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Dependence Potential of Quetiapine: Behavioral Pharmacology in Rodents.

Hye Jin CHA ; Hyun A LEE ; Joon Ik AHN ; Seol Hee JEON ; Eun Jung KIM ; Ho Sang JEONG

Biomolecules & Therapeutics.2013;21(4):307-312.

Quetiapine is an atypical or second-generation antipsychotic agent and has been a subject of a series of case report and suggested to have the potential for misuse or abuse. However, it is not a controlled substance and is not generally considered addictive. In this study, we examined quetiapine's dependence potential and abuse liability through animal behavioral tests using rodents to study the mechanism of quetiapine. Molecular biology techniques were also used to find out the action mechanisms of the drug. In the animal behavioral tests, quetiapine did not show any positive effect on the experimental animals in the climbing, jumping, and conditioned place preference tests. However, in the head twitch and self-administration tests, the experimental animals showed significant positive responses. In addition, the action mechanism of quetiapine was found being related to dopamine and serotonin release. These results demonstrate that quetiapine affects the neurological systems related to abuse liability and has the potential to lead psychological dependence, as well.
Animals ; Behavior, Animal ; Dopamine ; Head ; Molecular Biology ; Pharmacology* ; Rodentia* ; Serotonin ; Substance-Related Disorders ; Quetiapine Fumarate

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Ethanolic Extract of the Seed of Zizyphus jujuba var. spinosa Ameliorates Cognitive Impairment Induced by Cholinergic Blockade in Mice.

Hyung Eun LEE ; So Young LEE ; Ju Sun KIM ; Se Jin PARK ; Jong Min KIM ; Young Woo LEE ; Jun Man JUNG ; Dong Hyun KIM ; Bum Young SHIN ; Dae Sik JANG ; Sam Sik KANG ; Jong Hoon RYU

Biomolecules & Therapeutics.2013;21(4):299-306.

In the present study, we investigated the effect of ethanolic extract of the seed of Zizyphus jujuba var. spinosa (EEZS) on cholinergic blockade-induced memory impairment in mice. Male ICR mice were treated with EEZS. The behavioral tests were conducted using the passive avoidance, the Y-maze, and the Morris water maze tasks. EEZS (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in our present behavioral tasks without changes of locomotor activity. The ameliorating effect of EEZS on scopolamine-induced memory impairment was significantly reversed by a sub-effective dose of MK-801 (0.0125 mg/kg, s.c.). In addition, single administration of EEZS in normal naive mouse enhanced latency time in the passive avoidance task. Western blot analysis was employed to confirm the mechanism of memory-ameliorating effect of EEZS. Administration of EEZS (200 mg/kg) increased the level of memory-related signaling molecules, including phosphorylation of extracellular signal-regulated kinase or cAMP response element-binding protein in the hippocampal region. Also, the time-dependent expression level of brain-derived neurotrophic factor by the administration of EEZS was markedly increased from 3 to 9 h. These results suggest that EEZS has memory-ameliorating effect on scopolamine-induced cognitive impairment, which is mediated by the enhancement of the cholinergic neurotransmitter system, in part, via NMDA receptor signaling, and that EEZS would be useful agent against cognitive dysfunction such as Alzheimer's disease.
Alzheimer Disease ; Animals ; Blotting, Western ; Brain-Derived Neurotrophic Factor ; Cyclic AMP Response Element-Binding Protein ; Dizocilpine Maleate ; Ethanol* ; Humans ; Male ; Maze Learning ; Memory ; Mice* ; Mice, Inbred ICR ; Motor Activity ; N-Methylaspartate ; Neurotransmitter Agents ; Phosphorylation ; Phosphotransferases ; Scopolamine Hydrobromide ; Ziziphus*

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Effects of Calcium Gluconate, a Water Soluble Calcium Salt on the Collagen-Induced DBA/1J Mice Rheumatoid Arthritis.

Ki Cheul SOHN ; Su Jin KANG ; Joo Wan KIM ; Ki Young KIM ; Sae Kwang KU ; Young Joon LEE

Biomolecules & Therapeutics.2013;21(4):290-298.

This study examined the effects of calcium (Ca) gluconate on collagen-induced DBA mouse rheumatoid arthritis (CIA). A single daily dose of 200, 100 or 50 mg/kg Ca gluconate was administered orally to male DBA/1J mice for 40 days after initial collagen immunization. To ascertain the effects administering the collagen booster, CIA-related features (including body weight, poly-arthritis, knee and paw thickness, and paw weight increase) were measured from histopathological changes in the spleen, left popliteal lymph node, third digit and the knee joint regions. CIA-related bone and cartilage damage improved significantly in the Ca gluconate- administered CIA mice. Additionally, myeloperoxidase (MPO) levels in the paw were reduced in Ca gluconate-treated CIA mice compared to CIA control groups. The level of malondialdehyde (MDA), an indicator of oxidative stress, decreased in a dose-dependent manner in the Ca gluconate group. Finally, the production of IL-6 and TNF-alpha, involved in rheumatoid arthritis pathogenesis, were suppressed by treatment with Ca gluconate. Taken together, these results suggest that Ca gluconate is a promising candidate anti-rheumatoid arthritis agent, exerting anti-inflammatory, anti-oxidative and immunomodulatory effects in CIA mice.
Animals ; Arthritis ; Arthritis, Rheumatoid* ; Body Weight ; Calcium Gluconate* ; Calcium* ; Cartilage ; Collagen ; Humans ; Immunization ; Immunomodulation ; Interleukin-6 ; Knee ; Knee Joint ; Lymph Nodes ; Male ; Malondialdehyde ; Mice* ; Mice, Inbred DBA ; Oxidative Stress ; Peroxidase ; Spleen ; Tumor Necrosis Factor-alpha ; Water*

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Antidiabetic and Beta Cell-Protection Activities of Purple Corn Anthocyanins.

Su Hee HONG ; Jee In HEO ; Jeong Hyeon KIM ; Sang Oh KWON ; Kyung Mok YEO ; Anna M BAKOWSKA-BARCZAK ; Paul KOLODZIEJCZYK ; Ok Hyun RYU ; Moon Ki CHOI ; Young Hee KANG ; Soon Sung LIM ; Hong Won SUH ; Sung Oh HUH ; Jae Yong LEE

Biomolecules & Therapeutics.2013;21(4):284-289.

Antidiabetic and beta cell-protection activities of purple corn anthocyanins (PCA) were examined in pancreatic beta cell culture and db/db mice. Only PCA among several plant anthocyanins and polyphenols showed insulin secretion activity in culture of HIT-T15 cells. PCA had excellent antihyperglycemic activity (in terms of blood glucose level and OGTT) and HbA1c-decreasing activity when compared with glimepiride, a sulfonylurea in db/db mice. In addition, PCA showed efficient protection activity of pancreatic beta cell from cell death in HIT-T15 cell culture and db/db mice. The result showed that PCA had antidiabetic and beta cell-protection activities in pancreatic beta cell culture and db/db mice.
Animals ; Anthocyanins* ; Blood Glucose ; Cell Culture Techniques ; Cell Death ; Insulin ; Insulin-Secreting Cells ; Mice ; Passive Cutaneous Anaphylaxis ; Plants ; Polyphenols ; Zea mays*

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Inhibitory Effect of an Urotensin II Receptor Antagonist on Proinflammatory Activation Induced by Urotensin II in Human Vascular Endothelial Cells.

Sung Lyea PARK ; Bo Kyung LEE ; Young Ae KIM ; Byung Ho LEE ; Yi Sook JUNG

Biomolecules & Therapeutics.2013;21(4):277-283.

In this study, we investigated the effects of a selective urotensin II (UII) receptor antagonist, SB-657510, on the inflammatory response induced by UII in human umbilical vein endothelial cells (EA.hy926) and human monocytes (U937). UII induced inflammatory activation of endothelial cells through expression of proinflammatory cytokines (IL-1beta and IL-6), adhesion molecules (VCAM-1), and tissue factor (TF), which facilitates the adhesion of monocytes to EA.hy926 cells. Treatment with SB-657510 significantly inhibited UII-induced expression of IL-1beta, IL-6, and VCAM-1 in EA.hy926 cells. Further, SB-657510 dramatically blocked the UII-induced increase in adhesion between U937 and EA.hy926 cells. In addition, SB-657510 remarkably reduced UII-induced expression of TF in EA.hy926 cells. Taken together, our results demonstrate that the UII antagonist SB-657510 decreases the progression of inflammation induced by UII in endothelial cells.
Cytokines ; Endothelial Cells* ; Human Umbilical Vein Endothelial Cells ; Humans* ; Inflammation ; Interleukin-6 ; Monocytes ; Thromboplastin ; Vascular Cell Adhesion Molecule-1

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Fucoxanthin Protects Cultured Human Keratinocytes against Oxidative Stress by Blocking Free Radicals and Inhibiting Apoptosis.

Jian ZHENG ; Mei Jing PIAO ; Young Sam KEUM ; Hye Sun KIM ; Jin Won HYUN

Biomolecules & Therapeutics.2013;21(4):270-276.

Fucoxanthin is an important carotenoid derived from edible brown seaweeds and is used in indigenous herbal medicines. The aim of the present study was to examine the cytoprotective effects of fucoxanthin against hydrogen peroxide-induced cell damage. Fucoxanthin decreased the level of intracellular reactive oxygen species, as assessed by fluorescence spectrometry performed after staining cultured human HaCaT keratinocytes with 2',7'-dichlorodihydrofl uorescein diacetate. In addition, electron spin resonance spectrometry showed that fucoxanthin scavenged hydroxyl radical generated by the Fenton reaction in a cell-free system. Fucoxanthin also inhibited comet tail formation and phospho-histone H2A.X expression, suggesting that it prevents hydrogen peroxide-induced cellular DNA damage. Furthermore, the compound reduced the number of apoptotic bodies stained with Hoechst 33342, indicating that it protected keratinocytes against hydrogen peroxide-induced apoptotic cell death. Finally, fucoxanthin prevented the loss of mitochondrial membrane potential. These protective actions were accompanied by the down-regulation of apoptosis-promoting mediators (i.e., B-cell lymphoma-2-associated x protein, caspase-9, and caspase-3) and the up-regulation of an apoptosis inhibitor (B-cell lymphoma-2). Taken together, the results of this study suggest that fucoxanthin defends keratinocytes against oxidative damage by scavenging ROS and inhibiting apoptosis.
Apoptosis* ; B-Lymphocytes ; Caspase 9 ; Cell Death ; Cell-Free System ; DNA Damage ; Down-Regulation ; Electron Spin Resonance Spectroscopy ; Free Radicals* ; Humans* ; Hydrogen ; Hydroxyl Radical ; Keratinocytes* ; Membrane Potential, Mitochondrial ; Oxidative Stress* ; Reactive Oxygen Species ; Spectrometry, Fluorescence ; Spectrum Analysis ; Up-Regulation

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Silymarin's Protective Effects and Possible Mechanisms on Alcoholic Fatty Liver for Rats.

Wei ZHANG ; Rutao HONG ; Tulei TIAN

Biomolecules & Therapeutics.2013;21(4):264-269.

Silymarin has been introduced fairly recently as a hepatoprotective agent. But its mechanisms of action still have not been well established. The aim of this study was to make alcoholic fatty liver model of rats in a short time and investigate silymarin's protective effects and possible mechanisms on alcoholic fatty liver for rats. The model of rat's alcoholic fatty liver was induced by intragastric infusion of ethanol and high-fat diet for six weeks. Histopathological changes were assessed by hematoxylin and eosin staining (HE). The activities of alanine transarninase (ALT) and aspartate aminotransferase (AST), the levels of total bilirubin (TBIL), total cholesterol (TC) and triglyceride (TG) in serum were detected with routine laboratory methods using an autoanalyzer. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) and the level of malondialdehyde (MDA) in liver homogenates were measured by spectrophotometry. The TG content in liver tissue was determined by spectrophotometry. The expression of nuclear factor-kappaB (NF-kappaB), intercellular adhesion molecule-1 (ICAM-1) and interleukin-6 (IL-6) in the liver were analyzed by immunohistochemistry. Silymarin effectively protected liver from alcohol-induced injury as evidenced by improving histological damage situation, reducing ALT and AST activities and TBIL level in serum, increasing SOD and GPx activities and decreasing MDA content in liver homogenates and reducing TG content in liver tissue. Additionally, silymarin markedly downregulated the expression of NF-kappaB p65, ICAM-1 and IL-6 in liver tissue. In conclusion, Silymarin could protect against the liver injury caused by ethanol administration. The effect may be related to alleviating lipid peroxidation and inhibiting the expression of NF-kappaB.
Alanine ; Alcoholics* ; Animals ; Aspartate Aminotransferases ; Bilirubin ; Cholesterol ; Diet, High-Fat ; Eosine Yellowish-(YS) ; Ethanol ; Fatty Liver ; Fatty Liver, Alcoholic* ; Glutathione Peroxidase ; Hematoxylin ; Humans ; Immunohistochemistry ; Intercellular Adhesion Molecule-1 ; Interleukin-6 ; Lipid Peroxidation ; Liver ; Malondialdehyde ; Methods ; NF-kappa B ; Rats* ; Silymarin ; Spectrophotometry ; Superoxide Dismutase ; Triglycerides

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Silibinin Inhibits LPS-Induced Macrophage Activation by Blocking p38 MAPK in RAW 264.7 Cells.

Cha Kyung YOUN ; Seon Joo PARK ; Min Young LEE ; Man Jin CHA ; Ok Hyeun KIM ; Ho Jin YOU ; In Youp CHANG ; Sang Pil YOON ; Young Jin JEON

Biomolecules & Therapeutics.2013;21(4):258-263.

We demonstrate herein that silibinin, a polyphenolic flavonoid compound isolated from milk thistle (Silybum marianum), inhibits LPS-induced activation of macrophages and production of nitric oxide (NO) in RAW 264.7 cells. Western blot analysis showed silibinin inhibits iNOS gene expression. RT-PCR showed that silibinin inhibits iNOS, TNF-alpha, and IL1beta. We also showed that silibinin strongly inhibits p38 MAPK phosphorylation, whereas the ERK1/2 and JNK pathways are not inhibited. The p38 MAPK inhibitor abrogated the LPS-induced nitrite production, whereas the MEK-1 inhibitor did not affect the nitrite production. A molecular modeling study proposed a binding pose for silibinin targeting the ATP binding site of p38 MAPK (1OUK). Collectively, this series of experiments indicates that silibinin inhibits macrophage activation by blocking p38 MAPK signaling.
Adenosine Triphosphate ; Binding Sites ; Blotting, Western ; Gene Expression ; Macrophage Activation* ; Macrophages* ; MAP Kinase Signaling System ; Milk Thistle ; Models, Molecular ; Nitric Oxide ; p38 Mitogen-Activated Protein Kinases* ; Phosphorylation ; Tumor Necrosis Factor-alpha

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Sphingolipids and Antimicrobial Peptides: Function and Roles in Atopic Dermatitis.

Kyungho PARK ; Sinhee LEE ; Yong Moon LEE

Biomolecules & Therapeutics.2013;21(4):251-257.

Inflammatory skin diseases such as atopic dermatitis (AD) and rosacea were complicated by barrier abrogation and deficiency in innate immunity. The first defender of epidermal innate immune response is the antimicrobial peptides (AMPs) that exhibit a broad-spectrum antimicrobial activity against multiple pathogens, including Gram-positive and Gram-negative bacteria, viruses, and fungi. The deficiency of these AMPs in the skin of AD fails to protect our body against virulent pathogen infections. In contrast to AD where there is a suppression of AMPs, rosacea is characterized by overexpression of cathelicidin antimicrobial peptide (CAMP), the products of which result in chronic epidermal inflammation. In this regard, AMP generation that is controlled by a key ceramide metabolite S1P-dependent mechanism could be considered as alternate therapeutic approaches to treat these skin disorders, i.e., Increased S1P levels strongly stimulated the CAMP expression which elevated the antimicrobial activity against multiple pathogens resulting the improved AD patient skin.
Dermatitis, Atopic* ; Endoplasmic Reticulum Stress ; Fungi ; Gram-Negative Bacteria ; Humans ; Immunity, Innate ; Inflammation ; Peptides* ; Rosacea ; Skin ; Skin Diseases ; Sphingolipids*

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Enhanced Expression of TREK-1 Is Related with Chronic Constriction Injury of Neuropathic Pain Mouse Model in Dorsal Root Ganglion.

Hyo Jo HAN ; Seung Wook LEE ; Gyu Tae KIM ; Eun Jin KIM ; Byeonghun KWON ; Dawon KANG ; Hyun Jeong KIM ; Kwang Suk SEO

Biomolecules & Therapeutics.2016;24(3):252-259. doi:10.4062/biomolther.2016.038

Neuropathic pain is a complex state showing increased pain response with dysfunctional inhibitory neurotransmission. The TREK family, one of the two pore domain K+ (K2P) channel subgroups were focused among various mechanisms of neuropathic pain. These channels influence neuronal excitability and are thought to be related in mechano/thermosensation. However, only a little is known about the expression and role of TREK-1 and TREK-2, in neuropathic pain. It is performed to know whether TREK-1 and/or 2 are positively related in dorsal root ganglion (DRG) of a mouse neuropathic pain model, the chronic constriction injury (CCI) model. Following this purpose, Reverse Transcription Polymerase Chain Reaction (RT-PCR) and western blot analyses were performed using mouse DRG of CCI model and compared to the sham surgery group. Immunofluorescence staining of isolectin-B4 (IB4) and TREK were performed. Electrophysiological recordings of single channel currents were analyzed to obtain the information about the channel. Interactions with known TREK activators were tested to confirm the expression. While both TREK-1 and TREK-2 mRNA were significantly overexpressed in DRG of CCI mice, only TREK-1 showed significant increase (~9 fold) in western blot analysis. The TREK-1-like channel recorded in DRG neurons of the CCI mouse showed similar current-voltage relationship and conductance to TREK-1. It was easily activated by low pH solution (pH 6.3), negative pressure, and riluzole. Immunofluorescence images showed the expression of TREK-1 was stronger compared to TREK-2 on IB4 positive neurons. These results suggest that modulation of the TREK-1 channel may have beneficial analgesic effects in neuropathic pain patients.
Animals ; Blotting, Western ; Constriction* ; Diagnosis-Related Groups ; Fluorescent Antibody Technique ; Ganglia, Spinal* ; Humans ; Hydrogen-Ion Concentration ; Mice* ; Neuralgia* ; Neurons ; Polymerase Chain Reaction ; Reverse Transcription ; Riluzole ; RNA, Messenger ; Spinal Nerve Roots* ; Synaptic Transmission

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