In addition, along the same line, endogenous specialized pro-resolving mediators have been identified as regulators of infection and inflammation [ 77 ]. For example, activation of NRs by a variety of endo- and exogenous chemicals are elemental to induction and repression of drug-metabolism pathways.
The master xenobiotic-sensing NRs, the promiscuous pregnane X receptor PXR , and less-promiscuous constitutive androstane receptor CAR are crucial to initial ligand recognition, jump-starting the metabolic process [ 78 ]. In addition, phytoestrogens are natural endocrine disruptors that interfere with estrogenic pathways. Moreover, bisphenol A BPA is widely used as a component in polycarbonate plastics for food and beverage packaging, epoxy linings for canned foods, and dental sealants, among other applications. The most widely accepted speculation is that both narrow and broad specificity seen for receptors or proteins are a result of natural selection process [ 81 ].
Less specificity of receptors provides evolutionary advantage to organisms that had to conduct a broad set of biological activities with limited protein repertoire and also allowed the organisms to evolve new responses to many endogenous and external ligands [ 82 , 83 , 84 ].
Promiscuity of such receptors complicate identification of the physiological ligands that activate them in vivo [ 85 ]. One way to identify candidate ligands for orphan NRs is to identify their three dimensional structure [ 86 , 87 ]. However, receptor affinity for the ligand and the physiological concentrations of the ligand in the tissues have to be taken into account when determining the potential relevance of the specific ligand for the receptor function [ 85 , 88 ].
Additionally, if it is known that the promiscuous NRs require intracellular lipid binding proteins to shuttle the ligand toward it like PPAR utilizing certain FABPs—fatty acid binding proteins , the nuclear translocation of the particular protein in response to a compound can be used to determine potential ligands for the NR [ 85 ]. Nevertheless, identifying the potential endogenous ligands bound to the NR of interest in vivo by using mass spectroscopy, high-performance liquid chromatography HPLC or gas chromatography are the most relevant methods than the ones mentioned above [ 85 , 89 , 90 ].
We acknowledge that some of the fold changes shown in our tables are less than twofold. However, complex diseases such as diabetes, obesity, cancer, and autoimmune disorders are regulated by myriad of genes similar to quantitative traits [ 91 , 92 ]. Previously, for most of the continuous traits, the strongest genetic association could explain only a small fraction of the genetic variance [ 93 , 94 ].
However, later analyses revealed that casual loci with small effect size are also important in determining continuous traits and complex diseases such as schizophrenia [ 94 ]. Moreover, recent publications demonstrated that complex and chronic diseases are driven by accumulation of weak effects on the key genes and regulatory pathways [ 95 , 96 ].
It is evident that polygenic effects are important across a wide variety of traits and diseases such as diabetes [ 97 ]. Therefore, it is our understanding that even a low fold change in potent transcription factors such as NRs can significantly impact progression of complex diseases.
T cell co-stimulation and co-inhibition in cardiovascular disease: a double-edged sword
To improve our understanding on most NRs as anti-inflammatory sensors and regulators, we propose a new working model and classified most NRs as homeostasis-associated molecular pattern receptors HAMPRs as shown in Fig. Vascular inflammation and atherogenesis are activated via receptors for PAMPs and suppressed by regulatory t cells.
Drug Discov Today Ther Strateg. Inflammasomes are differentially expressed in cardiovascular and other tissues.
Int J Immunopathol Pharmacol. Inflammasomes: sensors of metabolic stresses for vascular inflammation.
Front Biosci. DAMPs from cell death to new life. Front Immunol. Lysophospholipid receptors, as novel conditional danger receptors and homeostatic receptors modulate inflammation—novel paradigm and therapeutic potential.
European Society of Human Genetics: For Media
J Cardiovasc Transl Res. Caspase-1 recognizes extended cleavage sites in its natural substrates. J Hematol Oncol. Early hyperlipidemia promotes endothelial activation via a caspasesirtuin 1 pathway. Arterioscler Thromb Vasc Biol. Inhibition of caspase-1 activation in endothelial cells improves angiogenesis—a novel therapeutic potential for ischemia.
J Biol Chem. Endothelial progenitor cells in ischemic stroke: an exploration from hypothesis to therapy. Caspase-1 mediates hyperlipidemia-weakened progenitor cell vessel repair. Front Biosci Landmark Ed. Caspase-1 plays a critical role in accelerating chronic kidney disease-promoted neointimal hyperplasia in the carotid artery. Caspase-1 inflammasome activation mediates homocysteine-induced pyrop-apoptosis in endothelial cells. Circ Res. Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study.
Analyses of caspaseregulated transcriptomes in various tissues lead to identification of novel IL-1beta-, IL and sirtuinindependent pathways. Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome. Genome Res. A unified nomenclature system for the nuclear receptor superfamily. Laudet V. Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor.
J Mol Endocrinol. Evans RM. The steroid and thyroid hormone receptor superfamily. Olefsky JM. Nuclear receptor minireview series. Nuclear receptors and lipid physiology: opening the X-files.
- Experiencing Abortion: A Weaving of Womens Words (Haworth Innovations in Feminist Studies).
- Internal Threat - A Technothriller.
- Journey to Jesus 5: Set the Spirit Free.
- Common Complex Disease.
Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog Horm Res. Nuclear receptors: decoding metabolic disease.
FEBS Lett. Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis. Expert Opin Drug Metab Toxicol. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Nuclear receptor expression links the circadian clock to metabolism. Perez-Schindler J, Philp A. Regulation of skeletal muscle mitochondrial function by nuclear receptors: implications for health and disease. Clin Sci Lond. Coalition of nuclear receptors in the nervous system.
J Cell Physiol. Regulation of neuronal oxygen responses in C.
- Upside Down and Back Again:Hope for the Caregiver Revised Edition (Volume 2).
- Conflict of Interest Statement.
- Programming the iPhone User Experience: Developing and Designing Cocoa Touch Applications.
J Neurosci. Regulation of homocysteine metabolism and methylation in human and mouse tissues. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Choubey D, Panchanathan R. IFI16, an amplifier of DNA-damage response: role in cellular senescence and aging-associated inflammatory diseases. Ageing Res Rev. Gurung P, Kanneganti TD. Immune responses against protozoan parasites: a focus on the emerging role of Nod-like receptors.