Mediators of Inflammation The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Oxidative Stress Biomarkers: Establishment of Reference Values for Isoprostanes, AOPP, and NPBI in Cord Blood Sun, 23 Apr 2017 00:00:00 +0000 Oxidative stress (OS) is a common pathogenic factor involved in the onset of several diseases in humans, from immunologic disorders to malignancy, being a serious public health problem. In perinatal period, OS has been associated with adverse outcome of pregnancy and neonatal diseases. Dangerous effects of OS are mediated by increased production of free radicals (FRs) following various mechanisms, such as hypoxia, ischemia reperfusion, hyperoxia, inflammation, mitochondrial dysfunction, Fenton chemistry, and prostaglandin metabolism. FRs have short half-life, and their measurement in vivo is faced with many challenges. However, oxyradical derivatives are stable and thus may be measured and monitored repeatedly. The quantification of OS is based on the measurement of specific biomarkers in biologic fluids and tissues, which reflect induced oxidative damage to lipids, proteins, and DNA. Prostanoids, non–protein-bound iron (NPBI), and advanced oxidation protein products (AOPP) are actually considered truly specific and reliable for neonatal injury. Defining reference values for these biomarkers is necessary to investigate their role in neonatal diseases or also to evaluate the success of treatments. In this work, we wanted to define laboratory reference values for biomarkers of OS in a healthy population of term newborns. Mariangela Longini, Elisa Belvisi, Fabrizio Proietti, Francesco Bazzini, Giuseppe Buonocore, and Serafina Perrone Copyright © 2017 Mariangela Longini et al. All rights reserved. Oncolytic Virus-Based Immunotherapies for Hepatocellular Carcinoma Thu, 20 Apr 2017 00:00:00 +0000 Hepatocellular carcinoma is highly refractory cancer which is resistant to conventional chemotherapy and radiotherapy, carrying a dismal prognosis. Although many anticancer drugs have been developed for treating HCC, sorafenib is the only effective treatment, but it only prolongs survival duration for about 3 months. Recently, oncolytic virotherapy has shown promising results in treating HCCs and the effects can be more enhanced by adopting immune modulatory molecules. This review discusses the current status of treating HCC and the effective strategy of oncolytic virus-based immunotherapy for the treatment of HCCs. So Young Yoo, Narayanasamy Badrinath, Hyun Young Woo, and Jeong Heo Copyright © 2017 So Young Yoo et al. All rights reserved. 15-Deoxy-Δ12,14-prostaglandin J2 Exerts Antioxidant Effects While Exacerbating Inflammation in Mice Subjected to Ureteral Obstruction Wed, 19 Apr 2017 00:00:00 +0000 Urinary obstruction is associated with inflammation and oxidative stress, leading to renal dysfunction. Previous studies have shown that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has both antioxidant and anti-inflammatory effects. Using a unilateral ureteral obstruction (UUO) mouse model, we examined the effects of 15d-PGJ2 on oxidative stress and inflammation in the kidney. Mice were subjected to UUO for 3 days and treated with 15d-PGJ2. Protein and RNA expression were examined using immunoblotting and qPCR. 15d-PGJ2 increased NF-E2-related nuclear factor erythroid-2 (Nrf2) protein expression in response to UUO, and heme oxygenase 1 (HO-1), a downstream target of Nrf2, was induced by 15d-PGJ2. Additionally, 15d-PGJ2 prevented protein carbonylation, a UUO-induced oxidative stress marker. Inflammation, measured by nuclear NF-κB, F4/80, and MCP-1, was increased in response to UUO and further increased by 15d-PGJ2. Renal injury was aggravated by 15d-PGJ2 treatment as measured by kidney injury molecule-1 (KIM-1) and cortical caspase 3 content. No effect of 15d-PGJ2 was observed on renal function in mice subjected to UUO. This study illustrates differentiated functioning of 15d-PGJ2 on inflammation and oxidative stress in response to obstructive nephropathy. High concentrations of 15d-PGJ2 protects against oxidative stress during 3-day UUO in mice; however, it aggravates the associated inflammation. Line Nilsson, Fredrik Palm, and Rikke Nørregaard Copyright © 2017 Line Nilsson et al. All rights reserved. Anti-Inflammatory Effects of the Mediterranean Diet in the Early and Late Stages of Atheroma Plaque Development Tue, 18 Apr 2017 00:00:00 +0000 Objective. To evaluate the long-term effects of a Mediterranean diet (MeDiet) intervention on the plasma concentrations of inflammatory and plaque stability-related molecules in elderly people at high risk for cardiovascular disease. Design and Setting. 66 participants from primary care centers affiliated with the Hospital Clinic of Barcelona were randomized into 3 groups: MeDiet plus extra virgin olive oil (EVOO) or nuts and a low-fat diet (LFD). At baseline and at 3 and 5 years, we evaluated the changes in the plasma concentrations of 24 inflammatory biomarkers related to the different stages of the atherosclerotic process by Luminex®. Results. At 3 and 5 years, both MeDiet groups showed a significant reduction of IL-6, IL-8, MCP-1, and MIP-1β (; all) compared to LFD. IL-1β, IL-5, IL-7, IL-12p70, IL-18, TNF-α, IFN-γ, GCSF, GMCSF, and ENA78 (; all) only decreased in the MeDiet+EVOO group and E-selectin and sVCAM-1 (; both) in the MeDiet+nuts group. Conclusions. Long-term adherence to MeDiet decreases the plasma concentrations of inflammatory biomarkers related to different steps of atheroma plaque development in elderly persons at high cardiovascular risk. Rosa Casas, Mireia Urpi-Sardà, Emilio Sacanella, Sara Arranz, Dolores Corella, Olga Castañer, Rosa-María Lamuela-Raventós, Jordi Salas-Salvadó, José Lapetra, Maria P. Portillo, and Ramón Estruch Copyright © 2017 Rosa Casas et al. All rights reserved. Novel Biomarkers and the Future Potential of Biomarkers in Inflammatory Bowel Disease Sun, 16 Apr 2017 00:00:00 +0000 There is increasing importance placed upon noninvasive assessment of gut inflammation. These tools are likely to be the key in differentiating intestinal inflammatory disease from functional disorders and in monitoring the response to intervention in individuals with known inflammatory conditions. Although various noninvasive markers are currently available, they have limitations and do not provide ideal utility. This review focuses on emerging markers of gut inflammation, highlighting the potential of specific markers. Gilles Duvoisin, Robert N. Lopez, Andrew S. Day, Daniel A. Lemberg, Richard B. Gearry, and Steven T. Leach Copyright © 2017 Gilles Duvoisin et al. All rights reserved. Transcriptional Profiling at High Temporal Resolution Reveals Robust Immune/Inflammatory Responses during Rat Sciatic Nerve Recovery Wed, 12 Apr 2017 00:00:00 +0000 After peripheral nerve injury, immune/inflammatory responses are triggered, which are critical for nerve regeneration. Despite their importance, the underlying molecular changes in immune/inflammatory responses remain largely unknown. In this study, we systematically analyzed differentially expressed genes in immune/inflammatory-related pathways at high temporal resolution and experimentally validated gene expression changes with RT-PCR following sciatic nerve crush in rats. We found that immune/inflammatory reactions not only occur in the acute injury but also remained activated over two weeks after injury. Detailed bioinformatic studies suggested that multiple immune/inflammatory pathways, including agranulocyte adhesion and diapedesis, granulocyte adhesion and diapedesis, IL-6 signaling, and IL-10 signaling, were sustained activated during nerve degeneration and regeneration. Our current study expands our understanding of the molecular basis of altered immune/inflammatory-related pathways following injury and thus might offer the possibility of targeting related molecules as therapeutic intervention for peripheral nerve regeneration. Lingyan Xing, Qiong Cheng, Guangbin Zha, and Sheng Yi Copyright © 2017 Lingyan Xing et al. All rights reserved. Toll-Like Receptor 9 Promotes Survival in SERCA2a KO Heart Failure Mice Tue, 11 Apr 2017 04:03:48 +0000 Aim. Inflammation is important in heart failure (HF). The role of the immune receptor toll-like receptor 9 (TLR9) in HF is not understood and not investigated in diastolic HF. We investigated the role of TLR9 in a murine diastolic HF model caused by cardiomyocyte SERCA2a excision. Methods and Results. We crossed SERCA2a KO and TLR9 KO mice to generate four mouse lines. Tamoxifen-induced cardiomyocyte SERCA2a gene excision was carried out in mice, causing diastolic HF. After 7.6 weeks, cardiac functions and dimensions were analyzed by echocardiography and heart tissues were processed. HF mice depleted of TLR9 demonstrated reduced survival compared to SERC2a KO mice, with a median life expectancy of 58 days compared to 63 days. Both HF groups displayed increased left atrium size, lung weight, fetal gene expressions, monocyte/macrophage infiltration, and fibrosis. However, there were no significant differences between the groups. Conclusion. In mice with SERCA2a KO-induced diastolic HF, the absence of TLR9 reduced median life expectancy. The cause remains elusive, as all investigated HF parameters were unaltered. Still, these findings support a salutary role of TLR9 in some subsets of HF conditions and underline the importance for future studies on the mechanisms of TLR9 in diastolic HF. Yangchen Dhondup, Ivar Sjaastad, Øystein Sandanger, Jan Magnus Aronsen, Muhammad Shakil Ahmed, Håvard Attramadal, Alexandra Vanessa Finsen, Lili Zhang, Trine Ranheim, Katrine Alfsnes, Pål Aukrust, Geir Christensen, Arne Yndestad, and Leif Erik Vinge Copyright © 2017 Yangchen Dhondup et al. All rights reserved. Higher-Order Chromatin Regulation of Inflammatory Gene Expression Sun, 09 Apr 2017 00:00:00 +0000 Whether it is caused by viruses and bacteria infection, or low-grade chronic inflammation of atherosclerosis and cellular senescence, the transcription factor (TF) NF-κB plays a central role in the inducible expression of inflammatory genes. Accumulated evidence has indicated that the chromatin environment is the main determinant of TF binding in gene expression regulation, including the stimulus-responsive NF-κB. Dynamic changes in intra- and interchromosomes are the key regulatory mechanisms promoting the binding of TFs. When an inflammatory process is triggered, NF-κB binds to enhancers or superenhancers, triggering the transcription of enhancer RNA (eRNA), driving the chromatin of the NF-κB-binding gene locus to construct transcriptional factories, and forming intra- or interchromosomal contacts. These processes reveal a mechanism in which intrachromosomal contacts appear to be cis-control enhancer-promoter communications, whereas interchromosomal regulatory elements construct trans-form relationships with genes on other chromosomes. This article will review emerging evidence on the genome organization hierarchy underlying the inflammatory response. Jin-Wen Xu, Shuang Ling, and Jun Liu Copyright © 2017 Jin-Wen Xu et al. All rights reserved. Adipokine Contribution to the Pathogenesis of Osteoarthritis Sun, 09 Apr 2017 00:00:00 +0000 Recent studies have shown that overweight and obesity play an important role in the development of osteoarthritis (OA). However, joint overload is not the only risk factor in this disease. For instance, the presence of OA in non-weight-bearing joints such as the hand suggests that metabolic factors may also contribute to its pathogenesis. Recently, white adipose tissue (WAT) has been recognized not only as an energy reservoir but also as an important secretory organ of adipokines. In this regard, adipokines have been closely associated with obesity and also play an important role in bone and cartilage homeostasis. Furthermore, drugs such as rosuvastatin or rosiglitazone have demonstrated chondroprotective and anti-inflammatory effects in cartilage explants from patients with OA. Thus, it seems that adipokines are important factors linking obesity, adiposity, and inflammation in OA. In this review, we are focused on establishing the physiological mechanisms of adipokines on cartilage homeostasis and evaluating their role in the pathophysiology of OA based on evidence derived from experimental research as well as from clinical-epidemiological studies. Daniel Azamar-Llamas, Gabriela Hernández-Molina, Bárbara Ramos-Ávalos, and Janette Furuzawa-Carballeda Copyright © 2017 Daniel Azamar-Llamas et al. All rights reserved. Anti-Inflammatory and Neuroprotective Role of Natural Product Securinine in Activated Glial Cells: Implications for Parkinson’s Disease Tue, 04 Apr 2017 07:40:03 +0000 Glial activation and subsequent release of neurotoxic proinflammatory factors are believed to play an important role in the pathogenesis of several neurological disorders including Parkinson’s disease (PD). Inhibition of glial activation and inflammatory processes may represent a therapeutic target to alleviate neurodegeneration. Securinine, a major natural alkaloid product from the root of the plant Securinega suffruticosa, has been reported to have potent biological activity and is used in the treatment of neurological conditions such as amyotrophic lateral sclerosis, poliomyelitis, and multiple sclerosis. In this study, we explored the underlying mechanisms of neuroprotection elicited by securinine, particularly its anti-inflammatory effects in glial cells. Our results demonstrate that securinine significantly and dose-dependently suppressed the nitric oxide production in microglia and astrocytic cultures. In addition, securinine inhibited the activation of the inflammatory mediator NF-κB, as well as mitogen-activated protein kinases in lipopolysaccharide- (LPS-) stimulated BV2 cells. Additionally, securinine also inhibited interferon-γ- (IFN-γ-) induced nitric oxide levels and iNOS mRNA expression. Furthermore, conditioned media (CM) from securinine pretreated BV2 cells significantly reduced mesencephalic dopaminergic neurotoxicity compared with CM from LPS stimulated microglia. These findings suggest that securinine may be a potential candidate for the treatment of neurodegenerative diseases related to neuroinflammation. Dmitri Leonoudakis, Anand Rane, Suzanne Angeli, Gordon J. Lithgow, Julie K. Andersen, and Shankar J. Chinta Copyright © 2017 Dmitri Leonoudakis et al. All rights reserved. Sex Differences in Spontaneous Degranulation Activity of Intrahepatic Natural Killer Cells during Chronic Hepatitis B: Association with Estradiol Levels Sun, 02 Apr 2017 00:00:00 +0000 Major sex differences are observed in the prevalence, intensity, and severity of hepatitis B virus (HBV) infection. Here, we investigated degranulation activity of circulating and intrahepatic natural killer (NK) cells from HBV and HCV chronically infected patients before any treatment (). The frequency of CD107+ NK cells in the female liver was significantly higher compared to that in males during chronic HBV infection () and correlated with the plasma levels of estradiol (correlation coefficient ; ). Our results clearly show sex differences in degranulation activity of intrahepatic NK cells of HBV-infected patients. This probably contributes to the ability of females to better deal with HBV disease. Zuzana Macek Jilkova, Thomas Decaens, Alice Marlu, Hélène Marche, Evelyne Jouvin-Marche, and Patrice N. Marche Copyright © 2017 Zuzana Macek Jilkova et al. All rights reserved. Leukocyte Trafficking in Cardiovascular Disease: Insights from Experimental Models Thu, 30 Mar 2017 00:00:00 +0000 Chemokine-induced leukocyte migration into the vessel wall is an early pathological event in the progression of atherosclerosis, the underlying cause of myocardial infarction. The immune-inflammatory response, mediated by both the innate and adaptive immune cells, is involved in the initiation, recruitment, and resolution phases of cardiovascular disease progression. Activation of leukocytes via inflammatory mediators such as chemokines, cytokines, and adhesion molecules is instrumental in these processes. In this review, we highlight leukocyte activation with the main focus being on the mechanisms of chemokine-mediated recruitment in atherosclerosis and the response postmyocardial infarction with key examples from experimental models of cardiovascular inflammation. Daniel P. Jones, Harry D. True, and Jyoti Patel Copyright © 2017 Daniel P. Jones et al. All rights reserved. The Protective Effect of Cordycepin on D-Galactosamine/Lipopolysaccharide-Induced Acute Liver Injury Tue, 28 Mar 2017 07:49:00 +0000 As the major active ingredient of Cordyceps militaris, cordycepin (3′-deoxyadenosine) has been well documented to alleviate inflammation and oxidative stress both in vitro and in vivo. To explore the potential protective effect of cordycepin in fulminant hepatic failure, mice were pretreated with cordycepin for 3 weeks followed by D-galactosamine (GalN)/lipopolysaccharide (LPS) injection. Then we found cordycepin (200 mg/kg) administration elevated survival rate, improved liver function, and suppressed hepatocyte apoptosis and necrosis in mice with severe hepatic damage by GalN/LPS treatment. Further, cordycepin inhibited hepatic neutrophil and macrophage infiltration and prevented proinflammatory cytokine production possibly through suppressing TLR4 and NF-κB signaling transduction. The blockade of reactive oxygen species (ROS) and lipid peroxidation production by cordycepin was associated with the decrease of NAD(P)H oxidase (NOX) activity. Besides, cordycepin significantly prevented excessive autophagy induced by GalN/LPS in the liver. These data suggested that cordycepin could be a promising therapeutic agent for GalN/LPS-induced hepatotoxicity. Jin Li, Liping Zhong, Haibo Zhu, and Fengzhong Wang Copyright © 2017 Jin Li et al. All rights reserved. Innate Immunity of Adipose Tissue in Rodent Models of Local and Systemic Staphylococcus aureus Infection Mon, 27 Mar 2017 00:00:00 +0000 Background. The role of adipose tissue in systemic inflammation during bacterial infection is unclear. Effects of Staphylococcus aureus infection on adipocytes in rodent models of experimental endocarditis and peritonitis, the impact of S. aureus infection on gene expression in epididymal and subcutaneous adipose tissue, and effects of S. aureus infection on the toll-like receptor-2- (TLR2-) cathelicidin pathway in vivo and in vitro were investigated. Material and methods. The rat model of catheter-induced S. aureus endocarditis and the mouse model of S. aureus-induced peritonitis were used for infection experiments, gene expression profiling in adipose tissue, and measurement of cytokines. 3T3-L1 adipocytes were analyzed for expression of the TLR2-cathelicidin pathway. Results. Upon systemic bacterial infection by S. aureus, there is a shift from anti- to proinflammatory cytokines in serum and in adipose tissue gene expression. The TLR2-cathelicidin pathway is increasingly expressed during adipocyte differentiation in vitro and is induced upon stimulation by synthetic lipopeptides. Conclusions. Systemic infection by Gram-positive bacteria induces proinflammatory transformation of adipose tissue sites distinct from infection sites, documented on the levels of gene expression and secreted mediators. The TLR2-cathelicidine pathway is expressed and highly inducible in adipocytes in vitro. Lipopeptides are important immune-modulators of adipocytes in both gene expression and protein secretion. Andreas Schmid, Thomas Karrasch, Miriam Thomalla, Jutta Schlegel, Bernd Salzberger, Andreas Schäffler, and Frank Hanses Copyright © 2017 Andreas Schmid et al. All rights reserved. Intrinsic Properties of Brown and White Adipocytes Have Differential Effects on Macrophage Inflammatory Responses Sun, 26 Mar 2017 07:37:04 +0000 Obesity is marked by chronic, low-grade inflammation. Here, we examined whether intrinsic differences between white and brown adipocytes influence the inflammatory status of macrophages. White and brown adipocytes were characterized by transcriptional regulation of UCP-1, PGC1α, PGC1β, and CIDEA and their level of IL-6 secretion. The inflammatory profile of PMA-differentiated U937 and THP-1 macrophages, in resting state and after stimulation with LPS/IFN-gamma and IL-4, was assessed by measuring IL-6 secretion and transcriptional regulation of a panel of inflammatory genes after mono- or indirect coculture with white and brown adipocytes. White adipocyte monocultures show increased IL-6 secretion compared to brown adipocytes. White adipocytes cocultured with U937 and THP-1 macrophages induced a greater increase in IL-6 secretion compared to brown adipocytes cocultured with both macrophages. White adipocytes cocultured with macrophages increased inflammatory gene expression in both types. In contrast, macrophages cocultured with brown adipocytes induced downregulation or no alterations in inflammatory gene expression. The effects of adipocytes on macrophages appear to be independent of stimulation state. Brown adipocytes exhibit an intrinsic ability to dampen inflammatory profile of macrophages, while white adipocytes enhance it. These data suggest that brown adipocytes may be less prone to adipose tissue inflammation that is associated with obesity. Louisa Dowal, Pooja Parameswaran, Sarah Phat, Syamala Akella, Ishita Deb Majumdar, Jyoti Ranjan, Chahan Shah, Saie Mogre, Kalyani Guntur, Khampaseuth Thapa, Stephane Gesta, Vivek K. Vishnudas, Niven R. Narain, and Rangaprasad Sarangarajan Copyright © 2017 Louisa Dowal et al. All rights reserved. TM4SF5-Mediated Roles in the Development of Fibrotic Phenotypes Sun, 26 Mar 2017 00:00:00 +0000 Transmembrane 4 L six family member 5 (TM4SF5) can form tetraspanin-enriched microdomains (TERMs) on the cell’s surface. TERMs contain protein-protein complexes comprised of tetraspanins, growth factor receptors, and integrins. These complexes regulate communication between extracellular and intracellular spaces to control diverse cellular functions. TM4SF5 influences the epithelial-mesenchymal transition (EMT), aberrant multilayer cellular growth, drug resistance, enhanced migration and invasion, circulation through the bloodstream, tumor-initiation property, metastasis, and muscle development in zebrafish. Here, current data on TM4SF5’s roles in the development of fibrotic phenotypes are reviewed. TM4SF5 is induced by transforming growth factor β1 (TGFβ1) signaling via a collaboration with epidermal growth factor receptor (EGFR) activation. TM4SF5, by itself or in concert with other receptors, transduces signals intracellularly. In hepatocytes, TM4SF5 expression regulates cell cycle progression, migration, and expression of extracellular matrix components. In CCl4-treated mice, TM4SF5, α-smooth muscle actin (α-SMA), and collagen I expression are observed together along the fibrotic septa regions of the liver. These fibrotic phenotypes are diminished by anti-TM4SF5 reagents, such as a specific small compound [TSAHC, 4′-(p-toluenesulfonylamido)-4-hydroxychalcone] or a chimeric antibody. This review discusses the antifibrotic strategies that target TM4SF5 and its associated protein networks that regulate the intracellular signaling necessary for fibrotic functions of hepatocytes. Jihye Ryu and Jung Weon Lee Copyright © 2017 Jihye Ryu and Jung Weon Lee. All rights reserved. Inflammation and Cardiovascular Cross Talk in Ischemic Vascular Diseases Sun, 26 Mar 2017 00:00:00 +0000 Giorgio Zauli, Veronica Tisato, Joseph D. Raffetto, and Mauro Vaccarezza Copyright © 2017 Giorgio Zauli et al. All rights reserved. Shear Stress Counteracts Endothelial CX3CL1 Induction and Monocytic Cell Adhesion Sun, 26 Mar 2017 00:00:00 +0000 Flow conditions critically regulate endothelial cell functions in the vasculature. Reduced shear stress resulting from disturbed blood flow can drive the development of vascular inflammatory lesions. On endothelial cells, the transmembrane chemokine CX3CL1/fractalkine promotes vascular inflammation by functioning as a surface-expressed adhesion molecule and by becoming released as soluble chemoattractant for monocytic cells expressing the receptor CX3CR1. Here, we report that endothelial cells from human artery, vein, or microvasculature constitutively express CX3CL1 when cultured under static conditions. Stimulation with TNFα under static or very low shear stress conditions strongly upregulates CX3CL1 expression. By contrast, CX3CL1 induction is profoundly reduced when cells are exposed to higher shear stress. When endothelial cells were grown and subsequently stimulated with TNFα under low shear stress, strong adhesion of monocytic THP-1 cells to endothelial cells was observed. This adhesion was in part mediated by transmembrane CX3CL1 as demonstrated with a neutralizing antibody. By contrast, no CX3CL1-dependent adhesion to stimulated endothelium was observed at high shear stress. Thus, during early stages of vascular inflammation, low shear stress typically seen at atherosclerosis-prone regions promotes the induction of endothelial CX3CL1 and monocytic cell recruitment, whereas physiological shear stress counteracts this inflammatory activation of endothelial cells. Aaron Babendreyer, Lisa Molls, Daniela Dreymueller, Stefan Uhlig, and Andreas Ludwig Copyright © 2017 Aaron Babendreyer et al. All rights reserved. The Metabolic Syndrome, Inflammation, and Colorectal Cancer Risk: An Evaluation of Large Panels of Plasma Protein Markers Using Repeated, Prediagnostic Samples Wed, 22 Mar 2017 06:53:01 +0000 Metabolic syndrome (MetS), a set of metabolic risk factors including obesity, dysglycemia, and dyslipidemia, is associated with increased colorectal cancer (CRC) risk. A putative biological mechanism is chronic, low-grade inflammation, both a feature of MetS and a CRC risk factor. However, excess body fat also induces a proinflammatory state and increases CRC risk. In order to explore the relationship between MetS, body size, inflammation, and CRC, we studied large panels of inflammatory and cancer biomarkers. We included 138 participants from the Västerbotten Intervention Programme with repeated sampling occasions, 10 years apart. Plasma samples were analyzed for 178 protein markers by proximity extension assay. To identify associations between plasma protein levels and MetS components, linear mixed models were fitted for each protein. Twelve proteins were associated with at least one MetS component, six of which were associated with MetS score. MetS alone was not related to any protein. Instead, BMI displayed by far the strongest associations with the biomarkers. One of the 12 MetS score-related proteins (FGF-21), also associated with BMI, was associated with an increased CRC risk (OR 1.71, 95% CI 1.19–2.47). We conclude that overweight and obesity, acting through both inflammation and other mechanisms, likely explain the MetS-CRC connection. Sophia Harlid, Robin Myte, and Bethany Van Guelpen Copyright © 2017 Sophia Harlid et al. All rights reserved. Recent Advances: The Imbalance of Cytokines in the Pathogenesis of Inflammatory Bowel Disease Tue, 21 Mar 2017 08:51:28 +0000 Cytokines play an important role in the immunopathogenesis of inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, where they drive and regulate multiple aspects of intestinal inflammation. The imbalance between proinflammatory and anti-inflammatory cytokines that occurs in IBD results in disease progression and tissue damage and limits the resolution of inflammation. Targeting cytokines have been novel strategies in the treatment of IBD. Recent studies show the beneficial effects of anticytokine treatments to IBD patients, and multiple novel cytokines are found to be involved in the pathogenesis of IBD. In this review, we will discuss the recent advances of novel biologics in clinics and clinical trials, and novel proinflammatory and anti-inflammatory cytokines found in IBD with focusing on IL-12 family and IL-1 family members as well as their relevance to the potential therapy of IBD. Qingdong Guan and Jiguo Zhang Copyright © 2017 Qingdong Guan and Jiguo Zhang. All rights reserved. All-Trans Retinoic Acid Modulates TLR4/NF-κB Signaling Pathway Targeting TNF-α and Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer Mon, 20 Mar 2017 00:00:00 +0000 Colitis associated cancer (CAC) is the colorectal cancer (CRC) subtype that is associated with bowel disease such as ulcerative colitis (UC). The data on role of NF-κB signaling in development and progression of CAC were derived from preclinical studies, whereas data from human are rare. The aim of this work was to study the contribution of NF-κB pathway during UC and CAC, as well as the immunomodulatory effect of all-trans retinoic acid (AtRA). We analyzed the expression of NOS2, TNF-α, TLR4, and NF-κB, in colonic mucosa. We also studied NO/TNF-α modulation by LPS in colonic mucosa pretreated with AtRA. A marked increase in TLR4, NF-κB, TNF-α, and NOS2 expression was reported in colonic mucosa. The relationship between LPS/TLR4 and TNF-α/NO production, as well as the role of NF-κB signaling, was confirmed by ex vivo experiments and the role of LPS/TLR4 in NOS2/TNF-α induction through NF-κB pathway was suggested. AtRA downregulates NOS2 and TNF-α expression. Collectively, our study indicates that AtRA modulates in situ LPS/TLR4/NF-κB signaling pathway targeting NOS2 and TNF-α expression. Therefore, we suggest that AtRA has a potential value in new strategies to improve the current therapy, as well as in the clinical prevention of CAC development and progression. Hayet Rafa, Sarra Benkhelifa, Sonia AitYounes, Houria Saoula, Said Belhadef, Mourad Belkhelfa, Aziza Boukercha, Ryma Toumi, Imene Soufli, Olivier Moralès, Yvan de Launoit, Hassen Mahfouf, M’hamed Nakmouche, Nadira Delhem, and Chafia Touil-Boukoffa Copyright © 2017 Hayet Rafa et al. All rights reserved. Thrombopoietin Receptor Agonist Mitigates Hematopoietic Radiation Syndrome and Improves Survival after Whole-Body Ionizing Irradiation Followed by Wound Trauma Mon, 20 Mar 2017 00:00:00 +0000 Ionizing radiation combined with trauma tissue injury (combined injury, CI) results in greater mortality and H-ARS than radiation alone (radiation injury, RI), which includes thrombocytopenia. The aim of this study was to determine whether increases in numbers of thrombocytes would improve survival and mitigate H-ARS after CI. We observed in mice that WBC and platelets remained very low in surviving RI animals that were given 9.5 Gy 60Co-γ-photon radiation, whereas only lymphocytes and basophils remained low in surviving CI mice that were irradiated and then given skin wounds. Numbers of RBC and platelets, hemoglobin concentrations, and hematocrit values remained low in surviving RI and CI mice. CI induced 30-day mortality higher than RI. Radiation delayed wound healing by approximately 14 days. Treatment with a thrombopoietin receptor agonist, Alxn4100TPO, after CI improved survival, mitigated body-weight loss, and reduced water consumption. Though this therapy delayed wound-healing rate more than in vehicle groups, it greatly increased numbers of platelets in sham, wounded, RI, and CI mice; it significantly mitigated decreases in WBC, spleen weights, and splenocytes in CI mice and decreases in RBC, hemoglobin, hematocrit values, and splenocytes and splenomegaly in RI mice. The results suggest that Alxn4100TPO is effective in mitigating CI. Juliann G. Kiang, Min Zhai, Pei-Jun Liao, Connie Ho, Nikolai V. Gorbunov, and Thomas B. Elliott Copyright © 2017 Juliann G. Kiang et al. All rights reserved. The Potential Role of Aerobic Exercise-Induced Pentraxin 3 on Obesity-Related Inflammation and Metabolic Dysregulation Sun, 19 Mar 2017 00:00:00 +0000 Obesity is defined as the excess accumulation of intra-abdominal body fat, resulting in a state of chronic, low-grade proinflammation that can directly contribute to the development of insulin resistance. Pentraxin 3 (PTX3) is an acute-phase protein that is expressed by a variety of tissue and cell sources and provides an anti-inflammatory property to downregulate the production of proinflammatory cytokines, in particular interleukin-1 beta and tumor necrosis factor alpha. Although PTX3 may therapeutically aid in altering the proinflammatory milieu in obese individuals, and despite elevated expression of PTX3 mRNA observed in adipose tissue, the circulating level of PTX3 is reduced with obesity. Interestingly, aerobic activity has been demonstrated to elevate PTX3 levels. Therefore, the purpose of this review is to discuss the therapeutic potential of PTX3 to positively regulate obesity-related inflammation and discuss the proposition for utilizing aerobic exercise as a nonpharmacological anti-inflammatory treatment strategy to enhance circulating PTX3 concentrations in obese individuals. Aaron L. Slusher, Chun-Jung Huang, and Edmund O. Acevedo Copyright © 2017 Aaron L. Slusher et al. All rights reserved. Key Role of STAT4 Deficiency in the Hematopoietic Compartment in Insulin Resistance and Adipose Tissue Inflammation Thu, 16 Mar 2017 00:00:00 +0000 Visceral adipose tissue (AT) inflammation is linked to the complications of obesity, including insulin resistance (IR) and type 2 diabetes. Recent data from our lab showed that germline deficiency in STAT4 reduces inflammation and improves IR in obese mice. The objective of this study was to determine the contribution of selective STAT4 deficiency in subsets of hematopoietic cells to IR and AT inflammation. To determine the contribution of hematopoietic lineage, we sublethally irradiated Stat4−/−C57Bl6 mice and reconstituted them with bone marrow cells (BMC) from Stat4+/+C57Bl6 congenic donors. We also established the contribution of selective STAT4 deficiency in CD4+ or CD8+ T cells using adoptive transfer in Rag1−/− mice. All mice received a HFD for 15 weeks (–12 mice/group). BMC that expressed STAT4 induced increases in glucose intolerance and IR compared to STAT4-deficient cells. Also, AT inflammation was increased and the numbers of CD8+ cells infiltrating AT were higher in mice with STAT4 expressing BMC. Studies in Rag1−/− mice further confirmed the prominent role of CD8+ cells expressing STAT4 in insulin resistance and AT and islet inflammation. Collectively our results show specific and dominant contribution of STAT4 in the hematopoietic compartment to metabolic health and inflammation in diet-induced obesity. Anca D. Dobrian, Kaiwen Ma, Lindsey M. Glenn, Margaret A. Hatcher, Bronson A. Haynes, Eric J. Lehrer, Mark H. Kaplan, and Jerry L. Nadler Copyright © 2017 Anca D. Dobrian et al. All rights reserved. Erratum to “Establishment of a Consistent L929 Bioassay System for TNF-α Quantitation to Evaluate the Effect of Lipopolysaccharide, Phytomitogens and Cytodifferentiation Agents on Cytotoxicity of TNF-α Secreted by Adherent Human Mononuclear Cells” Thu, 16 Mar 2017 00:00:00 +0000 Ming-Yuh Shiau, Hui-Ling Chiou, Yao-Ling Lee, Tzer-Min Kuo, and Yih-Hsin Chang Copyright © 2017 Ming-Yuh Shiau et al. All rights reserved. Acute Lung Injury, Repair, and Remodeling: Pulmonary Endothelial and Epithelial Biology Tue, 14 Mar 2017 08:20:07 +0000 Yutong Zhao, Karen Ridge, and Jing Zhao Copyright © 2017 Yutong Zhao et al. All rights reserved. Roles of Dietary Amino Acids and Their Metabolites in Pathogenesis of Inflammatory Bowel Disease Tue, 14 Mar 2017 00:00:00 +0000 Inflammatory Bowel Disease (IBD) is a kind of chronic inflammation, which has increasing incidence and prevalence in recent years. IBD mainly divides into Crohn’s disease (CD) and ulcerative colitis (UC). It is hard to cure IBD completely, and novel therapies are urgently needed. Amino acids (AAs) and their metabolites are regarded as important nutrients for humans and animals and also play an important role in IBD amelioration. In the present study, the potential protective effects of AAs and their metabolites on IBD had been summarized with the objective to provide insights into IBD moderating using dietary AAs and their metabolites as a potential adjuvant therapy. Xianying Bao, Zemeng Feng, Jiming Yao, Tiejun Li, and Yulong Yin Copyright © 2017 Xianying Bao et al. All rights reserved. HBV Viral Load and Liver Enzyme Levels May Be Associated with the Wild MBL2 AA Genotype Sun, 12 Mar 2017 00:00:00 +0000 The present study investigated the frequencies of rs1800450 (MBLB, G>A), rs1800451 (MBLC, G>A), and rs5030737 (MBLD, C>T) polymorphisms in exon 1 of the MBL2 gene among patients with chronic viral hepatitis. Blood samples from patients infected with hepatitis B virus (HBV; ), hepatitis C virus (HCV; ), and a noninfected control group () were investigated. The presence of polymorphisms was detected using a real-time polymerase chain reaction to correlate with liver disease pathogenesis and fibrosis staging according to the Metavir classification. The genotypic and allelic frequencies showed no significant differences between the groups, but patients with active HBV and the wild AA genotype presented a positive correlation between increased transaminase and HBV DNA levels and the presence of mild to moderate fibrosis. Patients with HCV and the wild AA genotype presented mild inflammation and higher HCV RNA levels, although the same association was not observed for the fibrosis scores. The results suggest that the mutations in exon 1 of the MBL2 gene do not contribute directly to the clinical and laboratory features of HCV and HBV infections, but further studies should be performed to confirm whether the wild AA genotype has indirect effect on disease progression. Tuane Carolina Ferreira Moura, Ednelza da Silva Graça Amoras, Mauro Sérgio Araújo, Maria Alice Freitas Queiroz, Simone Regina Souza da Silva Conde, Sâmia Demachki, Rosimar Neris Martins-Feitosa, Luiz Fernando Almeida Machado, Izaura Maria Vieira Cayres-Vallinoto, Ricardo Ishak, and Antonio Carlos Rosário Vallinoto Copyright © 2017 Tuane Carolina Ferreira Moura et al. All rights reserved. The Correlation of CD206, CD209, and Disease Severity in Behçet’s Disease with Arthritis Thu, 09 Mar 2017 00:00:00 +0000 The purpose of this study was to clarify the role of pattern recognition receptors in Behçet’s disease (BD). The frequencies of several pattern recognition receptors (CD11b, CD11c, CD32, CD206, CD209, and dectin-1) were analyzed in patients with BD by flow cytometry, and cytokine levels, interleukin- (IL-) 18, IL-23, and IL-17A, were compared in plasma. The analysis was performed in active () and inactive () stages of BD patients. Rheumatoid arthritis patients (), as a disease control, and healthy control (HC) () were enrolled. The frequencies of CD11b+ and CD32+ cells were significantly increased in active BD patients compared to HC. Disease severity score was correlated to CD11c+, CD206+, and CD209+ in whole leukocytes and CD11b+, CD11c+, CD206+, CD209+, and Dectin-1+ in granulocytes. The plasma levels of IL-17A were significantly different between HC and active BD. IL-18 showed significant difference between active and inactive BD patients. From this study, we concluded the expressions of several pattern recognition receptors were correlated to the joint symptoms of BD. Bunsoon Choi, Chang-Hee Suh, Hyoun-Ah Kim, Hasan M. Sayeed, and Seonghyang Sohn Copyright © 2017 Bunsoon Choi et al. All rights reserved. Cyanidin-3-O-Glucoside Modulates the In Vitro Inflammatory Crosstalk between Intestinal Epithelial and Endothelial Cells Wed, 08 Mar 2017 00:00:00 +0000 Intestinal epithelium represents a protective physical barrier and actively contributes to the mucosal immune system. Polarized basolateral intestinal secretion of inflammatory mediators, followed by activation of NF-κB signaling and inflammatory pathways in endothelial cells, efficiently triggers extravasation of neutrophils from the vasculature, therefore contributing to the development and maintenance of intestinal inflammation. Proper regulation of NF-κB activation at the epithelial interface is crucial for the maintenance of physiological tissue homeostasis. Many papers reported that anthocyanins, a group of compounds belonging to flavonoids, possess anti-inflammatory effects and modulate NF-κB activity. In this study, by using a coculture in vitro system, we aimed to evaluate the effects of TNF-α-stimulated intestinal cells on endothelial cells activation, as well as the protective effects of cyanidin-3-glucoside (C3G). In this model, TNF-α induced nuclear translocation of NF-κB and TNF-α and IL-8 gene expression in Caco-2 cells, whereas C3G pretreatment dose-dependently reduced these effects. Furthermore, TNF-α-stimulated Caco-2 cells induced endothelial cells activation with increased E-selectin and VCAM-1 mRNA, leukocyte adhesion, and NF-κB levels in HUVECs, which were inhibited by C3G. We demonstrated that selective inhibition of the NF-κB pathway in epithelial cells represents the main mechanism by which C3G exerts these protective effects. Thus, anthocyanins could contribute to the management of chronic gut inflammatory diseases. Daniela Ferrari, Francesco Cimino, Deborah Fratantonio, Maria Sofia Molonia, Romina Bashllari, Rossana Busà, Antonella Saija, and Antonio Speciale Copyright © 2017 Daniela Ferrari et al. All rights reserved.