Uncovering the pharmacological mechanisms of Xijiao Dihuang decoction combined with Yinqiao powder in treating influenza viral pneumonia by an integrative pharmacology strategy.

Xijiao Dihuang decoction combined with Yinqiao powder (XDD-YQP) is a classical combination formula; however, its therapeutic effects in treating influenza viral pneumonia and the pharmacological mechanisms remain unclear. The therapeutic effect of XDD-YQP in influenza viral pneumonia was evaluated in mice. Subsequently, an everted gut sac model coupled with UPLC/Q-TOF MS were used to screen and identify the active compounds of XDD-YQP. Furthermore, network pharmacological analysis was adopted to probe the mechanisms of the active compounds. Lastly, we verified the targets predicted from network pharmacological analysis by differential bioinformatics analysis. Animal experiments showed that XDD-YQP has a therapeutic effect on influenza viral pneumonia. Moreover, 113 active compounds were identified from intestinal absorbed solutions of XDD-YQP. Using network pharmacological analysis, 90 major targets were selected as critical in the treatment of influenza viral pneumonia through 12 relevant pathways. Importantly, the MAPK signaling pathway was found to be closely associated with the other 11 pathways. Moreover, seven key targets, EGFR, FOS, MAPK1, MAP2K1, HRAS, NRAS, and RELA, which are common targets in the MAPK signaling pathway, were investigated. These seven key targets were identified as differentially expressed genes (DEGs) between influenza virus-infected and uninfected individuals. Hence, the seven key targets in the MAPK signaling pathway may play a vital role in the treatment of influenza viral pneumonia with XDD-YQP. This research may offer an integrative pharmacology strategy to clarify the pharmacological mechanisms of traditional Chinese medicines. The results provide a theoretical basis for a broader clinical application of XDD-YQP.

Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial.

BACKGROUND: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. METHODS: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. FINDINGS: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care. INTERPRETATION: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study. FUNDING: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.

Possible role of vitamin D in Covid-19 infection in pediatric population.

PURPOSE: Covid-19 is a pandemic of unprecedented proportion, whose understanding and management is still under way. In the emergency setting new or available therapies to contrast the spread of COVID-19 are urgently needed. Elderly males, especially those affected by previous diseases or with comorbidities, are more prone to develop interstitial pneumonia that can deteriorate evolving to ARDS (acute respiratory distress syndrome) that require hospitalization in Intensive Care Units (ICUs). Even children and young patients are not spared by SARS-CoV 2 infection, yet they seem to develop a milder form of disease. In this setting the immunomodulatory role of Vitamin D, should be further investigated. METHODS: We reviewed the literature about the immunomodulatory role of Vitamin D collecting data from the databases Medline and Embase. RESULTS: Vitamin D proved to interact both with the innate immune system, by activating Toll-like receptors (TLRs) or increasing the levels of cathelicidins and ß-defensins, and adaptive immune system, by reducing immunoglobulin secretion by plasma cells and pro-inflammatory cytokines production, thus modulating T cells function. Promising results have been extensively described as regards the supplementation of vitamin D in respiratory tract infections, autoimmune diseases and even pulmonary fibrosis. CONCLUSIONS: In this review, we suggest that vitamin D supplementation might play a role in the prevention and/or treatment to SARS-CoV-2 infection disease, by modulating the immune response to the virus both in the adult and pediatric population.

Flow in the time of COVID-19: Findings from China.

In February 2020, the Novel Coronavirus (COVID-19) was raging in Wuhan, China and quickly spreading to the rest of the world. This period was fraught with uncertainty for those in the affected areas. The present investigation examined the role of two potential coping resources during this stressful period of uncertainty: flow and mindfulness. Participants in Wuhan and other major cities affected by COVID-19 (N = 5115) completed an online survey assessing subjective experiences of flow, mindfulness, and well-being. Longer quarantine was associated with poorer well-being; flow and mindfulness were associated with better well-being on some measures. However, flow-but not mindfulness-moderated the link between quarantine length and well-being, such that people who experienced high levels flow showed little or no association between quarantine length and poorer well-being. These findings suggest that experiencing flow (typically by engaging in flow-inducing activities) may be a particularly effective way to protect against potentially deleterious effects of a period of quarantine.

Application of Humanized Zebrafish Model in the Suppression of SARS-CoV-2 Spike Protein Induced Pathology by Tri-Herbal Medicine Coronil via Cytokine Modulation.

Zebrafish has been a reliable model system for studying human viral pathologies. SARS-CoV-2 viral infection has become a global chaos, affecting millions of people. There is an urgent need to contain the pandemic and develop reliable therapies. We report the use of a humanized zebrafish model, xeno-transplanted with human lung epithelial cells, A549, for studying the protective effects of a tri-herbal medicine Coronil. At human relevant doses of 12 and 58 µg/kg, Coronil inhibited SARS-CoV-2 spike protein, induced humanized zebrafish mortality, and rescued from behavioral fever. Morphological and cellular abnormalities along with granulocyte and macrophage accumulation in the swim bladder were restored to normal. Skin hemorrhage, renal cell degeneration, and necrosis were also significantly attenuated by Coronil treatment. Ultra-high-performance liquid chromatography (UHPLC) analysis identified ursolic acid, betulinic acid, withanone, withaferine A, withanoside IV-V, cordifolioside A, magnoflorine, rosmarinic acid, and palmatine as phyto-metabolites present in Coronil. In A549 cells, Coronil attenuated the IL-1ß induced IL-6 and TNF-α cytokine secretions, and decreased TNF-α induced NF-κB/AP-1 transcriptional activity. Taken together, we show the disease modifying immunomodulatory properties of Coronil, at human equivalent doses, in rescuing the pathological features induced by the SARS-CoV-2 spike protein, suggesting its potential use in SARS-CoV-2 infectivity.

Structure-based lead optimization of herbal medicine rutin for inhibiting SARS-CoV-2's main protease.

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic with very limited specific treatments. To fight COVID-19, various traditional antiviral medicines have been prescribed in China to infected patients with mild to moderate symptoms and received unexpected success in controlling the disease. However, the molecular mechanisms of how these herbal medicines interact with the SARS-CoV-2 virus that causes COVID-19 have remained elusive. It is well known that the main protease (Mpro) of SARS-CoV-2 plays an important role in maturation of many viral proteins such as the RNA-dependent RNA polymerase. Here, we explore the underlying molecular mechanisms of the computationally determined top candidate, namely, rutin which is a key component in many traditional antiviral medicines such as Lianhuaqinwen and Shuanghuanlian, for inhibiting the viral target-Mpro. Using in silico methods (docking and molecular dynamics simulations), we revealed the dynamics and energetics of rutin when interacting with the Mpro of SARS-CoV-2, suggesting that the highly hydrophilic rutin molecule can be bound inside the Mpro's pocket (active site) and possibly inhibit its biological functions. In addition, we optimized the structure of rutin and designed two more hydrophobic analogs, M1 and M2, which satisfy the rule of five for western medicines and demonstrated that they (M2 in particular) possess much stronger binding affinities to the SARS-COV-2s Mpro than rutin, due to the enhanced hydrophobic interaction as well as more hydrogen bonds. Therefore, our results provide invaluable insights into the mechanism of a ligand's binding inside the Mpro and shed light on future structure-based designs of high-potent inhibitors for SARS-CoV-2 Mpro.

COSMO-RS-Based Descriptors for the Machine Learning-Enabled Screening of Nucleotide Analogue Drugs against SARS-CoV-2.

Chemical similarity-based approaches employed to repurpose or develop new treatments for emerging diseases, such as COVID-19, correlates molecular structure-based descriptors of drugs with those of a physiological counterpart or clinical phenotype. We propose novel descriptors based on a COSMO-RS (short for conductor-like screening model for real solvents) σ-profiles for enhanced drug screening enabled by machine learning (ML). The descriptors' performance is hereby illustrated for nucleotide analogue drugs that inhibit the ribonucleic acid-dependent ribonucleic acid polymerase, key to viral transcription and genome replication. The COSMO-RS-based descriptors account for both chemical reactivity and structure, and are more effective for ML-based screening than fingerprints based on molecular structure and simple physical/chemical properties. The descriptors are evaluated using principal component analysis, an unsupervised ML technique. Our results correlate with the active monophosphate forms of the leading drug remdesivir and the prospective drug EIDD-2801 with nucleotides, followed by other promising drugs, and are superior to those from molecular structure-based descriptors and molecular docking. The COSMO-RS-based descriptors could help accelerate drug discovery for the treatment of emerging diseases.

Bioactive Natural Antivirals: An Updated Review of the Available Plants and Isolated Molecules.

Viral infections and associated diseases are responsible for a substantial number of mortality and public health problems around the world. Each year, infectious diseases kill 3.5 million people worldwide. The current pandemic caused by COVID-19 has become the greatest health hazard to people in their lifetime. There are many antiviral drugs and vaccines available against viruses, but they have many disadvantages, too. There are numerous side effects for conventional drugs, and active mutation also creates drug resistance against various viruses. This has led scientists to search herbs as a source for the discovery of more efficient new antivirals. According to the World Health Organization (WHO), 65% of the world population is in the practice of using plants and herbs as part of treatment modality. Additionally, plants have an advantage in drug discovery based on their long-term use by humans, and a reduced toxicity and abundance of bioactive compounds can be expected as a result. In this review, we have highlighted the important viruses, their drug targets, and their replication cycle. We provide in-depth and insightful information about the most favorable plant extracts and their derived phytochemicals against viral targets. Our major conclusion is that plant extracts and their isolated pure compounds are essential sources for the current viral infections and useful for future challenges.

Immune-Boosting, Antioxidant and Anti-inflammatory Food Supplements Targeting Pathogenesis of COVID-19.

The COVID-19 is an acute and contagious disease characterized by pneumonia and ARDS. The disease is caused by SARS-CoV-2, which belongs to the family of Coronaviridae along with MERS-CoV and SARS-CoV-1. The virus has the positive-sense RNA as its genome encoding for ~26 proteins that work together for the virus survival, replication, and spread in the host. The virus gets transmitted through the contact of aerosol droplets from infected persons. The pathogenesis of COVID-19 is highly complex and involves suppression of host antiviral and innate immune response, induction of oxidative stress followed by hyper inflammation described as the "cytokine storm," causing the acute lung injury, tissue fibrosis, and pneumonia. Currently, several vaccines and drugs are being evaluated for their efficacy, safety, and for determination of doses for COVID-19 and this requires considerable time for their validation. Therefore, exploring the repurposing of natural compounds may provide alternatives against COVID-19. Several nutraceuticals have a proven ability of immune-boosting, antiviral, antioxidant, anti-inflammatory effects. These include Zn, vitamin D, vitamin C, curcumin, cinnamaldehyde, probiotics, selenium, lactoferrin, quercetin, etc. Grouping some of these phytonutrients in the right combination in the form of a food supplement may help to boost the immune system, prevent virus spread, preclude the disease progression to severe stage, and further suppress the hyper inflammation providing both prophylactic and therapeutic support against COVID-19.

Clinical outcomes of coronavirus disease 2019 in patients with pre-existing liver diseases: A multicenter study in South Korea.

BACKGROUND/AIMS: Although coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, the implication of pre-existing liver disease on the outcome of COVID-19 remains unresolved.
. METHODS: A total of 1,005 patients who were admitted to five tertiary hospitals in South Korea with laboratory-confirmed COVID-19 were included in this study. Clinical outcomes in COVID-19 patients with coexisting liver disease as well as the predictors of disease severity and mortality of COVID-19 were assessed.
. RESULTS: Of the 47 patients (4.7%) who had liver-related comorbidities, 14 patients (1.4%) had liver cirrhosis. Liver cirrhosis was more common in COVID-19 patients with severe pneumonia than in those with non-severe pneumonia (4.5% vs. 0.9%, P=0.006). Compared to patients without liver cirrhosis, a higher proportion of patients with liver cirrhosis required oxygen therapy; were admitted to the intensive care unit; had septic shock, acute respiratory distress syndrome, or acute kidney injury; and died (P<0.05). The overall survival rate was significantly lower in patients with liver cirrhosis than in those without liver cirrhosis (log-rank test, P=0.003). Along with old age and diabetes, the presence of liver cirrhosis was found to be an independent predictor of severe disease (odds ratio, 4.52; 95% confidence interval [CI], 1.20-17.02;P=0.026) and death (hazard ratio, 2.86; 95% CI, 1.04-9.30; P=0.042) in COVID-19 patients.
. CONCLUSION: This study suggests liver cirrhosis is a significant risk factor for COVID-19. Stronger personal protection and more intensive treatment for COVID-19 are recommended in these patients.

Vitamin D and survival in COVID-19 patients: A quasi-experimental study.

Vitamin D may be a central biological determinant of COVID-19 outcomes. The objective of this quasi-experimental study was to determine whether bolus vitamin D3 supplementation taken during or just before COVID-19 was effective in improving survival among frail elderly nursing-home residents with COVID-19. Sixty-six residents with COVID-19 from a French nursing-home were included in this quasi-experimental study. The "Intervention group" was defined as those having received bolus vitamin D3 supplementation during COVID-19 or in the preceding month, and the "Comparator group" corresponded to all other participants. The primary and secondary outcomes were COVID-19 mortality and Ordinal Scale for Clinical Improvement (OSCI) score in acute phase, respectively. Age, gender, number of drugs daily taken, functional abilities, albuminemia, use of corticosteroids and/or hydroxychloroquine and/or antibiotics (i.e., azithromycin or rovamycin), and hospitalization for COVID-19 were used as potential confounders. The Intervention (n = 57; mean ± SD, 87.7 ± 9.3years; 79 %women) and Comparator (n = 9; mean, 87.4 ± 7.2years; 67 %women) groups were comparable at baseline, as were the COVID-19 severity and the use of dedicated COVID-19 drugs. The mean follow-up time was 36 ± 17 days. 82.5 % of participants in the Intervention group survived COVID-19, compared to only 44.4 % in the Comparator group (P = 0.023). The full-adjusted hazard ratio for mortality according to vitamin D3 supplementation was HR = 0.11 [95 %CI:0.03;0.48], P = 0.003. Kaplan-Meier distributions showed that Intervention group had longer survival time than Comparator group (log-rank P = 0.002). Finally, vitamin D3 supplementation was inversely associated with OSCI score for COVID-19 (ß=-3.84 [95 %CI:-6.07;-1.62], P = 0.001). In conclusion, bolus vitamin D3 supplementation during or just before COVID-19 was associated in frail elderly with less severe COVID-19 and better survival rate.

Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2.

Angiotensin converting enzyme 2 (ACE2) (EC:3.4.17.23) is a transmembrane protein which is considered as a receptor for spike protein binding of novel coronavirus (SARS-CoV2). Since no specific medication is available to treat COVID-19, designing of new drug is important and essential. In this regard, in silico method plays an important role, as it is rapid and cost effective compared to the trial and error methods using experimental studies. Natural products are safe and easily available to treat coronavirus affected patients, in the present alarming situation. In this paper five phytochemicals, which belong to flavonoid and anthraquinone subclass, have been selected as small molecules in molecular docking study of spike protein of SARS-CoV2 with its human receptor ACE2 molecule. Their molecular binding sites on spike protein bound structure with its receptor have been analyzed. From this analysis, hesperidin, emodin and chrysin are selected as competent natural products from both Indian and Chinese medicinal plants, to treat COVID-19. Among them, the phytochemical hesperidin can bind with ACE2 protein and bound structure of ACE2 protein and spike protein of SARS-CoV2 noncompetitively. The binding sites of ACE2 protein for spike protein and hesperidin, are located in different parts of ACE2 protein. Ligand spike protein causes conformational change in three-dimensional structure of protein ACE2, which is confirmed by molecular docking and molecular dynamics studies. This compound modulates the binding energy of bound structure of ACE2 and spike protein. This result indicates that due to presence of hesperidin, the bound structure of ACE2 and spike protein fragment becomes unstable. As a result, this natural product can impart antiviral activity in SARS CoV2 infection. The antiviral activity of these five natural compounds are further experimentally validated with QSAR study.

Perspective: The Potential Effects of Naringenin in COVID-19.

Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), was declared a pandemic by the World Health Organization in March 2020. Severe COVID-19 cases develop severe acute respiratory syndrome, which can result in multiple organ failure, sepsis, and death. The higher risk group includes the elderly and subjects with pre-existing chronic illnesses such as obesity, hypertension, and diabetes. To date, no specific treatment or vaccine is available for COVID-19. Among many compounds, naringenin (NAR) a flavonoid present in citrus fruits has been investigated for antiviral and anti-inflammatory properties like reducing viral replication and cytokine production. In this perspective, we summarize NAR potential anti-inflammatory role in COVID-19 associated risk factors and SARS-CoV-2 infection.

Nutraceuticals as immune-stimulating therapy to fight COVID-19. Combination of elements to improve the efficacy.

COVID-19 pandemic has underlined that unknown viral infections, which jump from animals to humans, can be extremely dangerous. In case of new viruses as SARS-CoV2, available drugs can fail to contrast the virus aggressiveness leading patients to death. Long time is necessary to create a vaccine, but immediate solutions are necessary to stop the mortality COVID-19 related. We have learned that the immune-system is the key to reduce the severity of COVID-19 and, through its modulation, it has been possible saving people's life. In this short communication, we discuss the use of nutraceuticals to modulate and stimulate the immune answer for reducing the severity of COVID-19 symptoms. The nutraceuticals are safe and can be administered to all ages. In addition, combination of natural anti-viral elements and immune-stimulating molecules already successfully tested against others upper-respiratory tract infections-could be efficient against SARS-CoV2. We believe that these natural molecules could really be a valid ally against COVID-19, especially in this moment in which a SARS-CoV2 vaccine is still not available.

A child infected with severe acute respiratory syndrome coronavirus 2 presenting with diarrhea without fever and cough: A case report.

RATIONALE: Coronavirus disease 2019 (COVID-19), now a global pandemic, has spread to a large number of countries around the world. Symptoms of COVID-19 can range from mild to severe, including fever, cough, shortness of breath, and pneumonia. Some cases even remain asymptomatic. Data regarding the epidemiological and clinical features of children with COVID-19 are limited. Symptoms in children are thought to be atypical when compared with adults. As a result, diagnosis in many children is likely to be missed. Children presenting with atypical symptoms, especially those with a history of exposure, should be referred to early screening. PATIENT CONCERNS: A 23-month-old boy presented with a 2-day history of diarrhea. Chest computed tomography scan showed pneumonia. After admission to the hospital, the patient exhibited no diarrhea or other symptoms. Positive presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, was confirmed by 5 consecutive rounds of nucleic acid amplification testing of nasopharyngeal swabs. The patient was also found to have liver damage. DIAGNOSIS: Swabs were obtained for detection of SARS-CoV-2 RNA by established methods. INTERVENTIONS: Chinese traditional medicine prescription OUTCOMES:: Following treatment, signs of pneumonia on computed tomography scans were observed to be partially absorbed, and 2 consecutive rounds of nucleic acid amplification testing of swab samples were negative. The patient was discharged on the 21st day after admission to the hospital. On the 21st day after discharge, the patient had no recurrence of disease, no recurrence of pulmonary lesions, and normal liver function. CONCLUSION: This case study suggests that diarrhea not explained by common causes, such as acute gastroenteritis, could be a preliminary symptom of SARS-CoV-2 infection in children. Despite the lack of the presence of a fever or cough, lung pulmonary lesions were present in this child. SARS-CoV-2 infection may also cause hepatic injury. Even during the SARS-CoV-2 pneumonia recovery period, IgM and IgG antibodies can be positive for a long time.

Light-based technologies for management of COVID-19 pandemic crisis.

The global dissemination of the novel coronavirus disease (COVID-19) has accelerated the need for the implementation of effective antimicrobial strategies to target the causative agent SARS-CoV-2. Light-based technologies have a demonstrable broad range of activity over standard chemotherapeutic antimicrobials and conventional disinfectants, negligible emergence of resistance, and the capability to modulate the host immune response. This perspective article identifies the benefits, challenges, and pitfalls of repurposing light-based strategies to combat the emergence of COVID-19 pandemic.

Traditional Chinese medicine for symptoms of upper respiratory tract of COVID-19: A protocol for systematic review and meta-analysis.

BACKGROUND: Assessing the effectiveness and safety of traditional Chinese medicine (TCM) for symptoms of upper respiratory tract of coronavirus disease 2019 is the main purpose of this systematic review protocol. METHODS: The following electronic databases will be searched from inception to Sep 2020: the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, TCM, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Chinese Scientific Journal Database (VIP database), and Wan-Fang Database. Search dates: from inception dates to June 2020. Language: English. Publication period: from inception dates to June 2020. The primary outcome is the time and rate of appearance of main symptoms (including coughing, pharyngalgia, and nasal obstruction). The secondary outcome is the length of hospital stay. Two independent reviewers will conduct the study selection, data extraction and assessment. RevMan V.5.3 will be used for the assessment of risk of bias and data synthesis. RESULTS: The results will provide a high-quality synthesis of current evidence for researchers in this subject area. CONCLUSION: The conclusion of our study will provide an evidence to judge whether TCM is effective and safe for the patients with symptoms of upper respiratory tract of coronavirus disease 2019. ETHICS AND DISSEMINATION: This protocol will not evaluate individual patient information or affect patient rights and therefore does not require ethical approval. Results from this review will be disseminated through peer-reviewed journals and conference reports. PROSPERO REGISTRATION NUMBER: CRD42020187422.