L. B. Gaiotte, R. C. Cesário, H. S. Silveira, Diego Augusto de Morais Oliveira, M. Cucielo, G. Romagnoli, R. Kaneno, D. A. P. de Campos Zuccari, R. Reiter, L. Chuffa
{"title":"Combination of melatonin with paclitaxel reduces the TLR4-mediated inflammatory pathway, PD-L1 levels, and survival of ovarian carcinoma cells","authors":"L. B. Gaiotte, R. C. Cesário, H. S. Silveira, Diego Augusto de Morais Oliveira, M. Cucielo, G. Romagnoli, R. Kaneno, D. A. P. de Campos Zuccari, R. Reiter, L. Chuffa","doi":"10.32794/mr112500118","DOIUrl":"https://doi.org/10.32794/mr112500118","url":null,"abstract":"Ovarian cancer (OC) has a high mortality rate. Although most patients respond to the conventional chemotherapy [e.g., paclitaxel (PTX)], some also develop drug resistance to make the treatment less effective. Since melatonin exhibits antioxidant, antitumor, and immunomodulatory functions in a variety of solid tumors, in this study the effects of a combination of PTX and melatonin on SKOV-3 human ovarian carcinoma cells were investigated and the focus was given to the Toll-like receptor (TLR)-mediated inflammatory pathway and cell signaling-related molecules. Flow cytometry showed that this combination significantly boosted the apoptosis/necrosis responses of the cancer cells. Cell migration was attenuated by melatonin alone, and the combination led to a reduced number of migrating and invasive cells. Melatonin alone and its combination also reduced the levels of TLR4, MyD88, TRIF, and PD-L1, but not TLR2. In addition, the combination significantly lowered the levels of NF-kB p65, PI3K, p-AKT, p38, ERK 1/2, JNK, CREB, p70s6K, and STAT5. The results suggested that this combination was effective in reducing the viability and the invasive capacity of SKOV-3 cells while increasing their apoptosis and necrosis rates. The potential mechanism of this combination is to attenuate the downstream molecules of the TLR4-mediated inflammatory pathway and cell signaling-related proteins in the cancer cells. Thus, melatonin improved the chemosensitivity of the cancer cells to PTX, serving as an effective adjuvant therapy against OC.","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73765212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Ko, Tien-hung Huang, Yuan-Ping Lin, Yi-ling Chen, H. Yip
{"title":"Accuracy and precision of 31P-MRS assessment for evaluating the effect of melatonin-pretreated mitochondria transferring on liver fibrosis of rats","authors":"S. Ko, Tien-hung Huang, Yuan-Ping Lin, Yi-ling Chen, H. Yip","doi":"10.32794/mr112500117","DOIUrl":"https://doi.org/10.32794/mr112500117","url":null,"abstract":"This study examined the reliability of 31phosphorus-magnetic resonance spectroscopy (31P-MRS) to measure parameters of liver metabolic function in the intact animals. These parameters can help us to evaluate the severity and prognosis of liver fibrosis. In addition, 31P-MRS was also used to examine the protective effects of melatonin on liver mitochondria. An animal model of liver fibrosis was established via intraperitoneal administration of thioacetamide (TAA) to rats. Rats were scanned at baseline, week 3 and 6 after TAA treatment, respectively, to measure the longitudinal changes of phosphorus metabolite levels by 31P-MRS at 9.4 T. The results showed a consistent decline in the levels of phosphorus metabolites (inorganic phosphate, α-ATP, γ-ATP and NADH) in rats with fibrosis. Impaired mitochondrial respiration capacity, collagen accumulation and the extent of fibrosis in liver were markedly associated with decreased concentrations of phosphorus metabolites. Melatonin-pretreated mitochondria transferring efficiently prevented TAA-induced liver damage mainly by restoring mitochondrial function. In conclusion, the levels of phosphorus metabolites could serve as the indicators of mitochondrial oxidative capacity and thus provides a novel tool to evaluate mitochondrial integrity in the in vivo condition by using 31P-MRS in the setting of liver fibrosis.","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"135-136 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86300701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Junko Igarashi-Migitaka, Yusuke Maruyama, A. Seki, J. Hirayama, A. Kamijo-Ikemori, K. Hirata, Ryoya Kawamura, H. Matsubara, A. Srivastav, Y. Tabuchi, H. Mishima, A. Hattori, N. Suzuki
{"title":"Oral administration of melatonin increases plasma calcium and magnesium and improves bone metabolism in aged male mice","authors":"Junko Igarashi-Migitaka, Yusuke Maruyama, A. Seki, J. Hirayama, A. Kamijo-Ikemori, K. Hirata, Ryoya Kawamura, H. Matsubara, A. Srivastav, Y. Tabuchi, H. Mishima, A. Hattori, N. Suzuki","doi":"10.32794/mr112500113","DOIUrl":"https://doi.org/10.32794/mr112500113","url":null,"abstract":"We previously reported that the oral administration of melatonin from 4 to 20 months to male mice improved femoral bone strength and bone density during the aging. Additionally, melatonin receptor, MT2, was immunologically detected in both osteoblasts and osteoclasts of the mouse femoral bone. Thus, melatonin can act on both osteoblasts and osteoclasts to maintain bone strength during the aging process. Here, we analyzed plasma calcium (Ca2+), magnesium (Mg2+), and inorganic phosphorus ([PO4]3-) in 20-month-old male mice with or without administration melatonin (15-20 mg/kg/day) in drinking water. We found that plasma Ca2+ and Mg2+ levels in melatonin-treated mice increased significantly as compared with control mice. In [PO4]3-, melatonin administration tended to increase its plasma level, but did not reach statistical significance. The potential association between these divalent ions and metabolism markers of femoral bone was also examined. In the femoral diaphysis, the plasma Ca2+ and Mg2+ concentrations were positively correlated with periosteal and endosteal circumference which were significantly associated with the Strength Strain Index. Therefore, melatonin treatment enlarged femoral diaphysis and enhanced bone strength by increasing mineral depositions. In addition, the plasma melatonin levels were significantly positive correlation with total bone density and critical thickness in the femoral diaphysis. Since we had not observed the primary trabecular bone and osteoclasts in 20-month-old mice previously, it is suggested that plasma Ca2+ and Mg2+ are not elevated due to bone resorption. The increased plasma Ca2+ and Mg2+ by melatonin may originate from the intestinal absorption of these ions since melatonin binds to the vitamin D3 receptor, its activation is known to promote the intestinal absorption of Ca2+. ","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74321032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ryan Bitar, Jorge L Torres-Garza, R. Reiter, W. Phillips
{"title":"Neural glymphatic system: Clinical implications and potential importance of melatonin","authors":"Ryan Bitar, Jorge L Torres-Garza, R. Reiter, W. Phillips","doi":"10.32794/mr112500111","DOIUrl":"https://doi.org/10.32794/mr112500111","url":null,"abstract":"The central nervous system was thought to lack a lymphatic drainage until the recent discovery of the neural glymphatic system. This highly specialized waste disposal network includes classical lymphatic vessels in the dura that absorb fluid and metabolic by-products and debris from the underlying cerebrospinal fluid (CSF) in the subarachnoid space. The subarachnoid space is continuous with the Virchow-Robin peri-arterial and peri-vascular spaces which surround the arteries and veins that penetrate into the neural tissue, respectively. The dural lymphatic vessels exit the cranial vault via an anterior and a posterior route and eventually drain into the deep cervical lymph nodes. Aided by the presence of aquaporin 4 on the perivascular endfeet of astrocytes, nutrients and other molecules enter the brain from peri-arterial spaces and form interstitial fluid (ISF) that baths neurons and glia before being released into peri-venous spaces. Melatonin, a pineal-derived secretory product which is in much higher concentration in the CSF than in the blood, is believed to follow this route and to clear waste products such as amyloid-β from the interstitial space. The clearance of amyloid-β reportedly occurs especially during slow wave sleep which happens concurrently with highest CSF levels of melatonin. Experimentally, exogenously-administered melatonin defers amyloid-β buildup in the brain of animals and causes its accumulation in the cervical lymph nodes. Clinically, with increased age CSF melatonin levels decrease markedly, co-incident with neurodegeneration and dementia. Collectively, these findings suggest a potential association between the loss of melatonin, decreased glymphatic drainage and neurocognitive decline in the elderly.","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77928163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Strategies to generate melatonin-enriched transgenic rice to respond to the adverse effects on rice production potentially caused by global warming","authors":"K. Back, D. Tan, R. Reiter","doi":"10.32794/mr112500108","DOIUrl":"https://doi.org/10.32794/mr112500108","url":null,"abstract":"Global warming is predicted to reduce the yield of rice, which feeds more than half of the world’s population. A rise in temperature will inevitably hamper rice production by causing drought and flooding. Melatonin has the capacity to ameliorate such adverse effects. Here, we propose multiple genetic means of producing melatonin-enriched, high-yield rice variants to adapt upcoming global warming. ","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"340 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86792640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Melatonin, tunneling nanotubes and anastasis: Cheating cell death","authors":"R. Reiter, Ramaswamy Sharma, S. Rosales‐Corral","doi":"10.32794/mr112500112","DOIUrl":"https://doi.org/10.32794/mr112500112","url":null,"abstract":"When healthy neurons are exposed to toxins or physiological insults such as ischemia, apoptosis is often initiated. Once underway, this mechanistically-well described process was thought to routinely run its course with the disintegration of the cell and phagocytosis of the debris. Within the last decade, the consistency of this process has been questioned. It is now known that some damaged cells can recover, i.e., they avoid death; this restoration process is referred to as anastasis. The reestablishment of a healthy cell phenotype is highly energy-requiring, so optimally functioning mitochondria are obviously beneficial during the regenerative process. Some healthy mitochondria that end up in regenerating cells are transferred there by adjacent healthier cells through tunneling nanotubes. Tunneling nanotubes generally form under stressful conditions when these micron-size tubules link adjacent cells. These tubules transfer soluble factors and organelles, including mitochondria, between the connected cells. When damaged cells receive high APT-producing mitochondria via this means, they support the ability of the cells to recover. Two recent comprehensive publications show that melatonin aids the transfer of mitochondria through nanotubes that connect neurons thereby likely assisting the recovery of the damaged recipient cell. Thus, melatonin not only protects normal neurons from damage by neutralizing the agents that initiate apoptosis, e.g., free radicals, etc., but also reverses this process once it is underway. ","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"120 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73133494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Functional characterization of tobacco (Nicotiana benthamiana) serotonin N-acetyltransferases (NbSNAT1 and NbSNAT2)","authors":"K. Back, Lee Hyoung Yool, Hwang Ok Jin","doi":"10.32794/mr112500109","DOIUrl":"https://doi.org/10.32794/mr112500109","url":null,"abstract":"Nicotiana benthamiana (tobacco) is an important dicotyledonous model plant; however, no serotonin N-acetyltransferases (SNATs) have been characterized in tobacco. In this study, we identified, cloned, and characterized the enzyme kinetics of two SNAT genes from N. benthamiana, NbSNAT1 and NbSNAT2. The substrate affinity (Km) and maximum reaction rate (Vmax) for NbSNAT1 were 579 µM and 136 pkat/mg protein for serotonin, and 945 µM and 298 pkat/mg protein for 5-methoxytryptamine, respectively. Similarly, the Km and Vmax values for NbSNAT2 were 326 µM and 26 pkat/mg protein for serotonin, and 872 µM and 92 pkat/mg protein for 5-methoxytryptamine, respectively. Moreover, we found that NbSNAT1 and NbSNAT2 localized to chloroplasts, similar to SNAT proteins from other plant species. The activities of the NbSNAT proteins were not affected by melatonin feedback inhibition in vitro. Finally, transgenic tobacco plants overexpressing either NbSNAT1 or NbSNAT2 did not exhibit increased melatonin levels, possibly due to the expression of catabolic enzymes. Generating transgenic tobacco plants with downregulated NbSNAT expression would provide further insight into the functional role of melatonin in tobacco plants. ","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72903493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Melatonin reduces the mortality of severely-infected COVID-19 patients","authors":"D. Tan, R. Reiter","doi":"10.32794/mr112500115","DOIUrl":"https://doi.org/10.32794/mr112500115","url":null,"abstract":"SARS-CoV-2 has ravaged the population of the world for two years. Scientists have not yet identified an effective therapy to reduce the mortality of severe COVID-19 patients. In a single-center, open-label, randomized clinical trial, it was observed that melatonin treatment lowered the mortality rate by 93% in severely-infected COVID-19 patients compared with the control group (see below). This is seemingly the first report to show such a huge mortality reduction in severe COVID-19 infected individuals with a simple treatment. If this observation is confirmed by more rigorous clinical trials, melatonin could become an important weapon to combat this pandemic.","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77281740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tahsine Kosksi, Arem Selmi, S. Mani, Mriem Ben Rhouma, Sana Boughammoura, Latifa Knani, Kaouthar Kessabi, I. Messaoudi
{"title":"Antinociceptive effect of melatonin in the animal model of Parkinson’s Disease","authors":"Tahsine Kosksi, Arem Selmi, S. Mani, Mriem Ben Rhouma, Sana Boughammoura, Latifa Knani, Kaouthar Kessabi, I. Messaoudi","doi":"10.32794/mr112500104","DOIUrl":"https://doi.org/10.32794/mr112500104","url":null,"abstract":"Several animal experimental and clinical studies have shown the effectiveness of melatonin in the treatment of some symptoms of Parkinson's disease (PD). However, the antinociceptive effect of melatonin against pain associated to PD has not been fully investigated. Thus, the present study investigated the possible antiallodynic and antinociceptive effects of acute and chronic melatonin treatments in Parkinsonian model of rats. This model was created by unilateral injection of 6-hydroxydopamine (6-OHDA) into the left medial forebrain bundle (MFB). The electronic von Frey test was used to analyze the antiallodynic effect of melatonin on this PD animal model. In addition, c-Fos immunostaining was also used as a marker of nociception to evaluate the neuronal activity related to the nociception processing. The results showed that unilateral injection of 6-OHDA induced a significant decrease in paw withdrawal threshold in both ipsilateral and contralateral paws, which indicate mechanical allodynia induction. This allodynia was transitorily reversed by apomorphine as a dopamine agonist. Melatonin treatment significantly increased threshold of allodynia. Melatonin administration of both acutely or chronically significantly downregulated the c-Fos expression of neurons in 6-OHDA treated animals. In conclusion, 6-OHDA treatment can induces a bilateral mechanical hypernociception in rats while melatonin treatment produces profound antinociceptive effect. This finding paves the way to use melatonin as an antinociceptive agent for PD clinically.","PeriodicalId":18604,"journal":{"name":"Melatonin Research","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79056094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}