Gut Microbiota: Potential Therapeutic Target for Sickle Cell Disease Pain and Complications.

Aim: Sickle cell disease has witnessed a 41.4% surge from 2000 to 2021, significantly affecting morbidity and mortality rates, particularly in children from regions with elevated under-5 mortality rates. Gut microbiota dysbiosis is increasingly recognised in SCD, exacerbating complications, particularly chronic pain, marked by significant alterations of proinflammatory bacteria abundance. This review explores the therapeutic potential of Akkermansia muciniphila and Roseburia spp. in alleviating SCD-related complications, emphasising their roles in maintaining gut barrier integrity, reducing inflammation, and modulating immune responses. Method: A literature search up to November 2023 using PubMed, MEDLINE, and Google Scholar databases explored SCD pathophysiology, gut microbiota composition, Akkermansia muciniphila and Roseburia spp. abundance, pain and gut dysbiosis in SCD, and butyrate therapy. Result: A. muciniphila and Roseburia spp. supplementation shows promise in alleviating chronic pain by addressing gut dysbiosis, offering new avenues for sustainable SCD management. This approach holds the potential for reducing reliance on reactive treatments and improving overall quality of life. This research underscores the pivotal role of the gut microbiome in SCD, advocating for personalised treatment approaches. Conclusion: Further exploration and clinical trials are needed to harness the full potential of these gut bacteria for individuals affected by this challenging condition.

The Lingzhi or Reishi Medicinal Mushroom Ganoderma lucidum (Agaricomycetes) Can Combat Cytokine Storm and Other COVID-19 Related Pathologies: A Review.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is characterized by acute respiratory distress syndrome (ARDS) facilitated by cytokine storm and other risk factors that increase susceptibility and complications leading to death. Emerging as a major global public health challenge, the disease has claimed more than 6 million lives and caused catastrophic global economic disruptions. However, there are concerns about the safety as well as the efficacy of drugs and vaccines presently used to control the pandemic, therefore necessitating intense global search for safe natural products that can effectively and safely combat it. This work reviews studies on lingzhi or reishi medicinal mushroom, Ganoderma lucidum and its properties that may potentially combat SARS-CoV-2 infection and the co-morbidities. Available evidence suggests that medicinal properties of the Ganoderma mushroom can combat the complications of SARS-CoV-2 infection and the co-morbidities that can aggravate the severity of the disease. Preclinical and clinical evaluation to establish dose, efficacy, and potential toxicity and possible use in the management of COVID-19 is recommended.

Identifying immunodominant multi-epitopes from the envelope glycoprotein of the Lassa mammarenavirus as vaccine candidate for Lassa fever.

Purpose: Lassa fever is a zoonotic acute viral hemorrhagic disease caused by Lassa virus (LASV). There is currently no licensed vaccine for the prevention of the disease. This study is aimed at discovering immunodominant epitopes from the envelope glycoprotein of the Lassa mammarenavirus and designing of a multi-epitope vaccine candidate (VC). Materials and Methods: The amino acid sequences of the envelope glycoprotein of 26 strains of LASV from five countries were selected. After evaluation for antigenicity, immunogenicity, allergenicity, and toxicity, immunodominant CD8, CD4, and linear B lymphocytes were also selected. The selected epitopes were modelled and a molecular docking with the appropriate major histocompatibility complex (MHC) proteins was performed. Using an adjuvant and linkers, a multi-epitope VC was designed. The VC was evaluated for its physicochemical and immunological properties and structurally refined, validated, and mutated (disulphide engineering). The complex formed by the VC and the toll-like receptor-4 receptor was subjected to molecular dynamic simulation (MDS) followed by in silico cloning in a plasmid vector. Results: A VC with 203 sequences, 22.13 kDa weight, isoelectric point of 9.85 (basic), instability index value of 27.62, aliphatic index of 68.87, and GRAVY value of -0.455 (hydrophilic) emerged. The VC is predicted to be non-allergenic with antigenicity, MHC I immunogenicity, and solubility upon overexpression values of 0.81, 2.04, and 0.86 respectively. The VC also has an estimated half-life greater than 10 hours in Escherichia coli and showed stability in all the parameters of MDS. Conclusion: The VC shows good promise in the prevention of Lassa fever but further tests are required to validate its safety and efficacy.

Targeting Specific Checkpoints in the Management of SARS-CoV-2 Induced Cytokine Storm.

COVID-19-infected patients require an intact immune system to suppress viral replication and prevent complications. However, the complications of SARS-CoV-2 infection that led to death were linked to the overproduction of proinflammatory cytokines known as cytokine storm syndrome. This article reported the various checkpoints targeted to manage the SARS-CoV-2-induced cytokine storm. The literature search was carried out using PubMed, Embase, MEDLINE, and China National Knowledge Infrastructure (CNKI) databases. Journal articles that discussed SARS-CoV-2 infection and cytokine storm were retrieved and appraised. Specific checkpoints identified in managing SARS-CoV-2 induced cytokine storm include a decrease in the level of Nod-Like Receptor 3 (NLRP3) inflammasome where drugs such as quercetin and anakinra were effective. Janus kinase-2 and signal transducer and activator of transcription-1 (JAK2/STAT1) signaling pathways were blocked by medicines such as tocilizumab, baricitinib, and quercetin. In addition, inhibition of interleukin (IL)-6 with dexamethasone, tocilizumab, and sarilumab effectively treats cytokine storm and significantly reduces mortality caused by COVID-19. Blockade of IL-1 with drugs such as canakinumab and anakinra, and inhibition of Bruton tyrosine kinase (BTK) with zanubrutinib and ibrutinib was also beneficial. These agents' overall mechanisms of action involve a decrease in circulating proinflammatory chemokines and cytokines and or blockade of their receptors. Consequently, the actions of these drugs significantly improve respiration and raise lymphocyte count and PaO2/FiO2 ratio. Targeting cytokine storms' pathogenesis genetic and molecular apparatus will substantially enhance lung function and reduce mortality due to the COVID-19 pandemic.

Identifying potential natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach.

BACKGROUND: Brucellosis is an infectious disease caused by bacteria of the genus Brucella. Although it is the most common zoonosis worldwide, there are increasing reports of drug resistance and cases of relapse after long term treatment with the existing drugs of choice. This study therefore aims at identifying possible natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach. METHODS: Using PyRx 0.8 virtual screening software, the target was docked against a library of natural compounds obtained from edible African plants. The compound, 2-({3-[(3,5-dichlorobenzyl) amino] propyl} amino) quinolin-4(1H)-one (OOU) which is a co-crystallized ligand with the target was used as the reference compound. Screening of the molecular descriptors of the compounds for bioavailability, pharmacokinetic properties, and bioactivity was performed using the SWISSADME, pkCSM, and Molinspiration web servers respectively. The Fpocket and PLIP webservers were used to perform the analyses of the binding pockets and the protein ligand interactions. Analysis of the time-resolved trajectories of the Apo and Holo forms of the target was performed using the Galaxy and MDWeb servers. RESULTS: The lead compounds, Strophanthidin and Isopteropodin are present in Corchorus olitorius and Uncaria tomentosa (Cat's-claw) plants respectively. Isopteropodin had a binding affinity score of -8.9 kcal / ml with the target and had 17 anti-correlating residues in Pocket 1 after molecular dynamics simulation. The complex formed by Isopteropodin and the target had a total RMSD of 4.408 and a total RMSF of 9.8067. However, Strophanthidin formed 3 hydrogen bonds with the target at ILE21, GLY262 and LEU294, and induced a total RMSF of 5.4541 at Pocket 1. CONCLUSION: Overall, Isopteropodin and Strophanthidin were found to be better drug candidates than OOU and they showed potentials to inhibit the Brucella melitensis Methionyl-tRNA synthetase at Pocket 1, hence abilities to treat brucellosis. In-vivo and in-vitro investigations are needed to further evaluate the efficacy and toxicity of the lead compounds.

An evidence-based review of neuronal cholesterol role in dementia and statins as a pharmacotherapy in reducing risk of dementia.

INTRODUCTION: Dementia is a progressive neurodegenerative disorder impairing memory and cognition. Alzheimer's Disease, followed by vascular dementia - the most typical form. Risk factors for vascular dementia include diabetes, cardiovascular disease, hyperlipidemia. Lipids' levels are significantly associated with vascular changes in the brain. AREAS COVERED: The present article reviews the cholesterol metabolism in the brain, which includes: the synthesis, transport, storage, and elimination process. Additionally, it reviews the role of cholesterol in the pathogenesis of dementia and statin as a therapeutic intervention in dementia. In addition to the above, it further reviews evidence in support of as well as against statin therapy in dementia, recent updates of statin pharmacology, and demerits of use of statin pharmacotherapy. EXPERT OPINION: Amyloid-ß peptides and intraneuronal neurofibrillary tangles are markers of Alzheimer's disease. Evidence shows cholesterol modulates the functioning of enzymes associated with Amyloid-ß peptide processing and synthesis. Lowering cholesterol using statin may help prevent or delay the progression of dementia. This paper reviews the role of statin in dementia and recommends extensive future studies, including genetic research, to obtain a precise medication approach for patients with dementia.

Camptothecin shows better promise than Curcumin in the inhibition of the Human Telomerase: A computational study.

OBJECTIVES: The Human Telomerase enzyme has become a drug target in the treatment of cancers and age-related disorders. This study aims to identify potential natural inhibitors of the Human Telomerase from compounds derived from edible African plants. MATERIALS AND METHODS: A library of 1,126 natural compounds was molecularly docked against the Telomerase Reverse Transcriptase (PDB ID: 5ugw), the catalytic subunit of the target protein. Curcumin, a known Telomerase inhibitor was used as the standard. The front-runner compounds were screened for bioavailability, pharmacokinetic properties, and bioactivity using the SWISSADME, PKCSM, and Molinspiration webservers respectively. The molecular dynamic simulation and analyses of the apo and holo proteins were performed by the Galaxy supercomputing webserver. RESULTS: The results of the molecular docking and virtual screening reveal Augustamine and Camptothecin as lead compounds. Augustamine has better drug-likeness and pharmacokinetic properties while Camptothecin showed better bioactivity and stronger binding affinity (-8.2 kcal/mol) with the target. The holo structure formed by Camptothecin showed greater inhibitory activity against the target with a total RMSF of 169.853, B-Factor of 20.164, and 108 anti-correlating residues. CONCLUSION: Though they both act at the same binding site, Camptothecin induces greater Telomerase inhibition and better molecular stability than the standard, Curcumin. Further tests are required to investigate the inhibitory activities of the lead compounds.

Fat-Soluble Vitamins and the Current Global Pandemic of COVID-19: Evidence-Based Efficacy from Literature Review.

The outbreak of pneumonia caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), later named COVID-19 by the World Health Organization (WHO), was initiated at Wuhan, Hubei, China, and there was a rapid spread of novel SARS-CoV-2 and the disease COVID-19 in late 2019. The entire world is now experiencing the challenge of COVID-19 infection. However, still very few evidence-based treatment options are available for the prevention and treatment of COVID-19 disease. The present review aims to summarize the publicly available information to give a comprehensive yet balanced scientific overview of all the fat-soluble vitamins concerning their role in SARS-CoV-2 virus infection. The roles of different fat-soluble vitamins and micronutrients in combating SARS-CoV-2 infection have been recently explored in several studies. There are various hypotheses to suggest their use to minimize the severity of COVID-19 infection. These vitamins are pivotal in the maintenance and modulation of innate and cell-mediated, and antibody-mediated immune responses. The data reported in recent literature demonstrate that deficiency in one or more of these vitamins compromises the patients' immune response and makes them more vulnerable to viral infections and perhaps worse disease prognosis. Vitamins A, D, E, and K boost the body's defense mechanism against COVID-19 infection and specifically prevent its complications such as cytokine storm and other inflammatory processes, leading to increased morbidity and mortality overemphasis. However, more detailed randomized double-blind clinical pieces of evidence are required to define the use of these supplements in preventing or reducing the severity of the COVID-19 infection.

Attenuating the Effects of Novel COVID-19 (SARS-CoV-2) Infection-Induced Cytokine Storm and the Implications.

The COVID-19 pandemic constitutes an arduous global health challenge, and the increasing number of fatalities calls for the speedy pursuit of a remedy. This review emphasizes the changing aspects of the COVID-19 disease, featuring the cytokine storm's pathological processes. Furthermore, we briefly reviewed potential therapeutic agents that may modulate and alleviate cytokine storms. The literature exploration was made using PubMed, Embase, MEDLINE, Google scholar, and China National Knowledge Infrastructure databases to retrieve the most recent literature on the etiology, diagnostic markers, and the possible prophylactic and therapeutic options for the management of cytokine storm in patients hospitalized with COVID-19 disease. The causative agent, severe acute respiratory coronavirus-2 (SARS-CoV-2), continually threatens the efficiency of the immune system of the infected individuals. As the first responder, the innate immune system provides primary protection against COVID-19, affecting the disease's progression, clinical outcome, and prognosis. Evidence suggests that the fatalities associated with COVID-19 are primarily due to hyper-inflammation and an aberrant immune function. Accordingly, the magnitude of the release of pro-inflammatory cytokines such as interleukin (IL)-1, (IL-6), and tumor necrosis alpha (TNF-α) significantly differentiate between mild and severe cases of COVID-19. The early prediction of a cytokine storm is made possible by several serum chemistry and hematological markers. The prompt use of these markers for diagnosis and the aggressive prevention and management of a cytokine release syndrome is critical in determining the level of morbidity and fatality associated with COVID-19. The prophylaxis and the rapid treatment of cytokine storm by clinicians will significantly enhance the fight against the dreaded COVID-19 disease.

The pandemic COVID-19: a tale of viremia, cellular oxidation and immune dysfunction.

COVID-19, caused by SARS-CoV-2 is a tester of the immune system. While it spares the healthy, it brings severe morbidity and in a few cases, mortality to its victims. This article aims at critically reviewing the key virulence factors of COVID-19 which are the viremia, cellular oxidation and immune dysfunction. The averse economic effect of certain disease control measures such as national lock-downs and social distancing, though beneficial, makes them unsustainable. Worse still is the fact that wild animals and domestic pets are carriers of SARS-CoV-2 suggesting that the disease would take longer than expected to be eradicated globally. A better understanding of the pathological dynamics of COVID-19 would help the general populace to prepare for possible infection by the invisible enemy. While the world prospects for vaccines and therapeutic agents against the SARS-CoV-2, clinicians should also seek to modulate the immune system for optimum performance. Immunoprophylactic and immunomodulatory strategies are recommended for the different strata of stakeholders combating the pandemic with the hope that morbidities and mortalities associated with COVID-19 would be drastically reduced.

The Activating Receptors of Natural Killer Cells and Their Inter-Switching Potentials.

The global incidence of cancer is on the increase and researchers are prospecting for specific and non-selective therapies derived from the immune system. The killer activating receptors of NK cells are known to be involved in immunosurveillance against tumor and virally-infected cells. These receptors belong to two main categories, namely the immunoglobulin like and C-lectin like families. Though they have different signal pathways, all the killer activating receptors have similar effector functions which include direct cytotoxicity and the release of inflammatory cytokines such as IFN-gamma and TNF-alpha. To transduce signals that exceed the activation threshold for cytotoxicity, most of these receptors require synergistic effort. This review profiles 21 receptors: 13 immunoglobulin-like, 5 lectin-like, and 3 others. It critically explores their structural uniqueness, role in disease, respective transduction signal pathways and their status as current and prospective targets for cancer immunotherapy. While the native ligands of most of these receptors are known, much work is required to prospect for specific antibodies, peptides and multi-target small molecules with high binding affinities.