Melatonin CAS NO.73-31-4

Melatonin ameliorates ER stress-mediated hepatic steatosis through miR-23a in the liver.[Pubmed: 25660457]

Biochem Biophys Res Commun. 2015 Mar 13;458(3):462-9.

The endoplasmic reticulum (ER) stress induces hepatic steatosis and inflammation in the liver. Although Melatonin ameliorates ER stress-target genes, it remains unknown whether Melatonin protects against hepatic steatosis as well as inflammation through regulation of miRNA. MicroRNAs have been identified as pivotal regulators in the field of gene regulation and their dysfunctions are a common feature in a variety of metabolic diseases. Especially, among miRNAs, miR-23a has been shown to regulate ER stress.
METHODS AND RESULTS:
Herein, we investigated the crucial roles of Melatonin in hepatic steatosis and inflammation in vivo. Tunicamycin challenge caused increase of hepatic triglyceride and intracellular calcium levels through activation of ER stress, whereas these phenomena were partially disrupted by Melatonin. We also demonstrated that expression of miR-23a stimulated with tunicamycin was rescued by Melatonin treatment, resulting in reduced ER stress in primary hepatocytes.
CONCLUSIONS:
Overall, these results suggest a new function of Melatonin that is involved in ameliorating ER stress-induced hepatic steatosis and inflammation by attenuating miR-23a. Melatonin may be useful as a pharmacological agent to protect against hepatic metabolic diseases due to its ability to regulate expression of miR-23a.

Melatonin reduces lead levels in blood, brain and bone and increases lead excretion in rats subjected to subacute lead treatment.[Pubmed: 25601058]

Toxicol Lett. 2015 Mar 4;233(2):78-83.

Melatonin, a hormone known for its effects on free radical scavenging and antioxidant activity, can reduce lead toxicity in vivo and in vitro.We examined the effects of Melatonin on lead bio-distribution.
METHODS AND RESULTS:
Rats were intraperitoneally injected with lead acetate (10, 15 or 20mg/kg/day) with or without Melatonin (10mg/kg/day) daily for 10 days. In rats intoxicated with the highest lead doses, those treated with Melatonin had lower lead levels in blood and higher levels in urine and feces than those treated with lead alone, suggesting that Melatonin increases lead excretion. To explore the mechanism underlying this effect, we first assessed whether lead/Melatonin complexes were formed directly. Electronic density functional (DFT) calculations showed that a lead/Melatonin complex is energetically feasible; however, UV spectroscopy and NMR analysis showed no evidence of such complexes. Next, we examined the liver mRNA levels of metallothioneins (MT) 1 and 2. Melatonin cotreatment increased the MT2 mRNA expression in the liver of rats that received the highest doses of lead. The potential effects of MTs on the tissue distribution and excretion of lead are not well understood.
CONCLUSIONS:
This is the first report to suggest that Melatonin directly affects lead levels in organisms exposed to subacute lead intoxication.

Melatonin in patients with cancer receiving chemotherapy: a randomized, double-blind, placebo-controlled trial.[Pubmed: 25503168]

Anticancer Res. 2014 Dec;34(12):7327-37.

The MIRCIT trial was a randomized, double-blind, placebo-controlled study of advanced Non-small cell lung cancer (NSCLC).
METHODS AND RESULTS:
Patients were randomized to receive 10 mg or 20 mg of Melatonin or placebo. Assessment of health-related quality of life (HRQoL) was completed at baseline, and at 2, 3 and 7 months. Survival and adverse events were collected. DNA damage marker 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) was measured during the first three months of chemotherapy. Patients in the Melatonin-treated group had better adjusted HRQoL scores, with a slightly significantly better score (2.69 points, 95% confidence interval (CI)=0.01-5.38, p=0.049) being found in social well-being. Median survival was 7.3 months (95% CI=3.42-11.14) without significant difference. A great amont of DNA damage marker was observed in the placebo-treated group, and this was associated with lower survival (r(2)=-0.656, p=0.02), implying the protective effect of Melatonin in healthy cells.
CONCLUSIONS:
Melatonin in combination with chemotherapy did not affect survival and adverse events of advanced patients with NSCLC, but there was a trend for better HRQoL.

Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells.[Pubmed: 25580987]

Cell Prolif. 2015 Feb;48(1):67-77.

Melatonin produces anti-cancer effects via several mechanisms, including by induction of apoptosis. In this way, it has been shown to be of use, in combination with chemotherapeutic drugs, for cancer treatment. The study described here has evaluated effects of Melatonin on cytotoxicity, apoptosis and cell cycle arrest induced with the chemotherapeutic agent cisplatin, in human lung adenocarcinoma cisplatin-sensitive cell line (SK-LU-1), which previously had only limit data.
METHODS AND RESULTS:
Cells of the SK-LU-1 line were treated with Melatonin alone at 1-5 mM concentration or cisplatin alone 10-200 μM, for 48 h in culture. Cytotoxicity was measured by MTT reduction assay. Apoptosis induction was detected by annexin V/PI staining using flow cytometric analysis and DAPI nuclear staining. Change in mitochondrial membrane potential (ΔΨm) was quantified using DiOC6(3) reagent and activities of caspases-3/7 were also investigated. DNA fractions were measured using propidium iodide (PI) staining. Melatonin or cisplatin alone had 50% (IC50 ) cytotoxicity at 5 mM or 34 μM concentrations respectively. Combination of 1 or 2 mM Melatonin and cisplatin significantly augmented cytotoxicity of cisplatin by reducing its IC50 to 11 and 4 μM, respectively. Consistently, combined treatment increased population of apoptotic cells by elevating mitochondrial membrane depolarization, activating caspases-3/7 and inducing cell cycle arrest in the S phase, compared to treatment with cisplatin alone.
CONCLUSIONS:
These data demonstrate that Melatonin enhanced cisplatin-induced cytotoxicity and apoptosis in SK-LU-1 lung cancer cells. SK-LU-1 cell population growth inhibition was mediated by cell cycle arrest in the S phase. These findings suggest that Melatonin has the potential to be used for NSCLC treatment in combination with a chemotherapeutic agent such as cisplatin.

Melatonin ameliorates dexamethasone-induced inhibitory effects on the proliferation of cultured progenitor cells obtained from adult rat hippocampus.[Pubmed: 25305353]

J Steroid Biochem Mol Biol. 2015 Jan;145:38-48.

Glucocorticoids, hormones that are released in response to stress, induce neuronal cell damage. The hippocampus is a primary target of glucocorticoids in the brain, the effects of which include the suppression of cell proliferation and diminished neurogenesis in the dentate gyrus. Our previous study found that Melatonin, synthesized primarily in the pineal, pretreatment prevented the negative effects of dexamethasone, the glucocorticoid receptor agonist, on behavior and neurogenesis in rat hippocampus.
METHODS AND RESULTS:
In the present study, we attempted to investigate the interrelationship between Melatonin and dexamethasone on the underlying mechanism of neural stem cell proliferation. Addition of dexamethasone to hippocampal progenitor cells from eight-week old rats resulted in a decrease in the number of neurospheres; pretreatment with Melatonin precluded these effects. The immunocytochemical analyses indicated a reduction of Ki67 and nestin-positive cells in the dexamethasone-treated group, which was minimized by Melatonin pretreatment. A reduction of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and G1-S phase cell cycle regulators cyclin E and CDK2 in dexamethasone-treated progenitor cells were prevented by pretreatment of Melatonin. Moreover, luzindole, a Melatonin receptor antagonist blocked the positive effect of Melatonin whereas RU48, the glucocorticoid receptor antagonist blocked the negative effect of dexamethasone on the number of neurospheres. Moreover, we also found that dexamethasone increased the glucocorticoid receptor protein but decreased the level of MT1 Melatonin receptor, whereas Melatonin increased the level of MT1 Melatonin receptor but decreased the glucocorticoid receptor protein.
CONCLUSIONS:
These suggest the crosstalk and cross regulation between the Melatonin receptor and the glucocorticoid receptor on hippocampal progenitor cell proliferation.