Bilateral keratouveitis associated with COVID-19 multisystem inflammatory syndrome in children.

We report the case of a 16-year-old girl admitted to hospital with multisystem inflammatory syndrome in children (MIS-C) secondary to COVID-19. Conjunctivitis-like symptoms prompted ocular examination, which demonstrated peripheral confluent corneal opacities and anterior uveitis. Uveitis laboratory investigations were negative, and with topical steroid treatment her signs and symptoms resolved completely. These features may be overlooked in the setting of MIS-C, where patients are systemically unwell and are typically examined at the bedside.

COVID-19 Vaccines, Effectiveness, and Immune Responses.

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has captivated the globe's attention since its emergence in 2019. This highly infectious, spreadable, and dangerous pathogen has caused health, social, and economic crises. Therefore, a worldwide collaborative effort was made to find an efficient strategy to overcome and develop vaccines. The new vaccines provide an effective immune response that safeguards the community from the virus' severity. WHO has approved nine vaccines for emergency use based on safety and efficacy data collected from various conducted clinical trials. Herein, we review the safety and effectiveness of the WHO-approved COVID-19 vaccines and associated immune responses, and their impact on improving the public's health. Several immunological studies have demonstrated that vaccination dramatically enhances the immune response and reduces the likelihood of future infections in previously infected individuals. However, the type of vaccination and individual health status can significantly affect immune responses. Exposure of healthy individuals to adenovirus vectors or mRNA vaccines causes the early production of antibodies from B and T cells. On the other hand, unhealthy individuals were more likely to experience harmful events due to relapses in their existing conditions. Taken together, aligning with the proper vaccination to a patient's case can result in better outcomes.

Nano-combination for Reviving the Activity of Fluconazole against Rhizopus delemar.

BACKGROUND: Rhizopus delemar, the main causative pathogen for the lethal mucormycosis and a severe threat during the COVID-19 pandemic, is resistant to most antifungals, including fluconazole, a known selective antifungal drug. On the other hand, antifungals are known to enhance fungal melanin synthesis. Rhizopus melanin plays an important role in fungal pathogenesis and in escaping the human defense mechanism, thus complicating the use of current antifungal drugs and fungal eradication. Because of drug resistance and the slow discovery of effective antifungals, sensitizing the activity of older ones seems a more promising strategy. METHODS: In this study, a strategy was employed to revive the use and enhance the effectiveness of fluconazole against R. delemar. UOSC-13, a compound synthesized in-house to target the Rhizopus melanin, was combined with fluconazole either as is or after encapsulation in poly (lactic-coglycolic acid) nanoparticles (PLG-NPs). Both combinations were tested for the growth of R. delemar, and the MIC50 values were calculated and compared. RESULTS: The activity of fluconazole was found to be enhanced several folds following the use of both combined treatment and nanoencapsulation. The combination of fluconazole with UOSC-13 caused a 5-fold reduction in the MIC50 value of fluconazole. Furthermore, encapsulating UOSC-13 in PLG-NPs enhanced the activity of fluconazole by an additional 10 folds while providing a wide safety profile. CONCLUSION: Consistent with previous reports, the encapsulation of fluconazole without sensitization showed no significant difference in activity. Collectively, sensitization of fluconazole represents a promising strategy to revive the use of outdated antifungal drugs back in the market.

Alpha to Omicron (Variants of Concern): Mutation Journey, Vaccines, and Therapy.

Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initially emerged in December 2019 and has subsequently expanded globally, leading to the ongoing pandemic. The extensive spread of various SARS-CoV-2 variants possesses a serious public health threat. An extensive literature search along with deep analysis was performed to describe and evaluate the characteristics of SARS-CoV-2 variants of concern in relation to the effectiveness of the current vaccines and therapeutics. The obtained results showed that several significant mutations have evolved during the COVID-19 pandemic. The developed variants and their various structural mutations can compromise the effectiveness of several vaccines, escape the neutralizing antibodies, and limit the efficiency of available therapeutics. Furthermore, deep analysis of the available data enables the prediction of the future impact of virus mutations on the ongoing pandemic along with the selection of appropriate vaccines and therapeutics.

SARS-CoV-2-free residual proteins mediated phenotypic and metabolic changes in peripheral blood monocytic-derived macrophages in support of viral pathogenesis.

The large-scale dissemination of coronavirus disease-2019 (COVID-19) and its serious complications have pledged the scientific research communities to uncover the pathogenesis mechanisms of its etiologic agent, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Methods of unveiling such mechanisms are rooted in understanding the viral agent's interactions with the immune system, including its ability to activate macrophages, due to their suggested role in prolonged inflammatory phases and adverse immune responses. The objective of this study is to test the effect of SARS-CoV-2-free proteins on the metabolic and immune responses of macrophages. We hypothesized that SARS-CoV-2 proteins shed during the infection cycle may dynamically induce metabolic and immunologic alterations with an inflammatory impact on the infected host cells. It is imperative to delineate such alterations in the context of macrophages to gain insight into the pathogenesis of these highly infectious viruses and their associated complications and thus, expedite the vaccine and drug therapy advent in combat of viral infections. Human monocyte-derived macrophages were treated with SARS-CoV-2-free proteins at different concentrations. The phenotypic and metabolic alterations in macrophages were investigated and the subsequent metabolic pathways were analyzed. The obtained results indicated that SARS-CoV-2-free proteins induced concentration-dependent alterations in the metabolic and phenotypic profiles of macrophages. Several metabolic pathways were enriched following treatment, including vitamin K, propanoate, and the Warburg effect. These results indicate significant adverse effects driven by residual viral proteins that may hence be considered determinants of viral pathogenesis. These findings provide important insight as to the impact of SARS-CoV-2-free residual proteins on the host cells and suggest a potential new method of management during the infection and prior to vaccination.

Comparative evaluation of flavonoids reveals the superiority and promising inhibition activity of silibinin against SARS-CoV-2.

Flavonoids are phenolic compounds naturally found in plants and commonly consumed in diets. Herein, flavonoids were sequentially evaluated by a comparative in silico study associated with systematic literature search. This was followed by an in vitro study and enzyme inhibition assays against vital SARS-CoV-2 proteins including spike (S) protein, main protease (Mpro ), RNA-dependent RNA-polymerase (RdRp), and human transmembrane serine protease (TMPRSS2). The results obtained revealed 10 flavonoids with potential antiviral activity. Out of them, silibinin showed promising selectivity index against SARS-CoV-2 in vitro. Screening against S protein discloses the highest inhibition activity of silibinin. Mapping the activity of silibinin indicated its excellent binding inhibition activity against SARS-CoV-2 S protein, Mpro and RdRP at IC50 0.029, 0.021, and 0.042 µM, respectively, while it showed no inhibition activity against TMPRSS2 at its IC50(SARS-CoV-2) . Silibinin was tested safe on human mammalian cells at >7-fold its IC50(SARS-CoV-2) . Additionally, silibinin exhibited >90% virucidal activity at 0.031 µM. Comparative molecular docking (MD) showed that silibinin possesses the highest binding affinity to S protein and RdRP at -7.78 and -7.15 kcal/mol, respectively. MDs showed that silibinin exhibited stable interaction with key amino acids of SARS-CoV-2 targets. Collectively, silibinin, an FDA-approved drug, can significantly interfere with SARS-CoV-2 entry and replication through multi-targeting activity.

Obesity and COVID-19: What are the Consequences?

Obesity is an increasing health problem all over the world. In combination with the current COVID-19 pandemic, this has turned into a massive challenge as individuals with overweight and obesity at all ages show a significant increase in their risk of getting severe COVID-19. Around 20% of all patients that were hospitalized for COVID-19 suffered from obesity alone, whereas obesity in combination with other metabolic comorbidities, such as type 2 diabetes and hypertension, account for up to 60% of all hospitalizations in relation to COVID-19. Therefore, it is of immense importance to put the spotlight on the high incidence of obesity present already in childhood both by changing the individual minds and by encouraging politicians and the whole society to commence preventive interventions for achieving a better nutrition for all social classes all over the world. In the current review, we aim to explain the different pathways and mechanisms that are responsible for the increased risk of severe COVID-19 in people with overweight and obesity. Furthermore, we discuss how the pandemic has led to weight gains in many people during lockdown. At the end, we discuss the importance of preventing such an interface between a non-communicable disease like obesity and a communicable disease like COVID-19 in the future.

Lipid-based therapies against SARS-CoV-2 infection.

Viruses have evolved to manipulate host lipid metabolism to benefit their replication cycle. Enveloped viruses, including coronaviruses, use host lipids in various stages of the viral life cycle, particularly in the formation of replication compartments and envelopes. Host lipids are utilised by the virus in receptor binding, viral fusion and entry, as well as viral replication. Association of dyslipidaemia with the pathological development of Covid-19 raises the possibility that exploitation of host lipid metabolism might have therapeutic benefit against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, promising host lipid targets are discussed along with potential inhibitors. In addition, specific host lipids are involved in the inflammatory responses due to viral infection, so lipid supplementation represents another potential strategy to counteract the severity of viral infection. Furthermore, switching the lipid metabolism through a ketogenic diet is another potential way of limiting the effects of viral infection. Taken together, restricting the access of host lipids to the virus, either by using lipid inhibitors or supplementation with exogenous lipids, might significantly limit SARS-CoV-2 infection and/or severity.

Estimating the viral loads of SARS-CoV-2 in the oral cavity when complicated with periapical lesions.

BACKGROUND: The oral cavity represents a main entrance of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), and transmembrane serine protease 2 (TMPRSS2) are essential for the entry of SARS-CoV-2 to the host cells. Both ACE-2 and NRP-1 receptors and TMPRSS2 have been identified in the oral cavity. However, there is limited knowledge about the impact of periapical lesions and their metabolites on the expression of these critical genes. This study aims to measure the impact of periapical lesions and their unique fatty acids (FAs) metabolites on the expression of the aforementioned genes, in addition to interleukin 6 (IL-6) gene and hence SARS-CoV-2 infection loads can be estimated. METHODS: Gene expression of ACE-2, NRP-1, TMPRSS2, and IL-6 was performed in periapical lesions in comparison to healthy oral cavity. Since FAs are important immunomodulators required for the lipid synthesis essential for receptors synthesis and viral replication, comparative FAs profiling was determined in oral lesions and healthy pulp tissues using gas chromatography-mass spectrometry (GC-MS). The effect of major identified and unique FAs was tested on mammalian cells known to express ACE-2, NRP-1, and TMPRSS2 genes. RESULTS: Gene expression analysis indicated that ACE-2, NRP-1, and TMPRSS2 were significantly upregulated in healthy clinical samples compared to oral lesions, while the reverse was true with IL-6 gene expression. Saturated and monounsaturated FAs were the major identified shared and unique FAs, respectively. Major shared FAs included palmitic, stearic and myristic acids with the highest percentage in the healthy oral cavity, while unique FAs included 17-octadecynoic acid in periapical abscess, petroselinic acid and L-lactic acid in periapical granuloma, and 1-nonadecene in the radicular cyst. Computational prediction showed that the binding affinity of identified FAs to ACE-2, TMPRSS2 and S protein were insignificant. Further, FA-treated mammalian cells showed significant overexpression of ACE-2, NRP-1 and TMPRSS2 genes except with L-lactic acid and oleic acid caused downregulation of NRP-1 gene, while 17-octadecynoic acid caused insignificant effect. CONCLUSION: Collectively, a healthy oral cavity is more susceptible to viral infection when compared to that complicated with periapical lesions. FAs play important role in viral infection and their balance can affect the viral loads. Shifting the balance towards higher levels of palmitic, stearic and 1-nonadecene caused significant upregulation of the aforementioned genes and hence higher viral loads. On the other hand, there is a reverse correlation between inflammation and expression of SARS-CoV-2 receptors. Therefore, a mouth preparation that can reduce the levels of palmitic, stearic and 1-nonadecene, while maintaining an immunomodulatory effect can be employed as a future protection strategy against viral infection.

Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity.

Unfortunately, COVID-19 is still a threat to humankind and has a dramatic impact on human health, social life, the world economy, and food security. With the limited number of suggested therapies under clinical trials, the discovery of novel therapeutic agents is essential. Here, a previously identified anti-SARS-CoV-2 compound named Compound 13 (1,2,5-Oxadiazole-3-carboximidic acid, 4,4'-(methylenediimino) bis,bis[[(2-hydroxyphenyl)methylene]hydrazide) was subjected to an iterated virtual screening against SARS-CoV-2 Mpro using a combination of Ligand Designer and PathFinder. PathFinder, a computational reaction enumeration tool, was used for the rapid generation of enumerated structures via default reaction library. Ligand designer was employed for the computerized lead optimization and selection of the best structural modification that resulted in a favorable ligand-protein complex. The obtained compounds that showed the best binding to Mpro were re-screened against TMPRSS2, leading to the identification of 20 shared compounds. The compounds were further visually inspected, which resulted in the identification of five shared compounds M1-5 with dual binding affinity. In vitro evaluation and enzyme inhibition assay indicated that M3, an analogue of Compound 13 afforded by replacing the phenolic moiety with pyridinyl, possesses an improved antiviral activity and safety. M3 displayed in vitro antiviral activity with IC50 0.016 µM and Mpro inhibition activity with IC50 0.013 µM, 7-fold more potent than the parent Compound 13 and potent than the antivirals drugs that are currently under clinical trials. Moreover, M3 showed potent activity against human TMPRSS2 and furin enzymes with IC50 0.05, and 0.08 µM, respectively. Molecular docking, WaterMap analysis, molecular dynamics simulation, and R-group analysis confirmed the superiority of the binding fit to M3 with the target enzymes. WaterMap analysis calculated the thermodynamic properties of the hydration site in the binding pocket that significantly affects the biological activity. Loading M3 on zinc oxide nanoparticles (ZnO NPs) increased the antiviral activity of the compound 1.5-fold, while maintaining a higher safety profile. In conclusion, lead optimized discovery following an iterated virtual screening in association with molecular docking and biological evaluation revealed a novel compound named M3 with promising dual activity against SARS-CoV-2. The compound deserves further investigation for potential clinical-based studies.

SARS-CoV-2 spike protein: pathogenesis, vaccines, and potential therapies.

PURPOSE: COVID-19 pandemic has emerged as a result of infection by the deadly pathogenic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing enormous threats to humans. Coronaviruses are distinguished by a clove-like spike (S) protein, which plays a key role in viral pathogenesis, evolutions, and transmission. The objectives of this study are to investigate the distinctive structural features of SARS-CoV-2 S protein, its essential role in pathogenesis, and its use in the development of potential therapies and vaccines. METHODOLOGY: A literature review was conducted to summarize, analyze, and interpret the available scientific data related to SARS-CoV-2 S protein in terms of characteristics, vaccines development and potential therapies. RESULTS: The data indicate that S protein subunits and their variable conformational states significantly affect the virus pathogenesis, infectivity, and evolutionary mutation. A considerable number of potential natural and synthetic therapies were proposed based on S protein. Additionally, neutralizing antibodies were recently approved for emergency use. Furthermore, several vaccines utilizing the S protein were developed. CONCLUSION: A better understanding of S protein features, structure and mutations facilitate the recognition of the importance of SARS-CoV-2 S protein in viral infection, as well as the development of therapies and vaccines. The efficacy and safety of these therapeutic compounds and vaccines are still controversial. However, they may potentially reduce or prevent SARS-CoV-2 infection, leading to a significant reduction of the global health burden of this pandemic.

Marine Sponge is a Promising Natural Source of Anti-SARS-CoV-2 Scaffold.

The current pandemic caused by SARS-CoV2 and named COVID-19 urgent the need for novel lead antiviral drugs. Recently, United States Food and Drug Administration (FDA) approved the use of remdesivir as anti-SARS-CoV-2. Remdesivir is a natural product-inspired nucleoside analogue with significant broad-spectrum antiviral activity. Nucleosides analogues from marine sponge including spongouridine and spongothymidine have been used as lead for the evolutionary synthesis of various antiviral drugs such as vidarabine and cytarabine. Furthermore, the marine sponge is a rich source of compounds with unique activities. Marine sponge produces classes of compounds that can inhibit the viral cysteine protease (Mpro) such as esculetin and ilimaquinone and human serine protease (TMPRSS2) such as pseudotheonamide C and D and aeruginosin 98B. Additionally, sponge-derived compounds such as dihydrogracilin A and avarol showed immunomodulatory activity that can target the cytokines storm. Here, we reviewed the potential use of sponge-derived compounds as promising therapeutics against SARS-CoV-2. Despite the reported antiviral activity of isolated marine metabolites, structural modifications showed the importance in targeting and efficacy. On that basis, we are proposing a novel structure with bifunctional scaffolds and dual pharmacophores that can be superiorly employed in SARS-CoV-2 infection.

Flavonoids are promising safe therapy against COVID-19.

Flavonoids are a class of phenolic natural products, well-identified in traditional and modern medicines in the treatment of several diseases including viral infection. Flavonoids showed potential inhibitory activity against coronaviruses including the current pandemic outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and designated as COVID-19. Here, we have collected all data related to the potential inhibitory mechanisms of flavonoids against SARS-CoV-2 infection and their significant immunomodulatory activities. The data were mapped and compared to elect major flavonoids with a promising role in the current pandemic. Further, we have linked the global existence of flavonoids in medicinal plants and their role in protection against COVID-19. Computational analysis predicted that flavonoids can exhibit potential inhibitory activity against SARS-CoV-2 by binding to essential viral targets required in virus entry and/ or replication. Flavonoids also showed excellent immunomodulatory and anti-inflammatory activities including the inhibition of various inflammatory cytokines. Further, flavonoids showed significant ability to reduce the exacerbation of COVID-19 in the case of obesity via promoting lipids metabolism. Moreover, flavonoids exhibit a high safety profile, suitable bioavailability, and no significant adverse effects. For instance, plants rich in flavonoids are globally distributed and can offer great protection from COVID-19. The data described in this study strongly highlighted that flavonoids particularly quercetin and luteolin can exhibit promising multi-target activity against SARS-CoV-2, which promote their use in the current and expected future outbreaks. Therefore, a regimen of flavonoid-rich plants can be recommended to supplement a sufficient amount of flavonoids for the protection and treatment from SARS-CoV-2 infection.

Promising anti-SARS-CoV-2 drugs by effective dual targeting against the viral and host proteases.

SARS-CoV-2 caused dramatic health, social and economic threats to the globe. With this threat, the expectation of future outbreak, and the shortage of anti-viral drugs, scientists were challenged to develop novel antivirals. The objective of this study is to develop novel anti-SARS-CoV-2 compounds with dual activity by targeting valuable less-mutated enzymes. Here, we have mapped the binding affinity of >500,000 compounds for potential activity against SARS-CoV-2 main protease (Mpro), papain protease (PLpro) and human furin protease. The enzyme inhibition activity of most promising hits was screened and tested in vitro on SARS-CoV-2 clinical isolate incubated with Vero cells. Computational modelling and toxicity of the compounds were validated. The results revealed that 16 compounds showed potential binding activity against Mpro, two of them showed binding affinity against PLpro and furin protease. Respectively, compounds 7 and 13 showed inhibition activity against Mpro at IC50 0.45 and 0.11 µM, against PLpro at IC50 0.085 and 0.063 µM, and against furin protease at IC50 0.29 µM. Computational modelling validated the binding affinity against all proteases. Compounds 7 and 13 showed significant inhibition activity against the virus at IC50 0.77 and 0.11 µM, respectively. Both compounds showed no toxicity on mammalian cells. The data obtained indicated that compounds 7 and 13 exhibited potent dual inhibition activity against SARS-CoV-2. The dual activity of both compounds can be of great promise not only during the current pandemic but also for future outbreaks since the compounds' targets are of limited mutation and critical importance to the viral infection.

Dyslipidemia in breast cancer patients increases the risk of SAR-CoV-2 infection.

Breast cancer (BC) is the most diagnosed and second leading cause of death among women worldwide. Elevated levels of lipids have been reported in BC patients. On the other hand, lipids play an important role in coronavirus infections including the newly emerged disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and designated COVID-19 by WHO. Cancer patients including BC have been reported to be at higher risk of SARS-CoV-2 infection, which is mostly attributed to the chronic immunosuppressive status of cancer patients along with the use of cytotoxic drugs. Here in this review, we highlighted the role of dyslipidemia associated with BC patients in the incidence and severity of SARS-CoV-2 infection. Elevated levels of lipids namely phospholipids, cholesterol, sphingolipids, and eicosanoids in the serum of BC patients and their re-localization to the alveolar spaces can increase susceptibility and/or severity due to SARA-CoV-2 infection. Therefore, manipulation of dyslipidemia in BC patients should be recommended as prophylactic and therapy against SARS-CoV-2 infection.

Switching Host Metabolism as an Approach to Dampen SARS-CoV-2 Infection.

BACKGROUND: COVID-19 pandemic, a global threat, adversely affects all daily lives, altered governmental plans around the world, and urges the development of therapeutics and prophylactics to avoid the expansion of the viral infection. With the recent gradual opening after long lockdown, several recommendations have been placed, with dietary modification as one of the most important approaches that have been appraised. SUMMARY: Here, we are reviewing how changing the host metabolism, particularly changing the host metabolic state from the carbohydrate-dependent glycolytic state to a fat-dependent ketogenic state, may affect viral replication. Furthermore, the impact of intermittent fasting (IF) in triggering metabolic switch along with the impact of supplementation with medium-chain triglycerides (MCTs) such as lauric acid in repressing the envelope formation and viral replication is also addressed. The amalgamation of IF and a ketogenic diet rich in MCTs is thought to work as a prophylactic measure for normal people and adjunct therapy for infected persons. Key Message: A diet regimen of ketogenic breakfast along with supplementation with two doses of lauric acid-rich MCTs at breakfast and lunch times, followed by 8-12-h IF and a dinner rich with fruits and vegetables, could be a potential prophylactic strategy and adjuvant therapy to combat SARS-CoV-2 infections.