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Mulberry fruit prevents LPS-induced NF-κB/pERK/MAPK signals in macrophages and suppresses acute colitis and colorectal tumorigenesis in mice.

Qian Z, Wu Z, Huang L, Qiu H, Wang L, Li L, Yao L, Kang K, Qu J, Wu Y, Luo J, Liu JJ, Yang Y, Yang W, Gou D - Sci Rep (2015)

Bottom Line: In vitro, LPS-induced nitric oxide (NO) production was significantly inhibited by MBF extracts via suppressing the expression of proinflammatory molecules, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-β) and IL-6.In vivo, DSS-induced acute colitis was significantly ameliorated in MBF-fed mice as gauged by weight loss, colon morphology and histological damage.In addition, MBF-fed MUC2(-/-) mice displayed significant decrease in intestinal tumor and inflammation incidence compared to control diet-fed group.

View Article: PubMed Central - PubMed

Affiliation: Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Sciences, Shenzhen University, Shenzhen, Guangdong, 518060, China.

ABSTRACT
Here, we investigated the impact of mulberry fruit (MBF) extracts on lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 macrophages, and the therapeutic efficacy of MBF diet in mice with dextran sulfate sodium (DSS)-induced acute colitis and MUC2(-/-) mice with colorectal cancer. In vitro, LPS-induced nitric oxide (NO) production was significantly inhibited by MBF extracts via suppressing the expression of proinflammatory molecules, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-β) and IL-6. Particularly, a dose-dependent inhibition on LPS-induced inflammatory responses was observed following treatment with MBF dichloromethane extract (MBF-DE), in which linoleic acid and ethyl linolenate were identified as two active compounds. Moreover, we elucidated that MBF-DE attenuated LPS-induced inflammatory responses by blocking activation of both NF-κB/p65 and pERK/MAPK pathways. In vivo, DSS-induced acute colitis was significantly ameliorated in MBF-fed mice as gauged by weight loss, colon morphology and histological damage. In addition, MBF-fed MUC2(-/-) mice displayed significant decrease in intestinal tumor and inflammation incidence compared to control diet-fed group. Overall, our results demonstrated that MBF suppressed the development of intestinal inflammation and tumorgenesis both in vitro and in vivo, and supports the potential of MBF as a therapeutic functional food for testing in human clinical trials.

No MeSH data available.


Related in: MedlinePlus

A schematic model that proposes the potential contribution of MBF in anti-inflammatory signaling pathways.LPS: lipopolysaccharide; MBF-DE: mulberry fruit dichloromethane extracts; NO: nitric oxide.
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f8: A schematic model that proposes the potential contribution of MBF in anti-inflammatory signaling pathways.LPS: lipopolysaccharide; MBF-DE: mulberry fruit dichloromethane extracts; NO: nitric oxide.

Mentions: It has been well recognized that NF-κB is a key transcription factor that plays a pivotal role in the onset of inflammation and tumor progression2935. In normal condition, functional NF-κB dimers are located in cytosol, combining with its inhibitor protein IκBα35. By contrast, in response to inflammatory stimuli, NF-κB was activated through the phosphorylation and subsequent degradation of IκBα/β by IKK complex36. The activated state of NF-κB dimer dissociates from IκBα/β in the cytosol and subsequently translocates to the nucleus, where it induces the expression of various inflammatory genes, including iNOS, COX-2 and TNF-α373839. Similarly, MAPKs as a large family of seine/threonine kinases can also largely mediated the inflammatory signaling from the cell surface to the nucleus. Upon extracellular stimulation, these cytoplasmic enzymes are activated and thus they can modulate the activities of other intracellular proteins by adding phosphate groups to their serine/threonine amino acids. Ultimately, various transcription factors present in cytoplasm or nucleus could be phosphorylated and activated by three major groups of MAPKs, i.e., ERK1/2, p38 and JNK, leading to expression of different inflammatory mediators mentioned above3839. In this work, both NF-κB and MAPK pathways were studied due to the strong inhibitory effects of MBF-DE on the expression of inflammatory genes (Fig. 2). Our study showed that MBF-DE inhibited the translocation of NF-κB p65 from cytoplasm to nucleus through blocking the LPS induced phosphorylation of IκBα (Figs 3 and 4), and suppressed the MAPK signals by suppressing the phosphorylation of ERK and p38 (Fig. 3). These findings suggested that MBF-DE treatment attenuated LPS induced inflammatory response, which could be attributable to the suppression of both NF-κB/p65 and MAPK/p38/ERK signals (Fig. 8). However, it should be noted that since the cell viability was not affected by the MBF-DE treatment (Fig. 1b), the inhibition of these two signals might not associated with the cell proliferation or apoptosis, although the exact molecular mechanism and functional target of MBF-DE need to be explored in future.


Mulberry fruit prevents LPS-induced NF-κB/pERK/MAPK signals in macrophages and suppresses acute colitis and colorectal tumorigenesis in mice.

Qian Z, Wu Z, Huang L, Qiu H, Wang L, Li L, Yao L, Kang K, Qu J, Wu Y, Luo J, Liu JJ, Yang Y, Yang W, Gou D - Sci Rep (2015)

A schematic model that proposes the potential contribution of MBF in anti-inflammatory signaling pathways.LPS: lipopolysaccharide; MBF-DE: mulberry fruit dichloromethane extracts; NO: nitric oxide.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663626&req=5

f8: A schematic model that proposes the potential contribution of MBF in anti-inflammatory signaling pathways.LPS: lipopolysaccharide; MBF-DE: mulberry fruit dichloromethane extracts; NO: nitric oxide.
Mentions: It has been well recognized that NF-κB is a key transcription factor that plays a pivotal role in the onset of inflammation and tumor progression2935. In normal condition, functional NF-κB dimers are located in cytosol, combining with its inhibitor protein IκBα35. By contrast, in response to inflammatory stimuli, NF-κB was activated through the phosphorylation and subsequent degradation of IκBα/β by IKK complex36. The activated state of NF-κB dimer dissociates from IκBα/β in the cytosol and subsequently translocates to the nucleus, where it induces the expression of various inflammatory genes, including iNOS, COX-2 and TNF-α373839. Similarly, MAPKs as a large family of seine/threonine kinases can also largely mediated the inflammatory signaling from the cell surface to the nucleus. Upon extracellular stimulation, these cytoplasmic enzymes are activated and thus they can modulate the activities of other intracellular proteins by adding phosphate groups to their serine/threonine amino acids. Ultimately, various transcription factors present in cytoplasm or nucleus could be phosphorylated and activated by three major groups of MAPKs, i.e., ERK1/2, p38 and JNK, leading to expression of different inflammatory mediators mentioned above3839. In this work, both NF-κB and MAPK pathways were studied due to the strong inhibitory effects of MBF-DE on the expression of inflammatory genes (Fig. 2). Our study showed that MBF-DE inhibited the translocation of NF-κB p65 from cytoplasm to nucleus through blocking the LPS induced phosphorylation of IκBα (Figs 3 and 4), and suppressed the MAPK signals by suppressing the phosphorylation of ERK and p38 (Fig. 3). These findings suggested that MBF-DE treatment attenuated LPS induced inflammatory response, which could be attributable to the suppression of both NF-κB/p65 and MAPK/p38/ERK signals (Fig. 8). However, it should be noted that since the cell viability was not affected by the MBF-DE treatment (Fig. 1b), the inhibition of these two signals might not associated with the cell proliferation or apoptosis, although the exact molecular mechanism and functional target of MBF-DE need to be explored in future.

Bottom Line: In vitro, LPS-induced nitric oxide (NO) production was significantly inhibited by MBF extracts via suppressing the expression of proinflammatory molecules, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-β) and IL-6.In vivo, DSS-induced acute colitis was significantly ameliorated in MBF-fed mice as gauged by weight loss, colon morphology and histological damage.In addition, MBF-fed MUC2(-/-) mice displayed significant decrease in intestinal tumor and inflammation incidence compared to control diet-fed group.

View Article: PubMed Central - PubMed

Affiliation: Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Sciences, Shenzhen University, Shenzhen, Guangdong, 518060, China.

ABSTRACT
Here, we investigated the impact of mulberry fruit (MBF) extracts on lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 macrophages, and the therapeutic efficacy of MBF diet in mice with dextran sulfate sodium (DSS)-induced acute colitis and MUC2(-/-) mice with colorectal cancer. In vitro, LPS-induced nitric oxide (NO) production was significantly inhibited by MBF extracts via suppressing the expression of proinflammatory molecules, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-β) and IL-6. Particularly, a dose-dependent inhibition on LPS-induced inflammatory responses was observed following treatment with MBF dichloromethane extract (MBF-DE), in which linoleic acid and ethyl linolenate were identified as two active compounds. Moreover, we elucidated that MBF-DE attenuated LPS-induced inflammatory responses by blocking activation of both NF-κB/p65 and pERK/MAPK pathways. In vivo, DSS-induced acute colitis was significantly ameliorated in MBF-fed mice as gauged by weight loss, colon morphology and histological damage. In addition, MBF-fed MUC2(-/-) mice displayed significant decrease in intestinal tumor and inflammation incidence compared to control diet-fed group. Overall, our results demonstrated that MBF suppressed the development of intestinal inflammation and tumorgenesis both in vitro and in vivo, and supports the potential of MBF as a therapeutic functional food for testing in human clinical trials.

No MeSH data available.


Related in: MedlinePlus