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Shu W, Wang Y, Li C, Zhang L, Zhuoma D, Yang P, Yan G, Chen C, Ba Y, Du P, Wang X. Single-cell Expression Atlas Reveals Cell Heterogeneity in the Creeping Fat of Crohn's Disease. Inflamm Bowel Dis 2023; 29:850-865. [PMID: 36715181 DOI: 10.1093/ibd/izac266] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND Creeping fat (CrF) has been recognized to play a positive role in Crohn's disease (CD) progression, yet the cellular compositions within mesenteric adipose tissue (MAT) and their potential mechanism in CrF formation are poorly understood. METHODS Analysis of 10X single-cell RNA sequencing was performed on 67 064 cells from 3 pairs of surgically resected samples of CrF and their uninvolved MAT. The results were validated in another cohort with 6 paired MAT samples by immunofluorescence. RESULTS All samples manifested excellent consistency and repeatability in our study, and 10 cell types from the transcriptome atlas, including 20 clusters, were identified. In CrF, a specific vascular endothelial cell subpopulation highly expressing lipoprotein lipase was first identified, with a significantly increased proportion. This vascular endothelial cell subpopulation manifested robust peroxisome proliferator-activated receptor γ (PPARγ) transcription activity and an upregulated PPAR signaling pathway and was involved in lipid metabolism and the antibacterial response. A novel fibroblast subpopulation (FC3) with remarkable GREM1 and RFLNB expression was identified and validated to predominantly accumulate in the CrF. The FC3 was annotated as inflammation-associated fibroblasts, which are characterized by inflammatory responses and the regulation of Smad phosphorylation related to intestinal fibrosis. The trajectory of fibroblasts revealed their pro-inflammatory and profibrotic conversion tendency during CrF formation with corresponding gene dynamics. Additionally, we unprecedently dissected the different origins and functions of 6 macrophage subclusters within the myeloid compartment. CONCLUSIONS Our results uncover the cellular heterogeneity in the MAT of CD and the role of these various cellular compositions in CrF development. This comprehensive understanding of CrF provides future directions for in-depth research on and potential targets for MAT-based treatment.
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Affiliation(s)
- Weigang Shu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yongheng Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Chuanding Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Lei Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Deji Zhuoma
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Pengyu Yang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Guorong Yan
- Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
| | - Chunqiu Chen
- Center for Difficult and Complicated Abdominal Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
| | - Yongbing Ba
- OE Biotech Co., Ltd., Shanghai 201114, China
| | - Peng Du
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200092, China
| | - Xiaolei Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China
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Liu X, Li J, Hao X, Sun H, Zhang Y, Zhang L, Jia L, Tian Y, Sun W. LC–MS-Based Urine Metabolomics Analysis for the Diagnosis and Monitoring of Medulloblastoma. Front Oncol 2022; 12:949513. [PMID: 35936679 PMCID: PMC9353006 DOI: 10.3389/fonc.2022.949513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/23/2022] [Indexed: 11/25/2022] Open
Abstract
Medulloblastoma (MB) is the most common type of brain cancer in pediatric patients. Body fluid biomarkers will be helpful for clinical diagnosis and treatment. In this study, liquid chromatography–mass spectrometry (LC–MS)-based metabolomics was used to identify specific urine metabolites of MB in a cohort, including 118 healthy controls, 111 MB patients, 31 patients with malignant brain cancer, 51 patients with benign brain disease, 29 MB patients 1 week postsurgery and 80 MB patients 1 month postsurgery. The results showed an apparent separation for MB vs. healthy controls, MB vs. benign brain diseases, and MB vs. other malignant brain tumors, with AUCs values of 0.947/0.906, 0.900/0.873, and 0.842/0.885, respectively, in the discovery/validation group. Among all differentially identified metabolites, 4 metabolites (tetrahydrocortisone, cortolone, urothion and 20-oxo-leukotriene E4) were specific to MB. The analysis of these 4 metabolites in pre- and postoperative MB urine samples showed that their levels returned to a healthy state after the operation (especially after one month), showing the potential specificity of these metabolites for MB. Finally, the combination of two metabolites, tetrahydrocortisone and cortolone, showed diagnostic accuracy for distinguishing MB from non-MB, with an AUC value of 0.851. Our data showed that urine metabolomics might be used for MB diagnosis and monitoring.
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Affiliation(s)
- Xiaoyan Liu
- Core Instrument Facility, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Jing Li
- Core Instrument Facility, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xiaolei Hao
- Department of Neurosurgery, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Haidan Sun
- Core Instrument Facility, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yang Zhang
- Department of Neurosurgery, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Liwei Zhang
- Department of Neurosurgery, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Lulu Jia
- Department of Pharmacy, Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
- *Correspondence: Wei Sun, ; Yongji Tian, ; Lulu Jia,
| | - Yongji Tian
- Department of Neurosurgery, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- *Correspondence: Wei Sun, ; Yongji Tian, ; Lulu Jia,
| | - Wei Sun
- Core Instrument Facility, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
- *Correspondence: Wei Sun, ; Yongji Tian, ; Lulu Jia,
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Nattagh-Eshtivani E, Gheflati A, Barghchi H, Rahbarinejad P, Hachem K, Shalaby MN, Abdelbasset WK, Ranjbar G, Olegovich Bokov D, Rahimi P, Gholizadeh Navashenaq J, Pahlavani N. The role of Pycnogenol in the control of inflammation and oxidative stress in chronic diseases: Molecular aspects. Phytother Res 2022; 36:2352-2374. [PMID: 35583807 DOI: 10.1002/ptr.7454] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/23/2022] [Accepted: 03/15/2022] [Indexed: 02/05/2023]
Abstract
The prevalence of chronic diseases has increased significantly with the rising trend of sedentary lifestyles, reduced physical activity, and dietary modifications in recent decades. Inflammation and oxidative stress play a key role in the pathophysiology of several chronic diseases, such as type II diabetes, cardiovascular diseases, and hepatic conditions. Therefore, reducing inflammation and oxidative stress may be beneficial in the prevention and treatment of various chronic disorders. Since chronic diseases are not completely curable, various methods have been proposed for their control. Complementary therapies and the use of natural antioxidant and antiinflammatory compounds are among these novel approaches. Pycnogenol (PYC) is a natural compound that could control inflammation and oxidative stress. Furthermore, some previous studies have shown that PYC could effectively reduce inflammation through signaling the downstream of insulin receptors, inhibiting the phosphorylation of the serine residues of insulin receptor substrate-1, reducing pro-inflammatory cytokines and oxidative stress indices through the stimulation of antioxidant pathways, increasing free radical scavenging activities, preventing lipid peroxidation, and protecting the erythrocytes in glucose-6-phosphate dehydrogenase-deficient individuals, although these effects have not been fully proved. The present study aimed to comprehensively review the evidence concerning the positive physiological and pharmacological properties of PYC, with an emphasis on the therapeutic potential of this natural component for enhancing human health.
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Affiliation(s)
- Elyas Nattagh-Eshtivani
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Gheflati
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanieh Barghchi
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Pegah Rahbarinejad
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kadda Hachem
- Laboratory of Biotoxicology, Pharmacognosy and Biological Valorization of Plants (LBPVBP), Faculty of Sciences, University of Saida- Dr Moulay Tahar, Saida, Algeria
| | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Ismailia, Egypt
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Golnaz Ranjbar
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, Moscow, Russian Federation
- Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow, Russian Federation
| | - Pegah Rahimi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Naseh Pahlavani
- Health Sciences Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
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Zhang C, Wang L, Li T, Mao W, Liu B, Cao J. EP2/4 Receptors Promote the Synthesis of PGE 2 Increasing Tissue Damage in Bovine Endometrial Explants Induced by Escherichia coli. J Pharmacol Exp Ther 2020; 372:175-184. [PMID: 31732699 DOI: 10.1124/jpet.119.262444] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/11/2019] [Indexed: 12/17/2022] Open
Abstract
The bovine uterine is easily contaminated with bacteria during coitus or parturition. A previous study suggested that prostaglandin E2 (PGE2) promoted Escherichia coli-infected bovine endometrial tissue inflammatory damage via cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1). However, it remains unclear which PGE2 receptors regulate the proinflammatory effect of PGE2 In this study, we evaluated the effect of PGE2 and its mediated receptors on E. coli-infected endometrium explants isolated from the bovine uterus. The E. coli-infected bovine endometrial explants were cultured in vitro, and the study used EP2/4 receptor agonists to investigate the responses of COX-2, mPGES-1, PGE2, proinflammatory factors, and damage-associated molecular patterns (DAMPs). The expression of COX-2, mPGES-1, PGE2, proinflammatory factors, and DAMPs was significantly increased after infection with E. coli; however, the high expression levels caused by E. coli were reduced following treatment with COX-2 and mPGES-1 inhibitors. In addition, the expression levels of COX-2, mPGES-1, PGE2, proinflammatory factors, and DAMPs were higher in treatment with EP2/4 receptor agonists in E. coli-infected endometrium explants, and their promotable effects were effectively blocked by EP2/4 receptor antagonists. These findings provide evidence that PGE2 may promote the progress of inflammation in endometrial explants infected with E. coli in bovines. Furthermore, EP2/4 may be involved in a positive feedback loop for COX-2 and mPGES-1 expression, and this may be responsible for the proinflammatory reaction of PGE2 in E. coli-infected uteri of bovines. SIGNIFICANCE STATEMENT: PGE2 promoted E. coli-infected bovine endometrial tissue damage via COX-2 and mPGES-1. However, this proinflammatory effect of PGE2 depends on which receptors are affected by PGE2, and this remains unclear. In this study, it was investigated that EP2 and EP4 may be involved in a positive feedback loop for COX-2 and mPGES-1 expression, and this may be responsible for the proinflammatory reaction of PGE2 in E. coli-infected uteri of bovines.
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Affiliation(s)
- Chao Zhang
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine (C.Z., L.W., T.L., W.M., B.L., J.C.), and Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture (C.Z., L.W., T.L., W.M., B.L., J.C.), Inner Mongolia Agricultural University, Huhhot, China
| | - Lingrui Wang
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine (C.Z., L.W., T.L., W.M., B.L., J.C.), and Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture (C.Z., L.W., T.L., W.M., B.L., J.C.), Inner Mongolia Agricultural University, Huhhot, China
| | - Tingting Li
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine (C.Z., L.W., T.L., W.M., B.L., J.C.), and Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture (C.Z., L.W., T.L., W.M., B.L., J.C.), Inner Mongolia Agricultural University, Huhhot, China
| | - Wei Mao
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine (C.Z., L.W., T.L., W.M., B.L., J.C.), and Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture (C.Z., L.W., T.L., W.M., B.L., J.C.), Inner Mongolia Agricultural University, Huhhot, China
| | - Bo Liu
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine (C.Z., L.W., T.L., W.M., B.L., J.C.), and Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture (C.Z., L.W., T.L., W.M., B.L., J.C.), Inner Mongolia Agricultural University, Huhhot, China
| | - Jinshan Cao
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine (C.Z., L.W., T.L., W.M., B.L., J.C.), and Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture (C.Z., L.W., T.L., W.M., B.L., J.C.), Inner Mongolia Agricultural University, Huhhot, China
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Lee H, Lee DS, Chang KJ, Kim SH, Cheong SH. Glucose-Taurine Reduced Exerts Neuroinflammatory Responses by Inhibition of NF-κB Activation in LPS-Induced BV2 Microglia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1155:857-867. [PMID: 31468452 DOI: 10.1007/978-981-13-8023-5_72] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
We want to find the anti-neuroinflammatory action of the taurine derivative Glucose-Taurine Reduced (G-T-R). The anti-neuroinflammatory action by G-T-R were investigated in lipopolysaccharide (LPS)-induced BV2 microglia. G-T-R inhibited the production of nitric oxide and prostaglandin E2, and down-regulated the protein expression of inducible NO synthase and cyclooxygenase-2. In addition, G-T-R reduced the cytokines secretion such as tumor necrosis factor (TNF-α), interleukin (IL) -1β and IL-6, in BV2 microglia treated with LPS. In addition, G-T-R dose-dependently decreased the activation of nuclear factor-kappa B. These findings confirmed the anti-neuroinflammatory activity of G-T-R, which may exert protective effects against neuroinflammatory-related diseases.
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Affiliation(s)
- Hwan Lee
- College of Pharmacy, Chosun University, Dong-gu, Gwangju, Republic of Korea
| | - Dong-Sung Lee
- College of Pharmacy, Chosun University, Dong-gu, Gwangju, Republic of Korea
| | - Kyung Ja Chang
- Department of Food and Nutrition, Inha University, Incheon, Republic of Korea
| | - Sung Hoon Kim
- Department of Chemistry, Konkuk University, Seoul, Republic of Korea
| | - Sun Hee Cheong
- Department of Marine Bio-Food Sciences, Chonnam National University, Yeosu, Republic of Korea
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Zhang H, Zhang D, Li H, Yan H, Zhang Z, Zhou C, Chen Q, Ye Z, Hang C. Biphasic activation of nuclear factor-κB and expression of p65 and c-Rel following traumatic neuronal injury. Int J Mol Med 2018; 41:3203-3210. [PMID: 29568960 PMCID: PMC5881643 DOI: 10.3892/ijmm.2018.3567] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 02/22/2018] [Indexed: 01/28/2023] Open
Abstract
The transcription factor nuclear factor-κB (NF-κB) has been shown to function as a key regulator of cell death or survival in neuronal cells. Previous studies indicate that the biphasic activation of NF-κB occurs following experimental neonatal hypoxia-ischemia and subarachnoid hemorrhage. However, the comprehensive understanding of NF-κB activity following traumatic brain injury (TBI) is incomplete. In the current study, an in vitro model of TBI was designed to investigate the NF-κB activity and expression of p65 and c-Rel subunits following traumatic neuronal injury. Primary cultured neurons were assigned to control and transected groups. NF-κB activity was detected by electrophoretic mobility shift assay. Western blotting and immunofluorescence were used to investigate the expression and distribution of p65 and c-Rel. Reverse transcription-quantitative polymerase chain reaction was performed to assess the downstream genes of NF-κB. Lactate dehydrogenase (LDH) quantification and trypan blue staining were used to estimate the neuronal injury. Double peaks of elevated NF-κB activity were observed at 1 and 24 h following transection. The expression levels of downstream genes exhibited similar changes. The protein levels of p65 also presented double peaks while c-Rel was elevated significantly in the late stage. The results of the trypan blue staining and LDH leakage assays indicated there was no sustained neuronal injury during the late peak of NF-κB activity. In conclusion, biphasic activation of NF-κB is induced following experimental traumatic neuronal injury. The elevation of p65 and c-Rel levels at different time periods suggests that within a single neuron, NF-κB may participate in different pathophysiological processes.
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Affiliation(s)
- Huasheng Zhang
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Dingding Zhang
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Hua Li
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Huiying Yan
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Zihuan Zhang
- Department of Neurosurgery, Zhongdu Hospital, Bengbu, Anhui 233004, P.R. China
| | - Chenhui Zhou
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Qiang Chen
- Department of Neurosurgery, Southern Medical University (Guangzhou), Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Zhennan Ye
- Department of Neurosurgery, Southern Medical University (Guangzhou), Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
| | - Chunhua Hang
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
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Oh YC, Jeong YH, Cho WK, Hwang YH, Ma JY. Inhibitory effects of Dianthi Herba ethanolic extract on inflammatory and nociceptive responses in murine macrophages and mouse models of abdominal writhing and ear edema. JOURNAL OF ETHNOPHARMACOLOGY 2018; 211:375-383. [PMID: 28917973 DOI: 10.1016/j.jep.2017.09.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 08/30/2017] [Accepted: 09/11/2017] [Indexed: 06/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Dianthi Herba is a traditional herbal medicine used to treat inflammatory-related diseases including acute pyelonephritis, cystitis, laryngopharyngitis, and urethritis. AIM OF THE STUDY We investigated the effects of Dianthi Herba ethanolic extract (DH) on lipopolysaccharide (LPS)-mediated inflammatory responses in murine macrophages including RAW 264.7 cell line and mouse peritoneal macrophages as well as nociceptive and edema mouse models. MATERIALS AND METHODS The biological effects of DH on inflammatory cytokine, mediator, and related protein production were assessed using enzyme-linked immunosorbent assay (ELISA), Western blotting, and real-time reverse transcription-polymerase chain reaction (real-time RT-PCR). Additionally, Western blotting was performed to investigate intracellular signaling pathways, and the anti-nociceptive activity of three doses of DH (100, 200, and 300mg/kg) against acetic acid-induced writhing responses and its inhibitory effects on xylene-induced ear edema were researched in mice through oral administration. RESULTS DH treatment significantly inhibited nitric oxide (NO) secretion and inflammatory cytokine production in RAW 264.7 cells and mouse peritoneal macrophages and induced heme oxygenase (HO)-1 expression. DH strongly inhibited the transcriptional activity of nuclear factor (NF)-κB and phosphorylation of mitogen-activated protein kinases (MAPK) in LPS-stimulated macrophages. Meanwhile, DH exerted anti-nociceptive effects on writhing responses and anti-edema effects in mice. CONCLUSION We confirmed the anti-inflammatory activities and inhibitory mechanism of DH in macrophages and clarified its inhibitory effects in vivo. These findings illustrate the therapeutic potential of DH as a natural anti-inflammatory agent.
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Affiliation(s)
- You-Chang Oh
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Republic of Korea
| | - Yun Hee Jeong
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Republic of Korea
| | - Won-Kyung Cho
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Republic of Korea
| | - Youn-Hwan Hwang
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Republic of Korea
| | - Jin Yeul Ma
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Republic of Korea.
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Mubashir K, Ganai BA, Ghazanfar K, Akbar S, Rah B, Tantry M, Masood A. Anti-inflammatory and immuno-modulatory studies on LC-MS characterised methanol extract of Gentiana kurroo Royle. Altern Ther Health Med 2017; 17:78. [PMID: 28129760 PMCID: PMC5273812 DOI: 10.1186/s12906-017-1593-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 01/20/2017] [Indexed: 12/30/2022]
Abstract
BACKGROUND In ayurvedic traditional medicine Gentiana kurroo Royle (family; Gentianaceae) is used to treat several metabolic diseases. This plant is rich in various compounds belonging to flavonoids and glycosides. Till now little work has been carried out on immunomodulatory and anti-inflammatory potential of this plant. This study confirms the presence of bioactive compounds and evaluates the anti-inflammatory and immunomodulatory effect of this plant. METHODS To carry out this work, the methanol extract was investigated in different doses using in vivo and in vitro models. In vivo study involved haemagglutination titre and DTH methods, and in vitro study was done using splenocyte proliferation assay and LPS stimulated macrophage culture. TNF-α, IL-6 and NO were assayed using ELISA kit methods, while NF-κB was evaluated by western blotting. LC-ESI-MS/MS was used for the characterization of the methanol extract. RESULTS The results showed suppression of both humoral and cell mediated immunity in vivo. This effect was also observed by inhibition of B and T cell proliferation in splenocyte proliferation assay. TNF-α, IL-6 and NO concentrations were also less in extract treated macrophage cultures. The NF-κB expression was also lowered in treated macrophages as compared to untreated macrophages. All these observations were found to be dose dependent. LC-MS characterization of this extract showed the presence of known compounds which are glycosides, alkaloids and flavonoids in nature. CONCLUSION The methanol extract of this plant was found to be rich in glycoside, alkaloid and flavonoid compounds. These compounds are probably responsible for the suppression of immune response and anti-inflammatory activity. The extract as such and identified bioactive compounds can be useful for the treatment of inflammatory disorders.
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Kim SY, Park SM, Hwangbo M, Lee JR, Byun SH, Ku SK, Cho IJ, Kim SC, Jee SY, Park SJ. Cheongsangbangpung-tang ameliorated the acute inflammatory response via the inhibition of NF-κB activation and MAPK phosphorylation. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:46. [PMID: 28086859 PMCID: PMC5237186 DOI: 10.1186/s12906-016-1501-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 12/06/2016] [Indexed: 01/20/2023]
Abstract
Background Cheongsangbangpung-tang (CBT) is a traditional herbal formula used in Eastern Asia to treat heat-related diseases and swellings in the skin. The present study was conducted to evaluate the anti-inflammatory effects of cheongsangbangpung-tang extract (CBTE) both in vitro and in vivo. Methods The in vitro effects of CBTE on the lipopolysaccharide (LPS)-induced production of inflammation-related proteins were examined in RAW 264.7 cells. The levels of nitric oxide (NO) were measured with the Griess reagent. Inflammatory cytokines and prostaglandin E2 (PGE2) were detected using the enzyme-linked immunosorbent assay (ELISA) method. Inflammation-related proteins were detected by Western blot. The effect of CBTE on acute inflammation in vivo was evaluated using carrageenan (CA)-induced paw oedema. To evaluate the anti-inflammatory effect, paw oedema volume, thickness of the dorsum and ventrum pedis skin, number of infiltrated inflammatory cells, and number of COX-2-, iNOS-immunoreactive cells were measured. Results In an in vitro study, CBTE inhibited the production of NO and PGE2 and also decreased the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) activity, interleukin (IL)-1β, IL-6 and tumuor necrosis factor-α. In LPS-activated macrophages, nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) signalling is a pivotal pathway in the inflammatory process. These plausible molecular mechanisms increased the phosphorylation of I-κBα, while the activation of NF-κB and the phosphorylation of MAPK by LPS were blocked by CBTE treatment. In our in vivo study, a CA-induced acute oedematous paw inflammation rat model was used to evaluate the anti-inflammatory effect of CBTE. CBTE significantly reduced the increases in paw swelling, skin thicknesses, infiltrated inflammatory cells and iNOS-, COX-2 positive cells induced by CA injection. Conclusions Based on these results, CBTE should favourably inhibit the acute inflammatory response through modulation of NF-κB activation and MAPK phosphorylation. Furthermore, the inhibition of CBTE in rat paw oedema induced by CA is considered to be clear evidence that CBTE may be a useful source to treat inflammation.
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Jeong YH, Oh YC, Cho WK, Lee B, Ma JY. Anti-Inflammatory Effects of Melandrii Herba Ethanol Extract via Inhibition of NF-κB and MAPK Signaling Pathways and Induction of HO-1 in RAW 264.7 Cells and Mouse Primary Macrophages. Molecules 2016; 21:molecules21060818. [PMID: 27338335 PMCID: PMC6272949 DOI: 10.3390/molecules21060818] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 06/15/2016] [Accepted: 06/20/2016] [Indexed: 12/27/2022] Open
Abstract
Melandrii Herba (MH) is a traditional Asian medicinal herb used to treat breast cancer, anuria, and diseases of lactation. However, its biological properties and molecular mechanisms have not been fully elucidated. The purpose of this study was to investigate the anti-inflammatory activity and underlying molecular mechanism of MH ethanol extract (MHE) on the lipopolysaccharide (LPS)-mediated inflammatory response in macrophages. MHE cytotoxicity was determined using a cell counting kit (CCK) assay. The effects of MHE on the production of NO, inflammatory cytokines, and related proteins and mRNAs were determined using the Griess test, ELISA, Western blotting, and real-time RT-PCR, respectively. In addition, intracellular signaling pathways, such as NF-κB, MAPK, and HO-1, were analyzed using Western blotting. Our results revealed that MHE treatment significantly inhibited the secretion of NO and inflammatory cytokines, including TNF-α, IL-6, and IL-1β in macrophages, at sub-cytotoxic concentrations. Furthermore, MHE treatment inhibited iNOS expression and induced HO-1 expression. Finally, the transcriptional activities of NF-κB and MAPK activation were significantly suppressed by MHE in LPS-stimulated macrophages. The results indicate that MHE exerts anti-inflammatory effects by suppressing inflammatory mediator production via NF-κB and MAPK signaling pathways inhibition and induction of HO-1 expression in macrophages. Therefore, our results suggest the potential value of MHE as an inflammatory therapeutic agent developed from a natural substance.
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Affiliation(s)
- Yun Hee Jeong
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Korea.
| | - You-Chang Oh
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Korea.
| | - Won-Kyung Cho
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Korea.
| | - Bohyoung Lee
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Korea.
| | - Jin Yeul Ma
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, 70, Cheomdanro, Dong-gu, Daegu 41062, Korea.
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11
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Mathew S, Abdel-Hafiz H, Raza A, Fatima K, Qadri I. Host nucleotide polymorphism in hepatitis B virus-associated hepatocellular carcinoma. World J Hepatol 2016; 8:485-498. [PMID: 27057306 PMCID: PMC4820640 DOI: 10.4254/wjh.v8.i10.485] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Revised: 12/04/2015] [Accepted: 03/09/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is etiologically linked with hepatitis B virus (HBV) and is the leading cause of death amongst 80% of HBV patients. Among HBV affected patients, genetic factors are also involved in modifying the risk factors of HCC. However, the genetic factors that regulate progression to HCC still remain to be determined. In this review, we discuss several single nucleotide polymorphisms (SNPs) which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection such as cyclooxygenase (COX)-2 expression specifically at COX-2 -1195G/A in Chinese, Turkish and Egyptian populations, tumor necrosis factor α and the three most commonly studied SNPs: PAT-/+, Lys939Gln (A33512C, rs2228001) and Ala499Val (C21151T, rs2228000). In genome-wide association studies, strong associations have also been found at loci 1p36.22, 11q22.3, 6p21 (rs1419881, rs3997872, rs7453920 and rs7768538), 8p12 (rs2275959 and rs37821974) and 22q11.21. The genes implicated in these studies include HLA-DQB2, HLA-DQA1, TCF19, HLA-C, UBE2L3, LTL, FDX1, MICA, UBE4B and PG. The SNPs found to be associated with the above-mentioned genes still require validation in association studies in order to be considered good prognostic candidates for HCC. Screening of these polymorphisms is very beneficial in clinical experiments to stratify the higher or lower risk for HCC and may help in designing effective and efficient HCC surveillance programs for chronic HBV-infected patients if further genetic vulnerabilities are detected.
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12
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Fan B, Dun SH, Gu JQ, Guo Y, Ikuyama S. Pycnogenol Attenuates the Release of Proinflammatory Cytokines and Expression of Perilipin 2 in Lipopolysaccharide-Stimulated Microglia in Part via Inhibition of NF-κB and AP-1 Activation. PLoS One 2015; 10:e0137837. [PMID: 26367267 PMCID: PMC4569068 DOI: 10.1371/journal.pone.0137837] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 08/22/2015] [Indexed: 01/29/2023] Open
Abstract
Over activation of microglia results in the production of proinflammatory agents that have been implicated in various brain diseases. Pycnogenol is a patented extract from French maritime pine bark (Pinus pinaster Aiton) with strong antioxidant and anti-inflammatory potency. The present study investigated whether pycnogenol may be associated with the production of proinflammatory mediators in lipopolysaccharide-stimulated BV2 (mouse-derived) microglia. It was found that pycnogenol treatment was dose-dependently associated with significantly less release of nitricoxide (NO), TNF-α, IL-6 and IL-1β, and lower levels of intercellular adhesion molecule1 (ICAM-1) and perilipin 2 (PLIN2). Furthermore, this effect was replicated in primary brain microglia. Levels of inducible NO synthase mRNA and protein were attenuated, whereas there was no change in the production of the anti-inflammatory cytokine IL-10. Further evidence indicated that pycnogenol treatment led to the suppression of NF-κB activation through inhibition of p65 translocation into the nucleus and inhibited DNA binding of AP-1, suggesting that these proinflammatory factors are associated with NF-κB and AP-1. We conclude that pycnogenol exerts anti-inflammatory effects through inhibition of the NF-κB and AP-1pathway, and may be useful as a therapeutic agent in the prevention of diseases caused by over activation of microglia.
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Affiliation(s)
- Bin Fan
- Department of Neurology, Shengjing Hospital, China Medical University, Shenyang, 110004, P. R. China
- * E-mail:
| | - Sai-Hong Dun
- Department of Neurology, Shengjing Hospital, China Medical University, Shenyang, 110004, P. R. China
| | - Jian-Qiu Gu
- Department of Endocrinology and Metabolism, First Affiliated Hospital, P. R. China Medical University, Shenyang, 110001, P. R. China
| | - Yang Guo
- Department of Neurology, Shengjing Hospital, China Medical University, Shenyang, 110004, P. R. China
| | - Shoichiro Ikuyama
- Department of Clinical Investigation & Department of Endocrine, Metabolic and Rheumatic Diseases, Oita San-ai Medical center, Oita, 870–1151, Japan
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Jnawali HN, Park YG, Jeon D, Lee E, Kim Y. Anti-Inflammatory Activities of Biapigenin Mediated by Actions on p38 MAPK Pathway. B KOREAN CHEM SOC 2015. [DOI: 10.1002/bkcs.10460] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Hum Nath Jnawali
- Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center; Konkuk University; Seoul 143-701 Korea
| | - Young-Guen Park
- Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center; Konkuk University; Seoul 143-701 Korea
| | - Dasom Jeon
- Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center; Konkuk University; Seoul 143-701 Korea
| | - Eunjung Lee
- Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center; Konkuk University; Seoul 143-701 Korea
| | - Yangmee Kim
- Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center; Konkuk University; Seoul 143-701 Korea
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Oh YC, Jeong YH, Cho WK, Ha JH, Lee SJ, Ma JY. Inhibitory Effects of Epimedium Herb on the Inflammatory Response In Vitro and In Vivo. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2015. [PMID: 26224028 DOI: 10.1142/s0192415x1550055x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Epimedium Herb (EH) is a medicinal herb used in traditional Eastern Asia. In this study described, we investigated the biological effects of Epimedium Herb water extract (EHWE) on lipopolysaccharide (LPS)-mediated inflammation in macrophages and local inflammation in vivo. We also investigated the biological effects of EHWE on the production of inflammatory mediators, pro-inflammatory cytokines and related products, as well as nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) activation in LPS-stimulated macrophages. The analgesic effect of the acetic acid-induced writhing response and inhibitory activity on xylene-induced ear edema was also evaluated in mice. EHWE exhibited anti-inflammatory effects by inhibiting the production of nitric oxide (NO), interleukin (IL)-6 and IL-1β. In addition, EHWE strongly suppressed inducible nitric oxide synthase (iNOS), a NO synthesis enzyme, induced heme oxygenase-1 (HO-1) expression, and inhibited NF-κB activation as well as MAPK pathway phosphorylation. Furthermore, EHWE exhibited an analgesic effect on the writhing response and an inhibitory effect on ear edema in mice. For the first time, we demonstrated the anti-inflammatory effects and inhibitory mechanism in macrophages, as well as the inhibitory activity of EHWE in vivo. Our results indicate a potential use of EHWE as an inflammatory therapeutic agent developed from a natural substance.
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Affiliation(s)
- You-Chang Oh
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Yuseong, Daejeon 305-811, Republic of Korea
| | - Yun Hee Jeong
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Yuseong, Daejeon 305-811, Republic of Korea
| | - Won-Kyung Cho
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Yuseong, Daejeon 305-811, Republic of Korea
| | - Jeong-Ho Ha
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Yuseong, Daejeon 305-811, Republic of Korea
| | - Sang-Joon Lee
- Toxicity Screening Research Center, Gyeongnam Department of Environmental Toxicology and Chemistry, Korea Institute of Toxicology, Jinju-si, Gyeongsangnam-do 660-844, Republic of Korea
| | - Jin Yeul Ma
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Yuseong, Daejeon 305-811, Republic of Korea
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Dutta S, Chakraborty C, Mandal RK, Basu P, Biswas J, Roychoudhury S, Panda CK. Persistent HPV16/18 infection in Indian women with the A-allele (rs6457617) of HLA-DQB1 and T-allele (rs16944) of IL-1β -511 is associated with development of cervical carcinoma. Cancer Immunol Immunother 2015; 64:843-51. [PMID: 25893807 PMCID: PMC11028726 DOI: 10.1007/s00262-015-1693-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Accepted: 03/26/2015] [Indexed: 11/29/2022]
Abstract
The aim of this study was to understand the association of human papillomavirus (HPV) type 16/18 infection and polymorphisms in the HLA-DQB1 (rs6457617) and IL-1β -511 (rs16944) loci with the development of uterine cervical cancer (CaCx). The distribution of HLA-DQB1 G > A and IL-1β -511 C/T polymorphisms was determined in HPV-negative cervical swabs from normal women (N = 111) and compared with cervical swabs of HPV-cleared normal women (once HPV infected followed by natural clearance of the infection, N = 86), HPV16/18-positive cervical intraepithelial neoplasia (CIN, N = 41) and CaCx biopsies (N = 107). The A-allele containing genotypes (i.e. G/A and A/A) of HLA-DQB1 was significantly associated with CaCx compared with HPV-negative [OR = 2.56(1.42-4.62), p = 0.001] or HPV-cleared [OR = 2.07(1.12-3.87), p = 0.01] normal women, whereas the T-allele containing genotypes (i.e. C/T and T/T) of IL-1β showed increased risk of CIN [OR = 3.68(0.97-16.35), p = 0.03; OR = 3.59(0.92-16.38), p = 0.03] and CaCx development [OR = 2.03(1.03-5.2), p = 0.02; OR = 2.25(0.96-5.31), p = 0.04] compared with HPV-negative or HPV-cleared normal women. Considering these two loci together, it was evident that the T- and A-alleles rendered significantly increased susceptibility for development of CIN and CaCx compared with HPV-negative and HPV-cleared normal women. Moreover, the T-allele of IL-1β showed increased susceptibility for CIN [OR = 3.62(0.85-17.95), p = 0.04] and CaCx [OR = 2.39(0.91-6.37), p = 0.05] development compared with the HPV-cleared women, even in the presence of the HLA-DQB1 G-allele. Thus, our data suggest that persistent HPV16/18 infection in the cervix due to the presence of the HLA-DQB1 A-allele and chronic inflammation due to the presence of the IL-1β -511 T-allele might predispose women to CaCx development.
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Affiliation(s)
- Sankhadeep Dutta
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, India
| | - Chandraditya Chakraborty
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, India
| | - Ranajit Kumar Mandal
- Department of Gynecologic Oncology, Chittaranjan National Cancer Institute, Kolkata, India
| | - Partha Basu
- Department of Gynecologic Oncology, Chittaranjan National Cancer Institute, Kolkata, India
- Present Address: Screening Group (SCR), Early Detection and Prevention Section (EDP), International Agency for Research on Cancer (IARC), World Health Organization (WHO), 150 cours Albert Thomas, 69372 Lyon, Cedex 08, France
| | - Jaydip Biswas
- Department of Surgical Oncology, Chittaranjan National Cancer Institute, Kolkata, India
| | - Susanta Roychoudhury
- Cancer Biology and Inflammatory Disorder Division, Indian Institute of Chemical Biology, Kolkata, India
| | - Chinmay Kumar Panda
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, India
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Oh YC, Jeong YH, Cho WK, Ha JH, Gu MJ, Ma JY. Anti-inflammatory and analgesic effects of pyeongwisan on LPS-stimulated murine macrophages and mouse models of acetic acid-induced writhing response and xylene-induced ear edema. Int J Mol Sci 2015; 16:1232-51. [PMID: 25569097 PMCID: PMC4307301 DOI: 10.3390/ijms16011232] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 11/17/2014] [Indexed: 01/15/2023] Open
Abstract
Pyeongwisan (PW) is an herbal medication used in traditional East Asian medicine to treat anorexia, abdominal distension, borborygmus and diarrhea caused by gastric catarrh, atony and dilatation. However, its effects on inflammation-related diseases are unknown. In this study, we investigated the biological effects of PW on lipopolysaccharide (LPS)-mediated inflammation in macrophages and on local inflammation in vivo. We investigated the biological effects of PW on the production of inflammatory mediators, pro-inflammatory cytokines and related products as well as the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) in LPS-stimulated macrophages. Additionally, we evaluated the analgesic effect on the acetic acid-induced writhing response and the inhibitory activity on xylene-induced ear edema in mice. PW showed anti-inflammatory effects by inhibiting the production of nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and interleukin-1β (IL-1β). In addition, PW strongly suppressed inducible nitric oxide synthase (iNOS), a NO synthesis enzyme, induced heme oxygenase-1 (HO-1) expression and inhibited NF-κB activation and MAPK phosphorylation. Also, PW suppressed TNF-α, IL-6 and IL-1β cytokine production in LPS-stimulated peritoneal macrophage cells. Furthermore, PW showed an analgesic effect on the writhing response and an inhibitory effect on mice ear edema. We demonstrated the anti-inflammatory effects and inhibitory mechanism in macrophages as well as inhibitory activity of PW in vivo for the first time. Our results suggest the potential value of PW as an inflammatory therapeutic agent developed from a natural substance.
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Affiliation(s)
- You-Chang Oh
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Korea.
| | - Yun Hee Jeong
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Korea.
| | - Won-Kyung Cho
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Korea.
| | - Jeong-Ho Ha
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Korea.
| | - Min Jung Gu
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Korea.
| | - Jin Yeul Ma
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Korea.
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17
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Oh YC, Jeong YH, Ha JH, Cho WK, Ma JY. Oryeongsan inhibits LPS-induced production of inflammatory mediators via blockade of the NF-kappaB, MAPK pathways and leads to HO-1 induction in macrophage cells. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 14:242. [PMID: 25023125 PMCID: PMC4223373 DOI: 10.1186/1472-6882-14-242] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 06/30/2014] [Indexed: 12/29/2022]
Abstract
BACKGROUND Oryeongsan (OR) is an herbal medication used in east-Asian traditional medicine to treat dysuresia, such as urinary frequency, hematuria, and dysuria due to renal disease and chronic nephritis. Recent studies showed that protective effect against acute gastric mucosal injury and an inhibitory effect on the renin-angiotensin-aldosterone pathway of OR. However, its effect on inflammation still remains unknown. In this study, to provide insight into the biological effects of OR, we investigated their effects on lipopolysaccharide (LPS)-mediated inflammation in the RAW 264.7 macrophage cells. METHODS We investigated the pharmacological and biological effects of OR on the production of pro-inflammatory cytokines, inflammatory mediators, and related products through Enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. Also, we examined the activation and suppression of nuclear factor (NF)-kappaB and mitogen-activated protein kinases (MAPKs) pathways in LPS-stimulated macrophages via Western blot analysis in order to explore inhibitory mechanism of OR. RESULTS OR had anti-inflammatory effects by inhibiting the production of nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1 beta. In addition, it strongly suppressed cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS), NO synthesizing enzymes. It also induced heme oxygenase (HO)-1 expression and inhibited NF-kappaB signaling pathway activation and phosphorylation of MAPKs. CONCLUSIONS We further demonstrate the anti-inflammatory effects and inhibitory mechanism of OR in LPS-stimulated macrophages for the first time. OR contains strong anti-inflammatory activity and affects various mechanism pathways including NF-kappaB, MAPKs and HO-1. Our results suggest that OR has potential value to be developed as an inflammatory therapeutic agent from a natural substance.
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Affiliation(s)
- You-Chang Oh
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon, Yuseong, Republic of Korea
| | - Yun Hee Jeong
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon, Yuseong, Republic of Korea
| | - Jeong-Ho Ha
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon, Yuseong, Republic of Korea
| | - Won-Kyung Cho
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon, Yuseong, Republic of Korea
| | - Jin Yeul Ma
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon, Yuseong, Republic of Korea
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König HG, Coughlan KS, Kinsella S, Breen BA, Prehn JHM. The BCL-2 family protein Bid is critical for pro-inflammatory signaling in astrocytes. Neurobiol Dis 2014; 70:99-107. [PMID: 24956542 DOI: 10.1016/j.nbd.2014.06.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 06/06/2014] [Accepted: 06/11/2014] [Indexed: 01/19/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons in the spinal cord, brainstem and motor cortex. Mutations in the superoxide dismutase 1 (SOD1) gene represent a frequent genetic determinant and recapitulate a disease phenotype similar to ALS when expressed in mice. Previous studies using SOD1(G93A) transgenic mice have suggested a paracrine mechanism of neuronal loss, in which cytokines and other toxic factors released from astroglia or microglia trigger motoneuron degeneration. Several pro-inflammatory cytokines activate death receptors and may downstream from this activate the Bcl-2 family protein, Bid. We here sought to investigate the role of Bid in astrocyte activation and non-cell autonomous motoneuron degeneration. We found that spinal cord Bid protein levels increased significantly during disease progression in SOD1(G93A) mice. Subsequent experiments in vitro indicated that Bid was expressed at relatively low levels in motoneurons, but was enriched in astrocytes and microglia. Bid was strongly induced in astrocytes in response to pro-inflammatory cytokines or exposure to lipopolysaccharide. Experiments in bid-deficient astrocytes or astrocytes treated with a small molecule Bid inhibitor demonstrated that Bid was required for the efficient activation of transcription factor nuclear factor-κB in response to these pro-inflammatory stimuli. Finally, we found that conditioned medium from wild-type astrocytes, but not from bid-deficient astrocytes, was toxic when applied to primary motoneuron cultures. Collectively, our data demonstrate a new role for the Bcl-2 family protein Bid as a mediator of astrocyte activation during neuroinflammation, and suggest that Bid activation may contribute to non-cell autonomous motoneuron degeneration in ALS.
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Affiliation(s)
- Hans-Georg König
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland
| | - Karen S Coughlan
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland
| | - Sinéad Kinsella
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland
| | - Bridget A Breen
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
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Oh YC, Jeong YH, Cho WK, Gu MJ, Ma JY. Inhibitory effects of palmultang on inflammatory mediator production related to suppression of NF-κB and MAPK pathways and induction of HO-1 expression in macrophages. Int J Mol Sci 2014; 15:8443-57. [PMID: 24828204 PMCID: PMC4057741 DOI: 10.3390/ijms15058443] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 04/11/2014] [Accepted: 04/17/2014] [Indexed: 01/18/2023] Open
Abstract
Palmultang (PM) is an herbal decoction that has been used to treat anorexia, anemia, general prostration, and weakness due to chronic illness since medieval times in Korea, China, and Japan. The present study focused on the inhibitory effects of PM on the production of inflammatory factors and on the activation of mechanisms in murine macrophages. PM suppressed the expression of nitric oxide (NO), inflammatory cytokines and inflammatory proteins by inhibiting nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways and by inducing heme oxygenase (HO)-1 expression. Collectively, our results explain the anti-inflammatory effect and inhibitory mechanism of PM in macrophages stimulated with lipopolysaccharide (LPS).
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Affiliation(s)
- You-Chang Oh
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Korea.
| | - Yun Hee Jeong
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Korea.
| | - Won-Kyung Cho
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Korea.
| | - Min-Jung Gu
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Korea.
| | - Jin Yeul Ma
- Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Korea.
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20
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Biswas A, Panigrahi R, Pal M, De BK, Chakrabarti S, Ghosh MK, Chandra Seth BC, Roychowdhury S, Chakravarty R. Association of Interleukin-1β and Gene Polymorphisms with Liver Pathogenesis in Hepatitis B Virus Infection among Eastern Indian Population. J Clin Exp Hepatol 2013; 3:281-7. [PMID: 25755515 PMCID: PMC3940093 DOI: 10.1016/j.jceh.2013.11.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Accepted: 11/11/2013] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Interleukin-1β (IL-1β) is an important member of the family of the proinflammatory cytokines that modulate outcome of hepatitis B virus (HBV) infection. OBJECTIVES This study was designed to investigate the relationship between the polymorphic genotypes of the interleukin-1β (IL-1β) promoter region and the interleukin-1 receptor antagonist gene (IL-1RN) and disease outcome in HBV-infected individuals. METHODS DNA was extracted from 395 study subjects including HBV carriers with varying clinical presentations, as well as healthy controls and spontaneously recovered cases (SRC). Polymorphisms in IL-1β (at position -511) and IL-1RN (variable nucleotide tandem repeats, VNTR) were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR based assay respectively. RESULTS Among the study subjects, different IL-1β (at position -511) (CC, CT and TT) and IL-1RN (1/1, 1/2, 2/2 and 1/3) polymorphic genotypes were found at variable proportions. Logistic regression analysis revealed, no notable difference at the level of IL-1β promoter (P = 0.244; OR = 0.78; 95% CI = 0.52-1.18) or IL-1RN genotype polymorphism (P = 0.840; OR = 1.03; 95% CI = 0.78-1.36) among the HBV carriers and controls or SRC cases. Pairwise proportion testing showed, IL-1β -511 genotype CC was significantly higher among asymptomatic carriers (ASC) in comparison with liver cirrhosis (LC) patients (P value = 0.028) and healthy control group (P-value = 0.036). IL-1RN genotype 2/2 was considerably higher in LC group than SRC as well as control group. Combinations of IL-1β (-511) and IL-1RN polymorphisms were associated with disease progression, such as CC-1/2 with ASC and TT-2/2 with LC. CONCLUSION IL-1β polymorphisms are found to be associated with disease severity. Different polymorphic combinations are associated with degree of disease severity. Overall this is the first report from Eastern India, which shows association of IL-1β polymorphisms with HBV-related hepatic complications.
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Key Words
- ASC, asymptomatic carriers
- CLD, chronic liver disease
- Eastern India
- HBV
- HBV, hepatitis B virus
- HCC, hepatocellular carcinoma
- IL-1RN, interleukin-1 receptor antagonist gene
- IL-1β, interleukin-1β
- LC, liver cirrhosis
- LR, logistic regression
- PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism
- SNP, single nucleotide polymorphisms
- SRC, spontaneously recovered cases
- USG, ultrasonography
- VNTR, variable nucleotide tandem repeats
- cirrhosis
- interleukin polymorphisms
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Affiliation(s)
- Avik Biswas
- ICMR Virus Unit Kolkata, ID & BG Hospital Campus, Kolkata, India
| | - Rajesh Panigrahi
- Department of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, USA
| | - Manisha Pal
- Department of Statistics, University of Calcutta, Kolkata, India
| | - Binay K. De
- Department of Medicine, Calcutta Medical College, Kolkata, India
| | | | | | | | | | - Runu Chakravarty
- ICMR Virus Unit Kolkata, ID & BG Hospital Campus, Kolkata, India,Address for correspondence: Runu Chakravarty, ICMR Virus Unit Kolkata, GB 4, 1st Floor, ID & BG Hospital Campus, 57, Dr. Suresh Chandra Banerjee Road, Kolkata 700010, India. Tel.: +91 33 2353 7425; fax: +91 33 2353 7424.
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Inhibition of Acute Phase Inflammation by Laminaria japonica through Regulation of iNOS-NF- κ B Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:439498. [PMID: 24288559 PMCID: PMC3833118 DOI: 10.1155/2013/439498] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 08/27/2013] [Indexed: 01/16/2023]
Abstract
Laminaria japonica has been frequently used as food supplements in many of the Asian countries and as a drug in traditional oriental medicine. This research investigated the effects of Laminaria japonica extract (LJE) on acute phase inflammation in a carrageenan-induced paw edema model, as assessed by histomorphometric and immunohistochemical analyses. The effect of LJE was also evaluated in Raw264.7 cells stimulated with lipopolysaccharide (LPS) in the aspect of the inhibition of nitric oxide (NO), prostaglandin E2 (PGE2), and proinflammatory cytokines production. NO, PGE2, tumor necrosis factor (TNF)-α, interleukin-1β, and interleukin-6 contents were assayed by ELISA, and inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 expressions were determined by western blot analyses. In rats, LJE treatment inhibited carrageenan-induced paw edema formation and infiltration of inflammatory cells in H&E staining. LJE treatment prevented the ability of LPS to increase the levels of iNOS and COX-2 protein in a concentration-dependent manner. Consistently, LJE suppressed the production of TNF-α, interleukin-1β, and interleukin-6. Treatment of the cells with LJE caused inhibition of inhibitor of κBα phosphorylation induced by LPS, suggesting LJE repression of nuclear factor-κB activity by LPS. In conclusion, this study shown here may be of help to understand the action mechanism of LJE and the anti-inflammatory use of L. japonica.
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Methanol Extract of Artemisia apiacea Hance Attenuates the Expression of Inflammatory Mediators via NF- κ B Inactivation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:494681. [PMID: 24250718 PMCID: PMC3819789 DOI: 10.1155/2013/494681] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 08/26/2013] [Indexed: 11/27/2022]
Abstract
Artemisia apiacea Hance is one of the most widely used herbs for the treatment of malaria, jaundice, and dyspeptic complaint in oriental medicine. This study investigated the effects of methanol extracts of A. apiacea Hance (MEAH) on the induction of inducible nitric oxide synthase (iNOS) and proinflammatory mediators by lipopolysaccharide (LPS) in Raw264.7 macrophage cells and also evaluated the in vivo effect of MEAH on carrageenan-induced paw edema in rats. MEAH treatment in Raw264.7 cells significantly decreased LPS-inducible nitric oxide production and the expression of iNOS in a concentration-dependent manner, while MEAH (up to 100 μg/mL) had no cytotoxic activity. Results from immunoblot analyses and ELISA revealed that MEAH significantly inhibited the expression of cyclooxygenase-2, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in LPS-activated cells. As a plausible molecular mechanism, increased degradation and phosphorylation of inhibitory-κBα and nuclear factor-κB accumulation in the nucleus by LPS were partly blocked by MEAH treatment. Finally, MEAH treatment decreased the carrageenan-induced formation of paw edema and infiltration of inflammatory cells in rats. These results demonstrate that MEAH has an anti-inflammatory therapeutic potential that may result from the inhibition of nuclear factor-κB activation, subsequently decreasing the expression of proinflammatory mediators.
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Biphasic activation of nuclear factor kappa B and expression of p65 and c-Rel after traumatic brain injury in rats. Inflamm Res 2013; 63:109-15. [DOI: 10.1007/s00011-013-0677-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Revised: 10/01/2013] [Accepted: 10/11/2013] [Indexed: 10/26/2022] Open
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Brenner M, Laragione T, Gulko PS. Arthritis severity locus Cia4 is an early regulator of IL-6, IL-1β, and NF-κB activators' expression in pristane-induced arthritis. Physiol Genomics 2013; 45:552-64. [PMID: 23695883 DOI: 10.1152/physiolgenomics.00029.2013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cia4 is a locus on rat chromosome 7 that regulates disease severity and joint damage in models of rheumatoid arthritis, including pristane-induced arthritis (PIA). To identify molecular processes regulated by Cia4, synovial tissues from MHC-identical DA (severe erosive) and DA.F344(Cia4) congenics (mild nonerosive) rats were collected at preclinical and recent onset stages following the induction of PIA and analyzed for gene expression levels. Il6 levels were significantly higher in DA compared with congenics on day 10 (135-fold) after PIA induction (preclinical stage) and remained increased on days 14 (47.7-fold) and 18 (29.41-fold). Il6 increased before Il1b suggesting that Il6 could be driving Il1b expression and early synovial inflammation; 187 genes had significantly different expression levels and included inflammatory mediators increased in DA such Slpi (10.94-fold), Ccl7 (5.17-fold), and Litaf (2.09-fold). Syk or NF-κB activating and interacting genes, including Cd74 Ccl21, were increased in DA; 59 genes implicated in cancer-related phenotypes were increased in DA. Genes involved in cell metabolism, transport across membranes, and tissue protection such as Dgat1, Dhcr7, and Slc1a1 were increased in DA.F344(Cia4) congenics; 21 genes differentially expressed or expressed in only one of the strains were located within the Cia4 interval and could be the gene accounting for the arthritis effect. In conclusion, the Cia4 interval contains at least one new arthritis gene that regulates early Il6, Il1b expression, and other inflammatory mediators. This gene regulates the expression of cancer genes that could mediate the development of synovial hyperplasia and invasion, and cartilage and bone destruction.
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Affiliation(s)
- Max Brenner
- Laboratory of Experimental Rheumatology, Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, New York, USA
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Chi PL, Luo SF, Hsieh HL, Lee IT, Hsiao LD, Chen YL, Yang CM. Cytosolic phospholipase A2 induction and prostaglandin E2 release by interleukin-1β via the myeloid differentiation factor 88-dependent pathway and cooperation of p300, Akt, and NF-κB activity in human rheumatoid arthritis synovial fibroblasts. ACTA ACUST UNITED AC 2013; 63:2905-17. [PMID: 21702012 DOI: 10.1002/art.30504] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Cytosolic phospholipase A2 (cPLA2) is a rate-limiting enzyme that plays a critical role in the biosynthesis of eicosanoids. The aim of this study was to investigate the mechanisms underlying interleukin-1β (IL-1β)-induced cPLA2 expression in human rheumatoid arthritis synovial fibroblasts (RASFs). METHODS Synovial tissue was obtained from patients with RA who were undergoing joint replacement surgery. In a mouse model of IL-1β-mediated inflammatory arthritis, neutrophil infiltration, bone erosion, and cPLA2 expression in ankle synovium were analyzed by immunohistochemistry. IL-1β-induced cPLA2 expression was determined by Western blotting, real-time polymerase chain reaction, and gene promoter assay using pharmacologic inhibitors and transfection with short hairpin RNAs or small interfering RNAs. The recruitment of NF-κB and p300 to the cPLA2 promoter was determined by chromatin immunoprecipitation assay. Prostaglandin E2 (PGE2) biosynthesis was evaluated by enzyme-linked immunosorbent assay. RESULTS IL-1β-induced cPLA2 expression and PGE2 release were mediated through a myeloid differentiation factor 88 (MyD88)/c-Src-dependent matrix metalloproteinase (MMP)/heparin-binding epidermal growth factor (HB-EGF) cascade linking to transactivation of the EGF receptor (EGFR)/phosphatidylinositol 3-kinase (PI 3-kinase)/Akt, p300, and NF-κB p65 pathways. IL-1β also stimulated Akt phosphorylation and nuclear translocation. Activation of Akt eventually led to the acetylation of histone residues by phosphorylation and recruitment of p300 and enhanced its histone acetyltransferase activity on the NF-κB elements of the cPLA2 promoter. IL-1β-induced NF-κB transcriptional activity was mediated through a PI 3-kinase/Akt-dependent cascade. Up-regulation of cPLA2 by IL-1β increased PGE(2) biosynthesis in RASFs. CONCLUSION IL-1β-induced cPLA2 expression is mediated through activation of the MyD88/c-Src, MMP/HB-EGF, EGFR/PI 3-kinase/Akt, p300, and NF-κB pathways. These results provide insights into the mechanisms underlying IL-1β-enhanced joint inflammatory responses in RA and may inspire new targeted therapeutic approaches.
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Affiliation(s)
- Pei-Ling Chi
- Department of Pharmacology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan
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Koontongkaew S, Meesuk L, Aupaphong V, Ayudhaya TDN, Poachanukoon O. Inhibitory effect of Zingiber cassumunar extracts on lipopolysaccharide-induced cyclooxygenase-2 and matrix metalloproteinase expression in human gingival fibroblasts. J Periodontal Res 2012; 48:507-16. [PMID: 23278498 DOI: 10.1111/jre.12033] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2012] [Indexed: 11/27/2022]
Abstract
BACKGROUND AND OBJECTIVE Lipopolysaccharides (LPS) induce the production of proinflammatory mediators such as prostaglandins and matrix metalloproteinases (MMPs) in human gingival fibroblasts (HGFs). Zingiber cassumunar is a medicinal plant that possesses anti-inflammatory properties. The aim of this study was to determine the effects of the Z. cassumunar extract on the expression of cyclooxygenase (COX)-1, COX-2 and MMP-2 in HGFs challenged with LPS. MATERIAL AND METHODS HGFs were treated with LPS in the presence or absence of Z. cassumunar extracts. The levels of expression of COX-1, COX-2 and MMP-2 mRNAs and of COX-1, COX-2 and MMP-2 proteins were detected by reverse transcription-polymerase chain reaction and western blotting, respectively. MMP-2 activities in cell-culture supernatants were determined using gelatin zymography. MAPK activation was evaluated by western blotting. RESULTS LPS treatment of HGFs resulted in the activation of ERK1/2, p38 and JNK. Z. cassumunar extracts significantly inhibited the phosphorylation of ERK1/2 and JNK in HGFs stimulated with LPS. A lesser inhibitory effect was observed for the phosphorylation of p38. RT-PCR and western blot analyses showed that Z. cassumunar extracts inhibited the LPS-induced expression of COX-2 mRNA and COX-2 protein, respectively, but not of COX-1 mRNA or COX-1 protein. Pretreatment of HGFs with Z. cassumunar also attenuated the induction of MMP-2 with LPS. CONCLUSION Our results indicate that Z. cassumunar extracts inhibit COX-2 and MMP-2 production by LPS-activated human gingival fibroblasts through blocking the proinflammatory signaling pathway involving ERK1/2, JNK and p38.
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Affiliation(s)
- S Koontongkaew
- Oral Biology Laboratory, Faculty of Dentistry, Thammasat University, Klong Luang, Prathumthani, Thailand.
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Oh YC, Cho WK, Jeong YH, Im GY, Lee KJ, Yang HJ, Ma JY. Anti-inflammatory effect of Sosihotang via inhibition of nuclear factor-κB and mitogen-activated protein kinases signaling pathways in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. Food Chem Toxicol 2012; 53:343-51. [PMID: 23246826 DOI: 10.1016/j.fct.2012.12.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Accepted: 12/04/2012] [Indexed: 11/25/2022]
Abstract
Sosihotang (SO) is an herbal medication, which has been widely used to treat fever, chill and vomiting due to common cold in east-Asian countries. In this study, to provide insight into the effects of SO on inflammation, we investigated its effect on pro-inflammatory mediator production in RAW 264.7 cells and mouse peritoneal macrophages using lipopolysaccharide (LPS) stimulation. SO significantly inhibited the production of nitric oxide (NO), tumor necrosis factor (TNF)-α and interleukin (IL)-6 as well as gene expression of inducible nitric oxide synthase (iNOS), its synthesizing enzyme. In addition, SO inhibited nuclear factor (NF)-κB activation and suppressed extracellular signal-regulated kinase (ERK), p38 and c- Jun NH(2)-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) phosphorylation. Furthermore, we found SO suppresses the production of NO and IL-6 in LPS-stimulated peritoneal macrophage cells. High performance liquid chromatography (HPLC) analysis showed SO contains many active anti-inflammatory constituents such as liquiritigenin, baicalin, baicalein, glycyrrhizin and wogonin. We first elucidated the inhibitory mechanism of SO on inflammation induced by LPS in macrophage cells. Our results suggest SO has potential to be developed as a therapeutic agent for various inflammatory diseases.
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Affiliation(s)
- You-Chang Oh
- Korean Medicine (KM)-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Republic of Korea
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Oh YC, Cho WK, Jeong YH, Im GY, Kim A, Hwang YH, Kim T, Song KH, Ma JY. A Novel Herbal Medicine KIOM-MA Exerts an Anti-Inflammatory Effect in LPS-Stimulated RAW 264.7 Macrophage Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2012; 2012:462383. [PMID: 23243447 PMCID: PMC3518860 DOI: 10.1155/2012/462383] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 10/24/2012] [Accepted: 10/24/2012] [Indexed: 12/22/2022]
Abstract
KIOM-MA was recently reported as a novel herbal medicine effective for atopic dermatitis and asthma. In this study, we have demonstrated the inhibitory effect of KIOM-MA on proinflammatory mediator produced in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. KIOM-MA significantly inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as nitric oxide (NO) and prostaglandin E(2) (PGE(2)). Consistent with the inhibitory effect on PGE(2), KIOM-MA suppresses the LPS-induced migration of macrophages and gelatinase activity and the expression of matrix metalloprotease-9 (MMP-9) in a dose-dependent manner. Additionally, KIOM-MA showed a strong suppressive effect on the inflammatory cytokines production such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We also found that KIOM-MA inhibits the activation of nuclear factor-κB (NF-κB) and represses the activity of extracellular signal-regulated kinase (ERK), p38, and c-Jun NH(2)-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs). Taken together, we elucidated the mechanism of anti-inflammatory effect of KIOM-MA using RAW 264.7 cells stimulated by LPS.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Jin Yeul Ma
- Korean Medicine (KM)-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, 461-24 Jeonmin-Dong, Yuseong, Daejeon 305-811, Republic of Korea
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Oh YC, Cho WK, Jeong YH, Im GY, Yang MC, Ma JY. Fermentation improves anti-inflammatory effect of sipjeondaebotang on LPS-stimulated RAW 264.7 cells. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2012; 40:813-31. [PMID: 22809034 DOI: 10.1142/s0192415x12500619] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sipjeondaebotang (SJ) has been used as a traditional drug in east-Asian countries. In this study, to provide insight into the biological effects of SJ and SJ fermented by Lactobacillus, we investigated their effects on lipopolysaccharide (LPS)-mediated inflammation in macrophages. The investigation was focused on whether SJ and fermented SJ could inhibit the production of pro-inflammatory mediators such as prostaglandin (PG) E(2) and nitric oxide (NO) as well as the expressions of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB in LPS-stimulated RAW 264.7 cells. We found that SJ modestly inhibited LPS-induced PGE(2), NO and TNF-α production as well as the expressions of COX-2 and iNOS. Interestingly, fermentation significantly increased its inhibitory effect on the expression of all pro-inflammatory mediators. Furthermore, fermented SJ exhibited increased inhibition of p38 MAPK and c-Jun NH(2)-terminal kinase (JNK) MAPK phosphorylation as well as NF-κB p65 translocation by reduced IκBα degradation compared with either untreated controls or unfermented SJ. High performance liquid chromatography (HPLC) analysis showed fermentation by Lactobacillus increases liquiritigenin and cinnamyl alcohol contained in SJ, which are known for their anti-inflammatory activities. Finally, SJ fermented by Lactobacillus exerted potent anti-inflammatory activity by inhibiting MAPK and NF-κB signaling in RAW 264.7 cells.
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Affiliation(s)
- You-Chang Oh
- Korean Medicine-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, Yuseong, Daejeon, Republic of Korea
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Oh YC, Cho WK, Jeong YH, Im GY, Yang MC, Hwang YH, Ma JY. Anti-inflammatory effect of Citrus Unshiu peel in LPS-stimulated RAW 264.7 macrophage cells. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2012; 40:611-29. [PMID: 22745074 DOI: 10.1142/s0192415x12500462] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Citrus Unshiu peel (CUP) has been traditionally used in East Asia as a drug for the treatment of vomiting and dyspepsia. However, its effects on inflammation remain unknown. In this study, we investigated the effects of CUP on the production of pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The research focused on determining whether CUP could inhibit the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and the activation of nuclear factor (NF)-κB, mitogen-activated protein kinases (MAPKs), as well as the secretion of nitric oxide (NO), prostaglandin (PG) E(2), tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in LPS-stimulated RAW 264.7 cells. We found that CUP represses LPS-induced iNOS and COX-2 gene expression as well as NO, PGE(2), TNF-α and IL-6 production. Additionally, CUP inhibited the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun NH(2)-terminal kinase (JNK) MAPK, and suppressed IκBα degradation and nuclear translocation of NF-κB. Collectively, our results indicate that CUP inhibits the production of various inflammatory mediators via blockade of MAPK phosphorylation pursuant to the inhibition of IκBα degradation and the nuclear translocation of NF-κB. These findings are the first to clarify the mechanism underlying the anti-inflammatory effect exerted by CUP in RAW 264.7 macrophage cells stimulated by inflammatory agents.
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Affiliation(s)
- You-Chang Oh
- Center for Herbal Medicine Improvement Research, Korea Institute of Oriental Medicine, Yuseong, Daejeon, Republic of Korea
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Arachidonic acid regulation of the cytosolic phospholipase A2α/cyclooxygenase-2 pathway in mouse endometrial stromal cells. Fertil Steril 2012; 97:1199-205.e1-9. [DOI: 10.1016/j.fertnstert.2012.02.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2011] [Revised: 02/08/2012] [Accepted: 02/08/2012] [Indexed: 11/22/2022]
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Anti-inflammatory effect of Lycium Fruit water extract in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. Int Immunopharmacol 2012; 13:181-9. [PMID: 22483979 DOI: 10.1016/j.intimp.2012.03.020] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Revised: 03/21/2012] [Accepted: 03/21/2012] [Indexed: 11/22/2022]
Abstract
Lycium Fruit has been used as a traditional drug for low back pain and chronic cough in east-Asian countries. However, inhibitory effects of Lycium Fruit water extract (LFWE) on inflammation remain unknown. In this study, we investigated the inhibitory effects of LFWE on pro-inflammatory mediator production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. LFWE inhibited LPS-induced nitric oxide (NO), prostaglandin (PG) E₂, tumor necrosis factor (TNF)-α and interleukin (IL)-6 production as well as their synthesizing enzyme inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 gene expression. Furthermore, LFWE inhibited phosphorylations of extracellular signal-regulated kinase (ERK), p38 and c-Jun NH₂-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) as well as suppression of IκBα degradation and nuclear translocation of nuclear factor (NF)-κB upon LPS stimulation. In addition, LFWE suppressed NO, PGE₂, TNF-α and IL-6 production in LPS-stimulated peritoneal macrophage cells. Taken together, our results suggest that LFWE inhibits the production of various inflammatory mediators via blockade on the MAPKs and NF-κB pathways. This finding first explains the mechanism of anti-inflammatory effect by LFWE in LPS-stimulated macrophage cells.
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Oh YC, Cho WK, Oh JH, Im GY, Jeong YH, Yang MC, Ma JY. Fermentation by Lactobacillus enhances anti-inflammatory effect of Oyaksungisan on LPS-stimulated RAW 264.7 mouse macrophage cells. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 12:17. [PMID: 22405334 PMCID: PMC3323419 DOI: 10.1186/1472-6882-12-17] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 03/12/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND Oyaksungisan (OY) has been used as a traditional drug in east-Asian countries. However, its effect on inflammation still remains unknown. In this study, to provide insight into the biological effects of OY and OY fermented by Lactobacillus, we investigated their effects on lipopolysaccharide (LPS)-mediated inflammation in the RAW 264.7 murine macrophage cells. METHODS The investigation was focused on whether OY and fermented OYs could inhibit the production of pro-inflammatory mediators such as nitric oxide (NO) and prostaglandin (PG) E2 as well as the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, interleukin (IL)-6, nuclear factor (NF)-κB and mitogen-activated protein kinases (MAPKs) in LPS-stimulated RAW 264.7 cells. RESULTS We found that OY inhibits a little LPS-induced NO, PGE2, TNF-α and IL-6 productions as well as the expressions of iNOS and COX-2. Interestingly, the fermentation significantly increased its inhibitory effect on the expression of all pro-inflammatory mediators. Furthermore, the fermented OYs exhibited elevated inhibition on the translocation of NF-κB p65 through reduced IκBα degradation as well as the phosphorylations of extracellular signal-regulated kinase (ERK), p38 and c-Jun NH2-terminal kinase (JNK) MAPKs than untreated control or original OY. CONCLUSIONS Finally, the fermentation by Lactobacillus potentiates the anti-inflammatory effect of OY by inhibiting NF-κB and MAPK activity in the macrophage cells.
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Affiliation(s)
- You-Chang Oh
- Traditional Korean Medicine (TKM)-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, Yuseong, Daejeon, Republic of Korea
| | - Won-Kyung Cho
- Traditional Korean Medicine (TKM)-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, Yuseong, Daejeon, Republic of Korea
| | - Jin Hui Oh
- Traditional Korean Medicine (TKM)-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, Yuseong, Daejeon, Republic of Korea
| | - Ga Young Im
- Traditional Korean Medicine (TKM)-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, Yuseong, Daejeon, Republic of Korea
| | - Yun Hee Jeong
- Traditional Korean Medicine (TKM)-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, Yuseong, Daejeon, Republic of Korea
| | - Min Cheol Yang
- Traditional Korean Medicine (TKM)-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, Yuseong, Daejeon, Republic of Korea
| | - Jin Yeul Ma
- Traditional Korean Medicine (TKM)-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, Yuseong, Daejeon, Republic of Korea
- Traditional Korean Medicine (TKM)-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong, Daejeon 305-811, Republic of Korea
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Gamble C, McIntosh K, Scott R, Ho KH, Plevin R, Paul A. Inhibitory kappa B Kinases as targets for pharmacological regulation. Br J Pharmacol 2012; 165:802-19. [PMID: 21797846 PMCID: PMC3312479 DOI: 10.1111/j.1476-5381.2011.01608.x] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Revised: 06/20/2011] [Accepted: 07/02/2011] [Indexed: 01/04/2023] Open
Abstract
The inhibitory kappa B kinases (IKKs) are well recognized as key regulators of the nuclear factor kappa B (NF-κB) cascade and as such represent a point of convergence for many extracellular agents that activate this pathway. The IKKs generally serve to transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes but also play a key role in the pathogenesis of a number of human diseases. Therefore, the catalytic IKKs represent attractive targets for intervention with small molecule kinase inhibitors. IKK isoforms are assembled as variable multi-subunit IKK complexes that regulate not only NF-κB dimers, but also protein substrates out-with this cascade. Consequently, close consideration of how these individual complexes transduce extracellular signals and more importantly what impact small molecule inhibitors of the IKKs have on functional outcomes are demanded. A number of adenosine triphosphate (ATP)-competitive IKKβ-selective inhibitors have been developed but have demonstrated a lack of activity against IKKα. A number of these chemicals have also exhibited detrimental outcomes such as cellular toxicity and immuno-suppression. The impact of small molecule inhibitors of IKK catalytic activity will therefore be reappraised, examining the advantages and potential disadvantages to this type of intervention strategy in the treatment of diseases such as arthritis, intestinal inflammation and cancer. Furthermore, we will outline some emerging strategies, particularly the disruption of protein-protein interactions within the IKK complex, as an alternative route towards the development of novel pharmacological agents. Whether these alternatives may negate the limitations of ATP-competitive molecules and potentially avoid the issues of toxicity will be discussed.
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Affiliation(s)
- Carly Gamble
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK
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Abstract
Although the level of heat shock protein (Hsp72) has been shown to be enhanced in rheumatoid arthritis (RA) synovial tissues and RA synovial fluid, it remains unclear what role extracellular Hsp72 plays in the pathogenesis of RA. This study was conducted to investigate the effects of recombinant human Hsp72 on collagen-induced arthritis (CIA) when administered therapeutically and elucidate its underlying mechanism. We demonstrated that recombinant Hsp72 significantly reduced disease severity. Hsp72-treated animals displayed significantly less cartilage and bone destruction than that in the controls. Hsp72 treatment also reduced the expression of tumor necrosis factor alpha and interleukin 6 in the sera. Furthermore, Hsp72 treatment significantly inhibited activation of nuclear factor kappa B (NF-κB) in synovial tissues of CIA mice. These findings suggest that recombinant Hsp72 effectively suppressed synovial inflammation and the development and progress of CIA, which is mediated through the reduction of production of proinflammatory cytokines and the suppression of activation of NF-κB pathway.
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Kanda N, Hau CS, Tada Y, Tatsuta A, Sato S, Watanabe S. Visfatin enhances CXCL8, CXCL10, and CCL20 production in human keratinocytes. Endocrinology 2011; 152:3155-64. [PMID: 21673103 DOI: 10.1210/en.2010-1481] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Psoriasis patients are frequently associated with metabolic syndromes. Such associations are possibly mediated by adipokines. We investigated the in vitro effects of visfatin (an adipokine) on chemokine expression in human keratinocytes. Normal human keratinocytes were incubated with visfatin, and their chemokine production was analyzed by ELISA and RT-PCR. Visfatin enhanced TNF-α-induced CXC chemokine ligand (CXCL) 8, CXCL10, and CC chemokine ligand (CCL) 20 secretion and mRNA expression in keratinocytes, although visfatin alone was ineffective. A small interfering RNA against nuclear factor-κB (NF-κB) p65 suppressed the visfatin-induced production of CXCL8, CXCL10, and CCL20 whereas a small interfering RNA against signal transducer and activator of transcription (STAT) 3 suppressed CXCL8 induction. This indicates the involvement of NF-κB in CXCL8, CXCL10, and CCL20 induction by visfatin and the involvement of STAT3 in CXCL8 induction. Visfatin alone increased the transcriptional activity and tyrosine phosphorylation of STAT3, which was suppressed by Janus kinase (JAK) 2 inhibitor. Visfatin enhanced basal and TNF-α-induced NF-κB activity and inhibitory κB (IκB) α phosphorylation, which was suppressed by IκB kinase inhibitor. Visfatin induced the tyrosine and serine phosphorylation of JAK2 and IκB kinase α/β, respectively. Intraperitoneal injection of visfatin elevated mRNA and protein levels of CXCL1, CXCL10, and CCL20 in murine skin. These results suggest that visfatin enhances CXCL8, CXCL10, and CCL20 production in human keratinocytes and homologous chemokine production in murine skin. Visfatin may induce the infiltration of type 1 or type 17 helper T cells or neutrophils to the skin via chemokine induction and thus link metabolic syndromes to psoriasis.
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Affiliation(s)
- N Kanda
- Department of Dermatology, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-Ku, Tokyo 173-8605, Japan.
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Wang P, You X, Yan Y, Singh GK, Li X, Zhou W, Liu W, Zhang F, Lv Y, Yang L. Cyclic mechanical stretch downregulates IL-1β-induced COX-2 expression and PGE(2) production in rheumatoid arthritis fibroblast-like synoviocytes. Connect Tissue Res 2011; 52:190-7. [PMID: 20887233 DOI: 10.3109/03008207.2010.508853] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) are one of the primary sources of inflammatory cytokines, including prostaglandins (PGs) and matrix metalloproteinases (MMPs) in joints that are detrimental to the bone, cartilage, and the surrounding tissue. Many studies, in recent years, have shown that physiotherapies play a beneficial effect on the maintenance of joint homeostasis in RA; however, the underlying mechanisms involved are still not fully elucidated. This study was performed to investigate cellular mechanism of mechanical strain-mediated actions in RA-FLS. RA-FLS were grown on collagen-coated silicone membranes and were exposed to 6% cyclic mechanical stretch at a frequency of 0.5 Hz for different times in the presence/absence of IL-1β. Real-time PCR and western blotting were used to detect the mRNA and protein level of cyclooxygenase-2 (COX-2) and MMP-1. The production of prostaglandin E(2) (PGE(2)) was quantified by ELISA method. Our results showed that 6% cyclic mechanical stretch significantly inhibited IL-1β-induced MMP-1 (gene) and COX-2 (gene and protein) expression at 15, 40, and 80 min. It also downregulated the IL-1β-induced production of PGE(2). Further investigation of nuclear factor kappa B (NF-κB) signal pathway-related effectors IκB-α and IκB-β revealed that 6% cyclic stretch inhibited their IL-1β-induced degradation in cytoplasm as well as reversed their gene transcription levels. Our data suggest that gentle level of cyclic mechanical stretch exerts a protective effect on RA-FLS as it downregulates the level of MMP-1 protease, COX-2, and proinflammatory PGE(2). The underlying mechanism appears to be, in part, executed through NF-κB and its upstream effectors.
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Affiliation(s)
- Ping Wang
- Key Laboratory of Biorheology Science and Technology under the ministry of Education, College of Bioengineering, Chongqing University , Chongqing , PR China
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Intratracheally instilled mannosylated cationic liposome/NFκB decoy complexes for effective prevention of LPS-induced lung inflammation. J Control Release 2011; 149:42-50. [DOI: 10.1016/j.jconrel.2009.12.016] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2009] [Revised: 12/14/2009] [Accepted: 12/16/2009] [Indexed: 01/25/2023]
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Oh YC, Choi JG, Lee YS, Brice OO, Lee SC, Kwak HS, Byun YH, Kang OH, Rho JR, Shin DW, Kwon DY. Tetrahydropalmatine Inhibits Pro-Inflammatory Mediators in Lipopolysaccharide-Stimulated THP-1 Cells. J Med Food 2010; 13:1125-32. [DOI: 10.1089/jmf.2009.1388] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- You-Chang Oh
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University Wonkwang Oriental Medicines Research Institute, Iksan, Republic of Korea
| | - Jang-Gi Choi
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University Wonkwang Oriental Medicines Research Institute, Iksan, Republic of Korea
| | - Young-Seob Lee
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University Wonkwang Oriental Medicines Research Institute, Iksan, Republic of Korea
| | - Obiang-Obounou Brice
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University Wonkwang Oriental Medicines Research Institute, Iksan, Republic of Korea
| | - Soo-Chan Lee
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University Wonkwang Oriental Medicines Research Institute, Iksan, Republic of Korea
| | - Hwa-Sun Kwak
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University Wonkwang Oriental Medicines Research Institute, Iksan, Republic of Korea
| | - Young-Ho Byun
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University Wonkwang Oriental Medicines Research Institute, Iksan, Republic of Korea
| | - Ok-Hwa Kang
- Department of Oceanography, Kunsan National University, Kunsan, Republic of Korea
| | - Jung-Rae Rho
- Department of Oceanography, Kunsan National University, Kunsan, Republic of Korea
| | - Dong-Won Shin
- Department of Oriental Medicine Resources, Sunchon National University, Sunchon, Republic of Korea
| | - Dong-Yeul Kwon
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang University Wonkwang Oriental Medicines Research Institute, Iksan, Republic of Korea
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Roh GS, Yi CO, Cho YJ, Jeon BT, Nizamudtinova IT, Kim HJ, Kim JH, Oh YM, Huh JW, Lee JH, Hwang YS, Lee SD, Lee JD. Anti-inflammatory effects of celecoxib in rat lungs with smoke-induced emphysema. Am J Physiol Lung Cell Mol Physiol 2010; 299:L184-91. [PMID: 20472710 DOI: 10.1152/ajplung.00303.2009] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Chronic airway inflammation is a characteristic feature of destructive cigarette smoking (CS)-induced lung disease, particularly in patients with emphysema. Celecoxib, a specific cyclooxygenase-2 (COX-2) inhibitor, is widely used to treat inflammation. However, the exact mechanisms underlying this drug's anti-inflammatory effects have not yet been determined in pulmonary emphysema. Here, we explore whether celecoxib attenuates CS-induced inflammation in rat lungs. Rats were exposed to smoke and received celecoxib via intragastric feeding daily for 20 wk. We found that celecoxib inhibited interalveolar wall distance and pulmonary inflammation in the lungs of CS-treated rats. Celecoxib inhibited serum NO production, iNOS, COX-2 expression, and PGE(2) production in CS-treated lung tissues. Our immunohistochemical data showed that CS-induced CD68 and COX-2 expression were inhibited by celecoxib. Furthermore, celecoxib attenuated the activation of phospho-IkappaBalpha and NF-kappaB in CS-treated rat lung. In addition, there was an inhibitory effect of celecoxib on the COX-2 expression and NF-kappaB activation in LPS-stimulated RAW 264.7 macrophages. Celecoxib also attenuated NF-kappaB activation in COX-2 siRNA-transfected RAW 264.7 macrophages. Thus, our findings suggest that the anti-inflammatory effects of celecoxib are mediated by its effects on NF-kappaB-regulated gene expression, which ultimately reduces the progression of CS-induced pulmonary emphysema.
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Affiliation(s)
- Gu Seob Roh
- Departments of Anatomy, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea
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Kim IT, Park HJ, Nam JH, Park YM, Won JH, Choi J, Choe BK, Lee KT. In-vitro and in-vivo anti-inflammatory and antinociceptive effects of the methanol extract of the roots of Morinda officinalis. J Pharm Pharmacol 2010; 57:607-15. [PMID: 15901350 DOI: 10.1211/0022357055902] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Abstract
The anti-inflammatory effects of the methanol extract of the roots of Morinda officinalis (MEMO) (Rubiaceae) were evaluated in-vitro and in-vivo. The effects of MEMO on lipopolysaccharide (LPS)-induced responses in the murine macrophage cell line RAW 264.7 were examined. MEMO potently inhibited the production of nitric oxide (NO), prostaglandin E2 and tumour necrosis factor-α (TNF-α) in LPS-stimulated RAW 264.7 macrophages. Consistent with these results, the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein level, and of iNOS, COX-2 and TNF-α at the mRNA level, was also inhibited by MEMO in a concentration-dependent manner. Furthermore, MEMO inhibited the nuclear factor kappa B (NF-κB) activation induced by LPS, and this was associated with the prevention of degradation of the inhibitor κB (IκB), and subsequently with attenuated p65 protein in the nucleus. The anti-inflammatory effect of MEMO was examined in rats using the carrageenan-induced oedema model. The antinociceptive effects of MEMO were assessed in mice using the acetic acid-induced abdominal constriction test and the hot-plate test. MEMO (100, 200 mg kg−1 per day, p.o.) exhibited anti-inflammatory and antinociceptive effects in these animal models. Taken together, the data demonstrate that MEMO has anti-inflammatory and antinociceptive activity, inhibiting iNOS, COX-2 and TNF-α expression by down-regulating NF-κB binding activity.
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Affiliation(s)
- In-Tae Kim
- College of Pharmacy, Kyung-Hee University, 1 Hoegi-Dong, Dongdaemun-gu, Seoul 130-701, Korea
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Okamoto K, Ishida C, Ikebuchi Y, Mandai M, Mimura K, Murawaki Y, Yuasa I. The genotypes of IL-1 beta and MMP-3 are associated with the prognosis of HCV-related hepatocellular carcinoma. Intern Med 2010; 49:887-95. [PMID: 20467172 DOI: 10.2169/internalmedicine.49.3268] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND AND AIM Cytokines and matrix metalloproteinases (MMPs) are involved in tumor growth, invasion, and remote metastasis in various cancers. Recently, functional gene polymorphisms in these cytokines and MMPs have been found, and some reports have revealed an association between these polymorphisms and the prognosis of various cancers. In this study, we examined the relationship between the gene polymorphisms of interleukin 1 beta (IL-1b), IL-1 receptor antagonist (IL-1 RN), transforming growth factor beta 1 (TGF-b1), MMP-1, MMP-3, and MMP-9 and the prognosis of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). METHODS We enrolled 92 HCV-related HCC patients in the study, and gene polymorphisms of IL-1b -31 C/T, IL-1 RN variable number of tandem repeats (VNTR), TGF-b1 +869 C/T, MMP-1 -1,607 1G/2G, MMP-3 -1,171 5A/6A, and MMP-9 -1,562 C/T were analyzed. RESULTS In HCC clinical features, TGF-b1 C carriers and MMP-3 5A carriers had significantly larger HCC diameters than TGF-b1 T and MMP-3 6A homozygotes. In HCC prognosis, IL-1b T homozygotes and MMP-3 5A carriers had a significantly poorer prognosis than IL-1b C carriers and MMP-3 6A homozygotes. Those with a combination of IL-1b T homozygosity and MMP-3 5A had synergistically poorer HCC prognosis. CONCLUSION The IL-1b -31 T allele and MMP-3 5A allele are cooperative risk factors for poor prognosis in HCC patients, suggesting that these gene polymorphisms might be potential markers for predicting the prognosis of HCC patients.
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Affiliation(s)
- Kinya Okamoto
- The Second Department of Internal Medicine, Tottori University School of Medicine, Yonago.
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Qin Z, Konaniah ES, Neltner B, Nemenoff RA, Hui DY, Weintraub NL. Participation of ATP7A in macrophage mediated oxidation of LDL. J Lipid Res 2009; 51:1471-7. [PMID: 19965596 DOI: 10.1194/jlr.m003426] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
ATP7A primarily functions to egress copper from cells, thereby supplying this cofactor to secreted copper-accepting enzymes. This ATPase has attracted significant attention since the discovery of its mutation leading to human Menkes disease and the demonstration of its distribution in various tissues. Recently, we reported that ATP7A is expressed in the human vasculature. In the present study, we investigated the cellular expression of ATP7A in atherosclerotic lesions of LDL receptor (-/-) mice. Subsequently, we examined the role of ATP7A in regulating the oxidation of LDL in a macrophage cell model. We observed that ATP7A is expressed in atherosclerotic murine aorta and colocalizes with macrophages. To investigate the function of ATP7A, we downregulated ATP7A expression in THP-1 derived macrophages using small interfering RNA (siRNA). ATP7A downregulation attenuated cell-mediated oxidation of LDL. Moreover, downregulation of ATP7A resulted in decreased expression and enzymatic activity of cytosolic phospholipase A(2) alpha (cPLA(2)alpha), a key intracellular enzyme involved in cell-mediated LDL oxidation. In addition, cPLA(2)alpha promoter activity was decreased after downregulation of ATP7A, suggesting that ATP7A transcriptionally regulates cPLA(2)alpha expression. Finally, cPLA(2)alpha overexpression increased LDL oxidation, which was blocked by coadministration of ATP7A siRNA oligonucleotides. These findings suggest a novel mechanism linking ATP7A to cPLA(2)alpha and LDL oxidation, suggesting that this copper transporter could play a previously unrecognized role in the pathogenesis of atherosclerosis.
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Affiliation(s)
- Zhenyu Qin
- Division of Cardiovascular Diseases, Genome Research Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
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Ling H, Jia X, Zhang Y, Gapter LA, Lim YS, Agarwal R, Ng KY. Pachymic acid inhibits cell growth and modulates arachidonic acid metabolism in nonsmall cell lung cancer A549 cells. Mol Carcinog 2009; 49:271-82. [PMID: 19918789 DOI: 10.1002/mc.20597] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Hui Ling
- Department of Pharmacy, National University of Singapore, Singapore, Republic of Singapore
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Aherne CM, McMorrow J, Kane D, FitzGerald O, Mix KS, Murphy EP. Identification of NR4A2 as a transcriptional activator of IL-8 expression in human inflammatory arthritis. Mol Immunol 2009; 46:3345-57. [DOI: 10.1016/j.molimm.2009.07.019] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2009] [Accepted: 07/26/2009] [Indexed: 01/27/2023]
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Sheeba MS, Asha VV. Cardiospermum halicacabum ethanol extract inhibits LPS induced COX-2, TNF-alpha and iNOS expression, which is mediated by NF-kappaB regulation, in RAW264.7 cells. JOURNAL OF ETHNOPHARMACOLOGY 2009; 124:39-44. [PMID: 19393729 DOI: 10.1016/j.jep.2009.04.020] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2007] [Revised: 02/10/2009] [Accepted: 04/06/2009] [Indexed: 05/27/2023]
Abstract
AIM OF THIS STUDY Cardiospermum halicacabum L. is well known for its anti-inflammatory, analgesic and antipyretic activities. It has been used in Ayurveda and folk medicine for the treatment of rheumatism, fever and earache. But its mechanism of anti-inflammatory and analgesic action is still unclear, hence in this context, the objective of our study is to reveal the mechanism of anti-inflammatory and analgesic activity of Cardiospermum halicacabum L. which would form an additional proof to the traditional knowledge of Cardiospermum halicacabum L. MATERIALS AND METHODS In this study the ethanolic extract of the whole plant was used to evaluate the anti-inflammatory action in mouse macrophage cell line RAW264.7 cells. The expression levels of cyclooxygenase (COX)-1, COX-2, tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS) and COX-2 protein expression by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot and nuclear factor kappa-B (NF-kappaB) binding activity by electrophoretic mobility shift assay (EMSA). RESULTS We found that the ethanol extract dose dependently inhibit mRNA expression of COX-2, TNF-alpha, iNOS and COX-2 protein expression. But the extract did not affect the expression of COX-1 mRNA expression. Furthermore, Cardiospermum halicacabum L. ethanol extract inhibited the TNF-alpha induced DNA binding activity of NF-kappaB, which was associated with decreased p65 protein level in the nucleus in Jurkat cells. CONCLUSION These results enabled to understand the mechanisms behind the anti-inflammatory and analgesic activity of Cardiospermum halicacabum L.
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Affiliation(s)
- M S Sheeba
- Bioprospecting and Molecular Pharmacology Laboratory, Department of Molecular Medicine and Cancer Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India
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Kanda N, Shibata S, Tada Y, Nashiro K, Tamaki K, Watanabe S. Prolactin enhances basal and IL-17-induced CCL20 production by human keratinocytes. Eur J Immunol 2009; 39:996-1006. [PMID: 19350575 DOI: 10.1002/eji.200838852] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Psoriasis vulgaris is an autoimmune dermatosis with Th17 infiltration. Prolactin (PRL) may participate in the pathogenesis of psoriasis. The chemokine CCL20 recruits Th17 cells, and CCL20 production by epidermal keratinocytes is enhanced in psoriatic lesions. We examined the in vitro effects of PRL on CCL20 production in human keratinocytes. PRL increased basal and IL-17-induced CCL20 secretion, and mRNA expression in keratinocytes. CCL20 production by PRL was suppressed by antisense oligonucleotides against the AP-1 components c-Fos and c-Jun, whereas that by IL-17 was suppressed by antisense NF-kappaB p50 and p65. CCL20 production induced by PRL plus IL-17 was suppressed by antisense c-Fos, c-Jun, p50, and p65. PRL alone increased the transcriptional activity of AP-1, and c-Fos and c-Jun expression; moderately enhanced NF-kappaB activity and IkappaBalpha phosphorylation; and potently increased IL-17-induced NF-kappaB activity. MEK and JNK inhibitors suppressed PRL- or PRL-plus-IL-17-induced CCL20 production and AP-1 activities. MEK inhibitor suppressed PRL-induced c-Fos expression, whereas JNK inhibitor suppressed c-Jun expression. PRL induced ERK and JNK phosphorylation. These results suggest that PRL may enhance basal and IL-17-induced CCL20 production in keratinocytes by AP-1 and NF-kappaB activation, which is partially mediated via MEK/ERK and JNK. PRL may promote Th17 infiltration into psoriatic lesions via CCL20.
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Affiliation(s)
- Naoko Kanda
- Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.
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Tatano Y, Fujinawa R, Kozutsumi Y, Takahashi T, Tsuji D, Takeuchi N, Tsuta K, Takada G, Sakuraba H, Itoh K. Tropoelastin regulates chemokine expression in fibroblasts in Costello syndrome. Biochem Biophys Res Commun 2008; 372:681-7. [PMID: 18533107 DOI: 10.1016/j.bbrc.2008.05.131] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2008] [Accepted: 05/19/2008] [Indexed: 11/17/2022]
Abstract
Costello syndrome is a multiple congenital anomaly associated with growth and mental retardation, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Comprehensive expression analysis revealed remarkable up-regulation of several cytokines and chemokines including Gro family proteins, interleukin-1beta (IL-1beta), IL-8 and MCP-1 but down-regulation of extracellular matrix components including collagens and proteoglycans of skin fibroblasts derived from a Japanese Costello syndrome patient characterized by significantly reduced tropoelastin mRNA, impaired elastogenesis and enhanced cell proliferation. In contrast, decreases in these chemokines and IL-1beta expression were observed in Costello fibroblastic cell lines stably expressing the bovine tropoelastin (btEln) gene and in restored elastic fibers. These results strongly suggest that the human TE gene (ELN) transfer could be applicable for the gene therapy of a group of Costello syndrome patients with reduced ELN gene expression.
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Affiliation(s)
- Yutaka Tatano
- Department of Medicinal Biotechnology, Institute for Medicinal Resources, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan
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Kanda N, Watanabe S. IL-12, IL-23, and IL-27 enhance human β-defensin-2 production in human keratinocytes. Eur J Immunol 2008; 38:1287-96. [DOI: 10.1002/eji.200738051] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Anti-inflammatory effect of a human prothrombin fragment-2-derived peptide, NSA9, in EOC2 microglia. Biochem Biophys Res Commun 2008; 368:779-85. [DOI: 10.1016/j.bbrc.2008.01.142] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2008] [Accepted: 01/30/2008] [Indexed: 12/14/2022]
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