Nitric Oxide Is a Signaling Molecule that Regulates Gene Expression
College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA. Methods in Enzymology
(Impact Factor: 2.09).
02/2005; 396:326-40. DOI: 10.1016/S0076-6879(05)96027-8
Nitric oxide (NO) is a dynamic and bioreactive molecule that can both participate in and inhibit the genesis of disease. Its ability to have an impact on a wide range of physiological events stems from its capacity to reversibly alter the expression of specific genes and the activities of a wide range of proteins and signaling pathways. Yet, NO* remains an enigmatic molecule. Recently developed technologies, including gene-chips, two-dimensional electrophoresis, RNA interference, matrix-assisted laser desorption ionization (MALDI)-TOF (time-of-flight) mass spectrometry, and protein arrays will allow us to better understand how NO* and associated reactive nitrogen species (RNS) regulate both physiology and disease states, toward the development of treatments using NO* synthase inhibitors or NO* donors.
Available from: PubMed Central
- "Nitric oxide (NO) is a signaling molecule that mediates a variety of physiological processes, including neurotransmission , vasodilation, and host cell defense. The expression of inducible nitric oxide synthase (iNOS) is induced by cytokines, AGEs, and NF-κB  , and its induction results in the release of excessive amounts of NO  . In several ocular diseases, including uveitis, retinitis, glaucoma, and cataract, the alteration of iNOS expression has been reported    . "
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ABSTRACT: Damage of lens epithelial cells (LECs) has been implicated in cataract formation. The aim of this study was to investigate the protective effect of KIOM-79, a combination of four plant extracts, on LECs. We examined the levels of advanced glycation end products (AGEs), nuclear factor-kappaB (NF-κB) activation and inducible nitric oxide synthase (iNOS) expression in LECs during cataract development using the Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes. KIOM-79 was orally administered by gavage to ZDF rats once a day for 13 weeks. Apoptosis was detected by TUNEL assay, and NF-κB activation and iNOS expression were studied by southwestern histochemistry and immunohistochemistry, respectively. In diabetic cataractous lenses, TUNEL-positive LECs were markedly increased 20-fold, and AGEs were highly accumulated (2.7-fold) in LECs. In addition, both NF-κB activation, and iNOS expression were significantly enhanced 3- to 5-fold, respectively, compared to levels found in normal ZL rats. However, the administration of KIOM-79 delayed the development of diabetic cataracts and prevented LEC apoptosis (70%) through the inhibition of AGEs, NF-κB-activation and iNOS expression. These observations suggest that KIOM-79 is useful in inhibiting diabetic cataractogenesis and acts through an antiapoptotic mechanism to protect LECs from injury.
Available from: Kylie J Mansfield
- "Many cells have the capacity to synthesize nitric oxide (NO), a readily diffusible, short-lived molecule that is produced by the action of nitric oxide synthase (NOS) on L-arginine. Two of three known cytoplasmic isoforms of NOS, endothelial cell NOS (eNOS/NOS-1) and neuronal NOS (nNOS/NOS-3), are expressed constitutively while the third, inducible NOS (iNOS/NOS-2), is generally expressed in response to immunological challenge or some other pathophysiological stimulus [1,2]. Transient stimulation of constitutive NOS activity results in relatively low levels of NO production whereas iNOS activity can produce much larger amounts of NO over several days [3,4]. "
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ABSTRACT: Nitric oxide (NO) is capable of promoting either cell death or cell survival depending on cell type and experimental conditions. In this study, the possible effects of NO on the viability of lens epithelial cells were investigated in an explant model used previously to identify cellular changes associated with posterior capsule opacification following cataract surgery.
Rat lens epithelial explants prepared from weanling rats were cultured in a serum-free medium for five days with or without the addition of the nitric oxide synthase inhibitor, L-N(omega)-nitro-L-arginine methyl ester (L-NAME), using the inactive enantiomer D-NAME as a control. Alternatively, explants were cultured for nine days with or without the NO donor, sodium nitroprusside. Explants were assessed morphologically and immunohistochemically or by determining DNA content.
In the presence of L-NAME but not in controls, progressive rounding up and detachment of cells from the lens capsule occurred, leading to extensive cell loss. Affected cells showed apoptosis-like cell-surface blebbing and nuclear fragmentation. Conversely, inclusion of sodium nitroprusside suppressed the morphological changes and spontaneous cell loss that occurred when sparsely covered explants were cultured for nine days, increased cell coverage fourfold during that period, and prevented the expression of the transdifferentiation markers alpha-smooth muscle actin and fibronectin. In addition, whereas L-NAME exacerbated cell loss induced by culturing with 50 pg/ml transforming growth factor-beta2, sodium nitroprusside offered protection.
This study points to a previously unidentified role for NO as an endogenously produced survival factor for lens epithelial cells, raising the possibility of using NO deprivation as a means of removing residual lens cells following cataract surgery and thereby preventing posterior capsule opacification.
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ABSTRACT: Severe injury induces immune dysfunction resulting in increased susceptibility to opportunistic infections. Previous studies from our laboratory have demonstrated that post-burn immunosuppression is mediated by nitric oxide (NO) due to the increased expression of macrophage inducible nitric oxide synthase (iNOS). In contrast, others suggest that injury causes a phenotypic imbalance in the regulation of Th1- and Th2 immune responses. It is unclear whether or not these apparently divergent mediators of immunosuppression are interrelated. To study this, C57BL/6 mice were subjected to major burn injury and splenocytes were isolated 7 days later and stimulated with antiCD3. Burn injury induced NO-mediated suppression of proliferative responses that was reversed in the presence of the NOS inhibitor L-monomethyl-L-arginine and subsequently mimicked by the addition of the NO donor, S-nitroso-N-acetyl-penicillamine (SNAP). SNAP also dose-dependently suppressed IFN-gamma and IL-2 (Th1), but not IL-4 and IL-10 (Th2) production. Delaying the addition of SNAP to the cultures by 24 h prevented the suppression of IFN-gamma production. The Th2 shift in immune phenotype was independent of cGMP and apoptosis. The addition of SNAP to cell cultures also induced apoptosis, attenuated mitochondrial oxidative metabolism and induced mitochondrial membrane depolarization. However, these detrimental cellular effects of NO were observed only at supra-physiologic concentrations (>250 microM). In conclusion, these findings support the concept that NO induces suppression of cell-mediated immune responses by selective action on Th1 T cells, thereby promoting a Th2 response.
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