Pulmonary prophylactic impact of melatonin and/or quercetin: A novel therapy for inflammatory hypoxic stress in rats

Al-Rasheed, Nouf M.; Fadda, Laila; Attia, Hala; Sharaf, Iman A.; Mohamed, Azza M.; Al-Rasheed, Nawal M.

doi:10.1515/acph-2017-0010

Cited by 20 publications

(14 citation statements)

References 27 publications

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“…Among conservative, well-tolerated therapeutic candidates, melatonin exerts a protective effect on vascular endothelia by inhibiting NF-κB induced expression of MMP-9 ( Qin et al., 2012 ). It is also reported to protect lung tissue from hypoxic stress by downregulating TNF, IL-6, and VEGF expression, with quercetin providing additional prophylactic effect ( Al-Rasheed et al., 2017 ). Vitamin D attenuates TLR-mediated induction of inflammatory cytokines ( Thota et al., 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

2020

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With the objective of linking early findings relating to the novel SARS-CoV-2 coronavirus with potentially informative findings from prior research literature and to promote investigation toward therapeutic response, a coherent cellular and molecular pathway is proposed for COVID-19. The pathway is consistent with a broad range of observed clinical features and biological markers and captures key mediators of pathophysiology. In this proposed pathway, membrane fusion and cytoplasmic entry of SARS-CoV-2 virus via ACE2 and TMPRSS2-expressing respiratory epithelial cells, including pulmonary type-II pneumocytes, provoke an initial immune response featuring inflammatory cytokine production coupled with a weak interferon response, particularly in IFN-l-dependent epithelial defense. Differentiation of non-classic pathogenic T-cells and pro-inflammatory intermediate monocytes contributes to a skewed inflammatory profile, mediated by membrane-bound immune receptor subtypes (e.g., FcgRIIA) and downstream signaling pathways (e.g., NF-kB p65 and p38 MAPK), followed by chemotactic infiltration of monocyte-derived macrophages and neutrophils into lung tissue. Endothelial barrier degradation and capillary leakage contribute to alveolar cell damage. Inflammatory cytokine release, delayed neutrophil apoptosis, and NETosis contribute to pulmonary thrombosis and cytokine storm. These mechanisms are concordant with observed clinical markers in COVID-19, including high expression of inflammatory cytokines on the TNF-a/ IL-6 axis, elevated neutrophil-to-lymphocyte ratio (NLR), diffuse alveolar damage via cell apoptosis in respiratory epithelia and vascular endothelia, elevated lactate dehydrogenase (LDH) and CRP, high production of neutrophil extracellular traps (NETs), depressed platelet count, and thrombosis. Although certain elements are likely to be revised as new findings emerge, the proposed pathway suggests multiple points of investigation for potential therapeutic interventions. Initial candidate interventions include prophylaxis to augment epithelial defense (e.g., AT1 receptor blockade, type III and type I interferons, melatonin, calcitriol, camostat, and lopinavir) and to reduce viral load (e.g., remdesivir, ivermectin, emetine, Abelson kinase inhibitors, dopamine D2 antagonists, and selective estrogen receptor modulators). Additional interventions focus on tempering inflammatory signaling and injury (e.g., dexamethasone, doxycycline, Ang1-7, estradiol, alpha blockers,

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Section: Discussionmentioning

confidence: 99%

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

2020

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“…Among conservative, well-tolerated therapeutic candidates, melatonin exerts a protective effect on vascular endothelia by inhibiting NF-kB induced expression of MMP-9 (Qin et al, 2012). It is also reported to protect lung tissue from hypoxic stress by downregulating TNF, IL-6, and VEGF expression, with quercetin providing additional prophylactic effect (Al-Rasheed et al, 2017). Vitamin D attenuates TLR-mediated induction of inflammatory cytokines (Thota et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Cellular and molecular pathways of COVID-19 and potential points of therapeutic intervention

Hussman¹

2020

Preprint

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With the objective of linking early findings relating to the novel SARS-CoV-2 coronavirus with potentially informative findings from prior research literature, and to promote investigation toward therapeutic response, a coherent cellular and molecular pathway is proposed for COVID-19, consistent with a broad range of observed clinical features and biological markers, and capturing key mediators of pathophysiology. In this proposed pathway, membrane fusion and cytoplasmic entry of SARS-CoV-2 virus via ACE2 and TMPRSS2-expressing respiratory epithelial cells, including pulmonary type-II pneumocytes, provokes an initial immune response featuring inflammatory cytokine production coupled with a weak interferon response, particularly in Type III interferon-dependent epithelial defense. Differentiation of non-classic pathogenic T-cells and pro-inflammatory intermediate monocytes contributes to a skewed inflammatory profile, mediated by membrane-bound immune receptor subtypes (e.g. FcgRIIA) and downstream signaling pathways (e.g. NF-kB p65, p38 MAPK), followed by chemotactic infiltration of monocyte-derived macrophages and neutrophils into lung tissue, with inflammatory cytokine release, delayed neutrophil apoptosis, and NETosis contributing to pulmonary thrombosis and cytokine storm. These mechanisms are concordant with observed clinical markers in COVID-19, including high expression of inflammatory cytokines on the TNF-alpha/IL-6 axis, elevated neutrophil-to-lymphocyte ratio (NLR), diffuse alveolar damage via cell apoptosis in respiratory epithelia and vascular endothelia, elevated lactate dehydrogenase (LDH) and C-reactive protein (CRP), high production of neutrophil extracellular traps (NETs), depressed platelet count, and thrombosis. Although certain elements are likely to be revised as new findings emerge, the proposed pathway suggests multiple points of investigation for potential therapeutic interventions, including prophylaxis to augment epithelial defense (e.g. AT1 receptor blockade, Type III and Type I interferons, camostat), reduce viral load (e.g. remdesivir + emetine, lopinavir, Abelson kinase inhibition, dopamine D2 antagonists, selective estrogen receptor modulators), and temper pro-inflammatory signaling (e.g. Ang1-7, estradiol, alpha blockers, DHA/EPA, pasireotide), as well as therapeutics targeted toward molecular mediators of the maladaptive COVID-19 immune response (e.g. IL-6, TNF-alpha, IL-17, JAK, CDK9).

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“…The pretreatment with melatonin combined or not with quercetin in rats with hypoxia-induced by sodium nitrite considerably reduced the plasma levels of IL-6, TNF-α, and CRP, heat shock protein 70 extracellular (Hsp70e), and VEGF. Additionally, melatonin enhanced the histopathological changes in the lungs of these animals, also suggesting powerful protective effects of melatonin at the pulmonary level [63]. Melatonin has a potent pulmonary protective effect in rats with lung injury induced by phosgene, and this protective mechanism can be associated with the elimination of free radicals and the inhibition of p38 MAPK activation and iNOS expression [64].…”

Section: Melatonin and Its Effects On Inflammation And Oxidation At Lung Levelmentioning

confidence: 99%

Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment

et al. 2020

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COVID-19 pandemic has a high mortality rate and is affecting practically the entire world population. The leading cause of death is severe acute respiratory syndrome as a consequence of exacerbated inflammatory response accompanied by uncontrolled oxidative stress as well as the inflammatory reaction at the lung level. Until now, there is not a specific and definitive treatment for this pathology that worries the world population, especially the older adults who constitute the main risk group. In this context, it results in a particular interest in the evaluation of the efficacy of existing pharmacological agents that may be used for overcoming or attenuating the severity of this pulmonary complication that has ended the lives of many people worldwide. Vitamin D and melatonin could be good options for achieving this aim, taking into account that they have many shared underlying mechanisms that are able to modulate and control the immune adequately and oxidative response against COVID-19 infection, possibly even through a synergistic interaction. The renin-angiotensin system exaltation with consequent inflammatory response has a leading role in the physiopathology of COVID-19 infection; and it may be down-regulated by vitamin D and melatonin in many organs. Therefore, it is also essential to analyze this potential therapeutic association and their relation with RAS as part of this new approach.

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Pulmonary prophylactic impact of melatonin and/or quercetin: A novel therapy for inflammatory hypoxic stress in rats

Cited by 20 publications

References 27 publications

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention

Cellular and molecular pathways of COVID-19 and potential points of therapeutic intervention

Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment

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