Patients' Experiences With Therapeutic Approaches for Post-COVID Syndrome: Results of a Crowdsourced Research Survey.

Some patients develop multiple protracted sequelae after infection with SARS-CoV-2, collectively known as post-COVID syndrome or long COVID. To date, there is no evidence showing benefit of specific therapies for this condition, and patients likely resort to self-initiated therapies. We aimed to obtain information about therapies used by and needs of this population via inductive crowdsourcing research. Patients completed an online questionnaire about their symptoms and experiences with therapeutic approaches. Responses of 499 participants suggested few approaches (eg, mind-body medicine, respiratory therapy) had positive effects and showed a great need for patient-centered communication (eg, more recognition of this syndrome). Our findings can help design clinical studies and underscore the importance of the holistic approach to care provided by family medicine.

Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy.

As of December 2021, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global emergency, and novel therapeutics are urgently needed. Here we describe human single-chain variable fragment (scFv) antibodies (76clAbs) that block an epitope of the SARS-CoV-2 spike protein essential for ACE2-mediated entry into cells. 76clAbs neutralize the Delta variant and other variants being monitored (VBMs) and inhibit spike-mediated pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. In two independent animal models, intranasal administration counteracted the infection. Because of their high efficiency, remarkable stability, resilience to nebulization, and low cost of production, 76clAbs may become a relevant tool for rapid, self-administrable early intervention in SARS-CoV-2-infected subjects independently of their immune status.

DNA aptamers masking angiotensin converting enzyme 2 as an innovative way to treat SARS-CoV-2 pandemic.

All the different coronavirus SARS-CoV-2 variants isolated so far share the same mechanism of infection mediated by the interaction of their spike (S) glycoprotein with specific residues on their cellular receptor: the angiotensin converting enzyme 2 (ACE2). Therefore, the steric hindrance on this cellular receptor created by a bulk macromolecule may represent an effective strategy for the prevention of the viral spreading and the onset of severe forms of Corona Virus disease 19 (COVID-19). Here, we applied a systematic evolution of ligands by exponential enrichment (SELEX) procedure to identify two single strand DNA molecules (aptamers) binding specifically to the region surrounding the K353, the key residue in human ACE2 interacting with the N501 amino acid of the SARS-CoV-2 S. 3D docking in silico experiments and biochemical assays demonstrated that these aptamers bind to this region, efficiently prevent the SARS-CoV-2 S/human ACE2 interaction and the viral infection in the nanomolar range, regardless of the viral variant, thus suggesting the possible clinical development of these aptamers as SARS-CoV-2 infection inhibitors. Our approach brings a significant innovation to the therapeutic paradigm of the SARS-CoV-2 pandemic by protecting the target cell instead of focusing on the virus; this is particularly attractive in light of the increasing number of viral mutants that may potentially escape the currently developed immune-mediated neutralization strategies.

Convalescent or standard plasma versus standard of care in the treatment of COVID-19 patients with respiratory impairment: short and long-term effects. A three-arm randomized controlled clinical trial.

BACKGROUND: The efficacy of early treatment with convalescent plasma in patients with COVID-19 is debated. Nothing is known about the potential effect of other plasma components other than anti-SARS-CoV-2 antibodies. METHODS: To determine whether convalescent or standard plasma would improve outcomes for adults in early phase of Covid19 respiratory impairment we designed this randomized, three-arms, clinical trial (PLACO COVID) blinded on interventional arms that was conducted from June 2020 to August 2021. It was a multicentric trial at 19 Italian hospitals. We enrolled 180 hospitalized adult patients with COVID-19 pneumonia within 5 days from the onset of respiratory distress. Patients were randomly assigned in a 1:1:1 ratio to standard of care (n = 60) or standard of care + three units of standard plasma (n = 60) or standard of care + three units of high-titre convalescent plasma (n = 60) administered on days 1, 3, 5 after randomization. Primary outcome was 30-days mortality. Secondary outcomes were: incidence of mechanical ventilation or death at day 30, 6-month mortality, proportion of days with mechanical ventilation on total length of hospital stay, IgG anti-SARS-CoV-2 seroconversion, viral clearance from plasma and respiratory tract samples, and variations in Sequential Organ Failure Assessment score. The trial was analysed according to the intention-to-treat principle. RESULTS: 180 patients (133/180 [73.9%] males, mean age 66.6 years [IQR 57-73]) were enrolled a median of 8 days from onset of symptoms. At enrollment, 88.9% of patients showed moderate/severe respiratory failure. 30-days mortality was 20% in Control arm, 23% in Convalescent (risk ratio [RR] 1.13; 95% confidence interval [CI], 0.61-2.13, P = 0.694) and 25% in Standard plasma (RR 1.23; 95%CI, 0.63-2.37, P = 0.544). Time to viral clearance from respiratory tract was 21 days for Convalescent, 28 for Standard plasma and 23 in Control arm but differences were not statistically significant. No differences for other secondary endpoints were seen in the three arms. Serious adverse events were reported in 1.7%, 3.3% and 5% of patients in Control, Standard and Convalescent plasma arms respectively. CONCLUSIONS: Neither high-titer Convalescent nor Standard plasma improve outcomes of COVID-19 patients with acute respiratory failure. Trial Registration Clinicaltrials.gov Identifier: NCT04428021. First posted: 11/06/2020.

In silico approach for the development of novel antiviral compounds based on SARS-COV-2 protease inhibition.

The COVID-19 pandemic emerged in 2019, bringing with it the need for greater stores of effective antiviral drugs. This paper deals with the conformation-independent, QSAR model, developed by employing the Monte Carlo optimization method, as well as molecular graphs and the SMILES notation-based descriptors for the purpose of modeling the SARS-CoV-3CLpro enzyme inhibition. The main purpose was developing a reproducible model involving easy interpretation, utilized for a quick prediction of the inhibitory activity of SAR-CoV-3CLpro. The following statistical parameters were present in the best-developed QSAR model: (training set) R 2 = 0.9314, Q 2 = 0.9271; (test set) R 2 = 0.9243, Q 2 = 0.8986. Molecular fragments, defined as SMILES notation descriptors, that have a positive and negative impact on 3CLpro inhibition were identified on the basis of the results obtained for structural indicators, and were applied to the computer-aided design of five new compounds with (4-methoxyphenyl)[2-(methylsulfanyl)-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazol-1-yl]methanone as a template molecule. Molecular docking studies were used to examine the potential inhibition effect of designed molecules on SARS-CoV-3CLpro enzyme inhibition and obtained results have high correlation with the QSAR modeling results. In addition, the interactions between the designed molecules and amino acids from the 3CLpro active site were determined, and the energies they yield were calculated. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-022-02170-8.

Understanding the immunological aspects of SARS-CoV-2 causing COVID-19 pandemic: A therapeutic approach.

In December 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a novel variant of coronavirus has emerged from Wuhan in China and has created havoc impulses across the world with a larger number of fatalities. At the same time, studies are on roll to discover potent vaccine against it or repurposing of approved drugs which are widely adopted are under trial to eradicate the SARS-CoV-2 causing COVID-19 pandemic. Reports have also shown that there are asymptomatic carriers of COVID-19 disease who can transmit the disease to others too. However, the first line defense of the viral attack is body's strong and well-coordinated immune response producing excessive inflammatory innate reaction, thus impaired adaptive host immune defense which lead to death upon the malfunctioning. Considerable works are going on to establish the relation between immune parameters and viral replication that, might alter both the innate and adaptive immune system of COVID-19 patient by up riding a massive cytokines and chemokines secretion. This review mainly gives an account on how SARS-CoV-2 interacts with our immune system and how does our immune system responds to it, along with that drugs which are being used or can be used in fighting COVID-19 disease. The curative therapies as treatment for it have also been addressed in the perspective of adaptive immunity of the patients.

MSC-derived exosomes carrying a cocktail of exogenous interfering RNAs an unprecedented therapy in era of COVID-19 outbreak.

BACKGROUND: The onset of the SARS-CoV-2 pandemic has resulted in ever-increasing casualties worldwide, and after 15 months, standard therapeutic regimens are yet to be discovered. MAIN BODY: Due to the regenerative and immunomodulatory function of MSCs, they can serve as a suitable therapeutic option in alleviating major COVID-19 complications like acute respiratory distress syndrome. However, the superior properties of their cognate exosomes as a cell-free product make them preferable in the clinic. Herein, we discuss the current clinical status of these novel therapeutic strategies in COVID-19 treatment. We then delve into the potential of interfering RNAs incorporation as COVID-19 gene therapy and introduce targets involved in SARS-CoV-2 pathogenesis. Further, we present miRNAs and siRNAs candidates with promising results in targeting the mentioned targets. CONCLUSION: Finally, we present a therapeutic platform of mesenchymal stem cell-derived exosomes equipped with exogenous iRNAs, that can be employed as a novel therapeutic modality in COVID-19 management aiming to prevent further viral spread within the lung, hinder the virus life cycle and pathogenesis such as immune suppression, and ultimately, enhance the antiviral immune response.

SARS-CoV-2 Myocarditis: Insights Into Incidence, Prognosis, and Therapeutic Implications.

PURPOSE OF REVIEW: In coronavirus disease 2019 (COVID-19), myocardial injury occurs frequently in severe or critically ill hospitalized patients, yet myocarditis is much less common. In this context, revisiting the definition of myocarditis is appropriate with a specific focus on diagnostic and management considerations in patients infected with SARS-CoV-2. RECENT FINDINGS: Pathologic cardiac specimens from patients with COVID-19 suggest a mixed inflammatory response involving lymphocytes and macrophages, and importantly, cellular injury occurs predominantly at the level of pericytes and endothelial cells, less often involving direct myocyte necrosis. In COVID-19, the diagnosis of myocarditis has understandably been based predominantly on clinical criteria, and the number of patients with clinically suspected myocarditis who would meet diagnostic histological criteria is unclear. Echocardiography and cardiac magnetic resonance are important diagnostic tools, although the prognostic implications of abnormalities are still being defined. Importantly, SARS-CoV2 myocarditis should be diagnosed within an appropriate clinical context and should not be based on isolated imaging findings. Therapies in COVID-19 have focused on the major clinical manifestation of pneumonia, but the promotion of viral clearance early in the disease could prevent the development of myocarditis, and further study of immunosuppressive therapies once myocarditis has developed are indicated. A strict and uniform approach is needed to diagnose myocarditis due to SARS-CoV-2 to better understand the natural history of this disease and to facilitate evaluation of potential therapeutic interventions. A methodological approach will also better inform the incidence of COVID-19 associated myocarditis and potential long-term health effects.

Anti-SARS-CoV-2 Strategies and the Potential Role of miRNA in the Assessment of COVID-19 Morbidity, Recurrence, and Therapy.

Recently, we have experienced a serious pandemic. Despite significant technological advances in molecular technologies, it is very challenging to slow down the infection spread. It appeared that due to globalization, SARS-CoV-2 spread easily and adapted to new environments or geographical or weather zones. Additionally, new variants are emerging that show different infection potential and clinical outcomes. On the other hand, we have some experience with other pandemics and some solutions in virus elimination that could be adapted. This is of high importance since, as the latest reports demonstrate, vaccine technology might not follow the new, mutated virus outbreaks. Thus, identification of novel strategies and markers or diagnostic methods is highly necessary. For this reason, we present some of the latest views on SARS-CoV-2/COVID-19 therapeutic strategies and raise a solution based on miRNA. We believe that in the face of the rapidly increasing global situation and based on analogical studies of other viruses, the possibility of using the biological potential of miRNA technology is very promising. It could be used as a promising diagnostic and prognostic factor, as well as a therapeutic target and tool.

Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach.

Improvement of COVID-19 clinical condition was seen in studies where combination of antiretroviral drugs, lopinavir and ritonavir, as well as immunomodulant antimalaric, chloroquine/hydroxychloroquine together with the macrolide-type antibiotic, azithromycin, was used for patient's treatment. Although these drugs are "old", their pharmacological and toxicological profile in SARS-CoV-2 - infected patients are still unknown. Thus, by using in silico toxicogenomic data-mining approach, we aimed to assess both risks and benefits of the COVID-19 treatment with the most promising candidate drugs combinations: lopinavir/ritonavir and chloroquine/hydroxychloroquine + azithromycin. The Comparative Toxicogenomics Database (CTD; http://CTD.mdibl.org), Cytoscape software (https://cytoscape.org) and ToppGene Suite portal (https://toppgene.cchmc.org) served as a foundation in our research. Our results have demonstrated that lopinavir/ritonavir increased the expression of the genes involved in immune response and lipid metabolism (IL6, ICAM1, CCL2, TNF, APOA1, etc.). Chloroquine/hydroxychloroquine + azithromycin interacted with 6 genes (CCL2, CTSB, CXCL8, IL1B, IL6 and TNF), whereas chloroquine and azithromycin affected two additional genes (BCL2L1 and CYP3A4), which might be a reason behind a greater number of consequential diseases. In contrast to lopinavir/ritonavir, chloroquine/hydroxychloroquine + azithromycin downregulated the expression of TNF and IL6. As expected, inflammation, cardiotoxicity, and dyslipidaemias were revealed as the main risks of lopinavir/ritonavir treatment, while chloroquine/hydroxychloroquine + azithromycin therapy was additionally linked to gastrointestinal and skin diseases. According to our results, these drug combinations should be administrated with caution to patients suffering from cardiovascular problems, autoimmune diseases, or acquired and hereditary lipid disorders.

Deubiquitinating Enzymes in Coronaviruses and Possible Therapeutic Opportunities for COVID-19.

Following the outbreak of novel severe acute respiratory syndrome (SARS)-coronavirus (CoV)2, the majority of nations are struggling with countermeasures to fight infection, prevent spread and improve patient survival. Considering that the pandemic is a recent event, no large clinical trials have been possible and since coronavirus specific drug are not yet available, there is no strong consensus on how to treat the coronavirus disease 2019 (COVID-19) associated viral pneumonia. Coronaviruses code for an important multifunctional enzyme named papain-like protease (PLP), that has many roles in pathogenesis. First, PLP is one of the two viral cysteine proteases, along with 3-chymotripsin-like protease, that is responsible for the production of the replicase proteins required for viral replication. Second, its intrinsic deubiquitinating and deISGylating activities serve to antagonize the host's immune response that would otherwise hinder infection. Both deubiquitinating and deISGylating functions involve the removal of the small regulatory polypeptides, ubiquitin and ISG15, respectively, from target proteins. Ubiquitin modifications can regulate the innate immune response by affecting regulatory proteins, either by altering their stability via the ubiquitin proteasome pathway or by directly regulating their activity. ISG15 is a ubiquitin-like modifier with pleiotropic effects, typically expressed during the host cell immune response. PLP inhibitors have been evaluated during past coronavirus epidemics, and have showed promising results as an antiviral therapy in vitro. In this review, we recapitulate the roles of PLPs in coronavirus infections, report a list of PLP inhibitors and suggest possible therapeutic strategies for COVID-19 treatment, using both clinical and preclinical drugs.

Corrigendum: The role of peroxisome proliferator-activated receptors in the modulation of hyperinflammation induced by SARS-CoV-2 infection: A perspective for COVID-19 therapy.

[This corrects the article DOI: 10.3389/fimmu.2023.1127358.].

Outcomes and Management of the SARS-CoV2 Omicron Variant in Recipients of Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy.

Hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell therapy (CAR-T) recipients who develop Coronavirus disease 2019 (COVID-19) can have decreased overall survival (OS), likely due to disease-inherent and therapy-related immunodeficiency. The availability of COVID-19-directed therapies and vaccines have improved COVID-19-related outcomes, but immunocompromised individuals remain vulnerable. Specifically, the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infections, including Omicron and its sublineages, particularly in HCT recipients, remain to be defined. The aim of this study was to compare the impact of SARS-CoV-2 Omicron infections in HCT/CAR-T recipients with outcomes previously reported for ancestral SARS-CoV-2 infections early in the pandemic (March to June 2020). This was a retrospective analysis of adult HCT/CAR-T recipients diagnosed with COVID-19 at Memorial Sloan Kettering Cancer Center between July 2021 and July 2022. We identified 353 patients (172 autologous HCT recipients [49%], 152 allogeneic HCT recipients [43%], and 29 CAR-T recipients [8%]), with a median time from HCT/CAR-T to SARS-CoV-2 infection of 1010 days (interquartile range, 300 to 2046 days). Forty-one patients (12%) were diagnosed with COVID-19 during the delta wave, and 312 patients (88%) were diagnosed during the Omicron wave. Risk factors associated with increased odds of COVID-19-related hospitalization were the presence of 2 or more comorbidities (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.4 to 10.7; P < .001), CAR-T therapy compared to allogeneic HCT (OR, 7.7; 95% CI, 3.0 to 20.0; P < .001), hypogammaglobulinemia (OR, 2.71; 95% CI, 1.06 to 6.40; P = .027), and age at COVID-19 diagnosis (OR, 1.03; 95% CI, 1.0 to 1.05; P = .04). In contrast, infection during the Omicron variant BA5/BA4-dominant period compared to variant BA1 (OR, .21; 95% CI, .03 to .73; P = .037) and more than 3 years from HCT/CAR-T therapy to COVID-19 diagnosis compared to early infection at <100 days (OR, .31; 95% CI, .12 to .79; P = .011) were associated with a decreased odds for hospitalization. The OS at 12 months from COVID-19 diagnosis was 89% (95% CI, 84% to 94%), with 6 of 26 deaths attributable to COVID-19. Patients with the ancestral strain of SAR-CoV-2 had a lower OS at 12 months, with 73% (95% CI, 62% to 84%) versus 89% (95% CI, 84% to 94%; P < .001) in the Omicron cohort. Specific COVID-19 treatment was administered in 62% of patients, and 84% were vaccinated with mRNA COVID-19 vaccines. Vaccinated patients had significantly better OS than unvaccinated patients (90% [95% CI, 86% to 95%] versus 82% [95% CI, 72% to 94%] at 12 months; P = .003). No significant difference in OS was observed in patients infected with the Omicron and those infected with the Delta variant (P = .4) or treated with specific COVID-19 treatments compared with those not treated (P = .2). We observed higher OS in HCT and CAR-T recipients infected with the Omicron variants compared to those infected with the ancestral strain of SARS-CoV2. The use of COVID-19 antivirals, mAbs, and vaccines might have contributed to the improved outcomes.

Synergism between remdesivir and ribavirin leads to SARS-CoV-2 extinction in cell culture.

BACKGROUND AND PURPOSE: There is a need for effective anti-COVID-19 treatments, mainly for individuals at risk of severe disease such as the elderly and the immunosuppressed. Drug repositioning has proved effective in identifying drugs that can find a new application for the control of coronavirus disease, in particular COVID-19. The purpose of the present study was to find synergistic antiviral combinations for COVID-19 based on lethal mutagenesis. EXPERIMENTAL APPROACH: The effect of combinations of remdesivir and ribavirin on the infectivity of SARS-CoV-2 in cell culture has been tested. Viral populations were monitored by ultra-deep sequencing, and the decrease of infectivity as a result of the treatment was measured. KEY RESULTS: Remdesivir and ribavirin exerted a synergistic inhibitory activity against SARS-CoV-2, quantified both by CompuSyn (Chou-Talalay method) and Synergy Finder (ZIP-score model). In serial passage experiments, virus extinction was readily achieved with remdesivir-ribavirin combinations at concentrations well below their cytotoxic 50 value, but not with the drugs used individually. Deep sequencing of treated viral populations showed that remdesivir, ribavirin, and their combinations evoked significant increases of the number of viral mutations and haplotypes, as well as modification of diversity indices that characterize viral quasi-species. CONCLUSION AND IMPLICATIONS: SARS-CoV-2 extinction can be achieved by synergistic combination treatments based on lethal mutagenesis. In addition, the results offer prospects of triple drug treatments for effective SARS-CoV-2 suppression.

Evaluation of the Efficacy of Remdesivir for the Treatment of Coronavirus Disease 2019.

Background: Coronavirus disease 2019 (COVID-19), caused by a novel coronavirus, SARS-CoV-2, has accounted for more than 1 000 000 deaths in the United States alone. In May 2020, the Food and Drug Administration issued an Emergency Use Authorization to allow the investigational use of intravenous remdesivir for the treatment of suspected or confirmed COVID-19 in hospitalized children and adults. Several other agents, such as hydroxychloroquine, dexamethasone, and tocilizumab have been investigated as potential treatment options; however, dexamethasone is currently the only agent that has been proven to reduce mortality in patients who require supplemental oxygen. The purpose of this study was to determine if initiation of remdesivir treatment in patients who presented with early symptoms of COVID-19 (defined as symptom onset < 7 days) had a significant impact on in-patient all-cause mortality compared to initiation of remdesivir treatment in patients who presented with symptom onset of at least 7 days. Methods: This ethics-committee-approved, retrospective, multicenter, double-arm study was conducted across 10 facilities in the HCA Healthcare West Florida Division. Adult inpatients age 18 and older with confirmed COVID-19 and administered intravenous remdesivir from May 1, 2020, to July 31, 2020, were included. Exclusion criteria included patients less than 18 years of age, the concomitant use of hydroxychloroquine or tocilizumab for any indication, or an estimated glomerular filtration rate less than 30 milliliters per minute. The primary outcome of this study was in-patient all-cause mortality. Secondary outcomes included total length of stay, time to discharge, oxygen requirements, and number of ventilator days. Results: A total of 217 patients from facilities in the HCA Healthcare West Florida Division were evaluated for inclusion. The primary outcome of all-cause mortality occurred in 34.9% of patients with symptom onset of fewer than 7 days versus 31.0% of patients with symptom onset of at least 7 days (P = .57). There were no statistical differences found among the secondary outcomes. Conclusion: Time since symptom onset did not result in a statistically significant difference in all-cause mortality in patients who received intravenous remdesivir for the treatment of COVID-19.

The role of peroxisome proliferator-activated receptors in the modulation of hyperinflammation induced by SARS-CoV-2 infection: A perspective for COVID-19 therapy.

Coronavirus disease 2019 (COVID-19) is a severe respiratory disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that affects the lower and upper respiratory tract in humans. SARS-CoV-2 infection is associated with the induction of a cascade of uncontrolled inflammatory responses in the host, ultimately leading to hyperinflammation or cytokine storm. Indeed, cytokine storm is a hallmark of SARS-CoV-2 immunopathogenesis, directly related to the severity of the disease and mortality in COVID-19 patients. Considering the lack of any definitive treatment for COVID-19, targeting key inflammatory factors to regulate the inflammatory response in COVID-19 patients could be a fundamental step to developing effective therapeutic strategies against SARS-CoV-2 infection. Currently, in addition to well-defined metabolic actions, especially lipid metabolism and glucose utilization, there is growing evidence of a central role of the ligand-dependent nuclear receptors and peroxisome proliferator-activated receptors (PPARs) including PPARα, PPARß/δ, and PPARγ in the control of inflammatory signals in various human inflammatory diseases. This makes them attractive targets for developing therapeutic approaches to control/suppress the hyperinflammatory response in patients with severe COVID-19. In this review, we (1) investigate the anti-inflammatory mechanisms mediated by PPARs and their ligands during SARS-CoV-2 infection, and (2) on the basis of the recent literature, highlight the importance of PPAR subtypes for the development of promising therapeutic approaches against the cytokine storm in severe COVID-19 patients.

Therapeutic Potential of Bioactive Compounds from Edible Mushrooms to Attenuate SARS-CoV-2 Infection and Some Complications of Coronavirus Disease (COVID-19).

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly infectious positive RNA virus, has spread from its epicenter to other countries with increased mortality and morbidity. Its expansion has hampered humankind's social, economic, and health realms to a large extent. Globally, investigations are underway to understand the complex pathophysiology of coronavirus disease (COVID-19) induced by SARS-CoV-2. Though numerous therapeutic strategies have been introduced to combat COVID-19, none are fully proven or comprehensive, as several key issues and challenges remain unresolved. At present, natural products have gained significant momentum in treating metabolic disorders. Mushrooms have often proved to be the precursor of various therapeutic molecules or drug prototypes. The plentiful bioactive macromolecules in edible mushrooms, like polysaccharides, proteins, and other secondary metabolites (such as flavonoids, polyphenols, etc.), have been used to treat multiple diseases, including viral infections, by traditional healers and the medical fraternity. Some edible mushrooms with a high proportion of therapeutic molecules are known as medicinal mushrooms. In this review, an attempt has been made to highlight the exploration of bioactive molecules in mushrooms to combat the various pathophysiological complications of COVID-19. This review presents an in-depth and critical analysis of the current therapies against COVID-19 versus the potential of natural anti-infective, antiviral, anti-inflammatory, and antithrombotic products derived from a wide range of easily sourced mushrooms and their bioactive molecules.

Mucoadhesive drug delivery systems: a promising noninvasive approach to bioavailability enhancement. Part II: formulation considerations.

INTRODUCTION: Mucoadhesive drug delivery systems (MDDS) are specifically designed to interact and bind to the mucosal layer of the epithelium for localized, prolonged, and/or targeted drug delivery. Over the past 4 decades, several dosage forms have been developed for localized as well as systemic drug delivery at different anatomical sites. AREAS COVERED: The objective of this review is to provide a detailed understanding of the different aspects of MDDS. Part II describes the origin and evolution of MDDS, followed by a discussion of the properties of mucoadhesive polymers. Finally, a synopsis of the different commercial aspects of MDDS, recent advances in the development of MDDS for biologics and COVID-19 as well as future perspectives are provided. EXPERT OPINION: A review of the past reports and recent advances reveal MDDS as highly versatile, biocompatible, and noninvasive drug delivery systems. The rise in the number of approved biologics, the introduction of newer highly efficient thiomers, as well as the recent advances in the field of nanotechnology have led to several excellent applications of MDDS, which are predicted to grow significantly in the future.

Overreactive macrophages in SARS-CoV-2 infection: The effects of ACEI.

Among various factors influencing the course of SARS-CoV-2 infection in humans, macrophage overactivation is considered the main cause of the cytokine storm that leads to severe complications of COVID-19. Moreover, the increased expression of angiotensin converting enzyme 2 (ACE2), an obligatory entry receptor of the coronavirus, caused by treatment with ACE inhibitors (ACEI) lowered overall confidence in the safety of these drugs. However, analysis of the course of coronavirus infection in patients treated with ACEI does not support these concerns. Instead, the beneficial effect of ACEI on macrophages has increasingly been emphasized. This includes their anti-inflammatory activation and the consequent reduction in the risk of severe disease and life-threatening complications. Herein, we summarize the current knowledge and understanding of the dual role of macrophages in SARS-CoV-2 infection, with a special focus on the postulated mechanisms underlying the beneficial effects of macrophage targeting by ACEI. These seem to involve the stimulation of macrophage angiotensin II type 2 and Mas receptors by angiotensin 1-7, intensively produced due to the up-regulation of ACE2 expression on macrophages, as well as the direct inhibition of macrophage hyper-responsiveness by ACEI. The impact of ACEI on macrophages may also lead to the activation of an effective antiviral response due to the increased expression of ACE2.

Efficacy of Remdesivir and Neutralizing Monoclonal Antibodies in Monotherapy or Combination Therapy in Reducing the Risk of Disease Progression in Elderly or Immunocompromised Hosts Hospitalized for COVID-19: A Single Center Retrospective Study.

INTRODUCTION: Remdesivir (REM) and monoclonal antibodies (mAbs) could alleviate severe COVID-19 in at-risk outpatients. However, data on their use in hospitalized patients, particularly in elderly or immunocompromised hosts, are lacking. METHODS: All consecutive patients hospitalized with COVID-19 at our unit from 1 July 2021 to 15 March 2022 were retrospectively enrolled. The primary outcome was the progression to severe COVID-19 (P/F < 200). Descriptive statistics, a Cox univariate-multivariate model, and an inverse probability treatment-weighted (IPTW) analysis were performed. RESULTS: Overall, 331 subjects were included; their median (q1-q3) age was 71 (51-80) years, and they were males in 52% of the cases. Of them, 78 (23%) developed severe COVID-19. All-cause in-hospital mortality was 14%; it was higher in those with disease progression (36% vs. 7%, p < 0.001). REM and mAbs resulted in a 7% (95%CI = 3-11%) and 14% (95%CI = 3-25%) reduction in the risk of severe COVID-19, respectively, after adjusting the analysis with the IPTW. In addition, by evaluating only immunocompromised hosts, the combination of REM and mAbs was associated with a significantly lower incidence of severe COVID-19 (aHR = 0.06, 95%CI = 0.02-0.77) when compared with monotherapy. CONCLUSIONS: REM and mAbs may reduce the risk of COVID-19 progression in hospitalized patients. Importantly, in immunocompromised hosts, the combination of mAbs and REM may be beneficial.