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Journal of Medicinal Chemistry Mar 2022Aldehyde dehydrogenases (ALDHs) are overexpressed in various tumor types including prostate cancer and considered a potential target for therapeutic intervention....
Aldehyde dehydrogenases (ALDHs) are overexpressed in various tumor types including prostate cancer and considered a potential target for therapeutic intervention. 4-(Diethylamino)benzaldehyde (DEAB) has been extensively reported as a pan-inhibitor of ALDH isoforms, and here, we report on the synthesis, ALDH isoform selectivity, and cellular potencies in prostate cancer cells of 40 DEAB analogues; three analogues (, , and ) showed potent inhibitory activity against ALDH1A3, and two analogues ( and ) showed potent inhibitory activity against ALDH3A1. Significantly, 16 analogues displayed increased cytotoxicity (IC = 10-200 μM) compared with DEAB (>200 μM) against three different prostate cancer cell lines. Analogues and were more potent than DEAB against patient-derived primary prostate tumor epithelial cells, as single agents or in combination treatment with docetaxel. In conclusion, our study supports the use of DEAB as an ALDH inhibitor but also reveals closely related analogues with increased selectivity and potency.
Topics: Aldehyde Dehydrogenase; Benzaldehydes; Humans; Male; Prostatic Neoplasms
PubMed: 35212533
DOI: 10.1021/acs.jmedchem.1c01367 -
Scientific Reports Sep 2021Skeletal muscles are important in glucose metabolism and are affected in type 2 diabetes (T2D) and its complications. This study investigated the effect of vanillin on...
Skeletal muscles are important in glucose metabolism and are affected in type 2 diabetes (T2D) and its complications. This study investigated the effect of vanillin on redox imbalance, cholinergic and purinergic dysfunction, and glucose-lipid dysmetabolism in muscles of rats with T2D. Male albino rats (Sprague-Dawley strain) were fed 10% fructose ad libitum for 2 weeks before intraperitoneally injecting them with 40 mg/kg streptozotocin to induce T2D. Low (150 mg/kg bodyweight (BW)) and high (300 mg/kg BW) doses of vanillin were orally administered to diabetic rats. Untreated diabetic rats and normal rats made up the diabetic control (DC) and normal control (NC) groups, respectively. The standard antidiabetic drug was metformin. The rats were humanely put to sleep after 5 weeks of treatment and their psoas muscles were harvested. There was suppression in the levels of glutathione, activities of SOD, catalase, ENTPDase, 5'Nucleotidase and glycogen levels on T2D induction. This was accompanied by concomitantly elevated levels of malondialdehyde, serum creatine kinase-MB, nitric oxide, acetylcholinesterase, ATPase, amylase, lipase, glucose-6-phosphatase (G6Pase), fructose-1,6-biphophastase (FBPase) and glycogen phosphorylase activities. T2D induction further resulted in the inactivation of fatty acid biosynthesis, glycerolipid metabolism, fatty acid elongation in mitochondria and fatty acid metabolism pathways. There were close to normal and significant reversals in these activities and levels, with concomitant reactivation of the deactivated pathways following treatment with vanillin, which compared favorably with the standard drug (metformin). Vanillin also significantly increased muscle glucose uptake ex vivo. The results suggest the therapeutic effect of vanillin against muscle dysmetabolism in T2D as portrayed by its ability to mitigate redox imbalance, inflammation, cholinergic and purinergic dysfunctions, while modulating glucose-lipid metabolic switch and maintaining muscle histology.
Topics: Animals; Benzaldehydes; Male; Muscle, Skeletal; Rats; Rats, Sprague-Dawley
PubMed: 34548565
DOI: 10.1038/s41598-021-98158-7 -
Ecotoxicology and Environmental Safety May 2022Large amounts of monocyclic aromatic hydrocarbons (MAHs) are emitted into the atmosphere, but it is unclear which compounds among MAHs are effectively removed by the...
Large amounts of monocyclic aromatic hydrocarbons (MAHs) are emitted into the atmosphere, but it is unclear which compounds among MAHs are effectively removed by the above-ground parts of plants. Although fumigation experiments of MAHs at unrealistically high concentrations (~ppmv) have been conducted, experiments with ambient concentrations have scarcely been conducted. In the present study, MAHs, including benzene, toluene, phenol, benzaldehyde, and benzyl alcohol, with concentrations ranging from several to several tens ppbv, were individually fumigated to four plant species, and the uptake was monitored using proton-transfer-reaction mass spectrometry and gas chromatography-mass spectrometry. No detectable uptake was observed for benzene and toluene, but phenol, benzaldehyde, and benzyl alcohol were significantly taken up by the plants. The uptake rate normalized to fumigated concentration varied from 3 to 50 mmol ms during the light period, depending on light intensity and compounds. The difference in uptake capability may be attributed not only to different metabolic activities but also to different values of Henry's law constant, which regulates the partitioning of these compounds into the liquid phase in leaves. The uptake of phenol, benzaldehyde, and benzyl alcohol was affected by stomatal conductance, suggesting that stomatal opening is the main factor regulating the uptake of the three MAHs. This is the first observation that anisole is emitted when phenol is fumigated to Spathiphyllum clevelandii, suggesting that phenol is methylated to anisole within plant leaves. Anisole is more volatile than phenol, meaning that methylation enhances the emission of xenobiotics into the atmosphere by converting them to more volatile compounds. This conversion ratio decreased with an increase in phenol concentration (from 1.3 to 143 ppbv). Considering low reaction rate coefficient of anisole with OH radicals and low conversion ratio from phenol to anisole, it is concluded that plants act to effectively remove oxygenated MAHs from the atmosphere.
Topics: Anisoles; Benzaldehydes; Benzene; Benzyl Alcohols; Hydrocarbons, Aromatic; Phenols; Plant Leaves; Plants; Toluene
PubMed: 35367882
DOI: 10.1016/j.ecoenv.2022.113433 -
Angewandte Chemie (International Ed. in... Oct 2022The combination of small-molecule catalysis and enzyme catalysis represents an underexploited area of research with huge potential in asymmetric synthetic chemistry due...
The combination of small-molecule catalysis and enzyme catalysis represents an underexploited area of research with huge potential in asymmetric synthetic chemistry due to both compatibility of reaction conditions and complementary reactivity. Herein, we describe the telescopic synthesis of chiral nitro alcohols starting from commercially available benzaldehyde derivatives through the one-pot three-step chemoenzymatic cascade combination of a Wittig reaction, chiral-thiourea-catalysed asymmetric conjugate addition, and ketoreductase-mediated reduction to access the corresponding target compounds in moderate to excellent overall isolated yields (36-80 %) and high diastereomeric and enantiomeric ratios (up to >97 : 3). This represents the first example of the combination of an organocatalysed asymmetric conjugate addition via iminium ion activation and a bioreduction step catalysed by ketoreductases.
Topics: Alcohols; Amino Alcohols; Benzaldehydes; Biocatalysis; Catalysis; Stereoisomerism; Thiourea
PubMed: 35983936
DOI: 10.1002/anie.202209159 -
Mediators of Inflammation 2021Inflammatory responses have been associated with delayed oral mucosal wound healing and the pathogenesis of the periodontal disease. The invasion of microbes into the...
BACKGROUND
Inflammatory responses have been associated with delayed oral mucosal wound healing and the pathogenesis of the periodontal disease. The invasion of microbes into the tissues and the establishment of a chronic infection may be due to impaired healing. The protracted inflammatory phase may delay wound healing and probably support tissue fibrosis and reduce tissue regeneration. Vanillin is a well-known natural compound with potential anti-inflammatory capacity. Hence, we hypothesized that Vanillin could accelerate wound healing reducing inflammation and especially cytokine production making the oral tissue repair process easier.
METHODS
Our hypothesis was tested using primary human gingival fibroblast (HGF) cell pretreated with Vanillin and primed with IL-1, as inductor of proinflammatory environment. After 24 hours of treatments, the gene expression and production of IL-6, TNF-, IL-8, COX-2, iNOS, and nitric oxide (NO) generation and the wound healing rate were determined.
RESULTS
In IL-1-primed cells, preincubation with Vanillin reduced IL-6, IL-8, COX-2, and iNOS expression and NO release, compared to IL-1-primed cells. Moreover, Vanillin determines the increased gene expression of nAChR7, leading us to hypothesize a role of Vanillin in the activation of the cholinergic anti-inflammatory pathway. Furthermore, in presence of mechanical injury, the Vanillin preincubation, wound closure may be reducing the expression and release of IL-6 and TNF- and upregulation of COX-2 and IL-8.
CONCLUSION
Together, the results of this study highlight the anti-inflammatory and tissue repair ability of Vanillin in IL-1-primed HGF. Therefore, Vanillin shows a potential therapeutic interest as an inflammatory modulator molecule with novel application in periodontal regeneration and oral health.
Topics: Anti-Inflammatory Agents; Benzaldehydes; Fibroblasts; Gingiva; Humans
PubMed: 34035660
DOI: 10.1155/2021/5562340 -
ELife Aug 2020Cellular senescence is a contributor to intervertebral disc (IVD) degeneration and low back pain. Here, we found that RG-7112, a potent mouse double-minute two protein...
Cellular senescence is a contributor to intervertebral disc (IVD) degeneration and low back pain. Here, we found that RG-7112, a potent mouse double-minute two protein inhibitor, selectively kills senescent IVD cells through apoptosis. Gene expression pathway analysis was used to compare the functional networks of genes affected by RG-7112, a pure synthetic senolytic with o-Vanillin a natural and anti-inflammatory senolytic. Both affected a functional gene network related to cell death and survival. O-Vanillin also affected networks related to cell cycle progression as well as connective tissue development and function. Both senolytics effectively decreased the senescence-associated secretory phenotype (SASP) of IVD cells. Furthermore, bioavailability and efficacy were verified ex vivo in the physiological environment of degenerating intact human discs where a single dose improved disc matrix homeostasis. Matrix improvement correlated with a reduction in senescent cells and SASP, supporting a translational potential of targeting senescent cells as a therapeutic intervention.
Topics: Benzaldehydes; Cellular Senescence; Female; Humans; Imidazolines; Intervertebral Disc Degeneration; Low Back Pain; Male
PubMed: 32821059
DOI: 10.7554/eLife.54693 -
Microbiology Spectrum Feb 2023Infection by fungal pathogens is the main factor leading to postharvest rot and quality deterioration of fruit and vegetables. Rotting caused by Alternaria alternata is...
Infection by fungal pathogens is the main factor leading to postharvest rot and quality deterioration of fruit and vegetables. Rotting caused by Alternaria alternata is a concerning disease for numerous crops in both production and postharvest stages, especially tomato black spots. In this study, the double Petri dish assay showed that the VOCs of Ceratocystis fimbriata WJSK-1 and Mby inhibited the mycelial growth of fungal pathogen A. alternata, with a percentage inhibition of 52.2% and 42.9%. Then, HS-SPME-GC-MS technology was used to analyze the volatiles produced by two strains of C. fimbriata (WJSK-1, Mby), a total of 42 volatile single components were obtained, the main volatiles compounds identified include nine esters, 10 ketones, five alcohols, four aldehydes, three aromatic hydrocarbons, three heterocycles, four alkenes, three alkanes, and one acid. After that, the antifungal activity of a single volatile component was evaluated both and , four single components with antifungal effects were screened out, namely, benzaldehyde, nonanal, 2-Phenylethanol and isoamyl acetate, with IC values show the smallest values for benzaldehyde and nonanal at 0.11 mL, 0.04 mL. A. alternata exposed to VOCs had abnormal morphology for hyphae, delayed sporulation, and inhibited spore germination. experiment shows that the four volatile components can effectively suppress disease incidence on fungal-inoculated fruit; the two aldehydes (benzaldehyde and nonanal) have more prominent effect on delaying fruit onset of disease. The results showed that VOCs produced by C. fimbriata have potential as a fumigant for controlling black rot in cherry tomatoes. In this research, the volatile organic compounds (VOCs) produced based on C. fimbriata exhibited strong antifungal activity against the fungal pathogen A. alternata. Our aim is to explore their bacteriostatic components. HS-SPME-GC-MS technology was used to analyze the volatiles produced by the C. fimbriata strain (WJSK-1, Mby). Postharvest cherry tomato fruit black rot caused by A. alternata was treated both and , with pure individual components produced by C. fimbriata. The benzaldehyde, nonanal, 2-Phenylethanol, and isoamyl acetate from C. fimbriata can effectively inhibit growth of A. alternata, and delay disease. It has the potential to be developed as a new type of fumigant, a potential replacement for fungicides in the future.
Topics: Antifungal Agents; Solanum lycopersicum; Benzaldehydes; Fruit; Phenylethyl Alcohol; Aldehydes
PubMed: 36625661
DOI: 10.1128/spectrum.02713-22 -
PloS One 2014In vitro toxicological studies together with atomistic molecular dynamics simulations show that occupational co-exposure with C60 fullerene may strengthen the health...
In vitro toxicological studies together with atomistic molecular dynamics simulations show that occupational co-exposure with C60 fullerene may strengthen the health effects of organic industrial chemicals. The chemicals studied are acetophenone, benzaldehyde, benzyl alcohol, m-cresol, and toluene which can be used with fullerene as reagents or solvents in industrial processes. Potential co-exposure scenarios include a fullerene dust and organic chemical vapor, or a fullerene solution aerosolized in workplace air. Unfiltered and filtered mixtures of C60 and organic chemicals represent different co-exposure scenarios in in vitro studies where acute cytotoxicity and immunotoxicity of C60 and organic chemicals are tested together and alone by using human THP-1-derived macrophages. Statistically significant co-effects are observed for an unfiltered mixture of benzaldehyde and C60 that is more cytotoxic than benzaldehyde alone, and for a filtered mixture of m-cresol and C60 that is slightly less cytotoxic than m-cresol. Hydrophobicity of chemicals correlates with co-effects when secretion of pro-inflammatory cytokines IL-1β and TNF-α is considered. Complementary atomistic molecular dynamics simulations reveal that C60 co-aggregates with all chemicals in aqueous environment. Stable aggregates have a fullerene-rich core and a chemical-rich surface layer, and while essentially all C60 molecules aggregate together, a portion of organic molecules remains in water.
Topics: Acetophenones; Air Pollutants, Occupational; Benzaldehydes; Benzyl Alcohol; Cell Line, Tumor; Cresols; Drug Interactions; Fullerenes; Humans; Hydrophobic and Hydrophilic Interactions; Interleukin-1beta; Macrophages; Molecular Dynamics Simulation; Thermodynamics; Toluene; Tumor Necrosis Factor-alpha
PubMed: 25473947
DOI: 10.1371/journal.pone.0114490 -
Chemical Research in Toxicology Jun 2019E-cigarette flavorings have not been thoroughly evaluated for inhalational toxicity. We have shown that the flavoring chemical cinnamaldehyde impairs human neutrophils,...
E-cigarette flavorings have not been thoroughly evaluated for inhalational toxicity. We have shown that the flavoring chemical cinnamaldehyde impairs human neutrophils, macrophages, and natural killer cells. Here we investigated the effects of other common e-liquid flavoring chemicals on phagocytosis and oxidative burst in neutrophils. We demonstrate that cinnamaldehyde and ethyl vanillin dose-dependently decrease oxidative burst and that benzaldehyde and benzaldehyde propylene glycol acetal dose-dependently impair phagocytosis. Isoamyl acetate did not affect either measure of neutrophil function. These data suggest that inhaling aromatic aldehydic flavoring chemicals, such as cinnamaldehyde, benzaldehyde, benzaldehyde propylene glycol acetal, or ethyl vanillin, could impair neutrophil function.
Topics: Acrolein; Benzaldehydes; Dose-Response Relationship, Drug; Electronic Nicotine Delivery Systems; Flavoring Agents; Humans; Molecular Structure; Neutrophils; Phagocytosis; Respiratory Burst; Structure-Activity Relationship
PubMed: 31117350
DOI: 10.1021/acs.chemrestox.9b00171 -
Journal of Dairy Science May 1992The effect of sodium caseinate and whey protein concentrate on benzaldehyde, d-limonene, and citral flavor intensity was determined by quantitative descriptive analysis...
The effect of sodium caseinate and whey protein concentrate on benzaldehyde, d-limonene, and citral flavor intensity was determined by quantitative descriptive analysis deviation from reference using a 12-member trained panel. The concentrations for the benzaldehyde, d-limonene, and citral flavor intensity references were 17.8, 53.0, and 19.8 ppm, respectively. The concentration for both protein references was .25%. Flavored protein solutions were held for 17 h at 6 degrees C and contained benzaldehyde (17.8 ppm), d-limonene (53 ppm), or citral (19.8 ppm) and 2.5% sucrose with 0, .125, .25, or .5% protein. Benzaldehyde flavor intensity declined as the whey protein concentrate concentration increased from 0 to .5%. There was no significant difference in benzaldehyde flavor intensity with casein compared with the reference. The d-limonene flavor intensity declined as the protein concentration increased. Panelists found no significant drop in citral flavor intensity with casein or whey protein. Decreased benzaldehyde and d-limonene flavor intensity in the presence of whey protein concentrate or casein may be due to nonpolar interactions (casein), interaction with nonpolar binding sites, cysteine-aldehyde condensation, or Schiff base formation (whey protein concentrate).
Topics: Acyclic Monoterpenes; Adult; Animals; Benzaldehydes; Caseins; Cyclohexenes; Female; Flavoring Agents; Humans; Limonene; Male; Middle Aged; Milk Proteins; Monoterpenes; Taste; Terpenes; Whey Proteins
PubMed: 1597575
DOI: 10.3168/jds.S0022-0302(92)77869-2