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Nature Sep 2022The mammalian immune system uses various pattern recognition receptors to recognize invaders and host damage and transmits this information to downstream immunometabolic...
The mammalian immune system uses various pattern recognition receptors to recognize invaders and host damage and transmits this information to downstream immunometabolic signalling outcomes. Laccase domain-containing 1 (LACC1) protein is an enzyme highly expressed in inflammatory macrophages and serves a central regulatory role in multiple inflammatory diseases such as inflammatory bowel diseases, arthritis and clearance of microbial infection. However, the biochemical roles required for LACC1 functions remain largely undefined. Here we elucidated a shared biochemical function of LACC1 in mice and humans, converting L-citrulline to L-ornithine (L-Orn) and isocyanic acid and serving as a bridge between proinflammatory nitric oxide synthase (NOS2) and polyamine immunometabolism. We validated the genetic and mechanistic connections among NOS2, LACC1 and ornithine decarboxylase 1 (ODC1) in mouse models and bone marrow-derived macrophages infected by Salmonella enterica Typhimurium. Strikingly, LACC1 phenotypes required upstream NOS2 and downstream ODC1, and Lacc1 chemical complementation with its product L-Orn significantly restored wild-type activities. Our findings illuminate a previously unidentified pathway in inflammatory macrophages, explain why its deficiency may contribute to human inflammatory diseases and suggest that L-Orn could serve as a nutraceutical to ameliorate LACC1-associated immunological dysfunctions such as arthritis or inflammatory bowel disease.
Topics: Animals; Arthritis; Citrulline; Cyanates; Humans; Inflammation; Inflammatory Bowel Diseases; Intracellular Signaling Peptides and Proteins; Macrophages; Mice; Nitric Oxide Synthase Type II; Ornithine; Ornithine Decarboxylase; Polyamines; Salmonella typhimurium
PubMed: 35978195
DOI: 10.1038/s41586-022-05111-3 -
Molecules (Basel, Switzerland) Sep 2022The (thio)urea and benzothiazole (BT) derivatives have been shown to have a broad spectrum of biological activities. These groups, when bonded, result in the... (Review)
Review
The (thio)urea and benzothiazole (BT) derivatives have been shown to have a broad spectrum of biological activities. These groups, when bonded, result in the 2-(thio)ureabenzothizoles (TBT and UBT), which could favor the physicochemical and biological properties. UBTs and TBTs are compounds of great importance in medicinal chemistry. For instance, Frentizole is a UBT derivative used for the treatment of rheumatoid arthritis and systemic lupus erythematosus. The UBTs Bentaluron and Bethabenthiazuron are commercial fungicides used as wood preservatives and herbicides in winter corn crops. On these bases, we prepared this bibliography review, which covers chemical aspects of UBTs and TBTs as potential therapeutic agents as well as their studies on the mechanisms of a variety of pharmacological activities. This work covers synthetic methodologies from 1935 to nowadays, highlighting the most recent approaches to afford UBTs and TBTs with a variety of substituents as illustrated in 42 schemes and 13 figures and concluded with 187 references. In addition, this interesting review is designed on chemical reactions of 2-aminobenzothiazoles (2ABTs) with (thio)phosgenes, iso(thio)cyanates, 1,1'-(thio)carbonyldiimidazoles [(T)CDI]s, (thio)carbamoyl chlorides, and carbon disulfide. This topic will provide information of utility for medicinal chemists dedicated to the design and synthesis of this class of compounds to be tested with respect to their biological activities and be proposed as new pharmacophores.
Topics: Benzothiazoles; Carbon Disulfide; Chlorides; Cyanates; Fungicides, Industrial; Herbicides; Urea
PubMed: 36144837
DOI: 10.3390/molecules27186104 -
Molecular Microbiology Mar 2023The pseudohypohalous acid hypothiocyanite/hypothiocyanous acid (OSCN /HOSCN) has been known to play an antimicrobial role in mammalian immunity for decades. It is a...
The pseudohypohalous acid hypothiocyanite/hypothiocyanous acid (OSCN /HOSCN) has been known to play an antimicrobial role in mammalian immunity for decades. It is a potent oxidant that kills bacteria but is non-toxic to human cells. Produced from thiocyanate (SCN ) and hydrogen peroxide (H O ) in a variety of body sites by peroxidase enzymes, HOSCN has been explored as an agent of food preservation, pathogen killing, and even improved toothpaste. However, despite the well-recognized antibacterial role HOSCN plays in host-pathogen interactions, little is known about how bacteria sense and respond to this oxidant. In this work, we will summarize what is known and unknown about HOSCN in innate immunity and recent advances in understanding the responses that both pathogenic and non-pathogenic bacteria mount against this antimicrobial agent, highlighting studies done with three model organisms, Escherichia coli, Streptococcus spp., and Pseudomonas aeruginosa.
Topics: Humans; Animals; Thiocyanates; Host Microbial Interactions; Peroxidases; Oxidants; Mammals
PubMed: 36718113
DOI: 10.1111/mmi.15025 -
Postepy Higieny I Medycyny... May 2016Carbamylation (carbamoylation) is a post-translational modification resulting from the nonenzymatic reaction between isocyanic acid and free functional groups of... (Review)
Review
Carbamylation (carbamoylation) is a post-translational modification resulting from the nonenzymatic reaction between isocyanic acid and free functional groups of proteins, in particular with the free amino groups. This reaction alters structural and functional properties of proteins and results in faster aging of proteins. Urea present in the body can be transformed into cyanate and its more reactive form, isocyanic acid. High concentration of urea is associated with some diseases, especially with chronic renal failure and atherosclerosis. In human tissues, urea and cyanate are in equilibrium in aqueous solutions. Surprisingly, concentration of isocyanate in the body is much lower than it would appear from the kinetic parameters of urea decomposition. The low concentration of isocyanic acid results from its high reactivity and short half-life. In this review we describe the biochemical mechanism of carbamylation of proteins and free amino acids. We summarize the literature data for carbamylation of hemoglobin, lipoproteins, albumin, membrane proteins and erythropoietin in chronic renal failure. In summary, the carbamylation of proteins may have a negative impact on their biological activity and may contribute to the deterioration of patients with chronic renal failure.
Topics: Amino Acids; Cyanates; Half-Life; Humans; Kidney Failure, Chronic; Protein Processing, Post-Translational; Proteins; Urea
PubMed: 27180968
DOI: 10.5604/17322693.1202189 -
FEMS Microbiology Reviews Oct 2000Carbonic anhydrases catalyze the reversible hydration of CO(2) [CO(2)+H(2)Oright harpoon over left harpoon HCO(3)(-)+H(+)]. Since the discovery of this zinc (Zn)... (Review)
Review
Carbonic anhydrases catalyze the reversible hydration of CO(2) [CO(2)+H(2)Oright harpoon over left harpoon HCO(3)(-)+H(+)]. Since the discovery of this zinc (Zn) metalloenzyme in erythrocytes over 65 years ago, carbonic anhydrase has not only been found in virtually all mammalian tissues but is also abundant in plants and green unicellular algae. The enzyme is important to many eukaryotic physiological processes such as respiration, CO(2) transport and photosynthesis. Although ubiquitous in highly evolved organisms from the Eukarya domain, the enzyme has received scant attention in prokaryotes from the Bacteria and Archaea domains and has been purified from only five species since it was first identified in Neisseria sicca in 1963. Recent work has shown that carbonic anhydrase is widespread in metabolically diverse species from both the Archaea and Bacteria domains indicating that the enzyme has a more extensive and fundamental role in prokaryotic biology than previously recognized. A remarkable feature of carbonic anhydrase is the existence of three distinct classes (designated alpha, beta and gamma) that have no significant sequence identity and were invented independently. Thus, the carbonic anhydrase classes are excellent examples of convergent evolution of catalytic function. Genes encoding enzymes from all three classes have been identified in the prokaryotes with the beta and gamma classes predominating. All of the mammalian isozymes (including the 10 human isozymes) belong to the alpha class; however, only nine alpha class carbonic anhydrase genes have thus far been found in the Bacteria domain and none in the Archaea domain. The beta class is comprised of enzymes from the chloroplasts of both monocotyledonous and dicotyledonous plants as well as enzymes from phylogenetically diverse species from the Archaea and Bacteria domains. The only gamma class carbonic anhydrase that has thus far been isolated and characterized is from the methanoarchaeon Methanosarcina thermophila. Interestingly, many prokaryotes contain carbonic anhydrase genes from more than one class; some even contain genes from all three known classes. In addition, some prokaryotes contain multiple genes encoding carbonic anhydrases from the same class. The presence of multiple carbonic anhydrase genes within a species underscores the importance of this enzyme in prokaryotic physiology; however, the role(s) of this enzyme is still largely unknown. Even though most of the information known about the function(s) of carbonic anhydrase primarily relates to its role in cyanobacterial CO(2) fixation, the prokaryotic enzyme has also been shown to function in cyanate degradation and the survival of intracellular pathogens within their host. Investigations into prokaryotic carbonic anhydrase have already led to the identification of a new class (gamma) and future research will undoubtedly reveal novel functions for carbonic anhydrase in prokaryotes.
Topics: Amino Acid Sequence; Archaea; Bacteria; Bacterial Proteins; Carbon Dioxide; Carbonic Anhydrases; Cyanates; Cyanobacteria; Escherichia coli; Methanosarcina; Molecular Sequence Data; Neisseria; Phylogeny; Protein Structure, Secondary; Salmonella typhimurium; Sequence Alignment
PubMed: 10978542
DOI: 10.1111/j.1574-6976.2000.tb00546.x -
Canadian Medical Association Journal Mar 1976Occupational asthma is probably much more common than is generally realized. Though many causes have been described, undoubtedly many more are yet to be recognized. One... (Review)
Review
Occupational asthma is probably much more common than is generally realized. Though many causes have been described, undoubtedly many more are yet to be recognized. One of the diagnostic difficulties lies in the fact that in most forms of this disease a late asthmatic reaction occurs in the evening rather than at work. The pathogenetic mechanisms differ in various forms of occupational asthma. In some, an immunologic mechanism is likely; in others, a "pharmacologic" action of the offending agent is implicated. Asthma due to inhalation of dusts of western red cedar, isocyanates, detergent enzymes and textiles is considered in detail. Periodic examination of workers at risk is of value for early diagnosis and prevention of irrversible airway obstruction.
Topics: Asthma; Cyanates; Detergents; Enzymes; Humans; Models, Biological; Occupational Diseases; Textiles; Trees; Wood
PubMed: 766943
DOI: No ID Found -
International Journal of Molecular... May 2023(Thio)ureas ((T)Us) and benzothiazoles (BTs) each have demonstrated to have a great variety of biological activities. When these groups come together, the... (Review)
Review
(Thio)ureas ((T)Us) and benzothiazoles (BTs) each have demonstrated to have a great variety of biological activities. When these groups come together, the 2-(thio)ureabenzothizoles [(T)UBTs] are formed, improving the physicochemical as well as the biological properties, making these compounds very interesting in medicinal chemistry. Frentizole, bentaluron and methabenzthiazuron are examples of UBTs used for treatment of rheumatoid arthritis and as wood preservatives and herbicides in winter corn crops, respectively. With this antecedent, we recently reported a bibliographic review about the synthesis of this class of compounds, from the reaction of substituted 2-aminobenzothiazoles (ABTs) with iso(thio)cyanates, (thio)phosgenes, (thio)carbamoyl chlorides, 1,1'-(thio)carbonyldiimidazoles, and carbon disulfide. Herein, we prepared a bibliographic review about those features of design, chemical synthesis, and biological activities relating to (T)UBTs as potential therapeutic agents. This review is about synthetic methodologies generated from 1968 to the present day, highlighting the focus to transform (T)UBTs to compounds containing a range substituents, as illustrated with 37 schemes and 11 figures and concluded with 148 references. In this topic, the scientists dedicated to medicinal chemistry and pharmaceutical industry will find useful information for the design and synthesis of this interesting group of compounds with the aim of repurposing these compounds.
Topics: Urea; Benzothiazoles; Cyanates
PubMed: 37298442
DOI: 10.3390/ijms24119488 -
Cancer Biology & Therapy Dec 2023Sinapine thiocyanate (ST), an alkaloid existed extensively in seeds of cruciferous plants, exhibits a number of pharmacological effects, including anti-inflammatory and...
Sinapine thiocyanate (ST), an alkaloid existed extensively in seeds of cruciferous plants, exhibits a number of pharmacological effects, including anti-inflammatory and anti-malignancy properties. However, it is still unknown what effects and molecular mechanisms ST has on colorectal cancer (CRC). In the current study, it was indicated that ST inhibited proliferation, colony formation, and apoptosis , as well as arrested the G1 phase of CRC cells. There was a significant repressive effects of ST on invasion and migration of CRC cells . RNA-sequencing indicated that 750 differentially expressed genes existed in CRC cells after ST treatment, and enrichment analysis demonstrated that ST obviously decreased the activation of keratinization pathways. Among DEGs enriched in keratinization, keratin 6A (KRT6A) was decreased the most significant, as well as its target gene S100 calcium-binding protein A2 (S100A2). Low expression of KRT6A and S100A2 signatures indicated a favorable prognosis in CRC patients. Moreover, we found overexpression of KRT6A relieved the inhibitory effects of ST in CRC cells. Furthermore, ST inhibited the CRC cell proliferation , and reduced KRT6A and KI67 expression in xenograft tumor. Taken together, we demonstrated that ST exhibited anti-CRC properties by inhibiting KRT6A/S100A2 axis. It is possible that ST can be used as a treatment for CRC.
Topics: Humans; Thiocyanates; Keratin-6; Apoptosis; Neoplasms; Chemotactic Factors; S100 Proteins
PubMed: 37647260
DOI: 10.1080/15384047.2023.2249170 -
Free Radical Research Jun 2015Thiocyanate (SCN(-)) is a ubiquitous molecule in mammalian biology, reaching up to mM concentrations in extracellular fluids. Two- electron oxidation of SCN(-) by H2O2... (Review)
Review
Thiocyanate (SCN(-)) is a ubiquitous molecule in mammalian biology, reaching up to mM concentrations in extracellular fluids. Two- electron oxidation of SCN(-) by H2O2 produces hypothiocyanous acid (HOSCN), a potent anti-microbial species. This reaction is catalyzed by chordate peroxidases (e.g., myeloperoxidase and lactoperoxidase), occurring in human secretory mucosa, including the oral cavity, airway, and alimentary tract, and regulates resident and transient flora as part of innate immunity. Increasing SCN(-) levels limits the concentrations of a family of 2-electron oxidants (H2O2, hypohalous acids, and haloamines) in favor of HOSCN formation, altering the oxidative impact on host tissue by substitution of repairable thiol and selenol oxidations instead of biomolecule degradation. This fine-tuning of inflammatory oxidation paradoxically associates with maintained host defense and decreased host injury during infections, due in part to phylogenetic differences in the thioredoxin reductase system between mammals and their pathogens. These differences could be exploited by pharmacologic use of SCN(-). Recent preclinical studies have identified anti-microbial and anti-inflammatory effects of SCN(-) in pulmonary and cardiovascular animal models, with implications for treatment of infectious lung disease and atherogenesis. Further research is merited to expand on these findings and identify other diseases where SCN(-) may be of use. High oral bioavailability and an increased knowledge of the biochemical effects of SCN(-) on a subset of pro-inflammatory reactions suggest clinical utility.
Topics: Animals; Anti-Bacterial Agents; Humans; Immunity, Innate; Inflammation; Oxidation-Reduction; Peroxidases; Thiocyanates; Thioredoxin-Disulfide Reductase
PubMed: 25564094
DOI: 10.3109/10715762.2014.1003372 -
Aging Jun 2019Carbamylation, which corresponds to the binding of isocyanic acid to the amino groups of proteins, is a nonenzymatic post-translational modification responsible for...
Carbamylation, which corresponds to the binding of isocyanic acid to the amino groups of proteins, is a nonenzymatic post-translational modification responsible for alterations of protein structural and functional properties. Tissue accumulation of carbamylation-derived products and their role in pathological processes such as atherosclerosis or chronic renal failure have been previously documented. However, few studies have focused on the carbamylation of intracellular proteins and their subsequent role in cellular aging. This study aimed to determine the extent of intracellular protein carbamylation, its impact on cell functions and the ability of cells to degrade these modified proteins. Fibroblasts were incubated with cyanate or urea and the carbamylation level was evaluated by immunostaining and homocitrulline quantification. The results showed that carbamylated proteins accumulated intracellularly and that all proteins were susceptible. The presence of intracellular carbamylated proteins did not modify cell proliferation or type I collagen synthesis nor did it induce cell senescence, but it significantly decreased cell motility. Fibroblasts were able to degrade carbamylated proteins through the ubiquitin-proteasome system. In conclusion, intracellular proteins are susceptible to carbamylation but their accumulation does not seem to deeply affect cell function, owing largely to their elimination by the ubiquitin-proteasome system.
Topics: Cellular Senescence; Cyanates; Fibroblasts; Humans; Proteasome Endopeptidase Complex; Protein Carbamylation; Skin; Urea
PubMed: 31170093
DOI: 10.18632/aging.102002