scholarly journals 2′, 5′-Oligoadenylate Synthetase 2 (OAS2) Inhibits Zika Virus Replication through Activation of Type Ι IFN Signaling Pathway

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 418 ◽  
Author(s):  
Xinzhong Liao ◽  
He Xie ◽  
Shilin Li ◽  
Haiyan Ye ◽  
Shuang Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Zika Virus ◽  
A549 Cells ◽  
Underlying Mechanism ◽  
Luciferase Assay ◽  
Oligoadenylate Synthetase ◽  
Zikv Infection ◽  
Stat Signaling ◽  
Plasmid Transfection

Background: 2′, 5′-oligoadenylate synthetase 2 (OAS2) has been known as an antiviral interferon-stimulated gene (ISG). However, the role of OAS2 on Zika virus (ZIKV) replication is still unknown. In this study, we sought to explore the effect of OAS2 on ZIKV replication and its underlying mechanism. Methods: We performed RNA-Seq in A549 cells with or without ZIKV infection. OAS2 or RIG-I was overexpressed by plasmid transfection or knocked down by siRNA in A549 cells. Expression levels of mRNA and protein of selected genes were detected by RT-qPCR and Western Blot, respectively. Interferon stimulated response element (ISRE) activity was examined by dual luciferase assay. Results: We found that ZIKV infection induced OAS2 expression through a RIG-I-dependent pathway. OAS2 overexpression inhibited ZIKV replication, while OAS2 knockdown increased ZIKV replication. We observed that OAS2 inhibited ZIKV replication through enhanced IFNβ expression, leading to the activation of the Jak/STAT signaling pathway. Conclusion: ZIKV infection induced OAS2 expression, which in turn exerted its anti-ZIKV activities through the IFN-activated Jak/STAT signaling pathway.

scholarly journals USP18 Mediates Interferon Resistance of Dengue Virus Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Haiyan Ye ◽  
Xiaoqiong Duan ◽  
Min Yao ◽  
Lan Kang ◽  
Yujia Li ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Western Blot ◽  
Signaling Pathway ◽  
Hela Cells ◽  
Denv Infection ◽  
Luciferase Assay ◽  
Type I ◽  
Qrt Pcr ◽  
Stat Signaling

Previous studies demonstrated that dengue virus (DENV) infection developed resistance to type-I interferons (IFNα/β). The underlying mechanism remains unclear. USP18 is a negative regulator of IFNα/β signaling, and its expression level is significantly increased following DENV infection in cell lines and patients’ blood. Our previous study revealed that increased USP18 expression contributed to the IFN-α resistance of Hepatitis C Virus (HCV). However, the role of USP18 in DENV replication and resistance to IFN-α is elusive. In this current study, we aimed to explore the role of USP18 in DENV-2 replication and resistance to IFN-α. The level of USP18 was up-regulated by plasmid transfection and down-regulated by siRNA transfection in Hela cells. USP18, IFN-α, IFN-β expression, and DENV-2 replication were monitored by qRT-PCR and Western blot. The activation of the Jak/STAT signaling pathway was assessed at three levels: p-STAT1/p-STAT2 (Western blot), interferon-stimulated response element (ISRE) activity (Dual-luciferase assay), and interferon-stimulated genes (ISGs) expression (qRT-PCR). Our data showed that DENV-2 infection increased USP18 expression in Hela cells. USP18 overexpression promoted DENV-2 replication, while USP18 silence inhibited DENV-2 replication. Silence of USP18 potentiated the anti-DENV-2 activity of IFN-α through activation of the IFN-α-mediated Jak/STAT signaling pathway as shown by increased expression of p-STAT1/p-STAT2, enhanced ISRE activity, and elevated expression of some ISGs. Our data indicated that USP18 induced by DENV-2 infection is a critical host factor utilized by DENV-2 to confer antagonism on IFN-α.

scholarly journals Uncover the Underlying Mechanism of Drug-Induced Myopathy by Using Systems Biology Approaches

2017 ◽  
Vol 2017 ◽  
pp. 1-7
Author(s):  
Dong Li ◽  
Aixin Li ◽  
Hairui Zhou ◽  
Xi Wang ◽  
Peng Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Side Effect ◽  
Chemical Structure ◽  
Safety Evaluation ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Drug Induced ◽  
Drug List ◽  
Rare Side Effect

Drug-induced myopathy (DIM) is a rare side effect; however, the consequence could be fatal. There are few reports to systematically assess the underlying mechanism of DIM. In this study, we curated the comprehensive DIM drug list based on structured labeling products (SPLs) and carried out the analysis based on chemical structure space, drug protein interaction, side effect space, and transcriptomic profiling space. Some key features are enriched from each of analysis. Specifically, the similarity of DIM drugs is more significant than random chance, which shows that the chemical structure could distinguish the DIM-positive drugs from negatives. The cytochrome P450 (CYP) was identified to be shared by DIM drugs, which indicated the important role of metabolism in DIM. Three pathways including pathways in cancer, MAPK signaling pathway, and GnRH signaling pathway enriched based on transcriptomic analysis may explain the underlying mechanism of DIM. Although the DIM is the current focus of the study, the proposed approaches could be applied to other toxicity assessments and facilitate the safety evaluation.

scholarly journals Study on the role of JAK/STAT signaling pathway during chicken spermatogonial stem cells generation based on RNA-Seq

2015 ◽  
Vol 14 (5) ◽  
pp. 939-948 ◽  
Author(s):  
Lei ZHANG ◽  
Qi-sheng ZUO ◽  
Dong LI ◽  
Chao LIAN ◽  
Kamel E Ahmed ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathway ◽  
Spermatogonial Stem Cells ◽  
Rna Seq ◽  
Stat Signaling

The epidermal growth factor receptor is a relevant host factor in the early stages of Zika virus life cycle in vitro

2021 ◽  
Author(s):  
Catarina Sabino ◽  
Daniela Bender ◽  
Marie-Luise Herrlein ◽  
Eberhard Hildt
Keyword(s):  
Life Cycle ◽  
Zika Virus ◽  
A549 Cells ◽  
Growth Factor Receptor ◽  
Viral Life Cycle ◽  
Infection Process ◽  
Zikv Infection ◽  
Early Stages ◽  
Egfr Expression

Zika virus (ZIKV) is a flavivirus well-known for the epidemic in the Americas in 2015-2016, where microcephaly in newborns and other neurological complications were connected to ZIKV infection. Many aspects of the viral life cycle, including binding and entry into the host cell, are still enigmatic. Based on the observation that CHO cells lack the expression of EGFR and are not permissive for various ZIKV strains, the relevance of EGFR for the viral life cycle was analyzed. Infection of A549 cells by ZIKV leads to a rapid internalization of EGFR that colocalizes with the endosomal marker EEA1. Moreover, the infection by different ZIKV strains is associated with an activation of EGFR and subsequent activation of the MAPK/ERK signaling cascade. However, treatment of the cells with MβCD, which on the one hand leads to an activation of EGFR but on the other hand prevents EGFR internalization, impairs ZIKV infection. Specific inhibition of EGFR or of the RAS-RAF-MEK-ERK signal transduction cascade hinders ZIKV infection by inhibition of ZIKV entry. In accordance to this, knockout of EGFR expression impedes ZIKV entry. In case of an already established infection, inhibition of EGFR or of downstream signaling does not affect viral replication. Taken together, these data demonstrate the relevance of EGFR in the early stages of ZIKV infection and identify EGFR as a target for antiviral strategies. Importance These data deepen the knowledge about the ZIKV infection process and demonstrate the relevance of EGFR for ZIKV entry. In light of the fact that a variety of specific and efficient inhibitors of EGFR and of EGFR-dependent signaling were developed and licensed, repurposing of these substances could be a helpful tool to prevent the spreading of ZIKV infection in an epidemic outbreak.

scholarly journals JAK/STAT Activation: A General Mechanism for Bone Development, Homeostasis, and Regeneration

2020 ◽  
Vol 21 (23) ◽  
pp. 9004
Author(s):  
Alexandra Damerau ◽  
Timo Gaber ◽  
Sarah Ohrndorf ◽  
Paula Hoff
Keyword(s):  
Signaling Pathway ◽  
Bone Development ◽  
Gene Knockout ◽  
Selective Inhibition ◽  
Janus Kinase ◽  
General Mechanism ◽  
Stat Signaling ◽  
Skeletal Phenotype ◽  
Pro Inflammatory Cytokines

The Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway serves as an important downstream mediator for a variety of cytokines, hormones, and growth factors. Emerging evidence suggests JAK/STAT signaling pathway plays an important role in bone development, metabolism, and healing. In this light, pro-inflammatory cytokines are now clearly implicated in these processes as they can perturb normal bone remodeling through their action on osteoclasts and osteoblasts at both intra- and extra-articular skeletal sites. Here, we summarize the role of JAK/STAT pathway on development, homeostasis, and regeneration based on skeletal phenotype of individual JAK and STAT gene knockout models and selective inhibition of components of the JAK/STAT signaling including influences of JAK inhibition in osteoclasts, osteoblasts, and osteocytes.

scholarly journals Autophagy in Zika Virus Infection: A Possible Therapeutic Target to Counteract Viral Replication

2019 ◽  
Vol 20 (5) ◽  
pp. 1048 ◽  
Author(s):  
Rossella Gratton ◽  
Almerinda Agrelli ◽  
Paola Tricarico ◽  
Lucas Brandão ◽  
Sergio Crovella
Keyword(s):  
Public Health ◽  
Viral Replication ◽  
Zika Virus ◽  
Health Concern ◽  
Mtor Signaling Pathway ◽  
Catabolic Pathway ◽  
Public Health Concern ◽  
Zikv Infection ◽  
Fundamental Process

Zika virus (ZIKV) still constitutes a public health concern, however, no vaccines or therapies are currently approved for treatment. A fundamental process involved in ZIKV infection is autophagy, a cellular catabolic pathway delivering cytoplasmic cargo to the lysosome for degradation—considered as a primordial form of innate immunity against invading microorganisms. ZIKV is thought to inhibit the Akt-mTOR signaling pathway, which causes aberrant activation of autophagy promoting viral replication and propagation. It is therefore appealing to study the role of autophagic molecular effectors during viral infection to identify potential targets for anti-ZIKV therapeutic intervention.

Role of VHL-JAK-STAT signaling pathway in central nervous system hemangioblastoma associated with von Hippel-Lindau disease

2020 ◽  
Vol 148 (1) ◽  
pp. 29-38 ◽  
Author(s):  
Hiroshi Kanno ◽  
Tetsuya Yoshizumi ◽  
Masamichi Shinonaga ◽  
Atsuhiko Kubo ◽  
Hidetoshi Murata ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Signaling Pathway ◽  
Von Hippel Lindau ◽  
Stat Signaling ◽  
Von Hippel Lindau Disease ◽  
Central Nervous System Hemangioblastoma

scholarly journals miR-32-5p Inhibits the Proliferation, Migration and Invasion of Thyroid Cancer Cells by Regulating Twist1

2021 ◽  
Author(s):  
Qing Liu ◽  
Ouyang Li ◽  
Chi Zhou ◽  
Yu Wang ◽  
Chunxue He ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Transition Process ◽  
Underlying Mechanism ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Thyroid Cancer Cells

Abstract Background: Thyroid cancer is the most prevalent malignancy and one of the leading causes of cancer-related deaths. Recent studies have revealed that microRNAs (miRNAs) play an important role in tumorigenesis in various cancer types by affecting the expression of its targets. However, the role of miR-32-5p in thyroid cancer remains limited. Methods: In this study, we attempt to explore the role of miR-32-5p in thyroid cancer and elucidate the underlying mechanism. Expression of miR-32-5p was determined by quantitative reverse transcription PCR. Functional assays were performed by CCK-8 assay, cell colony assay, cell apoptosis assay, cell migration and invasion assays, cell cycle assay and luciferase assay. Protein expression was analyzed by Western blot.Results: In the present study, the role of miR-32-5p in thyroid cancer was firstly explored. It is found that miR-32-5p was downregulated in thyroid cancer tissues and cells. Overexpression of miR-32-5p inhibited thyroid cancer cells proliferation, migration, invasion and epithelial‐mesenchymal transition process; while suppression of miR-32-5p exhibited an opposite effect on thyroid cancer cells. In addition, In addition, a luciferase assay showed Twist1 was identified as a direct target of miR-32-5p in thyroid cancer, and further study showed that restoration of Twist1 attenuated the biological effect of miR-32-5p on thyroid cancer cells. Conclusion: In conclusion, our results demonstrated miR-32-5p functions as a tumor suppressor by targeting Twist1 in thyroid cancer, providing a novel insight into thyroid cancer therapy.

scholarly journals Betulinic Acid Inhibits ROS-Mediated Pyroptosis in Spinal Cord Injury by Augmenting Autophagy via the AMPK-mTOR-TFEB Signaling Pathway

2020 ◽  
Author(s):  
Chenyu Wu ◽  
Huanwen Chen ◽  
Rong Zhuang ◽  
Yongli Wang ◽  
Xinli Hu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Signaling Pathway ◽  
Betulinic Acid ◽  
Neurological Diseases ◽  
Underlying Mechanism ◽  
Autophagy Flux ◽  
Wide Range ◽  
Cord Injury

Abstract Background：Spinal cord injury (SCI) results in a wide range of disabilities. Its complex pathophysiological process limits the effectiveness of many clinical treatments. Betulinic acid (BA) has been shown to be an effective treatment for some neurological diseases, but it has not been studied in SCI. In this study, we assessed the role of BA in SCI and investigated its underlying mechanism. Methods：Using a mouse model of SCI, survival and functional outcomes following injury were assessed. Western blotting, ELISA, and immunofluorescence techniques were employed to analyze levels of autophagy, mitophagy, and pyroptosis; ROS- and AMPK-related signaling pathways were also examined. Results：Our results showed that BA significantly improves functional recovery following SCI. Furthermore, autophagy, mitophagy, ROS-activity and pyroptosis were implicated in the mechanism of BA in the treatment of SCI. Specifically, our results suggest that BA restored autophagy flux following injury, which induces mitophagy to eliminate the accumulation of ROS and subsequently inhibits pyroptosis. Further mechanistic studies revealed that BA likely regulates autophagy and mitophagy via the AMPK-mTOR-TFEB signaling pathway. Conclusion: BA can significantly promote the recovery following SCI and that it may be a promising therapy for SCI.

scholarly journals MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation

2021 ◽  
Vol 11 ◽  
Author(s):  
Yinghui Hong ◽  
Mingliang Ye ◽  
Fan Wang ◽  
Jun Fang ◽  
Chun Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Signaling Pathway ◽  
Negative Regulator ◽  
Epigenetic Mechanism ◽  
Luciferase Assay ◽  
Rat Models ◽  
Cancer Pathogenesis ◽  
Tumor Stages

BackgroundHepatocellular carcinoma (HCC) remains a major global health burden due to its high prevalence and mortality. Emerging evidence reveals that microRNA (miRNA) plays a vital role in cancer pathogenesis and is widely involved in the regulation of signaling pathways via their targeting of downstream genes. MiR-21-3p, a liver-enriched miRNA, and SMAD7, the negative regulator of the TGF-β signaling pathway, likely exert a vital influence on HCC progression.AimsHere, we explore the role of the miR-21-3p-SMAD7/YAP1 axis on HCC pathogenesis.MethodsMiRNA microarray analysis was performed for miRNA screening. The dual-luciferase assay was adopted for target verification. Expression of miRNA and related genes were quantified via qRT-PCR, western blotting, and immunohistochemical staining. Flow cytometry and the transwell migration assay were used to detail cell apoptosis, invasion and metastases. Rat models were established to explore the role of the miR-21-3p-SMAD7/YAP1 axis in hepatocarcinogenesis. Bioinformatics analysis was conducted for exploring genes of clinical significance.ResultsMiR-21-3p levels were found to be significantly elevated in hepatocellular carcinoma and indicate poor overall survival. High miR-21-3p levels were associated with advanced tumor stages (P = 0.029), in particular T staging (P = 0.026). Low SMAD7/high YAP1 levels were confirmed in both HCC and rat models with advanced liver fibrosis and cirrhosis. Besides, SMAD7 was demonstrated to be the direct target of miR-21-3p. The effect of MiR-21-3p on tumor phenotypes and YAP1 upregulation could be partly reversed via the restoration of SMAD7 expression in HCC cell lines. Overexpression of YAP1 after miR-21-3p upregulation promoted expression of nuclear transcription effector connective tissue growth factor. Co-survival analysis indicated that lower miR-21-3p/higher SMAD7 (P = 0.0494) and lower miR-21-3p/lower YAP1 (P = 0.0379) group patients had better overall survival rates. Gene Set Variation Analysis revealed that gene sets related to miR-21-3p and SMAD7 were significantly associated with the TGF-β signaling pathway in HCC.ConclusionMiR-21-3p promotes migration and invasion of HCC cells and upregulation of YAP1 expression via direct inhibition of SMAD7, underscoring a major epigenetic mechanism in the pathogenesis of HCC.

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