Abstract:
:Liver fibrosis is scar tissue resulting from an uncontrolled wound-healing process in response to chronic liver injury. Liver damage generates an inflammatory reaction that activates hepatic stellate cells (HSC) that transdifferentiate from quiescent cells that control retinol metabolism to proliferative and migratory myofibroblasts that produce excessive amounts of extracellular matrix proteins, in particular collagen 1a1 (COL1A1). Although liver fibrosis is reversible, no effective drug therapy is available to prevent or reverse HSC activation. Melatonin has potent hepatoprotective properties in a variety of acute and chronic liver injury models and suppresses liver fibrosis. However, it remains unclear whether melatonin acts indirectly or directly on HSC to prevent liver fibrosis. Here, we studied the effect of melatonin on culture-activated rat HSC. Melatonin dose-dependently suppressed the expression of HSC activation markers Col1a1 and alpha-smooth muscle actin (αSMA, Acta2), as well as HSC proliferation and loss of lipid droplets. The nuclear melatonin sensor retinoic acid receptor-related orphan receptor-alpha (RORα/Nr1f1) was expressed in quiescent and activated HSC, while the membranous melatonin receptors (Mtrn1a and Mtrn1b) were not. The synthetic RORα agonist SR1078 more potently suppressed Col1a1 and αSma expression, HSC proliferation, and lipid droplet loss, while the RORα antagonist SR1001 blocked the antifibrotic features of melatonin. Melatonin and SR1078 inhibited the expression of Alox5, encoding 5-lipoxygenase (5-LO). The pharmacological 5-LO inhibitor AA861 reduced Acta2 and Col1a1 expression in activated HSC. We conclude that melatonin directly suppresses HSC activation via RORα-mediated inhibition of Alox5 expression, which provides novel drug targets to treat liver fibrosis.
journal_name
J Pineal Resjournal_title
Journal of pineal researchauthors
Shajari S,Laliena A,Heegsma J,Tuñón MJ,Moshage H,Faber KNdoi
10.1111/jpi.12271subject
Has Abstractpub_date
2015-10-01 00:00:00pages
391-401issue
3eissn
0742-3098issn
1600-079Xjournal_volume
59pub_type
杂志文章abstract::Both autophagy and melatonin play important roles in plant development and stress response. However, the direct correlation between autophagy and melatonin as well as the underlying mechanism remains elusive in plants. In this study, we discovered that the expression of three autophagy-associated genes (MeATG8b, 8c, a...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/jpi.12652
更新日期:2020-08-01 00:00:00
abstract::The effect of melatonin was evaluated on three phosphatidylcholine-based membrane models. Changes in liposome dynamics were monitored by fluorescence, following the response of the probe merocyanine-540, as well as by differential scanning calorimetry (DSC). Langmuir monolayers were investigated using molecular area m...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079X.2010.00782.x
更新日期:2010-09-01 00:00:00
abstract::The pineal hormone melatonin, due to its lipophilic nature, has access to every cell and every part of a cell in the body, suggesting that it could exert effects on blood immune cells. The regulation of the activation of monocytes may be important in a number of diseases, especially pathophysiological conditions assoc...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1999.tb00566.x
更新日期:1999-01-01 00:00:00
abstract::Bisphenol A (BPA) has been reported to adversely affect the mammalian reproductive system in both sexes. However, the underlying mechanisms regarding how BPA disrupts the mammalian oocyte quality and how to prevent it have not been fully defined. Here, we document that BPA weakens oocyte quality by impairing both oocy...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/jpi.12396
更新日期:2017-04-01 00:00:00
abstract::Constitutive activation and gemcitabine induction of nuclear factor-κB (NF-κB) contribute to the aggressive behavior and chemotherapeutic resistance of pancreatic ductal adenocarcinoma (PDAC). Thus, targeting the NF-κB pathway has proven an insurmountable challenge for PDAC therapy. In this study, we investigated whet...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/jpi.12285
更新日期:2016-01-01 00:00:00
abstract::Light and electron microscopic demonstrations for acid phosphatase (AcPase) activity in the chicken pineal gland were studied with special reference to the changes induced by the light-dark cycle. AcPase-positive lysosomes and Golgi cisternae and vesicles located in the pinealocyte in the light period are well develop...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1989.tb00407.x
更新日期:1989-01-01 00:00:00
abstract::The purpose of the present studies using artificial light was to determine how the timing and duration of exposure influence the light-induced suppression of pineal melatonin levels in hamsters. An 8-min exposure to 0.186 microW/cm2 of cool white fluorescent light caused a continued depression of pineal melatonin even...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1984.tb00202.x
更新日期:1984-01-01 00:00:00
abstract::Optic atrophy 1 (OPA1)-related mitochondrial fusion and mitophagy are vital to sustain mitochondrial homeostasis under stress conditions. However, no study has confirmed whether OPA1-related mitochondrial fusion/mitophagy is activated by melatonin and, consequently, attenuates cardiomyocyte death and mitochondrial str...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/jpi.12542
更新日期:2019-03-01 00:00:00
abstract::The frequency of mitoses of adrenaline (A) cells and noradrenaline (N) cells in the adrenal medulla of nonoperated (NO), sham-operated (SPX), and pinealectomized (PX) male, 53-day-old Holtzman rats (n = 133) was investigated by means of light microscopy. Animals were killed at eight time points during a standardized 2...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1990.tb00803.x
更新日期:1990-01-01 00:00:00
abstract::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, ...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/jpi.12615
更新日期:2020-01-01 00:00:00
abstract::Day and nighttime melatonin production in the pineal gland was compared in normal and cardiomyopathic (polydystrophic) adult male Syrian hamsters. These strains of hamsters were selected for comparison because the cardiomyopathetic hamster displays a deficient transmembrane Ca(2+)-pump in a number of tissues, and intr...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1991.tb00472.x
更新日期:1991-10-01 00:00:00
abstract::Previous studies have identified and characterized D1- and D2-dopamine receptors in bovine pineal glands. The data indicate that the density of D1-dopamine receptors (974 fmol/mg protein) far exceed that of D2-dopamine receptors (37 fmol/mg protein). The objective of this study was to identify the mRNAs for both D1- a...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1034/j.1600-079x.2003.00073.x
更新日期:2003-10-01 00:00:00
abstract::The effect of melatonin administration on nerve growth factor (NGF) was studied in the submandibular glands of adult Swiss male mice. Melatonin injection, at 1 microg daily for 30 days, resulted in an increase in the NGF content as detected by immunohistochemistry. The submandibular gland weight and the area of the gr...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1998.tb00369.x
更新日期:1998-03-01 00:00:00
abstract::We examined the association between 6-sulphatoxymelatonin (6-SMT) excretion and sleep in 68 volunteers 60-79 years of age who complained of insomnia or depression. An Actillume wrist monitor was worn for 5-7 consecutive days and nights in home-living conditions. Activity was used to estimate total sleep time (TST) and...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1998.tb00526.x
更新日期:1998-04-01 00:00:00
abstract::Diurnal variations in serum melatonin levels and pineal concentrations of serotonin (5-HT), N-acetylserotonin (NAS), 5-hydroxyindole acetic acid (5-HIAA), and melatonin were estimated in adult male Djungarian hamsters kept under long-day (LD 16:8) or short-day (LD 8:16) photoperiods. The nocturnal increase in melatoni...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1992.tb00039.x
更新日期:1992-04-01 00:00:00
abstract::Previous studies proved that melatonin protected against secondary brain damage by modulating oxidative stress after experimental subarachnoid hemorrhage (SAH), but it has not been evaluated yet about its effects on inflammatory pathway and secondary cognitive dysfunction in SAH model. This study was undertaken to eva...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/jpi.12087
更新日期:2013-11-01 00:00:00
abstract::Previously it has been found that pinealectomy in rats was associated with increased small bowel crypt cell proliferation. The hypothalamus is thought to play a role in the neural control of crypt cell proliferation and the pineal gland is known to be functionally connected with this component of the autonomic nervous...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1991.tb00813.x
更新日期:1991-01-01 00:00:00
abstract::Melatonin receptors play important roles in the regulation of circadian and seasonal rhythms, sleep, retinal functions, the immune system, depression, and type 2 diabetes development. Melatonin receptors are approved drug targets for insomnia, non-24-hour sleep-wake disorders, and major depressive disorders. In mammal...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/jpi.12540
更新日期:2019-03-01 00:00:00
abstract::Dim light exposure of the mother during pregnancy has been proposed as one of the environmental factors that affect the fetal brain development in schizophrenia. Melatonin circulating levels are regulated by the environmental light/dark cycle. This hormone stimulates neuronal differentiation in the adult brain. Howeve...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/jpi.12421
更新日期:2017-10-01 00:00:00
abstract::Production of melatonin in the pineal gland of inbred mice such as C57B1/6J, BALB/c and AKR strains is still a matter of debate. In previous studies, we and other authors showed that these strains of inbred mice have a clear-cut circadian rhythm of serum melatonin and urinary 6-hydroxy-melatonin-sulphate. In contrast,...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1996.tb00249.x
更新日期:1996-04-01 00:00:00
abstract::We tested whether combined melatonin (Mel) and exendin-4 (Ex4) treatment can better preserve glomerular structural integrity after ischemia-reperfusion (IR) injury compared with either alone. Adult male Sprague Dawley rats (n = 50) were equally divided into sham control (SC), IR, IR-Ex4 (10 μg/kg subcutaneously 30 min...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/jpi.12273
更新日期:2015-11-01 00:00:00
abstract::Melatonin was tested in an ongoing attempt to find the endogenous antagonists of quinolinic acid, an endogenous convulsant. Among a great number of metabolites that have been tried before, only a few were found (cerulein and quinaldic acid in mice and kynurenic acid in rats). In SHR (bred from Swiss) male mice, intrac...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1998.tb00535.x
更新日期:1998-05-01 00:00:00
abstract::Four weeks of administration of melatonin mixed in the diet (5 mg/kg of food) significantly reduced the incidence of gastric ulcers in young pigs. In control and melatonin supplemented animals, significantly higher levels of melatonin were found in the stomach tissues as compared to jejunum, ileum, or colon. Pigs with...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1998.tb00367.x
更新日期:1998-01-01 00:00:00
abstract::Urotoxicity is one of the major problems associated with cyclophosphamide (CP) chemotherapy in cancer patients. Melatonin is a potent antioxidant and reduces CP-induced urotoxicity. However, the molecular mechanisms of protection offered by melatonin are not yet clear. The present study investigated the role of nuclea...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079X.2010.00756.x
更新日期:2010-05-01 00:00:00
abstract::The circadian system comprises several peripheral oscillators and a central rhythm generator that, in mammals, is located in the suprachiasmatic nucleus of the hypothalamus. Expression of clock genes is a characteristic feature of the central rhythm generator and the peripheral oscillators. With regard to the rhythmic...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079X.2005.00279.x
更新日期:2006-01-01 00:00:00
abstract::We evaluated the antioxidant property of melatonin as it relates to the vasospastic effect of hydrogen peroxide (H2O2) on the human umbilical artery. Helical sections of umbilical arteries were obtained from healthy pregnant women who were delivered between weeks 37 and 39 of gestation. Changes in maximal potassium ch...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1997.tb00318.x
更新日期:1997-04-01 00:00:00
abstract::The effect of various cations on activity of hydroxyindole-O-methyltransferase (HIOMT) and N-acetyltransferase (NAT) from pineal gland was studied. Copper inhibited both enzymes while calcium and magnesium inhibited HIOMT; the mechanisms of these inhibitions are unknown at this stage. Calcium, magnesium, potassium, an...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079x.1987.tb00852.x
更新日期:1987-01-01 00:00:00
abstract::Senescence-accelerated mice (SAMP8) and senescence-accelerated resistant mice (SAMR1) were studied at 5 and 10 months of age, respectively. In the animals, neurodegenerative processes and how they were influenced by melatonin were examined. Melatonin (10 mg/kg) or vehicle (ethanol at 0.066%) treatments were administra...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079X.2008.00591.x
更新日期:2008-10-01 00:00:00
abstract::Despite high in-hospital mortality associated with acute respiratory distress syndrome (ARDS), there is no effective therapeutic strategy. We tested the hypothesis that combined melatonin-mitochondria treatment ameliorates 100% oxygen-induced ARDS in rats. Adult male Sprague-Dawley rats (n = 40) were equally categoriz...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/jpi.12199
更新日期:2015-03-01 00:00:00
abstract::Melatonin, a potent antioxidant, has shown to be beneficial in murine Venezuelan equine encephalomyelitis (VEE) virus infection. In addition, melatonin can induces the production of interleukin-1 beta (IL-1beta), a cytokine capable of inducing increased expression of inducible nitric oxide synthase; the activity of th...
journal_title:Journal of pineal research
pub_type: 杂志文章
doi:10.1111/j.1600-079X.2006.00381.x
更新日期:2007-03-01 00:00:00