• Archives of Pharmacal Research
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• v.27 no.7
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• pp.769-775
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• 2004

Hepatic ischemia and reperfusion (l/R) predisposes the liver to secondary stresses such as endotoxemia, possibly via dysregulation of the hepatic microcirculation secondary to an imbalanced regulation of the vascular stress genes. In this study, the effect of hepatic I/R on the hepatic vasoregulatory gene expression in response to endotoxin was determined. Rats were subjected to 90 min of hepatic ischemia and 6 h of reperfusion. Lipopolysaccharide (LPS, 1 mg/kg) was injected intraperitoneally after reperfusion. Plasma and liver samples were obtained 6 h after reperfusion for serum aminotransferase assays and RT-PCR analysis of the mRNA for the genes of interest： endothelin-1 (ET-1), its receptors $ET_A$ and $ET_B$, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1), cyciooxygenase-2 (COX-2), and tumor necrosis factor-a (TNF-${\alpha}$). The activities of serum aminotransferases were significantly increased in the I/R group. This increase was markedly potentiated by LPS treatment. The ET-1 mRNA was increased by LPS alone, and this increase was significantly greater in both the I/R alone and I/R ＋ LPS groups compared to the sham. There were no significant differences in ETA receptor mRNA levels among any of the experimental groups. $ET_B$ mRNA was increased by both LPS alone and I/R alone, with no significant difference between the I/R alone and I/R ＋ LPS groups. The eN OS and HO-1 transcripts were increased by I/R alone and further increased by I/R ＋ LPS. The iNOS mRNA levels were increased by I/R alone, but increased significantly more by both LPS alone and I/R ＋ LPS compared to I/R alone. The TNF-${\alpha}$ mRNA levels showed no change with I/R alone, but were increased by both LPS alone and I/R ＋ LPS. The COX-2 expression was increased significantly by I/R alone and significantly more by I/R ＋ LPS. Taken collectively, significantly greater induction of the vasodilator genes over the constriction forces was observed with I/R ＋ LPS. These results may partly explain the increased susceptibility of ischemic livers to injury as a result of endotoxemia.

• Journal of Yeungnam Medical Science
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• v.34 no.1
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• pp.43-54
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• 2017

Background: Extracellular sulfatases (Sulfs), sulfatase 1 (Sulf1) and sulfatase 2 (Sulf2), play a pivotal role in cell signaling by remodeling the 6-O-sulfation of heparan sulfate proteoglycans on the cell surface. The present study examined the effects of Sulfs on angiotensin II (Ang II)-induced hypertensive mediator expression and vascular smooth muscle cells (VSMCs) proliferation in spontaneously hypertensive rats (SHR). Methods: Ang II receptors, 12-lipoxygenase (12-LO), and endothelin-1 (ET-1) messenger RNA (mRNA) expressions in SHR VSMCs were analyzed by real-time polymerase chain reaction and Western blotting. VSMCs proliferation was determined by [$^3H$]-thymidine incorporation. Results: Basal Sulfs mRNAs expression and enzyme activity were elevated in SHR VSMCs. However, Sulfs had no effect on the basal or Ang II-induced 12-LO and ET-1 mRNA expression in SHR VSMCs. The inhibition of Ang II-induced 12-LO and ET-1 expression by blockade of the Ang II type 2 receptor ($AT_2\;R$) pathway was not observed in Sulf1 siRNA-transfected SHR VSMCs. However, Sulf2 did not affect the action of $AT_2\;R$ inhibitor on Ang II-induced 12-LO and ET-1 expression in SHR VSMCs. The down-regulation of Sulf1 induced a reduction of $AT_2\;R$ mRNA expression in SHR VSMCs. In addition, the inhibition of Ang II-induced VSMCs proliferation by blockade of the $AT_2\;R$ pathway was mediated by Sulf1 in SHR VSMCs. Conclusion: These findings suggest that extracellular sulfatase Sulf1 plays a modulatory role in the $AT_2\;R$ pathway that leads to an Ang II-induced hypertensive effects in SHR VSMCs.

• Proceedings of the SCSK Conference
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• 2003.09b
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• pp.73-86
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• 2003

Endothelins secreted from keratinocytes are intrinsic madiators for human melanocytes in UVB-induced pigmentation. Antimelanogenic ingredient, 1,2-Ο-diferulylglycerol(SM709) isolated from bamboo extract inhibited the melanin synthesis of Bl6F10 melanoma cells by 62%. To understand the cellular mechanism of antimelanogenic activity of SM709 in human melanocytes, the effects of SM709 on the ET-l-induced $Ca^{2+}$ mobilization were investigated. ET-l receptors in human melanocytes were characterized by using specific antagonist and found that ET-l increased intracellular $Ca^{2+}$ by activating ET-B receptor. SM709 completely blocked the ET-l-induced intracellular $Ca^{2+}$ increase and its inhibitory effect showed dose- and time- dependent manners. To investigate the role of SM709 on intracellular $Ca^{2+}$ store, when the $Ca^{2+}$ store was partially depleted by thapsigargin; a specific inhibitor of ER-type $Ca^{2+}$-ATPase, caffeine-induced $Ca^{2+}$ mobilization did not changed in the presence or absence of SM709, suggesting that SM709 has no effect on the $Ca^{2+}$ store. It is known that LPA receptor and P$_2$ receptor are linked to InsP$_3$ second messenger system. When these receptors in melanocytes were activated by LPA and ATP, the intracellular $Ca^{2+}$ signaling was observed even in the presence of SM709. From the above results, it can be suggested that SM709 has an antimelanogenic activity by antagonizing the ET-B receptor, resulting in subsequent intracellular $Ca^{2+}$ signaling, in UV induced pigmentation.nduced pigmentation.

• Journal of Life Science
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• v.33 no.5
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• pp.445-454
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• 2023

Hair graying is the result of a malfunction in the signaling pathways that control melanogenesis, and it is activated by UV light, melanocyte-stimulating hormone (MSH), stem cell factor (SCF), Wnt, and endothelin-1 (ET-1). To prevent hair graying, synthetic and natural compounds can be used to stimulate melanogenesis effectively under the control of tyrosinase, tyrosine hydroxylase, tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor (MITF). This article describes a crucial strategy to resolve the problem of hair graying, as well as recent advances in the signaling pathway related to melanogenesis and hair graying. In particular, the article reviews potentially effective therapeutic agents that promote melanogenesis, such as antioxidants that modulate catalase, methionine sulfoxide reductase, and sirtuin 1 (SIRT1) activators including resveratrol, fisetin, quercetin, and ginsenoside. It also discusses vitiligo inhibitors, such as corticosteroids, calcineurin inhibitors, and palmitic acid methyl ester, as well as activators of telomerase expression and activity, including estrogen, androgen, progesterone, and dihydrotestosterone. Furthermore, it explores compounds that can inhibit hair graying, such as latanoprost, erlotinib, imatinib, tamoxifen, and levodopa. In conclusion, this article focuses on recent research trends on compounds that promote melanin production related to hair graying.

• Journal of Ginseng Research
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• v.43 no.4
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• pp.550-561
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• 2019

Background: Gastric ulcer (GU) is a common gastrointestinal disease that can be induced by many factors. Finding an effective treatment method that contains fewer side effects is important. 20 (S)-ginsenoside Rg3 is a kind of protopanaxadiol and has shown superior antiinflammatory and antioxidant effects in many studies, especially cancer studies. In this study, we examined the treatment efficacy of 20 (S)-ginsenoside Rg3 on GU. Methods: Three kinds of GU models, including an alcohol GU model, a pylorus-ligated GU model, and an acetic acid GU model, were used. Mouse endothelin-1 (ET-1) and nitric oxide (NO) levels in blood and epidermal growth factor (EGF), superoxide dismutase, and NO levels in gastric mucosa were evaluated. Hematoxylin and eosin staining of gastric mucosa and immunohistochemical staining of ET-1, inducible nitric oxide synthase (NOS2), and epidermal growth factor receptors were studied. Ulcer index (UI) scores and UI ratios were also analyzed to demonstrate the GU conditions in different groups. Furthermore, Glide XP from $Schr{\ddot{o}}dinger$ was used for molecular docking to clarify the interactions between 20 (S)-ginsenoside Rg3 and EGF and NOS2. Results: 20 (S)-ginsenoside Rg3 significantly decreased the UI scores and UI ratios in all the three GU models, and it demonstrated antiulcer effects by decreasing the ET-1 and NOS2 levels and increasing the NO, superoxide dismutase, EGF, and epidermal growth factor receptor levels. In addition, high-dose 20 (S)-ginsenoside Rg3 showed satisfactory gastric mucosa protection effects. Conclusion: 20 (S)-ginsenoside Rg3 can inhibit the formation of GU and may be a potential therapeutic agent for GU.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2003.11a
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• pp.77-77
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• 2003

Sepsis remains common surgical problems with high morbidity and mortality despite improvement in the management for septic patient. Although hepatocellular dysfunction occurs during sepsis, the mechanism responsible for this remains unclear. In sepsis, a state of severe oxidative stress is encountered, with host endogenous antioxidant defenses overcome. Therefore, the aim of this study was to determine the effect of a-tocopherol (AT) vasoregulatory gene expression during polymicrobial sepsis. Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). AT (15 mg/kg) was intraperitonealy injected for 3 days prior to CLP. Blood samples were taken 24 h after CLP for measurement of the extent of hepatocellular damage. Liver samples were taken for RT-PCR analysis of mRNA for genes of interest: endothelin-l (ET-l), its receptors $ET_{A}$ and $ET_{B}$, nitric oxide synthases (iNOS and eNOS), cyclooxygenase-2 (COX -2), heme oxygenase-l (HO-l), and tumor necrosis factor-$\alpha$ (TNF-$\alpha$). The activities of serum alanine aminotransferase and lipid peroxidation level were significantly increased; an increase which was prevented by AT pretreatment. CLP significantly increased the mRNA levels of ET-1 and $ET_{B}$; an increase that was prevented by AT pretreatment. However, the level of $ET_{A}$ mRNA significantly decreased after CLP; a decrease that was not prevented by AT pretreatment. There were significant increases in the mRNA expression of iNOS, HO-l and COX -2 in CLP groups. This increase was prevented by AT pretreatment. The expression of eNOS and TNF-$\alpha$ mRNA significantly increased in CLP, which was not prevented by AT pretreatment. Our findings suggest that there was an imbalanced vasoregulatory gene expression in sepsis, and AT ameliorates this change through its free radical scavenging activity.

• Clinical and Experimental Pediatrics
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• v.59 no.6
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• pp.262-270
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• 2016

Purpose: Pulmonary arterial hypertension (PAH) leads to right ventricular failure (RVF) as well as an increase in pulmonary vascular resistance. Our purpose was to study the effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline (MCT)-induced RVF. Methods: The rats were distributed randomly into 3 groups. The control (C) group, the monocrotaline (M) group (MCT 60 mg/kg) and the sildenafil (S) group (MCT 60 mg/kg+ sildenafil 30 mg/kg/day for 28 days). Masson Trichrome staining was used for heart tissues. Western blot analysis and immunohistochemical staining were performed. Results: The mean right ventricular pressure (RVP) was significantly lower in the S group at weeks 1, 2, and 4. The number of intra-acinar arteries and the medial wall thickness of the pulmonary arterioles significantly lessened in the S group at week 4. The collagen content also decreased in heart tissues in the S group at week 4. Protein expression levels of B-cell lymphoma-2 (Bcl-2)-associated X, caspase-3, Bcl-2, interleukin (IL)-6, matrix metalloproteinase (MMP)-2, endothelial nitric oxide synthase (eNOS), endothelin (ET)-1 and ET receptor A (ERA) in lung tissues greatly decreased in the S group at week 4 according to immunohistochemical staining. According to Western blotting, protein expression levels of troponin I, brain natriuretic peptide, caspase-3, Bcl-2, tumor necrosis factor-${\alpha}$, IL-6, MMP-2, eNOS, ET-1, and ERA in heart tissues greatly diminished in the S group at week 4. Conclusion: Sildenafil alleviated right ventricular hypertrophy and mean RVP. These data suggest that sildenafil improves right ventricular function.

• Molecules and Cells
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• v.40 no.1
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• pp.66-72
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• 2017

Pathological hypertrophy of the heart is closely associated with endoplasmic reticulum stress (ERS), leading to maladaptations such as myocardial fibrosis, induction of apoptosis, and cardiac dysfunctions. Salubrinal is a known selective inhibitor of protein phosphatase 1 (PP1) complex involving dephosphorylation of phospho-eukaryotic translation initiation factor 2 subunit $(p-eIF2)-{\alpha}$, the key signaling process in the ERS pathway. In this study, the effects of salubrinal were examined on cardiac hypertrophy using the mouse model of transverse aortic constriction (TAC) and cell model of neonatal rat ventricular myocytes (NRVMs). Treatment of TAC-induced mice with salubrinal ($0.5mg{\cdot}kg^{-1}{\cdot}day^{-1}$) alleviated cardiac hypertrophy and tissue fibrosis. Salubrinal also alleviated hypertrophic growth in endothelin 1 (ET1)-treated NRVMs. Therefore, the present results suggest that salubrinal may be a potentially efficacious drug for treating pathological cardiac remodeling.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.21
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• pp.9505-9509
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• 2014

Objective: To investigate the effects of stellate ganglion block (SGB) on the peri-operative vasomotor cytokine content and intrapulmonary shunt in patients with esophagus cancer who underwent thoracotomy. Materials and Methods: Forty patients undergoing elective resection of esophageal cancer patients who had I~II American Society of Anesthesiologist (ASA) were randomly divided into total intravenous anesthesia group (group N, n=20) and total intravenous anesthesia combined with SGB group (group S, n=20, 0.12 mL/kg 1% lidocaine was used for SGB 10 min before induction). Heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), mean pulmonary arterial pressure (MPAP) and continuous cardiac output (CCO) were continuously monitored. The blood from internal jugular vein was drawn respectively before induction ($T_0$), and 30 min ($T_1$), 60 min ($T_2$) and 120 min ($T_3$) after one-lung ventilation (OLV), and 30 min (T4) after two-lung ventilation. The contents of plasma endothelin (ET), nitric oxide (NO) and calcitonin gene-related peptide (CGRP) were detected with enzyme linked immunosorbent assay (ELISA). Meanwhile, arterial and mixed venous blood samples were collected for determination of blood gas and calculation of intrapulmonary shunt fraction (Qs/Qt). Results: During OLV, ET contents were increased significantly in two groups (P<0.05), and no significant difference was presented (P>0.05). NO content in group S was obviously higher than in group N at T3 (P<0.05), whereas CGRP content in group N was markedly lower than in group S at each time point (P<0.05). Qs/Qt was significantly increased in both groups after OLV, but there was no statistical significant regarding the Qs/Qt at each time point between two groups. Conclusions: Total intravenous anesthesia combined with SGB is conducive to regulation of perioperative vasomotor cytokines in thoracotomy, and has little effect on intrapulmonary shunt at the time of OLV.

• Biomedical Science Letters
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• v.10 no.4
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• pp.459-465
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• 2004

The use of hemofiltration has been proposed to reduce excessive body fluid and inflammatory mediators produced during cardiac surgery with cardiopulmonary bypass (CPB) in infants and children. This study was undertaken to evaluate the efficacy of hemofiltration in adult cardiac surgery using (CPB). Twenty adult patients scheduled for elective cardiac surgery were randomly assigned to control group without hemofiltration (n=10) or hemofilter group with hemofiltration during CPB (n=lO). CBC and serum levels of interleukin-6 (IL-6), D-dimer, endothelin-l (ET-1), and cortisol were measured at before the initiation and immediately after the termination of CPB (Pre-CPB and End-CPB, respectively). Clinical data were assessed at postoperative period. In hemofilter group hematocrit was significantly higher (30.04±2.63％ vs 23.30±2.71％, P=0.0014) whereas total leukocyte count was lower than in control group (7.71±1.78×10³/㎣ vs 16.01 ±3.12x10³/㎣, P=0.021) at End-CPB. Increased rate of IL-6 (311.56±97.31％ vs 825.45±102.56％, P=0.012) and D-dimer levels (154.55±89.04％ vs 308.33±157.64％, P=0.026) at End-CPB were significantly less in hemofilter group than in control group. Postoperative blood transfusion in hemofilter group was low compared with that of control group (741.00±38.07 ml vs 1,137.50±169.82 ml, P=0.037). There were no significant differences between two groups in platelet count, ET -1, cortisol, pulmonary index, mechanical ventilation, postoperative blood loss, ICU-stay and hospitalization. Hemofiltration technique applied in the present study provided partly beneficial effect in adult cardiac surgery.