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γ-Hydroxybutyrate (GHB) is an important C4 platform chemical, serving as a crucial precursor for the synthesis of various bulk chemicals, including γ-butyrolactone (GBL) and 1,4-butanediol (1,4-BDO). In this study, we report the systematic metabolic engineering of Corynebacterium glutamicum for the biological production of GHB from glucose via the introduction of a glutamate-derived pathway. We showed that C. glutamicum is a promising host for producing GHB due to its higher tolerance to GHB as compared to other chassis. By screening key enzymes capable of converting glutamate into GHB and blocking byproduct synthesis pathways, an engineered C. glutamicum strain was developed that achieved a GHB production titer of 30.6 g/L. Comparative transcriptome analysis was subsequently employed to identify previously uncharacterized aldehyde dehydrogenases responsible for succinate accumulation, and knockout of the corresponding genes led to an increased GHB titer of 33.7 g/L. Ultimately, the integration of a phosphoketolase-mediated nonoxidative glycolysis (NOG) pathway further enhanced GHB production, resulting in an accumulation of 38.3 g/L of GHB with a yield of 0.615 mol/mol glucose during batch fermentation. The GHB in the fermentation broth can be efficiently converted into GBL by acid treatment with a yield of 0.970 mol/mol.

Introduction. The relationship between obesity and alcohol consumption is a topic of significant interest to public health. Alcoholic beverages contribute additional calories to the diet, which could be a relevant factor to the overweight risk. However, its association with weight gain is controversial and influenced by multiple factors. Objective. To analyze the relationship between moderate alcohol intake and body mass index, considering the variables that may influence this relationship. Materials and methods. The sample consisted of 155 individuals from Puerto Madryn (Argentina). Each participant completed a questionnaire about health, lifestyle, demographic, and socioeconomic factors. Anthropometric measurements were taken, and polymorphisms of 18 genes related to alcohol metabolism were genotyped. Results. We found that moderate alcohol consumption is associated with a lower body mass index, particularly in females. An increase of 14 grams of alcohol was associated with a risk of 0.68 for obesity and 0.71 for overweight. The T variant of the marker rs4646543 (ALDH1A1), a gene involved in alcohol metabolism and adipogenesis, was associated with a higher frequency of alcohol consumption. Conclusion. The findings of this study suggest that moderate alcohol consumption does not significantly contribute to body weight in the sample studied. Furthermore, the association with genetic variants, such as those of the ALDH1A1 gene, may provide a biological explanation for the inverse relationship observed between weight and alcohol consumption.

Background: Pyridoxine-dependent epilepsy is primarily characterized by early-onset refractory seizures. This condition can be caused by alpha-aminoadipic semialdehyde dehydrogenase deficiency due to a mutation in the ALDH7A1 gene, leading to the accumulation of certain substances that impact the production of various brain neurotransmitters and enzymes., Case Presentation: Our report presents the first documented case of pyridoxine dependency in Syria. The female infant, born to consanguineous parents, exhibited seizures on the second day of life. Despite the administration of multiple antiepileptic medications, seizures persisted. A comprehensive assessment, including metabolic evaluation, electroencephalography, and phenotypic characteristics of seizures, prompted genetic testing for pyridoxine-dependent epilepsy, which identified a homozygous likely pathogenic variant in the ALDH7A1 gene, confirming the diagnosis of this condition. Subsequently, the baby was put on oral pyridoxine, resulting in complete cessation of seizures., Conclusions: Due to its rarity, this condition was initially overlooked and led to an inappropriate therapeutic approach. Pyridoxine dependency should be considered after the manifestation of refractory seizures, as increased awareness can enable early diagnosis, appropriate treatment, and avoid unnecessary use of antiepileptic drugs. However, predicting the long-term outcome remains challenging., (© 2024. The Author(s).)

Parrots produce stunning plumage colors through unique pigments called psittacofulvins. However, the mechanism underlying their ability to generate a spectrum of vibrant yellows, reds, and greens remains enigmatic. We uncover a unifying chemical basis for a wide range of parrot plumage colors, which result from the selective deposition of red aldehyde- and yellow carboxyl-containing psittacofulvin molecules in developing feathers. Through genetic mapping, biochemical assays, and single-cell genomics, we identified a critical player in this process, the aldehyde dehydrogenase ALDH3A2 , which oxidizes aldehyde psittacofulvins into carboxyl forms in late-differentiating keratinocytes during feather development. The simplicity of the underlying molecular mechanism, in which a single enzyme influences the balance of red and yellow pigments, offers an explanation for the exceptional evolutionary lability of parrot coloration.

Aldehyde Dehydrogenases (ALDH), a group of enzymes, are associated with the detoxification of aldehydes, produced in plants during abiotic stress conditions. Salinity remains a pivotal abiotic challenge that poses a significant threat to cultivation and yield of sugarcane. In this study, an Aldehyde dehydrogenase gene (EaALDH7) from Erianthus arundinaceus was overexpressed in the commercial sugarcane hybrid cultivar Co 86032. The transgenic lines were evaluated at different NaCl concentrations ranging from 0 mM to 200 mM for various morpho-physiological and biochemical parameters. The control plants, subjected to salinity stress condition, exhibited morphological changes in protoxylem, metaxylem, pericycle and pith whereas the transgenic events were on par with plants under regular irrigation. The overexpressing (OE) lines showed less cell membrane injury and improved photosynthetic rate, transpiration rate, and stomatal conductance than the untransformed control plants under stress conditions. Elevated proline content, higher activity of enzymatic antioxidants such as sodium dismutase (SOD), catalase (CAT), glutathione reductase (GR) and ascorbate peroxidase (APX) and low level of malondialdehyde MDA and hydrogen peroxide (H 2 O 2 ) in the transgenic lines. The analysis of EaALDH7 expression revealed a significant upregulation in the transgenic lines compared to that of the untransformed control during salt stress conditions. The current study highlights the potentials of EaALDH7 gene in producing salinity-tolerant sugarcane cultivars., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interests exist., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glioblastoma (GB) is an aggressive malignant central nervous system tumor that is currently incurable. One of the main pitfalls of GB treatment is resistance to the chemotherapeutic standard of care, temozolomide (TMZ). The role of aldehyde dehydrogenases (ALDHs) in the glioma stem cell (GSC) subpopulation has been related to chemoresistance. ALDHs take part in processes such as cell proliferation, differentiation, invasiveness or metastasis and have been studied as pharmacological targets in cancer treatment. In the present work, three novel α,β-acetylenic amino thiolester compounds, with demonstrated efficacy as ALDH inhibitors, were tested in vitro on a panel of six human GB cell lines and one murine GB cell line. Firstly, the expression of the ALDH1A isoforms was assessed, and then inhibitors were tested for their cytotoxicity and their ability to inhibit cellular ALDH activity. Drug combination assays with TMZ were performed, as well as an assessment of the cell death mechanism and generation of ROS. A knockout of several ALDH genes was carried out in one of the human GB cell lines, allowing us to discuss their role in cell proliferation, migration capacity and resistance to treatment. Our results strongly suggest that ALDH inhibitors could be an interesting approach in the treatment of GB, with EC50 values in the order of micromolar, decreasing ALDH activity in GB cell lines to 40-50%.

Objective: To analyze the clinical diagnosis, treatment, and prognosis of the patients with pyridoxine-dependent epilepsy (PDE) characterized by infantile epileptic spasm syndrome (IESS)., Methods: A total of 75 PDE patients with ALDH7A1 variants were diagnosed at the Department of Pediatrics of Peking University First Hospital and Peking University People's Hospital from July 2012 to June 2024, and five PDE patients with the phenotype of IESS were selected. The clinical manifestations, treatment, blood biochemistry, metabolic screening, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and gene testing results of the five PDE patients were analyzed., Results: Among the five patients diagnosed with PDE, three were female and two were male, and the phenotype was consistent with IESS. The age at the last follow-up was from one year and 3 months to 11 years and 9 months. All the five cases were delivered at term. Two cases had anoxia and asphyxia at birth, and three cases had normal birth history. The onset age of seizure ranged from one day to 4 months after birth. One case presented with epileptic spasms (ES), and three cases presented with focal seizure and ES. The other patient was started with ES, followed by multiple seizure types, including focal seizure and generalized tonic-clonic seizure, and developed epileptic status which caused secondary brain injury. The interictal EEG results showed hypsarrhythmia in three cases, generalized and multifocal discharges in one cases, and multifocal discharges in one case. No abnormalities were found in brain MRI in three cases, and secondary cerebral atrophy and hydrocephalus were observed in two cases during the course of the disease. Gene analysis confirmed that the five patients carried compound heterozygous variants of ALDH7A1 , and two of them carried exon deletion variants. High dose pyridoxine treatment started at the end of 2 days, 4 years, 3 years, 4 days. and 2 months after the onset of the disease. Up to the last follow-up, seizures of four cases were controlled, followed by normal EEG. One patient with brain atrophy had uncontrolled seizures and EEG remained abnormal. The neurodevelopment of the three patients were severely delayed, and two were mildly delayed., Conclusion: IESS could be a rare phenotype of PDE. High doses of pyridoxine can control or reduce the frequency of seizures. Delayed diagnosis and treatment, secondary brain injury, and the genotype, especially deletions variants, were associated with poor prognosis.

Engineered microorganisms have emerged as viable alternatives for limonene production. However, issues such as low enzyme abundance or activities, and regulatory feedback/forward inhibition may reduce yields. To understand the underlying metabolism, we adopted a systems biology approach for an engineered limonene-producing Escherichia coli strain K-12 MG1655. Firstly, we generated time-series metabolomics data and, secondly, developed a dynamic model based on enzyme dynamics to track the native metabolic networks and the engineered mevalonate pathway. After several iterations of model fitting with experimental profiles, which also included 13 C-tracer studies, we performed in silico knockouts (KOs) of all enzymes to identify bottleneck(s) for optimal limonene yields. The simulations indicated that ALDH/ADH (aldehyde dehydrogenase/alcohol dehydrogenase) and LDH (lactate dehydrogenase) suppression, and HK (hexokinase) enhancement would increase limonene yields. Experimental confirmation was achieved, where ALDH-ADH and LDH KOs, and HK overexpression improved limonene yield by 8- to 11-fold. Our systems biology approach can guide microbial strain re-engineering for optimal target production., (© 2024. The Author(s).)

Objectives: Tumor-associated neutrophils (TANs) are among the most abundant inflammatory cells in tumor microenvironment (TME). Aldehyde dehydrogenase 3A1 (ALDH3A1) is significantly reduced in oral squamous cell carcinoma (OSCC), ALDH3A1 overexpression suppresses tumorigenesis by inhibiting inflammation. This study investigated the relationship and mechanisms underlying the crosstalk between ALDH3A1 and TANs in OSCC., Materials and Methods: Immunohistochemistry and immunofluorescence were performed to investigate the abundance of TANs and the expression of ALDH3A1. dHL-60 were induced with tumor-conditioned media and recombinant IL-6/IL-8. The expression of key proteins in PI3K/AKT/NF-κB pathway were detected by RT-PCR and western blot. A xenograft model was utilized to examine the effect of ALDH3A1 on tumorigenicity and polarization of TANs., Results: In patients with OSCC, TANs significantly increased and were associated with a worse prognosis. Additionally, ALDH3A1 negatively correlated with TANs infiltration and especially the N2 phenotype which was the prominent part in OSCC. Furthermore, our study demonstrated that tumor-derived IL-8 drives ALDH3A1-mediated TANs N2 polarization in the TME through PI3K/AKT/NF-κB pathway in vitro and in vivo., Conclusion: Our results indicate that TANs can serve as a prognostic biomarker and ALDH3A1 could be a promising therapeutic target for regulating TANs N2 polarization in antitumor therapy., (© 2024 Wiley Periodicals LLC.)

To determine the effects of microbial proteins on Qingzhuan tea sensory quality during tea pile fermentation, tea leaf metabolomic and microorganism proteomic analyses were performed. In total, 1835 differential metabolites and 443 differentially expressed proteins of the microorganisms were identified. Correlation analysis between metabolomics and proteomics data revealed that the levels of microbial proteins EG II and CBH I cellulase may play important roles in cell wall construction and permeability, which were crucial for the interaction between tea leaves and microorganisms. Microbial proteins heat shock proteins (HSP), alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and CuAO related to detoxification and stress responses showed a positive correlation with tea theanine, glutamine, γ-aminobutyric acid, glutamic acid, catechin, (-)-gallocatechin gallate, and (-)-catechin gallate, suggesting their effects on tea characteristic compound accumulation, thus affecting Qingzhuan tea sensory quality.

Protective effect of quercetin against acetaldehyde was evaluated using the cultured hepatocyte models with aldehyde dehydrogenase (ALDH) isozyme deficiency (aldh2-kd and aldh1a1-kd). The quercetin-induced cytoprotection against acetaldehyde in the ALDH1A1-deficient mutant (aldh1a1-kd) was weaker than that in the wild type. Furthermore, quercetin did not enhance the ALDH activity in aldh1a1-kd cells, suggesting that ALDH1A1 is involved in quercetin-induced cytoprotection., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: Although bone marrow-derived cells with high aldehyde dehydrogenase activity (ALDH br ) have shown therapeutic potential against various diseases in animal studies, clinical trials have failed to show concurrent findings. We aimed to clarify the optimal conditions for the efficacy of ALDH br cells by using a murine bleomycin-induced pulmonary fibrosis model., Methods: We intravenously transferred male or female donor C57BL/6 mice-derived ALDH br cells into recipient C57BL/6 mice under various conditions, and used mCherry-expressing mice as a donor to trace the transferred ALDH br cells., Results: Pulmonary fibrosis improved significantly when (1) female-derived, not male-derived, and (2) lineage (Lin)-negative, not lineage-positive, ALDH br cells were transferred during the (3) fibrotic, not inflammatory, phase. Consistent with the RNA-sequencing results, female-derived Lin - /ALDH br cells were more resistant to oxidative stress than male-derived cells in vitro, and transferred female-derived Lin - /ALDH br cells were more viable than male-derived cells in the fibrotic lung. The mechanism underlying the antifibrotic effects of Lin - /ALDH br cells was strongly associated with reduction of oxidative stress., Conclusions: Our results indicated that Lin - /ALDH br cell therapy could ameliorate pulmonary fibrosis by reducing oxidative stress and suggested that their efficacy was mediated by sex-related differences. Thus, sex-awareness strategies may be important for clinical application of bone marrow ALDH br cells as a therapeutic tool., (© 2024. The Author(s).)

Fusarium verticillioides is the primary pathogen causing ear rot and stalk rot in corn ( Zea mays ). It not only affects yields but also produces mycotoxins endangering both human and animal health. Aldehyde dehydrogenase (ALDH) is essential for the oxidation of aldehydes in living organisms, making it a potential target for human drug design. However, there are limited reports on its function in plant pathogenic fungus. In this study, we analyzed the expression levels and gene knockout mutants, revealing that ALDH genes FvALDH-43 and FvALDH-96 in F. verticillioides played significant roles in pathogenicity and resistance to low-temperature stress by affecting antioxidant capacity. Virtual screening for natural product inhibitors and molecular docking were performed targeting FvALDH-43 and FvALDH-96. Following the biological activity analysis, three natural flavonoid compounds featuring a 2-hydroxyphenol chromene were identified. Among these, Taxifolin exhibited the highest biological activity and low toxicity. Both in vitro and in vivo biological evaluations confirmed that Taxifolin targeted ALDH and inhibited its activity. These findings indicate that aldehyde dehydrogenase may serve as a promising target for the design of novel fungicides.

Since metastasis accounts for the majority of cancer morbidity and mortality, attempts are focused to block metastasis and metastasis initiating cellular programs. It is generally believed that hypoxia, reactive oxygen species (ROS) and the dysregulated redox pathways regulate metastasis. Although induction of epithelial to mesenchymal transition (EMT) can initiate cell motility to different sites other than the primary site, the initiation of a secondary tumor at a distant site depends on self-renewal property of cancer stem cell (CSC) property. That subset of metastatic cells possessing CSC property are referred to as metastasis initiating cells (MICs). Among the different cellular intermediates regulating metastasis in response to hypoxia by inducing EMT and self-renewal property, ALDH1A1 is a critical molecule, which can be used as a marker for MICs in a wide variety of malignancies. The cytosolic ALDHs can irreversibly convert retinal to retinoic acid (RA), which initiates RA signaling, important for self-renewal and EMT. The metastasis permissive tumor microenvironment increases the expression of ALDH1A1, primarily through HIF1α, and leads to metabolic reprograming through OXPHOS regulation. The ALDH1A1 expression and its high activity can reprogram the cancer cells with the transcriptional upregulation of several genes, involved in EMT through RA signaling to manifest hybrid EMT or Hybrid E/M phenotype, which is important for acquiring the characteristics of MICs. Thus, the review on this topic highlights the use of ALDH1A1 as a marker for MICs, and reporters for the marker can be effectively used to trace the population in mouse models, and to screen drugs that target MICs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aldehyde dehydrogenases (ALDHs) represent a superfamily of enzymes, which oxidize aldehydes to the corresponding acids. Certain families, namely ALDH9 and ALDH10, are best active with ω-aminoaldehydes arising from the metabolism of polyamines such as 3-aminopropionaldehyde and 4-aminobutyraldehyde. Plant ALDH10s show broad specificity and accept many different aldehydes (aliphatic, aromatic and heterocyclic) as substrates. This work involved the above-mentioned aminoaldehydes acylated with dicarboxylic acids, phenylalanine, and tyrosine. The resulting products were then examined with native ALDH10 from pea and recombinant ALDH7s from pea and maize. This investigation aimed to find a common efficient substrate for the two plant ALDH families. One of the best natural substrates of ALDH7s is aminoadipic semialdehyde carrying a carboxylic group opposite the aldehyde group. The substrate properties of the new compounds were demonstrated by mass spectrometry of the reaction mixtures, spectrophotometric assays and molecular docking. The N-carboxyacyl derivatives were good substrates of pea ALDH10 but were only weakly oxidized by the two plant ALDH7s. The N-phenylalanyl and N-tyrosyl derivatives of 3-aminopropionaldehyde were good substrates of pea and maize ALDH7. Particularly the former compound was converted very efficiently (based on the k cat /K m ratio), but it was only weakly oxidized by pea ALDH10. Although no compound exhibited the same level of substrate properties for both ALDH families, we show that these enzymes may possess more common substrates than expected., (© 2024. The Author(s).)

Formaldehyde (FA) is a recognized environmental and metabolic toxin implicated in cancer development and aging. Inherited mutations in the FA-detoxifying enzymes ADH5 and ALDH2 genes lead to FA overload in the severe multisystem AMeD syndrome. FA accumulation causes genome damage including DNA-protein-, inter- and intra-strand crosslinks and oxidative lesions. However, the influence of distinct DNA repair systems on organismal FA resistance remains elusive. We have here investigated the consequence of a range of DNA repair mutants in a model of endogenous FA overload generated by downregulating the orthologs of human ADH5 and ALDH2 in C. elegans. We have focused on the distinct components of nucleotide excision repair (NER) during developmental growth, reproduction and aging. Our results reveal three distinct modes of repair of FA-induced DNA damage: Transcription-coupled repair (TCR) operating NER-independently during developmental growth or through NER during adulthood, and, in concert with global-genome (GG-) NER, in the germline and early embryonic development. Additionally, we show that the Cockayne syndrome B (CSB) factor is involved in the resolution of FA-induced DNA-protein crosslinks, and that the antioxidant and FA quencher N-acetyl-l-cysteine (NAC) reverses the sensitivity of detoxification and DNA repair defects during development, suggesting a therapeutic intervention to revert FA-pathogenic consequences., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

In this issue of Cell Metabolism, Li et al. report that the highly expressed aldehyde dehydrogenase 1 family member A3 interacts with pyruvate kinase M2 (PKM2) in glioblastoma cells. Consequently, PKM2 tetramerization and activation promote lactate production, leading to the lactylation and nuclear translocation of XRCC1 for DNA damage repair and therapeutic resistance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The ALDH1A1 gene encodes a cytoplasmic member of the aldehyde dehydrogenase 1 family, which plays an important role in regulating animal reproductive performance, including estrus cycle and embryonic development. The aim of this study was to characterize ALDH1A1 activity in ovaries of 3-5 year-old yaks and to determine its effects on cell proliferation, apoptosis, and progesterone secretion in luteal cells (LCs). The coding sequence (CDS) of the ALDH1A1 gene was cloned by reverse transcription-PCR and immunohistochemical analysis was used to confirm localization of the ALDH1A1 protein in the ovary. To assess the activity of ALDH1A1 in regulating progesterone secretion, si-ALDH1A1 was transfected into LCs in vitro and progesterone levels in LC supernatants were measured by ELISA. The interference efficiency was assessed by real-time quantitative PCR (RT-qPCR) and immunofluorescence staining, and cell proliferation and apoptosis were evaluated by EdU and TUNEL staining, respectively. The cloned ALDH1A1 sequence contained 1462 bp, encoding 487 amino acids. Immunohistochemical analysis showed that ALDH1A1 protein expression, which was significantly higher in LCs, was mainly found in antral follicles and the corpus luteum (CL). The expression of ALDH1A1 mRNA in LCs was effectively inhibited by si-ALDH1A1transfection, and progesterone secretion was markedly decreased along with the significant down-regulation of progesterone pathway-related genes, STAR, CYP11A1, CYP19A1, CYP17A1, 3β-HSD, and HSD17B1. Knockdown of ALDH1A1 mRNA expression decreased cell proliferation and increased apoptosis in LCs. The mRNA expression of the proliferation-related genes, PCNA, CCND1, CCNB1 and CDC25A, was significantly down-regulated, while expression of the apoptosis-promoting CASP3 gene was significantly increased. In summary, we characterized the yak ALDH1A1 gene and revealed that ALDH1A1 knockdown promoted apoptosis, repressed cell proliferation, and decreased progesterone secretion by yak LCs, potentially by regulating the mRNA expression of genes related to proliferation, apoptosis, and progesterone synthesis and secretion., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Acute myocardial infarction (AMI) remains a leading cause of death worldwide. Increased formation of reactive oxygen species (ROS) during the early reperfusion phase is thought to trigger lipid peroxidation and disrupt redox homeostasis, leading to myocardial injury. Whilst the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) is chiefly recognised for its central role in ethanol metabolism, substantial experimental evidence suggests an additional cardioprotective role for ALDH2 independent of alcohol intake, which mitigates myocardial injury by detoxifying breakdown products of lipid peroxidation including the reactive aldehydes, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Epidemiological evidence suggests that an ALDH2 mutant variant with reduced activity that is highly prevalent in the East Asian population increases AMI risk. Additional studies have uncovered a strong association between coronary heart disease and this ALDH2 mutant variant. It appears this enzyme polymorphism (in particular, in ALDH2*2/2 carriers) has the potential to have wide-ranging effects on thiol reactivity, redox tone and therefore numerous redox-related signaling processes, resilience of the heart to cope with lifestyle-related and environmental stressors, and the ability of the whole body to achieve redox balance. In this review, we summarize the journey of ALDH2 from a mitochondrial reductase linked to alcohol metabolism, via pre-clinical studies aimed at stimulating ALDH2 activity to reduce myocardial injury to clinical evidence for its protective role in the heart., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Given the high prevalence of fast-metabolizing alcohol dehydrogenase-1B*2 (ADH1B*2 ) and inactive aldehyde dehydrogenase-2*2 (ALDH2*2 ) alleles in East Asians, we evaluated how the ADH1B / ALDH2 genotypes and alcohol flushing might affect the development of alcohol dependence (AD)., Methods: We evaluated how the ADH1B / ALDH2 genotypes and self-reported alcohol flushing affected history of drinking events and withdrawal symptoms and ICD-10 criteria in 4116 Japanese AD men., Results: The ADH1B*1/*1 group and ALDH2*1/*1 group were 1-5 years younger than the ADH1B*2 (+) and ALDH2*1/*2 groups, respectively, for all of the ages at onset of habitual drinking, blackouts, daytime drinking, uncontrolled drinking, withdrawal symptoms, and first treatment for AD, and the current age. Blackouts were more common in the ADH1B*1/*1 group and ALDH2*1/*1 group. Daytime drinking, uncontrolled drinking, and withdrawal symptoms, such as hand tremor, sweating, convulsions, and delirium tremens/hallucinations were more common in the ADH1B*1/*1 group. The ADH1B*1/*1 was positively associated with the ICD-10 criteria for 'tolerance' and 'withdrawal symptoms'. The ADH1B*1/*1 group and ALDH2*1/*2 group had a larger ICD-10 score. Never flushing was reported by 91.7% and 35.2% of the ALDH2*1/*1 and ALDH2*1/*2 carriers, respectively. After a 1-2-year delay in the onset of habitual drinking in the former-/current-flushing group, no differences in the ages of the aforementioned drinking milestones were found according to the flushing status., Conclusion: The ADH1B*1/*1 and ALDH2*1/*1 accelerated the development of drinking events and withdrawal symptoms in Japanese AD patients. ICD-10 score was larger in the ADH1B*1/*1 group and ALDH2*1/*2 group. The effects of alcohol flushing on drinking events were limited., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The mitogen-activated protein kinase (MAPK/ERK) pathway is pivotal in controlling the proliferation and survival of melanoma cells. Several mutations, including those in BRAF, exhibit an oncogenic effect leading to increased cellular proliferation. As a result, the combination therapy of a MEK inhibitor with a BRAF inhibitor demonstrated higher efficacy and lower toxicity than BRAF inhibitor alone. This combination has become the preferred standard of care for tumors driven by BRAF mutations. Aldehyde dehydrogenase 1A1 (ALDH1A1) is a known marker of stemness involved in drug resistance in several type of tumors, including melanoma. This study demonstrates that melanoma cells overexpressing ALDH1A1 displayed resistance to vemurafenib and trametinib through the activation of PI3K/AKT signaling instead of MAPK axis. Inhibition of PI3K/AKT signaling partially rescued sensitivity to the drugs. Consistently, pharmacological inhibition of ALDH1A1 activity downregulated the activation of AKT and partially recovered responsiveness to vemurafenib and trametinib. We propose ALDH1A1 as a new potential target for treating melanoma resistant to MAPK/ERK inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Aldehyde dehydrogenases (ALDHs) are a family of enzymes that catalyze the oxidation of aldehyde molecules into the corresponding carboxylic acid, regulate the balance of aldehydes and protect plants from the poisoning caused by excessive accumulation of aldehydes; however, this gene family has rarely been studied in cotton., Results: In the present study, genome-wide identification was performed, and a total of 114 ALDH family members were found in three cotton species, Gossypium hirsutum, Gossypium arboreum and Gossypium raimondii. The ALDH genes were divided into six subgroups by evolutionary analysis. ALDH genes in the same subgroup showed similar gene structures and conserved motifs, but some genes showed significant differences, which may result in functional differences. Chromosomal location analysis and selective pressure analysis revealed that the ALDH gene family had experienced many fragment duplication events. Cis-acting element analysis revealed that this gene family may be involved in the response to various biotic and abiotic stresses. The RT‒qPCR results showed that the expression levels of some members of this gene family were significantly increased under salt stress conditions. Gohir.A11G040800 and Gohir.D06G046200 were subjected to virus-induced gene silencing (VIGS) experiments, and the sensitivity of the silenced plants to salt stress was significantly greater than that of the negative control plants, suggesting that Gohir.A11G040800 and Gohir.D06G046200 may be involved in the response of cotton to salt stress., Conclusions: In total, 114 ALDH genes were identified in three Gossypium species by a series of bioinformatics analysis. Gene silencing of the ALDH genes of G. hirsutum revealed that ALDH plays an important role in the response of cotton to salt stress., (© 2024. The Author(s).)

Aldehyde dehydrogenase enzymes (ALDHs) are widely studied for their roles in disease propagation and cell metabolism. Their use in biocatalysis applications, for the conversion of aldehydes to carboxylic acids, has also been recognized. Understanding the structural features and functions of both prokaryotic and eukaryotic ALDHs is key to uncovering novel applications of the enzyme and probing its role in disease propagation. The thermostable enzyme ALDH Tt originating from Thermus thermophilus , strain HB27, possesses a unique extension of its C-terminus, which has been evolutionarily excluded from mesophilic counterparts and other thermophilic enzymes in the same genus. In this work, the thermophilic adaptation is studied by the expression and optimized purification of mutant ALDH Tt- 508, with a 22-amino acid truncation of the C-terminus. The mutant shows increased activity throughout production compared to native ALDH Tt , indicating an opening of the active site upon C-terminus truncation and giving rationale into the evolutionary exclusion of the C-terminal extension from similar thermophilic and mesophilic ALDH proteins. Additionally, the C-terminus is shown to play a role in controlling substrate specificity of native ALDH, particularly in excluding catalysis of certain large and certain aromatic ortho-substituted aldehydes, as well as modulating the protein's pH tolerance by increasing surface charge. Dynamic light scattering and size-exclusion HPLC methods are used to show the role of the C-terminus in ALDH Tt oligomeric stability at the cost of catalytic efficiency. Studying the aggregation rate of ALDH Tt with and without a C-terminal extension leads to the conclusion that ALDH Tt follows a monomolecular reaction aggregation mechanism.

Dysregulation of the aldehyde dehydrogenase (ALDH) family has been implicated in various pathological conditions, including cancer. However, a systematic evaluation of ALDH alterations and their therapeutic relevance in hepatocellular carcinoma (HCC) remains lacking. Herein, we found that 15 of 19 ALDHs were transcriptionally dysregulated in HCC tissues compared to normal liver tissues. A four gene signature, including ALDH2, ALDH5A1, ALDH6A1, and ALDH8A1, robustly predicted prognosis and defined a high-risk subgroup exhibiting immunosuppressive features like regulatory T cell (Tregs) infiltration. Single-cell profiling revealed selective overexpression of tumor necrosis factor receptor superfamily member 18 (TNFRSF18) on Tregs, upregulated in high-risk HCC patients. We identified ALDH2 as a tumor suppressor in HCC, with three novel phosphorylation sites mediated by protein kinase C zeta that enhanced enzymatic activity. Mechanistically, ALDH2 suppressed Tregs differentiation by inhibiting β-catenin/TGF-β1 signaling in HCC. Collectively, our integrated multi-omics analysis defines an ALDH-Tregs-TNFRSF18 axis that contributes to HCC pathogenesis and represents potential therapeutic targets for this aggressive malignancy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Aldehyde dehydrogenase 7A1 (ALDH7A1) catalyzes a step of lysine catabolism. Certain missense mutations in the ALDH7A1 gene cause pyridoxine dependent epilepsy (PDE), a rare autosomal neurometabolic disorder with recessive inheritance that affects almost 1:65,000 live births and is classically characterized by recurrent seizures from the neonatal period. We report a biochemical, structural, and computational study of two novel ALDH7A1 missense mutations that were identified in a child with rare recurrent seizures from the third month of life. The mutations affect two residues in the oligomer interfaces of ALDH7A1, Arg134 and Arg441 (Arg162 and Arg469 in the HGVS nomenclature). The corresponding enzyme variants R134S and R441C (p.Arg162Ser and p.Arg469Cys in the HGVS nomenclature) were expressed in Escherichia coli and purified. R134S and R441C have 10,000- and 50-fold lower catalytic efficiency than wild-type ALDH7A1, respectively. Sedimentation velocity analytical ultracentrifugation shows that R134S is defective in tetramerization, remaining locked in a dimeric state even in the presence of the tetramer-inducing coenzyme NAD + . Because the tetramer is the active form of ALDH7A1, the defect in oligomerization explains the very low catalytic activity of R134S. In contrast, R441C exhibits wild-type oligomerization behavior, and the 2.0 Å resolution crystal structure of R441C complexed with NAD + revealed no obvious structural perturbations when compared to the wild-type enzyme structure. Molecular dynamics simulations suggest that the mutation of Arg441 to Cys may increase intersubunit ion pairs and alter the dynamics of the active site gate. Our biochemical, structural, and computational data on two novel clinical variants of ALDH7A1 add to the complexity of the molecular determinants underlying pyridoxine dependent epilepsy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a rare autosomal recessive disorder due to a deficiency of α-aminoadipic semialdehyde dehydrogenase. This study aimed to systematically explore genotypic and phenotypic features and prognostic factors of neonatal-onset PDE. A literature search covering PubMed, Elsevier, and Web of Science was conducted from January 2006 to August 2023. We identified 56 eligible studies involving 169 patients and 334 alleles. The c.1279 G>C variant was the most common variant of neonatal-onset PDE (25.7 %). All patients were treated with pyridoxine; forty patients received dietary intervention therapy. 63.9 % of the patients were completely seizure-free; however, 68.6 % of the patients had neurodevelopmental delays. Additionally, homozygous c.1279 G>C variants were significantly associated with ventriculomegaly, abnormal white matter signal, and cysts (P<0.05). In contrast, homozygous c.1364 T>C was associated with clonic seizure (P=0.031). Pyridoxine used immediately at seizure onset was an independent protective factor for developmental delay (P=0.035; odds ratio [OR]: 3.14). Besides, pyridoxine used early in the neonatal period was a protective factor for language delay (P=0.044; OR: 4.59). In contrast, neonatal respiratory distress (P=0.001; OR: 127.44) and abnormal brain magnetic resonance imaging (P=0.049; OR: 3.64) were risk factors. Prenatal movement abnormality (P=0.041; OR: 20.56) and abnormal white matter signal (P=0.012; OR: 24.30) were risk factors for motor delay. Myoclonic seizure (P=0.023; OR: 7.13) and status epilepticus (P=0.000; OR: 9.93) were risk factors for breakthrough seizures. In conclusion, our study indicated that pyridoxine should be started immediately when unexplained neonatal seizures occur and not later than the neonatal period to prevent poor neurodevelopmental outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Acetaldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme in alcohol metabolism, and oral administration of ALDH2 is a promising method for alcohol detoxification. However, recombinant ALDH2 is susceptible to hydrolysis by digestive enzymes in the gastrointestinal tract and is expressed as inactive inclusion bodies in E. coli. In this study, we performed three rounds of rational design to address these issues. Specifically, the surface digestive sites of pepsin and trypsin were replaced with other polar amino acids, while hydrophobic amino acids were incorporated to reshape the catalytic cavity of ALDH2. The resulting mutant DE2-852 exhibited a 45-fold increase in soluble expression levels, while its stability against trypsin and pepsin increased by eightfold and twofold, respectively. Its catalytic efficiency (k cat /K m ) at pH 7.2 and 3.2 improved by more than four and five times, respectively, with increased V max and decreased K m values. The enhanced properties of DE2-852 were attributed to the D457Y mutation, which created a more compact protein structure and facilitated a faster collision between the substrate and catalytic residues. These results laid the foundation for the oral administration and mass preparation of highly active ALDH2 and offered insights into the oral application of other proteins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Chemoresistance is associated with tumor relapse and unfavorable prognosis. Multiple mechanisms underlying chemoresistance have been elucidated, including stemness and DNA damage repair. Here, the involvement of the WNT receptor, FZD5, in ovarian cancer (OC) chemoresistance was investigated., Methods: OC cells were analyzed using in vitro techniques including cell transfection, western blot, immunofluorescence and phalloidin staining, CCK8 assay, colony formation, flowcytometry, real-time PCR, and tumorisphere formation. Pearson correlation analysis of the expression levels of relevant genes was conducted using data from the CCLE database. Further, the behavior of OC cells in vivo was assessed by generation of a mouse xenograft model., Results: Functional studies in OC cells showed that FZD5 contributes to epithelial phenotype maintenance, growth, stemness, HR repair, and chemoresistance. Mechanistically, FZD5 modulates the expression of ALDH1A1, a functional marker for cancer stem-like cells, in a β-catenin-dependent manner. ALDH1A1 activates Akt signaling, further upregulating RAD51 and BRCA1, to promote HR repair., Conclusions: Taken together, these findings demonstrate that the FZD5-ALDH1A1-Akt pathway is responsible for OC cell survival, and targeting this pathway can sensitize OC cells to DNA damage-based therapy., (© 2024. The Author(s).)

In the ALDH2 rs671 variant, a guanine changes to an adenine, resulting in a dramatic decrease in the catalytic activity of the enzyme. Population-based data are contradictory about whether this variant increases the risk of Alzheimer's disease. In East Asian populations, the prevalence of the ALDH2 rs671 variant is 30-50%, making the National Human Brain Bank for Development and Function (the largest brain bank in East Asia) an important resource to explore the link between the ALDH2 rs671 polymorphism and Alzheimer's disease pathology. Here, using 469 postmortem brains, we find that while the ALDH2 rs671 variant is associated with increased plaque deposits and a higher Aβ40/42 ratio, it is not an independent risk factor for Alzheimer's disease. Mechanistically, we show that lower ALDH2 activity leads to 4-HNE accumulation in the brain. The (R)-4-HNE enantiomer adducts to residue Lys53 of C99, favoring Aβ40 generation in the Golgi apparatus. Decreased ALDH2 activity also lowers inflammatory factor secretion, as well as amyloid β phagocytosis and spread in brains of patients with Alzheimer's disease. We thus define the relationship between the ALDH2 rs671 polymorphism and amyloid β pathology, and find that ALDH2 rs671 is a key regulator of Aβ40 or Aβ42 generation., (© 2024. The Author(s).)

Purpose: DNA methylation causes silencing of tumor-suppressor and differentiation-associated genes, being linked to chemoresistance. Previous studies demonstrated that hypomethylating agents (HMA) resensitize ovarian cancer to chemotherapy. NTX-301 is a highly potent and orally bioavailable HMA, in early clinical development., Experimental Design: The antitumor effects of NTX-301 were studied in ovarian cancer models by using cell viability, stemness and ferroptosis assays, RNA sequencing, lipidomic analyses, and stimulated Raman spectroscopy., Results: Ovarian cancer cells (SKOV3, IC50 = 5.08 nmol/L; OVCAR5 IC50 = 3.66 nmol/L) were highly sensitive to NTX-301 compared with fallopian tube epithelial cells. NTX-301 downregulated expression of DNA methyltransferases 1-3 and induced transcriptomic reprogramming with 15,000 differentially expressed genes (DEG, P < 0.05). Among them, Gene Ontology enrichment analysis identified regulation of fatty acid biosynthesis and molecular functions related to aldehyde dehydrogenase (ALDH) and oxidoreductase, known features of cancer stem cells. Low-dose NTX-301 reduced the ALDH(+) cell population and expression of stemness-associated transcription factors. Stearoyl-coenzyme A desaturase 1 (SCD), which regulates production of unsaturated fatty acids (UFA), was among the top DEG downregulated by NTX-301. NTX-301 treatment decreased levels of UFA and increased oxidized lipids, and this was blunted by deferoxamine, indicating cell death via ferroptosis. NTX-301-induced ferroptosis was rescued by oleic acid. In vivo, monotherapy with NTX-301 significantly inhibited ovarian cancer and patient-derived xenograft growth (P < 0.05). Decreased SCD levels and increased oxidized lipids were detected in NTX-301-treated xenografts., Conclusions: NTX-301 is active in ovarian cancer models. Our findings point to a new mechanism by which epigenetic blockade disrupts lipid homeostasis and promotes cancer cell death., (©2024 American Association for Cancer Research.)

Ethnopharmacological Relevance: The dried fruit and peduncle of Hovenia dulcis Thunberg (Rhamnaceae) (HD) has been used as a folk medicine to treat liver disease, detoxify alcoholism, and prevent and cure hangovers., Aim of the Study: We investigated the pharmacology of HD on the kinetics of EtOH and on the enzymes related to alcohol metabolism to seek the scientific evidence of HD to prevent hangover, the effectiveness as a folk medicine., Materials and Methods: EtOH was orally administered 30 min after oral administration of HD boiling water extract in rats. Then, the profiles of blood EtOH concentrations were measured. Mice were reared with food containing powdered HD for 7 days, and the activities of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) in liver were measured. Hepa1c1c7 cells were cultured with the medium containing HD extract, and the activities of ADH and ALDH were measured., Results: HD extract reduced the blood EtOH concentrations in rats and induced the activities of ADH and ALDH and mRNA and protein expressions of ADH1B, ALDH1A1, and ALDH2 in the liver of mice and Hepa1c1c7 cells. Dihydromyricetin, one of the ingredients of HD, significantly induced the activities of ADH and ALDH in Hepa1c1c7 cells, however, the fractions containing hydrophilic organic compounds with small molecular weight contributed the most of the activities of HD extract., Conclusions: We clarified the experimental pharmacological evidences of HD as a folk medicine to detoxify alcoholism and prevent hangovers., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T.M. received grant support from Kuki Sangyo, Tsumura, Kracie Pharmaceutical, Taisho Pharmaceutical, and Kobayashi Pharmaceutical. Y.S. and T.O. are the employees of Matsuura Yakugyo., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The alcohol metabolite acetaldehyde is a potent human carcinogen linked to esophageal squamous cell carcinoma (ESCC) initiation and development. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulation causes genotoxic stress in cells expressing the dysfunctional ALDH2E487K dominant negative mutant protein linked to ALDH2*2, the single nucleotide polymorphism highly prevalent among East Asians. Heterozygous ALDH2*2 increases the risk for the development of ESCC and other alcohol-related cancers. Despite its prevalence and link to malignant transformation, how ALDH2 dysfunction influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three-dimensional organoids and xenograft models. We find that alcohol exposure and ALDH2*2 cooperate to increase putative ESCC cancer stem cells with high CD44 expression (CD44H cells) linked to tumor initiation, repopulation and therapy resistance. Concurrently, ALHD2*2 augmented alcohol-induced reactive oxygen species and DNA damage to promote apoptosis in the non-CD44H cell population. Pharmacological activation of ALDH2 by Alda-1 inhibits this phenotype, suggesting that acetaldehyde is the primary driver of these changes. Additionally, we find that Aldh2 dysfunction affects the response to cisplatin, a chemotherapeutic commonly used for the treatment of ESCC. Aldh2 dysfunction facilitated enrichment of CD44H cells following cisplatin-induced oxidative stress and cell death in murine organoids, highlighting a potential mechanism driving cisplatin resistance. Together, these data provide evidence that ALDH2 dysfunction accelerates ESCC pathogenesis through enrichment of CD44H cells in response to genotoxic stressors such as environmental carcinogens and chemotherapeutic agents., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Progression of β-cell loss in diabetes mellitus is significantly influenced by persistent hyperglycemia. At the cellular level, a number of signaling cascades affect the expression of apoptotic genes, ultimately resulting in β-cell failure; these cascades have not been elucidated. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays a central role in the detoxification of reactive aldehydes generated from endogenous and exogenous sources and protects against mitochondrial deterioration in cells. Here we report that under diabetogenic conditions, ALDH2 is strongly inactivated in β-cells through CDK5-dependent glutathione antioxidant imbalance by glucose-6-phosphate dehydrogenase (G6PD) degradation. Intriguingly, CDK5 inhibition strengthens mitochondrial antioxidant defense through ALDH2 activation. Mitochondrial ALDH2 activation selectively preserves β-cells against high-glucose-induced dysfunction by activating AMPK and Hydrogen Sulfide (H 2 S) signaling. This is associated with the stabilization and enhancement of the activity of G6PD by SIRT2, a cytoplasmic NAD + -dependent deacetylase, and is thereby linked to an elevation in the GSH/GSSG ratio, which leads to the inhibition of mitochondrial dysfunction under high-glucose conditions. Furthermore, treatment with NaHS, an H 2 S donor, selectively preserves β-cell function by promoting ALDH2 activity, leading to the inhibition of lipid peroxidation by high-glucose concentrations. Collectively, our results provide the first direct evidence that ALDH2 activation enhances H 2 S-AMPK-G6PD signaling, leading to improved β-cell function and survival under high-glucose conditions via the glutathione redox balance., Competing Interests: Declaration of competing interest Authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Pyrroloquinoline quinone (PQQ) is one of the important coenzymes in living organisms. In acetic acid bacteria (AAB), it plays a crucial role in the alcohol respiratory chain, as a coenzyme of alcohol dehydrogenase (ADH). In this work, the PQQ biosynthetic genes were overexpressed in Acetobacter pasteurianus CGMCC 3089 to improve the fermentation performance. The result shows that the intracellular and extracellular PQQ contents in the recombinant strain A. pasteurianus (pBBR1-p264-pqq) were 152.53% and 141.08% higher than those of the control A. pasteurianus (pBBR1-p264), respectively. The catalytic activity of ADH and aldehyde dehydrogenase increased by 52.92% and 67.04%, respectively. The results indicated that the energy charge and intracellular ATP were also improved in the recombinant strain. The acetic acid fermentation was carried out using a 5 L self-aspirating fermenter, and the acetic acid production rate of the recombinant strain was 23.20% higher compared with the control. Furthermore, the relationship between the PQQ and acetic acid tolerance of cells was analyzed. The biomass of recombinant strain was 180.2%, 44.3%, and 38.6% higher than those of control under 2%, 3%, and 4% acetic acid stress, respectively. After being treated with 6% acetic acid for 40 min, the survival rate of the recombinant strain was increased by 76.20% compared with the control. Those results demonstrated that overexpression of PQQ biosynthetic genes increased the content of PQQ, therefore improving the acetic acid fermentation and the cell tolerance against acetic acid by improving the alcohol respiratory chain and energy metabolism., One Sentence Summary: The increase in PQQ content enhances the activity of the alcohol respiratory chain of Acetobacter pasteurianus, and the increase in energy charge enhances the tolerance of cells against acetic acid, therefore, improving the efficiency of acetic acid fermentation., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society of Industrial Microbiology and Biotechnology.)

Rationale: Current therapies for metastatic osseous disease frequently fail to provide a durable treatment response. To date, there are only limited therapeutic options for metastatic prostate cancer, the mechanisms that drive the survival of metastasis-initiating cells are poorly characterized, and reliable prognostic markers are missing. A high aldehyde dehydrogenase (ALDH) activity has been long considered a marker of cancer stem cells (CSC). Our study characterized a differential role of ALDH1A1 and ALDH1A3 genes as regulators of prostate cancer progression and metastatic growth. Methods: By genetic silencing of ALDH1A1 and ALDH1A3 in vitro , in xenografted zebrafish and murine models, and by comparative immunohistochemical analyses of benign, primary tumor, and metastatic specimens from patients with prostate cancer, we demonstrated that ALDH1A1 and ALDH1A3 maintain the CSC phenotype and radioresistance and regulate bone metastasis-initiating cells. We have validated ALDH1A1 and ALDH1A3 as potential biomarkers of clinical outcomes in the independent cohorts of patients with PCa. Furthermore, by RNAseq, chromatin immunoprecipitation (ChIP), and biostatistics analyses, we suggested the molecular mechanisms explaining the role of ALDH1A1 in PCa progression. Results: We found that aldehyde dehydrogenase protein ALDH1A1 positively regulates tumor cell survival in circulation, extravasation, and metastatic dissemination, whereas ALDH1A3 plays the opposite role. ALDH1A1 and ALDH1A3 are differentially expressed in metastatic tumors of patients with prostate cancer, and their expression levels oppositely correlate with clinical outcomes. Prostate cancer progression is associated with the increasing interplay of ALDH1A1 with androgen receptor (AR) and retinoid receptor (RAR) transcriptional programs. Polo-like kinase 3 (PLK3) was identified as a transcriptional target oppositely regulated by ALDH1A1 and ALDH1A3 genes in RAR and AR-dependent manner. PLK3 contributes to the control of prostate cancer cell proliferation, migration, DNA repair, and radioresistance. ALDH1A1 gain in prostate cancer bone metastases is associated with high PLK3 expression. Conclusion: This report provides the first evidence that ALDH1A1 and PLK3 could serve as biomarkers to predict metastatic dissemination and radiotherapy resistance in patients with prostate cancer and could be potential therapeutic targets to eliminate metastasis-initiating and radioresistant tumor cell populations., Competing Interests: Competing Interests: In the past 5 years, Dr. Mechthild Krause received funding for her research projects by IBA (2016), Merck KGaA (2014-2018 for preclinical study; 2018-2020 for clinical study), Medipan GmbH (2014-2018). In the past 5 years, Dr. Krause, Dr. Linge and Dr. Löck have been involved in an ongoing publicly funded (German Federal Ministry of Education and Research) project with the companies Medipan, Attomol GmbH, GA Generic Assays GmbH, Gesellschaft für medizinische und wissenschaftliche genetische Analysen, Lipotype GmbH and PolyAn GmbH (2019-2021). For the present manuscript, none of the above-mentioned funding sources were involved., (© The author(s).)

Here, we propose a laboratory exercise to quickly determine single nucleotide polymorphisms (SNPs) in human alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) genes involved in alcohol metabolism. In this exercise, two different genotyping methods based on polymerase chain reaction (PCR), namely allele-specific (AS) PCR and a PCR-restriction fragment polymorphism (RFLP) analysis, can be performed under the same PCR program (2-step × 35 cycles, 35 min total) in parallel using a hair root lysate as a template. In AS-PCR, the target regions of the G- or A-alleles of both genes are allele-specifically amplified in a single PCR tube. In the PCR-RFLP analysis, the two genes are amplified simultaneously in a single tube, and then a portion of the PCR product is double-digested with restriction enzymes MslI and Eam1104I for 5 min. The resulting reaction products of each method are electrophoresed side by side, and the genotypes are determined from the DNA band patterns. With the optimized protocol, the whole process from template preparation to genotyping can be completed in about 75 min. During PCR, students also perform an ethanol patch test to estimate their ability to metabolize alcohol. This series of experiments can help students learn the principles and applications of PCR/SNP analyses. By comparing the genotypes revealed by PCR and the phenotypes revealed by the patch tests, students can gain a better understanding of the clinical value of genetic testing., (© 2023 International Union of Biochemistry and Molecular Biology.)

The white spot syndrome virus (WSSV) is the most lethal virus that infect shrimps, generating economic losses for aquaculture industry. Osmotic stress compromises the immune response in WSSV-infected shrimp. Betaine aldehyde dehydrogenase (BADH E.C. 1.2.1.8) is an enzyme that participates in the regulation of osmotic stress, and that is up-regulated in shrimp exposed to changes in salinity concentration. However, different gene expression studies in shrimp during WSSV infection focused in changes on the mechanisms of energy production and cellular defense genes, without considering genes sensitive to osmotic variation. In this work, we evaluate the mRNA levels and activity of the BADH enzyme, as well as glycine betaine (GB) accumulation, during WSSV infection in white shrimp. Shrimps were inoculated with WSSV and samples from the hepatopancreas were collected at 24 and 48 h post-infection. Our results demonstrate that WSSV infection increases the expression of BADH 1.5-fold at 48h and the enzyme activity increase 4.28- and 4.59-fold at 24 and 48 h, respectively. Also, higher accumulation of GB was observed during WSSV infection. These results suggest that BADH could participate in the cellular response during WSSV infection in white shrimp. [ABSTRACT FROM AUTHOR]

Background: This research investigated the genetic characteristic of two Chinese families with keratoconus (KC)., Methods: For all people in the two families with KC, their history, clinical data, and peripheral blood were collected. One hundred healthy participants without KC and 112 sporadic KC patients were recruited as the controls. Whole exome sequencing of the genomic DNA and polymerase chain reaction were conducted for all the controls and family members to verify the variants. Functional analyses of the variants was performed using the software programs., Results: A missense tuberous sclerosis 1 (TSC1) variant g.135797247A > G (c.622A > G, p.Ser208Gly) was detected in family 1. A single nucleotide polymorphism (SNP) rs761232139 (p.Gly235Arg) in aldehyde dehydrogenase 3 family member A1 (ALDH3A1) gene was detected in family 2. The variant c.622A > G in TSC1 and the SNP rs761232139 in ALDH3A1 were predicted as being probably damaging., Conclusions: Novel variant c.622A > G in TSC1 and SNP rs761232139 in ALDH3A1 have been detected in families with KC. These two findings may play a role in the pathogenesis of KC., (© 2023. The Author(s).)

Sodium glucose-cotransporter 2 (SGLT2) inhibitors have been reported to reduce cardiovascular events and heart failure in people with and without diabetes. These medications have been shown to counter regenerative cell exhaustion in the context of prevalent diabetes. This study sought to determine if empagliflozin attenuates regenerative cell exhaustion in people without diabetes. Peripheral blood mononuclear cells were collected at the baseline and 6-mo visits from individuals randomized to receive empagliflozin (10 mg/day) or placebo who were participating in the EMPA-HEART 2 CardioLink-7 trial. Precursor cell phenotypes were characterized by flow cytometry for cell-surface markers combined with high aldehyde dehydrogenase activity to identify precursor cell subsets with progenitor (ALDH hi ) versus mature effector (ALDH low ) cell attributes. Samples from individuals assigned to empagliflozin ( n = 25) and placebo ( n = 21) were analyzed. At baseline, overall frequencies of primitive progenitor cells (ALDH hi SSC low ), monocyte (ALDH hi SSC mid ), and granulocyte (ALDH hi SSC hi ) precursor cells in both groups were similar. At 6 mo, participants randomized to empagliflozin demonstrated increased ALDH hi SSC low CD133 + CD34 + proangiogenic cells ( P = 0.048), elevated ALDH hi SSC mid CD163 + regenerative monocyte precursors ( P = 0.012), and decreased ALDH hi SSC mid CD86  +  CD163 - proinflammatory monocyte ( P = 0.011) polarization compared with placebo. Empagliflozin promoted the recovery of multiple circulating provascular cell subsets in people without diabetes suggesting that the cardiovascular benefits of SGLT2 inhibitors may be attributed in part to the attenuation of vascular regenerative cell exhaustion that is independent of diabetes status. NEW & NOTEWORTHY Using an aldehyde dehydrogenase (ALDH) activity-based flow cytometry assay, we found that empagliflozin treatment for 6 mo was associated with parallel increases in circulating vascular regenerative ALDH hi -CD34/CD133-coexpressing progenitors and decreased proinflammatory ALDH hi -CD14/CD86-coexpressing monocyte precursors in individuals without diabetes but with cardiovascular risk factors. The rejuvenation of the vascular regenerative cell reservoir may represent a mechanism via which sodium glucose-cotransporter 2 (SGLT2) inhibitors limit maladaptive repair and delay the development and progression of cardiovascular diseases.

Inborn errors of metabolism are a diverse group of genetic disorders including many that cause neonatal-onset epilepsy such as pyridoxine-dependent epilepsy (PDE). PDE occurs secondary to biallelic pathogenic variants in ALDH7A1 and can present with refractory neonatal seizures and status epilepticus. Neonatal seizures and encephalopathy are modifiable with pyridoxine (vitamin B6) supplementation. However, the clinical response to pyridoxine supplementation can be delayed. We present the case of a full-term neonate with PDE in which seizure cessation was seen a few hours after intravenous pyridoxine load, but the improvement in EEG background and level of clinical encephalopathy occurred 5 days later. We share this case to provide an example in which clinical improvement in PDE was gradual and required continuation of treatment for several days illustrating the necessity of continuing vitamin B6 supplementation in suspected cases until confirmatory genetic testing is obtained or an alternate cause is found., (© 2023 American Academy of Neurology.)

The receptor protein PEX5, an important component of peroxisomes, regulates growth, development, and immunity in yeast and mammals. PEX5 also influences growth and development in plants, but whether it participates in plant immunity has remained unclear. Here, we report that knockdown of OsPEX5 enhances resistance to the rice blast fungus Magnaporthe oryzae. We demonstrate that OsPEX5 interacts with the E3 ubiquitin ligase APIP6, a positive regulator of plant immunity. APIP6 ubiquitinates OsPEX5 in vitro and promotes its degradation in vivo via the 26S proteasome pathway. In addition, OsPEX5 interacts with the aldehyde dehydrogenase OsALDH2B1, which functions in growth-defense trade-offs in rice. OsPEX5 stabilizes OsALDH2B1 to enhance its repression of the defense-related gene OsAOS2. Our study thus uncovers a previously unrecognized hierarchical regulatory mechanism in which an E3 ubiquitin ligase targets a peroxisome receptor protein that negatively regulates immunity in rice by stabilizing an aldehyde dehydrogenase that suppresses defense gene expression., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

As part of our studies of yeast aldehyde dehydrogenase (Ald4p) assembly, we identified a population of transformants (SWORD strain) that show more robust filament formation of GFP-tagged Ald4p (Ald4p-GFP) than that of a wild type ALD4::GFP strain. Sequencing of the ALD4 gene in the SWORD strain showed that the increased assembly was not due to changes to the ALD4 coding sequence, suggesting that a second mutation site was altering Ald4p assembly. Using short-read whole-genome sequencing, we identified spontaneous mutations in FLO9. Introduction of the SWORD allele of FLO9 into a wild-type ALD4::GFP yeast strain revealed that the changes to FLO9 were a contributor to the increased length of Ald4p-GFP filaments we observe in the SWORD strain and that this effect was not due to an increase in Ald4p protein levels. However, the expression of the FLO9 (SWORD) allele in wild-type yeast did not fully recapitulate the length control defect we observed in SWORD strains, arguing that there are additional genes contributing to the filament length phenotype. For our future work, this FLO9 from SWORD will be tested whether it could show global effect, promoting the assembly of some other filament-forming enzymes., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Introduction: Physiological and pathophysiological effects arising from detoxification of aldehydes in humans implicate the enzyme aldehyde dehydrogenase (ALDH) gene family comprising of 19 isoforms. The main function of this enzyme family is to metabolize reactive aldehydes to carboxylic acids. Dysregulation of ALDH activity has been associated with various diseases. Extensive research has since gone into studying ALHD isozymes, their structural biology and developing small-molecule inhibitors. Novel chemical strategies to enhance the selectivity of ALDH inhibitors have now appeared., Areas Covered: A comprehensive review of patent literature related to aldehyde dehydrogenase inhibitors in the last decade and half (2007-2022) is provided., Expert Opinion: Aldehyde dehydrogenase (ALDH) is an important enzyme that metabolizes reactive exogenous and endogenous aldehydes in the body through NAD(P)±dependent oxidation. Hence this family of enzymes possess important physiological as well as toxicological roles in human body. Significant efforts in the field have led to potent inhibitors with approved clinical agents for alcohol use disorder therapy. Further clinical translation of novel compounds targeting ALDH inhibition will validate the promised therapeutic potential in treating many human diseases.The scientific/patent literature has been searched on SciFinder-n, Reaxys, PubMed, Espacenet and Google Patents. The search terms used were 'ALDH inhibitors', 'Aldehyde Dehydrogenase Inhibitors'.

Colon cancer is the third leading cause of cancer death globally. Although early screenings and advances in treatments have reduced mortality since 1970, identification of novel targets for therapeutic intervention is needed to address tumor heterogeneity and recurrence. Previous work identified aldehyde dehydrogenase 1B1 (ALDH1B1) as a critical factor in colon tumorigenesis. To investigate further, we utilized a human colon adenocarcinoma cell line (SW480) in which the ALDH1B1 protein expression has been knocked down by 80% via shRNA. Through multi-omics (transcriptomics, proteomics, and untargeted metabolomics) analysis, we identified the impact of ALDH1B1 knocking down (KD) on molecular signatures in colon cancer cells. Suppression of ALDH1B1 expression resulted in 357 differentially expressed genes (DEGs), 191 differentially expressed proteins (DEPs) and 891 differentially altered metabolites (DAMs). Functional annotation and enrichment analyses revealed that: (1) DEGs were enriched in integrin-linked kinase (ILK) signaling and growth and development pathways; (2) DEPs were mainly involved in apoptosis signaling and cellular stress response pathways; and (3) DAMs were associated with biosynthesis, intercellular and second messenger signaling. Collectively, the present study provides new molecular information associated with the cellular functions of ALDH1B1, which helps to direct future investigation of colon cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ying Chen, Vasilis Vasiliou reports financial support was provided by National Institutes of Health., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Obesity and type 2 diabetes have reached pandemic proportion. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal. A missense Glu504Lys mutation of the ALDH2 gene is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We find that male Aldh2 knock-in mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver due to reduced adaptive thermogenesis and energy expenditure. We find reduced activity of ALDH2 of the brown adipose tissue from the male Aldh2 homozygous knock-in mice. Proteomic analyses of the brown adipose tissue from the male Aldh2 knock-in mice identifies increased 4-hydroxynonenal-adducted proteins involved in mitochondrial fatty acid oxidation and electron transport chain, leading to markedly decreased fatty acid oxidation rate and mitochondrial respiration of brown adipose tissue, which is essential for adaptive thermogenesis and energy expenditure. AD-9308 is a water-soluble, potent, and highly selective ALDH2 activator. AD-9308 treatment ameliorates diet-induced obesity and fatty liver, and improves glucose homeostasis in both male Aldh2 wild-type and knock-in mice. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for metabolic diseases., (© 2023. Springer Nature Limited.)

Aldehyde dehydrogenase 3A1 (ALDH3A1) is an NAD + -dependent enzyme that is closely related to tumor development. However, its role in non-small-cell lung cancer (NSCLC) has not been elucidated. This study aimed to clarify the mechanism of ALDH3A1 and identify potential therapeutic targets for NSCLC. Here, for the first time, we found that ALDH3A1 expression could be induced by a hypoxic environment in NSCLC. ALDH3A1 was highly expressed in NSCLC tissue, especially in some late-stage patients, and was associated with a poor prognosis. In mechanistic terms, ALDH3A1 enhances glycolysis and suppresses oxidative phosphorylation (OXPHOS) to promote cell proliferation by activating the HIF-1α/LDHA pathway in NSCLC. In addition, the results showed that ALDH3A1 was a target of β-elemene. ALDH3A1 can be downregulated by β-elemene to inhibit glycolysis and enhance OXPHOS, thus suppressing NSCLC proliferation in vitro and in vivo. In conclusion, hypoxia-induced ALDH3A1 is related to the energy metabolic status of tumors and the efficacy of β-elemene, providing a new theoretical basis for better clinical applications in NSCLC., (© 2023. The Author(s).)

It has been previously shown that the aldehyde dehydrogenase ( ALDH ) family member ALDH1A1 has a significant association with acute myeloid leukemia (AML) patient risk group classification and that AML cells lacking ALDH1A1 expression can be readily killed via chemotherapy. In the past, however, a redundancy between the activities of subgroup members of the ALDH family has hampered the search for conclusive evidence to address the role of specific ALDH genes. Here, we describe the bioinformatics evaluation of all nineteen member genes of the ALDH family as prospective actionable targets for the development of methods aimed to improve AML treatment. We implicate ALDH1A1 in the development of recurrent AML, and we show that from the nineteen members of the ALDH family, ALDH1A1 and ALDH2 have the strongest association with AML patient risk group classification. Furthermore, we discover that the sum of the expression values for RNA from the genes, ALDH1A1 and ALDH2 , has a stronger association with AML patient risk group classification and survival than either one gene alone does. In conclusion, we identify ALDH1A1 and ALDH2 as prospective actionable targets for the treatment of AML in high-risk patients. Substances that inhibit both enzymatic activities constitute potentially effective pharmaceutics.

Aldehyde dehydrogenase (ALDH) superfamily, comprising enzymes dependent on NAD + or NADP + , plays an important role in controlling plant growth and development, as well as in responsing to phytohormone and environmental stress. These enzymes possess the ability to prevent toxic effects of aldehydes by converting them into their corresponding carboxylic acids. However, the potential function of ALDH genes in moso bamboo (Phyllostachys edulis) remains largely unknown. In this study, the ALDH gene superfamily in moso bamboo was analyzed through genome-wide screening, the evolutionary relationship of expansion genes was conducted. Tissue-specific expression patterns of ALDH genes were observed in 26 different tissues. Plant hormone and environmental stress responsive cis-elements were identified in the promoter of ALDH genes, which were supported by public databases data on the expression patterns under various abiotic stresses and hormone treatments. ALDH activity was increased in moso bamboo seedlings exposed to drought, compared to control condition. Furthermore, PeALDH2B2 was found to physically interact with PeGPB1 in response to drought. Overall, the study provides a comprehensive analysis of the ALDH family in moso bamboo and contributes to our understanding of the function of ALDH genes in growth, development, and adaptation to drought stresses., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)