Anti‐Inflammatory Effect of Ascochlorin in LPS‐Stimulated RAW 264.7 Macrophage Cells Is Accompanied With the Down‐Regulation of iNOS, COX‐2 and Proinflammatory Cytokines Through NF‐κB, ERK1/2, and p38 Signaling Pathway

Lee, Sook-Hyun; Kwak, Choong Hwan; Lee, Sungkyun; Ha, Sun-Hyung; Park, Jun-Young; Chung, Tae‐Wook; Ha, Ki‐Tae; Suh, Suk-Jong; Chang, Young‐Chae; Chang, Hyeun Wook; Lee, Young Choon; Kang, Bong-Seok; Magae, Junji; Kim, Cheorl-Ho

doi:10.1002/jcb.25383

Cited by 91 publications

(71 citation statements)

References 36 publications

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“…Similar to results seen in ROS-generation assays, the addition of TUG-891 to cells overexpressing these constructs did not further the effect (data not shown), suggesting that heightened receptor numbers yield maximal activity that is not sensitive to further agonism. In Raw 264.7 macrophages, LPS-induced phosphorylation of ERK1/2, can be activated in part by Ca 2+ -dependent signals through PI3-Kinase, phospholipase-C, or PKC activity (33–35), as well as via TAK1 scaffolds that are upheld by β-arrestin-2 (13,36–37). Hence, we next examined the effects of FFA4 isoform and C-terminal mutant expression on LPS-mediated ERK1/2 phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages

Cheshmehkani

Senatorov

Dhuguru

et al. 2017

Biochemical Pharmacology

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Agonism of the G protein-coupled Free-Fatty Acid receptor-4 (FFA4) has been shown to promote numerous anti-inflammatory effects in macrophages that arise due to interaction with β-arrestin partner proteins. Humans express functionally distinct short and long FFA4 splice variants, such that FFA4-S signals through Gαq/11 and β-arrestin, while FFA4-L is intrinsically biased solely towards β-arrestin signaling. Recently, we and others have shown that phosphorylation of the FFA4 C-terminal tail is responsible for β-arrestin interactability and signaling. Given the significance of β-arrestin in the anti-inflammatory function of FFA4, the goal of this study was to examine the role of the C-terminal β-arrestin phosphosensor in FFA4 signaling induced by PMA and LPS in murine Raw 264.7 macrophages. Our data reveal for the first time that both FFA4 isoforms modulate PMA-induced ROS generation, and that abolishment of the FFA4-S, but not FFA4-L C-terminal phosphosensor, is detrimental to this effect. Furthermore, we show that while both isoforms reduce PMA-induced expression of COX-2, removal of the FFA4-S phosphosensor significantly decreases this response, suggesting that these effects of FFA4-S are β-arrestin mediated. On the contrary, FFA4-S, as well as the truncated C-terminal congener lacking the β-arrestin phosphosensor were both able to reduce LPS-induced NF-κB activity and ERK1/2 phosphorylation. However, FFA4-L and its corresponding mutant were incapable of modulating either, suggesting that these responses are mediated by G protein coupling. Taken together, our data reveal important structure-function and signaling differences between the two FFA4 isoforms, and for the first time link FFA4 to modulation of ROS in macrophages.

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Section: Resultsmentioning

confidence: 99%

Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages

Cheshmehkani

Senatorov

Dhuguru

et al. 2017

Biochemical Pharmacology

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“…ASC‐related compounds were originally characterized as antiviral antibiotics . ASC functions as an antibiotic, promotion hypolipidemic activity, anti‐diabetic, immunomodulation . In addition to ASC, ASC‐related derivatives like 4‐O‐carboxymethylascochlorin (AS‐6) and 4‐O‐methylascochlorin (MAC) have been reported to be therapeutic reagents for various physiological events .…”

Section: Introductionmentioning

confidence: 99%

Upregulation of AMPK by 4‐O‐methylascochlorin promotes autophagy via the HIF‐1α expression

Seok

Jeong

Hwang

et al. 2018

J Cellular Molecular Medi

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Abstract4‐O‐methylascochlorin (MAC) is a derivative of ascochlorin, a prenyl‐phenol compound antibiotic isolated from the fungus Ascochyta viciae. MAC induces caspase/poly (ADP‐ribose) polymerase‐mediated apoptosis in leukemia cells. However, the effects of MAC on autophagy in cancer cells and the underlying molecular mechanisms remain unknown. Here, we show that MAC induces autophagy in lung cancer cells. MAC significantly induced the expression of autophagy marker proteins including LC3‐II, Beclin1, and ATG7. MAC promoted AMP‐activated protein kinase (AMPK) phosphorylation and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream signalling proteins P70S6K and 4EBP1. The AMPK activator AICAR upregulated LC3‐II expression through the AMPK/mTOR pathway similar to the effects of MAC. MAC‐induced LC3‐II protein expression was slightly reduced in AMPK siRNA transfected cells. MAC upregulated hypoxia‐inducible factor‐1α (HIF‐1α) and BNIP3, which are HIF‐1α‐dependent autophagic proteins. Treatment with CoCl2, which mimics hypoxia, induced autophagy similar to the effect of MAC. The HIF‐1α inhibitor YC‐1 and HIF‐1α siRNA inhibited the MAC‐induced upregulation of LC3‐II and BNIP3. These results suggest that MAC induces autophagy via the AMPK/mTOR signalling pathway and by upregulating HIF‐1α and BNIP3 protein expression in lung cancer cells.

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“…NF-κB and COX-2 are two main factors in inflammatory reaction, and are associated with tumorigenesis and tumor progression [9]. Epithelial-messenchymal transition (EMT) is a basic step among various factors in tumor metastasis and invasion [10].…”

Section: Introductionmentioning

confidence: 99%

Ellagic acid inhibits the proliferation of human pancreatic carcinoma PANC-1 cells in vitro and in vivo

Cheng

Tang

et al. 2017

Oncotarget

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Ellagic aicd (EA), a dietary polyphenolic compound found in plants and fruits, possesses various pharmacological activities. This study investigated the effect of EA on human pancreatic carcinoma PANC-1 cells both in vitro and in vivo; and defined the associated molecular mechanisms. In vitro, the cell growth and repairing ability were assessed by CCK-8 assay and wound healing assay. The cell migration and invasion activity was evaluated by Tanswell assay. In vivo, PANC-1 cell tumor-bearing mice were treated with different concentrations of EA. We found that EA significantly inhibited cell growth, cell repairing activity, and cell migration and invasion in a dose-dependent manner. Treatment of PANC-1 xenografted mice with EA resulted in significant inhibition in tumor growth and prolong mice survival rate. Furthermore, flow cytometric analysis showed that EA increased the percentage of cells in the G1 phase of cell cycle. Western blot analysis revealed that EA inhibited the expression of COX-2 and NF-κB. In addition, EA reversed epithelial to mesenchymal transition by up-regulating E-cadherin and down-regulating Vimentin. In summary, the present study demonstrated that EA inhibited cell growth, cell repairing activity, cell migration and invasion in a dose-dependent manner. EA also effectively inhibit human pancreatic cancer growth in mice. The anti-tumor effect of EA might be related to cell cycle arrest, down-regulating the expression of COX-2 and NF-κB, reversing epithelial to mesenchymal transition by up-regulating E-cadherin and down-regulating Vimentin. Our findings suggest that the use of EA would be beneficial for the management of pancreatic cancer.

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Anti‐Inflammatory Effect of Ascochlorin in LPS‐Stimulated RAW 264.7 Macrophage Cells Is Accompanied With the Down‐Regulation of iNOS, COX‐2 and Proinflammatory Cytokines Through NF‐κB, ERK1/2, and p38 Signaling Pathway

Cited by 91 publications

References 36 publications

Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages

Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages

Upregulation of AMPK by 4‐O‐methylascochlorin promotes autophagy via the HIF‐1α expression

Ellagic acid inhibits the proliferation of human pancreatic carcinoma PANC-1 cells in vitro and in vivo

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