• 생명과학회지
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• 제27권1호
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• pp.8-14
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• 2017

치자 열매는 아시아에서 음식과 옷의 염료로 사용되어 왔다. 본 연구에서는 BV-2 소교세포에서 치자열매 열수추출물(GJ)의 항염증 효과를 관찰하고 그 작용 기전을 연구하였다. GJ는 세포에 독성을 유도하지 않으면서 lipopolysaccharide로 인한 nitric oxide (NO) 분비와 inducible nitric oxide synthase (iNOS) 생성 및 활성산소 생성을 억제하였다. 또한 GJ는 농도의존적으로 heme oxygenase-1 (HO-1)의 발현을 유도하였다. 더군다나 HO-1 siRNA를 처리했을 때는 GJ가 iNOS의 발현을 억제하지 못하였다. GJ는 HO-1의 발현에 관여하는 전사인자인 nuclear factor E2-related factor 2를 핵으로 이동시켰다. 또한 GJ에 의한 HO-1의 발현은 phosphatidylinositol 3-kinase(PI-3K) 및 p38 kinase 억제제에 의해 감소되었으며, GJ가 Akt와 p38 kinase의 인산화를 유도하였다. 이상의 결과를 종합해보면, GJ는 PI3K/Akt 및 p38 신호전달과정을 통해 HO-1의 발현을 유도함으로써 NO와 같은 염증매개물질의 생성을 억제한다는 것을 알 수 있다. 이러한 연구결과는 치자열매가 신경염증을 억제하는 새로운 기전을 밝힌 것이다.

• Asian Pacific Journal of Cancer Prevention
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• 제16권4호
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• pp.1343-1348
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• 2015

Human UHRF1 (ubiquitin-like PHD and RING finger domain-containing 1) has been reported to be over-expressed in many cancers, but its role in ovarian cancer remains elusive. Here, we determined whether knockdown of UHRF1 by lentivirus-mediated shRNA could inhibit ovarian cancer cell growth. Lentivirus-mediated short hairpin RNAs (lv-shRNAs-UHRF1) were designed to trigger the gene silencing RNA interference (RNAi) pathway. The efficiency of lentivirus-mediated shRNA infection into HO-8910 and HO-8910 PM cells was determined using fluorescence microscopy to observe lentivirus-mediated GFP expression and was confirmed to be over 80 percent. UHRF1 expression in infected HO-8910 and HO-8910 PM was evaluated by real-time PCR and Western blot analysis. The Cell Counting Kit-8 (CCK-8) assay was used to measure cell viability; flow cytometry and Hoechst 33342 assay was applied to measure cell cycle arrest and apoptosis. Cell invasion was assessed using transwell chambers. Our results demonstrated that the loss of UHRF1 promoted HO-8910 and HO-8910 PM cell apoptosis, while inhibiting cell proliferation. In addition, UHRF1 knockdown significantly inhibited the invasion of human ovarian cancer cells. In the present study, we also showed that depleting HO-8910 cells of UHRF1 caused activation of the DNA damage response pathway, with the cell cycle arrested in G2/M-phase. The DNA damage response in cells depleted of UHRF1 was illustrated by phosphorylation of CHK (checkpoint kinase) 2 on Thr68, phosphorylation of CDC25 (cell division control 25) on Ser 216 and phosphorylation of CDK1 (cyclin-dependent kinase 1) on Tyr 15.

• 생명과학회지
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• 제25권9호
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• pp.976-983
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• 2015

Achyranthoside C dimethyl ester (ACDE)는 우슬에서 분리한 oleanolic acid glycoside이다. 본 연구에서는 RAW264.7 대식세포에서 ACDE의 항염증 효과를 관찰하고 그 작용 기전을 연구하였다. ACDE는 세포에 독성을 유도하지 않으면서 heme oxygenase-1 (HO-1)의 발현을 유도하였다. ACDE 는 HO-1의 발현에 관여하는 전사인자인 nuclear factor E2-related factor 2 (Nrf2)를 핵으로 이동시켰다. 또한 ACDE에 의한 HO-1의 발현은 phosphatidylinositol 3-kinase (PI-3K) 및 mitogen activated protein kinases (MAPK) 억제제에 의해 감소되었으며, ACDE가 Akt, c-Jun kinase (JNK), extracellular signal regulated kinase (ERK), p38 kinase의 인산화를 유도하였다. 한편 ACDE는 lipopolysaccharide (LPS)로 인한 nitric oxide (NO)의 생성과 inducible NO synthase (iNOS) 발현을 억제하였으며 HO-1 siRNA를 처리했을 때 ACDE가 iNOS의 발현을 억제하지 못하였다. 이상의 결과를 종합해보면, ACDE는 대식세포에서 PI3K/Akt 및 MAPK와 Nrf2 신호전달과정을 통해 HO-1의 발현을 유도함으로써 NO와 같은 염증매개물질의 생성을 억제한다는 것을 알 수 있다. 이러한 연구결과는 ACDE가 항염증제로 사용될 수 있음을 시사한다.

• Molecules and Cells
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• 제38권4호
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• pp.327-335
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• 2015

Piperlongumine, a natural alkaloid isolated from the long pepper, selectively increases reactive oxygen species production and apoptotic cell death in cancer cells but not in normal cells. However, the molecular mechanism underlying piperlongumine-induced selective killing of cancer cells remains unclear. In the present study, we observed that human breast cancer MCF-7 cells are sensitive to piperlongumine-induced apoptosis relative to human MCF-10A breast epithelial cells. Interestingly, this opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1). Piperlongumine upregulated HO-1 expression through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) signaling in both MCF-7 and MCF-10A cells. However, knockdown of HO-1 expression and pharmacological inhibition of its activity abolished the ability of piperlongumine to induce apoptosis in MCF-7 cells, whereas those promoted apoptosis in MCF-10A cells, indicating that HO-1 has anti-tumor functions in cancer cells but cytoprotective functions in normal cells. Moreover, it was found that piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species. Instead, piperlongumine, which bears electrophilic ${\alpha},{\beta}$-unsaturated carbonyl groups, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1) through thiol modification, thereby activating the Nrf2/HO-1 pathway and subsequently upregulating HO-1 expression, which accounts for piperlongumine-induced apoptosis in cancer cells. Taken together, these findings suggest that direct interaction of piperlongumine with Keap1 leads to the upregulation of Nrf2-mediated HO-1 expression, and HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine.

• BMB Reports
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• 제47권10호
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• pp.569-574
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• 2014

Heme oxygenase-1 (HO-1) degrades heme to carbon dioxide, biliverdin, and $Fe^{2+}$, which play important roles in various biochemical processes. In this study, we examined the protective function of HO-1 against oxidative stress in SH-SY5Y cells and in a Parkinson's disease mouse model. Western blot and fluorescence microscopy analysis demonstrated that PEP-1-HO-1, fused with a PEP-1 peptide can cross the cellular membranes of human neuroblastoma SH-SY5Y cells. In addition, the transduced PEP-1-HO-1 inhibited generation of reactive oxygen species (ROS) and cell death caused by 1-methyl-4-phenylpyridinium ion ($MPP^+$). In contrast, HO-1, which has no ability to transduce into SH-SY5Y cells, failed to reduce $MPP^+$-induced cellular toxicity and ROS production. Furthermore, intraperitoneal injected PEP-1-HO-1 crossed the blood-brain barrier in mouse brains. In a PD mouse model, PEP-1-HO-1 significantly protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity and dopaminergic neuronal death. Therefore, PEP-1-HO-1 could be a useful agent in treating oxidative stress induced ailments including PD.

• BMB Reports
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• 제53권4호
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• pp.212-217
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• 2020

Activation of peroxisome proliferator-activated receptor γ (PPARγ) serves as a key factor in the proliferation and invasion of breast cancer cells and is a potential therapeutic target for breast cancer. However, the mechanisms underlying this effect remain largely unknown. Heme oxygenase-1 (HO-1) is induced and over-expressed in various cancers and is associated with features of tumor aggressiveness. Recent studies have shown that HO-1 is a major downstream target of PPARγ. In this study, we investigated the effects of induction of HO-1 by PPARγ on TPA-induced MMP-9 expression and cell invasion using MCF-7 breast cancer cells. TPA treatment increased NF-κB /AP-1 DNA binding as well as MMP-9 expression. These effects were significantly blocked by 15d-PGJ₂, a natural PPARγ ligand. 15d-PGJ₂ induced HO-1 expression in a dose-dependent manner. Interestingly, HO-1 siRNA significantly attenuated the inhibition of TPA-induced MMP-9 protein expression and cell invasion by 15d-PGJ₂. These results suggest that 15d-PGJ₂ inhibits TPA-induced MMP-9 expression and invasion of MCF-7 cells by means of a heme oxygenase-1-dependent mechanism. Therefore, PPARγ/HO-1 signaling-pathway inhibition may be beneficial for prevention and treatment of breast cancer.

• 동의생리병리학회지
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• 제20권5호
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• pp.1334-1336
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• 2006

Effects of twenty-three aqueous herbal extracts used in oriental medicines on heme oxygenase (HO)-1 expression were estimated in a mouse hippocampal cell line, HT22. HO-1 is one of the cytoprotective enzymes activated various stimuli, and Western blot analysis was used for evaluated HO-1 expression. Six aqueous extracts such as Rhei Rhizoma, Paeoniae Radix, Uncariae Ramulus et Uncus, Theae Folium, Prunellae Spica, and Coptidis Rhizoma significantly increased HO-1 expression in HT22 cells at the concentration of 300 ${\mu}$g/ml. In Addition, four aqueous extracts including Eucommiae Cortex, Moutan Cortex Radicis, Ginseng Radix Rubra, and Scutellariae Radix moderately increased HO-1 expression. These results would be usefulfor the isolation and identification of their neuroprotective principles.

• 한국방재학회지
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• 제4권1호
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• pp.73-83
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• 2004

• 한국영양학회:학술대회논문집
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• 한국영양학회 2003년도 연합학술대회
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• pp.185.1-185.1
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• 2003

• 한국방재학회지
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• 제1권1호
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• pp.10-16
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• 2001