6-Methoxyflavone
6-Methoxyflavone can be a potential candidate for the development of an effective immunomodulator via the suppression of NFAT-mediated T cell activation. The relative inactivity of 6-methoxyflavanone at α1β2 GABAA receptors and it's partial agonist action at ρ1W328 M GABA receptors suggest that it exhibits a unique profile not matched by other flavonoids.
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Journal of Immunology, 2014, 193(6):2772.
6-Methoxyflavone inhibits NFAT translocation into the nucleus and suppresses T cell activation.[Pubmed:
25114106]
NFAT plays a crucial role in the immune system by regulating the transcription of inducible genes during immune responses. In T cells, NFAT proteins govern various cellular events related to T cell development, activation, tolerance induction, and differentiation. We previously reported the NFAT1-dependent enhancer activity of conserved noncoding sequence (CNS)-9, a distal cis-acting element, in the regulation of IL-10 transcription in T cells.
METHODS AND RESULTS:
In this study, we developed a T cell-based reporter system to identify compounds that modulate the regulatory activity of CNS-9. Among the identified candidates, 6-Methoxyflavone (6-MF) significantly inhibited the enhancer activity of CNS-9, thereby reducing IL-10 expression in T cells without affecting cell viability. 6-MF also downregulated the transcription of NFAT1 target genes such as IL-4, IL-13, and IFN-γ. Treatment of 6-MF inhibited the translocation of NFAT1 into the nucleus, which consequently interrupted NFAT1 binding to the target loci, without affecting the expression or dephosphorylation of NFAT1. Treatment of 6-MF to CD4(+) T cells or B cells isolated from mice with atopic dermatitis significantly reduced disease-associated cytokine production, as well as the levels of IgE. In addition, oral administration of 6-MF to atopic dermatitis mice ameliorated disease symptoms by reducing serum IgE levels and infiltrating lymphocytes.
CONCLUSIONS:
Conclusively, our results suggest that 6-MF can be a potential candidate for the development of an effective immunomodulator via the suppression of NFAT-mediated T cell activation.
Neurochemical Research, 2014, 39(6):1068-1078.
Modulation of ionotropic GABA receptors by 6-methoxyflavanone and 6-methoxyflavone.[Pubmed:
24078264]
METHODS AND RESULTS:
We evaluated the effects of 6-methoxyflavanone and 6-Methoxyflavone on wild-type α1/α2β2γ2L GABAA and ρ1 GABAC receptors and on mutant ρ1I307S, ρ1W328 M, ρ1I307S/W328 M GABAC receptors expressed in Xenopus oocytes using two-electrode voltage clamp and radioligand binding. 6-Methoxyflavanone and 6-Methoxyflavone act as a flumazenil-insensitive positive allosteric modulator of GABA responses at human recombinant α1β2γ2L and α2β2γ2L GABAA receptors. However, unlike 6-Methoxyflavone, 6-methoxyflavanone was relatively inactive at α1β2 GABAA receptors. 6-Methoxyflavanone inhibited [(3)H]-flunitrazepam binding to rat brain membranes. Both flavonoids were found to be inactive as modulators at ρ1, ρ1I307S and ρ1W328 M GABA receptors but acted as positive allosteric modulators of GABA at the benzodiazepine sensitive ρ1I307S/W328 M GABA receptors. This double mutant retains ρ1 properties of being insensitive to bicuculline and antagonised by TPMPA and THIP. Additionally, 6-methoxyflavanone was also a partial agonist at ρ1W328 M GABA receptors.
CONCLUSIONS:
The relative inactivity of 6-methoxyflavanone at α1β2 GABAA receptors and it's partial agonist action at ρ1W328 M GABA receptors suggest that it exhibits a unique profile not matched by other flavonoids.
