UNASSIGNED: The mechanisms of intervertebral disc degeneration (IVDD) in low back pain (LBP) patients are multiples. In this study, we attempt to investigate whether melatonergic system plays a potential role in IVDD patients with LBP by analyzing their clinical specimens. The fucus will be given to the correlation between the melatonin receptor expression and intervertebral disc tissue apoptosis.
UNASSIGNED: In this clinical study, 107 lumbar intervertebral disc nucleus pulposus (NP) specimens from patients with LBP were collected with patients\' consents. The disc height (DH) discrepancy ratio, range of motion and sagittal parameters of the pathological plane were measured and Pfirrmann grade was used to classified the grades of IVDD level. Discs at grades 1-3 were served as normal control and grades 4-5 were considered as IVDD. The expression levels of melatonin receptor 1A (MT1) and 1B (MT2) were measured by immunohistochemistry. The apoptosis of NP was assessed using TUNEL staining. Their potential associations among MT1/2, DH, apoptosis, sagittal parameters with IVDD and LBP were evaluated with statistical analysis.
UNASSIGNED: The incidence of IVDD was positively associated with age and negatively related to VAS scores for LBP (p < 0.001). Patients with higher degree of IVDD also have higher DH discrepancy ratio (p < 0.001), higher prevalence of lumbar instability (p = 0.003) and higher cell apoptosis compared to the control. Nevertheless, no statistically significant correlation was identified between Pfirrmann grade and lumbar sagittal parameters. MT1 and MT2 both were highly expressed in the NP tissues. Importantly, MT1 expression but not MT2 was significantly increased in the intervertebral disc tissue of patients with IVDD and its level correlated well with cell apoptosis level and the severity of IVDD as well as lower VAS scores for LBP.
UNASSIGNED: The highly elevated MT1 expression was found in NP tissues of patients with IVDD and LBP compared to the control. This phenomenon probably reflects the compensating response of the body to the pathological alteration of the IVDD and LBP. Therefore, these findings provide the novel information to use selective agonists of MT1 to target IVDD and LBP clinically.

Cardiovascular diseases (CVDs) are the leading causes of death and illness worldwide. While there have been advancements in the treatment of CVDs using medication and medical procedures, these conventional methods have limited effectiveness in halting the progression of heart diseases to complete heart failure. However, in recent years, the hormone melatonin has shown promise as a protective agent for the heart. Melatonin, which is secreted by the pineal gland and regulates our sleep-wake cycle, plays a role in various biological processes including oxidative stress, mitochondrial function, and cell death. The Sirtuin (Sirt) family of proteins has gained attention for their involvement in many cellular functions related to heart health. It has been well established that melatonin activates the Sirt signaling pathways, leading to several beneficial effects on the heart. These include preserving mitochondrial function, reducing oxidative stress, decreasing inflammation, preventing cell death, and regulating autophagy in cardiac cells. Therefore, melatonin could play crucial roles in ameliorating various cardiovascular pathologies, such as sepsis, drug toxicity-induced myocardial injury, myocardial ischemia-reperfusion injury, hypertension, heart failure, and diabetic cardiomyopathy. These effects may be partly attributed to the modulation of different Sirt family members by melatonin. This review summarizes the existing body of literature highlighting the cardioprotective effects of melatonin, specifically the ones including modulation of Sirt signaling pathways. Also, we discuss the potential use of melatonin-Sirt interactions as a forthcoming therapeutic target for managing and preventing CVDs.

Identifying the target cells of a hormone is a key step in understanding its function. Once the molecular nature of the receptors for a hormone has been established, researchers can use several techniques to detect these receptors. Here I will review the different tools used over the years to localize melatonin receptors and the problems associated with each of these techniques. The radioligand 2-[125I] iodomelatonin was the first tool to allow localization of melatonin receptors on tissue sections. Once the MT1 and MT2 receptors were cloned, in situ hybridization could be used to detect the messenger RNA for these receptors. The deduced amino acid sequences for MT1 and MT2 receptors allowed the production of peptide immunogens to generate antibodies against the MT1 and MT2 receptors. Finally, transgenic reporters driven by the promoter elements of the MT1 and MT2 genes have been used to map the expression of MT1 and MT2 in the brain and the retina. Several issues have complicated the localization of melatonin receptors and the characterization of melatonin target cells over the last three decades. Melatonin receptors are expressed at low levels, leading to sensitivity issues for their detection. The second problem are specificity issues with antibodies directed against the MT1 and MT2 melatonin receptors. These receptors are G protein-coupled receptors and many antibodies directed against such receptors have been shown to present similar problems concerning their specificity. Despite these specificity problems which start to be seriously addressed by recent studies, antibodies will be important tools in the future to identify and phenotype melatonin target cells. However, we will have to be more stringent than previously when establishing their specificity. The results obtained by these antibodies will have to be confronted and be coherent with results obtained by other techniques.

Melatonin (N-acetyl-5-methoxytryptamine) is an indolamine that is synthesized from tryptophan in the pineal glands of vertebrates through four enzymatic reactions. Melatonin is a quite unique bioactive substance, characterized by a combination of both receptor-mediated and receptor-independent actions, which promote the diverse effects of melatonin. One of the main functions of melatonin, via its membrane receptors, is to regulate the circadian or seasonal rhythm. In mammals, light information, which controls melatonin synthesis, is received in the eye, and transmitted to the pineal gland, via the suprachiasmatic nucleus, where the central clock is located. Alternatively, in many vertebrates other than mammals, the pineal gland cells, which are involved in melatonin synthesis and secretion and in the circadian clock, directly receive light. Recently, it has been reported that melatonin possesses several metabolic functions, which involve bone and glucose, in addition to regulating the circadian rhythm. Melatonin improves bone strength by inhibiting osteoclast activity. It is also known to maintain brain activity during sleep by increasing glucose uptake at night, in an insulin-independent manner. Moreover, as a non-receptor-mediated action, melatonin has antioxidant properties. Melatonin has been proven to be a potent free radical scavenger and a broad-spectrum antioxidant, even protecting organisms against radiation from space. Melatonin is a ubiquitously distributed molecule and is found in bacteria, unicellular organisms, fungi, and plants. It is hypothesized that melatonin initially functioned as an antioxidant, then, in vertebrates, it combined this role with the ability to regulate rhythm and metabolism, via its receptors.

Melatonin is a neuroendocrine hormone that regulates the circadian rhythm and many other physiological processes. Its functions are primarily exerted through two subtypes of human melatonin receptors, termed melatonin type-1 (MT1) and type-2 (MT2) receptors. Both MT1 and MT2 receptors are generally classified as Gi-coupled receptors owing to their well-recognized ability to inhibit cAMP accumulation in cells. However, it remains an enigma as to why melatonin stimulates cAMP production in a number of cell types that express the MT1 receptor. To address if MT1 can dually couple to Gs and Gi proteins, we employed a highly sensitive luminescent biosensor (GloSensorTM) to monitor the real-time changes in the intracellular cAMP level in intact live HEK293 cells that express MT1 and/or MT2. Our results demonstrate that the activation of MT1, but not MT2, leads to a robust enhancement on the forskolin-stimulated cAMP formation. In contrast, the activation of either MT1 or MT2 inhibited cAMP synthesis driven by the activation of the Gs-coupled β2-adrenergic receptor, which is consistent with a typical Gi-mediated response. The co-expression of MT1 with Gs enabled melatonin itself to stimulate cAMP production, indicating a productive coupling between MT1 and Gs. The possible existence of a MT1-Gs complex was supported through molecular modeling as the predicted complex exhibited structural and thermodynamic characteristics that are comparable to that of MT1-Gi. Taken together, our data reveal that MT1, but not MT2, can dually couple to Gs and Gi proteins, thereby enabling the bi-directional regulation of adenylyl cyclase to differentially modulate cAMP levels in cells that express different complements of MT1, MT2, and G proteins.

Polycystic ovarian syndrome (PCOS) is a genetically complex disorder that involves the interplay of multiple genes and environmental factors. It is characterized by anovulation and irregular menses and is associated with type 2 diabetes. Neuroendocrine pathways and ovarian and adrenal dysfunctions are possibly implicated in the disorder pathogenesis. The melatonin system plays a role in PCOS. Melatonin receptors are expressed on the surface of ovarian granulosa cells, and variations in the melatonin receptor genes have been associated with increased risk of PCOS in both familial and sporadic cases. We have recently reported the association of variants in MTNR1A and MTNR1B genes with familial type 2 diabetes. In this study, we aimed to investigate whether MTNR1A and MTNR1B contribute to PCOS risk in peninsular families. In 212 Italian families phenotyped for PCOS, we amplified by microarray 14 variants in the MTNR1A gene and 6 variants in the MTNR1B gene and tested them for linkage and linkage disequilibrium with PCOS. We detected 4 variants in the MTNR1A gene and 2 variants in the MTNR1B gene significantly linked and/or in linkage disequilibrium with the risk of PCOS (P < 0.05). All variants are novel and have not been reported before with PCOS or any of its related phenotypes, except for 3 variants previously reported by us to confer risk for type 2 diabetes and 1 variant for type 2 diabetes-depression comorbidity. These findings implicate novel melatonin receptor genes\' variants in the risk of PCOS with potential functional roles.

Spinal cord injury (SCI) is a sudden onset of disruption to the spinal neural tissue, leading to loss of motor control and sensory function of the body. Oxidative stress is considered a hallmark in SCI followed by a series of events, including inflammation and cellular apoptosis. Melatonin was originally discovered as a hormone produced by the pineal gland. The subcellular localization of melatonin has been identified in mitochondria, exhibiting specific onsite protection to excess mitochondrial reactive oxygen species and working as an antioxidant in diseases. The recent discovery regarding the molecular basis of ligand selectivity for melatonin receptors and the constant efforts on finding synthetic melatonin alternatives have drawn researchers\' attention back to melatonin. This review outlines the application of melatonin in SCI, including 1) the relationship between the melatonin rhythm and SCI in clinic; 2) the neuroprotective role of melatonin in experimental traumatic and ischemia/reperfusion SCI, i.e., exhibiting anti-oxidative, anti-inflammatory, and anti-apoptosis effects, facilitating the integrity of the blood-spinal cord barrier, ameliorating edema, preventing neural death, reducing scar formation, and promoting axon regeneration and neuroplasticity; 3) protecting gut microbiota and peripheral organs; 4) synergizing with drugs, rehabilitation training, stem cell therapy, and biomedical material engineering; and 5) the potential side effects. This comprehensive review provides new insights on melatonin as a natural antioxidant therapy in facilitating rehabilitation in SCI.

Melatonin is a circadian hormone with antioxidant properties that protects against myocardial ischemia-reperfusion injury. Genetic variations of the melatonin receptor 1B gene (MTNR1B) play an important role in the development of type 2 diabetes, a risk factor for cardiovascular diseases. Accordingly, MTNR1B polymorphisms are crucial in numerous disorders of the cardiovascular system. Therefore, the aim of the present study was to investigate a possible association of MTNR1B polymorphisms with chronotype and susceptibility to myocardial infarction. The present case-control study included 199 patients with myocardial infarction (MI) (57% men) and 198 control participants (52% men) without previous cardiovascular diseases who underwent genotyping for the MTNR1B polymorphisms rs10830963, rs1387153, and rs4753426 from peripheral blood samples. Chronotype was determined using the Morningness-Eveningness Questionnaire (MEQ). As estimated by the chi-square test, no significant association was found in the distribution of alleles and genotypes between myocardial infarction patients and controls. In addition, there was no association between MTNR1B polymorphisms and chronotype in MI patients. As some previous studies have shown, the present negative results do not exclude the role of the MTNR1B polymorphisms studied in the development of myocardial infarction. Rather, they may indicate that MTNR1B polymorphisms are a minor risk factor for myocardial infarction.

Night-shift work and sleep disorders are associated with type 2 diabetes (T2DM), and circadian rhythm disruption is intrinsically involved. Studies have identified several signaling pathways that separately link two melatonin receptors (MT1 and MT2) to insulin secretion and T2DM occurrence, but a comprehensive explanation of the molecular mechanism to elucidate the association between these receptors to T2DM, reasonably and precisely, has been lacking. This review thoroughly explicates the signaling system, which consists of four important pathways, linking melatonin receptors MT1 or MT2 to insulin secretion. Then, the association of the circadian rhythm with MTNR1B transcription is extensively expounded. Finally, a concrete molecular and evolutionary mechanism underlying the macroscopic association between the circadian rhythm and T2DM is established. This review provides new insights into the pathology, treatment, and prevention of T2DM.

BACKGROUND: Melatonin is an endogenous hormone which modulates sleep-wake cycles. Previous studies have found a close correlation between melatonin and post-traumatic stress disorder (PTSD), a trauma- and stress-related psychiatric disorder with symptoms of sleep disturbance. However, it is still unclear if melatonin can have a therapeutic effect on PTSD.
OBJECTIVE: This study aimed to investigate the effects of melatonin on foot shocks induced PTSD-like behaviors and abnormal neuroendocrine levels in mice.
RESULTS: As compared to no-shock controls, PTSD-like mice spent significantly more time freezing and displayed less rearing in a contextual fear test, spent significantly less time in and had fewer entries into open arms in an elevated maze test, and spent significantly less time in and had fewer entries into a light box in a light-dark transition task. In addition, serum GABA and cortisol levels were both found to be significantly decreased, whereas epinephrine levels were significantly increased in the PTSD-like mice. Our results showed that intraperitoneal injections of melatonin (2 mM, but not 0.2 nor 20 mM, 0.1 ml/day for two consecutive weeks) alleviated PTSD-like behaviors and restored serum GABA and cortisol levels. Further, it was found that melatonin receptor 1/2 antagonist luzindole significantly blocked the beneficial effects of melatonin for PTSD-like behaviors and serum GABA and cortisol levels, whereas melatonin receptor 2 antagonist 4-P-PDOT slightly blocked these effects.
CONCLUSIONS: These results indicate that melatonin has a potential therapeutic effect on PTSD-like symptoms in mice, and melatonin receptor 1 mediated the effect.