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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

The inhibition of LPS-induced NO production in kidney mesangial cells by 6-methoxyflavone, 6-acetoxyflavone and flavone 6-sulfate.The total production of nitrite in the treatment media was measured with Griess assay at 48 h post 10 ng/mL LPS stimulation. IC50 values were obtained using the dose-response analysis provided by the Graphpad Prism software as shown in parenthesis.
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pone.0116409.g004: The inhibition of LPS-induced NO production in kidney mesangial cells by 6-methoxyflavone, 6-acetoxyflavone and flavone 6-sulfate.The total production of nitrite in the treatment media was measured with Griess assay at 48 h post 10 ng/mL LPS stimulation. IC50 values were obtained using the dose-response analysis provided by the Graphpad Prism software as shown in parenthesis.

Mentions: Even though 6-hydroxyflavone exhibited a high activity against the LPS-induced inflammatory stimuli, the consequential idiosyncratic toxicity due to the noncompetitive inhibition of cytochrome P450 2C9 by 6-hydroxyflavone [18] could be a major concern for drug development. Thus, three alternative compounds with chemical modification of the 6-hydroxyl group including 6-methoxy- and 6-acetoxyflavones and flavone 6-sulfate were investigated (Fig. 4). Methylation of the 6-hydroxyl group could potentially weaken the hydrogen bond between the hydroxylated flavone and the Leucine 102 residue of P450 2C9 to decrease the non-competitive binding [19] while the acetylation as a pro-drug design might significantly change the pharmacokinetic profile. Flavone 6-sulfate is one of possible phase II metabolic products of 6-hydroxyflavone in the liver with sulfation of the phenolic group for subsequent renal clearance, and thus has a high potential for the anti-inflammatory application in kidney cells. For our study, 6-methoxyflavone is commercially available while 6-acetoxyflavone and flavone 6-sulfate were facilely synthesized in one step as described above in the Methods Section.


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)

The inhibition of LPS-induced NO production in kidney mesangial cells by 6-methoxyflavone, 6-acetoxyflavone and flavone 6-sulfate.The total production of nitrite in the treatment media was measured with Griess assay at 48 h post 10 ng/mL LPS stimulation. IC50 values were obtained using the dose-response analysis provided by the Graphpad Prism software as shown in parenthesis.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0116409.g004: The inhibition of LPS-induced NO production in kidney mesangial cells by 6-methoxyflavone, 6-acetoxyflavone and flavone 6-sulfate.The total production of nitrite in the treatment media was measured with Griess assay at 48 h post 10 ng/mL LPS stimulation. IC50 values were obtained using the dose-response analysis provided by the Graphpad Prism software as shown in parenthesis.
Mentions: Even though 6-hydroxyflavone exhibited a high activity against the LPS-induced inflammatory stimuli, the consequential idiosyncratic toxicity due to the noncompetitive inhibition of cytochrome P450 2C9 by 6-hydroxyflavone [18] could be a major concern for drug development. Thus, three alternative compounds with chemical modification of the 6-hydroxyl group including 6-methoxy- and 6-acetoxyflavones and flavone 6-sulfate were investigated (Fig. 4). Methylation of the 6-hydroxyl group could potentially weaken the hydrogen bond between the hydroxylated flavone and the Leucine 102 residue of P450 2C9 to decrease the non-competitive binding [19] while the acetylation as a pro-drug design might significantly change the pharmacokinetic profile. Flavone 6-sulfate is one of possible phase II metabolic products of 6-hydroxyflavone in the liver with sulfation of the phenolic group for subsequent renal clearance, and thus has a high potential for the anti-inflammatory application in kidney cells. For our study, 6-methoxyflavone is commercially available while 6-acetoxyflavone and flavone 6-sulfate were facilely synthesized in one step as described above in the Methods Section.

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