Search Results (29)

The diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging. The use of metabolomics approaches seems promising in speeding up and simplifying the diagnostic process in HFpEF patients, which can lead to earlier treatment initiation and better improvement of patient condition. The aim of this study was to develop a diagnostic panel of metabolites (metabolomic biomarkers) for the detection and diagnosis of HF with preserved ejection fraction. The study included 76 participants with hypertension, 36 of whom were diagnosed with HFpEF. The blood plasma metabolomic profile, including 72 metabolites, was detected using high-performance liquid chromatography combined with mass spectrometry. There were 18 statistically significant differences in concentrations of metabolites and 3 differences in their ratios between HFpEF and hypertension groups. The prognostic model for detecting the possibility of HFpEF included seven metabolites and two ratios: hexadecenoylcarnitine, arginine, trimethylamine-N-oxide, asymmetric dimethylarginine (ADMA), arginine/ADMA ratio, kynurenine, kynurenine/tryptophan, neopterin, and anthranilic acid. The area under the ROC curve was 0.981 ± 0.017. The resulting model was statistically significant (p < 0.001). The metabolomic panel could be considered as an addition to the present HFpEF laboratory diagnostic criteria for blood plasma analysis in clinical practice. Full article

The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage—L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration. Full article

There is an increasing interest in biomarkers of nitric oxide dysregulation and oxidative stress to guide management and identify new therapeutic targets in patients with chronic obstructive pulmonary disease (COPD). We conducted a systematic review and meta-analysis of the association between circulating metabolites within the arginine (arginine, citrulline, ornithine, asymmetric, ADMA, and symmetric, SDMA dimethylarginine), transsulfuration (methionine, homocysteine, and cysteine) and folic acid (folic acid, vitamin B₆, and vitamin B₁₂) metabolic pathways and COPD. We searched electronic databases from inception to 30 June 2023 and assessed the risk of bias and the certainty of evidence. In 21 eligible studies, compared to healthy controls, patients with stable COPD had significantly lower methionine (standardized mean difference, SMD = −0.50, 95% CI −0.95 to −0.05, p = 0.029) and folic acid (SMD = −0.37, 95% CI −0.65 to −0.09, p = 0.009), and higher homocysteine (SMD = 0.78, 95% CI 0.48 to 1.07, p < 0.001) and cysteine concentrations (SMD = 0.34, 95% CI 0.02 to 0.66, p = 0.038). Additionally, COPD was associated with significantly higher ADMA (SMD = 1.27, 95% CI 0.08 to 2.46, p = 0.037), SDMA (SMD = 3.94, 95% CI 0.79 to 7.08, p = 0.014), and ornithine concentrations (SMD = 0.67, 95% CI 0.13 to 1.22, p = 0.015). In subgroup analysis, the SMD of homocysteine was significantly associated with the biological matrix assessed and the forced expiratory volume in the first second to forced vital capacity ratio, but not with age, study location, or analytical method used. Our study suggests that the presence of significant alterations in metabolites within the arginine, transsulfuration, and folic acid pathways can be useful for assessing nitric oxide dysregulation and oxidative stress and identifying novel treatment targets in COPD. (PROSPERO registration number: CRD42023448036.) Full article

Changes in serum concentration of methylarginines and amino acids after exercise are well documented, whereas the effects of exercise applied together with fasting are still debated and not thoroughly studied. Thus, we hypothesised that alterations in methylarginines such as ADMA, SDMA and L-NMMA might be responsible for decreased exercise performance after 8 days of fasting. Additionally, we propose that conditions in which the human body is exposed to prolonged fasting for more than a week elicit a distinctly different response to exercise than after overnight fasting. A group of 10 healthy men with previous fasting experience participated in the study. The exercise test was performed until exhaustion with a gradually increasing intensity before and after the 8-day fast. Blood samples were collected before and immediately after exercise. ADMA, SDMA, L-NMMA, dimethylamine and amino acids were analysed in serum samples by ID-LC-MS/MS. SDMA, L-NMMA and dimethylamine significantly decreased after 8 days of fasting, whereas ADMA did not change. BCAA, Phe, alanine and some other amino acids increased after fasting. Exercise-induced changes in amino acids were distinct after an 8-day fast compared to overnight fasting. A decrease in physical performance accompanied all of these alterations. In conclusion, our data indicate that neither methyl-arginine changes nor the Trp/BCAA ratio can explain exercise-induced fatigue after fasting. However, the observed decrease in hArg concentration suggests the limited synthesis of creatine, possibly contributing to reduced physical performance. Full article

Postmenopausal women (PMW) may experience endothelial dysfunction associated with arginine (ARG) deficiency relative to asymmetric dimethylarginine (ADMA) caused by oxidative stress. Endothelial dysfunction contributes to increased blood pressure (BP) responsiveness to sympathoexcitation induced by the cold pressor test (CPT). We investigated the effects of citrulline alone (CIT) and combined with the antioxidant glutathione (CIT+GSH) on vascular function. Forty-four healthy PMW were randomized to CIT (6 g), CIT+GSH (2 g + 200 mg: Setria^®) or placebo (PL) for 4 weeks. Brachial artery flow-mediated dilation (FMD), aortic stiffness (pulse wave velocity, PWV), brachial and aortic BP reactivity to CPT, and serum fasting blood glucose (FBG), ARG, and ARG/ADMA ratio were measured. Baseline FBG was higher in CIT+GSH vs. PL. FMD increased after CIT+GSH vs. PL (p < 0.05). CIT and CIT+GSH increased ARG/ADMA (p < 0.05), but did not affect aortic PWV. CIT+GSH attenuated the brachial and aortic systolic BP and mean arterial pressure (MAP) responses to CPT vs. PL and CIT (p < 0.05). The improvements in FMD were related to baseline FMD (r = −0.39, p < 0.05) and aortic MAP response to CPT (r = −0.33, p < 0.05). This study showed that CIT+GSH improved FMD and attenuated systolic BP and MAP reactivity in PMW. Although CIT increased ARG/ADMA, it did not improve FMD in healthy PMW. Full article

Endothelial dysfunction result from inflammation and excessive production of reactive oxygen species as part of the surgical stress response. Remote ischemic preconditioning (RIPC) potentially exerts anti-oxidative and anti-inflammatory properties, which might stabilise the endothelial function after non-cardiac surgery. This was a single centre randomised clinical trial including 60 patients undergoing sub-acute laparoscopic cholecystectomy due to acute cholecystitis. Patients were randomised to RIPC or control. The RIPC procedure consisted of four cycles of five minutes of ischaemia and reperfusion of one upper extremity. Endothelial function was assessed as the reactive hyperaemia index (RHI) and circulating biomarkers of nitric oxide (NO) bioavailability (L-arginine, asymmetric dimethylarginine (ADMA), L-arginine/ADMA ratio, tetra- and dihydrobiopterin (BH₄ and BH₂), and total plasma biopterin) preoperative, 2–4 h after surgery and 24 h after surgery. RHI did not differ between the groups (p = 0.07). Neither did levels of circulating biomarkers of NO bioavailability change in response to RIPC. L-arginine and L-arginine/ADMA ratio was suppressed preoperatively and increased 24 h after surgery (p < 0.001). The BH₄/BH₂-ratio had a high preoperative level, decreased 2–4 h after surgery and remained low 24 h after surgery (p = 0.01). RIPC did not influence endothelial function or markers of NO bioavailability until 24 h after sub-acute laparoscopic cholecystectomy. In response to surgery, markers of NO bioavailability increased, and oxidative stress decreased. These findings support that a minimally invasive removal of the inflamed gallbladder countereffects reduced markers of NO bioavailability and increased oxidative stress caused by acute cholecystitis. Full article

It is not fully understood how supplementation with omega-3 fatty acids affects the metabolism of amino acids required for the bioavailability/synthesis of NO, i.e., L-arginine (L-arg), asymmetric dimethylarginine (ADMA), their metabolites, and the L-arg/ADMA ratio and their impact on running economy (RE) in runners. Thus, 26 male amateur endurance runners completed a twelve-week study in which they were divided into two supplemented groups: the OMEGA group (n = 14; 2234 mg and 916 mg of eicosapentaenoic and docosahexaenoic acid daily) or the MCT group (n = 12; 4000 mg of medium-chain triglycerides daily). At the same time, all participants followed an endurance training program. Before and after the 12-week intervention, blood was collected from participants at two time points (at rest and immediately post-exercise) to determine EPA and DHA in red blood cells (RBCs) and plasma levels of L-arg, ADMA, and their metabolites. RBC EPA and DHA significantly increased in the OMEGA group (p < 0.001), which was related to the resting increase in L-arg (p = 0.001) and in the L-arg/ADMA ratio (p = 0.005) with no changes in the MCT group. No differences were found in post-exercise amino acid levels. A total of 12 weeks of omega-3 fatty acid supplementation at a dose of 2234 mg of EPA and 916 mg of DHA daily increased levels of L-arg and the L-arg/ADMA ratio, which indirectly indicates increased bioavailability/NO synthesis. However, these changes were not associated with improved RE in male amateur endurance runners. Full article

Previously, a relation between therapy with antiepileptic drugs (AEDs) and the levels of biochemical parameters was observed in adult patients suffering from epilepsy. Among these biochemical factors, arginine derivatives are often analyzed, i.e., asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and homoarginine (hArg) as they may be linked with increased risk for cardiovascular disease (CVD). Since the levels of arginine derivatives may increase during therapy, and the treatment of epilepsy often lasts many years, patients may experience CVD faster. The aim of the present study was to analyze the levels of arginine derivatives in children with epilepsy who were treated with multiple AEDs to answer the question whether pediatric patients may be at increased risk of CVD in the future. We prospectively analyzed 21 children suffering from epilepsy who took ≥2 AEDs for at least 6 months and 22 children without epilepsy (reference group). The levels of the arginine derivatives, e.g., ADMA, SDMA, and hArg, were determined in the blood serum using the HPLC method. No differences in both the mean levels of ADMA and SDMA, as well as in the mean values of the arginine derivative ratios, were observed between the groups. The tendency toward a lower level of hArg was found in epileptic patients more than in the reference group (p = 0.091). Epileptic children receiving three or more AEDs had significantly lower concentrations of hArg and values of the hArg/ADMA ratio than the reference group (p = 0.023 and p = 0.006, respectively). In turn, the mean hArg/ADMA ratio was lower in children receiving three or more AEDs compared to children receiving two AEDs (p = 0.002). There was also a positive correlation between the hArg and ADMA concentrations in children with epilepsy taking two AEDs; the higher the level of hArg, the greater the level of ADMA on average (r = 0.650, p = 0.022). Taking three or more AEDs by epileptic children resulted in lower levels of both hArg and the value of the hArg/ADMA ratio. Full article

Despite improvement in the management of modifiable cardiovascular risk factors, ischemic stroke remains the leading cause of morbidity and mortality in the adult population. The aim of this study was to analyze the time-dependent dynamic differences in expression of the nitric oxide (NO) metabolic pathway in the platelet and plasma compartment between subjects with and without ischemic stroke. Additionally, the interplay between these parameters and platelet aggregation was investigated. A total of 418 patients in acute phase of non-cardioembolic stroke were investigated. Following the inclusion and exclusion criteria, finally 40 subjects with stroke and 39 demographically matched healthy participants were enrolled. Neurological physical examination, followed by assessment of the platelet and plasma levels of the nitric oxide synthase (NOS) inhibitors, including asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), as well as NOS substrate-L-Arginine were performed dynamically three times within the first 24-h, then on the 3rd and 7th day after the stroke onset, which was compared with the healthy control. The platelet L-Arginine concentration was significantly higher on the 1st and 3rd day of stroke, while the plasma levels were significantly lower on exact days in comparison to the control. The competitive NOS-inhibitors in platelets were stably elevated in stroke subjects, whereas no significant differences in plasma compartment were noted. The arachidonic-acid-induced platelet aggregation was negatively associated with the platelet NOS substrate bioavailability, as assessed by the $\frac{L-Arginine }{ADMA}$-ratio on the 3rd and 7th day. Subjects with non-cardioembolic ischemic stroke are characterized by elevated platelet levels of NOS inhibitors. Management of stroke results in increasing the platelet L-Arginine concentration and subsequent NO bioavailability in the platelet compartment. Full article

(1) Background: L-arginine (L-ARG) and its metabolites are involved in some aspects of asthma pathogenesis (airway inflammation, oxidative stress, bronchial responsiveness, collagen deposition). Published data indicate that lungs are a critical organ for the regulation of L-ARG metabolism and that alterations in L-ARG metabolism may be significant for asthma. The aim of this study was to assess the levels of L-ARG and its metabolites in pediatric patients with asthma in serum and exhaled breath condensate (EBC) by mass spectrometric analysis and compare them with non-asthmatic children. (2) Methods: Sixty-five children (37 pediatric patients with bronchial asthma and 28 healthy control subjects) aged 6–17 participated in the study. All participants underwent a clinical visit, lung tests, allergy tests with common aeroallergens, and serum and EBC collection. The levels of biomarkers were determined in both serum and EBC. Analytical chromatography was conducted using an Acquity UPLC system equipped with a cooled autosampler and an Acquity HSS T3 column. Mass spectrometric analysis was conducted using the Xevo G2 QTOF MS with electrospray ionization (ESI) in positive ion mode. (3) Results: Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels in serum and EBC did not differ significantly in asthmatic children and healthy control subjects. We found no correlation between forced expiratory volume in one second (FEV1) and L-ARG and its metabolites, as well as between interleukin-4 (IL-4) serum level and L-ARG and its metabolites. Concentrations of ADMA, SDMA, citrulline (CIT), and ornithine (ORN) were higher in serum than EBC in asthmatics and non-asthmatics. By contrast, concentrations of dimethylarginine (DMA) were higher in EBC than serum. ADMA/L-ARG, SDMA/L-ARG, and DMA/L-ARG ratios were significantly higher in EBC than in serum in asthmatics and in non-asthmatics. (4) Conclusions: Serum and EBC concentrations of L-ARG and its metabolites were not an indicator of pediatric bronchial asthma in our study. Full article

Background: Recent metabolomics studies have found circulatory metabolism alterations in patients with asthma, indicating that altered metabolites played a significant role in asthma. However, the regulatory mechanisms in asthma, especially in young chronic persistent asthma remain underexplored. Methods: In this study, a prospective cohort of 162 patients diagnosed of asthma admitted to the First Affiliated Hospital of Xi’an Jiaotong University from January 2018 to December 2019 was used to perform a nested case-control study. Among them, we included 30 patients with chronic persistent asthma between 20 to 35 years old; 30 health control with evenly distributed age and sex were then recruited. Nontargeted metabolomics was applied to identify serum metabolic profiles and altered metabolic pathways. Results: In vitro, human bronchial epithelial cells (HBECs) line BEAS-2B with the addition of L-citrulline and/or asymmetric dimethylarginine (ADMA) model was utilized and the concentrations of nitric oxide (NO) metabolites were tested to evaluate the therapeutic potential of L-citrulline. The young patients with chronic persistent asthma displayed dysregulated serum metabolic profiles, especially enriched in arginine metabolism. The ratio of L-citrulline to ornithine is associated with blood eosinophil count. In vitro, adding L-citrulline could reverse ADMA-mediated reduction of NOx at lower L-arginine concentration (25 μM), but was ineffective in the higher L-arginine concentration (100 μM) media. Conclusions: The arginine metabolism balance is of vital importance during the pathogenesis and progression of chronic asthma. L-citrulline could be a powerful approach to restore airway NO production, potentially exhibiting therapeutic benefits among young patients with chronic asthma. Full article

Endothelial vasodilatory function is dependent on the NO synthesis from L-arginine by endothelial NO-synthetase (eNOS). eNOS can be inhibited by asymmetric dimethylarginine (ADMA) by competitive inhibition on the binding site, and symmetric dimethylarginine (SDMA) can reduce the L-arginine availability intracellularly through competing for transport over the cellular membrane. To study the NO synthesis after prolonged exercise, we assessed circulatory L-arginine, the L-arginine/ADMA ratio, and SDMA before, after, and on the day after the Norseman Xtreme triathlon, an Ironman distance triathlon. We found significantly reduced levels of L-arginine and the L-arginine/ADMA ratio and increased levels of SDMA after the race (all p < 0.05). L-arginine rose toward baseline levels the day after the race, but ADMA increased beyond baseline levels, and SDMA remained above baseline the day after the race. The reduced levels of L-arginine and the L-arginine/ADMA ratio, and increased SDMA, after the race indicate a state of reduced capability of NO production. Increased levels of ADMA and SDMA, and reduced L-arginine/ADMA ratio, as seen the day after the race, are known risk markers of atherosclerosis and warrant further studies. Full article

(1) Background: Type-2-diabetes-mellitus (DM) is one the most important cardiovascular-risk-factors. Among many molecules regulating vascular tone, nitric oxide appears to be the most pivotal. Although micro- and macrovascular-abnormalities are extensively studied, the alterations in the nitric-oxide-metabolic-pathway require further investigations. Additionally, the role of erythrocytes in the vascular tone regulation has not been extensively explored. The aim of this study was to evaluate the endothelial-function and the nitric-oxide-metabolic-pathway in erythrocytes and plasma of diabetic individuals. (2) Methods: A total of 80 subjects were enrolled in this cross-sectional study, including 35 patients with DM and 45 healthy individuals. The endothelial-function was evaluated in response to different stimuli. (3) Results: In the DM group, decreased Arginine and citrulline concentrations in the plasma compartment with reduced Arginine/ADMA and ADMA/DMA-ratios were observed. Preserved nitric-oxide-metabolism in erythrocytes with reduced citrulline level and significantly higher NO-bioavailability were noted. Significant endothelial dysfunction in DM individuals was proved in response to the heat-stimulus. (4) Conclusions: DM patients at an early stage of disease show significant differences in the nitric-oxide-metabolic-pathway, which are more pronounced in the plasma compartment. Erythrocytes constitute a buffer with a higher nitric-oxide-bioavailability, less affected by the DM-related deviations. Patients at an early-stage of DM reveal endothelial-dysfunction, which could be diagnosed earlier using the laser-Doppler-flowmetry. Full article

The gut microbiota plays a critical role in kidney disease and hypertension; however, whether maternal chronic kidney disease (CKD)-induced offspring hypertension is associated with alterations of the microbiota and microbial metabolites remains elusive. Using rat as an animal model, we conducted a maternal adenine-induced CKD model to examine whether adult male offspring develop hypertension and kidney disease. As resveratrol has antioxidant and prebiotic properties, we also aimed to elucidate whether its use in pregnancy and lactation can benefit hypertension programmed by maternal CKD via mediation of the gut microbiota and oxidative stress. Female Sprague-Dawley rats received regular chow (C) or chow supplemented with 0.5% adenine (CKD) from 3 weeks before pregnancy until lactation. One group of the adenine-induced CKD pregnant rats received resveratrol (R; 50 mg/L) in drinking water during gestation and lactation. Male offspring were divided into three groups: C, CKD, and CKD+R. The microbial metabolites analyzed were short chain fatty acids (SCFAs) in feces and trimethylamine (TMA)/trimethylamine N-oxide (TMAO) in plasma. We found perinatal resveratrol therapy protected against maternal CKD-induced hypertension in adult male offspring. The overall microbial compositions and diversity of bacterial community in the three groups were different. Resveratrol therapy increased α-diversity, decreased the Firmicutes to Bacteroidetes ratio, and increased the abundance of the genera Lactobacillus and Bifidobacterium. Perinatal resveratrol therapy increased plasma TMA levels but decreased the plasma TMAO-to-TMA ratio. Although resveratrol had negligible effect on fecal concentrations of SCFAs, it increased G-protein coupled receptor-41 (GPR41) protein levels in the offspring’s kidneys. Additionally, resveratrol therapy increased plasma levels of L-arginine and the L-arginine-to-ADMA ratio (AAR), and decreased oxidative stress. Overall, the protective effects of resveratrol against programmed hypertension are related to gut microbiome remodeling, including an increased abundance of beneficial microbes, mediation of the TMA-TMAO pathway, and alterations of SCFA receptors. Our results highlighted that targeting the microbiome and their metabolites might be potential therapeutic strategies to prevent maternal CKD-induced adverse pregnancy and offspring outcomes. Full article

(1) Background: In patients with shock, the L-arginine nitric oxide pathway is activated, causing an elevation of nitric oxide, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels. Whether these metabolites provide prognostic information in patients after out-of-hospital cardiac arrest (OHCA) remains unclear. (2) Methods: We prospectively included OHCA patients, recorded clinical parameters and measured plasma ADMA, SDMA and Arginine levels by liquid chromatography tandem mass spectrometry (LC-MS). The primary endpoint was 90-day mortality. (3) Results: Of 263 patients, 130 (49.4%) died within 90 days after OHCA. Compared to survivors, non-survivors had significantly higher levels of ADMA and lower Arginine and Arginine/ADMA ratios in univariable regression analyses. Arginine levels and Arginine/ADMA ratio were significantly associated with 90-day mortality (OR 0.51 (95%CI 0.34 to 0.76), p < 0.01 and OR 0.40 (95%CI 0.26 to 0.61), p < 0.001, respectively). These associations remained significant in several multivariable models. Arginine/ADMA ratio had the highest predictive value with an area under the curve (AUC) of 0.67 for 90-day mortality. Results for secondary outcomes were similar with significant associations with in-hospital mortality and neurological outcome. (4) Conclusion: Arginine and Arginine/ADMA ratio were independently associated with 90-day mortality and other adverse outcomes in patients after OHCA. Whether therapeutic modification of the L-arginine-nitric oxide pathway has the potential to improve outcome should be evaluated. Full article