Charlie Norwood VA Medical Center

About: Charlie Norwood VA Medical Center is a healthcare organization based out in Augusta, Georgia, United States. It is known for research contribution in the topics: Autophagy & Kidney. The organization has 349 authors who have published 490 publications receiving 16360 citations. The organization is also known as: Augusta VA Medical Center.

Discrete functions of GSK3α and GSK3β isoforms in prostate tumor growth and micrometastasis.

Abstract: Isoform specific function of glycogen synthase kinase-3 (GSK3) in cancer is not well defined. We report that silencing of GSK3α, but not GSK3β expression inhibited proliferation, survival and colony formation by the PC3, DU145 and LNCaP prostate cancer cells, and the growth of PC3 tumor xenografts in athymic nude mice. Silencing of GSK3α, but not GSK3β resulted in reduced proliferation and enhanced apoptosis in tumor xenografts. ShRNA-mediated knockdown of GSK3α and GSK3β equally inhibited the ability of prostate cancer cells to migrate and invade the endothelial-barrier in vitro, and PC3 cell micrometastasis to lungs in vivo. Mechanistically, whereas silencing GSK3α resulted in increased expression of pro-apoptotic markers cleaved caspase-3 and cleaved caspase-9 in LNCaP, PC3 and DU145 cells, silencing GSK3β resulted in the inhibition of cell scattering, establishment of cell-cell contacts, increased expression and membrane localization of β-catenin, and reduced expression of epithelial to mesenchymal transition (EMT) markers such as Snail and MMP-9. This indicated the specific role of GSK3β in EMT, acquisition of motility and invasive potential. Overall, our data demonstrated the isoform specific role of GSK3α and GSK3β in prostate cancer cells in vitro, and tumor growth and micrometastasis in vivo, via distinct molecular and cellular mechanisms.

Cell-cell junctions: structure and regulation in physiology and pathology.

Abstract: Epithelial and endothelial cell-cell contacts are established and maintained by several intercellular junctional complexes. These structurally and biochemically differentiated regions on the plasma membrane primarily include tight junctions (TJs), and anchoring junctions. While the adherens junctions (AJs) provide essential adhesive and mechanical properties, TJs hold the cells together and form a near leak-proof intercellular seal by the fusion of adjacent cell membranes. AJs and TJs play essential roles in vascular permeability. Considering their involvement in several key cellular functions such as barrier formation, proliferation, migration, survival, and differentiation, further research is warranted on the composition and signaling pathways regulating cell-cell junctions to develop novel therapeutics for diseases such as organ injuries. The current review article presents our current state of knowledge on various cell-cell junctions, their molecular composition, and mechanisms regulating their expression and function in endothelial and epithelial cells.

Sequential Therapy with Minocycline and Candesartan Improves Long-Term Recovery After Experimental Stroke

Abstract: Minocycline and candesartan have both shown promise as candidate therapeutics in ischemic stroke, with multiple, and somewhat contrasting, molecular mechanisms. Minocycline is an anti-inflammatory, antioxidant, and anti-apoptotic agent and a known inhibitor of matrix metalloproteinases (MMPs). Yet, minocycline exerts antiangiogenic effects both in vivo and in vitro. Candesartan promotes angiogenesis and activates MMPs. Aligning these therapies with the dynamic processes of injury and repair after ischemia is likely to improve success of treatment. In this study, we hypothesize that opposing actions of minocycline and candesartan on angiogenesis, when administered simultaneously, will reduce the benefit of candesartan treatment. Therefore, we propose a sequential combination treatment regimen to yield a better outcome and preserve the proangiogenic potential of candesartan. In vitro angiogenesis was assessed using human brain endothelial cells. In vivo, Wistar rats subjected to 90-min middle cerebral artery occlusion (MCAO) were randomized into four groups: saline, candesartan, minocycline, and sequential combination of minocycline and candesartan. Neurobehavioral tests were performed 1, 3, 7, and 14 days after stroke. Brain tissue was collected on day 14 for assessment of infarct size and vascular density. Minocycline, when added simultaneously, decreased the proangiogenic effect of candesartan treatment in vitro. Sequential treatment, however, preserved the proangiogenic potential of candesartan both in vivo and in vitro, improved neurobehavioral outcome, and reduced infarct size. Sequential combination therapy with minocycline and candesartan improves long-term recovery and maintains candesartan’s proangiogenic potential.

Overview and Update on Methods for Cargo Loading into Extracellular Vesicles.

Abstract: The enormous library of pharmaceutical compounds presents endless research avenues. However, several factors limit the therapeutic potential of these drugs, such as drug resistance, stability, off-target toxicity, and inadequate delivery to the site of action. Extracellular vesicles (EVs) are lipid bilayer-delimited particles and are naturally released from cells. Growing evidence shows that EVs have great potential to serve as effective drug carriers. Since EVs can not only transfer biological information, but also effectively deliver hydrophobic drugs into cells, the application of EVs as a novel drug delivery system has attracted considerable scientific interest. Recently, EVs loaded with siRNA, miRNA, mRNA, CRISPR/Cas9, proteins, or therapeutic drugs show improved delivery efficiency and drug effect. In this review, we summarize the methods used for the cargo loading into EVs, including siRNA, miRNA, mRNA, CRISPR/Cas9, proteins, and therapeutic drugs. Furthermore, we also include the recent advance in engineered EVs for drug delivery. Finally, both advantages and challenges of EVs as a new drug delivery system are discussed. Here, we encourage researchers to further develop convenient and reliable loading methods for the potential clinical applications of EVs as drug carriers in the future.