• The Journal of Korean Medicine
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• v.23 no.4
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• pp.161-168
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• 2002

Objectives: Hwangryunhaedok-tang (Huang-lian-jie-du-tang, HRHDT, 黃連解毒湯) is a traditional Korean herbal medicine that is formulated with Coptidis Rhizoma, Phellodendri Cortex, Scutellariae Radix and Gardeniae Fructus. HRHDT is cold (寒) and bitter (苦) in nature and has general properties of clearing heat and detoxifying (淸熱解毒), strengthening the stomach and settling the liver (健胃平肝), and reducing inflammation, fever and swelling. This formula can prevent and treat artherosclerosis, hyperplasia of the endothelium, cerebral fluid circulation, cerebral vascular deterioration through aging, impairment of neurotransmitters, or disruption of the functioning of the cerebral cortex following infection or trauma. The purpose of the study reported here was to determine the neuroprotective effect of HRHDT on global ischemia induced by 4-vessel occlusion in Wistar rats. Methods: HRHDT extract was lyophilized after extraction with 85% methanol and 100% water. Rats were induced to 10 minutes of forebrain ischemia by 4-vessel occlusion (4-VO) and reperfused again. HRHDT was administered with a dose of 100 mg/kg, and 500 mg/kg of 85% methanol extracts and 100 mg/kg of 100% water extracts, respectively, at 0 min and 90 min after 4-VO. Rats were killed at 7 days after ischemia and the number of CA1 pyramidal neurons was counted in hippocampal sections stained with cresyl violet. Results: Body temperature of animals showed no significant difference between saline-treated groups and HRHDT extracts-treated groups until 5 hours of reperfusion. This result indicated that neuroprotective effects of HRHDT extracts were not due to hypothermic effects. The administration of HRHDT showed a significant neuroprotective effect on hippocampal CA1 neurons at 7 days after ischemia compared to the saline-treated group (P<0.001). HRHDT methanol extracts of 100 mg/kg, 500 mg/kg and HRHDT water extracts of 100 mg/kg showed 88.5%, 98.3% and 95.1 % neuroprotection, respectively. Conclusions: The results of this study demonstrate that administration of HRHDT is highly effective in reducing neuronal damage in response to transient global cerebral ischemia. HRHDT may involve many mechanisms that might account for its high degree of efficacy. A number of factors including free radicals, glutamate, calcium overload, NO, and various cytokines have been proposed to have an important role in causing neuronal death after short periods of global ischemia. Further studies are needed to know the neuroprotective mechanisms of HRHDT.

• Asian-Australasian Journal of Animal Sciences
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• v.26 no.10
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• pp.1399-1405
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• 2013

The present study focused on establishing the effects of interferon-gamma (IFN-${\gamma}$) on interleukin-18 (IL-18) expression patterns and pregnancy outcomes in pregnant rats. Pregnant rats at the post-implantation stage were randomized into control, low IFN-${\gamma}$ (L-IFN-${\gamma}$) and high IFN-${\gamma}$ groups (H-IFN-${\gamma}$) that received normal saline, 100 IU/g of IFN-${\gamma}$ and 500 IU/g of IFN-${\gamma}$ vaginal muscular injection, respectively. The effects of IFN-${\gamma}$ on IL-18 expression and pregnancy outcomes were assessed systematically using several methods, including immunohistochemistry streptavidin-perosidase (SP), image pattern analysis, enzyme-linked immune-sorbent assay (ELISA), whole blood count (WBC) count, microscopy and visual observation. IL-18 was detected in the uteri of all pregnant rats, and mainly distributed in the endometrium, decidual cells, vascular endothelium and myometrium. Immunohistochemistry and image pattern analyses revealed significantly lower IL-18 expression in the H-IFN-${\gamma}$ group compared to the L-IFN-${\gamma}$ and control groups (p<0.01), indicating that high doses of IFN-${\gamma}$ induce downregulation of IL-18 in the uterus of pregnant rats. ELISA results disclosed that IL-18 expression in peripheral blood of the H-IFN-${\gamma}$ group was lower than that of the L-IFN-${\gamma}$ group (p<0.05), and significantly reduced compared to the control group (p<0.01). Moreover, the number of peripheral leukocytes in the H-IFN-${\gamma}$ group was significantly higher than those in the control and L-IFN-${\gamma}$ groups (p<0.01). Morphology analysis showed no evident differences between the L-IFN-${\gamma}$ and control groups. However, for the H-IFN-${\gamma}$ group, uterine mucosa bleeding, necrosis and excoriation were observed using microscopy. Visual observation revealed marroon, swelling, crassitude and no embryo in the uterus, which are obvious indicators of abortion. These results indicate that IFN-${\gamma}$ plays a regulatory role in IL-18 expression in the uterus and peripheral blood of pregnant rats at the post-implantation stage. Moreover, high levels (500 IU/g) of IFN-${\gamma}$ influence normal pregnancy at the early stages in rats by downregulating IL-18 expression in the uterus and peripheral blood and increasing the number of peripheral leukocytes, consequently triggering termination of pregnancy.

• The Korean Journal of Physiology and Pharmacology
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• v.17 no.3
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• pp.181-187
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• 2013

Reactive oxygen species (ROS) are generated in various cells, including vascular smooth muscle and endothelial cells, and regulate ion channel functions. $K_{Ca}3.1$ plays an important role in endothelial functions. However, the effects of superoxide and hydrogen peroxide radicals on the expression of this ion channel in the endothelium remain unclear. In this study, we examined the effects of ROS donors on $K_{Ca}3.1$ expression and the $K^+$ current in primary cultured human umbilical vein endothelial cells (HUVECs). The hydrogen peroxide donor, tert-butyl hydroperoxide (TBHP), upregulated $K_{Ca}3.1$ expression, while the superoxide donors, xanthine/xanthine oxidase mixture (X/XO) and lysophosphatidylcholine (LPC), downregulated its expression, in a concentration-dependent manner. These ROS donor effects were prevented by antioxidants or superoxide dismustase. Phosphorylated extracellular signal-regulated kinase (pERK) was upregulated by TBHP and downregulated by X/XO. In addition, repressor element-1-silencing transcription factor (REST) was downregulated by TBHP, and upregulated by X/XO. Furthermore, $K_{Ca}3.1$ current, which was activated by clamping cells with 1 ${\mu}M$ $Ca^{2+}$ and applying the $K_{Ca}3.1$ activator 1-ethyl-2-benzimidazolinone, was further augmented by TBHP, and inhibited by X/XO. These effects were prevented by antioxidants. The results suggest that hydrogen peroxide increases $K_{Ca}3.1$ expression by upregulating pERK and downregulating REST, and augments the $K^+$ current. On the other hand, superoxide reduces $K_{Ca}3.1$ expression by downregulating pERK and upregulating REST, and inhibits the $K^+$ current. ROS thereby play a key role in both physiological and pathological processes in endothelial cells by regulating $K_{Ca}3.1$ and endothelial function.

• YAKHAK HOEJI
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• v.41 no.6
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• pp.802-816
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• 1997

In order to investigate the pharmacological properties of New Woohwangehungsimwon Pill (NWCH). Effects of Woohwangehungsimwon Pill (WCH) and NWCH were compared using various experimental models. In isolated rat aorta, NWCH and WCH showed the relaxation of blood vessels in maximum contractile response to phenylephrine ($10^{-6}$M) without regard to endothelium containing or denuded rings of the rat aorta. Furthermore, the presence of the inhibitors of NO synthase and guanylate cyclase did not affect significantly the relaxative effects of NWCH and WCH. NWCH and WCH inhibited the vascular contractions induced by acethylcholine, prostaglandin endoperoxide or peroxide in a dose-dependent manner. In conscious spontaneously hypertensive rats(SHRs), NWCH and WCH decreased significantly heart rate. These, at high doses, had a negative inotropic effect that was a decrease of LVDP and (-dp/dt)/(+dp/dt) in the isolated perfused rat hearts, and also decreased the contractile force and heart rate in the isolated rat right atria. In excised guinea-pig papillary muscle, these had no effects on parameters of action potential at low doses, whereas inhibited the cardiac, contractility at high doses. Furthermore, these had a significant inhibitory effects on heart acceleration in normotensive rats and SHRs. These results suggested that NWCH and WCH have weak cardiovascular effects, and that there is no significant differences between two preparations.

• The Journal of the Korean bone and joint tumor society
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• v.15 no.1
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• pp.7-12
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• 2009

Purpose: This study was aimed to assess TLE1 as a target molecule of synovial sarcoma. Method: We obtained tissue samples and clinical data from 36 patients who were diagnosed and treated for synovial sarcoma in our hospital. Immunohistochemical staining was performed to detect the expression of TLE1 in synovial sarcoma and normal tissues such as fat, skeletal muscle, peripheral nerve, vascular endothelium, and epithelium. Univariate survival analysis was performed to find whether overexpression of TLE1 is correlated to poor prognosis. Results: TLE1 was expressed in 35 (97%) cases (grade 1 was 5 cases, grade 2 was 28 cases, grade 3 was 2 cases.). Normal tissues from mesenchymal origin did not express TLE1. However, epithelial and endothelial cells showed weak expression (grade 1) of TLE1. The level of TLE1 expression did not have any prognostic significance according to univariate survival analysis. Conclusion: TLE1 may be a new molecular target of synovial sarcoma that differentiates synovial sarcoma from normal mesenchymal cells.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.3
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• pp.323-330
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• 1998

Tetrahydroisoquinoline (THI) alkaloids can be considered as cyclized derivatives of simple phenylethylamines. Many of them, especially with 6,7-disubstitution, demonstrate a relatively high affinity for catecholamines. Present study examines the pharmacological action of limited series of THI, using rats' isolated atria and aorta. In addition, a $[^3H]$ prazosin displacement binding study with THI compounds was performed, using rat brain homogenates to investigate whether these probes have ?${\alpha}$-adrenoceptor affinity. We also compared the vascular relaxation potency of these probes with dobutamine. YS 49, YS 51, higenamine and dobutamine, concentration-dependently, relaxed endothelium-denuded rat thoracic aorta precontracted with phenylephrine (PE, 0.1 ${\mu}M$) in which $pEC_{50}$ were $5.56{\pm}0.32$ and $5.55{\pm}0.21$, $5.99{\pm}1.16$ and $5.57{\pm}0.34$, respectively. These probes except higenamine also relaxed KCl (65.4 mM)-contracted aorta. In isolated rat atria, all THIs and dobutamine increased heart rate and contractile force. In the presence of propranolol, the concentration response curves of YS 49 and YS 51 shifted to the right and resulted in $pA_2$ values of $8.07{\pm}0.84$ and $7.93{\pm}0.11$, respectively. The slope of each compound was not deviated from unity, indicating that these chemicals are highly competitive at the cardiac ?${\beta}-adrenoceptors$. YS 49, YS 51, and higenamine showed ?${\alpha)-adrenoceptor$ affinity in rat brain, in which the dissociation constant $(K_i)$ was 2.75, 2.81, and 1.02 ${\mu}M$, respectively. It is concluded, therefore, that THI alkaloids have weak affinity to ${\alpha)_1-adrenoceptor$ in rat aorta and brain, respectively, while these probes show relatively high affinity for cardiac ${\beta}-adrenoceptors$. Thus, these chemicals may be useful in the treatment of congestive heart failure.

• Journal of Veterinary Clinics
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• v.19 no.3
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• pp.299-302
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• 2002

Selectins are differentially expressed carbohydrate binding proteins involved in the initiation of tissue inflammation by mediating the rolling and tethering of leukocytes on the vascular endothelium. This primary event in initiation of inflammation, as occurs during reperfusion injury, can be therapeutically targeted using selectin inhibitors, which generally block binding of sLex to E-, P-, and L-selectins. The objective of this study was to determine the role of selectins in renal ischemia/reperfusion injury after kidney transplantation. Canine kidneys were subjected to 60-min warm ischemia, flushed with UW solution, cold stored for 24 h, and autotransplanted into the nephrectomized donor. Renal autografts were monitored for 7 days by serum creatinine in the first study and by histology and myeloperoxidase activity after 4-hour reperfusion in the second study. In each study, one group of animals received TBC1269 (selectin inhibitor) and the other received saline vehicle. Serum creatinine rose quickly after transplantation and was not different between the groups. TBC1269 abolished a reperfusion-induced 2-fold increase in renal cortex neutrophil infiltration and improved histologic signs of ischemia after 4 hours of reperfusion. Selectin blockade does not improve the course of injury caused by warm renal ischemia. A minor benefit associated with the inhibition of early inflammation during reperfusion after kidney transplantation seems to occur.

• The Korean Journal of Physiology and Pharmacology
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• v.25 no.1
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• pp.59-68
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• 2021

Arterial thrombosis and its associated diseases are considered to constitute a major healthcare problem. Arterial thrombosis, defined as blood clot formation in an artery that interrupts blood circulation, is associated with many cardiovascular diseases. Oxidative stress is one of many important factors that aggravates the pathophysiological process of arterial thrombosis. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ref-1) has a multifunctional role in cells that includes the regulation of oxidative stress and anti-inflammatory function. The aim of this study was to investigate the therapeutic effect of adenovirus-mediated Ref-1 overexpression on arterial thrombosis induced by 60% FeCl3 solution in rats. Blood flow was measured to detect the time to occlusion, thrombus formation was detected by hematoxylin and eosin staining, reactive oxygen species (ROS) levels were detected by high-performance liquid chromatography, and the expression of tissue factor and other proteins was detected by Western blot. FeCl3 aggravated thrombus formation in carotid arteries and reduced the time to artery occlusion. Ref-1 significantly delayed arterial obstruction via the inhibition of thrombus formation, especially by downregulating tissue factor expression through the Akt-GSK3β-NF-κB signaling pathway. Ref1 also reduced the expression of vascular inflammation markers ICAM-1 and VCAM-1, and reduced the level of ROS that contributed to thrombus formation. The results showed that adenovirus-mediated Ref-1 overexpression reduced thrombus formation in the rat carotid artery. In summary, Ref-1 overexpression had anti-thrombotic effects in a carotid artery thrombosis model and could be a target for the treatment of arterial thrombosis.

• Journal of Life Science
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• v.32 no.2
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• pp.175-188
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• 2022

Relaxin has been demonstrated to have regulatory functions on both the smooth muscle and extracellular matrix (ECM) of blood vessels and fibrotic organs. The diverse mechanisms by which relaxin acts on small resistance arteries and fibrotic organs, including the bladder, are reviewed here. Relaxin induces vasodilation by inhibiting the contractility of vascular smooth muscles and by increasing the passive compliance of vessel walls through the reduction of ECM components, such as collagen. The primary cellular mechanism whereby relaxin induces arterial vasodilation is mediated by the endothelium-dependent production of nitric oxide (NO) through the activation of RXFP1/PI3K, Akt phosphorylation, and eNOS. In addition, relaxin triggers different alternative pathways to enhance the vasodilation of renal and mesenteric arteries. In small renal arteries, relaxin stimulates the activation of the endothelial MMPs and EtB receptors and the production of VEGF and PlGF to inhibit myogenic contractility and collagen deposition, thereby bringing about vasodilation. Conversely, in small mesenteric arteries, relaxin augments bradykinin (BK)-evoked relaxation in a time-dependent manner. Whereas the rapid enhancement of the BK-mediated relaxation is dependent on IK_Ca channels and subsequent EDH induction, the sustained relaxation due to BK depends on COX activation and PGI₂. The anti-fibrotic effects of relaxin are mediated by inhibiting the invasion of inflammatory immune cells, the endothelial-to-mesenchymal transition (EndMT), and the differentiation and activation of myofibroblasts. Relaxin also activates the NOS/NO/cGMP/PKG-1 pathways in myofibroblasts to suppress the TGF-β1-induced activation of ERK1/2 and Smad2/3 signaling and deposition of ECM collagen.

• Journal of Industrial Convergence
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• v.21 no.10
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• pp.57-63
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• 2023

This study aims to elucidate the effect of glycyrrhizic acid on smooth muscle contraction and to determine the detailed mechanism incorporated. We hypothesized that glycyrrhizic acid played a role in the agonist-sensitive management of smooth muscle contraction. Stripped smooth muscles of Sprague-Dawley rats were prepared in organ baths and isometric tensions were converted, stored and analyzed by using isometric transducers, a physiograph and one way ANOVA. Interestingly, glycyrrhizic acid attenuated the thick filament regulating agonist (fluoride or thromboxane mimetic)-sensitive contraction (p=0.113, 0.008, 0.004 (Student's t-test), p=0.113, 0.008, 0.004 (One way ANOVA) at 0.01, 0.03, 0.1 mM fluoride, and p=0.156, 0.004, 0.003 (Student's t-test), p=0.156, 0.004, 0.003 (One way ANOVA) at 0.01, 0.03, 0.1 mM thromboxane mimetic) and did not attenuate the thin filament regulating agonist (phorbol ester)-induced contraction (p=0.392, 0.086, 0.065 (Student's t-test), p=0.392, 0.086, 0.065 (One way ANOVA) at 0.01, 0.03, 0.1 mM phorbol ester). It is suggesting that endothelial EDRF (NO) synthesis and accessory pathways besides endothelial EDRF (NO) synthesis such as ROCK restriction might be incorporated in the glycyrrhizic acid-induced modulation of smooth muscle contraction inhibiting acto-myosin interaction.