Simultaneous determination of cystine and other free aminothiols in blood plasma using capillary electrophoresis with pH-mediated stacking.

We developed a method of sensitive capillary electrophoresis using UV detection for the determination of certain free aminothiols (reduced cysteinylglycine (rCysGly), cysteine (rCys), glutathione (rGln), and cystine (CysS) in human blood plasma. The reduced thiols were derivatized with N-ethylmaleimide. The plasma was purified from proteins via ultrafiltration. Electrophoretic separation was performed using 115 mM Na phosphate with 7.5% (v/v) polyethylene glycol 600, pH 2.3. The in-capillary concentration of the analytes was achieved with a pH gradient created via the preinjection of triethanolamine and postinjection of phosphoric acid. The separation was carried out using a silica capillary (50 µm i.d.; total/effective separation length 42/35 cm) at a 25 kV voltage. The total analysis/regeneration time was 18 min. The quantification limits varied from 1.3 µM (rCysGly) to 5.4 µM (CysS). The accuracy was 95%-99%, and the repeatability and reproducibility were approximately 1.8%-3.8% and 1.9%-5.0%, respectively. An analysis of plasma samples from healthy volunteers (N = 41) showed that the mean levels of rCysGly, rCys, rGln, and CysS were 1.64, 10.6, 2.58, and 46.2 µM, respectively.

Cerium Dioxide-Dextran Nanocomposites in the Development of a Medical Product for Wound Healing: Physical, Chemical and Biomedical Characteristics.

PURPOSE OF THE STUDY: the creation of a dextran coating on cerium oxide crystals using different ratios of cerium and dextran to synthesize nanocomposites, and the selection of the best nanocomposite to develop a nanodrug that accelerates quality wound healing with a new type of antimicrobial effect. MATERIALS AND METHODS: Nanocomposites were synthesized using cerium nitrate and dextran polysaccharide (6000 Da) at four different initial ratios of Ce(NO3)3x6H2O to dextran (by weight)-1:0.5 (Ce0.5D); 1:1 (Ce1D); 1:2 (Ce2D); and 1:3 (Ce3D). A series of physicochemical experiments were performed to characterize the created nanocomposites: UV-spectroscopy; X-ray phase analysis; transmission electron microscopy; dynamic light scattering and IR-spectroscopy. The biomedical effects of nanocomposites were studied on human fibroblast cell culture with an evaluation of their effect on the metabolic and proliferative activity of cells using an MTT test and direct cell counting. Antimicrobial activity was studied by mass spectrometry using gas chromatography-mass spectrometry against E. coli after 24 h and 48 h of co-incubation. RESULTS: According to the physicochemical studies, nanocrystals less than 5 nm in size with diffraction peaks characteristic of cerium dioxide were identified in all synthesized nanocomposites. With increasing polysaccharide concentration, the particle size of cerium dioxide decreased, and the smallest nanoparticles (<2 nm) were in Ce2D and Ce3D composites. The results of cell experiments showed a high level of safety of dextran nanoceria, while the absence of cytotoxicity (100% cell survival rate) was established for Ce2D and C3D sols. At a nanoceria concentration of 10-2 M, the proliferative activity of fibroblasts was statistically significantly enhanced only when co-cultured with Ce2D, but decreased with Ce3D. The metabolic activity of fibroblasts after 72 h of co-cultivation with nano composites increased with increasing dextran concentration, and the highest level was registered in Ce3D; from the dextran group, differences were registered in Ce2D and Ce3D sols. As a result of the microbiological study, the best antimicrobial activity (bacteriostatic effect) was found for Ce0.5D and Ce2D, which significantly inhibited the multiplication of E. coli after 24 h by an average of 22-27%, and after 48 h, all nanocomposites suppressed the multiplication of E. coli by 58-77%, which was the most pronounced for Ce0.5D, Ce1D, and Ce2D. CONCLUSIONS: The necessary physical characteristics of nanoceria-dextran nanocomposites that provide the best wound healing biological effects were determined. Ce2D at a concentration of 10-3 M, which stimulates cell proliferation and metabolism up to 2.5 times and allows a reduction in the rate of microorganism multiplication by three to four times, was selected for subsequent nanodrug creation.

Influence of the Synthesis Scheme of Nanocrystalline Cerium Oxide and Its Concentration on the Biological Activity of Cells Providing Wound Regeneration.

In the ongoing search for practical uses of rare-earth metal nanoparticles, cerium dioxide nanoparticles (nanoceria) have received special attention. The purpose of this research was to study the biomedical effects of nanocrystalline forms of cerium oxide obtained by different synthesis schemes and to evaluate the effect of different concentrations of nanoceria (from 10-2 to 10-6 M) on cells involved in the regeneration of skin cell structures such as fibroblasts, mesenchymal stem cells, and keratinocytes. Two different methods of nanoceria preparation were investigated: (1) CeO-NPs-1 by precipitation from aqueous solutions of cerium (III) nitrate hexahydrate and citric acid and (2) CeO-NPs-2 by hydrolysis of ammonium hexanitratocerate (IV) under conditions of thermal autoclaving. According to the X-ray diffraction, transmission electron microscopy, and dynamic light scattering data, CeO2-1 consists of individual particles of cerium dioxide (3-5 nm) and their aggregates with diameters of 60-130 nm. CeO2-2 comprises small aggregates of 8-20 nm in diameter, which consist of particles of 2-3 nm in size. Cell cultures of human fibroblasts, human mesenchymal stem cells, and human keratinocytes were cocultured with different concentrations of nanoceria sols (10-2, 10-3, 10-4, 10-5, and 10-6 mol/L). The metabolic activity of all cell types was investigated by MTT test after 48 and 72 h, whereas proliferative activity and cytotoxicity were determined by quantitative cell culture counting and live/dead test. A dependence of biological effects on the method of nanoceria preparation and concentration was revealed. Data were obtained with respect to the optimal concentration of sol to achieve the highest metabolic effect in the used cell cultures. Hypotheses about the mechanisms of the obtained effects and the structure of a fundamentally new medical device for accelerated healing of skin wounds were formulated. The method of nanoceria synthesis and concentration fundamentally and significantly change the biological activity of cell cultures of different types-from suppression to pronounced stimulation. The best biological activity of cell cultures was determined through cocultivation with sols of citrate nanoceria (CeO-NPs-1) at a concentration of 10-3-10-4 M.

In Silico Computational Studies of Bioactive Secondary Metabolites from Wedelia trilobata against Anti-Apoptotic B-Cell Lymphoma-2 (Bcl-2) Protein Associated with Cancer Cell Survival and Resistance.

In the present study, the binding affinity of 52 bioactive secondary metabolites from Wedelia trilobata towards the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein (PDB: 2W3L) structure was identified by using in silico molecular docking and molecular dynamics simulation. The molecular docking results demonstrated that the binding energies of docked compounds with Bcl-2 protein ranged from -5.3 kcal/mol to -10.1 kcal/mol. However, the lowest binding energy (-10.1 kcal/mol) was offered by Friedelin against Bcl-2 protein when compared to other metabolites and the standard drug Obatoclax (-8.4 kcal/mol). The molecular dynamics simulations revealed that the Friedelin-Bcl-2 protein complex was found to be stable throughout the simulation period of 100 ns. Overall, the predicted Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties of Friedelin are relatively better than Obatoclax, with the most noticeable differences in many parameters where Friedelin has no AMES toxicity, hepatotoxicity, and skin sensitization. The ADMET profiling of selected compounds supported their in silico drug-likeness properties. Based on the computational analyses, the present study concluded that Friedelin of W. trilobata was found to be the potential inhibitor of the Bcl-2 protein, which merits attention for further in vitro and in vivo studies before clinical trials.

Design, Synthesis, Characterization, and Analysis of Antimicrobial Property of Novel Benzophenone Fused Azetidinone Derivatives through In Vitro and In Silico Approach.

A sequence of novel 2-(4-benzoyl-2-methyl-phenoxy)-N-(3-chloro-2-oxo-4-phenyl-azetidin-1-yl)-acetamide analogues 9(a−n) were synthesized by multistep synthesis. The newly synthesized compounds were well characterized, and their antimicrobial activities were carried out by disc diffusion and broth dilution methods. Further, all the novel series of compounds (9a−n), were tested against a variety of bacterial and fungal strains in comparison to Ketoconazole, Chloramphenicol, and Amoxicillin as standard drugs, respectively. Compounds 9a, 9e, and 9g as a lead molecule demonstrated a good inhibition against tested strains. Further, molecular docking studies have been performed for the potent compounds to check the three-dimensional geometrical view of the ligand binding to the targeted proteins.

Determination of glutathione in blood via capillary electrophoresis with pH-mediated stacking.

A new approach has been developed for the direct determination of reduced (glutathione [GSH]) and oxidized (glutathione disulfide [GSSG]) GSH in whole blood by means of capillary electrophoresis. Its features include GSH-stabilizing sample preparation, the use of an internal standard, and pH-mediated stacking. Blood stabilized with acid citrate and K3 EDTA was treated with acetonitrile with N-ethylmaleimide, and then the analytes were extracted with diethyl ether. The total analysis time was 8 min using a 50-µm (i.d.) by 32.5-cm (eff. length) silica capillary. The background electrolyte was 0.075-M citrate Na pH 5.8 with 200-µM cetyltrimethylammonium bromide and 5-µM sodium dodecyl sulfate, and the separation voltage was -14 kV. The quantification limit (S/N = 15) of the method was 1.5 µM for GSSG. The accuracy levels of GSH and GSSG analysis were 104% and 103%, respectively, and between-run precision levels were 2.6% and 3.2%, respectively. Analysis of blood samples from healthy volunteers (N = 24) showed that the levels of GSH and GSSG and the GSH/GSSG ratio in the whole blood were 1.05 ± 0.14 mM, 3.9 ± 1.25 µM, and 256 ± 94, respectively. Thus, the presented approach can be used in clinical and laboratory practice.

Dose-dependent effects of perfluorocarbon-based blood substitute on cardiac function in myocardial ischemia-reperfusion injury.

The main goal of this study was to investigate the cardioprotective properties in terms of effects on cardiodynamics of perfluorocarbon emulsion (PFE) in ex vivo-induced ischemia-reperfusion injury of an isolated rat heart. The first part of the study aimed to determine the dose of 10% perfluoroemulsion (PFE) that would show the best cardioprotective effect in rats on ex vivo-induced ischemia-reperfusion injury of an isolated rat heart. Depending on whether the animals received saline or PFE, the animals were divided into a control or experimental group. They were also grouped depending on the applied dose (8, 12, 16 ml/kg body weight) of saline or PFE. We observed the huge changes in almost all parameters in the PFE groups in comparison with IR group without any pre-treatment. Calculated in percent, dp/dt max was the most changed parameter in group treated with 8 mg/kg, while the dp/dt min, SLVP, DLVP, HR, and CF were the most changed in group treated with 16 mg/kg 10 h before ischemia. The effects of 10% PFE are more pronounced if there is a longer period of time from application to ischemia, i.e., immediate application of PFE before ischemia (1 h) gave the weakest effects on the change of cardiodynamics of isolated rat heart. Therefore, the future of PFE use is in new indications and application methods, and PFE can also be referred to as antihypoxic and antiischemic blood substitute with mild membranotropic effects.

In Vitro Anticancer Screening, Molecular Docking and Antimicrobial Studies of Triazole-Based Nickel(II) Metal Complexes.

Herein we describe the synthesis of a series of nickel(II) complexes (C1-C3) with Schiff bases (HL1-HL3) derived from 4-amino-5-mercapto-3-methyl-1,2,4-triazole and ortho/meta/para-nitrobenzaldehyde having composition [Ni(L)2(H2O)2]. The obtained ligands and their complexes were characterized using physico-chemical techniques viz., elemental analysis, magnetic moment study, spectral (electronic, FT-IR, 1H-NMR) and thermal analysis. The elemental analysis and spectral analysis revealed that Schiff bases behave as monoanionic bidentate ligands towards the Ni(II) ion. Whereas, the magnetic moment study suggested the octahedral geometry of all the Ni(II) complexes. The thermal behavior of the complexes has been studied by thermogravimetric analysis and agrees well with the composition of complexes. Further, the biological activities such as antimicrobial and antifungal studies of the Schiff bases and Ni(II) complexes have been screened against bacterial species (Staphylococcus aureus and Pseudomonas aeruginosa) and fungal species (Aspergillus niger and Candida albicans) activity by MIC method, the results of which revealed that metal complexes exhibited significant antimicrobial activities than their respective ligands against the tested microbial species. Furthermore, the molecular docking technique was employed to investigate the active sites of the selected protein, which indeed helped us to screen the potential anticancer agents among the synthesized ligand and complexes. Further, these compounds have been screened for their in vitro anticancer activity using OVCAR-3 cell line. The results revealed that the complexes are more active than the ligands.

Preparation, Characterization and In Vitro Biological Activities of New Diphenylsulphone Derived Schiff Base Ligands and Their Co(II) Complexes.

The present work describes the chemical preparation of Schiff bases derived from 4,4'-diaminodiphenyl sulfone (L1-L5) and their Co(II) metal complexes. The evaluation of antimicrobial and anticancer activities against MCF-7 cell line and human lung cancer cell line A-549 was performed. The aforementioned synthesized compounds are characterized by spectroscopic techniques and elemental analysis confirms successful synthesis. The results from the above analytical techniques revealed that the complexes are in an octahedral geometry. The antimicrobial activity of the synthesized Schiff base ligands and their metal complexes under study was carried out by using the agar well diffusion method. The ligand and complex interactions for biological targets were predicted using molecular docking and high binding affinities. Further, the anticancer properties of the synthesized compounds are performed against the MCF-7 cell line and human lung cancer cell line A-549 using adriamycin as the standard drug.

Nanoconjugate Synthesis of Elaeocarpus ganitrus and the Assessment of Its Antimicrobial and Antiproliferative Properties.

Cancer is one of the leading causes of death worldwide, accountable for a total of 10 million deaths in the year 2020, according to GLOBOCAN 2020. The advancements in the field of cancer research indicate the need for direction towards the development of new drug candidates that are instrumental in a tumour-specific action. The pool of natural compounds proves to be a promising avenue for the discovery of groundbreaking cancer therapeutics. Elaeocarpus ganitrus (Rudraksha) is known to possess antioxidant properties and after a thorough review of literature, it was speculated to possess significant biomedical potential. Green synthesis of nanoparticles is an environmentally friendly approach intended to eliminate toxic waste and reduce energy consumption. This approach was reported for the synthesis of silver nanoparticles from two different solvent extracts: aqueous and methanolic. These were characterized by biophysical and spectroscopic techniques, namely, UV-Visible Spectroscopy, FTIR, XRD, EDX, DLS, SEM, and GC-MS. The results showed that the nanoconjugates were spherical in geometry. Further, the assessment of antibacterial, antifungal, and antiproliferative activities was conducted which yielded results that were qualitatively positive at the nanoscale. The nanoconjugates were also evaluated for their anticancer properties using a standard MTT Assay. The interactions between the phytochemicals (ligands) and selected cancer receptors were also visualized in silico using the PyRx tool for molecular docking.

Exploration of Anti-HIV Phytocompounds against SARS-CoV-2 Main Protease: Structure-Based Screening, Molecular Simulation, ADME Analysis and Conceptual DFT Studies.

The ever-expanding pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has gained attention as COVID-19 and caused an emergency in public health to an unmatched level to date. However, the treatments used are the only options; currently, no effective and licensed medications are available to combat disease transmission, necessitating further research. In the present study, an in silico-based virtual screening of anti-HIV bioactive compounds from medicinal plants was carried out through molecular docking against the main protease (Mpro) (PDB: 6LU7) of SARS-CoV-2, which is a key enzyme responsible for virus replication. A total of 16 anti-HIV compounds were found to have a binding affinity greater than -8.9 kcal/mol out of 150 compounds screened. Pseudohypericin had a high affinity with the energy of -10.2 kcal/mol, demonstrating amino acid residual interactions with LEU141, GLU166, ARG188, and GLN192, followed by Hypericin (-10.1 kcal/mol). Moreover, the ADME (Absorption, Distribution, Metabolism and Excretion) analysis of Pseudohypericin and Hypericin recorded a low bioavailability (BA) score of 0.17 and violated Lipinski's rule of drug-likeness. The docking and molecular simulations indicated that the quinone compound, Pseudohypericin, could be tested in vitro and in vivo as potent molecules against COVID-19 disease prior to clinical trials.This was also supported by the theoretical and computational studies conducted. The global and local descriptors, which are the underpinnings of Conceptual Density FunctionalTheory (CDFT) have beenpredicted through successful model chemistry, hoping that they could be of help in the comprehension of the chemical reactivity properties of the molecular systems considered in this study.

Early predictive blood markers of hemorrhagic stroke - influence of cytoflavin therapy.

Examination of the patterns of free-radical processes (FRP) and changes of the early screening markers to predict the course of hemorrhagic stroke (HS) and applied pathophysiologically based therapy can be of great practical importance. This study aimed to determine early changes in the parameters of oxidative stress and routine biochemistry blood tests in patients with HS and to assess their relationship with clinical outcome. The effects of early applied cytoflavin were also investigated. The prospective study included 151 patients with HS. Forty-eight percent of patients in the standard conservative therapy were given cytoflavin antioxidant energy therapy from the first day of hospitalization. The neurological status, neuroimaging, biochemical blood tests and FRP were assessed on days 1, 5, 10, and 20 of hospitalization. In patients with HS, an imbalance of all stages of FRP was detected proportionately to the severity of HS. The malondialdehyde concentration above 5.3 µmol/L, the number of leukocytes above 15 800, glucose above 11.9 mmol/L, lactate dehydrogenase above 574 IU/L, and lactate above 2.5 mmol/L, detected on the first day, predetermined a high risk of death. Additional cytoflavin treatment allowed stabilizing the clinical laboratory picture of HS, improved the treatment results, and reduced hospital mortality rate.

Antimicrobial Activity of Citrate-Coated Cerium Oxide Nanoparticles.

The purpose of this study was to investigate the antimicrobial activity of citrate-stabilized sols of cerium oxide nanoparticles at different concentrations via different microbiological methods and to compare the effect with the peroxidase activity of nanoceria for the subsequent development of a regeneration-stimulating medical and/or veterinary wound-healing product providing new types of antimicrobial action. The object of this study was cerium oxide nanoparticles synthesized from aqueous solutions of cerium (III) nitrate hexahydrate and citric acid (the size of the nanoparticles was 3-5 nm, and their aggregates were 60-130 nm). Nanoceria oxide sols with a wide range of concentrations (10-1-10-6 M) as well as powder (the dry substance) were used. Both bacterial and fungal strains (Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Proteus vulgaris, Candida albicans, Aspergillus brasielensis) were used for the microbiological studies. The antimicrobial activity of nanoceria was investigated across a wide range of concentrations using three methods sequentially; the antimicrobial activity was studied by examining diffusion into agar, the serial dilution method was used to detect the minimum inhibitory and bactericidal concentrations, and, finally, gas chromatography with mass-selective detection was performed to study the inhibition of E. coli's growth. To study the redox activity of different concentrations of nanocerium, we studied the intensity of chemiluminescence in the oxidation reaction of luminol in the presence of hydrogen peroxide. As a result of this study's use of the agar diffusion and serial dilution methods followed by sowing, no significant evidence of antimicrobial activity was found. At the same time, in the current study of antimicrobial activity against E. coli strains using gas chromatography with mass spectrometry, the ability of nanoceria to significantly inhibit the growth and reproduction of microorganisms after 24 h and, in particular, after 48 h of incubation at a wide range of concentrations, 10-2-10-5 M (48-95% reduction in the number of microbes with a significant dose-dependent effect) was determined as the optimum concentration. A reliable redox activity of nanoceria coated with citrate was established, increasing in proportion to the concentration, confirming the oxidative mechanism of the action of nanoceria. Thus, nanoceria have a dose-dependent bacteriostatic effect, which is most pronounced at concentrations of 10-2-10-3 M. Unlike the effects of classical antiseptics, the effect was manifested from 2 days and increased during the observation. To study the antimicrobial activity of nanomaterials, it is advisable not to use classical qualitative and semi-quantitative methods; rather, the employment of more accurate quantitative methods is advised, in particular, gas chromatography-mass spectrometry, during several days of incubation.

Secondary metabolites of Trichoderma spp. as EGFR tyrosine kinase inhibitors: Evaluation of anticancer efficacy through computational approach.

The present study explores the epidermal growth factor receptor (EGFR) tyrosine kinase inhibition efficacy of secondary metabolites in Trichoderma spp. through molecular docking, molecular dynamics (MD) simulation and MM-PBSA approach. The result of molecular docking confirmed that out of 200 metabolites screened, three metabolites such as Harzianelactone A, Pretrichodermamide G and Aspochalasin M, potentially bound with the active binding site of EGFR tyrosine kinase domain(PDB ID: 1M17) with a threshold docking score of ≤- 9.0 kcal/mol when compared with the standard EGFR inhibitor (Erlotinib). The MD simulation was run to investigate the potential for stable complex formation in EGFR tyrosine kinase domain-unbound/lead metabolite (Aspochalasin M)-bound/standard inhibitor (Erlotinib)-bound complex. The MD simulation analysis at 100 ns revealed that Aspochalasin M formed the stable complex with EGFR. Besides, the in silico predication of pharmacokinetic properties further confirmed that Aspochalasin M qualified the drug-likeness rules with no harmful side effects (viz., hERG toxicity, hepatotoxicity and skin sensitization), non-mutagenicity and favourable logBB value. Moreover, the BOILED-Egg model predicted that Aspochalasin M showed a higher gastrointestinal absorption with improved bioavailability when administered orally and removed from the central nervous system (CNS). The results of the computational studies concluded that Aspochalasin M possessed significant efficacy in binding EGFR's active sites compared to the known standard inhibitor (Erlotinib). Therefore, Aspochalasin M can be used as a possible anticancer drug candidate and further in vitro and in vivo experimental validation of Aspochalasin M of Trichoderma spp. are required to determine its anticancer potential.

Computational exploration of Picrasma quassioides compounds as CviR-mediated quorum sensing inhibitors against Chromobacterium violaceum.

Chromobacterium violaceum an opportunistic human pathogenic bacterium, exhibits resistance to conventional antibiotics by exploiting its quorum sensing mechanism to regulate virulence factor expression. In light of this, disrupting the quorum sensing mechanism presents a promising avenue for treating infections caused by this pathogen. The study focused on using the cytoplasmic quorum sensing receptor CviR from C. violaceum as a model target to identify novel quorum sensing inhibitors from P. quassioides through in silico computational approaches. Molecular docking analyses unveiled that several phytochemicals derived from Picrasma quassioides exhibit the potential to inhibit quorum sensing by binding to CviR protein. Notably, the compounds such as Quassidine I (- 8.8 kcal/mol), Quassidine J (- 8.8 kcal/mol), Kumudine B (- 9.1 kcal/mol) and Picrasamide A (- 8.9 kcal/mol) exhibited high docking scores, indicating strong binding affinity to the CviR protein. The native ligand C6-HSL (N-hexanoyl-L-homoserine lactone) as a positive control/co-crystal inhibitor also demonstrated a significant binding energy of-7.7 kcal/mol. The molecular dynamics simulation for 200 ns showed the thermodynamic stability and binding affinity refinement of the top-ranked CviR inhibitor (Kumudine B) with its stable binding and minor fluctuations compared to positive control (C6-HSL). Pharmacokinetic predictions indicated that Kumudine B possesses favourable drug-like properties, which suggest its potential as a drug candidate. The study highlight Kumudine B as a potential agent for inhibiting the CviR protein in C. violaceum. The comprehensive evaluation of Kumudine B provides valuable insights into its pharmacological profiles, facilitating its assessment for diverse therapeutic applications and guiding future research activities, particularly as antibacterial agents for clinical drug development.

Exploration of Type III effector Xanthomonas outer protein Q (XopQ) inhibitor from Picrasma quassioides as an antibacterial agent using chemoinformatics analysis.

The present study was focused on exploring the efficient inhibitors of closed state (form) of type III effector Xanthomonas outer protein Q (XopQ) (PDB: 4P5F) from the 44 phytochemicals of Picrasma quassioides using cutting-edge computational analysis. Among them, Kumudine B showed excellent binding energy (-11.0 kcal/mol), followed by Picrasamide A, Quassidine I and Quassidine J with the targeted closed state of XopQ protein compared to the reference standard drug (Streptomycin). The molecular dynamics (MD) simulations performed at 300 ns validated the stability of top lead ligands (Kumudine B, Picrasamide A, and Quassidine I)-bound XopQ protein complex with slightly lower fluctuation than Streptomycin. The MM-PBSA calculation confirmed the strong interactions of top lead ligands (Kumudine B and QuassidineI) with XopQ protein, as they offered the least binding energy. The results of absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis confirmed that Quassidine I, Kumudine B and Picrasamide A were found to qualify most of the drug-likeness rules with excellent bioavailability scores compared to Streptomycin. Results of the computational studies suggested that Kumudine B, Picrasamide A, and Quassidine I could be considered potential compounds to design novel antibacterial drugs against X. oryzae infection. Further in vitro and in vivo antibacterial activities of Kumudine B, Picrasamide A, and Quassidine I are required to confirm their therapeutic potentiality in controlling the X. oryzae infection.

Integrated network pharmacology and molecular modeling approach for the discovery of novel potential MAPK3 inhibitors from whole green jackfruit flour targeting obesity-linked diabetes mellitus.

The current study investigates the effectiveness of phytocompounds from the whole green jackfruit flour methanol extract (JME) against obesity-linked diabetes mellitus using integrated network pharmacology and molecular modeling approach. Through network pharmacology, druglikeness and pharmacokinetics, molecular docking simulations, GO analysis, molecular dynamics simulations, and binding free energy analyses, it aims to look into the mechanism of the JME phytocompounds in the amelioration of obesity-linked diabetes mellitus. There are 15 predicted genes corresponding to the 11 oral bioactive compounds of JME. The most important of these 15 genes was MAPK3. According to the network analysis, the insulin signaling pathway has been predicted to have the strongest affinity to MAPK3 protein, which was chosen as the target. With regard to the molecular docking simulation, the greatest notable binding affinity for MAPK3 was discovered to be caffeic acid (-8.0 kJ/mol), deoxysappanone B 7,3'-dimethyl ether acetate (DBDEA) (-8.2 kJ/mol), and syringic acid (-8.5 kJ/mol). All the compounds were found to be stable inside the inhibitor binding pocket of the enzyme during molecular dynamics simulation. During binding free energy calculation, all the compounds chiefly used Van der Waal's free energy to bind with the target protein (caffeic acid: 102.296 kJ/mol, DBDEA: -104.268 kJ/mol, syringic acid: -100.171 kJ/mol). Based on these findings, it may be inferred that the reported JME phytocompounds could be used for in vitro and in vivo research, with the goal of targeting MAPK3 inhibition for the treatment of obesity-linked diabetes mellitus.

The Diagnostic and Prognostic Roles Played by Homocysteine and Other Aminothiols in Patients with Chronic Kidney Disease.

We examined standard clinical and laboratory biochemical parameters, as well as the levels of aminothiols in the blood and urine (homocysteine (Hcy), cysteine (Cys), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH)) via capillary electrophoresis in patients with CKD at stages II-V. Patient outcomes were assessed after five years. To complete forecasting, correlation and ROC analysis were performed. It was found that the levels of Cys and Hcy in blood plasma were earlier markers of CKD starting from stage II, while the levels of SAM and SAM/SAH in urine made it possible to differentiate between CKD at stages II and III. Blood plasma Hcy and urinary SAM and SAM/SAH correlated with mortality, but plasma Hcy concentrations were more significant. Thus, plasma Hcy, urine SAM, and SAM/SAH can be considered to be potential diagnostic and prognostic markers in patients with CKD.

Influence of Coronary Artery Bypass Grafts on Blood Aminothiols in Patients with Coronary Artery Disease.

Coronary artery disease (CAD) and the coronary artery bypass graft (CABG) are associated with a decreased blood glutathione (bGSH) level. Since GSH metabolism is closely related to other aminothiols (homocysteine and cysteine) and glucose, the aim of this study was to reveal the associations of bGSH with glucose and plasma aminothiols in CAD patients (N = 35) before CABG and in the early postoperative period. Forty-three volunteers with no history of cardiovascular disease formed the control group. bGSH and its redox status were significantly lower in CAD patients at admission. CABG had no significant effect on these parameters, with the exception of an increase in the bGSH/hemoglobin ratio. At admission, CAD patients were characterized by negative associations of homocysteine and cysteine with bGSH. All these associations disappeared after CABG. An association was found between an increase in oxidized GSH in the blood in the postoperative period and fasting glucose levels. Thus, CAD is associated with the depletion of the intracellular pool and the redox status of bGSH, in which hyperhomocysteinemia and a decrease in the bioavailability of the extracellular pool of cysteine play a role. The present study indicates that CABG causes disruptions in aminothiol metabolism and induces the synthesis of bGSH. Moreover, glucose becomes an important factor in the dysregulation of GSH metabolism in CABG.

The Role of Trace Elements and Minerals in Osteoporosis: A Review of Epidemiological and Laboratory Findings.

The objective of the present study was to review recent epidemiological and clinical data on the association between selected minerals and trace elements and osteoporosis, as well as to discuss the molecular mechanisms underlying these associations. We have performed a search in the PubMed-Medline and Google Scholar databases using the MeSH terms "osteoporosis", "osteogenesis", "osteoblast", "osteoclast", and "osteocyte" in association with the names of particular trace elements and minerals through 21 March 2023. The data demonstrate that physiological and nutritional levels of trace elements and minerals promote osteogenic differentiation through the up-regulation of BMP-2 and Wnt/ß-catenin signaling, as well as other pathways. miRNA and epigenetic effects were also involved in the regulation of the osteogenic effects of trace minerals. The antiresorptive effect of trace elements and minerals was associated with the inhibition of osteoclastogenesis. At the same time, the effect of trace elements and minerals on bone health appeared to be dose-dependent with low doses promoting an osteogenic effect, whereas high doses exerted opposite effects which promoted bone resorption and impaired bone formation. Concomitant with the results of the laboratory studies, several clinical trials and epidemiological studies demonstrated that supplementation with Zn, Mg, F, and Sr may improve bone quality, thus inducing antiosteoporotic effects.