Anti-HSP90 monoclonal antibody, clone 27G2 [Biotin]

Elucidating signaling driven by lemur tyrosine kinase 3 (LMTK3) could help drug development. Here, we solve the crystal structure of LMTK3 kinase domain to 2.1A resolution, determine its consensus motif and phosphoproteome, unveiling in vitro and in vivo LMTK3 substrates. Via high-throughput homogeneous time-resolved fluorescence screen coupled with biochemical, cellular, and biophysical assays, we identify a potent LMTK3 small-molecule inhibitor (C28). Functional and mechanistic studies reveal LMTK3 is a heat shock protein 90 (HSP90) client protein, requiring HSP90 for folding and stability, while C28 promotes proteasome-mediated degradation of LMTK3. Pharmacologic inhibition of LMTK3 decreases proliferation of cancer cell lines in the NCI-60 panel, with a concomitant increase in apoptosis in breast cancer cells, recapitulating effects of LMTK3 gene silencing. Furthermore, LMTK3 inhibition reduces growth of xenograft and transgenic breast cancer mouse models without displaying systemic toxicity at effective doses. Our data reinforce LMTK3 as a druggable target for cancer therapy.

The present study was conducted to evaluate the effects of astaxanthin (AST) against lipopolysaccharide (LPS)-induced lymphocyte viability, ultrastructural lesions, apoptosis, oxidative stress and inflammatory responses in Channa argus. Lymphocytes exposed to more than 10 mu g/ml LPS alone for 24 hr showed significantly decreased cell viability, elevated nitric oxide (NO) and malondialdehyde (MDA), lactate dehydrogenase (LDH) contents, and increased nuclear factor kappa B p65 (NF-kappa B p65), myeloid differential protein-88 (MyD88), tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-8 (IL-8), caspase-3, caspase-8 and caspase-9 gene expression. LPS at a concentration of 10 mu g/ml could induce oxidative stress and inflammatory responses in lymphocytes. The activities of antioxidant enzymes (catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD)) were significantly decreased after exposure to 10 mu g/ml LPS. Besides, AST strikingly antagonized the LPS-induced negative effects. AST significantly increased the expression of HSP70, HSP90, I kappa B-alpha, and glucocorticoid receptor (GR) and decreased inflammatory responses. Further study showed that AST can activate GR signalling pathway and inhibit p65 phosphorylation. In addition, AST attenuated LPS-induced apoptosis, mitochondrial swelling, degeneration and vacuolization. Collectively, these findings suggest that AST has protective roles in LPS-induced cell damage via modulating GR activation in C. argus lymphocytes.