Mechanistic insight and possible mechanism of seizure in Covid-19: The nuances and focal points.

Coronavirus disease 2019 (COVID-19) is a primary respiratory disease with an alarming impact worldwide. COVID-19 is caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and presents various neurological symptoms, including seizures. SARS-CoV-2 shows neuroinvasive and neurotropic capabilities through a neuronal angiotensin-converting enzyme 2 (ACE2), which is also highly expressed in both neuronal and glial cells. Therefore, SARS-CoV-2 can trigger neuroinflammation and neuronal hyperexcitability, increasing the risk of seizures'. Olfactory neurons could be an exceptional neuronal pathway for the neuroinvasion of respiratory viruses to access the central nervous system (CNS) from the nasal cavity, leading to neuronal injury and neuroinflammation. Although neuronal ACE2 has been widely studied, other receptors for SARS-CoV-2 in the brain have been proposed to mediate viral-neuronal interactions with subsequent neurological squeals. Thus, the objective of the present critical review was to find the association and mechanistic insight between COVID-19 and the risk of seizures.

COVID-19 and corticosteroids: a narrative review.

It has been reported that corticosteroid therapy was effective in the management of severe acute respiratory syndrome (SARS) and the Middle East Respiratory Syndrome (MERS), and recently in coronavirus disease 2019 (COVID-19). Corticosteroids are potent anti-inflammatory drugs that mitigate the risk of acute respiratory distress syndrome (ARDS) in COVID-19 and other viral pneumonia, despite a reduction of viral clearance; corticosteroids inhibit the development of cytokine storm and multi-organ damage. The risk-benefit ratio should be assessed for critical COVID-19 patients. In conclusion, corticosteroid therapy is an effective way in the management of COVID-19, it reduces the risk of complications primarily acute lung injury and the development of ARDS. Besides, corticosteroid therapy mainly dexamethasone and methylprednisolone are effective in reducing the severity of COVID-19 and associated comorbidities such as chronic obstructive pulmonary diseases (COPD), rheumatoid arthritis, and inflammatory bowel disease (IBD).

Selinexor and COVID-19: The Neglected Warden.

A novel severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2) has been confirmed as the cause of the global pandemic coronavirus disease 2019 (COVID-19). Different repurposed drugs have been trialed and used in the management of COVID-19. One of these agents was the anti-cancer Selinexor (SXR). SXR is an anti-cancer drug that acts by inhibition of nuclear exportin-1 (XPO1), which inhibits transport of nuclear proteins from the nucleus to the cytoplasm, leading to the induction of cell-cycle arrest and apoptosis. XPO1 inhibitors had antiviral effects, mainly against respiratory syncytial virus (RSV) and influenza virus. SXR inhibits transport of SARS-CoV-2 nuclear proteins to the cytoplasm with further inhibition of SARS-CoV-2 proliferation. SXR has the ability to prevent the development of a cytokine storm in COVID-19 by inhibiting the release of pro-inflammatory cytokines with the augmentation release of anti-inflammatory cytokines. In conclusion, SARS-CoV-2 infection is linked with activation of XPO1, leading to the triggering of inflammatory reactions and oxidative stress. Inhibition of XPO1 by Selinexor (SXR), a selective inhibitor of nuclear export (SINE), can reduce the proliferation of SARS-CoV-2 and associated inflammatory disorders. Preclinical and clinical studies are warranted in this regard.

The potential molecular implications of adiponectin in the evolution of SARS-CoV-2: Inbuilt tendency

Graphical Adiponectin (APN) is an adipokine concerned in the regulation of glucose metabolism, insulin sensitivity and fatty acid oxidation. APN plays a critical role in viral infections by regulating the immune response through its anti-inflammatory/pro-inflammatory axis. Reduction of APN may augment the severity of viral infections because APN inhibits immune cells’ response via suppression of inflammatory signaling pathways and stimulation of adenosine monophosphate protein kinase (AMPK). Moreover, APN inhibits the stimulation of nuclear factor kappa B (NF-κB) and regulates the release of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukins (IL-18, IL-6). In COVID-19, abnormalities of the fatty tissue due to oxidative stress (OS) and hyperinflammation may inhibit the production and release of APN. APN has lung-protective effect and can prevent SARS-CoV-2-induced acute lung injury (ALI) through the amelioration of endoplasmic reticulum (ER) stress, endothelial dysfunction (ED) and stimulation of peroxisome proliferator-activated receptor-alpha (PPAR-α). It has been established that there is a potential correlation between inflammatory signal transduction pathways and APN that contributes to the development of SARS-CoV-2 infections. Deregulation of these molecular pathways affects the expression of APN and vice versa. In addition, the reduction of APN effect in SARS-CoV-2 infection could be a potential cause of the exacerbation of pro-inflammatory effects which are associated with the disease severity. In this context, exploratory, developmental, and extensive prospective studies are necessary.

COVID-19 and erythrocrine function: The roller coaster and danger.

Erythrocrine function refers to erythrocytes' ability to synthesize and release active signaling molecules such as ATP and nitric oxide (NO). Erythrocyte NO regulates its deformability and increases its perfusion and circulation that prevent tissue hypoxia. Recently, there is a connotation between SARS-CoV-2 infection and erythrocrine function due to alteration in the release of NO and ATP from erythrocytes. SARS-CoV-2 binds erythrocyte band3 protein, which has a similar characteristic of ACE2, leading to alteration of erythrocyte physiology like oxygen transport with development of hypoxia. Similarly, SARS-CoV-2 infection activates erythrocyte protein kinase C alpha (PKC-α), causing significant changes in the erythrocyte functions. The erythrocytes can bind SARS-CoV-2 and its active particles with subsequent virus delivery to the liver and spleen macrophages. Thus, the erythrocytes act as elimination for SARS-CoV-2 in COVID-19. Moreover, the erythrocyte stored, release sphingosine-1 phosphate (S1P) improves endothelial and regulates lymphocyte functions. SARS-CoV-2 ORF8 protein binds the porphyrin part of hemoglobin heme at the ß1 chain, causing hemolysis and dysfunctional hemoglobin to reduce oxygen-carrying capacity. In conclusion, SARS-CoV-2 infection and associated pro-inflammatory disorders lead to abnormal erythrocrine function with subsequent inflammatory complications and endothelial dysfunction due to deficiency of protective released molecules (NO, G1P, and ATP) from functional erythrocytes. In vitro, preclinical, and clinical studies are mandatory in this regard.

The possible role of ursolic acid in Covid-19: A real game changer.

Ursolic acid (UA) is a pentacyclic terpenoid is usually found in the fruit peels and stem bark as secondary metabolites. UA has antiviral, antibacterial, and antiparasitic properties. UA has a wide spectrum of pharmacological activities against different infections. Because of the greatest antiviral and anti-inflammatory properties of UA, so it could be a plausible therapeutic herbal medicine in Covid-19 treatment. Covid-19 is a recent worldwide virulent disease pandemic due to severe acute respiratory coronavirus disease 2 (SARS-CoV-2). The pathogenesis of SARS-CoV-2 infection is related to the direct cytopathic effect and exaggerated immune response by which acute lung injury (ALI) and/or acute respiratory distress syndrome might be developed in critical cases. UA may inhibit main protease of SARS-CoV-2, and inhibits the interface flanked by SARS-CoV-2 viral proteins and its entry point commonly recognized as angiotensin converting enzyme 2 (ACE2). In addition, UA attenuates SARS-CoV-2-induced inflammatory reactions and oxidative stress. Therefore, UA could avert SARS-CoV-2 infection from causing ALI. This opinion proposed that UA might be a potential candidate therapy against Covid-19 and can mitigate post-Covid-19 complications such as lung fibrosis. In this regards, forthcoming studies are reasonable to substantiate the therapeutic role of UA in Covid-19. However, taken into account that Covid-19 is yet to be investigating for further evaluations, therefore, clinical trials are recommended regarding use and dose of UA in Covid-19 treatment, as well as secondary effects.

COVID-19-Related Mental Health Burdens: Impact of Educational Level and Relationship Status Among Low-Income Earners of Western Uganda.

Objective: The study aimed to investigate the relationship between mental health with the level of education, relationship status, and awareness on mental health among low-income earners in Western Uganda. Methods: This was a cross-sectional descriptive study carried out among 253 participants. Anxiety, anger, and depression were assessed using a modified generalized anxiety disorder (GAD-7), Spielberger's State-Trait Anger Expression Inventory-2, and Beck Depression Inventory item tools, respectively. Results: The majority of our respondents were male (n = 150/253, 59.3), had a secondary level of education (104/253, 41.1), and were single (137/253, 54.2). No formal education and primary education (r2 = 47.4% and 6.4%, respectively) had a negative correlation with awareness of mental health care. In addition, no formal education had a positive correlation with anger and depression (r2 = 1.9% and 0.3%, respectively). Singleness in this study had a negative correlation with awareness of mental health care, anger, and depression (r2 = 1.9, 0.8, and 0.3%, respectively), and a positive correlation with anxiety (r2 = 3.9%). Conclusion: It is evident that education and relationship status influenced awareness on mental health care and mental health state among low-income earners in Western Uganda during the first COVID-19 lockdown. Therefore, policymakers should strengthen social transformation through the proper engagement of low-income earners in this COVID-19 era.

Evaluation of Antimalarial Potential of Extracts from Alstonia boonei and Carica papaya in Plasmodium berghei-Infected Mice.

Extracts of Alstonia boonei and Carica papaya are used in herbal medicine for the treatment of malaria. This work investigated the phytochemical, antioxidant, and antimalarial effects of hydromethanolic extracts of Alstonia boonei and Carica papaya. A four-day chemosuppressive test was conducted to assess the ability of the extracts to prevent establishment of infection. Three doses of the extracts were administered-100, 200, and 400 mg/kg bw-prior to Plasmodium berghei challenge. Change in body weight, parasitemia, packed cell volume (PCV), and mean survival time was determined. A three-day curative test was also carried out on Plasmodium berghei-infected mice to determine the effects of the plant extracts (200 mg/kg bw) on parasitemia and biochemical indices of liver and kidney functions, lipid metabolism, and oxidative stress. The study revealed that the extracts possessed phenolic compounds (34.13 ± 1.90 mg GAE/g for Alstonia boonei and 27.99 ± 1.46 mg GAE/g for Carica papaya) and flavonoids (19.47 ± 1.89 mg QE/g for Alstonia boonei and 18.24 ± 1.36 mg QE/g for Carica papaya). In vitro antioxidant activity measured as total antioxidant power, total reducing power, and DPPH radical scavenging activity showed that the extracts possessed higher antioxidant activity than the reference compounds. The outcome of the chemosuppressive test revealed that whereas Plasmodium berghei-infected mice had high parasitemia, decreased mean survival time, exhibited loss of weight, and had low PCV, treatment with the extracts reversed the effects in a concentration-dependent manner. Similarly, the curative test revealed that the extracts significantly suppressed parasitemia compared with the malaria negative control group. This was mirrored by reversal of indices of hepatic toxicity (AST, ALT, and ALP levels), nephropathy (urea and creatinine levels), oxidative stress (SOD, CAT, GPx, GSH, and lipid peroxides), and dyslipidemia (TC, HDL, and TG levels and HMG-CoA reductase activity) in infected but treated mice compared with negative control. Put together, the results of this study demonstrate that the extracts of Alstonia boonei and Carica papaya possess antimalarial properties and are able to ameliorate metabolic dysregulations that characterize Plasmodium berghei infection. The phytoconstituents in these extracts are believed to be responsible for the pharmacological activity reported in this study.

Natural Products Modulating Angiotensin Converting Enzyme 2 (ACE2) as Potential COVID-19 Therapies.

The 2019 coronavirus disease (COVID-19) is a potentially fatal multisystemic infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Currently, viable therapeutic options that are cost effective, safe and readily available are desired, but lacking. Nevertheless, the pandemic is noticeably of lesser burden in African and Asian regions, where the use of traditional herbs predominates, with such relationship warranting a closer look at ethnomedicine. From a molecular viewpoint, the interaction of SARS-CoV-2 with angiotensin converting enzyme 2 (ACE2) is the crucial first phase of COVID-19 pathogenesis. Here, we review plants with medicinal properties which may be implicated in mitigation of viral invasion either via direct or indirect modulation of ACE2 activity to ameliorate COVID-19. Selected ethnomedicinal plants containing bioactive compounds which may prevent and mitigate the fusion and entry of the SARS-CoV-2 by modulating ACE2-associated up and downstream events are highlighted. Through further experimentation, these plants could be supported for ethnobotanical use and the phytomedicinal ligands could be potentially developed into single or combined preventive therapeutics for COVID-19. This will benefit researchers actively looking for solutions from plant bioresources and help lessen the burden of COVID-19 across the globe.

Role of leukotriene pathway and montelukast in pulmonary and extrapulmonary manifestations of Covid-19: The enigmatic entity.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the responsible agent for the coronavirus disease 2019 (Covid-19), has its entry point through interaction with angiotensin converting enzyme 2 (ACE2) receptors, highly expressed in lung type II alveolar cells and other tissues, like heart, pancreas, brain, and vascular endothelium. This review aimed to elucidate the potential role of leukotrienes (LTs) in the pathogenesis and clinical presentation of SARS-CoV-2 infection, and to reveal the critical role of LT pathway receptor antagonists and inhibitors in Covid-19 management. A literature search was done in PubMed, Scopus, Web of Science and Google Scholar databases to find the potential role of montelukast and other LT inhibitors in the management of pulmonary and extra-pulmonary manifestations triggered by SARS-CoV-2. Data obtained so far underline that pulmonary and extra-pulmonary manifestations in Covid-19 are attributed to a direct effect of SARS-CoV-2 in expressed ACE2 receptors or indirectly through NF-κB dependent induction of a cytokine storm. Montelukast can ameliorate extra-pulmonary manifestations in Covid-19 either directly through blocking of Cys-LTRs in different organs or indirectly through inhibition of the NF-κB signaling pathway.

Pleiotropic Effects of Tetracyclines in the Management of COVID-19: Emerging Perspectives.

Coronavirus disease 2019 (COVID-19) is a global infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Approximately 15% of severe cases require an intensive care unit (ICU) admission and mechanical ventilation due to development of acute respiratory distress syndrome (ARDS). Tetracyclines (TCs) are a group of bacteriostatic antibiotics, like tetracycline, minocycline, and doxycycline, effective against aerobic and anaerobic bacteria as well as Gram-positive and Gram-negative bacteria. Based on available evidences, TCs may be effective against coronaviruses and thus useful to treat COVID-19. Thus, this review aims to provide a brief overview on the uses of TCs for COVID-19 management. SARS-CoV-2 and other coronaviruses depend mainly on the matrix metalloproteinases (MMPs) for their proliferation, cell adhesion, and infiltration. The anti-inflammatory mechanisms of TCs are linked to different pathways. Briefly, TCs inhibit mitochondrial cytochrome c and caspase pathway with improvement of lymphopenia in early COVID-19. Specifically, minocycline is effective in reducing COVID-19-related complications, through attenuation of cytokine storm as apparent by reduction of interleukin (IL)-6, IL-1, and tumor necrosis factor (TNF)-α. Different clinical trials recommend the replacement of azithromycin by minocycline in the management of COVID-19 patients at high risk due to two main reasons: 1) minocycline does not prolong the QT interval and even inhibits ischemia-induced arrhythmia; 2) minocycline displays synergistic effect with chloroquine against SARS-CoV-2. Taken together, the data presented here show that TCs, mainly doxycycline or minocycline, may be potential partners in COVID-19 management, derived pneumonia, and related complications, such as acute lung injury (ALI) and ARDS.

Sequential doxycycline and colchicine combination therapy in Covid-19: The salutary effects.

Coronavirus virus disease 2019 (COVID-19) is a viral infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), actually considered as a global pandemic. The entry-point for SARS-CoV-2 is angiotensin converting enzyme 2 (ACE2) and dipeptidyl peptidase 4 (DPP4), which are highly expressed in the lung. Among other complications, COVID-19leads to fatal pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) due to development of cytokine storm (CS). The pathogenesis of SARS-CoV-2 infection depends on the viral load and human innate/adaptive immune response that are required for viral elimination in the first phase of COVID-19. However, an exaggerated immune response in the second phase of COVID-19 results in immune overreaction and CS-induced ALI and ARDS. Thus, in view of these considerations, we report here a series of five patients with COVID-19 pneumonia who developed ALI. In addition to the supportive therapy, the patients received doxycycline in the first week and doxycycline plus colchicine in the second week. Following sequential therapy with doxycycline and/or colchicine in patients with COVID-19 pneumonia, the patients had reduction of disease severity and symptoms with better clinical and radiological outcomes. However, it is tough to confirm the link between this therapeutic combination and recovery from COVID-19 pneumonia, as it is a small case-series report. Nevertheless, this study gives a rational for large-scale prospective studies to evaluate the dual sequential effect of doxycycline and colchicine on the COVID-19 severity. This case-series illustrated that use of colchicine: doxycycline combination is linked with marked improvements in the clinical, laboratory and radiological outcomes in patients with COVID-19 pneumonia. However, we cannot sketch any definitive conclusion from our observation, despite we hypothesize that this combination therapeutic regimen may attenuate and treat COVID-19. Further, namely prospective, randomized, and controlled clinical studies are recommended in this regard.

Recent updates in COVID-19 with emphasis on inhalation therapeutics: Nanostructured and targeting systems.

The current world health threat posed by the novel coronavirus disease of 2019 (COVID-19) calls for the urgent development of effective therapeutic options. COVID-19 needs daunting routes such as nano-antivirals. Hence, the role of nanotechnology is very critical in combating this nano-enemy "virus." Although substantial resources are under ongoing attention for prevention and care, we would like to start sharing with readers our vision of the role of inhaled nanomaterials and targeting systems that can play an important role in the fight against the COVID-19. In this review, we underline the genomic structure of COVID-19, recent modes of virus transmission with measures to control the infection, pathogenesis, clinical presentation of SARS-CoV-2, and how much the virus affects the lung. Additionally, the recent therapeutic approaches for managing COVID-19 with emphasis on the value of nanomaterial-based technical approaches are discussed in this review. This review also focuses on the safe and efficient delivery of useable targeted therapies using designed nanocarriers. Moreover, the effectiveness and availability of active targeting of certain specific receptors expressed on the coronavirus surfaces via tailored ligand nanoparticles are manipulated. It was also highlighted in this review the role of inhaled medicines including antivirals and repurposed drugs for fighting the associated lung disorders and efficiency of developed vaccines. Moreover, the inhalation delivery safety techniques were also highlighted.