Farrerol Ameliorates TNBS-Induced Colonic Inflammation by Inhibiting ERK1/2, JNK1/2, and NF-κB Signaling Pathway

Ran, Xin; Li, Yuhang; Chen, Guangxin; Fu, Shoupeng; He, Dewei; Huang, Bingxu; Wei, Libin; Lin, Yuanqing; Guo, Yingcheng; Hu, Guiqiu

doi:10.3390/ijms19072037

Cited by 42 publications

(25 citation statements)

References 50 publications

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“…These ndings suggest that HBEGF serves as a prophylactic or therapeutic agent for the prevention or treatment of intestinal diseases such as hypo-perfusion injury and peritonitis-induced sepsis. Extracellular signal-regulated kinase (ERK)1/2 MAPK, PI3K/AKT, nucleotide-binding oligomerization domain-containing protein 1/2, c-Jun N-terminal kinase (JNK)1/2, and STAT signaling pathways are involved in intestinal barrier function and wound healing (11,45,49). The present study reported that HBEGF ameliorates LPS-induced intestinal dysfunction via PI3K/AKT and P38 signaling pathways.…”

Section: Discussionmentioning

confidence: 70%

Eckol alleviates intestinal dysfunction during suckling-to-weaning transition via modulation of PDX1 and HBEGF

Lee

Kim

2020

Preprint

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Background Maintaining intestinal health in livestock is critical during weaning. Although intestinal dysfunction during this period can be alleviated by phlorotannins including eckol, the precise mechanisms are not fully understood. We addressed this question by evaluating changes in gene expression and intestinal function after treatment with eckol during the suckling-to-weaning transition. The biological roles of differentially expressed genes in intestinal development were investigated by assessing intestinal wound healing and barrier function and associated signaling pathways, along with oxidative stress levels. Results We identified 890 differentially expressed genes in the intestine whose expression was altered by eckol treatment including pancreatic and duodenal homeobox (PDX)1, which directly regulate the expression of heparin-binding epidermal growth factor-like growth factor (HBEGF) to preserve intestinal barrier function and promote wound healing via phosphoinositide 3-kinase (PI3K)/AKT and P38 signaling. Additionally, eckol alleviated H2O2-induced oxidative stress via PI3K/AKT, P38, and 5' AMP-activated protein kinase signaling, improved growth, and reduced oxidative stress and intestinal permeability in pigs during weaning. Conclusions Eckol modulates intestinal barrier function, wound healing, and oxidative stress via PDX/HBEGF and improves growth during the suckling-to-weaning transition, suggesting that it can be used as a feed supplement to preserve intestinal function during this process in pigs and other livestock.

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Section: Discussionmentioning

confidence: 70%

Eckol alleviates intestinal dysfunction during suckling-to-weaning transition via modulation of PDX1 and HBEGF

Lee

Kim

2020

Preprint

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“…These findings suggest that HBEGF serves as a prophylactic or therapeutic agent for preventing or treating intestinal disorders, such as hypo-perfusion injury and peritonitis-induced sepsis. The extracellular signal-regulated kinase (ERK)1/2 MAPK, PI3K/AKT, nucleotide-binding oligomerization domain-containing protein 1/2, c-Jun N-terminal kinase (JNK)1/2, and STAT signaling pathways are involved in intestinal barrier function and wound healing [ 11 , 44 , 48 ]. The present study showed that HBEGF alleviated LPS-induced intestinal dysfunction through PI3K/AKT and P38 signaling pathway activation.…”

Section: Discussionmentioning

confidence: 99%

Eckol Alleviates Intestinal Dysfunction during Suckling-to-Weaning Transition via Modulation of PDX1 and HBEGF

Lee

Kim

2020

IJMS

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Maintaining intestinal health in livestock is critical during the weaning period. The precise mechanisms of intestinal dysfunction during this period are not fully understood, although these can be alleviated by phlorotannins, including eckol. This question was addressed by evaluating the changes in gene expression and intestinal function after eckol treatment during suckling-to-weaning transition. The biological roles of differentially expressed genes (DEGs) in intestinal development were investigated by assessing intestinal wound healing and barrier functions, as well as the associated signaling pathways and oxidative stress levels. We identified 890 DEGs in the intestine, whose expression was altered by eckol treatment, including pancreatic and duodenal homeobox (PDX)1, which directly regulate heparin-binding epidermal growth factor-like growth factor (HBEGF) expression in order to preserve intestinal barrier functions and promote wound healing through phosphoinositide 3-kinase (PI3K)/AKT and P38 signaling. Additionally, eckol alleviated H2O2-induced oxidative stress through PI3K/AKT, P38, and 5’-AMP-activated protein kinase (AMPK) signaling, improved growth, and reduced oxidative stress and intestinal permeability in pigs during the weaning period. Eckol modulates intestinal barrier functions, wound healing, and oxidative stress through PDX/HBEGF, and improves growth during the suckling-to-weaning transition. These findings suggest that eckol can be used as a feed supplement in order to preserve the intestinal functions in pigs and other livestock during this process.

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“…Farrerol directly inhibited the kinase activity of GSK-3β to activate the Nrf2-ARE pathway and further attenuate oxidative stress damage in EA.hy926 cells. 15 Oxidative Medicine and Cellular Longevity…”

Section: Defensive Gene Expressionmentioning

confidence: 99%

“…Farrerol is the major bioactive component isolated from the leaves of traditional Chinese herb Rhododendron dauricum L. As a naturally occurring flavanone, it (Figure 1(a)) has the same core structure as naringenin but contains two additional methyl groups on the ring A. It has been documented that farrerol possesses many biological activities, such as antioxidative, anti-inflammatory, antibacterial, anticancer, and inhibition of VSMC proliferation [14][15][16][17][18]. Recent studies from our group also indicate that farrerol has a positive influence on cardiovascular disease.…”

Section: Introductionmentioning

confidence: 99%

Farrerol Directly Targets GSK-3β to Activate Nrf2-ARE Pathway and Protect EA.hy926 Cells against Oxidative Stress-Induced Injuries

Yan

Zhang

Miao

et al. 2020

Oxidative Medicine and Cellular Longevity

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Oxidative stress-mediated endothelial injury is considered to be involved in the pathogenesis of various cardiovascular diseases. Farrerol, a typical natural flavanone from the medicinal plant Rhododendron dauricum L., has been reported to show protective effects against oxidative stress-induced endothelial injuries in our previous study. However, its action molecular mechanisms and targets are still unclear. In the present study, we determined whether farrerol can interact with glycogen synthase kinase 3β- (GSK-3β-) nuclear factor erythroid 2-related factor 2- (Nrf2-) antioxidant response element (ARE) signaling, which is critical in defense against oxidative stress. Our results demonstrated that farrerol could specifically target Nrf2 negative regulator GSK-3β and inhibit its kinase activity. Mechanistic studies proved that farrerol could induce an inhibitory phosphorylation of GSK-3β at Ser9 without affecting the expression level of total GSK-3β protein and promote the nuclear translocation of Nrf2 as well as the mRNA and protein expression of its downstream target genes heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) in EA.hy926 cells. Further studies performed with GSK-3β siRNA and specific inhibitor lithium chloride (LiCl) confirmed that GSK-3β inhibition was involved in farrerol-mediated endothelial protection and Nrf2 signaling activation. Moreover, molecular docking and molecular dynamics studies revealed that farrerol could bind to the ATP pocket of GSK-3β, which is consistent with the ATP-competitive kinetic behavior. Collectively, our results firstly demonstrate that farrerol could attenuate endothelial oxidative stress by specifically targeting GSK-3β and further activating the Nrf2-ARE signaling pathway.

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Farrerol Ameliorates TNBS-Induced Colonic Inflammation by Inhibiting ERK1/2, JNK1/2, and NF-κB Signaling Pathway

Cited by 42 publications

References 50 publications

Eckol alleviates intestinal dysfunction during suckling-to-weaning transition via modulation of PDX1 and HBEGF

Eckol alleviates intestinal dysfunction during suckling-to-weaning transition via modulation of PDX1 and HBEGF

Eckol Alleviates Intestinal Dysfunction during Suckling-to-Weaning Transition via Modulation of PDX1 and HBEGF

Farrerol Directly Targets GSK-3β to Activate Nrf2-ARE Pathway and Protect EA.hy926 Cells against Oxidative Stress-Induced Injuries

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