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  • br Conclusions br Acknowledgements Implantable Microsystems

    2019-07-11


    Conclusions
    Acknowledgements Implantable Microsystems for Personalised Anti-Cancer Therapy is a EPSRC (Engineering and Physical Sciences Research Council, UK) ´╗┐funded grant (Ref. EP/K034510/1)
    Introduction Flemingia philippinensis, belonging to the legume family, is a polyphenol rich plant [1]. This species is well-known in folk medicine and has been used to cure rheumatism and to improve bone mineral density [2]. In southern China, F. philippinensis is cultivated on a large scale and widely consumed by local inhabitants as an important nutraceutical for nutritious and therapeutic purposes, especially against rheumatism and associated inflammatory ailments [3], [4]. The main bioactive constituents of F. philippinensis include flavanones, chalcones, isoflavones, steroids, and triterpenes, many of which have been proven to possess anti-inflammatory, anti-estrogenic, immunosuppressive, and antioxidant activities [5], [6], [7]. The prenylated isoflavones in this plant have predominately been investigated for their bacterial neuraminidase inhibition activity [8]. Similarly, chalcones and flavonoids have shown strong inhibitory effects against tyrosinase [9]. Recently, chromenedione derivatives have been shown to have protein tyrosine phosphate 1B (PTP1B) inhibitory properties [10]. As these compounds are a valuable source of therapeutic material, further work is needed to elucidate their health-promoting effects. Despite the traditional usage of F. philippinensis to treat rheumatoid arthritis, the effects of these compounds on neutrophil elastase (NE) activity, which has been shown to be involved in rheumatoid arthritis, have not been thoroughly investigated. Serine hydrolases are the most diverse and biologically vital (-)-Quinpirole hydrochloride structure in living organisms, as well as being one of the largest enzyme groups [11]. This class of enzymes has several members, including amidases, lipases, esterases, and proteases, which have been targeted by various clinically-approved drugs [12], [13]; among them, neutrophil elastase (NE, EC 3.4.21.37) is an important enzyme belonging to the chymotrypsin family of serine proteases [14]. Biologically active NE is stored in azurophilic granules inside neutrophils and primarily cleaves the peptide bonds in proteins upon release, resulting in breakdown of extracellular matrix proteins such as collagen, fibronectin, elastin, and numerous plasma proteins [15]. Further, NE stimulates the release of inflammatory cytokines such as interleukin (IL)-6, IL-8, and other cytokines, which further exacerbates the inflammatory process [16]. The unconstrained proteolytic activity of NE results in various inflammatory ailments such as rheumatoid arthritis, reperfusion injury, chronic obstructive pulmonary disease, cystic fibrosis, atherosclerosis, and lung injury [17], [18]. Especially, a deep correlation between rheumatoid arthritis (RA) and NE has been reported in several studies that showed higher levels of elastase-inhibitor complex (EIC) in active RA patients than in controls [19], [20]. Similarly, an increase in NE activity has been measured in synovial fluid from RA patients [21]. Owing to these diverse effects, NE inhibition might be a beneficial approach to retard the negative health effects associated with RA and further strengthen the ongoing efforts against inflammatory diseases in general. In this study, we investigated NE inhibitory isolates from F. philippinensis, with sixteen flavonoids isolated from the methanol extract of F. philippinensis root bark. Isolated compounds were analyzed for NE activity, and results showed that all compounds significantly inhibited the NE enzyme; however, the inhibitory potencies and mechanisms of inhibition differed according to their respective structures. We fully investigated inhibitory potencies, structure-activity relationships (SAR), and inhibitory mechanisms based on secondary plots using the Michaelis-Menten equation. Furthermore, the mutual affinity between inhibitor and enzyme was extensively examined using fluorescence quenching experiments.