Search Results (45)

Microbial detoxification, as an environmentally friendly strategy, has been widely applied for benzo[a]pyrene (BaP) degradation. Within this approach, food-derived microbial strains offer unique advantages in safety, specificity, and sustainability for detoxifying food-borne BaP. In this study, we aimed to explore the potential of such strains in BaP degradation. Bacillus mojavensis TC-5, a strain that degrades BaP, was isolated from kefir grains. Surprisingly, 12 genes encoding dehydrogenases, synthases, and oxygenases, including betB, fabHB, qdoI, cdoA, and bioI, which are related to BaP degradation, were up-regulated by 2.01-fold to 4.52-fold in TC-5. Two potential degradation pathways were deduced. In pathway I, dioxygenase, betaine aldehyde dehydrogenase, and beta-ketoacyl-ACP synthase III FabHB act sequentially on BaP to form 4H-pyran-4-one,2,3-dihydro-3,5-dihydroxy-6-methyl via the phthalic acid pathway. In the presence of the cytochrome P450 enzyme, BaP progressively mediates ring cleavage via the anthracene pathway, eventually forming 3-methyl-5-propylnonane in pathway II. Notably, TC-5 achieved an impressive BaP removal efficiency of up to 63.94%, with a degradation efficiency of 32.89%. These results suggest that TC-5 has significant potential for application in addressing food-borne BaP contamination. Moreover, our findings expand the application possibilities of Xinjiang fermented milk products and add to the available green strategies for BaP degradation in food systems. Full article

Diabetic cardiomyopathy (DCM) is a significant complication of diabetes, particularly affecting East Asian populations with a high prevalence of the ALDH2*2 (Glu504Lys) genetic variant. This variant impairs aldehyde detoxification, leading to increased oxidative stress, mitochondrial dysfunction, and chronic inflammation, exacerbating cardiac damage and fibrosis. This review aimed to systematically delineate the pathological role of ALDH2 enzyme deficiency in DCM by integrating clinical observations with mechanistic insights from experimental models and evaluating emerging therapies for genetically susceptible populations. In vitro and in vivo studies demonstrate that ALDH2*2 amplifies oxidative stress and disrupts mitochondrial homeostasis under hyperglycemic conditions, leading to enhanced cardiac fibrosis and functional decline. Additionally, ALDH2*2 carriers show heightened susceptibility to metabolic stress, further aggravating DCM. Given the high prevalence of ALDH2*2 in East Asian populations, targeted therapeutic strategies are urgently needed. Promising approaches include ALDH2 activators (e.g., Alda-1) that enhance detoxification of reactive aldehydes, and SGLT2 inhibitors (e.g., empagliflozin) that improve mitochondrial function and reduce oxidative damage. These therapies can mitigate oxidative stress and preserve cardiac function in ALDH2*2 carriers, thereby potentially reducing DCM burden, especially in high-risk East Asian populations. Further clinical investigations are warranted to validate these therapeutic approaches and optimize management for ALDH2-deficient individuals. Full article

Lignocellulosic biomass is widely recognized as a renewable resource for bioconversion. However, the presence of inhibitors such as furfural, 5-HMF, and acetic acid can inhibit cell growth, thereby affecting the overall efficiency of the bioconversion process. The studies on the degradation of lignocellulosic hydrolysate inhibitors by Saccharomyces cerevisiae have been limited. In this research, a yeast strain Kodamaea ohmeri can degrade inhibitors furfural, 5-HMF, and acetic acid, and the genome sequence of the strain was analyzed. Furthermore, the molecular detoxification mechanism of K. ohmeri SSK against lignocellulosic hydrolysate inhibitors was predicted using whole genome sequencing. Annotation based on the COG/KEGG databases identified 57 key detoxification genes, including the alcohol dehydrogenase (ADH) gene, aldo-keto/aldehyde reductase (AKR/ARI) gene, and aldehyde dehydrogenase (ALDH) gene. Stress tolerance experiments revealed that the maximum tolerance concentration for the strain was 5.2 g/L of furfural, 2.5 g/L of 5-HMF, and 5.9 g/L of acetic acid, respectively. A NAD(P)⁺-dependent bifunctional enzyme with possible ADH and ARI activities was found by conserved domain analysis. Phylogenetic analysis indicated that this enzyme shared 99% homology with the detoxification enzyme from S. cerevisiae S288C (GenBank: Q04894.1). This study represents the first comprehensive analysis of the inhibitor detoxification network in K. ohmeri SSK from a genome perspective, providing theoretical targets and design strategies for developing highly efficient biorefinery strains. Full article

Cancer stem cells (CSCs) account for 0.01 to 2% of the total tumor mass; however, they play a key role in tumor progression, metastasis and resistance to current cancer therapies. The generation and maintenance of CSCs are usually linked to the epithelial–mesenchymal transition (EMT), a dynamic process involved in reprogramming cancer cells towards a more aggressive and motile phenotype with increased stemness potential. Cells that undergo an EMT process have shown to be more resistant to conventional chemo/radiotherapies. In this context, aldehyde dehydrogenase (ALDH) enzymes, known for their role in the cellular detoxification of aldehydes and enhancement of cell survival, are often upregulated in cancer cells, promoting their resistance to conventional cancer treatments. Indeed, high ALDH levels have become a hallmark biomarker of CSCs and are often used to isolate this sub-population from the more abundant cancer cell populations. Herein, we isolated human breast cancer epithelial cells with higher ALDH abundance (ALDH^High) and compared them to those with low ALDH abundance (ALDH^Low). ALDH^High sub-populations exhibited more characteristic EMT biomarkers by adopting a more mesenchymal phenotype with increased stemness and enhanced migratory potential. Furthermore, ALDH^High sub-populations displayed elevated senescent markers. Moreover, these cells also demonstrated higher levels of mitochondria DNA/mass, as well as greater mitochondrial and glycolytic metabolic function. Conversely, ALDH^Low sub-populations showed a higher efficiency of mammosphere/colony formation and an increased proliferative capacity. Therefore, we demonstrated that these ALDH sub-populations have distinct characteristics, underscoring their role in EMT, the formation of tumors and the mechanisms of metastasis. Full article

Plant hormones play a central role in various physiological functions and mediate defense responses against (a)biotic stresses. Jasmonic acid (JA) has emerged as one of the key phytohormones involved in the response to necrotrophic pathogens. Under stressful conditions, plants can also produce small molecules, such as methylglyoxal (MG), a cytotoxic aldehyde. The enzymes glyoxalase I (GLYI) and glyoxalase II primarily detoxify MG. In Arabidopsis thaliana, GLYI4 has been recently characterized as having a crucial role in MG detoxification and emerging involvement in the JA pathway. Here, we investigated the impact of a GLYI4 loss-of-function on the Arabidopsis JA pathway and how MG affects it. The results showed that the glyI4 mutant plant had stunted growth, a smaller rosette diameter, reduced leaf size, and an altered pigment concentration. A gene expression analysis of the JA marker genes showed significant changes in the JA biosynthetic and signaling pathway genes in the glyI4 mutant. Disease resistance bioassays against the necrotroph Botrytis cinerea revealed altered patterns in the glyI4 mutant, likely due to increased oxidative stress. The MG effect has a further negative impact on plant performance. Collectively, these results contribute to clarifying the intricate interconnections between the GLYI4, MG, and JA pathways, opening up new avenues for further explorations of the intricate molecular mechanisms controlling plant stress responses. Full article

Aldehyde dehydrogenases (ALDHs) constitute a diverse superfamily of NAD(P)⁺-dependent enzymes pivotal in oxidizing endogenous and exogenous aldehydes to carboxylic acids. Beyond metabolic roles, ALDHs participate in essential biological processes, including differentiation, embryogenesis and the DNA damage response, while also serving as markers for cancer stem cells (CSCs). Aldehyde dehydrogenase 1B1 (ALDH1B1) is a mitochondrial enzyme involved in the detoxification of lipid peroxidation by-products and metabolism of various aldehyde substrates. This study examines the potential role of ALDH1B1 in human lung adenocarcinoma and its association with the CSC phenotype. To this end, we utilized the lung adenocarcinoma cell line A549, engineered to stably express the human ALDH1B1 protein tagged with green fluorescent protein (GFP). Overexpression of ALDH1B1 led to notable changes in cell morphology, proliferation rate and clonogenic efficiency. Furthermore, ALDH1B1-overexpressing A549 cells exhibited enhanced resistance to the chemotherapeutic agents etoposide and cisplatin. Additionally, ALDH1B1 overexpression correlated with increased migratory potential and epithelial–mesenchymal transition (EMT), mediated by the upregulation of transcription factors such as SNAI2, ZEB2 and TWIST1, alongside the downregulation of E-cadherin. Moreover, Spearman’s rank correlation coefficient analysis using data from 507 publicly available lung adenocarcinoma clinical samples revealed a significant correlation between ALDH1B1 and various molecules implicated in CSC-related signaling pathways, including Wnt, Notch, hypoxia, Hedgehog, retinoic acid, Hippo, NF-κΒ, TGF-β, PI3K/PTEN-AKT and glycolysis/gluconeogenesis. These findings provide insights into the role of ALDH1B1 in lung tumor progression and its relation to the lung CSC phenotype, thereby offering potential therapeutic targets in the clinical management of lung adenocarcinoma. Full article

Molybdenum (Mo) is an essential element for human life, acting as a cofactor in various enzymes crucial for metabolic homeostasis. This review provides a comprehensive insight into the latest advances in research on molybdenum-containing enzymes and their clinical significance. One of these enzymes is xanthine oxidase (XO), which plays a pivotal role in purine catabolism, generating reactive oxygen species (ROS) capable of inducing oxidative stress and subsequent organ dysfunction. Elevated XO activity is associated with liver pathologies such as non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Aldehyde oxidases (AOs) are also molybdenum-containing enzymes that, similar to XO, participate in drug metabolism, with notable roles in the oxidation of various substrates. However, beneath its apparent efficacy, AOs’ inhibition may impact drug effectiveness and contribute to liver damage induced by hepatotoxins. Another notable molybdenum-enzyme is sulfite oxidase (SOX), which catalyzes the conversion of sulfite to sulfate, crucial for the degradation of sulfur-containing amino acids. Recent research highlights SOX’s potential as a diagnostic marker for HCC, offering promising sensitivity and specificity in distinguishing cancerous lesions. The newest member of molybdenum-containing enzymes is mitochondrial amidoxime-reducing component (mARC), involved in drug metabolism and detoxification reactions. Emerging evidence suggests its involvement in liver pathologies such as HCC and NAFLD, indicating its potential as a therapeutic target. Overall, understanding the roles of molybdenum-containing enzymes in human physiology and disease pathology is essential for advancing diagnostic and therapeutic strategies for various health conditions, particularly those related to liver dysfunction. Further research into the molecular mechanisms underlying these enzymes’ functions could lead to novel treatments and improved patient outcomes. Full article

Aldehyde dehydrogenases (ALDHs) are a family of enzymes that aid in detoxification and are overexpressed in several different malignancies. There is a correlation between increased expression of ALDH and a poor prognosis, stemness, and resistance to several drugs. Several ALDH inhibitors have been generated due to the crucial role that ALDH plays in cancer stem cells. All of these inhibitors, however, are either ineffective, very toxic, or have yet to be subjected to rigorous testing on their effectiveness. Although various drug-like compounds targeting ALDH have been reported in the literature, none have made it to routine use in the oncology clinic. As a result, new potent, non-toxic, bioavailable, and therapeutically effective ALDH inhibitors are still needed. In this study, we designed and synthesized potent multi-ALDH isoform inhibitors based on the isatin and indazole pharmacophore. Molecular docking studies and enzymatic tests revealed that among all of the synthesized analogs, compound 3 is the most potent inhibitor of ALDH1A1, ALDH3A1, and ALDH1A3, exhibiting 51.32%, 51.87%, and 36.65% inhibition, respectively. The ALDEFLUOR assay further revealed that compound 3 acts as an ALDH broad spectrum inhibitor at 500 nM. Compound 3 was also the most cytotoxic to cancer cells, with an IC₅₀ in the range of 2.1 to 3.8 µM for ovarian, colon, and pancreatic cancer cells, compared to normal and embryonic kidney cells (IC₅₀ 7.1 to 8.7 µM). Mechanistically, compound 3 increased ROS activity due to potent multi-ALDH isoform inhibition, which increased apoptosis. Taken together, this study identified a potent multi-isoform ALDH inhibitor that could be further developed as a cancer therapeutic. Full article

Using an untargeted stable isotope-assisted metabolomics approach, we identify erythronate as a metabolite that accumulates in several human cancer cell lines. Erythronate has been reported to be a detoxification product derived from off-target glycolytic metabolism. We use chemical inhibitors and genetic silencing to define the pentose phosphate pathway intermediate erythrose 4-phosphate (E4P) as the starting substrate for erythronate production. However, following enzyme assay-coupled protein fractionation and subsequent proteomics analysis, we identify aldehyde dehydrogenase 1A1 (ALDH1A1) as the predominant contributor to erythrose oxidation to erythronate in cell extracts. Through modulating ALDH1A1 expression in cancer cell lines, we provide additional support. We hence describe a possible alternative route to erythronate production involving the dephosphorylation of E4P to form erythrose, followed by its oxidation by ALDH1A1. Finally, we measure increased erythronate concentrations in tumors relative to adjacent normal tissues from lung cancer patients. These findings suggest the accumulation of erythronate to be an example of metabolic reprogramming in cancer cells, raising the possibility that elevated levels of erythronate may serve as a biomarker of certain types of cancer. Full article

The superfamily of human aldehyde dehydrogenases (hALDHs) consists of 19 isoenzymes which are critical for several physiological and biosynthetic processes and play a major role in the organism’s detoxification via the NAD(P) dependent oxidation of numerous endogenous and exogenous aldehyde substrates to their corresponding carboxylic acids. Over the last decades, ALDHs have been the subject of several studies as it was revealed that their differential expression patterns in various cancer types are associated either with carcinogenesis or promotion of cell survival. Here, we attempt to provide a thorough review of hALDHs’ diverse functions and 3D structures with particular emphasis on their role in cancer pathology and resistance to chemotherapy. We are especially interested in findings regarding the association of structural features and their changes with effects on enzymes’ functionalities. Moreover, we provide an updated outline of the hALDHs inhibitors utilized in experimental or clinical settings for cancer therapy. Overall, this review aims to provide a better understanding of the impact of ALDHs in cancer pathology and therapy from a structural perspective. Full article

Soybeans are the main source of oils and protein for humans and animals; however, cold stress jeopardizes their growth and limits the soybean planting area. Aldehyde dehydrogenases (ALDH) are conserved enzymes that catalyze aldehyde oxidation for detoxification in response to stress. Additionally, transgenic breeding is an efficient method for producing stress-resistant germplasms. In this study, the peanut ALDH gene AhALDH2B6 was heterologously expressed in soybean, and its function was tested. We performed RNA-seq using transgenic and wild-type soybeans with and without cold treatment to investigate the potential mechanism. Transgenic soybeans developed stronger cold tolerance, with longer roots and taller stems than P3 soybeans. Biochemically, the transgenic soybeans exhibited a decrease in malondialdehyde activity and an increase in peroxidase and catalase content, both of which are indicative of stress alleviation. They also possessed higher levels of ALDH enzyme activity. Two phenylpropanoid-related pathways were specifically enriched in up-regulated differentially expressed genes (DEGs), including the phenylpropanoid metabolic process and phenylpropanoid biosynthetic process. Our findings suggest that AhALDH2B6 specifically up-regulates genes involved in oxidoreductase-related functions such as peroxidase, oxidoreductase, monooxygenase, and antioxidant activity, which is partially consistent with our biochemical data. These findings established the function of AhALDH2B6, especially its role in cold stress processes, and provided a foundation for molecular plant breeding, especially plant-stress-resistance breeding. Full article

Inhibitors from lignocellulosic biomass have become the bottleneck of biorefinery development. Gluconobacter oxydans DSM2003 showed a high performance of inhibitors degradation, which had a short lag time in non-detoxified corn stover hydrolysate and could convert 90% of aldehyde inhibitors to weaker toxic acids. In this study, an aldehyde dehydrogenase gene W826-RS0111485, which plays an important function in the conversion of aldehyde inhibitors in Gluconobacter oxydans DSM2003, was identified. W826-RS0111485 was found by protein profiling, then a series of enzymatic properties were determined and were heterologously expressed in E. coli. The results indicated that NADP is the most suitable cofactor of the enzyme when aldehyde inhibitor is the substrate, and it had the highest oxidation activity to furfural among several aldehyde inhibitors. Under the optimal reaction conditions (50 °C, pH 7.5), the Km and Vmax of the enzyme under furfural stress were 2.45 and 80.97, respectively, and the Kcat was 232.22 min⁻¹. The biodetoxification performance experiments showed that the recombinant E. coli containing the target gene completely converted 1 g/L furfural to furoic acid within 8 h, while the control E. coli only converted 18% furfural within 8 h. It was further demonstrated that W826-RS0111485 played an important role in the detoxification of furfural. The mining of this inhibitor degradation gene could provide a theoretical basis for rational modification of industrial strains to enhance its capacity of inhibitor degradation in the future. Full article

Alcohol and aldehyde dehydrogenases are especially relevant enzymes involved in metabolic and detoxification reactions that occur in living cells. The comparison between the gene expression, protein content, and enzymatic activities of cytosolic alcohol and aldehyde dehydrogenases of the wild-type strain and the Δsod1 mutant lacking superoxide dismutase 1, which is hypersensitive to alcohols and aldehydes, shows that the activity of these enzymes is significantly higher in the Δsod1 mutant, but this is not a mere consequence of differences in the enzymatic protein content nor in the expression levels of genes. The analysis of the NAD(H) and NADP(H) content showed that the higher activity of alcohol and aldehyde dehydrogenases in the Δsod1 mutant could be a result of the increased availability of pyridine nucleotide cofactors. The higher level of NAD⁺ in the Δsod1 mutant is not related to the higher level of tryptophan; in turn, a higher generation of NADPH is associated with the upregulation of the pentose phosphate pathway. It is concluded that the increased sensitivity of the Δsod1 mutant to alcohols and aldehydes is not only a result of the disorder of redox homeostasis caused by the induction of oxidative stress but also a consequence of the unbalance between pyridine nucleotide cofactors. Full article

Aldehydes, derivatives of lipids, are ubiquitously produced through non-enzymatic and enzymatic pathways in higher plants and participate in many physiological and biological processes. Increasing evidence demonstrates that aldehydes are involved in plants response to many abiotic stresses, such as light, drought, heat and nutrient deficiency. In plant cells, endogenously triggered or exogenously applied high concentrations of aldehydes can damage proteins and nucleic acid, disturb redox homeostasis, and consequently inhibit plant growth; therefore, they are considered cytotoxins. Aldehyde levels are also used as biomarkers to evaluate the health status of plants. Further genetic research shows that several enzymes have strong capacities to detoxify these electrophilic aldehydes. Small molecules, such as carnosine and glutathione, also exhibit the ability to scavenge aldehydes, effectively promoting plant growth. Recently, increasing evidence has shown that certain aldehydes at certain concentrations can upregulate survival genes, activate antioxidant responses, increase defense against pathogens and stimulate plant growth. This review summarizes recent studies of lipid-derived aldehydes in higher plants, mainly focusing on the generation pathway, toxic effects, and detoxification strategies. In addition, the signaling effects of aldehydes in plants are also discussed. Full article

To ameliorate diabetes mellitus-associated heart failure with preserved ejection fraction (HFpEF), we plan to lower diabetes-mediated oxidative stress-induced 4-hydroxy-2-nonenal (4HNE) accumulation by pharmacological agents that either decrease 4HNE generation or increase its detoxification.A cellular reactive carbonyl species (RCS), 4HNE, was significantly increased in diabetic hearts due to a diabetes-induced decrease in 4HNE detoxification by aldehyde dehydrogenase (ALDH) 2, a cardiac mitochondrial enzyme that metabolizes 4HNE. Therefore, hyperglycemia-induced 4HNE is critical for diabetes-mediated cardiotoxicity and we hypothesize that lowering 4HNE ameliorates diabetes-associated HFpEF. We fed a high-fat diet to ALDH2*2 mice, which have intrinsically low ALDH2 activity, to induce type-2 diabetes. After 4 months of diabetes, the mice exhibited features of HFpEF along with increased 4HNE adducts, and we treated them with vehicle, empagliflozin (EMP) (3 mg/kg/d) to reduce 4HNE and Alda-1 (10 mg/kg/d), and ALDH2 activator to enhance ALDH2 activity as well as a combination of EMP + Alda-1 (E + A), via subcutaneous osmotic pumps. After 2 months of treatments, cardiac function was assessed by conscious echocardiography before and after exercise stress. EMP + Alda-1 improved exercise tolerance, diastolic and systolic function, 4HNE detoxification and cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathways in ALDH2*2 mice with diabetes-associated HFpEF. This combination was even more effective than EMP alone. Our data indicate that ALDH2 activation along with the treatment of hypoglycemic agents may be a salient strategy to alleviate diabetes-associated HFpEF. Full article