• Radiation Oncology Journal
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• 제17권3호
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• pp.238-248
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• 1999

목적 : 방사선조사 후 발생하는 폐손상을 형태학적 측면에서 평가하고 captopril의 방사선조사 후 폐손상의 경감효과가 있는지를 확인하고 captopril의 방사선에 의한 폐손상의 영향에서 TNF-${\alpha}$와 TGF-${\beta}$의 변화을 알아보고자 하였다. 재료 및 방법 : Sprague-Dawley 종 수컷 흰쥐 30마리를 골라 방사선조사만 한 군, 방사선조사 후 captopril을 투여한 군으로 나누어 실험하였다. 방사선조사는 10 Gy, 20 Gy, 30 Gy를 우측 폐에 조사하였다. 방사선 단독 조사군은 방사선조사 후 각각 12 시간, 11주 후에 도살하고 방사선조사 후 captopril을 투여한 군(captopril 500 mg/L를 증류수에 타서 먹임)은 11주(fibrotic period) 후에 도살하여 광학현미경과 전자현미경으로 관찰하였다. 결과 : 방사선조사 후 12 시간내의 실험군의 폐는 부분적으로 폐실질의 허탈과 경화가 방사선조사량이 많아질수록 그 정도와 범위가 증가하였다. 방사선조사 후 11주에는 방사선 단독 조사군에서 폐섬유화의 정도와 범위가 방사선조사량이 많아질수록 증가하였고 captopril을 함께 사용한 군에서 방사선조사 단독군에 비해 폐섬유화의 경감효과가 현저하였다. 방사선 단독군에서는 방사선량이 많아질수록 비만세포의 수는 급격히 증가하였으며 Captoprll을 사용한 군이 사용하지 않은 군과 비교하여 비만세포 수의 증가 정도는 현저히 낮았고 교원질 침착의 정도도 현저히 감소되었다. TNF-${\alpha}$, TGF-${\beta}$는 방사선조사 직후(12 시간) 군에서는 방사선량이 증가함에 따라 그 발현이 증가하였으나 방사선조사 후 11주군에서는 TGF-${\beta}$는 방사선량이 많아짐에 따라 그 발현이 증가하였으며 captopril 투여군에서는 그 발현이 다소 감소하였다. Captopril을 사용한 군에서는 교원질의 양은 증가하였으나 방사선 단독군에 비해 교원질의 양이 적었고 혈관주위 비후의 정도와, 모세혈관의 변화정도, mast Cell의 수와 탈과립, 섬유모세포의 수도 적었다. 결론 : 방사선조사후 방사선 폐렴에서 captopril 영향은 방사선에 의한 비만세포의 출현을 억제시키고 교원질의 침착을 감소시킴으로써 방사선에 의한 섬유화를 예방할 것으로 생각된다. TNF-${\alpha}$와 TGF-${\beta}$의 발현은 방사선조사 후 초기에 증가하며 TGF-${\beta}$는 방사선조사 후 만성기에 방사선량이 많아질수록 발현이 증가하는 것으로 판단되었다. 본 연구 결과는 Captopril이 방사선조사 후 발생하는 폐손상을 감소시키는 기전을 밝히는 향후 연구에 중요한 자료가 될 것으로 생각된다.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• 제23권4호
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• pp.346-355
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• 2020

Purpose: Peroxisome proliferator-activated receptor gamma (PPAR-γ) has a key role in hepatic fibrogenesis by virtue of its effect on the hepatic stellate cells (HSCs). Although many studies have shown that PPAR-γ agonists inhibit liver fibrosis, the mechanism remains largely unclear, especially regarding the cross-talk between PPAR-γ and other potent fibrogenic factors. Methods: This experimental study involved 25 male Wistar rats. Twenty rats were subjected to bile duct ligation (BDL) to induce liver fibrosis, further divided into an untreated group (BDL; n=10) and a group treated with the PPAR-γ agonist thiazolidinedione (TZD), at 14 days post-operation (BDL+TZD; n=10). The remaining 5 rats had a sham operation (sham; n=5). The effect of PPAR-γ agonist on liver fibrosis was evaluated by histopathology, protein immunohistochemistry, and mRNA expression quantitative polymerase chain reaction. Results: Histology and immunostaining showed markedly reduced collagen deposition, bile duct proliferation, and HSCs in the BDL+TZD group compared to those in the BDL group (p<0.001). Similarly, significantly lower mRNA expression of collagen α-1(I), matrix metalloproteinase-2, platelet-derived growth factor (PDGF)-B chain, and connective tissue growth factor (CTGF) were evident in the BDL+TZD group compared to those in the BDL group (p=0.0002, p<0.035, p<0.0001, and p=0.0123 respectively). Moreover, expression of the transforming growth factor beta1 (TGF-β1) was also downregulated in the BDL+TZD group (p=0.0087). Conclusion: The PPAR-γ agonist inhibits HSC activation in vivo and attenuates liver fibrosis through several fibrogenic pathways. Potent fibrogenic factors such as PDGF, CTGF, and TGF-β1 were downregulated by the PPAR-γ agonist. Targeting PPAR-γ activity may be a potential strategy to control liver fibrosis.

• 대한한의학방제학회지
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• 제31권3호
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• pp.157-169
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• 2023

Gracilaria Verrucosa (GV), a seaweed used in traditional Korean medicine, was studied for its effects on MI-induced heart failure in rats. MI is caused by a blocked coronary artery, leading to severe cardiac dysfunction. The study used a rat model to assess cardiac changes over time and evaluate the impact of GV on heart failure. Ischemia was induced through LAD ligation surgery, and the extent of ischemic area was measured as a prognostic factor. GV extract administration significantly improved cardiac morphology and reduced cardiac weight compared to the MI group. GV treatment also improved cardiac function, as evidenced by positive effects on chamber dilation during MI-induced heart failure. Parameters such as ejection fraction (EF) and fractional shortening (FS) were measured. The MI group showed decreased EF and FS compared to the sham group, while these parameters improved in the GV group. GV treatment also reduced levels of LDH, CPK, and CK-MB in the serum, indicating reduced myocardial damage. Histological analysis revealed that GV treatment attenuated cardiac hypertrophy and fibrosis, with reduced collagen deposition in the myocardium. Immunohistochemistry analysis showed suppressed expression of TGF-β1 and collagen 1, involved in fibrosis. In conclusion, GV showed potential in improving cardiac function in a rat model of MI-induced heart failure. It alleviated myocardial damage, attenuated cardiac hypertrophy and fibrosis, and suppressed fibrotic markers. Further studies are needed to explore its clinical efficacy and underlying mechanisms in cardiac diseases beyond animal models.

• Journal of Ginseng Research
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• 제47권4호
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• pp.515-523
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• 2023

Background: 20(S)-protopanaxadiol (PPD), one of the main components of ginseng, has anti-inflammatory, anti-estrogenic, and anti-tumor activities. It is known that activated hepatic stellate cells (HSCs) are the primary producers of extracellular matrix (ECM) in the liver, and the Wnt/β-catenin pathway participates in the activation of HSCs. We aimed to explore whether PPD inhibits liver fibrosis is associated with the Wnt/β-catenin pathway inactivation. Methods: The anti-fibrotic roles of PPD were examined both in vitro and in vivo. We also examined the levels of Wnt inhibitory factor 1 (WIF1), DNA methyltransferase 1 (DNMT1) and WIF1 methylation. Results: PPD obviously ameliorated liver fibrosis in carbon tetrachloride (CCl₄)-treated mice and reduced collagen deposition. PPD also suppressed the activation and proliferation of primary HSCs. Notably, PPD inhibited the Wnt/β-catenin pathway, reduced TCF activity, and increased P-β-catenin and GSK-3β levels. Interestingly, WIF1 was found to mediate the inactivation of the Wnt/β-catenin pathway in PPD-treated HSCs. WIF1 silencing suppressed the inhibitory effects of PPD on HSC activation and also restored α-SMA and type I collagen levels. The downregulation of WIF1 expression was associated with the methylation of its promoter. PPD induced WIF1 demethylation and restored WIF1 expression. Further experiments confirmed that DNMT1 overexpression blocked the effects of PPD on WIF1 expression and demethylation and enhanced HSC activation. Conclusion: PPD up-regulates WIF1 levels and impairs Wnt/β-catenin pathway activation via the downregulation of DNMT1-mediated WIF1 methylation, leading to HSC inactivation. Therefore, PPD may be a promising therapeutic drug for patients with liver fibrosis.

• Archives of Plastic Surgery
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• 제38권6호
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• pp.733-739
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• 2011

Purpose: Cellulose is a natural substance from plants or bacteria. It is known that bacterial synthesized cellulose has an effect of wound healing. The aim of this study is to show the effect of bacterial synthesized cellulose from citrus on wound healing. Methods: Three full-thickness skin defects were made on the back of Sprague-Dawley rats. Three wounds were treated by vaseline gauze (Group V), Algisite $M^{(R)}$ (Group A) and bacterial synthesized cellulose from citrus (Group C) was used for dressing on skin defect on rats. We analyzed the gross, histological and biochemistry finding. Results: Group C showed more decrease of wound size compared to Group V (33% versus 7.2%) after 14 days. The histologic findings revealed Group C and Group A preceed the process of wound healing rather than Group V (More rapid collagen deposition and neovascularization and reduced inflammation). Also, the expressions of vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-${\beta}1$ were increased in the Group C and Group A compared with the Group V in 7 days. VEGF and TGF-${\beta}1$ expression were decreased in the Group C and Group A in 14 days, however Group V was not decreased at 14 day because of delayed wound healing process. Conclusion: Bacterial synthesized cellulose from citrus affects wound healing by reducing the inflammatory stage. And stimulates wound contracture by the deposition of extracellular matrix, thus preventing the formation of chronic wounds.

• The Journal of Advanced Prosthodontics
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• 제7권6호
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• pp.496-505
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• 2015

PURPOSE. To determine the effect of fibronectin (FN)-conjugated, microgrooved titanium (Ti) on osteoblast differentiation and gene expression in human bone marrow-derived mesenchymal stem cells (MSCs). MATERIALS AND METHODS. Photolithography was used to fabricate the microgrooved Ti, and amine functionalization (silanization) was used to immobilize fibronectin on the titanium surfaces. Osteoblast differentiation and osteoblast marker gene expression were analyzed by means of alkaline phosphatase activity assay, extracellular calcium deposition assay, and quantitative real-time PCR. RESULTS. The conjugation of fibronectin on Ti significantly increased osteoblast differentiation in MSCs compared with non-conjugated Ti substrates. On the extracellular calcium deposition assays of MSCs at 21 days, an approximately two-fold increase in calcium concentration was observed on the etched 60-${\mu}m$-wide/10-${\mu}m$-deep microgrooved surface with fibronectin (E60/10FN) compared with the same surface without fibronectin (E60/10), and a more than four-fold increase in calcium concentration was observed on E60/10FN compared with the non-etched control (NE0) and etched control (E0) surfaces. Through a series of analyses to determine the expression of osteoblast marker genes, a significant increase in all the marker genes except type I collagen ${\alpha}1$ mRNA was seen with E60/10FN more than with any of the other groups, as compared with NE0. CONCLUSION. The FN-conjugated, microgrooved Ti substrate can provide an effective surface to promote osteoblast differentiation and osteoblast marker gene expression in MSCs.

• 대한본초학회지
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• 제36권1호
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• pp.59-66
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• 2021

Objectives : Forsythiae Fructus has been reported to have anti-inflammatory effects in many diseases, and Corydalis Tuber has been used as a pain suppressor in Eastern Asia. However, the protective effects of individual water extract of Forsythiae Fructus (FF) and Corydalis Tuber (CT) and the mixture of FF and CT (FC) on chronic pancreatitis (CP) were not well-investigated. Therefore, we investigated the protective effects of FF, CT, and FC on CP in mice. Methods : To induce CP, cerulein was injected 6 times a day, 4 times a week for 3 weeks. 1 h before the every cerulein injection, 200 mg/kg of FF, CT, or FC was intraperitoneally injected to mice. Histological analysis of pancreas was examined by hematoxylin and eosin stain and collagen deposition was examined by Masson's trichrome stain. Fibrogenic parameters such as α-smooth muscle actin (α-SMA), extracellular matrix (ECM) deposition, and fibrotic cytokines such as transforming growth factor (TGF)-β1 and platelet-derived growth factor (PDGF) were also analyzed by immunofluorescence stain and real-time PCR. Results : Histological damages in pancreas were inhibited by pre-treatment of FF or FC but not CT. α-SMA and ECM in pancreas were inhibited by pre-treatment of CT or FC but not FF. Moreover, the expression of TGF-β1 and PDGF in pancreas were inhibited by FF, CT or FC. Conclusions : Our results suggest that FC have protective effect on CP in mice through inhibition of α-SMA, ECM, TGF-β1 and PDGF in pancreas, and these findings could suggest new clinical strategy for CP.

• Biomolecules & Therapeutics
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• 제21권5호
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• pp.371-380
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• 2013

Doxorubicin is still main drug in chemotherapy with limitation of use due to adverse drug reaction. Increased oxidative stress and alteration of nitric oxide control have been involved in cardiotoxicity of doxorubicin (DOX). A Disintegrin And Metalloproteinase (ADAMs) are transmembrane ectoproteases to regulate cell-cell and cell-matrix interactions, but role in cardiac disease is unclear. The aim of this study was to determine whether DOX activates peroxynitrite and ADAM 10 and thus ADAM and matrix metalloproteinase (MMP) induce cardiac remodeling in DOX-induced cardiomyopathy. Adult male Sprague-Dawley rats were subjected to cardiomyopathy by DOX (6 times of 2.5 mg/kg DOX over 2-weeks), and were randomized as four groups. Then followed by 3, 5, 7, and 14 days after cessation of DOX injection. DOX-injected animals significantly decreased left ventricular fractional shortening compared with control by M-mode echocardiography. The expressions of cardiac nitrotyrosine by immunohistochemistry were significant increased, and persisted for 2 weeks following the last injection. The expression of eNOS was increased by 1.9 times (p<0.05), and iNOS was marked increased in DOX-heart compared with control (p<0.001). Compared to control rats, cardiac ADAM10- and MMP 9- protein expressions increased by 20 times, and active/total MMP 9 proteolytic activity showed increase tendency at day 14 after cessation of DOX injection (n=10, each group). DOX-treated $H_9C_2$ cell showed increased ADAM10 protein expression with dose-dependency (p<0.01) and morphometric changes showed the increase of ventricular interstitial, nonvascular collagen deposition. These data suggest that activation of cardiac peroxynitrite with increased iNOS expression and ADAM 10-dependent MMP 9 expression may be a molecular mechanism that contributes to left ventricular remodeling in DOXinduced cardiomyopathy.

• Toxicological Research
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• 제26권3호
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• pp.217-222
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• 2010

Many studies have reported that bleomycin, anti-cancer drug, induces pulmonary fibrosis as a side effect. However, few investigations have focused on the dose-response effects of bleomycin on pulmonary fibrosis. Therefore, in the present study, we investigated the effects of different doses of bleomycin in male mice. ICR mice were given 3 consecutive doses of bleomycin: 1, 2, or 4 mg/kg in bleomycin-treated (BT) groups and saline only in vehicle control (VC) groups. The animals were sacrificed at 7 and 24 days postinstillation. The severity of pulmonary fibrosis was evaluated according to inflammatory cell count and lactate dehydrogenase (LDH) activity in the broncho alveolar lavage fluid (BALF), and lung tissues were histologically evaluated after hematoxylin and eosin (H&E), and Masson's trichrome staining. BT groups exhibited changed cellular profiles in BAL fluid compared to the VC group, which had an increased number of total cells, neutrophils, and lymphocytes and a modest increase in the number of macrophages at 7 days post-bleomycin instillation. Moreover, BT groups showed a dose-dependent increase in LDH levels and inflammatory cell counts. However, at 24 days after treatment, collagen deposition, interstitial thickening, and granulomatous lesions were observed in the alveolar spaces in addition to a decrease in inflammatory cells. These results indicate that pulmonary fibrosis induced by 4 mg/kg bleomycin was more severe than that induced by 1 or 2 mg/kg. These data will be utilized in experimental animal models and as basic data to evaluate therapeutic candidates through non-invasive monitoring using the pulmonary fibrosis mouse model established in this study.

• Tuberculosis and Respiratory Diseases
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• 제69권5호
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• pp.337-347
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• 2010

Background: Transglutaminase-2 (TG-2) has been reported to play an important role in the process of fibrosis. However, TG-2 studies on fibroproliferation of acute lung injury (ALI) are absent. The purpose of this study was to investigate the role of TG-2 in the fibroproliferation of lipopolysaccharide (LPS)-induced ALI. Methods: The male C57BL/6 mice of 5 weeks age were divided into 3 groups; control group (n=30) in which $50{\mu}L$ of saline was given intratracheally (IT), LPS group (n=30) in which LPS 0.5 mg/kg/$50{\mu}L$ of saline was given IT, and LPS+Cyst group treated with intraperitoneal 200 mg/kg of cystamine, competitive inhibitor of TG-2, after induction of ALI by LPS. TG-2 activity and nuclear factor $(NF)-{\kappa}B$ were measured in lung tissue homogenate. Tumor necrosis factor (TNF)-${\alpha}$, interleukin (IL)-$1{\beta}$, IL-6, myeloperoxidase (MPO), and transforming growth factor (TGF)-${\beta}1$ were measured using bronchoalveolar lavage fluids. Histopathologic ALI score and Mallory's phosphotunistic acid hematoxylin (PTAH) for collagen and fibronectin deposition were performed. Results: The TG-2 activities in the LPS group were significantly higher than the control and LPS+Cyst groups (p<0.05). The TNF-${\alpha}$ and IL-$1{\beta}$ concentrations and $NF-{\kappa}B$ activity were lower in the LPS+Cyst group than the LPS group (p<0.05). The LPS+Cyst group showed lower MPO, ALI score, TGF-${\beta}1$ concentration, and Mallory's PTAH stain than the LPS group, but the differences were not significant (p>0.05). Conclusion: Inhibition of TG-2 activity in the LPS-induced ALI prevented early inflammatory parameters, but had limited effects on late ALI and fibroproliferative parameters.