Mariana Gonçalves de Oliveira , José Britto-Junior , Douglas Rafael Martins Dias , Luise Gabriela Santos Pereira , Silvana Chiavegatto , Idam Hermawan , Hiroaki Shimokawa , Masato Tsutsui , Edson Antunes , Gilberto De Nucci
{"title":"Neurogenic-derived 6-nitrodopamine is the most potent endogenous modulator of the mouse urinary bladder relaxation","authors":"Mariana Gonçalves de Oliveira , José Britto-Junior , Douglas Rafael Martins Dias , Luise Gabriela Santos Pereira , Silvana Chiavegatto , Idam Hermawan , Hiroaki Shimokawa , Masato Tsutsui , Edson Antunes , Gilberto De Nucci","doi":"10.1016/j.niox.2024.10.010","DOIUrl":"10.1016/j.niox.2024.10.010","url":null,"abstract":"<div><div>6-Nitrodopamine (6-ND) modulates vas deferens, seminal vesicles, and corpus cavernosum contractility; however, its role on the lower urinary tract organs has not been evaluated. Investigations of isolated urinary bladders from wild-type (WT) mice revealed 6-ND release was comparable to that of dopamine and adrenaline, whereas noradrenaline was hardly detected, as assessed by liquid chromatography coupled to tandem mass spectrometry. <em>In vitro</em>, 6-ND induced concentration-dependent relaxations in carbachol pre-contracted bladders with high potency (pEC<sub>50</sub>: 8.04 ± 0.86), independently of eNOS/sGC activity. Co-incubation of 6-ND (1–10 μM) antagonizes the contractile effects of acetylcholine (p < 0.05). Experiments using nitric oxide synthase (NOS) knockout mice demonstrated that 6-ND release from isolated urinary bladder was significantly reduced by neuronal NOS (nNOS<sup>−/−</sup>) deletion and abolished by triple NOSs deletion (n/i/eNOS<sup>−/−</sup>), while no significant changes were observed in endothelial (eNOS<sup>−/−</sup>) or inducible (iNOS<sup>−/−</sup>) knockout mice. Incubation with tetrodotoxin resulted in a significant decrease in 6-ND release in bladders obtained from WT, but not in nNOS<sup>−/−</sup> mice. The bladders from nNOS<sup>−/−</sup> and n/i/eNOS<sup>−/−</sup> mice exhibited significantly higher contractile responses to electric field stimulation (EFS), compared to eNOS<sup>−/−</sup>, iNOS<sup>−/−</sup>, or WT bladders. The hyperreactivity observed in triple NOS knockouts was reversed by the incubation with bladder mucosal layer obtained from a donor WT mice, but not with the muscular layer. These findings clearly demonstrate 6-ND is the most potent endogenous relaxing agent of urinary bladder, and inhibition of its release is associated with bladder hyperreactivity.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anthea LoBue , Zhixin Li , Sophia K. Heuser , Junjie Li , Francesca Leo , Lukas Vornholz , Luke S. Dunaway , Tatsiana Suvorava , Brant E. Isakson , Miriam M. Cortese-Krott
{"title":"Generation and characterization of a conditional eNOS knock out mouse model for cell-specific reactivation of eNOS in gain-of-function studies","authors":"Anthea LoBue , Zhixin Li , Sophia K. Heuser , Junjie Li , Francesca Leo , Lukas Vornholz , Luke S. Dunaway , Tatsiana Suvorava , Brant E. Isakson , Miriam M. Cortese-Krott","doi":"10.1016/j.niox.2024.10.009","DOIUrl":"10.1016/j.niox.2024.10.009","url":null,"abstract":"<div><div>Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) in the vessel wall regulates blood pressure and cardiovascular hemodynamics. In this study, we generated conditional eNOS knock out (KO) mice characterized by a duplicated/inverted exon 2 flanked with two pairs of loxP regions (eNOS<sup>inv/inv</sup>); a Cre-recombinase activity induces cell-specific reactivation of eNOS, as a result of a flipping of the inverted exon 2 (eNOS<sup>fl</sup>). This work aimed to test the efficiency of the Cre-mediated cell-specific recombination and the resulting eNOS expression/function. As proof of concept, we crossed eNOS<sup>inv/inv</sup> mice with DeleterCre<sup>pos</sup> (DelCre<sup>pos</sup>) mice, expressing Cre recombinase in all cells. We generated heterozygous eNOS<sup>fl/inv</sup> or homozygous eNOS<sup>fl/fl</sup> mice, and eNOS<sup>inv/inv</sup> littermate mice. We found that both eNOS<sup>fl/fl</sup> and eNOS<sup>fl/inv</sup> mice express eNOS and the overall expression level depends on the number of mutated alleles, while eNOS<sup>inv/inv</sup> mice did not show any eNOS expression. Vascular endothelial function was restored in eNOS<sup>fl/fl</sup> and eNOS<sup>fl/inv</sup> mice, as determined by ACh-dependent vasodilation of aortic rings. Cre-dependent reactivation of eNOS in eNOS<sup>fl/fl</sup> and eNOS<sup>fl/inv</sup> mice rescued eNOS<sup>inv/inv</sup> (phenotypically global eNOS KO) mice from hypertension. These findings demonstrate that eNOS expression is restored in eNOS<sup>fl/fl</sup> mice at comparable physiological levels of WT mice, and its functional activity is independent on the number of the reactivated alleles. Therefore, eNOS<sup>inv/inv</sup> mice are a useful model for studying the effects of conditional reactivation of eNOS and gene dosage effects in specific cells for gain-of-function studies.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471018","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}
{"title":"A systematic review and dose‒response meta-analysis of the association between nitrate & nitrite intake and gastroesophageal cancer risk","authors":"Mohammadreza Ghasemi , Mohammad Bahrami koutenaei , Alireza Ghasemi , Reza Alizadeh-navaei , Mahmood Moosazadeh","doi":"10.1016/j.niox.2024.10.007","DOIUrl":"10.1016/j.niox.2024.10.007","url":null,"abstract":"<div><h3>Objective</h3><div>The objective of this systematic review and dose‒response meta-analysis was to assess the associations between the dietary consumption of nitrate and nitrite and the risk of gastric and esophageal cancer.</div></div><div><h3>Methods</h3><div>MEDLINE, Scopus, Embase, Web of Science, Proquest, and Google Scholar were searched until April 1, 2024. Articles were selected by two independent researchers on the basis of the inclusion and exclusion criteria. Data regarding the study design, type of exposure and outcomes, intervals of intake of nitrate or nitrite in each layer, OR/RR/HR of the relationship for each layer of intake, total sample size, and number of cases of gastric or esophageal cancer were extracted. The certainty of the evidence was rated via the GRADE method. The pooled odds ratios, risk ratios, and dose‒response analyses were calculated via Stata version 17.0. The best-fit dose‒response model was assessed by the P value for linearity and nonlinearity. Study heterogeneity was assessed via the I<sup>2</sup> and Q tests.</div></div><div><h3>Results</h3><div>We found 2124 nonredundant studies, 234 of which were potentially relevant. Eighteen articles met the inclusion criteria and were included in the review. The results of the meta-analysis revealed a significant positive association between nitrite intake and gastric cancer in both case‒control studies (OR = 1.29, 95 % CI = 1.09–1.52, P value = 0.001, I<sup>2</sup> = 1.91 %) and cohort studies (RR = 1.17, 95 % CI = 1.00–1.37, P value = 0.04, I<sup>2</sup> = 0.00 %). In addition, case‒control studies revealed a nonsignificant inverse association between nitrate intake and gastric cancer incidence (OR = 0.71, 95 % CI = 0.50–1.01, P value = 0.06, I<sup>2</sup> = 74.89 %), and cohort studies (RR = 0.89, 95 % CI = 0.73–1.09, P value = 0.27, I<sup>2</sup> = 0.00 %). Case‒control studies also revealed no significant correlation between nitrite intake and esophageal cancer incidence (OR = 1.48, 95 % CI = 0.91 to 2.42, P value = 0.12, I<sup>2</sup> = 0.001 %). Nitrites correlated linearly with gastric cancer (linearity P value = 0.001). The most appropriate fit models for the relationship between nitrate and gastric cancer were both piecewise linear and natural polynomial regression (quadratic) models (P values = 0.003 and 0.005, respectively). There was no significant publication bias.</div></div><div><h3>Conclusion</h3><div>According to this meta-analysis, high consumption of nitrites was associated with an increased risk of gastric cancer in case‒control and cohort studies with a linear regression model, and dietary nitrate intake was not associated with the risk of gastric cancer in either case‒control or cohort studies. These findings are inconclusive and require confirmation in future prospective studies with robust methodologies and adjustments for potential confounders.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471020","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}
Yuan Gao , Jiao Xu , Kaichuan He , Qi Guo , Lin Xiao , Sheng Jin , Danyang Tian , Xu Teng , Cuixia An , Hongmei Xue , Yuming Wu
{"title":"Hydrogen sulfide ameliorated endothelial dysfunction in hyperhomocysteinemia rats: Mechanism of IRE1α/JNK pathway-mediated autophagy","authors":"Yuan Gao , Jiao Xu , Kaichuan He , Qi Guo , Lin Xiao , Sheng Jin , Danyang Tian , Xu Teng , Cuixia An , Hongmei Xue , Yuming Wu","doi":"10.1016/j.niox.2024.10.008","DOIUrl":"10.1016/j.niox.2024.10.008","url":null,"abstract":"<div><div>Previous studies showed that hyperhomocysteinemia (HHcy) induced endothelial dysfunction by endoplasmic reticulum (ER) stress induction and autophagy stimulation. This study aimed to determine the effect of hydrogen sulfide (H<sub>2</sub>S) in homocysteine (Hcy)-induced endothelial dysfunction and observe the possible mechanism involved. Male Wistar rats (160–180g) were used and randomly divided into four groups: Control group, HHcy group, HHcy+Sodium hydrosulfide (NaHS) group and NaHS group. Rats were fed with 2% high methionine diet for 8 weeks to set up HHcy model. Plasma concentration of Hcy was measured by ELISA. Endothelium-dependent and non-endothelium-dependent vasodilation of rat renal arteries were determined by myograph. The protein expression of cystathionine-γ-lyase (CSE), ER stress- and autophagy-related proteins in renal arteries or human umbilical vein endothelial cells (HUVECs) were analyzed by western blotting. The endothelial function was impaired in HHcy rats and HUVECs. NaHS supplementation could improve the ACh-induced vasodilation, however it was eliminated by ER stress inducer Tunicamycin (TM) or autophagy inducer Rapamycin. Western blotting in renal arteries showed that Glucose-regulated protein 78 (GRP78) and three branches of ER stress (p-IRE1α, p-PERK, ATF6) , p-JNK1+p-JNK2 were downregulated, simultaneously the autophagy marker Beclin1, LC3BII/LC3BI ratio were decreased and p62 was increased with NaHS treatment in HHcy rats. In HUVECs, IRE1α-JNK induced autophagy was involved in HHcy-induced endothelial dysfunction, while NaHS stimulation reversed the protein expression in IRE1α/JNK-autophagy pathway with Hcy incubation. This study might suggest that endothelial dysfunction induced by HHcy might be correlated with IRE1α-JNK-autophagy axis pathway, which was suppressed by exogenous supplementation of H<sub>2</sub>S donor, NaHS.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An updated mechanistic overview of nitric oxide in drought tolerance of plants","authors":"Sakshi Saini , Priyanka Sharma , Pooja Pooja , Asha Sharma","doi":"10.1016/j.niox.2024.10.006","DOIUrl":"10.1016/j.niox.2024.10.006","url":null,"abstract":"<div><div>Drought stress, an inevitable global issue due to climate change, hinders plant growth and yield. Nitric oxide (NO), a tiny gaseous signaling compound is now gaining massive attention from the plant science community due to its unparalleled array of mechanisms for ameliorating various abiotic stresses, including drought. Supplementation of NO has shown its astounding effect in improving drought tolerance by prominently influencing its tendency to modulate stomatal movement and reduce oxidative stress; it can enormously affect the various other physio-biochemical processes such as root structure, photosynthesis, osmolyte cumulation, and seed establishment of plants due to its amalgamation with a wide range of molecules during drought conditions. The production and inhibition of root development majorly depend on NO concentration and/or experimental conditions. As a lipophilic free gasotransmitter, NO readily reacts with free metals and oxygen species and has been shown to enhance or reduce the redox homeostasis of plants, depending on whether acting in a chronic or acute mode. NO can easily alter the enzymes, protein activities, and genomic transcriptional and post-translational modifications that assist functional retrieval from water stress. Although progress is ongoing, much work remains to be done to describe the proper target site and mechanistic approach of this vibrant molecule in plant drought tolerance. This detailed review navigates through the comprehensive and clear picture of the mechanistic potential of NO in drought stress following molecular approaches and suggests effective physiological and biochemical strategies to overcome the negative impacts of drought. We explore its potential to increase crop production, thereby ensuring global food security in drought-prone areas. In an era marked by unrelenting climatic conditions, the implications of NO show a promising approach to sustainable farming, providing a beacon of hope for future crop productivity.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Nitric oxide-mediated regulation of macronutrients in plants","authors":"Roshani Gupta, Vijay Kumar, Nikita Verma, Rajesh Kumar Tewari","doi":"10.1016/j.niox.2024.10.005","DOIUrl":"10.1016/j.niox.2024.10.005","url":null,"abstract":"<div><div>In plant physiology, nitric oxide (NO) is a widely used signaling molecule. It is a free radical and an important component of the N-cycle. NO is produced endogenously inside plant cells, where it participates in multiple functions and provides protection against several abiotic and biotic stresses. NO and its interplay with macronutrients had remarkable effects on plant growth and development, the signaling pathway, and defense mechanisms. Its chemical properties, synthetic pathways, physiological effects, antioxidant action, signal transduction, and regulation of transporter genes and proteins have been studied. NO emerges as a key regulator under macronutrient deficiency. In plants, NO also affects reactive oxygen species (ROS), reactive nitrogen species (RNS), and post-translational modifications (PTMs). The function of NO and its significant control in the functions and adjustments of macronutrients under macronutrient deficit were summed up in this review. NO regulate functions of macronutrients and associated signaling events involved with macronutrient transporters in different plants.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400867","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}
Tathiany Igreja da Silva , Tamires da Cunha Fernandes , Emílio Telles de Sá Moreira , André da Costa Ferreira , Vanessa Estato , Hugo Caire de Castro Faria Neto , Patricia Alves Reis
{"title":"Role of Nitric oxide synthase II in cognitive impairment due to experimental cerebral malaria","authors":"Tathiany Igreja da Silva , Tamires da Cunha Fernandes , Emílio Telles de Sá Moreira , André da Costa Ferreira , Vanessa Estato , Hugo Caire de Castro Faria Neto , Patricia Alves Reis","doi":"10.1016/j.niox.2024.10.002","DOIUrl":"10.1016/j.niox.2024.10.002","url":null,"abstract":"<div><div>The role of nitric oxide (NO) in the pathogenesis of cerebral malaria and its cognitive sequelae remains controversial. Cerebral malaria is still the worst complication of <em>Plasmodium falciparum</em> infection, which is characterized by high rates of morbidity and mortality. Even after recovery from infection due to antimalarial therapy, the development of cognitive impairment in survivors reinforces the need to seek new therapies that demonstrate efficacy in preventing long-lasting sequelae. During disease pathogenesis, reactive oxygen and nitrogen species (RONS) are produced after the established intense inflammatory response. Increased expression of the enzyme inducible nitric oxide synthase (iNOS) seems to contribute to tissue injury and the onset of neurological damage. Elevated levels of NO developed by iNOS can induce the production of highly harmful nitrogen-reactive intermediates such as peroxynitrite. To address this, we performed biochemical and behavioral studies in C57BL6 mice, aminoguanidine (specific pharmacological inhibitor of the enzyme iNOS) treated and iNOS−/−, infected with Plasmodium berghei ANKA (PbA), with the aim of clarifying the impact of iNOS on the pathogenesis of cerebral malaria. Our findings underscore the effectiveness of both strategies in reducing cerebral malaria and providing protection against the cognitive impairment associated with the disease. Here, the absence or blockade of the iNOS enzyme was effective in reducing the signs of cerebral malaria detected after six days of infection. This was accompanied by a decrease in the production of pro-inflammatory cytokines and reactive oxygen and nitrogen species. In addition, nitrotyrosine (NT-3), a marker of nitrosative stress, was also reduced. Futher, cognitive dysfunction was analyzed fifteen days after infection in animals rescued from infection by chloroquine treatment (25 mg/kg bw). We observed that both interventions on the iNOS enzyme were able to improve memory and learning loss in mice. In summary, our data suggest that the iNOS enzyme has the potential to serve as a therapeutic target to prevent cognitive sequelae of cerebral malaria.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392173","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}
Martyn Ezra , Edit Franko , Desiree B. Spronk , Catherine Lamb , Thomas W. Okell , Kyle TS. Pattinson
{"title":"Trial of the cerebral perfusion response to sodium nitrite infusion in patients with acute subarachnoid haemorrhage using arterial spin labelling MRI","authors":"Martyn Ezra , Edit Franko , Desiree B. Spronk , Catherine Lamb , Thomas W. Okell , Kyle TS. Pattinson","doi":"10.1016/j.niox.2024.10.003","DOIUrl":"10.1016/j.niox.2024.10.003","url":null,"abstract":"<div><div>Aneurysmal subarachnoid haemorrhage (SAH) is a devastating subset of stroke. One of the major determinants of outcome is an evolving multifactorial injury occurring in the first 72 hours, known as early brain injury. Reduced nitric oxide (NO) bioavailability and an associated disruption to cerebral perfusion is believed to play an important role in this process. We sought to explore this relationship, by examining the effect on cerebral perfusion of the <em>in vivo</em> manipulation of NO levels using an exogenous NO donor (sodium nitrite).</div><div>We performed a double blind placebo controlled randomised experimental medicine study of the cerebral perfusion response to sodium nitrite infusion during the early brain injury period in 15 low grade (World Federation of Neurosurgeons grade 1–2) SAH patients. Patients were randomly assigned to receive sodium nitrite at 10 mcg/kg/min or saline placebo. Assessment occurred following endovascular aneurysm occlusion, mean time after ictus 66h (range 34–90h). Cerebral perfusion was quantified before infusion commencement and after 3 hours, using multi-post labelling delay (multi-PLD) vessel encoded pseudocontinuous arterial spin labelling (VEPCASL) magnetic resonance imaging (MRI).</div><div>Administration of sodium nitrite was associated with a significant increase in average grey matter cerebral perfusion. Group level voxelwise analysis identified that increased perfusion occurred within regions of the brain known to exhibit enhanced vulnerability to injury. These findings highlight the role of impaired NO bioavailability in the pathophysiology of early brain injury.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381354","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}
Yingying Cui , Kai Yang , Chunyu Guo , Zhengmei Xia , Benchun Jiang , Yanni Xue , Bingdong Song , Weirong Hu , Mingjie Zhang , Yanyan Wei , Cheng Zhang , Shichen Zhang , Jun Fang
{"title":"Carbon monoxide as a negative feedback mechanism on HIF-1α in the progression of metabolic-associated fatty liver disease","authors":"Yingying Cui , Kai Yang , Chunyu Guo , Zhengmei Xia , Benchun Jiang , Yanni Xue , Bingdong Song , Weirong Hu , Mingjie Zhang , Yanyan Wei , Cheng Zhang , Shichen Zhang , Jun Fang","doi":"10.1016/j.niox.2024.10.001","DOIUrl":"10.1016/j.niox.2024.10.001","url":null,"abstract":"<div><div>Metabolic-associated fatty liver disease (MAFLD) encompasses various chronic liver conditions, yet lacks approved drugs. Hypoxia-inducible factor-1α (HIF-1α) is pivotal in MAFLD development. Our prior research highlighted the efficacy of the nano-designed carbon monoxide (CO) donor, targeting HIF-1α in a mouse hepatic steatosis model. Given heme oxygenase-1 (HO-1, a major downstream molecule of HIF-1α) as the primary source of intrinsic CO, we hypothesized that upregulation of HO-1/CO, responsive to HIF-1α, forms a negative feedback loop regulating MAFLD progression. In this study, we explored the potential negative feedback mechanism of CO on HIF-1α and its downstream effects on MAFLD advancement. HIF-1α emerges early in hepatic steatosis induced by a high-fat (HF) diet, triggering increased HO-1 and inflammation. SMA/CORM2 effectively suppresses HIF-1α and steatosis progression when administered within the initial week of HF diet initiation but loses impact later. In adipose tissues, concurrent metabolic dysfunction and inflammation with HIF-1α activation suggest adipose tissue expansion initiates HF-induced steatosis, triggering hypoxia and liver inflammation. Notably, in an in vitro study using mouse hepatocytes treated with fatty acids, downregulating HO-1 intensified HIF-1α induction at moderate fatty acid concentrations. However, this effect diminished at high concentrations. These results suggest the HIF-1α–HO–1-CO axis as a feedback loop under physiological and mild pathological conditions. Excessive HIF-1α upregulation in pathological conditions overwhelms the CO feedback loop. Additional CO application effectively suppresses HIF-1α and disease progression, indicating potential application for MAFLD control.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381345","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}
Bingnan Guo , Bin Ma , Ming Li , Yuxin Li , Pengchong Liang , Dong Han , Xianliang Yan , Shuqun Hu
{"title":"The nitration of SIRT6 aggravates neuronal damage during cerebral ischemia-reperfusion in rat","authors":"Bingnan Guo , Bin Ma , Ming Li , Yuxin Li , Pengchong Liang , Dong Han , Xianliang Yan , Shuqun Hu","doi":"10.1016/j.niox.2024.10.004","DOIUrl":"10.1016/j.niox.2024.10.004","url":null,"abstract":"<div><div>Ischemic stroke is a major cause of death and disability. The activation of neuronal nitric oxide synthase (nNOS) and the resulting production of nitric oxide (NO) via NMDA receptor-mediated calcium influx play an exacerbating role in cerebral ischemia reperfusion injury. The NO rapidly reacts with superoxide (O<sup>2−</sup>) to form peroxynitrite (ONOO<sup>−</sup>), a toxic molecule may modify proteins through tyrosine residue nitration, ultimately worsening neuronal damage. SIRT6 has been proven to be crucial in regulating cell proliferation, death, and aging in various pathological settings. We have previous reported that human SIRT6 tyrosine nitration decreased its intrinsic catalytic activity <em>in vitro</em>. However, the exact role of SIRT6 function in the process of cerebral ischemia reperfusion injury is not yet fully elucidated. Herein, we demonstrated that an increase in the nitration of SIRT6 led to reduce its enzymatic activity and aggravated hippocampal neuronal damage in a rat model of four-artery cerebral ischemia reperfusion. In addition, reducing SIRT6 nitration resulted in increase the activity of SIRT6, alleviating hippocampal neuronal damage. Moreover, SIRT6 nitration affected its downstream molecule activity such as PARP1 and GCN5, promoting the process of neuronal ischemic injury in rat hippocampus. Additionally, treatment with NMDA receptor antagonist MK801, or nNOS inhibitor 7-NI, and resveratrol (an antioxidant) diminished SIRT6 nitration and the catalytic activity of downstream molecules like PARP1 and GCN5, thereby reducing neuronal damage. Finally, in the biochemical regulation of SIRT6 activity, tyrosine 257 was essential for its activity and susceptibility to nitration. Replacing tyrosine 257 with phenylalanine in rat SIRT6 attenuated the death of SH-SY5Y neurocytes under oxygen-glucose deprivation (OGD) conditions. These results may offer further understanding of SIRT6 function in the pathogenesis of cerebral ischemic diseases.</div></div>","PeriodicalId":19357,"journal":{"name":"Nitric oxide : biology and chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392177","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}