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Ingested inorganic nitrate (NO3⁻) has multiple effects in the human body including vasodilation, inhibition of platelet aggregation, and improved skeletal muscle function. The functional effects of oral NO3⁻ involve the in vivo reduction of NO3⁻ to nitrite (NO2⁻) and thence to nitric oxide (NO). However, the potential involvement of S-nitrosothiol (RSNO) formation is unclear. We hypothesised that the RSNO concentration ([RSNO]) in red blood cells (RBCs) and plasma is increased by NO3⁻-rich beetroot juice ingestion. In healthy human volunteers, we tested the effect of dietary supplementation with NO3⁻-rich beetroot juice (BR) or NO3⁻-depleted beetroot juice (placebo; PL) on [RSNO], [NO3⁻] and [NO2⁻] in RBCs, whole blood and plasma, as measured by ozone-based chemiluminescence. The median basal [RSNO] in plasma samples (n = 22) was 10 (5–13) nM (interquartile range in brackets). In comparison, the median values for basal [RSNO] in the corresponding RBC preparations (n = 19) and whole blood samples (n = 19) were higher (p, Graphical abstract Image 1, Highlights • Human ingestion of NO3⁻-rich beetroot juice caused increased plasma S-nitrosothiol levels compared with baseline. • Beetroot juice ingestion also caused increased S-nitrosothiol and NO2⁻ levels in red blood cells compared with baseline. • RSNO formation may contribute to the physiological effects of dietary NO3⁻.

Many oral bacteria reduce inorganic nitrate, a natural part of a vegetable-rich diet, into nitrite that acts as a precursor to nitric oxide, a regulator of vascular tone and neurotransmission. Aging is hallmarked by reduced nitric oxide production with associated detriments to cardiovascular and cognitive function. This study applied a systems-level bacterial co-occurrence network analysis across 10-day dietary nitrate and placebo interventions to test the stability of relationships between physiological and cognitive traits and clusters of co-occurring oral bacteria in older people. Relative abundances of Proteobacteria increased, while Bacteroidetes, Firmicutes and Fusobacteria decreased after nitrate supplementation. Two distinct microbiome modules of co-occurring bacteria, that were sensitive to nitrate supplementation, showed stable relationships with cardiovascular (Rothia-Streptococcus) and cognitive (Neisseria-Haemophilus) indices of health across both dietary conditions. A microbiome module (Prevotella-Veillonella) that has been associated with pro-inflammatory metabolism was diminished after nitrate supplementation, including a decrease in relative abundance of pathogenic Clostridium difficile. These nitrate-sensitive oral microbiome modules are proposed as potential pre- and probiotic targets to ameliorate age-induced impairments in cardiovascular and cognitive health.

Graphene has a promising future in applications such as disease diagnosis, cancer therapy, drug/gene delivery, bio-imaging and antibacterial approaches owing to graphene's unique physical, chemical and mechanical properties alongside minimal toxicity to normal cells, and photo-stability. However, these unique features and bioavailability of graphene are fraught with uncertainties and concerns for environmental and occupational exposure. Changes in the physicochemical properties of graphene affect biological responses including reactive oxygen species (ROS) production. Lower production of ROS by currently available theranostic agents, e.g. magnetic nanoparticles, carbon nanotubes, gold nanostructures or polymeric nanoparticles, restricts their clinical application in cancer therapy. Oxidative stress induced by graphene accumulated in living organs is due to acellular factors which may affect physiological interactions between graphene and target tissues and cells. Acellular factors include particle size, shape, surface charge, surface containing functional groups, and light activation. Cellular responses such as mitochondrial respiration, graphene-cell interactions and pH of the medium are also determinants of ROS production. The mechanisms of ROS production by graphene and the role of ROS for cancer treatment, are poorly understood. The aim of this review is to set the theoretical basis for further research in developing graphene-based theranostic platforms.

Imbalances in the oral microbial community have been associated with reduced cardiovascular and metabolic health. A possible mechanism linking the oral microbiota to health is the nitrate (NO3-)-nitrite (NO2-)-nitric oxide (NO) pathway, which relies on oral bacteria to reduce NO3- to NO2-. NO (generated from both NO2- and L-arginine) regulates vascular endothelial function and therefore blood pressure (BP). By sequencing bacterial 16S rRNA genes we examined the relationships between the oral microbiome and physiological indices of NO bioavailability and possible changes in these variables following 10 days of NO3- (12 mmol/d) and placebo supplementation in young (18–22 yrs) and old (70–79 yrs) normotensive humans (n = 18). NO3- supplementation altered the salivary microbiome compared to placebo by increasing the relative abundance of Proteobacteria (+225%) and decreasing the relative abundance of Bacteroidetes (−46%; P, Graphical abstract fx1, Highlights • Dietary nitrate alters the salivary microbiome of healthy young and old adults. • Nitrate supplementation decreases relative abundances of Prevotella and Veillonella. • Nitrate supplementation increases relative abundances of Rothia and Neisseria. • The salivary microbiome modulates nitric oxide bioavailability and blood pressure.

Tissue inflammation results in the production of numerous reactive oxygen, nitrogen and chlorine species, in addition to the products of lipid and sugar oxidation. Some of these products are capable of chemically modifying amino acids. This in turn results in changes to the structure and function of proteins. Increasing evidence demonstrates that such oxidative post-translational modifications result in the generation of neo-epitopes capable of eliciting both innate and adaptive immune responses. In this paper, we focus on how free radicals and related chemical species generated in inflammatory environments modulate the antigenicity of self-proteins, resulting in immune responses which involve the generation of autoantibodies against key autoantigens in autoimmune diseases. As examples, we will focus on Ro-60 and C1q in systemic lupus erythematosus, along with type-II collagen in rheumatoid arthritis. This review also covers some of the emerging literature which demonstrates that neo-epitopes generated by oxidation are conserved, as exemplified by the evolutionarily conserved pathogen-associated molecular patterns (PAMPs). We discuss how these observations relate to the pathogenesis of both human autoimmune diseases and inflammatory disease, such as atherosclerosis. The potential for these neo-epitopes and the immune responses against them to act as biomarkers or therapeutic targets is also discussed., Highlights • Oxidants can generate stable post-translational modifications (PTMs) on proteins. • Oxidative PTMs are recognised in evolutionarily-conserved innate immune responses. • These PTMs can represent neo-epitopes that break tolerance in autoimmune disease. • Antibodies targeting these PTMs in diseases e.g. RA and SLE, can be biomarkers., Graphical abstract

S-Nitroso moieties, such as the S-nitroso group within S-nitrosated albumin, constitute a potential endogenous reservoir of nitric oxide (NO.) in human tissues and other biological systems. Moreover, S-nitroso compounds are under investigation as therapeutic agents in humans. Therefore, it is important to be able to detect S-nitrosothiols (RSNOs) in human extracellular fluids, such as plasma and synovial fluid, as well as other biological samples. This chapter describes a method for the determination of S-nitrosothiols in biofluids. The method is based on electron paramagnetic resonance (EPR) spectrometry, in combination with spin trapping using a ferrous ion complex of the iron chelator N-methyl-d-glucamine dithiocarbamate under alkaline conditions. This iron complex mediates the decomposition of RSNO to NO., as well as spin trapping the generated NO.. The resulting spin adduct has a unique EPR signal that can be quantified.

Publisher Summary This chapter discusses evidence that many antioxidant compounds with anti-inflammatory properties are more likely to be acting through their effects on inflammatory cellular messenger systems than by direct prevention of freeradical-mediated damage to bio–molecules. Concentration is on the role of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) in mediating the activation of the transcription factor, nuclear factor- K B (NF- K B).Interest in the role of free radicals in diseases with an inflammatory component led to research into the role of free radicals; toward the putative role of ROI as damaging agents; on the oxidative modification of bio–molecules. The cyto–toxicity of free radicals and their reaction products were investigated, in relation to endothelial cell function. ROI can activate apoptosis, a programmed form of cell death.ROI appear to activate certain protein kinases involved in cellular signal transduction, and also activate, or suppress, various protein phosphatases.ROI have been implicated in the regulation of mammalian transcription factors and certain “heat shock,” or stress protein where ROI activity plays a critical role in regulating the expression of genes that encode either proteins with potential pro–inflammatory actions or proteins that may act in a protective fashion. The capacity of endogenous intracellular antioxidants or of repair mechanisms for oxidative DNA damage might determine the susceptibility of different cell populations to the induction of specific gene expression, killing, or even mutation. An increased susceptibility to the actions of ROI on target lymphocytes of patients with autoimmune disorders could thus be an important mechanism in the pathogenesis of diseases such as rheumatoid arthritis by inducing excessive inflammatory responses and increased clonal proliferation of auto–reactive lymphocytes via the activation of transcription factors. The chapter also discusses the action of anti-inflammatory drugs in the inhibition of NF- K B, and the cellular source of ROI Involved in NF- K B activation.

Publisher Summary This chapter discusses the mechanisms, antioxidant defenses, and consequences in relation to free-radical production in the inflamed rheumatoid joint, lipid abnormalities in rheumatoid arthritis (RA), the potential contribution of ox-LDL to RA, and the therapeutic aspects of chain-breaking antioxidant interventions in RA. It is a well-established view that the arthritic joint is a site of oxidative stress, where the overproduction of free radicals exceeds inherent antioxidant capacity, causing damage at the molecular, cellular, and tissue levels. A broad range of oxidized biomolecules have been detected in extracellular fluids in patients with RA. These altered biomolecules are markers of free-radical production and some play a crucial role in disease perpetuation. Phagocytosis, the formation of nitric oxide, and cycles of hypoxic reperfusion injury are mechanisms that generate free radicals within the inflamed rheumatoid joint, which are discussed in the chapter. Lipid abnormalities are associated with a wide spectrum of pathological conditions. In particular, recent advances have been made in understanding the role of lipoproteins in coronary heart disease.