The Intracellular Signalling that Associated with Influenza A Virus Infection

Khalil, Hany

doi:10.21767/2573-0282.100038

Cited by 7 publications

(8 citation statements)

References 36 publications

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“…The MAPK pathway is required to control many cellular processes, including cell differentiation, cell division, cell proliferation, programmed cell death, and inflammation. MAPK/ERK signaling pathway includes activation of Raf protein kinase, MEK1/2, and the transcription factor ERK1/2 (29, 30). This pathway is activated in cancer cells due to the activation of mutant K-Ras and mutant B-Raf proteins which responsible for the limitation of programmed cell death and for raising the production level of TGF-β and IL-8 (31, 32).…”

Section: Discussionmentioning

confidence: 99%

Selective Regulation of B-Raf Dependent K-Ras/Mitogen-Activated Protein by Natural Occurring Multi-kinase Inhibitors in Cancer Cells

et al. 2019

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Introduction: Cancer is one of the most difficult challenges faced by humanity due to its many associated issues, such as inability to prevent diseases, treatment safety, and high mortality rate. In cancer, a variety of cellular signaling is activated to ensure malignancy transformation, angiogenesis and metastasis. The most efficient signaling pathway in cancer is mitogen-activated protein kinase (MAPK), which controls malignancy and regulates apoptosis.Methods: Four different flavonoid glycosides have been isolated from Pulicaria jaubertii using the phytochemical characterization of hydro-methanol extract. The purified glycosides (PJs) were investigated for their potential repression of cancer development using human lung epithelial cells and hepatocellular carcinoma (HCC) and compared with Sorafenib (SOR), the standard systemic drug for HCC. In PJ-treated cells, the expression profile of K-Ras, B-Raf, and P53 were detected using qRT-PCR, flow cytometry, confocal microscopy and western blot. Steady-state mRNA and levels of transforming growth factor-beta (TGF-β) and interleukin 8 (IL-8) were monitored in the fluids media at different time points following treatment.Results: Our results showed that the qurictine glycosides (PJ-1 and PJ-9) selectively inhibited the mutant K-Ras/B-Raf proteins expression and interaction in both cancer cells; while SOR showed obvious depletion of total Raf-1 protein in cancer cells and normal cells as well. Interestingly, the combination of PJ-1 or PJ-9 with SOR exhibited restoring cell viability of normal cells via controlling Raf-1 and P53 genes expression. Further, these identified PJ agents significantly adjusted the levels of TGF-β and IL-8 in cancer treated cells accompanied by restoring the activation of P53 expression. These findings were confirmed by docking analysis of PJs ligand and the crystal structure of K-Ras, B-Raf, and ERK transcription factor.Conclusion: The current data provide novel and natural multi-kinase inhibitors with competitive regulation of the mutant proteins; K-Ras and B-Raf and sustained MAPK signaling without any detectable toxic effect in normal cells.

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Section: Discussionmentioning

confidence: 99%

Selective Regulation of B-Raf Dependent K-Ras/Mitogen-Activated Protein by Natural Occurring Multi-kinase Inhibitors in Cancer Cells

et al. 2019

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“…The activation of PI3K and its downstream targets Gbr2, pip3, PDK and Akt protein kinase has been detected at early stages upon influenza infection (5‐9 hours post infection) . The PI3K‐Akt pathway is known to play an antiapoptotic role; therefore the activation of the PI3K/Akt pathway limits virus‐induced cell death or apoptosis in infected cells (Figure ). Conversely, at late stages of infection (17‐20 hours after infection), the P13K‐Akt pathway is inactivated due to the activation of pro‐apoptotic p53 signaling and its related targets p21/waf .…”

Section: Discussionmentioning

confidence: 99%

“…Blocking of PI3K-Akt signaling by GFGs enables the activation of P53 and its related cytokines that control cell survival and virus replication. GFGs, guava flavonoid glycosides; IAV, influenza A virus activation of the PI3K/Akt pathway limits virus-induced cell death or apoptosis in infected cells 26,40,41 (Figure 6). Conversely, at late stages of infection (17-20 hours after infection), the P13K-Akt pathway is inactivated due to the activation of pro-apoptotic p53 signaling and its related targets p21/waf.…”

Section: Discussionmentioning

confidence: 99%

Guava flavonoid glycosides prevent influenza A virus infection via rescue of P53 activity

Khalil

Maksoud

Roshdey

et al. 2018

Journal of Medical Virology

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Influenza is a highly infectious disease caused by three types of viruses, including influenza A virus (IAV), influenza B virus, and, rarely, influenza C virus. IAV is a major, global public health threat, causing approximately 500 000 deaths per year worldwide. The new strains of IAV have emerged due to a mutation called antigenic shift, which results in a new subtype of the virus that shows resistance to common antiviral drugs. Here, guava and lemon extracts, including green leaves and flowers, were investigated for their activity against IAV replication in human A549 cells. Concomitantly, the cytotoxicity of a potent extract on host-cell multiplication was assessed. Our results reveal that guava extracts inhibit IAV replication, indicated by viral nucleoprotein expression profile and traditional plaque assay. Interestingly, treatment with guava extract inactivates Akt protein kinase and stimulates the pro-apoptotic protein P53, at early stages of infection. Furthermore, purified guava flavonoid glycosides (GFGs) show competitive inhibition of IAV-virus replication via early regulation of IL-1β and IL-8 in association with P53 gene expression. The docking analysis of GFGs and the protein structure of upstream targets for the Akt signaling pathway indicates a sufficient interaction and stabilization with Gbr2 protein. These data indicate that treatment with GFGs disturbs IAV replication via activation of P53 and its apoptotic related factors after infection. Collectively, these data show that targeting of essential host kinases that are involved in the replication cycle of IAV and rescue of P53 activity by GFGs could represent a new strategy to eradicate IAV.

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“…Additionally, in order to identify unknown methylation hot-spots or methylated CpG islands in the genome, several of genome-wide screen methods have been invented such as Restriction Landmark Genomic Scanning for Methylation (RLGS-M), and CpG island microarray. Several studies have implicated the biological role and molecular interaction of DNMTs in cancer, aging and hepatitis C virus infection [8]. The expression of DNMT1 is increased in cancer and induces DNA methylation of various tumor suppressor genes.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, autophagy has been shown to play an important role in cell growth, development and disease pathology [7]. Notably, several studies indicated the essential role of autophagic machinery in regulating viral infection [8]. Activation of autophagy machinery is one of the down-stream events of a class III phosphatidylinositl I 3-kinase (PI 3-K) complex.…”

Section: Introductionmentioning

confidence: 99%

Epigenetics Reprogramming of Autophagy is involved in Childhood Acute Lymphatic Leukemi

Hassen¹,

Bassiouny²,

El-Shenawy³

et al. 2017

Pediatric Infect Dis

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Cancer disease has been considered as a result of progressive genetic alterations such as mutations in tumor suppressor genes and oncogenes, chromosomal abnormality and epigenetics reprogramming. Epigenetic modification plays a crucial role in the tumor initiation and tumor evaluation via DNA methylation activity and chromatin alternation mechanism. Noteworthy, autophagy is a fundamental, conserved physiological process by which cells target long-lived cytosolic proteins and organelles for lysosomal degradation. Recently, autophagy has been showed to play critical role in cancer evaluation and therapeutical strategy. On the other hand, lymphatic leukaemia is a type of cancer which contains two major conditions, acute and chronic leukaemia. Acute lymphatic leukemia (ALL) is the most common cancer in the pediatric population. Therefore, in the current work we were interested to investigate the possible involvement of DNA methylation of cellular genes in blood samples that derived from children with ALL. Interestingly, the relative expression of DNA methyltransferase 1 (DNMT1) has been increased in ALL samples compared to healthy individual samples. Meanwhile, the relative expression of cellular autophagy genes (LC3B and Atg5) has been strongly decreased in ALL samples suggesting the possible involvement of DNA methylation of related autophagy molecules. Accordingly, digestion of LC3B gene segment with restriction enzyme (HpaII) that specifically targeted CpG position showed inactive digestion on ALL samples in comparison with control samples indicating the possible methyl alternation of cytosine nucleotides. Further, we found another methylation activity on promoter regions of Atg5 and LC3B in ALL derived samples. These data strongly suggest that the expression of cellular autophagy genes LC3B and Atg5 are reduced and subsequently autophagic machinery is interrupted in ALL cases most likely via DNA methylation activity.

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The Intracellular Signalling that Associated with Influenza A Virus Infection

Cited by 7 publications

References 36 publications

Selective Regulation of B-Raf Dependent K-Ras/Mitogen-Activated Protein by Natural Occurring Multi-kinase Inhibitors in Cancer Cells

Selective Regulation of B-Raf Dependent K-Ras/Mitogen-Activated Protein by Natural Occurring Multi-kinase Inhibitors in Cancer Cells

Guava flavonoid glycosides prevent influenza A virus infection via rescue of P53 activity

Epigenetics Reprogramming of Autophagy is involved in Childhood Acute Lymphatic Leukemi

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