Discovery of Potential Inhibitors of SARS-CoV-2 (COVID-19) Main Protease (Mpro) from Nigella Sativa (Black Seed) by Molecular Docking Study

Purpose: A new human coronavirus (SARS-CoV-2), triggering pneumonia, is termed as Coronavirus Disease-19 (COVID-19). There is an alarming situation now as this new virus is spreading around the world. At present, there are no specific treatments for COVID-19. Nigella sativa is known as Prophetic Medicine as its use has been mentioned in Prophetic Hadith, as a natural remedy for all the diseases except death. Seeds and oils of N. sativa have a long history of folklore usage in various systems of medicine such as Unani and Tibb, Ayurveda and Siddha in the treatment of different diseases and ailments. The aim of this research is to provide a potential inhibitor of SARS-CoV-2 Mpro. Method(s): The Molecular docking tool was used to optimize the binding affinities of chemical constituents of N. sativa with SARS-CoV-2 Mpro. Result(s): Many constituents from N. Sativa have shown better binding affinity than reported drugs with SARS-CoV-2 Mpro i.e., the alpha-hederin, Stigmasterol glucoside, Nigellidine-4-O-sulfite, Nigellidine, Sterol-3-beta-D-glucoside, Dithymoquinone, beta-sitosterol have binding affinities (kcal/mol) of-9,-8.1,-8,-7.7,-7.7,-7.4,-7.4, and-6.9 and number of hydrogen bonds formed are 06, 04, 03, 03, 03, 00, and 01, respectively. Conclusion(s): There is rationale and pre-clinical evidence of the effectiveness of N. Sativa that it may be helpful for the treatment of COVID-19 and can serve as a potential natural candidate. However, more studies should be conducted to collect high-quality data and scientific evidence of N. Sativa to use it against COVID-19 clinically.Copyright © 2021 Bentham Science Publishers.

'Medical Corona Science': Philosophical and systemic issues: Re-thinking medicine? On the epistemology of Corona medicine.

RATIONALE, AIMS, AND OBJECTIVES: The disciplinary profile and the quality of production of knowledge on Corona pandemic is studied. This scientific field is called 'Medical Corona Science'. METHODS: Criteria of analytical philosophy of science and science studies are systematically applied. RESULTS: It is shown that mainly auxiliary medical disciplines such as virology and epidemiology but not clinical disciplines provide Corona knowledge. We see a laboratory-centered, technology- and data-driven science, largely ignoring clinical issues. Therefore we call these approaches "Medical Corona Science" (MCS). We see the need to adapt to features of a 'post-normal science', a 'mode 2 science' and of 'Integration and Implementation Science', especially as clinical knowledge must be integrated. There is also a severe lack of theoretical considerations that could help to frame the pandemic as a complex dynamic system. CONCLUSIONS: We suggest a deeper meta-scientific discussion of the epistemic value of MCS and propose the application of tools from systems science.

Exploring Innovation with Scientific Thinking.

The mode of scientific thinking is undergoing rapid and profound changes. In the 21st century, macro and micro civilizations go parallel. A systematic and scientific methodology is required for the study of complex things. The thinking mode in modern medicine is gradually shifting from analytical, reductive thinking to holistic and systematic thinking. As such Western medicine and traditional Chinese medicine are gradually approaching the epistemology of health and disease state. The importance of scientific thinking in innovation has been expounded in this study. The development trends in medicine in the current era are analyzed, the importance of systems theory in the study of human bodies is discussed, and a new medical model named Novel Systems Medicine is proposed.

Unpacking COVID-19 Systems Biology in Lung and Whole Blood with Transcriptomics and miRNA Regulators.

COVID-19 is a systemic disease affecting tissues and organs, including and beyond the lung. Apart from the current pandemic context, we also have vastly inadequate knowledge of consequences of repeated exposures to SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus causing COVID-19, in multiple organ systems and the whole organism scales when the disease evolves from a pandemic to an endemic state. This calls for a systems biology and systems medicine approach and unpacking the effects of COVID-19 in lung as well as other tissues. We report here original findings from transcriptomics analyses and differentially expressed genes (DEGs) in lung samples from 60 patients and 27 healthy controls, and in whole blood samples from 255 patients and 103 healthy individuals. A total of 11 datasets with RNA-seq transcriptomic data were obtained from the Gene Expression Omnibus and the European Nucleotide Archive. The identified DEGs were used to construct protein interaction and functional networks and to identify related pathways and miRNAs. We found 35 DEGs common between lung and the whole blood, and importantly, 2 novel genes, namely CYP1B1 and TNFAIP6, which have not been previously implicated with COVID-19. We also identified four novel miRNA potential regulators, hsa-mir-192-5p, hsa-mir-221-3p, hsa-mir-4756-3p, and hsa-mir-10a-5p, implicated in lung or other diseases induced by coronaviruses. In summary, these findings offer new molecular leads and insights to unpack COVID-19 systems biology in a whole organism context and might inform future antiviral drug, diagnostics, and vaccine discovery efforts.

Six Pivotal Lessons Learned in South Korea for Whole-of-Government Approach to Successful COVID-19 Vaccine Rollout in Planetary Health.

The COVID-19 pandemic has underscored that systems medicine depends on health systems and services that can respond to planetary health threats in scale and with speed. After 2 years of the pandemic, there are lessons learned in South Korea, from governance to risk communication for planetary health. The learning is timely because COVID-19 likely signals future ecological crises and emerging pathogens amid the climate emergency in the 21st century. By the end of March 2022, South Korea, with a population of 51.6 million, administered more COVID-19 vaccine doses per 100 people than other developed countries, including United Kingdom, Italy, Australia, Israel, Germany, and United States. In South Korea, 233.47 doses of COVID-19 vaccine were administered per 100 people, while Italy (229.48), China (229.39), Australia (217.44), the United Kingdom (211.39), Israel (194.82), and the United States (170.59) fell behind in vaccine rollout. Korea's whole-of-government approach to robust COVID-19 vaccination rollout prompted broad interest in planetary health. Notwithstanding that vaccine rollout is a complex multifactorial outcome, six salient, and often interdependent, factors are identified in this study of South Korea: (1) governance system; (2) logistic capability; (3) delivery strategy and accessibility; (4) established public health infrastructure; (5) risk communication; and (6) public cooperation and engagement. Integration of these factors can create multisectoral synergy to achieve better outcomes in vaccine rollout. The lessons from South Korea can help cultivate planetary health action in other parts of the world during the current COVID-19 pandemic, and in ecological crises in the future.

Biopolitics of "Acquired Immunity": The War Discourse and Feminist Response-Abilities in Art, Science, and Technology During COVID-19.

If we are to adequately decipher and make sense of the COVID-19 pandemic, and the ways in which large populations as well as their immune systems have responded to the virus, we ought to map the broader sociomaterial contexts in which a planetary health crisis, such as COVID-19, has been situated. Adopting a biophilosophical approach and feminist versions of Science and Technology Studies (STS), this article problematizes the virality of the war discourse and its tactical uses for the sake of biopower during COVID-19. Also, a queering lens is used to question the military metaphors deployed during COVID-19. Queering is understood in this article as to make change, and to act in a way that is disruptive of allegedly oppressive power structures. Queering seeks to expose or otherwise uncover that norms are, in fact, just limitations on a far broader set of possibilities. With the aim of exploring how critical associations can extend their response-abilities for the exploitative, authoritarian, and racist forces of biopower, the article examines the skilled practices and intra-actions of a feminist collective, FEMeeting-Women in Art, Science and Technology. Acknowledging the social relevance of a core community for acquiring immunity and its role for the future, a feminist conception of the virus played a key role in queering all kinds of anthropocentric and essentialist views by biohacking, DIY (Do It Yourself) and DIWO (Do It With Others) techniques in the actions and coproductions of FEMeeting. Of note, the war metaphor operated as a tactic for camouflaging and obfuscating the facts in the course of the pandemic. The findings reveal that paratactical commoning, which is a self-reflexive collective knowledge production in artistic and hacktivist research, emerges as a way in which political ontological potentials can be critically activated within communities of action. The feminist lenses on COVID-19, and the paratactical commoning presented in this article, are of broad interest to systems scientists to explore the ways in which biopower, and the previously unchecked war discourse and militaristic metaphors coproduce COVID-19 acquired immunity and the social injustices. Understanding not only the biology but also the biopolitics of acquired immunity to the control of COVID-19 is, therefore, crucial for systems medicine and planetary (health) care that is at once effective, resilient, foreseeable, and just.

Ayurveda Practice during COVID-19 -Lessons from a Cross Sectional Survey

Methods: A cross-sectional study was conducted by sending a survey developed using SurveyMonkey. Local IRB approved the study. Responding to the survey was implied as providing consent. The survey was sent to all ayurveda professionals practicing in the United States. The list of professionals were obtained from the National Ayurveda Medical Association and through personal contacts of the principal investigator. The survey was open for 45 days and reminders were sent twice to the potential participants. Results: Eighty eight ayurvedic professionals completed the survey. Majority were females from California and belonged to Ayurveda Practitioner category and practiced mostly parttime. Ayurveda counselors and Ayurveda doctors (India based education) were the other categories of professionals, who also responded to the survey. The respondents reported that they adopted telehealth to continue their practice during the closures, but still majority reported that there was an economic impact of COVID-19 on their practices. Health promotion was the predominant type of service provided by these professionals. The methods included diet and lifestyle advices that incorporated dosha based diet and yoga and meditation practices. Additionally, they also provided some classical ayurveda formulas and simple herbal teas such as coriander tea and hot water to prevent easy susceptibility to viral infections. An important advice included a specific dosha based individual daily routine to improve general and mental health. Background: To understand the ayurveda practice patterns in the United States during COVID-19 Conclusion: Ayurveda, the oldest Indian System of Medicine may be a useful natural health care systemthat can be used for health promotion during a pandemic. The self-care practices do provide patient empowerment.

A Review of Herbal Regulations in India and Worldwide

This review highlights the regulatory status of herbal medicines in India and in specific countries. The herbal medicines are being used in different system of medicines like the Ayurveda, siddha, homeopathy, unani and Chinese system of medicine. The regulatory authorities and WHO are making efforts to collaborate in order to for a harmonized herbal medicine regulation. The Drugs and Cosmetics Act 1940 and Rules 1945 consist of the regulatory guidance and guidelines for Ayurveda, Unani, Siddha medicine. The herbal medicines are being categorized as Complimentary medicines, Natural health products, Prescription medicines, over the counter medicines, Supplements, Traditional herbal medicines globally.

Evaluation of Efficacy and Safety of Clevira as an Add on Drug in Mild to Moderate COVID-19 Positive Patients- A Randomised Control Trial

Introduction: Coronavirus Disease 2019 (COVID-19) has caused a devastating pandemic. Despite the worldwide efforts to find a therapeutic strategy and prophylaxis, we have not attained a complete success. Hence, there exists an urgent need for development of alternative solutions from Ayurveda system of medicine for COVID-19. Aim: To evaluate clevira, a polyherbal ayurvedic formulation, for its efficacy and safety in treatment of mild to moderate COVID-19 patients as an add on drug. Materials and Methods: This randomised control trial was carried out from May 2020 to July 2020, in 100 patients (50 in test group and 50 in control group) confirmed with COVID-19 infection (mild to moderate cases) by Reverse Transcription Polymerase Chain Reaction (RT-PCR) at a tertiary care Government Medical College and Hospital in Chennai, India. The test group received tablet clevira orally twice daily after food, in the morning and night for 14 days, as an add on, in addition to standard care of treatment as received by the control group. The primary outcome was assessment of clinical recovery, proportion of patients with swabs negative for COVID-19 in RT-PCR and reduction of Viral cycle threshold ratio. The results of the both group were analysed and compared using Chi-square test and student's t-test. Results: Significant improvement (p-value=0.0338) was seen in patients on day 5, who got treated with clevira as add on drug. An 86% (43) of patients turned out to be COVID-19 RT-PCR test negative on day 5 while in the control group 66% (33) of patients turned out to be negative. There was a statistically significant difference (p-value=0.0196) between the test and control groups on comparing the mean difference in CT value results between day 1 and day 5. Clevira when given in addition to the standard of care, showed a significant improvement in signs and symptoms of COVID-19 infection. Conclusion: Clevira, with its polyherbal ingredients show a significant antiviral action against coronavirus when given in addition to the standard of care medications suggested by Indian Council of Medical Research (ICMR), over a period of 14 days in treatment of mild to moderate COVID-19 patients.

Effect of time and titer in convalescent plasma therapy for COVID-19.

The clinical benefit of convalescent plasma (CP) for patients with coronavirus disease (COVID)-19 is still debated. In this systematic review and meta-analysis, we selected 10 randomized clinical trials (RCTs) and 15 non-randomized studies (total number of patients = 22,591) of CP treatment and evaluated two different scenarios: (1) disease stage of plasma recipients and (2) donated plasma antibody titer, considering all-cause mortality at the latest follow-up. Our results show that, when provided at early stages of the disease, CP significantly reduced mortality: risk ratio (RR) 0.72 (0.68, 0.77), p < 0.00001, while provided in severe or critical conditions, it did not (RR: 0.94 [0.86, 1.04], p = 0.22). On the other hand, the benefit on mortality was not increased by using plasma with a high-antibody titer compared with unselected plasma. This meta-analysis might promote CP usage in patients with early-stage COVID-19 in further RCTs to maximize its benefit in decreasing mortality, especially in less affluent countries.

Regulation of Inflammatory Reaction in Health and Disease.

Inflammation is a key mechanism for the clearance of infective agents and other inflammatory triggers and is pivotal for the repairing processes of the affected tissues. Inflammation is a multistep process driven by a great number of mediators which regulate specific aspects of the inflammatory response, in agreement with a well-defined chronobiological program. A great number of inflammation-related diseases show a deeply altered immune chronobiology (e.g., COVID-19-related cytokines storm). This aspect highlights the need for a deeper understanding of the inflammatory phenomenon. It is fundamental to study inflammation as a multilevel phenomenon. Of particular interest is the low-grade chronic inflammation, which is an etiological factor of many chronic diseases. Nowadays, the therapeutic approach to low grade chronic inflammation is one of the great challenges of traditional pharmacology. Currently, no drugs specifically designed for the treatment of chronic inflammatory forms are available. Today, bioregulatory systems medicine (BrSM) and low dose medicine (LDM), two pharmacological paradigms grounded in systems medicine, potentially represent new tools for the treatment of inflammation-related diseases. Scientific research has assessed the effectiveness and safety of both these therapeutic approaches, in particular for the management of chronic inflammatory conditions and chronic immunological dysregulations.

COVID-19 Is a Crisis in Planetary Health and Politics of Expertise: Time to Think Critically and Innovate Both.

This expert review offers an analysis of the global governance of the COVID-19 pandemic. The pandemic is not only a health crisis but also a crisis of global governance. For example, the nation states in dealing with the crises of the pandemic have turned inwards, toward native and national solutions, and therefore away from the much-needed global cooperation to respond to the pandemic. This is an important concern for systems medicine and integrative biology in both normative and instrumental sense. Moreover, if we are to "pandemic-proof" the planet and the life science innovation ecosystem, new ways of understanding global governance are called for. This article examines the ways in which national governments have reacted to the crises triggered and embodied by the COVID-19 pandemic, surfaces the different approaches and conflicts between scientific experts and policy makers, and reveals the failure of science and politics. I analyze the uneven and disjointed way Western democratic governments have responded to the crisis and the way unchecked normative values and ideas have influenced the pandemic policy and prevented effective measures to contain the pandemic. Finally, the complex relationships between politics, knowledge, science, and governments are explored and clarified, and the way the COVID-19 crisis highlighted the long-standing tensions between technocracy and democracy. In conclusion, it is time to think critically and reflexively for all knowledge actors in systems science and innovate both planetary health and its global governance.

The Quest for System-Theoretical Medicine in the COVID-19 Era.

Precision medicine and molecular systems medicine (MSM) are highly utilized and successful approaches to improve understanding, diagnosis, and treatment of many diseases from bench-to-bedside. Especially in the COVID-19 pandemic, molecular techniques and biotechnological innovation have proven to be of utmost importance for rapid developments in disease diagnostics and treatment, including DNA and RNA sequencing technology, treatment with drugs and natural products and vaccine development. The COVID-19 crisis, however, has also demonstrated the need for systemic thinking and transdisciplinarity and the limits of MSM: the neglect of the bio-psycho-social systemic nature of humans and their context as the object of individual therapeutic and population-oriented interventions. COVID-19 illustrates how a medical problem requires a transdisciplinary approach in epidemiology, pathology, internal medicine, public health, environmental medicine, and socio-economic modeling. Regarding the need for conceptual integration of these different kinds of knowledge we suggest the application of general system theory (GST). This approach endorses an organism-centered view on health and disease, which according to Ludwig von Bertalanffy who was the founder of GST, we call Organismal Systems Medicine (OSM). We argue that systems science offers wider applications in the field of pathology and can contribute to an integrative systems medicine by (i) integration of evidence across functional and structural differentially scaled subsystems, (ii) conceptualization of complex multilevel systems, and (iii) suggesting mechanisms and non-linear relationships underlying the observed phenomena. We underline these points with a proposal on multi-level systems pathology including neurophysiology, endocrinology, immune system, genetics, and general metabolism. An integration of these areas is necessary to understand excess mortality rates and polypharmacological treatments. In the pandemic era this multi-level systems pathology is most important to assess potential vaccines, their effectiveness, short-, and long-time adverse effects. We further argue that these conceptual frameworks are not only valid in the COVID-19 era but also important to be integrated in a medicinal curriculum.

Individuating Possibly Repurposable Drugs and Drug Targets for COVID-19 Treatment Through Hypothesis-Driven Systems Medicine Using CoVex.

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has developed into a pandemic causing major disruptions and hundreds of thousands of deaths in wide parts of the world. As of July 3, 2020, neither vaccines nor approved drugs for effective treatment are available. In this article, we showcase how to individuate drug targets and potentially repurposable drugs in silico using CoVex a recently presented systems medicine platform for COVID-19 drug repurposing. Starting from initial hypotheses, CoVex leverages network algorithms to individuate host proteins involved in COVID-19 disease mechanisms, as well as existing drugs targeting these potential drug targets. Our analysis reveals GLA, PLAT, and GGCX as potential drug targets, and urokinase, argatroban, dabigatran etexilate, betrixaban, ximelagatran and anisindione as potentially repurposable drugs.