• 대한약학회:학술대회논문집
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• 대한약학회 2000년도 춘계총회 및 학술대회
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• pp.211.1-211.1
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• 2000

• 약학회지
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• 제40권5호
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• pp.550-557
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• 1996

One of therapeutics in liver disease (morbus wilson) is D-penicillamin (D-pen: D-3-mercapto-valin). Especially the cross-linking of collagen molecules could be inhibited by D-pe n in extracellular space. In this study we investigated the antifibrotic effects of D-pen in rats that were induced the liver fibrosis by bile duct ligation and scission (BDL/S). Rats were treated for 4 weeks with D-pen after BDL/S operation or sham operation. The balance between fibrogenesis-marker (PNIIIP) and the fibrolysis-maker (PNIVP) were observed in sera by RIA (radioimmunoassay), and the parameter of collagen deposition in liver tissue (hydroxyproline: HYP) was measured by colorimetry. The weight of liver in BDL/S operated group was increased significantly in compared with sham operation group (15.2g${\pm}$1.1, vs 11.9g${\pm}$3.9: p<0.005, p<0.05). The rats group treated by D-pen showed the lower level of PNIIIP (6.7ng/ml${\pm}$1.5, vs 9.5ng/ml${\pm}$2.8) and the higher value of PIVCP (14.0ng/ml${\pm}$1.9, vs 7.9ng/ml${\pm}$1.5) in sera that compared to untreated rats. The content of HYP was decreased by 141% in BDL/S with D-pen treated group than that of it in BDL/S group. No correlation was revealed between collagen parameters in sera and HYP in liver tissue of BDL/S operated and D-pen treated rats. The group treated with D-pen showed the lower value of clinical biochemistry parameters (GOT: glutamate oxalacetate transaminase, Total-Bilirubin) in compared with only BDL/S operated rats, but the value of GPT (glutamate pyruvate transaminase) and Alkaline phosphatase in two BDL/S groups was nearly same. In the histological finding, we observed mild bile duct proliferation, weak inflammation and fibrosis in BDL/S with D-pen treated group, but BDL/S operated group showed the formation of septum (island of hepatocytes), massive bile duct proliferation. This result represents that the BDL/S operation induces liver fibrosis (cirrhosis) in 4 weeks, and D-pen inhibits the synthesis of collagen weakly and stimulates the degradation of collagen in the extracellular space. We conclude that the monitoring of PNIIIP, PIVCP in sera is useful parameter for screening of antifibrotic effect, and D-pen delay the liver fibrosis.

• Asian Pacific Journal of Cancer Prevention
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• 제13권1호
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• pp.289-294
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• 2012

Background: Myofibroblasts play an important role in the development of oral submucous fibrosis (OSF). In the current study, we investigate the effect of curcumin on growth and apoptosis of myofibroblasts derived from human oral mucosa. Methods: Myofibroblasts were generated by incubating fibroblasts, obtained from human oral mucosa, with transforming growth factor-${\beta}1$ (TGF-${\beta}1$). MTT, PI staining, and FACS assays were used to investigate curcumin's effect on proliferation and cell cycle of fibroblasts and myofibroblasts. Annexin V/PI binding and FACS assays were used to examine apoptosis of myofibroblasts, Western blotting to determine the levels of Bcl-2 and Bax, and enzyme-linked immunosorbant assay was employed to examine the levels of collagen type I and III in the supernatants of myofibroblasts. Results: Curcumin inhibits proliferation of fibroblasts and myofibroblasts; it also disturbs the cell cycle, induces apoptosis and decreases the generation of collagen type I and III in myofibroblasts, which are more sensitive to its effects than fibroblasts. Curcumin induces apoptosis in myofibroblasts by down-regulating the Bcl-2/ Bax ratio. Conclusion: Our results demonstrate the antifibrotic effect of curcumin in vitro. It may therefore be a candidate for the treatment of OSF.

• Biomolecules & Therapeutics
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• 제31권5호
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• pp.484-495
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• 2023

Idiopathic pulmonary fibrosis (IPF) can be defined as a progressive chronic pulmonary disease showing scarring in the lung parenchyma, thereby resulting in increase in mortality and decrease in the quality of life. The pathophysiologic mechanism of fibrosis in IPF is still unclear. Repetitive microinjuries to alveolar epithelium with genetical predisposition and an abnormal restorative reaction accompanied by excessive deposition of collagens are involved in the pathogenesis. Although the two FDA-approved drugs, pirfenidone and nintedanib, are under use for retarding the decline in lung function of patients suffered from IPF, they are not able to improve the survival rate or quality of life. Therefore, a novel therapeutic agent acting on the major steps of the pathogenesis of disease and/or, at least, managing the clinical symptoms of IPF should be developed for the effective regulation of this incurable disease. In the present review, we tried to find a potential of managing the clinical symptoms of IPF by natural products derived from medicinal plants used for controlling the pulmonary inflammatory diseases in traditional Asian medicine. A multitude of natural products have been reported to exert an antifibrotic effect in vitro and in vivo through acting on the epithelial-mesenchymal transition pathway, transforming growth factor (TGF)- β-induced intracellular signaling, and the deposition of extracellular matrix. However, clinical antifibrotic efficacy of these natural products on IPF have not been elucidated yet. Thus, those effects should be proven by further examinations including the randomized clinical trials, in order to develop the ideal and optimal candidate for the therapeutics of IPF.

• Journal of Applied Biological Chemistry
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• 제66권
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• pp.138-143
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• 2023

Liver fibrosis is caused by metabolic problems such as cholestasis, genetic problems, or viral infections. Inhibiting hepatic stellate cell (HSC) activation or inducing selective apoptosis of activated HSCs is used as a treatment strategy for liver fibrosis. It has been reported that when HSCs are activated, their apoptosis sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is enhanced because the expression of death receptor 5 is elevated. Finding a natural compound that can enhance the apoptotic effect of TRAIL on HSCs is a necessary strategy for liver fibrosis treatment. It was confirmed here that mangosteen-derived gartanin increased the effect of TRAIL-induced apoptosis by increasing the expression of DR5 in a p38-dependent manner in the hepatic stellate cell line LX-2. Combined treatment with gartanin and TRAIL accelerated DNA cleavage through caspase-3 activation and enhanced antifibrotic effects in LX-2 cells.

• Biomolecules & Therapeutics
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• 제10권1호
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• pp.12-18
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• 2002

Silymarin and curcumin have been used for supportive treatment of liver disease of difffrent etiology due to their hepatoprotective activities. The present study was carried out to investigate the hepatoprotective efffcts of silymarin and/or curcuma extract against hepatotoxins induced liver injury. To investigate hepatoprotective effects, the silymarin and/or curcuma extract were pre-treated orally to experimental animals. And thereafter a single dose of hepatotoxin, carbon tetrachloride ($CCl_4$) and acetaminophen were administered through oral or intraperitoneal route, respectively. Chronic liver damage was induced by subcutaneous injection of $CCl_4$ for 3 weeks (2 times/week). Hepatoprotective and therapeutic effects were monitored by estimating serurn ALT and AST levels and by measuring hepatic glutathione (GSH) and malondialdehyde (MDA)levels. Collagen type 1 was detected with irnrnunostaining to assess fibrosis. The results showed that the mix-ture of silymarin and curcuma extract significantly reduced serum biochemistry levels and MDA levels com-pared with those of control group in both acute and chronic animal models. In antifibrotic effect, the relative hepatic collagen content was significantly decreased by silymarin and/or curcuma extract treatment. It was concluded that the complex of silymarin and curcuma extract have a both hepatoprotective and therapeutic effect synergically in rat liver injury induced by heptotoxins.

• 동의생리병리학회지
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• 제17권1호
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• pp.118-122
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• 2003

Oxidative stress and its consequent lipid peroxidation exert harmful effects, which have been currently involved in the generation of carbon tetrachloride (CCl₄)-induced fibrosis(cirrhosis). In this study, it was investigated whether dried extract of 田螺(Concha Cipangopaludinae; CC) has liver functional improvement, antioxidative and antifibrotic effect in rats those were induced liver fibrosis by CCl₄ administration. The female Sprague-Dawley rats were divided into 3 groups(Normal, AC, AC-CC) and were observed in 6 weeks. Except for normal group, liver fibrosis(cirrhosis) in rats were developed by CCl₄ administration(0.8 ㎖/rat/week). And the rats were treated with prepared CC(p. o. 2 ㎖/day/rat). At the time of sacrifice, the liver, kidney and spleen were weighed and the ratio of organ weight/body weight was calculated. The MDA, hyp and biochemical parameters(AST, ALT, ALP, t-bili) were measured in sera and liver tissue of rats. The strong yellow color of urine was observed in all CCl₄-treated group compared with normal group, but jaundice didn't appear in CCl₄-treated group. The mortality of CCl₄-treated group is very low(<13%) during 6 weeks of observation time. The ratio of liver/body as well as the weight of liver in CCl₄-treated rats significantly increased compared with that in normal group(p<0.001). The level of clinical parameters in sera of all liver fibrosis(cirrhosis) developed rats were significantly higher than that of normal group(p<0.001-0.05). Especially the value of BUN, ALP, t-bilirubin in AC-CC group showed 20.9%, 19.6%, 47.9% lower than that in AC group. The content of hyp in CCl₄-treated rats was significantly higher than normal group(p<0.001～<0.05), and showed 12.2% lower value in the AC-CC group than AC group(p<0.05). The production of lipid peroxidation(MDA) in sera and liver tissue significantly increased under the fibrotic(cirrhotic) condition(p<0.001～<0.05). Especially the MDA value of AC-CC group in sera significantly 46.5% decreased compared with that of AC group(p<0.05), and the MDA value of AC-CC in liver tissue showed 21.4% lower than that of AC group. Concha Cipangopaludinae can be improved hepatic function, and maybe have effect of liver protection, antioxidation and antifibrosis.

• 대한치과교정학회지
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• 제50권6호
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• pp.391-400
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• 2020

Objective: Increased gingival elasticity has been implicated as the cause of relapse following orthodontic rotational tooth movement and approaches to reduce relapse are limited. This study aimed to investigate the effects of sulforaphane (SFN), an inhibitor of osteoclastogenesis, on gene expression in gingival fibroblasts and relapse after rotational tooth movement in beagle dogs. Methods: The lower lateral incisors of five beagle dogs were rotated. SFN or dimethylsulfoxide (DMSO) were injected into the supra-alveolar gingiva of the experimental and control group, respectively, and the effect of SFN on relapse tendency was evaluated. Changes in mRNA expression of extracellular matrix components associated with gingival elasticity in beagles were investigated by real-time polymerase chain reaction. Morphology and arrangement of collagen fibers were observed on Masson's trichrome staining of buccal gingival tissues of experimental and control teeth. Results: SFN reduced the amount and percentage of relapse of orthodontic rotation. It also decreased the gene expression of lysyl oxidase and increased the gene expression of matrix metalloproteinase (MMP) 1 and MMP 12, compared with DMSO control subjects. Histologically, collagen fiber bundles were arranged irregularly and were not well connected in the SFN-treated group, whereas the fibers extended in parallel and perpendicular directions toward the gingiva and alveolar bone in a more regular and well-ordered arrangement in the DMSO-treated group. Conclusions: Our findings demonstrated that SFN treatment may be a promising pharmacologic approach to prevent orthodontic rotational relapse caused by increased gingival elasticity of rotated teeth in beagle dogs.

• Journal of Applied Biological Chemistry
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• 제50권2호
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• pp.78-84
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• 2007

The anti-fibrotic effects of hot water extract of adventitious root culture of Panax ginseng (ARCP) and the possible mechanisms were investigated on $CCl_4-induced$ hepatotoxicity model mice. Fibrosis was induced by a mild treatment of $CCl_4$. Then silymarin as a positive control drug and ARCP or carrier alone as a negative control were treated. Serum GPT, GOT and ALP activity levels were lowered by 25, 21 and 11% for silymarin treated group and by 48, 39 and 14% for ARCP treated group compared to carrier treated alone. Hepatic collagen for ARCP treatment group was reduced by 18% and MDA contents decreased a little more. Pro-fibrotic gene ($TGF-{\beta}1$, TIMP-1 and ${\alpha}-SMA$) expression increased following the $CCl_4$ treatment, but both the silymarin and the ARCP treatments decreased the expressions of these genes by 20% to 50%. The antioxidant effect of ARCP was studied by DPPH free radical scavenging activity. In addition, a generation of reactive oxygen species (ROS) was also reduced in $H_2O_2-treated$ HepG2 cells upon the ARCP treatment. In summary, ARCP has antioxidant property, and can have some protection against oxidative stress; more importantly, ARCP can efficiently protect mice against $CCl_4-induced$ fibrosis.

• Tuberculosis and Respiratory Diseases
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• 제79권4호
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• pp.257-266
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• 2016

Background: Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet. NADH:quinone oxidoreductase 1 (NQO1) is a homodimeric enzyme that catalyzes the oxidation of NADH to $NAD^+$ by various quinones and thereby elevates the intracellular $NAD^+$ levels. In this study, we examined the effect of increase in cellular $NAD^+$ levels on bleomycin-induced lung fibrosis in mice. Methods: C57BL/6 mice were treated with intratracheal instillation of bleomycin. The mice were orally administered with ${\beta}$-lapachone from 3 days before exposure to bleomycin to 1-3 weeks after exposure to bleomycin. Bronchoalveolar lavage fluid (BALF) was collected for analyzing the infiltration of immune cells. In vitro, A549 cells were treated with transforming growth factor ${\beta}1$ (TGF-${\beta}1$) and ${\beta}$-lapachone to analyze the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT). Results: ${\beta}$-Lapachone strongly attenuated bleomycin-induced lung inflammation and fibrosis, characterized by histological staining, infiltrated immune cells in BALF, inflammatory cytokines, fibrotic score, and TGF-${\beta}1$, ${\alpha}$-smooth muscle actin accumulation. In addition, ${\beta}$-lapachone showed a protective role in TGF-${\beta}1$-induced ECM expression and EMT in A549 cells. Conclusion: Our results suggest that ${\beta}$-lapachone can protect against bleomycin-induced lung inflammation and fibrosis in mice and TGF-${\beta}1$-induced EMT in vitro, by elevating the $NAD^+$/NADH ratio through NQO1 activation.