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JAMA Cardiology Dec 2021Inflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Inflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. It is unclear how inflammation mediated by interleukin 6 (IL-6) in patients with CKD is linked to cardiovascular disease.
OBJECTIVE
To investigate associations between IL-6 and cardiovascular outcomes in patients with chronic coronary syndrome in association with kidney function.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter cohort study included patients enrolled at 663 centers in 39 countries with chronic coronary syndrome who were included in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial. Patients were enrolled between December 2008 and April 2010 and were followed up for a median length of 3.7 years. Analysis in this substudy began September 2020.
EXPOSURES
Exposures were IL-6 and creatinine estimated glomerular filtration rates (eGFR), which were collected at baseline. Associations between continuous and categorical levels (<2.0 ng/L vs ≥2.0 ng/L) of IL-6 and cardiovascular outcomes were tested in association with eGFR cutoffs (normal eGFR level [≥90 mL/min/1.73 m2], mildly decreased eGFR level [60-90 mL/min/1.73 m2], and moderately to severely decreased eGFR level [<60 mL/min/1.73 m2]).
MAIN OUTCOMES AND MEASURES
Main outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke.
RESULTS
This substudy of the STABILITY trial included 14 611 patients with available IL-6 levels at baseline. The median (interquartile range) age was 65 (59-71) years, and 2700 (18.5%) were female. During follow-up, MACE occurred in 1459 individuals (10.0%). Higher levels of IL-6 were in continuous models independently associated with risk of MACE (P < .001) in all CKD strata. Using predefined strata, elevated IL-6 level (≥2.0 vs <2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio, 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [hazard ratio, 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [hazard ratio, 1.60; 95% CI, 1.28-1.99]).
CONCLUSIONS AND RELEVANCE
In patients with chronic coronary syndrome, elevated levels of IL-6 were associated with risk of MACE in all CKD strata. Thus, IL-6 and CKD stage may help when identifying patients with chronic coronary syndrome for anti-inflammatory treatment.
Topics: Aged; Benzaldehydes; Biomarkers; Coronary Artery Disease; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Interleukin-6; Male; Middle Aged; Oximes; Phospholipase A2 Inhibitors; Prognosis; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Syndrome; Time Factors
PubMed: 34431970
DOI: 10.1001/jamacardio.2021.3079 -
Acta Pharmacologica Sinica Dec 2021Macrophage-mediated inflammation plays an important role in hypertensive cardiac remodeling, whereas effective pharmacological treatments targeting cardiac inflammation...
Macrophage-mediated inflammation plays an important role in hypertensive cardiac remodeling, whereas effective pharmacological treatments targeting cardiac inflammation remain unclear. Lipoprotein-associated phospholipase A2 (Lp-PLA2) contributes to vascular inflammation-related diseases by mediating macrophage migration and activation. Darapladib, the most advanced Lp-PLA2 inhibitor, has been evaluated in phase III trials in atherosclerosis patients. However, the role of darapladib in inhibiting hypertensive cardiac fibrosis remains unknown. Using a murine angiotensin II (Ang II) infusion-induced hypertension model, we found that Pla2g7 (the gene of Lp-PLA2) was the only upregulated PLA2 gene detected in hypertensive cardiac tissue, and it was primarily localized in heart-infiltrating macrophages. As expected, darapladib significantly prevented Ang II-induced cardiac fibrosis, ventricular hypertrophy, and cardiac dysfunction, with potent abatement of macrophage infiltration and inflammatory response. RNA sequencing revealed that darapladib strongly downregulated the expression of genes and signaling pathways related to inflammation, extracellular matrix, and proliferation. Moreover, darapladib substantially reduced the Ang II infusion-induced expression of nucleotide-binding oligomerization domain-like receptor with pyrin domain 3 (NLRP3) and interleukin (IL)-1β and markedly attenuated caspase-1 activation in cardiac tissues. Furthermore, darapladib ameliorated Ang II-stimulated macrophage migration and IL-1β secretion in macrophages by blocking NLRP3 inflammasome activation. Darapladib also effectively blocked macrophage-mediated transformation of fibroblasts into myofibroblasts by inhibiting the activation of the NLRP3 inflammasome in macrophages. Overall, our study identifies a novel anti-inflammatory and anti-cardiac fibrosis role of darapladib in Lp-PLA2 inhibition, elucidating the protective effects of suppressing NLRP3 inflammasome activation. Lp-PLA2 inhibition by darapladib represents a novel therapeutic strategy for hypertensive cardiac damage treatment.
Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Angiotensin II; Animals; Anti-Inflammatory Agents; Benzaldehydes; Cardiomegaly; Cardiotonic Agents; Enzyme Inhibitors; Fibrosis; Heart; Inflammasomes; Inflammation; Macrophages; Male; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Oximes; Mice
PubMed: 34226664
DOI: 10.1038/s41401-021-00703-7 -
Molecules (Basel, Switzerland) Feb 20202-Formylphenylboronic acids display many interesting features, not only from synthetic but also from an application as well as structural points of view....
2-Formylphenylboronic acids display many interesting features, not only from synthetic but also from an application as well as structural points of view. 5-Trifluoromethyl-2-formyl phenylboronic acid has been synthesized and characterized in terms of its structure and properties. The presence of an electron-withdrawing substituent results in a considerable rise in the acidity in comparison with its analogues. In some solutions, the title compound isomerizes with formation of the corresponding 3hydroxybenzoxaborole. Taking into account the probable mechanism of antifungal action of benzoxaboroles, which blocks the cytoplasmic leucyl-tRNA synthetase (LeuRS) of the microorganism, docking studies with the active site of the enzymes have been carried out. It showed possible binding of the cyclic isomer into the binding pocket of LeuRS, similar to that of the recently approved benzoxaborole antifungal drug (, Tavaborole, Kerydin). In case of LeuRS, the opened isomer displays a much higher inhibition constant in comparison with the cyclic one. The antimicrobial activity of the title compound was also investigated , showing moderate action against . The compound reveals higher activity against as well as bacteria such as and . In case of , the determined Minimum Inhibitory Concentration (MIC) value is lower than that of (Tavaborole). The results confirm potential of 2-formylphenylboronic acids as antibacterial agents and give a hint of their possible mechanism of action.
Topics: Anti-Bacterial Agents; Antifungal Agents; Benzaldehydes; Boronic Acids; Candida albicans; Escherichia coli; Leucine-tRNA Ligase; Microbial Sensitivity Tests
PubMed: 32059517
DOI: 10.3390/molecules25040799 -
Frontiers in Public Health 2022Environmental pollution sources may play a key role in the pathogenesis of nephrolithiasis, although the link between environmental aldehyde exposure and the incidence...
Environmental pollution sources may play a key role in the pathogenesis of nephrolithiasis, although the link between environmental aldehyde exposure and the incidence of nephrolithiasis is unclear. The researchers in this study set out to see whether adult kidney stone formation was linked to environmental aldehydes. We examined data from 10,175 adult participants over the age of 20 who took part in the 2013-2014 National Health and Nutrition Examination Survey (NHANES), which was a cross-sectional research. A logistic regression model was employed in this work to examine the relationship between aldehyde exposure and kidney stones, machine learning was utilized to predict the connection of different parameters with the development of kidney stones, and a subgroup analysis was performed to identify sensitive groups. After controlling for all confounding variables, the results revealed that isopentanaldehyde, benzaldehyde, and hexanaldehyde were risk factors for kidney stone formation, with odds ratio (OR) of 2.47, 1.12, and 1.17, respectively, and 95 percent confidence intervals (95% CI) of 1.15-5.34, 1.02-1.22, and 1.00-1.36. Kidney stones may be a result of long-term exposure to aldehydes, which may cause them to form. Environmental pollution-related aldehyde exposure might give a novel notion and direction for future study into the process of kidney stone production, even if the cause is yet unknown.
Topics: Adult; Humans; Nutrition Surveys; Benzaldehydes; Cross-Sectional Studies; Kidney Calculi; Aldehydes
PubMed: 36299743
DOI: 10.3389/fpubh.2022.978338 -
Molecules (Basel, Switzerland) Jul 2022A number of imines, including 12 new compounds, previously not reported in the literature, derived from variously fluorinated benzaldehydes and different anilines or...
A number of imines, including 12 new compounds, previously not reported in the literature, derived from variously fluorinated benzaldehydes and different anilines or chiral benzylamines were synthesized by a solvent-free mechanochemical method, which was based on the manual grinding of equimolar amounts of the substrates at the room temperature. In a very short reaction time of only 15 min, the method produced the expected products with good-to-excellent yields. The yields were comparable or significantly higher than those reported in the literature for the imines synthesized by other methods. Importantly, the conditions used for the reactions with aniline derivatives also resulted in the high yields of imines obtained from chiral benzylamines, and can be extended to the synthesis with other similar amines. Structures of all imines were confirmed by NMR spectroscopy: H, C and F. For four compounds, X-ray structures were also obtained. The synthetic approach presented in this paper contributes to the prevention of environmental pollution and can be easily extended for larger-scale syntheses. The mechanochemical solvent-free method provides a convenient strategy particularly useful for the preparation of fluorinated imines being versatile intermediates or starting material in the synthesis of drugs and other fine chemicals.
Topics: Amines; Benzaldehydes; Benzylamines; Imines; Magnetic Resonance Spectroscopy
PubMed: 35889430
DOI: 10.3390/molecules27144557 -
Blood Apr 2019
Topics: Anemia, Sickle Cell; Benzaldehydes; Humans; Patients; Polymerization; Pyrazines; Pyrazoles
PubMed: 31023742
DOI: 10.1182/blood-2019-02-898767 -
Communications Biology Sep 2023Lysosome-related organelles (LROs) play diverse roles and their dysfunction causes immunodeficiency. However, their primordial functions remain unclear. Here, we report...
Lysosome-related organelles (LROs) play diverse roles and their dysfunction causes immunodeficiency. However, their primordial functions remain unclear. Here, we report that C. elegans LROs (gut granules) promote organismal defenses against various stresses. We find that toxic benzaldehyde exposure induces LRO autofluorescence, stimulates the expression of LRO-specific genes and enhances LRO transport capacity as well as increases tolerance to benzaldehyde, heat and oxidative stresses, while these responses are impaired in glo-1/Rab32 and pgp-2 ABC transporter LRO biogenesis mutants. Benzaldehyde upregulates glo-1- and pgp-2-dependent expression of heat shock, detoxification and antimicrobial effector genes, which requires daf-16/FOXO and/or pmk-1/p38MAPK. Finally, benzaldehyde preconditioning increases resistance against Pseudomonas aeruginosa PA14 in a glo-1- and pgp-2-dependent manner, and PA14 infection leads to the deposition of fluorescent metabolites in LROs and induction of LRO genes. Our study suggests that LROs may play a role in systemic responses to stresses and in pathogen resistance.
Topics: Animals; Benzaldehydes; Caenorhabditis elegans; Lysosomes; Immunity
PubMed: 37704756
DOI: 10.1038/s42003-023-05246-7 -
Molecules (Basel, Switzerland) Sep 2021Products of natural origin remain important in the discovery of new bioactive molecules and are less damaging to the environment. Benzaldehyde is a product of the...
Products of natural origin remain important in the discovery of new bioactive molecules and are less damaging to the environment. Benzaldehyde is a product of the metabolism of plants, and similarly to oxygenated terpenes, it can have antibacterial activity against and toxic action against ; we aimed to verify these activities. The broth microdilution tests determined the minimum inhibitory concentration (MIC) of benzaldehyde alone and in association with antibiotics and ethidium bromide (EtBr). Toxicity against was determined by fumigation tests that measured lethality and damage to the locomotor system. The results indicated that there was an association of norfloxacin and ciprofloxacin with benzaldehyde, from 64 μg/mL to 32 μg/mL of ciprofloxacin in the strain K6028 and from 256 μg/mL to 128 μg/mL of norfloxacin in the strain 1199B; however, the associations were not able to interfere with the functioning of the tested efflux pumps. In addition, benzaldehyde had a toxic effect on flies. Thus, the results proved the ability of benzaldehyde to modulate quinolone antibiotics and its toxic effects on fruit flies, thus enabling further studies in this area.
Topics: Animals; Anti-Bacterial Agents; Benzaldehydes; Drosophila melanogaster; Microbial Sensitivity Tests; Staphylococcus aureus
PubMed: 34577039
DOI: 10.3390/molecules26185570 -
Biomedicine & Pharmacotherapy =... Sep 2022To better understand the pharmacological characters of syringaldehyde (SA), which is a key-odorant compound of whisky and brandy, this review article is the first to... (Review)
Review
To better understand the pharmacological characters of syringaldehyde (SA), which is a key-odorant compound of whisky and brandy, this review article is the first to compile the published literature for molecular docking that were subsequently validated by in vitro and in vivo assays to predict and develop insights into the medicinal properties of SA in terms of anti-oxidation, anti-inflammation, and anti-diabetes. The molecular docking displayed significantly binding affinity for SA towards tumor necrosis factor-α, interleukin-6, and antioxidant enzymes when inflammation from myocardial infarction and spinal cord ischemia. Moreover, SA nicely docked with dipeptidyl peptidase-IV, glucagon-like peptide 1 receptor, peroxisome proliferator-activated receptor, acetylcholine M2 receptor, and acetylcholinesterase in anti-diabetes investigations. These are associated with (1) an increase glucose utilization and insulin sensitivity to an anti-hyperglycemic effect; and (2) to potentiate intestinal contractility to abolish the α-amylase reaction when concurrently reducing retention time and glucose absorption of the intestinal tract to achieve a glucose-lowering effect. In silico screening of multi-targets concomitantly with preclinical tests could provide a potential exploration for new indications for drug discovery and development.
Topics: Acetylcholinesterase; Benzaldehydes; Diabetes Mellitus; Dipeptidyl Peptidase 4; Glucose; Humans; Hypoglycemic Agents; Molecular Docking Simulation; Pharmaceutical Preparations; Phenols
PubMed: 35780614
DOI: 10.1016/j.biopha.2022.113339 -
Journal of the American Chemical Society Oct 2022In all known genetic polymers, molecular recognition via hydrogen bonding between complementary subunits underpins their ability to encode and transmit information, to...
In all known genetic polymers, molecular recognition via hydrogen bonding between complementary subunits underpins their ability to encode and transmit information, to form sequence-defined duplexes, and to fold into catalytically active forms. Reversible covalent interactions between complementary subunits provide a different way to encode information, and potentially function, in sequence-defined oligomers. Here, we examine six oligoarylacetylene trimers composed of aniline and benzaldehyde subunits. Four of these trimers self-pair to form two-rung duplex structures, and two form macrocyclic 1,3-folded structures. The equilibrium proportions of these structures can be driven to favor each of the observed structures almost entirely depending upon the concentration of trimers and an acid catalyst. Quenching the acidic trimer solutions with an organic base kinetically traps all species such that they can be isolated and characterized. Mixtures of complementary trimers form exclusively sequence-specific 3-rung duplexes. Our results suggest that reversible covalent bonds could in principle guide the formation of more complex folded conformations of longer oligomers.
Topics: Aniline Compounds; Benzaldehydes; DNA; Nucleic Acid Conformation; Polymers
PubMed: 36174969
DOI: 10.1021/jacs.2c06268