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Flavonoids Extracted from Licorice Prevents Colitis-Associated Carcinogenesis in AOM/DSS Mouse Model

View Article: PubMed Central - PubMed

ABSTRACT

Inflammatory bowel disease (IBD) is generally considered as a major risk factor in the progression of colitis-associated carcinogenesis (CAC). Thus, it is well accepted that ameliorating inflammation creates a potential to achieve an inhibitory effect on CAC. Licorice flavonoids (LFs) possess strong anti-inflammatory activity, making it possible to investigate its pharmacologic role in suppressing CAC. The purpose of the present study was to evaluate the anti-tumor potential of LFs, and further explore the underlying mechanisms. Firstly, an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mouse model was established and administered with or without LFs for 10 weeks, and then the severity of CAC was examined macroscopically and histologically. Subsequently, the effects of LFs on expression of proteins associated with apoptosis and proliferation, levels of inflammatory cytokine, expression of phosphorylated-Janus kinases 2 (p-Jak2) and phosphorylated-signal transducer and activator of transcription 3 (p-Stat3), and activation of nuclear factor-κB (NFκB) and P53 were assessed. We found that LFs could significantly reduce tumorigenesis induced by AOM/DSS. Further study revealed that LFs treatment substantially reduced activation of NFκB and P53, and subsequently suppressed production of inflammatory cytokines and phosphorylation of Jak2 and Stat3 in AOM/DSS-induced mice. Taken together, LFs treatment alleviated AOM/DSS induced CAC via P53 and NFκB/IL-6/Jak2/Stat3 pathways, highlighting the potential of LFs in preventing CAC.

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Effects of LFs on pro-inflammatory cytokines and mediators. (A) Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α) levels in serum. ELISA kits specific to each cytokine were used to detected levels of IL-1β, IL-6, and TNF-α in serum. Data are presented as mean ± SD. ** p < 0.01 vs. model, ##p < 0.01 vs. vehicle control; (B) mRNA levels of IL-1β, IL-6, and TNF-α in the colonic tissues. qRT-PCR analysis was carried out to evaluate mRNA levels of IL-1β, IL-6, and TNF-α. Data are presented as mean ± SD. ** p < 0.01 vs. model, ##p < 0.01 vs. vehicle control; (C) mRNA levels of cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNOS) in the colonic tissues by qRT-PCR analysis. Data are presented as mean ± SD. ** p < 0.01 vs. model, ##p < 0.01 vs. vehicle control. (D) Immunohistochemical staining of Cox-2 in colonic tissues.
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ijms-17-01343-f004: Effects of LFs on pro-inflammatory cytokines and mediators. (A) Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α) levels in serum. ELISA kits specific to each cytokine were used to detected levels of IL-1β, IL-6, and TNF-α in serum. Data are presented as mean ± SD. ** p < 0.01 vs. model, ##p < 0.01 vs. vehicle control; (B) mRNA levels of IL-1β, IL-6, and TNF-α in the colonic tissues. qRT-PCR analysis was carried out to evaluate mRNA levels of IL-1β, IL-6, and TNF-α. Data are presented as mean ± SD. ** p < 0.01 vs. model, ##p < 0.01 vs. vehicle control; (C) mRNA levels of cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNOS) in the colonic tissues by qRT-PCR analysis. Data are presented as mean ± SD. ** p < 0.01 vs. model, ##p < 0.01 vs. vehicle control. (D) Immunohistochemical staining of Cox-2 in colonic tissues.

Mentions: Chronic inflammation is now widely accepted as a promoter of colitis-associated colon carcinogenesis. We therefore evaluated whether the anti-tumor activity of LFs was associated with its anti-inflammatory properties through inhibiting pro-inflammatory cytokines and mediators (IL-1β, IL-6, TNF-α, iNOS and Cox-2). As shown in Figure 4A, levels of IL-1β, IL-6, and TNF-α in serum were markedly elevated in AOM/DSS-induced mice, relative to that in the control group. High levels of IL-1β, IL-6, and TNF-α in serum were significantly inhibited by LFs treatment. Moreover, we observed that LFs treatment could dramatically decrease mRNA levels of IL-1β, IL-6, and TNF-α in colonic tissues at either 50 or 100 mg/kg (Figure 4B).


Flavonoids Extracted from Licorice Prevents Colitis-Associated Carcinogenesis in AOM/DSS Mouse Model
Effects of LFs on pro-inflammatory cytokines and mediators. (A) Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α) levels in serum. ELISA kits specific to each cytokine were used to detected levels of IL-1β, IL-6, and TNF-α in serum. Data are presented as mean ± SD. ** p < 0.01 vs. model, ##p < 0.01 vs. vehicle control; (B) mRNA levels of IL-1β, IL-6, and TNF-α in the colonic tissues. qRT-PCR analysis was carried out to evaluate mRNA levels of IL-1β, IL-6, and TNF-α. Data are presented as mean ± SD. ** p < 0.01 vs. model, ##p < 0.01 vs. vehicle control; (C) mRNA levels of cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNOS) in the colonic tissues by qRT-PCR analysis. Data are presented as mean ± SD. ** p < 0.01 vs. model, ##p < 0.01 vs. vehicle control. (D) Immunohistochemical staining of Cox-2 in colonic tissues.
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Related In: Results  -  Collection

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ijms-17-01343-f004: Effects of LFs on pro-inflammatory cytokines and mediators. (A) Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α) levels in serum. ELISA kits specific to each cytokine were used to detected levels of IL-1β, IL-6, and TNF-α in serum. Data are presented as mean ± SD. ** p < 0.01 vs. model, ##p < 0.01 vs. vehicle control; (B) mRNA levels of IL-1β, IL-6, and TNF-α in the colonic tissues. qRT-PCR analysis was carried out to evaluate mRNA levels of IL-1β, IL-6, and TNF-α. Data are presented as mean ± SD. ** p < 0.01 vs. model, ##p < 0.01 vs. vehicle control; (C) mRNA levels of cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNOS) in the colonic tissues by qRT-PCR analysis. Data are presented as mean ± SD. ** p < 0.01 vs. model, ##p < 0.01 vs. vehicle control. (D) Immunohistochemical staining of Cox-2 in colonic tissues.
Mentions: Chronic inflammation is now widely accepted as a promoter of colitis-associated colon carcinogenesis. We therefore evaluated whether the anti-tumor activity of LFs was associated with its anti-inflammatory properties through inhibiting pro-inflammatory cytokines and mediators (IL-1β, IL-6, TNF-α, iNOS and Cox-2). As shown in Figure 4A, levels of IL-1β, IL-6, and TNF-α in serum were markedly elevated in AOM/DSS-induced mice, relative to that in the control group. High levels of IL-1β, IL-6, and TNF-α in serum were significantly inhibited by LFs treatment. Moreover, we observed that LFs treatment could dramatically decrease mRNA levels of IL-1β, IL-6, and TNF-α in colonic tissues at either 50 or 100 mg/kg (Figure 4B).

View Article: PubMed Central - PubMed

ABSTRACT

Inflammatory bowel disease (IBD) is generally considered as a major risk factor in the progression of colitis-associated carcinogenesis (CAC). Thus, it is well accepted that ameliorating inflammation creates a potential to achieve an inhibitory effect on CAC. Licorice flavonoids (LFs) possess strong anti-inflammatory activity, making it possible to investigate its pharmacologic role in suppressing CAC. The purpose of the present study was to evaluate the anti-tumor potential of LFs, and further explore the underlying mechanisms. Firstly, an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mouse model was established and administered with or without LFs for 10 weeks, and then the severity of CAC was examined macroscopically and histologically. Subsequently, the effects of LFs on expression of proteins associated with apoptosis and proliferation, levels of inflammatory cytokine, expression of phosphorylated-Janus kinases 2 (p-Jak2) and phosphorylated-signal transducer and activator of transcription 3 (p-Stat3), and activation of nuclear factor-&kappa;B (NF&kappa;B) and P53 were assessed. We found that LFs could significantly reduce tumorigenesis induced by AOM/DSS. Further study revealed that LFs treatment substantially reduced activation of NF&kappa;B and P53, and subsequently suppressed production of inflammatory cytokines and phosphorylation of Jak2 and Stat3 in AOM/DSS-induced mice. Taken together, LFs treatment alleviated AOM/DSS induced CAC via P53 and NF&kappa;B/IL-6/Jak2/Stat3 pathways, highlighting the potential of LFs in preventing CAC.

No MeSH data available.


Related in: MedlinePlus