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3-(3-pyridylmethylidene)-2-indolinone reduces the severity of colonic injury in a murine model of experimental colitis.

Wang KP, Zhang C, Zhang SG, Liu ED, Dong L, Kong XZ, Cao P, Hu CP, Zhao K, Zhan YQ, Dong XM, Ge CH, Yu M, Chen H, Wang L, Yang XM, Li CY - Oxid Med Cell Longev (2015)

Bottom Line: The result suggests that treatment with PMID prior to colitis induction significantly reduced body weight loss, shortened colon length, and decreased disease activity index compared to control mice.Histopathological analysis of the colon revealed attenuated inflammation in PMID pretreated animals.The levels of inflammatory markers in colon tissue and serum were reduced associated with inhibition of NF-κB activation.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.

ABSTRACT
Nrf2 is the key transcription factor regulating the antioxidant response which is crucial for cytoprotection against extracellular stresses. Numerous in vivo studies indicate that Nrf2 plays a protective role in anti-inflammatory response. 3-(3-Pyridylmethylidene)-2-indolinone (PMID) is a synthesized derivative of 2-indolinone compounds. Our previous study suggested that PMID induces the activation of Nrf2/ARE pathway, then protecting against oxidative stress-mediated cell death. However, little is known regarding the anti-inflammatory properties of PMID in severe inflammatory phenotypes. In the present study we determined if PMID treatment protects mice from dextran sodium sulphate- (DSS-) induced colitis. The result suggests that treatment with PMID prior to colitis induction significantly reduced body weight loss, shortened colon length, and decreased disease activity index compared to control mice. Histopathological analysis of the colon revealed attenuated inflammation in PMID pretreated animals. The levels of inflammatory markers in colon tissue and serum were reduced associated with inhibition of NF-κB activation. The expression levels of Nrf2-dependent genes such as HO-1, NQO1, and Nrf2 were increased in PMID pretreated mice. However, PMID pretreatment did not prevent DSS-induced colitis in Nrf2 knockout mice. These data indicate that PMID pretreatment in mice confers protection against DSS-induced colitis in Nrf2-dependent manner, suggesting a potential role of PMID in anti-inflammatory response.

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Related in: MedlinePlus

NF-κB activation is decreased in colon tissue of DSS-induced ICR mice with PMID pretreatment. Mice were treated with the indicated doses of PMID per os for 7 days and then induced to colitis by DSS via drinking water for 7 days. Then the mice were sacrificed and nuclear extracts were prepared for NF-κB activity assay just as “Section 2” described (a). The RLU was normalized with the mean RLU from normal control group. Results represented mean ± SD. n = 3/group. The statistical difference between the samples was demonstrated as *P ≤ 0.05 or **P ≤ 0.01. (b) The p65 protein level in nuclear extracts was measured by Western blotting. Histone H2B was used as internal control.
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fig4: NF-κB activation is decreased in colon tissue of DSS-induced ICR mice with PMID pretreatment. Mice were treated with the indicated doses of PMID per os for 7 days and then induced to colitis by DSS via drinking water for 7 days. Then the mice were sacrificed and nuclear extracts were prepared for NF-κB activity assay just as “Section 2” described (a). The RLU was normalized with the mean RLU from normal control group. Results represented mean ± SD. n = 3/group. The statistical difference between the samples was demonstrated as *P ≤ 0.05 or **P ≤ 0.01. (b) The p65 protein level in nuclear extracts was measured by Western blotting. Histone H2B was used as internal control.

Mentions: The link between inflammation and NF-κB signaling pathway has been widely reported and the transcription of inflammatory cytokines is largely mediated by the NF-κB. Thus, we examined the NF-κB activation using a chemiluminescence-based assay kit after 7 days of DSS treatment. As shown in Figure 4(a), DSS treatment led to significant increase of NF-κB activity, and PMID pretreatment attenuated the activation level of NF-κB. Furthermore, we investigated the p65 protein level in nuclear extracts (Figure 4(b)), and the similar results were obtained. These data highlight that, with decreased inflammatory response in PMID pretreatment group, the NF-κB signaling pathway activation was also inhibited.


3-(3-pyridylmethylidene)-2-indolinone reduces the severity of colonic injury in a murine model of experimental colitis.

Wang KP, Zhang C, Zhang SG, Liu ED, Dong L, Kong XZ, Cao P, Hu CP, Zhao K, Zhan YQ, Dong XM, Ge CH, Yu M, Chen H, Wang L, Yang XM, Li CY - Oxid Med Cell Longev (2015)

NF-κB activation is decreased in colon tissue of DSS-induced ICR mice with PMID pretreatment. Mice were treated with the indicated doses of PMID per os for 7 days and then induced to colitis by DSS via drinking water for 7 days. Then the mice were sacrificed and nuclear extracts were prepared for NF-κB activity assay just as “Section 2” described (a). The RLU was normalized with the mean RLU from normal control group. Results represented mean ± SD. n = 3/group. The statistical difference between the samples was demonstrated as *P ≤ 0.05 or **P ≤ 0.01. (b) The p65 protein level in nuclear extracts was measured by Western blotting. Histone H2B was used as internal control.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4385690&req=5

fig4: NF-κB activation is decreased in colon tissue of DSS-induced ICR mice with PMID pretreatment. Mice were treated with the indicated doses of PMID per os for 7 days and then induced to colitis by DSS via drinking water for 7 days. Then the mice were sacrificed and nuclear extracts were prepared for NF-κB activity assay just as “Section 2” described (a). The RLU was normalized with the mean RLU from normal control group. Results represented mean ± SD. n = 3/group. The statistical difference between the samples was demonstrated as *P ≤ 0.05 or **P ≤ 0.01. (b) The p65 protein level in nuclear extracts was measured by Western blotting. Histone H2B was used as internal control.
Mentions: The link between inflammation and NF-κB signaling pathway has been widely reported and the transcription of inflammatory cytokines is largely mediated by the NF-κB. Thus, we examined the NF-κB activation using a chemiluminescence-based assay kit after 7 days of DSS treatment. As shown in Figure 4(a), DSS treatment led to significant increase of NF-κB activity, and PMID pretreatment attenuated the activation level of NF-κB. Furthermore, we investigated the p65 protein level in nuclear extracts (Figure 4(b)), and the similar results were obtained. These data highlight that, with decreased inflammatory response in PMID pretreatment group, the NF-κB signaling pathway activation was also inhibited.

Bottom Line: The result suggests that treatment with PMID prior to colitis induction significantly reduced body weight loss, shortened colon length, and decreased disease activity index compared to control mice.Histopathological analysis of the colon revealed attenuated inflammation in PMID pretreated animals.The levels of inflammatory markers in colon tissue and serum were reduced associated with inhibition of NF-κB activation.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.

ABSTRACT
Nrf2 is the key transcription factor regulating the antioxidant response which is crucial for cytoprotection against extracellular stresses. Numerous in vivo studies indicate that Nrf2 plays a protective role in anti-inflammatory response. 3-(3-Pyridylmethylidene)-2-indolinone (PMID) is a synthesized derivative of 2-indolinone compounds. Our previous study suggested that PMID induces the activation of Nrf2/ARE pathway, then protecting against oxidative stress-mediated cell death. However, little is known regarding the anti-inflammatory properties of PMID in severe inflammatory phenotypes. In the present study we determined if PMID treatment protects mice from dextran sodium sulphate- (DSS-) induced colitis. The result suggests that treatment with PMID prior to colitis induction significantly reduced body weight loss, shortened colon length, and decreased disease activity index compared to control mice. Histopathological analysis of the colon revealed attenuated inflammation in PMID pretreated animals. The levels of inflammatory markers in colon tissue and serum were reduced associated with inhibition of NF-κB activation. The expression levels of Nrf2-dependent genes such as HO-1, NQO1, and Nrf2 were increased in PMID pretreated mice. However, PMID pretreatment did not prevent DSS-induced colitis in Nrf2 knockout mice. These data indicate that PMID pretreatment in mice confers protection against DSS-induced colitis in Nrf2-dependent manner, suggesting a potential role of PMID in anti-inflammatory response.

Show MeSH
Related in: MedlinePlus