Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Oxidative-Nitrosative Stress and Myocardial Dysfunctions in Sepsis: Evidence from the Literature and Postmortem Observations Wed, 04 May 2016 13:06:09 +0000 Background. Myocardial depression in sepsis is common, and it is associated with higher mortality. In recent years, the hypothesis that the myocardial dysfunction during sepsis could be mediated by ischemia related to decreased coronary blood flow waned and a complex mechanism was invoked to explain cardiac dysfunction in sepsis. Oxidative stress unbalance is thought to play a critical role in the pathogenesis of cardiac impairment in septic patients. Aim. In this paper, we review the current literature regarding the pathophysiology of cardiac dysfunction in sepsis, focusing on the possible role of oxidative-nitrosative stress unbalance and mitochondria dysfunction. We discuss these mechanisms within the broad scenario of cardiac involvement in sepsis. Conclusions. Findings from the current literature broaden our understanding of the role of oxidative and nitrosative stress unbalance in the pathophysiology of cardiac dysfunction in sepsis, thus contributing to the establishment of a relationship between these settings and the occurrence of oxidative stress. The complex pathogenesis of septic cardiac failure may explain why, despite the therapeutic strategies, sepsis remains a big clinical challenge for effectively managing the disease to minimize mortality, leading to consideration of the potential therapeutic effects of antioxidant agents. M. Neri, I. Riezzo, C. Pomara, S. Schiavone, and E. Turillazzi Copyright © 2016 M. Neri et al. All rights reserved. Holding the Inflammatory System in Check: TLRs and Their Targeted Therapy in Asthma Wed, 04 May 2016 11:00:49 +0000 Inflammation is a complex biological response to detrimental stimuli and can be a double-edged sword. Inflammation plays a protective role in removing pathogenic factors, but dysregulated inflammation is associated with several major fatal diseases such as asthma, cancer, and cardiovascular diseases. Asthma is a complex heterogenous disease caused by genetic and environmental factors. TLRs are the primary proteins associated with the innate and adaptive immune responses to these fatal factors and play an important role in recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which initiates the downstream immune response. Due to the complex TLRs cascade and nowadays unsuccessful control in asthma, new studies are focused on TLRs and other potential targets in TLR cascade to minimize airway inflammation. Zhiyong Dong, Lingxin Xiong, Weijie Zhang, Peter G. Gibson, Ting Wang, Yanjiao Lu, Guoqiang Wang, Hui Li, and Fang Wang Copyright © 2016 Zhiyong Dong et al. All rights reserved. Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems Tue, 03 May 2016 13:57:11 +0000 Among the chemokines discovered to date, nineteen are presently considered to be relevant in heart disease and are involved in all stages of cardiovascular response to injury. Chemokines are interesting as biomarkers to predict risk of cardiovascular events in apparently healthy people and as possible therapeutic targets. Moreover, they could have a role as mediators of crosstalk between immune and cardiovascular system, since they seem to act as a “working-network” in deep linkage with the autonomic nervous system. In this paper we will describe the single chemokines more involved in heart diseases; then we will present a comprehensive perspective of them as a complex network connecting the cardiovascular system to both the immune and the autonomic nervous systems. Finally, some recent evidences indicating chemokines as a possible new tool to predict cardiovascular risk will be described. Veronica Dusi, Alice Ghidoni, Alice Ravera, Gaetano M. De Ferrari, and Laura Calvillo Copyright © 2016 Veronica Dusi et al. All rights reserved. Effects of Acute Endurance Exercise on Plasma Protein Profiles of Endurance-Trained and Untrained Individuals over Time Sat, 30 Apr 2016 11:21:04 +0000 Acute physical exercise and repeated exercise stimuli affect whole-body metabolic and immunologic homeostasis. The aim of this study was to determine plasma protein profiles of trained (EET, ) and untrained (SED, ) individuals at rest and in response to an acute bout of endurance exercise. Participants completed a bicycle exercise test at an intensity corresponding to 80% of their . Plasma samples were taken before, directly after, and three hours after exercise and analyzed using multiplex immunoassays. Seventy-eight plasma variables were included in the final analysis. Twenty-nine variables displayed significant acute exercise effects in both groups. Seven proteins differed between groups, without being affected by acute exercise. Among these A2Macro and IL-5 were higher in EET individuals while leptin showed elevated levels in SED individuals. Fifteen variables revealed group and time differences with elevated levels for IL-3, IL-7, IL-10, and TNFR2 in EET individuals. An interaction effect could be observed for nine variables including IL-6, MMP-2, MMP-3, and muscle damage markers. The proteins that differ between groups indicate a long-term exercise effect on plasma protein concentrations. These findings might be of importance in the development of exercise-based strategies in the prevention and therapy of chronic metabolic and inflammatory diseases and for training monitoring. Marius Schild, Gerrit Eichner, Thomas Beiter, Martina Zügel, Ilke Krumholz-Wagner, Jens Hudemann, Christian Pilat, Karsten Krüger, Andreas M. Niess, Jürgen M. Steinacker, and Frank C. Mooren Copyright © 2016 Marius Schild et al. All rights reserved. Inverse Relationship of the CMKLR1 Relative Expression and Chemerin Serum Levels in Obesity with Dysmetabolic Phenotype and Insulin Resistance Thu, 28 Apr 2016 17:08:30 +0000 Background. In obesity there is a subclinical chronic low-grade inflammatory response where insulin resistance (IR) may develop. Chemerin is secreted in white adipose tissue and promotes low-grade inflammatory process, where it expressed CMKLR1 receptor. The role of chemerin and CMKLR1 in inflammatory process secondary to obesity is not defined yet. Methods. Cross-sectional study with 134 individuals classified as with and without obesity by body mass index (BMI) and IR. Body fat storage measurements and metabolic and inflammatory markers were measured by routine methods. Soluble chemerin and basal levels of insulin by ELISA and relative expression of CMKLR1 were evaluated with qPCR and method. Results. Differences () were observed between obesity and lean individuals in body fat storage measurements and metabolic-inflammatory markers. Both CMKLR1 expression and chemerin levels were increased in obesity without IR. Soluble chemerin levels correlate with adiposity and metabolic markers (% to 38.5%), . Conclusion. The increment of CMKLR1 expression was associated with insulin production. Increased serum levels of chemerin in obesity were observed, favoring a dysmetabolic response. The results observed in this study suggest that both chemerin and CMKLR1 have opposite expression in the context of low-grade inflammatory response manifested in the development of IR. Fernanda-Isadora Corona-Meraz, Rosa-Elena Navarro-Hernández, Sandra-Luz Ruíz-Quezada, Perla-Monserrat Madrigal-Ruíz, Jorge Castro-Albarrán, Efraín Chavarría-Ávila, Milton-Omar Guzmán-Ornelas, Eduardo Gómez-Bañuelos, Marcelo-Herón Petri, Joel-Isidro Ramírez-Cedano, María-Elena Aguilar-Aldrete, Clara Ríos-Ibarra, and Mónica Vázquez-Del Mercado Copyright © 2016 Fernanda-Isadora Corona-Meraz et al. All rights reserved. Administration of Myelin Basic Protein Peptides Encapsulated in Mannosylated Liposomes Normalizes Level of Serum TNF-α and IL-2 and Chemoattractants CCL2 and CCL4 in Multiple Sclerosis Patients Thu, 28 Apr 2016 09:09:56 +0000 We have previously shown that immunodominant MBP peptides encapsulated in mannosylated liposomes (Xemys) effectively suppressed experimental allergic encephalomyelitis (EAE). Within the frames of the successfully completed phase I clinical trial, we investigated changes in the serum cytokine profile after Xemys administration in MS patients. We observed a statistically significant decrease of MCP-1/CCL2, MIP-1β/CCL4, IL-7, and IL-2 at the time of study completion. In contrast, the serum levels of TNF-α were remarkably elevated. Our data suggest that the administration of Xemys leads to a normalization of cytokine status in MS patients to values commonly reported for healthy subjects. These data are an important contribution for the upcoming Xemys clinical trials. Yakov Lomakin, Alexey Belogurov Jr., Irina Glagoleva, Alexey Stepanov, Konstantin Zakharov, John Okunola, Ivan Smirnov, Dmitry Genkin, and Alexander Gabibov Copyright © 2016 Yakov Lomakin et al. All rights reserved. Neuropilin-1highCD4+CD25+ Regulatory T Cells Exhibit Primary Negative Immunoregulation in Sepsis Wed, 27 Apr 2016 16:14:27 +0000 Regulatory T cells (Tregs) appear to be involved in sepsis-induced immune dysfunction; neuropilin-1 (Nrp-1) was identified as a surface marker for Tregs. In the current study, we investigated the negative immunoregulation of Tregs and the potential therapeutic value of Nrp-1 in sepsis. Splenic Tregs from cecal ligation and puncture (CLP) mouse models were further segregated into Tregs and Tregs; they were cocultured with CD4+CD25−  T cells. The expression of forkhead/winged helix transcription factor-3 (Foxp-3), cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), membrane associated transforming growth factor-β (TGF-), apoptotic rate, and secretive ability [including TGF-β and interleukin-10 (IL-10)] for various types of Tregs, as well as the immunosuppressive ability of Tregs on CD4+CD25−  T cells, were determined. Meanwhile, the impact of recombinant Nrp-1 polyclonal antibody on the demethylation of Foxp-3-TSDR (Treg-specific demethylated region) was measured in in vitro study. Sepsis per se markedly promoted the expression of Nrp-1 of Tregs. Foxp-3/CTLA-4/TGF- of Tregs were upregulated by septic challenge. Tregs showed strong resilience to apoptosis and secretive ability and the strongest immunosuppressive ability on CD4+CD25−  T cells. In the presence of lipopolysaccharide (LPS), the recombinant Nrp-1 polyclonal antibody reduced the demethylation of Foxp-3-TSDR. Tregs might reveal primary negative immunoregulation in sepsis; Nrp-1 could represent a new potential therapeutic target for the study of immune regulation in sepsis. Yu-Lei Gao, Yan-Fen Chai, An-Long Qi, Ying Yao, Yan-Cun Liu, Ning Dong, Li-Jun Wang, and Yong-Ming Yao Copyright © 2016 Yu-Lei Gao et al. All rights reserved. A Pathophysiological Insight into Sepsis and Its Correlation with Postmortem Diagnosis Wed, 27 Apr 2016 13:08:00 +0000 Background. Sepsis is among the leading causes of death worldwide and is the focus of a great deal of attention from policymakers and caregivers. However, sepsis poses significant challenges from a clinical point of view regarding its early detection and the best organization of sepsis care. Furthermore, we do not yet have reliable tools for measuring the incidence of sepsis. Methods based on analyses of insurance claims are unreliable, and postmortem diagnosis is still challenging since autopsy findings are often nonspecific. Aim. The objective of this review is to assess the state of our knowledge of the molecular and biohumoral mechanisms of sepsis and to correlate them with our postmortem diagnosis ability. Conclusion. The diagnosis of sepsis-related deaths is an illustrative example of the reciprocal value of autopsy both for clinicians and for pathologists. A complete methodological approach, integrating clinical data by means of autopsy and histological and laboratory findings aiming to identify and demonstrate the host response to infectious insults, is mandatory to illuminate the exact cause of death. This would help clinicians to compare pre- and postmortem findings and to reliably measure the incidence of sepsis. C. Pomara, I. Riezzo, S. Bello, D. De Carlo, M. Neri, and E. Turillazzi Copyright © 2016 C. Pomara et al. All rights reserved. Central Interleukin-1β Suppresses the Nocturnal Secretion of Melatonin Tue, 26 Apr 2016 16:20:41 +0000 In vertebrates, numerous processes occur in a rhythmic manner. The hormonal signal reliably reflecting the environmental light conditions is melatonin. Nocturnal melatonin secretion patterns could be disturbed in pathophysiological states, including inflammation, Alzheimer’s disease, and depression. All of these states share common elements in their aetiology, including the overexpression of interleukin- (IL-) 1β in the central nervous system. Therefore, the present study was designed to determine the effect of the central injection of exogenous IL-1β on melatonin release and on the expression of the enzymes of the melatonin biosynthetic pathway in the pineal gland of ewe. It was found that intracerebroventricular injections of IL-1β (50 µg/animal) suppressed nocturnal melatonin secretion in sheep regardless of the photoperiod. This may have resulted from decreased synthesis of the melatonin intermediate serotonin, which may have resulted, at least partially, from a reduced expression of tryptophan hydroxylase. IL-1β also inhibited the expression of the melatonin rhythm enzyme arylalkylamine-N-acetyltransferase and hydroxyindole-O-methyltransferase. However, the ability of IL-1β to affect the expression of these enzymes was dependent upon the photoperiod. Our study may shed new light on the role of central IL-1β in the aetiology of disruptions in melatonin secretion. A. P. Herman, J. Bochenek, K. Król, A. Krawczyńska, H. Antushevich, B. Pawlina, A. Herman, K. Romanowicz, and D. Tomaszewska-Zaremba Copyright © 2016 A. P. Herman et al. All rights reserved. Emerging Comorbidities in Adult Asthma: Risks, Clinical Associations, and Mechanisms Tue, 26 Apr 2016 12:17:19 +0000 Asthma is a heterogeneous disease with many phenotypes, and age at disease onset is an important factor in separating the phenotypes. Most studies with asthma have been performed in patients being otherwise healthy. However, in real life, comorbid diseases are very common in adult patients. We review here the emerging comorbid conditions to asthma such as obesity, metabolic syndrome, diabetes mellitus type 2 (DM2), and cardiac and psychiatric diseases. Their role as risk factors for incident asthma and whether they affect clinical asthma are evaluated. Obesity, independently or as a part of metabolic syndrome, DM2, and depression are risk factors for incident asthma. In contrast, the effects of comorbidities on clinical asthma are less well-known and mostly studies are lacking. Cross-sectional studies in obese asthmatics suggest that they may have less well controlled asthma and worse lung function. However, no long-term clinical follow-up studies with these comorbidities and asthma were identified. These emerging comorbidities often occur in the same multimorbid adult patient and may have in common metabolic pathways and inflammatory or other alterations such as early life exposures, systemic inflammation, inflammasome, adipokines, hyperglycemia, hyperinsulinemia, lung mechanics, mitochondrial dysfunction, disturbed nitric oxide metabolism, and leukotrienes. Hannu Kankaanranta, Paula Kauppi, Leena E. Tuomisto, and Pinja Ilmarinen Copyright © 2016 Hannu Kankaanranta et al. All rights reserved. Acute-Phase Inflammatory Response to Single-Bout HIIT and Endurance Training: A Comparative Study Tue, 26 Apr 2016 12:03:02 +0000 Objective. This study compared acute and late effect of single-bout endurance training (ET) and high-intensity interval training (HIIT) on the plasma levels of four inflammatory cytokines and C-reactive protein and insulin-like growth factor 1. Design. Cohort study with repeated-measures design. Methods. Seven healthy untrained volunteers completed a single bout of ET and HIIT on a cycle ergometer. ET and HIIT sessions were held in random order and at least 7 days apart. Blood was drawn before the interventions and 30 min and 2 days after the training sessions. Plasma samples were analyzed with ELISA for the interleukins (IL), IL-1β, IL-6, and IL-10, monocyte chemoattractant protein-1 (MCP-1), insulin growth factor 1 (IGF-1), and C-reactive protein (CRP). Statistical analysis was with Wilcoxon signed-rank tests. Results. ET led to both a significant acute and long-term inflammatory response with a significant decrease at 30 minutes after exercise in the IL-6/IL-10 ratio (−20%; ) and a decrease of MCP-1 (−17.9%; ). Conclusion. This study demonstrates that ET affects the inflammatory response more adversely at 30 minutes after exercise compared to HIIT. However, this is compensated by a significant decrease in MCP-1 at two days associated with a reduced risk of atherosclerosis. Felix Kaspar, Herbert F. Jelinek, Steven Perkins, Hayder A. Al-Aubaidy, Bev deJong, and Eugene Butkowski Copyright © 2016 Felix Kaspar et al. All rights reserved. Protective Effect of Adrenomedullin on Rat Leydig Cells from Lipopolysaccharide-Induced Inflammation and Apoptosis via the PI3K/Akt Signaling Pathway ADM on Rat Leydig Cells from Inflammation and Apoptosis Tue, 26 Apr 2016 12:00:00 +0000 This study was carried out to investigate whether ADM can modulate LPS-induced inflammation and apoptosis in rat Leydig cells. Leydig cells were treated with ADM before LPS-induced cytotoxicity. We determined the concentrations of ROS, MDA, GSH, LDH, and testosterone and the MMP. The mRNA levels of IL-1, IL-6, iNOS, and COX-2 were obtained, and the concentrations of IL-1, IL-6, NO, and PGE2 were determined. Apoptosis was assessed by TUNEL and detection of DNA fragmentation. The levels of mRNA and protein were determined for Bcl-2, Bax, caspase-3, and PARP. The protein contents for total and p-Akt were measured. ADM pretreatment significantly elevated the MMP and testosterone concentration and reduced the levels of ROS, MDA, GSH, and LDH. ADM pretreatment significantly decreased the mRNA levels of IL-1, IL-6, iNOS, and COX-2 and the concentrations of IL-1, IL-6, NO, and PGE2. LPS-induced TUNEL-positive Leydig cells were significantly decreased by ADM pretreatment, a result further confirmed by decreased DNA fragmentation. ADM pretreatment decreased apoptosis by significantly promoting Bcl-2 and inhibiting Bax, caspase-3, and PARP expressions. The LPS activity that reduced p-Akt level was significantly inhibited by ADM pretreatment. ADM protected rat Leydig cells from LPS-induced inflammation and apoptosis, which might be associated with PI3K/Akt mitochondrial signaling pathway. Pang-Hu Zhou, Wei Hu, Xiao-Bin Zhang, Wei Wang, and Li-Jun Zhang Copyright © 2016 Pang-Hu Zhou et al. All rights reserved. A Novel Inflammation-Based Stage (I Stage) in Patients with Resectable Esophageal Squamous Cell Carcinoma Tue, 26 Apr 2016 10:09:58 +0000 Background. Inflammation plays a key role in cancer. In the current study, we proposed a novel inflammation-based stage, named I stage, for patients with resectable esophageal squamous cell carcinoma (ESCC). Methods. Three hundred and twenty-three patients with resectable ESCC were enrolled in the current study. The I stage was calculated as follows: patients with high levels of C-reactive protein (CRP) (>10 mg/L), neutrophil-to-lymphocyte ratio (NLR) (>3.5), and platelet-count-to-lymphocyte ratio (PLR) (>150) were defined as I3. Patients with two, one, or no abnormal value were defined as I2, I1, or I0, respectively. The prognostic factors were evaluated by univariate and multivariate analyses. Results. There were 112 patients for I0, 97 patients for I1, 66 patients for I2, and 48 patients for I3, respectively. The 5-year cancer-specific survival (CSS) in patients with I0, I1, I2, and I3 was 50.0%, 30.9%, 18.2%, and 8.3%, respectively (I0 versus I1, ; I1 versus I2, ; I2 versus I3, ). Multivariate analyses revealed that I stage was an independent prognostic factor in patients with resectable ESCC (). Conclusion. The inflammation-based stage (I stage) is a novel and useful predictive factor for CSS in patients with resectable ESCC. Peng-Cheng Chen and Ji-Feng Feng Copyright © 2016 Peng-Cheng Chen and Ji-Feng Feng. All rights reserved. Immune Cells in Cancer Therapy and Drug Delivery Sun, 24 Apr 2016 12:47:44 +0000 Recent studies indicate the critical role of tumour associated macrophages, tumour associated neutrophils, dendritic cells, T lymphocytes, and natural killer cells in tumourigenesis. These cells can have a significant impact on the tumour microenvironment via their production of cytokines and chemokines. Additionally, products secreted from all these cells have defined specific roles in regulating tumour cell proliferation, angiogenesis, and metastasis. They act in a protumour capacity in vivo as evidenced by the recent studies indicating that macrophages, T cells, and neutrophils may be manipulated to exhibit cytotoxic activity against tumours. Therefore therapy targeting these cells may be promising, or they may constitute drug or anticancer particles delivery systems to the tumours. Herein, we discussed all these possibilities that may be used in cancer treatment. Ceren Eyileten, Kinga Majchrzak, Zofia Pilch, Katarzyna Tonecka, Joanna Mucha, Bartlomiej Taciak, Katarzyna Ulewicz, Katarzyna Witt, Alberto Boffi, Magdalena Krol, and Tomasz P. Rygiel Copyright © 2016 Ceren Eyileten et al. All rights reserved. Effect of High, Medium, and Low Molecular Weight Hyaluronan on Inflammation and Oxidative Stress in an In Vitro Model of Human Nasal Epithelial Cells Sun, 24 Apr 2016 06:15:45 +0000 IL-17A is involved in the activation of oxidative stress and inflammation in nasal epithelial cells. Hyaluronan (HA) in its high molecular weight form (HMW-HA) shows anti-inflammatory responses in contrast to low and medium molecular weight HA (LMW-HA and MMW-HA). The aim of this study was to investigate the pro- or anti-inflammatory biologic function of HA at different molecular weight in an in vitro model of nasal inflammation IL-17A mediated. We evaluated the ERK1/2 and IB phosphorylation, NF-B signal pathway activation, ROS production, IL-8 and NOX-4 protein, and mRNA levels, in nasal epithelial cells RPMI 2650 stimulated with recombinant human (rh) IL-17A. Furthermore, the cells were treated with HMW-HA, MMW-HA, LMW-HA, and U0126. Our results showed that rhIL-17A increased the ERK1/2, IB phosphorylation and NF-B signal pathway activation, ROS production, IL-8 and NOX-4 proteins, and mRNA levels. The addiction of HMW-HA or U0126 showed a significant downregulatory effect on inflammation due to the rhIL-17A stimulation in nasal epithelial cells. IL-17A is able to generate oxidative stress and inflammation via the activation of ERK1/2/NF-B pathway in nasal epithelial cells. The HMW-HA might represent a coadjuvant of the classic anti-inflammatory/antioxidative treatment of nasal epithelial cells during IL-17A nasal inflammation. Giusy Daniela Albano, Anna Bonanno, Luca Cavalieri, Eleonora Ingrassia, Caterina Di Sano, Liboria Siena, Loredana Riccobono, Rosalia Gagliardo, and Mirella Profita Copyright © 2016 Giusy Daniela Albano et al. All rights reserved. Correlation of A2bAR and KLF4/KLF15 with Obesity-Dyslipidemia Induced Inflammation in Uygur Population Thu, 21 Apr 2016 13:38:02 +0000 In this paper, the researchers collected visceral adipose tissue from the Uygur population, which were divided into two groups: the normal control group (NC, , 18.0 kg/m2 ≤ BMI ≤ 23.9 kg/m2) and the obese group (OB, , BMI ≥ 28 kg/m2), and then use real-time PCR to detect the mRNA expression level of key genes involved in inflammation signaling pathway. The findings suggest that, in obese status, the lower expression level of A2bAR, KLF4, and KLF15 of visceral adipose tissue may correlate with obese-dyslipidemia induced inflammation in Uygur population. Cuizhe Wang, Xiaodan Ha, Wei Li, Peng Xu, Yajuan Gu, Tingting Wang, Yan Wang, Jianxin Xie, and Jun Zhang Copyright © 2016 Cuizhe Wang et al. All rights reserved. Th17 Cytokines and Barrier Functions Thu, 21 Apr 2016 07:53:03 +0000 Guansong Wang, Musheng Bao, Xiang Zhang, Juraj Majtan, and Kong Chen Copyright © 2016 Guansong Wang et al. All rights reserved. Correlation between Serum Osteopontin and miR-181a Levels in Allergic Rhinitis Children Thu, 21 Apr 2016 07:50:10 +0000 Background. Osteopontin (OPN) has been proved to be associated with allergic airway inflammation. However, the roles of OPN and its regulation in childhood allergic rhinitis (AR) are poorly understood. Objective. This study aims to evaluate the expression of OPN and miR-181a in children with AR and their association with Th1/Th2 immune response. Methods. Children who suffered from AR were included along with control subjects. Serum was collected to examine the level of OPN and Th1/Th2 cytokines by enzyme-linked immunosorbent assay (ELISA) and the level of miR-181a by quantitative polymerase chain reaction (qPCR). Results. Children with AR had significantly higher serum levels of OPN and lower serum levels of miR-181a than healthy controls. Furthermore, serum levels of OPN were positively correlated with Th2 cytokine and negatively correlated with Th1 cytokine. On the contrary, miR-181a level had a negative correlation with IL-4/IL-5 and positive correlation with IFN-/IL-12. More importantly, there was also significant negative correlation between OPN and miR-181a. Conclusion. The OPN protein and miR-181a levels may serve as predictors of disease severity in childhood AR and appear to be promising targets for modulating AR. Wenlong Liu, Qingxiang Zeng, and Renzhong Luo Copyright © 2016 Wenlong Liu et al. All rights reserved. Nonessential Role for the NLRP1 Inflammasome Complex in a Murine Model of Traumatic Brain Injury Wed, 20 Apr 2016 13:54:40 +0000 Traumatic brain injury (TBI) elicits the immediate production of proinflammatory cytokines which participate in regulating the immune response. While the mechanisms of adaptive immunity in secondary injury are well characterized, the role of the innate response is unclear. Recently, the NLR inflammasome has been shown to become activated following TBI, causing processing and release of interleukin-1β (IL-1β). The inflammasome is a multiprotein complex consisting of nucleotide-binding domain and leucine-rich repeat containing proteins (NLR), caspase-1, and apoptosis-associated speck-like protein (ASC). ASC is upregulated after TBI and is critical in coupling the proteins during complex formation resulting in IL-1β cleavage. To directly test whether inflammasome activation contributes to acute TBI-induced damage, we assessed IL-1β, IL-18, and IL-6 expression, contusion volume, hippocampal cell death, and motor behavior recovery in Nlrp1−/−, Asc−/−, and wild type mice after moderate controlled cortical impact (CCI) injury. Although IL-1β expression is significantly attenuated in the cortex of Nlrp1−/− and Asc−/− mice following CCI injury, no difference in motor recovery, cell death, or contusion volume is observed compared to wild type. These findings indicate that inflammasome activation does not significantly contribute to acute neural injury in the murine model of moderate CCI injury. Thomas Brickler, Kisha Gresham, Armand Meza, Sheryl Coutermarsh-Ott, Tere M. Williams, Daniel E. Rothschild, Irving C. Allen, and Michelle H. Theus Copyright © 2016 Thomas Brickler et al. All rights reserved. Icariin Prevents Cartilage and Bone Degradation in Experimental Models of Arthritis Wed, 20 Apr 2016 08:04:47 +0000 Background. Icariin (ICA) is an active compound extracted from Epimedium brevicornum Maxim. Previous reports have shown that icariin has a clinically significant therapeutic effect on rheumatoid arthritis. However, little is known about the mechanism by which icariin inhibits cartilage and bone degradation. Methods. New Zealand rabbits were immunized with antigen-induced arthritis (AIA) and treated with icariin. Joint tissues from rabbits were studied by histological analysis, transmission electron microscopy (TEM), and micro-CT. The expression levels of receptor activator of nuclear factor-B ligand (RANKL) and osteoprotegerin (OPG) in joint tissues were determined using immunohistochemistry and real-time PCR analysis. Results. Histological analysis and TEM sections of cartilage in the ICA treated group showed a low level of chondrocyte destruction. Micro-CT analysis showed that the bone mineral density value and bone structural level in ICA treated rabbits were significantly higher compared with those in the AIA group. Immunohistochemistry and real-time PCR analysis showed that icariin treatment reduced RANKL expression and enhanced OPG expression levels, as compared to the AIA group. Conclusion. These data indicate that ICA suppresses articular bone loss and prevents joint destruction. This study also determined that ICA regulated articular bone loss in part by regulating RANKL and OPG expression. Chen Chao Wei, Dai Qi Ping, Fan Tian You, Chen Yong Qiang, and Che Tao Copyright © 2016 Chen Chao Wei et al. All rights reserved. Bigelovii A Protects against Lipopolysaccharide-Induced Acute Lung Injury by Blocking NF-κB and CCAAT/Enhancer-Binding Protein δ Pathways Tue, 19 Apr 2016 14:15:20 +0000 Optimal methods are applied to acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), but the mortality rate is still high. Accordingly, further studies dedicated to identify novel therapeutic approaches to ALI are urgently needed. Bigelovii A is a new natural product and may exhibit anti-inflammatory activity. Therefore, we sought to investigate its effect on lipopolysaccharide- (LPS-) induced ALI and the underlying mechanisms. We found that LPS-induced ALI was significantly alleviated by Bigelovii A treatment, characterized by reduction of proinflammatory mediator production, neutrophil infiltration, and lung permeability. Furthermore, Bigelovii A also downregulated LPS-stimulated inflammatory mediator expressions in vitro. Moreover, both NF-κB and CCAAT/enhancer-binding protein δ (C/EBPδ) activation were obviously attenuated by Bigelovii A treatment. Additionally, phosphorylation of both p38 MAPK and ERK1/2 (upstream signals of C/EBPδ activation) in response to LPS challenge was also inhibited by Bigelovii A. Therefore, Bigelovii A could attenuate LPS-induced inflammation by suppression of NF-κB, inflammatory mediators, and p38 MAPK/ERK1/2—C/EBPδ, inflammatory mediators signaling pathways, which provide a novel theoretical basis for the possible application of Bigelovii A in clinic. Chunguang Yan, Fuqin Guan, Yanfei Shen, Huifang Tang, Dong Yuan, Hongwei Gao, and Xu Feng Copyright © 2016 Chunguang Yan et al. All rights reserved. Th17 Cell Response in Mice following Motor Nerve Injury Mon, 18 Apr 2016 09:42:37 +0000 An increased risk of ALS has been reported for veterans, varsity athletes, and professional football players. The mechanism underlying the increased risk in these populations has not been identified; however, it has been proposed that motor nerve injury may trigger immune responses which, in turn, can accelerate the progression of ALS. Accumulating evidence indicates that abnormal immune reactions and inflammation are involved in the pathogenesis of ALS, but the specific immune cells involved have not been clearly defined. To understand how nerve injury and immune responses may contribute to ALS development, we investigated responses of CD4+ T cell after facial motor nerve axotomy (FNA) at a presymptomatic stage in a transgenic mouse model of ALS (B6SJL ). mice, compared with WT mice, displayed an increase in the basal activation state of CD4+ T cells and higher frequency of Th17 cells, which were further enhanced by FNA. In conclusion, mice exhibit abnormal CD4+ T cell activation with increased levels of Th17 cells prior to the onset of neurological symptoms. Motor nerve injury exacerbates Th17 cell responses and may contribute to the development of ALS, especially in those who carry genetic susceptibility to this disease. Allen Ni, Tao Yang, Nichole A. Mesnard-Hoaglin, Rafael Gutierrez, Evan B. Stubbs Jr., Susan O. McGuire, Virginia M. Sanders, Kathryn J. Jones, Eileen M. Foecking, and Junping Xin Copyright © 2016 Allen Ni et al. All rights reserved. e-Cadherin in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson Disease Sun, 17 Apr 2016 12:46:08 +0000 Today a large number of studies are focused on clarifying the complexity and diversity of the pathogenetic mechanisms inducing Parkinson disease. We used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that induces Parkinson disease, to evaluate the change of midbrain structure and the behavior of the anti-inflammatory factor e-cadherin, interleukin-6, tyrosine hydroxylase, phosphatase and tensin homolog, and caveolin-1. The results showed a strong expression of e-cadherin, variation of length and thickness of the heavy neurofilaments, increase of interleukin-6, and reduction of tyrosine hydroxylase known to be expression of dopamine cell loss, reduction of phosphatase and tensin homolog described to impair responses to dopamine, and reduction of caveolin-1 known to be expression of epithelial-mesenchymal transition and fibrosis. The possibility that the overexpression of the e-cadherin might be implicated in the anti-inflammatory reaction to MPTP treatment by influencing the behavior of the other analyzed molecules is discussed. Samuela Cataldi, Michela Codini, Stéphane Hunot, François-Pierre Légeron, Ivana Ferri, Paola Siccu, Angelo Sidoni, Francesco Saverio Ambesi-Impiombato, Tommaso Beccari, Francesco Curcio, and Elisabetta Albi Copyright © 2016 Samuela Cataldi et al. All rights reserved. Association between Serum Interleukin-17A Level and High-Altitude Deacclimatization Syndrome Thu, 14 Apr 2016 08:48:44 +0000 High-altitude deacclimatization syndrome (HADAS) is emerging as a severe public health issue that threatens the quality of life of individuals who return to lower altitude from high altitude. In this study, we measured serum levels of SOD, MDA, IL-17A, IL-10, TNF-α, and HADAS score in HADAS subjects at baseline and 50th and 100th days and to evaluate the relationship between interleukins, including IL-17A, and HADAS. Our data showed that and the serum IL-17A levels and HADAS score decreased over time in the HADAS group, and serum IL-17A levels were significantly higher in the HADAS group at baseline and 50th day compared with controls (). Furthermore, baseline serum levels of MDA and TNF-α were significantly higher, while SOD and IL-10 levels were lower in HADAS subjects compared with controls (). It is interesting that serum levels of IL-17A were clearly interrelated with HADAS incidence and severity (). ROC curve analysis showed that combined serum IL-17A and IL-10 levels were a better predictor of HADAS incidence than serum levels of IL-17A or IL-10 alone. These data suggest that serum levels of IL-17A are a novel predictive index of HADAS. Binfeng He, Hongli Li, Mingdong Hu, Weijie Dong, Zhenghua Wei, Jin Li, Wei Yao, and Xiaolan Guo Copyright © 2016 Binfeng He et al. All rights reserved. Histamine and Immune Biomarkers in CNS Disorders Wed, 13 Apr 2016 14:23:03 +0000 Neuroimmune dysregulation is a common phenomenon in different forms of central nervous system (CNS) disorders. Cross-links between central and peripheral immune mechanisms appear to be disrupted as reflected by a series of immune markers (CD3, CD4, CD7, HLA-DR, CD25, CD28, and CD56) which show variability in brain disorders such as anxiety, depression, psychosis, stroke, Alzheimer’s disease, Parkinson’s disease, attention-deficit hyperactivity disorder, migraine, epilepsy, vascular dementia, mental retardation, cerebrovascular encephalopathy, multiple sclerosis, brain tumors, cranial nerve neuropathies, mental retardation, and posttraumatic brain injury. Histamine (HA) is a pleiotropic monoamine involved in several neurophysiological functions, neuroimmune regulation, and CNS pathogenesis. Changes in brain HA show an age- and sex-related pattern, and alterations in brain HA levels are present in different CNS regions of patients with Alzheimer’s disease (AD). Brain HA in neuronal and nonneuronal compartments plays a dual role (neurotrophic versus neurotoxic) in a tissue-specific manner. Pathogenic mechanisms associated with neuroimmune dysregulation in AD involve HA, interleukin-1β, and TNF-α, whose aberrant expression contributes to neuroinflammation as an aggravating factor for neurodegeneration and premature neuronal death. Ramón Cacabelos, Clara Torrellas, Lucía Fernández-Novoa, and Francisco López-Muñoz Copyright © 2016 Ramón Cacabelos et al. All rights reserved. Walker 256 Tumor Growth Suppression by Crotoxin Involves Formyl Peptide Receptors and Lipoxin A4 Tue, 12 Apr 2016 11:51:01 +0000 We investigated the effects of Crotoxin (CTX), the main toxin of South American rattlesnake (Crotalus durissus terrificus) venom, on Walker 256 tumor growth, the pain symptoms associated (hyperalgesia and allodynia), and participation of endogenous lipoxin A4. Treatment with CTX (s.c.), daily, for 5 days reduced tumor growth at the 5th day after injection of Walker 256 carcinoma cells into the plantar surface of adult rat hind paw. This observation was associated with inhibition of new blood vessel formation and decrease in blood vessel diameter. The treatment with CTX raised plasma concentrations of lipoxin A4 and its natural analogue 15-epi-LXA4, an effect mediated by formyl peptide receptors (FPRs). In fact, the treatment with Boc-2, an inhibitor of FPRs, abolished the increase in plasma levels of these mediators triggered by CTX. The blockage of these receptors also abolished the inhibitory action of CTX on tumor growth and blood vessel formation and the decrease in blood vessel diameter. Together, the results herein presented demonstrate that CTX increases plasma concentrations of lipoxin A4 and 15-epi-LXA4, which might inhibit both tumor growth and formation of new vessels via FPRs. Patrícia Brigatte, Odair Jorge Faiad, Roberta Cornélio Ferreira Nocelli, Richardt G. Landgraf, Mario Sergio Palma, Yara Cury, Rui Curi, and Sandra Coccuzzo Sampaio Copyright © 2016 Patrícia Brigatte et al. All rights reserved. Epigenetic Control of Macrophage Polarisation and Soluble Mediator Gene Expression during Inflammation Sun, 10 Apr 2016 11:33:27 +0000 Macrophages function as sentinel cells, which constantly monitor the host environment for infection or injury. Macrophages have been shown to exhibit a spectrum of activated phenotypes, which can often be categorised under the M1/M2 paradigm. M1 macrophages secrete proinflammatory cytokines and chemokines, such as TNF-α, IL-6, IL-12, CCL4, and CXCL10, and induce phagocytosis and oxidative dependent killing mechanisms. In contrast, M2 macrophages support wound healing and resolution of inflammation. In the past decade, interest has grown in understanding the mechanisms involved in regulating macrophage activation. In particular, epigenetic control of M1 or M2 activation states has been shown to rely on posttranslational modifications of histone proteins adjacent to inflammatory-related genes. Changes in methylation and acetylation of histones by methyltransferases, demethylases, acetyltransferases, and deacetylases can all impact how macrophage phenotypes are generated. In this review, we summarise the latest advances in the field of epigenetic regulation of macrophage polarisation to M1 or M2 states, with particular focus on the cytokine and chemokine profiles associated with these phenotypes. Theodore S. Kapellos and Asif J. Iqbal Copyright © 2016 Theodore S. Kapellos and Asif J. Iqbal. All rights reserved. The Regulatory Role of Rolipram on Inflammatory Mediators and Cholinergic/Adrenergic Stimulation-Induced Signals in Isolated Primary Mouse Submandibular Gland Cells Thu, 07 Apr 2016 09:39:06 +0000 Exposure to bacterial lipopolysaccharides (LPS) induces inflammatory signals in salivary glands. We investigated the regulatory role of phosphodiesterase 4 (PDE4) inhibitor rolipram on inflammatory mediators and cholinergic/adrenergic stimulation-induced intracellular Ca2+ signaling in salivary acinar and ductal cells. Submandibular gland (SMG) expressed PDE4A through 4D mRNA and PDE4 was localized in the luminal membrane of SMG. LPS induced Ca2+ signaling and ROS production in SMG. Treatment with rolipram blocked LPS-induced Ca2+ increase and ROS production. The application of histamine evoked Ca2+ signals and ROS production, which were attenuated by rolipram in SMG cells. Moreover, LPS-induced NLRP3 inflammasome and cleaved caspase-1 were inhibited by rolipram. The inhibitory role of rolipram in ROS-induced Ca2+ signaling was mainly observed in acinar cells and not in ductal cells. Rolipram also protected SMG acinar but not ductal cells from LPS-induced cell membrane damage. In the case of cholinergic/adrenergic stimulation, carbachol/isoproterenol-induced Ca2+ signals were upregulated by the treatment of rolipram in SMG. In the case of cAMP-dependent ductal bicarbonate secretion by rolipram, no effect was observed on the modulation of ductal chloride/bicarbonate exchange activity. Rolipram could suppress the inflammatory signals and could be a potential therapeutic strategy against LPS-induced inflammation to protect the salivary gland cells. Dong Un Lee, Dong Min Shin, and Jeong Hee Hong Copyright © 2016 Dong Un Lee et al. All rights reserved. Increased Kappa/Lambda Hybrid Antibody in Serum Is a Novel Biomarker Related to Disease Activity and Inflammation in Rheumatoid Arthritis Wed, 06 Apr 2016 12:26:31 +0000 The hybrid antibodies in normal human serum were reported recently, but their clinical relevance has not yet been explored. Rheumatoid arthritis (RA) is one of the major joint diseases, and the early diagnosis and treatment of RA remain a challenge. Here, we developed a double-sandwich enzyme-linked immunosorbent assay system to quantify relative serum hybrid antibody levels in RA patients, osteoarthritis (OA) patients, and healthy controls (HC) in order to assess their potential use as a serological biomarker of early disease and clinical activity and to preliminarily investigate their immunomodulatory roles in RA. Surprisingly, we found that hybrid antibody was markedly increased in both early and established RA. Serum hybrid antibody levels were significantly correlated with clinical indexes and inflammatory markers in RA. Further analysis showed a positive correlation between hybrid antibody levels and the 28-joint disease activity score (DAS28). In conclusion, serum hybrid antibodies in RA were identified for the first time. High levels of hybrid antibody may be a useful tool in distinguishing early RA from OA and HC. We suggest hybrid antibody as a marker for disease activity. The increased hybrid antibodies were associated with inflammatory conditions in RA. Lang Yi, Mingju Hao, Tian Lu, Guigao Lin, Lida Chen, Ming Gao, Gaowei Fan, Dong Zhang, Guojing Wang, Xin Yang, Yulong Li, Kuo Zhang, Rui Zhang, Yanxi Han, Lunan Wang, and Jinming Li Copyright © 2016 Lang Yi et al. All rights reserved. IL-32: A Novel Pluripotent Inflammatory Interleukin, towards Gastric Inflammation, Gastric Cancer, and Chronic Rhino Sinusitis Wed, 06 Apr 2016 06:39:55 +0000 A vast variety of nonstructural proteins have been studied for their key roles and involvement in a number of biological phenomenona. Interleukin-32 is a novel cytokine whose presence has been confirmed in most of the mammals except rodents. The IL-32 gene was identified on human chromosome 16 p13.3. The gene has eight exons and nine splice variants, namely, IL-32α, IL-32β, IL-32γ, IL-32δ, IL-32ε, IL-32ζ, IL-32η, IL-32θ, and IL-32s. It was found to induce the expression of various inflammatory cytokines including TNF-α, IL-6, and IL-1β as well as macrophage inflammatory protein-2 (MIP-2) and has been reported previously to be involved in the pathogenesis and progression of a number of inflammatory disorders, namely, inflammatory bowel disease (IBD), gastric inflammation and cancer, rheumatoid arthritis, and chronic obstructive pulmonary disease (COPD). In the current review, we have highlighted the involvement of IL-32 in gastric cancer, gastric inflammation, and chronic rhinosinusitis. We have also tried to explore various mechanisms suspected to induce the expression of this extraordinary cytokine as well as various mechanisms of action employed by IL-32 during the mediation and progression of the above said problems. Muhammad Babar Khawar, Muddasir Hassan Abbasi, and Nadeem Sheikh Copyright © 2016 Muhammad Babar Khawar et al. All rights reserved.