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: Cantharidin (CTD), a naturally occurring small molecule isolated from a medicinal insect, possesses anti-cancer and pro-inflammatory properties. We aimed to examine the effect of CTD on human myeloid dendritic cells (DCs) by examining immature DCs differentiated and maturated from CD14+ monocytes. CTD added into a culture of starting CD14+ monocytes markedly and dose-dependently reduced viability of harvested DC. Mature DCs differentiated in the presence of CTD had much fewer, shorter membranous projections than those without CTD. Changes in morphological features characteristic of necrotic cells were also evident. Furthermore, CTD affected DC differentiation and maturation phenotypes including down-regulation of surface CD1a, CD83 and DC-SIGN. DCs derived in the presence of CTD possessed an impaired allostimulatory activity on naive CD4+CD45+RA+T cell in terms of proliferation and interferon-γ production. It suggests that CTD may redirect DC differentiation toward a less mature stage and that this effect is not solely due to its cytotoxicity. Whether this effect refers to immune suppression or tolerance to disease treatments with unwanted immune reactions needs further evaluation.Toxicology in Vitro 09/2011; 25(8):1740-7. · 2.65 Impact Factor
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ABSTRACT: We recently found that the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL)1 is essential for mediating adiponectin signal to induce liver kinase B (LKB)1 cytosloic translocation, an essential step for activation of AMP-activated protein kinase (AMPK) in cells. However, the underlying molecular mechanisms remain unknown. Here, we demonstrate that treating C2C12 myotubes with adiponectin promoted APPL1 interaction with protein phosphatase 2A (PP2A) and protein kinase Cζ (PKCζ), leading to the activation of PP2A and subsequent dephosphorylation and inactivation of PKCζ. The adiponectin-induced inactivation of PKCζ results in dephosphorylation of LKB1 at Ser(307) and its subsequent translocation to the cytosol, where it stimulates AMPK activity. Interestingly, we found that metformin also induces LKB1 cytosolic translocation, but the stimulation is independent of APPL1 and the PP2A-PKCζ pathway. Together, our study uncovers a new mechanism underlying adiponectin-stimulated AMPK activation in muscle cells and shed light on potential targets for prevention and treatment of insulin resistance and its associated diseases.Molecular Endocrinology 08/2011; 25(10):1773-85. · 4.75 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