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Article: COVID-19 Is an Endothelial Disease: Implications of Nitric Oxide.

Kidde, Jason / Gorabi, Armita Mahdavi / Jamialahmadi, Tannaz / Sahebkar, Amirhossein

Advances in experimental medicine and biology

2021 Volume 1321, Page(s) 109–113

Abstract: ... potential to mitigate COVID-19 severity. Inhaled nitric oxide appears to improve outcomes ... by nitric oxide deficiency, appear to have a more severe disease course. As such, nitric oxide has therapeutic ... Endothelial cells are a clinically important infection site for COVID-19, both as a mechanism ...

Abstract	Endothelial cells are a clinically important infection site for COVID-19, both as a mechanism for disease pathogenesis and as a therapeutic target. People with dysfunctional endothelium, defined by nitric oxide deficiency, appear to have a more severe disease course. As such, nitric oxide has therapeutic potential to mitigate COVID-19 severity. Inhaled nitric oxide appears to improve outcomes, although this strategy neglects systemic endothelium. Meanwhile, early studies have documented that endothelial protective medications, such as the administration of statins and ACE-inhibitors, are associated with less severe disease and reduced mortality. Importantly, these medications augment endothelial sources of nitric oxide, which may explain this effect.
MeSH term(s)	COVID-19 ; Endothelial Cells ; Endothelium, Vascular ; Humans ; Nitric Oxide ; SARS-CoV-2
Chemical Substances	Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2021-03-03
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-59261-5_9
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Article ; Online: Implications of microvascular dysfunction and nitric oxide mediated inflammation in severe COVID-19 infection.

Jani, Vinay P / Munoz, Carlos J / Govender, Krianthan / Williams, Alexander T / Cabrales, Pedro

The American journal of the medical sciences

2022 Volume 364, Issue 3, Page(s) 251–256

Abstract: ... Therefore, severe COVID-19 is a vascular disease that has systemic implications. The objective of this review is ... with a particular emphasis on dysfunction of the endothelial glycocalyx and nitric oxide mediated pathogenesis. ... infection is, in essence, a microvascular disease. This contention has been emphasized throughout the course ...

Abstract	Infection with COVID-19 has resulted in over 276,000 deaths in the United States and over 1.5 million deaths globally, with upwards of 15% of patients requiring hospitalization. Severe COVID-19 infection is, in essence, a microvascular disease. This contention has been emphasized throughout the course of the pandemic, particularly due to the clinical manifestation of severe infection. In fact, it has been hypothesized and shown in particular instances that microvascular function is a significant prognosticator for morbidity and mortality. Initially thought to be isolated to the pulmonary system and resulting in ARDS, patients with COVID-19 have been observed to have acute cardiac, renal, and thrombolytic complications. Therefore, severe COVID-19 is a vascular disease that has systemic implications. The objective of this review is to provide a mechanistic background for the microvascular nature of severe COVID-19 infection, with a particular emphasis on dysfunction of the endothelial glycocalyx and nitric oxide mediated pathogenesis.
MeSH term(s)	COVID-19/complications ; Humans ; Inflammation ; Nitric Oxide ; Pandemics
Chemical Substances	Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2022-04-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	82078-7
ISSN	1538-2990 ; 0002-9629
ISSN (online)	1538-2990
ISSN	0002-9629
DOI	10.1016/j.amjms.2022.04.015
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Article ; Online: Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection. The DEDALO project.

Isidori, Andrea M / Giannetta, Elisa / Pofi, Riccardo / Venneri, Mary A / Gianfrilli, Daniele / Campolo, Federica / Mastroianni, Claudio M / Lenzi, Andrea / d'Ettorre, Gabriella

Andrology

2020 Volume 9, Issue 1, Page(s) 33–38

Abstract: ... COVID-19 disease.: Materials and methods: We performed a systematic review of all evidence ... experimental studies have revealed a role for the nitric oxide (NO)-cyclic GMP-phosphodiesterase type 5 (PDE5 ... Background: A pandemic outbreak of COVID-19 has been sweeping the world since December. It begins ...

Abstract	Background: A pandemic outbreak of COVID-19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, "cytokines storm," that causes the systemic complications of COVID-19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability. Objectives: Numerous clinical and experimental studies have revealed a role for the nitric oxide (NO)-cyclic GMP-phosphodiesterase type 5 (PDE5) pathway in modulating low-grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti-inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID-19 disease. Materials and methods: We performed a systematic review of all evidence documenting any involvement of the NO-cGMP-PDE5 axis in the pathophysiology of COVID-19, presenting the ongoing clinical trials aimed at modulating this axis, including our own "silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID-19 (DEDALO trial)." Results: The reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID-19 by (i) counteracting the Ang-II-mediated downregulation of AT-1 receptor; (ii) acting on monocyte switching, thus reducing pro-inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage-necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications. Discussion and conclusion: If the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID-19 in developing countries.
MeSH term(s)	Antiviral Agents/adverse effects ; Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; COVID-19/enzymology ; COVID-19/virology ; Clinical Trials as Topic ; Cyclic GMP/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Host-Pathogen Interactions ; Humans ; Molecular Targeted Therapy ; Nitric Oxide/adverse effects ; Nitric Oxide/metabolism ; Nitric Oxide/therapeutic use ; Phosphodiesterase 5 Inhibitors/adverse effects ; Phosphodiesterase 5 Inhibitors/therapeutic use ; SARS-CoV-2/drug effects ; SARS-CoV-2/pathogenicity ; Signal Transduction ; Treatment Outcome
Chemical Substances	Antiviral Agents ; Phosphodiesterase 5 Inhibitors ; Nitric Oxide (31C4KY9ESH) ; Cyclic Nucleotide Phosphodiesterases, Type 5 (EC 3.1.4.35) ; Cyclic GMP (H2D2X058MU)
Keywords	covid19
Language	English
Publishing date	2020-07-03
Publishing country	England
Document type	Journal Article ; Systematic Review
ZDB-ID	2696108-8
ISSN	2047-2927 ; 2047-2919
ISSN (online)	2047-2927
ISSN	2047-2919
DOI	10.1111/andr.12837
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Article: Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection

Isidori, A M / Giannetta, E / Pofi, R / Venneri, M A / Gianfrilli, D / Campolo, F / Mastroianni, C M / Lenzi, A / d039, / Ettorre, G

Androl. (Online)

Abstract: ... have revealed a role for the nitric oxide (NO)-cyclic GMP-phosphodiesterase type 5 (PDE5) pathway ... A pandemic outbreak of COVID-19 has been sweeping the world since December. It begins ... that causes the systemic complications of COVID-19. The contraindications of these drugs and their cost raise ...

Abstract	A pandemic outbreak of COVID-19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, "cytokines storm", that causes the systemic complications of COVID-19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability. Numerous clinical and experimental studies have revealed a role for the nitric oxide (NO)-cyclic GMP-phosphodiesterase type 5 (PDE5) pathway in modulating low-grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti-inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID-19 disease. We performed a systematic review of all evidence documenting any involvement of the NO-cGMP-PDE5 axis in the pathophysiology of COVID-19, presenting the ongoing clinical trials aimed at modulating this axis, including our own "silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID-19 (DEDALO trial)". The reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID-19 by (i) counteracting the Ang-II-mediated downregulation of AT-1 receptor; (ii) acting on monocyte switching, thus reducing pro-inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage-necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications. If the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID-19 in developing countries.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #593690
Database	COVID19

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Article: Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection. The DEDALO project

Isidori, Andrea M / Giannetta, Elisa / Pofi, Riccardo / Venneri, Mary A / Gianfrilli, Daniele / Campolo, Federica / Mastroianni, Claudio M / Lenzi, Andrea / d039, / Ettorre, Gabriella

Androl. (Online)

Abstract: ... COVID-19 disease. MATERIALS AND METHODS: We performed a systematic review of all evidence documenting ... experimental studies have revealed a role for the nitric oxide (NO)-cyclic GMP-phosphodiesterase type 5 (PDE5 ... BACKGROUND: A pandemic outbreak of COVID-19 has been sweeping the world since December. It begins ...

Abstract	BACKGROUND: A pandemic outbreak of COVID-19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, "cytokines storm," that causes the systemic complications of COVID-19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability. OBJECTIVES: Numerous clinical and experimental studies have revealed a role for the nitric oxide (NO)-cyclic GMP-phosphodiesterase type 5 (PDE5) pathway in modulating low-grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti-inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID-19 disease. MATERIALS AND METHODS: We performed a systematic review of all evidence documenting any involvement of the NO-cGMP-PDE5 axis in the pathophysiology of COVID-19, presenting the ongoing clinical trials aimed at modulating this axis, including our own "silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID-19 (DEDALO trial)." RESULTS: The reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID-19 by (i) counteracting the Ang-II-mediated downregulation of AT-1 receptor; (ii) acting on monocyte switching, thus reducing pro-inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage-necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications. DISCUSSION AND CONCLUSION: If the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID-19 in developing countries.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #679523
Database	COVID19

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Article ; Online: Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection

Isidori, A M / Giannetta, E / Pofi, R / Venneri, M A / Gianfrilli, D / Campolo, F / Mastroianni, C M / Lenzi, A / d'Ettorre, G

2020

Abstract	A pandemic outbreak of COVID-19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, "cytokines storm", that causes the systemic complications of COVID-19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability. Numerous clinical and experimental studies have revealed a role for the nitric oxide (NO)-cyclic GMP-phosphodiesterase type 5 (PDE5) pathway in modulating low-grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti-inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID-19 disease. We performed a systematic review of all evidence documenting any involvement of the NO-cGMP-PDE5 axis in the pathophysiology of COVID-19, presenting the ongoing clinical trials aimed at modulating this axis, including our own "silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID-19 (DEDALO trial)". The reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID-19 by (i) counteracting the Ang-II-mediated downregulation of AT-1 receptor; (ii) acting on monocyte switching, thus reducing pro-inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage-necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications. If the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID-19 in developing countries.
Keywords	IL-6 ; pde5 inhibitors ; cytokine storm ; interstitial pneumonia ; pulmonary fibrosis ; type 2 diabetes mellitus ; covid19
Subject code	610
Language	English
Publishing country	it
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: The Natural-Mineral-Based Novel Nanomaterial IFMC Increases Intravascular Nitric Oxide without Its Intake: Implications for COVID-19 and beyond.

Akiyama, Tomohiro / Hirata, Takamichi / Fujimoto, Takahiro / Hatakeyama, Shinnosuke / Yamazaki, Ryuhei / Nomura, Tomohiro

Nanomaterials (Basel, Switzerland)

2020 Volume 10, Issue 9

Abstract: ... complications are rapidly emerging as a key threat of COVID-19. Existing nitric oxide (NO) therapies have been ... coronavirus disease 2019 (COVID-19), despite the urgent need. In addition to respiratory diseases, vascular ... of COVID-19. The present study examined if it could induce an increase of intravascular NO, vasodilation ...

Abstract	There are currently no promising therapy strategies for either the treatment or prevention of novel coronavirus disease 2019 (COVID-19), despite the urgent need. In addition to respiratory diseases, vascular complications are rapidly emerging as a key threat of COVID-19. Existing nitric oxide (NO) therapies have been shown to improve the vascular system; however, they have different limitations in terms of safety, usability and availability. In light of this, we hypothesise that a natural-mineral-based novel nanomaterial, which was developed based on NO therapy, might be a viable strategy for the treatment and prevention of COVID-19. The present study examined if it could induce an increase of intravascular NO, vasodilation and the consequent increase of blood flow rate and temperature in a living body. The intravascular NO concentration in the hepatic portal of rats was increased by 0.17 nM over 35.2 s on average after its application. An ultrasonic Doppler flow meter showed significant increases in the blood flow rate and vessel diameter, but no difference in the blood flow velocity. These were corroborated by measurements of human hand surface temperature. To our knowledge, this result is the first evidence where an increase of intravascular NO and vasodilation were induced by bringing a natural-mineral-based nanomaterial into contact with or close to a living body. The precise mechanisms remain a matter for further investigation; however, we may assume that endothelial NO synthase, haemoglobin and endothelium-derived hyperpolarising factor are deeply involved in the increase of intravascular NO.
Keywords	covid19
Language	English
Publishing date	2020-08-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662255-5
ISSN	2079-4991
ISSN	2079-4991
DOI	10.3390/nano10091699
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Article: The Natural-Mineral-Based Novel Nanomaterial IFMC Increases Intravascular Nitric Oxide without Its Intake: Implications for COVID-19 and beyond

Akiyama, Tomohiro / Hirata, Takamichi / Fujimoto, Takahiro / Hatakeyama, Shinnosuke / Yamazaki, Ryuhei / Nomura, Tomohiro

Nanomaterials

Abstract: ... complications are rapidly emerging as a key threat of COVID-19 Existing nitric oxide (NO) therapies have been ... coronavirus disease 2019 (COVID-19), despite the urgent need In addition to respiratory diseases, vascular ... of COVID-19 The present study examined if it could induce an increase of intravascular NO, vasodilation and ...

Abstract	There are currently no promising therapy strategies for either the treatment or prevention of novel coronavirus disease 2019 (COVID-19), despite the urgent need In addition to respiratory diseases, vascular complications are rapidly emerging as a key threat of COVID-19 Existing nitric oxide (NO) therapies have been shown to improve the vascular system;however, they have different limitations in terms of safety, usability and availability In light of this, we hypothesise that a natural-mineral-based novel nanomaterial, which was developed based on NO therapy, might be a viable strategy for the treatment and prevention of COVID-19 The present study examined if it could induce an increase of intravascular NO, vasodilation and the consequent increase of blood flow rate and temperature in a living body The intravascular NO concentration in the hepatic portal of rats was increased by 0 17 nM over 35 2 s on average after its application An ultrasonic Doppler flow meter showed significant increases in the blood flow rate and vessel diameter, but no difference in the blood flow velocity These were corroborated by measurements of human hand surface temperature To our knowledge, this result is the first evidence where an increase of intravascular NO and vasodilation were induced by bringing a natural-mineral-based nanomaterial into contact with or close to a living body The precise mechanisms remain a matter for further investigation;however, we may assume that endothelial NO synthase, haemoglobin and endothelium-derived hyperpolarising factor are deeply involved in the increase of intravascular NO
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #736709
Database	COVID19

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Article ; Online: The Natural-Mineral-Based Novel Nanomaterial IFMC Increases Intravascular Nitric Oxide without Its Intake

Tomohiro Akiyama / Takamichi Hirata / Takahiro Fujimoto / Shinnosuke Hatakeyama / Ryuhei Yamazaki / Tomohiro Nomura

Nanomaterials, Vol 10, Iss 1699, p

Implications for COVID-19 and beyond

2020 Volume 1699

Abstract	There are currently no promising therapy strategies for either the treatment or prevention of novel coronavirus disease 2019 (COVID-19), despite the urgent need. In addition to respiratory diseases, vascular complications are rapidly emerging as a key threat of COVID-19. Existing nitric oxide (NO) therapies have been shown to improve the vascular system; however, they have different limitations in terms of safety, usability and availability. In light of this, we hypothesise that a natural-mineral-based novel nanomaterial, which was developed based on NO therapy, might be a viable strategy for the treatment and prevention of COVID-19. The present study examined if it could induce an increase of intravascular NO, vasodilation and the consequent increase of blood flow rate and temperature in a living body. The intravascular NO concentration in the hepatic portal of rats was increased by 0.17 nM over 35.2 s on average after its application. An ultrasonic Doppler flow meter showed significant increases in the blood flow rate and vessel diameter, but no difference in the blood flow velocity. These were corroborated by measurements of human hand surface temperature. To our knowledge, this result is the first evidence where an increase of intravascular NO and vasodilation were induced by bringing a natural-mineral-based nanomaterial into contact with or close to a living body. The precise mechanisms remain a matter for further investigation; however, we may assume that endothelial NO synthase, haemoglobin and endothelium-derived hyperpolarising factor are deeply involved in the increase of intravascular NO.
Keywords	SARS-CoV-2 ; COVID-19 ; natural-mineral-based nanomaterial ; nitric oxide ; haemoglobin ; blood flow promotion ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: COVID-19 Is an Endothelial Disease: Implications of Nitric Oxide.

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Article ; Online: Implications of microvascular dysfunction and nitric oxide mediated inflammation in severe COVID-19 infection.

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Article ; Online: Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection. The DEDALO project.

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Article: Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection

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Article: Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection. The DEDALO project

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Article ; Online: Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection

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Article: The Natural-Mineral-Based Novel Nanomaterial IFMC Increases Intravascular Nitric Oxide without Its Intake: Implications for COVID-19 and beyond.

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Article: The Natural-Mineral-Based Novel Nanomaterial IFMC Increases Intravascular Nitric Oxide without Its Intake: Implications for COVID-19 and beyond

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Inter-library loan at ZB MED

Article ; Online: The Natural-Mineral-Based Novel Nanomaterial IFMC Increases Intravascular Nitric Oxide without Its Intake

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