Pub Date : 2025-01-07DOI: 10.1016/j.niox.2025.01.002
Kanchana Pandian , Rudmer Postma , Anton Jan van Zonneveld , Amy Harms , Thomas Hankemeier
COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily manifests as a flu-like illness with lung injury, often necessitating supplemental oxygen. Elderly individuals and those with pre-existing cardiovascular diseases are at increased risk of mortality. The endothelial barrier disruption observed in patients indicates systemic viral invasion and widespread endotheliitis. Endothelial dysfunction, characterized by impaired nitric oxide (NO) production, contributes to vasoconstriction, inflammation, and coagulation abnormalities seen in COVID-19. In this study, we investigated the impact of COVID-19 patient-derived plasma on the endothelium through NO metabolite analysis using an in vitro 3D micro vessel model. Our experiments revealed alterations in NO metabolites in response to COVID-19 patient plasma perfusion, with BH4+BH2 supplementation improving citrulline levels in severe COVID-19 patient models. Positive correlation between arginase activity and eNOS activity was observed in the severe COVID-19 patient model but not in the mild COVID-19 patient model. These findings underscore the importance of endothelial dysfunction in COVID-19 pathogenesis and highlight potential therapeutic targets for mitigating vascular complications associated with severe infection.
{"title":"Microvessels-on-chip: Exploring endothelial cells and COVID-19 plasma interaction with nitric oxide metabolites","authors":"Kanchana Pandian , Rudmer Postma , Anton Jan van Zonneveld , Amy Harms , Thomas Hankemeier","doi":"10.1016/j.niox.2025.01.002","DOIUrl":"10.1016/j.niox.2025.01.002","url":null,"abstract":"<div><div>COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily manifests as a flu-like illness with lung injury, often necessitating supplemental oxygen. Elderly individuals and those with pre-existing cardiovascular diseases are at increased risk of mortality. The endothelial barrier disruption observed in patients indicates systemic viral invasion and widespread endotheliitis. Endothelial dysfunction, characterized by impaired nitric oxide (NO) production, contributes to vasoconstriction, inflammation, and coagulation abnormalities seen in COVID-19. In this study, we investigated the impact of COVID-19 patient-derived plasma on the endothelium through NO metabolite analysis using an in vitro 3D micro vessel model. Our experiments revealed alterations in NO metabolites in response to COVID-19 patient plasma perfusion, with BH4+BH2 supplementation improving citrulline levels in severe COVID-19 patient models. Positive correlation between arginase activity and eNOS activity was observed in the severe COVID-19 patient model but not in the mild COVID-19 patient model. These findings underscore the importance of endothelial dysfunction in COVID-19 pathogenesis and highlight potential therapeutic targets for mitigating vascular complications associated with severe infection.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"155 ","pages":"Pages 12-19"},"PeriodicalIF":3.2,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-27DOI: 10.1016/j.niox.2024.12.003
Dong Ding , Ran Tian , Xiao Yang , Zhe Ren , Zhi-Cheng Jing , Xin-Tong Wu , Lian-Wen Sun
Background
Osteocytes are crucial for detecting mechanical stimuli and translating them into biochemical responses within the bone. The primary cilium, a cellular 'antenna,' plays a vital role in this process. However, there is a lack of direct correlation between cilium length changes and osteocyte mechanosensitivity changes. This study aims to reveal the relationship between ciliary length and nitric oxide (NO) release in osteocytes to show how primary cilia may be involved in reducing osteocyte mechanosensitivity caused by microgravity.
Materials and methods
We used the MLO-Y4 cell line and primary osteoblasts to adjust the ciliary length using chloral hydrate (CH) for shortening and lithium ions (Li+) for elongation. We then examined the impact of varied ciliary lengths on osteocyte response to fluid shear stress, focusing on the PC1/PC2–Ca2+-NO signaling pathway. Co-culture systems assessed downstream effects on osteoblast function, including collagen secretion and mineralization.
Results
We observed a significant correlation between ciliary length and osteocyte mechanosensitivity, with longer primary cilia enhancing Ca2+ influx and NO release in response to fluid shear stress. However, contrary to expectations, calmodulin (CaM) expression did not increase with ciliary length, suggesting alternative pathways, such as PKC or Akt/PKB, may modulate p-eNOS activity. Co-cultured osteoblasts showed altered osteogenic functions regulated by osteocyte-derived signals influenced by primary cilia length.
Conclusion
Our findings clarify the role of primary cilia length in modulating osteocyte mechanosensitivity and their influence on osteoblast function, highlighting a complex regulatory network that may not solely rely on CaM for NO release. These insights contribute to a deeper understanding of bone mechanotransduction and could have implications for developing therapeutic targets for osteocyte-related disorders.
{"title":"The impact of ciliary length on the mechanical response of osteocytes to fluid shear stress","authors":"Dong Ding , Ran Tian , Xiao Yang , Zhe Ren , Zhi-Cheng Jing , Xin-Tong Wu , Lian-Wen Sun","doi":"10.1016/j.niox.2024.12.003","DOIUrl":"10.1016/j.niox.2024.12.003","url":null,"abstract":"<div><h3>Background</h3><div>Osteocytes are crucial for detecting mechanical stimuli and translating them into biochemical responses within the bone. The primary cilium, a cellular 'antenna,' plays a vital role in this process. However, there is a lack of direct correlation between cilium length changes and osteocyte mechanosensitivity changes. This study aims to reveal the relationship between ciliary length and nitric oxide (NO) release in osteocytes to show how primary cilia may be involved in reducing osteocyte mechanosensitivity caused by microgravity.</div></div><div><h3>Materials and methods</h3><div>We used the MLO-Y4 cell line and primary osteoblasts to adjust the ciliary length using chloral hydrate (CH) for shortening and lithium ions (Li<sup>+</sup>) for elongation. We then examined the impact of varied ciliary lengths on osteocyte response to fluid shear stress, focusing on the PC1/PC2–Ca<sup>2+</sup>-NO signaling pathway. Co-culture systems assessed downstream effects on osteoblast function, including collagen secretion and mineralization.</div></div><div><h3>Results</h3><div>We observed a significant correlation between ciliary length and osteocyte mechanosensitivity, with longer primary cilia enhancing Ca<sup>2+</sup> influx and NO release in response to fluid shear stress. However, contrary to expectations, calmodulin (CaM) expression did not increase with ciliary length, suggesting alternative pathways, such as PKC or Akt/PKB, may modulate <em>p</em>-eNOS activity. Co-cultured osteoblasts showed altered osteogenic functions regulated by osteocyte-derived signals influenced by primary cilia length.</div></div><div><h3>Conclusion</h3><div>Our findings clarify the role of primary cilia length in modulating osteocyte mechanosensitivity and their influence on osteoblast function, highlighting a complex regulatory network that may not solely rely on CaM for NO release. These insights contribute to a deeper understanding of bone mechanotransduction and could have implications for developing therapeutic targets for osteocyte-related disorders.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"155 ","pages":"Pages 1-11"},"PeriodicalIF":3.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903238","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 : 2024-11-22DOI: 10.1016/j.niox.2024.11.009
Kang Yi , Tao Guo , Wen-Xin Wang , Shao-E He , Xin Zhang , Jian-Guo Xu , Zi-Qiang Wang , Fan-Ning Wang , Tao You
<div><h3>Background</h3><div>We performed the present study to better elucidate the correlation of nitric oxide synthase 3 (NOS3) gene polymorphism with the risk of pulmonary arterial hypertension (PAH).</div></div><div><h3>Material/methods</h3><div>According to the designed search strategy, a systematic literature search was performed through the PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP and Wan Fang databases to collect published case-control studies on the correlation between NOS3 gene polymorphism and PAH. The search deadline was December 26, 2023. Two reviewers independently screened the literature, extracted data and evaluated the quality according to the inclusion and exclusion criteria. Meta-analysis was performed using RevMan 5.4 software. The odds ratio (OR) and 95 % confidence interval (CI) of the genotype distribution were used as the effect indicators.</div></div><div><h3>Results</h3><div>A total of 11 eligible studies were included, involving three single nucleotide polymorphism (SNP) sites of the NOS3 gene: G894T (rs1799983), 4b/4a (rs61722009), and T-786C (rs2070744). The meta-analysis revealed that for PAH analysis, 4 genetic models of NOS3 G894T polymorphism increased the risk of PAH: the allele model (T vs G, OR = 1.9, 95%CI [1.16, 3.11],P = 0.01), the homozygote model (GG vs TT, OR = 1.91, 95%CI [1.04, 3.51], P = 0.04), the heterozygote model (GG vs GT, OR = 3.19, 95%CI [1.65, 6.19], P = 0.0006) and the dominant model (GT + TT vs GG, OR = 3.06, 95%CI [1.54, 6.09], P = 0.001). In the subgroups analysis, the NOS3 G894T polymorphism was found to be associated with the risk of PAH subgroups, including CHD combined with PAH and COPD combined with PAH, Particularly, there is a highly significant correlation with CHD combined with PAH. 2 genetic models of NOS3 4b/4a polymorphism increased the risk of PAH: the homozygote model (BB vs AA, OR = 2.1, 95%CI [1.02, 4.35], P = 0.04) and the recessive model (BB + BA vs AA, OR = 2.55, 95%CI [1.27, 5.11], P = 0.009). In the subgroups analysis, the NOS3 4b/4a polymorphism was found to be associated with the susceptibility of CHD combined with PAH. The results of the combined analysis of each gene model of NOS3 T-786C gene polymorphism sites were not statistically significant, and their P values were all>0.05. The NOS3 G894T and NOS3 4b/4a gene polymorphism had been found to be associated with the risk of PAH in different regional and racial subgroups. In contrast to the NOS3 G894T gene polymorphism, which increased the risk of PAH development in the yellow race subgroup, the NOS3 4b/4a gene polymorphism reduced the risk of PAH development in the white race subgroup and was a protective factor.</div></div><div><h3>Conclusions</h3><div>The NOS3 G894T (rs1799983) and NOS3 4b/4a (rs61722009) gene polymorphism have a strong correlation with the risk of PAH, with this association varying among different regions and ethnicities. However, it is still necessary to expand the sample
{"title":"The relationship of nitric oxide synthase 3(NOS3) gene polymorphism in the risk of pulmonary arterial hypertension: A systematic review and meta-analysis","authors":"Kang Yi , Tao Guo , Wen-Xin Wang , Shao-E He , Xin Zhang , Jian-Guo Xu , Zi-Qiang Wang , Fan-Ning Wang , Tao You","doi":"10.1016/j.niox.2024.11.009","DOIUrl":"10.1016/j.niox.2024.11.009","url":null,"abstract":"<div><h3>Background</h3><div>We performed the present study to better elucidate the correlation of nitric oxide synthase 3 (NOS3) gene polymorphism with the risk of pulmonary arterial hypertension (PAH).</div></div><div><h3>Material/methods</h3><div>According to the designed search strategy, a systematic literature search was performed through the PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP and Wan Fang databases to collect published case-control studies on the correlation between NOS3 gene polymorphism and PAH. The search deadline was December 26, 2023. Two reviewers independently screened the literature, extracted data and evaluated the quality according to the inclusion and exclusion criteria. Meta-analysis was performed using RevMan 5.4 software. The odds ratio (OR) and 95 % confidence interval (CI) of the genotype distribution were used as the effect indicators.</div></div><div><h3>Results</h3><div>A total of 11 eligible studies were included, involving three single nucleotide polymorphism (SNP) sites of the NOS3 gene: G894T (rs1799983), 4b/4a (rs61722009), and T-786C (rs2070744). The meta-analysis revealed that for PAH analysis, 4 genetic models of NOS3 G894T polymorphism increased the risk of PAH: the allele model (T vs G, OR = 1.9, 95%CI [1.16, 3.11],P = 0.01), the homozygote model (GG vs TT, OR = 1.91, 95%CI [1.04, 3.51], P = 0.04), the heterozygote model (GG vs GT, OR = 3.19, 95%CI [1.65, 6.19], P = 0.0006) and the dominant model (GT + TT vs GG, OR = 3.06, 95%CI [1.54, 6.09], P = 0.001). In the subgroups analysis, the NOS3 G894T polymorphism was found to be associated with the risk of PAH subgroups, including CHD combined with PAH and COPD combined with PAH, Particularly, there is a highly significant correlation with CHD combined with PAH. 2 genetic models of NOS3 4b/4a polymorphism increased the risk of PAH: the homozygote model (BB vs AA, OR = 2.1, 95%CI [1.02, 4.35], P = 0.04) and the recessive model (BB + BA vs AA, OR = 2.55, 95%CI [1.27, 5.11], P = 0.009). In the subgroups analysis, the NOS3 4b/4a polymorphism was found to be associated with the susceptibility of CHD combined with PAH. The results of the combined analysis of each gene model of NOS3 T-786C gene polymorphism sites were not statistically significant, and their P values were all>0.05. The NOS3 G894T and NOS3 4b/4a gene polymorphism had been found to be associated with the risk of PAH in different regional and racial subgroups. In contrast to the NOS3 G894T gene polymorphism, which increased the risk of PAH development in the yellow race subgroup, the NOS3 4b/4a gene polymorphism reduced the risk of PAH development in the white race subgroup and was a protective factor.</div></div><div><h3>Conclusions</h3><div>The NOS3 G894T (rs1799983) and NOS3 4b/4a (rs61722009) gene polymorphism have a strong correlation with the risk of PAH, with this association varying among different regions and ethnicities. However, it is still necessary to expand the sample ","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"154 ","pages":"Pages 51-76"},"PeriodicalIF":3.2,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695740","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}
Hydrogen sulfide has been known to humans for about 300 years and the previous studies emphasize only on its toxic side effects. In the last two decennium, researchers have varied their perspectives and insights towards H2S biology based on experimental findings. It has been found that H2S is an endogenic gaseous signaling molecule in many organisms and plays a crucial role in many systems and diseases. Early reports suggest that H2S as a neuromodulator influences calcium levels within the brain cells which ultimately control memory, learning, and cognition. It has also been observed that some complications in the pathogenesis of neurodegenerative diseases are due to anomalies in the biosynthesis and metabolism of H2S. This review focuses on the role of H2S in the pathophysiology of major neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Vascular dementia. H2S was observed to have a protective role in the above-mentioned neurological conditions and the H2S donor therapy may help in disease management. The H2S gas displays a neuroprotective role and protects against cellular damage thereby declining the neurological conditions. Some studies have revealed that treatment with H2S donors has improved neuronal damage, restored memory and cognition in animal models. In this review, we have discussed the role of H2S donors as neuroprotective agents with examples of some of the natural and synthetic H2S donors, and also briefly enumerated the molecules used to detect H2S in neurodegenerative diseases.
{"title":"Critical role of hydrogen sulfide in the management of neurodegenerative disease","authors":"Rajashree Pawar , Dheeraj Pandey , Saba Naqvi , Abha Sharma","doi":"10.1016/j.niox.2024.11.006","DOIUrl":"10.1016/j.niox.2024.11.006","url":null,"abstract":"<div><div>Hydrogen sulfide has been known to humans for about 300 years and the previous studies emphasize only on its toxic side effects. In the last two decennium, researchers have varied their perspectives and insights towards H<sub>2</sub>S biology based on experimental findings. It has been found that H<sub>2</sub>S is an endogenic gaseous signaling molecule in many organisms and plays a crucial role in many systems and diseases. Early reports suggest that H<sub>2</sub>S as a neuromodulator influences calcium levels within the brain cells which ultimately control memory, learning, and cognition. It has also been observed that some complications in the pathogenesis of neurodegenerative diseases are due to anomalies in the biosynthesis and metabolism of H<sub>2</sub>S. This review focuses on the role of H<sub>2</sub>S in the pathophysiology of major neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Vascular dementia. H<sub>2</sub>S was observed to have a protective role in the above-mentioned neurological conditions and the H<sub>2</sub>S donor therapy may help in disease management. The H<sub>2</sub>S gas displays a neuroprotective role and protects against cellular damage thereby declining the neurological conditions. Some studies have revealed that treatment with H<sub>2</sub>S donors has improved neuronal damage, restored memory and cognition in animal models. In this review, we have discussed the role of H<sub>2</sub>S donors as neuroprotective agents with examples of some of the natural and synthetic H<sub>2</sub>S donors, and also briefly enumerated the molecules used to detect H<sub>2</sub>S in neurodegenerative diseases.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"154 ","pages":"Pages 77-85"},"PeriodicalIF":3.2,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693321","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 : 2024-11-20DOI: 10.1016/j.niox.2024.11.007
Haoqi Li , Zijie Cheng , Dan Wu , Qingxun Hu
Nitric oxide (NO) has been highlighted as an important factor in cardiovascular system. As a signaling molecule in the cardiovascular system, NO can relax blood vessels, lower blood pressure, and prevent platelet aggregation. Mitochondria serve as a central hub for cellular metabolism and intracellular signaling, and their dysfunction can lead to a variety of diseases. Accumulating evidence suggests that NO can act as a regulator of mitochondria, affecting mitochondrial function and cellular activity, which in turn mediates the onset and progression of disease. However, there is a lack of comprehensive understanding of how NO regulates mitochondrial function in the cardiovascular system. This review aims to summarize the regulation of mitochondrial function by nitric oxide in cardiovascular related diseases, as well as the multifaceted and complex roles of NO in the cardiovascular system. Understanding the mechanism of NO mediated mitochondrial function can provide new insights for the prevention and treatment of cardiovascular diseases.
一氧化氮（NO）被认为是心血管系统的一个重要因素。作为心血管系统的信号分子，一氧化氮可以放松血管、降低血压和防止血小板聚集。线粒体是细胞新陈代谢和细胞内信号传导的中枢，其功能障碍可导致多种疾病。越来越多的证据表明，氮氧化物可作为线粒体的调节剂，影响线粒体功能和细胞活性，进而介导疾病的发生和发展。然而，人们对 NO 如何调节心血管系统线粒体功能还缺乏全面的了解。本综述旨在总结一氧化氮在心血管相关疾病中对线粒体功能的调控，以及一氧化氮在心血管系统中多方面的复杂作用。了解一氧化氮介导线粒体功能的机制可为预防和治疗心血管疾病提供新的见解。
{"title":"Nitric oxide and mitochondrial function in cardiovascular diseases","authors":"Haoqi Li , Zijie Cheng , Dan Wu , Qingxun Hu","doi":"10.1016/j.niox.2024.11.007","DOIUrl":"10.1016/j.niox.2024.11.007","url":null,"abstract":"<div><div>Nitric oxide (NO) has been highlighted as an important factor in cardiovascular system. As a signaling molecule in the cardiovascular system, NO can relax blood vessels, lower blood pressure, and prevent platelet aggregation. Mitochondria serve as a central hub for cellular metabolism and intracellular signaling, and their dysfunction can lead to a variety of diseases. Accumulating evidence suggests that NO can act as a regulator of mitochondria, affecting mitochondrial function and cellular activity, which in turn mediates the onset and progression of disease. However, there is a lack of comprehensive understanding of how NO regulates mitochondrial function in the cardiovascular system. This review aims to summarize the regulation of mitochondrial function by nitric oxide in cardiovascular related diseases, as well as the multifaceted and complex roles of NO in the cardiovascular system. Understanding the mechanism of NO mediated mitochondrial function can provide new insights for the prevention and treatment of cardiovascular diseases.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"154 ","pages":"Pages 42-50"},"PeriodicalIF":3.2,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693322","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 : 2024-11-19DOI: 10.1016/j.niox.2024.11.005
Guangjie Liu , Dengfeng Lu , Jie Wu , Shixin Wang , Aojie Duan , Yubo Ren , Yu Zhang , Lei Meng , Renjie Shou , Haiying Li , Zhong Wang , Zongqi Wang , Xiaoou Sun
Traumatic brain injury (TBI) has the highest incidence of all common neurological disorders, along with high mortality and disability rates. Pathological conversion of excess nitric oxide (NO) to S-nitrosoglutathion (GSNO) after TBI leads to high S-nitrosylation of intracellular proteins, causing nitrative stress. GSNO reductase (GSNOR) plays an important role by regulating GSNO and SNO-proteins (PSNOs) and as a redox regulator of the nervous system. However, the effect of GSNOR on protein S-nitrosylation in secondary brain injury after TBI is not clear. In vivo TBI model was established in male C57BL/6 mice via controlled cortical impact (CCI). Neuron-targeted GSNOR-overexpression adeno-associated virus (AAV) was constructed and administered to mice by stereotactic cortical injection. The results showed that NO, GSNO, neuronal protein S-nitrosylation and neuronal death increased after TBI, while the level and activity of GSNOR decreased. Overexpression of GSNOR by AAV decreased GSNO and NO and improved short-term neurobehavioral outcomes in mice. GSNOR overexpression can reduce endoplasmic reticulum stress and neuronal death by reducing the S-nitrosylation of ERO1α via H2O2 generation and plays a neuroprotective role. In conclusion, our results suggest that GSNOR regulating S-nitrosylation of ERO1α may participate in neuronal death, and overexpression of GSNOR in neurons after experimental brain injury alleviates secondary brain injury. Our research provides a potential therapeutic approach for the treatment of TBI.
{"title":"Enhancing S-nitrosoglutathione reductase decreases S-nitrosylation of ERO1α and reduces neuronal death in secondary traumatic brain injury","authors":"Guangjie Liu , Dengfeng Lu , Jie Wu , Shixin Wang , Aojie Duan , Yubo Ren , Yu Zhang , Lei Meng , Renjie Shou , Haiying Li , Zhong Wang , Zongqi Wang , Xiaoou Sun","doi":"10.1016/j.niox.2024.11.005","DOIUrl":"10.1016/j.niox.2024.11.005","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) has the highest incidence of all common neurological disorders, along with high mortality and disability rates. Pathological conversion of excess nitric oxide (NO) to S-nitrosoglutathion (GSNO) after TBI leads to high S-nitrosylation of intracellular proteins, causing nitrative stress. GSNO reductase (GSNOR) plays an important role by regulating GSNO and SNO-proteins (PSNOs) and as a redox regulator of the nervous system. However, the effect of GSNOR on protein S-nitrosylation in secondary brain injury after TBI is not clear. <em>In vivo</em> TBI model was established in male C57BL/6 mice via controlled cortical impact (CCI). Neuron-targeted GSNOR-overexpression adeno-associated virus (AAV) was constructed and administered to mice by stereotactic cortical injection. The results showed that NO, GSNO, neuronal protein S-nitrosylation and neuronal death increased after TBI, while the level and activity of GSNOR decreased. Overexpression of GSNOR by AAV decreased GSNO and NO and improved short-term neurobehavioral outcomes in mice. GSNOR overexpression can reduce endoplasmic reticulum stress and neuronal death by reducing the S-nitrosylation of ERO1α via H<sub>2</sub>O<sub>2</sub> generation and plays a neuroprotective role. In conclusion, our results suggest that GSNOR regulating S-nitrosylation of ERO1α may participate in neuronal death, and overexpression of GSNOR in neurons after experimental brain injury alleviates secondary brain injury. Our research provides a potential therapeutic approach for the treatment of TBI.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"154 ","pages":"Pages 29-41"},"PeriodicalIF":3.2,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681587","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 : 2024-11-17DOI: 10.1016/j.niox.2024.11.003
Lori M. Estes Bright , Arnab Mondal , Vicente Pinon , Anil Kumar , Stephen Thompson , Elizabeth J. Brisbois , Hitesh Handa
The persistent infection of medical devices by opportunistic pathogens has led to the development of antimicrobial medical device polymers. Nitric oxide (NO) is an endogenous antimicrobial molecule that is released through the degradation of synthetic donor molecules such as S-nitroso-N-acetylpenicillamine (SNAP) embedded into polymer membranes. It is hypothesized that the clinical success of these polymers is enhanced by the physiological release of NO and the consequent prevention of infection. However, such NO-releasing materials have never been evaluated against microbial loads that are commensurate with clinical infection levels. This study aimed to develop a standardized polymer film impregnated with SNAP that consistently releases NO and evaluates its efficacy against bacterial loads that represent clinical infection parameters. Microbial loads of 103, 105, and 108 (colony-forming units) CFU mL−1 were exposed to the NO-releasing polymer, corresponding to bloodstream infections, catheter-associated urinary tract infections, and standard laboratory exposure levels that have been reported in the scientific literature. By 24 h, SNAP films led to >1 log reduction of adhered and viable E. coli at all tested microbial loads compared to control polydimethylsiloxane (PDMS). Further, SNAP films displayed no viable adhered S. aureus at the 103 microbial level for the entire study and showed total planktonic killing by 8 h. NO localization within bacterial cells adhering to the films was evaluated, revealing higher NO uptake and consequent bacterial killing by SNAP samples. This unique study shows that NO-releasing polymers not only kill bacteria adhered to the polymer surface, but localized delivery leads to environmental planktonic bacterial killing that prevents adhesion from occurring. Furthermore, the promising findings of NO-releasing polymers in scientific research indicate their potential for successful application in clinical settings to prevent infections.
机会性病原体对医疗器械的持续感染促使人们开发抗菌医疗器械聚合物。一氧化氮（NO）是一种内源性抗菌气体，可通过嵌入聚合物膜的合成供体分子（如 S-亚硝基-N-乙酰青霉胺（SNAP））的降解释放出来。据推测，NO 的生理性释放可提高这些聚合物的临床疗效，从而预防感染。然而，此类释放 NO 的材料从未针对与临床感染水平相当的微生物负荷进行过评估。本研究旨在开发一种能持续释放 NO 的浸渍 SNAP 标准聚合物薄膜，并评估其对代表临床感染参数的细菌载量的功效。将 103、105 和 108（菌落形成单位）CFU mL-1 的微生物量暴露在释放 NO 的聚合物上，这与科学文献中报道的血流感染、导管相关性尿路感染和标准实验室暴露水平相对应。与对照组聚二甲基硅氧烷（PDMS）相比，在 24 小时内，SNAP 薄膜可使所有测试微生物负荷下的附着和存活大肠杆菌减少 > 1 log。此外，在整个研究过程中，SNAP 薄膜在 103 个微生物水平上没有显示出存活的粘附金黄色葡萄球菌，并在 8 小时内显示出完全的浮游杀菌效果。对粘附在薄膜上的细菌细胞内的 NO 定位情况进行了评估，结果表明 SNAP 样品对 NO 的吸收率更高，从而杀死了更多细菌。这项独特的研究表明，释放 NO 的聚合物不仅能杀死粘附在聚合物表面的细菌，而且局部递送还能杀死环境中的浮游细菌，防止发生粘附。此外，氮氧化物释放聚合物在科学研究中取得的令人鼓舞的成果表明，它们有望成功应用于临床环境，预防感染。
{"title":"Investigation of the susceptibility of clinical infection loads to nitric oxide antibacterial treatment","authors":"Lori M. Estes Bright , Arnab Mondal , Vicente Pinon , Anil Kumar , Stephen Thompson , Elizabeth J. Brisbois , Hitesh Handa","doi":"10.1016/j.niox.2024.11.003","DOIUrl":"10.1016/j.niox.2024.11.003","url":null,"abstract":"<div><div>The persistent infection of medical devices by opportunistic pathogens has led to the development of antimicrobial medical device polymers. Nitric oxide (NO) is an endogenous antimicrobial molecule that is released through the degradation of synthetic donor molecules such as <em>S</em>-nitroso-<em>N</em>-acetylpenicillamine (SNAP) embedded into polymer membranes. It is hypothesized that the clinical success of these polymers is enhanced by the physiological release of NO and the consequent prevention of infection. However, such NO-releasing materials have never been evaluated against microbial loads that are commensurate with clinical infection levels. This study aimed to develop a standardized polymer film impregnated with SNAP that consistently releases NO and evaluates its efficacy against bacterial loads that represent clinical infection parameters. Microbial loads of 10<sup>3</sup>, 10<sup>5</sup>, and 10<sup>8</sup> (colony-forming units) CFU mL<sup>−1</sup> were exposed to the NO-releasing polymer, corresponding to bloodstream infections, catheter-associated urinary tract infections, and standard laboratory exposure levels that have been reported in the scientific literature. By 24 h, SNAP films led to >1 log reduction of adhered and viable <em>E. coli</em> at all tested microbial loads compared to control polydimethylsiloxane (PDMS). Further, SNAP films displayed no viable adhered <em>S. aureus</em> at the 10<sup>3</sup> microbial level for the entire study and showed total planktonic killing by 8 h. NO localization within bacterial cells adhering to the films was evaluated, revealing higher NO uptake and consequent bacterial killing by SNAP samples. This unique study shows that NO-releasing polymers not only kill bacteria adhered to the polymer surface, but localized delivery leads to environmental planktonic bacterial killing that prevents adhesion from occurring. Furthermore, the promising findings of NO-releasing polymers in scientific research indicate their potential for successful application in clinical settings to prevent infections.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"154 ","pages":"Pages 19-28"},"PeriodicalIF":3.2,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676257","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 : 2024-11-14DOI: 10.1016/j.niox.2024.11.002
Kejin Song , Hongwei Li , Kunjian Yang , Tengfei Ma , Yingying Hu , Ji Chen , Shunqin Zhu , Wanhong Liu
As a donor of the gaseous signaling molecule nitric oxide (NO), sodium nitroprusside (SNP) has been shown to play a positive role in enhancing plant resistance to abiotic stress. However, its role in alleviating cadmium (Cd) toxicity in tobacco (Nicotiana tabacum L.) is not fully understood. This study found that Cd stress significantly inhibited tobacco growth. At the same time, 150 μM SNP was the most effective concentration in alleviating Cd toxicity in seedlings, restoring three stress tolerance indicators—MDA, H2O2, and proline—to control levels. Exogenous SNP mitigated Cd-induced oxidative stress by promoting the accumulation of non-enzymatic antioxidants (total phenolics and flavonoids) and activating key antioxidant enzymes (SOD, CAT, POD, APX, and GR) along with their gene expression. SNP also facilitated Cd accumulation in the root cell wall and prevented Cd translocation from roots to shoots. Additionally, SNP altered Cd's subcellular distribution, promoting its sequestration in vacuoles and cell walls, which may be related to the NO-mediated upregulation of the metallothionein gene NtMT2F and the phytochelatin gene NtPCS2. The addition of SNP significantly increased the proportion of Cd in less toxic chemical forms, with the residual Cd fraction in the Cd + SNP group reaching 7.30 %, higher than the 4.86 % in the Cd-only group. Furthermore, exogenous SNP counteracted Cd's inhibition of nitrate reductase (NR) activity, promoting endogenous NO production. This study systematically reveals the positive roles of exogenous SNP in mitigating Cd toxicity in tobacco, offering valuable insights for producing low-Cd tobacco.
作为气态信号分子一氧化氮（NO）的供体，硝普钠（SNP）已被证明在增强植物对非生物胁迫的抵抗力方面发挥了积极作用。然而，它在减轻烟草（Nicotiana tabacum L.）镉（Cd）毒性方面的作用还不完全清楚。本研究发现，镉胁迫会明显抑制烟草的生长。同时，150 μM SNP 是缓解烟苗镉毒性的最有效浓度，它能将三项胁迫耐受性指标--MDA、H2O2 和脯氨酸恢复到控制水平。外源 SNP 可促进非酶抗氧化剂（总酚类和类黄酮）的积累，激活关键抗氧化酶（SOD、CAT、POD、APX 和 GR）及其基因表达，从而减轻镉诱导的氧化应激。SNP 还能促进镉在根细胞壁中的积累，阻止镉从根向芽的转移。此外，SNP 还改变了镉的亚细胞分布，促进了镉在液泡和细胞壁中的螯合，这可能与 NO 介导的金属硫蛋白基因 NtMT2F 和植物螯合素基因 NtPCS2 的上调有关。加入 SNP 后，镉以毒性较低的化学形式存在的比例明显增加，Cd + SNP 组的残余镉比例达到 7.30%，高于纯 Cd 组的 4.86%。此外，外源性 SNP 抵消了镉对硝酸还原酶（NR）活性的抑制，促进了内源性 NO 的产生。这项研究系统地揭示了外源 SNP 在减轻烟草镉毒性方面的积极作用，为生产低镉烟草提供了宝贵的启示。
{"title":"Exogenous sodium nitroprusside exhibits multiple positive roles in alleviating cadmium toxicity in tobacco (Nicotiana tabacum L.)","authors":"Kejin Song , Hongwei Li , Kunjian Yang , Tengfei Ma , Yingying Hu , Ji Chen , Shunqin Zhu , Wanhong Liu","doi":"10.1016/j.niox.2024.11.002","DOIUrl":"10.1016/j.niox.2024.11.002","url":null,"abstract":"<div><div>As a donor of the gaseous signaling molecule nitric oxide (NO), sodium nitroprusside (SNP) has been shown to play a positive role in enhancing plant resistance to abiotic stress. However, its role in alleviating cadmium (Cd) toxicity in tobacco (<em>Nicotiana tabacum</em> L.) is not fully understood. This study found that Cd stress significantly inhibited tobacco growth. At the same time, 150 μM SNP was the most effective concentration in alleviating Cd toxicity in seedlings, restoring three stress tolerance indicators—MDA, H<sub>2</sub>O<sub>2</sub>, and proline—to control levels. Exogenous SNP mitigated Cd-induced oxidative stress by promoting the accumulation of non-enzymatic antioxidants (total phenolics and flavonoids) and activating key antioxidant enzymes (SOD, CAT, POD, APX, and GR) along with their gene expression. SNP also facilitated Cd accumulation in the root cell wall and prevented Cd translocation from roots to shoots. Additionally, SNP altered Cd's subcellular distribution, promoting its sequestration in vacuoles and cell walls, which may be related to the NO-mediated upregulation of the metallothionein gene <em>NtMT2F</em> and the phytochelatin gene <em>NtPCS2</em>. The addition of SNP significantly increased the proportion of Cd in less toxic chemical forms, with the residual Cd fraction in the Cd + SNP group reaching 7.30 %, higher than the 4.86 % in the Cd-only group. Furthermore, exogenous SNP counteracted Cd's inhibition of nitrate reductase (NR) activity, promoting endogenous NO production. This study systematically reveals the positive roles of exogenous SNP in mitigating Cd toxicity in tobacco, offering valuable insights for producing low-Cd tobacco.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"154 ","pages":"Pages 8-18"},"PeriodicalIF":3.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639332","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 : 2024-11-07DOI: 10.1016/j.niox.2024.11.001
Tapan A. Patel , Lie Gao , Shane H. Boomer , Xuefei Liu , Kaushik P. Patel , Hong Zheng
Activation of both renin-angiotensin system (RAS) and the sympathetic system is the primary etiologic event in developing cardiovascular complications in diabetes mellitus (DM). However, the precise mechanisms for sympathetic activation in DM have not been elucidated. Here we attempted to investigate diabetes-linked cardiovascular dysregulation due to angiotensin II (Ang II)-mediated reduction in neuronal nitric oxide (NO) synthase (nNOS) within the paraventricular neuleus (PVN). In the present study, we used Ins2+/−Akita (a spontaneous, insulin-dependent genetic diabetic non-obese murine model) and wild-type (WT) littermates mice as controls. At 14 weeks of age, we found the Akita mice had increased renal sympathetic nerve activity and elevated levels of plasma norepinephrine. There was decreased expression of nNOS protein (Akita 0.43 ± 0.11 vs. WT 0.75 ± 0.05, P < 0.05) in the PVN of Akita mice. Akita mice had increased expression of angiotensin-converting enzyme (ACE) (Akita 0.58 ± 0.05 vs. WT 0.34 ± 0.04, P < 0.05) and Ang II type 1 receptor (Akita 0.49 ± 0.03 vs. WT 0.29 ± 0.09, P < 0.05), decreased expressions of ACE2 (Akita 0.17 ± 0.05 vs. WT 0.27 ± 0.03, P < 0.05) and angiotensin (1–7) Mas receptor (Akita 0.46 ± 0.02 vs. WT 0.77 ± 0.07, P < 0.05). Futher, there were increased protein levels of protein inhibitor of nNOS (PIN) (Akita 1.75 ± 0.08 vs. WT 0.71 ± 0.09, P < 0.05) with concomitantly decreased catalytically active dimers of nNOS (Akita 0.11 ± 0.04 vs. WT 0.19 ± 0.02, P < 0.05) in the PVN in Akita mice. Our studies suggest that activation of the excitatory arm of RAS, leads to a decrease NO, causing an over-activation of the sympathetic drive in DM.
肾素-血管紧张素系统（RAS）和交感神经系统的激活是糖尿病（DM）心血管并发症的主要病因。然而，DM 中交感神经激活的确切机制尚未阐明。在此，我们试图研究血管紧张素 II（Ang II）介导的室旁神经节（PVN）内神经元一氧化氮（NO）合成酶（nNOS）减少导致的糖尿病相关心血管失调。在本研究中，我们使用 Ins2+/-Akita（一种自发性、胰岛素依赖型遗传糖尿病非肥胖小鼠模型）和野生型（WT）小鼠作为对照。我们发现秋田小鼠在 14 周龄时，肾交感神经活性增加，血浆去甲肾上腺素水平升高。秋田小鼠PVN中的nNOS蛋白表达量减少（秋田小鼠为0.43 ± 0.11，WT小鼠为0.75 ± 0.05，P < 0.05）。秋田小鼠血管紧张素转换酶（ACE）（秋田 0.58 ± 0.05 vs. WT 0.34 ± 0.04，P < 0.05）和 Ang II 1 型受体（秋田 0.49 ± 0.03 vs. WT 0.29 ± 0.09，P < 0.05），ACE2（秋田 0.17 ± 0.05 vs. WT 0.27 ± 0.03，P < 0.05）和血管紧张素（1-7）Mas 受体（秋田 0.46 ± 0.02 vs. WT 0.77 ± 0.07，P < 0.05）的表达减少。此外，秋田小鼠 PVN 中 nNOS 蛋白抑制剂（PIN）的蛋白水平升高（秋田 1.75 ± 0.08 vs. WT 0.71 ± 0.09，P < 0.05），同时 nNOS 催化活性二聚体的水平降低（秋田 0.11 ± 0.04 vs. WT 0.19 ± 0.02，P < 0.05）。我们的研究表明，RAS 兴奋臂的激活导致 NO 减少，从而引起 DM 中交感神经驱动的过度激活。
{"title":"Downregulation of neuronal nitric oxide synthase (nNOS) within the paraventricular nucleus in Ins2Akita-type-1 diabetic mice contributes to sympatho-excitation","authors":"Tapan A. Patel , Lie Gao , Shane H. Boomer , Xuefei Liu , Kaushik P. Patel , Hong Zheng","doi":"10.1016/j.niox.2024.11.001","DOIUrl":"10.1016/j.niox.2024.11.001","url":null,"abstract":"<div><div>Activation of both renin-angiotensin system (RAS) and the sympathetic system is the primary etiologic event in developing cardiovascular complications in diabetes mellitus (DM). However, the precise mechanisms for sympathetic activation in DM have not been elucidated. Here we attempted to investigate diabetes-linked cardiovascular dysregulation due to angiotensin II (Ang II)-mediated reduction in neuronal nitric oxide (NO) synthase (nNOS) within the paraventricular neuleus (PVN). In the present study, we used Ins2<sup>+/−</sup>Akita (a spontaneous, insulin-dependent genetic diabetic non-obese murine model) and wild-type (WT) littermates mice as controls. At 14 weeks of age, we found the Akita mice had increased renal sympathetic nerve activity and elevated levels of plasma norepinephrine. There was decreased expression of nNOS protein (Akita 0.43 ± 0.11 vs. WT 0.75 ± 0.05, P < 0.05) in the PVN of Akita mice. Akita mice had increased expression of angiotensin-converting enzyme (ACE) (Akita 0.58 ± 0.05 vs. WT 0.34 ± 0.04, P < 0.05) and Ang II type 1 receptor (Akita 0.49 ± 0.03 vs. WT 0.29 ± 0.09, P < 0.05), decreased expressions of ACE2 (Akita 0.17 ± 0.05 vs. WT 0.27 ± 0.03, P < 0.05) and angiotensin (1–7) Mas receptor (Akita 0.46 ± 0.02 vs. WT 0.77 ± 0.07, P < 0.05). Futher, there were increased protein levels of protein inhibitor of nNOS (PIN) (Akita 1.75 ± 0.08 vs. WT 0.71 ± 0.09, P < 0.05) with concomitantly decreased catalytically active dimers of nNOS (Akita 0.11 ± 0.04 vs. WT 0.19 ± 0.02, P < 0.05) in the PVN in Akita mice. Our studies suggest that activation of the excitatory arm of RAS, leads to a decrease NO, causing an over-activation of the sympathetic drive in DM.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"154 ","pages":"Pages 1-7"},"PeriodicalIF":3.2,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-19DOI: 10.1016/j.niox.2024.10.010
Mariana Gonçalves de Oliveira , José Britto-Junior , Douglas Rafael Martins Dias , Luise Gabriela Santos Pereira , Silvana Chiavegatto , Idam Hermawan , Hiroaki Shimokawa , Masato Tsutsui , Edson Antunes , Gilberto De Nucci
6-Nitrodopamine (6-ND) modulates vas deferens, seminal vesicles, and corpus cavernosum contractility; however, its role on the lower urinary tract organs has not been evaluated. Investigations of isolated urinary bladders from wild-type (WT) mice revealed 6-ND release was comparable to that of dopamine and adrenaline, whereas noradrenaline was hardly detected, as assessed by liquid chromatography coupled to tandem mass spectrometry. In vitro, 6-ND induced concentration-dependent relaxations in carbachol pre-contracted bladders with high potency (pEC50: 8.04 ± 0.86), independently of eNOS/sGC activity. Co-incubation of 6-ND (1–10 μM) antagonizes the contractile effects of acetylcholine (p < 0.05). Experiments using nitric oxide synthase (NOS) knockout mice demonstrated that 6-ND release from isolated urinary bladder was significantly reduced by neuronal NOS (nNOS−/−) deletion and abolished by triple NOSs deletion (n/i/eNOS−/−), while no significant changes were observed in endothelial (eNOS−/−) or inducible (iNOS−/−) knockout mice. Incubation with tetrodotoxin resulted in a significant decrease in 6-ND release in bladders obtained from WT, but not in nNOS−/− mice. The bladders from nNOS−/− and n/i/eNOS−/− mice exhibited significantly higher contractile responses to electric field stimulation (EFS), compared to eNOS−/−, iNOS−/−, or WT bladders. The hyperreactivity observed in triple NOS knockouts was reversed by the incubation with bladder mucosal layer obtained from a donor WT mice, but not with the muscular layer. These findings clearly demonstrate 6-ND is the most potent endogenous relaxing agent of urinary bladder, and inhibition of its release is associated with bladder hyperreactivity.
{"title":"Neurogenic-derived 6-nitrodopamine is the most potent endogenous modulator of the mouse urinary bladder relaxation","authors":"Mariana Gonçalves de Oliveira , José Britto-Junior , Douglas Rafael Martins Dias , Luise Gabriela Santos Pereira , Silvana Chiavegatto , Idam Hermawan , Hiroaki Shimokawa , Masato Tsutsui , Edson Antunes , Gilberto De Nucci","doi":"10.1016/j.niox.2024.10.010","DOIUrl":"10.1016/j.niox.2024.10.010","url":null,"abstract":"<div><div>6-Nitrodopamine (6-ND) modulates vas deferens, seminal vesicles, and corpus cavernosum contractility; however, its role on the lower urinary tract organs has not been evaluated. Investigations of isolated urinary bladders from wild-type (WT) mice revealed 6-ND release was comparable to that of dopamine and adrenaline, whereas noradrenaline was hardly detected, as assessed by liquid chromatography coupled to tandem mass spectrometry. <em>In vitro</em>, 6-ND induced concentration-dependent relaxations in carbachol pre-contracted bladders with high potency (pEC<sub>50</sub>: 8.04 ± 0.86), independently of eNOS/sGC activity. Co-incubation of 6-ND (1–10 μM) antagonizes the contractile effects of acetylcholine (p < 0.05). Experiments using nitric oxide synthase (NOS) knockout mice demonstrated that 6-ND release from isolated urinary bladder was significantly reduced by neuronal NOS (nNOS<sup>−/−</sup>) deletion and abolished by triple NOSs deletion (n/i/eNOS<sup>−/−</sup>), while no significant changes were observed in endothelial (eNOS<sup>−/−</sup>) or inducible (iNOS<sup>−/−</sup>) knockout mice. Incubation with tetrodotoxin resulted in a significant decrease in 6-ND release in bladders obtained from WT, but not in nNOS<sup>−/−</sup> mice. The bladders from nNOS<sup>−/−</sup> and n/i/eNOS<sup>−/−</sup> mice exhibited significantly higher contractile responses to electric field stimulation (EFS), compared to eNOS<sup>−/−</sup>, iNOS<sup>−/−</sup>, or WT bladders. The hyperreactivity observed in triple NOS knockouts was reversed by the incubation with bladder mucosal layer obtained from a donor WT mice, but not with the muscular layer. These findings clearly demonstrate 6-ND is the most potent endogenous relaxing agent of urinary bladder, and inhibition of its release is associated with bladder hyperreactivity.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"153 ","pages":"Pages 98-105"},"PeriodicalIF":3.2,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471019","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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