Aldehyde Dehydrogenase 2 as a Therapeutic Target in Oxidative Stress-Related Diseases: Post-Translational Modifications Deserve More Attention

Gao, Jie; Hao, Ya; Piao, Xiang‐Lan; Gu, Xianhong

doi:10.3390/ijms23052682

Cited by 19 publications

(28 citation statements)

References 230 publications

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“…These anti-ferroptotic parameters (Nrf2, GSH, GPX4, and ALDH2) were inactivated by the thiol-affinity of DE forming disulfides resulting in preventing the transcriptional activity (promotor binding) of Nrf2, irreversible oxidation of GSH, and inhibiting GPX4 and ALDH activities ( Brar et al, 2004 ; Abu-Serie & Eltarahony, 2021 ; Nie et al, 2022 ). These latter enzymes play key roles in the detoxification of lipid peroxide aldehydes ( Bekric et al, 2022 ; Gao et al, 2022 ). Recent studies have illustrated that ALDH2 protects against these reactive aldehydes (malondialdehyde and 4-hydroxy-2-nonenal) by converting them into malonic acid and hydroxy-2-nonenoic acid, respectively ( Zhao et al, 2019 ; Gao et al, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

“…These latter enzymes play key roles in the detoxification of lipid peroxide aldehydes ( Bekric et al, 2022 ; Gao et al, 2022 ). Recent studies have illustrated that ALDH2 protects against these reactive aldehydes (malondialdehyde and 4-hydroxy-2-nonenal) by converting them into malonic acid and hydroxy-2-nonenoic acid, respectively ( Zhao et al, 2019 ; Gao et al, 2022 ). Due to higher biodistribution of DF(II) NPs in tumor tissues, this antioxidant protective system was lower in LC-DF(II) NPs and subsequently, this group showed stronger elevation of ROS and lipid peroxidation than in LC-DF(II) group.…”

Section: Resultsmentioning

confidence: 99%

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Targeted ferroptotic potency of ferrous oxide nanoparticles-diethyldithiocarbamate nanocomplex on the metastatic liver cancer

Abu‐Serie

2023

Front. Pharmacol.

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Existing treatments are frequently ineffective in combating liver cancer (LC) due to its rapid growth, high metastatic potential, and chemoresistance. Thus, inducing ferroptosis, a new non-apoptotic regulated cell death-dependent massive iron overload-mediated lipid peroxidation, is an alternative effective approach for treating LC. The efficient trigger of ferroptosis requires blocking cellular antioxidant (anti-ferroptosis) response and selectivity to avoid harming other healthy tissues. In this study, green chemically synthesized ferrous oxide nanoparticles (F(II) NPs) were used for enhancing selective iron accumulation in tumor tissue, while diethyldithiocarbamate (DE) was for inhibiting the antioxidant system (glutathione and aldehyde dehydrogenase (ALDH) 2) which protects the tumor from damage-dependent lipid peroxides. Thus, F(II) NPs were used with DE as nanocomplex (DF(II) NPs) and its anti-LC activity compared to ferrous oxide DF(II). DF(II) NPs outperformed the typical complex of DF(II) in eradicating metastatic LC cells in HepG2 cells and a chemically induced metastatic LC animal model, as evidenced by flow cytometry, histological and immunohistochemical analyses, and α-fetoprotein depletion. The superior therapeutic potency-dependent ferroptotic activity of DF(II) NPs, attributed to their higher selective accumulation (∼77%) than DF(II) in tumor tissues (liver and lung), resulted in a strong elevation of cellular lipid peroxidation with extreme suppression of nuclear related factor 2 (Nrf2) transcriptional activity, glutathione (GSH), glutathione peroxidase 4, and ALDH2. Subsequently, a severe inhibition in the expression of oncogenes and metastatic cancer stem cell genes was recorded in DF(II) NPs-treated LC animal group. In contrast to DF(II), DF(II) NPs were able to normalize liver functions and did not show any variations in hematological and histological parameters in the blood and tissues of DF(II) NPs-treated normal mouse group. These findings validate the potency and safety of DF(II) nanocomplex as a promising nanodrug for combating metastatic LC.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Targeted ferroptotic potency of ferrous oxide nanoparticles-diethyldithiocarbamate nanocomplex on the metastatic liver cancer

Abu‐Serie

2023

Front. Pharmacol.

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“…In the development of nitrate tolerance, the role of mitochondrial oxidative stress was described in a mouse model that had a heterozygous deletion of the enzyme manganese superoxide dismutase (MnSOD), which is the mitochondrial isoform of this enzyme. In addition, ROS has been shown to be responsible for disrupting cross-talk to the cytoplasm and mitochondria [ 80 ]. Interestingly, nitrates are responsible for inhibiting ALDH2, which is responsible for decreasing or canceling the protective mechanism against oxidative stress [ 81 ].…”

Section: Vascular Endothelium and Endothelial Dysfunctionmentioning

confidence: 99%

The Generation of Nitric Oxide from Aldehyde Dehydrogenase-2: The Role of Dietary Nitrates and Their Implication in Cardiovascular Disease Management

Maiuolo

Oppedisano²,

Carresi³

et al. 2022

IJMS

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Reduced bioavailability of the nitric oxide (NO) signaling molecule has been associated with the onset of cardiovascular disease. One of the better-known and effective therapies for cardiovascular disorders is the use of organic nitrates, such as glyceryl trinitrate (GTN), which increases the concentration of NO. Unfortunately, chronic use of this therapy can induce a phenomenon known as “nitrate tolerance”, which is defined as the loss of hemodynamic effects and a reduction in therapeutic effects. As such, a higher dosage of GTN is required in order to achieve the same vasodilatory and antiplatelet effects. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a cardioprotective enzyme that catalyzes the bio-activation of GTN to NO. Nitrate tolerance is accompanied by an increase in oxidative stress, endothelial dysfunction, and sympathetic activation, as well as a loss of the catalytic activity of ALDH2 itself. On the basis of current knowledge, nitrate intake in the diet would guarantee a concentration of NO such as to avoid (or at least reduce) treatment with GTN and the consequent onset of nitrate tolerance in the course of cardiovascular diseases, so as not to make necessary the increase in GTN concentrations and the possible inhibition/alteration of ALDH2, which aggravates the problem of a positive feedback mechanism. Therefore, the purpose of this review is to summarize data relating to the introduction into the diet of some natural products that could assist pharmacological therapy in order to provide the NO necessary to reduce the intake of GTN and the phenomenon of nitrate tolerance and to ensure the correct catalytic activity of ALDH2.

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“…Owing to the increasing scope of ALDH2*2 association with disease, significant interest and research effort have been devoted to targeting ALDH2 in disease prevention and treatment ( Gao et al, 2022 ; Zhang and Fu, 2021 ; Kimura et al, 2019 ; Chen et al, 2014 ; Lee et al, 2021 ). Small-molecule ALDH2 enzyme activators, such as Alda-1 and Alda-64, that can enhance the wild-type ALDH2 activity and restore the structure and function of the ALDH2*2 variant enzyme have been reported and, if effective in humans, could reduce the risk of developing associated disease ( Chen et al, 2008 ; Perez-Miller et al, 2010 ; Chen et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

ALDH2 variance in disease and populations

Chen

Kraemer

Mochly‐Rosen

2022

Disease Models &Amp; Mechanisms

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The ALDH2*2 missense variant that commonly causes alcohol flushing reactions is the single genetic polymorphism associated with the largest number of traits in humans. The dysfunctional ALDH2 variant affects nearly 8% of the world population and is highly concentrated among East Asians. Carriers of the ALDH2*2 variant commonly present alterations in a number of blood biomarkers, clinical measurements, biometrics, drug prescriptions, dietary habits and lifestyle behaviors, and they are also more susceptible to aldehyde-associated diseases, such as cancer and cardiovascular disease. However, the interaction between alcohol and ALDH2-related pathology is not clearly delineated. Furthermore, genetic evidence indicates that the ALDH2*2 variant has been favorably selected for in the past 2000-3000 years. It is therefore necessary to consider the disease risk and mechanism associated with ALDH2 deficiency, and to understand the possible beneficial or protective effect conferred by ALDH2 deficiency and whether the pleiotropic effects of ALDH2 variance are all mediated by alcohol use.

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Aldehyde Dehydrogenase 2 as a Therapeutic Target in Oxidative Stress-Related Diseases: Post-Translational Modifications Deserve More Attention

Cited by 19 publications

References 230 publications

Targeted ferroptotic potency of ferrous oxide nanoparticles-diethyldithiocarbamate nanocomplex on the metastatic liver cancer

Targeted ferroptotic potency of ferrous oxide nanoparticles-diethyldithiocarbamate nanocomplex on the metastatic liver cancer

The Generation of Nitric Oxide from Aldehyde Dehydrogenase-2: The Role of Dietary Nitrates and Their Implication in Cardiovascular Disease Management

ALDH2 variance in disease and populations

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