Transient receptor potential vanilloid (TRPV) cation channels are polymodal sensors involved in a variety of physiological processes. TRPV2, a member of the TRPV family, is regulated by temperature, by ligands, such as probenecid and cannabinoids, and by lipids. TRPV2 has been implicated in many biological functions, including somatosensation, osmosensation and innate immunity. Here we present the atomic model of rabbit TRPV2 in its putative desensitized state, as determined by cryo-EM at a nominal resolution of ~4 Å. In the TRPV2 structure, the transmembrane segment 6 (S6), which is involved in gate opening, adopts a conformation different from the one observed in TRPV1. Structural comparisons of TRPV1 and TRPV2 indicate that a rotation of the ankyrin-repeat domain is coupled to pore opening via the TRP domain, and this pore opening can be modulated by rearrangements in the secondary structure of S6.
Wasp stings have been arising to be a severe public health problem in China in recent years. However, molecular information about lethal or toxic factors in wasp venom is extremely lacking. In this study, we used two pyrosequencing platforms to analyze the transcriptome of Vespa velutina, the most common wasp species native in China. Besides the substantial amount of transcripts encoding for allergens usually regarded as the major lethal factor of wasp sting, a greater abundance of hemostasis-impairing toxins and neurotoxins in the venom of V. velutina were identified, implying that toxic reactions and allergic effects are envenoming strategy for the dangerous outcomes. The pattern of differentially expressed genes before and after venom extraction clearly indicates that the manifestation of V. velutina stings depends on subtle regulations in the metabolic pathway required for toxin recruitment. This comparative analysis offers timely clues for developing clinical treatments for wasp envenoming in China and around the world.
An approach for the identification of multiple components in traditional Chinese medicine injections (TCMIs) using a combination of hydrophilic interaction chromatography (HILIC) and reversed-phase liquid chromatography (RPLC) coupled with time-of-flight mass spectrometry (TOFMS) was developed for the quality control of Guanxinning injection (GXNI), a widely used TCMI, composed of Salvia miltiorrhiza and Ligusticum Chuanxiong. A total of 50 compounds from five compound classes, including saccharides, amino acids, organic acids, phenolic acids and phthalides, were identified or tentatively characterized on the basis of accurate mass measurements and subsequent TOFMS product ions. Six groups of isomers of phenolic acids and saccharides were tentatively distinguished. It was observed that the ESI-TOFMS fragmentation behavior of phthalides was different in negative and positive ion mode, and the fragmentation pathways were tentatively elucidated using structurally-relevant product ions. Several highly polar constituents were characterized for the first time from GXNI by HILIC/TOFMS. In addition, all the constituents identified from GXNI were further assigned in the two individual crude drugs. The integrated strategy has provided a powerful approach for the separation and identification of the multiple components in GXNI, and it has also assisted in the establishment of methods for the comprehensive safety and quality evaluation of TCMIs.
Carrier-free nanomedicines mainly composed of drug nanocrystals are considered as promising candidates for next-generation nanodrug formulations. However, such nanomedicines still need to be stabilized by additive surfactants, synthetic polymers, or biologically based macromolecules. Based on the strong intermolecular interactions between indomethacin (IDM, a COX-2 inhibitor) and paclitaxel (PTX, a chemotherapy drug), we herein successfully engineered a novel kind of carrier-free nanomedicines that organized as IDM-induced PTX nanocrystal aggregates via one-pot self-assembly without any nonactive excipients. In the assemblies of IDM and PTX (IDM/PTX assemblies), PTX nanocrystals were casted with amorphous IDM molecules, like a "brick-cement" architecture. In serum, these nanoassemblies could rapidly collapse into a great number of smaller nanoparticles, thus targeting the tumor site through the EPR effect. Under the assistance of IDM on immunotherapy, the IDM/PTX assemblies showed obviously improved synergetic antitumor effects of immunotherapy and chemotherapy. The self-assembly of two synergistic active substances into nanomedicines without any nonactive excipients might open an alternative avenue and give inspiration to fabricate novel carrier-free nanomedicines in many fields.
The objective of this study was to analyse the distribution and antimicrobial resistance of bacterial uropathogens isolated from outpatients at Henan Provincial People's Hospital. A total of 1419 samples from 823 newly diagnosed and 596 recurrent UTI outpatients culture positive. Escherichia coli was the most common uropathogen. Compared with the recurrent group, the newly diagnosed group had a higher isolation rate of E. coli and Enterobacter cloacae but a lower isolation rate of Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp. Except for P. aeruginosa, the resistance of Gram-negative bacteria to most antibiotics was less than 30%. All Enterococcus and Staphylococcus spp. were sensitive to linezolid, vancomycin and teicoplanin. Both Gram-negative and -positive bacteria exhibited high susceptibility to fosfomycin. Uropathogens isolated from recurrent outpatients had higher resistance rates than did those isolated from newly diagnosed outpatients. Our study indicated that fosfomycin might be an excellent treatment option for outpatients with UTIs.
Hyperglycemia is reported to accelerate endothelial cell senescence that contributes to diabetic complications. The underlying mechanism, however, remains elusive. We previously demonstrated AQR as a susceptibility gene for type 2 diabetes mellitus (T2DM) and showed that it was increased in multiple tissues in models with T2DM or metabolic syndrome. This study aimed to investigate the role of AQR in hyperglycemia-induced senescence and its underlying mechanism. Here, we retrieved several datasets of the aging models and found the expression of AQR was increased by high glucose and by aging across species, including C. elegans (whole-body), rat (cardiac tissues), and monkey (blood). we validated the increased AQR expression in senescent human umbilical vein endothelial cells (HUVECs). When overexpressed, AQR promoted the endothelial cell senescence, confirmed by an increased number of cells stained with senescence-associated beta-galactosidase and upregulation of CDKN1A (P21) as well as the prohibited cellular colony formation and G2/M phase arrest. To explore the mechanism by which AQR regulated the cellular senescence, transcriptomic analyses of HUVECs with the overexpression and knockdown of the AQR were performed. We identified 52 co-expressed genes that were enriched, in the terms of plasminogen activation, innate immunity, immunity, and antiviral defense. Among co-expressed genes, PLAU was selected to evaluate its contribution to senescence for its highest strength in the enrichment of the biological process. We demonstrated that the knockdown of PLAU rescued senescence-related phenotypes, endothelial cell activation, and inflammation in models induced by AQR or TNF-α. These findings, for the first time, indicate that AQR/PLAU is a critical signaling axis in the modulation of endothelial cell senescence, revealing a novel link between hyperglycemia and vascular dysfunction. The study may have implications in the prevention of premature vascular aging associated with T2DM.
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