerebral microvascular endothelial cells (hCMEC/D3) were stimulated with either plasma (DKA-P or CON-P) or CM (DKA-CM or CON-CM) and assessed for polymorphonuclear leukocyte (PMN) adhesion. Stimulation of hCMEC/D3 with DKA-P or DKA-CM increased PMN adhesion to hCMEC/D3 under “flow” conditions. PMN adhesion to hCMEC/D3 was suppressed with neutralizing antibodies to CXCL1/CXCL8 or their hCMEC/D3 receptors CXCR1/CXCR2. DKA-P, but not DKA-CM, initiated oxidative stress in hCMEC/D3. Expression of ICAM-1, VCAM-1, and E-selectin were unaltered on hCMEC/D3 by either DKA-P or DKA-CM. In summary, DKA elicits inflammation in children associated with changes in circulating cytokines/chemokines. Increased CXCL1/CXCL8 instigated PMN adhesion to hCMEC/D3, possibly contributing to DKA-associated intracranial vascular complications.

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Section: Discussionmentioning

confidence: 75%

CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro

Omatsu

Cepinskas

Clarson

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Our data confirmed that Zn-depleted cells caused an increase in the activation of Caspase 3, in parallel with a higher percentage of apoptotic cells as measured via the CBMN-Cyt assay. Previous literature has shown that ZnC has a strong cytoprotective effect that might be due to the synergistic effect of Zn and L-carnosine (Nishida et al 2010;Omatsu et al 2010). However, there was no difference for the effect of the 2 different Zn forms when 2-way ANOVA analysis was performed.…”

Section: Discussionmentioning

confidence: 80%

Zinc deficiency or excess within the physiological range increases genome instability and cytotoxicity, respectively, in human oral keratinocyte cells

et al. 2011

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Zinc (Zn) is an essential component of Zn-finger proteins and acts as a cofactor for enzymes required for cellular metabolism and in the maintenance of DNA integrity. The study investigated the genotoxic and cytotoxic effects of Zn deficiency or excess in a primary human oral keratinocyte cell line and determined the optimal concentration of two Zn compounds (Zn Sulphate (ZnSO 4 ) and Zn Carnosine (ZnC)) to minimise DNA damage. Zn-deficient medium (0 lM) was produced using Chelex treatment, and the two Zn compounds ZnSO 4 and ZnC were tested at concentrations of 0.0, 0.4, 4.0, 16.0, 32.0 and 100.0 lM. Cell viability was decreased in Zndepleted cells (0 lM) as well as at 32 lM and 100 lM for both Zn compounds (P \ 0.0001) as measured via the MTT assay. DNA strand breaks, as measured by the comet assay, were found to be increased in Zn-depleted cells compared with the other treatment groups (P \ 0.05). The Cytokinesis Block Micronucleus Cytome assay showed a significant increase in the frequency of both apoptotic and necrotic cells under Zn-deficient conditions (P \ 0.05). Furthermore, elevated frequencies of micronuclei (MNi), nucleoplasmic bridges (NPBs) and nuclear buds (NBuds) were observed at 0 and 0.4 lM Zn, whereas these biomarkers were minimised for both Zn compounds at 4 and 16 lM Zn (P \ 0.05), suggesting these concentrations are optimal to maintain genome stability. Expression of PARP, p53 and OGG1 measured by western blotting was increased in Zn-depleted cells indicating that DNA repair mechanisms are activated. These results suggest that maintaining Zn concentrations within the range of 4-16 lM is essential for DNA damage prevention in cultured human oral keratinocytes.

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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. On the other hand, TNF-α is the prototypical member of a family of cytokines that also include the Fas, CD40 and TNF-related apoptosis inducing ligands, and that induce apoptosis, differentiation, cell activation, and inflammation (29).…”

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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Reactive oxygen species-quenching and anti-apoptotic effect of polaprezinc on indomethacin-induced small intestinal epithelial cell injury

Abstract: The protective effect of PZ on indomethacin-induced small intestinal injury may be dependent on its ROS-quenching effect.

Cited by 62 publications

References 52 publications

CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro

CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro

Zinc deficiency or excess within the physiological range increases genome instability and cytotoxicity, respectively, in human oral keratinocyte cells

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

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