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Biomolecules Nov 2015Drinking alcohol and smoking cigarettes results in the formation of reactive aldehydes in the lung, which are capable of forming adducts with several proteins and DNA.... (Review)
Review
Drinking alcohol and smoking cigarettes results in the formation of reactive aldehydes in the lung, which are capable of forming adducts with several proteins and DNA. Acetaldehyde and malondialdehyde are the major aldehydes generated in high levels in the lung of subjects with alcohol use disorder who smoke cigarettes. In addition to the above aldehydes, several other aldehydes like 4-hydroxynonenal, formaldehyde and acrolein are also detected in the lung due to exposure to toxic gases, vapors and chemicals. These aldehydes react with nucleophilic targets in cells such as DNA, lipids and proteins to form both stable and unstable adducts. This adduction may disturb cellular functions as well as damage proteins, nucleic acids and lipids. Among several adducts formed in the lung, malondialdehyde DNA (MDA-DNA) adduct and hybrid malondialdehyde-acetaldehyde (MAA) protein adducts have been shown to initiate several pathological conditions in the lung. MDA-DNA adducts are pre-mutagenic in mammalian cells and induce frame shift and base-pair substitution mutations, whereas MAA protein adducts have been shown to induce inflammation and inhibit wound healing. This review provides an insight into different reactive aldehyde adducts and their role in the pathogenesis of lung disease.
Topics: Aldehydes; Animals; DNA Adducts; Ethanol; Humans; Respiratory Tract Diseases; Smoking; Tobacco Smoke Pollution
PubMed: 26556381
DOI: 10.3390/biom5042987 -
Journal For Immunotherapy of Cancer Dec 2023Aldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme involved in endogenous aldehyde detoxification and has been implicated in tumor progression. However, its role in...
BACKGROUND
Aldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme involved in endogenous aldehyde detoxification and has been implicated in tumor progression. However, its role in tumor immune evasion remains unclear.
METHODS
Here, we analyzed the relationship between ALDH2 expression and antitumor immune features in multiple cancers. ALDH2 knockout tumor cells were then established using CRISPR/Cas9 system. In immunocompetent breast cancer EMT6 and melanoma B16-F10 mouse models, we investigated the impact of ALDH2 blockade on cytotoxic T lymphocyte function and tumor immune microenvironment by flow cytometry, mass cytometry, Luminex liquid suspension chip detection, and immunohistochemistry. Furthermore, RNA sequencing, flow cytometry, western blot, chromatin immunoprecipitation assay, and luciferase reporter assays were employed to explore the detailed mechanism of ALDH2 involved in tumor immune evasion. Lastly, the synergistic therapeutic efficacy of blocking ALDH2 by genetic depletion or its inhibitor disulfiram in combination with immune checkpoint blockade (ICB) was investigated in mouse models.
RESULTS
In our study, we uncovered a positive correlation between the expression level of ALDH2 and T-cell dysfunction in multiple cancers. Furthermore, blocking ALDH2 significantly suppressed tumor growth by enhancing cytotoxic activity of CD8 T cells and reshaping the immune landscape and cytokine milieu of tumors . Mechanistically, inhibiting ALDH2-mediated metabolism of aldehyde downregulated the expression of V-domain Ig suppressor of T-cell activation (VISTA) via inactivating the nucleotide oligomerization domain (NOD)/nuclear factor kappa-B (NF-κB) signaling pathway. As a result, the cytotoxic function of CD8 T cells was revitalized. Importantly, ALDH2 blockade markedly reinforced the efficacy of ICB treatment.
CONCLUSIONS
Our data delineate that ALDH2-mediated aldehyde metabolism drives tumor immune evasion by activating the NOD/NF-κB/VISTA axis. Targeting ALDH2 provides an effective combinatorial therapeutic strategy for immunotherapy.
Topics: Animals; Mice; Aldehyde Dehydrogenase; Aldehydes; CD8-Positive T-Lymphocytes; Neoplasms; NF-kappa B; Nucleotides; Tumor Escape; Tumor Microenvironment
PubMed: 38088186
DOI: 10.1136/jitc-2023-007487 -
Advances in Experimental Medicine and... 2019Aldehydes, which are present within the air as well as food and beverage sources, are highly reactive molecules that can be cytotoxic, mutagenic, and carcinogenic. To... (Review)
Review
Aldehydes, which are present within the air as well as food and beverage sources, are highly reactive molecules that can be cytotoxic, mutagenic, and carcinogenic. To prevent harm from reactive aldehyde exposure, the enzyme aldehyde dehydrogenase 2 (ALDH2) metabolizes reactive aldehydes to a less toxic form. However, the genetic variant of ALDH2, ALDH2*2, significantly reduces the ability to metabolize reactive aldehydes in humans. Therefore, frequent environmental aldehyde exposure, coupled with inefficient aldehyde metabolism, could potentially lead to an increased health risk for diseases such as cancer or cardiovascular disease.Here, we discuss the environmental sources of reactive aldehydes and the potential health implications particularly for those with an ALDH2*2 genetic variant. We also suggest when considering the ALDH2*2 genetic variant the safety limits of reactive aldehyde exposure may have to be reevaluated. Moreover, the ALDH2*2 genetic variant can also be used as an example for how to implement precision medicine in the field of environmental health sciences.
Topics: Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; Environmental Exposure; Humans
PubMed: 31368096
DOI: 10.1007/978-981-13-6260-6_2 -
American Journal of Physiology. Cell... Oct 2016In this perspective, we summarize and discuss critical advancements in the study of 4-hydroxy-2-nonenal (4-HNE) as it relates to diseases and clinical complications... (Review)
Review
In this perspective, we summarize and discuss critical advancements in the study of 4-hydroxy-2-nonenal (4-HNE) as it relates to diseases and clinical complications either caused or exacerbated by oxidative stress. Since its identification in 1980, 4-HNE has been extensively studied with an emphasis on its formation, its role in pathology, and its targets. As a reactive aldehyde, and a product of lipid peroxidation, studies corroborate its ability to disrupt signal transduction and protein activity, as well as induce inflammation and trigger cellular apoptosis in conditions of oxidative stress. Notably, we discuss the role of natural enzymes involved in the regulation of 4-HNE, and how they can be applied to its detoxification in various physiological conditions.
Topics: Aldehydes; Animals; Apoptosis; Humans; Lipid Peroxidation; Oxidative Stress; Signal Transduction
PubMed: 27385721
DOI: 10.1152/ajpcell.00101.2016 -
Cardiovascular Research Oct 2010Numerous conditions promote oxidative stress, leading to the build-up of reactive aldehydes that cause cell damage and contribute to cardiac diseases. Aldehyde... (Review)
Review
Numerous conditions promote oxidative stress, leading to the build-up of reactive aldehydes that cause cell damage and contribute to cardiac diseases. Aldehyde dehydrogenases (ALDHs) are important enzymes that eliminate toxic aldehydes by catalysing their oxidation to non-reactive acids. The review will discuss evidence indicating a role for a specific ALDH enzyme, the mitochondrial ALDH2, in combating oxidative stress by reducing the cellular 'aldehydic load'. Epidemiological studies in humans carrying an inactive ALDH2, genetic models in mice with altered ALDH2 levels, and small molecule activators of ALDH2 all highlight the role of ALDH2 in cardioprotection and suggest a promising new direction in cardiovascular research and the development of new treatments for cardiovascular diseases.
Topics: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; Animals; Enzyme Activation; Heart Diseases; Humans; Isoenzymes; Mitochondria, Heart; Myocardium; Oxidation-Reduction; Oxidative Stress
PubMed: 20558439
DOI: 10.1093/cvr/cvq192 -
Applied Microbiology and Biotechnology Dec 20182-Deoxy-D-ribose-5-phosphate aldolase (DERA) is a class I aldolase that offers access to several building blocks for organic synthesis. It catalyzes the stereoselective... (Review)
Review
2-Deoxy-D-ribose-5-phosphate aldolase (DERA) is a class I aldolase that offers access to several building blocks for organic synthesis. It catalyzes the stereoselective C-C bond formation between acetaldehyde and numerous other aldehydes. However, the practical application of DERA as a biocatalyst is limited by its poor tolerance towards industrially relevant concentrations of aldehydes, in particular acetaldehyde. Therefore, the development of proper experimental conditions, including protein engineering and/or immobilization on appropriate supports, is required. The present review is aimed to provide a brief overview of DERA, its history, and progress made in understanding the functioning of the enzyme. Furthermore, the current understanding regarding aldehyde resistance of DERA and the various optimizations carried out to modify this property are discussed.
Topics: Acetaldehyde; Aldehyde-Lyases; Aldehydes; Catalysis; Protein Conformation; Protein Engineering; Ribosemonophosphates; Substrate Specificity
PubMed: 30284013
DOI: 10.1007/s00253-018-9392-8 -
IARC Monographs on the Evaluation of... 1995
Review
Topics: Aldehydes; Animals; Carcinogenicity Tests; Carcinogens; Humans
PubMed: 9097101
DOI: No ID Found -
International Journal of Molecular... Apr 20238-hydroxyquinoline (oxine) is a widely known and frequently used chelating agent, and the pharmacological effects of the core molecule and its derivatives have been... (Review)
Review
8-hydroxyquinoline (oxine) is a widely known and frequently used chelating agent, and the pharmacological effects of the core molecule and its derivatives have been studied since the 19th century. There are several synthetic methods to modify this core. The Mannich reaction is one of the most easily implementable examples, which requires mild reaction conditions and simple chemical reagents. The three components of the Mannich reaction are a primary or secondary amine, an aldehyde and a compound having a hydrogen with pronounced activity. In the modified Mannich reaction, naphthol or a nitrogen-containing naphthol analogue (e.g., 8-hydroxyquinoline) is utilised as the active hydrogen provider compound, thus affording the formation of aminoalkylated products. The amine component can be ammonia and primary or secondary amines. The aldehyde component is highly variable, including aliphatic and aromatic aldehydes. Based on the pharmacological relevance of aminomethylated 8-hydroxyquinolines, this review summarises their syntheses via the modified Mannich reaction starting from 8-hydroxyquinoline, formaldehyde and various amines.
Topics: Oxyquinoline; Naphthols; Amines; Aldehydes; Hydrogen; Mannich Bases
PubMed: 37175622
DOI: 10.3390/ijms24097915 -
International Journal of Molecular... Nov 2022Aldehydes, particularly acetaldehyde, are carcinogenic molecules and their concentrations in foodstuffs should be controlled to avoid upper aerodigestive tract (UADT)... (Review)
Review
Aldehydes, particularly acetaldehyde, are carcinogenic molecules and their concentrations in foodstuffs should be controlled to avoid upper aerodigestive tract (UADT) and liver cancers. Highly reactive, acetaldehyde forms DNA and protein adducts, impairing physiological functions and leading to the development of pathological conditions. The consumption of aged beer, outside of the ethanol metabolism, exposes habitual drinkers to this carcinogen, whose concentrations can be over-increased due to post-brewing chemical and biochemical reactions. Storage-related changes are a challenge faced by the brewing industry, impacting volatile compound formation and triggering flavor instability. Aldehydes are among the volatile compounds formed during beer aging, recognized as off-flavor compounds. To track and understand aldehyde formation through multiple pathways during beer storage, consequent changes in flavor but particularly quality losses and harmful compound formation, this systematic review reunited data on volatile compound profiles through gas chromatography analyses from 2011 to 2021. Conditions to avoid flavor instability and successful methods for reducing beer staling, and consequent acetaldehyde accumulation, were raised by exploring the dynamic conversion between free and bound-state aldehydes. Future research should focus on implementing sensory analyses to investigate whether adding aldehyde-binding agents, e.g., cysteine and bisulfite, would contribute to consumer acceptance, restore beer flavor, and minimize acetaldehyde-related health damage.
Topics: Humans; Aged; Acetaldehyde; Aldehydes; Beer; Carcinogens; Carcinogenesis
PubMed: 36430619
DOI: 10.3390/ijms232214147 -
Chemical Research in Toxicology Jul 2014Aldehydes are electrophilic compounds to which humans are pervasively exposed. Despite a significant health risk due to exposure, the mechanisms of aldehyde toxicity are... (Review)
Review
Aldehydes are electrophilic compounds to which humans are pervasively exposed. Despite a significant health risk due to exposure, the mechanisms of aldehyde toxicity are poorly understood. This ambiguity is likely due to the structural diversity of aldehyde derivatives and corresponding differences in chemical reactions and biological targets. To gain mechanistic insight, we have used parameters based on the hard and soft, acids and bases (HSAB) theory to profile the different aldehyde subclasses with respect to electronic character (softness, hardness), electrophilic reactivity (electrophilic index), and biological nucleophilic targets. Our analyses indicate that short chain aldehydes and longer chain saturated alkanals are hard electrophiles that cause toxicity by forming adducts with hard biological nucleophiles, e.g., primary nitrogen groups on lysine residues. In contrast, α,β-unsaturated carbonyl derivatives, alkenals, and the α-oxoaldehydes are soft electrophiles that preferentially react with soft nucleophilic thiolate groups on cysteine residues. The aldehydes can therefore be grouped into subclasses according to common electronic characteristics (softness/hardness) and molecular mechanisms of toxicity. As we will discuss, the toxic potencies of these subgroups are generally related to corresponding electrophilicities. For some aldehydes, however, predictions of toxicity based on electrophilicity are less accurate due to inherent physicochemical variables that limit target accessibility, e.g., steric hindrance and solubility. The unsaturated aldehydes are also members of the conjugated type-2 alkene chemical class that includes α,β-unsaturated amide, ketone, and ester derivatives. Type-2 alkenes are electrophiles of varying softness and electrophilicity that share a common mechanism of toxicity. Therefore, exposure to an environmental mixture of unsaturated carbonyl derivatives could cause "type-2 alkene toxicity" through additive interactions. Finally, we propose that environmentally derived aldehydes can accelerate diseases by interacting with endogenous aldehydes generated during oxidative stress. This review provides a basis for understanding aldehyde mechanisms and environmental toxicity through the context of electronic structure, electrophilicity, and nucleophile target selectivity.
Topics: Aldehydes; Animals; Humans
PubMed: 24911545
DOI: 10.1021/tx5001046