Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner.

Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. We find that the HSCs in young Aldh2-/-Fancd2-/- mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition, and myeloid-biased differentiation quantified by single HSC transplantation. In addition, the p53 response is vigorously activated in Aldh2-/-Fancd2-/- HSCs, while p53 deletion rescued this aged HSC phenotype. To further define the origins of the myeloid differentiation bias, we use a GFP genetic reporter to find a striking enrichment of Vwf+ myeloid and megakaryocyte-lineage-biased HSCs. These results indicate that metabolism-derived formaldehyde-DNA damage stimulates the p53 response in HSCs to drive accelerated aging.

K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution.

Reactive aldehydes are produced by normal cellular metabolism or after alcohol consumption, and they accumulate in human tissues if aldehyde clearance mechanisms are impaired. Their toxicity has been attributed to the damage they cause to genomic DNA and the subsequent inhibition of transcription and replication. However, whether interference with other cellular processes contributes to aldehyde toxicity has not been investigated. We demonstrate that formaldehyde induces RNA-protein crosslinks (RPCs) that stall the ribosome and inhibit translation in human cells. RPCs in the messenger RNA (mRNA) are recognized by the translating ribosomes, marked by atypical K6-linked ubiquitylation catalyzed by the RING-in-between-RING (RBR) E3 ligase RNF14, and subsequently resolved by the ubiquitin- and ATP-dependent unfoldase VCP. Our findings uncover an evolutionary conserved formaldehyde-induced stress response pathway that protects cells against RPC accumulation in the cytoplasm, and they suggest that RPCs contribute to the cellular and tissue toxicity of reactive aldehydes.

Sustainable Photocatalytic Acylation of Transition Metal Dichalcogenides with Atom Economy.

Transition metal dichalcogenides (TMDs) are promising 2D nanomaterials for diverse applications, but their intrinsic chemical inertness hinders their modification. Herein, a novel approach is presented for the photocatalytic acylation of 2H-MoS2 and 2H-MoSe2, utilizing tetrabutyl ammonium decatungstate ((nBu4N)4W10O32) polyoxometalate complex as a catalyst and a conventional halogen lamp as a source of irradiation. By harnessing the semiconducting properties of TMDs, new avenues emerge for the functionalization of these materials. This novel photocatalytic protocol constitutes the first report on the chemical modification of 2D nanomaterials based on a catalytic protocol and applies to both aliphatic and aromatic substrates. The scope of the decatungstate-photocatalyzed acylation reaction of TMDs is explored by employing an alkyl and an aromatic aldehyde and the success of the methodology is confirmed by diverse spectroscopic, thermal, microscopy imaging, and redox techniques. This catalytic approach on modifying 2D nanomaterials introduces the principles of atom economy in a functionalization protocol for TMDs. It marks a transformative shift toward more sustainable and efficient methodologies in the realm of TMD modification and nanomaterial chemistry.

A Tight Contact: The Expanding Application of Salicylaldehydes in Lysine-Targeting Covalent Drugs.

The installation of aldehydes into synthetic protein ligands is an efficient strategy to engage protein lysine residues in remarkably stable imine bonds and augment the compound affinity and selectivity for their biological targets. The high frequency of lysine residues in proteins and the reversibility of the covalent ligand-protein bond support the application of aldehyde-bearing ligands, holding promises for their future use as drugs. This review highlights the increasing exploitation of salicylaldehyde modules in various classes of protein binders, aimed at the reversible-covalent engagement of lysine residues.

The white rot basidiomycete Gelatoporia subvermispora produces fatty aldehydes that enable fungal manganese peroxidases to degrade recalcitrant lignin structures.

The ability of some white rot basidiomycetes to remove lignin selectively from wood indicates that low molecular weight oxidants have a role in ligninolysis. These oxidants are likely free radicals generated by fungal peroxidases from compounds in the biodegrading wood. Past work supports a role for manganese peroxidases (MnPs) in the production of ligninolytic oxidants from fungal membrane lipids. However, the fatty acid alkylperoxyl radicals initially formed during this process are not reactive enough to attack the major structures in lignin. Here, we evaluate the hypothesis that the peroxidation of fatty aldehydes might provide a source of more reactive acylperoxyl radicals. We found that Gelatoporia subvermispora produced trans-2-nonenal, trans-2-octenal, and n-hexanal (a likely metabolite of trans-2,4-decadienal) during the incipient decay of aspen wood. Fungal fatty aldehydes supported the in vitro oxidation by MnPs of a nonphenolic lignin model dimer, and also of the monomeric model veratryl alcohol. Experiments with the latter compound showed that the reactions were partially inhibited by oxalate, the chelator that white rot fungi employ to detach Mn3+ from the MnP active site, but nevertheless proceeded at its physiological concentration of 1 mM. The addition of catalase was inhibitory, which suggests that the standard MnP catalytic cycle is involved in the oxidation of aldehydes. MnP oxidized trans-2-nonenal quantitatively to trans-2-nonenoic acid with the consumption of one O2 equivalent. The data suggest that when Mn3+ remains associated with MnP, it can oxidize aldehydes to their acyl radicals, and the latter subsequently add O2 to become ligninolytic acylperoxyl radicals.IMPORTANCEThe biodegradation of lignin by white rot fungi is essential for the natural recycling of plant biomass and has useful applications in lignocellulose bioprocessing. Although fungal peroxidases have a key role in ligninolysis, past work indicates that biodegradation is initiated by smaller, as yet unidentified oxidants that can infiltrate the substrate. Here, we present evidence that the peroxidase-catalyzed oxidation of naturally occurring fungal aldehydes may provide a source of ligninolytic free radical oxidants.

Photoredox/Bismuth Relay Catalysis Enabling Reductive Alkylation of Nitroarenes with Aldehydes.

The effective transition metal-free photoredox/bismuth dual catalytic reductive dialkylation of nitroarenes with benzaldehydes has been reported. The nitroarene reduction through visible light-driven photoredox catalysis was integrated with subsequent reductive dialkylation of anilines under bismuth catalysis to enable the cascade reductive alkylation of nitroarenes with carbonyls. Salient features of this relay catalysis system include mild reaction conditions, no requirement for transition metal catalysts, easy handling, step-economy, and high selectivity.

Metal-Free Selective Synthesis of α,ß-Unsaturated Aldehydes from Alkenes and Formaldehyde Catalyzed by Dimethylamine.

α,ß-Unsaturated aldehydes are important building blocks for the synthesis of a wide range of chemicals, including polymers. The synthesis of these molecules from cheap feedstocks such as alkenes remains a scientific challenge, mainly due to the low reactivity of alkenes. Here we report a selective and metal-free access to α,ß-unsaturated aldehydes from alkenes with formaldehyde. This reaction is catalyzed by dimethylamine and affords α,ß-unsaturated aldehydes in yields of up to 80 %. By combining Density Functional Theory (DFT) calculations and experiments, we elucidate the reaction mechanism which is based on a cascade of hydride transfer, hydrolysis and aldolization reactions. The reaction can be performed under very mild conditions (30-50 °C), in a theoretically 100 % carbon-economical fashion, with water as the only by-product. The reaction was successfully applied to non-activated linear 1-alkenes, thus opening an access to industrially relevant α,ß-unsaturated aldehydes from cheap and widely abundant chemicals at large scale.

Exocyclic DNA adducts and oxidative stress parameters: useful tools for biomonitoring exposure to aldehydes in smokers.

CONTEXT: Exocyclic DNA adducts have been shown to be potential biomarkers of cancer risk related to oxidative stress and exposure to aldehydes in smokers. In fact, aldehydes potentially arise from tobacco combustion directly and endogenously through lipid peroxidation. OBJECTIVE: This study aims to investigate the relationship between a profile of nine aldehydes-induced DNA adducts and antioxidant activities, in order to evaluate new biomarkers of systemic exposure to aldehydes. METHODS: Using our previously published UPLC-MS/MS method, adducts levels were quantified in the blood DNA of 34 active smokers. The levels of antioxidant vitamins (A, C and E), coenzyme Q10, ß-carotene, superoxide dismutase (SOD) and autoantibodies against oxidized low-density lipoprotein were measured. RESULTS: Adducts induced by tobacco smoking-related aldehydes were quantified at levels reflecting an oxidative production from lipid peroxidation. A significant correlation between SOD and crotonaldehyde-induced adducts (p = 0.0251) was also observed. ß-Carotene was negatively correlated with the adducts of formaldehyde (p = 0.0351) and acetaldehyde (p = 0.0413). Vitamin C tended to inversely correlate with acetaldehyde-induced adducts (p = 0.0584). CONCLUSION: These results are promising, and the study is now being conducted on a larger cohort with the aim of evaluating the impact of smoking cessation programs on the evolution of adducts profile and antioxidants activities.

Synthesis, biochemical and computational evaluations of novel bis-acylhydrazones of 2,2'-(1,1'-biphenyl)-4,4'-diylbis(oxy))di(acetohydrazide) as dual cholinesterase inhibitors.

A series of twenty-seven bis(acylhydrazones) were successfully synthesized with high yields through a multistep process, which entailed the esterification of hydroxyl groups, hydrazination with an excess of hydrazine hydrate, and subsequent reactions with various carbonyl moieties (aldehydes). In the final stage of synthesis, different chemical species including aromatic, heterocyclic, and aliphatic compounds were integrated into the framework. The resulting compounds were characterized using several spectroscopic techniques (1H NMR, 13C NMR, and mass spectrometry). Their anticholinesterase activities were assessed in vitro by examining their interactions with two cholinesterase enzymes: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among the synthesized hits, compounds 3, 5, 6, 9-12, and 14 exhibited good to moderate inhibition of AChE. Specifically, 10 (IC50 = 26.3 ± 0.4 µM) and 11 (IC50 = 28.4 ± 0.5 µM) showed good inhibitory activity against AChE, while 9, 12, 3, and 6 exhibited significant inhibition potential against AChE with IC50 values ranging from 35.2 ± 1.1 µM to 64.4 ± 0.3 µM. On the other hand, 5 (IC50 = 22.0 ± 1.1 µM) and 27 (IC50 = 31.3 ± 1.3 µM) displayed significant, and 19 (IC50 = 92.6 ± 0.4 µM) showed moderate inhibitory potential for BChE. Notably, 5 and 27 exhibited dual inhibition of AChE and BChE, with greater potency than the standard drug galantamine. The binding patterns of these molecules within the binding cavities of AChE and BChE were anticipated by molecular docking which showed good correlation with our in vitro findings. Further structural optimization of these molecules may yield more potent AChE and BChE inhibitors.

Fatty Acid Origin of Insect Pheromones.

Pheromones are utilized to a great extent in insects. Many of these pheromones are biosynthesized through a pathway involving fatty acids. This chapter will provide examples where the biosynthetic pathways of fatty acid-derived pheromones have been studied in detail. These include pheromones from Lepidoptera, Coleoptera, and Hymenoptera. Many species of Lepidoptera utilize fatty acids as precursors to pheromones with a functional group that include aldehydes, alcohols, and acetate esters. In addition, the biosynthesis of hydrocarbons will be briefly examined because many insects utilize hydrocarbons or modified hydrocarbons as pheromones.

Tungsten enzymes play a role in detoxifying food and antimicrobial aldehydes in the human gut microbiome.

Tungsten (W) is a metal that is generally thought to be seldom used in biology. We show here that a W-containing oxidoreductase (WOR) family is diverse and widespread in the microbial world. Surprisingly, WORs, along with the tungstate-specific transporter Tup, are abundant in the human gut microbiome, which contains 24 phylogenetically distinct WOR types. Two model gut microbes containing six types of WOR and Tup were shown to assimilate W. Two of the WORs were natively purified and found to contain W. The enzymes catalyzed the conversion of toxic aldehydes to the corresponding acid, with one WOR carrying out an electron bifurcation reaction coupling aldehyde oxidation to the simultaneous reduction of NAD+ and of the redox protein ferredoxin. Such aldehydes are present in cooked foods and are produced as antimicrobials by gut microbiome metabolism. This aldehyde detoxification strategy is dependent on the availability of W to the microbe. The functions of other WORs in the gut microbiome that do not oxidize aldehydes remain unknown. W is generally beyond detection (<6 parts per billion) in common foods and at picomolar concentrations in drinking water, suggesting that W availability could limit some gut microbial functions and might be an overlooked micronutrient.

Lipid Peroxidation-Related Redox Signaling in Osteosarcoma.

Oxidative stress and lipid peroxidation play important roles in numerous physiological and pathological processes, while the bioactive products of lipid peroxidation, lipid hydroperoxides and reactive aldehydes, act as important mediators of redox signaling in normal and malignant cells. Many types of cancer, including osteosarcoma, express altered redox signaling pathways. Such redox signaling pathways protect cancer cells from the cytotoxic effects of oxidative stress, thus supporting malignant transformation, and eventually from cytotoxic anticancer therapies associated with oxidative stress. In this review, we aim to explore the status of lipid peroxidation in osteosarcoma and highlight the involvement of lipid peroxidation products in redox signaling pathways, including the involvement of lipid peroxidation in osteosarcoma therapies.

4-Hydroxybenzoic Acid-Based Hydrazide-Hydrazones as Potent Growth Inhibition Agents of Laccase-Producing Phytopathogenic Fungi That Are Useful in the Protection of Oilseed Crops.

The research on new compounds against plant pathogens is still socially and economically important. It results from the increasing resistance of pests to plant protection products and the need to maintain high yields of crops, particularly oilseed crops used to manufacture edible and industrial oils and biofuels. We tested thirty-five semi-synthetic hydrazide-hydrazones with aromatic fragments of natural origin against phytopathogenic laccase-producing fungi such as Botrytis cinerea, Sclerotinia sclerotiorum, and Cerrena unicolor. Among the investigated molecules previously identified as potent laccase inhibitors were also strong antifungal agents against the fungal species tested. The highest antifungal activity showed derivatives of 4-hydroxybenzoic acid and salicylic aldehydes with 3-tert-butyl, phenyl, or isopropyl substituents. S. sclerotiorum appeared to be the most susceptible to the tested compounds, with the lowest IC50 values between 0.5 and 1.8 µg/mL. We applied two variants of phytotoxicity tests for representative crop seeds and selected hydrazide-hydrazones. Most tested molecules show no or low phytotoxic effect for flax and sunflower seeds. Moreover, a positive impact on seed germination infected with fungi was observed. With the potential for application, the cytotoxicity of the hydrazide-hydrazones of choice toward MCF-10A and BALB/3T3 cell lines was lower than that of the azoxystrobin fungicide tested.

Palladium-Catalyzed ß-C(sp3)-H Bond Arylation of Tertiary Aldehydes Facilitated by 2-Pyridone Ligands.

2-Pyridone ligand-facilitated palladium-catalyzed direct C-H bond functionalization via the transient directing group strategy has become an attractive topic. Here, we report a Pd-catalyzed direct ß-C(sp3)-H arylation reaction of tertiary aliphatic aldehydes by using an α-amino acid as a transient directing group in combination with a 2-pyridone ligand.

The TaCl5-Mediated Reaction of Dimethyl 2-Phenylcyclopropane-1,1-dicarboxylate with Aromatic Aldehydes as a Route to Substituted Tetrahydronaphthalenes.

It is found that the reaction of dimethyl 2-phenylcyclopropane-1,1-dicarboxylate with 2 equivalents each of aromatic aldehydes and TaCl5 in 1,2-dichloroethane at 23 °C for 24 h after hydrolysis gives substituted 4-phenyl-3,4-dihydronaphtalene-2,2(1H)-dicarboxylates in good yield. This represents a new type of reactions between 2-arylcyclopropane-1,1-dicarboxylates and aromatic aldehydes, yielding chlorinated tetrahydronaphthalenes with a cis arrangement of the aryl and chlorine substituents in the cyclohexene moiety. A plausible reaction mechanism is proposed.

Bioinspired Synthesis of Allysine for Late-Stage Functionalization of Peptides.

Inspired by the enzyme lysyl oxidase, which selectively converts the side chain of lysine into allysine, an aldehyde-containing post-translational modification, we report herein the first chemical method for the synthesis of allysine by selective oxidation of dimethyl lysine. This approach is highly chemoselective for dimethyl lysine on proteins. We highlight the utility of this biomimetic approach for generating aldehydes in a variety of pharmaceutically active linear and cyclic peptides at a late stage for their diversification with various affinity and fluorescent tags. Notably, we utilized this approach for generating small-molecule aldehydes from the corresponding tertiary amines. We further demonstrated the potential of this approach in generating cellular models for studying allysine-associated diseases.

Leveraging the Proximity and Distribution of Cu-Cs Sites for Direct Conversion of Methanol to Esters/Aldehydes.

Methanol serves as a versatile building-block for various commodity chemicals, and the development of industrially promising strategies for its conversion remains the ultimate goal in methanol chemistry. In this study, we design a dual Cu-Cs catalytic system that enables a one-step direct conversion of methanol and methyl acetate/ethanol into high value-added esters/aldehydes, with customized chain length and saturation by leveraging the proximity and distribution of Cu-Cs sites. Cu-Cs at a millimeter-scale intimacy triggers methanol dehydrogenation and condensation, involving proton transfer, aldol formation, and aldol condensation, to obtain unsaturated esters and aldehydes with selectivities of 76.3 % and 31.1 %, respectively. Cu-Cs at a micrometer-scale intimacy significantly promotes mass transfer of intermediates across catalyst interfaces and their subsequent hydrogenation to saturated esters and aldehydes with selectivities of 67.6 % and 93.1 %, respectively. Conversely, Cu-Cs at a nanometer-scale intimacy alters reaction pathway with a similar energy barrier for the rate-determining step, but blocks the acidic-basic sites and diverts the reaction to byproducts. More importantly, an unprecedented quadruple tandem catalytic production of methyl methacrylate (MMA) is achieved by further tailoring Cu and Cs distribution across the reaction bed in the configuration of Cu-Cs||Cs, outperforming the existing industrial processes and saving at least 15 % of production costs.

Development of iron-based single atom materials for general and efficient synthesis of amines.

Heterogeneous catalysts with highly active and at the same time stable isolated metal sites constitute a key factor for the advancement of sustainable and cost-effective chemical synthesis. In particular, the development of more practical, and durable iron-based materials is of central interest for organic synthesis, especially for the preparation of chemical products related to life science applications. Here, we report the preparation of Fe-single atom catalysts (Fe-SACs) entrapped in N-doped mesoporous carbon support with unprecedented potential in the preparation of different kinds of amines. The synthetic protocol of Fe-SACs is based on primary pyrolysis of Fe-nitrogen complexes on SiO2 and subsequent removal of silica resulting in the formation of unique mesoporous N-doped carbon support with the pore size controlled by the size of the original silica nanoparticles. The resulting stable and reusable Fe-SACs allow for the reductive amination of a broad range of aldehydes and ketones with ammonia and amines to produce diverse primary, secondary, and tertiary amines including N-methylated products as well as drugs, agrochemicals, and other biomolecules (amino acid esters and amides) utilizing green hydrogen.

Recent advances on the role of monoamine oxidases in cardiac pathophysiology.

Numerous physiological and pathological roles have been attributed to the formation of mitochondrial reactive oxygen species (ROS). However, the individual contribution of different mitochondrial processes independently of bioenergetics remains elusive and clinical treatments unavailable. A notable exception to this complexity is found in the case of monoamine oxidases (MAOs). Unlike other ROS-producing enzymes, especially within mitochondria, MAOs possess a distinct combination of defined molecular structure, substrate specificity, and clinically accessible inhibitors. Another significant aspect of MAO activity is the simultaneous generation of hydrogen peroxide alongside highly reactive aldehydes and ammonia. These three products synergistically impair mitochondrial function at various levels, ultimately jeopardizing cellular metabolic integrity and viability. This pathological condition arises from exacerbated MAO activity, observed in many cardiovascular diseases, thus justifying the exploration of MAO inhibitors as effective cardioprotective strategy. In this context, we not only summarize the deleterious roles of MAOs in cardiac pathologies and the positive effects resulting from genetic or pharmacological MAO inhibition, but also discuss recent findings that expand our understanding on the role of MAO in gene expression and cardiac development.

Regulation of the pleiotropic transcriptional regulator CodY on the conversion of branched-chain amino acids into branched-chain aldehydes in Lactococcus lactis.

IMPORTANCE: Branched-chain aldehydes are the primary compounds that contribute to the nutty flavor in cheddar cheese. Lactococcus lactis, which is often applied as primary starter culture, is a significant contributor to the nutty flavor of cheddar cheese due to its ability of conversion of BCAAs into branched-chain aldehydes. In the present study, we found that the regulatory role of CodY is crucial for the conversion. CodY acts as a pleiotropic transcriptional regulator via binding to various regulatory regions of key genes. The results presented valuable knowledge into the role of CodY on the regulation and biosynthetic pathway of branched-chain amino acids and the related aldehydes. Furthermore, it provided new insight for increasing the nutty flavor produced during the manufacture and ripening of cheese.