Search Results (519)

Background: Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options due to the lack of estrogen, progesterone, and HER2 receptors. This study investigated the synergistic anticancer effects of recombinant human apurinic/apyrimidinic endonuclease 1/redox factor-1 (rhAPE1/Ref-1) and acetylsalicylic acid (ASA), a combination that has not been previously tested in vivo. Methods: We treated MDA-MB-231 TNBC cells with rhAPE1/Ref-1, ASA, or their combination to assess cell viability and apoptosis in vitro. In vivo, a murine xenograft model was established to evaluate the efficacy of the combination treatment on tumor growth, tumor-specific biomarkers, and key apoptotic proteins. The safety profile of the combination therapy was also assessed by monitoring hematological parameters. Results: While monotherapy with either rhAPE1/Ref-1 or ASA had minimal effects, their combination significantly reduced cell viability and enhanced apoptosis in vitro by increasing DNA fragmentation. These synergistic cytotoxic effects were significantly inhibited by the receptor for advanced glycation end-products (RAGE) siRNA, suggesting that RAGE acts as an important mediator. In the xenograft model, the combination treatment suppressed tumor growth by approximately 70%, an effect comparable to paclitaxel (PTX). This was confirmed by a significant reduction in the plasma levels of TNBC biomarkers (CEA, CA27-29, and CA15-3) and increased tumor apoptosis via the upregulation of p53 and Bax and downregulation of Bcl-2. Notably, ASA, alone or combined with rhAPE1/Ref-1, induced the expression of RAGE in MDA-MB-231 tumors. In contrast to PTX, the combination of rhAPE1/Ref-1 and ASA did not cause hematological toxicity, such as anemia or thrombocytopenia. Conclusions: The combination of rhAPE1/Ref-1 and ASA represents a promising new therapeutic strategy for TNBC by enhancing apoptosis and significantly inhibiting tumor progression in a mouse xenograft model. Full article

Background: Diabetic bone disease affects over 537 million people with diabetes worldwide, characterized by increased fracture risk despite paradoxically normal or elevated bone mineral density (BMD) in Type 2 diabetes. This narrative review synthesizes current evidence on pathophysiology, diagnostic approaches, and management strategies. Methods: We performed a comprehensive literature search of the PubMed, Embase, and Cochrane databases (2007–2025), prioritizing systematic reviews, meta-analyses, large-scale population studies, and clinical trials examining bone health in diabetes, including bone density, quality, fracture risk, imaging techniques, biomarkers, and therapeutic interventions. Results: Advanced glycation end products fundamentally alter bone metabolism through mechanisms distinct from traditional osteoporosis. Type 1 and Type 2 diabetes produce contrasting skeletal phenotypes requiring tailored management. Recent umbrella reviews of 71 meta-analyses demonstrated skeletal benefits of metformin and GLP-1 receptor agonists, while confirming thiazolidinedione risks. Trabecular bone score enhances fracture prediction when DXA appears normal. Large-scale studies revealed heterogeneous risk patterns, with specific subgroups showing substantially elevated fracture risk. Advanced imaging revealed distinct microarchitectural changes between diabetes types. Diabetic patients experienced doubled healing complications, necessitating specialized perioperative protocols. Conclusions: Diabetic bone disease represents a distinct clinical entity requiring enhanced diagnostic strategies beyond traditional densitometry, evidence-based treatment selection considering skeletal and metabolic effects, and specialized management protocols extending beyond conventional osteoporosis care. Full article

High Mobility Group Box 1 (HMGB1) is a central pro-inflammatory mediator released from damaged or stressed cells, where it activates receptors such as the Receptor for Advanced Glycation Endproducts (RAGE). Dendritic polyglycerol sulfate (dPGS), a hyperbranched polyanionic polymer, is known for its anti-inflammatory activity. In this study, we examined how dPGS modulates HMGB1-driven signaling in RAW 264.7 macrophages and human microglia. Recombinant human HMGB1 expressed in Escherichia coli (E. coli) was purified by nickel-nitrilotriacetic acid (Ni-NTA) and heparin chromatography. Proximity ligation assays (PLA) revealed that dPGS significantly disrupted HMGB1/RAGE interactions, particularly under lipopolysaccharide (LPS) stimulation, thereby reducing inflammatory signaling complex formation. This correlated with reduced activation of the nuclear factor kappa B (NF-κB) pathway, demonstrated by decreased nuclear translocation and transcriptional activity. Reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time PCR (RT-qPCR) showed that dPGS suppressed HMGB1- and LPS-induced transcription of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Enzyme-linked immunosorbent assay (ELISA) and Griess assays confirmed reduced TNF-α secretion and nitric oxide production. Electron paramagnetic resonance (EPR) spectroscopy further showed that dPGS altered HMGB1/soluble RAGE (sRAGE) complex dynamics, providing mechanistic insight into its receptor-disruptive action. Full article

Diabetic nephropathy (DN) remains the leading cause of end-stage renal disease worldwide, with proximal tubular epithelial cells (PTECs) playing a central role in its pathogenesis. Under hyperglycemic conditions, PTECs drive a pathological triad of inflammation, apoptosis, and fibrosis. Recent advances reveal that these processes interact synergistically to form a self-perpetuating vicious cycle, rather than operating in isolation. This review systematically elucidates the molecular mechanisms underlying this crosstalk in PTECs. Hyperglycemia induces reactive oxygen species (ROS) overproduction, advanced glycation end products (AGEs) accumulation, and endoplasmic reticulum stress (ERS), which collectively activate key inflammatory pathways (NF-κB, NLRP3, cGAS-STING). The resulting inflammatory milieu triggers apoptosis via death receptor and mitochondrial pathways, while apoptotic cells release damage-associated molecular patterns (DAMPs) that further amplify inflammation. Concurrently, fibrogenic signaling (TGF-β1/Smad, Hippo-YAP/TAZ) promotes epithelial–mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. Crucially, the resulting fibrotic microenvironment reciprocally exacerbates inflammation and apoptosis through mechanical stress and hypoxia. Quantitative data from preclinical and clinical studies are integrated to underscore the magnitude of these effects. Current therapeutic strategies are evolving toward multi-target interventions against this pathological network. We contrast the paradigm of monotargeted agents (e.g., Finerenone, SGLT2 inhibitors), which offer high specificity, with that of multi-targeted natural product-based formulations (e.g., Huangkui capsule, Astragaloside IV), which provide synergistic multi-pathway modulation. Emerging approaches (metabolic reprogramming, epigenetic regulation, mechanobiological signaling) hold promise for reversing fibrosis. Future directions include leveraging single-cell technologies to decipher PTEC heterogeneity and developing kidney-targeted drug delivery systems. We conclude that disrupting the inflammation–apoptosis–fibrosis vicious cycle in PTECs is central to developing next-generation therapies for DN. Full article

Background: Advanced glycation end products (AGEs) and receptors for AGEs (RAGE) have been extensively implicated in metabolic and neurodegenerative disorders due to their capacity to alter protein structure and function through non-enzymatic glycation. More recently, methylglyoxal (MG), a highly reactive glycolytic byproduct, has gained attention as a critical mediator of AGE formation and an independent contributor to cellular distress, particularly in the context of diabetes mellitus and Alzheimer’s disease. Objectives: This review synthesizes evidence from experimental and clinical studies addressing MG generation and metabolism in brain tissue, emphasizing the glyoxalase system as the primary detoxification mechanism, the functional contribution of astrocytes, and the downstream consequences of MG accumulation. In addition, we examined the interplay between MG, RAGE signaling, unfolded protein response, and regulatory mechanisms involving the hexosamine biosynthesis pathway and O-GlcNAcylation of key proteins in glucose metabolism and insulin signaling. Results and Conclusions: Brain glucose hypometabolism is a consequence of insulin resistance and results in a metabolic rearrangement that expands the glycolytic pathway and generates more MG, which, in turn, can affect insulin signaling, further compromising the molecular basis of insulin resistance and creating a vicious cycle. Astrocytes are key cells in the generation and detoxification of MG in the brain, making them a therapeutic target. Full article

Receptor for advanced glycation end-products (RAGE) activation by hyperglycemia-induced AGE (advanced glycation end-products) accumulation is likely to play a crucial role in the development of complications such as diabetic peripheral neuropathy (DPN). RAGE signaling is mediated via its cytosolic tail. Through its cytosolic tail, RAGE recruits diaphanous-related formin 1 (Diaph1), a protein involved in actin filament organization. Disruption of RAGE–Diaph1 interactions using small molecules alleviates diabetic complications in mice; however, the role of Diaph1 in DPN progression has not been rigorously tested. In this study, we employed a Diaph1 knockout mouse (DKO) to investigate the role of Diaph1 in DPN progression. Herein, we demonstrate that, at the systemic level, CRISPR deletion of Diaph1 fails to ameliorate diabetes-induced weight loss in mice. Within the sciatic nerve (SCN), the lack of Diaph1 failed to prevent hyperglycemia-induced loss of β-actin in the nerve fibers. At a morphological level, the lack of Diaph1 leads to a partial rescue in DPN. While we observed improvements in axonal and fiber diameters in diabetic DKO mice, the g-ratio (an indicator of myelination) and myelin invaginations displayed incomplete rescue. Furthermore, the lack of Diaph1 failed to rescue motor or sensory nerve conduction defects resulting from hyperglycemia over 6 months. Overall, our data thus indicate that the complete loss of Diaph1 is insufficient to halt the progression of DPN. However, across a range of parameters including blood glucose levels, body weight measurements, axon and fiber diameters, and nerve conduction velocity, DKO diabetic mice show improvement when compared to wild-type diabetic mice. Full article

Alzheimer’s disease (AD) has been studied extensively and is characterized by plaques deposited throughout the brain. Plaques are made of beta-amyloid (Aβ) peptides which have undergone fibrillogenesis to form insoluble Aβ fibrils (fAβ) that are neurotoxic. Receptor for Advanced Glycation End end products (RAGE), toll-like receptors (TLRs) 2 and 4, and co-receptor CD14 recognize negatively charged binding regions on fAβ to activate microglia and release proinflammatory cytokines. In this study, we used two experimentally resolved fAβ structures (type I and II) isolated from AD brain tissue to elucidate binding patterns of fAβ with RAGE, TLR2, TLR4, and CD14 and investigated whether binding was affected by fibril structure or system pH. Receptors TLR2 and RAGE formed tight complexes with both type I and II fibrils, while TLR4 showed selectivity for type I. CD14 binding was less tight and selective for type II. Binding was pH dependent for CD14, TLR4, and RAGE but not TLR2. We explored the effects of familial mutations on fibril structure to determine whether mutants of type I or II structures are feasible. Finally, we investigated whether mutations affected binding interactions of fAβ with proteins. The Arctic (Glu22Gly), Dutch (Glu22Gln), and Iowa (Asp23Asn) mutations showed similar effects on binding affinity. Italian (Glu22Lys) mutations abrogated binding, whereas type I and II fibrils with Flemish (Ala21Gly) mutations were not shown to be feasible. Results highlight the adaptability of immune receptors in recognizing damaging molecules, with fibril structure and pH being the main recognition determinants predicated on disease progression. In silico mutations showed that aggregates similar to type I and II structures were plausible for some familial mutations. Full article

Frozen shoulder (FS), traditionally regarded as an idiopathic musculoskeletal disorder characterized by pain, stiffness, and capsular fibrosis, is increasingly recognized as the clinical manifestation of systemic endocrine, metabolic, vascular, and immunological dysfunctions. This narrative review reframes FS within a broader neuro–endocrine–immunometabolic model, emphasizing the central role of estrogen deficiency, resistance, and receptor-level disruption, together with their interactions with thyroid dysfunction, endothelial health, and lifestyle-related low-grade inflammation (LGI). Evidence from epidemiological, clinical, and mechanistic studies shows that estrogen signaling failure weakens anti-inflammatory, antifibrotic, and antioxidant defenses, predisposing peri- and postmenopausal women to more severe FS phenotypes. Thyroid dysfunction, particularly hypothyroidism, further contributes to fibrosis and pain sensitization. Endothelial dysfunction—driven by poor diet, advanced glycation end-products (AGEs), and oxidative stress—impairs vascular integrity and promotes local microvascular inflammation. In parallel, lifestyle factors such as sedentarism, circadian misalignment, psychosocial stress, and environmental exposures sustain systemic LGI and hormonal resistance. Together, these interconnected mechanisms suggest that FS is not merely a localized joint pathology but a systemic disorder requiring integrative clinical strategies that combine orthopedic management with endocrine evaluation, metabolic monitoring, dietary interventions, circadian health, and stress regulation. In addition, this review outlines specific clinical implications, highlighting how an integrative, personalized approach that targets hormonal, metabolic, vascular, and lifestyle dimensions may improve pain, function, and long-term prognosis in FS. This paradigm shift underscores the need for future research to focus on stratified patient profiling and interventional trials targeting hormonal, vascular, and lifestyle axes to improve outcomes, particularly in women who remain disproportionately affected by FS. Full article

Diabetes mellitus is a chronic metabolic disorder that facilitates the formation of advanced glycation end products (AGEs), which contribute to oxidative stress, inflammation, and vascular damage, causing complications including nephropathy, neuropathy, and atherosclerosis. AGEs are primarily synthesized through the Maillard reaction, alongside various signaling pathways. Activation of the receptor for AGE (RAGE) triggers inflammatory signaling pathway cascades, exacerbating tissue damage. Phenolic compounds found in plant-based foods, such as quercetin and resveratrol, have shown promise in counteracting AGE-related complications through their antioxidant and anti-inflammatory effects that inhibit AGE formation, reduce oxidative stress, and modulate RAGE signaling, while also enhancing insulin sensitivity and improving glucose homeostasis. Indeed, quercetin can help prevent AGE accumulation and reduce diabetic nephropathy, while resveratrol activates the SIRT1 pathway, improving insulin sensitivity. This review examines the mechanisms through which phenolic compounds mitigate AGE-induced diabetic complications, using computational, in vitro, preclinical, and clinical evidence. This review also explores the synergistic effects of these compounds with conventional antidiabetic drugs, addresses bioavailability challenges, and suggests future research directions. Overall, this review offers a comprehensive understanding of the role of phenolic compounds in managing diabetes, underscoring their potential as complementary agents in diabetes therapy and developing more effective natural treatments. Full article

Myofibroblasts drive wound healing and fibrotic disease through generation of contractile force to promote wound closure and production of matrix proteins to generate scar tissue. Platelets secrete many pro-wound healing molecules, including cytokines and growth factors. We previously reported that inorganic polyphosphate, secreted by activated platelets, is chemotactic for fibroblasts and induces a myofibroblast phenotype. Using NIH-3T3 cells and primary human fibroblasts, we examined the impact of inhibitors of cell-surface receptors and intracellular signaling molecules on polyphosphate-induced myofibroblast differentiation. We now report that polyphosphate-induced differentiation of fibroblasts to myofibroblasts occurs through a signaling pathway mediated by the receptor for advanced glycation end products (RAGE) and nuclear factor kappa B (NFκB) transcription factor. Inhibition of these signaling components ablated the effects of polyphosphate on fibroblasts. Platelet releasates also induced NFκB signaling and myofibroblast differentiation. Blocking the polyphosphate content of platelet releasates with a biocompatible polyP inhibitor rendered the releasates unable to induce myofibroblast differentiation. These results identify a cell-surface receptor and intracellular transcription factor utilized by platelet polyphosphate to promote wound healing through myofibroblast differentiation and may provide targets for promoting wound healing or altering the disease progression of fibrosis. Full article

Background/Objectives: Diabetic nephropathy (DN) is a major complication of diabetes and a leading cause of end-stage renal disease, a condition associated with high mortality risks. Recently, supplementation with probiotics and postbiotics has been attracting attention. Especially, metabolites of natural products bioconverted by beneficial bacteria have emerged as a novel therapeutic intervention for metabolic diseases, including diabetes, due to the enhanced bioavailability of their metabolites. This study investigated the alleviating effects of metabolites derived from guava leaf extract bioconverted by Limosilactobacillus fermentum (GBL) on renal inflammation in type 2 diabetic mice. Methods: For this purpose, diabetes was induced in male C57BL/6J mice by a high-fat diet and streptozotocin injection (80 mg/kg BW) twice. Subsequently, mice with fasting blood glucose levels higher than 300 mg/dL were administered metabolites of L. fermentum (LF) (50 mg/kg BW/day) or guava leaf extract bioconverted by L. fermentum (GBL) (50 mg/kg BW/day) by oral gavage for 15 weeks. Results: GBL demonstrated potential in alleviating hyperglycemia-induced DN in diabetic mice. It markedly improved hyperglycemia, glucose tolerance, and morphological alterations, which might stem from activation of key regulators of energy metabolism. GBL uniquely reduced advanced glycation end products (AGEs) and suppressed nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-driven inflammatory pathways, which significantly alleviated oxidative stress and apoptosis. Conclusions: This highlights the distinct therapeutic efficacy of GBL in addressing DN, primarily through its effects on renal inflammation. Taken together, GBL can be used as a promising nutraceutical to mitigate hyperglycemia and its associated renal inflammation, thereby alleviating the progression of DN. Full article

Glioblastoma (GBM) remains the most lethal primary brain tumor, owing to profound intratumoral heterogeneity and the limited efficacy of standard treatments. The mesenchymal (MES) molecular subtype is particularly aggressive, exhibiting heightened invasiveness, therapy resistance, and dismal patient survival compared with the proneural (PN) subtype. Emerging evidence implicates the High Mobility Group Box 1 (HMGB1) protein and its cognate receptor, the Receptor for Advanced Glycation End Products (RAGE), as drivers of malignant progression, yet their contribution to the PN-to-MES transition is incompletely defined. We integrated transcriptomic analyses of TCGA-GBM and TCGA-LGG cohorts with immunohistochemistry on in-house patient specimens. Functional studies in patient-derived and established GBM cell lines included migration and invasion assays, tumorsphere formation assays, shRNA knockdowns, and Seahorse XF metabolic profiling to interrogate the HMGB1-RAGE axis. HMGB1 and RAGE expression was markedly elevated in MES GBM tissues and cell lines. Importantly, higher HMGB1 expression correlated with shortened overall survival (p < 0.009). HMGB1 silencing curtailed cell motility and downregulated core epithelial-to-mesenchymal transition markers (N-cadherin, Snail). RAGE knockdown diminished tumorsphere formation efficiency and reduced transcription of stemness genes (OCT4), underscoring its role in sustaining tumor-initiating capacity. Metabolically, HMGB1/RAGE activation boosted both mitochondrial respiration and glycolysis, conferring the bioenergetic flexibility characteristic of MES GBM. The HMGB1-RAGE signaling axis orchestrates mesenchymal identity, invasiveness, stem cell-like properties, and metabolic reprogramming in GBM. Targeting this pathway may disrupt the PN-to-MES transition, mitigate therapeutic resistance, and ultimately improve outcomes for glioblastoma patients. Full article

Glyoxalase 1 (Glo1) functions as a catalyst that neutralizes methylglyoxal (MG), a highly reactive glycating agent predominantly produced during glycolysis—a metabolic pathway upregulated in cancer cells. MG primarily reacts with the amino groups of proteins (especially at arginine residues), leading to the formation of a major advanced glycation end product known as MG-derived hydroimidazolone 1 (MG-H1). We previously demonstrated in PC3 human prostate cancer (PCa) cells that the PTEN/PKM2/ERα axis promotes their aggressive phenotype by regulating the Glo1/MG-H1 pathway. In this study, after confirming our earlier findings, we investigated the downstream mechanisms of the PTEN/PKM2/ERα/Glo1/MG-H1 axis in controlling PC3 cell growth, focusing on the role of RAGE, a high-affinity receptor for MG-H1; hydrogen peroxide (H₂O₂); and Krev interaction trapped 1 (KRIT1), an emerging tumor suppressor. Using genetic approaches and specific inhibitors/scavengers, we demonstrated that the PTEN/PKM2/ERα/Glo1/MG-H1 axis promotes PC3 cell growth—measured by proliferation and etoposide-induced apoptosis resistance—through a mechanism involving MG-H1/RAGE pathway desensitization that leads to H₂O₂-mediated KRIT1 downregulation. These findings support and expand the role of PTEN signaling in PCa progression and shed light on novel mechanistic pathways driven by MG-dependent glycative stress, involving KRIT1, in this still incurable stage of the disease. Full article

Chronic rhinosinusitis (CRS) is characterized by sinonasal inflammation, mucus overproduction, and edematous mucosal tissue. This inflammatory condition is characterized by mucosal thickening, nasal obstruction, facial pain or pressure, hyposmia, and nasal discharge. The aim of this research was to clarify a potential role for the receptor for advanced glycation end-products (RAGE) in mouse nasoantral epithelium in perpetuating pro-inflammatory cytokine elaboration similarly expressed by CRS patients. Specifically, wild-type (WT) mice and transgenic (TG) mice overexpressing RAGE in sinonasal epithelium (RAGE TG mice) were maintained in room air or subjected to secondhand smoke exposure using a nose-only delivery system (Scireq Scientific, Montreal, QC, Canada) for five days per week over a 30-day period. Histological analysis was performed using staining for RAGE. Tissue lysates were analyzed for pro-inflammatory cytokines. We observed increased RAGE expression in sinus tissue following SHS exposure and in sinuses from RAGE TG mice in the absence of SHS. We also discovered elevated T helper (Th)1 products (TNF-α, IL-1β, IFN-γ) and Th2/Th17 (IL-5, IL-13, IL-17A) cytokine abundance in SHS-exposed WT and SHS-exposed RTG tissues compared to room air controls. These findings highlight the pivotal role of RAGE signaling in the exacerbation of inflammatory processes, particularly in the context of chronic inflammation induced by smoke exposure. The study expands our understanding of the RAGE signaling axis as a key contributor to the progression of smoke-related lung and sinonasal pathologies. Targeting RAGE-mediated pathways could represent a novel therapeutic strategy to mitigate the progression of chronic sinusitis associated with smoke exposure. Full article

The mechanisms underlying the abnormal activation of microglia affecting cognitive function under high-altitude hypobaric hypoxia (HAHH) have not been fully elucidated. This study aims to investigate the effects of HAHH on the expression of the receptor for advanced glycation end-products (RAGE) in hippocampal microglia of mice and to explore the role of RAGE inhibitors in alleviating HAHH-induced microglial inflammation and cognitive impairment. Mice were exposed to HAHH via a multi-environment simulation chamber, and RNA sequencing, qPCR, WB, flow cytometry and immunohistochemistry showed that HAHH exposome significantly increased RAGE expression in hippocampal microglia of mice (p < 0.001 vs. normoxia), which was closely related to microglial neuroinflammatory responses. RAGE inhibitor (FPS-ZM1) alleviated HAHH-induced microglial inflammation (TNF-α decreased by 64%, p < 0.001; CD86⁺ cells decreased by 42%, p < 0.001) and improved cognitive function in mice (Y-maze novel arm time: 28.08 ± 5.14 s vs. hypoxia 19.67 ± 4.68 s, p = 0.016; NORT recognition index: 0.52 ± 0.05 vs. hypoxia 0.33 ± 0.07, p < 0.001). Mechanistic studies revealed that RAGE inhibitors reduced microglial inflammation by inhibiting the MAPK pathway and decreasing nuclear translocation of NF-κB p65. Furthermore, high-mobility group box 1 (HMGB1) expression increased under hypoxic conditions (p < 0.001 vs. normoxia) and positively regulated RAGE expression. HMGB1 inhibitors reduced RAGE expression and attenuated HAHH-induced microglial inflammation. Overall, the HAHH exposome induces microglial inflammation via the HMGB1-RAGE-NF-κB pathway. RAGE and HMGB1 inhibitors may serve as novel therapeutic strategies to mitigate HAHH-induced cognitive impairment, providing a theoretical basis for the treatment of cognitive impairment. Full article