The P2Y14R is activated by UDP and UDP glucose and is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2Y14R antagonists and the crystallographic overlap study between PPTN and compound IV, a series of 3-substituted 5-amidobenzoate derivatives were designed, synthesized, and identified as promising P2Y14R antagonists. The optimal compound 45 (methyl 3-(1H-benzo[d]imidazol-2-yl)-5-(2-(p-tolyl) acetamido)benzoate, IC50 = 0.70 ± 0.01 nM) showed a strong binding ability to P2Y14R, high selectivity, moderate oral bioactivity, and improved pharmacokinetic profiles. In the LPS-induced acute lung injury model, compound 45 demonstrated significant anti-inflammatory efficacy, effectively mitigating the pulmonary infiltration of immune cells and inflammatory response through suppressing the NLRP3 signaling pathway. Thus, 45 with potent P2Y14R antagonistic activity, in vitro and vivo efficacy, and favorable druggability can be a strategy for treating acute lung injury and can be optimized in further studies.
Bivalent genes are ready for activation upon the arrival of developmental cues. Here, we report that BEND3 is a CpG island (CGI)-binding protein that is enriched at regulatory elements. The cocrystal structure of BEND3 in complex with its target DNA reveals the structural basis for its DNA methylation-sensitive binding property. Mouse embryos ablated of Bend3 died at the pregastrulation stage. Bend3 null embryonic stem cells (ESCs) exhibited severe defects in differentiation, during which hundreds of CGI-containing bivalent genes were prematurely activated. BEND3 is required for the stable association of polycomb repressive complex 2 (PRC2) at bivalent genes that are highly occupied by BEND3, which suggests a reining function of BEND3 in maintaining high levels of H3K27me3 at these bivalent genes in ESCs to prevent their premature activation in the forthcoming developmental stage.
Peroxiredoxins (Prxs), a large family of antioxidant enzymes, are abundant in all living organisms. Peroxiredoxin A (PrxA) from Arabidopsis thaliana belongs to the typical 2-Cys Prx family and is localized in the chloroplast. This article reports the crystal structure of a PrxA C119S mutant refined to 2.6 Å resolution. The protein exists as a decamer both in the crystal structure and in solution. The structure is in the reduced state suitable for the approach of peroxide, though conformational changes are needed for the resolving process.
Staphylococcus aureus is an opportunistic disease-causing pathogen that is widely found in the community and on medical equipment. A series of virulence factors secreted by S. aureus can trigger severe diseases such as sepsis, endocarditis and toxic shock, and thus have a great impact on human health. The transformation of S. aureus from a colonization state to a pathogenic state during its life cycle is intimately associated with the initiation of bacterial aggregation and biofilm accumulation. SdrC, an S. aureus surface protein, can act as an adhesin to promote cell attachment and aggregation by an unknown mechanism. Here, structural studies demonstrate that SdrC forms a unique dimer through intermolecular interaction. It is proposed that the dimerization of SdrC enhances the efficiency of bacteria–host attachment and therefore contributes to the pathogenicity of S. aureus .
Abstract Farrerol, a natural flavanone, promotes homologous recombination (HR) repair to improve genome-editing efficiency, but the specific protein that farrerol directly targets to regulate HR repair and the underlying molecular mechanisms have not been determined. Here, we find that the deubiquitinase UCHL3 is the direct target of farrerol. Mechanistically, farrerol enhanced the deubiquitinase activity of UCHL3 to promote RAD51 deubiquitination, thereby improving HR repair. Importantly, we find that embryos of somatic cell nuclear transfer (SCNT) exhibited defective HR repair, increased genomic instability and aneuploidy, and that the farrerol treatment post nuclear transfer enhances HR repair, restores transcriptional and epigenetic network, and promotes SCNT embryo development. Ablating UCHL3 significantly attenuates farrerol-mediated stimulation in HR and SCNT embryo development. In summary, we identify farrerol as an activator of the deubiquitinase UCHL3, highlighted the importance of HR and epigenetic changes in SCNT reprogramming and provide a feasible method to promote SCNT efficiency.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation and bone destruction, leading to severe complications. Previous research has suggested that high humidity conditions may exacerbate RA, however, the underlying mechanisms remain unclear. Furthermore, there is a lack of evidence linking humidity to the worsening of RA symptoms in animal models.
A sensitive electrochemical DNA biosensor was prepared based on mercaptoacetic acid (MAA)/gold nanoparticles (AuNPs) modified electrode. Probe DNA (NH 2 -DNA) was covalently linked to the carboxyl group of MAA in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxyl-succinimide (NHS). Scanning electron microscopy (SEM) and electrochemical impedance spectra (EIS) were used to investigate the film assembly process. The DNA hybridization events were monitored by differential pulse voltammetry (DPV), and adriamycin was used as the electrochemical indicator. Also the factors influencing the performance of the DNA hybridization were investigated in detail. Under the optimal conditions, the signal was linearly changed with target DNA concentration increased from 5.0 × 10 −13 to 1.0 × 10 −9 M and had a detection limit of 1.7 × 10 −13 M (signal/noise ratio of 3). In addition, the DNA biosensor showed good reproducibility and stability during DNA assay.
In order to probe the effects of the immunotherapy for swine cysticercosis with the genetic engineering vaccine,the pigs infected experimentally or naturally with cysticercosis were treated with the vaccine. 10 pigs which were infected experimentally cysticercosis were randomly divided into three groups: l)four pigs,each was injected the genetic engineering vaccine against swine cysticercosis after one month of infection for three times at interval of fifteen days; 2)four pigs,each was injected the vaccine as above after two months of infection; 3)two pigs,each was injected nothing.The sera CA of all the infected pigs were positive,which were detected by sandwich ELISA,and their OD values were between 0.9 and 1.42 after one month of infection.In the first group,the OD values began to decrease in one month of the first injection of the vaccine,and one of the CAs was negative in 2.0,2.5and 3.5 months,respectively,no cysticerci was found.In the second group,cysticerci was found in the detected muscles of all the four pigs:masseter,septonles,psoas,vastus medialis and scapulae externus.The number of cysticerci hosted in the detected pork was 3 to 7 per 40 cm 2.Their bile hatching rates were 15.4%.In the third group,the cysticerci were detected in the two pigs,the number of cysticerci hosted in the detected pork was 6 to 9 per 40 cm 2,their bile hatching rates were 90.4%.By epidemic investigation detecting the sera's CA,we confirmed that 25 pigs were infected naturally with cysticercosis.They were divided into three groups as their OD values and were injected with the genetic engineering vaccine as above: 1)7 pigs,their OD values between 0.68 and 0.90; 2)8 pigs,their OD values between 0.91 and 1.10; 3)10 pigs,their OD values between 1.11 and 1.54.Six months later,no cysticerci was found in all the pigs of the first group,in 5 pigs of the second group and in 2 pigs of the third group,respectively.These results revealed that the genetic engineering vaccine could play important role in the therapy to swine cysticercosis,and have better the effect in earlier therapy.
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