Fighting against amyotrophic lateral sclerosis (ALS) with flavonoids: a computational approach to inhibit superoxide dismutase (SOD1) mutant aggregation.

Protein aggregation is a biological process that occurs when proteins misfold. Misfolding and aggregation of human superoxide dismutase (hSOD1) cause a neurodegenerative disease called amyotrophic lateral sclerosis (ALS). Among the mutations occurring, targeting the E21K mutation could be a good choice to understand the pathological mechanism of SOD1 in ALS, whereof it significantly reduces life hopefulness in patients. Naturally occurring polyphenolic flavonoids have been suggested as a way to alleviate the amyloidogenic behavior of proteins. In this study, computational tools were used to identify promising flavonoid compounds that effectively inhibit the pathogenic behavior of the E21K mutant. Initial screening identified Pelargonidin, Curcumin, and Silybin as promising leads. Molecular dynamics (MD) simulations showed that the binding of flavonoids to the mutated SOD1 caused changes in the protein stability, hydrophobicity, flexibility, and restoration of lost hydrogen bonds. Secondary structure analysis indicated that the protein destabilization and the increased propensity of ß-sheet caused by the mutation were restored to the wild-type state upon binding of flavonoids. Free energy landscape (FEL) analysis was also used to differentiate aggregation, and results showed that Silybin followed by Pelargonidin had the most therapeutic efficacy against the E21K mutant SOD1. Therefore, these flavonoids hold great potential as highly effective inhibitors in mitigating ALS's fatal and insuperable effects.Communicated by Ramaswamy H. Sarma.

Coinhibition of S1PR1 and GP130 by siRNA-loaded alginate-conjugated trimethyl chitosan nanoparticles robustly blocks development of cancer cells.

There is an interconnected network between S1P/sphingosine-1-phosphate receptor 1 (S1PR1), IL-6/glycoprotein 130 (GP130), and signal transducer and activator of transcription 3 (STAT3) signaling pathways in the tumor microenvironment, which leads to cancer progression. S1P/S1PR1 and IL-6/GP130 signaling pathways phosphorylate and activate STAT3, and it then induces the expression of S1PR1 and interleukin-6 (IL-6) in a positive feedback loop leading to cancer progression. We hypothesized that blockade of this amplification loop can suppress the growth and development of cancer cells. Therefore, we silenced STAT3 upstream molecules including the S1PR1 and GP130 molecules in cancer cells using small interfering RNA (siRNA)-loaded alginate-conjugated trimethyl chitosan (ATMC) nanoparticles (NPs). The generated NPs had competent properties including the appropriate size, zeta potential, polydispersity index, morphology, high uptake of siRNA, high rate of capacity, high stability, and low toxicity. We evaluated the effects of siRNA loaded ATMC NPs on tumor hallmarks of three murine-derived cancer cell lines, including 4T1 (breast cancer), B16-F10 (melanoma), and CT26 (colon cancer). The results confirmed the tumor-suppressive effects of combinational targeting of S1PR1 and GP130. Moreover, combination therapy could potently suppress tumor growth as assessed by the chick chorioallantoic membrane assay. In this study, we targeted this positive feedback loop for the first time and applied this novel combination therapy, which provides a promising approach for cancer treatment. The development of a potent nanocarrier system with ATMC for this combination was also another aspect of this study, which should be further investigated in cancer animal models in further studies.