Recommended GLYCATION, Advanced glycation end-products, ROS (13)

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Receptors for AGE (RAGE)

RAGE, the receptor for advanced glycation endproducts is a 35 kDa transmembrane receptor of the immunoglobulin super family which was first characterized in 1992 by Neeper et al.[2] It is also called "AGER". Its name comes from its ability to bind advanced glycation end products (AGE), which include chiefly glycoproteins, the glycans of which have been modified non-enzymatically through the Maillard reaction.

The lower ATP level from dysfunctional mitochondria lower the housekeeping autophagy, and as a consequence the AGE products accumulate. The receptors for these products help to mark cells for destruction. See article below for an informative technical explanation. Much of the research has ended by 2000.

Schmidt, Marie, Shi Du Yan et al, Dec 2000, The biology of the receptor for advanced glycation end products and its ligands Dec2000 Schmidt, Marie, Shi Du Yan et al
The biology of the receptor for advanced glycation end products and its ligands

Receptor for advanced glycation end products (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules whose repertoire of ligands includes advanced glycation end products (AGEs), amyloid fibrils, amphoterins and S100/calgranulins. The overlapping distribution of these ligands and cells overexpressing RAGE results in sustained receptor expression which is magnified via the apparent capacity of ligands to upregulate the receptor. We hypothesize that RAGE-ligand interaction is a propagation factor in a range of chronic disorders, based on the enhanced accumulation of the ligands in diseased tissues. For example, increased levels of AGEs in diabetes and renal insufficiency, amyloid fibrils in Alzheimer’s disease brain, amphoterin in tumors and S100/calgranulins at sites of inflammation have been identified. The engagement of RAGE by its ligands can be considered the ‘first hit’ in a two-stage model, in which the second phase of cellular perturbation is mediated by superimposed accumulation of modified lipoproteins (in atherosclerosis), invading bacterial pathogens, ischemic stress and other factors. Taken together, these ‘two hits’ eventuate in a cellular response with a propensity towards tissue destruction rather than resolution of the offending pathogenic stimulus. Experimental data are cited regarding this hypothesis, though further studies will be required, especially with selective low molecular weight inhibitors of RAGE and RAGE knockout mice, to obtain additional proof in support of our concept.
. . . Several other features of RAGE biology are important to mention at the outset. First, there is an unusual sustained juxtaposition of ligand and receptor in tissues. At sites of accumulated advanced glycation end products (AGEs) in the vasculature, for example, there is increased expression of the receptor in cells of the vessel wall, including endothelium, vascular smooth muscle cells and invading mononuclear phagocytes [5]. Similarly, in amyloid-rich tissues, upregulation of RAGE is observed in parenchymal cells, such as neurons, as well as mononuclear phagocyte elements, including microglia in Alzheimer’s disease brain [3]. Based on the apparently activated state of cells expressing RAGE at such loci (as reflected by sustained activation of NF-κB, expression of cytokines and cell adherence molecules, etc.), we speculate that the overlapping distribution of receptor and ligand results in prolonged receptor activation. Our studies have demonstrated that one facet of RAGE-mediated cellular stimulation includes increased expression of the receptor itself. Thus, one can envision a positive feedback loop in which ligand-receptor interaction increases expression of the receptor, thereby augmenting subsequent RAGE-induced cellular activation. This situation contrasts with other receptors, such as the LDL receptor, in which increased levels of ligand decrease expression of the receptor [6]. In fact, the only means we know to strongly downregulate RAGE is to interrupt the cycle of ligand engagement of the receptor with soluble RAGE (see below) or blocking antibodies.
The multi-ligand character of RAGE allows it to participate in an apparently wide spectrum of pathologic events. A common denominator of these pathologies is the role of RAGE as a propagator of cellular dysfunction. . . . The important point is that from the myriad of pathways recruited by RAGE-induced cellular activation, it is virtually impossible, a priori, to predict with certainty the outcome of RAGE-dependent activation in a particular cell type 12 April 2006 Nicholas Houstis, Evan D. Rosen et al.
Reactive oxygen species have a causal role in multiple forms of insulin resistance
Insulin resistance is a cardinal feature of type 2 diabetes and is characteristic of a wide range of other clinical and experimental settings. Little is known about why insulin resistance occurs in so many contexts. Do the various insults that trigger insulin resistance act through a common mechanism? Or, as has been suggested1, do they use distinct cellular pathways? Here we report a genomic analysis of two cellular models of insulin resistance, one induced by treatment with the cytokine tumour-necrosis factor-α and the other with the glucocorticoid dexamethasone. Gene expression analysis suggests that reactive oxygen species (ROS) levels are increased in both models, and we confirmed this through measures of cellular redox state. ROS have previously been proposed to be involved in insulin resistance, although evidence for a causal role has been scant. We tested this hypothesis in cell culture using six treatments designed to alter ROS levels, including two small molecules and four transgenes; all ameliorated insulin resistance to varying degrees. One of these treatments was tested in obese, insulin-resistant mice and was shown to improve insulin sensitivity and glucose homeostasis. Together, our findings suggest that increased ROS levels are an important trigger for insulin resistance in numerous settings.

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Aging and the Role of Reactive Nitrogen Species
The role of reactive oxygen species and its effects on aging has received considerable attention in the past 47 years since Dr. Denham Harman first proposed the “free radical theory of aging.” Though not completely understood due to the incalculable number of pathways involved, the number of manuscripts that facilitate the understanding of the underlying effects of reactive radical species on the oxidative stress on lipids, proteins, and DNA and its contribution to the aging process increases nearly exponentially each year. More recently, the role of reactive nitrogen species, such as nitric oxide and its by‐products—nitrate (NO3−), nitrite (NO2−), peroxynitrite (ONOO−), and 3‐nitrotyrosine—have been shown to have a direct role in cellular signaling, vasodilation, and immune response. Nitric oxide is produced within cells by the actions of a group of enzymes called nitric oxide synthases. Presently, there are three distinct isoforms of nitric oxide synthase: neuronal (nNOS or NOS‐1), inducible (iNOS or NOS‐2), and endothelial (eNOS or NOS‐3), and several subtypes. While nitric oxide (NO•) is a relative unreactive radical, it is able to form other reactive intermediates, which could have an effect on protein function and on the function of the entire organism. These reactive intermediates can trigger nitrosative damage on biomolecules, which in turn may lead to age‐related diseases due to structural alteration of proteins, inhibition of enzymatic activity, and interferences of the regulatory function. This paper will critically review the evidence of nitration and the important role it plays with aging. Furthermore, it will summarize the physiological role of nitration as well as the mechanisms leading to proteolytic degradation of nitrated proteins within biological tissues.

Dr. Relman another former editor in chief of the NEJM said this in 2002
“The medical profession is being bought by the pharmaceutical industry, not only in terms of the practice of medicine, but also in terms of teaching and research. The academic institutions of this country are allowing themselves to be the paid agents of the pharmaceutical industry. I think it’s disgraceful”