Receptor For Advanced Glycation End Products Research Articles

Molecular dynamics simulation of the brain-isolated single-domain antibody/nanobody from camels through in vivo phage display screening.

During the last decade, there has been a significant rise in the use of therapeutic antibodies or passive immunotherapy for treating various conditions like inflammation and cancer. However, these proteins face challenges reaching the brain and often require specialized delivery methods such as single-domain antibodies (sdAbs). Traditional antibodies struggle to efficiently cross the blood-brain barrier (BBB), hindering their effectiveness. Receptor-mediated transcytosis (RMT) offers a promising pathway for transporting large molecules essential for brain function and treatment across the BBB. SdAbs and peptide ligands with an affinity for RMT receptors are commonly employed to enhance the transport of biotherapeutics compounds across the BBB. This research used a sdAbs phage-displayed library from 13 camelus dromedarius samples to identify sdABs that specifically bind to and are internalized by human BBB endothelial cells (ECs) through in vivo panning. One sdAb, defined as FB24, was isolated, sequenced, translated into an open reading frame (ORF), and subjected to three-dimensional (3D) modeling. Molecular docking and molecular dynamics simulations were carried out by the HADDOCK web server and GROMACS, respectively, to evaluate the interaction between FB24 and EC receptors in silico. The docking results revealed that FB24 exhibited binding activity against potential EC receptors with -1.7 to -2.7 ranged z score and maintained a stable structure. The docked complex of FB24-RAGE (receptor for advanced glycation end products, also known as advanced glycation end product receptor [AGER]) showed 18 hydrogen bonds and 213 non-bonded contacts. It was chosen for further analysis by molecular dynamics simulations by GROMACS. This complex showed a stable condition, and its root mean square deviation (RMSD) was 0.218 nm. The results suggest that FB24 could serve as a suitable carrier vector for transporting therapeutic and diagnostic agents across the BBB to the brain through a non-invasive route.

Localization of advanced glycation end-products and their receptor in tendinopathic lesions.

This study was designed to investigate the accumulation of advanced glycation end-products (AGEs) and the expression of the receptor of AGEs (RAGE) in tendinopathic tissues. In this study, tendinopathic posterior tibial tendons (PTT) were collected from patients (n=6). Redundant autografts of flexor digitorum longus tendon (FDL; n=3) were used for controls. The control and tendinopathic tendon tissues were used for extraction of proteins for western blot and sectioned for histology and immunohistochemistry. Tendinopathy of the PTT was confirmed histologically by the presentation of disorderly organized collagen fibers, high cellularity and increased vascularity. By immunohistochemistry, heterogeneous accumulation of AGEs was detected on the PTT sections and concentrated in areas, where collagen fibers were disorderly and tangled. In the PTT, roundish tenocytes were also AGEs-positive. In contrast, AGEs were diffuse, lightly stained in the FDL. A greater number of tenocytes within the tendinopathic lesions in the PTT were RAGE positive, compared to the tenocytes in the FDL. Western blot confirmed the expression of AGEs and RAGE in both tendinopathic PTT and control FDL but their band densities were not significantly different. The spatial relation of the accumulated AGEs and RAGE- positive tenocytes within the tendinopathic lesions indicates their involvement in the molecular pathology of tendinopathy.

The role of high mobility group box-1 on the development of diabetes complications: A plausible pharmacological target.

Diabetes mellitus has emerged as a pressing global concern, with a notable increase in recent years. Despite advancements in treatment, existing medications struggle to halt the progression of diabetes and its associated complications. Increasing evidence underscores inflammation as a significant driver in the onset of diabetes mellitus. Therefore, perspectives on new therapies must consider shifting focus from metabolic stress to inflammation. High mobility group box (HMGB-1), a nuclear protein regulating gene expression, gained attention as an endogenous danger signal capable of sparking inflammatory responses upon release into the extracellular environment in the late 1990s. Given the parallels between inflammatory responses and type 2 diabetes (T2D) development, this review paper explores HMGB-1's potential involvement in onset and progression of diabetes complications. Specifically, we will review and update the understanding of HMGB-1 and its inflammatory pathways in insulin resistance, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy. HMGB-1 and its receptors i.e. receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) present promising targets for antidiabetic interventions. Ongoing and future projects in this realm hold promise for innovative approaches targeting HMGB-1-mediated inflammation to ameliorate diabetes and its complications.

Integrated bioinformatic analysis of the molecular mechanisms between type 2 diabetes mellitus and osteoarthritis.

Type 2 diabetes mellitus (T2DM) is a metabolic syndrome that has been identified as an independent risk factor for osteoarthritis (OA) and may even trigger and exacerbate the progression of OA. However, the relationship between T2DM and OA is complex and has not yet been fully clarified by current research. In this study, we analyzed the potential mechanism of action between T2DM and OA by bioinformatics. Transcriptome sequencing data of T2DM (GSE25724) and OA (GSE55235) were downloaded from the gene expression omnibus. Differential expression analysis was performed for different subgroups to obtain differentially expressed genes. The protein-protein interaction network was constructed using overlapping genes and screened for hub targets. Then the enrichment analysis was performed separately for overlapping and hub targets. The GeneMANIA is used to predict functionally similar genes of hub genes. Differential expression analyses revealed that 184 genes are involved in both diseases together. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment results showed that the overlapping genes were mainly involved in the advanced glycation end products-receptor of advanced glycation end products signaling pathway, the NF-kappa B signaling pathway, the mitogen-activated protein kinases signaling pathway, and the interleukin-17 signaling pathway in diabetic complications. The functions of genes similar to the hub genes are focused on cell chemotaxis, positive regulation of cell migration, positive regulation of RNA polymerase II transcription, regulation of leukocyte migration, epithelial cell proliferation, and integrated stress response signaling. The transcription factor Jun and C-X-C motif chemokine 8 may play an important role in the inflammatory response caused by advanced glycation end products. This study improves our understanding of T2DM complicating OA and helps to stimulate more effective treatments.

FPS-ZM1 attenuates the deposition of lipid in the liver of diabetic mice by sterol regulatory element binding protein-1c

BackgroundNonalcoholic fatty liver disease (NAFLD) shares common pathogenic mechanisms of type 2 diabetes mellitus (T2DM) with upregulated advanced glycation end products (AGEs). Here, we aim to investigate the effect of FPS-ZM1, an inhibitor for receptor for AGEs (RAGE), on lipid deposition in the liver of mice.MethodsKK-Ay mice were used as models of T2DM with NAFLD, while C57BL/6j mice were controls. Additionally, KK-Ay mice were treated with DMSO (with a concentration of 1%), with or without FPS-ZM1 (3 mg/kg/day, i.p). Lipid deposition in hepatocytes was observed using oil red O stain. Levels of AGEs and RAGE were measured. Sterol regulatory element-binding protein-1c (SREBP-1c), as well as nuclear factor κB p65 (p65 nfκb) and mitogen-activated protein kinase p38 (p38 MAPK), were also detected.ResultsLipid deposition is increased in the hepatocytes of KK-Ay mice compared to C57BL/6j mice. In addition, not only were the levels of AGEs elevated in plasma, but also the levels of RAGE in liver tissue. Although total SREBP-1c levels did not change in the liver of diabetic mice, mature SREBP-1c increased in KK-Ay mice with diabetes mellitus. Moreover, diabetic mice showed increased levels of phosphorylated-p65 nfκb (p-p65 nfκb) and phosphorylated-p38 MAPK (p-p38 MAPK). On the contrary, FPS-ZM1 decreased lipid deposition in liver cells, as well as mature SREBP-1c, p-p65 nfκb and p-p38 MAPK levels in liver tissue.ConclusionGenerally, FPS-ZM1 may attenuate lipid deposition in hepatocytes of diabetic mice via SREBP-1c down-regulation. This may depend on the downregulation of p65 nfκb and p38 MAPK phosphorylation.

Early- and life-long intake of dietary advanced glycation end-products (dAGEs) leads to transient tissue accumulation, increased gut sensitivity to inflammation, and slight changes in gut microbial diversity, without causing overt disease

Dietary advanced glycation end-products (dAGEs) accumulate in organs and are thought to initiate chronic low-grade inflammation (CLGI), induce glycoxidative stress, drive immunosenescence, and influence gut microbiota. Part of the toxicological interest in glycation products such as dietary carboxymethyl-lysine (dCML) relies on their interaction with receptor for advanced glycation end-products (RAGE). It remains uncertain whether early or lifelong exposure to dAGEs contributes physiological changes and whether such effects are reversible or permanent. Our objective was to examine the physiological changes in Wild-Type (WT) and RAGE KO mice that were fed either a standard diet (STD − 20.8 ± 5.1 µg dCML/g) or a diet enriched with dCML (255.2 ± 44.5 µg dCML/g) from the perinatal period for up to 70 weeks. Additionally, an early age (6 weeks) diet switch (dCML→STD) was explored to determine whether potential harmful effects of dCML could be reversed. Previous dCML accumulation patterns described by our group were confirmed here, with significant RAGE-independent accumulation of dCML in kidneys, ileum and colon over the 70-week dietary intervention (respectively 3-fold, 17-fold and 20-fold increases compared with controls). Diet switching returned tissue dCML concentrations to their baseline levels. The dCML-enriched diet had no significative effect on endogenous glycation, inflammation, oxidative stress or senescence parameters. The relative expression of TNFα, VCAM1, IL6, and P16 genes were all upregulated (∼2-fold) in an age-dependent manner, most notably in the kidneys of WT animals. RAGE knockout seemed protective in this regard, diminishing age-related renal expression of TNFα. Significant increases in TNFα expression were detectable in the intestinal tract of the Switch group (∼2-fold), suggesting a higher sensitivity to inflammation perhaps related to the timing of the diet change. Minor fluctuations were observed at family level within the caecal microbiota, including Eggerthellaceae, Anaerovoracaceae and Marinifilaceae communities, indicating slight changes in composition. Despite chronic dCML consumption resulting in higher free CML levels in tissues, there were no substantial increases in parameters related to inflammageing. Age was a more important factor in inflammation status, notably in the kidneys, while the early-life dietary switch may have influenced intestinal susceptibility to inflammation. This study affirms the therapeutic potential of RAGE modulation and corroborates evidence for the disruptive effect of dietary changes occurring too early in life. Future research should prioritize the potential influence of dAGEs on disease aetiology and development, notably any exacerbating effects they may have upon existing health conditions.

Unraveling the RAGE-NF-κB pathway: implications for modulating inflammation in diabetic neuropathy through photobiomodulation therapy.

Diabetic peripheral neuropathy (DPN) is a primary complication observed in diabetes that severely affects quality of life. Recent evidence suggests that photobiomodulation (PBM) is a promising therapy against painful conditions and nerve damage. However, the effects of PBM on DPN remains mostly unknown. In the present study, we investigated the efficacy of PBM therapy in modulating proinflammatory cytokine expression in both central and peripheral nervous systems of rats with Streptozotocin (STZ)-induced type 1 diabetes. Male Wistar rats were allocated into control (naïve), diabetic (STZ), and treatment (STZ + PBM) groups. A single intraperitoneal (i.p.) injection of STZ (85mg/kg) was administered for the induction of diabetes. Animals were subjected to 10 treatment sessions, every other day. The results herein presented indicate that PBM treatment diminishes Receptor for Advanced Glycation End-products (RAGE) and Nuclear Factor Kappa B (NF-ϰB) expression in peripheral nervous system and suppresses TNF-α expression in central nervous system tissues. Furthermore, PBM-therapy in diabetic rats also induces increased levels of the anti-inflammatory protein IL-10 in both peripheral and central nervous system. Collectively, our findings demonstrate compelling evidence that PBM-therapy modulates cytokine dynamics and influences RAGE/NF-ϰB axis in a STZ-induced model of type 1 diabetes.

Soluble receptor for advanced glycation endproducts (sRAGE) as a new biomarker of asthma in children: a brief review of the literature and our own findings

In recent years, the receptor of glycosylation end products (RAGE) has increasingly attracted the attention of researchers and plays an important role in various in various diseases associated with tissue destruction, metabolic and neurodegenerative processes, infections, immune reactions and inflammation of various origins. The study of the soluble form of this receptor (sRAGE) as a potential biomarker for the diagnosis and monitoring of bronchial asthma (BA) in children is becoming particularly relevant. This article presents a brief review of the literature on the role of RAGE and its ligands in the pathogenesis of respiratory diseases, and analyzes our own data on the study of sRAGE levels in children with AD. We examined 101 children aged 7-18 years suffering from AD referred to the Children’s Allergy Center (Krasnoyarsk, Russia). Children with AD were divided into three groups: controlled (n = 45), partially controlled (n = 19) and uncontrolled asthma (n = 37) according to GINA-2023. The control group consisted of 92 age- and sex-matched children (virtually healthy children without signs of infection or allergy). Serum sRAGE levels were determined by magnetic immunoassay (MAGPIX, Luminex, USA; Merk Millipore, USA). Data are presented as median (25-75% quartiles). The Kruskal–Wallis test was used. Serum sRAGE levels were reduced only in uncontrolled AD in the examined children (Figure 1, p (Kruskal–Wallis test) = 0.001). In addition, serum sRAGE levels were reduced in the asthma exacerbation groups, regardless of exacerbation status caused by viral infection or allergens. Thus, serum sRAGE levels are closely related to asthma control and exacerbation status in children with AD in and may be used as a novel marker of loss of disease control and possibly as a potential target for therapeutic intervention.

Association of Acute Systemic Inflammation with Patient-Centric Postoperative Pulmonary Complications After Elective Cardiac Surgery.

Postoperative pulmonary complications (PPCs) occur frequently after cardiac surgery. Absolute postoperative values of biomarkers of inflammation (interleukin [IL]-6, IL-8, and tumor necrosis factor-alpha [TNF-α]) and alveolar epithelial injury (soluble receptor for advanced glycation end-products [sRAGE]) have been associated with hypoxia and prolonged ventilation. However, relationships between these biomarkers and PPCs, contextualized to preoperative inflammation and perioperative lung injury risk factors, are uncertain. We aimed to determine associations between perioperative increases in biomarkers of inflammation and alveolar epithelial injury with a patient-centric PPC definition in adult cardiac surgical patients, accounting for the influence of intraoperative risk factors for lung injury. Adults undergoing elective cardiac surgery were eligible for this observational cohort study. Blood concentrations of IL-6, IL-8, TNF-α, and sRAGE were collected after anesthesia induction (baseline) and on postoperative day 1 (POD 1). The primary outcome was the occurrence of moderate or severe PPCs, graded using a validated scale, in POD 0 to 7. We estimated the association between POD 1 IL-6, IL-8, TNF-α, and sRAGE concentrations and moderate/severe PPC presence using separate logistic regression models for each biomarker, adjusted for baseline biomarker values and risk factors for postoperative lung injury (age, baseline PaO2/FiO2, left ventricle ejection fraction [LVEF], procedural type, cardiopulmonary bypass duration, and transfusions). Covariables were chosen based on relevance to lung injury and unadjusted between-group differences among patients with versus without PPCs. The secondary outcome was postoperative ventilation duration, which was log-transformed and analyzed using linear regression, adjusted using the same variables as the primary outcome. We enrolled 204 patients from 2016 to 2018. Biomarkers were analyzed in 2023 among 175 patients with complete data. In adjusted analyses, POD 1 IL-8 and IL-6 were significantly associated with moderate/severe PPCs. The odds ratio (OR) for developing a PPC for every 50 pg/mL increase in POD 1 IL-8 was 7.19 (95% confidence interval [CI], 2.13-28.53, P = .003) and 1.42 (95% CI, 1.13-1.93, P = .01) for every 50 pg/mL increase in POD 1 IL-6. In adjusted analyses, postoperative ventilation duration was significantly associated with POD 1 sRAGE; each 50 pg/mL increase in sRAGE was associated with a 25% (95% CI, 2%-52%, P = .03) multiplicative increase in hours of ventilation. TNF-α was not significantly associated with PPCs or ventilation duration. Acute systemic inflammation is significantly associated with PPCs after elective cardiac surgery in adults when taking into consideration preoperative inflammatory burden and perioperative factors that may influence postoperative lung injury.

Low bone turnover is associated with advanced glycation end-products, oxidative stress, and inflammation induced by type 2 diabetes mellitus.

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.

Vinpocetine and Lactobacillus improve fatty liver in rats: role of adiponectin and gut microbiome

Therapeutics that interfere with the damage/pathogen-associated molecular patterns (DAMPs/PAMPs) have evolved as promising candidates for hepatic inflammation like that occurring in non-alcoholic fatty liver disease (NAFLD). In the current study, we examined the therapeutic impact of the phosphodiesterase-1 inhibitor vinpocetine (Vinpo), alone or when combined with Lactobacillus, on hepatic abnormalities caused by a 13-week high-fat diet (HFD) and diabetes in rats. The results show that Vinpo (10 and 20 mg/kg/day) dose-dependently curbed HFD-induced elevation of liver injury parameters in serum (ALT, AST) and tissue histopathology. These effects were concordant with Vinpo’s potential to ameliorate HFD-induced fibrosis (Histological fibrosis score, hydroxyproline, TGF-β1) and oxidative stress (MDA, NOx) alongside restoring the antioxidant-related parameters (GSH, SOD, Nrf-2, HO-1) in the liver. Mechanistically, Vinpo attenuated the hepatocellular release of DAMPs like high mobility group box (HMGB)1 alongside lowering the overactivation of the pattern recognition receptors including, toll-like receptor (TLR)4 and receptor for advanced glycation end-products (RAGE). Consequently, there was less activation of the transcription factor nuclear factor-kappa B that lowered production of the proinflammatory cytokines TNF-α and IL-6 in Vinpo-treated HFD/diabetes rats. Compared to Vinpo treatment alone, Lactobacillus probiotics as adjunctive therapy with Vinpo significantly improved the disease-associated inflammation and oxidative stress injury, as well as the insulin resistance and lipid profile abnormalities via enhancing the restoration of the symbiotic microbiota. In conclusion, combining Vinpo and Lactobacillus probiotics may be a successful approach for limiting NAFLD in humans.

Reciprocal effect on lateral diffusion of receptor for advanced glycation endproducts and toll-like receptor 4 in the HEK293 cell membrane.

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.

Crocetin Enhances Temozolomide Efficacy in Glioblastoma Therapy Through Multiple Pathway Suppression.

Glioblastoma multiforme (GBM) is an aggressive type of brain tumor that is difficult to remove surgically. Research suggests that substances from saffron, namely crocetin and crocin, could be effective natural treatments, showing abilities to kill cancer cells. Our study focused on evaluating the effects of crocetin on glioma using the U87 cell line. We specifically investigated how crocetin affects the survival, growth, and spread of glioma cells, exploring its impact at concentrations ranging from 75-150 μM. The study also included experiments combining crocetin with the chemotherapy drug Temozolomide (TMZ) to assess potential synergistic effects. Crocetin significantly reduced the viability, proliferation, and migration of glioma cells. It achieved these effects by decreasing the levels of Matrix Metallopeptidase 9 (MMP-9) and Ras homolog family member A (RhoA), proteins that are critical for cancer progression. Additionally, crocetin inhibited the formation of cellular structures necessary for tumor growth. It blocked multiple points of the Ak Strain Transforming (AKT) signaling pathway, which is vital for cancer cell survival. This treatment led to increased cell death and disrupted the cell cycle in the glioma cells. When used in combination with TMZ, crocetin not only enhanced the reduction of cancer cell growth but also promoted cell death and reduced cell replication. This combination therapy further decreased levels of high mobility group box 1 (HMGB1) and Receptor for Advanced Glycation End-products (RAGE), proteins linked to inflammation and tumor progression. It selectively inhibited certain pathways involved in the cellular stress response without affecting others. Our results underscore the potential of crocetin as a treatment for glioma. It targets various mechanisms involved in tumor growth and spread, offering multiple avenues for therapy. Further studies are essential to fully understand and utilize crocetin's benefits in treating glioma.

Mechanism of mangiferin in the treatment of oral submucous fibrosis based on Gene Expression Omnibus database chip mining combined with network pharmacology and molecular docking.

This study aims to investigate the primary target and potential mechanism of mangiferin (MF) in treating oral submucous fibrosis (OSF) through Gene Expression Omnibus (GEO) database chip mining, network pharmacology, and molecular docking techniques. Potential therapeutic targets for OSF were identified using GEO chip data. The potential targets of MF were predicted, and disease-related targets for OSF were collected from databases. A Venn diagram was created using the EVenn platform to identify overlapping targets. The protein-protein interaction (PPI) network was constructed using the STRING database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the DAVID platform. Cytoscape 3.10.1 software was used to visualize a drug-target-pathway-disease network, while AutoDocktools 1.5.6 software was employed for molecular docking analysis. A total of 356 potential targets for MF and 360 disease-related targets for OSF were obtained from multiple databases. The top 15 key target proteins in the PPI network were selected as significant candidates. GO function and KEGG pathway enrichment analyses revealed that MF treatment primarily involved advanced glycation end products-receptor (AGE-RAGE), epidermal growth factor receptor (EGFR), and other signaling pathways associated with OSF pathogenesis. Molecular docking analysis demonstrated that MF exhibited a strong binding activity toward AKT serine kinase 1 (AKT1), tumor necrosis factor (TNF), and other core targets. These findings suggest that MF may exert its therapeutic effects on OSF through a multitarget approach involving various signaling pathways.

Advanced Glycation End-Products Acting as Immunomodulators for Chronic Inflammation, Inflammaging and Carcinogenesis in Patients with Diabetes and Immune-Related Diseases.

Increased production of advanced glycation end products (AGEs) among reducing sugars (glucose, fructose, galactose, or ribose) and amino acids/proteins via non-enzymatic Maillard reaction can be found in lifestyle-related disease (LSRD), metabolic syndrome (MetS), and obesity and immune-related diseases. Increased serum levels of AGEs may induce aging, diabetic complications, cardiovascular diseases (CVD), neurodegenerative diseases (NDD), cancer, and inflamm-aging (inflammation with immunosenescence). The Maillard reaction can also occur among reducing sugars and lipoproteins or DNAs to alter their structure and induce immunogenicity/genotoxicity for carcinogenesis. AGEs, as danger-associated molecular pattern molecules (DAMPs), operate via binding to receptor for AGE (RAGE) or other scavenger receptors on cell surface to activate PI3K-Akt-, P38-MAPK-, ERK1/2-JNK-, and MyD88-induced NF-κB signaling pathways to mediate various pathological effects. Recently, the concept of "inflamm-aging" became more defined, and we have unveiled some interesting findings in relation to it. The purpose of the present review is to dissect the potential molecular basis of inflamm-aging in patients with diabetes and immune-mediated diseases caused by different AGEs.

Longitudinal importance of the soluble receptor for advanced glycation end-products in nonintubated hospitalized patients with COVID-19 pneumonia.

The soluble receptor for advanced glycation end-products (sRAGE) is a marker of alveolar type I cell injury associated with outcomes in COVID-19 pneumonia. How plasma sRAGE changes over time and whether it remains associated with long-term clinical outcomes beyond a single measurement in COVID-19 have not been well studied. We studied two cohorts in randomized clinical trials of monoclonal antibody treatment for COVID-19 (bamlanivimab and tixagevimab/cilgavimab). We first studied the association between baseline plasma sRAGE and 90-day clinical outcomes, which had been previously demonstrated in the bamlanivimab cohort, among hospitalized patients with COVID-19 supported with high-flow nasal oxygen (HFNO) or noninvasive ventilation (NIV) in the tixagevimab/cilgavimab study. Next, we investigated the relationship between day 3 sRAGE and 90-day outcomes and how plasma sRAGE changes over the first 3 days of hospitalization in both clinical trial cohorts. We found that plasma sRAGE in the highest quartile in the HFNO/NIV participants in the tixagevimab/cilgavimab trial was associated with a significantly lower rate of 90-day sustained recovery [recovery rate ratio = 0.31, 95% confidence interval (CI) = 0.14-0.71, P = 0.005] and with a significantly higher rate of 90-day mortality (hazard ratio = 2.49, 95% CI = 1.15-5.43, P = 0.021) compared with the lower three quartiles. Day 3 plasma sRAGE in both clinical trial cohorts remained associated with 90-day clinical outcomes. The trajectory of sRAGE was not influenced by treatment assignment. Our results indicate that plasma sRAGE is a valuable prognostic marker in COVID-19 up to 3 days after initial hospital presentation.NEW & NOTEWORTHY The soluble receptor for advanced glycation end-products (sRAGE) is a marker of alveolar type I epithelial cell injury associated with clinical outcomes in acute respiratory distress syndrome and, more recently, in hospitalized subjects with COVID-19. How plasma sRAGE changes over time and whether plasma sRAGE remains associated with long-term clinical outcomes beyond a single baseline measurement in patients with COVID-19 have not been well studied.

Clinical Factors and Biomarkers Associated with Depressive Disorders in Older Patients Affected by Chronic Kidney Disease (CKD): Does the Advanced Glycation End Products (AGEs)/RAGE (Receptor for AGEs) System Play Any Role?

Depressive disorders are highly prevalent among subjects suffering from chronic kidney disease (CKD). The aim of the present study is to evaluate clinical and biochemical factors associated with depressive disorders in a sample of older CKD patients, with a focus on advanced glycation end products (AGEs) and their soluble receptors (sRAGEs). A total of 115 older subjects affected by CKD (stages 3 to 5, not in dialysis) were selected for this study. These patients were divided into two groups according to the presence of depressive disorders defined by a score ≥ 10 on the 30-item Geriatric Depression Scale (GDS). The two groups were compared by independent sample t tests for continuous variables and χ2 tests for qualitative ones. Significant variables at univariate analyses were then inserted as predictors of a binary logistic regression model, with the presence or absence of depressive disorders as a dependent variable. The binary logistic regression model showed that patients with concomitant depressive disorders were more frequently of female gender (p < 0.01) and had lower MCP1 (p < 0.01) and AGE circulating levels (p < 0.01) than their counterparts. Depressive disorders in older CKD patients are more prevalent in women and seem to be inversely associated with systemic inflammation and circulating AGEs.

Exploring the mechanisms of Guizhifuling pills in the treatment of coronary spastic angina based on network pharmacology combined with molecular docking.

Coronary spastic angina (CSA) is common, and treatment options for refractory vasospastic angina are sometimes limited. Guizhifuling pills (GFP) have demonstrated efficacy in reducing CSA episodes, but their pharmacological mechanism remains unclear. To explore the mechanism of action of GFP in preventing and treating CSA, we employed network pharmacology and molecular docking to predict targets and analyze networks. We searched GFP chemical composition information and related targets from databases. The drug-target and drug-target pathway networks were constructed using Cytoscape. Then the protein-protein interaction was analyzed using the STRING database. Gene Ontology biological functions and Kyoto Encyclopedia of Genes and Genomes pathways were performed by the Metascape database, and molecular docking validation of vital active ingredients and action targets of GFP was performed using AutoDock Vina software. The 51 active components in GFP are expected to influence CSA by controlling 279 target genes and 151 signaling pathways. Among them, 6 core components, such as quercetin, β-sitosterol, and baicalein, may regulate CSA by affecting 10 key target genes such as STAT3, IL-6, TP53, AKT1, and EGFR. In addition, they are involved in various critical signaling pathways such as apelin, calcium, advanced glycation end product-receptor for advanced glycation end product, and necroptosis. Molecular docking analysis confirms favorable binding interactions between the active components of GFP and the selected target proteins. The effects of GFP in treating CSA involve multiple components, targets, and pathways, offering a theoretical basis for its clinical use and enhancing our understanding of how it works.

A Multifunctional Nanocomposite Hydrogel Delivery System Based on Dual-Loaded Liposomes for Scarless Wound Healing.

Increased inflammatory responses and oxidative stress at the wound site following skin trauma impair healing. Furthermore, skin scarring places fibroblasts under severe mechanical stress and aggravates pathological fibrosis. A novel liposomal composite hydrogel is engineered for wound microenvironment remodeling, incorporating dual-loaded liposomes into gelatin methacrylate to create a nanocomposite hydrogel. Notably, tetrahydrocurcumin (THC) and hepatocyte growth factor (HGF) are encapsulated in the hydrophobic and hydrophilic layers of liposomes, respectively. The composite hydrogel maintains porous nanoarchitecture, demonstrating sustainable THC and HGF release and enhanced mechanical properties and biocompatibility. This system effectively promotes cell proliferation and angiogenesis and attenuates apoptosis. It decreases the expression of the inflammatory factors by inhibiting the high-mobility group box /receptor for advanced glycation end product/NF-κB (HMGB1/RAGE/NF-κB)pathway and increases macrophage polarization from M1 to M2 in vitro, effectively controlling inflammatory responses. It exhibits remarkable antioxidant properties by scavenging excess reactive oxygen species and free radicals. Most importantly, it effectively prevents scar formation by restraining the transforming growth factor beta (TGF-β)/Smads pathway that downregulates associated fibrotic factors. It demonstrates strong therapeutic effects against inflammation and fibrosis in a rat skin wound model with biosafety, advancing the development of innovative hydrogel-based therapeutic delivery strategies for clinical scarless wound therapy.

Methylglyoxal-derived hydroimidazolone-1/RAGE axis induces renal oxidative stress and renal fibrosis in vitro and in vivo

Advanced glycation end products (AGEs) are important contributors to the progression of chronic kidney diseases (CKD), including renal fibrosis. Although the relationship between AGEs and renal fibrosis has been well studied, the mechanisms of individual AGE-induced renal injury remain poorly understood. This study investigated the adverse effect of methylglyoxal-derived hydroimidazolone-1 (MG-H1), a methylglyoxal (MG)-derived AGE generated by the glycation of MG and arginine residues, on kidney damage. We aimed to elucidate the molecular mechanisms of MG-H1-mediated renal injury and fibrosis, focusing on the receptor for AGEs (RAGE) signaling and its effects on the Wnt/β-catenin pathway, MAPK pathway, and inflammatory responses. Our results suggest that the MG-H1/RAGE axis plays a significant role in the pathogenesis of CKD and its downstream events involving MAPK kinase-related factors and inflammatory factors. MG-H1 treatment modulated the expression of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and MAPK proteins (ERK1/2, JNK, and p38).