• The Korea Journal of Herbology
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• v.38 no.6
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• pp.29-44
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• 2023

Objectives : This study was planned to evaluate the therapeutic effectiveness and possible underlying mechanism of TPE (Tetrapanax papyrifer stem(inner part of the stem Extract) and AQE (Akebiae quinata stem Extract) on osteoarthritis. Methods : Osteoarthritis models were induced through intra-articular injection of MIA (monosodium iodoacetate) 50 μL with 80 mg/ml in rats. Excluding the normal group, Osteoarthritis-induced rats were divided into 4 groups (Control, INDO, TPE, AQE). The drug concentrations were indomethacin 5 mg/kg, TPE 200 mg/kg, and AQE 200 mg/kg, and were orally administered once a day for a couple of weeks. After drug supplementation, the effects of TPE and AQE were measured with serum diagnosis, western blotting, and histopathological staining. Results : It was found that the DPPH and ABTS free radical erasure ability of AQE was better than that of TPE. AQE administration improved rear limb overload and it led to relieving pain. Both PTE and AQE significantly reduced the expression of inflammatory mediators COX-2, iNOS, and inflammatory cytokine IL-1β and IL-6 by inhibiting the phosphorylation of IκBα and deactivating the pathway of NF-κBp65. On the other hand, TNF-α was significantly reduced only by administration of AQE. In addition, histopathological analysis showed that the administration of AQE compared to PTE suppressed cartilage degeneration and effectively suppressed damage to proteoglycan, a component of ECM. Conclusion : Reviewing these experimental results, TPE and AQE possessed the effect of delaying the progress of osteoarthritis and protecting cartilage. In addition, the results of this study show that AQE has a better cartilage protection effect than TPE.

• Analytical Science and Technology
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• v.28 no.6
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• pp.361-369
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• 2015

The precise mechanism underlying the therapeutic efficacy of an extraction powder of Angelica gigas (AGE) for the treatment of degenerative osteoarthritis was investigated in primary cultured rabbit chondrocytes and in a monosodium-iodoacetate (MIA)-induced osteoarthritis rat model. The treatment with AGE (50 μg/mL) effectively inhibited NF-B activation. The anti-inflammatory mechanism was clarified by gelatin zymography and western blotting measurements of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) activities. The AGE (50 μg/mL) treatment significantly reduced MMP-9 activity. The constituents of AGE— decursinol, decursin, and decursinol angelate—were determined by LC-MS/MS after a 24 hr treatment of rabbit chondrocytes. The contents of the major products, decursin and decursinol angelate, were 3.62±0.47 and 2.14 ±0.36 μg/mg protein, respectively in AGE-treated (50 μg/mL) rabbit chondrocytes. An in vivo animal study on rats fed a diet containing 25, 50, and 100 mg/kg AGE for 3 weeks revealed a significant inhibition of the MMPs in the MIA-induced rat articular cartilage. The genetic expression of arthritic factors in the articular cartilage was examined by RT-PCR of collagen Type I, collagen Type II, aggrecan, and MMP (MMP3, MMP-9, MMP13). Specifically, AGE up-regulated the expression of collagen Type I, collagen Type II, and aggrecan and inhibited MMP levels at all tested concentrations. Collectively, AGE showed a strong specific site of action on MMP regulation and protected against the degeneration of articular cartilage via cellular regulation of MMP expression both in vitro and in vivo.

• Journal of Korean Medicine Rehabilitation
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• v.23 no.4
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• pp.39-57
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• 2013

Objectives The purpose of this study is to prove the effect of Kyejakjimotangkami(KMK) on osteoarthritis. Methods We checked antioxidant activity and measured production of $IL-1{\beta}$, IL-6, TNF-${\alpha}$ in RAW 264.7 cell after treat by KMK. Then we measured hind paw weight of Wister Rat with arthritis induced by MIA after KMK oral administration, checked Prostaglandin E2, IL-$1{\beta}$, IL-6, TNF-${\alpha}$, Osteocalcin, TIMP-1, MMP-9, LTB-4 in serum, ran histopathological test and ${\mu}CT$-arthrography. Results 1. DPPH radical Scavenging was increased depend on concentration of KMK ethanol extract in RAW 264.7 cell. 2. Production of NO was significantly decreased by KMK ethanol extract on concentration of $200{\mu}g/ml$ in RAW 264.7 cell. 3. Production of IL-$1{\beta}$ was significantly decreased by KMK ethanol extract on concentration of $200{\mu}g/ml$. And Production of IL-6, TNF-${\alpha}$ were significantly decreased KMK ethanol extract of every concentration in RAW 264.7 cell. 4. Result of checking hind paw weight when administered KMK ethanol extract to Wister Rat with arthritis induced by MIA was significantly higher than control group and similar to normal group. 5. Production of Prostaglandin E2, IL-$1{\beta}$, Osteocalcin, TIMP-1, MMP-9 and LTB-4 in serum was significantly decreased by KMK ethanol extract after administerd to Wister Rat with arthritis induced by MIA. 6. In Hematoxylin & Eosin staining and Safranin-O staining, we could find inflammation of synovial cell, infiltration of macrophage and granulocyte and degeneration of cartilage and bone were decreased in comparison with control group. 7. When checked cartilage volume to examine degree of cartilage degeneration using ${\mu}CT$-arthrography, volume of cartilage was increased in comparison with control group. Conclusions Comparison of the results for this study showed that KMK ethanol extract have anti-inflammatory effectiveness and can protect cartilage and bone. So we expect that KMK can be used as a effective drugs for osteoarthritis.

• The Journal of Internal Korean Medicine
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• v.41 no.1
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• pp.1-13
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• 2020

Objectives: Osteoarthritis (OA) is a chronic and degenerative joint disease characterized by progressive degeneration of articular cartilage. Inflammation is a recognized and important factor of OA progression. The present study was designed to investigate the protective effect of Corni Fructus water extract (CFW) on a monosodium iodoacetate (MIA)-induced rat model of OA. Methods: Osteoarthritis was induced by injection of MIA (50 µL; 80 mg/mL) into the knee joint cavity of rats. After an adaptation period for seven days, the rats were divided into 4 groups (n=8/group): normal, control, indomethacin-treated (5 mg/kg), and CFW-treated (200 mg/kg) groups. The rats were treated orally for 14 days. Pain was evaluated by determining hind paw weight distribution. For biochemical analyses, we measured the changes in reactive oxygen species (ROS) and peroxynitrite (ONOO^-) in the knee joint. The presence of anti-oxidant proteins and inflammatory proteins was determined by western blotting. Results: The administration of CFW significantly improved the hind paw weight distribution. The ROS and ONOO^- levels of knee joint were significantly decreased in the CFW group. CFW inhibited the production of inflammatory mediators, such as COX-2, and inflammatory cytokines, including IL-6 and IL-1β, via the NF-κB signaling pathway. The expression of anti-oxidant enzymes, such as catalase and GPx-1/2 also increased significantly. Conclusions: The findings indicate that CFW has a therapeutic and protective effect on OA by suppression of inflammation. Therefore, CFW could represent a potential and effective candidate for OA treatment.

• THE INTERNATIONAL COMMERCE & LAW REVIEW
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• v.14
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• pp.103-152
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• 2000

English contract law has traditionally taken the view that it is not the duty of the parties to a contract to give information voluntarily to each other. In English law, one of the principal distinctions between insurance contract law and general contract law is the existence of the doctrine of utmost good faith in insurance law. The doctrine gives rise to a variety of duties, some of which apply before formation of the contract while others apply post-formation. This article is, therefore, designed to analyse the overall structure and problems of the doctrine of utmost good faith in English marine insurance law. The results of analysis are as following : First, the requirement of utmost good faith in marine insurance law arises from the fact that many of the relevant circumstances are within the exclusive knowledge of the assured and it is impossible for the insurer to obtain the facts to make a appropriate calculation of the risk that he is asked to assume without this information. Secondly, the duty of utmost good faith provided in MIA 1906, s. 17 has the nature as a bilateral or reciprocal, overriding and absolute duty. Thirdly, the Court of Appeal in Skandia held that breach of the pre-formation duty of utmost good faith did not sound in damages since the duty did not arise out of an implied contractual term and the breach did not constitute a tort. Instead, the Court of Appeal held that the duty was an extra-contractual duty imposed by law in the form of a contingent condition precedent to the enforceability of the contract. Fourthly, the scope of the duty of utmost good faith is closely related to the test of materiality and the assured is required to disclose only material circumstances subject to MIA 1906, s. 18(1) and 20(1). The test of materiality, which had caused a great deal of debate in English courts over 30 years, was finally settled by the House of Lords in Pan Atlantic and the House of Lords rejected the 'decisive influence' test and the 'increased risk' test, and the decision of the House of Lords is thought to accept the 'mere influence' test in subsequent case by the Court of Appeal. Fifthly, the insurer is, in order to avoid contract, required to provide proof that he is induced to enter into the contract by reason of the non-disclosure or misrepresentation of the assured. Sixthly, the duty of utmost good faith is, in principle, terminated before contract is concluded, but it is undoubtful that the provision under MIA 1906, s. 17 is wide enough to include the post-formation duty. The post-formation duty is, however, based upon the terms of marine insurance contract, and the duty lies entirely outside s. 17. Finally, MIA 1906, s. 17 provides expressly for the remedy of avoidance of the contract for breach of the duty. This means rescission or retrospective avoidance of the entire contract, and the remedy is based upon a fairly crude 'all-or-nothing' approach. What is needed in English marine insurance law is to introduce a more sophiscated or proportionate remedy.

• Journal of Korean Medicine Rehabilitation
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• v.25 no.2
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• pp.15-35
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• 2015

Objectives This study was performed to investigate the effects of Bujasasim-tang ethanol extract (BST) on oxidative stress, inflammation and osteoarthritic rat model. Methods To ensure safety of BST, heavy metal levels were measured and cytotoxicity test was done. In vitro, To evaluate antioxidative effects of BST, total phenolic contents, 1,1-diphenyl-2-picryl-hydrazyl (DPPH), 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) scavenging activity, reactive oxygen species (ROS) levels were measured. Also, to evaluate anti-inflammatory effects of BST treated group, total nitric oxide (NO) and pro-inflammatory cytokines (IL-$1{\beta}$, IL-6, TNF-${\alpha}$) levels were measured in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In vivo, We injected MIA $50{\mu}l$ (60 mg/ml) into knee joints of rats to induce osteoarthritis. Rats were divided into total 3 groups (normal, control, BST treated group, each n=7). Normal group was not treated at all without inducing osteoarthritis and taken normal diet. Control group was induced osteoarthritis by MIA and taken with 2 ml of distilled water once a day for 4 weeks. BST treated group was induced osteoarthritis by MIA and taken BST 2 ml (200 mg/kg/mouse) once a day for 4 weeks. We evaluated dynamic weight bearing with the Incapacitance Test Meter. At the end of experiment, the rats were sacrificed to observe the functions of liver and kidney, changes of WBC, neutrophil, lymphocyte, monocyte levels in blood, to evaluate the levels of pro-inflammatory cytokines, tissue inhibitor of metallopreteinases-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9), prostaglandin $E_2$ ($PGE_2$), leukotriene $B_4$ ($LTB_4$) within serum. We observed change of articular structures by Hematoxylin & Eosin (H&E), safranin-O staining method and measured amount of cartilage by micro CT-arthrography. Statistical analysis was done by unpaired student's t-test with significance level at p<0.05 in SPSS 11.0 for windows. Results 1. Safety of the BST was identified. 2. AST, ALT, BUN, creatinine levels of BST treated group were within normal limit. In vitro, 1. DPPH and ABTS free radical scavenging activities of BST showed dose-dependent increase. 2. ROS production were significantly decreased. 3. Total nitric oxide (NO) and IL-$1{\beta}$ production were decreased. 4. IL-6 and TNF-${\alpha}$ production were significantly decreased. In vivo, 1. Weight bearing ability was significantly increased. 2. WBC, neutrophil, lymphocyte, monocyte levels in blood were decreased. 3. IL-$1{\beta}$ and TNF-${\alpha}$ levels in serum were significantly decreased. and the IL-6 level was decreased. 4. TIMP-1, MMP-9, $LTB_4$, $PGE_2$ levels in serum were significantly decreased. 5. Cartilage volume of BST treated group was significantly increased. Also changes of cartilage, synovial membrane, fibrous tissue were suppressed. Conclusions The results obtained in this study Bujasasim-tang have effects of antioxidative, anti-inflammatory, relieve pain and protection of cartilage. Therefore we expect that Bujasasim-tang is effective treatment for osteoarthritis.

• Journal of Korean Medicine Rehabilitation
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• v.21 no.4
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• pp.49-65
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• 2011

Objectives: This study was performed to investigate the effects of Gagamsosokmyeong-tang(Jiajianxiaoxuming-tang) on the monosodium iodoacetate(MIA) induced early state osteoarthritis in rats. Methods: Osteoarthritis was induced by injection of MIA(0.25 mg) into knee joints of rats. Osteoarthritis rats were divided into control(n=8) and treated=8 group respectively, Control group was taken distilled water and treated group was taken extracts of Gagamsosokmyeong-tang(Jiajianxiaoxuming-tang) by orally for 20 days. Body weight was measured at 0, 5, 10, 15, 20 days after MIA injection. At the end of experiment, gross and histopathological examination on the articular cartilages of the knee joints were performed. Proteoglycan(PG) content of articular cartilages were analysed by safranine O staining method. The content of tumor necrosis $factor-{\alpha}(TNF-{\alpha})$, $interleukin-1{\beta}(IL-1{\beta})$ in synovial fluids were analysed by enzyme-inked inmunosorbent assay(ELISA) method. And also cycloxygenase-2(COX-2), matrix metalloproteinase 3(MMP-3), inducible nitric oxide synthase(iNOS), calpain immunochistochemical examination on the knee joints were performed. Results: PG content in articular cartilages of the treated group was significantly increased compared with control group. Histopathological osteoarthritic score of the treated group was significantly decreased compared with control group. $TNF-{\alpha}$ content in synovial fluids, expression of iNOS and calpain in synovial membrane of the treated group were significantly decreased compared with control group. But body weight, $1L-1{\beta}$ content in synovial fluids, expression of iNOS and MMP-3 of the treated group were not significantly changed compared with control group. Conclusions: On the basis of these results, we conclude that Gagamsosokmyeong-tang(Jiajianxiaoxuming-tang) has anti-arthritic effects on the MIA induced early stage osteoarthritis in rats.

• Journal of the Korean Society of Food Science and Nutrition
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• v.43 no.1
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• pp.30-39
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• 2014

HanPoong Leading (HPL)-04 were prepared with different oriental medicines (balk of Kalopanax pictus balk, Chaenomelis Fructus, Angelica gigas root, Zingiber officinale, Raphanus sativus Linne and Saururus chinensis Baill.) to investigate the protective effects of HPL-04 on cartilage degradation in knee osteoarthritis (OA). Rat articular chondrocytes incubated with rhIL-$1{\alpha}$ markedly increased matrix metalloproteinase (MMP)-2 and 9 activities, decreased cell viability and reduced chondrogenic gene expression. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, MMP-2 and 9 activities and real time RT-PCR indicated that HPL-04 counteracted these harmful effects in dose-dependent manner. In addition, for experimental OA in vivo, monosodium iodoacetate (MIA, 0.5 mg/50 ${\mu}L$) was injected into knee joints of rats and administered HPL-04 to rats for 4 consecutive weeks after MIA treatment. The experimental data showed that treatment with HPL-04 significantly prevented of MMP-2 and 9 activities in articular cartilage. Histopathological and micro-CT evaluations of the knee joints also revealed that HPL-04 effectively ameliorated MIA-induced degenerative OA. In conclusion, HPL-04 has potential applicability for the prevention and treatment of degenerative OA.

• The Korea Journal of Herbology
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• v.37 no.5
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• pp.27-35
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• 2022

Objectives : 3-Acetyl-11-keto-𝛽-boswellic acid (AKBA) is a major active compound in Boswellia serrata. We investigated the arthritic changes following AKBA administration in monosodium iodoacetate (MIA)-induced osteoarthritis rats. Methods : All rats were randomly divided into five groups: Normal, Control, INDO (indomethacin 2 mg/kg treated), AKBA30 (AKBA 30 mg/kg treated), and AKBA60 (AKBA 60 mg/kg treated); drugs were given 2 weeks before MIA injection. For all groups except the normal group, 50 µL of sterile saline with MIA (80 mg/mL) was injected into the right knee joint 2 weeks after drug administration. The drug administration was continued for 4 weeks from 1 week after osteoarthritis induction. The histomorphological changes of knee joint cartilage were observed by H&E staining. Also, the levels of glycosaminoglycan (GAG), cartilage oligomeric matrix protein (COMP), 5-lipoxygenase (5-LOX), 5-LOX-activating protein (FLAP), and leukotriene B₄ (LTB₄) in the knee joint were determined by the ELISA kits. The expressions of mitogen-activated protein kinases (MAPKs), inflammatory cytokines, and matrix metalloproteinases (MMPs) in knee joint were detected by Western blot. Results : Data show that levels of 5-LOX, FLAP, LTB4, and COMP were downregulated significantly in the AKBA treated groups when compared to those in the Control group. On the other hand, GAG levels were significantly elevated. As a result of Western blot, the AKBA-treated groups significantly inhibited phosphorylation of MAPKs. In addition, significant downregulation of the expression of inflammatory cytokines and MMPs was found in the AKBA-treated groups. Conclusion : Our findings suggest that administration of AKBA could exert better chondroprotective and anti-inflammatory effects for MIA-induced osteoarthritis rats.

• Journal of Life Science
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• v.33 no.5
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• pp.429-435
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• 2023

Epidemiological studies suggest that maternal infection, maternal stress, and environmental risk factors during pregnancy increase the risk of brain development abnormalities associated with cognitive impairment in the offspring and increase susceptibility to schizophrenia and autism spectrum disorder. Several animal models have demonstrated that maternal immune activation (MIA) is sufficient to induce abnormal brain development and behavioral defects in the fetus. When polyinosine:polycytodylic acid (poly I:C) or lipopolysaccharide (LPS), which is commonly used in maternal immune activation animal models, was introduced into a pregnant dam, an increase in pro-inflammatory cytokines and microglial activity was observed in the offspring's brain. Microglia are brain-resident immune cells that play a mediating role in the central nervous system, and they are responsible for various functions, such as phagocytosis, synapse formation and branching, and angiogenesis. Several studies have reported that microglia are activated in MIA offspring and influence offspring behavior through interactions with various cytokines. In addition, it has been reported that they play an important role in brain circuits through interactions with neurons and astrocytes. However, there is controversy concerning whether microglia are essential to brain development or lead to behavioral defects, and the exact mechanism remains unknown. Therefore, for the potential diagnosis and treatment of brain developmental disorders, a functional study of microglia should be conducted using MIA animal models.