Melatonin Protects against Lung Fibrosis by Regulating the Hippo/YAP Pathway

Zhao, Xiaojun; Sun, Jian; Su, Wei; Shan, Huitong; Zhang, Bowen; Wang, Yining; Shabanova, Azaliia; Shan, Hongli; Liang, Haihai

doi:10.3390/ijms19041118

Cited by 50 publications

(42 citation statements)

References 39 publications

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“…The role of melatonin antioxidant properties in the prevention of COVID-19 post-infection complications should be addressed with no delay. Melatonin's ability to protect patients from pulmonary fibrosis through the Hippo/ YAP pathway has already been shown [99]. Considering that millions of people can be infected with COVID-19, while only several tens of thousands were with SARS-CoV-1, applying melatonin to prevent pulmonary fibrosis may be even more important than mitigating the acute SARS-CoV-2 infection per se.…”

Section: Melatonin As a Vaccine Adjuvant And Antiviral Immune Stimulantmentioning

confidence: 99%

Can melatonin reduce the severity of COVID-19 pandemic?

Shneider

Kudriavtsev

Vakhrusheva

2020

International Reviews of Immunology

147

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The current COVID-19 pandemic is one of the most devastating events in recent history. The virus causes relatively minor damage to young, healthy populations, imposing life-threatening danger to the elderly and people with diseases of chronic inflammation. Therefore, if we could reduce the risk for vulnerable populations, it would make the COVID-19 pandemic more similar to other typical outbreaks. Children don't suffer from COVID-19 as much as their grandparents and have a much higher melatonin level. Bats are nocturnal animals possessing high levels of melatonin, which may contribute to their high anti-viral resistance. Viruses induce an explosion of inflammatory cytokines and reactive oxygen species, and melatonin is the best natural antioxidant that is lost with age. The programmed cell death coronaviruses cause, which can result in significant lung damage, is also inhibited by melatonin. Coronavirus causes inflammation in the lungs which requires inflammasome activity. Melatonin blocks these inflammasomes. General immunity is impaired by anxiety and sleep deprivation. Melatonin improves sleep habits, reduces anxiety and stimulates immunity. Fibrosis may be the most dangerous complication after COVID-19. Melatonin is known to prevent fibrosis. Mechanical ventilation may be necessary but yet imposes risks due to oxidative stress, which can be reduced by melatonin. Thus, by using the safe over-the-counter drug melatonin, we may be immediately able to prevent the development of severe disease symptoms in coronavirus patients, reduce the severity of their symptoms, and/or reduce the immuno-pathology of coronavirus infection on patients' health after the active phase of the infection is over. ARTICLE HISTORY

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Section: Melatonin As a Vaccine Adjuvant And Antiviral Immune Stimulantmentioning

confidence: 99%

Can melatonin reduce the severity of COVID-19 pandemic?

Shneider

Kudriavtsev

Vakhrusheva

2020

International Reviews of Immunology

147

View full text Add to dashboard Cite

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“…Yes-associated protein (YAP) is a key downstream effector protein of Hippo. In patients with IPF, the activity of YAP increased, and the interaction of YAP and mTOR/p-S6 signaling pathways induced cell proliferation and migration, and inhibited epithelial cell differentiation [52].It has been shown that melatonin attenuated TGF-β1-induced brogenesis in pulmonary broblasts by activating the Hippo pathway and then promoting nuclear translocation and increasing the inactivation and degeneration of YAP1 in the cytoplasm [53].…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology-based mechanistic investigation of Jinshui Huanxian formula acing on idiopathic pulmonary fibrosis

Liu

et al. 2020

Preprint

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Background Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease with high incidence rate, morbidity and mortality. Jinshui Huanxian formula (JHF) is an empirical formula for the pathogenesis of lung-kidney qi deficiency and phlegm-blood stasis in pulmonary fibrosis. The purpose of this study is to explore the pharmacological mechanism of JHF action in IPF therapy by network interaction analysis. Methods The main active components and corresponding target genes of JHF were predicted using various databases. Two sets of IPF disease genes were obtained from the DisGeNET database and GEO database. Two sets of drug targets for IPF treatment were collected and the overlapping genes between disease genes and drug targets were analyzed. The target genes of JHF were intersected with the differentially expressed genes of IPF to obtain the predicted targets of JHF acting on IPF. The functions and pathways of predicted targets acting on IPF were analyzed by using DAVID and KEGG pathway database. Finally, the resulting drug target mechanisms were validated in a rat model of pulmonary fibrosis. Results 494 active compounds and 1304 corresponding targets were screened. Intersection analysis showed that 4 genes were common genes of JHF targets, IPF disease genes and anti-IPF drugs in KEGG database, and these genes were targeted by several compounds of JHF respectively. 72 JHF targets were closely related with IPF, and were thus considered therapeutically relevant. The targets were screened and participated in the regulation of IPF through 18 pathways. The molecular functions of targets included regulation of oxidoreductase activity, kinase regulator activity, phosphotransferase activity and transmembrane receptor protein kinase activity. In vivo experiments showed that JHF could alleviate the degree of pulmonary fibrosis, including the decrease of collagen deposition and epithelial-mesenchymal transition. Conclusions This study explored the mechanisms of JHF from a systematic point of view, trying to identify the specific target pathways acing on IPF. Pharmacological network with in vivo validation explained the potential roles and mechanisms of JHF in IPF therapy.

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“…Melatonin alleviated myocardial fibrosis in animal models of myocardial infarction [24], pulmonary hypertension [25], and chronic intermittent hypoxia [26]. Bleomycin-induced experimental lung fibrosis was also attenuated by treatment with melatonin [27]. In addition, melatonin has been shown to attenuate kidney fibrosis induced by CCl4 [28], unilateral ureteral obstruction [29], or diabetes [30].…”

Section: Discussionmentioning

confidence: 99%

Melatonin Inhibits Transforming Growth Factor-β1-Induced Epithelial–Mesenchymal Transition in AML12 Hepatocytes

Kim

Park

Kim

et al. 2019

Biology

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Recent studies showed that melatonin, a well-known pineal hormone that modulates the circadian rhythm, exerts beneficial effects against liver fibrosis. However, mechanisms for its protective action against the fibrotic processes remain incompletely understood. Here, we aimed to explore the effects of the hormone on transforming growth factor-β1 (TGF-β1)-stimulated epithelial–mesenchymal transition (EMT) in AML12 hepatocytes. Pretreatment with melatonin dose-dependently reversed downregulation of an epithelial marker and upregulation of mesenchymal markers after TGF-β1 stimulation. Additionally, melatonin dose-dependently suppressed an increased phosphorylation of Smad2/3 after TGF-β1 treatment. Besides the canonical Smad signaling pathway, an increase in phosphorylation of extracellular signal-regulated kinase 1/2 and p38 was also dose-dependently attenuated by melatonin. The suppressive effect of the hormone on EMT stimulated by TGF-β1 was not affected by luzindole, an antagonist of melatonin membrane receptors, suggesting that its membrane receptors are not required for the inhibitory action of melatonin. Moreover, melatonin suppressed elevation of intracellular reactive oxygen species (ROS) levels in TGF-β1-treated cells. Finally, TGF-β1-stimulated EMT was also inhibited by the antioxidant N-acetylcysteine. Collectively, these results suggest that melatonin prevents TGF-β1-stimulated EMT through suppression of Smad and mitogen-activated protein kinase signaling cascades by deactivating ROS-dependent mechanisms in a membrane receptor-independent manner.

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Melatonin Protects against Lung Fibrosis by Regulating the Hippo/YAP Pathway

Cited by 50 publications

References 39 publications

Can melatonin reduce the severity of COVID-19 pandemic?

Can melatonin reduce the severity of COVID-19 pandemic?

Network pharmacology-based mechanistic investigation of Jinshui Huanxian formula acing on idiopathic pulmonary fibrosis

Melatonin Inhibits Transforming Growth Factor-β1-Induced Epithelial–Mesenchymal Transition in AML12 Hepatocytes

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