Methylglyoxal induces cell death through endoplasmic reticulum stress‐associated <scp>ROS</scp> production and mitochondrial dysfunction

Chan, Chi‐Ming; Huang, Duen-Yi; Huang, Yi-Pin; Hsu, Shu-Hao; Kang, Lan-Ya; Shen, Chung-Min; Lin, Wan-Wan

doi:10.1111/jcmm.12893

Cited by 96 publications

(57 citation statements)

References 58 publications

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“…The death‐inducing ability of anticancer compounds has to do with ROS production and its capacity to induce ERS . Simultaneously, the presence of ROS and ERS stimulates the presentation of different damage‐associated molecular patterns, which can result in the death of cancer cells by different mechanisms .…”

Section: Resultsmentioning

confidence: 99%

A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti‐Ovarian‐Cancer Agent by Inhibiting TrxR and Activating ROS‐Mediated ERS

Bian

Sun

Liu

et al. 2020

Chemistry A European J

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Many cancer cells critically rely on antioxidant systems for cell survival and are vulnerable to furthero xidative impairment triggered by agentsg enerating reactive oxygen species (ROS). Therefore, the classical design and development of inhibitors that target antioxidant defense enzymes such as thioredoxin reductase (TrxR) can be ap romising anticancer strategy.H erein, it is shown that ag old(I) complex containing an oleanolic acid derivative (4b)i nduces apopto-sis of ovarian cancerA 2780 cells by activatinge ndoplasmic reticulum stress (ERS). It can inhibitT rxR enzymea ctivity to elevateR OS, mediate ERS and mitochondriald ysfunction, and finally leads to cell cycle arrest and apoptosis of A2780 cells. Notably,t his complex inhibits A2780 xenograft tumor growth accompanied by increased ERS level and decreased TrxR activity in tumor tissues.[a] Dr.[ + + ] These authors contributed equally to this work.[**] ERS:e ndoplasmic reticulums tress, ROS:r eactive oxygen species, TrxR:t hioredoxin reductase.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.

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Section: Resultsmentioning

confidence: 99%

A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti‐Ovarian‐Cancer Agent by Inhibiting TrxR and Activating ROS‐Mediated ERS

Bian

Sun

Liu

et al. 2020

Chemistry A European J

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“…Methylglyoxal, a metabolite increased in diabetes, induces cell death through endoplasmic reticulum stress–associated ROS production and mitochondrial dysfunction . It is associated with insulin resistance, vascular dysfunction, and neuropathies [7c].…”

Section: Discussionmentioning

confidence: 99%

Dual anti‐inflammatory and antiglycation propensities of a potentially novel class of functionalized fluoroquinolones

Hamdan

Kasabri

Al‐Hiari

et al. 2019

Journal of Heterocyclic Chem

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Promoted by elevated blood glucose concentrations in diabetes, glycation involves the nonenzymatic addition of reducing sugars and/or their reactive degradation products to amine groups on proteins. New synthetic approaches to 18 fluoroquinolones (FQs) have been developed on the basis of a promising antiglycation activity using 400μM methylglyoxal as the choice glucocytotoxicity concentration. Their anti-inflammatory and radical scavenging properties were elucidated in vitro. Intriguingly, FQs could exhibit an exceedingly more superior than or substantially comparable cytoprotection against methylglyoxal-induced carbonyl toxicity in RAW264.7 macrophages and antiglycation activity to aminoguanidine, as the reference compound. This kind of activity can suggestively be associated with the chelating properties possessed by the synthesized FQs as their DPPH radical scavenging activities proved to be significantly inferior to those of the reference compound, the ascorbic acid. The inhibitory bioactivities using the Griess assay were examined of the compounds against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Selectively, compounds R-2TCBA, R-4FACBA, R-3TCBA, and R-4CLACBA exerted an exceedingly remarkable and superior anti-inflammatory effects (P < .001 vs indomethacin IC 50 value of 101.07 ± 2.2 μM) while R-4TCBA and T-4BrACBA were moderately more efficacious than indomethacin. Compounds T-4CLACBA and R-4BrACBA displayed comparable activity with indomethacin. None of the tested compounds and indomethacin exerted any cytotoxicity against RAW 264.7 mouse macrophages. FQs possess potent duality of antiglycation-anti-inflammatory capacities and are devoid of undesirable side effects. FQs can, therefore, serve as scaffolds for the development and designing of new clinical deglycation and antiglycation therapeutic agents.

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“…Through testing the membrane potential, we found that the exposure to MGO markedly decreased ΔΨm levels, evidenced by a weak green fluorescence in the cells, indicating mitochondrial injury. Ray et al showed MGO inhibits electron flow through complex I leading to mitochondrial dysfunction [33, 34]. In addition, some reports revealed that AGEs can also trigger mitochondrial dysfunction [35, 36].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine

Liu¹,

Meng²,

Chen³

et al. 2017

Cell Physiol Biochem

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Background/Aim: Accumulation of advanced glycation end products (AGEs) is a major cause of diabetes mellitus (DM) skin complications. Methylglyoxal (MGO), a reactive dicarbonyl compound, is a crucial intermediate of AGEs generation. N-acetyl-L-cysteine (NAC), an active ingredient of some medicines, can induce endogenous GSH and hydrogen sulfide generation, and set off a condensation reaction with MGO. However, there is rare evidence to show NAC can alleviate DM-induced skin injury through inhibition of AGEs generation or toxicity. The present study aimed to observe the effects of NAC on MGO-induced inflammatory injury and investigate the roles of AGEs and its receptor (RAGE) in NAC’s dermal protection in human HaCaT keratinocytes. Methods: The cells were exposed to MGO to simulate a high MGO status in diabetic blood or tissues. The content of AGEs in serum or cell medium was measured with ELISA. The protective effects of NAC against MGO-induce injury were evaluated by administration before MGO one hour, in virtue of cell viability, mitochondrial membrane potential, inflammation reaction, nuclear factor (NF)-κB activation, matrix metalloproteinase (MMP)-9 expression, as well as cellular behavioral function. Results: We found the AGEs levels of patients with DM were elevated comparing with healthy volunteers. The in vitro AGEs generation was also able to be enhanced by the exposure of HaCaT cells to MGO, which reduced dose-dependently cellular viability, damaged mitochondrial function, triggered secretion of interleukin (IL)-6 and IL-8, activated NF-κB and upregulated MMP-9 expression. Furthermore, the exposure caused cellular adhesion and migration dysfunction, as well as collagen type I inhibition. Importantly, before the exposure to MGO, the preconditioning with NAC significantly attenuated MGO-induced AGEs generation, improved cellular viability and mitochondrial function, partially reversed the overexpression of proinflammatory factors and MMP-9, as well as the activation of NF-κB. Lastly, NAC blocked MGO-induced RAGE upregulation, and inhibition of RAGE with its neutralizing antibody significantly alleviated MGO-induced NF-κB activation, MMP-9 upregulation and inflammatory injury in HaCaT cells. Conclusion: The present work indicates the administration of NAC can prevent MGO-induced dermal inflammatory injury through inhibition of AGEs/RAGE signal, which may provide a basal support for the treatment of diabetic skin complications with NAC-containing medicines in the future.

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Methylglyoxal induces cell death through endoplasmic reticulum stress‐associated ROS production and mitochondrial dysfunction

Cited by 96 publications

References 58 publications

A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti‐Ovarian‐Cancer Agent by Inhibiting TrxR and Activating ROS‐Mediated ERS

A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti‐Ovarian‐Cancer Agent by Inhibiting TrxR and Activating ROS‐Mediated ERS

Dual anti‐inflammatory and antiglycation propensities of a potentially novel class of functionalized fluoroquinolones

Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine

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