Alginate-chitosan-microencapsulated tyrosols/oleuropein-rich olive mill waste extract for lipopolysaccharide-induced skin fibroblast inflammation treatment.

The Ca2+ ion-driven emulsification-ionotropic gelation method produced chitosan-alginate microspheres (CAMSs) with a narrow particle size distribution (PSD). Particle size distribution and zeta potential studies, as well as spectral electron microscopy, were used to assess the microspheres' physicochemical properties and morphology. The tyrosols (hydroxytyrosol (HT), tyrosol (TY), and oleuropein (OE) were loaded into these microspheres using a polyphenol extract (PPE) from Koroneki olive mill waste (KOMW). The microencapsulation efficiency and loading capacity of microspheres for PPE were 98.8% and 3.9%, respectively. Three simulated fluids, including gastric (pH = 1.2), intestinal (pH = 6.8), and colonic (pH = 7.4), were used to examine how the pH of the releasing medium affected the ability of CAMSs to release bioactive phenols. At a severely acidic pH (1.2, SGF), PPE release is nearly halted, while at pH 6.8 (SCF), release is at its maximum. Additionally, the PPE-CAMPs have ameliorated the endogenous antioxidant content SOD, GST, GPx with significant values from 0.05 to 0.01 in the treated LPS/human skin fibroblast cells. The anti-inflammatory response was appeared through their attenuations activity for the released cytokines TNF-α, IL6, IL1ß, and IL 12 with levels significantly from 0.01 to 0.001. Microencapsulation of PPE by CAMPs significantly improved its antioxidant and anti-inflammatory capabilities.

Development of Olive Oil Containing Phytosomal Nanocomplex for Improving Skin Delivery of Quercetin: Formulation Design Optimization, In Vitro and Ex Vivo Appraisals.

The objective of the current work was to fabricate, optimize and assess olive oil/phytosomal nanocarriers to improve quercetin skin delivery. Olive oil/phytosomal nanocarriers, prepared by a solvent evaporation/anti-solvent precipitation technique, were optimized using a Box-Behnken design, and the optimized formulation was appraised for in vitro physicochemical characteristics and stability. The optimized formulation was assessed for skin permeation and histological alterations. The optimized formulation (with an olive oil/PC ratio of 0.166, a QC/PC ratio of 1.95 and a surfactant concentration of 1.6%), and with a particle diameter of 206.7 nm, a zeta potential of -26.3 and an encapsulation efficiency of 85.3%, was selected using a Box-Behnken design. The optimized formulation showed better stability at ambient temperature when compared to refrigerating temperature (4 °C). The optimized formulation showed significantly higher skin permeation of quercetin when compared to an olive-oil/surfactant-free formulation and the control (~1.3-fold and 1.9-fold, respectively). It also showed alteration to skin barriers without remarkable toxicity aspects. Conclusively, this study demonstrated the use of olive oil/phytosomal nanocarriers as potential carriers for quercetin-a natural bioactive agent-to improve its skin delivery.

Exploring the potential of quercetin/aspirin-loaded chitosan nanoparticles coated with Eudragit L100 in the treatment of induced-colorectal cancer in rats.

Growing evidence suggests quercetin and aspirin may have anticancer properties, notably in the case of colorectal cancer. The goal of this study was to create Pluronic F127 and polyethylene glycol4000 solid dispersion-loaded chitosan nanoparticles for colonic quercetin and aspirin delivery. In 1:1 polymeric stoichiometric ratio, solubility and complex formation were verified. Solid dispersion-loaded chitosan nanoparticles with a diameter of 244.45 ± 8.5 nm, a surface charge of 34.1 ± 3.3 mV, and encapsulation effectiveness of 76.3 ± 4.3% were generated under ideal conditions. In some cases, coating with Eudragit L100 resulted in a decrease in zeta potential and an increase in particle size. The coated formulation released the actives in a pH-dependent manner, considering their physicochemical features. Surprisingly, when compared to the actives' suspension and uncoated formulation, the coated formulation had greater anti-inflammatory efficacy, with a substantial reduction of PGE2 and IL-8 production in colonic tissues (16.9 ± 7.9 ng/g tissue and 134.9 ± 10.1 pg/g tissue, respectively). It also reversed most of the dimethyl hydrazine-induced histological alterations in the colon. It also demonstrated a greater reduction in TNF expression in colonic tissues. As a result, Eudragit L100-coated QT/AS-loaded chitosan nanoparticles are suggested to provide a potential platform for colonic delivery of quercetin and aspirin.

A comprehensive review of recent advances in the biological activities of 1,2,4-oxadiazoles.

Nitrogen heterocycles play an essential role in medication development. The 1,2,4-oxadiazole heterocycle has been extensively studied, yielding a large variety of molecules with varied biological functions. The 1,2,4-oxadiazole shows bioisosteric equivalency with ester and amide moieties. In recent years, the 1,2,4-oxadiazole nucleus has received a lot of attention in medicinal chemistry. It was thought to be a pharmacophore component in the production of biologically intriguing drugs. This review presents a comprehensive overview of the recent achievements in the biological activities of 1,2,4-oxadiazoles as potential antimicrobial, anticancer, anti-inflammatory, neuroprotective, and antidiabetic agents. The structure-activity relationship and mechanisms of action are also reviewed.

Efficacy of ginsenoside Rg3 nanoparticles against Ehrlich solid tumor growth in mice.

Solid tumors are fairly common and face many clinical difficulties since they are hardly surgically resectable and broadly do not respond to radiation and chemotherapy. The current study aimed to fabricate ginsenoside Rg3 nanoparticles (Rg3-NPs) and evaluate their antitumor effect against Ehrlich solid tumors (EST) in mice. Rg3-NPs were fabricated using whey protein isolates (WPI), maltodextrin (MD), and gum Arabic (GA). EST was developed by the injection of mice with Ehrlich ascites cells (2.5 × 106). The mice were divided into a control group, EST group, and the EST groups that were treated orally 2 weeks for with normal Rg3 (3 mg/kg b.w.), Rg3-NPs at a low dose (3 mg/kg b.w.), and Rg3-NPs at a high dose (6 mg/kg b.w.). Serum and solid tumors were collected for different assays. The results revealed that synthesized Rg3-NPs showed a spherical shape with an average particle size of 20 nm and zeta potential of -5.58 mV. The in vivo study revealed that EST mice showed a significant increase in AFP, Casp3, TNF-α, MMP-9, VEGF, MDA, and DNA damage accompanied by a significant decrease in SOD and GPx. Treatment with Rg3 or Rg3-NPs decreased the tumor weight and size and induced a significant improvement in all the biochemical parameters. Rg3-NPs were more effective than Rg3, and the improvement was dose-dependent. It could be concluded that fabrication of Rg3-NPs enhanced the protective effect against EST development which may be due to the synergistic effect of Rg3 and MD, GA, and WPI.

Phenylboronic Acid-Grafted Chitosan Nanocapsules for Effective Delivery and Controllable Release of Natural Antioxidants: Olive Oil and Hydroxytyrosol.

Olives and virgin olive oil (VOO) are a staple of Mediterranean diets and are rich in several beneficial phenolic compounds, including hydroxytyrosol (HT). Therefore, VOO was extracted from Koroneiki olive fruits, and its volatile as well as phenolic components were identified. Meanwhile, in order to upgrade the pharmaceutical capabilities of VOO and HT, a new conjugate phenylboronic acid-chitosan nanoparticles (PBA-CSNPs, NF-1) was fabricated and applied as nanocapsules for implanting high loading and efficient delivery of VOO and HT nanoformulations (NF-2 and NF-3). Due to the H-bonding interactions and boronate ester formation between the hydroxyl groups of the phenolic content of VOO or HT and the PBA groups in the nanocapsules (NF-1), VOO and HT were successfully loaded into the PBA-CSNPs nanocapsules with high loading contents and encapsulation efficacies. The NF-2 and NF-3 nanoformulations demonstrated physicochemical stability, as revealed by their respective zeta potential values, and pH-triggered drug release characteristics. The in vitro studies demonstrated that the nascent nanocapsules were almost completely nontoxic to both healthy and cancer cells, whereas VOO-loaded (NF-2) and HT-loaded nanocapsules (NF-3) showed efficient anti-breast cancer efficiencies. In addition, the antimicrobial and antioxidant potentials of VOO and HT were significantly improved after nanoencapsulation.

The JAK inhibitor ruxolitinib abrogates immune hepatitis instigated by concanavalin A in mice.

Therapeutics that impair the innate immune responses of the liver during the inflammatory cytokine storm like that occurring in COVID-19 are greatly needed. Much interest is currently directed toward Janus kinase (JAK) inhibitors as potential candidates to mitigate this life-threatening complication. Accordingly, this study investigated the influence of the novel JAK inhibitor ruxolitinib (RXB) on concanavalin A (Con A)-induced hepatitis and systemic hyperinflammation in mice to simulate the context occurring in COVID-19 patients. Mice were orally treated with RXB (75 and 150 mg/kg) 2 h prior to the intravenous administration of Con A (20 mg/kg) for a period of 12 h. The results showed that RXB pretreatments were efficient in abrogating Con A-instigated hepatocellular injury (ALT, AST, LDH), necrosis (histopathology), apoptosis (cleaved caspase-3) and nuclear proliferation due to damage (PCNA). The protective mechanism of RXB were attributed to i) prevention of Con A-enhanced hepatic production and systemic release of the proinflammatory cytokines TNF-α, IFN-γ and IL-17A, which coincided with decreasing infiltration of immune cells (monocytes, neutrophils), ii) reducing Con A-induced hepatic overexpression of IL-1ß and CD98 alongside NF-κB activation, and iii) lessening Con A-induced consumption of GSH and GSH peroxidase and generation of oxidative stress products (MDA, 4-HNE, NOx) in the liver. In summary, JAK inhibition by RXB led to eminent protection of the liver against Con A-deleterious manifestations primarily via curbing the inflammatory cytokine storm driven by TNF-α, IFN-γ and IL-17A.

Influence of Stabilizer on the Development of Luteolin Nanosuspension for Cutaneous Delivery: An In Vitro and In Vivo Evaluation.

Luteolin is a natural drug used as an antioxidant and anti-inflammatory, but unfortunately, it possesses low water solubility, which hinders its delivery via the skin. The main objective of this study was to prepare a luteolin-loaded nanosuspension by the antisolvent precipitation/sonication technique and study the effects of four stabilizers (two nonionic stabilizers, Pluronic F127 and Tween 80, and two polymeric stabilizers, HPMC and alginate) on the physicochemical properties of the prepared formulations. The selected formulations were incorporated into a gel base to evaluate their skin permeability and anti-inflammatory efficacy. The particle size was in the nanosize range (in the range from 468.1 ± 18.6 nm to 1024.8 ± 15.9 nm), while the zeta potential was negative and in the range from -41.7 ± 6.3 mV to -15.3 ± 1.9 mV. In particular, alginate-stabilized nanosuspensions showed the smallest particle size, the highest zeta potential value, and excellent stability due to the dual stabilizing effects (electrostatic and steric effects). The DSC results revealed a less crystalline structure of luteolin in lyophilized NS2 and NS12. Formulations stabilized by 1% Pluronic (NS2) and 2% alginate (NS12) were incorporated into a carbopol 940 gel base and showed good organoleptic character (homogenous with no evidenced phase separation or grittiness). In vitro dissolution studies showed that NS12 enhanced luteolin release rates, indicating the effect of particle size on the drug release pattern. On the other hand, NS2 showed enhanced skin permeability and anti-inflammatory effect in a carrageenan-induced paw edema model, revealing the surface activity role of the stabilizers. In conclusion, while alginate increased the nanosuspension stability by means of dual stabilizing effects, Pluronic F127 improved the skin delivery and pharmacodynamic efficacy of luteolin.

Cholinesterase Inhibitory Activities of Selected Halogenated Thiophene Chalcones.

BACKGROUND: Dual-acting human monoamine oxidase B (hMAO-B) and cholinesterase (ChE) inhibitors are more effective than the classic one-drug one-target therapy for Alzheimer's disease (AD). METHODS: The ChE inhibitory ability of some halogenated thiophene chalcone-based molecules known to be selective hMAO-B inhibitors was evaluated. RESULTS: Based on the IC50 values, the selected compounds were found to moderately inhibit ChE, with IC50 values in the range of 14-70 µM. Among the synthesised molecules, T8 and T6 showed the most potent inhibitory activity against AChE and BChE, respectively. CONCLUSION: Taken together, the data revealed that T8 could be further optimized to enhance its AChE inhibitory activity.

Fe3 O4 nanoparticles mediated synthesis of novel spirooxindole-dihydropyrimidinone molecules as Hsp90 inhibitors.

Heat shock protein 90 (Hsp90) is a validated molecular chaperone considered as the new key recipient for cancer intervention. The current study illustrates the synthesis of novel spirooxindole-dihydropyrimidinones (4a-j) by Fe3 O4 nanoparticles intervened synthesis and their Hsp90 ATPase inhibitory activity was investigated by the malachite green assay. All the compounds in the study demonstrated a moderate to potent ATPase inhibitory profile, with IC50 values ranging from 0.18 to 6.80 µM. Compounds 4j, 4h, 4f, and 4i exhibited maximum inhibitory potential with IC50 values of 0.18, 0.20, 0.35, and 0.55 µM, respectively. They were found to be better than the standard drug, geldanamycin (Hsp9 ATPase inhibition IC50 = 0.90 µM). Compounds 4h and 4j with IC50 values of 22.82 ± 0.532, 20.78 ± 0.234 and 21.32 ± 0.765, 28.43 ± 0.653 µM showed significantly greater potencies against the MCF-7 and HepG2 cell lines, respectively. Compound 4j showed good antioxidant activities in the DPPH test and H2 O2 assay (IC50 = 20.13.23 ± 0.32 and 23.27 ± 0.32 µg/mL) when compared with the standard ascorbic acid (IC50 = 19.16 ± 0.20 and 20.66 ± 1.09 µg/mL). A molecular docking study was performed to observe the binding efficiency and steric interactions of the lead moiety.