Insights into Zika Virus Pathogenesis and Potential Therapeutic Strategies.

Zika virus (ZIKV) has emerged as a significant public health threat, reaching pandemic levels in 2016. Human infection with ZIKV can manifest as either asymptomatic or as an acute illness characterized by symptoms such as fever and headache. Moreover, it has been associated with severe neurological complications in adults, including Guillain-Barre syndrome, and devastating fetal abnormalities, like microcephaly. The primary mode of transmission is through Aedes spp. mosquitoes, and with half of the world's population residing in regions where Aedes aegypti, the principal vector, thrives, the reemergence of ZIKV remains a concern. This comprehensive review provides insights into the pathogenesis of ZIKV and highlights the key cellular pathways activated upon ZIKV infection. Additionally, we explore the potential of utilizing microRNAs (miRNAs) and phytocompounds as promising strategies to combat ZIKV infection.

Autophagy impairment by caspase-1-dependent inflammation mediates memory loss in response to ß-Amyloid peptide accumulation.

ß-Amyloid peptide accumulation in the cortex and in the hippocampus results in neurodegeneration and memory loss. Recently, it became evident that the inflammatory response triggered by ß-Amyloid peptides promotes neuronal cell death and degeneration. In addition to inflammation, ß-Amyloid peptides also induce alterations in neuronal autophagy, eventually leading to neuronal cell death. Thus, here we evaluated whether the inflammatory response induced by the ß-Amyloid peptides impairs memory via disrupting the autophagic flux. We show that male mice overexpressing ß-Amyloid peptides (5XFAD) but lacking caspase-1, presented reduced ß-Amyloid plaques in the cortex and in the hippocampus; restored brain autophagic flux and improved learning and memory capacity. At the molecular level, inhibition of the inflammatory response in the 5XFAD mice restored LC3-II levels and prevented the accumulation of oligomeric p62 and ubiquitylated proteins. Furthermore, caspase-1 deficiency reinstates activation of the AMPK/Raptor pathway while down-regulating AKT/mTOR pathway. Consistent with this, we found an inverse correlation between the increase of autophagolysosomes in the cortex of 5XFAD mice lacking caspase-1 and the presence of mitochondria with altered morphology. Together our results indicate that ß-Amyloid peptide-induced caspase-1 activation, disrupts autophagy in the cortex and in the hippocampus resulting in neurodegeneration and memory loss.

Merlin negative regulation by miR-146a promotes cell transformation.

Inactivation of the tumor suppressor Merlin, by deleterious mutations or by protein degradation via sustained growth factor receptor signaling-mediated mechanisms, results in cell transformation and tumor development. In addition to these mechanisms, here we show that, miRNA-dependent negative regulation of Merlin protein levels also promotes cell transformation. We provide experimental evidences showing that miR-146a negatively regulates Merlin protein levels through its interaction with an evolutionary conserved sequence in the 3´ untranslated region of the NF2 mRNA. Merlin downregulation by miR-146a in A549 lung epithelial cells resulted in enhanced cell proliferation, migration and tissue invasion. Accordingly, stable miR-146a-transfectant cells formed tumors with metastatic capacity in vivo. Together our results uncover miRNAs as yet another negative mechanism controlling Merlin tumor suppressor functions.

MiR-7 promotes epithelial cell transformation by targeting the tumor suppressor KLF4.

MicroRNAs (miRNAs) are endogenous small non-coding RNAs that have a pivotal role in the post-transcriptional regulation of gene expression and their misregulation is common in different types of cancer. Although it has been shown that miR-7 plays an oncogenic role in different cellular contexts, the molecular mechanisms by which miR-7 promotes cell transformation are not well understood. Here we show that the transcription factor KLF4 is a direct target of miR-7 and present experimental evidence indicating that the regulation of KLF4 by miR-7 has functional implications in epithelial cell transformation. Stable overexpression of miR-7 into lung and skin epithelial cells enhanced cell proliferation, cell migration and tumor formation. Alteration of these cellular functions by miR-7 resulted from misregulation of KLF4 target genes involved in cell cycle control. miR-7-induced tumors showed decreased p21 and increased Cyclin D levels. Taken together, these findings indicate that miR-7 acts as an oncomiR in epithelial cells in part by directly regulating KLF4 expression. Thus, we conclude that miR-7 acts as an oncomiR in the epithelial cellular context, where through the negative regulation of KLF4-dependent signaling pathways, miR-7 promotes cellular transformation and tumor growth.

CD43 promotes cells transformation by preventing merlin-mediated contact inhibition of growth.

In normal tissues, strict control of tissue size is achieved by regulating cell numbers. The mechanism that controls total cell number is known as contact inhibition of growth and it depends on the NF2/Merlin pathway. Negative regulation of this pathway by deleterious mutations or by oncogenes results in cell transformation and tumor progression. Here we provide evidence that the CD43 sialomucin cooperates with oncogenic signals to promote cell transformation by abrogating the contact inhibition of growth through a molecular mechanism that involves AKT-dependent Merlin phosphorylation and degradation. Accordingly, inhibition of endogenous CD43 expression by RNA interference in lung, cervix and colon human cancer cells impaired tumor growth in vivo. These data underscore a previously unidentified role for CD43 in non-hematopoietic tumor progression.