Revisiting Luteolin Against the Mediators of Human Metastatic Colorectal Carcinoma: A Biomolecular Approach.

Metastatic colorectal carcinoma (mCRC) is one of the prevalent subtypes of human cancers and is caused by the alterations of various lifestyle and diet-associated factors. ß-catenin, GSK-3ß, PI3K-α, AKT1, and NF-κB p50 are known to be the critical regulators of tumorigenesis and immunopathogenesis of mCRC. Unfortunately, current drugs have limited efficacy, side effects and can lead to chemoresistance. Therefore, searching for a nontoxic, efficacious anti-mCRC agent is crucial and of utmost interest. The present study demonstrates the identification of a productive and nontoxic anti-mCRC agent through a five-targets (ß-catenin, GSK-3ß, PI3K-α, AKT1, and p50)-based and three-tier (binding affinity, pharmacokinetics, and pharmacophore) screening strategy involving a series of 30 phytocompounds having a background of anti-inflammatory/anti-mCRC efficacy alongside 5-fluorouracil (FU), a reference drug. Luteolin (a phyto-flavonoid) was eventually rendered as the most potent and safe phytocompound. This inference was verified through three rounds of validation. Firstly, luteolin was found to be effective against the different mCRC cell lines (HCT-15, HCT-116, DLD-1, and HT-29) without hampering the viability of non-tumorigenic ones (RWPE-1). Secondly, luteolin was found to curtail the clonogenicity of CRC cells, and finally, it also disrupted the formation of colospheroids, a characteristic of metastasis. While studying the mechanistic insights, luteolin was found to inhibit ß-catenin activity (a key regulator of mCRC) through direct physical interactions, promoting its degradation by activating GSK3-ß and ceasing its activation by inactivating AKT1 and PI3K-α. Luteolin also inhibited p50 activity, which could be useful in mitigating mCRC-associated proinflammatory milieu. In conclusion, our study provides evidence on the efficacy of luteolin against the critical key regulators of immunopathogenesis of mCRC and recommends further studies in animal models to determine the effectiveness efficacy of this natural compound for treating mCRC in the future.

Targeting Myeloid Differentiation Primary Response Protein 88 (MyD88) and Galectin-3 to Develop Broad-Spectrum Host-Mediated Therapeutics against SARS-CoV-2.

Nearly six million people worldwide have died from the coronavirus disease (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although COVID-19 vaccines are largely successful in reducing the severity of the disease and deaths, the decline in vaccine-induced immunity over time and the continuing emergence of new viral variants or mutations underscore the need for an alternative strategy for developing broad-spectrum host-mediated therapeutics against SARS-CoV-2. A key feature of severe COVID-19 is dysregulated innate immune signaling, culminating in a high expression of numerous pro-inflammatory cytokines and chemokines and a lack of antiviral interferons (IFNs), particularly type I (alpha and beta) and type III (lambda). As a natural host defense, the myeloid differentiation primary response protein, MyD88, plays pivotal roles in innate and acquired immune responses via the signal transduction pathways of Toll-like receptors (TLRs), a type of pathogen recognition receptors (PRRs). However, recent studies have highlighted that infection with viruses upregulates MyD88 expression and impairs the host antiviral response by negatively regulating type I IFN. Galectin-3 (Gal3), another key player in viral infections, has been shown to modulate the host immune response by regulating viral entry and activating TLRs, the NLRP3 inflammasome, and NF-κB, resulting in the release of pro-inflammatory cytokines and contributing to the overall inflammatory response, the so-called "cytokine storm". These studies suggest that the specific inhibition of MyD88 and Gal3 could be a promising therapy for COVID-19. This review presents future directions for MyD88- and Gal3-targeted antiviral drug discovery, highlighting the potential to restore host immunity in SARS-CoV-2 infections.

Causes of Vaccine Hesitancy in Adults for the Influenza and COVID-19 Vaccines: A Systematic Literature Review.

BACKGROUND: Vaccine hesitancy was labelled as one of the top ten threats to global health by the World Health Organization in 2019 and is associated with negative health outcomes. Previous reviews on cause of vaccines have not included vaccine hesitancy related to the COVID-19 vaccine. This review aimed to fill this gap by synthesising the findings of studies identifying causes of vaccine hesitancy to the COVID-19 and influenza vaccines. METHODS: A systematic literature review was conducted. Searches were carried out in the PubMed, EMBASE and Cochrane databases. Following data extraction, a thematic analysis was conducted of the causes of vaccine hesitancy in adults for the influenza and COVID-19 vaccines. RESULTS: Fourteen papers were included. Four themes were identified as causes of vaccine hesitancy comprising: concerns over safety, lack of trust, lack of need for vaccination and cultural reasons. While concerns over safety were found in all countries, some of these were specific to particular countries and cultures. Our findings suggest that scientific knowledge of vaccines and size of clinical trials during their development reduce vaccine hesitancy. However, pharmaceutical companies were not a trusted source of information. CONCLUSION: Our findings build on those of previous research to suggest specific information that may be helpful in addressing vaccine hesitancy. Targeted approaches from trusted sources are needed to address specific safety concerns.