Journal of Pineal Research最新文献

Tumor necrosis factor (TNF) is a biomarker of inflammation whose levels are elevated in patients with several diseases associated with dysregulation of the immune response. The main limitations of currently used anti-TNF therapies are the induction of immunodepression, which in many cases leads to serious adverse effects such as infection and cancer, and the inability to cross the blood-brain barrier in neuroinflammatory conditions. Melatonin, in addition to being a chronobiotic compound, is widely known for its antioxidant and immunomodulatory capacity to control inflammatory processes in different pathological contexts. The aim of the present review is to address human-based studies that describe the effect of melatonin on TNF production. The review includes all the articles published in PubMed databases until April 15, 2024. After depuration, 45 studies were finally included in the review, 23 related to the in vitro action of melatonin in human cells and 22 in vivo studies in humans. Most of the data reviewed support the idea that melatonin has an immunosuppressive effect on TNF levels, which, together with its low toxicity profile, low cost, and ability to cross the blood-brain barrier, points to melatonin as a potential anti-TNF therapy. Therefore, improving our knowledge of the action of melatonin in regulating TNF through appropriate clinical trials would reveal the true potential of this molecule as a possible anti-TNF therapy.

While artificial light in urban environments was previously thought to override seasonality in humans, recent studies have challenged this assumption. We aimed to explore the relationship between seasonally varying environmental factors and changes in sleep architecture in patients with neuropsychiatric sleep disorders by comparing two consecutive years. In 770 patients, three-night polysomnography was performed at the Clinic for Sleep & Chronomedicine (St. Hedwig Hospital, Berlin, Germany) in 2018/2019. Sleep times were adjusted to patients' preferred schedules, patients slept in, and were unaware of day-night indicators. Digital devices and clocks were not allowed. Days were spent outside the lab with work or naps not allowed. After exclusions (mostly due to psychotropic medication), analysis was conducted on the second PSG-night in 377 patients (49.1 ± 16.8 year; 54% female). Sleep parameters were plotted as 90-day moving-averages (MvA) across date-of-record. Periodicity and seasonal windows in the MvA were identified by utilizing autocorrelations. Linear mixed-effect models were applied to seasonal windows. Sleep parameters were correlated with same-day photoperiod, temperature, and sunshine duration. The MvA of total sleep time (TST) and REM sleep began a 5-month-long decline shortly after the last occurrence of freezing 24-h mean temperatures (correlation of TST between 2018 and 2019 at 2-month lag: rs₃₆₁ = 0.87, p < 0.001; maximum peak-to-nadir amplitude: ΔTST ~ 62 min, ΔREM ~ 24 min). The MvA nadirs of slow wave sleep (SWS) occurred approximately at the autumnal equinox (correlation between 2018 and 2019: rs₃₆₁ = 0.83, p < 0.001). Post hoc testing following significant linear mixed-effect model indicate that TST and REM sleep were longer around November till February than May till August (ΔTST = 36 min; ΔREM = 14 min), while SWS was 23 min longer around February till May than August till November. Proportional seasonal variation of SWS and of REM sleep as percentages of TST differed profoundly (SWS = 31.6%; REM = 8.4%). In patients with neuropsychiatric sleep disorders living in an urban environment, data collected in 2018 show similar patterns and magnitudes in seasonal variation of sleep architecture as the 2019 data. Interestingly, whereas SWS patterns were consistent between years with possible links to photoperiod, annual variations of TST and REM sleep seem to be related to times of outside freezing temperature. For generalization, the data need to be confirmed in a healthy population. No clinical trial was registered.

Circadian rhythm disruption (CRD), stemming from sleep disorders and/or shift work, is a risk factor for reproductive dysfunction. CRD has been reported to disturb nocturnal melatonin signaling, which plays a crucial role in female reproduction as a circadian regulator and an antioxidant. The hypothalamic-pituitary-ovarian (HPO) axis regulates female reproduction, with luteinizing hormone (LH) pulse pattern playing a pivotal role in folliculogenesis and steroidogenesis. However, the effect of CRD on the HPO axis and the involvement of melatonin remains unclear. Female CBA/CaJ mice underwent CRD modeling, which involves alternating between standard light conditions and an 8-h advance schedule every 3 days for 8 weeks, whereas control mice were maintained under a standard 12:12-h light/dark (LD) cycle. Subsequent measurements of diurnal melatonin levels, LH pulse patterns assessments via serial tail-tip blood sampling and evaluations of ovarian function were conducted. CRD altered the circadian rhythms of wheel-running activity and melatonin secretion in mice and led to an augmented LH pulse pattern, evidenced by increased LH pulse frequency, mean LH levels, and pituitary LH beta-subunit (LHβ) expression, irregular estrous cycles, abnormal luteal function, altered endocrine function, and ovarian oxidative stress. Melatonin treatment (10 mg/kg/day for 4 weeks) significantly improved the HPO axis disorder in CRD mice, decreasing the enhanced LH pulse frequency and pituitary LHβ expression. These findings were further validated using an in vitro LβT2 cell perfusion model. Furthermore, melatonin restored ovarian function and scavenged reactive oxygen species, thereby preventing apoptosis and preserving ovarian function. This study offers new insights into the impact of CRD on the HPO axis and emphasizes the potential of melatonin supplementation in mitigating its effects on female reproduction.

In mice, variability in adult bone size and density has been observed among common inbred strains. Also, in the group of genes regulating circadian rhythmicity in mice, so called clock genes, changes in body size and skeletal parameters have been noted in knockout mice. Here, we studied the size and density of prominent bones of the axial and appendicular skeleton of clock gene Period-1-deficient (Per1^-/-) mice by means of microcomputed tomography. Our data show shorter spinal length, smaller and less dense femora and tibiae, but no significant changes in the shape of the skull and the length of the head. Together with the significantly lower total body weight of Per1^-/- mice, we conclude that Per1-deficiency in a melatonin-proficient mouse strain is associated with an altered body phenotype with smaller appendicular (hind limb) bone size, shorter spine length and lower total body weight while normal head length and brain weight. The observed changes suggest an involvement of secondary bone mineralisation with impact on long bones, but lesser impact on those of the skull. Evidence and overall physiological implications of these findings are discussed.

We explored predictors of shift work adaptation and how it relates to disease risk biomarker levels. These analyses included 38 male, rotating shift workers, sampled twice at the end of a 3-week night shift and a 3-week day shift rotation. Participants collected all 24-h urine voids, wore activity sensors, and responded to questionnaires during each shift. Using cosinor analysis, we derived the main period of urinary 6-sulfatoxymelatonin (aMT6s) production. Adaptation was defined as the overlap between the main aMT6s production period and sleep period assessed with actigraphy. We used linear models to identify predictors of adaptation to each shift and assessed associations between adaptation profiles and hormone, cytokine, and metabolite biomarker levels. The median duration of overlap (adaptation) was 3.85 h (IQR 2.59–5.03) in the night and 2.98 (IQR 2.17–4.11) in the day shift. In the night shift, a later chronotype (coeff: −1.16, 95% CI −1.87, −0.45) and increased light at night (coeff: −0.97, 95% CI −1.76, −0.18) were associated with poorer adaptation, while longer sleep duration was associated with better adaptation (coeff: 0.46, 95% CI 0.04, 0.88). In the day shift, later sleep onset was associated with worse adaptation (coeff: −0.06, 95% CI −0.12, −0.01), while longer sleep duration was associated with better adaptation (coeff: 0.54, 0.26, 0.81). Results suggest higher androgen and inflammatory marker levels and lower levels of several metabolite markers among less adapted individuals. Chronotype, sleep, and light at night were all associated with night or day shift adaptation. Given the small sample size, results should be viewed as exploratory, but may inform interventions to optimize adaptation of rotating shift workers.