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Cell Oct 2022Some people are more attractive to mosquitoes than others, but the mechanistic basis of this phenomenon is poorly understood. We tested mosquito attraction to human skin...
Some people are more attractive to mosquitoes than others, but the mechanistic basis of this phenomenon is poorly understood. We tested mosquito attraction to human skin odor and identified people who are exceptionally attractive or unattractive to mosquitoes. These differences were stable over several years. Chemical analysis revealed that highly attractive people produce significantly more carboxylic acids in their skin emanations. Mutant mosquitoes lacking the chemosensory co-receptors Ir8a, Ir25a, or Ir76b were severely impaired in attraction to human scent, but retained the ability to differentiate highly and weakly attractive people. The link between elevated carboxylic acids in "mosquito-magnet" human skin odor and phenotypes of genetic mutations in carboxylic acid receptors suggests that such compounds contribute to differential mosquito attraction. Understanding why some humans are more attractive than others provides insights into what skin odorants are most important to the mosquito and could inform the development of more effective repellents.
Topics: Animals; Humans; Aedes; Carboxylic Acids; Odorants; Insect Repellents; Anopheles
PubMed: 36261039
DOI: 10.1016/j.cell.2022.09.034 -
Scientific Reports Aug 2017Divergent synthesis of antimalarial troponoids, including naturally occurring compounds, some of which were identified and isolated by our group, has been achieved...
Divergent synthesis of antimalarial troponoids, including naturally occurring compounds, some of which were identified and isolated by our group, has been achieved utilizing the total synthetic route of puberulic acid. Structure-activity relationships of natural products and simple troponoids inspired us to explore more detailed properties of this class of compounds. Access to new derivatives was facilitated through intermediate compounds generated during the total synthesis of puberulic acid by a stepwise oxidation-aromatization sequence to provide 7-hydroxytropolones and bromination for conversion of the carboxylic acid moiety. The first total synthesis of viticolin A, as well as the synthesis of different methyl-substituted derivatives, has also been achieved. In vitro antimalarial activity and cytotoxicity of novel derivatives were evaluated and fundamental information to facilitate the discovery of more promising antimalarials was obtained.
Topics: Antimalarials; Biological Products; Carboxylic Acids; Cell Line; Cell Survival; Chemistry Techniques, Synthetic; Humans; Inhibitory Concentration 50; Molecular Structure; Oxidation-Reduction; Parasitic Sensitivity Tests; Plasmodium falciparum; Structure-Activity Relationship; Tropolone
PubMed: 28775291
DOI: 10.1038/s41598-017-07718-3 -
Science (New York, N.Y.) Jun 2017The widespread use of alkyl boronic acids and esters is frequently hampered by the challenges associated with their preparation. We describe a simple and practical...
The widespread use of alkyl boronic acids and esters is frequently hampered by the challenges associated with their preparation. We describe a simple and practical method to rapidly access densely functionalized alkyl boronate esters from abundant carboxylic substituents. This broad-scope nickel-catalyzed reaction uses the same activating principle as amide bond formation to replace a carboxylic acid moiety with a boronate ester. Application to peptides allowed expedient preparations of α-amino boronic acids, often with high stereoselectivity, thereby facilitating synthesis of the alkyl boronic acid drugs Velcade and Ninlaro as well as a boronic acid version of the iconic antibiotic vancomycin. The reaction also enabled the discovery and extensive biological characterization of potent human neutrophil elastase inhibitors, which offer reversible covalent binding properties.
Topics: Boron; Boronic Acids; Carboxylic Acids; Pharmaceutical Preparations
PubMed: 28408721
DOI: 10.1126/science.aam7355 -
The Journal of Biological Chemistry Mar 2003GPR41 and GPR43 are related members of a homologous family of orphan G protein-coupled receptors that are tandemly encoded at a single chromosomal locus in both humans...
GPR41 and GPR43 are related members of a homologous family of orphan G protein-coupled receptors that are tandemly encoded at a single chromosomal locus in both humans and mice. We identified the acetate anion as an agonist of human GPR43 during routine ligand bank screening in yeast. This activity was confirmed after transient transfection of GPR43 into mammalian cells using Ca(2+) mobilization and [(35)S]guanosine 5'-O-(3-thiotriphosphate) binding assays and by coexpression with GIRK G protein-regulated potassium channels in Xenopus laevis oocytes. Other short chain carboxylic acid anions such as formate, propionate, butyrate, and pentanoate also had agonist activity. GPR41 is related to GPR43 (52% similarity; 43% identity) and was activated by similar ligands but with differing specificity for carbon chain length, with pentanoate being the most potent agonist. A third family member, GPR42, is most likely a recent gene duplication of GPR41 and may be a pseudogene. GPR41 was expressed primarily in adipose tissue, whereas the highest levels of GPR43 were found in immune cells. The identity of the cognate physiological ligands for these receptors is not clear, although propionate is known to occur in vivo at high concentrations under certain pathophysiological conditions.
Topics: Amino Acid Sequence; Animals; Carboxylic Acids; DNA Primers; Humans; Immunohistochemistry; Molecular Sequence Data; Propionates; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Recombinant Proteins; Xenopus laevis
PubMed: 12496283
DOI: 10.1074/jbc.M211609200 -
Chemical & Pharmaceutical Bulletin 2021Novel derivatives of puberulic acid were synthesized and their antimalarial properties were evaluated in vitro against the Plasmodium falciparum K1 parasite strain,...
Novel derivatives of puberulic acid were synthesized and their antimalarial properties were evaluated in vitro against the Plasmodium falciparum K1 parasite strain, cytotoxicity against a human diploid embryonic cell line MRC-5, and in vivo efficacy using a Plasmodium berghei-infected mouse model. From previous information that three hydroxy groups on the tropone framework were essential for antimalarial activity, we converted the carboxylic acid moiety into the corresponding esters, amides, and ketones. These derivatives showed antimalarial activity against chloroquine-resistant Plasmodium in vitro equivalent to puberulic acid. We identified that the pentane-3-yl ester, cyclohexyl ester, iso-butyl ketone, cyclohexyl methyl ketone all show an especially potent antiparasitic effect in vivo at an oral dose of 15 mg/kg without any apparent toxicity. These esters were more effective than the existing commonly used antimalarial drug, artesunate.
Topics: Animals; Antimalarials; Carboxylic Acids; Cell Line; Cell Survival; Disease Models, Animal; Humans; Malaria; Male; Mice; Mice, Inbred ICR; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium; Tropolone
PubMed: 34078803
DOI: 10.1248/cpb.c21-00132 -
Cells Oct 2022T cells play central roles in the anti-tumor immunity, whose activation and differentiation are profoundly regulated by intrinsic metabolic reprogramming. Emerging... (Review)
Review
T cells play central roles in the anti-tumor immunity, whose activation and differentiation are profoundly regulated by intrinsic metabolic reprogramming. Emerging evidence has revealed that metabolic processes of T cells are generally altered by tumor cells or tumor released factors, leading to crippled anti-tumor immunity. Therefore, better understanding of T cell metabolic mechanism is crucial in developing the next generation of T cell-based anti-tumor immunotherapeutics. In this review, we discuss how metabolic pathways affect T cells to exert their anti-tumor effects and how to remodel the metabolic programs to improve T cell-mediated anti-tumor immune responses. We emphasize that glycolysis, carboxylic acid cycle, fatty acid oxidation, cholesterol metabolism, amino acid metabolism, and nucleotide metabolism work together to tune tumor-reactive T-cell activation and proliferation.
Topics: Amino Acids; Carboxylic Acids; Cholesterol; Fatty Acids; Humans; Neoplasms; Nucleotides; T-Lymphocytes
PubMed: 36231064
DOI: 10.3390/cells11193103 -
Cells Mar 2022Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both...
Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought to examine the differential expression signature of human DKD in the glomerulus and proximal tubule and corroborate our findings in the db/db mouse model of diabetes. A transcriptogram network analysis of RNAseq data from laser microdissected (LMD) human glomerulus and proximal tubule of DKD and reference nephrectomy samples revealed enriched pathways including rhodopsin-like receptors, olfactory signaling, and ribosome (protein translation) in the proximal tubule of human DKD biopsy samples. The translation pathway was also enriched in the glomerulus. Increased translation in diabetic kidneys was validated using polyribosomal profiling in the db/db mouse model of diabetes. Using single nuclear RNA sequencing (snRNAseq) of kidneys from db/db mice, we prioritized additional pathways identified in human DKD. The top overlapping pathway identified in the murine snRNAseq proximal tubule clusters and the human LMD proximal tubule compartment was carboxylic acid catabolism. Using ultra-performance liquid chromatography-mass spectrometry, the fatty acid catabolism pathway was also found to be dysregulated in the db/db mouse model. The Acetyl-CoA metabolite was down-regulated in db/db mice, aligning with the human differential expression of the genes ACOX1 and ACACB. In summary, our findings demonstrate that proximal tubular alterations in protein translation and carboxylic acid catabolism are key features in both human and murine DKD.
Topics: Animals; Carboxylic Acids; Diabetes Mellitus; Diabetic Nephropathies; Kidney; Kidney Glomerulus; Mice; Protein Biosynthesis
PubMed: 35406730
DOI: 10.3390/cells11071166 -
Molecules (Basel, Switzerland) Feb 2023The Ugi four-component reaction (Ugi-4CR) undoubtedly is the most prominent multicomponent reaction (MCRs) that has sparked organic chemists' interest in the field. It... (Review)
Review
The Ugi four-component reaction (Ugi-4CR) undoubtedly is the most prominent multicomponent reaction (MCRs) that has sparked organic chemists' interest in the field. It has been widely used in the synthesis of diverse heterocycle molecules such as potential drugs, natural product analogs, pseudo peptides, macrocycles, and functional materials. The Ugi-4CRs involve the use of an amine, an aldehyde or ketone, an isocyanide, and a carboxylic acid to produce an α-acetamido carboxamide derivative, which has significantly advanced the field of isocyanide-based MCRs. The so-called intermediate nitrilium ion could be trapped by a nucleophile such as azide, -hydroxyphthalimide, thiol, saccharin, phenol, water, and hydrogen sulfide instead of the original carboxylic acid to allow for a wide variety of Ugi-type reactions to occur.β In addition to isocyanide, there are alternative reagents for the other three components: amine, isocyanide, and aldehyde or ketone. All these alternative components render the Ugi reaction an aptly diversity-oriented synthesis of a myriad of biologically active molecules and complex scaffolds. Consequently, this review will delve deeper into alternative components used in the Ugi MCRs, particularly over the past ten years.
Topics: Peptides; Amines; Cyanides; Carboxylic Acids; Aldehydes
PubMed: 36838630
DOI: 10.3390/molecules28041642 -
Nature Communications Nov 2022The preparation of high value-added boronic acids from cheap and plentiful carboxylic acids is desirable. To date, the decarboxylative borylation of carboxylic acids is...
The preparation of high value-added boronic acids from cheap and plentiful carboxylic acids is desirable. To date, the decarboxylative borylation of carboxylic acids is generally realized through the extra step synthesized redox-active ester intermediate or in situ generated carboxylic acid covalent derivatives above 150 °C reaction temperature. Here, we report a direct decarboxylative borylation method of carboxylic acids enabled by visible-light catalysis and that does not require any extra stoichiometric additives or synthesis steps. This operationally simple process produces CO and proceeds under mild reaction conditions, in terms of high step economy and good functional group compatibility. A guanidine-based biomimetic active decarboxylative mechanism is proposed and rationalized by mechanistic studies. The methodology reported herein should see broad application extending beyond borylation.
Topics: Carboxylic Acids; Catalysis; Esters; Boronic Acids; Light
PubMed: 36402764
DOI: 10.1038/s41467-022-34833-1 -
International Journal of Molecular... May 2022Several metals belong to a group of non-biodegradable inorganic constituents that, at low concentrations, play fundamental roles as essential micronutrients for the... (Review)
Review
Several metals belong to a group of non-biodegradable inorganic constituents that, at low concentrations, play fundamental roles as essential micronutrients for the growth and development of plants. However, in high concentrations they can have toxic and/or mutagenic effects, which can be counteracted by natural chemical compounds called chelators. Chelators have a diversity of chemical structures; many are organic acids, including carboxylic acids and cyclic phenolic acids. The exogenous application of such compounds is a non-genetic approach, which is proving to be a successful strategy to reduce damage caused by heavy metal toxicity. In this review, we will present the latest literature on the exogenous addition of both carboxylic acids, including the Kreb's Cycle intermediates citric and malic acid, as well as oxalic acid, lipoic acid, and phenolic acids (gallic and caffeic acid). The use of two non-traditional organic acids, the phytohormones jasmonic and salicylic acids, is also discussed. We place particular emphasis on physiological and molecular responses, and their impact in increasing heavy metal tolerance, especially in crop species.
Topics: Carboxylic Acids; Chelating Agents; Metals, Heavy; Organic Chemicals; Plant Physiological Phenomena
PubMed: 35628249
DOI: 10.3390/ijms23105438