The advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) axis is a pro-inflammatory pathway promoting endothelial dysfunction and vascular remodelling. The soluble RAGE form (sRAGE), by blocking circulating AGE, protects against AGE-induced detrimental effects. We investigated the role of sRAGE as a marker of high blood pressure and hypertension risk in children.

sRAGE was quantified in 284 children/adolescents (mean age (SD) 11.1 (2.5); 52.1 % male) referred for high-normal blood pressure (systolic and/or diastolic values ≥ 90th, but both <95th percentile) or hypertension (systolic and/or diastolic blood pressure ≥95th percentile) and/or other cardiovascular risk factors (excess weight, dyslipidaemia and insulin resistance). In 22.2 % of the sample, systolic and/or diastolic blood pressure values were above the 90th percentile. The prevalence of excess weight (overweight/obesity), central obesity (waist-to-height-ratio >50%), and insulin resistance (HOMA-index ≥90th percentile) was high (82.7 %, 70.8 %, and 70.5 %, respectively). Few children had altered LDL cholesterol, triglyceride, and HDL cholesterol values (15.7 %, 15.4 %, and 13.6 %, respectively). The lowest sRAGE tertile was associated with the highest risk of having hypertension (p = 0.028), obesity (p < 0.001), central obesity (p = 0.007), and insulin resistance (p < 0.001). sRAGE levels were inversely associated with systolic blood pressure (p < 0.01) and BMI (p = 0.022) z-scores and waist-to-height-ratio (p = 0.001). sRAGE values were inversely associated with the presence of hypertension (p = 0.036) and obesity (p = 0.038).

The independent relationship between sRAGE, systolic blood pressure, and hypertension in children suggests that the AGE-RAGE axis may be altered early in life, and that sRAGE could be a compelling marker for pediatric cardiovascular risk stratification.

Mitochondrial dysfunction and mitophagy are closely linked with human diseases such as neurodegenerative diseases, metabolic diseases, and cancer. High-mobility group box 1 (HMGB1) has been shown to mediate a wide range of pathological responses by binding with the receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs). Extracellular HMGB1 and its ligand RAGE stimulate the growth, metastasis, invasiveness, and treatment resistance of different cancer cells. Through extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, HMGB1 and RAGE lead to the phosphorylation of Drp1-S616 and Drp1-mediated mitochondrial fission, which consequently causes autophagy. Although the structure of the RAGE and HMGB1 complex is not clearly known, the complex has emerged as a potential therapeutic target. In the present study, the structure of the RAGE and HMGB1 complex was determined at a resolution of 5.19 Å using cryogenic electron microscopy. The structure revealed that the residues P66, G70, P71, S74, and R77 in RAGE and E145, K146, E153, and E156 in HMGB1 were the sites of interaction between the two proteins. Additionally, an HMGB1 peptide (151 LKEKYEK 157) was synthesized based on the RAGE-HMGB1 complex. We investigated the inhibitory function of the HMGB1 peptide and demonstrated that it inhibits tumor growth, metastasis, and invasion by binding to the RAGE protein in lung cancers. The HMGB1 peptide significantly suppressed mitochondrial dysfunction and the initiation of autophagy. Furthermore, the HMGB1 peptide dramatically reduced cell viability, migration, and mitophagy in the colorectal and pancreatic cancer cell lines HCT-116 and AsPC-1, respectively.

Many gastroesophageal reflux disease (GORD) patients have heartburn symptoms despite PPI treatment, potentially via esophageal mucosa exposure to weakly acidic bile salts, leading to oxidative stress. High mobility group box 1 (HMGB1) is a nuclear protein secreted during oxidative stress that binds to receptors including TLR2, TLR4, and RAGE, inducing inflammatory signaling. We describe the release and potential downstream effects of HMGB1 in GORD.

Esophageal biopsies were obtained from healthy controls (HC), functional heartburn (FH), non-erosive reflux disease (NERD), and erosive reflux disease (ERD) patients. Biopsies were analyzed by RNA-sequencing, and the expression of TLR2, TLR4, and RAGE was assessed with immunohistochemistry. NE-1 cells were challenged with pH 5 media and/or 500 μM deoxycholate (DCA), with/without 2-h 5 or 50 μM curcumin pre-treatment. HMGB1 translocation was measured with immunofluorescence and release with ELISA.

HMGB1, alongside 12 additional oxidative stress-associated genes, is over-expressed in NERD and ERD patients compared to HC (adjusted p < 0.05). Weakly acidic bile salt (pH 5 + DCA) stimulated HMGB1 translocation (p < 0.0001) and release from NE-1 cells (p < 0.001), but ameliorated with curcumin pre-treatment. ERD biopsies had increased DAPI+TLR4+ cells (p < 0.05) and TLR4 fluorescence intensity (p < 0.05), compared to HC. RAGE was expressed on CD45+ cells, and the number of RAGE+CD45+ cells was higher in ERD compared to HC (p < 0.05).

Release of HMGB1 from esophageal epithelial cells by weakly acidic bile salts, inhibited by curcumin, and increased expression of TLR4 and RAGE in ERD mucosa suggest this pathway has a role in GORD. Modulating HMGB1 activity may be a strategy for treating recurrent symptoms.

The interaction between advanced glycation end products (AGEs) and their RAGE receptor (AGEs/RAGE axis) triggers several signaling pathways that lead to the development of diabetic nephropathy (DN). One of the most studied AGEs is Nε-(1-Carboxymethyl)-L-lysine (CML). Spinacia oleracea is an edible plant with beneficial health properties, but its effect on the AGE/RAGE axis in kidney damage is unknown.

We aimed to investigate the functional role of spinach methanolic extract (SME) on kidney damage in diabetic rats associated with the CML/RAGE axis.

Forty adult male Wistar rats were used in this study and divided into four groups: control rats (CTRL), SME-administered CTRL (400 mg/kg; SME), streptozotocin-induced diabetic nephropathy rats (STZ), and SME-treated STZ (STZ-SME); treatments were administered daily. After 12 weeks, serum AGEs, creatinine in urine, and lipid peroxidation in kidneys were measured. The distribution and expression levels of inflammatory and fibrotic mediators and RAGE signaling were evaluated through immunohistochemistry (NOX4, CML, RAGE, nuclear NF-κB, TNF-α, IL-1β, TGF-β1, SMAD2/3, CTGF, and a-SMA) and immunolocalization of CML/RAGE.

Glycoside flavonoid derivatives, such as patuletin and spinacetin, were primarily identified in the extract. Kidneys from the STZ group showed altered morphology, dead cells in the proximal tubules, and increased oxidative stress markers; notably, these effects were improved by SME treatment (STZ-SME). The STZ-SME group showed a lower staining intensity for CML and RAGE, which was associated with a decrease in the expression of inflammatory and fibrotic factors compared with the STZ group. In all groups, the distribution of these markers varied among proximal tubule, glomerular, and interstitial cells.

SME treatment may help to prevent or delay kidney damage in diabetic rats by regulating inflammatory and fibrotic processes associated with the AGEs/RAGE pathway, a mechanism involved in the development of nephropathy.

Acute Lung Injury (ALI) involves diffuse alveolar damage, neutrophil infiltration, and pulmonary edema, with unacceptable mortality. Bacterial lipopolysaccharide (LPS) activates inflammatory pathways in ALI, which are then regulated by transcriptional and post-transcriptional pathways to affect gene expression. RNA methylation, N6-methyladenosine, is the main m6A mRNA modification that controls the expression of various genes in different environments. There are very few facts about LPS's effect on m6A RNA methylation. This study will explore the m6A RNA methylation landscape in lung endothelial cells (ECs) to understand its role in lung inflammation. In this study, lung endothelial cells were treated with LPS, and the dynamics of mRNA m6A methylation were examined through m6A-methylated RNA sequencing. RNA abundance was measured with RNA-seq, and global protein expression and m6A-binding proteins were identified using mass spectrometry (MS). Following LPS treatment, global m6A methylation levels increased along with the upregulation and nuclear translocation of METTL3 protein, while demethylase activity remained unchanged. METTL3 drove LPS-induced m6A methylation and endothelial injury, as shown by selective METTL3 siRNA and the inhibitor STM2457. MeRIP-seq analyses revealed increased m6A sites near the 5' UTR in LPS-treated cells, with m6A methylation correlating positively with gene expression. The metabolic and apoptosis pathways were shown to be more enriched in different types of methylated exons. METTL3-mediated m6A methylation targeted inflammatory genes, enhancing protein expression in chemokine signaling and MAPK pathways. STM2457 effectively mitigated LPS- or CLP-induced experimental ALI. According to this paper, LPS-mediated m6A RNA methylation is described in terms of genomic structure. Modulation of m6A methylation exerts influence over LPS-mediated endothelial gene expression and the ensuing inflammatory response.

The oral bacterium Tannerella forsythia is associated with periodontitis, an inflammatory disease affecting tooth-supporting tissues. The bacterium produces a dicarbonyl compound, methylglyoxal (MGO), whose levels correlate with the severity of periodontitis. MGO can induce inflammation directly or via the generation of glycation products called advanced glycation end products (AGEs). T. forsythia-produced MGO has been shown to cause tissue collagen glycation, which in turn can induce pro-inflammatory cytokine secretion in monocytes via receptor for advanced glycation end product (RAGE) receptor activation. The current study investigated the impact of T. forsythia-secreted MGO on human gingival fibroblasts and endothelial cells. For assessing the in vivo impact of T. forsythia-secreted MGO, we employed an oral gavage-induced mouse model of periodontitis utilizing the wild-type and MGO-deficient strains of T. forsythia. Our results showed that the apoptotic activity was enhanced, and cell migration was reduced in fibroblasts exposed to collagen treated with the T. forsythia wild-type culture supernatant. Moreover, monocyte binding, reactive oxygen species production, and inflammatory cytokine secretion were increased in fibroblasts, and neutrophil transendothelial migration was enhanced in response to the T. forsythia wild type-treated collagen. In vivo, increased AGE accumulation in gingival tissues with increased alveolar bone loss was observed in wild-type T. forsythia as compared to the MGO-deficient strain-infected mice. These data demonstrated that T. forsythia-secreted MGO contributes to periodontal tissue destruction by mitigating gingival fibroblast-mediated tissue healing and promoting endothelial cell dysfunction. These findings provide a basis for targeting the T. forsythia-associated AGE-RAGE axis in alleviating periodontitis.

Glioblastoma is the most aggressive and lethal cancer of the central nervous system, presenting substantial treatment challenges. The current standard treatment, which includes surgical resection followed by temozolomide and radiation, offers limited success. While immunotherapies, such as immune checkpoint inhibitors, have proven effective in other cancers, they have not demonstrated significant efficacy in GBM. Emerging research highlights the pivotal role of tumor-associated macrophages (TAMs) in supporting tumor growth, fostering treatment resistance, and shaping an immunosuppressive microenvironment. Preclinical studies show promising results for therapies targeting TAMs, suggesting potential in overcoming these barriers. TAMs consist of brain-resident microglia and bone marrow-derived macrophages, both exhibiting diverse phenotypes and functions within the tumor microenvironment. This review delves into the origin, heterogeneity, and functional roles of TAMs in GBM, underscoring their dual roles in tumor promotion and suppression. It also summarizes recent progress in TAM-targeted therapies, which may, in combination with other treatments like immunotherapy, pave the way for more effective and personalized strategies against this aggressive malignancy.

This study investigated the relationship between the neutrophil-to-lymphocyte ratio (N/LPR) and its variability ratio (N/LPRR) with 30-day and 1-year mortality outcomes.

A total of 7,443 patients from the MIMIC-IV 2.2 database were included, with 1,765 having multiple N/LPR measurements. Mortality at 1 year and within 30 days served as the primary endpoints. Patients were stratified into four groups according to baseline N/LPRR quartiles. Receiver operating characteristic (ROC) curves assessed the predictive value of N/LPR and N/LPRR for mortality. Kaplan-Meier analysis estimated the risk of mortality events, while restricted cubic spline (RCS) analysis explored the non-linear associations between N/LPR, N/LPRR, and mortality. Cox proportional hazards regression identified the relationship between N/LPRR and all-cause mortality.

A total of 792 cases of 1-year mortality (44.9%) were recorded, with 437 deaths (24.8%) occurring within 30 days. ROC analysis revealed that N/LPRR outperformed N/LPR in predicting adverse outcomes. Higher N/LPR and N/LPRR were associated with increased mortality rates. RCS analysis indicated significant non-linear relationships between N/LPR, N/LPRR, and mortality risk (both p-values for nonlinearity < 0.001). Subgroup analyses confirmed the robustness of these findings.

In conclusion, elevated N/LPR and N/LPRR are linked to 30-day and 1-year mortality in patients with sepsis. N/LPRR, with its heightened sensitivity, offers clinicians valuable prognostic information on sepsis severity and progression.

Opioids are often prescribed for pain relief, yet they pose risks such as addiction, dependence, and overdose. Pregnant women have unique vulnerabilities to opioids and infants born to opioid-exposed mothers could develop neonatal opioid withdrawal syndrome (NOWS). The study of opioid-induced epigenetic changes in chronic pain is in its early stages. This study aimed to identify epigenetic changes in genes associated with chronic pain resulting from maternal opioid exposure during pregnancy.

We analyzed DNA methylation of chronic pain-related genes in 96 placental tissues using Illumina Infinium Methylation EPIC BeadChips. These samples comprised 32 from mothers with infants prenatally exposed to opioids who needed pharmacologic NOWS management (+Opioids/+NOWS), 32 from mothers with prenatally opioid-exposed infants not needing NOWS pharmacologic treatment (+Opioids/-NOWS), and 32 from unexposed control subjects (-Opioids/-NOWS).

The study identified significant methylation changes at 111 CpG sites in pain-related genes among opioid-exposed infants, with 54 CpGs hypomethylated and 57 hypermethylated. These genes play a crucial role in various biological processes, including telomere length regulation (NOS3, ESR1, ESR2, MAPK3); inflammation (TNF, MAPK3, IL1B, IL23R); glucose metabolism (EIF2AK3, CACNA1H, NOTCH3, GJA1); ion channel function (CACNA1C, CACNA1H, CLIC4, KCNQ5); autophagy (CTSS, ULK1, ULK4, ATG5); oxidative stress (NGF, NRG1, OPRM1, ATP1A2); aging (GRIA1, NGFR, PRLR, EIF4E); cytokine activity (TRPV4, RUNX1, CXCL8, IL18R1); and the risk of suicide (ADORA2A, ANKK1, GABRG2, IGSF9B). These epigenetic changes may influence 48 signaling pathways-including cAMP, MAPK, GnRH secretion, estrogen signaling, morphine addiction, circadian rhythms, and insulin secretion-profoundly affecting pain and inflammation-related processes.

The identified methylation alterations may shed light on pain, neurodevelopmental changes, and other biological mechanisms in opioid-exposed infants and mothers with OUD, offering insights into NOWS and maternal-infant health. These findings may also pave the way for targeted interventions and improved pain management, highlighting the potential for integrated care strategies to address the interconnected health of mothers and infants.

In the field of treatment and prevention of immune-related bone diseases, significant challenges persist, necessitating the urgent exploration of new and effective treatment methods. However, most existing Mendelian randomization (MR) studies are confined to a single analytical approach, which limits the comprehensive understanding of the pathogenesis and potential therapeutic targets of these diseases. In light of this, we propose the hypothesis that genetic variations in specific plasma proteins have a causal relationship with immune-related bone diseases through the MR mechanism, and that key therapeutic targets can be accurately identified using an integrated multi-omic analysis approach. This study comprehensively applied a variety of analytical methods. Firstly, the protein quantitative trait locus (pQTLs) data from two large plasma protein databases and the Genome-Wide Association Study (GWAS) data of nine immune-related bone diseases were used for Mendelian randomization (MR) analysis. At the same time, we employed the Summary-based Mendelian Randomization (SMR) method, combined with the Bayesian colocalization analysis method of coding genes, as well as the Linkage Disequilibrium Score Regression (LDSC) analysis method based on genetic correlation analysis, as methods to verify the genetic association between genes and complex diseases, thus comprehensively obtaining positive results. In addition, a Phenome-wide Association Study (PheWAS) was conducted on significantly positive genes, and their expression patterns in different tissues were also explored. Subsequently, we integrated Protein-Protein Interaction (PPI) network analysis, Gene Ontology (GO) analysis. Finally, based on the above analytical methods, drug prediction and molecular docking studies were carried out with the aim of accurately identifying key therapeutic targets. Through a comprehensive analysis using four methods, namely the Mendelian randomization (MR) analysis study, Summary-based Mendelian Randomization (SMR) analysis study, Bayesian colocalization analysis study, and Linkage Disequilibrium Score Regression (LDSC) analysis study. We found that through MR, SMR, and combined with Bayesian colocalization analysis, an association was found between rheumatoid arthritis (RA) and HDGF. Using the combination of MR and Bayesian colocalization analysis, as well as LDSC analysis, it was concluded that RA was related to CCL19 and TNFRSF14. Based on the methods of MR and Bayesian colocalization, an association was found between GPT and Crohn's disease-related arthritis, and associations were found between BTN1A1, EVI5, OGA, TNFRSF14 and multiple sclerosis (MS), and associations were found between ICAM5, CCDC50, IL17RD, UBLCP1 and psoriatic arthritis (PsA). Specifically, in the MR analysis of RA, HDGF (P_ivw = 0.0338, OR = 1.0373, 95%CI = 1.0028-1.0730), CCL19 (P_ivw = 0.0004, OR = 0.3885, 95%CI = 0.2299-0.6566), TNFRSF14 (P_ivw = 0.0007, OR = 0.6947, 95%CI = 0.5634-0.8566); in the MR analysis of MS, BTN1A1 (P_ivw = 0.0000, OR = 0.6101, 95%CI = 0.4813-0.7733), EVI5 (P_ivw = 0.0000, OR = 0.3032, 95%CI = 0.1981-0.4642), OGA (P_ivw = 0.0005, OR = 0.4599, 95%CI = 0.2966-0.7131), TNFRSF14 (P_ivw = 0.0002, OR = 0.4026, 95%CI = 0.2505-0.6471); in the MR analysis of PsA, ICAM5 (P_ivw = 0.0281, OR = 1.1742, 95%CI = 1.0174-1.3552), CCDC50 (P_ivw = 0.0092, OR = 0.7359, 95%CI = 0.5843-0.9269), IL17RD (P_ivw = 0.0006, OR = 0.7887, 95%CI = 0.6886-0.9034), UBLCP1 (P_ivw = 0.0021, OR = 0.6901, 95%CI = 0.5448-0.8741); in the MR analysis of Crohn's disease-related arthritis, GPT (P_ivw = 0.0006, OR = 0.0057, 95%CI = 0.0003-0.1111). In the Bayesian colocalization analysis of RA, HDGF (H4 = 0.8426), CCL19 (H4 = 0.9762), TNFRSF14 (H4 = 0.8016); in the Bayesian colocalization analysis of MS, BTN1A1 (H4 = 0.7660), EVI5 (H4 = 0.9800), OGA (H4 = 0.8569), TNFRSF14 (H4 = 0.8904); in the Bayesian colocalization analysis of PsA, ICAM5 (H4 = 0.9476), CCDC50 (H4 = 0.9091), IL17RD (H4 = 0.9301), UBLCP1 (H4 = 0.8862); in the Bayesian colocalization analysis of Crohn's disease-related arthritis, GPT (H4 = 0.8126). In the SMR analysis of RA, HDGF (p_SMR = 0.0338, p_HEIDI = 0.0628). In the LDSC analysis of RA, CCL19 (P = 0.0000), TNFRSF14 (P = 0.0258). By comprehensively analyzing plasma proteomic and transcriptomic data, we successfully identified key therapeutic targets for various clinical subtypes of immune-associated bone diseases. Our findings indicate that the significant positive genes associated with RA include HDGF, CCL19, and TNFRSF14; the positive gene linked to Crohn-related arthropathy is GPT; for MS, the positive genes are BTN1A1, EVI5, OGA, and TNFRSF14; and for PsA, the positive genes are ICAM5, CCDC50, IL17RD, and UBLCP1. Through this comprehensive analytical approach, we have screened potential therapeutic targets for different clinical subtypes of immune-related bone diseases. This research not only enhances our understanding of the pathogenesis of these conditions but also provides a solid theoretical foundation for subsequent drug development and clinical treatment, with the potential to yield significant advancements in the management of patients with immune-related bone diseases.

A comprehensive understanding of the molecular pathogenesis of chronic pancreatitis (CP), a fibroinflammatory disorder of the pancreas, is warranted for the development of targeted therapies. The current study focused on comparing the transcriptomes of pancreatic tissues obtained from patients with CP with those of two rodent models of chemically induced CP to identify dysregulated genes/signaling pathways.

Pancreatitis was induced in mice using cerulein and L-arginine. Pancreatic tissues were obtained from humans and mice. The RNA was isolated, and the transcriptomes were generated using the GeneChip Human Transcriptome Array 2.0 and Clariom D Mouse Array respectively. Differentially expressed genes with log2-fold changes ≥ +2 and ≤ -2 were considered for functional and signaling pathway enrichment analysis. The expression of NUCB2, which plays a role in β-cell function, was validated by ELISA in acute pancreatitis (AP) and immune cell responses in AP and CP using flow cytometry.

The current study identifies L-arginine-induced CP as a better model for investigating the pathogenesis of human CP, with greater similarity in dysregulated genes (22%), transcription factors (34%) and enriched pathways (58%) compared to cerulein model (2%, 11% and 9%) respectively. Nesfatin-1, encoded by NUCB2, was decreased in patients with AP (12% nondiabetic, 41% post pancreatitis diabetes). The Th1 immune cell response was greater in the patients with AP (44%), whereas Th17 immune response was greater in patients with CP (18%).

Our study highlights potential novel and unexplored pathways involved in inflammation, fibrosis, and pain in CP and paves the way for testing them as putative drug targets using a severe disease model.

IntroductionBreast cancer is the most common cancer among women, and metabolic syndrome (MetS) is a risk factor for breast cancer, especially postmenopausal breast cancer. We evaluated the role of the advanced glycated end products (AGEs) levels contributing to the association between MetS and breast cancer risk.MethodsPlasma AGEs were measured in a case-control study nested within the Hormones and Diet in the Etiology of Breast Tumors (ORDET) cohort, including 40 incident postmenopausal breast cancer cases (20 with MetS and 20 without) and 40 postmenopausal controls (20 with MetS and 20 without). The association between AGEs and breast cancer was analyzed using Bayesian logistic regression models. An informative prior for the exposure coefficient, modeled as a normal distribution, centered on the natural logarithm of an odds ratio ((OR)=1.635) derived from prior evidence, was employed alongside weakly informative priors (WIPs). Bayesian linear regression with WIPs was used to examine the association between MetS and AGEs. Estimates were reported with SDs and 90% and 95% credible intervals (CI).ResultsAGEs were associated with higher breast cancer risk both with the informative prior (OR = 1.745, SD):0.362; 90% CI:1.218-2.390; 95% CI:1.137-2.548) and the WIP (OR = 1.861, SD = 0.661; 90% CI:1.026-3.082; 95% CI:0.924-3.528) specification. Although the difference in plasma AGEs in women with and without MetS was not significant, we found a suggestion of higher levels in women with MetS (mean difference in standardized AGEs between individuals with and without MetS = 0.155, SD = 0.245; 90% CI:-0.246 to 0.553; 95% CI:-0.322 to 0.625).ConclusionsThese data, although from a small sample of women, support a role of endogenous AGEs in the pathological pathways underlying the association between MetS and breast cancer development.

The Receptor for Advanced Glycation End Products (RAGE), classically considered a mediator of acute and chronic inflammatory responses, has recently been implicated by genetic knockout studies as a regulator of skeletal muscle physiology during development and following acute injury. Yet, the role of its soluble isoform, soluble RAGE (sRAGE), in muscle regeneration remains relatively unexplored. To address this knowledge gap, Adeno-Associated Virus (AAV) mediated and genetic knockin supplementation strategies were developed to specifically assess the effects of changing levels of sRAGE on muscle regeneration. We evaluated general muscle physiology and histology, including central nucleation, and myofiber size. We found that acute induction of sRAGE in aged and atherosclerotic animals accelerates muscle repair after cryoinjury. Similarly, genetic modification of the endogenous Ager gene locus to favor production of sRAGE over transmembrane RAGE accelerates repair of cryo-damaged skeletal muscle. However, increasing sRAGE via AAV delivery or using our transgenic mouse lines had no impact on muscle repair in aged or diseased mice after barium chloride (BaCl2) injury. Together, these studies identify a unique muscle regulatory activity of sRAGE that is variable across injury models and may be targeted in a context-specific manner to alter the skeletal muscle microenvironment and boost muscle regenerative output.

Neurodegenerative diseases (NDs) are a group of neurological disorders characterized by the progressive loss of selected neurons. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common NDs. Pathologically, NDs are characterized by progressive failure of neural interactions and aberrant protein fibril aggregation and deposition, which lead to neuron loss and cognitive and behavioral impairments. Great efforts have been made to delineate the underlying mechanism of NDs. However, the very first trigger of these disorders and the state of the illness are still vague. Existing therapeutic strategies can relieve symptoms but cannot cure these diseases. The human immune system is a complex and intricate network comprising various components that work together to protect the body against pathogens and maintain overall health. They can be broadly divided into two main types: innate immunity, the first line of defense against pathogens, which acts nonspecifically, and adaptive immunity, which follows a defense process that acts more specifically and is targeted. The significance of brain immunity in maintaining the homeostatic environment of the brain, and its direct implications in NDs, has increasingly come into focus. Some components of the immune system have beneficial regulatory effects, whereas others may have detrimental effects on neurons. The intricate interplay and underlying mechanisms remain an area of active research. This review focuses on the effects of both innate and adaptive immunity on AD and PD, offering a comprehensive understanding of the initiation and regulation of brain immunity, as well as the interplay between innate and adaptive immunity in influencing the progression of NDs.

Ductular reaction (DR) is the hallmark of cholestatic diseases manifested in the proliferation of bile ductules lined by biliary epithelial cells (BECs). It is commonly associated with an increased risk of fibrosis and liver failure. The receptor for advanced glycation end products (RAGE) was identified as a critical mediator of DR during chronic injury. Yet, the direct link between RAGE-mediated DR and fibrosis as well as the mode of interaction between BECs and hepatic stellate cells (HSCs) to drive fibrosis remain elusive. Here, we delineate the specific function of RAGE on BECs during DR and its potential association with fibrosis in the context of cholestasis. Employing a biliary lineage tracing cholestatic liver injury mouse model, combined with whole transcriptome sequencing and in vitro analyses, we reveal a role for BEC-specific Rage activity in fostering a pro-fibrotic milieu. RAGE is predominantly expressed in BECs and contributes to DR. Notch ligand Jagged1 is secreted from activated BECs in a Rage-dependent manner and signals HSCs in trans, eventually enhancing fibrosis during cholestasis.

The progression of chronic obstructive pulmonary disease (COPD) results in irreversible pulmonary damage and sustained inflammatory responses. While alternative approaches have been explored, the specific role of alveolar epithelial cells in the pathogenesis of COPD remains unclear. Additionally, the association between emphysema and DAMP-RAGE signaling in COPD patients are not understood. Therefore, this study demonstrates to determine the therapeutic effect of a RAGE antagonist peptide (RAP), which we previously identified on the pathogenesis of COPD. We assessed the expression of RAGE ligands and RAGE binding signaling in COPD patients using GEO data. PPE-induced emphysema mouse model and AGER-/- mouse were employed, along treated with RAP. The association between RAGE and the development of emphysema was examined in H&E staining and western blot analysis in mouse lung tissue and BALF. We next analyzed the damage caused by oxidative stress and inflammation through CSE and RAP in human alveolar epithelial cell line A549. Our results show that inhibiting of RAGE alleviates emphysema by suppressing inflammation and MMP activity. Inhibition of RAGE in alveolar epithelial cells significantly induced the mitigation of lung injury, independent of macrophage infiltration. Furthermore, it was confirmed that RAP ameliorated CSE-induced oxidative stress, inflammation, and cell cycle arrest in human alveolar epithelial cells. These findings demonstrate that inhibiting RAGE in alveolar epithelial cells suppress lung injury and emphysema by inhibiting oxidative stress-induced inflammation and MMPs, while promoting alveolar epithelial cell proliferation. Furthermore, blocking of the DAMP-RAGE interaction through RAP offers a promising therapeutic approach for mitigating emphysema.

Osteoarthritis (OA) is a progressive degenerative disease affected by many factors, and there is currently no effective treatment. In recent years, the latest progress in metabolomics in OA research has revealed several metabolic pathways and new specific metabolites involved in OA. Metabolites play significant roles in the identification and management of OA. This review looks back on the development history of metabolomics and the progress of this technology in OA as well as its potential clinical applications. It summarizes the applications of metabolites in the field of OA and future research directions. This understanding will advance the identification of metabolic treatment goals for OA.

The development of metabolomics offers possibilities for the treatment of OA. This article reviews the relationship between metabolites associated with chondrocytes and OA. Selectively altering these three metabolic pathways and their associated metabolites may hold great potential as new focal points for OA treatment.

Isothiocyanates (ITCs), found in edible plants such as cruciferous vegetables, are a group of reactive organo-sulfur phytochemicals produced by the hydrolysis of precursors known as glucosinolates. ITCs have been studied extensively both in vivo and in vitro to define their therapeutic potential for the treatment of chronic health conditions. Therapeutically, they have shown an intrinsic ability to inhibit oxidative and inflammatory phenotypes to support enhanced health. This review summarizes the current evidence supporting the observation that the antioxidant and anti-inflammatory activities of ITCs temper the pathogenic effects of a group of reactive metabolites called advanced glycation end products (AGEs). AGE exposure has significantly increased across the lifespan due to health risk factors that include dietary intake, a sedentary lifestyle, and comorbid conditions. By contributing to a chronic cycle of inflammatory stress through the aberrant activation of the transmembrane receptor for AGE (RAGE), increased AGE bioavailability is associated with chronic disease onset, progression, and severity. This review debates the potential molecular mechanisms by which ITCs may inhibit AGE bioavailability to reduce RAGE-mediated pro-oxidant and pro-inflammatory phenotypes. Bringing to light the molecular impact that ITCs may have on AGE biogenesis may stimulate novel intervention strategies for reversing or preventing the impact of lifestyle factors on chronic disease risk.

The receptor for advanced glycation end-products (RAGE), a member of the immunoglobulin superfamily, is expressed in various cell types and mediates cellular responses to a wide range of ligands. The activation of RAGE triggers complex signaling pathways that drive inflammatory, oxidative, and proliferative responses, which are increasingly implicated in the pathogenesis of skin diseases. Despite its well-established roles in conditions such as diabetes, cancer, and chronic inflammation, the contribution of RAGE to skin pathologies remains underexplored. This review synthesizes current findings on RAGE's involvement in the pathophysiology of skin diseases, including conditions such as psoriasis, atopic dermatitis, and lichen planus, focusing on its roles in inflammatory signaling, tissue remodeling, and skin cancer progression. Additionally, it examines RAGE-modulating treatments investigated in dermatological contexts, highlighting their potential as therapeutic options. Given RAGE's significance in a variety of skin conditions, further research into its mediated pathways may uncover new opportunities for targeted interventions in skin-specific RAGE signaling.

Monocytes mainly contribute to the development and progression of vascular inflammatory conditions via the M1 polarization. The elevated levels of advanced glycation end products (AGEs) in diabetic environment lead to severe inflammation, and the release of pro-inflammatory mediators. This shifts the balance towards the pro-inflammatory state of monocytes.

The current study was aimed to determine the antiglycation activity of 1,2,4-triazine derivatives, and study of their molecular basis in regulating the AGEs-mediated inflammatory responses in THP-1 monocytes.

Primarily, the antiglycation activity of a series of 1,2,4-triazine derivatives was evaluated against MGO-AGEs in vitro. The toxicity of antiglycation compounds was determined by a metabolic assay, using human hepatocyte (HepG2) and monocyte (THP-1) cell lines. DCFH-DA probe was used to evaluate the antioxidant potential of the compounds. Immunocytochemistry, Western blotting, and ELISA techniques were employed to determine the levels of pro-inflammatory markers (NF-κB, RAGE, COX-1, COX-2, and PGE2) in THP-1 monocytes under in-vitro hyperglycemic conditions.

Results indicate that the triazine derivatives 22, and 23 were the most potent antiglycation agents among the entire series, while non-toxic to HepG2, and THP-1 cells. Both compounds inhibited the AGEs-induced upstream and downstream signaling of NADPH oxidase and inflammatory mediators p38 and NF-κβ, respectively, in THP-1 monocytes. They also inhibited the induction of COX-2 and its product PGE2 by suppressing AGE-RAGE interactions. Moreover, compounds 22, and 23 reversed the AGEs-mediated suppression of COX-1 in THP-1 monocytes.

In conclusion, 1,2,4-triazine derivatives 22, and 23 have the potential to suppress inflammatory responses under the diabetic environment through AGE-RAGE-NF-κβ/p38 nexus in THP-1 monocytes. These findings identify triazines 22, and 23 as compelling candidates for drug development, potentially beneficial for the diabetic patients with an elevated risk of vascular complications, such as atherosclerosis.

S100B is a multifunctional protein primarily found in the brain, where it plays crucial roles in cell proliferation, differentiation, and survival. It has intracellular and extracellular functions and, depending on S100B levels, can exhibit both neurotrophic and neurotoxic activities, both mediated by the receptor for advanced glycation end products (RAGEs). Here, we report the discovery and characterization of nanobodies (Nbs) targeting dimeric and tetrameric S100B, which are the two most abundant oligomeric functional forms of the protein, aiming to modulate S100B-mediated RAGE activation. Two Nbs were selected for detailed structural and functional studies and found to bind tetrameric S100B with high affinity, as determined by biolayer interferometry (BLI) analysis and size-exclusion chromatography-stable binary complex formation. Structural and docking analyses revealed preferential contact sites of Nbs with S100B regions implicated in interactions with RAGE, namely residues at the interfacial cleft on dimeric S100B and at hydrophobic cleft formed by the association of two homodimeric units in the tetramer. In accordance, assays in SH-SY5Y cells showed that Nbs modulate the RAGE-mediated neurotrophic activity of S100B by hindering its functional interactions with the receptor. BLI competition assays between tetrameric S100B and the RAGE-VC1 domain confirmed that Nbs selectively block S100B-mediated RAGE engagement, in agreement with cell activation experiments. These findings highlight Nbs as powerful tools for elucidating molecular and cellular mechanisms through the modulation of S100B and RAGE functions, inspiring potential therapeutic applications.

Advanced glycation end products (AGE), a diverse array of molecules generated through non-enzymatic glycosylation, in conjunction with the receptor of advanced glycation end products (RAGE), play a crucial role in the pathogenesis of diabetes and its associated complications. Recent studies have revealed that the AGE-RAGE axis potentially accelerated the progression of cardiovascular diseases, including heart failure, atherosclerosis, myocarditis, pulmonary hypertension, hypertension, arrhythmia, and other related conditions. The AGE-RAGE axis is intricately involved in the initiation and progression of cardiovascular diseases, independently of its engagement in diabetes. The mechanisms include oxidative stress, inflammation, alterations in autophagy flux, and mitochondrial dysfunction. Conversely, inhibition of AGE production, disruption of the binding between RAGE and its ligands, or silencing of RAGE expression could effectively impair the function of AGE-RAGE axis, thereby delaying or ameliorating the aforementioned diseases. AGE and the soluble receptor for advanced glycation end products (sRAGE) have the potential to be novel predictors of cardiovascular diseases. In this review, we provide an in-depth overview towards the biosynthetic pathway of AGE and elucidate the pathophysiological implications in various cardiovascular diseases. Furthermore, we delve into the profound role of RAGE in cardiovascular diseases, offering novel insights for further exploration of the AGE-RAGE axis and potential strategies for the prevention and management of cardiovascular disorders.

This study aimed to investigate whether the serum extracellular newly identified receptor for advanced glycation end products binding protein (EN-RAGE) and the soluble form of RAGE (sRAGE) measured at diagnosis are associated with all-cause mortality in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA).

Serum EN-RAGE and sRAGE were measured in 75 immunosuppressive drug-naïve MPA and GPA patients using an immunoassay, with their clinical and laboratory data reviewed. The optimal cut-off point of EN-RAGE and sRAGE was calculated by finding the threshold with the maximum sum of sensitivity and specificity. In addition, the least absolute shrinkage and selection operator regression was adopted to select variables included in the multivariable Cox proportional hazards (PH) regression model.

The median age of the patients was 67.0 years, and 34% were male. Neither serum EN-RAGE nor sRAGE at diagnosis was correlated with the Birmingham Vasculitis Activity Score. Furthermore, no correlation was observed between serum EN-RAGE and sRAGE. Deceased patients had significantly lower serum EN-RAGE and higher serum sRAGE at diagnosis compared to surviving patients. Patients with serum EN-RAGE at diagnosis ≤84.37 ng/mL and serum sRAGE at diagnosis ≥1.82 ng/mL showed significantly lower survival probabilities compared to those without. In multivariable Cox PH regression model, only serum sRAGE at diagnosis ≥1.82 ng/mL, rather than serum EN-RAGE at diagnosis ≤84.37 ng/mL, was independently associated with all-cause mortality (hazard ratio 7.094).

This study is the first to demonstrate that serum sRAGE at diagnosis may independently predict all-cause mortality during follow-up in patients with MPA and GPA.

Cardiovascular disease is the deadly disease that can result in sudden death, and inflammation plays an important role in its onset and progression. High mobility group box 1 (HMGB1) is a nuclear protein that regulates transcription, DNA replication, repair, and nucleosome assembly. HMGB1 is released passively by necrotic tissues and actively secreted by stressed cells. Extracellular HMGB1 functions as a damage associated molecular patterns molecule, producing numerous redox forms that induce a range of cellular responses by binding to distinct receptors and interactors, including tissue inflammation and regeneration. Extracellular HMGB1 inhibition reduces inflammation and is protective in experimental models of myocardial ischemia/reperfusion damage, myocarditis, cardiomyopathies caused by mechanical stress, diabetes, bacterial infection, or chemotherapeutic drugs. HMGB1 administration following a myocardial infarction followed by permanent coronary artery ligation improves cardiac function by stimulating tissue regeneration. HMGB1 inhibits contractility and produces hypertrophy and death in cardiomyocytes, while also stimulating cardiac fibroblast activity and promoting cardiac stem cell proliferation and differentiation. Maintaining normal nuclear HMGB1 levels, interestingly, protects cardiomyocytes from apoptosis by limiting DNA oxidative stress, and mice with HMGB1cardiomyocyte-specific overexpression are partially protected from cardiac injury. Finally, elevated levels of circulating HMGB1 have been linked to human heart disease. As a result, following cardiac damage, HMGB1 elicits both detrimental and helpful responses, which may be due to the formation and stability of the various redox forms, the particular activities of which in this context are mostly unknown. This review covers recent findings in HMGB1 biology and cardiac dysfunction.

In both type 1 diabetes (T1DM) and type 2 diabetes (T2DM), previous studies have yielded inconsistent findings regarding whether the levels of the soluble receptor for advanced glycation end products (sRAGE) are significantly altered. This meta-analysis aims to systematically evaluate the changes of sRAGE levels in patients with T1DM and T2DM.

PubMed, Embase, and Web of Science were systematically searched from inception until April 2024. We included studies reporting sRAGE levels in individuals with T1DM or T2DM, using non-diabetic healthy individuals as the control group. A random-effects model was applied to conduct a meta-analysis of effect measures (means and SDs).

49 datasets from 32 studies, involving 4948 subjects, met the inclusion criteria. A random-effects model meta-analysis showed that sRAGE levels in T1DM subjects (SMD 0.45, CI: 0.16-0.73, P = 0.002) and T2DM subjects with complications (SMD 1.59, CI: 0.77-2.41, P = 0.0001) were significantly higher than those in the control groups. No statistically significant change in sRAGE levels was observed in T2DM subjects without complications (SMD 0.01, CI: -0.61-0.64, P = 0.97). A decrease in sRAGE levels was observed in subjects with newly diagnosed T2DM (SMD-0.40, CI: -0.71- -0.09, P = 0.01).

This meta-analysis indicated that sRAGE levels increased in T1DM patients and T2DM patients with complications, while they decreased in newly diagnosed T2DM patients. No significant difference was observed in T2DM patients without complications. Clearly, changes in sRAGE levels in patients with T1DM or T2DM are not uniform, but depend on the different types and stages of the disease.

CRD42024521252.

Aging represents a natural and unavoidable phenomenon in organisms. With the acceleration of population aging, investigations into aging have garnered widespread global interest. One of the most striking aspects of human aging is the decline in brain function, a phenomenon intricately tied to the onset of neurodegenerative conditions. This study aimed to assess the impact of a fish hydrolysate, rich in low-molecular-weight peptides and n-3 LC-PUFAs, on cognitive function, inflammatory response, and oxidative stress via the AGE-RAGE axis in a mouse model of accelerated aging. This model induces cognitive decline and biochemical alterations akin to those observed during natural aging. The findings revealed that fish hydrolysate exhibited a protective effect against cognitive impairment induced by D-galactose. This effect was associated with increased protein expression of SOD1 and decreased genetic expression of IL-6 and advanced glycation end products (AGE). Consequently, within the realm of preventive and personalized nutrition, fish hydrolysate emerges as a promising avenue for mitigating age-related declines in memory function.

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.

While several risk factors for knee osteoarthritis (KOA) have been recognized, the pathogenesis of KOA and the causal relationship between modifiable risk factors and KOA in genetic epidemiology remain unclear. This study aimed to determine the causal relationship between KOA and its risk factors.

Data were obtained from published Genome-Wide Association study (GWAS) databases. A two-sample Mendelian randomization (MR) analysis was performed with genetic variants associated with risk factors as instrumental variables and KOA as outcome. First, inverse variance weighting was used as the main MR analysis method, and then a series of sensitivity analyses were conducted to comprehensively evaluate the causal relationship between them.

Univariate forward MR analysis revealed that genetically predicted hypothyroidism, hyperthyroidism/thyrotoxicosis, educational level, income level, metabolic syndrome (MS), essential hypertension, height, hot drink temperature, diet (abstaining from sugar-sweetened or wheat products), and psychological and psychiatric disorders (stress, depression, and anxiety) were causally associated with KOA. Reverse MR exhibits a causal association between KOA and educational attainment. Multivariate MR analysis adjusted for the inclusion of potential mediators, such as body mass index (BMI), smoking, alcohol consumption, and sex, exhibited some variation in causal effects. However, hyperthyroidism/thyrotoxicosis had a significant causal effect on KOA, and there was good evidence that height, hypothyroidism, educational level, psychological and psychiatric disorders (stress, depression, and anxiety), and abstaining from wheat products had an independent causal relationship. The mediating effect of BMI as a mediator was also identified.

This study used MR to validate the causal relationship between KOA and its risk factors, providing new insights for preventing and treating KOA in clinical practice and for developing public health policies.

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.

Oxidative stress (OS) develops in critically ill patients as a metabolic consequence of the immunoinflammatory and degenerative processes of the tissues. These induce increased and/or dysregulated fluxes of reactive species enhancing their pro-oxidant activity and toxicity. At the same time, OS sustains its own inflammatory and immunometabolic pathogenesis, leading to a pervasive and vitious cycle of events that contribute to defective immunity, organ dysfunction and poor prognosis. Protein damage is a key player of these OS effects; it generates increased levels of protein oxidation products and misfolded proteins in both the cellular and extracellular environment, and contributes to forms DAMPs and other proteinaceous material to be removed by endocytosis and proteostasis processes of different cell types, as endothelial cells, tissue resident monocytes-macrophages and peripheral immune cells. An excess of OS and protein damage in critical illness can overwhelm such cellular processes ultimately interfering with systemic proteostasis, and consequently with innate immunity and cell death pathways of the tissues thus sustaining organ dysfunction mechanisms. Extracorporeal therapies based on biocompatible/bioactive membranes and new adsorption techniques may hold some potential in reducing the impact of OS on the defective proteostasis of patients with critical illness. These can help neutralizing reactive and toxic species, also removing solutes in a wide spectrum of molecular weights thus improving proteostasis and its immunometabolic corelates. Pharmacological therapy is also moving steps forward which could help to enhance the efficacy of extracorporeal treatments. This narrative review article explores the aspects behind the origin and pathogenic role of OS in intensive care and critically ill patients, with a focus on protein damage as a cause of impaired systemic proteostasis and immune dysfunction in critical illness.

Metabolic syndrome (MetS) is significantly associated with osteoarthritis (OA), especially in MetS patients with blood glucose abnormalities, such as elevated fasting blood glucose (FG), which may increase OA risk. Dietary modifications, especially the intake of polyunsaturated fatty acids (PUFAs), are regarded as a potential means of preventing MetS and its complications. However, regarding the effects of FG, Omega-3s, and Omega-6s on OA, the research conclusions are conflicting, which is attributed to the complexity of the pathogenesis of OA. Therefore, it is imperative to thoroughly evaluate multiple factors to fully understand their role in OA, which needs further exploration and clarification.

Two-sample univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were employed to examine the causal effect of metabolic related factors on hip OA (HOA) or knee OA (KOA). The exposure and outcome datasets were obtained from Open GWAS IEU. All cases were independent European ancestry data. Three MR methods were performed to estimate the causal effect: inverse-variance weighting (IVW), weighted median method (WMM), and MR-Egger regression. Additionally, the intercept analysis in MR-Egger regression is used to estimate pleiotropy, and the IVW method and MR-Egger regression are used to test the heterogeneity.

The UVMR analysis revealed a causal relationship between FG and HOA. By MVMR analysis, the study discovered a significant link between FG (OR = 0.79, 95%CI: 0.64∼0.99, p = 0.036) and KOA after accounting for body mass index (BMI), age, and sex hormone-binding globulin (SHBG). However, no causal effects of FG on HOA were seen. Omega-3s and Omega-6s did not have a causal influence on HOA or KOA. No significant evidence of pleiotropy was identified.

The MR investigation showed a protective effect of FG on KOA development but no causal relationship between FG and HOA. No causal effect of Omega-3s and Omega-6s on HOA and KOA was observed. Shared genetic overlaps might also exist between BMI and age, SHBG and PUFAs for OA development. This finding offers a novel insight into the treatment and prevention of KOA from glucose metabolism perspective. The FG cutoff value should be explored in the future, and consideration should be given to demonstrating the study in populations other than Europeans.

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.

The receptor for advanced glycation end products (RAGE) is a protein of the immunoglobulin superfamily capable of regulating inflammation. Considering the role of this receptor in the initiation and establishment of neuroinflammation, and the limited understanding of the function of RAGE in the maintenance of this condition, this study describes the effects of RAGE inhibition in the brain, through an intranasal treatment with the antagonist FPS-ZM1, in an animal model of chronic neuroinflammation induced by acute intraperitoneal injection of lipopolysaccharide (LPS). Seventy days after LPS administration (2 mg/kg, i.p.), Wistar rats received, intranasally, 1.2 mg of FPS-ZM1 over 14 days. On days 88 and 89, the animals were submitted to the open-field test and were killed on day 90 after the intraperitoneal injection of LPS. Our results indicate that blockade of encephalic RAGE attenuates LPS-induced chronic neuroinflammation in different brain regions. Furthermore, we found that intranasal FPS-ZM1 administration reduced levels of gliosis markers, RAGE ligands, and α-synuclein in the substantia nigra pars compacta. Additionally, the treatment also reversed the increase in S100 calcium-binding protein B (RAGE ligand) in the cerebrospinal fluid and the cognitive-behavioral deficits promoted by LPS-less time spent in the central zone of the open-field arena (more time in the lateral zones), decreased total distance traveled, and increased number of freezing episodes. In summary, our study demonstrates the prominent role of RAGE in the maintenance of a chronic neuroinflammatory state triggered by a single episode of systemic inflammation and also points to possible future RAGE-based therapeutic approaches to treat conditions in which chronic neuroinflammation and increased α-synuclein levels could play a relevant role, such as in Parkinson's disease.

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor that belongs to the immunoglobulin superfamily and is extensively associated with chronic inflammation in non-transmissible diseases. As chronic inflammation is consistently present in neurodegenerative diseases, it was largely assumed that RAGE could act as a critical modulator of neuroinflammation in Parkinson's disease (PD), similar to what was reported for Alzheimer's disease (AD), where RAGE is postulated to mediate pro-inflammatory signaling in microglia by binding to amyloid-β peptide. However, accumulating evidence from studies of RAGE in PD models suggests a less obvious scenario. Here, we review physiological aspects of RAGE and address the current questions about the potential involvement of this receptor in the cellular events that may be critical for the development and progression of PD, exploring possible mechanisms beyond the classical view of the microglial activation/neuroinflammation/neurodegeneration axis that is widely assumed to be the general mechanism of RAGE action in the adult brain.

Acute lung injury (ALI) is caused by bacterial, fungal, and viral infections. When pathogens invade the lungs, the immune system responds by producing cytokines, chemokines, and interferons to promote the infiltration of phagocytic cells, which are essential for pathogen clearance. Their excess production causes an overactive immune response and a pathological hyper-inflammatory state, which leads to ALI. Until now, there is no particular pharmaceutical treatment available for ALI despite known inflammatory mediators like neutrophil extracellular traps (NETs) and reactive oxygen species (ROS).

Therefore, the primary objective of this review is to provide the clear overview on the mechanisms controlling NETs, ROS formation, and other relevant processes during the pathogenesis of ALI. In addition, we have discussed the significance of epithelial and endothelial damage indicators and several molecular signaling pathways associated with ALI.

The literature review was done from Web of Science, Scopus, PubMed, and Google Scholar for ALI, NETs, ROS, inflammation, biomarkers, Toll- and nucleotide-binding oligomerization domain (NOD)-like receptors, alveolar damage, pro-inflammatory cytokines, and epithelial/endothelial damage alone or in combination.

This review summarized the main clinical signs of ALI, including the regulation and distinct function of epithelial and endothelial biomarkers, NETs, ROS, and pattern recognition receptors (PRRs).

However, no particular drugs including vaccine for ALI has been established. Furthermore, there is a lack of validated diagnostic tools and a poor predictive rationality of current therapeutic biomarkers. Hence, extensive and precise research is required to speed up the process of drug testing and development by the application of artificial intelligence technologies, structure-based drug design, in-silico approaches, and drug repurposing.

AGEs, their receptor (RAGE), and the extracellular newly identified receptor for AGEs product-binding protein (EN-RAGE) are implicated in the pathogenesis of inflammation.

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.

Using the ELISA method, serum sRAGE, esRAGE, and EN-RAGE were measured before and after CR.

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.

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.

There is increasing evidence for blood-brain barrier (BBB) alterations in Parkinson's disease (PD), the second most common neurodegenerative disorder with rapidly rising prevalence. Altered tight junction and transporter protein levels, accumulation of α-synuclein and increase in inflammatory processes lead to extravasation of blood molecules and vessel degeneration. This could result in a self-perpetuating pathophysiology of inflammation and BBB alteration, which contribute to neurodegeneration. Toxin exposure or α-synuclein over-expression in animal models has been shown to initiate similar pathologies, providing a platform to study underlying mechanisms and therapeutic interventions. Here we provide a comprehensive review of the current knowledge on BBB alterations in PD patients and how rodent models that replicate some of these changes can be used to study disease mechanisms. Specific challenges in assessing the BBB in patients and in healthy controls are discussed. Finally, a potential role of BBB alterations in disease pathogenesis and possible implications for therapy are explored. The interference of BBB alterations with current and novel therapeutic strategies requires more attention. Brain region-specific BBB alterations could also open up novel opportunities to target specifically vulnerable neuronal subpopulations.