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Caldwell BA, Ie S, Lucas A, Li L. Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis. Sci Rep 2025; 15:2059. [PMID: 39814939 PMCID: PMC11735619 DOI: 10.1038/s41598-025-86103-x] [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: 09/10/2024] [Accepted: 01/08/2025] [Indexed: 01/18/2025] Open
Abstract
Sepsis is a leading cause of death worldwide, with most patient mortality stemming from lingering immunosuppression in sepsis survivors. This is due in part to immune dysfunction resulting from monocyte exhaustion, a phenotype of reduced antigen presentation, altered CD14/CD16 inflammatory subtypes, and disrupted cytokine production. Whereas previous research demonstrated improved sepsis survival in Ticam2-/- mice, the contribution of TICAM2 to long-term exhaustion memory remained unknown. Using a cecal slurry injection sepsis model, we monitored the establishment and recovery of monocyte exhaustion in Ticam2-/- mice. After one week of recovery, we profiled bone marrow and splenic reservoir monocytes in Ticam2-/- mice and found that, in contrast to the persistent exhaustion observed in wild-type monocytes, Ticam2-/- monocytes largely resembled healthy controls. To determine the impact of TICAM2 ablation on innate epigenetic memory in sepsis, we measured genome-wide DNA methylation in bone marrow monocytes and found that Ticam2-/- cells exhibit a unique profile of altered methylation at CEBPE binding sites and regulatory features for key immune genes such as Dmkn and Btg1. Bearing human translational relevance, a case study of time course blood samples collected from a sepsis patient presenting with SIRS and a positive qSOFA revealed a similar effect in human monocytes, which steadily transition into an exhausted memory characterized by a CD38high; CX3CR1low; HLA-DRlow state within four days of hospital admittance. Together, our data reveal the chronic preservation of monocyte exhaustion, partially controlled by TICAM2.
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Affiliation(s)
- Blake A Caldwell
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061-0910, USA
| | - Susanti Ie
- Carillion Roanoke Memorial Hospital, Roanoke, VA, 24014, USA
| | - Amy Lucas
- Carillion Roanoke Memorial Hospital, Roanoke, VA, 24014, USA
| | - Liwu Li
- Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061-0910, USA.
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Wan L, Chen X, Deng J, Zhang S, Tu F, Pei H, Hu R, Liu J, Yu H. Plasma exosome-derived B-cell translation gene 1: a predictive marker for the prognosis in patients with non-small cell lung cancer. J Cancer 2021; 12:1538-1547. [PMID: 33531999 PMCID: PMC7847650 DOI: 10.7150/jca.52320] [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: 08/24/2020] [Accepted: 12/04/2020] [Indexed: 12/14/2022] Open
Abstract
Objective: In this study, we wanted to investigate the plasma exosome-derived B-cell translocation gene 1 (BTG-1) level as a predictive marker for the prognosis in patients with Non-small cell lung cancer (NSCLC). Patients and Methods: The expression of BTG-1 protein and BTG-1 mRNA in NSCLC tissues and adjacent tissues of 98 enrolled patients were detected by immunohistochemistry (IHC), and RT-PCR. Exosome-rich fractions were isolated from the plasma of 262 NSCLC patients. ELISA was used to detect plasma exosome-derived BTG-1 levels to evaluate the predictive value for the prognosis in patients with NSCLC. Results: IHC staining showed that the positive expression rate of BTG-1 protein in NSCLC tissues was 58.16%, whereas that in adjacent tissues was 91.84%. RT-PCR showed that BTG-1 mRNA expression was significantly lower in NSCLC tissues than in adjacent tissues (52.04% vs 87.76%, P < 0.05). Moreover, low plasma exosome-derived BTG-1 levels were related to tumor diameter, stage, metastasis, the degree of tumor differentiation, and abnormal carcinoembryonic antigen (CEA) levels. Multivariate Cox regression analysis showed that both the disease-free survival (DFS) and overall survival (OS) were shorter in patients with low plasma exosome-derived BTG-1 level compared with patients with high plasma exosome-derived BTG-1 level. The AUROC of plasma exosome-derived BTG-1 for 3-year DFS and 3-year OS were 0.94(95% CI; 0.91-0.98) and 0.94(95% CI: 0.90-0.98), respectively. For 3-year DFS, plasma exosome-derived BTG-1 had a sensitivity 91.0% and a specificity 82.3% for 3-year DFS, and a sensitivity 81.7% and a specificity 93.0% for 3-year OS, respectively. Conclusions: Plasma exosome-derived BTG-1 may be a potential biomarker for the prognosis in patients with NSCLC.
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Affiliation(s)
- Lin Wan
- Department of Laboratory Medicine, Wuxi Second People's Hospital, Wuxi214000, China
| | - Xiaochun Chen
- Department of Laboratory Medicine, Taizhou Second People's Hospital, Taizhou 225300, China
| | - Jun Deng
- Department of Interventional Oncology, Wuxi Fifth People's Hospital, Wuxi214005, China
| | - Shiliang Zhang
- Department of Laboratory Medicine, Wuxi Fifth People's Hospital, Wuxi214005, China
| | - Fan Tu
- Department of Laboratory Medicine, Wuxi Fifth People's Hospital, Wuxi214005, China
| | - Hao Pei
- Department of Laboratory Medicine, Wuxi Fifth People's Hospital, Wuxi214005, China
| | - Renjing Hu
- Department of Laboratory Medicine, Wuxi Second People's Hospital, Wuxi214000, China
| | - Jun Liu
- Department of Laboratory Medicine, Wuxi Fifth People's Hospital, Wuxi214005, China
| | - Hao Yu
- Department of Interventional Oncology, Wuxi Fifth People's Hospital, Wuxi214005, China
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Chen XQ, Meng FQ, Xiong H, Wang YL, Tang WH, Zou YM. Identification of BTG1 Status in Solid Cancer for Future Researches Using a System Review and Meta-analysis. Curr Med Sci 2020; 40:85-94. [PMID: 32166669 DOI: 10.1007/s11596-020-2150-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 12/10/2019] [Indexed: 12/24/2022]
Abstract
Abundant studies have been conducted to identify how B-cell translocation gene 1 protein (BTG1) gene affects the differentiation, proliferation, metastasis of cancer cells, and how it further regulates the generation or development of diseases to influence the prognosis of patients. However, the data from single research were not powerful enough. The correlations between BTG1 expression and mechanisms of tumorigenesis or prognosis of patients are still in controversial. Our system review and meta-analysis provided a complete explanation about the association between BTG1 expression and clinicopathological features or prognosis of patients, which further laid a foundation for future research on BTG1. Fifteen eligible studies consisting of 1992 participants were included. We uncovered that BTG1 expression in solid tumors was associated with lymph node status (RR=0.66, 95% CI: 0.58-0.75, P=0.142), TMN stage status (RR=2.13, 95% CI: 1.71-2.65, P=0.001), T category (RR=1.90, 95% CI: 1.20-3.00, P=0.000), histological differentiation (RR=1.91, 95% CI: 1.55-2.37, P=0.012), vascular invasion (RR=0.90, 95% CI: 0.57-1.41, P=0.001). BTG1 low expression was significantly associated with overall survival (OS) (HR=0.47, 95% CI: 0.38-0.67, P=0.000). It concluded that BTG1 possessed the potential value for future research and could be recommended as a significant biomarker in solid tumor.
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Affiliation(s)
- Xiu-Qiong Chen
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | | | - Hua Xiong
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ya-Li Wang
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wen-Hua Tang
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yan-Mei Zou
- Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Deng J, Guo Y, Yuan F, Chen S, Yin H, Jiang X, Jiao F, Wang F, Ji H, Hu G, Ying H, Chen Y, Zhai Q, Xiao F, Guo F. Autophagy inhibition prevents glucocorticoid-increased adiposity via suppressing BAT whitening. Autophagy 2019; 16:451-465. [PMID: 31184563 DOI: 10.1080/15548627.2019.1628537] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
The mechanisms underlying glucocorticoid (GC)-increased adiposity are poorly understood. Brown adipose tissue (BAT) acquires white adipose tissue (WAT) cell features defined as BAT whitening under certain circumstances. The aim of our current study was to investigate the possibility and mechanisms of GC-induced BAT whitening. Here, we showed that one-week dexamethasone (Dex) treatment induced BAT whitening, characterized by lipid droplet accumulation, in vitro and in vivo. Furthermore, autophagy and ATG7 (autophagy related 7) expression was induced in BAT by Dex, and treatment with the autophagy inhibitor chloroquine or adenovirus-mediated ATG7 knockdown prevented Dex-induced BAT whitening and fat mass gain. Moreover, Dex-increased ATG7 expression and autophagy was mediated by enhanced expression of BTG1 (B cell translocation gene 1, anti-proliferative) that stimulated activity of CREB1 (cAMP response element binding protein 1). The importance of BTG1 in this regulation was further demonstrated by the observed BAT whitening in adipocyte-specific BTG1-overexpressing mice and the attenuated Dex-induced BAT whitening and fat mass gain in mice with BTG1 knockdown in BAT. Taken together, we showed that Dex induces a significant whitening of BAT via BTG1- and ATG7-dependent autophagy, which might contribute to Dex-increased adiposity. These results provide new insights into the mechanisms underlying GC-increased adiposity and possible strategy for preventing GC-induced side effects via the combined use of an autophagy inhibitor.Abbreviations: ACADL: acyl-Coenzyme A dehydrogenase, long-chain; ACADM: acyl-Coenzyme A dehydrogenase, medium-chain; ACADS: acyl-Coenzyme A dehydrogenase, short-chain; ADIPOQ: adiponectin; AGT: angiotensinogen; Atg: autophagy-related; BAT: brown adipose tissue; BTG1: B cell translocation gene 1, anti-proliferative; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; CIDEA: cell death-inducing DNA fragmentation factor, alpha subunit-like effector A; CPT1B: carnitine palmitoyltransferase 1b, muscle; CPT2: carnitine palmitoyltransferase 2; CQ: chloroquine; Dex: dexamethasone; eWAT: epididymal white adipose tissue; FABP4: fatty acid binding protein 4, adipocyte; FFAs: free fatty acids; GCs: glucocorticoids; NRIP1: nuclear receptor interacting protein 1; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PPARA: peroxisome proliferator activated receptor alpha; PPARG: peroxisome proliferator activated receptor gamma; PPARGC1A: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; PRDM16: PR domain containing 16; PSAT1: phosphoserine aminotransferase 1; RB1: RB transcriptional corepressor 1; RBL1/p107: RB transcriptional corepressor like 1; SQSTM1: sequestosome 1; sWAT: subcutaneous white adipose tissue; TG: triglycerides; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); WT: wild-type.
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Affiliation(s)
- Jiali Deng
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yajie Guo
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Feixiang Yuan
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Shanghai Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hanrui Yin
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiaoxue Jiang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Fuxin Jiao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Fenfen Wang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hongbin Ji
- State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Guohong Hu
- The Key Laboratory of Stem Cell Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Ying
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yan Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qiwei Zhai
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Fei Xiao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Feifan Guo
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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He C, Yu T, Shi Y, Ma C, Yang W, Fang L, Sun M, Wu W, Xiao F, Guo F, Chen M, Yang H, Qian J, Cong Y, Liu Z. MicroRNA 301A Promotes Intestinal Inflammation and Colitis-Associated Cancer Development by Inhibiting BTG1. Gastroenterology 2017; 152:1434-1448.e15. [PMID: 28193514 DOI: 10.1053/j.gastro.2017.01.049] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 01/15/2017] [Accepted: 01/24/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Intestinal tissues from patients with inflammatory bowel disease (IBD) and colorectal cancer have increased expression of microRNA-301a (MIR301A) compared with tissues from patients without IBD. We studied the mechanisms of MIR301A in the progression of IBD in human tissues and mice. METHODS We isolated intestinal epithelial cells (IECs) from biopsy samples of the colon from 153 patients with different stages of IBD activity, 6 patients with colitis-associated cancer (CAC), and 35 healthy individuals (controls), enrolled in the study in Shanghai, China. We measured expression of MIR301A and BTG anti-proliferation factor 1 (BTG1) by IECs using quantitative reverse-transcription polymerase chain reaction. Human colon cancer cell lines (HCT-116 and SW480) were transfected with a lentivirus that expresses MIR301A; expression of cytokines and tight junction proteins were measured by quantitative reverse transcription polymerase chain reaction, flow cytometry, and immunofluorescence staining. We generated mice with disruption of the microRNA-301A gene (MIR301A-knockout mice), and also studied mice that express a transgene-encoding BTG1. Colitis was induced in knockout, transgenic, and control (C57BL/B6) mice by administration of dextran sulfate sodium (DSS), and mice were given azoxymethane to induce colorectal carcinogenesis. Colons were collected and analyzed histologically and by immunohistochemistry; tumor nodules were counted and tumor size was measured. SW480 cells expressing the MIR301A transgene were grown as xenograft tumors in nude mice. RESULTS Expression of MIR301A increased in IECs from patients with IBD and CAC compared with controls. MIR301A-knockout mice were resistant to the development of colitis following administration of DSS; their colon tissues expressed lower levels of interleukin 1β (IL1β), IL6, IL8, and tumor necrosis factor than colons of control mice. Colon tissues from MIR301A-knockout mice had increased epithelial barrier integrity and formed fewer tumors following administration of azoxymethane than control mice. Human IECs expressing transgenic MIR301A down-regulated expression of cadherin 1 (also called E-cadherin or CDH1). We identified BTG1 mRNA as a target of MIR301A; levels of BTG1 mRNA were reduced in inflamed mucosa from patients with active IBD compared with controls. There was an inverse correlation between levels of BTG1 mRNA and levels of MIR301A in inflamed mucosal tissues from patients with active IBD. Human colon cancer cell lines that expressed a MIR301A transgene increased proliferation; they had increased permeability and decreased expression of CDH1 compared with cells transfected with a control vector, indicating reduced intestinal barrier function. BTG1 transgenic mice developed less severe colitis than control mice following administration of DSS. SW480 cells expressing anti-MIR301A formed fewer xenograft tumors in nude mice than cells expressing a control vector. CONCLUSIONS Levels of MIR301A are increased in IECs from patients with active IBD. MIR301A reduces expression of BTG1 to reduce epithelial integrity and promote inflammation in mouse colon and promotes tumorigenesis. Strategies to decrease levels of MIR301A in colon tissues might be developed to treat patients with IBD and CAC.
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Affiliation(s)
- Chong He
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Tianming Yu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Yan Shi
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Caiyun Ma
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Wenjing Yang
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Leilei Fang
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Mingming Sun
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Wei Wu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Fei Xiao
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, Shanghai, China
| | - Feifan Guo
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, Shanghai, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Hong Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jiaming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX.
| | - Zhanju Liu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
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Maria VL, Amorim MJB, Bebianno MJ, Dondero F. Transcriptomic effects of the non-steroidal anti-inflammatory drug Ibuprofen in the marine bivalve Mytilus galloprovincialis Lam. MARINE ENVIRONMENTAL RESEARCH 2016; 119:31-39. [PMID: 27209120 DOI: 10.1016/j.marenvres.2016.05.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 05/04/2016] [Accepted: 05/05/2016] [Indexed: 06/05/2023]
Abstract
The transcriptomic effects of Ibuprofen (IBU) in the digestive gland tissue of Mytilus galloprovincialis Lam. specimens exposed at low environmental concentrations (250 ng L(-1)) are presented. Using a 1.7 K feature cDNA microarray along with linear models and empirical Bayes statistical methods 225 differentially expressed genes were identified in mussels treated with IBU across a 15-day period. Transcriptional dynamics were typical of an adaptive response with a peak of gene expression change at day-7 (177 features, representing about 11% of sequences available for analysis) and an almost full recovery at the end of the exposure period. Functional genomics by means of Gene Ontology term analysis unraveled typical mussel stress responses i.e. aminoglycan (chitin) metabolic processes but also more specific effects such as the regulation of NF-κB transcription factor activity.
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Affiliation(s)
- Vera L Maria
- CIMA, Faculty of Science and Technology, University of Algarve, 8005-139 Faro, Portugal; CESAM, Department of Biology, University of Aveiro, 3830-169 Aveiro, Portugal
| | - Mónica J B Amorim
- CESAM, Department of Biology, University of Aveiro, 3830-169 Aveiro, Portugal
| | - Maria João Bebianno
- CIMA, Faculty of Science and Technology, University of Algarve, 8005-139 Faro, Portugal
| | - Francesco Dondero
- Department of Science and Technological Innovation (DISIT), Università del Piemonte Orientale Amedeo Avogadro, 15121 Alessandria, Italy.
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Xiao F, Deng J, Guo Y, Niu Y, Yuan F, Yu J, Chen S, Guo F. BTG1 ameliorates liver steatosis by decreasing stearoyl-CoA desaturase 1 (SCD1) abundance and altering hepatic lipid metabolism. Sci Signal 2016; 9:ra50. [PMID: 27188441 DOI: 10.1126/scisignal.aad8581] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Liver steatosis, a condition in which lipid accumulates in liver cells, is a leading cause of many liver diseases. The livers of patients with hepatocellular carcinoma, a cancer characterized by liver steatosis, have decreased abundance of the transcription cofactor BTG1 (B cell translocation gene 1). We showed that the livers of db/db mice, which are a genetic model of obesity, had decreased BTG1 mRNA and protein abundance. BTG1 overexpression ameliorated liver steatosis in db/db mice, whereas knockdown of BTG1 induced liver steatosis in wild-type mice. Consistent with these changes, we found that BTG1 decreased triglyceride accumulation in cultured hepatocytes. BTG1 overexpression inhibited the expression of the gene encoding stearoyl-CoA desaturase 1 (SCD1), an enzyme involved in the synthesis of fatty acids, by suppressing the activity of activating transcription factor 4 (ATF4). Knockdown of SCD1 prevented liver steatosis in wild-type mice induced by knockdown of BTG1. Conversely, the ability of BTG1 overexpression to ameliorate liver steatosis in db/db mice was negated by ATF4 overexpression. Moreover, BTG1 transgenic mice were resistant to liver steatosis induced by a high-carbohydrate diet. BTG1 abundance was decreased by this diet through a pathway that involved mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase 1 (S6K1), and cAMP response element-binding protein (CREB). Together, our study identifies a role of BTG1 in regulating hepatic lipid metabolism and specifically in preventing ATF4 and SCD1 from inducing liver steatosis.
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Affiliation(s)
- Fei Xiao
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jiali Deng
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yajie Guo
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yuguo Niu
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Feixiang Yuan
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Junjie Yu
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Shanghai Chen
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Feifan Guo
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
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Induction, Propagation, and Activity of Host Nitric Oxide: Lessons from Leishmania Infection. Trends Parasitol 2015; 31:653-664. [DOI: 10.1016/j.pt.2015.08.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/31/2015] [Accepted: 08/05/2015] [Indexed: 02/07/2023]
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Xiao F, Deng J, Yu J, Guo Y, Chen S, Guo F. A novel function of B‐cell translocation gene 1 (
BTG1
) in the regulation of hepatic insulin sensitivity in mice
via
c‐Jun. FASEB J 2015; 30:348-59. [DOI: 10.1096/fj.15-278689] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 09/08/2015] [Indexed: 12/17/2022]
Affiliation(s)
- Fei Xiao
- Key Laboratory of Nutrition and MetabolismInstitute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, the Graduate School of the Chinese Academy of SciencesChinese Academy of SciencesShanghaiChina
| | - Jiali Deng
- Key Laboratory of Nutrition and MetabolismInstitute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, the Graduate School of the Chinese Academy of SciencesChinese Academy of SciencesShanghaiChina
| | - Junjie Yu
- Key Laboratory of Nutrition and MetabolismInstitute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, the Graduate School of the Chinese Academy of SciencesChinese Academy of SciencesShanghaiChina
| | - Yajie Guo
- Key Laboratory of Nutrition and MetabolismInstitute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, the Graduate School of the Chinese Academy of SciencesChinese Academy of SciencesShanghaiChina
| | - Shanghai Chen
- Key Laboratory of Nutrition and MetabolismInstitute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, the Graduate School of the Chinese Academy of SciencesChinese Academy of SciencesShanghaiChina
| | - Feifan Guo
- Key Laboratory of Nutrition and MetabolismInstitute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, the Graduate School of the Chinese Academy of SciencesChinese Academy of SciencesShanghaiChina
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Lee WH, Wu HM, Lee CG, Sung DI, Song HJ, Matsui T, Kim HB, Kim SG. Specific oligopeptides in fermented soybean extract inhibit NF-κB-dependent iNOS and cytokine induction by toll-like receptor ligands. J Med Food 2014; 17:1239-46. [PMID: 25184943 PMCID: PMC4224054 DOI: 10.1089/jmf.2013.3070] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 06/12/2014] [Indexed: 12/24/2022] Open
Abstract
The ethanol extract of fermented soybean from Glycine max (chungkookjang, CHU) has been claimed to have chemopreventive and cytoprotective effects. In the present study, we examined the inhibitory effect of CHU on inducible nitric oxide synthase (iNOS) and cytokine induction by toll-like receptor (TLR) ligands treatment and attempted to identify the responsible active components. Nitric oxide (NO) content and iNOS levels in the media or RAW264.7 cells were measured using the Griess reagent and real-time polymerase chain reaction assays. CHU treatment inhibited NO production and iNOS induction elicited by lipopolysaccharide (LPS, TLR4L) in a concentration-dependent manner. Tumor necrosis factor-α and interleukin-6 productions were also diminished. Peptidoglycans (TLR2/6L) and CpG-oligodeoxynucleotides (TLR9L) from CHU inhibited iNOS induction, but not poly I:C (TLR3L) or loxoribine (TLF7L). The anti-inflammatory effect resulted from the inhibition of nuclear factor-kappa B (NF-κB) through the inhibition of inhibitory-κB degradation. Of the representative components in CHU, specific oligopeptides (AFPG and GVAWWMY) had the ability to inhibit iNOS induction by LPS, whereas others failed to do so. Daidzein, an isoflavone used for comparative purposes, was active at a relatively higher concentration. In an animal model, oral administration of CHU to rats significantly diminished carrageenan-induced paw edema and iNOS induction. Our results demonstrate that CHU has anti-inflammatory effects against TLR ligands by inhibiting NF-κB activation, which may result from specific oligopeptide components in CHU. Since CHU is orally effective, dietary applications of CHU and/or the identified oligopeptides may be of use in the prevention of inflammatory diseases.
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Affiliation(s)
- Woo Hyung Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Hong Min Wu
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Chan Gyu Lee
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Dae Il Sung
- Department of Biotechnology, The Research Institute for Basic Science, Hoseo University, Asan, Korea
| | - Hye Jung Song
- Department of Biotechnology, The Research Institute for Basic Science, Hoseo University, Asan, Korea
| | - Toshiro Matsui
- Department of Bioscience and Biotechnology, Graduate School of Kyushu University, Fukuoka, Japan
| | - Han Bok Kim
- Department of Biotechnology, The Research Institute for Basic Science, Hoseo University, Asan, Korea
| | - Sang Geon Kim
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
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11
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Wu X, Ding N, Hu W, He J, Xu S, Pei H, Hua J, Zhou G, Wang J. Down-regulation of BTG1 by miR-454-3p enhances cellular radiosensitivity in renal carcinoma cells. Radiat Oncol 2014; 9:179. [PMID: 25115181 PMCID: PMC4252025 DOI: 10.1186/1748-717x-9-179] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 08/08/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND B cell translocation gene 1 (BTG1) has long been recognized as a tumor suppressor gene. Recent reports demonstrated that BTG1 plays an important role in progression of cell cycle and is involved in cellular response to stressors. However, the microRNAs mediated regulatory mechanism of BTG1 expression has not been reported so far. MicroRNAs can effectively influence tumor radiosensitivity by preventing cell cycle progression, resulting in enhancement of the cytotoxicity of radiotherapy efficacy. This study aimed to demonstrating the effects of microRNAs on the BTG1 expression and cellular radiosensitivity. METHODS The human renal carcinoma 786-O cells were treated with 5 Gy of X-rays. Expressions of BTG1 gene and miR-454-3p, which was predicted to target BTG1 by software algorithm, were analyzed by quantitative polymerase chain reaction. Protein expressions were assessed by Western blot. Luciferase assays were used to quantify the interaction between BTG1 3'-untranslated region (3'-UTR) and miR-454-3p. The radiosensitivity was quantified by the assay of cell viability, colony formation and caspase-3 activity. RESULTS The expression of the BTG1 gene in 786-O cells was significantly elevated after treatments with X-ray irradiation, DMSO, or serum starvation. The up-regulation of BTG1 after irradiation reduced cellular radiosensitivity as demonstrated by the enhanced cell viability and colony formation, as well as the repressed caspase-3 activity. In comparison, knock down of BTG1 by siRNA led to significantly enhanced cellular radiosensitivity. It was found that miR-454-3p can regulate the expression of BTG1 through a direct interaction with the 3'-UTR of BTG1 mRNA. Decreasing of its expression level correlates well with BTG1 up-regulation during X-ray irradiation. Particularly, we observed that over-expression of miR-454-3p by transfection inhibited the BTG1 expression and enhanced the radiosensitivity. In addition, cell cycle analysis showed that over-expression of miR-454-3p shifted the cell cycle arrest from G2/M phase to S phase. CONCLUSIONS Our results indicate that BTG1 is a direct target of miR-454-3p. Down-regulation of BTG1 by miR-454-3p renders tumor cells sensitive to radiation. These results may shed light on the potential application in tumor radiotherapy.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Jufang Wang
- Department of Space Radiobiology, Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 509 Nanchang Road, Lanzhou 730000, China.
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12
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Fouz N, Amid A, Hashim YZHY. Gene Expression Analysis in MCF-7 Breast Cancer Cells Treated with Recombinant Bromelain. Appl Biochem Biotechnol 2014; 173:1618-39. [PMID: 24928548 DOI: 10.1007/s12010-014-0947-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 04/23/2014] [Indexed: 10/25/2022]
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13
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Erucin exerts anti-inflammatory properties in murine macrophages and mouse skin: possible mediation through the inhibition of NFκB signaling. Int J Mol Sci 2013; 14:20564-77. [PMID: 24132147 PMCID: PMC3821631 DOI: 10.3390/ijms141020564] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 09/25/2013] [Accepted: 09/30/2013] [Indexed: 02/07/2023] Open
Abstract
Erucin, an isothiocyanate, is a hydrolysis product of glucoerucin found in arugula and has recently been reported to have anti-cancer properties in various cancer cells. In this study, we assessed the anti-inflammatory effects of erucin and the underlying mechanisms, using lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages and 12-O-tetradecanoylphorbol-13-acetate-treated mouse skin. In RAW 264.7 cells, erucin (2.5, 5 μmol/L) inhibited LPS-induced production of nitric oxide and prostaglandin E2. Erucin inhibited LPS-induced degradation of the inhibitor of κBα and translocation of p65 to the nucleus and, subsequently, reduced LPS-induced nuclear factor κB (NFκB) DNA binding activities, as well as the transcriptional activity of NFκB, leading to the decreased expression of NFκB-target genes, including tumor necrosis factor-α, interleukin (IL)-6, IL-1β, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, as well as transcriptional activity of iNOS and COX-2. In mice, erucin (100, 300 nmoles) treatment significantly inhibited phorbol ester-induced formation of ear edema and expression of iNOS and COX-2 proteins. These results indicate that erucin exerts a potent anti-inflammatory activity by inhibiting the pro-inflammatory enzymes and cytokines, which may be mediated, at least in part, via the inhibition of NFκB signaling.
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14
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Zhao Y, Gou WF, Chen S, Takano Y, Xiu YL, Zheng HC. BTG1 expression correlates with the pathogenesis and progression of ovarian carcinomas. Int J Mol Sci 2013; 14:19670-80. [PMID: 24084718 PMCID: PMC3821579 DOI: 10.3390/ijms141019670] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Revised: 09/05/2013] [Accepted: 09/06/2013] [Indexed: 12/22/2022] Open
Abstract
BTG (B-cell translocation gene) can inhibit cell proliferation, metastasis, and angiogenesis and regulate cell cycle progression and differentiation in a variety of cell types. We aimed to clarify the role of BTG1 in ovarian carcinogenesis and progression. A BTG1-expressing plasmid was transfected into ovarian carcinoma cells and their phenotypes and related proteins were examined. BTG1 mRNA expression was detected in ovarian normal tissue (n = 17), ovarian benign tumors (n = 12), and ovarian carcinoma (n = 64) using real-time RT-PCR. Ectopic BTG1 expression resulted in lower growth rate, high cisplatin sensitivity, G1 arrest, apoptosis, and decreased migration and invasion. Phosphoinositide 3-kinase, protein kinase B, Bcl-xL, survivin, vascular endothelial growth factor, and matrix metalloproteinase-2 mRNA and protein expression was reduced in transfectants as compared to control cells. There was higher expression of BTG1 mRNA in normal tissue than in carcinoma tissue (p = 0.001) and in benign tumors than in carcinoma tissue (p = 0.027). BTG1 mRNA expression in International Federation of Gynecology and Obstetrics (FIGO) stage I/II ovarian carcinomas was higher than that in FIGO stage III/IV ovarian carcinomas (p = 0.038). Altered BTG1 expression might play a role in the pathogenesis and progression of ovarian carcinoma by modulating proliferation, migration, invasion, the cell cycle, and apoptosis.
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Affiliation(s)
- Yang Zhao
- Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang 110001, China; E-Mails: (Y.Z.); (S.C.); (Y.-L.X.)
| | - Wen-Feng Gou
- Department of Biochemistry and Molecular Biology, Institute of Pathology and Pathophysiology, College of Basic Medicine, China Medical University, Shenyang 110001, China; E-Mail:
| | - Shuo Chen
- Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang 110001, China; E-Mails: (Y.Z.); (S.C.); (Y.-L.X.)
| | - Yasuo Takano
- Clinical Cancer Institute, Kanagawa Cancer Center, Yokohama 241-0815, Japan; E-Mail:
| | - Yin-Ling Xiu
- Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang 110001, China; E-Mails: (Y.Z.); (S.C.); (Y.-L.X.)
| | - Hua-Chuan Zheng
- Department of Biochemistry and Molecular Biology, Institute of Pathology and Pathophysiology, College of Basic Medicine, China Medical University, Shenyang 110001, China; E-Mail:
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +86-187-0406-7718
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15
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Mechanisms by which licochalcone e exhibits potent anti-inflammatory properties: studies with phorbol ester-treated mouse skin and lipopolysaccharide-stimulated murine macrophages. Int J Mol Sci 2013; 14:10926-43. [PMID: 23708096 PMCID: PMC3709710 DOI: 10.3390/ijms140610926] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Revised: 05/15/2013] [Accepted: 05/15/2013] [Indexed: 11/30/2022] Open
Abstract
In this study we found that licochalcone E (LicE), a recently isolated retrochalcone from Glycyrrhiza inflata, exhibits potent anti-inflammatory effects in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema and lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophage models. Topical application of LicE (0.5–2 mg) effectively inhibited TPA-induced (1) ear edema formation; (2) phosphorylation of stress-activated protein kinase/c-Jun-N-terminal kinase (SAPK/JNK), c-Jun, and extracellular signal regulated kinase 1/2; and (3) expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 proteins in mouse skin. The treatment of RAW 264.7 cells with LicE (2.5–7.5 μmol/L) induced a profound reduction in LPS-induced (1) release of NO and prostaglandin E2; (2) mRNA expression and secretion of interleukin (IL)-6, IL-1β and tumor necrosis factor-α; (3) promoter activity of iNOS and COX-2 and expression of their corresponding mRNAs and proteins; (4) activation of AKT, p38 mitogen activated protein kinase (MAPK), SAPK/JNK and c-Jun; (5) phosphorylation of inhibitor of κB (IκB) kinase-αβ and IκBα, degradation of IκBα, translocation of p65 (RelA) to the nucleus and transcriptional activity of nuclear factor (NF)-κB; and (6) transcriptional activity of activator protein (AP)-1. These results indicate that the LicE inhibition of NF-κB and AP-1 transcriptional activity through the inhibition of AKT and MAPK activation contributes to decreases in the expression of pro-inflammatory cytokines and the inducible enzymes iNOS and COX-2.
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16
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Brulle F, Jeffroy F, Madec S, Nicolas JL, Paillard C. Transcriptomic analysis of Ruditapes philippinarum hemocytes reveals cytoskeleton disruption after in vitro Vibrio tapetis challenge. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2012; 38:368-76. [PMID: 22450167 DOI: 10.1016/j.dci.2012.03.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Revised: 02/28/2012] [Accepted: 03/06/2012] [Indexed: 02/08/2023]
Abstract
The Manila clam, Ruditapes philippinarum, is an economically-important, commercial shellfish; harvests are diminished in some European waters by a pathogenic bacterium, Vibrio tapetis, that causes Brown Ring disease. To identify molecular characteristics associated with susceptibility or resistance to Brown Ring disease, Suppression Subtractive Hybridization (SSH) analyzes were performed to construct cDNA libraries enriched in up- or down-regulated transcripts from clam immune cells, hemocytes, after a 3-h in vitro challenge with cultured V. tapetis. Nine hundred and ninety eight sequences from the two libraries were sequenced, and an in silico analysis identified 235 unique genes. BLAST and "Gene ontology" classification analyzes revealed that 60.4% of the Expressed Sequence Tags (ESTs) have high similarities with genes involved in various physiological functions, such as immunity, apoptosis and cytoskeleton organization; whereas, 39.6% remain unidentified. From the 235 unique genes, we selected 22 candidates based upon physiological function and redundancy in the libraries. Then, Real-Time PCR analysis identified 3 genes related to cytoskeleton organization showing significant variation in expression attributable to V. tapetis exposure. Disruption in regulation of these genes is consistent with the etiologic agent of Brown Ring disease in Manila clams.
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Affiliation(s)
- Franck Brulle
- Laboratoire des Sciences de l'Environnement Marin (LEMAR), UMR CNRS 6539, IUEM, Technopole Brest-Iroise, 29280 Plouzané, France
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17
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Lee YM, Cho HJ, Ponnuraj SP, Kim J, Kim JS, Kim SG, Park JHY. Phenethyl isothiocyanate inhibits 12-O-tetradecanoylphorbol-13-acetate-induced inflammatory responses in mouse skin. J Med Food 2011; 14:377-85. [PMID: 21303260 DOI: 10.1089/jmf.2010.1296] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Phenethyl isothiocyanate (PITC) is the hydrolysis product of the glucosinolate gluconasturtiin in cruciferous vegetables. This study was conducted to determine whether PITC inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation in the mouse ear. Topical application of 5 nmol of TPA to mouse ears markedly increased the ear weight, expression of the inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 protein, and phosphorylation of the inhibitor of κB (IκB) α, AKT, and extracellular signal-regulated protein kinase (ERK) 1/2 and reduced IκBα protein levels. Pretreatment with PITC (150-450 nmol) significantly suppressed these TPA-induced inflammatory responses. We also determined whether low concentrations of PITC (0.5-5 μmol/L) inhibited lipopolysaccharide (LPS)-stimulated inflammatory responses in Raw264.7 cells. PITC dose-dependently reduced the LPS-induced secretion of nitric oxide, prostaglandin E(2), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, as well as COX-2 and iNOS protein expression. PITC also attenuated LPS-induced increases in iNOS, COX-2, IL- 6, IL-1β, and TNF-α mRNA levels, as well as the promoter-dependent transcriptional activation of the genes for iNOS and COX-2. PITC inhibited LPS-induced IκBα phosphorylation and degradation and subsequently reduced LPS-induced p65 nuclear translocation and the transcriptional activity of nuclear factor-κB (NF-κB), which was accompanied by a reduction in ERK1/2 and AKT phosphorylation. The results of this study demonstrated that PITC effectively inhibits inflammatory responses in vivo and in vitro, which may be mediated via the inhibition of AKT and ERK1/2 activation, leading to subsequent inhibition of the transcriptional activity of NF-κB.
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Affiliation(s)
- Yeo Myeong Lee
- Department of Food Science and Nutrition, Hallym University, Chuncheon, Republic of Korea
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18
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Park HJ, Han ES, Park DK, Lee C, Lee KW. An extract of Phellinus linteus grown on germinated brown rice inhibits inflammation markers in RAW264.7 macrophages by suppressing inflammatory cytokines, chemokines, and mediators and up-regulating antioxidant activity. J Med Food 2010; 13:1468-77. [PMID: 20874228 DOI: 10.1089/jmf.2010.1131] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The immunomodulatory activity of an organic extract of Phellinus linteus grown on slightly germinated brown rice (PBR) was previously demonstrated. Here, we investigated the possible anti-inflammatory activity of the PBR extract by analyzing its effect on the expression of macrophage-derived cytokines, chemokines, and mediator genes that participate in immune and inflammatory responses and diseases. The extract profoundly inhibited the induction of cytokines and chemokines, including tumor necrosis factor-α, chemokine (C-X-C motif) ligand-10, granulocyte-macrophage colony-stimulating factor, and interleukin-6, in lipopolysaccharide (LPS)-stimulated RAW264.7 mouse macrophage cells. It also greatly inhibited LPS-stimulated production of nitric oxide (NO) and prostaglandin E(2) in RAW264.7 cells by suppressing the expression of inducible NO synthase and cyclooxygenase-2. PBR extract inhibited NO production with a twofold lower half-maximal inhibitory concentration value than P. linteus extract. To elucidate the underlying mechanism of action, we examined the effect of the PBR extract on the LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs) in RAW264.7 cells. PBR extract greatly inhibited extracellular signal-regulated kinase and c-Jun N-terminal kinase phosphorylation and slightly inhibited p38 MAPK phosphorylation. It also significantly increased intracellular glutathione peroxidase activity and heme oxygenase-1 protein expression. Thus, the PBR extract has anti-inflammatory activity in LPS-stimulated RAW264.7 cells by virtue of its ability to suppress the production of inflammatory cytokines and chemokines via inhibition of MAPK activation and up-regulation of antioxidant activities.
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Affiliation(s)
- Hye-Jin Park
- Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea.
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19
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Hexane/ethanol extract of Glycyrrhiza uralensis licorice exerts potent anti-inflammatory effects in murine macrophages and in mouse skin. Food Chem 2010. [DOI: 10.1016/j.foodchem.2010.01.027] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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20
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Benzyl isothiocyanate exhibits anti-inflammatory effects in murine macrophages and in mouse skin. J Mol Med (Berl) 2009; 87:1251-61. [DOI: 10.1007/s00109-009-0532-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2009] [Revised: 08/07/2009] [Accepted: 08/28/2009] [Indexed: 01/24/2023]
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21
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Chiu WT, Lin YL, Chou CW, Chen RM. Propofol inhibits lipoteichoic acid-induced iNOS gene expression in macrophages possibly through downregulation of toll-like receptor 2-mediated activation of Raf-MEK1/2-ERK1/2-IKK-NFkappaB. Chem Biol Interact 2009; 181:430-9. [PMID: 19573522 DOI: 10.1016/j.cbi.2009.06.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2009] [Revised: 06/19/2009] [Accepted: 06/22/2009] [Indexed: 01/30/2023]
Abstract
Our previous study showed that propofol suppressed Gram-negative bacterial LPS-induced NO biosynthesis. Lipoteichoic acid (LTA), an outer membrane component of Gram-positive bacteria, can induce septic shock. This study was further aimed to evaluate the effects of propofol on LTA-induced iNOS gene expression in macrophages and its possible molecular mechanisms. Exposure of macrophages to LTA increased production of nitrite and intracellular reactive oxygen species, but propofol reduced such enhancements in concentration- and time-dependent manners. Treatment of macrophages with LTA-induced iNOS mRNA and protein productions. Meanwhile, propofol at a clinically relevant concentration of 50 microM significantly inhibited LTA-caused augmentations of iNOS mRNA and protein syntheses. In parallel, exposure to LTA increased translocation of nuclear factor-kappa B (NFkappaB) from the cytoplasm to nuclei. Propofol at 50 microM decreased such translocation. Analyses by an electrophoretic mobility shift and reporter gene further showed that propofol could alleviate LTA-induced transactivation of NFkappaB. Sequentially, propofol decreased phosphorylation of IKK, ERK1/2, MEK1/2, and Raf in LTA-stimulated macrophages. Application of toll-like receptor 2 (TLR2) small interference (si)RNA decreased the translation of this receptor and Raf phosphorylation in LTA-stimulated macrophages. Co-treatment with propofol and TLR2 siRNA synergistically ameliorated LTA-induced iNOS mRNA expression and nitrite production. Thus, this study shows that propofol can downregulate NO biosynthesis via inhibiting iNOS gene expression. The suppressive mechanism occurs possibly through reduction of TLR2-mediated sequential activation of Raf-MEK1/2-ERK1/2-IKK-NFkappaB.
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Affiliation(s)
- Wen-Ta Chiu
- Department of Neurosurgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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22
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McMaster SK, Paul-Clark MJ, Walters M, Fleet M, Anandarajah J, Sriskandan S, Mitchell JA. Cigarette smoke inhibits macrophage sensing of Gram-negative bacteria and lipopolysaccharide: relative roles of nicotine and oxidant stress. Br J Pharmacol 2008; 153:536-43. [PMID: 18059323 PMCID: PMC2241791 DOI: 10.1038/sj.bjp.0707595] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2007] [Revised: 06/22/2007] [Accepted: 10/30/2007] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND AND PURPOSE Smoking cigarettes is a major risk factor for the development of cardiovascular and respiratory disease. Moreover, smokers are more prone to infections. This has been associated with a suppression of the immune system by smoke. However, it is not clear how cigarette smoke affects the ability of immune cells to sense pathogens. Cigarette smoke contains a large number of molecules which may mediate responses on immune cells and of these, nicotine and oxidants have both been identified as inhibitory for the sensing of bacterial lipopolysaccharide (LPS). Nitric oxide synthase (NOS) and tumour necrosis factor (TNF)-alpha are both induced in macrophages on stimulation with Gram negative bacteria or LPS. EXPERIMENTAL APPROACH We used murine macrophages stimulated with whole heat-killed bacteria or LPS. We measured output of NO (as nitrite) and TNFalpha, NOS protein by Western blotting and cellular oxidant stress. KEY RESULTS Cigarette smoke extract suppressed the ability of murine macrophages to release NO, but not TNFalpha in response to whole bacteria. Cigarette smoke extract also inhibited nitric oxide synthase II protein expression in response to LPS. The effects of cigarette smoke extract on nitrite formation stimulated by LPS were unaffected by inhibition of nicotinic receptors with alpha-bungarotoxin (100 units ml(-1)). However, the effects of cigarette smoke extract on LPS-induced nitrite formation were mimicked by hydrogen peroxide and reversed by the anti-oxidants N-acetyl cysteine and glutathione. CONCLUSIONS AND IMPLICATIONS We suggest that cigarette smoke exerts its immunosuppressive effects through an oxidant-dependent and not a nicotine-dependent mechanism.
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Affiliation(s)
- S K McMaster
- Department of Cardiothoracic Pharmacology, Unit of Critical Care Medicine, Cardiac Medicine, Royal Brompton Hospital, National Heart and Lung Institute London, UK
| | - M J Paul-Clark
- Department of Cardiothoracic Pharmacology, Unit of Critical Care Medicine, Cardiac Medicine, Royal Brompton Hospital, National Heart and Lung Institute London, UK
| | | | - M Fleet
- Department of Cardiothoracic Pharmacology, Unit of Critical Care Medicine, Cardiac Medicine, Royal Brompton Hospital, National Heart and Lung Institute London, UK
| | - J Anandarajah
- Department of Cardiothoracic Pharmacology, Unit of Critical Care Medicine, Cardiac Medicine, Royal Brompton Hospital, National Heart and Lung Institute London, UK
| | - S Sriskandan
- Department of Infectious Diseases and Immunity, Hammersmith Hospital, Imperial College London London, UK
| | - J A Mitchell
- Department of Cardiothoracic Pharmacology, Unit of Critical Care Medicine, Cardiac Medicine, Royal Brompton Hospital, National Heart and Lung Institute London, UK
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Cho HJ, Seon MR, Lee YM, Kim J, Kim JK, Kim SG, Park JHY. 3,3'-Diindolylmethane suppresses the inflammatory response to lipopolysaccharide in murine macrophages. J Nutr 2008; 138:17-23. [PMID: 18156398 DOI: 10.1093/jn/138.1.17] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
3,3'-Diindolylmethane (DIM), a major acid-condensation product of indole-3-carbinol, has been shown to have multiple anticancer effects in experimental models. Because recurrent or chronic inflammation has been implicated in the development of a variety of human cancers, this study examined the antiinflammatory effects of DIM and the underlying mechanisms using lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages. DIM significantly decreased the release of nitric oxide (NO), prostaglandin (PG)E2, tumor necrosis factor alpha, interleukin (IL)-6, and IL-1beta by RAW264.7 cells treated with LPS. DIM inhibited LPS-induced increases in protein levels of inducible NO synthase (iNOS), which were accompanied by decreased iNOS mRNA levels and transcriptional activity. The mRNA levels of phospholipase A2 decreased, whereas neither cyclooxygenases-2 protein nor transcript was altered by DIM. In addition, DIM suppressed LPS-induced nuclear factor-kappaB (NF-kappaB) transcriptional activity, NF-kappaB DNA-binding activity, translocation of p65 (RelA) to the nucleus, and degradation of inhibitor of kappaB alpha. Furthermore, DIM decreased LPS-induced transcriptional activity of activator protein (AP)-1, AP-1 DNA-binding activity, and phosphorylation of stress-activated protein kinase/Jun-N-terminal kinase and c-Jun. We demonstrate that DIM inhibits LPS-induced release of proinflammatory mediators in murine macrophages. Downregulation of NF-kappaB and AP-1 signaling may be one of the mechanisms by which DIM inhibits inflammatory responses.
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Affiliation(s)
- Han Jin Cho
- Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University, Chuncheon 200-702, South Korea
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Pingle SC, Jajoo S, Mukherjea D, Sniderhan LF, Jhaveri KA, Marcuzzi A, Rybak LP, Maggirwar SB, Ramkumar V. Activation of the adenosine A1 receptor inhibits HIV-1 tat-induced apoptosis by reducing nuclear factor-kappaB activation and inducible nitric-oxide synthase. Mol Pharmacol 2007; 72:856-67. [PMID: 17609415 DOI: 10.1124/mol.106.031427] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Human immunodeficiency virus dementia (HIV-D) is a nonfocal central nervous system manifestation characterized by cognitive, behavioral, and motor abnormalities. The pathophysiology of neuronal damage in HIV-D includes a direct toxic effect of viral proteins on neuronal cells and an indirect effect caused by the release of inflammatory mediators and neurotoxins by activated macrophages/microglia and astrocytes, culminating into neuronal apoptosis. Previous studies have documented that the nucleoside adenosine mediates neuroprotection by activating adenosine A(1) receptor subtype (A(1)AR) linked to suppression of neuronal excitability. In this study, we show that A(1)AR activation protects against HIV-1 Tat-induced toxicity in primary cultures of rat cerebellar granule neurons and in rat pheochromocytoma (PC12) cell. In PC12 cells, HIV-1 Tat increased [Ca(2+)](i) levels, release of nitric oxide (NO), and expression of inducible nitric-oxide synthase (iNOS) and A(1)AR. Activation of A(1)AR suppressed Tat-mediated increases in [Ca(2+)](i) and NO. Furthermore, A(1)AR agonists inhibited iNOS expression in a nuclear factor-kappaB (NF-kappaB)-dependent manner. It is noteworthy that activation of the A(1)AR or inhibition of NOS protected against Tat-induced apoptosis in PC12 cells and cerebellar granule cells. Moreover, activation of the A(1)AR-inhibited Tat-induced increases in the levels of proapoptotic proteins Bax and caspase-3. Taken together, our results demonstrate that the A(1)AR protects against HIV-1 toxicity by inhibiting NF-kappaB, thereby reducing the expression of iNOS and NO radicals and neuronal apoptosis.
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Affiliation(s)
- Sandeep C Pingle
- Department of Pharmacology, Southern Illinois University School of Medicine, PO Box 19629, Springfield, IL 62794-9629, USA
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Ramery E, Closset R, Bureau F, Art T, Lekeux P. Relevance of using a human microarray to study gene expression in heaves-affected horses. Vet J 2007; 177:216-21. [PMID: 17574458 DOI: 10.1016/j.tvjl.2007.04.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2007] [Revised: 04/27/2007] [Accepted: 04/28/2007] [Indexed: 11/16/2022]
Abstract
Environmental causes of heaves are well described, but the molecular mechanisms of the disease remain unclear. Previous studies have highlighted the implications of variations in gene expression, most using reverse transcription polymerase chain reaction (RT-PCR). This well-known technique limits the number of genes that can be studied in a single assay. Microarray appears to be a valuable tool to by-pass this limitation, but so far there has been no equine-specific microarray available on the market. The present study was performed to determine whether a human microarray could be used to study gene expression in nucleated cells originating from peripheral blood and bronchoalveolar lavage fluid (BALF) in heaves-affected horses. With a four-fold cut-off, a total of 46 candidates were identified with differentially regulated genes between heaves-affected horses and controls. A real-time quantitative RT-PCR (RT-QPCR) conducted on a selection of genes, determined on the basis of previous publications, was used to validate the microarray results. The microarray failed to detect the presence of interleukin (IL)-1beta and IL-8 mRNA in the nucleated cells from BALF otherwise confirmed by real-time RT-QPCR. Although some candidate genes have been identified using this method, a complete expression profile of genes related to heaves could not be obtained with the use of the human microarray.
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Affiliation(s)
- Eve Ramery
- Department for Functional Sciences, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.
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Kaliora AC, Stathopoulou MG, Triantafillidis JK, Dedoussis GVZ, Andrikopoulos NK. Chios mastic treatment of patients with active Crohn’s disease. World J Gastroenterol 2007; 13:748-53. [PMID: 17278198 PMCID: PMC4066008 DOI: 10.3748/wjg.v13.i5.748] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effectiveness of mastic administration on the clinical course and plasma inflammatory mediators of patients with active Crohn’s disease (CD).
METHODS: This pilot study was conducted in patients with established mild to moderately active CD, attending the outpatient clinics of the hospital, and in healthy controls. Ten patients and 8 controls were recruited for a 4-wk treatment with mastic caps (6 caps/d, 0.37 g/cap). All patients successfully completed the protocol. CD Activity Index (CDAI), Nutritional Risk Index (NRI), C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), and total antioxidant potential (TAP) were evaluated in the plasma at baseline and at the end of the treatment period. Results were expressed as mean values ± SE and P < 0.05 was considered to indicate statistical significance.
RESULTS: Patients exhibited significant reduction of CDAI (222.9 ± 18.7 vs 136.3 ± 12.3, P = 0.05) as compared to pretreament values. Plasma IL-6 was significantly decreased (21.2 ± 9.3 pg/mL vs 7.2 ± 2.8 pg/ mL, P = 0.027), and so did CRP (40.3 ± 13.1 mg/mL vs 19.7 ± 5.5, P = 0.028). TAP was significantly increased (0.15 ± 0.09 vs 0.57 ± 0.15 mmol/L uric acid, P = 0.036). No patient or control exhibited any kind of side effects.
CONCLUSION: The results suggest that mastic significantly decreased the activity index and the plasma levels of IL-6 and CRP in patients with mildly to moderately active CD. Further double-blind, placebo-controlled studies in a larger number of patients are required to clarify the role of this natural product in the treatment of patients with CD.
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Affiliation(s)
- Andriana C Kaliora
- Department of Science of Dietetics-Nutrition, Harokopio University of Athens, 70 El. Venizelou ave., Kallithea 17671, Athens, Greece.
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Kang KW, Wagley Y, Kim HW, Pokharel YR, Chung YY, Chang IY, Kim JJ, Moon JS, Kim YK, Nah SY, Kang HS, Oh JW. Novel role of IL-6/SIL-6R signaling in the expression of inducible nitric oxide synthase (iNOS) in murine B16, metastatic melanoma clone F10.9, cells. Free Radic Biol Med 2007; 42:215-27. [PMID: 17189827 DOI: 10.1016/j.freeradbiomed.2006.10.034] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2006] [Revised: 09/15/2006] [Accepted: 10/08/2006] [Indexed: 12/27/2022]
Abstract
Inducible nitric oxide synthase (iNOS) has been shown to be frequently expressed in melanomas; up-regulation of this enzyme is though to be associated with tumor progression. In this study, we investigated whether diverse cytokines such as: IL-6, TNF-alpha, IL-1beta, IFN-gamma and IL6RIL6 (a highly active fusion protein of the soluble form of the IL-6R (sIL-6R) and IL-6) enhance the iNOS gene expression in B16/F10.9 murine metastatic melanoma cells. An increase at iNOS expression and NO production was observed with the co-treatment of IL6RIL6 plus TNF-alpha. Gel shift and reporter gene analyses revealed that IL6RIL6 selectively activated AP-1; while TNF-alpha increased the activities of both NF-kappaB and AP-1. Persistent activation of AP-1 was also seen in cells treated with IL6RIL6 plus TNF-alpha. Stimulation of cells with IL6RIL6/TNF-alpha resulted in the activation of mitogen-activated protein kinases (MAPK) such as c-Jun N-terminal kinase (JNK) and p38, and the abrogation by pretreatment with JNK or p38 MAPK inhibitor. IL6RIL6 or IL6RIL6/TNFalpha-inducible AP-1 binding increase was supershifted by anti-c-Jun or c-Fos antibodies, and the activation of c-Jun and c-Fos was dependent on JNK and p38, respectively. These results suggest that IL-6/sIL-6R/gp130 complex signaling has an unexpected positive effect on iNOS gene expression through JNK/p38 MAPK mediated-AP-1 activation in melanoma cells.
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Affiliation(s)
- Keon Wook Kang
- College of Pharmacy, Chosun University, Gwangju 501-759, Korea
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