Metabolic aberrations in the form of altered flux through key metabolic pathways are the major hallmarks of several life-threatening malignancies including malignant gliomas. These adaptations play an important role in the enhancement of the survival and proliferation of gliomas at the expense of the surrounding normal/healthy tissues. Recent studies in the field of neurooncology have directly targeted the altered metabolic pathways of malignant tumor cells for the development of anti-cancer drugs. Aerobic glycolysis due to elevated production of lactate from pyruvate regardless of oxygen availability is a common metabolic alteration in most malignancies. Aerobic glycolysis offers survival advantages in addition to generating substrates such as fatty acids, amino acids and nucleotides required for the rapid proliferation of cells. This review outlines the role of pyruvate dehydrogenase kinase (PDK) in gliomas as an inhibitor of pyruvate dehydrogenase that catalyzes the oxidative decarboxylation of pyruvate. An in-depth investigation on the key metabolic enzyme PDK may provide a novel therapeutic approach for the treatment of malignant gliomas.
Amino Acids ; Decarboxylation ; Dichloroacetic Acid ; Fatty Acids ; Glioma* ; Glycolysis ; Lactic Acid ; Metabolic Networks and Pathways ; Nucleotides ; Oxidoreductases* ; Oxygen ; Phosphotransferases* ; Pyruvic Acid*

Axon guidance molecules (AGMs), such as Netrins, Semaphorins, and Ephrins, have long been known to regulate axonal growth in the developing nervous system. Interestingly, the chemotactic properties of AGMs are also important in the postnatal period, such as in the regulation of immune and inflammatory responses. In particular, AGMs play pivotal roles in inflammation of the nervous system, by either stimulating or inhibiting inflammatory responses, depending on specific ligand-receptor combinations. Understanding such regulatory functions of AGMs in neuroinflammation may allow finding new molecular targets to treat neurodegenerative diseases, in which neuroinflammation underlies aetiology and progression.
Axons ; Ephrins ; Inflammation ; Nervous System ; Neurodegenerative Diseases ; Neuroglia ; Semaphorins

Lipocalin-2 (LCN2) is a key mediator of various cellular processes. Recent studies have indicated that LCN2 also plays an important role in central nervous system (CNS) injuries and neurological diseases, such as spinal cord injury, stroke, experimental autoimmune encephalomyelitis, and neurodegenerative diseases. Here, we investigated the role of LCN2 in a rodent model of lipopolysaccharide (LPS)-induced neuroinflammation. At 24 hours after intraperitoneal injection of LPS, LCN2 expression was strongly induced in the brain; LCN2 was mainly expressed in endothelial cells, astrocytes, and microglia. Next, we used LCN2-deficient mice to further investigate the role of LCN2 in neuroinflammation. LCN2 deficiency attenuated LPS-induced glial activation in the brain. In a mechanistic study employing glia/neuron co-cultures, LCN2 deficiency reduced glial neurotoxicity. Our results indicate that LCN2 plays a central role in the neuroinflammatory responses following LPS administration, and that LCN2 might contribute to the uncontrolled neurotoxic glial activation under excessive and chronic inflammatory conditions.
Animals ; Astrocytes ; Brain ; Central Nervous System ; Coculture Techniques ; Encephalomyelitis, Autoimmune, Experimental ; Endothelial Cells ; Injections, Intraperitoneal ; Mice* ; Microglia ; Neurodegenerative Diseases ; Neurons ; Rodentia ; Spinal Cord Injuries ; Stroke

BACKGROUND: Glial cells are involved in immune and inflammatory responses in the central nervous system (CNS). Glial cells such as microglia and astrocytes also provide structural and functional support for neurons. Migration and morphological changes of CNS cells are associated with their physiological as well as pathological functions. The secreted protein lipocalin-2 (LCN2) has been previously implicated in regulation of diverse cellular processes of glia and neurons, including cell migration and morphology. METHODS: Here, we employed a zebrafish model to analyze the role of LCN2 in CNS cell migration and morphology in vivo. In the first part of this study, we examined the indirect effect of LCN2 on cell migration and morphology of microglia, astrocytes, and neurons cultured in vitro. RESULTS: Conditioned media collected from LCN2-treated astrocytes augmented migration of glia and neurons in the Boyden chamber assay. The conditioned media also increased the number of neuronal processes. Next, in order to further understand the role of LCN2 in the CNS in vivo, LCN2 was ectopically expressed in the zebrafish spinal cord. Expression of exogenous LCN2 modulated neuronal cell migration in the spinal cord of zebrafish embryos, supporting the role of LCN2 as a cell migration regulator in the CNS. CONCLUSION: Thus, LCN2 proteins secreted under diverse conditions may play an important role in CNS immune and inflammatory responses by controlling cell migration and morphology.
Astrocytes ; Cell Movement ; Central Nervous System ; Culture Media, Conditioned ; Embryonic Structures ; Microglia ; Neuroglia ; Neurons ; Proteins ; Spinal Cord ; Zebrafish

BACKGROUND: APRIL, originally known as a cytokine involved in B cell survival, is now known to regulate the inflammatory activation of macrophages. Although the signal initiated from APRIL has been demonstrated, its role in cellular activation is still not clear due to the presence of BAFF, a closely related member of TNF superfamily, which share same receptors (TACI and BCMA) with APRIL. METHODS: Through transfection of siRNA, BAFF-deficient THP-1 cells (human macrophage-like cells) were generated and APRIL-mediated inflammatory activities were tested. The expression patterns of APRIL were also tested in vivo. RESULTS: BAFF-deficient THP-1 cells responded to APRIL-stimulating agents such as monoclonal antibody against APRIL and soluble form of TACI or BCMA. Furthermore, co-incubation of the siBAFF-deficient THP-1 cells with a human B cell line (Ramos) resulted in an activation of THP-1 cells which was dependent on interactions between APRIL and TACI/BCMA. Immunohistochemical analysis of human pathologic samples detected the expression of both APRIL and TACI in macrophage-rich areas. Additionally, human macrophage primary culture expressed APRIL on the cell surface. CONCLUSION: These observations indicate that APRIL, which is expressed on macrophages in pathologic tissues with chronic inflammation, may mediate activation signals through its interaction with its counterparts via cell-to-cell interaction.
Cell Communication ; Cell Line ; Cell Survival ; Diphenylamine ; Humans ; Inflammation ; Macrophages ; RNA, Small Interfering ; Transfection

Contemporary studies illustrate that peripheral injuries activate glial components of the peripheral and central cellular circuitry. The subsequent release of glial stressors or activating signals contributes to neuropathic pain and neuroinflammation. Recent studies document the importance of glia in the development and persistence of neuropathic pain and neuroinflammation as a connecting link, thereby focusing attention on the glial pathology as the general underlying factor in essentially all age-related neurodegenerative diseases. There is wide agreement that excessive glial activation is a key process in nervous system disorders involving the release of strong pro-inflammatory cytokines, which can trigger worsening of multiple disease states. This review will briefly discuss the recent findings that have shed light on the molecular and cellular mechanisms of glia as a connecting link between neuropathic pain and neuroinflammation.
Aluminum Hydroxide ; Astrocytes ; Carbonates ; Cytokines ; Light ; Microglia ; Nervous System Diseases ; Neuralgia ; Neurodegenerative Diseases ; Neuroglia

BACKGROUND: CD147, as a cellular receptor for cyclophilin A (CypA), is a multifunctional protein involved in tumor invasion, inflammation, tissue remodeling, neural function, and reproduction. Recent observations showing the expression of CD147 in leukocytes indicate that this molecule may have roles in inflammation. METHODS: In order to investigate the role of CD147 and its ligand in the pathogenesis of atherosclerosis, human atherosclerotic plaques were analyzed for the expression pattern of CD147 and CypA. The cellular responses and signaling molecules activated by the stimulation of CD147 were then investigated in the human macrophage cell line, THP-1, which expresses high basal level of CD147 on the cell surface. RESULTS: Staining of both CD147 and CypA was detected in endothelial cell layers facing the lumen and macrophage-rich areas. Stimulation of CD147 with its specific monoclonal antibody induced the expression of matrix metalloproteinase (MMP)-9 in THP-1 cells and it was suppressed by inhibitors of both ERK and NF-kappaB. Accordingly, the stimulation of CD147 was observed to induce phosphorylation of ERK, phosphorylation-associated degradation of IkappaB, and nuclear translocation of NF-kappaB p65 and p50 subunits. CONCLUSION: These results suggest that CD147 mediates the inflammatory activation of macrophages that leads to the induction of MMP-9 expression, which could play a role in the pathogenesis of inflammatory diseases such as atherosclerosis.
Atherosclerosis ; Cell Line ; Cyclophilin A ; Endothelial Cells ; Humans ; Inflammation ; Leukocytes ; Macrophages ; NF-kappa B ; Phosphorylation ; Plaque, Atherosclerotic ; Reproduction

OBJECTIVE: Brain activity is known to be voluntarily controllable by neurofeedback, a kind of electroencephalographic (EEG) operant conditioning. Although its efficacy in clinical effects has been reported, it is yet to be uncovered whether or how a specific band activity is controllable. Here, we examined EEG spectral profiles along with conditioning training of a specific brain activity, theta band (4–8 Hz) amplitude, in rats. METHODS: During training, the experimental group received electrical stimulation to the medial forebrain bundle contingent to suppression of theta activity, while the control group received stimulation non-contingent to its own band activity. RESULTS: In the experimental group, theta activity gradually decreased within the training session, while there was an increase of theta activity in the control group. There was a significant difference in theta activity during the sessions between the two groups. The spectral theta peak, originally located at 7 Hz, shifted further towards higher frequencies in the experimental group. CONCLUSION: Our results showed that an operant conditioning technique could train rats to control their specific EEG activity indirectly, and it may be used as an animal model for studying how neuronal systems work in human neurofeedback.
Animals ; Brain ; Conditioning, Operant ; Electric Stimulation ; Electroencephalography ; Humans ; Medial Forebrain Bundle ; Models, Animal ; Neurofeedback ; Neurons ; Rats

Endoplasmic reticulum (ER) stress is involved in many neurological diseases and inflammatory responses. Inflammatory mediators induce neuronal damage and trigger the neuropathic or inflammatory pain. But there is very little data on the role of the ER stress response in pain mechanisms. In this study, we explored whether the ER stress response is involved in orofacial inflammatory pain by using a complete Freund's adjuvant (CFA)-injected rat model. The thermal pain hypersensitivity increased significantly after CFA injection. We found that the protein and mRNA levels of ER stress response genes, GRP78/Bip and p-eIF2alpha, increased significantly in trigeminal ganglion (TG) of CFA-injected rats compared to control animals. In immunofluorescence analysis, a significant increase of GRP78 and p-eIF2alpha immunopositive neurons was observed in CFA-injected TG compared to control TG. When we administered an ER stress modulator, salubrinal, CFA-induced thermal pain hypersensitivity was temporally reduced. Thus, our study suggests that ER stress responses in TG neurons contribute to CFA-induced inflammatory pain, and may comprise an important molecular mechanism underlying the orofacial inflammatory pain pathway.
Animals ; Endoplasmic Reticulum ; Endoplasmic Reticulum Stress* ; Facial Pain ; Fluorescent Antibody Technique ; Freund's Adjuvant ; Hypersensitivity ; Models, Animal ; Neurons ; Rats ; RNA, Messenger ; Trigeminal Ganglion

Lipocalin-2 (LCN2) is an acute-phase protein induced by injury, infection, or other inflammatory stimuli. LCN2 binds small hydrophobic ligands and interacts with cell surface receptor to regulate diverse cellular processes. The role of LCN2 as a chemokine inducer in the central nervous system (CNS) has been previously reported. Based on the previous participation of LCN2 in neuroinflammation, we investigated the role of LCN2 in formalin-induced nociception and pathological pain. Formalin-induced nociceptive behaviors (licking/biting) and spinal microglial activation were significantly reduced in the second or late phase of the formalin test in Lcn2 knockout mice. Likewise, antibody-mediated neutralization of spinal LCN2 attenuated the mechanical hypersensitivity induced by peripheral nerve injury in mice. Taken together, our results suggest that LCN2 can be therapeutically targeted, presumably for both prevention and reversal of acute inflammatory pain as well as pathological pain.
Acute-Phase Proteins* ; Animals ; Central Nervous System ; Hypersensitivity ; Ligands ; Mice ; Mice, Knockout ; Microglia ; Nociception* ; Pain Measurement ; Peripheral Nerve Injuries ; Spinal Cord