MicroRNA‑4485 ameliorates severe influenza pneumonia via inhibition of the STAT3/PI3K/AKT signaling pathway

Guo, Longfei; Wang, Quanhong; Zhang, Dongquan

doi:10.3892/ol.2020.12078

Cited by 14 publications

(13 citation statements)

References 28 publications

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“…Interestingly, EGFR activation can result in Src/FAK/BTK mediated activation of STAT3, thereby modulating the IFN and proinflammatory responses. As expected of H1N1 and H3N2 infections 96,97 , we observed a suppression of STAT3pY705 in untreated cells that was comparable to that observed following treatment with most NRTKIs. Surprisingly, we observed significant suppression of STATpY705 following DF treatment (85-90% of untreated infected cells).…”

Section: Discussionsupporting

confidence: 86%

“…Although STAT3 is dispensable for IFN signaling, it is activated by IFN-I and serves as a negative regulator to fine-tune the IFN response (reviewed in 95 ). Because STAT3 activation upregulates anti-apoptotic factors, H5N1 mediated STAT3pY705 allows prolonged viral production through delay of apoptosis; H1N1 is less efficient at STAT3pY705 and triggers apoptosis earlier 96,97 . Although the mechanism of differential suppression of STAT3 activation by IAV is not clear, it has been suggested to be mediated by NS1 87 .…”

Section: Discussionmentioning

confidence: 99%

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Ex Vivo Validation of Six FDA-Approved Non-Receptor Tyrosine Kinase Inhibitors (NRTKIs) as Antivirals to Pandemic and Seasonal Influenza A Viruses

Meineke

Stelz

Busch

et al. 2022

Preprint

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Influenza viruses are important respiratory pathogens that cause substantial morbidity and mortality annually. In addition to seasonal influenza outbreaks, new emerging influenza A viruses (IAV) can cause pandemic influenza outbreaks. Apart from effective vaccines, there is a need for better treatment options to combat infections with these viruses when vaccines are not available or show reduced efficacy (e.g., in immmunocompromised patients). The limited range of licensed antiviral drugs and emergence of drug-resistance mutations highlight the need for novel intervention strategies like host-targeted antivirals. Repurposing FDA-approved kinase inhibitors may offer a fast-track for a new generation of host-targeted antivirals. Small molecule kinase inhibitors (SMKIs) can inhibit replication of viruses and improve survival in vivo; however, no SMKI has been approved for clinical use against IAV infections. In the present study, we tested eight non-receptor tyrosine kinase-inhibitors (NRTKIs) used to treat cancer and autoimmune diseases for their antiviral potential. Six of those potently inhibited virus replication (≥1,000-fold) in A549 cells infected with either A(H1N1)pdm09 or seasonal A(H3N2) strains. These compounds were validated in a biologically relevant ex vivo model of human precision-cut lung slices (hPCLS) to provide proof of principle and show efficacy against contemporary seasonal and pandemic IAVs. We identified the steps of the virus infection cycle affected by these inhibitors and assessed the effect of these NRTKIs on the host response. Considering their established safety profiles, our studies show that the use of these NRTKI shows promise and warrants further development as an alternative strategy to treat influenza virus infections.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Ex Vivo Validation of Six FDA-Approved Non-Receptor Tyrosine Kinase Inhibitors (NRTKIs) as Antivirals to Pandemic and Seasonal Influenza A Viruses

Meineke

Stelz

Busch

et al. 2022

Preprint

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“…Previous studies found that miR-29c is implicated in bladder cancer via PI3 K/Akt (Fan et al 2014), and PTEN and NF-kB are of great significance in colon cancer (Zhang et al 2015). Moreover, it has been proved in the previous study that microRNA-4485 can improve SP by inhibiting the STAT3/PI3 K/AKT signaling pathway (Guo et al 2020). Another study indicated that pinitol could reduce LPS-induced pneumonia in experimental animals, which may play a role by inhibiting the TLR-4 and NF-κB/IκBα signaling cascade (Fan et al 2021).…”

Section: Discussionmentioning

confidence: 96%

Effects of the miR-29c/PTEN axis on the PI3 K/Akt/NF-kB pathway in a rat model of severe pneumonia

Zhang

Peng

et al. 2021

All Life

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This study aimed to investigate the effect of the miR-29c/PTEN axis on the PI3 K/Akt/NF-kB pathway in rats with severe pneumonia (SP). A total of 20 Sprague-Dawley rats were selected, of which 10 were randomly selected for modeling SP and included in the model group (MG) and the other 10 were included in the control group (CG). Expression levels of miR-29c and PTEN were measured in the peripheral blood and lung tissue. Pearson correlation coefficient analysis showed that miR-29c was positively correlated with PTEN in serum and lung tissue (r = 0.833 and 0.697, respectively; P < 0.05). The apoptosis rate was higher in the MG than in the CG (P < 0.05). Western blot analysis revealed that the relative expressions of PI3 K, Akt, and NF-kB proteins were higher in the MG than in the CG (P < 0.05). Protein expression in the miR-29c-mimics and sh-PTEN groups was higher than that in the other two groups, whereas the miR-29c-inhibitor group had the lowest protein expression (P < 0.05). MiR-29c/PTEN exhibited low expression levels in SP, which can promote pneumonia development by inhibiting the expression of PI3 K/Akt/NF-kB pathway proteins.

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“…Out of the remaining 17 differentially expressed miRNAs, miR-20a and hsa-let-7 have been reported to regulate antifungal responses, although only in Paracoccidioides brasiliensis (56). miR-16 and miR-4677 have been linked to antibacterial host responses (57,58), while miR-3074, miR-335, miR-34b, miR-4485, and miR-1246 have been associated with antiviral immune responses in various in vitro models (59)(60)(61)(62)(63). The remaining nine identified miRNA species have not yet been associated with microbe-induced inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

Oral Epithelial Cells Distinguish betweenCandidaSpecies with High or Low Pathogenic Potential through MicroRNA Regulation

et al. 2021

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Oral epithelial cells monitor microbiome composition and initiate immune response upon dysbiosis, as in the case of Candida imbalances. Candida species, such as C. albicans and C. parapsilosis, are the most prevalent yeasts in the oral cavity. Comparison of healthy oral epithelial cell responses revealed that while C. albicans infection robustly activated inflammation cascades, C. parapsilosis primarily activated various inflammation-independent pathways. In posttranscriptional regulatory processes, several miRNAs were altered by both species. For C. parapsilosis, the dose of yeast cells directly correlated with changes in transcriptomic responses with higher fungal burdens inducing significantly different and broader changes. MicroRNAs (miRNAs) associated with carbohydrate metabolism-, hypoxia-, and vascular development-related responses dominated with C. parapsilosis infection, whereas C. albicans altered miRNAs linked to inflammatory responses. Subsequent analyses of hypoxia-inducible factor 1α (HIF1-α) and hepatic stellate cell (HSC) activation pathways predicted target genes through which miRNA-dependent regulation of yeast-specific functions may occur, which also supported the observed species-specific responses. Our findings suggest that C. parapsilosis is recognized as a commensal at low doses by the oral epithelium; however, increased fungal burden activates different pathways, some of which overlap with the inflammatory processes robustly induced by C. albicans. IMPORTANCE A relatively new topic within the field of immunology involves the role of miRNAs in innate as well as adaptive immune response regulation. In recent years, posttranscriptional regulation of host-pathogenic fungal interactions through miRNAs was also suggested. Our study reveals that the distinct nature of human oral epithelial cell responses toward C. parapsilosis and C. albicans is possibly due to species-specific fine-tuning of host miRNA regulatory processes. The findings of this study also shed new light on the nature of early host cell transcriptional responses to the presence of C. parapsilosis and highlight the species’ potential inflammation-independent host activation processes. These findings contribute to our better understanding of how miRNA deregulation at the oral immunological barrier, in noncanonical immune cells, may discriminate between fungal species, particularly Candida species with high or low pathogenic potential.

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MicroRNA‑4485 ameliorates severe influenza pneumonia via inhibition of the STAT3/PI3K/AKT signaling pathway

Cited by 14 publications

References 28 publications

Ex Vivo Validation of Six FDA-Approved Non-Receptor Tyrosine Kinase Inhibitors (NRTKIs) as Antivirals to Pandemic and Seasonal Influenza A Viruses

Ex Vivo Validation of Six FDA-Approved Non-Receptor Tyrosine Kinase Inhibitors (NRTKIs) as Antivirals to Pandemic and Seasonal Influenza A Viruses

Effects of the miR-29c/PTEN axis on the PI3 K/Akt/NF-kB pathway in a rat model of severe pneumonia

Oral Epithelial Cells Distinguish betweenCandidaSpecies with High or Low Pathogenic Potential through MicroRNA Regulation

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