Methylglyoxal-mediated Gpd1 activation restores the mitochondrial defects in a yeast model of mitochondrial DNA depletion syndrome.

Human MPV17, an evolutionarily conserved mitochondrial inner-membrane channel protein, accounts for the tissue-specific mitochondrial DNA depletion syndrome. However, the precise molecular function of the MPV17 protein is still elusive. Previous studies showed that the mitochondrial morphology and cristae organization are severely disrupted in the MPV17 knockout cells from yeast, zebrafish, and mammalian tissues. As mitochondrial cristae morphology is strictly regulated by the membrane phospholipids composition, we measured mitochondrial membrane phospholipids (PLs) levels in yeast Saccharomyces cerevisiae MPV17 ortholog, SYM1 (Stress-inducible Yeast MPV17) deleted cells. We found that Sym1 knockout decreases the mitochondrial membrane PL, phosphatidyl ethanolamine (PE), and inhibits respiratory growth at 37 ̊C on rich media. Both the oxygen consumption rate and the steady state expressions of mitochondrial complex II and super-complexes are compromised. Apart from mitochondrial PE defect a significant depletion of mitochondrial phosphatidyl-choline (PC) was noticed in the sym1∆ cells grown on synthetic media at both 30 ̊C and 37 ̊C temperatures. Surprisingly, exogenous supplementation of methylglyoxal (MG), an intrinsic side product of glycolysis, rescues the respiratory growth of Sym1 deficient yeast cells. Using a combination of molecular biology and lipid biochemistry, we uncovered that MG simultaneously restores both the mitochondrial PE/PC levels and the respiration by enhancing cytosolic NAD-dependent glycerol-3-phosphate dehydrogenase 1 (Gpd1) enzymatic activity. Further, MG is incapable to restore respiratory growth of the sym1∆gpd1∆ double knockout cells. Thus, our work provides Gpd1 activation as a novel strategy for combating Sym1 deficiency and PC/PE defects.

Exogenous hydrogen sulfide and methylglyoxal alleviate cadmium-induced oxidative stress in Salix matsudana Koidz by regulating glutathione metabolism.

BACKGROUND: Cadmium (Cd) is a highly toxic element for plant growth. In plants, hydrogen sulfide (H2S) and methylglyoxal (MG) have emerged as vital signaling molecules that regulate plant growth processes under Cd stress. However, the effects of sodium hydrosulfide (NaHS, a donor of H2S) and MG on Cd uptake, physiological responses, and gene expression patterns of Salix to Cd toxicity have been poorly understood. Here, Salix matsudana Koidz. seedlings were planted in plastic pot with applications of MG (108 mg kg- 1) and NaHS (50 mg kg- 1) under Cd (150 mg kg- 1) stress. RESULTS: Cd treatment significantly increased the reactive oxygen species (ROS) levels and malondialdehyde (MDA) content, but decreased the growth parameters in S. matsudana. However, NaHS and MG supplementation significantly decreased Cd concentration, ROS levels, and MDA content, and finally enhanced the growth parameters. Cd stress accelerated the activities of antioxidative enzymes and the relative expression levels of stress-related genes, which were further improved by NaHS and MG supplementation. However, the activities of monodehydroascorbate reductase (MDHAR), and dehydroascorbate reductase (DHAR) were sharply decreased under Cd stress. Conversely, NaHS and MG applications restored the MDHAR and DHAR activities compared with Cd-treated seedlings. Furthermore, Cd stress decreased the ratios of GSH/GSSG and AsA/DHA but considerably increased the H2S and MG levels and glyoxalase I-II system in S. matsudana, while the applications of MG and NaHS restored the redox status of AsA and GSH and further improved glyoxalase II activity. In addition, compared with AsA, GSH showed a more sensitive response to exogenous applications of MG and NaHS and plays more important role in the detoxification of Cd. CONCLUSIONS: The present study illustrated the crucial roles of H2S and MG in reducing ROS-mediated oxidative damage to S. matsudana and revealed the vital role of GSH metabolism in regulating Cd-induced stress.

Effect of the simulated digestion process on the chlorogenic acid trapping activity against methylglyoxal.

Chlorogenic acids are hydroxycinnamic derivatives widespread in food or food by-products, known for their antioxidant effects and ability to interfere with the formation of advanced glycation end products (AGEs). AGEs are potential glycotoxins involved in age-related disorders, such as diabetes, cardiovascular diseases, and neurological disorders. The ability of chlorogenic acids to inhibit AGE formation under physiological conditions needs further investigation other than the in vitro assays. Therefore, in this study, the capacity of 5-caffeoylquinic acid (5-CQA) to effectively trap methylglyoxal (MGO), an AGE precursor compound also present in daily consumed food, was investigated by evaluating 5-CQA and MGO metabolic fate when subjected to digestion. Two different in vitro digestion approaches (static based on the Infogest protocol and dynamic based on a novel millifluidic gastrointestinal model) were set up and the samples collected at different steps of the static and dynamic processes were analyzed by a validated RP-HPLC-DAD method. The obtained results indicated that the gastrointestinal process strongly affected the 5-CQA capacity to trap MGO and its resulting antiglycation activity. Therefore, preliminary investigation using advanced in vitro tests, particularly dynamic approaches, should always be performed to predict the effect of the digestion process on the potential bioactives present in food, food by-products, or plant extracts.

Chemometric discrimination of Hylocereus undulatus from different geographical origins via their metabolic profiling and antidiabetic activity.

Hylocereus spp. known as dragon fruit is an exotic fruit that belongs to the Cactaceae family. LC-QTOF-MS and multivariate statistical tools were established to analyze differences in the composition of dragon fruit peel and pulp from Egypt, Germany, Philippines, and China. The α-glucosidase inhibitory effects of different extracts were carried out along with the anti-glycation end products (AGE) using BSA-fructose, BSA-methylglyoxal, and arginine-methylglyoxal assays. In addition, the total antioxidant capacity was investigated as a complementary mechanism to AGE formation. Principal component analysis revealed that dragon fruits from China and Egypt were the most distinct among all samples due to betalains content. Orthogonal projection to latent structures-discriminant analysis identified 16 compounds highly correlated to the antiglycation activity such as betanin, γ-aminobutyric acid, neobetanin, and portulacaxanthin II. Pulp extracts were more active than peels as inhibitors of α-glucosidase. While peels were more active as AGE formation inhibitors and as antioxidants.

Effects of exogenous taurine on growth, photosynthesis, oxidative stress, antioxidant enzymes and nutrient accumulation by Trifolium alexandrinum plants under manganese stress.

Plants essentially require manganese (Mn) for their normal metabolic functioning. However, excess Mn in the cellular environment is detrimental to plant growth, development, and physio-biochemical functions. Taurine (TAU) is an amino acid with potent antioxidant and anti-inflammatory properties in animals and humans. However, no previous study has investigated the potential of TAU in plant metal stress tolerance. The current study provides some novel insights into the effect of TAU in modulating the defense system of Trifolium alexandrinum plants under Mn toxicity. Manganese toxicity resulted in higher oxidative stress and membrane damage through increased superoxide radical, hydrogen peroxide, malondialdehyde, and methylglyoxal generation alongside enhanced lipoxygenase (LOX) activity. Mn toxicity also resulted in limited uptake of potassium (K+), phosphorus (P), calcium (Ca2+), and increased the accumulation of Mn in both leaf and roots. However, TAU circumvented the Mn-induced oxidative stress by upregulating the activities of antioxidant enzymes (ascorbate peroxidase, peroxidase, catalase, glutathione reductase, glutathione-S-transferase, and superoxide dismutase) and levels of ascorbic acid, proline, anthocyanins, phenolics, flavonoids and glutathione (GSH). Taurine conspicuously improved the growth, photosynthetic pigments, hydrogen sulphide (H2S), and nitric oxide (NO) levels of Mn stressed plants. Taurine also improved the uptake of K+, Ca2+, P and reduced the Mn content in stressed plants. Overall, exogenous taurine might be a suitable strategy to combat Mn stress in T. alexandrinum plants but applications at field levels for various crops and metal toxicities and economic suitability need to be addressed before final recommendations.

Insulin sensitizer and antihyperlipidemic effects of Cajanus cajan (L.) millsp. root in methylglyoxal-induced diabetic rats.

Cajanus cajan (L.) Millsp., known as pigeon pea, is one of the major grain legume crops of the tropical world. It recognizes as an ethnomedicine to possess various functions, such as helping in healing wound and cancer therapy. We investigated whether 95% ethanol extracts from C. cajan root (EECR) protect against methylglyoxal (MGO)-induced insulin resistance (IR) and hyperlipidemia in male Wistar rats and explored its possible mechanisms. The hypoglycemic potential of EECR was evaluated using α-amylase, α-glucosidase activities, and advanced glycation end products (AGEs) formation. For in vivo study, the rats were divided into six groups and orally supplemented with MGO except for Group 1 (controls). Group 2 was supplemented with MGO only, Group 3: MGO + metformin, Group 4: MGO + Low dose-EECR (L-EECR; 10 mg/kg bw), Group 5: MGO + Middle dose-EECR (M-EECR; 50 mg/kg bw), and Group 6: MGO + High dose-EECR (H-EECR; 100 mg/kg bw). EECR possessed good inhibition of α-glucosidase, α-amylase activities, and AGEs formation (IC50 = 0.12, 0.32, and 0.50 mg/mL), respectively. MGO significantly increased serum levels of blood glucose (GLU), glycosylated hemoglobin, homeostasis model assessment of IR, AGEs, lipid biochemical values, and atherogenic index, whereas EECR decreased these levels in a dose-dependent manner. EECR can also act as an insulin sensitizer, which significantly decreased (47%, P < 0.05) the blood GLU levels after intraperitoneal injection of insulin in the insulin tolerance tests. The hypoglycemic and antihyperlipidemic mechanisms of EECR are likely through several possible pathways including the inhibition of carbohydrate-hydrolyzing enzymes (α-glucosidase and α-amylase) and the enhancement of MGO-trapping effects on inhibition of AGEs formation.

Induction of the glycolysis product methylglyoxal on trimethylamine lyase synthesis in the intestinal microbiota from mice fed with choline and dietary fiber.

The present study investigated the induction of the glycolysis product methylglyoxal by trimethylamine (TMA) lyase synthesis in the intestinal microbiota and investigated the intervention mechanism of the effects of dietary fiber on methylglyoxal formation. Intestinal digesta samples, collected from the ceca of mice fed with choline-rich and fiber-supplemented diets, were incubated in an anaerobic environment at 37 °C and pH 7.0 with choline, glycine, and methylglyoxal as inductive factors. The differences between the gut microbiota and its metagenomic and metabonomics profiles were determined using 16S rRNA gene sequencing analysis. The results elucidated that the different dietary interventions could induce differences in the composition of the microbiota, gene expression profiles associated with glycine metabolism, and glycolysis. As compared to the gut microbiota of choline-diet fed mice, fiber supplementation effectively altered the composition of the microbiota and inhibited the genes involved in choline metabolism, glycine and methylglyoxal accumulation, and TMA lyase expression, and improved the methylglyoxal utilization by regulating the pathway related to pyruvate production. However, the intervention of exogenous methylglyoxal significantly decreased these effects. These findings successfully revealed the correlations between the TMA lyase expression and glycine level, as well as the inhibitory effects of dietary fiber on the glycine level, thereby highlighting the role of common glycolytic metabolites as a potential target for TMA production.

Dual l-Carnosine/Aloe vera Nanophytosomes with Synergistically Enhanced Protective Effects against Methylglyoxal-Induced Angiogenesis Impairment.

Microvascular complications are among the major outcomes of patients with type II diabetes mellitus, which are the consequences of impaired physiological functioning of small blood vessels and angiogenic responses in these patients. Overproduction and accumulation of methylglyoxal (MGO), a highly reactive dicarbonyl byproduct of glycolysis pathway, has been acclaimed as the main inducer of impaired angiogenic responses and microvascular dysfunction in diabetic patients with uncontrolled hyperglycemia. Hence, an effective approach to overcome diabetes-associated microvascular complications is to neutralize the deleterious activity of enhanced the concentration of MGO in the body. Owing to the glycation inhibitory activity of Aloe vera whole extract, and capability of l-carnosine, an endogenous dipeptide, in attenuating MGO's destructive activity, we examined whether application of a combination of l-carnosine and A. vera could be an effective way of synergistically weakening this reactive dicarbonyl's impaired angiogenic effects. Additionally, overcoming the poor cellular uptake and internalization of l-carnosine and A. vera, a nanophytosomal formulation of the physical mixture of two compounds was also established. Although l-carnosine and A. vera at whole studied combination ratios could synergistically enhance viability of human umbilical vein endothelial cells (HUVECs) treated with MGO, the 25:1 w/w ratio was the most effective one among the others (27 ± 0.5% compared to 12 ± 0.3 to 18 ± 0.4%; F (4, 15) = 183.9, P < 0.0001). Developing dual nanophytosomes of l-carnosine/A. vera (25:1) combination ratio, we demonstrated superiority of the nanophytosomal formulation in protecting HUVECs against MGO-induced toxicity following a 24-72 h incubation period (17.3, 15.8, and 12.4% respectively). Moreover, 500 µg/mL concentration of dual l-carnosine/A. vera nanophytosomes exhibited a superior free radical scavenging potency (63 ± 4 RFU vs 83 ± 5 RFU; F (5, 12) = 54.81, P < 0.0001) and nitric oxide synthesizing capacity (26.11 ± 0.19 vs 5.1 ± 0.33; F (5, 12) = 2537, P < 0.0001) compared to their physical combination counterpart. Similarly, 500 µg/mL dual l-carnosine/A. vera nanophytosome-treated HUVECs demonstrated a superior tube formation capacity (15 ± 3 vs 2 ± 0.3; F (5, 12) = 30.87, P < 0.001), wound scratch healing capability (4.92 ± 0.3 vs 3.07 ± 0.3 mm/h; F (5, 12) = 39.21, P < 0.0001), and transwell migration (586 ± 32 vs 394 ± 18; F (5, 12) = 231.8, P < 0.001) and invasion (172 ± 9 vs 115 ± 5; F (5, 12) = 581.1, P < 0.0001) activities compared to the physical combination treated ones. Further confirming the proangiogenic activity of the dual l-carnosine/A. vera nanophytosomes, a significant shift toward expression of proangiogenic genes including HIF-1α, VEGFA, bFGF, KDR, and Ang II was reported in treated HUVECs. Overall, dual l-carnosine/A. vera nanophytosomes could be a potential candidate for attenuating type II DM-associated microvascular complications with an impaired angiogenesis background.

Interaction between magnesium and methylglyoxal in diabetic polyneuropathy and neuronal models.

OBJECTIVE: The lack of effective treatments against diabetic sensorimotor polyneuropathy demands the search for new strategies to combat or prevent the condition. Because reduced magnesium and increased methylglyoxal levels have been implicated in the development of both type 2 diabetes and neuropathic pain, we aimed to assess the putative interplay of both molecules with diabetic sensorimotor polyneuropathy. METHODS: In a cross-sectional study, serum magnesium and plasma methylglyoxal levels were measured in recently diagnosed type 2 diabetes patients with (n = 51) and without (n = 184) diabetic sensorimotor polyneuropathy from the German Diabetes Study baseline cohort. Peripheral nerve function was assessed using nerve conduction velocity and quantitative sensory testing. Human neuroblastoma cells (SH-SY5Y) and mouse dorsal root ganglia cells were used to characterize the neurotoxic effect of methylglyoxal and/or neuroprotective effect of magnesium. RESULTS: Here, we demonstrate that serum magnesium concentration was reduced in recently diagnosed type 2 diabetes patients with diabetic sensorimotor polyneuropathy and inversely associated with plasma methylglyoxal concentration. Magnesium, methylglyoxal, and, importantly, their interaction were strongly interrelated with methylglyoxal-dependent nerve dysfunction and were predictive of changes in nerve function. Magnesium supplementation prevented methylglyoxal neurotoxicity in differentiated SH-SY5Y neuron-like cells due to reduction of intracellular methylglyoxal formation, while supplementation with the divalent cations zinc and manganese had no effect on methylglyoxal neurotoxicity. Furthermore, the downregulation of mitochondrial activity in mouse dorsal root ganglia cells and consequently the enrichment of triosephosphates, the primary source of methylglyoxal, resulted in neurite degeneration, which was completely prevented through magnesium supplementation. CONCLUSIONS: These multifaceted findings reveal a novel putative pathophysiological pathway of hypomagnesemia-induced carbonyl stress leading to neuronal damage and merit further investigations not only for diabetic sensorimotor polyneuropathy but also other neurodegenerative diseases associated with magnesium deficiency and impaired energy metabolism.

Glyoxalase system: A systematic review of its biological activity, related-diseases, screening methods and small molecule regulators.

The glyoxalase system is a ubiquitous enzymatic network which plays important roles in biological life. It consists of glyoxalase 1 (GLO1), glyoxalase 2 (GLO2), and reduced glutathione (GSH), which perform an essential metabolic function in cells by detoxifying methylglyoxal (MG) and other endogenous harmful metabolites into non-toxic d-lactate. MG and MG-derived advanced glycation endproducts (AGEs) are associated with various diseases, such as diabetes, cardiovascular disease, neurodegenerative disorders and cancer, and GLO1 is a key rate-limiting enzyme in the anti-glycation defense. The abnormal activity and expression of GLO1 in various diseases make this enzyme a promising target for drug design and development. This review focuses on the regulatory mechanism of GLO1 in diverse pathogenic conditions with a thorough discussion of GLO1 regulators since their discovery, including GLO1 activators and inhibitors. The different classes, chemical structure and structure-activity relationship are embraced. Moreover, assays for the discovery of small molecule regulators of the glyoxalase system are also introduced in this article. Compared with spectrophotometer-based assay, microplate-based assay is a more simple, rapid and quantitative high-throughput method. This review will be useful to design novel and potent GLO1 regulators and hopefully provide a convenient reference for researchers.

Manuka honey-derived methylglyoxal enhances microbial sensing by mucosal-associated invariant T cells.

Methylglyoxal (MGO) is the main antimicrobial determinant associated with using Manuka Honey as a topical dressing. While direct mechanisms of Manuka honey MGO's antimicrobial activity have been demonstrated, such as disruption of bacterial fimbria and flagella, no interaction of Manuka honey-derived MGO with antimicrobial effector cells of the immune system, such as mucosal-associated invariant T cells (MAIT cells), has yet been reported. MAIT cells are an abundant subset of human T cells, critical for regulating a diverse range of immune functions, including antimicrobial defense mechanisms but also mucosal barrier integrity. MAIT cells become activated by recognition of an important microbial metabolite, 5-amino-6-d-ribitylaminouracil (5-A-RU), which is produced by a wide range of microbial pathogens and commensals. Recognition is afforded when 5-A-RU condenses with mammalian-cell derived MGO to form the potent MAIT cell activator, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU). Formation of 5-OP-RU and its subsequent presentation to MAIT cells by major histocompatibility (MHC)-related molecule 1 (MR1) facilitates host-pathogen and host-commensal interactions. While MGO is a metabolite naturally present in mammalian cells, it is unclear whether exogenous dietary MGO sources, such as those obtained from Manuka honey intake, can contribute to 5-OP-RU formation and enhance MAIT cell activation. In this work, we report that endogenous MGO is the rate-limiting substrate for converting microbial 5-A-RU to 5-OP-RU and that Manuka honey-derived MGO significantly enhances MAIT cell activation in vitro. Our findings posit a novel mechanism by which intake of a food item, such as Manuka honey, can potentially support immune homeostasis by enhancing MAIT cell-specific microbial sensing.

Association of the 1q25 Diabetes-Specific Coronary Heart Disease Locus With Alterations of the γ-Glutamyl Cycle and Increased Methylglyoxal Levels in Endothelial Cells.

A chromosome 1q25 variant (rs10911021) has been associated with coronary heart disease (CHD) in type 2 diabetes. In human umbilical vein endothelial cells (HUVECs), the risk allele "C" is associated with lower expression of the adjacent gene GLUL encoding glutamine synthase, converting glutamic acid to glutamine. To further investigate the mechanisms through which this locus affects CHD risk, we measured 35 intracellular metabolites involved in glutamic acid metabolism and the γ-glutamyl cycle in 62 HUVEC strains carrying different rs10911021 genotypes. Eight metabolites were positively associated with the risk allele (17-58% increase/allele copy, P = 0.046-0.002), including five γ-glutamyl amino acids, ß-citryl-glutamate, N-acetyl-aspartyl-glutamate, and ophthalmate-a marker of γ-glutamyl cycle malfunction. Consistent with these findings, the risk allele was also associated with decreased glutathione-to-glutamate ratio (-9%, P = 0.012), decreased S-lactoylglutathione (-41%, P = 0.019), and reduced detoxification of the atherogenic compound methylglyoxal (+54%, P = 0.008). GLUL downregulation by shRNA caused a 40% increase in the methylglyoxal level, which was completely prevented by glutamine supplementation. In summary, we have identified intracellular metabolic traits associated with the 1q25 risk allele in HUVECs, including impairments of the γ-glutamyl cycle and methylglyoxal detoxification. Glutamine supplementation abolishes the latter abnormality, suggesting that such treatment may prevent CHD in 1q25 risk allele carriers.

Dietary Genistein Reduces Methylglyoxal and Advanced Glycation End Product Accumulation in Obese Mice Treated with High-Fat Diet.

Our previous study has found that dietary genistein could ameliorate high-fat diet (HFD)-induced obesity and especially lower methylglyoxal (MGO) and advanced glycation end product (AGE) accumulation in healthy mice exposed to genistein and HFD. However, it is still unclear whether dietary genistein intervention has a similar beneficial effect in obese mice. In this study, the mice were induced with obesity after being fed a HFD for nine weeks before being administered with two doses of genistein, 0.1% (G 0.1) and 0.2% (G 0.2), in the HFD for additional 19 weeks. After 19 week treatment, genistein supplementation reduced body and liver weights, plasma and liver MGO levels, and kidney AGE levels in mice. Mechanistically, genistein upregulated the expressions of glyoxalase I and II and aldose reductase to detoxify MGO, and genistein and its microbial metabolites, dihydrogenistein and 6'-hydroxy-O-demethylangolensin, were able to trap endogenous MGO via formation of MGO conjugates. Taken together, our results provide novel insights into the antiobesity and antiglycation roles of dietary genistein in obese subjects.

Glycation and Antioxidants: Hand in the Glove of Antiglycation and Natural Antioxidants.

The non-enzymatic interaction of sugar and protein resulting in the formation of advanced glycation end products responsible for cell signaling alterations ultimately leads to the human chronic disorders such as diabetes mellitus, cardiovascular diseases, cancer, etc. Studies suggest that AGEs upon interaction with receptors for advanced glycation end products (RAGE) result in the production of pro-inflammatory molecules and free radicals that exert altered gene expression effect. To date, many studies unveiled the potent role of synthetic and natural agents in inhibiting the glycation reaction at a lesser or greater extent. This review focuses on the hazards of glycation reaction and its inhibition by natural antioxidants, including polyphenols.

Assessment of chemically characterised Myristica fragrans essential oil against fungi contaminating stored scented rice and its mode of action as novel aflatoxin inhibitor.

The study reports chemically characterised Myristica fragrans essential oil (MFEO) as plant based food preservative against fungal and aflatoxin B1 (AFB1) contamination of scented rice varieties. The chemical profile of MFEO revealed elemicin (27.08%), myristicine (21.29%) and thujanol (18.55%) as major components. The minimum inhibitory and minimum aflatoxin inhibitory concentrations of MFEO were 2.75 and 1.5 mg/ml, respectively. The MFEO was efficacious against a broad spectrum of food deteriorating fungi. MFEO caused decrease in ergosterol content of fungal plasma membrane and enhanced leakage of cellular ions, depicting plasma membrane as the site of action. The MFEO caused reduction in cellular methylglyoxal content, the aflatoxin inducer. This is the first report on MFEO as aflatoxin suppressor. The essential oil may be recommended as plant based food preservative after large scale trials and reduction in methylglyoxal suggests its application for development of aflatoxin resistant varieties through green transgenics.

Inhibition of resveratrol glucosides (REs) on advanced glycation endproducts (AGEs) formation: inhibitory mechanism and structure-activity relationship.

The study on inhibitory effects of resveratrol glucosides (REs) on advanced glycation endproducts (AGEs) formation is still unmet. Herein, for the first time, the antiglycation activities of five REs in the fetal bovine serum proteins (FBS)/fructose system were evaluated, and its structure-activity relationship and antiglycation mechanism were further explored. These REs showed remarkable inhibition toward AGEs formation. Among them, Piceatannol-3'-O-glucoside (PG) exhibited highest antiglycation activity as reflected in approximately 80% inhibition of fluorescent AGEs at the concentration of 1.0 mM. The structure-activity relationship analysis indicated that glucoside attached to the B ring of resveratrol displays a superior antiglycation activity. Moreover, the results of antiglycation mechanism showed that the antiglycation activity of REs was proportional to their antioxidant capacity and methylglyoxal (MGO) trapping capacity. Therefore, the REs are promising candidates worthy of further exploration for preventing AGEs accumulation in vivo, thereby treating AGEs-associated diseases.

Melanoidins from Coffee, Cocoa, and Bread Are Able to Scavenge α-Dicarbonyl Compounds under Simulated Physiological Conditions.

Free amino residues react with α-dicarbonyl compounds (DCs) contributing to the formation of advanced glycation end products (AGEs). Phenolic compounds can scavenge DCs, thus controlling the dietary carbonyl load. This study showed that high-molecular weight cocoa melanoidins (HMW-COM), HMW bread melanoidins (HMW-BM), and especially HMW coffee melanoidins (HMW-CM) are effective DC scavengers. HMW-CM (1 mg/mL) scavenged more than 40% DCs within 2 h under simulated physiological conditions, suggesting some physiological relevance. Partial acid hydrolysis of HMW-CM decreased the dicarbonyl trapping capacity, demonstrating that the ability to react with glyoxal, methylglyoxal (MGO), and diacetyl was mainly because of polyphenols bound to macromolecules. Caffeic acid (CA) and 3-caffeoylquinic acid showed a DC-scavenging kinetic profile similar to that of HMW-CM, while mass spectrometry data confirmed that hydroxyalkylation and aromatic substitution reactions led to the formation of a stable adduct between CA and MGO. These findings corroborated the idea that antioxidant-rich indigestible materials could limit carbonyl stress and AGE formation across the gastrointestinal tract.

Salicylic acid enhances nickel stress tolerance by up-regulating antioxidant defense and glyoxalase systems in mustard plants.

The present study identified inverse relationships between nickel (Ni) levels and growth, photosynthesis and physio-biochemical attributes, but increasing levels of Ni stress enhanced methylglyoxal, electrolyte leakage, hydrogen peroxide, and lipid peroxidation content. Exogenous application of salicylic acid (SA) (10-5 M) ameliorated the ill-effects of Ni by restoring growth, photosynthesis and physio-biochemical attributes and increasing the activities of enzymes associated with antioxidant systems, especially the ascorbate-glutathione (AsA-GSH) cycle and glyoxalase system. In addition, SA application to Ni-stressed plants had an additive effect on the activities of the ascorbate and glutathione pools, and the AsA-GSH cycle enzymes (ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, glutathione reductase), superoxide dismutase, catalase, glutathione S-transferase, and osmolyte biosynthesis). This trend also follows in glyoxalase system viz. glyoxalase I and glyoxalase II enzymes. Nevertheless, exogenous SA supplementation restored mineral nutrient contents. Principal component analysis showed that growth, photosynthesis, and mineral nutrient parameters were positively correlated with each other and negatively correlated with antioxidant enzymes and oxidative stress biomarkers. Hence, SA is an alternative compound with potential application in the phytoremediation of Ni.

Silicon-induced antioxidant defense and methylglyoxal detoxification works coordinately in alleviating nickel toxicity in Oryza sativa L.

Nickel (Ni), an essential nutrient of plant but very toxic to plant at supra-optimal concentration that causes inhibition of seed germination emergence and growth of plants as a consequence of physiological disorders. Hence, the present study investigates the possible mechanisms of Ni tolerance in rice seedlings by exogenous application of silicon (Si). Thirteen-day-old hydroponically grown rice (Oryza sativa L. cv. BRRI dhan54) were treated with Ni (NiSO4.7H2O, 0.25 and 0.5 mM) sole or in combination with 0.50 mM Na2SiO3 for a period of 3 days to investigate the effect of Si supply for revoking the Ni stress. Nickel toxicity gave rise to reactive oxygen species (ROS) and cytotoxic methylglyoxal (MG), accordingly, initiated oxidative stress in rice leaves, and accelerated peroxidation of lipids and consequent damage to membranes. Reduced growth, biomass accumulation, chlorophyll (chl) content, and water balance under Ni-stress were also found. However, free proline (Pro) content increased in Ni-exposed plants. In contrast, the Ni-stressed seedlings fed with supplemental Si reclaimed the seedlings from chlorosis, water retrenchment, growth inhibition, and oxidative stress. Silicon up-regulated most of the antioxidant defense components as well as glyoxalase systems, which helped to improve ROS scavenging and MG detoxification. Hence, these results suggest that the exogenous Si application can improve rice seedlings' tolerance to Ni-toxicity.

Glutamatergic Alterations in STZ-Induced Diabetic Rats Are Reversed by Exendin-4.

Diabetes mellitus is a metabolic disorder that results in glucotoxicity and the formation of advanced glycated end products (AGEs), which mediate several systemic adverse effects, particularly in the brain tissue. Alterations in glutamatergic neurotransmission and cognitive impairment have been reported in DM. Exendin-4 (EX-4), an analogue of glucagon-like peptide-1 (GLP-1), appears to have beneficial effects on cognition in rats with chronic hyperglycemia. Herein, we investigated the ability of EX-4 to reverse changes in AGE content and glutamatergic transmission in an animal model of DM looking principally at glutamate uptake and GluN1 subunit content of the N-methyl-D-aspartate (NMDA) receptor. Additionally, we evaluated the effects of EX-4 on in vitro models and the signaling pathway involved in these effects. We found a decrease in glutamate uptake and GluN1 content in the hippocampus of diabetic rats; EX-4 was able to revert these parameters, but had no effect on the other parameters evaluated (glycemia, C-peptide, AGE levels, RAGE, and glyoxalase 1). EX-4 abrogated the decrease in glutamate uptake and GluN1 content caused by methylglyoxal (MG) in hippocampal slices, in addition to leading to an increase in glutamate uptake in astrocyte culture cells and hippocampal slices under basal conditions. The effect of EX-4 on glutamate uptake was mediated by the phosphatidylinositide 3-kinases (PI3K) signaling pathway, which could explain the protective effect of EX-4 in the brain tissue, since PI3K is involved in cell metabolism, inhibition of apoptosis, and reduces inflammatory responses. These results suggest that EX-4 could be used as an adjuvant treatment for brain impairment associated with excitotoxicity.