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Green synthesis of gold nanoparticles (GNPs) with plant extracts has gained considerable interest in the field of biomedicine. Recently, the bioreduction nature of herbal extracts has helped to synthesize spherical GNPs of different potential from gold salt. In this study, a fast ecofriendly method was adopted for the synthesis of GNPs using fresh peel (aqueous) extracts of Benincasa hispida, which acted as reducing and stabilizing agents. The biosynthesized GNPs were characterized by UV–VIS and Fourier transform infrared spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering. In addition, the in vitro antibacterial and anticancer activities of synthesized GNPs were investigated. The formation of gold nanoparticles was confirmed by the existence of a sharp absorption peak at 520 nm, corresponding to the surface plasmon resonance (SPR) band of the GNPs. TEM analysis revealed that the prepared GNPs were spherical in shape and had an average particle size of 22.18 ± 2 nm. Most importantly, the synthesized GNPs exhibited considerable antibacterial activity against different Gram-positive and Gram-negative bacteria. Furthermore, the biosynthesized GNPs exerted remarkable in vitro cytotoxicity against human cervical cancer cell line, while sparing normal human primary osteoblast cells. Such cytotoxic effect was attributed to the increased production of reactive oxygen species (ROS) that contributed to the damage of HeLa cells. Collectively, peel extracts of B. hispida can be efficiently used for the synthesis of GNPs, which can be adopted as a natural source of antimicrobial and anticancer agent.

Alveolar macrophages are the first line of defense against intruding pathogens and play a critical role in cancer immunology. The Toll-like receptor (TLR) family mediates an important role in recognizing and mounting an immune response against intruding microbes. TLR-9 is a member of the intracellular TLR family, which recognizes unmethylated CG motifs from the prokaryotic genome. Upon its activation, TLR-9 triggers downstream of the MyD-88-dependent transcriptional activation of NF-κB, and subsequently results in abundant inflammatory cytokines expression that induces a profound inflammatory milieu. The present exploratory investigation aimed at elucidating the potency of schizophyllan for entrapping ODN 1826 (SPG-ODN 1826)-mediated stimulation of TLR-9 in provoking an inflammatory-type response in murine alveolar macrophages. Schizophyllan (SPG), a representative of the β-glucan family, was used in the present study as a nanovehicle for endosomal trafficking of CpG ODN 1826. TEM analysis of SPG-ODN 1826 nanovehicles revealed that the prepared nanovehicles are spherical and have an average size of about 100 nm. Interestingly, SPG-ODN 1826 nanovehicles were competent in delivering their therapeutic payload within endosomes of murine alveolar macrophage (J774A.1) cells. Exposure of these nanovehicles within LPS stimulated J774A.1, resulted in a significant provocation of reactive oxygen species (ROS) (p < 0.01) in comparison to CpG ODN 1826 alone. Moreover, the formulated nanovehicles succeeded in generating a profound Th1-based cytokine profile constituted by enhanced expression of IFN-γ (p < 0.001) and IL-1β (p < 0.001) inflammatory cytokines. These findings clearly indicated the immunostimulatory potential of SPG-ODN 1826 nanovehicles for inducing the Th1-type phenotype, which would certainly assist in skewing M2 phenotype into the much-desired M1 type during lung cancer.

Despite decades of research, breast cancer therapy remains a great challenge. Docetaxel is an antimicrotubule agent that is effectively used for the treatment of breast cancer. However, its clinical use is significantly hampered by its low water solubility and systemic toxicity. The current study was designed to prepare docetaxel (DXL)-loaded silk-fibroin-based nanoparticles (SF-NPs) and to screen their potential antitumor activity against breast cancer cell lines. DXL-loaded SF-NPs were prepared using a nanoprecipitation technique and were evaluated for particle size, zeta potential, entrapment efficiency, and in vitro release profile. In addition, DXL-loaded SF-NPs were screened for in vitro cytotoxicity, cellular uptake, and apoptotic potential against MCF-7 and MDA-MB-231 breast cancer cell lines. The prepared DXL-loaded SF-NPs were 178 to 198 nm in diameter with a net negative surface charge and entrapment efficiency ranging from 56% to 72%. In vitro release studies exhibited a biphasic release profile of DXL from SF-NPs with sustained drug release for 72 h. In vitro cell studies revealed that entrapment of DXL within SF-NPs significantly improved cytotoxic potential against breast cancer cell lines, compared to the free drug, and enhanced cellular uptake of DXL by breast cancer cells. Furthermore, the accumulation in the G2/M phase was significantly higher in cells treated with DXL-loaded SF-NPs than in cells treated with free DXL. Collectively, the superior antitumor activities of DXL-loaded SF-NPs against breast cancer cells, compared to free DXL, could be ascribed to improved apoptosis and cell cycle arrest. Our results highlighted the feasibility of using silk fibroin nanoparticles as a nontoxic biocompatible delivery vehicle for enhanced therapeutic outcomes in breast cancer.

Pseudomonas aeruginosa can cause a variety of healthcare-associated infections by its arsenal of virulence factors. Virulence factor production is largely controlled by the cell-to-cell communication system termed quorum sensing (QS). Targeting QS may be a good approach to inhibit the production of virulence factors and attenuate pathogenicity without exerting selective stress on bacterial growth. This will greatly reduce the emergence of resistant mutants. In this work, we investigated the anti-virulence and anti-QS activities of the FDA-approved drug allopurinol against the P. aeruginosa PAO1 strain. Allopurinol at 200 µg/mL (1/10 MIC) significantly decreased the production of the QS-controlled Chromobacterium violaceum CV026 violet pigment violacein and other P. aeruginosa QS-controlled virulence factors phenotypically. Furthermore, allopurinol reduced the infiltration of P. aeruginosa and leucocytes and diminished the congestion in the liver and kidney tissues of infected mice. In silico study showed that allopurinol could compete with the autoinducers on binding to the receptors LasR and RhlR by hydrogen bonding. On the molecular level, qRT-PCR proved that allopurinol showed a significant downregulating effect on all tested QS-encoding genes that regulate virulence factor production. In summary, allopurinol is a promising QS inhibitor that may be useful in the future treatment of P. aeruginosa infection.

The bacterial resistance development due to the incessant administration of antibiotics has led to difficulty in their treatment. Natural adjuvant compounds can be co-administered to hinder the pathogenesis of resistant bacteria. Sotolon is the prevailing aromatic compound that gives fenugreek its typical smell. In the current work, the anti-virulence activities of sotolon on Pseudomonas aeruginosa have been evaluated. P. aeruginosa has been treated with sotolon at sub-minimum inhibitory concentration (MIC), and production of biofilm and other virulence factors were assessed. Moreover, the anti-quorum sensing (QS) activity of sotolon was in-silico evaluated by evaluating the affinity of sotolon to bind to QS receptors, and the expression of QS genes was measured in the presence of sotolon sub-MIC. Furthermore, the sotolon in-vivo capability to protect mice against P. aeruginosa was assessed. Significantly, sotolon decreased the production of bacterial biofilm and virulence factors, the expression of QS genes, and protected mice from P. aeruginosa. Conclusively, the plant natural substance sotolon attenuated the pathogenicity of P. aeruginosa, locating it as a plausible potential therapeutic agent for the treatment of its infections. Sotolon can be used in the treatment of bacterial infections as an alternative or adjuvant to antibiotics to combat their high resistance to antibiotics.

Over the last years, extensive motivation has emerged towards the application of supercritical carbon dioxide (SCCO2) for particle engineering. SCCO2 has great potential for application as a green and eco-friendly technique to reach small crystalline particles with narrow particle size distribution. In this paper, an artificial intelligence (AI) method has been used as an efficient and versatile tool to predict and consequently optimize the solubility of oxaprozin in SCCO2 systems. Three learning methods, including multi-layer perceptron (MLP), Kriging or Gaussian process regression (GPR), and k-nearest neighbors (KNN) are selected to make models on the tiny dataset. The dataset includes 32 data points with two input parameters (temperature and pressure) and one output (solubility). The optimized models were tested with standard metrics. MLP, GPR, and KNN have error rates of 2.079 × 10−8, 2.173 × 10−9, and 1.372 × 10−8, respectively, using MSE metrics. Additionally, in terms of R-squared, they have scores of 0.868, 0.997, and 0.999, respectively. The optimal inputs are the same as the maximum possible values and are paired with a solubility of 1.26 × 10−3 as an output.

Olaparib (OLP) is an orally active poly (ADP-ribose) polymerase enzyme inhibitor, approved for treatment for the metastatic stage of prostate, pancreatic, breast and ovarian cancer. Due to its low bioavailability, an increase in dose and frequency is required to achieve therapeutic benefits, which also results in associated toxicity in patients. In the current study, OLP-loaded poly (d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) (OLP-PLGA NPs) and a coating of OLP-PLGA NPs with chitosan (CS) (OLP-CS-PLGA NPs) were prepared successfully in order to improve the dissolution rate and bioavailability. The developed OLP-PLGA NPs were evaluated for hydrodynamic particle size (392 ± 5.3 nm), PDI (0.360 ± 0.03), ZP (−26.9 ± 2.1 mV), EE (71.39 ± 5.5%) and DL (14.86 ± 1.4%), and OLP-CS-PLGA NPs, hydrodynamic particle size (622 ± 9.5 nm), PDI (0.321 ± 0.02), ZP (+36.0 ± 1.7 mV), EE (84.78 ± 6.3%) and DL (11.05 ± 2.6%). The in vitro release profile of both developed NPs showed a sustained release pattern. Moreover, the pharmacokinetics results exhibited a 2.0- and 4.75-fold increase in the bioavailability of OLP-PLGA NPs and OLP-CS-PLGA NPs, respectively, compared to normal OLP suspension. The results revealed that OLP-CS-PLGA NPs could be an effective approach to sustaining and improving the bioavailability of OLP.

Computational analysis of drug solubility was carried out using machine learning approach. The solubility of Decitabine as model drug in supercritical CO 2 was studied as function of pressure and temperature to assess the feasibility of that for production of nanomedicine to enhance the solubility. The data was collected for solubility optimization of Decitabine at the temperature 308–338 K, and pressure 120–400 bar used as the inputs to the machine learning models. A dataset of 32 data points and two inputs (P and T) have been applied to optimize the solubility. The only output is Y = solubility, which is Decitabine mole fraction solubility in the solvent. The developed models are three models including Kernel Ridge Regression (KRR), Decision tree Regression (DTR), and Gaussian process (GPR), which are used for the first time as a novel model. These models are optimized using their hyper-parameters tuning and then assessed using standard metrics, which shows R 2 -score, KRR, DTR, and GPR equal to 0.806, 0.891, and 0.998. Also, the MAE metric shows 1.08E−04, 7.40E−05, and 9.73E−06 error rates in the same order. The other metric is MAPE, in which the KRR error rate is 4.64E−01, DTR shows an error rate equal to 1.63E−01, and GPR as the best mode illustrates 5.06E−02. Finally, analysis using the best model (GPR) reveals that increasing both inputs results in an increase in the solubility of Decitabine. The optimal values are (P = 400, T = 3.38E + 02, Y = 1.07E−03).

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.

Nicotinamide adenine dinucleotide (NAD + ), a coenzyme for more than 500 enzymes, plays a central role in energy production, metabolism, cellular signaling, and DNA repair. Until recently, NAD + was primarily considered to be an intracellular molecule (iNAD + ), however, its extracellular species (eNAD + ) has recently been discovered and has since been associated with a multitude of pathological conditions. Therefore, accurate quantification of eNAD + in bodily fluids such as plasma is paramount to answer important research questions. In order to create a clinically meaningful and reliable quantitation method, we analyzed the relationship of cell lysis, routine clinical laboratory parameters, blood collection techniques, and pre-analytical processing steps with measured plasma eNAD + concentrations. Initially, NAD + levels were assessed both intracellularly and extracellularly. Intriguingly, the concentration of eNAD + in plasma was found to be approximately 500 times lower than iNAD + in peripheral blood mononuclear cells (0.253 ± 0.02 μM vs. 131.8 ± 27.4 μM, p  = 0.007, respectively). This stark contrast suggests that cellular damage or cell lysis could potentially affect the levels of eNAD + in plasma. However, systemic lactate dehydrogenase in patient plasma, a marker of cell damage, did not significantly correlate with eNAD + ( n  = 33; r  = −0.397; p  = 0.102). Furthermore, eNAD + was negatively correlated with increasing c-reactive protein (CRP, n  = 33; r  = −0.451; p  = 0.020), while eNAD + was positively correlated with increasing hemoglobin ( n  = 33; r  = 0.482; p  = 0.005). Next, variations in blood drawing, sample handling and pre-analytical processes were examined. Sample storage durations at 4°C (0–120 min), temperature (0° to 25°C), cannula sizes for blood collection and tourniquet times (0 – 120 s) had no statistically significant effect on eNAD + ( p  > 0.05). On the other hand, prolonged centrifugation (> 5 min) and a faster braking mode of the centrifuge rotor (< 4 min) resulted in a significant decrease in eNAD + levels ( p  < 0.05). Taken together, CRP and hemoglobin appeared to be mildly correlated with eNAD + levels whereas cell damage was not correlated significantly to eNAD + levels. The blood drawing trial did not show any influence on eNAD + , in contrast, the preanalytical steps need to be standardized for accurate eNAD + measurement. This work paves the way towards robust eNAD + measurements, for use in future clinical and translational research, and provides an optimized hands-on protocol for reliable eNAD + quantification in plasma.