Receptor For Advanced Glycation End Products Research Articles

Dementia Is Induced via the AGEs/Iba1/iNOS Pathway in Aged KK-Ay/Tajcl Mice.

The onset and exacerbation of dementia have been observed in elderly patients with type 2 diabetes. However, the underlying mechanism remains unclear. In this study, we investigated the effects of aging on the cognitive function in a mouse model of type 2 diabetes. Pathogen-free KK-Ay/TaJcl mice were used in this study. The cognitive abilities and memory declined in the mice and worsened in the 50-week-olds. The levels of advanced glycation end products (AGEs), receptor for AGE (RAGE), and Iba1 in the hippocampus were increased in the mice compared to those in the control mice. Hippocampal levels of CC-chemokine receptor 7 and inducible nitric oxide synthase, which are from M1-type macrophages that shift from microglia, were higher in KK-Ay/TaJcl mice than in control mice. Tumor necrosis factor (TNF)-α and nitric oxide (NO) levels secreted by M1-type macrophages were similarly elevated in the mice and were even higher at the age of 50 weeks. NO levels were markedly elevated in the 50-week-old mice. In contrast, differentiation of CD163 and arginase-1 did not change in both mouse types. Memory and learning declined with age in diabetic mice, and the AGEs/RAGE/M1-type macrophage/NO and TNF-α pathways played an important role in exacerbating memory and learning in those mice.

Dry heat whole Sorghum BRS 305 flour modulate satiety and improves antioxidant response in brain of Wistar rats fed with high-fat high-fructose diet

Sorghum BRS 305 (Sorghum bicolor L. Moench) is a cereal with high tannins and anthocyanins content and keep better the resistant starch when submitted to dry heat treatment. Our objective was to investigate the effects of BRS 305 dry heat treatment whole sorghum flour on satiety and antioxidant response in brain and adipose tissue of Wistar rats fed with a high fat high fructose diet (HFHF). Male Wistar rats were divided in two groups: control (n = 8) and HFHF (n = 16) for eight weeks. After, animals of HFHF group were divided: HFHF (n = 8) and HFHF + BRS 305 sorghum whole flour (n = 8), for 10 weeks. Sorghum consumption reduced gene expression of leptin, resistin, and endocannabinoid receptor 1 type (CB1) in adipose and brain tissues compared to HFHF group. In brain, sorghum consumption also promotes reduction in neuropeptide Y (NPY) gene expression. BRS305 sorghum consumption improved gene expression of sirtuin-1 (SIRT1) in adipose tissue, and in the brain increased heat shock protein 72 (HSP72), erythroid-derived nuclear factor 2 (NRF2), peroxisome proliferator-activated receptor alpha (PPARα), superoxide dismutase (SOD) and catalase activity compared to HFHF. In silicoanalysis showed interaction with PPARα, CB1, and leptin receptors. Advanced glycation end products (AGEs) concentrations in group HFHF + sorghum did not differ from HFHF group. Advanced glycation end products receptors (RAGEs) concentrations did not differ among experimental groups. Then, BRS 305 sorghum submitted to dry treatment was able to modulate gene expression of markers related to satiety and improve antioxidant capacity of rats fed with HFHF diet.

Echinacoside-Zinc Nanomaterial Inhibits Skin Glycation by Suppressing the Transcriptional Activation of the Receptor for Advanced Glycation End-Products.

Glycation is a nonenzymatically catalyzed spontaneous reaction that eventually leads to the formation of advanced glycation end-products (AGEs), which can bind to the receptor for AGEs (RAGE). The consequences are oxidative damage, an inflammatory response, and aging. In this work, we synthesized echinacoside-zinc coordination polymers (ECH-Zn) by using the coordination interaction between the catechol group of ECH and zinc ions. ECH-Zn was further wrapped with hyaluronic acid/poly (ethylenimine) (HA-PEI) to obtain spherical nanoparticle polymers of HA-PEI-coated ECH-Zn (PPZn). PPZn can enhance the uptake and utilization of ECH-Zn and also have a better antiglycation effect in the skin under the effect of promoting transdermal absorption of HA-PEI. Mechanistic studies at the cellular level showed that MDM2 can interact with STAT2 to form a transcriptional complex and thus promote RAGE transcriptional activation. In vitro and in vivo studies revealed that PPZn can decrease the expression and inhibit the interaction of the MDM2/STAT2 complex. It inhibited the function of the MDM2/STAT2 complex and suppressed the transcriptional activation of RAGE, thereby exerting antiglycation effects. In conclusion, this work provides a nanomaterial and elucidated a mechanism of anti-skin glycation.

High mobility group box 1 levels as potential predictors of asthma severity.

High mobility group box 1 levels as potential predictors of asthma severity.

High-Mobility Group Box 1 (HMGB1) Protein in Parkinson's Disease Research: A 10-Year Bibliometric Analysis.

Parkinson's disease (PD), the most prevalent motoric neurodegenerative disease, has been intensively studied to better comprehend its complicated pathogenesis. Chronic neuroinflammation is a major factor contributing to the development of PD. Reportedly, high-mobility group box 1 (HMGB1) protein is capable of mediating neuroinflammatory response. In this regard, knowledge mapping of the research linking HMGB1 to PD is necessary. Herein, we perform a dynamic and longitudinal bibliometric analysis to explore the hotspots and current trends of HMGB1-related PD publications during the past decade. All PD publications focusing on HMGB1 protein were retrieved from the PubMed database using the search terms "Parkinson's disease" and "hmgb1". Using filters, only English articles published between 2011 and 2022 were selected. The Bibliometrix and Biblioshiny packages from R software were used to conduct the bibliometric analysis. The filtered search identified 47 articles (34 original articles and 13 review articles), published between 2011 and 2022. There was an increase trend in the number of articles published, with an annual growth rate of 19.35 percent. In terms of research and scientific collaboration in this field, the United States is in the lead, followed by China, Malaysia, and Australia. Compared to other countries, the United States and China had the highest level of collaboration in this research area. Neuroinflammation, microglia, and receptor for advanced glycation end-products (RAGE) represent the top three frontiers and hotspots for HMGB1-related PD research. According to the thematic evolution analysis, over the last decade, PD, HMGB1 and microglia were addressed individually, however, since 2017, these topics were frequently discussed within the same cluster: neuroinflammation. Furthermore, PD, HMGB1, and neuroinflammation domains co-occurred in majority of the research discussion. The link between HMGB1 and PD was realized a decade ago and becomes increasingly important over time. Our findings can aid scholars in comprehending the global context of HMGB1/PD relationship and provide significant insights for future PD research.

Serum and follicular fluid levels of soluble receptor for advanced glycation end-products in women with and without polycystic ovary syndrome

BackgroundAdvanced glycation end products (AGEs) are known to associate with the pathogenesis of several chronic diseases via interaction with their corresponding receptor (RAGE). The soluble forms of RAGE (sRAGE) are considered as anti-inflammatory agents by inhibiting the consequent adverse effects of AGE. We aimed at comparing sRAGE levels in the follicular fluid (FF) and serum of women with or without Polycystic Ovary Syndrome (PCOS) who underwent controlled ovarian stimulation for in vitro fertilisation (IVF).MethodsA total of forty-five eligible women (26 non-PCOS (control) and 19 patients with PCOS (case)) were included the study. sRAGEs in FF and blood serum were measured using ELISA kit.ResultsNo statistically significant differences were found in FF and serum sRAGE between case and control groups. Correlation analysis showed a significant and positive relationship between serum levels of sRAGE and FF sRAGE in PCOS (r = 0.639; p = 0.004), in control participants (r = 0.481; p = 0.017), and in total participants (r = 0.552; p = 0.000). Data revealed a statistically significant difference in FF sRAGE concentration among all participants by body mass index (BMI) categories (p = 0.01) and in controls (p = 0.022). Significant differences were found for all the nutrients and AGEs consumption according to Food Frequency Questionnaire in both groups (p = 0.0001). A significant reverse relationship was found between FF levels of sRAGE and AGE in PCOS (r = -0.513; p = 0.025). The concentration of sRAGE in serum and FF is the same in PCOS and control.ConclusionThe present study revealed for the first time that there are no statistically significant differences between the concentration of serum sRAGE and FF sRAGE among Iranian women with and without PCOS. However, BMI and dietary intake of AGEs have more significant effects on sRAGE concentration in Iranian women. Future studies in developed and developing countries with larger sample sizes are required to determine the long-term consequences of chronic AGE over consumption and the optimal strategies for minimizing AGE-related pathology, specifically in low income and developing countries.

421-P: Methylglyoxal-Derived Advanced Glycation End Products Are Prognostic Biomarkers for Diabetic Complications and Drivers of Endothelial Dysfunction

Diabetic kidney disease (DKD) affects over 30% of individuals with T1D, significantly increasing mortality risk in this population. Canonical tools to predict DKD such as glomerular filtration rate (GFR) or albumin excretion rate (AER) alone may not be sufficient to predict disease risk, as they often do not become apparent until significant kidney damage has already occurred. Therefore, there is an unmet need to identify additional clinically useful biomarkers to predict DKD risk. Methylglyoxal (MG) is an abundant, reactive electrophile produced during metabolic flux from glycolysis and protein and lipid metabolism. MG covalently modifies macromolecules such as DNA, RNA, and protein forming MG-advanced glycation end products (MG-AGEs). Both MG and MG-AGEs have been correlated with diabetes and cancer, but the ability of nucleoside MG-AGEs to predict DKD risk has not been examined. Using a novel mass spectrometry method, we measured levels of MG-AGEs in patient urinary samples collected from the DCCT/EDIC study and found MG-AGEs independently predicted DKD risk up to 16 years pre-diagnosis. This association was more significant than the association of AER, GFR, or HbA1c with DKD. In DKD, endothelial cells (ECs) become dysfunctional, which contributes to the development of the disease. To understand the extent to which MG-AGEs impact EC dysfunction, we synthesized pure MG-AGEs and exposed human umbilical vein endothelial cells (HUVECS) to these compounds. We found MG-AGEs activated pathways associated with the receptor for AGEs (RAGE) and EC dysfunction as evidenced by increased leukocyte adhesion, oxidative stress, pro-inflammatory gene expression, and NFkB activation. This suggests that MG-AGEs are not only predictive of DKD, but may also contribute to EC dysfunction preceding disease. Disclosure S.Lai: None. E.D.J.Lopez gonzalez: None. S.Shuck: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (X01DK118575); National Institutes of Health (1R21DK127285); Wanek Family Project to Cure T1D; Diabetes Complications Consortium

Serum levels of high mobility group box-1 protein (HMGB1) and soluble receptors of advanced glycation end-products (RAGE) in depressed patients treated with electroconvulsive therapy.

High mobility group box-1 (HMGB1) is one of the damage-associated molecular patterns produced by stress and induces inflammatory responses mediated by receptors of advanced glycation end-products (RAGE) on the cell surface. Meanwhile, soluble RAGE (sRAGE) exhibits an anti-inflammatory effect by capturing HMGB1. Animal models have shown upregulation of HMGB1 and RAGE in the brain or blood, suggesting the involvement of these proteins in depression pathophysiology. However, there have been no reports using blood from depressed patients, nor ones focusing on HMGB1 and sRAGE changes associated with treatment and their relationship to depressive symptoms. Serum HMGB1 and sRAGE concentrations were measured by enzyme-linked immunosorbent assay in a group of patients with severe major depressive disorder (MDD) (11 males and 14 females) who required treatment with electroconvulsive therapy (ECT), and also in a group of 25 age- and gender-matched healthy subjects. HMGB1 and sRAGE concentrations were also measured before and after a course of ECT. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAMD). There was no significant difference in HMGB1 and sRAGE concentrations in the MDD group compared to healthy subjects. Although ECT significantly improved depressive symptoms, there was no significant change in HMGB1 and sRAGE concentrations before and after treatment. There was also no significant correlation between HMGB1 and sRAGE concentrations and the HAMD total score or subitem scores. There were no changes in HMGB1 and sRAGE in the peripheral blood of severely depressed patients, and concentrations had no relationship with symptoms or ECT.

Oleic Acid Status Positively Correlates with the Soluble Receptor for Advanced Glycation End-Products (sRAGE) in Healthy Adults Who Are Homozygous for G Allele of RAGE G82S Polymorphism.

The soluble form of receptor for advanced glycation end products (sRAGE) have been implicated in the prevention of numerous pathologic states, and highlights as an attractive therapeutic target. Because diets rich in monounsaturated fatty acids (MUFA) reduce postprandial oxidative stress and inflammation that is related to better health during aging, we investigated the association between red blood cell (RBC) fatty acids with circulatory AGE biomarkers and further stratified this correlation based on GG and GA + AA genotype. A total of 172 healthy participants (median age = 53.74 ± 0.61 years) were recruited for the study. RBC fatty acid was analysed using gas chromatography and sRAGE was measured using a commercial ELISA kit. The result showed a non-significant correlation between total MUFA with sRAGE however oleic acid (C18:1) exhibited a positive correlation (r = 0.178, p = 0.01) that remained statistically significant (β = 0.178, p = 0.02) after a stepwise multivariate regression analysis after adjusting for age, BMI and gender. In a univariate analysis, a positive significant correlation between C18:1 and sRAGE in GG genotype (r = 0.169, p = 0.02) and a non-significant correlation with GA + AA genotype (r = 0.192, p = 0.21) was evident. When C18:1 was stratified, a significant difference was observed for oleic acid and G82S polymorphism: low C18:1/GA + AA versus high C18:1/GG (p = 0.015) and high C18:1/GA + AA versus high C18:1/GG (p = 0.02). Our study suggests that increased levels of C18:1 may be a potential therapeutic approach in increasing sRAGE in those with GG genotype and play a role in modulating AGE metabolism.

Effects of sevoflurane on lung epithelial permeability in experimental models of acute respiratory distress syndrome

BackgroundPreclinical studies in acute respiratory distress syndrome (ARDS) have suggested that inhaled sevoflurane may have lung-protective effects and clinical trials are ongoing to assess its impact on major clinical outcomes in patients with ARDS. However, the underlying mechanisms of these potential benefits are largely unknown. This investigation focused on the effects of sevoflurane on lung permeability changes after sterile injury and the possible associated mechanisms.MethodsTo investigate whether sevoflurane could decrease lung alveolar epithelial permeability through the Ras homolog family member A (RhoA)/phospho-Myosin Light Chain 2 (Ser19) (pMLC)/filamentous (F)-actin pathway and whether the receptor for advanced glycation end-products (RAGE) may mediate these effects. Lung permeability was assessed in RAGE−/− and littermate wild-type C57BL/6JRj mice on days 0, 1, 2, and 4 after acid injury, alone or followed by exposure at 1% sevoflurane. Cell permeability of mouse lung epithelial cells was assessed after treatment with cytomix (a mixture of TNFɑ, IL-1β, and IFNγ) and/or RAGE antagonist peptide (RAP), alone or followed by exposure at 1% sevoflurane. Levels of zonula occludens-1, E-cadherin, and pMLC were quantified, along with F-actin immunostaining, in both models. RhoA activity was assessed in vitro.ResultsIn mice after acid injury, sevoflurane was associated with better arterial oxygenation, decreased alveolar inflammation and histological damage, and non-significantly attenuated the increase in lung permeability. Preserved protein expression of zonula occludens-1 and less increase of pMLC and actin cytoskeletal rearrangement were observed in injured mice treated with sevoflurane. In vitro, sevoflurane markedly decreased electrical resistance and cytokine release of MLE-12 cells, which was associated with higher protein expression of zonula occludens-1. Improved oxygenation levels and attenuated increase in lung permeability and inflammatory response were observed in RAGE−/− mice compared to wild-type mice, but RAGE deletion did not influence the effects of sevoflurane on permeability indices after injury. However, the beneficial effect of sevoflurane previously observed in wild-type mice on day 1 after injury in terms of higher PaO2/FiO2 and decreased alveolar levels of cytokines was not found in RAGE−/− mice. In vitro, RAP alleviated some of the beneficial effects of sevoflurane on electrical resistance and cytoskeletal rearrangement, which was associated with decreased cytomix-induced RhoA activity.ConclusionsSevoflurane decreased injury and restored epithelial barrier function in two in vivo and in vitro models of sterile lung injury, which was associated with increased expression of junction proteins and decreased actin cytoskeletal rearrangement. In vitro findings suggest that sevoflurane may decrease lung epithelial permeability through the RhoA/pMLC/F-actin pathway.Graphical

Beneficial effects of protocatechuic acid on diabetic retinopathy in streptozocin-induced diabetic rats.

To determine the effects of protocatechuic acid (PCA) on streptozocin-induced diabetic retinopathy (DR) in rats. Wistar rats were given a 50 mg/kg intraperitoneal injection of streptozocin to induce diabetes. Animals were assigned randomly one of four groups (8 rats per group): control, diabetic, diabetic plus PCA (25 mg/kg·d), and diabetic plus PCA (50 mg/kg·d). After inducing diabetes, treatments were started one week later and continued for eight weeks. After the experiment, the rats were sacrificed, and their retinas were taken for biochemical and molecular analysis. PCA administration diminished the blood glucose and glycated haemoglobin levels relative to the diabetic group. In diabetic rats, PCA lowered elevated levels of advanced glycosylated end products (AGEs) and receptor for AGEs (RAGE). In the retina of diabetic rats, PCA effectively decreased inflammatory cytokine, nuclear factor-κB, tumour necrosis factor-α, interleukin-1β, and vascular endothelial growth factor, and increased antioxidant markers glutathione, superoxide dismutase, and catalase. The protective benefits of PCA against DR may be attributable to its suppression of the AGEs and RAGE and its antioxidant and anti-inflammatory properties.

Tozorakimab (MEDI3506): an anti-IL-33 antibody that inhibits IL-33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction

Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33red) and oxidized IL-33 (IL-33ox) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 107 M−1 s−1, to effectively neutralize IL-33 following rapid release from damaged tissue. An innovative antibody generation campaign identified tozorakimab, an antibody with a femtomolar affinity for IL-33red and a fast association rate (8.5 × 107 M−1 s−1), which was comparable to soluble ST2. Tozorakimab potently inhibited ST2-dependent inflammatory responses driven by IL-33 in primary human cells and in a murine model of lung epithelial injury. Additionally, tozorakimab prevented the oxidation of IL-33 and its activity via the RAGE/EGFR signalling pathway, thus increasing in vitro epithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33red and IL-33ox signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease.

#3635 THERAPEUTIC STRATEGIES TARGETING RAGE IMPROVES RENAL OUTCOME IN LUPUS NEPHRITIS

Abstract Background and Aims Lupus nephritis (LN) occurs in up to 60% of patients with systemic lupus erythematosus (SLE). Despite of current development of immunosuppressant agents, LN still impairs the survival and quality of life in SLE patients. Receptor for advanced glycation endproducts (RAGE) is a multi-ligand receptor that belongs to the immunoglobulin superfamily, which is strongly associated with innate immune system. In the present study, we examined whether RAGE is involved in the development of LN. Further, we explored the therapeutic impact of DNA-aptamer directed against RAGE on lupus-related kidney injury. Method [Protocol 1] RAGE expression in kidneys and urinary RAGE excretion (uRAGE) were determined at 8, 12, 16, 18, 20-week-old by real-time PCR and ELISA, respectively in MRL/lpr, SLE-prone mice. [Protocol 2] LN was induced by peritoneally injecting pristane in wild type and RAGE globally knockout mice. [Protocol 3] MRL/lpr mice were subcutaneously administrated with DNA-aptamer raised against RAGE (RAGE-apt) or Control-aptamer (Ctrl-apt) for 10weeks. Results [Protocol 1] uRAGE, but not urinary protein excretion, was increased in 8-week-old MRL/lpr mice when compared to that of the control of MRL/MPJ mice. uRAGE is positively correlated with urinary NAG, a tubular injury marker, suggesting that uRAGE can predict the onset and the progression of LN. Immunofluorescence staining demonstrated that RAGE was upregulated in distal tubules but not in glomerulus in early stage, meanwhile RAGE started to be extensively expressed in nephron at late stage of LN. Not only tubules, but RAGE was also found in infiltrated macrophages in glomerulus. In proximal tubules (PTC), RAGE was co-localized with cathepsine D, a lysosomal aspartyl protease, and Rab7, a marker of late endocytosis, suggesting that PTC RAGE is involved in endosome-related protein degradation. [Protocol 2] Pristane-induced the increase in systolic blood pressure was reduced with improvement of renal dysfunction in RAGE knockouts. RAGE knockouts also showed less fibrosis with the decrease in macrophage infiltration when compared to wild type mice in pristane-induced lupus nephritis. [Protocol 3] Similar to RAGE knockouts, administration of RAGE-apt reduced systolic blood pressure and attenuated the renal dysfunction. RAGE-apt also ameliorated mesangial expansion, crescent formation, and macrophage infiltration into glomerulus in MRL/lpr mice. The level of pro-inflammatory cytokines gene expression including IL-6, TNF-a, and MCP-1 was reduced by RAGE-apt, but not Ctrl-apt, in MRL/lpr mice. Conclusion RAGE could be involved in the pathogenesis of LN, and RAGE-DNA aptamer might be one of the promising therapeutic strategies for preventing the development of LN.

Nε-(1-Carboxymethyl)-L-lysine, an advanced glycation end product, exerts malignancy on chondrosarcoma via the activation of cancer stemness.

Despite epidemiological evidence that suggests diabetes mellitus is a risk factor for cancer, the link between diabetes mellitus and primary bone cancer is rarely discussed. Chondrosarcomas are primary malignant cartilage tumors with poor prognosis and high metastatic potential. It remains unclear whether hyperglycemia affects the stemness and malignancy of chondrosarcoma cells. Nε-(1-Carboxymethyl)-L-lysine (CML), an advanced glycation end product (AGE), is a major immunological epitope detected in the tissue proteins of diabetic patients. We hypothesized that CML could enhance cancer stemness in chondrosarcoma cells. CML enhanced tumor-sphere formation and the expression of cancer stem cell markers in human chondrosarcoma cell lines. Migration and invasion ability and the epithelial-mesenchymal transition (EMT) process were also induced by CML treatment. Moreover, CML increased the protein expression levels of the receptor for AGE (RAGE), phosphorylated NFκB-p65, and decreased the phosphorylation of AKT and GSK-3. We also found that hyperglycemia with high CML levels facilitated tumor metastasis, whereas tumor growth was not affected in the streptozotocin (STZ)-induced diabetic NOD/SCID tumor xenograft mouse models. Our results indicate that CML enhances chondrosarcoma stemness and metastasis, which may reveal the relationship between AGE and bone cancer metastasis.

Protective effect of Schizonepeta tenuifolia Briq. ethanolic extract against UVB-induced skin aging and photodamage in hairless mice.

The purpose of this study was to illuminate the mechanism by which Schizonepeta tenuifolia Briq. (ST) ethanolic extract prevents skin photoaging in HR-1 hairless mice (HR-1). The ST ethanolic extract alleviated wrinkle formation, epidermal skin thickness, and collagen degradation in skin tissues of ultraviolet B (UVB)-irradiated HR-1 mice. Expression of matrix metalloproteinases (a wrinkle-related marker) was reduced, and tissue inhibitor of metalloproteinase 1 expression was upregulated following application of ST ethanolic extract. Furthermore, skin dehydration and levels of hyaluronidase-1 and -2 (enzymes that break hyaluronic acid) were decreased. Moreover, protein expression of hyaluronan synthases (markers of skin hydration) and hyaluronic acid levels increased following ST ethanolic extract treatment in UVB-induced photoaging HR-1 mice. In addition, the phosphorylation of mitogen-activated protein kinases (MAPKs), including p38, extracellular signal-regulated kinase, and Jun N-terminal kinase was suppressed, and expression of nuclear factor-kappa was reduced. Treatment with ST ethanolic extract also reduced advanced glycation end product (AGE) accumulation and expression of the receptor for AGE (RAGE) in skin tissue. These results suggest that ST ethanolic extract moderates skin damage caused by UVB irradiation via regulating the expression of wrinkle- and hydration-related proteins, MAPKs, and RAGE.

Association of Inflammatory and Oxidative Status Markers with Metabolic Syndrome and Its Components in 40-to-45-Year-Old Females: A Cross-Sectional Study.

Oxidative stress and sterile inflammation play roles in the induction and maintenance of metabolic syndrome (MetS). This study cohort included 170 females aged 40 to 45 years who were categorized according to the presentation of MetS components (e.g., central obesity, insulin resistance, atherogenic dyslipidemia, and elevated systolic blood pressure) as controls not presenting a single component (n = 43), those with pre-MetS displaying one to two components (n = 70), and females manifesting MetS, e.g., ≥3 components (n = 53). We analyzed the trends of seventeen oxidative and nine inflammatory status markers across three clinical categories. A multivariate regression of selected oxidative status and inflammatory markers on the components of MetS was performed. Markers of oxidative damage (malondialdehyde and advanced-glycation-end-products-associated fluorescence of plasma) were similar across the groups. Healthy controls displayed lower uricemia and higher bilirubinemia than females with MetS; and lower leukocyte counts, concentrations of C-reactive protein, interleukine-6, and higher levels of carotenoids/lipids and soluble receptors for advanced glycation end-products than those with pre-MetS and MetS. In multivariate regression models, levels of C-reactive protein, uric acid, and interleukine-6 were consistently associated with MetS components, although the impacts of single markers differed. Our data suggest that a proinflammatory imbalance precedes the manifestation of MetS, while an imbalance of oxidative status accompanies overt MetS. Further studies are needed to elucidate whether determining markers beyond traditional ones could help improve the prognosis of subjects at an early stage of MetS.

Biomarkers and the outcomes of ischemic stroke.

Biomarkers are measurable substances that could be used as objective indicators for disease diagnosis, responses to treatments, and outcomes predictions. In this review, we summarized the data on a number of important biomarkers including glutamate, S100B, glial fibrillary acidic protein, receptor for advanced glycation end-products, intercellular adhesion molecule-1, von willebrand factor, matrix metalloproteinase-9, interleukin-6, tumor necrosis factor-a, activated protein C, copeptin, neuron-specific enolase, tau protein, gamma aminobutyric acid, blood glucose, endothelial progenitor cells, and circulating CD34-positive cells that could be potentially used to indicate the disease burden and/or predict clinical outcome of ischemic stroke. We examined the relationship between specific biomarkers and disease burden and outcomes and discussed the potential mechanisms underlying the relationship. The clinical significance and implications of these biomarkers were also discussed.

A preclinical study to evaluate the combination of azeliragon, an inhibitor of the receptor for advanced glycation endproducts (RAGE), with radiation therapy as a potential treatment of glioblastoma.

e14056 Background: Systemic lymphopenia, which is independently associated with poor overall survival, is observed in approximately 30-50% of patients with glioblastoma (GBM) after chemoradiotherapy. We recently found that cranial irradiation of GBM tumors increases circulating myeloid-derived suppressor cells (MDSC) contributing to systemic lymphopenia. Additionally, we found that cranial radiation increases circulating levels of the RAGE ligands S100A8/9 and HMGB1, which have been reported to increase MDSC and their immunosuppressive effects through binding RAGE. We, therefore, hypothesized that targeting RAGE receptors on MDSC could prevent immunosuppression and improve survival in preclinical GBM models. Methods: We orthotopically implanted GBM cells (GL261 and CT2A) into immunocompetent C57BL6 mice. The GBM tumor-bearing mice were treated with five doses of fractionated radiation therapy (RT, 2 Gy/day for 5 consecutive days) to the whole head in combination with RAGE inhibitor azeliragon (0.1mg/mice/day i.p starting one day before RT for up to 10 days). We evaluated the immune cells in the tumor microenvironment (TME) and spleen at 14 days post-tumor implantation. We also evaluated the circulating immune cells and RAGE ligands (HMGB1 and S100A8/A9) in the plasma at 7, 14, and 21 days post-tumor implantation and monitored the mice for survival up to 60 days. Results: GBM tumor-bearing mice (GL261 & CT2A) treated with RT plus azeliragon had significantly improved survival when compared to RT alone or azeliragon alone. RT plus azeliragon significantly reduced the accumulation of granulocytic-MDSC (G-MDSC), monocytic-MDSC (M-MDSC), tumor-associated macrophages (TAM), and regulatory T cells (Treg), while increasing infiltrating CD8 T cells in the TME as compared to RT alone. RT alone significantly increased the accumulation of G-MDSC and M-MDSC in the spleen, which was significantly reduced with concurrent azeliragon. Concurrent administration of azeliragon with RT did not significantly affect the radiation-induced increase of circulating M-MDSC as well as plasma HMGB1 and S100A8/A9 concentration, though there was a modest reduction of circulating G-MDSC. Conclusions: Our study indicates that azeliragon, by blocking RAGE interaction with its ligands, helps to overcome the MDSC-mediated immunosuppression that occurs after RT. The combination of azeliragon with RT enhances survival in preclinical models. Clinical trials evaluating the safety and efficacy of azeliragon in combination with RT for newly diagnosed GBM are currently under development.

Analysis of the receptor for advanced glycation end-products proteome and protein-protein interactome in PANC-1 cancer cells

Background: Pancreatic adenocarcinoma (PA) remains one of the leading causes of cancer related deaths worldwide. The pathogenesis of PA is unclear. However, studies show that the receptor for advanced glycation end-products (RAGE), a member of the immunoglobulin superfamily and pattern recognition receptor, likely plays a role in oncogenesis and cell proliferation. RAGE has multiple functions including amplification and perpetuation of the inflammatory response, protein transport and degradation, maintaining cell polarity, and promoting cell differentiation and division. RAGE may contribute to oncogenesis of PA through dysregulation of ubiquitin and tumor suppressor genes such as p53.

Increased Alveolar Epithelial Damage Markers and Inflammasome-Regulated Cytokines Are Associated with Pulmonary Superinfection in ARDS.

Acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure defined by dysregulated immune homeostasis and alveolar epithelial and endothelial damage. Up to 40% of ARDS patients develop pulmonary superinfections, contributing to poor prognosis and increasing mortality. Understanding what renders ARDS patients highly susceptible to pulmonary superinfections is therefore essential. We hypothesized that ARDS patients who develop pulmonary superinfections display a distinct pulmonary injury and pro-inflammatory response pattern. Serum and BALF samples from 52 patients were collected simultaneously within 24 h of ARDS onset. The incidence of pulmonary superinfections was determined retrospectively, and the patients were classified accordingly. Serum concentrations of the epithelial markers soluble receptor for advanced glycation end-products (sRAGE) and surfactant protein D (SP-D) and the endothelial markers vascular endothelial growth factor (VEGF) and angiopoetin-2 (Ang-2) as well as bronchoalveolar lavage fluid concentrations of the pro-inflammatory cytokines interleukin 1ß (IL-1ß), interleukin 18 (IL-18), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-a) were analyzed via multiplex immunoassay. Inflammasome-regulated cytokine IL-18 and the epithelial damage markers SP-D and sRAGE were significantly increased in ARDS patients who developed pulmonary superinfections. In contrast, endothelial markers and inflammasome-independent cytokines did not differ between the groups. The current findings reveal a distinct biomarker pattern that indicates inflammasome activation and alveolar epithelial injury. This pattern may potentially be used in future studies to identify high-risk patients, enabling targeted preventive strategies and personalized treatment approaches.