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Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines.

Dashdorj A, Jyothi KR, Lim S, Jo A, Nguyen MN, Ha J, Yoon KS, Kim HJ, Park JH, Murphy MP, Kim SS - BMC Med (2013)

Bottom Line: The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.

ABSTRACT

Background: MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation.

Methods: Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.

Results: Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.

Conclusion: Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

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Therapeutic potential of MitoQ for dextran sulfate sodium-induced colitis. (A) Experimental design for DSS-induced colitis in mice. 4% DSS was administered to WT mice from day 0 to day 7 followed by 1% of DSS for the duration of the experiment. Two groups of mice additionally received dTPP and MitoQ from day 7. (B) Body weight of mice was measured every 3 days and presented as a percentage of their initial weight, n = 5 mice per group. (C) Bloody stool score on the 10th day. (D) Lengths of the freshly removed colons were measured from rectum to ileocecal junction. (E) Representative distal colon sections stained with hematoxylin and eosin. The magnification is indicated. (F) Crypt damage. (G) Colitis score. For all samples, results are expressed as mean ±SE. n = 3, *P <0.001. DSS+dTPP, DSS with dTPP-treated mice; DSS+MitoQ, DSS with MitoQ-treated mice; NS, not significant; WT, control mice; WT+DSS, DSS-treated mice.
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Figure 2: Therapeutic potential of MitoQ for dextran sulfate sodium-induced colitis. (A) Experimental design for DSS-induced colitis in mice. 4% DSS was administered to WT mice from day 0 to day 7 followed by 1% of DSS for the duration of the experiment. Two groups of mice additionally received dTPP and MitoQ from day 7. (B) Body weight of mice was measured every 3 days and presented as a percentage of their initial weight, n = 5 mice per group. (C) Bloody stool score on the 10th day. (D) Lengths of the freshly removed colons were measured from rectum to ileocecal junction. (E) Representative distal colon sections stained with hematoxylin and eosin. The magnification is indicated. (F) Crypt damage. (G) Colitis score. For all samples, results are expressed as mean ±SE. n = 3, *P <0.001. DSS+dTPP, DSS with dTPP-treated mice; DSS+MitoQ, DSS with MitoQ-treated mice; NS, not significant; WT, control mice; WT+DSS, DSS-treated mice.

Mentions: Since elevated ROS levels and changes in mitochondrial function seemed to correlate with the pathogenesis of IBD, we investigated the therapeutic effect of MitoQ on DSS-induced mouse colitis. To induce severe colitis, we treated mice with 4% DSS for 7 days and then 1% DSS for another 14 days in their drinking water. MitoQ or dTPP was administered from day 7 until the end of the experiment (Figure 2A). dTPP, which contains the same lipophilic cation as MitoQ but lacks antioxidant activity, was used as a negative control. Body weight loss was significantly increased in mice with DSS-induced colitis, and treatment with dTPP did not reverse this weight loss. However, mice with DSS-induced colitis treated with MitoQ gained weight similar to control mice (Figure 2B). The colon length shortening and bloody stool score were also significantly increased in mice treated with DSS or DSS+dTPP. Once again, MitoQ administration inhibited the DSS-induced bloody stool and decreased the colon length shortening (Figure 2C,D). Distal colonic sections from DSS and DSS+dTPP-treated mice revealed multifocal inflammatory cell infiltration and edema with crypt and epithelial cell destruction and ulceration. By contrast, no mucosal inflammation was observed in colonic sections of DSS+MitoQ-treated mice (Figure 2E,F). Colitis score was also significantly lower in MitoQ-treated colitis mice than in the DSS and DSS+dTPP-treated mice (Figure 2G). These data reveal that MitoQ inhibits clinical and histological changes in the colon associated with DSS-induced colitis.


Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines.

Dashdorj A, Jyothi KR, Lim S, Jo A, Nguyen MN, Ha J, Yoon KS, Kim HJ, Park JH, Murphy MP, Kim SS - BMC Med (2013)

Therapeutic potential of MitoQ for dextran sulfate sodium-induced colitis. (A) Experimental design for DSS-induced colitis in mice. 4% DSS was administered to WT mice from day 0 to day 7 followed by 1% of DSS for the duration of the experiment. Two groups of mice additionally received dTPP and MitoQ from day 7. (B) Body weight of mice was measured every 3 days and presented as a percentage of their initial weight, n = 5 mice per group. (C) Bloody stool score on the 10th day. (D) Lengths of the freshly removed colons were measured from rectum to ileocecal junction. (E) Representative distal colon sections stained with hematoxylin and eosin. The magnification is indicated. (F) Crypt damage. (G) Colitis score. For all samples, results are expressed as mean ±SE. n = 3, *P <0.001. DSS+dTPP, DSS with dTPP-treated mice; DSS+MitoQ, DSS with MitoQ-treated mice; NS, not significant; WT, control mice; WT+DSS, DSS-treated mice.
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Figure 2: Therapeutic potential of MitoQ for dextran sulfate sodium-induced colitis. (A) Experimental design for DSS-induced colitis in mice. 4% DSS was administered to WT mice from day 0 to day 7 followed by 1% of DSS for the duration of the experiment. Two groups of mice additionally received dTPP and MitoQ from day 7. (B) Body weight of mice was measured every 3 days and presented as a percentage of their initial weight, n = 5 mice per group. (C) Bloody stool score on the 10th day. (D) Lengths of the freshly removed colons were measured from rectum to ileocecal junction. (E) Representative distal colon sections stained with hematoxylin and eosin. The magnification is indicated. (F) Crypt damage. (G) Colitis score. For all samples, results are expressed as mean ±SE. n = 3, *P <0.001. DSS+dTPP, DSS with dTPP-treated mice; DSS+MitoQ, DSS with MitoQ-treated mice; NS, not significant; WT, control mice; WT+DSS, DSS-treated mice.
Mentions: Since elevated ROS levels and changes in mitochondrial function seemed to correlate with the pathogenesis of IBD, we investigated the therapeutic effect of MitoQ on DSS-induced mouse colitis. To induce severe colitis, we treated mice with 4% DSS for 7 days and then 1% DSS for another 14 days in their drinking water. MitoQ or dTPP was administered from day 7 until the end of the experiment (Figure 2A). dTPP, which contains the same lipophilic cation as MitoQ but lacks antioxidant activity, was used as a negative control. Body weight loss was significantly increased in mice with DSS-induced colitis, and treatment with dTPP did not reverse this weight loss. However, mice with DSS-induced colitis treated with MitoQ gained weight similar to control mice (Figure 2B). The colon length shortening and bloody stool score were also significantly increased in mice treated with DSS or DSS+dTPP. Once again, MitoQ administration inhibited the DSS-induced bloody stool and decreased the colon length shortening (Figure 2C,D). Distal colonic sections from DSS and DSS+dTPP-treated mice revealed multifocal inflammatory cell infiltration and edema with crypt and epithelial cell destruction and ulceration. By contrast, no mucosal inflammation was observed in colonic sections of DSS+MitoQ-treated mice (Figure 2E,F). Colitis score was also significantly lower in MitoQ-treated colitis mice than in the DSS and DSS+dTPP-treated mice (Figure 2G). These data reveal that MitoQ inhibits clinical and histological changes in the colon associated with DSS-induced colitis.

Bottom Line: The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.

ABSTRACT

Background: MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation.

Methods: Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.

Results: Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.

Conclusion: Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

Show MeSH
Related in: MedlinePlus