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)-a. 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.The authors thank all members of the College of Medicine, Al-Mustansiyria University. NC-M acknowledges the Portuguese Foundation for Science and Technology under the Horizon 2020 Program (PTDC/PSI-GER/28076/2017)

Involvement of Antioxidant in the Prevention of Cellular Damage

Oxidative stress occurs when the body’s enzymatic or non-enzymatic antioxidants are outweighed by endogenous or exogenous free radicals. Oxidative radicals, reactive oxygen species, and other biomolecule-damaging free radicals can be generated during normal cellular metabolism and react with proteins, lipids, and DNA. In the domains of biology and medicine, free radicals have become increasingly important. They can accumulate in a variety of ways, both endogenously and exogenously. Mitochondria are the primary source of cell-level endogenous reactive oxygen species. In several chronic and degenerative disorders, this results in tissue destruction. In addition to being produced endogenously, antioxidants can also be delivered exogenously to the biological system, most frequently through nutrition. Antioxidants are generally used to counteract the effects of free radicals produced by metabolic processes. In this chapter, the crucial function of reactive oxygen species in human health, as well as exploring the functioning of antioxidative defense systems in reducing toxicity caused by excess reactive oxygen species were discussed

Silver nanoparticles restrict microbial growth by promoting oxidative stress and DNA damage

Bacterial infections remain a serious health issue; hence there is a need for continuous search for improved antimicrobials. In addition, it is important to understand the antibacterial mechanism of prospective antimicrobials to fully harness their benefits. In this study, the antimicrobial action of silver nanoparticles was investigated. The antimicrobial potential of silver nanoparticles against different strains of bacteria was evaluated after which Escherichia coli and Staphylococcus aureus were selected as model for gram-negative and gram-positive bacteria respectively. Additionally, to determine mechanism of action, some biochemical assays including determination of kynurenine level, DNA fragmentation, lipid peroxidation and antioxidant status were carried out. Results showed that silver nanoparticles caused DNA damage and induced oxidative stress as reflected in elevated nitric oxide production and lipid peroxidation level. In contrast silver nanoparticles increased the antioxidant capacity viz-a-viz, elevated levels of total thiol, superoxide dismutase (SOD), and total antioxidant capacity (TAC) compared to untreated cells. They also initiated inconsistent alteration to the kynurenine pathway. Taken together, the findings indicate that silver nanoparticles exhibited antimicrobial action through the promotion of oxidative stress

Potential surface active agent production using very low grade and cheap substrate by Bacillus subtilis as microbial cell factory

Bio-surfactants are surface-active molecules which are produced by the wide range of microbes including bacteria, fungi, moulds, and yeast. This study was conducted to identify bio-surfactants by Bacillus subtilis combined with use of cheap substrates and industrial wastes (Mustard cake, Whey and Soya cake) which are found locally in Nepal. Bacillus subtilis, one of the most potential bio-surfactants producer; was isolated from soil sample of hydrocarbon contaminated site. Isolates were grown in a Minimal Salt Media (MSM) with 10% (v/v) mustard oil cake, whey and soya cake separately. The presence and potential of surfactant was determined by the oil spreading technique, emulsification index (%E24) and surface tension measurement. It was revealed that the surface tensions of cell free extract were 54.41, 60.02 and 56.64 mN/m for from mustard cake, whey and soya cake respectively as compared to distilled water (72.09) at 25oC. The emulsification index values was found to be highest in engine oil from the bio-surfactant extracted from mustard cake, soya cake and whey respectively. Similarly, mustard oil showed the lowest value of emulsification index. The highest emulsification activity was shown in mustard oil i.e. 1.13 from the cell free extract from mustard oil and lowest in engine oil i.e., 0.07, by the extract from soya cake medium, when measured in spectrophotometer at 540 nm. In conclusion, strain of Bacillus subtilis was found to be the potential surface active agent producers on the mustard oil cake, which can be useful medium for various environmental, food, medicinal and industrial processes

COVID-19 in relation to hyperglycemia and diabetes mellitus

Coronavirus disease 2019 (COVID-19), triggered by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), may lead to extrapulmonary manifestations like diabetes mellitus (DM) and hyperglycemia, both predicting a poor prognosis and an increased risk of death. SARS-CoV-2 infects the pancreas through angiotensin-converting enzyme 2 (ACE2), where it is highly expressed compared to other organs, leading to pancreatic damage with subsequent impairment of insulin secretion and development of hyperglycemia even in non-DM patients. Thus, this review aims to provide an overview of the potential link between COVID-19 and hyperglycemia as a risk factor for DM development in relation to DM pharmacotherapy. For that, a systematic search was done in the database of MEDLINE through Scopus, Web of Science, PubMed, Embase, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), and Wanfang Data. Data obtained underline that SARS-CoV-2 infection in DM patients is more severe and associated with poor clinical outcomes due to preexistence of comorbidities and inflammation disorders. SARS-CoV-2 infection impairs glucose homeostasis and metabolism in DM and non-DM patients due to cytokine storm (CS) development, downregulation of ACE2, and direct injury of pancreatic beta-cells. Therefore, the potent anti-inflammatory effect of diabetic pharmacotherapies such as metformin, pioglitazone, sodium-glucose co-transporter-2 inhibitors (SGLT2Is), and dipeptidyl peptidase-4 (DPP4) inhibitors may mitigate COVID-19 severity. In addition, some antidiabetic agents and also insulin may reduce SARS-CoV-2 infectivity and severity through the modulation of the ACE2 receptor expression. The findings presented here illustrate that insulin therapy might seem as more appropriate than other anti-DM pharmacotherapies in the management of COVID-19 patients with DM due to low risk of uncontrolled hyperglycemia and diabetic ketoacidosis (DKA). From these findings, we could not give the final conclusion about the efficacy of diabetic pharmacotherapy in COVID-19; thus, clinical trial and prospective studies are warranted to confirm this finding and concern

Physostigmine: A Plant Alkaloid Isolated from Physostigma venenosum: A Review on Pharmacokinetics, Pharmacological and Toxicological Activities

Medicinal plants have been documented as an important source for discovering new pharmaceutical molecules that have been used to treat serious diseases. Strikingly, previous reports stated that natural products and their derived compounds exhibit lesser side effects and improved efficacy than other synthetic counterparts. Physostigmine, a parasympathomimetic plant alkaloid isolated from the West African perennial shrub Physostigma venenosum, it shows a narrow therapeutic index and a short life span, despite its ability to penetrate the blood-brain barrier (BBB). It is a widely known reversible butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) inhibitor and has been documented to treat various ailments such as Alzheimer’s disease. Pharmacologically, physostigmine was first reported as an antidote for atropine scopolamine and belladonna alkaloids toxicity. Recently, it has been documented as a therapy for treating several ailments including glaucoma, myasthenia gravis and the intoxication caused by tricyclic antidepressant overdoses, anti-histamines, antipsychotics, and benzodiazepines. Physostigmine has been reported to be absorbed from the gastrointestinal tract and showed short half-life, as, after the oral administration of 2 mg of physostigmine salicylate, the peak plasma concentration reached to 30 minutes. This review examines the biological activities, pharmacokinetics, and toxicity of physostigmine extracted from P. venenosum. Keywords: Physostigma venenosum, Physostigmine, pharmacological activities, acetylcholinesterase and butyrylcholinesterase inhibitor

Pirfenidone and post-Covid-19 pulmonary fibrosis: invoked again for realistic goals

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGPirfenidone (PFN) is an anti-fbrotic drug with signifcant anti-infammatory property used for treatment of fbrotic conditions such as idiopathic pulmonary fbrosis (IPF). In the coronavirus disease 2019 (Covid-19) era, severe acute respiratory syndrome 2 (SARS-CoV-2) could initially lead to acute lung injury (ALI) and in severe cases may cause acute respiratory distress syndrome (ARDS) which is usually resolved with normal lung function. However, some cases of ALI and ARDS are progressed to the more severe critical stage of pulmonary fbrosis commonly named post-Covid-19 pulmonary fbrosis which needs an urgent address and proper management. Therefore, the objective of the present study was to highlight the potential role of PFN in the management of post-Covid-19 pulmonary fbrosis. The precise mechanism of post-Covid-19 pulmonary fbrosis is related to the activation of transforming growth factor beta (TGF-β1), which activates the release of extracellular proteins, fbroblast proliferation, fbroblast migration and myofbroblast conversion. PFN inhibits accumulation and recruitment of infammatory cells, fbroblast proliferation, deposition of extracellular matrix in response to TGFβ1 and other pro-infammatory cytokines. In addition, PFN suppresses furin (TGFβ1 convertase activator) a protein efector involved in the entry of SARS-CoV-2 and activation of TGFβ1, and thus PFN reduces the pathogenesis of SARS-CoV-2. Besides, PFN modulates signaling pathways such as Wingless/Int (Wnt/β-catenin), Yes-Associated Protein (YAP)/Transcription CoActivator PDZ Binding Motif (TAZ) and Hippo Signaling Pathways that are involved in the pathogenesis of post-Covid-19 pulmonary fbrosis. In conclusion, the anti-infammatory and anti-fbrotic properties of PFN may attenuate post-Covid-19 pulmonary fbrosis

Fenofibrate for COVID-19 and related complications as an approach to improve treatment outcomes: the missed key for Holy Grail

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGIntroduction Fenofbrate is an agonist of peroxisome proliferator activated receptor alpha (PPAR-α), that possesses antiinfammatory, antioxidant, and anti-thrombotic properties. Fenofbrate is efective against a variety of viral infections and diferent infammatory disorders. Therefore, the aim of critical review was to overview the potential role of fenofbrate in the pathogenesis of SARS-CoV-2 and related complications. Results By destabilizing SARS-CoV-2 spike protein and preventing it from binding angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 entry, fenofbrate can reduce SARS-CoV-2 entry in human cells Fenofbrate also suppresses infammatory signaling pathways, which decreases SARS-CoV-2 infection-related infammatory alterations. In conclusion, fenofbrate anti-infammatory, antioxidant, and antithrombotic capabilities may help to minimize the infammatory and thrombotic consequences associated with SARSCoV-2 infection. Through attenuating the interaction between SARS-CoV-2 and ACE2, fenofbrate can directly reduce the risk of SARS-CoV-2 infection. Conclusions As a result, fenofbrate could be a potential treatment approach for COVID-19 control

Extraction of Bioactive Compounds from Medicinal Plants and Herbs

Human beings have relied on herbs and medicinal plants as sources of food and remedy from time immemorial. Bioactive compounds from plants are currently the subject of much research interest, but their extraction as part of phytochemical and/or biological investigations present specific challenges. Herbalists or scientists have developed many protocols of extraction of bioactive ingredients to ensure the effectiveness and the efficacy of crude drugs that were used to get relief from sickness. With the advent of new leads from plants such as morphine, quinine, taxol, artemisinin, and alkaloids from Voacanga species, a lot of attention is paid to the mode of extraction of active phytochemicals to limit the cost linked to the synthesis and isolation. Thus, the extraction of active compounds from plants needs appropriate extraction methods and techniques that provide bioactive ingredients-rich extracts and fractions. The extraction procedures, therefore, play a critical role in the yield, the nature of phytochemical content, etc. This chapter aims to present, describe, and compare extraction procedures of bioactive compounds from herbs and medicinal plants

Perspective Chapter: Appraisal of Paclitaxel (Taxol) Pros and Cons in the Management of Cancer - Prospects in Drug Repurposing

Paclitaxel (Taxol) is potent natural anticancer drug that has evolved over the years. It has been useful in the management of many cancers. Hence, this review aims to appraise the pros and cons of paclitaxel in the management of cancers using literature. Paclitaxel acts by obstructing mitotic spindle formation attributed to clampdown of mitotic clampdown hence arresting the cell cycle at the G2/M phase. Some of the notable side effects of paclitaxel usage include: hair loss, numbness, bone marrow suppression, muscle pain, allergic reactions, diarrhea, etc. Among the mechanism of paclitaxel resistance are P-glycoprotein efflux pumps, mutation in tubulin and alterations in binding regions of β-tubulin, altered function of cytokine expression as well as apoptotic Bcl-2 and p53. Combination of paclitaxel with cisplatin clearly improves the duration of progression-free survival and of overall survival of breast cancer. Paclitaxel which is a valuable natural anticancer drug seems promising in the management of non-cancer diseases such as COVID-19, renal and hepatic fibrosis, inflammation, skin disorders, axon regeneration, limb salvage, and coronary artery restenosis. With the advancement of technology, it is expected that the biosynthesis, chemo-resistance as well as its targeted delivery would unfold and perhaps open new uses and vista to the old drug of about five decades ago