Despite the clinical success of BRAF inhibitors like vemurafenib in treating metastatic melanoma, resistance has emerged through "paradoxical MEK/ERK signaling" where transactivation of one protomer occurs as a result of drug inhibition of the other partner in the activated dimer. The importance of the dimerization interface in the signaling potential of wildtype BRAF in cells expressing oncogenic Ras has recently been demonstrated and proposed as a site of therapeutic intervention in targeting cancers resistant to ATP competitive drugs. Proof of concept for a structure-guided approach targeting the dimerization interface is described through the design and synthesis of macrocyclic peptides that bind with high affinity to BRAF and that block paradoxical signalling in malignant melanoma cells occurring through this drug target. The lead compounds identified are type IV kinase inhibitors and represent an ideal framework for conversion into next generation BRAF inhibitors through macrocyclic drug discovery.
Vitamin E (VE) or α-tocopherol is the major fat-soluble antioxidant in the human body. It is a sensitive, easily oxidized in the air, molecule, so it must be protected from pro-oxidant elements which could affect its physiological benefits. Encapsulation constitutes a promising approach to maintain VE native properties over time and increase its concentration in aqueous media. Liposomes have been studied as sustained delivery systems, being biodegradable, non-toxic and non-immunogenic. A new liposome/β-lactoglobulin (β-Lg) formulation has been developed and characterized as a possible stable delivery system for VE. β-Lg has been selected due to its property to bind a variety of hydrophobic molecules. The aim of this study was the preparation of β-Lg-liposome formulation and the determination of VE encapsulation efficiency, in order to develop a new more efficient carrier for VE in aqueous media.
Vitamin A (VA) is an essential nutrient needed in small amounts by humans and supports a wide range of biological actions. Retinol, the most common and most biologically active form of VA has also been found to inhibit peroxidation processes in membranes and it has been widely used as an ingredient with pharmaceutical and nutritional applications. VA is a lipophilic molecule, sensitive to air, oxidizing agents, ultraviolet light and low pH levels. For these reasons, it is necessary for VA to be protected against oxidation. Another disadvantage in the application of VA is its low solubility in aqueous media. Both issues (sensitivity and solubility) can be solved by employing encapsulation techniques. Liposomes can efficiently encapsulate lipid-soluble materials, such as VA. The encapsulated materials are protected from environmental and chemical changes. A new liposome/β-lactoglobulin formulation has been developed as a stable delivery system for VA. The aim of this study was the encapsulation of VA into β-lactoglobulin-liposome complexes, recently developed in our laboratory. The in vivo bioavailability characterization of VA was tested after administration in laboratory animals (mice). In this report, we demonstrate that VA could be efficiently entrapped and delivered in a phospholipid-sterol-protein membrane resembling system, a newly synthesized promising carrier. Based on this finding, the phospholipid-sterol-protein membrane resembling system may be one of the promising approaches to enhance VA absorption and to overcome the formulation difficulties associated with lipophilic means. The carrier system described here has huge potential in food fortification applications to treat VA deficiency.
Mastic gum is a resinous sap produced by Pistacia lentiscus growing in the island of Chios (Greece) and has been recognized since Antiquity for its distinctive aroma as well as medical properties (antimicrobial, antioxidant, anti-inflammatory ones). The oral absorption of Chios Mastic gum (an insoluble polymer of poly-β-myrcene is among the most abundant contents) is poor due to its low water-solubility. We report in this study, two different Chios mastic gum extracts, the acidic mastic gum extract—AMGE—and the neutral one—NMGE, both prepared after removal of the contained polymer in order to ameliorate solubility and enhance in vivo activity. Liposomes are presented as a promising delivery system due to their physicochemical and biophysical properties to increase stability and absorption efficiency of the mastic gum extracts within the gastrointestinal (GI) tract. The aim of this study was to evaluate the stability in GI simulated conditions together with cytotoxic and antimicrobial activity of the two extracts (AMGE and NMGE) after encapsulation in a well characterized liposome formulation. Liposomes-AMGE complex showed an improved stability behavior in GI simulated conditions. Both assayed extracts showed significant dose dependent inhibition against the growth of liver cancer HepG2 cells and an interesting antimicrobial activity against several microorganisms. Conclusively, encapsulation could be evaluated as a beneficial procedure for further applications of mastic resin.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.