• Title/Summary/Keyword: TGF-$\alpha$

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Histomorphologic Change of Radiation Pneumonitis in Rat Lungs : Captopril Reduces Rat Lung Injury Induced by Irradiation (X-선 조사로 생긴 흰쥐 폐장 상해의 형태학적 변화: Captopril에 의한 폐장 상해의 경감 효과)

  • Kim, Jin-Hee
    • Radiation Oncology Journal
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    • v.17 no.3
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    • pp.238-248
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    • 1999
  • Purpose : To assess the histomorphologic changes in the rat lung injury induced by radiation, to determine whether captopril reduces the rat lung injury and to evaluate change in TNF-${\alpha}$ and TGF-${\beta}$ in rat lung damage by radiation and captopril Methods and material : Right lungs in male Sprague-Dawley rats were divided irradiation alone (10, 20, 30 Gy) or radiation (same dose with radiation alone group) with captopril (500 mg/L). Radiation alone group were sacrificed at twelve hours and eleven weeks after radiation and radiation with captopril group (captopril group) were sacrificed at eleven weeks after radiation with captopril. We examined the light microscope and electron microscopic features in the groups. Results : In radiation alone group, there were patch parenchymal collapse and consolidation at twelve hours after radiation. The increase of radiation dose shows more prominent the severity and broader the affected areas. Eleven weeks after radiation, the severity and areas of fibrosis had increased in proportion to radiation dose given in the radiation alone group. There was notable decrease of lung fibrosis in captopril group than in radiation alone group. The number of mast cells rapidly increased with increase of radiation dose in radiation alone group and the degree of increase of mast cell number and severity of collagen accumulation more decreased in captopril group than in radiation alone group. In radiation alone group, expression of TNF-${\alpha}$ and TGF-${\beta}$ increased according to increase of radiation dose at twelve hours after radiation in both group. At eleven weeks after radiation, expression of TGF-${\beta}$ increased according to increase of radiation dose in radiation group but somewhat decreased in captopril group. In the captopril group the collagen deposition increased but less dense than those of radiation alone group. The severity of perivascular thickening, capillary change, the number and degranulation of mast cells more decreased in the captopril group than in the radiation alone group. Conclusion : It is concluded that the effect of captopril in the rat lungs after radiation was considered to be due to its effect on inhibition of mast cells and reduction of collagen deposition, and captopril may be protect in lung damage after radiation. We observed expression of TNF-${\alpha}$ and TGF-${\beta}$ increased at the early phase after radiation and expression of TGF-${\beta}$ increased in proportion to increase of radiation dose at the chronic phase after radiation. This results will contribute to future investigation in reduction mechanism of captopril in lung damage after radiation.

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Amelioration of Bleomycin-induced Pulmonary Fibrosis of Rats by an Aldose Reductase Inhibitor, Epalrestat

  • Li, Xianwei;Shen, Yuanyuan;Lu, Yining;Yang, Jieren
    • The Korean Journal of Physiology and Pharmacology
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    • v.19 no.5
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    • pp.401-411
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    • 2015
  • Aldose reductase (AR) is known to play a crucial role in the mediation of diabetic and cardiovascular complications. Recently, several studies have demonstrated that allergen-induced airway remodeling and ovalbumin-induced asthma is mediated by AR. Epalrestat is an aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Whether AR is involved in pathogenesis of pulmonary fibrosis and whether epalrestat attenuates pulmonary fibrosis remains unknown. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in rats. Primary pulmonary fibroblasts were cultured to investigate the proliferation by BrdU incorporation method and flow cytometry. The expression of AR, TGF-${\beta}_1$, ${\alpha}$-SMA and collagen I was analyzed by immunohistochemisty, real-time PCR or western blot. In vivo, epalrestat treatment significantly ameliorated the bleomycin-mediated histological fibrosis alterations and blocked collagen deposition concomitantly with reversing bleomycin-induced expression up-regulation of TGF-${\beta}_1$, AR, ${\alpha}$-SMA and collagen I (both mRNA and protein). In vitro, epalrestat remarkably attenuated proliferation of pulmonary fibroblasts and expression of ${\alpha}$-SMA and collagen I induced by TGF-${\beta}_1$, and this inhibitory effect of epalrestat was accompanied by inhibiting AR expression. Knockdown of AR gene expression reversed TGF-${\beta}_1$-induced proliferation of fibroblasts, up-regulation of ${\alpha}$-SMA and collagen I expression. These findings suggest that AR plays an important role in bleomycin-induced pulmonary fibrosis, and epalrestat inhibited the progression of bleomycin-induced pulmonary fibrosis is mediated via inhibiting of AR expression.

Characterization of Mouse B Lymphoma Cells (CH12F3-2A) for the Study of IgA Isotype Switching (IgA Isotype Switching 연구를 위한 마우스 B Lymphoma Cell (CH12F3-2A)의 특성 연구)

  • Jang, Young-Saeng;Choi, Seo-Hyeun;Park, Seok-Rae;Kim, Hyun-A;Park, Jae-Bong;Kim, Pyeung-Hyeun
    • IMMUNE NETWORK
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    • v.4 no.4
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    • pp.216-223
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    • 2004
  • Background: It is well known that IgA isotype switching is induced by $TGF-{\beta}1$. LPS-activated mouse normal B cells well differentiate into IgA secreting plasma cells under the influence of $TGF-{\beta}1$. Nevertheless, there are lots of difficulties in studying normal B cells in detail because it is not simple to obtain highly purified B cells, showing low reproducibility and transfection efficacy, moreover impossible to keep continuous culture. To overcome these obstacles, it is desperately needed to develop B cell line which acts like normal B cells. In the present study, we investigated whether CH12F3-2A lymphoma cells are appropriate for studying IgA isotype switching event. Methods: CH12F3-2A B cell line was treated with LPS and $TGF-{\beta}1$, then levels of germ-line (GL) transcripts were measured by RT-PCR, and $GL{\alpha}$ promoter activity was measured by luciferase assay. In addition, membrane IgA (mIgA) expression and IgA secretion were determined by FACS and ELISA, respectively. Results: $TGF-{\beta}1$, regardless of the presence of LPS, increased level of $GL{\alpha}$ transcripts but not $GL{\gamma}2b$ transcripts. However, IgA secretion was increased dramatically by co-stimulation of LPS and $TGF-{\beta}1$. Both mIgA and IgA secretion in the presence of $TGF-{\beta}1$ were further increased by over-expression of Smad3/4. Finally, $GL{\alpha}$ promoter activity was increased by $TGF-{\beta}1$. Conclusion: CH12F3-2A cell line acts quite similarly to the normal B cells which have been previously reported regarding IgA expression. Thus, CH12F3-2A lymphoma cell line appears to be adequate for the investigation of the mechanism(s) of IgA isotype switching at the cellular and molecular levels.

TGF-$\alpha$로 분화 유도된 인간 배아줄기세포 이식에 따른 파킨슨 동물 모델 생쥐의 행동 개선

  • 이금실;김용식;신현아;조황윤;김은영;이원돈;박세필;임진호
    • Proceedings of the KSAR Conference
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    • 2004.06a
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    • pp.271-271
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    • 2004
  • 본 실험은 TGF-a를 처리하여 분화가 유도된 인간배아 줄기세포를 파킨슨 동물모델에 이식하여 숙주세포에서의 생존 및 이식효과를 검토하고자 실시하였다. TGF-a로 분화된 세포의 이식효과를 판정하고자 배양시 TGF-a처리군과 처리하지 않은 군으로 나누어 분화를 유도한 인간배아 줄기세포를 hoechst33342로 표지 하여 병변 유발과 동일한 방법으로 동측 선조체내에 4×10⁴개/2ul가 되도록 이식하고(이식 위치: AP 0.7, ML 2.0, DV3.4) 이식 후 2, 4주에서 행동학적 변화를 관찰하고 4주에 동물을 희생시켜 4% PFA를 이용하여 뇌 조직을 고정하고 뇌 조직은 40㎛ 두께로 동결 절편을 만들어 면역조직화학염색을 시행하여 신경세포로의 분화 및 TH 발현 여부를 관찰하였고 분화의 표지물질로 nestin, NF200, GFAP, TH를 사용하여 형태학적 변화를 관찰하였다. (중략)

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Polyamines Modulate Growth factor-Induced Membrane Protein Phosphorylation in MCF-7 Human Breast Cancer Cells (MCF-7 유방암세포에 있어서 growth factor에 의해 유도된 막 단백질의 인산화에 대한 폴리아민의 조절)

  • Lee, Ji-Young;Kim, Ji-Hyun;Lee, Kyeong-Hee;Kim, Byeong-Gee
    • Journal of Life Science
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    • v.12 no.2
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    • pp.164-172
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    • 2002
  • Breast cancer cell lines display a wide variety of growth factor receptors, and considerable evidences implicate the importance of signalings from those receptors. A useful prognostic indicator would be the level of activity of a second messenger protein used in common by these receptors. Our studies were designed to obtain preliminary information on the possible role of polyamine as a mediator of the membrane-associated protein phosphorylation and as a regulator of second messenger in mitogenic signal of estrogen or growth factors in MCF-7 human breast lancer cells. DFMO significantly inhibited the phosphorylation induced by $E_2$, TGF-$\alpha$ and EGF in membrane-associated proteins (154, 134, 116, and 104 kDa). Exogenous polyamines abolished the inhibitory effect of DFMO. Tyrosine phosphorylations of membrane-associated proteins were not increased by $E_2$ or growth factor treatments and not affected DFMO treatment. Polyamine administration markedly enhanced the tyrosine phosphorylation of membrane-associated proteins (154, 134, and 116 kDa). In the present study, $E_2$ and TGF-$\alpha$ and EGF enhanced protein phosphorylation in the almost same levels. These data indicate that $E_2$ and growth factor signaling pathway may cross-talk through various protein kinase which phosphorylated many substrate proteins (154, 134, 116 and 104 kDa). Polyamines may be involved in growth signaling pathway of $E_2$ and TGF-$\alpha$ or EGF for the cross-talk through regulation of the protein phosphorylation such as 154, 134, 116 and 104 kDa. Polyamine may also selectively interfere with several different protein kinases, and the specific steps in signal transduction system were effected by polyamines.

The Measurements of Plasma Cytokines in Radiation-induced Pneumonitis in Lung Cancer Patients (폐암환자에서 방사선 폐렴 예측을 위한 혈장 Cytokine측정)

  • Hur Won Joo;Youn Seon Min;Lee Hyung Sik;Yang Kwang Mo;Sin Geun Ho;Son Choon Hee;Han Jin Yeong;Lee Ki Nam;Jeong Min Ho
    • Radiation Oncology Journal
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    • v.18 no.4
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    • pp.314-320
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    • 2000
  • Purpose :To investigate whether changes in plasma concentrations of transforming growth factor-$\beta$1(TGF-$\beta$1), tumor necrosis factor-alpha (TNF-$\alpha$) and interleukin-6 (IL-6) could be used to identify the development of radiation-induced pneumonitis in the lung cancer patients. Methods and Materials :Seventeen patients with lung cancer (11 NSCLC, 6 SCLC) were enrolled in a prospective study designed to evaluate clinical and molecular biologic correlation of radiation-induced pneumonitis. The study began in May 1998 and completed in July 1999. All patients were treated with radiotherapy with curative intent : 1.8 Gy per day, 5 fractions per week. Serial measurements of plasma TGF-$\beta$1, TNF-$\alpha$ and IL-6 were obtained in all patients before, weekly during radiotherapy and at each follow-up visits after completion of treatment. These measurements were quantified using enzyme linked immunosorbent assay (ELISA). All patients were evaluated for signs and symptoms of pneumonitis at each follow-up visit after completion of radiotherapy. High resolution CT (HRCT) scans were obtained when signs and symptoms of pneumonitis were developed after completion of radiotherapy. Results : Thirteen patients eventually developed signs and symptoms of clinical pneumonitis 씬file four patients did not. TGF-$\beta$ 1 levels were elevated in all 13 patients with pneumonitis, which showed characteristic pattern of elevation (38.45 ng/ml at pretreatment, 13.66 ng/ml during radiotherapy, then 60.63 ng/ml at 2-4 weeks after completion of radiotherapy). The levels of TNF- $\alpha$ and IL-6 were also elevated In the group of patients who developed pneumonitis but the pattern was not characteristic. Conclusions : Changes in plasma TGF$\beta$-1 levels before, during and after radiotherapy appears to be a useful means by which to identify patients at risk for the development of symptomatic pneumonitis. Other cytokines like TNF- $\alpha$ and IL-6 shows no meaningful changes in association with radiation pneumonitis.

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Effects of Neurotrophic Factors on the Generation of Functional Dopamine Secretory Neurons Derived from in vitro Differentiated Human Embryonic Stem Cells (신경성장촉진 인자가 인간 배아줄기세포 유래 도파민 분비 신경세포형성에 미치는 영향)

  • Lee, Keum-Sil;Kim, Eun-Young;Shin, Hyun-Ah;Cho, Hwang-Yoon;Wang, Kyu-Chang;Kim, Yong-Sik;Lee, Hoon-Taek;Chung, Kil-Saeng;Lee, Won-Don;Park, Se-Pill;Lim, Jin-Ho
    • Clinical and Experimental Reproductive Medicine
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    • v.31 no.1
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    • pp.19-27
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    • 2004
  • Objective: This study was to examine the in vitro neural cell differentiation patterns of human embryonic stem (hES) cells following treatment of various neurotrophic factors [basic fibroblast growth factor (bFGF), retinoic acid (RA), brain derived neurotrophic factor (BDNF) and transforming growth factor (TGF)-$\alpha$], particulary in dopaminergic neuron formation. Methods: The hES cells were induced to differentiate by bFGF and RA. Group I) In bFGF induction method, embryoid bodies (EBs, for 4 days) derived from hES were plated onto gelatin dish, selected for 8 days in ITSFn medium and expanded at the presence of bFGF (10 ng/ml) for another 6 days followed by a final differentiation in N2 medium for 7, 14 and 21 days. Group II) For RA induction, EBs were exposed of RA ($10^{-6}M$) for 4 days and allowed to differentiate in N2 medium for 7, 14 and 21 days. Group III) To examine the effects of additional neurotrophic factors, bFGF or RA induced cells were exposed to either BDNF (10 ng/ml) or TGF-$\alpha$ (10 ng/ml) during the 21 days of final differentiation. Neuron differentiation and dopamine secretion were examined by indirect immunocytochemistry and HPLC, respectively. Results: The bFGF or RA treated hES cells were resulted in similar neural cell differentiation patterns at the terminal differentiation stage, specifically, 75% neurons and 11% glial cells. Additionally, treatment of hES cells with BDNF or TGF-$\alpha$ during the terminal differentiation stage led to significantly increased tyrosine hydroxylase (TH) expression of a dopaminergic neuron marker, compared to control (p<0.05). In contrast, no effect was observed on the rate of mature neuron (NF-200) or glutamic acid decarboxylase-positive neurons. Immunocytochemistry and HPLC analyses revealed the higher levels of TH expression (20.3%) and dopamine secretion (265.5 $\pm$ 62.8 pmol/mg) in bFGF and TGF-sequentially treated hES cells than those in $\alpha$ RA or BDNF treated hES cells. Conclusion: These results indicate that the generation of dopamine secretory neurons from in vitro differentiated hES cells can be improved by TGF-$\alpha$ addition in the bFGF induction protocol.

Bevacizumab accelerates corneal wound healing by inhibiting TGF-βexpression in alkali-burned mouse cornea

  • Lee, Sung-Ho;Leem, Hyun-Sung;Jeong, Seon-Mi;Lee, Koon-ja
    • BMB Reports
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    • v.42 no.12
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    • pp.800-805
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    • 2009
  • This study investigated the effect of subconjunctival injections of bevacizumab, an anti-VEGF antibody, on processes involved in corneal wound healing after alkali burn injury. Mice were divided into three groups: Group 1 was the saline-treated control, group 2 received subconjunctival injection of bevacizumab 1hr after injury and group 3 received bevacizumab 1 hr and 4 days after injury. Cornea neovascularization and opacity were observed using a slit lamp microscope. Corneal repair was assessed through histological analysis and immunostaining for CD31, $\alpha$-SMA, collagen I, and TGF-$\beta$2 7 days post-injury. In group 3, injection of bevacizumab significantly lowered neovascularization and improved corneal transparency. Immunostaining analysis demonstrated a reduction in CD31, $\alpha$-SMA and TGF-$\beta$2 levels in stroma compared to group 1. These results indicate that bevacizumab may be useful in reducing neovascularization and improving corneal transparency following corneal alkali burn injury by accelerating regeneration of the basement membrane.

Inhibitory Effect of Rutaecarpine on Thioacetamide (TAA)-induced Hepatic Fibrosis

  • Ahn, Hyunjin;Lee, Sung-Jin;Nam, Kung-Woo;Mar, Woongchon
    • Natural Product Sciences
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    • v.20 no.4
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    • pp.262-268
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    • 2014
  • Rutaecarpine is one of the major alkaloids present in the fruits of Evodia rutaecarpa. In this study, rutaecarpine was evaluated, both in vitro and in vivo, for its hepatoprotective properties against thioacetamide (TAA)-induced hepatic fibrosis. The results showed that rutaecarpine inhibited TAA-induced cytotoxicity, reduced the expression of the fibrogenic cytokine transforming growth factor ${\beta}1$ ($TGF-{\beta}1$), and induced the expression of bcl-2. To evaluate its in vivo effects, animal models with TAA-induced hepatic fibrosis were utilized. Levels of liver tissue injury-associated enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were monitored. $TGF-{\beta}1$ and the ${\alpha}$-smooth muscle actin (${\alpha}$-SMA) were measured as markers of the protective effects on hepatic fibrosis. The AST and ALT levels in blood were greatly enhanced by TAA and completely blunted by rutaecarpine. Rutaecarpine led to the down-regulation of $TGF-{\beta}$ and Bax mRNA expression, as well as the up-regulation of Bcl-2 and $Bcl-X_L$ mRNA levels. In conclusion, rutaecarpine inhibited TAA-induced hepatic fibrosis and apoptosis by inducing the expression of Bcl-2 while blocking $TGF-{\beta}1$ in our TAA-intoxicated model.

Mast Cells are Responsible for Expression of α-Smooth Muscle Actin in Stromal Cells of the Uterine Cervix during Epithelial Neoplastic Changes (자궁경부상피의 악성변화에서 비만세포가 간질세포의 α-Smooth Muscle Actin 발현에 미치는 영향)

  • Jekal, Seung-Joo;Choi, Young-Ja;Lee, Kwang-Joo;Roh, Jong-Sup
    • Korean Journal of Clinical Laboratory Science
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    • v.39 no.3
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    • pp.210-216
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    • 2007
  • There is increasing evidence that stromal reaction in cancer has an important diagnostic and prognostic significance. The aim of our study is to analyze the relation between the increase in mast cell number and the expression CD34 and alpha-smooth muscle actin (${\alpha}$-SMA) in the stroma of cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC). We investigated a total of 29 CIN (1,2,3) and 21 SCC (microinvasive and invasive) specimens and compared the distribution of $CD34^+$ stromal cells, ${\alpha}-SMA^+$ cells, transforming growth factor-${\beta}1$ $(TGF-{\beta}1)^+$ cells, and the density of mast cells using immunohistochemistry with antibodies against CD34, ${\alpha}$-SMA, TGF-${\beta}1$, and c-Kit (CD117) respectively. Computerized image analysis was to evaluate the positive area (%) and density of the respective immunoreactive cells. In CIN $CD34^+$ cells were abundant in the stroma but no ${\alpha}-SMA^+$ cells were identified except the wall of blood vessels. $CD34^+$ cells were progressively decreased along the continuum from CIN 2 to microinvasive SCC and not observed in the stroma of invasive SCC. Whereas ${\alpha}-SMA^+$ cells were only observed in the stroma of microinvasive and invasive SCC. We found more intense TGF-${\beta}1$ expression in the increased mast cells in the stroma of invasive SCCs than that in the stroma of CIN. These results indicate that disappearance of $CD34^+$ stromal cells and appearance of ${\alpha}-SMA^+$ cells are associated with the stromal change of CIN to SCC and the transformation of $CD34^+$ stromal cells into ${\alpha}-SMA^+$ cells is mediated by TGF-${\beta}1$ secretions in the stromal mast cell of SCC.

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