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1.
Spatiotemporal analysis identifies ABF2 and ABF3 as key hubs of endodermal response to nitrate.
Contreras-López, O, Vidal, EA, Riveras, E, Alvarez, JM, Moyano, TC, Sparks, EE, Medina, J, Pasquino, A, Benfey, PN, Coruzzi, GM, et al
Proceedings of the National Academy of Sciences of the United States of America. 2022;(4)
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Abstract
Nitrate is a nutrient and a potent signal that impacts global gene expression in plants. However, the regulatory factors controlling temporal and cell type-specific nitrate responses remain largely unknown. We assayed nitrate-responsive transcriptome changes in five major root cell types of the Arabidopsis thaliana root as a function of time. We found that gene-expression response to nitrate is dynamic and highly localized and predicted cell type-specific transcription factor (TF)-target interactions. Among cell types, the endodermis stands out as having the largest and most connected nitrate-regulatory gene network. ABF2 and ABF3 are major hubs for transcriptional responses in the endodermis cell layer. We experimentally validated TF-target interactions for ABF2 and ABF3 by chromatin immunoprecipitation followed by sequencing and a cell-based system to detect TF regulation genome-wide. Validated targets of ABF2 and ABF3 account for more than 50% of the nitrate-responsive transcriptome in the endodermis. Moreover, ABF2 and ABF3 are involved in nitrate-induced lateral root growth. Our approach offers an unprecedented spatiotemporal resolution of the root response to nitrate and identifies important components of cell-specific gene regulatory networks.
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Moving beyond inclusion: Methodological considerations for the menstrual cycle and menopause in research evaluating effects of dietary nitrate on vascular function.
Baranauskas, MN, Freemas, JA, Tan, R, Carter, SJ
Nitric oxide : biology and chemistry. 2022;:39-48
Abstract
Recent reports have acknowledged the underrepresentation of women in the field of dietary nitrate (NO3-) research. Undoubtedly, greater participation from women is warranted to clarify potential sex differences in the responses to dietary NO3- interventions. However, careful consideration for the effects of sex hormones - principally 17β-estradiol - on endogenous nitric oxide (NO) synthesis and dietary NO3- reductase capacity is necessary for improved interpretation and reproducibility of such investigations. From available literature, we present a narrative review describing how hormonal variations across the menstrual cycle, as well as with menopause, may impact NO biosynthesis catalyzed by NO synthase enzymes and NO3- reduction via the enterosalivary pathway. In doing so, we address methodological considerations related to the menstrual cycle and hormonal contraceptive use relevant for the inclusion of premenopausal women along with factors to consider when testing postmenopausal women. Adherence to such methodological practices may explicate the utility of dietary NO3- supplementation as a means to improve vascular function among women across the lifespan.
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Efficacy and safety of nitrate supplementation on exercise tolerance in chronic obstructive pulmonary disease: A systematic review and meta-analysis.
Yang, H, He, S, Chen, F, Liang, L, Pan, J
Medicine. 2022;(2):e28578
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Abstract
BACKGROUND Exercise intolerance was prevalent in people with chronic obstructive pulmonary disease (COPD) and had a detrimental effect on the quality of life. We aimed to evaluate the efficacy and safety of nitrate supplementation in exercise tolerance of people with COPD. METHODS We searched medical databases including Cochrane Library, EMBASE, and PubMed from inception to October 2020 for randomized control trials in treating COPD with nitrate supplementation. RESULTS Nine trials were identified. Compared with placebo, nitrate supplementation has no significant effect on the following variables: exercise endurance time (standard mean difference [SMD]: 0.06; 95% confidence interval [CI]: -0.39 to 0.52; P = .79), exercise capacity (SMD: 0.30; 95% CI: -0.21 to 0.80; P = .25), oxygen consumption (SMD: -0.04; 95% CI: -0.33 to 0.25; P = .80), resting systolic blood pressure (MD: -2.84; 95% CI: -8.46 to 2.78; P = .32), systolic blood pressure after exercise (MD: -4.66; 95% CI -15.66 to 6.34; P = .41), resting diastolic blood pressure (MD: 0.89; 95% CI: -4.41 to 6.19; P = .74), diastolic blood pressure after exercise (MD: -0.21; 95% CI: -5.51 to 5.10; P = .94), heart rate (MD: -2.52; 95% CI: -7.76 to 2.73; P = .35), and arterial oxygen saturation (MD: -0.44; 95% CI: -2.38 to 1.49; P = .65). No severe adverse effects from nitrate supplementation were reported in the included trails. CONCLUSION Current evidence suggests that nitrate supplementation may be safe but ineffective for improving exercise tolerance in people with COPD.
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The Efficacy of Nitrates for Bone Health: A Systematic Review and Meta-Analysis of Observational and Randomized Controlled Studies.
Liu, W, Meng, Z, Wang, G
Frontiers in endocrinology. 2022;:833932
Abstract
BACKGROUND Although some studies have found that nitrates were beneficial for bone health, the findings are inconsistent. To assess the efficacy of nitrates for bone health, we conducted a meta-analysis. METHODS PubMed, EMBASE databases, Cochrane Library for relevant articles published before December 2021 were searched. All observational and randomized controlled studies that reporting bone mineral density (BMD), fractures with nitrates use were included. A meta-analysis was performed to calculate risk ratios (RRs) for fractures, change differences for bone mineral density. RESULTS Four cohort studies and two case-control studies examining the association between nitrates use and fractures were identified. The nitrates use was not associated with any fracture risk (RR = 0.97; 95% CI, 0.94-1.01; I2 = 31.5%) and hip fracture (RR = 0.88; 95% CI, 0.76-1.02; I2 = 74.5%). Subgroup analyses revealed no differences in fracture risk, whereas two cohort studies revealed a reduced risk of hip fracture (RR = 0.71, 95% CI, 0.58-0.86, I2 = 0.0%). There were no statistically significant differences in BMD percent changes at lumbar spine (WMD = -0.07, 95% CI,-0.78-0.65; I2 = 0.0%), total hip (WMD = -0.42, 95% CI,-0.88-0.04; I2 = 0.0%), femoral neck (WMD = -0.38, 95% CI,-1.02-0.25; I2 = 0.0%), or total body (WMD = -0.17, 95% CI,-0.51-0.17; I2 = 0.0%) in two randomized controlled trials (RCTs) compared with a placebo. Another two RCTs compared nitrates with alendronate. Nitrates were comparable to alendronate in increasing bone mineral density at lumbar spine (WMD = 0.00, 95% CI,-0.01-0.02; I2 = 0.0%). Besides, the most common adverse effect was headache, contributing to low adherence to therapy. CONCLUSION Our meta-analysis showed no association between nitrates use and fractures in observational studies. The results of RCTs on the usage of nitrates and their effects on BMD were inconsistent. High-quality, long-term studies are needed to clarify the efficacy of nitrates for bone health.
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Feasibility and acceptability of a nutritional intervention testing the effects of nitrate-rich beetroot juice and folic acid on blood pressure in Tanzanian adults with elevated blood pressure.
Kandhari, N, Prabhakar, M, Shannon, O, Fostier, W, Koehl, C, Rogathi, J, Temu, G, Stephan, BCM, Gray, WK, Haule, I, et al
International journal of food sciences and nutrition. 2021;(2):195-207
Abstract
Sub-Saharan African countries are experiencing an alarming increase in hypertension prevalence. This study evaluated the feasibility and acceptability of nitrate-rich beetroot and folate supplementation, alone or combined, for the reduction of blood pressure (BP) in Tanzanian adults with elevated BP. This was a three-arm double-blind, placebo-controlled, parallel randomised clinical trial. Forty-eight participants were randomised to one of three groups to follow a specific 60-day intervention which included a: (1) combined intervention (beetroot juice + folate), (2) single intervention (beetroot juice + placebo), and (3) control group (nitrate-depleted beetroot juice + placebo). Forty-seven participants (age: 50-70 years) completed the study. The acceptability of the interventions was high. Self-reported compliance to the interventions was more than 90% which was confirmed by the significant increase in nitrate and folate concentrations in plasma and saliva samples in the treatment arms. This study provides important information for the design of high-nitrate interventions to reduce BP in Sub-Saharan African countries.
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Body mass-normalized moderate dose of dietary nitrate intake improves endothelial function and walking capacity in patients with peripheral artery disease.
Pekas, EJ, Wooden, TK, Yadav, SK, Park, SY
American journal of physiology. Regulatory, integrative and comparative physiology. 2021;(2):R162-R173
Abstract
Peripheral artery disease (PAD) is characterized by the accumulation of atherosclerotic plaques in the lower extremity conduit arteries, which impairs blood flow and walking capacity. Dietary nitrate has been used to reduce blood pressure (BP) and improve walking capacity in PAD. However, a standardized dose for PAD has not been determined. Therefore, we sought to determine the effects of a body mass-normalized moderate dose of nitrate (0.11 mmol nitrate/kg) as beetroot juice on serum nitrate/nitrite, vascular function, walking capacity, and tissue oxygen utilization capacity in patients with PAD. A total of 11 patients with PAD received either nitrate supplement or placebo in a randomized crossover design. Total serum nitrate/nitrite, resting BP, brachial and popliteal artery endothelial function (flow-mediated dilation, FMD), arterial stiffness (pulse-wave velocity, PWV), augmentation index (AIx), maximal walking distance and time, claudication onset time, and skeletal muscle oxygen utilization were measured pre- and postnitrate and placebo intake. There were significant group × time interactions (P < 0.05) for serum nitrate/nitrite, FMD, BP, walking distance and time, and skeletal muscle oxygen utilization. The nitrate group showed significantly increased serum nitrate/nitrite (Δ1.32 μM), increased brachial and popliteal FMD (Δ1.3% and Δ1.7%, respectively), reduced peripheral and central systolic BP (Δ-4.7 mmHg and Δ-8.2 mmHg, respectively), increased maximal walking distance (Δ92.7 m) and time (Δ56.3 s), and reduced deoxygenated hemoglobin during walking. There were no changes in PWV, AIx, or claudication (P > 0.05). These results indicate that a body-mass normalized moderate dose of nitrate may be effective and safe for reducing BP, improving endothelial function, and improving walking capacity in patients with PAD.
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Aerosol microphysics and chemistry reveal the COVID19 lockdown impact on urban air quality.
Eleftheriadis, K, Gini, MI, Diapouli, E, Vratolis, S, Vasilatou, V, Fetfatzis, P, Manousakas, MI
Scientific reports. 2021;(1):14477
Abstract
Air quality in urban areas and megacities is dependent on emissions, physicochemical process and atmospheric conditions in a complex manner. The impact on air quality metrics of the COVID-19 lockdown measures was evaluated during two periods in Athens, Greece. The first period involved stoppage of educational and recreational activities and the second severe restrictions to all but necessary transport and workplace activities. Fresh traffic emissions and their aerosol products in terms of ultrafine nuclei particles and nitrates showed the most significant reduction especially during the 2nd period (40-50%). Carbonaceous aerosol both from fossil fuel emissions and biomass burning, as well as aging ultrafine and accumulation mode particles showed an increase of 10-20% of average before showing a decline (5 to 30%). It is found that removal of small nuclei and Aitken modes increased growth rates and migration of condensable species to larger particles maintaining aerosol volume.
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The effect of dietary nitrate on exercise capacity in chronic kidney disease: a randomized controlled pilot study.
Ramick, MG, Kirkman, DL, Stock, JM, Muth, BJ, Farquhar, WB, Chirinos, JA, Doulias, PT, Ischiropoulos, H, Edwards, DG
Nitric oxide : biology and chemistry. 2021;:17-23
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Abstract
BACKGROUND Chronic Kidney Disease (CKD) patients exhibit a reduced exercise capacity that impacts quality of life. Dietary nitrate supplementation has been shown to have favorable effects on exercise capacity in disease populations by reducing the oxygen cost of exercise. This study investigated whether dietary nitrates would acutely improve exercise capacity in CKD patients. METHODS AND RESULTS In this randomized, double-blinded crossover study, 12 Stage 3-4 CKD patients (Mean ± SEM: Age, 60 ± 5yrs; eGFR, 50.3 ± 4.6 ml/min/1.73 m2) received an acute dose of 12.6 mmol of dietary nitrate in the form of concentrated beetroot juice (BRJ) and a nitrate depleted placebo (PLA). Skeletal muscle mitochondrial oxidative function was assessed using near-infrared spectroscopy. Cardiopulmonary exercise testing was performed on a cycle ergometer, with intensity increased by 25 W every 3 min until volitional fatigue. Plasma nitric oxide (NO) metabolites (NOm; nitrate, nitrite, low molecular weight S-nitrosothiols, and metal bound NO) were determined by gas-phase chemiluminescence. Plasma NOm values were significantly increased following BRJ (BRJ vs. PLA: 1074.4 ± 120.4 μM vs. 28.4 ± 6.6 μM, p < 0.001). Total work performed (44.4 ± 10.6 vs 39.6 ± 9.9 kJ, p = 0.03) and total exercise time (674 ± 85 vs 627 ± 86s, p = 0.04) were significantly greater following BRJ. Oxygen consumption at the ventilatory threshold was also improved by BRJ (0.90 ± 0.08 vs. 0.74 ± 0.06 L/min, p = 0.04). These changes occurred in the absence of improved skeletal muscle mitochondrial oxidative capacity (p = 0.52) and VO2peak (p = 0.35). CONCLUSIONS Our findings demonstrate that inorganic nitrate can acutely improve exercise capacity in CKD patients. The effects of chronic nitrate supplementation on CKD related exercise intolerance should be investigated in future studies.
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Calcium signaling networks mediate nitrate sensing and responses in Arabidopsis.
Liu, L, Gao, H, Li, S, Han, Z, Li, B
Plant signaling & behavior. 2021;(10):1938441
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Abstract
Nitrate signaling integrates and coordinates the expression of a wide range of genes, metabolic pathways and ultimately, plant growth and development. Calcium signaling is proved to be involved in the primary nitrate response pathway. However, it is much less understood how calcium signaling mediates nitrate sensing and responses from the extracellular space to cytoplasm, then to the nucleus. In this review, we describe how transceptor-channel complex (cyclic nucleotide-gated channel protein 15 interacting with nitrate transceptor, CNGC15-NRT1.1), calcineurin B-like proteins (CBLs, CBL1, CBL9), CBL-interacting protein kinases (CIPKs), phospholipase C (PLC) and calcium-dependent protein kinases (CDPKs, also CPKs), acting as key players, complete a potential backbone of the nitrate-signaling pathway, from the plasma membrane to the nucleus. NRT1.1 together with CBL1/9-CIPK23 and CBL-CIPK8 links the NO3- signaling to cytoplasmic and nuclear regulators and triggers downstream NO3- responses. PLCs and inositol 1, 4, 5-triphosphate (IP3) connect NO3- signaling and cytoplasmic Ca2+ signature. CPK10/30/32 fill the gap between NRT1.1 and NIN-like protein (NLP) transcription factors. The arabidopsis nitrate regulated1 (ANR1) is induced from the endosome by the Ca2+-CPKs-NLPs signaling pathway activated by the unphosphorylated form of NRT1.1 (NRT1.1 T101A) at high nitrate condition. Understanding how calcium signaling interconnects the upstream nitrate sensor complex with downstream multiple sensors of the nitrate-signaling pathway is key to completing the nutrient-growth regulatory networks.
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Effect of hypoxia and nitrate supplementation on different high-intensity interval-training sessions.
Sousa, A, Viana, JL, Milheiro, J, Reis, VM, Millet, GP
European journal of applied physiology. 2021;(9):2585-2594
Abstract
PURPOSE To test the hypothesis that interval-training (IHT) would be impaired by hypoxia to a larger extent than repeated-sprint training (RSH) and that dietary nitrate (NO3-) would mitigate the detrimental effect of hypoxia to a larger extent during IHT than RSH. METHODS Thirty endurance-trained male participants performed IHT (6 × 1 min at 90%∆ with 1 min active recovery) and RSH (2 sets of 6 × 10 s "all-out" efforts with 20 s active recovery) on a cycle ergometer, allocated in one of three groups: normobaric hypoxia (~ 13% FiO2) + NO3- - HNO, n = 10; normobaric hypoxia + placebo - HPL, n = 10; normoxia (20.9% FiO2) + placebo - CON, n = 10. Submaximal oxygen uptake ([Formula: see text]O2), time spent above 90% of maximal [Formula: see text]O2 (≥ 90 [Formula: see text]O2max) and heart rate (≥ 90 HRmax) were compared between IHT and RSH sessions and groups. Additionally, mean power output (MPO), decrement score and % of power associated with [Formula: see text]O2max (%p[Formula: see text]O2max) in RSH sessions were analyzed. RESULTS [Formula: see text]O2 at sub-maximal intensities did not differ between training protocols and groups (~ 27 ml kg-1 min-1). ≥ 90 HRmax was significantly higher in IHT compared to RSH session (39 ± 8 vs. 30 ± 8%, p = 0.03) but only in HNO group. MPO (range 360-490 W) and decrement score (10-13%) were similar between groups although %p[Formula: see text]O2max was significantly higher (p = 0.04) in CON (166 ± 16 W) compared with both HPL (147 ± 15 W) and HNO (144 ± 10 W) groups. CONCLUSION IHT responses were neither more impaired by hypoxia than RSH ones. Moreover, dietary NO3- supplementation impacted equally IHT and RSH training responses' differences between hypoxia and normoxia.