• Biomolecules & Therapeutics
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• 제25권6호
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• pp.599-608
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• 2017

Tanshinone IIA (Tan IIA) is a pharmacologically active substance extracted from the rhizome of Salvia miltiorrhiza Bunge (also known as the Chinese herb Danshen), and is widely used to treat atherosclerosis. The pregnane X receptor (PXR) is a nuclear receptor that is a key regulator of xenobiotic and endobiotic detoxification. Tan IIA is an efficacious PXR agonist that has a potential protective effect on endothelial injuries induced by xenobiotics and endobiotics via PXR activation. Previously numerous studies have demonstrated the possible effects of Tan IIA on human umbilical vein endothelial cells, but the further mechanism for its exerts the protective effect is not well established. To study the protective effects of Tan IIA against hydrogen peroxide ($H_2O_2$) in human umbilical vein endothelial cells (HUVECs), we pretreated cells with or without different concentrations of Tan IIA for 24 h, then exposed the cells to $400{\mu}M$ $H_2O_2$ for another 3 h. Therefore, our data strongly suggests that Tan IIA may lead to increased regeneration of glutathione (GSH) from the glutathione disulfide (GSSG) produced during the GSH peroxidase-catalyzed decomposition of $H_2O_2$ in HUVECs, and the PXR plays a significant role in this process. Tan IIA may also exert protective effects against $H_2O_2$-induced apoptosis through the mitochondrial apoptosis pathway associated with the participation of PXR. Tan IIA protected HUVECs from inflammatory mediators triggered by $H_2O_2$ via PXR activation. In conclusion, Tan IIA protected HUVECs against $H_2O_2$-induced cell injury through PXR-dependent mechanisms.

• Environmental Analysis Health and Toxicology
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• 제21권3호
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• pp.275-282
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• 2006

In order to get insight into the mechanism of cadmium (Cd)-induced brain injury, we investigated the effects of Cd on the induction of COX-2 in bEnd.3 mouse brain endothelial cells. Cd induced COX-2 expression and $PGE_2$ release, which were attenuated by thiol-reducing antioxidant N-acetylcysteine (NAC) indicating oxidative components might contribute to these events. Indeed, Cd increased cellular reactive oxygen species (ROS) level and DNA binding activity of nuclear factor-kB (NF-kB), an oxidative stress sensitive transcription factor. Cd-induced $PGE_2$ production and COX-2 expression were significantly attenuated by Bay 11 7082, a specific inhibitor of NF-kB and by SB203580, a specific inhibitor of p38 mitogen activated protein kinase (MAPK). These data suggest that Cd induces COX-2 expression through activation of NF-kB and p38 MAPK, the oxidative stress-sensitive signaling molecules, in brain endothelial cells.

• The Journal of Korean Physical Therapy
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• 제15권3호
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• pp.16-44
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• 2003

Skeletal muscle regeneration is a vital process for various muscle myopathies and muscular adaptation to physiological overload. Angiogenesis is the key event in the process of muscle regeneration, and vascular endothelial growth factor(VEGF) plays an important role in it. The purpose of this study was to evaluate the effect of GaAlAs(830nm) laser and immunoreactivity of VEGF on angiogenesis after muscle contusion injury. Muscle contusion injury was induced in the triceps surae muscle by dropping a metal bead(31.4g). GaAlAs laser irradiation(power 20 mW, frequency 2000 Hz, treatment time 15 min) was applied directly to the skin of injured muscle daily for seven days. The experimental group I was irradiated immediately by laser after injury, whereas the experimental group II was irradiated after 1 day of injury. The control group was non-irradiated. The results of this study were as follows. 1. In morphological observation, there were no significant changes in experimental and control groups for 7 days. At 3 days, however, the splited muscle fibers were observed in experimental groups, and the muscle atrophy and granular tissue viewed at 7 days in control group. 2. The VEGF was expressed in muscle fiber that located in the interspace between gastrocnemius and soleus muscles. As the time coursed, the immunoreactivity of VEGF also seemed to be strong in the individual muscle fibers. 3. The experimental group I & II showed higher immunoreactivity of VEGF than control group(p<0.05). Then, the experimental group I showed higher than group II especially(p<0.05). These data suggest GaAlAs semiconduct diode laser irradiation(830nm) enhanced angiogenesis in the skeletal muscle induced contusion injury, and immediate laser irradiation after injury promoted the angiogenesis greatly than after 1 day of injury.

• Biomolecules & Therapeutics
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• 제28권1호
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• pp.45-57
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• 2020

In the neurovascular unit, the neuronal and vascular systems communicate with each other. O₂ and nutrients, reaching endothelial cells (ECs) through the blood stream, spread into neighboring cells, such as neural stem cells, and neurons. The proper function of neural circuits in adults requires sufficient O₂ and glucose for their metabolic demands through angiogenesis. In a central nervous system (CNS) injury, such as glioma, Parkinson's disease, and Alzheimer's disease, damaged ECs can contribute to tissue hypoxia and to the consequent disruption of neuronal functions and accelerated neurodegeneration. This review discusses the current evidence regarding the contribution of oxygen deprivation to CNS injury, with an emphasis on hypoxia-inducible factor (HIF)-mediated pathways and Notch signaling. Additionally, it focuses on adult neurological functions and angiogenesis, as well as pathological conditions in the CNS. Furthermore, the functional interplay between HIFs and Notch is demonstrated in pathophysiological conditions.

• 고려인삼학회:학술대회논문집
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• 고려인삼학회 1993년도 학술대회지
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• pp.36-39
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• 1993

We reported earlier (Br. J. Pharmac. 82. 485 - 491. 1984) that ginsenosides from Panax ginseng CA. Meyer antagonized noradrenaline or prostaglandin $F_{2\alpha}-induced$ contractions of pulmonary and intrapulmonary arterial rings of rabbits. Because this effect resembled that of acetylcholine (ACh). we questioned whether these acitons were due to release of nitric oxide from vaseular endothelium. We therefore determined whether ginsenosides could vasodilate preconstricted lungs and also protect against free radical injury. which normally eliminates the vasodilator response to ACh(J. Appl. Physiol. 71. 821 - 825. 1991 J. We found that ginsenoside $Rg_1$ or a mixture of saponins could ,a) vasodilate perfused. $U_{46619}-preconstricted$ lungs. b) promote increased synthesis of nitric oxide by endothelial cells in culture and c) prevent the pulmonary edema often associated with free radical injury (Biochem. Biophys. Res. Comm. 189. 670 - 676. 1992). Thus, vasodilator and protective effects of ginsenosides against free radical injury may reflect enhanced synthesis and release of nitric oxide. These data suggest that ginsenosides may be useful in treatment of pulmonary and systemic hypertension. Aided by grants from the National Institutes of Health. Bethesda.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1995년도 춘계학술대회
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• pp.92-92
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• 1995

It has been suggested that oxygen-derived free radicals have an important role in the pathophysiology of acute gastric ulceration induced by NSAIDs and ischemia-reperfusion. Taurine is hypothetized to exert its protective effect on NSAIDS-induced gastric injury by its antioxidant properties, Protect ive effect of taurine on indomethacin-induced gastric mucosal lesion and its protective mechanism were investigated. Intragastric administration of 25 mg/kg of indomethacin induced hemorrhagic lesions on the glandular stomach in rats, Pretreatment with 0.25 g/kg of taurine for 3 days significantly reduced the gastric lesion formation and Inhibited the elevation of lipid peroxide level In gastric mucosa. Both resting and FMLP-induced luminol-dependent chemiluminescence of rat peritoneal neutrophils increased immediately after treatment of indomethacin. 5-20mM of taurine inhibited chemiluminescence of neutrophils activated by indomethacin and/or FMLP. Human neutrophils (polymorphonuclear leukocytes) significantly adhered to confluent monolayer of human umbilical vein endothelial cells(HUVEC) after coincubation with aspirin or indomethacin. Also taurine prevented neutrophil adhesion induced by these drugs to HUVEC in dose-dependent manner. These results indicate that the protective effect of taurine against NSAIDS-induced gastric mucosal Injury is due to its antioxidant effect, which inhibits lipid peroxidation and neutrophil activation.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2004년도 Annual Meeting of KSAP : New Drug Development from Natural Products
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• pp.3-10
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• 2004

Oxidative stress is a constant threat to all living organisms and an immense repertoire of cellular defense systems is being employed by most pro- and eukaryotic systems to eliminate or to attenuate oxidative stress. Ischemia and reperfusion is characterized by both a significant oxidative stress and characteristic changes in the antioxidant defense. Heme oxigenase-l (HO-l) is up-regulated by various stimuli including oxidative stress so that it is thought to participate in general cellular defense mechanisms against ischemic injury in mammalian cells. Higenamine, an active ingredient of Aconite tuber, has been shown to have antioxidant activity along with inhibitory action of inducible nitric oxide synthase (iNOS) expression in various cells. In the present study, we investigated whether higenamine and related analogs protect cells from oxidative cellular injuries by modulating antioxidant enzymes, such as HO-l, MnSOD etc. R-form of YS-51 was the most potent inducer of HO-l in bovine endothelial cells, which inhibited apoptotic cell death by H$_2$O$_2$. HO-1 induction by YS 51 was mediated by PI3 kinase activation in which PKA- as well as PKG pathway is considered as important regulators. YS-51 also induced Mn-SOD mRNA expression by activating c-jun N-terminal kinase in endothelial cells and Hela cells. In ROS 17/2.1 cells, higenamine and enetiomers of related compounds inhibited iNOS expression by cytokine mixtures. Taken together, higenamine and related compounds can be developed as possible protective agents from oxidative cell injury or death.

• Molecules and Cells
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• 제41권2호
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• pp.93-102
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• 2018

Discoidin domain receptor 1 (DDR1) is involved in tumorigenesis and angiogenesis. However, its role in lymphangiogenesis has been unknown. Here, we tested whether downregulation of DDR1 expression by miR-199a/b can suppress lymphangiogenesis. We also aimed to identify miRNA target site(s) in the 3' untranslated region (UTR) of DDR1. Transfection with miR-199a/b-5p mimics reduced expression of DDR1 and tube formation in primary human dermal lymphatic endothelial cells, whereas miR-199a/b-5p inhibitors showed the opposite effects. Critically, injection of miR-199a/b-5p mimics suppressed DDR1 expression and lymphangiogenesis in a corneal alkali-burn rat model. The three well-conserved seed matched sites for miR-199a/b-5p in the DDR1 3'-UTR were targeted, and miRNA binding to at least two sites was required for DDR1 inhibition. Our data suggest that DDR1 promotes enhanced lymphangiogenesis during eye injury, and miR-199a/b-5p suppresses this activity by inhibiting DDR1 expression. Thus, this miRNA may be useful for the treatment of lymphangiogenesis-related eye diseases.

• The Korean Journal of Physiology and Pharmacology
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• 제10권2호
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• pp.85-94
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• 2006

A splanchic artery occlusion for 90 min followed by reperfusion of the mesenteric circulation resulted in a severe form of circulatory shock, characterized by endothelial dysfunction, severe hypotension, marked intestinal tissue injury, and a high mortality rate. The effect of defibrotide, a complex of single-stranded polydeoxyribonucleotides having antithrombotic effect, was investigated in a model of splanchnic artery occlusion (SAO) shock in urethane anesthetized rats. Occlusion of the superior mesenteric artery for 90 min produced a severe shock state, resulting in a fatal outcome within 120 min of reperfusion in many rats. Defibrotide (10 mg/kg body weight) 10 min prior to reperfusion significantly improved mean arterial blood pressure in comparison to vehicle treated rats (p＜0.05). Defibrotide treatment also significantly attenuated in the increase of plasma amino nitrogen concentration, intestinal myeloperoxidase activity, intestinal lipid peroxidation, infiltration of neutrophils in intestine and thrombin induced adherence of neutrophils to superior mesentric artery segments. Superoxide anion and hydrogen peroxide production in $1{\mu}M$ formylmethionylleucylphenylalanine (fMLP)-activated PMNs was inhibited by defibrotide in a dose-dependent fashion. Defibrotide effectively scavenged hydrogen peroxide, but not hydroxyl radical. Treatment of SAO rats with defibrotide inhibited tumor necrosis factor-${\alpha}$, and interleukin-1${\beta}$ productions in blood in comparison with untreated rats. These results suggest that defibrotide partly provides beneficial effects by preserving endothelial function, attenuating neutrophil accumulation, and antioxidant in the ischemic reperfused splanchnic circulation

• Journal of Korean Neurosurgical Society
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• 제38권3호
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• pp.221-226
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• 2005

Objective : Reactive oxygen metabolites and polymorphonuclear leukocytes have been implicated in the pathophysiology of reperfusion injury. The mechanisms involved in superoxide-mediated leukocyte adherence remain unclear, however, nitric oxide[NO] may contribute to this response. The present study is undertaken to elucidate mechamisms controlling NO based mechanisms that regulated leukocyte-endothelial interactions in the cerebral vasculature after global cerebral ischemia and reperfusion. Methods : Pial venular leukocyte adherence of anesthetized newborn piglets was quantified by in situ fluorescence videomicroscopy through closed cranial windows during basal conditions and during 2hours of reperfusion after global ischemia induced by 9minutes of asphyxia. Nitric oxide synthase[NOS] was inhibited by local window superfusion of L-nitroarginine[NA]; superfusion of sodium nitroprusside[SNP] was used to donate NO. Results : The mean number of adherent leukocytes to cerebral venules in the 9minutes asphyxia and 2hours reperfusion group were $161{\pm}19$ compared with $13{\pm}4$ in the nonasphyxial group. Superfusion of L-NA through the cranial window for 2hours resulted in leukocyte adherence similar to that observed during the initial 2hours of reperfusion after asphyxia. Leukocyte adherence was not additionally increased in asphyxic animal treated with L-NA. SNP inhibited asphyxia induced leukocyte adherence back to control levels. Conclusions : Nitric oxide inhibits leukocyte adherence to cerebral venules during the initial hours of reperfusion after asphyxia, and that NO supplementation inhibit asphyxia induced leukocyte adherence back to control levels. These results indicate that NO is an important factor in ischemia-reperfusion induced leukocyte adherence.