• International Journal of Oral Biology
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• 제45권4호
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• pp.225-231
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• 2020

Glial cells, including astrocytes and microglia, interact closely with neurons and modulate pain transmission, particularly under pathological conditions. In this study, we examined the excitability of substantia gelatinosa (SG) neurons of the spinal dorsal horn using a patch clamp recording to investigate the roles of microglial activation in the nociceptive processes of rats. We used xanthine/xanthine oxidase (X/XO), a generator of superoxide anion (O2·-), to induce a pathological pain condition. X/XO treatment induced an inward current and membrane depolarization. The inward current was significantly inhibited by minocycline, a microglial inhibitor, and fluorocitrate, an astrocyte inhibitor. To examine whether toll-like receptor 4 (TLR4) in microglia was involved in the inward current, we used lipopolysaccharide (LPS), a highly specific TLR4 agonist. The LPS induced inward current, which was decreased by pretreatment with Tak-242, a TLR4-specific inhibitor, and phenyl N-t-butylnitrone, a reactive oxygen species scavenger. The X/XO-induced inward current was also inhibited by pretreatment with Tak-242. These results indicate that the X/XO-induced inward current of SG neurons occurs through activation of TLR4 in microglial cells, suggesting that neuroglial cells modulate the nociceptive process through central sensitization.

• 대한한의학회지
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• 제25권2호
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• pp.207-219
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• 2004

Objectives : We investigated to find the relationship between single-nucleotide polymorphism (SNP) of IL4R, IL-10 and bee venom therapy efficacy in patients with RA treated with bee venom for 8 weeks. Methods : Korean RA patients (n=114) and healthy subjects (n=109) were included in this prospective study. Korean bee venom was dissolved in saline (diluted 1:3000) and administrated into acupuncture points. Bee venom therapy was applied twice a week and continued for 8 weeks. The clinical response was evaluated using various assessments before and after treatment. Disease severity was measured by determining the number of tender joints and swollen joints. Laboratory studies included ESR, CRP, and rheumatoid factor. Genotyping for IL-4R and IL-10 polymorphism was done by pyrosequencing analysis. Results : 1. In IL4R genotypes, there was significant difference between RA ptitients tind controls group. 2. In IL4R genotypes, there was significant difference among Good, Mild and Bad responders to in RA patients, but in the frequency of alleles and carriers, there were no significant difference. 3. There was no significant difference between RA patients and controls group in IL-10 gene genotypes. 4. In IL-10 genotypes, there was no significant difference among Good, Mild and Bad responders to in RA patients. 5. There was no significant difference in the improvement of ESR, CRP and KHAQ scores after bee venom therapy in RA patients among the IL4R or IL-10 genotypes. Conclusions : In IL-4R genotypes, there was significant difference between RA patients and control group, and among Good, Mild and Bad responders in RA patients. However, in IL-10 genotypes, there was no significant difference between RA patients and controls group and among Good, Mild and Bad responders in RA patients.

• Asian Pacific Journal of Cancer Prevention
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• 제16권3호
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• pp.903-907
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• 2015

Background: Among human epidermal growth factor receptor 2 (HER2)-positive breast cancer, more than half are also hormone receptor (HR)-positive. Although HR is a predictive factor for the efficacy of hormone therapy, there are still some uncertainties in regard to the effects on patients with HR-positive and HER2-positive metastatic breast cancers due to the potential resistance to hormone therapy caused by co-expression of HR and HER2. There are no clinical trials directly comparing the efficacy of hormonal therapy with chemotherapy. Materials and Methods: To examine the real-world effect of hormone therapy on patients with HR-positive and HER2-positive metastatic breast cancers, a cross-sectional study of a representative sample of the Chinese population was conducted. The study included 113 patients who received first-line and second-line palliative treatment between 2005 and 2010 in the Cancer Institute and Hospital, Chinese Academy of Medical Science. The effect of hormone therapy on overall survival (OS) was studied. Results: The patients who received hormone therapy (n=51) had better overall survival in contrast to those who received chemotherapy with anti-HER2 therapy (n=62) in first- or second-line treatment. The difference was of borderline statistical significance (51.8m vs 31.9m, p=0.065). In addition, the effect of hormone therapy did not differ significantly with other prognostic factors, including age (${\leq}50$ years or >50 years), disease free survival (${\geq}2$ years or < 2 years) and site of metastasis (visceral or bone/soft tissue). On multivariate analysis, administration of hormone therapy was associated with a trend toward a favorable prognosis (p=0.148, HR=0.693, 95%CI 0.422-1.139). Age more than 50 years was the sole independent harmful prognostic factor (p<0.001, HR=2.797, 95%CI 1.676-4.668). Conclusions: Our data suggest that hormonel therapy may improve outcomes of the patients with ER-positive and HER2-positive metastatic breast cancer.

• The Korean Journal of Physiology and Pharmacology
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• 제12권1호
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• pp.13-23
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• 2008

The aim of the present study was designed to establish comparatively the inhibitory effects of $D_1$-like and $D_2$-like dopaminergic receptor agonists, SKF81297 and R(-)-TNPA on the release of catecholamines (CA) evoked by cholinergic stimulation and membrane depolarization from the isolated perfused model of the rat adrenal medulla. SKF81297 $(30{\mu}M)$ and R-(-)-TNPA $(30{\mu}M)$ perfused into an adrenal vein for 60 min, produced great inhibition in the CA secretory responses evoked by ACh $(5.32{\times}10^{-3}\;M)$, DMPP $(10^{-4}\;M)$, McN-A-343 $(10^{-4}\;M)$, high $K^+$ $(5.6{\times}10^{-2}\;M)$, Bay-K-8644 $(10{\mu}M)$, and cyclopiazonic acid $(10{\mu}M)$, respectively. For the release of CA evoked by ACh, high $K^+$, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid, the following rank order of inhibitory potency was obtained: SKF81297>R-(-)-TNPA. However, R(+)-SCH23390, a selectve $D_1$-like dopaminergic receptor antagonist, and S(-)-raclopride, a selectve $D_2$-like dopaminergic receptor antagonist, enhanced the CA secretory responses evoked by ACh, high $K^+$, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid only for $0{\sim}4$ min. The rank order for the enhancement of CA release evoked by high $K^+$, McN-A-343 and cyclopiazonic acid was R(+)-SCH23390>S(-)-raclopride. Also, the rank order for ACh, DMPP and Bay-K-8644 was S(-)-raclopride > R(+)-SCH23390. Taken together, these results demonstrate that both SKF81297 and R-(-)-TNPA inhibit the CA release evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors and the membrane depolarization from the isolated perfused rat adrenal gland without affecting the basal release, respectively, but both R(+)-SCH23390 and S(-)-raclopride facilitate the CA release evoked by them. It seems likely that the inhibitory effects of SKF81297 and R-(-)-TNPA are mediated by the activation of $D_1$-like and $D_2$-like dopaminergic receptors located on the rat adrenomedullary chromaffin cells, respectively, whereas the facilitatory effects of R(+)-SCH23390 and S(-)-raclopride are mediated by the blockade of $D_1$-like and $D_2$-like dopaminergic receptors, respectively: this action is possibly associated with extra- and intracellular calcium mobilization. Based on these results, it is thought that the presence of dopaminergic $D_1$ receptors may play an important role in regulation of the rat adrenomedullary CA secretion, in addition to well-known dopaminergic $D_2$ receptors.

• Biomolecules & Therapeutics
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• 제2권2호
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• pp.114-119
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• 1994

[$^3$H]Ouabain binding parameters ( $K_{D}$ and $B_{max}$) to control rat ventricular strips and Langendorff preparations which were not previously exposed to ouabain were compared with those to both preparations that had been first exposed to a complete ouabain dose range of dose-response curve (10$^{-8}$ to 10$^{4}$M). In rat ventricular strips and Langendorff perfused heart preparations, cumulative dose-response curves of ouabain revealed biphasic positive inotropic effects, a "low-dose" effect and a "high-dose" effect with E $d_{50}$ values of 0.5 $\mu$M and 35 $\mu$M ouabain, respectively. The "low-dose" effect in ventricular strip disappeared or was diminished significantly when the ouabain dose-response curve was repeated after the washout of the effects of the first dose-response curve, whereas there were no significant differences in the maximal "high-dose"effect in both exposures to oubain. However, both of the control and ouabain-preexposed Langendorff perfused hearts revealed the same low-dose effects. The $K_{D}$ value for [$^3$H] ouabain binding and the ouabain binding site concentration ( $B_{max}$) estimated by [$^3$H]ouabain displacement assay in control preparations were 230 nM and 2 pmol/mg protein, respectively. [$^3$H]Ouabain binding parameters were not changed by repeated exposure to high concentrations of ouabain. These results suggest that digitalis receptor desensitization in the rat ventricular strip may due to the change of post-receptor events induced by ouabain binding to a high affinity site ($\alpha$$_2$isoform).).).).).

• 동의생리병리학회지
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• 제22권4호
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• pp.993-999
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• 2008

Ischemic brain injury such as cerebral infarction is characterized by acute local inflammatory response mediated by cytokines. The mechanism of cytokines involved in cerebral infarction progression are uncompletely revealed yet. We investigated to find out the relationship between single nucleotide polymorphism (SNP) of interleukin 4 receptor(IL4R) and Oriental Medicine therapy efficacy in patients with cerebral infarction for 2 weeks. Oriental Korean Medicine therapies (herbal medicine and acupuncture) were applied daily and motor functions of patients were assessed using the modified cerebral vascular accident (MCVA) scores. Genotyping for IL4R polymorphism was done by pyrosequencing analysis. In IL4R genotypes and the frequency of alleles, there was no significant difference between cerebral infarction patients (n=124) and controls group (n=175). And there was also no significant difference among good and bad responders in cerebral infarction patients. In this study the IL4R genotype might not be the risk factor or a good predictive genetic marker for good and bad responders in cerebral infarction patients in Korean. Further studies including different cytokine genes will be necessary for the exact genetic markers.

• 생물정신의학
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• 제3권1호
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• pp.51-56
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• 1996

The effects of 3 week treatment with haloperidol(2mg/kg/day, i.p.) on dopamine(DA) D2 receptor and DA metabolism in rat striata were studied at various time points after withdrawal from the drug treatment. Striatal DA D2 receptors were characterized with the radioligand 0.5nM [$^3H$]Spiperone. Dopamine(DA), homovanillic acid(HVA), 3,4-dihydroxyphenyl acetic acid(DOPAC) in rat striatum were measured with the high performance liquid chromatography. Drug withdrawal for 1 week induced significant increase in the number of D2 receptor in striatum after withdrawal for 1 week(p<0.05), and then this change was restored to control level during the withdrawal time of 2 and 4 weeks. There was no difference in striatal concentrations of DA and its metabolites among the groups. In conclusion, one-week withdrawal from chronic haloperidol treatment induced DA D2 receptor supersensitivity in the striatum, and that was normalized rapidly. Though this adaptive change in DA receptors, it may not affect the metabolism of DA in striatum.

• Journal of Ginseng Research
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• 제19권3호
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• pp.219-224
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• 1995

The modulatory effects of total ginseng saponin (TGS) on the 1, 6, and opioid receptor binding in morphine tolerance and dependence were examined in this study. The specific [$^{3}H$]DAGO ([D-$Ala^2$, N-$Mephe^4$, $Glyco^4$] enkephalin) binding was significantly increased in chronic morphine (10 mg/kg, i.p.) treated mouse striatum. The specific [$^{3}H$]DPDPE ([D-$Pen^2$, D-$Pen^5$] enkephalin) binding was ignificantly increased following morphine treatment in the mouse striatum and cortex. Also, an apparent decrease in the affinity of [$^{3}H$]DPN (diprenorphine) was observed after chronic morphine treatment in mouse striatum and cortex. 7GS produced a sleight increase of specific [$^{3}H$]DAGO, [$^{3}H$]DPDPE binding and a significant increase of specific [$^{3}H$]DPN binding in the mouse brain striatum. In cortex, TGS produced an inhibition of specific [$^{3}H$]DAGO and [$^{3}H$]DPDPE binding and increase of the specific [$^{3}H$]DPN binding. The prolonged administration of TGS (25, 50, 100, and 150 mg/kg, i.p., 3 wks) produced an inhibition of increased [$^{3}H$]DAGO specific binding following morphine without significant changes in the agonist binding to and receptors in mouse striatum and cortex. These contracted alterations in $\mu$, $\gamma$ and $\kappa$ opiate receptor binding were dependent in TGS dogs and brain sites.

• Archives of Pharmacal Research
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• 제22권2호
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• pp.157-164
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• 1999

LB50016 was characterized as a selective and potent$ 5-HT_{1A}$ receptor agonist and evaluate it anxiolytic and antidepressant activities. It shows high affinity for $ 5-HT_{1A}$receptor, moderate affinity for $\alpha$2 adrenergic and $ 5-HT_{2A}$receptors and no significant affinity for other receptors tested. Hypothermia and increased serum corticosterone level were observed in LB50016-treated rats, which are mediated mostly by post synaptic $ 5-HT_{1A}$ receptor activation. In the mouse forced swim model for depression, LB50016-elicited dose-dependent reductions in immobility time, showing $ED_{50}$ of approximately 3 mg/kg i.p., which was blocked by pretreatment of NAN-190, $ 5-HT_{1A}$antagonist. In face-to-face test for anxiolytic activity in mice, estimated $ED_{50}$ was 2 mg/kg, i.p.. In isolation-induced aggression test with mice, fifty-fold increases in latency to attack were observed at 30 min and last up to 4 h after LB50016 treatment (3 mg/kg, i.p.). Taken together, LB50016-induced pharmacological activities are mediated by activation of $ 5-HT_{1A}$receptors, offering an effective therapeutic candidate in the management of anxiety and depression in humans.

• Molecules and Cells
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• 제25권2호
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• pp.253-257
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• 2008

Acrolein is a highly electrophilic ${\alpha},{\beta}$-unsaturated aldehyde present in a number of environmental sources, especially cigarette smoke. It reacts strongly with the thiol groups of cysteine residues by Michael addition and has been reported to inhibit nuclear $factor-{\kappa}B$ ($NF-{\kappa}B$) activation by lipopolysaccharide (LPS). The mechanism by which it inhibits $NF-{\kappa}B$ is not clear. Toll-like receptors (TLRs) play a key role in sensing microbial components and inducing innate immune responses, and LPS-induced dimerization of TLR4 is required for activation of downstream signaling pathways. Thus, dimerization of TLR4 may be one of the first events involved in activating TLR4-mediated signaling pathways. Stimulation of TLR4 by LPS activates both myeloid differential factor 88 (MyD88)- and TIR domain-containing adapter inducing $IFN{\beta}$ (TRIF)-dependent signaling pathways leading to activation of $NF-{\kappa}B$ and IFN-regulatory factor 3 (IRF3). Acrolein inhibited $NF-{\kappa}B$ and IRF3 activation by LPS, but it did not inhibit $NF-{\kappa}B$ or IRF3 activation by MyD88, inhibitor ${\kappa}B$ kinase $(IKK){\beta}$, TRIF, or TNF-receptor-associated factor family member-associated $NF-{\kappa}B$ activator (TANK)-binding kinase 1 (TBK1). Acrolein inhibited LPS-induced dimerization of TLR4, which resulted in the down-regulation of $NF-{\kappa}B$ and IRF3 activation. These results suggest that activation of TLRs and subsequent immune/inflammatory responses induced by endogenous molecules or chronic infection can be modulated by certain chemicals with a structural motif that enables Michael addition.