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Activation of Lysophosphatidic Acid Receptor Is Coupled to Enhancement of $Ca^{2+}$ -Activated Potassium Channel Currents

  • Choi, Sun-Hye;Lee, Byung-Hwan;Kim, Hyeon-Joong;Hwang, Sung-Hee;Lee, Sang-Mok;Nah, Seung-Yeol
    • The Korean Journal of Physiology and Pharmacology
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    • v.17 no.3
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    • pp.223-228
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    • 2013
  • The calcium-activated $K^+$ ($BK_{Ca}$) channel is one of the potassium-selective ion channels that are present in the nervous and vascular systems. $Ca^{2+}$ is the main regulator of $BK_{Ca}$ channel activation. The $BK_{Ca}$ channel contains two high affinity $Ca^{2+}$ binding sites, namely, regulators of $K^+$ conductance, RCK1 and the $Ca^{2+}$ bowl. Lysophosphatidic acid (LPA, 1-radyl-2-hydroxy-sn-glycero-3-phosphate) is one of the neurolipids. LPA affects diverse cellular functions on many cell types through G protein-coupled LPA receptor subtypes. The activation of LPA receptors induces transient elevation of intracellular $Ca^{2+}$ levels through diverse G proteins such as $G{\alpha}_{q/11}$, $G{\alpha}_i$, $G{\alpha}_{12/13}$, and $G{\alpha}s$ and the related signal transduction pathway. In the present study, we examined LPA effects on $BK_{Ca}$ channel activity expressed in Xenopus oocytes, which are known to endogenously express the LPA receptor. Treatment with LPA induced a large outward current in a reversible and concentration-dependent manner. However, repeated treatment with LPA induced a rapid desensitization, and the LPA receptor antagonist Ki16425 blocked LPA action. LPA-mediated $BK_{Ca}$ channel activation was also attenuated by the PLC inhibitor U-73122, $IP_3$ inhibitor 2-APB, $Ca^{2+}$ chelator BAPTA, or PKC inhibitor calphostin. In addition, mutations in RCK1 and RCK2 also attenuated LPA-mediated $BK_{Ca}$ channel activation. The present study indicates that LPA-mediated activation of the $BK_{Ca}$ channel is achieved through the PLC, $IP_3$, $Ca^{2+}$, and PKC pathway and that LPA-mediated activation of the $BK_{Ca}$ channel could be one of the biological effects of LPA in the nervous and vascular systems.

Inhibition of Hydrogen Sulfide-induced Angiogenesis and Inflammation in Vascular Endothelial Cells: Potential Mechanisms of Gastric Cancer Prevention by Korean Red Ginseng

  • Choi, Ki-Seok;Song, Heup;Kim, Eun-Hee;Choi, Jae-Hyung;Hong, Hua;Han, Young-Min;Hahm, Ki-Baik
    • Journal of Ginseng Research
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    • v.36 no.2
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    • pp.135-145
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    • 2012
  • Previously, we reported that Helicobacter pylori-associated gastritis and gastric cancer are closely associated with increased levels of hydrogen sulfide ($H_2S$) and that Korean red ginseng significantly reduced the severity of H. pylori-associated gastric diseases by attenuating $H_2S$ generation. Because the incubation of endothelial cells with $H_2S$ has been known to enhance their angiogenic activities, we hypothesized that the amelioration of $H_2S$-induced gastric inflammation or angiogenesis in human umbilical vascular endothelial cells (HUVECs) might explain the preventive effect of Korean red ginseng on H. pylori-associated carcinogenesis. The expression of inflammatory mediators, angiogenic growth factors, and angiogenic activities in the absence or presence of Korean red ginseng extracts (KRGE) were evaluated in HUVECs stimulated with the $H_2S$ generator sodium hydrogen sulfide (NaHS). KRGE efficiently decreased the expression of cystathionine ${\beta}$-synthase and cystathionine ${\gamma}$-lyase, enzymes that are essential for $H_2S$ synthesis. Concomitantly, a significant decrease in the expression of inflammatory mediators, including cyclooxygenase-2 and inducible nitric oxide synthase, and several angiogenic factors, including interleukin (IL)-8, hypoxia inducible factor-1a, vascular endothelial growth factor, IL-6, and matrix metalloproteinases, was observed; all of these factors are normally induced after NaHS. An in vitro angiogenesis assay demonstrated that NaHS significantly increased tube formation in endothelial cells, whereas KRGE pretreatment significantly attenuated tube formation. NaHS activated p38 and Akt, increasing the expression of angiogenic factors and the proliferation of HUVECs, whereas KRGE effectively abrogated this $H_2S$-activated angiogenesis and the increase in inflammatory mediators in vascular endothelial cells. In conclusion, KRGE was able to mitigate $H_2S$-induced angiogenesis, implying that antagonistic action against $H_2S$-induced angiogenesis may be the mechanism underlying the gastric cancer preventive effects of KRGE in H. pylori infection.

Pharmacological Characterization of (10bS)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline Oxalate (YSL-3S) as a New ${\alpha}_2$-Adrenoceptor Antagonist

  • Chung, Sung-Hyun;Yook, Ju-Won;Min, Byung-Jun;Lee, Jae-Yeol;Lee, Yong-Sup;Jin, Chang-Bae
    • Archives of Pharmacal Research
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    • v.23 no.4
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    • pp.353-359
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    • 2000
  • ${\alpha}_2$-Adrenoceptor antagonists, which can enhance synaptic norepinephrine levels by blocking feedback inhibition processes, are potentially useful in the treatment of disease states such. as depression, memory impairment, impotence and sexual dysfunction. (10bS)-1,2,3,5,6,10b-Hexahydropyrrolo[2,1-a]isoquinoline oxalate (YSL-3S) was evaluated in several in vitro biological tests to establish its pharmacological profile of activities as an ${\alpha}_2$-adrenoceptor antagonist. Saturation binding assay revealed that$^{3}[H]$rauwolscine bound to the $\alpha$$_2$-adrenoceptors with a Kd value of 6.3$\pm$0.5 nM and a Bmax value of 25l$\pm$39 fmol/mg protein in rat cortical synaptic membranes. Competitive binding assay showed that YSL-3S inhibited the binding of$^3[H]$rauwolscine (1 nM) in a concentration-dependent manner with a Ki value of 98.2$\pm$12.1 nM while it did not inhibit the binding of [$^3$H]cytisine (1.25 nM) to neuronal nicotinic cholinergic receptors. The Ki values of yohimbine, clonidine and norepinephrine for $^3[H]$rauwolscine binding were 15.8$\pm$1.0, 40.1$\pm$5.9 and 40.0$\pm$11.5 nM, respectively. In addition, the binding affinity of YSL-3S for ${\alpha}_2$-adrenoceptors was higher than that of its antipode and the racemic mixture. The functional activity of YSL-3S at the presynaptic ${\alpha}_2$-adrenoceptors was assessed using the prostatic portion of the rat vas deferens. Clonidine inhibited field-stimulated contractions of the vas deference in a dose-dependent manner. The presence of YSL-3S or yohimbine caused a parallel, rightward the dose-response curve of clonidine in a dose-dependent manner, indicating an antagonistic action at the presynaptic ${\alpha}_2$-adrenoceptors. The $pA_2$values of yohimbine and YSL-3S were 7.66$\pm$0.13 and 6.64$\pm$0.18, respectively. The results indicate that YSL-3S acts as a competitive antagonist at presynaptic ${\alpha}_2$ -adrenoceptors with a potency approximately ten times lower than yohimbine, but is devoid of binding affinity for neuronal nicotinic cholinergic receptors.

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Diagnosing Railway Incident Response Manuals and Their Improvement (철도사고 대응매뉴얼 과부하에 대한 진단과 개선방안 연구)

  • Lim, Kwang-kyun;Yun, Gyeong-cheol
    • Journal of the Korean Society for Railway
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    • v.19 no.5
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    • pp.698-707
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    • 2016
  • An emergency manual is designed to minimize the extent and effect of lives and assets; it is not designed to prevent an accident. There have been continuous arguments in terms of manual effectiveness regardless of the fact that much effort and great cost have been invested in emergency planning and operations. The problems are that there are a number of different emergency manuals, that these manuals are hard to understand and rarely used due to their complexity, that they provide little direction toward the taking of action, and that coordination is difficult between those involved; all of these problems are related to two different pieces of legislations that define emergency manuals in different ways in terms of the contents required. The study has tried to respond to these arguments by exploring relevant legislation to identify emergency manuals that can be used to respond to rail incidents/accidents, for which previous responses have seemed inefficient. Further, some parts of the emergency manual contents are found to overlap, including the ways of differentiating incident responses, personnel roles and responsibilities by types of accident, and threat levels, all of which has resulted in unnecessary pages of the manuals. In preparing and operating such manuals, this study recommends that one piece of legislation that directly affects rail undertakings must be applied in an effort to increase effectiveness.

Evaluation for Deformability of RC Members Failing in Bond after Flexural Yielding (휨항복 후 부착파괴하는 철근콘크리트 부재의 부착 연성 평가)

  • Choi, Han-Byeol;Lee, Jung-Yoon
    • Journal of the Korea Concrete Institute
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    • v.24 no.3
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    • pp.259-266
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    • 2012
  • A general earthquake resistant design philosophy of ductile frame buildings allows beams to form plastic hinges adjacent to beam-column connections. In order to carry out this design philosophy, the ultimate bond or shear strength of the beam should be greater than the flexural yielding force and should not degrade before reaching its required ductility. The behavior of RC members dominated by bond or shear action reveals a dramatic reduction of energy dissipation in the hysteretic response due to the severe pinching effects. In this study, a method was proposed to predict the deformability of reinforced concrete members with short-span-to-depth-ratios, which would result in bond failure after flexural yielding. Repeated or cyclic loading produces a progressive deterioration of bond that may lead to failure at lower cyclic bond stress levels. Accumulation of bond damage is caused by the propagation of micro-cracks and progressive crushing of concrete in front of the lugs. The proposed method takes into account bond deterioration due to the degradation of concrete in the post yield range. In order to verify bond deformability of the proposed method, the predicted results were compared with the experimental results of RC members reported in the technical literature. Comparisons between the observed and calculated bond deformability of the tested RC members showed reasonably good agreement.

Analysis of Environmental Correlates with Walking among Older Urban Adults (도시 노인들의 걷기활동 참여에 영향을 주는 물리적 환경요인 분석)

  • Lee, Hyung-Sook;Ahn, Joon-Suk;Chun, Seung-Hoon
    • Journal of the Korean Institute of Landscape Architecture
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    • v.39 no.2
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    • pp.65-72
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    • 2011
  • Since walking and physical activity are critical for older adults to maintain their health, it is important to provide neighborhood environments which encourage their walking in daily life. The purposes of the present study were to investigate walking activity patterns of older people in an urban setting and to identify environmental correlates with walking of older adults. This study examined spatial and temporal patterns of physical activities, environmental barriers and motivations, satisfaction levels and demands on the physical environment. In-depth interviews with older adults over age sixty residing in Seoul metropolitan areas revealed that most respondents have a positive perception on walking in daily life, and many of them walk regularly for their health. A primary purpose of walking for older adults was exercise for health rather than transportation. The study result demonstrated that parks and trails were the most preferred places for walking by older adults, and there is an association between frequency of walking participation and access or convenience to parks, traffic safety, and street lights. Most respondents were concerned about traffic safety when they walk in their neighborhoods due to traffic speeds and unsafe streets. Lack of separate sidewalks or benches, stairs and slopes were barriers to older adults' walking habits. This data suggests that the promotion of walking behavior among older adults, some level of public health action, and community support are needed to ensure safe physical environments within communities.

Inhibitory Action of YJA20379, a New Proton Pump Inhibitor on Helicobacter Pylori Growth and Urease

  • Woo, Tae-Wook;Chang, Man-Sik;Chung, Young-Kuk;Kim, Kyu-Bong;Sohn, Sang-Kwon;Kim, Sung-Gyu;Choi, Wahn-Soo
    • Archives of Pharmacal Research
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    • v.21 no.1
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    • pp.6-11
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    • 1998
  • The activities of two types of antiulcer agents against 9 strains of Helicobacter pylori (H. pylori) were determined by the agar dilution method. The antiulcer agents were YJA20379, a newly synthesized proton pump inhibitor developed by Yung-jin Pharmaceutical company, and omeprazole. Both compounds were found to have significant activities against this organism. The MIC values of YJA20379 and omeprazole were 11.7 and $31.25{\mu.g/ml}$ respectively. In addition, the inhibitory potency of both compounds was investigated on H. pylori urease which is believed to be an important colonization and virulence factor in the pathogenesis of gastritis and peptic ulcers. These compounds dose-dependently inhibited urease extracted with distilled water and their $IC_50$ values were $16.4{\times}10^{-5} M and 14.3{\times}10^{-5}M,$ respectively. In addition, a pH-dependent study to determine whether inhibitory potency would be activated by acid condition was performed. It was found that unlike omeprazole, YJA20379 was not affected by acid condition. To determine the inhibition pattern and optimal concentration of substrate, kinetics were evaluated at various pH levels (pH 5.0, 7.0, and 8.5). The data show that YJA20379 noncompetitively inhibited H. pylori urease and $K_M/K_i$values were 0.96 $mM/60{\mu}M (pH 5.0), 0.56 mM/141.5 {\mu}M (pH 7.0)$, and $1.94mM/34{\mu}M (pH 8.5)$, respectively. Based on data obtained, it is concluded that YJA20379 is a significant inhibitor of H. pylori growth and urease and therefore, taking these results into consideration, YJA20379 might be a beneficial therapy for gastritis and peptic ulcers induced by H. pylori.

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Flexible Intelligent Exit Sign Management of Cloud-Connected Buildings

  • Lee, Minwoo;Mariappan, Vinayagam;Lee, Junghoon;Cho, Juphil;Cha, Jaesang
    • International Journal of Advanced Culture Technology
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    • v.5 no.1
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    • pp.58-63
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    • 2017
  • Emergencies and disasters can happen any time without any warning, and things can change and escalate very quickly, and often it is swift and decisive actions that make all the difference. It is a responsibility of the building facility management to ensure that a proven evacuation plan in place to cover various worst scenario to handled automatically inside the facility. To mapping out optimal safe escape routes is a straightforward undertaking, but does not necessarily guarantee residents the highest level of protection. The emergency evacuation navigation approach is a state-of-the-art that designed to evacuate human livings during an emergencies based on real-time decisions using live sensory data with pre-defined optimum path finding algorithm. The poor decision on causalities and guidance may apparently end the evacuation process and cannot then be remedied. This paper propose a cloud connected emergency evacuation system model to react dynamically to changes in the environment in emergency for safest emergency evacuation using IoT based emergency exit sign system. In the previous researches shows that the performance of optimal routing algorithms for evacuation purposes are more sensitive to the initial distribution of evacuees, the occupancy levels, and the type and level of emergency situations. The heuristic-based evacuees routing algorithms have a problem with the choice of certain parameters which causes evacuation process in real-time. Therefore, this paper proposes an evacuee routing algorithm that optimizes evacuation by making using high computational power of cloud servers. The proposed algorithm is evaluated via a cloud-based simulator with different "simulated casualties" are then re-routed using a Dijkstra's algorithm to obtain new safe emergency evacuation paths against guiding evacuees with a predetermined routing algorithm for them to emergency exits. The performance of proposed approach can be iterated as long as corrective action is still possible and give safe evacuation paths and dynamically configure the emergency exit signs to react for real-time instantaneous safe evacuation guidance.

Effect of loading velocity on the seismic behavior of RC joints

  • Wang, Licheng;Fan, Guoxi;Song, Yupu
    • Earthquakes and Structures
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    • v.8 no.3
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    • pp.665-679
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    • 2015
  • The strain rate of reinforced concrete (RC) structures stimulated by earthquake action has been generally recognized as in the range from $10^{-4}/s$ to $10^{-1}/s$. Because both concrete and steel reinforcement are rate-sensitive materials, the RC beam-column joints are bound to behave differently under different strain rates. This paper describes an investigation of seismic behavior of RC beam-column joints which are subjected to large cyclic displacements on the beam ends with three loading velocities, i.e., 0.4 mm/s, 4 mm/s and 40 mm/s respectively. The levels of strain rate on the joint core region are correspondingly estimated to be $10^{-5}/s$, $10^{-4}/s$, and $10^{-2}/s$. It is aimed to better understand the effect of strain rates on seismic behavior of beam-column joints, such as the carrying capacity and failure modes as well as the energy dissipation. From the experiments, it is observed that with the increase of loading velocity or strain rate, damage in the joint core region decreases but damage in the plastic hinge regions of adjacent beams increases. The energy absorbed in the hysteresis loops under higher loading velocity is larger than that under quasi-static loading. It is also found that the yielding load of the joint is almost independent of the loading velocity, and there is a marginal increase of the ultimate carrying capacity when the loading velocity is increased for the ranges studied in this work. However, under higher loading velocity the residual carrying capacity after peak load drops more rapidly. Additionally, the axial compression ratio has little effect on the shear carrying capacity of the beam-column joints, but with the increase of loading velocity, the crack width of concrete in the joint zone becomes narrower. The shear carrying capacity of the joint at higher loading velocity is higher than that calculated with the quasi-static method proposed by the design code. When the dynamic strengths of materials, i.e., concrete and reinforcement, are directly substituted into the design model of current code, it tends to be insufficiently safe.

Biochemical Studies of Ginseng Saponin on RNA and Protein Biosynthesis in the Rat Liver (간에서의 RNA, 단백질 생합성에 미치는 인삼성분의 생화학적 연구)

  • Oura Hikokichi
    • Proceedings of the Ginseng society Conference
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    • 1988.08a
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    • pp.1-10
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    • 1988
  • Previously. we reported that the intraperitoneal administration of ginseng crude saponin increased: (I) nuclear RNA polymerase activity. (2) nuclear RNA synthesis. (3) cytoplasmic RNA synthesis. (4) cytoplasmic heavy polyrioosome content. (5) amino acid incorporation in vitro of microsome and polysome isolated rat liver. and (6) the incorporation rate of labeled amino acids into serum protein. In addition, a spectacular increase in the rough endoplasmic reticulum of hepatocyte administered crude saponin for four weeks orally was shown through electron microscopy. An increase in polysomal content in membrane-hound ribosome was shown through ultracentrifugation. Recently, successive intraperitoneal. administration .of $ginsenosid-Rb_2$ was given to streptozotocin (STZ) diaoetic rats of hypoproteinemia. The blood urea nitrogen and hepatic urea concentration were decreased significantly. The total protein and alhumin levels in the serum were increased in comparison to control values. In contrast. the $ginsenoside-Rb_2$ treated group of STZ diahetic rats showed a significant increase in liver RNA. total ribosome and membrane-bound ribosomal contents. The administration of $ginsenoside-Rb_2$ increased the incorporation rate of labeled - precursor into total serum protein. Additionally $ginsenoside-Rb_2$ improved the nitrogen balance of diabetic rats. On the bases of these experimental results, ginseng saponin has a metabolic stimulatory or anabolic action on RNA and protein synthesis.

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