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6-Hydroxyflavone and derivatives exhibit potent anti-inflammatory activity among mono-, di- and polyhydroxylated flavones in kidney mesangial cells.

Wang X, Wang Z, Sidhu PS, Desai UR, Zhou Q - PLoS ONE (2015)

Bottom Line: Interestingly, the anti-inflammatory activity was not due to direct quenching of NO radicals.Investigation on derivatives with methylation, acetylation or sulfation of 6-hydroxyl group revealed that 6-methoxyflavone was the most potent with an IC50 of 192 nM.Mechanistic study indicated that the anti-inflammatory activity of 6-methoxyflavone arose via the inhibition of LPS-induced downstream inducible NO synthase in mesangial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.

ABSTRACT
Inflammatory responses by kidney mesangial cells play a critical role in the glomerulonephritis. The anti-inflammatory potential of nineteen mono-, di- and polyhydroxylated flavones including fisetin, quercetin, morin, tricetin, gossypetin, apigenin and myricetin were investigated on rat mesangial cells with lipopolysaccharide (LPS) as the inflammatory stimuli. 6-Hydroxyflavone and 4',6-dihydroxyflavone exhibited high activity with IC50 in the range of 2.0 μM, a much better inhibition potential in comparison to the well-studied polyhydroxylated flavones. Interestingly, the anti-inflammatory activity was not due to direct quenching of NO radicals. Investigation on derivatives with methylation, acetylation or sulfation of 6-hydroxyl group revealed that 6-methoxyflavone was the most potent with an IC50 of 192 nM. Mechanistic study indicated that the anti-inflammatory activity of 6-methoxyflavone arose via the inhibition of LPS-induced downstream inducible NO synthase in mesangial cells. The identification of 6-hydroxyflavone and 6-methoxyflavone with potent anti-inflammatory activity in kidney mesangial cells provides a new flavone scaffold and direction to develop naturally derived products for potential nephritis prevention and treatment.

No MeSH data available.


Related in: MedlinePlus

Western blot analysis of potential molecular targets by 6-methoxyflavone in kidney mesangial cells with LPS as the inflammatory stimuli.Cells were pretreated with 6-methoxyflavone or resveratrol for 12 h and then LPS was added. Cell lysate were collected after 15 min and 24 h incubation for activated NF-κB pathway and iNOS protein, respectively.
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pone.0116409.g005: Western blot analysis of potential molecular targets by 6-methoxyflavone in kidney mesangial cells with LPS as the inflammatory stimuli.Cells were pretreated with 6-methoxyflavone or resveratrol for 12 h and then LPS was added. Cell lysate were collected after 15 min and 24 h incubation for activated NF-κB pathway and iNOS protein, respectively.

Mentions: The inhibitory activity on the LPS-induced NO production by these modified 6-hydroxyflavones (9–10) was found to be impressively high with IC50 at 192 nM, 0.60 and 2.1 μM for 6-methoxyflavone, 6-acetoxyflavone and flavone 6-sulfate, respectively (Fig. 4). Specially, the activity of 6-methoxyflavone was almost 10-fold more potent than that of 6-hydroxyflavone (IC50 1.7 μM). In addition, only weak cytotoxicity was observed on mesangial cells by 6-methoxyflavone at 1.0 μM, 6-acetoxyflavone at 10 μM and minimal for flavone 6-sulfate at 10 μM (see S1 Table). The underlying inhibitory mechanism was then focused on the LPS-stimulated cellular NF-κB pathway and 6-methoxyflavone due to its potency. Western blot analysis revealed that NF-κB pathway was activated upon the addition of LPS with significantly elevated levels of phosphorylated p65 protein (Fig. 5). Unfortunately, there was no observable inhibition of p65 activation by 6-methoxyflavone up to 1.0 μM. On the other hand, significant inhibition of the downstream inducible NO synthase (iNOS) upon LPS stimulation was consistently found with 6-methoxyflavone from 200 nM to 1.0 μM (Fig. 5). In addition, only weak inhibition was observed with the positive control resveratrol at 10 μM. Thus, these results suggested that the high activity of 6-methoxyflavone against the LPS-induced inflammatory stimuli was attributed to the potent inhibition of the downstream iNOS protein expression in kidney mesangial cells.


6-Hydroxyflavone and derivatives exhibit potent anti-inflammatory activity among mono-, di- and polyhydroxylated flavones in kidney mesangial cells.

Wang X, Wang Z, Sidhu PS, Desai UR, Zhou Q - PLoS ONE (2015)

Western blot analysis of potential molecular targets by 6-methoxyflavone in kidney mesangial cells with LPS as the inflammatory stimuli.Cells were pretreated with 6-methoxyflavone or resveratrol for 12 h and then LPS was added. Cell lysate were collected after 15 min and 24 h incubation for activated NF-κB pathway and iNOS protein, respectively.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4366162&req=5

pone.0116409.g005: Western blot analysis of potential molecular targets by 6-methoxyflavone in kidney mesangial cells with LPS as the inflammatory stimuli.Cells were pretreated with 6-methoxyflavone or resveratrol for 12 h and then LPS was added. Cell lysate were collected after 15 min and 24 h incubation for activated NF-κB pathway and iNOS protein, respectively.
Mentions: The inhibitory activity on the LPS-induced NO production by these modified 6-hydroxyflavones (9–10) was found to be impressively high with IC50 at 192 nM, 0.60 and 2.1 μM for 6-methoxyflavone, 6-acetoxyflavone and flavone 6-sulfate, respectively (Fig. 4). Specially, the activity of 6-methoxyflavone was almost 10-fold more potent than that of 6-hydroxyflavone (IC50 1.7 μM). In addition, only weak cytotoxicity was observed on mesangial cells by 6-methoxyflavone at 1.0 μM, 6-acetoxyflavone at 10 μM and minimal for flavone 6-sulfate at 10 μM (see S1 Table). The underlying inhibitory mechanism was then focused on the LPS-stimulated cellular NF-κB pathway and 6-methoxyflavone due to its potency. Western blot analysis revealed that NF-κB pathway was activated upon the addition of LPS with significantly elevated levels of phosphorylated p65 protein (Fig. 5). Unfortunately, there was no observable inhibition of p65 activation by 6-methoxyflavone up to 1.0 μM. On the other hand, significant inhibition of the downstream inducible NO synthase (iNOS) upon LPS stimulation was consistently found with 6-methoxyflavone from 200 nM to 1.0 μM (Fig. 5). In addition, only weak inhibition was observed with the positive control resveratrol at 10 μM. Thus, these results suggested that the high activity of 6-methoxyflavone against the LPS-induced inflammatory stimuli was attributed to the potent inhibition of the downstream iNOS protein expression in kidney mesangial cells.

Bottom Line: Interestingly, the anti-inflammatory activity was not due to direct quenching of NO radicals.Investigation on derivatives with methylation, acetylation or sulfation of 6-hydroxyl group revealed that 6-methoxyflavone was the most potent with an IC50 of 192 nM.Mechanistic study indicated that the anti-inflammatory activity of 6-methoxyflavone arose via the inhibition of LPS-induced downstream inducible NO synthase in mesangial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.

ABSTRACT
Inflammatory responses by kidney mesangial cells play a critical role in the glomerulonephritis. The anti-inflammatory potential of nineteen mono-, di- and polyhydroxylated flavones including fisetin, quercetin, morin, tricetin, gossypetin, apigenin and myricetin were investigated on rat mesangial cells with lipopolysaccharide (LPS) as the inflammatory stimuli. 6-Hydroxyflavone and 4',6-dihydroxyflavone exhibited high activity with IC50 in the range of 2.0 μM, a much better inhibition potential in comparison to the well-studied polyhydroxylated flavones. Interestingly, the anti-inflammatory activity was not due to direct quenching of NO radicals. Investigation on derivatives with methylation, acetylation or sulfation of 6-hydroxyl group revealed that 6-methoxyflavone was the most potent with an IC50 of 192 nM. Mechanistic study indicated that the anti-inflammatory activity of 6-methoxyflavone arose via the inhibition of LPS-induced downstream inducible NO synthase in mesangial cells. The identification of 6-hydroxyflavone and 6-methoxyflavone with potent anti-inflammatory activity in kidney mesangial cells provides a new flavone scaffold and direction to develop naturally derived products for potential nephritis prevention and treatment.

No MeSH data available.


Related in: MedlinePlus