PMID: 

Ann Clin Lab Sci. 2020 Jan ;50(1):65-72. PMID: 32161013

Abstract Title: 

Melatonin Inhibits TE-1 Esophageal Cancer Cells Metastasis by Suppressing the NF-κB Signaling Pathway and Decreasing MMP-9.

Abstract: 

Melatonin is an amine hormone produced by mammals and the human pineal gland. Modern biomedical research has shown that melatonin has antitumor effects. However, the underlying mechanisms of these effects remain unclear. In this study, we explore the effect of melatonin on TE-1 esophageal cancer cells metastasis and study the roles of the NF-κB signaling pathway and MMP9 in this process. We found that melatonin significantly suppressed the migration and invasion of TE-1 esophageal cancer cells, inhibited the activation NF-κB signaling pathway, and decreased the expression of MMP9. When adding NF-κB inhibitor, the results show that the expression of MMP9 decreased while E-cadherin increased. Taken together, the results indicate that melatonin inhibits esophageal cancer cell metastasis by down-regulating the NF-κB signaling pathway and MMP9. Therefore, melatonin may be a new drug for the effective treatment of esophageal cancer.

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PMID: 

Pathol Res Pract. 2020 Mar 9:152919. Epub 2020 Mar 9. PMID: 32171553

Abstract Title: 

Targeting cancer stem cells by melatonin: Effective therapy for cancer treatment.

Abstract: 

Melatonin is a physiological hormone produced by the pineal gland. In recent decades, enormous investigations showed that melatonin can prompt apoptosis in cancer cells and inhibit tumor metastasis and angiogenesis in variety of malignancies such as ovarian, melanoma, colon, and breast cancer; therefore, its possible therapeutic usage in cancer treatment was confirmed. CSCs, which has received much attention from researchers in past decades, are major challenges in the treatment of cancer. Because CSCs are resistant to chemotherapeutic drugs and cause recurrence of cancer and also have the ability to be regenerated; they can cause serious problems in the treatment of various cancers. For these reasons, the researchers are trying to find a solution to destroy these cells within the tumor mass. In recent years, the effect of melatonin on CSCs has been investigated in some cancers. Given the importance of CSCs in the process of cancer treatment, this article reviewed the studies conducted on the effect of melatonin on CSCs as a solution to the problems caused by CSCs in the treatment of various cancers.

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PMID: 

J Med Signals Sens. 2019 Oct-Dec;9(4):267-273. Epub 2019 Oct 24. PMID: 31737556

Abstract Title: 

Bromelain Inhibitory Effect on Colony Formation: AnStudy on Human AGS, PC3, and MCF7 Cancer Cells.

Abstract: 

Bromelain is dotted with anticancer properties on various cancer cell lines. Anticancer pathways of bromelain, as well related intervening signalization are under investigation. Investigating the inhibitory potential of bromelain on AGS, PC3, and MCF7 cells proliferation and colony formation. The bromelain inhibitory potential on AGS, PC3, and MCF7 cells proliferation at various bromelain concentrations was assessed by MTT; thereby, bromelain potency on colony formation impediment was evaluated using clonogenic assays at determined 50% inhibitory concentrations (IC) on four different cell densities (10, 50, 100, and 200 cells per well). Bromelain inhibits AGS, PC3, and MCF7 cells proliferation in such a dose-dependent manner. Determined ICto AGS, PC3, and MCF7 cells were 65, 60 and 65μg/ml respectively. At IC, bromelain significantly suppressed the AGS, PC3, and MCF7 cells colony formation at four treated densities (10, 50, 100 and 200 cells per well). Plating efficiency percentage and cell surviving fraction were decreased after bromelain treatment to AGS, PC3, and MCF7 human cancer cells as a function of initial cell density. The 50, 50 or 100, and 10 or 50 cells per well were considered to be optimum number of initial cell density for AGS, PC3, and MCF7 cells. Cell proliferative and colony formation inhibition are two pathways tobromelain anticancer effects. The current study displayed a dose-dependent inhibitory effect of bromelain, as well impeding colony formation AGS, PC3, and MCF7 human cancer cells.

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PMID: 

Integr Cancer Ther. 2019 Jan-Dec;18:1534735419880258. PMID: 31752555

Abstract Title: 

Bromelain Enhances the Anti-tumor Effects of Cisplatin on 4T1 Breast Tumor Model In Vivo.

Abstract: 

This study aimed to evaluate the antitumor enhancing effect of bromelain consumption on 4T1-challenged mice treated with cisplatin.Mice challenged with 4T1 triple-negative breast cancer cells received water, bromelain, cisplatin, or bromelain + cisplatin treatment for 28 days. Tumor size was measured, and lung metastasis was evaluated by clonogenic assay. Expression of tumor inflammatory genes of the harvested tumor was quantified by polymerase chain reaction array and ELISA (enzyme-linked immunosorbent assay).: All treatments significantly reduced the size of tumor and lung metastasis, with combination treatment showing the best effect. Also, bromelain alone and combination treatment showed downregulation of the expression of tumor inflammatory genes (Gremlin [GREM1], interleukin 1β [IL-1β], interleukin-4 [IL-4], nuclear factor κB subunit 1 [NFκB1], and prostaglandin-endoperoxide synthase 2 [PTGS2]), tumor nitric oxide level, and serum IL-1β, and IL-4 levels. On the other hand, cisplatin treatment increased the expression of selected inflammatory markers.This study suggests that bromelain treatment could potentiate the antitumor effect of cisplatin on triple-negative breast cancer 4T1 cells through modulating the tumor environmental inflammation.

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PMID: 

Korean J Pain. 2020 Jan 1 ;33(1):13-22. PMID: 31888313

Abstract Title: 

Antinociceptive and neuroprotective effects of bromelain in chronic constriction injury-induced neuropathic pain in Wistar rats.

Abstract: 

Background: The continuous search for a novel neuropathic pain drug with few or no side effects has been a main focus of researchers for decades. This study investigated the antinociceptive and neuroprotective effects of bromelain in sciatic nerve ligation-induced neuropathic pain in Wistar rats.Methods: Forty-eight Wistar rats randomly divided into eight groups comprised of six animals each were used for this study. Peripheral neuropathy was inducedchronic constriction of the common sciatic nerve. Thermal hyperalgesic and mechanical allodynia were assessed using a hotplate and von Frey filaments, respectively. The functional recovery and structural architecture of the ligated sciatic nerve were evaluated using the sciatic functional index test and a histological examination of the transverse section of the sciatic nerve. The neuroprotective effects of bromelain were investigated in the proximal sciatic nerve tissue after 21 days of treatment.Results: Bromelain significantly (

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PMID: 

Int Immunopharmacol. 2020 Mar 12 ;83:106365. Epub 2020 Mar 12. PMID: 32172204

Abstract Title: 

Melatonin prevents endothelial dysfunction in SLE by activating the nuclear receptor retinoic acid-related orphan receptor-α.

Abstract: 

Atherosclerotic cardiovascular disease confers significant morbidity and mortality in patients with systemic lupus erythematosus (SLE). A substantial proportion of patients with SLE display accelerated endothelial dysfunction, which precedes cardiovascular disease. Melatonin and its nuclear receptor retinoid-related orphan receptor alpha (RORα) have been reported to have some protective effects on the development of atherosclerosis. However, the function of melatonin in SLE-induced endothelial dysfunction and the role that RORα plays are still unknown. In this study, we found that RORα protein expression was decreased in aortas of lupus-prone mice and in human umbilical vein endothelial cells (HUVECs) cultured with medium containing sera of patients with SLE. Melatonin-treated HUVECs showed a decrease of pro-inflammatory mRNAs [interleukin-1beta (IL-1β), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α)] under the stimulation of SLE medium. Melatonin increased nitric oxide and antioxidant mRNAs (SOD1, GPX1, and CAT) and downregulated reactive oxygen species (ROS) level in HUVECs, which may subsequently delay endothelial senescence and promote HUVEC proliferation and repair after injury. Melatonin inhibited SLE medium-induced RAW264.7 macrophage migration. HUVECs pretreated with melatonin expressed less adhesion-related proteins (ICAM-1 and VCAM-1); as a result, these cells adhered to fewer peripheral blood monocytes. In addition, we also showed that the protective effects of melatonin on endothelial cells were largely diminished when RORα was knockdown in HUVECs. In conclusion, by targeting the nuclear receptor RORα, melatonin preserves normal functions of endothelium in SLE by its anti-inflammatory, antioxidant, and anti-senescence effects. RORα may have the potential to become a prophylactic or therapeutic target in preventing endothelial dysfunction and atherosclerotic cardiovascular disease in patients with SLE.

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PMID: 

Sci Rep. 2020 Mar 16 ;10(1):4790. Epub 2020 Mar 16. PMID: 32179814

Abstract Title: 

Usefulness of melatonin as complementary to chemotherapeutic agents at different stages of the angiogenic process.

Abstract: 

Chemotherapeutics are sometimes administered with drugs, like antiangiogenic compounds, to increase their effectiveness. Melatonin exerts antitumoral actions through antiangiogenic actions. We studied if melatonin regulates the response of HUVECs to chemotherapeutics (docetaxel and vinorelbine). The inhibition that these agents exert on some of the processes involved in angiogenesis, such as, cell proliferation, migratory capacity or vessel formation, was enhanced by melatonin. Regarding to estrogen biosynthesis, melatonin impeded the negative effect of vinorelbine, by decreasing the activity and expression of aromatase and sulfatase. Docetaxel and vinorelbine increased the expression of VEGF-A, VEGF-B, VEGF-C, VEGFR-1, VEGFR-3, ANG1 and/or ANG-2 and melatonin inhibited these actions. Besides, melatonin prevented the positive actions that docetaxel exerts on the expression of other factors related to angiogenesis like JAG1, ANPEP, IGF-1, CXCL6, AKT1, ERK1, ERK2, MMP14 and NOS3 and neutralized the stimulating actions of vinorelbine on the expression of FIGF, FGFR3, CXCL6, CCL2, ERK1, ERK2, AKT1, NOS3 and MMP14. In CAM assay melatonin inhibited new vascularization in combination with chemotherapeutics. Melatonin further enhanced the chemotherapeutics-induced inhibition of p-AKT and p-ERK and neutralized the chemotherapeutics-caused stimulatory effect on HUVECs permeability by modifying the distribution of VE cadherin. Our results confirm that melatonin blocks proangiogenic and potentiates antiangiogenic effects induced by docetaxel and vinorelbine enhancing their antitumor effectiveness.

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PMID: 

J Clin Invest. 2020 Mar 17. Epub 2020 Mar 17. PMID: 32182222

Abstract Title: 

Melatonin inhibits cytosolic mitochondrial-DNA induced neuroinflammatory signaling in accelerated aging and neurodegeneration.

Abstract: 

Chronic inflammation is a pathologic feature of neurodegeneration and aging; however, the mechanism regulating this process is not understood. Melatonin, an endogenous free radical scavenger synthesized by neuronal mitochondria, decreases with aging and neurodegeneration. We proposed that insufficient melatonin levels impair mitochondrial homeostasis resulting in mitochondrial DNA (mtDNA) release, activation of cytosolic DNA mediated inflammatory response in neurons. We found increased mitochondrial oxidative stress and decreased mitochondrial membrane potential with higher mitochondrial DNA (mtDNA) release in brain and primary cerebro-cortical neurons of melatonin deficient aralkylamine N-acetyltransferase (AANAT) knockout mice. Cytosolic mtDNA activated the cGAS/STING/IRF3 pathway, stimulating inflammatory cytokine generation. We found that Huntington's disease mice increased mtDNA release, cGAS activation, and inflammation, all inhibited by exogenous melatonin. Thus, we demonstrated that cytosolic mtDNA activated the inflammatory response in aging and neurodegeneration, a process modulated by melatonin. Furthermore, our data suggest that AANAT knockout mice are a model of accelerated aging.

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PMID: 

Antioxidants (Basel). 2020 Mar 16 ;9(3). Epub 2020 Mar 16. PMID: 32187996

Abstract Title: 

Effects of Bisphenol A on Oxidative Stress in the Rat Brain.

Abstract: 

We investigated the effect of bisphenol A (BPA) on oxidative stress and tau-related proteins in adult rat brains. BPA (10 mg/L) was administered to rats for eight weeks through their drinking water. The reactive oxygen species (ROS) scavenging capacity for hydroxyl radicals in the plasma was reduced after two weeks. In the hippocampus, four and eight weeks of BPA increased the ratio of oxidized DJ-1/DJ-1 (PARK7). The ratio of phosphorylated-GSK3β/GSK3β and phosphorylated-AKT/AKT increased after one week of BPA treatment. The ratio of phosphorylated JNK/JNK and phosphorylated-ERK/ERK increased after eight weeks of BPA; the elevation could be related to tau phosphorylation. Protein phosphatase 2A (PP2A) in the hippocampus decreased after eight weeks of BPA treatment. At that time, SOD1 was significantly induced, but no changes in SOD2 expression were apparent in the hippocampus. Furthermore, the ratio of phosphorylated-tau (PHF-1, Ser396/ Ser404) to total tau level did not change. However, PHF-1 or other sites of tau could be phosphorylated after eight weeks in the hippocampi of rats. BPA induced systemic oxidative stress and could change ROS-induced signaling pathways in the brain. These results suggest that mitochondrial dysfunction possibly is not responsible for oxidative stress and neurodegeneration due to low doses of BPA.

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PMID: 

Mol Reprod Dev. 2020 Feb 28. Epub 2020 Feb 28. PMID: 32109339

Abstract Title: 

Neonatal exposure to bisphenol A advances pubertal development in female rats.

Abstract: 

Neonatal exposure to bisphenol A (BPA) is hypothesized to advance pubertal development. However, the effects of neonatal BPA exposure on pubertal development has not been described. In this study, female Sprague-Dawley rats were exposed to 0.05, 0.5, 5, or 10 mg·kg·dayBPA, or corn oil vehicle alone from postnatal day 1 (PND1) to PND10 via subcutaneous injection. We evaluated day of vaginal opening (DVO), ovarian morphology, serum hormone concentrations, and hypothalamic expression of Gnrh1 and Kiss1 in female rats at PND35. DVO was significantly advanced in rats exposed to 5 and 10 mg·kg·dayBPA. Serum hormone concentrations increased as BPA dose increased. Additionally, hypothalamic Gnrh1 and Kiss1 expression were increased with BPA exposure; rats exposed to 10 mg·kg·dayBPA had significantly upregulated hypothalamic Gnrh1 and Kiss1 expressions in terms of both messenger RNA and protein levels. Our results suggest that exposure to a 10 mg·kg·daydose of BPA might advance pubertal development significantly. In addition, within the range of 0 to 10 mg·kg·day, neonatal exposure to BPA may affect pubertal development in a dose-dependent manner.

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