PGA2-induced expression of HO-1 is mediated by transcriptional upregulation of Nrf2

Sang-sun Lee,Yun-Jeong Choe,Hyein Lee,Sun-Young Lee,Ho-Shik Kim 대한독성 유전단백체 학회 2019 Molecular & cellular toxicology Vol.15 No.2

Backgrounds: Prostaglandin (PG) A2 reportedly stimulated expression of heme oxygenase (HO)-1 at the level of transcription via the activation of p38MAPK. Details of the mechanism, however, have not been provided, and this includes identification of the transcription factors responsible for PGA2-induced HO-1 expression. Herein is described an analysis of the role of nuclear factor erythroid 2 related factor 2 (Nrf2) and how PGA2 increases the activity of Nrf2 during PGA2-induced HO-1 expression. Methods: Expressions of HO-1 and Nrf2 were analyzed at the levels of both mRNA and protein. Nrf2 siRNA, SB203580, an inhibitor of p38MAPK, and scavengers of reactive oxygen species (ROS) were used to identify the effects of Nrf2, p38MAPK and ROS on PGA2-induced HO-1 expression. Results: Although SB203580 suppressed PGA2-induced HO-1 expression, genetic activation of p38MAPK could not stimulate the transcription of HO-1. Cycloheximide (CHX), an inhibitor of protein translation, almost completely prevented PGA2-induced increase of HO-1 transcription, but it did not prevent the phosphorylation of p38MAPK, which suggests that both de novo protein synthesis and p38MAPK activity are required to induce the transcription of HO-1 in response to PGA2 treatment. In addition, PGA2 increased the level of both Nrf2 mRNA and protein in a dose-dependent manner. Knockdown of Nrf2 using small interfering RNA (siRNA) suppressed PGA2-induced HO-1 expression. The PGA2-induced transcription of Nrf2 was prevented by ROS scavengers such as n-acetyl-l-cysteine and tempol but not CHX. Furthermore, siRNA against p38MAPK did not change the level of nuclear Nrf2 protein. Conclusion: These findings suggest that PGA2 induces HO-1 transcription via an increase in Nrf2 protein, the transcription of which is initiated by an accumulation of ROS that is independent of the p38MAPK activation pathway.

PGA2-induced HO-1 attenuates G2M arrest by modulating GADD45α expression

Yun-Jeong Choe,고경원,Hyein Lee,이선영,Byung-Chul Kim,Ho-Shik Kim,Ho-Shik Kim 대한독성 유전단백체 학회 2015 Molecular & cellular toxicology Vol.11 No.4

Prostaglandin (PG) A2, a cyclopentenone PG, arrested the growth of U2OS cells in the G2M phase. While inducing G2M arrest, PGA2 increased the expression of heme oxygenase-1 (HO-1) at the level of transcription along with the accumulation of ROS and the activation of MAPKs including JNK, p38MAPK, and ERK1/2. Among the MAPKs, the inhibition of p38MAPK by a specific chemical inhibitor SB203580, or by RNA interference, but not JNK or ERK1/2, attenuated the PGA2-induced transcription of HO-1. Nacetylcysteine (NAC), a ROS scavenger, prevented PGA2-induced G2M arrest, p38MAPK activation and transcriptional induction of HO-1. PGA2 also stimulated GADD45α expression at the level of transcription, and the knockdown of GADD45α repressed PGA2- induced G2M arrest. Finally, the knockdown of the HO-1 protein elevated PGA2-induced GADD45α expression as well as G2M arrest. Collectively, these results suggest that PGA2 causes an increase in ROS accumulation which initiates both HO-1 transcription via p38MAPK, and G2M arrest via GADD45α transcription, and HO-1 attenuates G2M arrest by modulating the expression of GADD45α.

PGA2 induces the expression of HO-1 by activating p53 in HCT116 cells

Hyein Lee,Sang-Sun Lee,Ji-Young Park,Yun-Jeong Choe,이선영,Ho-Shik Kim,H.-S. Kim 대한독성 유전단백체 학회 2017 Molecular & cellular toxicology Vol.13 No.2

Prostaglandin (PG) A2 which is a cytotoxic PG, was reported to induce the expression of heme oxygenase (HO)-1 via activation of p38MAPK to keep U2OS cells from cell cycle arrest in G2M phase. The expression of HO-1 is primarily regulated at the level of transcription. But the transcription factors that are responsible for PGA2-induced HO-1 expression were not clarified yet. Here, we report that PGA2-induced transcription of HO-1 is mediated by p53, a tumor suppressive transcription factor. In HCT116 cells, PGA2 treatment led to the phosphorylation of p53 and an increase of p21WAF1 transcription as well as the activation of HO-1 transcription. Knocking p53 down via RNA interference or inhibiting the p53’s transcriptional activity by pifithrin-α treatment led to suppression of the increase in the level of both HO-1 expression and activity of HO-1 promoter. Pretreatment of NU- 7441, a chemical inhibitor of DNA-activated protein kinase (DNA-PK), prevented both the PGA2-induced phosphorylation of p53 and an increase of HO-1 transcription. In addition, N-acetyl-l-cysteine, a scavenger of reactive oxygen species (ROS), also mimicked the effect of NU-7441 on the PGA2-induced activation of p53 and HO-1 transcription. Collectively, these results suggest that PGA2 induces the expression of HO-1 via activation of p53, which is mediated by the ROSDNA- PK pathway.

Nutlin-3 induces HO-1 expression by activating JNK in a transcription-independent manner of p53

CHOE, YUN-JEONG,LEE, SUN-YOUNG,KO, KYUNG WON,SHIN, SEOK JOON,KIM, HO-SHIK Spandidos Publications 2014 International journal of oncology Vol.44 No.3

A recent study reported that p53 can induce HO-1 by directly binding to the putative p53 responsive element in the HO-1 promoter. In this study, we report that nutlin-3, a small molecule antagonist of HDM2, induces the transcription of HO-1 in a transcription-independent manner of p53. Nutlin-3 induced HO-1 expression at the level of transcription in human cancer cells such as U2OS and RKO cells. This induction of HO-1 did not occur in SAOS cells in which p53 was mutated and was prevented by knocking down the p53 protein using p53 siRNA transfection, but not by PFT-alpha, an inhibitor of the transcriptional activity of p53. Accompanying HO-1 expression, nutlin-3 stimulated the accumulation of ROS and the phosphorylation of MAPKs such as JNK, p38 MAPK and ERK1/2. Nutlin-3-induced HO-1 expression was suppressed by TEMPO, a ROS scavenger, and chemical inhibitors of JNK and p38 MAPK but not ERK1/2. In addition, nutlin-3-induced phosphorylation of JNK but not p38 MAPK was inhibited by TEMPO. Notably, the levels of nutlin-3-induced ROS were correlated with the mitochondrial translocation of p53 and this induction was prevented by PFT-beta, an inhibitor of the mitochondrial translocation of p53. Consistent with the effect of the ROS scavenger and MAPK inhibitors, PFT-beta reduced HO-1 expression and the phosphorylation of JNK induced by nutlin-3. In the experiments of analyzing cell death, the knockdown of HO-1 augmented nutlin-3-induced apoptosis. Collectively, these results suggest that nutlin-3 induces HO-1 expression via the activation of both JNK which is dependent on ROS generated by p53 translocated to the mitochondria and p38 MAPK which appears to be stimulated by a ROS-independent mechanism, and this HO-1 induction may inhibit nutlin-3-induced apoptosis, constituting a negative feedback loop of p53-induced apoptosis.

무작위 대조 이중맹검 시험을 통한 봉독 약침의 류마티스 관절염 치료 효과 연구

이상훈,홍승재,김수영,양형인,이재동,최도영,이두익,이윤호 WHO COLLABORATING CENTRE FOR TRADITIONAL MEDICINE 2003 東西醫學硏究所 論文集 Vol.2003 No.-

Objective : This study was performed in order to evaluate the effect of bee venom therapy on rheumatoid arthritis by randomized controlled double blind method. Method : RA patients were recruited and divided into an experiment group and a control group by random selection. As a double blind test, the experiment group was treated with bee venom injection on acupoints, and the control group was treated with normal saline injection on acupoints twice a week for 8 weeks. Tender joint count, swollen joint count, morning stiffness, pain, health assessment questionnaire, ESR. and CRP were estimated and analyzed at baseline, and at 1 month and 2 months after bee venom therapy Results : Compared to the control group, the experiment group showed significant decrease in tender joint count swollen joint count, morning stiffness, and health assessment questionnaire after 2 months. Pain, ESR and CRP showed significant decrease in the experiment group after 1 & 2 months. Conclusions : These results suggests that bee venom therapy could be an effective method in the treatment of patients with rheumatoid arthritis.

Antioxidant and hepatoprotective effects of Korean ginseng extract GS-KG9 in a D-galactosamine-induced liver damage animal model

Yun Ho Jo,Hwan Lee,Myeong Hwan Oh,Gyeong Hee Lee,You Jin Lee,Ji Sun Lee,Min Jung Kim,Won Yong Kim,Jin Seong Kim,Dae Seok Yoo,Sang Won Cho,Seon Woo Cha,Mi Kyung Pyo 한국영양학회 2020 Nutrition Research and Practice Vol.14 No.4

BACKGROUND/OBJECTIVES: This study was designed to investigate the improvement effect of white ginseng extract (GS-KG9) on D-galactosamine (Ga1N)-induced oxidative stress and liver injury. SUBJECTS/METHODS: Sixty Sprague-Dawley rats were divided into 6 groups. Rats were orally administrated with GS-KG9 (300, 500, or 700 mg/kg) or silymarin (25 mg/kg) for 2 weeks. The rats of the GS-KG9- and silymarin-treated groups and a control group were then intraperitoneally injected Ga1N at a concentration of 650 mg/kg for 4 days. To investigate the protective effect of GS-KG9 against GalN-induced liver injury, blood liver function indicators, anti-oxidative stress indicators, and histopathological features were analyzed. RESULTS: Serum biochemical analysis indicated that GS-KG9 ameliorated the elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) in GalN-treated rats. The hepatoprotective effects of GS-KG9 involved enhancing components of the hepatic antioxidant defense system, including glutathione, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT). In addition, GS-KG9 treatment inhibited reactive oxygen species (ROS) production induced by GalN treatment in hepatocytes and significantly increased the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins, which are antioxidant proteins. In particular, by histological analyses bases on hematoxylin and eosin, Masson"s trichrome, α-smooth muscle actin, and transforming growth factor-β1 staining, we determined that the administration of 500 mg/kg GS-KG9 inhibited hepatic inflammation and fibrosis due to the excessive accumulation of collagen. CONCLUSIONS: These findings demonstrate that GS-KG9 improves GalN-induced liver inflammation, necrosis, and fibrosis by attenuating oxidative stress. Therefore, GS-KG9 may be considered a useful candidate in the development of a natural preventive agent against liver injury.

봉독약침이 류마티스 관절염 환자의 관절 통증, 종창 및 급성 염증 반응에 미치는 영향

이상훈,이현종,백용현,김수영,박재경,홍승재,양형인,김건식,이재동,최도영,이두익,이윤호 WHO COLLABORATING CENTRE FOR TRADITIONAL MEDICINE 2003 東西醫學硏究所 論文集 Vol.2003 No.-

Objective In order to study the effects of bee venom(BV) on the pain, edema, and acute inflammatory reactant of rheumatoid arthritis(RA) patients. Methods Patients with RA who met the ACR(American College of Rheumatology) 1987 revised criteria for the diagnosis of RA were treated with the BV therapy twice a week for 3 months. Tender Joint counts, swollen joint counts, Visual analog scale(VAS), morning stiffness, ESR. C-reactive protein(CRP) were analyzed before and after BV therapy. Results The results as follows. 1. Tender joint counts in patients after BV therapy were significantly lower than those before BV therapy(9.0±7.9 vs 15± 11.4, p=0.002). 2. Swollen joint counts of the patients after BV therapy were significantly lower than those before BV therapy(50±61 vs 15±23, p=0.001). 3. VAS in patients after BV therapy was significantly lower than those before BV therapy(608± 17.6 vs 380± 159, p=0.000). 4. Duration of morning stiffness in patients after BV therapy was significantly reduced compared with that before BV therapy(119.1± 112.6 min vs 59.0±89.7 min, p=0.009). 5. ESR and CRP were not significantly changed before and after BV therapy, suggesting BV itself could make inflammatory reaction as well as therapeutic effect. Conclusions BV therapy improved tender joint counts, swollen joint counts and duration of morning stiffness in this study, and further study is needed on long-term effect of BV therapy.

봉독약침이 류마티스 관절염 환자의 기능회복 및 삶의 질에 미치는 영향

이상훈,이현종,박상민,김수영,박재경,홍승재,양형인,이재동,최도영,김건식,이두익,이윤호 WHO COLLABORATING CENTRE FOR TRADITIONAL MEDICINE 2003 東西醫學硏究所 論文集 Vol.2003 No.-

Objective: To evaluate the effects of bee venom acupuncture(BVA) on the rehabilitation and quality of life in rheumatoid arthritis(RA) patients Methods: Patients with RA were treated with the BVA therapy twice a week for 3 months. Tender joint counts, swollen joint counts, morning stiffness, Erythrocyte Sedimentation Rate(ESR), C-reactive protein(CRP), patient global assessment, physician global assessment, Korean health assessment questionnaire(KHAQ) were estimated and analyzed before and after BVA therapy. Results: Tender joint counts, swollen joint counts, morning stiffness showed significant decrease after BVA therapy. But, as acute inflammatory reactants, ESR showed no significant difference and CRP showed significant increase after BVA therapy. Patient global assessment physician global assessment, and KHAQ index showed significant improvement after BVA therapy. Conclusions: BVA therapy can improve rehabilitation and health-related quality of life RA patients as well as clinical symptom and signs. Further study is required in more population with large scale including acute inflammatory reaction of BVA therapy.

뇌졸중 후 중추성 통증 환자에 대한 동서협진이 진통과 재활에 미치는 영향

이현종,김수영,이상훈,서동민,이두익,김건식,이재동,이윤호,양형인,박재경,최도영 WHO COLLABORATING CENTRE FOR TRADITIONAL MEDICINE 2003 東西醫學硏究所 論文集 Vol.2003 No.-

Purpose : In order to study the effectiveness of East-West pain treatment on central poststroke pain(CPSP), we evaluated its effect on alleviation of pain and rehabilitation of CPSP Patients who were treated with electroacupuncture and west pain treatment for four weeks. Methods : Twenty four patients diagnosed by their pain characteristics of central pain from stroke were treated with sympathetic nerve block, gabapentin, amitriptyline, and electroacupuncture for four weeks. Pain intensity through the visual analogue scale(VAS), and improvements of mobility and rehabilitation through the modified Barthel index(MBI) and Rankin scale(RS), respectively, before and after pain treatment were also assessed. Results : VAS pain scores were significantly improved from 7.7±1.7 to 4.4±2.0 with pain treatment(p<0.05). In accordance with improvement of pain scores, RS and MBI scores were also improved from 2.88±0.95 to 2.13± 1.01 and from 83.0± 16.9 to 94.7±9.5(p<0.05), respectively, with pain treatment(p<0.05). Conclusions : It was suggested that the active pain treatment was contributed to the rehabilitation of CPSP patients, resulting in improvement of quality of life of CPSP patients. Futhermore, East pain treatment in combination with West pain treatment may be useful modality to alleviate CPSP.

전격성 경과를 취한 만성 호산구성 폐렴 환자 1예

윤호상,진춘조,유광하,이상엽,이수인,정상만,김선두,이순제,이길도,전혜정 건국대학교 의과학연구소 2000 건국의과학학술지 Vol.10 No.-

Chronic eosinophilic pneumonia(CEP) is a rare disease of unknown etiology characterized by chronic infiltration of the lung with eosinophils. It presents with profound systemic symptoms comprising fever, night sweats, weight loss, dyspnea and blood eosinophilia with nonsegmental air-space consolidation confined to the outer third of the lung, the "photographic negative of pulmonary edema". Histopathologic features of chronic eosinophilic pneumonia are intraalveolar and interstitial infiltrations with eosinophils, histiocytes, giant cells, scattered lymphocytes and plasma cells. Glucocorticoid therapy cause prompt resolution of symptoms as well as disappearans of blood eosinophils, elevated serum Ig E levels and the roentgenographic lesions. Infrequent radiographic findings include nodular infiltrates, consolidations, cavitations, atelectasis and pleural effusions. Deaths from CEP although rare, have been reported, but the majorities of CEP have benign courses and do not need a therapy with ventilator. We report a case of chronic eosinophilic pneumonia, which had a sudden course associated with diffuse pneumonic consolidations on the both lung and bilateral pleural effusion.