Receptor For Advanced Glycation End Products Research Articles

CTIM-26. PHASE II STUDY OF AZELIRAGON IN COMBINATION WITH RADIATION THERAPY IN NEWLY DIAGNOSED PATIENTS WITH MGMT-UNMETHYLATED GLIOBLASTOMA

Abstract BACKGROUND Myeloid-derived suppressor cells (MDSCs) exacerbate immunosuppression and immune exhaustion in glioblastoma (GBM) and promote resistance to chemoradiotherapy. Preclinical data demonstrate that inhibiting the receptor for advanced glycation end-products (RAGE) pathway using azeliragon, when combined with radiation therapy (RT), can modulate MDSC accumulation in the tumor microenvironment and improve tumor control. CAN-401 is a phase II study evaluating the safety and preliminary clinical efficacy of combining azeliragon with RT for newly diagnosed IDH-wildtype MGMT-unmethylated glioblastoma (GBM). METHODS This multi-institutional, single-arm, open-label phase II study combines azeliragon with RT (60 Gy/30 fractions). Azeliragon is administered orally with a loading dose of 30 mg twice daily for 6 days before RT, followed by 20 mg daily during and after RT. If more than one dose-limiting toxicity occurs during the safety run-in of 6 patients, additional patients will be treated at de-escalated dose levels using the rolling six design. The study hypothesizes that azeliragon and RT will improve median progression-free survival (PFS) to 9.7 months compared to historical control of 5.7 months, corresponding to a hazard ratio of 0.58. The study aims to enroll 30 evaluable patients. RESULTS From December 2023 to May 2024, 10 patients were enrolled and treated with 20 mg of azeliragon daily, including 6 patients in the safety run-in. No dose-limiting toxicity was observed, hence no dose de-escalation was needed. The most common treatment-related adverse events (AEs) were grade 1, including fatigue and lymphopenia. There were no dose modifications or discontinuations due to treatment-related AEs. Enrollment is ongoing, and updated clinical outcomes will be reported. CONCLUSIONS Azeliragon at 20 mg per day with concurrent RT is well tolerated in patients with GBM. The phase II study is currently enrolling across 8 institutions in the United States (NCT05986851).

PHB2 alleviates retinal pigment epithelium cell fibrosis by suppressing the AGE-RAGE pathway.

Fibrosis is the primary cause of retinal detachment and visual decline. Here, we investigated the role of Prohibitin 2 (PHB2) in modulating fibrosis in ARPE-19 cells stimulated by transforming growth factor (TGF)-β2. The proliferation, migration, and apoptosis of ARPE-19 cells were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound healing, and flow cytometry assays, and levels of fibrosis-associated and pathway-related proteins were determined by performing western blotting. To examine the mechanisms underlying ARPE-19 cell fibrosis, we performed RNA sequencing, protein-protein interaction network, and enrichment analyses. We detected increases in the expression of the fibrosis-related proteins fibronectin and collagen I in response to TGF-β2 treatment, whereas the expression of PHB2 was downregulated. PHB2 overexpression suppressed the proliferation and migration of TGF-β2-stimulated ARPE-19 cells, promoted apoptosis, and inhibited fibrosis and Smad and non-Smad pathways. PHB2 overexpression inhibited the advanced glycation end-product (AGE)-receptor of advanced glycation end-product (RAGE) pathway activated by TGF-β2 treatment, which contributed to enhancing the effects of PHB2 on cellular processes, fibrosis, and Smad and non-Smad pathways. Conversely, exogenous application of AGE counteracted the effects of PHB2 overexpression. We conclude that by suppressing the AGE-RAGE pathway, PHB2 exerts an inhibitory effect on TGF-β2-induced fibrosis in ARPE-19 cells.

Methylglyoxal: A Key Factor for Diabetic Retinopathy and Its Effects on Retinal Damage

Background: Diabetic retinopathy is the most common retinal vascular disease, affecting the retina’s blood vessels and causing chronic inflammation, oxidative stress, and, ultimately, vision loss. Diabetes-induced elevated glucose levels increase glycolysis, the main methylglyoxal (MGO) formation pathway. MGO is a highly reactive dicarbonyl and the most rapid glycation compound to form endogenous advanced glycation end products (AGEs). MGO can act both intra- and extracellularly by glycating molecules and activating the receptor for AGEs (RAGE) pathway. Conclusions: This review summarizes the sources of MGO formation and its actions on various cell pathways in retinal cells such as oxidative stress, glycation, autophagy, ER stress, and mitochondrial dysfunction. Finally, the detoxification of MGO by glyoxalases is discussed.

Quantitative assessments of white matter hyperintensities and plasma biomarkers can predict cognitive impairment and cerebral microbleeds in cerebral small vessel disease patients

The objective of this study is to examine the efficacy of magnetic resonance imaging (MRI) features and peripheral blood biomarkers in assessing cognitive function in patients with cerebral small vessel disease (CSVD). A total of 58 CSVD patients were recruited. Six features of white matter hyperintensities (WMHs) were derived from MRI scans. Additionally, five neurodegenerative biomarkers (Aβ40, Aβ42, t-tau, p-tau181, NfL) and 13 serum inflammatory cytokines (VILIP-1, CCL2, IL-6, IL-18, TNF-α, CX3CL, sTREM-1/2, VEGF, s-RAGE, BNDF, TGF-β1, β-NGF) were quantified. Cognitive assessments were conducted using standardized neuropsychological scales. Spearman analysis revealed that the volumetric characteristics (absolute area, upper area, bottom area, absolute area percentage, upper percentage, and bottom percentage) of WMHs were negatively correlated with performance on all cognitive scale measures except the verbal fluency test (VFT) (r < -0.3, p > 0.05), while they were positively correlated with plasma neurofilament light (NFL) levels (r > 0.4, p < 0.05). Additionally, serum tumor necrosis factor-α (TNF-α) and soluble receptor for advanced glycation end-products (s-RAGE) showed significant correlations with scales of speech function. An integrated model incorporating WMHs features, neurodegenerative biomarkers, and neuroinflammatory markers was developed, demonstrating high predictive accuracy for cognitive impairment with an area under the curve (AUC) of 0.95 (accuracy 0.88, sensitivity 0.87, specificity 0.89). Another integrated model that includes features of WMHs and inflammatory cytokines for predicting cerebral microbleeds (CMBs) achieved an AUC of 0.95 (accuracy 0.88, sensitivity 0.82, specificity 0.92). Our findings suggest that these markers have the potential to be used for the early detection of cognitive decline and CMBs in patients with CSVD.

SRAGE attenuates myocardial ischemia-reperfusion injury by recruiting Tregs through chemokine CCL4

Abstract Background Immune response has recently been shown to play a crucial role in myocardial ischemia-reperfusion (MIR). Our previous studies have confirmed that soluble receptors for advanced glycation end-products (sRAGE) could reduce myocardial ischemia-reperfusion injury (MIRI) by increasing the number of regulatory T cells (Tregs). However, the precise mechanism is still incompletely understood. Purpose The present study aimed to determine which kind of chemokines play a major role in recruiting Tregs during MIRI. The potential mechanism of sRAGE on the chemokine production was further explored. Methods We modeled mice with cardiac-specific overexpression of sRAGE by crossing the floxed sRAGE mouse model with the cardiomyocyte-specific Cre transgenic mouse. Experimental models were established utilizing left anterior descending coronary artery ligation in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Transcriptomics, quantitative real-time polymerase chain reaction, immunohistochemistry, flow cytometry, and western blotting were used to determine the chemokines and related pathways involved in the recruitment of Tregs during MIRI. Results Using transcriptomics, quantitative real-time polymerase chain reaction, and western blotting approach, we identify the chemokine CCL4 plays a crucial role during regulatory T cell recruitment in the heart after MIRI. In vivo studies show that depletion of CCL4 reduces Tregs infiltration into the ischemic myocardium, subsequently deteriorating cardiac injury post-MIR. Mechanistically, sRAGE promotes cardiomyocytes to express and secrete CCL4 via the JNK/AP-1 pathway in vitro. Selective inhibition of the JNK/AP-1 pathway could decrease CCL4 production in sRAGE overexpression cardiomyocytes. Conclusions sRAGE induces Tregs recruitment and alleviates MIRI via the JNK/AP-1/CCL4 pathway, preserving myocardial function and impeding inflammation and apoptosis, providing new perspectives for immunotherapeutic targets in MIRI treatment.

The predictive capacity of biomarkers for clinical pulmonary oedema in patients with severe falciparum malaria is low: a prospective observational study

BackgroundPulmonary oedema is a feared and difficult to predict complication of severe malaria that can emerge after start of antimalarial treatment. Proinflammatory mediators are thought to play a central role in its pathogenesis.MethodsAn exploratory study was conducted to evaluate the predictive capacity of biomarkers for development of clinical pulmonary oedema in patients with severe falciparum malaria at two hospitals in Bangladesh. Plasma concentrations of interleukin-6 (IL-6), IL-8, tumour necrosis factor (TNF), soluble Receptor of Advanced Glycation End-products (sRAGE), surfactant protein-D (SP-D), club cell secretory protein (CC16), and Krebs von den Lungen-6 (KL-6) on admission were compared with healthy controls. Correlations between these biomarker and plasma lactate and Plasmodium falciparum histidine-rich protein 2 (PfHRP2) levels were evaluated. Receiver Operating Characteristic (ROC) curves were constructed to assess the predictive capacity for clinical pulmonary oedema of the biomarkers of interest.ResultsOf 106 screened patients with falciparum malaria, 56 were classified as having severe malaria with a mortality rate of 29%. Nine (16%) patients developed clinical pulmonary oedema after admission. Plasma levels of the biomarkers of interest were higher in patients compared to healthy controls. IL-6, IL-8, TNF, sRAGE, and CC16 levels correlated well with plasma PfHRP2 levels (rs = 0.39; P = 0.004, rs = 0.43; P = 0.001, rs = 0.54; P < 0.001, rs = 0.44; P < 0.001, rs = 0.43; P = 0.001, respectively). Furthermore, IL-6 and IL-8 levels correlated well with plasma lactate levels (rs = 0.37; P = 0.005, rs = 0.47; P < 0.001, respectively). None of the biomarkers of interest had predictive capacity for development of clinical pulmonary oedema.ConclusionsIL-6, IL-8, TNF, sRAGE, SP-D, CC16 and KL-6 cannot be used in predicting clinical pulmonary oedema in severe malaria patients.

Pathophysiological Markers of Acute Respiratory Distress Syndrome Severity Are Correlated With Ventilation-Perfusion Mismatch Measured by Electrical Impedance Tomography.

Pulmonary ventilation/perfusion (V/Q) mismatch measured by electrical impedance tomography (EIT) is associated with the outcome of patients with the acute respiratory distress syndrome (ARDS), but the underlying pathophysiological mechanisms have not been fully elucidated. The present study aimed to verify the correlation between relevant pathophysiological markers of ARDS severity and V/Q mismatch. Prospective observational study. General ICU of a university-affiliated hospital. Deeply sedated intubated adult patients with ARDS under controlled mechanical ventilation. Measures of V/Q mismatch by EIT, respiratory mechanics, gas exchange, lung imaging, and plasma biomarkers. Unmatched V/Q units were assessed by EIT as the fraction of ventilated nonperfused plus perfused nonventilated lung units. At the same time, plasma biomarkers with proven prognostic and mechanistic significance for ARDS (carbonic anhydrase 9 [CA9], hypoxia-inducible factor 1 [HIF1], receptor for advanced glycation endproducts [RAGE], angiopoietin 2 [ANG2], gas exchange, respiratory mechanics, and quantitative chest CT scans were measured. Twenty-five intubated ARDS patients were included with median unmatched V/Q units of 37.1% (29.2-49.2%). Unmatched V/Q units were correlated with plasma levels of CA9 (rho = 0.47; p = 0.01), HIF1 (rho = 0.40; p = 0.05), RAGE (rho = 0.46; p = 0.02), and ANG2 (rho = 0.42; p = 0.03). Additionally, unmatched V/Q units correlated with plateau pressure (r = 0.38; p = 0.05) and with the number of quadrants involved on chest radiograph (r = 0.73; p < 0.01). Regional unmatched V/Q units were correlated with the corresponding fraction of poorly aerated lung tissue (r = 0.62; p = 0.01) and of lung tissue weight (rho: 0.51; p = 0.04) measured by CT scan. In ARDS patients, unmatched V/Q units are correlated with pathophysiological markers of lung epithelial and endothelial dysfunction, increased lung stress, and lung edema. Unmatched V/Q units could represent a comprehensive marker of ARDS severity, reflecting the complex organ pathophysiology and reinforcing their prognostic significance.

Soluble receptors for advanced glycation endproducts are predictors of insulin sensitivity and affected by weight loss

BackgroundMice experiments have underscored the efficacy of pharmacological inhibition of advanced glycation endproducts (AGEs) through the use of soluble receptors for advanced glycation endproducts (sRAGE) in mitigating obesity-linked metabolic disruptions and insulin resistance. However, human studies have presented conflicting findings regarding the correlation between circulating sRAGE levels and insulin resistance, as well as glucose tolerance. Here, we aimed to delve deeper into the relationship between sRAGE levels and systemic insulin sensitivity.MethodsPlasma sRAGE levels, hyperinsulinemic-euglycemic clamp, and continuous glucose monitoring were measured in two independent cross-sectional case-control studies [cohort 1 (n = 180) and cohort 2 (n = 124)]. In addition, a subgroup of 42 participants with obesity were followed for 12 months. In 14 of these participants, weight loss was achieved through bariatric surgery intervention.ResultsOur results revealed a significant association between plasma sRAGE levels and both insulin sensitivity and glycemic control parameters, even after adjustments for age, sex, and BMI. Furthermore, longitudinal analysis demonstrated that interventions aimed at weight loss led to reductions in fasting glucose and HbA1c levels, concurrently with increases in sRAGE levels.ConclusionsThese findings underscore that sRAGE levels were strongly associated with insulin sensitivity and glycemic control, suggesting a possible role of sRAGE in preserving insulin sensitivity and maintaining glycemic control, which should be confirmed in further studies.

Extracellular RIPK3 Acts as a Danger-Associated Molecular Pattern to Exaggerate Cardiac Ischemia/Reperfusion Injury.

Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease. Currently, there is no effective therapy for reducing cardiac I/R injury. Damage-associated molecular patterns are endogenous molecules released after cellular damage to exaggerate tissue inflammation and injury. RIPK3 (receptor-interacting protein kinase 3), a well-established intracellular mediator of cell necroptosis and inflammation, serves as a circulating biomarker of multiple diseases. However, whether extracellular RIPK3 also exerts biological functions in cardiac I/R injury remains totally unknown. Patients with acute myocardial infarction receiving percutaneous coronary intervention (PCI) were recruited independently in the discovery cohort (103 patients) and validation cohort (334 patients), and major adverse cardiovascular events were recorded. Plasma samples were collected before and after PCI (6 and 24 h) for RIPK3 concentration measurement. Cultured neonatal rat ventricular myocytes, macrophages and endothelial cells, and in vivo mouse models with myocardial injury induced by I/R (or hypoxia/reoxygenation) were used to investigate the role and mechanisms of extracellular RIPK3. Another cohort including patients with acute myocardial infarction receiving PCI and healthy volunteers was recruited to further explore the mechanisms of extracellular RIPK3. In the discovery cohort, elevated plasma RIPK3 levels after PCI are associated with poorer short- and long-term outcomes in patients with acute myocardial infarction, as confirmed in the validation cohort. In both cultured cells and in vivo mouse models, recombinant RIPK3 protein exaggerated myocardial I/R (or hypoxia/reoxygenation) injury, which was alleviated by the RIPK3 antibody. Mechanistically, RIPK3 acted as a damage-associated molecular pattern and bound with RAGE (receptor of advanced glycation end-products), subsequently activating CaMKII (Ca2+/calmodulin-dependent kinase II) to elicit the detrimental effects. The positive correlation between plasma RIPK3 concentrations and CaMKII phosphorylation in human peripheral blood mononuclear cells was confirmed. We identified the positive relationship between plasma RIPK3 concentrations and the risk of major adverse cardiovascular events in patients with acute myocardial infarction receiving PCI. As a damage-associated molecular pattern, extracellular RIPK3 plays a causal role in multiple pathological conditions during cardiac I/R injury through RAGE/CaMKII signaling. These findings expand our understanding of the physiological and pathological roles of RIPK3, and also provide a promising therapeutic target for myocardial I/R injury and the associated complications.

Targeting RAGE-signaling pathways in the repair of rotator-cuff injury.

Rotator cuff injury (RCI) is a common musculoskeletal problem that can have a significant impact on the quality of life and functional abilities of those affected. Novel therapies, including proteomics-based, stem cells, platelet-rich plasma, and exosomes, are being developed to promote rotator-cuff healing. The receptor for advanced glycation end-products (RAGE) is a multifunctional receptor that is expressed on several cell types and is implicated in several physiologic and pathological processes, such as tissue repair, inflammation, and degeneration. Because of its capacity to bind with a variety of ligands and initiate signaling pathways that lead to inflammatory responses in RCI, RAGE plays a crucial role in inflammation. In this critical review article, we discussed the role of RAGE-mediated persistent inflammation in RCI followed by novel factors including PKCs, TIRAP, DIAPH1, and factors related to muscle injury with their therapeutic potential in RCI. These factors involve various aspects of muscle injury and signaling and the possibility of targeting these factors to improve the clinical outcomes in RCI still needsfurther investigation.

Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies.

Age-related macular degeneration (AMD) and related macular dystrophies (MDs) primarily affect the retinal pigment epithelium (RPE) in the eye. A hallmark of AMD/MDs that drives later-stage pathologies is drusen. Drusen are sub-RPE lipid-protein-rich extracellular deposits, but how drusen forms and accumulates is not known. We utilized human induced pluripotent stem cell (iPSC)-derived RPE from patients with AMD and three distinct MDs to demonstrate that reduced activity of RPE-secreted matrix metalloproteinase 2 (MMP2) contributes to drusen in multiple maculopathies in a genotype-agnostic manner by instigating sterile inflammation and impaired lipid homeostasis via damage-associated molecular pattern molecule (DAMP)-mediated activation of receptor for advanced glycation end-products (RAGE) and increased secretory phospholipase 2-IIA (sPLA2-IIA) levels. Therapeutically, RPE-specific MMP2 supplementation, RAGE-antagonistic peptide, and a small molecule inhibitor of sPLA2-IIA ameliorated drusen accumulation in AMD/MD iPSC-RPE. Ultimately, this study defines a causal role of the MMP2-DAMP-RAGE-sPLA2-IIA axis in AMD/MDs.

437 (PB425): Glycation status in breast and endometrial tumors assessed based on the expression of MAGE – the novel glycation end-products and RAGE – receptor for advanced glycation-end products

437 (PB425): Glycation status in breast and endometrial tumors assessed based on the expression of MAGE – the novel glycation end-products and RAGE – receptor for advanced glycation-end products

From small‐scale studies to an encompassing view: Inhibiting inflammation and clinically relevant enzymes with various extracts of Primula vulgaris using in vitro and in silico techniques

AbstractThe genus Primula holds great importance as a source of traditional remedies in various folk medicine systems. In the present study, we investigated the chemical composition and biological properties of different extracts (ethyl acetate, ethanol, ethanol/water, and water) of aerial parts and rhizomes of Primula vulgaris. To determine the chemical profile, the extracts were analyzed using ultrahigh performance liquid chromatography‐high‐resolution mass spectrometry (UHPLC‐HRMS) technique and flavonoids were a major group in this profile. The antioxidant capacity was demonstrated by in vitro chemical tests and in general the ethanol/water extract was found to be the most potent. Enzyme inhibition was studied against various enzymes and ethanol and ethanol/water extracts were more active than others. To assess the anti‐inflammatory potential of the extracts at the molecular level, human dermal fibroblasts (HDF) were treated with lipopolysaccharide (LPS). In vitro experiments showed that the levels of nuclear factor kappa B (NFKB), receptor for advanced glycation endproducts (RAGE), activator protein‐1 (AP‐1), interleukin 6 (IL‐6), interleukin 17 (IL‐17) and tumor necrosis factor (TNF)‐alpha were significantly reduced after treatment with the tested extracts. In addition, the extracts showed an inhibitory effect on the enzymes collagenase, elastase, and hyaluronidase, which are involved in the inflammatory process and destabilization of the extracellular matrix (ECM). P. vulgaris has been observed to modulate matrix metalloproteinase (MMP) synthesis by decreasing the concentration of cellular reactive oxygen species (ROS) during LPS‐induced inflammation. This study also examined the molecular binding and dynamic behavior of various enzymes and proteins associated with skin and infections using ligands derived from the tested extracts. Simulations with AutoDock Vina V1.1.2 and GROMACS 2023.1 showed that isoquercetin in particular showed superior performance in interactions with hyaluronidase. These findings are important for the development of potential therapeutic strategies for skin health and infection control. In summary, P. vulgaris can be considered as an important source of natural bioactive compounds for the development of effective health‐promoting applications in nutraceuticals, pharmaceuticals, and cosmetics

Efficient purification of soluble receptor for advanced glycation end-products from Sus scrofa lung tissue and synthesis of its binding ligand, glycated bovine serum albumin

A receptor for advanced glycation end products (RAGE) has emerged as a crucial player in various pathological conditions due to its involvement in inflammation and cellular dysfunction. Its soluble isoform, sRAGE, has garnered significant attention for its competitive inhibitory effects and potential therapeutic applications. However, obtaining sRAGE with appropriate glycosylation patterns for binding to glycated proteins has been challenging, often requiring costly expression systems. Here, we present a novel approach for producing and purifying sRAGE from Sus scrofa lungs, bypassing the need for expensive expression systems. Previous protocols for sRAGE extraction faced reproducibility issues due to high viscosity and haemoglobin content of the solution. To address this, we developed a method for selective haemoglobin precipitation using a zinc-containing buffer, enabling purification via various chromatographic methods. Through a combination of chromatographic techniques, we obtained sRAGE in suitable purity, identified using HPLC-MS/MS. Additionally, producing glycated proteins for RAGE receptor activation often involved lengthy protocols or inadequate separation from reactants. Thus, we devised a rapid method for producing and purifying pure BSA glycated with ribose, addressing a critical gap in the field. Functional studies, conducted using Native PAGE, demonstrated the capability of purified proteins to bind to each other.

PM2.5 Exposure Aggravates Inflammatory Response and Mucus Production in 16HBE Cells through Inducing Oxidative Stress and RAGE Expression.

Particulate matter 2.5 (PM2.5)-induced oxidative stress has been extensively proposed as a pivotal event in lung diseases. Receptor for advanced glycation end-products (RAGE) is a receptor of pro-inflammatory ligands that has been supported to be implied in the progression of multiple lung diseases. This study attempts to delineate the specific effects of PM2.5 on human bronchial epithelial 16HBE cells in vitro and figure out whether PM2.5 functions via mediating oxidative stress and RAGE. In PM2.5-challenged 16HBE cells, MTT assay detected cell viability. ELISA estimated inflammatory levels. Flow cytometry analysis measured ROS activity and related assay kits examined oxidative stress levels. Western blot tested nuclear factor E2-related factor 2 (Nrf2), RAGE, β-catenin, and mucin 5AC (MUC5AC) expression. Immunofluorescence staining evaluated nuclear translocation of β-catenin. It was noticed that PM2.5 exposure exacerbated inflammatory response, oxidative stress, and mucus production. Additionally, PM2.5 elevated RAGE expression while declined Nrf2 expression as well as stimulated the nuclear translocation of β-catenin. Furthermore, RAGE inhibition or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor VAS2870 mitigated inflammatory response, oxidative stress, and mucus generation in PM2.5-exposed 16HBE cells. In addition, RAGE inhibition or VAS2870 raised Nrf2 expression, reduced RAGE expression, and hampered β-catenin nuclear translocation. Briefly, PM2.5 might act as a leading driver of inflammatory response and mucus production in lung injury, the mechanism of which might be related to the activation of oxidative stress and the up-regulation of RAGE.

Role of Receptor for Advanced Glycation End-Products in Endometrial Cancer: A Review.

Endometrial cancer (EC) is the most common gynecological malignancy. EC is associated with metabolic disorders that may promote non-enzymatic glycation and activate the receptor for advanced glycation end-products (RAGE) signaling pathways. Thus, we assumed that RAGE and its ligands may contribute to EC. Of particular interest is the interaction between diaphanous-related formin 1 (Diaph1) and RAGE during the progression of human cancers. Diaph1 is engaged in the proper organization of actin cytoskeletal dynamics, which is crucial in cancer invasion, metastasis, angiogenesis, and axonogenesis. However, the detailed molecular role of RAGE in EC remains uncertain. In this review, we discuss epigenetic factors that may play a key role in the RAGE-dependent endometrial pathology. We propose that DNA methylation may regulate the activity of the RAGE pathway in the uterus. The accumulation of negative external factors, such as hyperglycemia, inflammation, and oxidative stress, may interfere with the DNA methylation process. Therefore, further research should take into account the role of epigenetic mechanisms in EC progression.

Engineered Macrophage Membrane-Coated S100A9-siRNA for Ameliorating Myocardial Ischemia-Reperfusion Injury.

Despite the widespread adoption of emergency coronary reperfusion therapy, reperfusion-induced myocardial injury remains a challenging issue in clinical practice. Following myocardial reperfusion, S100A8/A9 molecules are considered pivotal in initiating and regulating tissue inflammatory damage. Effectively reducing the S100A8/A9 level in ischemic myocardial tissue holds significant therapeutic value in salvaging damaged myocardium. In this study, HA (hemagglutinin)- and RAGE (receptor for advanced glycation end products)- comodified macrophage membrane-coated siRNA nanoparticles (MMM/RNA NPs) with siRNA targeting S100A9 (S100A9-siRNA) are successfully prepared. This nanocarrier system is able to target effectively the injured myocardium in an inflammatory environment while evading digestive damage by lysosomes. In vivo, migration of MMM/RNA NPs to myocardial injury lesions is confirmed in a myocardial ischemia-reperfusion injury (MIRI) mouse model. Intravenous injection of MMM/RNA NPs significantly reduced S100A9 levels in serum and myocardial tissues, further decreasing myocardial infarction area and improving cardiac function. Targeted reduction of S100A8/A9 by genetically modified macrophage membrane-coated nanoparticles may represent a new therapeutic intervention for MIRI.

S100A9 and HMGB1 orchestrate MDSC-mediated immunosuppression in melanoma through TLR4 signaling

BackgroundImmunotherapies for malignant melanoma are challenged by the resistance developed in a significant proportion of patients. Myeloid-derived suppressor cells (MDSC), with their ability to inhibit antitumor T-cell responses, are a...

Modulatory Effects of 830 nm on Diabetic Wounded Fibroblast Cells: An In Vitro Study on Inflammatory Cytokines.

Background:After skin damage, a complicated set of processes occur for epidermal and dermal wound healing. This process is hindered under diabetic conditions, resulting in nonhealing diabetic ulcers. In diabetes there is an increase in inflammation and proinflammatory cytokines. Modulating cells using photobiomodulation (PBM) may have an effect on inflammation and cell viability, which are crucial for the healing of wounds. Objective: This study explored the impact of PBM in the near-infrared spectrum (830 nm; 5 J/cm2) on inflammation in diabetic wound healing. Materials and Methods: Five cell models, namely normal, wounded, diabetic, diabetic wounded, and wounded with d-galactose were used. Cell morphology and migration rate were assessed, while cellular response measures included viability (Trypan blue and adenosine triphosphate), apoptosis (annexin-V/PI), proinflammatory cytokines interleukin-6, tumor necrosis factor-alpha (TNF-α), and cyclooxygenase-2, nuclear translocation of nuclear factor kappa B (NF-κB), and gene expression of advanced glycation end product receptor (AGER). Results: PBM resulted in increased levels of TNF-α, supported by activation of NF-κB. PBM stimulated translocation of NF-κB and upregulation of AGER. Conclusions: PBM modulates diabetic wound healing in vitro at 830 nm through stimulated NF-κB signaling activated by TNF-α.

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.