• Journal of Ginseng Research
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• v.45 no.5
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• pp.575-582
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• 2021

Background: In ginseng, there exists a glycolipoprotein complex with a special form of lipid LPAs called Gintonin. The purpose of this study is to show that Gintonin has a therapeutic effect on rheumatoid arthritis through LPA2 receptors. Methods: Fibroblast-like synoviocytes (FLS) were treated with Gintonin and stimulated with interleukin (IL)-1β. The antioxidant effect of Gintonin was measured using MitoSOX and H₂DCFDA experiments. The anti-arthritic efficacy of Gintonin was examined by analyzing the expression levels of inflammatory mediators, phosphorylation of mitogen-activated protein kinase (MAPK) pathways, and translocation of nuclear factor kappa B (NF-κB)/p65 into the nucleus through western blot. Next, after treatment with LPAR2 antagonist, western blot analysis was performed to measure inflammatory mediator expression levels, and NF-κB signaling pathway. Carrageenan/kaolin-induced arthritis rat model was used. Rats were orally administered with Gintonin (25, 50, and 100 mg/kg) every day for 6 days. The knee joint thickness, squeaking score, and weight distribution ratio (WDR) were measured as the behavioral parameters. After sacrifice, H&E staining was performed for histological analysis. Results: Gintonin significantly inhibited the expression of iNOS, TNF-α, IL-6 and COX-2. Gintonin prevented NF-κB/p65 from moving into the nucleus through the JNK and ERK MAPK phosphorylation in FLS cells. However, pretreatment with an LPA2 antagonist significantly reversed these effects of Gintonin. In the arthritis rat model, Gintonin suppressed all parameters that were measured. Conclusion: This study suggests that LPA2 receptor plays a key role in mediating the anti-arthritic effects of Gintonin by modulating inflammatory mediators, the MAPK and NF-κB signaling pathways.

• Korean Journal of Acupuncture
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• v.24 no.2
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• pp.163-184
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• 2007

Objectives & Methods : The purpose of this study is to observe the effects of Phellodendri Cortex Herbal-acupuncture solution (PC-HAS) at Joksamni (ST36) on collagen II induced arthritis in DBA-1J mice. The author performed several experimental items to analyze arthritis evaluation, change of weight, spleen size and adhesion rate, change of cytokine level, IgG, IgM and anti-collagen II, chang of immunocyte count, histological change of CIA mouse joint. Results : 1. In the PC-HA group, arthritis index, the incidence of arthritis and joint edema were significantly decreased. 2. In the PC-HA group, the change of spleen size, spleen adhesion rate and the knee joint were significantly decreased. 3. The levels of $IL-1{\beta}$, IL-6 and INF- in serum of the CIA mouse were significantly decreased by PC-HA. 4. The levels of IgG, IgM and anti-collagen II in serum of the CIA mouse were significantly decreased by PC-HA. 5. In the CIA mouse spleen cell culture, the levels of IFN- , IFN- / IL-4, IL-10 were significantly decreased by PC-HA, but the level of IL-4 was significantly increased by PC-HA. 6. In the PC-HA group, the ratios of $CD3e^+$ to $CD45R^+$ cell, $CD4^+$ to $CD8^+$ cell and $CD4^+/CD25^+$ cell were similarly maintained as normal group in the CIA mouse spleen cell. 7. In the PC-HA group, $CD4^+CD25^+$ and $CD45R^+/CD69^+$ cell were significantly decreased in the lymph nodes. 8. In the PC-HA group, $CD3^+/CD69^+$ and $CD11b^+/Gr-1^+$ cell were significantly decreased in knee joint. 9. In histology, the cartilage destruction and synovial cell proliferation in the PC-HA group were similar with that of the normal group and the collagen fiber expressions in the PC-HA group were similar with that of the normal group. Conclusions : Form the result above, the results suggest that the PC-HA at ST36 has significant effect on collagen-induced arthritis, and can be put to practical use in the future rheumatoid arthritis clinic.

• Journal of Korean Medicine Rehabilitation
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• v.20 no.1
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• pp.37-59
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• 2010

Objectives : The object of this study was to observe the favorable anti arthritic effects of Euiiin-tang($y{\grave{i}}y{\breve{i}}r{\acute{e}}n-t{\bar{a}}ng$) aqueous extract(EIITe), has been traditionally used in Korean medicine for treating rheumatoid arthritis on collagen induced arthritic(CIA) DBA/1 mice. Methods : In the present study, effects of EIITe on the releases of human tumor necrosis factor(TNF)-${\alpha}$, interleukin(IL)-$1{\beta}$, matrix metalloproteinase(MMP)-13 and production of Nitric oxide(NO) were observed by in vitro. In addition, to observe the effects on the CIA mice, three different dosages of EIITe, 300, 150 and 150 mg/kg were orally administered once a day for 18 days from 24hrs after antigen challenges(type II collagen) on 21 days after immunization using Type II collagen Freund's complete adjuvant. Six groups, each of 8 DBA/1 mice per group were used in the present study as follows. Changes on the body weights, macroscopic arthritis scores, splenic weights, splenic TNF-${\alpha}$ and IL-6 contents, articular cartilage(femur and tibia) collagen and glycosaminoglycans-chondroitin sulphate, sulphate and hyaluronic acid contents, histopathological observations(microscopic arthritis scores, thicknesses of femur and tibia cartilage thicknesses were monitored, compared to that of dexamethasone, a potent anti inflammatory agents, 1 mg/kg treated mice. Results : As results of collagen challenges, marked decreases of body weights and gains, articular cartilage collagen and glycosaminoglycan - chondroitin sulphate, sulphate and hyaluronic acid contents were observed with increases of macroscopic arthritis scores, splenic weights, splenic TNF-${\alpha}$ and IL-6 contents, articular cartilage(in the both femur and tibia) loss and damages. However, these CIA signs were significantly and dosages dependently inhibited by treatment of EIITe 300 and 150 mg/kg as compared with CIA control, respectively. In addition, the releases of TNF-${\alpha}$, IL-$1{\beta}$, NO and MMP-13 were markedly and dose dependently inhibited by treatment of EIITe, invitro. Although CIA were more favorably inhibited by treatment of dexamethasone 1 mg/kg as compared with EIITe 300 mg/kg, marked decreases of body weights were detected in dexamethasone 1 mg/kg treated mice. Conclusions : The results obtained in this study suggest that over 150 mg/kg of EIITe showed favorable anti arthritic effects on the CIA mediated by immunomodulatory and/or anti oxidative effects. However, detail mechanism studies should be conduced in future with the screening of the biological active compounds in this herb. lthough CIA were more favorably inhibited by treatment of dexamethasone 1 mg/kg as compared with EIITe 300 mg/kg, marked decreases of body weights were detected in dexamethasone 1 mg/kg treated mice, in the present study.

• The Journal of Pediatrics of Korean Medicine
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• v.28 no.3
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• pp.47-58
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• 2014

Objectives GyejigaChulBuTang (GCBT) is a prescription used to treat acute and chronic arthritis in Korea, China, and Japan. This study assessed the anti-inflammatory and anti-oxidant activities of GCBT on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Methods Raw264.7 cells were pretreated with or without GCBT for 1 hour prior to incubation with LPS. Anti-inflammatory activity of GCBT was evaluated with reference to gene expression and production levels of proinflammatory cytokines ($TNF{\alpha}$, IL-$1{\beta}$, IL-6, GM-CSF and $INF{\gamma}$) and inflammatory mediators (iNOS, COX-2, NO and $PGE_2$). In addition, intracellular ROS generation and signal transduction of MAPK family, PI3K/Akt and $I{\kappa}B{\alpha}/NF{\kappa}B$ was investigated. Results Prior treatment with GCBT inhibited elevation of $TNF{\alpha}$, IL-$1{\beta}$, IL-6, GM-CSF, $INF{\gamma}$, NO and $PGE_2$, together with their cognate mRNAs in a dose-dependent manner. Intracellular ROS contents were similarly reduced. These effects were due to inhibition of LPS-induced phosphorylation of MAPK family, PI3K/Akt and $I{\kappa}B{\alpha}$ as well as nuclear translocation of $NF{\kappa}B$. Conclusions GCBT suppresses pro-inflammatory mediators. GCBT has potential in the treatment of juvenile rheumatoid arthritis associated with inflammation.

• Journal of Animal Reproduction and Biotechnology
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• v.37 no.4
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• pp.246-254
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• 2022

Current studies have revealed the capacity of mesenchymal stem cells (MSCs) in term of immunomodulatory properties, and this distinct potential is downgraded according to the disease duration of patients-derived MSCs. In order to enhance the immunomodulatory and anti-tumorigenic properties of the rheumatoid arthritis (RA) joints-derived MSCs, we aggregate synovial fluid-derived MSCs from RA joints (RA-hMSCs) into 3D-spheroids by the use of hanging drop culture method. Cells were isolated from synovial fluids of RA joints with longstanding active status over 13 years. For aggregation of RA-hMSCs into 3D-spheroids, cells were plated in hanging drops in 30 μL of advanced DMEM (ADMEM) containing 25,000-30,000 cells/drop and cultured for 48 h. To analyze the comparative immunomodulatory effects of 3D-spheroid and 2D monolayer cultured RA-hMSCs and then cells were cultured in ADMEM supplemented with 20% of synovial fluids of RA patients for 48 h and were evaluated by qRT-PCR for their expression of mRNA levels of inflammatory and anti-inflammatory markers. Cellular aggregation of RA-hMSCs was observed and cells were aggregate into a single sphere. Following treatment of RA patient's synovial fluids into the RA-hMSCs, spheroids formed RA-hMSCs showed significantly (p < 0.05) higher expression of TNFα stimulated gene/protein 6 (TSG-6) than the monolayer cultured RA-hMSCs. Therefore, the 3D-spheroid culture methods of RA-hMSCs were more effective than 2D monolayer cultures in suppressing inflammatory response treated with 20% of RA-synovial fluids by expression of TNFα (TSG-6) according to the immune response and enhanced secretion of inflammatory factors.

• Journal of Veterinary Clinics
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• v.23 no.4
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• pp.400-404
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• 2006

This study demonstrates the anti-arthritic effect of topical application of ketoprofen gel containing N-methyl-2-pyrrolidone (NMP) in adjuvant arthritis therapy. Adjuvant arthritis was induced by a single injection of Freund's complete adjuvant (FCA). Mature female Sprague-Dawley rats were designated to 3 groups such as control group, K10 group (ketoprofen 10 mg/rat), and NK10 group (ketoprofen 10 mg/rat containing NMP). The anti-arthritic activity of ketoprofen containing NMP was tested not only as to its capability to suppress the inflammatory edema, but also bone damage (X-ray score and regional bone uptake) of the hind paw in arthritis-induced rats. These results showed a higher efficacy of ketoprofen containing NMP than ketoprofen treatment in the adjuvant-induced arthritis. Ketoprofen containing NMP has good intrinsic characteristics for formulation in an efficacious anti-inflammatory topical application.

• Food Science and Biotechnology
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• v.17 no.1
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• pp.38-45
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• 2008

Antioxidant and anti-rheumatoid activities of Cirsium japonicum leaf extract (CJLE) were investigated in this study. CJLE had similar DPPH radical scavenging activity and reducing power to ascorbic acid and several flavonoids. Rheumatoid arthritis (RA) is a chronic inflammatory tissue-destructive disease, partly related with functions of hyaluronidases (HAases) and collgenases. CJLE ($1,000\;{\mu}g/mL$) had approximately 60.7 and 31.9% inhibition of HAase and collagenase activity, respectively. Also, CJLE inhibited lipopolysaccharide (LPS)-induced nitrite production in a dose-dependent manner, and CJLE ($1,000\;{\mu}g/mL$) suppressed approximately 70% of LPS-induced nitrite production effectively in RAW 264.7 macrophage cells. CJLE had inhibitory effects on the adherence of monocytic THP-1 to human umbilical vein endothelial cell (HUVEC) monolayers to the basal level. Inhibitory effect of CJLE on the adhesion was caused by suppression of tumor necrosis factor-a-upregulated expression of vascular cellular adhesion molecule-1 (VCAM-1) and E-selectin. We expect that CJLE may alleviate the inflammatory process in rheumatoid synovium, and these findings will raise the possibility of the usage of C. japonicum as a traditional pharmaceutical of anti-rheumatoid arthritis.

• Journal of Physiology & Pathology in Korean Medicine
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• v.24 no.3
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• pp.490-503
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• 2010

This study was carried out to know the effects of Gwanjul9-bang (hereinafter reffered to GJ9) on the inhibition of arthritis induced by collagen on DBA/1J mouse. For this purpose, GJ9 was orally administered to mouse with arthritis induced by collagen II. Cytotoxicity, hepatotoxicity, arthritis index, value of immunocyte in draining lymph node and paw joint, rheumatoid factor (IgG, IgM) in serum were measured in vivo. The cytotoxicity against hFCs was not measured in any concentration. The hepatotoxicity was low in GJ9 treated group compared with MTX group. The arthritis index was decreased significantly. In total cell counts of DLN and paw joint, the cells in DLN increased significantly while there was significantly decrease in paw joint. In lymph nodes, $CD19^+$, $CD3^+$, $CD4^+$, $CD3^+CD69^+$, $CD8^+$, $CD4^+CD25^+$, $CD3^+CD49b^+$, $CD4^+CD44^+$, $CD3^+CD8^+$ cells increased significantly, $B220^+CD23^+$cells decreased significantly. In joints, $CD3^+$, $CD4^+$, $CD4^+CD25^+$, $CD11b^+Gr-1^+$ cells decreased significantly. The levels of IgG and IgM was significantly decreased compared with control. Anti-collagen II in serum was significantly decreased compared with control. The degree of arthritis induced damage of joint of GJ9 group is slight compared with control group in histopathologic observation (Hematoxylin & Eosin, Masson's Trichrome). Comparison of the results for this study showed that GJ9 had immunomodulatory effects. So we expect that GJ9 should be used as a effective drugs for not only rheumatoid arthritis but also another auto-immune disease. Therefore we have to survey continuously in looking for the effective substance and mechanism in the future.

• Journal of Acupuncture Research
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• v.23 no.2
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• pp.125-137
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• 2006

Objectives : The effect of water extract of the pilose antler of Cervus korean TEMMINCK var. mantchuricus Swinhoe (Nokyong), a traditional immuno-suppressive and immuno-activating Korean oriental medicine, on collagen-induced arthritis (CIA) mice model was studied. Identification of common Nokyong capable of affording protection or modulating the onset and severity of arthritis may have important human health implications. Methods : Nokyong has shown to possess anti-inflammatory and anticarcinogenic properties in experimental animals. In this study we determined the effect of DAE on collagen-induced arthritis in mice. Results : In three independent experiments mice given DAE in water exhibited significantly reduced incidence of arthritis (33% to 50%) as compared with mice given no DAE in water (84% to 100%). The arthritis index also was significantly lower in DAE-fed animals. Western blot analysis showed a marked reduction in the expression of inflammatory mediators such as cyclooxygenase 2 (Cox-2), $Interferon-{\gamma}\;(INF-{\gamma})$, and tumor necrosis factor ${\alpha}\;(TNF-{\alpha})$ in arthritic joints of DAE-fed mice. The neutral endopeptidase (NEP) activity was approximately 6-fold higher in arthritic joints of non-DAE-fed mice in comparison to nonarthritic joints of nonimmunized mice whereas it was only 2-fold higher in the arthritic joints of DAE-fed mice. Additionally, total IgG and type II collagen-specific IgG levels were lower in the arthritic joints of DAE-fed mice. Conclusion : Taken together our studies suggest that DAE may be useful in the prevention of onset and severity of arthritis.

• Journal of Korean Medicine Rehabilitation
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• v.20 no.2
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• pp.17-34
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• 2010

Objectives : This study was carried out to know the effects of Gwanjul8-bang(here in after reffered to GJ8) on the inhibition of arthritis induced by collagen on DBA/1J mice. Methods : For this purpose, GJ8 was orally administered to mouse with arthritis induced by collagen II. Cytotoxicity, hepatotoxicity, arthritis index, value of immunocyte in draining lymph node(DLN) and paw joint, cytokine in serum were measured in vivo. Results : 1. The arthritis index was decreased significantly. 2. In total cell counts of DLN and paw joint, the cells in DLN increased significantly while there was a significant decrease in paw joint. 3. In lymph nodes, $CD19^+$, $CD3^+$, $CD4^+/CD25^+$ cells increased significantly, and $B220^+/CD23^+$ cells decreased significantly. 4. In joints, $CD3^+$, $CD4^+$, $CD11b^+/Gr-1^+$ cells decreased significantly. 5. The levels of $TNF-{\alpha}$, IL-6, IL-17, MCP-1 and vascular endothelial growth factor(VEGF) in serum was significantly decreased compared with control. 6. Anti-collagen II in serum was significantly decreased compared with control. 7. The degree of arthritis induced damage of joint of GJ8 group is slight compared with control group in histopathologic observation(hematoxylin & eosin(H&E), Masson-Trichrome(MT) staining). Conclusions : Comparison of the results for this study showed that GJ8 had immunomodulatory effects. So we expect that GJ8 should be used as a effective drugs for not only rheumatoid arthritis but also another auto-immune disease. Therefore there seems to be many clinical research needed in the future.