Increase in Cellular Lysophosphatidylserine Content Exacerbates Inflammatory Responses in LPS-Activated Microglia.

Mutations in alpha/beta-hydrolase domain containing (ABHD) 12 gene, which encodes lysophosphatidylserine (LysoPS) lipase, cause the neurodegenerative disease PHARC (Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa, Cataract). Since ABHD12 is expressed by microglia in the central nervous system and is localized to the endoplasmic reticulum, accumulation of intracellular LysoPS by ABHD12 mutations is assumed to be one of the pathological mechanisms associated with microglial activation in PHARC. However, the role of microglia in the PHARC brain and the relationship between microglial function and cellular LysoPS content remains unclear.

Extracellular Vesicles Derived From Canine Mesenchymal Stromal Cells in Serum Free Culture Medium Have Anti-inflammatory Effect on Microglial Cells.

Mesenchymal stem/stromal cells (MSCs) have been used as cell sources for treating dogs with naturally-occurring diseases. Extracellular vesicles (EVs) derived from MSCs are now recognized as pivotal to modulating the immune response and supporting tissue repair. Manufacture of MSC-EVs for clinical application mandates removal of the xeno-proteins, including fetal bovine serum.

Lysophosphatidylinositol, an Endogenous Ligand for G Protein-Coupled Receptor 55, Has Anti-inflammatory Effects in Cultured Microglia.

Lysophosphatidylinositol (LysoPI), an endogenous ligand for G protein-coupled receptor (GPR) 55, has been known to show various functions in several tissues and cells; however, its roles in the central nervous system (CNS) are not well known. In particular, the detailed effects of LysoPI on microglial inflammatory responses remain unknown. Microglia is the immune cell that has important functions in maintaining immune homeostasis of the CNS.

Acetate Suppresses Lipopolysaccharide-stimulated Nitric Oxide Production in Primary Rat Microglia but not in BV-2 Microglia Cells.

Aims: To show that acetate attenuates neuroinflammatory responses in activated microglia.

Background: Dietary acetate supplementation alleviates neuroglial activation in a rat model of neuroinflammation induced by intraventricular administration of lipopolysaccharide (LPS). However, the precise mechanism(s) underlying the anti-inflammatory effect of acetate, is not fully understood.

Pivotal role of inter-organ aspartate metabolism for treatment of mitochondrial aspartate-glutamate carrier 2 (citrin) deficiency, based on the mouse model.

Previous studies using citrin/mitochondrial glycerol-3-phosphate (G3P) dehydrogenase (mGPD) double-knockout mice have demonstrated that increased dietary protein reduces the extent of carbohydrate-induced hyperammonemia observed in these mice. This study aimed to further elucidate the mechanisms of this effect. Specific amino acids were initially found to decrease hepatic G3P, or increase aspartate or citrulline levels, in mGPD-knockout mice administered ethanol.

Lauric Acid Alleviates Neuroinflammatory Responses by Activated Microglia: Involvement of the GPR40-Dependent Pathway.

In several neurodegenerative diseases such as Alzheimer's disease (AD), microglia are hyperactivated and release nitric oxide (NO) and proinflammatory cytokines, resulting its neuropathology. Mounting evidence indicates that dietary supplementation with coconut oil (CNO) reduces the cognitive deficits associated with AD; however, the precise mechanism(s) underlying the beneficial effect of CNO are unknown. In the present study, we examined the effects of lauric acid (LA), a major constituent of CNO, on microglia activated experimentally by lipopolysaccharide (LPS), using primary cultured rat microglia and the mouse microglial cell line, BV-2.

-Equol, a Major Isoflavone from Soybean, Inhibits Nitric Oxide Production in Lipopolysaccharide-Stimulated Rat Astrocytes Partially via the GPR30-Mediated Pathway.

Cumulative evidence indicates that estrogen receptor (ER) agonists attenuate neuroinflammation. Equol, a major isoflavone from soybean, exhibits estrogen-like biological activity, but their effect on inflammatory response has not been well established. Here, we investigated the effect of -equol on nitric oxide (NO) production, well-known inflammatory change in astrocytes stimulated by LPS.

Zinc Potentiates Lipopolysaccharide-induced Nitric Oxide Production in Cultured Primary Rat Astrocytes.

Zn plays a crucial role in the CNS where it accumulates in synaptic vesicles and is released during neurotransmission. Synaptically released Zn is taken up by neurons and astrocytes. The majority of previous work has focused on neuronal damage caused by excess Zn.

Insulin expression in cultured astrocytes and the decrease by amyloid β.

Insulin resistance in brain has been reported in Alzheimer's diseases (AD). Insulin signaling is important for homeostasis in brain function and reported to be disturbed in neurons leading to tau phosphorylation and neurofibrillary tangles. Many investigations of insulin in neurons have been reported; however, it has not been reported whether astrocytes also produce insulin.

Inhibition of Gap Junction Elevates Glutamate Uptake in Cultured Astrocytes.

Glutamate uptake is a main function of astrocytes to keep extracellular glutamate levels low and protect neurons against glutamate-induced excitotoxicity. On the other hand, astrocyte networks formed by gap junctions, which are consisted with connexins and connecting neighboring cells, are reported to play a critical role in maintaining the homeostasis in the brain. In the present study, we examined the effects of gap junction inhibitors on the glutamate uptake activity in cultured rat cortical astrocytes.

Microglia Endocytose Amyloid β Through the Binding of Transglutaminase 2 and Milk Fat Globule EGF Factor 8 Protein.

Activation of glial cells has been observed in neurodegenerative diseases including Alzheimer's disease (AD). Aggregation of amyloid β (Aβ) is profusely observed as characteristic pathology in AD brain. In our previous study using microglial cell line BV-2, tissue-type transglutaminase (TG2) was found to be involved in phagocytosis (Kawabe et al.

Transglutaminases Derived from Astrocytes Accelerate Amyloid β Aggregation.

Activation of astrocytes has been observed in neurodegenerative diseases including Alzheimer's disease (AD). Transglutaminase (TG) is a crosslinking enzyme and contributes to cell adhesion, cytoskeleton construct, extracellular matrix formation, and so on. One of the isozymes, tissue-type TG (TG2) is reported to be activated in AD.

A dibenzoylmethane derivative inhibits lipopolysaccharide-induced NO production in mouse microglial cell line BV-2.

Microglial activation has been suggested to play important roles in various neurodegenerative diseases by phagocytosis and producing various factors such as nitric oxide (NO), proinflammatory cytokines. Excessive production of NO, as a consequence of increased inducible nitric oxide synthase (iNOS) in microglia, contributes to the neurodegeneration. During a search for compounds that regulate endoplasmic reticulum (ER) stress, a dibenzoylmethane derivative, 2,2'-dimethoxydibenzoylmethane (DBM 14-26) was identified as a novel neuroprotective agent (Takano et al.

Amphotericin B Increases Transglutaminase 2 Expression Associated with Upregulation of Endocytotic Activity in Mouse Microglial Cell Line BV-2.

Amphotericin B (AmB), a polyene antibiotic, is reported to cause the microglial activation to induce nitric oxide (NO) production and proinflammatory cytokines expression, and change neurotrophic factors expression in cultured microglia (Motoyoshi et al. in Neurochem Int 52:1290-1296, 2008). On the other hand, tissue-type transglutaminase (TG2) is involved in connection to phagocytes with apoptotic cells.

Acetate Attenuates Lipopolysaccharide-Induced Nitric Oxide Production Through an Anti-Oxidative Mechanism in Cultured Primary Rat Astrocytes.

The biomolecule acetate can be utilized for energy production, lipid synthesis, and several metabolic processes. Acetate supplementation reduces neuroglial activation in a model of neuroinflammation induced by intraventricular injection of lipopolysaccharide (LPS). To investigate the mechanisms underlying the anti-inflammatory effect of acetate on glial cells, we examined the effect of acetate on nitric oxide (NO) production, which was experimentally activated by LPS, in cultured primary rat astrocytes.

Mechanism for increased hepatic glycerol synthesis in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse: Urine glycerol and glycerol 3-phosphate as potential diagnostic markers of human citrin deficiency.

The mitochondrial aspartate-glutamate carrier isoform 2 (citrin) and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) double-knockout mouse has been a useful model of human citrin deficiency. One of the most prominent findings has been markedly increased hepatic glycerol 3-phosphate (G3P) following oral administration of a sucrose solution. We aimed to investigate whether this change is detectable outside of the liver, and to explore the mechanism underlying the increased hepatic G3P in these mice.

Lipopolysaccharide-Stimulated Transglutaminase 2 Expression Enhances Endocytosis Activity in the Mouse Microglial Cell Line BV-2.

Objectives: In peripheral macrophages, tissue-type transglutaminase (TG2) is reported to be involved in phagocytosis of apoptotic cells. However, the contribution of TG2 to microglial phagocytosis has not been investigated. In this study, using a microglial cell line, BV-2, we examined the changes in TG2 expression, phagocytosis and pinocytosis in cells stimulated by lipopolysaccharide (LPS).

Amphotericin B induces glial cell line-derived neurotrophic factor in the rat brain.

Amphotericin B (AmB) is a polyene antifungal drug and is reported to be one of a few reagents having therapeutic effects on prion diseases, that is, a delay in the appearance of clinical signs and prolongation of the survival time in an animal model. In prion diseases, glial cells have been suggested to play important roles; however, the therapeutic mechanism of AmB on prion diseases remains elusive. We have previously reported that AmB changed the expression of neurotrophic factors in microglia and astrocytes (Motoyoshi et al.

Theophylline potentiates lipopolysaccharide-induced NO production in cultured astrocytes.

Elucidation of the functions of astrocytes is important for understanding of the pathogenic mechanism of various neurodegenerative diseases. Theophylline is a common drug for bronchial asthma and occasionally develops side-effects, such as acute encephalopathy; although the pathogenic mechanism of the side-effects is unknown. The lipopolysaccharide (LPS)-induced nitricoxide (NO) production is generally used for an index of the activation of astrocyte in vitro.

Activation of cultured astrocytes by amphotericin B: stimulation of NO and cytokines production and changes in neurotrophic factors production.

Amphotericin B (AmB) is a polyene antibiotic and reported to be one of a few reagents having therapeutic effects on prion diseases, such as the delay in the appearing of the clinical signs and the prolongation of the survival time. In prion diseases, glial cells have been suggested to play important roles by proliferating and producing various factors such as nitric oxide, proinflammatory cytokines, and neurotrophic factors. However, the therapeutic mechanism of AmB on prion diseases remains elusive.

Imipramine induces brain-derived neurotrophic factor mRNA expression in cultured astrocytes.

Depression is one of the most prevalent and livelihood-threatening forms of mental illnesses and the neural circuitry underlying depression remains incompletely understood. Recent studies suggest that the neuronal plasticity involved with brain-derived neurotrophic factor (BDNF) plays an important role in the recovery from depression. Some antidepressants are reported to induce BDNF expression in vivo; however, the mechanisms have been considered solely in neurons and not fully elucidated.

Extracellular superoxide dismutase induced by dopamine in cultured astrocytes.

Under some pathological conditions in brain, a large amount of superoxide anion (O(2)(-)) is produced, causing various cellular damages. Among three isozymes of superoxide dismutase (SOD), extracellular (EC)-SOD should play a role to detoxify O(2)(-) in extracellular space; however, a little is known about EC-SOD in brain. Although dopamine (DA) stored in the synaptic vesicle is stable, the excess leaked DA is spontaneously oxidized to yield O(2)(-) and reactive DA quinones, causing damages of dopaminergic neurons.

Extracellular superoxide dismutase in cultured astrocytes: decrease in cell-surface activity and increase in medium activity by lipopolysaccharide-stimulation.

Under pathological conditions such as ischemia/reperfusion, a large amount of superoxide anion (O(2) (-)) is produced and released in brain. Among three isozymes of superoxide dismutase (SOD), extracellular (EC)-SOD, known to be excreted outside cells and bound to extracellular matrix, should play a role to detoxify O(2) (-) in extracellular space; however, a little is known about EC-SOD in brain. In order to evaluate the SOD activity in extracellular space of CNS as direct as possible, we attempted to measure the cell-surface SOD activity on primary cultured rat brain cells by the inhibition of color development of a water-soluble tetrazolium due to O(2) (-) generation by xanthine oxidase/hypoxanthine added into extracellular medium of intact cells.

A carbazole derivative protects cells against endoplasmic reticulum (ER) stress and glutathione depletion.

Enhanced levels of intracellular stresses such as oxidative stress and endoplasmic reticulum (ER) stress are implicated in various neuropathological conditions including brain ischemia and neurodegeneration. During a search for compounds that regulate ER stress and ER stress-induced cell death, we identified a carbazole derivative 16-14 [9-(3-cyanobenzyl)-1,4-dimethylcarbazole] that protected against both ER stress and glutathione depletion. 16-14 suppressed tunicamycin (Tm)-induced cell death in both F9 Herp KO cells and PC12 cells, and its regulation of ER stress was associated with reduced levels of unfolded protein response (UPR) signaling.

Effects of Amphotericin B on the expression of neurotoxic and neurotrophic factors in cultured microglia.

Amphotericin B (AmB) is a polyene antibiotic and reported to have therapeutic effects on prion diseases, in which the microglial activation has been suggested to play important roles by proliferating and producing various factors such as nitric oxide, proinflammatory cytokines, and so on. However, the therapeutic mechanism of AmB on prion diseases remains elusive. In the present study, we investigated the effects of AmB on cellular functions of rat primary cultured microglia.