Pub Date : 2025-10-05DOI: 10.1016/j.niox.2025.10.002
Zahra Bahadoran , Asghar Ghasemi
Diabetic peripheral neuropathy (DPN) is one of the most prevalent long-term complications in type 1 (T1DM) and type 2 (T2DM) diabetes mellitus and is characterized by structural (microangiopathy, axonal atrophy, impaired myelination, and disrupted Schwann cell-axon interactions) and functional (impaired axonal transport and sensory and motor disorders) changes in neurons. Nitric oxide (NO) contributes to the development and progression of DPN as it has a role in the perfusion and electrophysiological functions of neurons. NO is essential for sustaining nerve conduction velocity (NCV) through modulation of Na+/K+-ATPase activity. Isoform-specific alterations in NO synthase (NOS) expression and activity occur during the development of DPN. Neural NOS (nNOS) generally exhibits consistent downregulation, especially in T2DM models, whereas inducible NOS (iNOS) tends to be upregulated in the T1DM model. NO has been proposed as a potential therapeutic agent for DPN because of its potent vasodilatory effects. NO-donating derivatives (e.g., NCX1404, PRG150) have demonstrated both symptomatic and disease-modifying effects in DPN. In conclusion, NO plays a role in the pathophysiology of DPN and is a therapeutic target for managing neuropathy in diabetes.
{"title":"Diabetic peripheral neuropathy: Role of nitric oxide","authors":"Zahra Bahadoran , Asghar Ghasemi","doi":"10.1016/j.niox.2025.10.002","DOIUrl":"10.1016/j.niox.2025.10.002","url":null,"abstract":"<div><div>Diabetic peripheral neuropathy (DPN) is one of the most prevalent long-term complications in type 1 (T1DM) and type 2 (T2DM) diabetes mellitus and is characterized by structural (microangiopathy, axonal atrophy, impaired myelination, and disrupted Schwann cell-axon interactions) and functional (impaired axonal transport and sensory and motor disorders) changes in neurons. Nitric oxide (NO) contributes to the development and progression of DPN as it has a role in the perfusion and electrophysiological functions of neurons. NO is essential for sustaining nerve conduction velocity (NCV) through modulation of Na<sup>+</sup>/K<sup>+</sup>-ATPase activity. Isoform-specific alterations in NO synthase (NOS) expression and activity occur during the development of DPN. Neural NOS (nNOS) generally exhibits consistent downregulation, especially in T2DM models, whereas inducible NOS (iNOS) tends to be upregulated in the T1DM model. NO has been proposed as a potential therapeutic agent for DPN because of its potent vasodilatory effects. NO-donating derivatives (e.g., NCX1404, PRG150) have demonstrated both symptomatic and disease-modifying effects in DPN. In conclusion, NO plays a role in the pathophysiology of DPN and is a therapeutic target for managing neuropathy in diabetes.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 147-160"},"PeriodicalIF":3.2,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244786","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 : 2025-10-01DOI: 10.1016/j.niox.2025.09.006
Handan Gunes, Ercan Ozdemir, Ahmet Sevki Taskiran
Epilepsy is a disease affecting the quality of life, characterized by neuronal excessive discharges resulting from the disruption of the balance between excitatory and inhibitory systems in the brain, and its pathophysiology has not been fully elucidated. In this study, we investigated the effects of serotonin 7 (5-HT7) receptor antagonist SB 269970 on seizures in a pentylenetetrazol (PTZ)-induced epilepsy model. Seventy male Wistar Albino rats (weight 230–250 g) were used in the study and the rats were randomly assigned to control and drug groups. Predetermined doses of SB 269970 (3 mg/kg), 5-HT7 agonist AS 19 (5 mg/kg), 7-NI (nNOS inhibitor, 50 mg/kg), YC-1 (guanylate cyclase activator, 10 μg/kg) were administered to the rats. PTZ (35 mg/kg) was injected intraperitoneally to induce seizures. The Racine scale was used to evaluate seizure stages. After electrocorticography (ECoG) and video recordings, the rats were sacrificed and nitric oxide (NO), cGMP, nNOS and proinflammatory cytokines (TNF-α, IL-1β and IL-6) levels in hippocampal tissue were measured by biochemical methods. The study results showed that the seizure threshold increased and the number of seizures decreased in rats administered SB 269970. In addition, the levels of proinflammatory cytokines (TNF-α, IL-6, IL-1β) and NO, cGMP and nNOS, which are increased with seizures in the hippocampal tissue, were significantly decreased by the administration of SB 269970. In contrast, the administration of 5-HT7 agonist AS-19 increased the number of seizures and caused an increase in the levels of hippocampal proinflammatory cytokines and NO, cGMP and nNOS. In conclusion, the findings of this study revealed that SB 269970 causes anticonvulsant activity by inhibiting the NO/cGMP pathway and proinflammatory cytokine (TNF-α, IL-1β and IL-6) levels in the hippocampal tissue. However, further molecular studies are needed for 5-HT7 antagonist drugs to be an option in the treatment of epilepsy.
{"title":"5-HT7 receptor antagonist SB269970 attenuates seizures by modulating NO/cGMP signaling pathway and neuroinflammation in a pentylenetetrazol-induced epilepsy model in rats","authors":"Handan Gunes, Ercan Ozdemir, Ahmet Sevki Taskiran","doi":"10.1016/j.niox.2025.09.006","DOIUrl":"10.1016/j.niox.2025.09.006","url":null,"abstract":"<div><div>Epilepsy is a disease affecting the quality of life, characterized by neuronal excessive discharges resulting from the disruption of the balance between excitatory and inhibitory systems in the brain, and its pathophysiology has not been fully elucidated. In this study, we investigated the effects of serotonin 7 (5-HT7) receptor antagonist SB 269970 on seizures in a pentylenetetrazol (PTZ)-induced epilepsy model. Seventy male Wistar Albino rats (weight 230–250 g) were used in the study and the rats were randomly assigned to control and drug groups. Predetermined doses of SB 269970 (3 mg/kg), 5-HT7 agonist AS 19 (5 mg/kg), 7-NI (nNOS inhibitor, 50 mg/kg), YC-1 (guanylate cyclase activator, 10 μg/kg) were administered to the rats. PTZ (35 mg/kg) was injected intraperitoneally to induce seizures. The Racine scale was used to evaluate seizure stages. After electrocorticography (ECoG) and video recordings, the rats were sacrificed and nitric oxide (NO), cGMP, nNOS and proinflammatory cytokines (TNF-α, IL-1β and IL-6) levels in hippocampal tissue were measured by biochemical methods. The study results showed that the seizure threshold increased and the number of seizures decreased in rats administered SB 269970. In addition, the levels of proinflammatory cytokines (TNF-α, IL-6, IL-1β) and NO, cGMP and nNOS, which are increased with seizures in the hippocampal tissue, were significantly decreased by the administration of SB 269970. In contrast, the administration of 5-HT7 agonist AS-19 increased the number of seizures and caused an increase in the levels of hippocampal proinflammatory cytokines and NO, cGMP and nNOS. In conclusion, the findings of this study revealed that SB 269970 causes anticonvulsant activity by inhibiting the NO/cGMP pathway and proinflammatory cytokine (TNF-α, IL-1β and IL-6) levels in the hippocampal tissue. However, further molecular studies are needed for 5-HT7 antagonist drugs to be an option in the treatment of epilepsy.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 78-88"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145220300","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}
Modulating intracellular nitric oxide (NO) levels offers a promising strategy to enhance tumor cell sensitivity to nanoparticle-based therapies. In this study, we investigated the impact of intracellular NO modulation in prostate cancer cells (PC3) using S-nitrosoglutathione (GSNO, a NO donor) and L-nitro arginine methyl ester (l-NAME, a nitric oxide synthase (NOS) inhibitor), in combination with cisplatin-loaded zinc oxide nanoparticles (ZnO/CisPt NPs). These nanoparticles, previously shown to exert selective cytotoxicity against PC3 cells, had their therapeutic performance further enhanced by NO modulation, which led to reduced NOS expression and regulation of inflammatory cytokines. Interestingly, both the increase and the depletion of intracellular S-NO levels contributed to tumor cell sensitization to the nanoparticle-based treatment. These results indicate that altering NO balance, regardless of direction, plays a key role in how cells respond to therapy. Our results reinforce the relevance of NO signaling in augmenting the efficacy of nanomedicine approaches while minimizing tumor-associated inflammation, offering a safer and more targeted strategy for prostate cancer treatment with potential for broader applications in oncology.
{"title":"Nitric oxide tuning enhances cytotoxicity and reduces inflammation in prostate cancer nanotherapy.","authors":"Joana Claudio Pieretti, Giovana Marchini Armentano, Marcela Sorelli Carneiro-Ramos, Amedea Barozzi Seabra","doi":"10.1016/j.niox.2025.08.001","DOIUrl":"10.1016/j.niox.2025.08.001","url":null,"abstract":"<p><p>Modulating intracellular nitric oxide (NO) levels offers a promising strategy to enhance tumor cell sensitivity to nanoparticle-based therapies. In this study, we investigated the impact of intracellular NO modulation in prostate cancer cells (PC3) using S-nitrosoglutathione (GSNO, a NO donor) and L-nitro arginine methyl ester (l-NAME, a nitric oxide synthase (NOS) inhibitor), in combination with cisplatin-loaded zinc oxide nanoparticles (ZnO/CisPt NPs). These nanoparticles, previously shown to exert selective cytotoxicity against PC3 cells, had their therapeutic performance further enhanced by NO modulation, which led to reduced NOS expression and regulation of inflammatory cytokines. Interestingly, both the increase and the depletion of intracellular S-NO levels contributed to tumor cell sensitization to the nanoparticle-based treatment. These results indicate that altering NO balance, regardless of direction, plays a key role in how cells respond to therapy. Our results reinforce the relevance of NO signaling in augmenting the efficacy of nanomedicine approaches while minimizing tumor-associated inflammation, offering a safer and more targeted strategy for prostate cancer treatment with potential for broader applications in oncology.</p>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":" ","pages":"124-131"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794981","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}
Conserved across the phylogeny, S-nitrosylation and S-denitrosylation of biological thiols is a reversible protein post-translational modification of cysteine thiol residues involving nitric oxide (NO) and NO•-derived metabolites. S-nitrosylation of proteins is observed to transduce signalling pathways with significant pathological and physiological relevance. Although endogenous S-nitrosylation is also an obligate non-classical cellular signalling pathway of NO• in single-celled organisms, but very little information is available in prokaryotes. Hitherto unknown, we present experimental evidence for the first time in vivo S-nitrosylation (without using any NO•/RNS donor) of proteins of the enteropathogenic, Gram-negative bacteria O1 El Tor strains of Vibrio cholerae N16961 and C6706. In the present study, PSNO was quantified by 2, 3-diaminonaphthalene (DAN) using a spectrofluorometer, which was further supported by confocal microscopy. Western blot and mass spectrometry-based proteomic analyses identified ten S-nitrosylated proteins via DMPO-nitrone adduct formation. V. cholerae contained high amounts of the in vivo pool of S-nitrosylated proteome in different respiratory conditions. Experimental evidence shows that physiological levels of glutathione (GSH) can efficiently S-denitrosylate Vibrio cholerae PSNO in a concentration-dependent manner, suggesting that the intracellular GSH tends to reset the redox state of these protein thiols. Our data suggests that V. cholerae possesses more amount of in vivo PSNO during semi-anaerobic respiration than aerobic respiration and irrespective of media and strain used; stationary phase cells are relatively more stable to GSH-catalyzed S-denitrosylation than their log-phase counterparts. Additionally, the in vivo PSNO accumulation was found to be elevated in the nitrate reductase deletion mutant (ΔnapA), indicating the role of napA in the nitroso-oxidative stress response mechanism of V. cholerae. This could aid in its remarkable adaptability and survivability in the hostile conditions of the human intestine, thereby paving the way for cholera, a highly contagious diarrheal disease.
{"title":"Detection and proteomic identification of in vivo S-nitrosylated proteins in Vibrio cholerae: A novel evidence","authors":"Shuddhasattwa Samaddar , Surupa Chakraborty , Rajib Sengupta , Sanjay Ghosh","doi":"10.1016/j.niox.2025.09.005","DOIUrl":"10.1016/j.niox.2025.09.005","url":null,"abstract":"<div><div>Conserved across the phylogeny, S-nitrosylation and S-denitrosylation of biological thiols is a reversible protein post-translational modification of cysteine thiol residues involving nitric oxide (NO) and NO<sup>•</sup>-derived metabolites. S-nitrosylation of proteins is observed to transduce signalling pathways with significant pathological and physiological relevance. Although endogenous S-nitrosylation is also an obligate non-classical cellular signalling pathway of NO<sup>•</sup> in single-celled organisms, but very little information is available in prokaryotes. Hitherto unknown, we present experimental evidence for the first time in vivo S-nitrosylation (without using any NO<sup>•</sup>/RNS donor) of proteins of the enteropathogenic, Gram-negative bacteria O1 El Tor strains of <em>Vibrio cholerae</em> N16961 and C6706. In the present study, PSNO was quantified by 2, 3-diaminonaphthalene (DAN) using a spectrofluorometer, which was further supported by confocal microscopy. Western blot and mass spectrometry-based proteomic analyses identified ten S-nitrosylated proteins <em>via</em> DMPO-nitrone adduct formation. <em>V. cholerae</em> contained high amounts of the in vivo pool of S-nitrosylated proteome in different respiratory conditions. Experimental evidence shows that physiological levels of glutathione (GSH) can efficiently S-denitrosylate <em>Vibrio cholerae</em> PSNO in a concentration-dependent manner, suggesting that the intracellular GSH tends to reset the redox state of these protein thiols. Our data suggests that <em>V. cholerae</em> possesses more amount of in vivo PSNO during semi-anaerobic respiration than aerobic respiration and irrespective of media and strain used; stationary phase cells are relatively more stable to GSH-catalyzed S-denitrosylation than their log-phase counterparts. Additionally, the in vivo PSNO accumulation was found to be elevated in the nitrate reductase deletion mutant <em>(</em>Δ<em>napA</em>), indicating the role of <em>napA</em> in the nitroso-oxidative stress response mechanism of <em>V. cholerae</em>. This could aid in its remarkable adaptability and survivability in the hostile conditions of the human intestine, thereby paving the way for cholera, a highly contagious diarrheal disease.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 63-77"},"PeriodicalIF":3.2,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213349","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 : 2025-09-12DOI: 10.1016/j.niox.2025.09.003
Brenda da Silva , Fernanda Tibolla Viero , Caren Tatiane de David Antoniazzi , Sabrina Qader Kudsi , Diulle Spat Peres , Ricardo Iuri Felix Morais , Leonardo Gomes Pereira , Gabriela Trevisan
Multiple sclerosis (MS) is a complex neuroinflammatory disease often associated with migraine and anxiety, both of which impair quality of life. MS pathology involves intense inflammatory and oxidative processes, including increased nitric oxide (NO) production. However, the role of NO in MS-related migraine symptoms remains unclear. This study evaluated whether repeated administration of 7-nitroindazole (7-NI), a selective neuronal nitric oxide synthase (nNOS) inhibitor, could alleviate migraine-like nociception, anxiety-like behavior, and neuroinflammatory biomarkers in a relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) mouse model. RR-EAE was induced in female C57BL/6 mice (20–30 g) using myelin oligodendrocyte glycoprotein (MOG35-55) and Quillaja saponin as an adjuvant. Mice received daily intragastric 7-NI (120 mg/kg) from day 20–35 post-induction. Disease progression, mechanical/spontaneous allodynia, and anxiety-like behavior were assessed. At the end of the protocol, oxidative and inflammatory biomarkers were analyzed. 7-NI treatment significantly reduced disease severity and nociception, exerted an anxiolytic effect, and improved myelin quality parameters. It inhibited the increase of oxidative and nitrosative markers (NOx, H2O2) in the brainstem, trigeminal ganglion, and plasma. Treatment also prevented plasma calcitonin gene-related peptide elevation and increased anti-inflammatory cytokines (IL-4, IL-10), suggesting positive modulation of neuroinflammation in RR-EAE. These findings highlight the therapeutic potential of 7-NI in MS; however, further studies are required to confirm its safety and efficacy in different populations and chronic disease contexts.
{"title":"7-Nitroindazole, an nNOS inhibitor, reduces migraine-like nociception, demyelination, and anxiety-like behavior in a mouse model of relapsing-remitting multiple sclerosis","authors":"Brenda da Silva , Fernanda Tibolla Viero , Caren Tatiane de David Antoniazzi , Sabrina Qader Kudsi , Diulle Spat Peres , Ricardo Iuri Felix Morais , Leonardo Gomes Pereira , Gabriela Trevisan","doi":"10.1016/j.niox.2025.09.003","DOIUrl":"10.1016/j.niox.2025.09.003","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is a complex neuroinflammatory disease often associated with migraine and anxiety, both of which impair quality of life. MS pathology involves intense inflammatory and oxidative processes, including increased nitric oxide (NO) production. However, the role of NO in MS-related migraine symptoms remains unclear. This study evaluated whether repeated administration of 7-nitroindazole (7-NI), a selective neuronal nitric oxide synthase (nNOS) inhibitor, could alleviate migraine-like nociception, anxiety-like behavior, and neuroinflammatory biomarkers in a relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) mouse model. RR-EAE was induced in female C57BL/6 mice (20–30 g) using myelin oligodendrocyte glycoprotein (MOG35-55) and Quillaja saponin as an adjuvant. Mice received daily intragastric 7-NI (120 mg/kg) from day 20–35 post-induction. Disease progression, mechanical/spontaneous allodynia, and anxiety-like behavior were assessed. At the end of the protocol, oxidative and inflammatory biomarkers were analyzed. 7-NI treatment significantly reduced disease severity and nociception, exerted an anxiolytic effect, and improved myelin quality parameters. It inhibited the increase of oxidative and nitrosative markers (NOx, H<sub>2</sub>O<sub>2</sub>) in the brainstem, trigeminal ganglion, and plasma. Treatment also prevented plasma calcitonin gene-related peptide elevation and increased anti-inflammatory cytokines (IL-4, IL-10), suggesting positive modulation of neuroinflammation in RR-EAE. These findings highlight the therapeutic potential of 7-NI in MS; however, further studies are required to confirm its safety and efficacy in different populations and chronic disease contexts.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 51-62"},"PeriodicalIF":3.2,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065441","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 : 2025-09-06DOI: 10.1016/j.niox.2025.09.001
Dong Ding , Ran Tian , Xiao Yang , Zhe Ren , Zhi-Cheng Jing , Xin-Tong Wu , Lian-Wen Sun
{"title":"Corrigendum to “The impact of ciliary length on the mechanical response of osteocytes to fluid shear stress” [Nitric Oxide 155 2025 1–11]","authors":"Dong Ding , Ran Tian , Xiao Yang , Zhe Ren , Zhi-Cheng Jing , Xin-Tong Wu , Lian-Wen Sun","doi":"10.1016/j.niox.2025.09.001","DOIUrl":"10.1016/j.niox.2025.09.001","url":null,"abstract":"","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 38-39"},"PeriodicalIF":3.2,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145004508","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 : 2025-09-05DOI: 10.1016/j.niox.2025.09.002
Laxman Poudel , Thilini Karunarathna , Stephen Baker , Elmira Alipour , Matthew R. Dent , Jesús Tejero , Mark T. Gladwin , Anthony W. DeMartino , Daniel B. Kim-Shapiro
We recently demonstrated a rapid reaction between labile ferric heme and nitric oxide (NO) in the presence of reduced glutathione (GSH) or other small thiols in a process called thiol-catalyzed reductive nitrosylation, yielding a novel signaling molecule, labile nitrosyl ferrous heme (NO-ferroheme), which we and others have shown can regulate vasodilation and platelet homeostasis. Red blood cells (RBCs) contain high concentrations of GSH, and NO can be generated in the RBC via nitrite reduction and/or RBC endothelial nitric oxide synthase (eNOS) so that NO-ferroheme could, in principle, be formed in the RBC. NO-ferroheme may also form in other cells and compartments, including in plasma, where another small and reactive thiol species, hydrogen sulfide (H2S/HS−), is also present and may catalyze NO-ferroheme formation akin to GSH. Here, we compare the reactivity of GSH and hydrogen sulfide with hemin in physiologically relevant media, including human serum albumin (HSA) and RBC membranes. Strikingly, hydrogen sulfide demonstrated a second-order rate constant over 10 times higher than GSH. We propose that the increased solubility of H2S vs GSH in lipophilic environments – where labile heme is most readily found – and the increased steric hindrance of the bulkier GSH account for the faster reaction kinetics observed with hydrogen sulfide. Our findings suggest that the hydrogen sulfide-catalyzed reductive nitrosylation reaction produces thionitrous acid (HSNO), which readily undergoes further reactions with excess hydrogen sulfide to form nitrosopersulfide (SSNO−) and polysulfides. These results suggest a common theme in thiol-catalyzed reductive nitrosylation of labile ferric heme that could play an important role in NO signaling.
{"title":"Role of hydrogen sulfide in catalyzing the formation of NO-ferroheme","authors":"Laxman Poudel , Thilini Karunarathna , Stephen Baker , Elmira Alipour , Matthew R. Dent , Jesús Tejero , Mark T. Gladwin , Anthony W. DeMartino , Daniel B. Kim-Shapiro","doi":"10.1016/j.niox.2025.09.002","DOIUrl":"10.1016/j.niox.2025.09.002","url":null,"abstract":"<div><div>We recently demonstrated a rapid reaction between labile ferric heme and nitric oxide (NO) in the presence of reduced glutathione (GSH) or other small thiols in a process called thiol-catalyzed reductive nitrosylation, yielding a novel signaling molecule, labile nitrosyl ferrous heme (NO-ferroheme), which we and others have shown can regulate vasodilation and platelet homeostasis. Red blood cells (RBCs) contain high concentrations of GSH, and NO can be generated in the RBC via nitrite reduction and/or RBC endothelial nitric oxide synthase (eNOS) so that NO-ferroheme could, in principle, be formed in the RBC. NO-ferroheme may also form in other cells and compartments, including in plasma, where another small and reactive thiol species, hydrogen sulfide (H<sub>2</sub>S/HS<sup>−</sup>), is also present and may catalyze NO-ferroheme formation akin to GSH. Here, we compare the reactivity of GSH and hydrogen sulfide with hemin in physiologically relevant media, including human serum albumin (HSA) and RBC membranes. Strikingly, hydrogen sulfide demonstrated a second-order rate constant over 10 times higher than GSH. We propose that the increased solubility of H<sub>2</sub>S vs GSH in lipophilic environments – where labile heme is most readily found – and the increased steric hindrance of the bulkier GSH account for the faster reaction kinetics observed with hydrogen sulfide. Our findings suggest that the hydrogen sulfide-catalyzed reductive nitrosylation reaction produces thionitrous acid (HSNO), which readily undergoes further reactions with excess hydrogen sulfide to form nitrosopersulfide (SSNO<sup>−</sup>) and polysulfides. These results suggest a common theme in thiol-catalyzed reductive nitrosylation of labile ferric heme that could play an important role in NO signaling.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 40-50"},"PeriodicalIF":3.2,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008359","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 : 2025-09-02DOI: 10.1016/j.niox.2025.08.005
Katty Anne Amador de Lucena Medeiros , Auderlan Mendonça de Gois , Rodolfo Silva dos Santos , Milena Caroline Nunes Monteiro , Heitor Franco Santos , Marina Freire de Souza , Thassya Fernanda Oliveira dos Santos , Marco Aurelio M. Freire , Mariza Bortolanza , Elaine Del-Bel , José Ronaldo Santos , Murilo Marchioro
Introduction
Fear is a response to real aversive stimuli. Studies on phylogenetically distant species like reptiles can offer valuable insights into the neural mechanisms of fear.
Objective
To investigate the activation and distribution of nitrergic neurons in the telencephalon of Tropidurus hispidus lizards and evaluate the role of glutamatergic modulation via NMDA receptors following exposure to an aversive stimulus.
Methods
Lizards were exposed to a live cat, and 24 h later, NADPH-diaphorase histochemistry was performed in the telencephalon to quantify neuron number and optical density. In the second stage, animals received i.c.v. injections of the NMDA receptor antagonist AP5 (1.25, 2.5, or 5.0 μg/μl), followed by cat exposure and histochemical analysis.
Results
Exposure to the cat led to increased freezing time in lizards. These animals also showed an increased number of nitrergic neurons in the dorsal cortex, anterior dorsal ventricular ridge (ADVR), and dorsolateral amygdala, as well as elevated integrated optical density (IOD) in the striatum, ADVR, dorsolateral amygdala and lateral amygdaloid nucleus. The AP5 1.25 and 5.0 μg/μl groups exhibited some head or limb movements even in the presence of the cat. The 1.25 μg/μl group showed reduced neuron counts and IOD in the dorsolateral amygdala; the 2.5 μg/μl and 5.0 μg/μl groups showed reduced IOD and neuron counts in the striatum.
Conclusion
Tropidurus hispidus lizards show fear-like behavior and decreased exploration after aversive stimuli, with nitric oxide in the telencephalon – particularly in the striatum and dorsolateral amygdala – modulating this response via NMDA receptor activation.
{"title":"Distribution and activation of nitrergic neurons in response to aversive stimulus exposure in the Tropidurus hispidus lizard: Involvement of glutamatergic circuitry","authors":"Katty Anne Amador de Lucena Medeiros , Auderlan Mendonça de Gois , Rodolfo Silva dos Santos , Milena Caroline Nunes Monteiro , Heitor Franco Santos , Marina Freire de Souza , Thassya Fernanda Oliveira dos Santos , Marco Aurelio M. Freire , Mariza Bortolanza , Elaine Del-Bel , José Ronaldo Santos , Murilo Marchioro","doi":"10.1016/j.niox.2025.08.005","DOIUrl":"10.1016/j.niox.2025.08.005","url":null,"abstract":"<div><h3>Introduction</h3><div>Fear is a response to real aversive stimuli. Studies on phylogenetically distant species like reptiles can offer valuable insights into the neural mechanisms of fear.</div></div><div><h3>Objective</h3><div>To investigate the activation and distribution of nitrergic neurons in the telencephalon of <em>Tropidurus hispidus</em> lizards and evaluate the role of glutamatergic modulation via NMDA receptors following exposure to an aversive stimulus.</div></div><div><h3>Methods</h3><div>Lizards were exposed to a live cat, and 24 h later, NADPH-diaphorase histochemistry was performed in the telencephalon to quantify neuron number and optical density. In the second stage, animals received i.c.v. injections of the NMDA receptor antagonist AP5 (1.25, 2.5, or 5.0 μg/μl), followed by cat exposure and histochemical analysis.</div></div><div><h3>Results</h3><div>Exposure to the cat led to increased freezing time in lizards. These animals also showed an increased number of nitrergic neurons in the dorsal cortex, anterior dorsal ventricular ridge (ADVR), and dorsolateral amygdala, as well as elevated integrated optical density (IOD) in the striatum, ADVR, dorsolateral amygdala and lateral amygdaloid nucleus. The AP5 1.25 and 5.0 μg/μl groups exhibited some head or limb movements even in the presence of the cat. The 1.25 μg/μl group showed reduced neuron counts and IOD in the dorsolateral amygdala; the 2.5 μg/μl and 5.0 μg/μl groups showed reduced IOD and neuron counts in the striatum.</div></div><div><h3>Conclusion</h3><div><em>Tropidurus hispidus</em> lizards show fear-like behavior and decreased exploration after aversive stimuli, with nitric oxide in the telencephalon – particularly in the striatum and dorsolateral amygdala – modulating this response via NMDA receptor activation.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 23-37"},"PeriodicalIF":3.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Red blood cells (RBCs) express functional endothelial nitric oxide synthase (eNOS), which regulates blood pressure (BP) independently of eNOS in endothelial cells (ECs) and provides cardioprotection during acute myocardial infarction (AMI). The functional role of RBC- and EC- eNOS in anemia remains unknown. This study evaluated the effects of RBC- or EC-specific eNOS deletion on hemodynamics and cardiac function in blood loss anemia.
Methods
and resultsAnemia was induced in EC- or RBC-specific eNOS knockout (KO) mice and their respective controls. In vivo flow-mediated dilation (FMD) was preserved in RBC-eNOS-KO mice under both baseline and anemic conditions but was impaired in EC-eNOS-KO mice compared to their respective controls. Wire myograph analysis of aortic rings showed preserved endothelium-dependent relaxation (EDR) in anemic RBC-eNOS-KO mice, while EDR was abolished in anemic EC-eNOS-KO mice relative to controls. Miller catheter BP measurements revealed elevated systolic and diastolic BP in EC-eNOS-KO mice under both baseline and anemic conditions. Both systolic and diastolic BP were increased in RBC-eNOS-KO mice compared to controls, whereas these parameters remained unchanged in anemic RBC-eNOS-KO mice compared to their respective controls. Echocardiography demonstrated preserved cardiac function across all genotypes at baseline, 3 days post-anemia, and 24 h post-reperfused AMI. However, infarct size was significantly increased in anemic RBC-eNOS-KO mice compared to controls.
Conclusions
Anemia mitigates the BP elevation caused by RBC-eNOS deletion, while hypertension persists in the absence of endothelial eNOS, highlighting vascular eNOS as the predominant regulator of BP under anemic conditions. RBC-eNOS limits infarct size under anemic conditions.
{"title":"Divergent roles of endothelial and red blood cell nitric oxide synthase in regulating cardiovascular function during anemia","authors":"Vithya Yogathasan , Patricia Wischmann , Isabella Solga , Lilly Jäger , Stefanie Becher , Miriam M. Cortese-Krott , Norbert Gerdes , Malte Kelm , Christian Jung , Ramesh Chennupati","doi":"10.1016/j.niox.2025.08.004","DOIUrl":"10.1016/j.niox.2025.08.004","url":null,"abstract":"<div><h3>Background</h3><div>Red blood cells (RBCs) express functional endothelial nitric oxide synthase (eNOS), which regulates blood pressure (BP) independently of eNOS in endothelial cells (ECs) and provides cardioprotection during acute myocardial infarction (AMI). The functional role of RBC- and EC- eNOS in anemia remains unknown. This study evaluated the effects of RBC- or EC-specific eNOS deletion on hemodynamics and cardiac function in blood loss anemia.</div></div><div><h3>Methods</h3><div>and resultsAnemia was induced in EC- or RBC-specific eNOS knockout (KO) mice and their respective controls. In vivo flow-mediated dilation (FMD) was preserved in RBC-eNOS-KO mice under both baseline and anemic conditions but was impaired in EC-eNOS-KO mice compared to their respective controls. Wire myograph analysis of aortic rings showed preserved endothelium-dependent relaxation (EDR) in anemic RBC-eNOS-KO mice, while EDR was abolished in anemic EC-eNOS-KO mice relative to controls. Miller catheter BP measurements revealed elevated systolic and diastolic BP in EC-eNOS-KO mice under both baseline and anemic conditions. Both systolic and diastolic BP were increased in RBC-eNOS-KO mice compared to controls, whereas these parameters remained unchanged in anemic RBC-eNOS-KO mice compared to their respective controls. Echocardiography demonstrated preserved cardiac function across all genotypes at baseline, 3 days post-anemia, and 24 h post-reperfused AMI. However, infarct size was significantly increased in anemic RBC-eNOS-KO mice compared to controls.</div></div><div><h3>Conclusions</h3><div>Anemia mitigates the BP elevation caused by RBC-eNOS deletion, while hypertension persists in the absence of endothelial eNOS, highlighting vascular eNOS as the predominant regulator of BP under anemic conditions. RBC-eNOS limits infarct size under anemic conditions.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"159 ","pages":"Pages 1-10"},"PeriodicalIF":3.2,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-21DOI: 10.1016/j.niox.2025.08.002
Zheyu Liu , Bo Cui , Hao Ju , Tuantuan Tan , Jinchun Wu , Manqi Yang , Saeed Kashkooli , Mian Cheng , Gang Wu , Tao Liu
{"title":"Corrigendum to “Catestatin alleviates PASMC phenotypic switching-mediated pulmonary arterial remodeling in a rat model of MCT-induced pulmonary arterial hypertension by promoting endothelium-derived NO synthesis” [Nitric Oxide158 (2025) 93–105]","authors":"Zheyu Liu , Bo Cui , Hao Ju , Tuantuan Tan , Jinchun Wu , Manqi Yang , Saeed Kashkooli , Mian Cheng , Gang Wu , Tao Liu","doi":"10.1016/j.niox.2025.08.002","DOIUrl":"10.1016/j.niox.2025.08.002","url":null,"abstract":"","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":"158 ","pages":"Pages 132-133"},"PeriodicalIF":3.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144963242","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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