Targeting NF-κB signaling cascades of glioblastoma by a natural benzophenone, garcinol, via in vitro and molecular docking approaches

Glioblastoma multiforme (GBM) is regarded as the most aggressive form of brain tumor delineated by high cellular heterogeneity; it is resistant to conventional therapeutic regimens. In this study, the anti-cancer potential of garcinol, a naturally derived benzophenone, was assessed against GBM. During the analysis, we observed a reduction in the viability of rat glioblastoma C6 cells at a concentration of 30 µM of the extract (p < 0.001). Exposure to garcinol also induced nuclear fragmentation and condensation, as evidenced by DAPI-stained photomicrographs of C6 cells. The dissipation of mitochondrial membrane potential in a dose-dependent fashion was linked to the activation of caspases. Furthermore, it was observed that garcinol mediated the inhibition of NF-κB (p < 0.001) and decreased the expression of genes associated with cell survival (Bcl-XL, Bcl-2, and survivin) and proliferation (cyclin D1). Moreover, garcinol showed interaction with NF-κB through some important amino acid residues, such as Pro275, Trp258, Glu225, and Gly259 during molecular docking analysis. Comparative analysis with positive control (temozolomide) was also performed. We found that garcinol induced apoptotic cell death via inhibiting NF-κB activity in C6 cells, thus implicating it as a plausible therapeutic agent for GBM

Anti-Adhesion and Antibiofilm Activity of Eruca sativa Miller Extract Targeting Cell Adhesion Proteins of Food-Borne Bacteria as a Potential Mechanism: Combined In Vitro-In Silico Approach

Bacterial cells have the ability to form biofilm onto the surfaces of food matrixes and on food processing equipment, leading to a source of food contamination posing serious health implications. Therefore, our study aimed to determine the effect of Eruca sativa Miller (E. sativa) crude extract against biofilms of food-borne bacteria along with in silico approaches to investigate adhesion proteins responsible for biofilm activity against the identified phytochemicals. The antibacterial potential of crude extract was evaluated using agar well diffusion technique and combinations of light and scanning electron microscopy to assess the efficacy of crude extract against the developed biofilms. Our results showed that crude extract of E. sativa was active against all tested food-borne bacteria, exhibiting a rapid kinetics of killing bacteria in a time-dependent manner. MIC and MBC values of E. sativa crude extract were found to be ranging from 125 to 500 µg/mL and 250 to 1000 µg/mL respectively. Furthermore, inhibition of developed biofilm by E sativa was found to be ranging from 58.68% to 73.45% for all the tested strains. The crude extract also reduced the viability of bacterial cells within biofilms and amount of EPS (ranging 59.73–82.77%) in the biofilm matrix. Additionally, the microscopic images also revealed significant disruption in the structure of biofilms. A molecular docking analysis of E. sativa phytochemicals showed interaction with active site of adhesion proteins Sortase A, EspA, OprD, and type IV b pilin of S. aureus, E. coli, P. aeruginosa, and S. enterica ser. typhi, respectively. Thus, our findings represent the first demonstration of E. sativa crude extract’s bioactivity and potency against food-borne bacteria in their planktonic forms, as well as against the developed biofilms. Therefore, a possible mechanistic approach for inhibition of biofilm via targeting adhesion proteins can be explored further to target biofilm producing food-borne bacterial pathogens

Development and Characterization of PEGDA Microneedles for Localized Drug Delivery of Gemcitabine to Treat Inflammatory Breast Cancer

Inflammatory breast cancer (IBC) is one of the most belligerent types of breast cancer. While various modalities exist in managing/treating IBC, drug delivery using microneedles (MNs) is considered to be the most innovative method of localized delivery of anti-cancer agents. Localized drug delivery helps to treat IBC could limit their adverse reactions. MNs are nothing but small needle like structures that cause little or no pain at the site of administration for drug delivery via layers of the skin. The polyethylene glycol diacrylate (PEGDA) based MNs were fabricated by using three dimensional (3D) technology called Projection Micro-Stereo Lithography (PµSL). The fabricated microneedle patches (MNPs) were characterized and coated with a coating formulation comprising of gemcitabine and sodium carboxymethyl cellulose by a novel and inventive screen plate method. The drug coated MNPs were characterized by various instrumental methods of analysis and release profile studies were carried out using Franz diffusion cell. Coat-and-poke strategy was employed in administering the drug coated MNPs. Overall, the methods employed in the present study not only help in obtaining MNPs with accurate dimensions but also help in obtaining uniformly drug coated MNPs of gemcitabine for treatment of IBC. Most importantly, 100% drug release was achieved within the first one hour only

3-Methoxy Carbazole Impedes the Growth of Human Breast Cancer Cells by Suppressing NF-κB Signaling Pathway

Breast cancer represents the most frequently occurring cancer globally among women. As per the recent report of the World Health Organization (WHO), it was documented that by the end of the year 2020, approximately 7.8 million females were positively diagnosed with breast cancer and in 2020 alone, 685,000 casualties were documented due to breast cancer. The use of standard chemotherapeutics includes the frontline treatment option for patients; however, the concomitant side effects represent a major obstacle for their usage. Carbazole alkaloids are one such group of naturally-occurring bioactive compounds belonging to the Rutaceae family. Among the various carbazole alkaloids, 3-Methoxy carbazole or C13H11NO (MHC) is obtained from Clausena heptaphylla as well as from Clausena indica. In this study, MHC was investigated for its anti-breast cancer activity based on molecular interactions with specific proteins related to breast cancer, where the MHC had predicted binding affinities for NF-κB with −8.3 kcal/mol. Furthermore, to evaluate the biological activity of MHC, we studied its in vitro cytotoxic effects on MCF-7 cells. This alkaloid showed significant inhibitory effects and induced apoptosis, as evidenced by enhanced caspase activities and the cellular generation of ROS. It was observed that a treatment with MHC inhibited the gene expression of NF-kB in MCF-7 breast cancer cells. These results suggest that MHC could be a promising medical plant for breast cancer treatment. Further studies are needed to understand the molecular mechanisms behind the anticancer action of MHC