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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 -
Journal of Biotechnology Oct 2019Carboxylic acid reductases (CARs) are an emerging biocatalyst platform for the synthesis of a diverse array of aldehydes from carboxylic acids, operating... (Review)
Review
Carboxylic acid reductases (CARs) are an emerging biocatalyst platform for the synthesis of a diverse array of aldehydes from carboxylic acids, operating chemoselectively and under mild aqueous conditions. As such, there is growing interest in the industrial application of these enzymes, both for the synthesis of aldehyde end-products, which are particularly prevalent in the flavor and fragrance industries, and aldehyde intermediates in multi-enzyme cascades. This perspective aims to review recent developments in the applications of CARs with a focus on the challenges and considerations involved in their implementation, as well as potential solutions with a view to increased industrial utility.
Topics: Aldehydes; Bioreactors; Carboxylic Acids; Odorants; Oxidoreductases; Protein Engineering
PubMed: 31430498
DOI: 10.1016/j.jbiotec.2019.08.010 -
Journal of Agricultural and Food... Apr 2022Vegetable proteins are in high demand due to current issues surrounding meat consumption and changes in eating habits, but they are still not accepted by consumers due... (Review)
Review
Vegetable proteins are in high demand due to current issues surrounding meat consumption and changes in eating habits, but they are still not accepted by consumers due to their strong bitterness, astringent taste, and "beany" off-flavor. This review aimed to give an overview of the "beany" off-flavor and the potential of microorganisms to decrease it. Twenty-six volatile compounds were identified from the literature as contributing to the "beany" off-flavor, and their formation pathways were identified in a legume matrix, pea. Biotechnological ways to improve the flavor by reducing these volatile compounds were then looked over. As aldehydes and ketones are the main type of compounds directly linked to the "beany" off-flavor, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) were focused on. By converting aldehyde and ketones into alcohols or carboxylic acids, these two enzymes have the potential to decrease the off-flavor. The presence of the two enzymes in a selection of microorganisms (, , , , , and ) was done with a catabolism and a bioinformatical study. Finally, the correlation between the presence of the enzyme and the efficacy to improve the flavor was investigated by comparison with the literature. The presence of ADH and/or ALDH in the strain metabolism seems linked to an odor improvement. Especially, a constitutive enzyme (ADH or ALDH) in the catabolism should give better results, showing that some fermentative types are more inclined to better the flavor. Obligatory fermentative strains, with a constitutive ADH, or acetic acid bacteria, with constitutive ADH and ALDH, show the best results and should be favored to reduce the amount of compounds involved in the "beany" off-flavor and diminish that off-flavor in legume proteins.
Topics: Alcohol Dehydrogenase; Aldehyde Dehydrogenase; Aldehydes; Fabaceae; Ketones; Odorants; Taste; Vegetables; Volatile Organic Compounds
PubMed: 35384667
DOI: 10.1021/acs.jafc.1c07505 -
Biomolecules Oct 2022Reactive oxygen species (ROS), a by-product of aerobic life, are highly reactive molecules with unpaired electrons. The excess of ROS leads to oxidative stress,... (Review)
Review
Reactive oxygen species (ROS), a by-product of aerobic life, are highly reactive molecules with unpaired electrons. The excess of ROS leads to oxidative stress, instigating the peroxidation of polyunsaturated fatty acids (PUFA) in the lipid membrane through a free radical chain reaction and the formation of the most bioactive aldehyde, known as 4-hydroxynonenal (4-HNE). 4-HNE functions as a signaling molecule and toxic product and acts mainly by forming covalent adducts with nucleophilic functional groups in proteins, nucleic acids, and lipids. The mitochondria have been implicated as a site for 4-HNE generation and adduction. Several studies clarified how 4-HNE affects the mitochondria's functions, including bioenergetics, calcium homeostasis, and mitochondrial dynamics. Our research group has shown that 4-HNE activates mitochondria apoptosis-inducing factor (AIFM2) translocation and facilitates apoptosis in mice and human heart tissue during anti-cancer treatment. Recently, we demonstrated that a deficiency of 2 in the conditional-specific cardiac knockout mouse increases ROS, and subsequent production of 4-HNE inside mitochondria leads to the adduction of several mitochondrial respiratory chain complex proteins. Moreover, we highlighted the physiological functions of HNE and discussed their relevance in human pathophysiology and current discoveries concerning 4-HNE effects on mitochondria.
Topics: Mice; Humans; Animals; Reactive Oxygen Species; Lipid Peroxidation; Aldehydes; Oxidative Stress; Mitochondria
PubMed: 36358905
DOI: 10.3390/biom12111555 -
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 -
The Journal of Organic Chemistry Apr 2022A concise total synthesis of rucaparib, an FDA-approved drug for ovarian and prostate cancers, is reported. The Heck reaction of the commercially available aryl iodide...
A concise total synthesis of rucaparib, an FDA-approved drug for ovarian and prostate cancers, is reported. The Heck reaction of the commercially available aryl iodide with acrylonitrile provided the desired ()-2-aminocinnamonitrile derivative. A subsequent imino-Stetter reaction of the aldimine derived from 2-aminocinnamonitrile and aldehyde furnished indole-3-acetonitrile bearing the desired substituents at appropriate positions. The construction of the final azepinone scaffold via reduction of the nitrile group followed by seven-membered lactamization afforded rucaparib. Notably, the synthesis of rucaparib is achieved using commercially available starting materials in only three separation operations with 54% overall yield.
Topics: Aldehydes; Indoles
PubMed: 35319896
DOI: 10.1021/acs.joc.2c00083 -
European Heart Journal Nov 2023Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and...
BACKGROUND AND AIMS
Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure.
METHODS
Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets.
RESULTS
4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure.
CONCLUSIONS
4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure.
Topics: Humans; Rats; Animals; MicroRNAs; Ribonuclease III; Heart Failure; Aldehydes; Protein Processing, Post-Translational; Aldehyde Dehydrogenase, Mitochondrial
PubMed: 37944136
DOI: 10.1093/eurheartj/ehad662 -
Molecules (Basel, Switzerland) Feb 2023Carbonyl olefinations are among the most important organic syntheses that form C=C bonds, as they usually have high yields and in addition offer excellent... (Review)
Review
Carbonyl olefinations are among the most important organic syntheses that form C=C bonds, as they usually have high yields and in addition offer excellent stereoselectivity. Due to these advantages, carbonyl olefinations have important pharmaceutical and industrial applications. These reactions contain an additional step of an α-functionalized carbanion to an aldehyde or ketone to produce alkenes, but syntheses performed using metal carbene complexes are also known. The Wittig reaction is an example of carbonyl olefination, one of the best ways to synthesize alkenes. This involves the chemical reaction between an aldehyde or ketone with a so-called Wittig reagent, for instance phosphonium ylide. Triphenylphosphine-derived ylides and trialkylphosphine-derived ylides are the most common phosphorous compounds used as Wittig reagents. The Wittig reaction is commonly involved in the synthesis of novel anti-cancer and anti-viral compounds. In recent decades, the use of ultrasound on the Wittig reaction (and on different modified Wittig syntheses, such as the Wittig-Horner reaction or the aza-Wittig method) has been studied as a green synthesis. In addition to the advantage of green synthesis, the use of ultrasounds in general also improved the yield and reduced the reaction time. All of these chemical syntheses conducted under ultrasound will be described further in the present review.
Topics: Molecular Structure; Sonication; Alkenes; Aldehydes
PubMed: 36838946
DOI: 10.3390/molecules28041958 -
Molecules (Basel, Switzerland) Jun 2022Essential oils (EOs) are intricate combinations of evaporative compounds produced by aromatic plants and extracted by distillation or expression. EOs are natural... (Review)
Review
Essential oils (EOs) are intricate combinations of evaporative compounds produced by aromatic plants and extracted by distillation or expression. EOs are natural secondary metabolites derived from plants and have been found to be useful in food and nutraceutical manufacturing, perfumery and cosmetics; they have also been found to alleviate the phenomenon of antimicrobial resistance (AMR) in addition to functioning as antibacterial and antifungal agents, balancing menstrual cycles and being efficacious as an immune system booster. Several main aldehyde constituents can be found in different types of EOs, and thus, aldehydes and their derivatives will be the main focus of this study with regard to their antimicrobial, antioxidative, anti-inflammatory and immunomodulatory effects. This brief study also explores the activity of aldehydes and their derivatives against pathogenic bacteria for future use in the clinical setting.
Topics: Aldehydes; Anti-Bacterial Agents; Anti-Infective Agents; Bacteria; Microbial Sensitivity Tests; Oils, Volatile
PubMed: 35684521
DOI: 10.3390/molecules27113589 -
Biomacromolecules Apr 2024Polysaccharides are biodegradable, abundant, sustainable, and often benign natural polymers. The achievement of selective modification of polysaccharides is important... (Review)
Review
Polysaccharides are biodegradable, abundant, sustainable, and often benign natural polymers. The achievement of selective modification of polysaccharides is important for targeting specific properties and structures and will benefit future development of highly functional, sustainable materials. The synthesis of polysaccharides containing aldehyde or ketone moieties is a promising tool for achieving this goal because of the rich chemistry of aldehyde or ketone groups, including Schiff base formation, nucleophilic addition, and reductive amination. The obtained polysaccharide aldehydes or ketones themselves have rich potential for making useful materials, such as self-healing hydrogels, polysaccharide-protein therapeutic conjugates, or drug delivery vehicles. Herein, we review recent advances in synthesizing polysaccharides containing aldehyde or ketone moieties and briefly introduce their reactivity and corresponding applications.
Topics: Aldehydes; Ketones; Polysaccharides; Drug Delivery Systems; Polymers; Hydrogels
PubMed: 38490188
DOI: 10.1021/acs.biomac.4c00020