• Clinical and Experimental Reproductive Medicine
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• v.47 no.2
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• pp.108-113
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• 2020

Objective: Endometrial fibrosis, the primary pathological feature of intrauterine adhesion, may lead to disruption of endometrial tissue structure, menstrual abnormalities, infertility, and recurrent pregnancy loss. At present, no ideal therapeutic strategy exists for this fibrotic disease. Eupatilin, a major pharmacologically active flavone from Artemisia, has been previously reported to act as a potent inducer of dedifferentiation of fibrotic tissue in the liver and lung. However, the effects of eupatilin on endometrial fibrosis have not yet been investigated. In this study, we present the first report on the impact of eupatilin treatment on transforming growth factor beta (TGF-β)-induced endometrial fibrosis. Methods: The efficacy of eupatilin on TGF-β-induced endometrial fibrosis was assessed by examining changes in morphology and the expression levels of fibrosis markers using immunofluorescence staining and quantitative real-time reverse-transcription polymerase chain reaction. Results: Eupatilin treatment significantly reduced the fibrotic activity of TGF-β-induced endometrial fibrosis in Ishikawa cells, which displayed more circular shapes and formed more colonies. Additionally, the effects of eupatilin on fibrotic markers including alpha-smooth muscle actin, hypoxia-inducible factor 1 alpha, collagen type I alpha 1 chain, and matrix metalloproteinase-2, were evaluated in TGF-β-induced endometrial fibrosis. The expression of these markers was highly upregulated by TGF-β pretreatment and recovered to the levels of control cells in response to eupatilin treatment. Conclusion: Our findings suggest that suppression of TGF-β-induced signaling by eupatilin might be an effective therapeutic strategy for the treatment of endometrial fibrosis.

• Molecules and Cells
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• v.39 no.8
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• pp.625-630
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• 2016

The RNA-binding protein Rbfox3 is a well-known splicing regulator that is used as a marker for post-mitotic neurons in various vertebrate species. Although recent studies indicate a variable expression of Rbfox3 in non-neuronal tissues, including lung tissue, its cellular function in lung cancer remains largely unknown. Here, we report that the number of RBFOX3-positive cells in tumorous lung tissue is lower than that in normal lung tissue. As the transforming growth factor-${\beta}$ (TGF-${\beta}$) signaling pathway is important in cancer progression, we investigated its role in RBFOX3 expression in A549 lung adenocarcinoma cells. TGF-${\beta}1$ treatment inhibited RBFOX3 expression at the transcriptional level. Further, RBFOX3 depletion led to a change in the expression levels of a subset of proteins related to epithelial-mesenchymal transition (EMT), such as E-cadherin and Claudin-1, during TGF-${\beta}1$-induced EMT. In immunofluorescence microscopic analysis, mesenchymal morphology was more prominent in RBFOX3-depleted cells than in control cells. These findings show that TGF-${\beta}$-induced RBFOX3 inhibition plays an important role in EMT and propose a novel role for RBFOX3 in cancer progression.

• Biomaterials and Biomechanics in Bioengineering
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• v.2 no.1
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• pp.23-32
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• 2015

Facile immobilization of growth factors in hyaluronic acid (HA) hydrogels using dual enzymes is reported in the paper. The hydrogels were formed by using horseradish peroxidase (HRP) and hydrogen peroxide ($H_2O_2$) and transforming growth factor-${\beta}3$ (TGF-${\beta}3$) was covalently conjugated on the hydrogels in situ using tyrosinase (Ty) without any modifications. For the preparation of hydrogels, HA was grafted with poly(ethylene glycol) (PEG), which was modified with a tyrosine. The gelation times of the HA hydrogels were ranging from 415 to 17 s and the storage moduli was dependent on the concentration of $H_2O_2$ and Ty (470-1600 Pa). A native TGF-${\beta}3$ (200 ng/mL) was readily encapsulated in the HA hydrogels and 17% of the TGF-${\beta}3$ was released over 1 month at the Ty concentration of 0.5 KU/mL, while the release was faster when 0.3 KU/mL of Ty was used for the encapsulation (27%). It can be suggested that the growth factors resident in the hydrogels for a long period of time may lead cells proliferating and differentiating, whereas the growth factors that are initially released from the hydrogels can induce the ingrowth of cells into the matrices. Therefore, the dual enzymatic methods as facile gel forming and loading of various native growth factors or therapeutic proteins could be highly promising for tissue regenerative medicines.

• Korean Journal of Pharmacognosy
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• v.48 no.2
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• pp.148-154
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• 2017

Crinum asiaticum var. japonicum and its active component, norgalanthamine have been reported to have hair growth-promoting effect via the proliferation of dermal papilla cells. In this study, we investigated the other mechanisms of C. asiaticum extract var. japonicum and norgalanthamine on the hair growth. The C. asiaticum var. japonicum extract inhibited $5{\alpha}$-reductase activity by 16%, which converts testosterone to dihydrotestosterone (DHT), a main cause of androgenetic alopecia, whereas the C. asiaticum var. japonicum extract didn't function as an opener of the $K_{ATP}$ channel. On the other hand, we examined whether norgalanthamine can inhibit transforming growth factor-${\beta}$ (TGF-${\beta}$) signal pathway, which is essential in the regression induction of hair growth. Norgalanthamine inhibited the phosphorylation of Smad2/3 on TGF-${\beta}1$-induced canonical pathway in human keratinocyte HaCaT cells. These results suggested that the C. asiaticum var. japonicum extract and norgalanthamine had the potential to influence hair growth through the inhibition of $5{\alpha}$-reductase activity and TGF-${\beta}1$-induced canonical pathway.

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

• The Journal of Korean Medicine
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• v.30 no.6
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• pp.35-43
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• 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-${\beta}1$.

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

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

• Archives of Pharmacal Research
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• v.28 no.8
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• pp.948-955
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• 2005

Glomerular mesangial cells (GMCs) in diverse renal diseases undergo cell proliferation and/or hypertrophy, and gangliosides have been reported to play an important role in modulating cell structure and function. This study compared the effects of transforming growth $factor-\beta\; (TGF­\beta1)$ and the effects of the application of exogenous gangliosides on GMCs and investigated whether the application of exogenous gangliosides regulated cellular proliferation and hypertrophy. Human GMCs were cultured with exogenous gangliosides and $TGF-\beta1$ in a media containing $10\%$ fetal bovine serum and in a media without the fetal bovine serum. Exogenous gangliosides biphasically changed the proliferation of human GMCs (0.1-1.0 mg/mL). A low concentration (0.1 mg/mL) of gangliosides mainly increased the number of human GMCs, whereas cellular proliferation was significantly reduced by raising the concentration of exogenous gangliosides. $TGF-\beta1$ greatly reduced the number of human GMCs in a concentration­dependent manner (1-10 ng/mL). Serum deprivation accelerated the gangliosides- and $TGF­\beta1-induced$ inhibition of mesangial cell proliferation to a greater extent. Gangliosides (1.0 mg/ mL) and $TGF-\beta1$ (10 ng/mL) both caused a significant increase in the incorporation of $[^3H]leucine$ per cell in the serum-deprived condition, whereas it was completely reversed in serum­supplemented condition. Similar results to the $[^3H]leucine$ incorporation were also observed in the changes in cell size measured by flow cytometric analysis. These results show that exogenous gangliosides modulate cell proliferation and hypertrophy in cultured human GMCs, and these cellular responses were regulated differently based on whether the media contained serum or not. Results from the present study raise new possibilities about the potential involvement of gangliosides in the development of mesangial cell proliferation and hypertrophy.

• 대한예방의학회:학술대회논문집
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• 2002.10a
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• pp.539-540
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• 2002