14-3-3 Family of Proteins: Biological Implications, Molecular Interactions, and Potential Intervention in Cancer, Virus and Neurodegeneration Disorders.

The 14-3-3 family of proteins are highly conserved acidic eukaryotic proteins (25-32 kDa) abundantly present in the body. Through numerous binding partners, the 14-3-3 is responsible for many essential cellular pathways, such as cell cycle regulation and gene transcription control. Hence, its dysregulation has been linked to the onset of critical illnesses such as cancers, neurodegenerative diseases and viral infections. Interestingly, explorative studies have revealed an inverse correlation of 14-3-3 protein in cancer and neurodegenerative diseases, and the direct manipulation of 14-3-3 by virus to enhance infection capacity has dramatically extended its significance. Of these, COVID-19 has been linked to the 14-3-3 proteins by the interference of the SARS-CoV-2 nucleocapsid (N) protein during virion assembly. Given its predisposition towards multiple essential host signalling pathways, it is vital to understand the holistic interactions between the 14-3-3 protein to unravel its potential therapeutic unit in the future. As such, the general structure and properties of the 14-3-3 family of proteins, as well as their known biological functions and implications in cancer, neurodegeneration, and viruses, were covered in this review. Furthermore, the potential therapeutic target of 14-3-3 proteins in the associated diseases was discussed.

The anti-allergic potential of stingless bee honey from different botanical sources via modulation of mast cell degranulation.

BACKGROUND: Allergy is an inflammatory disorder affecting around 20% of the global population. The adverse effects of current conventional treatments give rise to the increased popularity of using natural food products as complementary and alternative medicine against allergic diseases. Stingless bee honey, commonly known as Kelulut honey (KH) in Malaysia, has been used locally as a traditional remedy to relieve cough and asthma. This study evaluated the anti-allergic potential of KH collected from four different botanical sources on phorbol ester 12-myristate-3-acetate and calcium ionophore-activated human mast cells. METHODS: The present study examined the inhibitory effects of all collected honey on the release of selected inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-4, IL-6, IL-8, histamine, and ß-hexosaminidase in an activated HMC. Besides that, all honey's total phenolic content (TPC) was also examined, followed by using liquid chromatography with tandem mass spectrometry (LC-MS/MS) to identify the phytochemicals in the honey. Further examination of the identified phytochemicals on their potential interaction with selected signaling molecules in an activated mast cell was conducted using computational methods. RESULTS: The results indicated that there were significant inhibitory effects on all selected inflammatory mediators' release by KH sourced from bamboo (BH) and rubber tree (RH) at 0.5% and 1%, but not KH sourced from mango (AH) and noni (EH). BH and RH were found to have higher TPC values and were rich in their phytochemical profiles based on the LC-MS/MS results. Computational studies were employed to determine the possible molecular target of KH through molecular docking using HADDOCK and PRODIGY web servers. CONCLUSIONS: In short, the results indicated that KH possesses anti-allergic effects towards an activated HMC, possibly by targeting downstream MAPKs. However, their anti-allergic effects may vary according to their botanical sources. Nevertheless, the present study has provided insight into the potential application of stingless bee honey as a complementary and alternative medicine to treat various allergic diseases.

Evolution of SARS-CoV-2 Variants: Implications on Immune Escape, Vaccination, Therapeutic and Diagnostic Strategies.

The COVID-19 pandemic caused by SARS-CoV-2 is associated with a lower fatality rate than its SARS and MERS counterparts. However, the rapid evolution of SARS-CoV-2 has given rise to multiple variants with varying pathogenicity and transmissibility, such as the Delta and Omicron variants. Individuals with advanced age or underlying comorbidities, including hypertension, diabetes and cardiovascular diseases, are at a higher risk of increased disease severity. Hence, this has resulted in an urgent need for the development of better therapeutic and preventive approaches. This review describes the origin and evolution of human coronaviruses, particularly SARS-CoV-2 and its variants as well as sub-variants. Risk factors that contribute to disease severity and the implications of co-infections are also considered. In addition, various antiviral strategies against COVID-19, including novel and repurposed antiviral drugs targeting viral and host proteins, as well as immunotherapeutic strategies, are discussed. We critically evaluate strategies of current and emerging vaccines against SARS-CoV-2 and their efficacy, including immune evasion by new variants and sub-variants. The impact of SARS-CoV-2 evolution on COVID-19 diagnostic testing is also examined. Collectively, global research and public health authorities, along with all sectors of society, need to better prepare against upcoming variants and future coronavirus outbreaks.

SARS-CoV-2 Non-Structural Proteins and Their Roles in Host Immune Evasion.

Coronavirus disease 2019 (COVID-19) has caused an unprecedented global crisis and continues to threaten public health. The etiological agent of this devastating pandemic outbreak is the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). COVID-19 is characterized by delayed immune responses, followed by exaggerated inflammatory responses. It is well-established that the interferon (IFN) and JAK/STAT signaling pathways constitute the first line of defense against viral and bacterial infections. To achieve viral replication, numerous viruses are able to antagonize or hijack these signaling pathways to attain productive infection, including SARS-CoV-2. Multiple studies document the roles of several non-structural proteins (NSPs) of SARS-CoV-2 that facilitate the establishment of viral replication in host cells via immune escape. In this review, we summarize and highlight the functions and characteristics of SARS-CoV-2 NSPs that confer host immune evasion. The molecular mechanisms mediating immune evasion and the related potential therapeutic strategies for controlling the COVID-19 pandemic are also discussed.

Repurposing Molnupiravir for COVID-19: The Mechanisms of Antiviral Activity.

Molnupiravir is a ß-d-N4-hydroxycytidine-5'-isopropyl ester (NHC) compound that exerts antiviral activity against various RNA viruses such as influenza, SARS, and Ebola viruses. Thus, the repurposing of Molnupiravir has gained significant attention for combatting infection with SARS-CoV-2, the etiological agent of COVID-19. Recently, Molnupiravir was granted authorization for the treatment of mild-to-moderate COVID-19 in adults. Findings from in vitro experiments, in vivo studies and clinical trials reveal that Molnupiravir is effective against SARS-CoV-2 by inducing viral RNA mutagenesis, thereby giving rise to mutated complementary RNA strands that generate non-functional viruses. To date, the data collectively suggest that Molnupiravir possesses promising antiviral activity as well as favorable prophylactic efficacy, attributed to its effective mutagenic property of disrupting viral replication. This review discusses the mechanisms of action of Molnupiravir and highlights its clinical utility by disabling SARS-CoV-2 replication, thereby ameliorating COVID-19 severity. Despite relatively few short-term adverse effects thus far, further detailed clinical studies and long-term pharmacovigilance are needed in view of its mutagenic effects.

Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action against SARS-CoV-2 replication.

Ivermectin (IVM) is an FDA approved macrocyclic lactone compound traditionally used to treat parasitic infestations and has shown to have antiviral potential from previous in-vitro studies. Currently, IVM is commercially available as a veterinary drug but have also been applied in humans to treat onchocerciasis (river blindness - a parasitic worm infection) and strongyloidiasis (a roundworm/nematode infection). In light of the recent pandemic, the repurposing of IVM to combat SARS-CoV-2 has acquired significant attention. Recently, IVM has been proven effective in numerous in-silico and molecular biology experiments against the infection in mammalian cells and human cohort studies. One promising study had reported a marked reduction of 93% of released virion and 99.98% unreleased virion levels upon administration of IVM to Vero-hSLAM cells. IVM's mode of action centres around the inhibition of the cytoplasmic-nuclear shuttling of viral proteins by disrupting the Importin heterodimer complex (IMPα/ß1) and downregulating STAT3, thereby effectively reducing the cytokine storm. Furthermore, the ability of IVM to block the active sites of viral 3CLpro and S protein, disrupts important machinery such as viral replication and attachment. This review compiles all the molecular evidence to date, in review of the antiviral characteristics exhibited by IVM. Thereafter, we discuss IVM's mechanism and highlight the clinical advantages that could potentially contribute towards disabling the viral replication of SARS-CoV-2. In summary, the collective review of recent efforts suggests that IVM has a prophylactic effect and would be a strong candidate for clinical trials to treat SARS-CoV-2.

SARS coronavirus outbreaks past and present-a comparative analysis of SARS-CoV-2 and its predecessors.

The Coronavirus Disease 2019 (COVID-19), a pneumonic disease caused by the SARS Coronavirus 2 (SARS-CoV-2), is the 7th Coronavirus to have successfully infected and caused an outbreak in humans. Genome comparisons have shown that previous isolates, the SARS-related coronavirus (SARSr-CoV), including the SARS-CoV are closely related, yet different in disease manifestation. Several explanations were suggested for the undetermined origin of SARS-CoV-2, in particular, bats, avian and Malayan pangolins as reservoir hosts, owing to the high genetic similarity. The general morphology and structure of all these viral isolates overlap with analogous disease symptoms such as fever, dry cough, fatigue, dyspnoea and headache, very similar to the current SARS-CoV-2. Chest CT scans for SARS-CoV-2, SARS-CoV and MERS-CoV reveal pulmonary lesions, bilateral ground-glass opacities, and segmental consolidation in the lungs, a common pathological trait. With greatly overlapping similarities among the previous coronavirus, the SARS-CoV, it becomes interesting to observe marked differences in disease severity of the SARS-CoV-2 thereby imparting it the ability to rapidly transmit, exhibit greater stability, bypass innate host defences, and increasingly adapt to their new host thereby resulting in the current pandemic. The most recent B.1.1.7, B.1.351 and P.1 variants of SARS-CoV-2, highlight the fact that changes in amino acids in the Spike protein can contribute to enhanced infection and transmission efficiency. This review covers a comparative analysis of previous coronavirus outbreaks and highlights the differences and similarities among different coronaviruses, including the most recent isolates that have evolved to become easily transmissible with higher replication efficiency in humans.