Chronic inorganic nitrate supplementation does not improve metabolic health and worsens disease progression in mice with diet-induced obesity.

Inorganic nitrate (NO) has been proposed to be of therapeutic use as a dietary supplement in obesity and related conditions including the metabolic syndrome (MetS), type II diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Administration of NO to endothelial nitric oxide synthase-deficient mice reversed aspects of MetS; however, the impact of NO supplementation in diet-induced obesity is not well understood. Here we investigated the whole body metabolic phenotype and cardiac and hepatic metabolism in mice fed a high-fat, high-sucrose (HFHS) diet for up to 12 mo of age, supplemented with 1 mM NaNO (or NaCl) in their drinking water.

Oxidative stress, redox status and surfactant metabolism in mechanically ventilated patients receiving different approaches to oxygen therapy (MecROX): An observational study protocol for mechanistic evaluation.

Background: MecROX is a mechanistic sub-study of the UK-ROX trial which was designed to evaluate the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care. This is based on the scientific rationale that excess oxygen is harmful. Epithelial cell damage with alveolar surfactant deficiency is characteristic of hyperoxic acute lung injury.

Individualised Exercise Training Enhances Antioxidant Buffering Capacity in Idiopathic Pulmonary Fibrosis.

Exercise training is recommended for patients with idiopathic pulmonary fibrosis (IPF); however, the mechanism(s) underlying its physiological benefits remain unclear. We investigated the effects of an individualised aerobic interval training programme on exercise capacity and redox status in IPF patients. IPF patients were recruited prospectively to an 8-week, twice-weekly cardiopulmonary exercise test (CPET)-derived structured responsive exercise training programme (SRETP).

An Explorative Study into the Aetiology of Developmental Dysplasia of the Hip Using Targeted Urine Metabolomics.

Developmental dysplasia of the hip (DDH) is the most prevalent congenital musculoskeletal disorder, yet its cause remains unknown. Adequate nutrient provision and coordinated electron exchange (redox) processes are critical for foetal growth and tissue development. This novel study sought to explore specific biochemical pathways in skeletal development for potential involvement in the aetiology of DDH.

On the origin of nitrosylated hemoglobin in COVID-19: Endothelial NO capture or redox conversion of nitrite?: Experimental results and a cautionary note on challenges in translational research.

In blood, the majority of endothelial nitric oxide (NO) is scavenged by oxyhemoglobin, forming nitrate while a small part reacts with dissolved oxygen to nitrite; another fraction may bind to deoxyhemoglobin to generate nitrosylhemoglobin (HbNO) and/or react with a free cysteine to form a nitrosothiol. Circulating nitrite concentrations in healthy individuals are 200-700 nM, and can be even lower in patients with endothelial dysfunction. Those levels are similar to HbNO concentrations ([HbNO]) recently reported, whereby EPR-derived erythrocytic [HbNO] was lower in COVID-19 patients compared to uninfected subjects with similar cardiovascular risk load.

Divergent trajectories of cellular bioenergetics, intermediary metabolism and systemic redox status in survivors and non-survivors of critical illness.

Background: Numerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting the efficacy of modern life-support.

Methods: To explore the hypothesis that survival from critical illness relates to changes in cellular bioenergetics, we combined assessment of mitochondrial respiration with metabolomic, lipidomic and redox profiling in skeletal muscle and blood, at multiple timepoints, in 21 critically ill patients and 12 reference patients.

Green tea polyphenolic antioxidants oxidize hydrogen sulfide to thiosulfate and polysulfides: A possible new mechanism underpinning their biological action.

Matcha and green tea catechins such as (-)-epicatechin (EC), (-)-epigallocatechin (EGC) and (-)-epigallocatechin gallate (EGCG) have long been studied for their antioxidant and health-promoting effects. Using specific fluorophores for HS (AzMC) and polysulfides (SSP4) as well as IC-MS and UPLC-MS/MS-based techniques we here show that popular Japanese and Chinese green teas and select catechins all catalytically oxidize hydrogen sulfide (HS) to polysulfides with the potency of EGC > EGCG >> EG. This reaction is accompanied by the formation of sulfite, thiosulfate and sulfate, consumes oxygen and is partially inhibited by the superoxide scavenger, tempol, and superoxide dismutase but not mannitol, trolox, DMPO, or the iron chelator, desferrioxamine.

Sodium thiosulfate improves renal function and oxygenation in L-NNA-induced hypertension in rats.

Sodium thiosulfate, a reversible oxidation product of hydrogen sulfide, has vasodilating and anti-oxidative properties, making it an attractive agent to alleviate damaging effects of hypertension. In experimental settings, inhibition of nitric oxide synthase causes hypertension, renal dysfunction and damage. We hypothesized that thiosulfate would attenuate renal injury and improve renal function, hemodynamics and the efficiency of oxygen utilization for sodium reabsorption in hypertensive renal disease.

Nitrosopersulfide (SSNO) Is a Unique Cysteine Polysulfidating Agent with Reduction-Resistant Bioactivity.

The aim of the present study was to investigate the biochemical properties of nitrosopersulfide (SSNO), a key intermediate of the nitric oxide (NO)/sulfide cross talk. We obtained corroborating evidence that SSNO is indeed a major product of the reaction of S-nitrosothiols with hydrogen sulfide (HS). It was found to be relatively stable (t ∼1 h at room temperature) in aqueous solution of physiological pH, stabilized by the presence of excess sulfide and resistant toward reduction by other thiols.

Sodium Thiosulfate in the Pregnant Dahl Salt-Sensitive Rat, a Model of Preeclampsia.

Aberrant production of hydrogen sulfide (HS) has been linked to preeclampsia. We hypothesized that sodium thiosulfate (STS), a HS donor, reduces hypertension and proteinuria, and diminishes fetal growth restriction in the Dahl salt-sensitive (S) rat, a spontaneous model of superimposed preeclampsia. In addition to a control group (n = 13), two groups received STS via drinking water at a dose of 2 g (n = 9) or 3 g per kg body weight per day (n = 8) from gestational day (GD) 10 to 20.

Manganese Porphyrin-Based SOD Mimetics Produce Polysulfides from Hydrogen Sulfide.

Manganese-centered porphyrins (MnPs), MnTE-2-PyP (MnTE), MnTnHex-2-PyP (MnTnHex), and MnTnBuOE-2-PyP (MnTnBuOE) have received considerable attention because of their ability to serve as superoxide dismutase (SOD) mimetics thereby producing hydrogen peroxide (HO), and oxidants of ascorbate and simple aminothiols or protein thiols. MnTE-2-PyP and MnTnBuOE-2-PyP are now in five Phase II clinical trials warranting further exploration of their rich redox-based biology. Previously, we reported that SOD is also a sulfide oxidase catalyzing the oxidation of hydrogen sulfide (HS) to hydrogen persulfide (HS) and longer-chain polysulfides (HS, = 3-7).

Early Oxidative Stress Response in Patients with Severe Aortic Stenosis Undergoing Transcatheter and Surgical Aortic Valve Replacement: A Transatlantic Study.

Myocardial ischemia/reperfusion-related oxidative stress as a result of cardiopulmonary bypass is thought to contribute to the adverse clinical outcomes following surgical aortic valve replacement (SAVR). Although the acute response following this procedure has been well characterized, much less is known about the nature and extent of oxidative stress induced by the transcatheter aortic valve replacement (TAVR) procedure. We therefore sought to examine and directly compare the oxidative stress response in patients undergoing TAVR and SAVR.

Inorganic nitrate and nitrite supplementation fails to improve skeletal muscle mitochondrial efficiency in mice and humans.

Background: Inorganic nitrate, abundant in leafy green vegetables and beetroot, is thought to have protective health benefits. Adherence to a Mediterranean diet reduces the incidence and severity of coronary artery disease, whereas supplementation with nitrate can improve submaximal exercise performance. Once ingested, oral commensal bacteria may reduce nitrate to nitrite, which may subsequently be reduced to nitric oxide during conditions of hypoxia and in the presence of "nitrite reductases" such as heme- and molybdenum-containing enzymes.

Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides, and oxidation of protein kinase G1α redox signalling.

Aims: Under hypoxic conditions, nitrite (NO2-) can be reduced to nitric oxide (NO) eliciting vasorelaxation. However, nitrite also exerts vasorelaxant effects of potential therapeutic relevance under normal physiological conditions via undetermined mechanisms. We, therefore, sought to investigate the mechanism(s) by which nitrite regulates the vascular system in normoxia and, specifically, whether the biological effects are a result of NO generation (as in hypoxia) or mediated via alternative mechanisms involving classical downstream targets of NO [e.

Blueberries improve biomarkers of cardiometabolic function in participants with metabolic syndrome-results from a 6-month, double-blind, randomized controlled trial.

Background: Anthocyanin-rich blueberry intake is associated with reduced type 2 diabetes and cardiovascular disease (CVD) risk in prospective studies, although long-term randomized controlled trials (RCTs) have not been conducted in at-risk populations.

Objective: In the longest-duration RCT to date, we examined the effect of 6-mo blueberry intake on insulin resistance and cardiometabolic function in metabolic syndrome.

Methods: A double-blind, parallel RCT (n = 115; age 63 ± 7 y; 68% male; body mass index 31.

Chemistry, pharmacology, and cellular uptake mechanisms of thiometallate sulfide donors.

Background And Purpose: A clinical need exists for targeted, safe, and effective sulfide donors. We recently reported that ammonium tetrathiomolybdate (ATTM) belongs to a new class of sulfide-releasing drugs. Here, we investigated the cellular uptake mechanisms of this drug class compared to sodium hydrosulfide (NaHS) and the effects of a thiometallate tungsten congener of ATTM, ammonium tetrathiotungstate (ATTT).

Pushing arterial-venous plasma biomarkers to new heights: A model for personalised redox metabolomics?

The chemical and functional interactions between Reactive Oxygen (ROS), Nitrogen (RNS) and Sulfur (RSS) species allow organisms to detect and respond to metabolic and environmental stressors, such as exercise and altitude exposure. Whether redox markers and constituents of this 'Reactive Species Interactome' (RSI) differ in concentration between arterial and venous blood is unknown. We hypothesised that such measurements may provide useful insight into metabolic/redox regulation at the whole-body level and would be consistent between individuals exposed to identical challenges.

Speciation of reactive sulfur species and their reactions with alkylating agents: do we have any clue about what is present inside the cell?

Unlabelled: BACKGROUND AND PURPOSE: Posttranslational modifications of cysteine residues represent a major aspect of redox biology, and their reliable detection is key in providing mechanistic insights. The metastable character of these modifications and cell lysis-induced artifactual oxidation render current state-of-the-art protocols to rely on alkylation-based stabilization of labile cysteine derivatives before cell/tissue rupture. An untested assumption in these procedures is that for all cysteine derivatives, alkylation rates are faster than their dynamic interchange.

A robust and versatile mass spectrometry platform for comprehensive assessment of the thiol redox metabolome.

Several diseases are associated with perturbations in redox signaling and aberrant hydrogen sulfide metabolism, and numerous analytical methods exist for the measurement of the sulfur-containing species affected. However, uncertainty remains about their concentrations and speciation in cells/biofluids, perhaps in part due to differences in sample processing and detection principles. Using ultrahigh-performance liquid chromatography in combination with electrospray-ionization tandem mass spectrometry we here outline a specific and sensitive platform for the simultaneous measurement of 12 analytes, including total and free thiols, their disulfides and sulfide in complex biological matrices such as blood, saliva and urine.

Inorganic Nitrate in Angina Study: A Randomized Double-Blind Placebo-Controlled Trial.

Background: In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina.

Methods And Results: Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo-nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests.