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Background Enterotoxigenic Escherichia coli (ETEC) is responsible for piglet diarrhea and causes substantial economic loss in the pig industry. Along with the restriction of antibiotics, natural compounds targeting bacterial virulence factors are supposed to be efficacious and attractive alternatives for controlling ETEC infection. This study aimed to investigate the influence of dihydromyricetin (DMY), a natural flavonoid compound, on the expression of virulence factors of ETEC and intestinal inflammatory injury. Results DMY interfered with the quorum sensing (QS) of ETEC K88 since it decreased AI-2 secretion and downregulated the expression of LuxS and Pfs, which dominate AI-2 production, and decreased the expression mRNA level of genes ( lsrA , lsrB , lsrC , lsrD , lsrK , and lsrR ) that are involved in AI-2 internalization and signal transduction. Additionally, DMY markedly dampened the expression of QS-related virulence genes ( elt-1 , estB , fliC , faeG ), biofilm formation, cell adhesion, and stress tolerance of ETEC K88. Furthermore, DMY treatment applied to the ETEC K88 infection in mice model resulted in decreased amount of heat-labile (LT) and heat-stable (ST) enterotoxins, reduced production of cAMP and cGMP, downregulated protein level of CFTR and upregulated expression of NHE3 in the ileum. In addition, the mRNA expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and histological damage in the ileum were significantly decreased by DMY treatment. Conclusions DMY can inhibit the AI-2 QS and virulence factor expression, thereby attenuating the virulence of ETEC and alleviating intestinal inflammatory damage in ETEC K88-challenged mice. This study indicated that DMY has the potential to be a promising antivirulence agent for combating ETEC infection.

The E3 ligase-degron interaction determines the specificity of the ubiquitin‒proteasome system. We recently discovered that FEM1B, a substrate receptor of Cullin 2-RING ligase (CRL2), recognizes C-degrons containing a C-terminal proline. By solving several cryo-EM structures of CRL2 FEM1B bound to different C-degrons, we elucidate the dimeric assembly of the complex. Furthermore, we reveal distinct dimerization states of unmodified and neddylated CRL2 FEM1B to uncover the NEDD8-mediated activation mechanism of CRL2 FEM1B . Our research also indicates that, FEM1B utilizes a bipartite mechanism to recognize both the C-terminal proline and an upstream aromatic residue within the substrate. These structural findings, complemented by in vitro ubiquitination and in vivo cell-based assays, demonstrate that CRL2 FEM1B -mediated polyubiquitination and subsequent protein turnover depend on both FEM1B-degron interactions and the dimerization state of the E3 ligase complex. Overall, this study deepens our molecular understanding of how Cullin-RING E3 ligase substrate selection mediates protein turnover. A key question in the ubiquitin-proteasome system is how E3 ligases select their substrates. Here, the authors reveal that CRL2 FEM1B E3 ligase functions as a dimer and employs a bipartite mode of substrate recognition, requiring a C-terminal proline and an upstream aromatic residue in the target.

Emerging studies support that RNA-binding proteins （RBPs） play critical roles in human biology and pathogenesis. RBPs are essential players in RNA processing and metabolism, including pre-mRNA splicing, polyadenylation, transport, surveillance, mRNA localization, mRNA stability control, translational control and editing of various types of RNAs. Aberrant expression of and mutations in RBP genes affect various steps of RNA processing, altering target gene function. RBPs have been associ- ated with various diseases, including neurological diseases. Here, we mainly focus on selected RNA-binding proteins including Nova-i/Nova-2, HuR/HuB/HuC/HuD, TDP-43, Fus, Rbfoxl/Rbfox2, QKI and FMRP, discussing their function and roles in human diseases.

Aflatoxin B 1 (AFB 1 ) is classified as a Class I carcinogen and common pollutant in human and animal food products. Prolonged exposure to AFB 1 can induce hepatocyte apoptosis and lead to hepatotoxicity. Therefore, preventing AFB 1 -induced hepatotoxicity remains a critical issue and is of great significance. Baicalin, a polyphenolic compound derived from Scutellaria baicalensis Georgi , has a variety of pharmacodynamic activities, such as antiapoptotic and anticancer activities. This study systematically investigated the alleviating effect of baicalin on AFB 1 -induced hepatotoxicity from the perspective of apoptosis and explored the possible molecular mechanism. In the normal human liver cell line L02, baicalin treatment significantly inhibited AFB 1 -induced c-Jun-N-terminal Kinase (JNK) activation and cell apoptosis. In addition, the in vitro mechanism study demonstrated that baicalin alleviates AFB 1 -induced hepatocyte apoptosis through suppressing the translocation of phosphorylated JNK to the nucleus and decreasing the phosphorylated c-Jun/c-Jun ratio and the Bax/Bcl2 ratio. Molecular docking and drug affinity responsive target stability assays demonstrated that baicalin has the potential to target JNK. This study provides a basis for the therapeutic effect of baicalin on hepatocyte apoptosis caused by AFB 1 , indicating that the development of baicalin and JNK pathway inhibitors has broad application prospects in the prevention of hepatotoxicity, especially hepatocyte apoptosis.

The current study was conducted to investigate effects of hydroxyselenomethionine (HMBSe) with symmetrical and chelated chemical structure, a novel organic selenium (Se) source, on lactation performance, anti-oxidative status and immunities, and transfer efficiencies for early lactation dairy cows compared with that of sodium selenite (SS). Forty-five multiparous early-lactating dairy cows with similar days in milk, 56.0 d and milk yield 36.1 kg/d, were fed with same basal diet containing 0.04 mg of Se/kg of dry matter (DM) basis. They were assigned to 1 of 3 treatments according to one-way ANOVA design: control (basal diet, without Se supplementation), SS (0.30 mg of Se/kg of DM), or HMBSe (0.30 mg of Se/kg of DM). The experiment lasted for 9 weeks, with the first week as adaptation. Results showed that the organic HMBSe cows increased the milk yield, 4% fat-corrected milk yield, the numbers of red blood cells in whole blood, Se concentrations in milk and serum, ratio of milk to serum significantly (P < 0.01); feed efficiency, energy-corrected milk yield, contents of superoxide dismutase in serum, hemoglobin, and the numbers of white blood cells in whole blood significantly (P < 0.05) compared to control and SS. Moreover, HMBSe cows had trends to increase glutathione peroxidase activities (P = 0.09), total antioxidant capacity (P = 0.06), and had trends to decrease the contents of malonaldehyde (P = 0.07) in serum compared to control and SS. In conclusion, HMBSe was more effective on the lactation performances, anti-oxidative status, and immunities and Se transfer efficiencies for early-lactating dairy cows compared to control and SS, which was very meaningful to develop the enriched Se milk products.

2,4-dinitrotoluene (2,4-DNT) is a common environmental pollutant, and was classified as a group 2B human carcinogenic compound by the International Agency for Research on Cancer. This study determined the toxic effects of 2,4-DNT exposure on zebrafish at the embryo-larvae stage, in terms of organ morphogenesis and the expression pattern of selected target genes related to lipid metabolism and oxygen transportation. The results showed that the 120-h post-fertilization LC50 of 2,4-DNT was 9.59 mg/L with a 95% confidence interval of 8.89–10.44 mg/L. The larvae treated with 2,4-DNT showed toxic symptoms including smaller body, less skin pigment production, yolk malabsorption, and disordered liver development. Further studies on the expression of genes related to lipid transport and metabolism, and respiration indicated that they were significantly affected by 2,4-DNT. It is concluded that 2,4-DNT exposure perturbed liver development and yolk absorption in early-life zebrafish, and disturbed the lipid metabolism /oxygen transport gene expression.

Aflatoxin B (AFB ) is classified as a Class I carcinogen and common pollutant in human and animal food products. Prolonged exposure to AFB can induce hepatocyte apoptosis and lead to hepatotoxicity. Therefore, preventing AFB -induced hepatotoxicity remains a critical issue and is of great significance. Baicalin, a polyphenolic compound derived from Scutellaria baicalensis Georgi, has a variety of pharmacodynamic activities, such as antiapoptotic and anticancer activities. This study systematically investigated the alleviating effect of baicalin on AFB -induced hepatotoxicity from the perspective of apoptosis and explored the possible molecular mechanism. In the normal human liver cell line L02, baicalin treatment significantly inhibited AFB -induced c-Jun-N-terminal Kinase (JNK) activation and cell apoptosis. In addition, the in vitro mechanism study demonstrated that baicalin alleviates AFB -induced hepatocyte apoptosis through suppressing the translocation of phosphorylated JNK to the nucleus and decreasing the phosphorylated c-Jun/c-Jun ratio and the Bax/Bcl2 ratio. Molecular docking and drug affinity responsive target stability assays demonstrated that baicalin has the potential to target JNK. This study provides a basis for the therapeutic effect of baicalin on hepatocyte apoptosis caused by AFB , indicating that the development of baicalin and JNK pathway inhibitors has broad application prospects in the prevention of hepatotoxicity, especially hepatocyte apoptosis.

In this paper, a series of Eu/PMMA and Eu/PMMA/SiO 2 luminescent films have been designed, fabricated and characterized. Thermo-gravimetric analysis and photo-luminescence results indicated the Eu-complex precursor was successfully immobilized in PMMA matrix through the interaction between the Eu-complex and the –C=O groups of the PMMA matrix. The emission spectra of the Eu-complex and Eu/PMMA films recorded at 25 °C exhibited the characteristic bands arising from the 5 D 0 / 7 F J . The fact that the quantum efficiencies (η) of the doped film increased significantly indicated that PMMA matrix acted as an efficient co-sensitizer for Eu 3+ ions luminescent center, and therefore enhanced the η of the emitter 5 D 0 level. Especially, with the doping nano-SiO 2 into Eu/PMMA-5 % system, the T d -5 % of Eu/PMMA/SiO 2 has obviously improved. Due to the carrying effect of nano-SiO 2 and interaction between –C=O of PMMA chain and Eu 3+ ions, the η of Eu/PMMA/SiO 2 films have been greatly enhanced. To the best of our knowledge, the η of Eu/PMMA/SiO 2 -3 % film (78.57 %) is found to be the highest so far reported in the literature. These Eu/PMMA/SiO 2 luminescent films show excellent luminescent properties and therefore have potential applications in light-conversion molecular device.

The E3 ligase-degron interaction determines the specificity of the ubiquitin‒proteasome system. We recently discovered that FEM1B, a substrate receptor of Cullin 2-RING ligase (CRL2), recognizes C-degrons containing a C-terminal proline. By solving several cryo-EM structures of CRL2 bound to different C-degrons, we elucidate the dimeric assembly of the complex. Furthermore, we reveal distinct dimerization states of unmodified and neddylated CRL2 to uncover the NEDD8-mediated activation mechanism of CRL2 . Our research also indicates that, FEM1B utilizes a bipartite mechanism to recognize both the C-terminal proline and an upstream aromatic residue within the substrate. These structural findings, complemented by in vitro ubiquitination and in vivo cell-based assays, demonstrate that CRL2 -mediated polyubiquitination and subsequent protein turnover depend on both FEM1B-degron interactions and the dimerization state of the E3 ligase complex. Overall, this study deepens our molecular understanding of how Cullin-RING E3 ligase substrate selection mediates protein turnover.