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Zhou JQ, Liu ZX, Zhong HF, Liu GQ, Ding MC, Zhang Y, Yu B, Jiang N. Single nucleotide polymorphisms in the development of osteomyelitis and prosthetic joint infection: a narrative review. Front Immunol 2024; 15:1444469. [PMID: 39301021 PMCID: PMC11410582 DOI: 10.3389/fimmu.2024.1444469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 08/08/2024] [Indexed: 09/22/2024] Open
Abstract
Currently, despite advancements in diagnostic and therapeutic modalities, osteomyelitis and prosthetic joint infection (PJI) continue to pose significant challenges for orthopaedic surgeons. These challenges are primarily attributed to the high degree of heterogeneity exhibited by these disorders, which are influenced by a combination of environmental and host factors. Recent research efforts have delved into the pathogenesis of osteomyelitis and PJI by investigating single nucleotide polymorphisms (SNPs). This review comprehensively summarizes the current evidence regarding the associations between SNPs and the predisposition to osteomyelitis and PJI across diverse populations. The findings suggest potential linkages between SNPs in genes such as IL-1, IL-6, IFN-γ, TNF-α, VDR, tPA, CTSG, COX-2, MMP1, SLC11A1, Bax, NOS2, and NLRP3 with the development of osteomyelitis. Furthermore, SNPs in genes like IL-1, IL-6, TNF-α, MBL, OPG, RANK, and GCSFR are implicated in susceptibility to PJI. However, it is noted that most of these studies are single-center reports, lacking in-depth mechanistic research. To gain a more profound understanding of the roles played by various SNPs in the development of osteomyelitis and PJI, future multi-center studies and fundamental investigations are deemed necessary.
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Affiliation(s)
- Jia-Qi Zhou
- Division of Orthopaedics & Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Orthopaedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
- Guangdong Engineering Technology Research Center of Functional Repair of Bone Defects and Biomaterials, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zi-Xian Liu
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China
| | - Hong-Fa Zhong
- Department of Trauma Emergency Center, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, China
| | - Guan-Qiao Liu
- Division of Orthopaedics & Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ming-Cong Ding
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China
| | - Yu Zhang
- Department of Orthopaedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
- Guangdong Engineering Technology Research Center of Functional Repair of Bone Defects and Biomaterials, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Bin Yu
- Division of Orthopaedics & Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Nan Jiang
- Division of Orthopaedics & Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Trauma Emergency Center, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, China
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Wang W, Zheng Z, Chen J, Duan T, He H, Tang S. Characterization of metabolite landscape distinguishes wild from cultivated Polygonati Rhizomes by UHPLC-Q-TOF-MS untargeted metabolomics. FOOD BIOSCI 2023. [DOI: 10.1016/j.fbio.2023.102574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023]
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Wu L, Zhou Y, Fu J. KIAA1429 Promotes Nasopharyngeal Carcinoma Progression by Mediating m6A Modification of PTGS2. Crit Rev Immunol 2023; 43:15-27. [PMID: 37830191 DOI: 10.1615/critrevimmunol.2023050249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2023]
Abstract
Emerging evidence suggests that dysregulation of a N6-methyladenosine (m6A) methyltransferase KIAA1429 participates in the pathogenesis of multiple cancers except for nasopharyngeal carcinoma (NPC). This study is aimed to explore the function of KIAA1429 in NPC progression. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to confirm the mRNA expression in NPC by bioinformatic analysis. The levels of KIAA1429 and PTGS2 was detected by quantitative reverse transcription polymerase chain reaction and Western blotting. To investigate the effects of KIAA1429/PTGS2 knockdown or overexpression vectors on NPC cell malignancy, cell and animal experiments were performed. Finally, MeRIP and mRNA stability assays were used to verify the m6A modification and mRNA stability, respectively. KIAA1429 was upregulated in NPC tissues and cells. After transfecting KIAA1429 knockdown or overexpression vectors in NPC cells, we proved that KIAA1429 overexpression promoted proliferation, migration, invasion, and tumor growth, whereas KIAA1429 knockdown showed the opposite effect. Our results also indicated that KIAA1429 mediated m6A modification of PTGS2, enhancing PTGS2 mRNA stability in NPC cells. In addition, PTGS2 could also regulate the effects of KIAA1429 on NPC cell malignancy. This study confirmed the oncogenic function of KIAA1429 in NPC through m6A-modification of PTGS2, suggesting that targeting KIAA1429-mediated m6A modification of PTGS2 might provide a new therapeutic strategy for NPC.
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Affiliation(s)
- Lingling Wu
- Department of Otolaryngology, Airborne Army Hospital, Wuhan 430012, Hubei, China
| | - Yuanhong Zhou
- Department of Otolaryngology Head and Neck Surgery, Wuhan Asia General Hospital, Wuhan 430056, Hubei, China
| | - Jun Fu
- Department of Otolaryngology, Airborne Army Hospital, Wuhan 430012, Hubei, China
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Nasry WHS, Martin CK. Intersecting Mechanisms of Hypoxia and Prostaglandin E2-Mediated Inflammation in the Comparative Biology of Oral Squamous Cell Carcinoma. Front Oncol 2021; 11:539361. [PMID: 34094895 PMCID: PMC8175905 DOI: 10.3389/fonc.2021.539361] [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] [Received: 02/29/2020] [Accepted: 04/22/2021] [Indexed: 12/12/2022] Open
Abstract
The importance of inflammation in the pathogenesis of cancer was first proposed by Rudolph Virchow over 150 years ago, and our understanding of its significance has grown over decades of biomedical research. The arachidonic acid pathway of inflammation, including cyclooxygenase (COX) enzymes, PGE2 synthase enzymes, prostaglandin E2 (PGE2) and PGE2 receptors has been extensively studied and has been associated with different diseases and different types of cancers, including oral squamous cell carcinoma (OSCC). In addition to inflammation in the tumour microenvironment, low oxygen levels (hypoxia) within tumours have also been shown to contribute to tumour progression. Understandably, most of our OSCC knowledge comes from study of this aggressive cancer in human patients and in experimental rodent models. However, domestic animals develop OSCC spontaneously and this is an important, and difficult to treat, form of cancer in veterinary medicine. The primary goal of this review article is to explore the available evidence regarding interaction between hypoxia and the arachidonic acid pathway of inflammation during malignant behaviour of OSCC. Overlapping mechanisms in hypoxia and inflammation can contribute to tumour growth, angiogenesis, and, importantly, resistance to therapy. The benefits and controversies of anti-inflammatory and anti-angiogenic therapies for human and animal OSCC patients will be discussed, including conventional pharmaceutical agents as well as natural products.
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Affiliation(s)
- Walaa Hamed Shaker Nasry
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada
| | - Chelsea K Martin
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada
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DNA Methylation in Pulmonary Fibrosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1255:51-62. [PMID: 32949389 DOI: 10.1007/978-981-15-4494-1_4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
DNA methylations, including global methylation pattern and specific gene methylation, are associated with pathogenesis and progress of pulmonary fibrosis. This chapter illustrates alteration of DNA methylation in pulmonary fibrosis as a predictive or prognostic factor. Treatment with the DNA methylation inhibitors will be an emerging anti-fibrosis therapy, although we are still in the pre-clinical stage of using epigenetic markers as potential targets for biomarkers and therapeutic interventions.
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Association of plasma cyclooxygenase-2 levels and genetic polymorphisms with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults. J Hypertens 2020; 38:1745-1754. [DOI: 10.1097/hjh.0000000000002473] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Abstract
PURPOSE Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (COXibs) inhibit the progression of endometrial cancer, ovarian cancer and cervical cancer. However, concerning the adverse effects of NSAIDs and COXibs, it is still urgent and necessary to explore novel and specific anti-inflammation targets for potential chemoprevention. The signaling of cyclooxygenase 2-prostaglandin E2-prostaglandin E2 receptors (COX-2-PGE2-EPs) is the central inflammatory pathway involved in the gynecological carcinogenesis. METHODS Literature searches were performed to the function of COX-2-PGE2-EPs in gynecological malignancies. RESULTS This review provides an overview of the current knowledge of COX-2-PGE2-EPs signaling in endometrial cancer, ovarian cancer and cervical cancer. Many studies demonstrated the upregulated expression of the whole signaling pathway in gynecological malignancies and some focused on the function of COX-2 and cAMP-linked EP2/EP4 and EP3 signaling pathway in gynecological cancer. By contrast, roles of EP1 and the exact pathological mechanisms have not been completely clarified. The studies concerning EP receptors in gynecological cancers highlight the potential advantage of combining COX enzyme inhibitors with EP receptor antagonists as therapeutic agents in gynecological cancers. CONCLUSION EPs represent promising anti-inflammation biomarkers for gynecological cancer and may be novel treatment targets in the near future.
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Jayawardena TU, Fernando IPS, Lee WW, Sanjeewa KKA, Kim HS, Lee DS, Jeon YJ. Isolation and purification of fucoidan fraction in Turbinaria ornata from the Maldives; Inflammation inhibitory potential under LPS stimulated conditions in in-vitro and in-vivo models. Int J Biol Macromol 2019; 131:614-623. [PMID: 30898597 DOI: 10.1016/j.ijbiomac.2019.03.105] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 03/01/2019] [Accepted: 03/17/2019] [Indexed: 12/22/2022]
Abstract
Fucoidan, referred to as fucose containing sulfated polysaccharides (FCSP), is a polymer from brown algae cell wall that is reported to exhibit potential anti-inflammatory activity. In the present study, the fucoidans are extracted from Turbinaria ornata (TO) from the Maldives. The method involves enzyme assisted extraction and is modified in order to improve the effectiveness and purity of final product. Purified fucoidan fraction was identified as F10, and its chemical properties were verified via FTIR, 1H NMR and monosaccharide analysis. Selected inflammatory mediators were studied to evaluate the anti-inflammatory potential using RAW 264.7 macrophages. F10 successfully inhibited NO production (IC50 = 30.83 ± 1.02 μg mL-1). F10 dose-dependently down-regulated iNOS, COX-2, and pro-inflammatory cytokines including PGE2 levels. The in vivo experiments were assisted by zebrafish embryo model. This exhibited reduction in ROS, NO expression levels. To our knowledge, this is the first report to illustrate potential anti-inflammatory activity of FCSPs' extracted from the brown algae T. ornata. Concisely, the results suggest that fucoidan purified from T. ornata increases the macrophage cellular and zebrafish embryo resistance against LPS-induced inflammation. Based on the observations, the fucoidans are promising candidates to be used in the pharmaceutical and cosmeceutical sectors.
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Affiliation(s)
- Thilina U Jayawardena
- Department of Marine Life Science, Jeju National University, Jeju 690-756, Republic of Korea
| | | | - Won Woo Lee
- Freshwater Bioresources Utilization Division, Nakdonggang National Institute of Biological Resources, Sangju 37242, Republic of Korea
| | - K K Asanka Sanjeewa
- Department of Marine Life Science, Jeju National University, Jeju 690-756, Republic of Korea
| | - Hyun-Soo Kim
- Department of Marine Life Science, Jeju National University, Jeju 690-756, Republic of Korea
| | - Dae-Sung Lee
- Department of Applied Research, National Marine Biodiversity Institute of Korea, Seocheon, Republic of Korea.
| | - You-Jin Jeon
- Department of Marine Life Science, Jeju National University, Jeju 690-756, Republic of Korea.
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Salem SAM, Aly DG, Amr KS, Abdel-Hamid MF. Study of the relation between two common cyclooxygenase 2 gene polymorphisms with risk of developing and subtypes of vitiligo in Egyptian patients. Indian J Dermatol Venereol Leprol 2019; 84:696-700. [PMID: 29094684 DOI: 10.4103/ijdvl.ijdvl_813_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Background/Purpose Genetic factors play an important role in the pathogenesis of vitiligo. Cyclooxygenase 2 (COX2) gene induced by ultraviolet radiation controls the synthesis of prostaglandins, which are are found to be beneficial in treating vitiligo. COX2 gene polymorphism has been previously evaluated in Chinese population. We aimed to study the relation between two common COX2 gene polymorphisms with vitiligo and its subtypes amongEgyptian patients. Patients and Methods This study included 200 participants (100 vitiligo patients and 100 healthy controls). COX2-765G/C and -1195A/G gene polymorphism was studied by restriction fragment length polymorphism polymerase chain reaction analysis and the results were compared between the two groups and among different subtypes of vitiligo. Results Frequency of COX2-1195 AA, AG, GG genotypes showed no significant association among patients with vitiligo (P = 0.626, 0.321, 0.08, respectively); those with generalized vitiligo (P = 0.739, 0.291, 0.101, respectively) and those with segmental vitiligo (P = 0.410, 1.00, 0.676, respectively) compared to the control group. Regarding COX2-765G/C genotypes, GG genotype was more frequent among patients with vitiligo [84 (84%)] compared to controls [63 (63%)] (P = 0.001). GC genotype was significantly less frequent [15 (15%)] among patients compared to controls [32 (32%)] (P = 0.005). Generalized and segmental types of vitiligo also showed no significant difference in the frequency of COX2-765G/C genotypes compared with controls. Limitations Being a pilot study, a relatively small number of participants were included. Conclusion COX2-1195A/G gene polymorphism is not associated with the risk of developing vitiligo or with vitiligo subtypes. COX2-765 GG genotype is associated with vitiligo, especially of the generalized type.
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Affiliation(s)
- Samar Abdallah M Salem
- Department of Dermatology, Venereology and Andrology, Ain Shams University, Cairo, Egypt
| | - Dalia Gamal Aly
- Department of Dermatology and Venereology, National Research Centre, Giza, Egypt
| | - Khalda Sayed Amr
- Department of Medical Molecular Genetics, National Research Centre, Giza, Egypt
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Wang L, Jiang N, Lin QR, Qin CH, Hu YJ, Yu B. Cyclooxygenase-2 (COX-2) polymorphism rs689466 may contribute to the increased susceptibility to post-traumatic osteomyelitis in Chinese population. Infect Dis (Lond) 2017; 49:817-823. [PMID: 28682162 DOI: 10.1080/23744235.2017.1347816] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Lei Wang
- Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Nan Jiang
- Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Qing-rong Lin
- Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Cheng-he Qin
- Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Yan-jun Hu
- Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
| | - Bin Yu
- Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
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Influence of the Cyclooxygenase-2 Gene -765G/C and -1195G/A Polymorphisms on Development of Ischemic Stroke. J Stroke Cerebrovasc Dis 2016; 25:2126-35. [PMID: 27363623 DOI: 10.1016/j.jstrokecerebrovasdis.2016.06.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/16/2016] [Accepted: 06/02/2016] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Many studies have investigated the association between the cyclooxygenase-2 (COX-2) gene polymorphism and ischemic stroke. However, results of these studies still remain controversial. To better explain the association between COX-2 polymorphisms (-765G/C and -1195G/A) and ischemic stroke risk, a meta-analysis was performed. METHODS Relevant studies were identified from 4 Chinese databases (Chinese Biological Medical Literature database, Chinese National Knowledge Infrastructure database, Chongqing VIP database, and Chinese WANFANG database), PUBMED and EMBASE prior to December 2015. The strength of association between COX-2 polymorphism and ischemic stroke was evaluated by the odds ratio (OR) with 95% confidence interval (CI). Inconsistency index (I(2)) and the Cochran's Q statistic were used to check heterogeneity. Publication bias was evaluated by funnel plots and Egger's regression test. RESULTS A total of 4086 ischemic stroke cases and 4747 controls were identified. Significant association between COX-2 -765G/C polymorphism and the risk of ischemic stroke was found in Brazilians and the African-Americans. The OR of (CC+GC versus GG) for the Brazilians and African-Americans were (6.328, 95% CI = 2.295-17.448) and (1.644, 95% CI = 1.060-2.551). In addition, the recessive model of the Brazilians gave an OR of 3.621 (95% CI: 1.519-8.630). Furthermore, the (GC versus GG) and the allele model of the African-Americans were (OR: 1.615, 95% CI = 1.015-2.572) and (OR: 1.422, 95% CI = 1.033-1.957). Significant association was also observed for COX-2 -1195G/A polymorphism in the subtypes of small vessel disease (SVD) of ischemic stroke. CONCLUSIONS Our study suggests that COX-2 -765G/C and -1195G/A polymorphisms may contribute to susceptibility of ischemic stroke, specifically in Brazilians and the African-Americans, and those of SVD.
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Jawanjal P, Salhan S, Dhawan I, Das N, Aggarwal R, Tripathi R, Rath G. Augmented Activity of Cyclooxygenase-2 in Tissue and Serum of Patients With Cervical Cancer. J Clin Lab Anal 2016; 30:1198-1207. [PMID: 27292107 DOI: 10.1002/jcla.22003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 04/21/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Cyclooxygenase-2 (Cox-2) is frequently overexpressed in cervical carcinoma, but little is known about its altered serum concentration. Hence, this study evaluates clinical utility of cellular and serum level of Cox-2 enzyme in cervical cancer. METHODS The expression of Cox-2 was evaluated in cervical tissues and serum samples collected from normal controls (n = 100; n = 68), cervical intraepithelial neoplasia patients (CIN, n = 67; n = 12), and invasive squamous cell carcinoma patients (SCCs; n = 153; n = 127) by immunohistochemical and enzyme-linked immunosorbent assay (ELISA) analyses. RESULTS The significant cytoplasmic overexpression of Cox-2 was noted in 50.7% of CIN and 69.9% of SCCs as compared with normal (P = 0.0001). Serum level of Cox-2 was also found to be elevated both in CIN (median 4.35 ng/ml) and in SCCs (median 19.39 ng/ml) with respect to normal (median 0.44 ng/ml; P = 0.0001), respectively. The ROC analysis revealed the potential of serum Cox-2 over its cellular expression to distinguish CIN and SCCs from normal. CONCLUSION Augmented Cox-2 activity is implicated in the pathogenesis of cervical cancer, and its serum level could serve a potential to distinguish this malignancy. Therefore, it is suggested that serum Cox-2 may be useful in monitoring the diagnosis and treatment outcome of patients.
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Affiliation(s)
- Poonam Jawanjal
- Department of Anatomy, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
| | - Sudha Salhan
- Department of Obstetrics and Gynecology, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
| | - Indrani Dhawan
- Department of Histopathology, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
| | - Nirmalendu Das
- Department of Radiotherapy, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
| | - Ruby Aggarwal
- Department of Anatomy, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
| | - Richa Tripathi
- Division of Molecular Genetics & Biochemistry, Institute of Cytology and Preventive Oncology (ICPO), ICMR, Noida, India
| | - Gayatri Rath
- Department of Anatomy, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India. ,
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Cyclooxygenase-2 genetic polymorphism and stroke subtypes in Chinese. J Mol Neurosci 2013; 51:467-73. [PMID: 23907768 DOI: 10.1007/s12031-013-0078-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Accepted: 07/15/2013] [Indexed: 12/29/2022]
Abstract
BACKGROUND Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins that contribute to the inflammation in atherosclerosis. The aim of the present study was to investigate the relationship between two polymorphisms (-1195G>A and -765G>C) in the COX-2 gene and subtypes of ischemic stroke in a Chinese population. METHODS Genomic DNA of 224 patients with large artery atherosclerosis (LAA), 329 patients with small vessel occlusion (SVO), and 450 controls were genotyped for the COX-2 1195G>A (rs689466) and -765G>C (rs20417) polymorphisms using polymerase chain reaction-restriction fragment length polymorphism. Chi-square test and logistic regression analysis were performed for association analysis. RESULTS The frequencies of variant allele with -1195G>A and -765G>C polymorphisms were 0.46 and 0.22, respectively. The -1195GA genotype and 1195A allele carriers were identified independently to be related with ischemic stroke (adjusted OR = 1.51, 95 % CI: 1.09-2.10, P = 0.02; OR = 1.45, 95 % CI: 1.06-1.97, P = 0.02) and SVO (adjusted OR = 1.57, 95 % CI: 1.07-2.30, P = 0.02; OR = 1.50, 95 % CI: 1.05-2.16, P = 0.03). In contrast, the 1195G>A polymorphism was not associated with LAA. No relationship between the -765G>C polymorphism and risk of either ischemic stroke was observed. The linkage disequilibrium analysis showed that -1195G>A and -765G>C SNPs are moderate linkage disequilibrium in this study population (D' = 0.72, r (2) = 0.16). Compared with G-1195-G-765 haplotype, the haplotype of A-1195-G-765 showed significant increased risk of ischemic stroke (OR = 1.27, 95 % CI: 1.05-1.54, P = 0.02) and SVO (OR = 1.27, 95 % CI: 1.02-1.58, P = 0.03) but not LAA. CONCLUSIONS In conclusion, we found that -1195G>A polymorphism and A-1195-G-765 haplotype of COX-2 were associated with susceptibility to ischemic stroke in a Chinese population. The effects were confined to SVO among the stroke subtypes rather than to LAA.
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Shan XY, Chen GZ, Cheng GP, Tao HM. Cyclooxygenase 2 genetic polymorphism may increase the risk of developing leukoaraiosis in Chinese. J Mol Neurosci 2013; 51:461-6. [PMID: 23852948 DOI: 10.1007/s12031-013-0066-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 07/01/2013] [Indexed: 12/30/2022]
Abstract
Cyclooxygenase-2 (COX-2) is a key enzyme involved in the conversion of arachidonic acid into prostaglandins, which are important mediators of inflammation. To clarify the role of inflammation in the pathogenesis of cerebral small vessel disease (SVD), we investigate the possible modulating effect of the functional COX-2 polymorphisms -1195G > A (rs689466) and -765G > C (rs20417) on the risk for development of cerebral SVD in a Chinese population. Genomic DNA of 116 patients with lacunar infarction (LI), 334 patients with leukoaraiosis (LA) and 450 control subjects was genotyped for the COX-2 -1195G > A and -765G > C polymorphisms using polymerase chain reaction-restriction fragment length polymorphism. Distribution of genotypes and haplotypes in patients and controls were compared. The genotype distribution of the -765G > C polymorphism was not different between the patients with LI or LA and the control group. The 1195A allele carriers was identified independently to be related with LA (adjusted OR = 1.41, 95 % confidence interval (CI) = 1.09-2.10, P = 0.03) but not associated with LI. The linkage disequilibrium analysis showed that -1195G > A and -765G > C SNPs are moderate linkage disequilibrium in this study population (D' = 0.70, r(2) = 0.16). Compared with G-1195-G-765 haplotype, the haplotype of A-1195-G-765 showed significantly increased the risk of LA (OR = 1.24, 95 % CI = 1.10-1.55, P = 0.04) but not LI. In conclusion, we found that -1195G > A polymorphism and A-1195-G-765 haplotype of COX-2 were associated with susceptibility to LA in a Chinese population.
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Affiliation(s)
- Xiao-yun Shan
- Department of Clinical Laboratory, Jinhua Municipal Central Hospital, Jinhua, 321000, Zhejiang Province, People's Republic of China
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Kim HS, Kim T, Kim MK, Suh DH, Chung HH, Song YS. Cyclooxygenase-1 and -2: molecular targets for cervical neoplasia. J Cancer Prev 2013; 18:123-134. [PMID: 25337538 PMCID: PMC4189449 DOI: 10.15430/jcp.2013.18.2.123] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2013] [Revised: 06/18/2013] [Accepted: 06/20/2013] [Indexed: 01/29/2023] Open
Abstract
Cyclooxygenase (COX) is a key enzyme responsible for inflammation, converting arachidonic acid to prostaglandin and thromboxane. COX has at least two isoforms, COX-1 and COX-2. While COX-1 is constitutively expressed in most tissues for maintaining physiologic homeostasis, COX-2 is induced by inflammatory stimuli including cytokines and growth factors. Many studies have shown that COX-2 contributes to cancer development and progression in various types of malignancy including cervical cancer. Human papillomavirus, a necessary cause of cervical cancer, induces COX-2 expression via E5, E6 and E7 oncoproteins, which leads to prostaglandin E2 increase and the loss of E-cadherin, promotes cell proliferation and production of vascular endothelial growth factor. It is strongly suggested that COX-2 is associated with cancer development and progression such as lymph node metastasis. Many studies have suggested that non-selective COX-2 inhibitors such as non-steroidal anti-inflammatory drugs (NSAIDs), and selective COX-2 inhibitors might show anti-cancer activity in COX-2 -dependent and -independent manners. Two phase II trials for patients with locally advanced cervical cancer showed that celecoxib increased toxicities associated with radiotherapy. Contrary to these discouraging results, two phase II clinical trials, using rofecoxib and celecoxib, demonstrated the promising chemopreventive effect for patients with cervical intraepithelial neoplasia 2 or 3. However, these agents cause a rare, but serious, cardiovascular complication in spite of gastrointestinal protection in comparison with NSAIDs. Recent pharmacogenomic studies have showed that the new strategy for overcoming the limitation in clinical application of COX-2 inhibitors shed light on the use of them as a chemopreventive method.
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Affiliation(s)
- Hee Seung Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul
| | - Taehun Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul
| | - Mi-Kyung Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul
| | - Dong Hoon Suh
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam
| | - Hyun Hoon Chung
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul
| | - Yong Sang Song
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul
- Cancer Research Institute, Seoul National University College of Medicine
- Major in Biomodulation, World Class University, Seoul National University, Seoul, Korea
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Xie XY, Yin JB, Lv ZW, Qi XS. Advancements of cyclooxygenase inhibitor in the prevention and treatment of hepatoma. Shijie Huaren Xiaohua Zazhi 2009; 17:158-163. [DOI: 10.11569/wcjd.v17.i2.158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
It was reported that the cyclooxygenase-2 (COX-2) and its products were over-expressed in many malignant tumors. Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit COX activity, and also can reduce proliferation, enhance apoptosis, decrease angiogenesis and invasiveness of tumor cells. Hepatoma is one of common malignancies worldwide, and its prognosis is still extremely poor and the cellular mechanisms contributing to hepatic carcinogenesis are relatively unknown. Therefore, the prevention and treatment of liver cancer are limited. At present, it is important to find new drugs and investigate their action mechanisms. This article provides a brief review on the research progress of COX inhibitor in the prevention and treatment of hepatoma.
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Association of COX2 functional polymorphisms and the risk of vitiligo in Chinese populations. J Dermatol Sci 2008; 53:176-81. [PMID: 19004621 DOI: 10.1016/j.jdermsci.2008.09.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2008] [Revised: 09/20/2008] [Accepted: 09/25/2008] [Indexed: 11/21/2022]
Abstract
BACKGROUND Cyclooxygenase-2 (COX2) plays an important role in the production of prostaglandin E2 (PGE2), which is made by epidermal keratinocytes in response to ultraviolet radiation (UVR). PGE2 is important for the proliferation and melanogenesis of epidermal melanocytes, the loss of which leads to vitiligo. COX2-1195A>G, -765G>C, and -8473T>C polymorphisms may influence the mRNA levels of COX2 and affect the production of PGE2 subsequently. Therefore, we supposed that these polymorphisms may be associated with vitiligo. OBJECTIVE The aim of the study was to elucidate the association between three functional COX2 polymorphisms and the risk of vitiligo. METHODS This was a hospital-based, case-control study of 755 vitiligo patients and 774 vitiligo-free controls who were frequency matched by age and sex. We genotyped COX2-1195A>G, -765G>C, and -8473T>C polymorphisms by using PCR-restriction fragment length polymorphism (RFLP) method and assessed their respective associations with the risk of vitiligo in Han Chinese populations. RESULTS We found a statistically significant increased risk of vitiligo to be associated with the COX2-1195 G variant allele (p=0.004). Significantly higher vitiligo risks were found among subgroups with these characteristics: age >20 years, male, active, nonsegmental vitiligo, and onset age >20 years. In addition, the interaction between COX2-1195 and COX2-8473 was statistically significant (p=0.004). CONCLUSION For the first time, we provide evidence that functional polymorphisms in the COX2 gene may influence the risk of vitiligo in Han Chinese populations, suggesting new clues that help to clarify the pathogenesis of vitiligo. Larger studies are needed to verify these findings.
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Takahashi S, Ushida M, Komine R, Shimodaira A, Uchida T, Ishihara H, Shibano T, Watanabe G, Ikeda Y, Murata M. Platelet responsiveness to in vitro aspirin is independent of COX-1 and COX-2 protein levels and polymorphisms. Thromb Res 2008; 121:509-17. [PMID: 17631383 DOI: 10.1016/j.thromres.2007.05.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2006] [Revised: 04/27/2007] [Accepted: 05/22/2007] [Indexed: 10/23/2022]
Abstract
Aspirin's inhibitory effect on platelet function has been shown to be highly heterogeneous. However, due to the considerable individual variation in pharmacokinetics after aspirin intake, it has been difficult to investigate the mechanism of aspirin resistance empirically. Our objective was to examine whether platelet responsiveness to in vitro aspirin treatment could be affected by cyclooxygenase (COX)-1/2 protein levels in platelets or single-nucleotide polymorphisms (SNPs), which could possibly change specific activity of enzymes and/or aspirin susceptibility. Collagen/epinephrine closure time (CEPI-CT) of PFA-100 in blood from 178 healthy males was assessed with/without aspirin. Platelet COX-1 protein levels and the sequences of COX-1 gene exons were examined in three groups categorized by CEPI-CT: PR (Poor responders to aspirin), 10 people showing the shortest CEPI-CT under aspirin; GR-High or GR-Low (good responders to aspirin with high or low platelet basal reactivity), 10 people showing CEPI-CT over 300 s under aspirin and having the shortest or longest basal CEPI-CT, respectively. We analyzed the three groups, representing phenotypic extremes, aiming to increase statistical power to investigate the possible relevance of COXs to platelet response to aspirin. Western blot analysis revealed that COX-1 was abundantly expressed in platelets at comparable levels among the three groups, whereas COX-2 was undetectable. The frequencies of nonsynonymous COX-1/2 SNPs were unlikely to explain the difference in aspirin responsiveness considering the observed genotype frequencies and wide individual variation in platelet response. These results suggest that heterogeneity in platelet responsiveness to in vitro aspirin is independent of COX-1/2 protein levels and SNPs.
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Affiliation(s)
- Shinichi Takahashi
- The Keio-Daiichi Project on Genetics of Thrombosis, Keio University, Tokyo 160-8582, Japan
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Candore G, Balistreri CR, Grimaldi MP, Vasto S, Listì F, Chiappelli M, Licastro F, Lio D, Caruso C. Age-related inflammatory diseases: role of genetics and gender in the pathophysiology of Alzheimer's disease. Ann N Y Acad Sci 2007; 1089:472-86. [PMID: 17261790 DOI: 10.1196/annals.1386.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western societies mainly accounts for clinical dementia. A high proportion of women are affected by this disease, especially at a very advanced age, which might to a large extent be associated with the fact that women live longer. However, some studies suggest that incidence rates may be really increased in women. For this reason the influence of estrogens on the brain and the decrease of it during menopause are of special interest. After menopause, circulating levels of estrogens markedly decline, influencing several brain processes predicted to influence AD risk. The control of estrogens on oxidative stress, inflammation, and the cerebral vasculature might also be expected to increase AD risk. During the Women's Health Initiative Memory Study--a randomized, placebo-controlled trial of women 65-79 years of age--oral estrogen plus progestin was seen to double the rate of developing dementia, with risk appearing soon after the treatment was initiated. On the basis of current evidence, hormone therapy (HT) is thus not indicated for the prevention of AD. Inflammation clearly occurs in pathologically vulnerable regions of the AD brain and the search for genetic factors influencing the pathogenesis of AD has led to the identification of numerous gene polymorphisms that act as susceptibility modifiers. Accordingly, several reports have indicated that the risk of AD is substantially influenced by several genetic polymorphisms in the promoter region, or other untranslated regions, of genes encoding inflammatory mediators. Here we review several data suggesting that inflammatory genetic variation may contribute to higher AD susceptibility in women too. All together this information may represent the basis both for future recognition of individuals at risk as well as for a pharmacogenomic approach in achieving drug responsiveness.
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Affiliation(s)
- Giuseppina Candore
- Gruppo di Studio sull' Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Corso Tukory 211, 90134 Palermo, Italy.
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Abstract
Many epidemiological studies demonstrate that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) reduce the incidence and mortality of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase (COX) enzymes are well-known targets of NSAIDs. However, conventional NSAIDs non-selectively inhibit both the constitutive form COX-1, and the inducible form COX-2. Recent evidence indicates that COX-2 is an important molecular target for anticancer therapies. Its expression is undetectable in most normal tissues, and is highly induced by pro-inflammatory cytokines, mitogens, tumor promoters and growth factors. It is now well-established that COX-2 is chronically overexpressed in many premalignant, malignant, and metastastic cancers, including hepatocellular carcinoma (HCC). Overexpression of COX-2 in patients with HCC is generally higher in well-differentiated HCCs compared with less-differentiated HCCs or histologically normal liver, suggesting that COX-2 may be involved in the early stages of hepatocarcinogenesis, and increased expression of COX-2 in noncancerous liver tissue has been significantly associated with shorter disease-free survival in patients with HCC.
In tumors, overexpression of COX-2 leads to an increase in prostaglandin (PG) levels, which affect many mechanisms involved in carcinogenesis, such as angiogenesis, inhibition of apoptosis, stimulation of cell growth as well as the invasiveness and metastatic potential of tumor cells.
The availability of novel agents that selectively inhibit COX-2 (COXIB), has contributed to shedding light on the role of this molecule. Experimental studies on animal models of liver cancer have shown that NSAIDs, including both selective and non-selective COX-2 inhibitors, exert chemopreventive as well as therapeutic effects. However, the key mechanism by which COX-2 inhibitors affect HCC cell growth is as yet not fully understood.
Increasing evidence suggests the involvement of molecular targets other than COX-2 in the anti-proliferative effects of COX-2 selective inhibitors. Therefore, COX-inhibitors may use both COX-2-dependent and COX-2-independent mechanisms to mediate their antitumor properties, although their relative contributions toward the in vivo effects remain less clear.
Here we review the features of COX enzymes, the role of the expression of COX isoforms in hepatocarcinogenesis and the mechanisms by which they may contribute to HCC growth, the pharmacological properties of COX-2 selective inhibitors, the antitumor effects of COX inhibitors, and the rationale and feasibility of COX-2 inhibitors for the treatment of HCC.
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22
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Park JY, Pillinger MH, Abramson SB. Prostaglandin E2 synthesis and secretion: The role of PGE2 synthases. Clin Immunol 2006; 119:229-40. [PMID: 16540375 DOI: 10.1016/j.clim.2006.01.016] [Citation(s) in RCA: 546] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2005] [Revised: 01/24/2006] [Accepted: 01/25/2006] [Indexed: 12/15/2022]
Abstract
Prostaglandin E2 (PGE2) is a principal mediator of inflammation in diseases such as rheumatoid arthritis and osteoarthritis. Nonsteroidal anti-inflammatory medications (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors reduce PGE2 production to diminish the inflammation seen in these diseases, but have toxicities that may include both gastrointestinal bleeding and prothrombotic tendencies. In cells, arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES). Accumulating data suggest that the interaction of various enzymes in the PGE2 synthetic pathway is complex and tightly regulated. In this review, we summarize the synthesis and secretion of PGE2. In particular, we focus on the three isoforms of the terminal PGES, and discuss the potential of targeting PGES as a more precise strategy for inhibiting PGE2 production.
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Affiliation(s)
- Jean Y Park
- The Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
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23
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Abdullah L, Ait-Ghezala G, Crawford F, Crowell TA, Barker WW, Duara R, Mullan M. The cyclooxygenase 2 -765 C promoter allele is a protective factor for Alzheimer's disease. Neurosci Lett 2005; 395:240-3. [PMID: 16309832 DOI: 10.1016/j.neulet.2005.10.090] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2005] [Revised: 10/23/2005] [Accepted: 10/31/2005] [Indexed: 11/23/2022]
Abstract
The cyclooxygenase-2 enzyme (COX-2) is of particular importance in the inflammatory response and recent findings have demonstrated a considerable role in Alzheimer's disease (AD) pathogenesis. In order to assess the possible putative role of a COX-2 polymorphism (765G/C) in AD, we examined its distribution in 161 community-based controls and 168 AD clinic-based cases previously recruited from memory disorder clinics in Tampa and Miami, Florida. There were no significant differences between the two groups in age/age of onset or gender. A significant difference was observed in the distribution of the COX-2 -765 alleles between AD cases and controls (chi(2) = 6.565, p = .010; OR = .596; CI = [.401-.888], p = .011), with the frequency of the C allele being higher in controls. In addition, a significant difference was observed for this polymorphism by genotype (chi(2) = 6.561, p = .038) and by presence or absence of C+ genotypes (chi(2) = 6.207, p = .013; OR = .464, CI = [.351-.885], p = .013). In this sample, the C allele of COX-2 -765 promoter polymorphism is associated with decreased risk of Alzheimer's disease, a finding which further supports the involvement of COX-2 in AD etiology.
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Affiliation(s)
- Laila Abdullah
- Roskamp Institute, 2040 Whitfield Ave. Sarasota, FL, USA.
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24
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Zha S, Yegnasubramanian V, Nelson WG, Isaacs WB, De Marzo AM. Cyclooxygenases in cancer: progress and perspective. Cancer Lett 2004; 215:1-20. [PMID: 15374627 DOI: 10.1016/j.canlet.2004.06.014] [Citation(s) in RCA: 313] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2004] [Accepted: 06/07/2004] [Indexed: 12/13/2022]
Abstract
Aspirin has been used to control pain and inflammation for over a century. Epidemiological studies first associated a decreased incidence of colorectal cancer with the long-term use of aspirin in the early 1980s. Near the same time the first reports showing regression of colorectal adenomas in response to the non-steroidal anti-inflammatory drug (NSAID) sulindac were reported. In subsequent years, the use of other NSAIDs, which inhibit cyclooxygenase (COX) enzymes, was linked to reduced cancer risk in multiple tissues including those of the breast, prostate, and lung. Together these studies resulted in the identification of a new cancer preventive and/or therapeutic target-COX enzymes, especially COX-2. Meanwhile, the overexpression of COX-2, and less consistently, the upstream and downstream enzymes of the prostaglandin synthesis pathway, was demonstrated in multiple cancer types and some pre-neoplastic lesions. Direct interactions of prostaglandins with their receptors through autocrine or paracrine pathways to enhance cellular survival or stimulate angiogenesis have been proposed as the molecular mechanisms underlying the pro-carcinogenic functions of COX-2. The rapid development of safe and effective inhibitors targeting individual COX enzymes not only dramatically improved our understanding of the function of COX-2, but also resulted in discovery of COX independent functions of NSAIDs, providing important hints for future drug design. Here we review the fundamental features of COX enzymes, especially as related to carcinogenesis, their expression and function in both animal tumor models and clinical cancers and the proposed mechanisms behind their roles in cancer.
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Affiliation(s)
- Shan Zha
- Brady Urological Institute, The Johns Hopkins University, Baltimore, MD, USA
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Romano M, Claria J. Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB J 2003; 17:1986-95. [PMID: 14597668 DOI: 10.1096/fj.03-0053rev] [Citation(s) in RCA: 169] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cyclooxygenase (COX) and lipoxygenase (LO) metabolic pathways are emerging as key regulators of cell proliferation and neo-angiogenesis. COX and LO inhibitors are being investigated as potential anticancer drugs and results from clinical trials seem to be encouraging. In this article we will review evidence of COX-2 and 5-LO involvement in cancer pathobiology, propose a model of integrated control of cell proliferation by these enzymes, and discuss the pharmacologic implications of this model.
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Affiliation(s)
- Mario Romano
- Department of Biomedical Sciences, University G. D'Annunzio, Ce.S.I., 66013 Chieti, Italy.
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26
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Tanabe T, Tohnai N. Cyclooxygenase isozymes and their gene structures and expression. Prostaglandins Other Lipid Mediat 2002; 68-69:95-114. [PMID: 12432912 DOI: 10.1016/s0090-6980(02)00024-2] [Citation(s) in RCA: 288] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The cyclooxygenase (COX, prostaglandin endoperoxide synthase) is a key enzyme in prostaglandin biosynthesis. Two isoforms of COX, COX-1 and COX-2, have been identified by molecular biological methods. The amino acid sequence homology between COX-1 and COX-2 is about 60% for the human enzymes. COX-1 is constitutively expressed in most tissues and cells in animal species. The COX-1 promoter region lacks a canonical TATA or CAAT box and is GC-rich. These features are consistent with those of a housekeeping gene. On the other hand, COX-2 is an inducible enzyme and is induced by various cytokines and mitogenic factors. The induction of COX-2 is suppressed by dexamethasone and PGJ2. There are many consensus cis-elements in the 5'-flanking region to regulate the expression of COX-2. Among them, a CRE, an NF-kappaB site, a NF-IL6 motif and an E-box, regulate transcription independently or synergistically. Most of the transcriptional signaling pathways require activation of the mitogen-activated protein kinase (MAPK) cascade. Moreover, MAPK signaling pathways are involved in regulating COX-2 gene expression at the post-transcriptional level.
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Affiliation(s)
- Tadashi Tanabe
- Department of Pharmacology, National Cardiovascular Center Research Institute, Suita, Osaka, Japan.
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Flyckt L, Wiesel FA, Borg J, Edman G, Ansved T, Sydow O, Borg K. Neuromuscular and psychomotor abnormalities in patients with schizophrenia and their first-degree relatives. J Psychiatr Res 2000; 34:355-64. [PMID: 11104850 DOI: 10.1016/s0022-3956(00)00031-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
In previous studies of schizophrenic patients, neuromuscular (histopathological and electrophysiological) and psychomotor (finger tapping) abnormalities were found. The present study was designed to investigate relationships between these abnormalities and a family history of psychosis in 14 schizophrenic patients and 25 unaffected first-degree relatives compared to 14 healthy controls. Muscle biopsies were performed in either m. tibialis anterior or m. lateralis. Macro EMG recordings were made from m. tibialis anterior. A finger tapping test was used to investigate psychomotor performance. Neuromuscular abnormalities (muscle biopsies and/or macro EMG) and/or aberrant psychomotor performance (finger tapping test) were found in 13 (93%) patients, 14 (56%) first-degree relatives and in three (21%) controls. A statistically significant relationship for the psychomotor, but not neuromuscular changes to a family history of psychosis was found using a logistic regression method. The percentage of patients, relatives and healthy controls exhibiting were 36/40/7% in the muscle biopsy, 50/20/0% in the macro EMG, and 71/82/14% in the finger tapping investigations. A higher frequency of neuromuscular and psychomotor abnormalities was found in patients with schizophrenia and their first-degree relatives compared to healthy controls. The relationship between psychomotor findings and a family history of psychosis indicate that central aspects of motor aberrations are associated with a hereditary disposition of psychosis. The neuromuscular as well as psychomotor changes indicate that schizophrenia may be a systemic disease involving the central nervous system as well as peripheral organs. An altered cell membrane is suggested to be an underlying factor based on the type of neuromuscular findings.
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Affiliation(s)
- L Flyckt
- FoUU Department of Psychiatry, Karolinska Institutet, Danderyd's Hospital, S-182 88 Danderyd, Stockholm, Sweden.
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Abstract
The past years have seen considerable progress in the characterization of hereditary factors in primary open-angle glaucoma. Epidemiologic studies strengthened our knowledge of the hereditary factors in this multifactorial disease. Several loci in the human genome have been described, which segregate with different glaucoma phenotypes. Mutations of the MYOC/TIGR (myocilin/trabecular meshwork inducible glucocorticoid response) gene on chromosome 1q account for most, but probably not all, cases of glaucoma linked to chromosome 1q, and other additional pathologic factors may be implicated. The properties of the normal myocilin protein point to a crucial role in the regulation of intraocular pressure. However, in spite of the knowledge obtained so far, routinely performed genetic screening of patients at risk for primary open-angle glaucoma is not yet clinically useful.
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Affiliation(s)
- W M Budde
- Department of Ophthalmology, Friedrich-Alexander Universität Erlangen-Nürnberg, Germany.
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Bingham CO, Austen KF. Phospholipase A2 enzymes in eicosanoid generation. PROCEEDINGS OF THE ASSOCIATION OF AMERICAN PHYSICIANS 1999; 111:516-24. [PMID: 10591080 DOI: 10.1046/j.1525-1381.1999.99321.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Phospholipase A2 (PLA2) enzymes cleave esterified fatty acids from membrane glycerophospholipids. The 20-carbon polyunsaturated fatty acid, arachidonic acid, is used as substrate by intermediate enzymes for the generation of eicosanoids, including leukotrienes and prostanoid products. An expanding number of PLA2 enzymes has now been identified that may participate in arachidonic acid release and thus serve a rate-limiting role in eicosanoid biosynthesis. Cellular PLA2 function for various members is regulated by constitutive or elicited expression, as well as by posttranslational events such as phosphorylation. In addition, the function of some cellular PLA2 enzymes is regulated by a requirement for calcium or by localization to a particular subcellular compartment. Finally, some PLA2 enzymes are secreted from the cell where they may directly interact with plasma membrane or transmembrane receptors to function as autocrine or paracrine mediators. Evaluating the roles of a number of these functionally similar PLA2 enzymes in the biosynthesis of leukotrienes and other eicosanoids is the focus of this review.
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Affiliation(s)
- C O Bingham
- Department of Medicine, Harvard Medical School, Boston, MA, USA
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Abstract
The metabolism of AA reflects a carefully balanced series of biochemical pathways. The level of free arachidonate in a cells is controlled by de novo synthesis, dietary uptake, and transcellular metabolism. Lysophospholipids are key controlling substrates for a variety of acyl transferase and transacylase reactions, whose combined effect is to remodel cellular membranes placing AA in up to 20 different molecular species of phospholipids. PLA2 enzymes, both cytosolic and secretory, can release AA for subsequent metabolism via lipoxygenase, COX, and cytochrome P450 enzymes into a variety of eicosanoid products. Reactions are often tissue- and cell-specific, and provide a spectrum of inflammatory mediator release in which many of the molecular details remain to be elucidated.
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Affiliation(s)
- M C Seeds
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA
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Hashimoto K, Okamura K, Yamaguchi H, Ototake M, Nakanishi T, Kurosawa Y. Conservation and diversification of MHC class I and its related molecules in vertebrates. Immunol Rev 1999; 167:81-100. [PMID: 10319253 DOI: 10.1111/j.1600-065x.1999.tb01384.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The elucidation of the complete peptide-binding domains of the highly polymorphic shark MHC class I genes offered us an opportunity to examine the characteristics of their predicted protein products in the light of the latest advance in the structural studies of the MHC class I molecules. The results suggest that the fundamental characteristics in the T-cell recognition of the MHC class I molecule/peptide complex are expected to have been established at the early stage of the vertebrate evolution. The elucidation of the typical classical class I molecules from fishes and also of some MHC class I-related molecules may help us-to explore the common denominator of the ancient class I molecules.
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Affiliation(s)
- K Hashimoto
- Institute for Comprehensive Medical Science, Fujita Health University, Aichi, Japan.
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Abstract
The aim of this pilot study was to evaluate a potential skin test for schizophrenia based on the effect of aqueous methyl nicotinate (AMN) on the production of prostaglandin D2 (PGD2) from skin macrophages and the resultant cutaneous capillary vasodilatation. Four concentrations of AMN were applied topically to the forearm skin in patients and controls, and any resulting vasodilatation was rated as redness after 5 min. The test was carried out on 38 patients with schizophrenia diagnosed according to DSM-III-R criteria, and 22 normal control subjects. At all concentrations of AMN, the schizophrenics were highly significantly different from the controls. One concentration gave the greatest degree of differentiation: at this concentration at 5 min, 83% of schizophrenics but only 23% of controls had a zero or minimal response to AMN. The skin flushing seen after oral administration of nicotinic acid is due to the same reaction, and this has been normal in those with affective illness and neurosis; cyclo-oxygenase inhibitors, e.g., aspirin, give a false-positive result (failure of vasodilatation). This result is consistent with the concept of reduced membrane arachidonic acid levels in schizophrenia. This test may contribute to the reliable diagnosis of schizophrenia.
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Affiliation(s)
- P E Ward
- Craig Dunain Hospital, Inverness, UK
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Affiliation(s)
- C C Leslie
- Division of Basic Science, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
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Walsh MT, Divane A, Whitehead AS. Fine mapping of the human pentraxin gene region on chromosome 1q23. Immunogenetics 1996; 44:62-9. [PMID: 8613143 DOI: 10.1007/bf02602657] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The 1q21 to 25 region of human chromosome 1 contains genes which encode proteins with immune- and inflammation-associated functions. These include the pentraxin genes, for C-reactive protein (CRP), serum amyloid P (SAP) protein (APCS),a nd a CRP pseudogene (CRPP1). The region of chromosome 1 containing this cluster is syntenic with distal mouse chromosome 1. We constructed an approximately 1.4 megabase yeast artificial chromosome (YAC) contig with the pentraxin genes at its core. This four-YAC contig includes other genes with immune functions including the FCER1A gene, which encodes the alpha-subunit of the IgE high-affinity Fc receptor and the IFI-16 gene, an interferon-gamma-induced gene. In addition, it contains the histone H3F2 and H4F2 genes and the gene for erythroid alpha-spectrin (SPTA1). The gene order is cen.-SPTA1-H4F2-H3F2-IFI-16-CRP-CRPP1-APCS -FCER1A- tel. The contig thus consists of a cluster of genes whose products either have immunological importance, bind DNA, or both.
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Affiliation(s)
- M T Walsh
- Department of Genetics and Biotechnology Institute, University of Dublin, Trinity College, Dublin, Ireland
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Hack N, Schultz A, Clayman P, Goldberg H, Skorecki KL. Transmembrane signaling in kidney health and disease. Pediatr Nephrol 1995; 9:514-25. [PMID: 7577422 DOI: 10.1007/bf00866743] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Transmembrane signal transduction is the process whereby a ligand binds to the external surface of the cell membrane and elicits a physiological response specific for that ligand and cell type. It is now appreciated that numerous disease states represent disturbances in normal transmembrane signaling mechanisms. In the current paper, we focus our attention on the mesangial cell of the glomerular microcirculation as a prototypical model system for understanding normal and abnormal transmembrane signaling processes. Among the major receptor and effector mechanisms for transmembrane signal transduction in the mesangial cell, this paper emphasizes the phospholipase effector response to growth factors and vasoactive hormones. The post-translational and transcriptional pathways for regulation of phospholipase C and phospholipase A2 are described, including consideration of perturbations in these systems that characterize two disease models, namely: acute cyclosporine nephrotoxicity and early diabetic glomerulopathy.
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Affiliation(s)
- N Hack
- Department of Medicine, Toronto Hospital, Canada
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Tay A, Simon JS, Squire J, Hamel K, Jacob HJ, Skorecki K. Cytosolic phospholipase A2 gene in human and rat: chromosomal localization and polymorphic markers. Genomics 1995; 26:138-41. [PMID: 7782073 DOI: 10.1016/0888-7543(95)80093-2] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
We report the chromosomal localization and a simple sequence repeat (SSR) in the cytosolic phospholipase A2 (cPLA2) gene in both human and rat. A (CA)18 repeat in the promoter of the rat gene was determined to exhibit length polymorphism when analyzed using the polymerase chain reaction (PCR) in 19 different inbred rat strains. Genotyping for this marker in 234 F2 progeny of a SHR x BN intercross mapped the gene to rat chromosome 13. Using a PCR strategy, a fragment of the promoter for the human gene was isolated, and a (CA)18 repeat was identified. Since this marker displayed a low heterozygosity index, we also identified a mononucleotide repeat in the promoter for cPLA2 that displayed a polymorphism information content value of 0.76. The human gene was mapped using fluorescence in situ hybridization (FISH) to chromosome 1q25. Of interest, the gene encoding the enzyme prostaglandin-endoperoxide synthase 2 (cyclooxygenase-2), which acts on the arachidonic acid product of cPLA2, was previously localized to this same chromosomal region, raising the possibility of coordinate regulation. Identification of intragenic markers may facilitate studies of polymorphic variants of these genes as candidates for disorders in which perturbations of the eicosanoid cascade may play a role.
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Affiliation(s)
- A Tay
- Membrane Biology Group, Hospital for Sick Children, Toronto, Canada
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