Background & Aims: Fibrosis, a cardinal feature of a dysfunctional liver, significantly contributes to the ever-increasing mortality due to end-stage chronic liver diseases. The cross-talk, between hepatocytes and hepatic stellate cells, is suggested to play a key role in fibrosis progression. While ample efforts have been devoted to elucidate hepatic stellate cells' functions during liver fibrosis, the regulatory functions of hepatocytes remain elusive. Methods: Using an unbiased functional microRNA screening, we investigated the ability of hepatocytes to regulate fibrosis by fine-tuning gene expression via microRNA modulation. The in vivo functional analyses were performed by inhibiting microRNA in hepatocytes using adeno-associated virus in carbon-tetrachloride-and 3,5-di diethoxycarbonyl-1,4-dihydrocollidine-induced liver fibrosis. Results: We discovered that blocking microRNA-221-3p function in hepatocytes during chronic liver injury facilitates recovery of the liver and faster resolution of the deposited extracellular matrix. Further, we demonstrate that reduced secretion of CC motif chemokine ligand 2, due to post-transcriptional regulation of G protein alpha inhibiting activity polypeptide 2 by microRNA-221-3p, mitigates liver fibrosis. Page%5%of%44% % % Conclusions: Collectively, microRNA modulation in hepatocytes, an easy-to-target cell type in the liver, may serve as a potential therapeutic approach for liver fibrosis.
In this paper, we describe two independent isolates of a new member of the subfamily Autographivirinae, Pseudomonas phage KNP. The type strain (KNP) has a linear, 40,491-bp-long genome with GC content of 57.3%, and 50 coding DNA sequences (CDSs). The genome of the second strain (WRT) contains one CDS less, encodes a significantly different tail fiber protein and is shorter (40,214 bp; GC content, 57.4%). Phylogenetic analysis indicates that both KNP and WRT belong to the genus T7virus. Together with genetically similar Pseudomonas phages (gh-1, phiPSA2, phiPsa17, PPPL-1, shl2, phi15, PPpW-4, UNO-SLW4, phiIBB-PF7A, Pf-10, and Phi-S1), they form a divergent yet coherent group that stands apart from the T7-like viruses (sensu lato). Analysis of the diversity of this group and its relatedness to other members of the subfamily Autographivirinae led us to the conclusion that this group might be considered as a candidate for a new genus.Electronic supplementary materialThe online version of this article (doi:10.1007/s00705-017-3419-9) contains supplementary material, which is available to authorized users.
In our previous work we demonstrated that a small protein called affibody can be used for a cytotoxic conjugate development. The anti-HER2 affibody was armed with one moiety of a highly potent auristatin E and specifically killed HER2-positive cancer cells with a nanomolar IC50. The aim of this study was to improve the anti-HER2 affibody conjugate by increasing its size and the number of conjugated auristatin molecules. The affibody was fused to the Fc fragment of IgG1 resulting in a dimeric construct with the molecular weight of 68 kDa, referred to as ZHER2:2891-Fc, ensuring its prolonged half-life in the blood. Due to the presence of four interchain cysteines, the fusion protein could carry four drug molecules. Notably, the in vitro tests of the improved anti-HER2 conjugate revealed that it exhibits the IC50 of 130 pM for the HER2-positive SK-BR-3 cells and 98 nM for the HER2-negative MDA-MB-231 cells. High efficacy and specificity of the auristatin conjugate based on ZHER2:2891-Fc indicate that this construct is suitable for further in vivo evaluation.
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