• The Korean Journal of Physiology and Pharmacology
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• 제10권4호
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• pp.217-222
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• 2006

Atherosclerosis is considered as a chronic inflammatory process. However, the nature of the oxidant signaling that regulates monocyte adhesion and its underlying mechanism is poorly understood. We investigated the role of reactive oxygen species on the vascular cell adhesion molecule-1 (VCAM-1) and monocyte adhesion in the cultured endothelial cells. $TNF-{\alpha}$ at a range of $1{\sim}30\;ng/ml$ induced VCAM-1 expression dose-dependently. BCECF-AM-labeled U937 cells firmly adhered on the surface of endothelial cells when the endothelial cells were incubated with $TNF-{\alpha}$ (15 ng/ml). Ten $\;{\mu}mol/L$ of SB203580, an inhibitor of p38 MAPK, significantly reduced $TNF-{\alpha}-induced$ VCAM-1 expression, compared to the JNK inhibitor ($40\;{\mu}mol/L$ of SP60015) or ERK inhibitor ($40\;{\mu}mol/L$ of U0126). Also, SB203580 significantly inhibited $TNF-{\alpha}-induced$ monocyte adhesion in HUVEC. Superoxide production was minimal in the basal condition, however, treatment of $TNF-{\alpha}$ induced superoxide production in the dihydroethidineloaded endothelial cells. Diphenyleneiodonium (DPI, $10\;{\mu}mol/L$), an inhibitor of NADPH oxidase, and rotenone $(1\;{\mu}mol/L)$, an inhibitor of mitochondrial complex I inhibited $TNF-{\alpha}-induced$ superoxide production, VCAM-1 expression and monocyte adhesion in the endothelial cells. Taken together, our data suggest that NADPH oxidase and mitochondrial ROS were involved in $TNF-{\alpha}-induced$ VCAM-1 and monocyte adhesion in the endothelial cells.

• BMB Reports
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• 제37권2호
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• pp.185-191
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• 2004

Tissue transglutaminase (tTGase) regulates various biological processes, including extracellular matrix organization, cellular differentiation, and apoptosis. Here we report the protective role of tTGase in the cell death that is induced by the tumor necrosis factor $\alpha$ (TNF-$\alpha$) and ceramide, a product of the TNF-$\alpha$ signaling pathway, in human neuroblastoma SH-SY5Y cells. Treatment with retinoic acid (RA) induced the differentiation of the neuroblastoma cells with the formation of extended neurites. Immunostaining and Western blot analysis showed the tTGase expression by RA treatment. TNF-$\alpha$ or $C_2$ ceramide, a cell permeable ceramide analog, induced cell death in normal cells, but cell death was largely inhibited by the RA treatment. The inhibition of tTGase by the tTGase inhibitors, monodansylcadaverine and cystamine, eliminated the protective role of RA-treatment in the cell death that is caused by TNF-$\alpha$ or $C_2$-ceramide. In addition, the co-treatment of TNF-$\alpha$ and cycloheximide ecreased the protein level of tTGase and cell viability in the RA-treated cells, supporting the role of tTGase in the protection of cell death. DNA fragmentation was also induced by the co-treatment of TNF-$\alpha$ and cycloheximide. These results suggest that tTGase expressed by RA treatment plays an important role in the protection of cell death caused by TNF-$\alpha$ and ceramide.

• BMB Reports
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• 제49권3호
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• pp.185-190
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• 2016

Crotamine is a peptide toxin found in the venom of the rattlesnake Crotalus durissus terrificus and has antiproliferative, antimicrobial, and antifungal activities. Herein, we show that crotamine dose-dependently induced macrophage phagocytic and cytostatic activity by the induction of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α). Moreover, the crotamineinduced expression of iNOS and TNF-α is mediated through the phosphorylation of p38 and the NF-κB signaling cascade in macrophages. Notably, pretreatment with SB203580 (a p38-specific inhibitor) or BAY 11-7082 (an NF-κB inhibitor) inhibited crotamine-induced NO production and macrophage phagocytic and cytotoxic activity. Our results show for the first time that crotamine stimulates macrophage phagocytic and cytostatic activity by induction of NO and TNF-α via the p38 and NF-κB signaling pathways and suggest that crotamine may be a useful therapeutic agent for the treatment of inflammatory disease.

• Journal of Ginseng Research
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• 제32권1호
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• pp.39-47
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• 2008

본 실험은 홍삼 혼합물 (KTNG0345)을 이용한 주름 예방 및 개선효과가 있는 건강기능 식품을 개발하기 위한 기초자료로 활용하기 위하여 시료를 경구투여한 무모생쥐의 피부조직 으로부터 MMP-3의 발현양상과 작용 메커니즘을 연구하였다. MMP-3의 발현정도는 농도 의존적으로 현저한 감소를 나타내었으며, 유전자와 단백질 모두에서 동일한 양상을 보였다. PAK는 변화가 없었지만, p38, p-p38 그리고 c-Jun, p-c-Jun 을 통계적으로 유의하게 감소시킴으로써 MMPs의 발현 감소를 가져온 것으로 보인다. 뿐만 아니라 자외선에 의한 $TNF-{\alpha}$의 생성 또는 유입을 억제함으로써 $TNF-{\alpha}$ receptor에 의해 매개되는 신호전달 경로를 둔화시켜 MMPs의 발현을 감소시킨 것으로 보인다. 이렇게 KTNG0345는 복합적인 활성으로 작용하여 주름생성 억제 활성을 보이는 것으로 판단된다.

• 한국식품과학회지
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• 제50권5호
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• pp.555-563
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• 2018

보리는 높은 비율로 식이섬유를 함유하고 있어, 일반적으로 영양학적으로는 전곡 형태로의 섭취가 추천되고 있지만, 조직감과 소화율을 고려하여 발효물 형태의 소비가 바람직한 것으로 판단되고 있다. 본 연구는 효소당화 후, 효모 및 유산균 발효를 거쳐 조제한 보리발효물로부터 조다당 BF-CP를 분리하고, 대식세포에 대한 면역증강 효과 및 세포 내 신호전달을 규명하여 기능성 소재로의 이용방안을 모색하기 위해 계획되었다. BF-CP 획분의 일반화학적 특성을 분석한 결과 70.7% 글루코스 11.4% 자일로스 및 9.0% 아라비노스를 포함하여 91.1%의 중성당으로 이루어진 중성다당이었다. BF-CP는 RAW 264.7 대식세포주에서 농도의존적으로 IL-6, $TNF-{\alpha}$와 같은 사이토카인 및 NO의 생산능을 유도하는 등 높은 대식세포 활성능을 나타냈다. 또한 qPCR 분석을 통해, BF-CP 획분을 대식세포주에 처리하였을 때, 처리 농도에 비례하여 IL-6, $TNF-{\alpha}$ 및 iNOS의 mRNA 유전자 발현을 증가시킴을 확인할 수 있었다. 한편 Western blot을 활용한 신호전달 단백질 추적실험에서 BF-CP 획분을 대식세포주에 처리하였을 때, JNK, ERK 및 p38과 같은 MAPK 경로와 $NF-{\kappa}B$ 경로의 관련 단백질을 인산화시킴이 확인되었으며 그 활성은 BF-CP 농도에 의존적이었다. 이상의 결과로부터 보리발효물 유래 다당 BF-CP는 MAPK와 $NF-{\kappa}B$ 경로를 통해 대식세포를 활성화시키며, 이를 통하여 NO, IL-6 및 $TNF-{\alpha}$와 같은 면역활성화 관련 물질의 생산을 높은 비율로 유도시킨다는 것을 최종 확인할 수 있었다.

• IMMUNE NETWORK
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• 제24권1호
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• pp.4.1-4.19
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• 2024

TNF, a pleiotropic proinflammatory cytokine, is important for protective immunity and immunopathology during Mycobacterium tuberculosis (Mtb) infection, which causes tuberculosis (TB) in humans. TNF is produced primarily by phagocytes in the lungs during the early stages of Mtb infection and performs diverse physiological and pathological functions by binding to its receptors in a context-dependent manner. TNF is essential for granuloma formation, chronic infection prevention, and macrophage recruitment to and activation at the site of infection. In animal models, TNF, in cooperation with chemokines, contributes to the initiation, maintenance, and clearance of mycobacteria in granulomas. Although anti-TNF therapy is effective against immune diseases such as rheumatoid arthritis, it carries the risk of reactivating TB. Furthermore, TNF-associated inflammation contributes to cachexia in patients with TB. This review focuses on the multifaceted role of TNF in the pathogenesis and prevention of TB and underscores the importance of investigating the functions of TNF and its receptors in the establishment of protective immunity against and in the pathology of TB. Such investigations will facilitate the development of therapeutic strategies that target TNF signaling, which makes beneficial and detrimental contributions to the pathogenesis of TB.

• Biomolecules & Therapeutics
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• 제23권6호
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• pp.549-556
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• 2015

Consumption of herbal tea [flower buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry (Myrtaceae)] is associated with health beneficial effects against multiple diseases including diabetes, asthma, and inflammatory bowel disease. Emerging evidences have reported that High mobility group box 1 (HMGB1) is considered as a key "late" proinflammatory factor by its unique secretion pattern in aforementioned diseases. Dimethyl cardamonin (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone, DMC) is a major ingredient of C. operculatus flower buds. In this study, the anti-inflammatory effects of DMC and its underlying molecular mechanisms were investigated on lipopolysaccharide (LPS)-induced macrophages. DMC notably suppressed the mRNA expressions of TNF-${\alpha}$, IL-$1{\beta}$, IL-6, and HMGB1, and also markedly decreased their productions in a time- and dose-dependent manner. Intriguingly, DMC could notably reduce LPS-stimulated HMGB1 secretion and its nucleo-cytoplasmic translocation. Furthermore, DMC dose-dependently inhibited the activation of phosphatidylinositol 3-kinase (PI3K), phosphoinositide-dependent kinase 1 (PDK1), and protein kinase C alpha (PKC${\alpha}$). All these data demonstrated that DMC had anti-inflammatory effects through reducing both early (TNF-${\alpha}$, IL-$1{\beta}$, and IL-6) and late (HMGB1) cytokines expressions via interfering with the PI3K-PDK1-PKC${\alpha}$ signaling pathway.

• BMB Reports
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• 제51권12호
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• pp.611-612
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• 2018

$C1q/TNF-{\alpha}-Related$ Protein 1 (CTRP1) has recently been shown to act as a blood pressure regulator, as it induces vasoconstriction. In the aorta, CTRP1 facilitates recruitment of angiotensin II receptor 1 (AT1R) to plasma membrane, through activation of the AKT/AS160 signaling pathway. This leads to activation of the Ras homolog gene family (Rho)/Rho kinase (ROCK) signaling pathway, resulting in vasoconstriction. Accordingly, mice overexpressing Ctrp1 have hypertensive phenotype. Patients with hypertension also display higher circulating CTRP1 levels, compared to healthy individuals, indicating that excessive CTRP1 may affect development of hypertension. Conversely, CTRP1 is regarded as an 'innate blood pressure modulator' because CTRP1 increases blood pressure under dehydration to prevent hypotension. Mice lacking Ctrp1 fail to maintain normotension under dehydration conditions, resulting in hypotension, suggesting that CTRP1 is an essential protein for maintaining blood pressure homeostasis. In conclusion, CTRP1 is a novel, anti-hypotensive vasoconstrictor that increases blood pressure during dehydration-induced hypotension.

• Journal of Microbiology and Biotechnology
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• 제21권11호
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• pp.1174-1178
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• 2011

Exopolysaccharides (EPSs) are microbial polysaccharides that are released outside of the bacterial cell wall. There have been few studies on EPS-producing lactic acid bacteria that can enhance macrophage activity and the underlying signaling mechanism for cytokine expression. In the current study, EPS-overproducing Lactobacillus (L.) paracasei KB28 was isolated from kimchi and cultivated in conditioned media containing glucose, sucrose, and lactose. The whole bacterial cells were obtained with their EPS being attached, and the cytokine-inducing activities of these cells were investigated. Gas chromatography analysis showed the presence of glucose, galactose, mannose, xylose, arabinose, and rhamnose in EPS composition. EPS-producing L. paracasei KB28 induced the expression of tumor necrosis factor (TNF)-${\alpha}$, interleukin (IL)-6, and IL-12 in mouse macrophages. This strain also caused the degradation of $I{\kappa}B{\alpha}$ and phosphorylation of the major MAPKs: Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK)1/2. The use of pharmacological inhibitors showed that different signaling pathways were involved in the induction of TNF-${\alpha}$, IL-6 and IL-12 by L. paracasei KB28. Our results provide information for a better understanding of the molecular mechanisms of the immunomodulatory effect of food-derived EPS-producing lactic acid bacteria.

• 한국식생활문화학회지
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• 제33권4호
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• pp.337-344
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• 2018

Germinated brown rice (GBR, Orysa sartiva L.) has been reported to have anti-obesity and anti-inflammatory effects. However, the mechanisms underlying these effects in adipocytes are not fully understood. Therefore, this study was conducted to explore the anti-inflammatory mechanisms of GBR on lipopolysaccharide (LPS)-stimulated 3T3-L1 adipocytes. 3T3-L1 adipocytes were pretreated with GBR extracts (0-20 mg/mL) 1 h before LPS stimulation. The mRNA expression of adipokines and Toll-like receptor 4 (TLR4) were measured by RT-PCR. The protein expressions of TLR4-related molecules were detected by western blotting and nuclear factor-${\kappa}B$ ($NF-{\kappa}B$) activation was measured. Our results showed that GBR extract dose-dependently inhibited mRNA expression of LPS-induced tumor necrosis factor-${\alpha}$ ($TNF-{\alpha}$), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). GBR extract was found to inhibit LPS-induced mRNA expression of TLR4 and protein expression of both myeloid differentiation factor 88 (MyD88) and TNF receptor-associated factor 6 (TRAF6). Furthermore, GBR extract significantly inhibited extracellular receptor-activated kinase (ERK) phosphorylation and $NF-{\kappa}B$ activation. These results suggest that GBR extract has the anti-inflammatory effects on LPS-induced inflammation via inhibition of TLR4 signaling, includingthe ERK and $NF-{\kappa}B$ signaling pathways, in adipocytes.