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Summary Nitric oxide (NO) is perfectly suited for the role of a redox signalling molecule. A key route for NO bioactivity occurs via protein S-nitrosation, and involves the addition of a NO moiety to a protein cysteine (Cys) thiol (–SH) to form an S-nitrosothiol (SNO). This process is thought to underpin a myriad of cellular processes in plants that are linked to development, environmental responses and immune function. Here we collate emerging evidence showing that NO bioactivity regulates a growing number of diverse post-translational modifications including SUMOylation, phosphorylation, persulfidation and acetylation. We provide examples of how NO orchestrates these processes to mediate plant adaptation to a variety of cellular cues.

Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concentrations in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and xenobiotics. Recent studies have highlighted the importance of GSH in key signal transduction reactions as a controller of cell differentiation, proliferation, apoptosis, ferroptosis and immune function. Molecular changes in the GSH antioxidant system and disturbances in GSH homeostasis have been implicated in tumor initiation, progression, and treatment response. Hence, GSH has both protective and pathogenic roles. Although in healthy cells it is crucial for the removal and detoxification of carcinogens, elevated GSH levels in tumor cells are associated with tumor progression and increased resistance to chemotherapeutic drugs. Recently, several novel therapies have been developed to target the GSH antioxidant system in tumors as a means for increased response and decreased drug resistance. In this comprehensive review we explore mechanisms of GSH functionalities and different therapeutic approaches that either target GSH directly, indirectly or use GSH-based prodrugs. Consideration is also given to the computational methods used to describe GSH related processes for in silico testing of treatment effects.

Nitric oxide (NO) is a signal molecule regarded as being involved in myriad functions in plants under physiological, pathogenic, and adverse environmental conditions. Hydrogen sulfide (H₂S) has also recently been recognized as a new gasotransmitter with a diverse range of functions similar to those of NO. Depending on their respective concentrations, both these molecules act synergistically or antagonistically as signals or damage promoters in plants. Nevertheless, available evidence shows that the complex biological connections between NO and H₂S involve multiple pathways and depend on the plant organ and species, as well as on experimental conditions. Cysteine-based redox switches are prone to reversible modification; proteomic and biochemical analyses have demonstrated that certain target proteins undergo post-translational modifications such as S-nitrosation, caused by NO, and persulfidation, caused by H₂S, both of which affect functionality. This review provides a comprehensive update on NO and H₂S in physiological processes (seed germination, root development, stomatal movement, leaf senescence, and fruit ripening) and under adverse environmental conditions. Existing data suggest that H₂S acts upstream or downstream of the NO signaling cascade, depending on processes such as stomatal closure or in response to abiotic stress, respectively.

Plant peroxisomes are organelles enclosed by a single membrane whose biochemical composition has the capacity to adapt depending on the plant tissue, developmental stage, as well as internal and external cellular stimuli. Apart from the peroxisomal metabolism of reactive oxygen species (ROS), discovered several decades ago, new molecules with signaling potential, including nitric oxide (NO) and hydrogen sulfide (H S), have been detected in these organelles in recent years. These molecules generate a family of derived molecules, called reactive nitrogen species (RNS) and reactive sulfur species (RSS), whose peroxisomal metabolism is autoregulated through posttranslational modifications (PTMs) such as -nitrosation, nitration and persulfidation. The peroxisomal metabolism of these reactive species, which can be weaponized against pathogens, is susceptible to modification in response to external stimuli. This review aims to provide up-to-date information on crosstalk between these reactive species families and peroxisomes, as well as on their cellular environment in light of the well-recognized signaling properties of H O , NO and H S.

Post-translational modifications (PTMs) mediated by nitric oxide (NO)-derived molecules have become a new area of research, as they can modulate the function of target proteins. Proteomic data have shown that ascorbate peroxidase (APX) is one of the potential targets of PTMs mediated by NO-derived molecules. Using recombinant pea cytosolic APX, the impact of peroxynitrite (ONOO–) and S-nitrosoglutathione (GSNO), which are known to mediate protein nitration and S-nitrosylation processes, respectively, was analysed. While peroxynitrite inhibits APX activity, GSNO enhances its enzymatic activity. Mass spectrometric analysis of the nitrated APX enabled the determination that Tyr5 and Tyr235 were exclusively nitrated to 3-nitrotyrosine by peroxynitrite. Residue Cys32 was identified by the biotin switch method as S-nitrosylated. The location of these residues on the structure of pea APX reveals that Tyr235 is found at the bottom of the pocket where the haem group is enclosed, whereas Cys32 is at the ascorbate binding site. Pea plants grown under saline (150mM NaCl) stress showed an enhancement of both APX activity and S-nitrosylated APX, as well as an increase of H2O2, NO, and S-nitrosothiol (SNO) content that can justify the induction of the APX activity. The results provide new insight into the molecular mechanism of the regulation of APX which can be both inactivated by irreversible nitration and activated by reversible S-nitrosylation.

Protein S-nitrosation (SNO-protein), the nitric oxide-mediated posttranslational modification of cysteine thiols, is an important regulatory mechanism of protein function in both physiological and pathological pathways. A key first step toward elucidating the mechanism by which S-nitrosation modulates a protein’s function is identification of the targeted cysteine residues. Here, we present a strategy for the simultaneous identification of SNO-cysteine sites and their cognate proteins to profile the brain of the CK-p25–inducible mouse model of Alzheimer’s disease-like neurodegeneration. The approach—SNOTRAP (SNO trapping by triaryl phosphine)—is a direct tagging strategy that uses phosphine-based chemical probes, allowing enrichment of SNO-peptides and their identification by liquid chromatography tandem mass spectrometry. SNOTRAP identified 313 endogenous SNO-sites in 251 proteins in the mouse brain, of which 135 SNO-proteins were detected only during neurodegeneration. S-nitrosation in the brain shows regional differences and becomes elevated during early stages of neurodegeneration in the CK-p25 mouse. The SNO-proteome during early neurodegeneration identified increased S-nitrosation of proteins important for synapse function, metabolism, and Alzheimer’s disease pathology. In the latter case, proteins related to amyloid precursor protein processing and secretion are S-nitrosated, correlating with increased amyloid formation. Sequence analysis of SNO-cysteine sites identified potential linear motifs that are altered under pathological conditions. Collectively, SNOTRAP is a direct tagging tool for global elucidation of the SNO-proteome, providing functional insights of endogenous SNO proteins in the brain and its dysregulation during neurodegeneration.

[EN] Plants are sessile organisms that need to complete their life cycle by the integration of different abiotic and biotic environmental signals, tailoring developmental cues and defense concomitantly. Commonly, stress responses are detrimental to plant growth and, despite the fact that intensive efforts have been made to understand both plant development and defense separately, most of the molecular basis of this trade-off remains elusive. To cope with such a diverse range of processes, plants have developed several strategies including the precise balance of key plant growth and stress regulators [i.e. phytohormones, reactive nitrogen species (RNS), and reactive oxygen species (ROS)]. Among RNS, nitric oxide (NO) is a ubiquitous gasotransmitter involved in redox homeostasis that regulates specific checkpoints to control the switch between development and stress, mainly by post-translational protein modifications comprising S-nitrosation of cysteine residues and metals, and nitration of tyrosine residues. In this review, we have sought to compile those known NO molecular targets able to balance the crossroads between plant development and stress, with special emphasis on the metabolism, perception, and signaling of the phytohormones abscisic acid and salicylic acid during abiotic and biotic stress responses.

ObjectiveGastric carcinoma development is triggered by Helicobacter pylori. Chronic H. pylori infection leads to reduced acid secretion, which may allow the growth of a different gastric bacterial community. This change in the microbiome may increase aggression to the gastric mucosa and contribute to malignancy. Our aim was to evaluate the composition of the gastric microbiota in chronic gastritis and in gastric carcinoma.DesignThe gastric microbiota was retrospectively investigated in 54 patients with gastric carcinoma and 81 patients with chronic gastritis by 16S rRNA gene profiling, using next-generation sequencing. Differences in microbial composition of the two patient groups were assessed using linear discriminant analysis effect size. Associations between the most relevant taxa and clinical diagnosis were validated by real-time quantitative PCR. Predictive functional profiling of microbial communities was obtained with PICRUSt.ResultsThe gastric carcinoma microbiota was characterised by reduced microbial diversity, by decreased abundance of Helicobacter and by the enrichment of other bacterial genera, mostly represented by intestinal commensals. The combination of these taxa into a microbial dysbiosis index revealed that dysbiosis has excellent capacity to discriminate between gastritis and gastric carcinoma. Analysis of the functional features of the microbiota was compatible with the presence of a nitrosating microbial community in carcinoma. The major observations were confirmed in validation cohorts from different geographic origins.ConclusionsDetailed analysis of the gastric microbiota revealed for the first time that patients with gastric carcinoma exhibit a dysbiotic microbial community with genotoxic potential, which is distinct from that of patients with chronic gastritis.

Nitrate levels in our water resources have increased in many areas of the world largely due to applications of inorganic fertilizer and animal manure in agricultural areas. The regulatory limit for nitrate in public drinking water supplies was set to protect against infant methemoglobinemia, but other health effects were not considered. Risk of specific cancers and birth defects may be increased when nitrate is ingested under conditions that increase formation of N-nitroso compounds. We previously reviewed epidemiologic studies before 2005 of nitrate intake from drinking water and cancer, adverse reproductive outcomes and other health effects. Since that review, more than 30 epidemiologic studies have evaluated drinking water nitrate and these outcomes. The most common endpoints studied were colorectal cancer, bladder, and breast cancer (three studies each), and thyroid disease (four studies). Considering all studies, the strongest evidence for a relationship between drinking water nitrate ingestion and adverse health outcomes (besides methemoglobinemia) is for colorectal cancer, thyroid disease, and neural tube defects. Many studies observed increased risk with ingestion of water nitrate levels that were below regulatory limits. Future studies of these and other health outcomes should include improved exposure assessment and accurate characterization of individual factors that affect endogenous nitrosation.

Plants are sessile organisms presenting different adaptation mechanisms that allow their survival under adverse situations. Among them, reactive oxygen and nitrogen species (ROS, RNS) and H2S are emerging as components not only of cell development and differentiation but of signaling pathways involved in the response to both biotic and abiotic attacks. The study of the posttranslational modifications (PTMs) of proteins produced by those signaling molecules is revealing a modulation on specific targets that are involved in many metabolic pathways in the different cell compartments. These modifications are able to translate the imbalance of the redox state caused by exposure to the stress situation in a cascade of responses that finally allow the plant to cope with the adverse condition. In this review we give a generalized vision of the production of ROS, RNS, and H2S in plant mitochondria. We focus on how the principal mitochondrial processes mainly the electron transport chain, the tricarboxylic acid cycle and photorespiration are affected by PTMs on cysteine residues that are produced by the previously mentioned signaling molecules in the respiratory organelle. These PTMs include S-oxidation, S-glutathionylation, S-nitrosation, and persulfidation under normal and stress conditions. We pay special attention to the mitochondrial Thioredoxin/Peroxiredoxin system in terms of its oxidation-reduction posttranslational targets and its response to environmental stress.