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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 -
Food Chemistry Aug 2023The reactions between malondialdehyde and 2,5-dimethylresorcinol, orcinol, olivetol, and alkylresocinols were studied in an attempt to investigate both if this lipid...
The reactions between malondialdehyde and 2,5-dimethylresorcinol, orcinol, olivetol, and alkylresocinols were studied in an attempt to investigate both if this lipid oxidation product is trapped by phenolics analogously to other reactive carbonyls and to elucidate the chemical structures of the produced adducts. After being formed, malondialdehyde is both partially fractionated to acetaldehyde and oligomerized into dimers and trimers. All these compounds react with phenolics producing three main kinds of derivatives: 5(or 7)-alkyl-7(or 5)-hydroxy-4-methyl-4H-chromene-3-carbaldehydes, 7-alkyl-9-hydroxy-6H-2,6-methanobenzo[d][1,3]dioxocine-5-carbaldehydes, and 4-(3-formylphenyl)-7-hydroxy-4H-chromene-3-carbaldehydes. A total of twenty-four adducts were isolated by semipreparative high-performance liquid chromatography (HPLC) and characterized by mono- and bi-dimensional nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Reaction pathways to explain the formation of all these compounds are proposed. Obtained results show that phenolics can trap malondialdehyde producing stable derivatives. The function(s) that such derivatives can play in foods remain(s) to be elucidated.
Topics: Malondialdehyde; Phenols; Acetaldehyde; Food; Magnetic Resonance Spectroscopy
PubMed: 36933433
DOI: 10.1016/j.foodchem.2023.135915 -
Nucleic Acids Research Aug 2023In the late 19th century, formalin fixation with paraffin-embedding (FFPE) of tissues was developed as a fixation and conservation method and is still used to this day... (Review)
Review
In the late 19th century, formalin fixation with paraffin-embedding (FFPE) of tissues was developed as a fixation and conservation method and is still used to this day in routine clinical and pathological practice. The implementation of state-of-the-art nucleic acid sequencing technologies has sparked much interest for using historical FFPE samples stored in biobanks as they hold promise in extracting new information from these valuable samples. However, formalin fixation chemically modifies DNA, which potentially leads to incorrect sequences or misinterpretations in downstream processing and data analysis. Many publications have concentrated on one type of DNA damage, but few have addressed the complete spectrum of FFPE-DNA damage. Here, we review mitigation strategies in (I) pre-analytical sample quality control, (II) DNA repair treatments, (III) analytical sample preparation and (IV) bioinformatic analysis of FFPE-DNA. We then provide recommendations that are tested and illustrated with DNA from 13-year-old liver specimens, one FFPE preserved and one fresh frozen, applying target-enriched sequencing. Thus, we show how DNA damage can be compensated, even when using low quantities (50 ng) of fragmented FFPE-DNA (DNA integrity number 2.0) that cannot be amplified well (Q129 bp/Q41 bp = 5%). Finally, we provide a checklist called 'ERROR-FFPE-DNA' that summarises recommendations for the minimal information in publications required for assessing fitness-for-purpose and inter-study comparison when using FFPE samples.
Topics: DNA; Formaldehyde; Paraffin Embedding; Sequence Analysis, DNA; Tissue Fixation
PubMed: 37351572
DOI: 10.1093/nar/gkad519 -
Communications Biology Sep 2023Lysosome-related organelles (LROs) play diverse roles and their dysfunction causes immunodeficiency. However, their primordial functions remain unclear. Here, we report...
Lysosome-related organelles (LROs) play diverse roles and their dysfunction causes immunodeficiency. However, their primordial functions remain unclear. Here, we report that C. elegans LROs (gut granules) promote organismal defenses against various stresses. We find that toxic benzaldehyde exposure induces LRO autofluorescence, stimulates the expression of LRO-specific genes and enhances LRO transport capacity as well as increases tolerance to benzaldehyde, heat and oxidative stresses, while these responses are impaired in glo-1/Rab32 and pgp-2 ABC transporter LRO biogenesis mutants. Benzaldehyde upregulates glo-1- and pgp-2-dependent expression of heat shock, detoxification and antimicrobial effector genes, which requires daf-16/FOXO and/or pmk-1/p38MAPK. Finally, benzaldehyde preconditioning increases resistance against Pseudomonas aeruginosa PA14 in a glo-1- and pgp-2-dependent manner, and PA14 infection leads to the deposition of fluorescent metabolites in LROs and induction of LRO genes. Our study suggests that LROs may play a role in systemic responses to stresses and in pathogen resistance.
Topics: Animals; Benzaldehydes; Caenorhabditis elegans; Lysosomes; Immunity
PubMed: 37704756
DOI: 10.1038/s42003-023-05246-7 -
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 -
Nature Communications Sep 2023Identifying the primary site of metastatic cancer is critical to guiding the subsequent treatment. Approximately 3-9% of metastatic patients are diagnosed with cancer of...
Identifying the primary site of metastatic cancer is critical to guiding the subsequent treatment. Approximately 3-9% of metastatic patients are diagnosed with cancer of unknown primary sites (CUP) even after a comprehensive diagnostic workup. However, a widely accepted molecular test is still not available. Here, we report a method that applies formalin-fixed, paraffin-embedded tissues to construct reduced representation bisulfite sequencing libraries (FFPE-RRBS). We then generate and systematically evaluate 28 molecular classifiers, built on four DNA methylation scoring methods and seven machine learning approaches, using the RRBS library dataset of 498 fresh-frozen tumor tissues from primary cancer patients. Among these classifiers, the beta value-based linear support vector (BELIVE) performs the best, achieving overall accuracies of 81-93% for identifying the primary sites in 215 metastatic patients using top-k predictions (k = 1, 2, 3). Coincidentally, BELIVE also successfully predicts the tissue of origin in 81-93% of CUP patients (n = 68).
Topics: Humans; DNA Methylation; Paraffin Embedding; Neoplasms, Second Primary; Neoplasms, Unknown Primary; Formaldehyde
PubMed: 37709764
DOI: 10.1038/s41467-023-41015-0 -
Nature Cell Biology May 2024DNA-protein crosslinks (DPCs) induced by aldehydes interfere with replication and transcription. Hereditary deficiencies in DPC repair and aldehyde clearance processes...
DNA-protein crosslinks (DPCs) induced by aldehydes interfere with replication and transcription. Hereditary deficiencies in DPC repair and aldehyde clearance processes cause progeria, including Ruijs-Aalfs syndrome (RJALS) and AMeD syndrome (AMeDS) in humans. Although the elimination of DPC during replication has been well established, how cells overcome DPC lesions in transcription remains elusive. Here we show that endogenous aldehyde-induced DPC roadblocks are efficiently resolved by transcription-coupled repair (TCR). We develop a high-throughput sequencing technique to measure the genome-wide distribution of DPCs (DPC-seq). Using proteomics and DPC-seq, we demonstrate that the conventional TCR complex as well as VCP/p97 and the proteasome are required for the removal of formaldehyde-induced DPCs. TFIIS-dependent cleavage of RNAPII transcripts protects against transcription obstacles. Finally, a mouse model lacking both aldehyde clearance and TCR confirms endogenous DPC accumulation in actively transcribed regions. Collectively, our data provide evidence that transcription-coupled DPC repair (TC-DPCR) as well as aldehyde clearance are crucial for protecting against metabolic genotoxin, thus explaining the molecular pathogenesis of AMeDS and other disorders associated with defects in TCR, such as Cockayne syndrome.
Topics: Animals; DNA Repair; Transcription, Genetic; Humans; Aldehydes; Proteasome Endopeptidase Complex; Mice; DNA; DNA Damage; Mice, Knockout; Valosin Containing Protein; RNA Polymerase II; Mice, Inbred C57BL; Formaldehyde; Excision Repair
PubMed: 38600234
DOI: 10.1038/s41556-024-01401-2 -
Doklady Biological Sciences :... Aug 2023A total of 11 ascomycete strains destructing technical nonylphenol (NP) and 4-tert-octylphenol (4-t-OP) were isolated from NP-contaminated soddy-podzolic loamy soil...
A total of 11 ascomycete strains destructing technical nonylphenol (NP) and 4-tert-octylphenol (4-t-OP) were isolated from NP-contaminated soddy-podzolic loamy soil (Leningrad Region, Russia). The isolates proved capable of degrading NP and 4-t-OP at a high load (300 mg/L). The most efficient Fusarium solani strain 8F degraded alkylphenols (APs) both in cometabolic conditions and in the absence of additional carbon and energy sources. A decrease in APs was due to biodegradation or biotransformation by the strain and, to a minor extent, absorption by fungal cells. NP and 4-t-OP half-lives were, respectively, 3.5 and 6.4 h in cometabolic conditions and 9 and 19.7 h in the absence of additional carbon and energy sources. Amounts of the lipid peroxidation product malondialdehyde (MDA) and reduced glutathione (GSH) increased during NP and 4-t-OP biodegradation in cometabolic conditions by 1.7 and 2 times, respectively, as compared with a control. A high GSH level in F. solani 8F cells potentially implicated the metabolite in both AP biodegradation and strain resistance to oxidative stress. The study is the first to report on the NP and 4-t-OP degradation by the ascomycete F. solani in cometabolic conditions and in the absence of additional carbon and energy sources. The high AP degradation potential of soil ascomycetes was assumed to provide a basis for new environmentally safe bioremediation technologies for purification of soils and natural and waste waters contaminated with endocrine disruptors.
Topics: Biodegradation, Environmental; Oxidative Stress; Ascomycota; Malondialdehyde; Carbon
PubMed: 37833577
DOI: 10.1134/S0012496623700515 -
International Journal of Molecular... Sep 2023It is reported that retinal abnormities are related to Alzheimer's disease (AD) in patients and animal models. However, it is unclear whether the retinal abnormities...
It is reported that retinal abnormities are related to Alzheimer's disease (AD) in patients and animal models. However, it is unclear whether the retinal abnormities appear in the mouse model of sporadic Alzheimer's disease (sAD) induced by acrolein. We investigated the alterations of retinal function and structure, the levels of β-amyloid (Aβ) and phosphorylated Tau (p-Tau) in the retina, and the changes in the retinal vascular system in this mouse model. We demonstrated that the levels of Aβ and p-Tau were increased in the retinas of mice from the acrolein groups. Subsequently, a decreased amplitudes of b-waves in the scotopic and photopic electroretinogram (ERG), decreased thicknesses of the retinal nerve fiber layer (RNFL) in the retina, and slight retinal venous beading were found in the mice induced by acrolein. We propose that sAD mice induced by acrolein showed abnormalities in the retina, which may provide a valuable reference for the study of the retina in sAD.
Topics: Animals; Mice; Alzheimer Disease; Acrolein; Retina; Amyloid beta-Peptides; Disease Models, Animal
PubMed: 37686379
DOI: 10.3390/ijms241713576 -
Ecotoxicology and Environmental Safety Sep 2023Aldehydes are recognized environmental toxicants that may affect lipid metabolism. For instance, acrolein has been found to increase serum triglyceride (TG) levels...
Aldehydes are recognized environmental toxicants that may affect lipid metabolism. For instance, acrolein has been found to increase serum triglyceride (TG) levels exclusively. However, it remains unclear whether other aldehydes are also associated with hypertriglyceridemia (HTG), and what mechanisms may be involved. This cross-sectional study analyzed data from the National Health and Nutrition Examination Survey (NHANES, 2013-2014) to identify associations between serum aldehydes, liver enzymes, and HTG. Serum aldehydes included crotonaldehyde (CRAL), propanaldehyde (3AL), butyraldehyde (4AL), pentanaldehyde (5AL), isopentanaldehyde (I5AL), and heptanaldehyde (7AL). Liver enzymes included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT). HTG was defined as fasting TG levels ≥ 1.7 mmol/L. Aldehyde co-exposure was quantified using weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR), while mediation analysis was performed to investigate the role of liver enzymes. Among 1474 participants (mean age 38.6 years, male 50.0%), 426 were diagnosed with HTG. 4AL, 5AL, I5AL, and 7AL were shown to be positively associated with HTG (all P values <0.05). Aldehydes co-exposure was also positively associated with HTG (OR 1.706, 95%CI 1.299-2.240), with 5AL contributing the highest weight (35.3%). Furthermore, aldehydes co-exposure showed positive associations with ALT, AST, and GGT (all P values <0.05), and all four liver enzymes were positively associated with HTG (all P values <0.05). Mediation analysis revealed that liver enzymes (ALT, AST, and GGT) may mediate the associations of 5AL and 7AL with HTG (all P values <0.05). This study identified a positive association between aldehyde co-exposure and HTG, which may be partially mediated by liver enzymes.
Topics: Humans; Male; Adult; Nutrition Surveys; Cross-Sectional Studies; Bayes Theorem; Hypertriglyceridemia; Alanine Transaminase; gamma-Glutamyltransferase; Aspartate Aminotransferases; Aldehydes; Liver
PubMed: 37579588
DOI: 10.1016/j.ecoenv.2023.115346