RESUMEN
This study aimed to formulate and statistically optimize cubosomal formulations of metformin (MTF) to enhance its breast anticancer activity. A Box Behnken design was employed using Design-Expert® software. The formulation variables were glyceryl monooleate concentration (GMO) w/w%, Pluronic F-127 concentration (PF127) w/w% and Tween 80 concentration w/w% whereas Entrapment efficiency (EE%), Vesicles' size (VS) and Zeta potential (ZP) were set as the dependent responses. The design expert software was used to perform the process of optimization numerically. X ray diffraction (XRD), Transmission electron microscope (TEM), in-vitro release study, short-term stability study, and in in-vitro cell proliferation assay on the MDA-MB-231 breast cancer and LOVO cancer cell lines were used to validate the optimized cubosomal formulation. The optimized formulation had a composition of 4.35616 (w/w%) GMO, 5 (w/w%) PF127 and 7.444E-6 (w/w%) Tween 80 with a desirability of 0.733. The predicted values for EE%, VS and ZP were 78.0592%, 307.273 nm and - 26.8275 mV, respectively. The validation process carried out on the optimized formula revealed that there were less than a 5% variance from the predicted responses. The XRD thermograms showed that MTF was encapsulated inside the cubosomal vesicles. TEM images of the optimized MTF cubosomal formulation showed spherical non-aggregated nanovesicles. Moreover, it revealed a sustained release profile of MTF in comparison to the MTF solution. Stability studies indicated that optimum cubosomal formulation was stable for thirty days. Cytotoxicity of the optimized cubosomal formulation was enhanced on the MDA-MB-231 breast and LOVO cancer cell lines compared to MTF solution even at lower concentrations. However, it showed superior cytotoxic effect on breast cancer cell line. So, cubosomes could be considered a promising carrier of MTF to treat breast and colon cancers.
RESUMEN
Autism spectrum disorder (ASD) is a multifaceted developmental condition that first appears in infancy. The condition is characterized by recurrent patterns in behavior and impairments in social and vocalization abilities. Methylmercury is a toxic environmental pollutant, and its derivatives are the major source of organic mercury to human beings. Inorganic mercury, which is released from a variety of pollutants into oceans, rivers, and streams, is transformed into methylmercury by bacteria and plankton in the water, which later builds up in fish and shellfish, and then enters humans through the consumption of fish and shellfish and increases the risk of developing ASD by disturbing the oxidant-antioxidant balance. However, there has been no prior research to determine the effect of juvenile exposure of methylmercury chloride on adult BTBR mice. Therefore, the current study evaluated the effect of methylmercury chloride administered during the juvenile stage on autism-like behavior (three-chambered sociability, marble burying, self-grooming tests) and oxidant-antioxidant balance (specifically Nrf2, HO-1, SOD-1, NF-kB, iNOS, MPO, and 3-nitrotyrosine) in the peripheral neutrophils and cortex of adult BTBR and C57BL/6 (B6) mice. Our results show that exposure to methylmercury chloride at a juvenile stage results in autism-like symptoms in adult BTBR mice which are related to a lack of upregulation of the Nrf2 signaling pathway as demonstrated by no significant changes in the expression of Nrf2, HO-1, and SOD-1 in the periphery and cortex. On the other hand, methylmercury chloride administration at a juvenile stage increased oxidative inflammation as depicted by a significant increase in the levels of NF-kB, iNOS, MPO, and 3-nitrotyrosine in the periphery and cortex of adult BTBR mice. This study suggests that juvenile exposure to methylmercury chloride contributes to the worsening of autism-like behavior in adult BTBR mice through the disruption of the oxidant-antioxidant balance in the peripheral compartment and CNS. Strategies that elevate Nrf2 signaling may be useful to counteract toxicant-mediated worsening of ASD and may improve quality of life.
RESUMEN
5-Fluorouracil (5-FU) is an anticancer drug with intestinal mucositis (IM) as a deleterious side effect. Thymol is a monoterpene phenol which has been reported to possess an antioxidant and anti-inflammatory activity versus 5-FU-induced IM. The Notch pathway affects multiple cellular activities, such as cellular proliferation, in addition to inflammatory responses modulation. Accordingly, this work was carried out in order to elucidate the role of the Notch pathway in 5-FU-induced IM and to further elucidate the immunomodulatory protective mechanisms of thymol. Experimental rats were divided randomly into four groups: Control, 5-FU, 5-FU+thymol (60 mg/kg/day), and 5-FU+thymol (120 mg/kg/day). 5-FU was injected intraperitoneally at a dose of 150 mg/kg on days 6 and 7, while thymol was orally administered daily for 11 days. By the end of the study, intestinal tissues were collected for the determination of IL-17, CD4, CD8, Notch1, Hes-1, pSTAT3, and STAT-3 protein expressions. The effect of thymol on 5-FU cytotoxicity was also examined using WST1 assay. 5-FU induced a marked increase in IL-17 levels, along with a marked downregulation of CD4 and the upregulation of CD8, Notch1, Hes-1 protein expressions, and activation of STAT3 in the intestinal tissue when compared with the control group. Thymol ameliorated the changes that occurred in these parameters. Additionally, cytotoxicity testing revealed that thymol augmented the antiproliferative action of 5-FU against breast and colorectal human cancer cell lines. This study was the first to show that the IL-17/Notch1/STAT3 pathway is involved in the molecular mechanism of 5-FU-induced IM, as well as the immunomodulatory activity of thymol.