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Biomedical subjects

Guang Chen

Publications and source records attributed to Guang Chen.

31 records · Page 2Linked to original sources
PubMed2004

In vivo evidence in the brain for lithium inhibition of glycogen synthase kinase-3.

There is considerable interest in the possibility that small-molecule glycogen synthase kinase-3 inhibitors may have utility in the treatment of bipolar disorder, since glycogen synthase kinase-3 is a target of lithium. Although the in vitro inhibition of glycogen synthase kinase-3 by lithium occurs with a K(i) of 1-2 mM, the degree of inhibition of this enzyme in the mammalian brain at therapeutically relevant concentrations has not fully been established. The transcription factor beta-catenin is an established marker of glycogen synthase kinase-3 inactivation because cytoplasmic levels are increased by inhibition of the enzyme. In this study, we measured beta-catenin protein levels after treatment with therapeutically relevant doses of lithium, valproate, and carbamazepine. Western blot revealed that 9 days of treatment with lithium and valproate, but not carbamazepine, increased beta-catenin protein levels in soluble fractions from the frontal cortex. The level of beta-catenin in the particulate fraction, which is not directly regulated by glycogen synthase kinase-3, did not change with any of the three drugs. Furthermore, real-time PCR revealed that lithium significantly decreased beta-catenin mRNA levels, which may represent compensation for an increase in beta-catenin stability. These results strongly suggest that lithium significantly inhibits brain glycogen synthase kinase-3 in vivo at concentrations relevant for the treatment of bipolar disorder.

Analysis of Variance↗
PubMed2004

Glutamate-induced over-expression of GAD is down-regulated by acetyl-L-carnitine in rat islet cells.

Glutamic acid decarboxylase (GAD65 and GAD67) in pancreatic beta cells is the target of autoantibodies and autoreactive T cells in insulin-dependent diabetes mellitus (IDDM). Regulating expression of GAD perhaps is a practical approach to treat IDDM. In this study, we established an in vitro system, in which GAD was expressed and glutamate treatment produced over-expression of GAD67 and GAD65 in rat islet cells. By using the system we were able to demonstrate basal level of expression of GAD and effects of glutamate and the antioxidant, acetyl-L-carnitine (ALC) on expression of GAD. We found that GAD67 expressed in 10% of islets cells, whereas GAD65 was localized in only 4% of the cells. Glutamate treatment resulted in significant over-expression of GAD67, but not GAD65. Such glutamate-induced overexpression of GAD67 was attenuated by pretreatment with ALC (100 microM). These findings suggest that the over-expression of GAD67 induced by glutamate in islet cells of rat may act as a suitable cellular model to study GAD autoreactivity during the development of IDDM. Meanwhile, it indicates that ALC, an ester of the trimethylated amino acid, can block glutamate-induced over-expression of GAD67, a key beta-cell autoantigen, suggesting a therapeutic potential of ALC in IDDM.

Acetylcarnitine↗
PubMed2004

[Possible involvement of protein kinase C in the pathophysiology and treatment of bipolar disorder].

Over the past decade, the focus of research into the pathophysiology of bipolar disorder has shifted from an interest in the biogenic amines to an emphasis on second messenger systems within cells. Emerging evidence implicates protein kinase C (PKC) intracellular signaling cascade in the pathophysiology and treatment of bipolar disorder. This review explores the possible involvement of PKC in bipolar disorder summarizing results from laboratory and clinical studies. Bipolar patients were demonstrated to have altered PKC levels, activity or distribution in platelets and in the brain. Chronic administration of lithium and valproate produced a striking reduction in protein kinase C (PKC) human cells and in rats. PKC inhibition in animals resulted in altered affective-like behavior and in a small study, tamoxifen (a PKC inhibitor) had marked antimanic efficacy. The results of studies at the molecular, cellular, animal and clinical levels all suggest that regulation of PKC signaling pathways may play a major part in the pathophysiology and treatment of bipolar disorder. Therefore, this pathway may be a promising candidate for the development of new, more specific drugs for the disease.

Antimanic Agents↗
PubMed2004

[Study of photocatalytic activity, characterization and preparation of supersuspended nano-TiO2. II. Study of photocatalytic activity].

From the change in the absorption of methyl-orange solution at 470 nm, the photocatalytic activity of nano-TiO2 prepared by pyrolysis method, and then by cooling treatment in silicon oil and in air respectively, was studied with methyl-orange solution as model waste water under irradiation by UV-lamp. Their photocatalytic mechanisms, the percentage of degradation in 35 min and the kinetic reactive process were also analyzed. The results show that the photocatalytic activity of both products is obvious with little difference. However, the nano-TiO2 powder modified with silicone oil can degrade harmful components more effectively on the surface of waste water with sunlight and other extra light.

English Abstract↗
PubMed2003

The role of the extracellular signal-regulated kinase signaling pathway in mood modulation.

The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressive illness, and therapeutic mechanism of mood stabilizers are largely unknown. The extracellular signal-regulated kinase (ERK) pathway is activated by neurotrophins and other neuroactive chemicals to produce their effects on neuronal differentiation, survival, regeneration, and structural and functional plasticity. We found that lithium and valproate, commonly used mood stabilizers for the treatment of manic-depressive illness, stimulated the ERK pathway in the rat hippocampus and frontal cortex. Both drugs increased the levels of activated phospho-ERK44/42, activated phospho-ribosomal protein S6 kinase-1 (RSK1) (a substrate of ERK), phospho-CREB (cAMP response element-binding protein) and phospho-B cell lymphoma protein-2 antagonist of cell death (substrates of RSK), and BDNF. Inhibiting the ERK pathway with the blood-brain barrier-penetrating mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK) kinase inhibitor SL327, but not with the nonblood-brain barrier-penetrating MEK inhibitor U0126, decreased immobility time and increased swimming time of rats in the forced-swim test. SL327, but not U0126, also increased locomotion time and distance traveled in a large open field. The behavioral changes in the open field were prevented with chronic lithium pretreatment. SL327-induced behavioral changes are qualitatively similar to the changes induced by amphetamine, a compound that induces relapse in remitted manic patients and mood elevation in normal subjects. These data suggest that the ERK pathway may mediate the antimanic effects of mood stabilizers.

Affect↗
PubMed2003

Post-mortem interval effects on the phosphorylation of signaling proteins.

Post-mortem brain tissue provides a unique opportunity to uncover the genes or proteins involved in the pathophysiology of neuropsychiatric disorders. Protein phosphorylation is a common protein modification within intracellular signaling pathways that affects the distribution and function of protein, and has been hypothesized to be of major importance in both the pathophysiology and treatment of major neuropsychiatric disorders. Thus, we were interested in ascertaining the stability of the phosphorylated forms of proteins that are involved in cellular signaling. Antibodies against phospho-tyrosine, phospho-threonine, and phospho-PKA substrates were used to examine the PMI effects on the general amounts of proteins in their phosphorylated form. Phospho-specific antibodies for ERK, JNK, RSK, CREB, and ATF-2 were used to test the effects of PMI on specific proteins whose functioning are known to be regulated markedly by phosphorylation. We found that PMI rapidly decreased the levels of proteins in their phosphorylated states and also decreased the total levels of certain proteins. The PMI effects were observed in the samples stored at both 4 degrees C and room temperature, in both frontal cortex and hippocampus. Thus, it appears that measurements (such as two-dimensional gel electrophoresis and functional assays) that rely on the phosphorylation state of proteins would be extremely sensitive to PMI.

Animals↗
PubMed2003

Effect of three triterpenoid compounds isolated from root bark of Aralia elata on stimulus-induced superoxide generation and tyrosyl phosphorylation and translocation of p47(phox) and p67(phox) to cell membrane in human neutrophil.

BACKGROUND: Root bark of Aralia elata is used as a folk medicine for neurasthenia, rheumatism, diabetes, hepatitis virus and spasm of the stomach in China, Japan and Russia. METHODS: The effect of three triterpenoid compounds isolated from root bark of A. elata on stimulus-induced superoxide generation and tyrosyl phosphorylation and translocation of p47(phox) and p67(phox) to cell membrane was investigated. The three compounds examined were Elatoside A, Elatoside C, and Tarasaponin V. RESULTS: When the cells were preincubated with these compounds, the superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was suppressed in a low concentration range. However, the superoxide generation was significantly enhanced by 40 micromol/l triterpenoid, and was again suppressed in the higher concentration range. In the case of superoxide generation induced by phorbol 12-myristate 13-acetate (PMA), the compounds had no obvious effect on the superoxide generation in low concentration but suppressed that at 40 micromol/l. These compounds also efficiently suppressed the superoxide generation induced by arachidonic acid (AA) at 10 micromol/l. In parallel to the effect on the fMLP-induced superoxide generation, these compounds suppressed fMLP-induced tyrosyl phosphorylation and the translocation to membrane of cytosolic compounds, p47(phox) and p67(phox) at 10 and 80 micromol/l but not at 40 micromol/l. CONCLUSIONS: Triterpenoid saponins examined in this study effect stimulus-induced superoxide generation and tyrosyl phosphorylation and translocation to membrane of p47(phox) and p67(phox) in a concentration-dependent manner, and may have some pharmaceutical applications.

Arachidonic Acid↗
PubMed2003

Support of retinal ganglion cell survival and axon regeneration by lithium through a Bcl-2-dependent mechanism.

PURPOSE: To explore whether lithium, a long-standing mood-stabilizing drug, can be used to induce expression of Bcl-2 and support the survival and regeneration of axons of retinal ganglion cells (RGCs). METHODS: Levels of expression of Bcl-2 in the retina were assessed with quantitative reverse transcription-polymerase chain reaction. To determine whether lithium directly supports the survival of and axon-regenerative functions of RGCs, various amounts of lithium were added to cultures of isolated RGCs. Anti-Thy1.2 antibodies-conjugated to magnetic beads were used to isolate the RGCs. In addition, retina-brain slice cocultures were prepared from tissues of Bcl-2-deficient or Bcl-2-transgenic mice and treated with various amounts of lithium. The effects of the expression of Bcl-2 on lithium-mediated functions were then analyzed. RESULTS: Normal mouse retina expressed very low levels of Bcl-2 after birth. Addition of lithium in the culture increased mRNA levels of Bcl-2 in retinas of postnatal mice in a dose-dependent manner. Moreover, lithium promoted not only the survival of RGCs but also the regeneration of their axons. Depleting or forcing the expression of Bcl-2 in RGCs eliminated the effects of lithium. CONCLUSIONS: Lithium supports both the survival and regeneration of RGC axons through a Bcl-2-dependent mechanism. This suggests that lithium may be used to treat glaucoma, optic nerve neuritis, the degeneration of RGCs and their nerve fibers, and other brain and spinal cord disorders involving nerve damage and neuronal cell loss. To achieve full regeneration of the severed optic nerve, it may be essential to combine lithium therapy with other drugs that mediate induction of a permissive environment in the mature central nervous system.

Animals↗
PubMed2002

Effect of five triterpenoid compounds isolated from leaves of Diospyros kaki on stimulus-induced superoxide generation and tyrosyl phosphorylation in human polymorphonuclear leukocytes.

BACKGROUND: The crude drug "kaki-yô" is a traditional medicine used in Japan as a hypotensive drug. METHODS: The effect of five triterpenoid compounds, isolated from leaves of Diospyros kaki on stimulus-induced superoxide generation and phosphorylation of tyrosine residues of protein in human neutrophils was investigated. The five compounds examined were alpha-amyrin (A), uvaol (UV), ursolic acid (UA), 19 alpha-hydroxy ursolic acid (HU) and 19 alpha,24-dihydroxy ursolic acid (DHU). RESULTS: When the cells were preincubated with these compounds, the superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was significantly suppressed in a concentration-dependent manner. These compounds also suppressed the superoxide generation induced by arachidonic acid (AA) in high concentrations. In the case of the superoxide generation induced by phorbol 12-myristate 13-acetate (PMA), UA, HU and DHU suppressed the superoxide generation but A and UV gave no effect. When the cells were incubated with fMLP in UA, HU and DHU, fMLP-induced tyrosyl phosphorylation of 45 kDa proteins of the cells was dose-dependently suppressed in parallel to the suppression of fMLP-induced superoxide generation. CONCLUSIONS: Triterpenoid compounds suppress stimulus-induced superoxide generation and tyrosyl phosphorylation and may have pharmaceutical applications.

Antihypertensive Agents↗
PubMed2002

Effect of three triterpenoids, lupeol, betulin, and betulinic acid on the stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils.

BACKGROUND: The roots of Anemone raddeana are used in Chinese folk medicine for curing rheumatism and neuralgia. METHODS: The three triterpenoids lupeol, betulin and betulinic acid were isolated from ethanol extracts of the roots of A. raddeana. The effect of these triterpenoids on superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils was investigated. RESULTS: The superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was significantly suppressed by betulin and lupeol depending on the concentration of the triterpenoids. The suppressive effect of betulinic acid was low. The phorbol 12-myristate 13-acetate (PMA)-induced superoxide generation was suppressed by betulin in a concentration-dependent manner, but not by lupeol and betulinic acid. In contrast, the superoxide generation induced by arachidonic acid (AA) was suppressed by lupeol, while betulin and betulinic acid weakly enhanced the AA-induced superoxide generation. Lupeol and betulin suppressed tyrosyl phosphorylation of a 45.0-kDa protein in fMLP-treated human neutrophils in parallel to the suppression of fMLP-induced superoxide generation, but betulinic acid did not. Lupeol, betulin and betulinic acid showed no hemolytic effect even at a concentration of 500 micromol/l. CONCLUSIONS: Lupeol and betulin suppress superoxide generation by preventing tyrosyl phosphorylation of a 45.0-kDa protein in human neutrophils, and may have pharmaceutical applications.

Anemone↗
PubMed2002

Effect of five flavonoid compounds isolated from leaves of Diospyros kaki on stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils.

BACKGROUND: The crude drug "kaki-yô" is a traditional medicine used in Japan as a hypotensive drug. METHODS: The effect of five flavonoid compounds isolated from the leaves of Diospyros kaki was investigated on the stimulus-induced superoxide generation and phosphorylation of tyrosine residues of protein in human neutrophils. The five compounds examined were kaempferol 3-O-beta-D-galactopyranoside (TR), kaempferol 3-O-beta-D-glucopyranoside (AS), isorhamnetin 3-O-beta-D-glucopyranoside (IS), quercetin 3-O-beta-D-galactopyranoside (HY), quercetin 3-O-beta-D-glucopyranosyl-(6-->1)-alpha-L-rhamnopyranoside (RU). RESULTS: When the cells were preincubated with these five compounds, the superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was significantly suppressed in a concentration-dependent manner. The arachidonic acid (AA)-induced superoxide generation was suppressed by TR, AS, HY and RU. On the other hand, the superoxide generation was weakly enhanced by IS in low concentration (5-20 micromol/l), but was suppressed in high concentration (50 micromol/l). The superoxide generation induced by phorbol 12-myristate 13-acetate (PMA) suppressed the TR, IS, HY and RU, but AS gave no effect. When the cells were incubated with fMLP in the presence of TR, IS and RU, fMLP-induced tyrosyl phosphorylation of 45-kDa proteins of the cells was dose-dependently suppressed in parallel to the suppression of fMLP-induced superoxide generation. These five flavonoids showed almost no hemolytic effect even at a concentration of 500 micromol/l. CONCLUSION: Flavonoid compounds suppressed stimulus-induced superoxide generation and tyrosyl phosphorylation and may have pharmaceutical application.

Antihypertensive Agents↗
PubMed2002

Effect of S-(1,2-dicarboxyethyl) glutathione and S-(1,2-dicarboxyethyl) cysteine on the stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils.

We investigated the effects of S-(1,2-dicarboxyethyl) glutathione (DCEG) and S-(1,2-dicarboxyethyl) cysteine (DCEC) on the stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils. When the cells were preincubated with DCEG, the superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was enhanced in concentration-dependent manner but DCEC showed no effect. The influence of DCEG and DCEC on phorbol 12-myristate 13-acetate-induced superoxide generation showed no effect. On the other hand, the superoxide generation induced by arachidonic acid was markedly suppressed by DCEG and DCEC in concentration-dependent manner. The suppression of DCEG was more effective than that of DCEC. The superoxide generation induced by fMLP in the DCEG-treated cells was suppressed by genistein. DCEG enhanced tyrosyl phosphorylation of 80.0 kDa, 60.0 kDa, and 45.0 kDa proteins in human neutrophils. The tyrosyl phosphorylation of 80.0 kDa, 60.0 kDa, and 45.0 kDa proteins was suppressed by genistein. The enhancement of tyrosyl phosphorylation of these proteins in the DCEG-treated cells was parallel to the enhancement of the fMLP-induced superoxide generation.

Arachidonic Acid↗