Apoptotic and anti-angiogenic effects of propolis against human bladder cancer: molecular docking and in vitro screening.

INTRODUCTION: Bladder cancer is still of unknown initiation and progression, it is difficult to treat the patient once bladder cancer have a distant metastasis. MATERIALS AND METHODS: In the present study, propolis extract was evaluated against bladder cancer cells (T24). Two independent pathways were investigated, apoptosis and angiogenesis, Bax, Bcl-2, P53, and caspase-3 for apoptosis, vascular endothelial growth factor receptor and protein kinase A as angiogenesis potential targets. OBJECTIVES: Molecular docking studies will be conducted for the major known constituents of Egyptian propolis into apoptotic and angiogenic protein targets, to give better insights to the possible binding mode and interactions and investigate the ability of propolis constituents to target both apoptotic and angiogenic pathways. RESULTS: Propolis showed anti-proliferative activity against T24 cancer cell line, the IC50 value was 6.36 µg/ml. Also significant effects of propolis on Bax, Bcl-2, P53, and caspase-3 were observed. DISCUSSION: These obtained results proved the ability of propolis to induce cell death. Also it has revealed noticeable effects on protein kinase A and vascular endothelial growth factor receptor. CONCLUSION: The obtained results can encourage us to say that propolis extract can induce a programmed cell death in human bladder cancer cells, and also affect angiogenesis.

Discovery of new 1,3-diphenylurea appended aryl pyridine derivatives as apoptosis inducers through c-MET and VEGFR-2 inhibition: design, synthesis, in vivo and in silico studies.

Interest has been generated in VEGFR-2 and c-MET as potential receptors for the treatment of different malignancies. Using aryl pyridine derivatives with 1,3-diphenylurea attached, a number of promising dual VEGFR-2 and c-MET inhibitors were developed and synthesized. Regarding the molecular target, compounds 2d, 2f, 2j, 2k, and 2n had potent IC50 values of 65, 24, 150, 170, and 18 nM against c-MET, respectively. Additionally, they had potent IC50 values of 310, 35, 290, 320, and 24 nM against VEGFR-2, respectively. Regarding cytotoxicity, compounds 2d, 2f, 2j, 2k and 2n exhibited potent cytotoxicity against MCF-7 with IC50 values in the range 0.76-21.5 µM, and they showed promising cytotoxic activity against PC-3 with IC50 values in the range 1.85-3.42 µM compared to cabozantinib (IC50 = 1.06 µM against MCF-7 and 2.01 µM against PC-3). Regarding cell death, compound 2n caused cell death in MCF-7 cells by 87.34-fold; it induced total apoptosis by 33.19% (8.04% for late apoptosis, 25.15% for early apoptosis), stopping their growth in the G2/M phase, affecting the expression of apoptosis-related genes P53, Bax, caspases 3 and 9 and the anti-apoptotic gene, Bcl-2. In vivo study illustrated the anticancer activity of compound 2n by reduction of tumor mass and volume, and the tumor inhibition ratio reached 56.1% with an improvement of hematological parameters. Accordingly, compound 2n can be further developed as a selective target-oriented chemotherapeutic against breast cancer.

Exploring the sedative properties of natural molecules from hop cones (Humulus lupulus) as promising natural anxiolytics through GABA receptors and the human serotonin transporter.

This research work aimed to identify the main components that are responsible for the sedative properties of hop cones and allocate their targets. This investigation was performed through molecular docking, molecular dynamic simulations, root mean square fluctuation (RMSF) analysis, and DFT calculation techniques. The tested compounds from Humulus lupulus were compared to diazepam and paroxetine. Molecular docking showed that two-thirds of the compounds had a good affinity to gamma-aminobutyric acid (GABA), outperforming diazepam, while only three surpassed paroxetine on the SERT. Compounds 3,5-dihydroxy-4,6,6-tris(3-methylbut-2-en-1-yl)-2-(3-methylbutanoyl)cyclohexa-2,4-dien-1-one (5) and (S,E)-8-(3,7-dimethylocta-2,6-dien-1-yl)-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one (15) showed stable binding and favorable energy parameters, indicating their potential for targeting GABA receptors and the SERT. This study provides a basis for future clinical research on these promising compounds.

Curcumin and vitamin C improve immunity of kidney via gene expression against diethyl nitrosamine induced nephrotoxicity in rats:In vivo and molecular docking studies.

Kidney has a crucial role in immunity, so any toxicity occurs for the kidney will result in reduced immunity. The aim of this study is to improve the immune response of insufficient kidneys through immune-related genes. Diethyl Nitrosamine has been used to cause kidney damage in animal models, vitamin C and curcumin have been used to treat impaired kidney. Renal function (urea, uric acid and creatinine) and oxidative stress parameters (superoxide dismutase, malondialdehyde and glutathione peroxidase) will be evaluated in this research work. Molecular docking also will be performed to investigate the role of vitamin C and curcumin in targeting immune response proteins. Also, Complementary component 3, Lipocalin-2, Toll-like receptor 2,Toll-like receptor 4, Kidney injury molecule-1, Interleukin 6, Interleukin-10, Tumor necrosis factor and p38 mitogen-activated protein kinases will be investigated. The obtained results showed that vitamin C and curcumin have good effects in the treatment of impaired kidneys, this was also observed in renal function and oxidative stress parameters, expression levels of proteins and histopathological examinations.

Adhesin degradation accelerates delivery of heat-labile toxin by enterotoxigenic Escherichia coli.

Many enteric pathogens, including enterotoxigenic Escherichia coli (ETEC), produce one or more serine proteases that are secreted via the autotransporter (or type V) bacterial secretion pathway. These molecules have collectively been referred to as SPATE proteins (serine protease autotransporter of the Enterobacteriaceae). EatA, an autotransporter previously identified in ETEC, possesses a functional serine protease motif within its secreted amino-terminal passenger domain. Although this protein is expressed by many ETEC strains and is highly immunogenic, its precise function is unknown. Here, we demonstrate that EatA degrades a recently characterized adhesin, EtpA, resulting in modulation of bacterial adhesion and accelerated delivery of the heat-labile toxin, a principal ETEC virulence determinant. Antibodies raised against the passenger domain of EatA impair ETEC delivery of labile toxin to epithelial cells suggesting that EatA may be an effective target for vaccine development.

Biological Effect of Quercetin in Repairing Brain Damage and Cerebral Changes in Rats: Molecular Docking and In Vivo Studies.

This study examined the protective effect of quercetin against high-altitude-induced brain damage in rats. A molecular docking study was performed to investigate the potential effect of quercetin in reducing brain damages through its ability to target the oxidative stress enzymes. Biomarker assessment screening assays were also performed then followed by in vivo studies. Three groups of rats were divided into the control group, an untreated animal model group with induced brain damage, and finally, the quercetin treated group that received quercetin dose equal to 20 mg/kg of their body weights. Molecular docking studies and biomarker assessment screening assays proved the potential effect of quercetin to affect the level of representative biomarkers glutathione (GSH), glutathione reductase (GR), glutathione-S-transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA). Additionally, the protective effect of quercetin against high altitude, low pressure, and low oxygen was also investigated by exploring the brain histopathology of experimental rats. Brain damage was observed in the untreated animal model group. After treatment with quercetin, the cerebral edema in the brain tissues was improved significantly, confirming the protective effects of quercetin. Therefore, quercetin can be used as a natural food additive to protect from the highaltitude-induced brain damage.