Diabetes mellitus (DM) is a major independent risk factor for cardiovascular disease, but also leads to cardiomyopathy. However, the etiology of the cardiac disease is unknown. Therefore, the aim of this study was to identify molecular mechanisms underlying diabetic heart disease. High glucose treatment of isolated cardiac fibroblasts, macrophages and cardiomyocytes led to a sustained induction of HMGB1 on the RNA and protein level followed by increased NF-κB binding activity with consecutively sustained TNF-α and IL-6 expression. Short interference (si) RNA knock-down for HMGB1 and RAGE in vitro confirmed the importance of this axis in diabetes-driven chronic inflammation. In a murine model of post-myocardial infarction remodeling in type 1 diabetes, cardiac HMGB1 expression was significantly elevated both on RNA and protein level paralleled by increased expression of pro-inflammatory cytokines up to 10 weeks. HMGB1-specific blockage via box A treatment significantly reduced post-myocardial infarction remodeling and markers of tissue damage in vivo. The protective effects of box A indicated an involvement of the mitogen-activated protein-kinases jun N-terminal kinase and extracellular signal-regulated kinase 1/2, as well as the transcription factor nuclear factor-kappaB. Interestingly, remodeling and tissue damage were not affected by administration of box A in RAGE(-/-) mice. In conclusion, HMGB1 plays a major role in DM and post-I/R remodeling by binding to RAGE, resulting in activation of sustained pro-inflammatory pathways and enhanced myocardial injury. Therefore, blockage of HMGB1 might represent a therapeutic strategy to reduce post-ischemic remodeling in DM.

The family of RAGE ligands, including Advanced Glycation Endproducts (AGEs), S100/calgranulins, High Mobility Group Box-1 (HMGB1) and amyloid beta peptide (Abeta) and beta-sheet fibrils are highly enriched in immune and inflammatory foci. In parallel, upregulation of Receptor for AGE (RAGE) is noted in diverse forms of inflammation and autoimmunity, based on experiments examining human tissues as well as animal models. Indeed, prior to the demonstration that S100/calgranulins were signal transduction ligands of RAGE, these molecules were considered "biomarkers" of disease and disease activity in disorders such as colitis and arthritis. Premiere roles for RAGE in advancing cellular migration implicate this receptor in targeting immune cells to vulnerable foci. Once engaged, ligand-RAGE interaction in inflammatory and vascular cells amplifies upregulation of inflammatory cytokines, adhesion molecules and matrix metalloproteinases (MMPs). Discerning the primal versus chronic injury-provoking roles for this ligand-receptor interaction is a challenge in delineating the functions of the ligand/RAGE axis. As RAGE is expressed by many of the key cell types linked integrally to the immune response, we propose that the sites and time course of ligand-RAGE stimulation determine the phenotype produced by this axis. Ultimately, drawing the fine line between antagonism versus stimulation of the receptor in health and disease will depend on the full characterization of RAGE in repair versus injury.

Receptor for advanced glycation end product (RAGE)-dependent signaling has been implicated in ischemia/reperfusion injury in the heart, lung, liver, and brain. Because macrophages contribute to vascular perturbation and tissue injury in hypoxic settings, we tested the hypothesis that RAGE regulates early growth response-1 (Egr-1) expression in hypoxia-exposed macrophages. Molecular analysis, including silencing of RAGE, or blockade of RAGE with sRAGE (the extracellular ligand-binding domain of RAGE), anti-RAGE IgG, or anti-AGE IgG in THP-1 cells, and genetic deletion of RAGE in peritoneal macrophages, revealed that hypoxia-induced up-regulation of Egr-1 is mediated by RAGE signaling. In addition, the observation of increased cellular release of RAGE ligand AGEs in hypoxic THP-1 cells suggests that recruitment of RAGE in hypoxia is stimulated by rapid production of RAGE ligands in this setting. Finally, we show that mDia-1, previously shown to interact with the RAGE cytoplasmic domain, is essential for hypoxia-stimulated regulation of Egr-1, at least in part through protein kinase C betaII, ERK1/2, and c-Jun NH(2)-terminal kinase signaling triggered by RAGE ligands. Our findings highlight a novel mechanism by which an extracellular signal initiated by RAGE ligand AGEs regulates Egr-1 in a manner requiring mDia-1.

Advanced glycation end products, AGEs, and its specific receptor, RAGE, are involved in vascular complications. A role for the soluble form of RAGE (sRAGE), which acts as a decoy for AGE, has been documented in patients with diabetes but no information is available in non-diabetic subjects. The aim of this study was to investigate the association of plasma levels of sRAGE with cardiometabolic risk factors in the general population. In addition we evaluated the relation of the common -374A/T polymorphism of RAGE with plasma levels of sRAGE. One hundred and seventy-six healthy subjects free of diabetes or coronary artery disease untreated for hypertension, dyslipidemia or cardiometabolic related diseases were randomly selected for this study from the general population. Plasma sRAGE were negatively and significantly correlated with BMI, waist/hip circumference ratio and fasting glycemia, while a positive correlation was observed with apolipoprotein A-I. These correlations were observed mainly in women who showed significantly higher sRAGE levels (1744+/-660 pg/mL vs 1414+/-649 pg/mL; P<0.05). In a stepwise regression analysis waist circumference was independently associated with sRAGE and, when waist circumference was excluded, BMI was independently associated with sRAGE. Finally in overweight subjects (BMI>25 kg/m(2)) plasma sRAGE was significantly lower compared to lean subjects (1460+/-640 pg/mL vs 1710+/-693 pg/mL; P<0.05). In healthy subjects plasma levels of sRAGE were negatively correlated with BMI and waist/hip ratio supporting a possible protective role for these proteins before any evidence of diabetic or vascular complications.

OBJECTIVE

High mobility group box-1 (HMGB1) protein is an alarmin, a normal cell constituent, which is released into the extracellular environment upon cellular stress/damage and capable of activating inflammation and tissue repair. The receptor for advanced glycation end products (RAGE) can bind HMGB1. RAGE, in turn, can induce the production of pro-inflammatory cytokines; this may be modulated by the soluble truncated forms of RAGE, including soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE). The objectives of this study were to determine whether: 1) clinical chorioamnionitis at term is associated with changes in amniotic fluid concentrations of HMGB1, sRAGE and esRAGE; and 2) the amniotic fluid concentration of HMGB1 changes with labor or as a function of gestational age.

METHODS

Amniotic fluid samples were collected from the following groups: 1) mid-trimester (n = 45); 2) term with (n = 48) and without labor (n = 22) without intra-amniotic infection; and 3) term with clinical chorioamnionitis (n = 46). Amniotic fluid concentrations of HMGB1, sRAGE and esRAGE concentrations were determined by ELISA.

RESULTS

1) the median amniotic fluid HMGB1 concentration was higher in patients at term with clinical chorioamnionitis than in those without this condition (clinical chorioamnionitis: median 3.8 ng/mL vs. term in labor: median 1.8 ng/mL, p = 0.007; and vs. term not in labor: median 1.1 ng/mL, p = 0.003); 2) in contrast, patients with clinical chorioamnionitis had a lower median sRAGE concentration than those without this condition (clinical chorioamnionitis: median 9.3 ng/mL vs. term in labor: median 18.6 ng/mL, p = 0.001; and vs. term not in labor median: 28.4 ng/mL, p < 0.001); 3) amniotic fluid concentrations of esRAGE did not significantly change in patients with clinical chorioamnionitis at term (clinical chorioamnionitis: median 5.4 ng/mL vs. term in labor: median 6.1 ng/mL, p = 0.9; and vs. term not in labor: median 9.5 ng/mL, p = 0.06); and 4) there was no significant difference in the median AF HMGB1 concentration between women at term in labor and those not in labor (p = 0.4) and between women in the mid-trimester and those at term not in labor (mid-trimester: median 1.5 ng/mL; p = 0.2).

CONCLUSIONS

An increase in the amniotic fluid HMGB1 concentration and a decrease in sRAGE were observed in clinical chorioamnionitis at term. This finding provides evidence that an alarmin, HMGB1, and one of its receptors, sRAGE, are engaged in the process of clinical chorioamnionitis at term. These changes are quite different from those observed in cases of intra-amniotic infection/inflammation in preterm gestations.

Long-standing diabetes causes cardiovascular complications including direct cardiac muscle weakening known as diabetic cardiomyopathy. This is characterized by disturbances in both cardiac contraction and relaxation, which are maintained by calcium homeostasis in cardiac cells. Our recent in vitro and in vivo studies have shown that advanced glycation endproducts (AGE) account for diabetic vasculopathy through their engagement of the receptor for AGE (RAGE). Here we show that AGE and RAGE may directly affect the myocardial Ca(2+) homeostasis. We created transgenic mice that overexpressed human RAGE in the heart and analyzed the Ca(2+) transients in cultivated cardiac myocytes (CM) from the RAGE-transgenic and non-transgenic control fetuses. RAGE overexpression was found to reduce the systolic and diastolic intracellular calcium concentration ([Ca(2+)](i)). Exposure to AGE caused a significant prolongation of the decay time of [Ca(2+)](i) in CM from control mice, and this response was augmented in CM from the RAGE transgenic mice. The results suggest that the AGE and RAGE could play an active role in the development of diabetes-induced cardiac dysfunction.

In the genesis of Alzheimer's disease (AD), converging lines of evidence suggest that amyloid-beta peptide (Abeta) triggers a pathogenic cascade leading to neuronal loss. It was long assumed that Abeta had to be assembled into extracellular amyloid fibrils or aggregates to exert its cytotoxic effects. Over the past decade, characterization of soluble oligomeric Abeta species in the brains of AD patients and in transgenic models has raised the possibility that different conformations of Abeta may contribute to AD pathology via different mechanisms. The receptor for advanced glycation end products (RAGE), a member of the Ig superfamily, is a cellular binding site for Abeta. Here, we investigate the role of RAGE in apoptosis induced by distinct well characterized Abeta conformations: Abeta oligomers (AbetaOs), Abeta fibrils (AbetaFs), and Abeta aggregates (AbetaAs). In our in vitro system, treatment with polyclonal anti-RAGE antibodies significantly improves SHSY-5Y cell and neuronal survival exposed to either AbetaOs or AbetaAs but does not affect AbetaF toxicity. Interestingly, using site-specific antibodies, we demonstrate that targeting of the V(d) domain of RAGE attenuates AbetaO-induced toxicity in both SHSY-5Y cells and rat cortical neurons, whereas inhibition of AbetaA-induced apoptosis requires the neutralization of the C(1d) domain of the receptor. Thus, our data indicate that distinct regions of RAGE are involved in Abeta-induced cellular and neuronal toxicity with respect to the Abeta aggregation state, and they suggest the blockage of particular sites of the receptor as a potential therapeutic strategy to attenuate neuronal death.

Substantial attention has been paid to the role of the toll-like receptor (TLR) ligands of late and their role in regulating the innate immune response. They serve as exogenous danger signals important in informing and driving the distal adaptive immune response to pathogens. Less clear has been the role of the nominal endogenous danger signals released and recognized in stressed cells following genotoxic or metabolic stress as occurs in progressively growing tumors. HMGB1 (high-mobility group B1) is a nuclear protein well characterized for its ability to modify DNA access to transcriptional proteins that is released from necrotic cells as well as secreted through the endosomal route from hematopoietic cells, serving as a late mediator of sepsis. It interacts with high-affinity RAGE (receptor for advanced glycation end products) and TLR2 receptors. Here we show that HMGB1 enhances interferon gamma release from macrophage (but not dendritic cell)-stimulated NK cells. This is effective only when coupled with other pro-inflammatory cytokines particularly with IL-2 in combination with IL-1 or IL-12. We have used this information to suggest that HMGB1, which also promotes epithelial migration and proliferation, drives repair in the absence or inhibition of other factors but enhances inflammation in their presence. The implications for tumorigenesis and tumor progression are quite important as they may be for other states of chronic inflammation.

OBJECTIVE

The purpose of this study was to evaluate a magnetization-prepared-rapid gradient-echo (MP-RAGE) sequence as a three-dimensional (3D) T1-weighted MR imaging technique to reveal lymph node metastases from carcinoma of the bladder and the prostate.

METHODS

Using a 3D T1-weighted MP-RAGE sequence, MR images of 134 consecutive patients with prostatic carcinoma (n = 63) or urinary bladder carcinoma (n = 71) who were scheduled for radical prostatectomy or radical cystectomy were correlated with histopathologic findings after fine-needle aspiration biopsy (FNAB) (n = 6), open or laparoscopic pelvic lymph node dissection (n = 127), or autopsy (n = 1). MR imaging was used 10 times to guide FNAB in nine patients.

RESULTS

The sensitivity, specificity, accuracy, and positive predictive valve of the technique were 75%, 98%, 90%, and 94%, respectively. Thin-slice (1.2-mm) multiplanar reconstructed images correctly revealed diseased nodes in 33 patients. However, MR imaging failed to reveal microscopic metastatic deposits in normally sized nodes in 11 patients. Two other patients had enlarged nodes without metastasis. Furthermore, FNAB guided by MR imaging revealed metastases in six of nine patients.

CONCLUSIONS

MR imaging with a 3D MP-RAGE sequence was accurate in revealing nodal metastases from carcinoma of the prostate and bladder. This imaging technique can be used to select patients for biopsy or laparoscopic pelvic lymph node dissection.

Approaching epidemic levels, diabetic kidney disease (DKD) is now the leading cause of end-stage renal disease (ESRD). Microalbuminuria is an early clinical marker of DKD that results from damage to the glomerular filtration barrier at the level of the highly differentiated glomerular podocyte cells. Injury to these epithelial cells, podocytopathies, includes cellular hypertrophy, foot process effacement, detachment from the glomerular basement membrane, and apoptosis. Here we review the role of a number of recently identified factors that contribute to podocytopathies in DKD. These factors include members of the renin-angiotensin system (RAS), including angiotensin-converting enzyme (ACE) types 1 and 2, prorenin and its receptor, reactive oxygen species (ROS), prostanoids, peroxisome proliferator-activated receptors (PPAR), advanced glycation end-products (AGEs) and their receptors (RAGE), adiponectin, and microRNAs. As the number of therapeutic options that slow, but do not halt, the progression of DKD to ESRD remains limited, a more comprehensive understanding of the signaling events that contribute to this increasingly prevalent disease may identify novel avenues for treatment and prevention.

C-reactive protein (CRP) and serum amyloid A (SAA) increase in the blood of patients with inflammatory conditions and CRP-induced monocyte tissue factor (TF) may contribute to inflammation-associated thrombosis. This study demonstrates that SAA is a potent and rapid inducer of human monocyte TF. SAA induced TF mRNA in PBMC within 30 min and optimal procoagulant activity within 4 h, whereas CRP (25 mug/ml)-induced activity was minimal at this time. Unlike CRP, SAA did not synergize with LPS. Procoagulant activity was inhibited by anti-TF and was dependent on factors VII and X, and TF Ag levels were elevated on CD14(+) monocytes. Responses were optimal with lymphocytes, although these were not obligatory. Inhibitor studies indicate activation of NF-kappaB through the ERK1/2 and p38 MAPK pathways; the cyclo-oxygenase pathway was not involved. SAA-induced TF was partially inhibited by high-density lipoprotein, but not by low-density lipoprotein or by apolipoprotein A-I. SAA is a ligand for the receptor for advanced glycation end products (RAGE), and TF generation was suppressed by approximately 50% by a RAGE competitor, soluble RAGE, and by approximately 85% by anti-RAGE IgG. However, another RAGE ligand, high mobility group box-1 protein, capable of inducing monocyte chemotactic protein-1 mRNA in 2 h, did not induce TF within 24 h. Cross-linking studies confirmed SAA binding to soluble RAGE. Elevated SAA is a marker of disease activity in patients with rheumatoid arthritis, and PBMC from patients with rheumatoid arthritis were more sensitive to SAA than normals, suggesting a new link between inflammation and thrombosis.

Background: The global battle to contain the novel coronavirus disease 2019 (COVID-19) pandemic rages on. Previous studies described the clinical characteristics of COVID-19, but knowledge gaps remain in the Middle East region. Identifying these features will help in mapping the disease and guiding pandemic management. A multi-center, retrospective cross-sectional study was initiated to describe the demographic data, clinical characteristics, and outcomes of COVID-19 cases across all the regions of Saudi Arabia.

Methods: The analysis included all laboratory-confirmed positive COVID-19 patients from the 1st of March 2020 to 31st of March 2020 across all regions of Saudi Arabia. Demographic data, clinical characteristics, incubation periods, laboratory findings, and patient outcomes data were retrieved from 1519 cases in the Health Electronic Surveillance Network Database.

Results: The median age was 36 years and 54.3% (n = 825) of the patients were men. Patients working in health care facilities represented 12.5% of the cases (n = 190) and 9.3% of cases were asymptomatic. The median incubation period was 6 days. The most common symptoms were cough (89.4%), fever (85.6%), and sore throat (81.6%); 20.1% of the patients had underlying comorbidities. Hypertension was seen in 8.8% and diabetes in 7.6% of all the cases. The percentage of cases with temperatures >38֯C was 20.3% (n = 129), and 1.6% of patients had heart rates ≥125 beats/min and 4.7% of them had respiratory rates of >24 breaths/min. Lymphocytopenia occurred in 37.5% of cases. Overall, 71.6% of patients were admitted to hospitals and 4.7% required ICU treatment. We could not completely assess the clinical courses or final outcomes of COVID-19 patients.

Conclusion: In this multi-center retrospective study, fever and cough were common symptoms. Special attention should be addressed toward asymptomatic carriers and workers in health care facilities as they play a key role in disease transmission.

Keywords: COVID-19; Clinical characteristics; Coronavirus; Outbreak; Saudi Arabia.

In chronic glomerulopathic disease, renal function correlates more with the degree oftubulointerstitial injury than that of the glomerular lesions. Proteinuria may be one of the pathologic links between these two intrarenal compartments. It is apparent that the proximal tubular epithelial cell (PTEC) assumes a proinflammatory and profibrotic role during proteinuria in which the PTEC expresses a variety of chemokines and injury signals that culminate in progressive interstitial inflammation and fibrosis. During diabetes, other substrates including advanced glycation end products (AGEs), AGE intermediates, and high glucose (HG) may provoke the PTEC even further. Glycated albumin, but not the equivalent dose of bovine serum albumin (BSA), stimulates tubular IL-8 and ICAM-1 expression via NF-κB-, MAPK- and STAT-1-dependent pathways. Human biopsies of diabetic nephropathy (DN) reveal colocalization of AGE and ICAM-1 in proximal tubules. The biologically active carbonyl intermediates methylglyoxal-BSA-AGE and AGE-BSA upregulate tubular expression of CTGF, TGF-β, and VEGF, whereas carboxymethyllysine-BSA stimulates tubular expression of IL-6, CCL-2, CTGF, TGF-β, and VEGF via RAGE activation and NF-κB signal transduction. Hyperglycemia (30 mM), but not the equivalent dose of mannitol, promotes proinflammatory (IL-6 and CCL-2), profibrotic (TGF-β) and angiogenic (VEGF) responses in tubular cells via MAPK and PKC signaling and induces epithelial mesenchymal transition, which is TGF-β1 mediated. It has recently been shown that toll-like receptor (TLR) is implicated in the diabetic kidney. In human DN biopsies and PTEC, TLR4is upregulated and plays a permissive role in HG-induced IL-6 and CCL-2 overexpression and monocyte transmigration. In streptozotocin-induced rat DN and PTEC, TLR2 appears to be upregulated. Other novel mediators that become activated in PTEC exposed to HG include macrophage inflammatory protein-3-α, Krüppel-like factor 6 and thioredoxin-interacting protein, which may be attenuated by peroxisome proliferator-activate dreceptor-γ activation. Collectively, these phenomena suggest that the renal tubules are heavily involved in the pathogenesis of DN. These pathophysiologic responses may be collectively described as diabetic tubulopathy.

Recent studies have suggested an important relationship linking cytokines, immunity and aggressive behavior. Clinical reports describe increasing levels of hostility, anger, and irritability in patients who receive cytokine immunotherapy, and there are reports of a positive correlation between cytokine levels and aggressive behavior in non-patient populations. On the basis of these reports and others describing the presence or actions of different cytokines in regions of the brain associated with aggressive behavior, our laboratory embarked upon a program of research designed to identify and characterize the role of IL-1 and IL-2 in the hypothalamus and midbrain periaqueductal gray (PAG)--two regions functionally linked through reciprocal anatomical connections--in the regulation of feline defensive rage. A paradigm involved cytokine microinjections into either medial hypothalamus and elicitation of defensive rage behavior from the PAG or vice versa. These studies have revealed that both cytokines have potent effects in modulating defensive rage behavior. With respect to IL-1, this cytokine facilitates defensive rage when microinjected into either the medial hypothalamus or PAG and these potentiating effects are mediated through 5-HT2 receptors. In contrast, the effects of IL-2 are dependent upon the anatomical locus. IL-2 microinjected into the medial hypothalamus suppresses defensive rage and this suppression is mediated through GABA(A) receptors, while microinjections of IL-2 in the PAG potentiate defensive rage, in which these effects are mediated through NK-1 receptors. Present research is designed to further delineate the roles of cytokines in aggressive behavior and to begin to unravel the possible signaling pathways involved this process.

Human apolipoprotein E (APOE) exists in three isoforms ɛ2, ɛ3, and ɛ4, of which APOE4 is the main genetic risk factor of Alzheimer's disease (AD). As cerebrovascular defects are associated with AD, we tested whether APOE genotype has an impact on the integrity and function of the blood-brain barrier (BBB) in human APOE-targeted replacement mice. Using the quantitative in situ brain perfusion technique, we first found lower (13.0% and 17.0%) brain transport coefficient (Clup) of [(3)H]-diazepam in APOE4 mice at 4 and 12 months, compared with APOE2 and APOE3 mice, reflecting a decrease in cerebral vascularization. Accordingly, results from immunohistofluorescence experiments revealed a structurally reduced cerebral vascularization (26% and 38%) and thinner basement membranes (30% and 35%) in 12-month-old APOE4 mice compared with APOE2 and APOE3 mice, suggesting vascular atrophy. In addition, APOE4 mice displayed a 29% reduction in [(3)H]-d-glucose transport through the BBB compared with APOE2 mice without significant changes in the expression of its transporter GLUT1 in brain capillaries. However, an increase of 41.3% of receptor for advanced glycation end products (RAGE) was found in brain capillaries of 12-month-old APOE4 mice. In conclusion, profound divergences were observed between APOE genotypes at the cerebrovascular interface, suggesting that APOE4-induced BBB anomalies may contribute to AD development.

The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor that binds to diverse ligands and initiates a downstream proinflammatory signaling cascade. RAGE activation has been linked to diabetic complications, Alzheimer disease, infections, and cancers. RAGE is known to mediate cell signaling and downstream proinflammatory gene transcription activation, although the precise mechanism surrounding receptor-ligand interactions is still being elucidated. Recent fluorescence resonance energy transfer evidence indicates that RAGE may form oligomers on the cell surface and that this could be related to signal transduction. To investigate whether RAGE forms oligomers, protein-protein interaction assays were carried out. Here, we demonstrate the interaction between RAGE molecules via their N-terminal V domain, which is an important region involved in ligand recognition. By protein cross-linking using water-soluble and membrane-impermeable cross-linker bis(sulfosuccinimidyl) suberate and nondenaturing gels, we show that RAGE forms homodimers at the plasma membrane, a process potentiated by S100B and advanced glycation end products. Soluble RAGE, the RAGE inhibitor, is also capable of binding to RAGE, similar to V peptide, as shown by surface plasmon resonance. Incubation of cells with soluble RAGE or RAGE V domain peptide inhibits RAGE dimerization, subsequent phosphorylation of intracellular MAPK proteins, and activation of NF-kappaB pathways. Thus, the data indicate that dimerization of RAGE represents an important component of RAGE-mediated cell signaling.

AGE/RAGE signaling has been a well-studied cascade in many different disease states, particularly diabetes. Due to the complex nature of the receptor and multiple intersecting pathways, the AGE/RAGE signaling mechanism is still not well understood. The purpose of this review is to highlight key areas of AGE/RAGE mediated vascular calcification as a complication of diabetes. AGE/RAGE signaling heavily influences both cellular and systemic responses to increase bone matrix proteins through PKC, p38 MAPK, fetuin-A, TGF-β, NFκB, and ERK1/2 signaling pathways in both hyperglycemic and calcification conditions. AGE/RAGE signaling has been shown to increase oxidative stress to promote diabetes-mediated vascular calcification through activation of Nox-1 and decreased expression of SOD-1. AGE/RAGE signaling in diabetes-mediated vascular calcification was also attributed to increased oxidative stress resulting in the phenotypic switch of VSMCs to osteoblast-like cells in AGEs-induced calcification. Researchers found that pharmacological agents and certain antioxidants decreased the level of calcium deposition in AGEs-induced diabetes-mediated vascular calcification. By understanding the role the AGE/RAGE signaling cascade plays diabetes-mediated vascular calcification will allow for pharmacological intervention to decrease the severity of this diabetic complication.

Advanced glycation end products (AGEs) are a heterogenous group of molecules formed during a non-enzymatic reaction between proteins and sugar residues. Recently, AGEs and their receptor (receptor for AGEs; RAGE) play a central role in the pathogenesis of cardiovascular disease (CVD), which accounts for disability and high mortality rate in patients with diabetes. AGEs initiate diabetic micro- and macrovascular complications through the structural modification and functional alteration of the extracellular matrix proteins as well as intracellular signaling molecules. Engagement of RAGEs with AGEs elicits intracellular reactive oxygen species (ROS) generation and subsequently activates mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling, followed by production of several inflammatory and/or profibrotic factors such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1), thereby being involved in the progression of atherosclerosis. Administration of soluble form of RAGE (sRAGE) could work as a decoy receptor for AGEs and might inhibit the binding of AGEs to RAGE, preventing the development and progression of atherosclerosis in animal models. Furthermore, AGEs/high mobility group box-1 (HMGB-1)-RAGE interaction is involved in heart failure, abdominal aortic aneurysm (AAA) and vascular calcification as well. Thus, blockade of the AGEs/HMGB-1-RAGE system may be a promising therapeutic target for preventing diabetes- and/or age-related CVD. We review here the pathological role of the AGEs/HMGB-1-RAGE system in various types of CVD.

Pituitary adenylate cyclase-activating polypeptide (PACAP) has neuroprotective and neurotrophic properties and is a potent α-secretase activator. As PACAP peptides and their specific receptor PAC1 are localized in central nervous system areas affected by Alzheimer's disease (AD), this study aims to examine the role of the natural peptide PACAP as a valuable approach in AD therapy. We investigated the effect of PACAP in the brain of an AD transgenic mouse model. The long-term intranasal daily PACAP application stimulated the nonamyloidogenic processing of amyloid precursor protein (APP) and increased expression of the brain-derived neurotrophic factor and of the antiapoptotic Bcl-2 protein. In addition, it caused a strong reduction of the amyloid β-peptide (Aβ) transporter receptor for advanced glycation end products (RAGE) mRNA level. PACAP, by activation of the somatostatin-neprilysin cascade, also enhanced expression of the Aβ-degrading enzyme neprilysin in the mouse brain. Furthermore, daily PAC1-receptor activation via PACAP resulted in an increased mRNA level of both the PAC1 receptor and its ligand PACAP. Our behavioral studies showed that long-term PACAP treatment of APP[V717I]-transgenic mice improved cognitive function in animals. Thus, nasal application of PACAP was effective, and our results indicate that PACAP could be of therapeutic value in treating AD.

Debate continues to rage between enthusiasts for climate change versus humans as a cause of the catastrophic faunal extinctions that have occurred in the wake of human arrival in previously uninhabited regions of the world. A global pattern of human arrival to such landmasses, followed by faunal collapse and other ecological changes, appears without known exception. This strongly suggests to some investigators that a more interesting extinction debate lies within the realm of potential human-caused explanations and how climate might exacerbate human impacts. New observations emerging from refined dating techniques, paleoecology and modeling suggest that the megafaunal collapses of the Americas and Australia, as well as most prehistoric island biotic losses, trace to a variety of human impacts, including rapid overharvesting, biological invasions, habitat transformation and disease.

This review addresses the phenomenology of mania/bipolar disorder from a developmental psychopathology perspective and uses cases with longitudinal information to illustrate major points. Beginning with a summary of the phenomenology of bipolar illness as it occurs in adults, the authors identify diagnostic complexities unique to children and adolescents. These include the challenges of characterizing elation and grandiosity; differentiating mania from comorbid symptoms, rages, sequelae of maltreatment, and typical developmental phenomena; and the unique manifestations of psychosis. We conclude with the observation that a significant difference between early and later onset bipolar disorder is that, in the former, there appears to be a global delay or arrest in the development of appropriate affect regulation; whereas in adult-onset bipolar illness, emotion dysregulation generally presents as an intermittent phenomenon. At this juncture, the study of childhood bipolar illness would benefit from a developmental psychopathology perspective to move beyond the level of cross-sectional symptom description to begin to study individuals over time, focusing on developmental, environmental, genetic, and neurobiological influences on manifest behavior.

BACKGROUND

Total circulating soluble receptor for advanced glycation endproducts (sRAGE) and a more defined endogenous secretory splice variant of the receptor (esRAGE) were shown to be associated with different markers of cardiovascular risk in patients with diabetes. Since previous data were partly divergent, the aim of this study was to compare sRAGE and esRAGE in a head-to-head analysis in patients with type 2 diabetes (T2DM) with albuminuria.

METHODS

sRAGE and esRAGE were studied in plasma of 110 T2DM patients using enzyme-linked immunosorbant assays (ELISA) detecting either sRAGE or esRAGE only. Both sRAGE and esRAGE were compared with regard to applicability as markers for vascular disease and glucose control in T2DM.

RESULTS

In bivariate analysis, sRAGE correlated with age (R = 0.22, p = 0.02) and the 24 hour albumin excretion rate (R = 0.18, p = 0.05), while esRAGE correlated positively with age only (R = 0.23, p = 0.02). In contrast to previous reports, neither sRAGE nor esRAGE correlated with glucose control or intima-media-thickness (IMT) as a predictor of macrovascular disease. In multivariate regression models, the associations between sRAGE and albuminuria as well as esRAGE and age were shown to be independent of glucose control, diabetes duration, body-mass index, glomerular filtration rate, blood pressure and gender.

CONCLUSIONS

This is the first study comparing sRAGE and esRAGE as markers of vascular complications in patients with T2DM. sRAGE but not esRAGE is independently associated with albuminuria in these patients while neither sRAGE nor esRAGE are associated with markers of glucose control or macrovascular disease.

The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA-RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA.

Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell-surface molecules. Blockade of RAGE has been reported to considerably improve liver function and accelerate regeneration after hepatectomy. The aim of this study was to investigate the cell type-specific expression of RAGE, and to examine whether transdifferentiation of hepatic stellate cells (HSC) into myofibroblasts (MFB) is associated with changes in RAGE expression. Northern blot analysis revealed that RAGE mRNA was exclusively expressed by HSC isolated from rat liver, while no transcripts were seen in hepatocytes, Kupffer cells, or sinusoidal endothelial cells. Expression of RAGE mRNA was up-regulated during transdifferentiation of HSC into MFB. Concomitantly, expression of RAGE protein was increased as confirmed by Western blotting and immunohistochemistry. As assessed by radioactive labeling, transforming growth factor beta(1) (TGF-beta(1)) induced a time-dependent 2- to 15-fold increase in the de novo synthesis of RAGE protein, which was completely abolished using PD098059, a specific inhibitor of the mitogen-activated protein kinase (MAPK) kinase. As shown by double-immunofluorescence staining, RAGE colocalized with alpha-smooth muscle actin, and immunoelectron microscopy demonstrated the most prominent labeling for RAGE at filopodial membranes of MFB. In conclusion, this study demonstrates that expression of RAGE is restricted to rat HSC, and that expression is up-regulated during activation of HSC and transition to MFB. The preferential immunogold labeling of RAGE to focal membrane areas of filopodia of MFB is suggestive of a role of RAGE in the spreading and migration of activated HSC/MFB, major players in liver fibrogenesis.