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Aldehyde Toxicity and Metabolism
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Aldehyde Toxicity and Metabolism

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biological Factors".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 40545

Special Issue Editors

Prof. Eric R. Gross

E-Mail Website
Guest Editor
School of Medicine, Stanford University, Stanford, CA 94305, USA
Prof. Che-Hong Chen

E-Mail Website
Guest Editor
School of Medicine, Stanford University, Stanford, CA 94305, USA

Special Issue Information

Dear Colleagues,

The goal of this special issue will be to highlight the topic of aldehyde toxicity and metabolism.

Reactive aldehydes are toxic chemicals that form DNA and protein adducts.  Within the environment, many sources of aldehydes exist.  For example, aldehydes can be inhaled or consumed when smoking tobacco cigarettes or drinking alcohol.  There are also endogenous sources of aldehyde production resulting from lipid peroxidation during cellular stress.  Reactive aldehydes can impair cellular functions and exacerbate organ injury, acute pain, and inflammation.  Frequent aldehyde exposure has also been linked to human disease pathology, including cancers and cardiovascular disease.

To combat aldehyde toxicity, the body metabolizes aldehydes by the enzyme aldehyde dehydrogenase 2 (ALDH2) to less toxic acids.  However, for 40% of East Asians (~540 million people in the world) an ALDH2 variant ALDH2*2 exists that severely limits aldehyde metabolism.  The ALDH2*2 variant is identified by facial flushing, tachycardia, and acetaldehyde accumulation after alcohol consumption and a result of a single base pair change in ALDH2.  Those with an ALDH2*2 genetic variant are more susceptible to aldehyde toxicity. 

Prof. Eric R. Gross
Prof. Che-Hong Chen
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • aldehyde
  • ALDH2
  • ALDH2*2
  • rs671
  • acetaldehyde
  • alcohol
  • cigarettes
  • cancer
  • heart
  • injury

Published Papers (12 papers)

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Editorial

Jump to: Research, Review

6 pages, 4402 KiB  
Editorial
Aldehydes, Aldehyde Metabolism, and the ALDH2 Consortium
by Freeborn Rwere, Xuan Yu, Che-Hong Chen and Eric R. Gross
Biomolecules 2022, 12(6), 763; https://doi.org/10.3390/biom12060763 - 30 May 2022
Cited by 2 | Viewed by 2259
Abstract
The discovery of aldehydes dates back to 1774 when Carl Wilhelm Scheele synthesized acetaldehyde [...] Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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Research

Jump to: Editorial, Review

13 pages, 3147 KiB  
Article
Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice
by Bárbara B. Martins, Natália G. Hösch, Queren A. Alcantara, Grant R. Budas, Che-Hong Chen, Daria Mochly-Rosen, Julio C. B. Ferreira and Vanessa O. Zambelli
Biomolecules 2021, 11(12), 1798; https://doi.org/10.3390/biom11121798 - 30 Nov 2021
Cited by 7 | Viewed by 2872
Abstract
Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for [...] Read more.
Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain. Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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17 pages, 2633 KiB  
Article
Variant Aldehyde Dehydrogenase 2 (ALDH2*2) as a Risk Factor for Mechanical LA Substrate Formation and Atrial Fibrillation with Modest Alcohol Consumption in Ethnic Asians
by Chung-Lieh Hung, Kuo-Tzu Sung, Shun-Chuan Chang, Yen-Yu Liu, Jen-Yuan Kuo, Wen-Hung Huang, Cheng-Huang Su, Chuan-Chuan Liu, Shin-Yi Tsai, Chia-Yuan Liu, An-Sheng Lee, Szu-Hua Pan, Shih-Wei Wang, Charles Jia-Yin Hou, Ta-Chuan Hung and Hung-I Yeh
Biomolecules 2021, 11(11), 1559; https://doi.org/10.3390/biom11111559 - 21 Oct 2021
Cited by 6 | Viewed by 1992
Abstract
Aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism is a common genetic variant in Asians that is responsible for defective toxic aldehyde and lipid peroxidation metabolism after alcohol consumption. The extent to which low alcohol consumption may cause atrial substrates to trigger atrial fibrillation (AF) [...] Read more.
Aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism is a common genetic variant in Asians that is responsible for defective toxic aldehyde and lipid peroxidation metabolism after alcohol consumption. The extent to which low alcohol consumption may cause atrial substrates to trigger atrial fibrillation (AF) development in users with ALDH2 variants remains to be determined. We prospectively enrolled 249 ethnic Asians, including 56 non-drinkers and 193 habitual drinkers (135 (70%) as ALDH2 wild-type: GG, rs671; 58 (30%) as ALDH2 variants: G/A or A/A, rs671). Novel left atrial (LA) mechanical substrates with dynamic characteristics were assessed using a speckle-tracking algorithm and correlated to daily alcohol consumption and ALDH2 genotypes. Despite modest and comparable alcohol consumption by the habitual alcohol users (14.3 [8.3~28.6] and 12.3 [6.3~30.7] g/day for those without and with ALDH2 polymorphism, p = 0.31), there was a substantial and graded increase in the 4-HNE adduct and prolonged PR, and a reduction in novel LA mechanical parameters (including peak atrial longitudinal strain (PALS) and phasic strain rates (reservoir, conduit, and booster pump functions), p < 0.05), rather than an LA emptying fraction (LAEF) or LA volume index across non-drinkers, and in habitual drinkers without and with ALDH2 polymorphism (all p < 0.05). The presence of ALDH2 polymorphism worsened the association between increasing daily alcohol dose and LAEF, PALS, and phasic reservoir and booster functions (all Pinteraction: <0.05). Binge drinking superimposed on regular alcohol use exclusively further worsened LA booster pump function compared to regular drinking without binge use (1.66 ± 0.57 vs. 1.97 ± 0.56 1/s, p = 0.001). Impaired LA booster function further independently helped to predict AF after consideration of the CHARGE-AF score (adjusted 1.68 (95% CI: 1.06–2.67), p = 0.028, per 1 z-score increment). Habitual modest alcohol consumption led to mechanical LA substrate formation in an ethnic Asian population, which was more pronounced in subjects harboring ALDH2 variants. Impaired LA booster functions may serve as a useful predictor of AF in such populations. Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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19 pages, 5890 KiB  
Article
Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy
by Masataka Shimonosono, Koji Tanaka, Samuel Flashner, Satoshi Takada, Norihiro Matsuura, Yasuto Tomita, Uma M. Sachdeva, Eishi Noguchi, Veena Sangwan, Lorenzo Ferri, Fatemeh Momen-Heravi, Angela J. Yoon, Andres J. Klein-Szanto, J. Alan Diehl and Hiroshi Nakagawa
Biomolecules 2021, 11(10), 1479; https://doi.org/10.3390/biom11101479 - 07 Oct 2021
Cited by 9 | Viewed by 3827
Abstract
Background: Alcohol (ethanol) consumption is a major risk factor for head and neck and esophageal squamous cell carcinomas (SCCs). However, how ethanol (EtOH) affects SCC homeostasis is incompletely understood. Methods: We utilized three-dimensional (3D) organoids and xenograft tumor transplantation models to investigate how [...] Read more.
Background: Alcohol (ethanol) consumption is a major risk factor for head and neck and esophageal squamous cell carcinomas (SCCs). However, how ethanol (EtOH) affects SCC homeostasis is incompletely understood. Methods: We utilized three-dimensional (3D) organoids and xenograft tumor transplantation models to investigate how EtOH exposure influences intratumoral SCC cell populations including putative cancer stem cells defined by high CD44 expression (CD44H cells). Results: Using 3D organoids generated from SCC cell lines, patient-derived xenograft tumors, and patient biopsies, we found that EtOH is metabolized via alcohol dehydrogenases to induce oxidative stress associated with mitochondrial superoxide generation and mitochondrial depolarization, resulting in apoptosis of the majority of SCC cells within organoids. However, CD44H cells underwent autophagy to negate EtOH-induced mitochondrial dysfunction and apoptosis and were subsequently enriched in organoids and xenograft tumors when exposed to EtOH. Importantly, inhibition of autophagy increased EtOH-mediated apoptosis and reduced CD44H cell enrichment, xenograft tumor growth, and organoid formation rate. Conclusions: This study provides mechanistic insights into how EtOH may influence SCC cells and establishes autophagy as a potential therapeutic target for the treatment of EtOH-associated SCC. Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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14 pages, 1452 KiB  
Article
Activation of Aldehyde Dehydrogenase 2 Ameliorates Glucolipotoxicity of Pancreatic Beta Cells
by Shiau-Mei Chen, Siow-Wey Hee, Shih-Yun Chou, Meng-Wei Liu, Che-Hong Chen, Daria Mochly-Rosen, Tien-Jyun Chang and Lee-Ming Chuang
Biomolecules 2021, 11(10), 1474; https://doi.org/10.3390/biom11101474 - 06 Oct 2021
Cited by 3 | Viewed by 2248
Abstract
Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction [...] Read more.
Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction and apoptosis induced by glucolipotoxicity, and its potential mechanisms of action. Glucose-stimulated insulin secretion (GSIS) in MIN6 cells and insulin secretion from isolated islets in perifusion experiments were measured. The intracellular ATP concentrations and oxygen consumption rates of MIN6 cells were assessed. Furthermore, the cell viability, apoptosis, and mitochondrial and intracellular reactive oxygen species (ROS) levels were determined. Additionally, the pro-apoptotic, apoptotic, and anti-apoptotic signaling pathways were investigated. We found that Alda-1 enhanced GSIS by improving the mitochondrial function of pancreatic beta cells. Alda-1 rescued MIN6 cells from MG- and 4-HNE-induced beta cell death, apoptosis, mitochondrial dysfunction, and ROS production. However, the above effects of Alda-1 were abolished in Aldh2 knockdown MIN6 cells. In conclusion, we reported that the activator of ALDH2 not only enhanced GSIS, but also ameliorated the glucolipotoxicity of beta cells by reducing both the mitochondrial and intracellular ROS levels, thereby improving mitochondrial function, restoring beta cell function, and protecting beta cells from apoptosis and death. Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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16 pages, 952 KiB  
Article
Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)
by Che-Hong Chen, Benjamin R. Kraemer, Lucia Lee and Daria Mochly-Rosen
Biomolecules 2021, 11(10), 1423; https://doi.org/10.3390/biom11101423 - 29 Sep 2021
Cited by 12 | Viewed by 2442
Abstract
Human aldehyde dehydrogenase (ALDH) is a multigene family with 19 functional members encoding a class of diverse but important enzymes for detoxification or biotransformation of different endogenous and exogenous aldehyde substrates. Genetic mutations in the ALDH genes can cause the accumulation of toxic [...] Read more.
Human aldehyde dehydrogenase (ALDH) is a multigene family with 19 functional members encoding a class of diverse but important enzymes for detoxification or biotransformation of different endogenous and exogenous aldehyde substrates. Genetic mutations in the ALDH genes can cause the accumulation of toxic aldehydes and abnormal carbonyl metabolism and serious human pathologies. However, the physiological functions and substrate specificity of many ALDH genes are still unknown. Although many genetic variants of the ALDH gene family exist in human populations, their phenotype or clinical consequences have not been determined. Using the most comprehensive global human Genome Aggregation Database, gnomAD, we annotated here 1350 common variants in the 19 ALDH genes. These 1350 common variants represent all known genetic polymorphisms with a variant allele frequency of ≥0.1% (or an expected occurrence of ≥1 carrier per 500 individuals) in any of the seven major ethnic groups recorded by gnomAD. We detailed 13 types of DNA sequence variants, their genomic positions, SNP ID numbers, and allele frequencies among the seven major ethnic groups worldwide for each of the 19 ALDH genes. For the 313 missense variants identified in the gnomAD, we used two software algorithms, Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant From Tolerant (SIFT), to predict the consequences of the variants on the structure and function of the enzyme. Finally, gene constraint analysis was used to predict how well genetic mutations were tolerated by selection forces for each of the ALDH genes in humans. Based on the ratio of observed and expected variant numbers in gnomAD, the three ALDH1A gene members, ALDH1A1, ALDH1A2, and ALDH1A3, appeared to have the lowest tolerance for loss-of-function mutations as compared to the other ALDH genes (# observed/# expected ratio 0.15–0.26). These analyses suggest that the ALDH1A1, ALDH1A2, and ALDH1A3 enzymes may serve a more essential function as compared with the other ALDH enzymes; functional loss mutations are much less common in healthy human populations than expected. This informatic analysis may assist the research community in determining the physiological function of ALDH isozymes and associate common variants with clinical phenotypes. Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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12 pages, 933 KiB  
Article
The Aldehyde Dehydrogenase ALDH2*2 Allele, Associated with Alcohol Drinking Behavior, Dates Back to Prehistoric Times
by Chih-Lang Lin, Rong-Nan Chien, Li-Wei Chen, Ting-Shuo Huang, Yu-Chiau Shyu, Chau-Ting Yeh and Kung-Hao Liang
Biomolecules 2021, 11(9), 1376; https://doi.org/10.3390/biom11091376 - 17 Sep 2021
Cited by 3 | Viewed by 2363
Abstract
Human alcohol-consumption behavior is partly genetically encoded. The alcohol consumption of 987 residents in Keelung, Taiwan, was evaluated by using the Alcohol Use Disorder Identification Test (AUDIT). We assessed ~750,000 genomic variants of 71 residents who drank hazardously (AUDIT score ≥ 8) and [...] Read more.
Human alcohol-consumption behavior is partly genetically encoded. The alcohol consumption of 987 residents in Keelung, Taiwan, was evaluated by using the Alcohol Use Disorder Identification Test (AUDIT). We assessed ~750,000 genomic variants of 71 residents who drank hazardously (AUDIT score ≥ 8) and 126 residents who did not drink in their daily lives (AUDIT score = 0), using high-density single nucleotide polymorphism (SNP) arrays. The rs671 G > A manifests the highest significance of the association with drinking behavior (Fisher’s exact P = 8.75 × 10−9). It is a pleiotropic, non-synonymous variant in the aldehyde dehydrogenase 2 (ALDH2) gene. The minor allele “A”, commonly known as ALDH2*2, is associated with non-drinkers. Intriguingly, identity-by-descent haplotypes encompassing genomic regions with a median length of 1.6 (0.6–2.0) million nucleotide bases were found in all study participants with either heterozygous or homozygous ALDH2*2 (n = 81 and 13, respectively). We also analyzed a public-domain dataset with genome-wide genotypes of 2000 participants in Guangzhou, a coastal city in Southern China. Among them, 175 participants have homozygous ALDH2*2 genotype, and again, long ALDH2*2-carrying haplotypes were found in all 175 participants without exceptions. The median length of the ALDH2*2-carrying haplotype is 1.7 (0.5–2.8) million nucleotide bases. The haplotype lengths in the Keelung and Guangzhou cohorts combined indicate that the origin of the ALDH2*2 allele dates back to 7935 (7014–9381) years ago. In conclusion, the rs671 G > A is the leading genomic variant associated with the long-term drinking behavior among residents of Keelung, Taiwan. The ALDH2*2 allele has been in Asian populations since prehistoric times. Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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16 pages, 1640 KiB  
Article
Acetaldehyde Enhances Alcohol Sensitivity and Protects against Alcoholism: Evidence from Alcohol Metabolism in Subjects with Variant ALDH2*2 Gene Allele
by Yi-Chyan Chen, Li-Fang Yang, Ching-Long Lai and Shih-Jiun Yin
Biomolecules 2021, 11(8), 1183; https://doi.org/10.3390/biom11081183 - 10 Aug 2021
Cited by 9 | Viewed by 3856
Abstract
Alcoholism is a complex behavior trait influenced by multiple genes as well as by sociocultural factors. Alcohol metabolism is one of the biological determinants that can significantly influence drinking behaviors. Alcohol sensitivity is thought to be a behavioral trait marker for susceptibility to [...] Read more.
Alcoholism is a complex behavior trait influenced by multiple genes as well as by sociocultural factors. Alcohol metabolism is one of the biological determinants that can significantly influence drinking behaviors. Alcohol sensitivity is thought to be a behavioral trait marker for susceptibility to develop alcoholism. The subjective perceptions would be an indicator for the alcohol preference. To investigate alcohol sensitivity for the variants ADH1B*2 and ALDH2*2, sixty healthy young males with different combinatory ADH1B and ALDH2 genotypes, ADH1B*2/*2–ALDH2*1/*1 (n = 23), ADH1B*2/*2–ALDH2*1/*2 (n = 27), and ADH1B*1/*1–ALDH2*1/*1 (n = 10), participated in the study. The subjective perceptions were assessed by a structured scale, and blood ethanol and acetaldehyde were determined by GC and HPLC after an alcohol challenge in two dose sessions (0.3 g/kg or 0.5 g/kg ethanol). The principal findings are (1) dose-dependent increase of blood ethanol concentration, unaffected by ADH1B or ALDH2; (2) significant build-up of blood acetaldehyde, strikingly influenced by the ALDH2*2 gene allele and correlated with the dose of ingested alcohol; (3) the increased heart rate and subjective sensations caused by acetaldehyde accumulation in the ALDH2*2 heterozygotes; (4) no significant effect of ADH1B polymorphism in alcohol metabolism or producing the psychological responses. The study findings provide the evidence of acetaldehyde potentiating the alcohol sensitivity and feedback to self-control the drinking amount. The results indicate that ALDH2*2 plays a major role for acetaldehyde-related physiological negative responses and prove the genetic protection against development of alcoholism in East Asians. Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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14 pages, 1696 KiB  
Article
The Role of Alcohol, LPS Toxicity, and ALDH2 in Dental Bony Defects
by Hsiao-Cheng Tsai, Che-Hong Chen, Daria Mochly-Rosen, Yi-Chen Ethan Li and Min-Huey Chen
Biomolecules 2021, 11(5), 651; https://doi.org/10.3390/biom11050651 - 28 Apr 2021
Cited by 4 | Viewed by 2375
Abstract
It is estimated that 560 million people carry an East Asian-specific ALDH2*2 dominant-negative mutation which leads to enzyme inactivation. This common ALDH2 polymorphism has a significant association with osteoporosis. We hypothesized that the ALDH2*2 mutation in conjunction with periodontal Porphyromonas gingivalis bacterial infection [...] Read more.
It is estimated that 560 million people carry an East Asian-specific ALDH2*2 dominant-negative mutation which leads to enzyme inactivation. This common ALDH2 polymorphism has a significant association with osteoporosis. We hypothesized that the ALDH2*2 mutation in conjunction with periodontal Porphyromonas gingivalis bacterial infection and alcohol drinking had an inhibitory effect on osteoblasts and bone regeneration. We examined the prospective association of ALDH2 activity with the proliferation and mineralization potential of human osteoblasts in vitro. The ALDH2 knockdown experiments showed that the ALDH2 knockdown osteoblasts lost their proliferation and mineralization capability. To mimic dental bacterial infection, we compared the dental bony defects in wild-type mice and ALDH2*2 knockin mice after injection with purified lipopolysaccharides (LPS), derived from P. gingivalis which is a bacterial species known to cause periodontitis. Micro-computed tomography (micro-CT) scan results indicated that bone regeneration was significantly affected in the ALDH2*2 knockin mice with about 20% more dental bony defects after LPS injection than the wild-type mice. Moreover, the ALDH2*2 knockin mutant mice had decreased osteoblast growth and more dental bone loss in the upper left jaw region after LPS injection. In conclusion, these results indicated that the ALDH2*2 mutation with alcohol drinking and chronic exposure to dental bacterial-derived toxin increased the risk of dental bone loss. Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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20 pages, 2218 KiB  
Article
Identification of New Markers of Alcohol-Derived DNA Damage in Humans
by Valeria Guidolin, Erik S. Carlson, Andrea Carrà, Peter W. Villalta, Laura A. Maertens, Stephen S. Hecht and Silvia Balbo
Biomolecules 2021, 11(3), 366; https://doi.org/10.3390/biom11030366 - 27 Feb 2021
Cited by 17 | Viewed by 3036
Abstract
Alcohol consumption is a risk factor for the development of several cancers, including those of the head and neck and the esophagus. The underlying mechanisms of alcohol-induced carcinogenesis remain unclear; however, at these sites, alcohol-derived acetaldehyde seems to play a major role. By [...] Read more.
Alcohol consumption is a risk factor for the development of several cancers, including those of the head and neck and the esophagus. The underlying mechanisms of alcohol-induced carcinogenesis remain unclear; however, at these sites, alcohol-derived acetaldehyde seems to play a major role. By reacting with DNA, acetaldehyde generates covalent modifications (adducts) that can lead to mutations. Previous studies have shown a dose dependence between levels of a major acetaldehyde-derived DNA adduct and alcohol exposure in oral-cell DNA. The goal of this study was to optimize a mass spectrometry (MS)-based DNA adductomic approach to screen for all acetaldehyde-derived DNA adducts to more comprehensively characterize the genotoxic effects of acetaldehyde in humans. A high-resolution/-accurate-mass data-dependent constant-neutral-loss-MS3 methodology was developed to profile acetaldehyde-DNA adducts in purified DNA. This resulted in the identification of 22 DNA adducts. In addition to the expected N2-ethyldeoxyguanosine (after NaBH3CN reduction), two previously unreported adducts showed prominent signals in the mass spectra. MSn fragmentation spectra and accurate mass were used to hypothesize the structure of the two new adducts, which were then identified as N6-ethyldeoxyadenosine and N4-ethyldeoxycytidine by comparison with synthesized standards. These adducts were quantified in DNA isolated from oral cells collected from volunteers exposed to alcohol, revealing a significant increase after the exposure. In addition, 17 of the adducts identified in vitro were detected in these samples confirming our ability to more comprehensively characterize the DNA damage deriving from alcohol exposures. Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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Review

Jump to: Editorial, Research

17 pages, 2385 KiB  
Review
Chemistry and Biochemistry Aspects of the 4-Hydroxy-2,3-trans-nonenal
by Anna Bilska-Wilkosz, Małgorzata Iciek and Magdalena Górny
Biomolecules 2022, 12(1), 145; https://doi.org/10.3390/biom12010145 - 16 Jan 2022
Cited by 10 | Viewed by 2996
Abstract
4-hydroxy-2,3-trans-nonenal (C9H16O2), also known as 4-hydroxy-2E-nonenal (C9H16O2; HNE) is an α,β-unsaturated hydroxyalkenal. HNE is a major aldehyde, formed in the peroxidation process of ω-6 polyunsaturated fatty acids (ω-6 PUFAs), [...] Read more.
4-hydroxy-2,3-trans-nonenal (C9H16O2), also known as 4-hydroxy-2E-nonenal (C9H16O2; HNE) is an α,β-unsaturated hydroxyalkenal. HNE is a major aldehyde, formed in the peroxidation process of ω-6 polyunsaturated fatty acids (ω-6 PUFAs), such as linoleic and arachidonic acid. HNE is not only harmful but also beneficial. In the 1980s, the HNE was regarded as a “toxic product of lipid peroxidation” and the “second toxic messenger of free radicals”. However, already at the beginning of the 21st century, HNE was perceived as a reliable marker of oxidative stress, growth modulating factor and signaling molecule. Many literature data also indicate that an elevated level of HNE in blood plasma and cells of the animal and human body is observed in the course of many diseases, including cancer. On the other hand, it is currently proven that cancer cells divert to apoptosis if they are exposed to supraphysiological levels of HNE in the cancer microenvironment. In this review, we briefly summarize the current knowledge about the biological properties of HNE. Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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22 pages, 2584 KiB  
Review
TRP Channels as Sensors of Aldehyde and Oxidative Stress
by Katharina E. M. Hellenthal, Laura Brabenec, Eric R. Gross and Nana-Maria Wagner
Biomolecules 2021, 11(10), 1401; https://doi.org/10.3390/biom11101401 - 24 Sep 2021
Cited by 19 | Viewed by 4194
Abstract
The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade [...] Read more.
The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade that can lead to disease pathophysiology. The body is not only exposed to exogenous aldehydes via tobacco products or alcoholic beverages, but also to endogenous aldehydes triggered by lipid peroxidation. In response to lipid peroxidation from inflammation or organ injury, polyunsaturated fatty acids undergo lipid peroxidation to aldehydes, such as 4-hydroxynonenal. Reactive aldehydes activate TRP channels via aldehyde-induced protein adducts, leading to the release of pro-inflammatory mediators driving the pathophysiology caused by cellular injury, including inflammatory pain and organ reperfusion injury. Recent studies have outlined how aldehyde dehydrogenase 2 protects against aldehyde toxicity through the clearance of toxic aldehydes, indicating that targeting the endogenous aldehyde metabolism may represent a novel treatment strategy. An addition approach can involve targeting specific TRP channel regions to limit the triggering of a cellular cascade induced by aldehydes. In this review, we provide a comprehensive summary of aldehydes, TRP channels, and their interactions, as well as their role in pathological conditions and the different therapeutical treatment options. Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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