In the current medical era, spirooxindole motif stands out as a privileged heterospirocyclic scaffold that represents the core for a wide range of bioactive naturally isolated products (such as Strychnofoline and spirotryprostatins A and B) and synthetic compounds. Interestingly, no much attention has been paid to develop spirooxindole derivatives with dual antioxidant and anticancer activities. In this context, a series of spirooxindoles 6a-p was examined for their anticancer effect towards HepG2 hepatocellular carcinoma and PC-3 prostate cancer cell lines. Spirooxindole 6a was found to be an efficient anti-proliferative agent towards both HepG2 and PC-3 cells (IC50 = 6.9 and 11.8 µM, respectively). Afterwards, spirooxindole 6a was assessed for its apoptosis induction potential in HepG2 cells, where its pro-apoptotic impact was approved via the significant elevation in the Bax/Bcl-2 ratio and the expression levels of caspase-3,

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.

Pseudomonas aeruginosa is a significant human pathogen, it possesses almost all of the known antimicrobial resistance mechanisms. Quorum sensing (QS) is an intercellular communication system that orchestrates bacterial virulence and its targeting is an effective approach to diminish its pathogenesis. Repurposing of drugs is an advantageous strategy, in this study we aimed to repurpose the anti-diabetic drugs sitagliptin, metformin and vildagliptin as anti-QS in P. aeruginosa. The effects of sub-inhibitory concentrations of the tested drugs on the expression of QS-encoding genes and QS-regulated virulence factors were assessed. The protective activity of tested drugs on P. aeruginosa pathogenesis was evaluated in vivo on mice. In silico analysis was performed to evaluate the interference capabilities of the tested drugs on QS-receptors. Although the three drugs reduced the expression of QS-encoding genes, only sitagliptin inhibited the P. aeruginosa virulence in vitro and protected mice from it. In contrast, metformin showed significant in vitro anti-QS activities but failed to protect mice from P. aeruginosa. Vildagliptin did not show any in vitro or in vivo efficacy. Sitagliptin is a promising anti-QS agent because of its chemical nature that hindered QS-receptors. Moreover, it gives an insight to consider their similar chemical structures as anti-QS agents or even design new chemically similar anti-QS pharmacophores.

Multidrug resistant (MDR) methicillin-resistant Staphylococcus aureus (MRSA) is a superbug pathogen that causes serious diseases. One of the main reasons for the lack of the effectiveness of antibiotic therapy against infections caused by this resistant pathogen is the recalcitrant nature of MRSA biofilms, which results in an increasingly serious situation worldwide. Consequently, the development of innovative biofilm inhibitors is urgently needed to control the biofilm formation by this pathogen. In this work, we thus sought to evaluate the biofilm inhibiting ability of some promising antibiofilm agents such as zinc oxide nanoparticles (Zno NPs), proteinase K, and hamamelitannin (HAM) in managing the MRSA biofilms. Different phenotypic and genotypic methods were used to identify the biofilm producing MDR MRSA isolates and the antibiofilm/antimicrobial activities of the used promising agents. Our study demonstrated strong antibiofilm activities of ZnO NPs, proteinase K, and HAM against MRSA biofilms along with their transcriptional modulation of biofilm (intercellular adhesion A, icaA) and quorum sensing (QS) (agr) genes. Interestingly, only ZnO NPs showed a powerful antimicrobial activity against this pathogen. Collectively, we observed overall positive correlations between the biofilm production and the antimicrobial resistance/agr genotypes II and IV. Meanwhile, there was no significant correlation between the toxin genes and the biofilm production. The ZnO NPs were recommended to be used alone as potent antimicrobial and antibiofilm agents against MDR MRSA and their biofilm-associated diseases. On the other hand, proteinase-K and HAM can be co-administrated with other antimicrobial agents to manage such types of infections.

Foodborne pathogens have been associated with severe and complicated diseases. Therefore, these types of infections are a concern for public health officials and food and dairy industries. Regarding the wide-spread multidrug resistant (MDR) and extensively drug resistant (XDR) foodborne pathogens such as Salmonella Enteritidis (S. Enteritidis), new and alternative therapeutic approaches are urgently needed. Therefore, we investigated the antimicrobial, anti-virulence, and immunostimulant activities of a stable formulation of thymol as thymol nanoemulsion in an in vivo approach. Notably, treatment with 2.25% thymol nanoemulsion led to a pronounced improvement in the body weight gain and feed conversion ratio in addition to decreases in the severity of clinical findings and mortality percentages of challenged chickens with XDR S. Enteritidis confirming its pronounced antimicrobial activities. Moreover, thymol nanoemulsion, at this dose, had protective effects through up-regulation of the protective cytokines and down-regulation of XDR S. Enteritidis sopB virulence gene and interleukins (IL)-4 and IL-10 cytokines as those hinder the host defenses. Furthermore, it enhanced the growth of gut Bifidobacteria species, which increases the strength of the immune system. For that, we suggested the therapeutic use of thymol nanoemulsion against resistant foodborne pathogens. Finally, we recommended the use of 2.25% thymol nanoemulsion as a feed additive for immunocompromised individuals as well as in the veterinary fields.

This study explored the in vivo wound healing potential of Vitis vinifera seed extract using an excision wound model with focus on wound healing molecular targets including TGFBR1, VEGF, TNF-α, and IL-1β. The wound healing results revealed that V. vinifera seed extract enhanced wound closure rates (p < 0.001), elevated TGF-β and VEGF levels, and significantly downregulated TNF-α and IL-1β levels in comparison to the Mebo^®-treated group. The phenotypical results were supported by biochemical and histopathological findings. Phytochemical investigation yielded a total of 36 compounds including twenty-seven compounds (1–27) identified from seed oil using GC-MS analysis, along with nine isolated compounds. Among the isolated compounds, one new benzofuran dimer (28) along with eight known ones (29–36) were identified. The structure of new compound was elucidated utilizing 1D/2D NMR, with HRESIMS analyses. Moreover, molecular docking experiments were performed to elucidate the molecular targets (TNF-α, TGFBR1, and IL-1β) of the observed wound healing activity. Additionally, the in vitro antioxidant activity of V. vinifera seed extract along with two isolated compounds (ursolic acid 34, and β-sitosterol-3-O-glucopyranoside 36) were explored. Our study highlights the potential of V. vinifera seed extract in wound repair uncovering the most probable mechanisms of action using in silico analysis.