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Biomedicine & Pharmacotherapy =... Nov 2023Sepsis-induced myocardial dysfunction (SIMD) is one of the serious health-affecting problems worldwide. At present, the mechanisms of SIMD are still not clearly... (Review)
Review
Sepsis-induced myocardial dysfunction (SIMD) is one of the serious health-affecting problems worldwide. At present, the mechanisms of SIMD are still not clearly elucidated. The NOD-like receptor protein 3 (NLRP3) inflammasome has been assumed to be involved in the pathophysiology of SIMD by regulating multiple biological processes. NLRP3 inflammasome and its related signaling pathways might affect the regulation of inflammation, autophagy, apoptosis, and pyroptosis in SIMD. A few molecular specific inhibitors of NLRP3 inflammasome (e.g., Melatonin, Ulinastatin, Irisin, Nifuroxazide, and Ginsenoside Rg1, etc.) have been developed, which showed a promising anti-inflammatory effect in a cellular or animal model of SIMD. These experimental findings indicated that NLRP3 inflammasome could be a promising therapeutic target for SIMD treatment. However, the clinical translation of NLRP3 inhibitors for treating SIMD still requires robust in vivo and preclinical trials.
PubMed: 37741253
DOI: 10.1016/j.biopha.2023.115497 -
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 -
Molecular Neurobiology Jan 2024Melatonin, the 'hormone of darkness' is a neuronal hormone secreted by the pineal gland and other extra pineal sites. Responsible for the circadian rhythm and seasonal... (Review)
Review
Melatonin, the 'hormone of darkness' is a neuronal hormone secreted by the pineal gland and other extra pineal sites. Responsible for the circadian rhythm and seasonal behaviour of vertebrates and mammals, melatonin is responsible for regulating various physiological conditions and the maintenance of sleep, body weight and the neuronal activities of the ocular sites. With its unique amphiphilic structure, melatonin can cross the cellular barriers and elucidate its activities in the subcellular components, including mitochondria. Melatonin is a potential scavenger of oxygen and nitrogen-reactive species and can directly obliterate the ROS and RNS by a receptor-independent mechanism. It can also regulate the pro- and anti-inflammatory cytokines in various pathological conditions and exhibit therapeutic activities against neurodegenerative, psychiatric disorders and cancer. Melatonin is also found to show its effects on major organs, particularly the brain, liver and heart, and also imparts a role in the modulation of the immune system. Thus, melatonin is a multifaceted candidate with immense therapeutic potential and is still considered an effective supplement on various therapies. This is primarily due to rectification of aberrant circadian rhythm by improvement of sleep quality associated with risk development of neurodegenerative, cognitive, cardiovascular and other metabolic disorders, thereby enhancing the quality of life.
PubMed: 38206471
DOI: 10.1007/s12035-024-03915-0 -
Faculty Reviews 2023Postoperative delirium (POD) is a major public health problem associated with poor patient outcomes such as increased hospital lengths of stay, loss of functional... (Review)
Review
Postoperative delirium (POD) is a major public health problem associated with poor patient outcomes such as increased hospital lengths of stay, loss of functional independence, and higher mortality. Depending on the study, the reported incidence ranges from 5% to 65%, with the highest incidence in hip and cardiac surgery. Anesthesiologists should be familiar with the predisposing and precipitating factors of POD, particularly screening for preoperative cognitive impairment and frailty syndrome. Screening tools, for example, the Mini-Mental State Exam, Mini-Cog, 4 A's test for delirium screening, and Montreal Cognitive Assessment, can be used to assess for cognitive impairment and the Clinical Frailty Scale to assess for frailty syndrome. The Hospital Elder Life Program is the standard prevention protocol that is tried and tested in reducing the incidence of POD. Prehabilitation, lung protective strategies, pharmacologic agents such as ramelteon, a melatonin receptor agonist, glucocorticoids, dexmedetomidine, and non-pharmacologic agents, such as noise reduction strategies and the encouragement of nocturnal sleep, have all led to a decrease in the incidence of POD and are being studied for their efficacy. However, the data are inconclusive to date. Intraoperatively, preventing hypotension and blood pressure swings, ensuring adequate pain control and anesthetic depth, and using age-adjusted minimum alveolar concentration (MAC) titration reduce the incidence of POD. The incidence of POD using regional or general anesthesia is similar. In this narrative review, we will discuss the current understanding of the predictors, pathophysiology, prevention, and management of POD and identify areas of further research.
PubMed: 37529149
DOI: 10.12703/r/12-19 -
Life Sciences Sep 2023Melatonin is known to inhibit platelet aggregation induced by arachidonic acid (AA). In the present study we investigated whether agomelatine (Ago), an antidepressant...
AIMS
Melatonin is known to inhibit platelet aggregation induced by arachidonic acid (AA). In the present study we investigated whether agomelatine (Ago), an antidepressant with agonist activity at melatonin receptor 1 (MT1) and MT2 could reduce platelets aggregation and adhesion.
MAIN METHODS
Human platelets from healthy donors were used to test the in vitro effects of Ago in the presence of different platelet activators. We performed aggregation and adhesion assays, thromboxane B (TxB), cAMP and cGMP measurements, intra-platelet calcium registration and flow cytometry assays.
KEY FINDINGS
Our data revealed that different concentrations of Ago reduced AA- and collagen-induced human platelet aggregation in vitro. Ago also reduced AA-induced increase in thromboxane B (TxB) production, intracellular calcium levels and P-selectin expression at plasma membrane. The effects of Ago in AA-activated platelets were likely dependent on MT1 as they were blocked by luzindole (a MT1/MT2 antagonist) and mimicked by the MT1 agonist UCM871 in a luzindole-sensitive manner. The MT2 agonist UCM924 was also able to inhibit platelet aggregation, but this response was not affected by luzindole. On the other hand, although UCM871 and UCM924 reduced collagen-induced platelet aggregation and adhesion, inhibition of collagen-induced platelet aggregation by Ago was not mediated by melatonin receptors because it was not affected by luzindole.
SIGNIFICANCE
The present data show that Ago suppresses human platelet aggregation and suggest that this antidepressant may have the potential to prevent atherothrombotic ischemic events by reducing thrombus formation and vessel occlusion.
Topics: Humans; Platelet Aggregation; Receptors, Melatonin; Calcium; Blood Platelets; Collagen; Antidepressive Agents; Thromboxanes; Thromboxane B2
PubMed: 37394096
DOI: 10.1016/j.lfs.2023.121906 -
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 -
General Hospital Psychiatry 2023Delirium is a complex and heterogeneous condition that significantly affects patient outcome. This study aimed to conduct a systematic review and meta-analysis to... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Delirium is a complex and heterogeneous condition that significantly affects patient outcome. This study aimed to conduct a systematic review and meta-analysis to investigate the effects of melatonin and melatonin receptor agonists (MRAs) on delirium prevention and treatment.
METHOD
Randomized controlled studies, using MRAs as an intervention and placebo as a control were included. We conducted meta-analyses with random-effects model and trial sequential analysis.
RESULTS
A total of 33 studies involving 4850 participants were included. The meta-analysis revealed a significant preventive effect of MRAs on delirium (risk ratio = 0.65, p < 0.01), while no significant therapeutic effect was observed. Additionally, MRAs were associated with a significant reduction in mortality rate (risk ratio = 0.90, p = 0.02) in delirium prevention studies. Furthermore, subgroup analyses revealed that assessment scales and the frequency of delirium detection may be significant moderators of the delirium-preventive efficacy of MRAs.
CONCLUSION
This study provides evidence of the potential effects of MRAs in preventing delirium and reducing mortality. Further research is required to elucidate the therapeutic potential of MRAs for delirium and identify specific patient populations that may benefit from this agent.
Topics: Humans; Delirium; Receptors, Melatonin; Randomized Controlled Trials as Topic; Hypnotics and Sedatives; Melatonin
PubMed: 37826886
DOI: 10.1016/j.genhosppsych.2023.08.011 -
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