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Environmental Science and Pollution... Feb 2021Urban particulate matter (PM), a great danger to public health, is associated with increasing risk of pulmonary diseases. However, the involved key genes and signaling...
Urban particulate matter (PM), a great danger to public health, is associated with increasing risk of pulmonary diseases. However, the involved key genes and signaling pathways mediating the cellular responses to urban PM are largely unknown. In this study, human bronchial epithelial cells BEAS-2B was exposed to Standard reference material (SRM) 1649b, followed by RNA-sequencing (RNA-seq) and a combination of different bioinformatics analysis. A total of 201 genes (111 upregulated and 90 downregulated) were identified as the differentially expressed genes (DEGs). Moreover, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) unveiled several significant genes and pathways involved in PM-induced lung toxicity. Protein-protein interaction (PPI) network was performed with the Search Tool for the Retrieval of Interacting Genes (STRING), and the hub gene modules were recognized by Molecular Complex Detection (MCODE), a plug-in of Cytoscape. Moreover, Connectivity Map (CMap) analysis found six candidate small molecular compounds to reverse PM-altered gene expression, including aminohippuric acid, captopril, cinoxacin, fasudil, pargyline, and altizide. Finally, the expressions of part vital genes related to inflammation (IL-1β, CXCL2, CXCL5, CXCL8), ferroptosis (HMOX1, GCLM), and autophagy (BECN1, MAPK1LC3B) were in accordance with the RNA-seq data, with a concentration-dependent manner. This study may be helpful in revealing the complex molecular mechanisms underlying PM-induced lung toxicity and provide some new therapeutic targets for PM-related pulmonary diseases.
Topics: Epithelial Cells; Gene Expression Profiling; Gene Ontology; Humans; Particulate Matter; Transcriptome
PubMed: 33150508
DOI: 10.1007/s11356-020-11347-1 -
ELife Nov 2020extensively modulates the host ubiquitin network to create the Legionella-containing vacuole (LCV) for its replication. Many of its virulence factors function as...
extensively modulates the host ubiquitin network to create the Legionella-containing vacuole (LCV) for its replication. Many of its virulence factors function as ubiquitin ligases or deubiquitinases (DUBs). Here, we identify Lem27 as a DUB that displays a preference for diubiquitin formed by K6, K11, or K48. Lem27 is associated with the LCV where it regulates Rab10 ubiquitination in concert with SidC and SdcA, two bacterial E3 ubiquitin ligases. Structural analysis of the complex formed by an active fragment of Lem27 and the substrate-based suicide inhibitor ubiquitin-propargylamide (PA) reveals that it harbors a fold resembling those in the OTU1 DUB subfamily with a Cys-His catalytic dyad and that it recognizes ubiquitin via extensive hydrogen bonding at six contact sites. Our results establish Lem27 as a DUB that functions to regulate protein ubiquitination on phagosomes by counteracting the activity of bacterial ubiquitin E3 ligases.
Topics: Amino Acid Motifs; Amino Acid Sequence; Bacterial Proteins; Deubiquitinating Enzymes; Legionella pneumophila; Pargyline; Phagosomes; Propylamines; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination; Vacuoles
PubMed: 33136002
DOI: 10.7554/eLife.58114 -
Identification of 7,8-dihydroxy-3-phenylcoumarin as a reversible monoamine oxidase enzyme inhibitor.Journal of Biochemical and Molecular... Feb 2021We herein report the biological evaluation of 3-arylcoumarin derivatives (3a-l) as potential human monoamine oxidase-A and -B (hMAO-A and hMAO-B) inhibitors. The result...
We herein report the biological evaluation of 3-arylcoumarin derivatives (3a-l) as potential human monoamine oxidase-A and -B (hMAO-A and hMAO-B) inhibitors. The result indicated that 7,8-dihydroxy-3-(4-nitrophenyl)coumarin (3j) was most effective against MAO-A (inhibition concentration [IC ] = 6.46 ± 0.02 µM) and MAO-B (IC = 3.8 ± 0.3 µM) enzymes than other synthesized compounds and reference compounds (pargyline and moclobemide). Furthermore, compound (3j) showed (a) nonselectivity against hMAO enzymes, (b) reversible hMAO enzymes inhibition, and (c) neuroprotection against H O -treated human neuroblastoma (N2a) cells. Finally, a molecular modeling study revealed that the hMAO enzymes inhibitory activity of the compound (3j) may be due to the orientation where the nitro (NO ) group lies deep into the receptor and the phenyl ring directed toward flavin adenosine dinucleotide via hydrogen bond interaction, and possible π-π interaction with various important residues. Thus, the results of the present study demonstrate that compound (3j) can be considered as a promising scaffold for the development of hMAO-A and hMAO-B inhibitors.
Topics: Cell Line, Tumor; Crystallography, X-Ray; Humans; Inhibitory Concentration 50; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase Inhibitors; Structure-Activity Relationship
PubMed: 33085988
DOI: 10.1002/jbt.22651 -
International Journal of Biological... Dec 2020The magnetically isolable nanobiocomposites have significant impact as the modified new generation catalysts in recent days. This has persuaded us to design and...
The magnetically isolable nanobiocomposites have significant impact as the modified new generation catalysts in recent days. This has persuaded us to design and synthesis of a novel Ag NPs decorated biguanidine-chitosan (Bigua-CS) dual biomolecular functionalized core-shell type magnetic nanocomposite (Ag/Bigua-CS@FeO). Bigua-CS could be introducing polysaccharide materials as potential coating agent to immobilizing and stabilizing metal nanoparticles. The material was characterized using several advanced techniques like fourier transformed infrared spectroscopy (FT-IR), inductively coupled plasma (ICP), field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDX), atomic mapping, high resolution transmission electron microscopy (HR-TEM), vibrating sample magnetometer (VSM) and X-ray diffraction (XRD). Towards the chemical applications of the material, we headed the multicomponent synthesis of diverse propargylamines by A coupling in water, which ended up with excellent yields. Due to strong paramagnetism, the catalyst was easily isolable and reused in 9cycles without any leaching and considerable change in reactivity. In addition, the catalyst was engaged in biological assays like study of anti-oxidant properties by DPPH mediated free radical scavenging test using BHT as a reference molecule. Thereafter, on having a significant IC value in radical scavenging assay, we extended the bio-application of the catalyst in anticancer study of adenocarcinoma cells of human lungs. The three different cancer cell lines, PC-14, LC-2/ad and HLC-1 were used in this regard. The best result was achieved in the case of PC-14 cell line with strong IC values.
Topics: Antineoplastic Agents; Cell Line, Tumor; Chitosan; Coated Materials, Biocompatible; Guanidines; Humans; Lung Neoplasms; Magnetite Nanoparticles; Metal Nanoparticles; Pargyline; Propylamines; Silver
PubMed: 32991899
DOI: 10.1016/j.ijbiomac.2020.09.193 -
International Journal of Molecular... Aug 2020Kidney cancer is one of the most difficult cancers to treat by targeted and radiation therapy. Therefore, identifying key regulators in this cancer is especially...
Kidney cancer is one of the most difficult cancers to treat by targeted and radiation therapy. Therefore, identifying key regulators in this cancer is especially important for finding new drugs. We focused on androgen receptor (AR) regulation by its epigenetic co-regulator lysine-specific histone demethylase 1 (LSD1) in kidney cancer development. LSD1 knock-down in kidney cancer cells decreased expression of AR target genes. Moreover, the binding of AR to target gene promoters was reduced and histone methylation status was changed in LSD1 knock-down kidney cancer cells. LSD1 knock-down also slowed growth and decreased the migration ability of kidney cancer cells. We found that pargyline, known as a LSD1 inhibitor, can reduce AR activity in kidney cancer cells. The treatment of kidney cancer cells with pargyline delayed growth and repressed epithelial-mesenchymal transition (EMT) markers. These effects were additively enhanced by co-treatment with the AR inhibitor enzalutamide. Down-regulation of LSD1 in renal cancer cells (RCC) attenuated in vivo tumor growth in a xenograft mouse model. These results provide evidence that LSD1 can regulate kidney cancer cell growth epigenetic control of AR transcription factors and that LSD1 inhibitors may be good candidate drugs for treating kidney cancer.
Topics: Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Cells, Cultured; Disease Progression; Gene Expression Regulation, Neoplastic; HEK293 Cells; Histone Demethylases; Humans; Kidney Neoplasms; Male; Mice; Mice, Inbred NOD; Mice, SCID; Receptors, Androgen; Signal Transduction
PubMed: 32847068
DOI: 10.3390/ijms21176089 -
Journal of the American Chemical Society Sep 2020An efficient catalytic method to convert an α-C-H bond of -alkylamines into an α-C-alkynyl bond was developed. In the past, such transformations were carried out under...
Direct Conversion of -Alkylamines to -Propargylamines through C-H Activation Promoted by Lewis Acid/Organocopper Catalysis: Application to Late-Stage Functionalization of Bioactive Molecules.
An efficient catalytic method to convert an α-C-H bond of -alkylamines into an α-C-alkynyl bond was developed. In the past, such transformations were carried out under oxidative conditions, and the enantioselective variants were confined to tetrahydroisoquinoline derivatives. Here, we disclose a method for the union of -alkylamines and trimethylsilyl alkynes, without the presence of an external oxidant and promoted through cooperative actions of two Lewis acids, B(CF) and a Cu-based complex. A variety of propargylamines can be synthesized in high diastereo- and enantioselectivity. The utility of the approach is demonstrated by the late-stage site-selective modification of bioactive amines. Kinetic investigations that shed light on various mechanistic nuances of the catalytic process are presented.
Topics: Amines; Catalysis; Copper; Lewis Acids; Molecular Structure; Organometallic Compounds; Pargyline; Propylamines; Stereoisomerism
PubMed: 32830966
DOI: 10.1021/jacs.0c08599 -
Bioorganic & Medicinal Chemistry Letters Sep 2020A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the...
A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC values in the low nanomolar range.
Topics: Administration, Oral; Antiviral Agents; Genotype; Hepacivirus; Hepatitis C; Humans; Mutation; Pargyline; Pyrazines; Structure-Activity Relationship; Viral Nonstructural Proteins; Virus Replication
PubMed: 32738974
DOI: 10.1016/j.bmcl.2020.127361 -
Nature Metabolism Sep 2020Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta cells. Pluripotent stem cells can now be differentiated into beta cells, thus raising...
Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta cells. Pluripotent stem cells can now be differentiated into beta cells, thus raising the prospect of a cell replacement therapy for T1D. However, autoimmunity would rapidly destroy newly transplanted beta cells. Using a genome-scale CRISPR screen in a mouse model for T1D, we show that deleting RNLS, a genome-wide association study candidate gene for T1D, made beta cells resistant to autoimmune killing. Structure-based modelling identified the U.S. Food and Drug Administration-approved drug pargyline as a potential RNLS inhibitor. Oral pargyline treatment protected transplanted beta cells in diabetic mice, thus leading to disease reversal. Furthermore, pargyline prevented or delayed diabetes onset in several mouse models for T1D. Our results identify RNLS as a modifier of beta cell vulnerability and as a potential therapeutic target to avert beta cell loss in T1D.
Topics: Animals; Autoimmunity; CRISPR-Cas Systems; Diabetes Mellitus, Type 1; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Female; Genome-Wide Association Study; Induced Pluripotent Stem Cells; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Monoamine Oxidase; Mutation; Pargyline
PubMed: 32719542
DOI: 10.1038/s42255-020-0254-1 -
Carbohydrate Research Aug 2020An efficient three component coupling of aromatic aldehyde, deoxy sugar based alkyne (α-2-deoxy propargyl glycoside) and heterocyclic amine have been refluxed to...
An efficient three component coupling of aromatic aldehyde, deoxy sugar based alkyne (α-2-deoxy propargyl glycoside) and heterocyclic amine have been refluxed to synthesize stereoselective chiral propargylamines with good to excellent yield using only CuI catalyst along with bifunctional ligand l-proline. This method has proved to be applicable in wide range of substrates and found highly enantioselective with respect to earlier reported methods. In addition, l-proline was found as a chiral source which demonstrated that it could be developed as a highly enantioselective method for the construction of deoxy sugar based chiral propargylamines. The ligand l-proline was used for the first time in enantioselective A-coupling reaction of α-2-deoxy propargyl glycosides involving substituted aromatic aldehyde and heterocyclic amines. Herein, we have synthesized 15 novel compounds based on A-coupling reaction and structures of all the enantioselective compounds were characterised by TLC and NMR spectroscopy.
Topics: Copper; Deoxy Sugars; Ligands; Molecular Structure; Pargyline; Proline; Propylamines; Stereoisomerism
PubMed: 32559510
DOI: 10.1016/j.carres.2020.108053 -
Molecules (Basel, Switzerland) May 2020Previously synthesized novel chalcone oxime ethers (COEs) were evaluated for inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE)....
Previously synthesized novel chalcone oxime ethers (COEs) were evaluated for inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Twenty-two of the 24 COEs synthesized, except and , had potent and/or significant selective inhibitory effects on MAO-B. potently inhibited MAO-B with an IC value of 0.018 µM, which was 105, 2.3, and 1.1 times more potent than clorgyline, lazabemide, and pargyline (reference drugs), respectively. , and were also active against MAO-B, both had an IC value of 0.028 µM, which was 67 and 1.5 times lower than those of clorgyline and lazabemide, respectively. Most of the COEs exhibited weak inhibitory effects on MAO-A and AChE. most potently inhibited MAO-A (IC = 0.88 µM) and also significantly inhibited MAO-B (IC = 0.13 µM), and it could be considered as a potential nonselective MAO inhibitor. and inhibited AChE with IC values of 5.35 and 4.39 µM, respectively. The selectivity index (SI) of for MAO-B was higher than that of (SI = 778.6 vs. 222.2), but the IC value (0.028 µM) was slightly lower than that of (0.018 µM). In reversibility experiments, inhibitions of MAO-B by and were recovered to the levels of reference reversible inhibitors and both competitively inhibited MAO-B, with K values of 0.0075 and 0.010 µM, respectively. Our results show that and are potent, selective MAO-B inhibitors, and is a candidate of dual-targeting molecule for MAO-B and AChE.
Topics: Acetylcholinesterase; Chalcone; Cholinesterase Inhibitors; Ethers; Humans; Kinetics; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Oximes
PubMed: 32443652
DOI: 10.3390/molecules25102356