Epigenetic Mechanisms of Integrative Medicine

Since time immemorial humans have utilized natural products and therapies for their healing properties. Even now, in the age of genomics and on the cusp of regenerative medicine, the use of complementary and alternative medicine (CAM) approaches represents a popular branch of health care. Furthermore, there is a trend towards a unified medical philosophy referred to as Integrative Medicine (IM) that represents the convergence of CAM and conventional medicine. The IM model not only considers the holistic perspective of the physiological components of the individual, but also includes psychological and mind-body aspects. Justification for and validation of such a whole-systems approach is in part dependent upon identification of the functional pathways governing healing, and new data is revealing relationships between therapies and biochemical effects that have long defied explanation. We review this data and propose a unifying theme: IM’s ability to affect healing is due at least in part to epigenetic mechanisms. This hypothesis is based on a mounting body of evidence that demonstrates a correlation between the physical and mental effects of IM and modulation of gene expression and epigenetic state. Emphasis on mapping, deciphering, and optimizing these effects will facilitate therapeutic delivery and create further benefits

Central Nicotinic and Muscarinic Receptors in Health and Disease

Without acetylcholine (ACh) no skeletal muscle contraction, no preganglionic sympathetic or parasympathetic activity can be obtained. This can result in dysregulation of cardiac, respiratory, gastrointestinal, and renal functions as well as disruption of fluid secretion from various glands such as tears, saliva, digestive juices, sweat, and milk. Importantly, ACh deficiency in the brain can have severe cognitive consequences. The action of ACh is mediated by two distinct classes of receptors, namely the muscarinic (mAChRs), which are G-protein coupled (metabotropic) receptors and nicotinic receptors (nAChRs), which are ligand-gated ion channels (ionotropic receptors). The focus of this chapter is on interaction of these two distinct receptor classes and its implication in health and disease. Thus, following a brief description of ACh actions and its central circuitry, an update on mAChRs and nAChRs and how their interaction may impact neuropsychiatric/neurodegenerative diseases will be provided. Moreover, potential novel therapeutic intervention based on these interactions, particularly in relationship to Alzheimer’s and Parkinson’s diseases will be touched upon

Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing(1,2). Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q - the inheritance of both copies of this material from one parent - and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders(3,4), revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo ( that is, newly arisen and not inherited) single-base substitution, G608G( GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62684/1/nature01629.pd

Methylthioadenosine reprograms macrophage activation through adenosine receptor stimulation

Regulation of inflammation is necessary to balance sufficient pathogen clearance with excessive tissue damage. Central to regulating inflammation is the switch from a pro-inflammatory pathway to an anti-inflammatory pathway. Macrophages are well-positioned to initiate this switch, and as such are the target of multiple therapeutics. One such potential therapeutic is methylthioadenosine (MTA), which inhibits TNFα production following LPS stimulation. We found that MTA could block TNFα production by multiple TLR ligands. Further, it prevented surface expression of CD69 and CD86 and reduced NF-KB signaling. We then determined that the mechanism of this action by MTA is signaling through adenosine A2 receptors. A2 receptors and TLR receptors synergized to promote an anti-inflammatory phenotype, as MTA enhanced LPS tolerance. In contrast, IL-1β production and processing was not affected by MTA exposure. Taken together, these data demonstrate that MTA reprograms TLR activation pathways via adenosine receptors to promote resolution of inflammation. © 2014 Keyel et al