Heme oxygenase-1 induced by desoxo-narchinol-A attenuated the severity of acute pancreatitis via blockade of neutrophil infiltration

Bae, Gi-Sang,Kim, Dong-Goo,Jo, Il-Joo,Choi, Sun-Bok,Kim, Myoung-Jin,Shin, Joon Yeon,Kim, Dong-Uk,Song, Ho-Joon,Joo, Myungsoo,Park, Sung-Joo ELSEVIER 2019 INTERNATIONAL IMMUNOPHARMACOLOGY Vol.69 No.-

<P><B>Abstract</B></P> <P>Heme oxygenase-1 (HO-1) has an anti-inflammatory action in acute pancreatitis (AP). However, its mechanism of action and natural compounds/drugs to induce HO-1 in pancreas are not well understood. In this study, we investigated the regulatory mechanisms of HO-1 during AP using desoxo-narchinol-A (DN), the natural compound inducing HO-1 in the pancreas. Female C57/BL6 Mice were intraperitoneally injected with supramaximal concentrations of cerulein (50 μg/kg) hourly for 6 h to induce AP. DMSO or DN was administered intraperitoneally, then mice were sacrificed 6 h after the final cerulein injection. Administration of DN increased pancreatic HO-1 expression through activation of activating protein-1, mediated by mitogen-activated protein kinases. Furthermore, DN treatment reduced the pancreatic weight-to-body weight ratio as well as production of digestive enzymes and pro-inflammatory cytokines. Inhibition of HO-1 by tin protoporphyrin IX abolished the protective effects of DN on pancreatic damage. Additionally, DN treatment inhibited neutrophil infiltration into the pancreas via regulation of chemokine (C-X-C motif) ligand 2 (CXCL2) by HO-1. Our results suggest that DN is an effective inducer of HO-1 in the pancreas, and that HO-1 regulates neutrophil infiltration in AP via CXCL2 inhibition.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Desoxo-narchinol-A (DN) is a natural compound of HO-1 inducer in pancreas. </LI> <LI> Mechanism of DN-induced HO-1 is mediated by MAPK/Activator Protein-1/HO-1 signaling. </LI> <LI> DN-induced HO-1 blocks neutrophil infiltration into pancreas via inhibition of CXCL2. </LI> <LI> DN inhibits cerulein-induced acute pancreatitis (AP) and AP-associated lung injury. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Upregulation of heme oxygenase-1 by ginsenoside Ro attenuates lipopolysaccharide-induced inflammation in macrophage cells

Kim, Sokho,Oh, Myung-Hoon,Kim, Bum-Seok,Kim, Won-Il,Cho, Ho-Seong,Park, Byoung-Yong,Park, Chul,Shin, Gee-Wook,Kwon, Jungkee The Korean Society of Ginseng 2015 Journal of Ginseng Research Vol.39 No.4

Background: The beneficial effects of ginsenoside species have been well demonstrated in a number of studies. However, the function of ginsenoside Ro (GRo), an oleanane-type saponin, has not been sufficiently investigated. Thus, the aim of the present study was to investigate the anti-inflammatory effects of GRo in vitro using the Raw 264.7 mouse macrophage cell line treated with lipopolysaccharide (LPS), and to clarify the possible mechanism of GRo involving heme oxygenase-1 (HO-1), which itself plays a critical role in self-defense in the presence of inflammatory stress. Methods: Raw 264.7 cells were pretreated with GRo (up to $200{\mu}M$) for 1 h before treatment with 1 mg/mL LPS, and both cell viability and inflammatory markers involving HO-1 were evaluated. Results: GRo significantly increased cell viability in a dose dependent manner following treatment with LPS, and decreased levels of reactive oxygen species and nitric oxide. GRo decreased inflammatory cytokines such as nitric oxide synthase and cyclooxygenase-2 induced by LPS. Moreover, GRo increased the expression of HO-1 in a dose dependent manner. Cotreatment of GRo with tin protoporphyrin IX, a selective inhibitor of HO-1, not only inhibited upregulation of HO-1 induced by GRo, but also reversed the anti-inflammatory effect of GRo in LPS treated Raw 264.7 cells. Conclusion: GRo induces anti-inflammatory effects following treatment with LPS via upregulation of HO-1.

Upregulation of heme oxygenase-1 by ginsenoside Ro attenuates lipopolysaccharide-induced inflammation in macrophage cells

Sokho Kim,Myung-Hoon Oh,Bum-Seok Kim,Won-Il Kim,Ho-Seong Cho,Byoung-Yong Park,Chul Park,Gee-Wook Shin,Jungkee Kwon 고려인삼학회 2015 Journal of Ginseng Research Vol.39 No.4

Background: The beneficial effects of ginsenoside species have been well demonstrated in a number of studies. However, the function of ginsenoside Ro (GRo), an oleanane-type saponin, has not been suffi- ciently investigated. Thus, the aim of the present study was to investigate the anti-inflammatory effects of GRo in vitro using the Raw 264.7 mouse macrophage cell line treated with lipopolysaccharide (LPS), and to clarify the possible mechanism of GRo involving heme oxygenase-1 (HO-1), which itself plays a critical role in self-defense in the presence of inflammatory stress. Methods: Raw 264.7 cells were pretreated with GRo (up to 200mM) for 1 h before treatment with 1 mg/ mL LPS, and both cell viability and inflammatory markers involving HO-1 were evaluated. Results: GRo significantly increased cell viability in a dose dependent manner following treatment with LPS, and decreased levels of reactive oxygen species and nitric oxide. GRo decreased inflammatory cytokines such as nitric oxide synthase and cyclooxygenase-2 induced by LPS. Moreover, GRo increased the expression of HO-1 in a dose dependent manner. Cotreatment of GRo with tin protoporphyrin IX, a selective inhibitor of HO-1, not only inhibited upregulation of HO-1 induced by GRo, but also reversed the anti-inflammatory effect of GRo in LPS treated Raw 264.7 cells. Conclusion: GRo induces anti-inflammatory effects following treatment with LPS via upregulation of HO-1.

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.

무증상의 현미경적 혈뇨를 동반한 성인 환자에서 신조직 검 사의 유용성

김형종,최훈영,김동기,김현진,장제현,김현욱,최규헌,이호영,한대석,강신욱 대한신장학회 2003 대한신장학회잡지 Vol.22 No.6

Fluoxetine and Sertraline Attenuate Postischemic Brain Injury in Mice

Shin, Tae-Kyeong,Kang, Mi-Sun,Lee, Ho-Youn,Seo, Moo-Sang,Kim, Si-Geun,Kim, Chi-Dae,Lee, Won-Suk The Korean Society of Pharmacology 2009 The Korean Journal of Physiology & Pharmacology Vol.13 No.3

This study aimed to investigate whether selective serotonin reuptake inhibitors (SSRIs) attenuate brain injury and facilitate recovery following photothrombotic cortical ischemia in mice. Male ICR mice were anesthetized and systemically administered Rose Bengal. Permanent focal ischemia was induced in the medial frontal and somatosensory cortices by irradiating the skull with cold light laser. The animals were treated with fluoxetine or sertraline once a day for 14 d starting 1 h after ischemic insult. Treatment with fluoxetine and sertraline significantly reduced the infarct size. The Evans blue extravasation indices of the fluoxetine- and sertraline-treated groups were significantly lower than that of the vehicle group. Treatment with fluoxetine and sertraline shifted the lower limit of the mean arterial blood pressure for cerebral blood flow autoregulation toward normal, and significantly increased the expression of heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1 ${\alpha}$ (HIF-1 ${\alpha}$) proteins in the ischemic region. These results suggest that SSRIs, such as fluoxetine and sertraline, facilitate recovery following photothrombotic cortical ischemia via enhancement of HO-1 and HIF-1 ${\alpha}$ proteins expression, thereby providing a benefit in therapy of cerebral ischemia.

조직학적 진단된 chronic necrotizing pulmonary aspergillosis 2예

김연숙,정숙인,기현균,김춘관,김신우,한정호,김성민,백경란,송재훈 대한화학요법학회 2000 대한화학요법학회지 Vol.18 No.1

CNPA는 기존의 폐질환 및 폐절제술로 인해 국소방어기전에 저하가 있거나 비특이적 전신면역상태저하를 갖고 있는 환자들에게서 주로 발생하는 만성적인 공동성 폐질환이다. 현재까지 우리나라에서는 CNPA의 보고가 없는 상태이고, 저자들은 최근 조직학적으로 진단된 CNPA 2예를 경험하였기에 보고하는 바이다. 저자들이 경험한 CNPA 환자들은 만성알코올 중독 및 기관지확장증과 같은 기저질환과 폐절제술을 받은 병력이 있었다. Aspergillus가 폐실질을 침윤하고 있는 조직소견과 조직배양에서 Aspergillus가 검출되어 조직학적 진단이 가능하였고, amphotericin B의 정주요법 및 경구 itraconazole 투여와 폐절제술 등으로 성공적으로 치료되었다. 아직 많은 임상의들에게는 낯선 질환인 CNPA의 치료성적은 환자의 동반질환 및 CNPA 자체의 중증도, 진단과 치료 시작의 지연 등에 의해 크게 좌우되므로 만성적으로 진행하는 공동성 폐병변을 갖고 있는 환자에게서 CNPA를 감별하는 것이 중요하다. Chronic necrotizing pulmonary aspergillosis (CNPA) is a chronic cavitary form of pulmonary aspergillosis. Dozens of CNPA cases have been reported in patients with systemic immunologic dysfunction or altered local defense mechanism from preexisting pulmonary disease. Review of literatures revealed that no CNPA cases have been reported in Korea yet. We experienced two cases of CNPA proven by lung biopsy. A 53-year-old alcoholic male in poor nutritional state was admitted with generalized weakness and weight loss. Chest CT revealed a cavitary nodule surrounded with ground-glass attenuation. CT-guided fine needle aspiration and biopsy was done. The biopsy specimen demonstrated dichotomously branching septated hyphae consistent with those of Aspergillus sp. Another case was a 39-year-old man with bronchiectasis who was admitted with persistent hemoptysis. He had a past history of pulmonary tuberculosis. A parahilar lesion with intracavitary soft tissue mass was incidentally detected in high-resolution GT. Left lingular segmentectomy was done due to uncontrolled hemoptysis and CNPA was histologically diagnosed. Both patients were successfully treated with intravenous amphotericin B followed by oral itraconazole. Even though CNPA is unfamiliar to most clinicians, it should be included in differential diagnoses of chronic progressive cavitary pulmonary lesion, especially in patients with immunologic dysfunction.

만성 견비통에 대한 동씨침 치료의 무작위 대조군의 임상 연구

김찬영,권나현,신예지,남동우,김건형,김종인,최도영,이윤호,이재동 WHO COLLABORATING CENTRE FOR TRADITIONAL MEDICINE 2007 東西醫學硏究所 論文集 Vol.2007 No.-

Objectives : To observe the effect of acupuncture treatment in chronic shoulder pain patients. Methods : 36 voluntary patients were randomly assigned to an acupuncture treatment group(E GrouP, n=18) and a control group(C GrouP, n=18). The E Group patients received acupuncture treatment on LI_(15), TE_(14), GB_(21) and Master Dong's acupuncture points, Shin-gwan and Gyun-joong, twice a week for four weeks. The C Group patients received no treatment. All patients in both groups were instructed to practise self exercise in their daily lives. Evaluations were made at baseline and after four weeks of study. The Constant Shoulder Assessment(CSA), Shoulder Pain and Disability Index(SPADI) and the patient's subjective pain was measured by Visual Analogue Scale(VAS). The obtained data was analyzed. Results '. The E Group showed significant(p<0.05) improvement in CSA, SPADI and VAS after four weeks of treatment. The C Group showed significant(p<0.05) improvement in CSA, but the change of SPADI and VAS was insignificant(P>0.05). CSA and SPADI of E Group significantly(p<0.05) improved compared to the C GrouP, but the difference of VAS change in the two groups was insignificant(p>0.05). Conclusions : Four weeks of acupuncture treatment significantly improved CSA, SPADI and VAS. The improvement of CSA and SPADI was significant(p<0.05) compared to untreated patients.

혈액암환자에서 조혈모세포 이식 후 따르는 헤르페스 바이러스 감영 양상

이호섭,탁희상,신성훈,김양수,남성진,김혜수,박진희,정수현,김성빈,김예나 고신대학교 의과대학 2010 고신대학교 의과대학 학술지 Vol.25 No.1

배경 : 헤르페스바이러스과에는 단순포진 바이러스(HERPES SIMPLEX VIRUS, HSV), 수두대상포진 바이러스 (VARICELLA-ZOSTER VIRUS, VZV), 엡스타인-바 바이러스 (EPSTEIN-BARR VIRUS, EBV), 그리고 거대세포 바이러스 (CYTOMEGALOVIRUS, CMV) 등이 있다. 헤르페스바이러스 감염은 혈액암환자에서 조혈모세포 이식 환자에서 전파 (dissemination), 이차감염, 세균 중복 감염의 심각한 합병증을 일으킬 수 있다. 하지만 항암약물치료를 받는 림파종 환자에서 항 바이러스 약제의 사용 용량과 기간에 대한 concensus는 없다. 헤르페스바이러스 감염에 대한 발생율과 위험인자를 후향성으로 분석하였다. 방법 : 고신대학교 복음 병원에서 1995년 6월부터 2009 년 2월 사이에 새롭게 진단되어 조혈모세포 이식을 받은 전체 58명의 환자들이 후향적으로 현 연구에 등록했다. 헤르페스 바이러스 감염은 임상적 진단, 혈청학적 검사 또는 병리학적 진단에 기초하여 확진한다. 환자들의 특성은 다음과 같다: 평균 연령은 44세 (범위 19-62세)였고 남녀비는 30:28이었다. 등록된 질환은 백혈병 (n=9, 15.5%), 림프종 (n=30, 51.7%), 다발성 골수종 (n=12, 20.7%), 재생불량성 빈혈 (n=6, 10.3%) 그리고 골수이형성증후군 (n=1, 1.7%)이 포함되었다. 결과는 chi-squre test나 independent samples T test를 사용하여 분석되었다. Multivariate analysises에 대해 logistic regression test를 사용하였다. 결과 : 15명의 환자들 (25.9%)에서 조혈모세포 이식후 헤르페스 바이러스 감염이 발생하였다. 조혈모세포 이식 5년간 누적 발생율은 53.9%였다. Univariate analyses에서 헤르페스 바이러스 감염에 대한 유의한 위험 인자는 없었다. 하지만 조혈모세포 이식후 생존 기간(40.18 ± 30.14 months vs 20.06 ± 26.67 months, p=0.018)은 헤르페스 바이러스 감염의 낮은 발병율과 유의한 관련성이 있었다. 이식 편대 숙주질환 (GVHD)의 존재 (37.5% in developed GVHD vs 0% in no GVHD, p=0.200), 동종조혈 모세포 이식에서 면역억제요법의 기간 (15.98 ± 14.02 months vs 6.78 ± 3.67 months, p = 0.374)은 헤르페스 바이러스 감염에 대한 위험인자가 아니었다. 결론 : 조혈모세포 이식 후 생존 기간은 어사이클로비어 예방을 받은 혈액암 환자에서 헤르페스 바이러스 감염의 낮은 발병율과 연관성이 있는 것으로 보인다. 저용량의 어사이클로비어 예방은 헤르페스 바이러스 감염의 고위험군인 조혈모세포 이식을 받은 혈액암 환자에 필요하리라 생각된다. Background : Herpesviridae family includes herpes simplex virus, varicella zoster virus, Epstein-Barr virus, and cytomegalovirus, etc. Herpesviridae viral infection (HVI) can lead to serious complications including dissemination, secondary infection, bacterial superinfection in patients with hematologic malignancy following hematopoietic stem cell transplantation (HSCT). But there was no consensus on the dose and duration of antiviral agents prophylaxis in patients undergoing chemotherapy. We retrospectively analyzed the incidence and the risk factors for HVI. Method : A total of 58 patients who newly diagnosed and received HSCT with prophylaxis of acyclovir at the Kosin University Gospel Hospital, Busan, Korea between June 1995 and February 2009 were enrolled retrospectively in the current study. HVI was confirmed based on clinical diagnosis, serologic test or pathologic diagnosis. The characteristics of the patients were as follows: the median age was 44 years (range 19-62 years) with a female-to-male ratio of 30:28. The enrolled diseases included leukemia (n=9, 15.5%), lymphoma (n=30, 51.7%), multiple myeloma (n=12, 20.7%), aplastic anemia (n=6, 10.3%) and myelodysplastic syndrome (n=1, 1.7%). The results were analyzed using a chi-square test and independent samples T test. For the multivariate analysis, we used logistic regression test. Results : Fifteen patients (25.9%) developed HVI after HSCT. The cumulative incidence of HVI was 53.8% at 5 years after HSCT. In univariate analysis, there was no significant risk factor for HVI. The presence of graft-versus-host disease (GVHD) (37.5% in developed GVHD vs. 0% in no GVHD, p=0.200), duration of immunosuppressive therapy (IST) in allo-SCT (15.98 ± 14.02 months vs. 6.78 ± 3.67 months, p = 0.374) were not risk factors for HVI. Conclusion : The incidence of HVI was similar to that in historical other studies. There was no risk factor associated with development of HVI. Most of the HVI occurred within the first 24 months after transplantation. So long term use of antiviral prophylaxis may be needed to prevention of HVI after HSCT.

신경세포의 Outgrowth 향상을 위한 마이크로 파이버 지지체와 전단응력의 영향

김인애,박수아,김영직,김수향,신호준,이용재,신지원,신정욱 한국공작기계학회 2005 한국공작기계학회 춘계학술대회논문집 Vol.2005 No.-

We introduced mechanical stimuli and micro patterned substrate with micro fibers to investigate the effects of those on neurite outgrowth along with nerve growth factor (NGF) in vitro. Micro fiber substrates were fabricated using an electros pinning process. And PC-12 cells cultured on substrates were simulated with newer growth factor and laminar flow shear stress in a fluid flow system. The results suggest that micro fiber substrates and fluid-induced shear stress are promising for simulating neuronal regeneration in a desired direction.