Astragaloside IV promotes the pyroptosis of airway smooth muscle cells in childhood asthma by suppressing HMGB1/RAGE axis to inactivate NF-κb pathway.

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

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

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

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

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

Brain and Lung Biomarker Responses to Hyperoxic Hypobaric Decompression.

INTRODUCTION: Biomarker responses to intensive decompression indicate systemic proinflammatory responses and possible neurological stress. To further investigate responses, 12 additional brain and lung biomarkers were assayed.METHODS: A total of 15 healthy men (20 to 50 yr) undertook consecutive same-day ascents to 25,000 ft (7620 m), following denitrogenation, breathing 100% oxygen. Venous blood was sampled at baseline (T0), after the second ascent (T8), and next morning (T24). Soluble protein markers of brain and lung insult were analyzed by enzyme-linked immunosorbent assay with plasma microparticles quantified using flow cytometry.RESULTS: Levels of monocyte chemoattractant protein-1 and high mobility group box protein 1 were elevated at T8, by 36% and 16%, respectively, before returning to baseline. Levels of soluble receptor for advanced glycation end products fell by 8%, recovering by T24. Brain-derived neurotrophic factor rose by 80% over baseline at T24. Monocyte microparticle levels rose by factors of 3.7 at T8 and 2.7 at T24 due to early and late responses in different subjects. Other biomarkers were unaffected or not detected consistently.DISCUSSION: The elevated biomarkers at T8 suggest a neuroinflammatory response, with later elevation of brain-derived neurotrophic factor at T24 indicating an ongoing neurotrophic response and incomplete recovery. A substantial increase at T8 in the ratio of high mobility group box protein 1 to soluble receptor for advanced glycation end products suggests this axis may mediate the systemic inflammatory response to decompression. The mechanism of neuroinflammation is unclear but elevation of monocyte microparticles and monocyte chemoattractant protein-1 imply a key role for activated monocytes and/or macrophages.Connolly DM, Madden LA, Edwards VC, Lee VM. Brain and lung biomarker responses to hyperoxic hypobaric decompression. Aerosp Med Hum Perform. 2024; 95(9):667-674.

Antox targeting AGE/RAGE cascades to restore submandibular gland viability in rat model of type 1 diabetes.

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

Relationship between high-mobility group box-l and cognitive impairments induced by myocardial ischemia-reperfusion in elderly rats.

BACKGROUND: Myocardial ischemia-reperfusion (MI/R) can lead to structural and functional abnormalities in the hippocampal neurons of the brain. High-mobility group box-l (HMGB1) is implicated in the activation of immune cells and the stimulation of inflammatory responses. However, the specific role of HMGB1 in cognitive impairment induced by MI/R in elderly rats has yet to be elucidated. METHODS: Elderly rats underwent surgical procedures to induce MI/R. To evaluate the learning and memory abilities of these rats, a water maze test and a new-object recognition test were administered. Nissl staining was utilised to examine hippocampal neuron damage. Enzyme-linked immunosorbent assay, western blotting, and real-time quantitative polymerase chain reaction (RT-qPCR) analyses were conducted to measure the expression levels of HMGB1, inflammatory cytokines, and molecular pathways. RESULTS: The study found that MI/R induced cognitive impairment in elderly rats. There was an observed increase in serum HMGB1 levels, along with elevated concentrations of pro-inflammatory cytokines in the plasma and hippocampus, accompanied by a decrease in anti-inflammatory cytokines. Moreover, substantial damage was evident in the hippocampal neurons of rats exposed to MI/R. In the brains of these rats, there was an increased expression of HMGB1, the receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), phosphorylated p65, interleukin-1ß (IL-1ß), IL-6, IL-23, tumour necrosis factor-α (TNF-α), caspase-3, and Bax. In contrast, the expression of B-cell lymphoma 2 was decreased. The RT-qPCR analyses indicated elevated levels of HMGB1, RAGE, TLR4, IL-1ß, IL-6, IL-23, TNF-α, caspase-3, and Bax mRNA. CONCLUSION: The increased concentration of serum and hippocampal inflammatory factors in the brains of elderly rats subjected to MI/R suggests that cognitive impairment may be induced through the activation of the HMGB1/TLR4/NF-κB signalling pathway.

A One-Month Advanced Glycation End Products-Restricted Diet Improves CML, RAGE, Metabolic and Inflammatory Profile in Patients with End-Stage Renal Disease Undergoing Haemodialysis.

Exogenous and endogenous advanced glycation end products (AGEs) contribute to the pathogenesis and progression of renal disease. This is a one-month controlled dietary counseling trial that restricts nutritional AGEs in patients with end-stage renal disease (ESRD) undergoing haemodialysis (n = 22 participants in the intervention and n = 20 participants in the control group). Haematological, biochemical markers, the soluble form of the receptor for AGEs (sRAGE), and carboxymethyl lysine (CML) were measured at baseline and at follow-up. Mononuclear cells were isolated and the protein expression of RAGE and the inflammatory marker COX-2 was measured using Western immunoblotting. The intervention group presented a lower increase in CML compared to the control group (12.39% median change in the intervention vs. 69.34% in the control group, p = 0.013), while RAGE (% mean change -56.54 in the intervention vs. 46.51 in the control group, p < 0.001) and COX-2 (% mean change -37.76 in the intervention vs. 0.27 in the control group, p < 0.001) were reduced compared to the control group. sRAGE was reduced in both groups. In addition, HbA1c (at two months), total cholesterol, and triglycerides were reduced in the intervention versus the control group. The adoption of healthy cooking methods deserves further research as a possible way of modulating inflammatory markers in patients with CKD.

RAGE mediates hippocampal pericyte responses and neurovascular unit lesions after TBI.

Traumatic brain injury impairs brain function through various mechanisms. Recent studies have shown that alterations in pericytes in various diseases affect neurovascular function, but the effects of TBI on hippocampal pericytes remain unclear. Here, we investigated the effects of RAGE activation on pericytes after TBI using male C57BL/6 J mice. Hippocampal samples were collected at different time points within 7 days after TBI, the expression of PDGFR-ß, NG2 and the HMGB1-S100B/RAGE signaling pathway was assessed by Western blotting, and the integrity of the hippocampal BBB at different time points was measured by immunofluorescence. RAGE-associated BBB damage in hippocampal pericytes occurred early after cortical impact. By culturing primary mouse brain microvascular pericytes, we determined the different effects of HMGB1-S100B on pericyte RAGE. To investigate whether RAGE blockade could protect neurological function after TBI, we reproduced the process of CCI by administering FPS-ZM1 to RAGE-/- mice. TEM images and BBB damage-related assays showed that inhibition of RAGE resulted in a significant improvement in the number of hippocampal vascular basement membranes and tight junctions and a reduction in perivascular oedema compared with those in the untreated group. In contrast, mouse behavioural testing and doublecortin staining indicated that targeting the HMGB1-S100B/RAGE axis after CCI could protect neurological function by reducing pericyte-associated BBB damage. In conclusion, the present study provides experimental evidence for the strong correlation between the pericyte HMGB1-S100B/RAGE axis and NVU damage in the hippocampus at the early stage of TBI and further demonstrates that pericyte RAGE serves as an important target for the protection of neurological function after TBI.

RAGE/DIAPH1 and atherosclerosis through an evolving lens: Viewing the cell from the "Inside - Out".

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

New Glycotoxin Inhibitor from Sesuvium sesuvioides Mitigates Symptoms of Insulin Resistance and Diabetes by Suppressing AGE-RAGE Axis in Skeletal Muscle.

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

Liraglutide, a glucagon-like peptide-1 receptor agonist, ameliorates inflammation and apoptosis via inhibition of receptor for advanced glycation end products signaling in AGEs induced chondrocytes.

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

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.

Breath of fresh air: Investigating the link between AGEs, sRAGE, and lung diseases.

Advanced glycation end products (AGEs) are compounds formed via non-enzymatic reactions between reducing sugars and amino acids or proteins. AGEs can accumulate in various tissues and organs and have been implicated in the development and progression of various diseases, including lung diseases. The receptor of advanced glycation end products (RAGE) is a receptor that can bind to advanced AGEs and induce several cellular processes such as inflammation and oxidative stress. Several studies have shown that both AGEs and RAGE play a role in the pathogenesis of lung diseases, such as chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, and acute lung injury. Moreover, the soluble form of the receptor for advanced glycation end products (sRAGE) has demonstrated its ability to function as a decoy receptor, possessing beneficial characteristics such as anti-inflammatory, antioxidant, and anti-fibrotic properties. These qualities make it an encouraging focus for therapeutic intervention in managing pulmonary disorders. This review highlights the current understanding of the roles of AGEs and (s)RAGE in pulmonary diseases and their potential as biomarkers and therapeutic targets for preventing and treating these pathologies.

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.

Lindera obtusiloba Blume Alleviates Non-Alcoholic Fatty Liver Disease Promoted by Nε-(carboxymethyl)lysine.

Non-alcoholic fatty liver disease (NAFLD) is a major issue because it is closely associated with metabolic diseases. Advanced glycation end products (AGEs) are implicated as risk factors for steatosis during NAFLD progression. AGEs influence NAFLD progression through a receptor-independent pathway involving AGE cross-link formation and a receptor-dependent pathway that binds to receptors like receptors for advanced glycation end products (RAGE). The objectives of this study are to examine the effect of Lindera obtusiloba Blume (LO) on NAFLD promoted by Nε-(carboxymethyl)lysine (CML), one of the most common dietary AGEs. The anti-glycation effects of LO were evaluated by inhibiting the AGEs formation and AGEs-collagen cross-links breaking. The efficacy of LO against NAFLD promoted by CML was assessed using both in vitro and in vivo models. NAFLD was induced in mice by feeding a high-fat diet and orally administering CML over a period of 12 weeks, and the effects of LO on lipid metabolism and its regulatory mechanisms were investigated. LO showed the effect of inhibited AGEs formation and breakage, and collagen cross-linking. Fed a high-fat diet with administered CML by gavage, LO administration resulted in a reduction in body weight, fat mass, serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels. LO reduced hepatic CML accumulation and RAGE expression in mice fed a high-fat diet and orally administered CML. LO alleviated hepatic steatosis accompanied by lipid accumulation and histological damage by suppressing the expression of sterol regulatory element-binding protein 1c, carbohydrate response element binding protein, fatty acid synthase, stearoyl-CoA desaturase1, tumor necrosis factor-α, and interleukin-1ß. LO alleviated the MAPK/NF-κB expression by attenuating CML and RAGE expression. Taken together, our results demonstrate that LO alleviates the progression of NAFLD by lowering the levels of AGEs by downregulating CML/RAGE expression.

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.

HMGB1 as an extracellular pro-inflammatory cytokine: Implications for drug-induced organic damage.

Drug-induced organic damage encompasses various intricate mechanisms, wherein HMGB1, a non-histone chromosome-binding protein, assumes a significant role as a pivotal hub gene. The regulatory functions of HMGB1 within the nucleus and extracellular milieu are interlinked. HMGB1 exerts a crucial regulatory influence on key biological processes including cell survival, inflammatory regulation, and immune response. HMGB1 can be released extracellularly from the cell during these processes, where it functions as a pro-inflammation cytokine. HMGB1 interacts with multiple cell membrane receptors, primarily Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE), to stimulate immune cells and trigger inflammatory response. The excessive or uncontrolled HMGB1 release leads to heightened inflammatory responses and cellular demise, instigating inflammatory damage or exacerbating inflammation and cellular demise in different diseases. Therefore, a thorough review on the significance of HMGB1 in drug-induced organic damage is highly important for the advancement of pharmaceuticals, ensuring their effectiveness and safety in treating inflammation as well as immune-related diseases. In this review, we initially outline the characteristics and functions of HMGB1, emphasizing their relevance in disease pathology. Then, we comprehensively summarize the prospect of HMGB1 as a promising therapeutic target for treating drug-induced toxicity. Lastly, we discuss major challenges and propose potential avenues for advancing the development of HMGB1-based therapeutics.

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.

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.