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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Metabolites".

Deadline for manuscript submissions: closed (28 February 2015) | Viewed by 53773

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Dr. Claudio Battilocchio

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Guest Editor

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Interests: sustainable development; flow chemistry; organic synthesis; pharmaceutical and agrochemical synthesis

Special Issue Information

Dear Colleagues,

Nitric oxide (NO) is recognised as a very attractive biomolecule in many biological and physiological processes. Valid contributions to this special issue will be focused on the following themes:
-preparation of nitric oxide releasing molecules and materials;
-methods for detecting nitric oxide;
-application of nitric oxide releasing molecules with specific reference to the biological or pharmacological activity of the compounds investigated; -biological/pharmacological/physiological studies on nitric oxide and/or its release;
-reviews regarding nitric oxide and nitric oxide releasing molecules.

I highly encourage authors to submit original papers and reviews for this special issue.

Dr. Claudio Battilocchio
Guest Editor

Manuscript Submission Information

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Keywords

nitric oxide
nitric oxide releasing molecules
nitric oxide releasing material
nitric oxide detection
nitric oxide signalling

Published Papers (7 papers)

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Research

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2365 KiB

Open AccessArticle

Nitric Oxide-Releasing Aspirin Suppresses NF-κB Signaling in Estrogen Receptor Negative Breast Cancer Cells in Vitro and in Vivo

by Niharika Nath, Mitali Chattopadhyay, Deborah B. Rodes, Anna Nazarenko, Ravinder Kodela and Khosrow Kashfi

Molecules 2015, 20(7), 12481-12499; https://doi.org/10.3390/molecules200712481 - 09 Jul 2015

Cited by 15 | Viewed by 6768

Abstract

Estrogen receptor negative (ER(−)) breast cancer is aggressive, responds poorly to current treatments and has a poor prognosis. The NF-κB signaling pathway is implicated in ER(−) tumorigenesis. Aspirin (ASA) is chemopreventive against ER(+) but not for ER(−) breast cancers. Nitric oxide-releasing aspirin (NO-ASA) is a safer ASA where ASA is linked to an NO-releasing moiety through a spacer. In vitro, we investigated anti-proliferation effects of NO-ASA (para- and meta-isomers) against ER(−) breast cancer cells MDA-MB-231 and SK-BR-23, effects on NF-κB signaling, and reactive oxygen species by standard techniques. In vivo, effects of NO-ASA were evaluated in a mouse xenograft model using MDA-MB-231 cells. p-NO-ASA inhibited the growth of MDA-MB-231 and SK-BR-3 cells at 24 h, the respective IC₅₀s were 13 ± 2 and 17 ± 2 μM; ASA had an IC₅₀ of >3000 μM in both cell lines. The IC₅₀s for m-NO-ASA in MDA-MB-231 and SK-BR-3 were 173 ± 15 and 185 ± 12 μM, respectively, therefore, implying p-NO-ASA as a stronger inhibitor of growth p-NO-ASA reduced cell growth by inhibiting proliferation, inducing apoptosis and causing G₀/G₁ cell cycle block. Activation of NF-κB was inhibited by both isomers as demonstrated by decreases in NF-κB-DNA binding and luciferase activity at 24 h, However, m-NO-ASA produced transient effects at 3 h such as increased NF-κB-DNA-binding, increased levels of nuclear p50, even though both isomers inhibited IκB degradation. Increase in nuclear p50 by m-NO-ASA was associated with translocation of p50 in to the nucleus as observed by immunoflouresence at 3 h. NO-ASA induced reactive oxygen species (ROS) as evidenced by overall increases in both H₂DCFDA (2′,7′-dichlorodihydrofluorescein) and DHE (dihydroethidium)-derived fluorescence. Inhibition of ROS by N-acetyl-cysteine reversed the m-NO-ASA-mediated translocation of p50 in to the nucleus. In xenografts, p-NO-ASA inhibited tumor growth by inhibiting proliferation (PCNA and tumor volume), inducing apoptosis (TUNEL positive cells) and reducing NF-κB expression. Both isomers inhibit cancer cells, inhibit NF-κB pathway and induce ROS, and have potential as anticancer compounds. Full article

(This article belongs to the Special Issue Nitric Oxide (NO) Release Chemistry)

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717 KiB

Open AccessArticle

Pretreatment with Relaxin Does Not Restore NO-Mediated Modulation of Calcium Signal in Coronary Endothelial Cells Isolated from Spontaneously Hypertensive Rats

by Silvia Nistri, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Matteo Zanardelli, Daniele Bani and Paola Failli

Molecules 2015, 20(6), 9524-9535; https://doi.org/10.3390/molecules20069524 - 26 May 2015

Cited by 5 | Viewed by 5700

Abstract

We demonstrated that in coronary endothelial cells (RCEs) from normotensive Wistar Kyoto rats (WKY), the hormone relaxin (RLX) increases NO production and reduces calcium transients by a NO-related mechanism. Since an impairment of the NO pathway has been described in spontaneously hypertensive rats (SHR), the present study was aimed at exploring RLX effects on RCEs from SHR, hypothesizing that RLX could restore calcium responsiveness to NO. RCEs were isolated from WKY and SHR. Calcium transients were evaluated by image analysis after the administration of angiotensin II or α-thrombin. Angiotensin II (1 µM) caused a prompt rise of [Ca²⁺]i in WKY and SHR RCEs and a rapid decrease, being the decay time higher in SHR than in WKY. NOS inhibition increased calcium transient in WKY, but not in SHR RCEs. Whereas RLX pretreatment (24 h, 60 ng/mL) was ineffective in SHR, it strongly reduced calcium transient in WKY in a NO-dependent way. A similar behavior was measured using 30 U/mL α-thrombin. The current study offers evidence that RLX cannot restore NO responsiveness in SHR, suggesting an accurate selection of patients eligible for RLX treatment of cardiovascular diseases. Full article

(This article belongs to the Special Issue Nitric Oxide (NO) Release Chemistry)

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10557 KiB

Open AccessArticle

BMP Signaling Regulates Bone Morphogenesis in Zebrafish through Promoting Osteoblast Function as Assessed by Their Nitric Oxide Production

by Thomas Windhausen, Steeve Squifflet, Jörg Renn and Marc Muller

Molecules 2015, 20(5), 7586-7601; https://doi.org/10.3390/molecules20057586 - 24 Apr 2015

Cited by 19 | Viewed by 8686

Abstract

Bone morphogenetic proteins (BMPs) control many developmental and physiological processes, including skeleton formation and homeostasis. Previous studies in zebrafish revealed the crucial importance of proper BMP signaling before 48 h post-fertilization (hpf) for cartilage formation in the skull. Here, we focus on the involvement of the BMP pathway between 48 and 96 hpf in bone formation after 96 hpf. Using BMP inhibitors and the expression of a dominant-negative BMP receptor, we analyze whether the loss of BMP signaling affects osteoblastogenesis, osteoblast function and bone mineralization. To this end, we used the transgenic zebrafish line Tg(osterix:mCherry), detection of nitric oxide (NO) production, and alizarin red staining, respectively. We observed that inhibition of BMP signaling between 48 and 72 hpf led to a reduction of NO production and bone mineralization. Osteoblast maturation and chondrogenesis, on the other hand, seemed unchanged. Osteoblast function and bone formation were less affected when BMP signaling was inhibited between 72 and 96 hpf. These results suggest that for the onset of bone formation, proper BMP signaling between 48 and 72 hpf is crucial to ensure osteoblast function and ossification. Furthermore, detection of NO in developing zebrafish larvae appears as an early indicator of bone calcification activity. Full article

(This article belongs to the Special Issue Nitric Oxide (NO) Release Chemistry)

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4846 KiB

Open AccessArticle

Nitric Oxide Plays a Central Role in Water Stress-Induced Tanshinone Production in Salvia miltiorrhiza Hairy Roots

by Xuhong Du, Chenlu Zhang, Wanli Guo, Weibo Jin, Zongsuo Liang, Xijun Yan, Zhixin Guo, Yan Liu and Dongfeng Yang

Molecules 2015, 20(5), 7574-7585; https://doi.org/10.3390/molecules20057574 - 24 Apr 2015

Cited by 13 | Viewed by 5664

Abstract

Nitric oxide (NO), a well-known signaling molecule plays an important role in abiotic and biotic stress-induced production of plant secondary metabolites. In this study, roles of NO in water stress-induced tanshinone production in Salvia miltiorrhiza hairy roots were investigated. The results showed that accumulations of four tanshinone compounds in S. miltiorrhiza hairy roots were significantly stimulated by sodium nitroprusside (SNP, a NO donor) at 100 μM. Effects of SNP were just partially arrested by the mevalonate (MVA) pathway inhibitor (mevinolin), but were completely inhibited by the 2-C-methyl-d-erythritol-4-phosphate pathway (MEP) inhibitor (fosmidomycin). The increase of tanshinone accumulation and the up-regulation of HMGR and DXR expression by PEG and ABA treatments were partially inhibited by an inhibitor of NO biosynthesis (N^ω-nitro-L-arginine methyl ester (L-NAME)) and a NO scavenger (2-(4-Carboxyphenyl)- 4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO)). Simultaneously, NO generation in the hairy roots was triggered by PEG and ABA, and the effects were also arrested by c-PTIO and L-NAME. These results indicated that NO signaling probably plays a central role in water stress-induced tanshinone production in S. miltiorrhiza hairy roots. SNP mainly stimulated the MEP pathway to increase tanshinone accumulation. Full article

(This article belongs to the Special Issue Nitric Oxide (NO) Release Chemistry)

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1216 KiB

Open AccessArticle

Nitric Oxide Released from Luminal S-Nitroso-N-Acetylcysteine Increases Gastric Mucosal Blood Flow

by Gabriela F. P. De Souza, Patricia Taladriz-Blanco, Lício A. Velloso and Marcelo G. De Oliveira

Molecules 2015, 20(3), 4109-4123; https://doi.org/10.3390/molecules20034109 - 04 Mar 2015

Cited by 12 | Viewed by 7282

Abstract

Nitric oxide (NO)-mediated vasodilation plays a key role in gastric mucosal defense, and NO-donor drugs may protect against diseases associated with gastric mucosal blood flow (GMBF) deficiencies. In this study, we used the ex vivo gastric chamber method and Laser Doppler Flowmetry to characterize the effects of luminal aqueous NO-donor drug S-nitroso-N-acetylcysteine (SNAC) solution administration compared to aqueous NaNO₂ and NaNO₃ solutions (pH 7.4) on GMBF in Sprague-Dawley rats. SNAC solutions (600 μM and 12 mM) led to a rapid threefold increase in GMBF, which was maintained during the incubation of the solutions with the gastric mucosa, while NaNO₂ or NaNO₃ solutions (12 mM) did not affect GMBF. SNAC solutions (600 μM and 12 mM) spontaneously released NO at 37 °C at a constant rate of 0.3 or 14 nmol·mL⁻¹·min⁻¹, respectively, while NaNO₂ (12 mM) released NO at a rate of 0.06 nmol·mL⁻¹·min⁻¹ and NaNO₃ (12 mM) did not release NO. These results suggest that the SNAC-induced GMBF increase is due to their higher rates of spontaneous NO release compared to equimolar NaNO₂ solutions. Taken together, our data indicate that oral SNAC administration is a potential approach for gastric acid-peptic disorder prevention and treatment. Full article

(This article belongs to the Special Issue Nitric Oxide (NO) Release Chemistry)

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Review

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2201 KiB

Open AccessReview

Gaseous Mediators Nitric Oxide and Hydrogen Sulfide in the Mechanism of Gastrointestinal Integrity, Protection and Ulcer Healing

by Marcin Magierowski, Katarzyna Magierowska, Slawomir Kwiecien and Tomasz Brzozowski

Molecules 2015, 20(5), 9099-9123; https://doi.org/10.3390/molecules20059099 - 19 May 2015

Cited by 89 | Viewed by 11926

Abstract

Nitric oxide (NO) and hydrogen sulfide (H₂S) are known as biological messengers; they play an important role in human organism and contribute to many physiological and pathophysiological processes. NO is produced from l-arginine by constitutive NO synthase (NOS) and inducible NOS enzymatic pathways. This gaseous mediator inhibits platelet aggregation, leukocyte adhesion and contributes to the vessel homeostasis. NO is known as a vasodilatory molecule involved in control of the gastric blood flow (GBF) and the maintenance of gastric mucosal barrier integrity in either healthy gastric mucosa or that damaged by strong irritants. Biosynthesis of H₂S in mammals depends upon two enzymes cystathionine-β-synthase and cystathionine γ-lyase. This gaseous mediator, similarly to NO and carbon monoxide, is involved in neuromodulation, vascular contractility and anti-inflammatory activities. For decades, H₂S has been known to inhibit cytochrome c oxidase and reduce cell energy production. Nowadays it is generally considered to act through vascular smooth muscle ATP-dependent K⁺ channels, interacting with intracellular transcription factors and promote sulfhydration of protein cysteine moieties within the cell, but the mechanism of potential gastroprotective and ulcer healing properties of H₂S has not been fully explained. The aim of this review is to compare current results of the studies concerning the role of H₂S and NO in gastric mucosa protection and outline areas that may pose new opportunities for further development of novel therapeutic targets. Full article

(This article belongs to the Special Issue Nitric Oxide (NO) Release Chemistry)

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658 KiB

Open AccessReview

Nitric Oxide Donors and Selective Carbonic Anhydrase Inhibitors: A Dual Pharmacological Approach for the Treatment of Glaucoma, Cancer and Osteoporosis

by Simone Carradori, Adriano Mollica, Celeste De Monte, Arianna Granese and Claudiu T. Supuran

Molecules 2015, 20(4), 5667-5679; https://doi.org/10.3390/molecules20045667 - 31 Mar 2015

Cited by 39 | Viewed by 7138

Abstract

Due to the recognized biological role of nitric oxide (NO) donating derivatives and of selective inhibitors of specific human carbonic anhydrase isoforms (CA, EC 4.2.1.1), promising compounds having an aromatic/heterocyclic primary sulfonamide and functionalized with NO-releasing moieties have been designed. These bifunctional agents have been tested in vitro and in vivo to assess their dual pharmacological activity. According to the encouraging results they could be proposed for the treatment of angle-open glaucoma, cancer regression and osteoporosis, in which both NO and CA activities are involved. Full article

(This article belongs to the Special Issue Nitric Oxide (NO) Release Chemistry)

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