Hypoxia-Responsive MicroRNA-101 Promotes Angiogenesis <i>via</i> Heme Oxygenase-1/Vascular Endothelial Growth Factor Axis by Targeting Cullin 3

Kim, Ji-Hee,Lee, Kwang-Soon,Lee, Dong-Keon,Kim, Joohwan,Kwak, Su-Nam,Ha, Kwon-Soo,Choe, Jongseon,Won, Moo-Ho,Cho, Byung-Ryul,Jeoung, Dooil,Lee, Hansoo,Kwon, Young-Guen,Kim, Young-Myeong Mary Ann Liebert 2014 Antioxidants & redox signaling Vol.21 No.18

<P>Aims: Hypoxia induces expression of various genes and microRNAs (miRs) that regulate angiogenesis and vascular function. In this study, we investigated a new functional role of new hypoxia-responsive miR-101 in angiogenesis and its underlying mechanism for regulating heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) expression. Results: We found that hypoxia induced miR-101, which binds to the 3 ' untranslated region of cullin 3 (Cul3) and stabilizes nuclear factor erythroid-derived 2-related factor 2 (Nrf2) via inhibition of the proteasomal degradation pathway. miR-101 overexpression promoted Nrf2 nuclear accumulation, which was accompanied with increases in HO-1 induction, VEGF expression, and endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) production. The elevated NO-induced S-nitrosylation of Kelch-like ECH-associated protein 1 and subsequent induction of Nrf2-dependent HO-1 lead to further elevation of VEGF production via a positive feedback loop between the Nrf2/HO-1 and VEGF/eNOS axes. Moreover, miR-101 promoted angiogenic signals and angiogenesis both in vitro and in vivo, and these events were attenuated by inhibiting the biological activity of HO-1, VEGF, or eNOS. Moreover, these effects were also observed in aortic rings from HO-1(+/-) and eNOS(-/-) mice. Local overexpression of miR-101 improved therapeutic angiogenesis and perfusion recovery in the ischemic mouse hindlimb, whereas antagomiR-101 diminished regional blood flow. Innovation: Hypoxia-responsive miR-101 stimulates angiogenesis by activating the HO-1/VEGF/eNOS axis via Cul3 targeting. Thus, miR-101 is a novel angiomir. Conclusion: Our results provide new mechanistic insights into a functional role of miR-101 as a potential therapeutic target in angiogenesis and vascular remodeling. Antioxid. Redox Signal. 21, 2469-2482.</P>

Morin exerts cytoprotective effects against oxidative stress in C2C12 myoblasts via the upregulation of Nrf2-dependent HO-1 expression and the activation of the ERK pathway

Lee, Moon Hee,Han, Min Ho,Lee, Dae-Sung,Park, Cheol,Hong, Su-Hyun,Kim, Gi-Young,Hong, Sang Hoon,Song, Kyoung Seob,Choi, Il-Whan,Cha, Hee-Jae,Choi, Yung Hyun UNKNOWN 2017 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE Vol.39 No.2

<P>In the present study, we investigated the cytoprotective efficacy of morin, a natural flavonoid, against oxidative stress and elucidated the underlying mechanisms in C2C12 myoblasts. Our results indicated that morin treatment prior to hydrogen peroxide (H2O2) exposure significantly increased cell viability and prevented the generation of reactive oxygen species. H2O2-induced comet-like DNA formation and gamma H2AX phosphorylation were also markedly suppressed by morin with a parallel inhibition of apoptosis in C2C12 myoblasts, suggesting that morin prevented H2O2-induced cellular DNA damage. Furthermore, morin markedly enhanced the expression of heme oxygenase-1 (HO-1) associated with the induction and phosphorylation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and the inhibition of Kelch-like ECH-associated protein 1 (Keapl) expression. Notably, these events were eliminated by transient transfection with Nrf2-specific small interfering RNA. Additional experiments demonstrated that the activation of the Nrf2/HO-1 pathway by morin was mediated by the extracellular signal-regulated kinase (ERK) signaling cascade. This phenomenon was confirmed with suppressed Nrf2 phosphorylation and consequently diminished HO-1 expression in cells treated with a pharmacological inhibitor of ERK. Collectively, these results demonstrated that morin augments the cellular antioxidant defense capacity through the activation of Nrf2/HO-1 signaling, which involves the activation of the ERK pathway, thereby protecting C2C12 myoblasts from H2O2,-induced oxidative cytotoxicity.</P>

Sauchinone Suppresses Pro-inflammatory Mediators by Inducing Heme Oxygenase-1 in RAW264.7 Macrophages

Li, Bin,Lee, Dong-Sung,Choi, Hyun-Gyu,Kim, Kyoung-Su,Kang, Dae-Gil,Lee, Ho-Sub,Jeong, Gil-Saeng,Kim, Youn-Chul Pharmaceutical Society of Japan 2011 BIOLOGICAL & PHARMACEUTICAL BULLETIN Vol.34 No.10

<P>Sauchinone, a biologically active lignan isolated from the roots of <I>Saururus chinensis</I> (L<SMALL>OUR</SMALL>.) B<SMALL>AILL</SMALL>. (Saururaceae), is reported to exert a variety of biological activities, such as hepatoprotective, anti-inflammatory actions and inhibitory effects on bone resorption. In this study, we investigated the effect of sauchinone in suppressing cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, leading to a reduction in COX-2-derived prostaglandin E<SUB>2</SUB> (PGE<SUB>2</SUB>) and iNOS-derived nitric oxide (NO) production in lipopolysaccharide (LPS) stimulated RAW264.7 macrophages. Present study also demonstrates the effects of sauchinone in inducing heme oxygenase-1 (HO-1) expression and an increase in heme oxygenase (HO) activity in RAW264.7 macrophages. The effects of sauchinone on LPS-induced PGE<SUB>2</SUB>, NO, tumor necrosis factor-α (TNF-α) and interlukine-1β (IL-1β) production were partially reversed by the HO-1 inhibitor Tin protoporphyrin was also seen in this study. In addition, we found that treatment with extracellular signal-regulated kinase (ERK) inhibitor (PD98059) reduced sauchinone-induced HO-1 expression. Sauchinone also increased ERK phosphorylation. These results suggest that sauchinone inhibits pro-inflammatory mediators through expression of anti-inflammatory HO-1 <I>via</I> ERK pathway.</P>

Antioxidant and cytoprotective effects of morin against hydrogen peroxide-induced oxidative stress are associated with the induction of Nrf-2-mediated HO-1 expression in V79-4 Chinese hamster lung fibroblasts

Lee, Moon Hee,Cha, Hee-Jae,Choi, Eun Ok,Han, Min Ho,Kim, Sung Ok,Kim, Gi-Young,Hong, Su Hyun,Park, Cheol,Moon, Sung-Kwon,Jeong, Soon-Jeong,Jeong, Moon-Jin,Kim, Wun-Jae,Choi, Yung Hyun Spandidos Publications 2017 International journal of molecular medicine Vol.39 No.3

<P>Natural phytochemicals of plant origin, including flavonoids, have been found to be potent antioxidants providing beneficial effects against oxidative stress-related diseases. The present study was carried out to investigate the antioxidant properties of morin, a flavonoid originally isolated from the flowering plants of the Moraceae family. Superoxide dismutase (SOD)-like activity and 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(center dot+)) radical scavenging activity were determined. We also investigated the cytoprotective effects of morin against hydrogen peroxide (H2O2)-induced DNA damage and apoptosis in V79-4 Chinese hamster lung fibroblasts. Our results demonstrated that morin had strong scavenging effects against ABTS' radicals with enhanced SOD activity, which varied in a dose-dependent manner. Morin was found to reduce H2O2-induced intracellular reactive oxygen species generation and nuclear DNA damage, and it recovered cell viability damaged by H2O2 via inhibition of mitochondrial dysfunction-mediated apoptosis. Notably, the treatment of V79-4 cells with morin markedly enhanced the expression of heme oxygenase-1 (HO-1) but not quinone oxidoreductase-1, which was associated with the increased expression and phosphorylation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and the downregulation of Kelch-like ECH-associated protein 1 expression. Based on our findings, we conclude that morin effectively ameliorated oxidative stress-induced DNA damage through intrinsic free radical scavenging activity and activation of the Nrf2/HO-1 pathway.</P>

편두통 환자의 임상 양상 및 생체전기 자율반응과의 상관성 고찰

이현종,정인태,김수영,이두익,김건식,이재동,이윤호,최도영 WHO COLLABORATING CENTRE FOR TRADITIONAL MEDICINE 2004 東西醫學硏究所 論文集 Vol.2004 No.-

Objective : We had a clinical report in headache but didn't in migraine. We have planned this study in order to get the basic data of migraine in oriental medicine. Methods : The patient of 36 in migraine checked sec, age, onset, family history, severity of pain, influences of life, induced cause, clinical pain characteristics, associated symptom, treatment style, and paescription, frequency, using period of analgesics by a questionnaire and differentiated syndromes in migraine and evaluated autonomic bioelectric response recorder(ABR-2000). Results : There are 23.4% in prevalence rate of migraine. The ratio of sex is M: F=1:17. The age of an attack is the highest in thirties. The patient are the most in forties. The mean duration of illness is 12.0±9.9 years. 83.4% had a family history. 61.1% had a moderate grade in severity of pain. 77.8% selected fatigue in induced cause of migraine. 69.4% had tingling sense, nausea and vomiting in the associated symptoms. 91.7% used analgesics for treatment and 51.5% of them used analgesics voluntarily. 61.9% of them take analgesics less than once in a week. 33.6% had the phlegm syncope headache in differentiation of syndrome. In ABR-2000 results, item of graph showed low tendency mostly. Conclusions : We expected that this re port of clinical progress, differentiation of syndromes and ABR-2000 results in migraine would be used basic data by oriental medicine to treat migraine.

퇴행성 슬관절염 환자의 증상 중증도 측정을 위한 적외선 체열상의 유용성

이두익,김건식,김수영,최도영,이상훈,이재동,이윤호 EAST-WEST MEDICAL RESEARCH INSTITUTE KYUNG HEE UNI 2005 東西醫學硏究所 論文集 Vol.2005 No.-

Objectives: To investigate the applicability of thermography as severity measurement in the patients with osteoarthritis (OA) of the knee. Methods: Data were obtained from 80 patiens with OA of the knee. They were asked to answer two disease-specific questionnaire (Western Ontario and McMaster Universities (WOMAC) OA index, Lequesne's Functional Index (LEI)), one generic instrument (Korean Health Assessment Questionnaire (KHAQ)), Visual Analogue Scale (VAS) pain intensities in order to assess the severity of disease, quality of life, and degree of pain and taken thermography in standardized environment before and after treatment, respectively. Results: The thermal differences between ipsilateral side and contralateral side in lateral aspect, medial aspect, patella region and suprapatella of both knees were correlated with pain lesion sites. Age, duration of disease, duration of morning stiffness, sex, and crepitus of knee were not correlated with the thermal differences of each regions. And also LFI, WOMAC, WOMAC pain subscale, WOMAC stiffness subscale, WOMAC physical function, KHAQ, were not correlated with the thermal differences of each region. But, the changes of VAS pain intensities were highly correlated with the thermal differences of each regions, especially in patelaa and suprapatella of knees after teratment. Conclusions: Although several specific evaluation indices for osteoarthritis of knee were not correlated with the degree of thermal differences between both knees, the differences of pain intensity (VAS) were quit correlated with thermal differences after treatment. And infrared thermography might be a very useful devices fot the evaluation of OA of knee and its treatment. Further study on the thermography on OA of the knee in more size of patients with appropriate severity grade and the standardization of analysis of thermographic data were recommended.

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.

대호 간척기 토양의 염농도별 밭작물의 염해 평가

이승헌,류순호,설수일,안열,정영상,이상모 江原大學校 附設 環境硏究所 2001 環境硏究 Vol.18 No.-

This study was carried out to obtain the basic data for selecting the applicable crops in reclaimed land during desalinization period. A pot experiment was conducted with 5 different electrical conductivities of the saturated extracts (ECe 1, 3, 9, 14, and 16 dS·m^(-1)) of soils taken from the Dae-Ho reclaimed tidal lands. Eight crops (Chinese cabbage, radish, tomato, red pepper, buckwheat, soybean, sesame, and green perilla) were grown for 37days. Plant height and number of leaves were surveyed on 2 and 4 weeks after seeding, and on harvest time (5 weeks). After harvest, dry weights of harvested crops were measured and soil chemical properties were analyzed. Emergence rates of crops were comparatively high except sesame. For sesame, there was no emergence at ECe over 3 dS·m^(-1). Growth and dry weight decreased significantly as increasing ECe. The ECe which decreased 50% of dry weight index were 14.2 dS·m^(-1) for radish, 11.4 dS·m^(-1) for Chinese cabbage, 10.2 dS·m^(-1) for tomato for red pepper, 8.9 dS·m^(-1) for buckwheat and green perilla, 8.6 dS·m^(-1) for soybean, and 8.9 dS·m^(-1) for tomato. At higher ECe that start the growth inhibition, increasing 1 dS·m^(-1) in ECe, 7.7, 6.5, 5.9, 5.6, 5.2, and 4.9% of dry weight decreased for buckwheat, green perilla, Chinese cabbage, radish, soybean, and tomato (red pepper), respectively. The critical value of ECe for crop survival except sesame was 15.4~23.1 dS·m^(-1).

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.