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The melatonin agonist ramelteon induces duration-dependent clock gene expression through cAMP signaling in pancreatic INS-1 ?-cells.

ABSTRACT: Prolonged exposure to melatonin improves glycemic control in animals. Although glucose metabolism is controlled by circadian clock genes, little is known about the role of melatonin signaling and its duration in the regulation of clock gene expression in pancreatic ?-cells. Activation of MT1 and MT2 melatonin receptors inhibits cAMP signaling, which mediates clock gene expression. Therefore, this study investigated exposure duration-dependent alterations in cAMP element-binding protein (CREB) phosphorylation and clock gene expression that occur during and after exposure to ramelteon, a selective melatonin agonist used to treat insomnia. In rat INS-1 cells, a pancreatic ?-cell line endogenously expressing melatonin receptors, ramelteon persistently decreased CREB phosphorylation during the treatment period (2-14 h), whereas the subsequent washout induced an enhancement of forskolin-stimulated CREB phosphorylation in a duration- and concentration-dependent manner. This augmentation was blocked by forskolin or the melatonin receptor antagonist luzindole. Similarly, gene expression analyses of 7 clock genes revealed the duration dependency of the effects of ramelteon on Rev-erb? and Bmal1 expression through melatonin receptor-mediated cAMP signaling; longer exposure times (14 h) resulted in greater increases in the expression and signaling of Rev-erb?, which is related to ?-cell functions. Interestingly, this led to amplified oscillatory Rev-erb? and Bmal1 expression after agonist washout and forskolin stimulation. These results provide new insights into the duration-dependent effects of ramelteon on clock gene expression in INS-1 cells and may improve the understanding of its effect in vivo. The applicability of these results to pancreatic islets awaits further investigation.

SUBMITTER: Nishiyama K

PROVIDER: S-EPMC4094524 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The melatonin agonist ramelteon induces duration-dependent clock gene expression through cAMP signaling in pancreatic INS-1 β-cells.

Nishiyama Keiji K Hirai Keisuke K

PloS one 20140711 7

Prolonged exposure to melatonin improves glycemic control in animals. Although glucose metabolism is controlled by circadian clock genes, little is known about the role of melatonin signaling and its duration in the regulation of clock gene expression in pancreatic β-cells. Activation of MT1 and MT2 melatonin receptors inhibits cAMP signaling, which mediates clock gene expression. Therefore, this study investigated exposure duration-dependent alterations in cAMP element-binding protein (CREB) ph ...[more]

PMID: 25013953

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Project description:BackgroundThe SARS-Cov-2(severe acute respiratory syndrome coronavirus 2) infection affecting human populations worldwide is now a very concerning issue considering the morbidity and mortality rates. Despite several measures followed by the medical fraternity and general public, there is no resolution. Therapeutic measures to tackle the infection have been based on researching new designer drug molecules that could prevent viral entry into the human host. Melatonin has been tried as an adjuvant in the management of COVID 19(coronavirus disease) illness but its specific antiviral role has not been investigated. Objectives: The objectives of the present study were to conduct an in-silico analysis to investigate if melatonin and related drugs namely ramelteon and agomelatine could be used as antiviral agents in SARS-CoV-2 infection based on their binding to the SARS-CoV-2 receptor binding site (RBD) and Angiotensin-converting enzyme 2 (ACE 2).MethodsFor docking studies (Pdb Id 1M0J), the SARS-CoV-2 spike protein receptor-binding domain (RBD) crystal structure which was ACE2 cell receptor bounded was employed. From the PubChem database, the three-dimensional configuration of the ligands melatonin, ramelteon, and agomelatine was retrieved, and conceptual density functional theory (CDFT) was performed to determine molecular descriptors. Charges were added and optimized with the universal force field to prepare the ligands for the process of docking. For facilitation of readability by the AutoDock software conversion to PDBQT(Protein Data Bank, Partial Charge (Q), & Atom Type (T)) format was performed. AutoDock version 4.2.6 docking program and AutoDock Tools (ADT) version 1.5.6 were used for molecular docking. Desmond, a Package of Schrödinger LLC was used to simulate molecular dynamics for hundred nanoseconds using.ResultsData from the present study reveal that melatonin, ramelteon, and agomelatine demonstrate significant binding with SARS-CoV-2 RBD and ACE 2 demonstrating the fact that they can strongly prevent viral entry into the host cells through dual binding effects. However, Ramelteon was found to be the most superior amongst the 3 drugs analyzed in its antiviral properties against SARS-CoV-2.ConclusionResults advocate further research in exploring the potential therapeutic applications of melatonin, ramelteon, and agomelatine for the management of SARS-CoV-2 infection.

Project description:In certain diseases of the pancreas, pancreatic stellate cells form an important part of fibrosis and are critical for the development of cancer cells. A hypoxic condition develops within the tumor, to which pancreatic stellate cells adapt and are able to proliferate. The consequence is the growth of the tumor. Melatonin, the product of the pineal gland, is gaining attention as an agent with therapeutic potential against pancreatic cancers. Its actions on tumor cells lead, in general, to a reduction in cell viability and proliferation. However, its effects on pancreatic stellate cells subjected to hypoxia are less known. In this study, we evaluated the actions of pharmacological concentrations of melatonin (1 mM-1 µM) on pancreatic stellate cells subjected to hypoxia. The results show that melatonin induced a decrease in cell viability at the highest concentrations tested. Similarly, the incorporation of BrdU into DNA was diminished by melatonin. The expression of cyclins A and D also was decreased in the presence of melatonin. Upon treatment of cells with melatonin, increases in the expression of major markers of ER stress, namely BIP, phospho-eIF2α and ATF-4, were detected. Modulation of apoptosis was noticed as an increase in caspase-3 activation. In addition, changes in the phosphorylated state of p44/42, p38 and JNK MAPKs were detected in cells treated with melatonin. A slight decrease in the content of α-smooth muscle actin was detected in cells treated with melatonin. Finally, treatment of cells with melatonin decreased the expression of matrix metalloproteinases 2, 3, 9 and 13. Our observations suggest that melatonin, at pharmacological concentrations, diminishes the proliferation of pancreatic stellate cells subjected to hypoxia through modulation of cell cycle, apoptosis and the activation of crucial MAPKs. Cellular responses might involve certain ER stress regulator proteins. In view of the results, melatonin could be taken into consideration as a potential therapeutic agent for pancreatic fibrosis.

Dataset Information

The melatonin agonist ramelteon induces duration-dependent clock gene expression through cAMP signaling in pancreatic INS-1 ?-cells.

Publications

The melatonin agonist ramelteon induces duration-dependent clock gene expression through cAMP signaling in pancreatic INS-1 β-cells.

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