xanthatin and Inflammation

Xanthatin (XT) is a sesquiterpene lactone isolated from the Chinese herb Xanthium, which belongs to the Asteraceae family. In this study, we developed an inflammation model via stimulating macrophage cell line (RAW 264.7 cells) with lipopolysaccharide (LPS), which was applied to assess the anti-inflammatory effect and probable mechanisms of xanthatin. When compared with the only LPS-induced group, cells that were pretreated with xanthatin were found to decrease the amount of nitric oxide (NO), reactive oxygen species (ROS) and associated pro-inflammatory factors (TNF-α, IL-1β and IL-6), and downregulate the mRNA expression of iNOS, COX-2, TNF-α, IL-1β, and IL-6. Interestingly, phosphorylated levels of related proteins (STAT3, ERK1/2, SAPK/JNK, IκBα, p65) were notably increased only with the LPS-activated cells, while the expression of these could be reverted by pre-treatment with xanthatin in a dose-dependent way. Meanwhile, xanthatin was also found to block NF-κB p65 from translocating into the nucleus and activating inflammatory gene transcription. Collectively, these results demonstrated that xanthatin suppresses the inflammatory effects through downregulating the nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STATs) signaling pathways. Taken together, xanthatin possesses the potential to act as a good anti-inflammatory medication candidate.

Topics: Animals; Anti-Inflammatory Agents; Furans; Inflammation; Interleukin-6; Lipopolysaccharides; Macrophages; Mice; Mitogen-Activated Protein Kinases; NF-kappa B; RAW 264.7 Cells; Tumor Necrosis Factor-alpha

Here, we aimed to investigate the role of Xanthatin in asthma and its underlying mechanism. BALB/c mice were treated with ovalbumin (OVA) to establis a mouse model of asthma. Our results showed that OVA injection significantly increased inflammatory cell infiltration and goblet cell hyperplasia in lung issues, while Xanthatin treatment and STAT3 inhibitor C188-9 administration relieved these symptoms. Moreover, OVA-induced OVA-specific immunoglobulin E level in serum and the number of total cell, macrophages, lymphocytes, neutrophils, and eosinophils in bronchoalveolar lavage fluid (BALF) were markedly reduced by Xanthatin treatment and signal transducer and activator of transcription 3 (STAT3) inhibition. Additionally, Xanthatin treatment and STAT3 inhibition was also significantly decreased the levels of inflammatory cytokines in BALF in asthmatic mice. We further demonstrated that the STAT3/nuclear factor-kappaB (NF-κB) pathway was blocked by Xanthatin in asthmatic mice. Overall, we conclude that Xanthatin attenuates airway inflammation in asthmatic mice through blocking the STAT3/NFκB signaling pathway, indicating the potential of Xanthatin as a useful therapeutic agent for asthma.

Topics: Animals; Asthma; Cytokines; Disease Models, Animal; Furans; Inflammation; Male; Mice; Mice, Inbred BALB C; Naphthols; NF-kappa B; Random Allocation; Signal Transduction; STAT3 Transcription Factor; Sulfonamides

Aberrant activation of the signal transducer and activator of transcription 3 (STAT3) and the nuclear factor-κB (NF-κB) signalling pathways is associated with the development of cancer and inflammatory diseases. JAKs and IKKs are the key regulators in the STAT3 and NF-κB signalling respectively. Therefore, the two families of kinases have been the major targets for developing drugs to regulate the two signalling pathways. Here, we report a natural compound xanthatin from the traditional Chinese medicinal herb Xanthium L. as a potent inhibitor of both STAT3 and NF-κB signalling pathways. Our data demonstrated that xanthatin was a covalent inhibitor and its activities depended on its α-methylene-γ-butyrolactone group. It preferentially interacted with the Cys243 of JAK2 and the Cys412 and Cys464 of IKKβ to inactivate their activities. In doing so, xanthatin preferentially inhibited the growth of cancer cell lines that have constitutively activated STAT3 and p65. These data suggest that xanthatin may be a promising anticancer and anti-inflammation drug candidate.

Topics: Carcinoma, Hepatocellular; Furans; Humans; I-kappa B Kinase; Inflammation; Janus Kinases; Liver Neoplasms; NF-kappa B; Phosphorylation; Signal Transduction; STAT3 Transcription Factor; Tumor Cells, Cultured