Chemical, biochemical, and physiological aspects of nitric oxide, S-nitrosothiols, and protein disulfide isomerase.
Bibliographic record
Abstract
Nitric oxide (NO•), S-nitrosothiols (RSNO), and cell surface protein disulfide isomerase (csPDI) are involved in many cellular processes. In this work, we investigate the participation of NO• and RSNO with respect to csPDI physiology. Omapatrilat (Omap) is developed by Bristol-Meyers Squibb for the treatment of hypertension. The effect of Omap treatment on two aspects of endothelial cell NO• metabolism was examined. Incubation with Omap resulted in an increase in the relative efficiency of L-arginine uptake (Vmax/K m), a precursor for NO• synthesis. Upon nitrosating the free sulthydryl group on Omap, we demonstrated its ability to deliver NO• to the cytosol via csPDI. In addition, treatment with Omap increased the affinity of csPDI for S-nitroso-albumin. We introduce O-aminobenzoyl-S-nitrosohomocysteine (AbzHcysNO) as a novel probe for use in cell surface thiol quantification. The chemical properties of AbzHcysNO allow for the detection of thiols with a limit of 30 pmol, using a fluorescence plate reader. Furthermore, it will be shown that this sensitivity is sufficient for determining the cell-surface thiol levels of cultured mammalian cells. PDI exhibits both disulfide exchange and denitrosation activities and has been recently located on the surface of platelets. The disulfide exchange activity of csPDI has been shown to regulate platelet adhesion, activation, and aggregation. Herein we have shown the denitrosation activity of csPDI catalyses the release of NO• from GSNO which inhibits platelet aggregation through the GC/PKG pathway. Additionally, the presence of extracellular RSNOs occupied the active site of PDI, thus preventing the integrin-ligand disulfide exchange required for platelet adhesion. The presence of NADPH oxidase (NOX) on the surface of platelets alludes to the possibility that NOX activity may play a role in switching csPDI between its disulfide exchange and denitrosation activities. Monitoring the activities of NOX and csPDI in an animal model of early insulin resistance, as well as in NIDDM humans, indicated that platelet NOX activity was enhanced while csPDI activity was diminished compared to controls. This suggested that, in NIDDM, elevated NOX activity turns off the denitrosation activity of csPDI and promotes the pro-aggregatory disulfide integrin-ligand coupling, thus resulting in platelet hyperactivity.Dept. of Chemistry and Biochemistry. Paper copy at Leddy Library: Theses & Major Papers - Basement, West Bldg. / Call Number: Thesis2004 .R66. Source: Dissertation Abstracts International, Volume: 66-07, Section: B, page: 3697. Thesis (Ph.D.)--University of Windsor (Canada), 2005.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".