Superior rat wound-healing activity of green synthesized silver nanoparticles from acetonitrile extract of Juglans regia L: Pellicle and leaves.

The process of wound healing is complicated. Antimicrobial silver has been one of the substances used for wounds since ancient times. Moreover, traditional medicine has long used Juglans regia L. to promote wound healing. Since eco-friendly nanotechnology has various uses in biomedical research, the aim of this study was to assess the wound-healing capacity of bio-reduced silver nanoparticles (AgNPs). UV, DLS, TEM, and FTIR were used to characterize the prepared AgNPs. Pellicle's bioreduced AgNP (AgNP/P) has a better polydispersity index (PI) of 0.336 compared to its chemically synthesized peers, which have a PI of 0.67. Using incision and excision wound healing models, AgNPs and extracts were compared to Solcoseryl®. Skin-breaking strength, wound contraction, epithelialization time, histology, and cytokines were all assessed. Juglans regia L. pellicle extract (P) has shown significant effectiveness in both models, as well as their bio-reduced partner AgNP/P. The skin's tensile strength following AgNP/P therapy (871 g, p value < 0.05) is comparable to that after Solcoseryl® (928 g), both of which are significantly better than AgNP (592 g) in the incision wound model. Epithelialization time (16.0 and 16.5 days) did not substantially differ from Solcoseryl® (15.3 days) (P value < 0.05). There was an elevated collagen content. Low levels of IL1ß (189.0 pg/g) and high levels of TNF-α (1007.1 pg/g) in the case of AgNP/P suggest various cellular kinds of maturation and various wound healing structures that are evident in histopathology investigations. The bioreduced AgNP/P could find use as a pharmaceutical agent for wound healing dressings.

Topical Analgesic and Anti-Inflammatory Properties of Bioengineered Juglans regia L. Silver Nanoparticles.

<b>Background and Objective:</b> Research has demonstrated the antibacterial, anti-angiogenetic, antiviral, anti-inflammatory, anticancer and antioxidant properties of colloidal silver due to its biological, optical and electrical properties. The aim of this study was the anti-inflammatory effect of the silver bioengineered nanoparticles by using the acetonitrile-unripe fruit extract of <i>Juglans regia</i> L., on experimental animal model. <b>Materials and Methods:</b> The study uses various techniques to characterize nanoparticles, including ultraviolet spectra, dynamic light scattering and Fourier transform infrared. The study used carrageenan-induced rat paw edema as an induction model for inflammation and assessed its antinociceptive effects in mice using the formalin test. As well as evaluation of proinflammatory cytokines IL-6, TNF and IL-1. <b>Results:</b> The produced AgNPs were more compact and stable, according to physical characterization methods compared to chemical prepared nanoparticles. The formulation combining unripe fruit bio-reduced nanoparticles and extract, UF, shows a greater acute anti-inflammatory effect, while leaf extract has a better late anti-inflammatory effect. These bioengineered nanoparticles show efficient <i>in vivo</i> anti-acute inflammation, reducing skin inflammation through decreased cellular infiltrates and cytokine release. <b>Conclusion:</b> <i>Juglans regia</i> L., extract and silver nanoparticles show notable effects in both the early and late stages of the antinociceptive formalin test. While, bioengineered NP/UF and NP/LV can be used as topical analgesics. The potent topical anti-inflammatory and analgesic effects of these medications provide a sufficient basis for the use of this plant material in dermatological products.

Folic acid-hydrophilic polymer coated mesoporous silica nanoparticles target doxorubicin delivery.

Mesoporous silica nanoparticles (MSNs) gained significant attention, particularly in the pharmaceutical field. Folic acid (FA) shows marked promise as a targeting agent for its specific interaction with the folate receptor. This receptor is over-expressed on the cell surface of several cancerous cells like breast cancer. Polyethylene glycol (PE), as well as polypropylene glycol (PEG), is used to decorate nanoparticles to improve their biodistribution. Moreover, carboxymethyl beta-cyclodextrin (CM-ß-CD), is used as a complexation molecule. In this study, we described the chemical synthesis, in vitro drug release and antiproliferative activity of doxorubicin-loaded/decorated MSNs further coupled with FA in two conditions: chemically bound or as a complex with CM-ß-CD. Fourier Transform Infrared Spectroscopy with Transmission Electron Microscopy confirmed the successful surface change. Dynamic Light Scattering confirmed the change in surface characters like zeta potential, polydispersity index (PI), and size. PI improved from 0.58 to 0.23 while the size enlarged from 200 to 348 and 532 nm. Functionalized nanoparticles demonstrated more significant drug entrapment with (97%) while undecorated MSNs only showed (63%). Accordingly, we effectively synthesized FA-PEG2000-MSNs with IC50: 0.015 mg/mL targeting HeLa cells. This approach may allow potential applications as a drug delivery system in cancer chemotherapy.HighlightsMesoporous silica nanoparticles (MSNs) with a carboxylic acid or amine surface group can be successfully decorated with long-chain hydrophilic polymer via an amide bond.Carboxymethyl-ß-cyclodextrin coupled with long-chain polymer as host to form a complex with targeting molecule folic acid.Folic acid can be anchored directly to a polymer coat.TEM; DLS and FTIR confirmed the surface modification.The drug encapsulation efficiency; cytotoxicity and selectivity of functionalized nanoparticles with PEG and conjugated with FA were the best.Chemical modification has improved cytotoxicity of doxorubicin and selectivity against Hela cells.

Discovery of new Gyrase ß inhibitors via structure based modeling.

Gyrase B is an essential enzyme in the prokaryotes which became an attractive target for antibacterial agents. In our study, we implemented a wide range of docking configurations to dock 120 inhibitors into the in the ATP- binding pocket of Gyrase B enzyme (PDB code: 4GEE). LigandFit docking engines and six scoring functions were utilized in the study. Furthermore, the ligands were docked in their ionized and unionized forms into the hydrous and anhydrous binding pocket. We used docking-based Comparative Intermolecular Contacts Analysis (db-CICA) which is a novel methodology to validate and identify the optimal docking configurations. Three docking configurations were found to achieve self-consistent db-CICA models. The resulting db-CICA models were used to construct corresponding pharmacophoric models that were used to screen the National Cancer Institute (NCI) list of compounds. In-vitro study represents antibacterial activities for twelve hit molecules with the most active having IC50 of 20.9 µM.

Haloperidol inhibits Memapsin 2: innovation by docking simulation and in vitro assay.

A number of drugs exhibit unexpected pharmacological effects related to their ability to bind more than one receptor in humans. Haloperidol a typical antipsychotic drug appeared in several reports to be used in schizophrenia patients in which the significant of Alzheimer's disease has been reduced. The etiology of the disease is characterized by aggregates of amyloid plaques, largely composed of amyloid-ß peptide formed from the amyloid precursor protein cleaved by Memapsin 2. To investigate if haloperidol can bind to Memapsin 2 active site, an initial molecular docking was performed as a preliminary in-silico screening test followed by in vitro enzyme inhibition assay. Haloperidol was found to fit readily in Memapsin binding site with IC(50)value 250mM. Haloperidol can be considered as important lead or important target can be modified for more inhibitory activity, with the intention of protection or treatment for Alzheimer's disease.

Discovery of nanomolar phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using ligand-based modeling and virtual screening followed by in vitro analysis.

Phosphoinositide 3-kinase gamma (PI3Kγ) is member of a family of enzymes involved in cancer pathogenesis. Accordingly, considerable efforts have been carried out to develop new PI3Kγ inhibitors. Towards this end we explored the pharmacophoric space of PI3Kγ using three diverse sets of inhibitors. Subsequently, we employed genetic algorithm-based QSAR analysis to select optimal combination of pharmacophoric models and physicochemical descriptors that can explain bioactivity variation within training inhibitors. Interestingly, two successful pharmacophores were selected within two statistically consistent QSAR models. The close similarity among the two binding models prompted us to merge them in a hybrid pharmacophore. The resulting model showed superior receiver operator characteristic curve (ROC) and closely resembled binding interactions seen in crystallographic ligand-PI3Kγ complexes. The resulting model was employed to screen the national cancer institute (NCI) list of compounds to search for new PI3Kγ ligands. After testing captured hits in vitro, 19 compounds showed nanomolar IC50 values against PI3Kγ. The chemical structures and purities of most potent hits were validated using NMR and MS experiments.

Discovery of new renin inhibitory leads via sequential pharmacophore modeling, QSAR analysis, in silico screening and in vitro evaluation.

The renin-angiotensin-aldosterone system is a major target for the clinical management of hypertension. Development of renin inhibitors has proven to be problematic due to poor bioavailability and complex synthesis. In this study, we combined pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis to explore the structural requirements for potent renin inhibitors employing 119 known renin ligands. Genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and physicochemical descriptors to yield self-consistent and predictive QSAR. Two binding pharmacophore models emerged in the optimal QSAR equation (r(96)(2)=0.746, F-statistic=43.552, r(LOO)(2)=0.697, r(PRESS)(2) against 23 test inhibitors=0.527). The successful pharmacophores were complemented with exclusion spheres to optimize their receiver operating characteristic curve (ROC) profiles. The QSAR equations and their associated pharmacophore models were validated by the identification and experimental evaluation of new promising renin inhibitory leads retrieved from the National Cancer Institute (NCI) structural database. The most potent hits illustrated IC(50) value of 2.6 µM. Successful pharmacophore models were found to be comparable with crystallographically resolved renin binding pocket.

Antioxidant, antihyperuricemic and xanthine oxidase inhibitory activities of Hyoscyamus reticulatus.

CONTEXT: Xanthine oxidase (XO) is a key enzyme in the pathophysiological homeostasis of hyperuricemia. It catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid, the reaction involves the formation of free radical intermediates and superoxide byproducts. OBJECTIVES: This study was undertaken to investigate the antioxidant, antihyperuricemic, and xanthine oxidase inhibitory potentials of Hyoscyamus reticulatus L. (Solanaceae) extract. MATERIALS AND METHODS: The antioxidant potency was measured using the ABTS•+ scavenging capacity system, which includes Trolox as a standard. The xanthine oxidase inhibitory activity of the extract was quantitated in vitro by measuring the decline in the catalytic rate of xanthine oxidase following incubations with the plant extracts and using xanthine as a substrate. The hypouricemic potential of the extract was evaluated using an in vivo model for hyperuricemia. We tested three different doses of the extract and allopurinol was used as standard antihyperuricemic positive control. RESULTS: H. reticulatus aqueous extract exhibited significant antioxidant scavenging properties (533.26 µmol TE/g dry extract weight) and inhibitory effect on xanthine oxidase activity (IC50 12.8 µg/mL). Furthermore, oral administration of the aqueous extract significantly reduced serum urate levels in oxonate-induced hyperuricemic mice in a dose-dependent manner. DISCUSSION AND CONCLUSION: Our results suggest that the aqueous extract of H. reticulatus aerial parts might have great potential as an antioxidant and a hypouricemic agent. Our lab is currently identifying the active compounds in the extract to which the biological activities could be attributed.

Elaborate ligand-based pharmacophore exploration and QSAR analysis guide the synthesis of novel pyridinium-based potent beta-secretase inhibitory leads.

Beta-secretase (BACE) inhibitors have potential as anti-Alzheimer's disease treatments prompting us to explore the pharmacophoric space of 129 known BACE inhibitors. QSAR analysis was employed to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of explaining bioactivity variation (r(2)=0.88, F=60.48, r(LOO)(2)=0.85, r(PRESS)(2) against 25 external test inhibitors=0.71). We were obliged to use ligand efficiency as the response variable because the logarithmic transformation of bioactivities failed to access self-consistent QSAR models. Three pharmacophoric models emerged in the successful QSAR equation suggesting at least three binding modes accessible to ligands within BACE binding pocket. QSAR equation and pharmacophoric models were validated through ROC curves and were employed to guide synthesis of novel pyridinium-based BACE inhibitors. The best inhibitor illustrated an IC(50) value of 1.0 microM against BACE.