NO emissions from soils and ecosystems are of outstanding importance for atmospheric chemistry. Here we review the current knowledge on processes involved in the formation and consumption of NO in ...soils, the importance of NO for the physiological functioning of different organisms, and for inter- and intra-species signaling and competition, e.g. in the rooting zone between microbes and plants. We also show that prokaryotes and eukaryotes are able to produce NO by multiple pathways and that unspecific enzymo-oxidative mechanisms of NO production are likely to occur in soils. Nitric oxide production in soils is not only linked to NO production by nitrifying and denitrifying microorganisms, but also linked to extracellular enzymes from a wide range of microorganisms.
Further investigations are needed to clarify molecular mechanisms of NO production and consumption, its controlling factors, and the significance of NO as a regulator for microbial, animal and plant processes. Such process understanding is required to elucidate the importance of soils as sources (and sinks) for atmospheric NO.
•Abiotic and biotic pathways of NO transformation are discussed.•Interrelation between NO transformation processes is discussed.•Unspecific enzymo-oxidative mechanisms of NO transformation are proposed.•Physiological NO functions/effects in/for various groups of organisms are shown.•Importance of bacterial NO as signaling substance for others organisms is highlighted.
Nitric oxide: what's new to NO? Ghimire, Kedar; Altmann, Helene M; Straub, Adam C ...
American Journal of Physiology: Cell Physiology,
03/2017, Letnik:
312, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Nitric oxide (NO) is one of the critical components of the vasculature, regulating key signaling pathways in health. In macrovessels, NO functions to suppress cell inflammation as well as adhesion. ...In this way, it inhibits thrombosis and promotes blood flow. It also functions to limit vessel constriction and vessel wall remodeling. In microvessels and particularly capillaries, NO, along with growth factors, is important in promoting new vessel formation, a process termed angiogenesis. With age and cardiovascular disease, animal and human studies confirm that NO is dysregulated at multiple levels including decreased production, decreased tissue half-life, and decreased potency. NO has also been implicated in diseases that are related to neurotransmission and cancer although it is likely that these processes involve NO at higher concentrations and from nonvascular cell sources. Conversely, NO and drugs that directly or indirectly increase NO signaling have found clinical applications in both age-related diseases and in younger individuals. This focused review considers recently reported advances being made in the field of NO signaling regulation at several levels including enzymatic production, receptor function, interacting partners, localization of signaling, matrix-cellular and cell-to-cell cross talk, as well as the possible impact these newly described mechanisms have on health and disease.
Abstract
Aims
Recent clinical trials indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain ...unknown. We explored the direct effects of canagliflozin, an SGLT2 inhibitor with mild SGLT1 inhibitory effects, on myocardial redox signalling in humans.
Methods and results
Study 1 included 364 patients undergoing cardiac surgery. Right atrial appendage biopsies were harvested to quantify superoxide (O2.−) sources and the expression of inflammation, fibrosis, and myocardial stretch genes. In Study 2, atrial tissue from 51 patients was used ex vivo to study the direct effects of canagliflozin on NADPH oxidase activity and nitric oxide synthase (NOS) uncoupling. Differentiated H9C2 and primary human cardiomyocytes (hCM) were used to further characterize the underlying mechanisms (Study 3). SGLT1 was abundantly expressed in human atrial tissue and hCM, contrary to SGLT2. Myocardial SGLT1 expression was positively associated with O2.− production and pro-fibrotic, pro-inflammatory, and wall stretch gene expression. Canagliflozin reduced NADPH oxidase activity via AMP kinase (AMPK)/Rac1signalling and improved NOS coupling via increased tetrahydrobiopterin bioavailability ex vivo and in vitro. These were attenuated by knocking down SGLT1 in hCM. Canagliflozin had striking ex vivo transcriptomic effects on myocardial redox signalling, suppressing apoptotic and inflammatory pathways in hCM.
Conclusions
We demonstrate for the first time that canagliflozin suppresses myocardial NADPH oxidase activity and improves NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings reveal a novel mechanism contributing to the beneficial cardiac effects of canagliflozin.
Graphical Abstract
Proposed mechanism of canagliflozin-induced improvement of myocardial redox state. Canagliflozin increases intracellular AMP/ATP ratio through inhibition of SGLT1, which can activate AMPK/NOS signalling and increase NO that suppresses pro-inflammatory signalling. AMPK activation also inhibits activation of Rac1 and membrane translocation of Rac1 and p47phox, which decrease NADPH oxidase activity and superoxide (O2.−) production, attenuates inflammatory and apoptotic pathways and increasing the bioavailability of tetrahydrobiopterin (BH4), a key factor for NOS coupling.
Adenocarcinoma not otherwise specified (NOS) is a malignant salivary gland tumor without the histological characteristics of other salivary gland tumors. It rarely occurs in the small salivary glands ...and development in the molar glands is extremely rare. We report a case of adenocarcinoma NOS occurring in the retromolar pad. The patient was a 75-year-old woman with a protrusive 10 × 15 mm mass in the retromolar region. The lesion was elastic soft and had an irregular surface. Biopsy resulted in a histopathological diagnosis of adenocarcinoma NOS. No regional or distant metastasis was observed in imaging. The tumor was successfully resected under general anesthesia. The postoperative course was uneventful and there has been no recurrence or metastasis seven years after the surgery.
► Structures of intact eNOS±CaM have been derived from cryo-electron micrographs. ► The reductase domains appear to be mobile with respect to the oxygenase domain dimer. ► Densities consistent with ...oxygenase-docked FMN modules are observed in the presence of CaM. ► Additional densities are observed that are proposed to be bound and docked CaM. ► A novel model is suggested in which docking of CaM promotes docking of the FMN modules.
We have derived structures of intact calmodulin (CaM)-free and CaM-bound endothelial nitric oxide synthase (eNOS) by reconstruction from cryo-electron micrographs. The CaM-free reconstruction is well fitted by the oxygenase domain dimer, but the reductase domains are not visible, suggesting they are mobile and thus delocalized. Additional protein is visible in the CaM-bound reconstruction, concentrated in volumes near two basic patches on each oxygenase domain. One of these corresponds with a presumptive docking site for the reductase domain FMN-binding module. The other is proposed to correspond with a docking site for CaM. A model is suggested in which CaM binding and docking position the reductase domains near the oxygenase domains and promote docking of the FMN-binding modules required for electron transfer.
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is cytologically and phenotypically heterogeneous. Retinoic acid–related orphan receptor-γt (RORγt) is a transcription factor that ...regulates the differentiation of naïve CD4+ helper T cells to Th17 cells. In the present study, we immunohistochemically confirmed the expression of RORγt in PTCL-NOS. Pathological and clinical investigations were performed for 170 cases of PTCL-NOS. RORγt-positive cases accounted for 17.6% (30/170) of the total cases, and they showed a significantly higher frequency of CD8 positivity (P = .033), lower counts of white blood cells (P = .030) and neutrophils (P = .039) in the peripheral blood, higher levels of hypergammaglobulinemia (P = .031), a higher frequency of a complete response (P = .009), and a tendency for a lower International Prognostic Index (P = .061) and better overall survival (P = .0806). These results suggest that RORγt-positive PTCL-NOS could be a subpopulation of PTCL-NOS. Further research associated with this genomic abnormality at the transcriptional level is needed to confirm the results of this study.
•We investigated RORγt expression in patients with PTCL-NOS.•RORγt-positive PTCL-NOS showed a tendency for better overall survival.•RORγt-positive PTCL-NOS could be a subpopulation of PTCL-NOS.
Odontogenic tumors (OGTs), which originate from cells of odontogenic apparatus and their remnants, are rare entities. Primary intraosseous carcinoma NOS (PIOC), is one of the OGTs, but it is even ...rarer and has a worse prognosis. The precise characteristics of PIOC, especially in immunohistochemical features and its pathogenesis, remain unclear. We characterized a case of PIOC arising from the left mandible, in which histopathological findings showed a transition from the odontogenic keratocyst to the carcinoma. Remarkably, the tumor lesion of this PIOC prominently exhibits malignant attributes, including invasive growth of carcinoma cell infiltration into the bone tissue, an elevated Ki-67 index, and lower signal for CK13 and higher signal for CK17 compared with the non-tumor region, histopathologically and immunohistopathologically. Further immunohistochemical analyses demonstrated increased expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C) (accompanying expression of β-catenin in the nucleus) and yes-associated protein (YAP) in the tumor lesion. On the other hand, YAP was expressed and the expression of ARL4C was hardly detected in the non-tumor region. In addition, quantitative RT-PCR analysis using RNAs and dot blot analysis using genomic DNA showed the activation of Wnt/β-catenin signaling and epigenetic alterations, such as an increase of 5mC levels and a decrease of 5hmC levels, in the tumor lesion. A DNA microarray and a gene set enrichment analysis demonstrated that various types of intracellular signaling would be activated and several kinds of cellular functions would be altered in the pathogenesis of PIOC. Experiments with the GSK-3 inhibitor revealed that β-catenin pathway increased not only mRNA levels of ankyrin repeat domain1 (ANKRD1) but also protein levels of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) in oral squamous cell carcinoma cell lines. These results suggested that further activation of YAP signaling by Wnt/β-catenin signaling may be associated with the pathogenesis of PIOC deriving from odontogenic keratocyst in which YAP signaling is activated.
Nitric oxide (NO) is a small free radical generated by a family of enzymes, the nitric oxide synthases (NOSs). Following injury to a tendon, NO is induced by all three isoforms of NOS and NOS ...activity is also upregulated in tendinopathy. In animal models when NOS activity is inhibited by competitive inhibitors of NOS, tendon healing is reduced. When additional NO is added, tendon healing is enhanced. In humans, in three randomised clinical trials, we have shown that NO delivered via a transdermal patch enhances the subjective and objective recovery of patients with tennis elbow, Achilles tendinosis and supraspinatus tendinosis.
Nitric oxide (·NO) is a key signaling molecule in different physiological processes of animals and plants. However, little is known about the metabolism of endogenous ·NO and other reactive nitrogen ...species (RNS) in plants under abiotic stress conditions. Using pea plants exposed to six different abiotic stress conditions (high light intensity, low and high temperature, continuous light, continuous dark and mechanical wounding), several key components of the metabolism of RNS including the content of ·NO, S-nitrosothiols (RSNOs) and nitrite plus nitrate, the enzyme activities of l-arginine-dependent nitric oxide synthase (NOS) and S-nitrosogluthathione reductase (GSNOR), and the profile of protein tyrosine nitration (NO2-Tyr) were analyzed in leaves. Low temperature was the stress that produced the highest increase of NOS and GSNOR activities, and this was accompanied by an increase in the content of total ·NO and S-nitrosothiols, and an intensification of the immunoreactivity with an antibody against NO2-Tyr. Mechanical wounding, high temperature and light also had a clear activating effect on the different indicators of RNS metabolism in pea plants. However, the total content of nitrite and nitrate in leaves was not affected by any of these stresses. Considering that protein tyrosine nitration is a potential marker of nitrosative stress, the results obtained suggest that low and high temperature, continuous light and high light intensity are abiotic stress conditions that can induce nitrosative stress in pea plants.
► The FMN-heme IET kinetics in full length and truncated oxygenase/FMN construct iNOS proteins were determined at 283–304K. ► This is the first study of temperature dependence of the NOS IET ...kinetics. ► Eyring equation was used to analyze the temperature dependence data. ► The magnitude of activation entropy for the IET in the oxygenase/FMN construct is only one-fifth of that for the holoenzyme. ► The results indicate that the FMN domain in the holoenzyme needs to sample more conformations before the IET takes place.
The FMN-heme interdomain (intraprotein) electron transfer (IET) kinetics in full length and oxygenase/FMN (oxyFMN) construct of human iNOS were determined by laser flash photolysis over the temperature range from 283 to 304K. An appreciable increase in the rate constant value was observed with an increase in the temperature. Our previous viscosity study indicated that the IET process is conformationally gated, and Eyring equation was thus used to analyze the temperature dependence data. The obtained magnitude of activation entropy for the IET in the oxyFMN construct is only one-fifth of that for the holoenzyme. This indicates that the FMN domain in the holoenzyme needs to sample more conformations before the IET takes place, and that the FMN domain in the oxyFMN construct is better poised for efficient IET.
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