Lipocalin-type prostaglandin (PG) D
2
synthase (L-PGDS) catalyzes the isomerization of PGH
2
, a common precursor of the two series of PGs, to produce PGD
2
. PGD
2
stimulates three distinct types of ...G protein-coupled receptors: (1) D type of prostanoid (DP) receptors involved in the regulation of sleep, pain, food intake, and others; (2) chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) receptors, in myelination of peripheral nervous system, adipocyte differentiation, inhibition of hair follicle neogenesis, and others; and (3) F type of prostanoid (FP) receptors, in dexamethasone-induced cardioprotection. L-PGDS is the same protein as β-trace, a major protein in human cerebrospinal fluid (CSF). L-PGDS exists in the central nervous system and male genital organs of various mammals, and human heart; and is secreted into the CSF, seminal plasma, and plasma, respectively. L-PGDS binds retinoic acids and retinal with high affinities (Kd < 100 nM) and diverse small lipophilic substances, such as thyroids, gangliosides, bilirubin and biliverdin, heme, NAD(P)H, and PGD
2
, acting as an extracellular carrier of these substances. L-PGDS also binds amyloid β peptides, prevents their fibril formation, and disaggregates amyloid β fibrils, acting as a major amyloid β chaperone in human CSF. Here, I summarize the recent progress of the research on PGD
2
and L-PGDS, in terms of its “molecular properties,” “cell culture studies,” “animal experiments,” and “clinical studies,” all of which should help to understand the pathophysiological role of L-PGDS and inspire the future research of this multifunctional lipocalin.
Dietary Zinc Acts as a Sleep Modulator Cherasse, Yoan; Urade, Yoshihiro
International journal of molecular sciences,
11/2017, Letnik:
18, Številka:
11
Journal Article
Recenzirano
Odprti dostop
While zinc is known to be important for many biological processes in animals at a molecular and physiological level, new evidence indicates that it may also be involved in the regulation of sleep. ...Recent research has concluded that zinc serum concentration varies with the amount of sleep, while orally administered zinc increases the amount and the quality of sleep in mice and humans. In this review, we provide an exhaustive study of the literature connecting zinc and sleep, and try to evaluate which molecular mechanism is likely to be involved in this phenomenon. A better understanding should provide critical information not only about the way zinc is related to sleep but also about how sleep itself works and what its real function is.
Protein kinase R-like endoplasmic reticulum kinase (PERK) is one of the endoplasmic reticulum (ER) stress sensors. PERK loss-of-function mutations are known to cause Wolcott-Rallison syndrome. This ...disease is characterized by early-onset diabetes mellitus, skeletal dysplasia, and cardiac valve malformation. To understand the role of PERK in valve formation in vivo, we used an endothelial-specific PERK conditional knockout mice as well as in vitro PERK inhibition assays. We used ProteoStat dyes to visualize the accumulation of misfolded proteins in the endocardial cushion and valve mesenchymal cells (VMCs). Then, VMCs were isolated from E12.5 fetal mice, by fluorescence assisted cell sorting. Proteomic analysis of PERK-deleted VMCs identified the suppression of proteins related to fatty acid oxidation (FAO), especially carnitine palmitoyltransferase II (CPT2). CPT2 is a critical regulator of endocardial-mesenchymal transformation (EndoMT); however how TGF-β downstream signaling controls CPT2 expression remains unclear. Here, we showed that PERK inhibition suppressed, not only EndoMT but also CPT2 protein expression in human umbilical vein endothelial cells (HUVECs) under TGF-β1 stimulation. As a result, PERK inhibition suppressed mitochondrial metabolic activity. Taken together, these results demonstrate that PERK signaling is required for cardiac valve formation via FAO and EndoMT.
Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause ...inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5'-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a 'calm down' signal. DOI: http://dx.doi.org/10.7554/eLife.02172.001.
Highlights • The dorsal striatum enhances wakefulness and the nucleus accumbens promotes sleep. • The external globus pallidus regulates sleep–wake behavior through cortical activation. • Adenosine ...A2A receptors in the nucleus accumbens shell are critical for caffeine arousal. • The nucleus accumbens has an intrinsic role in the sleep/wake regulatory network. • The motivational state is a fundamental regulator of sleep and wakefulness.
Peripartum cardiomyopathy (PPCM) is a life-threatening heart failure occurring in the peripartum period. Although mal-angiogenesis, induced by the 16-kDa N-terminal prolactin fragment (16 K PRL), is ...involved in the pathogenesis, the effect of full-length prolactin (23 K PRL) is poorly understood. We transfected neonate rat cardiomyocytes with plasmids containing 23 K PRL or 16 K PRL in vitro and found that 23 K PRL, but not 16 K PRL, upregulated protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling, and hypoxia promoted this effect. During the perinatal period, cardiomyocyte-specific PERK homogenous knockout (CM-KO) mice showed PPCM phenotypes after consecutive deliveries. Downregulation of PERK or JAK/STAT signaling and upregulation of apoptosis were observed in CM-KO mouse hearts. Moreover, in bromocriptine-treated CM-KO mice, cardiac function did not improve and cardiomyocyte apoptosis was not suppressed during the peripartum period. These results demonstrate that interaction between 23 K PRL and PERK signaling is cardioprotective during the peripartum term.
This paper presents an overview of the current knowledge about the role of adenosine in the sleep-wake regulation with a focus on adenosine in the central nervous system, regulation of adenosine ...levels, adenosine receptors, and manipulations of the adenosine system by the use of pharmacological and molecular biological tools. The endogenous somnogen prostaglandin (PG) D(2) increases the extracellular level of adenosine under the subarachnoid space of the basal forebrain and promotes physiological sleep. Adenosine is neither stored nor released as a classical neurotransmitter and is thought to be formed inside cells or on their surface, mostly by breakdown of adenine nucleotides. The extracellular concentration of adenosine increases in the cortex and basal forebrain during prolonged wakefulness and decreases during the sleep recovery period. Therefore, adenosine is proposed to act as a homeostatic regulator of sleep and to be a link between the humoral and neural mechanisms of sleep-wake regulation. Both the adenosine A(1) receptor (A(1)R) and A(2A)R are involved in sleep induction. The A(2A)R plays a predominant role in the somnogenic effects of PGD(2). By use of gene-manipulated mice, the arousal effect of caffeine was shown to be dependent on the A(2A)R. On the other hand, inhibition of wake-promoting neurons via the A(1)R also mediates the sleep-inducing effects of adenosine, whereas activation of A(1)R in the lateral preoptic area induces wakefulness, suggesting that A(1)R regulates the sleep-wake cycle in a site-dependent manner. The potential therapeutic applications of agonists and antagonists of these receptors in sleep disorders are briefly discussed.
Narcolepsy is the most well-characterized hypersomnia in both clinical and basic research fields. Narcolepsy is caused by degeneration of hypocretin-producing neurons in the hypothalamus. Although ...hypocretin receptor antagonists have been developed as sleep-inducing drugs, a high dose of suvorexant, a hypocretin receptor antagonist, inhibits gene expression of prepro-hypocretin to induce narcoleptic attack in wild-type mice. Prostaglandin D
is the most potent endogenous sleep-promoting substance. Overproduction of prostaglandin D
is involved in hypersomnia in patients with mastocytosis and African sleeping sickness or in mice after a pentylenetetrazole-induced seizure. Commercialized sleep-promoting supplements also may induce hypersomnia in humans.
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