Simultaneous regulation of AGE/RAGE signaling and MMP-9 expression by an immunomodulating hydrogel accelerates healing in diabetic wounds.

PURPOSE: In chronic hyperglycemia, the advanced glycation end product (AGE) interacts with its receptor (RAGE) and contributes to impaired wound healing by inducing oxidative stress, generating dysfunctional macrophages, and prolonging the inflammatory response. Additionally, uncontrolled levels of proteases, including metallomatrix protease-9 (MMP-9), in the diabetic wound bed degrade the extracellular matrix (ECM) and biological cues that augment healing. A multifunctional antimicrobial hydrogel (Immuno-gel) containing RAGE and MMP-9 inhibitors can regulate the wound microenvironment and promote scar-free healing. RESULTS: Immuno-gel was characterized and the wound healing efficacy was determined in vitro cell culture and in vivo diabetic Wistar rat wound model using ELISA, Western blot, and Immunofluorescence staining. The Immuno-gel exhibited a highly porous morphology with excellent in vitro cytocompatibility. AGE-stimulated macrophages treated with the Immuno-gel released higher levels of pro-healing cytokines in vitro. In the hydrogel-wound interface of diabetic Wistar rats, Immuno-gel treatment significantly reduced MMP-9 and NF-κB expression and enhanced pro-healing (M2) macrophage population and pro-healing cytokines. CONCLUSION: Altogether, this study suggests that Immuno-gel simultaneously attenuates macrophage dysfunction through the inhibition of AGE/RAGE signaling and reduces MMP-9 overexpression, both of which favor scar-free healing. The combinatorial treatment with RAGE and MMP-9 inhibitors via Immuno-gel simultaneously modulates the diabetic wound microenvironment, making it a promising novel treatment to accelerate diabetic wound healing.

Luteolin Mitigates D-Galactose-Induced Brain Ageing in Rats: SIRT1-Mediated Neuroprotection.

Luteolin is an essential natural polyphenol found in a variety of plants. Numerous studies have supported its protective role in neurodegenerative diseases, yet the research for its therapeutic utility in D-galactose (D-gal)-induced brain ageing is still lacking. In this study, the potential neuroprotective impact of luteolin against D-gal-induced brain ageing was explored. Forty rats were randomly divided into four groups: control, luteolin, D-gal, and luteolin-administered D-gal groups. All groups were subjected to behavioural, cholinergic function, and hippocampal mitochondrial respiration assessments. Hippocampal oxidative, neuro-inflammatory, senescence and apoptotic indicators were detected. Gene expressions of SIRT1, BDNF, and RAGE were assessed. Hippocampal histopathological studies, along with GFAP and Ki67 immunoreactivity, were performed. Our results demonstrated that luteolin effectively alleviated D-gal-induced cognitive impairment and reversed cholinergic abnormalities. Furthermore, luteolin administration substantially mitigated hippocampus oxidative stress, mitochondrial dysfunction, neuro-inflammation, and senescence triggered by D-gal. Additionally, luteolin treatment considerably attenuated neuronal apoptosis and upregulated hippocampal SIRT1 mRNA expression. In conclusion, our findings revealed that luteolin administration attenuated D-gal-evoked brain senescence, improving mitochondrial function and enhancing hippocampal neuroregeneration in an ageing rat model through its antioxidant, senolytic, anti-inflammatory, and anti-apoptotic impacts, possibly due to upregulation of SIRT1. Luteolin could be a promising therapeutic modality for brain aging-associated abnormalities.

The dynamic roles of advanced glycation end products.

Advanced glycation end products (AGEs) are a heterogeneous group of potentially harmful molecules that can form as a result of a non-enzymatic reaction between reducing sugars and proteins, lipids, or nucleic acids. The total body pool of AGEs reflects endogenously produced AGEs as well as exogeneous AGEs that come from sources such as diet and the environment. Engagement of AGEs with their cellular receptor, the receptor for advanced glycation end products (RAGE), which is expressed on the surface of various cell types, converts a brief pulse of cellular activation to sustained cellular dysfunction and tissue destruction. The AGEs/RAGE interaction triggers a cascade of intracellular signaling pathways such as mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinases, transforming growth factor beta, c-Jun N-terminal kinases (JNK), and nuclear factor kappa B, which leads to the production of pro-inflammatory cytokines, chemokines, adhesion molecules, and oxidative stress. All these events contribute to the progression of several chronic diseases. This chapter will provide a comprehensive understanding of the dynamic roles of AGEs in health and disease which is crucial to develop interventions that prevent and mitigate the deleterious effects of AGEs accumulation.

Glycation in the cardiomyocyte.

Glycation is a protein post-translational modification that can occur on lysine and arginine residues as a result of a non-enzymatic process known as the Maillard reaction. This modification is irreversible, so the only way it can be removed is by protein degradation and replacement. Small reactive carbonyl species, glyoxal and methylglyoxal, are the primary glycating agents and are elevated in several conditions associated with an increased risk of cardiovascular disease, including diabetes, rheumatoid arthritis, smoking, and aging. Thus, how protein glycation impacts the cardiomyocyte is of particular interest, to both understand how these conditions increase the risk of cardiovascular disease and how glycation might be targeted therapeutically. Glycation can affect the cardiomyocyte through extracellular mechanisms, including RAGE-based signaling, glycation of the extracellular matrix that modifies the mechanical environment, and signaling from the vasculature. Intracellular glycation of the cardiomyocyte can impact calcium handling, protein quality control and cell death pathways, as well as the cytoskeleton, resulting in a blunted contractility. While reducing protein glycation and its impact on the heart has been an active area of drug development, multiple clinical trials have had mixed results and these compounds have not been translated to the clinic-highlighting the challenges of modulating myocyte glycation. Here we will review protein glycation and its effects on the cardiomyocyte, therapeutic attempts to reverse these, and offer insight as to the future of glycation studies and patient treatment.

Advanced Glycation End Products-Induced Alzheimer's Disease and Its Novel Therapeutic Approaches: A Comprehensive Review.

Advanced glycation end products (AGEs) accumulate in the brain, leading to neurodegenerative conditions such as Alzheimer's disease (AD). The pathophysiology of AD is influenced by receptors for AGEs and toll-like receptor 4 (TLR4). Protein glycation results in irreversible AGEs through a complicated series of reactions involving the formation of Schiff's base, the Amadori reaction, followed by the Maillard reaction, which causes abnormal brain glucose metabolism, oxidative stress, malfunctioning mitochondria, plaque deposition, and neuronal death. Amyloid plaque and other stimuli activate macrophages, which are crucial immune cells in AD development, triggering the production of inflammatory molecules and contributing to the disease's pathogenesis. The risk of AD is doubled by risk factors for atherosclerosis, dementia, advanced age, and type 2 diabetic mellitus (DM). As individuals age, the prevalence of neurological illnesses such as AD increases due to a decrease in glyoxalase levels and an increase in AGE accumulation. Insulin's role in proteostasis influences hallmarks of AD-like tau phosphorylation and amyloid ß peptide clearance, affecting lipid metabolism, inflammation, vasoreactivity, and vascular function. The high-mobility group box 1 (HMGB1) protein, a key initiator and activator of a neuroinflammatory response, has been linked to the development of neurodegenerative diseases such as AD. The TLR4 inhibitor was found to improve memory and learning impairment and decrease Aß build-up. Therapeutic research into anti-glycation agents, receptor for advanced glycation end products (RAGE) inhibitors, and AGE breakers offers hope for intervention strategies. Dietary and lifestyle modifications can also slow AD progression. Newer therapeutic approaches targeting AGE-related pathways are needed.

Bongkrekic acid alleviates airway inflammation via breaking the mPTP/mtDAMPs/RAGE feedback loop in a steroid-insensitive asthma model.

Mitochondrial dysfunction is critical in the pathogenesis of asthma. Mitochondrial permeability transition pore (mPTP) regulates the release of mitochondrial damage-associated molecular patterns (mtDAMPs) to maintain mitochondrial homeostasis. Bongkrekic acid (BKA) is a highly selective inhibitor of mPTP opening, participates the progression of various diseases. This research investigated the exact roles of BKA and mPTP in the pathogenesis of asthma and elucidated its underlying mechanisms. In the present study, cytochrome c, one of the mtDAMPs, levels were elevated in asthmatic patients, and associated to airway inflammation and airway obstruction. BKA, the inhibitor of mPTP markedly reversed TDI-induced airway hyperresponsiveness, airway inflammation, and mitochondrial dysfunction. Pretreatment with mitochondrial precipitation, to simulate the release of mtDAMPs, further increased TDI-induced airway inflammation and the expression of RAGE in mice. Administration of the inhibitor of RAGE, FPS-ZM1, alleviated the airway inflammation, the abnormal open of mPTP and mitochondrial dysfunction induced by mtDAMPs and TDI. Furthermore, stimulation with different mtDAMPs activated RAGE signaling in human bronchial epithelial cells. Accordingly, our study indicated that mPTP was important and BKA was efficient in alleviating inflammation in TDI-induced asthma. A positive feedback loop involving mPTP, mtDAMPs and RAGE was present in TDI-induced asthma, indicating that mPTP might serve as a potential therapeutic target for asthma.

Receptor for Advanced Glycation End Product (RAGE) Modulates Inflammation During Feeding of the Hard Tick, Haemaphysalis longicornis in Mice.

Ticks are notorious blood-sucking ectoparasites that affect both humans and animals. They serve as a unique vector of various deadly diseases. Here, we have shown the roles of the receptor for advanced glycation end products (RAGE) during repeated infestations by the tick Haemaphysalis longicornis using RAGE-/- mice. In primary infestation, a large blood pool developed, which was flooded with numerous RBCs, especially during the rapid feeding phase of the tick both in wild-type (wt) and RAGE-/- mice. Very few inflammatory cells were detected around the zones of haemorrhage in the primary infestations. However, the number of inflammatory cells gradually increased in the subsequent tick infestations, and during the third infestations, the number of inflammatory cells reached to the highest level (350.3 ± 16.8 cells/focus). The site of attachment was totally occupied by the inflammatory cells in wt mice, whereas very few cells were detected at the ticks' biting sites in RAGE-/- mice. RAGE was highly expressed during the third infestation in wt mice. In the third infestation, infiltration of CD44+ lymphocytes, eosinophils and expression of S100A8 and S100B significantly increased at the biting sites of ticks in wt, but not in RAGE-/- mice. In addition, peripheral eosinophil counts significantly increased in wt but not in RAGE-/- mice. Taken together, our study revealed that RAGE-mediated inflammation and eosinophils played crucial roles in the tick-induced inflammatory reactions.

THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation.

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus characterized by heart failure and cardiac remodeling. Previous studies show that tetrahydroberberrubine (THBru) retrogrades cardiac aging by promoting PHB2-mediated mitochondrial autophagy and prevents peritoneal adhesion by suppressing inflammation. In this study we investigated whether THBru exerted protective effect against DCM in db/db mice and potential mechanisms. Eight-week-old male db/db mice were administered THBru (25, 50 mg·kg-1·d-1, i.g.) for 12 weeks. Cardiac function was assessed using echocardiography. We showed that THBru administration significantly improved both cardiac systolic and diastolic function, as well as attenuated cardiac remodeling in db/db mice. In primary neonatal mouse cardiomyocytes (NMCMs), THBru (20, 40 µM) dose-dependently ameliorated high glucose (HG)-induced cell damage, hypertrophy, inflammatory cytokines release, and reactive oxygen species (ROS) production. Using Autodock, surface plasmon resonance (SPR) and DARTS analyses, we revealed that THBru bound to the domain of the receptor for advanced glycosylation end products (RAGE), subsequently leading to inactivation of the PI3K/AKT/NF-κB pathway. Importantly, overexpression of RAGE in NMCMs reversed HG-induced inactivation of the PI3K/AKT/NF-κB pathway and subsequently counteracted the beneficial effects mediated by THBru. We conclude that THBru acts as an inhibitor of RAGE, leading to inactivation of the PI3K/AKT/NF-κB pathway. This action effectively alleviates the inflammatory responses and oxidative stress in cardiomyocytes, ultimately leading to ameliorated DCM.

Luteolin targets the AGE-RAGE signaling to mitigate inflammation and ferroptosis in chronic atrophic gastritis.

Chronic atrophic gastritis (CAG) is a chronic inflammatory disease and precancerous lesion in stomach cancer. Abnormal activation cellular ferroptosis further damages gastric tissue, which is susceptible to inflammation. Luteolin has powerful anti-inflammatory and regulatory potential for cellular ferroptosis. We aimed to clarify the involvement of luteolin in inflammation and ferroptosis during CAG. Luteolin targets were searched to identify intersecting genes in the chronic atrophic gastritis disease database. The AGE-RAGE pathway is a potential target of luteolin for the treatment of chronic atrophic gastritis and a binding site between luteolin and RAGE was predicted through a computer simulation of molecular docking. We established a CAG rat model using N-methyl-N-nitro-N-nitroguanidine. The therapeutic effect of luteolin on CAG was detected using western blotting, qPCR, hematoxylin and eosin staining, lipid oxidation (MDA), and Fe2+ assays. Luteolin inhibited the AGE-RAGE signaling pathway and reduced the inflammatory response in gastric tissues. Additionally, luteolin downregulated the concentration of (MDA) and Fe2+, and CAG downregulated the expression levels of ACSL4 and NOX1 and upregulated the expression levels of FIH1 and GPX4 ferroptosis-related proteins, thus inhibiting the ferroptosis of gastric tissue cells, which had a therapeutic effect on CAG.

Ge-Gen-Qin-Lian decoction alleviates the symptoms of type 2 diabetes mellitus with inflammatory bowel disease via regulating the AGE-RAGE pathway.

BACKGROUND: This study aimed to explore the mechanism of Ge-Gen-Qin-Lian decoction (GGQLD) in the alleviation of symptoms of type 2 diabetes mellitus (T2DM) with inflammatory bowel disease (IBD) by network pharmacology and experimental validation. METHODS: The active components and targets of GGQLD were identified from the TCMSP database. The potential therapeutic targets of T2DM and IBD were identified from the GEO database and 4 online disease target databases. The PPI network and KEGG/GO analyses were performed with the common targets among GGQLD, T2DM and IBD. Molecular docking was carried out between the core compounds and hub targets. To verify the above results, UHPLC-MS technology was used to identify the chemical compounds in GGQLD, and a T2DM with IBD rat model was used to explore the mechanism by which GGQLD treats T2DM with IBD. RESULTS: Totally, 70 potential therapeutic targets were identified among GGQLD, T2DM and IBD. Ten hub genes were selected from the PPI network. KEGG analysis revealed that GGQLD is tightly involved in the AGE-RAGE signaling pathway. Berberine, baicalein, wogonin, and quercitrin are the main active compounds of GGQLD. Animal experiments showed that GGQLD could decrease blood glucose and alleviate intestinal inflammation. Notably, the concentrations of AGEs, the expression of RAGE, c-JUN and NF-κB and the expression of inflammatory cytokines were decreased by GGQLD. CONCLUSIONS: Our study initially demonstrated that GGQLD has favorable anti-hyperglycemic and anti-intestinal inflammation effects in a T2DM with IBD rat model, and the AGE-RAGE pathway plays a vital role in this process.

Involvement of RAGE in radiation-induced acquisition of malignant phenotypes in human glioblastoma cells.

Glioblastoma (GBM), a highly aggressive malignant tumor of the central nervous system, is mainly treated with radiotherapy. However, since irradiation may lead to the acquisition of migration ability by cancer cells, thereby promoting tumor metastasis and invasion, it is important to understand the mechanism of cell migration enhancement in order to prevent recurrence of GBM. The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor activated by high mobility group box 1 (HMGB1). In this study, we found that RAGE plays a role in the enhancement of cell migration by γ-irradiation in human GBM A172 cells. γ-Irradiation induced actin remodeling, a marker of motility acquisition, and enhancement of cell migration in A172 cells. Both phenotypes were suppressed by specific inhibitors of RAGE (FPS-ZM1 and TTP488) or by knockdown of RAGE. The HMGB1 inhibitor ethyl pyruvate similarly suppressed γ-irradiation-induced enhancement of cell migration. In addition, γ-irradiation-induced phosphorylation of STAT3 was suppressed by RAGE inhibitors, and a STAT3 inhibitor suppressed γ-irradiation-induced enhancement of cell migration, indicating that STAT3 is involved in the migration enhancement downstream of RAGE. Our results suggest that HMGB1-RAGE-STAT3 signaling is involved in radiation-induced enhancement of GBM cell migration, and may contribute to GBM recurrence by promoting metastasis and invasion.

Anisotropic longitudinal water proton relaxation in white matter investigated ex vivo in porcine spinal cord with sample rotation.

A variation of the longitudinal relaxation time T 1 in brain regions that differ in their main fiber direction has been occasionally reported, however, with inconsistent results. Goal of the present study was to clarify such inconsistencies, and the origin of potential T 1 orientation dependence, by applying direct sample rotation and comparing the results from different approaches to measure T 1 . A section of fixed porcine spinal cord white matter was investigated at 3 T with variation of the fiber-to-field angle θ FB . The experiments included one-dimensional inversion-recovery, MP2RAGE, and variable flip-angle T 1 measurements at 22 °C and 36 °C as well as magnetization-transfer (MT) and diffusion-weighted acquisitions. Depending on the technique, different degrees of T 1 anisotropy (between 2 and 10%) were observed as well as different dependencies on θ FB (monotonic variation or T 1 maximum at 30-40°). More pronounced anisotropy was obtained with techniques that are more sensitive to MT effects. Furthermore, strong correlations of θ FB -dependent MT saturation and T 1 were found. A comprehensive analysis based on the binary spin-bath model for MT revealed an interplay of several orientation-dependent parameters, including the transverse relaxation times of the macromolecular and the water pool as well as the longitudinal relaxation time of the macromolecular pool.

Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches.

Dysregulation of the insulin-like growth factor (IGF) system determines the onset of various pathological conditions, including cancer. Accordingly, therapeutic strategies have been developed to block this system in tumor cells, but the results of clinical trials have been disappointing. After decades of research in the field, it is safe to say that one of the major reasons underlying the poor efficacy of anti-IGF-targeting agents is derived from an underestimation of the molecular complexity of this axis. Genetic, transcriptional, post-transcriptional and functional interactors interfere with the activity of canonical components of this axis, supporting the need for combinatorial approaches to effectively block this system. In addition, cancer cells interface with a multiplicity of factors from the extracellular compartment, which strongly affect cell destiny. In this review, we will cover novel extracellular mechanisms contributing to IGF system dysregulation and the implications of such dangerous liaisons for cancer hallmarks and responses to known and new anti-IGF drugs. A deeper understanding of both the intracellular and extracellular microenvironments might provide new impetus to better decipher the complexity of the IGF axis in cancer and provide new clues for designing novel therapeutic approaches.

Oxymatrine attenuates sepsis-induced inflammation and organ injury via inhibition of HMGB1/RAGE/NF-κB signaling pathway.

Sepsis is a life-threatening organ dysfunction that endangers patient lives and is caused by an imbalance in the host defense against infection. Sepsis continues to be a significant cause of morbidity and mortality in critically sick patients. Oxymatrine (OMT), a quinolizidine alkaloid derived from the traditional Chinese herb Sophora flavescens Aiton, has been shown to have anti-inflammatory effects on a number of inflammatory illnesses according to research. In this study, we aimed to evaluate the therapeutic effects of OMT on sepsis and explore the underlying mechanisms. We differentiated THP-1 cells into THP-1 macrophages and studied the anti-inflammatory mechanism of OMT in a lipopolysaccharide (LPS)-induced THP-1 macrophage sepsis model. Activation of the receptor for advanced glycation end products (RAGE), as well as NF-κB, was assessed by Western blot analysis and immunofluorescence staining. ELISA was used to measure the levels of inflammatory factors. We found that OMT significantly inhibited HMGB1-mediated RAGE/NF-κB activation and downstream inflammatory cytokine production in response to LPS stimulation. Finally, an in vivo experiment was performed on septic mice to further study the effect of OMT on injured organs. The animal experiments showed that OMT significantly inhibited HMGB1-mediated RAGE/NF-κB activation, protected against the inflammatory response and organ injury induced by CLP, and prolonged the survival rate of septic mice. Herein, we provide evidence that OMT exerts a significant therapeutic effect on sepsis by inhibiting the HMGB1/RAGE/NF-κB signaling pathway.

The role of HMGB1 on SiC NPs-induced inflammation response in lung epithelial-macrophage co-culture system.

In recent years, carbonized silicon nanoparticles (SiC NPs) have found widespread scientific and engineering applications, raising concerns about potential human health risks. SiC NPs may induce pulmonary damage through sustained inflammatory responses and oxidative stress, with unclear toxicity mechanisms. This study uses an in vitro co-culture model of alveolar macrophages (NR8383) and alveolar epithelial cells (RLE-6TN) to simulate the interaction between airway epithelial cells and immune cells, providing initial insights into SiC NP-triggered inflammatory responses. The research reveals that increasing SiC NP exposure prompts NR8383 cells to release high mobility group box 1 protein (HMGB1), which migrates into RLE-6TN cells and activates the receptor for advanced glycation end-products (RAGE) and Toll-like receptor 4 (TLR4). RAGE and TLR4 synergistically activate the MyD88/NF-κB inflammatory pathway, ultimately inducing inflammatory responses and oxidative stress in RLE-6TN cells, characterized by excessive ROS generation and altered cytokine levels. Pretreatment with RAGE and TLR4 inhibitors attenuates SiC-induced HMGB1 expression and downstream pathway proteins, reducing inflammatory responses and oxidative damage. This highlights the pivotal role of RAGE-TLR4 crosstalk in SiC NP-induced pulmonary inflammation, providing insights into SiC NP cytotoxicity and nanomaterial safety guidelines.

Notoginsenoside R1 (NGR1) regulates the AGE-RAGE signaling pathway by inhibiting RUNX2 expression to accelerate ferroptosis in breast cancer cells.

Ferroptosis is a new way of cell death, and stimulating the process of cell ferroptosis is a new strategy to treat breast cancer. NGR1 has good anti-cancer activity and is able to slow the progression of breast cancer. However, NGR1 has not been reported in the field related to ferroptosis. By searching the online database for potential targets of NGR1 and the breast cancer disease database, among 11 intersecting genes we focused on Runt-related transcription factor 2 (RUNX2), which is highly expressed in breast cancer, and KEGG pathway enrichment showed that the intersecting genes were mainly enriched in the AGE (advanced glycosylation end products)-RAGE (receptor of AGEs) signaling pathway. After that, we constructed overexpression and down-regulation breast cancer cell lines of RUNX2 in vitro, and tested whether NGR1 treatment induced ferroptosis in breast cancer cells by regulating RUNX2 to inhibit the AGE-RAGE signaling pathway through phenotyping experiments of ferroptosis, Western blot experiments, QPCR experiments, and electron microscopy observation. The results showed that NGR1 was able to inhibit the expression level of RUNX2 and suppress the AGE/PAGE signaling pathway in breast cancer cells. NGR1 was also able to promote the accumulation of Fe2+ and oxidative damage in breast cancer cells by regulating RUNX2 and then down-regulating the expression level of GPX4, FIH1 and up-regulating the expression level of ferroptosis-related proteins such as COX2, ACSL4, PTGS2 and NOX1, which eventually led to the ferroptosis of breast cancer cells.

The TOX-RAGE axis mediates inflammatory activation and lung injury in severe pulmonary infectious diseases.

Thymocyte selection-associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX-RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS.

Assessment of EN-RAGE, sRAGE, and its isoforms: cRAGE, esRAGE in obese patients treated by moderate caloric restriction combined with physical activity conducted in hospital condition.

BACKGROUND: AGEs, their receptor (RAGE), and the extracellular newly identified receptor for AGEs product-binding protein (EN-RAGE) are implicated in the pathogenesis of inflammation. AIM: We analyzed serum EN-RAGE, soluble RAGE (sRAGE), and their isoforms: endogenous secretory - esRAGE and cleaved - cRAGE concentrations in lean controls (n = 74) and in patients with obesity (n = 71) treated for three weeks with moderate calorie restriction (CR) combined with physical activity in a hospital condition. METHODS: Using the ELISA method, serum sRAGE, esRAGE, and EN-RAGE were measured before and after CR. RESULTS: The serum level of sRAGE and esRAGE in patients with obesity was lower than that in non-obese individuals, contrary to cRAGE. EN-RAGE concentration was about three times higher in obese patients. Gradually, a rise in BMI resulted in sRAGE, esRAGE reduction, and EN-RAGE increase. The sRAGE concentration was sex-dependent, indicating a higher value in lean men. A moderate negative correlation was observed between BMI and all RAGE isoforms, whereas EN-RAGE displays a positive correlation. CR resulted in an expected decrease in anthropometric, metabolic, and proinflammatory parameters and EN-RAGE, but no RAGE isoforms. The ratio EN-RAGE/sRAGE was higher in obese humans than in control and was not modified by CR. CONCLUSION: Obesity decreases sRAGE and esRAGE and increases EN-RAGE concentration. Moderate CR and physical activity by decreasing inflammation reduces EN-RAGE but is insufficient to increase sRAGE and esRAGE to the extent observed in lean patients. EN-RAGE instead of sRAGE could be helpful to indicate a better outcome of moderate dietary intervention in obese subjects.

The gastroprotective effect of Yucca filamentosa standardized crude leaves extract versus its nano-cubosomal formulation in ethanol-induced gastric injury.

Yucca filamentosa (YF) is widely used in folk medicine for its anti-inflammatory effects. Our study aimed to evaluate the chemical profile of YF extracts. Additionally, the gastroprotective efficacy of its crude leaf extract and nano-cubosomal formulation was assessed in a rat model of ethanol-induced gastric injury by altering the HMGB-1/RAGE/TLR4/NF-κB pathway. The phytochemical composition of YF was investigated using FTIR spectroscopy and LC-MS/MS techniques. Standardization was further accomplished using HPLC. Rats were treated orally with yucca crude extract or its nano-cubosomal formulation at doses of 25, 50, and 100 mg/kg. Famotidine (50 mg/kg, IP) was used as a reference drug. After 1 h, rats were administered ethanol (1 ml, 95 %, orally). One hour later, the rats were sacrificed, and the serum was separated to determine TNF-α and IL-6 levels. Stomachs were excised for the calculation of the ulcer index and histopathological examinations. Stomach tissue homogenate was used to determine MDA and catalase levels. Additionally, the expression levels of HMGB-1/RAGE/TLR4/NF-κB were assessed. Phytochemical analysis confirmed the predominance of steroidal saponins, sucrose, organic and phenolic acids, and kaempferol. The nano-cubosomal formulation demonstrated enhanced gastroprotective, anti-oxidant, and anti-inflammatory efficacy compared to the crude extract at all tested doses. The most prominent effect was observed in rats pretreated with the YF nano-cubosomal formulation at a dose of 100 mg/kg, which was similar to normal control and famotidine-treated rats. Our results highlighted the enhanced gastroprotective impact of the yucca nano-cubosomal formulation in a dose-dependent manner. This suggests its potential use in preventing peptic ulcer recurrence.

Activation and modulation of the AGEs-RAGE axis: Implications for inflammatory pathologies and therapeutic interventions - A review.

Chronic inflammation is a common foundation for the development of many non-communicable diseases, particularly diabetes, atherosclerosis, and tumors. The activation of the axis involving Advanced Glycation End products (AGEs) and their receptor RAGE is a key promotive factor in the chronic inflammation process, influencing the pathological progression of these diseases. The accumulation of AGEs in the body results from an increase in glycation reactions and oxidative stress, especially pronounced in individuals with diabetes. By binding to RAGE, AGEs activate signaling pathways such as NF-κB, promoting the release of inflammatory factors, exacerbating cell damage and inflammation, and further advancing the formation of atherosclerotic plaques and tumor development. This review will delve into the molecular mechanisms by which the AGEs-RAGE axis activates chronic inflammation in the aforementioned diseases, as well as strategies to inhibit the AGEs-RAGE axis, aiming to slow or halt the progression of chronic inflammation and related diseases. This includes the development of AGEs inhibitors, RAGE antagonists, and interventions targeting upstream and downstream signaling pathways. Additionally, the early detection of AGEs levels and RAGE expression as biomarkers provides new avenues for the prevention and treatment of diabetes, atherosclerosis, and tumors.