-
Cell Chemical Biology Aug 2023The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly recognized. Recently, the presence of G protein-coupled...
The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly recognized. Recently, the presence of G protein-coupled melatonin MT receptors in mitochondria has been revealed, in addition to the plasma membrane. Melatonin is highly cell permeant, activating plasma membrane and mitochondrial receptors equally. Here, we present MCS-1145, a melatonin derivative bearing a triphenylphosphonium cation for specific mitochondrial targeting and a photocleavable o-nitrobenzyl group releasing melatonin upon illumination. MCS-1145 displayed low affinity for MT and MT but spontaneously accumulated in mitochondria, where it was resistant to washout. Uncaged MCS-1145 and exogenous melatonin recruited β-arrestin 2 to MT in mitochondria and inhibited oxygen consumption in mitochondria isolated from HEK293 cells only when expressing MT and from mouse cerebellum of WT mice but not from MT-knockout mice. Overall, we developed the first mitochondria-targeted photoactivatable melatonin ligand and demonstrate that melatonin inhibits mitochondrial respiration through mitochondrial MT receptors.
Topics: Animals; Humans; Mice; Receptor, Melatonin, MT1; Melatonin; HEK293 Cells; Receptors, G-Protein-Coupled; Mitochondria; Respiration
PubMed: 37572668
DOI: 10.1016/j.chembiol.2023.07.009 -
Ecotoxicology and Environmental Safety Dec 2023Fine particulate matter (PM2.5) is a source of pollution worldwide, that causes inflammation and liver fibrosis. Melatonin, as the predominant hormone secreted by the...
OBJECTIVE
Fine particulate matter (PM2.5) is a source of pollution worldwide, that causes inflammation and liver fibrosis. Melatonin, as the predominant hormone secreted by the pineal gland, can inhibit PM2.5-induced lung injury by activating nuclear factor erythroid 2-related factor 2 (Nrf2) to inhibit ferroptosis. However, the possible role of melatonin in PM2.5-induced liver damage remains unclear.
EXPERIMENTAL APPROACH
In vitro, the effects of melatonin on PM2.5-induced oxidative stress and LX-2 cell activation were examined. In vivo, a PM2.5-induced inflammation and liver fibrosis mouse model was used to evaluate the hepatoprotective effect of melatonin.
RESULTS
In vitro, melatonin induced the expression of Nrf2 and its downstream genes and inhibited PM2.5-induced reactive oxygen species (ROS) production and mitochondrial damage. Melatonin also ameliorated the PM2.5-induced oxidative stress and fibrogenic marker upregulation. However, the antifibrotic effect of melatonin was abolished in siNrf2-treated LX-2 cells. In vivo, we observed mitochondrial abnormalities and mitochondrial fragmentation, which were accompanied by increased PTEN-induced kinase 1 (PINK1) and Parkin expression, in PM2.5-treated mouse hepatocytes. These changes were partially reversed by melatonin. In addition, melatonin activated the Nrf2 signaling pathway and protected against PM2.5-induced oxidative stress. Furthermore, melatonin alleviated inflammation and liver fibrosis. Moreover, Nrf2-KO mice exhibited more severe inflammation and liver fibrosis after PM2.5 exposure than wild-type mice, and the protective effect of melatonin on PM2.5- treated Nrf2-KO mice was greatly compromised.
CONCLUSION
These data suggest that melatonin effectively inhibits PM2.5-induced liver fibrosis by activating Nrf2 and inhibiting ROS-mediated mitophagy and inflammation.
Topics: Animals; Mice; Inflammation; Liver Cirrhosis; Melatonin; Mitophagy; NF-E2-Related Factor 2; Particulate Matter; Reactive Oxygen Species
PubMed: 37992643
DOI: 10.1016/j.ecoenv.2023.115717 -
Reproductive Biomedicine Online Mar 2024Many women undergoing IVF take supplements during treatment. The purpose of this review was to systematically review these nutritional supplements. The therapies studied... (Review)
Review
Many women undergoing IVF take supplements during treatment. The purpose of this review was to systematically review these nutritional supplements. The therapies studied are dehydroepiandrosterone (DHEA), melatonin, co-enzyme Q10 (CoQ1O), carnitine, selenium, vitamin D, myo-inositol, omega-3, Chinese herbs and dietary interventions. A literature search up to May 2023 was undertaken. The data suggest that a simple nutritional approach would be to adopt a Mediterranean diet. With regards to supplements to treat a potential poor ovarian response to ovarian stimulation, starting DHEA and COQ-10 before cycle commencement is better than control therapies. Furthermore, medication with CoQ10 may have some merit, although it is unclear whether its place is for older women, for those with a poor response to ovarian stimulation or for poor embryonic development. There appears a benefit for some IVF outcomes for the use of melatonin, although it is unclear what group of patients would derive the benefit and the appropriate dosing regimen. For women with polycystic ovary syndrome, there may be a benefit to the use of myo-inositol, although again the dosing regimen is unclear. Furthermore, the place of vitamin D supplementation has yet to be clarified, and supplementation with omega-3 free fatty acids may lead to improvements in clinical and embryological IVF outcomes.
Topics: Pregnancy; Humans; Female; Aged; Melatonin; Fertilization in Vitro; Dietary Supplements; Inositol; Vitamin D; Dehydroepiandrosterone; Ovulation Induction
PubMed: 38184959
DOI: 10.1016/j.rbmo.2023.103770 -
Journal of Clinical Psychopharmacology
Topics: Humans; Melatonin; Pyrimidines; Acrylamides; Aniline Compounds
PubMed: 38011040
DOI: 10.1097/JCP.0000000000001775 -
Biomolecules Dec 2023Sarcopenia is an age-related condition that involves a progressive decline in muscle mass and function, leading to increased risk of falls, frailty, and mortality.... (Review)
Review
Sarcopenia is an age-related condition that involves a progressive decline in muscle mass and function, leading to increased risk of falls, frailty, and mortality. Although the exact mechanisms are not fully understood, aging-related processes like inflammation, oxidative stress, reduced mitochondrial capacity, and cell apoptosis contribute to this decline. Disruption of the circadian system with age may initiate these pathways in skeletal muscle, preceding the onset of sarcopenia. At present, there is no pharmacological treatment for sarcopenia, only resistance exercise and proper nutrition may delay its onset. Melatonin, derived from tryptophan, emerges as an exceptional candidate for treating sarcopenia due to its chronobiotic, antioxidant, and anti-inflammatory properties. Its impact on mitochondria and organelle, where it is synthesized and crucial in aging skeletal muscle, further highlights its potential. In this review, we discuss the influence of clock genes in muscular aging, with special reference to peripheral clock genes in the skeletal muscle, as well as their relationship with melatonin, which is proposed as a potential therapy against sarcopenia.
Topics: Humans; Sarcopenia; Melatonin; Aging; Muscle, Skeletal; Oxidative Stress
PubMed: 38136651
DOI: 10.3390/biom13121779 -
Investigative Ophthalmology & Visual... Aug 2023This study aimed to investigate the age-dependent anti-angiogenic capability of melatonin in choroidal neovascularization (CNV) and to explore the underlying molecular...
PURPOSE
This study aimed to investigate the age-dependent anti-angiogenic capability of melatonin in choroidal neovascularization (CNV) and to explore the underlying molecular mechanisms.
METHODS
In the present study, a laser-induced CNV model was established in both young (three months of age) and old (18 months of age) mice, and the size of CNV lesions and vascular leakage was detected by morphological and imaging examination. Next, Western blot and immunostaining were used to observe the levels of M2 markers, senescence-related markers, and molecules involved in IL-10/STAT3 pathway. Additionally, colivelin was used to study the effect of IL-10/STAT3 pathway activation on the expression of M2 markers and senescence-related markers by Western blot and immunostaining. Finally, the effects of colivelin on melatonin-induced reduction of CNV size and vascular leakage in mice at different ages were assessed using morphological and imaging examination.
RESULTS
Our results revealed that aging promoted M2 macrophage/microglia polarization, and aggravated CNV and vascular leakage. Melatonin significantly inhibited the M2 polarization of senescent macrophage/microglia and reduced the CNV area and vascular leakage. Moreover, melatonin markedly suppressed IL-10/STAT3 pathway activation in the macrophage/microglia of old mice, and STAT3 activator colivelin reversed the suppressive effect of melatonin on M2 polarization of senescent macrophage/microglia and laser-induced CNV in old mice.
CONCLUSIONS
Our data demonstrated that melatonin significantly prevented the M2 polarization of senescent macrophage/microglia by inhibiting the IL-10/STAT3 pathway, and eventually attenuated senescence-associated CNV. These findings suggested that melatonin could serve as a promising therapeutic agent to treat CNV and other age-related ocular diseases.
Topics: Mice; Animals; Microglia; Melatonin; Interleukin-10; Choroidal Neovascularization; Macrophages; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37578424
DOI: 10.1167/iovs.64.11.19 -
Current Molecular Medicine 2024Melatonin is a neuroendocrine hormone secreted by the pineal gland. The secretion of melatonin follows a circadian rhythm controlled by the suprachiasmatic nucleus, and... (Review)
Review
Melatonin is a neuroendocrine hormone secreted by the pineal gland. The secretion of melatonin follows a circadian rhythm controlled by the suprachiasmatic nucleus, and its secretion is synchronized with the changes in light and dark periods in nature, with the highest secretion level at night. Melatonin is a critical hormone that coordinates external light stimulation and cellular responses of the body. It transmits information about the environmental light cycle, including the circadian and seasonal rhythms, to the relevant tissues and organs in the body, which, along with changes in its secretion level, ensures that its regulated functional activities are adapted in response to changes in the outside environment. Melatonin takes beneficial actions mainly through the interaction with specific membrane-bound receptors, termed MT and MT. Melatonin also acts as a scavenger of free radicals non-receptor-mediated mechanism. For more than half of acentury melatonin has been associated with vertebrate reproduction, especially in the context of seasonal breeding. Though modern humans show little remaining reproductive seasonality, the relationships between melatonin and human reproduction continue to attract extensive attention. Melatonin plays important roles in improving mitochondrial function, reducing the damage of free radicals, inducing oocyte maturation, increasing fertilization rate and promoting embryonic development, which improves the outcomes of in vitro fertilization and embryo transfer. The present article reviews the progress that has been made in our evolving understanding of the physiological role of melatonin in reproduction and its potential clinical applications in reproductive medicine.
Topics: Melatonin; Humans; Reproduction; Animals; Circadian Rhythm; Seasons
PubMed: 37070447
DOI: 10.2174/1566524023666230417103201 -
Journal of Reproductive Immunology Dec 2023Sleep deprivation is a common problem during pregnancy, but its impact on the fetus remains unclear. We aimed to investigate the effect of sleep deprivation during...
Sleep deprivation is a common problem during pregnancy, but its impact on the fetus remains unclear. We aimed to investigate the effect of sleep deprivation during pregnancy on fetal outcomes and its mechanism in Sprague-Dawley rats. Sleep deprivation was performed from gestational day(GD) 1-19 using a multiplatform method for 18 h/day. Rats were sacrificed on GD20, and their blood and placentas were collected. Fetal and placental parameters were ascertained. Melatonin, adrenocorticotropic hormone (ACTH) and corticosterone were also measured in serum. The levels of arylalkylamine N-acetyltransferase (AANAT) and two melatonin receptors MT1 and MT2, in placental tissues were detected by western blotting. The inflammatory status and oxidative stress in serum and placentas were investigated. Miscarriage and intrauterine growth restriction were observed in the sleep deprivation group. Sleep deprivation resulted in an increased fetal absorption rate, while fetal weight, crown-rump length and placental weight were reduced. Placental histopathology showed that the labyrinth ratio in the sleep deprivation group was significantly reduced, with hypoplastic villi and obviously decreased blood vessels. Sleep deprivation decreased melatonin in serum and the expression of AANAT, MT1 and MT2 in placental tissues, elevated the oxidative stress products 8-hydroxy-deoxyguanosine (8-OHdG) and malondialdehyde(MDA) in serum and 4-hydroxynonenal (4HNE) in the placenta, and decreased the antioxidants superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) in serum. Serum proinflammatory cytokines including interleukin-1-beta (IL-1β), interleukin-6 (IL-6), necrotizing factor-alpha (TNF-α), and interleukin-8(IL-8), were all elevated by sleep deprivation, and the inflammatory regulatory factor nuclear factor-κB p65 (NF-κB p65) in the placenta was enhanced when examined by immunohistochemistry. Corticosterone levels were comparable between the two groups, although ACTH levels were elevated significantly in the sleep deprivation group. Our study revealed that sleep deprivation during pregnancy can adversely impact fetal outcomes. Melatonin may play an important role in this pathology through the oxido-inflammatory process.
Topics: Rats; Pregnancy; Female; Animals; Rats, Sprague-Dawley; Placenta; Sleep Deprivation; Melatonin; Corticosterone; Interleukin-6; Fetus; Adrenocorticotropic Hormone
PubMed: 37925864
DOI: 10.1016/j.jri.2023.104166 -
Biochimie Apr 2024Melatonin is a pleiotropic neurohormone found in different animal, plant, and microorganism species. It is a product resulting from tryptophan metabolism in the pineal... (Review)
Review
Melatonin is a pleiotropic neurohormone found in different animal, plant, and microorganism species. It is a product resulting from tryptophan metabolism in the pineal gland and is widely known for its ability to synchronize the circadian rhythm to antitumor functions in different types of cancers. The molecular mechanisms responsible for its immunomodulatory, antioxidant and cytoprotective effects involve binding to high-affinity G protein-coupled receptors and interactions with intracellular targets that modulate signal transduction pathways. In vitro and in vivo studies have reported the therapeutic potential of melatonin in different infectious and parasitic diseases. In this review, the protective and pathophysiological roles of melatonin in fighting protozoan and helminth infections and the possible mechanisms involved against these stressors will be discussed.
Topics: Animals; Melatonin; Pineal Gland; Antioxidants; Parasitic Diseases; Helminths; Circadian Rhythm
PubMed: 37541568
DOI: 10.1016/j.biochi.2023.07.021 -
Free Radical Biology & Medicine Nov 2023Aging-associated histone modification changes in oocytes have been sporadically reported, but the underlying mechanisms remain elusive. Here, we systematically...
Aging-associated histone modification changes in oocytes have been sporadically reported, but the underlying mechanisms remain elusive. Here, we systematically characterize multiple histone modifications in oocytes during aging. We find that maternal and postovulatory aging markedly alter the status of histone modifications, specifically H4K12ac and H3K4me3, in both mouse and porcine oocytes. Meanwhile, we identify a substantial reduction in HDAC1 (histone deacetylase 1) protein in aged oocytes, which contributes to the changes in H4K12ac and H3K4me3. Moreover, by employing methylglyoxal (MG) and site-directed mutagenesis, we demonstrate that the elevated reactive carbonyl species (RCS) level induces HDAC1 degradation, likely through attacking the cysteine residues, thereby influences histone modification state. Importantly, supplementation of melatonin not only prevents the loss of HDAC1 protein, but also partially corrects the H4K12ac and H3K4me3 status in aged oocytes. To sum up, this study established the link between redox disequilibrium and histone modification alterations during mammalian oocyte aging.
Topics: Animals; Mice; Alkylation; Histone Code; Histones; Mammals; Melatonin; Oocytes; Swine; Histone Deacetylase 1; Aging
PubMed: 37625658
DOI: 10.1016/j.freeradbiomed.2023.08.023