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1.
Journal of Biological Chemistry ; : 102511, 2022.
Article in English | ScienceDirect | ID: covidwho-2031421

ABSTRACT

Revealing the mechanisms of SARS-CoV-2 entry and cell-to-cell spread might provide insights for understanding the underlying mechanisms of viral pathogenesis, tropism, and virulence. The signaling pathways involved in SARS-CoV-2 entry and viral spike-mediated cell-to-cell fusion remain elusive. In the current study, we found that macropinocytosis inhibitors significantly suppressed SARS-CoV-2 infection at both the entry and viral spike-mediated cell-to-cell fusion steps. We demonstrated that SARS-CoV-2 entry required the small GTPase Rac1 and its effector kinase p21-activated kinase 1 (Pak1) by dominant-negative and RNAi assays in HEK293T-ACE2 cells and that the serine protease TMPRSS2 reversed the decrease in SARS-CoV-2 entry caused by the macropinocytosis inhibitors. Moreover, in the cell-to-cell fusion assay, we confirmed that macropinocytosis inhibitors significantly decreased viral spike-mediated cell-to-cell fusion. Overall, we provided evidence that SARS-CoV-2 utilizes a macropinocytosis pathway to enter target cells and to efficiently promote viral spike-mediated cell-to-cell fusion.

2.
Dental Nursing ; 18(9):450-450, 2022.
Article in English | CINAHL | ID: covidwho-2030355

ABSTRACT

The article presents a survey revealed the increase in the number of mothers in employment, along with mentions that how Covid-19 pandemic has led to more flexible working hours, with the additional opportunity to work from home.

3.
Microbiol Spectr ; : e0109722, 2022 Aug 04.
Article in English | MEDLINE | ID: covidwho-2029474

ABSTRACT

Human adenovirus type 26 (HAdV26) has been recognized as a promising platform for vaccine vector development, and very recently vaccine against COVID-19 based on HAdV26 was authorized for emergency use. Nevertheless, basic biology of this virus, namely, pathway which HAdV26 uses to enter the cell, is still insufficiently known. We have shown here that HAdV26 infection of human epithelial cells expressing low amount of αvß3 integrin involves clathrin and is caveolin-1-independent, while HAdV26 infection of cells with high amount of αvß3 integrin does not involve clathrin but is caveolin-1-dependent. Thus, this study demonstrates that caveolin-1 is limiting factor in αvß3 integrin-mediated HAdV26 infection. Regardless of αvß3 integrin expression, HAdV26 infection involves dynamin-2. Our data provide for the first-time description of HAdV26 cell entry pathway, hence increase our knowledge of HAdV26 infection. Knowing that functionality of adenovirus vector is influenced by its cell entry pathway and intracellular trafficking, our results will contribute to better understanding of HAdV26 immunogenicity and antigen presentation when used as vaccine vector. IMPORTANCE In order to fulfill its role as a vector, adenovirus needs to successfully deliver its DNA genome to the host nucleus, a process highly influenced by adenovirus intracellular translocation. Thus, cell entry pathway and intracellular trafficking determine functionality of human adenovirus-based vectors. Endocytosis of HAdV26, currently extensively studied as a vaccine vector, has not been described so far. We present here that HAdV26 infection of human epithelial cells with high expression of αvß3 integrin, one of the putative HAdV26 receptors, is caveolin-1- and partially dynamin-2-dependent. Since caveolin containing domains provide a unique environment for specific signaling events and participate in inflammatory signaling one can imagine that directing HAdV26 cell entry toward caveolin-1-mediate pathway might play role in immunogenicity of this virus. Therefore, our results contribute to better understanding of HAdV26 infection pathway, hence, can be helpful in explaining induction of immune response and antigen presentation by HAdV26-based vaccine vector.

4.
2022 International Conference on Machine Learning, Big Data, Cloud and Parallel Computing, COM-IT-CON 2022 ; : 137-140, 2022.
Article in English | Scopus | ID: covidwho-2029202

ABSTRACT

COVID-19 is an ongoing global pandemic and is continuing to be a fast-spreading virus all over the world. It transmits when people breathe in air contaminated by droplets and small airborne particles containing the virus. The risk becomes highest when people are nearby, but they can be over longer distances, while indoors. It is necessary to isolate such infected persons in public places with large gatherings. In addition to screening them, individual protection measures can also be taken.Two primary requirements that fulfil the entry to the public are by scanning of temperature to prevent person suspected and also to ensure one has masked face properly to permit entry. At the moment, all places use this system. But they are manual and depend on the person inspecting temperature and mask. There are few automated processes, but they do not have automatic entry control. Thus, there are risks of false entry of people inside the public place.In this paper, an integrated approach in mask detection and temperature scanning, indicated visually by LED and LCD Display, and further control entry with the operation of boom barrier has been presented. The information is also recorded to identify each entry. Open CV is used to detect masks and obtain better accuracy. An infrared temperature sensor and a proper guide to scan the temperature are used. Each step of the process is implemented on one Raspberry PI-based board. The system is suitably packaged and demonstrated. © 2022 IEEE.

5.
Bioengineering & Translational Medicine ; 7(3), 2022.
Article in English | ProQuest Central | ID: covidwho-2027315

ABSTRACT

Advanced therapeutic medicinal products (ATMPs) have emerged as novel therapies for untreatable diseases, generating the need for large volumes of high‐quality, clinically‐compliant GMP cells to replace costly, high‐risk and limited scale manual expansion processes. We present the design of a fully automated, robot‐assisted platform incorporating the use of multiliter stirred tank bioreactors for scalable production of adherent human stem cells. The design addresses a needle‐to‐needle closed process incorporating automated bone marrow collection, cell isolation, expansion, and collection into cryovials for patient delivery. AUTOSTEM, a modular, adaptable, fully closed system ensures no direct operator interaction with biological material;all commands are performed through a graphic interface. Seeding of source material, process monitoring, feeding, sampling, harvesting and cryopreservation are automated within the closed platform, comprising two clean room levels enabling both open and closed processes. A bioprocess based on human MSCs expanded on microcarriers was used for proof of concept. Utilizing equivalent culture parameters, the AUTOSTEM robot‐assisted platform successfully performed cell expansion at the liter scale, generating results comparable to manual production, while maintaining cell quality postprocessing.

6.
Sustainability ; 14(16):10191, 2022.
Article in English | ProQuest Central | ID: covidwho-2024145

ABSTRACT

In a similar manner, the following paper by Saleh and Atan demonstrates that a link exists between sustainable talent management practices, organizational culture, and employee job satisfaction. By focusing on the case of the higher education sector in North Lebanon, the paper’s findings suggest that a strong and significant positive relationship between the sustainable talent management practices and employee’s job satisfaction exists. The key findings of this paper reveal that while research on the gig economy proliferates, the distinction between the “platform” and “gig” economies frequently remains blurred in the analysis. [...]the discussion on gig economy is largely dispersed, and a clearer research agenda is needed to streamline the discussion to improve its exploratory and explanatory potential. Kwon, J.;Kim, C.;Lee, K.C. Moderating Effect of the Continental Factor on the Business Strategy and M&A Performance in the Pharmaceutical Industry for Sustainable International Business.

7.
Frontiers in Immunology ; 13, 2022.
Article in English | Web of Science | ID: covidwho-2022749

ABSTRACT

Class 1 and 2 monoclonal antibodies inhibit SARS-CoV-2 entry by blocking the interaction of the viral receptor-binding domain with angiotensin-converting enzyme 2 (ACE2), while class 3 antibodies target a highly conserved epitope outside the ACE2 binding site. We aimed to investigate the plasticity of the spike protein by propagating wild-type SARS-CoV-2 in the presence of class 3 antibody S309. After 12 weeks, we obtained a viral strain that was completely resistant to inhibition by S309, due to successively evolving amino acid exchanges R346S and P337L located in the paratope of S309. The antibody lost affinity to receptor-binding domains carrying P337L or both amino acid exchanges, while ACE2 binding was not affected. The resistant strain replicated efficiently in human CaCo-2 cells and was more susceptible to inhibition of fusion than the original strain. Overall, SARS-CoV-2 escaped inhibition by class 3 antibody S309 through a slow, but targeted evolution enabling immune escape and altering cell entry. This immune-driven enhancement of infectivity and pathogenicity could play an important role in the future evolution of SARS-CoV-2, which is under increasing immunological pressure from vaccination and previous infections.

8.
Archives of Disease in Childhood ; 107(Suppl 2):A422-A423, 2022.
Article in English | ProQuest Central | ID: covidwho-2019920

ABSTRACT

837 Table 1Compariosn between palivizumab arm and control arm 837 Table 2Doses given vs RSV positive caseloadConclusionThis study suggested that RSV-prophylaxis was cost beneficial. RSV-prophylaxis reduced length of stay due to RSV bronchiolitis;2 days (palivizumab arm) vs. 39 (control group) (table 1). Of the 6 patients who completed a full 5-dose course of palivizumab, 0 contracted RSV positive bronchiolitis (table 2). Cardiac patients who did not complete a full course of palivizumab were at higher risk of contracting RSV bronchiolitis. Numbers were far too limited to reach statistical reliability and a second audit cycle was not run as RSV rates diminished due to the effect of COVID-19 lockdown and the previous seasonal pattern of RSV prevalence was not observed.2 Earlier patient identification, closer monitoring & stewardship of palivizumab eligible cardiac patients needed across the regional network to facilitate better uptake, delivery & concordance of RSV prophylaxis regimen over the winter period.ReferencesLiao et al. British Congenital Cardiac Association Annual Conference poster. 2021.Agha R, Avner JR. Delayed seasonal RSV surge observed during the COVID-19 pandemic. Pediatrics 2021;148:e2021052089.

9.
J Drug Target ; : 1-14, 2022 Aug 08.
Article in English | MEDLINE | ID: covidwho-2017089

ABSTRACT

Developing numerous nanotechnological designed tools to monitor the existence of SARS-CoV-2, and modifying its interactions address the global needs for efficient remedies required for the management of COVID-19. Herein, through a multidisciplinary outlook encompassing different fields such as the pathophysiology of SARS-CoV-2, analysis of symptoms, and statistics of neurological complications caused by SARS-CoV-2 infection in the central and peripheral nervous systems have been testified. The anosmia (51.1%) and ageusia (45.5%) are reported the most frequent neurological manifestation. Cerebrovascular disease and encephalopathy were mainly related to severe clinical cases. In addition, we focus especially on the various concerned physiological routes, including BBB dysfunction, which transpired due to SARS-CoV-2 infection, direct and indirect effects of the virus on the brain, and also, the plausible mechanisms of viral entry to the nerve system. We also outline the characterisation, and the ongoing pharmaceutical applications of quantum dots as smart nanocarriers crossing the blood-brain barrier and their importance in neurological diseases, mainly SARS-CoV-2 related manifestations Moreover, the market status, six clinical trials recruiting quantum dots, and the challenges limiting the clinical application of QDs are highlighted.

10.
J Lipid Res ; : 100256, 2022 Jul 31.
Article in English | MEDLINE | ID: covidwho-2015714

ABSTRACT

The Spike protein of SARS-CoV-2 and other coronaviruses mediates host cell entry and is S-acylated on multiple phylogenetically conserved cysteine residues. Multiple protein acyltransferase enzymes have been reported to post-translationally modify Spike proteins; however, strategies to exploit this modification are currently lacking. Using resin-assisted capture mass spectrometry, we demonstrate here the Spike protein is S-acylated in SARS-CoV-2-infected human and monkey cells. We further show increased abundance of the human acyltransferase ZDHHC5 associates with increased S-acylation of the Spike protein, whereas ZDHHC5 knockout cells had a 40% reduction in the incorporation of an alkynyl-palmitate using click chemistry detection. We also find the S-acylation of the Spike protein is not limited to palmitate, as clickable versions of myristate and stearate were also found on the immunocaptured protein. Yet, we observed ZDHHC5 was only modified when incubated with alkyne-palmitate, suggesting it has specificity for this acyl-CoA, and that other ZDHHC enzymes may use additional fatty acids to modify the Spike protein. Since multiple ZDHHC isoforms may modify the Spike protein, we also examined the ability of the fatty acid synthase inhibitor TVB-3166 to prevent S-acylation of the Spike proteins of SARS-CoV-2 and human CoV-229E. We show treating cells with TVB-3166 inhibited S-acylation of ectopically expressed Spike and attenuated the ability of SARS-CoV-2 and human CoV-229E to spread in vitro. Our findings further substantiate the necessity of CoV Spike protein S-acylation and demonstrate that de novo fatty acid synthesis is critical for the proper S-acylation of the Spike protein.

11.
Current topics in medicinal chemistry ; 2022.
Article in English | MEDLINE | ID: covidwho-2009797

ABSTRACT

Recently, people worldwide have experienced several outbreaks caused by viruses that have attracted much interest globally, such as HIV, Zika, Ebola, and the one being faced, SARSCoV-2 viruses. Unfortunately, the availability of drugs giving satisfying outcomes in curing those diseases is limited. Therefore, it is necessary to dig deeper to provide compounds that can tackle the causative viruses. Meanwhile, the efforts to explore marine natural products have been gaining great interest as the products have consistently shown several promising biological activities, including antiviral activity. This review summarizes some products extracted from marine organisms, such as seaweeds, seagrasses, sponges, and marine bacteria, reported in recent years to have potential antiviral activities tested through several methods. The mechanisms by which those compounds exert their antiviral effects are also described here, with several main mechanisms closely associated with the ability of the products to block the entry of the viruses into the host cells, inhibiting replication or transcription of the viral genetic material, and disturbing the assembly of viral components. In addition, the structure-activity relationship of the compounds is also highlighted by focusing on six groups of marine compounds, namely sulfated polysaccharides, phlorotannins, terpenoids, lectins, alkaloids, and flavonoids. In conclusion, due to their uniqueness compared to substances extracted from terrestrial sources, marine organisms provide abundant products having promising activities as antiviral agents that can be explored to tackle virus-caused outbreaks.

12.
iScience ; : 105082, 2022.
Article in English | ScienceDirect | ID: covidwho-2007783

ABSTRACT

The SARS-CoV-2 virus has triggered a worldwide pandemic. According to the BioGrid database, CLN7 (MFSD8) is thought to interact with several viral proteins. The aim of this work was to investigate a possible involvement of CLN7 in the infection process. Experiments on a CLN7-deficient HEK293T cell line exhibited a 90% reduced viral load compared to wild-type cells. This observation may be linked to the finding that CLN7 ko cells have a significantly reduced GM1 content in their cell membrane. GM1 is found highly enriched in lipid rafts, which are thought to play an important role in SARS-CoV-2 infection. In contrast, overexpression of CLN7 led to an increase in viral load. This study provides evidence that CLN7 is involved in SARS-CoV-2 infection. This makes it a potential pharmacological target for drug development against COVID-19. Furthermore, it provides insights into the physiological function of CLN7 where still only little is known about.

13.
Russian Archives of Internal Medicine ; 12(4):245-253, 2022.
Article in Russian | EMBASE | ID: covidwho-2006639

ABSTRACT

The safety of proton pump inhibitors (PPIs) use in coronavirus infection (COVID-19) is not well understood. PPIs are potent suppressors of gastric secretion and become one of the ten most widely used drugs in the world. They are expected to influence virus susceptibility, severity, and outcomes in patients diagnosed with COVID-19. This concern is based on their mechanism of action — suppression of gastric acidity, which is considered the first line of defense against infections. Taken together, the results of most studies and meta-analyses support that PPIs use has been associated with increased risk of COVID-19 and severe outcomes. However, taking into account all potential risk factors for disease severity seems impossible in the real world in the context of COVID-19, so conclusions about causal relationships between PPI use and COVID-19 should be treated with great caution. An additional interesting point about the use of PPIs in the pandemic is that it reduced absorption of certain vitamins. On the other hand, several studies have appeared in the literature regarding the protective therapeutic effects of PPIs. There is growing evidence of an immunomodulatory and antifibrotic role of PPIs that could be used in the treatment of COVID-19. In addition, their ability to alkalize the contents of endosomes and lysosomes serves as an obstacle to the penetration of the virus into host cells. This review analyzes the possible effects of PPIs in patients with COVID-19.

14.
Frontiers in Cellular and Infection Microbiology ; 12, 2022.
Article in English | EMBASE | ID: covidwho-2005849

ABSTRACT

An outbreak of coronavirus disease 2019 (COVID-19) emerged in China in December 2019 and spread so rapidly all around the globe. It’s continued and spreading more dangerously in India and Brazil with higher mortality rate. Understanding of the pathophysiology of COVID-19 depends on unraveling of interactional mechanism of SARS-CoV-2 and human immune response. The immune response is a complex process, which can be better understood by understanding the immunological response and pathological mechanisms of COVID-19, which will provide new treatments, increase treatment efficacy, and decrease mortality associated with the disease. In this review we present a amalgamate viewpoint based on the current available knowledge on COVID-19 which includes entry of the virus and multiplication of virus, its pathological effects on the cellular level, immunological reaction, systemic and organ presentation. T cells play a crucial role in controlling and clearing viral infections. Several studies have now shown that the severity of the COVID-19 disease is inversely correlated with the magnitude of the T cell response. Understanding SARS-CoV-2 T cell responses is of high interest because T cells are attractive vaccine targets and could help reduce COVID-19 severity. Even though there is a significant amount of literature regarding SARS-CoV-2, there are still very few studies focused on understanding the T cell response to this novel virus. Nevertheless, a majority of these studies focused on peripheral blood CD4+ and CD8+ T cells that were specific for viruses. The focus of this review is on different subtypes of T cell responses in COVID-19 patients, Th17, follicular helper T (TFH), regulatory T (Treg) cells, and less classical, invariant T cell populations, such as δγ T cells and mucosal-associated invariant T (MAIT) cells etc that could influence disease outcome.

15.
Advanced Nanobiomed Research ; 2022.
Article in English | Web of Science | ID: covidwho-2003589

ABSTRACT

Due to the worldwide impact of viruses such as SARS-CoV-2, researchers have paid extensive attention to antiviral reagents against viruses. Despite extensive research on two-dimensional (2D) transition metal carbides (MXenes) in the field of biomaterials, their antiviral effects have received little attention. In this work, heparan sulfate analogue (sodium 3-mercapto-1-propanesulfonate, MPS) modified 2D MXene nanocomposites (Ti3C2-Au-MPS) for prevention of viral infection are prepared and investigated using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus and porcine reproductive and respiratory syndrome virus (PRRSV) as two model viruses. Ti3C2-Au-MPS nanocomposites are shown to possess antiviral properties in the different stages of PRRSV proliferation, such as direct interaction with PRRS virions and inhibiting their adsorption and penetration in the host cell. Additionally, Ti3C2-Au-MPS nanocomposites can strongly inhibit the infection of SARS-CoV-2 pseudovirus as shown by the contents of its reporter gene GFP and luciferase. These results demonstrate the potential broad-spectrum antiviral property of Ti3C2-Au-MPS nanocomposites against viruses with the receptor of heparin sulfate. This work sheds light on the specific antiviral effects of MXene-based nanocomposites against viruses and may facilitate further exploration of their antiviral applications.

16.
European Journal of Hospital Pharmacy. Science and Practice ; 29(5):299-300, 2022.
Article in English | ProQuest Central | ID: covidwho-2001872

ABSTRACT

EMA guidance supports development of new antibiotics As part of its efforts to support a global approach to the development of new antimicrobial medicines, the European Medicines Agency (EMA) has published the final revised guideline on the evaluation of human medicines for the treatment of bacterial infections. The revised document reflects the outcome of these discussions, and also includes: clarifications on recommended clinical development programmes for antimicrobials intended to address an unmet need;guidance on clinical trials to support treatment of uncomplicated urinary tract infections and uncomplicated gonorrhoea;updated guidance on displaying microbiological and clinical efficacy data in the summary of product characteristics. Health determinants for health promotion and disease prevention Diabetes Cardiovascular diseases Chronic respiratory diseases Mental health and neurological disorders The guidance document that was published includes recommendations to address risk factors such as unhealthy lifestyles.

17.
Technology in Society ; : 102093, 2022.
Article in English | ScienceDirect | ID: covidwho-1996579

ABSTRACT

We theoretically and empirically examine how acquiring new skills and increased financial worries influenced entrepreneurship entry and exit intentions during the pandemic. To that end, we analyze primary individual-level survey data we collected in the aftermath of the COVID-19's first wave in Russia, which has had one of the highest COVID-19 infection rates globally. Our results show that acquiring new skills during the pandemic helped owners keep their existing businesses and encouraged start-ups in sectors other than information technology (IT). For IT start-ups, having previous experience matters more than new skills. While the pandemic-driven financial worries are associated with business closure intentions, they inspire new business start-ups, highlighting the pandemic's creative destruction power. Furthermore, preferences for formal employment and remote work also matter for entrepreneurial intentions. Our findings enhance the understanding of entrepreneurship formation and closure in a time of adversity and suggest that implementing entrepreneurship training and upskilling policies during recurring waves of the COVID-19 pandemic can be an important policy tool for innovative small business development.

18.
European Research Studies ; 25(2B):72-83, 2022.
Article in English | ProQuest Central | ID: covidwho-1989983

ABSTRACT

Purpose: Professional drivers are one of the most important links in the network of business relationships in road transport. Their importance for the effective functioning of transport, both domestic and international, is enormous. The large scale of the shortage of drivers, analyzed in the context of their significance for modern supply chains, is currently one of the most pressing problems of road hauliers. The main purpose of the article is presentation the current and future trends related to the impact of the COVID-19 pandemic on the labour market of drivers in the context of determining the reasons for which they leave the profession or change employers. In addition, the current and future barriers to entering the profession, especially for young drivers, will be presented through the prism of their professional competences on the domestic and international transport market. Design/Methodology/Approach: Description, systematization and conclusions resulting from the analysis of facts covered by the topic of the paper and forecasts regarding the labour market for professional drivers in road transport. The method used results from the adopted goal and assumed outcomes and focuses on analyzing scientific sources and publications from the transport and freight forwarding market as well as own experiences. Findings: The labour market in terms of the availability of professional drivers will become increasingly difficult for transport companies. Poland is facing the problem of societal aging and shrinking population, which means that new resources of potential drivers are limited. Fully autonomous vehicles are therefore a long-awaited revolution - companies that will be able to use this technology first will gain a significant competitive advantage. This perspective is not that long away in time. Changes awaited already before the pandemic and the future labour market forecasts seem to be a harbinger of a new quality of work, but they also pose many challenges for educational and business institutions and employers. Originality/Value: We argue that both the problems related to the number and structure of professional drivers in Poland and the consequences of COVID-19 should be treated as one of the key analytical areas in road transport.

19.
EC Microbiol ; 18(4): 1-12, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1990183

ABSTRACT

Brilacidin (PMX-30063), a non-peptide defensin-mimetic small molecule, inhibits SARS-CoV-2 viral infection but the anti-viral mechanism is not defined. Here we determined its effect on the specific step of the viral life cycle. Brilacidin blocked SARS-CoV-2 infection but had no effect after viral entry. Brilacidin inhibited pseudotyped SARS-CoV-2 viruses expressing spike proteins from the P.1 Brazil strain and the B.1.1.7 UK strain. Brilacidin affected viral attachment in hACE2-dependent and independent manners depending on the concentrations. The inhibitory effect on viral entry was not mediated through blocking the binding of either the spike receptor-binding domain or the spike S1 protein to hACE2 proteins. Taken together, brilacidin inhibits SARS-CoV-2 infection by blocking viral entry and is active against SARS-CoV-2 variants.

20.
Cancer Research ; 82(12), 2022.
Article in English | EMBASE | ID: covidwho-1986495

ABSTRACT

As of November 2021, there were 21 million confirmed active cases of COVID-19, including 77,016 patients in serious or critical condition (virusncov.com). However, there are no effective oral drugs for the treatment of severe COVID 19 patients. We here discuss the mechanism of action for Proxalutaminde to treat mild, moderate and severe COVID-19 Patients. Cellular entry and infection of SARS-CoV-2 virus are mediated by two key proteins in host cells, angiotensin converting enzyme 2 (ACE2), a host transmembrane protein, providing the binding sites for SARS-CoV-2 on the host cell surface, and transmembrane protease serine 2 protein (TMPRSS2), priming the S protein of SARS-Cov-2 to facilitate the viral entry into the host cells. Both ACE2 and TMPRSS2 proteins are regulated by androgen receptor (AR) signaling. Previously, Proxalutamide has been reported to downregulate the expression of ACE2 and TMPRSS2 in cells derived from prostate, lung cancer and normal lung epithelial cells. In this study, we demonstrate that Proxalutamide inhibited the infection of SARS-COV-2 wild type, alpha and delta variants, with IC50s of 69, 48 and 39 nM, respectively. Moreover, Proxalutamide reduced SARS-COV-2 viral load in outpatients with COVID-19 (82% viral RT-PCR negative rate in active group vs. 31% in placebo group after treatment for 7 days (p-value<0.0001). Severe COVID-19 disease leads to cytokine storm resulting in pulmonary inflammation and extensive damage in lung and other organs. Anti-inflammatory drugs, including Baricitinib and dexamethasone, have shown limited clinical benefit for hospitalized COVID-19 patients. Therefore, more effective drugs are in urgent need for patients suffering from severe COVID-19. Recently, Proxalutamide has been reported to reduce the mortality rate (HR=0.16) and lung injury (by 57%, active drug vs placebo groups) in hospitalized patients with COVID-19 in an IIT phase III study. We presented here the mechanism of action of Proxalutamide for targeting cytokine storm in severe COVID-19 patients. Proxalutamide was demonstrated to activate nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages, which stimulates the antioxidant response element (ARE) for reducing cytokine storm-induced organ damage in COVID-19. In addition, Proxalutamide inhibited TNF alpha and IL-6 expression and blocked INF gamma signaling by downregulating STAT1 expression in immune cells. Importantly, Proxalutamide reduced inflammatory cells in lungs in a Poly (I:C), pseudoviral induced-lung injury animal models. Further, Proxalutamide decreased C-reactive protein, D-Dimer and improved lymphocyte count, biomarkers for COVID-19 progression in clinical studies. Together, these results provide a strong rationale for the treatment of severe COVID-19 patients with Proxalutamide.

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