Inhibition of TNF-α-Induced Inflammation by Sesquiterpene Lactones from Saussurea lappa and Semi-Synthetic Analogues

Abstract

We investigated the tumor necrosis factor-alpha (TNF-) inhibitory activity of sesquiterpenes from root extracts. According to the hexane and EtOAc extracts showing significant activity with IC values of 0.5 and 1.0 µg/mL, respectively, chromatographic fractionation of the extracts was performed and led to the isolation of 10 sesquiterpenes (1: -10: ). Costunolide (1: ), a major compound, and dehydrocostus lactone (4: ) exhibited high efficiency in decreasing TNF- levels, with IC values of 2.05 and 2.06 µM, respectively. In addition, sesquiterpene analogues were synthesized to establish their structure-activity relationship (SAR) profile. Among the semi-synthetic analogues, compounds 6A: and 16: showed the most potent activity with IC values of 1.84 and 1.97 µM, respectively. More importantly, compound 6A: showed less toxicity than costunolide and 16: . These results provided the first SAR profile of sesquiterpene lactones and indicated that the -methylene--lactone moiety plays a crucial role in TNF- inhibition. Additionally, the epoxide derivative 6A: might represent a lead compound for further anti-TNF- therapies, owing to its potent activity and reduced toxicity.

Ambrosin, a potent NF-κβ inhibitor, ameliorates lipopolysaccharide induced memory impairment, comparison to curcumin

“…TNF-α plays an important role in mediating the neuroinflammation due to systemic LPS administration [16]. STL from Saussurea attenuated the release of TNF-α produced by RAW macrophages upon stimulation by LPS [40]. It was demonstrated that α-methylene-γ-lactone moiety was essential for such an activity.…”

The protective effects of dehydrocostus lactone against TNF-α-induced degeneration of extracellular matrix (ECM) in SW1353 cells

“…Importantly, studies have demonstrated that TNF-α and IL-1β are responsible for the degradation of the ECM as they upregulate the expression of MMPs and ADAMTS, thereby triggering the expression of downstream cytokines and pro-inflammatory signaling pathways [ 34 , 35 ]. DHC has demonstrated an inhibitory effect against TNF-α and IL-1β in both in vitro and in vivo models [ 36 , 37 ]. In the present study, our findings indicate that DHC exerts a distinct dose-dependent inhibitory effect against the expression of IL-1β and IL-6 induced by TNF-α in chondrocytes ( Figures 3A and 3B ).…”

“…In this study, we demonstrated that TNF-α stimulation significantly increased the expression of MMPs and ADAMTS, especially MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMT-5. MMPs are the major hydrolytic enzymes involved in the cleavage of type II collagen [ 16 , 37 ]. Meanwhile, ADAMTS-4 and ADAMTS-5 are responsible for the degradation of aggrecan [ 38 , 39 ].…”

Clinical significance of Saussurea Costus in thyroid treatment

“…45 Sesquiterpene lactones from S. costus root extracts and semi synthetic sesquiterpene analogues play a role in tumor necrosis factor, an inflammatory cytokine inhibition. 46 In-vitro study has shown that in hepatocellular carcinoma, the volatile oil from S. costus inhibits the epithelial growth factor receptor thyrosine kinasemediated signalling pathway and exerts its antitumor effect. 47 In a small human study Upadhyay et al 48 showed that Aquous extract of S. costus improved clinical and biochemical parameters, coronary circulation and myocardial function in patients suffering from ischemic heart disease.…”

“…45 Antioxidant properties of various plant extracts may be an important mechanism involved in potentiating their medicinal use in various ailments. 46 Renal, hepatic and lipid abnormalities are seen in thyroid dysfunction. 50,51 Ethanoic extract of S. costus has shown hepatoprotective effect in rats, poisoned with carbon tetrachloride.…”