Epigenetic Mechanisms of Integrative Medicine

Figure 4

Direct, indirect, and combined epigenetic pathways of Integrative Medicine. The figure represents a summary of the epigenetic mechanisms underlying different IM approaches. The cell is represented as oval pink structure with a yellow nucleus. The fine structure of chromatin comprised of DNA wrapped around histones in the nucleus is the ultimate regulatory component through which IM approaches manifest their outcomes. Red marks on histones represent acetyl groups on histone tails (histone acetylation) and blue marks represent methyl groups on DNA (DNA methylation). (a) Type 1 direct pathway: Traditional Chinese Medicine. Traditional Chinese Medicine (TCM) compounds like Ningposides C (NPC) and Monomethylcurcumin (MMC) (represented by green triangles) act as HDAC2 (represented by purple cylinder) inhibitors that inhibit deacetylation of histones and relax the chromatin structure. The mode of action of NPC and MMC is through a Type 1 direct pathway since they directly interfere with the epigenetic enzyme HDAC. (b) Type 2 direct pathway: herbal methionine. Dietary compounds like herbal methionine (HM) that donate methyl groups and increase SAMe levels in the body are important regulators of nuclear DNA methylation. An increased production of SAMe from HM increases the bioavailability of methyl groups (metabolite) that contribute to the constitution of epigenetic tags, specifically affecting DNA methylation levels. Thus, HM follows the Type 2 direct pathway by interfering with the bioavailability of compounds that constitute epigenetic tags. (c) Indirect pathway: Astragalus. Astragalus extract has anti-inflammatory properties and can promote its effects through two different pathways. Firstly, it inhibits p38 MAPK and ERK1/2 via stimulation of MPK that in turn blocks the nuclear translocation of AP-1 (lavender diamond) responsible for expression of proinflammatory cytokine IL-6. Secondly, it interferes with the nuclear translocation of NF-κB (pink hexagon) and inhibits NF-κB-mediated transcription that in turn activates proinflammatory genes. Thus, Astragalus follows an indirect epigenetic pathway by interfering with cellular signaling pathways. (d) Combined pathway: curcumin. Curcumin (orange oval) possesses anti-inflammatory activity that operates through a combination of direct and indirect pathways. Through the direct epigenetic pathway, it specifically inhibits a specific p300/CBP HAT (blue semicircle) thereby reducing histone acetylation and through the indirect epigenetic pathway it blocks pathways involving the transcription factor NF-κB (pink hexagon) that in turn block the production of COX-2. Thus, curcumin operates through a combination of direct and indirect pathways.

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