Timosaponin B-II inhibits lipopolysaccharide-induced acute lung toxicity via TLR/NF-κB pathway

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Abstract

Timosaponin B-II (TB), a main bioactive compound in Anemarrhena asphodeloides Bunge, has various kinds of pharmacological activities, the present study aimed to investigate the protective role of TB on lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced in mice by intratracheal instillation of LPS, and TB (20 and 60 mg/kg) was given orally 1 h prior to LPS administration. After 6 h, bronchoalveolar lavagefluid (BALF) and lung tissue were collected. TB decreased LPS-induced evident lung histopathological changes, lung wet-to-dry weight (W/D) ratio and lung myeloperoxidase (MPO) activity. In addition, TB inhibited inflammatory cells and cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in BALF. Furthermore, we demonstrated that TB inhibited the Toll-like receptor-2 (TLR2), Toll-like receptor-4 (TLR4), myeloid differentiation primary response gene-88 (MyD88), nuclear factor-κB (NF-κB) p65 in LPS-induced ALI. These results showed that administration of TB prior to LPS improves ALI, possibly mediating ALI through suppressing TLR/NF-κB pathway activation.

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Toll-like receptors: critical proteins linking innate and acquired immunity.

S Akira, K Takeda, T Kaisho (2001)

Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (pathogen-associated molecular patterns), which are shared by large groups of microorganisms. Toll-like receptors (TLRs) function as the PRRs in mammals and play an essential role in the recognition of microbial components. The TLRs may also recognize endogenous ligands induced during the inflammatory response. Similar cytoplasmic domains allow TLRs to use the same signaling molecules used by the interleukin 1 receptors (IL-1Rs): these include MyD88, IL-1R--associated protein kinase and tumor necrosis factor receptor--activated factor 6. However, evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.

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Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway.

Z. Chen, J. Hagler, V. J. Palombella … (1995)

The transcription factor NF-kappa B is sequestered in the cytoplasm by the inhibitor protein I kappa B alpha. Extracellular inducers of NF-kappa B activate signal transduction pathways that result in the phosphorylation and subsequent degradation of I kappa B alpha. At present, the link between phosphorylation of I kappa B alpha and its degradation is not understood. In this report we provide evidence that phosphorylation of serine residues 32 and 36 of I kappa B alpha targets the protein to the ubiquitin-proteasome pathway. I kappa B alpha is ubiquitinated in vivo and in vitro following phosphorylation, and mutations that abolish phosphorylation and degradation of I kappa B alpha in vivo prevent ubiquitination in vitro. Ubiquitinated I kappa B alpha remains associated with NF-kappa B, and the bound I kappa B alpha is degraded by the 26S proteasome. Thus, ubiquitination provides a mechanistic link between phosphorylation and degradation of I kappa B alpha.