Pub Date : 2026-02-01Epub Date: 2025-11-20DOI: 10.1016/j.niox.2025.11.006
Talisa Bühl , Stefano Cenci , Stefano Gianni , Bijan Safaee Fakhr , Carlo Valsecchi , Binglan Yu , Edward A. Bittner , Lorenzo Berra
Background
High-dose inhaled nitric oxide (iNO), defined as doses exceeding 20 parts per million (ppm) and reaching up to 300 ppm, has demonstrated promising antimicrobial properties. However, elevated concentrations of nitric oxide (NO) can increase the formation of methemoglobin (MetHb), which can impair oxygen transport. Understanding factors influencing MetHb formation is essential to guide safe clinical use of iNO therapy.
Methods
We conducted a retrospective analysis of 660 high-dose iNO treatments administered to 71 individuals between April 2020 and January 2022 under three prospective protocols at a large academic medical center. The study protocols included healthy volunteers, non-pregnant patients with COVID-19 pneumonia, and pregnant patients with COVID-19 pneumonia. MetHb levels were recorded at baseline and post-treatment using CO-oximeter. Mixed-effects modeling was used to identify predictors of MetHb formation with repeated measures.
Results
iNO concentration was positively associated with MetHb formation, while COVID-19 pneumonia, older age, higher baseline MetHb, and increased respiratory rate were inversely associated. No significant associations were found for sex, race, or hemoglobin concentration. Nitrogen dioxide levels remained within normal ranges, and no systemic hypotension or toxicity were observed. In tachypneic patients with COVID-19 pneumonia, high-dose iNO reduced respiratory rate.
Conclusion
High-dose iNO up to 300 ppm was well tolerated across diverse patient populations. MetHb formation was influenced not only by iNO doses but also by individual physiological factors. These findings support the safety of high-dose iNO and provide a basis for individualized delivery strategies.
{"title":"Predictors of methemoglobin formation in high-dose inhaled nitric oxide therapy: A retrospective cohort study","authors":"Talisa Bühl , Stefano Cenci , Stefano Gianni , Bijan Safaee Fakhr , Carlo Valsecchi , Binglan Yu , Edward A. Bittner , Lorenzo Berra","doi":"10.1016/j.niox.2025.11.006","DOIUrl":"10.1016/j.niox.2025.11.006","url":null,"abstract":"<div><h3>Background</h3><div>High-dose inhaled nitric oxide (iNO), defined as doses exceeding 20 parts per million (ppm) and reaching up to 300 ppm, has demonstrated promising antimicrobial properties. However, elevated concentrations of nitric oxide (NO) can increase the formation of methemoglobin (MetHb), which can impair oxygen transport. Understanding factors influencing MetHb formation is essential to guide safe clinical use of iNO therapy.</div></div><div><h3>Methods</h3><div>We conducted a retrospective analysis of 660 high-dose iNO treatments administered to 71 individuals between April 2020 and January 2022 under three prospective protocols at a large academic medical center. The study protocols included healthy volunteers, non-pregnant patients with COVID-19 pneumonia, and pregnant patients with COVID-19 pneumonia. MetHb levels were recorded at baseline and post-treatment using CO-oximeter. Mixed-effects modeling was used to identify predictors of MetHb formation with repeated measures.</div></div><div><h3>Results</h3><div>iNO concentration was positively associated with MetHb formation, while COVID-19 pneumonia, older age, higher baseline MetHb, and increased respiratory rate were inversely associated. No significant associations were found for sex, race, or hemoglobin concentration. Nitrogen dioxide levels remained within normal ranges, and no systemic hypotension or toxicity were observed. In tachypneic patients with COVID-19 pneumonia, high-dose iNO reduced respiratory rate.</div></div><div><h3>Conclusion</h3><div>High-dose iNO up to 300 ppm was well tolerated across diverse patient populations. MetHb formation was influenced not only by iNO doses but also by individual physiological factors. These findings support the safety of high-dose iNO and provide a basis for individualized delivery strategies.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"160 ","pages":"Pages 35-43"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-04DOI: 10.1016/j.niox.2025.11.001
Tomoaki Ida , Shingo Kasamatsu , Mahiro Kuryu , Haruka Nitta , Wakana Nagamura , Hina Yoshida , Ayaka Kinno , Aoi Morishita , Takaaki Akaike , Hideshi Ihara
Supersulfides are sulfur species with catenated sulfur atoms, such as cysteine hydropersulfide (CysSSH). Although supersulfides are biologically important metabolites owing to their unique chemical properties, their transformation in plants via microbial fermentation remains unknown. Natto is a traditional Japanese food prepared from soybeans fermented using Bacillus subtilis var. natto and is an excellent model for investigating this transformation. Compared to unfermented soybeans, natto contains higher supersulfide contents; however, the specific molecular changes that occur during fermentation remain unclear. Herein, we investigated the molecular profiles of supersulfides in natto using mass spectrometry-based supersulfide omics. Quantitative supersulfide profiling revealed an increase in soybean supersulfide content during fermentation using B. subtilis var. natto. However, the total sulfur content did not significantly change, suggesting that microorganisms may play a role in the biotransformation of sulfur-containing molecules into supersulfides. Furthermore, quantitative supersulfide metabolomics and untargeted polysulfide omics revealed time-dependent fermentation increases in the levels of both reduced supersulfides, including CysSSH and cysteine hydrotrisulfide, and oxidized supersulfides, such as cystine trisulfide. Moreover, high-molecular-weight supersulfides were detected. Thus, the supersulfide content significantly increased during B. subtilis var. natto fermentation. Supersulfidated proteins were not detected in natto, likely because soybean-derived proteins were degraded by B. subtilis var. natto. Conversely, supersulfide proteomics revealed the presence of various supersulfide-modified proteins in soybeans, particularly the supersulfidation of 11S glycinin. This is the first study to reveal that microbial fermentation significantly transforms the supersulfide profile in plants. Moreover, the diverse supersulfides abundantly present in natto may contribute to its health-promoting properties.
{"title":"Dynamic transformation of the sulfur metabolome during natto fermentation: Supersulfide omics study","authors":"Tomoaki Ida , Shingo Kasamatsu , Mahiro Kuryu , Haruka Nitta , Wakana Nagamura , Hina Yoshida , Ayaka Kinno , Aoi Morishita , Takaaki Akaike , Hideshi Ihara","doi":"10.1016/j.niox.2025.11.001","DOIUrl":"10.1016/j.niox.2025.11.001","url":null,"abstract":"<div><div>Supersulfides are sulfur species with catenated sulfur atoms, such as cysteine hydropersulfide (CysSSH). Although supersulfides are biologically important metabolites owing to their unique chemical properties, their transformation in plants <em>via</em> microbial fermentation remains unknown. Natto is a traditional Japanese food prepared from soybeans fermented using <em>Bacillus subtilis</em> var. <em>natto</em> and is an excellent model for investigating this transformation. Compared to unfermented soybeans, natto contains higher supersulfide contents; however, the specific molecular changes that occur during fermentation remain unclear. Herein, we investigated the molecular profiles of supersulfides in natto using mass spectrometry-based supersulfide omics. Quantitative supersulfide profiling revealed an increase in soybean supersulfide content during fermentation using <em>B. subtilis</em> var. <em>natto</em>. However, the total sulfur content did not significantly change, suggesting that microorganisms may play a role in the biotransformation of sulfur-containing molecules into supersulfides. Furthermore, quantitative supersulfide metabolomics and untargeted polysulfide omics revealed time-dependent fermentation increases in the levels of both reduced supersulfides, including CysSSH and cysteine hydrotrisulfide, and oxidized supersulfides, such as cystine trisulfide. Moreover, high-molecular-weight supersulfides were detected. Thus, the supersulfide content significantly increased during <em>B. subtilis</em> var. <em>natto</em> fermentation. Supersulfidated proteins were not detected in natto, likely because soybean-derived proteins were degraded by <em>B. subtilis</em> var. <em>natto</em>. Conversely, supersulfide proteomics revealed the presence of various supersulfide-modified proteins in soybeans, particularly the supersulfidation of 11S glycinin. This is the first study to reveal that microbial fermentation significantly transforms the supersulfide profile in plants. Moreover, the diverse supersulfides abundantly present in natto may contribute to its health-promoting properties.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"160 ","pages":"Pages 14-23"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145458865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-23DOI: 10.1016/j.niox.2025.11.007
Peixuan Wu , Hao Zhuang , Zhendong Zhao , Zeyu Liu , Mingle Li , Tawfik Khattab , Yang Zhou , Yuanyuan Liu
Bacterial infections are a major global health challenge. Although antibiotics are the dominant therapeutic approach, the problem of resistance resulting from their widespread use has led to an urgent need to develop new, safe, and effective alternative antimicrobial strategies. In this work, antimicrobial SNAP-HA microspheres with controlled release of NO were successfully prepared by loading S-nitroso-N-acetyl penicillamine (SNAP) in hydroxyapatite (HA). The loading of SNAP in SNAP-HA microspheres ranged from 1.05 % to 16.42 %. The NO release from SNAP-HA microspheres was measured by chemiluminescence, and the longest NO release time reached ∼66 h 1H NMR also characterized the decomposition products of SNAP. In addition, the structure, thermal properties, and morphology of SNAP-HA microspheres were fully characterized. SNAP was present in HA microspheres in the amorphous form. In antibacterial studies, the SNAP-HA microspheres were able to reach 100 % of the optimal antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). SNAP-HA microspheres are antimicrobial by releasing NO gas, which does not stimulate the development of drug-resistant strains of bacteria and is expected to be a new alternative antimicrobial product.
{"title":"Rapid fabrication of nitric oxide releasing hydroxyapatite microspheres using liquid nitrogen as an antibiotic-free alternative","authors":"Peixuan Wu , Hao Zhuang , Zhendong Zhao , Zeyu Liu , Mingle Li , Tawfik Khattab , Yang Zhou , Yuanyuan Liu","doi":"10.1016/j.niox.2025.11.007","DOIUrl":"10.1016/j.niox.2025.11.007","url":null,"abstract":"<div><div>Bacterial infections are a major global health challenge. Although antibiotics are the dominant therapeutic approach, the problem of resistance resulting from their widespread use has led to an urgent need to develop new, safe, and effective alternative antimicrobial strategies. In this work, antimicrobial SNAP-HA microspheres with controlled release of NO were successfully prepared by loading S-nitroso-N-acetyl penicillamine (SNAP) in hydroxyapatite (HA). The loading of SNAP in SNAP-HA microspheres ranged from 1.05 % to 16.42 %. The NO release from SNAP-HA microspheres was measured by chemiluminescence, and the longest NO release time reached ∼66 h <sup>1</sup>H NMR also characterized the decomposition products of SNAP. In addition, the structure, thermal properties, and morphology of SNAP-HA microspheres were fully characterized. SNAP was present in HA microspheres in the amorphous form. In antibacterial studies, the SNAP-HA microspheres were able to reach 100 % of the optimal antibacterial activity against <em>Escherichia coli</em> (<em>E. coli</em>) and <em>Staphylococcus aureus</em> (<em>S. aureus</em>). SNAP-HA microspheres are antimicrobial by releasing NO gas, which does not stimulate the development of drug-resistant strains of bacteria and is expected to be a new alternative antimicrobial product.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"160 ","pages":"Pages 47-55"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-19DOI: 10.1016/j.niox.2025.12.001
Guia Tagliapietra , Tom Citherlet , Antoine Raberin , Benjamin J. Narang , Giorgio Manferdelli , Guido Giardini , Tadej Debevec , Vincent Pialoux , Grégoire P. Millet
High altitude may alter redox balance and promote inflammation. It remains unclear if ovarian hormone fluctuations influence redox status. We sought to investigate the impact of menstrual cycle (MC) phases on oxidative stress, nitric oxide metabolism, inflammation, iron biomarkers and acute mountain sickness (AMS) during high-altitude sojourns in eumenorrheic women. Venous blood samples were collected at low altitude (1224 m) and after one night at 3375 m (Rifugio Torino, inspired O2 pressure: 96 ± 1 mmHg) during both the early follicular (EF) and mid-luteal (ML) phases. At high altitude, xanthine oxidase (XO: 0.140 ± 0.077 vs. 0.165 ± 0.084 μmol L−1 min −1; p = 1.00), total nitrites and nitrates (NOx: 38.9 ± 10.8 vs. 32.8 ± 6.1 μmol L−1; p = 1.00), interleukin-6 (IL-6: 17.3 ± 13.6 vs. 14.5 ± 13.2 ng mL−1; p = 1.00) and serum iron concentration (19.7 ± 6.8 vs. 22.1 ± 4.6 μmol L−1; p = 1.00) were not significantly different between EF and ML. However, total protein concentrations were significantly lower in EF compared to ML (75.5 ± 2.0 vs. 80.0 ± 5.1 g L−1; p = 0.010). No significant differences were observed in Lake Louise scores (AMS) between EF and ML (2.17 ± 1.64 vs. 1.50 ± 1.83; p = 0.180). High-altitude exposure increased XO, IL-6 and erythropoietin levels and decreased NOx, when compared to low altitude. These findings suggest that redox balance, nitric oxide bioavailability, inflammation and iron homeostasis are not influenced by the MC at high altitude. Overall, susceptibility to AMS was similar across MC phases.
高海拔可能改变氧化还原平衡，促进炎症。目前尚不清楚卵巢激素波动是否影响氧化还原状态。我们试图研究月经周期（MC）阶段对经期女性在高海拔居住期间氧化应激、一氧化氮代谢、炎症、铁生物标志物和急性高原反应（AMS）的影响。在低海拔（1224 m）和3375 m (Rifugio Torino，吸气氧压：96±1 mmHg) 1晚采集卵泡早期（EF）和黄体中期（ML）的静脉血。在高海拔、黄嘌呤氧化酶(XO: 0.140±0.077和0.165±0.084μ摩尔·l·敏1;p = 1.00),亚硝酸盐和硝酸盐(氮氧化物:38.9±10.8和32.8±6.1μ摩尔·l - 1; p = 1.00),白细胞介素- 6 (il - 6: 17.3±13.6和14.5±13.2 ng·mL-1; p = 1.00)和血清铁浓度(19.7±6.8和22.1±4.6μ摩尔·l - 1; p = 1.00)没有显著不同EF和毫升。然而,总蛋白浓度显著降低相比,EF毫升(75.5±2.0和80.0±5.1 g·l - 1;P = 0.010)。EF组与ML组的Lake Louise评分（AMS）差异无统计学意义（2.17±1.64∶1.50±1.83;p = 0.180）。与低海拔相比，高海拔暴露增加了XO、IL-6和促红细胞生成素水平，降低了NOx。这些结果表明，氧化还原平衡、一氧化氮生物利用度、炎症和铁体内平衡不受高海拔MC的影响。总体而言，不同MC阶段对AMS的敏感性相似。
{"title":"Impact of the menstrual cycle on oxidative stress, inflammation and iron status at high altitude","authors":"Guia Tagliapietra , Tom Citherlet , Antoine Raberin , Benjamin J. Narang , Giorgio Manferdelli , Guido Giardini , Tadej Debevec , Vincent Pialoux , Grégoire P. Millet","doi":"10.1016/j.niox.2025.12.001","DOIUrl":"10.1016/j.niox.2025.12.001","url":null,"abstract":"<div><div>High altitude may alter redox balance and promote inflammation. It remains unclear if ovarian hormone fluctuations influence redox status. We sought to investigate the impact of menstrual cycle (MC) phases on oxidative stress, nitric oxide metabolism, inflammation, iron biomarkers and acute mountain sickness (AMS) during high-altitude sojourns in eumenorrheic women. Venous blood samples were collected at low altitude (1224 m) and after one night at 3375 m (Rifugio Torino, inspired O<sub>2</sub> pressure: 96 ± 1 mmHg) during both the early follicular (EF) and mid-luteal (ML) phases. At high altitude, xanthine oxidase (XO: 0.140 ± 0.077 vs. 0.165 ± 0.084 μmol L<sup>−1</sup> min <sup>−1</sup>; <em>p</em> = 1.00), total nitrites and nitrates (NOx: 38.9 ± 10.8 vs. 32.8 ± 6.1 μmol L<sup>−1</sup>; <em>p</em> = 1.00), interleukin-6 (IL-6: 17.3 ± 13.6 vs. 14.5 ± 13.2 ng mL<sup>−1</sup>; <em>p</em> = 1.00) and serum iron concentration (19.7 ± 6.8 vs. 22.1 ± 4.6 μmol L<sup>−1</sup>; <em>p</em> = 1.00) were not significantly different between EF and ML. However, total protein concentrations were significantly lower in EF compared to ML (75.5 ± 2.0 vs. 80.0 ± 5.1 g L<sup>−1</sup>; <em>p</em> = 0.010). No significant differences were observed in Lake Louise scores (AMS) between EF and ML (2.17 ± 1.64 vs. 1.50 ± 1.83; <em>p</em> = 0.180). High-altitude exposure increased XO, IL-6 and erythropoietin levels and decreased NOx, when compared to low altitude. These findings suggest that redox balance, nitric oxide bioavailability, inflammation and iron homeostasis are not influenced by the MC at high altitude. Overall, susceptibility to AMS was similar across MC phases.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"160 ","pages":"Pages 56-62"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-19DOI: 10.1016/j.niox.2025.11.005
Xiaoyan Wu , Chuanqing Zhang , Zhiqing Zhuang , Jingjing Yin , Wei Jiang , Lin Song , Jing Wang , Jiangquan Yu , Ruiqiang Zheng
<div><h3>Background</h3><div>Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by refractory hypoxemia resulting from ventilation-perfusion (V/Q) mismatch. Studies have shown that inhaled nitric oxide (iNO) and prone position (PP) ventilation may improve V/Q mismatch and oxygenation when used separately. Despite the known individual benefits of iNO and PP, few studies have investigated their potential synergistic effects. The aim of this study was to evaluate iNO combined with PP on V/Q matching and oxygenation in patients with moderate-to-severe ARDS.</div></div><div><h3>Methods</h3><div>A 2 × 2 factorial design was adopted in this study. Patients admitted to the Intensive Care Unit of Northern Jiangsu People's Hospital from January 2024 to December 2024, who met the diagnostic criteria for moderate-to-severe ARDS (aged 18–80 years, oxygenation index <150 mmHg, and requiring mechanical ventilation), were enrolled. The patients were administered with a combination of iNO therapy at 20 ppm while in the supine position (SP) and prone position (PP). Various clinical variables were collected at baseline in the SP, as well as at 4 and 12-h during PP, and after 30–60 min of iNO treatment (SP, SP + iNO, PP, PP + iNO). The pulmonary ventilation-perfusion status, such as the global inhomogeneity (GI) index of ventilation and perfusion, dead space fraction, intrapulmonary shunt fraction, and V/Q matching was monitored using electrical impedance tomography (EIT). Additionally, respiratory mechanics, gas exchange, and hemodynamic parameters were recorded.</div></div><div><h3>Results</h3><div>A total of 24 patients with severe ARDS were enrolled, including 17 males and 7 females. The mean oxygenation index PaO<sub>2</sub>/FiO<sub>2</sub> (P/F) at enrollment was 131.68 ± 33.11 mmHg. PP markedly improved static compliance (Cst),P/F and V/Q matching (p < 0.05), increased dorsal ventilation and perfusion, and decreased GI of ventilation and perfusion, as well as dead space ventilation (p < 0.05). Similarly, iNO significantly increased P/F and V/Q matching, while reducing perfusion GI, intrapulmonary shunt, and dead space ventilation (p < 0.05). Factorial analysis revealed that iNO was associated with a nonsignificant increase in the P/F ratio compared to the non-iNO group. (95 % CI: 6.037 to 84.927, p = 0.088). In contrast, PP significantly increased P/F compared to SP (95 % CI: 42.032 to 132.997, p < 0.001). The interaction effect between iNO and PP on P/F was not statistically significant (95 % CI: 63.099 to 65.544, p = 0.970). Regarding V/Q matching, iNO significantly improved outcomes compared to the non-iNO group (95 % CI: 1.902 to 15.363, p = 0.013), as did PP compared to SP (95 % CI: 1.255 to 14.717, p = 0.021). However, no significant interaction was observed between iNO and PP (95 % CI: 13.470 to 5.568, p = 0.412).</div></div><div><h3>Conclusion</h3><div>In patients with moderate-to-severe ARDS, both iNO and P
{"title":"Investigating the effect of inhaled nitric oxide combined with prone position ventilation on ventilation/perfusion matching in patients with moderate-to-severe acute respiratory distress syndrome","authors":"Xiaoyan Wu , Chuanqing Zhang , Zhiqing Zhuang , Jingjing Yin , Wei Jiang , Lin Song , Jing Wang , Jiangquan Yu , Ruiqiang Zheng","doi":"10.1016/j.niox.2025.11.005","DOIUrl":"10.1016/j.niox.2025.11.005","url":null,"abstract":"<div><h3>Background</h3><div>Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by refractory hypoxemia resulting from ventilation-perfusion (V/Q) mismatch. Studies have shown that inhaled nitric oxide (iNO) and prone position (PP) ventilation may improve V/Q mismatch and oxygenation when used separately. Despite the known individual benefits of iNO and PP, few studies have investigated their potential synergistic effects. The aim of this study was to evaluate iNO combined with PP on V/Q matching and oxygenation in patients with moderate-to-severe ARDS.</div></div><div><h3>Methods</h3><div>A 2 × 2 factorial design was adopted in this study. Patients admitted to the Intensive Care Unit of Northern Jiangsu People's Hospital from January 2024 to December 2024, who met the diagnostic criteria for moderate-to-severe ARDS (aged 18–80 years, oxygenation index <150 mmHg, and requiring mechanical ventilation), were enrolled. The patients were administered with a combination of iNO therapy at 20 ppm while in the supine position (SP) and prone position (PP). Various clinical variables were collected at baseline in the SP, as well as at 4 and 12-h during PP, and after 30–60 min of iNO treatment (SP, SP + iNO, PP, PP + iNO). The pulmonary ventilation-perfusion status, such as the global inhomogeneity (GI) index of ventilation and perfusion, dead space fraction, intrapulmonary shunt fraction, and V/Q matching was monitored using electrical impedance tomography (EIT). Additionally, respiratory mechanics, gas exchange, and hemodynamic parameters were recorded.</div></div><div><h3>Results</h3><div>A total of 24 patients with severe ARDS were enrolled, including 17 males and 7 females. The mean oxygenation index PaO<sub>2</sub>/FiO<sub>2</sub> (P/F) at enrollment was 131.68 ± 33.11 mmHg. PP markedly improved static compliance (Cst),P/F and V/Q matching (p < 0.05), increased dorsal ventilation and perfusion, and decreased GI of ventilation and perfusion, as well as dead space ventilation (p < 0.05). Similarly, iNO significantly increased P/F and V/Q matching, while reducing perfusion GI, intrapulmonary shunt, and dead space ventilation (p < 0.05). Factorial analysis revealed that iNO was associated with a nonsignificant increase in the P/F ratio compared to the non-iNO group. (95 % CI: 6.037 to 84.927, p = 0.088). In contrast, PP significantly increased P/F compared to SP (95 % CI: 42.032 to 132.997, p < 0.001). The interaction effect between iNO and PP on P/F was not statistically significant (95 % CI: 63.099 to 65.544, p = 0.970). Regarding V/Q matching, iNO significantly improved outcomes compared to the non-iNO group (95 % CI: 1.902 to 15.363, p = 0.013), as did PP compared to SP (95 % CI: 1.255 to 14.717, p = 0.021). However, no significant interaction was observed between iNO and PP (95 % CI: 13.470 to 5.568, p = 0.412).</div></div><div><h3>Conclusion</h3><div>In patients with moderate-to-severe ARDS, both iNO and P","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"160 ","pages":"Pages 28-34"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-10-07DOI: 10.1016/j.niox.2025.10.005
Simon Gissing , Eva-Maria Pferschy-Wenzig , Ramona Jeitler , Michael Russwurm , Astrid Schrammel , Bernd Mayer , Alexander Kollau
As key enzyme in the NO/cGMP pathway, soluble guanylyl cyclase (sGC) has become an important therapeutic target in the treatment of cardiovascular diseases. In addition to activating compounds, inhibitors of sGC are necessary tools in research and may even be desirable as therapeutic agents in certain situations, like migraine.
In a previous study we observed reversible inhibition of isolated sGC by aqueous extracts from tobacco cigarette smoke. In the current study, we found that extracts prepared from cured tobacco share these properties. The active compounds were isolated and identified as unsaturated fatty acids. Further characterization of the inhibitory effect indicated a potential interaction with the heme binding site. In addition, initial experiments with vascular endothelial cells suggest that the observed effect may be relevant to blood vessels function in vivo.
{"title":"Unsaturated fatty acids identified as reversible soluble guanylyl cyclase inhibitors","authors":"Simon Gissing , Eva-Maria Pferschy-Wenzig , Ramona Jeitler , Michael Russwurm , Astrid Schrammel , Bernd Mayer , Alexander Kollau","doi":"10.1016/j.niox.2025.10.005","DOIUrl":"10.1016/j.niox.2025.10.005","url":null,"abstract":"<div><div>As key enzyme in the NO/cGMP pathway, soluble guanylyl cyclase (sGC) has become an important therapeutic target in the treatment of cardiovascular diseases. In addition to activating compounds, inhibitors of sGC are necessary tools in research and may even be desirable as therapeutic agents in certain situations, like migraine.</div><div>In a previous study we observed reversible inhibition of isolated sGC by aqueous extracts from tobacco cigarette smoke. In the current study, we found that extracts prepared from cured tobacco share these properties. The active compounds were isolated and identified as unsaturated fatty acids. Further characterization of the inhibitory effect indicated a potential interaction with the heme binding site. In addition, initial experiments with vascular endothelial cells suggest that the observed effect may be relevant to blood vessels function <em>in vivo</em>.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 115-125"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-09-02DOI: 10.1016/j.niox.2025.08.005
Katty Anne Amador de Lucena Medeiros , Auderlan Mendonça de Gois , Rodolfo Silva dos Santos , Milena Caroline Nunes Monteiro , Heitor Franco Santos , Marina Freire de Souza , Thassya Fernanda Oliveira dos Santos , Marco Aurelio M. Freire , Mariza Bortolanza , Elaine Del-Bel , José Ronaldo Santos , Murilo Marchioro
Introduction
Fear is a response to real aversive stimuli. Studies on phylogenetically distant species like reptiles can offer valuable insights into the neural mechanisms of fear.
Objective
To investigate the activation and distribution of nitrergic neurons in the telencephalon of Tropidurus hispidus lizards and evaluate the role of glutamatergic modulation via NMDA receptors following exposure to an aversive stimulus.
Methods
Lizards were exposed to a live cat, and 24 h later, NADPH-diaphorase histochemistry was performed in the telencephalon to quantify neuron number and optical density. In the second stage, animals received i.c.v. injections of the NMDA receptor antagonist AP5 (1.25, 2.5, or 5.0 μg/μl), followed by cat exposure and histochemical analysis.
Results
Exposure to the cat led to increased freezing time in lizards. These animals also showed an increased number of nitrergic neurons in the dorsal cortex, anterior dorsal ventricular ridge (ADVR), and dorsolateral amygdala, as well as elevated integrated optical density (IOD) in the striatum, ADVR, dorsolateral amygdala and lateral amygdaloid nucleus. The AP5 1.25 and 5.0 μg/μl groups exhibited some head or limb movements even in the presence of the cat. The 1.25 μg/μl group showed reduced neuron counts and IOD in the dorsolateral amygdala; the 2.5 μg/μl and 5.0 μg/μl groups showed reduced IOD and neuron counts in the striatum.
Conclusion
Tropidurus hispidus lizards show fear-like behavior and decreased exploration after aversive stimuli, with nitric oxide in the telencephalon – particularly in the striatum and dorsolateral amygdala – modulating this response via NMDA receptor activation.
{"title":"Distribution and activation of nitrergic neurons in response to aversive stimulus exposure in the Tropidurus hispidus lizard: Involvement of glutamatergic circuitry","authors":"Katty Anne Amador de Lucena Medeiros , Auderlan Mendonça de Gois , Rodolfo Silva dos Santos , Milena Caroline Nunes Monteiro , Heitor Franco Santos , Marina Freire de Souza , Thassya Fernanda Oliveira dos Santos , Marco Aurelio M. Freire , Mariza Bortolanza , Elaine Del-Bel , José Ronaldo Santos , Murilo Marchioro","doi":"10.1016/j.niox.2025.08.005","DOIUrl":"10.1016/j.niox.2025.08.005","url":null,"abstract":"<div><h3>Introduction</h3><div>Fear is a response to real aversive stimuli. Studies on phylogenetically distant species like reptiles can offer valuable insights into the neural mechanisms of fear.</div></div><div><h3>Objective</h3><div>To investigate the activation and distribution of nitrergic neurons in the telencephalon of <em>Tropidurus hispidus</em> lizards and evaluate the role of glutamatergic modulation via NMDA receptors following exposure to an aversive stimulus.</div></div><div><h3>Methods</h3><div>Lizards were exposed to a live cat, and 24 h later, NADPH-diaphorase histochemistry was performed in the telencephalon to quantify neuron number and optical density. In the second stage, animals received i.c.v. injections of the NMDA receptor antagonist AP5 (1.25, 2.5, or 5.0 μg/μl), followed by cat exposure and histochemical analysis.</div></div><div><h3>Results</h3><div>Exposure to the cat led to increased freezing time in lizards. These animals also showed an increased number of nitrergic neurons in the dorsal cortex, anterior dorsal ventricular ridge (ADVR), and dorsolateral amygdala, as well as elevated integrated optical density (IOD) in the striatum, ADVR, dorsolateral amygdala and lateral amygdaloid nucleus. The AP5 1.25 and 5.0 μg/μl groups exhibited some head or limb movements even in the presence of the cat. The 1.25 μg/μl group showed reduced neuron counts and IOD in the dorsolateral amygdala; the 2.5 μg/μl and 5.0 μg/μl groups showed reduced IOD and neuron counts in the striatum.</div></div><div><h3>Conclusion</h3><div><em>Tropidurus hispidus</em> lizards show fear-like behavior and decreased exploration after aversive stimuli, with nitric oxide in the telencephalon – particularly in the striatum and dorsolateral amygdala – modulating this response via NMDA receptor activation.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 23-37"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Red blood cells (RBCs) express functional endothelial nitric oxide synthase (eNOS), which regulates blood pressure (BP) independently of eNOS in endothelial cells (ECs) and provides cardioprotection during acute myocardial infarction (AMI). The functional role of RBC- and EC- eNOS in anemia remains unknown. This study evaluated the effects of RBC- or EC-specific eNOS deletion on hemodynamics and cardiac function in blood loss anemia.
Methods
and resultsAnemia was induced in EC- or RBC-specific eNOS knockout (KO) mice and their respective controls. In vivo flow-mediated dilation (FMD) was preserved in RBC-eNOS-KO mice under both baseline and anemic conditions but was impaired in EC-eNOS-KO mice compared to their respective controls. Wire myograph analysis of aortic rings showed preserved endothelium-dependent relaxation (EDR) in anemic RBC-eNOS-KO mice, while EDR was abolished in anemic EC-eNOS-KO mice relative to controls. Miller catheter BP measurements revealed elevated systolic and diastolic BP in EC-eNOS-KO mice under both baseline and anemic conditions. Both systolic and diastolic BP were increased in RBC-eNOS-KO mice compared to controls, whereas these parameters remained unchanged in anemic RBC-eNOS-KO mice compared to their respective controls. Echocardiography demonstrated preserved cardiac function across all genotypes at baseline, 3 days post-anemia, and 24 h post-reperfused AMI. However, infarct size was significantly increased in anemic RBC-eNOS-KO mice compared to controls.
Conclusions
Anemia mitigates the BP elevation caused by RBC-eNOS deletion, while hypertension persists in the absence of endothelial eNOS, highlighting vascular eNOS as the predominant regulator of BP under anemic conditions. RBC-eNOS limits infarct size under anemic conditions.
{"title":"Divergent roles of endothelial and red blood cell nitric oxide synthase in regulating cardiovascular function during anemia","authors":"Vithya Yogathasan , Patricia Wischmann , Isabella Solga , Lilly Jäger , Stefanie Becher , Miriam M. Cortese-Krott , Norbert Gerdes , Malte Kelm , Christian Jung , Ramesh Chennupati","doi":"10.1016/j.niox.2025.08.004","DOIUrl":"10.1016/j.niox.2025.08.004","url":null,"abstract":"<div><h3>Background</h3><div>Red blood cells (RBCs) express functional endothelial nitric oxide synthase (eNOS), which regulates blood pressure (BP) independently of eNOS in endothelial cells (ECs) and provides cardioprotection during acute myocardial infarction (AMI). The functional role of RBC- and EC- eNOS in anemia remains unknown. This study evaluated the effects of RBC- or EC-specific eNOS deletion on hemodynamics and cardiac function in blood loss anemia.</div></div><div><h3>Methods</h3><div>and resultsAnemia was induced in EC- or RBC-specific eNOS knockout (KO) mice and their respective controls. In vivo flow-mediated dilation (FMD) was preserved in RBC-eNOS-KO mice under both baseline and anemic conditions but was impaired in EC-eNOS-KO mice compared to their respective controls. Wire myograph analysis of aortic rings showed preserved endothelium-dependent relaxation (EDR) in anemic RBC-eNOS-KO mice, while EDR was abolished in anemic EC-eNOS-KO mice relative to controls. Miller catheter BP measurements revealed elevated systolic and diastolic BP in EC-eNOS-KO mice under both baseline and anemic conditions. Both systolic and diastolic BP were increased in RBC-eNOS-KO mice compared to controls, whereas these parameters remained unchanged in anemic RBC-eNOS-KO mice compared to their respective controls. Echocardiography demonstrated preserved cardiac function across all genotypes at baseline, 3 days post-anemia, and 24 h post-reperfused AMI. However, infarct size was significantly increased in anemic RBC-eNOS-KO mice compared to controls.</div></div><div><h3>Conclusions</h3><div>Anemia mitigates the BP elevation caused by RBC-eNOS deletion, while hypertension persists in the absence of endothelial eNOS, highlighting vascular eNOS as the predominant regulator of BP under anemic conditions. RBC-eNOS limits infarct size under anemic conditions.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 1-10"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-10-06DOI: 10.1016/j.niox.2025.10.006
Joseph A. Bauer , Annette M. Sysel , Michael J. Dunphy
Nitric oxide (NO) is a central mediator of vascular, neurological, and immune functions, and its dysregulation is implicated in a broad spectrum of diseases. Despite its significance, direct measurement of NO in human samples is limited by its transient nature and rapid conversion to nitrate and nitrite. Accurate, rapid, and accessible quantification of these NO metabolites in clinical and research settings remains a key need. We present a vanadium(III)-based chemiluminescence protocol for the reliable detection of nitrate and nitrite in human biological fluids, including serum, urine, and cerebrospinal fluid. In addition, this method supports headspace gas analysis, enabling precise determination of nitric oxide release kinetics and half-life from NO-producing compounds. This approach offers a cost-effective and scalable solution suitable for routine analysis in both diagnostic and research laboratories.
{"title":"A versatile vanadium(III)-based chemiluminescence protocol for nitric oxide metabolite quantification and NO release kinetics","authors":"Joseph A. Bauer , Annette M. Sysel , Michael J. Dunphy","doi":"10.1016/j.niox.2025.10.006","DOIUrl":"10.1016/j.niox.2025.10.006","url":null,"abstract":"<div><div>Nitric oxide (NO) is a central mediator of vascular, neurological, and immune functions, and its dysregulation is implicated in a broad spectrum of diseases. Despite its significance, direct measurement of NO in human samples is limited by its transient nature and rapid conversion to nitrate and nitrite. Accurate, rapid, and accessible quantification of these NO metabolites in clinical and research settings remains a key need. We present a vanadium(III)-based chemiluminescence protocol for the reliable detection of nitrate and nitrite in human biological fluids, including serum, urine, and cerebrospinal fluid. In addition, this method supports headspace gas analysis, enabling precise determination of nitric oxide release kinetics and half-life from NO-producing compounds. This approach offers a cost-effective and scalable solution suitable for routine analysis in both diagnostic and research laboratories.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 161-167"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-10-05DOI: 10.1016/j.niox.2025.10.003
Yuriy E. Kolupaev , Tetiana O. Yastreb , Alla Yemets , Yaroslav Blume
Polyamines, γ-aminobutyric acid (GABA), proline, and glycine betaine (GB) are important plant stress metabolites that are interconnected in common metabolic cycles. These compounds have a multifunctional protective effect on plant cells under stress conditions, acting as osmoregulators, antioxidants, chaperones, and intracellular pH stabilizers, among other roles. The key role of these compounds, however, lies in their involvement in the signaling network of plant cells. Stress metabolites, in particular, engage in a complex functional interaction with reactive oxygen species (ROS) and nitric oxide (NO). Nevertheless, information detailing the links between NO and major nitrogen-containing stress metabolites is fragmented. Consequently, a holistic understanding of these interactions, even at the theoretical model level, has yet to be presented in the literature. The review investigates the phenomenology and mechanisms of NO's involvement as a signaling mediator in the stress-protective function of polyamines and GABA in plants. It also analyses the effect of NO on the content of polyamines, GABA, proline, and GB under normal and stressful conditions. The latest data on the role of S-nitrosation processes of enzymes involved in the regulation of content of low-molecular nitrogen-containing compounds in plant adaptation, and on the effect of polyamines on S-nitrosation of the proteome are summarized. Particular attention is paid to the links between nitric oxide and other signaling mediators (primarily ROS and Ca2+) during its functional interaction with stress metabolites. Regulation of NO and stress metabolite levels is considered one of the promising tools for managing plant stress resistance.
{"title":"Nitric oxide functional relationships with nitrogen-containing stress metabolites: Role in plant adaptation to adverse abiotic factors","authors":"Yuriy E. Kolupaev , Tetiana O. Yastreb , Alla Yemets , Yaroslav Blume","doi":"10.1016/j.niox.2025.10.003","DOIUrl":"10.1016/j.niox.2025.10.003","url":null,"abstract":"<div><div>Polyamines, γ-aminobutyric acid (GABA), proline, and glycine betaine (GB) are important plant stress metabolites that are interconnected in common metabolic cycles. These compounds have a multifunctional protective effect on plant cells under stress conditions, acting as osmoregulators, antioxidants, chaperones, and intracellular pH stabilizers, among other roles. The key role of these compounds, however, lies in their involvement in the signaling network of plant cells. Stress metabolites, in particular, engage in a complex functional interaction with reactive oxygen species (ROS) and nitric oxide (NO). Nevertheless, information detailing the links between NO and major nitrogen-containing stress metabolites is fragmented. Consequently, a holistic understanding of these interactions, even at the theoretical model level, has yet to be presented in the literature. The review investigates the phenomenology and mechanisms of NO's involvement as a signaling mediator in the stress-protective function of polyamines and GABA in plants. It also analyses the effect of NO on the content of polyamines, GABA, proline, and GB under normal and stressful conditions. The latest data on the role of S-nitrosation processes of enzymes involved in the regulation of content of low-molecular nitrogen-containing compounds in plant adaptation, and on the effect of polyamines on S-nitrosation of the proteome are summarized. Particular attention is paid to the links between nitric oxide and other signaling mediators (primarily ROS and Ca<sup>2+</sup>) during its functional interaction with stress metabolites. Regulation of NO and stress metabolite levels is considered one of the promising tools for managing plant stress resistance.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 126-146"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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