不同光照方式对慢性阻塞性肺疾病急性加重 患者血清褪黑素水平及近期预后的影响

目的 探讨不同光照方式对慢性阻塞性肺疾病急性加重（acute exacerbation of chronic obstructive pulmonary disease,AECOPD）患者血清褪黑素（melatonin,Mel）及近期预后的影响。方法 选取2019年7月至2020年12月浙江省人民医院收治的96例AECOPD患者为研究对象,按照随机数字表法分为对照组（n=46）和观察组（n=50）。对照组患者给予24h持续光照,观察组患者采用间断光照方式,8:00至20:00给予持续光照,20:00至次日8:00关闭光照并为患者佩戴黑色眼罩,连续观察10d。比较两组患者血清Mel及尿6-羟基硫酸褪黑素（6-sulphatoxymelatonin,6-SMT）水平变化及撤机成功率、重症监护室（intensive care unit,ICU）停留时间、多器官功能障碍综合征（multiple organ dysfunction syndrome,MODS）发生率、住院28 d生存率差异。结果 观察组患者7:00和22:00的血清Mel及尿6-SMT水平均呈现升高趋势,且入院后第5天和第10天上述指标均显著高于同期对照组（P<0.05）。观察组患者撤机成功率显著高于对照组,ICU停留时间显著短于对照组,MODS发生率显著低于对照组（P<0.05）。观察组患者住院28d的生存率略高于对照组,但两组比较差异无统计学意义（84.0% vs 73.9%,χ2=0.390,P=0.532）。结论 对AECOPD患者实施间断光照能够明显提高患者体内Mel及其代谢产物水平,改善近期预后,值得在临床中推广应用。     

Determination of melatonin content in traditional Thai herbal remedies used as sleeping aids

Background

Melatonin content was screened in leaves of seven edible herbs used as sleeping aids in Thai traditional medicine. These plants are Piper nigrum L, Sesbania glandiflora (L.) Desv., Sesbania sesban (L.) Merr., Senna tora (L.) Roxb., Moringa oleifera Lam., Momordica charantia L. and Baccaurea ramiflora Lour. Dried leaves were extracted by sonication in methanol for six hours at room temperature, and then melatonin was purified by C18 solid phase extraction (SPE). Melatonin was then quantified by a validated RP-C18 HPLC method with fluorescent detection.

Findings

Melatonin contents in extracts of B. ramiflora, S. glandiflora, M. charantia, S. tora and S. sesban were 43.2, 26.3, 21.4, 10.5 and 8.7 ng/g of dry sample weight, respectively. The highest melatonin content was from P. nigrum extract (1092.7 ng/g of dry sample weight). Melatonin was not detected in the extract of M. oleifera. Melatonin identification was confirmed by ELISA.

Conclusions

Melatonin was found in six of the seven herbs in the traditional Thai sleeping recipe. One of these, P. nigrum, exhibited an encouragingly high amount of melatonin.     

Potential use of melatonin supplementation to protect vitrified testicular grafts from hypoxic–ischaemic damage

This study aimed to assess the morphological changes in neonate vitrified testicular grafts after host treatment with melatonin. Neonate vitrified testes, candidates for transplantation to treated and nontreated groups receiving melatonin, were thawed in media containing or not containing 100 μm melatonin. Following transplantation, melatonin (20 mg kg^?1 per day) and saline were given to the treated and nontreated groups for up to 9 weeks. The testicular status was assayed by terminal deoxynucleotidyl transferase (TdT)‐mediated deoxyuridine triphosphate (dUTP)‐biotin nick‐end labelling TUNEL, semi‐thin section and ultra‐structure studies. Chi‐squared test was used to compare categorical variables between the groups. Overall, the degenerative and apoptosis changes in the vitrified testis parenchyma were not significant. However, atrophic seminiferous cords and jumbled appearance of the interstitial space were more often observed in the nontreated group than in the treated ones. Semi‐thin sections showed that the germinal epithelium was taken in a normal arrangement on the testicular grafts of both groups. Nevertheless, ultrastructural analysis revealed that the characteristics of interstitial space cells, basement membrane BM and epithelial cells of seminiferous tubules in the treated group were better than those in the nontreated group. The study revealed a beneficial effect of melatonin on vitrified neonatal testes and after that, on restoring testicular grafts.     

Melatonin alterations and brain acetylcholine lesions in sleep disorders in Cockayne syndrome

Background: Cockayne syndrome (CS) is a genetic disorder caused by deficient nucleotide excision repair. Patients with CS exhibit progeroid features, developmental delay, and various neurological disorders; they are also known to suffer from sleep problems, which have never been investigated in detail. Objective: The aim of this study is to investigate the pathogenesis of sleep disorders in patients with CS. Methods: We performed a questionnaire survey of the families of patients with CS, enzyme-linked immunosorbent analyses of the melatonin metabolite, 6-sulphatoxymelatonin (6-SM), in the patients’ urine, and immunohistochemistry in the hypothalamus, the basal nucleus of Meynert (NbM), and the pedunculopontine tegmental nucleus (PPN) in four autopsy cases. Results: Sleep–wakefulness rhythms were disturbed in patients with CS, and these disturbances seemed to be related to a reduced urinary excretion of 6-SM. In addition, although the hypothalamic nuclei were comparatively preserved, acetylcholine neurons (AchNs) were severely decreased in the NbM and PPN. Conclusions: AchNs modulate both arousal and rapid eye movement sleep, and selective lesions of AchNs in the PPN and/or NbM in combination with disturbed melatonin metabolism might be involved in the sleep disorders in CS.     

The melatonin analog 5-MCA-NAT increases endogenous dopamine levels by binding NRH:quinone reductase enzyme in the developing chick retina

NRH:quinone reductase (QR2) is present in the retinas of embryonic and post-hatched (PH) chicks. 5-Methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) is a QR2 ligand that increases cAMP levels in developing retinas, but it does not affect cAMP levels in CHO-QR2 cells. The dopamine quinone reductase activity of QR2 retrieves dopamine, which increases cAMP levels in developing retinas. The objective of the present study was to investigate whether 5-MCA-NAT increases endogenous dopamine levels in retinas from chick embryos and post-hatched chicks. Endogenous dopamine was measured by enzyme-linked immunosorbent assay (ELISA). 5-MCA-NAT increased retinal endogenous dopamine levels at all developmental stages studied and in PH chicks (−log EC50 = 11.62 ± 0.34 M). This effect was inhibited by non-selective antagonists of receptors and melatonin binding sites N-acetyl-2-benzyltryptamine (luzindole, 5 μM), but it was not inhibited by the Mel1b melatonin receptor antagonist 4-phenyl-2-propionamidotetralin (4-P-PDOT, 10 nM). The QR2 cosubstrate, N-methyl-dihydronicotinamide (NMH) (−log EC50 = 6.74 ± 0.26 M), increased endogenous dopamine levels in controls and in retinas stimulated with 5-MCA-NAT (3 nM). The QR2 inhibitor benzo[e]pyrene inhibited endogenous dopamine levels in both control (−log IC50 = 7.4 ± 0.28 M) and NMH-stimulated (at 100 nM and 1 μM benzo[e]pyrene concentrations) retinas. Theoretical studies using Molegro Virtual Docking software corroborated these experimental results. We conclude that 5-MCA-NAT increases the level of endogenous dopamine via QR2. We suggest that this enzyme triggers double reduction of the dopamine quinone, recovering dopamine in retinal development.     

Anti-aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts

Targeting the estrogen pathway has been proven effective in the treatment for estrogen receptor positive breast cancer. There are currently two common groups of anti-estrogenic compounds used in the clinic; Selective Estrogen Receptor Modulators (SERMs, e.g. tamoxifen) and Selective Estrogen Enzyme Modulators (SEEMs e.g. letrozole). Among various naturally occurring, biologically active compounds, resveratrol and melatonin have been suggested to act as aromatase inhibitors, which make them potential candidates in hormonal treatment of breast cancer. Here we used a co-culture model in which we previously demonstrated that primary human breast adipose fibroblasts (BAFs) can convert testosterone to estradiol, which subsequently results in estrogen receptor-mediated breast cancer T47D cell proliferation. In the presence of testosterone in this model, we examined the effect of letrozole, resveratrol and melatonin on cell proliferation, estradiol (E₂) production and gene expression of CYP19A1, pS2 and Ki-67. Both melatonin and resveratrol were found to be aromatase inhibitors in this co-culture system, albeit at different concentrations. Our co-culture model did not provide any indications that melatonin is also a selective estrogen receptor modulator. In the T47D-BAF co-culture, a melatonin concentration of 20 nM and resveratrol concentration of 20 μM have an aromatase inhibitory effect as potent as 20 nM letrozole, which is a clinically used anti-aromatase drug in breast cancer treatment. The SEEM mechanism of action of especially melatonin clearly offers potential advantages for breast cancer treatment.     

A combination of melatonin,vitamin B6 and medicinal plants in the treatment of mild-to-moderate insomnia: A prospective pilot study

ObjectivesCurrently available pharmaceutical therapies for sleep disorders have significant side effects and dependence potential, thus necessitating the need for alternative treatment approaches. This study investigated the effect of a combination of melatonin, vitamin B6 and medicinal plants in patients with mild-to-moderate sleep disorders.Design and settingThis was a 4-week, single-center, single-arm, open-label study conducted in 40 participants with mild-to-moderate insomnia, in Poland.InterventionParticipants received Novanuit^® Triple Action (melatonin, vitamin B6, California poppy extract, passionflower extract, and lemon balm extract) capsules per day for two weeks.OutcomesUsing a daily electronic sleep diary, information was collected on sleep quality (assessed on a 0–10 scale), total sleep duration, sleep onset latency, sleep-related daytime impairment, and safety of the study medication.ResultsThere was a statistically significant (p < 0.001) improvement in sleep quality by the end of the 2-week treatment period, with mean sleep quality score increasing by 1.9 points from pre-treatment (5.4 points) to post-treatment (7.3 points). Similarly, statistically significant improvements were observed following treatment completion in sleep onset latency, total sleep duration, and sleep-related daytime parameters (p < 0.01 for all outcomes). Administration of the combination of melatonin, vitamin B6, and medicinal plants was associated with high compliance (39/40; 97.5%). No serious adverse events were reported.ConclusionsThis pilot study suggests that the combination of melatonin, vitamin B6, and medicinal plants may be beneficial in mild-to-moderate insomnia.     

Effect of photoperiod manipulation on the daily rhythms of melatonin and reproductive hormones in caged European sea bass (Dicentrarchus labrax)

Reproduction in fish is cyclical and timed to guarantee the survival of the offspring. Seasonal variations in reproductive hormones of fish have been deeply investigated in fish over the last years. However, there are few studies regarding the daily changes in reproductive hormone profiles in teleosts. The aim of the present research was to investigate the effects of photoperiod manipulation on melatonin and reproductive hormones (pituitary sbGnRH, pituitary LH and plasma LH, testosterone [T], and 11-ketotestosterone [11KT]) daily rhythms in male sea bass, kept in net cages under farming conditions in winter (9L:15D). Fish were distributed in two groups, one under constant long photoperiod (18L:6D) and the other under natural photoperiod. The photoperiod strongly influenced the daily melatonin profile, so that the duration of the nocturnal melatonin rise was longer in the control group than in the group exposed to the artificial photoperiod (18L:6D). A daily rhythm was observed in the pituitary sbGnRH profile in both groups, showing the lowest levels during the dark period. A daily rhythm of pituitary LH was detected in the control group, which was suppressed in the group under long photoperiod. Daily variations in plasma LH were observed, the highest levels being found in the dark phase in both groups, although this profile was significantly altered by artificial light, maintaining a fixed relationship between the first nocturnal rise of melatonin and the nocturnal peaks of plasma LH in both groups. Plasma T levels showed significant fluctuations in their daily cycle following a sinusoidal pattern with an acrophase around sunrise in both groups, without any influence of light regime. No significant daily variations in plasma levels of 11-KT were observed in none of the groups. Our results provide the first evidence of the presence of daily variations in pituitary sbGnRH content, pituitary and plasma LH, and plasma T in sea bass. Artificial lights suppressed the circulating melatonin and significantly affected the daily rhythm of LH storage and release.