Search Results (1,403)

Dietary patterns associated with high glycemic load and recurrent postprandial glucose excursions may influence skin physiology through mechanisms involving oxidative stress, insulin–IGF-1 signaling, chronic low-grade inflammation, and advanced glycation end product (AGE) formation. Disturbances in glucose homeostasis have been associated with alterations in epidermal barrier integrity, sebaceous gland activity, extracellular matrix remodeling, and tissue repair processes. These mechanisms have been investigated primarily in relation to several dermatological conditions, particularly acne vulgaris, impaired wound healing, xerosis, and skin aging. This narrative review summarizes current evidence regarding the relationship between glycemic dysregulation and skin health, with emphasis on metabolic and molecular pathways potentially involved in cutaneous dysfunction. To reflect the current strength of evidence, mechanistic studies, observational studies, and clinical investigations are distinguished throughout this review whenever possible. Particular focus is placed on postprandial glycemic variability, oxidative stress, hormonal signaling, and glycation-related tissue damage. Current evidence supports biologically plausible associations between metabolic dysregulation and several aspects of skin dysfunction, although direct evidence specifically addressing glycemic variability remains limited. Most available studies are observational or mechanistic in nature, and relatively few clinical investigations have evaluated dermatological outcomes directly. Further research is needed to clarify the clinical relevance of glycemic-targeted dietary and metabolic interventions in dermatology. Full article

Background and Objectives: Diabetes mellitus is a major systemic modifier of oral infection, periodontal inflammation, and tissue healing. Persistent hyperglycemia may intensify oxidative stress, immune dysfunction, dysbiotic biofilm activity, and advanced glycation end-product/receptor signaling, thereby reducing the predictability of periapical and periodontal healing. In patients with endo-periodontal lesions, these mechanisms may interact with pulpal infection and periodontal breakdown, complicating diagnosis, prognosis, and therapeutic sequencing. This review summarizes current evidence on diabetes, glycated hemoglobin (HbA1c), and endo-periodontal outcomes and proposes an HbA1c-guided clinical framework for risk stratification and treatment planning. Materials and Methods: A structured narrative review with an expert-informed clinical framework was conducted using the literature published between January 2016 and December 2025. Eligible sources included consensus reports, clinical practice guidelines, systematic reviews, meta-analyses, umbrella reviews, randomized and non-randomized clinical studies, observational studies, and selected mechanistic studies or contemporary narrative reviews with direct relevance to the framework. Case reports, animal studies, and in vitro investigations without direct relevance to the clinical framework were excluded from the main synthesis. Results: Diabetes is associated with increased periodontal severity, impaired periodontal treatment response, a higher prevalence of radiolucent periapical lesions in root-filled teeth, delayed periapical healing, and increased non-retention of endodontically treated teeth. Periodontal therapy is safe in diabetic patients and may be associated with modest reductions in HbA1c, especially when baseline metabolic control is poor. Conclusions: HbA1c should complement, not replace, pulpal testing, periodontal charting, and radiographic assessment. The proposed framework prioritizes endodontic infection control when pulpal necrosis or active intracanal infection is present, adapts periodontal intervention to metabolic risk, and postpones elective surgical or regenerative procedures in poorly controlled diabetes until medical stabilization is achieved. Full article

Diabetes Mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia resulting from the body’s inability to produce insulin or effectively respond to it. In this review, we summarize the cellular and molecular mechanisms involved in common clinical manifestations of DM, including neuropathy, retinopathy, nephropathy, sensorineural hearing loss, cardiovascular disease, stroke, immune dysfunction, and chronic wounds. Common pathways explored in these dysfunctions include the polyol pathway, formation of advanced glycation end products (AGEs) and their interaction with the receptor for advanced glycation end products (RAGE), mitochondrial dysfunctions leading to overproduction of reactive oxygen species (ROS), and the chronic state of inflammation and inflammatory cytokines. Furthermore, we explore current and developing treatments for DM, along with more targeted therapies for the clinical manifestations of DM. In summary, this review gives a comprehensive overview of the pathways involved in the clinical manifestations of DM, and how these pathways are targets for therapeutics and treatments. Full article

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that requires novel therapeutic targets and selective repurposed drugs with low systemic toxicity. Here, we evaluated the clinically approved M3 muscarinic receptor antagonist, Darifenacin (DF), against Jurkat and MOLT-4 T-ALL cells, as well as healthy human T lymphocytes, under identical conditions. DF induced selective, concentration-dependent cytotoxicity with IC₅₀ values of 26.7 ± 1.07 µM (Jurkat) and 30.5 ± 1.54 µM (MOLT-4), whereas healthy T lymphocytes exhibited an apparent IC₅₀ of 197.9 ± 1.29 µM, corresponding to a 6.5–7.4-fold therapeutic window. Mechanistically, DF decreased M3 receptor and choline acetyltransferase expression and increased acetylcholinesterase activity. Convergent multi-assay validation confirmed that this cytotoxicity was driven by activation of the intrinsic mitochondrial apoptotic pathway, as evidenced by increased Bax, decreased Bcl-2, and cleavage of the executioner caspase-3. Furthermore, DF induced glycative stress through the accumulation of methylglyoxal (MG) and advanced glycation end products (AGEs), and selectively inhibited lysosomal Cathepsins B and C. Molecular docking predicted highly favorable molecular binding within the catalytic cavities of these proteases. These findings suggest that DF exhibits selective antileukemic activity by simultaneously disrupting cholinergic signaling, inducing glycative stress, inhibiting cathepsins, and triggering apoptosis. Thus, DF emerges as a promising candidate for multi-target drug repurposing in T-ALL therapy. Full article

Background. Cardiometabolic diseases are the leading cause of morbidity and mortality worldwide and are driven by risk factors such as hypertension, diabetes mellitus, and dyslipidemia. Early vascular aging (EVA) is a pathological process characterized by accelerated arterial stiffness and endothelial dysfunction, which increase the risk of cardiovascular events. Key markers of EVA include advanced glycation end products (AGEs), aortic pulse wave velocity (a-PWV), glycated hemoglobin A1c (HbA1c) and pulse pressure (PP). Although these markers are individually associated with cardiovascular outcomes, there is still limited evidence from longitudinal studies evaluating their combined association with cardiometabolic diseases and hypertension, particularly with consideration of gender differences. Therefore, in this study, data from the two-year EVasCu cohort were used to analyze the associations between EVA and cardiometabolic diseases and hypertension; the associations between EVA related parameters (AGEs, a-PWV, HbA1c and PP) were evaluated, and these associations were assessed by gender. Methods. AGE, a-PWV, HbA1c and PP were measured as indicators of EVA, in addition to sociodemographic and clinical variables. Logistic regression was applied to assess the association between EVA and cardiometabolic diseases (including hypertension, diabetes mellitus, acute myocardial infarction (AMI), dyslipidemia, angina pectoris, and heart failure (HF)) and hypertension, adjusting for age, gender and risk factors. Results. A 2-year longitudinal study was conducted with 200 adults in Cuenca, Spain. EVA was significantly associated with the development of cardiometabolic diseases (OR = 1.38; p = 0.028) and hypertension (OR = 1.63; p = 0.015), which was more pronounced in females. Cardiometabolic diseases and hypertension were associated with a-PWV and PP, but not with AGEs or HbA1c. Conclusions. a-PWV and PP are predictors of cardiometabolic diseases and hypertension, especially in females. Early detection and preventive strategies are essential for detecting cardiovascular risk and mitigating consequences. Further studies are needed to investigate the relationships between EVA and cardiometabolic factors. Full article

As a typical marker of dietary advanced glycation end products (AGEs), Nε-carboxymethyllysine (CML) exists in both free and protein-bound forms in foods, exhibiting distinct intestinal transport behaviors. This study aimed to characterize the transepithelial transport, intracellular accumulation and transport pathways of free CML (FC) and protein-bound CML (BC, BSA-CML) using Caco-2 cell monolayers. Since protein-bound CML undergoes digestion in the gastrointestinal tract, BC was subjected to simulated gastrointestinal digestion before transport experiments to better mimic human digestion (BC digests). The results showed that FC exhibited significantly greater transepithelial transport across Caco-2 cell monolayers than BC digests. The transport rate of CML from FC across Caco-2 cell monolayers was 13.04%, significantly higher than that of BC digests (0.99%). Consistently, the intracellular accumulation of total CML was higher for FC (2.62%) than for BC digests (0.14%). Furthermore, FC transport appeared to occur mainly via simple diffusion, whereas the transepithelial transport of CML derived from BC digests likely involved a peptide transporter 1 (PepT1)-associated transport pathway. These findings provide insights into the transepithelial transport pathways and intracellular accumulation of dietary free and bound AGEs. Full article

Organogermanium compounds, particularly carboxyethyl germanium sesquioxide (Ge-132), have been studied for decades because of their diverse biological effects, especially their antioxidant properties. However, the available literature remains fragmented and highly heterogeneous, which limits mechanistic interpretation. Although antiglycative activity has been described at the biochemical level, the downstream transcriptional effects of Ge-132 under glycative stress remain poorly characterized. Here, we combined an evidence-mapping analysis with targeted molecular analysis in a standardized cellular model to examine whether the antiglycative effects of Ge-132 are accompanied by coordinated transcriptional responses. The mapping guided selection of markers associated with glycative stress, including carbonyl detoxification, redox adaptation, autophagy, lysosomal function, and inflammatory signaling. Gene expression analysis revealed limited and selective transcriptional modulation under glycative stress conditions. In parallel, protein analysis showed reduced intracellular accumulation of advanced glycation end products (AGEs) in Ge-132–treated. These findings suggest that reduction of glycative damage can occur without proportional transcriptional activation of stress-response pathways under the conditions tested. However, alternative explanations, such as model constraints, acute exposure duration, or limited gene panel sensitivity, cannot be excluded. Full article

Women with polycystic ovary syndrome (PCOS) and insulin resistance (IR) commonly have elevated serum advanced glycation end-products (AGEs) that accumulate in their ovaries, potentially altering ovarian function. AGEs have been shown to interfere with insulin signaling in granulosa cells (GCs) by suppressing the translocation of glucose transporters. Additionally, PCOS has been associated with insulin receptor substrate (IRS)-1 polymorphisms and upregulation in IRS-1 gene expression in GCs. We hypothesize that AGEs are partly responsible for ovarian IR by altering IRS-1 in human GCs. Cumulus granulosa cells from women undergoing IVF were cultured in control media or media containing human glycated albumin (HGA) as a source of AGEs. The quantification of mRNA expression was compared using RT-PCR for receptors for AGEs (RAGE), IRS-1, IRS-2, Glucose Transporter Type (GLUT)-1, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In addition, IRS-1 protein intensity was assessed by immunofluorescence. Compared to the control group, HGA-treated GCs showed a statistically significant upregulation in RAGE mRNA by 314% and in IRS-1 mRNA by 423%. Even though there was a 183% increase in GLUT-1 mRNA, it did not reach statistical significance. There was no change in IRS-2 or NF-κB mRNA expression levels. Immunofluorescence showed that IRS-1 deposition was visualized in GCs, and the addition of HGA resulted in a significant increase in the intensity of IRS-1 protein compared to control cells. The AGE-induced upregulation in IRS-1, the primary insulin receptor substrate, in GCs could indicate compensation for insulin action deficiency and potentially IR. Additionally, immunofluorescence analysis of GLUT-4 revealed a statistically significant reduction in cytoplasmic GLUT-4 signal in HGA-treated GCs compared to controls (2.10 ± 0.21 vs. 3.81 ± 0.22 arbitrary units; p = 0.010), consistent with AGE-mediated disruption of glucose transporter localization. These results suggest that AGE exposure may initiate early molecular changes consistent with altered insulin signaling, but do not establish insulin resistance per se. Full article

Exploration of the gene-level changes that occur during post-ischemic neurodegeneration in the frontal cortex is crucial for understanding the development of dementia. An ischemic model of Alzheimer’s disease was used to evaluate changes in the expression of the receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein 1 (LRP1), which are associated with amyloid and tau protein, in the frontal cortex after 10 min of cerebral ischemia, with survival at 2, 7, and 30 days and 0.5, 1, 1.5, and 2 years. LRP1 and RAGE expression was assessed by reverse transcription-quantitative polymerase chain reaction. After two days and 1.5 and 2 years post-ischemia, LRP1 expression was increased, after 7 days and 0.5 years it was decreased, and after 30 days and 1 year it oscillated around control values. The decrease in RAGE expression was statistically significant compared to the control group after 2 and 7 days and after 0.5 years, and after 30 days it oscillated around the control value, while after 1–2 years it increased significantly. RAGE and LRP1 expression showed the same pattern of changes from day 7 to year 2, peaking at 1 and 1.5 years, respectively. Another peak of RAGE overexpression was noted 2 years after ischemia. After 1, 1.5 and 2 years, overexpression of RAGE and LRP1 was observed after ischemia, with the dynamics of LRP1 changes being lower. Overall, the data showed a predominance of RAGE expression over LRP1 expression at 1-, 1.5-, and 2-years post-ischemia. The modification of LRP1 and RAGE after ischemia is useful in studying the molecular ischemic pathways involved in the development of Alzheimer’s disease. Full article

Acute inflammatory disorders, including acute lung injury, acute pancreatitis, ischaemia–reperfusion injury, and sepsis, are major clinical challenges characterised by rapid progression, a characteristic cytokine storm, and high mortality rates. The receptor for advanced glycation end-products (RAGE) serves as a pivotal multi-ligand pattern recognition receptor that integrates PAMPs and DAMPs. Excessive RAGE engagement triggers detrimental signalling cascades, notably NF-κB and MAPKs, which exacerbate hyperinflammation and lead to progressive organ dysfunction. Consequently, the RAGE axis represents a potent therapeutic target for mitigating hyperinflammation and improving clinical outcomes in acute inflammatory disorders. While initial pharmacological efforts focused on synthetic inhibitors and biologics, there is a shifting focus toward bioactive alternatives with high safety profiles. Here, we present recent molecular insights into RAGE-mediated pathogenesis in acute inflammatory disorders and evaluate current therapeutic strategies. Furthermore, we emphatically summarise the bioactive natural products, including terpenoids, flavonoids, alkaloids, and a xanthone, that prevent and treat acute inflammatory disorders by disrupting RAGE–ligand interactions and suppressing downstream oxidative stress and cytokine release. Integrating these molecular mechanisms with the pharmacological profiling of natural RAGE modulators provides a robust foundation for the development of next-generation therapeutic strategies to improve clinical outcomes in acute inflammatory disorders. Full article

The structure, functionality, nutritional value, and sensory properties of food are significantly influenced by interactions between proteins and carbohydrates. These interactions occur through hydrogen bonding, electrostatic forces, hydrophobic interactions, and, in many cases, the covalent attachment of sugars to proteins via the Maillard reaction. High starch content in food matrices promotes interactions between proteins and starch components such as amylose and amylopectin, affecting gelation, retrogradation, and thickening. These interactions improve shelf stability and product quality. Additionally, protein–carbohydrate interactions regulate nutrient digestibility and glycemic response, playing a crucial role in the development of functional foods for diabetes and weight management. In silico studies have demonstrated that dietary fibers like pectin and cellulose can improve water retention and textural properties in processed meat products. Furthermore, processing techniques such as enzymatic hydrolysis, fermentation, pulsed electric fields (PEF), and low-temperature drying have been found to improve the functional properties and shelf life of food products. This review synthesizes recent findings on protein–carbohydrate interactions and highlights their potential in creating healthier, more appealing, and sustainable foods that align with modern consumer preferences. Full article

The valorization of culinary by-products into functional bioactive resources represents a significant advancement in sustainable biotechnology. This study characterizes an extract derived from “battuto toscano” by-products, a traditional blend of garlic, onion, carrot, and celery trimmings, recovered through circular economy principles. Comprehensive antioxidant profiling was performed alongside biological evaluations on human cell lines and anti-glycation assays. Results from Folin–Ciocalteu, FRAP, and TEAC assays confirmed a high concentration of secondary metabolites with significant scavenging capacity. In vitro testing on primary human fibroblasts and HaCaT keratinocytes revealed a concentration- and time-dependent biological response, with lower concentrations showing better compatibility and transiently enhancing HaCaT metabolic activity. Furthermore, BTE reduced AGE-associated fluorescence in the BSA–glucose model, particularly at 5 mg/mL, supporting its potential anti-glycation activity. These findings establish “battuto toscano” by-products as a reservoir of sustainable biomolecules. This study offers a transformative resource for the pharma/nutraceutical sectors by bridging culinary tradition with biomedical innovation. Full article

Regenerative medicine integrates interdisciplinary approaches towards restoring the function of diseased organs. This study examined alterations that occurred in the liver under a high-fat diet (HFD) with the development of obesity and fatty liver, and changes in metabolic homeostasis and glucose levels, in mice. HFD nutrition causes hyperglycemia, leading to the formation and accumulation of advanced glycation end-products (AGEs) promoting protein post-translational modifications (PTMs) and introducing crosslinking in the extracellular matrix (ECM). Using histological and gene expression analyses, we detected an increase in adiposity, as well as in ECM protein deposition in the liver. Further, decellularization of the liver yielded the isolated ECM organ scaffold, allowing us to analyze the chemical modification in proteins by various imaging methods combined with spectroscopy. The measurements of intrinsic protein fluorescence are consistent with increased AGE-associated levels. SEM allows for the visualization of ECM fiber thickening as a result of protein crosslinking. Using cathodoluminescence, a label-free imaging method, we confirmed the protein modifications. The combination of innovative technologies highlights the ECM structural alterations associated with impaired glucose regulation and liver adiposity. These findings provide novel views on liver-scaffold ECM structure under metabolic diseases that will play a significant role in accelerating the understanding of effective regenerative therapies. Full article

Cyclocarya paliurus leaves, commonly consumed as “sweet tea”, remain underutilized after spring harvest. This pilot study investigated harvest month-associated changes in bioactivity-related properties and volatile profiles of mature leaves collected from May to September (Q5–Q9) at one site in 2024. Aqueous extracts were analyzed for TPC, TFC, TP, TSC, DPPH and ABTS•+ radical scavenging activities, and inhibition of advanced glycation end-products (AGEs) formation in glucose/fructose-BSA models, with aminoguanidine as a positive reference. Dried leaf powders were profiled by SPME-GC-MS for tentative VOC annotation. TPC, TFC, TP, and TSC ranged from 28.04 to 28.87, 15.42 to 40.22, 2.14 to 2.51, and 23.15 to 25.30 mg/g, respectively. Q9 showed the strongest radical scavenging response, with the lowest DPPH and ABTS•+ IC50 values (0.119 and 0.131 mg/mL), while Q6 also exhibited relatively strong activity. Furthermore, Q6 and Q9 exhibited superior advanced glycation end-product (AGE) inhibitory responses, with Q9 being particularly effective in the fructose-BSA model. VOC profiles varied markedly by month, shifting from alkene/terpene predominance in Q5–Q6 to alcohol enrichment in Q7 and renewed alkene/terpene predominance in Q9. Integrated heatmap and Pearson correlation analyses identified clear temporal co-variations and pairwise associations between distinct VOC classes and bioactivity indices. Collectively, these results provide preliminary, site- and year-specific evidence that harvest month is associated with changes in the bioactivity-related properties and aroma-related phytochemical profiles of mature C. paliurus leaves, offering a cautious reference for harvest-stage-oriented utilization. Full article

Adipose tissue expansion in obesity is accompanied by extracellular matrix (ECM) remodeling, regulated by matrix metalloproteinases (MMPs). Visceral adipose tissue (VAT) is metabolically more active than subcutaneous adipose tissue (SAT). However, depot-specific differences in proteolytic activity and protein glycooxidation remain incompletely characterized. In this case–control study, we assessed the activity of six matrix metalloproteinases (MMP-1, -2, -7, -9, -11, and -13) using a fluorescence resonance energy transfer (FRET) assay and quantified advanced glycation- and glycooxidation-related markers in paired VAT, SAT, and plasma samples obtained from 40 patients with obesity and 21 non-obese controls. The activities of all assessed MMPs were greater in patients with obesity than in the control group (p < 0.01 for all MMPs). Direct tissue-compartment comparisons showed that MMP activity and glycooxidation-related markers were most pronounced in VAT, with markedly higher values in obese individuals compared with controls. In VAT of obese individuals, median MMP activity was approximately 50–60% higher compared with controls. Amyloid cross-β-structure, vesperlysine, and pentosidine were significantly elevated in VAT in obesity, whereas plasma levels were markedly lower and showed limited group differences. No significant differences were observed between obese participants with and without metabolic syndrome. Obesity is associated with a depot-specific molecular profile characterized by enhanced proteolytic and glycooxidative activity predominantly within visceral adipose tissue. These findings highlight the importance of tissue-compartment-specific assessment in obesity. Full article