Pub Date : 2025-06-01Epub Date: 2025-02-24DOI: 10.1016/j.niox.2025.02.002
Yu-Bo Shi , Lin Cheng , Yue Lyu , Ze-Jing Shi
Cancer metastasis is the leading cause of death in cancer patients, which renders heavy burdens to family and society. Cancer metastasis is a complicated process in which a large variety of biological molecules, cells and signaling pathways are involved. Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are common air pollutants which are harmful to human bodies and environments. However, recent studies show that these gases, which are collectively termed gasotransmitters, play significant roles in physiological homeostasis and pathogenesis including immunological responses, neuronal regulations, respiratory as well as cardiovascular diseases, metabolic disorders and cancers. These gases are abnormally expressed in cancer cells or tissues, along with the gas-producing enzymes. They have been demonstrated to participate in cancer metastasis intensively by modulating diverse signaling axes. This review introduces the nature of gasotransmitters, summaries novel research progression in gasotransmitters-induced cancer metastasis and elucidates multifaceted mechanisms how the process is modulated, with an effort to bring new therapeutic targets for cancer management in the future.
{"title":"The new perspective of gasotransmitters in cancer metastasis","authors":"Yu-Bo Shi , Lin Cheng , Yue Lyu , Ze-Jing Shi","doi":"10.1016/j.niox.2025.02.002","DOIUrl":"10.1016/j.niox.2025.02.002","url":null,"abstract":"<div><div>Cancer metastasis is the leading cause of death in cancer patients, which renders heavy burdens to family and society. Cancer metastasis is a complicated process in which a large variety of biological molecules, cells and signaling pathways are involved. Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H<sub>2</sub>S) are common air pollutants which are harmful to human bodies and environments. However, recent studies show that these gases, which are collectively termed gasotransmitters, play significant roles in physiological homeostasis and pathogenesis including immunological responses, neuronal regulations, respiratory as well as cardiovascular diseases, metabolic disorders and cancers. These gases are abnormally expressed in cancer cells or tissues, along with the gas-producing enzymes. They have been demonstrated to participate in cancer metastasis intensively by modulating diverse signaling axes. This review introduces the nature of gasotransmitters, summaries novel research progression in gasotransmitters-induced cancer metastasis and elucidates multifaceted mechanisms how the process is modulated, with an effort to bring new therapeutic targets for cancer management in the future.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"156 ","pages":"Pages 1-8"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516265","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 (H2S), previously known as a toxic gas, is currently considered one of the most important gaseous transmitters in plants. This novel signaling molecule has been determined to play notable roles in plant growth, development, and maturation. In addition, pharmacological and genetic evidence indicated that this regulatory molecule effectively ameliorates various plant stress conditions. H2S is involved in these processes by changing gene expression, enzyme activities, and metabolite concentrations. During its regulatory function, H2S interacts with other signaling pathways such as hydrogen peroxide (H2O2), nitric oxide (NO), Ca2+, carbon monoxide (CO), phosphatidic acid (PA), phytohormones, etc. The H2S mechanism of action may depend on the persulfidation post-translational modification (PTM), which attacks the cysteine (Cys) residues on the target proteins and changes their structure and activities. This review summarized H2S biosynthesis pathways, its role in sulfide state, and its donors in plant biology. We also discuss recent progress in the research on the interactions of H2S with other signaling molecules, as well as the role of persulfidation in modulating various plant reactions.
{"title":"Hydrogen sulfide mechanism of action in plants; from interaction with regulatory molecules to persulfidation of proteins","authors":"Shirin Mohammadbagherlou , Elaheh Samari , Mostafa Sagharyan , Meisam Zargar , Moxian Chen , Abazar Ghorbani","doi":"10.1016/j.niox.2025.02.001","DOIUrl":"10.1016/j.niox.2025.02.001","url":null,"abstract":"<div><div>Hydrogen sulfide (H<sub>2</sub>S), previously known as a toxic gas, is currently considered one of the most important gaseous transmitters in plants. This novel signaling molecule has been determined to play notable roles in plant growth, development, and maturation. In addition, pharmacological and genetic evidence indicated that this regulatory molecule effectively ameliorates various plant stress conditions. H<sub>2</sub>S is involved in these processes by changing gene expression, enzyme activities, and metabolite concentrations. During its regulatory function, H<sub>2</sub>S interacts with other signaling pathways such as hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), nitric oxide (NO), Ca<sup>2+</sup>, carbon monoxide (CO), phosphatidic acid (PA), phytohormones, etc. The H<sub>2</sub>S mechanism of action may depend on the persulfidation post-translational modification (PTM), which attacks the cysteine (Cys) residues on the target proteins and changes their structure and activities. This review summarized H<sub>2</sub>S biosynthesis pathways, its role in sulfide state, and its donors in plant biology. We also discuss recent progress in the research on the interactions of H<sub>2</sub>S with other signaling molecules, as well as the role of persulfidation in modulating various plant reactions.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"156 ","pages":"Pages 27-41"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537526","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 : 2025-06-01Epub Date: 2025-02-28DOI: 10.1016/j.niox.2025.02.004
Jennifer Daw , Su Chung , Cheng-Yu Chen , Ronald L. Heimark , William R. Montfort
Inflammation is increasingly linked to disease progression, particularly in cancer, where elevated levels of inducible nitric oxide synthase (iNOS or NOS2), driven by tumor inflammation, is correlated with aggressive tumors and poor outcomes. Measuring nitric oxide levels in tumor cells is hampered by the reactive nature of the molecule and generally inferred through indirect measurement of reaction products such as nitrate and nitrite. Here, we adapt the oxyhemoglobin detection method to tissue culture and examine nitric oxide production in tumor cells in response to inflammatory cytokines. Our assay provides real-time nitric oxide measurement, is highly sensitive, linear for at least an hour, inexpensive, and easy to implement. We show that triple negative breast and colorectal cancer cells respond to interferon gamma (IFNγ), interleukin 1-β (IL1-β) and tumor necrosis factor α (TNFα) to generate surprisingly high levels of NOS2 protein and nitric oxide, as high as seen in activated macrophages for fighting infection. NO detection levels reach 1.3 pmol NO/min/μg total cellular protein. The assay is readily adapted to assessing IC50 values for NOS2 inhibition, inhibition rates, and inhibition persistence. Using triple negative breast cancer cell line 4T1, a syngeneic murine tumor model, we estimate an IC50 = 3.4 μM for NOS2-specific inhibitor 1400W, which displays a low nanomolar binding constant to isolated protein. Inhibition is rapid (<10 min) and persists for at least an hour. These results highlight the importance of nitric oxide production in the tumor and provide a means for developing new therapeutic strategies.
{"title":"Real-time nitric oxide detection in cytokine stimulated cancer cells and macrophages","authors":"Jennifer Daw , Su Chung , Cheng-Yu Chen , Ronald L. Heimark , William R. Montfort","doi":"10.1016/j.niox.2025.02.004","DOIUrl":"10.1016/j.niox.2025.02.004","url":null,"abstract":"<div><div>Inflammation is increasingly linked to disease progression, particularly in cancer, where elevated levels of inducible nitric oxide synthase (iNOS or NOS2), driven by tumor inflammation, is correlated with aggressive tumors and poor outcomes. Measuring nitric oxide levels in tumor cells is hampered by the reactive nature of the molecule and generally inferred through indirect measurement of reaction products such as nitrate and nitrite. Here, we adapt the oxyhemoglobin detection method to tissue culture and examine nitric oxide production in tumor cells in response to inflammatory cytokines. Our assay provides real-time nitric oxide measurement, is highly sensitive, linear for at least an hour, inexpensive, and easy to implement. We show that triple negative breast and colorectal cancer cells respond to interferon gamma (IFNγ), interleukin 1-β (IL1-β) and tumor necrosis factor α (TNFα) to generate surprisingly high levels of NOS2 protein and nitric oxide, as high as seen in activated macrophages for fighting infection. NO detection levels reach 1.3 pmol NO/min/μg total cellular protein. The assay is readily adapted to assessing IC50 values for NOS2 inhibition, inhibition rates, and inhibition persistence. Using triple negative breast cancer cell line 4T1, a syngeneic murine tumor model, we estimate an IC<sub>50</sub> = 3.4 μM for NOS2-specific inhibitor 1400W, which displays a low nanomolar binding constant to isolated protein. Inhibition is rapid (<10 min) and persists for at least an hour. These results highlight the importance of nitric oxide production in the tumor and provide a means for developing new therapeutic strategies.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"156 ","pages":"Pages 42-49"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537529","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 : 2025-06-01Epub Date: 2025-03-22DOI: 10.1016/j.niox.2025.03.002
Liang Cao , Chen Chen , Wenjun Pi , Yi Zhang , Sara Xue , Voon Wee Yong , Mengzhou Xue
Hemorrhagic stroke (HS) is a neurological disorder caused by the rupture of cerebral blood vessels, resulting in blood seeping into the brain parenchyma and causing varying degrees of neurological impairment, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). Current treatment methods mainly include hematoma evacuation surgery and conservative treatment. However, these methods have limited efficacy in enhancing neurological function and prognosis. The current challenge in treating HS lies in inhibiting the occurrence and progression of secondary brain damage after bleeding, which is a key factor affecting the prognosis of HS patients. Studies have shown that medical gas therapy is gaining more attention and has demonstrated various levels of neuroprotective effects on central nervous system disorders, such as hyperbaric oxygen, hydrogen sulfide, nitric oxide, carbon monoxide, and other inhalable gas molecules. These medical gas molecules primarily improve brain tissue damage and neurological dysfunction by regulating inflammation, oxidative stress, apoptosis, and other processes. However, many of these medical gasses also possess neurotoxic properties. Therefore, the use of medical gases in HS deserves further exploration and research. In this review, we will elucidate the therapeutic effects and study the advances in medical gas molecules in HS.
{"title":"Exploring medical gas therapy in hemorrhagic stroke treatment: A narrative review","authors":"Liang Cao , Chen Chen , Wenjun Pi , Yi Zhang , Sara Xue , Voon Wee Yong , Mengzhou Xue","doi":"10.1016/j.niox.2025.03.002","DOIUrl":"10.1016/j.niox.2025.03.002","url":null,"abstract":"<div><div>Hemorrhagic stroke (HS) is a neurological disorder caused by the rupture of cerebral blood vessels, resulting in blood seeping into the brain parenchyma and causing varying degrees of neurological impairment, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). Current treatment methods mainly include hematoma evacuation surgery and conservative treatment. However, these methods have limited efficacy in enhancing neurological function and prognosis. The current challenge in treating HS lies in inhibiting the occurrence and progression of secondary brain damage after bleeding, which is a key factor affecting the prognosis of HS patients. Studies have shown that medical gas therapy is gaining more attention and has demonstrated various levels of neuroprotective effects on central nervous system disorders, such as hyperbaric oxygen, hydrogen sulfide, nitric oxide, carbon monoxide, and other inhalable gas molecules. These medical gas molecules primarily improve brain tissue damage and neurological dysfunction by regulating inflammation, oxidative stress, apoptosis, and other processes. However, many of these medical gasses also possess neurotoxic properties. Therefore, the use of medical gases in HS deserves further exploration and research. In this review, we will elucidate the therapeutic effects and study the advances in medical gas molecules in HS.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"156 ","pages":"Pages 94-106"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701050","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 : 2025-06-01Epub Date: 2025-03-13DOI: 10.1016/j.niox.2025.03.001
Anna Pedrinolla , Gianluigi Dorelli , Simone Porcelli , Mia Burleigh , Martina Mendo , Camilla Martignon , Cristina Fonte , Luca Giuseppe Dalle Carbonare , Chris Easton , Ettore Muti , Federico Schena , Massimo Venturelli
<div><div>Poor vascular function and reduced nitric oxide (NO)-bioavailability have been recognized to be involved in aging and Alzheimer's Disease (AD). A non-pharmacological treatment that is gaining clinical interest in the context of vascular function is dietary inorganic nitrate (<span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span>) supplementation which increases NO-bioavailability through the <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span> -nitrite (<span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>2</mn><mo>−</mo></msubsup></mrow></math></span>) - NO pathway. This treatment has been demonstrated to improve vascular function in several clinical populations, but no study has investigated the effects in individuals with AD. Therefore, changes in plasma <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span> and <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>2</mn><mo>−</mo></msubsup></mrow></math></span> and vascular responsiveness (hyperemic response to single-passive leg movement (ΔPLM)) were measured in individuals with AD (n = 10, 76 ± 9 years), healthy elderly (OLD, n = 10, 75 ± 6 years), and young individuals (YN, n = 10, 25 ± 4 years) before (T0) and hourly for 4 h (T1, T2, T3, and T4) after ingestion of either <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span>-rich beetroot juice (BR) or a placebo (PLA). No changes in <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span> and <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>2</mn><mo>−</mo></msubsup></mrow></math></span>, nor ΔPLM were detected in any group following PLA intake. Plasma <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span> and <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>2</mn><mo>−</mo></msubsup></mrow></math></span> increased significantly in all three groups at T1 (p < 0.001) and remained elevated for the rest of the trial. The same trend was found in ΔPLM, which significantly increased in all three groups over the time (p < 0.001). However, AD exhibited significantly lower ΔPLM values at any time point compared to YN (p < 0.001) and OLD (p < 0.001). These data suggest that AD-individuals included in this study were able to reduce <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span> to <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>2</mn><mo>−</mo></msubsup></mrow></math></span> and to increase NO-mediated vascular responsiveness as non-AD-individuals. Other mechanisms, beyond NO-bioavailability, may be involved in vascular dysfunction in patients with AD. This resea
{"title":"Increasing nitric oxide availability via ingestion of nitrate-rich beetroot juice improves vascular responsiveness in individuals with Alzheimer's Disease","authors":"Anna Pedrinolla , Gianluigi Dorelli , Simone Porcelli , Mia Burleigh , Martina Mendo , Camilla Martignon , Cristina Fonte , Luca Giuseppe Dalle Carbonare , Chris Easton , Ettore Muti , Federico Schena , Massimo Venturelli","doi":"10.1016/j.niox.2025.03.001","DOIUrl":"10.1016/j.niox.2025.03.001","url":null,"abstract":"<div><div>Poor vascular function and reduced nitric oxide (NO)-bioavailability have been recognized to be involved in aging and Alzheimer's Disease (AD). A non-pharmacological treatment that is gaining clinical interest in the context of vascular function is dietary inorganic nitrate (<span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span>) supplementation which increases NO-bioavailability through the <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span> -nitrite (<span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>2</mn><mo>−</mo></msubsup></mrow></math></span>) - NO pathway. This treatment has been demonstrated to improve vascular function in several clinical populations, but no study has investigated the effects in individuals with AD. Therefore, changes in plasma <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span> and <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>2</mn><mo>−</mo></msubsup></mrow></math></span> and vascular responsiveness (hyperemic response to single-passive leg movement (ΔPLM)) were measured in individuals with AD (n = 10, 76 ± 9 years), healthy elderly (OLD, n = 10, 75 ± 6 years), and young individuals (YN, n = 10, 25 ± 4 years) before (T0) and hourly for 4 h (T1, T2, T3, and T4) after ingestion of either <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span>-rich beetroot juice (BR) or a placebo (PLA). No changes in <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span> and <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>2</mn><mo>−</mo></msubsup></mrow></math></span>, nor ΔPLM were detected in any group following PLA intake. Plasma <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span> and <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>2</mn><mo>−</mo></msubsup></mrow></math></span> increased significantly in all three groups at T1 (p < 0.001) and remained elevated for the rest of the trial. The same trend was found in ΔPLM, which significantly increased in all three groups over the time (p < 0.001). However, AD exhibited significantly lower ΔPLM values at any time point compared to YN (p < 0.001) and OLD (p < 0.001). These data suggest that AD-individuals included in this study were able to reduce <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>3</mn><mo>−</mo></msubsup></mrow></math></span> to <span><math><mrow><msubsup><mrow><mi>N</mi><mi>O</mi></mrow><mn>2</mn><mo>−</mo></msubsup></mrow></math></span> and to increase NO-mediated vascular responsiveness as non-AD-individuals. Other mechanisms, beyond NO-bioavailability, may be involved in vascular dysfunction in patients with AD. This resea","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"156 ","pages":"Pages 50-56"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634231","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 : 2025-06-01Epub Date: 2025-03-24DOI: 10.1016/j.niox.2025.03.003
Hao Wang , Mingming Chen , Yang Li , Wenjun Cui , Qian An , Xiangyang Yin , Bing Wang
Peripheral artery disease (PAD) is a circulatory disorder caused by atherosclerosis, leading to the narrowing or blockage of peripheral arteries, often affecting the arteries in the lower limbs. This condition can result in intermittent claudication and severe limb ischemia, significantly reducing patients' quality of life. In recent years, increasing evidence suggests that dietary interventions play a crucial role in the prevention and management of PAD, offering a safe and non-invasive treatment option. Beetroot, a natural root vegetable, demonstrates significant health benefits through its various bioactive compounds. It is rich in nitrate and betaine, which are metabolized in the body via the nitrate-nitrite- nitric oxide (NO) pathway, increasing the bioavailability of NO. NO is an important vasodilator that can improve blood flow and lower blood pressure. Additionally, the active compounds in beetroot may further enhance its health effects by altering the activity of the oral microbiome. This review explores the potential therapeutic effects of beetroot juice (BRJ) in the management of PAD. The findings indicate that BRJ can improve exercise performance, lower blood pressure, improve endothelial function, enhance skeletal muscle microvascular function and central autonomic nervous system function. Based on these findings, beetroot and its rich bioactive compounds hold promise as a novel supportive therapy for improving PAD.
{"title":"Exploring the therapeutic potential of beetroot juice in patients with peripheral artery disease: A Narrative review","authors":"Hao Wang , Mingming Chen , Yang Li , Wenjun Cui , Qian An , Xiangyang Yin , Bing Wang","doi":"10.1016/j.niox.2025.03.003","DOIUrl":"10.1016/j.niox.2025.03.003","url":null,"abstract":"<div><div>Peripheral artery disease (PAD) is a circulatory disorder caused by atherosclerosis, leading to the narrowing or blockage of peripheral arteries, often affecting the arteries in the lower limbs. This condition can result in intermittent claudication and severe limb ischemia, significantly reducing patients' quality of life. In recent years, increasing evidence suggests that dietary interventions play a crucial role in the prevention and management of PAD, offering a safe and non-invasive treatment option. Beetroot, a natural root vegetable, demonstrates significant health benefits through its various bioactive compounds. It is rich in nitrate and betaine, which are metabolized in the body via the nitrate-nitrite- nitric oxide (NO) pathway, increasing the bioavailability of NO. NO is an important vasodilator that can improve blood flow and lower blood pressure. Additionally, the active compounds in beetroot may further enhance its health effects by altering the activity of the oral microbiome. This review explores the potential therapeutic effects of beetroot juice (BRJ) in the management of PAD. The findings indicate that BRJ can improve exercise performance, lower blood pressure, improve endothelial function, enhance skeletal muscle microvascular function and central autonomic nervous system function. Based on these findings, beetroot and its rich bioactive compounds hold promise as a novel supportive therapy for improving PAD.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"156 ","pages":"Pages 57-66"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715957","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 : 2025-06-01Epub Date: 2025-03-24DOI: 10.1016/j.niox.2025.03.004
Renan S. Nunes, Kelli C. Freitas Mariano, Joana C. Pieretti, Roberta A. dos Reis, Amedea B. Seabra
Cardiovascular diseases remain the leading cause of death worldwide, imposing a substantial impact on healthcare systems due to high morbidity, mortality, and associated economic costs. Nitric oxide (NO), a key signaling molecule in the cardiovascular system, plays a critical role in regulating vascular homeostasis, angiogenesis, and inflammation. Despite its therapeutic potential, direct NO delivery in the cardiovascular system is limited by its reactivity, short half-life, and poor bioavailability. The development of NO-releasing nanomaterials addresses these challenges by enabling controlled, targeted, and sustained NO delivery, mitigating systemic toxicity and improving therapeutic outcomes. This review provides a comprehensive overview of recent advancements in the design, functionalization, and application of NO-releasing nanomaterials for cardiovascular therapies. Key topics include the use of in vitro and in vivo models to evaluate efficacy in conditions such as myocardial ischemia-reperfusion injury, thrombosis, and atherosclerosis, as well as the role of stimuli-responsive systems and hybrid nanomaterials in enhancing delivery precision. Advances in nanotechnology, such as stimuli-responsive systems and hybrid functionalized nanomaterials for targeted delivery, have enhanced the precision and effectiveness of NO therapeutic effects for treating a wide spectrum of cardiovascular conditions. However, challenges like scalable production, biocompatibility, and integration with existing therapies remain. Future research should focus on interdisciplinary approaches to optimize these materials for clinical translation, ensuring accessibility and addressing the global problem of cardiovascular diseases.
{"title":"Innovative nitric oxide-releasing nanomaterials: Current progress, trends, challenges, and perspectives in cardiovascular therapies","authors":"Renan S. Nunes, Kelli C. Freitas Mariano, Joana C. Pieretti, Roberta A. dos Reis, Amedea B. Seabra","doi":"10.1016/j.niox.2025.03.004","DOIUrl":"10.1016/j.niox.2025.03.004","url":null,"abstract":"<div><div>Cardiovascular diseases remain the leading cause of death worldwide, imposing a substantial impact on healthcare systems due to high morbidity, mortality, and associated economic costs. Nitric oxide (NO), a key signaling molecule in the cardiovascular system, plays a critical role in regulating vascular homeostasis, angiogenesis, and inflammation. Despite its therapeutic potential, direct NO delivery in the cardiovascular system is limited by its reactivity, short half-life, and poor bioavailability. The development of NO-releasing nanomaterials addresses these challenges by enabling controlled, targeted, and sustained NO delivery, mitigating systemic toxicity and improving therapeutic outcomes. This review provides a comprehensive overview of recent advancements in the design, functionalization, and application of NO-releasing nanomaterials for cardiovascular therapies. Key topics include the use of <em>in vitro</em> and <em>in vivo</em> models to evaluate efficacy in conditions such as myocardial ischemia-reperfusion injury, thrombosis, and atherosclerosis, as well as the role of stimuli-responsive systems and hybrid nanomaterials in enhancing delivery precision. Advances in nanotechnology, such as stimuli-responsive systems and hybrid functionalized nanomaterials for targeted delivery, have enhanced the precision and effectiveness of NO therapeutic effects for treating a wide spectrum of cardiovascular conditions. However, challenges like scalable production, biocompatibility, and integration with existing therapies remain. Future research should focus on interdisciplinary approaches to optimize these materials for clinical translation, ensuring accessibility and addressing the global problem of cardiovascular diseases.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"156 ","pages":"Pages 67-81"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726145","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 : 2025-04-01Epub Date: 2025-01-08DOI: 10.1016/j.niox.2025.01.001
Mohamed Okda , Stefano Spina , Bijan Safaee Fakhr , Ryan W. Carroll
Nitric oxide (NO) is a versatile endogenous molecule with multiple physiological roles, including neurotransmission, vasodilation, and immune regulation. As part of the immune response, NO exerts antimicrobial effects by producing reactive nitrogen species (RNS). These RNS combat pathogens via mechanisms such as DNA deamination, S-nitrosylation of thiol groups, and lipid peroxidation, leading to disruptions in microbial cell membranes and vital protein functions. Due to these broad actions, NO targets many pathogens, including bacteria, fungi, and viruses, with minimal risk of resistance development. Given its potent antimicrobial properties, the therapeutic potential of exogenous NO has been recently studied. Various preparations, such as NO donors, inhaled gaseous NO, and topical preparations, have shown promising results in preclinical and clinical settings. This literature review examines the antimicrobial effects of exogenous NO reported in in vitro studies, animal models, and human clinical trials. We provide an overview of the mechanisms by which NO exerts its antimicrobial activity, highlighting its efficacy against diverse pathogens. By presenting the current findings, we aim to contribute to the growing body of evidence supporting the use of NO as a versatile antimicrobial agent in clinical practice.
{"title":"The antimicrobial effects of nitric oxide: A narrative review","authors":"Mohamed Okda , Stefano Spina , Bijan Safaee Fakhr , Ryan W. Carroll","doi":"10.1016/j.niox.2025.01.001","DOIUrl":"10.1016/j.niox.2025.01.001","url":null,"abstract":"<div><div>Nitric oxide (NO) is a versatile endogenous molecule with multiple physiological roles, including neurotransmission, vasodilation, and immune regulation. As part of the immune response, NO exerts antimicrobial effects by producing reactive nitrogen species (RNS). These RNS combat pathogens via mechanisms such as DNA deamination, S-nitrosylation of thiol groups, and lipid peroxidation, leading to disruptions in microbial cell membranes and vital protein functions. Due to these broad actions, NO targets many pathogens, including bacteria, fungi, and viruses, with minimal risk of resistance development. Given its potent antimicrobial properties, the therapeutic potential of exogenous NO has been recently studied. Various preparations, such as NO donors, inhaled gaseous NO, and topical preparations, have shown promising results in preclinical and clinical settings. This literature review examines the antimicrobial effects of exogenous NO reported in <em>in vitro</em> studies, animal models, and human clinical trials. We provide an overview of the mechanisms by which NO exerts its antimicrobial activity, highlighting its efficacy against diverse pathogens. By presenting the current findings, we aim to contribute to the growing body of evidence supporting the use of NO as a versatile antimicrobial agent in clinical practice.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"155 ","pages":"Pages 20-40"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966124","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 : 2025-04-01Epub 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":"2025-04-01","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 : 2025-04-01Epub 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":"2025-04-01","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}
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