Cottonerichsen9517

Resistance to chemotherapy in advanced cancers can be mediated by different factors such as epidermal growth factor receptor (EGFR) overexpression and DNA repair enzymes. Therefore, current standards of care usually involve combinations of multiple treatments. Here, to reduce the adverse effects of multiple drug combinations and improve outcome, we proposed a single drug approach to block multiple overlapping effects that characterize chemoresistance. Thus, we designed a new linker that allows assembly of multiple functions (e.g., inhibition of EGFR phosphorylation, induction of DNA lesions, and blockade of their repair) into a single molecule. Entinostat This led to the successful synthesis of a novel and potent combi-molecule JS230. Here, we demonstrated that in resistant prostate cancer cells overexpressing EGFR, it was capable of (a) inhibiting EGFR in a dose-dependent manner, (b) damaging DNA, and (c) sustaining the damage by inhibiting the DNA repair protein poly(ADP-ribose) polymerase (PARP). The triple mechanism of action of JS230 cumulated into growth inhibitory potency superior to that of classical two- or three-drug combinations.Light-driven synthesis of plasmonic metal nanostructures has garnered broad scientific interests. Although it has been widely accepted that surface plasmon resonance (SPR)-generated energetic electrons play an essential role in this photochemical process, the exact function of plasmon-generated hot holes in regulating the morphology of nanostructures has not been fully explored. Herein, we discover that those hot holes work with surface adsorbates collectively to control the anisotropic growth of gold (Au) nanostructures. Specifically, it is found that hot holes stabilized by surface adsorbed iodide enable the site-selective oxidative etching of Au0, which leads to nonuniform growths along different lateral directions to form six-pointed Au nanostars. Our studies establish a molecular-level understanding of the mechanism behind the plasmon-driven synthesis of Au nanostars and illustrate the importance of cooperation between charge carriers and surface adsorbates in regulating the morphology evolution of plasmonic nanostructures.The integration of photochromic molecules into semiconducting polymer matrices via blending has recently attracted a great deal of attention, as it provides the means to reversibly modulate the output signal of electronic devices by using light as a remote control. However, the structural and electronic interactions between photochromic molecules and semiconducting polymers are far from being fully understood. Here we perform a comparative investigation by combining two photochromic diarylethene moieties possessing similar energy levels yet different propensity to aggregate with five prototypical polymer semiconductors exhibiting different energy levels and structural order, ranging from amorphous to semicrystalline. Our in-depth photochemical, structural, morphological, and electrical characterization reveals that the photoresponsive behavior of thin-film transistors including polymer/diarylethenes blends as the active layer is governed by a complex interplay between the relative position of the energy levels and the polymer matrix microstructure. By matching the energy levels and optimizing the molecular packing, high-performance optically switchable organic thin-film transistors were fabricated. These findings represent a major step forward in the fabrication of light-responsive organic devices.Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) provides a unique opportunity for molecular analysis of natural complex mixtures. In many geochemical and environmental studies structure-propertry relations are based solely on the elemental compositional information. Several calculated parameters were proposed to increase reliability of structural attribution, among which aromaticity indices (AI and AImod) are widely used. Herein, we applied a combination of selective labeling reactions in order to obtain direct structural information on the individual components of lignin-derived polyphenolic material. Carboxylic (COOH), carbonyl (C═O), and hydroxyl (OH) groups were enumerated by esterification, reducing, and acetylation reactions, respectively, followed by FTICR MS analyses. Obtained information was enabled to constrain aromaticity accounting for the carbon skeleton only. We found that actual aromaticity of components may be both higher or lower than approximated values depending on the abundance of COOH, C═O, and OH groups. The results are of importance for the geochemical community studying terrestrial NOM with structural gradients.Fraxinellone, a furanoid, is one of the bioactive and potentially hepatotoxic constituents from Dictamnus dasycarpus Turcz, which is extensively spread throughout Asian countries. This herb was reported to cause liver injury in clinical application. However, the mechanism behind is still not fully understood. This study mainly focused on the hepatotoxicity of fraxinellone and the underlying mechanism. The current study demonstrated that fraxinellone resulted in a significant elevation of serum alanine aminotransferase and aspartate aminotransferase in a dose-dependent manner in mice after oral administration. Pretreatment with ketoconazole for three successive days could significantly alleviate the hepatotoxicity of fraxinellone. Considering that fraxinellone has a structural alert of furan ring, it is believed that the hepatotoxicity caused by fraxinellone required cytochrome P450-mediated bioactivation. Bioactivation studies were subsequently carried out in vitro and in vivo. Fraxinellone was metabolized into cis-enedial intermediate, an electrophile that was prone to react with glutathione or N-acetyl-lysine through 1,2- or 1,4-addition to form stable conjugates. Ketoconazole significantly inhibited the formation of the glutathione conjugates (M1 and M2) in microsomal incubation and similar finding was obtained in vivo. Phenotyping study indicated that CYP3A4 was the principal enzyme responsible for the bioactivation of fraxinellone. This study suggested that CYP3A4-mediated bioactivation plays an indispensable role in fraxinellone-induced hepatotoxicity. The work performed herein enables us to better understand the hepatotoxicity of fraxinellone as well as the mechanism behind.