An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
B-cell chronic lymphocytic leukemia (CLL) is a clonal B cell malignancy of morphologically mature, functionally immature B cells. B-cell CLL cells are known to be resistant to killing by anticancer and other agents. This resistance is associated with alterations in apoptosis and cell cycle regulated genes. In our earlier studies, we have demonstrated that CLL cells have differential expression of genes that are associated with apoptosis and cell cycle regulation, including elevated expression of Bcl-2, DAD-1, Cyclin D3 and cyclin dependent kinase 4 inhibitor. Therefore, in this study, in an attempt to study the role of Cyclin D3 in the resistant behavior of CLL cells, Cyclin D3 was down regulated using antisense oligonucleotide (AS-ODN) in WSU-CLL, a human CLL cell line. The down regulation of Cyclin D3 was confirmed by RT-PCR and flow cytometry techniques. The Cyclin D3 expression down-regulated WSU-CLL cells were then tested for their susceptibility to fludarabine, a chemotherapeutic agent. Our results showed that the Cyclin D3 expression down-regulated WSU-CLL cells were more susceptible to fludarabine mediated killing. Following treatment with fludarabine, there was a significant increase in the number of cells undergoing apoptosis in Cyclin D3 expression down-regulated WSU-CLL cells as determined by Annexin-V assay, cell cycle analysis for DNA content, and cytomorphology. Thus, our results indicate Cyclin D3 down regulation increases the killing of WSU-CLL cells with fludarabine by increasing the number of cells undergoing apoptosis.
Abstract Inhibitory GABA-ergic neurotransmission is fundamental for the adult vertebrate central nervous system and requires low chloride concentration in neurons, maintained by KCC2, a neuroprotective ion transporter that extrudes intracellular neuronal chloride. To identify Kcc2 gene expression‑enhancing compounds, we screened 1057 cell growth-regulating compounds in cultured primary cortical neurons. We identified kenpaullone (KP), which enhanced Kcc2/KCC2 expression and function in cultured rodent and human neurons by inhibiting GSK3ß. KP effectively reduced pathologic pain-like behavior in mouse models of nerve injury and bone cancer. In a nerve-injury pain model, KP restored Kcc2 expression and GABA-evoked chloride reversal potential in the spinal cord dorsal horn. Delta-catenin, a phosphorylation-target of GSK3ß in neurons, activated the Kcc2 promoter via KAISO transcription factor. Transient spinal over-expression of delta-catenin mimicked KP analgesia. Our findings of a newly repurposed compound and a novel, genetically-encoded mechanism that each enhance Kcc2 gene expression enable us to re-normalize disrupted inhibitory neurotransmission through genetic re-programming.
Tissue-resident macrophages (TRMs) are sentinel cells for maintaining tissue homeostasis and organ function. In this study, we discovered that lipopolysaccharide (LPS) administration dramatically reduced TRM populations and suppressed their self-renewal capacities in multiple organs. Using loss- and gain-of-function approaches, we define Sectm1a as a novel regulator of TRM self-renewal. Specifically, at the earlier stage of endotoxemia, Sectm1a deficiency exaggerated acute inflammation-induced reduction of TRM numbers in multiple organs by suppressing their proliferation, which was associated with more infiltrations of inflammatory monocytes/neutrophils and more serious organ damage. By contrast, administration of recombinant Sectm1a enhanced TRM populations and improved animal survival upon endotoxin challenge. Mechanistically, we identified that Sectm1a-induced upregulation in the self-renewal capacity of TRM is dependent on GITR-activated T helper cell expansion and cytokine production. Meanwhile, we found that TRMs may play an important role in protecting local vascular integrity during endotoxemia. Our study demonstrates that Sectm1a contributes to stabling TRM populations through maintaining their self-renewal capacities, which benefits the host immune response to acute inflammation. Therefore, Sectm1a may serve as a new therapeutic agent for the treatment of inflammatory diseases.
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