Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities

As of January 2021, SARS-CoV-2 has killed over 2 million individuals across the world. As such, there is an urgent need for vaccines and therapeutics to reduce the burden of COVID-19. Several vaccines, including mRNA, vector-based vaccines, and inactivated vaccines, have been approved for emergency use in various countries. However, the slow roll-out of vaccines and insufficient global supply remains a challenge to turn the tide of the pandemic. Moreover, vaccines are important tools for preventing the disease but therapeutic tools to treat patients are also needed. As such, since the beginning of the pandemic, repurposed FDA-approved drugs have been sought as potential therapeutic options for COVID-19 due to their known safety profiles and potential anti-viral effects. One of these drugs is ivermectin (IVM), an antiparasitic drug created in the 1970s. IVM later exerted antiviral activity against various viruses including SARS-CoV-2. In this review, we delineate the story of how this antiparasitic drug was eventually identified as a potential treatment option for COVID-19. We review SARS-CoV-2 lifecycle, the role of the nucleocapsid protein, the turning points in past research that provided initial 'hints' for IVM's antiviral activity and its molecular mechanism of action- and finally, we culminate with the current clinical findings

Chemical composition, antioxidant, and antimicrobial activities of Leaves of Ajuga iva

The main objective of this research was to study the biological characteristics in terms of antioxidant and antimicrobial activities of Ajuga iva and determine the best analytical and extraction methods applicable to this specie and studied compounds. A short screening of its nutritional value in terms of chemical composition is also included. A. iva leaves were analyzed for crude protein (CP), cell wall [neutral detergent fiber (NDF), acid detergent fiber (ADF), and acid detergent lignin (ADL)], minerals, fatty acids, essential oils, and phenolic compounds. Mature aerial parts of A. iva were randomly collected during the Spring season from Mograne-Zaghouan, Tunisia. Leaves of A. iva contained 13.4 ± 0.4% CP, 26.3 ± 0.35% NDF, 20.2 ± 0.42% ADF, and 5.13 ± 0.21% ADL. Mineral content (13.0 ± 0.45%) was mainly composed of potassium (4.5% g DM) and magnesium (4.25% DM). Leaves of A. iva had linolenic (26.29 ± 0.760%) and linoleic (37.66 ± 2.35%) acids as the main components of the acid profile. Thymol was found to be the most dominant (23.43%) essential oil, followed by 4-vinylguaiacol (14.27%) and linalool (13.66%). HPLC-PDA-ESI-MS/MS analysis pointed out the presence of phytoecdysteroids. Phenolic acids and flavonoids, such as glycosylated derivatives of naringenin, eriodyctiol, and apigenin, were detected in the methanol extract of A. iva leaves. Our results underline the importance of choosing proper extraction methods and solvents to extract and characterize the described compounds profile of A. iva leaves. Results also show A. iva leaves as a potential source of functional ingredients with beneficial health-promoting properties. Overall, leaves of A. iva have low biological activities (antioxidant and antimicrobial activities) with a chemical composition suitable as a feed for ruminants in rangeland pasture. It also has low-grade antibacterial or medicinal characteristics when fed to ruminants

Ziziphus nummularia attenuates the malignant phenotype of human pancreatic cancer cells: Role of ros

Pancreatic cancer (PC) is the fourth leading cause of all cancer-related deaths. Despite major improvements in treating PC, low survival rate remains a major challenge, indicating the need for alternative approaches, including herbal medicine. Among medicinal plants is Ziziphus nummu-laria (family Rhamnaceae), which is a thorny shrub rich in bioactive molecules. Leaves of Ziziphus nummularia have been used to treat many pathological conditions, including cancer. However, their effects on human PC are still unknown. Here, we show that the treatment of human pancreatic ductal adenocarcinoma cells (Capan-2) with Ziziphus nummularia ethanolic extract (ZNE) (100–300 µg/mL) attenuated cell proliferation in a time-and concentration-dependent manner. Pretreatment with N-acetylcysteine, an ROS scavenger, attenuated the anti-proliferative effect of ZNE. In addition, ZNE significantly decreased the migratory and invasive capacity of Capan-2 with a concomitant downregulation of integrin α2 and increased cell–cell aggregation. In addition, ZNE inhibited in ovo angiogenesis as well as reduced VEGF and nitric oxide levels. Furthermore, ZNE downregulated the ERK1/2 and NF-κB signaling pathways, which are known to drive tumorigenic and metastatic events. Taken together, our results suggest that ZNE can attenuate the malignant phenotype of Capan-2 by inhibiting hallmarks of PC. Our data also provide evidence for the potential anticancer effect of Ziziphus nummularia, which may represent a new resource of novel anticancer compounds, especially ones that can be utilized for the management of PC

Burden and disease pathogenesis of influenza and other respiratory viruses in diabetic patients

Over the past two decades, diabetes mellitus (DM) has been receiving increasing attention among autoimmune diseases. The prevalence of type 1 and type 2 diabetes has increased rapidly and has become one of the leading causes of death worldwide. Therefore, a better understanding of the genetic and environmental risk factors that trigger the onset of DM would help develop more efficient therapeutics and preventive measures. The role and mechanism of respiratory viruses in inducing autoimmunity have been frequently reported. On the other hand, the association of DM with respiratory infections might result in severe complications or even death. Since influenza is the most common respiratory infection, DM patients experience disease severity and increased hospitalization during influenza season. Vaccinating diabetic patients against influenza would significantly reduce hospitalization due to disease severity. However, recent studies also report the role of viral vaccines in inducing autoimmunity, specifically diabetes. This review reports causes of diabetes, including genetic and viral factors, with a special focus on respiratory viruses. We further brief the burden of influenza-associated complications and the effectiveness of the influenza vaccine in DM patients

Epidemiology of respiratory infections among adults in Qatar (2012-2017).

Limited data is available about the etiology of influenza like illnesses (ILIs) in Qatar. This study aimed at providing preliminary estimates of influenza and other respiratory infections circulating among adults in Qatar. We retrospectively collected data of about 44,000 patients who visited Hamad General Hospital clinics, sentinel sites, and all primary healthcare centers in Qatar between 2012 and 2017. All samples were tested for influenza viruses, whereas about 38,000 samples were tested for influenza and a panel of respiratory viruses using Fast Track Diagnostics (FTD) RT-PCR kit. Among all ILIs cases, 20,278 (46.5%) tested positive for at least one respiratory pathogen. Influenza virus was predominating (22.6%), followed by human rhinoviruses (HRVs) (9.5%), and human coronaviruses (HCoVs) (5%). A detection rate of 2-3% was recorded for mycoplasma pneumonia, adenoviruses, human parainfluenza viruses (HPIVs), respiratory syncytial virus (RSV), and human metapneumovirus (HMPV). ILIs cases were reported throughout the year, however, influenza, RSV, and HMPV exhibited strong seasonal peaks in the winter, while HRVs circulated more during fall and spring. Elderly (>50 years) had the lowest rates of influenza A (13.9%) and B (4.2%), while presenting the highest rates of RSV (3.4%) and HMPV (3.3%). While males had higher rates of HRVs (11.9%), enteroviruses (1.1%) and MERS CoV (0.2%), females had higher proportions of influenza (26.3%), HPIVs (3.2%) and RSV (3.6%) infections. This report provides a comprehensive insight about the epidemiology of ILIs among adults in the Qatar, as a representative of Gulf States. These results would help in improvement and optimization of diagnostic procedures, as well as control and prevention of the respiratory infections.This study was supported by funds from Hamad Medical Corporation (grant # 16335/16) and Qatar University (grant # QUCG-BRC-2018/2019-1)

Synthesis of New Chromene Derivatives Targeting Triple-Negative Breast Cancer Cells

Breast cancer continues to be the leading cause of cancer-related deaths among women worldwide. The most aggressive type of breast cancer is triple-negative breast cancer (TNBC). Indeed, not only does TNBC not respond well to several chemotherapeutic agents, but it also frequently develops resistance to various anti-cancer drugs, including taxane mitotic inhibitors. This necessitates the search for newer, more efficacious drugs. In this study, we synthesized two novel chromene derivatives (C1 and C2) and tested their efficacy against a battery of luminal type A and TNBC cell lines. Our results show that C1 and C2 significantly and specifically inhibited TNBC cell viability but had no effect on the luminal A cell type. In addition, these novel compounds induced mitotic arrest, cell multinucleation leading to senescence, and apoptotic cell death through the activation of the extrinsic pathway. We also showed that the underlying mechanisms for these actions of C1 and C2 involved inhibition of microtubule polymerization and disruption of the F-actin cytoskeleton. Furthermore, both compounds significantly attenuated migration of TNBC cells and inhibited angiogenesis in vitro. Finally, we performed an in silico analysis, which revealed that these novel variants bind to the colchicine binding site in β-tubulin. Taken together, our data highlight the potential chemotherapeutic properties of two novel chromene compounds against TNBC.Scopu

Follow up and comparative assessment of IgG, IgA, and neutralizing antibody responses to SARS-CoV-2 between mRNA-vaccinated naïve and unvaccinated naturally infected individuals over 10 months

BackgroundEvidence on the effectiveness of vaccination-induced immunity compared to SARS-CoV-2 natural immunity is warranted to inform vaccination recommendations. AimIn this study, we aimed to conduct a comparative assessment of antibody responses between vaccinated naïve (VN) and unvaccinated naturally infected individuals (NI) over 10 Months. MethodThe study comprised fully-vaccinated naïve individuals (VN; n = 596) who had no history of SARS-CoV-2 infection, and received two doses of either BNT162b2 or mRNA-1273, and naturally infected individuals who had a documented history of SARS-CoV-2 infection and no vaccination record (NI cohort; n = 218). We measured the levels of neutralizing total antibodies (NtAbs), anti-S-RBD IgG, and anti-S1 IgA titers among VN and NI up to ∼10 months from administration of the first dose, and up to ∼7 months from SARS-CoV-2 infection, respectively. To explore the relationship between the antibody responses and time, Spearman's correlation coefficient was computed. Furthermore, correlations between the levels of NtAbs/anti-S-RBD IgG and NtAbs/anti-S1 IgA were examined through pairwise correlation analysis. ResultsUp to six months, VN individuals had a significantly higher NtAb and anti-S-RBD IgG antibody responses compared to NI individuals. At the 7th month, there was a significant decline in antibody responses among VN individuals, but not NI individuals, with a minimum decrease of 3.7-fold (p < 0.001). Among VN individuals, anti-S1 IgA levels began to decrease significantly (1.4-fold; p = 0.007) after two months, and both NtAb and S-RBD IgG levels began to decline significantly (NtAb: 2.0-fold; p = 0.042, S-RBD IgG: 2.4-fold; p = 0.035) after three months. After 10 months, the most significant decline among VN individuals was observed for S-RBD-IgG (30.0-fold; P < 0.001), followed by NtAb (15.7-fold; P < 0.001) and S-IgA (3.7-fold; P < 0.001) (most stable). Moreover, after 5 months, there was no significant difference in the IgA response between the two groups. ConclusionThese findings have important implications for policymakers in the development of vaccination strategies, particularly in the consideration of booster doses to sustain long-lasting protection against COVID-19.This work was made possible by WHO grant number COVID-19-22-43 and grant number UREP28-173-3-057 from the Qatar National Research Fund (a member of Qatar Foundation). The statements made herein are solely the responsibility of the authors

Detection of Antinuclear Antibodies Targeting Intracellular Signal Transduction, Metabolism, Apoptotic Processes and Cell Death in Critical COVID-19 Patients

Background and Objectives: The heterogeneity of the coronavirus disease of 2019 (COVID-19) lies within its diverse symptoms and severity, ranging from mild to lethal. Acute respiratory distress syndrome (ARDS) is a leading cause of mortality in COVID-19 patients, characterized by a hyper cytokine storm. Autoimmunity is proposed to occur as a result of COVID-19, given the high similarity of the immune responses observed in COVID-19 and autoimmune diseases. Here, we investigate the level of autoimmune antibodies in COVID-19 patients with different severities. Results: Initial screening for antinuclear antibodies (ANA) IgG using ELISA revealed that 1.58% (2/126) and 4% (5/126) of intensive care unit (ICU) COVID-19 cases expressed strong and moderate ANA levels, respectively. An additional sample was positive with immunofluorescence assays (IFA) screening. However, all the non-ICU cases (n=273) were ANA negative using both assays. Samples positive for ANA were further confirmed with large-scale autoantibody screening by phage immunoprecipitation-sequencing (PhIP-Seq). The majority of the ANA-positive samples showed "speckled" ANA pattern by microscopy and revealed autoantibody specificities that targeted proteins involved in intracellular signal transduction, metabolism, apoptotic processes, and cell death by PhIP-Seq; further denoting reactivity to nuclear and cytoplasmic antigens. Conclusion: Our results further support the notion of routine screening for autoimmune responses in COVID-19 patients, which might help improve disease prognosis and patient management. Further, results provide compelling evidence that ANA-positive individuals should be excluded from being donors for convalescent plasma therapy in the context of COVID-19.This study was supported by funds from QNRF, grant # NPRP11S-1212-170092

SARS-CoV-2 infection hospitalization, severity, criticality, and fatality rates

AbstractBackgroundThis study aimed to estimate the age-stratified and overall morbidity and mortality rates of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based on an analysis of the pervasive SARS-CoV-2 epidemic in Qatar, a country with &lt;9% of the population being ≥50 years of age.MethodsInfection disease outcomes were investigated using a Bayesian approach applied to an age-structured mathematical model describing SARS-CoV-2 transmission and disease progression in the population. The model was fitted to infection and disease time-series and age-stratified data. Two separate criteria for classifying morbidity were used: one based on actual recorded hospital admission (acute-care or intensive-care-unit hospitalization) and one based on clinical presentation as per World Health Organization classification of disease severity or criticality.ResultsAll outcomes showed very strong age dependence, with low values for those &lt;50 years of age, but rapidly growing rates for those ≥50 years of age. The strong age dependence was particularly pronounced for infection criticality rate and infection fatality rate. Infection acute-care and intensive-care-unit bed hospitalization rates were estimated at 13.10 (95% CI: 12.82-13.24) and 1.60 (95% CI: 1.58-1.61) per 1,000 infections, respectively. Infection severity and criticality rates were estimated at 3.06 (95% CI: 3.01-3.10) and 0.68 (95% CI: 0.67-0.68) per 1,000 infections, respectively. Infection fatality rate was estimated at 1.85 (95% CI: 1.74-1.95) per 10,000 infections.ConclusionsSARS-CoV-2 severity and fatality in Qatar was not high and demonstrated a very strong age dependence with &lt;4 infections in every 1,000 being severe or critical and &lt;2 in every 10,000 being fatal. Epidemic expansion in nations with young populations may lead to lower disease burden than previously thought.</jats:sec

COVID-19 risk score as a public health tool to guide targeted testing: A demonstration study in Qatar

We developed a Coronavirus Disease 2019 (COVID-19) risk score to guide targeted RTPCR testing in Qatar. The Qatar national COVID-19 testing database, encompassing a total of 2,688,232 RT-PCR tests conducted between February 5, 2020-January 27, 2021, was analyzed. Logistic regression analyses were implemented to derive the COVID-19 risk score, as a tool to identify those at highest risk of having the infection. Score cut-off was determined using the ROC curve based on maximum sum of sensitivity and specificity. The score's performance diagnostics were assessed. Logistic regression analysis identified age, sex, and nationality as significant predictors of infection and were included in the risk score. The ROC curve was generated and the area under the curve was estimated at 0.63 (95% CI: 0.63-0.63). The score had a sensitivity of 59.4% (95% CI: 59.1%-59.7%), specificity of 61.1% (95% CI: 61.1%-61.2%), a positive predictive value of 10.9% (95% CI: 10.8%- 10.9%), and a negative predictive value of 94.9% (94.9%-95.0%). The concept and utility of a COVID-19 risk score were demonstrated in Qatar. Such a public health tool can have considerable utility in optimizing testing and suppressing infection transmission, while maximizing efficiency and use of available resources. 2022 Abu-Raddad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited