Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox

Lee, Jung‐Hee; Ryu, Hoon; Ferrante, Robert J.; Morris, Sidney M.; Ratan, Rajiv R.

doi:10.1073/pnas.0735876100

Cited by 318 publications

(243 citation statements)

References 41 publications

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“…NO is produced from the semiessential amino acid L-arginine by two constitutive isoforms of nitric oxide synthase (NOS), endothelial NOS (eNOS, NOS3) and neuronal NOS (nNOS, NOS1). L-arginine is both the substrate and the regulator of NOS (2). The third isoform (iNOS, NOS2) is induced in inflammatory, endothelial, muscle and other cells by a wide range of inflammatory agents, especially cytokines (3), and bacterial endotoxines.…”

Section: Introductionmentioning

confidence: 99%

Plasma nitrite/nitrate concentrations in patients with schizophrenia

Djordjević¹,

Stojanović²,

Stankovic-Ferlez³

et al. 2010

Clinical Chemistry and Laboratory Medicine

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Background: Nitric oxide (NO) is known to be a signaling molecule with many physiogical functions including apoptotic process regulation. Since apoptosis may contribute to the pathophysiology of schizophrenia, this study was undertaken to determine the plasma concentrations of NO in schizophrenics. Methods: Nitrite/nitrate (NO 2 -/NO 3 -) concentrations were measured in plasma from 40 patients with schizophrenia, and 36 age-and gender-matched healthy persons using a colorimetric test. Results: Plasma NO 2 -/NO 3 -concentrations were significantly higher in patients with schizophrenia (102.8"34.7

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Section: Introductionmentioning

confidence: 99%

Plasma nitrite/nitrate concentrations in patients with schizophrenia

Djordjević¹,

Stojanović²,

Stankovic-Ferlez³

et al. 2010

Clinical Chemistry and Laboratory Medicine

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“…Many factors have been previously implicated in the suppressive function of MDSCs, including the generation of reactive oxygen species (ROS) and NO by NADPH oxidase 41 and iNOS, 42 the deprivation of extracellular arginine and cysteine by arginase 42 and cysteine transporter X c À , 43 and Fas. 18 The suppressive function of MDSCs seems to be regulated by several transcription factors, including STAT3 and C/EBPb, and several recent studies have shown the STAT3-regulated suppressive functions of MDSCs.…”

Section: Discussionmentioning

confidence: 99%

“…24 Briefly, the syngeneic splenocytes were divided into equal numbers and either loaded with 1 lg/ml cytotoxic T lymphocyte (CTL) epitope peptide (human Her-2/neu p63 [TYLPTNASL] peptide or a mixture of E6 [41][42][43][44][45][46][47][48][49][50] [EVYD-FAFRDL] and E7 [49][50][51][52][53][54][55][56][57] [RAHYNIVTF] peptides) or left unpulsed. Peptide-pulsed splenocytes were labeled with chloromethylfluorescein diacetate succinimidyl ester (CFSE; Invitrogen, Carlsbad, CA) at 20 lM, and unpulsed splenocytes were labeled with 2 lM CFSE.…”

Section: In Vivo Cytotoxicity Assaymentioning

confidence: 99%

Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid‐derived suppressor cells

Hong

Chang

Lee

et al. 2012

Intl Journal of Cancer

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Myd88 is an important adaptor molecule for the activation of NADPH oxidase and arginase-1, which are responsible for the suppressive function of myeloid-derived suppressor cells (MDSCs). When wild-type and Myd88 2/2 mice were subcutaneously injected with CT26 colon cancer cells expressing human Her-2/neu, tumor growth was retarded in Myd88 2/2 mice than in wild-type mice. Although the generation of CD11b 1 Gr-1 1 MDSCs was less in Myd88 2/2 mice than in wild-type mice, Myd88 2/2 mice having tumor masses still had significant quantities of MDSCs, suggesting that MDSC generation might be independent of Myd88 signaling. However, MDSCs obtained from tumor-bearing Myd88 2/2 mice failed to suppress antigenspecific proliferation of CD8 1 T cells and CD4 1 T cells, whereas MDSCs from wild-type mice significantly suppressed both types of T cells. Consistent with this, we found that the levels of costimulatory molecules and MHC class II were significantly increased in MDSCs obtained from Myd88 2/2 mice compared with wild-type mice after tumor challenge. Furthermore, CD4 1 T cells residing in tumor-draining lymph nodes of Myd88 2/2 mice secreted more TNF-a than those of wild-type mice. Finally, the blockade of Myd88 signaling by treatment with Myd88 inhibitory peptide, during later tumor stages, significantly inhibited the growth of immunogenic tumors. Overall, these data suggest that signaling through the Myd88 adaptor molecule is critical for the direct suppressive function of MDSCs and approaches to block Myd88-mediated signaling in MDSCs might be effective to inhibit the immunosuppressive function of MDSCs.

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“…Interestingly, arginine transporters have been held responsible for the 'arginine-paradox', the observation that endothelial NO synthesis can be regulated by varying the extracellular arginine concentration, despite the fact that the reported intracellular arginine concentrations (0.1-1.0 mM) greatly exceed the K m of endothelial nitric oxide synthase (NOS) for arginine (2.9 mM) (Wu & Morris Jr, 1998). Interstingly, Lee et al (2003) recently demonstrated in an in vitro model that arginine concentration upregulates iNOS expression via translational control of iNOS mRNA.…”

Section: Discussionmentioning

confidence: 99%

High plasma arginine concentrations in critically ill patients suffering from hepatic failure

et al. 2004

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Objective: In physiological conditions, the liver plays an important role in the regulation of plasma arginine concentrations by taking up large amounts of arginine from the hepatic circulation. When hepatic failure is present, arginine metabolism may be disturbed. Therefore, we hypothesized high arginine plasma concentrations in critically ill patients suffering from hepatic failure. Design: We prospectively collected blood samples from a cross-section of intensive care unit patients. Setting: Surgical intensive care unit of a Dutch university medical center. Subjects: A total of 52 critically ill patients with clinical evidence of dysfunction of more than two organs were recruited. Measurements: Plasma arginine concentrations were determined by HPLC. We identified correlations of arginine concentrations with organ failure scores and laboratory variables by univariate and multiple regression analyses. Results: High plasma arginine concentrations were found in critically ill patients developing organ failure. Patients who were in the highest quartile of plasma arginine concentrations had significantly lower fibrinogen concentrations, higher lactic acid concentrations, and longer prothrombin time. Stepwise multiple regression analysis showed that concentrations of arginine were independently associated with the presence of hepatic failure (P ¼ 0.03) and renal failure (P ¼ 0.048). In addition, lactic acid proved to be an independent determinant of plasma arginine concentration (P ¼ 0.014). Conclusions: Critically ill patients who suffer from hepatic failure have elevated plasma arginine concentrations. Additional arginine in the treatment of these patients can be harmful, and therefore should not be used as a standard nutritional regimen until further evaluation.

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Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox

Cited by 318 publications

References 41 publications

Plasma nitrite/nitrate concentrations in patients with schizophrenia

Plasma nitrite/nitrate concentrations in patients with schizophrenia

Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid‐derived suppressor cells

High plasma arginine concentrations in critically ill patients suffering from hepatic failure

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