Research

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18 pages, 5127 KiB

Open AccessArticle

New Nitric Oxide-Releasing Compounds as Promising Anti-Bladder Cancer Drugs

by María Varela, Miriam López, Mariana Ingold, Diego Alem, Valentina Perini, Karen Perelmuter, Mariela Bollati-Fogolín, Gloria V. López and Paola Hernández

Biomedicines 2023, 11(1), 199; https://doi.org/10.3390/biomedicines11010199 - 12 Jan 2023

Cited by 1 | Viewed by 1697

Abstract

Bladder cancer is a worldwide problem and improved therapies are urgently needed. In the search for newer strong antitumor compounds, herein, we present the study of three nitric oxide-releasing compounds and evaluate them as possible therapies for this malignancy. Bladder cancer cell lines [...] Read more.

Bladder cancer is a worldwide problem and improved therapies are urgently needed. In the search for newer strong antitumor compounds, herein, we present the study of three nitric oxide-releasing compounds and evaluate them as possible therapies for this malignancy. Bladder cancer cell lines T24 and 253J were used to evaluate the antiproliferative, antimigratory, and genotoxic effects of compounds. Moreover, we determined the NF-κB pathway inhibition, and finally, the survivin downregulation exerted by our molecules. The results revealed that compounds 1 and 3 exerted a high antiproliferative activity against bladder cancer cells through DNA damage and survivin downregulation. In addition, compound 3 reduced bladder cancer cell migration. We found that nitric oxide donors are promising molecules for the development of a new therapeutic targeting the underlying mechanisms of tumorigenesis and progression of bladder cancer. Full article

(This article belongs to the Special Issue Role of NO in Disease: Good, Bad or Ugly)

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11 pages, 1241 KiB

Open AccessArticle

Alveolar Nitric Oxide in Chronic Obstructive Pulmonary Disease—A Two-Year Follow-Up

by Marieann Högman, Andreas Palm, Johanna Sulku, Björn Ställberg, Karin Lisspers, Kristina Bröms, Christer Janson and Andrei Malinovschi

Biomedicines 2022, 10(9), 2212; https://doi.org/10.3390/biomedicines10092212 - 07 Sep 2022

Cited by 1 | Viewed by 1252

Abstract

Chronic obstructive pulmonary disease (COPD) affects the airways and gas exchange areas. Nitric oxide (NO) production from the airways is presented as F_ENO₅₀ and from the gas exchange areas as alveolar NO (C_ANO). We aimed to evaluate, over [...] Read more.

Chronic obstructive pulmonary disease (COPD) affects the airways and gas exchange areas. Nitric oxide (NO) production from the airways is presented as F_ENO₅₀ and from the gas exchange areas as alveolar NO (C_ANO). We aimed to evaluate, over two years, the consistency of the C_ANO estimations in subjects with COPD. A total of 110 subjects (45 men) who completed the study were included from primary and secondary care settings. C_ANO was estimated using the two-compartment model. C_ANO increased slightly during the two-year follow-up (p = 0.01), but F_ENO₅₀ remained unchanged (p = 0.24). Among the subjects with a low C_ANO (<1 ppb) at inclusion, only 2% remained at a low level. For those at a high level (>2 ppb), 29% remained so. The modified Medical Research Council dyspnoea scale (mMRC) score increased at least one point in 29% of the subjects, and those subjects also increased in C_ANO from 0.9 (0.5, 2.1) ppb to 1.8 (1.1, 2.3) ppb, p = 0.015. We conclude that alveolar NO increased slightly over two years, together with a small decline in lung function. The increase in C_ANO was found especially in those whose levels of dyspnoea increased over time. Full article

(This article belongs to the Special Issue Role of NO in Disease: Good, Bad or Ugly)

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19 pages, 4140 KiB

Open AccessArticle

Biological Sensing of Nitric Oxide in Macrophages and Atherosclerosis Using a Ruthenium-Based Sensor

by Achini K. Vidanapathirana, Jarrad M. Goyne, Anna E. Williamson, Benjamin J. Pullen, Pich Chhay, Lauren Sandeman, Julien Bensalem, Timothy J. Sargeant, Randall Grose, Mark J. Crabtree, Run Zhang, Stephen J. Nicholls, Peter J. Psaltis and Christina A. Bursill

Biomedicines 2022, 10(8), 1807; https://doi.org/10.3390/biomedicines10081807 - 27 Jul 2022

Cited by 5 | Viewed by 2322

Abstract

Macrophage-derived nitric oxide (NO) plays a critical role in atherosclerosis and presents as a potential biomarker. We assessed the uptake, distribution, and NO detection capacity of an irreversible, ruthenium-based, fluorescent NO sensor (Ru-NO) in macrophages, plasma, and atherosclerotic plaques. In vitro, incubation of [...] Read more.

Macrophage-derived nitric oxide (NO) plays a critical role in atherosclerosis and presents as a potential biomarker. We assessed the uptake, distribution, and NO detection capacity of an irreversible, ruthenium-based, fluorescent NO sensor (Ru-NO) in macrophages, plasma, and atherosclerotic plaques. In vitro, incubation of Ru-NO with human THP1 monocytes and THP1-PMA macrophages caused robust uptake, detected by Ru-NO fluorescence using mass-cytometry, confocal microscopy, and flow cytometry. THP1-PMA macrophages had higher Ru-NO uptake (+13%, p < 0.05) than THP1 monocytes with increased Ru-NO fluorescence following lipopolysaccharide stimulation (+14%, p < 0.05). In mice, intraperitoneal infusion of Ru-NO found Ru-NO uptake was greater in peritoneal CD11b⁺F4/80⁺ macrophages (+61%, p < 0.01) than CD11b⁺F4/80⁻ monocytes. Infusion of Ru-NO into Apoe^−/− mice fed high-cholesterol diet (HCD) revealed Ru-NO fluorescence co-localised with atherosclerotic plaque macrophages. When Ru-NO was added ex vivo to aortic cell suspensions from Apoe^−/− mice, macrophage-specific uptake of Ru-NO was demonstrated. Ru-NO was added ex vivo to tail-vein blood samples collected monthly from Apoe^−/− mice on HCD or chow. The plasma Ru-NO fluorescence signal was higher in HCD than chow-fed mice after 12 weeks (37.9%, p < 0.05). Finally, Ru-NO was added to plasma from patients (N = 50) following clinically-indicated angiograms. There was lower Ru-NO fluorescence from plasma from patients with myocardial infarction (−30.7%, p < 0.01) than those with stable coronary atherosclerosis. In conclusion, Ru-NO is internalised by macrophages in vitro, ex vivo, and in vivo, can be detected in atherosclerotic plaques, and generates measurable changes in fluorescence in murine and human plasma. Ru-NO displays promising utility as a sensor of atherosclerosis. Full article

(This article belongs to the Special Issue Role of NO in Disease: Good, Bad or Ugly)

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Review

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13 pages, 820 KiB

Open AccessReview

Kidney Renin Release under Hypoxia and Its Potential Link with Nitric Oxide: A Narrative Review

by Weiwei Kong, Yixin Liao, Liang Zhao, Nathan Hall, Hua Zhou, Ruisheng Liu, Pontus B. Persson and Enyin Lai

Biomedicines 2023, 11(11), 2984; https://doi.org/10.3390/biomedicines11112984 - 06 Nov 2023

Viewed by 972

Abstract

The renin–angiotensin system (RAS) and hypoxia have a complex interaction: RAS is activated under hypoxia and activated RAS aggravates hypoxia in reverse. Renin is an aspartyl protease that catalyzes the first step of RAS and tightly regulates RAS activation. Here, we outline kidney [...] Read more.

The renin–angiotensin system (RAS) and hypoxia have a complex interaction: RAS is activated under hypoxia and activated RAS aggravates hypoxia in reverse. Renin is an aspartyl protease that catalyzes the first step of RAS and tightly regulates RAS activation. Here, we outline kidney renin expression and release under hypoxia and discuss the putative mechanisms involved. It is important that renin generally increases in response to acute hypoxemic hypoxia and intermittent hypoxemic hypoxia, but not under chronic hypoxemic hypoxia. The increase in renin activity can also be observed in anemic hypoxia and carbon monoxide-induced histotoxic hypoxia. The increased renin is contributed to by juxtaglomerular cells and the recruitment of renin lineage cells. Potential mechanisms regulating hypoxic renin expression involve hypoxia-inducible factor signaling, natriuretic peptides, nitric oxide, and Notch signaling-induced renin transcription. Full article

(This article belongs to the Special Issue Role of NO in Disease: Good, Bad or Ugly)

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15 pages, 1173 KiB

Open AccessReview

The Multiple Faces of Nitric Oxide in Chronic Granulomatous Disease: A Comprehensive Update

by Juan Agustín Garay, Juan Eduardo Silva, María Silvia Di Genaro and Roberto Carlos Davicino

Biomedicines 2022, 10(10), 2570; https://doi.org/10.3390/biomedicines10102570 - 14 Oct 2022

Cited by 2 | Viewed by 1818

Abstract

Nitric oxide (NO), a signaling molecule, regulates multiple biological functions, including a variety of physiological and pathological processes. In this regard, NO participates in cutaneous inflammations, modulation of mitochondrial functions, vascular diseases, COVID-19, neurologic diseases, and obesity. It also mediates changes in the [...] Read more.

Nitric oxide (NO), a signaling molecule, regulates multiple biological functions, including a variety of physiological and pathological processes. In this regard, NO participates in cutaneous inflammations, modulation of mitochondrial functions, vascular diseases, COVID-19, neurologic diseases, and obesity. It also mediates changes in the skeletal muscle function. Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by the malfunction of phagocytes caused by mutations in some of the genes encoding subunits of the superoxide-generating phagocyte NADPH (NOX). The literature consulted shows that there is a relationship between the production of NO and the NADPH oxidase system, which regulates the persistence of NO in the medium. Nevertheless, the underlying mechanisms of the effects of NO on CGD remain unknown. In this paper, we briefly review the regulatory role of NO in CGD and its potential underlying mechanisms. Full article

(This article belongs to the Special Issue Role of NO in Disease: Good, Bad or Ugly)

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20 pages, 1964 KiB

Open AccessReview

Enhancement of Nitric Oxide Bioavailability by Modulation of Cutaneous Nitric Oxide Stores

by Christoph V. Suschek, Dennis Feibel, Maria von Kohout and Christian Opländer

Biomedicines 2022, 10(9), 2124; https://doi.org/10.3390/biomedicines10092124 - 29 Aug 2022

Cited by 6 | Viewed by 2284

Abstract

The generation of nitric oxide (NO) in the skin plays a critical role in wound healing and the response to several stimuli, such as UV exposure, heat, infection, and inflammation. Furthermore, in the human body, NO is involved in vascular homeostasis and the [...] Read more.

The generation of nitric oxide (NO) in the skin plays a critical role in wound healing and the response to several stimuli, such as UV exposure, heat, infection, and inflammation. Furthermore, in the human body, NO is involved in vascular homeostasis and the regulation of blood pressure. Physiologically, a family of enzymes termed nitric oxide synthases (NOS) generates NO. In addition, there are many methods of non-enzymatic/NOS-independent NO generation, e.g., the reduction of NO derivates (NODs) such as nitrite, nitrate, and nitrosylated proteins under certain conditions. The skin is the largest and heaviest human organ and contains a comparatively high concentration of these NODs; therefore, it represents a promising target for many therapeutic strategies for NO-dependent pathological conditions. In this review, we give an overview of how the cutaneous NOD stores can be targeted and modulated, leading to a further accumulation of NO-related compounds and/or the local and systemic release of bioactive NO, and eventually, NO-related physiological effects with a potential therapeutical use for diseases such as hypertension, disturbed microcirculation, impaired wound healing, and skin infections. Full article

(This article belongs to the Special Issue Role of NO in Disease: Good, Bad or Ugly)

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17 pages, 1047 KiB

Open AccessReview

Endothelial Nitric Oxide Synthase in the Perivascular Adipose Tissue

by Andy W. C. Man, Yawen Zhou, Ning Xia and Huige Li

Biomedicines 2022, 10(7), 1754; https://doi.org/10.3390/biomedicines10071754 - 21 Jul 2022

Cited by 15 | Viewed by 2541

Abstract

Perivascular adipose tissue (PVAT) is a special type of ectopic fat depot that adheres to most vasculatures. PVAT has been shown to exert anticontractile effects on the blood vessels and confers protective effects against metabolic and cardiovascular diseases. PVAT plays a critical role [...] Read more.

Perivascular adipose tissue (PVAT) is a special type of ectopic fat depot that adheres to most vasculatures. PVAT has been shown to exert anticontractile effects on the blood vessels and confers protective effects against metabolic and cardiovascular diseases. PVAT plays a critical role in vascular homeostasis via secreting adipokine, hormones, and growth factors. Endothelial nitric oxide synthase (eNOS; also known as NOS3 or NOSIII) is well-known for its role in the generation of vasoprotective nitric oxide (NO). eNOS is primarily expressed, but not exclusively, in endothelial cells, while recent studies have identified its expression in both adipocytes and endothelial cells of PVAT. PVAT eNOS is an important player in the protective role of PVAT. Different studies have demonstrated that, under obesity-linked metabolic diseases, PVAT eNOS may be even more important than endothelium eNOS in obesity-induced vascular dysfunction, which may be attributed to certain PVAT eNOS-specific functions. In this review, we summarized the current understanding of eNOS expression in PVAT, its function under both physiological and pathological conditions and listed out a few pharmacological interventions of interest that target eNOS in PVAT. Full article

(This article belongs to the Special Issue Role of NO in Disease: Good, Bad or Ugly)

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20 pages, 687 KiB

Open AccessReview

Therapeutic Effects of Inhaled Nitric Oxide Therapy in COVID-19 Patients

by Nikolay O. Kamenshchikov, Lorenzo Berra and Ryan W. Carroll

Biomedicines 2022, 10(2), 369; https://doi.org/10.3390/biomedicines10020369 - 03 Feb 2022

Cited by 20 | Viewed by 3627

Abstract

The global COVID-19 pandemic has become the largest public health challenge of recent years. The incidence of COVID-19-related acute hypoxemic respiratory failure (AHRF) occurs in up to 15% of hospitalized patients. Antiviral drugs currently available to clinicians have little to no effect on [...] Read more.

The global COVID-19 pandemic has become the largest public health challenge of recent years. The incidence of COVID-19-related acute hypoxemic respiratory failure (AHRF) occurs in up to 15% of hospitalized patients. Antiviral drugs currently available to clinicians have little to no effect on mortality, length of in-hospital stay, the need for mechanical ventilation, or long-term effects. Inhaled nitric oxide (iNO) administration is a promising new non-standard approach to directly treat viral burden while enhancing oxygenation. Along with its putative antiviral affect in COVID-19 patients, iNO can reduce inflammatory cell-mediated lung injury by inhibiting neutrophil activation, lowering pulmonary vascular resistance and decreasing edema in the alveolar spaces, collectively enhancing ventilation/perfusion matching. This narrative review article presents recent literature on the iNO therapy use for COVID-19 patients. The authors suggest that early administration of the iNO therapy may be a safe and promising approach for the treatment of COVID-19 patients. The authors also discuss unconventional approaches to treatment, continuous versus intermittent high-dose iNO therapy, timing of initiation of therapy (early versus late), and novel delivery systems. Future laboratory and clinical research is required to define the role of iNO as an adjunct therapy against bacterial, viral, and fungal infections. Full article

(This article belongs to the Special Issue Role of NO in Disease: Good, Bad or Ugly)

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