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RSC Medicinal Chemistry May 2024A simple assay involving the measurement of IL-6 production in human synovial fibroblasts from rheumatoid arthritis patients has been utilised to select candidates from...
A new class of 7-deazaguanine agents targeting autoimmune diseases: dramatic reduction of synovial fibroblast IL-6 production from human rheumatoid arthritis patients and improved performance against murine experimental autoimmune encephalomyelitis.
A simple assay involving the measurement of IL-6 production in human synovial fibroblasts from rheumatoid arthritis patients has been utilised to select candidates from a targeted library of queuine tRNA ribosyltransferase (QTRT) substrates for subsequent screening in murine experimental autoimmune encephalomyelitis (EAE - a model of multiple sclerosis). The activity assay discriminated between poor and excellent 7-deazaguanine QTRT substrates and allowed the identification of several structures which subsequently outperformed the previous lead in EAE. Two molecules were of significant promise: one rigidified analogue of the lead, and another considerably simpler structure incorporating an oxime motif which differs structurally from the lead to a considerable extent. These studies provide data from human cells for the first time and have expanded both the chemical space and current understanding of the structure-activity relationship underpinning the remarkable potential of 7-deazguanines in a Multiple Sclerosis disease model.
PubMed: 38784475
DOI: 10.1039/d4md00028e -
JCO Precision Oncology May 2024This report highlights the first pediatric case of pilocytic astrocytoma with BRAF V599ins mutation, successfully treated with dabrafenib.
This report highlights the first pediatric case of pilocytic astrocytoma with BRAF V599ins mutation, successfully treated with dabrafenib.
Topics: Humans; Astrocytoma; Proto-Oncogene Proteins B-raf; Oximes; Imidazoles; Mutation; Brain Neoplasms; Male; Female; Child
PubMed: 38781546
DOI: 10.1200/PO.24.00055 -
Chemistry (Weinheim An Der Bergstrasse,... May 2024Research on the chemoselective metal-catalyzed hydrogenation of conjugated π-systems has mostly been focussed on enones. Herein, we communicate the understudied...
Research on the chemoselective metal-catalyzed hydrogenation of conjugated π-systems has mostly been focussed on enones. Herein, we communicate the understudied asymmetric hydrogenation of enimines catalyzed by N,P-iridium complexes and chemoselective toward the alkene. A number of enoxime ethers underwent hydrogenation smoothly to yield the desired products in high yield and stereopurity (up to 99 % yield, up to 99 % ee). No hydrogenation of the C=N π-bond was observed under the applied reaction conditions (20 bar H, rt, DCM). It was demonstrated that the chiral oxime ether could be hydrolyzed into the ketone with complete preservation of the installed stereogenity at the α-carbon. At last, a binding mode of the substrate to the active iridium catalyst and the consequence for the stereoselective outcome was proposed.
PubMed: 38779790
DOI: 10.1002/chem.202401333 -
Cell Communication and Signaling : CCS May 2024Extracellular vesicles (EVs) constitute a vital component of intercellular communication, exerting significant influence on metastasis formation and drug resistance...
Extracellular vesicles (EVs) constitute a vital component of intercellular communication, exerting significant influence on metastasis formation and drug resistance mechanisms. Malignant melanoma (MM) is one of the deadliest forms of skin cancers, because of its high metastatic potential and often acquired resistance to oncotherapies. The prevalence of BRAF mutations in MM underscores the importance of BRAF-targeted therapies, such as vemurafenib and dabrafenib, alone or in combination with the MEK inhibitor, trametinib. This study aimed to elucidate the involvement of EVs in MM progression and ascertain whether EV-mediated metastasis promotion persists during single agent BRAF (vemurafenib, dabrafenib), or MEK (trametinib) and combined BRAF/MEK (dabrafenib/trametinib) inhibition.Using five pairs of syngeneic melanoma cell lines, we assessed the impact of EVs - isolated from their respective supernatants - on melanoma cell proliferation and migration. Cell viability and spheroid growth assays were employed to evaluate proliferation, while migration was analyzed through mean squared displacement (MSD) and total traveled distance (TTD) measurements derived from video microscopy and single-cell tracking.Our results indicate that while EV treatments had remarkable promoting effect on cell migration, they exerted only a modest effect on cell proliferation and spheroid growth. Notably, EVs demonstrated the ability to mitigate the inhibitory effects of BRAF inhibitors, albeit they were ineffective against a MEK inhibitor and the combination of BRAF/MEK inhibitors. In summary, our findings contribute to the understanding of the intricate role played by EVs in tumor progression, metastasis, and drug resistance in MM.
Topics: Melanoma; Extracellular Vesicles; Proto-Oncogene Proteins B-raf; Humans; Cell Movement; Cell Line, Tumor; Protein Kinase Inhibitors; Cell Proliferation; Vemurafenib; Pyrimidinones; Pyridones; Imidazoles; Oximes
PubMed: 38778340
DOI: 10.1186/s12964-024-01660-4 -
International Journal of Biological... Jun 2024In light of the depletion of petrochemical resources and increase in environmental pollution, there has been a significant focus on utilizing natural biomass,...
In light of the depletion of petrochemical resources and increase in environmental pollution, there has been a significant focus on utilizing natural biomass, specifically lignin, to develop sustainable and functional materials. This research presents the development of a lignin-based polyurethane (DLPU) with photothermal-responsiveness by incorporating lignin and oxime-carbamate bonds into polyurethane network. The abundant hydrogen bonds between lignin and the polyurethane matrix, along with its cross-linked structure, contribute to DLPU's excellent mechanical strength (30.2 MPa) and toughness (118.7 MJ·m). Moreover, the excellent photothermal conversion ability of DLPU (54.4 %) activates dynamic reversible behavior of oxime-carbamate bonds and hydrogen bonds, thereby endowing DLPU with exceptional self-healing performance. After 15 min of near-infrared irradiation, DLPU achieves self-healing efficiencies of 96.0 % for tensile strength and 96.3 % for elongation at break. Additionally, DLPU exhibits photocontrolled solid-state plasticity as well as an excellent phototriggered shape-memory effect (70 s), with shape fixity and recovery ratios reaching 98.8 % and 95.3 %, respectively. By exploiting the spatial controllability and photothermal-responsiveness of DLPU, we demonstrate multi-dimensional responsive materials with self-healing and shape-shifting properties. This work not only promotes the development of multi-functional polyurethanes but also provides a pathway for the high-value utilization of lignin.
Topics: Polyurethanes; Lignin; Tensile Strength; Temperature; Hydrogen Bonding; Mechanical Phenomena
PubMed: 38777014
DOI: 10.1016/j.ijbiomac.2024.132499 -
Preferential Door for Ligand Binding and Unbinding Pathways in Inhibited Human Acetylcholinesterase.The Journal of Physical Chemistry... May 2024Rising global population and increased food demands have resulted in the increased use of organophosphate pesticides (OPs), leading to toxin accumulation and...
Rising global population and increased food demands have resulted in the increased use of organophosphate pesticides (OPs), leading to toxin accumulation and transmission to humans. Pralidoxime (2-PAM), an FDA-approved drug, serves as an antidote for OP therapy. However, the atomic-level detoxification mechanisms regarding the design of novel antidotes remain unclear. This is the first study to examine the binding and unbinding pathways of 2-PAM to human acetylcholinesterase (HuAChE) through three identified doors using an enhanced sampling method called ligand-binding parallel cascade selection molecular dynamics (LB-PaCS-MD). Remarkably, LB-PaCS-MD could identify a predominant in-line binding mechanism through the acyl door at 63.79% ± 6.83%, also implicating it in a potential unbinding route (90.14% ± 4.22%). Interestingly, crucial conformational shifts in key residues, W86, Y341, and Y449, and the Ω loop significantly affect door dynamics and ligand binding modes. The LB-PaCS-MD technique can study ligand-binding pathways, thereby contributing to the design of antidotes and covalent drugs.
Topics: Humans; Acetylcholinesterase; Antidotes; Binding Sites; Cholinesterase Inhibitors; Ligands; Molecular Dynamics Simulation; Pralidoxime Compounds; Protein Binding
PubMed: 38768263
DOI: 10.1021/acs.jpclett.4c00514 -
Thoracic Cancer Jun 2024Although dabrafenib plus trametinib has been approved for BRAF V600E mutation positive advanced non-small cell lung cancer (NSCLC), data on its efficacy against uncommon...
Although dabrafenib plus trametinib has been approved for BRAF V600E mutation positive advanced non-small cell lung cancer (NSCLC), data on its efficacy against uncommon BRAF mutations are still limited due to their rare frequency. We report a case of 70-year-old woman with BRAF V600_W604 deletion-insertion R-positive stage IVA lung adenocarcinoma, who was successfully treated with dabrafenib plus trametinib. Herein, we discuss the oncogenic role of uncommon BRAF mutations and highlight the importance of performing comprehensive genomic profiling on patients without any targetable gene alterations in companion diagnostics.
Topics: Humans; Pyridones; Oximes; Pyrimidinones; Proto-Oncogene Proteins B-raf; Imidazoles; Female; Aged; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mutation; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38766698
DOI: 10.1111/1759-7714.15330 -
Carbohydrate Polymers Aug 2024The dynamic interplay between cells and their native extracellular matrix (ECM) influences cellular behavior, imposing a challenge in biomaterial design. Dynamic...
The dynamic interplay between cells and their native extracellular matrix (ECM) influences cellular behavior, imposing a challenge in biomaterial design. Dynamic covalent hydrogels are viscoelastic and show self-healing ability, making them a potential scaffold for recapitulating native ECM properties. We aimed to implement kinetically and thermodynamically distinct crosslinkers to prepare self-healing dynamic hydrogels to explore the arising properties and their effects on cellular behavior. To do so, aldehyde-substituted hyaluronic acid (HA) was synthesized to generate imine, hydrazone, and oxime crosslinked dynamic covalent hydrogels. Differences in equilibrium constants of these bonds yielded distinct properties including stiffness, stress relaxation, and self-healing ability. The effects of degree of substitution (DS), polymer concentration, crosslinker to aldehyde ratio, and crosslinker functionality on hydrogel properties were evaluated. The self-healing ability of hydrogels was investigated on samples of the same and different crosslinkers and DS to obtain hydrogels with gradient properties. Subsequently, human dermal fibroblasts were cultured in 2D and 3D to assess the cellular response considering the dynamic properties of the hydrogels. Moreover, assessing cell spreading and morphology on hydrogels having similar modulus but different stress relaxation rates showed the effects of matrix viscoelasticity with higher cell spreading in slower relaxing hydrogels.
Topics: Hyaluronic Acid; Hydrogels; Humans; Fibroblasts; Schiff Bases; Cross-Linking Reagents; Biocompatible Materials; Extracellular Matrix; Cells, Cultured
PubMed: 38763720
DOI: 10.1016/j.carbpol.2024.122173 -
Chemico-biological Interactions Jun 2024Nerve agents pose significant threats to civilian and military populations. The reactivation of acetylcholinesterase (AChE) is critical in treating acute poisoning, but...
Nerve agents pose significant threats to civilian and military populations. The reactivation of acetylcholinesterase (AChE) is critical in treating acute poisoning, but there is still lacking broad-spectrum reactivators, which presents a big challenge. Therefore, insights gained from the reactivation kinetic analysis and molecular docking are essential for understanding the behavior of reactivators towards intoxicated AChE. In this research, we present a systematic determination of the reactivation kinetics of three V agents-inhibited four human ChEs [(AChE and butyrylcholinesterase (BChE)) from either native or recombinant resources, namely, red blood cell (RBC) AChE, rhAChE, hBChE, rhBChE) reactivated by five standard oximes. We unveiled the effect of native and recombinant ChEs on the reactivation kinetics of V agents ex vitro, where the reactivation kinetics characteristic of Vs-inhibited BChE was reported for the first time. In terms of the inhibition type, all of the five oxime reactivators exhibited noncompetitive inhibition. The inhibition potency of these reactivators would not lead to the difference in the reactivation kinetics between native and recombinant ChE. Despite the significant differences between the native and recombinant ChEs observed in the inhibition, aging, and spontaneous reactivation kinetics, the reactivation kinetics of V agent-inhibited ChEs by oximes were less differentiated, which were supported by the ligand docking results. We also found differences in the reactivation efficiency between five reactivators and the phosphorylated enzyme, and molecular dynamic simulations can further explain from the perspectives of conformational stability, hydrogen bonding, binding free energies, and amino acid contributions. By Poisson-Boltzmann surface area (MM-PBSA) calculations, the total binding free energy trends aligned well with the experimental k values.
Topics: Humans; Molecular Docking Simulation; Oximes; Kinetics; Nerve Agents; Cholinesterase Inhibitors; Acetylcholinesterase; Butyrylcholinesterase; Molecular Dynamics Simulation; Cholinesterase Reactivators; Recombinant Proteins
PubMed: 38763347
DOI: 10.1016/j.cbi.2024.111061 -
Spectrochimica Acta. Part A, Molecular... Oct 2024pH and Cu ion concentration changes are linked to disorders like Alzheimer's and cancer. Rapid detection of pH and Cu ions is critical for public health and...
pH and Cu ion concentration changes are linked to disorders like Alzheimer's and cancer. Rapid detection of pH and Cu ions is critical for public health and environmental concerns. The semi-salamo-type probe (E)-2-hydroxy-1-naphthaldehyde O-(2-(aminooxy)ethyl) oxime (NSS) demonstrated substantial dual-functional performance, sensing pH change and Cu ions. A single excitation and double emission characteristic on the probe NSS made it distinctive. Probe NSS exhibits pH-dependent excited state intramolecular proton transfer (ESIPT), and its optical properties vary based on the pH environment. Probe NSS detects pH changes from 2 to 11 by changing the "off-on-off" of the excited state intra-molecular proton transfer (ESIPT) mechanism, exhibiting rapid, reversible, and selective responses. In addition, the luminescent salamo-like naphthalene-based probe NSS can coordinate with Cu ions, achieving great selectivity and sensitivity to identify Cu ions with a detection limit of 0.84 ppb (13.2 nM) Probe NSS can detect Cu ions in actual water samples such as tap water and yellow river water. The test strip loaded with probe NSS enabled quick and accurate detection of Cu ions in water samples. Consequently, the versatile salamo-type probe NSS lays the foundation for developing high sensitivity and fast-response dual-mode pH meters as well as Cu sensing.
PubMed: 38763017
DOI: 10.1016/j.saa.2024.124386