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J B, J S, M D. The history of ankylosing spondylitis/axial spondyloarthritis - what is the driving force of new knowledge? Semin Arthritis Rheum 2025; 71:152611. [PMID: 39827646 DOI: 10.1016/j.semarthrit.2024.152611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 11/29/2024] [Accepted: 12/16/2024] [Indexed: 01/22/2025]
Abstract
The history of (axial) spondyloarthritis has started several centuries ago. Since the end of the 19th century major achievements have been made. This historical review tries to show how closely the advances in clinical medicine in rheumatology have been related to advances made in basic sciences.
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Affiliation(s)
- Braun J
- Ruhr University, Bochum, and Rheumatologisches Versorgungszentrum Steglitz, Berlin, Germany.
| | - Sieper J
- Universitätsmedizin Charité Berlin, Germany
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2
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Kan X, Zhou Z, Liu L, Aiskikaer R, Zou Y. Significance of non-steroidal anti-inflammatory drugs in the prevention and treatment of cervical cancer. Heliyon 2025; 11:e42055. [PMID: 39916829 PMCID: PMC11800076 DOI: 10.1016/j.heliyon.2025.e42055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 02/09/2025] Open
Abstract
Cervical cancer, ranking as the fourth most common cancer in women globally, is closely linked to chronic inflammation resulting from persistent human papillomavirus (HPV) infection. Chronic inflammation mediated by cyclooxygenase (COX) has been identified as a factor in cancer onset and progression, with HPV oncoproteins E6 and E7 inducing COX activation. Nonsteroidal anti-inflammatory drugs (NSAIDs) have demonstrated the capability to significantly inhibit COX activity, playing a crucial preventive and therapeutic role in various tumors. This paper explores the therapeutic value and potential clinical applications of NSAIDs in cervical cancer by examining the mechanistic interactions between HPV and COX and the carcinogenic effects of COX in cervical cancer.
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Affiliation(s)
- Xun Kan
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Zhenhuan Zhou
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Lianlian Liu
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Reziwanguli Aiskikaer
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yinggang Zou
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
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Ma ZY, Ding XJ, Zhu ZZ, Chen Q, Wang DB, Qiao X, Xu JY. Pt(iv) derivatives of cisplatin and oxaliplatin bearing an EMT-related TMEM16A/COX-2-selective dual inhibitor against colorectal cancer cells HCT116. RSC Med Chem 2024:d4md00327f. [PMID: 39185449 PMCID: PMC11342162 DOI: 10.1039/d4md00327f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 07/30/2024] [Indexed: 08/27/2024] Open
Abstract
Colorectal cancer represents the over-expression of TMEM16A and COX-2, offering a promising therapeutic strategy. Two Pt(iv) conjugates derived from Pt(ii) drug (cisplatin or oxaliplatin) and niflumic acid, complexes 1 and 2, were designed and prepared to exert the positive impact of multiple biological targets of DNA/TMEM16A/COX-2 against colorectal cancer. Complex 2 afforded higher cytotoxicity than 1 and the combination of an intermediate of oxidized oxaliplatin and NFA against cancer cells A549, HeLa, MCF-7, and HCT116. Especially for colorectal cancer cells HCT116, 2 was significantly more toxic (22-fold) and selective to cancer cells against normal HUVEC cells (4-fold) than first-line oxaliplatin. The outstanding anticancer activity of 2 is partly attributed to its dramatic increase in cellular uptake, DNA damage, and apoptosis. Mechanistic studies indicated that 2 inhibited HCT116 cell metastasis by triggering TMEM16A, COX-2, and their downstream signaling pathways, including EGFR, STAT3, E-cadherin and N-cadherin.
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Affiliation(s)
- Zhong-Ying Ma
- Department of Chemical Biology and Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University Tianjin 300070 China
| | - Xiao-Jing Ding
- Department of Chemical Biology and Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University Tianjin 300070 China
| | - Zhen-Zhen Zhu
- Department of Chemical Biology and Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University Tianjin 300070 China
| | - Qian Chen
- Department of Chemical Biology and Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University Tianjin 300070 China
| | - Dong-Bo Wang
- Department of Chemical Biology and Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University Tianjin 300070 China
| | - Xin Qiao
- Department of Chemical Biology and Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University Tianjin 300070 China
| | - Jing-Yuan Xu
- Department of Chemical Biology and Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University Tianjin 300070 China
- Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Tianjin Medical University Tianjin 300070 China
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Li T, Ding N, Guo H, Hua R, Lin Z, Tian H, Yu Y, Fan D, Yuan Z, Gonzalez FJ, Wu Y. A gut microbiota-bile acid axis promotes intestinal homeostasis upon aspirin-mediated damage. Cell Host Microbe 2024; 32:191-208.e9. [PMID: 38237593 PMCID: PMC10922796 DOI: 10.1016/j.chom.2023.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/18/2023] [Accepted: 12/21/2023] [Indexed: 02/17/2024]
Abstract
Aspirin-related gastrointestinal damage is of growing concern. Aspirin use modulates the gut microbiota and associated metabolites, such as bile acids (BAs), but how this impacts intestinal homeostasis remains unclear. Herein, using clinical cohorts and aspirin-treated mice, we identified an intestinal microbe, Parabacteroides goldsteinii, whose growth is suppressed by aspirin. Mice supplemented with P. goldsteinii or its BA metabolite, 7-keto-lithocholic acid (7-keto-LCA), showed reduced aspirin-mediated damage of the intestinal niche and gut barrier, effects that were lost with a P. goldsteinii hdhA mutant unable to generate 7-keto-LCA. Specifically, 7-keto-LCA promotes repair of the intestinal epithelium by suppressing signaling by the intestinal BA receptor, farnesoid X receptor (FXR). 7-Keto-LCA was confirmed to be an FXR antagonist that facilitates Wnt signaling and thus self-renewal of intestinal stem cells. These results reveal the impact of oral aspirin on the gut microbiota and intestinal BA metabolism that in turn modulates gastrointestinal homeostasis.
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Affiliation(s)
- Ting Li
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Ning Ding
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Hanqing Guo
- Department of Gastroenterology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Rui Hua
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zehao Lin
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Huohuan Tian
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yue Yu
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Daiming Fan
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zuyi Yuan
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
| | - Frank J Gonzalez
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Yue Wu
- Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
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5
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Dai M, Peng W, Lin L, Wu ZE, Zhang T, Zhao Q, Cheng Y, Lin Q, Zhang B, Liu A, Rao Q, Huang J, Zhao J, Gonzalez FJ, Li F. Celastrol as an intestinal FXR inhibitor triggers tripolide-induced intestinal bleeding: Underlying mechanism of gastrointestinal injury induced by Tripterygium wilfordii. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 121:155054. [PMID: 37738906 DOI: 10.1016/j.phymed.2023.155054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 08/16/2023] [Accepted: 08/29/2023] [Indexed: 09/24/2023]
Abstract
BACKGROUND Tripterygium wilfordii has been widely used for the treatment of rheumatoid arthritis, which is frequently accompanied by severe gastrointestinal damage. The molecular mechanism underlying the gastrointestinal injury of Tripterygium wilfordii are yet to be elucidated. METHODS Transmission electron microscopy, and pathological and biochemical analyses were applied to assess intestinal bleeding. Metabolic changes in the serum and intestine were determined by metabolomics. In vivo (time-dependent effect and dose-response) and in vitro (double luciferase reporter gene system, DRATs, molecular docking, HepG2 cells and small intestinal organoids) studies were used to identify the inhibitory role of celastrol on intestinal farnesoid X receptor (FXR) signaling. Fxr-knockout mice and FXR inhibitors and agonists were used to evaluate the role of FXR in the intestinal bleeding induced by Tripterygium wilfordii. RESULTS Co-treatment with triptolide + celastrol (from Tripterygium wilfordii) induced intestinal bleeding in mice. Metabolomic analysis indicated that celastrol suppressed intestinal FXR signaling, and further molecular studies revealed that celastrol was a novel intestinal FXR antagonist. In Fxr-knockout mice or the wild-type mice pre-treated with pharmacological inhibitors of FXR, triptolide alone could activate the duodenal JNK pathway and induce intestinal bleeding, which recapitulated the pathogenic features obtained by co-treatment with triptolide and celastrol. Lastly, intestinal bleeding induced by co-treatment with triptolide and celastrol could be effectively attenuated by the FXR or gut-restricted FXR agonist through downregulation of the duodenal JNK pathway. CONCLUSIONS The synergistic effect between triptolide and celastrol contributed to the gastrointestinal injury induced by Tripterygium wilfordii via dysregulation of the FXR-JNK axis, suggesting that celastrol should be included in the quality standards system for evaluation of Tripterygium wilfordii preparations. Determining the mechanism of the FXR-JNK axis in intestinal bleeding could aid in the identification of additional therapeutic targets for the treatment of gastrointestinal hemorrhage diseases. This study also provides a new standard for the quality assessment of Tripterygium wilfordii used in the treatment of gastrointestinal disorders.
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Affiliation(s)
- Manyun Dai
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; School of Public Health, Ningbo University Health Science Center, Ningbo 315211, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Wan Peng
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lisha Lin
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Zhanxuan E Wu
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ting Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Qi Zhao
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yan Cheng
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiuxia Lin
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Binbin Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Aiming Liu
- School of Public Health, Ningbo University Health Science Center, Ningbo 315211, China
| | - Qianru Rao
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jianfeng Huang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Jinhua Zhao
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430074, China.
| | - Frank J Gonzalez
- Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Fei Li
- Department of Integrated Traditional Chinese and Western Medicine, Laboratory of Metabolomics and Drug-induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
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Zhou L, Zhang Z, Tian Y, Li Z, Liu Z, Zhu S. The critical role of platelet in cancer progression and metastasis. Eur J Med Res 2023; 28:385. [PMID: 37770941 PMCID: PMC10537080 DOI: 10.1186/s40001-023-01342-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 09/04/2023] [Indexed: 09/30/2023] Open
Abstract
Platelets play a crucial role in cancer blood metastasis. Various cancer-related factors such as Toll-like receptors (TLRs), adenosine diphosphate (ADP) or extracellular matrix (ECM) can activate these small particles that function in hemostasis and thrombosis. Moreover, platelets induce Epithelial Mesenchymal Transition (EMT) to promote cancer progression and invasiveness. The activated platelets protect circulating tumor cells from immune surveillance and anoikis. They also mediate tumor cell arrest, extravasation and angiogenesis in distant organs through direct or indirect modulation, creating a metastatic microenvironment. This review summarizes the recent advances and progress of mechanisms in platelet activation and its interaction with cancer cells in metastasis.
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Affiliation(s)
- Lin Zhou
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, 90095, USA
| | - Zhe Zhang
- Department of Gastrointestinal Surgery, Huizhou Municipal Central Hospital, Huizhou, Guangdong, 516001, People's Republic of China
| | - Yizhou Tian
- Department of Oncology, Zhoushan Hospital of Traditional Chinese Medicine (Affiliated to Zhejiang University of Traditional Chinese Medicine), Zhoushan, 316000, China
| | - Zefei Li
- Department of Oncology, Zhoushan Hospital of Traditional Chinese Medicine (Affiliated to Zhejiang University of Traditional Chinese Medicine), Zhoushan, 316000, China
| | - Zhongliang Liu
- Department of Oncology, Zhoushan Hospital of Traditional Chinese Medicine (Affiliated to Zhejiang University of Traditional Chinese Medicine), Zhoushan, 316000, China.
| | - Sibo Zhu
- Department of Oncology, Zhoushan Hospital of Traditional Chinese Medicine (Affiliated to Zhejiang University of Traditional Chinese Medicine), Zhoushan, 316000, China.
- School of Life Sciences, Fudan University, Shanghai, 200438, China.
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ElGamal RA, Galala AA, Abdel-Kader MS, Badria FA, Soliman AF. Microbial Transformation of the Sesquiterpene Lactone, Vulgarin, by Aspergillus niger. Molecules 2023; 28:molecules28093729. [PMID: 37175138 PMCID: PMC10180108 DOI: 10.3390/molecules28093729] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/15/2023] Open
Abstract
The biotransformation of vulgarin (1), an eudesmanolides-type sesquiterpene lactone obtained from Artemisia judaica, by the microorganism, Aspergillus niger, was carried out to give three more polar metabolites; 1-epi-tetrahydrovulgarin (1α,4α-dihydroxy-5αH,6,11βH-eudesman-6,12-olide (2), 20% yield, 1α,4α-dihydroxyeudesm-2-en-5αH,6,11βH-6,12-olide (3a), 10% yield, and C-1 epimeric mixture (3a, b), 4% yield, in a ratio of 4:1, 3a/3b. The structures of vulgarin and its metabolites were elucidated by 1 and 2D NMR spectroscopy in conjunction with HRESIMS. Metabolites (3a) and (3b) are epimers, and they are reported here for the first time as new metabolites obtained by biotransformation by selective reduction at C-1. Vulgarin and its metabolites were evaluated as anti-inflammatory agents using the human cyclooxygenase (COX) inhibitory assay. The obtained data showed that (1) exhibited a good preferential inhibitory activity towards COX-2 (IC50 = 07.21 ± 0.10) and had a moderate effect on COX-1 (IC50 = 11.32 ± 0.24). Meanwhile, its metabolite (3a) retained a selective inhibitory activity against COX-1 (IC50 = 15.70 ± 0.51). In conclusion, the results of this study revealed the necessity of the presence α, β unsaturated carbonyl group in (1) for better COX-2 inhibitory activity. On the other hand, the selectivity of (1) as COX-1 inhibitor may be enhanced via the reduction of C-1 carbonyl group.
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Affiliation(s)
- Reem A ElGamal
- Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, El Mansoura 35516, Egypt
| | - Amal A Galala
- Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, El Mansoura 35516, Egypt
| | - Maged S Abdel-Kader
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
- Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria 21215, Egypt
| | - Farid A Badria
- Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, El Mansoura 35516, Egypt
| | - Amal F Soliman
- Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, El Mansoura 35516, Egypt
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Lari S, Hiyari S, de Araújo Silva DN, de Brito Bezerra B, Ishii M, Monajemzadeh S, Cui ZK, Tetradis S, Lee M, Pirih FQ. Local delivery of a CXCR3 antagonist decreases the progression of bone resorption induced by LPS injection in a murine model. Clin Oral Investig 2022; 26:5163-5169. [PMID: 35462591 PMCID: PMC9710470 DOI: 10.1007/s00784-022-04484-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 04/05/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVES This experimental study was carried out to investigate the effects of locally delivered nanoparticles (AMG-487 NP) containing a CXCR3 antagonist in inhibiting the progression of LPS-induced inflammation, osteoclastic activity, and bone resorption on a murine model. MATERIALS AND METHODS Thirty, 7-week-old C57BL/6 J male mice were used. Inflammatory bone loss was induced by Porphyromonas gingivalis-lipopolysaccharide (P.g.-LPS) injections between the first and second maxillary molars, bilaterally, twice a week for 6 weeks (n = 20). AMG-487 NP were incorporated into a liposome carrier and locally delivered on sites where P.g.-LPS was injected. Control mice (n = 10) were injected with vehicle only. Experimental groups included (1) control, (2) LPS, and (3) LPS + NP. At the end of 1 and 6 weeks, mice were euthanized, maxillae harvested, fixed, and stored for further analysis. RESULTS Volumetric bone loss analysis revealed, at 1 week, an increase in bone loss in the LPS group (47.9%) compared to control (27.4%) and LPS + NP (27.8%) groups. H&E staining demonstrated reduced inflammatory infiltrate in the LPS + NP group compared to LPS group. At 6 weeks, volumetric bone loss increased in all groups; however, treatment with the CXCR3 antagonist (LPS + NP) significantly reduced bone loss compared to the LPS group. CXCR3 antagonist treatment significantly reduced osteoclast numbers when compared to LPS group at 1 and 6 weeks. CONCLUSIONS This study showed that local delivery of a CXCR antagonist, via nanoparticles, in a bone resorption model, induced by LPS injection, was effective in reducing inflammation, osteoclast numbers, and bone loss. CLINICAL RELEVANCE CXCR3 blockade can be regarded as a novel target for therapeutic intervention of bone loss. It can be a safe and convenient method for periodontitis treatment or prevention applicable in clinical practice.
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Affiliation(s)
- Soma Lari
- School of Dentistry, Section of Periodontics, University of California, Los Angeles, Los Angeles, Los Angeles, CA, USA
| | - Sarah Hiyari
- School of Dentistry, Section of Periodontics, University of California, Los Angeles, Los Angeles, Los Angeles, CA, USA
| | - Davi Neto de Araújo Silva
- School of Dentistry, Section of Periodontics, University of California, Los Angeles, Los Angeles, Los Angeles, CA, USA
- Dentistry Department, Rio Grande do Norte Federal University, Natal, RN, Brazil
| | - Beatriz de Brito Bezerra
- School of Dentistry, Section of Periodontics, University of California, Los Angeles, Los Angeles, Los Angeles, CA, USA
| | - Makiko Ishii
- Division of Periodontology, Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, Urayasu, Japan
| | - Sepehr Monajemzadeh
- School of Dentistry, Section of Periodontics, University of California, Los Angeles, Los Angeles, Los Angeles, CA, USA
| | - Zhong-Kai Cui
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Sotirios Tetradis
- School of Dentistry, Section of Oral Radiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Min Lee
- School of Dentistry, Section of Biomaterials Science, University of California, Los Angeles, Los Angeles, CA, USA
| | - Flavia Q Pirih
- School of Dentistry, Section of Periodontics, University of California, Los Angeles, Los Angeles, Los Angeles, CA, USA.
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Maruyama K, Goto K, Hiramoto K, Tanaka S, Ooi K. Indomethacin, a non-steroidal anti-inflammatory drug, induces skin dryness via PPARγ in mice. Biol Pharm Bull 2021; 45:77-85. [PMID: 34719578 DOI: 10.1248/bpb.b21-00532] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cyclooxygenase (COX)-1-selective inhibitors have side effects such as itching and dryness of the skin. In this study, the degree of skin dryness and the onset mechanism of this condition were investigated by comparing the effects of three non-steroidal anti-inflammatory drugs (NSAIDs) in mice. Mice were orally administered either indomethacin, loxoprofen sodium, or celecoxib (n = 5 per group) once daily for four consecutive days, and blood samples as well as skin and jejunal tissues were isolated on day 5. In the mice treated with indomethacin, transepidermal water loss was significantly increased, and dry skin was observed. In addition, the expression of matrix metalloproteinase (MMP)-I, mast cells, CD163, CD23, CD21, histamine, and peroxisome proliferation-activated receptor (PPAR)γ in the skin and jejunum was increased, and the blood levels of interleukin-10 and immunoglobulin E were also increased. In contrast, the expression of collagen type I in the skin was decreased. These results show that indomethacin activates PPARγ in the skin and jejunum, changes the polarity of macrophages, increases the secretion of MMP-1 from mast cells, and decomposes collagen type I, leading to dry skin.
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Affiliation(s)
- Kiyoko Maruyama
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science
| | - Kenji Goto
- Research Laboratories, Nichinichi Pharmaceutical Co., Ltd
| | - Keiichi Hiramoto
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science
| | - Shota Tanaka
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science
| | - Kazuya Ooi
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science
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10
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Wu Y, Hao R, Lan B, Mu Y, Dang F, Wang R. The protective effects of naproxen against interleukin-1β (IL-1β)- induced damage in human umbilical vein endothelial cells (HUVECs). Bioengineered 2021; 12:5361-5372. [PMID: 34427537 PMCID: PMC8806478 DOI: 10.1080/21655979.2021.1955560] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely used medications in the world. Naproxen is an NSAID with relatively low selectivity for cyclooxygenase-2 (COX-2), thereby having decreased risk for cardiovascular (CV) events. However, it is unclear whether naproxen might provide protection against atherosclerosis, an underlying cause of numerous cardiovascular diseases (CVDs). In the present study, we exposed human umbilical vein endothelial cells to interleukin-1β (IL-1β), a key cytokine involved in atherogenesis, with or without naproxen. Our findings indicate that naproxen could protect against IL-1β-induced damage by improving cell viability and preventing cell death. Additionally, naproxen suppressed the expression of the cytokines IL-6, IL-12, and tumor necrosis factor-α (TNF-α), and downregulated the expression of vascular endothelial growth factor (VEGF) and tissue factor (TF) induced by IL-1β. Importantly, naproxen also inhibited the attachment of monocytes to endothelial cells, which was achieved through Krüppel-like factor 6 (KLF6)-mediated reduced expression of intracellular adhesion molecule-1 (ICAM-1) and E-selectin. These findings suggest that naproxen may aid in the prevention of atherosclerosis by exerting cardioprotective effects beyond low COX-2-selectivity.
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Affiliation(s)
- Yuliang Wu
- Department of Cardiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ruina Hao
- Department of Cardiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Beidi Lan
- Department of Structural Heart Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yiping Mu
- Department of Medical Information Management Office, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Fuping Dang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ruitao Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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11
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Lane Starr NM, Evans MD, Lee KE, Gern JE, Denlinger LC. Ensemble Analysis Identifies Nasal 15-Keto-PGE2 as a Predictor of Recovery in Experimental Rhinovirus Colds. J Infect Dis 2021; 224:839-849. [PMID: 33681993 DOI: 10.1093/infdis/jiab015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 01/24/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Symptom intensity during a common cold is highly variable, particularly after the illness peaks, contributing to delay in recovery. Rhinoviruses frequently cause colds and, during acute infections, generate leukotriene B4 and prostaglandin E2 (PGE2). PGE2 is known to initiate oxylipin class switching and resolution of acute inflammation. Thus, we hypothesized that during acute rhinovirus colds, oxylipins with pro-resolving capabilities reduce symptom severity and speed recovery. METHODS Four groups of healthy volunteers were inoculated with placebo or 3 different doses of rhinovirus A16. Participants kept daily records of symptoms and contributed serial nasal lavage fluid samples. We collected semi-quantitative mass spectrometry data for 71 oxylipins in these acute samples from all participants. An ensemble analysis approach was used to further reduce this dataset. RESULTS Levels of 15-keto-PGE2 at day 3 of the cold were consistently among the top candidates in these models of recovery symptoms. 15-keto-PGE2 was the only oxylipin with an interaction between inoculum dose and time. Acute 15-keto-PGE2 levels were inversely associated with symptoms during cold recovery in a multivariable analysis (P = .0043). CONCLUSIONS These findings show that high 15-keto-PGE2 levels during the acute cold are associated with fewer symptoms during recovery.
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Affiliation(s)
- Nicole M Lane Starr
- Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Michael D Evans
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Kristine E Lee
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - James E Gern
- Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.,Allergy and Immunology, Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Loren C Denlinger
- Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
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12
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Bhuvaneswari K, Sivaguru P, Lalitha A. Synthesis, anticancer evaluation, and docking studies of some novel azo chromene derivatives. J CHIN CHEM SOC-TAIP 2020. [DOI: 10.1002/jccs.201900481] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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13
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Neurochemical Plasticity of nNOS-, VIP- and CART-Immunoreactive Neurons Following Prolonged Acetylsalicylic Acid Supplementation in the Porcine Jejunum. Int J Mol Sci 2020; 21:ijms21062157. [PMID: 32245119 PMCID: PMC7139762 DOI: 10.3390/ijms21062157] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 03/04/2020] [Accepted: 03/13/2020] [Indexed: 12/13/2022] Open
Abstract
Aspirin, also known as acetylsalicylic acid (ASA), is a commonly used anti-inflammatory drug that has analgesic and antipyretic properties. The side effects are well known, however, knowledge concerning its influence on gastric and intestinal innervation is limited. The enteric nervous system (ENS) innervates the whole gastrointestinal tract (GIT) and is comprised of more than one hundred million neurons. The capacity of neurons to adapt to microenvironmental influences, termed as an enteric neuronal plasticity, is an essential adaptive response to various pathological stimuli. Therefore, the goal of the present study was to determine the influence of prolonged ASA supplementation on the immunolocalization of neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide (VIP) and cocaine- and amphetamine- regulated transcript peptide (CART) in the porcine jejunum. The experiment was performed on 8 Pietrain × Duroc immature gilts. Using routine double-labelling immunofluorescence, we revealed that the ENS nerve cells underwent adaptive changes in response to the induced inflammation, which was manifested by upregulated or downregulated expression of the studied neurotransmitters. Our results suggest the participation of nNOS, VIP and CART in the development of inflammation and may form the basis for further neuro-gastroenterological research.
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14
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Sharma V, Mamontov E, Tyagi M. Effects of NSAIDs on the nanoscopic dynamics of lipid membrane. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183100. [DOI: 10.1016/j.bbamem.2019.183100] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 08/16/2019] [Accepted: 09/19/2019] [Indexed: 01/30/2023]
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15
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Gedawy EM, Kassab AE, El Kerdawy AM. Design, synthesis and biological evaluation of novel pyrazole sulfonamide derivatives as dual COX-2/5-LOX inhibitors. Eur J Med Chem 2020; 189:112066. [PMID: 31982653 DOI: 10.1016/j.ejmech.2020.112066] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/11/2020] [Accepted: 01/11/2020] [Indexed: 12/13/2022]
Abstract
The current therapeutic demand focuses more on the discovery of safer NSAIDs rather than exploring more potent alternatives. The dual COX-2/5-LOX inhibition is a promising strategy for designing compounds with an enhanced efficacy, reduced side-effects and a broader anti-inflammatory spectrum in comparison to classical NSAIDs. In the present study, a hybridization strategy was adopted to combine the binding features of the non-selective COX inhibitor "sulindac" and the selective COX-2 inhibitor "celecoxib" which show 5-LOX inhibitory activity with that of licofelone and a celecoxib pyridone analogue which show dual COX-2/5-LOX inhibitory activity to design new series of pyrazole sulfonamide derivatives which, by design, should possess dual COX-2/5-LOX inhibitory activity. All the newly synthesized compounds were initially tested for their potential analgesic activity, then candidates that showed potential analgesic activity, were selected for the subsequent anti-inflammatory activity evaluation, as well as, ulcerogenicity testing. Moreover, in vitro assessment of their COX-1, COX-2 and 5-LOX inhibitory activities were performed. The benzothiophen-2-yl pyrazole carboxylic acid derivative 5b showed the most potent analgesic and anti-inflammatory activities surpassing that of celecoxib and indomethacin. It showed potent COX-1, COX-2 and 5-LOX inhibitory activity with IC50 of 5.40, 0.01 and 1.78 μM, respectively, showing a selectivity index of 344.56 that was much better than the used reference standards and its parent compounds, confirming its selectivity towards COX-2 over COX-1. The prodrug ester derivatives 6c and 6d showed equipotent activity to their parent compound 5b with no gastric ulcerogenicity. Molecular docking simulations confirmed that the newly synthesized compounds possess the structural features required for binding to the target enzymes COX-2 and 5-LOX.
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Affiliation(s)
- Ehab M Gedawy
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Industries, Badr University in Cairo BUC, Cairo, Egypt
| | - Asmaa E Kassab
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
| | - Ahmed M El Kerdawy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt
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16
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Sharma VK, Nagao M, Rai DK, Mamontov E. Membrane softening by nonsteroidal anti-inflammatory drugs investigated by neutron spin echo. Phys Chem Chem Phys 2019; 21:20211-20218. [PMID: 31486459 DOI: 10.1039/c9cp03767e] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
In spite of their well-known side effects, the nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed medications for their antipyretic and anti-inflammatory actions. Interaction of NSAIDs with the plasma membrane plays a vital role in their therapeutic actions and defines many of their side effects. In the present study, we investigate the effects of three NSAIDs, aspirin, ibuprofen, and indomethacin, on the structure and dynamics of a model plasma membrane using a combination of small angle neutron scattering (SANS) and neutron spin echo (NSE) techniques. The SANS and NSE measurements were carried out on a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) membrane, with and without NSAIDs, at two different temperatures, 11 °C and 37 °C, where the DMPC membrane is in the gel and fluid phase, respectively. SANS data analysis shows that incorporation of NSAIDs leads to bilayer thinning of the membrane in both the phases. The dynamic properties of the membrane are represented by the intermediate scattering functions for NSE data, which are successfully described by the Zilman and Granek model. NSE data analysis shows that in both gel and fluid phases, addition of NSAIDs results in a decrease in the bending rigidity and compressibility modulus of the membrane, which is more prominent when the membrane is in the gel phase. The magnitude of the effect of NSAIDs on the bending rigidity and compressibility modulus of the membrane in the gel phase follows an order of ibuprofen > aspirin > indomethacin, whereas in the fluid phase, it is in the order of aspirin > ibuprofen > indomethacin. We find that the interaction between NSAIDs and phospholipid membranes is strongly dependent on the chemical structure of the drugs and physical state of the membrane. Mechanical properties of the membrane can be quantified by the membrane's bending rigidity. Hence, the present study reveals that incorporation of NSAIDs modulates the mechanical properties of the membrane, which may affect several physiological processes, particularly those linked to the membrane curvature.
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Affiliation(s)
- V K Sharma
- Solid State Physics Division, Bhabha Atomic Research Centre, Mumbai 400085, India.
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17
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Kim HG, Ryu SY, Lee KH, Lee JH, Kim DY. Quantitative analysis of COX-2 promoter methylation in gastric carcinoma. Ann Surg Treat Res 2018; 95:55-63. [PMID: 30079321 PMCID: PMC6073046 DOI: 10.4174/astr.2018.95.2.55] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 11/28/2017] [Accepted: 12/22/2017] [Indexed: 11/30/2022] Open
Abstract
Purpose To determine the occurrence of COX-2 methylation in gastric carcinoma (GC), the status and level of CpG methylation in the promoter region of cyclooxygenase-2 (COX-2) were analyzed in early and advanced GCs, as well as in normal gastric tissues. Methods The extent of promoter methylation of the COX-2 gene was assessed quantitatively using pyrosequencing in 60 early and 60 advanced GCs samples harvested upon gastrectomy, and 40 normal gastric mucosa samples from patients with benign gastric diseases as controls. Results The methylation frequency for the COX-2 gene was significantly higher in early than in advanced GCs (40.0% vs. 20.0%, P < 0.05). A significant difference was found in COX-2 methylation between GCs and normal gastric tissues (30.0% vs. 10.0%, by PS; P < 0.05). COX-2 gene methylation was significantly associated with the depth of invasion (P = 0.003), lymph node metastasis (P = 0.009), distant metastasis (P = 0.036), and TNM staging (P = 0.007). The overall survival of patients with COX-2 methylation was significantly lower than that of patients without COX-2 methylation (P = 0.005). Conclusion These results demonstrated that COX-2 promoter methylation was significantly higher in tumor tissues, and was an early event for GC, thus, COX-2 gene methylation may be important in the initial development of gastric carcinogenesis. Thus, GCs with methylation in COX-2 may not be good candidates for treatment with COX-2 inhibitors. Furthermore, COX-2 methylation could be a significant prognostic factor predicting a favorable effect on GC patient outcome when downregulated.
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Affiliation(s)
- Ho Goon Kim
- Division of Gastroenterologic Surgery, Department of Surgery, Chonnam National University Medical School, Gwangju, Korea
| | - Seong Yeob Ryu
- Division of Gastroenterologic Surgery, Department of Surgery, Chonnam National University Medical School, Gwangju, Korea
| | - Kyung Hwa Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju, Korea
| | - Jae Hyuk Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju, Korea
| | - Dong Yi Kim
- Division of Gastroenterologic Surgery, Department of Surgery, Chonnam National University Medical School, Gwangju, Korea
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18
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Singh P, Kumar R, Singh AK, Yadav P, Khanna RS, Vinayak M, Tewari AK. Synthesis and crystal structure of quinolinium salt: Assignment on nonsteroidal anti-inflammatory activity and DNA cleavage activity. J Mol Struct 2018. [DOI: 10.1016/j.molstruc.2018.02.115] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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19
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Wang S, Li Z, Xu R. Human Cancer and Platelet Interaction, a Potential Therapeutic Target. Int J Mol Sci 2018; 19:ijms19041246. [PMID: 29677116 PMCID: PMC5979598 DOI: 10.3390/ijms19041246] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 03/30/2018] [Accepted: 04/16/2018] [Indexed: 12/12/2022] Open
Abstract
Cancer patients experience a four-fold increase in thrombosis risk, indicating that cancer development and progression are associated with platelet activation. Xenograft experiments and transgenic mouse models further demonstrate that platelet activation and platelet-cancer cell interaction are crucial for cancer metastasis. Direct or indirect interaction of platelets induces cancer cell plasticity and enhances survival and extravasation of circulating cancer cells during dissemination. In vivo and in vitro experiments also demonstrate that cancer cells induce platelet aggregation, suggesting that platelet-cancer interaction is bidirectional. Therefore, understanding how platelets crosstalk with cancer cells may identify potential strategies to inhibit cancer metastasis and to reduce cancer-related thrombosis. Here, we discuss the potential function of platelets in regulating cancer progression and summarize the factors and signaling pathways that mediate the cancer cell-platelet interaction.
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Affiliation(s)
- Shike Wang
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
| | - Zhenyu Li
- Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536, USA.
| | - Ren Xu
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
- Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, KY 40536, USA.
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20
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Bjarnason I, Scarpignato C, Holmgren E, Olszewski M, Rainsford KD, Lanas A. Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs. Gastroenterology 2018; 154:500-514. [PMID: 29221664 DOI: 10.1053/j.gastro.2017.10.049] [Citation(s) in RCA: 301] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 10/28/2017] [Accepted: 10/31/2017] [Indexed: 12/13/2022]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, causing widespread morbidity and mortality. Although mechanisms of damage involve the activities of prostaglandin-endoperoxide synthase 1 (PTGS1 or cyclooxygenase [COX] 1) and PTGS1 (COX2), other factors are involved. We review the mechanisms of gastrointestinal damage induction by NSAIDs via COX-mediated and COX-independent processes. NSAIDs interact with phospholipids and uncouple mitochondrial oxidative phosphorylation, which initiates biochemical changes that impair function of the gastrointestinal barrier. The resulting increase in intestinal permeability leads to low-grade inflammation. NSAID inhibition of COX enzymes, along with luminal aggressors, results in erosions and ulcers, with potential complications of bleeding, protein loss, stricture formation, and perforation. We propose a model for NSAID-induced damage to the gastrointestinal tract that includes these complex, interacting, and inter-dependent factors. This model highlights the obstacles for the development of safer NSAIDs.
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Affiliation(s)
- Ingvar Bjarnason
- Department of Gastroenterology, King's College Hospital, London, United Kingdom.
| | - Carmelo Scarpignato
- Department of Clinical and Experimental Medicine, University of Parma, Italy
| | - Erik Holmgren
- Department of Gastroenterology, King's College Hospital, London, United Kingdom
| | - Michael Olszewski
- Department of Gastroenterology, King's College Hospital, London, United Kingdom
| | - Kim D Rainsford
- Biomedical Sciences, Biomedical Research Centre, Sheffield Hallam University, Sheffield, United Kingdom
| | - Angel Lanas
- Department of Gastroenterology, University of Zaragoza School of Medicine, IIS Aragón, CIBERehd, Zaragoza, Spain
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21
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Oxyphenbutazone promotes cytotoxicity in rats and Hep3B cellsvia suppression of PGE2 and deactivation of Wnt/β-catenin signaling pathway. Mol Cell Biochem 2017; 444:187-196. [PMID: 29204817 DOI: 10.1007/s11010-017-3243-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Accepted: 11/27/2017] [Indexed: 12/23/2022]
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22
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Xu Y, Zhao W, Li T, Bu H, Zhao Z, Zhao Y, Song S. Effects of acupoint-stimulation for the treatment of primary dysmenorrhoea compared with NSAIDs: a systematic review and meta-analysis of 19 RCTs. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:436. [PMID: 28859645 PMCID: PMC5580316 DOI: 10.1186/s12906-017-1924-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 08/11/2017] [Indexed: 12/05/2022]
Abstract
Background Primary dysmenorrhoea (PD), defined as painful menses in women with normal pelvic anatomy, is one of the most common gynaecological syndromes. Acupoint-stimulation could potentially be an effective intervention for PD. Our aim was to determine the effectiveness of acupoint-stimulation compared with Non-Steroidal Anti-Inflammatory Drugs (NASIDs) in the treatment of PD. Methods Six databases were searched to December 2014. Sixteen studies involving 1679 PD patients were included. We included randomized controlled trials that compared acupoint-stimulation with NASIDs for the treatment of PD. The main outcomes assessed were clinical effectiveness rate, symptom score, visual analogue score, variation in peripheral blood prostaglandin F2α (PGF2α) and side effects. All analyses were performed using Comprehensive Meta-Analysis statistical software. Results (1) The total efficacy was better than control group: odds ratio = 5.57; 95% confidence interval (95% CI) = 3.96, 7.83; P < 0.00001; (2) The effect of intervention was positive in relieving the severity of PD symptoms: mean difference (MD) = 2.99; 95%CI = 2.49, 3.49; P < 0.00001; (3) No statistical difference existed between two groups in terms of a reduction in the VAS: MD = 1.24; 95%CI = −3.37, 5.85; P = 0.60; (4) The effect of intervention on the variation in peripheral blood PGF2α between two groups was positive: MD = 7.55; 95%CI = 4.29,10.82; P < 0.00001; (5) The side effects of control groups was more than the acupoint-stimulation group: OR = 0.03; 95%CI =0.00,0.22; P = 0.0005. Conclusions According to this article, acupoint-stimulation can relieve pain effectively in the treatment of PD and offers advantages in increasing the overall effectiveness.
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Lichtenberger LM, Fang D, Bick RJ, Poindexter BJ, Phan T, Bergeron AL, Pradhan S, Dial EJ, Vijayan KV. Unlocking Aspirin's Chemopreventive Activity: Role of Irreversibly Inhibiting Platelet Cyclooxygenase-1. Cancer Prev Res (Phila) 2016; 10:142-152. [PMID: 27998883 DOI: 10.1158/1940-6207.capr-16-0241] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 11/29/2016] [Accepted: 11/30/2016] [Indexed: 12/21/2022]
Abstract
The mechanism by which aspirin consumption is linked to significant reductions in the incidence of multiple forms of cancer and metastatic spread to distant tissues, resulting in increased cancer patient survival is not well understood. In this study, using colon cancer as an example, we provide both in vitro (cell culture) and in vivo (chemically induced mouse model of colon cancer) evidence that this profound antineoplastic action may be associated with aspirin's ability to irreversibly inhibit COX-1-mediated platelet activation, thereby blocking platelet-cancer cell interactions, which promote cancer cell number and invasive potential. This process may be driven by platelet-induced epithelial-mesenchymal transition (EMT), as assessed using confocal microscopy, based upon changes in cell morphology, growth characteristics and fibronectin expression, and biochemical/molecular analysis by measuring changes in the expression of the EMT markers; vimentin, β-catenin, and SNAIL. We also provide evidence that a novel, gastrointestinal-safe phosphatidylcholine (PC)-associated aspirin, PL2200 Aspirin, possesses the same or more pronounced actions versus unmodified aspirin with regard to antiplatelet effects (in vitro: reducing platelet activation as determined by measuring the release of thromboxane and VEGF in culture medium; in vivo: inhibiting platelet number/activation and extravasation into tumor tissue) and chemoprevention (in vitro: inhibiting colonic cell growth and invasive activity; in vivo: inhibiting colonic dysplasia, inflammation, and tumor mass). These results suggest that aspirin's chemopreventive effects may be due, in part, to the drug blocking the proneoplastic action of platelets, and the potential use of Aspirin-PC/PL2200 as an effective and safer chemopreventive agent for colorectal cancer and possibly other cancers. Cancer Prev Res; 10(2); 142-52. ©2016 AACR.
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Affiliation(s)
- Lenard M Lichtenberger
- Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas.
| | - Dexing Fang
- Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas
| | - Roger J Bick
- Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas
| | - Brian J Poindexter
- Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas
| | - Tri Phan
- Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas
| | - Angela L Bergeron
- Department of Medicine, Baylor College of Medicine and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Subhashree Pradhan
- Department of Medicine, Baylor College of Medicine and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Elizabeth J Dial
- Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas
| | - K Vinod Vijayan
- Department of Medicine, Baylor College of Medicine and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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Ogata S, Kubota Y, Yamashiro T, Takeuchi H, Ninomiya T, Suyama Y, Shirasuna K. Signaling Pathways Regulating IL-1α-induced COX-2 Expression. J Dent Res 2016; 86:186-91. [PMID: 17251521 DOI: 10.1177/154405910708600215] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Interleukin-1α(IL-1α) stimulates the production of prostaglandin E2 (PGE2) in odontogenic keratocyst fibroblasts. However, the signaling pathways remain obscure. In this study, we investigated IL-1αsignaling pathways that regulate cyclooxygenase-2 (COX-2) expression in odontogenic keratocyst fibroblasts. IL-1αincreased the expression of COX-2 mRNA and protein, and PGE2 secretion in the fibroblasts. IL-1αincreased the phosphorylation of extracellular signal-regulated protein kinase-1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK). PD-98059, SB-203580, SP-600125, and PDTC—which are inhibitors of ERK1/2, p38, JNK, and nuclear factor-κB (NF-κB), respectively—attenuated the IL-1α-induced COX-2 mRNA expression and activated protein kinase C PGE2 secretion. IL-1α(PKC), and PKC inhibitor staurosporine inhibited IL-1α-induced phosphorylation of ERK1/2, p38, and JNK, and decreased IL-1α-induced COX-2 mRNA expression. Thus, in odontogenic keratocyst fibroblasts, IL-1αmay stimulate COX-2 expression both through the PKC-dependent activation of ERK1/2, p38, and JNK signaling pathways, and through the NF-κB cascade.
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Affiliation(s)
- S Ogata
- Department of Oral and Maxillofacial Surgery, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Huang Y, Lichtenberger LM, Taylor M, Bottsford-Miller JN, Haemmerle M, Wagner MJ, Lyons Y, Pradeep S, Hu W, Previs RA, Hansen JM, Fang D, Dorniak PL, Filant J, Dial EJ, Shen F, Hatakeyama H, Sood AK. Antitumor and Antiangiogenic Effects of Aspirin-PC in Ovarian Cancer. Mol Cancer Ther 2016; 15:2894-2904. [PMID: 27638860 PMCID: PMC5136300 DOI: 10.1158/1535-7163.mct-16-0074] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 08/08/2016] [Accepted: 08/21/2016] [Indexed: 02/07/2023]
Abstract
To determine the efficacy of a novel and safer (for gastrointestinal tract) aspirin (aspirin-PC) in preclinical models of ovarian cancer, in vitro dose-response studies were performed to compare the growth-inhibitory effect of aspirin-PC versus aspirin on three human (A2780, SKOV3ip1, and HeyA8) and a mouse (ID8) ovarian cancer cell line over an 8-day culture period. In the in vivo studies, the aspirin test drugs were studied alone and in the presence of a VEGF-A inhibitor (bevacizumab or B20), due to an emerging role for platelets in tumor growth following antiangiogenic therapy, and we examined their underlying mechanisms. Aspirin-PC was more potent (vs. aspirin) in blocking the growth of both human and mouse ovarian cancer cells in monolayer culture. Using in vivo model systems of ovarian cancer, we found that aspirin-PC significantly reduced ovarian cancer growth by 50% to 90% (depending on the ovarian cell line). The efficacy was further enhanced in combination with Bevacizumab or B20. The growth-inhibitory effect on ovarian tumor mass and number of tumor nodules was evident, but less pronounced for aspirin and the VEGF inhibitors alone. There was no detectable gastrointestinal toxicity. Both aspirin and aspirin-PC also inhibited cell proliferation, angiogenesis, and increased apoptosis of ovarian cancer cells. In conclusion, PC-associated aspirin markedly inhibits the growth of ovarian cancer cells, which exceeds that of the parent drug, in both cell culture and in mouse model systems. We also found that both aspirin-PC and aspirin have robust antineoplastic action in the presence of VEGF-blocking drugs. Mol Cancer Ther; 15(12); 2894-904. ©2016 AACR.
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Affiliation(s)
- Yan Huang
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Lenard M Lichtenberger
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas
| | - Morgan Taylor
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Justin N Bottsford-Miller
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Monika Haemmerle
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael J Wagner
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yasmin Lyons
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sunila Pradeep
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wei Hu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rebecca A Previs
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jean M Hansen
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Dexing Fang
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas
| | - Piotr L Dorniak
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Justyna Filant
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Elizabeth J Dial
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas
| | - Fangrong Shen
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hiroto Hatakeyama
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Heimburger D, Gam-Derouich S, Decorse P, Mangeney C, Pinson J. Reversible Trapping of Functional Molecules at Interfaces Using Diazonium Salts Chemistry. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2016; 32:9714-9721. [PMID: 27589560 DOI: 10.1021/acs.langmuir.6b02468] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Developing thin polymeric films for trapping, releasing, delivering, and sensing molecules is important for many applications in chemistry, biotechnology, and environment. Hence, a facile and scalable technique for loading specific molecules on surfaces would rapidly translate into applications. This work presents a novel method for the trapping of functional molecules at interfaces by exploiting diazonium salt chemistry. We demonstrate the efficiency of this approach by trapping two different molecules, 4-nitrobenzophenone and paracetamol, within polycarboxyphenyl layers grafted on gold and glassy carbon (GC) and by releasing them in acidic medium. The former molecule was chosen as a proof of concept for its electrochemical and spectroscopic properties, and the latter one was selected as an example of a pharmaceutical molecule. Advantages of the present approach rely on the simplicity, rapidity, and efficiency of the procedure for the reversible, on demand, trapping and release of functional molecules.
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Affiliation(s)
- Doriane Heimburger
- Univ Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR 7086 CNRS, 15 rue J-A de Baïf, 75205 Cedex 13 Paris, France
| | - Sarra Gam-Derouich
- Univ Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR 7086 CNRS, 15 rue J-A de Baïf, 75205 Cedex 13 Paris, France
| | - Philippe Decorse
- Univ Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR 7086 CNRS, 15 rue J-A de Baïf, 75205 Cedex 13 Paris, France
| | - Claire Mangeney
- Univ Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR 7086 CNRS, 15 rue J-A de Baïf, 75205 Cedex 13 Paris, France
| | - Jean Pinson
- Univ Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR 7086 CNRS, 15 rue J-A de Baïf, 75205 Cedex 13 Paris, France
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Munkarah AR, Morris R, Baumann P, Deppe G, Malone J, Diamond MP, Saed GM. Effects of Prostaglandin E2 on Proliferation and Apoptosis of Epithelial Ovarian Cancer Cells. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/107155760200900309] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
| | | | | | | | | | - M. P. Diamond
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan
| | - G. M. Saed
- Department of Obsterics and Gnecology, Wayne State University, 4707 St. Antoine -5 West, Detroit, MI 48201
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Sakamoto T, Kondo K, Yamasoba T, Sugasawa M, Kaga K. Elevated Expression of Cyclooxygenase-2 in Adenocarcinoma of the Parotid Gland: Insights into Malignant Transformation of Pleomorphic Adenoma. Ann Otol Rhinol Laryngol 2016; 113:930-5. [PMID: 15562904 DOI: 10.1177/000348940411301113] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Pleomorphic adenoma, the most common type of tumor of the parotid gland, may transform into a malignant tumor. In the current study, we investigated whether the expression of cyclooxygenase-2 (COX-2) is elevated in adenocarcinoma as compared to pleomorphic adenoma. Ten pleomorphic adenomas and 10 adenocarcinomas were examined. The tumor specimens were immunohistochemically stained with antibodies against COX-2 and Ki-67. The labeling indices of COX-2 in pleomorphic adenoma and adenocarcinoma were 6.0% ± 4.1% and 16.1% ± 4.6%, respectively, and those of Ki-67 in pleomorphic adenoma and adenocarcinoma were 0.77% ± 0.62% and 6.9% ± 6.6%, respectively. The labeling indices of both COX-2 and Ki-67 were significantly greater (p < .001) in adenocarcinoma than in pleomorphic adenoma. Together with the biological effects of COX-2, these results suggest that overexpression of COX-2 plays a crucial role in the pathogenesis of malignant transformation of pleomorphic adenoma in the parotid gland.
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Affiliation(s)
- Takashi Sakamoto
- Dept of Otorhinolaryngology, Mutual Aid Association for Tokyo Metropolitan Teachers and Officials, Sanraku Hospital, Kandasurugadai 2-5, Chiyoda-ku, Tokyo 101-8326, Japan
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29
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TGF-β in jaw tumor fluids induces RANKL expression in stromal fibroblasts. Int J Oncol 2016; 49:499-508. [PMID: 27279422 PMCID: PMC4922833 DOI: 10.3892/ijo.2016.3548] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 05/16/2016] [Indexed: 12/24/2022] Open
Abstract
Odontogenic tumors and cysts, arising in the jawbones, grow by resorption and destruction of the jawbones. However, mechanisms underlying bone resorption by odontogenic tumors/cysts remain unclear. Odontogenic tumors/cysts comprise odontogenic epithelial cells and stromal fibroblasts, which originate from the developing tooth germ. It has been demonstrated that odontogenic epithelial cells of the developing tooth germ induce osteoclastogenesis to prevent the tooth germ from invading the developing bone to maintain its structure in developing bones. Thus, we hypothesized that odontogenic epithelial cells of odontogenic tumors/cysts induce osteoclast formation, which plays potential roles in tumor/cyst outgrowth into the jawbone. The purpose of this study was to examine osteoclastogenesis by cytokines, focusing on transforming growth factor-β (TGF-β), produced by odontogenic epithelial cells. We observed two pathways for receptor activator of NF-κB ligand (RANKL) induction by keratocystic odontogenic tumor fluid: the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway through interleukin-1α (IL-1α) signaling and non-COX-2/PGE2 pathway through TGF-β receptor signaling. TGF-β1 and IL-1α produced by odontogenic tumors/cysts induced osteoclastogenesis directly in the osteoclast precursor cells and indirectly via increased RANKL induction in the stroma.
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Frazão JB, Thain A, Zhu Z, Luengo M, Condino-Neto A, Newburger PE. Regulation of CYBB Gene Expression in Human Phagocytes by a Distant Upstream NF-κB Binding Site. J Cell Biochem 2016; 116:2008-17. [PMID: 25752509 DOI: 10.1002/jcb.25155] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 03/03/2015] [Indexed: 12/30/2022]
Abstract
The human CYBB gene encodes the gp91-phox component of the phagocyte oxidase enzyme complex, which is responsible for generating superoxide and other downstream reactive oxygen species essential to microbial killing. In the present study, we have identified by sequence analysis a putative NF-κB binding site in a DNase I hypersensitive site, termed HS-II, located in the distant 5' flanking region of the CYBB gene. Electrophoretic mobility assays showed binding of the sequence element by recombinant NF-κB protein p50 and by proteins in nuclear extract from the HL-60 myeloid leukemia cell line corresponding to p50 and to p50/p65 heterodimers. Chromatin immunoprecipitation demonstrated NF-κB binding to the site in intact HL-60 cells. Chromosome conformation capture (3C) assays demonstrated physical interaction between the NF-κB binding site and the CYBB promoter region. Inhibition of NF-κB activity by salicylate reduced CYBB expression in peripheral blood neutrophils and differentiated U937 monocytic leukemia cells. U937 cells transfected with a mutant inhibitor of κB "super-repressor" showed markedly diminished CYBB expression. Luciferase reporter analysis of the NF-κB site linked to the CYBB 5' flanking promoter region revealed enhanced expression, augmented by treatment with interferon-γ. These studies indicate a role for this distant, 15 kb upstream, binding site in NF-κB regulation of the CYBB gene, an essential component of phagocyte-mediated host defense.
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Affiliation(s)
- Josias B Frazão
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Alison Thain
- Departments of Pediatrics and of Molecular, Cellular, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655
| | - Zhiqing Zhu
- Departments of Pediatrics and of Molecular, Cellular, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655
| | - Marcos Luengo
- Center for Investigation in Pediatrics, State University of Campinas Medical School, Campinas, SP 13081-970, Brazil
| | - Antonio Condino-Neto
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Peter E Newburger
- Departments of Pediatrics and of Molecular, Cellular, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, 01655
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El-Zahry MR, Refaat IH, Mohamed HA, Lendl B. Sequential SERS determination of aspirin and vitamin C using in situ laser-induced photochemical silver substrate synthesis in a moving flow cell. Anal Bioanal Chem 2016; 408:4733-41. [DOI: 10.1007/s00216-016-9562-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 04/06/2016] [Accepted: 04/12/2016] [Indexed: 11/30/2022]
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Yokoyama S, Hiramoto K, Koyama M, Ooi K. Skin disruption is associated with indomethacin-induced small intestinal injury in mice. Exp Dermatol 2016; 23:659-63. [PMID: 25041031 DOI: 10.1111/exd.12499] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/06/2014] [Indexed: 01/12/2023]
Abstract
One mechanism by which non-steroidal anti-inflammatory drugs (NSAIDs) cause intestinal injury is by inducing matrix metalloproteinases (MMPs) that degrade and remodel the extracellular matrix. In addition to the intestinal mucosa, MMPs are expressed in the skin and can be activated by mast cell-secreted tryptase. We therefore investigated whether intestinal injury resulting from treatment with the NSAID indomethacin induced MMPs in the skin of mice and caused an associated disruption of skin function. Hairless mice and mast cell-deficient mice were administered indomethacin, after which damage to the jejuna and skin was assessed with immunohistochemistry and Western blotting. The plasma concentration of inflammatory mediators was assessed to evaluate potential pathways for signalling skin disruption in response to intestinal injury. In hairless mice with intestinal injury, transepidermal water loss (TEWL) was higher and skin hydration was lower than in control mice. The expression levels of mast cells, tryptase, MMP-1 and MMP-9 were also increased, with concurrent degradation of types I and IV collagen. In contrast, no changes in skin TEWL or skin hydration were observed in mast cell-deficient mice with indomethacin-induced intestinal injury. In all mice evaluated, the plasma concentrations of IgE, IgA, histamine and TNF-α were increased in response to indomethacin treatment. Skin disruption was strongly associated with indomethacin-induced small intestinal injury, and the activation of mast cells and induction of tryptase, MMP-1 and MMP-9 are critical to this association.
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Affiliation(s)
- Satoshi Yokoyama
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan
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Zhang Y, Zeng HM, Nie XR, Zhang L, Ma JL, Li JY, Pan KF, You WC. Alterations of Cyclooxygenase-2 Methylation Levels Before and After Intervention Trial to Prevent Gastric Cancer in a Chinese Population. Cancer Prev Res (Phila) 2016; 9:484-90. [PMID: 27020655 DOI: 10.1158/1940-6207.capr-15-0389] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 03/16/2016] [Indexed: 11/16/2022]
Abstract
To explore the epigenetic mechanisms underlying the effects of anti-Helicobacter pylori (H. pylori) alone and combined with COX-2 inhibitor (celecoxib), we dynamically evaluated the associations between COX-2 methylation alterations and gastric lesion evolution during the process of interventions. In a total of 809 trial participants COX-2 methylation levels were quantitatively detected before and after treatment. The self-comparison at the same stomach site for each subject showed significant methylation alteration differences among intervention groups (P < 0.001). With placebo group as reference, COX-2 methylation levels were decreased in anti-H. pylori [OR, 3.30; 95% confidence interval (CI), 2.16-5.02], celecoxib (OR, 2.04; 95% CI, 1.36-3.07), and anti-H. pylori followed by celecoxib (OR, 2.10; 95% CI, 1.38-3.17) groups. When stratified by baseline histology, the three active arms significantly decreased COX-2 methylation levels in indefinite dysplasia/dysplasia subjects, and ORs were 3.65 (95% CI, 1.96-6.80) for anti-H. pylori, 2.43 (95% CI 1.34-4.39) for celecoxib, and 2.80 (95% CI, 1.52-5.15) for anti-H. pylori followed by celecoxib, respectively. No additive effect on COX-2 methylation was found for anti-H. pylori followed by celecoxib than two treatments alone. Compared with subjects without methylation reduction, higher opportunity for gastric lesion regression was found in subjects with decreased COX-2 methylation levels, especially for indefinite dysplasia/dysplasia subjects (OR, 1.92; 95% CI, 1.03-3.60). These findings suggest that anti-H. pylori or celecoxib treatment alone could decrease COX-2 methylation levels in gastric mucosa. COX-2 methylation alteration was associated with the regression of indefinite dysplasia/dysplasia, which might serve as a potential biomarker for chemoprevention efficacy. Cancer Prev Res; 9(6); 484-90. ©2016 AACR.
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Affiliation(s)
- Yang Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing, China. Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Hong-Mei Zeng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing, China. Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiao-Rui Nie
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing, China. Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Lian Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing, China. Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jun-Ling Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing, China. Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Ji-You Li
- Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Kai-Feng Pan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing, China. Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Wei-Cheng You
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing, China. Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China.
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Lee EY, Kang JY, Kim KW. Expression of cyclooxygenase-2, peroxiredoxin I, peroxiredoxin 6 and nuclear factor-κB in oral squamous cell carcinoma. Oncol Lett 2015; 10:3129-3136. [PMID: 26722300 DOI: 10.3892/ol.2015.3705] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 07/16/2015] [Indexed: 11/05/2022] Open
Abstract
Tumor development and progression are multistep processes that involve local tumor growth and invasion, followed by metastasis. The aggressiveness of the tumor is the major determinant of the mortality of oral cancer patients. The present study investigates whether the expression levels of cyclooxygenase-2 (COX-2), nuclear factor-κB (NF-κB), peroxiredoxin 1 (PRDX1) and PRDX6 are associated with the development, proliferation, differentiation and recurrence of oral squamous cell carcinoma (OSCC). The mRNA expression levels of COX-2, NF-κB, PRDX1 and PRDX6 were examined in 50 OSCC specimens and 19 normal oral mucosae by quantitative polymerase chain reaction (qPCR). qPCR analysis showed that the mRNA levels of COX-2 in OSCC were significantly higher than those in the normal oral mucosae (P=0.021). The expression levels of PRDX1 in high-stage tumors (T3 and T4) were significantly elevated compared with those in low-stage tumors (T1) (P=0.047). Additionally, the expression levels of NF-κB in the high-grade tumor were significantly elevated compared with those in the low-grade tumors (P=0.030). Overall, it was indicated that the expression of COX-2 is strongly associated with the development of OSCC. Moreover, the enhanced expression of PRDX1 and NF-κB may function in the progression of OSCC, which serves as a useful marker for prognosis in patients with oral cancer.
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Affiliation(s)
- Eun-Young Lee
- Department of Oral and Maxillofacial Surgery, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Chungbuk 361-711, Republic of Korea
| | - Ji-Yeon Kang
- Department of Oral and Maxillofacial Surgery, Dongtan Sacred Heart Hospital, Hallym University, Hwaseong, Gyeonggi 445-170, Republic of Korea
| | - Kyoung-Won Kim
- Department of Oral and Maxillofacial Surgery, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Chungbuk 361-711, Republic of Korea
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Soriano-Hernandez AD, Madrigal-Pérez D, Galvan-Salazar HR, Martinez-Fierro ML, Valdez-Velazquez LL, Espinoza-Gómez F, Vazquez-Vuelvas OF, Olmedo-Buenrostro BA, Guzman-Esquivel J, Rodriguez-Sanchez IP, Lara-Esqueda A, Montes-Galindo DA, Delgado-Enciso I. Anti-inflammatory drugs and uterine cervical cancer cells: Antineoplastic effect of meclofenamic acid. Oncol Lett 2015; 10:2574-2578. [PMID: 26622892 DOI: 10.3892/ol.2015.3580] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 05/22/2015] [Indexed: 01/26/2023] Open
Abstract
Uterine cervical cancer (UCC) is one of the main causes of cancer-associated mortality in women. Inflammation has been identified as an important component of this neoplasia; in this context, anti-inflammatory drugs represent possible prophylactic and/or therapeutic alternatives that require further investigation. Anti-inflammatory drugs are common and each one may exhibit a different antineoplastic effect. As a result, the present study investigated different anti-inflammatory models of UCC in vitro and in vivo. Celecoxib, sulindac, nimesulide, dexamethasone, meclofenamic acid, flufenamic acid and mefenamic acid were tested in UCC HeLa, VIPA, INBL and SiHa cell lines. The cytotoxicity of the drugs was evaluated in vitro. Celecoxib, sulindac, nimesulide, mefenamic acid and flufenamic acid presented with slight to moderate toxicity (10-40% of cell death corresponding to 100 µM) in certain cell lines, while meclofenamic acid exhibited significant cytotoxicity in all essayed cell lines (50-90% of cell death corresponding to 100 µM). The meclofenamic acid was tested in murine models (immunodeficient and immunocompetent) of UCC, which manifested a significant reduction in tumor growth and increased mouse survival. It was demonstrated that of the evaluated anti-inflammatory drugs, meclofenamic acid was the most cytotoxic, with a significant antitumor effect in murine models. Subsequent studies are necessary to evaluate the clinical utility of this drug.
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Affiliation(s)
- Alejandro D Soriano-Hernandez
- School of Medicine, University of Colima, Colima, Colima 28030, Mexico ; Cancerology State Institute, Colima State Health Services, Colima, Colima 28000, Mexico
| | | | - Hector R Galvan-Salazar
- School of Medicine, University of Colima, Colima, Colima 28030, Mexico ; Cancerology State Institute, Colima State Health Services, Colima, Colima 28000, Mexico
| | - Margarita L Martinez-Fierro
- Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences, Autononous University of Zacatecas, Zacatecas, Zacatecas 98160, Mexico
| | | | | | | | | | - Jose Guzman-Esquivel
- General Hospital of Zone No. 1, Mexican Institute of Social Security, Colima, Colima 28000, Mexico
| | - Iram P Rodriguez-Sanchez
- Department of Genetics, School of Medicine, Nuevo Leon Autonomous University, Monterrey, Nuevo León 64460, Mexico
| | - Agustin Lara-Esqueda
- Cancerology State Institute, Colima State Health Services, Colima, Colima 28000, Mexico
| | - Daniel A Montes-Galindo
- School of Medicine, University of Colima, Colima, Colima 28030, Mexico ; School of Chemistry, University of Colima, Coquimatlán, Colima 28400, Mexico
| | - Ivan Delgado-Enciso
- School of Medicine, University of Colima, Colima, Colima 28030, Mexico ; Cancerology State Institute, Colima State Health Services, Colima, Colima 28000, Mexico
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36
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Gadgeel SM. Cyclooxygenase 2 inhibition in patients with non-small cell lung cancer: Is this still a valid target for therapy? Cancer 2015; 121:3197-200. [PMID: 26033783 DOI: 10.1002/cncr.29479] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 05/06/2015] [Indexed: 11/09/2022]
Affiliation(s)
- Shirish M Gadgeel
- Division of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
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37
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Acute and chronic toxicity, cytochrome p450 enzyme inhibition, and HERG channel blockade studies with a polyherbal, ayurvedic formulation for inflammation. BIOMED RESEARCH INTERNATIONAL 2015; 2015:971982. [PMID: 25893199 PMCID: PMC4381553 DOI: 10.1155/2015/971982] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 02/20/2015] [Accepted: 02/20/2015] [Indexed: 12/13/2022]
Abstract
Ayurvedic plants are known for thousands of years to have anti-inflammatory and antiarthritic effect. We have recently shown that BV-9238, a proprietary formulation of Withania somnifera, Boswellia serrata, Zingiber officinale, and Curcuma longa, inhibits LPS-induced TNF-alpha and nitric oxide production from mouse macrophage and reduces inflammation in different animal models. To evaluate the safety parameters of BV-9238, we conducted a cytotoxicity study in RAW 264.7 cells (0.005–1 mg/mL) by MTT/formazan method, an acute single dose (2–10 g/kg bodyweight) toxicity study and a 180-day chronic study with 1 g and 2 g/kg bodyweight in Sprague Dawley rats. Some sedation, ptosis, and ataxia were observed for first 15–20 min in very high acute doses and hence not used for further chronic studies. At the end of 180 days, gross and histopathology, blood cell counts, liver and renal functions were all at normal levels. Further, a modest attempt was made to assess the effects of BV-9238 (0.5 µg/mL) on six major human cytochrome P450 enzymes and 3H radioligand binding assay with human hERG receptors. BV-9238 did not show any significant inhibition of these enzymes at the tested dose. All these suggest that BV-9238 has potential as a safe and well tolerated anti-inflammatory formulation for future use.
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Kröger IL, May A. Central effects of acetylsalicylic acid on trigeminal-nociceptive stimuli. J Headache Pain 2014; 15:59. [PMID: 25201152 PMCID: PMC4161265 DOI: 10.1186/1129-2377-15-59] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 08/19/2014] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Acetylsalicylic acid is one of the most used analgesics to treat an acute migraine attack. Next to the inhibitory effects on peripheral prostaglandin synthesis, central mechanisms of action have also been discussed. METHODS Using a standardized model for trigeminal-nociceptive stimulation during fMRI scanning, we investigated the effect of acetylsalicylic acid on acute pain compared to saline in 22 healthy volunteers in a double-blind within-subject design. Painful stimulation was applied using gaseous ammonia and presented in a pseudo-randomized order with several control stimuli. All participants were instructed to rate the intensity and unpleasantness of every stimulus on a VAS scale. Based on previous results, we hypothesized to find an effect of ASA on central pain processing structures like the ACC, SI and SII as well as the trigeminal nuclei and the hypothalamus. RESULTS Even though we did not find any differences in pain ratings between saline and ASA, we observed decreased BOLD signal changes in response to trigemino-nociceptive stimulation in the ACC and SII after administration of ASA compared to saline. This finding is in line with earlier imaging results investigating the effect of ASA on acute pain. Contrary to earlier findings from animal studies, we could not find an effect of ASA on the trigeminal nuclei in the brainstem or within the hypothalamic area. CONCLUSION Taken together our study replicates earlier findings of an attenuating effect of ASA on pain processing structures, which adds further evidence to a possibly central mechanism of action of ASA.
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Affiliation(s)
| | - Arne May
- Department of Systems Neuroscience, University Medical Center Hamburg- Eppendorf, Martinistr, 52, Hamburg D-20246, Germany.
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Chen J, Liu Z, Yang Y. In vitro screening of LPS-induced miRNAs in leukocytes derived from cord blood and their possible roles in regulating TLR signals. Pediatr Res 2014; 75:595-602. [PMID: 24513687 DOI: 10.1038/pr.2014.18] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Accepted: 11/03/2013] [Indexed: 01/12/2023]
Abstract
BACKGROUND microRNAs (miRNAs) are involved in a wide variety of biological processes and play roles in the regulation of Toll-like receptor (TLR) signals. We hypothesized that lipopolysaccharide (LPS)-induced miRNAs in the leukocytes from cord blood (CB) play an important role in newborn innate immunity, specifically in the regulation of the TLR signaling pathway. METHODS The expression profiles of LPS-induced miRNAs and TLR-related genes were studied by microarray and PCR arrays, respectively. A bioinformatics analysis was used to identify the potential biological processes and targets involved in the TLR signals affected by these miRNAs. RESULTS A total of 85 miRNAs and 41 TLR-related genes were differentially expressed. The bioinformatics analysis showed that the potential target genes of these miRNAs were involved in regulation of cellular biosynthetic process, regulation of gene expression, regulation of macromolecule biosynthetic process, etc. Thirteen potential miRNA-mRNA interaction sites were found within the cDNA sequences of 11 differentially expressed TLR signaling pathway genes. CONCLUSION We identified a global miRNA expression signature occurring during LPS-induced acute inflammation in leukocytes derived from CB. The target genes were mainly involved in several biological processes, and these miRNAs may play important roles in the regulation of TLR signals. However, the precise mechanisms require further validation.
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Affiliation(s)
- Jiande Chen
- 1] Key Laboratory of Neonatal Diseases, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China [2] Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China
| | - Zhiwei Liu
- 1] Key Laboratory of Neonatal Diseases, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China [2] Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China
| | - Yi Yang
- 1] Key Laboratory of Neonatal Diseases, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China [2] Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China
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Kawashima M, Fujikawa Y, Itonaga I, Takita C, Tsumura H. The effect of selective cyclooxygenase-2 inhibitor on human osteoclast precursors to influence osteoclastogenesis in vitro. Mod Rheumatol 2014. [DOI: 10.3109/s10165-008-0149-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Masayuki Kawashima
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University,
1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan
| | - Yosuke Fujikawa
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University,
1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan
| | - Ichiro Itonaga
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University,
1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan
| | - Chikahiro Takita
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University,
1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan
| | - Hiroshi Tsumura
- Department of Orthopaedic Surgery, Faculty of Medicine, Oita University,
1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan
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Attenuation of Proinflammatory Responses by S-[6]-Gingerol via Inhibition of ROS/NF-Kappa B/COX2 Activation in HuH7 Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:146142. [PMID: 23843863 PMCID: PMC3697228 DOI: 10.1155/2013/146142] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Revised: 05/17/2013] [Accepted: 05/24/2013] [Indexed: 02/06/2023]
Abstract
Introduction. Hepatic inflammation underlies the pathogenesis of chronic diseases such as insulin resistance and type 2 diabetes mellitus. S-[6]-Gingerol has been shown to have anti-inflammatory properties. Important inflammatory mediators of interleukins include nuclear factor κ B (NF κ B) and cyclooxygenase 2 (COX2). We now explore the mechanism of anti-inflammatory effects of S-[6]-gingerol in liver cells. Methods. HuH7 cells were stimulated with IL1β to establish an in vitro hepatic inflammatory model. Results. S-[6]-Gingerol attenuated IL1β-induced inflammation and oxidative stress in HuH7 cells, as evidenced by decreasing mRNA levels of inflammatory factor IL6, IL8, and SAA1, suppression of ROS generation, and increasing mRNA levels of DHCR24. In addition, S-[6]-gingerol reduced IL1β-induced COX2 upregulation as well as NF κ B activity. Similar to the protective effects of S-[6]-gingerol, both NS-398 (a selective COX2 inhibitor) and PDTC (a selective NF κ B inhibitor) suppressed mRNA levels of IL6, IL8, and SAA1. Importantly, PDTC attenuated IL1β-induced overexpression of COX2. Of particular note, the protective effect of S-[6]-gingerol against the IL1β-induced inflammatory response was similar to that of BHT, an ROS scavenger. Conclusions. The findings of this study demonstrate that S-[6]-gingerol protects HuH7 cells against IL1β-induced inflammatory insults through inhibition of the ROS/NF κ B/COX2 pathway.
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Suemasu S, Yamakawa N, Ishihara T, Asano T, Tahara K, Tanaka KI, Matsui H, Okamoto Y, Otsuka M, Takeuchi K, Suzuki H, Mizushima T. Identification of a unique nsaid, fluoro-loxoprofen with gastroprotective activity. Biochem Pharmacol 2012; 84:1470-81. [DOI: 10.1016/j.bcp.2012.09.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Revised: 09/18/2012] [Accepted: 09/18/2012] [Indexed: 01/01/2023]
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Wan J, Gong X, Jiang R, Zhang Z, Zhang L. Antipyretic and Anti-inflammatory Effects of Asiaticoside in Lipopolysaccharide-treated Rat through Up-regulation of Heme Oxygenase-1. Phytother Res 2012; 27:1136-42. [DOI: 10.1002/ptr.4838] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 07/30/2012] [Accepted: 08/15/2012] [Indexed: 11/06/2022]
Affiliation(s)
- JingYuan Wan
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology; Chongqing Medical University; Chongqing; 400016; China
| | - Xia Gong
- Department of Anatomy; Chongqing Medical University; Chongqing; 400016; China
| | - Rong Jiang
- Laboratory of Stem Cell and Tissue Engineering; Chongqing Medical University; Chongqing; 400016; China
| | - Zhuo Zhang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology; Chongqing Medical University; Chongqing; 400016; China
| | - Li Zhang
- Department of Pathophysiology; Chongqing Medical University; Chongqing; 400016; China
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Huntjens DR, Spalding DJ, Danhof M, Pasqua OED. Differences in the sensitivity of behavioural measures of pain to the selectivity of cyclo-oxygenase inhibitors. Eur J Pain 2012; 13:448-57. [DOI: 10.1016/j.ejpain.2008.06.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2007] [Revised: 05/10/2008] [Accepted: 06/15/2008] [Indexed: 02/02/2023]
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Grangeiro NMG, Aguiar JA, Chaves HV, Silva AAR, Lima V, Benevides NMB, Brito GAC, da Graça JRV, Bezerra MM. Heme oxygenase/carbon monoxide-biliverdin pathway may be involved in the antinociceptive activity of etoricoxib, a selective COX-2 inhibitor. Pharmacol Rep 2011; 63:112-9. [PMID: 21441618 DOI: 10.1016/s1734-1140(11)70405-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2010] [Revised: 08/06/2010] [Indexed: 01/24/2023]
Abstract
The aim of this study was to assess the interaction between the heme oxygenase-1/ biliverdin/carbon monoxide (HO-1/BVD/CO) and cyclooxygenase-2 (COX-2) pathways in the writhing test. Mice were pretreated with 0.1, 1 or 10 mg/kg, ip etoricoxib, a selective COX-2 inhibitor, or with one of the following HO-1/BVD/CO pathway modulators: 1, 3 or 9 mg/kg, sc ZnPP IX, a specific HO-1 inhibitor, 0.3, 1 or 3 mg/kg, sc hemin, a substrate of the HO-1/BVD/CO pathway; or 0.00025, 0.025 or 2.5 μmol/kg, sc DMDC, a CO donor. Mice pretreated with etoricoxib or one of the HO-1/BVD/CO pathway modulators received an injection of acetic acid (ip) after 30 and 60 min, respectively. Next, the number of writhes was quantified between 0 and 30 min after stimulus injection. In another series of experiments, ineffective doses of etoricoxib were co-administered with hemin or DMDC and an effective dose of etoricoxib with ZnPP IX, followed by an acetic acid injection. Four hours after the acetic acid injection, levels of bilirubin, which is a product of BVD conversion by the BVD reductase enzyme, in the peritoneal lavage were determined. Hemin or DMDC reduced (p<0.05) the number of writhes, but ZnPP IX potentiated (p<0.05) the effect of acetic acid by increasing (p < 0.05) the number of writhes. The co-administration of etoricoxib with hemin or DMDC reduced (p<0.05) the number of writhes. However, the analgesic effect of etoricoxib was not observed in the presence of ZnPP IX. Pretreatment with ZnPP IX reduced bilirubin levels, but etoricoxib pretreatment significantly increased the bilirubin concentration in peritoneal exudates. The data obtained from these experiments showed that the HO-1/BVD/CO pathway was activated in the acetic acid-induced abdominal writhing model. The analgesic effect of etoricoxib was at least partially dependent on the participation of the HO-1/BVD/CO pathway.
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Affiliation(s)
- Niedja M G Grangeiro
- Faculty of Medicine of Sobral, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceará, Brazil
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Hsieh MS, Wang KT, Tseng SH, Lee CJ, Chen CH, Wang CC. Using 18F-FDG microPET imaging to measure the inhibitory effects of Clematis chinensis Osbeck on the pro-inflammatory and degradative mediators associated with inflammatory arthritis. JOURNAL OF ETHNOPHARMACOLOGY 2011; 136:511-517. [PMID: 20599489 DOI: 10.1016/j.jep.2010.06.042] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2010] [Revised: 05/22/2010] [Accepted: 06/23/2010] [Indexed: 05/29/2023]
Abstract
AIM OF THE STUDY This study examined the modulating effects of Clematis chinensis Osbeck (Ranunculaeae) on pro-inflammatory and degradative mediators associated with inflammatory arthritis. MATERIALS AND METHODS Primary human chondrocytes (PHC) were stimulated with IL-1β or lipopolysaccharide (LPS) to induce the enhanced release of prostaglandin E(2) (PGE(2)), metalloproteinase (MMP-3 and -13), and cyclooxygenase-2 (COX-2) protein expression. The (18)F-FDG microPET imaging system was used to evaluate the anti-arthritic effects of Clematis chinensisin vivo. RESULTS The acetone extracted Clematis chinensis (CC6) contained the most total saponins compared to other solvent's extracts and showed significant and dose-dependent inhibitory effects on PGE(2), MMP-3, -13, and COX-2 productions by LPS-stimulated PHC. Furthermore, CC6 also exerted inhibitory effects on 2-(18)F-fluoro-2-deoxy-d-glucose ((18)F-FDG) uptake when assessed by positron emission tomography (PET) uptake in the joints and serum PGE(2) of rabbits with knee joints injected with LPS. CONCLUSION The results suggest the significant chondroprotective effects of Clematis chinensis are through its anti-inflammatory and MMPs inhibitory abilities. Meanwhile, we established a new analysis method to evaluate the Chinese herbal anti-arthritic effects.
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Affiliation(s)
- Ming-Shium Hsieh
- School of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan
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Sharma BK, Singh P, Pilania P, Shekhawat M, Prabhakar YS. QSAR of 2-(4-methylsulphonylphenyl)pyrimidine derivatives as cyclooxygenase-2 inhibitors: simple structural fragments as potential modulators of activity. J Enzyme Inhib Med Chem 2011; 27:249-60. [PMID: 21679051 DOI: 10.3109/14756366.2011.587414] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The cyclooxygenase-2 (COX-2) inhibitory activity of 2-(4-methylsulphonylphenyl)pyrimidine derivatives has been quantitatively analyzed in terms of Dragon descriptors. The derived QSAR models have provided rationales to explain the activity of titled derivatives. The descriptors (Me, Mp, GATS1p and GATS5p) identified in CP-MLR analysis have highlighted the role of atomic properties, such as Sanderson electronegativity and polarizability, to explain the inhibitory activity. Additionally, prevalence of aromatic ether functionality (descriptor nRORPh) and certain structural fragments (number of Me groups, C-001; number of H attached to heteroatom, H-050 and number of H attached to α-C, H-051) in a molecular structure are helpful to rationalize the COX-2 inhibitory activity of pyrimidine derivatives. The partial least square (PLS) analysis has also confirmed the dominance of information content of CP-MLR-identified descriptors for modelling the activity.
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Affiliation(s)
- B K Sharma
- Department of Chemistry, S.K. Government College, Sikar, India.
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