The naturally occurring biflavonoid, ochnaflavone, inhibits LPS-induced iNOS expression, which is mediated by ERK1/2 via NF-κB regulation, in RAW264.7 cells

Suh, Sungho; Chung, Tae‐Wook; Son, Min Jung; Kim, Sung Hoon; Moon, Tae Chul; Son, Kun Ho; Kim, Hyun Pyo; Chang, Hyeun Wook; Kim, Cheorl-Ho

doi:10.1016/j.abb.2006.01.016

Cited by 93 publications

(70 citation statements)

References 36 publications

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“…Moreover, in the present study, the ERK1/2 inhibitor decreased in LPS-induced iNOS mRNA and protein expressions in cells. Suh et al (2006) have also shown that U0126, an inhibitor of ERK, significantly down-regulates LPS-induced iNOS expression. These findings suggest that salbutamol inhibits LPS-induced iNOS expression at least in part through the MAPK signal-transduction pathway and subsequent increase in IL-6.…”

Section: Resultsmentioning

confidence: 97%

Salbutamol inhibits lipopolysaccharide-induced inflammatory responses in rat peritoneal macrophages

et al. 2010

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-Acute and chronic inflammatory diseases are associated with the induction of inducible nitric oxide synthase (iNOS) and inducible heme oxygenase (HO-1). These inducible enzymes are upregulated in macrophages subjected to inflammatory stimuli and oxidative stress. β 2 -Adrenoceptor (AR) agonists, which function as bronchial dilators, are widely used for the treatment of asthma and chronic obstructive pulmonary disease (COPD). We examined whether salbutamol, a classical β 2 -AR agonist, inhibits the induction of proinflammatory cytokines and stress inducible proteins. Rat macrophages obtained from the abdominal cavity were incubated with lipopolysaccharide (LPS) with or without salbutamol. Induction by LPS of tumor necrosis factor (TNF)-α and interleukin (IL)-6 was significantly inhibited (P < 0.05) by salbutamol treatment. Induction by LPS of iNOS mRNA and protein was also significantly inhibited (P < 0.05) by salbutamol. LPS-mediated increases in HO-1 mRNA and protein were not appreciably affected by salbutamol. One of the anti-inflammatory mechanisms of salbutamol was thus found to be inhibition of induction by LPS of extracellular stimulus-responsive kinase (ERK) 1/2 in macrophages. These findings suggest that salbutamol has the potential for use as an anti-inflammatory agent due to its suppression of LPS-induced TNF-α, and IL-6 and iNOS via ERK pathway without affecting HO-1 expression.Key words: Salbutamol, TNF-α, IL-6, iNOS, LPS Correspondence: Satoru Tanaka (E-mail: satoru_tanaka@pharm.kissei.co.jp) Original ArticleThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.35, No.3, 327-334, 2010 Vol. 35 No. 3 327 enzymes play roles in the pathogenesis of and may therefore be useful as targets in the treatment of asthma and COPD. β 2 -adrenoceptor (AR) agonists such as salbutamol are mainstay bronchodilators in the treatment of asthma and COPD. Malfait et al. (1999) demonstrated that salbutamol exhibited therapeutic effects against rheumatoid arthritis model rats with collagen-induced arthritis. In a clinical study, inhalation of a long-acting β 2 -AR agonist by patients with mild asthma yielded a novel antineutrophilic effect (Jeffery et al., 2002).Based on these findings we examined whether β 2 -AR agonists inhibit proinflammatory cytokine and stressinducible protein production by in vitro cultured abdominal macrophages, in an attempt to determine novel targets in the treatment of inflammatory diseases. MATERIALS AND METHODS MaterialsSalbutamol (hemisulfate, minimum purity 98%) and PD98059, an extracellular stimulus-responsive kinase (ERK) 1/2 inhibitor, were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). LPS from Escherichia coli and ICI118551, a selective β 2 -adrenoceptor antagonist, were purchased from Sigma-Aldrich Inc. (St. Louis, MO, USA). The rat IL-6 Immunoassay KIT and rat TNF-α ELISA KIT were purchased from BioSource International Inc. (Camarillo, CA, USA). Primer sets, including those for iNOS oligo (RA008296), HO-1 oligo (RA008256), and β-actin oligo (RA006...

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Section: Resultsmentioning

confidence: 97%

Salbutamol inhibits lipopolysaccharide-induced inflammatory responses in rat peritoneal macrophages

et al. 2010

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“…2,3) Recently, it was reported that this compound inhibits LPS-induced iNOS expression, which is mediated by ERK1/2 via NF-kB regulation, in RAW264.7 cells. 4) In addition, biflavonoids such as ginkgetin and ochnaflavone (OC) were reported to be dual inhibitor of cyclooxygenase-2 and 5-lipoxygenase from the mast cells as well as inhibit the release of the archidonic acid metabolites from the rat peritoneal macrophages stimulated by either phorbol ester or calcium ionophore, A 23187 . [5][6][7] It has been suggested that CCl 4 -induced stimulation of peroxide breaks down the membrane lipids, which leads to PLA 2 activation.…”

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confidence: 99%

Ochnaflavone, Naturally Occurring Biflavonoid, Inhibits Phospholipase A2 Dependent Phosphatidylethanolamine Degradation in a CCl4-Induced Rat Liver Microsome

Moon

Hwang

Quan

et al. 2006

Biological & Pharmaceutical Bulletin

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This study investigated the protective effects of a group IIA secretory phospholipase A 2 (sPLA 2 -IIA) inhibitor, ochnaflavone, on the progression of carbon tetrachloride (CCl 4 )-induced acute liver injury in rat liver microsomes in vitro. When rat liver was incubated at 37°C in the presence of CCl 4 , the level of phosphatidylethanolamine (PE) degradation increased markedly compared with the control. The rat 14 kDa platelet PLA 2 antibody, R377, suppressed the degradation of PE. Pretreating the microsome with ochnaflavone (2-16 m mM) reduced the level of PE degradation in a dose dependent manner. In addition, p-bromophenacy bromide (p-BPB), which is a PLA 2 inhibitor, also inhibited PE degradation. However, the inhibitory activity was weaker than that of ochnaflavone. Further investigation showed that ochnaflavone not only inhibited the purified rat platelet sPLA 2 activity in a dose dependent manner with an IC 50 value of 3.45 m mM, when arachidonyl PE was used as a substrate, but also inhibited lipid peroxidation in a dose dependent manner with an IC 50 value of 7.16 m mM. This result suggests that ochnaflavone prevents the progression of CCl 4 -induced PE hydrolysis by inhibiting the endogenous sPLA 2 activity.

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“…The anti-artherogenic activity of ochnaflavone was also revealed with the correlation of inhibition of human vascular smooth muscle cell proliferation induced by TNF-α via regulation of cell cycle related proteins, ERK and MMP-9 (Suh et al, 2006b). Recent study also exhibited the inhibitory activity of CCl4-induced PE degradation in rat liver microsome and anti-inflammatory effects with the downregulation of inducible nitric oxide, cyclooxygenase-2 and 5-lipoxygenase through NF-κB and ERK pathway by ochnaflavone Suh et al, 2006a). However, the anti-proliferative effect of ochnaflavone against human cancer cells has been poorly elucidated yet.…”

Section: Introductionmentioning

confidence: 86%

“…Various compounds derived from natural products have been reported to modulate the growth of colorectal cancer cells and thus are considered to be cancer chemopreventive agents (Bhanot and Möller, 2009). Ochnaflavone is a natural biflavonoid and has been demonstrated to have anti-inflammatory and anti-arthreogenic activites (Lee et al, 1997;Moon et al, 2006;Son et al, 2006;Suh et al, 2006a;Suh et al, 2006b;Kim et al, 2008). Since chronic inflammation is highly correlated with colorectal carcinogenesis (Wada, 2009;Bhanot and Möller, 2009), anti-inflammatory effect of ochnaflavone might suggest its possible role in colon cancer chemoprevention.…”

Section: Discussionmentioning

confidence: 99%

Ochnaflavone, a Natural Biflavonoid, Induces Cell Cycle Arrest and Apoptosis in HCT-15 Human Colon Cancer Cells

Kang¹,

Min²,

Hong³

et al. 2009

Biomolecules and Therapeutics

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-Ochnaflavone is a natural biflavonoid and mainly found in the caulis of Lonicera japonica (Caprifoliaceae). Biological activities such as anti-inflammatory and anti-atherogenic effects have been previously reported. The anticancer activity of ochnaflavone, however, has been poorly elucidated yet. In the present study, we investigated the effect of ochnaflavone on the growth inhibitory activity in cultured human colon cancer cell line HCT-15. Ochnaflavone inhibited the proliferation of the cancer cells with an IC 50 value of 4.1 μM. Flow cytometric analysis showed that ochnaflavone arrested cell cycle progression in the G2/M phase, and induced the increase of sub-G1 peak in a concentration-dependent manner. Induction of cell cycle arrest was correlated with the modulation of the expression of cell cycle regulating proteins including cdc2 (Tyr15), cyclin A, cyclin B1 and cyclin E. The increase of sub-G1 peak by the higher concentrations of ochnaflavone (over 20 μM) was closely related to the induction of apoptosis, which was evidenced by the induction of DNA fragmentation, activation of caspase-3, -8 and -9, and cleavage of poly-(ADP-ribose) polymerase. These findings suggest that the cell cycle arrest and induction of apoptosis might be one possible mechanism of actions for the anti-proliferative activity of ochnaflavone in human colon cancer cells.

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The naturally occurring biflavonoid, ochnaflavone, inhibits LPS-induced iNOS expression, which is mediated by ERK1/2 via NF-κB regulation, in RAW264.7 cells

Cited by 93 publications

References 36 publications

Salbutamol inhibits lipopolysaccharide-induced inflammatory responses in rat peritoneal macrophages

Salbutamol inhibits lipopolysaccharide-induced inflammatory responses in rat peritoneal macrophages

Ochnaflavone, Naturally Occurring Biflavonoid, Inhibits Phospholipase A2 Dependent Phosphatidylethanolamine Degradation in a CCl4-Induced Rat Liver Microsome

Ochnaflavone, a Natural Biflavonoid, Induces Cell Cycle Arrest and Apoptosis in HCT-15 Human Colon Cancer Cells

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