The melatonergic pathway and its interactions in modulating respiratory system disorders

Mazzoccoli, Gianluigi; Kvetnoy, I. M.; Mironova, Ekaterina; Yаblonskiy, Petr; Соколович, Е. Г.; Krylova, Julia; Carbone, Annalucia; Anderson, Geoffrey M.; Polyakova, V. O.

doi:10.1016/j.biopha.2021.111397

Cited by 12 publications

(11 citation statements)

References 170 publications

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“…Melatonin (N-acetyl-5-methoxytryptamine, C 13 H 16 N 2 O 2 ), a kind of neuroendocrine hormone, is mainly synthesized and secreted by the pineal gland of brains and exerts effects via its membrane receptors (MT1 and MT2) [ 20 , 21 ]. Melatonin is also synthesized in respiratory epithelia and bone marrow cells as well as macrophages [ 22 , 23 ]. It is widely recognized that melatonin is in charge of regulating sleep and circadian rhythm and also plays important roles in anti-inflammation and antioxidation [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Suppresses Macrophage M1 Polarization and ROS-Mediated Pyroptosis via Activating ApoE/LDLR Pathway in Influenza A-Induced Acute Lung Injury

Kang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Influenza virus infection is one of the strongest pathogenic factors for the development of acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS). However, the underlying cellular and molecular mechanisms have not been clarified. In this study, we aim to investigate whether melatonin modulates macrophage polarization, oxidative stress, and pyroptosis via activating Apolipoprotein E/low-density lipoprotein receptor (ApoE/LDLR) pathway in influenza A-induced ALI. Here, wild-type (WT) and ApoE-/- mice were instilled intratracheally with influenza A (H3N2) and injected intraperitoneally with melatonin for 7 consecutive days. In vitro, WT and ApoE-/- murine bone marrow-derived macrophages (BMDMs) were pretreated with melatonin before H3N2 stimulation. The results showed that melatonin administration significantly attenuated H3N2-induced pulmonary damage, leukocyte infiltration, and edema; decreased the expression of proinflammatory M1 markers; enhanced anti-inflammatory M2 markers; and switched the polarization of alveolar macrophages (AMs) from M1 to M2 phenotype. Additionally, melatonin inhibited reactive oxygen species- (ROS-) mediated pyroptosis shown by downregulation of malonaldehyde (MDA) and ROS levels as well as inhibition of the NLRP3/GSDMD pathway and lactate dehydrogenase (LDH) release. Strikingly, the ApoE/LDLR pathway was activated when melatonin was applied in H3N2-infected macrophages and mice. ApoE knockout mostly abrogated the protective impacts of melatonin on H3N2-induced ALI and its regulatory ability on macrophage polarization, oxidative stress, and pyroptosis. Furthermore, recombinant ApoE3 (re-ApoE3) inhibited H3N2-induced M1 polarization of BMDMs with upregulation of MT1 and MT2 expression, but re-ApoE2 and re-ApoE4 failed to do this. Melatonin combined with re-ApoE3 played more beneficial protective effects on modulating macrophage polarization, oxidative stress, and pyroptosis in H3N2-infected ApoE-/- BMDMs. Our study indicated that melatonin attenuated influenza A- (H3N2-) induced ALI by inhibiting the M1 polarization of pulmonary macrophages and ROS-mediated pyroptosis via activating the ApoE/LDLR pathway. This study suggested that melatonin-ApoE/LDLR axis may serve as a novel therapeutic strategy for influenza virus-induced ALI.

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Section: Introductionmentioning

confidence: 99%

Melatonin Suppresses Macrophage M1 Polarization and ROS-Mediated Pyroptosis via Activating ApoE/LDLR Pathway in Influenza A-Induced Acute Lung Injury

Kang

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Melatonin has been synthesized as an internal sleep facilitator to treat sleep problems and improve sleep [79]. Additionally, melatonin is a biogenic amine that exhibits a wide range of biological functions, including anti-inflammatory, antioxidant, anti-aging, anticancer, antiviral, antidiabetic, and neuroprotective properties [80].…”

Section: Melatonin and Sleep Physiologymentioning

confidence: 99%

Could Melatonin Be an Alternative to Benzodiazepine for Chronic Obstructive Pulmonary Disease With Insomnia?

Park

2022

Chronobiol Med

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Chronic obstructive pulmonary disease (COPD) is common, with a 10% global prevalence and a significant health problem, and is one of the main causes of morbidity. Patients with COPD experience various types of sleep problems with insomnia as the most common sleep disorder. The presence of sleep disorders further deteriorates their quality of life. Benzodiazepines (BZDs) are commonly prescribed drugs for insomnia. Several meta-analyses have shown that BZDs effectively reduce insomnia; however, severe side effects including rebound insomnia, next-day hangover, anterograde amnesia, and cognitive impairment occur. Since COPD patients often complain of symptoms such as shortness of breath, safe treatment for sleep disorders is needed. Melatonin supplements have a safe profile and are well-tolerated. Therefore, melatonin can be safely prescribed to treat insomnia in patients with COPD. In addition, due to the anti-inflammatory activity of melatonin, it can be an alternative to BZDs for improving insomnia symptoms without exacerbating respiratory symptoms. It would be helpful to more actively screen and detect sleep disorders in adults with COPD, and to provide safe melatonin treatment for improving their quality of life.

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“…It is noteworthy that clinical trials and studies with animal models indicate that supplementation with melatonin may be a valid strategy to tackle symptomatology and halt the progression of COVID-19 [134][135][136], perhaps because the indoleamine helps to counteract the debilitating phenotype of aging [137] and predisposing pathologies [133,138,139]. In this regard, based on the orchestration of endocrine, paracrine, and autocrine responses, melatonin may be considered a smart controller of the innate and adaptive immunity [140] and inflammation [141], a neuroimmune-endocrine regulator [142] that collaborates with the maintenance of the internal environment and the mitigation of cell/tissue perturbations. Consequently, the homeostatic mediation of melatonin must be understood as a cell protector endowed with multiple restorative capacities of metabolic and immunoinflammatory disturbances and with particular potential utility in respiratory and lung viral infections [142].…”

Section: Melatonin Impact From An Immune-metabolic Perspectivementioning

confidence: 99%

“…In this regard, based on the orchestration of endocrine, paracrine, and autocrine responses, melatonin may be considered a smart controller of the innate and adaptive immunity [140] and inflammation [141], a neuroimmune-endocrine regulator [142] that collaborates with the maintenance of the internal environment and the mitigation of cell/tissue perturbations. Consequently, the homeostatic mediation of melatonin must be understood as a cell protector endowed with multiple restorative capacities of metabolic and immunoinflammatory disturbances and with particular potential utility in respiratory and lung viral infections [142]. Recently, mitochondria have revealed themselves as the core target of melatonin activity [143,144], and hence, normalization of mitochondrial function and reduction of nitro-oxidative stress are the backbone of pleiotropic action performed by the indoleamine therein [145].…”

Section: Melatonin Impact From An Immune-metabolic Perspectivementioning

confidence: 99%

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The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy

et al. 2021

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Viral infections constitute a tectonic convulsion in the normophysiology of the hosts. The current coronavirus disease 2019 (COVID-19) pandemic is not an exception, and therefore the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, like any other invading microbe, enacts a generalized immune response once the virus contacts the body. Melatonin is a systemic dealer that does not overlook any homeostasis disturbance, which consequently brings into play its cooperative triad, antioxidant, anti-inflammatory, and immune-stimulant backbone, to stop the infective cycle of SARS-CoV-2 or any other endogenous or exogenous threat. In COVID-19, the corporal propagation of SARS-CoV-2 involves an exacerbated oxidative activity and therefore the overproduction of great amounts of reactive oxygen and nitrogen species (RONS). The endorsement of melatonin as a possible protective agent against the current pandemic is indirectly supported by its widely demonstrated beneficial role in preclinical and clinical studies of other respiratory diseases. In addition, focusing the therapeutic action on strengthening the host protection responses in critical phases of the infective cycle makes it likely that multi-tasking melatonin will provide multi-protection, maintaining its efficacy against the virus variants that are already emerging and will emerge as long as SARS-CoV-2 continues to circulate among us.

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The melatonergic pathway and its interactions in modulating respiratory system disorders

Cited by 12 publications

References 170 publications

Melatonin Suppresses Macrophage M1 Polarization and ROS-Mediated Pyroptosis via Activating ApoE/LDLR Pathway in Influenza A-Induced Acute Lung Injury

Melatonin Suppresses Macrophage M1 Polarization and ROS-Mediated Pyroptosis via Activating ApoE/LDLR Pathway in Influenza A-Induced Acute Lung Injury

Could Melatonin Be an Alternative to Benzodiazepine for Chronic Obstructive Pulmonary Disease With Insomnia?

The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy

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