Melatonin protects against cisplatin-induced ovarian damage in mice via the MT1 receptor and antioxidant activity†

Barberino, Ricássio de Sousa; Menezes, Vanúzia Gonçalves; Ribeiro, Anita Eugênia Alencar Santos; Palheta, Raimundo C.; Jiang, Xuejun; Smitz, Johan; Matos, Maria Helena Tavares de

doi:10.1093/biolre/iox053

Cited by 97 publications

(76 citation statements)

References 54 publications

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“…In mice, the melatonin treatment can protect ovary from cisplatin-induced damage depends on both its antioxidant capacity and MT1 receptor mediating signal pathway. 60 In current research, melatonin treatment improved the expression of MT1 receptor, AMPK and p-AMPK. This indicates that MT1 may mediate the protective effects of melatonin on female's fertility.…”

Section: Discussionmentioning

confidence: 76%

Melatonin regulates the activities of ovary and delays the fertility decline in female animals via MT1/AMPK pathway

Zhang

Wang

et al. 2019

Journal of Pineal Research

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Female fertility irreversibly declines with aging, and this is primarily associated with the decreased quality and quantity of oocytes. To evaluate whether a long‐term of melatonin treatment would improve the fertility of aged mice, different concentrations of melatonin (10−3, 10−5, 10−7 mol/L) were supplemented into drinking water. Melatonin treatments improved the litter sizes of mice at the age of 24 weeks. Mice treated with 10−5 mol/L melatonin had the largest litter size among other concentrations. At this optimal concentration, melatonin not only significantly increased the total number of oocytes but also their quality, having more oocytes with normal morphology that could generate more blastocyst after in vitro fertilization in melatonin (10−5 mol/L)‐treated group than that in the controls. When these blastocysts were transferred to recipients, the litter size was also significantly larger in melatonin treated mice than that in controls. The increases in TAOC and SOD level and decreases in MDA were detected in ovaries and uterus from melatonin‐treated mice compared to the controls. Melatonin reduced ROS level and maintained mitochondrial membrane potential in the oocytes cultured in vitro. Mechanistically studies revealed that the beneficial effects of melatonin on oocytes were mediated by MT1 receptor and AMPK pathway. Thereafter, MT1 knocking out (MT1‐KO) were generated and shown significantly reduced number of oocytes and litter size. The expression of SIRT1, C‐myc, and CHOP were downregulated in the ovary of MT1‐KO mice, but SIRT1 and p‐NF‐kB protein level were elevated in response to disturbed redox balance. The results have convincingly proven that melatonin administration delays ovary aging and improves fertility in mice via MT1/AMPK pathway.

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Section: Discussionmentioning

confidence: 76%

Melatonin regulates the activities of ovary and delays the fertility decline in female animals via MT1/AMPK pathway

Zhang

Wang

et al. 2019

Journal of Pineal Research

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“…Terminal deoxynucleotidyl transferase (TdT)‐mediated dUTP nick‐end labeling (TUNEL) and PCNA analyses were performed in the fresh control and in treatments that showed the best results for normal follicles as previously described (Barberino et al, ).…”

Section: Methodsmentioning

confidence: 99%

“…Evaluation of PCNA was performed according to Barberino et al (2017). The sections were mounted in Starfrost slides (Knittel) and incubated in citrate buffer (Dinâmica) at 95°C in a deckloaking chamber (Biocare) for 40 min.…”

Section: Pcna Immunohistochemistrymentioning

confidence: 99%

Resveratrol promotes in vitro activation of ovine primordial follicles by reducing DNA damage and enhancing granulosa cell proliferation via phosphatidylinositol 3‐kinase pathway

Bezerra

Gouveia

Barberino

et al. 2018

Reprod Domestic Animals

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We aimed to study the effects of resveratrol on the morphology, DNA fragmentation, follicular activation and cell proliferation after in vitro culture of ovine ovarian tissue, and to verify if PI3K pathway is involved in resveratrol action in the sheep ovary. Ovaries were collected and divided into fragments. One fragment was fixed for histology (fresh control). The remaining fragments were cultured for 7 days in control medium (α-MEM ) alone or with resveratrol (2, 10 or 30 µM). After culture, ovarian tissue was destined to morphological analysis. TUNEL and proliferating cell nuclear antigen (PCNA) analyses were performed in the fresh control, α-MEM and 2 µM resveratrol. Inhibition of PI3K activity was performed through pre-treatment with LY294002. The percentage of normal follicles was similar between α-MEM and 2 µM resveratrol, and higher than those in other resveratrol treatments. An increase in follicular activation was observed in all treatments compared to fresh control. DNA fragmentation decreased in tissues cultured in 2 µM resveratrol compared to α-MEM . Moreover, PCNA-positive cells were higher in 2 µM resveratrol than in α-MEM . LY294002 inhibited follicular activation stimulated by α-MEM and 2 µM resveratrol. In conclusion, 2 µM resveratrol promotes primordial follicle activation compared to the fresh control by reducing DNA fragmentation and stimulating granulosa cell proliferation through activation of the PI3K pathway.

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“…In general, melatonin is considered a classic antioxidant molecule. Most studies on the new medicinal uses and mechanisms of melatonin have found that melatonin can play an antioxidant role through the following two pathways: receptor-dependent signal transduction pathway to activate the antioxidant system [30,31]; Or nonreceptordependent mechanism as the antioxidant substrates directly neutralize oxidants [32].…”

Section: Discussionmentioning

confidence: 99%

Neu-p11 induces NLRP3 inflammasome-induced pyroptosis via provoking NOX4-mediated mitochondrial oxidative injury in chordoma cells

Zhang

2020

Preprint

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Chordoma is a rarely malignant bone tumor with highly resistance to radiotherapy and chemotherapy. Melatonin has been shown to inhibit tumor cell invasion, metastasis and induce apoptosis in several types of cancer. Activation of melatonin receptor inhibit cancer stemness of chordoma, which suggesting that melatonin receptor agonists have potential therapeutic value for the clinical treatment of chordoma. The present study aimed to investigate the anticancer action and molecular mechanism of Piromelatine (Neu-P11) in chordoma cells, a high-efficacy agonist of melatonin receptor-1/melatonin receptor-2 (MT1/MT2). We used Neu-p11 (1, 10, 100, 1000 μM) or vehicle to treat chordoma cell lines U-CH1 and MUG-Chor for 36 hours. CCK-8 assay and LDH activity assay showed that Neu-p11 had dose-dependent cytotoxic effect on chordoma cells. Neu-p11 induced NLRP3 and Cleaved-Caspase-1 expression, while Caspase-1 specific inhibitor Z-YVAD-FMK and NLRP3 specific inhibitor MCC950 independently blocked the cytotoxic effect of Neu-p11 on chordoma cells, indicating that Neu-p11 induced a NLRP3-dependent cell pyroptosis. Neu-p11 promoted NADPH oxidase 4 (NOX4) translocation to mitochondria, resulting in a significant increase in mitochondria-derived ROS and decreased expressions of mitochondrial antioxidant proteins (MnSOD, Sirt3) and mitochondrial DNA replication factor (Tfam), which could be attenuated by NOX4 specific inhibitor GKT137831. Further investigation revealed that Neu-p11 resulted in decreased copy number of mtDNA and increased mtDNA releasing in cytoplasm. Decreased oxygen consumption, reduced membrane potential and ultrastructural damage of mitochondrial were detected in Neu-p11 treated chordoma cells, which could be attenuated by GKT137831. GKT137831 inhibited mitochondria-translocation of NLRP3 and attenuated activation of NLRP3 inflammasome caused by Neu-p11 treatment. Collectively, we demonstrated that Neu-p11 induces mitochondrial translocation of NOX4 leads to oxidative damage of mitochondria, mediating chordoma cells NLRP3-dependent pyroptosis. Neu-p11 may be a a new strategy for chordoma treatment. Graphic abstractAbbreviations Neu-p11, Piromelatine; NOX4, NADPH oxidase 4; NLRP3, NLR Family Pyrin Domain Containing 3; MnSOD, Manganese superoxide dismutase; Sirt3, NADdependent deacetylase sirtuin-3; Tfam, mitochondrial transcription factor A; mtROS, mitochondria-derived reactive oxygen species; mitochondrial membrane potential (MMP, ΔΨm); mtDNA, mitochondrial DNA.

show abstract

Melatonin protects against cisplatin-induced ovarian damage in mice via the MT1 receptor and antioxidant activity†

Cited by 97 publications

References 54 publications

Melatonin regulates the activities of ovary and delays the fertility decline in female animals via MT1/AMPK pathway

Melatonin regulates the activities of ovary and delays the fertility decline in female animals via MT1/AMPK pathway

Resveratrol promotes in vitro activation of ovine primordial follicles by reducing DNA damage and enhancing granulosa cell proliferation via phosphatidylinositol 3‐kinase pathway

Neu-p11 induces NLRP3 inflammasome-induced pyroptosis via provoking NOX4-mediated mitochondrial oxidative injury in chordoma cells

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