Search Results (773)

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the etiologic agent that causes the coronavirus disease (COVID-19) identified in Wuhan, in 2019. Men are more prone to developing severe manifestations than women, suggesting a possible crucial role of sex hormones. 17,β-Estradiol (E2) and 1,25 α dihydroxyvitamin D₃ (calcitriol) act upon gene pathways as immunomodulators in several infectious respiratory diseases. In this study, we aimed to evaluate the influence of E2 and calcitriol on the VSV-based pseudovirus SARS-CoV-2 and SARS-CoV-2 infection in vitro. We infected Vero E6 cells with the recombinant VSV-based pseudovirus SARS-CoV-2 and the SARS-CoV-2 viruses according to the pre-treatment and pre–post-treatment models. The Angiotensin-Converting Enzyme 2 (ACE2) and Vitamin D Receptor (VDR) gene expression did not change under different treatments. The VSV-based pseudovirus SARS-CoV-2 infection showed a significant decrease in the focus-forming unit count in the presence of E2 and calcitriol (either alone or in combination) in the pre-treatment model, while in the pre–post-treatment model, the infection was inhibited only in the presence of E2. Th SARS-CoV-2 infection highlighted a decrease in viral titres in the presence of E2 and calcitriol only in the pre–post-treatment model. 17,β-Estradiol and calcitriol can exert an inhibitory effect on SARS-CoV-2 infections, demonstrating their protective role against viral infections. Full article

The synthesis and structural characterization of three new triple-stranded helical complexes ([Dy₂(L²)₃]2Cl∙15H₂O (C1), [Y₂(L²)₃]3(NO₃)Cl∙14H₂O∙DMSO (C2), and [Eu₂(L⁴)₃]∙12H₂O (C3), where L² and L⁴ are ligands derived from pyridoxal hydrochloride and succinic or adipic acid dihydrazides, respectively, were described. The X-ray data, combined with spectroscopic measurements, indicated that L² and L⁴ act as bis-tridentate ligands, presenting two tridentate chelating cavities O,N,O to obtain the dinuclear complexes C1–C3. Their antiviral profile was predicted via in silico calculations in terms of interaction with the structural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein in the down- and up-states and complexed with the cellular receptor angiotensin-converting enzyme 2 (ACE2). The best affinity energy values (−9.506, −9.348, and −9.170 kJ/mol for C1, C2, and C3, respectively) were obtained for the inorganic complexes docked in the model spike-ACE2, with C1 being suggested as the most promising candidate for a future in vitro validation. The obtained in silico antiviral trend was supported by the prediction of the electronic and physical–chemical properties of the inorganic complexes via the density functional theory (DFT) approach, representing an original and relevant contribution to the bioinorganic and medicinal chemistry fields. Full article

The renin–angiotensin system (RAS) plays a central role in cardiovascular regulation and has gained prominence in the pathogenesis of Coronavirus Disease 2019 (COVID-19) due to the critical function of angiotensin-converting enzyme 2 (ACE2) as the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin IV, but not angiotensin II, has recently been reported to enhance the binding between the viral spike protein and ACE2. To investigate the virological significance of this effect, we developed a single-round infection assay using SARS-CoV-2 viral-like particles expressing the spike protein. Our results demonstrate that while angiotensin II does not affect viral infectivity across concentrations ranging from 40 nM to 400 nM, angiotensin IV enhances viral entry at a low concentration but exhibits dose-dependent inhibition at higher concentrations. These findings highlight the unique dual role of angiotensin IV in modulating SARS-CoV-2 entry. In silico molecular docking simulations indicate that angiotensin IV was predicted to associate with the S1 domain near the receptor-binding domain in the open spike conformation. Given that reported plasma concentrations of angiotensin IV range widely from 17 pM to 81 nM, these levels may be sufficient to promote, rather than inhibit, SARS-CoV-2 infection. This study identifies a novel link between RAS-derived peptides and SARS-CoV-2 infectivity, offering new insights into COVID-19 pathophysiology and informing potential therapeutic strategies. Full article

Angiotensin-converting enzyme 2 (ACE2) is a cell-surface receptor that helps the body regulate blood pressure and endocrine secretions. Transmembrane serine protease 2 (TMPRSS2) is a cell surface protein expressed mainly by endothelial cells of the respiratory and digestive tract, which participates in the cleavage of protein peptide bonds with serine as the active site. These two proteins have been studied to be highly associated with infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soybean trypsin inhibitor (SBTI) has special bioactivities such as anticarcinogenic and anti-inflammatory functions, which can be widely used in functional foods or drugs. Our study involved in vitro and in vivo experiments to elucidate the effect of SBTI on SARS-CoV-2 host invasion. First, it was confirmed that being under 250 μg/mL of SBTI was not toxic to HepG2, HEK293T, and Calu-3 cells. The animal study administered SBTI to mice once daily for 14 days. In the lungs, liver, and kidneys, the histopathologic findings of the SBTI group were not different from those of the control group, but the expression of ACE2, TMPRSS2, and CD147 was reduced. Thus, our findings suggest that the inhibition of ACE2, TMPRSS,2 and CD147 proteins by SBTI shows promise in potentially inhibiting SARS-CoV-2 infection. Full article

The renin-angiotensin-aldosterone system (RAAS) is a hormone system that controls blood pressure and fluid and electrolyte balance. Angiotensin II, a key effector, is produced from angiotensin I by angiotensin-converting enzyme (ACE) and exerts its effects through binding to its type 1 (AT1R) or type 2 (AT2R) receptors. AT1R activation promotes vasoconstriction, oxidative stress, endothelial dysfunction, peripheral vascular resistance, and atherosclerosis, all of which substantially contribute to cellular senescence and organismal ageing. Conversely, AT2R activation counteracts these effects by inducing vascular relaxation and attenuating vascular cell proliferation and migration, offering protection against occlusive vascular disease. Additionally, conversion of angiotensin II to angiotensin (1-7) or angiotensin I to angiotensin (1-9) by ACE2 provides further cardiovascular protection by lowering oxidative stress, inflammation, and abnormal cell growth. Bearing these in mind, measures to control angiotensin II synthesis or receptor activity have been at the forefront of antihypertensive treatment. This paper briefly reviews the RAAS and explores the dual role of angiotensin II in promoting disease and mediating vascular protection, with a focus on its impact on ageing and cardiovascular pathology. Full article

Chicken feathers constitute a major by-product from the poultry industry, with a potential environmental impact and significant difficulties in their management. This study aimed to develop a sustainable method to hydrolyse chicken feathers and evaluate the effects of microwave (MW) irradiation pre-treatment in the generation of bioactive hydrolysates by simple or sequential hydrolysis with Alcalase. The hydrolysate with MW irradiation pre-treatment and Alcalase (2%, 2 h) (MWA) showed the highest overall antioxidant activity and neprilysin-inhibitory activity (55%), whereas samples without MW irradiation pre-treatment exerted the highest inhibitory activity of dipeptidyl peptidase IV (DPP IV) and angiotensin-converting enzyme (ACE-I), with values close to 50 and 70%, respectively. Mass spectrometry in tandem of bioactive hydrolysates was performed, and an in silico approach was used to characterise the obtained sequences. These results confirmed that MW irradiation pre-treatment improved Alcalase hydrolysis, leading to the generation of bioactive peptides with potential multifunctional properties, including antioxidant, antidiabetic, and antihypertensive activities. Moreover, this study highlights the potential of combining MW irradiation and enzymatic hydrolysis as a sustainable strategy for the revalorisation of chicken feathers. Full article

Background/Objectives: Chloroquine (CQ) and hydroxychloroquine (HCQ) have been the subject of debate in the treatment of COVID-19 due to the lack of conclusive evidence regarding their efficacy and safety. Our study aims to investigate the molecular interaction between the enantiomers of CQ and HCQ with angiotensin-converting enzyme 2 (ACE2), focusing on the binding mechanism, affinity, and selectivity. Methods: We used in silico methods, including molecular docking, molecular dynamics, and binding free energy calculations using the MM-PBSA method, to evaluate the interaction between the enantiomers of CQ and HCQ with ACE2. Results: We identified three main interaction sites on ACE2 (α, β, and γ) with distinct characteristics based on the pocket size, hydrophilic/hydrophobic characteristics, and affinity energy. We observed that protonation states and ionic strength significantly influence the binding affinity and specificity. In particular, the selectivity of the β-site, characterized by its smaller size and hydrophilic residues, is preferential for species with the (R) configuration, whereas the α and γ binding sites, with a larger size and amphiphilic residues, have greater affinity for the (S) enantiomer of CQ and HCQ. Furthermore, ionic strength can affect ligand binding by modulating electrostatic interactions, molecular conformation, solvation, and the stability of the complex. Conclusions: Our findings reveal that protonation states and the ionic strength substantially impact the binding affinity and specificity, regulated by spatial and polar–electrostatic complementarity, as well as hydrophobic contributions. These results suggest that understanding the interaction between CQ and HCQ enantiomers with ACE2 could be useful for the design of novel therapies against COVID-19. Full article

The diversity of structural types of carrageenans (CRGs)—sulfated polysaccharides of red algae—determines their different biological activities. The different types of CRGs (kappa, lambda, kappa/beta-CRGs) were isolated from the red algae of the Pacific coast. Molecular docking was performed to determine potential interactions of CRGs with the receptor-binding domain (RBD) of SARS-CoV-2 and its cellular receptor—angiotensin—converting enzyme type 2 (ACE2). CRGs interacted with ACE2 and RBD via hydrogen bonding and ionic interactions. The strongest binding affinity of CRGs and ACE2 was observed for kappa-CRG. Molecular docking was confirmed by results studying the effects of CRGs against SARS-CoV-2 in vitro. The ability of CRGs, as well as the complex CRG with sea urchin echinochrome (Ech), to inhibit SARS-CoV-2 replication in Vero E6 cells was studied using cytopathic effect (CPE) inhibition and RT-PCR assays. The simultaneous treatment of cells with CRGs and the virus revealed that kappa-CRG exhibited the most significant antiviral effect among all the polysaccharides, with a selective index (SI) of 33. The kappa-CRG/Ech complex exhibited the highest virucidal effect on SARS-CoV-2 particles with an SI above 70 (more than two times higher than that of CRG and Ech) and reduced viral RNA levels by 45% (IC = 45%). Our results illustrate that CRGs and kappa-CRG/Ech complex can act as protective agents against SARS-CoV-2. Full article

This study explored the development of a novel whey-based fermented beverage enriched with juice concentrates and health-promoting ingredients, emphasizing its bioactive properties. The formulation included whey protein isolate (5%), juice concentrates (10% apple, raspberry, and cranberry), and inulin (4%). Fermentation was carried out with the following strains: Lacticaseibacillus rhamnosus (LGG), Lacticaseibacillus casei (431), and Lactobacillus helveticus (R0052) at 2%. Antimicrobial activity was evaluated against pathogens including Listeria monocytogenes (strains 33423 and 33413), Staphylococcus aureus (113 and Newman), Bacillus cereus (DPC 6089), Escherichia coli (NCTC 9001), and Salmonella Enteritidis (NCTC 6676). Antioxidant capacity was measured using 2,2-Diphenyl-1-picrylhydrazylradical (DPPH) and Ferric Reducing Antioxidant Power (FRAP) assays, and angiotensin-converting enzyme (ACE) inhibitory activity was assessed. All bioactivities were found to be high in fermented whey beverage and a further significant increase was observed after simulated gastrointestinal digestion. This fruit-flavored whey beverage demonstrated notable antimicrobial and antioxidant activities, highlighting its potential for functional food applications aimed at combating harmful bacteria and oxidative stress. Full article

Background: The COVID-19 (coronavirus disease 19) pandemic has underscored the urgent need for effective antiviral agents targeting viral entry mechanisms. This study investigated the inhibitory effects of heparan sulfate (HS) and enoxaparin (EX) on the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor. Methods: A pseudovirus model was employed to evaluate the efficacy of HS and EX under different treatment strategies: pre-treatment of host cells, pre-treatment of the viral particles, and simultaneous co-treatment. Results: Both compounds significantly inhibited viral entry. EX exhibited a dose-dependent effect under all treatment conditions. In cell pre-treatment, EX achieved the highest levels of inhibition, whereas HS demonstrated consistent inhibitory activity that was largely concentration-independent. Viral pre-treatment revealed that both compounds effectively reduced infectivity by interfering directly with viral particles. In the co-treatment experiments, HS demonstrated superior inhibitory activity at lower concentrations compared to EX. Conclusions: The results suggested that HS and EX inhibit SARS-CoV-2 entry via distinct mechanisms. HS likely acts via competitive inhibition at the host cell surface, while EX may bind directly to the spike protein, thereby preventing engagement with the ACE2 receptor. These findings highlight the therapeutic potential of HS and EX as entry inhibitors targeting the early stages of SARS-CoV-2 infection. Further studies are warranted to evaluate their efficacy against emerging variants and in vivo models. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, remains a major global health threat. The virus enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. Several small-molecule antiviral drugs, including molnupiravir, favipiravir, remdesivir, and nirmatrelvir have been shown to inhibit SARS-CoV-2 replication and are approved for treating SARS-CoV-2 infections. Nirmatrelvir inhibits the viral main protease (M^pro), a key enzyme for processing polyproteins in viral replication. In contrast, molnupiravir, favipiravir, and remdesivir are prodrugs that target RNA-dependent RNA polymerase (RdRp), which is crucial for genome replication and subgenomic RNA production. However, undergoing extensive metabolism profoundly impacts their therapeutic effects. Carboxylesterases (CES) are a family of enzymes that play an essential role in the metabolism of many drugs, especially prodrugs that require activation through hydrolysis. Molnupiravir is activated by carboxylesterase-2 (CES2), while remdesivir is hydrolytically activated by CES1 but inhibits CES2. Nirmatrelvir and remdesivir are oxidized by the same cytochrome P450 (CYP) enzyme. Additionally, various transporters are involved in the uptake or efflux of these drugs and/or their metabolites. It is well established that drug-metabolizing enzymes and transporters are differentially expressed depending on the cell type, and these genes exhibit significant polymorphisms. In this review, we examine how CES-related cellular and genetic factors influence the therapeutic activities of these widely used COVID-19 medications. This article highlights implications for improving product design, targeted inhibition, and personalized medicine by exploring genetic variations and their impact on drug metabolism and efficacy. Full article

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for Coronavirus Disease 2019 (COVID-19), utilizes its spike protein to infect host cells. In addition to angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1), AXL acts as a spike protein receptor and mediates infection, especially in respiratory cells with low ACE2 expression. Angiotensin II (1–8) can be cleaved into shorter peptides within the biological system. Antibody-based binding assays showed that angiotensin II causes a two-fold increase in the binding between the spike protein and AXL, but not ACE2 or NRP1. While a longer peptide, angiotensin I (1–10), did not affect the spike–AXL binding, shorter lengths of angiotensin peptides exhibited enhancing effects. The C-terminal deletions of angiotensin II to angiotensin (1–7) or angiotensin (1–6) resulted in peptides with enhanced activity toward spike–AXL binding with a similar capacity as angiotensin II. In contrast, the N-terminal deletions of angiotensin II to angiotensin III (2–8) or angiotensin IV (3–8) as well as the N-terminal deletions of angiotensin (1–7) to angiotensin (2–7) or angiotensin (5–7) produced peptides with a more potent ability to enhance spike–AXL binding (2.7-fold increase with angiotensin IV). When valine was substituted for tyrosine at position 4 in angiotensin II or when tyrosine at position 4 was phosphorylated, spike–AXL binding was increased, suggesting that modifications to tyrosine trigger enhancement. Angiotensin IV also enhances spike protein binding to ACE2 and NRP1. Thus, angiotensin peptides may contribute to COVID-19 pathogenesis by enhancing spike protein binding and thus serve as therapeutic targets. Full article

(1) Background: Heart failure (HF) and dementia are commonly associated with the elderly. A significant percentage of patients with HF are at high risk of cognitive decline and progression to dementia. Cognitive impairment is associated with both diseases. However, the molecules and mechanisms that affect the HF–dementia axis are poorly understood. (2) Objective: In this work, we aim to identify potential proteins that modulate HF and dementia. (3) Methods: We applied a pipeline using bioinformatic tools that robustly perform a literature search. (4) Results: Our results show that apolipoprotein E (APOE), c-reactive protein (CRP), interleukin 6 (IL6), renin (REN), and angiotensin-converting enzyme (ACE) proteins are important for maintaining homeostasis in the heart–brain axis. Additionally, deregulated levels of these proteins are associated with neuronal and cardiovascular diseases. (5) Conclusions: Our work highlights proteins that may help in understanding the pathophysiological relationship between HF and dementia. Moreover, these proteins may also be potential biomarkers and/or therapeutic targets. Full article

Post-COVID-19 is a chronic infection-related syndrome, including exacerbations of pre-existing or newly diagnosed conditions that have been established after the acute phase of COVID-19 and have demonstrated a wide range of systemic effects beyond the lungs. SARS-CoV-2 attaches to its receptor, angiotensin-converting enzyme 2 (ACE-2). Transmembrane serine protease 2 (TMPRSS2) facilitates viral entry and spread. ACE-2 receptors are detectable in several tissues, including the respiratory mucosa, digestive tract, heart, kidney, and brain. Several investigations have demonstrated an increase in digestive manifestations post-acute COVID-19, likely related to an alteration in the intestinal microbiota following infection. These changes can lead to a loss of species diversity, resulting in an overgrowth of opportunistic pathogens and deprivation of commensal bacteria. In this context, post-infection irritable bowel syndrome shows an increased incidence compared to controls. Growing evidence also suggests the enduring presence of SARS-CoV-2 in the gut tissue. Studies are ongoing to investigate antiviral agents that counteract prolonged COVID-19 symptoms. Therefore, the objectives of this review were to summarize the digestive manifestations, focusing on irritable bowel syndrome and therapeutic strategies. This review gives an overview of studies published in English in the last two years on the PubMed database. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic that devastated the world. While this is a respiratory virus, one feature of the SARS-CoV-2 infection was recognized to cause pathogenesis of other organs. Because the membrane fusion protein of SARS-CoV-2, the spike protein, binds to its major host cell receptor angiotensin-converting enzyme 2 (ACE2), which regulates a critical mediator of cardiovascular diseases, angiotensin II, COVID-19 is largely associated with vascular pathologies. The present study examined the pulmonary vasculature of COVID-19 patients using large sample sizes and provides mechanistic information through histological observations. We studied 56 postmortal lung samples from COVID-19 patients. The comparative group consisted of 17 postmortal lung samples from patients who died of influenza A virus subtype H1N1. The examination of 56 autopsy lung samples showed thickened vascular walls of small pulmonary arteries after 14 days of disease compared to H1N1 influenza patients who died before the COVID-19 pandemic started. Pulmonary vascular remodeling in COVID-19 patients was associated with hypertrophy of the smooth muscle layer, perivascular fibrosis, edema and lymphostasis, inflammatory infiltration, perivascular hemosiderosis, and neoangiogenesis. We found a correlation between the duration of hospital stay and the thickness of the muscular layer of the pulmonary arterial walls. These results demonstrate that COVID-19 significantly affected the pulmonary vasculature in fatal-course patients, also suggesting the need for careful follow-up in non-fatal cases, at risk of pulmonary hypertension. Full article