Silymarin, a phyto-constituent derived from the plant Silybum marianum, has been widely acknowledged for its hepatoprotective activities. Nevertheless, its clinical utility is adversely hampered by its poor water-solubility and its limited oral bioavailability. The aim of this study was to investigate the efficacy of phospholipid-based phytosomes for enhancing the oral bioavailability of silymarin. The phytosomes were prepared using the solvent evaporation technique and were optimized using a full factorial design. The optimized silymarin phytosomal formulation was then characterized for particle size, surface morphology, aqueous solubility, and in vitro drug release. Furthermore, in vivo antioxidant activity, hepatoprotective activity and oral bioavailability of the optimized formula were investigated in a rat model. The prepared silymarin phytosomes were discrete particles with a porous, nearly smooth surface and were 218.4 ± 2.54 nm in diameter. In addition, the optimized silymarin phytosomal formulation showed a significant improvement in aqueous solubility (~360 µg/mL) compared to pure silymarin and manifested a higher rate and extent of silymarin release from the optimized formula in dissolution studies. The in vivo assessment studies revealed that the optimized silymarin phytosomal formulation efficiently exerted a hepatoprotective effect in a CCl₄-induced hepatotoxicity rat model via restoring the normal levels of antioxidant enzymes and ameliorating cellular abnormalities caused by CCl₄-intoxication. Most notably, as compared to pure silymarin, the optimized silymarin phytosomal formulation significantly improved silymarin oral bioavailability, as indicated by a 6-fold increase in the systemic bioavailability. Collectively, phytosomes might represent a plausible phospholipid-based nanocarrier for improving the oral bioavailability of phyto-constituents with poor aqueous solubility.

Glaucoma is a progressive optic neuropathy characterized by a rise in the intraocular pressure (IOP) leading to optic nerve damage. Bimatoprost is a prostaglandin analogue used to reduce the elevated IOP in patients with glaucoma. The currently available dosage forms for Bimatoprost suffer from relatively low ocular bioavailability. The objective of this study was to fabricate and optimize solid lipid nanoparticles (SLNs) containing Bimatoprost for ocular administration for the management of glaucoma. Bimatoprost-loaded SLNs were fabricated by solvent evaporation/ultrasonication technique. Glyceryl Monostearate (GMS) was adopted as solid lipid and poloxamer 407 as surfactant. Optimization of SLNs was conducted by central composite design. The optimized formulation was assessed for average particle size, entrapment efficiency (%), zeta potential, surface morphology, drug release study, sterility test, isotonicity test, Hen’s egg test-chorioallantoic membrane (HET-CAM) test and histopathology studies. The optimized Bimatoprost-loaded SLNs formulation had an average size of 183.3 ± 13.3 nm, zeta potential of −9.96 ± 1.2 mV, and encapsulation efficiency percentage of 71.8 ± 1.1%. Transmission electron microscopy (TEM) study revealed the nearly smooth surface of formulated particles with a nano-scale size range. In addition, SLNs significantly sustained Bimatoprost release for up to 12 h, compared to free drug (p < 005). Most importantly, HET-CAM test nullified the irritancy of the formulation was verified its tolerability upon ocular use, as manifested by a significant reduction in mean irritation score, compared to positive control (1% sodium dodecyl sulfate; p < 0.001). Histopathology study inferred the absence of any signs of cornea tissue damage upon treatment with Bimatoprost optimized formulation. Collectively, it was concluded that SLNs might represent a viable vehicle for enhancing the corneal permeation and ocular bioavailability of Bimatoprost for the management of glaucoma.

Salmonella enterica is an invasive intracellular pathogen and hires diverse systems to manipulate its survival in the host cells. Salmonella could eavesdrop on the host cells, sensing and responding to the produced adrenergic hormones and other neurotransmitters, which results in the augmentation of its virulence and establishes its accommodation in host cells. The current study aims to assess the anti-virulence effect of α-adrenergic antagonist terazosin on S. Typhimurium. Our findings show that terazosin significantly reduced S. Typhimurium adhesion and biofilm formation. Furthermore, terazosin significantly decreased invasion and intracellular replication of S. Typhimurium. Interestingly, in vivo, terazosin protected the mice from S. Typhimurium pathogenesis. To understand the terazosin anti-virulence activity, its effect on quorum sensing (QS), bacterial espionage, and type three secretion system (T3SS) was studied. Strikingly, terazosin competed on the membranal sensors that sense adrenergic hormones and down-regulated their encoding genes, which indicates the ability of terazosin to diminish the bacterial eavesdropping on the host cells. Moreover, terazosin significantly reduced the Chromobacterium violaceum QS-controlled pigment production and interfered with the QS receptor Lux-homolog Salmonella SdiA, which indicates the possible terazosin-mediated anti-QS activity. Furthermore, terazosin down-regulated the expression of T3SS encoding genes. In conclusion, terazosin may mitigate S. Typhimurium virulence owing to its hindering QS and down-regulating T3SS encoding genes besides its inhibition of bacterial espionage.

To discover anti-acetylcholinesterase agents for the treatment of Alzheimer’s disease (AD), a series of novel Schiff base-coumarin hybrids was rationally designed, synthesized successfully, and structurally characterized using Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR), and High-Resolution Mass Spectrometry (HRMS) analyses. These hybrids were evaluated for their potential inhibitory effect on acetylcholinesterase (AChE). All of them exhibited excellent inhibitory activity against AChE. The IC₅₀ values ranged from 87.84 to 515.59 μg/mL; hybrids 13c and 13d with IC₅₀ values of 0.232 ± 0.011 and 0.190 ± 0.004 µM, respectively, showed the most potent activity as acetylcholinesterase inhibitors (AChEIs). The reference drug, Galantamine, yielded an IC₅₀ of 1.142 ± 0.027 µM. Reactivity descriptors, including chemical potential (μ), chemical hardness (η), electrophilicity (ω), condensed Fukui function, and dual descriptors are calculated at wB97XD/6-311++ G (d,p) to identify reactivity changes of the designed compounds. An in-depth investigation of the natural charge pattern of the studied compounds led to a deep understanding of the important interaction centers between these compounds and the biological receptors of AChE. The molecular electrostatic surface potential (MESP) of the most active site in these derivatives was determined using high-quality information and visualization. Molecular docking analysis was performed to predict binding sites and binding energies. The structure-activity-property relationship studies indicated that the proposed compounds exhibit good oral bioavailability properties. To explore the stability and dynamic behavior of the ligand-receptor complexes, molecular dynamics simulations (MDS) were performed for 100 ns on the two best docked derivatives, 13c and 13d, with the AChE (4EY7) receptor. A popular method for determining the free binding energies (MM/GBSA) is performed using snapshots taken from the systems’ trajectories at 100 ns. These results revealed that the complex system of compound 13d acquired a relatively more stable conformation and exhibited better descriptors than the complex system of compound 13c and the Galantamine drug, suggesting its potential as an effective inhibiting drug. The binding free energy analysis revealed that the 13d-4EY7 complex exhibited greater stability with AChE receptors compared to other complexes.

The development of bacterial resistance is an increasing global concern that requires discovering new antibacterial agents and strategies. Bacterial quorum sensing (QS) systems play important roles in controlling bacterial virulence, and their targeting could lead to diminishing bacterial pathogenesis. In this context, targeting QS systems without significant influence on bacterial growth is assumed as a promising strategy to overcome resistance development. This study aimed at evaluating the anti-QS and anti-virulence activities of the β-adrenoreceptor antagonist propranolol at sub-minimal inhibitory concentrations (sub-MIC) against two Gram-negative bacterial models Pseudomonas aeruginosa and Serratia marcescens. The effect of propranolol on the expression of QS-encoding genes was evaluated. Additionally, the affinity of propranolol to QS receptors was virtually attested. The influence of propranolol at sub-MIC on biofilm formation, motility, and production of virulent factors was conducted. The outcomes of the propranolol combination with different antibiotics were assessed. Finally, the in vivo protection assay in mice was performed to assess propranolol’s effect on lessening the bacterial pathogenesis. The current findings emphasized the significant ability of propranolol at sub-MIC to reduce the formation of biofilms, motility, and production of virulence factors. In addition, propranolol at sub-MIC decreased the capacity of tested bacteria to induce pathogenesis in mice. Furthermore, propranolol significantly downregulated the QS-encoding genes and showed significant affinity to QS receptors. Finally, propranolol at sub-MIC synergistically decreased the MICs of different antibiotics against tested bacteria. In conclusion, propranolol might serve as a plausible adjuvant therapy with antibiotics for the treatment of serious bacterial infections after further pharmacological and pharmaceutical studies.

Carvedilol (CRV) is a non-selective third generation beta-blocker used to treat hypertension, congestive heart failure and angina pectoris. Oral administration of CRV showed poor bioavailability (25%), which might be ascribed to its extensive first-pass metabolism. Buccal delivery is known to boost drugs bioavailability. The aim of this study is to investigate the efficacy of bilosomes-based mucoadhesive carvedilol nanosponge for enhancing the oral bioavailability of CRV. The bilosomes were prepared, optimized and characterized for particle size, surface morphology, encapsulation efficiency and ex-vivo permeation studies. Then, the optimized formula was incorporated into a carboxymethyl cellulose/hydroxypropyl cellulose (CMC/HPC) composite mixture to obtain buccal nanosponge enriched with CRV bilosomes. The optimized bilosome formula (BLS9), showing minimum vesicle size, maximum entrapment, and highest cumulative in vitro release, exhibited a spherical shape with 217.2 nm in diameter, 87.13% entrapment efficiency, and sustained drug release for up to 24 h. In addition, ex-vivo drug permeation across sheep buccal mucosa revealed enhanced drug permeation with bilosomal formulations, compared to aqueous drug suspension. Consecutively, BLS9 was incorporated in a CMC/HPC gel and lyophilized for 24 h to obtain bilosomal nanosponge to enhance CRV buccal delivery. Morphological analysis of the prepared nanosponge revealed improved swelling with a porosity of 67.58%. The in vivo assessment of rats indicated that CRV-loaded nanosponge efficiently enhanced systolic/diastolic blood pressure, decreased elevated oxidative stress, improved lipid profile and exhibited a potent cardio-protective effect. Collectively, bilosomal nanosponge might represent a plausible nanovehicle for buccal delivery of CRV for effective management of hypertension.