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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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Blockade of STAT3 in T Cells Inhibits Germinal Center Reactions against Intranasal Allergens.

Garam CHOI ; Yeonseok CHUNG

Biomolecules & Therapeutics.2016;24(3):244-251. doi:10.4062/biomolther.2015.160

Understanding the developmental mechanisms of humoral immunity against intranasal antigens is essential for the development of therapeutic approaches against air-borne pathogens as well as allergen-induced pulmonary inflammation. Follicular helper T (Tfh) cells expressing CXCR5 are required for humoral immunity by providing IL-21 and ICOS costimulation to activated B cells. However, the regulation of Tfh cell responses against intranasal antigens remains unclear. Here, we found that the generation of Tfh cells and germinal center B cells in the bronchial lymph node against intranasal proteinase antigens was independent of TGF-β. In contrast, administration of STAT3 inhibitor STA-21 suppressed the generation of Tfh cells and germinal center B cells. Compared with wild-type OT-II T cells, STAT3-deficient OT-II T cells transferred into recipients lacking T cells not only showed significantly reduced frequency Tfh cells, but also induced diminished IgG as well as IgE specific for the intranasal antigens. Co-transfer study of wild-type OT-II and STAT3-deficient OT-II T cells revealed that the latter failed to differentiate into Tfh cells. These findings demonstrate that T cell-intrinsic STAT3 is required for the generation of Tfh cells to intranasal antigens and that targeting STAT3 might be an effective approach to ameliorate antibody-mediated pathology in the lung.
Allergens* ; B-Lymphocytes ; Germinal Center* ; Immunity, Humoral ; Immunoglobulin E ; Immunoglobulin G ; Immunoglobulins ; Lung ; Lymph Nodes ; Pathology ; Pneumonia ; T-Lymphocytes*

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Clinical and Neurobiological Relevance of Current Animal Models of Autism Spectrum Disorders.

Ki Chan KIM ; Edson Luck GONZALES ; María T LÁZARO ; Chang Soon CHOI ; Geon Ho BAHN ; Hee Jeong YOO ; Chan Young SHIN

Biomolecules & Therapeutics.2016;24(3):207-243. doi:10.4062/biomolther.2016.061

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments, as well as repetitive and restrictive behaviors. The phenotypic heterogeneity of ASD has made it overwhelmingly difficult to determine the exact etiology and pathophysiology underlying the core symptoms, which are often accompanied by comorbidities such as hyperactivity, seizures, and sensorimotor abnormalities. To our benefit, the advent of animal models has allowed us to assess and test diverse risk factors of ASD, both genetic and environmental, and measure their contribution to the manifestation of autistic symptoms. At a broader scale, rodent models have helped consolidate molecular pathways and unify the neurophysiological mechanisms underlying each one of the various etiologies. This approach will potentially enable the stratification of ASD into clinical, molecular, and neurophenotypic subgroups, further proving their translational utility. It is henceforth paramount to establish a common ground of mechanistic theories from complementing results in preclinical research. In this review, we cluster the ASD animal models into lesion and genetic models and further classify them based on the corresponding environmental, epigenetic and genetic factors. Finally, we summarize the symptoms and neuropathological highlights for each model and make critical comparisons that elucidate their clinical and neurobiological relevance.
Animals* ; Autism Spectrum Disorder* ; Autistic Disorder* ; Comorbidity ; Complement System Proteins ; Epigenomics ; Models, Animal* ; Models, Genetic ; Neurodevelopmental Disorders ; Population Characteristics ; Risk Factors ; Rodentia ; Seizures

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Comparison of Piroxicam Pharmacokinetics and Anti-Inflammatory Effect in Rats after Intra-Articular and Intramuscular Administration.

Chan Woong PARK ; Kyung Wan MA ; Sun Woo JANG ; Miwon SON ; Myung Joo KANG

Biomolecules & Therapeutics.2014;22(3):260-266.

This study evaluated the pharmacokinetic profile and therapeutic efficacy of piroxicam (PX), a long acting non-steroidal anti-inflammatory drug for the treatment of arthritis, following intra-articular (IA) injection in comparison to the pharmacokinetic profile and therapeutic efficacy of PX after intramuscular (IM) injection. In the pharmacokinetic study in rats, systemic exposure and pharmacokinetic parameters of PX after a single IA dose were compared with systemic exposure and pharmacokinetic parameters of PX after administration of the same dose IM (0.6 mg/kg). The anti-inflammatory and analgesic effects of IA PX were evaluated simultaneously in a monoiodoacetate-induced osteoarthritis rat model. The plasma PX concentration rapidly rose following IA injection, and it was comparable to the plasma PX concentration following IM injection, suggesting the rapid efflux of the drug molecule from the joint cavity. However, in the efficacy study, the IA PX administration significantly reduced the knee swelling by reducing the level of prostaglandin E2 in the joint, compared to that following administration of IA vehicle and after administration of the IM PX dose. In addition, we found that the anti-inflammatory and anti-nociceptive efficacies of IA PX were synergistically increased upon co-treatment with hyaluronic acid (HA), a potent agent for the treatment of osteoarthritis, at the weight ratio of 1:1 or 1:2, and these effects were more pronounced than those following administration of HA or PX alone. In conclusion, this study demonstrated the efficacy of the IA use of PX alone and/or in combination with HA in osteoarthritis.
Animals ; Arthritis ; Dinoprostone ; Hyaluronic Acid ; Injections, Intra-Articular ; Joints ; Knee ; Models, Animal ; Osteoarthritis ; Pharmacokinetics* ; Piroxicam* ; Plasma ; Rats*

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Enhancement of Platelet Aggregation by Ursolic Acid and Oleanolic Acid.

Mikyung KIM ; Chang ho HAN ; Moo Yeol LEE

Biomolecules & Therapeutics.2014;22(3):254-259.

The pentacyclic triterpenoid ursolic acid (UA) and its isomer oleanolic acid (OA) are ubiquitous in food and plant medicine, and thus are easily exposed to the population through natural contact or intentional use. Although they have diverse health benefits, reported cardiovascular protective activity is contentious. In this study, the effect of UA and OA on platelet aggregation was examined on the basis that alteration of platelet activity is a potential process contributing to cardiovascular events. Treatment of UA enhanced platelet aggregation induced by thrombin or ADP, which was concentration-dependent in a range of 5-50 microM. Quite comparable results were obtained with OA, in which OA-treated platelets also exhibited an exaggerated response to either thrombin or ADP. UA treatment potentiated aggregation of whole blood, while OA failed to increase aggregation by thrombin. UA and OA did not affect plasma coagulation assessed by measuring prothrombin time and activated partial thromboplastin time. These results indicate that both UA and OA are capable of making platelets susceptible to aggregatory stimuli, and platelets rather than clotting factors are the primary target of them in proaggregatory activity. These compounds need to be used with caution, especially in the population with a predisposition to cardiovascular events.
Adenosine Diphosphate ; Blood Platelets ; Insurance Benefits ; Oleanolic Acid* ; Partial Thromboplastin Time ; Plants ; Plasma ; Platelet Aggregation* ; Prothrombin Time ; Thrombin

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Neuroprotective Effect of Steamed and Fermented Codonopsis lanceolata.

Jin Bae WEON ; Bo Ra YUN ; Jiwoo LEE ; Min Rye EOM ; Hyun Jeong KO ; Hyeon Yong LEE ; Dong Sik PARK ; Hee Chul CHUNG ; Jae Youn CHUNG ; Choong Je MA

Biomolecules & Therapeutics.2014;22(3):246-253.

Codonopsis lanceolata has been used as an herbal medicine for several lung infl ammatory diseases, such as asthma, tonsillitis, and pharyngitis. Previously, we showed the neuroprotective effect of steamed and fermented C. lanceolata (SFC) in vitro and in vivo. In the current study, the treatment of HT22 cells with SFC decreased glutamate-induced cell death, suggesting that SFC protected HT22 cells from glutamate-induced cytotoxicity. Based on these, we sought to elucidate the mechanisms of the neuroprotective effect of SFC by measuring the oxidative stress parameters and the expression of Bax and caspase-3 in HT22 cells. SFC reduced contents of ROS, Ca2+ and NO. Moreover, SFC restored contents of glutathione and glutathione reductase as well as inhibited Bax and caspase-3 activity in HT22 cells. These results indicate that steamed and fermented C. lanceolata (SFC) extract protected HT22 cells by anti-oxidative effect and inhibition of the expression of Bax and caspase-3.
Asthma ; Caspase 3 ; Cell Death ; Codonopsis* ; Glutathione ; Glutathione Reductase ; Herbal Medicine ; Lung ; Neuroprotective Agents* ; Oxidative Stress ; Palatine Tonsil ; Pharyngitis ; Steam* ; Tonsillitis

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Luteolin Inhibits the Activity, Secretion and Gene Expression of MMP-3 in Cultured Articular Chondrocytes and Production of MMP-3 in the Rat Knee.

Bun Jung KANG ; Jiho RYU ; Choong Jae LEE ; Sun Chul HWANG

Biomolecules & Therapeutics.2014;22(3):239-245.

We investigated whether luteolin affects the gene expression, secretion and activity of matrix metalloproteinase-3 (MMP-3) in primary cultured rabbit articular chondrocytes, as well as production of MMP-3 in the rat knee to evaluate the potential chondroprotective effects of luteolin. Rabbit articular chondrocytes were cultured in a monolayer and IL-1beta-induced gene expression levels of MMP-3, MMP-1, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4), ADAMTS-5 and type II collagen were measured by reverse transcription - polymerase chain reaction (RT-PCR). Effects of luteolin on interleukin-1beta (IL-1beta)-induced secretion and enzyme activity of MMP-3 in rabbit articular chondrocytes were investigated by western blot analysis and casein zymography, respectively. The effect of luteolin on MMP-3 protein production was also examined in vivo. The results were as follows: (1) luteolin inhibited the gene expression levels of MMP-3, MMP-1, MMP-13, ADAMTS-4 and ADAMTS-5. However, it increased the gene expression level of collagen in rabbit articular chondrocytes; (2) luteolin inhibited the secretion and activity of MMP-3; (3) luteolin inhibited in vivo production of MMP-3 protein. These results suggest that luteolin can regulate the gene expression, secretion and activity of MMP-3, by directly acting on articular chondrocytes.
Animals ; Blotting, Western ; Caseins ; Chondrocytes* ; Collagen ; Collagen Type II ; Gene Expression* ; Interleukin-1beta ; Knee* ; Luteolin* ; Osteoarthritis ; Polymerase Chain Reaction ; Rats* ; Reverse Transcription ; Thrombospondins

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Amelioration of Cognitive Dysfunction in APP/PS1 Double Transgenic Mice by Long-Term Treatment of 4-O-Methylhonokiol.

Yu Yeon JUNG ; Young Jung LEE ; Dong Young CHOI ; Jin Tae HONG

Biomolecules & Therapeutics.2014;22(3):232-238.

Alzheimer's disease (AD) is the most common neurodegenerative disease without known ways to cure. A key neuropathologic manifestation of the disease is extracellular deposition of beta-amyloid peptide (Abeta). Specific mechanisms underlying the development of the disease have not yet been fully understood. In this study, we investigated effects of 4-O-methylhonokiol on memory dysfunction in APP/PS1 double transgenic mice. 4-O-methylhonokiol (1 mg/kg for 3 month) significantly reduced deficit in learning and memory of the transgenic mice, as determined by the Morris water maze test and step-through passive avoidance test. Our biochemical analysis suggested that 4-O-methylhonokiol ameliorated Abeta accumulation in the cortex and hippocampus via reduction in beta-site APP-cleaving enzyme 1 expression. In addition, 4-O-methylhonokiol attenuated lipid peroxidation and elevated glutathione peroxidase activity in the double transgenic mice brains. Thus, suppressive effects of 4-O-methylhonokiol on Abeta generation and oxidative stress in the brains of transgenic mice may be responsible for the enhancement in cognitive function. These results suggest that the natural compound has potential to intervene memory deficit and progressive neurodegeneration in AD patients.
Alzheimer Disease ; Animals ; Brain ; Glutathione Peroxidase ; Hippocampus ; Humans ; Learning ; Lipid Peroxidation ; Maze Learning ; Memory ; Memory Disorders ; Mice ; Mice, Transgenic* ; Neurodegenerative Diseases ; Oxidative Stress

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Cordycepin-Enriched WIB801C from Cordyceps militaris Inhibits Collagen-Induced Ca2+i Mobilization via cAMP-Dependent Phosphorylation of Inositol 1, 4, 5-Trisphosphate Receptor in Human Platelets.

Dong Ha LEE ; Hyun Hong KIM ; Hyun Jeong CHO ; Young Bin YU ; Hyo Chan KANG ; Jong Lae KIM ; Jong Jin LEE ; Hwa Jin PARK

Biomolecules & Therapeutics.2014;22(3):223-231.

In this study, we prepared cordycepin-enriched (CE)-WIB801C, a n-butanol extract of Cordyceps militaris-hypha, and investigated the effect of CE-WIB801C on collagen-induced human platelet aggregation. CE-WIB801C dose-dependently inhibited collagen-induced platelet aggregation, and its IC50 value was 175 microg/ml. CE-WIB801C increased cAMP level more than cGMP level, but inhibited collagen-elevated [Ca2+]i mobilization and thromboxane A2 (TXA2) production. cAMP-dependent protein kinase (A-kinase) inhibitor Rp-8-Br-cAMPS increased the CE-WIB801C-downregulated [Ca2+]i level in a dose dependent manner, and strongly inhibited CE-WIB801C-induced inositol 1, 4, 5-trisphosphate receptor (IP3R) phosphorylation. These results suggest that the inhibition of [Ca2+]i mobilization by CE-WIB801C is resulted from the cAMP/A-kinase-dependent phosphorylation of IP3R. CE-WIB801C suppressed TXA2 production, but did not inhibit the activities of cyclooxygenase-1 (COX-1) and TXA2 synthase (TXAS). These results suggest that the inhibition of TXA2 production by WIB801C is not resulted from the direct inhibition of COX-1 and TXAS. In this study, we demonstrate that CE-WIB801C with cAMP-dependent Ca2+-antagonistic antiplatelet effects may have preventive or therapeutic potential for platelet aggregation-mediated diseases, such as thrombosis, myocardial infarction, atherosclerosis, and ischemic cerebrovascular disease.
1-Butanol ; Atherosclerosis ; Blood Platelets ; Cordyceps* ; Cyclic AMP-Dependent Protein Kinases ; Cyclooxygenase 1 ; Humans ; Inhibitory Concentration 50 ; Inositol* ; Myocardial Infarction ; Phosphorylation* ; Platelet Aggregation ; Thrombosis ; Thromboxane A2

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L-Tetrahydropalmatine Ameliorates Development of Anxiety and Depression-Related Symptoms Induced by Single Prolonged Stress in Rats.

Bombi LEE ; Bongjun SUR ; Mijung YEOM ; Insop SHIM ; Hyejung LEE ; Dae Hyun HAHM

Biomolecules & Therapeutics.2014;22(3):213-222.

Abnormal adaptation of the stress-response system following traumatic stress can lead to alterations in the hypothalamic-pituitary-adrenal (HPA) axis that may contribute to the development of post-traumatic stress disorder (PTSD). The present study used several behavioral tests to investigate the anxiolytic-like and antidepressant activity of L-tetrahydropalmatine (L-THP) in an experimental rat model of anxiety and depression induced by single prolonged stress (SPS), an animal model of PTSD. Male rats were treated intraperitoneally (i.p.) with vehicle or varied doses of THP 30 min prior to SPS for 8 consecutive days. Daily THP (50 mg/kg) administration significantly increased the number and duration of open arm visits in the elevated plus maze (EPM) test, reduced the anxiety index, increased the risk assessment, and increased the number of head dips over the borders of the open arms after SPS. THP was also associated with increased time spent at the center of the open field, reduced grooming behaviors in the EPM test, and reduced time spent immobile in the forced swimming test (FST). It also blocked the decrease in neuropeptide Y (NPY) and the increase in corticotrophin-releasing factor (CRF) expression in the hypothalamus. This is the first study to determine that THP exerts pronounced anxiolytic-like and antidepressant effects on the development of the behavioral and biochemical symptoms associated with PTSD, indicating its prophylactic potential. Thus, THP reversed several behavioral impairments triggered by the traumatic stress of SPS and is a potential non-invasive therapeutic intervention for PTSD.
Animals ; Anxiety* ; Arm ; Axis, Cervical Vertebra ; Depression ; Grooming ; Head ; Humans ; Hypothalamus ; Male ; Models, Animal ; Neuropeptide Y ; Physical Exertion ; Rats* ; Risk Assessment ; Stress Disorders, Post-Traumatic

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