Inhibitory effect of cantharidin on osteoclast differentiation and bone resorption.
ABSTRACT Regulation of receptor activator of nuclear factor kappaB-ligand (RANKL)-induced osteoclast differentiation is of current interest in the development of antiresorptive agents. We identified the inhibitory effects of cantharidin on RANKL-induced differentiation and bone resorptive activities of osteoclasts in macrophage-like RAW264.7 cells. Interestingly, cantharidin significantly inhibited RANKL-induced ERK/MAP kinase activation and protein phosphatase 2A (PP2A) activity. In addition, cantharidin significantly inhibited RANKL-induced mRNA expression of transcription factors and osteoclast-specific genes (especially Fra-2 and cathepsin K, respectively). Although further studies might be required to elucidate the precise mechanism of cantharidin's action on osteoclast differentiation and bone resorptive activities, our results suggested that cantharidin-mediated inactivation of PP2A could prevent RANKLinduced activation of ERK/MAP kinase and transcription factors such as AP-1 and NFATc1, with subsequent inhibition of osteoclast-specific gene expression required for efficient osteoclast differentiation and bone resorption.
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ABSTRACT: High mobility group box 1 (HMGB1), a non-histone chromosomal protein, is a proinflammatory cytokine. There are two known pathways for the release of HMGB1 into the extracellular milieu-passive and active. The passive pathway is attributable to cell death from damage or necrosis, and the active pathway is secretion from immunocompetent cells activated by proinflammatory stimuli. Recent studies have shown that post-translational modifications of HMGB1, including phosphorylation, are involved in the relocation of HMGB1 to the cytoplasm and subsequent secretion. With regard to the HMGB1 phosphorylation, Youn and Shin reported that treatment of the murine macrophage RAW264.7 with okadaic acid resulted in nucleocytoplasmic translocation and secretion of HMGB1 [Youn, J. H., and Shin, J. S. (2006) J. Immunol. 177, 7889-7897]. Herein, we demonstrate the physical interaction between HMGB1 and protein phosphatase 2A (PP2A) in the RAW264.7. The results of in vitro phosphatase assay further indicate that PP2A dephosphorylates specific phosphoserine residues within one of the two nuclear localization signals (NLSs) of HMGB1. The cytoplasmic relocation of HMGB1 through PP2A inhibition was markedly suppressed by replacement of the Ser residues within the NLS with Ala. These consequences imply that PP2A correlates in the nucleocytoplasmic shuttling of HMGB1.Journal of Biochemistry 06/2013; · 3.07 Impact Factor
Article: Cantharidin toxicosis in 2 alpacas.[Show abstract] [Hide abstract]
ABSTRACT: Two adult alpacas were presented for recumbency and reluctance to rise. Cantharidin toxicosis was suspected based on clinical and ancillary diagnostic findings. The diagnosis was confirmed by gas chromatography-mass spectrometry of gastric contents and urine. Despite medical treatment, neither alpaca survived. Blister beetle toxicosis has not been previously described in camelids. Challenges in treatment of affected ruminants or pseudoruminants are noted.The Canadian veterinary journal. La revue veterinaire canadienne 05/2013; 54(5):456-62. · 0.77 Impact Factor
Conference Paper: Simulated-annealing type Markov chains and their order balance equations[Show abstract] [Hide abstract]
ABSTRACT: Generalized simulated-annealing-type Markov chains are considered where the transition probabilities are proportional to powers of a vanishingly small parameter. It is possible to associate with each state an order of recurrence which quantifies the asymptotic behavior of the state occupation probability. These orders of recurrence satisfy a fundamental balance equation across every edge-cut in the graph of the Markov chain. Moreover, the Markov chain converges in a Cesaro sense to the set of states having the largest recurrence orders. The authors provide graph-theoretic algorithms to determine the solutions of the balance equations. By applying these results to the problem of optimization by simulated annealing, they show that the sum of the recurrence order and the cost is a constant for all states in a certain connected set, whenever a weak reversibility condition is satisfiedDecision and Control, 1988., Proceedings of the 27th IEEE Conference on; 01/1989