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정시정 ( Jeong Si Jeong ),김청수 ( Kim Cheong Su ),장재원 ( Jang Jae Won ),김순배 ( Kim Sun Bae ),이상구 ( Lee Sang Gu ),박정식 ( Park Jeong Sig ) 대한신장학회 2003 Kidney Research and Clinical Practice Vol.22 No.3
배 경 : Monocyte chmoattractant protein-1 (MCP-1)과 reactive oxygen species (ROS)는 사구체 손상의 유발 및 진행에 중요한 역할을 담당하는 것으로 알려져 있다. 연구자들은 사람의 메산지움세포에서 pro-inflammatory cytokine에 의한 MCP-1 발현 및 lysophosphatidylcholine에 의한 세포 내 ROS 형성에 아스피린의 체내 대사산물인 salicylate가 미치는 영향을 알아보고자 하였다. 방 법 : 메산지움세포를 salicylate로 전처리 한 후 tumor necrosis factor-α(TNF-α)와 interleukin-1β(IL-1β)로 자극하여 salicylate가 MCP-1 발현 및 nuclear factor-κB (NF-κB)에 미치는 영향을 알아보았다. MCP-1 mRNA와 단백의 발현 정도는 각각 Northern blot analysis와 효소면역측정법을 이용하여 측정하였고 NF-κB의 활성도 및 NF-κB 억제 단백인 IκB-α의 발현은 각각 electrophoretic mobility shift assay와 Western blot analysis를 이용하여 측정하였다. Lysophosphatidylcholine에 의한 세포 내 ROS의 형성은 2`7`-dichlorofluorescein diacetate를 이용하여 flow cytometry로 측정하였다. 결 과 : Salicylate는 TNF-α와 IL-1β에 의한 MCP-1 mRNA 및 MCP-1 단백 발현을 농도에 비례하여 (1-20 mM) 억제하였으며 이런 억제 효과는 cycloheximide에 의해 영향을 받지 않았다. 또한 salicylate TNF-α와 IL-1β에 의한 NF-κB의 활성화를 농도에 비례하여 (1-20 mM) 억제하였으며 TNF-α에 의한 IκB-α단백의 분해도 억제하였다. 1 mM 이하의 저 농도 salicylate (0.05-1 mM)도 lysophosphatidylcholine에 의한 세포 내 ROS의 생성을 억제 하였다. 결 론 : Salicylate는 사람의 메산지움세포에서 TNF-α와 IL-1β에 의한 MCP-1 mRNA 및 단백 발현을 억제하였으며 이러한 효과는 적어도 일부는 IκB-α단백의 분해 억제 따른 NF-κB의 활성화 억제에 기인하였다. 그러나 이런 효과를 나타내기 위해서는 1 mM 이상의 고농도의 salicylate가 필요하였다. 반면 lysophosphatidylcholine에 의한 세포 내 ROS 생성 억제 효과는 1 mM 이하의 저농도에서도 관찰할 수 있었다. Background: Monocyte chemoattractant protein-1 (MCP-1) and reactive oxygen species (ROS) play an important role during glomerular inflammation. We investigated the effect of aspirin metabolite, salicylate on the pro-inflammatory cytokine-induced MCP-1 expression and lysophosphatidylcholine -induced in-tracellular ROS formation in human mesangial cells. Methods: Cells were pretreated with salicylate, and then timulated with tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β). The expression of MCP-1 mRNA and MCP-1 protein were measured by Northern blot analysis and enzyme-linked immunosorbent assay, respectively. Nuclear factor-κB (NF-κB) activity was measured by electrophoretic mobility shift assay. Degradation of IκB-α was assessed by Western blot analysis. Intracellular ROS production was monitored by flow cytometry using 2`7`-dichlorofluorescin diacetate. Results: Salicylate inhibited the TNF-α- or IL-1β induced MCP-1 mRNA expression in a dose dependent manner (1-20 mM) and also suppressed the MCP-1 protein expression. Its effect was not attributable to de novo synthesis of intermediary proteins. Salicylate inhibited the TMF-α- of IL-1β-induced NF-κB binding activity and also suppressed the TNF-α-induced IκB-α degradation. Low concentration of salicylate (0.01-1 mM) suppressed the lysophosphatidylcholine-induced ROS formation. Conclusion: Milimolar concentration of salicylate inhibited the MCP-1 expression at least in part, via suppression of NF-κB by reducing the degradation of IκB-α. On the other hand, lower concentration of salicylate could suppress th lysophosphatidylcho-line-induced intracellular ROS formation. (Krean J Nephrol 2003;22(3):261-272)
사람의 복막중피세포에서 Interleukin-1β 자극에 의한 Fibronectin 생성의 세포내 신호전달에 있어 Atypical Protein Kinase C의 역할
양원석 ( Yang Won Seog ),김병식 ( Kim Byeong Sig ),김순배 ( Kim Sun Bae ),박수길 ( Park Su Gil ),박정식 ( Park Jeong Sig ) 대한신장학회 2003 Kidney Research and Clinical Practice Vol.22 No.4
배 경 : Protein kinase C (PKC)에는 diacylglycerol (DAG)에 의해 활성화되는 conventional type (PKC-α, -βⅠ, -βⅡ, -γ )과 novel type (PKC-δ, -ε, -θ, -η)외에 DAG에 의해 활성화되지 않는 atypical type (PKC-ζ, -ι)이 있다. Glucose 자극에 의한 fibronectin 생성 과정에 관여하는 PKC isoenzyme은 DAG에 의해 활성화되는 PKC로 알려져 있다. 본 실험에서는 사람의 복막중피세포에서 IL-1β자극에 의한 fibronectin 생성의 신호전달 과정에 PKC가 관여하는 지와 그 isoenzyme에 대해 알아보고자 하였다. 방 법 : Fibronectin mRNA양은 northern blot assay로 측정하였고, 세포내 phosphorylated PKC ζ/ι 단백질 양은 western blot으로 비교하였다. 결 과 : 복막중피세포를 PKC억제제인 calphostin C (500, 750, 1000 nM)로 전처치 한 다음 IL-1β (1 ng/mL)로 자극하였을 때 fibronectin mRNA 발현은 calphostin C 용량에 비례하여 억제되었다. 다른 PKC억제제인 GF109203X (1, 5, 10 μM)도 IL-1β 자극에 의한 fibronectin mRNA 발현을 용량에 비례하여 억제시켰다. 반면에, conventional 및 novel PKC 자극제인 phorbol 12-myristate 13-acetate (PMA)는 fibronectin mRNA 발현을 증가시켰다. PMA를 72시간 작용시켜 PKC를 소모시킨 상태에서 PMA를 다시 투여해도 fibronectin mRNA 발현이 자극되지 않는 반면, IL-1β(1 ng/mL)는 fibronectin mRNA 발현을 자극하였다. Myristoylated PKC ζ/ι pseudosubstrate (5, 10, 15, 20 μM)는 IL-1β자극에 의한 fibronectin mRNA 발현을 용량에 비례하여 억제시켰고, 20 μM에서는 IL-1β자극에 의한 fibronectin mRNA 발현을 완전히 억제하였다. 대조군으로 투여한 myristoylated PKC [19-27] pseudosubstrate (20 μM)는 IL-1β자극에 의한 fibronectin mRNA 발현에 영향을 주지 않았다. IL-1β 자극에 의해 PKC ζ/ι가 활성화되는 지를 보기 위해 시행한 western blot에서는 IL-1β자극에 의해 PKC ζ/ι의 활성화된 형태인 phosphorylated PKC ζ/ι가 증가하였다. 결 론 : 이상의 결과는 복막중피세포에서 IL-1β에 의한 fibronectin 생성이 atypical PKC인 PKC ζ/ι 활성화를 통해 일어남을 시사한다. Background : Protein kinase C (PKC)s consist of three groups of isoenzyme; conventional, novel and atypical PKCs. Diacylglycerol (DAG) activates both conventional and novel PKCs, but not atypical PKCs. High glucose-induced fibronection production was shown to be mediated by activation of DAG-sensitive PKCs. In this study, we investigated whether PKC mediates IL-1β-induced fibronectin mRNA expression, and the subtypes of PKC involved in the process. Methods : Fibronection mRNA level and phosphorylated PKC ζ/ι in total cell lysate were measured by Northern blot and Western blot, respectively. Results : Pretreatment of HPMCs with calphostin C, a pan-PKC inhibitor, at doses of 500, 750 and 1,000 nM caused dose-dependent inhibition of IL-1β (1 ng.mL)-induced fibronection mRNA level. GF109203X, another pan-PKC inhibitor, at doses of 1, 5 and 10 ㎛ also downregulated IL-1β (1 ng/mL)-induced fibornectin mRNA level in a dose-de-pendent manner. Phorbol 12-myristate 13-acetate(PMA), an activator of conventional and novel PKCs, stimulated fibornectin mRNA level at doses of 1, 10 and 100nM. After prolonged treatment of the cells for 72 hr with PMA, another dose of PMA did not increase fibronectin mRNA level, while IL-1β (1 ng/mL) still stimulated it. Pretreatment of the cells with 5, 10, 15 and 20 ㎛ of myristoylated PKC ζ/ι pseudosubstrate inhibited IL-1β (1 ng/mL)-in-duced fibronectin mRNA level in a dose-dependent manner, while 20 ㎛ of myristoylated PKC [19-27] pseudosubstrate, given as a control, had no effect. Stimulation of fibronectin mRNA level by IL-1β (1 ng/mL) was completely prevented by 20 ㎛of myristoylated PKC ζ/ιpseudosubstrate. IL-1β (1 ng/mL) increased phosphorylated PKC ζ/ι, an active form of the enzyme. Conclusion : IL-1β-induced fibronectin production in HPMCs occurs by way of activation of atypical PKCs (PKC ζ/ι). (Korean J Nephrol 2003;22(4):340-348)
포스터 발표 : 막성 사구체신염 환자에서 스테로이드 치료 중 발생한 Kaposi 육종 치험 1예
이호철 ( Lee Ho Cheol ),김향 ( Kim Hyang ),박정식 ( Park Jeong Sig ),이규백 ( Lee Gyu Baeg ),유재학 ( Yu Jae Hag ),박문향 ( Park Mun Hyang ) 대한신장학회 2002 춘계학술대회 초록집 Vol.21 No.1
Membranous glomerulonephropathy is a common cause of nephrotoc sundrome in adults. Kaposi sarcoma is a well-known entity with distinct clinical forms such as nodular cutaneous lesions, generalized lymphadenopathy and visceral involvement. Incidence of Kaposi sarcoma is greater in patients with immunosuppression, particularly those having undergone renal transplantation, but also in patients with other underlying disorders treated with immunosuppressive therapy, notably, corticosteroids. We present a case of Kaposi sarcoma in patient with membranous glomerulopathy during corticosteroid therapy. A 49-year-old man was admitted with a complain of facial and leg edema, 5-kg weight gain for 1 month and foamy urine. Kidney biopsy showed membranous glomerulopathy. We started corticosteroid therapy to the patient. Two month later, his 24 hrurinary protein was decreased to 2.1 g/day. But, the well defined, various-sized, purple-colored papules and plaque appeared on the both hands and feet. He underwent skin biopsy, which revealed abnormally proliferated and dilated vessels, vascular slits, spindle-shaped cells and extravasated erythrocytes in the dermis. The findings were in accordance with Kaposi sarcoma. So he received cryotherapy with discontinuing corticosteroid. Four months after cryotherapy, skin lesions were cleared leaving slight hypopigmentation and amount of proteinuria was preserved without definite aggravation.