ABSTRACT
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.
ABSTRACT
Osteoarthritis is the most common human joint disease in the world. It is also one of the most common skeletal muscle defects, destructive joint changes, and the leading cause of disability and reduced quality of life. Destructive changes in inflammatory joints are associated with a range of biochemical events, including the overproduction of inflammatory cytokines. Cytokines are protein compounds that play an essential role in causing and regulating inflammation. A balance between pro-inflammatory and anti-inflammatory cytokines is crucial in maintaining a stable body. In some inflammatory diseases, including osteoarthritis, the balance between these compounds is disturbed, and the balance shifts to pre-inflammatory cytokines. For this reason, researchers today are trying to find an effective way to reduce inflammation and treat osteoarthritis by using certain compounds. Current treatments for osteoarthritis, including nonsteroidal antiinflammatory drugs, glucocorticoids, and hyaluronic acid, are mainly based on reducing pain and inflammation. However, they have limited effects in controlling symptoms and improving the patient's quality of life. Also, due to the high level of side effects, synthetic drugs have led to the identification of compounds of natural origin to give patients a chance to use painkillers and antiinflammatory drugs with fewer side effects. This review study aimed to present the role of quercetin as a natural compound in reducing the expression of pro-inflammatory cytokines in osteoarthritis. This study also discusses the relationship between inflammation and cartilage destruction and other inflammation-related factors caused by cytokines.