• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.9
• /
• pp.4137-4142
• /
• 2015

The zinc finger transcription factor EGR 1 has a role in controlling synaptic plasticity, wound repair, female reproductive capacity, inflammation, growth control, apoptosis and tumor progression. Recent studies mainly focused on its role in growth control and apoptosis, however, little is known about its role in epithelial-mesenchymal transition (EMT). Here, we aim to explore whether EGR 1 is involved in TGF-${\beta}1$-induced EMT in non-smallcell lung cancer cells. Transforming growth factor (TGF)-${\beta}1$ was utilized to induce EMT in this study. Western blotting, RT-PCR, and transwell chambers were used to identify phenotype changes. Western blotting was also used to observe changes of the expression of EGR 1. The lentivirus-mediated EGR 1 vector was used to increase EGR 1 expression. We investigated the change of migration to evaluate the effect of EGR 1 on non-small-cell lung cancer cells migration by transwell chambers. After stimulating with TGF-${\beta}1$, almost all A549 cells and Luca 1 cells (Non-small-cell lung cancer primary cells) changed to mesenchymal phenotype and acquired more migration capabilities. These cells also had lower EGR 1 protein expression. Overexpression of EGR 1 gene with EGR 1 vector could decrease tumor cell migration capabilities significantly after adding TGF-${\beta}1$. These data s howed an important role of EGR 1 in the EMT of non-small-cell lung cancer cells, as well as migration.

• The Journal of Internal Korean Medicine
• /
• v.29 no.3
• /
• pp.787-799
• /
• 2008

Objective : Diabetic nephropathy is the most common cause of end stage renal disease. AGE, $TGF-{\beta}1$ type IV collagen, and macrophage/monocyte infiltration are the main factors of diabetic nephropathy. We investigated the effects of Salvia miltiorrhiza on renal function and histopathological changes in streptozotocin(STZ)-induced diabetic nephropathy rat model. Methods : Diabetes was induced in male Sprague-Dawley rats(290${\pm}$10g) by injecting STZ(45mg/kg) into the tail vein. Rats were divided into 3 groups(n = 6): normal, control, and salvia. After 8 weeks of administration of Salvia miltiorrhiza extract on the Salvia group, we checked 24 hrs urine, blood biochemistry and renal tissue to evaluate renal function and histopathological changes by examining parameters including albuminuria, BUN, creatinine, cholesterol, LDL, TG, macrophage/monocyte antigen(ED-1), $TGF-{\beta}1$, AGE, and type IV collagen. Results : Salvia miltiorrhiza decreased the amount of 24hrs proteinuria, and inhibited histopathological changes of diabetic nephropathy including the expression and accumulation of various factors which could promote development of diabetic nephropathy. Conclusion : These findings suggest that Salvia miltiorrhiza might protect the renal function and inhibit the development of renal injury by regulating factors including AGE, $TGF-{\beta}1$ Type IV collagen, macrophage and monocyte infiltration. So Salvia miltiorrhiza can be used for diabetic patients to prevent the progression of diabetic nephropathy.

• Asian-Australasian Journal of Animal Sciences
• /
• v.16 no.3
• /
• pp.335-341
• /
• 2003

Carcass weight and backfat thickness are two of important elements in determining the carcass trait in pigs and are studied on animal genetics, nutrition, and endocrinology. Growth factors stimulate or inhibit the proliferation and differentiation of various cells. In particular, insulin-like growth factors (IGFs), transforming growth factor (TGF)-$\beta$, and epidermal growth factor (EGF) are involved in the growth and maintenance of muscle. Also, dehydroepiandrosterone-sulfate (DHEA-S) and cortisol are known to be related to the obesity and subcutaneous fat depth in pigs. Therefore, this study was performed to relate growth factors (IGFs, TGF-${\beta}1$, and EGF) and hormones (cortisol and DHEA-S) concentrations at antemortem and postmortem periods to carcass traits including carcass weight and backfat thickness. Blood and m. Longissimus were collected in pigs at antemortem (30 days before slaughter) and postmortem periods. After slaughtered, carcass weight and backfat thickness were measured. Growth factors and hormones in serum and m. Longissimus were measured by radioimmunoassay or enzyme-linked imuunosorbent assay. Before antemortem period, serum IGF-I and -II concentrations were positively correlated with the carcass weight and backfat thickness in gilts, and the concentrations of TGF- ${\beta}1$ and cortisol in barrows show the correlation with only carcass weight. Also, the positive correlations of muscular IGFs and TGF-${\beta}1$ at postmortem 45 min with the carcass weight and backfat thickness were detected. Consequently, these results suggest that the serum and muscular endocrine factors are involved in the carcass weight and backfat thickness in pigs.

• The Journal of Korean Medicine
• /
• v.30 no.6
• /
• pp.35-43
• /
• 2009

Objectives: Hwangryunhaedok-tang (HRHDT), a prescription composed of four herbs, has been wi dely used in Oriental Medicine for the treatment of cerebral infarction. However, the mechanisms by which the herbal formula affects on the production of pro- and anti-inflammatory cytokines in cerebral infarction patients remain unknown yet. Methods: The levels of pro- and anti-inflammatory cytokines, including tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6, IL-10, and TGF-${\beta}1$ were determined in peripheral blood mononuclear cells (PBMCs) from cerebral infarction patients under our experimental conditions. Results: The secretory levels of pro- and anti-inflammatory cytokines, including tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6, and IL-10 were significantly increased in phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from cerebral infarction patients. However, pretreatment with HRHDT significantly inhibited the secretion of pro- and anti-inflammatory in PBMCs. Also, HRHDT induced a significant increase of transforming growth factor (TGF)-b1 in PBMCs. Conclusions: These data indicate that HRHDT may be beneficial in the suppression of inflammatory processes of cerebral infarct through suppression of TNF-$\alpha$, IL-$1{\beta}$, IL-6, and IL-10 and induction of TGF-${\beta}1$.

• Maxillofacial Plastic and Reconstructive Surgery
• /
• v.35 no.2
• /
• pp.73-81
• /
• 2013

Purpose: Smad4 is a central mediator for transforming growth factor-${\beta}$/bone morphogenetic protein ($TGF-{\beta}/BMP$) signals, which are involved in regulating cranial neural crest cell formation, migration, proliferation, and fate determination. Accumulated evidences indicate that $TGF-{\beta}/BMP$ signaling plays key roles in the early tooth morphogenesis. However, their roles in the late tooth formation, such as cellular differentiation and matrix formation are not clearly understood. The objective of this study is to understand the roles of Smad4 in vivo during enamel and dentin formation through tissue-specific inactivation of Smad4. Methods: We generated and analyzed mice with dental epithelium-specific inactivation of the Smad4 gene (K14-Cre:$Smad4^{fl/fl}$) and dental mesenchyme-specific inactivation of Smad4 gene (Osr2Ires-Cre:$Smad4^{fl/fl}$). Results: In the tooth germs of K14-Cre:$Smad4^{fl/fl}$, ameloblast differentiation was not detectable in inner enamel epithelial cells, however, dentin-like structure was formed in dental mesenchymal cells. In the tooth germs of Osr2Ires-Cre:$Smad4^{fl/fl}$ mice, ameloblasts were normally differentiated from inner enamel epithelial cells. Interestingly, we found that bone-like structures, with cellular inclusion, were formed in the dentin region of Osr2Ires-Cre:$Smad4^{fl/fl}$ mice. Conclusion: Taken together, our study demonstrates that Smad4 plays a crucial role in regulating ameloblast and odontoblast differentiation, as well as in regulating epithelial-mesenchymal interactions during tooth development.

• The Korean Journal of Physiology and Pharmacology
• /
• v.19 no.5
• /
• pp.401-411
• /
• 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.

• Maxillofacial Plastic and Reconstructive Surgery
• /
• v.28 no.5
• /
• pp.445-453
• /
• 2006

Cyclosporine A (CsA) is a powerful immunosuppresive agent used to prevent graft rejection of organ and treat autoimmune disease. One of the major side effects associated with CsA treatment is the development of gingival overgrowth. The purpose of this study was to investigate the mRNA expression and association of the several growth factors in gingival overgrowth induced by CsA, respectively. Gingival fibroblasts were obtained from gingival tissues of healthy donor and the patients treated with CsA. The cultured gingival fibroblasts were incubated with increasing concentrations of CsA for 24 hours, and the expression of MMP-1, TIMP-1, $TGF-{\beta}_1$, p21 were determined by reverse transcription-polymerase chain reaction (RT-PCR). The expressions of MMP-1 was slightly increased according to the concentration of treated CsA, but there was no statistical significance. TIMP-1 showed the increased expression at the CsA concentration of 250 and 500 ng/ml and significantly decreased at the CsA concentration of 750ng/ml. $TGF-{\beta}_1$ showed the increased expression at the CsA concentration of 500 and 750 ng/ml. The expression of p21 was not changed significantly. We concluded that the gingival hyperplasia induced by CsA was more related with $TGF-{\beta}_1$ than MMP-1 or TIMP-1 on gingival collagen metabolism in patients treated with CsA.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.25 no.5
• /
• pp.807-815
• /
• 2011

This study was designed to investigate the effects of Mokhyangjoki-san extract (MJS) on the improvement in cerebral blood flow (rCBF) in cerebral ischemic rats, and further to determine cytokines production (IL-1${\beta}$, TNF-${\alpha}$, IL-10, TGF-${\beta}$) of MJS. The results in cerebral ischemic rats were as follows ; The rCBF was significantly and stably increased by MJS (10 mg/kg, i.p.) during the period of cerebral reperfusion, which contrasted with the findings of rapid and marked increase in control group. In cytokine production in serum from femoral arterial blood 1 hr after middle cerebral arterial occlusion, MJS significantly decreased IL-1${\beta}$ and TNF-${\alpha}$ production, and increased IL-10 production compared with control group. In cytokine production in serum from femoral arterial blood 1 hr after reperfusion, MJS significantly decreased IL-1${\beta}$ and TNF-${\alpha}$ production compared with control group. IL-10 and TGF-${\beta}$1 production in MJS group were significantly increased compared with control group. These results suggested that MJS significantly and stably increased rCBF by inhibiting the production IL-1${\beta}$ and TNF-${\alpha}$, and accelerating that of IL-10 and TGF-${\beta}$. The result in nerve cells was as follows ; MJS significantly inhibited lactate dehydrogenase activity in vitro in a dose-dependent manner. This result suggested that MJS prevented the neuronal death.

• Tuberculosis and Respiratory Diseases
• /
• v.55 no.2
• /
• pp.140-153
• /
• 2003

Background : The cell-mediated immune reaction to tuberculosis infection involves a complex network of cytokines. The extent of inflammation, tissue damage and severity of the disease suggested to be determined by the balance between extent and duration of the proinflammatory cytokine response versus those of the suppressive cytokines. The systemic cytokine response in pathogenesis of tuberculosis can be assessed by measuring serum cytokine levels. Method : Serum interleukin-1 beta(IL-$1{\beta}$), IL-2, IL-4, IL-6, IL-10, IL-12(p40), tumor necrosis factor-alpha(TNF-${\alpha}$), interferon-gamma(IFN-${\gamma}$) and transforming growth factor-beta(TGF-${\beta}$) levels were measured in 83 patients with pulmonary tuberculosis, 10 patients with endobronchial tuberculosis before treatment and 20 healthy subjects by using a sandwich ELISA. In patients with pulmonary tuberculosis, they were divided into mild, moderate and far advanced group according to the severity by ATS guidelines. To compare with those of pretreatment levels, we measured serum IL-$1{\beta}$, IL-2, IL-4, IL-6, IL-10, IL-12(p40), TNF-${\alpha}$, IFN-${\gamma}$ and TGF-${\beta}$ levels in 45 of 83 patients with pulmonary tuberculosis after 2 and 6 months of treatment. Results : 1) In sera of patients with active pulmonary tuberculosis(n=83), IL-$1{\beta}$, IL-6(p<0.05), TNF-${\alpha}$, and IFN-${\gamma}$ were elevated and TGF-${\beta}$ was decreased comparing to control. IL-2, Il-12(p40), IL-4 and IL-10 were similar between the patients with tuberculosis and control. 2) In endobronchial tuberculosis, IL-6 and TNF-${\alpha}$ were elevated and TGF-${\beta}$ was decreased comparing to control. IL-12(p40) seemed to be elevated comparing to pulmonary tuberculosis. 3) Far advanced tuberculosis showed markedly elevated IL-6 and IFN-${\gamma}$ level(p<0.05). 4) The significant correlations were noted between IL-1, IL-6 AND TNF-${\alpha}$ and between IL-12, Il-2 and IL-4(p<0.01). 5) After 2 and 6 months of standard treatment, the level of IL-6 and IFN-${\gamma}$ was significantly decreased(p<0.05). Conclusion : These results showed that an altered balance between cytokines is likely to be involved in the extent of inflammation, tissue damage and severity of the disease tuberculosis. But, it should be considered diversities of cytokine response according to type of tuberculosis and immunity in clinical application and interpreting future studies.

• Biomolecules & Therapeutics
• /
• v.24 no.6
• /
• pp.623-629
• /
• 2016

(1S,2S,3E,7E,11E)-3,7,11,15-cembratetraen-17,2-olide (LS-1), a marine cembrenolide diterpene, has anticancer activity against colon cancer cells such as HT-29, SNU-C5/5-FU (fluorouracil-resistant SNU-C5) and SNU-C5. However, the action mechanism of LS-1 on SNU-C5 human colon cancer cells has not been fully elucidated. In this study, we investigated whether the anticancer effect of LS-1could result from apoptosis via the modulation of $Wnt/{\beta}$-catenin and the TGF-${\beta}$ pathways. When treated with the LS-1, we could observe the apoptotic characteristics such as apoptotic bodies and the increase of sub-G1 hypodiploid cell population, increase of Bax level, decrease of Bcl-2 expression, cleavage of procaspase-3 and cleavage of poly (ADP-ribose) polymerase in SNU-C5 cells. Furthermore, the apoptosis induction of SNU-C5 cells upon LS-1 treatment was also accompanied by the down-regulation of $Wnt/{\beta}$-catenin signaling pathway via the decrease of GSK-$3{\beta}$ phosphorylation followed by the decrease of ${\beta}$-catenin level. In addition, the LS-1 induced the activation of TGF-${\beta}$ signaling pathway with the decrease of carcinoembryonic antigen which leads to decrease of c-Myc, an oncoprotein. These data suggest that the LS-1 could induce the apoptosis via the down-regulation of $Wnt/{\beta}$-catenin pathway and the activation of TGF-${\beta}$ pathway in SNU-C5 human colon cancer cells. The results support that the LS-1 might have potential for the treatment of human colon cancer.