International Journal of Molecular Sciences

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23 pages, 3271 KiB

Open AccessArticle

S-Nitrosylation of Tissue Transglutaminase in Modulating Glycolysis, Oxidative Stress, and Inflammatory Responses in Normal and Indoxyl-Sulfate-Induced Endothelial Cells

by Cheng-Jui Lin, Chun Yu Chiu, En-Chih Liao, Chih-Jen Wu, Ching-Hu Chung, Charles S. Greenberg and Thung-S. Lai

Int. J. Mol. Sci. 2023, 24(13), 10935; https://doi.org/10.3390/ijms241310935 - 30 Jun 2023

Cited by 2 | Viewed by 1452

Abstract

Circulating uremic toxin indoxyl sulfate (IS), endothelial cell (EC) dysfunction, and decreased nitric oxide (NO) bioavailability are found in chronic kidney disease patients. NO nitrosylates/denitrosylates a specific protein’s cysteine residue(s), forming S-nitrosothios (SNOs), and the decreased NO bioavailability could interfere with NO-mediated signaling [...] Read more.

Circulating uremic toxin indoxyl sulfate (IS), endothelial cell (EC) dysfunction, and decreased nitric oxide (NO) bioavailability are found in chronic kidney disease patients. NO nitrosylates/denitrosylates a specific protein’s cysteine residue(s), forming S-nitrosothios (SNOs), and the decreased NO bioavailability could interfere with NO-mediated signaling events. We were interested in investigating the underlying mechanism(s) of the reduced NO and how it would regulate the S-nitrosylation of tissue transglutaminase (TG2) and its substrates on glycolytic, redox and inflammatory responses in normal and IS-induced EC injury. TG2, a therapeutic target for fibrosis, has a Ca²⁺-dependent transamidase (TGase) that is modulated by S-nitrosylation. We found IS increased oxidative stress, reduced NADPH and GSH levels, and uncoupled eNOS to generate NO. Immunoblot analysis demonstrated the upregulation of an angiotensin-converting enzyme (ACE) and significant downregulation of the beneficial ACE2 isoform that could contribute to oxidative stress in IS-induced injury. An in situ TGase assay demonstrated IS-activated TG2/TGase aminylated eNOS, NFkB, IkBα, PKM2, G6PD, GAPDH, and fibronectin (FN), leading to caspases activation. Except for FN, TGase substrates were all differentially S-nitrosylated either with or without IS but were denitrosylated in the presence of a specific, irreversible TG2/TGase inhibitor ZDON, suggesting ZDON-bound TG2 was not effectively transnitrosylating to TG2/TGase substrates. The data suggest novel roles of TG2 in the aminylation of its substrates and could also potentially function as a Cys-to-Cys S-nitrosylase to exert NO’s bioactivity to its substrates and modulate glycolysis, redox, and inflammation in normal and IS-induced EC injury. Full article

(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation)

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10 pages, 2936 KiB

Open AccessArticle

Glucose 6-P Dehydrogenase Overexpression Improves Aging-Induced Endothelial Dysfunction in Aorta from Mice: Role of Arginase II

by Eva Serna, Maria D Mauricio, Teresa San-Miguel, Sol Guerra-Ojeda, David Verdú, Alicia Valls, Coralie Arc-Chagnaud, Adrián De la Rosa and José Viña

Int. J. Mol. Sci. 2023, 24(4), 3622; https://doi.org/10.3390/ijms24043622 - 11 Feb 2023

Viewed by 1390

Abstract

The increase of vascular arginase activity during aging causes endothelial dysfunction. This enzyme competes with the endothelial nitric oxide synthase (eNOS) for L-arginine substrate. Our hypothesis is that glucose 6-P dehydrogenase (G6PD) overexpression could improve the endothelial function modulating the arginase pathway in [...] Read more.

The increase of vascular arginase activity during aging causes endothelial dysfunction. This enzyme competes with the endothelial nitric oxide synthase (eNOS) for L-arginine substrate. Our hypothesis is that glucose 6-P dehydrogenase (G6PD) overexpression could improve the endothelial function modulating the arginase pathway in aorta from mice. For this study, three groups of male mice were used: young wild type (WT) (6–9 months), old WT (21–22 months) and old G6PD-Tg (21–22 months) mice. Vascular reactivity results showed a reduced acetylcholine-dependent relaxation in the old WT but not old G6PD-Tg group. Endothelial dysfunction was reverted by nor-NOHA, an arginase inhibitor. Mice overexpressing G6PD underexpressed arginase II and also displayed a lower activity of this enzyme. Moreover, histological analyses demonstrated that age causes a thickness of aortic walls, but this did not occur in G6PD-Tg mice. We conclude that the overexpressing G6PD mouse is a model to improve vascular health via the arginase pathway. Full article

(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation)

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17 pages, 2684 KiB

Open AccessArticle

A Common Target of Nitrite and Nitric Oxide for Respiration Inhibition in Bacteria

by Wei Wang, Jiahao Wang, Xue Feng and Haichun Gao

Int. J. Mol. Sci. 2022, 23(22), 13841; https://doi.org/10.3390/ijms232213841 - 10 Nov 2022

Cited by 3 | Viewed by 1361

Abstract

Nitrite and nitric oxide (NO) are well-known bacteriostatic agents with similar biochemical properties. However, many studies have demonstrated that inhibition of bacterial growth by nitrite is independent of NO. Here, with Shewanella oneidensis as the research model because of its unusually high cytochrome (cyt) [...] Read more.

Nitrite and nitric oxide (NO) are well-known bacteriostatic agents with similar biochemical properties. However, many studies have demonstrated that inhibition of bacterial growth by nitrite is independent of NO. Here, with Shewanella oneidensis as the research model because of its unusually high cytochrome (cyt) c content, we identify a common mechanism by which nitrite and NO compromise cyt c biosynthesis in bacteria, and thereby inhibit respiration. This is achieved by eliminating the inference of the cyclic adenosine monophosphate-catabolite repression protein (cAMP-Crp), a primary regulatory system that controls the cyt c content and whose activity is subjected to the repression of nitrite. Both nitrite and NO impair the CcmE of multiple bacteria, an essential heme chaperone of the System I cyt c biosynthesis apparatus. Given that bacterial targets of nitrite and NO differ enormously and vary even in the same genus, these observations underscore the importance of cyt c biosynthesis for the antimicrobial actions of nitrite and NO. Full article

(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation)

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28 pages, 3656 KiB

Open AccessArticle

Aberrant Transferrin and Ferritin Upregulation Elicits Iron Accumulation and Oxidative Inflammaging Causing Ferroptosis and Undermines Estradiol Biosynthesis in Aging Rat Ovaries by Upregulating NF-Κb-Activated Inducible Nitric Oxide Synthase: First Demonstration of an Intricate Mechanism

by Stephen Cho Wing Sze, Liang Zhang, Shiqing Zhang, Kaili Lin, Tzi Bun Ng, Man Ling Ng, Kai-Fai Lee, Jenny Ka Wing Lam, Zhang Zhang and Ken Kin Lam Yung

Int. J. Mol. Sci. 2022, 23(20), 12689; https://doi.org/10.3390/ijms232012689 - 21 Oct 2022

Cited by 16 | Viewed by 3276

Abstract

We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile [...] Read more.

We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile ferrous iron and total iron levels escalated with age in rats. Oxidative stress markers, such as nitrite/nitrate, 3-nitrotyrosine, and 4-hydroxy-2-nonenal, accumulated in the aging ovaries due to an aberrant upregulation of the ovarian transferrin, ferritin light/heavy chains, and iron regulatory protein 2(IRP2)-mediated transferrin receptor 1 (TfR1). Ferritin inhibited estradiol biosynthesis in ovarian granulosa cells in vitro via the upregulation of a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and p65/p50-induced oxidative and inflammatory factor inducible nitric oxide synthase (iNOS). An in vivo study demonstrated how the age-associated activation of NF-κB induced the upregulation of iNOS and the tumor necrosis factor α (TNFα). The downregulation of the keap1-mediated nuclear factor erythroid 2-related factor 2 (Nrf2), that induced a decrease in glutathione peroxidase 4 (GPX4), was observed. The aberrant transferrin and ferritin upregulation triggered an iron accumulation via the upregulation of an IRP2-induced TfR1. This culminates in NF-κB-iNOS-mediated ovarian oxi-inflamm-aging and serum estradiol decrement in naturally aging rats. The iron accumulation and the effect on ferroptosis-related proteins including the GPX4, TfR1, Nrf2, Keap1, and ferritin heavy chain, as in testicular ferroptosis, indicated the triggering of ferroptosis. In young rats, an intraovarian injection of an adenovirus, which expressed iron regulatory proteins, upregulated the ovarian NF-κB/iNOS and downregulated the GPX4. These novel findings have contributed to a prompt translational research on the ovarian aging-associated iron metabolism and aging-associated ovarian diseases. Full article

(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation)

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18 pages, 2527 KiB

Open AccessArticle

Assessment of DDAH1 and DDAH2 Contributions to Psychiatric Disorders via In Silico Methods

by Alena A. Kozlova, Anastasia N. Vaganova, Roman N. Rodionov, Raul R. Gainetdinov and Nadine Bernhardt

Int. J. Mol. Sci. 2022, 23(19), 11902; https://doi.org/10.3390/ijms231911902 - 07 Oct 2022

Cited by 1 | Viewed by 1470

Abstract

The contribution of nitric oxide synthases (NOSs) to the pathophysiology of several neuropsychiatric disorders is recognized, but the role of their regulators, dimethylarginine dimethylaminohydrolases (DDAHs), is less understood. This study’s objective was to estimate DDAH1 and DDAH2 associations with biological processes implicated in [...] Read more.

The contribution of nitric oxide synthases (NOSs) to the pathophysiology of several neuropsychiatric disorders is recognized, but the role of their regulators, dimethylarginine dimethylaminohydrolases (DDAHs), is less understood. This study’s objective was to estimate DDAH1 and DDAH2 associations with biological processes implicated in major psychiatric disorders using publicly accessible expression databases. Since co-expressed genes are more likely to be involved in the same biologic processes, we investigated co-expression patterns with DDAH1 and DDAH2 in the dorsolateral prefrontal cortex in psychiatric patients and control subjects. There were no significant differences in DDAH1 and DDAH2 expression levels in schizophrenia or bipolar disorder patients compared to controls. Meanwhile, the data suggest that in patients, DDAH1 and DDHA2 undergo a functional shift mirrored in changes in co-expressed gene patterns. This disarrangement appears in the loss of expression level correlations between DDAH1 or DDAH2 and genes associated with psychiatric disorders and reduced functional similarity of DDAH1 or DDAH2 co-expressed genes in the patient groups. Our findings evidence the possible involvement of DDAH1 and DDAH2 in neuropsychiatric disorder development, but the underlying mechanisms need experimental validation. Full article

(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation)

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Review

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21 pages, 1574 KiB

Open AccessReview

Nitric Oxide Function and Nitric Oxide Synthase Evolution in Aquatic Chordates

by Annamaria Locascio, Giovanni Annona, Filomena Caccavale, Salvatore D’Aniello, Claudio Agnisola and Anna Palumbo

Int. J. Mol. Sci. 2023, 24(13), 11182; https://doi.org/10.3390/ijms241311182 - 06 Jul 2023

Cited by 4 | Viewed by 1478

Abstract

Nitric oxide (NO) is a key signaling molecule in almost all organisms and is active in a variety of physiological and pathological processes. Our understanding of the peculiarities and functions of this simple gas has increased considerably by extending studies to non-mammal vertebrates [...] Read more.

Nitric oxide (NO) is a key signaling molecule in almost all organisms and is active in a variety of physiological and pathological processes. Our understanding of the peculiarities and functions of this simple gas has increased considerably by extending studies to non-mammal vertebrates and invertebrates. In this review, we report the nitric oxide synthase (Nos) genes so far characterized in chordates and provide an extensive, detailed, and comparative analysis of the function of NO in the aquatic chordates tunicates, cephalochordates, teleost fishes, and amphibians. This comprehensive set of data adds new elements to our understanding of Nos evolution, from the single gene commonly found in invertebrates to the three genes present in vertebrates. Full article

(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation)

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33 pages, 4047 KiB

Open AccessReview

Effects of iNOS in Hepatic Warm Ischaemia and Reperfusion Models in Mice and Rats: A Systematic Review and Meta-Analysis

by Richi Nakatake, Mareike Schulz, Christina Kalvelage, Carina Benstoem and René H. Tolba

Int. J. Mol. Sci. 2022, 23(19), 11916; https://doi.org/10.3390/ijms231911916 - 07 Oct 2022

Cited by 2 | Viewed by 1723

Abstract

Warm ischaemia is usually induced by the Pringle manoeuver (PM) during hepatectomy. Currently, there is no widely accepted standard protocol to minimise ischaemia-related injury, so reducing ischaemia-reperfusion damage is an active area of research. This systematic review and meta-analysis focused on inducible nitric [...] Read more.

Warm ischaemia is usually induced by the Pringle manoeuver (PM) during hepatectomy. Currently, there is no widely accepted standard protocol to minimise ischaemia-related injury, so reducing ischaemia-reperfusion damage is an active area of research. This systematic review and meta-analysis focused on inducible nitric oxide synthase (iNOS) as an early inflammatory response to hepatic ischaemia reperfusion injury (HIRI) in mouse- and rat-liver models. A systematic search of studies was performed within three databases. Studies meeting the inclusion criteria were subjected to qualitative and quantitative synthesis of results. We performed a meta-analysis of studies grouped by different HIRI models and ischaemia times. Additionally, we investigated a possible correlation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) regulation with iNOS expression. Of 124 included studies, 49 were eligible for the meta-analysis, revealing that iNOS was upregulated in almost all HIRIs. We were able to show an increase of iNOS regardless of ischemia or reperfusion time. Additionally, we found no direct associations of eNOS or NO with iNOS. A sex gap of primarily male experimental animals used was observed, leading to a higher risk of outcomes not being translatable to humans of all sexes. Full article

(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation)

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21 pages, 2388 KiB

Open AccessReview

Nitric Oxide, Nitric Oxide Formers and Their Physiological Impacts in Bacteria

by Jinghua Chen, Lulu Liu, Weiwei Wang and Haichun Gao

Int. J. Mol. Sci. 2022, 23(18), 10778; https://doi.org/10.3390/ijms231810778 - 15 Sep 2022

Cited by 7 | Viewed by 2785

Abstract

Nitric oxide (NO) is an active and critical nitrogen oxide in the microbe-driven nitrogen biogeochemical cycle, and is of great interest to medicine and the biological sciences. As a gas molecule prior to oxygen, NO respiration represents an early form of energy generation [...] Read more.

Nitric oxide (NO) is an active and critical nitrogen oxide in the microbe-driven nitrogen biogeochemical cycle, and is of great interest to medicine and the biological sciences. As a gas molecule prior to oxygen, NO respiration represents an early form of energy generation via various reactions in prokaryotes. Major enzymes for endogenous NO formation known to date include two types of nitrite reductases in denitrification, hydroxylamine oxidoreductase in ammonia oxidation, and NO synthases (NOSs). While the former two play critical roles in shaping electron transport pathways in bacteria, NOSs are intracellular enzymes catalyzing metabolism of certain amino acids and have been extensively studied in mammals. NO interacts with numerous cellular targets, most of which are redox-active proteins. Doing so, NO plays harmful and beneficial roles by affecting diverse biological processes within bacterial physiology. Here, we discuss recent advances in the field, including NO-forming enzymes, the molecular mechanisms by which these enzymes function, physiological roles of bacterial NOSs, and regulation of NO homeostasis in bacteria. Full article

(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation)

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14 pages, 592 KiB

Open AccessReview

The Effects of Acidosis on eNOS in the Systemic Vasculature: A Focus on Early Postnatal Ontogenesis

by Dina K. Gaynullina, Olga S. Tarasova, Anastasia A. Shvetsova, Anna A. Borzykh and Rudolf Schubert

Int. J. Mol. Sci. 2022, 23(11), 5987; https://doi.org/10.3390/ijms23115987 - 26 May 2022

Cited by 5 | Viewed by 2148

Abstract

The activity of many vasomotor signaling pathways strongly depends on extracellular/intracellular pH. Nitric oxide (NO) is one of the most important vasodilators produced by the endothelium. In this review, we present evidence that in most vascular beds of mature mammalian organisms metabolic or [...] Read more.

The activity of many vasomotor signaling pathways strongly depends on extracellular/intracellular pH. Nitric oxide (NO) is one of the most important vasodilators produced by the endothelium. In this review, we present evidence that in most vascular beds of mature mammalian organisms metabolic or respiratory acidosis increases functional endothelial NO-synthase (eNOS) activity, despite the observation that direct effects of low pH on eNOS enzymatic activity are inhibitory. This can be explained by the fact that acidosis increases the activity of signaling pathways that positively regulate eNOS activity. The role of NO in the regulation of vascular tone is greater in early postnatal ontogenesis compared to adulthood. Importantly, in early postnatal ontogenesis acidosis also augments functional eNOS activity and its contribution to the regulation of arterial contractility. Therefore, the effect of acidosis on total peripheral resistance in neonates may be stronger than in adults and can be one of the reasons for an undesirable decrease in blood pressure during neonatal asphyxia. The latter, however, should be proven in future studies. Full article

(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation)

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