Ameliorative effect of zinc oxide-chitosan conjugates on the anticancer activity of cisplatin: Approach for breast cancer treatment.

Breast cancer is the second most prevalent cancer affecting both males and females, comprising nearly 30 % of all cancer cases. While chemotherapeutic agents, such as cisplatin (Cis), have proven successful in cancer treatment, concerns persist regarding their efficacy and the potentially dangerous side effects. Consequently, there is a crucial and ongoing need to develop approaches that minimize side effects associated with chemotherapy. In the present work, various types of nanoparticles (NPs) were synthesized and loaded with Cis. Cis was conjugated with nanocarriers such as zinc oxide (ZnO), ZnO modified with mandelic acid and graphene oxide (GO), chitosan (CS), and CS modified with ZnO and GO to enhance the selectivity of Cis towards cancer cells. Zeta potentials and particles size were assessed using electrophoretic light scattering and dynamic light scattering. NPs were characterized using transmission electron microscopy, Fourier-transform infrared spectroscopy, and X-ray diffraction. The impact of standalone Cis as well as its nanoconjugated form on the behavior of MCF-7 cell line was investigated using WST-1 cell proliferation and apoptosis/necrosis assays. Experimental findings revealed that among the various NPs tested, ZnO, and CS NPs exhibited the highest loading percentage of Cis, surpassing the loading percentages achieved with other NPs. Cytotoxicity assay showed the enhanced effect of Cis when conjugated with ZnO and CS NPs. Flow cytometry-based assays and confocal microscopy confirmed that ZnO/Cis and CS/Cis induced apoptosis. The cisplatin-nanocomplex exhibited a descending order of early apoptosis and late apoptosis in the following order: ZnO, Cis, CS, ZnO-M, CS-GO, ZnO-GO, CS-ZnO, and CS-ZnO, Cis, CS, CS-GO, ZnO-M, ZnO, ZnO-GO, respectively. None of the nanoparticle complexes displayed a significant percentage of necrotic cells, with the highest percentage reaching 4.65 % in the case of CS-GO/Cis.

Targeting of HPV E6 at the binding sites to the host-cell E6AP, p53, and the endoplasmic reticulum-resident chaperone, GRP78.

Background: Human papillomavirus (HPV) represents an etiological factor for many cancer types, especially cervical cancer. Its oncoprotein E6 sheds drug designers who aim to stop its cellular protein associations, such as p53 and E6AP. Recently, it was discovered that the host-cell chaperone glucose-regulated protein 78 (GRP78) plays a crucial function in HPV infectivity by association with the viral E6 and E7 proteins. Therefore, we aimed to test small molecules inhibitor that could contradict the association between E6 and cellular factors E6AP, GRP78, and p53. Methods: In this study, molecular docking protocol was elaborated to test 115 small molecule compounds against the three binding sites of HPV E6 to the host-cell proteins; E6AP, p53, and GRP78. After that, molecular dynamics simulation and free energy calculations were performed on the best three complexes. Results: The results reveal the potency of 18 compounds against the HPV E6 at different binding sites, which give lower free energies than paclitaxel (positive control). The best two compounds, hypericin, and anabsinthin, could bind effectively and stably during the 100 ns MD simulation period to HPV E6. The calculated average free energies for hypericin and anabsinthin are -18.76 and -14.40 kcal/mol, respectively. They formed stable complexes with the three binding sites by forming hydrophobic contacts. The key residues that stabilize the two ligands in HPV E6 binding sites are V31, Y32, V62, and Y70 (E6AP), P13, C16, T22, I23 and A46 (p53), and M1, V31, L50, L67, and Q107 (GRP78). Conclusions: The best two compounds, hypericin, and anabsinthin, are potential candidates against HPV E6 at the host-cell factors binding sites, hence could block the oncoprotein activity of E6 in infected cells. Further experimental validation is yet to be performed and suggested as future work.Communicated by Ramaswamy H. Sarma.

Electrophysiological and Neurochemical Assessment of Selenium Alone or Combined with Carbamazepine in an Animal Model of Epilepsy.

The present study aims to evaluate the efficacy of selenium (Se) alone or combined with carbamazepine (CBZ) against the adverse effects induced by the chemoconvulsant pentylenetetrazole (PTZ) in the cortex of adult male rats. Electrocorticogram (ECoG) and oxidative stress markers were implemented to evaluate the differences between treated and untreated animals. Animals were divided into five groups: control group that received i.p. saline injection, PTZ-treated group that received a single i.p. injection of PTZ (60 mg/kg) for induction of seizures followed by a daily i.p. injection of saline, Se-treated group that received an i.p. injection of sodium selenite (0.3 mg/kg/day) after PTZ administration, CBZ-treated group that received orally CBZ (80 mg/kg/day) after PTZ administration, and combination (Se plus CBZ)-treated group that received an oral administration of CBZ (80 mg/kg/day) followed by an i.p. injection of sodium selenite (0.3 mg/kg/day) after PTZ administration. Quantitative analyses of the ECoG indices and the neurochemical parameters revealed that Se and CBZ have mitigated the adverse effects induced by PTZ. The main results were decrease in the number of epileptic spikes, restoring the normal distribution of slow and fast ECoG frequencies and attenuation of most of the oxidative stress markers. However, there was an increase in lipid perioxidation marker in combined treatment of CBZ and Se. The electrophysiological and neurochemical data proved the potential of these techniques in evaluating the treatment's efficiency and suggest that supplementation of Se with antiepileptic drugs (AEDs) may be beneficial in ameliorating most of the alterations induced in the brain as a result of seizure insults and could be recommended as an adjunct therapy with AEDs.

Ascorbic acid prevents cellular uptake and improves biocompatibility of chitosan nanoparticles.

Chitosan nanoparticles have many applications, such as gene and drug delivery, due to their biocompatibility. Chitosan nanoparticles are currently produced by dissolution in acetic acid that affects the biocompatibility at acidic pH. Here, we synthesized and characterized chitosan (CS) and ascorbate chitosan (AsCS) nanoparticles and investigated their cytotoxic effects, internalization, and distribution in the human colon carcinoma cell line using confocal laser scanning microscopy (CLSM). The CS and AsCS nanoparticles were spherical with average particle sizes of 44±8.4nm and 87±13.6nm, respectively. CS nanoparticles were taken up by the cells and showed dose-dependent cytotoxicity. By contrast, AsCS nanoparticles were not internalized and showed no cytotoxicity. Therefore, AsCS nanoparticles are more biocompatible than CS nanoparticles and may be more suitable for extracellular drug delivery.

Electroencephalographic and biochemical long-lasting abnormalities in animal model of febrile seizure.

Febrile seizures (FS) are convulsions associated with high body temperature. It has a high incidence in children from the age of 6months to 5years and may have adverse consequences in adulthood. The experimental model of FS could be induced in animals via hyperthermia. The present study was designed to investigate persistent electroencephalographic (EEG), neurochemical and behavioral alterations in adult animals that had experienced complex FS at their immature age. EEG signals were obtained from the cortex of both FS and control normothermic groups of animals. A spectrophotometric assay was carried out to determine oxidative stress parameters (malondialdehyde, nitric oxide, reduced glutathione) and acetylcholinesterase activity in the cortex and hippocampus of FS and control animals. Behavioral assessment of seizure threshold and severity were investigated via a sub-convulsive dose of nicotine in adult animals. Alterations in the oxidant/antioxidant system and AChE activity were obtained in the cortex and hippocampus of FS animals in comparison to control animals. EEG spectral analysis displayed significant changes in all EEG frequency bands. A decrease in seizure latency and an increase in seizure severity were also observed. The present study provides evidence for long-lasting abnormalities in the cortex and hippocampus of adult animals subjected to complex FS at their developmental age, which may be correlated to the underlying mechanism of epileptogenesis and its related co-morbidities.

Validation of a simple analytical model for in-air outputfactor calculation for SL-15 Philips-Elekta linear accelerator.

A simple aralytical approach to model extrafocal radiation (EFR) and monitor chamber backscatter (MBS)-and consequently collimator scattar factor-is investigated. The model has been applied to 6 and 10 MV photon beams produced by a Philips-Elekta SL-15 medical linear accelerator. Both EFR and MBS are determined simultaneously using conventional measured data at the isocenter and the calculated in-air output factors (S(c)) were in good agreement with the measured values. When the square field size changes from 4x4 to 40x40 cm(2), the total intensities of EFR were 17.6% and 13%, while the MBS contributions to S(c) were 0.1% and 0.2% for 6 and 10 mv, respectively. The model was also used to calculate S(c) for symmetric or asymmetric rectangular jaws-defined fields with an accuracy of less than 0.2% at extended or shortened source detector distances Moreover, the model was verified for both very small field sizes (2x2 cm(2) down to 0.6x0.6 cm(2)) and for field sizes defined by micro multi-leaf collimator to check its applicability for stereotactic radiotherapy dose calculations. A simple programme is designed to facilitate the calculation process of S(c) for a medical linear accelerator at different situations either for commissioning or verification of the model at different energies.

Selection of optimal quantity of hydroxyethyl starch in the cardiopulmonary bypass prime.

Ringer's solution prime reduces colloid osmotic pressure and causes edema during cardiopulmonary bypass, while hydroxyethyl starch (HES) can be used to attenuate this effect. Fifty patients were classified into five equal groups: Group I (preoperative patients) is the control group and the other four groups (II, III, IV, V) received different volume ratios of Ringer's solution to HES (1:0, 2:1, 1:2, 0:1, respectively). This study was aimed at evaluating the optimal quantity of HES regarding body fluids expansion, ventilation and recovery time, blood rheologic properties, clotting parameters, platelet counts, blood loss and red blood cell membrane properties. The results showed a reduction in interstitial fluid (ISF) expansion, changes in blood rheologic properties with the increase in HES quantity and shorter ventilation and recovery times in Groups IV and V. We concluded that the optimal HES quantity in the prime is two thirds, which insures an 85% reduction of ISF relative to Group II, shorter ventilation and recovery times and avoidance of the hazards of high levels of HES.