Faganriise5297

This work also highlighted the importance of ligand density for tumor targeting.

Hepatic stellate cells (HSC) activation and proliferation mediated the pathogenic development of hepatic fibrosis (HF). However, the underlying mechanisms remain poorly understood. In this study, we aimed to investigate the miR-29a-3p and its effects on PIK3R3 expression in HF pathogenesis.

LX-2cells treated with TGF-β1 was used as the invitro HF model. The expression of microRNAs and proteins in LX-2cells were detected by quantitative RT-PCR and western blotting. Then, miR-29a-3p expression in LX-2cells were altered via transfection with specific mimics or inhibitors, followed by cell proliferation measured through CCK-8, Edu staining and colony formation. The dual luciferase reporter assay was done to assess binding of miR-29a-3p with PIK3R3 gene sequences. Moreover, PIK3R3 gene overexpression in LX-2cell was realized through transfection with recombinant pcDNA3.0-PIK3R3 plasmids.

Successful establishment of cellular HF model was validated through the increased Col-I and a-SMA expression in TGF-β1-treated LX-2cells shown by qRT-PCR and Western blot. In such model, miR-29a-3p expression in LX-2cells showed the greatest decrease among four candidate microRNAs in response to TGF-β1 treatment. Also, miR-29a-3p directly binds with the 3' UTR region of the PIK3R3 gene to suppress its expression in LX-2cells. selleck kinase inhibitor Furthermore, PIK3R3 gene overexpression effectively abrogated the changes of LX-2cell proliferation, AKT phosphorylation and Col-I and a-SMA expression caused by miR-29a-3p mimics.

MiR-29a-3p regulates hepatic stellate cell proliferation and hepatic fibrosis pathogenesis by targeting PIK3R3 expression and modulating the PI-3K/AKT signaling.

MiR-29a-3p regulates hepatic stellate cell proliferation and hepatic fibrosis pathogenesis by targeting PIK3R3 expression and modulating the PI-3K/AKT signaling.Hepatic ischemia-reperfusion (I/R) injury is a complex pathophysiological process that often times occurs in liver transplantation, hepatectomy, and ischemic shock. Aberrant activation of inflammatory responses has been implicated in hepatic I/R injury. In this study, we aimed to investigate the role of circadian clock gene Rev-erbα (a well-known regulator of inflammation) in hepatic I/R injury. We first showed that Rev-erbα ablation sensitized mice to hepatic I/R injury as evidenced by higher levels of plasma alanine aminotransferase and aspartate aminotransferase, an increased histological score, as well as enhanced hepatic myeloperoxidase activity in Rev-erbα-/- mice. More severe hepatic I/R injury in Rev-erbα-/- mice was accompanied by higher expression of pro-inflammatory cytokines, exacerbated activation of Nlrp3 inflammasome, and more extensive infiltration of inflammatory cells. Moreover, pharmacological activation of Rev-erbα by SR9009 significantly alleviated the hepatic damage and inflammatory responses. In addition, I/R operation started at ZT18 (corresponding to low Rev-erbα expression) caused more severe liver damage and inflammatory responses in wild-type mice as compared to operation started at ZT6 (corresponding to high Rev-erbα expression), supporting a protective effect of Rev-erbα on hepatic I/R injury. Collectively, Rev-erbα protects hepatic I/R injury probably via repression of inflammatory responses, and targeting Rev-erbα may be a promising approach for management of hepatic I/R injury.Transcription factor EVI1 is essential for normal hematopoiesis in embryos but is aberrantly elevated in bone marrow cells of myelodysplastic syndrome (MDS) patients. EVI1 and its downstream GATA-2 appear to be a possible therapeutic target of MDS. Here we found that treatment of EVI1-expressing K562 cells with arsenite (As(III)) reduced the mRNA and protein levels of EVI1 and GATA-2. A gel shift assay using the nuclear extract of K562 cells showed that As(III) suppressed the DNA-binding activity of EVI1. The DNA-binding activity of the recombinant EVI1 protein was also suppressed by As(III) but was recovered by excess amounts of dithiothreitol, suggesting the involvement of cysteine residues of EVI1. Since the 7th Zn finger domain of EVI1, having a motif of CCHC, is known to be involved in DNA-binding, the synthetic peptide of 7th Zn finger domain was reacted with As(III) and subjected to MALDI-TOF-MS analysis. The results showed that As(III) binds to this peptide via three cysteine residues. As(III)-induced reduction of the DNA-binding activity of the recombinant EVI1 was abolished by the mutations of each of three cysteine residues to alanine in the 7th Zn finger domain. These results demonstrate that As(III) causes the down-regulation of EVI1 and GATA-2 by inhibiting the transcriptional activity of EVI1 through the binding to the cysteine residues of CCHC-type Zn finger domain.Ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) plays a key role in influencing mitochondrial function. Increasing evidence supports that UQCRC1 overexpression takes part in cardioprotection. However, it remains unclear about the signaling pathway mediating the protective role of UQCRC1 overexpression. Thus, the current study aimed to investigate the signaling pathway. Inhibition of PI3K completely abolished the protective effects of UQCRC1 overexpression on cell viability and mitochondrial membrane potential after OGD or hydrogen peroxide injury in H9c2 cardiac cells, while inhibition of ERK only partially abolished these effects. Moreover, UQCRC1 overexpression dramatically increased the phosphorylation of PI3K downstream signal molecules including Akt and GSK-3β. Finally, UQCRC1 overexpression upregulated the expression of antiapoptotic protein Bcl-2, downregulated the expression of proapoptotic protein Bax, decreased active caspase 3 expression and cell apoptosis, which were completely abolished by inhibition of PI3K. In conclusion, UQCRC1 overexpression protects H9c2 cardiac cells against mimic ischemia/reperfusion injury through mediating PI3K/Akt/GSK-3β pathway to regulate apoptosis-related proteins.Clock genes express circadian rhythms in most organs. These rhythms are organized throughout the whole body, regulated by the suprachiasmatic nucleus (SCN) in the brain. Disturbance of these clock gene expression rhythms is a risk factor for diseases such as obesity and cancer. To understand the mechanism of regulating clock gene expression rhythms in vivo, multiple real time recording systems are required. In the present study, we developed a double recording system of Period1 expression rhythm in peripheral tissue (liver) and the brain. In peripheral tissue, quantification of gene expression in a steadily moving target was achieved by using a photomultiplier tube (PMT) attached to a tissue contact optical sensor (TCS). Using this technique, we were able to analyze circadian rhythms of clock gene expression over a prolonged period in the liver and olfactory bub (OB) of the brain. The present double recording system has no effect on behavioral activity or rhythm. Our novel system thus successfully quantifies clock gene expression in deep areas of the body in freely moving mice for a period sufficient to analyze circadian dynamics.