Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Immune-Endocrine Cross-Talk in Reproductive Biology and Pathology Thu, 24 Apr 2014 07:23:51 +0000 António M. Galvão, Graça M. Ferreira-Dias, Anna Chełmonska-Soyta, Izabela Wocławek-Potocka, and Dariusz J. Skarżyński Copyright © 2014 António M. Galvão et al. All rights reserved. Activation of Adenosine A3 Receptor Alleviates TNF-α-Induced Inflammation through Inhibition of the NF-κB Signaling Pathway in Human Colonic Epithelial Cells Tue, 22 Apr 2014 09:27:29 +0000 To investigate the expression of adenosine A3 receptor (A3AR) in human colonic epithelial cells and the effects of A3AR activation on tumor necrosis factor alpha (TNF-α-) induced inflammation in order to determine its mechanism of action in human colonic epithelial cells, human colonic epithelial cells (HT-29 cells) were treated with different concentrations of 2-Cl-IB-MECA prior to TNF-α stimulation, followed by analysis of NF-κB signaling pathway activation and downstream IL-8 and IL-1β production. A3AR mRNA and protein were expressed in HT-29 cells and not altered by changes in TNF-α or 2-Cl-IB-MECA. Pretreatment with 2-Cl-IB-MECA prior to stimulation with TNF-α attenuated NF-κB p65 nuclear translocation as p65 protein decreased in the nucleus of cells and increased in the cytoplasm, inhibited the degradation of IκB-α, and reduced phosphorylated-IκB-α level significantly, compared to TNF-α-only-treated groups. Furthermore, 2-Cl-IB-MECA significantly decreased TNF-α-stimulated IL-8 and IL-1β mRNA expression and secretion, compared to the TNF-α-only treated group. These results confirm that A3AR is expressed in human colonic epithelial cells and demonstrate that its activation has an anti-inflammatory effect, through the inhibition of NF-κB signaling pathway, which leads to inhibition of downstream IL-8 and IL-1β expression. Therefore, A3AR activation may be a potential treatment for gut inflammatory diseases such as inflammatory bowel disease. Tianhua Ren, Yumei Qiu, Weiyun Wu, Xiao Feng, Shicai Ye, Zhuang Wang, Ting Tian, Yanting He, Caiyuan Yu, and Yu Zhou Copyright © 2014 Tianhua Ren et al. All rights reserved. Chemokine CXCL16 Expression Suppresses Migration and Invasiveness and Induces Apoptosis in Breast Cancer Cells Tue, 22 Apr 2014 00:00:00 +0000 Background. Increasing evidence argues that soluble CXCL16 promotes proliferation, migration, and invasion of cancer cells in vitro. However, the role of transmembrane or cellular CXCL16 in cancer remains relatively unknown. In this study, we determine the function of cellular CXCL16 as tumor suppressor in breast cancer cells. Methods. Expression of cellular CXCL16 in breast cancer cell lines was determined at both RNA and protein levels. In vitro and in vivo studies that overexpressed or downregulated CXCL16 were conducted in breast cancer cells. Results. We report differential expression of cellular CXCL16 in breast cancer cell lines that was negatively correlated with cell invasiveness and migration. Overexpression of CXCL16 in MDA-MB-231 cells led to a decrease in cell invasion and migration and induced apoptosis of the cells; downregulation of CXCL16 in MCF-7 cells increased cell migration and invasiveness. Consistent with the in vitro data, CXCL16 overexpression inhibited tumorigenesis in vivo. Conclusions. Cellular CXCL16 suppresses invasion and metastasis of breast cancer cells in vitro and inhibits tumorigenesis in vivo. Targeting of cellular CXCL16 expression is a potential therapeutic strategy for breast cancer. Yeying Fang, Fraser C. Henderson Jr., Qiong Yi, Qianqian Lei, Yan Li, and Nianyong Chen Copyright © 2014 Yeying Fang et al. All rights reserved. Physical Exercise Reduces the Expression of RANTES and Its CCR5 Receptor in the Adipose Tissue of Obese Humans Thu, 17 Apr 2014 16:46:47 +0000 RANTES and its CCR5 receptor trigger inflammation and its progression to insulin resistance in obese. In the present study, we investigated for the first time the effect of physical exercise on the expression of RANTES and CCR5 in obese humans. Fifty-seven adult nondiabetic subjects (17 lean and 40 obese) were enrolled in a 3-month supervised physical exercise. RANTES and CCR5 expressions were measured in PBMCs and subcutaneous adipose tissue before and after exercise. Circulating plasma levels of RANTES were also investigated. There was a significant increase in RANTES and CCR5 expression in the subcutaneous adipose tissue of obese compared to lean. In PBMCs, however, while the levels of RANTES mRNA and protein were comparable between both groups, CCR5 mRNA was downregulated in obese subjects (). Physical exercise significantly reduced the expression of both RANTES and CCR5 () in the adipose tissue of obese individuals with a concomitant decrease in the levels of the inflammatory markers TNF-α, IL-6, and P-JNK. Circulating RANTES correlated negatively with anti-inflammatory IL-1ra () and positively with proinflammatory IP-10 and TBARS levels (). Therefore, physical exercise may provide an effective approach for combating the deleterious effects associated with obesity through RANTES signaling in the adipose tissue. Engin Baturcam, Jehad Abubaker, Ali Tiss, Mohamed Abu-Farha, Abdelkrim Khadir, Fahad Al-Ghimlas, Irina Al-Khairi, Preethi Cherian, Naser Elkum, Maha Hammad, Jeena John, Sina Kavalakatt, Cynthia Lehe, Samia Warsame, Kazem Behbehani, Said Dermime, and Mohammed Dehbi Copyright © 2014 Engin Baturcam et al. All rights reserved. Protective Effect of Astaxanthin on Liver Fibrosis through Modulation of TGF-1 Expression and Autophagy Thu, 17 Apr 2014 13:10:30 +0000 Liver fibrosis is a common pathway leading to cirrhosis and a worldwide clinical issue. Astaxanthin is a red carotenoid pigment with antioxidant, anticancer, and anti-inflammatory properties. The aim of this study was to investigate the effect of astaxanthin on liver fibrosis and its potential protective mechanisms. Liver fibrosis was induced in a mouse model using CCL4 (intraperitoneal injection, three times a week for 8 weeks), and astaxanthin was administered everyday at three doses (20, 40, and 80 mg/kg). Pathological results indicated that astaxanthin significantly improved the pathological lesions of liver fibrosis. The levels of alanine aminotransferase aspartate aminotransferase and hydroxyproline were also significantly decreased by astaxanthin. The same results were confirmed in bile duct liagtion, (BDL) model. In addition, astaxanthin inhibited hepatic stellate cells (HSCs) activation and formation of extracellular matrix (ECM) by decreasing the expression of NF-B and TGF-1 and maintaining the balance between MMP2 and TIMP1. In addition, astaxanthin reduced energy production in HSCs by downregulating the level of autophagy. These results were simultaneously confirmed in vivo and in vitro. In conclusion, our study showed that 80 mg/kg astaxanthin had a significant protective effect on liver fibrosis by suppressing multiple profibrogenic factors. Miao Shen, Kan Chen, Jie Lu, Ping Cheng, Ling Xu, Weiqi Dai, Fan Wang, Lei He, Yan Zhang, Wang Chengfen, Jingjing Li, Jing Yang, Rong Zhu, Huawei Zhang, Yuanyuan Zheng, Yingqun Zhou, and Chuanyong Guo Copyright © 2014 Miao Shen et al. All rights reserved. Angiogenin Reduces Immune Inflammation via Inhibition of TANK-Binding Kinase 1 Expression in Human Corneal Fibroblast Cells Thu, 17 Apr 2014 06:45:00 +0000 Angiogenin (ANG) is reportedly multifunctional, with roles in angiogenesis and autoimmune diseases. This protein is involved in the innate immune system and has been implicated in several inflammatory diseases. Although ANG may be involved in the anti-inflammatory response, there is no evidence that it has direct anti-inflammatory effects. In this study we sought to determine whether ANG has an anti-inflammatory effect in human corneal fibroblasts (HCFs) exposed to media containing tumor necrosis factor-alpha (TNF-α). We found that ANG reduced the mRNA expression of interleukin-1 beta (IL-1β), -6, -8 and TNF-α receptors (TNFR) 1 and 2. In contrast, ANG increased the mRNA expression of IL-4 and -10. Protein levels of TANK-binding kinase 1 (TBK1) were reduced by ANG in HCFs treated with TNF-α. Moreover, ANG diminished the expression of IL-6 and -8 and monocyte chemotactic protein- (MCP-) 1. The protein expression of nuclear factor-κB (NF-κB) was downregulated by ANG treatment. These findings suggest that ANG suppressed the TNF-α-induced inflammatory response in HCFs through inhibition of TBK1-mediated NF-κB nuclear translocation. These novel results are likely to play a significant role in the selection of immune-mediated inflammatory therapeutic targets and may shed light on the pathogenesis of immune-mediated inflammatory diseases. Seung Hoon Lee, Kyoung Woo Kim, Kyong-Mi Min, Kyu-Wan Kim, Soo-Ik Chang, and Jae Chan Kim Copyright © 2014 Seung Hoon Lee et al. All rights reserved. Astrocyte Elevated Gene-1 Mediates Glycolysis and Tumorigenesis in Colorectal Carcinoma Cells via AMPK Signaling Wed, 16 Apr 2014 15:57:29 +0000 To investigate the role of AEG-1 in glycolysis and tumorigenesis, we construct myc-AEG-1 expression vector and demonstrate a novel mechanism that AEG-1 may increase the activity of AMPK by Thr172 phosphorylation. The higher expression levels of AEG-1 in colorectal carcinoma cells were found but showed significant difference in different cell lines. To study the role of AEG-1 in colorectal cells, myc-AEG-1 vector was constructed and transfected into NCM460 colonic epithelial cells. We observed consistent increasing of glucose consumption and lactate production, typical features of anaerobic glycolysis, suggesting that AEG-1 may promote anaerobic glycolysis. Moreover, we noted that AMPK phosphorylation at Thr172 as well as pPFK2 (Ser466) was increased in NCM460 cells overexpressing AEG-1. Compound C may block AMPK and PFK2 phosphorylation in both control and AEG-1-overexpressed cells and decrease the glucose consumption and lactate production. The present findings indicated that reduced AEG-1 protein levels by RNAi may decrease the glucose consumption and lactate production in HCT116 colorectal carcinoma cells. The present identified AEG-1/AMPK/PFK2 glycolysis cascade may be essential to cell proliferation and tumor growth. The present results may provide us with a mechanistic insight into novel targets controlled by AEG-1, and the components in the AEG-1/AMPK/PFK2 glycolysis process may be targeted for the clinical treatment of cancer. Hong-tao Song, Yu Qin, Guo-dong Yao, Zhen-nan Tian, Song-bin Fu, and Jing-shu Geng Copyright © 2014 Hong-tao Song et al. All rights reserved. Korean Red Ginseng Saponin Fraction Rich in Ginsenoside-Rb1, Rc and Rb2 Attenuates the Severity of Mouse Collagen-Induced Arthritis Wed, 16 Apr 2014 15:56:52 +0000 Despite a multitude of reports on anti-inflammatory properties of ginseng extracts or individual ginsenosides, data on antiarthritic effect of ginseng saponin preparation with mixed ginsenosides is limited. On the other hand, a combined therapy of safe and inexpensive plant-derived natural products such as ginsenosides can be considered as an alternative to treat arthritis. Our previous in vitro data displayed a strong anti-inflammatory action of red ginseng saponin fraction-A (RGSF-A). We, herein, report a marked antiarthritic property of RGSF-A rich in ginsenoside Rb1, Rc, and Rb2. Collagen-induced arthritic (CIA) mice were treated with RGSF-A or methotrexate (MTX) for 5 weeks. Joint pathology, serum antibody production and leukocye activation, cytokine production in the circulation, lymph nodes, and joints were examined. RGSF-A markedly reduced severity of arthritis, cellular infiltration, and cartilage damage. It suppressed CD3+/CD69+, CD4+/CD25+, CD8+ T-cell, CD19+, B220/CD23+ B-cell, MHCII+/CD11c+, and Gr-1+/CD11b+ cell activations. It further suppressed anti-CII- or anti-RF-IgG/IgM, TNF-α, IL-1β, IL-17, and IL-6 secretions but stimulated IL-10 levels in the serum, joint, or splenocyte. RGSF-A attenuated arthritis severity, modified leukocyte activations, and restored cytokine imbalances, suggesting that it can be considered as an antiarthritic agent with the capacity to ameliorate the immune and inflammatory responses in CIA mice. Mehari Endale, Eun Ju Im, Joo Young Lee, Sung Dae Kim, Taddesse Yayeh, Yong-Bum Song, Yi-Seong Kwak, Chaekyun Kim, Seung-Hyung Kim, Seong-Soo Roh, Jae Youl Cho, and Man Hee Rhee Copyright © 2014 Mehari Endale et al. All rights reserved. Protective Effects of Pretreatment with Oleanolic Acid in Rats in the Acute Phase of Hepatic Ischemia-Reperfusion Injury: Role of the PI3K/Akt Pathway Wed, 16 Apr 2014 07:59:45 +0000 Oleanolic acid (OA) has been used to treat liver disorders, but whether it can attenuate hepatic ischemia-reperfusion- (IR-) associated liver dysfunction remains unexplored. In the present study, 160 male Sprague-Dawley rats were equally divided into five groups: group SH received neither hepatic IR nor drugs; group IR received hepatic IR without drugs; group CM and group OA received 0.5% sodium carboxymethylcellulose and 100 mg/kg OA, intragastrically, once a day for seven days before the hepatic IR, respectively; on the basis of treatment in group OA, group OA+wortmannin further received 15 g/kg of PI3K inhibitor wortmannin, intraperitoneally, 30 min before the hepatic IR. Then each group was equally divided into four subgroups according to four time points (preoperation, 0 h, 3 h, and 6 h after reperfusion). Serum ALT activity, IL-1 concentration, and hepatic phosphorylation of PI3K, Akt, and GSK-3 protein expression were serially studied. We found that OA pretreatment improved histological status and decreased serum ALT and IL-1 levels. It also increased p-PI3K, p-Akt, and p-GSK-3 protein expression at all the four time points. Prophylactic wortmannin partially reversed OA’s protective effects. The data indicate that OA pretreatment protects liver from IR injury during the acute phase partially through PI3K/Akt-mediated inactivation of GSK-3. Bo Gui, Fuzhou Hua, Jie Chen, Zeping Xu, Hongbin Sun, and Yanning Qian Copyright © 2014 Bo Gui et al. All rights reserved. Change in Growth Differentiation Factor 15, but Not C-Reactive Protein, Independently Predicts Major Cardiac Events in Patients with Non-ST Elevation Acute Coronary Syndrome Tue, 15 Apr 2014 13:25:57 +0000 Among the numerous emerging biomarkers, high-sensitivity C-reactive protein (hsCRP) and growth-differentiation factor-15 (GDF-15) have received widespread interest, with their potential role as predictors of cardiovascular risk. The concentrations of inflammatory biomarkers, however, are influenced, among others, by physiological variations, which are the natural, within-individual variation occurring over time. The aims of our study are: (a) to describe the changes in hsCRP and GDF-15 levels over a period of time and after an episode of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and (b) to examine whether the rate of change in hsCRP and GDF-15 after the acute event is associated with long-term major cardiovascular adverse events (MACE). Two hundred and Fifty five NSTE-ACS patients were included in the study. We measured hsCRP and GDF-15 concentrations, at admission and again 36 months after admission (end of the follow-up period). The present study shows that the change of hsCRP levels, measured after 36 months, does not predict MACE in NSTEACS-patients. However, the level of GDF-15 measured, after 36 months, was a stronger predictor of MACE, in comparison to the acute unstable phase. Alberto Dominguez-Rodriguez, Pedro Abreu-Gonzalez, Idaira F. Hernandez-Baldomero, Pablo Avanzas, and Francisco Bosa-Ojeda Copyright © 2014 Alberto Dominguez-Rodriguez et al. All rights reserved. Bone Remodelling Markers in Rheumatoid Arthritis Tue, 15 Apr 2014 13:13:15 +0000 Bone loss in rheumatoid arthritis (RA) patients results from chronic inflammation and can lead to osteoporosis and fractures. A few bone remodeling markers have been studied in RA witnessing bone formation (osteocalcin), serum aminoterminal propeptide of type I collagen (PINP), serum carboxyterminal propeptide of type I collagen (ICTP), bone alkaline phosphatase (BAP), osteocalcin (OC), and bone resorption: C-terminal telopeptide of type 1 collagen (I-CTX), N-terminal telopeptide of type 1 collagen (I-NTX), pyridinolines (DPD and PYD), and tartrate-resistant acid phosphatase (TRAP). Bone resorption can be seen either in periarticular bone (demineralization and erosion) or in the total skeleton (osteoporosis). Whatever the location, bone resorption results from activation of osteoclasts when the ratio between osteoprotegerin and receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) is decreased under influence of various proinflammatory cytokines. Bone remodeling markers also allow physicians to evaluate the effect of drugs used in RA like biologic agents, which reduce inflammation and exert a protecting effect on bone. We will discuss in this review changes in bone markers remodeling in patients with RA treated with biologics. Patrice Fardellone, Alice Séjourné, Julien Paccou, and Vincent Goëb Copyright © 2014 Patrice Fardellone et al. All rights reserved. Crocin Suppresses LPS-Stimulated Expression of Inducible Nitric Oxide Synthase by Upregulation of Heme Oxygenase-1 via Calcium/Calmodulin-Dependent Protein Kinase 4 Tue, 15 Apr 2014 12:54:47 +0000 Crocin is a water-soluble carotenoid pigment that is primarily used in various cuisines as a seasoning and coloring agent, as well as in traditional medicines for the treatment of edema, fever, and hepatic disorder. In this study, we demonstrated that crocin markedly induces the expression of heme oxygenase-1 (HO-1) which leads to an anti-inflammatory response. Crocin inhibited inducible nitric oxide synthase (iNOS) expression and nitric oxide production via downregulation of nuclear factor kappa B activity in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. These effects were abrogated by blocking of HO-1 expression or activity. Crocin also induced Ca2+ mobilization from intracellular pools and phosphorylation of Ca2+/calmodulin-dependent protein kinase 4 (CAMK4). CAMK4 knockdown and kinase-dead mutant inhibited crocin-mediated HO-1 expression, Nrf2 activation, and phosphorylation of Akt, indicating that HO-1 expression is mediated by CAMK4 and that Akt is a downstream mediator of CAMK4 in crocin signaling. Moreover, crocin-mediated suppression of iNOS expression was blocked by CAMK4 inhibition. Overall, these results suggest that crocin suppresses LPS-stimulated expression of iNOS by inducing HO-1 expression via Ca2+/calmodulin-CAMK4-PI3K/Akt-Nrf2 signaling cascades. Our findings provide a novel molecular mechanism for the inhibitory effects of crocin against endotoxin-mediated inflammation. Ji-Hee Kim, Ga-Young Park, Soo Young Bang, Sun Young Park, Soo-Kyung Bae, and YoungHee Kim Copyright © 2014 Ji-Hee Kim et al. All rights reserved. The Regulation of Inflammatory Mediators in Acute Kidney Injury via Exogenous Mesenchymal Stem Cells Tue, 15 Apr 2014 08:20:04 +0000 Acute kidney injury (AKI) remains to be an independent risk factor for mortality and morbidity. Inflammation is believed to play a major role in the pathophysiology of AKI. Exogenous mesenchymal stem cells (MSCs) are now under extensive investigation as a potential therapy for AKI. Various preclinical studies indicated the beneficial effects of MSCs in alleviating renal injury and accelerating tissue repair. However the mechanisms responsible for these effects are incompletely understood. In the recent years, anti-inflammatory/immunoregulatory properties of MSCs have become one of the important issues in the treatment of AKI. This review will summarize the current literature on the regulation of inflammatory mediators via exogenous MSCs contributing to the recovery from AKI. Tao Du and Ying-Jian Zhu Copyright © 2014 Tao Du and Ying-Jian Zhu. All rights reserved. Lysophosphatidic Acid Signaling in Late Cleavage and Blastocyst Stage Bovine Embryos Tue, 15 Apr 2014 00:00:00 +0000 Lysophosphatidic acid (LPA) is a known cell signaling lipid mediator in reproductive tissues. In the cow, LPA is involved in luteal and early pregnancy maintenance. Here, we evaluated the presence and role of LPA in bovine early embryonic development. In relevant aspects, bovine embryos reflect more closely the scenario occurring in human embryos than the mouse model. Transcription of mRNA and protein expression of enzymes involved in LPA synthesis (ATX and cPLA2) and of LPA receptors (LPAR1–4) were detected in Days 5 and 8 in vitro produced embryos. Embryonic LPA production into culture medium was also detected at both stages of development. Supplementation of culture medium with LPA (10−5 M) between Days 2 and 8 had no effect on embryo yield and quality and on blastocyst relative mRNA abundance of genes involved in prostaglandin synthesis (PTGS2, PGES, and PGFS) and steroidogenesis (3βHSD). However, LPA treatment affected transcription levels of embryo quality markers, decreasing BAX (apoptotic) and increasing BCL2 (antiapoptotic) and IGF2R (growth marker) gene transcription levels. Blastocyst transcription of OCT4 (pluripotency marker) was not affected by LPA stimulation. In conclusion, LPA is an early bovine embryonic autocrine/paracrine signaling mediator, and LPA action may be relevant in early embryo-maternal interactions leading to embryonic survival. Ana Catarina Torres, Dorota Boruszewska, Mariana Batista, Ilona Kowalczyk-Zieba, Patricia Diniz, Emilia Sinderewicz, Jean Sebastian Saulnier-Blache, Izabela Woclawek-Potocka, and Luis Lopes-da-Costa Copyright © 2014 Ana Catarina Torres et al. All rights reserved. Immunomodulatory Effect of Red Onion (Allium cepa Linn) Scale Extract on Experimentally Induced Atypical Prostatic Hyperplasia in Wistar Rats Sun, 13 Apr 2014 16:36:42 +0000 Red onion scales (ROS) contain large amounts of flavonoids that are responsible for the reported antioxidant activity, immune enhancement, and anticancer property. Atypical prostatic hyperplasia (APH) was induced in adult castrated Wistar rats by both s.c. injection of testosterone (0.5 mg/rat/day) and by smearing citral on shaved skin once every 3 days for 30 days. Saw palmetto (100 mg/kg) as a positive control and ROS suspension at doses of 75, 150, and 300 mg/kg/day were given orally every day for 30 days. All medications were started 7 days after castration and along with testosterone and citral. The HPLC profile of ROS methanolic extract displayed two major peaks identified as quercetin and quercetin-4′-β-O-D-glucoside. Histopathological examination of APH-induced prostatic rats revealed evidence of hyperplasia and inflammation with cellular proliferation and reduced apoptosis Immunohistochemistry showed increased tissue expressions of IL-6, IL-8, TNF-α, IGF-1, and clusterin, while TGF-β1 was decreased, which correlates with the presence of inflammation. Both saw palmetto and RO scale treatment have ameliorated these changes. These ameliorative effects were more evident in RO scale groups and were dose dependent. In conclusion, methanolic extract of ROS showed a protective effect against APH induced rats that may be attributed to potential anti-inflammatory and immunomodulatory effects. Ahmed A. Elberry, Shagufta Mufti, Jaudah Al-Maghrabi, Essam Abdel Sattar, Salah A. Ghareib, Hisham A. Mosli, and Salah A. Gabr Copyright © 2014 Ahmed A. Elberry et al. All rights reserved. Actions of Allergens and Mediators in Allergy Sun, 13 Apr 2014 07:46:08 +0000 Shaoheng He, Huiyun Zhang, and Peisong Gao Copyright © 2014 Shaoheng He et al. All rights reserved. ADAM Metallopeptidase Domain 33 (ADAM33): A Promising Target for Asthma Thu, 10 Apr 2014 14:07:29 +0000 Over the last few years, a significant progress has been made in understanding the role of a disintegrin and metalloproteinase 33 (ADAM33) in asthma. The previous observations for the association with asthma have been replicated in over 33 different population samples worldwide. We and others have performed association analysis and meta-analysis and provided further evidence that several polymorphisms in the ADAM33 are risk factors for asthma, especially in the Asian population. Further, several studies have suggested that alterations in epigenetic marks alter the patterns of DNA methylation of ADAM33 and result in potentially adverse biological effects. Finally, while the biological activities of ADAM33 are as yet unknown, ADAM33 may play a possible role in airway remodeling because of its high expression in epithelium, myo/fibroblasts, and airway smooth muscle cells (ASMCs) and its role in promoting angiogenesis and stimulating cell proliferation and differentiation. Thus, ADAM33 represents a promising target for asthma. However, further investigations are clearly needed to discover functional ADAM33 gene polymorphisms and the role of genetic/epigenetic factors in conferring genetic susceptibility to environmental exposure induced asthma as well as biological function in asthma. This, in turn, will unlock the possibility of ADAM33 as a target for asthma therapy. Priya Tripathi, Shally Awasthi, and Peisong Gao Copyright © 2014 Priya Tripathi et al. All rights reserved. Oral Complications in Hematopoietic Stem Cell Recipients: The Role of Inflammation Thu, 10 Apr 2014 12:15:13 +0000 Hematopoietic stem cell transplantation (HSCT) is widely used as a potentially curative treatment for patients with various hematological malignancies, bone marrow failure syndromes, and congenital immune deficiencies. The prevalence of oral complications in both autologous and allogeneic HSCT recipients remains high, despite advances in transplant medicine and in supportive care. Frequently encountered oral complications include mucositis, infections, oral dryness, taste changes, and graft versus host disease in allogeneic HSCT. Oral complications are associated with substantial morbidity and in some cases with increased mortality and may significantly affect quality of life, even many years after HSCT. Inflammatory processes are key in the pathobiology of most oral complications in HSCT recipients. This review article will discuss frequently encountered oral complications associated with HSCT focusing on the inflammatory pathways and inflammatory mediators involved in their pathogenesis. T. M. Haverman, J. E. Raber-Durlacher, W. M. H. Rademacher, S. Vokurka, J. B. Epstein, C. Huisman, M. D. Hazenberg, J. J. de Soet, J. de Lange, and F. R. Rozema Copyright © 2014 T. M. Haverman et al. All rights reserved. Metabolic and Genetic Screening of Electromagnetic Hypersensitive Subjects as a Feasible Tool for Diagnostics and Intervention Wed, 09 Apr 2014 08:06:24 +0000 Growing numbers of “electromagnetic hypersensitive” (EHS) people worldwide self-report severely disabling, multiorgan, non-specific symptoms when exposed to low-dose electromagnetic radiations, often associated with symptoms of multiple chemical sensitivity (MCS) and/or other environmental “sensitivity-related illnesses” (SRI). This cluster of chronic inflammatory disorders still lacks validated pathogenetic mechanism, diagnostic biomarkers, and management guidelines. We hypothesized that SRI, not being merely psychogenic, may share organic determinants of impaired detoxification of common physic-chemical stressors. Based on our previous MCS studies, we tested a panel of 12 metabolic blood redox-related parameters and of selected drug-metabolizing-enzyme gene polymorphisms, on 153 EHS, 147 MCS, and 132 control Italians, confirming MCS altered –0.0001) glutathione-(GSH), GSH-peroxidase/S-transferase, and catalase erythrocyte activities. We first described comparable—though milder—metabolic pro-oxidant/proinflammatory alterations in EHS with distinctively increased plasma coenzyme-Q10 oxidation ratio. Severe depletion of erythrocyte membrane polyunsaturated fatty acids with increased ω6/ω3 ratio was confirmed in MCS, but not in EHS. We also identified significantly altered distribution-versus-control of the CYP2C19*1/*2 SNP variants in EHS, and a 9.7-fold increased risk (OR: 95% C.–74.5) of developing EHS for the haplotype (null)GSTT1 + (null)GSTM1 variants. Altogether, results on MCS and EHS strengthen our proposal to adopt this blood metabolic/genetic biomarkers’ panel as suitable diagnostic tool for SRI. Chiara De Luca, Jeffrey Chung Sheun Thai, Desanka Raskovic, Eleonora Cesareo, Daniela Caccamo, Arseny Trukhanov, and Liudmila Korkina Copyright © 2014 Chiara De Luca et al. All rights reserved. Major Histocompatibility Complex I Mediates Immunological Tolerance of the Trophoblast during Pregnancy and May Mediate Rejection during Parturition Wed, 09 Apr 2014 07:29:09 +0000 During pregnancy in larger mammals, the maternal immune system must tolerate the fetus for months while resisting external infection. This tolerance is facilitated by immunological communication between the fetus and the mother, which is mediated by Major Histocompatibility Complex I (MHC I) proteins, by leukocytes, and by the cytokines secreted by the leukocytes. Fetal-maternal immunological communication also supports pregnancy by inducing physiological changes in the mother. If the mother “misunderstands” the signal sent by the fetus during pregnancy, the fetus will be miscarried or delivered preterm. Unlike any other maternal organ, the placenta can express paternal antigens. At parturition, paternal antigens are known to be expressed in cows and may be expressed in horses, possibly so that the maternal immune system will reject the placenta and help to expel it. This review compares fetal-maternal crosstalk that is mediated by the immune system in three species with pregnancies that last for nine months or longer: humans, cattle, and horses. It raises the possibility that immunological communication early in pregnancy may prepare the mother for successful expulsion of fetal membranes at parturition. Anna Rapacz-Leonard, Małgorzata Dąbrowska, and Tomasz Janowski Copyright © 2014 Anna Rapacz-Leonard et al. All rights reserved. Sitagliptin Prevents Inflammation and Apoptotic Cell Death in the Kidney of Type 2 Diabetic Animals Tue, 08 Apr 2014 09:07:54 +0000 This study aimed to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in preventing the deleterious effects of diabetes on the kidney in an animal model of type 2 diabetes mellitus; the Zucker diabetic fatty (ZDF) rat: 20-week-old rats were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks. Glycaemia and blood levels were monitored, as well as kidney function and lesions. Kidney mRNA and/or protein content/distribution of DPP-IV, GLP-1, GLP-1R, TNF-, IL-1, BAX, Bcl-2, and Bid were evaluated by RT-PCR and/or western blotting/immunohistochemistry. Sitagliptin treatment improved glycaemic control, as reflected by the significantly reduced levels of glycaemia and (by about 22.5% and 1.2%, resp.) and ameliorated tubulointerstitial and glomerular lesions. Sitagliptin prevented the diabetes-induced increase in DPP-IV levels and the decrease in GLP-1 levels in kidney. Sitagliptin increased colocalization of GLP-1 and GLP-1R in the diabetic kidney. Sitagliptin also decreased IL-1 and TNF- levels, as well as, prevented the increase of BAX/Bcl-2 ratio, Bid protein levels, and TUNEL-positive cells which indicates protective effects against inflammation and proapoptotic state in the kidney of diabetic rats, respectively. In conclusion, sitagliptin might have a major role in preventing diabetic nephropathy evolution due to anti-inflammatory and antiapoptotic properties. Catarina Marques, Cristina Mega, Andreia Gonçalves, Paulo Rodrigues-Santos, Edite Teixeira-Lemos, Frederico Teixeira, Carlos Fontes-Ribeiro, Flávio Reis, and Rosa Fernandes Copyright © 2014 Catarina Marques et al. All rights reserved. Inhibition of Age-Related Cytokines Production by ATGL: A Mechanism Linked to the Anti-Inflammatory Effect of Resveratrol Tue, 08 Apr 2014 08:39:07 +0000 Ageing is characterized by the expansion and the decreased vascularization of visceral adipose tissue (vAT), disruption of metabolic activities, and decline of the function of the immune system, leading to chronic inflammatory states. We previously demonstrated that, in vAT of mice at early state of ageing, adipocytes mount a stress resistance response consisting in the upregulation of ATGL, which is functional in restraining the production of inflammatory cytokines. Here, we found that, in the late phase of ageing, such an adaptive response is impaired. In particular, 24-months-old mice and aged 3T3-L1 adipocytes display affected expression of ATGL and its downstream PPARα-mediated lipid signalling pathway, leading to upregulation of TNFα and IL-6 production. We show that the natural polyphenol compound resveratrol (RSV) efficiently suppresses the expression of TNFα and IL-6 in an ATGL/PPARα dependent manner. Actually, adipocytes downregulating ATGL do not show a restored PPARα expression and display elevated cytokines production. Overall the results obtained highlight a crucial function of ATGL in inhibiting age-related inflammation and reinforce the idea that RSV could represent a valid natural compound to limit the onset and/or the exacerbation of the age-related inflammatory states. Daniele Lettieri Barbato, Giuseppe Tatulli, Katia Aquilano, and Maria R. Ciriolo Copyright © 2014 Daniele Lettieri Barbato et al. All rights reserved. A Polymorphism of ORAI1 rs7135617, Is Associated with Susceptibility to Rheumatoid Arthritis Tue, 08 Apr 2014 00:00:00 +0000 Rheumatoid arthritis (RA), a chronic inflammatory disease usually occurring in synovial tissues and joints, is highly associated with genetic and environmental factors. ORAI1, a gene related to cellular immune system, has been shown to be involved in the pathogenesis of chronic inflammatory diseases and immune diseases. To identify whether ORAI1 gene contributes to RA susceptibility, we enrolled 400 patients with RA and 621 healthy individuals for a case-control genetic association study. Five tagging single nucleotides polymorphisms (tSPNs) within ORAI1 gene were selected for genotyping. An SNP, rs7135617, showed a significant correlation with the risk of RA. Our results indicated that genetic polymorphism of ORAI1 gene is involved in the susceptibility of RA in a Taiwanese population. Jeng-Hsien Yen, Che-Mai Chang, Yu-Wen Hsu, Chih-Hung Lee, Mei-Shin Wu, Daw-Yang Hwang, Ben-Kuen Chen, Hsien-Tzung Liao, Man-Tzu Marcie Wu, and Wei-Chiao Chang Copyright © 2014 Jeng-Hsien Yen et al. All rights reserved. Salidroside Attenuates Concanavalin A-Induced Hepatitis via Modulating Cytokines Secretion and Lymphocyte Migration in Mice Mon, 07 Apr 2014 14:06:05 +0000 Salidroside, isolated from the medicinal plant Rhodiola, was reported to serve as an “adaptogen.” This study was designed to explore the protective effect of salidroside on concanavalin A- (Con A-) induced hepatitis in mice and investigate potential mechanisms. C57BL/6 mice were randomly divided into control group, Con A group, and salidroside group. Salidroside (50 mg/kg) was injected intravenously followed by Con A administration. The levels of ALT, AST, inflammatory cytokines and CXCL-10 were examined. The pathological damage of livers was assessed, the amounts of phosphorylated IκBα and p65 were measured, and the numbers of CD4+ and CD8+ T lymphocytes in the blood, spleen and infiltrated in the liver were calculated. Our results showed that salidroside pretreatment reduced the levels of ALT, AST dramatically and suppressed the secretion of proinflammatory cytokines through downregulating the activity of NF-κB partly. Salidroside altered the distribution of CD4+ and CD8+ T lymphocyte in the liver and spleen through regulating CXCL-10 and decreased the severity of liver injuries. In conclusion, these results confirm the efficacy of salidroside in the prevention of immune mediated hepatitis in mice. Baoji Hu, Yun Zou, Shanshan Liu, Jun Wang, Jiali Zhu, Jinbao Li, Lulong Bo, and Xiaoming Deng Copyright © 2014 Baoji Hu et al. All rights reserved. The Relationship between the Antitumor Effect of the IL-12 Gene Therapy and the Expression of Th1 Cytokines in an HPV16-Positive Murine Tumor Model Mon, 07 Apr 2014 08:18:23 +0000 Objective. The goal of the present study was to investigate the effect of IL-12 expressed in plasmid on the Th1 cytokine profile in an experimental HPV16-positive murine tumor model and the association with the IL-12’s antitumor effect. Methods. Mice were injected with BMK-16/myc cells to establish HPV16-positive tumor and then pNGVL3-mIL-12 plasmid; pcDNA3 plasmid or PBS was injected directly into tumor site. The antitumor effect of the treatment was evaluated and the cytokines expression profile in each tumor tissue was analyzed. Results. Treatment with pNGVL3-mIL-12 plasmid had a significant antitumor effect, and a Th2-Th3-type cytokines prolife was detected in the murine tumor model with expression of the cytokines IL-10, IL-4, and TGF-β1. However, after the tumor was treated with three intratumoral injections of plasmid containing IL-12 cDNA, it showed a cytokine profile associated with Th1 with expression of IL-2, IL-12, and IFN-γ cytokines and reduced expression of IL-10, IL-4, and TGF-β1. Conclusions. The treatment with the IL-12 gene in the experimental HPV16-positive tumor model promoted the activation of the cellular immune response via expression of a Th1-type cytokine profile and was associated with the inhibition of tumor growth. Thus, IL-12 treatment represents a novel approach for gene therapy against cervical cancer. Flor García Paz, Vicente Madrid Marina, Ausencio Morales Ortega, Abimelec Santander González, Oscar Peralta Zaragoza, Ana Burguete García, Kirvis Torres Poveda, José Moreno, Juan Alcocer González, Eva Hernandez Marquez, and Victor Bermúdez Morales Copyright © 2014 Flor García Paz et al. All rights reserved. C-Reactive Protein and Coronary Heart Disease: All Said—Is Not It? Mon, 07 Apr 2014 06:09:54 +0000 C-reactive protein (CRP) and coronary heart disease (CHD) have been the subject of intensive investigations over the last decades. Epidemiological studies have shown an association between moderately elevated CRP levels and incident CHD whereas genetic studies have shown that polymorphisms associated with elevated CRP levels do not increase the risk of ischemic vascular disease, suggesting that CRP might be a bystander rather than a causal factor in the progress of atherosclerosis. Beside all those epidemiological and genetic studies, the experimental investigations also try to reveal the role of CRP in the progress of atherosclerosis. This review will highlight the complex results of genomic, epidemiological, and experimental studies on CRP and will show why further studies investigating the relationship between CRP and atherosclerosis might be needed. Frederik Strang and Heribert Schunkert Copyright © 2014 Frederik Strang and Heribert Schunkert. All rights reserved. Circulating Biomarkers of Immune Activation Distinguish Viral Suppression from Nonsuppression in HAART-Treated Patients with Advanced HIV-1 Subtype C Infection Sun, 06 Apr 2014 12:22:05 +0000 Few studies have examined immune activation profiles in patients with advanced HIV-1 subtype C infection or assessed their potential to predict responsiveness to HAART. BioPlex, ELISA, and nephelometric procedures were used to measure plasma levels of inflammatory biomarkers in HIV-1 subtype C-infected patients sampled before and after 6 months of successful HAART ; in patients failing HAART ; and in uninfected controls . Prior to HAART, CXCL9, CXCL10, β2M, sTNF-R1, TGF-β1, IFN-γ, IL-6, TNF, and sCD14 were significantly elevated in HIV-1-infected patients compared to controls . All of these markers, with the exception of sTNF-R1, were also elevated in patients failing HAART . The persistently elevated levels of CXCL9, CXCL10, and β2M in patients failing therapy in the setting of a marked reduction in these markers in patients on successful HAART suggest that they may be useful not only to monitor immune activation during HAART, but also to distinguish between good and poor responders. In the case of sCD14 and TGF-β1, the levels of these biomarkers remained persistently elevated despite HAART-induced virological suppression, a finding that is consistent with ongoing monocyte-macrophage activation, underscoring a potential role for adjuvant anti-inflammatory therapy. Glen Malherbe, Helen C. Steel, Sharon Cassol, Tulio de Oliveira, Christopher J. Seebregts, Ronald Anderson, Edana Cassol, and Theresa M. Rossouw Copyright © 2014 Glen Malherbe et al. All rights reserved. An Asp49 Phospholipase A2 from Snake Venom Induces Cyclooxygenase-2 Expression and Prostaglandin E2 Production via Activation of NF-κB, p38MAPK, and PKC in Macrophages Sun, 06 Apr 2014 11:45:46 +0000 Phospholipases A2 (PLA2) are key enzymes for production of lipid mediators. We previously demonstrated that a snake venom sPLA2 named MT-III leads to prostaglandin (PG)E2 biosynthesis in macrophages by inducing the expression of cyclooxygenase-2 (COX-2). Herein, we explored the molecular mechanisms and signaling pathways leading to these MT-III-induced effects. Results demonstrated that MT-III induced activation of the transcription factor NF-κB in isolated macrophages. By using NF-κB selective inhibitors, the involvement of this factor in MT-III-induced COX-2 expression and PGE2 production was demonstrated. Moreover, MT-III-induced COX-2 protein expression and PGE2 release were attenuated by pretreatment of macrophages with SB202190, and Ly294002, and H-7-dihydro compounds, indicating the involvement of p38MAPK, PI3K, and PKC pathways, respectively. Consistent with this, MT-III triggered early phosphorylation of p38MAPK, PI3K, and PKC. Furthermore, SB202190, H-7-dihydro, but not Ly294002 treatment, abrogated activation of NF-κB induced by MT-III. Altogether, these results show for the first time that the induction of COX-2 protein expression and PGE2 release, which occur via NF-κB activation induced by the sPLA2-MT-III in macrophages, are modulated by p38MAPK and PKC, but not by PI3K signaling proteins. Vanessa Moreira, Bruno Lomonte, Marco Aurélio Ramirez Vinolo, Rui Curi, José María Gutiérrez, and Catarina Teixeira Copyright © 2014 Vanessa Moreira et al. All rights reserved. Low Intraprostatic DHT Promotes the Infiltration of CD8+ T Cells in BPH Tissues via Modulation of CCL5 Secretion Sun, 06 Apr 2014 11:40:22 +0000 Clinical studies suggested thatandrogen might be associated with infiltrating T cells in prostate of benign prostatic hyperplasia (BPH) patients, but detail of T-cell subset and mechanism still remained unclear. The present study tested the hypothesis that intraprostatic 5α-dihydrotestosterone (DHT) exerts effects on T cells recruitment by BPH epithelial cells. Prostate tissues from 64 cases of BPH patients after transurethral resection of prostate (TURP) were divided into 2 groups: (1) no medication history; (2) administration of 5α-reductase type II inhibitor-finasteride 5 mg daily for at least 6 months before surgery. Group 2 presented significantly higher CD8+ T cells infiltration than group 1, but no changes in CD4+ T cells (immunohistochemistry and flow cytometry). In vitro study more CD8+ T cell migrated to the prostate tissue lysates from group 2 and BPH-1 cells in low DHT condition. Transcription of chemokine (C-C motif) Ligand 5 (CCL5) mRNA in BPH-1 cells and chemokine (C-C motif) receptor 5 (CCR5) mRNA in CD8+ T cells were upregulated in low DHT condition (q-PCR). CCL5 expression was also identified to be higher in group 2 prostate tissues by IHC. This study suggested that intraprostatic DHT may participate in regulating inflammatory response which was induced by human prostatic epithelial cell, via modulating CCL5 secretion. Yu Fan, Shuai Hu, Jie Liu, Fei Xiao, Xin Li, Wei Yu, Yun Cui, Mengkui Sun, Tianjing Lv, Qun He, and Jie Jin Copyright © 2014 Yu Fan et al. All rights reserved. Danger Signals in Cardiovascular Disease Sun, 06 Apr 2014 07:12:48 +0000 Stefan Frantz, Claudia Monaco, and Fatih Arslan Copyright © 2014 Stefan Frantz et al. All rights reserved.