• Korean Journal of Pharmacognosy
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• v.40 no.3
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• pp.233-237
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• 2009

Lindera obtusiloba has been used for centuries as a traditional medicine in Korea and recently known to have an anti-fibrotic effect. In this report, we investigated the effect of hot water extract from L. obtusiloba (WELB) on the mast cell-mediated allergic inflammation and studied its possible mechanisms of action. WELB inhibited phorbol-12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-induced histamine release in HMC-1 human mast cells. WELB reduced PMACI-induced gene expression and secretion of proinflammatory cytokines such as tumor necrosis factor-$\alpha$, interleukin (IL)-$1{\beta}$, IL-6, and IL-8. The inhibitory effect of WELB on the expression of proinflammatory cytokines was c-jun N-terminal kinase and nuclear factor-${\kappa}B$ dependent. These results indicate that WELB may be beneficial in the treatment of mast cell-mediated allergic inflammation.

• The Journal of Internal Korean Medicine
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• v.44 no.3
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• pp.402-417
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• 2023

Objective: Liver fibrosis is a highly conserved wound-healing response and the final common pathway of chronic inflammatory injury. This study aimed to evaluate the potential anti-fibrotic effect of the combination of Rhei Radix et Rhizoma water extract (RW) and silymarin in a thioacetamide (TAA)-induced liver fibrosis model. Methods: The liver fibrosis mouse model was established through the intraperitoneal injection of TAA (1 week 100 mg/kg, 2-3 weeks 200 mg/kg, 4-8 weeks 400 mg/kg) three times per week for eight weeks. Animal experiments were conducted in five groups; Normal, Control (TAA-induced liver fibrosis mice), Sily (silymarin 50 mg/kg), RSL (RW 50 mg/kg+silymarin 50 mg/kg), and RSH (RW 100 mg/kg+silymarin 50 mg/kg). Biochemical analyses were measured in serum, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA), and ammonia levels. Liver inflammatory cytokines and fibrous biomarkers were measured by Western blot analysis, and liver histopathology was evaluated through tissue staining. Results: A significant decrease in the liver function markers AST and ALT and a reduction in ammonia and total bilirubin were observed in the group treated with RSL and RSH. Measurement of reactive oxygen species and MDA revealed a significant decrease in the RSL and RSH administration group compared to the TAA induction group. The expression of extracellular matrix-related proteins, such as transforming growth factor β1, α-smooth muscle actin, and collagen type I alpha 1, was likewise significantly decreased. All drug-administered groups had increased matrix metalloproteinase-9 but a decreasing tissue inhibitor of matrix metalloproteinase-1. RSL and RSH exerted a significant upregulation of NADPH oxidase 2, p22^phox, and p47^phox, which are oxidative stress-related factors. Furthermore, pro-inflammatory proteins such as cyclooxygenase 2 and interleukin-1β were markedly suppressed through the inhibition of nuclear factor kappa B activation. Conclusions: The administration of RW and silymarin suppressed the NADPH oxidase factor protein level and showed a tendency to reduce inflammation-related enzymes. These results suggest that the combined administration of RW and silymarin improves acute liver injury induced by TAA.

• The Journal of Internal Korean Medicine
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• v.25 no.2
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• pp.298-306
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• 2004

Objective : The main purpose of this study was to determine if Rehmanniae Radix has significant effects on lung fibrosis. Materials and Methods : C57BL/6J mice were devided into three groups. These were the normal group, which were not treated, the control group, given Intratracheal instillation(IT) of Bleomycin, the sample group, given IT of bleomycin and water-extracted Rehmanniae Radix. Animals were sacrificed 14 days after IT treatment. Lung fibrosis was evaluated by analysis of bronchoalveolar larvage(BAL) total WBC, percentage of macrophage, lymphocyte and neutrophil. This was done histologically by semiquantitative histological index(SHT) of lung tissue. Results : The sample group in coparison with control group showed a decrease in the BAL, total WBC, lower percentage of lymphocyte and neutrophil(p<0.05) and correspondingly a lower percentage of macrophage(p<0.01). The Sample group showed a significant decrease of collagen accumulation with respect to the control group in SHI of lung tissue(p<0.01). INF-${\gamma}$ and IL-4 levels in BALF of mice significantly decreased in the control group(p<0.05). Conclusions : Results suggest that Rehmanniae Radix has an anti-imflamatory effect and anti-fibrotic effect on the lungs through decrease of IL-4 and total WBC count for not only macrophage, but also lymphocyte and neutrophil. The degradation of INF-${\gamma}$ calls for research beyond the scope of this study.

• The Korea Journal of Herbology
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• v.28 no.4
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• pp.49-55
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• 2013

Objectives : Mori Folium was popularly used as one of the traditional medicinal herbs. Although M. Folium has been cultivated for rearing silkworm historically, it's use has been expanded as natural therapeutic agent for the treatment of filariasis, diabetes and dropsy in East Asia. However, little has been known about the effect of M. Folium on liver fibrosis. Therefore, we would like to explore an anti-fibrogenic potential of M. Folium extract (MFE) using immortalized human hepatic stellate cell line, LX-2 cells. Methods : We examined the effects of MFE on the transforming growth factor ${\beta}1$ ($TGF{\beta}1$)-induced liver fibrosis in LX-2 cells. Cell viability, Smad binding element-driven luciferase activity, phosphorylations level of Smad 2/3, and expression level of $TGF{\beta}1$-dependent target genes were monitored in the MFE-treated LX-2 cells. Results : Up to 30 ${\mu}g/ml$ MFE treatment did not show any possible toxic effect in LX-2 cells. MFE inhibited $TGF{\beta}1$-inducible Smad binding element-driven luciferase activity and decreased the $TGF{\beta}1$-inducible phosphorylations of Smad 2 and Smad 3 in hepatic stellate cell in a dose dependent manner. Furthermore, increases of plasminogen activator inhibitor type 1, $TGF{\beta}1$ and matrix metalloproteinases 2 genes by $TGF{\beta}1$ were also attenuated by MFE treatment. Conclusions : These findings suggested that MFE would be used as a potential therapeutic agent for the treatment liver fibrosis, which might be mediated by the inhibition of $TGF{\beta}1$-inducible Smad 2/3 transactivation and target genes expression.

• Korean Journal of Veterinary Research
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• v.43 no.4
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• pp.683-688
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• 2003

Caffeine (1,3,7-trimethylxanthine), a central nervous system stimulant, is contained in various foods, beverages and over-the-counter medications. Sulfadimethoxine (SDM) is one of the anti-thyroid agents and induces proliferation of thyroid capsule in two stage thyroid carcinogenesis model using N-bis(2-hydroxypropyl)nitrosamine (DHPN). In this study, we examined the effect of caffeine on fibrous proliferation of thyroid capsule in DHPN and SDM-treated rats. Five-week-old male F344 rats were given a single subcutaneous injection of DHPN (2,800 mg/kg, body weight). Starting one week thereafter, SDM (1,000 ppm in drinking water) with or without caffeine (1,500 ppm in diet) was administered for 12 weeks. All animals were autopsied and histopathological examination of the thyroid glands was performed. Thyroid follicular proliferative changes were induced in all rats treated with DHPN+SDM. In addition, the proliferation of perithyroidal fibrous tissue and pleomorphic thyroid follicular cells within the capsule were observed in DHPN+SDM treated group. Caffeine would not be related to these lesions in this experimental condition. although pentoxifylline, a methyl xanthine derivative, has an anti fibrotic effects.

• Herbal Formula Science
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• v.10 no.2
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• pp.225-241
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• 2002

The inhibitory effects of Injinseulki including extracts of melanian snail plus phytomedicinal plants on $CCl_4$-induced fibrosis, $IFN-{\gamma}$ plus LPS-induced production of NO, PMA-stimulated production $O_2$, and tacrine-induced hepatic injury were investigated in rats, RAW 264.7 or HepG2 cells. The ethanol extracts of melanian snail significantly inhibited tarcrine-induced inury of HepG2 cells. Injinseulki inhibited the production of NO and $O_2$ in a dose-dependent manner in activated RAW 264.7 macrophages. Injinseulki significantly inhibited chemical-induced fibrosis in Rats. These results show that Injinseulki including extracts of melanian snail plus phytomedicinal plants may explain some known biological activities of Injinseulki including their anti-inflammatory and anti-fibrotic effect, and is of considerable benefit in the treatment for live diseases.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.4
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• pp.357-363
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• 2015

The purpose of this study was to compare the inhibitory effect of bevacizumab on human Tenon's fibroblasts (HTFs) cultured from primary and recurrent pterygium. Cultured HTFs were exposed to 2.0, 5.0, 7.5, and 15.0 mg/mL concentration of bevacizumab for 24 hours. The 3-[4,5-dimethylthiazol- 2-yl]-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase leakage assays were then performed to assess fibroblast metabolism and viability. The matrix metalloproteinase (MMP), procollagen type I C terminal propeptide (PIP), and laminin immunoassays were performed to examine extracellular matrix production. Changes in cellular morphology were examined by phase-contrast and transmission electron microscopy. Both metabolic activity and viability of primary and recurrent pterygium HTFs were inhibited by bevacizumab in a dose-dependent manner, especially at concentrations greater than 7.5 mg/mL. Both types of HTFs had significant decreases in MMP-1, PIP, and laminin levels. Distinctly, the inhibitory effect of bevacizumab on MMP-1 level related with collagenase in primary pterygium HTFs was significantly higher than that of recurrent pterygium. Significant changes in cellular density and morphology both occurred at bevacizumab concentrations greater than 7.5 mg/mL. Only primary pterygium HTFs had a reduction in cellular density at a bevacizumab concentration of 5.0 mg/mL. Bevacizumab inhibits primary and recurrent pterygium HTFs in a dose-dependent manner, especially at concentrations greater than 7.5 mg/mL. As the primary HTFs produces larger amounts of MMP-1 compared to recurrent HTFs, significant reduction in MMP-1 level in primary pterygium HTFs after exposure to bevacizumab is likely to be related to the faster cellular density changes in primary pterygium HTFs.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5405-5408
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• 2012

Curcumin (CM), a biphenyl compound, possesses anti-inflammatory, antioxidant and antimicrobial activity. MicroRNAs (miRNAs) are small noncoding RNAs which regulate gene expression and the molecular mechanisms of several biological processes. Liver fibrosis is a major cause of hepatic dysfunction and cancer and there are few effective therapies emphasizing the need for new approaches to control. The present study was conducted to investigate the effect of curcumin (CM) on liver fibrosis through modulating the expression level of miRNAs (199 and 200), the main miRNAs associated with liver fibrosis. Induction of liver fibrosis by carbon tetrachloride ($CCL_4$) was confirmed by histopathological examination. Mice were divided into 3 groups: group 1 were i.p injected with 10% $CCL_4$ twice weekly for 4 weeks and then once a week for the next 4 weeks followed by 4 weeks with olive oil only. Group 2 were i.p injected with 10% $CCL_4$ twice weekly for 4 weeks and then once a week for the next 4 weeks followed by curcumin (5 mg/mouse/day) once daily for the next 4 weeks. The third group was injected with olive oil. The expression level of miR-199 and miR-200 and some of their targeted genes were measured by real time PCR. miRNA (199 and 200) levels were significantly elevated in liver fibrotic tissues compared to control groups. Curcumin was significantly returned the expression levels of mir-199 and -200 with their associated target gene nearly to their normal levels. This is the first study that highlighted the effect of curcumin on liver fibrosis through regulation of miRNAs.

• Herbal Formula Science
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• v.9 no.1
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• pp.231-250
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• 2001

In order to determine the effects of annexing bile extracts of bears on the anti-fibrotic effect of Injinhotang. Mix compound of Injinhotang and bile extracts of bears were administered to the carbon tetrachloride ($CCl_4$)-induced cirrhotic rats during 20 days and the changes of serum levels of GOT (glutamic-oxalacetic transaminase), GPT (glutamic pyruvic transaminase), LDH (lactate dehydrogenase), ALP (alanine phosphatase), GGT (gamma glutamyl transpeptidase) and T-BIL (total bilirubin) were monitored with comparison to the results of Injinhotang administered group. The results were summarized as follows. 1. A significant (p<0.01) increase of serum GOT levels were observed in control group compared to those of normal group but these increased levels were dramatically decreased in Injinhotang and Injinhotang with Fel Ursi-administered group. In addition, a significant (p<0.05) increase were also detected In Injinhotang with Fel Ursi-administered group compared to that of Injinhotang-administered group. 2. A significant (p<0.01) increase of serum GPT levels were observed in control group compared to those of normal group but these increased levels were dramatically decreased in Injinhotang and Injinhotang with Fel Ursi-administered group. Although significances were not recorded, increase of serum GPT levels were also detected in Injinhotang with Fel Ursi-administered group compared to that of Injinhotang-administered group. 3. A significant (p<0.01) increase of serum LDH levels were observed in control group compared to those of normal group but these increased levels were dramatically decreased in Injinhotang and Injinhotang with Fel Ursi-administered group. Although significances were not recorded, increase of serum LDH levels were also detected in Injinhotang with Fel Ursi-administered group compared to that of Injinhotang-administered group. 4. A significant (p<0.01 or p<0.05) increase of serum ALP levels were observed in control group compared to those of normal group but these increased levels were dramatically decreased in Injinhotang and Injinhotang with Fel Ursi-administered group. In addition, a significant (p<0.05) increase were also detected in Injinhotang with Fel Ursi-administered group compared to that of Injinhotang-administered group. 5. A significant (p<0.01) increase of serum GGT levels were observed in control and Injinhotang-administered group compared to those of normal group but these increased levels were dramatically decreased in Injinhotang with Fel Ursi-administered group. 6. A significant (p<0.01) increase of serum T-BIL levels were observed in control group compared to those of normal group but these increased levels were dramatically decreased in Injinhotang and Injinhotang with Fel Ursi-administered group. Although significances were not recorded, increase of serum T-BIL levels were also detected in Injinhotang with Fel Ursi-administered group compared to that of Injinhotang-administered group. In conclusion, it is considered that bile extract of bears has some additional effect to the anti-fibrotic effect of Injinhotang but to know the exact mechanism of suitable dose and duration of administration, further studies such as pharmacokinetics and dose-dependent pharmacological studies were needed

• IMMUNE NETWORK
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• v.23 no.6
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• pp.45.1-45.22
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• 2023

Interstitial lung disease (ILD) involves persistent inflammation and fibrosis, leading to respiratory failure and even death. Adult tissue-derived mesenchymal stem cells (MSCs) show potential in ILD therapeutics but obtaining an adequate quantity of cells for drug application is difficult. Daewoong Pharmaceutical's MSCs (DW-MSCs) derived from embryonic stem cells sustain a high proliferative capacity following long-term culture and expansion. The aim of this study was to investigate the therapeutic potential of DW-MSCs in experimental mouse models of ILD. DW-MSCs were expanded up to 12 passages for in vivo application in bleomycin-induced pulmonary fibrosis and collagen-induced connective tissue disease-ILD mouse models. We assessed lung inflammation and fibrosis, lung tissue immune cells, fibrosis-related gene/protein expression, apoptosis and mitochondrial function of alveolar epithelial cells, and mitochondrial transfer ability. Intravenous administration of DWMSCs consistently improved lung fibrosis and reduced inflammatory and fibrotic markers expression in both models across various disease stages. The therapeutic effect of DW-MSCs was comparable to that following daily oral administration of nintedanib or pirfenidone. Mechanistically, DW-MSCs exhibited immunomodulatory effects by reducing the number of B cells during the early phase and increasing the ratio of Tregs to Th17 cells during the late phase of bleomycin-induced pulmonary fibrosis. Furthermore, DW-MSCs exhibited anti-apoptotic effects, increased cell viability, and improved mitochondrial respiration in alveolar epithelial cells by transferring their mitochondria to alveolar epithelial cells. Our findings indicate the strong potential of DW-MSCs in the treatment of ILD owing to their high efficacy and immunomodulatory and anti-apoptotic effects.