Pub Date : 2025-03-01DOI: 10.1016/j.niox.2025.02.003
Nazar M. Shareef Mahmood, Almas M.R. Mahmud, Ismail M. Maulood
The renin-angiotensin system (RAS) plays a pivotal role in regulating vascular homeostasis, while angiotensin 1-8 (Ang 1–8) traditionally dominates as a vasoconstrictor factor. However, the discovery of angiotensin 1-7 (Ang 1–7) and Ang 1–8 has revealed counter-regulatory mechanisms mediated through endothelial-derived relaxing factors (EDRFs) and endothelial-derived hyperpolarizing factors (EDHFs). This review delves into the vascular actions of Ang 1–7 and Ang 1–8 in both non-diabetes mellitus (non-DM) and diabetes mellitus (DM) conditions, highlighting their effects on vascular endothelial cell (VECs) function as well. In a non-DM vasculature context, Ang 1–8 demonstrate dual effect including vasoconstriction and vasodilation, respectively. Additionally, Ang 1–7 induces vasodilation upon nitric oxide (NO) production as a prominent EDRFs in distinct mechanisms. Further research elucidating the precise mechanisms underlying the vascular actions of Ang 1–7 and Ang 1–8 in DM will facilitate the development of tailored therapeutic interventions aimed at preserving vascular health and preventing cardiovascular complications.
{"title":"Vascular actions of Ang 1–7 and Ang 1–8 through EDRFs and EDHFs in non-diabetes and diabetes mellitus","authors":"Nazar M. Shareef Mahmood, Almas M.R. Mahmud, Ismail M. Maulood","doi":"10.1016/j.niox.2025.02.003","DOIUrl":"10.1016/j.niox.2025.02.003","url":null,"abstract":"<div><div>The renin-angiotensin system (RAS) plays a pivotal role in regulating vascular homeostasis, while angiotensin 1-8 (Ang 1–8) traditionally dominates as a vasoconstrictor factor. However, the discovery of angiotensin 1-7 (Ang 1–7) and Ang 1–8 has revealed counter-regulatory mechanisms mediated through endothelial-derived relaxing factors (EDRFs) and endothelial-derived hyperpolarizing factors (EDHFs). This review delves into the vascular actions of Ang 1–7 and Ang 1–8 in both non-diabetes mellitus (non-DM) and diabetes mellitus (DM) conditions, highlighting their effects on vascular endothelial cell (VECs) function as well. In a non-DM vasculature context, Ang 1–8 demonstrate dual effect including vasoconstriction and vasodilation, respectively. Additionally, Ang 1–7 induces vasodilation upon nitric oxide (NO) production as a prominent EDRFs in distinct mechanisms. Further research elucidating the precise mechanisms underlying the vascular actions of Ang 1–7 and Ang 1–8 in DM will facilitate the development of tailored therapeutic interventions aimed at preserving vascular health and preventing cardiovascular complications.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"156 ","pages":"Pages 9-26"},"PeriodicalIF":3.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542838","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":"2025-02-28","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 : 2025-02-28DOI: 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":"2025-02-28","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 : 2025-02-24DOI: 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":"2025-02-24","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}
As an endogenous gas signaling molecule, hydrogen sulfide (H2S) has been proved to have a variety of biological activities. Studies have shown that in some disease state H2S concentration in the body is lower than normal state. Based on these findings, exogenous H2S supplementation is expected to be an effective treatment for many diseases. In recent years, a lot of H2S-releasing substances, namely H2S donors, have emerged as H2S sources. Specifically, various H2S donors also could be connected to drugs or compounds to form H2S donor conjugates. Many studies have found that H2S donor conjugates can not only retain the activity of the parent drug, but also reduce the adverse effects of the parent drug, this makes H2S donor conjugates to be a new kind of drug candidates. In this article, H2S donor conjugates will be reviewed and classified according to different diseases, such as inflammation, cardiovascular and cerebrovascular diseases, diseases of central nervous system and cancer. This review aims to provide an idea for researchers for further study of H2S and H2S donor conjugates.
{"title":"Application of hydrogen sulfide donor conjugates in different diseases","authors":"Rui Zhang, Wumei Shi, Xiaoyan Wu, Qingfeng Yu, Ying Xiao","doi":"10.1016/j.niox.2024.11.008","DOIUrl":"10.1016/j.niox.2024.11.008","url":null,"abstract":"<div><div>As an endogenous gas signaling molecule, hydrogen sulfide (H<sub>2</sub>S) has been proved to have a variety of biological activities. Studies have shown that in some disease state H<sub>2</sub>S concentration in the body is lower than normal state. Based on these findings, exogenous H<sub>2</sub>S supplementation is expected to be an effective treatment for many diseases. In recent years, a lot of H<sub>2</sub>S-releasing substances, namely H<sub>2</sub>S donors, have emerged as H<sub>2</sub>S sources. Specifically, various H<sub>2</sub>S donors also could be connected to drugs or compounds to form H<sub>2</sub>S donor conjugates. Many studies have found that H<sub>2</sub>S donor conjugates can not only retain the activity of the parent drug, but also reduce the adverse effects of the parent drug, this makes H<sub>2</sub>S donor conjugates to be a new kind of drug candidates. In this article, H<sub>2</sub>S donor conjugates will be reviewed and classified according to different diseases, such as inflammation, cardiovascular and cerebrovascular diseases, diseases of central nervous system and cancer. This review aims to provide an idea for researchers for further study of H<sub>2</sub>S and H<sub>2</sub>S donor conjugates.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"154 ","pages":"Pages 128-139"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813841","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 : 2025-02-01DOI: 10.1016/j.niox.2024.12.001
Filipe Rodolfo Moreira Borges Oliveira , Thiele Osvaldt Rosales , Daiane Mara Bobermin, Marina Delgobo, Alfeu Zanotto-Filho, Regina Sordi, Jamil Assreuy
Aim
Sepsis and septic shock remain are significant causes of mortality in the world. The inflammatory response should be at the basis of all organ dysfunction such as cardiovascular dysfunction, characterized by severe hypotension refractory to volume replacement and vasoconstrictor therapy. Nitric oxide (NO) has been implicated as a key element in both inflammatory and cardiovascular components of sepsis. In addition to activating soluble guanylate cyclase and potassium channels, NO also modifies proteins post-translationally by reacting with protein thiol groups, yielding S-nitrosothiols (RS-NO), which can act as endogenous NO reservoirs. Besides its use in quantifying free sulfhydryl groups of proteins and non-protein thiols, DTNB [5,5′-dithiobis-(2-nitrobenzoic acid)] has also been used as a pharmacological tool due to its specificity for oxidizing reactive sulfhydryl groups. Here we aimed to investigate the effects of DTNB in the inflammatory aspects of a sepsis model and to verify whether its effects can be attributed to S-denitrosylation.
Methods
Anesthetized female Swiss mice were intratracheally injected with 1 × 108 CFU of K. pneumoniae. Twelve hours after pneumonia-induced sepsis, the animals were injected with vehicle (sodium bicarbonate 5 %, s.c.) or DTNB (31.5, 63 and 126 μmol/kg, s.c.). Twenty-four hours post-sepsis induction, plasma, bronchoalveolar lavage (BAL), and lung tissues were collected for assays (protein, cell count, nitrite + nitrate levels (NOx), cytokine levels, and sulfhydryl groups). In addition, lung S-nitrosylated proteins were visualized by a modified tissue assay for S-nitrosothiols.
Results
Sepsis induced a significant vascular leakage in the lungs and elevated NOx levels in BAL, both reduced by DTNB. BAL leukocytosis and elevated IL-1β induced by sepsis were also reduced by DTNB, whereas it did not affect bacterial dissemination to liver, heart and BAL. Sepsis reduced free sulfhydryl groups in BAL and lung and DTNB did not change it. On the other hand, DTNB substantially reduced protein S-nitrosylation levels in the lung parenchyma and halved sepsis-induced mortality in septic mice.
Conclusion
Our results show that the administration of DTNB 12 h after bacterial instillation reduced most of the local inflammatory parameters and, more importantly, decreased mortality. These beneficial effects may be due to S-denitrosylation of RS-NO pools carried out by DTNB. Since DTNB was effective in reducing the inflammatory process after its onset, this mechanism of action could serve as a valuable proof of concept for compounds that can be useful to interfere with sepsis outcome.
{"title":"S-Denitrosylation counteracts local inflammation and improves survival in mice infected with K. pneumoniae","authors":"Filipe Rodolfo Moreira Borges Oliveira , Thiele Osvaldt Rosales , Daiane Mara Bobermin, Marina Delgobo, Alfeu Zanotto-Filho, Regina Sordi, Jamil Assreuy","doi":"10.1016/j.niox.2024.12.001","DOIUrl":"10.1016/j.niox.2024.12.001","url":null,"abstract":"<div><h3>Aim</h3><div>Sepsis and septic shock remain are significant causes of mortality in the world. The inflammatory response should be at the basis of all organ dysfunction such as cardiovascular dysfunction, characterized by severe hypotension refractory to volume replacement and vasoconstrictor therapy. Nitric oxide (NO) has been implicated as a key element in both inflammatory and cardiovascular components of sepsis. In addition to activating soluble guanylate cyclase and potassium channels, NO also modifies proteins post-translationally by reacting with protein thiol groups, yielding S-nitrosothiols (RS-NO), which can act as endogenous NO reservoirs. Besides its use in quantifying free sulfhydryl groups of proteins and non-protein thiols, DTNB [5,5′-dithiobis-(2-nitrobenzoic acid)] has also been used as a pharmacological tool due to its specificity for oxidizing reactive sulfhydryl groups. Here we aimed to investigate the effects of DTNB in the inflammatory aspects of a sepsis model and to verify whether its effects can be attributed to S-denitrosylation.</div></div><div><h3>Methods</h3><div>Anesthetized female Swiss mice were intratracheally injected with 1 × 10<sup>8</sup> CFU of <em>K. pneumoniae</em>. Twelve hours after pneumonia-induced sepsis, the animals were injected with vehicle (sodium bicarbonate 5 %, s.c.) or DTNB (31.5, 63 and 126 μmol/kg, s.c.). Twenty-four hours post-sepsis induction, plasma, bronchoalveolar lavage (BAL), and lung tissues were collected for assays (protein, cell count, nitrite + nitrate levels (NOx), cytokine levels, and sulfhydryl groups). In addition, lung S-nitrosylated proteins were visualized by a modified tissue assay for S-nitrosothiols.</div></div><div><h3>Results</h3><div>Sepsis induced a significant vascular leakage in the lungs and elevated NOx levels in BAL, both reduced by DTNB. BAL leukocytosis and elevated IL-1β induced by sepsis were also reduced by DTNB, whereas it did not affect bacterial dissemination to liver, heart and BAL. Sepsis reduced free sulfhydryl groups in BAL and lung and DTNB did not change it. On the other hand, DTNB substantially reduced protein S-nitrosylation levels in the lung parenchyma and halved sepsis-induced mortality in septic mice.</div></div><div><h3>Conclusion</h3><div>Our results show that the administration of DTNB 12 h after bacterial instillation reduced most of the local inflammatory parameters and, more importantly, decreased mortality. These beneficial effects may be due to S-denitrosylation of RS-NO pools carried out by DTNB. Since DTNB was effective in reducing the inflammatory process after its onset, this mechanism of action could serve as a valuable proof of concept for compounds that can be useful to interfere with sepsis outcome.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"154 ","pages":"Pages 105-114"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795063","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 : 2025-02-01DOI: 10.1016/j.niox.2024.12.002
Kexin Zhang , Geng Wu , Yonglan Chen , Qunying Hu , Yuanyuan Li , Xinyue Jiang , Chunfu Gu , Na Zhang , Fusheng Zhao
Our previous study has shown that hydrogen sulfide (H2S) can attenuate cigarette smoke exposure (CSE)-induced placental injury in rats. This study investigated whether H2S alleviates CSE-induced endothelial glycocalyx (eGC) impairment and promotes placental angiogenesis in rats. Twenty-four pregnant rats were randomly divided into four groups: control, NaHS (a donor of H2S), CSE, and CSE + NaHS. On gestational day 21, rat placentas were collected to detect H2S levels and protein expression of the H2S-synthesizing enzymes, cystathionine beta synthase (CBS), cystathionine gamma-lyase (CGL), and 3-mercaptopyruvate sulfurtransferase (3-MST), using a C-7Az fluorescent probe, H2S testing kit, and western blotting, respectively. Transmission electron microscopy and double immunofluorescence staining were performed to observe the placental eGC alterations. Placental angiogenesis, vascular endothelial proliferation and apoptosis, and protein expression levels of the PI3K/AKT/mTOR signaling pathway were assessed in rat placentas. The results showed that the administration of NaHS markedly attenuated the reduction in H2S levels and the decrease in CBS, CGL, and 3-MST expression caused by CSE in rat placentas. Notably, NaHS treatment distinctly alleviated eGC damage and facilitated placental angiogenesis in CSE-treated rats. NaHS administration effectively promoted placental vascular endothelial proliferation and suppressed endothelial apoptosis in CSE-treated rats. Furthermore, NaHS treatment markedly elevated the phosphorylation of PI3K, AKT, and mTOR in the placenta of CSE-treated rats. Taken together, these results indicate that exogenous administration of H2S can alleviate CSE-induced eGC damage and promote placental angiogenesis in CSE-treated rats, suggesting that H2S may be a novel therapeutic agent for the treatment of CSE-associated vascular disease.
{"title":"Hydrogen sulfide alleviates endothelial glycocalyx damage and promotes placental angiogenesis in rats exposed to cigarette smoke","authors":"Kexin Zhang , Geng Wu , Yonglan Chen , Qunying Hu , Yuanyuan Li , Xinyue Jiang , Chunfu Gu , Na Zhang , Fusheng Zhao","doi":"10.1016/j.niox.2024.12.002","DOIUrl":"10.1016/j.niox.2024.12.002","url":null,"abstract":"<div><div>Our previous study has shown that hydrogen sulfide (H<sub>2</sub>S) can attenuate cigarette smoke exposure (CSE)-induced placental injury in rats. This study investigated whether H<sub>2</sub>S alleviates CSE-induced endothelial glycocalyx (eGC) impairment and promotes placental angiogenesis in rats. Twenty-four pregnant rats were randomly divided into four groups: control, NaHS (a donor of H<sub>2</sub>S), CSE, and CSE + NaHS. On gestational day 21, rat placentas were collected to detect H<sub>2</sub>S levels and protein expression of the H<sub>2</sub>S-synthesizing enzymes, cystathionine beta synthase (CBS), cystathionine gamma-lyase (CGL), and 3-mercaptopyruvate sulfurtransferase (3-MST), using a C-7Az fluorescent probe, H<sub>2</sub>S testing kit, and western blotting, respectively. Transmission electron microscopy and double immunofluorescence staining were performed to observe the placental eGC alterations. Placental angiogenesis, vascular endothelial proliferation and apoptosis, and protein expression levels of the PI3K/AKT/mTOR signaling pathway were assessed in rat placentas. The results showed that the administration of NaHS markedly attenuated the reduction in H<sub>2</sub>S levels and the decrease in CBS, CGL, and 3-MST expression caused by CSE in rat placentas. Notably, NaHS treatment distinctly alleviated eGC damage and facilitated placental angiogenesis in CSE-treated rats. NaHS administration effectively promoted placental vascular endothelial proliferation and suppressed endothelial apoptosis in CSE-treated rats. Furthermore, NaHS treatment markedly elevated the phosphorylation of PI3K, AKT, and mTOR in the placenta of CSE-treated rats. Taken together, these results indicate that exogenous administration of H<sub>2</sub>S can alleviate CSE-induced eGC damage and promote placental angiogenesis in CSE-treated rats, suggesting that H<sub>2</sub>S may be a novel therapeutic agent for the treatment of CSE-associated vascular disease.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"154 ","pages":"Pages 115-127"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791849","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 : 2025-02-01DOI: 10.1016/j.niox.2024.11.010
Agata Płoska , Adrianna Radulska , Anna Siekierzycka , Paulina Cieślik , Michał Santocki , Iwona T. Dobrucki , Leszek Kalinowski , Joanna M. Wierońska
l-arginine derivatives (ADMA, SDMA, NMMA) are endogenous inhibitors of nitric oxide (NO֗) production, which is essential in critical brain processes including blood-brain barrier (BBB) integrity and long-term potentiation (LTP). ADMA and NMMA are degraded by dimethylarginine dimethylaminohydrolase 1 (DDAH1) and protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues. There is no data concerning the impact of metabotropic glutamate receptors (mGlu) ligands on this aspect of brain physiology.
In the present studies the impact of positive allosteric modulators (PAM) of mGlu5 (CDPPB) and mGlu2 (LY487379) receptors on l-arginine derivatives, DDAH1 and PRMT5 expression in mouse models of cognitive dysfunction induced with MK-801(0.3 mg/kg) or scopolamine (1 mg/kg), was investigated. Experiments were performed both after acute and chronic (14 days) administration of the compounds, which were administered at the doses 0.1–5 mg/kg (CDBBB) and 0.1–1 mg/kg (LY487379).
The chronic administration of both compounds normalized the level of l-arginine derivatives in MK-801 model (in brain and plasma) and only low dose of CDPPB prevented scopolamine-induced changes. The expression of DDAH1 and PRMT5 was modulated by CDPPB and LY487379, both in MK-801 and scopolamine models.
In the novel object recognition (NOR) test low doses of the compounds, inactive after single administration, prevented cognitive decline after chronic injections.
Our findings highlight the potential of mGlu receptor modulators in treating schizophrenia and possibly dementia by normalizing l-arginine derivatives production, preventing from nitric oxide synthases uncoupling.
{"title":"The impact of mGlu2 or mGlu5 receptor activators on the production of l-arginine derivatives and the expression of PRMT5 or DDAH1 enzymes in animal models of cognitive decline","authors":"Agata Płoska , Adrianna Radulska , Anna Siekierzycka , Paulina Cieślik , Michał Santocki , Iwona T. Dobrucki , Leszek Kalinowski , Joanna M. Wierońska","doi":"10.1016/j.niox.2024.11.010","DOIUrl":"10.1016/j.niox.2024.11.010","url":null,"abstract":"<div><div><span>l</span>-arginine derivatives (ADMA, SDMA, NMMA) are endogenous inhibitors of nitric oxide (NO֗) production, which is essential in critical brain processes including blood-brain barrier (BBB) integrity and long-term potentiation (LTP). ADMA and NMMA are degraded by dimethylarginine dimethylaminohydrolase 1 (DDAH1) and protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues. There is no data concerning the impact of metabotropic glutamate receptors (mGlu) ligands on this aspect of brain physiology.</div><div>In the present studies the impact of positive allosteric modulators (PAM) of mGlu5 (CDPPB) and mGlu2 (LY487379) receptors on <span>l</span>-arginine derivatives, DDAH1 and PRMT5 expression in mouse models of cognitive dysfunction induced with MK-801(0.3 mg/kg) or scopolamine (1 mg/kg), was investigated. Experiments were performed both after acute and chronic (14 days) administration of the compounds, which were administered at the doses 0.1–5 mg/kg (CDBBB) and 0.1–1 mg/kg (LY487379).</div><div>The chronic administration of both compounds normalized the level of <span>l</span>-arginine derivatives in MK-801 model (in brain and plasma) and only low dose of CDPPB prevented scopolamine-induced changes. The expression of DDAH1 and PRMT5 was modulated by CDPPB and LY487379, both in MK-801 and scopolamine models.</div><div>In the novel object recognition (NOR) test low doses of the compounds, inactive after single administration, prevented cognitive decline after chronic injections.</div><div>Our findings highlight the potential of mGlu receptor modulators in treating schizophrenia and possibly dementia by normalizing <span>l</span>-arginine derivatives production, preventing from nitric oxide synthases uncoupling.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"154 ","pages":"Pages 140-151"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786297","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 : 2025-02-01DOI: 10.1016/j.niox.2024.11.004
Kuo Li, Chuansuo Zhang, Li xuan Wang, Xiaoxuan Wang, Ruyue Wang
This study examines KLF4's role in endothelial cells (ECs), emphasizing its effects on nitric oxide (NO) production, microvascular formation, and oxidative stress regulation following ischemic stroke. Through high-throughput sequencing, we identified eight cell subpopulations in carotid artery tissues post-stroke, with KLF4 notably elevated in ECs. KLF4 overexpression in ECs promoted NO synthesis, enhanced endothelial tube formation, mitigated oxidative stress, and improved smooth muscle cells (SMCs) function, collectively boosting blood flow in ischemic regions. These findings highlight KLF4 as pivotal in vascular regeneration and oxidative stress reduction, positioning it as a promising target for cardiovascular and cerebrovascular therapies.
{"title":"KLF4's role in regulating nitric oxide production and promoting microvascular formation following ischemic stroke","authors":"Kuo Li, Chuansuo Zhang, Li xuan Wang, Xiaoxuan Wang, Ruyue Wang","doi":"10.1016/j.niox.2024.11.004","DOIUrl":"10.1016/j.niox.2024.11.004","url":null,"abstract":"<div><div>This study examines KLF4's role in endothelial cells (ECs), emphasizing its effects on nitric oxide (NO) production, microvascular formation, and oxidative stress regulation following ischemic stroke. Through high-throughput sequencing, we identified eight cell subpopulations in carotid artery tissues post-stroke, with KLF4 notably elevated in ECs. KLF4 overexpression in ECs promoted NO synthesis, enhanced endothelial tube formation, mitigated oxidative stress, and improved smooth muscle cells (SMCs) function, collectively boosting blood flow in ischemic regions. These findings highlight KLF4 as pivotal in vascular regeneration and oxidative stress reduction, positioning it as a promising target for cardiovascular and cerebrovascular therapies.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"154 ","pages":"Pages 86-104"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667841","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 : 2025-01-08DOI: 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":"2025-01-08","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号