• 제목/요약/키워드: MMP-13

검색결과 222건 처리시간 0.035초

7α,25-Dihydroxycholesterol-Induced Oxiapoptophagic Chondrocyte Death via the Modulation of p53-Akt-mTOR Axis in Osteoarthritis Pathogenesis

  • Jeong-Yeon Seo;Tae-Hyeon Kim;Kyeong-Rok Kang;HyangI Lim;Moon-Chang Choi;Do Kyung Kim;Hong Sung Chun;Heung-Joong Kim;Sun-Kyoung Yu;Jae-Sung Kim
    • Molecules and Cells
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    • 제46권4호
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    • pp.245-255
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    • 2023
  • This study aimed to exploring the pathophysiological mechanism of 7α,25-dihydroxycholesterol (7α,25-DHC) in osteoarthritis (OA) pathogenesis. 7α,25-DHC accelerated the proteoglycan loss in ex vivo organ-cultured articular cartilage explant. It was mediated by the decreasing extracellular matrix major components, including aggrecan and type II collagen, and the increasing expression and activation of degenerative enzymes, including matrix metalloproteinase (MMP)-3 and -13, in chondrocytes cultured with 7α,25-DHC. Furthermore, 7α,25-DHC promoted caspase-dependent chondrocyte death via extrinsic and intrinsic pathways of apoptosis. Moreover, 7α,25-DHC upregulated the expression of inflammatory factors, including inducible nitric oxide synthase, cyclooxygenase-2, nitric oxide, and prostaglandin E2, via the production of reactive oxygen species via increase of oxidative stress in chondrocytes. In addition, 7α,25-DHC upregulated the expression of autophagy biomarkers, including beclin-1 and microtubule-associated protein 1A/1B-light chain 3 via the modulation of p53-Akt-mTOR axis in chondrocytes. The expression of CYP7B1, caspase-3, and beclin-1 was elevated in the degenerative articular cartilage of mouse knee joint with OA. Taken together, our findings suggest that 7α,25-DHC is a pathophysiological risk factor of OA pathogenesis that is mediated a chondrocyte death via oxiapoptophagy, which is a mixed mode of apoptosis, oxidative stress, and autophagy.

Safety Assessment of Ovarian Cryopreservation and Transplantation in Nude Mice Bearing Human Epithelial Ovarian Cancer

  • Zhu, Gen-Hai;Wang, Sheng-Tan;Yang, Zhao-Xin;Cai, Jun-Hong;Chen, Chun-Ying;Yao, Mao-Zhong;Hong, Lan;He, Guo-Li;Yang, Shu-Ying
    • Asian Pacific Journal of Cancer Prevention
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    • 제13권9호
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    • pp.4669-4675
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    • 2012
  • Objective: Nude mice with orthotopic transplantation of human ovarian epithelial cancer were used to investigate screening criteria for paraneoplastic normal ovarian tissue and the security of the freezing and thawing for ovarian tissue transplantation. Methods: Expression of CK-7, CA125, P53, survivin, MMP-2/TIMP-2 in paraneoplastic normal ovarian tissues were detected by RT-PCR as well as immunohistochemistry. The tissues of the groups with all negative indicators of RT-PCR, all negative indicators of immunohistochemistry, negative expression of CK-7, CA125 and survivin, positive expression of CK-7, CA125 and survivin, cancer tissues and normal ovarian tissues of nude mice were used for freezing and thawing transplantation, to analyze overt and occult carcinogenesis rates after transplantation. Results: When all indicators or the main indicators, CK-7, CA125 and survivin, were negative, tumorigenesis did not occur after transplantation. In addition the occult carcinogenesis rate was lower than in the group with positive expression of CK-7, CA125 and survivin (P<0.01). After subcutaneous and orthotopic transplantation of ovarian tissues, rates did not change (P>0.05). There was no statistical significance among rates after transplantation of ovarian tissues which were obtained under different severity conditions (P>0.05). Conclusion: Negative expression of CK-7, CA125 and survivin can be treated as screening criteria for security of ovarian tissues for transplantation. Immunohistochemical methods can be used as the primary detection approach. Both subcutaneous and orthotopic transplantation are safe. The initial severity does not affect the carcinogenesis rate after tissue transplantation. Freezing and thawing ovarian tissue transplantation in nude mice with human epithelial ovarian carcinoma is feasible and safe.

Beta-asarone Induces LoVo Colon Cancer Cell Apoptosis by Up-regulation of Caspases through a Mitochondrial Pathway in vitro and in vivo

  • Zou, Xi;Liu, Shen-Lin;Zhou, Jin-Yong;Wu, Jian;Ling, Bo-Fan;Wang, Rui-Ping
    • Asian Pacific Journal of Cancer Prevention
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    • 제13권10호
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    • pp.5291-5298
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    • 2012
  • Beta-asarone is one of the main bioactive constituents in traditional Chinese medicine Acorus calamu. Previous studies have shown that it has antifungal and anthelmintic activities. However, little is known about its anticancer effects. This study aimed to determine inhibitory effects on LoVo colon cancer cell proliferation and to clarify the underlying mechanisms in vitro and in vivo. Dose-response and time-course anti-proliferation effects were examined by MTT assay. Our results demonstrated that LoVo cell viability showed dose- and time-dependence on ${\beta}$-asarone. We further assessed anti-proliferation effects as ${\beta}$-asarone-induced apoptosis by annexin V-fluorescein isothiocyanate/propidium iodide assay usinga flow cytometer and observed characteristic nuclear fragmentation and chromatin condensation of apoptosis by microscopy. Moreover, we found the apoptosis to be induced through the mitochondrial/caspase pathway by decreasing mitochondrial membrane potential (MMP) and reducing the Bcl-2-to-Bax ratio, in addition to activating the caspase-9 and caspase-3 cascades. Additionally, the apoptosis could be inhibited by a pan-caspase inhibitor, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK). When nude mice bearing LoVo tumor xenografts were treated with ${\beta}$-asarone, tumor volumes were reduced and terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assays of excised tissue also demonstrated apoptotic changes. Taken together, these findings for the first time provide evidence that ${\beta}$-asarone can suppress the growth of colon cancer and the induced apoptosis is possibly mediated through mitochondria/caspase pathways.

T세포와 양방향 작용을 통한 마우스 림프절로부터 분리된 fibroblastic reticular cell의 기능적 분석 (Functional Analysis of Fibroblastic Reticular Cells Derived from Mouse Lymph Node via Bidirectional Crosstalk with T Cells)

  • 박성희;이종환
    • 생명과학회지
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    • 제23권10호
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    • pp.1199-1208
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    • 2013
  • Fibroblastic reticular cells (FRC)는 림프절 T세포 지역에 구조적 골격 형성을 하며 유입 T 세포의 안내길을 제공한다. FRC는 림프절에서 T세포 생물학 발달에 기여한다. 따라서, 이것이 FRC와 T세포 사이에서 FRC의 세포생물학적 근본 기능을 알아보게 하였다. FRC 배양 상등액은 T세포 사멸을 저해하였다. FRC 상등액은 doxorubicin에 대하여 T세포에 Bcl-xL의 발현을 증가시켰다. FRC와 T세포의 공배양은 FRC의 액틴 골격의 변화와 형태적 변화를 유도하였다. 또한, FRC와 T세포의 공배양은 T 세포가 FRC 단일층에 부착하는 결과를 유도하였고 막결합형 intercellular adhesion molecule (ICAM)-1 단백질의 발현은 약간 증가한 반면 용해성 ICAM-1 (sICAM-1) 발현은 시간 의존적으로 드라마틱하게 증가하였다. FRC는 T세포에 의해 분비되는 tumor necrosis factor (TNF) 패밀리들에 의해 CCL5, CXCL1, CXCL5, CXCL16, CCL8, CXCL13와 같은 케모카인들과 ICAM-1 그리고 MMPs의 발현량을 증가시켰다. $TNF{\alpha}$가 FRC에 처리 되었을때 $NF{\kappa}B$ canonical pathway의 RelA는 핵으로 전좌 되었지만, agonistic anti-$LT{\beta}R$ antibody로 처리된 FRC에서 non-canonical $NF{\kappa}B$ pathway의 RelB의 카운터 파트너인 p100의 분해산물 p52는 핵주변부로 축적되었다. 결론적으로 FRC는 FRC와 T세포 양방향 협력을 통해 T세포 생물학적 기능을 증진한다. 이러한 상호협력 관계는 면역반응 동안 조직의 통합성과 기능을 유지하는데 도움을 줄 것으로 사료된다.

육종용약침의 항암작용(抗癌作用) 및 면역효과(免疫效果)에 대(對)한 실험적(實驗的) 연구(硏究) (Study on the Anti-cancer, Anti-metastasis and Immune response improvement of Aqua-acupuncture with Cistanches Herba infusion solution)

  • 이은용;이병렬
    • Journal of Acupuncture Research
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    • 제17권1호
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    • pp.251-286
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    • 2000
  • To study the effects of anti-cancer, anti-metastasis and immune response improvement of aqua-acupuncture with Cistanches Herba infusion solution, we used Cistanches Herba infusion solution(taken by water-alcohol method) put into Chung-wan(CV12) and Chok-Samni(S36) of BALB/c or C57BL/6 which are corresponding to human body. We observed the cytotoxicity, the effect on the expression of MMP-9 gene, the ability to control cancer cell proliferation, change of body weight, surviving number, MST, ILS, changes in amount of WBC, RBC, PLT, total protein, creatinine, glucose and LDH, weight of spleen, number of pulmonary colony, histological analysis on tissue metastasis of lung and liver, splenic cell proliferation, the expression of cytokine gene, the number of $CD4^+$, $CD8^+$, $CD19^+$ and NK cell, and concluded like this. The results were obtained as follows : 1. The cytotoxicity about B16-F10 cell line of $2^0$, $2^{-1}$, $2^{-2}$, $2^{-5}$ diluent groups in Cistanches Herba infusion solution treatment was inhibited significantly, compared with control group. 2. The cytotoxicity about HT1080 cell line of $2^0$, $2^{-1}$, $2^{-2}$, $2^{-3}$, $2^{-5}$, $2^{-8}$ diluent groups in Cistanches Herba infusion solution treatment was inhibited significantly, compared with control group. 3. The effect on expression of MMP-9 gene was decreased in all the sample groups, compared with control group. 4. The effect on the control-ability on the cancer cell proliferation showed cytotooicity significantly in $2^0$, $2^{-1}$, $2^{-2}$, $2^{-3}$, $2^{-4}$, $2^{-5}$ diluent groups. 5. S-180 cancer cell line transplants in BALB/c mice were inhibited significantly in weight increase in all the sample groups, compared with control group. The surviving number increased in almost sample groups, except one group put into Chok-Samni(S36) with 20% Cistanches Herba infusion solution treatment group that showed same number of the control group. 6. S-180 cancer cell line transplants in BALB/c mice showed high MST and ILS significantly in almost sample groups, compared with control group. But one group put into Chok-Samni(S36) with 20% Cistanches Herba infusion solution treatment group showed low MST and ILS than control group. 7. The sample group injected in vein with B16-F10 cancer cell line in C57BL/6 mice showed increased ILS compared with control group significantly in anti-metastasis test. 8. The sample group injected in vein with B16-F10 cancer cell line in C57BL/6 mice were increased significantly in the number of WBC and glucose, and decreased significantly in the amount of LDH, compared with control group. However, there's no significant increase or decrease in number of RBC, PLT, total protein and creatinine. 9. We couldn't find any significant relation in spleen weight of the sample group. 10. In pulmonary colony, sample group was decreased significantly, compared with control group. 11. Histological analysis of sample group inhivited compared with that of control group in both of lung and liver. 12. In immune system, all the sample groups showed having more relevancy to the effect on splenic cell proliferation than normal group. 13. The effect on cytokine gene expression of all the sample groups were increased than control group. 14. In flow cytometry there's no significant relation in number of $CD8^+$, $CD19^+$ cell, however, the number of $CD4^+$ cell and NK cell in sample groups were increased than in control group. Above the results showed that aqua-acupuncture of Cistanches Herba infusion solution has effects of anti-cancer, anti-metastasis and immune response improvement.

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Ursodeoxycholic Acid Ameliorates Pain Severity and Cartilage Degeneration in Monosodium Iodoacetate-Induced Osteoarthritis in Rats

  • Moon, Su-Jin;Jeong, Jeong-Hee;Jhun, Joo Yeon;Yang, Eun Ji;Min, Jun-Ki;Choi, Jong Young;Cho, Mi-La
    • IMMUNE NETWORK
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    • 제14권1호
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    • pp.45-53
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    • 2014
  • Osteoarthritis (OA) is a degenerative joint disease characterized by a progressive loss of cartilage. And, increased oxidative stress plays a relevant role in the pathogenesis of OA. Ursodeoxycholic acid (UDCA) is a used drug for liver diseases known for its free radical-scavenging property. The objectives of this study were to investigate the in vivo effects of UDCA on pain severity and cartilage degeneration using an experimental OA model and to explore its mode of actions. OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration UDCA was initiated on the day of MIA injection. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Samples were analyzed macroscopically and histologically. Immunohistochemistry was used to investigate the expression of interleukin-$1{\beta}$ (IL-$1{\beta}$), IL-6, nitrotyrosine and inducible nitric oxide synthase (iNOS) in knee joints. UDCA showed an antinociceptive property and attenuated cartilage degeneration. OA rats given oral UDCA significantly exhibited a decreased number of osteoclasts in subchondral bone legion compared with the vehicle-treated OA group. UDCA reduced the expression of IL-$1{\beta}$, IL-6, nitrotyrosine and iNOS in articular cartilage. UDCA treatment significantly attenuated the mRNA expression of matrix metalloproteinase-3 (MMP-3), -13, and ADAMTS5 in IL-$1{\beta}$-stimulated human OA chondrocytes. These results show the inhibitory effects of UDCA on pain production and cartilage degeneration in experimentally induced OA. The chondroprotective properties of UDCA were achieved by suppressing oxidative damage and inhibiting catabolic factors that are implicated in the pathogenesis of cartilage damage in OA.

각종 암환자 69례에 대한 항암단의 항전이 및 재발억제효과 (The Effects of HangAmDan(HAD) on Anti-Metastasis and Preventing Relapses, Administered to 69 Cancer Patients)

  • 이용연;송기철;최병렬;서상훈;조정효;이연월;손창규;조종관;유화승
    • 대한한방내과학회지
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    • 제23권2호
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    • pp.165-173
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    • 2002
  • Purpose : Among numerous biological symptoms of cancer, matrix metalloproteinases (MMPs) are essential for tumor invasion and metastasis. HAD is used as an inhibitor of MMP gene. This study was designed to evaluate the effects of HAD on anti metastasis and preventing recurrence in cancer patients. Materials and Methods : We retrospectively analyzed the medical records of 69 cancer patients who had been administered with HAD for over 12 months continuously in East-West Cancer Center of Oriental Hospital of Daejeon University, from January 1993 to May 2002. Results : We analyzed gender, portion, stage and anti-metastasis & recurrence rates of cancer patients. Analysis of sex cases showed that the percentage of male is 62.3%, female is 37.7%. Analysis of cancer portion showed that the percentage of stomach is 31.9%, colorectum is 26.1%, lung is 21.7%, liver is 8.7%, breast is 8.7% Analysis of stage showed that the rate of III is 78.3%, IV is 13.0% and II is 8.7%. Analysis of anti-metastasis and recurrence rates showed that colorectal cancer is 77.8%, stomach cancer is 63.6%, lung cancer is 33.4% and breast cancer is 33.3% (mean : 53.6%). Conclusions : HAD has significant effects on anti-metastasis and preventing recurrence of tumor on cancer patients. So it helps to prolong the survival rates of cancer patients.

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인진청간탕(茵蔯淸肝湯)이 DMN 유발 간섬유화와 단백질 발현에 미치는 영향 (The Effects of Injinchunggan-tang(Yinchenqinggan-tang) on DMN-induced Liver Damage by Applying Proteomics)

  • 박상백;김영철;이장훈;우홍정
    • 대한한방내과학회지
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    • 제29권1호
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    • pp.200-218
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    • 2008
  • Objectives : The purpose of this study was to investigate the effects of Injinchunggan-tang (Yinchenchinggan-tang) on DMN-induced liver damage by applying proteomics. Materials and Methods : Sprague-Dawley rats were used in this experiment and were divided into the normal group (normal saline), the control group (DMN) and the sample group (DMN+IJCGT). DMN was injected i.p. once a day three times a week for 3 weeks in the control group. Normal saline instead of DMN was administered to the normal group. In the sample group, Injinchunggan-tang (Yinchenchinggan-tang) extract was orally administered once a day for 10 days after DMN was induced. The livers of each group were processed and analyzed by histology, Western blot, $Oxyblot^{TM}$, CBB and 2-dimensional electrophoresis. Results : In the histological findings of the liver, IJCGT reduced collagen deposition and liver damage in DMN-induced hepatic fibrosis. IJCGT increased MMP-13 protein production assessed by western blot. Protein oxidation induced by DMN treatment was decreased by IJCGT. In the 2-dimensional electrophoresis finding, the level of the increased proteins induced by DMN treatment such as GRP 75, 58kDa glucose regulated protein and heat shock 70kDa protein 5 were decreased by IJCGT. IJCGT was considered to have the protective effects on hepatotoxicity induced by DMN. In the 2-dimensional electrophoresis finding, the level of increased oxidized proteins such as heat shock 70 protein, mitochondrial malonyltransferase, calreticulin precursor, actin, NADP-isocitrate dehydrogenase, ankyrin repeat and SOCS box protein 11 were decreased by IJCGT. IJCGT was considered to have protective effect on the protein production induced by DMN treatment. Conclusion : Injinchunggan-tang (Yinchenchinggan-tang) exerts an inhibitory effect against the fibrosis and protein oxidation induced by DMN treatment in the rat liver. IJCGT was considered to have protective effects on the hepatotoxicity and protein production induced by DMN treatment.

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지질 다당질 인지경로에서 기질금속단백분해효소-8 분비에 대한 CD14와 Toll-like receptors의 역할 연구 (The role of CD14 and Toll-like receptors on the release of MMP-B in the LPS recognition pathway)

  • 양승민;김태일;설양조;이용무;구영;정종평;한수부;류인철
    • Journal of Periodontal and Implant Science
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    • 제36권3호
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    • pp.579-590
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    • 2006
  • 1. 연구배경 교원질 분해작용을 하는 호중구의 세포질 효소인 기질금속단백분해효소-8은 치주질환, 류마티스 관절염, 그리고 궤양결장염과 같은 염증성 질환에서 농도가 증가한다고 알려져 있다. 최근에는 A. actinomycetemcomitans의 leukotoxin이 사람호중구에서 기질금속단백분해효소-8의 분비를 유도하는 것이 보고되었다. 이 연구의 목적은 선천면역 체계에서 세포표면 항원무리14, Toll-like 수용기, 그리고 $NF-{\kappa}$ B경로를 통하여 A. actinomycetemcomitans의 지질다당질로 유도된 기질금속단백분해효소-8의 분비 여부와 세포기전을 알아보고자 하였다. 2. 연구재료 및 방법 건강한 개인 제공자(남자 13명, 여자 3명)로부터 얻은 개개인의 20ml 말초혈액을 제조사의 지침에 따라 호중구를 추출한 후 항세포표면 항원무리14와 함께 $4^{\circ}C$에서 30분간 전배양 한 후, $37^{\circ}C$에서 9시간 동안 배양시켰다. 추출한 호중구에 Toll-like 수용기 억제제 또는 $NF-{\kappa}$ B억제제인 TPCK를 첨가한 후 $37^{\circ}C$에서 1시간 동안 전배양하고 $37^{\circ}C$에서 9시간 동안 배양시켰다. 호중구에 세포뼈대 억제제인 cholchicine, nocodazole, demecolcine, 그리고 cytochalasin B를 A. actinomycetemcomitans의 지질다당질과 함께 $37^{\circ}C$에서 9시간 동안 배양시켰다. 기질금속단백분해효소-8 분비량은 효소면역측정법을 통해 결정하였다. 통계처리는 일원배치 분산분석법을 이용하였다(p<0.05). 3. 결과 A. actinomycetemcomitans 지질다당질은 기질금속단백분해효소-8의 분비를 증가시켰다. 기질금속단백분해효소-8의 분비는 항세포표면 항원무리14에 의해서 억제되었지만, 항 Toll-like 수용기2, 항 Toll-like 수용기4 항체는 억제시키지 못했다. $NF-{\kappa}$ B 억제제는 A. actinomycetemcomitans의 지질다당질로 유도된 $NF-{\kappa}$ B 결합 활성도와 기질금속단백분해효소-8 분비를 억제하였다. 미세섬유 중합반응 억제제는 A. actinomycetemcomitans의 지질다당질로 유도된 기질금속단백분해효소-8의 분비를 억제시켰으나, 미세관 중합반응억제제는 억제시키지 못했다. 4. 결론 위의 연구결과를 종합하여 볼 때, 기질금속단백분해효소-8은 A. actinomycetemcomitans의 지질다당질로 유도되며, 세포표면 항원무리-$NF-{\kappa}$ B 경로를 통하여 분비되고, 이 분비 과정은 미세섬유 계통이 관여하는 것으로 보인다.

Vitamin D Attenuates Pain and Cartilage Destruction in OA Animals via Enhancing Autophagic Flux and Attenuating Inflammatory Cell Death

  • JooYeon Jhun;Jin Seok Woo;Ji Ye Kwon;Hyun Sik Na;Keun-Hyung Cho;Seon Ae Kim;Seok Jung Kim;Su-Jin Moon;Sung-Hwan Park;Mi-La Cho
    • IMMUNE NETWORK
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    • 제22권4호
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    • pp.34.1-34.19
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    • 2022
  • Osteoarthritis (OA) is the most common form of arthritis associated with ageing. Vitamin D has diverse biological effect on bone and cartilage, and observational studies have suggested it potential benefit in OA progression and inflammation process. However, the effect of vitamin D on OA is still contradictory. Here, we investigated the therapeutic potential of vitamin D in OA. Six-week-old male Wistar rats were injected with monosodium iodoacetate (MIA) to induce OA. Pain severity, cartilage destruction, and inflammation were measured in MIA-induced OA rats. Autophagy activity and mitochondrial function were also measured. Vitamin-D (1,25(OH)2D3) and celecoxib were used to treat MIA-induced OA rats and OA chondrocytes. Oral supplementation of vitamin D resulted in significant attenuations in OA pain, inflammation, and cartilage destruction. Interestingly, the expressions of MMP-13, IL-1β, and MCP-1 in synovial tissues were remarkably attenuated by vitamin D treatment, suggesting its potential to attenuate synovitis in OA. Vitamin D treatment in OA chondrocytes resulted in autophagy induction in human OA chondrocytes and increased expression of TFEB, but not LC3B, caspase-1 and -3, in inflamed synovium. Vitamin D and celecoxib showed a synergistic effect on antinociceptive and chondroprotective properties in vivo. Vitamin D showed the chondroprotective and antinociceptive property in OA rats. Autophagy induction by vitamin D treatment may be a promising treatment strategy in OA patients especially presenting vitamin D deficiency. Autophagy promoting strategy may attenuate OA progression through protecting cells from damage and inflammatory cell death.