S100 calcium-binding protein P (S100P) is a secretory protein that is expressed in various healthy tissues and tumors. Megakaryocyte-secreted S100P promotes osteoclast differentiation and function; however, its receptor and cellular signaling in osteoclasts remain unclear. Receptor for advanced glycation end products (RAGE), which is the receptor for S100P on cancer cells, was expressed in osteoclast precursors, and S100P-RAGE binding was confirmed through co-immunoprecipitation. Additionally, the phosphorylation of ERK and NF-κB was increased in S100P-stimulated osteoclast precursors but was inhibited by addition of the RAGE antagonistic peptide (RAP). S100P-induced osteoclast differentiation and excessive bone resorption activity were also reduced by the addition of RAP. This study demonstrates that S100P, upon binding with RAGE, activates the ERK and NF-κB signaling pathways in osteoclasts, leading to increased cell differentiation and bone resorption activity.

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UNASSIGNED: In hyperglycemia, inflammation, oxidative stress and aging, Damage Associated Molecular Patterns (DAMPs) accumulate in conditions such as atherosclerosis. Binding of DAMPs to receptors such as the receptor for advanced glycation end products (RAGE) activates signal transduction cascades that contribute to cellular stress. The cytoplasmic domain (tail) of RAGE (ctRAGE) binds to the formin Diaphanous1 (DIAPH1), which is important for RAGE signaling. This Review will detail the evidence linking the RAGE/DIAPH1 signaling pathway to atherosclerosis and envisages future therapeutic opportunities from the \"inside-out\" point of view in affected cells.
UNASSIGNED: PubMed was searched using a variety of search terms, including \"receptor for advanced glycation end products\" along with various combinations including \"and atherosclerosis,\" \"soluble RAGE and atherosclerosis,\" \"statins and RAGE,\" \"PPAR and RAGE\" and \"SGLT2 inhibitor and RAGE.\"
UNASSIGNED: In non-diabetic and diabetic mice, antagonism or global deletion of Ager (the gene encoding RAGE) retards progression and accelerates regression of atherosclerosis. Global deletion of Diaph1 in mice devoid of the low density lipoprotein receptor (Ldlr) significantly attenuates atherosclerosis; mice devoid of both Diaph1 and Ldlr display significantly lower plasma and liver concentrations of cholesterol and triglyceride compared to mice devoid of Ldlr. Associations between RAGE pathway and human atherosclerosis have been identified based on relationships between plasma/serum concentrations of RAGE ligands, soluble RAGEs and atherosclerosis.
UNASSIGNED: Efforts to target RAGE/DIAPH1 signaling through a small molecule antagonist therapeutic strategy hold promise to quell accelerated atherosclerosis in diabetes and in other forms of cardiovascular disease.

The current study intended to investigate the role of new natural compounds derived from the Sesuvium sesuvioides plant in mitigating symptoms of diabetes and insulin resistance in the diabetic mice model. Anti-advanced glycation activity, insulin, and adiponectin were quantified by enzyme-linked immunosorbent assay (ELISA). Glucose uptake was performed using enzymatic fluorescence assay, and glycogen synthesis was measured using PAS staining. Gene and protein expression was assessed using real time PCR (RT-PCR), and immunoblotting and fluorescent microscopy, respectively. The new flavonoid glycoside eupalitin 3-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside 1 isolated from S. sesuvioides exhibited anti-AGE activity by reducing human glycated albumin in liver cells. In a diabetic mouse model treated with compound 1, we observed improved glucose tolerance, increased adiponectin levels, and decreased insulin resistance. We also observed alleviated AGEs induced reduction in glucose uptake and restored glycogen synthesis in the compound 1-treated diabetic mice muscles. Exploring the molecular mechanism of action in skeletal muscle tissue of diabetic mice, we found that 1 reduced AGE-induced reactive oxygen species and the inflammatory gene in the muscle of diabetic mice. Additionally, 1 exhibited these effects by reducing the gene and protein expression of receptor for advanced glycation end products (RAGE) and inhibiting protein kinase C (PKC) delta activation. This further led us to demonstrate that compound 1 reduced serine phosphorylation of IRS-1, thereby restoring insulin sensitivity. We conclude that a new flavonoid glycoside from S. sesuvioides could be a therapeutic target for the treatment of symptoms of insulin resistance and diabetes.

Type 2 diabetes mellitus (T2DM) can lead to multiple complications. T2DM-related bone damage has been linked to abnormal bone turnover, but it cannot fully explain the mechanisms of T2DM bone disease. This study attempts to elucidate the underlying mechanisms of poor bone quality in T2DM. Hence, T2DM model was induced by a high-fat diet combined with a single streptozotocin injection in 7-week-old male SD rats. Osteoblasts derived from SD rats were cultured in high glucose to mimic hyperglycemia. Low bone turnover was observed in T2DM bone with elevated levels of advanced glycation end-products (AGEs) and receptor for AGEs (RAGE). Additionally, higher levels of oxidative stress and inflammatory factors were found in T2DM bone. AGEs content in bone was pairwise correlated with RAGE, hydrogen peroxide, and inflammatory factors. Serum levels of RAGE, oxidative stress, and inflammatory factors were higher in T2DM, while AGEs content tended to be lower. Besides, 35 differentially expressed metabolites were screened in T2DM serum. Osteoblasts exposed to high glucose displayed analogous abnormal changes in these biomarkers. Thus, low bone turnover in T2DM might be partially due to excess oxidative stress and inflammation induced by AGE-RAGE signaling. Furthermore, these biomarker levels in serum were mostly consistent with bone, demonstrating their possibility for predicting bone quality in T2DM.

Diabetes mellitus (DM) is a chronic disorder of glucose metabolism that threatens several organs, including the submandibular (SMG) salivary glands. Antox (ANX) is a strong multivitamin with significant antioxidant benefits. The goal of this study was to demonstrate the beneficial roles of ANX supplementation in combination with insulin in alleviating diabetic SMG changes. For four weeks, 30 rats were divided into equal five groups (n = 6): (1) control group; (2) diabetic group (DM), with DM induced by streptozotocin (STZ) injection (50 mg/kg i.p.); (3) DM + ANX group: ANX was administrated (10 mg/kg/day/once daily/orally); (4) DM + insulin group: insulin was administrated 1U once/day/s.c.; and (5) DM + insulin + ANX group: co-administrated insulin. The addition of ANX to insulin in diabetic rats alleviated hyposalivation and histopathological alterations associated with diabetic rats. Remarkably, combined ANX and insulin exerted significant antioxidant effects, suppressing inflammatory and apoptotic pathways associated with increased salivary advanced glycation end-product (AGE) production and receptor for advanced glycation end-product expression (RAGE) activation in diabetic SMG tissues. Combined ANX and insulin administration in diabetic rats was more effective in alleviating SMG changes (functions and structures) than administration of insulin alone, exerting suppressive effects on AGE production and frustrating RAGE downstream pathways.

Childhood asthma, a common chronic childhood disease, leads to high mortality and morbidity in the world. Airway smooth muscle cells (ASMCs) is a group of multifunctional cells that has been found to be correlated with the pathogenesis of asthma. Astragaloside IV (AS-IV) is a compound extracted from Astragalus membranaceus, which has the anti-asthmatic effect. However, the role of molecular mechanisms regulated by AS-IV in the biological processes of ASMCs in asthma remains unclear. Our current study aims to investigate the downstream molecular mechanism of AS-IV in modulating the aberrant proliferation and pyroptosis of ASMCs in asthma. At first, we determined that the viability of ASMCs could be efficiently suppressed by AS-IV treatment (200 μM). Moreover, AS-IV promoted the pyroptosis and suppressed PDGF-BB-induced aberrant proliferation. Through mechanism investigation, we confirmed that AS-IV could suppress high mobility group box 1 (HMGB1) expression and prevent it from entering the cytoplasm. Subsequently, AS-IV blocked the interaction between HMGB1 and advanced glycosylation end product-specific receptor (RAGE) to inactivate NF-κB pathway. Finally, in vivo experiments demonstrated that AS-IV treatment can alleviate the lung inflammation in asthma mice. Collectively, AS-IV alleviates asthma and suppresses the pyroptosis of AMSCs through blocking HMGB1/RAGE axis to inactivate NF-κB pathway.

BACKGROUND: This study aimed to investigate functions of GLP-1R agonist by liraglutide (LIRA) and revealing the mechanism related to AGEs/RAGE in chondrocytes.
METHODS: To illustrate potential effect of GLP-1R agonist on AGEs induced chondrocytes, chondrocytes were administrated by AGEs with LIRA and GLP-1R inhibitor exendin. Inflammatory factors were assessed using ELISA. Real-time PCR was used to evaluate the catabolic activity MMPs and ADAMTS mRNA level, as well as anabolic activity (aggrecan and collagen II). RAGE expression was investigated by Western blotting. TUNEL, caspase3 activity and immunofluorescence were performed to test the apoptotic activity.
RESULTS: Our results showed that treatment with LIRA at > 100 nM attenuated the AGE-induced chondrocyte viability. Western bolt demonstrated that GLP-1R activation by LIRA treatment reduced RAGE protein expression compared with the AGEs groups. ELISA showed that LIRA hindered the AGEs-induced production of inflammatory cytokines (IL-6, IL-12 and TNF-α) in primary chondrocytes. AGEs induced catabolism levels (MMP-1, -3, -13 and ADAMTS-4, 5) are also attenuated by LIRA, causing the retention of more extracellular matrix (Aggrecan and Collagen II). TUNEL, caspase3 activity and immunofluorescence results indicated that LIRA inhibited the AGEs-induced production of inflammatory cytokines in primary chondrocytes and attenuated the caspase 3 level, leading to the reduced apoptotic activity. All the protective effects are reversed by exendin (GLP-1R blockers).
CONCLUSIONS: The present study demonstrates for the first time that LIRA, an agonist for GLP-1R which is commonly used in type 2 diabetes reverses AGEs induced chondrocyte inflammation and apoptosis through suppressing RAGE signaling, contributing to reduced catabolism and retention of more extracellular matrix. The above results indicate the possible effect of GLP-1R agonist on treating OA.

UNASSIGNED: Diabetes has been recognized as an independent risk factor for periodontitis. Increasing evidences indicate that hyperglycemia aggravates inflammatory response of human periodontal ligament cells (hPDLCs). Carbon monoxide-releasing molecule-3 (CORM-3) is a water-soluble compound that can release carbon monoxide (CO) in a controllable manner. CORM-3 has been shown the anti-inflammatory effect in different cell lineages.
UNASSIGNED: We stimulated periodontal ligament cells with LPS and high glucose. The expression of inflammatory cytokine was detected by ELISA. RT-qPCR, Western blot and immunofluorescence were used to detect the expression of TLR2, TLR4, RAGE and the activation of NF-κB pathway. We performed silencing and overexpression treatment of RAGE targeting the role of RAGE. We performed the immunostaining of paraffin sections of the periodontitis model in diabetes rats.
UNASSIGNED: The results showed that CORM-3 significantly inhibited the expression of inflammatory cytokine in hPDLCs stimulated with LPS and high glucose. CORM-3 also inhibited LPS and high glucose-induced expression of RAGE/NF-κB pathway and TLR2/TLR4/NF-κB pathway. Silence of RAGE resulted in significantly decreased expression of proteins above. Overexpression of RAGE significantly enhanced the expression of these factors. CORM-3 abrogated the effect of RAGE partially. In animal model, CORM-3 suppressed the inflammatory response of periodontal tissues in experimental periodontitis of diabetic rats.
UNASSIGNED: Our research proved CORM-3 reduced the inflammatory response via RAGE/NF-κB pathway and TLR2/TLR4/NF-κB pathway in the process of high glucose exacerbated periodontitis. These findings demonstrated the role of RAGE in the process of high glucose exacerbated periodontitis and suggested that CORM3 be a potential therapeutic strategy for the treatment of diabetes patients with periodontitis.

Receptor for advanced glycation endproducts (RAGE) and toll-like receptor 4 (TLR4) are pattern-recognition receptors that bind to molecular patterns associated with pathogens, stress, and cellular damage. Diffusion plays an important role in receptor functionality in the cell membrane. However, there has been no prior investigation of the reciprocal effect of RAGE and TLR4 diffusion properties in the presence and absence of each receptor. This study reports how RAGE and TLR4 affect the mobility of each other in the human embryonic kidney (HEK) 293 cell membrane. Diffusion properties were measured using single-particle tracking (SPT) with quantum dots (QDs) that are selectively attached to RAGE or TLR4. The Brownian diffusion coefficients of RAGE and TLR4 are affected by the presence of the other receptor, leading to similar diffusion coefficients when both receptors coexist in the cell. When TLR4 is present, the average Brownian diffusion coefficient of RAGE increases by 40%, while the presence of RAGE decreases the average Brownian diffusion coefficient of TLR4 by 32%. Diffusion in confined membrane domains is not altered by the presence of the other receptor. The mobility of the cell membrane lipid remains constant whether one or both receptors are present. Overall, this work shows that the presence of each receptor can affect a subset of diffusion properties of the other receptor without affecting the mobility of the membrane.