Advanced glycation end products (AGEs) are produced through the non enzymatic glycation and oxidation of proteins, lipids and nucleic acids. Enhanced formation of AGEs occurs particularly in conditions associated with hyperglycaemia such as diabetes mellitus (DM). AGEs are believed to have a key role in the development and progression of cardiovascular disease in patients with DM through the modification of the structure, function and mechanical properties of tissues through crosslinking intracellular as well as extracellular matrix proteins and through modulating cellular processes through binding to cell surface receptors [receptor for AGEs (RAGE)]. A number of studies have shown a correlation between serum AGE levels and the development and severity of heart failure (HF). Moreover, some studies have suggested that therapies targeted against AGEs may have therapeutic potential in patients with HF. The purpose of this review is to discuss the role of AGEs in cardiovascular disease and in particular in heart failure, focussing on both cellular mechanisms of action as well as highlighting how targeting AGEs may represent a novel therapeutic strategy in the treatment of HF.

Human S100A7 (psoriasin) is overexpressed in inflammatory diseases. The recently discovered, co-evolved hS100A15 is almost identical in sequence and up-regulated with hS100A7 during cutaneous inflammation. The functional role of these closely related proteins for inflammation remains undefined. By generating specific Abs, we demonstrate that hS100A7 and hS100A15 proteins are differentially expressed by specific cell types in the skin. Although highly homologous, both proteins are chemoattractants with distinct chemotactic activity for leukocyte subsets. We define RAGE (receptor for advanced glycation end products) as the hS100A7 receptor, whereas hS100A15 functions through a Gi protein-coupled receptor. hS100A7-RAGE binding, signaling, and chemotaxis are zinc-dependent in vitro, reflecting the previously reported zinc-mediated changes in the hS100A7 dimer structure. When combined, hS100A7 and hS100A15 potentiate inflammation in vivo. Thus, proinflammatory synergism in disease may be driven by the diverse biology of these almost identical proteins that have just recently evolved. The identified S100A7 interaction with RAGE may provide a novel therapeutic target for inflammation.

Endocannabinoids and cannabinoid 1 (CB(1)) receptors have been implicated in cardiac dysfunction, inflammation, and cell death associated with various forms of shock, heart failure, and atherosclerosis, in addition to their recognized role in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes. In this study, we explored the role of CB(1) receptors in myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type 1 diabetic cardiomyopathy. Diabetic cardiomyopathy was characterized by increased myocardial endocannabinoid anandamide levels, oxidative/nitrative stress, activation of p38/Jun NH(2)-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs), enhanced inflammation (tumor necrosis factor-α, interleukin-1β, cyclooxygenase 2, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1), increased expression of CB(1), advanced glycation end product (AGE) and angiotensin II type 1 receptors (receptor for advanced glycation end product [RAGE], angiotensin II receptor type 1 [AT(1)R]), p47(phox) NADPH oxidase subunit, β-myosin heavy chain isozyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a). Pharmacological inhibition or genetic deletion of CB(1) receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathological alterations. Activation of CB(1) receptors by endocannabinoids may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating MAPK activation, AT(1)R expression/signaling, AGE accumulation, oxidative/nitrative stress, inflammation, and fibrosis. Conversely, CB(1) receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications.

This review focuses on the current findings regarding interaction between amyloid beta peptide (Abeta) and receptor for advanced glycation endproducts (RAGE) and its roles in the pathogenesis of Alzheimer's disease (AD). As a ubiquitously expressed cell surface receptor, RAGE mediates the effects of Abeta on microglia, blood-brain barrier (BBB) and neurons through activating different signaling pathways. Data from autopsy brain tissues, in vitro cell cultures and transgenic mouse models suggest that Abeta-RAGE interaction exaggerates neuronal stress, accumulation of Abeta, impaired learning memory, and neuroinflammation. Blockade of RAGE protects against Abeta-mediated cellular perturbation. These findings may have an important therapeutic implication for neurodegenerative disorders relevant to AD.

RAGE [receptor for AGEs (advanced glycation end-products)] plays an important role in the development and progression of vascular disease. Studies in cultured cells and small animal models of disease have clearly demonstrated that RAGE is central to the pathogenesis of vascular disease of the macro- and micro-vessels in both the diabetic and non-diabetic state. Emerging results from human clinical studies have revealed that levels of circulating soluble RAGE in the plasma may reflect the presence and/or extent of vascular disease state. Additionally, genetic variants of the RAGE gene (AGER in HUGO nomenclature) have been associated with vascular disease risk. Combining RAGE circulating protein levels and the presence of particular RAGE polymorphisms may be a useful clinical tool for the prediction of individuals at risk for vascular disease. Therapeutic intervention targeted at the RAGE gene may therefore be a useful means of treating pathologies of the vasculature.

A common endpoint of hyperglycemia dependent cellular changes is the generation of reactive oxygen intermediates (ROIs) and the presence of elevated oxidative stress. Therefore, oxidative stress is supposed to play an important role in the development of late diabetic complications. Formation of advanced glycation end products (AGE's) due to elevated nonenzymatic glycation of proteins, lipids and nucleic acids is accompanied by oxidative, radical-generating reactions and thus represents a major source for oxygen free radicals under hyperglycemic conditions. Once formed, AGE's can influence cellular function by binding to several binding sites including the receptor for AGE's, RAGE. Binding of AGE's (and other ligands) to RAGE results in generation of intracellular oxidative stress and subsequent activation of the redox-sensitive transcription factor NF-kappaB in vitro and in vivo. Consistently, activation of NF-kappaB in diabetic patients correlates with the quality of glycemic control and can be reduced by treatment with the antioxidant alpha-lipoic acid. The development of techniques allowing for a tissue culture independent measurement of NF-kappaB activation in patients with diabetes mellitus gives insights into the molecular mechanisms linking diabetes mellitus and hyperglycemia with formation of advanced glycated endproducts and generation of oxidative stress finally resulting in oxidative stress mediated cellular activation.

Although the pathogenesis of sporadic Alzheimer disease (AD) is not clearly understood, it is likely dependent on several age-related factors. Diabetes is a risk factor for AD, and multiple mechanisms connecting the 2 diseases have been proposed. Hyperglycemia enhances the formation of advanced glycation end products (AGEs) that result from the auto-oxidation of glucose and fructose. The interaction of AGEs with their receptor, named RAGE, elicits the formation of reactive oxygen species that are also believed to be an early event in AD pathology. To investigate a functional link between the disorders diabetes and AD, the effect of 2 AGEs, pentosidine and glyceraldehydes-derived pyridinium (GLAP), was studied on BACE1 expression both in vivo, in streptozotocin treated rats, and in vitro in differentiated neuroblastoma cells. We showed that pentosidine and GLAP were able to upregulate BACE1 expression through their binding with RAGE and the consequent activation of NF-κB. In addition, both pentosidine and GLAP were found to be increased in the brain in sporadic AD patients. Our findings demonstrate that activation of the AGEs/RAGE axis, by upregulating the key enzyme for amyloid-β production, provides a pathologic link between diabetes mellitus and AD.

Ligation of the receptor for advanced glycation end products (RAGE) occurs during inflammation. Engagement of RAGE results in enhanced expression of addressins and it is therefore, not surprising that previous studies have shown a role of RAGE/ligand interactions in immune responses including cell/cell contact but the role of RAGE in spontaneous autoimmunity has not been clearly defined. To study the role of RAGE/ligand interactions in autoimmune diabetes, we tested the ability of soluble RAGE, a scavenger of RAGE ligands, in late stages of diabetes development in the NOD mouse-disease transferred with diabetogenic T cells and recurrent disease in NOD/scid recipients of syngeneic islet transplants. RAGE expression was detected on CD4(+), CD8(+), and B cells from diabetic mice and transferred to NOD/scid recipients. RAGE and its ligand, S100B, were found in the islets of NOD/scid mice that developed diabetes. Treatment of recipient NOD/scid mice with soluble RAGE prevented transfer of diabetes and delayed recurrent disease in syngeneic islet transplants. RAGE blockade was associated with increased expression of IL-10 and TGF-beta in the islets from protected mice. RAGE blockade reduced the transfer of disease with enriched T cells, but had no effect when diabetes was transferred with the activated CD4(+) T cell clone, BDC2.5. We conclude that RAGE/ligand interactions are involved in the differentiation of T cells to a mature pathogenic phenotype during the late stages of the development of diabetes.

Although the features of diabetic cardiomyopathy, atherosclerosis, and nephropathy have been clinically characterized, the pathogenesis and the mechanisms underlying the abnormalities in the diabetic heart and kidney are not fully understood. During the past several years, in an attempt to discover interventions for diabetes-related complications, researchers have refocused their attention from the hemodynamic aspects of the disease to the biochemical interactions of glucose and proteins. Diabetes is a disorder of chronic hyperglycemia, and glucose participates in diabetic complications such as atherosclerosis, cardiac dysfunction, and nephropathy. Chronic hyperglycemia accelerates the reaction between glucose and proteins and leads to the formation of advanced glycation end products (AGE), which form irreversible cross-links with many macromolecules such as collagen. In diabetes, these AGE accumulate in tissues at an accelerated rate. The development of the novel compound dimethyl-3-phenacylthiazolium chloride (alagebrium chloride), which chemically breaks AGE cross-links, led to several preclinical animal studies that showed an attenuation or reversal of disease processes of the heart and kidney. In diabetes, AGE not only structurally stiffen structural collagen backbones but also act as agonists to AGE receptors (RAGE) on various cell types, which stimulate the release of profibrotic growth factors, promote collagen deposition, increase inflammation, and ultimately lead to tissue fibrosis. In the heart, large vessels, and kidney, these reactions produce diastolic dysfunction, atherosclerosis, and renal fibrosis. Administration of the cross-link breaker alagebrium chloride in these diabetic animals attenuates these pathologic phenomena, restoring functionality to the heart, vasculature, and kidney.

Diabetic cardiomyopathy is manifested by compromised systolic and diastolic function. This study was designed to examine the role of advanced glycation endproduct (AGE) and AGE receptor (RAGE) in diabetic cardiomyopathy. Heart function was assessed in isolated control and streptozotocin-induced diabetic hearts following in vivo RAGE gene knockdown using RNA interference. Cardiomyocyte mechanical properties were evaluated including peak shortening (PS), time-to-PS (TPS) and time-to-90% relengthening (TR(90)). RAGE was assayed by RT-PCR and immunoblot. Diabetes significantly enhanced cardiac MG, AGE and RAGE levels accompanied with colocalization of AGE and RAGE in cardiomyocytes. Diabetes-elicited increase in RAGE was inhibited by in vivo siRNA interference. The AGE formation inhibitor benfotiamine significantly attenuated diabetes-induced elevation in MG, AGE, RAGE and collagen cross-linking without affecting hypertriglyceridaemia and hypercholesterolaemia in diabetes. Diabetes markedly decreased LV contractility, as evidenced by reduced +/-dP/dt and LV developed pressure (LVDP), which were protected by RAGE gene knockdown. In addition, MG-derived AGE (MG-AGE) up-regulated cardiac RAGE mRNA and triggered cardiomyocyte contractile dysfunction reminiscent of diabetic cardiomyopathy. The MG-AGE-elicited prolongation of TPS and TR(90) was ablated by an anti-RAGE antibody in cardiomyocytes. Interestingly, MG-AGE-induced cardiomyocyte dysfunction was associated with mitochondrial membrane potential (MMP) depolarization and reduced GSK-3beta inactivation in control cardiomyocytes, similar to those from in vivo diabetes. Treatment with siRNA-RAGE ablated diabetes-induced MMP depolarization and GSK-3beta inactivation. Collectively, our result implicated a role of AGE-RAGE in the pathogenesis of diabetic cardiomyopathy.

The enhanced generation and accumulation of advanced glycation endproducts (AGEs) have been linked to increased risk for macrovascular and microvascular complications associated with diabetes mellitus. AGEs result from the nonenzymatic reaction of reducing sugars with proteins, lipids, and nucleic acids, potentially altering their function by disrupting molecular conformation, promoting cross-linking, altering enzyme activity, reducing their clearance, and impairing receptor recognition. AGEs may also activate specific receptors, like the receptor for AGEs (RAGE), which is present on the surface of all cells relevant to atherosclerotic processes, triggering oxidative stress, inflammation and apoptosis. Understanding the pathogenic mechanisms of AGEs is paramount to develop strategies against diabetic and cardiovascular complications.

The receptor for advanced glycation end products (RAGE) is thought to be involved in the pathogenesis of a broad range of inflammatory, degenerative and hyperproliferative diseases. It binds to diverse ligands and activates multiple intracellular signaling pathways. Despite these pivotal functions, molecular events just downstream of ligand-activated RAGE have been surprisingly unknown. Here we show that the cytoplasmic domain of RAGE is phosphorylated at Ser391 by PKCζ upon binding of ligands. TIRAP and MyD88, which are known to be adaptor proteins for Toll-like receptor-2 and -4 (TLR2/4), bound to the phosphorylated RAGE and transduced a signal to downstream molecules. Blocking of the function of TIRAP and MyD88 largely abrogated intracellular signaling from ligand-activated RAGE. Our findings indicate that functional interaction between RAGE and TLRs coordinately regulates inflammation, immune response and other cellular functions.

BACKGROUND

The receptor for advanced glycation end products (RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD.

OBJECTIVE

To test the association of soluble RAGE (sRAGE) levels with PGD in a prospective, multicenter cohort study.

METHODS

We measured plasma levels of sRAGE at 6 and 24 hours after allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was grade 3 PGD (Pa(O(2))/Fi(O(2)) < 200 with alveolar infiltrates) within the first 72 hours after transplantation.

RESULTS

Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P = 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P < 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P = 0.003) and 24 hours (P < 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearman's rho = 0.39, P = 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P = 0.02).

CONCLUSIONS

Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass.

BACKGROUND

Monckeberg's calcification in diabetes, known as medial artery calcification, is an independent predictor of cardiovascular mortality. However, the mechanism underlying this phenomenon remains to be elucidated. We demonstrate that advanced glycation end products (AGEs) induce calcification of vascular smooth muscle cells through the receptor for AGE (RAGE)/p38 mitogen-activated protein kinase (MAPK) signaling pathway.

METHODS

We detected vascular calcification by von Kossa staining. Alkaline phosphatase (ALP) activity was determined by measuring p-nitrophenol. Osteocalcin concentrations were measured using ELISA. Western blotting for protein phosphorylation and real-time RT-PCR for expression of mRNA were used.

RESULTS

AGEs induced calcification of vascular smooth muscle cells. AGEs also induced the expression of Runx2 mRNA. In addition, AGEs increased ALP activity and osteocalcin secretion. Furthermore, AGEs induced phosphorylation of p38 MAPK, and this phosphorylation was inhibited by the anti-RAGE blocking antibody. Increased ALP activity was inhibited by the p38 MAPK inhibitor or anti-RAGE blocking antibody. Furthermore, the p38 MAPK inhibitor and anti-RAGE blocking antibody both inhibited AGE-induced calcification of vascular smooth muscle cells. Diabetic serum induced calcification of smooth muscle cells and the calcification was inhibited by RAGE blocking.

CONCLUSIONS

Our findings indicate that AGEs induce calcification of vascular smooth muscle cells by osteoblast-like differentiation of smooth muscle cells through RAGE/p38 MAPK.

High Mobility Group Box 1 (HMGB1) is a nuclear non-histone protein discovered to be released in the extracellular medium as a response to various stimuli and implicated in cancerogenesis. High HMGB1 levels are reported in a variety of tumor types, but there are few data relating HMGB1 to the histological grade or to a particular cell type and cellular localization. We studied the expression of HMGB1 protein in malignant human tumors of different differentiation level and in tumor metastasis. In all tumor tissues, the protein level is elevated. In moderately differentiated carcinomas, the localization of the protein is perinuclear, while in the low differentiated; there is a tendency for non-specific nuclear localization. HMGB1 protein and its receptor RAGE are identified as a ligand-receptor pair that plays an important role in regulating the invasiveness of tumor cells. RAGE is not produced in all of the tested tumor specimens. We found high level of expression in hepatocellular, colorectal, and breast cribriform carcinomas, but not in malignant testicular specimens. Probably, the RAGE synthesis is related to distinctive tumor types. In metastatic cells, RAGE exhibits higher level of expression losing its specific granular cytosolic pattern characteristic for the primary tumors.

BACKGROUND

The receptor for advanced glycation end products (RAGE) is a cell surface receptor that has been implicated in vascular disease and neurodegeneration. Low levels of its secreted isoform, soluble RAGE (sRAGE), have been regarded as a putative risk factor for atherosclerosis. In addition, administration of sRAGE has been shown to reduce development of cerebral beta-amyloidosis in an Alzheimer disease mouse model.

OBJECTIVE

To investigate the role of sRAGE as a biological marker for Alzheimer disease and vascular dementia.

METHODS

Cross-sectional study of 152 patients with a clinical diagnosis of Alzheimer disease, 91 with vascular dementia and 161 control subjects.

METHODS

Plasma levels of sRAGE.

RESULTS

Levels of sRAGE were significantly reduced in the plasma of patients with Alzheimer disease compared with that for those with either vascular dementia (P<.05) or with controls (P<.001).

CONCLUSIONS

Patients with Alzheimer disease have reduced levels of sRAGE in plasma compared with patients with vascular dementia and controls. The striking reduction of circulating sRAGE in Alzheimer disease further supports a role for the RAGE axis in this clinical entity and requires further investigation.

In mammals, changes in the metabolic state, including obesity, fasting, cold challenge, and high-fat diets (HFDs), activate complex immune responses. In many strains of rodents, HFDs induce a rapid systemic inflammatory response and lead to obesity. Little is known about the molecular signals required for HFD-induced phenotypes. We studied the function of the receptor for advanced glycation end products (RAGE) in the development of phenotypes associated with high-fat feeding in mice. RAGE is highly expressed on immune cells, including macrophages. We found that high-fat feeding induced expression of RAGE ligand HMGB1 and carboxymethyllysine-advanced glycation end product epitopes in liver and adipose tissue. Genetic deficiency of RAGE prevented the effects of HFD on energy expenditure, weight gain, adipose tissue inflammation, and insulin resistance. RAGE deficiency had no effect on genetic forms of obesity caused by impaired melanocortin signaling. Hematopoietic deficiency of RAGE or treatment with soluble RAGE partially protected against peripheral HFD-induced inflammation and weight gain. These findings demonstrate that high-fat feeding induces peripheral inflammation and weight gain in a RAGE-dependent manner, providing a foothold in the pathways that regulate diet-induced obesity and offering the potential for therapeutic intervention.

Receptor for advanced glycation endproducts (RAGE) is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. Driven by rapid accumulation and expression of key ligands such as advanced glycation endproducts (AGE) and S100/calgranulins in diabetic tissues, upregulation and activation of RAGE magnifies cellular perturbation in tissues affected by hyperglycemia, such as the large blood vessels and the kidney. In the diabetic glomerulus, RAGE is expressed principally by glomerular visceral epithelial cells (podocytes). Blockade of RAGE in the hyperglycemic db/db mouse suppresses functional and structural alterations in the kidney, in the absence of alterations in blood glucose. Recent studies in homozygous RAGE null mice support a key role for RAGE in glomerular perturbation in diabetes. Importantly, beyond diabetes, studies in other settings of glomerulopathies support a critical RAGE-dependent pathway in podocytes linked to albuminuria, mesangial expansion, and glomerular sclerosis. A new paradigm is proposed in glomerular injury, and it is suggested that blockade of the RAGE axis may provide a novel means to prevent irreparable glomerular injury in diabetes and other sclerosing glomerulopathies.

Measures of structural brain change based on longitudinal MR imaging are increasingly important but can be degraded by intensity non-uniformity. This non-uniformity can be more pronounced at higher field strengths, or when using multichannel receiver coils. We assessed the ability of the non-parametric non-uniform intensity normalization (N3) technique to correct non-uniformity in 72 volumetric brain MR scans from the preparatory phase of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Normal elderly subjects (n=18) were scanned on different 3-T scanners with a multichannel phased array receiver coil at baseline, using magnetization prepared rapid gradient echo (MP-RAGE) and spoiled gradient echo (SPGR) pulse sequences, and again 2 weeks later. When applying N3, we used five brain masks of varying accuracy and four spline smoothing distances (d=50, 100, 150 and 200 mm) to ascertain which combination of parameters optimally reduces the non-uniformity. We used the normalized white matter intensity variance (standard deviation/mean) to ascertain quantitatively the correction for a single scan; we used the variance of the normalized difference image to assess quantitatively the consistency of the correction over time from registered scan pairs. Our results showed statistically significant (p<0.01) improvement in uniformity for individual scans and reduction in the normalized difference image variance when using masks that identified distinct brain tissue classes, and when using smaller spline smoothing distances (e.g., 50-100 mm) for both MP-RAGE and SPGR pulse sequences. These optimized settings may assist future large-scale studies where 3-T scanners and phased array receiver coils are used, such as ADNI, so that intensity non-uniformity does not influence the power of MR imaging to detect disease progression and the factors that influence it.

The incidence and severity of atherosclerosis is increased in patients with diabetes. Indeed, accelerated macrovascular disease in diabetic patients has emerged as a leading cause of morbidity and mortality in the United States and worldwide. Multiple investigations have suggested that there are numerous potential contributory factors that underlie these observations. Our laboratory has focused on the contribution of receptor for advanced glycation endproducts (RAGE) and its proinflammatory ligands, advanced glycation endproducts (AGEs) and S100/calgranulins in vascular perturbation, manifested as enhanced atherogenesis or accelerated restenosis after angioplasty. In rodent models of diabetic complications, blockade of RAGE suppressed vascular hyperpermeability, accelerated atherosclerotic lesion area and complexity in diabetic apolipoprotein E-deficient mice, and prevented exaggerated neointimal formation in hyperglycemic fatty Zucker rats subjected to injury of the carotid artery. In this review, we summarize these findings and provide an overview of distinct mechanisms that contribute to the development of accelerated diabetic macrovascular disease. Insights into therapeutic strategies to prevent or interrupt these processes are presented.

We previously have found that advanced glycation end products (AGE), senescent macroproteins formed at an accelerated rate in diabetes, arise in vivo not only from glucose but also from reducing sugars. Furthermore, we recently have shown that glyceraldehyde- and glycolaldehyde-derived AGE (glycer- and glycol-AGE) are mainly involved in loss of pericytes, the earliest histopathological hallmark of diabetic retinopathy. However, the effects of these AGE proteins on angiogenesis, another vascular derangement in diabetic retinopathy, remain to be elucidated. In this study, we investigated whether these AGE proteins elicit changes in cultured endothelial cells that are associated with angiogenesis. When human skin microvascular endothelial cells (EC) were cultured with glycer-AGE or glycol-AGE, growth and tube formation of EC, the key steps of angiogenesis, were significantly stimulated. The AGE-induced growth stimulation was significantly enhanced in AGE receptor (RAGE)-overexpressed EC. Furthermore, AGE increased transcriptional activity of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) and then up-regulated mRNA levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in EC. Cerivastatin, a hydroxymethylglutaryl CoA reductase inhibitor; pyrrolidinedithiocarbamate; or curcumin was found to completely prevent the AGE-induced increase in NF-kB and AP-1 activity, VEGF mRNA up-regulation, and the resultant increase in DNA synthesis in microvascular EC. These results suggest that the AGE-RAGE interaction elicited angiogenesis through the transcriptional activation of the VEGF gene via NF-kB and AP-1 factors. By blocking AGE-RAGE signaling pathways, cerivastatin might be a promising remedy for treating patients with proliferative diabetic retinopathy.

The effect of type 1 diabetes on bone healing and bone formation in standardized craniotomy defects created in BALB/cByJ mice was determined. The hypothesis that advanced glycation end products (AGEs) contribute to diminished bone healing in diabetes was evaluated by assessing for the presence of the receptor for advanced glycation end products (RAGE) by immunohistochemistry in healing craniotomy defects in diabetic animals. The effect of local application of a known RAGE protein ligand, N(epsilon)-(carboxymethyl)lysine (CML)-mouse serum albumin (MSA), on craniotomy defect healing in normal animals was then assessed and compared to the effects of control MSA. Finally, evidence in support of the expression of RAGE mRNA and protein in osteoblastic cells was obtained. The results indicated that craniotomy defects in diabetic animals healed approximately 40% of the degree to which they healed in nondiabetic animals (P < 0.05). RAGE was expressed at higher levels in healing bone tissues in diabetic compared to control animals. Further studies in nondiabetic animals indicated that bone healing was reduced by 63 and 42% in lesions treated with 900 and 90 micro g CML-MSA, respectively, compared to in animals treated with MSA alone (P < 0.05). Evidence for the expression of RAGE was obtained in mouse and rat osteoblastic cultures. These results support the contribution of AGEs to diminished bone healing in type 1 diabetes, possibly mediated by RAGE.

Pancreatic cancer is an almost uniformly lethal disease, characterized by late diagnosis, early metastasis, resistance to chemotherapy, and early mutation of the Kras oncogene. Here we show that the receptor for advanced glycation endproducts (RAGE) is required for the activation of interleukin 6 (IL-6)-mediated mitochondrial signal transducers and activators of transcription 3 (STAT3) signaling in pancreatic carcinogenesis. RAGE expression correlates with elevated levels of autophagy in pancreatic cancer in vivo and in vitro, and this heightened state of autophagy is required for IL-6-induced STAT3 activation. To further explore the intersection of RAGE, autophagy, and pancreatic carcinogenesis, we created a transgenic murine model, backcrossing RAGE-null mice to a spontaneous mouse model of pancreatic cancer, Pdx1-Cre:Kras(G12D/+) (KC). Targeted ablation of Rage in KC mice delayed neoplasia development, decreased levels of autophagy, and inhibited mitochondrial STAT3 activity and subsequent ATP production. Our results suggest a critical role for RAGE expression in the earliest stages of pancreatic carcinogenesis, potentially acting as the "autophagic switch," regulating mitochondrial STAT3 signaling.

Humans and their ancestors are unique in being a fire-making species, but 'natural' (i.e. independent of humans) fires have an ancient, geological history on Earth. Natural fires have influenced biological evolution and global biogeochemical cycles, making fire integral to the functioning of some biomes. Globally, debate rages about the impact on ecosystems of prehistoric human-set fires, with views ranging from catastrophic to negligible. Understanding of the diversity of human fire regimes on Earth in the past, present and future remains rudimentary. It remains uncertain how humans have caused a departure from 'natural' background levels that vary with climate change. Available evidence shows that modern humans can increase or decrease background levels of natural fire activity by clearing forests, promoting grazing, dispersing plants, altering ignition patterns and actively suppressing fires, thereby causing substantial ecosystem changes and loss of biodiversity. Some of these contemporary fire regimes cause substantial economic disruptions owing to the destruction of infrastructure, degradation of ecosystem services, loss of life, and smoke-related health effects. These episodic disasters help frame negative public attitudes towards landscape fires, despite the need for burning to sustain some ecosystems. Greenhouse gas-induced warming and changes in the hydrological cycle may increase the occurrence of large, severe fires, with potentially significant feedbacks to the Earth system. Improved understanding of human fire regimes demands: (1) better data on past and current human influences on fire regimes to enable global comparative analyses, (2) a greater understanding of different cultural traditions of landscape burning and their positive and negative social, economic and ecological effects, and (3) more realistic representations of anthropogenic fire in global vegetation and climate change models. We provide an historical framework to promote understanding of the development and diversification of fire regimes, covering the pre-human period, human domestication of fire, and the subsequent transition from subsistence agriculture to industrial economies. All of these phases still occur on Earth, providing opportunities for comparative research.