Search Results (1,338)

The skin is a complex immunological organ in which reactive oxygen species (ROS)-related pathways and host–microbe interactions synergically maintain immune homeostasis. Dysregulation of several oxidative mechanisms, including lipid peroxidation, mitochondrial dysfunction, ferroptosis, and impaired antioxidant defenses, alongside gut microbiome imbalance, is increasingly recognized as a key modulator of the immune response involved in disease onset and progression. However, their role in immune-mediated dermatoses remains incompletely defined. This narrative review aims to provide a comprehensive overview of the contribution of these altered pathways to the pathogenesis and prognosis of the major immune-mediated skin diseases. Across all conditions examined, elevated oxidative biomarkers, such as malondialdehyde (MDA), advanced glycation end-products (AGEs), advanced oxidation protein products (AOPPs), 8-hydroxydeoxyguanosine (8-OHdG), and reduced antioxidant capacity are consistently reported. Ferroptosis, driven by iron-dependent lipid peroxidation and dysfunction of Glutathione peroxidase 4 (GPX4), emerges as a relevant cell death pathway, particularly in psoriasis and atopic dermatitis (AD). In parallel, dysbiosis of the gut and skin microbiomes, characterized by depletion of short-chain fatty acid (SCFA)-producing taxa such as Faecalibacterium prausnitzii, Bifidobacterium, and Akkermansia muciniphila, has been reported across multiple diseases. Particular attention is given to shared molecular axes, such as the disruption of epithelial barrier integrity, activation of innate and adaptive immune responses, and the role of microbial-derived metabolites in modulating redox signaling, unraveling a bidirectional crosstalk. Emerging therapeutic strategies targeting these bidirectional crosstalks show biological plausibility and promising preliminary results. Integrating redox and microbial profiling into clinical practice may improve patient stratification and foster the development of more personalized therapeutic approaches beyond conventional immunological treatments. Full article

Background/Objective: With rising per capita sugar consumption, skin glycation-related issues including dullness, homeostasis disruption and accelerated wrinkling have gained widespread attention. However, globally standardized and rigorous evaluation criteria for anti-glycation efficacy remain lacking. This study aimed to establish stage-specific glycation injury cell models and elucidate the stage-dependent molecular mechanisms of glycation-induced fibroblast damage, providing a standardized reference for anti-glycation efficacy assessment. Methods: Three glycation injury models were constructed in human foreskin fibroblasts (HFF-1): early-stage (glucose-induced), intermediate-stage (glyoxal-induced), and late-stage (advanced glycation end products (AGEs)-induced). Core biomarkers including Nε-(carboxymethyl)lysine (CML), collagen type I (Col I) and elastin (ELN) were used to optimize modeling conditions via Cell Counting Kit-8 (CCK-8) and enzyme-linked immunosorbent assay (ELISA). Untargeted metabolomics based on ultra-high-performance liquid chromatography (UHPLC)-Q Exactive Orbitrap was applied to identify differential metabolites and perturbed pathways, following Metabolomics Standards Initiative (MSI) Level 2 identification criteria. Results: Optimal conditions were determined as 50 mmol/L glucose for 48 h, 0.5 mmol/L glyoxal for 48 h, and 200 μg/mL AGEs for 24 h. A total of 319, 34 and 148 differential metabolites were identified in the three groups, respectively. Six key pathways were significantly perturbed. Early and intermediate models shared similar mechanisms (purine metabolism disturbance), while the late model showed distinct alterations in pyrimidine, nicotinate, arachidonic acid and steroid hormone metabolism. Conclusions: Three stable stage-specific glycation models were successfully established in HFF-1 cells. Significant differences in metabolic profiles and mechanisms exist across the three stages, providing a rational basis for model selection and theoretical support for anti-glycation efficacy evaluation. Full article

The advanced glycation end products generated from protein glycation are associated with the development of diabetic complications. This study aimed to investigate the inhibitory mechanisms of isoliquiritigenin on protein glycation and compare its anti-glycation activity in PBS versus a macromolecular crowding environment. The results showed that in PBS, 500 μmol/L isoliquiritigenin showed an advanced glycation end product inhibition rate of 37.78%, outperforming aminoguanidine. Meanwhile, isoliquiritigenin inhibited the protein carbonylation process, reduced the generation of protein oxidation products, and inhibited the formation of β-crosslinking structures with a rate of 34.20%. Molecular docking results indicated that isoliquiritigenin bound to site I of bovine serum albumin, effectively blocked glycation reactions by occupying multiple arginine residues and contributed to stabilizing the secondary structure of bovine serum albumin. In addition, isoliquiritigenin exhibited significant hydroxyl radical scavenging and Fe²⁺-chelating abilities, achieving a 34.35% trapping efficiency for methylglyoxal. Isoliquiritigenin exerted its anti-glycation activity through multiple pathways, including scavenging free radicals, protecting protein structure, interacting with bovine serum albumin, and trapping methylglyoxal. However, in the crowding environment, the excluded volume effect and higher viscosity might lead to limited isoliquiritigenin binding to bovine serum albumin, reducing its inhibition of glycation and decreasing advanced glycation end product inhibition to 16.38%. This study realistically evaluated the inhibitory effects of isoliquiritigenin in complex crowding environments and provided a theoretical basis for isoliquiritigenin as a functional food ingredient for the prevention of diabetes complications. Future studies need to establish animal models to further explore its effects in vivo. Full article

The aim of this study was to identify and examine materials that have a long history of use in folk medicine and exhibit biological activity but have not been fully utilized. This study evaluated the reactivity of Japanese maca powder in cultured human dermal cells subjected to aging stress (UV irradiation, AGE treatment, or H₂O₂ treatment). The mRNA levels of three stress parameters (collagen, elastin, and hyaluronic acid synthase) were measured using quantitative reverse transcription polymerase chain reaction. The activity of a prototype Japanese maca powder sample was compared with that of samples subjected to fermentation, room-temperature enzyme, and rapid freeze-drying treatments. Inhibitory effects on reactive oxygen species (ROS) were measured, and the expression of genes involved in senescent cell removal (JAG1) and regeneration promotion (EGF) was examined. Finally, the expression of molecules involved in senescent cell phagocytosis (STAB1) and stem cell phagocytosis signaling and regeneration promotion (FGF2) in macrophages was evaluated. The four types of maca samples altered the mRNA levels of the three stress parameters, conferred resistance to various aging stresses, and delayed suppressed intracellular ROS accumulation. These findings suggest that Japanese maca may help to protect skin cells from age-related stress. Full article

Background/Objectives: Neutrophils express the receptor for advanced glycation end products (RAGE), yet its role in antibacterial responses remains incompletely defined. This study aims to elucidate the dual functionality of RAGE as a membrane-bound signaling sensor and a source of soluble RAGE (sRAGE) in human neutrophils challenged with Salmonella typhimurium, a clinically relevant Gram-negative pathogen. Methods: Human peripheral neutrophils from healthy donors were isolated and stimulated with S. typhimurium, LPS, or fMLP. Calcium flux, ROS/RNS production, and phagocytosis were assessed using fluorescent probes and spectroscopy. RAGE expression and localization were analyzed by immunofluorescence microscopy and flow cytometry. Soluble RAGE in supernatants was quantified by ELISA, and its molecular forms were characterized by Western blotting. Results: Resting neutrophils exhibited minimal surface RAGE but a substantial intracellular pool. RAGE inhibition with FPS-ZM1 attenuated bacteria-induced Ca²⁺ mobilization, oxidative burst, nitrosative output, and phagocytosis, with the most pronounced defect at the pathogen-attachment stage—consistent with impaired cytoskeletal remodeling. Upon activation, neutrophils rapidly released sRAGE (peak at ~10 min) via combined metalloprotease-dependent shedding and regulated secretion of pre-formed intracellular stores. Paradoxically, FPS-ZM1 amplified sRAGE release while suppressing membrane-proximal signaling. Conclusions: Neutrophil RAGE functions as a dynamic, multi-compartmental regulator: membrane-associated RAGE licenses effector responses to Gram-negative bacteria, while concomitant sRAGE release provides a fast negative-feedback loop to limit excessive inflammation. This self-limiting circuit balances antimicrobial defense with tissue protection, and its dysregulation may contribute to pathological outcomes in acute and chronic infections. Full article

Background/objectives: Alpha-synuclein (aSyn) is best known for its role in Parkinson’s disease. Increasing evidence suggests a bidirectional relationship between diabetes mellitus and synuclein pathology. Carboxymethyllysine (CML), an advanced glycation end-product, serves as a marker of cumulative glycation stress and tissue damage in diabetes. Our study aimed to evaluate epidermal phosphorylated alpha-synuclein at Ser129 (p-aSyn) immunoreactivity in relation to CML accumulation in epidermis. Methods: Skin punch biopsies were obtained from seven diabetic patients with long-standing type 2 diabetes (T2DM), and from seven healthy volunteers. Tissue samples were processed and analyzed by immunohistochemical DAB-staining for p-aSyn and CML. Quantitative analysis was performed by measuring the percentage area of positive staining using Fiji/ImageJ2. Integrated density was also assessed as a complementary threshold-limited measure of staining signal intensity. Statistical analysis and data visualization were conducted using GraphPad Prism. Comparisons between groups were performed using the exact two-tailed Mann–Whitney U test. Results: Area-fraction analysis showed significantly greater CML-positive staining in diabetic epidermis than in controls (median 10.18 vs. 8.955, p = 0.0262), whereas p-aSyn-positive area fraction did not differ significantly between groups (13.53 vs. 14.64, p = 0.8048). In the complementary integrated density analysis, p-aSyn signal was significantly higher in diabetic epidermis than in controls (21,365 vs. 10,960, p = 0.0023), whereas the increase in CML integrated density did not reach statistical significance (14,165 vs. 6585, p = 0.1282). In diabetic epidermis, both markers showed a more widespread distribution, involving basal keratinocyte cytoplasm and extension into suprabasal layers. Control samples showed staining largely restricted to basal cell contours. In serial sections, p-aSyn and CML showed a similar topographic distribution in diabetic skin. Conclusions: These preliminary observations suggest that chronic diabetic skin changes are associated with increased epidermal CML burden when assessed by area fraction and with higher p-aSyn signal intensity when assessed by integrated density. However, because the study was small and based on semiquantitative DAB immunohistochemistry, the findings should be interpreted cautiously and require validation in larger multimodal studies. Full article

Methylglyoxal (MG) is a reactive dicarbonyl compound generated mainly as a byproduct of glycolysis. Excess accumulation of MG can promote protein glycation and the formation of advanced glycation end-products (AGEs), which have been associated with oxidative stress, inflammation, mitochondrial dysfunction, and cellular damage. These processes are implicated in the development of several chronic conditions, including diabetes, neurodegenerative disorders, cardiovascular disease, and age-related decline. The glyoxalase system, comprising Glyoxalase I (Glo1) and Glyoxalase II (Glo2), serves as a key cellular defense mechanism that detoxifies MG and helps maintain dicarbonyl homeostasis. Among these enzymes, Glo1 catalyzes the conversion of MG into less reactive intermediates in a glutathione (GSH)-dependent manner. A range of natural compounds and dietary phytochemicals, including sulforaphane, resveratrol, α-lipoic acid, selenium, vitamin D3, and N-acetylcysteine, have been reported to modulate Glo1 activity through transcriptional regulation, antioxidant effects, or support of intracellular GSH levels. Evidence from preclinical and limited human studies suggests that these compounds may help reduce MG burden and AGE formation, although their effects are often indirect and context-dependent. However, several challenges remain, including variable bioavailability, dose-dependent responses, disease-specific differences in Glo1 regulation, and the lack of standardized biomarkers and adequate clinical validation. This review examines the MG–Glo1 axis as a mechanistic framework linking metabolic stress to disease and evaluates natural compounds as context-dependent modulators of this pathway. By integrating mechanistic insights with emerging in vivo and clinical evidence, this work highlights the potential, while acknowledging the limitations, of targeting Glo1 as a translational strategy for managing glycation-associated disorders. Full article

Glycation of biomolecules leads to the formation of advanced glycation end products (AGEs) and is implicated in molecular mechanisms of human chronic diseases. We compared the glycation properties of D-ribose and methylglyoxal on human high-density lipoprotein (HDL). The increase in fluorescent AGEs in HDL samples treated with methylglyoxal confirms that HDLs are sensitive to glycation treatment. Our results demonstrated that even D-ribose glycates HDL as shown by changes induced by D-ribose on HDL apoprotein. Biochemical markers of lipid and protein oxidative damage were also evaluated. The increase in protein carbonyl contents and thiobarbituric acid reactive substances (TBARS) demonstrates a glyco-oxidative stress occurs in D-ribose treated HDL. In addition, HDL treated with D-ribose showed a significant decrease in the activity of the enzyme paraoxonase 1 and an increased HDL redox activity. These data demonstrate that D-ribose-induced glycation of HDL may impair lipoprotein functionality and may contribute to molecular mechanisms of dysmetabolic diseases. Full article

Background: Advanced glycation end products (AGEs) and oxidative stress (OS) have been linked to bone complications related to type 2 diabetes mellitus (T2DM). However, the effects of AGEs and OS on bone marrow mesenchymal stromal cells (BMMSCs), which play a key role in bone homeostasis and repair, remain unclear. Objectives: This study aimed to investigate the effects of AGEs on BMMSCs function and the ability of N-acetylcysteine (NAC) to alleviate AGE-induced OS in a T2DM context. Methods: Bone marrow (BM) and BMMSCs were isolated from Zucker diabetic fatty (ZDF) rats, which serve as a T2DM model, and their lean littermates (ZL, controls) at 24 weeks of age. Results: The results show that long-standing T2DM leads to changes in the BM’s cellular composition and BMMSCs function that are distinct from age-related changes. In vitro, AGEs decreased BMMSCs viability, proliferation, and migration. The effects of AGEs were stronger in BMMSCs derived from a T2DM microenvironment. In both T2DM- and ZL-BMMSCs, AGEs induced cytoplasmic ROS, which was differentially reduced by NAC. The effect of NAC on T2DM-BMMSCs was greater when the cells were pre-treated with NAC 24 h before exposure to AGEs, whereas simultaneous exposure to both resulted in a smaller effect. Conclusions: These results show that AGEs impair BMMSCs expansion and functionality. AGE-induced ROS generation may be a critical factor in this impairment, while NAC was able to reduce OS in BMMSCs from a T2DM context. These findings highlight the vicious negative effects of the T2DM microenvironment on BMMSCs and underscore the need for further studies to better understand the underlying mechanisms and to explore strategies aimed at mitigating OS in the T2DM context. Full article

Background: Diabetic peripheral neuropathy (DPN) affects up to 50% of diabetes patients and is driven by hyperglycemia-induced oxidative stress, mitochondrial dysfunction, polyol pathway activation, advanced glycation end-product formation, and inflammation. Current management is largely symptomatic, prompting interest in metabolic/nutritional therapies. This review critically evaluates the mechanistic rationale and clinical evidence for alpha-lipoic acid (ALA) and benfotiamine as adjunctive treatments for DPN. Methods: A structured narrative review of PubMed/MEDLINE was conducted using predefined keywords for DPN, oxidative stress, metabolic therapy, and thiamine derivatives. Randomized controlled trials, clinical studies, systematic reviews, and relevant experimental studies were included. Evidence was synthesized qualitatively with emphasis on mechanistic plausibility, clinical efficacy, intervention duration, and methodological rigor. Results: ALA consistently improves short-term symptoms across multiple randomized trials. The long-term NATHAN 1 trial reported a marginal, borderline significant effect on the primary composite endpoint (NIS-LL, p = 0.05) without significant improvements in nerve conduction studies; therefore, evidence for functional stabilization is very limited and inconclusive. ALA’s effects are attributed to antioxidant activity, mitochondrial protection, and improved microvascular function. Benfotiamine has a strong biochemical rationale (transketolase activation, diversion of glycolytic intermediates from damaging pathways), but clinical evidence remains limited to short-duration, symptom-based studies, with no large-scale, long-term trials published. Conclusions: Both agents target key pathways in DPN pathogenesis. ALA is the most established adjunctive metabolic therapy for symptomatic DPN, although no study has demonstrated structural nerve regeneration or a definitive disease-modifying effect. Benfotiamine is biologically plausible but requires further validation in long-term randomized trials with structural and biomarker-based endpoints. Outside of documented thiamine deficiency, its routine use cannot be recommended based on current evidence. Full article

Chronic kidney disease (CKD) is an established risk factor for Parkinson’s disease (PD), but the molecular mechanisms linking these two conditions remain elusive. We performed a systems biology analysis by retrieving high-confidence gene–disease associations from DisGeNET v7.0 (PD: score ≥ 0.8, EI ≥ 0.4; CKD: score ≥ 0.6, EI ≥ 0.4) and constructing a protein–protein interaction (PPI) network via STRING v11.5 (confidence ≥ 0.700). Direct “molecular bridges” between CKD and PD proteins were identified and validated using independent databases. To corroborate biological feasibility, candidate proteins were cross-referenced with ExoCarta and Vesiclepedia databases for exosomal localization. Functional enrichment, tissue expression, and pathway analyses were conducted. Despite zero gene overlap (64 PD genes, 17 CKD genes), the PPI network showed significant convergence (81 nodes, 280 edges, PPI enrichment p < 1.0 × 10⁻¹⁶). Fifteen high-confidence molecular bridges were identified, including the Apolipoprotein A1 (APOA1)–α-synuclein (SNCA) interaction (combined score 0.883), which was independently validated by IntAct. Functional enrichment revealed specific association of APOA1–SNCA with “amyloid fiber formation” (false discovery rate (FDR) = 0.038). Both APOA1 and SNCA are annotated as exosome components (Kyoto Encyclopedia of Genes and Genomes (KEGG) ko04147) and were confirmed as consistent cargo in plasma, urine, and platelet-derived extracellular vesicles within proteomic databases (ExoCarta IDs: 335, 6622). Global pathway analysis highlighted inflammation, oxidative stress, and the advanced glycation end product (AGE)–receptor for AGE (RAGE) pathway. We propose an integrative model wherein CKD-induced dysregulation of APOA1 promotes α-synuclein misfolding and aggregation, and the co-packaging of these proteins into exosomes provides a plausible vehicle for kidney-to-brain propagation. This framework offers testable hypotheses and potential therapeutic targets for PD-CKD comorbidity. Full article

The emergence of clinical resistance to conventional antigiardials underscores the need for compounds with novel mechanisms of action. This study demonstrates that indirubin exerts antigiardial activity by targeting important metabolic enzymes in Giardia lamblia. Indirubin induced a concentration-dependent decrease in trophozoite proliferation and viability, correlating with reduced activity of native triosephosphate isomerase and aldose reductase. Using recombinant enzymes, indirubin directly inhibited triosephosphate isomerase and aldose reductase, with the parasite enzymes showing greater susceptibility than their human orthologs. Structural and computational analyses suggest preferential binding of indirubin at the dimer interface of triosephosphate isomerase and within the NADP(H)-binding pocket of aldose reductase. The dual enzymatic inhibition was concordant with methylglyoxal accumulation, extensive protein carbonylation, and the formation of advanced glycation end products. These effects culminated in apoptotic-like death and severe ultrastructural damage, including alteration of the adhesive disc and microtubule networks. By targeting vulnerabilities in the metabolic and redox pathways of G. lamblia through a multifactorial mechanism distinct from current therapies, our findings support indirubin as a promising candidate for the treatment of giardiasis. Full article

This study focused on the inhibitory effects of wheat bran feruloyl oligosaccharides (FOs) on the formation of AGEs in three bovine serum albumin (BSA)-based non-enzymatic glycation models, namely BSA-fructose, BSA-methylglyoxal (MGO), and BSA-glyoxal (GO). In the BSA-fructose model, FOs at 0.25 mg/mL achieved a 62% inhibition rate of fructosamine, equivalent to approximately 78% of the activity of the positive control aminoguanidine (AG), and reduced fluorescent AGEs by over 50% on day 12. Additionally, FOs suppressed the accumulation of α-dicarbonyl compounds, key intermediates in the glycation pathway. In the BSA-MGO and BSA-GO system, the decreased fluorescence intensity of tryptophan residues indicated that FOs bound to BSA, inducing conformational changes in the protein microenvironment; this binding also inhibited protein carbonyl formation and the loss of thiol groups, thereby modulating the protein glycation process. Compared with their precursors (ferulic acid, FA; xylooligosaccharides, XOS), FOs exhibited comparable or even superior inhibitory activity against specific AGE subtypes, suggesting a synergistic effect between the feruloyl and oligosaccharide moieties. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed that FOs reduced the band intensity of 90 kDa AGEs in the glycation system, indicating the inhibition of protein-fructose cross-linking. Fluorescence spectroscopy confirmed that FOs dynamically quenched BSA with a single binding site, and thermodynamic calculations demonstrated that the binding was spontaneous (ΔG < 0), primarily driven by hydrogen bonds and van der Waals forces (ΔH < 0, ΔS < 0). This study systematically investigated the anti-glycation activities of FOs and their precursors. The findings demonstrate that FOs are promising natural glycation inhibitors and provide important theoretical and experimental support for related research. Furthermore, this study establish a basis for the green and high-value utilization of agricultural by-products like wheat bran. Full article

Diabetes mellitus is a growing health concern that causes numerous complications. Glycation produces advanced glycation end-products (AGEs), which promote diabetic complications. Targeting glycation is a strategy for combating the progression of diabetic complications. Pioglitazone enhances insulin sensitivity in patients with type 2 diabetes mellitus, but its impact on glycation remains unclear. This study aims to evaluate whether pioglitazone can inhibit glucose-induced glycation of human serum albumin (HSA), using in vitro assays and in silico tools. Pioglitazone inhibited >70% of early glycation products and >75% of AGEs. The treatment also reduced free lysine modification and improved biochemical markers, including carbonyl and free thiol levels. Pioglitazone exhibited moderate binding affinity for HSA, with a binding constant of 10⁴ M⁻¹. The interaction between pioglitazone and HSA was both spontaneous and entropically favourable. Molecular dynamics simulations revealed that the HSA–pioglitazone complex remained quite stable, with RMSF, RMSD, SASA, R_g, and HSA’s secondary structure showing minimal changes throughout the simulation. The overall binding energy for HSA–pioglitazone complex formation was −30.06 ± 0.31 kcal mol⁻¹, as obtained from MD simulations. The findings suggest that pioglitazone likely interacts with glycation-prone regions of HSA, as indicated by spectroscopic and docking analyses, and contributes to the reduction of glycation. Full article

Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes mellitus which affects individuals with both type 1 and type 2 diabetes mellitus (T2DM), presenting with sensory loss, pain, and progressive nerve dysfunction. DPN pathogenesis is multifactorial: chronic hyperglycemia activates the polyol, hexosamine, and protein kinase C (PKC) pathways, increases advanced glycation end-products, and drives oxidative stress, mitochondrial dysfunction, inflammation, and impaired neurotrophic signaling. In addition to hyperglycemia-driven mechanisms, dyslipidemia and microvascular insufficiency exacerbate neural ischemia and metabolic stress. Recent mechanistic, animal, and associative human studies further implicate amyloidogenic toxicity, particularly from human islet amyloid polypeptide (hIAPP), as a plausible contributory factor in peripheral nerve degeneration in T2DM, linking protein misfolding and aggregation to axonal damage and demyelination in DPN. Despite increased understanding of these mechanisms, current treatments remain mainly symptomatic. Emerging therapeutic strategies, including antioxidants, anti-inflammatory agents, modulators of mitochondrial function, amyloid oligomer modulators, neurotrophic enhancers, and regenerative approaches such as stem cells and gene-based therapies, offer potential to modify disease progression. The strength of evidence across these methods varies, ranging from mechanistic and animal studies to early human research and, in some cases, randomized clinical trials. Therefore, although several candidates show potential to alter the disease, few have demonstrated consistent benefits on objective measures of nerve structure or function in large clinical trials. This review summarizes the key mechanisms driving DPN in T2DM and highlights promising therapeutic innovations poised for clinical translation. Full article