Chebulic Acid Prevents Methylglyoxal-Induced Mitochondrial Dysfunction in INS-1 Pancreatic β-Cells

Abstract

To investigate the anti-diabetic properties of chebulic acid (CA) associated with the prevention of methyl glyoxal (MG)-induced mitochondrial dysfunction in INS-1 pancreatic β-cells, INS-1 cells were pre-treated with CA (0.5, 1.0, and 2.0 μM) for 48 h and then treated with 2 mM MG for 8 h. The effects of CA and MG on INS-1 cells were evaluated using the following: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; glyoxalase 1 (Glo-1) expression via Western blot and enzyme activity assays; Nrf-2, nuclear factor erythroid 2-related factor 2 protein expression via Western blot assay; reactive oxygen species (ROS) production assay; mRNA expression of mitochondrial dysfunction related components (UCP2, uncoupling protein 2; VDAC1, voltage-dependent anion-selective channel-1; cyt c, cytochrome c via quantitative reverse transcriptase-PCR; mitochondrial membrane potential (MMP); adenosine triphosphate (ATP) synthesis; glucose-stimulated insulin secretion (GSIS) assay. The viability of INS-1 cells was maintained upon pre-treating with CA before exposure to MG. CA upregulated Glo-1 protein expression and enzyme activity in INS-1 cells and prevented MG-induced ROS production. Mitochondrial dysfunction was alleviated by CA pretreatment; this occurred via the downregulation of UCP2, VDAC1, and cyt c mRNA expression and the increase of MMP and ATP synthesis. Further, CA pre-treatment promoted the recovery from MG-induced decrease in GSIS. These results indicated that CA could be employed as a therapeutic agent in diabetes due to its ability to prevent MG-induced development of insulin sensitivity and oxidative stress-induced dysfunction of β-cells.

The m6A Methyltransferase METTL3 Ameliorates Methylglyoxal-Induced Impairment of Insulin Secretion in Pancreatic β Cells by Regulating MafA Expression

“…Upregulation of Glo-1 reduced hyperglycemia-induced carbonyl stress, AGE accumulation, and oxidative stress in diabetic rats (35). Similar to previous studies (26)(27)(28)(29), Glo-1 expression was markedly suppressed in NIT-1 cells following MG treatment, which promoted intracellular accumulation of MG. The results showed that Glo-1 silencing increased the intracellular concentration of MG and further reduced METTL3 expression and m 6 A RNA levels.…”

“…Glo-1 is the main component of the glyoxalase system and is essential for MG detoxification in all mammalian cells (7). Similar to previous studies (26)(27)(28)(29), MG treatment decreased Glo-1 expression in NIT-1 cells (Figures 4A, B). Interestingly, Glo-1 knockdown further reduced METTL3 expression (decreased by 50.2% versus MG treated, p < 0.05; Figures 4A, C) and m 6 A RNA levels (decreased by 52.3% versus MG treated, p < 0.05; Figure 4E) in MG-treated NIT-1 cells.…”

Trapping Methylglyoxal by Taxifolin and Its Metabolites in Mice

“…Methylglyoxal (MGO) is primarily generated endogenously as a by-product from glycolysis by the nonenzymatic degradation of triose phosphates, such as glyceraldehyde 3-phosphate and dihydroxyacetone-phosphate and exogenously due to autoxidation of sugar, the Maillard reaction, degradation of lipids, and fermentation during food and drink processing. Formation of MGO accounts for only 0.1% of glucotriose flux with a rate of about 125 μmol/kg cell mass per day under physiological conditions. − Increasing evidence indicates that MGO, containing two reactive carbonyl groups, is the leading cause (20 000 times more reactive than glucose) for the formation of advanced glycation end products (AGEs) by binding to and modifying arginine, lysine, and cysteine residues in organisms. , Over the last few decades, AGEs and MGO have received increasingly more attention and been recognized as pathogenetic mediators in chronic diseases, including diabetes, diabetic complications, , cardiovascular disease, Alzheimer’s disease, and so on. Multiple therapeutic options are available to trap MGO or prevent the formation and accumulation of AGEs or alleviate MGO/AGE-induced chronic diseases .…”

Methylglyoxal‐induced neurotoxic effects in primary neuronal‐like cells transdifferentiated from human mesenchymal stem cells: Impact of low concentrations

“…Glo-1 decrease was also observed after 8 h treatment with 2 mM MG (2-8 h) in rat INS-1 pancreatic Beta-cells (Yoo et al, 2020) and after 24 h treatment with 500 μM of MG in primary cultures of cerebellar neurons from P5 C57/BL6 mice (Frandsen & Narayanasamy, 2017).…”

“…For instance, MG either induced or impaired the glyoxalase system in immortalized mouse hippocampal HT22 cells (Dafre et al, 2015): 300 μM MG produced an increase in Glo‐2 expression at 24 h, and a decrease in Glo‐1 activity after 24 h exposure to 750 μM MG. A significantly decrease of Glo‐1 levels or its protein expression was also observed in several in vitro studies, and once again, this effect was induced by high MG concentrations, that is, 400 μM MG after 48 h in SK‐N‐MC cells (Suh et al, 2022), and 500 μM after 24 h treatment in SH‐SY5Y (Tseng et al, 2019), as forecastable when using human neuroblastoma cell line. Glo‐1 decrease was also observed after 8 h treatment with 2 mM MG (2–8 h) in rat INS‐1 pancreatic Beta‐cells (Yoo et al, 2020) and after 24 h treatment with 500 μM of MG in primary cultures of cerebellar neurons from P5 C57/BL6 mice (Frandsen & Narayanasamy, 2017).…”