Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Pharmacologic approaches of inhibiting GSNOR activity have r

    2022-08-11

    Pharmacologic approaches of inhibiting GSNOR activity have reached the point of clinical development with the recent announcement of the first cystic fibrosis patients treated with the first-in-class GSNOR inhibitor, N6022 (N30 Pharmaceuticals). Clinical development is ongoing for other indications including asthma. Our results suggest that GSNOR deficiency can increase sensitivity to K. pneumoniae, a common cause of nosocomial infection. Thus, clinical trials using S-nitrosylation agents or GSNOR inhibitors should closely monitor patients for signs of infection.
    Disclosure of potential conflicts of interest
    Acknowledgment This work was supported by the National Institutes of Health (R01CA55578 and R01CA122359 to L.L.).
    Introduction Plants are overwhelmingly resistant to the majority of potential pathogens due to the presence of a sophisticated series of integrated defence mechanisms [1]. Potential pathogens first encounter a battery of pattern recognition receptors (PRRs) present at the plant's cell surface, which recognise conserved structural features shared between large groups of pathogens termed microbial associated molecular patterns (MAMPS) [2]. Pathogen recognition by one or more PRRs activates, although relatively weakly, a phalanx of defensive mechanisms that convey basal resistance. In addition, a collection of predominantly intracellular resistance (R) gene products have evolved to recognize pathogen effector proteins delivered inside host cells, some of which attempt to suppress basal resistance [3]. This so called effector triggered immunity initiates the hypersensitive response (HR) a conspicuous feature of which is the programmed execution of plant 234 2 australia at the site of attempted infection [4]. Changes in intracellular redox status are a common feature of eukaryotic immune responses [5], [6]. In this context, production of reactive nitrogen intermediates (RNIs) in parallel with an oxidative burst is a conspicuous attribute of the HR and associated cell death [7]. Growing evidence suggests that nitric oxide (NO) plays a key role in both defence signal transduction and the orchestration of hypersensitive cell death [8], [9]. In this context, NO has been linked with the accumulation of the immune activators SA, JA and ethylene [10], [11], the transcriptional activation of defence genes [12] and MAMP triggered ABA mediated stomatal closure [13]. Despite these oxidative and associated reductive waves being central to the control of plant immune function the molecular details of their management remains largely opaque.
    NO synthesis in the plant immune response Isoforms of nitric oxide synthase (NOS) catalyze the NADP-dependent oxidation of arginine (Arg) to NO in mammals [14]. However, a similar enzyme has not been identified in higher plants despite the completion of a plethora of plant genome sequences. Nevertheless, a NOS ortholog has recently been identified in Ostreococcus tauri, a single-celled green alga [15]. This enzyme exhibited NOS activity in vitro and possessed similar properties to animal NOSs in terms of the K for arginine and the rate of NADPH oxidation. Further, this work suggested a mechanistic link between NOS activity and microalgal physiology. Classical NOS enzymes therefore appear to be present within the green plant lineage but may have been lost during the evolution of higher plants. Despite these findings, the production of NO from Arg by higher plant cell extracts has been reported and this activity was reduced by well established animal NOS inhibitors [16]. These data therefore infer the existence of a higher plant NOS, which presumably must be structurally distinct from the mammalian protein. The emerging evidence suggests that plants may posses an alternative enzymatic source for NO biosynthesis. Located in the cytosol, nitrate reductase (NR) is encoded by two genes in Arabidopsis, designated NIA1 and NIA2, with NIA2 encoding the enzyme responsible for the majority of NR activity [17]. NR has been shown to reduce nitrate to nitrite utilizing NAD(P)H in vitro[18]. However, the efficiency of this reaction is low and requires low oxygen tensions and high nitrite levels [18]. Nevertheless, a number of independent reports have implicated a role for NR in the generation of NO during plant immune function [19], [20]. However, the source(s) of NO biosynthesis during the plant defence response remains a controversial issue [21].