• The Korean Journal of Physiology and Pharmacology
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• v.22 no.2
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• pp.193-201
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• 2018

Connective tissue growth factor (CTGF) is a novel fibrotic mediator, which is considered to mediate fibrosis through extracellular matrix (ECM) synthesis in diabetic cardiovascular complications. Statins have significant immunomodulatory effects and reduce vascular injury. We therefore examined whether fluvastatin has anti-fibrotic effects in vascular smooth muscle cells (VSMCs) and elucidated its putative transduction signals. We show that advanced glycation end products (AGEs) stimulated CTGF mRNA and protein expression in a time-dependent manner. AGE-induced CTGF expression was mediated via ERK1/2, JNK, and Egr-1 pathways, but not p38; consequently, cell proliferation and migration and ECM accumulation were regulated by CTGF signaling pathway. AGE-stimulated VSMC proliferation, migration, and ECM accumulation were blocked by fluvastatin. However, the inhibitory effect of fluvastatin was restored by administration of CTGF recombinant protein. AGE-induced VSMC proliferation was dependent on cell cycle arrest, thereby increasing G1/G0 phase. Fluvastatin repressed cell cycle regulatory genes cyclin D1 and Cdk4 and augmented cyclin-dependent kinase inhibitors p27 and p21 in AGE-induced VSMCs. Taken together, fluvastatin suppressed AGE-induced VSMC proliferation, migration, and ECM accumulation by targeting CTGF signaling mechanism. These findings might be evidence for CTGF as a potential therapeutic target in diabetic vasculature complication.

• YAKHAK HOEJI
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• v.46 no.1
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• pp.18-23
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• 2002

Ailanthus altissima has been used to settle an upset stomach, to alleviate a fever and as an insecticide. We reported that the water extract of A. altissima induced apoptotic cell death in Jurkat T-acute Iymphoblastic leukemia cells. Here, we showed the dose-dependent inhibitions of cell viability by the extract, as measured by cell morphology. The cell cycle control genes are considered to play important roles in tumorigenesis. The purpose of the present study is also to investigate the effect of A. altissima on cell cycle progression and its molecular mechanism in the cells. The level of p21 protein was increased after treatment of the extract, whereas both Bcl-2 and Bax protein levels were not changed. These results suggest that A. altissima induces apoptotic cell death via p21-dependent signaling pathway in Jurkat cells which delete wild type p53. Gl checkpoint related gene products tested (cyclin D3, cyclin dependent kinase 4, retinoblastoma, E2Fl) were decreased in their protein levels in a dose-dependent manner after treatment of the extract Taken together, these results indicate that the increase of apoptotic cell death by A. altissima may be due to the inhibition of cell cycle in Jurkat cells.

• Biomolecules & Therapeutics
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• v.26 no.3
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• pp.313-321
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• 2018

Anti-cancer drug resistance is a major problem in colorectal cancer (CRC) research. Although several studies have revealed the mechanism of cancer drug resistance, molecular targets for chemotherapeutic combinations remain elusive. To address this issue, we focused on the expression of cellular prion protein ($PrP^C$) in 5-FU-resistant CRC cells. In 5-FU-resistant CRC cells, $PrP^C$ expression is significantly increased, compared with that in normal CRC cells. In the presence of 5-FU, $PrP^C$ increased CRC cell survival and proliferation by maintaining the activation of the PI3K-Akt signaling pathway and the expression of cell cycle-associated proteins, including cyclin E, CDK2, cyclin D1, and CDK4. In addition, $PrP^C$ inhibited the activation of the stress-associated proteins p38, JNK, and p53. Moreover, after treatment of 5-FU-resistant CRC cells with 5-FU, silencing of $PrP^C$ triggered apoptosis via the activation of caspase-3. These results indicate that $PrP^C$ plays a key role in CRC drug resistance. The novel strategy of combining chemotherapy with $PrP^C$ targeting may yield efficacious treatments of colorectal cancer.

• The Journal of Internal Korean Medicine
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• v.31 no.1
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• pp.84-101
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• 2010

Objectives : This study aimed to evaluate the protective effects of Seonpyejeongcheon-tang (SJT) on elastase-induced lung injury. Materials and Methods : The extract of SJT was treated to A549 cells and an elastase-induced lung injury mouse model. Then, various parameters such as cell-based cytoprotective activity and histopathological findings were analyzed. Results : SJT showed a protective effect on elastase-induced cytotoxicity in A549 cells. This effect was correlated with analysis for caspase 3 levels, collagen and elastin contents, protein level of cyclin B 1, Cdk1, and Erk1/2, and gene expression of TNF-$\alpha$ and IL-$1{\beta}$ in A549 cells. SJT treatment also revealed a protective effect on elastase-induced lung injury in mouse model. This effect was evidenced via histopathological findings, including immunofluoresence stains against elastin, collagen, and caspase 3, and protein levels of cyclin B1, Cdc2, and Erk1/2 in lung tissue. Conclusion : These data suggest that SJT has pharmaceutical properties on lung injury. This study thus provides scientific evidence for the efficacy of SJT for clinical application to patients with chronic obstructive pulmonary disease.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.3041-3044
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• 2013

Background: The non-steroidal anti-inflammatory drug (NSAID) aspirin (acetylsalicylic acid) is an inhibitor of cyclooxygenase enzymes. Recent studies have shown that aspirin could be used as an anti-tumor drug. Triptolide, the major compound extracted from the Chinese herb Tripteryglum wilfordii Hook.f, has now been shown that it can inhibit tumor growth. The aim of this study was to analyze the anti-tumor efficiency of aspirin and triptolide in cervical cancer cells. Methods: Viability of cervical cancer cell lines was assessed by the MTT method at various concentrations of aspirin and triptolide. Siha and HeLa cell apoptotic analysis was performed by flow cytometry. Real time-PCR and Western Blotting were used to analyze the expression of Bcl-2/Bax, Cyclin D1 and p16. Results: Viability in the combination group was significantly decreased as compared with either drug used alone. Expression change of Bcl-2/Bax, CyclinD1 and p16 appeared to play an important role in the synergistic killing effect on cervical cancer cell apoptosis. Conclusion: Aspirin and triptolide combination treatment may have synergistic anti-tumor effects on cervical cancer cells.

• Reproductive and Developmental Biology
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• v.35 no.4
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• pp.407-414
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• 2011

The development of embryos reconstructed by somatic cell nuclear transfer (SCNT) is dependent upon numerous factors. Central to development is the quality and developmental competence of the recipient cytoplast and the type of the donor nucleus. Typically metaphase of the second meiotic division (MII) has become the cytoplast of choice. Production of a cytoplast requires removal of the recipient genetic material, however, it may remove proteins which are essential for development or reduce the levels of cytoplasmic proteins to influence subsequent reprogramming of the donor nucleus. In this study, enucleation at MII did not affect the activities of either MPF or MAPK kinases. Immunocytochemical staining showed that both Cyclin B1 (MPF) and Erk1/2 (MAPK) were associated with the meiotic spindle of AI/TI oocytes with little staining in the cytoplasm, however, at MII association of both proteins with the spindle had reduced and a greater degree of cytoplasmic distribution was observed. The analysis of oocyte proteins removed during enucleation is a difficult approach to the identification of factors which may be depleted in the cytoplast. This is primarily due to the large numbers of aspirated karyoplasts which would be required for the analysis.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.5
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• pp.299-304
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• 2010

Losartan is a selective angiotensin II (Ang II) type 1 ($AT_1$) receptor antagonist which inhibits vascular smooth muscle cells (VSMCs) contraction and proliferation. We hypothesized that losartan may prevent cell proliferation by activating AMP-activated protein kinase (AMPK) in VSMCs. VSMCs were treated with various concentrations of losartan. AMPK activation was measured by Western blot analysis and cell proliferation was measured by MTT assay and flowcytometry. Losartan dose- and time-dependently increased the phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC) in VSMCs. Losartan also significantly decreased the Ang II- or 15% FBS-induced VSMC proliferation by inhibiting the expression of cell cycle associated proteins, such as p-Rb, cyclin D, and cyclin E. Compound C, a specific inhibitor of AMPK, or AMPK siRNA blocked the losartan-induced inhibition of cell proliferation and the $G_0/G_1$ cell cycle arrest. These data suggest that losartan-induced AMPK activation might attenuate Ang II-induced VSMC proliferation through the inhibition of cell cycle progression.

• Biomolecules & Therapeutics
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• v.19 no.1
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• pp.21-26
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• 2011

Ceramide is an important lipid mediator of extracellular signals that control various cellular functions, including apoptosis. In this study, we showed that ceramide induced apoptosis in U373MG human glioblastoma cells associated with G1 cell cycle arrest. Treatment of cells with ceramide increased proapoptotic Bax expression and inhibited the expression of antiapoptotic Bcl-2 and Bcl-xL Ceramide also downregulated cyclin E, cyclin D1, cdk 2, and cdk4 which are involved in regulating cell cycle. In addition, ceramide suppressed phosphorylation of Akt, Bad, p70 S6 kinase, and 4E-BP1, suggesting the involvement of Akt/mTOR signaling pathway. Additionally, okadaic acid, an inhibitor of protein phosphatase 2A, partially blocked the ceramide mediated inhibition of phosphorylation of Akt and 4E-BP1. These results suggest that ceramide induces apoptosis in U373MG glioblastoma cells by regulating multiple signaling pathways that involve cell cycle arrest associated with Akt signaling pathway.

• Korean Journal of Pharmacognosy
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• v.33 no.1 s.128
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• pp.29-34
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• 2002

Albizzia julibrissin belonging to the family Leguminosae has been used for the treatment of contusion, sore throat, amnesia, and insomnia in Oriental traditional medicine. The water extract of A. julibrissin induced apoptosis in Jurkat T-acute lymphoblastic leukemia (ALL) cells as measured by cell morphology. The capability of this herb medicine to induce apoptosis was associated with proteolytic cleavage of specific target protein such as beta-catenin protein suggesting the possible involvement of caspases. The purpose of the present study is also to investigate the effect of A. julibrissin on cell cycle progression. Our results showed that GI checkpoint related gene products (cyclin D1, cyclin dependent kinase 4, retinoblastoma, E2F1) were decreased in their protein levels in a dose-dependent manners after treatment of the extract. These results indicate that the increase of apoptotic cell death by A. julibrissin may be due to the inhibition of cell cycle progression in wild type p53-lacking Jurkat cells.

• Journal of Physiology & Pathology in Korean Medicine
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• v.24 no.6
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• pp.1042-1052
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• 2010

This study aimed to evaluate the protective effects of Mundongcheongpye-eum (MCE) on elastase-induced lung injury. The extract of MCE was treated to A549 cells and elastase-induced lung injury mice model. Then, various parameters such as cell-based cyto-protective activity and histopathological finding were analyzed. MCE showed a protective effect on elastase-induced cytotoxicity in A549 cells. This effect was correlated with analysis for caspase 3 levels, collagen and elastin contents, protein level of cyclin B1, Cdc2, and Erk1/2, and gene expression of TNF-${\alpha}$ and IL-$1{\beta}$ in A549 cells. MCE treatment also revealed the protective effect on elastase-induced lung injury in mice model. This effect was evidenced via histopathological finding including immunofluence stains against elastin, collagen, caspase 3, and protein level of cyclin B1, Cdc2, and Erk1/2 in lung tissue. These data suggest that MCE has a pharmaceutical properties on lung injury. This study would provide an scientific evidence for the efficacy of MCE for clinical application to patients with chronic obstructive pulmonary disease.