Journal of Pineal Research最新文献

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons and aggregation of α-synuclein (α-syn). Ferroptosis, a form of cell death induced by iron accumulation and lipid peroxidation, is involved in the pathogenesis of PD. It is unknown whether melatonin receptor 1 (MT1) modulates α-syn and ferroptosis in PD. Here, we used α-syn preformed fibrils (PFFs) to induce PD models in vivo and in vitro. In PD mice, α-syn aggregation led to increased iron deposition and ferroptosis. MT1 knockout exacerbated these changes and resulted in more DA neuronal loss and severe motor impairment. MT1 knockout also suppressed the Sirt1/Nrf2/Ho1/Gpx4 pathway, reducing resistance to ferroptosis, and inhibited expression of ferritin Fth1, leading to more release of ferrous ions. In vitro experiments confirmed these findings. Knockdown of MT1 enhanced α-syn PFF-induced intracellular α-syn aggregation and suppressed expression of the Sirt1/Nrf2/Ho1/Gpx4 pathway and Fth1 protein, thereby aggravating ferroptosis. Conversely, overexpression of MT1 reversed these effects. Our findings reveal a novel mechanism by which MT1 activation prevents α-syn-induced ferroptosis in PD, highlighting the neuroprotective role of MT1 in PD.

Zhou H, Du W, Li Y, et al. Effects of melatonin on fatty liver disease: the role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy. J Pineal Res. 2018;64:e12450. https://doi.org/10.1111/jpi.12450

Upon the publication of the article, the authors have discovered inaccuracies in one representative Oil Red image presented in Figure 2A. Specifically, errors occurred during the figure assembly process, resulting in the inclusion of the wrong representative image for the LFD+WT group in Figure 2A. It is important to emphasize that these corrections do not compromise the scientific integrity of the study's conclusions. The authors unanimously support this corrigendum and sincerely apologize for any inconvenience caused by this oversight. The accurate images, obtained during the original experimental procedures, are provided below.

Hyaluronic acid (HA) is a glycosaminoglycan and the main component of the extracellular matrix (ECM), which has been reported to interact with its receptor CD44 to play critical roles in the self-renewal and maintenance of cancer stem cells (CSCs) of multiple malignancies. Melatonin is a neuroendocrine hormone with pleiotropic antitumor properties. However, whether melatonin could regulate HA accumulation in the ECM to modulate the stemness of head and neck squamous cell carcinoma (HNSCC) remains unknown. In this study, we found that melatonin suppressed CSC-related markers, such as CD44, of HNSCC cells and decreased the tumor-initiating frequency of CSCs in vivo. In addition, melatonin modulated HA synthesis of HNSCC cells by downregulating the expression of hyaluronan synthase 3 (HAS3). Further study showed that the Fos-like 1 (FOSL1)/HAS3 axis mediated the inhibitory effects of melatonin on HA accumulation and stemness of HNSCC in a receptor-independent manner. Taken together, melatonin modulated HA synthesis through the FOSL1/HAS3 axis to inhibit the stemness of HNSCC cells, which elucidates the effect of melatonin on the ECM and provides a novel perspective on melatonin in HNSCC treatment.

Melatonin exhibits potential for pain relief and long-term safety profile. We examined the analgesic effects of oral melatonin on osteoarthritis (OA) and investigated the underlying mechanism. Using data from a UK primary care database, we conducted a cohort study in individuals with OA to compare the number of oral analgesic prescriptions and the risk of knee/hip replacement between melatonin initiators and hypnotic benzodiazepines (i.e., active comparator) initiators using quantile regression models and Cox-proportional hazard models, respectively. To elucidate causation, we examined the effects of melatonin on pain behaviors and explored several metabolites that may serve as potential regulatory agents of melatonin in the monoiodoacetate rat model of OA. Using data from another community-based cohort study, that is, the Xiangya OA Study, we verified the association between the key serum metabolite and incident symptomatic knee OA. Compared with the hypnotic benzodiazepines cohort (n = 8135), the melatonin cohort (n = 813) had significantly fewer subsequent prescriptions of oral analgesics (50th percentile: 5 vs. 7, 75th percentile: 19 vs. 29, and 99th percentile: 140 vs. 162) and experienced a lower risk of knee/hip replacement (hazard ratio = 0.47, 95% Cl: 0.30–0.73) during the follow-up period. In rats, oral melatonin alleviated pain behaviors and increased serum levels of glycine. There was an inverse association between baseline serum glycine levels and the risk of incident symptomatic knee OA in humans (n = 760). In conclusion, our findings indicate that oral melatonin shows significant potential to be a novel treatment for OA pain. The potential role of glycine in its analgesic mechanism warrants further investigation.

Cecon E, Ivanova A, Luka M, Gbahou F, Friederich A, Guillaume JL, Keller P, Knoch K, Ahmad R, Delagrange P, Solimena M, Jockers R. Detection of recombinant and endogenous mouse melatonin receptors by monoclonal antibodies targeting the C-terminal domain. J Pineal Res. 2018 Nov 26:e12540. doi:10.1111/jpi.12540

In Figure 3B, lanes for NT and mMT1 for antibody mAB-H04 were incorrect. In Figure 3C, lanes for NT and hMT2 for antibodies mAB-A84 and mAB-I81 were incorrect (switched image of NT lane with hMT2 lane in both cases). In Figure 3D, lanes for NT and rMT2 for mAB-84 were incorrect. All the incorrect lanes correspond to lanes without any specific signals, which resulted in an erroneous assembly of lanes at the final stage of the figure preparation. None of these errors has any impact on the conclusion of the article. Original western blots and the corrected figure is provided.

We apologize for this error.

The labeled ligand commonly employed in competition binding studies for melatonin receptor ligands, 2-[¹²⁵I]iodomelatonin, showed slow dissociation with different half-lives at the two receptor subtypes. This may affect the operational measures of affinity constants, which at short incubation times could not be obtained in equilibrium conditions, and structure–activity relationships, as the K_i values of tested ligands could depend on either interaction at the binding site or the dissociation path. To address these issues, the kinetic and saturation binding parameters of 2-[¹²⁵I]iodomelatonin as well as the competition constants for a series of representative ligands were measured at a short (2 h) and a long (20 h) incubation time. Concurrently, we simulated by molecular modeling the dissociation path of 2-iodomelatonin from MT₁ and MT₂ receptors and investigated the role of interactions at the binding site on the stereoselectivity observed for the enantiomers of the subtype-selective ligand UCM1014. We found that equilibrium conditions for 2-[¹²⁵I]iodomelatonin binding can be reached only with long incubation times, particularly for the MT₂ receptor subtype, for which a time of 20 h approximates this condition. On the other hand, measured K_i values for a set of ligands including agonists, antagonists, nonselective, and subtype-selective compounds were not significantly affected by the length of incubation, suggesting that structure–activity relationships based on data collected at shorter time reflect different interactions at the binding site. Molecular modeling simulations evidenced that the slower dissociation of 2-iodomelatonin from the MT₂ receptor can be related to the restricted mobility of a gatekeeper tyrosine along a lipophilic path from the binding site to the membrane bilayer. The enantiomers of the potent, MT₂-selective agonist UCM1014 were separately synthesized and tested. Molecular dynamics simulations of the receptor–ligand complexes provided an explanation for their stereoselectivity as due to the preference shown by the eutomer at the binding site for the most abundant axial conformation adopted by the ligand in solution. These results suggest that, despite the slow-binding kinetics occurring for the labeled ligand, affinity measures at shorter incubation times give robust results consistent with known structure–activity relationships and with interactions taken at the receptor binding site.

Stability of metabolites in harsh environments such as drought, temperature, and light suggest their untapped potential in processes the plants utilize in mitigation of abiotic and biotic stresses. Such metabolites could be nonspecific to microorganisms, plants, or animals. Many of the indoleamines are ubiquitous throughout species and have been shown to mitigate a wide range of stresses. We tested the role of indoleamine metabolites via exogenous application of the precursor tryptophan (TRP) on strawberry due to the short reproductive life cycle and its temperate traits. Seasonal responses appeared to be perturbed with exogenous application of TRP as a combination of foliar (3 mg/L) and ground drench (100 mg/L) or ground drench only (100 mg/L). The treatment yielded growth stimulatory responses besides mitigating stress, that is, short photoperiod and cold temperature. Plants preparing into dormancy reverted to produce green foliage and flowers that set fruit in unfavorable climate in the month of November where the untreated plants senesced. Analyses of the endogenous indoleamines in flowers and fruits of the treated plants indicated that the titers and ratios of the metabolites NAS, 2-hydroxymelatonin, and N(1)-acetyl-N(2)-formyl-5-methoxykynuramine assisted in the stress mitigation. The ASMT and M2H gene regulations emphasized the stability of intermediate metabolites of TRP. The TDC and T5H regulation explained the detection of a rare to find compound, 5-hydroxytryptophan, in strawberry. This is the first report on detection of eight indoleamines in strawberry alongside the regulatory genes in the indoleamine pathway. Inclining climate crisis demands climate-resilient plants in quick time and the indoleamine toolkit may offer the opportunity to develop simple and effective practices to manage stress tolerance in plants.

Several myeloid cell leukemia sequence 1 protein (MCL1) inhibitors including S64315 have undergone clinical testing for leukemia. Because of the toxicities after MCL1 inhibition, including hematopoietic, hepatic, and cardiac toxicities, there is substantial interest in finding agents that can sensitize leukemia cells to these MCL1 inhibitors. Melatonin is a chronobiotic that promotes chemo-induced cancer cell death while protecting normal cells from cytotoxic effects. In this study, we found melatonin sensitizes over 10 leukemia cell lines to the MCL1 inhibitors S63845 (S64315 analog) and A-1210477. Further studies demonstrate that melatonin sensitizes Jurkat cells to S63845 and A-1210477 independent of melatonin receptors MT1 and MT2, but through multiple mechanisms, including upregulating the death receptor pathway, increasing mitochondrial reactive oxygen species (ROS), inhibiting nuclear factor-κB (NF-κB) signaling, and causing cell cycle arrest. First, death receptor pathway inhibition only slightly diminishes the melatonin sensitization of S63845, while inhibiting mitochondrial ROS partially reduces the S63845/melatonin combination-induced apoptosis and depletion of the mitochondrial pathway totally abolishes it, indicating that both death receptor and mitochondrial apoptosis pathways are involved. Second, transcriptome sequencing analysis found that NF-κB signaling is downregulated by melatonin that inhibition of NF-κB signaling by parthenolide also dramatically sensitizes Jurkat cells to S63845. Third, melatonin induces G1 cell cycle arrest and upregulates NOXA while NOXA knockdown diminishes the sensitization to S63845 by melatonin. In addition, a xenograft model suggests that melatonin in combination with S63845 causes shrinkage of leukemic deposit while S63845 or melatonin monotherapy only has limited effects. Thus, our results demonstrate that melatonin efficiently sensitizes various leukemia to the MCL1 inhibitors, potentially allowing the usage of lower doses.

Women typically sleep and wake earlier than men and have been shown to have earlier circadian timing relative to the light/dark cycle that synchronizes the clock. A potential mechanism for earlier timing in women is an altered response of the circadian system to evening light. We characterized individual-level dose–response curves for light-induced melatonin suppression using a within-subjects protocol. Fifty-six participants (29 women, 27 men; aged 18–30 years) were exposed to a range of light illuminances (10, 30, 50, 100, 200, 400, and 2000 lux) using melatonin suppression relative to a dim control (<1 lux) as a marker of light sensitivity. Women were free from hormonal contraception. To examine the potential influence of sex hormones, estradiol and progesterone was examined in women and testosterone was examined in a subset of men. Menstrual phase was monitored using self-reports and estradiol and progesterone levels. Women exhibited significantly greater melatonin suppression than men under the 400-lux and 2000-lux conditions, but not under lower light conditions (10–200 lux). Light sensitivity did not differ by menstrual phase, nor was it associated with levels of estradiol, progesterone, or testosterone, suggesting the sex differences in light sensitivity were not acutely driven by circulating levels of sex hormones. These results suggest that sex differences in circadian timing are not due to differences in the response to dim/moderate light exposures typically experienced in the evening. The finding of increased bright light sensitivity in women suggests that sex differences in circadian timing could plausibly instead be driven by a greater sensitivity to phase-advancing effects of bright morning light.