• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1519-1529
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• 2016

Background: Matrix metalloproteinase -2 (gelatinase-A, Mr 72,000 type IV collagenase, MMP-2) and -9 (gelatinase-B, Mr 92,000 type IV collagenase, MMP-9) are key molecules that play roles in tumor growth, invasion, tissue remodeling, metastasis and stem-cell regulation by digesting extracellular matrix barriers. MMP-2 and -9 are well known to impact on solid cancer susceptibility, whereas, in hematological malignancies, a paucity of data is available to resolve the function of these regulatory molecules in bone marrow mononuclear cells (BM-MNCs) and stromal cells of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Objectives: The present study aimed to investigate mRNA expression and gelatinase A and B secretion from BM-MNCs in vitro and genotypic associations of MMP-2 (-1306 C/T; rs243865), MMP-9 (-1562 C/T; rs3918242), tissue inhibitor of metalloproteinase -1 (TIMP-1) (372T/C; rs4898, Exon 5) and TIMP-2 (-418G/C; rs8179090) in MDS and AML. Results: The study covered cases of confirmed MDS (n=50), AML (n=32) and healthy controls (n=110). MMP-9 mRNA expression revealed 2 fold increased expression in MDS-RAEB II and 2.5 fold in AML M-4 (60-70% blasts). Secretion of gelatinase-B also revealed the MMP-9 mRNA expression and ELISA data also supported these data. We noted that those patients having more blast crises presented with more secretion of MMP-9 and its mRNA expression. In contrast MMP-9 (-1562 C/T) showed significant polymorphic associations in MDS (p<0.02) and AML (p<0.02). MMP-9 mRNA expression of C/T and T/T genotypes were 1.5 and 2.5 fold increased in MDS and AML respectively. In AML, MMP-2 C/T and T/T genotypes showed 2.0 fold mRNA expression. Only MMP-9 (-1306 C/T) showed significant 4 fold (p<0.001) increased risk with chemical and x-ray exposed MDS, while tobacco and cigarette smokers have 3 fold (p<0.04) risk in AML. Conclusions: In view of our results, MMP-9 revealed synergistic secretion and expression in blast crises of MDS and AML with 'gene' polymorphic effects and is significantly associated with increased risk with tobacco, cigarette and environmental exposure. Release and secretion of these enzymes may influence hematopoietic cell behavior and may be important in the clinical point of view. It may offer valuable tools for diagnosis and prognosis, as well as possible targets for the treatments.

• THE JOURNAL OF KOREAN ORIENTAL ONCOLOGY
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• v.9 no.1
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• pp.1-14
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• 2003

Objective : Ikiyangeumhaedoc-tang(IYHT) has an effect of nourishing Yin(陰) and Jin(津), and has been used to cancer patient effectively. In order to prove the anticancer's and antimetastic effect of IYHT experimentally, studies were done. Methods : We evaluated the cytotoxic activity on HT-1080 cells as well as inhibitory effect on activity of DNA topoisomerase Ⅰ, cell adhesion, cell invasion and proliferation of HUVEC cells induced by bFGF and measured the expression of mRNA(uPA, MMP2, TIMP2), p-ERK protein, recovery effect of gap junctional intercellular communication by $H_{2}O_2$ and survival time of ICR mice bearing sacoma-180. Results : IYHT showed the inhibitory effect on DNA topoisomerase Ⅰ in the concentration of $100{\mu}g/ml,\;500{\mu}g/ml$ and the dosage-dependent inhibitory effect on the adhesion of HT-1080. The concentration of 1mg/ml of IYHT inhibited 15% of adhesion compared with control. IYHT decreased the expression of uPA, but not in MMP2, TIMP2 by RT-PCR and inhibited the expression of p-ERK effectively in the concentration of more than $500{\mu}g/ml.$ IYHT recovered the inhibited gap junctional intercellular communication by $H_{2}O_2$ to the level of 60% of normal control in the concentration of $400{\mu}g/ml$ but, did not extended the mean survival time of sarcoma 180-bearing mouse. Conclusions : It was concluded that IYHT could be applied usefully for prevention and treatment of human cancer, And also experimental study for the evaluation of molecular biological study and antimetastatic research would be recommended in the near future.

• Journal of Microbiology and Biotechnology
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• v.28 no.7
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• pp.1199-1208
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• 2018

Osteoarthritis is a disease that affects the articular cartilage and osseous tissue, and can be worsened by aging, overweight status, and post-traumatic arthritis. The present study aimed to evaluate the effect of ID-CBT5101 (tyndallized Clostridium butyricum) on bone metabolism and the inflammatory response in a monosodium iodoacetate-induced rat model of osteoarthritis. ID-CBT5101 was administered orally at doses of $10^8$ or $10^{10}CFU/day$ for 2 weeks before direct injection of monosodium iodoacetate ($3mg/50{\mu}l$ of 0.9% saline) into the intra-articular space of the rats' right knees. The rats subsequently received the same doses of oral ID-CBT5101 for another 4 weeks. We evaluated the treatment effects based on serum biomarkers, mRNA expression, morphological and histopathological analyses of the knee joints, and weight-bearing distribution analysis. Compared with those in control rats, the ID-CBT5101 treatments significantly reduced the serum concentration of inflammation and bone metabolism markers (i.e., COX-2, IL-6, $LTB_4$, and COMP), and significantly increased the concentration of $IFN-{\gamma}$ and glycosaminoglycans. In addition, the ID-CBT5101 treatments inhibited the mRNA expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases (i.e., MMP-2, MMP-3, MMP-9, MMP-13, TIMP-1, and TIMP-2). Furthermore, the ID-CBT5101 treatments effectively preserved the knee cartilage and synovial membrane, and significantly decreased the amount of fibrous tissue. Moreover, compared with that of the negative control group, the ID-CBT5101 treatments increased the weight-bearing distribution by ${\geq}20%$. The results indicate that ID-CBT5101 prevented and alleviated osteoarthritis symptoms. Thus, ID-CBT5101 may be a novel therapeutic option for the management of osteoarthritis.

• The Journal of Internal Korean Medicine
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• v.31 no.2
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• pp.314-330
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• 2010

Objective : This study was performed to investigate the anti-fibrogenic effect and changes of inflammation-related genes by YBR I and YBR II (YBR I: Arteisiae Capillaris Herba, Atractylodis Rhizoma Alba, Hoelen/ YBR II: YBR I +Sanguisorbae Radix, Biotae Cacumen, Cirsii Japonici Herba) on HSC(hepatic stellate cells)-T6 and TAA-induced rat liver tissue. Materials and Methods : HSC-T6 were treated with various concentrations of distilled-water extract YBR I and YBR II extract for 24, 48 and 72 hours. After the treatment, cell viability, proliferation, procollagen levels and IL-6 levels were measured by using MTT Assay, BrdU Assay, Procollagen Type 1 C-peptide EIA kit, and Murine IL-6 ELISA Development kit. Rat liver fibrosis was induced by intraperitoneal TAA injection of 150mg/kg 3 times a week for 6 weeks. After the treatment, body weight, liver & spleen weights, liver function test, complete blood cell count and change of portal pressure were studied. In addition, gene expressions of ASMA, IL-6, MMP-2, TIMP-1 and TIMP-2, all of which are known to be associated with liver fibrosis, were analyzed by using Real-Time PCR. After YBR I and YBR IItreatment, percentages of collagen in TAA-induced rat liver tissue were measured. Results : The viability and proliferation of the HSC-T6 decreased as the concentration increased. The production of procollagen decreased as the concentration increased. The production of IL-6 was little influenced by YBR I and YBR II. There was no difference in rat body weight between the TAA-only group and the YBR groups. Compared with rat liver weight of TAA-only group, that of the YBR groups increased. In the YBR I group, the serum level of AST elevated by TAA injection significantly decreased and in the YBR I and II group, the serum level of ALP and ALT elevated by TAA injection decreased. In the YBR I group, white blood cell count elevated by TAA injection decreased but platelets increased. In the YBR I group, the portal pressure elevated by TAA injection significantly decreased. Decreases in the gene expression of ASMA and MMP-2 were observed in the YBR I group. The gene expression of IL-6 was little influenced by YBR I and YBR II -treated groups. In the histological finding, TAA injections caused severe fibrosis, but YBR I and YBR II treatment significantly reduced the amounts of hepatic collagens. Conclusions : These results suggest that YBR I and II have inhibitory effects on the hepatic fibrogenesis.

• 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.

• Korean Journal of Plant Resources
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• v.28 no.5
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• pp.591-599
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• 2015

Osteoarthritis (OA) is a degenerative disease characterized by the progressive degradation of joint cartilage and is accompanied by secondary inflammation of synovial membranes. The purpose of this study describes a preliminary evaluation of the anti-inflammatory activity on test material of Litsea japonica. fruit (LJTM) Also, this study was to evaluate the effects of LJTM on the joint cartilage of rat with OA induced by monosodium iodoacetate (MIA). To study for anti-inflammatory agents effectively, we first examined the inhibitory effect of the LJTM on the production of pro-inflammatory factors and cytokines stimulated with lipopolysaccharide. We identified anti-nociceptive effects of the LJTM by using in vivo peripheral and central nervous pain models. In addition, the aim of this study was to evaluate the effects on mRNA expression of MMP-2, -3, -7, -9, -13, TIMP-1 and –2 in cartilage of OA. In the LJTM inhibited production of pro-inflammatory mediators (NO and PGE₂) and pro-inflammatory cytokines (TNF-α and IL-6). In cartilage, Expression of MMPs and TIMPs mRNA was suppressed in LJTM treatment group than in the control group. This study suggests that LJTM are potential candidates as anti-inflammation and anti-osteoarthritis agents (painkillers) for the treatment of OA.

• Journal of Korean Medicine Rehabilitation
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• v.25 no.4
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• pp.1-20
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• 2015

Objectives This study was intended to clarify the anti-inflammation and anti-oxidation effects of gamikyejakjimo-tang herbal acupuncture (GKHA) for osteoarthritis. Methods Osteoarthritis was induced by injection of MIA into right knee joint cavities of rats. Rats were divided into a total of 4 groups (n=8). The 4 groups were normal group, control group, positive comparison group and expeimental group. Indomethacin and GKHA were medicated for a total of 4 weeks. After that, functions of liver and kidney by AST, ALT, creatinine, BUN, DPPH and ABTS free radical scavenging activity, ROS (reactive oxygen species) production, NO (Total Nitric oxide), IL-$1{\beta}$, IL-6, TNF-${\alpha}$ production, weight changes in the hind legs of MIA-induced osteoarthritis rat, serum PGE2, TIMP-1, MMP-2, MMP-9, LTB4, hs-CRP, and white blood cells, neutrophils, lymphocytes, monocytes were measured. The volume of cartilage was observed by micro CT arthrography. H&E and Safranin-O staining were used to examine the injury of synovial tissue. Results 1. In the hind leg weight bearing measurement, level of weight was increased. 2. AST, ALT, BUN, creatinine were decreased. 3. The production of total white blood cell was decreased, and the production of neutrophils, lymphocytes, monocytes were significantly decreased. 4. The production of NO, PGE2, TIMP-1, MMP-2, MMP-9, LTB4 were significantly decreased, and the production of hs-CRP was also decreased but with no significance. 5. The cartilage volume was significantly increased. 6. In H&E staining and Safranin-O staning, the cartilage cell appeared to be proliferated, and proteoglycans appeared to be increased. Conclusions Based on the results above, Gamikyejakjimo-tang Herbal Acupuncture has anti-oxidation and anti-inflammation effects, which leads to suppressing the underlying causes and the progression of osteoarthritis.

• Journal of Ginseng Research
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• v.45 no.3
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• pp.408-419
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• 2021

Background: The decreased renal function is known to be associated with biological aging, of which the main pathological features are chronic inflammation and renal interstitial fibrosis. In previous studies, we reported that total saponins from Panax japonicus (SPJs) can availably protect acute myocardial ischemia. We proposed that SPJs might have similar protective effects for aging-associated renal interstitial fibrosis. Thus, in the present study, we evaluated the overall effect of SPJs on renal fibrosis. Methods: Sprague-Dawley (SD) aging rats were given SPJs by gavage beginning from 18 months old, at 10 mg/kg/d and 60 mg/kg/d, up to 24 months old. After the experiment, changes in morphology, function and fibrosis of their kidneys were detected. The levels of serum uric acid (UA), β2-microglobulin (β2-MG) and cystatin C (Cys C) were assayed with ELISA kits. The levels of extracellular matrix (ECM), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), inflammatory factors and changes of oxidative stress parameters were examined. Results: After SPJs treatment, SD rats showed significantly histopathological changes in kidneys accompanied by decreased renal fibrosis and increased renal function; As compared with those in 3-month group, the levels of serum UA, Cys C and β2-MG in 24-month group were significantly increased (p < 0.05). Compared with those in the 24-month group, the levels of serum UA, Cys C and β2-MG in the SPJ-H group were significantly decreased. While ECM was reduced and the levels of MMP-2 and MMP-9 were increased, the levels of TIMP-1, TIMP-2 and transforming growth factor-β1 (TGF-β1)/Smad signaling were decreased; the expression level of phosphorylated nuclear factor kappa-B (NF-κB) was down-regulated with reduced inflammatory factors; meanwhile, the expression of nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) signaling was aggrandized. Conclusion: These results suggest that SPJs treatment can improve age-associated renal fibrosis by inhibiting TGF-β1/Smad, NFκB signaling pathways and activating Nrf2-ARE signaling pathways and that SPJs can be a potentially valuable anti-renal fibrosis drug.

• Journal of Life Science
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• v.33 no.2
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• pp.208-215
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• 2023

In recent decades, the field of aging research has progressed from the genetic and cellular levels to in vivo models of blood exchange. Since genes capable of extending the lifespan in C. elegance have been reported, various potential target molecules have been discovered through genomics, proteomics, metabolomics, and transcriptomics. Accordingly, research on the interactions between target molecules has also been increasing. The parabiosis method, in which two experimental animals are surgically combined, was introduced, and a factor that could reverse the aging phenomenon was discovered using this method. The parabiosis method is used to find more accurate and effective aging-reversal factors that could exist in young blood. As more new evidence has been revealed, the parabiosis method has established a new paradigm for aging research. Moreover, a device capable of exchanging blood elaborately in laboratory animals was published in 2022 and presented new results necessary for aging reversal. Since GDF11, was reported, many other anti-aging candidates that are soluble factors in blood, such as β2m, TIMP2, VCAM1, Gpld1, and clusterin, have been discovered. In addition, mcicroglia cells and neuroinflammation have been directly proven to be aging factors. These latest research results were obtained by parabiosis, the newly designed device for plasmapheresis, and injecting young blood or conditioned blood methods. In this review, we discuss the latest research results using the device and young blood administration in old mice.

• Korean Journal of Acupuncture
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• v.39 no.4
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• pp.152-171
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• 2022

Objectives : This study was designed to investigate the effects of Sunbanghwalmyung-eum gamibang on Monosodium iodoacetate-induced osteoarthritis rats. Methods : Forty Sprague-Dawley (SD) rats were divided into 5 groups of 8 rats each. Osteoarthritis (OA) was induced by injecting MIA (2 mg/50 µl) into the joint cavity of the left knee of SD rats belonging to the experimental group, and normal saline was injected into the joint cavity of the left knee instead of MIA in the normal group. To the normal group and the controlled group (OA group), 2 ml of distilled water was orally administered. To the positive control group (Indomethacin group), indomethacin 2 ml at a concentration of 2 mg/kg, to the low concentration group of SHG (Low group), 2 ml of SHG at a concentration of 2 mg/kg, and to the high concentration group of SHG (High group), 2 ml of SHG at a concentration of 4 mg/kg ml was orally administered. The drug was administered for a total of 4 weeks, and histological changes were analyzed by Hematoxylin-Eosin staining and Safranin-O staining. In addition, inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and MMP-13, TIMP-1, and GAGs were immunohistochemically analyzed. Finally, hematological examination, blood biochemical examination, and liver and kidney biopsy were performed. Results : SHG groups (Low and High) inhibited the matrix destruction and damage of the knee joint cartilage in SD rat model, and significantly prevented the reduction in cartilage thickness. In SHG groups, the expressions of TNF-α, IL-1β, IL-6 and MMP-13 were significantly decreased, and the expressions of TIMP-1, GAGs were significantly increased compared with OA group. The safety indicators had no significant differences among five groups. Conclusions : These results show that SHG has cartilage protection capacity, anti-inflammatory effect.