SuperNatural 3.0-a database of natural products and natural product-based derivatives.

Natural products (NPs) are single chemical compounds, substances or mixtures produced by a living organism - found in nature. Evolutionarily, NPs have been used as healing agents since thousands of years and still today continue to be the most important source of new potential therapeutic preparations. Natural products have played a key role in modern drug discovery for several diseases. Furthermore, following consumers' increasing demand for natural food ingredients, many efforts have been made to discover natural low-calorie sweeteners in recent years. SuperNatural 3.0 is a freely available database of natural products and derivatives. The updated version contains 449 058 natural compounds along with their structural and physicochemical information. Additionally, information on pathways, mechanism of action, toxicity, vendor information if available, drug-like chemical space prediction for several diseases as antiviral, antibacterial, antimalarial, anticancer, and target specific cells like the central nervous system (CNS) are also provided for the natural compounds. The updated version of the database also provides a valuable pool of natural compounds in which potential highly sweet compounds are expected to be found. The possible taste profile of the natural compounds was predicted using our published VirtualTaste models. The SuperNatural 3.0 database is freely available via http://bioinf-applied.charite.de/supernatural_3, without any login or registration.

Increased incidence of adult-onset Still's disease in association with COVID-19 vaccination and SARS-CoV-2 infection.

BACKGROUND: Adult-onset Still's disease (AOSD) is a multi-system, auto-inflammatory disease characterized by fever, arthralgia, typical rash, leukocytosis, sore throat, and liver dysfunction, among other symptoms. Retrospective studies about the frequencies of AOSD have shown that this disease is very rare. However, there has been an increased scientific interest in the last 2 years, as numerous case studies on AOSD have been published. These case studies describe the occurrence of AOSD after SARS-CoV-2 infection and/or COVID-19 vaccination. METHODS: We analyzed the incidence of AOSD to examine a potential association between AOSD and SARS-CoV-2 infection and/or COVID-19 vaccination. The TriNetX dataset consists of 90 million patients. We found 8474 AOSD cases, which we analyzed regarding SARS-CoV-2 infection and/or vaccination status. We also analyzed the cohorts considering demographic data, lab values, co-diagnoses and treatment pathways. RESULTS: We divided the AOSD cases into four cohorts: primary cohort (AOSD), Cov cohort (AOSD + SARS-CoV-2 infection), Vac cohort (AOSD + COVID-19 vaccination) and Vac + Cov cohort (AOSD + COVID-19 vaccination + SARS-CoV-2 infection). For the primary cohort, we found an annual incidence of 0.35 per 100.000. We found an association between AOSD and SARS-CoV-2 infection and/or COVID-19 vaccination. According to the numerical analysis, the incidence of AOSD doubled for the Cov cohort and Vac cohort. Moreover, the incidence of AOSD was 4.82 times higher for Vac + Cov cohort. The lab values for inflammatory markers were increased. Co-diagnoses such as rash, sore throat, and fever appeared in all AOSD cohorts, with the highest occurrences in the AOSD + COVID-19 vaccination + SARS-CoV-2 infection cohort. We identified several lines of treatments, mainly in association with adrenal corticosteroids. CONCLUSIONS: This research supports the assumption of an association between AOSD and SARS-CoV-2 infection and/or COVID-19 vaccination. However, AOSD remains a rare disease and the usage of vaccines to fight the COVID-19 pandemic should not be questioned because of the increased incidence of AOSD.

Dupilumab use is associated with protection from COVID-19 mortality: A retrospective analysis.

We previously found that type 2 immunity promotes COVID-19 pathogenesis in a mouse model. To test relevance to human disease we used electronic health record databases and determined that patients on dupilumab (anti-IL-4R monoclonal antibody that blocks IL-13 and IL-4 signaling) at the time of COVID-19 infection had lower mortality.

Comparison of Computerized Prescription Support Systems in COVID-19 Patients: INTERCheck and Drug-PIN.

The coronavirus disease 19 (COVID-19) infection requires major efforts in healthcare systems, due to the high risk of mortality, particularly in subjects with significant comorbidity (≥ 2 pathologies) and polypharmacy (≥ 5 drugs). The treatment of COVID-19 needs a careful evaluation, to reduce the risk of potentially adverse drug reactions. The aim of the study was to examine the use of computerized prescription support in the management and treatment of the COVID-19 infection. We evaluated n.33 patients (51% females) admitted to the west COVID Low-Medium Intensity of Care of Sant'Andrea Hospital during the period March-April 2020 and n.42 subjects (50% females) admitted to the Internal Medicine ward (as control group), by INTERCheck® and Drug-PIN®. The comorbidity (n. pathologies), polypharmacy (n. drugs), and total INTERCheck score in COVID-19 patients and controls were, respectively (mean ± standard deviation): 5.8 ± 3.8, 7.9 ± 4.5, and 9.2 ± 7.1 and 6.8 ± 2.6, 8.0 ± 2.6, and 4.9 ± 3.8 (statistically significant for comorbidity p < 0.01 and INTERCheck score p < 0.01). The correlation between the scores obtained by the INTERCheck and Drug-PIN software was statistically significant, either at admission (p < 0.0000001) or during hospitalization (p < 0.00000001). Both the computerized prescription support systems, INTERCheck® and Drug-PIN®, are useful to better characterize the patients and to ameliorate the drugs prescriptions in COVID-19 infection, with particular attention to the elderly population.

Onset of Oral Lichenoid Lesions and Oral Lichen Planus Following COVID-19 Vaccination: A Retrospective Analysis of about 300,000 Vaccinated Patients.

INTRODUCTION: Onset of oral lichenoid lesions (OLL) or oral lichen planus (OLP) can be rare adverse reactions to vaccines. Recently, the first solitary cases were reported after COVID-19 vaccination. The aim of the present study was to assess if an increased frequency of OLL/OLP can be found after COVID-19 vaccination within a large real-world cohort. It was assumed that the incidence of OLL/OLP was significantly higher in subjects who received COVID-19 vaccine (cohort I) compared to individuals who were not vaccinated (cohort II). PATIENTS AND METHODS: Initial cohorts of 274,481 vaccinated and 9,429,892 not vaccinated patients were retrieved from the TriNetX database (TriNetX, Cambridge, Massachusetts, USA), and matched for age, gender and the frequency of use of non-steroidal anti-inflammatory drugs, beta blockers, and angiotensin-converting enzyme inhibitors. RESULTS: After matching each cohort, we accounted for 217,863 patients. Among cohort I, 146 individuals had developed OLL/OLP within 6 days after COVID-19 vaccination (88 and 58 subjects had received mRNA- and adenovirus vector-based vaccines), whereas in cohort II, 59 patients were newly diagnosed with OLL/OLP within 6 days after having visited the clinic for any other reason. The risk of developing OLL/OLP was calculated as 0.067% vs. 0.027%, for cohorts I and II, whereby the risk difference was highly significant (p < 0.001; log-rank test). RR and OR were 2.475 (95% CI = 1.829; 3.348) and 2.476 (95% CI = 1.830; 3.350), respectively. DISCUSSION: The hypothesis was confirmed. Accordingly, the obtained results suggest that the onset of OLL/OLP is a rare adverse drug reaction to COVID-19 vaccines, especially to mRNA vaccines. Thus far, it remains unknown if specific components of the formulations cause a type IV hypersensitive reaction corresponding to OLL, or if the immune response post vaccination triggers a T cell-driven autoimmune reaction directed against the basal layer of keratinocytes of the oral mucosa in terms of OLP. Although OLL and OLP are both classified as premalignant lesions, spontaneous remission may be expected over time, at least in the case of OLL. Therefore, the presented findings should not place any limitation toward the use of COVID-19-vaccines in broad levels of the population.

A Comparative Analysis of COVID-19 Vaccines Based on over 580,000 Cases from the Vaccination Adverse Event Reporting System.

BACKGROUND: The COVID-19 pandemic is being battled via the largest vaccination campaign in history, with more than eight billion doses administered thus far. Therefore, discussions about potentially adverse reactions, and broader safety concerns, are critical. The U.S. Vaccination Adverse Event Reporting System (VAERS) has recorded vaccination side effects for over 30 years. About 580,000 events have been filed for COVID-19 thus far, primarily for the Johnson & Johnson (New Jersey, USA), Pfizer/BioNTech (Mainz, Germany), and Moderna (Cambridge, USA) vaccines. METHODS: Using available databases, we evaluated these three vaccines in terms of the occurrence of four generally-noticed adverse reactions-namely, cerebral venous sinus thrombosis, Guillain-Barré syndrome (a severe paralytic neuropathy), myocarditis, and pericarditis. Our statistical analysis also included a calculation of odds ratios (ORs) based on total vaccination numbers, accounting for incidence rates in the general population. RESULTS: ORs for a number of adverse events and patient groups were (largely) increased, most notably for the occurrence of cerebral venous sinus thrombosis after vaccination with the Johnson & Johnson vaccine. The overall population OR of 10 increases to 12.5 when limited to women, and further yet (to 14.4) among women below age 50 yrs. In addition, elevated risks were found (i) for Guillain-Barré syndrome (OR of 11.6) and (ii) for myocarditis/pericarditis (ORs of 5.3/4.1, respectively) among young men (<25 yrs) vaccinated with the Pfizer/BioNTech vaccine. CONCLUSIONS: Any conclusions from such a retrospective, real-world data analysis must be drawn cautiously, and should be confirmed by prospective double-blinded clinical trials. In addition, we emphasize that the adverse events reported here are not specific side effects of COVID vaccines, and the significant, well-established benefits of COVID-19 vaccination outweigh the potential complications surveyed here.

Sensitive to Infection but Strong in Defense-Female Sex and the Power of Oestradiol in the COVID-19 Pandemic.

The incidence of SARS-CoV2 infections is around 15% higher in premenopausal women compared to age matched men, yet the fatality rate from COVID-19 is significantly higher in men than women for all age strata. Sex differences have also been observed in recent epidemics including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), with SARS-CoV 2 virus infection sex differences appear more dramatic. The regulation and expression of the angiotensin converting enzyme 2 (ACE2) is the key for this special coronavirus SARS-CoV-2 to enter the cell. 17ß-oestradiol increases expression level and activity of angiotensin converting enzyme-2 (ACE2) and the alternative signaling pathway of Ang II via the angiotensin II receptor type II (AT2R) and the Mas receptor is more dominant in female sex than in male sex. Maybe a hint to explain the higher infection risk in women. The same hormonal milieu plays a major role in protecting women where morbidity and mortality are concerned, since the dominant female hormone, oestradiol, has immune-modulatory properties that are likely to be protective against virus infections. It is also known that the X chromosome contains the largest number of immune-related genes, potentially conferring an advantage to women in efficient immune responsiveness. Lifestyle factors are also likely to be contributory. Premenopausal women could possibly face higher exposure to infection (hence higher infection rates) because economic conditions are often less favorable for them with less opportunity for home office work because of jobs requiring mandatory attendance. Due to the additional task of childcare, it is likely that contact times with other people will be longer. Women generally make healthier lifestyle choices, thus reducing the disease burden that confers high risk of mortality in COVID-19 infected men. This narrative review aims to present key concepts and knowledge gaps on the effects of oestrogen associated with SARS-CoV2 infection and COVID-19 disease.

Translational suppression of SARS-COV-2 ORF8 protein mRNA as a Viable therapeutic target against COVID-19: Computational studies on potential roles of isolated compounds from Clerodendrum volubile leaves.

The open reading frame 8 (ORF8) protein of SARS-CoV-2 has been implicated in the onset of cytokine storms, which are responsible for the pathophysiology of COVID-19 infection. The present study investigated the potential of isolated compounds from Clerodendrum volubile leaves to stall oxidative bursts in vitro and interact with ORF8 mRNA segments of the SARS-CoV-2 whole genome using computational tools. Five compounds, namely, harpagide, 1-(3-methyl-2-butenoxy)-4-(1-propenyl)benzene, ajugoside, iridoid glycoside and erucic acid, were isolated from C. volubile leaves, and their structures were elucidated using conventional spectroscopy tools. Iridoid glycoside is being reported for the first time and is thus regarded as a new compound. The ORF8 mRNA sequences of the translation initiation sites (TIS) and translation termination sites (TTSs) encoding ORF8 amino acids were retrieved from the full genome of SARS-CoV-2. Molecular docking studies revealed strong molecular interactions of the isolated compounds with the TIS and TTS of ORF8 mRNA. Harpagide showed the strongest binding affinity for TIS, while erucic acid was the strongest for TTS. The immunomodulatory potentials of the isolated compounds were investigated on neutrophil phagocytic respiratory bursts using luminol-amplified chemiluminescence technique. The compounds significantly inhibited oxidative burst, with 1-(3-methyl-2-butenoxy)-4-(1-propenyl)benzene having the best activity. Ajugoside and erucic acid showed significant inhibitory activity on T-cell proliferation. These results indicate the potential of C. volubile compounds as immunomodulators and can be utilized to curb cytokine storms implicated in COVID-19 infection. These potentials are further corroborated by the strong interactions of the compounds with the TIS and TTS of ORF8 mRNA from the SARS-CoV-2 whole genome.

A Birds-Eye (Re)View of Acid-Suppression Drugs, COVID-19, and the Highly Variable Literature.

This Perspective examines a recent surge of information regarding the potential benefits of acid-suppression drugs in the context of COVID-19, with a particular eye on the great variability (and, thus, confusion) that has arisen across the reported findings, at least as regards the popular antacid famotidine. The degree of inconsistency and discordance reflects contradictory conclusions from independent, clinical-based studies that took roughly similar approaches, in terms of both experimental design (retrospective, observational, cohort-based, etc.) and statistical analysis workflows (propensity-score matching and stratification into sub-cohorts, etc.). The contradictions and potential confusion have ramifications for clinicians faced with choosing therapeutically optimal courses of intervention: e.g., do any potential benefits of famotidine suggest its use in a particular COVID-19 case? (If so, what administration route, dosage regimen, duration, etc. are likely optimal?) As succinctly put this March in Freedberg et al. (2021), "…several retrospective studies show relationships between famotidine and outcomes in COVID-19 and several do not." Beyond the pressing issue of possible therapeutic indications, the conflicting data and conclusions related to famotidine must be resolved before its inclusion/integration in ontological and knowledge graph (KG)-based frameworks, which in turn are useful for drug discovery and repurposing. As a broader methodological issue, note that reconciling inconsistencies would bolster the validity of meta-analyses which draw upon the relevant data-sources. And, perhaps most broadly, developing a system for treating inconsistencies would stand to improve the qualities of both 1) real world evidence-based studies (retrospective), on the one hand, and 2) placebo-controlled, randomized multi-center clinical trials (prospective), on the other hand. In other words, a systematic approach to reconciling the two types of studies would inherently improve the quality and utility of each type of study individually.

Reynoutria Rhizomes as a Natural Source of SARS-CoV-2 Mpro Inhibitors-Molecular Docking and In Vitro Study.

More than a year has passed since the world began to fight the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the Coronavirus disease 2019 (COVID-19) pandemic, and still it spreads around the world, mutating at the same time. One of the sources of compounds with potential antiviral activity is Traditional Chinese Medicinal (TCM) plants used in China in the supportive treatment of COVID-19. Reynoutria japonica is important part of the Shu Feng Jie Du Granule/Capsule-TCM herbal formula, recommended by China Food and Drug Administration (CFDA) for treatment of patients with H1N1- and H5N9-induced acute lung injury and is also used in China to treat COVID-19, mainly combined with other remedies. In our study, 25 compounds from rhizomes of R. japonica and Reynoutria sachalinensis (related species), were docked into the binding site of SARS-CoV-2 main protease. Next, 11 of them (vanicoside A, vanicoside B, resveratrol, piceid, emodin, epicatechin, epicatechin gallate, epigallocatechin gallate, procyanidin B2, procyanidin C1, procyanidin B2 3,3'-di-O-gallate) as well as extracts and fractions from rhizomes of R. japonica and R. sachalinensis were tested in vitro using a fluorescent peptide substrate. Among the tested phytochemicals the best results were achieved for vanicoside A and vanicoside B with moderate inhibition of SARS-CoV-2 Mpro, IC50 = 23.10 µM and 43.59 µM, respectively. The butanol fractions of plants showed the strongest inhibition of SARS-CoV-2 Mpro (IC50 = 4.031 µg/mL for R. sachalinensis and IC50 = 7.877 µg/mL for R. japonica). As the main constituents of butanol fractions, besides the phenylpropanoid disaccharide esters (e.g., vanicosides), are highly polymerized procyanidins, we suppose that they could be responsible for their strong inhibitory properties. As inhibition of SARS-CoV-2 main protease could prevent the replication of the virus our research provides data that may explain the beneficial effects of R. japonica on COVID-19 and identify the most active compounds worthy of more extensive research.

IL-13 is a driver of COVID-19 severity.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2-infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13-induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13-mediated HA synthesis in pulmonary pathology.

Allosteric Modulation of the CB1 Cannabinoid Receptor by Cannabidiol-A Molecular Modeling Study of the N-Terminal Domain and the Allosteric-Orthosteric Coupling.

The CB1 cannabinoid receptor (CB1R) contains one of the longest N termini among class A G protein-coupled receptors. Mutagenesis studies suggest that the allosteric binding site of cannabidiol (CBD) involves residues from the N terminal domain. In order to study the allosteric binding of CBD to CB1R we modeled the whole N-terminus of this receptor using the replica exchange molecular dynamics with solute tempering (REST2) approach. Then, the obtained structures of CB1R with the N terminus were used for ligand docking. A natural cannabinoid receptor agonist, Δ9-THC, was docked to the orthosteric site and a negative allosteric modulator, CBD, to the allosteric site positioned between extracellular ends of helices TM1 and TM2. The molecular dynamics simulations were then performed for CB1R with ligands: (i) CBD together with THC, and (ii) THC-only. Analyses of the differences in the residue-residue interaction patterns between those two cases allowed us to elucidate the allosteric network responsible for the modulation of the CB1R by CBD. In addition, we identified the changes in the orthosteric binding mode of Δ9-THC, as well as the changes in its binding energy, caused by the CBD allosteric binding. We have also found that the presence of a complete N-terminal domain is essential for a stable binding of CBD in the allosteric site of CB1R as well as for the allosteric-orthosteric coupling mechanism.

Oestrogen-mediated upregulation of the Mas receptor contributes to sex differences in acute lung injury and lung vascular barrier regulation.

Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; however, sex-dependent incidence of acute respiratory distress syndrome (ARDS) remains controversial and the sex-dependent mechanisms of endothelial barrier regulation are unknown. In premenopausal women, increased signalling of angiotensin (Ang)(1-7) via the Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang(1-7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang(1-7)/Mas signalling may protect females over males in ALI/ARDS.Clinical data were collected from Charité inpatients (Berlin) and sex differences in ALI were assessed in wild-type (WT) and Mas-receptor deficient (Mas-/- ) mice. Endothelial permeability was assessed as weight change in isolated lungs and as transendothelial electrical resistance (TEER) in vitroIn 734 090 Charité inpatients (2005-2016), ARDS had a higher incidence in men as compared to women. In murine ALI, male WT mice had more lung oedema, protein leaks and histological evidence of injury than female WT mice. Lung weight change in response to platelet-activating factor (PAF) was more pronounced in male WT and female Mas-/- mice than in female WT mice, whereas Mas-receptor expression was higher in female WT lungs. Ovariectomy attenuated protection in female WT mice and reduced Mas-receptor expression. Oestrogen increased Mas-receptor expression and attenuated endothelial leakage in response to thrombin in vitro This effect was alleviated by Mas-receptor blockade.Improved lung endothelial barrier function protects female mice from ALI-induced lung oedema. This effect is partially mediated via enhanced Ang(1-7)/Mas signalling as a result of oestrogen-dependent Mas expression.

Computational Prediction of Potential Inhibitors of the Main Protease of SARS-CoV-2.

The rapidly developing pandemic, known as coronavirus disease 2019 (COVID-19) and caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently spread across 213 countries and territories. This pandemic is a dire public health threat-particularly for those suffering from hypertension, cardiovascular diseases, pulmonary diseases, or diabetes; without approved treatments, it is likely to persist or recur. To facilitate the rapid discovery of inhibitors with clinical potential, we have applied ligand- and structure-based computational approaches to develop a virtual screening methodology that allows us to predict potential inhibitors. In this work, virtual screening was performed against two natural products databases, Super Natural II and Traditional Chinese Medicine. Additionally, we have used an integrated drug repurposing approach to computationally identify potential inhibitors of the main protease of SARS-CoV-2 in databases of drugs (both approved and withdrawn). Roughly 360,000 compounds were screened using various molecular fingerprints and molecular docking methods; of these, 80 docked compounds were evaluated in detail, and the 12 best hits from four datasets were further inspected via molecular dynamics simulations. Finally, toxicity and cytochrome inhibition profiles were computationally analyzed for the selected candidate compounds.

Evidence for treatment with estradiol for women with SARS-CoV-2 infection.

BACKGROUND: Given that an individual's age and gender are strongly predictive of coronavirus disease 2019 (COVID-19) outcomes, do such factors imply anything about preferable therapeutic options? METHODS: An analysis of electronic health records for a large (68,466-case), international COVID-19 cohort, in 5-year age strata, revealed age-dependent sex differences. In particular, we surveyed the effects of systemic hormone administration in women. The primary outcome for estradiol therapy was death. Odds ratios (ORs) and Kaplan-Meier survival curves were analyzed for 37,086 COVID-19 women in two age groups: pre- (15-49 years) and peri-/post-menopausal (> 50 years). RESULTS: The incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is higher in women than men (by about + 15%) and, in contrast, the fatality rate is higher in men (about + 50%). Interestingly, the relationships between these quantities are linked to age: pre-adolescent girls and boys had the same risk of infection and fatality rate, while adult premenopausal women had a significantly higher risk of infection than men in the same 5-year age stratum (about 16,000 vs. 12,000 cases). This ratio changed again in peri- and postmenopausal women, with infection susceptibility converging with men. While fatality rates increased continuously with age for both sexes, at 50 years, there was a steeper increase for men. Thus far, these types of intricacies have been largely neglected. Because the hormone 17ß-estradiol influences expression of the human angiotensin-converting enzyme 2 (ACE2) protein, which plays a role in SARS-CoV-2 cellular entry, propensity score matching was performed for the women's sub-cohort, comparing users vs. non-users of estradiol. This retrospective study of hormone therapy in female COVID-19 patients shows that the fatality risk for women > 50 years receiving estradiol therapy (user group) is reduced by more than 50%; the OR was 0.33, 95% CI [0.18, 0.62] and the hazard ratio (HR) was 0.29, 95% CI [0.11,0.76]. For younger, pre-menopausal women (15-49 years), the risk of COVID-19 fatality is the same irrespective of estradiol treatment, probably because of higher endogenous estradiol levels. CONCLUSIONS: As of this writing, still no effective drug treatment is available for COVID-19; since estradiol shows such a strong improvement regarding fatality in COVID-19, we suggest prospective studies on the potentially more broadly protective roles of this naturally occurring hormone.

PROMISCUOUS 2.0: a resource for drug-repositioning.

The development of new drugs for diseases is a time-consuming, costly and risky process. In recent years, many drugs could be approved for other indications. This repurposing process allows to effectively reduce development costs, time and, ultimately, save patients' lives. During the ongoing COVID-19 pandemic, drug repositioning has gained widespread attention as a fast opportunity to find potential treatments against the newly emerging disease. In order to expand this field to researchers with varying levels of experience, we made an effort to open it to all users (meaning novices as well as experts in cheminformatics) by significantly improving the entry-level user experience. The browsing functionality can be used as a global entry point to collect further information with regards to small molecules (∼1 million), side-effects (∼110 000) or drug-target interactions (∼3 million). The drug-repositioning tab for small molecules will also suggest possible drug-repositioning opportunities to the user by using structural similarity measurements for small molecules using two different approaches. Additionally, using information from the Promiscuous 2.0 Database, lists of candidate drugs for given indications were precomputed, including a section dedicated to potential treatments for COVID-19. All the information is interconnected by a dynamic network-based visualization to identify new indications for available compounds. Promiscuous 2.0 is unique in its functionality and is publicly available at http://bioinformatics.charite.de/promiscuous2.

Evidence-Based Considerations Exploring Relations between SARS-CoV-2 Pandemic and Air Pollution: Involvement of PM2.5-Mediated Up-Regulation of the Viral Receptor ACE-2.

The COVID-19/SARS-CoV-2 pandemic struck health, social and economic systems worldwide, and represents an open challenge for scientists -coping with the high inter-individual variability of COVID-19, and for policy makers -coping with the responsibility to understand environmental factors affecting its severity across different geographical areas. Air pollution has been warned of as a modifiable factor contributing to differential SARS-CoV-2 spread but the biological mechanisms underlying the phenomenon are still unknown. Air quality and COVID-19 epidemiological data from 110 Italian provinces were studied by correlation analysis, to evaluate the association between particulate matter (PM)2.5 concentrations and incidence, mortality rate and case fatality risk of COVID-19 in the period 20 February-31 March 2020. Bioinformatic analysis of the DNA sequence encoding the SARS-CoV-2 cell receptor angiotensin-converting enzyme 2 (ACE-2) was performed to identify consensus motifs for transcription factors mediating cellular response to pollutant insult. Positive correlations between PM2.5 levels and the incidence (r = 0.67, p < 0.0001), the mortality rate (r = 0.65, p < 0.0001) and the case fatality rate (r = 0.7, p < 0.0001) of COVID-19 were found. The bioinformatic analysis of the ACE-2 gene identified nine putative consensus motifs for the aryl hydrocarbon receptor (AHR). Our results confirm the supposed link between air pollution and the rate and outcome of SARS-CoV-2 infection and support the hypothesis that pollution-induced over-expression of ACE-2 on human airways may favor SARS-CoV-2 infectivity.