Phillyrin (KD-1) exerts anti-viral and anti-inflammatory activities against novel coronavirus (SARS-CoV-2) and human coronavirus 229E (HCoV-229E) by suppressing the nuclear factor kappa B (NF-κB) signaling pathway

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has extensively and rapidly spread in the world, causing an outbreak of acute infectious pneumonia. However, no specific antiviral drugs or vaccines can be used. Phillyrin (KD-1), a representative ingredient of Forsythia suspensa, possesses anti-inflammatory, anti-oxidant, and antiviral activities. However, little is known about the antiviral abilities and mechanism of KD-1 against SARS-CoV-2 and human coronavirus 229E (HCoV-229E).PurposeThe study was designed to investigate the antiviral and anti-inflammatory activities of KD-1 against the novel SARS-CoV-2 and HCoV-229E and its potential effect in regulating host immune response in vitro.MethodsThe antiviral activities of KD-1 against SARS-CoV-2 and HCoV-229E were assessed in Vero E6 cells using cytopathic effect and plaque-reduction assay. Proinflammatory cytokine expression levels upon infection with SARS-CoV-2 and HCoV-229E infection in Huh-7 cells were measured by real-time quantitative PCR assays. Western blot assay was used to determine the protein expression of nuclear factor kappa B (NF-κB) p65, p-NF-κB p65, IκBα, and p-IκBα in Huh-7 cells, which are the key targets of the NF-κB pathway.ResultsKD-1 could significantly inhibit SARS-CoV-2 and HCoV-229E replication in vitro. KD-1 could also markedly reduce the production of proinflammatory cytokines (TNF-α, IL-6, IL-1β, MCP-1, and IP-10) at the mRNA levels. Moreover, KD-1 could significantly reduce the protein expression of p-NF-κB p65, NF-κB p65, and p-IκBα, while increasing the expression of IκBα in Huh-7 cells.ConclusionsKD-1 could significantly inhibit virus proliferation in vitro, the up-regulated expression of proinflammatory cytokines induced by SARS-CoV-2 and HCoV-229E by regulating the activity of the NF-кB signaling pathway. Our findings indicated that KD-1 protected against virus attack and can thus be used as a novel strategy for controlling the coronavirus disease 2019.     

Broad antiviral and anti-inflammatory activity of Qingwenjiere mixture against SARS-CoV-2 and other human coronavirus infections

BackgroundQingwenjiere Mixture (QJM) is a traditional Chinese medicine (TCM) that has been shown to have remarkable clinical efficacy against COVID-19. However, little is known about the antiviral and anti-inflammatory activities of QJM against a wider range of human coronavirus (HCoV) strains.PurposeThe study aims to investigate the antiviral and anti-inflammatory activities of QJM, as well as the underlying mechanisms against HCoV infections.MethodsThe chemical compositions from QJM were analyzed by LC-MS. The inhibitory effect of QJM on infections of HCoV-OC43, HCoV-229E, HCoV-NL63, and SARS-CoV-2 was evaluated in HRT-18 cells, Huh7 cells, LLC-MK2 cells, and Vero-E6 cells, respectively, by using cytopathic effect (CPE) inhibition assay or RT-qPCR detection of viral n, s, or RdRp/Hel genes. The expression of pro-inflammatory cytokines induced by HCoV-OC43, HCoV-229E, and SARS-CoV-2, as well as the host ace2 gene was also determined by RT-qPCR assay. Furthermore, the expression of key molecules in the NF-κB/MAPKs signaling pathways was determined by western blot.ResultsIn alcohol-extraction groups of QJM and reference decoction pieces, 53 similar ion peaks were identified, the majority of which were phenylpropanoids, iridoids, and flavonoids. In addition, QJM reduced CPE caused by HCoVs and the expression of viral n genes or N protein. Pretreatment with QJM also exerted inhibitory effect on viral n gene expression. QJM also inhibited the expression of RdRp/Hel and s genes of SARS-CoV-2, as well as the host ace2 gene. Besides, QJM markedly reduced virus-induced mRNA expression of a panel of pro-inflammatory cytokines, such as IL-6, CXCL-8/IL-8, CXCL-10/IP-10, CCL-5/RANTES, TNF-α, IFN-α, CCL-2/MCP-1, CXCL-9/MIG, and IL1-α. We further showed that QJM inhibited the phosphorylation of NF-κB p65, and JNK, ERK 1/2, and p38 MAPKs in HCoV-OC43-infected HRT-18 cells.ConclusionsQJM has broad antiviral and anti-inflammatory activity against both common and newly emerged HCoVs possibly by inhibiting the activation of key components in NF-κB/MAPKs signaling pathway. QJM also has a prevention effect against HCoV infections and inhibits the host receptor required for virus entry. These results indicate that QJM may have the therapeutic potential in the treatment of diseases caused by a broad range of HCoVs.     

Antiviral drug treatment for nonsevere COVID-19: a systematic review and network meta-analysis

Background:Randomized trial evidence suggests that some antiviral drugs are effective in patients with COVID-19. However, the comparative effectiveness of antiviral drugs in nonsevere COVID-19 is unclear.Methods:We searched the Epistemonikos COVID-19 L·OVE (Living Overview of Evidence) database for randomized trials comparing antiviral treatments, standard care or placebo in adult patients with nonsevere COVID-19 up to Apr. 25, 2022. Reviewers extracted data and assessed risk of bias. We performed a frequentist network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.Results:We identified 41 trials, which included 18 568 patients. Compared with standard care or placebo, molnupiravir and nirmatrelvir–ritonavir each reduced risk of death with moderate certainty (10.9 fewer deaths per 1000, 95% confidence interval [CI] 12.6 to 4.5 fewer for molnupiravir; 11.7 fewer deaths per 1000, 95% CI 13.1 fewer to 2.6 more). Compared with molnupiravir, nirmatrelvir–ritonavir probably reduced risk of hospital admission (27.8 fewer admissions per 1000, 95% CI 32.8 to 18.3 fewer; moderate certainty). Remdesivir probably has no effect on risk of death, but may reduce hospital admissions (39.1 fewer admissions per 1000, 95% CI 48.7 to 13.7 fewer; low certainty).Interpretation:Molnupiravir and nirmatrelvir–ritonavir probably reduce risk of hospital admissions and death among patients with nonsevere COVID-19. Nirmatrelvir–ritonavir is probably more effective than molnupiravir for reducing risk of hospital admissions. Most trials were conducted with unvaccinated patients, before the emergence of the Omicron variant; the effectiveness of these drugs must thus be tested among vaccinated patients and against newer variants.

Most trials addressing the treatment of patients with COVID-19 have targeted patients admitted to hospital with severe or critical disease.¹ However, more recently, several treatments, including antiviral drugs, antidepressants, monoclonal antibodies and inhaled corticosteroids, have been studied for patients with nonsevere COVID-19.² Preliminary evidence from ongoing or recently completed trials suggests that 2 novel antiviral drugs — molnupiravir and nirmatrelvir–ritonavir (Paxlovid) — may be effective at reducing risk of hospital admission.^3–5 To date, evidence on antiviral drugs for nonsevere COVID-19 has not been systematically synthesized or appraised. Furthermore, although efficacy data from trials of molnupiravir, nirmatrelvir–ritonavir and remdesivir are promising, no head-to-head trials have compared these drugs.A network meta-analysis allows for comparison of treatments that have not been compared in randomized controlled trials (RCTs), using pooled estimates from direct and indirect evidence. They can provide guidance to clinicians and evidence users in determining which treatments are superior. This is particularly important as health care systems attempt to prioritize access to effective COVID-19 treatments in the early stages of the disease.We sought to compare the effectiveness of antiviral drugs for patients with nonsevere COVID-19.     

Traditional Chinese herbal medicine at the forefront battle against COVID-19: Clinical experience and scientific basis

BackgroundThroughout the 5000-year history of China, more than 300 epidemics were recorded. Traditional Chinese herbal medicine (TCM) has been used effectively to combat each of these epidemics’ infections, and saved many lives. To date, there are hundreds of herbal TCM formulae developed for the purpose of prevention and treatment during epidemic infections. When COVID-19 ravaged the Wuhan district in China in early January 2020, without a deep understanding about the nature of COVID-19, patients admitted to the TCM Hospital in Wuhan were immediately treated with TCM and reported later with >90% efficacy.ApproachWe conducted conduct a systematic survey of various TCM herbal preparations used in Wuhan and to review their efficacy, according to the published clinical data; and, secondly, to find the most popular herbs used in these preparations and look into the opportunity of future research in the isolation and identification of bioactive natural products for fighting COVID-19.ResultsAlthough bioactive natural products in these herbal preparations may have direct antiviral activities, TCM employed for fighting epidemic infections was primarily based on the TCM theory of restoring the balance of the human immune system, thereby defeating the viral infection indirectly. In addition, certain TCM teachings relevant to the meridian system deserve better attention. For instance, many TCM herbal preparations target the lung meridian, which connects the lung and large intestine. This interconnection between the lung, including the upper respiratory system, and the intestine, may explain why certain TCM formulae showed excellent relief of lung congestion and diarrhea, two characteristics of COVID-19 infection.ConclusionThere is good reason for us to learn from ancient wisdom and accumulated clinical experience, in combination with cutting edge science and technologies, to fight with the devastating COVID-19 pandemic now and emerging new coronaviruses in the future.     

Therapeutic options of TCM for organ injuries associated with COVID-19 and the underlying mechanism

BackgroundCoronavirus disease-2019 (COVID-19) caused by infection with severe acute respiratory coronavirus-2 (SARS-CoV-2) has been spreading rapidly throughout China and in other countries since the end of 2019. The World Health Organization (WHO) has declared that the epidemic is a public health emergency of international concerns. The timely and appropriate measures for treating COVID-19 in China, which are inseparable from the contribution of traditional Chinese medicine (TCM), have won much praise of the world.PurposeThis review aimed to summarize and discuss the essential role of TCM in protecting tissues from injuries associated with COVID-19, and accordingly to clarify the possible action mechanisms of TCM from the perspectives of anti-inflammatory, antioxidant and anti-apoptotic effects.MethodsElectronic databases such as Pubmed, ResearchGate, Science Direct, Web of Science, medRixv and Wiley were used to search scientific literatures.ResultsThe present review found that traditional Chinese herbs commonly used for the clinical treatment of organ damages caused by COVID-19, such as Scutellaria baicalensis, Salvia miltiorrhizaSalvia miltiorrhiza, and ginseng, could act on multiple signaling pathways involved in inflammation, oxidative stress and apoptosis.ConclusionTCM could protect COVID-19 patients from tissue injuries, a protection that might be, at least partially, attributed to the anti-inflammatory, antioxidant and anti-apoptotic effects of the TCM under investigation. This review provides evidence and support for clinical treatment and novel drug research using TCM.     

Knowledge,attitude and practices of healthcare professionals of Riyadh,Saudi Arabia towards covid-19: A cross-sectional study

Background & objectivesCOVID-19 is an emerging pandemic that necessitates the implementation of effective infection prevention and control steps. The knowledge, attitudes, and practices (KAP) of healthcare professionals toward COVID-19 affect their compliance to prevention and control initiatives. During the evolving pandemic, we examined the KAP among healthcare professionals against COVID-19 in this research.Materials and methodsThis was a cross-sectional study conducted among Riyadh region health care professionals from the beginning of December 2020 to the end of February 2021 using a validated self-administered questionnaire. The knowledge questionnaire contained questions about COVID-19 clinical characteristics, prevention, and management. The evaluation of attitudes and practices included questions regarding actions and adjustments in COVID-19 response activities. Knowledge scores were measured and compared using demographic characteristics, as well as attitudes and practices toward COVID-19. Using SPSS-IBM 25, bivariate statistics were done to analyze the data.Results146 healthcare professionals completed the survey. Physicians were the most prominent party in the survey, accounting for 74 (51 percent), followed by nurses 44 (30 percent) and pharmacists 28 (19 percent). The participants' average age was 39.69 ± 8.48 years. The participant's mean knowledge, attitude, and practice scores were 11.43 ± 1.34, 3.89 ± 0.93, and 3.85 ± 0.81, respectively. With a positive attitude, the mean knowledge score was 11.52, and with proper practice, it was 11.32. With an improvement in knowledge, the attitude score increased significantly (r = 0.172, P = 0.001). Besides, there was a greater association between attitudes and practices (r = 0.170, P = 0.029). A significant enhancement in the practice score of the professionals was noted with an increase in knowledge score (r = 0.095, P = 0.010), an indicator for a positive correlation between practice and knowledge scores.Interpretation & conclusionHealthcare practitioners have a good understanding of COVID-19. Improved knowledge and a positive attitude toward COVID-19 infection are linked to appropriate practice. There is a need for more manpower, better COVID-19 management training, and strategies to reduce anxiety among healthcare professionals.     

Lycorine,a non-nucleoside RNA dependent RNA polymerase inhibitor,as potential treatment for emerging coronavirus infections

Background: Highly effective novel treatments need to be developed to suppress emerging coronavirus (CoV) infections such as COVID-19. The RNA dependent RNA polymerase (RdRp) among the viral proteins is known as an effective antiviral target. Lycorine is a phenanthridine Amaryllidaceae alkaloid isolated from the bulbs of Lycoris radiata (L'Hér.) Herb. and has various pharmacological bioactivities including antiviral function.Purpose: We investigated the direct-inhibiting action of lycorine on CoV's RdRp, as potential treatment for emerging CoV infections.Methods: We examined the inhibitory effect of lycorine on MERS-CoV, SARS-CoV, and SARS-CoV-2 infections, and then quantitatively measured the inhibitory effect of lycorine on MERS-CoV RdRp activity using a cell-based reporter assay. Finally, we performed the docking simulation with lycorine and SARS-CoV-2 RdRp.Results: Lycorine efficiently inhibited these CoVs with IC₅₀ values of 2.123 ± 0.053, 1.021 ± 0.025, and 0.878 ± 0.022 μM, respectively, comparable with anti-CoV effects of remdesivir. Lycorine directly inhibited MERS-CoV RdRp activity with an IC₅₀ of 1.406 ± 0.260 μM, compared with remdesivir's IC₅₀ value of 6.335 ± 0.731 μM. In addition, docking simulation showed that lycorine interacts with SARS-CoV-2 RdRp at the Asp623, Asn691, and Ser759 residues through hydrogen bonding, at which the binding affinities of lycorine (−6.2 kcal/mol) were higher than those of remdesivir (−4.7 kcal/mol).Conclusions: Lycorine is a potent non-nucleoside direct-acting antiviral against emerging coronavirus infections and acts by inhibiting viral RdRp activity; therefore, lycorine may be a candidate against the current COVID-19 pandemic.     

Prevalence and characteristics of malaria among COVID-19 individuals: A systematic review,meta-analysis,and analysis of case reports

BackgroundThe world population is currently at a very high risk of Coronavirus disease-2019 (COVID-19), caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). People who live in malaria-endemic areas and get infected by SARS-CoV-2 may be at increased risk of severe COVID-19 or unfavorable disease outcomes if they ignore their malaria status. Therefore, the present study aimed to synthesize, qualitatively and quantitatively, information on the prevalence and characteristics of malaria infection among COVID-19-infected individuals. The findings will help us better understand this particular comorbidity during the COVID-19 pandemic.MethodsThe systematic review protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO) with the identification number: CRD42021247521. We searched for studies reporting on the coinfection of COVID-19 and malaria in PubMed, Web of Science, and Scopus from inception to March 27, 2021 using Medical Subject Headings (MeSH) terms. The study’s methodological quality in the search output was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tools for cross-sectional study. The pooled prevalence of Plasmodium spp. infection among patients infected with COVID-19 was estimated using the random effect model and then graphically presented as forest plots. The heterogeneity among the included studies was assessed using Cochrane Q and I² statistics. The characteristics of patients co-infected with COVID-19 and malaria were derived from case reports and series and were formally analyzed using simple statistics.ResultsTwelve of 1,207 studies reporting the coinfection of COVID-19 and malaria were selected for further analysis. Results of quantitative synthesis show that the pooled prevalence of Plasmodium spp. infection (364 cases) among COVID–19 individuals (1,126 cases) is 11%, with a high degree of heterogeneity (95% CI: 4%–18%, I²: 97.07%, 5 studies). Most of the coinfections were reported in Nigeria (336 cases), India (27 cases), and the Democratic Republic of Congo (1 case). Results of qualitative synthesis indicate that patients with coinfection are typically symptomatic at presentation with mild or moderate parasitemia. An analysis of case reports and series indicates that co-infected individuals often display thrombocytopenia, lymphopenia, and elevated bilirubin levels. Among four patients (30%) who required treatment with intravenous artesunate, one experienced worsened clinical status after administering the drug. One serious outcome of coinfection involved a pregnant woman who experienced fetal abortion due to the initial misdiagnosis of malaria.ConclusionsAll individuals in malaria-endemic regions who are febrile or display symptoms of COVID-19 should be evaluated for malaria to avoid serious complications. Further prospective studies are required to investigate the burden and outcomes of COVID-19 in malaria-endemic regions. Prompt management is required to prevent serious outcomes in individuals co-infected with COVID-19 and malaria.     

Combination of obesity and co-morbidities leads to unfavorable outcomes in COVID-19 patients

ObjectiveObesity has been described as a significant independent risk factors of COVID-19. We aimed to study the association between obesity, co-morbidities and clinical outcomes of COVID-19.MethodsClinical data from 417 patients were collected retrospectively from the Al Kuwait Hospital, Ministry of Health and Prevention (MOHAP), Dubai, United Arab Emirates, who were admitted between March and June 2020. Patients were divided according to their body mass index (BMI). Various clinical outcomes were examined: presenting symptoms, severity, major co-morbidities, ICU admission, death, ventilation, ARDS, septic shock and laboratory parameters.ResultsThe average BMI was 29 ± 6.2 kg/m². BMI alone was not associated with the outcomes examined. However, class II obese patients had more co-morbidities compared to other groups. Hypertension was the most significant co-morbidity associated with obesity. Patients with BMI above the average BMI (29 kg/m²) and presence of underlying co-morbidities showed significant increase in admission to ICU compared to patients below 29 kg/m² and underlying co-morbidities (21.7% Vs. 9.2%), ARDS development (21.7% Vs. 10.53%), need for ventilation (8.3% Vs. 1.3%), and mortality (10% Vs. 1.3%).ConclusionsOur data suggests that presence of underlying co-morbidities and high BMI work synergistically to affect the clinical outcomes of COVID-19.     

COVID-19 May Increase the Risk of Insulin Resistance in Adult Patients Without Diabetes: A 6-Month Prospective Study

ObjectiveDuring the coronavirus disease 2019 (COVID-19) pandemic, exploring insulin resistance and beta-cell activity is important for understanding COVID-19‒associated new-onset diabetes. We assessed insulin sensitivity and fasting insulin secretion in patients with COVID-19 without diabetes on admission and at 3 and 6 months after discharge.MethodsThis 6-month prospective study assessed data from the records of 64 patients without diabetes diagnosed with COVID-19 at Wenzhou Central Hospital, China. Each patient was followed up at 3 and 6 months after discharge. Repeated measures analysis of variance was used to investigate differences in multiple measurements of the same variable at different times. Linear regression analysis was performed to analyze the contributor for changes in the triglyceride-glucose (TyG) index.ResultsFasting C-peptide levels in patients at baseline were lower than the normal range. Compared with the baseline results, patients had significantly elevated fasting C-peptide levels (0.35 ± 0.24 vs 2.36 ± 0.98 vs 2.52 ± 1.11 μg/L; P < .001), homeostasis model assessment for beta-cell function (0.42, interquartile range [IQR] 0.36-0.62 vs 2.54, IQR 1.95-3.42 vs 2.90, IQR 2.02-4.23; P < .001), and TyG indices (8.57 ± 0.47 vs 8.73 ± 0.60 vs 8.82 ± 0.62; P = .006) and decreased fasting glucose levels (5.84 ± 1.21 vs 4.95 ± 0.76 vs 5.40 ± 0.68 mmol/L; P = .003) at the 3- and 6-month follow-up. Male gender, age, interferon-alfa treatment during hospitalization, and changes in total cholesterol and high-density lipoprotein levels were significantly associated with changes in the TyG index.ConclusionOur study provided the first evidence that COVID-19 may increase the risk of insulin resistance in patients without diabetes.     

Antiviral activity of green tea and black tea polyphenols in prophylaxis and treatment of COVID-19: A review

BackgroundThe rapid spread of novel coronavirus called SARS-CoV-2 or nCoV has caused countries all over the world to impose lockdowns and undertake stringent preventive measures. This new positive-sense single-stranded RNA strain of coronavirus spreads through droplets of saliva and nasal discharge.PurposeUS FDA has authorized the emergency use of Remdesivir looking at the increasing number of cases of COVID-19, however there is still no drug approved to treat COVID-19. An alternative way of treatment could be the use of naturally derived molecules with known antiviral properties.MethodWe reviewed the antiviral activities of two polyphenols derived from tea, epigallocatechin-3-gallate (EGCG) from green tea and theaflavins from black tea. Both green tea and black tea polyphenols have been reported to exhibit antiviral activities against various viruses, especially positive-sense single-stranded RNA viruses.ResultsRecent studies have revealed the possible binding sites present on SARS-CoV-2 and studied their interactions with tea polyphenols. EGCG and theaflavins, especially theaflavin-3,3′-digallate (TF3) have shown a significant interaction with the receptors under consideration in this review. Some docking studies further emphasize on the activity of these polyphenols against COVID-19.ConclusionThis review summarizes the available reports and evidences which support the use of tea polyphenols as potential candidates in prophylaxis and treatment of COVID-19.     

Caffeic acid derivatives (CAFDs) as inhibitors of SARS-CoV-2: CAFDs-based functional foods as a potential alternative approach to combat COVID-19

BackgroundSARS-CoV-2, an emerging strain of coronavirus, has affected millions of people from all the continents of world and received worldwide attention. This emerging health crisis calls for the urgent development of specific therapeutics against COVID-19 to potentially reduce the burden of this emerging pandemic.PurposeThis study aims to evaluate the anti-viral efficacy of natural bioactive entities against COVID-19 via molecular docking and molecular dynamics simulation.MethodsA library of 27 caffeic-acid derivatives was screened against 5 proteins of SARS-CoV-2 by using Molegro Virtual Docker 7 to obtain the binding energies and interactions between compounds and SARS-CoV-2 proteins. ADME properties and toxicity profiles were investigated via www.swissadme.ch web tools and Toxtree respectively. Molecular dynamics simulation was performed to determine the stability of the lead-protein interactions.ResultsOur obtained results has uncovered khainaoside C, 6-O-Caffeoylarbutin, khainaoside B, khainaoside C and vitexfolin A as potent modulators of COVID-19 possessing more binding energies than nelfinavir against COVID-19 M^pro, Nsp15, SARS-CoV-2 spike S2 subunit, spike open state and closed state structure respectively. While Calceolarioside B was identified as pan inhibitor, showing strong molecular interactions with all proteins except SARS-CoV-2 spike glycoprotein closed state. The results are supported by 20 ns molecular dynamics simulations of the best complexes.ConclusionThis study will hopefully pave a way for development of phytonutrients-based antiviral therapeutic for treatment or prevention of COVID-19 and further studies are recommended to evaluate the antiviral effects of these phytochemicals against SARS-CoV-2 in in vitro and in vivo models.     

Molnupiravir,favipiravir and other antiviral drugs with proposed potentials for management of COVID-19: a concern on antioxidant aspect

COVID-19 is an important global public health problem that causes millions of infections worldwide. The specific antiviral drug for this new infection is still under research. Some new antiviral drugs, including molnupiravir and favipiravir, are proposed for usefulness in management of COVID-19. Additionally, some classic antiviral drugs used for other viral infections are also reproposed for the potentials for management of COVID-19. In the management of COVID-19, there are several pharmacological actions. An important consideration in antiviral therapy is the management of oxidative stress, which plays important roles in viral infections including to COVID-19. The analysis of antioxidative properties of alternative drugs for management of COVID-19 is interesting and can give basic data for further new antiviral drug researching. Here, the authors perform a molecular analysis on molnupiravir, favipiravir and other antiviral drugs with proposed potentials for management of COVID-19 to determine their antioxidative properties. Data from electron acceptor and donor calculation for each drug is used for further estimating overall antioxidative characteristic. Based on the present study, all studied drugs have overall antioxidative properties. Hence, the advantage of molnupiravir, favipiravir and other antiviral drugs with proposed potentials for the management of COVID-19 is their direct action on viral molecule via binding-blocking process as well as antixodiative process. For management of COVID-19 antioxidative stress, other non-antiviral drugs that are proposed for clinical advantage might also be useful.     

Bioactivity,bioavailability, and gut microbiota transformations of dietary phenolic compounds: implications for COVID-19

The outbreak of mysterious pneumonia at the end of 2019 is associated with widespread research interest worldwide. The coronavirus disease-19 (COVID-19) targets multiple organs through inflammatory, immune, and redox mechanisms, and no effective drug for its prophylaxis or treatment has been identified until now. The use of dietary bioactive compounds, such as phenolic compounds (PC), has emerged as a putative nutritional or therapeutic adjunct approach for COVID-19. In the present study, scientific data on the mechanisms underlying the bioactivity of PC and their usefulness in COVID-19 mitigation are reviewed. In addition, antioxidant, antiviral, anti-inflammatory, and immunomodulatory effects of dietary PC are studied. Moreover, the implications of digestion on the putative benefits of dietary PC against COVID-19 are presented by addressing the bioavailability and biotransformation of PC by the gut microbiota. Lastly, safety issues and possible drug interactions of PC and their implications in COVID-19 therapeutics are discussed.     

Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages

How the innate and adaptive host immune system miscommunicate to worsen COVID-19 immunopathology has not been fully elucidated. Here, we perform single-cell deep-immune profiling of bronchoalveolar lavage (BAL) samples from 5 patients with mild and 26 with critical COVID-19 in comparison to BALs from non-COVID-19 pneumonia and normal lung. We use pseudotime inference to build T-cell and monocyte-to-macrophage trajectories and model gene expression changes along them. In mild COVID-19, CD8⁺ resident-memory (T_RM) and CD4⁺ T-helper-17 (T_H17) cells undergo active (presumably antigen-driven) expansion towards the end of the trajectory, and are characterized by good effector functions, while in critical COVID-19 they remain more naïve. Vice versa, CD4⁺ T-cells with T-helper-1 characteristics (T_H1-like) and CD8⁺ T-cells expressing exhaustion markers (T_EX-like) are enriched halfway their trajectories in mild COVID-19, where they also exhibit good effector functions, while in critical COVID-19 they show evidence of inflammation-associated stress at the end of their trajectories. Monocyte-to-macrophage trajectories show that chronic hyperinflammatory monocytes are enriched in critical COVID-19, while alveolar macrophages, otherwise characterized by anti-inflammatory and antigen-presenting characteristics, are depleted. In critical COVID-19, monocytes contribute to an ATP-purinergic signaling-inflammasome footprint that could enable COVID-19 associated fibrosis and worsen disease-severity. Finally, viral RNA-tracking reveals infected lung epithelial cells, and a significant proportion of neutrophils and macrophages that are involved in viral clearance.Subject terms: Genome-wide analysis of gene expression, Innate immunity, Bioinformatics     

间充质干细胞在2019新型冠状病毒肺炎(COVID-19)中的治疗潜能、临床研究与应用前景*

当前因SARS-CoV-2感染而引起的2019新型冠状病毒肺炎(COVID-19)肆虐全球,严重危害人类健康。SARS-CoV-2感染性强,危重症患者死亡率高,尽管各种各样的治疗正在进行临床试验,但目前尚无有效的治疗方法。间充质干细胞(mesenchymal stem cell,MSC)在临床前试验中对多种疾病有良好的治疗效果,因而受到了广泛地关注。MSC可能利用分化潜能诱导分化成功能性肺样细胞、免疫调节与免疫细胞互作、抑制炎症来降低促炎细胞因子分泌、迁移和归巢靶向损伤肺部、抗病毒作用来减少肺上皮细胞中的病毒复制、产生细胞外囊泡来修复受损的组织,进而使COVID-19患者肺功能逐渐恢复正常,缓解并达到治疗COVID-19的目的。综合讨论了COVID-19的基本特征和当前主要治疗手段,同时总结了MSC在COVID-19中的临床研究和当前面临的挑战,探讨了MSC治疗COVID-19的应用前景,为MSC在COVID-19中的治疗提供了理论基础和现实依据。     

Detection of significant antiviral drug effects on COVID-19 with reasonable sample sizes in randomized controlled trials: A modeling study

BackgroundDevelopment of an effective antiviral drug for Coronavirus Disease 2019 (COVID-19) is a global health priority. Although several candidate drugs have been identified through in vitro and in vivo models, consistent and compelling evidence from clinical studies is limited. The lack of evidence from clinical trials may stem in part from the imperfect design of the trials. We investigated how clinical trials for antivirals need to be designed, especially focusing on the sample size in randomized controlled trials.Methods and findingsA modeling study was conducted to help understand the reasons behind inconsistent clinical trial findings and to design better clinical trials. We first analyzed longitudinal viral load data for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) without antiviral treatment by use of a within-host virus dynamics model. The fitted viral load was categorized into 3 different groups by a clustering approach. Comparison of the estimated parameters showed that the 3 distinct groups were characterized by different virus decay rates (p-value < 0.001). The mean decay rates were 1.17 d⁻¹ (95% CI: 1.06 to 1.27 d⁻¹), 0.777 d⁻¹ (0.716 to 0.838 d⁻¹), and 0.450 d⁻¹ (0.378 to 0.522 d⁻¹) for the 3 groups, respectively. Such heterogeneity in virus dynamics could be a confounding variable if it is associated with treatment allocation in compassionate use programs (i.e., observational studies).Subsequently, we mimicked randomized controlled trials of antivirals by simulation. An antiviral effect causing a 95% to 99% reduction in viral replication was added to the model. To be realistic, we assumed that randomization and treatment are initiated with some time lag after symptom onset. Using the duration of virus shedding as an outcome, the sample size to detect a statistically significant mean difference between the treatment and placebo groups (1:1 allocation) was 13,603 and 11,670 (when the antiviral effect was 95% and 99%, respectively) per group if all patients are enrolled regardless of timing of randomization. The sample size was reduced to 584 and 458 (when the antiviral effect was 95% and 99%, respectively) if only patients who are treated within 1 day of symptom onset are enrolled. We confirmed the sample size was similarly reduced when using cumulative viral load in log scale as an outcome.We used a conventional virus dynamics model, which may not fully reflect the detailed mechanisms of viral dynamics of SARS-CoV-2. The model needs to be calibrated in terms of both parameter settings and model structure, which would yield more reliable sample size calculation.ConclusionsIn this study, we found that estimated association in observational studies can be biased due to large heterogeneity in viral dynamics among infected individuals, and statistically significant effect in randomized controlled trials may be difficult to be detected due to small sample size. The sample size can be dramatically reduced by recruiting patients immediately after developing symptoms. We believe this is the first study investigated the study design of clinical trials for antiviral treatment using the viral dynamics model.

Using a viral dynamics model, Shingo Iwami and colleagues investigate the sample sizes required to detect significant antiviral drug effects on COVID-19 in randomized controlled trials.     

Effect and safety of Chinese herbal medicine granules in patients with severe coronavirus disease 2019 in Wuhan,China: a retrospective,single-center study with propensity score matching

BackgroundChinese herbal medicine (CHM) has been used for severe illness caused by coronavirus disease 2019 (COVID-19), but its treatment effects and safety are unclear.PurposeThis study reviews the effect and safety of CHM granules in the treatment of patients with severe COVID-19.MethodsWe conducteda single-center, retrospective study on patients with severe COVID-19 in a designated hospital in Wuhan from January 15, 2020 to March 30, 2020. The propensity score matching (PSM) was used to assess the effect and safety of the treatment using CHM granules. The ratio of patients who received treatment with CHM granules combined with usual care and those who received usual care alone was 1:1. The primary outcome was the time to clinical improvement within 28 days, defined as the time taken for the patients’ health to show improvement by decline of two categories (from the baseline) on a modified six-category ordinal scale, or to be dischargedfrom the hospital before Day 28.ResultsUsing PSM, 43 patients (45% male) aged 65.6 (57–70) yearsfrom each group were exactly matched. No significant difference was observed in clinical improvement of patients treated with CHM granules compared with those who received usual (p = 0.851). However, the use of CHM granules reduced the 28-day mortality (p = 0.049) and shortened the duration of fever (4 days vs. 7 days, p = 0.002). The differences in the duration of cough and dyspnea and the difference in lung lesion ratio on computerized tomography scans were not significant.Commonly,patients in the CHM group had an increased D-dimer level (p = 0.036).ConclusionForpatients with severe COVID-19, CHM granules, combined with usual care, showed no improvement beyond usual care alone. However, the use of CHM granules reduced the 28-day mortality rate and the time to fever alleviation. Nevertheless, CHM granules may be associated with high risk of fibrinolysis.     

Euthyroid Sick Syndrome as a Prognostic Indicator of COVID-19 Pulmonary Involvement,Associated With Poorer Disease Prognosis and Increased Mortality

ObjectiveThe prevalence of euthyroid sick syndrome (ESS) and its association with the prognosis of COVID-19 and mortality in patients with lung involvement in COVID-19 have not yet been elucidated.MethodsClinical and laboratory data of patients with COVID-19 with or without ESS were collected retrospectively and analyzed on admission. All subjects were admitted to the Department of Internal Diseases and Clinical Pharmacology at Bieganski Hospital between December 2020 and April 2021.ResultsIn total, 310 medical records of patients with COVID-19 were analyzed retrospectively. Among 215 enrolled patients, 82 cases of ESS were diagnosed. The patients with ESS had higher pro-inflammatory factor levels, longer hospitalizations, and a higher risk of requiring high-flow nasal oxygen therapy or intubation than the patients without ESS. The Kaplan-Meier curve indicated that the patients with ESS had a lower probability of survival when computed tomography showed ≤50% parenchymal involvement compared with that in patients without ESS. However, no differences in mortality were noted in those with more than 50% parenchymal involvement. The survival curve showed that ESS was associated with a higher risk of mortality during hospitalization.ConclusionESS is closely associated with a poor prognosis, including longer hospitalizations, more frequent intubation, transfer to the intensive care unit, and a higher mortality rate in patients with COVID-19. ESS is a potential prognostic predictor of survival, regardless of lung involvement in COVID-19.