A purine derivative, paraxanthine, promotes cysteine uptake for glutathione synthesis.

Purine derivatives such as caffeine and uric acid have neuroprotective activities and are negatively correlated with the incidence of both Alzheimer's disease and Parkinson's disease. We have reported that an increment of intracellular glutathione (GSH) via cysteine uptake in neuronal cells is one of the mechanisms by which caffeine and uric acid confer neuroprotection. Here, we investigated whether caffeine metabolites such as paraxanthine, theophylline, theobromine, 1,7-dimethyluric acid and monomethylxanthines would increase cysteine uptake in mouse hippocampal slices.

Inhibition of miR-96-5p in the mouse brain increases glutathione levels by altering NOVA1 expression.

Glutathione (GSH) is an important antioxidant that plays a critical role in neuroprotection. GSH depletion in neurons induces oxidative stress and thereby promotes neuronal damage, which in turn is regarded as a hallmark of the early stage of neurodegenerative diseases. The neuronal GSH level is mainly regulated by cysteine transporter EAAC1 and its inhibitor, GTRAP3-18.

MicroRNA: A Key Player for the Interplay of Circadian Rhythm Abnormalities, Sleep Disorders and Neurodegenerative Diseases.

Circadian rhythms are endogenous 24-h oscillators that regulate the sleep/wake cycles and the timing of biological systems to optimize physiology and behavior for the environmental day/night cycles. The systems are basically generated by transcription-translation feedback loops combined with post-transcriptional and post-translational modification. Recently, evidence is emerging that additional non-coding RNA-based mechanisms are also required to maintain proper clock function.

Rab1a rescues the toxicity of PRAF3.

The PRA1-superfamily member PRAF3 plays pivotal roles in membrane traffic as a GDI displacement factor via physical interaction with a variety of Rab proteins, as well as in the modulation of antioxidant glutathione through its interaction with EAAC1 (SLC1A1). Overproduction of PRAF3 is known to be toxic to the host cells, although the factors capable of cancelling the toxicity remained unknown. We here show that Rab1a can rescue the cytotoxicity caused by PRAF3 possibly by "positively" regulating ER-Golgi trafficking, cancelling the "negative" modulation by PRAF3.

Facilitation of yeast-lethal membrane protein production by detoxifying with GFP tagging.

Recombinant techniques for target protein production have been rapidly established and widely utilised in today's biological research. Nevertheless, methods for membrane protein production have yet to be developed, since membrane proteins generally tend to be expressed at low levels, easily aggregated, and/or even toxic to their host cells. Here we report that a GFP-tagging technique can be applied for the stable production of membrane proteins that are toxic to their host cells when overexpressed, paving the way for future advances in membrane protein biochemistry and drug development.

A simple and effective method for detecting precipitated proteins in MALDI-TOF MS.

MALDI-TOF MS has developed rapidly into an essential analytical tool for the life sciences. Cinnamic acid derivatives are generally employed in routine molecular weight determinations of intact proteins using MALDI-TOF MS. However, a protein of interest may precipitate when mixed with matrix solution, perhaps preventing MS detection.

Neuroprotection afforded by circadian regulation of intracellular glutathione levels: A key role for miRNAs.

Circadian rhythms are approximately 24-h oscillations of physiological and behavioral processes that allow us to adapt to daily environmental cycles. Like many other biological functions, cellular redox status and antioxidative defense systems display circadian rhythmicity. In the central nervous system (CNS), glutathione (GSH) is a critical antioxidant because the CNS is extremely vulnerable to oxidative stress; oxidative stress, in turn, causes several fatal diseases, including neurodegenerative diseases.

GTRAP3-18 regulates food intake and body weight by interacting with pro-opiomelanocortin.

Pro-opiomelanocortin (POMC)-expressing neurons provide α-melanocyte-stimulating hormone (α-MSH), which stimulates melanocortin 4 receptor to induce hypophagia by AMPK inhibition in the hypothalamus. α-MSH is produced by POMC cleavage in secretory granules and released. However, it is not known yet whether any posttranscriptional regulatory mechanism of POMC signaling exists upstream of the secretory granules in neurons.

Glutathione in Cellular Redox Homeostasis: Association with the Excitatory Amino Acid Carrier 1 (EAAC1).

Reactive oxygen species (ROS) are by-products of the cellular metabolism of oxygen consumption, produced mainly in the mitochondria. ROS are known to be highly reactive ions or free radicals containing oxygen that impair redox homeostasis and cellular functions, leading to cell death. Under physiological conditions, a variety of antioxidant systems scavenge ROS to maintain the intracellular redox homeostasis and normal cellular functions.

Expression of bioactive soluble human stem cell factor (SCF) from recombinant Escherichia coli by coproduction of thioredoxin and efficient purification using arginine in affinity chromatography.

Stem cell factor (SCF) known as the c-kit ligand is a two disulfide bridge-containing cytokine in the regulation of the development and function of hematopoietic cell lineages and other cells such as mast cells, germ cells, and melanocytes. The secreted soluble form of SCF exists as noncovalently associated homodimer and exerts its activity by signaling through the c-Kit receptor. In this report, we present the high level expression of a soluble recombinant human SCF (rhSCF) in Escherichia coli.

Isobolographic analysis of the mechanisms of action of anticonvulsants from a combination effect.

The nature of the pharmacodynamic interactions of drugs is influenced by the drugs׳ mechanisms of action. It has been hypothesized that drugs with different mechanisms are likely to interact synergistically, whereas those with similar mechanisms seem to produce additive interactions. In this review, we describe an extensive investigation of the published literature on drug combinations of anticonvulsants, the nature of the interaction of which has been evaluated by type I and II isobolographic analyses and the subthreshold method.

Rhythmic oscillations of the microRNA miR-96-5p play a neuroprotective role by indirectly regulating glutathione levels.

Glutathione (GSH) is a key antioxidant that plays an important neuroprotective role in the brain. Decreased GSH levels are associated with neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Here we show that a diurnal fluctuation of GSH levels is correlated with neuroprotective activity against oxidative stress in dopaminergic cells.

Impaired glutathione synthesis in neurodegeneration.

Glutathione (GSH) was discovered in yeast cells in 1888. Studies of GSH in mammalian cells before the 1980s focused exclusively on its function for the detoxication of xenobiotics or for drug metabolism in the liver, in which GSH is present at its highest concentration in the body. Increasing evidence has demonstrated other important roles of GSH in the brain, not only for the detoxication of xenobiotics but also for antioxidant defense and the regulation of intracellular redox homeostasis.

Alpha(1A)-adrenergic control of piloerection and palpebral fissure width in rats.

We determined the receptor subtypes of α1-adrenoceptor, which is involved in autonomic functions induced by methamphetamine (METH) in rats. An intraperitoneal injection of METH provoked the autonomic responses piloerection, eyelid retraction, and ejaculation. Pretreatment with prazosin, a nonselective α1-adrenoceptor antagonist, completely abolished the above METH-induced responses.

Neuroprotective properties of the excitatory amino acid carrier 1 (EAAC1).

Extracellular glutamate should be maintained at low levels to conserve optimal neurotransmission and prevent glutamate neurotoxicity in the brain. Excitatory amino acid transporters (EAATs) play a pivotal role in removing extracellular glutamate in the central nervous system (CNS). Excitatory amino acid carrier 1 (EAAC1) is a high-affinity Na⁺-dependent neuronal EAAT that is ubiquitously expressed in the brain.

Involvement of the α(1D)-adrenergic receptor in methamphetamine-induced hyperthermia and neurotoxicity in rats.

Methamphetamine (METH) is a psychostimulant that damages nigrostriatal dopaminergic terminals, primarily by enhancing dopamine and glutamate release. α₁-adrenergic receptor (AR) subtype involved in METH-induced neurotoxicity in rats was investigated using selective α₁-AR antagonists. METH neurotoxicity was evaluated by (1) measuring body temperature; (2) determining tyrosine hydroxylase (TH) immunoreactivity levels; (3) examining levels of dopamine and its metabolites; and (4) assessing glial fibrillary acidic protein (GFAP) and microglial immunoreactivity in the striatum.

Anticonvulsant action of indazole.

Here we report that indazole is characterized as a potential anticonvulsant, inhibiting pentylenetetrazole-, electroshock- and strychnine-induced convulsions in mice (ED50's: 39.9, 43.2 and 82.

Inhibition of GTRAP3-18 may increase neuroprotective glutathione (GSH) synthesis.

Glutathione (GSH) is a tripeptide consisting of glutamate, cysteine, and glycine; it has a variety of functions in the central nervous system. Brain GSH depletion is considered a preclinical sign in age-related neurodegenerative diseases, and it promotes the subsequent processes toward neurotoxicity. A neuroprotective mechanism accomplished by increasing GSH synthesis could be a promising approach in the treatment of neurodegenerative diseases.

CK2 as anti-stress factor.

Misfolded proteins are prone to form aggregates, which interfere with normal cellular functions. In general, the ubiquitin-proteasome system degrades such misfolded proteins to avoid aggregation. If this system becomes impaired or overloaded, an inclusion-body-like organelle, aggresome will operate.

Increased neuronal glutathione and neuroprotection in GTRAP3-18-deficient mice.

Glutathione (GSH) is an important neuroprotective molecule in the brain. The strategy to increase neuronal GSH level is a promising approach to the treatment of neurodegenerative diseases. However, the regulatory mechanism by which neuron-specific GSH synthesis is facilitated remains elusive.

Protein kinase CK2 regulates the formation and clearance of aggresomes in response to stress.

Misfolded protein aggregates elicit a stress response, and their clearance is crucial for cell survival. These aggregates are transported by cytoplasmic deacetylase HDAC6 and dynein motors to the aggresome via the microtubule network, and are removed by autophagic degradation. HDAC6 activity is necessary for both the transport and clearance of protein aggregates.

Modulation of neuronal glutathione synthesis by EAAC1 and its interacting protein GTRAP3-18.

Glutathione (GSH) plays essential roles in different processes such as antioxidant defenses, cell signaling, cell proliferation, and apoptosis in the central nervous system. GSH is a tripeptide composed of glutamate, cysteine, and glycine. The concentration of cysteine in neurons is much lower than that of glutamate or glycine, so that cysteine is the rate-limiting substrate for neuronal GSH synthesis.

Suppression of phosphorylation of extracellular-signal-regulated kinase and p38 mitogen-activated protein kinase in polymorphonuclear leukocytes by the proton pump inhibitor lansoprazole.

Lansoprazole (LPZ) is a proton pump inhibitor that suppresses gastric secretion and exerts anti-inflammatory effects on immune cells. Recently, LPZ has been used for the treatment of peptic ulcer and gastritis, which can be caused by Helicobacter pylori, due to its potent acid-suppressive effects. We focused the aim to the anti-inflammatory effects on the over-activation of neutrophils, and investigated the effects of LPZ on the signal transduction of the mitogen-activated protein kinase (MAPK) family.

Induction of regulatory T cells and indefinite survival of fully allogeneic cardiac grafts by ursodeoxycholic acid in mice.

Background: Ursodeoxycholic acid (UDCA) has been used to treat patients with cholestatic and autoimmune liver diseases. Several studies have addressed whether UDCA can inhibit graft rejection in experimental and clinical transplantation, but the results have varied. We investigated the effect of UDCA and the mechanism of its effect on alloimmune responses in a murine model of cardiac transplantation.