Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. CRP and SAA1 Haplotypes Are Associated with Both C-Reactive Protein and Serum Amyloid A Levels: Role of Suppression Effects Wed, 25 May 2016 14:23:22 +0000 To test the statistical association of the CRP and SAA1 locus variants with their corresponding circulating levels and metabolic and inflammatory biomarker levels by using mediation analysis, a sample population of 599 Taiwanese subjects was enrolled and five CRP and four SAA1 variants were genotyped. Correlation analysis revealed that C-reactive protein (CRP) and serum amyloid A (SAA) levels were significantly associated with multiple metabolic phenotypes and inflammatory marker levels. Our data further revealed a significant association of CRP and SAA1 variants with both CRP and SAA levels. Mediation analysis revealed that SAA levels suppressed the association between SAA1 genotypes/haplotypes and CRP levels and that CRP levels suppressed the association between CRP haplotypes and SAA levels. In conclusion, genetic variants at the CRP and SAA1 loci independently affect both CRP and SAA levels, and their respective circulating levels act as suppressors. These results provided further evidence of the role of the suppression effect in biological science and may partially explain the missing heritability in genetic association studies. Yu-Lin Ko, Lung-An Hsu, Semon Wu, Ming-Sheng Teng, and Hsin-Hua Chou Copyright © 2016 Yu-Lin Ko et al. All rights reserved. Neuroinvasion and Inflammation in Viral Central Nervous System Infections Wed, 25 May 2016 08:33:04 +0000 Neurotropic viruses can cause devastating central nervous system (CNS) infections, especially in young children and the elderly. The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) have been described as relevant sites of entry for specific viruses as well as for leukocytes, which are recruited during the proinflammatory response in the course of CNS infection. In this review, we illustrate examples of established brain barrier models, in which the specific reaction patterns of different viral families can be analyzed. Furthermore, we highlight the pathogen specific array of cytokines and chemokines involved in immunological responses in viral CNS infections. We discuss in detail the link between specific cytokines and chemokines and leukocyte migration profiles. The thorough understanding of the complex and interrelated inflammatory mechanisms as well as identifying universal mediators promoting CNS inflammation is essential for the development of new diagnostic and treatment strategies. Tobias Dahm, Henriette Rudolph, Christian Schwerk, Horst Schroten, and Tobias Tenenbaum Copyright © 2016 Tobias Dahm et al. All rights reserved. The Vascular Endothelial Growth Factors-Expressing Character of Mesenchymal Stem Cells Plays a Positive Role in Treatment of Acute Lung Injury In Vivo Tue, 24 May 2016 06:47:33 +0000 Recently, mesenchymal stem cells (MSC) have been proved to be beneficial in acute respiratory distress syndrome (ARDS). Vascular endothelial growth factor (VEGF) is an important angiogenesis factor that MSC release. However, the precise role of VEGF-expressing character of MSC in the MSC treatment for ARDS remains obscure. Here, we firstly knocked down the gene VEGF in MSC (MSC-ShVEGF) with lentiviral transduction. Then we injected the MSC-ShVEGF to rats with lipopolysaccharide-induced acute lung injury (ALI) via the tail vein. Data showed that MSC transplantation significantly increased VEGF levels in the lung, reduced lung permeability, protected lung endothelium from apoptosis, facilitated VE-cadherin recovery, controlled inflammation, and attenuated lung injury. However, VEGF gene knockdown in MSC led to relatively insufficient VEGF expression in the injured lung and significantly diminished the therapeutic effects of MSC on ALI, suggesting an important role of VEGF-expressing behavior of MSC in the maintenance of VEGF in the lung and the MSC treatment for ALI. Hence, we conclude that MSC restores the lung permeability and attenuates lung injury in rats with ALI in part by maintaining a “sufficient” VEGF level in the lung and the VEGF-expressing character of MSC plays a positive role in the therapeutic effects of MSC on ARDS. Yi Yang, Shuling Hu, Xiuping Xu, Jinze Li, Airan Liu, Jibin Han, Songqiao Liu, Ling Liu, and Haibo Qiu Copyright © 2016 Yi Yang et al. All rights reserved. Inhibition of Macrophage Migration Inhibitory Factor Protects against Inflammation and Matrix Deposition in Kidney Tissues after Injury Mon, 23 May 2016 11:16:39 +0000 Background. Macrophage migration inhibitory factor (MIF) is an important immunoregulatory cytokine involved in inflammation, which may be one important reason resulting in matrix deposition in renal tissues after injury. However, the underlying mechanisms have not yet been elucidated. Methods and Results. We uncovered a crucial role of MIF in inflammation and collagen deposition in vivo and in vitro. In rats, ureteral obstruction induced tubular injury, matrix accumulation, and inflammatory cell infiltration. Additionally, enhanced MIF levels in the obstructed kidneys were closely related to the increasing numbers of CD68-positive macrophages. These obstruction-induced injuries can be relieved by recanalization, consequently resulting in downregulated expression of MIF and its receptor CD74. Similarly, ischemia reperfusion induced renal injury, and it was accompanied by elevated MIF levels and macrophages infiltration. In cultured tubular epithelial cells (TECs), aristolochic acid (AA) promoted matrix production and increased MIF expression, as well as the release of macrophage-related factors. Inhibition of MIF with an antagonist ISO-1 resulted in the abolishment of these genotypes in AA-treated TECs. Conclusion. MIF plays an important role in macrophage-related inflammation and matrix deposition in kidney tissues following injury. MIF as a specific inhibitor may have therapeutic potential for patients with inflammatory and fibrotic kidney diseases. Hong Lu, Yongyu Bai, Lianfeng Wu, Weilong Hong, Yong Liang, Bicheng Chen, and Yongheng Bai Copyright © 2016 Hong Lu et al. All rights reserved. Plasma Periostin Levels Are Increased in Chinese Subjects with Obesity and Type 2 Diabetes and Are Positively Correlated with Glucose and Lipid Parameters Mon, 23 May 2016 06:17:31 +0000 The purpose of this study is to examine the relations among plasma periostin, glucose and lipid metabolism, insulin resistance and inflammation in Chinese patients with obesity (OB), and type 2 diabetes mellitus (T2DM). Plasma periostin levels in the T2DM group were significantly higher than the NGT group (). Patients with both OB and T2DM had the highest periostin levels. Correlation analysis showed that plasma periostin levels were positively correlated with weight, waist circumference (WC), body mass index (BMI), waist-hip ratio (WHR), fasting plasma glucose (FPG), 2 h postchallenge plasma glucose (2 h PG), glycated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), TNF-α, and IL-6 ( or 0.001) and negatively correlated with high-density lipoprotein cholesterol (HDL-C) (). Multiple linear regression analysis showed that TG, TNF-α, and HOMA-IR were independent related factors in influencing the levels of plasma periostin (). These results suggested that Chinese patients with obesity and T2DM had significantly higher plasma periostin levels. Plasma periostin levels were strongly associated with plasma TG, chronic inflammation, and insulin resistance. Yuanyuan Luo, Hua Qu, Hang Wang, Huili Wei, Jing Wu, Yang Duan, Dan Liu, and Huacong Deng Copyright © 2016 Yuanyuan Luo et al. All rights reserved. Macrophage Migration Inhibitory Factor and Malondialdehyde as Potential Predictors of Vascular Risk Complications in Type 2 Diabetes Mellitus: Cross-Sectional Case Control Study in Saudi Arabia Thu, 19 May 2016 16:34:08 +0000 Background. Malondialdehyde (MDA) has been implicated in the development of many acute inflammatory, autoimmune diseases as well as chronic inflammatory metabolic disorders. Involvement of inflammatory response and oxidative stress is currently suggested as a mechanism underlying development of diabetes and its complications. Objective. To evaluate the clinical utility of MDA, macrophage migration inhibitory factor (MIF), LDL-C/HDL-C, and TG/HDL-C ratio as noninvasive laboratory markers for prediction of T2DM vascular complications. Method. 63 Saudi T2DM patients and 16 age and sex matched controls were included. Serum MDA and MIF were assayed by thiobarbituric acid reactive substances and ELISA, respectively. TG/HDL-C and LDL-C/HDL-C ratios were calculated. Results. Uncontrolled DM patients had significantly higher levels of MDA, MIF, TG/HDL-C, and LDL-C/HDL-C ratios when compared with controlled DM patients and control group (). MDA had 100% sensitivity and 88% specificity. MIF showed 97% sensitivity and 100% specificity and LDL-C/HDL-C had 97% sensitivity and 95% specificity. Meanwhile, TG/HDL-C had the lowest sensitivity and specificity in identifying diabetic patients who would suffer from vascular complications. Conclusion. MDA, MIF, and LDL-C/HDL-C could be new predictors of metabolic disturbance which promote vascular complications in T2DM. Heba Kamal Morsi, Manar Mohammad Ismail, Hassan Abdelaziz Hassan Gaber, and Amani Abdelhamid Elbasmy Copyright © 2016 Heba Kamal Morsi et al. All rights reserved. Autocrine Acetylcholine, Induced by IL-17A via NFκB and ERK1/2 Pathway Activation, Promotes MUC5AC and IL-8 Synthesis in Bronchial Epithelial Cells Thu, 19 May 2016 14:12:11 +0000 IL-17A is overexpressed in the lung during acute neutrophilic inflammation. Acetylcholine (ACh) increases IL-8 and Muc5AC production in airway epithelial cells. We aimed to characterize the involvement of nonneuronal components of cholinergic system on IL-8 and Muc5AC production in bronchial epithelial cells stimulated with IL-17A. Bronchial epithelial cells were stimulated with recombinant human IL-17A (rhIL-17A) to evaluate the ChAT expression, the ACh binding and production, the IL-8 release, and the Muc5AC production. Furthermore, the effectiveness of PD098,059 (inhibitor of MAPKK activation), Bay11-7082 (inhibitor of IkBα phosphorylation), Hemicholinium-3 (HCh-3) (choline uptake blocker), and Tiotropium bromide (Spiriva®) (anticholinergic drug) was tested in our in vitro model. We showed that rhIL-17A increased the expression of ChAT, the levels of ACh binding and production, and the IL-8 and Muc5AC production in stimulated bronchial epithelial cells compared with untreated cells. The pretreatment of the cells with PD098,059 and Bay11-7082 decreased the ChAT expression and the ACh production/binding, while HCh-3 and Tiotropium decreased the IL-8 and Muc5AC synthesis in bronchial epithelial cells stimulated with rhIL-17A. IL-17A is involved in the IL-8 and Muc5AC production promoting, via NFκB and ERK1/2 pathway activation, the synthesis of ChAT, and the related activity of autocrine ACh in bronchial epithelial cells. Angela Marina Montalbano, Giusy Daniela Albano, Anna Bonanno, Loredana Riccobono, Caterina Di Sano, Maria Ferraro, Liboria Siena, Giulia Anzalone, Rosalia Gagliardo, Michael Paul Pieper, Mark Gjomarkaj, and Mirella Profita Copyright © 2016 Angela Marina Montalbano et al. All rights reserved. An EP2 Agonist Facilitates NMDA-Induced Outward Currents and Inhibits Dendritic Beading through Activation of BK Channels in Mouse Cortical Neurons Thu, 19 May 2016 13:20:46 +0000 Prostaglandin E2 (PGE2), a major metabolite of arachidonic acid produced by cyclooxygenase pathways, exerts its bioactive responses by activating four E-prostanoid receptor subtypes, EP1, EP2, EP3, and EP4. PGE2 enables modulating N-methyl-D-aspartate (NMDA) receptor-mediated responses. However, the effect of E-prostanoid receptor agonists on large-conductance Ca2+-activated K+ (BK) channels, which are functionally coupled with NMDA receptors, remains unclear. Here, we showed that EP2 receptor-mediated signaling pathways increased NMDA-induced outward currents (), which are associated with the BK channel activation. Patch-clamp recordings from the acutely dissociated mouse cortical neurons revealed that an EP2 receptor agonist activated , whereas an EP3 receptor agonist reduced it. Agonists of EP1 or EP4 receptors showed no significant effects on . A direct perfusion of 3,5′-cyclic adenosine monophosphate (cAMP) through the patch pipette facilitated , which was abolished by the presence of protein kinase A (PKA) inhibitor. Furthermore, facilitation of caused by an EP2 receptor agonist was significantly suppressed by PKA inhibitor. Finally, the activation of BK channels through EP2 receptors facilitated the recovery phase of NMDA-induced dendritic beading in the primary cultured cortical neurons. These results suggest that a direct activation of BK channels by EP2 receptor-mediated signaling pathways plays neuroprotective roles in cortical neurons. Yoshinori Hayashi, Saori Morinaga, Xia Liu, Jing Zhang, Zhou Wu, Takeshi Yokoyama, and Hiroshi Nakanishi Copyright © 2016 Yoshinori Hayashi et al. All rights reserved. Maternal Vitamin D Level Is Associated with Viral Toll-Like Receptor Triggered IL-10 Response but Not the Risk of Infectious Diseases in Infancy Thu, 19 May 2016 06:34:30 +0000 Reports on the effect of prenatal vitamin D status on fetal immune development and infectious diseases in childhood are limited. The aim of this study was to investigate the role of maternal and cord blood vitamin D level in TLR-related innate immunity and its effect on infectious outcome. Maternal and cord blood 25 (OH)D level were examined from 372 maternal-neonatal pairs and their correlation with TLR-triggered TNF-α, IL-6, and IL-10 response at birth was assessed. Clinical outcomes related to infection at 12 months of age were also evaluated. The result showed that 75% of the pregnant mothers and 75.8% of the neonates were vitamin deficient. There was a high correlation between maternal and cord 25(OH)D levels (, ). Maternal vitamin D level was inversely correlated with IL-10 response to TLR3 () and TLR7-8 stimulation (). However, none of the TLR-triggered cytokine productions were associated with cord 25(OH)D concentration. There was no relationship between maternal and cord blood vitamin D status with infectious diseases during infancy. In conclusion, our study had shown that maternal vitamin D, but not cord vitamin D level, was associated with viral TLR-triggered IL-10 response. Sui-Ling Liao, Shen-Hao Lai, Ming-Han Tsai, Man-Chin Hua, Kuo-Wei Yeh, Kuan-Wen Su, Chi-Hsin Chiang, Shih-Yin Huang, Chuan-Chi Kao, Tsung-Chieh Yao, and Jing-Long Huang Copyright © 2016 Sui-Ling Liao et al. All rights reserved. The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation Wed, 18 May 2016 11:46:19 +0000 Toll-like receptor 4 (TLR4) belongs to the family of pattern recognition receptors (PRRs). They are highly conserved receptors that recognize conserved pathogen-associated molecular patterns (PAMPs), thus representing the first line of defense against infections. TLR4 has been long recognized as the sensing receptor for gram-negative lipopolysaccharide (LPS). In addition, it also binds endogenous molecules produced as a result of tissue injury. Hence, TLR4 represents a key receptor on which both infectious and noninfectious stimuli converge to induce a proinflammatory response. TLR4-mediated inflammation, triggered by exogenous or endogenous ligands, is also involved in several acute and chronic diseases, having a pivotal role as amplifier of the inflammatory response. This review focuses on the research progress about the role of TLR4 activation in infectious and noninfectious (e.g., sterile) inflammation and the effects of TLR4 signaling in some pathological conditions. Monica Molteni, Sabrina Gemma, and Carlo Rossetti Copyright © 2016 Monica Molteni et al. All rights reserved. Cardiovascular Involvement in Sepsis Wed, 18 May 2016 06:56:04 +0000 Emanuela Turillazzi, Vittorio Fineschi, Cristian Palmiere, and Consolato Sergi Copyright © 2016 Emanuela Turillazzi et al. All rights reserved. Photobiomodulation Therapy Decreases Oxidative Stress in the Lung Tissue after Formaldehyde Exposure: Role of Oxidant/Antioxidant Enzymes Tue, 17 May 2016 13:59:25 +0000 Formaldehyde is ubiquitous pollutant that induces oxidative stress in the lung. Several lung diseases have been associated with oxidative stress and their control is necessary. Photobiomodulation therapy (PBMT) has been highlighted as a promissory treatment, but its mechanisms need to be better investigated. Our objective was to evaluate the effects of PBMT on the oxidative stress generated by FA exposure. Male Wistar rats were submitted to FA exposure of 1% or vehicle (3 days) and treated or not with PBMT (1 and 5 h after each FA exposure). Rats treated only with laser were used as control. Twenty-four hours after the last FA exposure, we analyzed the effects of PBMT on the generation of nitrites and hydrogen peroxide, oxidative burst, glutathione reductase, peroxidase, S-transferase enzyme activities, the gene expression of nitric oxide, cyclooxygenase, superoxide dismutase, the catalase enzyme, and heme oxygenase-1. PBMT reduced the generation of nitrites and hydrogen peroxide and increased oxidative burst in the lung cells. A decreased level of oxidant enzymes was observed which were concomitantly related to an increased level of antioxidants. This study provides new information about the antioxidant mechanisms of PBMT in the lung and might constitute an important tool for lung disease treatment. Rodrigo Silva Macedo, Mayara Peres Leal, Tarcio Teodoro Braga, Éric Diego Barioni, Stephanie de Oliveira Duro, Anna Carolina Ratto Tempestini Horliana, Niels Olsen Saraiva Câmara, Tânia Marcourakis, Sandra Helena Poliselli Farsky, and Adriana Lino-dos-Santos-Franco Copyright © 2016 Rodrigo Silva Macedo et al. All rights reserved. Angelica acutiloba Kitagawa Extract Attenuates DSS-Induced Murine Colitis Tue, 17 May 2016 13:35:45 +0000 We examined the protective effects of Angelica acutiloba Kitagawa (AAK) extract on a murine model of acute experimental colitis. Colitis was induced by 4% dextran sulfate sodium (DSS) in the drinking water of male C57BL/6 mice, for 7 consecutive days. Oral administration of AAK extract (500 mg/kg/day) significantly alleviated DSS-induced symptoms such as anorexia, weight loss, events of diarrhea or bloody stools, and colon shortening. Histological damage was also ameliorated, as evidenced by the architectural preservation and suppression of inflammatory cell infiltration in colonic samples. Treatment improved the colonic mRNA expression of different inflammatory markers: cytokines, inducible enzymes, matrix metalloproteinases, and tight junction-related proteins. In the isolated serum, IgE levels were downregulated. Collectively, these findings indicate the therapeutic potentials of AAK as an effective complementary or alternative modality for the treatment of ulcerative colitis. Jong-Chan Jang, Kang Min Lee, and Seong-Gyu Ko Copyright © 2016 Jong-Chan Jang et al. All rights reserved. Inflammatory Response in Preterm and Very Preterm Newborns with Sepsis Mon, 16 May 2016 12:11:18 +0000 The response of the adaptive immune system is usually less intense in premature neonates than term neonates. The primary objective of this study was to determine whether immunological parameters vary between preterm (PT) neonates (≥32 weeks of gestational age) and very preterm (VPT) neonates (<32 weeks of gestational age). A cross-sectional study was designed to prospectively follow PT and VPT neonates at risk of developing sepsis. Plasma concentrations of IFN-γ, TNF-α, IL-6, IL-4, and IL-10 were detected using flow cytometry. C-reactive protein (C-RP) and the complex SC5b-9 were detected in the plasma using commercial kits. A total of 83 patients were included. The laboratory results and clinical histories showed that 26 patients had sepsis; 14 were VPT, and 12 were PT. The levels of C-RP, SC5b-9 (innate immune response mediators), and IL-10 or IL-4 (anti-inflammatory cytokines) were elevated during sepsis in both groups. IFN-γ, TNF-α, and IL-6 (proinflammatory cytokines) were differentially elevated only in PT neonates. The VPT neonates with sepsis presented increases in C-RP, SC5b-9, and anti-inflammatory cytokines but not in proinflammatory cytokines, whereas PT neonates showed increases in all studied mediators of inflammation. Enrique Segura-Cervantes, Javier Mancilla-Ramírez, Jorge González-Canudas, Erika Alba, René Santillán-Ballesteros, Deneb Morales-Barquet, Gabriela Sandoval-Plata, and Norma Galindo-Sevilla Copyright © 2016 Enrique Segura-Cervantes et al. All rights reserved. Shikonin Attenuates Concanavalin A-Induced Acute Liver Injury in Mice via Inhibition of the JNK Pathway Mon, 16 May 2016 11:44:40 +0000 Objective. Shikonin possesses anti-inflammatory effects. However, its function in concanavalin A-induced acute liver injury remains uncertain. The aim of the present study was to investigate the functions of shikonin and its mechanism of protection on ConA-induced acute liver injury. Materials and Methods. Balb/C mice were exposed to ConA (20 mg/kg) via tail vein injection to establish acute liver injury; shikonin (7.5 mg/kg and 12.5 mg/kg) was intraperitoneally administered 2 h before the ConA injection. The serum liver enzyme levels and the inflammatory cytokine levels were determined at 3, 6, and 24 h after ConA injection. Results. After the injection of ConA, inflammatory cytokines IL-1β, TNF-α, and IFN-γ were significantly increased. Shikonin significantly ameliorated liver injury and histopathological changes and suppressed the release of inflammatory cytokines. The expressions of Bcl-2 and Bax were markedly affected by shikonin pretreatment. LC3, Beclin-1, and p-JNK expression levels were decreased in the shikonin-pretreated groups compared with the ConA-treated groups. Shikonin attenuated ConA-induced liver injury by reducing apoptosis and autophagy through the inhibition of the JNK pathway. Conclusion. Our results indicated that shikonin pretreatment attenuates ConA-induced acute liver injury by inhibiting apoptosis and autophagy through the suppression of the JNK pathway. Tong Liu, Yujing Xia, Jingjing Li, Sainan Li, Jiao Feng, Liwei Wu, Rong Zhang, Shizan Xu, Keran Cheng, Yuqing Zhou, Shunfeng Zhou, Weiqi Dai, Kan Chen, Fan Wang, Jie Lu, Yingqun Zhou, and Chuanyong Guo Copyright © 2016 Tong Liu et al. All rights reserved. Targeting Endothelial Adhesion Molecule Transcription for Treatment of Inflammatory Disease: A Proof-of-Concept Study Mon, 16 May 2016 09:09:44 +0000 Targeting the endothelial adhesion molecules that control leukocyte trafficking into a tissue has been explored as a biological therapy for inflammatory diseases. However, these molecules also participate in leukocyte migration for immune surveillance, and inhibiting the physiological level of an adhesion molecule might promote infection or malignancy. We explored the concept of targeting endothelial adhesion molecule transcription during inflammation in a human system. Intercellular adhesion molecule 1 (ICAM-1) mediates leukocyte migration across the retinal endothelium in noninfectious posterior uveitis. We observed an increase in the transcription factor, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1), in parallel with ICAM-1, in human retinal endothelial cells treated with tumor necrosis factor-alpha (TNF-α), and identified putative binding sites for NF-κB1 within the ICAM-1 regulatory region. We targeted induced NF-κB1 expression in endothelial cells with small interfering (si)RNA. Knockdown of NF-κB1 significantly decreased cell surface expression of ICAM-1 protein induced by TNF-α but did not reduce constitutive ICAM-1 expression. Consistently, NF-κB1 knockdown significantly reduced leukocyte binding to cell monolayers in the presence of TNF-α but did not impact baseline binding. Findings of this proof-of-concept study indicate that induced transcription of endothelial adhesion molecules might be targeted therapeutically for inflammatory disease in humans. Liam M. Ashander, Binoy Appukuttan, Yuefang Ma, Dione Gardner-Stephen, and Justine R. Smith Copyright © 2016 Liam M. Ashander et al. All rights reserved. Inflammation to Pulmonary Diseases Mon, 16 May 2016 07:11:00 +0000 Kang-Yun Lee, Kazuhiro Ito, and Kittipong Maneechotesuwan Copyright © 2016 Kang-Yun Lee et al. All rights reserved. Plasma MicroRNA-21 Predicts Postoperative Pulmonary Complications in Patients Undergoing Pneumoresection Thu, 12 May 2016 13:43:42 +0000 Postoperative pulmonary complication (PPC) remains the most common postoperative complication in patients undergoing noncardiac thoracic surgery. We conducted the clinical study to determine the diagnostic role of miRNA-21 in noncardiac thoracic surgery. 368 patients undergoing noncardiac thoracic surgery were recruited. Blood samples were collected before anesthesia and 2 hours after incision during surgery for RT-PCR measurement of miRNA-21. PPC occurrence, extrapulmonary complications, duration of ICU stay, and death within 1 year were evaluated. The overall rate of PPCs following surgery was 10.32%. A high relative miRNA-21 level was an independent risk factor for PPCs within 7 days (OR, 2.69; 95% CI, 1.25–5.66; and ). High miRNA-21 was also associated with an increased risk of extrapulmonary complications (OR, 3.62; 95% CI, 2.26–5.81; and ), prolonged ICU stay (OR, 6.54; 95% CI, 2.26–18.19; and ), increased death within 30 days (OR, 6.17; 95% CI, 2.11–18.08; and ), and death within 1 year (OR, 7.30; 95% CI, 2.76–19.28; and ). In summary, plasma miRNA-21 may serve as a novel biomarker of PPCs for patients undergoing noncardiac thoracic surgery. Yaling Liu, Peiying Li, Xinyu Cheng, Weifeng Yu, Liqun Yang, and Hui Zhu Copyright © 2016 Yaling Liu et al. All rights reserved. CETP Lowers TLR4 Expression Which Attenuates the Inflammatory Response Induced by LPS and Polymicrobial Sepsis Thu, 12 May 2016 13:35:19 +0000 Sepsis is a systemic inflammatory response to infection eliciting high mortality rate which is a serious health problem. Despite numerous studies seeking for therapeutic alternatives, the mechanisms involved in this disease remain elusive. In this study we evaluated the influence of cholesteryl ester transfer protein (CETP), a glycoprotein that promotes the transfer of lipids between lipoproteins, on the inflammatory response in mice. Human CETP transgenic mice were compared to control mice (wild type, WT) after polymicrobial sepsis induced by cecal ligation and puncture (CLP), aiming at investigating their survival rate and inflammatory profiles. Macrophages from the peritoneal cavity were stimulated with LPS in the presence or absence of recombinant CETP for phenotypic and functional studies. In comparison to WT mice, CETP mice showed higher survival rate, lower IL-6 plasma concentration, and decreased liver toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH) protein. Moreover, macrophages from WT mice to which recombinant human CETP was added decreased LPS uptake, TLR4 expression, NF-κB activation and IL-6 secretion. This raises the possibility for new therapeutic tools in sepsis while suggesting that lowering CETP by pharmacological inhibitors should be inconvenient in the context of sepsis and infectious diseases. Tatiana Martins Venancio, Roberta Marcondes Machado, Angela Castoldi, Mariane Tami Amano, Valeria Sutti Nunes, Eder Carlos Rocha Quintao, Niels Olsen Saraiva Camara, Francisco Garcia Soriano, and Patrícia Miralda Cazita Copyright © 2016 Tatiana Martins Venancio et al. All rights reserved. Pleiotropic Effects of IL-2 on Cancer: Its Role in Cervical Cancer Thu, 12 May 2016 11:43:38 +0000 IL-2 receptor (IL-2R) signalling is critical for normal lymphocyte proliferation, but its role in cervical cancer is not fully understood. The receptor is composed of three chains: IL-2α, IL-2β, and IL-2γ. Intracellular signalling is initiated by ligand-induced heterodimerization of the IL-2β and IL-2γ chains, resulting in the activation of multiple intracellular kinases. Recently, IL-2R was shown to be expressed on nonhaematopoietic cells, especially on several types of tumour cells. However, the function of this receptor on malignant cells has not been clearly defined. The expression of IL-2R and the production of IL-2 in cervical cancer cells have been documented as well as expression of molecules of the JAK-STAT pathway. In the current review we have highlighted the differences in the responses of molecules downstream from the IL-2R in normal lymphocytes and tumour cells that could explain the presence of tumour cells in an environment in which cytotoxic lymphocytes also exist and compete and also the effect of different concentrations of IL-2 that could activate effector cells of the immune system cells, which favour the elimination of tumour cells, or concentrations that may promote a regulatory microenvironment in which tumour cells can easily grow. Arturo Valle-Mendiola, Adriana Gutiérrez-Hoya, María del Carmen Lagunas-Cruz, Benny Weiss-Steider, and Isabel Soto-Cruz Copyright © 2016 Arturo Valle-Mendiola et al. All rights reserved. Differential Expression of Inflammation-Related Genes in Children with Down Syndrome Wed, 11 May 2016 07:30:37 +0000 Objective. The aim of the study was to investigate the expression patterns of a specific set of genes involved in the inflammation process in children with Down Syndrome (DS) and children without the syndrome (control group) to identify differences that may be related to the immune abnormalities observed in DS individuals. Method. RNA samples were obtained from peripheral blood, and gene expression was quantified using the TaqMan® Array Plate Human Inflammation Kit, which facilitated the investigation into 92 inflammation-related genes and four reference genes using real-time polymerase chain reaction (qPCR). Results. Twenty genes showed differential expression in children with DS; 12 were overexpressed (PLA2G2D, CACNA1D, ALOX12, VCAM1, ICAM1, PLCD1, ADRB1, HTR3A, PDE4C, CASP1, PLA2G5, and PLCB4), and eight were underexpressed (LTA4H, BDKRB1, ADRB2, CD40LG, ITGAM, TNFRSF1B, ITGB1, and TBXAS1). After statistically correcting for the false discovery rate, only the genes BDKRB1 and LTA4H showed differential expression, and both were underexpressed within the DS group. Conclusion. DS children showed differential expression of inflammation-related genes that were not located on chromosome 21 compared with children without DS. The BDKRB1 and LTA4H genes may differentiate the case and control groups based on the inflammatory response, which plays an important role in DS pathogenesis. Cláudia Regina Santos Silva, Joice Matos Biselli-Périco, Bruna Lancia Zampieri, Wilson Araujo Silva Jr., Jorge Estefano Santana de Souza, Matheus Carvalho Bürger, Eny Maria Goloni-Bertollo, and Érika Cristina Pavarino Copyright © 2016 Cláudia Regina Santos Silva et al. All rights reserved. Epstein-Barr Virus-Induced Gene 3 (EBI3) Blocking Leads to Induce Antitumor Cytotoxic T Lymphocyte Response and Suppress Tumor Growth in Colorectal Cancer by Bidirectional Reciprocal-Regulation STAT3 Signaling Pathway Tue, 10 May 2016 07:59:01 +0000 Epstein-Barr virus-induced gene 3 (EBI3) is a member of the interleukin-12 (IL-12) family structural subunit and can form a heterodimer with IL-27p28 and IL-12p35 subunit to build IL-27 and IL-35, respectively. However, IL-27 stimulates whereas IL-35 inhibits antitumor T cell responses. To date, little is known about the role of EBI3 in tumor microenvironment. In this study, firstly we assessed EBI3, IL-27p28, IL-12p35, gp130, and p-STAT3 expression with clinicopathological parameters of colorectal cancer (CRC) tissues; then we evaluated the antitumor T cell responses and tumor growth with a EBI3 blocking peptide. We found that elevated EBI3 may be associated with IL-12p35, gp130, and p-STAT3 to promote CRC progression. EBI3 blocking peptide promoted antitumor cytotoxic T lymphocyte (CTL) response by inducing Granzyme B, IFN-γ production, and p-STAT3 expression and inhibited CRC cell proliferation and tumor growth to associate with suppressing gp130 and p-STAT3 expression. Taken together, these results suggest that EBI3 may mediate a bidirectional reciprocal-regulation STAT3 signaling pathway to assist the tumor escape immune surveillance in CRC. Yanfang Liang, Qianqian Chen, Wenjing Du, Can Chen, Feifei Li, Jingying Yang, Jianyu Peng, Dongping Kang, Bihua Lin, Xingxing Chai, Keyuan Zhou, and Jincheng Zeng Copyright © 2016 Yanfang Liang et al. 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.