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.

Gene Expression Analysis Indicates Divergent Mechanisms in DEN-Induced Carcinogenesis in Wild Type and Bid-Deficient Livers.

Abstract: Bid is a Bcl-2 family protein In addition to its pro-apoptosis function, Bid can also promote cell proliferation, maintain S phase checkpoint, and facilitate inflammasome activation Bid plays important roles in tissue injury and regeneration, hematopoietic homeostasis, and tumorigenesis Bid participates in hepatic carcinogenesis but the mechanism is not fully understood Deletion of Bid resulted in diminished tumor burden and delayed tumor progression in a liver cancer model In order to better understand the Bid-regulated events during hepatic carcinogenesis we performed gene expression analysis in wild type and bid-deficient mice treated with a hepatic carcinogen, diethylnitrosamine We found that deletion of Bid caused significantly fewer alterations in gene expression in terms of the number of genes affected and the number of pathways affected In addition, the expression profiles were remarkably different In the wild type mice, there was a significant increase in the expression of growth regulation-related and immune/inflammation response-related genes, and a significant decrease in the expression of metabolism-related genes, both of which were diminished in bid-deficient livers These data suggest that Bid could promote hepatic carcinogenesis via growth control and inflammation-mediated events

Surface‐bound matrix metalloproteinase‐8 on macrophages: Contributions to macrophage pericellular proteolysis and migration through tissue barriers

Abstract: Objective MMP-8 binds to surface-bound tissue inhibitor of metalloproteinase-1 (TIMP-1) on PMNs to promote pericellular proteolysis during the development of inflammatory diseases associated with tissue destruction. Little is known about the biology of MMP-8 in macrophages. We tested the hypotheses that: (1) MMP-8 and TIMP-1 are also expressed on the surface of activated macrophages, (2) surface-bound MMP-8 on macrophages promotes TIMP-resistant pericellular proteolysis and macrophage migration through tissue barriers, and (3) MMP-8 binds to surface-bound TIMP-1 on macrophages. Methods Surface MMP-8 and TIMP-1 levels were measured on human monocyte-derived macrophages (MDM) and/or murine macrophages using immunostaining, biotin-labeling, and substrate cleavage methods. The susceptibility of membrane-bound Mmp-8 on activated macrophages from wild-type (WT) mice to TIMPs was measured. Migration of WT and Mmp-8-/- macrophages through models of tissue barriers in vitro and the accumulation of peritoneal macrophages in WT versus Mmp-8-/- mice with sterile peritonitis was compared. Surface levels of Mmp-8 were compared on activated macrophages from WT and Timp-1-/- mice. Results Lipopolysaccharides and a cluster of differentiation 40 ligand increased surface MMP-8 and/or TIMP-1 staining and surface type I collagenase activity on MDM and/or murine macrophages. Activated Mmp-8-/- macrophages degraded less type I collagen than activated WT macrophages. The surface type-I collagenase activity on WT macrophages was resistant to inhibition by Timp-1. Peritoneal macrophage accumulation was similar in WT and Mmp-8-/- mice with sterile acute peritonitis. However, Mmp-8-/- macrophages migrated less efficiently through models of tissue barriers (especially those containing type I collagen) than WT cells. Activated WT and Timp-1-/- macrophages had similar surface-bound Mmp-8 levels. Conclusions MMP-8 and TIMP-1 are expressed on the surface of activated human MDM and murine macrophages, but Mmp-8 is unlikely to bind to surface-bound Timp-1 on these cells. Surface-bound MMP-8 contributes to TIMP-resistant monocyte/macrophage pericellular proteolysis and macrophage migration through collagen-containing tissue barriers.

Inhibition of glypican-1 expression induces an activated fibroblast phenotype in a human bone marrow-derived stromal cell-line.

Abstract: Cancer-associated fibroblasts (CAFs) are the most abundant stromal cell type in the tumor microenvironment. CAFs orchestrate tumor-stromal interactions, and contribute to cancer cell growth, metastasis, extracellular matrix (ECM) remodeling, angiogenesis, immunomodulation, and chemoresistance. However, CAFs have not been successfully targeted for the treatment of cancer. The current study elucidates the significance of glypican-1 (GPC-1), a heparan sulfate proteoglycan, in regulating the activation of human bone marrow-derived stromal cells (BSCs) of fibroblast lineage (HS-5). GPC-1 inhibition changed HS-5 cellular and nuclear morphology, and increased cell migration and contractility. GPC-1 inhibition also increased pro-inflammatory signaling and CAF marker expression. GPC-1 induced an activated fibroblast phenotype when HS-5 cells were exposed to prostate cancer cell conditioned media (CCM). Further, treatment of human bone-derived prostate cancer cells (PC-3) with CCM from HS-5 cells exhibiting GPC-1 loss increased prostate cancer cell aggressiveness. Finally, GPC-1 was expressed in mouse tibia bone cells and present during bone loss induced by mouse prostate cancer cells in a murine prostate cancer bone model. These data demonstrate that GPC-1 partially regulates the intrinsic and extrinsic phenotype of human BSCs and transformation into activated fibroblasts, identify novel functions of GPC-1, and suggest that GPC-1 expression in BSCs exerts inhibitory paracrine effects on the prostate cancer cells. This supports the hypothesis that GPC-1 may be a novel pharmacological target for developing anti-CAF therapeutics to control cancer.

Dimensions of Religiosity and PTSD Symptom Clusters in US Veterans and Active Duty Military

Abstract: We examined multiple dimensions of religiosity and their relationship to the four DSM-5 PTSD symptom clusters among US Veterans and Active Duty Military (ADM), hypothesizing that religiosity would be most strongly inversely related to negative cognitions/emotions (Criterion D symptoms) and less strongly to neurobiologically based symptom clusters (B, C, and E). This cross-sectional multisite study involved 591 Veterans and ADM from across the southern USA. Inclusion criteria were having served in a combat theater and the presence of PTSD symptoms. Measures of religious beliefs/practices, social involvement, and PTSD symptoms were administered, and bivariate and multivariate analyses were conducted in the overall sample, and in exploratory analyses, in the sample stratified by race (White, Black, and Hispanic). In the overall sample, multivariate analyses revealed that the only PTSD symptom cluster inversely related to religiosity was Criterion D, and only to organizational (b = − 0.08, P = 0.028) and cognitive/intrinsic religiosity (b = − 0.06, P = 0.049), relationships that were fully explained by social factors. Religious struggles, in contrast, were positively related to all four symptom clusters. Inverse relationships with Criterion D symptoms were particularly strong in Blacks, in whom inverse relationships were also present with Criterion E symptoms. In contrast, only positive relationships with PTSD symptom clusters were found in Hispanics, and no relationships (except for religious struggles) were present in Whites. As hypothesized, the inverse relationship between religious involvement and PTSD symptoms in Veterans and ADM was strongest (though modest) for Criterion D negative cognitions/emotions, especially in Blacks.