Receptor For Advanced Glycation End Products Research Articles

Diabetes Driven Oncogenesis and Anticancer Potential of Repurposed Antidiabetic Drug: A Systemic Review.

Diabetes and cancer are two prevalent disorders, pose significant public health challenges and contribute substantially to global mortality rates, with solely 10 million reported cancer-related deaths in 2020. This review explores the pathological association between diabetes and diverse cancer progressions, examining molecular mechanisms and potential therapeutic intersections. From altered metabolic landscapes to dysregulated signaling pathways, the intricate links are delineated, offering a comprehensive understanding of diabetes as a modulator of tumorigenesis. Cancer cells develop drug resistance through mechanisms like enhanced drug efflux, genetic mutations, and altered drug metabolism, allowing them to survive despite chemotherapeutic agent. Glucose emerges as a pivotal player in diabetes progression, and serving as a crucial energy source for cancer cells, supporting their biosynthetic needs and adaptation to diverse microenvironments. Glycation, a non-enzymatic process that produces advanced glycation end products (AGEs), has been linked to the etiology of cancer and has been shown in a number of tumor forms, such as leiomyosarcomas, adenocarcinomas, and squamous cell carcinomas. Furthermore, in aggressive and metastatic breast cancer, the receptor for AGEs (RAGE) is increased, which may increase the malignancy of the tumor. Reprogramming glucose metabolism manifests as hallmark cancer features, including accelerated cell proliferation, angiogenesis, metastasis, and evasion of apoptosis. This manuscript encapsulates the dual narrative of diabetes as a driver of cancer progression and the potential of repurposed antidiabetic drugs as formidable countermeasures. The amalgamation of mechanistic understanding and clinical trial outcomes establishes a robust foundation for further translational research and therapeutic advancements in the dynamic intersection of diabetes and cancer.

Differential Rates of Glycation following Exposure to Unique Monosaccharides

A complication of reducing sugars is that they can undergo Maillard chemical reactions, forming advanced glycation end-products (AGEs) that can induce oxidative stress and inflammation via engagements with the main receptor for AGEs (RAGE) in various tissues. Certain sugars, such as glucose and fructose, are well known to cause AGE formation. Recently, allulose has emerged as a rare natural sugar that is an epimer of fructose and which is of low caloric content that is minimally metabolized, leading to it being introduced as a low-calorie sugar alternative. However, the relative ability of allulose to generate AGEs compared to glucose and fructose is not known. Here we assess the accumulation of AGEs in cell-free, in vitro, and in vivo conditions in response to allulose and compare it to glycation mediated by glucose or fructose. AGEs were quantified in cell-free samples, cell culture media and lysates, and rat serum with glycation-specific ELISAs. In cell-free conditions, we observed concentration and time-dependent increases in AGEs when bovine serum albumin (BSA) was incubated with glucose or fructose and significantly less glycation when incubated with allulose. AGEs were significantly elevated when pulmonary alveolar type II-like cells were co-incubated with glucose or fructose; however, significantly less AGEs were detected when cells were exposed to allulose. AGE quantification in serum obtained from rats fed a high-fat, low-carb (HFLC) Western diet for 2 weeks revealed significantly less glycation in animals co-administered allulose compared to those exposed to stevia. These results suggest allulose is associated with less AGE formation compared to fructose or glucose, and support its safety as a low-calorie sugar alternative.

Hepatoprotective effects of zingerone on sodium arsenite-induced hepatotoxicity in rats: Modulating the levels of caspase-3/Bax/Bcl-2, NLRP3/NF-κB/TNF-α and ATF6/IRE1/PERK/GRP78 signaling pathways

ObjectiveLong-term exposure to arsenic has been linked to several illnesses, including hypertension, diabetes, hepatic and renal diseases and cardiovascular malfunction. The aim of the current investigation was to determine whether zingerone (ZN) could shield rats against the hepatotoxicity that sodium arsenite (SA) causes. MethodsThe following five groups of thirty-five male Sprague Dawley rats were created: I) Control; received normal saline, II) ZN; received ZN, III) SA; received SA, IV) SA + ZN 25; received 10 mg/kg body weight SA + 25 mg/kg body weight ZN, and V) SA + ZN 50; received 10 mg/kg body weight SA + 50 mg/kg body weight ZN. The experiment lasted 14 days, and the rats were sacrificed on the 15th day. While oxidative stress parameters were studied by spectrophotometric method, apoptosis, inflammation and endoplasmic reticulum stress parameters were measured by RT-PCR method. ResultsThe SA disrupted the histological architecture and integrity of the liver and enhanced oxidative damage by lowering antioxidant enzyme activity, such as those of glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), glutathione (GSH) level and increasing malondialdehyde (MDA) level in the liver tissue. Additionally, SA increased the mRNA transcript levels of Bcl2 associated x (Bax), caspases (−3, −6, −9), apoptotic protease-activating factor 1 (Apaf-1), p53, tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), interleukin-1β (IL-1β), interleukin-6 (IL-6), c-Jun NH2-terminal kinase (JNK), mitogen-activated protein kinase 14 (MAPK14), MAPK15, receptor for advanced glycation endproducts (RAGE) and nod-like receptor family pyrin domain-containing 3 (NLRP3) in the liver tissue. Also produced endoplasmic reticulum stress by raising the mRNA transcript levels of activating transcription factor 6 (ATF-6), protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and glucose-regulated protein 78 (GRP-78). These factors together led to inflammation, apoptosis, and endoplasmic reticulum stress. On the other hand, liver tissue treated with ZN at doses of 25 and 50 mg/kg showed significant improvement in oxidative stress, inflammation, apoptosis and endoplasmic reticulum stress. ConclusionsOverall, the study's data suggest that administering ZN may be able to lessen the liver damage caused by SA toxicity.

RAGE inhibition to decrease cancer therapy related cardiotoxicity in women with early breast cancer (RAGE).

TPS619 Background: Anthracyclines are commonly used to treat high risk early-stage breast cancer (BC). Anthracycline-induced myocardial toxicity is a rare but morbid complication in BC survivors. The mechanism is not completely elucidated but may involve the generation of reactive oxygen species and other inflammatory mediators. RAGE, the receptor for advanced glycation end-products, signaling is upregulated in inflammatory conditions and has been linked to the development and progression of cardiovascular disease and cancer. In experimental models, blocking RAGE protects against cardiac damage and reduces the development of metastases. TTP488 is an orally bioavailable small molecule inhibitor of RAGE. This project is designed to characterize the role of TTP488 to decrease therapy related cardiac toxicity, and it will provide preliminary data about the safety, tolerability, and pharmacokinetics (PK) of common BC (neo)adjuvant chemotherapy agents in the presence of TTP488. Methods: Eligible patients have stage I-III breast cancer and are planned to receive chemotherapy. Enrolled patients will be assigned to 1 of 4 cohorts based on the chemotherapy regimen assigned for the last 2 doses of planned therapy. In Cohort 1, 6 patients will receive dose dense paclitaxel (ddT). In Cohort 2, 6 patients will receive docetaxel and cyclophosphamide (TC). In Cohort 3, 6 patients will receive docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP). In Cohort 4, 6 patients will receive dose dense doxorubicin and cyclophosphamide (ddAC). All chemotherapy is dosed per standard institutional operational practice. For each patient, the first dose of chemotherapy is given in the absence of study drug to serve as the control for the safety and PK assessments. On day -7, prior to the 2nd dose of chemotherapy, TTP 488, 60mg daily for 6 days followed by 20mg daily, is administered and then subjects receive the 2nd dose of chemotherapy. With each cycle, hs-troponin and B-type natriuretic peptide (BNP) are collected prior to chemotherapy administration, and at 4hrs(hs-troponin only) and 24hrs after chemotherapy administration. With each cycle, PK sampling occurs prior to and immediately after chemotherapy (0hr), 1hr, 4hr, and 24hrs after chemotherapy. Primary objectives are to evaluate the change in high sensitivity troponin level before and during treatment with TTP488 and to evaluate the safety and tolerability of TTP488 when administered with chemotherapy. The secondary objective is to characterize the PK and bioavailability of chemotherapy agents with TTP488. Descriptive statistics for the change in troponin level and safety will be summarized. As of 2/1/24, 4 patients have been enrolled, with 4 undergoing screening. At the completion of this trial, we plan a randomized trial to evaluate the role of TTP488 to decrease cardiotoxicity, cancer related cognitive decline and disease recurrence. Clinical trial information: NCT05256745 .

DNMT3A-mutant clonal haematopoiesis and the recovery of patients with acute ST-elevation myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart foundation Background Haematopoietic stem cells can acquire mutations and produce mutant blood cells. When this occurs in the absence of overt blood disease, it is clonal haematopoiesis of indeterminate potential (CHIP). CHIP is a novel, independent risk factor for ischaemic heart disease and heart failure (HF)(1). However, the molecular mechanisms are poorly understood. Myocardial infarction (MI) is a leading cause of HF due to ventricular remodelling and scar formation(2). We postulate CHIP mutations result in aberrant inflammation that contributes to maladaptive ventricular remodelling following MI. We investigated clinical outcomes and immune cell biology in CHIP and non-CHIP patients (pts) with acute ST-segment elevation MI (STEMI). Purpose Identify and quantify mutations with variant allele frequency (VAF)≥1% in STEMI pts. Assess leukocyte mutational burden. Investigate transcription profiles and leukocyte function in CHIP and non-CHIP STEMI pts. Methods 119 pts diagnosed with STEMI were prospectively recruited (REC19/SC/0362). We collected clinical data, including echocardiogram (echo) parameters and isolated plasma and peripheral blood mononucleated cells (PBMCs) from blood collected 48-96 hours post onset of chest pain. PBMCs were screened for mutations and analysed by flow cytometry. We assessed CHIP VAF with digital droplet PCR in flow-sorted monocytes (Mono), T and B-cells. We performed single-cell RNAseq (10x Genomics) on PBMCs. Luminex or ELISA kits were used to measure plasma proteins. Results 59/119 recruited pts had CHIP (VAF≥1%). CHIP pts were significantly older than non-CHIP pts. DNMT3A was the most commonly mutated gene (28%), followed by TET2 (17%) and ASXL1 (5.3%). 53 pts had impaired LV ejection fraction (LVEF) at admission and a follow-up Echo at median 4.6 months (2.5-8 IQR) post STEMI. They were classified as responder (R) n=24, Δ LVEF≥5% or non-responder (NR) n=29, ΔLVEF<5%. Pts with DNMT3A CHIP were 12 times more likely to be NR (p=0.02). Baseline LVEF was similar in CHIP and non-CHIP pts, but ΔLVEF was significantly reduced in DNMT3A vs non-CHIP pts (p<0.01). DNMT3A mutations were highest in Mono (mean VAF 6.3%), present in B cells (3%) but rare in T cells (1.7%). Within the Mono population, DNMT3A mutant pts had significantly higher proportions of classical Mono compared to non-CHIP (p=0.02). Using scRNAseq, we computed Mono trajectories and differential gene expression. Compared to non-CHIP, DNMT3A-mutant samples upregulated receptor for advanced glycation end-products (RAGE) and toll-like receptor signaling gene signatures. Despite this, we did not observe raised leukocyte count or detect increased levels of inflammatory cytokines in DNMT3A-mutant pts plasma samples. Conclusions DNMT3A CHIP is associated with poor LVEF recovery post-STEMI due to a dysregulated inflammatory response to acute myocardial injury. Furthermore, our data suggests that this may occur via different mechanisms than non-CHIP NR.

Lycopene in Combination with Insulin Triggers Antioxidant Defenses and Increases the Expression of Components That Detoxify Advanced Glycation Products in Kidneys of Diabetic Rats.

Biochemical events provoked by oxidative stress and advanced glycation may be inhibited by combining natural bioactives with classic therapeutic agents, which arise as strategies to mitigate diabetic complications. The aim of this study was to investigate whether lycopene combined with a reduced insulin dose is able to control glycemia and to oppose glycoxidative stress in kidneys of diabetic rats. Streptozotocin-induced diabetic rats were treated with 45 mg/kg lycopene + 1 U/day insulin for 30 days. The study assessed glycemia, insulin sensitivity, lipid profile and paraoxonase 1 (PON-1) activity in plasma. Superoxide dismutase (SOD) and catalase (CAT) activities and the protein levels of advanced glycation end-product receptor 1 (AGE-R1) and glyoxalase-1 (GLO-1) in the kidneys were also investigated. An effective glycemic control was achieved with lycopene plus insulin, which may be attributed to improvements in insulin sensitivity. The combined therapy decreased the dyslipidemia and increased the PON-1 activity. In the kidneys, lycopene plus insulin increased the activities of SOD and CAT and the levels of AGE-R1 and GLO-1, which may be contributing to the antialbuminuric effect. These findings demonstrate that lycopene may aggregate favorable effects to insulin against diabetic complications resulting from glycoxidative stress.

The Gly82Ser polymorphism in the receptor for advanced glycation endproducts increases the risk for coronary events in the general population

The receptor for advanced glycation endproducts (RAGE) has pro-inflammatory and pro-atherogenic effects. Low plasma levels of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands, have been associated with increased risk for major adverse coronary events (MACE) in the general population. We performed a genome-wide association study to identify genetic determinants of plasma sRAGE in 4338 individuals from the cardiovascular arm of the Malmö Diet and Cancer study (MDC-CV). Further, we explored the associations between these genetic variants, incident first-time MACE and mortality in 24,640 unrelated individuals of European ancestry from the MDC cohort. The minor alleles of four single nucleotide polymorphisms (SNPs): rs2070600, rs204993, rs116653040, and rs7306778 were independently associated with lower plasma sRAGE. The minor T (vs. C) allele of rs2070600 was associated with increased risk for MACE [HR 1.13 95% CI (1.02–1.25), P = 0.016]. Neither SNP was associated with mortality. This is the largest study to demonstrate a link between a genetic sRAGE determinant and CV risk. Only rs2070600, which enhances RAGE function by inducing a Gly82Ser polymorphism in the ligand-binding domain, was associated with MACE. The lack of associations with incident MACE for the other sRAGE-lowering SNPs suggests that this functional RAGE modification is central for the observed relationship.

Understanding the interactions between repurposed drugs sertindole and temoporfin with receptor for advanced glycation endproducts: Therapeutic implications in cancer and metabolic diseases.

In the pursuit of novel therapeutic possibilities, repurposing existing drugs has gained prominence as an efficient strategy. The findings from our study highlight the potential of repurposed drugs as promising candidates against receptor for advanced glycation endproducts (RAGE) that offer therapeutic implications in cancer, neurodegenerative conditions and metabolic syndromes. Through careful analyses of binding affinities and interaction patterns, we identified a few promising candidates, ultimately focusing on sertindole and temoporfin. These candidates exhibited exceptional binding affinities, efficacy, and specificity within the RAGE binding pocket. Notably, they displayed a pronounced propensity to interact with the active site of RAGE. Our investigation further revealed that sertindole and temoporfin possess desirable pharmacological properties that highlighted them as attractive candidates for targeted drug development. Overall, our integrated computational approach provides a comprehensive understanding of the interactions between repurposed drugs, sertindole and temoporfin and RAGE that pave the way for future experimental validation and drug development endeavors. We present an integrated approach utilizing molecular docking and extensive molecular dynamics (MD) simulations to evaluate the potential of FDA-approved drugs, sourced from DrugBank, against RAGE. To gain deeper insights into the binding mechanisms of the elucidated candidate repurposed drugs, sertindole and temoporfin with RAGE, we conducted extensive all-atom MD simulations, spanning 500nanoseconds (ns). These simulations elucidated the conformational dynamics and stability of the RAGE-sertindole and RAGE-temoporfin complexes.

Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling.

Astrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence the activity of astrocytes is poorly understood. Receptor interacting protein kinase-3 (RIPK3) signaling has recently been described as a key regulator of neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death has not yet been studied. Here, we used the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine model of Parkinson's disease to show that activation of astrocytic RIPK3 drives dopaminergic cell death and axon damage. Transcriptomic profiling revealed that astrocytic RIPK3 promoted gene expression associated with neuroinflammation and movement disorders, and this coincided with significant engagement of damage-associated molecular pattern signaling. In mechanistic experiments, we showed that factors released from dying neurons signaled through receptor for advanced glycation endproducts to induce astrocytic RIPK3 signaling, which conferred inflammatory and neurotoxic functional activity. These findings highlight a mechanism of neuron-glia crosstalk in which neuronal death perpetuates further neurodegeneration by engaging inflammatory astrocyte activation via RIPK3.

Dl-3-n-butylphthalide promotes microglial phagocytosis and inhibits microglial inflammation via regulating AGE-RAGE pathway in APP/PS1 mice

Alzheimer's disease (AD) stands as the most prevalent neurodegenerative condition worldwide, and its correlation with microglial function is notably significant. Dl-3-n-butylphthalide (NBP), derived from the seeds of Apium graveolens L. (Chinese celery), has demonstrated the capacity to diminish Aβ levels in the brain tissue of Alzheimer’s transgenic mice. Despite this, its connection to neuroinflammation and microglial phagocytosis, along with the specific molecular mechanism involved, remains undefined. In this study, NBP treatment exhibited a substantial improvement in learning deficits observed in AD transgenic mice (APP/PS1 transgenic mice). Furthermore, NBP treatment significantly mitigated the total cerebral Aβ plaque deposition. This effect was attributed to the heightened presence of activated microglia surrounding Aβ plaques and an increase in microglial phagocytosis of Aβ plaques. Transcriptome sequencing analysis unveiled the potential involvement of the AGE (advanced glycation end products) -RAGE (receptor for AGE) signaling pathway in NBP’s impact on APP/PS1 mice. Subsequent investigation disclosed a reduction in the secretion of AGEs, RAGE, and proinflammatory factors within the hippocampus and cortex of NBP-treated APP/PS1 mice. In summary, NBP alleviates cognitive impairment by augmenting the number of activated microglia around Aβ plaques and ameliorating AGE-RAGE-mediated neuroinflammation. These findings underscore the related mechanism of the crucial neuroprotective roles of microglial phagocytosis and anti-inflammation in NBP treatment for AD, offering a potential therapeutic target for the disease.

Availability of receptors for advanced glycation end-products (RAGE) influences differential transcriptome expression in mice exposed to chronic secondhand smoke

The receptor for advanced glycation end-products (RAGE) has a central function in orchestrating inflammatory responses in multiple disease states. RAGE is a transmembrane pattern recognition receptor with particular interest in lung disease due to its naturally abundant pulmonary expression. Our previous research demonstrated an inflammatory role for RAGE following acute exposure to secondhand smoke (SHS). However, chronic inflammatory mechanisms associated with RAGE remain unclear. In this study, we assessed transcriptional outcomes in mice exposed to chronic smoke in the context of RAGE expression. RAGE knockout (RKO) and wild type (WT) mice were exposed to SHS five times weekly via a nose-only delivery system (Scireq Scientific, Montreal, Canada) for six months and compared to mice exposed to room air (RA) only. Total lung RNA was isolated using the Direct-zol RNA MiniPrep kit (Zymo Research, Irvine, CA) and mRNA was purified using poly-T oligo-attached magnetic beads. Synthesis of cDNA, library construction, and sequencing was performed using standard approaches. We specifically compared the phenotypic and environmental conditions from WT+RA, WT+SHS, and RKO+SHS mice. Preprocessing and analysis of RNA-sequencing gene expression data included read trimming, mapping and quantifying the reads to transcripts, and calculating significant differentially expressed genes. The results of these analyses were summarized and compared via Venn diagrams, volcano plots, and functional gene cluster enrichment analysis. Notable gene clusters were specific to cytoskeletal elements, inflammatory signaling, and ciliogenesis. Finally, gene ontologies (GO) demonstrated significant biological pathways that were differentially impacted by the presence of RAGE. These data collectively identify several opportunities to further dissect RAGE signaling in the context of SHS exposure and foreshadow possible therapeutic modalities. This work was supported by funding from the National Institutes of Health (NIH 1R15-HL152257). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Phlorofucofuroeckol-A from Ecklonia Cava attenuates methylglyoxal-induced nephrotoxicity by regulating RAGE and inhibiting the formation of advanced glycosylated end products

Diabetic nephropathy (DN) is the most prevalent and fatal complication of diabetes. The progression of the DN is acceleated by both the formation and accumulation of advanced glycation end products (AGEs). Several synthetic compounds have been proposed to inhibit AGE formation; however, their use is associated with certain side effects. In this study, a natural compound derived from the brown seaweed Ecklonia cava was explored as a natural agent for the prevention and alleviation of DN. Specifically, the protective effect of phlorofucofuroeckol-A (PFFA) was investigated against methylglyoxal-derived AGE-induced apoptosis in mesangial cells. PFFA reduced methylglyoxal glycation and the accumulation of methylglyoxal-derived AGEs. Moreover, PFFA inhibited the interaction between the receptor for AGE (RAGE) and AGEs by forming stable ligands with RAGE. The mechanism underlying the prevention of apoptosis by PFFA was found to involve the inhibition of the phosphorylation of mitogen-activated kinase-related proteins, reversal of the downregulation of intracellular oxidative stress-associated proteins, and normalization of the levels of proteins regulating mitochondria-related intrinsic apoptosis. These findings highlight PFFAs as promising natural therapeutic agents for the prevention or alleviation of DN.

Regulation of the Novel MSTN-GAL3-NOX1 Axis Reverses Obesity-Induced Skeletal Muscle Quality Decline Resulting in Improved Glycemic Indices and Restored Angiogenesis Following Ischemia

Objective: To test the hypothesis that restored muscle quality achieved through myostatin KO improves angiogenesis in obese mice through the resolution of GAL3-NOX1-mediated endothelial dysfunction.Methods: db/db mice, a well-described model of obesity, were crossed with mice lacking myostatin (MSTN KO), a myokine that negatively regulates muscle differentiation and growth, galectin-3 (GAL3 KO), a pro-inflammatory/atherogenic RAGE (receptor for advanced glycation endproducts), and NADPH oxidase-1 (NOX1 KO), a TGF-b-stimulated primary producer of the reactive oxygen species (ROS) O2−, to generate db+/−-MSTN+/−, db+/−-GAL3+/−, and db+/−-NOX1+/− mice. We utilized nuclear magnetic resonance (NMR) spectroscopy to assess skeletal muscle (SKM) lean/fat content in db+/−-MSTN+/− mice. Muscle and plasma lipid content were analyzed via mass spectrometry. Mice were placed in metabolic cages and monitored with CLAMS (Comprehensive Lab Animal Monitoring System) in order to determine their whole-body metabolism. Insulin metabolism indices were determined via appropriate blood and plasma testing kits. Morphology of SKM was determined via microscopy of H&E and Mason’s Trichrome-stained gastrocnemius cross sections. Femoral artery ligation was used to stimulate in vivo angiogenesis in response to hind limb ischemia (HLI); whereas 1mm aortic rings cultured in ECBM (2% FBS) were used to study ex vivo angiogenesis. Gene expression was assessed by RNA-Seq and RT-qPCR. Results: MSTN deletion results in significantly increased SKM mass and restored SKM quality (i.e. morphology and metabolic function) without altering whole-body mass, fat percentage, or activity in obese (db−) mice. We observed that obesity inhibits and MSTN KO restores angiogenesis in both HLI and aortic ring assay models. Previous studies in our lab revealed that MSTN deletion was suffcient to restore endothelial function in db/db mice. Additionally, our lab has shown that GAL3 or NOX1 KO in db/db mice phenocopied the vascular improvements seen in db−-MSTN− mice without restoring SKM size or quality. RNA-Seq and RT-qPCR analysis of SKM and endothelial cells (ECs) revealed significant upregulation of GAL3 and NOX1 expression in db−-MSTN+ mice but not in db−-MSTN− and db−-GAL3− mice. Finally, either GAL3 or NOX1 deletion results in amended angiogenesis in obese animals. Conclusion: In summary, restoration of muscle quality in obese individuals provides potent protection of vascular and metabolic health. A correlate of this improvement is the attenuation of a novel MSTN-GAL3-NOX1 axis, which we have shown to mediate vascular inflammation/redox signaling in obesity. These data suggest that pharmacological targeting of upstream MSTN, downstream GAL3 and/or NOX1 could be effective in treating cardiovascular disease in the context of obesity and metabolic syndrome. A. C. Speese is supported by NIH 1F31HL165858-01A1. D.W. Stepp and D. J. Fulton are supported by NIH 1R01HL147159. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A Protein Complex of Liver Origin Activates a Pro-inflammatory Program That Drives Hepatic and Intestinal Injury in Alcohol-Associated Liver Disease

There is limited information on how the liver-to-gut axis contributes to alcohol-associated liver disease (AALD). We previously identified that high-mobility group box-1 (HMGB1) undergoes oxidation in hepatocytes and demonstrated elevated serum levels of oxidized HMGB1 ([O] HMGB1) in alcoholic patients. Since interleukin-1 beta (IL1B) increases in AALD, we hypothesized hepatocyte-derived [O] HMGB1 could interact with IL1B to activate a pro-inflammatory program that, besides being detrimental to the liver, drives intestinal barrier dysfunction. Alcohol-fed RageΔMye mice exhibited decreased NFκB signaling, a pro-inflammatory signature, and reduced total intestinal permeability, resulting in protection from AALD. Additionally, [O] HMGB1 bound and signaled through the receptor for advanced-glycation end-products (RAGE) in myeloid cells, driving hepatic inflammation, intestinal permeability, and increased portal blood lipopolysaccharide in AALD. We identified that [O] HMGB1 formed a complex with IL1B, which was found in the livers of patients with acute alcoholic hepatitis and mice with AALD. This complex originated from the liver, as it was absent in the intestine when hepatocytes did not produce [O] HMGB1. Mechanistically, the complex bound RAGE in Kupffer cells and macrophages induces a pro-inflammatory program. Moreover, it bound RAGE in intestinal macrophages and epithelial cells, leading to intestinal inflammation, altered intestinal epithelial cell tight junction protein expression, increased intestinal permeability, and elevated portal blood lipopolysaccharide, enhancing AALD pathogenesis. We identified a protein complex of liver origin that amplifies the pro-inflammatory feedback loop in AALD; therefore, targeting this complex could have significant therapeutic potential.

Availability of Receptors for Advanced Glycation End-Products (RAGE) Influences Differential Transcriptome Expression in Lungs from Mice Exposed to Chronic Secondhand Smoke (SHS).

The receptor for advanced glycation end-products (RAGE) has a central function in orchestrating inflammatory responses in multiple disease states including chronic obstructive pulmonary disease (COPD). RAGE is a transmembrane pattern recognition receptor with particular interest in lung disease due to its naturally abundant pulmonary expression. Our previous research demonstrated an inflammatory role for RAGE following acute exposure to secondhand smoke (SHS). However, chronic inflammatory mechanisms associated with RAGE remain ambiguous. In this study, we assessed transcriptional outcomes in mice exposed to chronic SHS in the context of RAGE expression. RAGE knockout (RKO) and wild-type (WT) mice were delivered nose-only SHS via an exposure system for six months and compared to control mice exposed to room air (RA). We specifically compared WT + RA, WT + SHS, RKO + RA, and RKO + SHS. Analysis of gene expression data from WT + RA vs. WT + SHS showed FEZ1, Slpi, and Msln as significant at the three-month time point; while RKO + SHS vs. WT + SHS identified cytochrome p450 1a1 and Slc26a4 as significant at multiple time points; and the RKO + SHS vs. WT + RA revealed Tmem151A as significant at the three-month time point as well as Gprc5a and Dynlt1b as significant at the three- and six-month time points. Notable gene clusters were functionally analyzed and discovered to be specific to cytoskeletal elements, inflammatory signaling, lipogenesis, and ciliogenesis. We found gene ontologies (GO) demonstrated significant biological pathways differentially impacted by the presence of RAGE. We also observed evidence that the PI3K-Akt and NF-κB signaling pathways were significantly enriched in DEGs across multiple comparisons. These data collectively identify several opportunities to further dissect RAGE signaling in the context of SHS exposure and foreshadow possible therapeutic modalities.

Erjingwan and Alzheimer's disease: research based on network pharmacology and experimental confirmation.

Alzheimer's disease (AD), a challenging neurodegenerative condition, has emerged as a significant global public health concern. The Chinese medicine decoction Erjingwan (EJW) has shown promising efficacy in AD treatment, though its mechanism remains unclear. This study aims to elucidate the mechanism by which EJW treats AD through network pharmacology analysis and in vivo experiments. We identified EJW's components using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and determined AD-related targets from various databases. A network comprising herbs-compounds-targets was established, and EJW's core targets were ascertained through protein-protein interaction (PPI) analysis. This study assessed the cognitive abilities of APP/PS1 mice using Morris water mazes and Y mazes, in addition to analyzing blood samples for triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels. Brain tissues were examined histologically with HE staining, Nissl staining, and immunohistochemistry (IHC) for amyloid β-protein (Aβ) detection. Superoxide dismutase (SOD), reactive oxygen species (ROS), Interleukin-1β (IL-1β), and Interleukin-6 (IL-6) levels in the hippocampal region were measured by ELISA. mRNA expression of apolipoprotein A-I (APOA-I), apolipoprotein B (APOB), apolipoprotein E4 (APOE4), advanced glycation end products (AGE), the receptor for AGE (RAGE), and nuclear factor kappa-B (NF-κB) was evaluated by quantitative PCR (q-PCR). Western blotting was used to detect the expression of AGE, RAGE, NF-κB, and Tau protein. Screening identified 57 chemical components and 222 potential targets of EJW. Ten core targets for AD treatment were identified, with enrichment analysis suggesting EJW's effects are related to lipid metabolism and AGEs/RAGE pathways. EJW enhanced learning and memory in APP/PS1 mice, protected neuronal structure in the hippocampal region, reduced Aβ deposition, and altered levels of TG, TC, LDL, IL-1β, and IL-6, and the expression of APOE4, AGEs, RAGE, NF-κB, and Tau protein, while increasing SOD, APOA-I, and APOB mRNA expression. The study identified four core components of EJW-iosgenin, baicalein, beta-sitosterol, quercetin-and ten core targets including AKT1, IL6, VEGFA, TP53, CASP3, for treating AD. Experimental results demonstrate EJW's capacity to modulate lipid profiles, reduce pathological markers such as Aβ1-42, Tau, IL-6, IL-1β, reactive oxygen species, SOD, and enhance cognitive functions in APP/PS1 mice, potentially through inhibiting the AGEs/RAGE/NF-κB pathway.

Modulating intestinal health: Impact of chitooligosaccharide molecular weight on suppressing RAGE expression and inflammatory response in methylglyoxal-induced advanced glycation end-products

The accumulation of methylglyoxal (MGO) produced in high-temperature processed foods and excessive production in the body contributes to intestinal barrier dysfunction. In this study, we investigated the effects of chitooligosaccharides (COSs) of different molecular weights (<1 kDa, 1–3 kDa, 3–5 kDa, 5–10 kDa, and >10 kDa) on MGO-induced intestinal barrier dysfunction. We investigated the effect of COSs on inhibiting intracellular MGO accumulation/MGO-derived AGEs production and regulating the receptor for AGE (RAGE)-mediated downstream protein expression, including proteins related to apoptosis and inflammation, intestinal barrier integrity, and paracellular permeability. Pretreatment with COSs ameliorated MGO-induced increased RAGE protein expression, activation of apoptotic cascade/inflammatory response, loss of intestinal epithelial barrier integrity, and increased paracellular permeability, ameliorating intestinal dysfunction through MGO scavenging. 1–3 kDa COSs most effectively ameliorated MGO-induced intestinal dysfunction. Our results suggest the potential of COSs in improving intestinal health by ameliorating intestinal barrier dysfunction by acting as an MGO scavenger and highlighting the need for the optimization of the molecular weight of COSs to optimize its protective effects.

Oxytocin transported from the blood across the blood-brain barrier by receptor for advanced glycation end-products (RAGE) affects brain function related to social behavior

Oxytocin (OT) is a neuropeptide that primarily functions as a hormone controlling female reproductive processes. Since numerous recent studies have shown that single and repetitive administrations of OT increase trust, social interaction, and maternal behaviors in humans and animals, OT is considered a key molecule that regulates social memory and behavior. Furthermore, OT binds to receptors for advanced glycation end-products (RAGE), and it has been demonstrated that loss of RAGE in the brain vascular endothelial cells of mice fails to increase brain OT concentrations following peripheral OT administration. This leads to the hypothesis that RAGE is involved in the direct transport of OT, allowing it access to the brain by transporting it across the blood–brain barrier; however, this hypothesis is only based on limited evidence. Herein, we review the recent results related to this hypothesis, such as the mode of transport of OT in the blood circulation to the brain via different forms of RAGE, including membrane-bound full-length RAGE and soluble RAGE. We further review the modulation of brain function and social behavior, which seem to be mediated by RAGE-dependent OT. Overall, this review mostly confirms that RAGE enables the recruitment of circulating OT to the brain, thereby influencing social behavior. The requirement for further studies considering the physiological aspects of RAGE is also discussed.

Tempeh-Based Supplement Decreases Blood Glucose Levels Through Inhibiting Rage and NF-κB Activity in Type 2 Diabetes Mellitus Mice Model

Objective: Hyperglycemia promotes inflammation through inducing the formation of AGE products, which bind with receptor AGE (RAGE) products in cell membranes, leading to the activation of necrosis factor–kappa beta (NF-κB). This study aimed to analyze the effects of tempeh-based supplement (TBS) preparations of γ-amino butyric acid (GABA) tempeh against mRNA expressions of RAGE and NF-κB on the pancreas of a type 2 diabetes mellitus (DM) mice model. Material and Methods: This research was a quasi-experiment, with pre and post-tests with a control design for blood glucose levels; and post-test only utilizing control for mRNA RAGE and NF-κB expressions. A total of 30 male mice, 8-10 weeks old, weighing 20-25 g were divided into 6 treatment groups: non-diabetic, Diabetic, Diabetic+metformin, Diabetic+TBS 10 mg/100 g BW, Diabetic+TBS 20 mg/100 g BW, and Diabetic+TBS 40 mg/100 g BW. STZ induction once a day for two days was preceded by NA to create a DM mice model; meanwhile, TBS was administrated once a day for 21 days.Results: The mean difference of fasting glucose levels in the diabetic+TBS 40 mg/100 g BW group was the highest when compared to the diabetic group (159.52±1.85) mg/dL. One-way ANOVA revealed statistically significant differences in fasting glucose levels, RAGE and NF-κB expressions in the Diabetic+TBS group at various dosage levels compared to the diabetic control group. Relative mRNA expressions of RAGE and NF-κB were downregulated in the treatment group compared to the diabetic control group. Conclusion: TBS can decrease fasting blood glucose levels and downregulate relative mRNA expressions of RAGE and NF-κB in type 2 DM mice.

Frailty Influences the Relationship between the Soluble Receptor for Advanced Glycation-End Products and Mortality in Older Adults with Diabetes Mellitus

Introduction: Frailty is prevalent among older adults with diabetes mellitus. Elevated serum levels of the soluble receptor for advanced glycation-end products (sRAGE) predict mortality in frail older adults. The evidence that sRAGE is also related to higher mortality in older adults with diabetes mellitus is inconsistent. Therefore, this study explored if frailty status influences the relationship between sRAGE and mortality in older adults with this condition. Methods: We analysed data of 391 participants with diabetes mellitus (median age, 76 years) from four European cohorts enrolled in the FRAILOMIC project. Frailty was evaluated at baseline using Fried’s criteria. Serum sRAGE was determined by ELISA. Participants were stratified by frailty status (n = 280 non-frail and 111 frail). Multivariate Cox proportional hazards regression and Kaplan-Meier survival analysis were used to assess the relationship between sRAGE and mortality. Results: During 6 years of follow-up, 98 participants died (46 non-frail and 52 frail). Non-survivors had significantly higher baseline levels of sRAGE than survivors (median [IQR]: 1,392 [962–2,043] pg/mL vs. 1,212 [963–1,514], p = 0.008). High serum sRAGE (>1,617 pg/mL) was associated with increased mortality in the whole diabetes sample after adjustment for relevant confounders (HR 2.06, 95% CI: 1.36–3.11, p < 0.001), and there was an interaction between sRAGE and frailty (p = 0.006). Accordingly, the association between sRAGE and mortality was stronger in the frail group compared to the non-frail group (HR 2.52, 95% CI: 1.30–4.90, p = 0.006 vs. HR 1.71, 95% CI: 0.91–3.23, p = 0.099, respectively). Likewise, Kaplan-Meier curves showed a significant difference in survival rates between frail participants with high sRAGE and those with low sRAGE (p = 0.001), whereas no survival difference was seen in the non-frail group (p = 0.09). Conclusions: Frailty status influences the relationship between sRAGE and mortality in older adults with diabetes mellitus. Determination of sRAGE in this population could be a useful tool for risk stratification.