Brain cancer is regarded among the deadliest forms of cancer worldwide. The distinct tumor microenvironment and inherent characteristics of brain tumor cells virtually render them resistant to the majority of conventional and advanced therapies. Oxidative stress (OS) is a key disruptor of normal brain homeostasis and is involved in carcinogenesis of different forms of brain cancers. Thus, antioxidants may inhibit tumorigenesis by preventing OS induced by various oncogenic factors. Antioxidants are hypothesized to inhibit cancer initiation by endorsing DNA repair and suppressing cancer progression by creating an energy crisis for preneoplastic cells, resulting in antiproliferative effects. These effects are referred to as chemopreventive effects mediated by an antioxidant mechanism. In addition, antioxidants minimize chemotherapy-induced nonspecific organ toxicity and prolong survival. Antioxidants also support the prooxidant chemistry that demonstrate chemotherapeutic potential, particularly at high or pharmacological doses and trigger OS by promoting free radical production, which is essential for activating cell death pathways. A growing body of evidence also revealed the roles of exogenous antioxidants as adjuvants and their ability to reverse chemoresistance. In this review, we explain the influences of different exogenous and endogenous antioxidants on brain cancers with reference to their chemopreventive and chemotherapeutic roles. The role of antioxidants on metabolic reprogramming and their influence on downstream signaling events induced by tumor suppressor gene mutations are critically discussed. Finally, the review hypothesized that both pro- and antioxidant roles are involved in the anticancer mechanisms of the antioxidant molecules by killing neoplastic cells and inhibiting tumor recurrence followed by conventional cancer treatments. The requirements of pro- and antioxidant effects of exogenous antioxidants in brain tumor treatment under different conditions are critically discussed along with the reasons behind the conflicting outcomes in different reports. Finally, we also mention the influencing factors that regulate the pharmacology of the exogenous antioxidants in brain cancer treatment. In conclusion, to achieve consistent clinical outcomes with antioxidant treatments in brain cancers, rigorous mechanistic studies are required with respect to the types, forms, and stages of brain tumors. The concomitant treatment regimens also need adequate consideration.
Experimental Pharmacology By Mn Ghosh Free Download Rar Full
Structurally stable communities at the Rar1-CHORD2 interface are formed via cooperative interactions with the Hsp90-NTD and Sgt1-CS residues (Figures 6 C,D). In one of these communities Rar1-F187, Rar1-F204, and Rar1-F207 are interconnected with Hsp90-F49. Another prominent community is formed through the interactions of Rar1-E175 and Rar1-W217 with the Sgt1-CS residues Q184 and H239 (Figures 6 C,D). The interactions of Rar1-F187 support the proper positioning of the imidazole ring of Rar1-H188 interacting directly in the crystal structure with the β-phosphate of ADP in the Hsp90-NTD [40]. The experimental studies confer a broad functional role of the Rar1-CHORD2 residues F204, F207, and W217 involved in the formation of interaction communities. In particular, yeast two-hybrid assays have demonstrated that mutation of these Rar1 residues in the Rar1-CHORD2 domain only, but not in full length Rar1, substantially reduced the interaction with Hsp90 and destabilized the ternary complex [40]. According to these experimental studies, mutations of W217 could disrupt the interaction with Sgt1 in yeast two hybrid assay and in vivo co-immunoprecipitation assay. Moreover, these mutations are detrimental to the activity of the Hsp90-Sgt1-Rar1 complex by causing resistance to tobacco mosaic virus conferred by the NLR client protein [40]. 2ff7e9595c
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