Associated Fungal Infections, Related to the Global Covid-19 Pandemic (Literature Review)

The 2019 coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has swept the globe. Based on a retrospective analysis of SARS and influenza data from China and around the world, we suggest that fungal co-infections associated with global COVID-19 may be missed or misdiagnosed. Although there are few publications, patients with COVID-19, especially severely ill or immunocompromised patients, are more likely to develop invasive mycoses. Aspergillus and Candida infections in patients with COVID-19 will require early detection by comprehensive diagnostic intervention (histopathology, direct microscopy, culture, (Arabian: 2004, Tilavberdiev: 2016) -β-D-glucan, galactomannan, and PCR assays) to ensure effective treatment. We consider it appropriate to assess risk factors, types of invasive mycoses, strengths and weaknesses of diagnostic methods, clinical conditions, and the need for standard or individual treatment

Role of glycogen synthase kinase 3 beta (GSK3β) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells

Histone deacetylase inhibitors (HDACIs) have been shown to induce apoptotic and autophagic cell death in vitro and in vivo. The molecular mechanisms that underlie these cytotoxic effects are not yet clearly understood. Recently, HDACIs were shown to induce Akt dephosphorylation by disrupting HDAC-protein phosphatase 1 (PP1) complexes. This disruption results in the increased association of PP1 with Akt, resulting in the dephosphorylation and consequent inactivation of the kinase. Akt enhances cellular survival through the phosphorylation-dependent inhibition of several pro-apoptotic proteins. Akt is an important negative regulator of GSK3β, a kinase that has been shown to regulate apoptosis in response to various stimuli. In the present study, we investigated the role of GSK3β in mediating the cytotoxic effects in MCF-7 breast cancer cells treated with trichostatin A (TSA), a prototype HDACI. We show that TSA induces Akt dephosphorylation in a PP1-dependent manner, resulting in activation of GSK3β in MCF-7 cells. Similarly, knockdown of HDAC1 and-2 by small interfering RNA (siRNA) resulted in the dephosphorylation of Akt and GSK3β. Selective inhibition of GSK3β attenuated TSA induced cytotoxicity and resulted in enhanced proliferation following drug removal. Our findings identify GSK3β as an important mediator of TSA-induced cytotoxicity in MCF-7 breast cancer cells

FOXM1 is a transcriptional target of ERα and has a critical role in breast cancer endocrine sensitivity and resistance

In this study, we investigated the regulation of FOXM1 expression by estrogen receptor α (ERα) and its role in hormonal therapy and endocrine resistance. FOXM1 protein and mRNA expression was regulated by ER-ligands, including estrogen, tamoxifen (OHT) and fulvestrant (ICI182780; ICI) in breast carcinoma cell lines. Depletion of ERα by RNA interference (RNAi) in MCF-7 cells downregulated FOXM1 expression. Reporter gene assays showed that ERα activates FOXM1 transcription through an estrogen-response element (ERE) located within the proximal promoter region. The direct binding of ERα to the FOXM1 promoter was confirmed in vitro by mobility shift and DNA pull-down assays and in vivo by chromatin immunoprecipitation (ChIP) analysis. Our data also revealed that upon OHT treatment ERα recruits histone deacetylases to the ERE site of the FOXM1 promoter, which is associated with a decrease in histone acetylation and transcription activity. Importantly, silencing of FOXM1 by RNAi abolished estrogen-induced MCF-7 cell proliferation and overcame acquired tamoxifen resistance. Conversely, ectopic expression of FOXM1 abrogated the cell cycle arrest mediated by the anti-estrogen OHT. OHT repressed FOXM1 expression in endocrine sensitive but not resistant breast carcinoma cell lines. Furthermore, qRT–PCR analysis of breast cancer patient samples revealed that there was a strong and significant positive correlation between ERα and FOXM1 mRNA expression. Collectively, these results show FOXM1 to be a key mediator of the mitogenic functions of ERα and estrogen in breast cancer cells, and also suggest that the deregulation of FOXM1 may contribute to anti-estrogen insensitivity