PMID: 

Chronobiol Int. 2019 Dec 2:1-12. Epub 2019 Dec 2. PMID: 31790604

Abstract Title: 

Melatonin ingestion after exhaustive late-evening exercise attenuate muscle damage, oxidative stress, and inflammation during intense short term effort in the following day in teenage athletes.

Abstract: 

The present study aimed to investigate whether nocturnal melatonin (MEL) ingestion has beneficial effects against exercise-induced oxidative stress and muscle damage in young athletes. Fourteen healthy-trained teenagers performed two-test sessions separated by at least, 1 week. During each session, participants completed the Running-Based Anaerobic Sprint Test (RAST) at 20:00 h. Then, they ingested a single 10-mg tablet of MEL or Placebo (PLA) in a double-blind randomized order at 22:00 h. The following morning (i.e., 07:30 h), participants performed the same test as the previous night. Blood samples were taken before and after exercise. MEL intake increased the peak power (P) (

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PMID: 

J Gastrointest Cancer. 2019 Dec 2. Epub 2019 Dec 2. PMID: 31792737

Abstract Title: 

The Role of Melatonin in Colorectal Cancer.

Abstract: 

The prevalence and mortality rate of colorectal cancer have been dramatically rising globally. Currently, colorectal cancer is emerging as the fourth leading cause of death and the third most common malignancy worldwide. The major drawback in colorectal cancer treatment is related to severe adverse events of both chemotherapy and radiation therapy that lead to toxicity and inflammation. Recently, melatonin as an antioxidant, immune-stimulant, and antimutagenic agent has been noticed. Different studies worked on the molecular role of melatonin on carcinogenesis progression. Overall, the anticancer activity of melatonin, combined with its actions via multiple signaling pathways, is considered hugely exciting to use this drug as a possible treatment strategy to cure cancer. Apart from its anticancer potential, this drug has shown to induce modulation of chemotherapy toxicity and improving its therapeutic efficacy. The present review aimed to discuss the possible role of melatonin usage in management of colorectal cancer.

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PMID: 

CNS Neurosci Ther. 2019 Dec ;25(12):1353-1362. PMID: 31793209

Abstract Title: 

Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti-inflammatory phenotype through STAT3 pathway.

Abstract: 

AIMS: Microglia and infiltrated macrophages play important roles in inflammatory processes after ischemic stroke. Modulating microglia/macrophage polarization from pro-inflammatory phenotype to anti-inflammatory state has been suggested as a potential therapeutic approach in the treatment of ischemic stroke. Melatonin has been shown to be neuroprotective in experimental stroke models. However, the effect of melatonin on microglia polarization after stroke and underlying mechanisms remain unknown.METHODS: In vivo, cerebral ischemia was induced by distal middle cerebral artery occlusion (dMCAO) in C57BL/6J mice. Melatonin was injected intraperitoneally (20 mg/kg) at 0 and 24 hours after ischemia. In vitro, the microglial cell line BV2 was stimulated to the pro-inflammatory state with conditioned media (CM) collected from oxygen-glucose deprivation (OGD) challenged neuronal cell line Neuro-2a (N2a). Real-time PCR was utilized to detect the mRNA expression of microglia phenotype markers. Activation of signal transducer and activator of transcription 3 (STAT3) pathway was determined by Western blot of phosphorylated STAT3 (pSTAT3). A neuron-microglia co-culture system was used to determine whether melatonin can inhibit the neurotoxic effect of pro-inflammatory microglia to post-OGD neurons.RESULTS: Melatonin treatment reduced brain infarct and improved neurological functions 3 days after dMCAO, which was accompanied by decreased expression of pro-inflammatory markers and increased expression of anti-inflammatory markers in the ischemic brain. In vitro studies confirmed that melatonin directly inhibited the pro-inflammatory responses in BV2 cells upon exposure to OGD neuron CM. The microglia possessing pro-inflammatory phenotype exacerbated post-OGD N2a cells death, whereas melatonin reduced such neurotoxic effect. Further, melatonin enhanced the otherwise inhibited pSTAT3 expression in BV2 cells treated with OGD neuron CM. STAT3 blockade significantly reduced theeffect of melatonin on microglial phenotype shift.CONCLUSION: Melatonin treatment ameliorates brain damage at least partially through shifting microglia phenotype from pro-inflammatory to anti-inflammatory polarity in a STAT3-dependent manner.

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PMID: 

Cancer Cell Int. 2019 ;19:319. Epub 2019 Nov 29. PMID: 31798348

Abstract Title: 

Melatonin: an anti-tumor agent for osteosarcoma.

Abstract: 

Osteosarcoma is the most common bone tumors which consisted of malignant mesenchymal cells generating osteoid and immature bone. It has been showed that osteosarcoma is common in children and adolescents and shows high mortality rate. A variety of therapeutic approaches (i.e., resection surgery, combined with chemotherapy and radiotherapy) have been used as conventional treatments in patients with osteosarcoma. Despite several attempts to improve therapeutic response, the rate of survival for osteosarcoma has not changed during the past 3 decades. Therefore, the discovery and developing new effective therapeutic platforms are required. Along to the established anti-cancer agents, some physiological regulators such melatonin, have been emerged as new anti-cancer agents. Melatonin is an indolamine hormone which is secreted from the pineal glands during the night and acts as physiological regulator. Given that melatonin shows a wide spectrum anti-tumor impacts. Besides different biologic activities of melatonin (e.g., immunomodulation and antioxidant properties), melatonin has a crucial role in the formation of bones, and its deficiency could be directly related to bone cancers. Several in vitro and in vivo experiments evaluated the effects of melatonin on osteosarcoma and other types of bone cancer. Taken together, the results of these studies indicated that melatonin could be introduced as new therapeutic candidate or as adjuvant in combination with other anti-tumor agents in the treatment of osteosarcoma. Herein, we summarized the anti-tumor effects of melatonin for osteosarcoma cancer as well as its mechanism of action.

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PMID: 

Fundam Clin Pharmacol. 2019 Dec 6. Epub 2019 Dec 6. PMID: 31808968

Abstract Title: 

The effects of melatonin on signaling pathways and molecules involved in glioma.

Abstract: 

Glioblastoma is one of the most common brain tumors with high invasion and malignancy. Despite extensive research in this area and the use of new and advanced therapies, the survival rate in this disease is very low. In addition, resistance to treatment has also been observed in this disease. One of the reasons for rapid progression and failure in treatment for this disease is the presence of a class of cells with high proliferation and high differentiation, a class called glioblastoma stem-like cells (GSCs) shown as being the source of glioblastoma tumors. It has been reported that several oncogenes are expressed in this disease. One important issue in recognizing the pathogenesis of this disease, and which could improve the treatment process, is the identification of involved oncogenes as well as molecules that affect the reduction of the expression of these oncogenes. Melatonin regulates the biologic rhythm and inhibits the proliferation of malignant glioma cells due to antioxidant and anti-apoptotic effects. Melatonin has been considered in biological processes and in signaling pathways involved in the development of glioma. The aim of this review is to investigate the effects of melatonin on signaling pathways and molecules involved in the progression of glioma.

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PMID: 

Toxicol Mech Methods. 2019 Dec 11:1-9. Epub 2019 Dec 11. PMID: 31809235

Abstract Title: 

Melatonin protects bone against cadmium-induced toxicity via activation of Wnt/β-catenin signaling pathway.

Abstract: 

Among heavy metals, cadmium (Cd) is one of the most toxic for health due to it accumulation in several tissues including bone. Since melatonin (MLT) favors new bone formation through several pathways including Wnt/β-catenin, here we assessed whether MLT has a protective role against Cd induced toxicity in the rat bone tissue. Adult male Wistar rats receiving 50 mg CdCl/L and/or 3 mg/L MLT were used and were sacrificed 30 days after the treatment. Femurs and plasma were collected and analyzed by various biochemicals, molecular and histological investigation. The results showed that Cd exposure induced bone disorder characterized by histopathological alterations, a decreased alkaline phosphatase activity and plasmatic concentration of osteocalcin. Moreover, also the expression levels of some osteogenic-related genes (Runx2, Ocn and Alp) were down-regulated after Cd treatment. Since mechanistically Cd toxicity reduced the Kinase activity of GSK3β and protein levelsof Wnt3a and β-catenin, we observed that MLT administration significantly ameliorated the toxic effects induced by the metal. Our findings provide clues about a potential protective effect of MLT against Cd-induced bone metabolism destruction and that the protection was partially mediated via the Wnt/β-catenin signaling pathway.

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PMID: 

Aging (Albany NY). 2019 Dec 7 ;11. Epub 2019 Dec 7. PMID: 31811815

Abstract Title: 

Melatonin protects blood-brain barrier integrity and permeability by inhibiting matrix metalloproteinase-9 via the NOTCH3/NF-κB pathway.

Abstract: 

The pathophysiological mechanism of white matter hyperintensities of cerebral small vessel disease (CSVD) includes an impaired blood-brain barrier (BBB) with increased permeability. Neuroinflammation likely contributes to the disruption of the BBB in CSVD. Therefore, understanding the molecular mechanism of how neuroinflammation causes BBB damage is essential to preventing BBB disruption in CSVD. Matrix metalloproteinase 9 (MMP-9) contributes to BBB damage in neuroinflammatory diseases. In this study, we observed that interleukin-1β (IL-1β)-induced MMP-9 secretion in pericytes increased BBB permeability to sodium fluorescein (Na-F) by damaging the disruption of VE-cadherin, occludin, claudin-5, and zonula occludin-1 (ZO-1). Melatonin reduced BBB permeability to Na-F and inhibited the disruption of the adherens and tight junction proteins. Melatonin also downregulatedand upregulated tissue inhibitor of metalloproteinases 1 () gene expression, which decreased the MMP-9/TIMP-1 ratio. In addition, nuclear translocation of NF-κB/p65 induced by IL-1β in pericytes upregulated MMP-9 expression, which was inhibited by the NF-κB inhibitor PDTC. However, the NOTCH3 inhibitor DAPT significantly inhibited NF-κB/p65 translocation to the nucleus, while melatonin in combination with DAPT significantly prevented NF-κB/p65 translocation than DAPT alone. Our results suggest that melatonin reduced MMP-9-induced permeability of the BBB. Melatonin reduced MMP-9 expression and activity, which was induced by IL-1β through the regulation of the NOTCH3/NF-κB signaling pathway in pericytes, suggesting that pericytes regulate BBBintegrity and function.

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PMID: 

Biol Trace Elem Res. 2019 Dec 11. Epub 2019 Dec 11. PMID: 31828722

Abstract Title: 

Fluoride Compromises Testicular Redox Sensor, Gap Junction Protein, and Metabolic Status: Amelioration by Melatonin.

Abstract: 

The excess fluoride intake has been shown to adversely affect male reproductive health. The aim of the present study was to investigate the key mechanism underlying fluoride-induced testicular dysfunction and the role of melatonin as a modulator of testicular metabolic, oxidative, and inflammatory load. The present results indicated that sodium fluoride (NaF) exposure to adult male golden hamsters severely impairs reproductive physiology as evident from markedly reduced sperm count/viability, testosterone level, androgen receptor (AR), testicular glucose transporter (GLUT-1), gap junction (connexin-43), and survival (Bcl-2) protein expression. NaF exposure markedly increased testicular oxidative load, inflammatory (NF-kB/COX-2), and apoptotic (caspase-3) protein expression. However, melatonin treatment remarkably restored testicular function as evident by normal histoarchitecture, increased sperm count/viability, enhanced antioxidant enzyme activities (SOD and Catalase), and decreased lipid peroxidation (LPO) level. In addition, melatonin treatment upregulated testicular Nrf-2/HO-I, SIRT-1/ FOXO-1, and downregulated NF-kB/COX-2 expression. Further, melatonin ameliorated NaF-induced testicular metabolic stress by modulating testicular GLUT-1expression, glucose level, and LDH activity. Furthermore, melatonin treatment enhanced testicular PCNA, Bcl-2, connexin-43, and reduced caspase-3 expression. In conclusion, we propose the molecular mechanism of fluoride-induced testicular damages and ameliorative action(s) of melatonin.

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PMID: 

Int Immunopharmacol. 2019 Dec 10 ;78:106041. Epub 2019 Dec 10. PMID: 31835081

Abstract Title: 

Melatonin alleviates oxidative stress in sleep deprived mice: Involvement of small intestinal mucosa injury.

Abstract: 

BACKGROUND: Previous research demonstrated that sleep deprivation (SD) resulted in intestinal homeostasis disorder in colon. The present study was further performed to clarify the role of melatonin in SD-induced small intestinal (SI) mucosal injury.METHODS: We successfully established a multiplatform 72 h SD mouse model with or without melatonin supplementation to explore the improvement of melatonin in the destruction of SI induced by SD.RESULTS: Melatonin supplementation suppressed an increase of corticosterone level and a decrease of melatonin level caused by SD. Meanwhile, we observed that melatonin supplementation in sleep deprived mice markedly reversed a decrease of the villi length/crypt depth (V/C) ratio and the number of goblet cells, PCNA positive cells, the expressions of MUC2 and tight junction proteins, as well as an upregulation of the expressions of autophagic proteins in the duodenum, jejunum and ileum. Furthermore, melatonin supplementation inverted the SD-induced the decline of antioxidant enzyme activities (T-AOC and CAT etc) and anti-inflammatory cytokines (IL-10 and IFN-γ) and the increase of oxidative product MDA, pro-inflammatory cytokines (IL-6 and TNF-α), p-P65 and p-IκB proteins in the SI.CONCLUSIONS: These findings suggested that melatonin may be used as a probiotic agent to reverse SD-induced SI mucosa injury by suppressing oxidative stress and NF-κB pathway activation.

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PMID: 

Nutr Health. 2019 Nov 24:260106019887890. Epub 2019 Nov 24. PMID: 31760860

Abstract Title: 

Prevention of dental caries by grape seed extract supplementation: A systematic review.

Abstract: 

BACKGROUND: Dental caries are the most prominent chronic disease of children and adults worldwide, and facilitating evidence-based, preventative care for their prevention is critical. Caries are traditionally and successfully prevented by regular fluoride use, but there are opportunities to halt and restore caries with alternative agents in addition to fluoride use. Grape seed extract (GSE) is a readily available plant-based supplement that, due to its concentrated levels of proanthocyanidins, has promising characteristics that may assist in dental caries prevention.AIM: The goal of this review was to investigate whether current research supports use of grape seed extract to prevent dental caries formation.METHODS: A systematic review of articles related to grape seed extract, prevention of dental caries, inhibition of, and remineralization was conducted. Articles were first chosen by inclusion of dental models that used grape seed extract as an intervention, and then by strength of study design.RESULTS: Twenty articles were reviewed. Studies overall supported three unique grape seed extract properties facilitating dental caries prevention. In the first articles reviewed, grape seed extract inhibited proliferation of bacterial biofilms on tooth surfaces. In addition, studies reviewed indicated that grape seed extract promoted dental remineralization.CONCLUSIONS: Caries prevention by grape seed extract may be unique compared with fluoride, and is linked to grape seed extract's bacteriostatic and collagen crosslinking properties. Future research should investigate potential delivery methods, and benefits of combined grape seed extract use with known caries preventative agents, in human participants.

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