Transcription Factor Driven Gene Regulation in COVID-19 Patients.

SARS-CoV-2 and its many variants have caused a worldwide emergency. Host cells colonised by SARS-CoV-2 present a significantly different gene expression landscape. As expected, this is particularly true for genes that directly interact with virus proteins. Thus, understanding the role that transcription factors can play in driving differential regulation in patients affected by COVID-19 is a focal point to unveil virus infection. In this regard, we have identified 19 transcription factors which are predicted to target human proteins interacting with Spike glycoprotein of SARS-CoV-2. Transcriptomics RNA-Seq data derived from 13 human organs are used to analyse expression correlation between identified transcription factors and related target genes in both COVID-19 patients and healthy individuals. This resulted in the identification of transcription factors showing the most relevant impact in terms of most evident differential correlation between COVID-19 patients and healthy individuals. This analysis has also identified five organs such as the blood, heart, lung, nasopharynx and respiratory tract in which a major effect of differential regulation mediated by transcription factors is observed. These organs are also known to be affected by COVID-19, thereby providing consistency to our analysis. Furthermore, 31 key human genes differentially regulated by the transcription factors in the five organs are identified and the corresponding KEGG pathways and GO enrichment are also reported. Finally, the drugs targeting those 31 genes are also put forth. This in silico study explores the effects of transcription factors on human genes interacting with Spike glycoprotein of SARS-CoV-2 and intends to provide new insights to inhibit the virus infection.

Intertwined Dysregulation of Ribosomal Proteins and Immune Response Delineates SARS-CoV-2 Vaccination Breakthroughs.

Globally, COVID-19 vaccines have emerged as a boon, especially during the severe pandemic phases to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, saving millions of lives. However, mixed responses to vaccination with breakthrough challenges provided a rationale to explore the immune responses generated postvaccination, which plausibly alter the subsequent course of infection. In this regard, we comprehensively profiled the nasopharyngeal transcriptomic signature of double-dose-vaccinated individuals with breakthrough infections in comparison to unvaccinated infected persons. The vaccinated individuals demonstrated a gross downregulation of ribosomal proteins along with immune response genes and transcription/translational machinery that methodically modulated the entire innate immune landscape toward immune tolerance, a feature of innate immune memory. This coordinated response was orchestrated through 17 transcription factors captured as differentially expressed in the vaccination breakthroughs, including epigenetic modulators of CHD1 and LMNB1 and several immune response effectors, with ELF1 emerging as one of the important transcriptional regulators of the antiviral innate immune response. Deconvolution algorithm using bulk gene expression data revealed decreased T-cell populations with higher expression of memory B cells in the vaccination breakthroughs. Thus, vaccination might synergize the innate immune response with humoral and T-cell correlates of protection to more rapidly clear SARS-CoV-2 infections and reduce symptoms within a shorter span of time. An important feature invariably noted after secondary vaccination is downregulation of ribosomal proteins, which might plausibly be an important factor arising from epigenetic reprogramming leading to innate immune tolerance. IMPORTANCE The development of multiple vaccines against SARS-CoV-2 infection is an unprecedented milestone achieved globally. Immunization of the mass population is a rigorous process for getting the pandemic under control, yet continuous challenges are being faced, one of them being breakthrough infections. This is the first study wherein the vaccination breakthrough cases of COVD-19 relative to unvaccinated infected individuals have been explored. In the context of vaccination, how do innate and adaptive immune responses correspond to SARS-CoV-2 infection? How do these responses culminate in a milder observable phenotype with shorter hospital stay in vaccination breakthrough cases compared with the unvaccinated? We identified a subdued transcriptional landscape in vaccination breakthroughs with decreased expression of a large set of immune and ribosomal proteins genes. We propose a module of innate immune memory, i.e., immune tolerance, which plausibly helps to explain the observed mild phenotype and fast recovery in vaccination breakthroughs.

Cytokines and microRNAs in SARS-CoV-2: What do we know?

The coronavirus disease 2019 (COVID-19) pandemic constitutes a global health emergency. Currently, there are no completely effective therapeutic medications for the management of this outbreak. The cytokine storm is a hyperinflammatory medical condition due to excessive and uncontrolled release of pro-inflammatory cytokines in patients suffering from severe COVID-19, leading to the development of acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS) and even mortality. Understanding the pathophysiology of COVID-19 can be helpful for the treatment of patients. Evidence suggests that the levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1 and IL-6 are dramatically different between mild and severe patients, so they may be important contributors to the cytokine storm. Several serum markers can be predictors for the cytokine storm. This review discusses the cytokines involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, focusing on interferons (IFNs) and ILs, and whether they can be used in COVID-19 treatment. Moreover, we highlight several microRNAs that are involved in these cytokines and their role in the cytokine storm caused by COVID-19.

Induced pluripotent stem cells: Generation methods and a new perspective in COVID-19 research.

Induced pluripotent stem cells (iPSCs) exhibit an unlimited ability to self-renew and produce various differentiated cell types, thereby creating high hopes for both scientists and patients as a great tool for basic research as well as for regenerative medicine purposes. The availability and safety of iPSCs for therapeutic purposes require safe and highly efficient methods for production of these cells. Different methods have been used to produce iPSCs, each of which has advantages and disadvantages. Studying these methods would be very helpful in developing an easy, safe, and efficient method for the generation of iPSCs. Since iPSCs can be generated from somatic cells, they can be considered as valuable cellular resources available for important research needs and various therapeutic purposes. Coronavirus disease 2019 (COVID-19) is a disease that has endangered numerous human lives worldwide and currently has no definitive cure. Therefore, researchers have been rigorously studying and examining all aspects of COVID-19 and potential treatment modalities and various drugs in order to enable the treatment, control, and prevention of COVID-19. iPSCs have become one of the most attractive and promising tools in this field by providing the ability to study COVID-19 and the effectiveness of drugs on this disease outside the human body. In this study, we discuss the different methods of generation of iPSCs as well as their respective advantages and disadvantages. We also present recent applications of iPSCs in the study and treatment of COVID-19.

Evaluation of Tcell exhaustion based on the expression of EOMES, Tbet and co-inhibitory receptors in severe and non-severe covid-19 patients.

During viral infections, especially Covid-19, Tcell exhaustion plays a crucial role in reducing the activity of lymphocytes and the immune system's antiviral activities. This research aimed to investigate the co-inhibitory receptors and transcription factors involved in the Tcell exhaustion process in ICU-admitted (ICUA) compared to non-ICU admitted (non-ICUA) Covid-19 patients. A total of 60 Covid-19 patients (30 patients in the severe group who were admitted in the ICU (ICUA) and 30 patients in the mild group who were admitted in departments other than the ICU (non-ICUA)) and 10 healthy individuals were included in this study. Laboratory tests and the level of gene expressions related to 4 inhibitory co-receptors, including LAG-3, TIM-3, TIGIT, PD-1, and T-bet and Eomes transcription factors involved in the process of Tcell exhaustion in severe and mild patients of Covid-19 were investigated. The results showed lymphopenia and an increase in other hematologic laboratory factors such as NLR, PLR, CRP, ALT, and AST in people with a severe form of the disease (ICUA) compared to mild groups (non-ICUA) (P < 0.001). Furthermore, a significant increase in 3 co-inhibitory receptors, TIM-3, LAG-3, and PD-1, was observed in severe patients compared to mild and healthy people (P < 0.001). An increase in TIGIT gene expression was lesser than the other three mentioned receptors (P < 0.05). Concerning the transcription factors, we observed a significant increase in Eomes in ICUA patients compared to the non-ICUA group (P < 0.001), and this increment in T-bet gene expression was minor compared to Eomes (P < 0.05). In conclusion, Patients with a severe form of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represented a higher level of gene expressions in terms of co-inhibitory receptors and transcription factors involved in the T cell exhaustion process.

Therapeutic Targeting of NF-κB in Acute Lung Injury: A Double-Edged Sword.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating disease that can be caused by a variety of conditions including pneumonia, sepsis, trauma, and most recently, COVID-19. Although our understanding of the mechanisms of ALI/ARDS pathogenesis and resolution has considerably increased in recent years, the mortality rate remains unacceptably high (~40%), primarily due to the lack of effective therapies for ALI/ARDS. Dysregulated inflammation, as characterized by massive infiltration of polymorphonuclear leukocytes (PMNs) into the airspace and the associated damage of the capillary-alveolar barrier leading to pulmonary edema and hypoxemia, is a major hallmark of ALI/ARDS. Endothelial cells (ECs), the inner lining of blood vessels, are important cellular orchestrators of PMN infiltration in the lung. Nuclear factor-kappa B (NF-κB) plays an essential role in rendering the endothelium permissive for PMN adhesion and transmigration to reach the inflammatory site. Thus, targeting NF-κB in the endothelium provides an attractive approach to mitigate PMN-mediated vascular injury, not only in ALI/ARDS, but in other inflammatory diseases as well in which EC dysfunction is a major pathogenic mechanism. This review discusses the role and regulation of NF-κB in the context of EC inflammation and evaluates the potential and problems of targeting it as a therapy for ALI/ARDS.

Synthesis and Inhibitory Activity of Machaeridiol-Based Novel Anti-MRSA and Anti-VRE Compounds and Their Profiling for Cancer-Related Signaling Pathways.

Three unique 5,6-seco-hexahydrodibenzopyrans (seco-HHDBP) machaeridiols A-C, reported previously from Machaerium Pers., have displayed potent activities against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium, and E. faecalis (VRE). In order to enrich the pipeline of natural product-derived antimicrobial compounds, a series of novel machaeridiol-based analogs (1-17) were prepared by coupling stemofuran, pinosylvin, and resveratrol legends with monoterpene units R-(-)-α-phellandrene, (-)-p-mentha-2,8-diene-1-ol, and geraniol, and their inhibitory activities were profiled against MRSA ATCC 1708, VRE ATCC 700221, and cancer signaling pathways. Compounds 5 and 11 showed strong in vitro activities with MIC values of 2.5 µg/mL and 1.25 µg/mL against MRSA, respectively, and 2.50 µg/mL against VRE, while geranyl analog 14 was found to be moderately active (MIC 5 µg/mL). The reduction of the double bonds of the monoterpene unit of compound 5 resulted in 17, which had the same antibacterial potency (MIC 1.25 µg/mL and 2.50 µg/mL) as its parent, 5. Furthermore, a combination study between seco-HHDBP 17 and HHDBP machaeriol C displayed a synergistic effect with a fractional inhibitory concentrations (FIC) value of 0.5 against MRSA, showing a four-fold decrease in the MIC values of both 17 and machaeriol C, while no such effect was observed between vancomycin and 17. Compounds 11 and 17 were further tested in vivo against nosocomial MRSA at a single intranasal dose of 30 mg/kg in a murine model, and both compounds were not efficacious under these conditions. Finally, compounds 1-17 were profiled against a panel of luciferase genes that assessed the activity of complex cancer-related signaling pathways (i.e., transcription factors) using T98G glioblastoma multiforme cells. Among the compounds tested, the geranyl-substituted analog 14 exhibited strong inhibition against several signaling pathways, notably Smad, Myc, and Notch, with IC50 values of 2.17 µM, 1.86 µM, and 2.15 µM, respectively. In contrast, the anti-MRSA actives 5 and 17 were found to be inactive (IC50 > 20 µM) across the panel of these cancer-signaling pathways.

Vitamin d in transcriptional regulation of immune response and inflammation

The predominance of the expression of pro-inflammatory genes is a sign of the inflammation onset. Overwhelming evidence suggests a role for vitamin D3 sufficiency or supplementation in reducing the inflammatory response. In addition to mineral and bone homeostasis, vitamin D3 has important effects, which include modulating innate and adaptive immunity and maintaining a tight balance between pro- and anti-inflammatory responses. In recent years, genome-wide and transcriptome-wide studies have led to a deeper understanding of the signaling network, which is responsible for cell-specific and locus-dependent gene activation by ligandregulated transcription factors. Modulation of transcription factors such as NF-?B, STAT, NFAT, AP-1, HIF-1, SMAD, PPAR etc., as well as glucocorticoid receptor signaling, may play a crucial role in the immunomodulatory activity of the hormonally active form of vitamin D3 - 1a,25(OH)2D3. Acting through the vitamin D receptor (VDR), which is a member of the nuclear receptor family of ligandregulated transcription factors, 1a,25(OH)2D3 may ensure a reduction of the inflammatory response by direct and/or indirect mechanisms. Therefore, this chapter focuses on the cross-talk of the VDR with other transcription factors in the context of antiinflammatory defense. The mechanisms involved in this modulation are usually associated with competitive binding and interactions between signaling pathways at different levels, including the gene level. We have summarized recent discoveries regarding the immunomodulatory effects of vitamin D3 on human health, with an emphasis on the interplay of transcription factors. In light of the global spread of the novel COVID-19 disease, the newly discovered importance of proper vitamin D3 status for an adequate immune response to the SARS-CoV-2 coronavirus has also been elucidated. We reviewed the most recent recommendations based on new clinical evidence for vitamin D3 dosages for the prevention and treatment of COVID-19. © 2021 by Nova Science Publishers, Inc. All rights reserved.

Exploring the mechanism of Platycodonis Radix-Licorice for prevention and treatment of COVID-19 based on network pharmacology and molecular docking

Objective: To investigate the possible mechanism of Platycodonis Radix-Licorice drug pair in the intervention of COVID-19 by using network pharmacology and molecular docking technique. Methods The database TCMSP was retrieved for the chemical constituents and targets of Platycodonis Radix-Licorice drug pair. Coronavirus disease targets were screened by the Gene Cards, OMIM,TTD, PharmGkb and DrugBank database. Cytoscape 3.7.2 software was used to construct the drug-component-target network. The PPI(protein-protein interaction) network was obtained by drug-disease intersection targets, and the core genes were found through CytoNCA plug-in. Meanwhile, GO(gene ontology) analysis and KEGG(Kyoto encyclopedia of genes and genomes) pathway analysis were performed by using Bioconductor database to predict the mechanism. AutoDock Tools 1.5.6 software was used to simulate the molecular docking of the main active ingredients with the novel coronavirus key binding site protein [SARS-CoV-2 main protease(severe acute respiratory syndrome coronavirus 2 main protease, Mpro) and ACE2(angiotensin converting enzyme 2)]. Results A total of 7 active ingredients of Platycodonis Radix,92 active ingredients of Licorice,2766 drug targets, and 674 disease targets were obtained, and 67 drug-disease common targets were excavated. The key targets involved RELA,STAT1,MAPK3,TP53,MAPK1,MAPK8,STAT3,MAPK14,IL1 B and TNF by the database STRING and CytoNCA plug-in.Go enrichment analysis showed that the main functions of Platycodonis Radix-Licorice drug pair on the intervention of COVID-19 were antioxidant reaction, cell respond to chemical stress, regulation of apoptotic signaling pathways, reaction to lipopolysaccharides and reaction to bacteria-derived molecules, etc.. KEGG pathways involved Coronavirus disease-COVID-19 pathway, IL-17 signaling pathway and so on, were mainly associated with immune response, inflammation-related pathways, inhibition of viral infection, and other inhibition of cancer. The molecular docking results showed that glepidotin A,quercetin, licochalcone a and luteolin had good binding ability with Mpro and ACE2. Conclusion Platycodonis Radix-Licorice drug pair act on SARS-CoV-2 through multiple components, multiple targets, and multiple channel combination. And the main active ingredients have a fine binding ability with Mpro and ACE2. The method can provide theoretical support for the possibility of traditional Chinese medicine(TCM) against COVID-19.

Clinical Connections

The article offers information about the role of lysine-specific demethylase I in metabolically integrating osteoclast differentiation and inflammatory bone resorption through hypoxia0inducible factor 1-alpha and E2FI. It mentions that osteoclasts are the primary cells responsible for bone resorption in rheumatoid arthritis (RA).

Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity

Comparing SARS-CoV-2 infection-induced gene expression signatures to drug treatment-induced gene expression signatures is a promising bioinformatic tool to repurpose existing drugs against SARS-CoV-2. The general hypothesis of signature-based drug repurposing is that drugs with inverse similarity to a disease signature can reverse disease phenotype and thus be effective against it. However, in the case of viral infection diseases, like SARS-CoV-2, infected cells also activate adaptive, antiviral pathways, so that the relationship between effective drug and disease signature can be more ambiguous. To address this question, we analysed gene expression data from in vitro SARS-CoV-2 infected cell lines, and gene expression signatures of drugs showing anti-SARS-CoV-2 activity. Our extensive functional genomic analysis showed that both infection and treatment with in vitro effective drugs leads to activation of antiviral pathways like NFkB and JAK-STAT. Based on the similarity—and not inverse similarity—between drug and infection-induced gene expression signatures, we were able to predict the in vitro antiviral activity of drugs. We also identified SREBF1/2, key regulators of lipid metabolising enzymes, as the most activated transcription factors by several in vitro effective antiviral drugs. Using a fluorescently labeled cholesterol sensor, we showed that these drugs decrease the cholesterol levels of plasma-membrane. Supplementing drug-treated cells with cholesterol reversed the in vitro antiviral effect, suggesting the depleting plasma-membrane cholesterol plays a key role in virus inhibitory mechanism. Our results can help to more effectively repurpose approved drugs against SARS-CoV-2, and also highlights key mechanisms behind their antiviral effect.

How May Obesity-Induced Oxidative Stress Affect the Outcome of COVID-19 Vaccines? Lesson Learned from the Infection

Concomitantly, the reduced sources of antioxidants, including superoxide dismutase, glutathione peroxidase, catalase, vitamin A, E, C and carotenoids in obese patients promotes a vulnerability to oxidative damage and consequently increases susceptibility to infections [14]. [...]obesity is associated with a state of metaflammation—chronic low-grade inflammation—a condition that, among other factors, contributes to inducing systemic OS. Characteristic hyperlipidaemia observed in obese patients stimulates monocytes and macrophages and induces the production of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α and interleukin (IL)-6 [16,18,19]. [...]in obese COVID-19 patients, the already pre-existing effects prompted by the lipid peroxidation-dependent OS could be further aggravated by SARS-CoV-2 infection [20], affecting the immune control system in response to infection and potentially increasing the severity of the lung disease and contributing to multiorgan failure. The results of the study demonstrated that the antibody titre was significantly higher in young and female participants compared to the male and older population. [...]the humoral response was significantly more efficient in subjects with lower and normal weight compared to overweight and obese subjects. [...]the consequence of OS on immunological functions and the evidence of weakened virus vaccine effectiveness in obese patients raise concerns about COVID-19 vaccine responsiveness in this population.

Molecular Hydrogen as Medicine: An Assessment of Administration Methods

Since the late 18th century, molecular hydrogen (H2) has been shown to be well tolerated, firstly in animals, and then in humans. However, although research into the beneficial effects of molecular hydrogen in both plant and mammalian physiology is gaining momentum, the idea of utilising this electrochemically neutral and non-polar diatomic compound for the benefit of health has yet to be widely accepted by regulatory bodies worldwide. Due to the precise mechanisms of H2 activity being as yet undefined, the lack of primary target identification, coupled with difficulties regarding administration methods (e.g., dosage and dosage frequencies, long-term effects of treatment, and the patient’s innate antioxidant profile), there is a requirement for H2 research to evidence how it can reasonably and most effectively be incorporated into medical practice. This review collates and assesses the current information regarding the many routes of molecular hydrogen administration in animals and humans, whilst evaluating how targeted delivery methods could be integrated into a modern healthcare system.

Bioinformatics analysis reveals molecular connections between non-alcoholic fatty liver disease (NAFLD) and COVID-19.

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has devastatingly impacted people's lives. Non-alcoholic fatty liver disease (NAFLD) is fatal comorbidity of COVID-19 seen with potential risk factors to develop severe symptoms. This research focuses on determining and elucidating the molecular factors and connections that might contribute to the severity of SARS-CoV-2 infection in NAFLD patients. Here, we comprehensively inspected the genes involved in NAFLD and SARS-CoV-2 entry factors (SCEFs) found by searching through the DisGeNet database and literature review, respectively. Further, we identified the SCEFs-related proteins through protein-protein interaction (PPI) network construction, MCODE, and Cytohubba. Next, the shared genes involved in NAFLD and SARS-CoV-2 entry, and hub gene were determined, followed by the GO and KEGG pathways analysis. X2K database was used to construct the upstream regulatory network of hub genes, as well as to identify the top ten candidates of transcription factors (TFs) and protein kinases (PKs). PPI analysis identified connections between 4 top SCEFs, including ACE, ADAM17, DPP4, and TMPRSS2 and NAFLD-related genes such as ACE, DPP4, IL-10, TNF, and AKT1. GO and KEGG analysis revealed the top ten biological processes and pathways, including cytokine-mediated signaling, PI3K-Akt, AMPK, and mTOR signaling pathways. The upstream regulatory network revealed that AKT1 and MAPK14 as important PKs and HIF1A and SP1 as important TFs associated with AKT1, IL-10, and TNF. The molecular connections identified between COVID-19 and NAFLD may shed light on discovering the causes of the severity of SARS-CoV-2 infected NAFLD patients.

Novel Combination Treatment for Ovarian Granulosa Cell Tumors

Ovarian granulosa cell tumors (GCT) are hormonally-active neoplasms characterized by endocrine manifestations, an indolent course and late recurrence. Treatment involves surgery, and chemo- or hormonal-therapy have limited efficacy. This proposal will address the development of a novel GCT specific therapeutic strategy. The survival transcription factor, NFkB, is activated in these tumors;inhibition of this pathway promotes apoptosis. Peroxisome proliferator-activated receptor-gamma protein (PPARgamma), a transcription factor that impedes growth and promotes differentiation, is overexpressed in GCT, but transrepressed by NFkB signaling in GCT. An NFkB-induced protein, X-linked inhibitor of apoptosis protein (XIAP), is also overexpressed in GCT and is critical in preventing GCT cell apoptosis and represents an attractive therapeutic target. We hypothesize that 1) PPARgamma and XIAP play fundamental roles in the regulation of granulosa cell (GC) apoptosis, and/or terminal differentiation, albeit in a reciprocal manner, and 2) that combined targeting of PPARgamma and XIAP presents a novel therapeutic strategy for GCT treatment.

Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis.

The coronavirus-disease 2019 (COVID-19) was announced as a global pandemic by the World Health Organization. Challenges arise concerning how to optimally support the immune system in the general population, especially under self-confinement. An optimal immune response depends on an adequate diet and nutrition in order to keep infection at bay. For example, sufficient protein intake is crucial for optimal antibody production. Low micronutrient status, such as of vitamin A or zinc, has been associated with increased infection risk. Frequently, poor nutrient status is associated with inflammation and oxidative stress, which in turn can impact the immune system. Dietary constituents with especially high anti-inflammatory and antioxidant capacity include vitamin C, vitamin E, and phytochemicals such as carotenoids and polyphenols. Several of these can interact with transcription factors such as NF-kB and Nrf-2, related to anti-inflammatory and antioxidant effects, respectively. Vitamin D in particular may perturb viral cellular infection via interacting with cell entry receptors (angiotensin converting enzyme 2), ACE2. Dietary fiber, fermented by the gut microbiota into short-chain fatty acids, has also been shown to produce anti-inflammatory effects. In this review, we highlight the importance of an optimal status of relevant nutrients to effectively reduce inflammation and oxidative stress, thereby strengthening the immune system during the COVID-19 crisis.

Co-Regulation of Protein Coding Genes by Transcription Factor and Long Non-Coding RNA in SARS-CoV-2 Infected Cells: An In Silico Analysis.

Altered expression of protein coding gene (PCG) and long non-coding RNA (lncRNA) have been identified in SARS-CoV-2 infected cells and tissues from COVID-19 patients. The functional role and mechanism (s) of transcriptional regulation of deregulated genes in COVID-19 remain largely unknown. In the present communication, reanalyzing publicly available gene expression data, we observed that 66 lncRNA and 5491 PCG were deregulated in more than one experimental condition. Combining our earlier published results and using different publicly available resources, it was observed that 72 deregulated lncRNA interacted with 3228 genes/proteins. Many targets of deregulated lncRNA could also interact with SARS-CoV-2 coded proteins, modulated by IFN treatment and identified in CRISPR screening to modulate SARS-CoV-2 infection. The majority of the deregulated lncRNA and PCG were targets of at least one of the transcription factors (TFs), interferon responsive factors (IRFs), signal transducer, and activator of transcription (STATs), NFκB, MYC, and RELA/p65. Deregulated 1069 PCG was joint targets of lncRNA and TF. These joint targets are significantly enriched with pathways relevant for SARS-CoV-2 infection indicating that joint regulation of PCG could be one of the mechanisms for deregulation. Over all this manuscript showed possible involvement of lncRNA and mechanisms of deregulation of PCG in the pathogenesis of COVID-19.

Further insights into the molecular complexity of the human sinus node - The role of 'novel' transcription factors and microRNAs.

RESEARCH PURPOSE: The sinus node (SN) is the heart's primary pacemaker. Key ion channels (mainly the funny channel, HCN4) and Ca2+-handling proteins in the SN are responsible for its function. Transcription factors (TFs) regulate gene expression through inhibition or activation and microRNAs (miRs) do this through inhibition. There is high expression of macrophages and mast cells within the SN connective tissue. 'Novel'/unexplored TFs and miRs in the regulation of ion channels and immune cells in the SN are not well understood. Using RNAseq and bioinformatics, the expression profile and predicted interaction of key TFs and cell markers with key miRs in the adult human SN vs. right atrial tissue (RA) were determined. PRINCIPAL RESULTS: 68 and 60 TFs significantly more or less expressed in the SN vs. RA respectively. Among those more expressed were ISL1 and TBX3 (involved in embryonic development of the SN) and 'novel' RUNX1-2, CEBPA, GLI1-2 and SOX2. These TFs were predicted to regulate HCN4 expression in the SN. Markers for different cells: fibroblasts (COL1A1), fat (FABP4), macrophages (CSF1R and CD209), natural killer (GZMA) and mast (TPSAB1) were significantly more expressed in the SN vs. RA. Interestingly, RUNX1-3, CEBPA and GLI1 also regulate expression of these cells. MiR-486-3p inhibits HCN4 and markers involved in immune response. MAJOR CONCLUSIONS: In conclusion, RUNX1-2, CSF1R, TPSAB1, COL1A1 and HCN4 are highly expressed in the SN but not miR-486-3p. Their complex interactions can be used to treat SN dysfunction such as bradycardia. Interestingly, another research group recently reported miR-486-3p is upregulated in blood samples from severe COVID-19 patients who suffer from bradycardia.

Unraveling the molecular crosstalk between Atherosclerosis and COVID-19 comorbidity.

BACKGROUND: Corona virus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has created ruckus throughout the world. Growing epidemiological studies have depicted atherosclerosis as a comorbid factor of COVID-19. Though both these diseases are triggered via inflammatory rage that leads to injury of healthy tissues, the molecular linkage between them and their co-influence in causing fatality is not yet understood. METHODS: We have retrieved the data of differentially expressed genes (DEGs) for both atherosclerosis and COVID-19 from publicly available microarray and RNA-Seq datasets. We then reconstructed the protein-protein interaction networks (PPIN) for these diseases from protein-protein interaction data of corresponding DEGs. Using RegNetwork and TRRUST, we mapped the transcription factors (TFs) in atherosclerosis and their targets (TGs) in COVID-19 PPIN. RESULTS: From the atherosclerotic PPIN, we have identified 6 hubs (TLR2, TLR4, EGFR, SPI1, MYD88 and IRF8) as differentially expressed TFs that might control the expression of their 17 targets in COVID-19 PPIN. The important target proteins include IL1B, CCL5, ITGAM, IFIT3, CXCL1, CXCL2, CXCL3 and CXCL8. Consequent functional enrichment analysis of these TGs have depicted inflammatory responses to be overrepresented among the gene sets. CONCLUSION: Finally, analyzing the DEGs in cardiomyocytes infected with SARS-CoV-2, we have concluded that MYD88 is a crucial linker of atherosclerosis and COVID-19, the co-existence of which lead to fatal outcomes. Anti-inflammatory therapy targeting MYD88 could be a potent strategy for combating this comorbidity.