• Biomolecules & Therapeutics
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• v.26 no.2
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• pp.139-145
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• 2018

The present study was undertaken to investigate the influence of hypothermia on endothelium-independent vascular smooth muscle contractility and to determine the mechanism underlying the relaxation. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Hypothermia significantly inhibited fluoride-, thromboxane $A_{2-}$, phenylephrine-, and phorbol ester-induced vascular contractions regardless of endothelial nitric oxide synthesis, suggesting that another pathway had a direct effect on vascular smooth muscle. Hypothermia significantly inhibited the fluoride-induced increase in pMYPT1 level and phorbol ester-induced increase in pERK1/2 level, suggesting inhibition of Rho-kinase and MEK activity and subsequent phosphorylation of MYPT1 and ERK1/2. These results suggest that the relaxing effect of moderate hypothermia on agonist-induced vascular contraction regardless of endothelial function involves inhibition of Rho-kinase and MEK activities.

• Journal of Korean Medicine Rehabilitation
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• v.23 no.1
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• pp.25-49
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• 2013

Objectives : This study was carried out to know the anti-osteroarthritic effects of Bangkibokryeong-tang(Fanjifuling-tang(BBT)) on the papain-induced osteoarthritis C57BL/10 mouse. Methods : Osteoarthritis was induced by injection of papain(6 ${\mu}l$) into knee joint of mouse. Osteoarthritic mice were divided into 4 groups(normal, control, joins(R), BBT). The injection did not fit the normal group. A week later, after the injection of papain, control group was taken normal saline 200 ${\mu}l$, positive control group was taken joins(R)(100 mg/kg), treated group was taken extract of Bangkibokryeong-tang(Fanjifuling-tang(BBT))(400 mg/kg). After then, we examined hepatotoxicity, nephrotoxicity, inflammation cytokines, expression of inflammation factor mRNA, hemotology, histology through the micro CT-arthrography, and etc. Results : 1. Hepatotoxicity and nephrotoxicity have not expressed. 2. The levels of IL-$1{\beta}$, TNF-${\alpha}$, IL-6, MCP-1, Thromboxane B2, Leukotriene B4, Prostaglandin E2 in serum were significantly decreased. 3. In hematology, the levels of neutrophils and monocytes were significantly decreased. 4. The expression of inflammation factor mRNA like TNF-${\alpha}$ and IL-6, COX-2, iNOS-II were significantly inhibited. 5. In micro CT-arthrography, cartilage volume was less decreased. 6. The degree of osteoarthritis induced damage of joint of BBT group is low in histopathologic observation(hematoxylin&eosin(H&E), Safranin-O). Conclusions : According to this study, BBT has effect of anti-osteoarthritis. Further clinical research for the cartilage protective effect is necessary.

• Journal of Ginseng Research
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• v.41 no.2
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• pp.120-126
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• 2017

Background: The present study investigated the effect of ginseng berry hot water extract (GBx) on blood flow via the regulation of lipid metabolites and blood coagulation in rats fed a high-fat diet (HFD). Methods: Sixty rats were divided into five groups in descending order of body weight. Except for the control group, the other four groups were fed a HFD containing 45% kcal from fat for 11 wk without GBx. GBx groups were then additionally treated by gastric gavage with GBx dissolved in distilled water at 50 (GBx 50) mg/kg, 100 (GBx 100) mg/kg, or 150 (GBx 150) mg/kg body weight for 6 wk along with the HFD. To investigate the effects of GBx on rats fed a HFD, biochemical metabolite, blood coagulation assay, and histological analysis were performed. Results: In the experiments to measure the serum levels of leptin and apolipoprotein B/A, GBx treatment attenuated the HFD-induced increases in these metabolites (p < 0.05). Adiponectin and apolipoprotein E levels in GBx-treated groups were significantly higher than the HFD group. Prothrombin time and activated partial thromboplastin time were increased in all GBx-treated groups. In the GBx-treated groups, the serum levels of thromboxane $A_2$ and serotonin were decreased and concentrations of serum fibrinogen degradation products were increased (p < 0.05). Moreover, histomorphometric dyslipidemia-related atherosclerotic changes were significantly improved by treatment with GBx. Conclusion: These results suggest the possibility that GBx can ameliorate blood flow by decreasing intima-media thickness via the regulation of blood coagulation factors related to lipid metabolites in rats fed a HFD.

• BMB Reports
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• v.44 no.6
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• pp.415-420
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• 2011

Diabetes is a well-known independent risk factor for vascular disease. However, its underlying mechanism remains unclear. It has been reported that increased influx of the hexosamine biosynthesis pathway (HBP) induces O-GlcNAcylation of proteins, leading to insulin resistance. In this study, we determined whether or not O-GlcNAc modification of proteins could increase vessel contraction. Using an endothelium-denuded aortic ring, we observed that glucosamine induced OGlcNAcylation of proteins and augmented vessel contraction stimulated by U46619, a thromboxane $A_2$ agonist, via augmentation of the phosphorylation of MLC20$MLC_{20}$, MYPT1(Thr855), and CPI17, but not phenylephrine. Pretreatment with OGT inhibitor significantly ameliorated glucosamine-induced vessel constriction. Glucosamine treatment also increased RhoA activity, which was also attenuated by OGT inhibitor. In conclusion, glucosamine, a product of glucose influx via the HBP in a diabetic state, increases vascular contraction, at least in part, through activation of the RhoA/Rho kinase pathway, which may be due to O-GlcNAcylation.

• Preventive Nutrition and Food Science
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• v.18 no.3
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• pp.181-187
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• 2013

Artemisia princeps Pampanini (AP) has been used as a traditional medicine in Korea, China and Japan and reported to exhibit various beneficial biological effects including anti-inflammatory, antioxidant, anti-atherogenic and lipid lowering activities; however, its antiplatelet and anticoagulant properties have not been studied. In the present study, we evaluated the effects of an ethanol extract of Artemisia princeps Pampanini (EAP) and its major flavonoids, eupatilin and jaceosidin, on platelet aggregation and coagulation. To determine the antiplatelet activity, arachidonic acid (AA)-, collagen- and ADP (adenosine diphosphate)-induced platelet aggregation were examined along with serotonin and thromboxane A2 ($TXA_2$) generation in vitro. The anticoagulant activity was determined by monitoring the activated partial thromboplastin time (aPTT) and prothrombin time (PT) in vitro. The data showed that EAP and its major flavonoids, eupatilin and jaceosidin, significantly reduced AA-induced platelet aggregation and the generation of serotonin and $TXA_2$, although no significant change in platelet aggregation induced by collagen and ADP was observed. Moreover, EAP significantly prolonged the PT and aPTT. The PT and/or aPTT were significantly increased in the presence of eupatilin and jaceosidin. Thus, these results suggest that EAP may have the potential to prevent or improve thrombosis by inhibiting platelet activation and blood coagulation.

• Biomolecules & Therapeutics
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• v.27 no.2
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• pp.134-144
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• 2019

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased with the incidence of obesity; however, the underlying mechanisms are unknown. In this study, high-resolution metabolomics (HRM) along with transcriptomics were applied on animal models to draw a mechanistic insight of NAFLD. Wild type (WT) and catalase knockout (CKO) mice were fed with normal fat diet (NFD) or high fat diet (HFD) to identify the changes in metabolic and transcriptomic profiles caused by catalase gene deletion in correspondence with HFD. Integrated omics analysis revealed that cholic acid and $3{\beta}$, $7{\alpha}$-dihydroxy-5-cholestenoate along with cyp7b1 gene involved in primary bile acid biosynthesis were strongly affected by HFD. The analysis also showed that CKO significantly changed all-trans-5,6-epoxy-retinoic acid or all-trans-4-hydroxy-retinoic acid and all-trans-4-oxo-retinoic acid along with cyp3a41b gene in retinol metabolism, and ${\alpha}/{\gamma}$-linolenic acid, eicosapentaenoic acid and thromboxane A2 along with ptgs1 and tbxas1 genes in linolenic acid metabolism. Our results suggest that dysregulated primary bile acid biosynthesis may contribute to liver steatohepatitis, while up-regulated retinol metabolism and linolenic acid metabolism may have contributed to oxidative stress and inflammatory phenomena in our NAFLD model created using CKO mice fed with HFD.

• Journal of Rheumatic Diseases
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• v.24 no.4
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• pp.192-202
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• 2017

Objective. Rebampide is a gastroprotective agent used to treat gastritis. It possesses anti-inflammatory and anti-arthritis effects, but the mechanisms of these effects are not well understood. The objective of this study was to explore mechanisms underlying the therapeutic effects of rebamipide in inflammatory arthritis. Methods. Collagen-induced arthritis (CIA) was induced in DBA/1J mice. DBA/1J mice were immunized with chicken type II collagen, then treated intraperitoneally with rebamipide (10 mg/kg or 30 mg/kg) or vehicle (10% carboxymethylcellulose solution) alone. Seven weeks later, plasma samples were collected. Plasma metabolic profiles were analyzed using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolomics study and metabolite biomarkers were identified through multivariate data analysis. Results. Low dose rebamipide treatment reduced the clinical arthritis score compared with vehicle treatment, whereas high dose rebamipide in CIA aggravated arthritis severity. Based on multivariate analysis, 17 metabolites were identified. The plasma levels of metabolites associated with fatty acids and phospholipid metabolism were significantly lower with rebamipide treatment than with vehicle. The levels of $15-deoxy-^{{\Delta}12,14}$ prostaglandin J2 and thromboxane B3 decreased only in high dose-treated groups. Certain peptide molecules, including enterostatin (VPDPR) enterostatin and bradykinin dramatically increased in rebamipide-treated groups at both doses. Additionally, corticosterone increased in the low dose-treated group and decreased in the high dose-treated group. Conclusion. Metabolomics analysis revealed the anti-inflammatory effects of rebamipide and suggested the potential of the drug repositioning in metabolism- and lipid-associated diseases.

• Journal of Ginseng Research
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• v.45 no.4
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• pp.490-497
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• 2021

Background and objective: Synthetic ginsenoside compounds G-Rp (1,3, and 4) and natural ginsenosides in Panax ginseng 20(S)-Rg3, Rg6, F4 and Ro have inhibitory actions on human platelets. However, the inhibitory mechanism of ginsenoside Rk1 (G-Rk1) is still unclear thus, we initiated investigation of the anti-platelet mechanism by G-Rk1 from Panax ginseng. Methodology: Our study focused to investigate the action of G-Rk1 on agonist-stimulated human platelet aggregation, inhibition of platelet signaling molecules such as fibrinogen binding with integrin α_IIbβ₃ using flow cytometry, intracellular calcium mobilization, fibronectin adhesion, dense granule secretion, and thromboxane B2 secretion. Thrombin-induced clot retraction was also observed in human platelets. Key Results: Collagen, thrombin, and U46619-stimulated human platelet aggregation were dose-dependently inhibited by G-Rk1, while it demonstrated a more effective suppression on collagen-stimulated platelet aggregation using human platelets. Moreover, G-Rk1 suppressed collagen-induced elevation of Ca²⁺ release from endoplasmic reticulum, granule release, and α_IIbβ₃ activity without any cytotoxicity. Conclusions and implications: These results indicate that G-Rk1 possess strong anti-platelet effect, proposing a new drug candidate for treatment and prevention of platelet-mediated thrombosis in cardiovascular disease.

• Journal of Industrial Convergence
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• v.20 no.7
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• pp.131-137
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• 2022

In the study, we endeavored to assess the convergence effect of Silybum marianum-derived silymarin and epidemiologically-correlated alcohol intake on vascular contractility and to determine the mechanism involved. There were few reports addressing the question whether thin or thick filament modulation is included in ethanol and silymarin-induced regulation. We hypothesized that ethanol at a low concentration and silymarin play a role in agonist-dependent regulation of vascular contractility. Denuded arterial muscles of Sprague-Dawley male rats were suspended in organ baths and isometric tensions were transduced and recorded using isometric transducers and an automatic data acquisition system. Interestingly, both silymarin and ethanol didn't encourage silymarin alone-induced inhibition in agonists-induced contraction suggesting that endothelial nitric oxide synthesis might be involved in ethanol or silymarin-induced modulation of vascular contractility and additional pathways besides endothelial nitric oxide synthesis such as ROCK inactivation might be involved in the silymarin-induced modulation of vascular contractility.

• Biomolecules & Therapeutics
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• v.5 no.3
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• pp.239-245
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• 1997

Trimetoquinol (TMQ) and its analogs are known to have thromboxane $A_2$ antagonistic action. We also reported that GS389, chemically similar to TMQ, has competitive antagonistic action in rat aorta and human platelets. In the present study, we investigated the pharmacological characteristics of GS283 and GS 386, analogs of GS389, using vascular smooth muscle, human platelets and rat brain homogenates. In isolated pig coronary artery (PCA), both of GS283 and GS386 relaxed U46619-contracted rings in concentration dependent manner. Pretreatment with several concentrations of GS283 and GS386 shifted the dose-response curves to the right, and reduced of maximum contration dose-dependently. Furthermore, GS283 and GS386 strongly inhibited $Ca^{2+}$ -induced contraction in the PCA. In human platelets, U46619- and A23187-induced platelet aggregation was inhibited by GS283 and GS386, concentration-dependently. Anti-platelet aggregation was related to the compound\`s ability to inhibit ATP release at each stimulation. In rat brain homogenates, receptor-binding assay resulted that both GS283 and GS386 have a relative affinity to $\alpha$-adrenergic receptor. Taken together. we concluded that the mechamism of action of GS283 and GS86 is not related with in TXA$_2$ receptor but concerned with calcium antagonistic action and a-blocking action.n.