Mediators of Metabolism: An Unconventional Role for NOD1 and NOD2

In addition to their classical roles as bacterial sensors, NOD1 and NOD2 have been implicated as mediators of metabolic disease. Increased expression of NOD1 and/or NOD2 has been reported in a range of human metabolic diseases, including obesity, diabetes, non-alcoholic fatty liver disease, and metabolic syndrome. Although NOD1 and NOD2 share intracellular signaling pathway components, they are differentially upregulated on a cellular level and have opposing impacts on metabolic disease development in mouse models. These NOD-like receptors may directly mediate signaling downstream of cell stressors, such as endoplasmic reticulum stress and calcium influx, or in response to metabolic signals, such as fatty acids and glucose. Other studies suggest that stimulation of NOD1 or NOD2 by their bacterial ligands can result in inflammation, altered insulin responses, increased reactive oxygen signaling, and mitochondrial dysfunction. The activating stimuli for NOD1 and NOD2 in the context of metabolic disease are controversial and may be a combination of both metabolic and circulating bacterial ligands. In this review, we will summarize the current knowledge of how NOD1 and NOD2 may mediate metabolism in health and disease, as well as highlight areas of future investigation.

Chloroplast quality control pathways are dependent on plastid DNA synthesis and nucleotides provided by cytidine triphosphate synthase two

SummaryReactive oxygen species (ROS) produced in chloroplasts cause oxidative damage, but also signal to initiate chloroplast quality control pathways, cell death, and gene expression. The mechanisms behind these signals are largely unknown.The Arabidopsis thaliana plastid ferrochelatase two (fc2) mutant produces the ROS singlet oxygen in chloroplasts that activates such signaling pathways. Here we mapped one fc2 suppressor mutation to CYTIDINE TRIPHOSPHATE SYNTHASE TWO (CTPS2), which encodes one of five enzymes in Arabidopsis necessary for de novo cytoplasmic CTP (and dCTP) synthesis.The ctps2 mutation reduces chloroplast transcripts and DNA content without similarly affecting mitochondria. Chloroplast nucleic acid content and singlet oxygen signaling are restored by exogenous feeding of the dCTP precursor deoxycytidine, suggesting ctps2 blocks signaling by limiting nucleotides for chloroplast genome maintenance.An investigation of CTPS orthologs in Brassicaceae showed CTPS2 is a member of an ancient lineage distinct from CTPS3. Complementation studies confirmed this analysis; CTPS3 was unable to compensate for CTPS2 function in providing nucleotides for chloroplast DNA and signaling.Our studies link cytoplasmic nucleotide metabolism with chloroplast quality control pathways. Such a connection is achieved by a conserved clade of CTPS enzymes that may have evolved specialized functions in providing nucleotides to specific subcellular compartments.

How To Combine Ozone Therapies With Other Modalities For Maximum Efficacy

In order to use Bio-Oxidative Therapies effectively, a small shift in thinking is needed. One needs to shift from Disease Literacy to Healing Literacy This shift in thinking leads to the inevitable conclusion that: Impaired Oxygen Signaling is the common denominator for all disease. Impaired Oxygen Signaling affects: • O2 driven energetics • O2's detergent function • O2's cellular repair function • O2's renewal function It is important to be aware of Oxygen's multiple functions in order to appreciate the importance of the role bio-oxidative therapies play in the reversal of disease conditions. In fact, no treatment of chronic disease can be complete without addressing ALL Oxygen-related issues relevant to a particular patient. What are these oxygen related issues that need to be addressed? There are 4 distinct steps that lead to disease manifestation linked to Oxygen: · Dysfunctional Oxygen Metabolism · Acidosis · Oxidative Coagulation · Oxidized Lymph Once the above conditions are understood, it becomes clear that combining bio-oxidative therapies with other modalities can improve the outcome of those modalities. Examples of how to combine therapies to create effective protocols for improved clinical outcome will be discussed. In Summary: A clear understanding of the Oxygen Model of Disease will enable the practitioner to customize and create innovative combinations for the individual patient.