Handelin

The herbs of Dendranthema indicum

Highly Selective Activation of Heat Shock Protein 70 by Allosteric Regulation Provides an Insight into Efficient Neuroinflammation Inhibition.[Pubmed:28807514]

EBioMedicine. 2017 Sep;23:160-172.

Heat shock protein 70 (Hsp70) is widely involved in immune disorders, making it as an attractive drug target for inflammation diseases. Nonselective induction of Hsp70 upregulation for inflammation therapy could cause extensive interference in inflammation-unrelated protein functions, potentially resulting in side effects. Nevertheless, direct pharmacological activation of Hsp70 via targeting specific functional amino acid residue may provide an insight into precise Hsp70 function regulation and a more satisfactory treatment effect for inflammation, which has not been extensively focused. Here we show a cysteine residue (Cys306) for selective Hsp70 activation using natural small-molecule Handelin. Covalent modification of Cys306 significantly elevates Hsp70 activity and shows more satisfactory anti-neuroinflammation effects. Mechanism study reveals Cys306 modification by Handelin induces an allosteric regulation to facilitate adenosine triphosphate hydrolysis capacity of Hsp70, which leads to the effective blockage of subsequent inflammation signaling pathway. Collectively, our study offers some insights into direct pharmacological activation of Hsp70 by specially targeting functional cysteine residue, thus providing a powerful tool for accurately modulating neuroinflammation pathogenesis in human with fewer undesirable adverse effects.

Suppression of inflammatory responses by handelin, a guaianolide dimer from Chrysanthemum boreale, via downregulation of NF-kappaB signaling and pro-inflammatory cytokine production.[Pubmed:24689881]

J Nat Prod. 2014 Apr 25;77(4):917-24.

The anti-inflammatory activity of Handelin (1), a guaianolide dimer from Chrysanthemum boreale flowers, was evaluated in vivo, and the effects on mediators nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) and the nuclear factor-kappaB (NF-kappaB) and ERK/JNK signaling pathways were investigated in vitro. Compound 1 inhibited lipopolysaccharide (LPS)-induced production of NO and PGE2 in cultured mouse macrophage RAW 264.7 cells. The suppression of NO and PGE2 production by 1 was correlated with the downregulation of mRNA and protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Compound 1 also suppressed the induction of pro-inflammatory cytokines TNF-alpha and IL-1beta in LPS-stimulated RAW 264.7 cells. To further clarify the transcriptional regulatory pathway in the expression of iNOS and COX-2 by 1, the role of NF-kappaB was determined in RAW 264.7 cells. Compound 1 inhibits the binding activity of NF-kappaB into the nuclear proteins. The transcriptional activity of NF-kappaB stimulated with LPS was also suppressed by 1, which coincided with the inhibition of IkappaB degradation. Compound 1 also suppressed the activation of mitogen-activated protein kinases, including ERK and JNK signaling. In addition, the LPS-stimulated upregulation of miRNA-155 expression was suppressed by 1. The oral administration of 1 inhibited acute inflammation in carrageenan-induced paw and 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear edema models. The serum level of IL-1beta was also inhibited by 1 in a carrageenan-induced paw edema model. These findings suggest that the suppression of NF-kappaB activation and pro-inflammatory cytokine production may be a plausible mechanism of action for the anti-inflammatory activity of Handelin.

Handelin is a guaianolide dimer from Chrysanthemum boreale that has potent anti-inflammatory activity by down-regulating NF-κB signaling and pro-inflammatory cytokine production.

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