• Journal of Life Science
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• v.23 no.12
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• pp.1532-1540
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• 2013

T-box transcription factor 2 (Tbr2) is a member of the T-box family of transcription factors and it plays an important role in brain development, progenitor cell proliferation, and the modulation of differentiation and function in immune cells, such as CD8+ T cells and natural killer cells. This study aims to elucidate the involvement of Tbr2 in the pathophysiological events following pilocarpine-induced status epilepticus in mice. Status epilepticus resulted in prominent neuronal cell death in discrete brain regions, such as CA3, the hilus, and the piriform cortex. Interestingly, when the immunoreactivity of Tbr2 was examined two days after status epilepticus, it was transiently increased in CA3 and in the piriform cortex. Tbr2-positive cells in CA3 and the piriform cortex were double-labeled with CD11b, a marker of microglia and a subset of white blood cells, such as monocytes, CD8+ T cells, and natural killer cells. Moreover, the double-labeled cells with Tbr2 and CD11b showed amoeboid morphology, and this data indicates that Tbr2-expressing cells may be reactive microglia or infiltrating white blood cells. Furthermore, clustered Tbr2-positive cells were observed in the platelet endothelial cell adhesion molecule-1 (PECAM-1)-positive blood vessels near the CA3 area, which suggests that Tbr2-positive cells may be infiltrating the white blood cells. Based on this data, this study is the first to indicate the involvement of Tbr2 in neuropathophysiology in status epilepticus.

• Korean Journal of Pharmacognosy
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• v.45 no.1
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• pp.1-10
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• 2014

Ginsenoside Rg3 (G-Rg3) is one of protopanaxadiol ginsenosides characteristic of red ginseng, steamed and dried ginseng (Panax ginseng), which has recently attracted much attention for its antitumor properties in vitro and in vivo animal models. Experimental studies have demonstrated that it could promote cancer cell apoptosis, inhibit cancer cell growth, the apoptosis of cancer cells, adhesion, invasion and metastasis, and also prevent an angiogenetic formation in prostate, breast, ovarian, colorectal, gastric, liver and lung cancer etc. It has shown the antitumor activities by modulation of diverse signaling pathways, including regulation of cell proliferation mediators (CDKs and cyclins), growth factors (vascular endothelial growth factor), tumor suppressors (p53 and p21), cell death mediators (caspases, Bcl-2, Bax), inflammatory response molecules ($NF-{\kappa}B$ and COX-2), protein kinases (JNK, Akt, and AMP-activated protein kinase) and Wnt/${\beta}$-catenin signaling. In addition, the combination of Rg3 and chemotherapeutic agents have synergistically enhanced therapeutic efficacy and reduced antagonistically side effects. Furthermore, it can reverse the multidrug resistance of cancer cells, prolong the survival duration and improve life quality of cancer patients. Taken together, accumulating evidences could provide the potential of G-Rg3 in the treatment of cancers and the feasibility of further randomized placebo controlled clinical trials.

• The Journal of Internal Korean Medicine
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• v.34 no.1
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• pp.100-111
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• 2013

Objectives : This study investigated the impact of Caesalpinia sappan L. on oxidative damage and inflammatory relevant factor in RAW 264.7 cells and human umbilical vein endothelial cells (HUVEC). Methods : We determined whether fractionated EtOH extracts of Caesalpinia sappan L. (CSL) inhibit free radical generation such as 2,2-diphenyl-1-picrylhydrazyl (DPPH), reactive oxygen species (ROS) and nitric oxide (NO) and pro-inflammatory cytokines in lipopolysaccharide (LPS)-treated RAW 264.7 cells and HUVEC. Result : 1. DPPH removal capacity was increased by CSL. 2. LPS-induced ROS, and NO inhibitory capacity were increased by CSL. 3. LPS-induced cell death of Raw 264.7 cells was decreased by CSL. 4. The amount of cytokine generation in Raw 264.7 cell was decreased significantly by CSL. 5. The amount of cytokine generation in HUVEC was decreased significantly by CSL. Conclusions : These results suggest that CSL supplement may attenuate oxidative stress by elevated antioxidative processes, and suppress inflammatory mediator activation.

• International Journal of Stem Cells
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• v.16 no.1
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• pp.1-15
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• 2023

Liver organoids have gained much attention in recent years for their potential applications to liver disease modeling and pharmacologic drug screening. Liver organoids produced in vitro reflect some aspects of the in vivo physiological and pathological conditions of the liver. However, the generation of liver organoids with perfusable luminal vasculature remains a major challenge, hindering precise and effective modeling of liver diseases. Furthermore, vascularization is required for large organoids or assembloids to closely mimic the complexity of tissue architecture without cell death in the core region. A few studies have successfully generated liver organoids with endothelial cell networks, but most of these vascular networks produced luminal structures after being transplanted into tissues of host animals. Therefore, formation of luminal vasculature is an unmet need to overcome the limitation of liver organoids as an in vitro model investigating different acute and chronic liver diseases. Here, we provide an overview of the unique features of hepatic vasculature under pathophysiological conditions and summarize the biochemical and biophysical cues that drive vasculogenesis and angiogenesis in vitro. We also highlight recent progress in generating vascularized liver organoids in vitro and discuss potential strategies that may enable the generation of perfusable luminal vasculature in liver organoids.

• International Journal of Stem Cells
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• v.15 no.2
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• pp.217-226
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• 2022

Background and Objectives: Stroke is the most common cause of human death and functional disability, resulting in more than 5 million deaths worldwide each year. Bone marrow mesenchymal stem cells (BMSCs) are a kind of stem cell that are able to self-renew and differentiate into many types of tissues. Therefore, BMSCs have the potential to replace damaged neurons and promote the reconstruction of nerve conduction pathways and connective tissue. However, it remains unknown whether transplanted BMSCs promote angiogenesis or improve the tissue microenvironment directly or indirectly through paracrine interactions. This study aimed to determine the therapeutic effect of BMSCs on ischemic stroke with hypertension in a rodent model and to explore the possible mechanisms underlying any benefits. Methods and Results: Middle cerebral artery occlusion was used to establish the experimental stroke model. The area of cerebral infarction, expression of vascular endothelial growth factor (VEGF) and glial cell line-derived neurotrophic factor (GDNF), and increment of astrocyte were measured by TTC staining, western blot, real-time quantitative polymerase chain reaction (RT-qPCR) and immunocytochemistry. The results showed a smaller area of cerebral infarction and improved neurological function scores in animals treated with BMSCs compared to controls. The results of RT-qPCR and western blot assays showed higher expression of VEGF and GDNF in BMSC-treated animals compared with controls. Our study also showed that one round of BMSCs transplantation significantly promoted the proliferation of subventricular zone and cortical cells, especially astrocytes, on the ischemic side following cerebral ischemia. Conclusions: Above findings support that BMSCs have therapeutic effects for ischemic stroke complicated with hypertension, which may occur via up-regulated expression of VEGF and GDNF and reduction of neuronal apoptosis, thereby promoting the recovery of nerve function.

• Clinical and Experimental Pediatrics
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• v.46 no.1
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• pp.56-66
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• 2003

Purpose : Human umbilical vein endothelial cells(HUVECs) play an important role in regulating blood flow by releasing vasoactive substances. It has been reported that endothelial impairment and dysfunction might be a primary cause of placental vascular disease, which is manifested clinically as preeclampsia in mother and intrauterine growth restriction in fetus. Furthermore, the frequency of apoptotic changes is increased in umbilical and placental tissues from growth-restricted pregnancies. However, the various mechanisms of umbilical endothelial cell apoptosis have not been broadly proposed. We investigate the effects of amiloride derivatives on apoptotic death of HUVECs and identify their ionic mechanism. Methods : HUVECs were purchased from Clonetics, and cultured on endothelial cell growth medium. MTT assay and flow cytometry were used for assessing cytotoxic effect and confirming the apoptosis. Changes in intracellular ion concentrations were measured with specific fluorescent dyes and fluorescence imaging analysis system. Results : Amiloride derivatives elicited cytotoxic effects on HUVECs with dose-dependent manners and the rank order of potency is HMA($IC_{50}\;11.2{\mu}M$), MIA>EIPA>>amiloride. HMA-induced cytotoxicity is dependent on extra- and intracellular pH, that is, increase extra- and intracellular pH augmented the cytotoxic effects of HMA. HMA dose-dependently reduced intracellular major ions, such as $K^+$ and $Cl^-$. Interestingly, the depletion of intracellular ions induced by HMA was also significantly enhanced at alkaline extracellular pH. Conclusion : Amiloride derivatives induce apoptosis of HUVECs with dose and pH dependent manners. They reduce intracellular $K^+$ and $Cl^-$ concentration, which is also extracellular pH dependent.

• Journal of Physiology & Pathology in Korean Medicine
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• v.18 no.5
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• pp.1382-1386
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• 2004

This study was performed for the investigation of vasodilatory efficacy and its underlying mechanisms of Samhwangsasim-tang(SST), herbal remedy. SST relaxed vascular strips precontracted with phenylephrine or KCI(51 mM), but the magnitude of relaxation was greater in phenylephrine(PE) induced contraction. The relaxation effects of SST was endothelium-independent. L-NAME, iNOS inhibitor, and methyl en blue(MB), cGMP inhibitor, did not attenuate the relaxation responses of SST. In the absence of extracellular Ca2+, pre-incubation of the aortic rings with SST significantly reduced the contraction by PE, suggesting that the relaxant action of the SST includes inhibition of Ca/sup 2+/ influx and release of Ca/sup 2+/ from intracellular stores (SR). In addition, the cell death was induced by SST in human aortic smooth muscle cells but not that of human umbilical vein endothelial cells. We conclude that in rat thoracic aorta, SST may induce in part vasodilation through inhibition of Ca/sup 2+/ influx and release of Ca/sup 2+/ from intracellular stores.

• BMB Reports
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• v.56 no.11
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• pp.575-583
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• 2023

Mitochondria, fundamental cellular organelles that govern energy metabolism, hold a pivotal role in cellular vitality. While consuming dioxygen to produce adenosine triphosphate (ATP), the electron transfer process within mitochondria can engender the formation of reactive oxygen species that exert dual roles in endothelial homeostatic signaling and oxidative stress. In the context of the intricate electron transfer process, several metal ions that include copper, iron, zinc, and manganese serve as crucial cofactors in mitochondrial metalloenzymes to mediate the synthesis of ATP and antioxidant defense. In this mini review, we provide a comprehensive understanding of the coordination chemistry of mitochondrial cuproenzymes. In detail, cytochrome c oxidase (CcO) reduces dioxygen to water coupled with proton pumping to generate an electrochemical gradient, while superoxide dismutase 1 (SOD1) functions in detoxifying superoxide into hydrogen peroxide. With an emphasis on the catalytic reactions of the copper metalloenzymes and insights into their ligand environment, we also outline the metalation process of these enzymes throughout the copper trafficking system. The impairment of copper homeostasis can trigger mitochondrial dysfunction, and potentially lead to the development of copper-related disorders. We describe the current knowledge regarding copper-mediated toxicity mechanisms, thereby shedding light on prospective therapeutic strategies for pathologies intertwined with copper dyshomeostasis.

• Proceedings of the Korean Society of Developmental Biology Conference
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• 2003.10a
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• pp.71-71
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• 2003

Human umbilical cord blood cells(HUCBC) are rich in mesenchymal progenitor cells, endothelial cell precursors and hematopoietic cells. HUCBC have been used as a source of transplantable stem and progenitor cells. However, little is known about survival and development of HUCBC transplantation in the CNS. Estrogen has a neuroprotective potential against oxidative stress-induced cell death so has an effect on reducing infarct size of ischemic brain. We investigated the potential use of HUCBC as donor cells and tested whether estrogen mediates intravenously infused HUCBC enter and survive in ischemic brain. PKH26 labeled mononuclear fraction of HUCBC were injected into the tail vein of ischemic OVX rat brain with or without $17\beta$-estradiol valerate(EV). Under fluorescence microscopy, labeled cells were observed in the brain section. Significantly more cells were found in the ischemic brain than in the non-ischemic brain. HUCBC transplanted into ischemic brain could migrate and survive. Some of cells have shown neuronal like cells in hippocampus, striatum and cortex tissues. These result suggest that estrogen reduces ischemic damage and increases the migration of human umbilical cord blood cells. This Study was supported by the Korea Science and Engineering Foundation(KOSEF) though the Biohealth Products Research Center(BPRC), Inje University, Korea.

• Journal of Ginseng Research
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• v.31 no.1
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• pp.1-13
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• 2007

We found that the main bacterial metabolite M1 is an active component of orally administered protopanxadiol-type ginsenosides, and that the anti-metastatic effect by oral administration of ginsenosides may be primarily mediated through the inhibition of tumor invasion, migration and growth of tumor cells by their metabolite M1. Pharmacokinetic study after oral administration of ginsenoside Rb1 revealed that M1 was detected in serum for 24 h by HPLC analysis but Rb1 was not detected. M1, with anti-metastatic property, inhibited the proliferation of murine and human tumor cells in a time- and concentration-dependent manner in vitro, and also induced apoptotic cell death (the ladder fragmentation of the extracted DNA). The induction of apoptosis by M1 involved the up-regulation of the cyclin-dependent kinase(CDK) inhibitor $p27^{Kip1}$ as well as the down-regulation of a proto-oncogene product c-Myc and cyclin D1 in a time-dependent manner. Thus, M1 might cause the cell-cycle arrest (G1 phase arrest) in honor cells through the up/down-regulation of these cell-growth related molecules, and consequently induce apoptosis. The nucleosomal distribution of fluorescence-labeled M1 suggests that the modification of these molecules is induced by transcriptional regulation. Tumor-induced angiogenesis (neovascularization) is one of the most important events concerning tumor growth and metastasis. Neovascularization toward and into tumor is a crucial step for the delivery of nutrition and oxygen to tumors, and also functions as the metastatic pathway to distant organs. M1 inhibited the tube-like formation of hepatic sinusoidal endothelial (HSE) cells induced by the conditioned medium of colon 26-L5 cells in a concentration-dependent manner. However, M1 at the concentrations used in this study did not affect the growth of HSE cells in vitro.