Explore the vast range of titles available.

The present article describes the successful performance of crossed aldol reactions of the CF[sub.3]-containing pseudo-C[sub.2] symmetric cyclic imide with various aldehydes. The utilization of HMPA as an additive attained the preferential formation of the anti-products in good to excellent yields, which contrasts with our previous method without this additive, proceeding to furnish the corresponding syn-isomers. The effective participation of ketones and α,β-unsaturated carbonyl compounds in reactions with this imide was also demonstrated to expand the application of this imide.

Rate coefficients for the reaction of NO.sub.3 radicals with a series of aromatic aldehydes were measured in a 7300 L simulation chamber at ambient temperature and pressure by relative and absolute methods. The rate coefficients for benzaldehyde (BA), ortho-tolualdehyde (O-TA), meta-tolualdehyde (M-TA), para-tolualdehyde (P-TA), 2,4-dimethyl benzaldehyde (2,4-DMBA), 2,5-dimethyl benzaldehyde (2,5-DMBA) and 3,5-dimethyl benzaldehyde (3,5-DMBA) were k.sub.1 = 2.6 ± 0.3, k.sub.2 = 8.7 ± 0.8, k.sub.3 = 4.9 ± 0.5, k.sub.4 = 4.9 ± 0.4, k.sub.5 = 15.1 ± 1.3, k.sub.6 = 12.8 ± 1.2 and k.sub.7 = 6.2 ± 0.6, respectively, in the units of 10.sup.-15 cm.sup.3 molec..sup.-1 s.sup.-1 at 298 ± 2 K. The rate coefficient k.sub.13 for the reaction of the NO.sub.3 radical with deuterated benzaldehyde (benzaldehyde-d.sub.1) was found to be half that of k.sub.1 . The end product of the reaction in an excess of NO.sub.2 was measured to be C.sub.6 H.sub.5 C(O)O.sub.2 NO.sub.2 . Theoretical calculations of aldehydic bond energies and reaction pathways indicate that the NO.sub.3 radical reacts primarily with aromatic aldehydes through the abstraction of an aldehydic hydrogen atom. The atmospheric implications of the measured rate coefficients are briefly discussed.

Introduction and objective:Formaldehyde is a common toxic substance in the environment, formed both naturally and as a result of human activity. Due to its widespread use, it can pose a threat to a significant portion of the population. The aim of this study was to analyze scientific research on environmental exposure to formaldehyde and its effects on human health.Abbreviated description of the state of knowledge:The concentration of formaldehyde in indoor air of buildings reaches much higher values than in the open air. It most often enters the human body through the respiratory tract, less often through the skin. Formaldehyde can be one of the causes of sick building syndrome or non-specific building-related health symptoms. Occupational exposure to formaldehyde most often affects workers in the health care, factory, construction and garment industries. The results of the study analysis suggest that formaldehyde exposure may be associated with a higher risk of cancer, especially nasopharyngeal cavity cancer and leukemia. Formaldehyde exposure can also cause the development of asthma in both children and adults, as well as some brain diseases.Summary:Many workers, by virtue of their occupation, are exposed to concentrations of formaldehyde that exceed permissible levels. This can become the cause of the development of many diseases. Adequate education of workers, provision of protective measures, and exposure prevention systems can reduce the risk of adverse health effects.

Aldehyde dehydrogenases (ALDHs) are multifunctional enzymes that oxidize diverse endogenous and exogenous aldehydes. We conducted a meta-analysis based on The Cancer Genome Atlas and Gene Expression Omnibus data and detected genetic alterations in ALDH1A1, ALDH1A3, or ALDH3A1, 86% of which were gene amplification or mRNA upregulation, in 31% of nonsmall cell lung cancers (NSCLCs). The expression of these isoenzymes impacted chemoresistance and shortened survival times in patients. We hypothesized that these enzymes provide an oxidative advantage for the persistence of NSCLC. To test this hypothesis, we used genetic and pharmacological approaches with DIMATE, an irreversible inhibitor of ALDH1/3. DIMATE showed cytotoxicity in 73% of NSCLC cell lines tested and demonstrated antitumor activity in orthotopic xenografts via hydroxynonenal-protein adduct accumulation, GSTO1-mediated depletion of glutathione and increased H2O2. Consistent with this result, ALDH1/3 disruption synergized with ROS-inducing agents or glutathione synthesis inhibitors to trigger cell death. In lung cancer xenografts with high to moderate cisplatin resistance, combination treatment with DIMATE promoted strong synergistic responses with tumor regression. These results indicate that NSCLCs with increased expression of ALDH1A1, ALDH1A3, or ALDH3A1 may be targeted by strategies involving inhibitors of these isoenzymes as monotherapy or in combination with chemotherapy to overcome patient-specific drug resistance.

Aldehyde dehydrogenases (ALDHs) are promising cancer drug targets, as certain isoforms are required for the survival of stem-like tumor cells. We have discovered selective inhibitors of ALDH1B1, a mitochondrial enzyme that promotes colorectal and pancreatic cancer. We describe bicyclic imidazoliums and guanidines that target the ALDH1B1 active site with comparable molecular interactions and potencies. Both pharmacophores abrogate ALDH1B1 function in cells; however, the guanidines circumvent an off-target mitochondrial toxicity exhibited by the imidazoliums. Our lead isoform-selective guanidinyl antagonists of ALDHs exhibit proteome-wide target specificity, and they selectively block the growth of colon cancer spheroids and organoids. Finally, we have used genetic and chemical perturbations to elucidate the ALDH1B1-dependent transcriptome, which includes genes that regulate mitochondrial metabolism and ribosomal function. Our findings support an essential role for ALDH1B1 in colorectal cancer, provide molecular probes for studying ALDH1B1 functions and yield leads for developing ALDH1B1-targeting therapies.Aldehyde dehydrogenase 1B1-specific small-molecule inhibitors are identified that block the growth of colon cancer spheroids and organoids and are shown to potentially regulate mitochondrial metabolism and ribosomal function.

Reactive aldehydes are common carcinogens. They are also by-products of several metabolic pathways and, without enzymatic catabolism, may accumulate and cause DNA damage. Ethanol, which is metabolised to acetaldehyde, is both carcinogenic and teratogenic in humans. Here we find that the Fanconi anaemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Our results show that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd2 −/− embryos. Nevertheless, acetaldehyde-catabolism-competent mothers ( Aldh2 +/− ) can support the development of double-mutant ( Aldh2 −/− Fancd2 −/− ) mice. However, these embryos are unusually sensitive to ethanol exposure in utero , and ethanol consumption by postnatal double-deficient mice rapidly precipitates bone marrow failure. Lastly, Aldh2 −/− Fancd2 −/− mice spontaneously develop acute leukaemia. Acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well as to abnormal development, haematopoietic failure and cancer predisposition in Fanconi anaemia patients. Aldehyde toxicity in Fanconi anaemia Individuals with Fanconi anaemia exhibit developmental defects, stem-cell failure and a strong predisposition to leukaemia. Cells derived from patients with Fanconi anaemia are susceptible to DNA damage caused by DNA crosslinking agents such as cisplatin and mitomycin C. These are cancer chemotherapeutics, so cells are not normally exposed to them, prompting the question: what is the natural source of DNA damage repaired by this pathway? Experiments with mice deficient in Fancd2 (one of several Fanconi anaemia genes) and Aldh2 (which encodes an enzyme that detoxifies aldehydes) suggest that acetaldehyde is an endogenous source of DNA damage in Fanconi anaemia, contributing to cancer predisposition and haematopoeitic failure. Intriguingly, these mouse models also suggest a possible mechanism for the damaging effects of fetal alcohol exposure during pregnancy.

We have reported one-pot, three-component Mannich type reaction of aldehyde, amines and ketone (acetone and acetophenones), catalyzed by deep eutectic solvent (choline chloride/zinc chloride) at room temperature to give [beta]-amino carbonyls in good yields. The catalyst could be recycled at least four times without remarkable decrease in its catalytic activity. The general method is easy, fast and environmental friendly.

The function of haematopoietic stem and progenitor cells is impaired by damaged DNA; here, endogenously generated aldehydes are found to be one source of such damage, which is repaired by the Fanconi anaemia pathway. Bone-marrow failure in Fanconi anaemia Haematopoietic stem cells handle DNA-damage stress through enzymatic detoxification and DNA repair. Dismantling both protective mechanisms predisposes mice to leukaemia and susceptibility to exogenous aldehyde. Ketan Patel and colleagues now show that even if these mice escape leukaemia, they spontaneously develop features of Fanconi anaemia, such as aplastic anaemia and bone-marrow failure. The authors find that Aldh2 is the key enzyme protecting haematopoietic stem and progenitor cells from endogenous aldehyde toxicity. This genomic protection mechanism is dispensable in the more mature blood cells. These findings suggest that bone-marrow failure in Fanconi anaemia results from aldehyde-mediated genotoxicity in the haematopoietic stem- and progenitor-cell pool. Haematopoietic stem cells (HSCs) regenerate blood cells throughout the lifespan of an organism. With age, the functional quality of HSCs declines, partly owing to the accumulation of damaged DNA 1 , 2 , 3 . However, the factors that damage DNA and the protective mechanisms that operate in these cells are poorly understood. We have recently shown that the Fanconi anaemia DNA-repair pathway counteracts the genotoxic effects of reactive aldehydes 4 , 5 . Mice with combined inactivation of aldehyde catabolism (through Aldh2 knockout) and the Fanconi anaemia DNA-repair pathway ( Fancd2 knockout) display developmental defects, a predisposition to leukaemia, and are susceptible to the toxic effects of ethanol—an exogenous source of acetaldehyde 4 . Here we report that aged Aldh2 −/− Fancd2 −/− mutant mice that do not develop leukaemia spontaneously develop aplastic anaemia, with the concomitant accumulation of damaged DNA within the haematopoietic stem and progenitor cell (HSPC) pool. Unexpectedly, we find that only HSPCs, and not more mature blood precursors, require Aldh2 for protection against acetaldehyde toxicity. Additionally, the aldehyde-oxidizing activity of HSPCs, as measured by Aldefluor stain, is due to Aldh2 and correlates with this protection. Finally, there is more than a 600-fold reduction in the HSC pool of mice deficient in both Fanconi anaemia pathway-mediated DNA repair and acetaldehyde detoxification. Therefore, the emergence of bone marrow failure in Fanconi anaemia is probably due to aldehyde-mediated genotoxicity restricted to the HSPC pool. These findings identify a new link between endogenous reactive metabolites and DNA damage in HSCs, and define the protective mechanisms that counteract this threat.

Aldehyde dehydrogenase 2 (ALDH2) has both dehydrogenase and esterase activity; its dehydrogenase activity is closely related to the metabolism of aldehydes produced under oxidative stress (OS). In this review, we recapitulate the enzyme activity of ALDH2 in combination with its protein structure, summarize and show the main mechanisms of ALDH2 participating in metabolism of aldehydes in vivo as comprehensively as possible; we also integrate the key regulatory mechanisms of ALDH2 participating in a variety of physiological and pathological processes related to OS, including tissue and organ fibrosis, apoptosis, aging, and nerve injury-related diseases. On this basis, the regulatory effects and application prospects of activators, inhibitors, and protein post-translational modifications (PTMs, such as phosphorylation, acetylation, S-nitrosylation, nitration, ubiquitination, and glycosylation) on ALDH2 are discussed and prospected. Herein, we aimed to lay a foundation for further research into the mechanism of ALDH2 in oxidative stress-related disease and provide a basis for better use of the ALDH2 function in research and the clinic.

Mammalian aldehyde oxidases (AOXs) are molybdo-flavoenzymes which are present in many tissues in various mammalian species, including humans and rodents. Different species contain a different number of AOX isoforms. In particular, the reasons why mammals other than humans express a multiplicity of tissue-specific AOX enzymes is unknown. In mouse, the isoforms mAOX1, mAOX3, mAOX4 and mAOX2 are present. We previously established a codon-optimized heterologous expression systems for the mAOX1-4 isoforms in Escherichia coli that gives yield to sufficient amounts of active protein for kinetic characterizations and sets the basis in this study for site-directed mutagenesis and structure-function studies. A direct and simultaneous comparison of the enzymatic properties and characteristics of the four enzymes on a larger number of substrates has never been performed. Here, thirty different structurally related aromatic, aliphatic and N-heterocyclic compounds were used as substrates, and the kinetic parameters of all four mAOX enzymes were directly compared. The results show that especially mAOX4 displays a higher substrate selectivity, while no major differences between mAOX1, mAOX2 and mAOX3 were identified. Generally, mAOX1 was the enzyme with the highest catalytic turnover for most substrates. To understand the factors that contribute to the substrate specificity of mAOX4, site-directed mutagenesis was applied to substitute amino acids in the substrate-binding funnel by the ones present in mAOX1, mAOX3, and mAOX2. An increase in activity was obtained by the amino acid exchange M1088V in the active site identified to be specific for mAOX4, to the amino acid identified in mAOX3.