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.

Pressure-independent cerebrovascular remodelling and changes in myogenic reactivity in diabetic Goto-Kakizaki rat in response to glycaemic control.

Abstract: Aim: We have shown hypertrophic cerebrovascular remodelling in the Goto-Kakizaki (GK) rat model of diabetes. This study tested the hypotheses that (1) vascular remodelling develops as the disease progresses and alters myogenic reactivity of resistance vessels important for regulation of cerebral blood flow (CBF), and (2) glycaemic control prevents cerebrovascular remodelling and myogenic dysfunction. Methods: Middle cerebral artery (MCA) lumen diameter, media : lumen (M : L) ratio, cross-sectional area (CSA) and myogenic tone were measured in 10- and 18-week-old control Wistar and diabetic GK rats using pressurized arteriograph (n = 8–14/group). Mean arterial blood pressure (MAP) was measured with telemetry (n = 5/group). Additional GK rats were treated with metformin (300 mg kg−1 day−1) for glycaemic control starting at 7 weeks after the onset of diabetes until 18 weeks (n = 9). Results: In the control group, there was no difference in remodelling indices, myogenic tone or MAP between ages. Eighteen week diabetic rats displayed increased M : L ratio and CSA, but decreased lumen diameter and myogenic tone compared to 10-week GK or 18-week control rats. MAP increased starting around 10 weeks of age and remained slightly higher in the GK rats. Glycaemic control normalized M : L ratio, CSA, lumen diameter and myogenic tone with no effect on blood pressure. Conclusions: These findings suggest that diabetic rats develop MCA remodelling as the disease progresses but this is associated with impaired myogenic reactivity which may ultimately affect CBF. Our results also provide evidence that glycaemic control is an effective therapeutic strategy to prevent cerebrovascular remodelling and dysfunction.

Metformin: Experimental and clinical evidence for a potential role in emphysema treatment

Abstract: Rationale: Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, and emphysema, as well as systemic pathologies. Metformin is ben...

Epigenetic regulation of ganglioside expression in neural stem cells and neuronal cells

Abstract: The structural diversity and localization of cell surface glycosphingolipids (GSLs), including gangliosides, in glycolipid-enriched microdomains (GEMs, also known as lipid rafts) render them ideally suited to play important roles in mediating intercellular recognition, interactions, adhesion, receptor function, and signaling. Gangliosides, sialic acid-containing GSLs, are most abundant in the nerve tissues. The quantity and expression pattern of gangliosides in brain change drastically throughout development and these changes are mainly regulated through stage-specific expression of glycosyltransferase genes. We previously demonstrated for the first time that efficient histone acetylation of the glycosyltransferase genes in mouse brain contributes to the developmental alteration of ganglioside expression. We further demonstrated that acetylation of histones H3 and H4 on the N-acetylgalactosaminyltransferase I (GalNAcT, GA2/GM2/GD2/GT2-synthase; B4galnt1) gene promoter resulted in recruitment of trans-activation factors. In addition, we showed that epigenetic activation of the GalNAcT gene was detected and accompanied by an apparent induction of neuronal differentiation of neural stem cells (NSCs) responding to an exogenous supplement of ganglioside GM1. Most recently, we found that nuclear GM1 binds with acetylated histones on the promoters of the GalNAcT as well as on the NeuroD1 genes in differentiated neurons. Here, we will introduce epigenetic regulation of ganglioside synthase genes in neural development and neuronal differentiation of NSCs.

Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover.

Abstract: Vascular permeability regulated by the vascular endothelial growth factor (VEGF) through endothelial-barrier junctions is essential for inflammation. Mechanisms regulating vascular permeability remain elusive. Although 'Akt' and 'Src' have been implicated in the endothelial-barrier regulation, it is puzzling how both agents that protect and disrupt the endothelial-barrier activate these kinases to reciprocally regulate vascular permeability. To delineate the role of Akt1 in endothelial-barrier regulation, we created endothelial-specific, tamoxifen-inducible Akt1 knockout mice and stable ShRNA-mediated Akt1 knockdown in human microvascular endothelial cells. Akt1 loss leads to decreased basal and angiopoietin1-induced endothelial-barrier resistance, and enhanced VEGF-induced endothelial-barrier breakdown. Endothelial Akt1 deficiency resulted in enhanced VEGF-induced vascular leakage in mice ears, which was rescued upon re-expression with Adeno-myrAkt1. Furthermore, co-treatment with angiopoietin1 reversed VEGF-induced vascular leakage in an Akt1-dependent manner. Mechanistically, our study revealed that while VEGF-induced short-term vascular permeability is independent of Akt1, its recovery is reliant on Akt1 and FoxO-mediated claudin expression. Pharmacological inhibition of FoxO transcription factors rescued the defective endothelial barrier due to Akt1 deficiency. Here we provide novel insights on the endothelial-barrier protective role of VEGF in the long term and the importance of Akt1-FoxO signaling on tight-junction stabilization and prevention of vascular leakage through claudin expression.

Mitochondria in kidney injury: When the power plant fails

Abstract: Mitochondrial damage or dysfunction contribute critically to the pathogenesis of various diseases, including AKI. Upon stress, mitochondrial dynamics are disrupted and membrane integrity is compromised, resulting in the release of apoptogenic factors, mitochondrial permeability transition (MPT),