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  • Structural characterization of melatonin as an inhibitor of the Wnt deacylase Notum
    J. Pineal. Res. (IF 15.221) Pub Date : 2020-01-24
    Yuguang Zhao; Jingshan Ren; James Hillier; Margaret Jones; Weixian Lu; Edith Yvonne Jones

    The hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/β‐catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N‐[2‐(5‐fluoro‐1H‐indol‐3‐yl)ethyl]acetamide that is structurally similar to melatonin came to our attention. We then soaked melatonin and its precursor N‐acetylserotonin into Notum crystals and obtained high‐resolution structures (≤1.5 Å) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid, and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 µmol/L), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which upregulation of Wnt signalling may be beneficial.

    更新日期:2020-01-26
  • Melatonin alleviates vascular calcification and ageing through exosomal miR‐204/miR‐211 cluster in a paracrine manner
    J. Pineal. Res. (IF 15.221) Pub Date : 2020-01-14
    Feng Xu; Jia‐Yu Zhong; Xiao Lin; Su‐Kang Shan; Guo Bei; Ming‐Hui Zheng; Yi Wang; Fuxingzi Li; Rong‐Rong Cui; Feng Wu; En Zhou; Xiao‐Bo Liao; You‐Shuo Liu; Ling‐Qing Yuan

    In the elderly with atherosclerosis, hypertension, and diabetes, vascular calcification and ageing are ubiquitous. Melatonin (MT) has been demonstrated to impact the cardiovascular system. In this study we have shown that MT alleviates vascular calcification and ageing, and the underlying mechanism involved. We found that both osteogenic differentiation and senescence of vascular smooth muscle cells (VSMCs) were attenuated by MT in an MT membrane receptor‐dependent manner. Moreover, exosomes isolated from VSMCs or calcifying vascular smooth muscle cells (CVSMCs) treated with MT could be uptaken by VSMCs and attenuated the osteogenic differentiation and senescence of VSMCs or CVSMCs, respectively. Moreover, we used conditional medium from MT treated VSMCs and transwell assay to confirm exosomes secreted by MT treated VSMCs attenuated the osteogenic differentiation and senescence of VSMCs through paracrine mechanism. We also found exosomal miR‐204/miR‐211 mediated the paracrine effect of exosomes secreted by VSMCs. A potential target of these two miRs was revealed to be BMP2. Furthermore, treatment of MT alleviated vascular calcification and ageing in 5/6‐nephrectomy plus high phosphate diet treated (5/6 NTP) mice, while these effects were partially reversed by GW4869. Exosomes derived from MT‐treated VSMCs were internalized into mice artery detected by in vivo fluorescence image, and these exosomes reduced vascular calcification and ageing of 5/6 NTP mice, but both effects were largely abolished by inhibition of exosomal miR‐204 or miR‐211. In summary, our present study revealed that exosomes from MT‐treated VSMCs could attenuate vascular calcification and ageing in a paracrine manner through an exosomal miR‐204/miR‐211.

    更新日期:2020-01-14
  • Two indoleamines are secreted from rat pineal gland at night and act on melatonin receptors but are not night hormones
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-12-30
    Bo Hyun Lee; Ivana L. Bussi; Horacio O. de la Iglesia; Chris Hague; Duk‐Su Koh; Bertil Hille

    At night, the pineal gland produces the indoleamines, melatonin, N‐acetylserotonin (NAS), and N‐acetyltryptamine (NAT). Melatonin is accepted as a hormone of night. Could NAS and NAT serve that role too? Methods: Concentration‐response measurements with overexpressed human melatonin receptors MT1 and MT2; mass spectrometry analysis of norepinephrine‐stimulated secretions from isolated rat pineal glands; analysis of 24‐hour periodic samples of rat blood. Results: We show that NAT and NAS do activate melatonin receptors MT1 and MT2, although with lower potency than melatonin, and that in vitro, melatonin and NAS are secreted from stimulated, isolated pineal glands in roughly equimolar amounts, but secretion of NAT was much less. All three were found at roughly equal concentrations in blood during the night. However, during the day, serum melatonin fell to very low values creating a high‐amplitude circadian rhythm that was absent after pinealectomy, whereas NAS and NAT showed only small or no circadian variation. Conclusion: Blood levels of NAS and NAT were insufficient to activate peripheral melatonin receptors, and they were invariant, so they could not serve as circulating hormones of night. However, they could instead act in paracrine circadian fashion near the pineal gland or via other higher‐affinity receptors.

    更新日期:2019-12-30
  • Circadian regulation and molecular role of the Bsx homeobox gene in the adult pineal gland
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-12-30
    Mikkel B. Carstensen; Henrik Hertz; Tenna Bering; Morten Møller; Kristian Rohde; David C. Klein; Steven L. Coon; Martin F. Rath

    The pineal gland is a neuroendocrine organ responsible for production of the nocturnal hormone melatonin. A specific set of homeobox gene‐encoded transcription factors govern pineal development, and some are expressed in adulthood. The brain‐specific homeobox gene (Bsx) falls into both categories. We here examined regulation and function of Bsx in the mature pineal gland of the rat. We report that Bsx is expressed from prenatal stages into adulthood, where Bsx transcripts are localized in the melatonin‐synthesizing pinealocytes, as revealed by RNAscope in situ hybridization. Bsx transcripts were also detected in the adult human pineal gland. In the rat pineal gland, Bsx was found to exhibit a 10‐fold circadian rhythm with a peak at night. By combining in vivo adrenergic stimulation and surgical denervation of the gland in the rat with in vitro stimulation and transcriptional inhibition in cultured pinealocytes, we show that rhythmic expression of Bsx is controlled at the transcriptional level by the sympathetic neural input to the gland acting via adrenergic stimulation with cyclic AMP as a second messenger. siRNA‐mediated knockdown (>80% reduction) in pinealocyte cultures revealed Bsx to be a negative regulator of other pineal homeobox genes, including paired box 4 (Pax4), but no effect on genes encoding melatonin‐synthesizing enzymes was detected. RNA sequencing analysis performed on siRNA‐treated pinealocytes further revealed that downstream target genes of Bsx are mainly involved in developmental processes. Thus, rhythmic Bsx expression seems to govern other developmental regulators in the mature pineal gland.

    更新日期:2019-12-30
  • Characterization of serotonin and N‐acetylserotonin systems in the human epidermis and skin cells
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-12-20
    Andrzej T. Slominski; Tae‐Kang Kim; Konrad Kleszczyński; Igor Semak; Zorica Janjetovic; Trevor Sweatman; Cezary Skobowiat; Jeffery D. Steketee; Zongtao Lin; Arnold Postlethwaite; Wei Li; Russel J. Reiter; Desmond J. Tobin

    Tryptophan hydroxylase (TPH) activity was detected in cultured epidermal melanocytes and dermal fibroblasts with respective Km of 5.08 and 2.83 mM and Vmax of 80.5 and 108.0 µmol/min. Low but detectable TPH activity was also seen in cultured epidermal keratinocytes. Serotonin and/or its metabolite and precursor to melatonin, N‐acetylserotonin (NAS), were identified by LC/MS in human epidermis and serum. Endogenous epidermal levels were 113.18 ± 13.34 and 43.41 ± 12.45 ng/mg protein for serotonin (n = 8/8) and NAS (n = 10/13), respectively. Their production was independent of race, gender, and age. NAS was also detected in human serum (n = 13/13) at a concentration 2.44 ± 0.45 ng/mL, while corresponding serotonin levels were 295.33 ± 17.17 ng/mL (n = 13/13). While there were no differences in serum serotonin levels, serum NAS levels were slightly higher in females. Immunocytochemistry studies showed localization of serotonin to epidermal and follicular keratinocytes, eccrine glands, mast cells, and dermal fibrocytes. Endogenous production of serotonin in cultured melanocytes, keratinocytes, and dermal fibroblasts was modulated by UVB. In conclusion, serotonin and NAS are produced endogenously in the epidermal, dermal, and adnexal compartments of human skin and in cultured skin cells. NAS is also detectable in human serum. Both serotonin and NAS inhibited melanogenesis in human melanotic melanoma at concentrations of 10−4‐10−3 M. They also inhibited growth of melanocytes. Melanoma cells were resistant to NAS inhibition, while serotonin inhibited cell growth only at 10−3 M. In summary, we characterized a serotonin‐NAS system in human skin that is a part of local neuroendocrine system regulating skin homeostasis.

    更新日期:2019-12-21
  • Melatonin duration gates photoperiodic vocal state change in a songbird
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-12-18
    Clifford E. Harpole; Meredith D. Miles; Vincent M. Cassone

    Seasonally breeding animals concentrate courtship to a particular time of year such that their offspring will be reared in a favorable environment. In house sparrows, Passer domesticus, primary (gonads) and secondary (song, plumage, beak color, etc) sexual characteristics are expressed differentially depending on the photoperiod. Removal of the pineal gland (PINX) has no effect on seasonal rhythms in gonad size but alters the photostimulated increase in vocal rate and complexity. Administration of long durations of melatonin, indicative of short days of winter, prevents seasonal recrudescence of song control nuclei in photostimulated house sparrows. In this study, male PINX house sparrows were exposed to three durations of melatonin, while vocalization and locomotor behavior were recorded as they were transitioned from short photoperiod to equinoctial photoperiods of spring. Birds receiving short duration melatonin or vehicle control increased dawn and dusk choruses as well as call complexity. Long durations of melatonin prevented this expansion to a spring‐like vocal state observed in birds receiving the short duration of melatonin or vehicle control. The daily distribution of locomotor activity, beak color, and testis size was unaffected by treatment. Vocal state change was defined by our measures in two capacities: (i) increased dawn and dusk choruses, and (ii) an increase in calls associated with territory and mate attraction compared to the winter‐like “social song.” We conclude that house sparrows use the calendar information provided by melatonin duration to control seasonal vocalization behavior, independent of effects on and of the gonads.

    更新日期:2019-12-19
  • Melatonin enhances mitochondrial biogenesis and protects against rotenone‐induced mitochondrial deficiency in early porcine embryos
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-12-18
    Ying‐Jie Niu; Wenjun Zhou; Zheng‐Wen Nie; Kyung‐Tae Shin; Xiang‐Shun Cui

    Melatonin, a major hormone of the pineal gland, exerts many beneficial effects on mitochondria. Several studies have shown that melatonin can protect against toxin‐induced oocyte quality impairment during maturation. However, there is little information regarding the beneficial effects of melatonin on toxin‐exposed early embryos, and the mechanisms underlying such effects have not been determined. Rotenone, a chemical widely used in agriculture, induces mitochondrial toxicity, therefore, damaging the reproductive system, impairing oocyte maturation, ovulation, and fertilization. We investigated whether melatonin attenuated rotenone exposure‐induced impairment of embryo development by its mitochondrial protection effect. Activated oocytes were randomly assigned to four groups: the control, melatonin treatment, rotenone‐exposed, and “rotenone + melatonin” groups. Treatment with melatonin abrogated rotenone‐induced impairment of embryo development, mitochondrial dysfunction, and ATP deficiency, and significantly decreased oxidative stress and apoptosis. Melatonin also increased SIRT1 and PGC‐1α expression, which promoted mitochondrial biogenesis. SIRT1 knockdown or pharmacological inhibition abolished melatonin's ability to revert rotenone‐induced impairment. Thus, melatonin rescued rotenone‐induced impairment of embryo development by reducing ROS production and promoting mitochondrial biogenesis. This study shows that melatonin rescues toxin‐induced impairment of early porcine embryo development by promoting mitochondrial biogenesis.

    更新日期:2019-12-19
  • Melatonin ameliorates SGLT2 inhibitor‐induced diabetic ketoacidosis by inhibiting lipolysis and hepatic ketogenesis in type 2 diabetic mice
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-12-06
    Jae‐Hyung Park, Incheol Seo, Hae‐min Shim, Hochan Cho

    Sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) are effective hypoglycemic agents that can induce glycosuria. However, there are increasing concerns that they might induce diabetic ketoacidosis. This study investigated the effect of melatonin on SGTL2i‐induced ketoacidosis in insulin‐deficient type 2 diabetic (T2D) mice. The SGLT2i dapagliflozin reduced blood glucose level and plasma insulin concentrations in T2D mice, but induced increases in the concentrations of plasma β‐hydroxybutyrate, acetoacetate, and free fatty acid and a decrease in the concentration of plasma bicarbonate, resulting in ketoacidosis. Melatonin inhibited dapagliflozin‐induced ketoacidosis without inducing any change in blood glucose level or plasma insulin concentration. In white adipose tissue, melatonin inhibited lipolysis and downregulated phosphorylation of PKA, HSL, and perilipin‐1. In liver tissue, melatonin suppressed cellular cyclic AMP levels and downregulated phosphorylation of PKA, AMPK, and acetyl‐CoA carboxylase (ACC). In addition, melatonin increased hepatic ACC activity, but decreased hepatic CPT1a activity and acetyl‐CoA content. These effects of melatonin on lipolysis and hepatic ketogenesis were blocked by pretreatment with melatonin receptor antagonist or PKA activator. Collectively, these results suggest that melatonin can ameliorate SGLT2i‐induced ketoacidosis by inhibiting lipolysis and hepatic ketogenesis though cyclic AMP/PKA signaling pathways in T2D mice. Thus, melatonin treatment may offer protection against SGLT2i‐induced ketoacidosis.

    更新日期:2019-12-06
  • Increased plasma melatonin in presymptomatic Huntington disease sheep (Ovis aries): Compensatory neuroprotection in a neurodegenerative disease?
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-12-06
    A. Jennifer Morton, Benita Middleton, Skye Rudiger, C. Simon Bawden, Timothy R. Kuchel, Debra J. Skene

    Melatonin is a pleiotrophic hormone, synthesised primarily by the pineal gland under the control of the suprachiasmatic nuclei (SCN). It not only provides a hormonal signal of darkness but also has neuroprotective properties. Huntington's disease (HD) is a progressive neurodegenerative disorder characterised by abnormal motor, cognitive and psychiatric symptoms. There is growing evidence, particularly from animal models, that circadian rhythms may also be disturbed in HD. We measured two circadian‐regulated hormones, melatonin and cortisol, in plasma samples collected around‐the‐clock from normal and presymptomatic transgenic HD sheep (Ovis aries) at 5 and 7 years of age, to assess SCN‐driven rhythms and the effect of genotype, sex and age. Melatonin‐related precursors and metabolites (tryptophan, serotonin, kynurenine) were also measured by liquid chromatography (LC)‐mass spectrometry (MS). At 5 years of age in both rams and ewes, plasma melatonin levels were significantly elevated in HD sheep. In ewes measured 2 years later, there was still a significant elevation of nocturnal melatonin. Furthermore, the daytime baseline levels of melatonin were significantly higher in HD sheep. Since increased melatonin could have global beneficial effects on brain function, we suggest that the increased melatonin measured in presymptomatic HD sheep is part of an autoprotective response to mutant huntingtin toxicity that may account, at least in part, for the late onset of disease that characterises HD.

    更新日期:2019-12-06
  • Melatonin activates cell death programs for the suppression of uterine leiomyoma cell proliferation
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-11-28
    Po‐Han Lin, Yen‐Ting Tung, Hsin‐Yuan Chen, Yi‐Fen Chiang, Hui‐Chih Hong, Ko‐Chieh Huang, Sung‐Po Hsu, Tsui‐Chin Huang, Shih‐Min Hsia

    The circadian nature of melatonin has a protective effect on the progression of female reproductive cancers, including breast and ovarian cancers. However, the effect of melatonin on the growth of uterine leiomyoma is still unclear. In this study, we found that the growth of uterine leiomyoma ELT3 cells was reduced by treatment with melatonin. Treatment with melatonin increased the distribution of sub‐G1 phase and increased DNA condensation in ELT3 cells. Melatonin‐induced apoptosis and autophagy cell death progression were observed in ELT3 cells. Melatonin exerts a highly selective effect on primary normal human uterine smooth muscle (UtSMC) cells. The UtSMC cell cycle was arrested by melatonin treatment through up‐regulation of p21, p27, and PTEN protein expression, but melatonin did not further promote apoptosis program activation. Melatonin reduced cell proliferation in ELT3 cells underlying the activation of melatonin MT1 and MT2 receptors, which in turn down‐regulated the Akt‐ERK1/2‐NFκB signaling pathway. Melatonin reduced ELT3 tumor growth in both xenograft and orthotopic uterine tumor mice models. The extracellular matrix of the tumor was also reduced by melatonin treatment. Taken together, these results suggest that melatonin potentially plays a role in suppression of uterine leiomyoma growth.

    更新日期:2019-11-29
  • Melatonin promotes the development of immature oocytes from the COH cycle into healthy offspring by protecting mitochondrial function
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-11-28
    Huijuan Zou, Beili Chen, Ding Ding, Ming Gao, Dawei Chen, Yajing Liu, Yan Hao, Weiwei Zou, Dongmei Ji, Ping Zhou, Zhaolian Wei, Yunxia Cao, Zhiguo Zhang

    Melatonin (MT) regulates reproductive performance as a potent antioxidant; however, its beneficial effects on oocyte development remain largely unknown, especially in human oocytes. The collected 193 immature oocytes from the controlled ovarian hyperstimulation (COH) cycle underwent in vitro maturation (IVM) in IVM medium contained 10 μmol/L MT (n = 105, M group) and no MT (n = 88, NM group), followed by insemination and embryo culture. The results showed that the high‐quality blastocyst formation rate in the M group (28.4%) was significantly higher than that in the NM group (2.0%) (P = .0001), and the aneuploidy rate was low (15.8%). In the subsequent clinical trials, three healthy infants were delivered. Next, single‐cell RNA‐seq data revealed 1026 differentially expressed genes (DEGs) between the two groups, KEGG enrichment analysis revealed that the majority of DEGs involved in oxidative phosphorylation pathway, which associated with ATP generation, was upregulated in the M group. Finally, confocal fluorescence staining results revealed that the mitochondrial membrane potential in the oocytes significantly increased and intracellular ROS and Ca2+ levels greatly decreased in the M group. Melatonin can promote the development of immature human oocytes retrieved from the COH cycle into healthy offspring by protecting mitochondrial function.

    更新日期:2019-11-29
  • Melatonin alleviates circadian system disruption induced by chronic shifts of the light‐dark cycle in Octodon degus
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-11-18
    Beatriz Bano‐Otalora, Juan Antonio Madrid, Maria Angeles Rol

    Modern 24‐h society lifestyle is associated with experiencing frequent shifts in the lighting conditions which can negatively impact human health. Here, we use the degus, a species exhibiting diurnal and nocturnal chronotypes, to: (a) assess the impact of chronic shifts of the light:dark (LD) cycle in the animal's physiology and behaviour and (b) test the therapeutic potential of melatonin in enhancing rhythmicity under these conditions. Degus were subjected to a “5d + 2d” LD‐shifting schedule for 19 weeks. This protocol aims to mimic lighting conditions experienced by humans during shift work: LD cycle was weekly delayed by 8h during 5 “working” days (Morning, Afternoon and Night schedule); during weekends (2 days), animals were kept under Morning schedule. After 9 weeks, melatonin was provided daily for 6h in the drinking water. The “5d + 2d” shifting LD schedule led to a disruption in wheel‐running activity (WRA) and body temperature (Tb) rhythms which manifested up to three separate periods in the circadian range. This chronodisruption was more evident in nocturnal than in diurnal degus, particularly during the Afternoon schedule when a phase misalignment between WRA and Tb rhythms appeared. Melatonin treatment and, to a lesser extent, water restriction enhanced the 24‐h component, suggesting a potential role in ameliorating the disruptive effects of shift work.

    更新日期:2019-11-18
  • The Lhx4 homeobox transcript in the rat pineal gland: Adrenergic regulation and impact on transcripts encoding melatonin‐synthesizing enzymes
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-11-11
    Henrik Hertz, Mikkel B. Carstensen, Tenna Bering, Kristian Rohde, Morten Møller, Agnete M. Granau, Steven L. Coon, David C. Klein, Martin F. Rath

    Homeobox genes generally encode transcription factors involved in regulating developmental processes. In the pineal gland, a brain structure devoted to nocturnal melatonin synthesis, a number of homeobox genes are also expressed postnatally; among these is the LIM homeobox 4 gene (Lhx4). We here report that Lhx4 is specifically expressed in the postnatal pineal gland of rats and humans. Circadian analyses revealed a fourfold rhythm in Lhx4 expression in the rat pineal gland, with rhythmic expression detectable from postnatal day 10. Pineal Lhx4 expression was confirmed to be positively driven by adrenergic signaling, as evidenced by in vivo modulation of Lhx4 expression by pharmacological (isoprenaline injection) and surgical (superior cervical ganglionectomy) interventions. In cultured pinealocytes, Lhx4 expression was upregulated by cyclic AMP, a second messenger of norepinephrine. By use of RNAscope technology, Lhx4 transcripts were found to be exclusively localized in melatonin‐synthesizing pinealocytes. This prompted us to investigate the possible role of Lhx4 in regulation of melatonin‐producing enzymes. By use of siRNA technology, we knocked down Lhx4 by 95% in cultured pinealocytes; this caused a reduction in transcripts encoding the melatonin‐producing enzyme arylalkylamine N‐acetyl transferase (Aanat). Screening the transcriptome of siRNA‐treated pinealocytes by RNAseq revealed a significant impact of Lhx4 on the phototransduction pathway and on transcripts involved in development of the nervous system and photoreceptors. These data suggest that rhythmic expression of Lhx4 in the pineal gland is controlled via an adrenergic‐cyclic AMP mechanism and that Lhx4 acts to promote nocturnal melatonin synthesis.

    更新日期:2019-11-11
  • Identification of a novel melatonin‐binding nuclear receptor: Vitamin D receptor
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-11-11
    Nan Fang, Chunyi Hu, Wenqi Sun, Ying Xu, Yeqi Gu, Le Wu, Qing Peng, Russel J. Reiter, Lifeng Liu

    Previous studies confirmed that melatonin regulates Runx2 expression but the mechanism is unclear. There is a direct interaction between Runx2 and the vitamin D receptor (VDR). Herein, we observed a direct interaction between melatonin and the VDR but not Runx2 using isothermal titration calorimetry. Furthermore, this direct binding was detected only in the C‐terminal ligand binding domain (LBD) of the VDR but not in the N‐terminal DNA‐binding domain (DBD) or the hinge region. Spectrophotometry indicated that melatonin and vitamin D3 (VD3) had similar uptake rates, but melatonin's uptake was significantly inhibited by VD3 until the concentration of melatonin was obviously higher than that of VD3 in a preosteoblastic cell line MC3T3‐E1. GST pull‐down and yeast two‐hybrid assay showed that the interactive smallest fragments were on the 319‐379 position of Runx2 and the N‐terminus 110‐amino acid DBD of the VDR. Electrophoretic mobility shift assay (EMSA) demonstrated that Runx2 facilitated the affinity between the VDR and its specific DNA substrate, which was further documented by a fluorescent EMSA assay where Cy3 labeled Runx2 co‐localized with the VDR‐DNA complex. Another fluorescent EMSA assay confirmed that the binding of the VDR to Runx2 was significantly enhanced with an increasing concentrations of the VDR, especially in the presence of melatonin; it was further documented using a co‐immunoprecipitation assay that this direct interaction was markedly enhanced by melatonin treatment in the MC3T3‐E1 cells. Thus, the VDR is a novel melatonin‐binding nuclear receptor, and melatonin indirectly regulates Runx2 when it directly binds to the LBD and the DBD of the VDR, respectively.

    更新日期:2019-11-11
  • Melatonin attenuates epidermal growth factor‐induced cathepsin S expression in ARPE‐19 cells: Implications for proliferative vitreoretinopathy
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-11-10
    Shun‐Fa Yang, Yong‐Syuan Chen, Hsiang‐Wen Chien, Kai Wang, Chia‐Liang Lin, Hui‐Ling Chiou, Chia‐Yi Lee, Pei‐Ni Chen, Yi‐Hsien Hsieh

    Abnormal proliferation and motility of retinal pigment epithelial cells leads to proliferative vitreoretinopathy (PVR). Melatonin is a known effective antitumour and anti‐invasive agent, but whether it affects the formation and underlying mechanisms of PVR remains unclear. In this study, the results of the MTT assay, colony formation and propidium iodide (PI) staining with flow cytometry revealed that melatonin dose dependently inhibited epidermal growth factor (EGF)‐induced proliferation of human ARPE‐19 cells. Furthermore, melatonin reduced EGF‐induced motility by suppressing cathepsin S (CTSS) expression. Pretreatment with ZFL (a CTSS inhibitor) or overexpression of CTSS (pCMV‐CTSS) significantly inhibited EGF‐induced cell motility when combined with melatonin. Epidermal growth factor induced the phosphorylation of AKT(S473)/mTOR (S2448) and transcription factor (c‐Jun/Sp1) signaling pathways. Pretreatment of LY294002 (a PI3K inhibitor) or rapamycin (an mTOR inhibitor) markedly reduced EGF‐induced motility and p‐AKT/p‐mTOR/c‐Jun/Sp1 expression when combined with melatonin. Taken together, these data indicate that melatonin inhibited EGF‐induced proliferation and motility of human ARPE‐19 cells by activating the AKT/mTOR pathway, which is dependent on CTSS modulation of c‐Jun/Sp1 signalling. Melatonin may be a promising therapeutic drug against PVR.

    更新日期:2019-11-11
  • Corrigendum.
    J. Pineal. Res. (IF 15.221) Pub Date : 2019-10-28

    更新日期:2019-11-01
  • HDAC1 inhibition by melatonin leads to suppression of lung adenocarcinoma cells via induction of oxidative stress and activation of apoptotic pathways.
    J. Pineal. Res. (IF 15.221) Pub Date : 2015-07-18
    Chongxi Fan,Yunhu Pan,Yang Yang,Shouyin Di,Shuai Jiang,Zhiqiang Ma,Tian Li,Zhipei Zhang,Weimiao Li,Xiaofei Li,Russel J Reiter,Xiaolong Yan

    Melatonin is an indoleamine synthesized in the pineal gland that shows a wide range of physiological and pharmacological functions, including anticancer effects. In this study, we investigated the effect of melatonin on drug-induced cellular apoptosis against the cultured human lung adenocarcinoma cells and explored the role of histone deacetylase (HDAC) signaling in this process. The results showed that melatonin treatment led to a dose- and time-dependent decrease in the viability of human A549 and PC9 lung adenocarcinoma cells. Additionally, melatonin exhibited potent anticancer activity in vitro, as evidenced by reductions of the cell adhesion, migration, and the intracellular glutathione (GSH) level and increases in the apoptotic index, caspase 3 activity, and reactive oxygen species (ROS) in A549 and PC9 cells. Melatonin treatment also influenced the expression of HDAC-related molecules (HDAC1 and Ac-histone H3), upregulated the apoptosis-related molecules (PUMA and Bax), and downregulated the proliferation-related molecule (PCNA) and the anti-apoptosis-related molecule (Bcl2). Furthermore, the inhibition of HDAC signaling using HDAC1 siRNA or SAHA (a potent pan-inhibitor of HDACs) sensitized A549 and PC9 cells to the melatonin treatment. In summary, these data indicate that in vitro-administered melatonin is a potential suppressor of lung adenocarcinoma cells by the targeting of HDAC signaling and suggest that melatonin in combination with HDAC inhibitors may be a novel therapeutic intervention for human lung adenocarcinoma.

    更新日期:2019-11-01
  • Melatonin rescues cardiovascular dysfunction during hypoxic development in the chick embryo.
    J. Pineal. Res. (IF 15.221) Pub Date : 2015-10-08
    Nozomi Itani,Katie L Skeffington,Christian Beck,Youguo Niu,Dino A Giussani

    There is a search for rescue therapy against fetal origins of cardiovascular disease in pregnancy complicated by chronic fetal hypoxia, particularly following clinical diagnosis of fetal growth restriction (FGR). Melatonin protects the placenta in adverse pregnancy; however, whether melatonin protects the fetal heart and vasculature in hypoxic pregnancy independent of effects on the placenta is unknown. Whether melatonin can rescue fetal cardiovascular dysfunction when treatment commences following FGR diagnosis is also unknown. We isolated the effects of melatonin on the developing cardiovascular system of the chick embryo during hypoxic incubation. We tested the hypothesis that melatonin directly protects the fetal cardiovascular system in adverse development and that it can rescue dysfunction following FGR diagnosis. Chick embryos were incubated under normoxia or hypoxia (14% O2) from day 1 ± melatonin treatment (1 mg/kg/day) from day 13 of incubation (term ~21 days). Melatonin in hypoxic chick embryos rescued cardiac systolic dysfunction, impaired cardiac contractility and relaxability, increased cardiac sympathetic dominance, and endothelial dysfunction in peripheral circulations. The mechanisms involved included reduced oxidative stress, enhanced antioxidant capacity and restored vascular endothelial growth factor expression, and NO bioavailability. Melatonin treatment of the chick embryo starting at day 13 of incubation, equivalent to ca. 25 wk of gestation in human pregnancy, rescues early origins of cardiovascular dysfunction during hypoxic development. Melatonin may be a suitable antioxidant candidate for translation to human therapy to protect the fetal cardiovascular system in adverse pregnancy.

    更新日期:2019-11-01
  • Melatonin modulates the fetal cardiovascular defense response to acute hypoxia.
    J. Pineal. Res. (IF 15.221) Pub Date : 2015-04-25
    Avnesh S Thakor,Beth J Allison,Youguo Niu,Kimberley J Botting,Maria Serón-Ferré,Emilio A Herrera,Dino A Giussani

    Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability.

    更新日期:2019-11-01
  • Melatonin protects against isoproterenol-induced alterations in cardiac mitochondrial energy-metabolizing enzymes, apoptotic proteins, and assists in complete recovery from myocardial injury in rats.
    J. Pineal. Res. (IF 15.221) Pub Date : 2012-10-11
    Debasri Mukherjee,Arnab K Ghosh,Arun Bandyopadhyay,Anjali Basu,Santanu Datta,Sanjib K Pattari,Russel J Reiter,Debasish Bandyopadhyay

    The present study was undertaken to explore the protective effect of melatonin against isoproterenol bitartrate (ISO)-induced rat myocardial injury and to test whether melatonin has a role in preventing myocardial injury and recovery when the ISO-induced stress is withdrawn. Treatment for rats with ISO altered the activities of some of the key mitochondrial enzymes related to energy metabolism, the levels of some stress proteins, and the proteins related to apoptosis. These changes were found to be ameliorated when the animals were pretreated with melatonin at a dose of 10 mg/kg BW, i.p. In addition to its ability to reduce ISO-induced mitochondrial dysfunction, we also studied the role of melatonin in the recovery of the cardiac tissue after ISO-induced damage. Continuation of melatonin treatment in rats after the withdrawal of ISO treatment was found to reduce the activities of cardiac injury biomarkers including serum glutamate oxaloacetate transaminase (SGOT), lactate dehydrogenase (LDH), and cardio-specific LDH1 to control levels. The levels of tissue lipid peroxidation and reduced glutathione were also brought back to that seen in control animals by continued melatonin treatment. Continuation of melatonin treatment in post-ISO treatment period was also found to improve cardiac tissue morphology and heart function. Thus, the findings indicate melatonin’s ability to provide cardio protection at a low pharmacological dose and its role in the recovery process. Melatonin, a molecule with very low or no toxicity may be considered as a therapeutic for the treatment for ischemic heart disease.

    更新日期:2019-11-01
  • Melatonin suppresses tumor angiogenesis by inhibiting HIF-1alpha stabilization under hypoxia.
    J. Pineal. Res. (IF 15.221) Pub Date : 2010-05-08
    Shi-Young Park,Won-Jun Jang,Eui-Yeun Yi,Ji-Yeong Jang,Yunjin Jung,Joo-Won Jeong,Yung-Jin Kim

    Angiogenesis is an important mediator of tumor progression. As tumors expand, diffusion distances from the existing vascular supply increases, resulting in hypoxia in the cancer cells. Sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and nutrients. The key regulator of hypoxia-induced angiogenesis is the transcription factor known as hypoxia-inducible factor (HIF)-1. HIF-1alpha is stabilized by hypoxia-induced reactive oxygen species (ROS) and enhances the expression of several types of hypoxic genes, including that of the angiogenic activator known as vascular endothelial cell growth factor (VEGF). In this study, we found that melatonin, a small lipophilic molecule secreted primarily by the pineal gland, destabilizes hypoxia-induced HIF-1alpha protein levels in the HCT116 human colon cancer cell line. This destabilization of HIF-1alpha resulted from the antioxidant activity of melatonin against ROS induced by hypoxia. Moreover, under hypoxia, melatonin suppressed HIF-1 transcriptional activity, leading to a decrease in VEGF expression. Melatonin also blocked in vitro tube formation and invasion and migration of human umbilical vein endothelial cells induced by hypoxia-stimulated conditioned media of HCT116 cells. These findings suggest that melatonin could play a pivotal role in tumor suppression via inhibition of HIF-1-mediated angiogenesis.

    更新日期:2019-11-01
  • Actions of melatonin mixed with collagenized porcine bone versus porcine bone only on osteointegration of dental implants.
    J. Pineal. Res. (IF 15.221) Pub Date : 2010-05-06
    José Luis Calvo-Guirado,Gerardo Gómez-Moreno,Laura López-Marí,Javier Guardia,José María Marínez-González,Antonio Barone,Isabel F Tresguerres,Sergio D Paredes,Lorena Fuentes-Breto

    This study evaluated the effect of the topical application of melatonin mixed with collagenized porcine bone on the osteointegration on the rough discrete calcium deposit (DCD) surface implants in Beagle dogs 3 months after their insertion. In preparation for subsequent insertion of dental implants, lower molars were extracted from 12 Beagle dogs. Each mandible received two parallel wall expanded platform implants with a DCD surface of 4 mm in diameter and 10 mm in length. The implants were randomly assigned to the distal sites on each mandible in the molar area and the gaps were filled with 5 mg lyophilized powdered melatonin and porcine bone and collagenized porcine bone alone. Ten histological sections per implant were obtained for histomorphometric studies. After a 4-wk treatment period, melatonin plus porcine bone significantly increased the perimeter of bone that was in direct contact with the treated implants (P < 0.0001), bone density (P < 0.0001), and new bone formation (P < 0.0001) in comparison with porcine bone alone around the implants. Melatonin plus collagenized porcine bone on DCD surface may act as a biomimetic agent in the placement of endo-osseous dental implants and enhance the osteointegration. Melatonin combined with porcine bone on DCD implants reveals more bone in implant contact at 12 wk (84.5 +/- 1.5%) compared with porcine bone alone treated area (67.17 +/- 1.2%).

    更新日期:2019-11-01
  • Role of melatonin in mucosal gastroprotection against aspirin-induced gastric lesions in humans.
    J. Pineal. Res. (IF 15.221) Pub Date : 2010-05-06
    P C Konturek,S J Konturek,K Celinski,M Slomka,H Cichoz-Lach,W Bielanski,R J Reiter

    Melatonin and its precursor, l-tryptophan, have been shown to exert gastroprotective effects in animals, but their influence on the gastric damage by aspirin (ASA) in humans has been sparingly investigated. In this study, we designed to determine the effects of melatonin and l-tryptophan on ASA-induced gastric mucosal damage, gastric microbleeding, mucosal generation of prostaglandin E(2), and plasma melatonin, and gastrin levels. Three groups of healthy male volunteers (n = 30) with intact gastric mucosa received daily for 11 days either ASA alone or that combined with melatonin or tryptophan. Gastric blood loss and mucosal damage were evaluated at 3rd, 7th, and 11th days of ASA administration by endoscopy using Lanza score. ASA alone caused a marked rise of gastric damage and gastric blood loss, mainly at day 3rd and 7th, but they were significantly reduced at 11th day. Pretreatment with melatonin or tryptophan remarkably reduced ASA induced gastric lesions and microbleeding. Gastric mucosal generation of PGE(2) was suppressed by about 90% in all subjects treated with ASA alone without or with addition of melatonin or tryptophan. Plasma melatonin was markedly increased after treatment with melatonin or tryptophan plus ASA, but it was also raised significantly after application of ASA alone. Plasma gastrin levels were raised in subjects given melatonin or tryptophan plus ASA, but not in those with ASA alone. We conclude that melatonin and its precursor tryptophan given orally significantly reduce gastric lesions induced by ASA possibly due to (a) direct gastroprotective action of exogenous melatonin or that generated from tryptophan and (b) gastrin released from the gastric mucosa by melatonin or tryptophan.

    更新日期:2019-11-01
  • Photo-degradation of melatonin: influence of argon, hydrogenperoxide, and ethanol.
    J. Pineal. Res. (IF 15.221) Pub Date : 2008-04-24
    Hans-Jürgen Brömme,Elmar Peschke,Gunter Israel

    When organic compounds are irradiated with UV light at 254 nm, part of their covalent bonds can dissociate if the compound absorbs light at that wavelength. Therefore, photo-degradation depends strongly on the wavelength used. The energy of a light quanta at 254 nm amounts to approximately 110 kcal/mol quanta, which is in many cases higher than the binding energy of a variety of covalent bonds. As a consequence, the absorbing molecule is degraded. As melatonin absorbs light at 254 nm, this compound is vulnerable to UV light. In order to minimize undesired effects of other absorbing substances, we used as solvent mostly pure water and analyzed the influence of lambda irr = 254 nm on the disappearance of the educt (melatonin) as well as on the appearance of products derived from melatonin in the presence of oxygen, argon, hydrogen peroxide, and ethanol by UV-VIS spectroscopy and high-performance liquid chromatography (HPLC) technique. N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) appears to be the main, but obviously not the only product of photo-degradation of melatonin, independently of whether the system contains oxygen or not. If the system contains additionally hydrogen peroxide, a very strong oxidant, the hydroxyl radical (*OH), is formed. Under such conditions, melatonin is not solely photo-degraded but also attacked by the formed *OH which interact similarly with the formed main photo-product AFMK. Ethanol, as a potent scavenger of *OH, efficiently blocks the effect of this aggressive radical even at low concentrations of that scavenger (0.1% v/v) but is less effective in preventing photo-degradation of melatonin.

    更新日期:2019-11-01
  • Melatonin reduces cholesterol accumulation and prooxidant state induced by high cholesterol diet in the plasma, the liver and probably in the aorta of C57BL/6J mice.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-03-11
    Göksel Sener,Jale Balkan,Ugur Cevikbaş,Meral Keyer-Uysal,Müjdat Uysal

    We examined the hypolipidemic and antioxidative effects of melatonin in plasma, liver and aorta of C57BL/6J mice fed on a high cholesterol (HC) diet. Mice were fed normal mice chow containing 1.5% cholesterol and 0.5% cholic acid for 4 months with or without melatonin (10 mg/L in drinking water) treatment. HC diet was observed to increase cholesterol, triglyceride and diene conjugate (DC) levels in plasma and liver. There was a tendency towards an increase in cholesterol level in the aorta following HC diet. In addition, aortic DC levels were higher than those of control group. No fatty streaks or plaques developed in the aorta of mice following HC diet, but in some sections, derangement of the endothelial layer was detected. Melatonin treatment was found to reduce plasma, liver cholesterol and DC levels as well as liver triglyceride levels in hypercholesterolemic mice. Aortic cholesterol and DC levels were also reduced in hypercholesterolemic mice when given melatonin, although not statistically significant. There were no differences in aortic histopathological findings of mice fed on a HC diet with and without melatonin treatment. In conclusion, our results indicate that melatonin reduces HC diet-induced cholesterol accumulation and prooxidant state in the plasma, liver and probably in the aorta.

    更新日期:2019-11-01
  • MT-1 melatonin receptor expression increases the antiproliferative effect of melatonin on S-91 murine melanoma cells.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-03-11
    Ana Luisa Kadekaro,Luciana N S Andrade,Lucile M Floeter-Winter,Mark D Rollag,Victoria Virador,Wilfred Vieira,Ana Maria de L Castrucci

    Melatonin, a derivative of tryptophan that is present in all vertebrates, was first described in bovine pineal gland. It is known that melatonin is a highly conserved molecule, present also in unicellular organisms and plants. Several effects of melatonin have been described, including receptor- and non-receptor-mediated actions. Herein, we studied the effects of melatonin on in vitro and in vivo cell proliferation of Cloudman S-91 murine melanoma cells. We demonstrated that melatonin treatment significantly inhibits S-91 melanoma cell proliferation in vitro (EC50 = 10-7 m) as well as reduces tumor growth in vivo. We also demonstrated that melatonin directly increases the activity of the antioxidant enzymes catalase and glutathione peroxidase. These effects are most likely triggered through the direct intracellular action of melatonin, since the presence of receptors could not be demonstrated in this cell line. Expression of MT-1 melatonin receptor by stable transfection, mediated a dramatic antiproliferative melatonin effect (EC50 = 10-10 m) in S-91 cells. The expressed receptor is negatively coupled to the adenylyl cyclase/cyclic AMP signaling pathway via Gi protein. These results suggest that expression of the MT-1 melatonin receptor in melanoma cells is a potential alternative approach to specifically target cells in cancer therapeutic treatment.

    更新日期:2019-11-01
  • Melatonin protects against piroxicam-induced gastric ulceration.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-03-11
    Debashis Bandyopadhyay,Goutam Ghosh,Arun Bandyopadhyay,Russel J Reiter

    The antiulcer effect of melatonin on gastric lesions caused by piroxicam was studied with the intent of determining the mechanism of action of this agent. Melatonin dose-dependently lowered piroxicam and indomethacin-induced gastric damage with more than 90% inhibition at a dose of 60 mg/kg BW. Increased lipid peroxidation, augmented protein oxidation and decreased glutathione content of the gastric tissue following piroxicam treatment indicated a possible involvement of oxidative stress in this nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. Pretreatment of rats with melatonin prevented these changes. Oral administration of piroxicam to rats caused a threefold increase in the tissue levels of hydroxyl radical generation, a change significantly attenuated by melatonin. Furthermore, a decrease in the activity of gastric peroxidase and an increase in the activity of gastric superoxide dismutase(s) (SOD) because of piroxicam treatment was attenuated by melatonin pretreatment indicating that the indole possibly exerts its gastroprotective effects through its direct as well as indirect antioxidant activities. The results of the present studies also reveal that melatonin may influence the expression of Cu-Zn SOD, catalase, cyclooxygenase as well as alpha-actinin whose levels were found to be altered, following piroxicam treatment. The current studies, therefore, document melatonin's gastroprotective ability against piroxicam-induced gastric damage and the findings raise the possibility of melatonin being considered as a co-therapy with piroxicam or other NSAIDs in reducing the gastropathy when long-term use of these nonsteroidal agents are unavoidable.

    更新日期:2019-11-01
  • Evening melatonin and bright light administration induce additive phase shifts in dim light melatonin onset.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-03-11
    Anna Wirz-Justice,Kurt Kräuchi,Christian Cajochen,Konstantin V Danilenko,Claudia Renz,Jakob M Weber

    In healthy young men, administration of a single light pulse (5000 lux for 3 hr) or a single melatonin pill (5 mg) at 20:40 hr under controlled constant routine conditions of <10 lux, yielded a phase delay and a phase advance, respectively, in the circadian marker of dim light melatonin onset 24 hr later. Phase shifts after combining the two interventions were additive. Melatonin suppression is not necessary for a phase shift by light, and melatonin is not a 'weak' Zeitgeber relative to bright light when ambient lighting is strictly controlled.

    更新日期:2019-11-01
  • Melatonin protects SH-SY5Y neuroblastoma cells from calyculin A-induced neurofilament impairment and neurotoxicity.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-03-11
    Shu Peng Li,Yan Qiu Deng,Xiao Chuan Wang,Yi Peng Wang,Jian-Zhi Wang

    Hyperphosphorylation of cytoskeletal proteins seen in Alzheimer's disease is most probably the result of an imbalanced regulation in protein kinases and protein phosphatases (PP) in the affected neurons. Previous studies have revealed that PP-2A and PP-1 play important roles in the pathogenesis. Employing human neuroblastoma cells, we found that 10 nM calyculin A (CA), a selective inhibitor of PP-2A and PP-1, significantly increased phosphorylation and accumulation of neurofilament (NF) in the cells. Levels of NF-M (middle chain) and NF-L (light chain) mRNA decreased after CA treatment. Additionally, CA led to a decreased cell viability determined by MTT and crystal violet assay. Melatonin efficiently protects the cell from CA-induced alterations in NF hyperphosphorylation and accumulation, suppressed NF gene expression as well as decreased cell viability. It is concluded that inhibition of PP-2A/PP-1 by CA induces abnormalities in NF metabolism and cell survival, and melatonin efficiently arrests the lesions.

    更新日期:2019-11-01
  • Circadian rhythms of dopamine, glutamate and GABA in the striatum and nucleus accumbens of the awake rat: modulation by light.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-03-11
    Tamara R Castañeda,Blanca Marquez de Prado,David Prieto,Francisco Mora

    Using microdialysis, we investigated the circadian rhythms of the extracellular concentrations of dopamine, glutamate and gamma-aminobutyric acid (GABA) in the striatum and nucleus accumbens of the awake rat. Wistar rats were maintained in a 12 hr dark:12 hr light (12:12) cycle for 2 wk before the experiment began. The neurotransmitter levels were measured every 30 min for 30 hr in control (maintaining the 12:12 cycle) or in experimental conditions under a 24-h light period (continuous light) or under a 24-h dark interval (continuous dark). The dopamine metabolites, DOPAC and HVA, and the main serotonin metabolite, 5-HIAA, were measured along with arginine and glutamine under all conditions. In 12:12 conditions, a circadian rhythm of dopamine, glutamate and GABA was found in both the striatum and nucleus accumbens. Again under 12:12 conditions, DOPAC, HVA, 5-HIAA, and arginine, but not glutamine, fluctuated in a circadian rhythm. In the striatum under constant light conditions, there was a circadian rhythm of dopamine, glutamate, GABA, DOPAC and HVA, but not 5-HIAA. By contrast, when the rats were kept under continuous dark, dopamine and its metabolites, DOPAC and HVA (but not glutamate and GABA), did not fluctuate in a circadian rhythm. In the nucleus accumbens, under both constant light or dark conditions, no changes were found in the circadian rhythm in any of the neurotransmitters and metabolites studied. These findings show that in the striatum, dopamine but not glutamate and GABA, seem to be influenced by light. In the nucleus accumbens, however, the three neurotransmitters had a circadian rhythm, which was independent of light.

    更新日期:2019-11-01
  • Melatonin reduces disseminate neuronal death after mild focal ischemia in mice via inhibition of caspase-3 and is suitable as an add-on treatment to tissue-plasminogen activator.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-03-11
    Ertugrul Kilic,Ulkan Kilic,Burak Yulug,Dirk M Hermann,Russel J Reiter

    The effects of i.p. melatonin (4 + 4 mg/kg, after induction of ischemia and at reperfusion onset) administered either alone or in combination with the thrombolytic tissue-plasminogen activator (t-PA, 10 mg/kg), on cerebral laser Doppler flow (LDF) and ischemic injury were studied after 30 min of middle cerebral artery (MCA) thread occlusion in male C57BL/6 mice. Thread occlusions resulted in reproducible focal ischemias, followed by hyperperfusion reactions immediately after thread withdrawal, as revealed by LDF measurements. Compared with animals receiving normal saline (peak LDF after reperfusion: 172.0 +/- 24.2%), postischemic LDF was significantly attenuated in animals treated with melatonin (105.1 +/- 6.7%, P < 0.05). Delivery of t-PA (132.8 +/- 22.3%) or t-PA plus melatonin (164.7 +/- 36.7%), on the contrary, did not influence postischemic LDF recordings. Twenty-four hours after reperfusion, melatonin treated mice had significantly increased neuronal survival and decreased disseminate cell injury in the ischemia-vulnerable striatum, as investigated by cresyl violet and terminal transferase biotinylated-dUTP nick end labeling stainings. The protective effects were associated with inhibition of caspase-3 activity. Melatonin administration also increased neuronal survival after 30 min MCA occlusion in animals treated with t-PA, although t-PA itself already decreased the degree of injury in a significant manner. Our data demonstrate that melatonin reduces disseminated neuronal injury in the striatum after mild focal ischemia. Brain protection is independent of hemodynamic changes and involves inhibition of caspase-3.

    更新日期:2019-11-01
  • Age-related changes in murine CNS mRNA gene expression are modulated by dietary melatonin.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-03-11
    Edward H Sharman,Kaizhi G Sharman,Yuan-Wen Ge,Debomoy K Lahiri,Stephen C Bondy

    Brain cellular functions decline with normal aging, accompanied by a changing profile of gene expression. Gene array analysis was used to quantitatively estimate messenger RNA (mRNA) expression levels in the cerebral cortex of both young (4-month) and old (27-month) B6C3F1 male mice. A stringent degree of significance was obtained by using multiple gene chips. Out of 12,423 mRNA levels, only 25 changed significantly with age. Nine of these genes coded for inflammatory proteins, all of which were elevated in aged, relative to younger mice. Melatonin (200 p.p.m.) included in the diet of aged animals for 8 wk elevated serum and cortical melatonin and reversed 13 of the 25 genes altered with age. In no case did melatonin potentiate age-related changes in gene expression. The restoration of a more youthful gene profile to brains of aged animals by melatonin, to a large extent, involves reversal of age-induced elevation of basal inflammatory parameters.

    更新日期:2019-11-01
  • Melatonin and its precursor, L-tryptophan: influence on pancreatic amylase secretion in vivo and in vitro.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-03-11
    Jolanta Jaworek,Katarzyna Nawrot,Stanisław J Konturek,Anna Leja-Szpak,Piotr Thor,Wiesław W Pawlik

    Melatonin, considered as a main pineal product, may be also synthetized in the gastrointestinal tract from L-tryptophan. Melatonin has been recently shown to affect insulin release and its receptors have been characterized in the pancreas however, the effects of melatonin on the pancreatic enzyme secretion have not been examined. The aim of this study was to investigate the effects of melatonin or L-tryptophan on amylase secretion in vivo in anaesthetized rats with pancreato-biliary fistulas, and in vitro using isolated pancreatic acini. Melatonin (1, 5 or 25 mg/kg) or L-tryptophan (10, 50 or 250 mg/kg) given to the rats as a intraperitoneal (i.p.) bolus injection produced significant and dose-dependent increases in pancreatic amylase secretion under basal conditions or following stimulation of enzyme secretion by diversion of bile-pancreatic juice. This was accompanied by a dose-dependent rise in melatonin plasma level. Stimulation of pancreatic enzyme secretion caused by melatonin or L-tryptophan was completely abolished by vagotomy, deactivation of sensory nerves with capsaicin or pretreatment with CCK1 receptor antagonists (tarazepide or L-364,718). Pretreatment with luzindole, an antagonist of melatonin MT(2) receptor failed to affect melatonin- or L-tryptophan-induced amylase secretion. Administration of melatonin (1, 5 or 25 mg/kg i.p.) or L-tryptophan (10, 50 or 250 mg/kg i.p.) to the rats resulted in the dose-dependent increase of cholecystokinin (CCK) plasma immunoreactivity. Enzyme secretion from isolated pancreatic acini was not significantly affected by melatonin or L-tryptophan used at doses of 10(-8) -10(-5) M. We conclude that exogenous melatonin, as well as that produced endogenously from L-tryptophan, stimulates pancreatic enzyme secretion in vivo while increasing CCK release. Stimulatory effect of melatonin or L-tryptophan on the exocrine pancreas involves vagal sensory nerves and the CCK release by these substances.

    更新日期:2019-11-01
  • Melatonin prevents lipopolysaccharide-induced hyporeactivity in rat.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-03-11
    Roberta d'Emmanuele di Villa Bianca,Stefania Marzocco,Rosanna Di Paola,Giuseppina Autore,Aldo Pinto,Salvatore Cuzzocrea,Raffaella Sorrentino

    Melatonin (MT) is the principal secretory product of the pineal gland and its role as an immumo-modulator is well established. Recent evidence shows that MT exerts protective effects in septic shock, hemorrhagic shock and inflammation. Lipopolysaccharide (LPS), from Escherichia coli, administered to animals directly stimulates a number of cells and systems to produce various inflammatory mediators. LPS-induced septic shock is characterized by hypotension and vascular hyporeactivity to contracting agents. In particular, the reactive oxygen species such as superoxide and nitric oxide (NO) contribute to the pathophysiology of septic shock. In this study, we demonstrate that MT pretreatment prevents the hyporeactivity to phenylephrine in vivo and in aorta rings collected from rats treated with the endotoxin. The beneficial effect of MT seems related to its antioxidant properties and with inhibition of inducible nitric oxide synthase (iNOS) protein expression, reduction of NO production and nitrotyrosine formation, in aorta, preventing vascular, and endothelial injury. Additionally, we first demonstrate, that MT inhibited nuclear enzyme poly (ADP-ribose) synthetase activation in vascular tissue. The current study underlined the protective effect of MT on the vascular dysfunction associated with septic shock, data that could support the clinical use of MT in human endotoxemia.

    更新日期:2019-11-01
  • Differential effects of light wavelength in phase advancing the melatonin rhythm.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-02-14
    Helen R Wright,Leon C Lack,David J Kennaway

    Shorter wavelength light has been shown to be more effective than longer wavelengths in suppressing nocturnal melatonin and phase delaying the melatonin rhythm. In the present study, different wavelengths of light were evaluated for their capacity to phase advance the saliva melatonin rhythm. Two long wavelengths, 595 nm (amber) and 660 nm (red) and three shorter wavelengths, 470 nm (blue), 497 nm (blue/green), and 525 nm (green) were compared with a no-light control condition. Light was administered via a portable light source comprising two light-emitting diodes per eye, with the irradiance of each diode set at 65 microW/cm(2). Forty-two volunteers participated in up to six conditions resulting in 15 per condition. For the active light conditions, a 2-hr light pulse was administered from 06:00 hr on two consecutive mornings. Half-hourly saliva samples were collected on the evening prior to the first light pulse and the evening following the second light pulse. The time of melatonin onset was calculated for each night and the difference was calculated as a measure of phase advance. The shorter wavelengths of 470, 495 and 525 nm showed the greatest melatonin onset advances ranging from approximately 40-65 min while the longer wavelengths produced no significant phase advance. These results strengthen earlier findings that the human circadian system is more sensitive to the short wavelengths of light than the longer wavelengths.

    更新日期:2019-11-01
  • Pinealectomy induces malformation of the spine and reduces the mechanical strength of the vertebrae in Atlantic salmon, Salmo salar.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-02-14
    Per Gunnar Fjelldal,Sindre Grotmol,Harald Kryvi,Nils Roar Gjerdet,Geir Lasse Taranger,Tom Hansen,Mark J R Porter,Geir K Totland

    This study describes the long-term effects of surgical ablation of the pineal gland on the spine of 3-yr-old Atlantic salmon (Salmo salar L.) with a mean weight of 3.2 kg. Radiographic examinations showed that 82% of the pinealectomized fish developed marked lateral (scoliosis) and dorso-ventral spinal curvatures. The proportions of the individual vertebral bodies and their mechanical properties were also altered. The stiffness, yield limit and resilience of the vertebral bodies, as measured by compression in the cranio-caudal direction, were significantly lower in the pinealectomized than in the sham-pinealectomized group. Calcium, phosphorous and total mineral content of the vertebral bodies were also significantly lower in the pinealectomized fish, while these parameters were similar in scales in the two groups. Alterations of the spinal curve accompanied by changes in the proportions, mechanical strength and mineral content of the vertebral bodies of the pinealectomized salmon indicate that melatonin has several functions related to vertebral bone growth. As the lesions found in salmon are similar to the spinal malformations observed in avian species and mammals after pinealectomy, this study strengthens the hypothesis of a phylogenetically conserved function of the pineal gland related to skeletal development.

    更新日期:2019-11-01
  • Attenuation of cold-induced apoptosis by exogenous melatonin in carrot suspension cells: the possible involvement of polyamines.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-02-14
    Xiao-Yong Lei,Rui-Yu Zhu,Gui-You Zhang,Yao-Ren Dai

    Pretreatment with 43 nM (10 ng/mL) to 86 nM melatonin for 5 days significantly attenuated cold-induced apoptosis in carrot suspension cells (Daucus carota L.) as evidenced by the TUNEL procedure, DNA fragmentation and the morphological changes revealed by electronic microscopy observations. The antiapoptotic effect of melatonin was initially thought to be a result of its antioxidant actions. In our study, however, reactive oxygen species (ROS) generation remained unaffected by melatonin treatment, suggesting that melatonin plays its protective role not related to its direct ROS scavenger. At the same time, notable increases in putrescine and spermidine levels were observed in melatonin-treated cells, which may be responsible for the alleviation of the cold-induced apoptosis. The possible involvement of polyamines in the antiapoptotic effect of melatonin was further confirmed by the inhibitory effect of exogenous polyamines on apoptosis as displayed by the DNA laddering assay.

    更新日期:2019-11-01
  • Effect of melatonin on temporal changes of reactive oxygen species and glutathione after MPP(+) treatment in human astrocytoma U373MG cells.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-02-14
    Jih-Ing Chuang,Tsung-Hung Chen

    1-Methyl-4-phenylpyridinium (MPP(+)) ion, a toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, is produced by monoamine oxidase B in astrocytes. MPP(+) causes a selective dopaminergic neurodegeneration, the pathophysiologic hallmark of Parkinson disease. However, the toxic effect of MPP(+) on astrocytes remains unclear. Here, we examined the effect of MPP(+) on human astrocytoma U373MG cells, with particular attention to the temporal interaction of glutathione (GSH) and reactive oxygen species (ROS) (H2O2 and O). MPP(+) induced astrocyte apoptosis in a dose-dependent manner 48 hr after treatment. Distinctive early (<6 hr) and late (24-48 hr) responses were observed. ROS production and the oxidized GSH (GSSG)/GSH ratio, indicators of oxidative stress, rose dramatically after 24 hr of MPP(+) exposure, whereas the H2O2 level transiently decreased at 6 hr. ROS overproduction and GSH dysfunction were concomitantly associated with caspase-3 activation and finally led to cell apoptosis. Moreover, GSH depletion by diethyl maleate, but not buthionine sulfoximine, caused cells to die quickly and potentiated the cytotoxicity of MPP(+). Co-treatment with melatonin, a known antioxidant secreted by the pineal gland, significantly prevented cell apoptosis by inhibiting oxidative stress and caspase-3 activation, but it did not affect that the early changes due to MPP(+) treatment. Our results demonstrate that in astrocytes, GSH is involved in the early decrease and late increase in ROS levels induced by MPP(+) treatment. Melatonin remedies the dysfunction of GSH system to block caspase-3 activation and cell apoptosis induced by oxidative stress during the long-term exposure of MPP(+).

    更新日期:2019-11-01
  • Melatonin receptor agonist 2-iodomelatonin prevents apoptosis of cerebellar granule neurons via K(+) current inhibition.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-02-14
    Song Jiao,Ming-Ming Wu,Chang-Long Hu,Zhi-Hong Zhang,Yan-Ai Mei

    Activation of K(+) current plays a critical role in the control of programmed cell death. In the present study, whole-cell patch-clamp recording, a caspase-3 activity assay, and flow cytometric analysis were used to examine the effects of the MT2 melatonin receptor agonist 2-iodomelatonin on the delayed-rectifier K(+) current (IK) and the prevention of apoptosis. It was found that apoptosis of cerebellar granular neurons induced by low-K(+) (5 mm) incubation was associated with an increase in IK amplitude and caspase-3 activity. After 6 hr of low-K(+) treatment, IK was increased by 45% (n = 86). Flow cytometry showed that the apoptosis rate increased by 333% compared with the control neurons. In addition, exposure of cultured granule cells to low K(+) also resulted in a significant activation of caspase-3, by 466%. 2-Iodomelatonin (10 microm in injection pipette) inhibited the IK amplitude recorded from control cells and from cells undergoing apoptosis. However, 2-iodomelatonin only modified the IK-channel activation kinetics of cells under both conditions. Furthermore, 2-iodomelatonin reduced the rate of apoptosis and caspase-3 activation, by 66 and 64%, respectively. The melatonin receptor antagonist, 4P-PDOT, abrogated the effect of 2-iodomelatonin on the IK augmentation, caspase-3 activity, and apoptosis. These results suggest that the neuroprotective effects of melatonin are not only because of its function as a powerful antioxidant, but also to its interactions with specific receptors. The effect of 2-iodomelatonin against apoptosis may be mediated by activating a melatonin receptor, which modulates IK channels and reduces K(+) efflux.

    更新日期:2019-11-01
  • Central nervous alpha1-adrenoceptor stimulation induces duodenal luminal release of melatonin.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-02-14
    Markus Sjöblom,Gunnar Flemström

    Intracerebroventricular (i.c.v.) infusion of the alpha1-adrenoceptor agonist phenylephrine elicits vagal and sympathetic neural stimulation of the bicarbonate secretion by the duodenal mucosa. Melatonin originating from mucosal enterochromaffin cells (EC cells) has been proposed to mediate this centrally elicited stimulation. However, the release of intestinal melatonin has not been studied. Rats were anesthetized with thiobarbiturate, a 12-mm segment of duodenum with intact blood supply was cannulated in situ and bicarbonate secretion titrated by pH-stat. The mean arterial blood pressure was continuously recorded. Melatonin in the duodenal luminal perfusate was determined by high-performance liquid chromatography with electrochemical detection. Intracerebroventricular infusion of phenylephrine (12.2 microM/kg/hr) induced more than 10-fold increase in release of melatonin into the duodenal lumen and an increase in HCO secretion from 7.6 +/- 0.5 to 18.6 +/- 2.1 microEq/cm/hr. The melatonin receptor (MT2 > MT1) antagonist luzindole (600 nM/kg, i.v.) almost abolished the marked rise in bicarbonate secretion induced by i.c.v. phenylephrine but, in contrast, did not affect the release of melatonin. These results strongly suggest that release of melatonin from the mucosa mediates the duodenal secretory response to centrally elicited neural stimulation.

    更新日期:2019-11-01
  • Indole-based analogs of melatonin: in vitro antioxidant and cytoprotective activities.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-02-14
    Marco Mor,Claudia Silva,Federica Vacondio,Pier Vincenzo Plazzi,Simona Bertoni,Gilberto Spadoni,Giuseppe Diamantini,Annalida Bedini,Giorgio Tarzia,Morena Zusso,Davide Franceschini,Pietro Giusti

    The known neuroprotective actions of melatonin could be due to its antioxidant or radical scavenging activity, or they could be due to specific interactions of the indole with its receptors. A study of structure-activity relationships may provide useful information when a validated macromolecular target has not been (or is not) identified. A set of indole derivatives, with changes in the 5-methoxy and acylamino groups, the side chain position and the lipophilic/hydrophilic balance, were selected and tested for their in vitro antioxidant potency in the ABTS (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid disodium salt) and thiobarbituric acid reactive substances (TBARS) assays and for their cytoprotective activity against kainate excitotoxicity on cerebellar cell cultures. No quantitative model was able to relate the potencies obtained in the two antioxidant assays, probably because they are related to different physico-chemical properties. However, the lipophilicity of the compounds and the antioxidant potency in the TBARS assay were linearly correlated. This may be due to improved access to the lipidic substrate, where the antioxidant action occurs. In the cytoprotection assay, most compounds showed potencies comparable with or lower than melatonin. An exception was N-[2-(5-methoxy-1H-indol-2-yl)ethyl]acetamide (12), yielding, at 50 microM, percentages of cell vitality higher than 75%, while melatonin EC50 was 333 microM. No correlation was observed between cytoprotective and antioxidant potencies, nor with MT1 or MT(2) receptor affinity. Compound 12 is a low-affinity antagonist at melatonin membrane receptors, and one of the most potent compounds in the antioxidant assays; its cytoprotective potency and the absence of agonist activity at melatonin membrane receptors make it a valid candidate for further investigations.

    更新日期:2019-11-01
  • Acutely administered melatonin decreases somatostatin-binding sites and the inhibitory effect of somatostatin on adenylyl cyclase activity in the rat hippocampus.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-02-14
    Rosa María Izquierdo-Claros,María del Carmen Boyano-Adánez Md,Eduardo Arilla-Ferreiro

    Melatonin is known to increase neuronal activity in the hippocampus, an effect contrary to that of somatostatin (somatotropin release-inhibiting factor, SRIF). Thus, the aim of this study was to investigate whether the somatostatinergic system is implicated in the mechanism of action of melatonin in the rat hippocampus. One group of rats was injected a single dose of melatonin [25 microg/kg subcutaneously (s.c.)] or saline containing ethanol (0.5%, s.c.) and killed 5 hr later. Melatonin significantly decreased the SRIF-like immunoreactivity levels and induced a significant decrease in the density of SRIF receptors as well as in the dissociation constant (Kd). SRIF-mediated inhibition of basal and forskolin-stimulated adenylyl cyclase activity was markedly decreased in hippocampal membranes from melatonin-treated rats. The functional activity of Gi proteins was similar in hippocampal membranes from melatonin-treated and control rats. Western blot analyses revealed that melatonin administration did not alter Gialpha1 or Gialpha2 levels. To determine if the changes observed were related to melatonin-induced activation of central melatonin receptors, a melatonin receptor antagonist, luzindole, was administered prior to melatonin injection. Pretreatment with luzindole (10 mg/kg, s.c.) did not alter the melatonin-induced effects on the above-mentioned parameters and luzindole, alone, had no observable effect. The present results demonstrate that melatonin decreases the activity of the SRIF receptor-effector system in the rat hippocampus, an effect which is apparently not mediated by melatonin receptors. As SRIF exerts an opposite effect to that of melatonin on hippocampal neuronal activity, it is possible that the SRIFergic system could be implicated in the mechanism of action of melatonin in the rat.

    更新日期:2019-11-01
  • Suppression of melatonin biosynthesis in the chicken pineal gland by retinally perceived light - involvement of D1-dopamine receptors.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-02-14
    Jolanta B Zawilska,Małgorzata Berezińska,Jolanta Rosiak,Debra J Skene,Berthe Vivien-Roels,Jerzy Z Nowak

    In this study the role of retinal dopamine (DA) receptors in the light-induced suppression of melatonin biosynthesis in the chicken pineal gland was examined. Exposure of dark-adapted chickens to low intensity light (4 lux) at night significantly decreased the activity of serotonin N-acetyltransferase (AA-NAT; the penultimate and key regulatory enzyme in melatonin production) and melatonin content in the pineal gland. This suppressive action of light was blocked by intraocular (i.oc.) administration of SCH 23390 (a selective antagonist of D1-DA receptors), but was not affected by sulpiride (a selective antagonist of D2-DA receptors). Injection of DA (i.oc.) to dark-adapted chickens significantly decreased pineal AA-NAT activity and melatonin content in a dose- and time-dependent manner. The action of DA was mimicked by selective agonists of D1-DA receptors, SKF 38393 and SKF 81297, and non-hydrolyzable analogs of cyclic AMP (cAMP), dibutyryl-cAMP and 8-bromo-cAMP. However, i.oc. administration of quinpirole, a selective agonist of D2-DA receptors, did not modify pineal AA-NAT activity. In contrast, quinpirole potently decreased nocturnal AA-NAT activity in the retina. Systemic administration of SCH 23390 to chickens blocked the i.oc. DA-evoked decline in nighttime pineal AA-NAT activity, whereas sulpiride was ineffective. These findings indicate that light activation of retinal dopaminergic neurotransmission, with concomitant stimulation of D1-DA receptors positively coupled to the cAMP generating system, plays an important role in a cascade of events regulating pineal activity.

    更新日期:2019-11-01
  • Melatonin and viral infections.
    J. Pineal. Res. (IF 15.221) Pub Date : 2004-02-14
    Ernesto Bonilla,Nereida Valero,Leonor Chacín-Bonilla,Shirley Medina-Leendertz

    The therapeutic effects of melatonin against viral infections, with emphasis on the Venezuelan equine encephalomyelitis (VEE), are reviewed. Melatonin has been shown to prevent paralysis and death in mice infected with the encephalomyocarditis virus and to decrease viremia. Melatonin also postpones the onset of the disease produced by Semliki Forest virus inoculation and reduces the mortality of West Nile virus-infected mice stressed by either isolation or dexamethasone injection. An increase in the host resistance to the virus via a peripheral immunostimulatory activity is considered responsible for these effects. It has also been demonstrated that melatonin protects some strains of mink against Aleutian disease, and prevents the reduction of B- and T-cells as well as Th1 cytokine secretion in mice infected with leukemia retrovirus. In VEE-infected mice, melatonin postpones the onset of the disease and death for several days and reduces the mortality rate. This protective effect seems to be due to the increase in the production of interleukin-1beta (IL-1beta), as 100% of the infected mice treated with melatonin die when IL-1beta is blocked with antimurine IL-1beta antibodies. Although melatonin administration raises serum levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), the mortality observed in neutralization experiments with the corresponding anticytokine antibodies, suggests that neither TNF-alpha nor IFN-gamma are essential for the protective effect of melatonin on murine VEE virus infection. Melatonin treatment also enhances the efficiency of immunization against the VEE virus. Reactive oxygen species have been implicated in the dissemination of this virus, and their deleterious effects may be diminished by melatonin. This indole inhibits nitric oxide synthetase activity and it is a potent scavenger of nitric oxide, which also plays an important role in the spread of the VEE virus. In conclusion, the immunomodulatory, antioxidant, and neuroprotective effects of melatonin suggest that this indole must be considered as an additional therapeutic alternative to fight viral diseases.

    更新日期:2019-11-01
  • Synthesis of internal labeled standards of melatonin and its metabolite N1-acetyl-N2-formyl-5-methoxykynuramine for their quantification using an on-line liquid chromatography-electrospray tandem mass spectrometry system.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-12-17
    Eduardo A Almeida,Clécio F Klitzke,Glaucia R Martinez,Marisa H G Medeiros,Paolo Di Mascio

    Melatonin (N-acetyl-5-methoxytryptamine) is implicated in physiologic changes related to light-dark cycles and has been recently found to display antioxidant properties. It is known that the reaction of melatonin with certain reactive oxygen and nitrogen species, such as hydrogen peroxide and singlet oxygen, produces N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK). We report herein on the development of a new liquid chromatography/tandem mass spectrometry (LC/ESI/MS-MS) assay to quantitatively determine melatonin and AFMK. The stable isotopic internal standard of melatonin-D3 was synthesized by the reaction of 5-methoxytryptamine with deuterated acetyl chloride (CD3COCl). Labeled AFMK (AFMK-D3) was obtained after photooxidation of melatonin-D3. The predominant ion [M + H]+ in the full scan mass spectra of melatonin, melatonin-D3, AFMK and AFMK-D3 were located, respectively, at m/z = 233, 236, 265 and 268. The collision-induced dissociation of the molecules revealed a predominant fragment at m/z = 174 for melatonin and melatonin-D3 (loss of the N-acetyl group), and at m/z = 178 for AFMK and AFMK-D3 (loss of both the N-acetyl and the N-formyl groups). The m/z transitions from 233 to 174 (melatonin), from 236 to 174 (melatonin-D3), from 265 to 178 (AFMK), and from 268 to 178 (AFMK-D3) were therefore chosen for the multiple reaction monitoring detection experiments, ensuring a high specificity and an accurate quantification of melatonin and AFMK in human plasma.

    更新日期:2019-11-01
  • Protective effect of melatonin on random pattern skin flap necrosis in pinealectomized rat.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-12-17
    Ali Gurlek,Hakan Aydogan,Hakan Parlakpinar,Aysun Bay-Karabulut,Mehmet Celik,Nurzen Sezgin,Ahmet Acet

    Random pattern skin flaps are still widely used in plastic surgery. However, necrosis in the distal portion resulting from ischemia is a serious problem, increasing the cost of treatment and hospitalization. Free oxygen radicals and increased neutrophil accumulation play an important role in tissue injury and may lead to partial or complete flap necrosis. To enhance skin flap viability, a variety of pharmacological agents have been intensively investigated. The aim of this study is to test the effects of melatonin, the chief secretory product of the pineal gland and a highly effective antioxidant, on random pattern skin flap survival in rats. Herein, to investigate the physiological and pharmacological role of melatonin on dorsal skin flap survival. Pharmacological (0.4, 4 and 40 mg/kg) levels of melatonin were given intraperitoneally (i.p.). For this, pinealectomized (Px) and sham operated (non-Px) rats were used. The effects of melatonin on levels of malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH) and the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were measured in the skin flap. The ratio of skin flap necrosis was compared among the experimental groups by using planimetry. MDA and NO levels were found to be higher in Px than non-Px rats; while GSH levels and GSH-Px, and SOD activities were reduced. Melatonin administration to Px rats reduced MDA and NO levels and increased GSH, GSH-Px, SOD levels. Melatonin also reduced the ratio of flap necrosis determined by using planimetry and supported through the photography. In conclusion, these results show that both physiological and pharmacological concentrations of melatonin improve skin flap viability.

    更新日期:2019-11-01
  • Melatonin attenuates rat carotid chemoreceptor response to hypercapnic acidosis.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-12-17
    Yung Wui Tjong,Yueping Chen,Emily C Liong,Shing Fat Ip,George L Tipoe,Man Lung Fung

    Respiratory activity is under circadian modulation and the physiological mechanisms may involve the pineal secretory product, melatonin, and the carotid chemoreceptor. We hypothesized that melatonin modulates the carotid chemoreceptor response to hypercapnic acidosis. To determine whether the effect of melatonin on the chemoreceptor response to hypercapnic acidosis is mediated by melatonin receptors in the chemosensitive cells, cytosolic calcium ([Ca2+]i) was measured by spectrofluorometry in fura-2-loaded glomus cells dissociated from rat carotid bodies. Melatonin (0.01-10 nm) per se did not change the [Ca2+]i levels of the glomus cells but it concentration-dependently attenuated the peak [Ca2+]i response to hypercapnic acidosis in the glomus cells. In addition, the [Ca2+]i response was attenuated by 2-iodomelatonin, an agonist of melatonin receptors. The melatonin-induced attenuation of the [Ca2+]i response to hypercapnic acidosis was abolished by pretreatment with an non-selective mt1/MT2 antagonist, luzindole, and by MT2 antagonists, 4-phenyl-2-propionamidotetraline or DH97. In situ hybridization study with antisense mt1 and MT2 receptor mRNA oligonucleotide probes showed an expression of mt1 and MT2 receptors in the rat carotid body. Also, melatonin attenuated the carotid afferent response to hypercapnic acidosis in single- or pauci-fibers recorded from the sinus nerve in isolated carotid bodies superfused with bicarbonate-buffer saline. Results suggest that an activation of the melatonin receptors expressed in the glomus cells of the rat carotid body reduces the chemoreceptor response to hypercapnic acidosis. This modulation may play a physiological role in the influence of the circadian rhythms on the chemoreflex.

    更新日期:2019-11-01
  • The melatonin receptor subtype MT1 is expressed in human gallbladder epithelia.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-12-17
    Sylvia Aust,Theresia Thalhammer,Susanne Humpeler,Walter Jäger,Martin Klimpfinger,Gerhard Tucek,Peter Obrist,Wolfgang Marktl,Edward Penner,Cem Ekmekcioglu

    Based on the fact that human bile and, particularly gallbladder bile, contains high physiological levels of the antioxidant melatonin, the aim of this study was to investigate whether the melatonin receptor MT1 is present in human gallbladder. Expression and localization of MT1 was assessed by RT-PCR, Western blotting and immunofluorescence analysis in gallbladder samples from patients with cholelithiasis and with advanced gallbladder carcinoma. Additionally, we monitored mRNA expression of the two key enzymes of melatonin synthesis, i.e. arylalkylamine-N-acetyltransferase (AANAT) and hydroxyindole-O-methyltransferase (HIOMT). MT1 mRNA and protein were present in all cholelithiasis (n = 10) and gallbladder carcinoma (n = 5) samples. As indicated from RT-PCR and Western blot studies, MT1 is located in gallbladder epithelia. Epithelial expression was further proven by immunofluorescence staining of MT1 in paraffin-embedded cholelithiasis and gallbladder carcinoma sections. Analysis of AANAT and HIOMT mRNA expression showed that HIOMT mRNA is present in gallbladder. Surprisingly, AANAT was not detectable under conditions where it was found in a human colon specimen. The absence of AANAT suggests that in human gallbladder, HIOMT might be involved in the formation of 5-hydroxytryptamine products other than melatonin. In summary, our results provide the first evidence for the presence of MT1 in human gallbladder epithelia. Therefore, in addition to its profound antioxidative effects in the biliary system, melatonin might also act through MT1-mediated signal transduction pathways. Thereby, it might be involved in the regulation of gallbladder function.

    更新日期:2019-11-01
  • Delayed treatment with melatonin enhances electrophysiological recovery following transient focal cerebral ischemia in rats.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-12-17
    E-Jian Lee,Tian-Shung Wu,Ming-Yang Lee,Tsung-Ying Chen,Yi-Yin Tsai,Jih-Ing Chuang,Guan-Liang Chang

    Melatonin has been reported to reduce infarct volumes induced by transient middle cerebral artery (MCA) occlusion. We examined whether melatonin could improve electrophysiological and neurobehavioral recoveries in rats after 72 hr of reperfusion following 1.5 hr of MCA occlusion. Melatonin (5 mg/kg) or vehicle was given intravenously at the commencement of reperfusion. Neurobehavioral outcome was serially examined, and somatosensory evoked potentials (SSEP) were recorded prior to ischemia and at 72 hr after the onset of reperfusion. Brain infarction was assessed upon killing. Before ischemia-reperfusion, stable SSEP waveforms were consistently recorded after individual fore- or hindpaw stimulation. The amplitude between the first positive (P1) and the first negative (N1) peaks and the P1 latency did not differ significantly between controls and melatonin-treated animals. At 72 hr of reperfusion, controls had severely depressant SSEPs recorded from ischemic fore- and hindpaw cortical fields, and the amplitudes decreased to 36 and 35% of baselines, respectively (P < 0.001). These animals also had transcallosal electrophysiological diaschisis in the SSEPs recorded at the contralateral hindpaw cortical field (P < 0.01). Relative to controls, melatonin-treated animals not only had significantly improved amplitudes of the SSEPs recorded from both ischemic fore- and hindpaw cortical fields, by 33 and 37% of baselines, respectively (P < 0.001), but also exhibited diminished transcallosal electrophysiological diaschisis following ischemia-reperfusion. In addition, melatonin improved sensory and motor neurobehavioral outcomes by 40 and 28%, respectively (P < 0.001), and reduced cortical and striatal infarct sizes by 32 and 40%, respectively (P < 0.05). Thus, delayed intravenous administration with melatonin both enhances electrophysiological and neurobehavioral recoveries and reduces cortical and striatal infarct sizes after cerebral ischemia and reperfusion injury.

    更新日期:2019-11-01
  • Melatonin protects against oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the mouse nigrostriatum.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-12-17
    Bobby Thomas,Kochupurackal P Mohanakumar

    We tested the hypothesis that melatonin acts as a powerful hydroxyl radical (*OH) scavenger in vivo in the brain, and interferes with oxidative stress caused by the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We investigated the effect of melatonin on in vitro *OH production employing a Fenton-like reaction in test tubes, and ex vivo *OH generation in isolated mitochondria induced by 1-methyl-4-phenyl pyridinium (MPP+), as well as on in vivo *OH formation in the mouse striatum following systemic administration of MPTP. We also measured reduced glutathione (GSH) levels, and superoxide dismutase (SOD) activity in the nucleus caudatus putamen (NCP) and substantia nigra (SN), 7 days following MPTP and/or melatonin administration. Melatonin caused a significant and dose-dependent inhibition of the production of *OH in the in vitro, ex vivo and in vivo experimental conditions. Melatonin caused no changes in monoamine oxidase-B activity, in vitro in mitochondrial P2 fractions or in vivo following systemic administration. MPTP treatment in mice caused a significant depletion of GSH, and increased the specific activity of SOD both in SN and NCP on the seventh day. MPTP-induced GSH depletion was dose-dependently blocked in SN and NCP by melatonin. Higher doses of melatonin exhibited a synergistic effect on MPTP-induced increase in the SOD activity in the SN. These results suggest that while GSH inhibition is a direct consequence of *OH generation following neurotoxin administration, the increase in SOD activity is a compensatory mechanism for removing superoxide radicals generated as the result of MPTP. Our results not only point to the potency of melatonin in blocking the primary insults caused by MPTP, but also provide evidence for triggering secondary neuroprotective mechanisms, suggesting its use as a therapeutic agent in neurodegenerative disorders, such as Parkinson's disease.

    更新日期:2019-11-01
  • Melatonin suppresses cerebral edema caused by middle cerebral artery occlusion/reperfusion in rats assessed by magnetic resonance imaging.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-12-17
    Kunio Torii,Hisayuki Uneyama,Hitoo Nishino,Takashi Kondoh

    Melatonin, a pineal secretory product synthesized from tryptophan, has been found to be effective against neurotoxicity. The present study was aimed at demonstrating the effectiveness of melatonin in vivo in reducing ischemia-induced cerebral edema using magnetic resonance imaging (MRI). Rats were subjected to middle cerebral artery (MCA) occlusion/reperfusion surgery. Melatonin was administered twice (6.0 mg/kg, p.o.) just prior to 1 hr of MCA occlusion and 1 day after the surgery. T2-weighted multislice spin-echo images were acquired 1 day after the surgery. In the saline-treated control rats, increases in T2-weighted signals (water content) were clearly observed in the striatum and in the cerebral cortex. In the melatonin-treated group, total volume of edema was reduced by 51.6% compared with control group (P < 0.01). The protective effect of melatonin against edema was more clearly observed in the cerebral cortex (reduced by 59.8%, P < 0.01) than in the striatum (reduced by 34.2%, P < 0.05). Edema volume in a coronal slice was the greatest at the level of the bregma. Suppression of cerebral edema by melatonin was more effective posterior than anterior to the bregma. Melatonin appeared to reduce the volume of the edematous sites rather than to shift the signal intensity distribution. The present MRI study clearly demonstrates the effectiveness of melatonin against cerebral edema formation in ischemic animals in vivo, especially in the cerebral cortex. Melatonin may be highly useful in preventing cortical dysfunctions such as motor, sensory, memory, and psychological impairments associated with ischemic stroke.

    更新日期:2019-11-01
  • Melatonin prevents disruption of hepatic reactive oxygen species metabolism in rats treated with carbon tetrachloride.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-12-17
    Yoshiji Ohta,Mutsumi Kongo-Nishimura,Tatsuya Matsura,Kazuo Yamada,Akira Kitagawa,Teruaki Kishikawa

    We reported that melatonin prevents the progression of carbon tetrachloride (CCl4)-induced acute liver injury in rats possibly by attenuating enhanced lipid peroxidation and reduced glutathione depletion. Herein, we examined the effect of melatonin on the changes in hepatic reactive oxygen species (ROS) metabolism in rats with a single intraperitoneal injection of CCl4 (1.6 g/kg body weight); the intent was to clarify the therapeutic mechanism of the indoleamine on CCl4-induced acute liver injury. Rats with and without CCl4 treatment received a single oral dose of melatonin (10, 50 or 100 mg/kg body weight) 6 hr after CCl4 treatment. Hepatic concentrations of ascorbic acid (ASC) and vitamin E (VE) and hepatic activities of superoxide dismutase (SOD), catalase (CAT), Se-glutathione peroxidase (Se-GSH-Px), glutathione reductase (GSSG-R), glucose-6-phosphate dehydrogenase (G-6-PDH), and xanthine oxidase (XO) were determined 6 and 24 hr after CCl4 treatment. The liver of CCl4-treated rats showed reductions in ASC concentrations, and SOD activity and an increase in G-6-PDH activity at 6 hr after treatment and further decreases in ACS concentrations and SOD activity and also further increase in G-6-PDH activity in addition to decreases in CAT and GSSG-R activities and increases in VE concentrations and XO activity at 24 hr after treatment. Melatonin attenuated the reductions in hepatic ASC concentrations and SOD, CAT and GSSG-R activities and the increase in hepatic XO activity in a dose-dependent manner without affecting either hepatic Se-GSH-Px activity or the increased hepatic VE concentration and G-6-PDH activity at 24 hr after CCl4 treatment. No dose of melatonin influenced hepatic ACS and VE concentrations and SOD, CAT, Se-GSH-Px, G-6-PDH, and XO activities in CCl4-untreated rats. These results indicate that melatonin postadministered at pharmacological doses prevents the disruption of hepatic ROS metabolism associated with ASC, SOD, CAT, GSSG-R, and XO, in addition to reduced glutathione, in CCl4-treated rats.

    更新日期:2019-11-01
  • Regulation of antioxidant enzymes: a significant role for melatonin.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-12-17
    Carmen Rodriguez,Juan C Mayo,Rosa M Sainz,Isaac Antolín,Federico Herrera,Vanesa Martín,Russel J Reiter

    Antioxidant enzymes form the first line of defense against free radicals in organisms. Their regulation depends mainly on the oxidant status of the cell, given that oxidants are their principal modulators. However, other factors have been reported to increase antioxidant enzyme activity and/or gene expression. During the last decade, the antioxidant melatonin has been shown to possess genomic actions, regulating the expression of several genes. Melatonin also influences both antioxidant enzyme activity and cellular mRNA levels for these enzymes. In the present report, we review the studies which document the influence of melatonin on the activity and expression of the antioxidative enzymes glutathione peroxidase, superoxide dismutases and catalase both under physiological and under conditions of elevated oxidative stress. We also analyze the possible mechanisms by which melatonin regulates these enzymes.

    更新日期:2019-11-01
  • Urinary 6-hydroxy-melatonin-sulfate excretion and circadian rhythm in patients with restless legs syndrome.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-10-03
    Gotthard G Tribl,Franz Waldhauser,Thomas Sycha,Eduard Auff,Josef Zeitlhofer

    The precise etiology of the restless legs syndrome (RLS) is unknown. Sensory and motor symptoms of RLS worsen during evening/night, coincident with the physiological peak of pineal melatonin excretion. Decreased melatonin levels have been reported in insomnia, which is an associated feature of RLS. Melatonin substitution improved insomnia. A potential association between the idiopathic RLS (iRLS) and alterations in melatonin excretion was therefore explored. Daytime (7:00-22:00 hr) and night-time (22:00-7:00 hr) urinary excretion of 6-OH-melatonin-sulfate (aMLTs) was measured in 15 patients with iRLS and 11 controls by a radioimmunoassay. There was no significant difference between daytime and night-time urinary aMLTs excretion in iRLS as compared with controls (daytime: 6.14 +/- 5.20 ng versus 5.02 +/- 5.11 ng, NS; night-time: 21.07 +/- 17.05 ng versus 22.92 +/- 16.52 ng, NS). Our data do not provide evidence for a decrease of cumulative melatonin production in iRLS. Insomnia in RLS does not seem to be correlated with a deficit of melatonin.

    更新日期:2019-11-01
  • Protective effect of melatonin against fractionated irradiation-induced epiphyseal injury in a weanling rat model.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-10-03
    Melek N Yavuz,A Aydin Yavuz,Cunay Ulku,Muhittin Sener,Ersin Yaris,Polat Kosucu,Ihsan Karslioglu

    The effects of melatonin, a free-radical scavenger and a general antioxidant, on radiation-induced growth plate injury have not been studied previously. The purpose of this study was to determine the potential benefits of sparing longitudinal bone growth by fractionated radiotherapy alone compared with pretreatment with melatonin that provides differential radioprotection of normal cells. Weanling 4-wk-old (75-100 g) male Sprague-Dawley rats were randomly assigned to one of three groups: Group R received fractionated radiation alone (n = 8); groups M5 (n = 8) and M15 (n = 7) received 5 or 15 mg/kg melatonin prior to fractionated radiation, respectively. The distal femur and proximal tibia in the right leg of each animal were exposed to a therapeutic X-irradiation dose (25 Gy total in three fractions) with the contralateral left leg as the non-irradiated control. Melatonin was administered intraperitoneally to the animals 30 min before radiation exposure. Six weeks after treatment, the rats were killed and the lower limbs disarticulated, skeletonized, radiographed, and bone growth was calculated based on measurement of the bone lengths. Fractionated radiation resulted in a mean percent overall limb growth loss of 41.2 +/- 9.5 and a mean percent overall limb discrepancy of 11.2 +/- 2.2. The administration of 5 or 15 mg/kg melatonin before each of the three fractions of radiotherapy reduced the mean percent overall limb growth loss to 33.9 +/- 5.8 and 32.2 +/- 4.5, respectively, and the mean percent overall limb discrepancy to 9.4 +/- 1.6 and 8.9 +/- 1.1, respectively; these values were significantly different compared with irradiation alone (range: P = 0.01-0.04). When compared with Group R, the growth arrest recovered by 5 or 15 mg/kg melatonin was 19.7 and 24.1% for the tibia, 7 and 18.6% for the femur, and 17.7 and 21.8% for the total limb, respectively. These results support further investigation of melatonin in combination with fractionation for potential use in growing children requiring radiotherapy to the extremity for malignant tumors.

    更新日期:2019-11-01
  • Perfusion of melatonin into the prefrontal cortex disrupts the circadian rhythm of acetylcholine but not of locomotor activity.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-10-03
    Blanca Marquez de Prado,Russel J Reiter,Francisco Mora

    Extracellular concentrations of acetylcholine (ACh) in the prefrontal cortex displayed a circadian rhythm, with a maximum increase in the dark phase of the light:dark cycle. The increase in ACh related well to the circadian rhythm of the same rats in which a maximal increase of locomotor activity in the dark phase also was observed. Local perfusion of melatonin (200-500 microm), in a dose-dependent manner, disrupted the ACh rhythm in the prefrontal cortex but did not affect the circadian rhythm of locomotor activity. It is suggested that the change in the cholinergic transmission during a circadian period in the prefrontal cortex may be under the control of the biological clock through the action of melatonin; however, the prefrontal cortical ACh cycle seems not to be related to the regulation of locomotor activity.

    更新日期:2019-11-01
  • Protective effect of indoleamines on in vitro ascorbate-Fe2+ dependent lipid peroxidation of rod outer segment membranes of bovine retina.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-10-03
    Margarita H Guajardo,Ana M Terrasa,Angel Catalá

    Rod outer segment membranes (ROS) are highly vulnerable to autooxidation because of their high content of long chain polyunsaturated fatty acids (PUFAs). Melatonin and N-acetylserotonin are indoleamines synthesized in the pineal gland, retina and other tissues. These compounds are free radical scavengers and indirect antioxidants because of their stimulatory effect on antioxidative enzymes. We compared the in vitro protective effect of melatonin and N-acetylserotonin on the ascorbate-Fe2+ induced lipid peroxidation of PUFAs located in ROS membranes. This process was measured by chemiluminescence and fatty acid composition of total lipids of ROS. We assayed increasing concentrations of melatonin (0-10 mm) and N-acetylserotonin (0-2 mm). In both cases the total cpm originated from light emission (chemiluminescence) was found to be lower in those membranes incubated in the presence of either melatonin or N-acetylserotonin; this decreased proportional to the concentration of the indole. Thus, 10 mm melatonin and 2 mm N-acetylserotonin produced a reduction of 51 +/- 6 and 100% in the total chemiluminescene (lipid peroxidation), respectively. We also noticed a PUFAs protection: the docosahexaenoic acid content decreased considerably when the membranes were submitted to oxidative damage. This reduction was from 37.6 +/- 2.1% in the native membranes to 6.2 +/- 0.8% in those which were peroxidized. These changes were less pronounced in treated ROS membranes; as an example in the presence of 10 mm melatonin or 2 mm N-acetylserotonin we observed a content preservation of 22:6 n-3 (23.6 +/- 1.2 and 39.1 +/- 1.2% respectively). The concentration of each compound required to inhibit 50% of the lipid peroxidation (IC50) was 9.82 mm for melatonin and 0.43 mm for N-acetylserotonin, respectively. N-acetylserotonin shows a protective effect about 20 times higher than that of melatonin.

    更新日期:2019-11-01
  • Melatonin: structural characterization of its non-enzymatic mono-oxygenate metabolite.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-10-03
    Pasquale Agozzino,Giuseppe Avellone,David Bongiorno,Leopoldo Ceraulo,Felice Filizzola,Maria C Natoli,Maria A Livrea,Luisa Tesoriere

    Oxidation of melatonin by Fenton reagents as well as with hypochlorous acid or oxoferryl hemoglobin has been investigated. Analysis of products by low resolution/mass spectra (MS), high resolution/MS, 1H-nuclear magnetic resonance (NMR), 13C-NMR, correlated spectroscopy (COSY) and heterocorrelated spectroscopy (HETCOR) 2D NMR reveals the formation of a single mono-oxygenated product under all conditions and unequivocally assigns the N-[2-(5-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-ethyl]-acetamide structure, which had not been previously considered.

    更新日期:2019-11-01
  • Melatonin protects against pro-oxidant enzymes and reduces lipid peroxidation in distinct membranes induced by the hydroxyl and ascorbyl radicals and by peroxynitrite.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-10-03
    Adriana Teixeira,Marcos P Morfim,Clarissa A S de Cordova,Carla C T Charão,Vânia R de Lima,Tânia B Creczynski-Pasa

    We have investigated the action of melatonin against lipid peroxidation in membranes including brain homogenates (BH), brain and liver microsomes (MIC), and phosphatidylcholine (PC) liposomes, as well as its effect on the activity of pro-oxidant enzymes such as constitutive neuronal nitric oxide synthase (cnNOS), xanthine oxidase (XO) and myeloperoxidase (MPO). The liposomes were reconstituted by a dialysis method, lipid peroxidation was monitored using the thiobarbituric reactive substances (TBARS) method and enzyme activities were measured spectrophotometrically. The ascorbyl and hydroxyl free radicals were generated by the reaction of ascorbic acid + FeSO4 and H2O2 + FeCl2, respectively, and peroxynitrite using a mixture of NaNO2 in an alkaline medium. Melatonin protected against lipid peroxidation induced by distinct reactive oxygen species (ROS) in all membranes tested although with different potency, in the following order BH < MIC < PC. The K0.5 for enzyme inhibition by melatonin was determined for nNOS (2.0 +/- 0.1 mm), for XO (0.8 +/- 0.1 mm) and for MPO (0.063 +/- 0.003 mm), the latter one with high affinity. Melatonin showed a weak effect as a nitrogen monoxide (NO) scavenger in the presence of sodium nitroprusside (NO donor) and low reactivity with 1,1-diphenyl-2-picryl hydrazyl (DPPH). These results demonstrate the antioxidant action of melatonin, principally that related to the activity of pro-oxidant enzymes such as XO and MPO.

    更新日期:2019-11-01
  • Melatonin protects against myocardial doxorubicin toxicity in rats: role of physiological concentrations.
    J. Pineal. Res. (IF 15.221) Pub Date : 2003-10-03
    Engin Sahna,Hakan Parlakpinar,Mehmet K Ozer,Feral Ozturk,Fikret Ozugurlu,Ahmet Acet

    Doxorubicin (Dox) is a widely used antineoplastic drug. Oxygen radical-induced injury of membrane lipids is considered to be the most important factor responsible for the development of Dox-induced cardiotoxicity. The pineal secretory product, melatonin, is known to be a potent free radical scavenger and its pharmacological concentrations have been shown to reduce Dox-induced cardiac damage. However, the physiological role of melatonin in the prevention of this damage is unknown. We investigated physiological and pharmacological effects of melatonin on Dox-induced changes in the levels of malondialdehyde (MDA), a lipid peroxidation product, and morphological changes in heart. Rats were pinealectomized (Px) or sham-operated (control) 2 months before the studies. Melatonin was administered [4 mg/kg, intraperitoneally (i.p.)] 1 hr before or 24 hr after the administration of a single dose of Dox (20 mg/kg, i.p.) and continued for 2 days. The levels of MDA Dox was found to be significantly higher in the Px rats (55.9 +/- 0.6 nmol/g tissue) than intact control animals (42.6 +/- 0.4). Dox administration to Px and non-Px rats significantly increased the MDA levels. Pre- and post-treatment with melatonin in both Px and intact rats significantly reduced MDA levels. Morphological changes parallelled the MDA alterations. These findings strongly suggest that both physiological and pharmacological concentrations of melatonin are important in protecting the heart from Dox-induced damage in rats. It would seem valuable to test melatonin in clinical trials for prevention of possible heart damage associated with Dox.

    更新日期:2019-11-01
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