An Appraisal of the Current Scenario in Vaccine Research for COVID-19

The recent coronavirus disease 2019 (COVID-19) outbreak has drawn global attention, affecting millions, disrupting economies and healthcare modalities. With its high infection rate, COVID-19 has caused a colossal health crisis worldwide. While information on the comprehensive nature of this infectious agent, SARS-CoV-2, still remains obscure, ongoing genomic studies have been successful in identifying its genomic sequence and the presenting antigen. These may serve as promising, potential therapeutic targets in the effective management of COVID-19. In an attempt to establish herd immunity, massive efforts have been directed and driven toward developing vaccines against the SARS-CoV-2 pathogen. This review, in this direction, is aimed at providing the current scenario and future perspectives in the development of vaccines against SARS-CoV-2

An overview of vaccine development for COVID-19

The COVID-19 pandemic continues to endanger world health and the economy. The causative SARS-CoV-2 coronavirus has a unique replication system. The end point of the COVID-19 pandemic is either herd immunity or widespread availability of an effective vaccine. Multiple candidate vaccines - peptide, virus-like particle, viral vectors (replicating and nonreplicating), nucleic acids (DNA or RNA), live attenuated virus, recombinant designed proteins and inactivated virus - are presently under various stages of expansion, and a small number of vaccine candidates have progressed into clinical phases. At the time of writing, three major pharmaceutical companies, namely Pfizer and Moderna, have their vaccines under mass production and administered to the public. This review aims to investigate the most critical vaccines developed for COVID-19 to date

Targeting eosinophils in respiratory diseases: Biological axis, emerging therapeutics and treatment modalities

Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders

Interplay between Endoplasmic Reticular Stress and Survivin in Colonic Epithelial Cells

Sustained endoplasmic reticular stress (ERS) is implicated in aggressive metastasis of cancer cells and increased tumor cell proliferation. Cancer cells activate the unfolded protein response (UPR), which aids in cellular survival and adaptation to harsh conditions. Inhibition of apoptosis, in contrast, is a mechanism adopted by cancer cells with the help of the inhibitor of an apoptosis (IAP) class of proteins such as Survivin to evade cell death and gain a proliferative advantage. In this study, we aimed to reveal the interrelation between ERS and Survivin. We initially verified the expression of Survivin in Winnie (a mouse model of chronic ERS) colon tissues by using immunohistochemistry (IHC) and immunofluorescence (IF) in comparison with wild type Blk6 mice. Additionally, we isolated the goblet cells and determined the expression of Survivin by IF and protein validation. Tunicamycin was utilized at a concentration of 10 µg/mL to induce ERS in the LS174T cell line and the gene expression of the ERS markers was measured. This was followed by determination of inflammatory cytokines. Inhibition of ERS was carried out by 4Phenyl Butyric acid (4PBA) at a concentration of 10 mM to assess whether there was a reciprocation effect. The downstream cell death assays including caspase 3/7, Annexin V, and poly(ADP-ribose) polymerase (PARP) cleavage were evaluated in the presence of ERS and absence of ERS, which was followed by a proliferative assay (EdU click) with and without ERS. Correspondingly, we inhibited Survivin by YM155 at a concentration of 100 nM and observed the succeeding ERS markers and inflammatory markers. We also verified the caspase 3/7 assay. Our results demonstrate that ERS inhibition not only significantly reduced the UPR genes (Grp78, ATF6, PERK and XBP1) along with Survivin but also downregulated the inflammatory markers such as IL8, IL4, and IL6, which suggests a positive correlation between ERS and the inhibition of apoptosis. Furthermore, we provided evidence that ERS inhibition promoted apoptosis in LS174T cells and shortened the proliferation rate. Moreover, Survivin inhibition by YM155 led to a comparable effect as that of ERS inhibition, which includes attenuation of ERS genes and inflammatory markers as well as the promotion of programmed cell death via the caspase 3/7 pathway. Together, our results propose the interrelation between ERS and inhibition of apoptosis assigning a molecular and therapeutic target for cancer treatment

In-vitro suppression of IL-6 and IL-8 release from human pulmonary epithelial cells by non-anticoagulant fraction of enoxaparin.

Enoxaparin, a mixture of anticoagulant and non-anticoagulant fractions, is widely used as an anticoagulant agent. However, it is also reported to possess anti-inflammatory properties. Our study indicated that enoxaparin inhibits the release of IL-6 and IL-8 from A549 pulmonary epithelial cells. Their release causes extensive lung tissue damage. The use of enoxaparin as an anti-inflammatory agent is hampered due to the risk of bleeding associated with its anticoagulant fractions. Therefore, we aimed to identify the fraction responsible for the observed anti-inflammatory effect of enoxaparin and to determine the relationship between its structure and biological activities.A549 pulmonary epithelial cells were pre-treated in the presence of enoxaparin and its fractions. The levels of IL-6 and IL-8 released from the trypsin-stimulated cells were measured by ELISA. The anticoagulant activity of the fraction responsible for the effect of enoxaparin was determined using an anti-factor-Xa assay. The fraction was structurally characterised using nuclear magnetic resonance. The fraction was 2-O, 6-O or N-desulfated to determine the position of sulfate groups required for the inhibition of interleukins. High-performance size-exclusion chromatography was performed to rule out that the observed effect was due to the interaction between the fraction and trypsin or interleukins.Enoxaparin (60 μg/mL) inhibited the release of IL-6 and IL-8 by >30%. The fraction responsible for this effect of enoxaparin was found to be a disaccharide composed of α-L-iduronic-acid and α-D-glucosamine-6-sulfate. It (15 μg/mL) inhibited the release of interleukins by >70%. The 6-O sulphate groups were responsible for its anti-inflammatory effect. The fraction did not bind to trypsin or interleukins, suggesting the effect was not due to an artefact of the experimental model.The identified disaccharide has no anticoagulant activity and therefore eliminates the risk of bleeding associated with enoxaparin. Future in-vivo studies should be designed to validate findings of the current study

Therapeutic Potential of Enoxaparin in Lichen Planus: Exploring Reasons for Inconsistent Reports

Lichen planus (LP) is an uncommon mucocutaneous inflammatory condition, that is immunologically mediated, typically pruritic and often recurs. The currently advocated therapies are either not highly effective or associated with severe side effects. Enoxaparin, a widely used anticoagulant, is composed of both anticoagulant and non-anticoagulant fragments. Enoxaparin is reported to have anti-inflammatory properties and it was found to be effective in LP. However, the results from clinical studies have varied substantially and, therefore, the clinical role of enoxaparin in LP remains uncertain. This review focuses on potential reasons for the reported inconsistent outcomes, as well as proposing solutions; these include identifying batch-to-batch inconsistency in the composition of enoxaparin. The potential therapeutic value of enoxaparin in LP must be explored using well-designed clinical trials, combined with experimental studies that focus on identifying the anti-inflammatory fragments of enoxaparin and elucidating the mechanism of action of these non-anticoagulant fragments

Role of Oxidative Stress in the Pathology and Management of Human Tuberculosis

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, is the leading cause of mortality worldwide due to a single infectious agent. The pathogen spreads primarily via aerosols and especially infects the alveolar macrophages in the lungs. The lung has evolved various biological mechanisms, including oxidative stress (OS) responses, to counteract TB infection. M. tuberculosis infection triggers the generation of reactive oxygen species by host phagocytic cells (primarily macrophages). The development of resistance to commonly prescribed antibiotics poses a challenge to treat TB; this commonly manifests as multidrug resistant tuberculosis (MDR-TB). OS and antioxidant defense mechanisms play key roles during TB infection and treatment. For instance, several established first-/second-line antitubercle antibiotics are administered in an inactive form and subsequently transformed into their active form by components of the OS responses of both host (nitric oxide, S-oxidation) and pathogen (catalase/peroxidase enzyme, EthA). Additionally, M. tuberculosis has developed mechanisms to survive high OS burden in the host, including the increased bacterial NADH/NAD+ ratio and enhanced intracellular survival (Eis) protein, peroxiredoxin, superoxide dismutases, and catalases. Here, we review the interplay between lung OS and its effects on both activation of antitubercle antibiotics and the strategies employed by M. tuberculosis that are essential for survival of both drug-susceptible and drug-resistant bacterial subtypes. We then outline potential new therapies that are based on combining standard antitubercular antibiotics with adjuvant agents that could limit the ability of M. tuberculosis to counter the host’s OS response