Search Results (74)

A dietary supplement, trans-resveratrol and hesperetin (tRES+HESP)—also known as GlucoRegulate—induces increased expression of glyoxalase 1 (Glo1) by activation of transcription factor Nrf2, countering accumulation of the reactive dicarbonyl glycating agent, methylglyoxal. tRES+HESP corrected insulin resistance and decreased fasting and postprandial plasma glucose and low-grade inflammation in overweight and obese subjects in a clinical trial. The aim of this study was to explore, for the first time, health-beneficial gene expression other than Glo1 induced by tRES+HESP in human endothelial cells and fibroblasts in primary culture and HepG2 hepatoma cell line and activity of cis-resveratrol (cRES) as a Glo1 inducer. We measured antioxidant response element-linked gene expression in these cells in response to 5 µM tRES+HESP by the NanoString method. tRES+HESP increases gene expression linked to the prevention of dicarbonyl stress, lipid peroxidation, oxidative stress, proteotoxicity and hyperglycemia-linked glycolytic overload. Downstream benefits were improved regulation of glucose and lipid metabolism and decreased inflammation, extracellular matrix remodeling and senescence markers. The median effective concentration of tRES was ninefold lower than cRES in the Glo1 inducer luciferase reporter assay. The GlucoRegulate supplement provides a new treatment option for the prevention of type 2 diabetes and metabolic dysfunction–associated steatotic liver disease and supports healthy aging. Full article

As the size of the elderly population increases, the need for an improved understanding of what leads to the age-related decline in physiological function continues to grow. SAMP8 mice were selected for their accelerated aging phenotype. The low levels of glyoxalase 1 (Glo1), the main enzyme that removes the reactive dicarbonyl methylglyoxal (MGO), in the cerebral cortex of SAMP8 mice prompted us to produce the first transgenic mice overexpressing Glo1 against the SAMP8 background, aimed at rescuing the accelerated aging phenotype. Selected health and biochemical endpoints were assessed in ten-month-old SAMP8 mice overexpressing Glo1. Glo1 overexpression increased median survival in males (21%) and females (4.6%), which was associated with better memory performance. Glo1 overexpression also increased synaptic markers (synaptophysin and SNAP25) as well as markers of mitochondrial function (NDUFB8, SDHB) and negative modulators of oxytosis/ferroptosis (NQO1, FTH1, and GPx4) in the cerebral cortex. For all parameters analyzed, the effect of Glo1 overexpression was more pronounced in males. Overall, the data support the beneficial effects of overexpressing Glo1 in multiple tissues, especially in SAMP8 males, suggesting a possible gender effect of MGO in aging. Both modulation of oxytosis/ferroptosis and mitochondrial metabolism warrant further investigation as potential mechanisms underlying the improved health span of Glo1 mice. Full article

Background: Previous proteomic studies provided valuable information about cataracts, but unclarified issues, such as sex and ethnicity-associated differences, remain. This study aimed to provide additional data on cataract-related proteins regarding age, sex, and cataract type. Methods: Twenty-six female and seven male Turkish cataract patients were screened for visual acuity and dysfunctional lens index. A nano-LC-MS/MS system and Progenesis QI software v3.0 were used for protein identification and quantification. The remaining data were evaluated with SPSS Version 29.0 software. Results: Proteins that showed age-associated changes were mainly involved in cytoskeletal organization. A glyoxalase enzyme, caveolin 1, and HS90B were lower, and RAB8B and ATP6V1B1 were higher in lenses in women. Proteins with lower levels in cataractous lenses than in transparent lenses included filensin and phakinin, concurrent with previous publications, and LCTL, GDI, HSPB1, and EIF4A2, not reported before. Corticonuclear cataracts constituted the only group showing depletions in putatively protective proteins, while the cortical type was the least influenced. ANXA1 and DNHD1 positively, and TCPD, SEC14L2, and PRPS1 proteins negatively correlated with visual acuity. Conclusions: This study revealed cataract-related proteins concurrent with earlier studies and new ones hitherto unreported. Despite the low number of patients investigated, the results merit further research, as these new proteins are highly likely to be involved in cataractogenesis. Full article

The neurotransmitter acetylcholine (ACh) plays a pro-carcinogenic role in various cancer types, including prostate cancer (PCa). The existing body of knowledge concerning the mechanisms that underpin the protumoral role of ACh in PCa is limited. Glyoxalase 1 (Glo1) is a metabolic enzyme that removes methylglyoxal (MG), an endogenous post-translational modification agent, generating 5-hydro-5-methylimidazolone (MG-H1). The Glo1/MG-H1 axis is involved in PCa tumorigenesis and progression. By using LNCaP and PC3 PCa cells, representing extensively studied cell models of poorly aggressive and bone metastasis-derived PCa, respectively, we found that ACh specifically sustains LNCaP cell migration, invasion and proliferation through Glo1-dependent MG-H1 accumulation with the involvement of osteopontin (OPN), thus providing a novel mechanism underlying ACh’s protumoral role in PCa cells. The findings of this study unveil a hitherto unidentified mechanism implicated in the progression of PCa, which is initiated by ACh and involves both the Glo1/MG-H1 axis and OPN. This discovery provides the basis for new avenues of in vivo investigation into the physiological relevance of the roles of the ACh-driven Glo1/MG-H1 axis and OPN in PCa progression and for further research aimed at exploring new ways of managing PCa progression, with the aim of preventing the disease from becoming incurable. Full article

Glycation is a process in which reducing sugars bind to proteins, resulting in the formation of advanced glycation end products (AGEs). These AGEs accumulate in the skin, promote excessive collagen crosslinking, and disrupt the extracellular matrix (ECM), impairing normal cellular functions and contributing to skin aging. To evaluate the anti-glycation efficacy of lotus stamen extract (LSE), we employed the BSA–fructose system and a high glucose (HG)-induced fibroblast glycation model. The results demonstrated that LSE effectively inhibited cellular glycation and also exhibited anti-inflammatory, antioxidative, and anti-senescent effects in HG-induced human skin fibroblasts (HSF). Further investigation into the anti-glycation mechanism and component analysis of the lotus stamen ethyl acetate extract (LSEE) led to the identification of 15 flavonoids. The anti-glycation results indicated that these flavonoids are likely the primary active constituents in LSE. Mechanistic studies revealed that GLO1 plays a crucial role in cellular resistance to glycation, and LSEE enhanced GLO1 expression through the Nrf2/Keap1 pro-survival pathway, thereby mitigating intracellular AGE production. In summary, LSEE and its multiple flavonoid components exhibit potent intracellular anti-glycation activity and present significant potential to be developed as a natural and organic product for cosmetic and healthcare applications. Full article

Advanced glycation end products (AGEs) are a series of structurally complex and harmful compounds formed through the reaction between the carbonyl group of reducing sugars (such as glucose and fructose) and the free amino groups of proteins, lipids, or nucleic acids. Excessive accumulation of AGEs in the body can trigger oxidative stress, induce inflammatory responses, and contribute to the development of diabetes, atherosclerosis, and neurological disorders. Within the category of dicarbonyl compounds, methylglyoxal (MGO)—a byproduct resulting from glucose degradation—serves as a pivotal precursor in the formation of AGEs and the induction of neurotoxicity. Specifically, AGEs generated from MGO display significant cytotoxicity toward cells in the central nervous system. Therefore, we aimed to investigate the role of MGO-AGEs in neuroinflammation mediated by CUMS. Interestingly, we found that the overexpression of glyoxalase 1 (GLO1) reduced the levels of MGO in corticosterone-treated microglia, thereby alleviating the inflammatory response. Furthermore, overexpression of GLO1 in the hippocampus of chronically stressed mice reduced MGO levels, mitigating CUMS-induced neuroinflammation and cognitive impairment. Additionally, when using the receptor for advanced glycation end products (RAGE) inhibitor FPS-ZM1 in primary microglia cells, we observed that despite corticosterone-induced elevation of MGO, no significant inflammatory response occurred. This suggests that RAGE clearance can reduce MGO-AGE-mediated neurotoxicity. Subsequently, we used FPS-ZM1 to treat chronically stressed mice and found that it significantly ameliorated neuroinflammation and cognitive dysfunction. These results suggest that targeting MGO metabolism could serve as a therapeutic approach to manage neuroinflammation in stress-related mental disorders. Full article

Cardiomyocyte dysfunction and cardiovascular diseases (CVDs) can be classified as ischemic or non-ischemic. We consider the induction of cardiac tissue dysfunction by intracellular advanced glycation end-products (AGEs) in cardiomyocytes as a novel type of non-ischemic CVD. Various types of AGEs can be generated from saccharides (glucose and fructose) and their intermediate/non-enzymatic reaction byproducts. Recently, certain types of AGEs (N^ε-carboxymethyl-lycine [CML], 2-ammnonio-6-[4-(hydroxymetyl)-3-oxidopyridinium-1-yl]-hexanoate-lysine [4-hydroxymethyl-OP-lysine, hydroxymethyl-OP-lysine], and N^δ-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine [MG-H1]) were identified and quantified in the ryanodine receptor 2 (RyR2) and F-actin–tropomyosin filament in the cardiomyocytes of mice or patients with diabetes and/or heart failure. Under these conditions, the excessive leakage of Ca²⁺ from glycated RyR2 and reduced contractile force from glycated F-actin–tropomyosin filaments induce cardiomyocyte dysfunction. CVDs are included in lifestyle-related diseases (LSRDs), which ancient people recognized and prevented using traditional medicines (e.g., Kampo medicines). Various natural compounds, such as quercetin, curcumin, and epigallocatechin-3-gallate, in these drugs can inhibit the generation of intracellular AGEs through mechanisms such as the carbonyl trap effect and glyoxalase 1 activation, potentially preventing CVDs caused by intracellular AGEs, such as CML, hydroxymethyl-OP, and MG-H1. These investigations showed that bioactive herbal extracts obtained from traditional medicine treatments may contain compounds that prevent CVDs. Full article

Glyoxalase 1 (Glo1) is an essential enzyme to detoxify methylglyoxal (MGO), a cytotoxic byproduct of glycolysis. Accumulating studies have shown an important role of Glo1 in regulating cortical development and neurogenesis, potentially contributing to the pathogenesis of autism spectrum disorder (ASD) when impaired. We have previously shown that prenatal exposure to non-apoptotic low-dose methylmercury (MeHg), an environmental pollutant, induces premature cortical neurogenesis and ASD-like behaviors in a rodent model. In this study, we aimed to determine the underlying molecular mechanisms that mediate prenatal MeHg-induced premature neuronal differentiation and abnormal neurodevelopment. Using single-cell RNA sequencing (scRNA-seq) and real-time quantitative PCR (RT-qPCR), we found that prenatal MeHg exposure at a non-apoptotic dose significantly reduced Glo1 gene expression in embryonic cultured radial glia precursors (RGPs). In cultured RGPs, the knockdown of Glo1 expression increased neuronal production at the expense of the cultured RGPs population, while overexpression of Glo1 restored MeHg-induced neuronal differentiation back to normal levels. Furthermore, we found that co-treatment with both MeHg and multiple MGO scavengers or a CREB inhibitor (iCREB) mitigated MeHg-induced premature neuronal differentiation, reinforcing the role of Glo1 and CREB in mediating MeHg-induced neuronal differentiation. Our findings demonstrate a direct link between MeHg exposure and expression of an ASD risk gene Glo1 in cortical development, supporting the important role of gene–environment interaction in contributing to the etiology of neural developmental disorders, such as ASD. Full article

Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events, culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC), has a narrow therapeutic window, and early treatment is essential for a satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end products (AGEs) and the consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase 1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in the APAP-mediated activation of RAGE and downstream cell death cascades. Constitutive Glo-1-knockout mice (GKO) and a cofactor of Glo-1, ψ-GSH, were used as tools. Our findings showed elevated oxidative stress resulting from the activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild-type controls. A unique feature of the hepatic necrosis in GKO mice was the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than the inflammation seen in the wild type. The GSH surrogate and general antioxidant ψ-GSH alleviated APAP toxicity irrespective of the Glo-1 status, suggesting that oxidative stress is the primary driver of APAP toxicity. Overall, the exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against the initial stages of APAP overdose. Full article

Background: Biochemical events provoked by oxidative stress and advanced glycation may be inhibited by combining natural bioactives with classic therapeutic agents, which arise as strategies to mitigate diabetic complications. The aim of this study was to investigate whether lycopene combined with a reduced insulin dose is able to control glycemia and to oppose glycoxidative stress in kidneys of diabetic rats. Methods: Streptozotocin-induced diabetic rats were treated with 45 mg/kg lycopene + 1 U/day insulin for 30 days. The study assessed glycemia, insulin sensitivity, lipid profile and paraoxonase 1 (PON-1) activity in plasma. Superoxide dismutase (SOD) and catalase (CAT) activities and the protein levels of advanced glycation end-product receptor 1 (AGE-R1) and glyoxalase-1 (GLO-1) in the kidneys were also investigated. Results: An effective glycemic control was achieved with lycopene plus insulin, which may be attributed to improvements in insulin sensitivity. The combined therapy decreased the dyslipidemia and increased the PON-1 activity. In the kidneys, lycopene plus insulin increased the activities of SOD and CAT and the levels of AGE-R1 and GLO-1, which may be contributing to the antialbuminuric effect. Conclusions: These findings demonstrate that lycopene may aggregate favorable effects to insulin against diabetic complications resulting from glycoxidative stress. Full article

The underlying molecular mechanisms for the development of non-alcoholic fatty liver (NAFL) and its progression to advanced liver diseases remain elusive. Glyoxalase 1 (Glo1) loss, leading to elevated methylglyoxal (MG) and dicarbonyl stress, has been implicated in various diseases, including obesity-related conditions. This study aimed to investigate changes in the glyoxalase system in individuals with non-pathological liver fat. Liver biopsies were obtained from 30 individuals with a narrow range of BMI (24.6–29.8 kg/m²). Whole-body insulin sensitivity was assessed using HOMA-IR. Liver biopsies were analyzed for total triglyceride content, Glo1 and Glo2 mRNA, protein expression, and activity. Liquid chromatography–tandem mass spectrometry determined liver dicarbonyl content and oxidation and glycation biomarkers. Liver Glo1 activity showed an inverse correlation with HOMA-IR and liver triglyceride content, but not BMI. Despite reduced Glo1 activity, no associations were found with elevated liver dicarbonyls or glycation markers. A sex dimorphism was observed in Glo1, with females exhibiting significantly lower liver Glo1 protein expression and activity, and higher liver MG-H1 content compared to males. This study demonstrates that increasing liver fat, even within a non-pathological range, is associated with reduced Glo1 activity. Full article

This comprehensive exploration delves into the intricate interplay of methylglyoxal (MG) and glyoxalase 1 (GLO I) in various physiological and pathological contexts. The linchpin of the narrative revolves around the role of these small molecules in age-related issues, diabetes, obesity, cardiovascular diseases, and neurodegenerative disorders. Methylglyoxal, a reactive dicarbonyl metabolite, takes center stage, becoming a principal player in the development of AGEs and contributing to cell and tissue dysfunction. The dual facets of GLO I—activation and inhibition—unfold as potential therapeutic avenues. Activators, spanning synthetic drugs like candesartan to natural compounds like polyphenols and isothiocyanates, aim to restore GLO I function. These molecular enhancers showcase promising outcomes in conditions such as diabetic retinopathy, kidney disease, and beyond. On the contrary, GLO I inhibitors emerge as crucial players in cancer treatment, offering new possibilities in diseases associated with inflammation and multidrug resistance. The symphony of small molecules, from GLO I activators to inhibitors, presents a nuanced understanding of MG regulation. From natural compounds to synthetic drugs, each element contributes to a molecular orchestra, promising novel interventions and personalized approaches in the pursuit of health and wellbeing. The abstract concludes with an emphasis on the necessity of rigorous clinical trials to validate these findings and acknowledges the importance of individual variability in the complex landscape of health. Full article

Type 2 diabetes mellitus (DM) continues to escalate, necessitating innovative therapeutic approaches that target distinct pathways and address DM complications. Flavonoids have been shown to possess several pharmacological activities that are important for DM. This study aimed to evaluate the in vivo effects of the flavonoid melanoxetin using Goto-Kakizaki rats. Over a period of 14 days, melanoxetin was administered subcutaneously to investigate its antioxidant, anti-inflammatory, and antidiabetic properties. The results show that melanoxetin reduced insulin resistance in adipose tissue by targeting protein tyrosine phosphatase 1B. Additionally, melanoxetin counteracted oxidative stress by reducing nitrotyrosine levels and modulating superoxide dismutase 1 and hemeoxygenase in adipose tissue and decreasing methylglyoxal-derived hydroimidazolone (MG-H1), a key advanced glycation end product (AGE) implicated in DM-related complications. Moreover, the glyoxalase 1 expression decreased in both the liver and the heart, correlating with reduced AGE levels, particularly MG-H1 in the heart. Melanoxetin also demonstrated anti-inflammatory effects by reducing serum prostaglandin E₂ levels, and increasing the antioxidant status of the aorta wall through enhanced acetylcholine-dependent relaxation in the presence of ascorbic acid. These findings provide valuable insights into melanoxetin’s therapeutic potential in targeting multiple pathways involved in type 2 DM, particularly in mitigating oxidative stress and glycation. Full article

Endurance exercise training is a promising cardioprotective strategy in type 2 diabetes mellitus (T2DM), but the impact of its intensity is not clear. We aimed to investigate whether and how isocaloric moderate-intensity exercise training (MIT) and high-intensity interval exercise training (HIIT) could prevent the adverse cardiac remodeling and dysfunction that develop T2DM in rats. Male rats received a Western diet (WD) to induce T2DM and underwent a sedentary lifestyle (n = 7), MIT (n = 7) or HIIT (n = 8). Insulin resistance was defined as the HOMA-IR value. Cardiac function was assessed with left ventricular (LV) echocardiography and invasive hemodynamics. A qPCR and histology of LV tissue unraveled underlying mechanisms. We found that MIT and HIIT halted T2DM development compared to in sedentary WD rats (p < 0.05). Both interventions prevented increases in LV end-systolic pressure, wall thickness and interstitial collagen content (p < 0.05). In LV tissue, HIIT tended to upregulate the gene expression of an ROS-generating enzyme (NOX4), while both modalities increased proinflammatory macrophage markers and cytokines (CD86, TNF-α, IL-1β; p < 0.05). HIIT promoted antioxidant and dicarbonyl defense systems (SOD2, glyoxalase 1; p < 0.05) whereas MIT elevated anti-inflammatory macrophage marker expression (CD206, CD163; p < 0.01). We conclude that both MIT and HIIT limit WD-induced T2DM with diastolic dysfunction and pathological LV hypertrophy, possibly using different adaptive mechanisms. Full article