MicroRNA interplay between hepatic stellate cell quiescence and activation.

Abstract Liver fibrosis is a common pathologic stage of the development of liver failure. It has showed that exosomes loaded with therapeutic circRNAs can be manufactured in bulk by exosome secreted cells in vitro, thus enabling personalized treatment. This study aimed to investigate the role of exosome-based delivery of circDIDO1 in liver fibrosis. Levels of genes and proteins were examined by qRT-PCR and Western blot. Cell proliferation, apoptosis, and cell cycle were analyzed by using cell counting kit-8 (CCK-8) assay, EdU assay, and flow cytometry, respectively. The binding between circDIDO1 and miR-141-3p was confirmed by dual-luciferase reporter, RNA pull-down and RIP assays. Exosomes were isolated by ultracentrifugation, and qualified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blot. CircDIDO1 overexpression or miR-141-3p inhibition suppressed the proliferation, reduced pro-fibrotic markers, and induced apoptosis as well as cell cycle arrest in hepatic stellate cells (HSCs) by blocking PTEN/AKT pathway. Mechanistically, circDIDO1 acted as an endogenous sponge for miR-141-3p, further rescue experiments showed that circDIDO1 suppressed HSC activation by targeting miR-141-3p. Extracellular circDIDO1 could be incorporated into exosomes isolated from mesenchymal stem cells (MSCs), and transmitted to HSCs to restrain HSC activation. Clinically, low levels of serum circDIDO1 in exosome were correlated with liver failure, and serum exosomal circDIDO1 had a well diagnostic value for liver fibrosis in liver failure patients. Transfer of circDIDO1 mediated by MSC-isolated exosomes suppressed HSC activation through the miR-141-3p/PTEN/AKT pathway, gaining a new insight into the prevention of liver fibrosis in liver failure patients.

https://www.tandfonline.com/doi/pdf/10.1080/10717544.2022.2030428?needAccess=true

Mesenchymal stem cell-originated exosomal circDIDO1 suppresses hepatic stellate cell activation by miR-141-3p/PTEN/AKT pathway in human liver fibrosis

MicroRNA-155 and antiviral immune responses.

Liver fibrosis (LF) is a healing response to wounds resulting in liver injury that can cause liver failure or even cancer without functional prevention. Resveratrol (RSV) has been suggested to exert biological effects against various human diseases. MicroRNA‑20a (miRNA/miR‑20a) has been shown to promote disease progression. The present study aimed to assess the mechanisms through which RSV induces autophagy and activates the miR‑20a‑mediated phosphatase and tensin homolog (PTEN)/PI3K/AKT signaling pathway in LF. First, a rat model of carbon tetrachloride (CCL4)‑induced LF and a cell model of platelet‑derived growth factor (PDGF)‑BB‑stimulated HSC‑T6 cells were established for use in subsequent experiments. Subsequently, RSV at a range of concentrations was injected into the model rats with LF. Indicators related to liver injury, oxidative stress and fibrosis were determined in the rats with LF. The RSV‑treated HSC‑T6 cells were subjected to transfection with miR‑20a mimic and PTEN overexpression plasmid to assess the levels of liver injury and LF. A dual‑luciferase reporter gene assay was performed to verify the binding sites between PTEN and miR‑20a. RSV was found to alleviate LF in rats, and autophagy was enhanced in the rats with LF following RSV treatment. Furthermore, the activation of the PTEN/PI3K/AKT axis attenuated LF, which was reversed by transfection with miR‑20a mimic. RSV reversed the inhibitory effects of miR‑20a on PTEN expression, reducing miR‑20a expression and promoting PTEN, PI3K and p‑AKT protein expression, thus attenuating LF. On the whole, the present study demonstrates that RSV induces autophagy and activates the miR‑20a‑mediated PTEN/PI3K/AKT signaling pathway to attenuate LF. These findings may lead to the development of potential therapeutic strategies for LF.

/pdf/resveratrol-contributes-to-the-inhibition-of-liver-fibrosis-4go5tuiasl.pdf

Resveratrol contributes to the inhibition of liver fibrosis by inducing autophagy via the microRNA‑20a‑mediated activation of the PTEN/PI3K/AKT signaling pathway.

Interferon regulatory factor (IRF) 7 was originally identified as master transcriptional factor that produced IFN-I and regulated innate immune response, subsequent studies have revealed that IRF7 performs a multifaceted and versatile functions in multiple biological processes. In this review, we provide a comprehensive overview on the current knowledge of the role of IRF7 in immunity and autoimmunity. We focus on the latest regulatory mechanisms of IRF7 in IFN-I, including signaling pathways, transcription, translation, and post-translational levels, the dimerization and nuclear translocation, and the role of IRF7 in IFN-III and COVID-19. In addition to antiviral immunity, we also discuss the role and mechanism of IRF7 in autoimmunity, and the further research will expand our understanding of IRF7.

IRF7: role and regulation in immunity and autoimmunity

The activation of hepatic stellate cells (HSCs) caused by stimulating factors or fibrogenic cytokines is the critical stage of liver fibrosis. Recent studies have demonstrated the influence of microRNAs (miRNAs or miRs) on HSC activation and transformation; however, the function and underlying mechanisms of miRNAs in HSC activation have not yet been completely clarified. In the present study, transforming growth factor β1 (TGF‑β1) was used to treat human HSC lines (HSC‑T6 and LX2 cells) to simulate the activation of HSCs in vivo and whether the expression of miRNAs in HSCs was affected by TGF‑β1 treatment was examined using a miRNA microarray. It was observed that miR‑141 was one of the most upregulated miRNAs during HSC activation. Functional analyses revealed that miR‑141 knockdown suppressed the viability of HSCs and inhibited the expression levels of pro‑fibrotic markers. In addition, phosphatase and tensin homolog (PTEN), a well‑known suppressor of the AKT/mammalian target of rapamycin (mTOR) pathway, was found to be directly targeted by miR‑141 in HSCs. More importantly, the knockdown of PTEN markedly reversed the suppressive effects of miR‑141 inhibition on the viability of and the expression levels of pro‑fibrotic markers during HSC activation. Finally, it was observed that the downregulation of miR‑141 blocked the TGF‑β1‑induced activation of the AKT/mTOR pathway in HSCs. On the whole, the findings of the present study indicate that miR‑141 inhibition suppresses HSC activation via the AKT/mTOR pathway by targeting PTEN, highlighting that miR‑141 may serve as a novel therapeutic target for liver fibrosis.

https://www.spandidos-publications.com/10.3892/ijmm.2020.4578/download

Downregulation of miR‑141 deactivates hepatic stellate cells by targeting the PTEN/AKT/mTOR pathway.

Personal purchases of novel coronavirus antigen detection reagents (ADRs) for self-detection have contributed to the optimization of medical resources and containment of the COVID-19 pandemic. The recurring occurrence of false testing results in China has generated concerns regarding the quality of ADRs and the testing mechanism for medical devices. Academic viewpoints and remarks on the sensitivity, application possibilities, and product innovation of ADRs may be found in the extant scientific literature. However, the current research does not explore the microscopic product quality concerns that emerge throughout the production and marketing of ADRs. To explore strategic equilibrium circumstances and behavioral evolution processes, an evolutionary game model was developed to include ADR manufacturers, third-party medical device inspection agencies, and regulatory authorities. The results reveal that the quantity of illegal incentives, the cost of regulation, and the loss of government credibility have a major impact on the decisions of regulatory authorities and determine three potential systemic equilibrium states. To maximize social welfare, ADRs should be incorporated into China's medication price monitoring system in order to manage market prices. To cut regulatory expenses, the government should employ blockchain technology for traceable network regulation of ADR product quality. The government should also protect the people's right to free speech and encourage online reporting of adverse incidents caused by ADRs. The conclusions of this article can provide many developing nations with important insights for regulating the quality of ADR products.

Regulating the product quality of COVID-19 antigen testing reagents: A tripartite evolutionary game analysis under China's legal framework

Enterovirus 71 (EV71), the major cause of hand-foot-and-mouth disease (HFMD), has evolved diverse strategies to counter the type I interferon (IFN-I) response during infection. Recently, microRNAs have regulatory roles in host innate immune responses to viral infections; however, whether EV71 escapes the IFN-I antiviral response through regulation of miRNAs remains unclear. Using a microarray assay, microRNA-155-5p (miR-155-5p) was found to be significantly up-regulated in serum from patients with EV71 infection and the increased expression of miR-155-5p was further confirmed in vivo and in vitro in response to EV71 infection. miR-155-5p overexpression suppressed EV71 titers and VP1 protein level, while miR-155-5p inhibition had an opposite result. Moreover, we found that miR-155-5p overexpression enhanced EV71 triggered IFN I production and the expressions of IFN-stimulated genes (ISGs), while inhibition of miR-155-5p suppressed these processes. Furthermore, bioinformatics analysis and luciferase reporter assay demonstrated that miR-155-5p directly targeted forkhead box protein O3 (FOXO3) and negatively regulated FOXO3/IRF7 axis, an important regulatory pathway for type I IFN production during EV71 infection. Inhibition of FOXO3 reversed the effects of miR-155-5p inhibitor on EV71 replication and the type I IFN production. Importantly, in EV71 infection mice, agomir-155-5p injection resulted in a significant reduction of viral VP1 protein expressions in brain and lung tissues, increased IFN-α/β production and increased mice survival rate. In contrast, antagomir-155-5p enhanced EV71 induced these effects. Collectively, our study indicates that weaken miR-155-5p facilitates EV71 replication through suppression of type I IFN response by FOXO3/IRF7 pathway, thereby suggesting a novel strategy for developing effective antiviral therapy.

https://www.tandfonline.com/doi/pdf/10.1080/15384101.2019.1704512

Downregulation of miR-155-5p facilitates enterovirus 71 replication through suppression of type I IFN response by targeting FOXO3/IRF7 pathway.

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Downregulation of miR‑141 deactivates hepatic stellate cells by targeting the PTEN/AKT/mTOR pathway.

Regulating the product quality of COVID-19 antigen testing reagents: A tripartite evolutionary game analysis under China's legal framework

Downregulation of miR-155-5p facilitates enterovirus 71 replication through suppression of type I IFN response by targeting FOXO3/IRF7 pathway.