Lycopene in Combination with Insulin Triggers Antioxidant Defenses and Increases the Expression of Components That Detoxify Advanced Glycation Products in Kidneys of Diabetic Rats.

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.

Glyoxalase 1: Emerging biomarker and therapeutic target in cervical cancer progression.

INTRODUCTION: Cervical cancer presents a significant global health challenge, disproportionately impacting underserved populations with limited access to healthcare. Early detection and effective management are vital in addressing this public health concern. This study focuses on Glyoxalase-1 (GLO1), an enzyme crucial for methylglyoxal detoxification, in the context of cervical cancer. METHODS: We assessed GLO1 expression in cervical cancer patient samples using immunohistochemistry. In vitro experiments using HeLa cells were conducted to evaluate the impact of GLO1 inhibition on cell viability and migration. Single-cell RNA sequencing (scRNA-seq) and gene set variation analysis were utilized to investigate the role of GLO1 in the metabolism of cervical cancer. Additionally, public microarray data were analyzed to determine GLO1 expression across various stages of cervical cancer. RESULTS: Our analysis included 58 cervical cancer patients, and showed that GLO1 is significantly upregulated in cervical cancer tissues compared to normal cervical tissues, independent of pathological findings and disease stage. In vitro experiments indicated that GLO1 inhibition by S-p-bromobenzylglutathione cyclopentyl diester decreased cell viability and migration in cervical cancer cell lines. Analyses of scRNA-seq data and public gene expression datasets corroborated the overexpression of GLO1 and its involvement in cancer metabolism, particularly glycolysis. An examination of expression data from precancerous lesions revealed a progressive increase in GLO1 expression from normal tissue to invasive cervical cancer. CONCLUSIONS: This study highlights the critical role of GLO1 in the progression of cervical cancer, presenting it as a potential biomarker and therapeutic target. These findings contribute valuable insights towards personalized treatment approaches and augment the ongoing efforts to combat cervical cancer. Further research is necessary to comprehensively explore GLO1's potential in clinical applications.

Methylglyoxal detoxifying gene families in tomato: Genome-wide identification, evolution, functional prediction, and transcript profiling.

Methylglyoxal (MG) is a highly cytotoxic molecule produced in all biological systems, which could be converted into non-toxic D-lactate by an evolutionarily conserved glyoxalase pathway. Glutathione-dependent glyoxalase I (GLYI) and glyoxalase II (GLYII) are responsible for the detoxification of MG into D-lactate in sequential reactions, while DJ-1 domain containing glyoxalase III (GLYIII) catalyzes the same reaction in a single step without glutathione dependency. Afterwards, D-lactate dehydrogenase (D-LDH) converts D-lactate into pyruvate, a metabolically usable intermediate. In the study, a comprehensive genome-wide investigation has been performed in one of the important vegetable plants, tomato to identify 13 putative GLYI, 4 GLYII, 3 GLYIII (DJ-1), and 4 D-LDH genes. Expression pattern analysis using microarray data confirmed their ubiquitous presence in different tissues and developmental stages. Moreover, stress treatment of tomato seedlings and subsequent qRT-PCR demonstrated upregulation of SlGLYI-2, SlGLYI-3, SlGLYI-6A, SlGLYII-1A, SlGLYII-3B, SlDJ-1A, SlDLDH-1 and SlDLDH-4 in response to different abiotic stresses, whereas SlGLYI-6B, SlGLYII-1B, SlGLYII-3A, SlDJ-1D and SlDLDH-2 were downregulated. Expression data also revealed SlGLYII-1B, SlGLYI-1A, SlGLYI-2, SlDJ-1D, and SlDLDH-4 were upregulated in response to various pathogenic infections, indicating the role of MG detoxifying enzymes in both plant defence and stress modulation. The functional characterization of each of these members could lay the foundation for the development of stress and disease-resistant plants promoting sustainable agriculture and production.

Placental Methylglyoxal in Preeclampsia: Vascular and Biomarker Implications.

BACKGROUND: Preeclampsia is a multifaceted syndrome that includes maternal vascular dysfunction. We hypothesize that increased placental glycolysis and hypoxia in preeclampsia lead to increased levels of methylglyoxal (MGO), consequently causing vascular dysfunction. METHODS: Plasma samples and placentas were collected from uncomplicated and preeclampsia pregnancies. Uncomplicated placentas and trophoblast cells (BeWo) were exposed to hypoxia. The reactive dicarbonyl MGO and advanced glycation end products (Nε-(carboxymethyl)lysine [CML], Nε-(carboxyethyl)lysine [CEL], and MGO-derived hydroimidazolone [MG-H]) were quantified using liquid chromatography-tandem mass spectrometry. The activity of GLO1 (glyoxalase-1), that is, the enzyme detoxifying MGO, was measured. The impact of MGO on vascular function was evaluated using wire/pressure myography. The therapeutic potential of the MGO-quencher quercetin and mitochondrial-specific antioxidant mitoquinone mesylate (MitoQ) was explored. RESULTS: MGO, CML, CEL, and MG-H2 levels were elevated in preeclampsia-placentas (+36%, +36%, +25%, and +22%, respectively). Reduced GLO1 activity was observed in preeclampsia-placentas (-12%) and hypoxia-exposed placentas (-16%). Hypoxia-induced MGO accumulation in placentas was mitigated by the MGO-quencher quercetin. Trophoblast cells were identified as the primary source of MGO. Reduced GLO1 activity was also observed in hypoxia-exposed BeWo cells (-26%). Maternal plasma concentrations of CML and the MGO-derived MG-H1 increased as early as 12 weeks of gestation (+16% and +17%, respectively). MGO impaired endothelial barrier function, an effect mitigated by MitoQ, and heightened vascular responsiveness to thromboxane A2. CONCLUSIONS: This study reveals the accumulation of placental MGO in preeclampsia and upon exposure to hypoxia, demonstrates how MGO can contribute to vascular impairment, and highlights plasma CML and MG-H1 levels as promising early biomarkers for preeclampsia.

Novel anthraquinone amide derivatives as potential glyoxalase-I inhibitors.

This study aimed to identify novel Glyoxalase-I (Glo-I) inhibitors with potential anticancer properties, focusing on anthraquinone amide-based derivatives. We synthesized a series of these derivatives and conducted in silico docking studies to predict their binding interactions with Glo-I. In vitro assessments were performed to evaluate the anti-Glo-I activity of the synthesized compounds. A comprehensive structure-activity relationship (SAR) analysis identified key features responsible for specific binding affinities of anthraquinone amide-based derivatives to Glo-I. Additionally, a 100 ns molecular dynamics simulation assessed the stability of the most potent compound compared to a co-crystallized ligand. Compound MQ3 demonstrated a remarkable inhibitory effect against Glo-I, with an IC50 concentration of 1.45 µM. The inhibitory potency of MQ3 may be attributed to the catechol ring, amide functional group, and anthraquinone moiety, collectively contributing to a strong binding affinity with Glo-I. Anthraquinone amide-based derivatives exhibit substantial potential as Glo-I inhibitors with prospective anticancer activity. The exceptional inhibitory efficacy of compound MQ3 indicates its potential as an effective anticancer agent. These findings underscore the significance of anthraquinone amide-based derivatives as a novel class of compounds for cancer therapy, supporting further research and advancements in targeting the Glo-I enzyme to combat cancer.

Melatonin induced reversibility of vanadium toxicity in muskmelon by regulating antioxidant defense and glyoxalase systems.

Agricultural lands with vanadium (V), pose a significant and widespread threat to crop production worldwide. The study was designed to explore the melatonin (ME) treatment in reducing the V-induced phytotoxicity in muskmelon. The muskmelon seedlings were grown hydroponically and subjected to V (40 mg L-1) stress and exogenously treated with ME (100 µmol L-1) to mitigate the V-induced toxicity. The results showed that V toxicity displayed a remarkably adverse effect on seedling growth and biomass, primarily by impeding root development, the photosynthesis system and the activities of antioxidants. Contrarily, the application of ME mitigated the V-induced growth damage and significantly improved root attributes, photosynthetic efficiency, leaf gas exchange parameters and mineral homeostasis by reducing V accumulation in leaves and roots. Additionally, a significant reduction in the accumulation of reactive oxygen species (ROS), malondialdehyde (MDA) along with a decrease in electrolyte leakage was observed in muskmelon seedlings treated with ME under V-stress. This reduction was attributed to the enhancement in the activities of antioxidants in leaves/roots such as ascorbate (AsA), superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), glutathione peroxidase (GPX), glutathione S-transferase (GST) as compared to the V stressed plants. Moreover, ME also upregulated the chlorophyll biosynthesis and antioxidants genes expression in muskmelon. Given these findings, ME treatment exhibited a significant improvement in growth attributes, photosynthesis efficiency and the activities of antioxidants (enzymatic and non-enzymatic) by regulating their expression of genes against V-stress with considerable reduction in oxidative damage.

Effect of BvAgNP on growth, development, and glyoxalase gene expression analysis in Mammillaria bombycina and Selenicereus undatus.

BACKGROUND: Silver nanoparticles (AgNPs) have been used in plant tissue culture as growth stimulants, promoting bud initiation, germination, and rooting. In prior studies, AgNPs were synthesized and characterized by green synthesis using extracts from Beta vulgaris var. cicla (BvAgNP), and their functionality as seed disinfectant and antimicrobial was verified. In this study, we evaluated the effect of BvAgNP on the growth and development of Mammillaria bombycina and Selenicereus undatus in vitro, as well as the expression of glyoxalase genes. METHODS: Explants from M. bombycina and S. undatus in vitro were treated with 25, 50, and 100 mg/L of BvAgNP. After 90 days, morphological characteristics were evaluated, and the expression of glyoxalase genes was analyzed by qPCR. RESULTS: All treatments inhibited rooting for M. bombycina and no bud initiation was observed. S. undatus, showed a maximum response in rooting and bud generation at 25 mg/L of BvAgNP. Scanning electron microscopy (SEM) results exhibited a higher number of vacuoles in stem cells treated with BvAgNP compared to the control for both species. Expression of glyoxalase genes in M. bombycina increased in all treatments, whereas it decreased for S. undatus, however, increasing in roots. CONCLUSIONS: This study presents the effects of BvAgNP on the growth and development of M. bombycina and S. undatus, with the aim of proposing treatments that promote in vitro rooting and bud initiation.

Is Methylglyoxal a Potential Biomarker for the Warburg Effect Induced by the Lipopolysaccharide Neuroinflammation Model?

Methylglyoxal (MG) is considered a classical biomarker of diabetes mellitus and its comorbidities. However, a role for this compound in exacerbated immune responses, such as septicemia, is being increasingly observed and requires clarification, particularly in the context of neuroinflammatory responses. Herein, we used two different approaches (in vivo and acute hippocampal slice models) to investigate MG as a biomarker of neuroinflammation and the neuroimmunometabolic shift to glycolysis in lipopolysaccharide (LPS) inflammation models. Our data reinforce the hypothesis that LPS-induced neuroinflammation stimulates the cerebral innate immune response by increasing IL-1ß, a classical pro-inflammatory cytokine, and the astrocyte reactive response, via elevating S100B secretion and GFAP levels. Acute neuroinflammation promotes an early neuroimmunometabolic shift to glycolysis by elevating glucose uptake, lactate release, PFK1, and PK activities. We observed high serum and cerebral MG levels, in association with a reduction in glyoxalase 1 detoxification activity, and a close correlation between serum and hippocampus MG levels with the systemic and neuroinflammatory responses to LPS. Findings strongly suggest a role for MG in immune responses.

Glyoxalase System in Breast and Ovarian Cancers: Role of MEK/ERK/SMAD1 Pathway.

The glyoxalase system, comprising GLO1 and GLO2 enzymes, is integral in detoxifying methylglyoxal (MGO) generated during glycolysis, with dysregulation implicated in various cancer types. The MEK/ERK/SMAD1 signaling pathway, crucial in cellular processes, influences tumorigenesis, metastasis, and angiogenesis. Altered GLO1 expression in cancer showcases its complex role in cellular adaptation and cancer aggressiveness. GLO2 exhibits context-dependent functions, contributing to both proapoptotic and antiapoptotic effects in different cancer scenarios. Research highlights the interconnected nature of these systems, particularly in ovarian cancer and breast cancer. The glyoxalase system's involvement in drug resistance and its impact on the MEK/ERK/SMAD1 signaling cascade underscore their clinical significance. Furthermore, this review delves into the urgent need for effective biomarkers, exemplified in ovarian cancer, where the RAGE-ligand pathway emerges as a potential diagnostic tool. While therapeutic strategies targeting these pathways hold promise, this review emphasizes the challenges posed by context-dependent effects and intricate crosstalk within the cellular milieu. Insights into the molecular intricacies of these pathways offer a foundation for developing innovative therapeutic approaches, providing hope for enhanced cancer diagnostics and tailored treatment strategies.

Trapping mechanism by di-d-psicose anhydride with methylglyoxal for prevention of diabetic nephropathy.

Di-d-psicose anhydride (DPA), derived from functional rare saccharide as d-psicose, is investigated for its strong chelating ability. Methylglyoxal (MGO), an important precursor of advanced glycation end-products (AGEs), promotes obesity, and causes complications such as diabetic nephropathy. On mesangial cells, DPA can substantially reduce the negative effects of MGO. DPA effectively trapping MGO in mesangial cells. The bonding properties of the DPA-MGO adduct were discussed by mass spectrometry and nuclear magnetic resonance (NMR). The NMR spectra of the DPA-MGO adduct provide evidence for chelation bonding. The inhibition of AGE formation and the mass spectrometry results of the DPA-MGO adduct indicate that DPA can scavenge MGO at a molar ratio of 1:1. DPA suppressed 330 % of the up-regulated receptor for an AGEs protein expression to a normal level and restored the suppressed glyoxalase 1 level to 86 % of the normal group. This research provides important evidence and theoretical basis for the development of AGE inhibitors derived from rare saccharide.

Role of methylglyoxal and glyoxalase in the regulation of plant response to heavy metal stress.

KEY MESSAGE: Methylglyoxal and glyoxalase function a significant role in plant response to heavy metal stress. We update and discuss the most recent developments of methylglyoxal and glyoxalase in regulating plant response to heavy metal stress. Methylglyoxal (MG), a by-product of several metabolic processes, is created by both enzymatic and non-enzymatic mechanisms. It plays an important role in plant growth and development, signal transduction, and response to heavy metal stress (HMS). Changes in MG content and glyoxalase (GLY) activity under HMS imply that they may be potential biomarkers of plant stress resistance. In this review, we summarize recent advances in research on the mechanisms of MG and GLY in the regulation of plant responses to HMS. It has been discovered that appropriate concentrations of MG assist plants in maintaining a balance between growth and development and survival defense, therefore shielding them from heavy metal harm. MG and GLY regulate plant physiological processes by remodeling cellular redox homeostasis, regulating stomatal movement, and crosstalking with other signaling molecules (including abscisic acid, gibberellic acid, jasmonic acid, cytokinin, salicylic acid, melatonin, ethylene, hydrogen sulfide, and nitric oxide). We also discuss the involvement of MG and GLY in the regulation of plant responses to HMS at the transcriptional, translational, and metabolic levels. Lastly, considering the current state of research, we present a perspective on the future direction of MG research to elucidate the MG anti-stress mechanism and offer a theoretical foundation and useful advice for the remediation of heavy metal-contaminated environments in the future.

Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation.

Chronic, systemic inflammation is a pathophysiological manifestation of metabolic disorders. Inflammatory signaling leads to elevated glycolytic flux and a metabolic shift towards aerobic glycolysis and lactate generation. This rise in lactate corresponds with increased generation of lactoylLys modifications on histones, mediating transcriptional responses to inflammatory stimuli. Lactoylation is also generated through a non-enzymatic S-to-N acyltransfer from the glyoxalase cycle intermediate, lactoylglutathione (LGSH). Here, we report a regulatory role for LGSH in mediating histone lactoylation and inflammatory signaling. In the absence of the primary LGSH hydrolase, glyoxalase 2 (GLO2), RAW264.7 macrophages display significant elevations in LGSH and histone lactoylation with a corresponding potentiation of the inflammatory response when exposed to lipopolysaccharides. An analysis of chromatin accessibility shows that lactoylation is associated with more compacted chromatin than acetylation in an unstimulated state; upon stimulation, however, regions of the genome associated with lactoylation become markedly more accessible. Lastly, we demonstrate a spontaneous S-to-S acyltransfer of lactate from LGSH to CoA, yielding lactoyl-CoA. This represents the first known mechanism for the generation of this metabolite. Collectively, these data suggest that LGSH, and not intracellular lactate, is the primary driving factor facilitating histone lactoylation and a major contributor to inflammatory signaling.

Pyramiding D-lactate dehydrogenase with the glyoxalase pathway enhances abiotic stress tolerance in plants.

Methylglyoxal is a common cytotoxic metabolite produced in plants during multiple biotic and abiotic stress. To mitigate the toxicity of MG, plants utilize the glyoxalase pathway comprising glyoxalase I (GLYI), glyoxalase II (GLYII), or glyoxalase III (GLYIII). GLYI and GLYII are the key enzymes of glyoxalase pathways that play an important role in abiotic stress tolerance. Earlier research showed that MG level is lower when both GLYI and GLYII are overexpressed together, compared to GLYI or GLYII single gene overexpressed transgenic plants. D-lactate dehydrogenase (D-LDH) is an integral part of MG detoxification which metabolizes the end product (D-lactate) of the glyoxalase pathway. In this study, two Arabidopsis transgenic lines were constructed using gene pyramiding technique: GLYI and GLYII overexpressed (G-I + II), and GLYI, GLYII, and D-LDH overexpressed (G-I + II + D) plants. G-I + II + D exhibits lower MG and D-lactate levels and enhanced abiotic stress tolerance than the G-I + II and wild-type plants. Further study explores the stress tolerance mechanism of G-I + II + D plants through the interplay of different regulators and plant hormones. This, in turn, modulates the expression of ABA-dependent stress-responsive genes like RAB18, RD22, and RD29B to generate adaptive responses during stress. Therefore, there might be a potential correlation between ABA and MG detoxification pathways. Furthermore, higher STY46, GPX3, and CAMTA1 transcripts were observed in G-I + II + D plants during abiotic stress. Thus, our findings suggest that G-I + II + D has significantly improved MG detoxification, reduced oxidative stress-induced damage, and provided a better protective mechanism against abiotic stresses than G-I + II or wild-type plants.

Application of biochar and humic acid improves the physiological and biochemical processes of rice (Oryza sativa L.) in conferring plant tolerance to arsenic-induced oxidative stress.

Biochar (BC) and humic acid (HA) are well-documented in metal/metalloid detoxification, but their regulatory role in conferring plant oxidative stress under arsenic (As) stress is poorly understood. Therefore, we aimed at investigating the role of BC and HA (0.2 and 0.4 g kg-1 soil) in the detoxification of As (0.25 mM sodium arsenate) toxicity in rice (Oryza sativa L. cv. BRRI dhan75). Arsenic exhibited an increased lipid peroxidation, hydrogen peroxide, electrolyte leakage, and proline content which were 32, 30, 9, and 89% higher compared to control. In addition, the antioxidant defense system of rice consisting of non-enzyme antioxidants (18 and 43% decrease in ascorbate and glutathione content) and enzyme activities (23-50% reduction over control) was decreased as a result of As toxicity. The damaging effect of As was prominent in plant height, biomass acquisition, tiller number, and relative water content. Furthermore, chlorophyll and leaf area also exhibited a decreasing trend due to toxicity. Arsenic exposure also disrupted the glyoxalase system (23 and 33% decrease in glyoxalase I and glyoxalase II activities). However, the application of BC and HA recovered the reactive oxygen species-induced damages in plants, upregulated the effectiveness of the ascorbate-glutathione pool, and accelerated the activities of antioxidant defense and glyoxalase enzymes. These positive roles of BC and HA ultimately resulted in improved plant characteristics with better plant-water status and regulated proline content that conferred As stress tolerance in rice. So, it can be concluded that BC and HA effectively mitigated As-induced physiology and oxidative damage in rice plants. Therefore, BC and HA could be used as potential soil amendments in As-contaminated rice fields.

Association between GLO1 variants and gestational diabetes mellitus susceptibility in a Chinese population: a preliminary study.

Background: Glyoxalase 1 (GLO1) plays a crucial role in defending against glycation. Single nucleotide polymorphism (SNP) variants in the GLO1 gene may affect gene expression and alter enzyme activity. However, there have been limited studies evaluating the association between GLO1 and diabetes, especially gestational diabetes mellitus (GDM). Therefore, this study is the first to explore the association of GLO1 SNPs and GDM risk. Methods: The study included a total of 500 GDM patients and 502 control subjects. The SNPscan™ genotyping assay was used to genotype rs1781735, rs4746 and rs1130534. To assess the disparities in genotype, allele, and haplotype distributions and their correlation with GDM risk, the independent sample t-test, logistic regression, and chi-square test were employed during the data processing phase. Furthermore, one-way ANOVA was conducted to determine the differences in genotype and blood glucose and methylglyoxal(MG) levels. Results: Significant differences were observed in prepregnancy body mass index (pre-BMI), age, systolic blood pressure (SBP), diastolic blood pressure (DBP), and parity between GDM and healthy subjects (P < 0.05). After adjusting for these factors, GLO1 rs1130534 TA remained associated with an increased risk of GDM (TA vs. TT + AA: OR = 1.320; 95% CI: 1.008-1.728; P = 0.044), especially in the pre-BMI ≥ 24 subgroup (TA vs. TT + AA: OR = 2.424; 95% CI: 1.048-5.607; P = 0.039), with fasting glucose levels being significantly elevated in the TA genotype compared to the TT genotype (P < 0.05). Conversely, the GLO1 rs4746 TG was associated with a decreased risk of GDM (TG vs. TT: OR = 0.740; 95% CI: 0.548-0.999; P = 0.049; TG vs. TT + GG: OR = 0.740; 95% CI: 0.548-0.998; P = 0.048). Additionally, the haplotype T-G-T of rs1781735, rs4746 and rs1130534 was associated with a decreased risk of GDM among individuals with a pre-BMI ≥ 24 (OR = 0.423; 95% CI: 0.188-0.955; P = 0.038). Furthermore, the rs1781735 GG genotype was found to be more closely related to maternal MG accumulation and neonatal weight gain (P < 0.05). Conclusion: Our findings suggested that GLO1 rs1130534 was associated with an increased susceptibility to GDM and higher blood glucose levels, but GLO1 rs4746 was associated with a decreased risk of GDM. The rs1781735 has been associated with the accumulation of maternal MG and subsequent weight gain in neonates.

MiR-205-3p suppresses bladder cancer progression via GLO1 mediated P38/ERK activation.

MicroRNAs (miRNAs) have been reported to serve as potential biomarkers in bladder cancer and play important roles in cancer progression. This study aimed to investigate the biological role of miR-205-3p in bladder cancer. We showed that miR-205-3p was significantly down-regulated in bladder cancer tissues and cells. Moreover, overexpression of miR-205-3p inhibited bladder cancer progression in vitro. Then we confirmed that GLO1, a downstream target of miR-205-3p, mediated the effect of miR-205-3p on bladder cancer cells. In addition, we found that miR-205-3p inhibits P38/ERK activation through repressing GLO1. Eventually, we confirmed that miR-205-3p inhibits the occurrence and progress of bladder cancer by targeting GLO1 in vivo by nude mouse tumorigenesis and immunohistochemistry. In a word, miR-205-3p inhibits proliferation and metastasis of bladder cancer cells by activating the GLO1 mediated P38/ERK signaling pathway and that may be a potential therapeutic target for bladder cancer.

Proline-mediated activation of glyoxalase II improve methylglyoxal detoxification in Oryza sativa L. under chromium injury: Clarification via vector analysis of enzymatic activities and gene expression.

Environmental factors affect plants in several ways including the excessive accumulation of methylglyoxal (MG), resulting in dysfunctions of many biological processes. Exogenous proline (Pro) application is one of the successful strategies to increase plant tolerance against various environmental stresses, including chromium (Cr). This study highlights the alleviation role of exogenous Pro on MG detoxification in rice plants induced by Cr(Vl) through modifying the expression of glyoxalase I (Gly I)- and glyoxalase II (Gly II)-related genes. The MG content in rice roots was significantly reduced by Pro application under Cr(VI) stress, however, there was little effect on the MG content in shoots. In this connection, the vector analysis was used to compare the involvement of Gly l and Gly II on MG detoxification in 'Cr(VI)' and 'Pro+Cr(VI)' treatments. Results exhibited that vector strength in rice roots increased with an increase in Cr concentrations, while there was a negligible difference in the shoots. The comparative analysis demonstrated that the vector strengths in roots under 'Pro+Cr(VI)' treatments were higher than 'Cr(VI)' treatments, suggesting that Pro improved Gly II activity more efficiently to reduce MG content in roots. Calculation of the gene expression variation factors (GEFs) indicated a positive effect of Pro application on the expression of Gly I and Gly ll-related genes, wherein a stronger impact was in roots than the shoots. Together, the vector analysis and gene expression data reveal that exogenous Pro chiefly improved Gly ll activity in rice roots which subsequently enhanced MG detoxification under Cr(VI) stress.

Overexpressing glyoxalase 1 attenuates acute hyperglycemia-exacerbated neurological deficits of ischemic stroke in mice.

Stress-induced hyperglycemia (SIH) is associated with poor functional recovery and high mortality in patients with acute ischemic stroke (AIS). However, intensive controlling of blood glucose by using insulin was not beneficial in patients with AIS and acute hyperglycemia. This study investigated the therapeutic effects of the overexpression of glyoxalase I (GLO1), a detoxifying enzyme of glycotoxins, on acute hyperglycemia-aggravated ischemic brain injury.  In the present study, adeno-associated viral (AAV)-mediated GLO1 overexpression reduced infarct volume and edema level but did not improve neurofunctional recovery in the mice with middle cerebral artery occlusion (MCAO). AAV-GLO1 infection significantly enhanced neurofunctional recovery in the MCAO mice with acute hyperglycemia but not in the mice with normoglycemia. Methylglyoxal (MG)-modified proteins expression significantly increased in the ipsilateral cortex of the MCAO mice with acute hyperglycemia. AAV-GLO1 infection attenuated the induction of MG-modified proteins, ER stress formation, and caspase 3/7 activation in MG-treated Neuro-2A cells, and reductions in synaptic plasticity and microglial activation were mitigated in the injured cortex of the MCAO mice with acute hyperglycemia. Treatment with ketotifen, a potent GLO1 stimulator, after surgery, alleviated neurofunctional deficits and ischemic brain damage in the MCAO mice with acute hyperglycemia.  Altogether, our data substantiate that, in ischemic brain injury, GLO1 overexpression can alleviate pathologic alterations caused by acute hyperglycemia. Upregulation of GLO1 may be a therapeutic strategy for alleviating SIH-aggravated poor functional outcomes in patients with AIS.

Metformin inhibits methylglyoxal-induced retinal pigment epithelial cell death and retinopathy via AMPK-dependent mechanisms: Reversing mitochondrial dysfunction and upregulating glyoxalase 1.

Diabetic retinopathy (DR) is a major cause of blindness in adult, and the accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is a precursor of AGEs. Although the therapeutic potential of metformin for retinopathy disorders has recently been elucidated, possibly through AMPK activation, it remains unknown how metformin directly affects the MGO-induced stress response in retinal pigment epithelial cells. Therefore, in this study, we compared the effects of metformin and the AMPK activator A769662 on MGO-induced DR in mice, as well as evaluated cytotoxicity, mitochondrial dynamic changes and dysfunction in ARPE-19 cells. We found MGO can induce mitochondrial ROS production and mitochondrial membrane potential loss, but reduce cytosolic ROS level in ARPE-19 cells. Although these effects of MGO can be reversed by both metformin and A769662, we demonstrated that reduction of mitochondrial ROS production rather than restoration of cytosolic ROS level contributes to cell protective effects of metformin and A769662. Moreover, MGO inhibits AMPK activity, reduces LC3II accumulation, and suppresses protein and gene expressions of MFN1, PGC-1α and TFAM, leading to mitochondrial fission, inhibition of mitochondrial biogenesis and autophagy. In contrast, these events of MGO were reversed by metformin in an AMPK-dependent manner as evidenced by the effects of compound C and AMPK silencing. In addition, we observed an AMPK-dependent upregulation of glyoxalase 1, a ubiquitous cellular enzyme that participates in the detoxification of MGO. In intravitreal drug-treated mice, we found that AMPK activators can reverse the MGO-induced cotton wool spots, macular edema and retinal damage. Functional, histological and optical coherence tomography analysis support the protective actions of both agents against MGO-elicited retinal damage. Metformin and A769662 via AMPK activation exert a strong protection against MGO-induced retinal pigment epithelial cell death and retinopathy. Therefore, metformin and AMPK activator can be therapeutic agents for DR.

The thioesterase APT1 is a bidirectional-adjustment redox sensor.

The adjustment of cellular redox homeostasis is essential in when responding to environmental perturbations, and the mechanism by which cells distinguish between normal and oxidized states through sensors is also important. In this study, we found that acyl-protein thioesterase 1 (APT1) is a redox sensor. Under normal physiological conditions, APT1 exists as a monomer through S-glutathionylation at C20, C22 and C37, which inhibits its enzymatic activity. Under oxidative conditions, APT1 senses the oxidative signal and is tetramerized, which makes it functional. Tetrameric APT1 depalmitoylates S-acetylated NAC (NACsa), and NACsa relocates to the nucleus, increases the cellular glutathione/oxidized glutathione (GSH/GSSG) ratio through the upregulation of glyoxalase I expression, and resists oxidative stress. When oxidative stress is alleviated, APT1 is found in monomeric form. Here, we describe a mechanism through which APT1 mediates a fine-tuned and balanced intracellular redox system in plant defence responses to biotic and abiotic stresses and provide insights into the design of stress-resistant crops.