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Poly(HPMA-co-NIPAM) copolymer as an option to polyethylene glycol-based pharmacokinetic modulation associated with therapeutic proteins.
PIM kinases are a family of serine/threonine protein kinases that potentiate the progression of the cell cycle and inhibit apoptosis. Because of this, they are considered to be proto-oncogenes, and they represent an interesting target for the development of anticancer drugs. In mammals, three PIM kinases exist (PIM-1, PIM-2 and PIM-3), and different inhibitors have been developed to block their activity. In addition to their involvement in cancer, some publications have reported that the PIM kinases have pro-viral activity, and different mechanisms where PIM kinases favour viral infections have been proposed. Zebrafish possess more than 300 Pim kinase members in their genome, and by using RNA-Seq analysis, we found a high number of Pim kinase genes that were significantly induced after infection with spring viraemia of carp virus (SVCV). Moreover, analysis of the miRNAs modulated by this infection revealed that some of them could be involved in the post-transcriptional regulation of Pim kinase abundance. AM1241 Cannabinoid Receptor agonist To elucidate the potential role of the 16 overexpressed Pim kinases in the infectivity of SVCV, we used three different pan-PIM kinase inhibitors (SGI-1776, INCB053914 and AZD1208), and different experiments were conducted both in vitro and in vivo. We observed that the PIM kinase inhibitors had a protective effect against SVCV, indicating that, similar to what is observed in mammals, PIM kinases are beneficial for the virus in zebrafish. Moreover, zebrafish Pim kinases seem to facilitate viral entry into the host cells because when ZF4 cells were pre-incubated with the virus and then were treated with the inhibitors, the protective effect of the inhibitors was abrogated. Although more investigation is necessary, these results show that pan-PIM kinase inhibitors could serve as a useful treatment for preventing the spread of viral diseases. Oil-adjuvant formulated formalin killed cells of Flavobacterium psychrophilum (FKC + Adj) is strongly effective against bacterial cold-water disease (BCWD) in ayu Plecoglossus altivelis. In this study, we aimed to understand mechanisms underlying the strong protection by the vaccine in ayu. Antibody titer of FKC + Adj and formalin-killed cells (FKC) group was significantly higher than those of modified cytophaga broth injected (MCY) group and MCY with the adjuvant (MCY + Adj) group. The highest antibody titer was observed in FKC + Adj group. Granulomatous inflammation without lymphocyte cuff was observed in the spleen and trunk kidney of FKC + Adj and MCY + Adj group, while the size of the granuloma was bigger in FKC + Adj than in MCY + Adj group. Gene expression level for IL-8 was significantly up-regulated in FKC + Adj group at 4 weeks after the vaccination. In contrast, IL-10 gene expression level was significantly suppressed in FKC + Adj at 4 weeks after the vaccination. F. psychrophilum was almost cleared in the spleen and trunk kidney of FKC + Adj group within 2 days after the challenge. Fluorescent immunohistochemistry showed that a lot of bacterial signals were detected in the spleen and trunk kidney of challenged fish in MCY, FKC and MCY + Adj group. However, the fluorescent signal was not detected in the organs of FKC + Adj group after the challenge. These data suggest that F. psychrophilum is immediately cleared in FKC + Adj vaccinated fish and both specific antibody and activation of phagocytes are essential to clear F. psychrophilum in ayu. Grouper (Epinephelus coioides) is an important commercial maricultural fish, which suffers from nervous necrosis virus (NNV) infection. The molecular mechanisms underlying the pathogenesis of the viral infection are not clear. In this study, we combined deep RNA sequencing and label-free mass spectrum for the first time to analyze the transcriptomic and proteomic profiles in infected/dead, infected/survival (persistent), and infection-free (control)orange-spotted groupers in the larval stage. Further analyses showed that the transcriptome and proteome changed dramatically among the three distinct groups, especially differentially-expressed genes in the infected/dead and infected/survival larvae enriched for pathways related to immune response. Notably, the overlapped genes between transcriptomes and proteomes identified that genes related to collagen synthesis and adhesion molecules were enhanced in the persistent (infected/survival) stage, which might contribute to suppressing the acute and lethal immune responses upon NNV infection. These transcriptomic and proteomic datasets enable the investigation of molecular mechanisms underlying NNV infection, thus may help further development of molecular breeding in marine fishery. The present study evaluated the effects of (2-Carboxyethyl)dimethylsulfonium Bromide (Br-DMPT) supplementation on the intestinal immune function and potential mechanisms of on-growing grass carp (Ctenopharyngodon idella) by feeding fish (initial weight 216.49 ± 0.29 g) five diets with gradational Br-DMPT (0-520 mg/kg diet) concentrations for 60 days and then infecting them with Aeromonas hydrophila for 14 days. Our results firstly indicated that compared with the control group, appropriate Br-DMPT supplementation increased the number of beneficial bacteria Lactobacillus and Bifidobacterium and enteritis resistance, decreased the number of detrimental bacteria Aeromonas and E. coli, and relieved the intestinal histopathological symptoms of fish. In addition, compared with the control group, appropriate Br-DMPT supplementation (1) increased lysozyme (LZ) and acid phosphatase (ACP) activities, as well as complement 3 (C3), C4 and immunoglobulin M (IgM) content; (2) upregulated the mRNA levels of anti-microbial substance liver expressed anti-microbial peptide (LEAP) -2A, LEAP-2B, hepcidin, β-defensin-1 and Mucin2; (3) partially downregulated the mRNA levels of pro-inflammatory cytokines [interleukin 1β (IL-1β), IL-6, IL-8, IL-12p40, IL-15, IL-17D, tumour necrosis factor α (TNF-α) and interferon γ2 (IFN-γ2)] by inhibiting [IKKβ/IκBα/(NF-κBp65 and c-Rel)] signalling; and (4) partially upregulated the mRNA levels of anti-inflammatory cytokines [IL-4/13A, IL-10, IL-11, transforming growth factor (TGF)-β1] by activating [TOR/(S6K1 and 4E-BP)] signalling. The aforementioned results indicated that appropriate amount of Br-DMPT exerted a positive effect on the regulation of intestinal immune function in fish. Finally, based on enteritis morbidity, the IgM content and the lysozyme activity in the PI, the appropriate levels of Br-DMPT supplementation for on-growing grass carp were established as 295.43, 301.73 and 320.36 mg/kg diet, respectively.
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