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2-Iodo-4'-Methoxychalcone Attenuates Methylglyoxal-Induced Neurotoxicity by Activation of GLP-1 Receptor and Enhancement of Neurotrophic Signal, Antioxidant Defense and Glyoxalase Pathway.

ABSTRACT: Methylglyoxal (MG) acts as a reactive precursor of advanced glycation end products (AGEs). This compound is often connected with pathologies such as diabetes, neurodegenerative processes and diseases of aging. 2-iodo-4'-methoxychalcone (CHA79), a synthetic halogen-containing chalcone derivative, has been reported its anti-diabetic activity. This study aims to investigate the potential protective capability of CHA79 against MG-mediated neurotoxicity in SH-SY5Y cells. Results indicated CHA79 increased viability of cells and attenuated the rate of apoptosis in MG-exposed SH-SY5Y. CHA79 up-regulated expression of anti-apoptotic protein (Bcl-2) and down-regulated apoptotic proteins (Bax, cytochrome c, caspase-3, caspase-9). Moreover, CHA79 significantly up-regulated expression of neurotrophic factors, including glucagon-like peptide-1 receptor (GLP-1R), brain derived neurotrophic factor (BDNF), p75NTR, p-TrkB, p-Akt, p-GK-3? and p-CREB. CHA79 attenuated MG-induced ROS production and enhanced the antioxidant defense including nuclear factor erythroid 2-related factor 2 (Nrf2), HO-1, SOD and GSH. Furthermore, CHA79 attenuated MG-induced reduction of glyoxalase-1 (GLO-1), a vital enzyme on removing AGE precursors. In conclusion, CHA79 is the first novel synthetic chalcone possessing the GLP-1R and GLO-1 activating properties. CHA 79 also exhibits neuroprotective effects against MG toxicity by enhancing neurotrophic signal, antioxidant defense and anti-apoptosis pathway.

SUBMITTER: Tseng YT

PROVIDER: S-EPMC6631972 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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2-Iodo-4'-Methoxychalcone Attenuates Methylglyoxal-Induced Neurotoxicity by Activation of GLP-1 Receptor and Enhancement of Neurotrophic Signal, Antioxidant Defense and Glyoxalase Pathway.

Tseng Yu-Ting YT Tsai Yi-Hong YH Fülöp Ferenc F Chang Fang-Rong FR Lo Yi-Ching YC

Molecules (Basel, Switzerland) 20190616 12

Methylglyoxal (MG) acts as a reactive precursor of advanced glycation end products (AGEs). This compound is often connected with pathologies such as diabetes, neurodegenerative processes and diseases of aging. 2-iodo-4'-methoxychalcone (CHA79), a synthetic halogen-containing chalcone derivative, has been reported its anti-diabetic activity. This study aims to investigate the potential protective capability of CHA79 against MG-mediated neurotoxicity in SH-SY5Y cells. Results indicated CHA79 incre ...[more]

PMID: 31208152

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Project description:Soil acidity causes proton (H+) rhizotoxicity, inhibits plant growth and development, and is a major yield-limiting factor for wheat production worldwide. Therefore, we investigated the physiological and biochemical responses of wheat (Triticum aestivum L.) to acidity stress in vitro. Five popular wheat cultivars developed by Bangladesh Agricultural Research Institute (BARI), namely, BARI Gom-21, BARI Gom-24, BARI Gom-25, BARI Gom-26, and BARI Gom-30, were studied in growing media under four different pH levels (3.5, 4.5, 5.5, and 6.5). We evaluated the cultivars based on their relative water content, proline (Pro) content, growth, biomass accumulation, oxidative damage, membrane stability, and mineral composition, as well as the performance of the antioxidant defense and glyoxalase systems. Although decrements of pH significantly reduced the tested morphophysiological and biochemical attributes in all the cultivars, there was high variability among the cultivars in response to the varying pH of the growing media. Acidity stress reduced growth, biomass, water content, and chlorophyll content in all the cultivars. However, BARI Gom-26 showed the least damage, with the lowest H2O2 generation, lipid peroxidation (MDA), and greater membrane stability, which indicate better tolerance against oxidative damage. In addition, the antioxidant defense components, ascorbate (AsA) and glutathione (GSH), and their redox balance were higher in this cultivar. Maximum H2O2 scavenging due to upregulation of the antioxidant enzymes [AsA peroxidase (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), GSH reductase (GR), GSH peroxidase (GPX), and GSH-S-transferase (GST)] was observed in BARI Gom-26, which also illustrated significant enhancement of methylglyoxal (MG) detoxification by upregulating glyoxalase I (Gly I) and glyoxalase II (Gly II). This study also showed that balanced essential nutrient content as well as lower toxic micronutrient content was found in BARI Gom-26. Therefore, considering the physiological and biochemical attributes and growth, we conclude that BARI Gom-26 can withstand acidity stress during the early seedling stage, by regulating the coordinated action of the antioxidant defense and glyoxalase systems as well as maintaining nutrient balance.

Project description:ObjectiveDiabetic retinopathy (DR) is induced by an accumulation of reactive metabolites such as ROS, RNS, and RCS species, which were reported to modulate the activity of cation channels of the TRPC family. In this study, we use Trpc1/4/5/6-/- compound knockout mice to analyze the contribution of these TRPC proteins to diabetic retinopathy.MethodsWe used Nanostring- and qPCR-based analysis to determine mRNA levels of TRPC channels in control and diabetic retinae and retinal cell types. Chronic hyperglycemia was induced by Streptozotocin (STZ) treatment. To assess the development of diabetic retinopathy, vasoregression, pericyte loss, and thickness of individual retinal layers were analyzed. Plasma and cellular methylglyoxal (MG) levels, as well as Glyoxalase 1 (GLO1) enzyme activity and protein expression, were measured in WT and Trpc1/4/5/6-/- cells or tissues. MG-evoked toxicity in cells of both genotypes was compared by MTT assay.ResultsWe find that Trpc1/4/5/6-/- mice are protected from hyperglycemia-evoked vasoregression determined by the formation of acellular capillaries and pericyte drop-out. In addition, Trpc1/4/5/6-/- mice are resistant to the STZ-induced reduction in retinal layer thickness. The RCS metabolite methylglyoxal, which represents a key mediator for the development of diabetic retinopathy, was significantly reduced in plasma and red blood cells (RBCs) of STZ-treated Trpc1/4/5/6-/- mice compared to controls. GLO1 is the major MG detoxifying enzyme, and its activity and protein expression were significantly elevated in Trpc1/4/5/6-deficient cells, which led to significantly increased resistance to MG toxicity. GLO1 activity was also increased in retinal extracts from Trpc1/4/5/6-/- mice. The TRPCs investigated here are expressed at different levels in endothelial and glial cells of the retina.ConclusionThe protective phenotype in diabetic retinopathy observed in Trpc1/4/5/6-/- mice is suggestive of a predominant action of TRPCs in Müller cells and microglia because of their central position in the retention of a proper homoeostasis of the neurovascular unit.

Dataset Information

2-Iodo-4'-Methoxychalcone Attenuates Methylglyoxal-Induced Neurotoxicity by Activation of GLP-1 Receptor and Enhancement of Neurotrophic Signal, Antioxidant Defense and Glyoxalase Pathway.

Publications

2-Iodo-4'-Methoxychalcone Attenuates Methylglyoxal-Induced Neurotoxicity by Activation of GLP-1 Receptor and Enhancement of Neurotrophic Signal, Antioxidant Defense and Glyoxalase Pathway.

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