Sivelestat (Neutrophil Elastase Inhibitor) as an Anti-inflammatory and Anti-viral Agent: An In Silico Study.

Background Sivelestat is a potent and specific neutrophil elastase inhibitor. It is clinically used in treating lung injury and respiratory distress syndrome. This engaged us to undertake the present study in which sivelestat was studied as an anti-inflammatory and anti-viral agent. Methodology The docking study of sivelestat on matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), chikungunya virus nonstructural protein-2 (CVnsP2) protease, and influenza A (H1N9) virus neuraminidase was assessed using the Chemistry at Harvard Macromolecular Mechanics (CHARMM) Dock (CDOCK) method. Furthermore, molecular physicochemical; bioactivity; absorption, distribution, metabolism, and excretion (ADME); toxicity; and Search Tool for Interacting Chemicals (STITCH) analyses were performed by using the Molinspiration (Molinspiration Cheminformatics, Slovensky Grob, Slovak Republic), SwissADME SwissADME (Swiss Institute of Bioinformatics, Quartier Sorge - Bâtiment Amphipôle, Switzerland), pkCSM (University of Melbourne, Melbourne, Australia), and STITCH-free online tools. Results The molecular physicochemical assessment of the ligand (sivelestat) showed no (zero) violation and agreed with the thumb rule of five, otherwise known as Lipinski's rule of five. ADME prediction of the ligand (sivelestat) is shown to possess a low gastrointestinal absorption (GIA) property. Similarly, toxicity analysis of the ligand (sivelestat) is predicted to have a hepatotoxicity effect. STITCH analysis reveals that the ligand (sivelestat) has exhibited interactions with the three human proteins. Conclusions The present molecular docking studies showed that the ligand (sivelestat) has successfully docked with all four enzymes of interest. Hence, the current finding has provided a good understanding of sivelestat as an effective suppressor activity against all four enzymes: MMP-2, MMP-9, CVnsP2 protease, and influenza neuraminidase.

In Silico Analysis of Selected Mikania Constituents As Human HMG-CoA Reductase, Human Inducible Nitric Oxide Synthase, and Human Squalene Synthase Inhibitory Agents.

Background Numerous pharmacological activities have been reportedin Mikania species. In the present investigation, we aimed to evaluate 26 selected constituents of Mikania as potent inhibitory agents of human HMG-CoA reductase (hHMGR), human inducible nitric oxide synthase (hiNOS), and human squalene synthase (hSQS) using the in silico method. Methodology Twenty-six selected constituents of Mikania were investigated based on the docking behavior of three target enzymes, namely hHMGR, hiNOS, and hSQS, using the Cdocker method (Discovery Studio® 3.1, Accelrys, Inc., San Diego, CA). Results Docking analysis showed that methyl-3,5-di-O-caffeoyl quinate (MCQ) has the maximum binding energy (BE) (-39.63, -50.65, and -58.56 kcal/mol) with hHMGR, hiNOS, and hSQS enzymes. On the other hand, six ligands (kaurenoic acid (KAA), stigmasterol (SS), grandifloric acid (GA), kaurenol (KA), spathlenol (SP), and taraxerol (TA)) of Mikania failed to dock with either of the target enzymes (hHMGR, hiNOS, or hSQS). Conclusions The findings of the current study provide new insight regarding 26 selected ligands of Mikania as potent inhibitory agents of hHMGR, hiNOS, and hSQS.

In Silico Analysis of Selected Glycyrrhiza glabra (Licorice) Constituents: Exploring Their Modulatory Effects on Human Superoxide Dismutase, Human Phosphodiesterase-9 and Human Dipeptidyl Peptidase-4.

Background Glycyrrhiza glabra (Licorice) has been known for its various biological activities. In the current investigation, we aimed to evaluate 11 (10 natural and one synthetic) selected constituents of G. glabra as potent modulatory agents of human superoxide dismutase (hSOD), human phosphodiesterase-9 (hPDE 9) and human dipeptidyl peptidase-4 (hDPP 4) using in silico method. Methodology The 11 selected constituents of G. glabra (Licorice) were investigated on the docking behaviour of hSOD, hPDE 9 and hDPP 4 by using the PatchDock method. In addition to docking, toxicity analysis was also carried out using the pkCSM free online server (University of Melbourne, Melbourne, AUS). Results Toxicity analysis has shown that four ligands (36%) of G. glabra (Licorice) are predicted to have human ether-a-go-go-related gene-2 (hERG 2) inhibition activity. The docking analysis showed that glabridin (-224.13 kcal/mol) has shown the highest atomic contact binding energy with the hSOD enzyme, whereas carbenoxolone has shown the maximum atomic contact binding energy with both the hPDE 9 and hDPP 4 enzymes (-239.57 and -173.50 kcal/mol) respectively. Conclusion Thus the present finding provides new information about 11 selected ligands of G. glabra (Licorice) as potent modulatory agents of hSOD, hPDE 9 and hDPP 4.

An In Silico Analysis of Synthetic and Natural Compounds as Inhibitors of Nitrous Oxide Reductase (N2OR) and Nitrite Reductase (NIR).

Nitrification inhibitors are recognized as a key approach that decreases the denitrification process to inhibit the loss of nitrogen to the atmosphere in the form of N2O. Targeting denitrification microbes directly could be one of the mitigation approaches. However, minimal attempts have been devoted towards the development of denitrification inhibitors. In this study, we aimed to investigate the molecular docking behavior of the nitrous oxide reductase (N2OR) and nitrite reductase (NIR) involved in the microbial denitrification pathway. Specifically, in silico screening was performed to detect the inhibitors of nitrous oxide reductase (N2OR) and nitrite reductase (NIR) using the PatchDock tool. Additionally, a toxicity analysis based on insecticide-likeness, Bee-Tox screening, and a STITCH analysis were performed using the SwissADME, Bee-Tox, and pkCSM free online servers, respectively. Among the twenty-two compounds tested, nine ligands were predicted to comply well with the TICE rule. Furthermore, the Bee-Tox screening revealed that none of the selected 22 ligands exhibited toxicity on honey bees. The STITCH analysis showed that two ligands, namely procyanidin B2 and thiocyanate, have interactions with both the Paracoccus denitrificans and Hyphomicrobium denitrificans microbial proteins. The molecular docking results indicated that ammonia exhibited the second least atomic contact energy (ACE) of -15.83 kcal/mol with Paracoccus denitrificans nitrous oxide reductase (N2OR) and an ACE of -15.20 kcal/mol with Hyphomicrobium denitrificans nitrite reductase (NIR). The inhibition of both the target enzymes (N2OR and NIR) supports the view of a low denitrification property and suggests the potential future applications of natural/synthetic compounds as significant nitrification inhibitors.

Bacterial Pathogenesis in Various Fish Diseases: Recent Advances and Specific Challenges in Vaccine Development.

Aquaculture is a fast-growing food sector but is plagued by a plethora of bacterial pathogens that infect fish. The rearing of fish at high population densities in aquaculture facilities makes them highly susceptible to disease outbreaks, which can cause significant economic loss. Thus, immunity development in fish through vaccination against various pathogens of economically important aquaculture species has been extensively studied and has been largely accepted as a reliable method for preventing infections. Vaccination studies in aquaculture systems are strategically associated with the economically and environmentally sustainable management of aquaculture production worldwide. Historically, most licensed fish vaccines have been developed as inactivated pathogens combined with adjuvants and provided via immersion or injection. In comparison, live vaccines can simulate a whole pathogenic illness and elicit a strong immune response, making them better suited for oral or immersion-based therapy methods to control diseases. Advanced approaches in vaccine development involve targeting specific pathogenic components, including the use of recombinant genes and proteins. Vaccines produced using these techniques, some of which are currently commercially available, appear to elicit and promote higher levels of immunity than conventional fish vaccines. These technological advancements are promising for developing sustainable production processes for commercially important aquatic species. In this review, we explore the multitude of studies on fish bacterial pathogens undertaken in the last decade as well as the recent advances in vaccine development for aquaculture.

Solid-State NMR-Based Metabolomics Imprinting Elucidation in Tissue Metabolites, Metabolites Inhibition, and Metabolic Hub in Zebrafish by Chitosan.

In this study, we demonstrated that chitosan-applied zebrafish (Danio rerio) tissue metabolite alteration, metabolic discrimination, and metabolic phenotypic expression occurred. The spectroscopy of solid-state 1H nuclear magnetic resonance (ss 1H-NMR) has been used. Chitosan has no, or low, toxicity and is a biocompatible biomaterial; however, the metabolite mechanisms underlying the biological effect of chitosan are poorly understood. The zebrafish is now one of the most popular ecotoxicology models. Zebrafish were exposed to chitosan concentrations of 0, 50, 100, 200, and 500 mg/L, and the body tissue was subjected to metabolites-targeted profiling. The zebrafish samples were measured via solvent-suppressed and T2-filtered methods with in vivo zebrafish metabolites. The metabolism of glutamate, glutamine, glutathione (GSH), taurine, trimethylamine (TMA), and its N-oxide (TMAO) is also significantly altered. Here, we report the quantification of metabolites and the biological application of chitosan. The metabolomics profile of chitosan in zebrafish has been detected, and the results indicated disturbed amino acid metabolism, the TCA cycle, and glycolysis. Our results demonstrate the potential of comparative metabolite profiling for discovering bioactive metabolites and they highlight the power of chitosan-applied chemical metabolomics to uncover new biological insights.

Metabolomic Signatures in Doxorubicin-Induced Metabolites Characterization, Metabolic Inhibition, and Signaling Pathway Mechanisms in Colon Cancer HCT116 Cells.

Doxorubicin (DOX) is a chemotherapeutic agent is used for various cancer cells. To characterize the chemical structural components and metabolic inhibition, we applied a DOX to HCT116 colon cancer cells using an independent metabolites profiling approach. Chemical metabolomics has been involved in the new drug delivery systems. Metabolomics profiling of DOX-applied HCT116 colon cancer cellular metabolisms is rare. We used 1H nuclear magnetic resonance (NMR) spectroscopy in this study to clarify how DOX exposure affected HCT116 colon cancer cells. Metabolomics profiling in HCT116 cells detects 50 metabolites. Tracking metabolites can reveal pathway activities. HCT116 colon cancer cells were evenly treated with different concentrations of DOX for 24 h. The endogenous metabolites were identified by comparison with healthy cells. We found that acetate, glucose, glutamate, glutamine, sn-glycero-3-phosphocholine, valine, methionine, and isoleucine were increased. Metabolic expression of alanine, choline, fumarate, taurine, o-phosphocholine, inosine, lysine, and phenylalanine was decreased in HCT116 cancer cells. The metabolic phenotypic expression is markedly altered during a high dose of DOX. It is the first time that there is a metabolite pool and phenotypic expression in colon cancer cells. Targeting the DOX-metabolite axis may be a novel strategy for improving the curative effect of DOX-based therapy for colon cancer cells. These methods facilitate the routine metabolomic analysis of cancer cells.

In Silico Analysis of Cissus rotundifolia Constituents as Human Neutrophil Elastase (HNE), Matrix Metalloproteinases (MMP 2 and MMP 9), and Tyrosinase Inhibitors.

Cissus rotundifolia has been reported to possess various biological activities such as anti-diabetic, anti-fertility, anti-hyperlipidemic, anti-malarial, anti-osteoporotic, and anti-parasitic activities. Therefore in the present study, eleven selected constituents of Cissus rotundifolia which includes aconitic acid, astragalin, acteoside, aliospiroside A, beta amyrin, bergenin, formononetin, gallic acid, isovitexin, isoorientin, and isoquercitrin were studied on the docking behavior of human neutrophil elastase (HNE), matrix metalloproteinases (MMP 2 and MMP 9), and tyrosinase by using PatchDock method. Furthermore, molecular physicochemical, bioactivity score/drug-likeness, ADME (absorption, distribution, metabolism, and excretion), and toxicity analyses were also carried out using Molinspiration, Swiss ADME, and ProTox-II methods, respectively. The molecular physicochemical investigation showed that three ligands such as acteoside, aliospiroside A, and isoorientin have three violations for Lipinski's rule of five. Similarly, ADME analysis one ligand (formononetin) predicated to have high blood-brain barrier (BBB) permeability effect. The docking studies showed that isovitexin exhibited the highest atomic contact energy (-341.61 kcal/mol) for human neutrophil elastase (HNE), more over alliospiroside A has shown maximum atomic contact energy for both matrix metalloproteinases (MMP 2 [-618.00 kcal/mol] and MMP 9 [-634.73 kcal/mol]). Furthermore, isoquercitrin has exhibited the highest atomic contact energy (-145.70 kcal/mol) for tyrosinase. Thus, the present investigation outcome provides new knowledge in understanding eleven Cissus rotundifolia constituents as possible novel inhibitors against HNE, MMP 2, MMP 9, and tyrosinase.

Alternative splicing and insect ryanodine receptor.

Phylogenetic tree of the ryanodine receptor (RyR) family based on maximum likelihood estimation.

The multi-faceted potential of plant-derived metabolites as antimicrobial agents against multidrug-resistant pathogens.

Multidrug-resistant (MDR) pathogens are currently causing serious problems globally in the medical setting. Improper and extensive usage of antibiotics results in a selective pressure supporting the rise of antibiotic-resistant microbes. Many key cellular bacterial components, including enzymes and small noncoding RNAs (sRNAs), and their involvement in MDR have been well studied, but exploiting such components in eradicating these pathogens requires further study. Delineation of many mechanisms that underpin the known MDR pathways necessitates urgent development of new specific strategies to control the rise of MDR pathogens. Botanical derivatives are comparatively safer than currently used antibiotics and exert multiple therapeutic benefits associated with their high efficacy. Numerous plant-derived compounds display synergistic activity with antibiotics against many MDR pathogens. Such plant derivatives include alkaloids, flavonoids, terpenoids, and tannins. A synthetic biological approach, e.g., metabolic engineering of secondary metabolites, can be utilized to exploit the natural metabolic pathways against MDR microbes. In this review, we focused on the major threats of antibiotic resistance, and the utilization of plant-derived compounds as alternative therapeutic agents to limit the rise of MDR pathogens.