• 통합자연과학논문집
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• 제6권3호
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• pp.125-137
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• 2013

Promising evidence suggests that amyloid beta peptide ($A{\beta}$), a key mediator in age-dependent neuronal and cerebrovascular degeneration, activates death signalling processes leading to neuronal as well as non-neuronal cell death in the central nervous system. A major cellular event in $A{\beta}$-induced apoptosis of non-neuronal cells, including cerebral endothelial cells, astrocytes and oligodendrocytes, is mitochondrial dysfunction. The apoptosis signalling cascade upstream of mitochondria entails $A{\beta}$ activation of neutral sphingomyelinase, resulting in the release of ceramide from membrane sphingomyelin. Ceramide then activates protein phosphatase 2A (PP2A), a member in the ceramide-activated protein phosphatase (CAPP) family. PP2A dephosphorylation of Akt and FKHRL1 plays a pivotal role in $A{\beta}$-induced Bad translocation to mitochondria and transactivation of Bim. Bad and Bim are pro-apoptotic proteins that cause mitochondrial dysfunction characterized by excessive ROS formation, mitochondrial DNA (mtDNA) damage, and release of mitochondrial apoptotic proteins including cytochrome c, apoptosis inducing factor (AIF), endonuclease G and Smac. The cellular events activated by $A{\beta}$ to induce death of non-neuronal cells are complex. Understanding these apoptosis signalling processes will aid in the development of more effective strategies to slow down age-dependent cerebrovascular degeneration caused by progressive cerebrovascular $A{\beta}$ deposition.

• 한국어병학회지
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• 제16권1호
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• pp.39-49
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• 2003

Cytosolic oxidation by 4-hydroxy-2-nonenal (4HNE) and tert-butyl hydroperoxide (t-BHP) results in cell death of bovine aortic endothelial cells (BAEC). In this study, we have investigated the roles of antioxidants such as 2,3,6-tribromo-4,5-dihydroxy benzyl methyl ether (TDB) and phloroglucinol in preventing cell death. After treatment with oxidants for 6h, cells became compact and showed nuclear condensation, which were characteristics of early apoptosis. After l2h treatment, morphologic features including severe cytoplasm condensation, membrane blebbing, and apoptotic bodies were prominent and these findings were interpreted as characteristics of late-apoptosis. When the apoptotic cells were treated with antioxidants for 12h, both early and late apoptotic cells did show no significant change. After oxidant treated cells were incubated with antioxidant for 24h, the characteristics of early-apoptosis were eliminated but cells in lateapoptosis could not return to normal cells. These results suggest that TDB and phloroglucinol prevent the cells from dying through apoptosis induced by 4HNE and t-BHP in early stage.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.1
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• pp.229.2-230
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• 2003

Among the aldehydes derived from lipid peroxidation, 4-hydroxynonenal (HNE) that can be produced from arachidonic acids. linoleic acids, or their hydroperoxides in relatively large amounts in response to oxidative insult. Therefore, HNE might be an important mediator of Oxidative stress-induced apoptosis. To study the hypothesis that HNE may induce apoptosis, we estimated cytotoxicity of HNE on YPEN-1 rat prostatic endothelial cells. (omitted)

• The Korean Journal of Physiology and Pharmacology
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• 제25권5호
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• pp.425-437
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• 2021

Although the contributions of sitagliptin to endothelial dysfunction in diabetes mellitus were previously reported, the mechanisms still undefined. Autophagy plays an important role in the development of diabetes mellitus, but its role in diabetic macrovascular complications is unclear. This study aims to observe the effect of sitagliptin on macrovascular endothelium in diabetes and explore the role of autophagy in this process. Diabetic rats were induced through administration of high-fat diet and intraperitoneal injection of streptozotocin. Then diabetic rats were treated with or without sitagliptin for 12 weeks. Endothelial damage and autophagy were measured. Human umbilical vein endothelial cells were cultured either in normal glucose or in high glucose medium and intervened with different concentrations of sitagliptin. Rapamycin was used to induce autophagy. Cell viability, apoptosis and autophagy were detected. The expressions of proteins in c-Jun N-terminal kinase (JNK)-Bcl-2-Beclin-1 pathway were measured. Sitagliptin attenuated injuries of endothelium in vivo and in vitro. The expression of microtubuleassociated protein 1 light chain 3 II (LC3II) and beclin-1 were increased in aortas of diabetic rats and cells cultured with high-glucose, while sitagliptin inhibited the over-expression of LC3II and beclin-1. In vitro pre-treatment with sitagliptin decreased rapamycin-induced autophagy. However, after pretreatment with rapamycin, the protective effect of sitagliptin on endothelial cells was abolished. Further studies revealed sitagliptin increased the expression of Bcl-2, while inhibited the expression of JNK in vivo. Sitagliptin attenuates injuries of vascular endothelial cells caused by high glucose through inhibiting over-activated autophagy. JNK-Bcl-2-Beclin-1 pathway may be involved in this process.

• Archives of Pharmacal Research
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• 제29권1호
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• pp.1-15
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• 2006

Vascular endothelial cell injury or dysfunction has been implicated in the onset and' progression of cardiovascular diseases including atherosclerosis. A number of previous studies have demonstrated that the pro-oxidative and pro-inflammatory pathways within vascular endothelium play an important role in the initiation and progression of atherosclerosis, Recent evidence has provided compelling evidence to indicate that interleukin-4 (IL-4) can induce proc inflammatory environment via oxidative stress-mediated up-regulation of inflammatory mediators such as cytokine, chemokine, and adhesion molecules in vascular endothelial cells. In addition, apoptotic cell death within vascular endothelium has been hypothesized to be involved in the development of atherosclerosis. Emerging evidence has demonstrated that IL-4 can induce apoptosis of human vascular endothelial cells through the caspase-3-dependent pathway, suggesting that IL-4 can increase endothelial cell turnover by accelerated apoptosis, the event which may cause the dysfunction of the vascular endothelium. These studies will have a high probability of revealing new directions that lead to the development of clinical strategies toward the prevention and/or treatment for individuals with inflammatory vascular diseases including atherosclerosis.

• 대한방사선협회지
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• 제25권1호
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• pp.317-323
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• 1999

The response of endothelial cells to ionizing radiation is thought to be an important factor in the overall response of normal tissue. It has been reported that basic fibroblast growth factor (bFGF), a potent mitogen for endothelial cells, protects endoth

• Clinical and Experimental Pediatrics
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• 제46권1호
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• pp.56-66
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• 2003

목 적 : 제대정맥은 모체의 혈액을 태아로 운반하여 산소와 영양물질을 공급하는 유일한 통로이다. 이러한 제대 혈류의 장애가 있을 시 자궁내 성장제한, 임신성 고혈압 등을 초래할 수 있다. 제대-태반 혈관의 내피세포 손상을 유발하는 원인 중 amiloride 유도체들을 중심으로 내피세포에 미치는 amiloride 유도체들의 작용을 밝히고, 세포 내 이온농도 변화와 apoptosis 간의 관계를 규명하고자 하였다. 방 법 : 인간 제대정맥 내피세포는 Clonetics로부터 구입하였으며, 내피세포 성장에 필요한 여러 성장인자가 포함된 배지에서 배양하였다. MTT 방법과 flow cytometry 방법을 이용하여 세포독성 효과 및 apoptosis를 확인하였다. 세포 내 이온농도 변화를 측정하기 위해서는 각각의 목적에 적합한 형광염료들을 세포 내에 부하시켜 놓은 뒤, 형광 현미경과 연결된 영상분석장치를 이용하여 관찰하였다. 결 과 : 1) Amiloride 유도체들은 농도 의존적으로 HUVEC의 사멸을 나타내었으며, 각각의 정도는 HMA($IC_{50}$; $11.2{\mu}M$), MIA($13.6{\mu}M$)>EIPA($30.8{\mu}M$)>>amiloride($106{\mu}M$) 순이었다. 2) 세포주기 분석결과 apoptosis의 특징적인 sub $G_0/G_1$ ploidy peak를 나타냈으며, 이러한 작용은 caspase 억제제에 의해 감소되었다. 3) Annexin-V와 propidium iodide 이중 염색 결과 apoptosis로 진행된 세포의 비율(73.0%)을 대조군(11.3%)에 비해 현저히 증가시켰다. 4) HMA에 의한 apoptosis 효과는 세포외액의 pH를 높이거나, $NH_4Cl$을 투여하여 세포내액의 pH를 높일 경우 크게 증가하였다. 5) HMA는 농도 의존적으로 세포내 주요 이온인 $K^+$ 및 $Cl^-$의 세포내 농도를 감소시켰으며, 이러한 효과 역시 세포외액의 pH를 높일수록 현저하게 증가하였다. 결 론 : 이상의 결과들로 미루어 볼 때, HUVEC에서 amiloride 유도체들에 의한 apoptosis 과정에 세포내 주요 이온 농도 감소가 일부 관여하고 있을 것이라 생각된다.

• 한국식품영양과학회지
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• 제31권4호
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• pp.672-678
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• 2002

본 연구에서는 free radicals의 산화적인 손상에 의한 세포사멸에 있어서 녹차성분의 하나인 (-)epigallocatechin gallate의 억제효과를 규명하였다. 우선 radicals 소거작용에 있어서 (-)epigallocatechin gallate는 탁월한 항산화력을 발휘하였다. 혈관손상과 직결되는 혈관내피세포를 이용하여 hydroxyl radical의 $H_2O$$_2$에 의한 산화적인 손상을 유발시켜 세포생존율을 조사하였는데, (-)epigallocatechin gallate는 100 $\mu\textrm{m}$ 이하의 농도에서는 그 자체 독성이 없었고 $H_2O$$_2$의 산화적 독성효과를 경감시키는 것으로 나타났다. 그러나 flavone인 apigenin은 고농도에서 독성을 가지며 radical 소거활성이 미약하고 $H_2O$$_2$의 산화독성은 경감시키지 못하였다. 다양한 세포사멸 검출법을 이용하여 세포 및 세포핵의 형태학적 양상을 조사한 결과, 0.25mM $H_2O$$_2$에 의한 24시간 이내의 세포죽음은 세포사멸현상에 의하여 초래되었다. 그러나 이러한 세포사멸과정을 겪고 있는 혈관내피세포에 50 $\mu\textrm{m}$ (-)epigallocatechin gallate를 처리한 경우에 세포핵의 응축이나 DNA fragmentation은 사라지고 세포사멸작용을 억제시키는 효과를 보여주었다. 예상한 바와 같이 apigenin의 flavone은 세포사멸 억제효과를 나타내지 못하였다. (-)Epigallocatechin gallate는 녹차에 함유된 catechins의 하나로서 free radicals의 산화적 손상에 의한 세포사멸에 있어서 탁월한 방어적 인 세포생리학적인 기능을 지니고 있으며, 혈관노화 및 혈관손상과 함께 유발되는 세포사멸성 심혈관질환의 예방과 치료에 기능성 식품 신소재로서 활용될 수 있으리라 본다.

• 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.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제34권1호
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• pp.59-70
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• 2008

Purpose: We evaluated the therapeutic effect of AEE788, a dual inhibitor of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) receptor tyrosine kinases on human salivary adenoid cystic carcinoma (ACC) cells growing in nude mice. Experimental Design: We examined the effects of AEE788 on salivary ACC cell growth and apoptosis. To determine the in vivo effects of AEE788, nude mice with orthotopic parotid tumors were randomized to receive oral AEE788 (50 mg/kg) three times per week, injected paclitaxel ($200{\mu}g$) once per week, AEE788 plus paclitaxel, or placebo. Mechanisms of in vivo AEE788 activity were determined by immunohistochemical analysis. Results: Treatment of salivary ACC cells with AEE788 led to growth inhibition and induction of apoptosis. AEE788 inhibited tumor growth and prevented lung metastasis in nude mice. Furthermore, AEE788 potentiated growth inhibition and apoptosis of ACC tumor cells mediated by paclitaxel. Tumors of mice treated with AEE788 and AEE788 plus paclitaxel exhibited down-regulation of activated EGFR and its downstream mediators (Akt and MAPK), increased tumor and endothelial cell apoptosis, and decreased microvessel den-sity, which correlated with a decrease in the level of MMP-9, MMP-2 and bFGF expression and a decrease in the incidence of vascular metastasis. Conclusions: These data show that tumor-associated endothelial cells are important in the process of tumor-metastasis. And VEGFR can be a molecular target for therapy of metastatic lung lesion of salivary ACC.