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Severe viral infections, including SARS-COV-2, could trigger disruption of the balance between pro-oxidant and antioxidant mediators; the magnitude of which could reflect the severity of infection and lung injury. Using publicly available COVID-19 transcriptomic datasets, we conducted an in-silico analyses to evaluate the expression levels of 125 oxidative stress genes, including 37 pro-oxidant genes, 32 oxidative-responsive genes, and 56 antioxidant genes. Seven oxidative stress genes were found to be upregulated in whole blood and lung autopsies (MPO, S100A8, S100A9, SRXN1, GCLM, SESN2, and TXN); these genes were higher in severe versus non-severe COVID-19 leucocytes. Oxidative genes were upregulated in inflammatory cells comprising macrophages and CD8+ T cells isolated from bronchioalveolar fluid (BALF), and neutrophils isolated from peripheral blood. MPO, S100A8, and S100A9 were t/opmost upregulated oxidative markers within COVID-19's lung autopsies, whole blood, leucocytes, BALF derived macrophages and circulating neutrophils. The calprotectin's, S100A8 and S100A9 were upregulated in SARS-COV-2 infected human lung epithelium. To validate our in-silico analysis, we conducted qRT-PCR to measure MPO and calprotectin's levels in blood and saliva samples. Relative to uninfected donor controls, MPO, S100A8 and S100A9 were significantly higher in blood and saliva of severe versus asymptomatic COVID-19 patients. Compared to other different viral respiratory infections, coronavirus infection showed a prominent upregulation in oxidative stress genes with MPO and calprotectin at the top of the list. In conclusion, SARS-COV-2 induce the expression of oxidative stress genes via both immune as well as lung structural cells. The observed correlation between oxidative stress genes dysregulation and COVID-19 disease severity deserve more attention. Mechanistical studies are required to confirm the correlation between oxidative stress gene dysregulation, COVID-19 severity, and the net oxidative stress balance., Graphical abstract Image 1

The ability of vitamin D (VitD) to modulate immune responses in the clinical setting of COVID-19 infection is not well investigated. This study aimed to evaluate the ability of VitD to attenuate inflammatory responses in patients with severe COVID-19.Blood samples and nasopharyngeal swabs were obtained from patients with severe COVID-19 who had been treated (20 patients), or not (25 patients), with VitD, during their stay in the intensive care unit. Western blotting was used to evaluate the expressions of STAT3, JNK and AKT signaling pathways and ELISA was used to measure levels of IL-6, IL-17, and IL-1β in blood of these patients.Reduced levels of STAT3, JNK and AKT pathways and lower levels of proinflammatory cytokines such as IL-6, IL-17, and IL-1β were observed in VitD treated patients (50,000 IU of cholecalciferol weekly for 3 weeks), and in vitro following treatment of poly I:C stimulated PBMCs with VitD (50 nM of calcitriol). Moreover, lower circulatory levels of these proinflammatory cytokines following treatment with VitD were associated with lower serum levels of COVID-19-related severity markers such as D-dimer and C-reactive proteins (P 0.001) which in overall resulted in shorter length of ICU stay for VitD treated compared to untreated patients (18 days for VitD treated vs. 28 days for VitD untreated; P = 0.01).This study reveals that VitD plays immunomodulatory role during COVID-19 infection, which further emphasizes the importance of maintaining a normal level of this vitamin for the prevention of hyperinflammatory conditions associated with COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people and crippled economies worldwide. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for this pandemic has triggered avid research on its pathobiology to better understand the pathophysiology of COVID-19. In the absence of approved antiviral therapeutic strategies or vaccine platforms capable of effectively targeting this global threat, the hunt for effective therapeutics has led to many candidates being actively evaluated for their efficacy in controlling or preventing COVID-19. In this review, we gathered current evidence on the innate nucleic acid-sensing pathways expected to be elicited by SARS-CoV-2 and the immune evasion mechanisms they have developed to promote viral replication and infection. Within the nucleic acid-sensing pathways, SARS-CoV-2 infection and evasion mechanisms trigger the activation of NOD-signaling and NLRP3 pathways leading to the production of inflammatory cytokines, IL-1β and IL-6, while muting or blocking cGAS-STING and interferon type I and III pathways, resulting in decreased production of antiviral interferons and delayed innate response. Therefore, blocking the inflammatory arm and boosting the interferon production arm of nucleic acid-sensing pathways could facilitate early control of viral replication and dissemination, prevent disease progression, and cytokine storm development. We also discuss the rationale behind therapeutic modalities targeting these sensing pathways and their implications in the treatment of COVID-19.

The immune system is tightly regulated by the activity of stimulatory and inhibitory immune receptors. This immune homeostasis is usually disturbed during chronic viral infection. Using publicly available transcriptomic datasets, we conducted an in-silico analyses to evaluate the expression pattern of 38 selected immunoinhibitory receptors (IRs) associated with different myeloid and lymphoid immune cells during COVID-19 infection. Our analyses revealed a pattern of overall upregulation of IRs mRNA during SARS-CoV-2 infection. A large number of IRs expressed on both lymphoid and myeloid cells were upregulated in nasopharyngeal swabs (NPs), while lymphoid associated IRs were specifically upregulated in autopsies, reflecting severe, terminal stage, COVID-19 disease. Eight genes (BTLA, LAG3, FCGR2B, PDCD1, CEACAM1, CTLA4, CD72, and SIGLEC7), shared by NPs and autopsies, were more expressed in autopsies and were directly correlated with viral levels. Single-cell data from blood and bronchioalveolar samples also reflected the observed association between IRs upregulation and disease severity. Moreover, compared to SARS-CoV-1, influenza and respiratory syncytial virus infections, the number and intensities of upregulated IRs were higher in SARS-CoV-2 infections. In conclusion, the immunopathology and severity of COVID-19 could be attributed to dysregulation of different immune inhibitors. Targeting one or more of these immune inhibitors could represent an effective therapeutic approach for the treatment of COVID-19 early and late immune dysregulations., Graphical Abstract, The immune system is tightly regulated by the activity of stimulatory and inhibitory immune receptors. Using gene expression datasets, Halwani and coworkers showed a pattern of overall upregulation of immune inhibitor receptors on different myeloid and lymphoid cells during SARS-CoV-2 infection. This dysregulation may contribute to the immunopathology and severity of COVID-19.

Background Breast cancer is the first leading cause of women cancer-related deaths worldwide. While there are many proposed treatments for breast cancer, low efficacy, toxicity, and resistance are still major therapeutic obstacles. Thus, there is a need for safer and more effective therapeutic approaches. Because of the direct link between obesity and carcinogenesis, energy restriction mimetic agents (ERMAs) such as the antidiabetic agent, metformin was proposed as a novel antiproliferative agent. However, the anticancer dose of metformin alone is relatively high and impractical to be implemented safely in patients. The current work aimed to sensitize resistant breast cancer cells to metformin's antiproliferative effect using the natural potential anticancer agent, tangeretin. Methods The possible synergistic combination between metformin and tangeretin was initially evaluated using MTT cell viability assay in different breast cancer cell lines (MCF-7, MDA-MB-231, and their resistant phenotype). The possible mechanisms of synergy were investigated via Western blotting analysis, reactive oxygen species (ROS) measurement, annexin/PI assay, cell cycle analysis, and wound healing assay. Results The results indicated the ability of tangeretin to improve the anticancer activity of metformin. Interestingly, the improved activity was almost equally observed in both parental and resistant cancer cells, which underlines the importance of this combination in cases of the emergence of resistance. The synergy was mediated through the enhanced activation of AMPK and ROS generation in addition to the improved inhibition of cell migration, induction of cell cycle arrest, and apoptosis in cancer cells. Conclusion The current work underscores the importance of metformin as an ERMA in tackling breast cancer and as a novel approach to boost its anticancer activity via a synergistic combination with tangeretin.