Inhibition of Nitrosylation, Nitration, Lymphocyte Proliferation, and Gene Expression in Acute and Delayed Cardiac Allograft Rejection by an Orally Active Dithiocarbamate

Q4 · MEDICINE

Article

Author: Hilton, Gail ; Adams, Mark B. ; Felix, Christopher C. ; Kampalath, Bal N. ; Johnson, Christopher P. ; Roza, Allan M. ; Pieper, Galen M. ; Khanna, Ashwani K.

Dithiocarbamate derivatives sequester metals such as iron and may have benefits in inflammatory diseases. We examined the actions of a new dithiocarbamate-based oral formulation, NOX-700, on protein modification by nitric oxide (NO), gene expression, and lymphocyte proliferation in a model of acute and delayed cardiac rejection. Chronic treatment with NOX-700 prolonged graft survival. In combination with low-dose cyclosporine (CsA), NOX-700 produced a synergistic action to prolong graft survival. NOX-700 decreased myocardial heme nitrosylation. A single bolus injection with NOX-700 in untreated recipients did not decrease heme nitrosylation but normalized NO metabolites and caused the formation of a mononitrosyl iron complex indicating NO scavenging in vivo. NOX-700 alone given with CsA inhibited protein nitration. NOX-700 or CsA each alone decreased intragraft inflammatory cell infiltration. NOX-700 also potentiated the CsA-induced inhibition of splenocyte proliferation ex vivo stimulated by concanavalin A. In splenocytes derived from treated rats but stimulated ex vivo in a mixed lymphocyte response (MLR), interferon-gamma and cyclin D3 gene expression was inhibited by NOX-700 suggesting down-regulation of lymphocyte activation and proliferation by in vivo treatment. These studies suggest that NOX-700 is protective in cardiac rejection, in part, by scavenging of NO and by limiting lymphocyte activation infiltration.

01 Jan 2004·Inflammation ResearchQ3 · MEDICINE

Spatial distribution and temporal onset of NF-kB activation and inducible nitric oxide synthase within pancreatic islets in the pre-diabetic stage of genetic, diabetic-prone BB rats: Attenuation by drug intervention decreases inflammatory cell infiltration and incidence of diabetes

Q3 · MEDICINE

Article

Author: J. D. Henderson ; C. M. Pieper ; C.-S. Lai ; Y.-R. Zhu ; A. M. Roza

OBJECTIVE AND DESIGNTo document in vivo immunolocalization and activation of nuclear factor-kappaB (NF-kappaB) and inducible nitric oxide synthase (iNOS) expression in prediabetic stages of diabetes mellitus.MATERIAL OR SUBJECTSGenetic, diabetic-prone or diabetic-resistant BB rats (total = 189).TREATMENTVarious doses of an oral dithiocarbamate derivative, NOX-700, or cyclosporine (2.5 mg/kg) starting at 30 or 60 days of age.METHODSImmunohistochemistry, electrophoretic mobility shift assays, plasma glucose.RESULTSNF-kappaB and iNOS was increased in pancreas of hyperglycemic, diabetic-prone rats but not normoglycemic, diabetic-resistant rats. Immunostaining for NF-kappaB and iNOS was largely confined to islets and occurred in diabetic-prone rats prior to overt hyperglycemia. NOX-700 decreased cell infiltration, delayed the onset of disease and decreased the incidence of hyperglycemia to levels achieved by immunosuppressant therapy. NOX-700 also decreased the intensity of immunoreactive NF-kappaB and iNOS within pancreatic islets.CONCLUSIONSThese studies support a role of NF-kB and iNOS in diabetogenesis in vivo.

01 Jul 2003·European Journal of PharmacologyQ3 · MEDICINE

Chronic or delayed treatment with an oral dithiocarbamate analog decreases glycation and protects diabetic arteries

Q3 · MEDICINE

Article

Author: Galen M. Pieper ; Wolfgang Siebeneich ; Cara L. Olds ; Ching-San Lai

In the present study, we examined the efficacy of a dithiocarbamate-based compound, denoted as NOX-700, on diabetes-induced endothelial dysfunction and glycosylation of hemoglobin (Hb). Streptozotocin-induced diabetic rats received 3 mg/ml NOX-700 in drinking water beginning at 72 h or 4 weeks and continued to 8 weeks. Oxidative and glycooxidative stress were examined by electrophoretic mobility shift assay (EMSA) for nuclear factor-kappaB (NF-kappaB) in nuclear fractions of aortic homogenates and by glycosylated Hb, respectively. Vascular reactivity was examined in aortic ring segments ex vivo. Treatment with NOX-700 inhibited glycosylated Hb formation when given long-term or after delayed administration. NOX-700 improved endothelium-dependent relaxation to acetylcholine but did not alter reactivity to norepinephrine or nitroglycerin, suggesting selective protection of the endothelium. Nuclear factor-kappaB (NF-kappaB) nuclear binding activity was significantly increased in diabetic aortas and abrogated by NOX-700. Thus, vascular protection by NOX-700 is believed to be mediated, in part, by an antioxidant mechanism and decreased protein glycation.

100 Deals associated with NOX-700

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Phase 2	-	Medinox, Inc.	-

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