Heme oxygenase-1 prevents murine intestinal inflammation

Takagi, Tomohisa; Naito, Yuji; Mizushima, Katsura; Hirai, Yasuko; Harusato, Akihito; Okayama, Tetsuya; Katada, Kazhuhiro; Kamada, Kazuhiro; Uchiyama, Kazuhiko; Handa, Osamu; Ishikawa, Takeshi; Itoh, Yoshito

doi:10.3164/jcbn.17-133

Cited by 26 publications

(21 citation statements)

References 25 publications

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“…Similarly, Nrf2 is a key regulator of the thioredoxin based antioxidant response system required for the recycling of oxidized protein thiols (Stamler and Slivka, 1996). One limitation of the current study is that while we report global expression of Nrf2 in colon tissue, we have not investigated the nuclear component which is responsible for activation of antioxidant genes (Takagi et al, 2018). Nonetheless, elevated HO-1 expression as demonstrated here is an indication of stimulation of Nrf2 nuclear component.…”

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confidence: 67%

The Synthetic Myeloperoxidase Inhibitor AZD3241 Ameliorates Dextran Sodium Sulfate Stimulated Experimental Colitis

et al. 2020

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Chronic inflammatory bowel disease (IBD) is a condition with multifactorial pathophysiology. To date, there is no permanent cure and the disease is primarily managed by immunosuppressive drugs; long-term use promotes serious side effects including increased risk malignancies. The current study aimed to target neutrophilmyeloperoxidase, a key contributor to the pathogenesis of IBD, through the use of AZD3241that inhibits extracellular myeloperoxidase. Experimental colitis was induced in C57BL/6 male mice by 2% dextran sodium sulfate in drinking water ad libitum over 9 days. Mice received either normal drinking water and peanut butter (control), 2% DSS in drinking water and peanut butter or 2% DSS in drinking water and AZD3241 (30 mg/kg) dispersed in peanut butter daily for 9 days. Administered AZD3241 attenuated body weight loss (10% p<0.05) and improved clinical score (9 fold p<0.05; a score comprising the timedependent assessment of stool consistency and extent of rectal bleeding), loss of colonic crypts (p<0.001), preserved surface epithelium (p<0.001) and enhanced expression of the transcription factor Nrf-2 (regulator of antioxidants) and enhanced expression of the downstream antioxidant response element haeoxygenase-1 (HO-1) in the colon tissue. Also, the concentration of fecal hemoglobin and the myeloperoxidase specific oxidative damage biomarker 3-chlorotyrosine in the colon were significantly decreased in the presence of AZD3241. This latter result was consistent with AZD3241 inhibiting MPO activity in vitro. Overall, AZD3241 ameliorated the course and severity of experimental colitis through ameliorating MPO derived tissue damage and could be considered a potential therapeutic option, subject to further validation in chronic IBD models.

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confidence: 67%

The Synthetic Myeloperoxidase Inhibitor AZD3241 Ameliorates Dextran Sodium Sulfate Stimulated Experimental Colitis

et al. 2020

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“…A basal level of expression is seen under physiological conditions, but HO-1 is highly expressed in response to stressful stimuli [ 35 , 51 ]. This increased HO-1 expression offers protection during intestinal inflammation [ 52 , 53 ]. Dose-dependent increases in expression of HO-1 mRNA observed in the NED-treated group may provide protection from inflammation.…”

Section: Discussionmentioning

confidence: 99%

Nerolidol Mitigates Colonic Inflammation: An Experimental Study Using both In Vivo and In Vitro Models

et al. 2020

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Nerolidol (NED) is a naturally occurring sesquiterpene alcohol present in various plants with potent anti-inflammatory effects. In the current study, we investigated NED as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were administered 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. Six groups received either vehicle alone or DSS alone or DSS with oral NED (50, 100, and 150 mg/kg body weight/day by oral gavage) or DSS with sulfasalazine. Disease activity index (DAI), colonic histology, and biochemical parameters were measured. TNF-α-treated HT-29 cells were used as in vitro model of colonic inflammation to study NED (25 µM and 50 µM). NED significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue Myeloperoxidase (MPO) concentrations, neutrophil and macrophage mRNA expression (CXCL2 and CCL2), and proinflammatory cytokine content (IL-1β, IL-6, and TNF-α) both at the protein and mRNA level were significantly reduced by NED. The increase in content of the proinflammatory enzymes, COX-2 and iNOS induced by DSS were also significantly inhibited by NED along with tissue nitrate levels. NED promoted Nrf2 nuclear translocation dose dependently. NED significantly increased antioxidant enzymes activity (Superoxide dismutase (SOD) and Catalase (CAT)), Hemeoxygenase-1 (HO-1), and SOD3 mRNA levels. NED treatment in TNF-α-challenged HT-29 cells significantly decreased proinflammatory chemokines (CXCL1, IL-8, CCL2) and COX-2 mRNA levels. NED supplementation attenuates colon inflammation through its potent antioxidant and anti-inflammatory activity both in in vivo and in vitro models of colonic inflammation.

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“…For comparison, the expression of the gene heme oxygenase 1 ( HMOX1 ) was analyzed by quantitative real-time polymerase chain reaction (qPCR) in a parallel set of experiments with the same concentrations of DBPs and exposure durations. We selected to perform the confirmatory real-time qPCR on HMOX1 , which: a ) was detected consistently in a quantitative manner in our microarray experiments for all tested DBPs; b ) has an established role in the response to oxidative stress (Poss and Tonegawa 1997); and c ) was previously shown to be dysregulated in response to inflammation in mice (Takagi et al. 2018).…”

Section: Methodsmentioning

confidence: 99%

Global Transcriptional Analysis of Nontransformed Human Intestinal Epithelial Cells (FHs 74 Int) after Exposure to Selected Drinking Water Disinfection By-Products

Prochazka

Melvin

Escher

et al. 2019

Environ Health Perspect

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Background:Drinking water disinfection inadvertently leads to the formation of numerous disinfection by-products (DBPs), some of which are cytotoxic, mutagenic, genotoxic, teratogenic, and potential carcinogens both in vitro and in vivo.Objectives:We investigated alterations to global gene expression (GE) in nontransformed human small intestine epithelial cells (FHs 74 Int) after exposure to six brominated and two chlorinated DBPs: bromoacetic acid (BAA), bromoacetonitrile (BAN), 2,6-dibromo-p-benzoquinone (DBBQ), bromoacetamide (BAM), tribromoacetaldehyde (TBAL), bromate (BrO3−), trichloroacetic acid (TCAA), and trichloroacetaldehyde (TCAL).Methods:Using whole-genome cDNA microarray technology (Illumina), we examined GE in nontransformed human cells after 4h exposure to DBPs at predetermined equipotent concentrations, identified significant changes in gene expression (p≤0.01), and investigated the relevance of these genes to specific toxicity pathways via gene and pathway enrichment analysis.Results:Genes related to activation of oxidative stress–responsive pathways exhibited fewer alterations than expected based on prior work, whereas all DBPs induced notable effects on transcription of genes related to immunity and inflammation.Discussion:Our results suggest that alterations to genes associated with immune and inflammatory pathways play an important role in the potential adverse health effects of exposure to DBPs. The interrelationship between these pathways and the production of reactive oxygen species (ROS) may explain the common occurrence of oxidative stress in other studies exploring DBP toxicity. Finally, transcriptional changes and shared induction of toxicity pathways observed for all DBPs caution of additive effects of mixtures and suggest further assessment of adverse health effects of mixtures is warranted. https://doi.org/10.1289/EHP4945

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Heme oxygenase-1 prevents murine intestinal inflammation

Cited by 26 publications

References 25 publications

The Synthetic Myeloperoxidase Inhibitor AZD3241 Ameliorates Dextran Sodium Sulfate Stimulated Experimental Colitis

The Synthetic Myeloperoxidase Inhibitor AZD3241 Ameliorates Dextran Sodium Sulfate Stimulated Experimental Colitis

Nerolidol Mitigates Colonic Inflammation: An Experimental Study Using both In Vivo and In Vitro Models

Global Transcriptional Analysis of Nontransformed Human Intestinal Epithelial Cells (FHs 74 Int) after Exposure to Selected Drinking Water Disinfection By-Products

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