Vitamin D supplementation modulates glycated hemoglobin (HBA1c) in diabetes mellitus.

Diabetes is a metabolic illness that increases protein glycosylation in hyperglycemic conditions, which can have an impact on almost every organ system in the body. The role of vitamin D in the etiology of diabetes under RAGE (receptor for advanced glycation end products) stress has recently received some attention on a global scale. Vitamin D's other skeletal benefits have generated a great deal of research. Vitamin D's function in the development of type 1 and type 2 diabetes is supported by the discovery of 1,25 (OH)2D3 and 1-Alpha-Hydroylase expression in immune cells, pancreatic beta cells, and several other organs besides the bone system. A lower HBA1c level, metabolic syndrome, and diabetes mellitus all seems to be associated with vitamin D insufficiency. Most of the cross-sectional and prospective observational studies that were used to gather human evidence revealed an inverse relationship between vitamin D level and the prevalence or incidence of elevated HBA1c in type 2 diabetes. Several trials have reported on the impact of vitamin D supplementation for glycemia or incidence of type 2 diabetes, with varying degrees of success. The current paper examines the available data for a relationship between vitamin D supplementation and HBA1c level in diabetes and discusses the biological plausibility of such a relationship.

High-fat diet causes endothelial dysfunction in the mouse ophthalmic artery.

Obesity is a significant health concern that leads to impaired vascular function and subsequent abnormalities in various organs. The impact of obesity on ocular blood vessels, however, remains largely unclear. In this study, we examined the hypothesis that obesity induced by high-fat diet produces vascular endothelial dysfunction in the ophthalmic artery. Mice were subjected to a high-fat diet for 20 weeks, while age-matched controls were maintained on a standard diet. Reactivity of isolated ophthalmic artery segments was assessed in vitro. Reactive oxygen species (ROS) were quantified in cryosections by dihydroethidium (DHE) staining. Redox gene expression was determined in ophthalmic artery explants by real-time PCR. Furthermore, the expression of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), the receptor for advanced glycation end products (RAGE), and of the lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) was determined in cryosections using immunofluorescence microscopy. Ophthalmic artery segments from mice on a high-fat diet exhibited impaired vasodilation responses to the endothelium-dependent vasodilator acetylcholine, while endothelium-independent responses to nitroprusside remained preserved. DHE staining intensity in the vascular wall was notably stronger in mice on a high-fat diet. Messenger RNA expression for NOX2 was elevated in the ophthalmic artery of mice subjected to high fat diet. Likewise, immunostainings revealed increased expression of NOX2 and of RAGE, but not of LOX-1. These findings suggest that a high-fat diet triggers endothelial dysfunction by inducing oxidative stress in the ophthalmic artery via involvement of RAGE and NOX2.

Immunological methods for the determination of AGE-RAGE axis generated glutathionylated and carbonylated proteins as oxidative stress markers.

Interaction of advanced glycation end products (AGE) with their receptor i.e. receptor for advanced glycation end products (RAGE), better understood as AGE-RAGE axis, generates oxidative and inflammatory stress. The generated stress extent, in turn aggravates the AGE and RAGE levels through a vicious self propagation cycle. The associated oxidation and inflammation culminates in modifications and subsequent detrimental state of cellular macromolecules, including nucleic acids and proteins, manifesting multiple diseased conditions. Under normal physiological state, fewer carbonyl group(s) and glutathione, a tripeptide antioxidant may be added to proteins during post-translational modifications, recognized as carbonylation and glutathionylation, respectively. However, under oxidative and inflammatory stress conditions, protein carbonylation and glutathionylation are caused to considerably greater extents, leading to numerous diseased complications. Thereby, increased protein carbonylation and glutathionylation could be used as predictive markers of oxidative and inflammatory stress. The AGE-RAGE axis generated oxidatively modified proteins can be screened via assessing the protein carbonylation and glutathionylation. The present article focuses on most widely used protein carbonylation and glutathionylation based assays for quantifying the AGE-RAGE axis mediated oxidative and inflammatory stress.

Leukocyte surface biomarkers implicate deficits of innate immunity in sporadic Alzheimer's disease.

INTRODUCTION: Blood-based diagnostics and prognostics in sporadic Alzheimer's disease (AD) are important for identifying at-risk individuals for therapeutic interventions. METHODS: In three stages, a total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses. RESULTS: We identified leukocyte markers differentially expressed in the patients with AD. Pathway analysis revealed a complex network involving upregulation of complement inhibition and downregulation of cargo receptor activity and Aß clearance. A proposed panel including four leukocyte markers - CD11c, CD59, CD91, and CD163 - predicts patients' PET Aß status with an area under the curve (AUC) of 0.93 (0.88 to 0.97). CD163 was the top performer in preclinical models. These findings have been validated in two independent cohorts. CONCLUSION: Our finding of changes on peripheral leukocyte surface antigens in AD implicates the deficit in innate immunity. Leukocyte-based biomarkers prove to be both sensitive and practical for AD screening and diagnosis.

RAGE mediates airway inflammation via the HDAC1 pathway in a toluene diisocyanate-induced murine asthma model.

BACKGROUND: Exposure to toluene diisocyanate (TDI) is a significant pathogenic factor for asthma. We previously reported that the receptor for advanced glycation end products (RAGE) plays a key role in TDI-induced asthma. Histone deacetylase (HDAC) has been reported to be important in asthmatic pathogenesis. However, its effect on TDI-induced asthma is not known. The aim of this study was to determine the role of RAGE and HDAC in regulating airway inflammation using a TDI-induced murine asthma model. METHODS: BALB/c mice were sensitized and challenged with TDI to establish an asthma model. FPS-ZM1 (RAGE inhibitor), JNJ-26482585 and romidepsin (HDAC inhibitors) were administered intraperitoneally before each challenge. In vitro, the human bronchial epithelial cell line 16HBE was stimulated with TDI-human serum albumin (TDI-HSA). RAGE knockdown cells were constructed and evaluated, and MK2006 (AKT inhibitor) was also used in the experiments. RESULTS: In TDI-induced asthmatic mice, the expression of RAGE, HDAC1, and p-AKT/t-AKT was upregulated, and these expressions were attenuated by FPS-ZM1. Airway reactivity, Th2 cytokine levels in lymph supernatant, IgE, airway inflammation, and goblet cell metaplasia were significantly increased in the TDI-induced asthmatic mice. These increases were suppressed by JNJ-26482585 and romidepsin. In addition, JNJ-26482585 and romidepsin ameliorated the redistribution of E-cadherin and ß-catenin in TDI-induced asthma. In TDI-HSA-stimulated 16HBE cells, knockdown of RAGE attenuated the upregulation of HDAC1 and phospho-AKT (p-AKT). Treatment with the AKT inhibitor MK2006 suppressed TDI-induced HDAC1 expression. CONCLUSIONS: These findings indicate that RAGE modulates HDAC1 expression via the PI3K/AKT pathway, and that inhibition of HDAC prevents TDI-induced airway inflammation.

Inhibitory Effects of Saururus chinensis Extract on Receptor for Advanced Glycation End-Products-Dependent Inflammation and Diabetes-Induced Dysregulation of Vasodilation.

Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) are implicated in inflammatory reactions and vascular complications in diabetes. Signaling pathways downstream of RAGE are involved in NF-κB activation. In this study, we examined whether ethanol extracts of Saururus chinensis (Lour.) Baill. (SE) could affect RAGE signaling and vascular relaxation in streptozotocin (STZ)-induced diabetic rats. Treatment with SE inhibited AGEs-modified bovine serum albumin (AGEs-BSA)-elicited activation of NF-κB and could compete with AGEs-BSA binding to RAGE in a dose-dependent manner. Tumor necrosis factor-α (TNF-α) secretion induced by lipopolysaccharide (LPS)-a RAGE ligand-was also reduced by SE treatment in wild-type Ager+/+ mice as well as in cultured peritoneal macrophages from Ager+/+ mice but not in Ager-/- mice. SE administration significantly ameliorated diabetes-related dysregulation of acetylcholine-mediated vascular relaxation in STZ-induced diabetic rats. These results suggest that SE would inhibit RAGE signaling and would be useful for the improvement of vascular endothelial dysfunction in diabetes.

Dual Nature of RAGE in Host Reaction and Nurturing the Mother-Infant Bond.

Non-enzymatic glycation is an unavoidable reaction that occurs across biological taxa. The final products of this irreversible reaction are called advanced glycation end-products (AGEs). The endogenously formed AGEs are known to be bioactive and detrimental to human health. Additionally, exogenous food-derived AGEs are debated to contribute to the development of aging and various diseases. Receptor for AGEs (RAGE) is widely known to elicit biological reactions. The binding of RAGE to other ligands (e.g., high mobility group box 1, S100 proteins, lipopolysaccharides, and amyloid-ß) can result in pathological processes via the activation of intracellular RAGE signaling pathways, including inflammation, diabetes, aging, cancer growth, and metastasis. RAGE is now recognized as a pattern-recognition receptor. All mammals have RAGE homologs; however, other vertebrates, such as birds, amphibians, fish, and reptiles, do not have RAGE at the genomic level. This evidence from an evolutionary perspective allows us to understand why mammals require RAGE. In this review, we provide an overview of the scientific knowledge about the role of RAGE in physiological and pathological processes. In particular, we focus on (1) RAGE biology, (2) the role of RAGE in physiological and pathophysiological processes, (3) RAGE isoforms, including full-length membrane-bound RAGE (mRAGE), and the soluble forms of RAGE (sRAGE), which comprise endogenous secretory RAGE (esRAGE) and an ectodomain-shed form of RAGE, and (4) oxytocin transporters in the brain and intestine, which are important for maternal bonding and social behaviors.

RAGE signaling antagonist suppresses mouse macrophage foam cell formation.

The engagement of the receptor for advanced glycation end-products (receptor for AGEs, RAGE) with diverse ligands could elicit chronic vascular inflammation, such as atherosclerosis. Binding of cytoplasmic tail RAGE (ctRAGE) to diaphanous-related formin 1 (Diaph1) is known to yield RAGE intracellular signal transduction and subsequent cellular responses. However, the effectiveness of an inhibitor of the ctRAGE/Diaph1 interaction in attenuating the development of atherosclerosis is unclear. In this study, using macrophages from Ager+/+ and Ager-/- mice, we validated the effects of an inhibitor on AGEs-RAGE-induced foam cell formation. The inhibitor significantly suppressed AGEs-RAGE-evoked Rac1 activity, cell invasion, and uptake of oxidized low-density lipoprotein, as well as AGEs-induced NF-κB activation and upregulation of proinflammatory gene expression. Moreover, expression of Il-10, an anti-inflammatory gene, was restored by this antagonist. These findings suggest that the RAGE-Diaph1 inhibitor could be a potential therapeutic drug against RAGE-related diseases, such as chronic inflammation and atherosclerosis.

Receptor for Advanced Glycation End Products (RAGE) and Its Polymorphic Variants as Predictive Diagnostic and Prognostic Markers of NSCLCs: a Perspective.

PURPOSE OF REVIEW: Non-small cell lung cancers (NSCLCs) account for ~ 85% of all lung cancers, and 5-year survival in Europe and the USA is ~ 13-17%. In this review, we focus on the significance of Receptor for Advanced Glycation End products (RAGE) as a diagnostic or post-therapeutic prognostic marker for various forms of NSCLCs. RECENT FINDINGS: The lungs have the highest levels of basal RAGE expression in mammals. The physiologic RAGE in lungs may be involved in adhesion and spreading of AT-1 cells and maintenance of pulmonary homeostasis. However, high level expression of RAGE complicates various diseases including acute lung injury. In NSCLCs, while a number of studies report decreased RAGE expression, inferring a protective role, others suggest that RAGE expression may contribute to NSCLC pathogenesis. Genetic polymorphisms of RAGE are reportedly associated with NSCLC development and complications. RAGE and its polymorphic variants may be useful diagnostic or post-therapeutic prognostic markers of NSCLCs.

Implication of RAGE Polymorphic Variants in COPD Complication and Anti-COPD Therapeutic Potential of sRAGE.

Chronic obstructive pulmonary disease (COPD) is a slowly progressive and poorly reversible airway obstruction disease. It is caused either alone or in combination of emphysema, chronic bronchitis (CB), and small airways disease. COPD is thought to be a multi-factorial disorder in which genetic susceptibility, environmental factors and tobacco exposure could be doubly or simultaneously implicated. Available medicines against COPD include anti-inflammatory drugs, such as ß2-agonists and anticholinergics, which efficiently reduce airflow limitation but are unable to avert disease progression and mortality. Advanced glycation end products (AGE) and their receptors i.e. receptor for advanced glycation end products (RAGE) are some molecules that have been implicated in the complication of COPD. Several RAGE single nucleotide polymorphic (SNP) variants are produced by the mammalian cells. Based on the ethnicity some SNPs aggravate the COPD severity. Mammalian cells produce several alternative RAGE splice variants including a soluble RAGE (sRAGE) and an endogenous soluble RAGE (esRAGE). Both of these act as decoy receptor and thus may help to arrest the COPD complications. Several lines of evidences indicate a decreased level of sRAGE in the COPD subjects. One of the new strategies to reduce COPD complication may be sRAGE therapeutic administration to the COPD subjects. This comprehensive discussion sheds light on the role of RAGE and its polymorphic variants in the COPD complication along with sRAGE therapeutic significance in the COPD prevention.

The importance of BDNF and RAGE in diabetes-induced dementia.

Diabetes-induced dementia is an emerging neurodisorder all over the world. The prevalence rates of dementia and diabetes have been gradually increasing worldwide. Diabetes has been known to lead to oxidative stress, inflammation aggravation, and hyperglycemia conditions in the brain. Various diabetic implications cause the lower secretion of brain-derived neurotrophic factor (BDNF) and the increase of receptor for advanced glycation end products (RAGE), ultimately leading to both cerebrovascular dysfunction and cognitive decline. Here, we summarized the significant evidences highlighting the specific mechanisms between BDNF and RAGE and cerebrovascular dysfunction and memory function and how these relate to diabetes-induced dementia. Especially, we review that the association between BDFN and RAGE in neuroinflammation, the reduction of long-term potentiation, and the vascular implications in brain.

RAGE modulatory effects on cytokines network and histopathological conditions in malarial mice.

This study was aimed at investigating the involvement of Receptor for Advanced Glycation End Products (RAGE) during malaria infection and the effects of modulating RAGE on the inflammatory cytokines release and histopathological conditions of affected organs in malarial animal model. Plasmodium berghei (P. berghei) ANKA-infected ICR mice were treated with mRAGE/pAb and rmRAGE/Fc Chimera drugs from day 1 to day 4 post infection. Survival and parasitaemia levels were monitored daily. On day 5 post infection, mice were sacrificed, blood were drawn for cytokines analysis and major organs including kidney, spleen, liver, brain and lungs were extracted for histopathological analysis. RAGE levels were increased systemically during malaria infection. Positive correlation between RAGE plasma concentration and parasitaemia development was observed. Treatment with RAGE related drugs did not improve survival of malaria-infected mice. However, significant reduction on the parasitaemia levels were recorded. On the other hand, inhibition and neutralization of RAGE production during the infection significantly increased the plasma levels of interleukin (IL-4, IL-17A, IL-10 and IL-2) and reduced interferon (IFN)-γ secretion. Histopathological analysis revealed that all treated malarial mice showed a better outcome in histological assessment of affected organs (brain, liver, spleen, lungs and kidney). RAGE is involved in malaria pathogenesis and targeting RAGE could be beneficial in malaria infected host in which RAGE inhibition or neutralization increased the release of anti-inflammatory cytokines (IL-10 and IL-4) and reduce pro-inflammatory cytokine (IFNγ) which may help alleviate tissue injury and improve histopathological conditions of affected organs during the infection.

Receptor for advanced glycation end products mediates sepsis-triggered amyloid-ß accumulation, Tau phosphorylation, and cognitive impairment.

Patients recovering from sepsis have higher rates of CNS morbidities associated with long-lasting impairment of cognitive functions, including neurodegenerative diseases. However, the molecular etiology of these sepsis-induced impairments is unclear. Here, we investigated the role of the receptor for advanced glycation end products (RAGE) in neuroinflammation, neurodegeneration-associated changes, and cognitive dysfunction arising after sepsis recovery. Adult Wistar rats underwent cecal ligation and perforation (CLP), and serum and brain (hippocampus and prefrontal cortex) samples were obtained at days 1, 15, and 30 after the CLP. We examined these samples for systemic and brain inflammation; amyloid-ß peptide (Aß) and Ser-202-phosphorylated Tau (p-TauSer-202) levels; and RAGE, RAGE ligands, and RAGE intracellular signaling. Serum markers associated with the acute proinflammatory phase of sepsis (TNFα, IL-1ß, and IL-6) rapidly increased and then progressively decreased during the 30-day period post-CLP, concomitant with a progressive increase in RAGE ligands (S100B, Nϵ-[carboxymethyl]lysine, HSP70, and HMGB1). In the brain, levels of RAGE and Toll-like receptor 4, glial fibrillary acidic protein and neuronal nitric-oxide synthase, and Aß and p-TauSer-202 also increased during that time. Of note, intracerebral injection of RAGE antibody into the hippocampus at days 15, 17, and 19 post-CLP reduced Aß and p-TauSer-202 accumulation, Akt/mechanistic target of rapamycin signaling, levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and behavioral deficits associated with cognitive decline. These results indicate that brain RAGE is an essential factor in the pathogenesis of neurological disorders following acute systemic inflammation.

Insights into the effects of N-glycosylation on the characteristics of the VC1 domain of the human receptor for advanced glycation end products (RAGE) secreted by Pichia pastoris.

Advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs), resulting from non-enzymatic modifications of proteins, are potentially harmful to human health. They directly act on proteins, affecting structure and function, or through receptor-mediated mechanisms. RAGE, a type I transmembrane glycoprotein, was identified as a receptor for AGEs. RAGE is involved in chronic inflammation, oxidative stress-based diseases and ageing. The majority of RAGE ligands bind to the VC1 domain. This domain was successfully expressed and secreted by Pichia pastoris. Out of two N-glycosylation sites, one (Asn25) was fully occupied while the other (Asn81) was under-glycosylated, generating two VC1 variants, named p36 and p34. Analysis of N-glycans and of their influence on VC1 properties were here investigated. The highly sensitive procainamide labeling method coupled to ES-MS was used for N-glycan profiling. N-glycans released from VC1 ranged from Man9GlcNAc2- to Man15GlcNAc2- with major Man10GlcNAc2- and Man11GlcNAc2- species for p36 and p34, respectively. Circular dichroism spectra indicated that VC1 maintains the same conformation also after removal of N-glycans. Thermal denaturation curves showed that the carbohydrate moiety has a small stabilizing effect on VC1 protein conformation. The removal of the glycan moiety did not affect the binding of VC1 to sugar-derived AGE- or malondialdehyde-derived ALE-human serum albumin. Given the crucial role of RAGE in human pathologies, the features of VC1 from P. pastoris will prove useful in designing strategies for the enrichment of AGEs/ALEs from plasma, urine or tissues, and in characterizing the nature of the interaction.

The receptor for advanced glycation end-products (RAGE) is an important pattern recognition receptor (PRR) for inflammaging.

The receptor for advanced glycation end-products (RAGE) was initially characterized and named for its ability to bind to advanced glycation end-products (AGEs) that form upon the irreversible and non-enzymatic interaction between nucleophiles, such as lysine, and carbonyl compounds, such as reducing sugars. The concentrations of AGEs are known to increase in conditions such as diabetes, as well as during ageing. However, it is now widely accepted that RAGE binds with numerous ligands, many of which can be defined as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The interaction between RAGE and its ligands mainly results in a pro-inflammatory response, and can lead to stress events often favouring mitochondrial dysfunction or cellular senescence. Thus, RAGE should be considered as a pattern recognition receptor (PRR), similar to those that regulate innate immunity. Innate immunity itself plays a central role in inflammaging, the chronic low-grade and sterile inflammation that increases with age and is a potentially important contributory factor in ageing. Consequently, and in addition to the age-related accumulation of PAMPs and DAMPs and increases in pro-inflammatory cytokines from senescent cells and damaged cells, PRRs are therefore important in inflammaging. We suggest here that, through its interconnection with immunity, senescence, mitochondrial dysfunction and inflammasome activation, RAGE is a key contributor to inflammaging and that the pro-longevity effects seen upon blocking RAGE, or upon its deletion, are thus the result of reduced inflammaging.

Aß1-42 oligomer induces alteration of tight junction scaffold proteins via RAGE-mediated autophagy in bEnd.3 cells.

Compelling evidences have shown that amyloid-ß (Aß) peptide is one of the major pathogenic factors resulting in blood-brain barrier (BBB) disruption in Alzheimer's disease (AD). However, the mechanism underlying BBB breakdown remains elusive. In our present study, we employed murine brain capillary endothelial cells (bEnd.3) as an in vitro BBB model to investigate the role of autophagy in Aß1-42 oligo induced BBB disruption. We first identified Aß1-42 oligo cytotoxicity to bEnd.3 cells as observed in the reduced cell viability and downregulation of ZO-1, Occludin and Claudin-5. Based on the observation that both downregulated expression of p-mTOR/m-TOR and upregulated ratio of LC3-II/ß-actin were induced by Aß1-42 oligo, we then applied 3-MA, an inhibitor of autophagy, to test the role of autophagy in Aß1-42 oligo induced Tight junction (TJ) proteins damage. Results have shown that 3-MA partially reversed Aß1-42 oligo induced downregulation of ZO-1, Occludin and Claudin-5, which was further determined by LC3 siRNA. We also used rapamycin to activate autophagy and found that TJ proteins damage induced by Aß1-42 was deteriorated even further. Given that the receptor of advanced glycation end-products (RAGE) is a pivotal receptor that mediates Aß toxicity, RAGE siRNA was utilized to identify the involvement of RAGE in Aß1-42 oligo induced autophagy. The results demonstrated a suppressed autophagy with increased p-mTOR/m-TOR and decreased LC3-II/ß-actin as well as increased ZO-1, Occludin and Claudin-5 in transfected cells after Aß1-42 oligo treatment, as compared to the non-transfected group. In summary, these results suggested that Aß1-42 oligo induced TJ proteins disruption via a RAGE-dependent autophagy pathway.

Effects of Receptor for Advanced Glycation End-Products (RAGE) Signaling on Intestinal Ischemic Damage in Mice.

OBJECTIVE: Superior mesenteric artery ischemia and nonocclusive mesenteric ischemia are representative diseases of the vascular emergency known as irreversible transmural intestinal necrosis (ITIN). The receptor for advanced glycation end-products (RAGE) belongs to the immunoglobulin superfamily of extracellular ligands, which also includes high-mobility group box 1 (HMGB-1) and proteins of the S100 family. The HMGB-1 ligands have been implicated in the pathogenesis of various inflammatory disorders. This study was designed to investigate the relation between RAGE and ITIN in a murine acute intestinal ischemic model. MATERIALS AND METHODS: ITIN was induced by clipping the cranial mesenteric artery and the peripheral blood vessels. Mucosal and blood samples were collected and analyzed by reverse-transcription PCR and immunohistochemistry for mucosal inflammation and levels of RAGE-related proteins. The influence of RAGE signaling on intestinal cell reproduction was investigated using the cell scratch test, an in vitro wound-healing assay. Finally, RAGE-related proteins and their respective inhibitors were administered intraperitoneally to ITIN model mice to determine their effects. RESULTS: RAGE-expressing cells were located at the base of the intestinal crypts at day 0. As ITIN progressed, most of the damaged intestinal cells expressed RAGE, and ligands of RAGE such as HMGB-1, S100 A8/A9, and S100ß were present in the crypt cells from the bottom to the top. The quantities of S100 A8/A9 and S100ß were particularly high, above the levels found in other diseases. When S100 A8/A9 and S100ß were applied to small intestinal epithelial cells in vitro, regeneration was significantly impeded. Inflammatory Gr1+ neutrophils and F4/80+ macrophages are involved in tissue ischemia. S100 A8/A9 enhances inflammatory myeloid cell influx. CONCLUSIONS: RAGE-related proteins are elevated in ITIN model mice and impede intestinal regeneration in vitro. RAGE-related proteins may be a new therapeutic target or a new marker for ITIN.

Clinical Implications of Extracellular HMGA1 in Breast Cancer.

The unconventional secretion of proteins is generally caused by cellular stress. During the tumorigenesis, tumor cells experience high levels of stress, and the secretion of some theoretically intracellular proteins is activated. Once in the extracellular space, these proteins play different paracrine and autocrine roles and could represent a vulnerability of cancer. One of these proteins is the high mobility group A1 (HMGA1), which is frequently overexpressed in tumors and presents a low expression in normal adult tissues. We have recently described that HMGA1 establishes an autocrine loop in invasive triple-negative breast cancer (TNBC) cells. The secretion of HMGA1 and its binding to the receptor for advanced glycation end products (RAGE) mediates the migration, invasion, and metastasis of TNBC cells and predicts the onset of metastasis in these patients. In this review, we summarized different strategies to exploit the novel tumorigenic phenotype mediated by extracellular HMGA1. We envisioned future clinical applications where the association between its change in subcellular localization and breast cancer progression could be used to predict tumor aggressiveness and guide treatment decisions. Furthermore, we proposed that targeting extracellular HMGA1 as monotherapy using monoclonal antibodies, or in combination with chemotherapy and other targeted therapies, could bring new therapeutic options for TNBC patients.

The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review.

BACKGROUND: Traditional risk factors are insufficient to explain all cases of coronary artery disease (CAD) in patients with diabetes mellitus (DM). Advanced glycation end-products (AGEs) and their receptors may play important roles in the development and progression of CAD. BODY: Hyperglycemia is the hallmark feature of DM. An increase in the incidence of both micro-and macrovascular complications of diabetes has been observed with increased duration of hyperglycemia. This association persists even after glycemic control has been achieved, suggesting an innate mechanism of "metabolic memory." AGEs are glycated proteins that may serve as mediators of metabolic memory due to their increased production in the setting of hyperglycemia and generally slow turnover. Elevated AGE levels can lead to abnormal cross linking of extracellular and intracellular proteins disrupting their normal structure and function. Furthermore, activation of AGE receptors can induce complex signaling pathways leading to increased inflammation, oxidative stress, enhanced calcium deposition, and increased vascular smooth muscle apoptosis, contributing to the development of atherosclerosis. Through these mechanisms, AGEs may be important mediators of the development of CAD. However, clinical studies regarding the role of AGEs and their receptors in advancing CAD are limited, with contradictory results. CONCLUSION: AGEs and their receptors may be useful biomarkers for the presence and severity of CAD. Further studies are needed to evaluate the utility of circulating and tissue AGE levels in identifying asymptomatic patients at risk for CAD or to identify patients who may benefit from invasive intervention.

Mdia1 is Crucial for Advanced Glycation End Product-Induced Endothelial Hyperpermeability.

BACKGROUND/AIMS: Disruption of endothelial barrier integrity in response to advanced glycation end products (AEGs) stimulation contributes to vasculopathy associated with diabetes mellitus. Mammalian diaphanous-related formin (mDia1) has been reported to bind to the cytoplasmic domain of the receptor for advanced glycation end products (RAGE), which induces a series of cellular processes. This study directly evaluated the participation of mDia1 in AGE-induced hyperpermeability and revealed the precise intracellular signal transductions of this pathological process. METHODS: Human umbilical vein endothelial cells (HUVECs) were used in the in vitro studies. Trans-endothelial electric resistance and permeability coefficient for dextran (Pd) were measured to analyze cell permeability. Western blotting, immunofluorescence staining and flow cytometry assay were performed to investigate the underlying mechanism. Dextran flux across the mesentery in mice was monitored to investigate in vivo microvascular permeability. RESULTS: we found that AGEs evoked Nox4 membrane translocation, reactive oxygen species production, phosphorylation of Src and VE-cadherin, dissociation of adherens junctions and eventual endothelial hyperpermeability through RAGE-mDia1 binding. Cells overexpressing mDia1 by recombinant adenovirus infection showed stronger cellular responses induced by AGEs. Down-regulation of mDia1 by infection with an adenovirus encoding siRNA or blockade of RAGE-mDia1 binding by transfection with RAGE mutant plasmids into HUVECs abolished these AGE-induced effects. Furthermore, knockdown of mDia1 using an adenovirus or genetical knockout of RAGE in C57 mice rescued AGE-evoked microvascular hyperpermeability. CONCLUSION: Our study revealed that mDia1 plays a critical role in AGE-induced microvascular hyperpermeability through binding to RAGE.