Ciprofloxacin (CIP), a potent anti-bacterial agent of the fluroquinolone family, shows poor solubility and permeability, thus leading to the development of intracellular pathogens induced multi-drug resistance and biofilms formation. To synergistically improve the biopharmaceutical parameters of CIP, a hyaluronic acid (FDA approved biocompatible polymer) functionalized self-nano emulsifying drug delivery system (HA-CIP-SNEDDS) was designed in the present study. SNEDDS formulations were tested via solubility, droplet size, zeta potential, a polydispersity index, thermodynamic stability, surface morphology, solid-state characterization, drug loading/release, cellular uptake, and biocompatibility. The final (HA-CIP-SNEDDS) formulation exhibited a mean droplet size of 50 nm with the 0.3 poly dispersity index and negative zeta potential (−11.4 mV). HA-based SNEDDS containing CIP showed an improved ability to permeate goat intestinal mucus. After 4 h, CIP-SNEDDS showed a 2-fold and HA-CIP-SNEDDS showed a 4-fold permeation enhancement as compared to the free CIP. Moreover, 80% drug release of HA-CIP-SNEDDS was demonstrated to be superior and sustained for 72 h in comparison to free CIP. However, anti-biofilm activity of HA-CIP-SNEDDS against Salmonella typhi was higher than CIP-SNEDDS and free CIP. HA-CIP-SNEDDS exhibited increased biocompatibility and improved oral pharmacokinetics as compared to free CIP. Taken together, HA-CIP-SNEDDS formulation seems to be a promising agent against Salmonella typhi with a strong targeting potential.

Colorectal cancer (CRC) is the third leading cause of death in men and the fourth in women worldwide and is characterized by deranged cellular energetics. Thymoquinone, an active component from Nigella sativa, has been extensively studied against cancer, however, its role in affecting deregulated cancer metabolism is largely unknown. Further, the phosphoinositide 3-kinase (PI3K) pathway is one of the most activated pathways in cancer and its activation is central to most deregulated metabolic pathways for supporting the anabolic needs of growing cancer cells. Herein, we provide evidence that thymoquinone inhibits glycolytic metabolism (Warburg effect) in colorectal cancer cell lines. Further, we show that such an abrogation of deranged cell metabolism was due, at least in part, to the inhibition of the rate-limiting glycolytic enzyme, Hexokinase 2 (HK2), via modulating the PI3/AKT axis. While overexpression of HK2 showed that it is essential for fueling glycolytic metabolism as well as sustaining tumorigenicity, its pharmacologic and/or genetic inhibition led to a reduction in the observed effects. The results decipher HK2 mediated inhibitory effects of thymoquinone in modulating its glycolytic metabolism and antitumor effects. In conclusion, we provide evidence of metabolic perturbation by thymoquinone in CRC cells, highlighting its potential to be used/repurposed as an antimetabolite drug, though the latter needs further validation utilizing other suitable cell and/or preclinical animal models.

Summary: Recent studies have proposed that adequate intake of Vitamin K (VK) is associated with a low risk of fracture and high bone mineral density (BMD) to improve skeletal health in adults. This systematic review was designed to summarize the most relevant and updated evidence discussing the relationship between VK and bone. It explores the effect of VK deficiency and its supplementation on various bone parameters. Methods: The distinct databases such as PubMed, the Cochrane Library, Google Scholar, National Clinical Trials, Current Controlled Trials, and Clinical Trials were searched up to Jan 2020 to identify eligible trials. All relevant randomized controlled trial studies with any oral dosage form of VK supplement administered for at least six months and assessing BMD or fracture in adults were extracted. Finally, two independent reviewers identified 20 relevant citations for the systematic review and extracted data in tabular form. Results: The meta-analysis was performed with all studies, including postmenopausal and osteoporotic females, for both total clinical and vertebral fracture outcomes. The quantitative analysis showed that the odds ratios (OR) of any fracture were lower for VK as compared to control [OR 0.42 (95% CI 0.27 to 0.66)] for vertebral fractures and OR of 0.44 (95% CI 0.23 to 0.88) for clinical fracture. For the BMD, a meta-analysis of the pooled effect of interventional studies suggested a non-significant association between the use of VK and improvement in femoral BMD (CI 95%, p = 0.08 [−0.03–0.20]). Conclusion: VK decreases general fracture risk, and it can be an option to counter bone loss disorders. However, insufficient evidence is available regarding the significant impact of VK on femoral neck BMD. Therefore, further studies are required to establish the therapeutic value of VK as a treatment for osteoporosis.

P-glycoprotein (P-gP) efflux-mediated multidrug resistance is a fundamental aspect of chemotherapeutic failure in oncology. The current study aims to deliver paclitaxel (PTX) specifically at the target site with improved in vivo efficacy of poorly permeable PTX against solid tumors. Multifunctional polymeric micelles as targeted delivery have been devised for loading and release of PTX. Mucoadhesion, permeation enhancement, oral pharmacokinetics, biodistribution, and toxicological studies were carried out to fully elucidate the therapeutic outcomes of the polymeric micelles. Ex vivo permeation studies indicated a 7.89-fold enhancement in the permeation of PTX with mucopermeating papain functionalized thiolated redox micelles (PT-R-Ms) compared to the pure PTX. Moreover, PT-R-Ms exhibited a higher percentage of apoptotic cells (42.9 ± 0.07%) compared to pure PTX. Biodistribution studies revealed that fluorotagged PT-RMs accumulated in excised tumors and organs. The higher fluorescence intensity indicated the mucopermeation of micelles across the intestine. The orally administered PT-R-Ms efficiently overcome intestinal barriers and inhibit the P-gP efflux pump, resulting in increased bioavailability of PTX (up to 8-fold) in comparison to pure PTX. The enhanced anti-tumor efficacy and reduced toxic effects are key aspects of efficient cancer therapy. This study demonstrates that the use of mucopermeating PT-R-Ms is an encouraging approach to overwhelm the permeation barrier in cancer treatment.

In the present work, novel modality for lung cancer intervention has been explored. Primary literature has established the potential role of cyclooxygenase-2 (COX-2) inhibitor in regression of multiple forms of carcinomas. To overcome its poor water solubility and boost anticancer activity, etoricoxib (ETO) was chosen as a therapeutic candidate for repurposing and formulated into a nanoemulsion (NE). The prepared ETO loaded NE was characterized for the surface charge, droplet size, surface morphology, and in vitro release. The optimized ETO loaded NE was then investigated for its anticancer potential employing A549 lung cancer cell line via cytotoxicity, apoptotic activity, mitochondrial membrane potential activity, cell migration assay, cell cycle analysis, Caspase-3, 9, and p53 activity by ELISA and molecular biomarker analysis through RT-PCR test. The developed ETO-NE formulation showed adequate homogeneity in the droplet size distribution with polydispersity index (PDI) of (0.2 ± 0.03) and had the lowest possible droplet size (124 ± 2.91 nm) and optimal negative surface charge (−8.19 ± 1.51 mV) indicative of colloidal stability. The MTT assay results demonstrated that ETO-NE exhibited substantial anticancer activity compared to the free drug. The ETO-NE showed a substantially potent cytotoxic effect against lung cancer cells, as was evident from the commencement of apoptosis/necrotic cell death and S-phase cell cycle arrests in A549 cells. The study on these molecules through RT-PCR confirmed that ETO-NE is significantly efficacious in mitigating the abundance of IL-B, IL-6, TNF, COX-2, and NF-kB as compared to the free ETO and control group. The current study demonstrates that ETO-NE represents a feasible approach that could provide clinical benefits for lung cancer patients in the future.