Herein, a disulfide-catalyzed electrophilic iodination of aromatic compounds using 1,3-diiodo-5,5-dimethylhydantoin (DIH) has been developed. The disulfide activates DIH as a Lewis base to promote ...the iodination reaction in acetonitrile under mild conditions. This system is applicable to a wide range of electron-rich aromatic compounds, including acetanilide, anisole, imidazole, and pyrazole derivatives.
The anticancer activity of immune checkpoint inhibitors is attracting attention in various clinical sites. Since green tea catechin has cancer-preventive activity in humans, whether green tea ...catechin supports the role of immune checkpoint inhibitors was studied. We here report that (-)-epigallocatechin gallate (EGCG) inhibited programmed cell death ligand 1 (PD-L1) expression in non⁻small-cell lung cancer cells, induced by both interferon (IFN)-γ and epidermal growth factor (EGF). The mRNA and protein levels of IFN-γ⁻induced PD-L1 were reduced 40⁻80% after pretreatment with EGCG and green tea extract (GTE) in A549 cells, via inhibition of JAK2/STAT1 signaling. Similarly, EGF-induced PD-L1 expression was reduced about 37⁻50% in EGCG-pretreated Lu99 cells through inhibition of EGF receptor/Akt signaling. Furthermore, 0.3% GTE in drinking water reduced the average number of tumors per mouse from 4.1 ± 0.5 to 2.6 ± 0.4 and the percentage of PD-L1 positive cells from 9.6% to 2.9%, a decrease of 70%, in lung tumors of A/J mice given a single intraperitoneal injection of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In co-culture experiments using F10-OVA melanoma cells and tumor-specific CD3+ T cells, EGCG reduced
mRNA expression about 30% in F10-OVA cells and restored
mRNA expression in tumor-specific CD3+ T cells. The results show that green tea catechin is an immune checkpoint inhibitor.
Cancer stem cells (H1299-sdCSCs) were obtained from tumour spheres of H1299 human lung cancer cells. We studied low stiffness, a unique biophysical property of cancer cells, in H1299-sdCSCs and ...parental H1299. Atomic force microscopy revealed an average Young's modulus value of 1.52 kPa for H1299-sdCSCs, which showed low stiffness compared with that of H1299 cells, with a Young's modulus value of 2.24 kPa. (-)-Epigallocatechin gallate (EGCG) reversed the average Young's modulus value of H1299-sdCSCs to that of H1299 cells. EGCG treatment inhibited tumour sphere formation and ALDH1A1 and SNAI2 (Slug) expression. AXL receptor tyrosine kinase is highly expressed in H1299-sdCSCs and AXL knockdown with siAXLs significantly reduced tumour sphere formation and ALDH1A1 and SNAI2 (Slug) expression. An AXL-high population of H1299-sdCSCs was similarly reduced by treatment with EGCG and siAXLs. Transplantation of an AXL-high clone isolated from H1299 cells into SCID/Beige mice induced faster development of bigger tumour than bulk H1299 cells, whereas transplantation of the AXL-low clone yielded no tumours. Oral administration of EGCG and green tea extract (GTE) inhibited tumour growth in mice and reduced p-AXL, ALDH1A1, and SLUG in tumours. Thus, EGCG inhibits the stemness and tumourigenicity of human lung cancer cells by inhibiting AXL.
Abstract
G-quadruplexes (G4s) regulate various biological processes in cells. However, cellular imaging of dynamically forming G4s in biomolecular condensates using small molecules has been poorly ...investigated. Herein, we present a fluorescent light-up probe with the ability to selectively stabilize G4s and enhance fluorescence upon G4 binding. The foci of the probe were mainly observed in the nucleoli. These were co-localized with anti-fibrillarin antibodies and anti-G4 antibodies (BG4). Moreover, we tested detection of G4 in stress granules using the developed probe. Stress granules were induced through treatment with not only thapsigargin, but also known G4 ligands (pyridostatin, RHPS4, and BRACO-19). In the stress granules, co-localization between the probe, BG4, and stress granule markers (TIA1 and G3BP1) was detected. We present a practical light-up probe for G4s in stress granules, providing potential targets for G4 ligands.
N6-methyladenine (m6A) is the most abundant RNA modification in eukaryotic RNA. Further, m6A has been identified in the genomic DNA of both eukaryotes and prokaryotes. The G-quadruplex (G4) structure ...is a non-canonical nucleic acid structure formed by the stacking of G:G:G:G tetrads. In this study, we evaluated the effect of m6A modifications on G4 structures formed by GGA repeat oligonucleotides, d(GGA)8, d(GGA)4, and r(GGA)4. The d(GGA)8 forms an intramolecular tetrad:heptad:heptad:tetrad G4 structure, while d(GGA)4 forms a dimerized intermolecular tetrad:heptad:heptad:tetrad G4 structure. r(GGA)4 forms a dimerized intermolecular tetrad:hexad:hexad:tetrad G4 structure. Circular dichroism melting analysis demonstrated that (1) m6A modifications destabilized the G4 structure formed by d(GGA)8, (2) m6A modification at A3 disrupted the G4 structure formed by d(GGA)4, and (3) m6A modification at A3 destabilized the G4 structure formed by r(GGA)4. m6A modifications may be involved in controlling G4 structure formation to regulate biological functions.
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•m6A modifications destabilize the G4 structure formed by d(GGA)8.•m6A modification at A3 inhibits formation of the G4 structure formed by d(GGA)4.•m6A modification at A3 destabilizes the G4 structure formed by r(GGA)4.
Guanine-rich human telomeric DNA can adopt secondary structures known as G-quadruplexes, which can be targeted by small molecules to achieve anticancer effects. So far, the structural information on ...complexes between human telomeric DNA and ligands is limited to the parallel G-quadruplex conformation, despite the high structural polymorphism of human telomeric G-quadruplexes. No structure has been yet resolved for the complex with telomestatin, one of the most promising G-quadruplex-targeting anticancer drug candidates. Here we present the first high-resolution structure of the complex between an intramolecular (3 + 1) human telomeric G-quadruplex and a telomestatin derivative, the macrocyclic hexaoxazole L2H2-6M(2)OTD. This compound is observed to interact with the G-quadruplex through π-stacking and electrostatic interactions. This structural information provides a platform for the design of topology-specific G-quadruplex-targeting compounds and is valuable for the development of new potent anticancer drugs.
It is well accepted that the electrooxidation of ethanol on Pt in aqueous solution proceeds via two parallel pathways: C1-pathway, which is the complete oxidation of ethanol to CO2 via COad ...intermediate, and C2-pathway, which produces acetaldehyde and also acetic acid with further oxidation. Water plays important roles for the oxidation, i.e., for the oxidative removal of COad in the C1-pathway and for the oxidation of acetaldehyde to acetic acid in the C2-pathway. In the present work, however, we show that the ethanol oxidation proceeds in the absence of water. Detailed study using surface-enhanced infrared absorption spectroscopy and high-performance liquid chromatography reveals that COad reacts with ethanol to form ethyl formate, which is designated as C3-pathway, and also that the ethanol oxidation produces ethyl acetate, which is designated as C4-pathway.
•Hydroxyzine, a histamine H1 receptor antagonist, augmented α and δ bicoherence in both sevoflurane anesthesia and propofol anesthesia.•Hydroxyzine augmented θ bicoherence in sevoflurane anesthesia ...but not in propofol anesthesia.•Hydroxyzine enhances both sevoflurane anesthesia and propofol anesthesia at surgical anesthetic depth probably by facilitation of GABAergic neural circuit mechanisms.
The aim of this study was to determine the anesthesia-promoting effects of hydroxyzine on electroencephalograms during sevoflurane anesthesia and during propofol anesthesia.
We analyzed 40 patients scheduled for elective surgery under sevoflurane anesthesia (n = 20) or propofol anesthesia (n = 20). Anesthesia was adjusted at a bispectral index value of 50–60, and then 0.5 mg/kg of hydroxyzine was administered intravenously. We analyzed frontal electroencephalograms before and after hydroxyzine injection with power spectral and bicoherence analyses, which are suitable for assessing the anesthetic depth induced by γ-aminobutyric acid (GABA)ergic anesthetics.
Hydroxyzine increased the α bicoherence peaks in both sevoflurane anesthesia (mean difference, 11.2%; 95% confidence interval (CI), 7.6 to 14.8; P < 0.001) and propofol anesthesia (mean difference, 5.6%; 95% CI, 1.7 to 9.4; P = 0.008). Hydroxyzine increased the averaged δ bicoherence values in both sevoflurane anesthesia (mean difference, 5.5%; 95% CI, 2.1 to 8.8; P = 0.003) and propofol anesthesia (mean difference, 3.9%; 95% CI, 1.0 to 6.8; P = 0.011).
Hydroxyzine enhances both sevoflurane anesthesia and propofol anesthesia probably by facilitation of GABAergic neural circuit mechanisms.
The findings provide a new insight into the role of histaminergic neurons during general anesthesia in humans.
Prenylated indole alkaloids bearing more than one prenyl or reverse-prenyl group show various biological activities. Among them, synthesis of trisubstituted-type prenylated indoles have not been well ...explored because of the difficulty in regioselective introduction of multiple prenyl and reverse-prenyl groups due to steric hindrance problems. Herein, we describe a synthesis of 2,6,7-trisubstituted prenylated indole using aza-Claisen rearrangement under mild conditions to introduce a prenyl group at C7 in the presence of the prenyl group at C6.
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