Pub Date : 2025-12-29DOI: 10.1016/j.niox.2025.12.002
Michelle Menon Miyake , Ipsita Mohanty , Sylvia N. Michki , Edwin Tamashiro , Noam A. Cohen , Harry Ischiropoulos
Nitric oxide metabolites (NOm) in biological fluids have been widely used as surrogate markers to inform changes in nitric oxide-mediated signaling, which is critical for many biological functions. One method for quantifying NOm employs chemical reduction to convert the various metabolites into nitric oxide, followed by ozone-based chemiluminescence detection. Herein, we tested and quantified the bioanalytical parameters of the reduction-chemiluminescence assay and propose conditions for optimizing the assay. The slopes of the standard curves used for quantifying the metabolites showed a 3.8 % intra-assay and 7.6 % inter-assay relative standard deviation (%RSD). An 8 % and 8.5 % RSD was measured for two separate quality control serum samples, and a Levey-Jennings plot showed that all individual values fell within 1 standard deviation of the mean of all measurements. Repeat analysis of human serum samples (n = 51) resulted in an average incurred sample reanalysis of 7.7 %, with 49 samples having repeated results above the original value, indicating no loss of NOm over the four-week period. This was further confirmed by recovery experiments, which indicated average recovery rates of 100.4 ± 8.2 % and 99.3 ± 4.3 % for two operators, respectively. ANOVA of data from two operators indicated that sample-to-sample variability was the main contributor to the total variance. Overall, our results demonstrate that the assay provides appropriate and reproducible quantification of NOm, supporting its use for both exploratory and routine laboratory applications.
{"title":"Analytic performance characteristics of the chemical-reduction gas phase-chemiluminescence assay for the quantification of nitric oxide metabolites","authors":"Michelle Menon Miyake , Ipsita Mohanty , Sylvia N. Michki , Edwin Tamashiro , Noam A. Cohen , Harry Ischiropoulos","doi":"10.1016/j.niox.2025.12.002","DOIUrl":"10.1016/j.niox.2025.12.002","url":null,"abstract":"<div><div>Nitric oxide metabolites (NOm) in biological fluids have been widely used as surrogate markers to inform changes in nitric oxide-mediated signaling, which is critical for many biological functions. One method for quantifying NOm employs chemical reduction to convert the various metabolites into nitric oxide, followed by ozone-based chemiluminescence detection. Herein, we tested and quantified the bioanalytical parameters of the reduction-chemiluminescence assay and propose conditions for optimizing the assay. The slopes of the standard curves used for quantifying the metabolites showed a 3.8 % intra-assay and 7.6 % inter-assay relative standard deviation (%RSD). An 8 % and 8.5 % RSD was measured for two separate quality control serum samples, and a Levey-Jennings plot showed that all individual values fell within 1 standard deviation of the mean of all measurements. Repeat analysis of human serum samples (n = 51) resulted in an average incurred sample reanalysis of 7.7 %, with 49 samples having repeated results above the original value, indicating no loss of NOm over the four-week period. This was further confirmed by recovery experiments, which indicated average recovery rates of 100.4 ± 8.2 % and 99.3 ± 4.3 % for two operators, respectively. ANOVA of data from two operators indicated that sample-to-sample variability was the main contributor to the total variance. Overall, our results demonstrate that the assay provides appropriate and reproducible quantification of NOm, supporting its use for both exploratory and routine laboratory applications.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"161 ","pages":"Pages 1-8"},"PeriodicalIF":3.2,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878752","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 : 2025-12-28DOI: 10.1016/j.niox.2025.12.003
Xiaofan Wu , Jiahe Zhao , Zhengqi Xu , Feng Jiang , Moran Wang , Jingwen Tao , Cuntai Zhang , Li Lin , Sheng Li
Objective
Patients with chronic kidney disease (CKD) usually exhibit high incidence and mortality rates of cardiovascular disease (CVD). Patients with CKD typically exhibit endothelial dysfunction, which represents one of the risk factors for CVD. As a signaling molecule, S-nitroso-l-cysteine (CSNO) plays a pivotal role in endothelial function. In this study, we explored the therapeutic value of CSNO on eNOS-KO CKD mice.
Methods
Male eNOS-KO mice were randomly assigned to one of three groups: control, adenine-induced CKD, and CKD with CSNO nebulization (88 ppm, 20 min/day for 6 weeks). Cardiac function was assessed via Doppler echocardiography. Fibrosis, hypertrophy, lipid accumulation, ROS production, and apoptosis were evaluated by HE, Masson, WGA, Oil Red O, DHE, and TUNEL staining, respectively.
Results
CSNO treatment significantly increased the kidney-to-body weight ratio compared to the eNOS-KO CKD group, and urinary creatinine levels exhibited an increasing trend, although this change was not statistically significant. Furthermore, CSNO markedly attenuated renal lipid accumulation. Echocardiography revealed that CSNO significantly enhanced left ventricular ejection fraction (LVEF) and tissue Doppler E'/A′ ratio. The E/A ratio also increased in the CSNO treatment group, but this change was not statistically significant. Moreover, CSNO alleviated cardiac hypertrophy, decreased ROS production, apoptosis, and lipid accumulation compared to the eNOS-KO CKD group.
Conclusion
Collectively, the findings of the present study demonstrated that CSNO improved cardiorenal function in eNOS-KO CKD mice, thereby affording a novel therapeutic approach to treat CKD patients with endothelial dysfunction.
目的：慢性肾脏疾病（CKD）患者通常表现为心血管疾病（CVD）的高发病率和死亡率。CKD患者通常表现为内皮功能障碍，这是心血管疾病的危险因素之一。作为一种信号分子，s -亚硝基半胱氨酸在内皮功能中起着至关重要的作用。在本研究中，我们探讨了CSNO对eNOS-KO CKD小鼠的治疗价值。方法：将雄性eNOS-KO小鼠随机分为三组：对照组、腺嘌呤诱导的CKD组和CSNO雾化组（88 ppm， 20分钟/天，持续6周）。通过多普勒超声心动图评估心功能。分别通过HE、Masson、WGA、Oil Red O、DHE和TUNEL染色评估纤维化、肥大、脂质积累、ROS产生和凋亡。结果：与eNOS-KO CKD组相比，CSNO治疗显著增加了肾体重比，尿肌酐水平呈上升趋势，但这种变化无统计学意义。此外，CSNO可显著减轻肾脏脂质积聚。超声心动图显示，CSNO显著提高左室射血分数（LVEF）和组织多普勒E‘/A’比值。CSNO治疗组E/A比值升高，但无统计学意义。此外，与eNOS-KO CKD组相比，CSNO减轻了心脏肥厚，减少了ROS的产生，细胞凋亡和脂质积累。结论：总的来说，本研究的结果表明，CSNO改善eNOS-KO CKD小鼠的心肾功能，从而为治疗伴有内皮功能障碍的CKD患者提供了一种新的治疗方法。
{"title":"Therapeutic potential of S-nitroso-l-cysteine in improving cardiorenal function in eNOS-KO CKD mice","authors":"Xiaofan Wu , Jiahe Zhao , Zhengqi Xu , Feng Jiang , Moran Wang , Jingwen Tao , Cuntai Zhang , Li Lin , Sheng Li","doi":"10.1016/j.niox.2025.12.003","DOIUrl":"10.1016/j.niox.2025.12.003","url":null,"abstract":"<div><h3>Objective</h3><div>Patients with chronic kidney disease (CKD) usually exhibit high incidence and mortality rates of cardiovascular disease (CVD). Patients with CKD typically exhibit endothelial dysfunction, which represents one of the risk factors for CVD. As a signaling molecule, S-nitroso-<span>l</span>-cysteine (CSNO) plays a pivotal role in endothelial function. In this study, we explored the therapeutic value of CSNO on eNOS-KO CKD mice.</div></div><div><h3>Methods</h3><div>Male eNOS-KO mice were randomly assigned to one of three groups: control, adenine-induced CKD, and CKD with CSNO nebulization (88 ppm, 20 min/day for 6 weeks). Cardiac function was assessed via Doppler echocardiography. Fibrosis, hypertrophy, lipid accumulation, ROS production, and apoptosis were evaluated by HE, Masson, WGA, Oil Red O, DHE, and TUNEL staining, respectively.</div></div><div><h3>Results</h3><div>CSNO treatment significantly increased the kidney-to-body weight ratio compared to the eNOS-KO CKD group, and urinary creatinine levels exhibited an increasing trend, although this change was not statistically significant. Furthermore, CSNO markedly attenuated renal lipid accumulation. Echocardiography revealed that CSNO significantly enhanced left ventricular ejection fraction (LVEF) and tissue Doppler E'/A′ ratio. The E/A ratio also increased in the CSNO treatment group, but this change was not statistically significant. Moreover, CSNO alleviated cardiac hypertrophy, decreased ROS production, apoptosis, and lipid accumulation compared to the eNOS-KO CKD group.</div></div><div><h3>Conclusion</h3><div>Collectively, the findings of the present study demonstrated that CSNO improved cardiorenal function in eNOS-KO CKD mice, thereby affording a novel therapeutic approach to treat CKD patients with endothelial dysfunction.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"161 ","pages":"Pages 9-17"},"PeriodicalIF":3.2,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145864434","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 : 2025-12-19DOI: 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":"2025-12-19","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 : 2025-11-28DOI: 10.1016/j.niox.2025.11.008
Stefano Spina , Timothy G. Gaulton
{"title":"Prone positioning and inhaled nitric oxide in patients with acute respiratory distress syndrome: synergism or independent effects?","authors":"Stefano Spina , Timothy G. Gaulton","doi":"10.1016/j.niox.2025.11.008","DOIUrl":"10.1016/j.niox.2025.11.008","url":null,"abstract":"","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"160 ","pages":"Pages 44-46"},"PeriodicalIF":3.2,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649035","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 : 2025-11-23DOI: 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":"2025-11-23","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 : 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":"2025-11-20","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 : 2025-11-19DOI: 10.1016/j.niox.2025.11.004
Ryosuke Shinkai , Takashi Tomita
Sauna bathing, a traditional health practice in Finland and Japan, has been associated with reduced cardiovascular and neurological risks. Circulatory recovery, marked by a shift from sympathetic to parasympathetic dominance, underlies the relaxation state known as “totonou.” Traditionally attributed to nitric oxide (NO), this effect may also involve hydrogen sulfide (H2S), a gaseous mediator with vasodilatory, antioxidant, and anti-inflammatory properties. We hypothesize that H2S facilitates sauna-induced circulatory recovery and that environmental exposure may modulate this process. This perspective highlights H2S as a novel regulator and calls for basic, clinical, and epidemiological studies to test this hypothesis.
{"title":"Hydrogen sulfide and the physiology of “totonou”: a hypothesis on sauna-induced vascular recovery","authors":"Ryosuke Shinkai , Takashi Tomita","doi":"10.1016/j.niox.2025.11.004","DOIUrl":"10.1016/j.niox.2025.11.004","url":null,"abstract":"<div><div>Sauna bathing, a traditional health practice in Finland and Japan, has been associated with reduced cardiovascular and neurological risks. Circulatory recovery, marked by a shift from sympathetic to parasympathetic dominance, underlies the relaxation state known as “totonou.” Traditionally attributed to nitric oxide (NO), this effect may also involve hydrogen sulfide (H<sub>2</sub>S), a gaseous mediator with vasodilatory, antioxidant, and anti-inflammatory properties. We hypothesize that H<sub>2</sub>S facilitates sauna-induced circulatory recovery and that environmental exposure may modulate this process. This perspective highlights H<sub>2</sub>S as a novel regulator and calls for basic, clinical, and epidemiological studies to test this hypothesis.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"160 ","pages":"Pages 24-27"},"PeriodicalIF":3.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564708","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 : 2025-11-19DOI: 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":"2025-11-19","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}
{"title":"Corrigendum to “Detection and proteomic identification of in vivo S-nitrosylated proteins in Vibrio cholerae: A novel evidence” [Nitric Oxide 159 (2025) 63–77]","authors":"Shuddhasattwa Samaddar , Surupa Chakraborty , Rajib Sengupta , Sanjay Ghosh","doi":"10.1016/j.niox.2025.11.003","DOIUrl":"10.1016/j.niox.2025.11.003","url":null,"abstract":"","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"160 ","pages":"Page 63"},"PeriodicalIF":3.2,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145549741","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}
Nitric oxide (NO) is a vital bioactive molecule, but its rapid degradation limits therapeutic applications. To enhance stability and controlled release, two novel systems were synthesized: MnFe2O4@Cap-SNO nanoparticles and Cs@Cap-SNO hydrogel. MnFe2O4@Cap-SNO, incorporating captopril (Cap) as an NO donor, demonstrated prolonged NO release for up to 16h upon light exposure, following zero-order kinetics, ensuring sustained delivery. Cs@Cap-SNO, a chitosan-based hydrogel integrating nitrosated captopril (Cap-SNO), exhibited faster NO release governed by Korsmeyer-Peppas kinetics. UV–Vis spectrophotometry confirmed successful nitrosation with distinct absorption bands at 335nm and 545nm. MnFe2O4@Cap-SNO displayed superior stability, outperforming Cs@Cap-SNO and free Cap-SNO in NO preservation. These findings suggest MnFe2O4@Cap-SNO as an effective NO-stabilizing carrier for biomedical applications, particularly intargeted drug delivery. Future studies will focus on in vitro and in vivo validation to assess therapeutic efficacy.
{"title":"Stabilizing nitric oxide: MnFe2O4@Cap-SNO nanoparticles and chitosan hydrogels for controlled therapeutic delivery","authors":"Soodabeh Gharibeh , Melika JaberebnAnsari , Elham Askarizadeh , Azhdar Heydari","doi":"10.1016/j.niox.2025.10.008","DOIUrl":"10.1016/j.niox.2025.10.008","url":null,"abstract":"<div><div>Nitric oxide (NO) is a vital bioactive molecule, but its rapid degradation limits therapeutic applications. To enhance stability and controlled release, two novel systems were synthesized: MnFe<sub>2</sub>O<sub>4</sub>@Cap-SNO nanoparticles and Cs@Cap-SNO hydrogel. MnFe<sub>2</sub>O<sub>4</sub>@Cap-SNO, incorporating captopril (Cap) as an NO donor, demonstrated prolonged NO release for up to 16h upon light exposure, following zero-order kinetics, ensuring sustained delivery. Cs@Cap-SNO, a chitosan-based hydrogel integrating nitrosated captopril (Cap-SNO), exhibited faster NO release governed by Korsmeyer-Peppas kinetics. UV–Vis spectrophotometry confirmed successful nitrosation with distinct absorption bands at 335nm and 545nm. MnFe<sub>2</sub>O<sub>4</sub>@Cap-SNO displayed superior stability, outperforming Cs@Cap-SNO and free Cap-SNO in NO preservation. These findings suggest MnFe<sub>2</sub>O<sub>4</sub>@Cap-SNO as an effective NO-stabilizing carrier for biomedical applications, particularly intargeted drug delivery. Future studies will focus on in vitro and in vivo validation to assess therapeutic efficacy.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"160 ","pages":"Pages 1-13"},"PeriodicalIF":3.2,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477101","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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