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Charlie Norwood VA Medical Center

HealthcareAugusta, Georgia, United States
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.


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Journal ArticleDOI
TL;DR: The findings indicate the importance of the Akt‐mTOR signaling pathway in TGF‐mediated fibrogenic events in vivo, and regulate mTOR at the translational level.
Abstract: A number of pro-fibrogenic stimuli, such as growth factors, cytokines, and extracellular matrix (ECM) proteins, involve Akt and its downstream substrates in mediating their effects. We previously reported that absence of Akt1, which is the predominant isoform of the three gene Akt family in vascular cells, resulted in impaired ECM remodeling in skin and vasculature. In the current study, we investigated the importance of Akt1 in TGFβ- and bleomycin-induced synthesis and secretion of ECM proteins by fibroblasts. We observed that both TGFβ and bleomycin stimulated the synthesis of ECM proteins in a dose- and time-dependent manner. Treatment with TGFβ and bleomycin also resulted in increased phosphorylation of Akt, mammalian target of rapamycin (mTOR) and their downstream signaling partners, p70S6 Kinase, Ribosomal S6 protein and 4E-BP1, resulting in the activation of this pathway. The effects of TGFβ and bleomycin on ECM synthesis were blunted by pre-treatment with an mTOR inhibitor rapamycin. Whereas mTOR is responsible for the transcriptional regulation of a number of ECM proteins, adhesion molecules and matrix metalloproteases (MMPs), synthesis of major ECM proteins such as fibronectin and collagens (types I, II and V) by fibroblasts in response to TGFβ and bleomycin is regulated by mTOR at the translational level. These findings indicate the importance of the Akt-mTOR signaling pathway in TGF-mediated fibrogenic events in vivo.

52 citations

Journal ArticleDOI
TL;DR: Deletion of A2 was found to be beneficial in reducing neurovascular degeneration after I/R, and ERG showed improved positive scotopic threshold response with A2 deletion.
Abstract: Retinal ischemia is a major cause of visual impairment and blindness and is involved in various disorders including diabetic retinopathy, glaucoma, optic neuropathies and retinopathy of prematurity. Neurovascular degeneration is a common feature of these pathologies. Our lab has previously reported that the ureahydrolase arginase 2 (A2) is involved in ischemic retinopathies. Here, we are introducing A2 as a therapeutic target to prevent neurovascular injury after retinal ischemia/reperfusion (I/R) insult. Studies were performed with mice lacking both copies of A2 (A2-/-) and wild-type (WT) controls (C57BL6J). I/R insult was conducted on the right eye and the left eye was used as control. Retinas were collected for analysis at different times (3 h-4 week after injury). Neuronal and microvascular degeneration were evaluated using NeuN staining and vascular digests, respectively. Glial activation was evaluated by glial fibrillary acidic protein expression. Necrotic cell death was studied by propidium iodide labeling and western blot for RIP-3. Arginase expression was determined by western blot and quantitative RT-PCR. Retinal function was determined by electroretinography (ERG). A2 mRNA and protein levels were increased in WT I/R. A2 deletion significantly reduced ganglion cell loss and microvascular degeneration and preserved retinal morphology after I/R. Glial activation, reactive oxygen species formation and cell death by necroptosis were significantly reduced by A2 deletion. ERG showed improved positive scotopic threshold response with A2 deletion. This study shows for the first time that neurovascular injury after retinal I/R is mediated through increased expression of A2. Deletion of A2 was found to be beneficial in reducing neurovascular degeneration after I/R.

51 citations

Journal ArticleDOI
TL;DR: The results show how tumor cells use the SETD1B-H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSCs when they are generated under pathologic conditions.
Abstract: Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T-cell receptor and STAT1, thus inhibiting T-cell activation and the antitumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b+Gr1− and immature CD11b+Gr1+ myeloid cells in vivo. Strikingly, although IRF8 was silenced in tumor-induced MDSCs, iNOS expression was significantly elevated in tumor-induced MDSCs, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathologic conditions. Furthermore, tumor-induced MDSCs exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSCs showed increased SETD1B expression as compared with their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSCs, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSCs. Our results show how tumor cells use the SETD1B–H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSCs when they are generated under pathologic conditions. Cancer Res; 77(11); 2834–43. ©2017 AACR.

51 citations

Journal ArticleDOI
TL;DR: The MISS-M-SF is a reliable and valid measure of MI symptoms that can be used to screen for MI and monitor response to treatment in veterans and active duty military with PTSD.
Abstract: Introduction To develop a short form (SF) of the 45-item multidimensional Moral Injury Symptom Scale - Military Version (MISS-M) to use when screening for moral injury and monitoring treatment response in veterans and active duty military with PTSD. Methods A total of 427 veterans and active duty military with PTSD symptoms were recruited from VA Medical Centers in Augusta, GA; Los Angeles, CA; Durham, NC; Houston, TX; and San Antonio, TX; and from Liberty University, Lynchburg, Virginia. The sample was randomly split in two. In the first half (n = 214), exploratory factor analysis identified the highest loading item on each of the 10 MISS scales (guilt, shame, moral concerns, loss of meaning, difficulty forgiving, loss of trust, self-condemnation, religious struggle, and loss of religious faith) to form the 10-item MISS-M-SF; confirmatory factor analysis was then performed to replicate results in the second half of the sample (n = 213). Internal reliability, test-retest reliability, and convergent, discriminant, and concurrent validity were examined in the overall sample. The study was approved by the institutional review boards and the Research & Development (R&D) Committees at Veterans Administration medical centers in Durham, Los Angeles, Augusta, Houston, and San Antonio, and the Liberty University and Duke University Medical Center institutional review boards. Findings The 10-item MISS-M-SF had a median of 50 and a range of 12-91 (possible range 10-100). Over 70% scored a 9 or 10 (highest possible) on at least one item. Cronbach's alpha was 0.73 (95% CI 0.69-0.76), and test-retest reliability was 0.87 (95% CI 0.79-0.92). Convergent validity with the 45-item MISS-M was r = 0.92. Discriminant validity was demonstrated by relatively weak correlations with social, religious, and physical health constructs (r = 0.21-0.35), and concurrent validity was indicated by strong correlations with PTSD, depression, and anxiety symptoms (r = 0.54-0.58). Discussion The MISS-M-SF is a reliable and valid measure of MI symptoms that can be used to screen for MI and monitor response to treatment in veterans and active duty military with PTSD.

50 citations

Journal ArticleDOI
TL;DR: The results indicate that the lncRNA TCONS_00016233 is upregulated in plasma of sepsis-associated non-AKI and AKI patients, but a higher cutoff threshold provided a higher sensitivity and specificity for the detection of AKI.
Abstract: The prediction of mortality for septic acute kidney injury (AKI) has been assessed by a number of potential biomarkers, including long noncoding RNAs (lncRNAs). However, the validation of lncRNAs as biomarkers, particularly for the early stages of septic AKI, is still warranted. Our results indicate that the lncRNA TCONS_00016233 is upregulated in plasma of sepsis-associated non-AKI and AKI patients, but a higher cutoff threshold (9.5 × 105, copy number) provided a sensitivity of 71.9% and specificity of 89.6% for the detection of AKI. The plasma TCONS_00016233 was highly correlated with serum creatinine, tissue inhibitor metalloproteinase-2 (TIMP-2), insulin-like growth factor binding protein-7 (IGFBP7), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), C-reactive protein (CRP), and urinary TCONS_00016233. Lipopolysaccharide (LPS) induced the expression of lncRNA TCONS_00016233 via the Toll-like receptor 4 (TLR4)/p38 mitogen-activated protein kinase (MAPK) signal pathway in human renal tubular epithelial (HK-2) cells. Furthermore, TCONS_00016233 mediates the LPS-induced HK-2 cell apoptosis and the expression of IL-1β and TNF-α. Mechanistically, TCONS_00016233 acts as a competing endogenous RNA (ceRNA) to prevent microRNA (miR)-22-3p-mediated downregulation of the apoptosis-inducing factor mitochondrion-associated 1 (AIFM1). Finally, overexpression of TCONS_00016233 is capable of aggravating the LPS- and cecal ligation and puncture (CLP)-induced septic AKI by targeting the miR-22-3p/AIFM1 axis. Taken together, our data indicate that TCONS_00016233 may serve as an early diagnosis marker for the septic AKI, possibly acting as a novel therapeutic target for septic AKI.

49 citations


Authors

Showing all 353 results

NameH-indexPapersCitations
Zheng Dong7028324123
Lin Mei6924515903
Wen Cheng Xiong6419412171
Ruth B. Caldwell6021412314
Darrell W. Brann6018811066
Steven S. Coughlin5630312401
Martha K. Terris5537512346
Susan C. Fagan5317910135
Adviye Ergul481887678
Kebin Liu461287271
Maribeth H. Johnson451255189
Azza B. El-Remessy441235746
Yutao Liu431525657
William D. Hill411019870
Yuqing Huo411149815
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
20231
20226
202163
202050
201942
201846