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.

The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT1 and MT2, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT1 receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT1 receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT1 receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT1 receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT1 rs2165666 variant. Overall, this work lends support to the potentiality of MT1 receptors as target for the treatment of BD.

BACKGROUND: The purpose of this study is to investigate the association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers.
METHODS: A case-control study was conducted in the Tangsteel company in Tangshan, China. The sample sizes of the case group and control group were 251 and 451, respectively. The logistic regression, log-linear model and generalized multifactor dimensionality (GMDR) method were used to investigate the interaction between circadian clock gene, melatonin receptor genes and rotating night shift work on type 2 diabetes among steelworkers. Relative excess risk due to interaction (RERI) and attributable proportions (AP) were used to evaluate additive interactions.
RESULTS: Rotating night shift work, current shift status, duration of night shifts, and average frequency of night shifts were associated with an increased risk of type 2 diabetes after adjustment for confounders. Rs1387153 variants in MTNR1B was found to be associated with an increased risk of type 2 diabetes, which was not found between MTNR1A gene rs2119882 locus, CLOCK gene rs1801260 locus and the risk of type 2 diabetes. The association between rotating night shift work and risk of type 2 diabetes appeared to be modified by MTNR1B gene rs1387153 locus (RERI = 0.98, (95% CI, 0.40-1.55); AP = 0.60, (95% CI, 0.07-1.12)). The interaction between MTNR1A gene rs2119882 locus and CLOCK gene rs1801260 locus was associated with the risk of type 2 diabetes (RERI = 1.07, (95% CI, 0.23-1.91); AP = 0.77, (95% CI, 0.36-1.17)). The complex interaction of the MTNR1A-MTNR1B-CLOCK-rotating night shift work model based on the GMDR methods may increase the risk of type 2 diabetes (P = 0.011).
CONCLUSIONS: Rotating night shift work and rs1387153 variants in MTNR1B were associated with an increased risk of type 2 diabetes among steelworkers. The complex interaction of MTNR1A-MTNR1B-CLOCK-rotating night shift work may increase the risk of type 2 diabetes.

Polycystic ovary syndrome (PCOS) is an endocrine disorder seen in women of reproductive age and has been gradually increasing over the years. The mechanism of the syndrome has still not been clearly understood. In this study, the possible effects of exogenously administrated melatonin on melatonin (MT1) receptor, Growth Differentiation Factor-9 (GDF9), and Bone Morphogenetic Protein-15 (BMP15) in experimental PCOS were investigated. Thirty-two 6-8-week-old Sprague-Dawley rats were randomly divided into four groups (n = 8 in each) as Sham control (Group 1), Melatonin (Group 2), PCOS (Group 3), and PCOS + Melatonin (Group 4) groups. At the end of the 21st day, the experiment was terminated, the ovary tissues were taken, and Hematoxylin-Eosin staining, MT1, GDF9, BMP15 immunohistochemical labeling, western blot, and quantitative real-time polymerase chain reaction (qPCR) analyses were performed. Serum Luteinizing Hormone (LH)/Follicle Stimulating Hormone (FSH) levels and colpo-cytological examinations were also carried out. The results revealed that melatonin administration increased the expression levels of the MT1 receptor, GDF9, and BMP15 in PCOS at protein and mRNA levels. It was determined that melatonin administration reduced the microscopic symptoms of PCOS. Melatonin was found to be effective via the MT1 receptor in the pathogenesis of PCOS, and it suppressed the transport pathways of GDF9 to granulosa cells in antral follicles.

Melatonin has been suggested to play important roles in lipid metabolism as well as circadian rhythm; however, very few studies explored the effects of ramelteon, a selective melatonin receptor agonist, on serum lipid profiles. In this study effects of ramelteon on serum lipid profiles were explored, comparing to those of other sleep-promoting drugs including benzodiazepines and non-benzodiazepines, in patients with insomnia. We retrospectively reviewed medical charts of outpatients who were treated with ramelteon (8 mg/d) or other sleep-promoting drugs for no less than 8 weeks during the period between October 1st, 2011 and September 30th, 2014, and compared the changes in serum lipid profiles between the two groups. Patients with regular dialysis or malignant diseases treated with cytotoxic anti-cancer drugs, or whose lipid-lowering drugs were altered during the study period, were excluded. Among 365 or 855 outpatients treated with ramelteon or other sleep-promoting drugs, 35 or 46 patients, respectively, had complete serum low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) data. Serum LDL-C was significantly reduced from 103.1±4.4 to 94.6±4.2 mg/dL (8.2% reduction, p<0.05, n=31) in the ramelteon group, and was not significantly changed (p=0.23, n=40) in the other sleep-promoting drug group. Non-HDL-C was significantly decreased from 138.8±6.0 to 130.6±4.9 mg/dL (5.9% reduction, p<0.05, n=32) in the ramelteon group, and was not significantly altered (p=0.29, n=42) in the other sleep-promoting drug group. Ramelteon, but not other sleep-promoting drugs, specifically lowers serum LDL-C and non-HDL-C levels.

The activation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) via phosphorylation in the hippocampus is an important signaling mechanism for enhancing memory processing. Although melatonin is known to increase CREB expression in various animal models, the signaling mechanism between melatonin and CREB has been unknown in vitro. Thus, we confirmed the signaling pathway between the melatonin receptor 1 (MT1) and CREB using melatonin in HT-22 cells. Melatonin increased MT1 and gradually induced signals associated with long-term memory processing through phosphorylation of Raf, ERK, p90RSK, CREB, and BDNF expression. We also confirmed that the calcium, JNK, and AKT pathways were not involved in this signaling pathway by melatonin in HT-22 cells. Furthermore, we investigated whether melatonin regulated the expressions of CREB-BDNF associated with long-term memory processing in aged HT-22 cells. In conclusion, melatonin mediated the MT1-ERK-p90RSK-CREB-BDNF signaling pathway in the in vitro long-term memory processing model and increased the levels of p-CREB and BDNF expression in melatonin-treated cells compared to untreated HT-22 cells in the cellular aged state. Therefore, this paper suggests that melatonin induces CREB signaling pathways associated with long-term memory processing in vitro.

The pineal neuroindole melatonin exerts an exceptional variety of systemic functions. Some of them are exerted through its specific membrane receptors type 1 and type 2 (MT1 and MT2) while others are mediated by receptor-independent mechanisms. A potential transport of melatonin through facilitative glucose transporters (GLUT/SLC2A) was proposed in prostate cancer cells. The prostate cells have a particular metabolism that changes during tumor progression. During the first steps of carcinogenesis, oxidative phosphorylation is reactivated while the switch to the \"Warburg effect\" only occurs in advanced tumors and in the metastatic stage. Here, we investigated whether melatonin might change prostate cancer cell metabolism. To do so, 13C stable isotope-resolved metabolomics in androgen sensitive LNCaP and insensitive PC-3 prostate cancer cells were employed. In addition to metabolite 13C-labeling, ATP/AMP levels, and lactate dehydrogenase or pentose phosphate pathway activity were measured. Melatonin reduces lactate labeling in androgen-sensitive cells and it also lowers 13C-labeling of tricarboxylic acid cycle metabolites and ATP production. In addition, melatonin reduces lactate 13C-labeling in androgen insensitive prostate cancer cells. Results demonstrated that melatonin limits glycolysis as well as the tricarboxylic acid cycle and pentose phosphate pathway in prostate cancer cells, suggesting that the reduction of glucose uptake is a major target of the indole in this tumor type.

The optimal long-term management strategy for bipolar I disorder patients is not yet established. Evidence supports the rationale for circadian rhythm regulation to prevent mood episode relapse in bipolar patients. This study evaluated the efficacy and safety of a new sublingual formulation of the melatonin receptor agonist ramelteon (ramelteon SL) as adjunctive therapy in the maintenance treatment of bipolar I patients.
In a double-blinded trial in the United States and Latin America, adult bipolar I disorder patients stable for ≥ 8 weeks before baseline and with a mood episode 8 weeks to 9 months before screening, were randomized to once-daily ramelteon SL 0.1mg (n = 164), 0.4mg (n = 160), or 0.8mg (n = 154), or placebo (n = 164), in addition to their existing treatment. The primary endpoint was time from randomization to relapse of symptoms. The prespecified futility criterion in a planned, unblinded, independent interim analysis was the failure of all ramelteon SL doses to achieve a conditional power ≥ 30% compared with placebo.
No significant differences between any dose of ramelteon SL and placebo were observed. The study was terminated after meeting the futility criteria. Ramelteon SL was well tolerated, with a safety profile consistent with that for oral ramelteon.
A low rate of relapse events precluded detection of any statistically significant difference between groups.
The study failed to demonstrate the efficacy of ramelteon SL as adjunctive maintenance therapy for bipolar disorder. Interim analyses for futility in clinical studies are valuable in preventing unnecessary exposure of subjects to interventions.

OBJECTIVE: To study the antidepressant agomelatine (M1/M2 agonist and 5-HT2C antagonist) in pathological gambling (PG) (ICD-10 item F63.0).
METHODS: An open label 8-week trial was carried out in 22 outpatients (17 male and 5 female, mean age 38±7). PG severity was assessed by the Yale-Brown Obsessive-Compulsive Scale adapted for Pathological Gambling (PG-YBOCS). Anxiety and depression level was measured by the Hospital Anxiety Depression Scale (HADS).
RESULTS: Agomelatine significantly decreased PG-YBOCS scores from the second week of the trial (12.6±3.0 compared to 24.2±2.1 at baseline, p<0.05). In the end of the trial, PG-YBOCS score decreased to 5.3. The total HADS score decreased significantly in the end of the study (from 23.6±2.9 to 11.4±1.9, p<0.05). There was an improvement in behavior as well.
CONCLUSIONS: Thus, agomelatine has demonstrated efficacy in PG patients.
Цель исследования - изучение антидепрессанта агомелатина (агонист М1/М2- и антагонист 5-НТ2С-рецепторов) при патологическом гемблинге (ПГ) (по МКБ-10 F63.0). Материал и методы. Провели открытое пилотное 8-недельное исследование. Лечили 22 амбулаторных больных, 17 мужчин и 5 женщин, средний возраст которых был 38±7 лет). Тяжесть ПГ оценивалась с помощью обсессивно-компульсивной шкалы Йейла-Брауна, адаптированной для ПГ (PG-YBOCS), уровень тревоги и депрессии измерялся по госпитальной шкале тревоги и депрессии (HADS). Результаты и заключение. Было установлено, что агомелатин существенно снижал показатели PG-YBOCS начиная со 2-й недели (12,6±3,0 по сравнению с 24,2±2,1 до терапии (р<0,05), к концу исследования - до 5,3. Показатели HADS также существенно снизились: с 23,6±2,9 до 11,4±1,9 (р<0,05). Этим изменениям соответствовали и положительные поведенческие сдвиги. Сделан вывод об эффективности агомелатина при ПГ.

OBJECTIVE: The melatonin receptor (MTNR) gene, reported to be associated with insulin sensitivity, diabetes and metabolic syndrome, could be a plausible candidate gene for polycystic ovary syndrome (PCOS). This study was designed to investigate whether an association exists between two single nucleotide polymorphism (SNP) variants (rs2119882 and rs10830963) of the MTNR gene and PCOS in Han Chinese.
METHODS: In total, 263 family trios (789 participants) were enrolled in this family-based transmission disequilibrium test (TDT). Genotypes were obtained by sequencing. In total, 135 trios of rs2119882 and 127 trios of rs10830963 were tested.
RESULTS: An association was detected between rs2119882 (p=0.0209) and PCOS, suggesting that the MTNR gene may indicate increased susceptibility to PCOS in Chinese. No significant association was found for rs10830963 (transmitted:non-transmitted=76:51, p=0.1573). The association between the MTNR gene variants and clinical characteristics of women with PCOS was investigated. CC genotype carriers had higher levels of clinical and metabolic features than the TC and TT genotypes. A significant difference in transmission of allele C of rs2119882 was found between obese and non-obese women with PCOS (Chi-squared=5.5983, p=0.018).
CONCLUSIONS: This study may provide a basis for further studies of the MTNR gene in the aetiology of PCOS.