Search Results (1,265)

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

Advanced glycation end products (AGEs) are molecules formed via non-enzymatic reactions between reactive dicarbonyls and macromolecules, including proteins, lipids, or DNA. Mitochondria sense and integrate stress signals and induce changes in cellular function by regulating metabolism, redox balance, and proteostasis to maintain homeostasis, a process known as mitohormesis. Dysregulation of cellular metabolism and redox imbalance are the major driving forces behind the increased production of intracellular reactive dicarbonyls and AGEs. Although the association between increased reactive dicarbonyl levels and cancer development has been investigated, its causal relationship remains controversial. This review integrates recent evidence on the association between increased levels of reactive dicarbonyls and mitochondrial dysfunction and provides mechanistic insights into carcinogenesis associated with AGE-mediated disruption of mitohormesis. 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

Frying food can provide an attractive flavor relatively quickly; however, it inevitably produces some safety risks during high-temperature processing, with potentially adverse human health effects. Prolonged exposure to high temperatures during frying might raise the concentration of some harmful compounds that accumulate from the complex chemical reactions taking place inside the food matrix. This review elaborates on the development of food risk factors during frying, adding acrylamide (AA) and advanced glycation end products (AGEs), which are involved in various health problems, including chronic illnesses and carcinogenesis. The two commonly recognized pathways for acrylamide formation include the Maillard reaction pathway and the acrylic acid pathway, with the Maillard reaction considered to be the primary pathway for AGE formation. The processing conditions and food components that affect the formation of these toxic compounds are then specified, demonstrating the importance of factors including type of oil, composition of food (such as moisture and fat content), frying temperature, and duration. Finally, the corresponding health hazards posed by the risk factors are summarized, with an emphasis on the long-term effects of acrylamide and AGE exposure on human health. Increased risks of neurotoxicity, cancer, inflammation, and metabolic diseases have been associated with both compounds. The aim is to clarify the formation pathways, influencing factors, and health impacts of risk factors in frying food and to provide a reference for the prevention of food safety problems caused by acrylamide and advanced glycation end products. Full article

Advanced glycation end-products (AGEs) are associated with the dysfunction of proximal tubular epithelial (PTE) cells in lifestyle diseases. Urinary stones induce cytotoxicity in PTE cells, and various medicines have been developed to mitigate or prevent their generation/accumulation. The leaves of Quercus salicina Blume/Q. stenophylla Makino—used in Japanese folk medicine—contain quercetin, hesperidin, and p-hydroxycinnamic (p-coumaric) acid, which can suppress the cytotoxicity of intra-/extracellular AGEs. This review investigated the effects of quercetin, hesperidin, and p-coumaric acid on PTE cells in terms of their metabolism following oral administration and the associated organs and bacteria. Current evidence indicates that, in PTE cells, non-metabolized quercetin and p-coumaric acid may suppress intra-/extracellular AGE-induced cytotoxicity, whereas the metabolites of quercetin and hesperidin may inhibit the generation of AGEs. However, little is known of the effects of p-coumaric acid metabolites. Quercetin, hesperidin, and p-coumaric acid may collectively suppress the cytotoxicity of intra-/extracellular AGEs in PTE cells. This review on the current paradigm of Q. salicina/Q. stenophylla extract provides a useful baseline for the design of further preclinical and clinical investigations. Full article

Oral mucositis (stomatitis) is a painful condition that affects the mouth lining. Kampo medicines (e.g., Hangeshashinto [Chinese name, Ban-Xia-Xie-Xin-Tang], Orento, and Orengedokuto) have been widely used to treat stomatitis, such as gargling with Hangeshashinto. However, the mechanisms by which Kampo medicines work are not widely understood due to their oral administration and the subsequent digestion, absorption, and metabolization of their components. Stomatitis is associated with advanced glycation end-products (AGEs) in patients with lifestyle diseases, and can be induced by both intra- and extracellular AGEs (blood and dietary AGEs). Various natural products inhibit intracellular AGE generation and suppress cytotoxicity, such as inflammation caused by extracellular AGEs. This review summarizes 19 natural products identified in the Hangeshashinto water extract and 16 natural products identified in the crude drug extract. The data show that several natural products, such as glycyrrhizin, baicalin, 6-shogaol, quercetin, epigallocatechin-3-galate, and genistein, inhibit intracellular AGEs and suppress extracellular AGE inflammation. Furthermore, several natural products in the Hangeshashito water extract can suppress cytotoxicity in stomatitis. 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

Background/Objectives: The accumulation of Nε-carboxymethyllysine (CML), a major advanced glycation end product (AGE), has been implicated in neuronal dysfunction by promoting oxidative stress, endoplasmic reticulum (ER) stress, and dysregulation of amyloid-β (Aβ) metabolism. This study evaluated the neuroprotective properties of coixol, a naturally occurring polyphenolic compound derived from the outer layers of Coix lacryma-jobi L. var. ma-yuen, in a CML-induced injury model using IMR-32 human neuronal-like cells. Methods: Cells were pretreated with coixol (1 μmol/L), N-acetyl-L-cysteine (NALC, 1 mmol/L), or 4-phenylbutyric acid (4-PBA, 200 μmol/L) for 1 h prior to CML (100 μmol/L) exposure for 24 h. Cell viability was determined by colorimetric analysis of 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide, while intracellular reactive oxygen species (ROS) generation was quantified using a fluorescence-based oxidative stress probe. Activities of key antioxidant enzymes and caspase-3 were determined using commercial assay kits. The expression of Aβ isoforms, amyloidogenic enzymes, ER stress markers, and apoptosis-related signaling proteins was quantified through validated immunoassays. Results: Coixol pretreatment significantly enhanced cell viability by attenuating ROS accumulation and restoring antioxidant enzyme activities. Concurrently, coixol suppressed ER stress signaling via downregulation of the protein kinase R-like ER kinase/C/EBP homologous protein axis and modulated apoptosis by increasing B-cell lymphoma (Bcl)-2, reducing Bcl-2-associated X protein expression, and inhibiting caspase-3 activation and DNA fragmentation. Furthermore, coixol regulated Aβ metabolism by inhibiting the expression of β-site amyloid precursor protein-cleaving enzyme 1 and presenilin 1, while restoring insulin-degrading enzyme and neprilysin levels, leading to reduced accumulation of Aβ40 and Aβ42. Conclusions: Compared to NALC and 4-PBA, coixol demonstrated comparable or superior modulation across multiple pathological pathways. These findings highlight coixol’s potential as a neuroprotective candidate in AGE-associated neurodegenerative conditions. 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

Advanced glycation end products (AGEs) are reactive compounds formed through non-enzymatic glycation in a process known as the Maillard reaction. While humans produce AGEs endogenously, these compounds can also enter the body through dietary sources, food preparation methods, and exposure to agricultural and food-related chemicals. AGEs can accumulate within cells and impair cellular function. In addition, when AGEs bind to receptors for advanced glycation end products (RAGE), they activate intracellular signaling pathways that promote the generation of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation. Sustained AGE-RAGE signaling drives chronic inflammation contributing to the development of various ailments, including neurodegenerative diseases. This review examines AGE formation, metabolism, and accumulation, with an emphasis on dietary sources as modifiable contributors to AGE-RAGE mediated pathology. We highlight the need for further research on dietary AGE restriction as a potential strategy to prevent or slow the progression of neurodegenerative and neuroinflammatory disorders. Full article

Gout and calcium pyrophosphate crystal deposition disease (CPPD) are frequently associated with comorbid disorders, including coronary artery disease and osteoarthritis, in which ectopic calcification with basic calcium phosphate crystals commonly affects arteries and articular cartilage, respectively. Accepting the 2024 G-CAN Gold Medal, I review my research philosophy for translational etiopathogenesis investigation in gout and CPPD, atherosclerosis, responses to arterial injury, and osteoarthritis. Since molecular homeostasis points to pathophysiology and vice versa, I have followed selected molecular players and pathways to phenotypes. Typically, behind each disease target is another target. Illuminating passageways between etiopathogenic pathways is especially productive when using approaches beyond conventional “omics” to reveal the impact of specific post-translational protein modifications, and changes in protein conformation, complex assembly, and interactomes. Highlighting these concepts, I review my past studies on specific molecular pathways, and current perspectives for the following: (i) PP_i, NPP1, ANKH, and transglutaminase 2 (TG2); (ii) relationships between NPP1, ANKH, Vanin-1 Pantetheinase, and ectopic chondrogenesis; (iii) intersections between adenosine, AMPK, CXCL8 and its receptor CXCR2, the receptor for advanced glycation endproducts (RAGE) and chondrocyte hypertrophy; (iv) lubricin homeostasis and proteolysis; (v) receptor for advanced glycation endproducts (RAGE) and TG2-catalyzed post-translational calgranulin modification; (vi) complement activation and C5b-9 assembly, and the nucleotide-bound conformation of TG2. The inescapable conclusion is that these molecular pathways tightly knit crystal arthropathy with both arterial and osteoarthritis comorbidity. Full article

Background/Objectives: Frailty is increasingly recognised as an important contributor to outcomes following cardiac surgery. There are various measures of frailty described, but many include subjective assessments impacting reliability and reproducibility of measurement. A potential biomarker: advanced glycation end products (AGEs) have been suggested to closely correlate with frailty. This may offer the opportunity to objectively measure frailty and have potential use in preoperative risk assessment. The objective and aim of this narrative review is to assess the association between AGEs and outcomes following surgery, in order to evaluate the use of AGEs for preoperative risk assessment. Methods: This review involved searching five databases including the following: MEDLINE (through Ovid), Embase, Cochrane, ClinicalTrials.gov, and a specified Google Scholar search for studies published between database inception and 20 February 2025. The 1142 identified articles were then subjected to various inclusion and exclusion criteria. This exclusion criteria included all articles that were not in the English language, studies involving patients under 18 years of age, and studies that were incomplete or for whom the data was not yet available. This left 11 articles for which a ‘related articles’ search was performed on Google Scholar on 6 March 2025, as per the PRISMA-S extension guidelines, to obtain all relevant articles available. In the end, data analysis was conducted on 13 articles with a total of 2402 participants. These were categorised by type of surgery before analysis was performed for each surgical category. The quality of evidence was assessed using ROBINS-I tool and a risk of bias table has been provided. This study was provided no external sources of funding. Results: Four out of the five studies in cardiac surgery showed a statistically significant association between AGE levels and post-operative complications and outcomes. This association was also seen across thoracic and general surgery. Association was demonstrated with various post-operative complications as well as mortality. These relationships are supported by various pathophysiological mechanisms, including the ability of AGEs to induce oxidative stress, activate inflammatory mediators, and cause endothelial dysfunction. Conclusions: There is a body of evidence supporting the association between AGEs level and cardiac surgical outcomes. This objective measure of frailty could have significant utility in preoperative risk assessment and offer the opportunity to identify patients who will benefit from undergoing prehabilitation. Full article

Background: Metabolic memory refers to the long-term adverse effects of short-term disturbances in glucose metabolism. Recent evidence indicates that hyperglycemia-induced metabolic memory contributes to sustained cellular damage even after glycemic control, driven by increased production of reactive oxygen species (ROS), activation of inflammatory pathways, and accumulation of advanced glycation end products (AGEs). Although well characterized in endothelial and smooth muscle cells, this phenomenon may also occur in other cell types, including glial cells. Objective: This study aimed to evaluate the persistence of high-glucose (HG)-induced alterations after returning to normal glucose (NG) conditions in primary mixed glial cell (MGC) cultures. Methods: Primary MGCs were obtained from neonatal Wistar rat pups and cultured under three conditions for 21 days: NG (5.5 mM glucose), HG (25 mM glucose), and HG-NG (14 days in HG followed by 7 days in NG). Cell proliferation, apoptosis, ROS production, lipid peroxidation, mitochondrial activity, TNF-α, IL-6, and AGE formation were assessed. Results: MGCs cultured under HG and HG-NG conditions exhibited reduced proliferation without increased apoptosis. Both HG and HG-NG conditions promoted ROS overproduction accompanied by reduced mitochondrial activity, whereas only HG increased lipid peroxidation. Notably, TNF-α and AGE levels were elevated in both HG and HG-NG conditions, while IL-6 production decreased exclusively in HG-NG. Conclusions: These findings demonstrate the persistence of deleterious effects induced by HG in MGCs, even after restoration to NG conditions. Full article

Objectives: Skin aging, often accelerated by dietary advanced glycation end products (AGEs), poses both cosmetic and health challenges. This study explores the protective effects of hydroxytyrosol (HT), a potent antioxidant found in olives, against AGEs-induced skin aging in mice. Methods: A total of forty-eight 8-month-old specific pathogen-free (SPF) male C57BL/6J mice were randomly assigned to one of four groups: control, model, low-dose hydroxytyrosol (HT25), and high-dose hydroxytyrosol (HT50). An additional group of six 6-week-old SPF male C57BL/6J mice served as the youth group. The experimental period lasted 16 weeks. Following the intervention, skin, serum, and ileum samples were collected. Results: The results demonstrated that HT50 significantly increased skin moisture, epidermal thickness, and dermal thickness (p < 0.05). HT50 also significantly elevated hydroxyproline levels as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the skin while reducing malondialdehyde (MDA) content (p < 0.05). Furthermore, HT50 significantly reduced the levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) (p < 0.05). Regarding intestinal integrity, hydroxytyrosol intervention (either HT25 or HT50) significantly increased the positive staining ratios of zonula occludens-1 (ZO-1) and occludin in the ileum (p < 0.05). Conclusions: HT improves skin hydration, thickness, and collagen levels while reducing oxidative stress and inflammation. Notably, HT also enhances intestinal barrier function, suggesting a role for the gut–skin axis. These findings highlight HT’s potential as a natural intervention for skin aging. Full article