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Peucedanum ostruthium Inhibits E-Selectin and VCAM-1 Expression in Endothelial Cells through Interference with NF-?B Signaling.

ABSTRACT: Twenty natural remedies traditionally used against different inflammatory diseases were probed for their potential to suppress the expression of the inflammatory markers E-selectin and VCAM-1 in a model system of IL-1 stimulated human umbilical vein endothelial cells (HUVEC). One third of the tested extracts showed in vitro inhibitory effects comparable to the positive control oxozeaenol, an inhibitor of TAK1. Among them, the extract derived from the roots and rhizomes of Peucedanum ostruthium (i.e., Radix Imperatoriae), also known as masterwort, showed a pronounced and dose-dependent inhibitory effect. Reporter gene analysis demonstrated that inhibition takes place on the transcriptional level and involves the transcription factor NF-?B. A more detailed analysis revealed that the P. ostruthium extract (PO) affected the phosphorylation, degradation, and resynthesis of I?B?, the activation of IKKs, and the nuclear translocation of the NF-?B subunit RelA. Strikingly, early effects on this pathway were less affected as compared to later ones, suggesting that PO may act on mechanism(s) that are downstream of nuclear translocation. As the majority of cognate NF-?B inhibitors affect upstream events such as IKK2, these findings could indicate the existence of targetable signaling events at later stages of NF-?B activation.

SUBMITTER: Lammel C

PROVIDER: S-EPMC7563923 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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<i>Peucedanum ostruthium</i> Inhibits E-Selectin and VCAM-1 Expression in Endothelial Cells through Interference with NF-κB Signaling.

Lammel Christoph C Zwirchmayr Julia J Seigner Jaqueline J Rollinger Judith M JM de Martin Rainer R

Biomolecules 20200821 9

Twenty natural remedies traditionally used against different inflammatory diseases were probed for their potential to suppress the expression of the inflammatory markers E-selectin and VCAM-1 in a model system of IL-1 stimulated human umbilical vein endothelial cells (HUVEC). One third of the tested extracts showed in vitro inhibitory effects comparable to the positive control oxozeaenol, an inhibitor of TAK1. Among them, the extract derived from the roots and rhizomes of <i>Peucedanum ostruthiu ...[more]

PMID: 32825714

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Project description:Axonal degeneration is a common pathological feature in many acute and chronic neurological diseases such as spinal cord injury (SCI). SARM1 (sterile alpha and TIR motif-containing 1), the fifth TLR (Toll-like receptor) adaptor, has diverse functions in the immune and nervous systems, and recently has been identified as a key mediator of Wallerian degeneration (WD). However, the detailed functions of SARM1 after SCI still remain unclear. Methods: Modified Allen's method was used to establish a contusion model of SCI in mice. Furthermore, to address the function of SARM1 after SCI, conditional knockout (CKO) mice in the central nervous system (CNS), SARM1Nestin-CKO mice, and SARM1GFAP-CKO mice were successfully generated by Nestin-Cre and GFAP-Cre transgenic mice crossed with SARM1flox/flox mice, respectively. Immunostaining, Hematoxylin-Eosin (HE) staining, Nissl staining and behavioral test assays such as footprint and Basso Mouse Scale (BMS) scoring were used to examine the roles of SARM1 pathway in SCI based on these conditional knockout mice. Drugs such as FK866, an inhibitor of SARM1, and apoptozole, an inhibitor of heat shock protein 70 (HSP70), were used to further explore the molecular mechanism of SARM1 in neural regeneration after SCI. Results: We found that SARM1 was upregulated in neurons and astrocytes at early stage after SCI. SARM1Nestin-CKO and SARM1GFAP-CKO mice displayed normal development of the spinal cords and motor function. Interestingly, conditional deletion of SARM1 in neurons and astrocytes promoted the functional recovery of behavior performance after SCI. Mechanistically, conditional deletion of SARM1 in neurons and astrocytes promoted neuronal regeneration at intermediate phase after SCI, and reduced neuroinflammation at SCI early phase through downregulation of NF-κB signaling after SCI, which may be due to upregulation of HSP70. Finally, FK866, an inhibitor of SARM1, reduced the neuroinflammation and promoted the neuronal regeneration after SCI. Conclusion: Our results indicate that SARM1-mediated prodegenerative pathway and neuroinflammation promotes the pathological progress of SCI and anti-SARM1 therapeutics are viable and promising approaches for preserving neuronal function after SCI.

Dataset Information

Peucedanum ostruthium Inhibits E-Selectin and VCAM-1 Expression in Endothelial Cells through Interference with NF-?B Signaling.

Publications

<i>Peucedanum ostruthium</i> Inhibits E-Selectin and VCAM-1 Expression in Endothelial Cells through Interference with NF-κB Signaling.

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