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

Methods for the analysis of histone H3 and H4 acetylation in blood

LBH589 is one of the many histone deacetylase inhibitors (HDACi) that are currently in clinical trial. Despite their wide-spread use, there is little literature available describing the typical levels of histone acetylation in untreated peripheral blood, the treatment and storage of samples to retain optimal measurement of histone acetylation nor methods by which histone acetylation analysis may be monitored and measured during the course of a patient’s treatment. In this study, we have used cord or peripheral blood as a source of human leukocytes, performed a comparative analysis of sample processing methods and developed a flow cytometric method suitable for monitoring histone acetylation in isolated lymphocytes and liquid tumors. Western blotting and immunohistochemistry techniques have also been addressed. We have tested these methods on blood samples collected from four patients treated with LBH589 as part of an Australian Children’s Cancer Clinical Trial (CLBH589AAU03T) and show comparable results when comparing in vitro and in vivo data. This paper does not seek to correlate histone acetylation levels in peripheral blood with clinical outcome but describes methods of analysis that will be of interest to clinicians and scientists monitoring the effects of HDACi on histone acetylation in blood samples in clinical trials or in related research studies

A Novel Histone Deacetylase Inhibitor Exhibits Antitumor Activity via Apoptosis Induction, F-Actin Disruption and Gene Acetylation in Lung Cancer

BACKGROUND: Lung cancer is the leading cause of cancer mortality worldwide, yet the therapeutic strategy for advanced non-small cell lung cancer (NSCLC) is limitedly effective. In addition, validated histone deacetylase (HDAC) inhibitors for the treatment of solid tumors remain to be developed. Here, we propose a novel HDAC inhibitor, OSU-HDAC-44, as a chemotherapeutic drug for NSCLC. METHODOLOGY/PRINCIPAL FINDINGS: The cytotoxicity effect of OSU-HDAC-44 was examined in three human NSCLC cell lines including A549 (p53 wild-type), H1299 (p53 null), and CL1-1 (p53 mutant). The antiproliferative mechanisms of OSU-HDAC-44 were investigated by flow cytometric cell cycle analysis, apoptosis assays and genome-wide chromatin-immunoprecipitation-on-chip (ChIP-on-chip) analysis. Mice with established A549 tumor xenograft were treated with OSU-HDAC-44 or vehicle control and were used to evaluate effects on tumor growth, cytokinesis inhibition and apoptosis. OSU-HDAC-44 was a pan-HDAC inhibitor and exhibits 3-4 times more effectiveness than suberoylanilide hydroxamic acid (SAHA) in suppressing cell viability in various NSCLC cell lines. Upon OSU-HDAC-44 treatment, cytokinesis was inhibited and subsequently led to mitochondria-mediated apoptosis. The cytokinesis inhibition resulted from OSU-HDAC-44-mediated degradation of mitosis and cytokinesis regulators Auroroa B and survivin. The deregulation of F-actin dynamics induced by OSU-HDAC-44 was associated with reduction in RhoA activity resulting from srGAP1 induction. ChIP-on-chip analysis revealed that OSU-HDAC-44 induced chromatin loosening and facilitated transcription of genes involved in crucial signaling pathways such as apoptosis, axon guidance and protein ubiquitination. Finally, OSU-HDAC-44 efficiently inhibited A549 xenograft tumor growth and induced acetylation of histone and non-histone proteins and apoptosis in vivo. CONCLUSIONS/SIGNIFICANCE: OSU-HDAC-44 significantly suppresses tumor growth via induction of cytokinesis defect and intrinsic apoptosis in preclinical models of NSCLC. Our data provide compelling evidence that OSU-HDAC-44 is a potent HDAC targeted inhibitor and can be tested for NSCLC chemotherapy

Trichostatin A enhances acetylation as well as protein stability of ERα through induction of p300 protein

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract Introduction Trichostatin A (TSA) is a well-characterized histone deacetylase (HDAC) inhibitor. TSA modifies the balance between HDAC and histone acetyltransferase activities that is important in chromatin remodeling and gene expression. Although several previous studies have demonstrated the role of TSA in regulation of estrogen receptor alpha (ERα), the precise mechanism by which TSA affects ERα activity remains unclear. Methods Transient transfection was performed using the Welfect-EX™Plus procedure. The mRNA expression was determined using RT-PCR. Protein expression and interaction were determined by western blotting and immunoprecipitation. The transfection of siRNAs was performed using the Oligofectamine™ reagent procedure. Results TSA treatment increased acetylation of ERα in a dose-dependent manner. The TSA-induced acetylation of ERα was accompanied by an increased stability of ERα protein. Interestingly, TSA also increased the acetylation and the stability of p300 protein. Overexpression of p300 induced acetylation and stability of ERα by blocking ubiquitination. Knockdown of p300 by RNA interference decreased acetylation as well as the protein level of ERα, indicating that p300 mediated the TSA-induced stabilization of ERα. Conclusions We report that TSA enhanced acetylation as well as the stability of the ERα protein by modulating stability of p300. These results may provide the molecular basis for pharmacological functions of HDAC inhibitors in the treatment of human breast cancer

Enhancement of Vaccinia Virus Based Oncolysis with Histone Deacetylase Inhibitors

Histone deacetylase inhibitors (HDI) dampen cellular innate immune response by decreasing interferon production and have been shown to increase the growth of vesicular stomatitis virus and HSV. As attenuated tumour-selective oncolytic vaccinia viruses (VV) are already undergoing clinical evaluation, the goal of this study is to determine whether HDI can also enhance the potency of these poxviruses in infection-resistant cancer cell lines. Multiple HDIs were tested and Trichostatin A (TSA) was found to potently enhance the spread and replication of a tumour selective vaccinia virus in several infection-resistant cancer cell lines. TSA significantly decreased the number of lung metastases in a syngeneic B16F10LacZ lung metastasis model yet did not increase the replication of vaccinia in normal tissues. The combination of TSA and VV increased survival of mice harbouring human HCT116 colon tumour xenografts as compared to mice treated with either agent alone. We conclude that TSA can selectively and effectively enhance the replication and spread of oncolytic vaccinia virus in cancer cells

Role of retinoic receptors in lung carcinogenesis

Several in vitro and in vivo studies have examined the positive and negative effects of retinoids (vitamin A analogs) in premalignant and malignant lesions. Retinoids have been used as chemopreventive and anticancer agents because of their pleiotropic regulator function in cell differentiation, growth, proliferation and apoptosis through interaction with two types of nuclear receptors: retinoic acid receptors and retinoid X receptors. Recent investigations have gradually elucidated the function of retinoids and their signaling pathways and may explain the failure of earlier chemopreventive studies

Inhibitory effect of HGF on invasiveness of aggressive MDA-MB231 breast carcinoma cells, and role of HDACs

Hepatocyte growth factor (HGF), through Met receptor binding, fulfils numerous functions in invasive tumour growth (survival/proliferation, motility, apoptosis), but epigenetic control of gene expression in this process is poorly understood. In HGF-treated breast cancer cells we studied (a) the chemoinvasion towards CXCL12 (ligand of the chemokine-receptor CXCR4) and (b) the mechanistic basis, that is, the transduction pathways that regulate CXCR4-mediated invasion, and the role played by histone deacetylases (HDACs) after blockade with trichostatin A (TSA). In highly invasive and metastatic MDA-MB231 cells HGF had a dual inhibitory effect, reducing spontaneous migration and specific chemoinvasion towards CXCL12, the latter by decreasing CXCR4 transactivation and protein level. After HGF the levels of phosphorylated (therefore active) c-Src and Akt persistently increased, indicating a role of these signal transducers in the HGF-dependent cellular and molecular effects. c-Src wild-type expression vector (Srcwt) increased active c-Src and mimicked the HGF-dependent inhibition of CXCR4 transactivation. Our findings indicate that HDACs participated in the HGF-inhibitory effects. In fact, blockade of HDACs hindered the HGF- and Srcwt-dependent reductions of CXCR4 transactivation and invasiveness, while inhibition of endogenous c-Src was additive with HGF, further reducing specific chemoinvasion. In conclusion, in MDA-MB231 cells HDAC blockade with TSA partly counteracted the HGF-dependent effects through molecular events that included enhancement of the expression of the genes for invasiveness Met and CXCR4 (depending on serum conditions), reduction of endogenous phospho-c-Src/c-Src and phosphoAkt/Akt ratios and triggering of apoptosis. The potential therapeutic use of TSA should take into account the variable aggressiveness of breast carcinoma cells and microenvironment signals such as HGF at the secondary growth site of the tumour. It was interesting that HGF reduced motility and CXCR4 functionality only of MDA-MB231 cells, and not of low-invasive MCF-7 cells, suggesting a mechanism implicated in metastatic cell homing