Mediators of Inflammation The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Proportions of Proinflammatory Monocytes Are Important Predictors of Mortality Risk in Hemodialysis Patients Sun, 22 Oct 2017 00:00:00 +0000 Despite the continuous progression in dialysis medicine, mortality and the burden of cardiovascular disease (CVD) among hemodialysis patients are still substantial. Substantial evidence suggests that proinflammatory (CD16+) monocytes contribute to the development of atherosclerosis. A cohort of 136 stable hemodialysis patients (follow-up: 6.25 year) was assessed to investigate the association between the proportion of CD16+ monocytes for all-cause and CVD mortalities. The CD16+ monocytes were associated with both mortalities after adjusting for a preexisting CVD history. Compared to the reference group (CD16+ monocytes within [15.6–18.6], the first and second quartile), patients with CD16+ monocytes above the highest quartile level (>21.5) had an adjusted hazard ratio (HR) of 30.85 (95% confidence interval [CI]: 7.12–133.8) for CVD mortality and 5.28 (2.07–13.49) for all-cause mortality, and those with CD16+ monocytes below the lowest quartile ≤15.6), had significantly elevated death risks after 3.5-year follow-up (HR [95% CI]: 10.9 [2.42–48.96] and 4.38 [1.45–13.24] for CV and all-cause mortalities, respectively). The hemodialysis patients with CD16+ monocyte level in a low but mostly covering normal range also portended a poor prognosis. The findings shed some light for nephrologists on future prospects of early recognizing immune dysfunction and improving early intervention outcomes. Yachung Jeng, Paik Seong Lim, Ming Ying Wu, Tien-Yu Tseng, Chang Hsu Chen, Hung Ping Chen, and Tsai-Kun Wu Copyright © 2017 Yachung Jeng et al. All rights reserved. Prevention of Memory Impairment and Neurotrophic Factors Increased by Lithium in Wistar Rats Submitted to Pneumococcal Meningitis Model Sun, 22 Oct 2017 00:00:00 +0000 The aim of this study was to investigate the effects of lithium on brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) expression in the hippocampus and on memory in experimental pneumococcal meningitis. The mood-stabilizer lithium is known as a neuroprotective agent with many effects on the brain. In this study, animals received either artificial cerebrospinal fluid or Streptococcus pneumoniae suspension at a concentration of 5 × 109 CFU/mL. Eighteen hours after induction, all animals received ceftriaxone. The animals received saline or lithium (47.5 mg/kg) or tamoxifen (1 mg/kg) as adjuvant treatment, and they were separated into six groups: control/saline, control/lithium, control/tamoxifen, meningitis/saline, meningitis/lithium, and meningitis/tamoxifen. Ten days after meningitis induction, animals were subjected to open-field habituation and the step-down inhibitory avoidance tasks. Immediately after these tasks, the animals were killed and their hippocampus was removed to evaluate the expression of BDNF, NGF, and GDNF. In the meningitis group, treatment with lithium and tamoxifen resulted in improvement in memory. Meningitis group showed decreased expression of BDNF and GDNF in the hippocampus while lithium reestablished the neurotrophin expression. Lithium was able to prevent memory impairment and reestablishes hippocampal neurotrophin expression in experimental pneumococcal meningitis. Lutiana R. Simões, Roberta R. E. S. Abreu, Jaqueline S. Generoso, Jéssica A. Goularte, Allan Collodel, Vijayasree Vayalanellore Giridharan, Anitha Christy Sigamani Arumanayagam, Samira S. Valvassori, João Quevedo, and Tatiana Barichello Copyright © 2017 Lutiana R. Simões et al. All rights reserved. Davallia mariesii Moore Improves FcεRI-Mediated Allergic Responses in the Rat Basophilic Leukemia Mast Cell Line RBL-2H3 and Passive Cutaneous Anaphylaxis in Mice Thu, 19 Oct 2017 00:00:00 +0000 Davallia mariesii Moore (Drynaria rhizome extract (DRE)) is widely known for its efficacy in treating inflammation, arteriosclerosis, and bone injuries. This study evaluated whether treatment with DRE inhibited FcɛRI-mediated allergic responses in the RBL-2H3 mast cells and investigated the early- and late-phase mechanisms by which DRE exerts its antiallergic effects. IgE anti-DNP/DNP-HSA-sensitized RBL-2H3 mast cells were tested for cytotoxicity to DRE, followed by the assessment of β-hexosaminidase release. We measured the amounts of inflammatory mediators (e.g., histamine, PGD2, TNF-α, IL-4, and IL-6) and examined the expression of genes involved in arachidonate and FcεRI signaling pathways. In addition, we confirmed the antiallergic effects of DRE on passive cutaneous anaphylaxis (PCA) in mice. DRE inhibited RBL-2H3 mast cell degranulation and production of allergic mediators in them. In early allergic responses, DRE reduced expression of FcεRI signaling-related genes (e.g., Syk, Lyn, and Fyn) and extracellular signal-regulated kinase phosphorylation in mast cells. In late allergic responses, DRE reduced PGD2 release and COX-2 expression and cPLA2 phosphorylation in FcɛRI-mediated mast cells. Lastly, 250–500 mg/kg DRE significantly attenuated the IgE-induced PCA reaction in mice. These findings provide novel information on the molecular mechanisms underlying the antiallergic effects of DRE in FcɛRI-mediated allergic responses. Hyun Ju Do, Tae Woo Oh, Ju Hye Yang, Kwang Il Park, and Jin Yeul Ma Copyright © 2017 Hyun Ju Do et al. All rights reserved. Triggering Receptor Expressed on Myeloid Cells 2 Overexpression Inhibits Proinflammatory Cytokines in Lipopolysaccharide-Stimulated Microglia Wed, 18 Oct 2017 06:08:03 +0000 Microglia play an important role in mediating inflammatory processes in the central nervous system (CNS). Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor and could decrease neuropathology in Alzheimer’s disease (AD). However, the detailed mechanism remains unclear. This study was designed to elucidate the effect of TREM2 on microglia. We showed that lipopolysaccharide (LPS) stimulation significantly increases proinflammatory cytokines and suppressed TREM2 in microglia. In addition, TREM2 overexpression inhibited LPS-induced microglia activation and elevated M2 phenotype of microglia. Together, our results demonstrate that TREM2 overexpression reduced LPS-induced proinflammatory cytokine release in microglia and increased M2 phenotype of microglia. These findings provide novel insights that the regulation of microglia polarization may be an approach for ameliorating microglia inflammation in neurodegenerative diseases. Xiaobao Zhang, Fang Yan, Jizheng Cui, Yong Wu, Hengfei Luan, Miaomiao Yin, Zhibin Zhao, Jiying Feng, and Jinwei Zhang Copyright © 2017 Xiaobao Zhang et al. All rights reserved. IL-33-ST2 Axis in Liver Disease: Progression and Challenge Wed, 18 Oct 2017 05:11:58 +0000 The new member of the IL-1 family, interleukin-33 (IL-33), participates in the progression of a variety of diseases through binding with its receptor ST2. Recently, much clinical evidence and experimental data have indicated that IL-33 is associated with various liver diseases. This review primarily addresses the relationship between IL-33 and several hepatic diseases. IL-33 can alleviate high-fat diet- (HFD-) induced hepatic steatosis and insulin resistance, and IL-33 acts as an alarmin, which quickly triggers the immune system to respond to virus invasion and toxic damage to the liver. However, when liver injury is chronic, IL-33 promotes Th2 reactions and hepatic stellate cell (HSC) activity, facilitating progression to liver fibrosis. The complicated functions of IL-33 should be considered before its clinical application. Zijian Sun, Binxia Chang, Miaomiao Gao, Jiyuan Zhang, and Zhengsheng Zou Copyright © 2017 Zijian Sun et al. All rights reserved. Skin Immune Landscape: Inside and Outside the Organism Wed, 18 Oct 2017 00:00:00 +0000 The skin is an essential organ to the human body protecting it from external aggressions and pathogens. Over the years, the skin was proven to have a crucial immunological role, not only being a passive protective barrier but a network of effector cells and molecular mediators that constitute a highly sophisticated compound known as the “skin immune system” (SIS). Studies of skin immune sentinels provided essential insights of a complex and dynamic immunity, which was achieved through interaction between the external and internal cutaneous compartments. In fact, the skin surface is cohabited by microorganisms recognized as skin microbiota that live in complete harmony with the immune sentinels and contribute to the epithelial barrier reinforcement. However, under stress, the symbiotic relationship changes into a dysbiotic one resulting in skin disorders. Hence, the skin microbiota may have either positive or negative influence on the immune system. This review aims at providing basic background information on the cutaneous immune system from major cellular and molecular players and the impact of its microbiota on the well-coordinated immune responses in host defense. Florence Abdallah, Lily Mijouin, and Chantal Pichon Copyright © 2017 Florence Abdallah et al. All rights reserved. Toll-Like Receptor 4 Signalling and Its Impact on Platelet Function, Thrombosis, and Haemostasis Tue, 17 Oct 2017 07:32:45 +0000 Platelets are anucleated blood cells that participate in a wide range of physiological and pathological functions. Their major role is mediating haemostasis and thrombosis. In addition to these classic functions, platelets have emerged as important players in the innate immune system. In particular, they interact with leukocytes, secrete pro- and anti-inflammatory factors, and express a wide range of inflammatory receptors including Toll-like receptors (TLRs), for example, Toll-like receptor 4 (TLR4). TLR4, which is the most extensively studied TLR in nucleated cells, recognises lipopolysaccharides (LPS) that are compounds of the outer surface of Gram-negative bacteria. Unlike other TLRs, TLR4 is able to signal through both the MyD88-dependent and MyD88-independent signalling pathways. Notably, despite both pathways culminating in the activation of transcription factors, TLR4 has a prominent functional impact on platelet activity, haemostasis, and thrombosis. In this review, we summarise the current knowledge on TLR4 signalling in platelets, critically discuss its impact on platelet function, and highlight the open questions in this area. Thomas M. Vallance, Marie-Theres Zeuner, Harry F. Williams, Darius Widera, and Sakthivel Vaiyapuri Copyright © 2017 Thomas M. Vallance et al. All rights reserved. Suppressed Programmed Death 1 Expression on CD4+ and CD8+ T Cells in Psoriatic Patients Tue, 17 Oct 2017 00:00:00 +0000 Psoriasis is a chronic inflammatory disease mediated by T cell immunity. Programmed death 1 (PD-1), a coinhibitory receptor, plays an important role in immune regulation and maintaining peripheral tolerance. The aim of the study was to compare the expression of PD-1 on the peripheral T cells between psoriatic patients and healthy controls. The study included 75 psoriatic patients and 52 healthy volunteers. The percentages and absolute numbers of CD3+, CD4+, CD8+, CD4+PD-1+, and CD8+PD-1+ T cells were analyzed using flow cytometry. The absolute numbers and percentages of CD4+PD-1+ and CD8+PD-1+ T cells were significantly decreased in the psoriatic patients in comparison with the control group. No significant correlations were found between the absolute numbers and percentages of CD4+PD-1+ or CD8+PD-1+ T cells and clinical characteristics of psoriasis. Decreased PD-1 expression on the T cells may be responsible for impaired negative regulation of immune response in psoriasis pathogenesis. Joanna Bartosińska, Ewelina Zakrzewska, Dorota Raczkiewicz, Joanna Purkot, Anna Michalak-Stoma, Małgorzata Kowal, Dorota Krasowska, Grażyna Chodorowska, and Krzysztof Giannopoulos Copyright © 2017 Joanna Bartosińska et al. All rights reserved. Corrigendum to “Hydrogen-Rich Saline Attenuates Cardiac and Hepatic Injury in Doxorubicin Rat Model by Inhibiting Inflammation and Apoptosis” Tue, 17 Oct 2017 00:00:00 +0000 Yunan Gao, Hongxiao Yang, Yanbin Fan, Lin Li, Jiahui Fang, and Wei Yang Copyright © 2017 Yunan Gao et al. All rights reserved. Retracted: Treadmill Training Increases SIRT-1 and PGC-1α Protein Levels and AMPK Phosphorylation in Quadriceps of Middle-Aged Rats in an Intensity-Dependent Manner Mon, 16 Oct 2017 00:00:00 +0000 Mediators of Inflammation Copyright © 2017 Mediators of Inflammation. All rights reserved. Antioxidant and Anti-Inflammatory Activities in Extracts from Minke Whale (Balaenoptera acutorostrata) Blubber Sun, 08 Oct 2017 07:32:33 +0000 Intake of long-chain omega-3 polyunsaturated fatty acids (LC-n3-PUFA) is commonly recognized to reduce cardiovascular disease (CVD). In previous studies, cold-pressed whale oil (CWO) and cod liver oil (CLO) were given as a dietary supplement to healthy volunteers. Even though CWO contains less than half the amount of LC-n3-PUFA of CLO, CWO supplement resulted in beneficial effects on anti-inflammatory and CVD risk markers compared to CLO. In the present study, we prepared virtually lipid-free extracts from CWO and CLO and evaluated the antioxidative capacity (AOC) and anti-inflammatory effects. Oxygen radical absorbance capacity (ORAC) and ferric reducing antioxidant power (FRAP) assays were used to test the AOC, and the results indicated high levels of antioxidants present in all extracts. The anti-inflammatory effects of the extracts were tested with lipopolysaccharide- (LPS-) treated THP-1 cells, measuring its ability to reduce cytokine and chemokine secretion. Several CWO extracts displayed anti-inflammatory activity, and a butyl alcohol extract of CWO most effectively reduced TNF-α (50%, ) and MCP-1 (85%, ) secretion. This extract maintained a stable effect of reducing MCP-1 secretion (60%, ) even after long-term storage. In conclusion, CWO has antioxidant and anti-inflammatory activities that may act in addition to its well-known LC-n3-PUFA effects. Mari Johannessen Walquist, Svein Kristian Stormo, Ida-Johanne Jensen, Bjarne Østerud, and Karl-Erik Eilertsen Copyright © 2017 Mari Johannessen Walquist et al. All rights reserved. The Intricate Link among Gut “Immunological Niche,” Microbiota, and Xenobiotics in Intestinal Pathology Sun, 08 Oct 2017 00:00:00 +0000 Inflammatory bowel diseases (IBDs) are diseases characterized by various degrees of inflammation involving the gastrointestinal tract. Ulcerative colitis and Crohn’s disease are characterized by a dysregulated immune response leading to structural gut alterations in genetically predisposed individuals. Diverticular disease is characterized by abnormal immune response to normal gut microbiota. IBDs are linked to a lack of physiological tolerance of the mucosal immune system to resident gut microbiota and pathogens. The disruption of immune tolerance involves inflammatory pathways characterized by an unbalance between the anti-inflammatory regulatory T cells and the proinflammatory Th1/Th17 cells. The interaction among T cell subpopulations and their related cytokines, mediators of inflammation, gut microbiota, and the intestinal mucosa constitute the gut “immunological niche.” Several evidences have shown that xenobiotics, such as rifaximin, can positively modulate the inflammatory pathways at the site of gut immunological niche, acting as anti-inflammatory agents. Xenobiotics may interfere with components of the immunological niche, leading to activation of anti-inflammatory pathways and inhibition of several mediators of inflammation. In summary, xenobiotics may reduce disease-related gut mucosal alterations and clinical symptoms. Studying the complex interplay between gut immunological niche and xenobiotics will certainly open new horizons in the knowledge and therapy of intestinal pathologies. Danilo Pagliari, Giovanni Gambassi, Ciriaco A. Piccirillo, and Rossella Cianci Copyright © 2017 Danilo Pagliari et al. All rights reserved. Associations of Functional MicroRNA Binding Site Polymorphisms in IL23/Th17 Inflammatory Pathway Genes with Gastric Cancer Risk Sun, 08 Oct 2017 00:00:00 +0000 IL23/Th17 axis acts as an inflammatory pathway in gastric carcinogenesis. MicroRNA- (miRNA-) binding site single-nucleotide polymorphisms (SNPs) of inflammatory genes may alter gastric cancer (GC) susceptibility. In this study, four miRNA binding site SNPs (rs3748067 of IL17A, rs887796, rs1468488 of IL17RA, and rs10889677 of IL23R) were genotyped from 500 patients and 500 controls. Unconditional logistic regression analyses and multifactor dimensionality reduction software were used to evaluate the relationships of SNPs with GC and gene-environment interactions, respectively. Quantitative real-time PCR, Western blot analysis, and luciferase report gene assay were applied for function verification. We found that CT (ORadj = 0.59; 95% CI: 0.44–0.79), CT + TT (ORadj = 0.58; 95% CI: 0.43–0.77) genotypes, and T allele (ORadj = 0.77; 95% CI: 0.47–0.80) of rs3748067 reduced GC risk; the rs10889677 CC genotype (ORadj = 2.22; 95% CI: 1.27–3.87) and C allele (ORadj = 1.24; 95% CI: 1.02–1.52) increased GC risk. A meaningful interaction among ever smoked, family history of GC, and rs3748068 could intensify GC risk by 2.25-fold. Functional tests demonstrated the inhibitory effect of miR-10a-3p on IL17A expression in SGC-7901 cells. These results suggested that miRNA binding site SNPs within IL23/Th17 inflammatory pathway genes and their interactions with environmental factors could be associated with GC risk. Kaiyan Dong, Yajuan Xu, Qian Yang, Jiachen Shi, Jicheng Jiang, Yi Chen, Chunhua Song, and Kaijuan Wang Copyright © 2017 Kaiyan Dong et al. All rights reserved. The Light and Shadow of Senescence and Inflammation in Cardiovascular Pathology and Regenerative Medicine Sun, 08 Oct 2017 00:00:00 +0000 Recent epidemiologic studies evidence a dramatic increase of cardiovascular diseases, especially associated with the aging of the world population. During aging, the progressive impairment of the cardiovascular functions results from the compromised tissue abilities to protect the heart against stress. At the molecular level, in fact, a gradual weakening of the cellular processes regulating cardiovascular homeostasis occurs in aging cells. Atherosclerosis and heart failure are particularly correlated with aging-related cardiovascular senescence, that is, the inability of cells to progress in the mitotic program until completion of cytokinesis. In this review, we explore the intrinsic and extrinsic causes of cellular senescence and their role in the onset of these cardiovascular pathologies. Additionally, we dissect the effects of aging on the cardiac endogenous and exogenous reservoirs of stem cells. Finally, we offer an overview on the strategies of regenerative medicine that have been advanced in the quest for heart rejuvenation. Laura Iop, Eleonora Dal Sasso, Leonardo Schirone, Maurizio Forte, Mariangela Peruzzi, Elena Cavarretta, Silvia Palmerio, Gino Gerosa, Sebastiano Sciarretta, and Giacomo Frati Copyright © 2017 Laura Iop et al. All rights reserved. Mediators of Allergic Asthma and Rhinosinusitis Wed, 04 Oct 2017 05:16:54 +0000 Young Hyo Kim, Tsuguhisa Nakayama, and Da-Tian Bau Copyright © 2017 Young Hyo Kim et al. All rights reserved. Differential Effects of Angelicin Analogues on NF-κB Activity and IL-8 Gene Expression in Cystic Fibrosis IB3-1 Cells Wed, 27 Sep 2017 00:00:00 +0000 The angelicin analogue 4,6,4′-trimethylangelicin (TMA) was recently reported as a strong inhibitor of nuclear factor-κB (NF-κB) activity and of the expression of the interleukin-8 (IL-8) gene in bronchial epithelial cells in which the inflammatory response has been challenged with P. aeruginosa, the most common bacterium found in the airways of patients affected by cystic fibrosis (CF). These findings encouraged us to analyze new synthetic analogues of TMA in order to evaluate their biological activities on human bronchial epithelial CF IB3-1 cells and to find more potent anti-NF-κB agents exhibiting only minor antiproliferative effects. Analogues able to inhibit NF-κB/DNA interaction at lower concentration than TMA were found and selected to investigate their biological activity on IB3-1 cells induced with TNF-α. In this biological system, NF-κB-mediated IL-8 gene expression was investigated. Some analogues showed similar activity to the lead compound TMA. Other analogues displayed higher activities; in particular, the most interesting compounds showing relevant anti-inflammatory effects were found to cause 56–83% reduction of IL-8 mRNA expression at low concentrations (1–10 μM), without changes in cell proliferation pattern, demonstrating their potential interest for a possible development of anti-inflammatory therapy of cystic fibrosis. Ilaria Lampronti, Maria Giulia Manzione, Gianni Sacchetti, Davide Ferrari, Susanna Spisani, Valentino Bezzerri, Alessia Finotti, Monica Borgatti, Maria Cristina Dechecchi, Giorgia Miolo, Giovanni Marzaro, Giulio Cabrini, Roberto Gambari, and Adriana Chilin Copyright © 2017 Ilaria Lampronti et al. All rights reserved. Resistin as a Prooxidant Factor and Predictor of Endothelium Damage in Patients with Mild Acute Pancreatitis Exposed to Tobacco Smoke Xenobiotics Tue, 26 Sep 2017 05:02:10 +0000 Objectives. The study was aimed to assess the influence of tobacco smoke exposure on the intensity of inflammation measured by IL-6, α1-antitripsin (AAT) and α1-acid glycoprotein (AGP) concentrations, and Cd level and oxidative stress intensity measured by advanced oxidation protein product (AOPP) concentration in the blood of healthy subjects and AP patients during hospitalization. Endothelin-1 (ET-1) and resistin concentrations, markers of endothelium injury, were determined. Results. An increased IL-6 concentration in healthy smokers compared to nonsmokers and AP patients compared to controls was shown. An increased AAT and AGP concentrations during hospitalization of AP patients were noted, in both smokers (AAT, AGP) and nonsmokers (AAT). In comparison to control groups, in AP patients, a 2-fold increased resistin concentration correlating with ET-1 concentration and decreased albumin concentration accompanied by increased AOPP concentration were demonstrated. AOPP concentration was higher in smokers with AP compared to nonsmokers and gradually enhanced during their hospitalization. Conclusions. Tobacco smoke exposure can have a proinflammatory effect in both healthy subjects and AP patients. Increased resistin concentration in AP patients negatively correlating with albumin concentration has prooxidative effect on this protein resulting in enhanced AOPP level. Increased resistin concentration can intensify AAT and AGP production during AP. Milena Ściskalska, Grzegorz Marek, Zygmunt Grzebieniak, and Halina Milnerowicz Copyright © 2017 Milena Ściskalska et al. All rights reserved. Inflammatory and Anti-Inflammatory Equilibrium, Proliferative and Antiproliferative Balance: The Role of Cytokines in Multiple Myeloma Tue, 26 Sep 2017 00:00:00 +0000 Multiple myeloma (MM) is typically exemplified by a desynchronized cytokine system with increased levels of inflammatory cytokines. We focused on the contrast between inflammatory and anti-inflammatory systems by assessing the role of cytokines and their influence on MM. The aim of this review is to summarize the available information to date concerning this equilibrium to provide an overview of the research exploring the roles of serum cytokines in MM. However, the association between MM and inflammatory cytokines appears to be inadequate, and other functions, such as pro-proliferative or antiproliferative effects, can assume the role of cytokines in the genesis and progression of MM. It is possible that inflammation, when guided by cancer-specific Th1 cells, may inhibit tumour onset and progression. In a Th1 microenvironment, proinflammatory cytokines (e.g., IL-6 and IL-1) may contribute to tumour eradication by attracting leucocytes from the circulation and by increasing CD4 + T cell activity. Hence, caution should be used when considering therapies that target factors with pro- or anti-inflammatory activity. Drugs that may reduce the tumour-suppressive Th1-driven inflammatory immune response should be avoided. A better understanding of the relationship between inflammation and myeloma will ensure more effective therapeutic interventions. Caterina Musolino, Alessandro Allegra, Vanessa Innao, Andrea Gaetano Allegra, Giovanni Pioggia, and Sebastiano Gangemi Copyright © 2017 Caterina Musolino et al. All rights reserved. Expression Profiling of Long Noncoding RNA Splice Variants in Human Microvascular Endothelial Cells: Lipopolysaccharide Effects In Vitro Mon, 25 Sep 2017 06:31:18 +0000 Endothelial cell interactions with lipopolysaccharide (LPS) involve both activating and repressing signals resulting in pronounced alterations in their transcriptome and proteome. Noncoding RNAs are now appreciated as posttranscriptional and translational regulators of cellular signaling and responses, but their expression status and roles during endothelial interactions with LPS are not well understood. We report on the expression profile of long noncoding (lnc) RNAs of human microvascular endothelial cells in response to LPS. We have identified a total of 10,781 and 8310 lncRNA transcripts displaying either positive or negative regulation of expression, respectively, at 3 and 24 h posttreatment. A majority of LPS-induced lncRNAs are multiexonic and distributed across the genome as evidenced by their presence on all chromosomes. Present among these are a total of 44 lncRNAs with known regulatory functions, of which 41 multiexonic lncRNAs have multiple splice variants. We have further validated splice variant-specific expression of EGO (NONHSAT087634) and HOTAIRM1 (NONHSAT119666) at 3 h and significant upregulation of lnc-IL7R at 24 h. This study illustrates the genome-wide regulation of endothelial lncRNA splice variants in response to LPS and provides a foundation for further investigations of differentially expressed lncRNA transcripts in endothelial responses to LPS and pathophysiology of sepsis/septic shock. Imran H. Chowdhury, Hema P. Narra, Abha Sahni, Kamil Khanipov, Casey L. C. Schroeder, Jignesh Patel, Yuriy Fofanov, and Sanjeev K. Sahni Copyright © 2017 Imran H. Chowdhury et al. All rights reserved. Increased Levels of sRAGE in Diabetic CKD-G5D Patients: A Potential Protective Mechanism against AGE-Related Upregulation of Fibroblast Growth Factor 23 and Inflammation Mon, 25 Sep 2017 05:57:17 +0000 Advanced glycation end products (AGEs) may induce cardiac remodeling in kidney disease by promoting fibroblast growth factor 23 (FGF-23) expression. Since AGEs are increased in diabetes mellitus (DM), our first aim was to evaluate the existence of any potential association between AGEs, FGF-23, inflammation, and increased cardiovascular risk in DM patients on dialysis (CKD-G5D). Secondarily, we explored the potential role of the soluble receptor for AGEs (sRAGE) as a marker of heart failure. Levels of glycated albumin (GA), sRAGE, c-terminal FGF-23 (cFGF-23), brain natriuretic peptide (BNP), and inflammatory mediators were compared between DM and non-DM CKD-G5D patients. The levels of sRAGE, cFGF-23, BNP, and proinflammatory markers were over the ranges of normality in both DM and non-DM groups. Only GA and sRAGE levels were increased in DM compared to non-DM patients. Plasma levels of sRAGE and CRP were the only independent predictors of BNP concentration. In conclusion, in DM CKD-G5D patients, sRAGE appeared to be a marker of cardiac remodeling. Indeed, its increase could be a potential protective mechanism against the increased risk of cardiovascular complications related to AGEs and inflammation. The causal relationship between sRAGE and cardiovascular risk in these patients needs to be further confirmed by mechanistic studies. Elena Dozio, Valentina Corradi, Elena Vianello, Elisa Scalzotto, Massimo de Cal, Massimiliano Marco Corsi Romanelli, and Claudio Ronco Copyright © 2017 Elena Dozio et al. All rights reserved. Metformin Suppressed CXCL8 Expression and Cell Migration in HEK293/TLR4 Cell Line Sun, 24 Sep 2017 00:00:00 +0000 Chronic inflammation is associated with cancer. CXCL8 promotes tumor microenvironment construction through recruiting leukocytes and endothelial progenitor cells that are involved in angiogenesis. It also enhances tumor cell proliferation and migration. Metformin, type II diabetes medication, demonstrates anticancer properties via suppressing inflammation, tumor cell proliferation, angiogenesis, and metastasis. This study intended to address the role of metformin in regulation of CXCL8 expression and cell proliferation and migration. Our data indicated that metformin suppressed LPS-induced CXCL8 expression in a dose-dependent manner through inhibiting NF-κB, but not AP-1 and C/EBP, activities under the conditions we used. This inhibitory effect of metformin is achieved through dampening LPS-induced NF-κB nuclear translocation. Cell migration was inhibited by metformin under high dose (10 mM), but not cell proliferation. Zhihui Xiao, Wenjun Wu, and Vladimir Poltoratsky Copyright © 2017 Zhihui Xiao et al. All rights reserved. Evidences of a New Psychobiotic Formulation on Body Composition and Anxiety Sun, 24 Sep 2017 00:00:00 +0000 Background. Gut microbiota is implied in obesity, because of its ability to harvest energy from diet, and in the regulation of behavior. Given the link between gut microbiota, body composition, obesity, and anxiety, the aim of this study was to evaluate the effects of a new psychobiotic formulation. Methods. Eligible patients were randomly divided into three groups: psychobiotics oral suspension group (POSG); dietary treatment group (DTG); combined treatment group (CTG). All subjects underwent body composition and psychological profile evaluation. Results. Significant changes in body composition parameters in each group were relieved after all treatments. Hamilton anxiety rating scale (HAM-A) highlighted a significant reduction of the total score for all study population after treatments in POSG () and CTG (). A reduction of HAM-A total score in anxious subjects in POSG or CTG and a significant reduction of positive subjects for HAM-A in POSG () and in CDG () were shown. Discussion. Three-week intake of selected POS represents a good approach to solve problems related to obesity and behavior disorders. However, new clinical trials need to be performed on a larger population and for a longer period of treatment before definitive conclusions can be made. This trial is registered with NCT01890070. Carmela Colica, Ennio Avolio, Patrizio Bollero, Renata Costa de Miranda, Simona Ferraro, Paola Sinibaldi Salimei, Antonino De Lorenzo, and Laura Di Renzo Copyright © 2017 Carmela Colica et al. All rights reserved. Exhaled Nitric Oxide Is Useful in Symptomatic Radioactive Pneumonia: A Retrospective Study Sun, 24 Sep 2017 00:00:00 +0000 The aim was to defect the exhaled nitric oxide (eNO) prediction value of symptomatic radioactive pneumonia (SRP). 64 cases of lung cancer or esophagus cancer, who had the primary radiotherapy (intensity-modulated radiation therapy), were included from 2015 June to 2016 January. During the following, the patients were divided: the symptomatic radiation pneumonia group (SRP, with the CTCAE v4.0 score > 2) and the asymptomatic radiation pneumonia group (ASRP, with CTCAE v4.0 score ≤ 1). All the patients were measured eNO before and at the end of thoracic radiotherapy and gain the posttherapy eNO value and the eNO ratio (posttherapy eNO value/pretherapy eNO value), then the predictive values of eNO toward SRP were measured using the receiver-operating characteristic (ROC). 17 cases were included in the SRP group and the other 47 were included in the ASRP group. The posttherapy eNO was 29.35 (19~60) bbp versus 20.646 (11~37) (), and the ratio was 1.669 (0.61~3.5) versus 0.920 (0.35~1.5) () (symptomatic versus asymptomatic). ROC showed that the cutoff value of SRP was 19.5 bbp (posttherapy eNO, area under concentration-time curve (AUC) = 0.879) and 1.305 (eNO ratio, AUC = 0.774), which meant that posttherapy eNO and eNO ratio were useful in finding SRP. Jiancheng Li, Xiaobin Fu, and Jie Fu Copyright © 2017 Jiancheng Li et al. All rights reserved. Paradoxical Association of Postoperative Plasma Sphingosine-1-Phosphate with Breast Cancer Aggressiveness and Chemotherapy Sun, 24 Sep 2017 00:00:00 +0000 Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that has been shown to serve an important regulatory function in breast cancer progression. This study analyzes plasma S1P levels in breast cancer patients undergoing adjuvant therapy as compared to healthy control volunteers. 452 plasma S1P samples among 158 breast cancer patients, along with 20 healthy control volunteers, were analyzed. Mean S1P levels did not significantly differ between cancer patients and controls. Smoking was associated with higher S1P levels in cancer patients. Baseline S1P levels had weak inverse correlation with levels of the inflammatory mediator interleukin- (IL-) 17 and CCL-2 and positive correlation with tumor necrosis factor alpha (TNF-α). Midpoint S1P levels during adjuvant therapy were lower than baseline, with near return to baseline after completion, indicating a relationship between chemotherapy and circulating S1P. While stage of disease did not correlate with plasma S1P levels, they were lower among patients with Her2-enriched and triple-negative breast cancer as compared to luminal-type breast cancer. Plasma S1P levels are paradoxically suppressed in aggressive breast cancer and during adjuvant chemotherapy, which raises the possibility that postoperative plasma S1P levels do not reflect S1P secretion from resected breast cancer. Rajesh Ramanathan, Ali Raza, Jamie Sturgill, Debra Lyon, Jessica Young, Nitai C. Hait, and Kazuaki Takabe Copyright © 2017 Rajesh Ramanathan et al. All rights reserved. Curcumin Attenuation of Wear Particle-Induced Osteolysis via RANKL Signaling Pathway Suppression in Mouse Calvarial Model Wed, 20 Sep 2017 06:33:30 +0000 Wear particle-induced chronic inflammation and osteoclastogenesis are two critical factors in the osteolytic process. Curcumin (CUR) is an active compound of the medicinal herb Curcuma longa and has anti-inflammatory and antiosteoclastogenic properties. Our study tested the hypothesis that CUR might attenuate polymethylmethacrylate- (PMMA-) induced inflammatory osteolysis using mouse calvaria osteolysis model in vivo and in vitro. The mice were divided into four groups: phosphate-buffered saline group, CUR, PMMA, and PMMA + CUR groups. Three days before PMMA particle implantation, the mice were intraperitoneally injected with CUR (25 mg/kg/day). Ten days after the operation, the mouse calvaria was harvested for microcomputed tomography, histomorphometry, and molecular biology analysis. As expected, CUR markedly reduced the secretion of tumor necrosis factor-α, interleukin- (IL-) 1β, and IL-6 in the calvarial organ culture. Moreover, CUR suppressed osteoclastogenesis and decreased bone resorption in vivo compared with PMMA-stimulated calvaria. Furthermore, CUR downregulated the osteoclast-specific gene expression and reversed the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin messenger RNA and protein ratio in PMMA particle-stimulated mice. These results suggest that CUR attenuated PMMA particle-induced inflammatory osteolysis by suppressing the RANKL signaling pathway in the murine calvarium, which could be a candidate compound to prevent and treat AL. Tao Cheng, Yaochao Zhao, Bin Li, Mengqi Cheng, Jiaxing Wang, and Xianlong Zhang Copyright © 2017 Tao Cheng et al. All rights reserved. Osteopontin Augments M2 Microglia Response and Separates M1- and M2-Polarized Microglial Activation in Permanent Focal Cerebral Ischemia Wed, 20 Sep 2017 05:47:31 +0000 Background. Focal cerebral ischemia induces distinct neuroinflammatory processes. We recently reported the extracellular phosphor-glyco-protein osteopontin (OPN) to directly affect primary microglia in vitro, promoting survival while shifting their inflammatory profile towards a more neutral phenotype. We here assessed the effects of OPN on microglia after stroke in vivo, with focus on infarct demarcation. Methods. Animals underwent focal photothrombotic stroke and were injected intracerebroventricularly with 500 μg OPN or vehicle. Immunohistochemistry assessed neuronal damage and infarct volume, neovascularisation, glial scar formation, microglial activation, and M1 and M2 polarisation. Results. After photothrombotic stroke, areas covered by M1 and M2 microglia substantially overlapped. OPN treatment reduced that overlap, with microglia appearing more spread out and additionally covering the infarct core. OPN additionally modulated the quantity of microglia subpopulations, reducing iNOS+ M1 cells while increasing M2 microglia, shifting the M1/M2 balance towards an M2 phenotype. Moreover, OPN polarized astrocytes towards the infarct. Conclusion. Microglial activation and M1 and M2 polarization have distinct but overlapping spatial patterns in permanent focal ischemia. Data suggest that OPN is involved in separating M1 and M2 subpopulations, as well as in shifting microglia polarization towards the M2 phenotype modulating beneficially inflammatory responses after focal infarction. Anne Ladwig, Helene Luise Walter, Jörg Hucklenbroich, Antje Willuweit, Karl-Josef Langen, Gereon Rudolph Fink, Maria Adele Rueger, and Michael Schroeter Copyright © 2017 Anne Ladwig et al. All rights reserved. Aloperine Protects Mice against DSS-Induced Colitis by PP2A-Mediated PI3K/Akt/mTOR Signaling Suppression Tue, 19 Sep 2017 07:11:13 +0000 Colitis is a major form of inflammatory bowel disease which involved mucosal immune dysfunction. Aloperine is an alkaloid isolated from the shrub Sophora alopecuroides L. and has been recognized as an effective treatment for inflammatory and allergic diseases. The present study aimed to examine the molecular mechanisms underlying aloperine-mediated colitis protection. We found that aloperine treatment improved colitis induced by dextran sodium sulfate (DSS) based on body weight, disease activity index, colonic length, and spleen index. Aloperine also effectively attenuated DSS-induced intestinal inflammation based on the pathological score and myeloperoxidase expression and activity in colon tissues. In addition, aloperine regulated T-cell proportions and promoted Foxp3 expression in the spleens and mesenteric lymph nodes of DSS-induced colitis mice and in the spleens of the Foxp3GFP mice. Aloperine inhibited Jurkat and mouse naïve T-cell apoptosis. Furthermore, aloperine inhibited PI3K/Akt/mTOR signaling and upregulated PP2A expression in the DSS-induced colitis mice and in Jurkat cells, but LB-100 (PP2A inhibitor) resulted in an elevated Akt activity in Jurkat cells, activated T-cells, and human splenic mononuclear cells. Aloperine inhibited T-cell and lymphocyte proliferation, but LB-100 reverse these effects. In conclusion, aloperine regulates inflammatory responses in colitis by inhibiting the PI3K/Akt/mTOR signaling in a PP2A-dependent manner. Xiaoxia Fu, Fei Sun, Faxi Wang, Junai Zhang, Biying Zheng, Jixin Zhong, Tiantian Yue, Xuebao Zheng, Jun-Fa Xu, and Cong-Yi Wang Copyright © 2017 Xiaoxia Fu et al. All rights reserved. Acid-Sensing Ion Channels as Potential Therapeutic Targets in Neurodegeneration and Neuroinflammation Tue, 19 Sep 2017 00:00:00 +0000 Acid-sensing ion channels (ASICs) are a family of proton-sensing channels that are voltage insensitive, cation selective (mostly permeable to Na+), and nonspecifically blocked by amiloride. Derived from 5 genes (ACCN1–5), 7 subunits have been identified, 1a, 1b, 2a, 2b, 3, 4, and 5, that are widely expressed in the peripheral and central nervous system as well as other tissues. Over the years, different studies have shown that activation of these channels is linked to various physiological and pathological processes, such as memory, learning, fear, anxiety, ischemia, and multiple sclerosis to name a few, so their potential as therapeutic targets is increasing. This review focuses on recent advances that have helped us to better understand the role played by ASICs in different pathologies related to neurodegenerative diseases, inflammatory processes, and pain. Audrey Ortega-Ramírez, Rosario Vega, and Enrique Soto Copyright © 2017 Audrey Ortega-Ramírez et al. All rights reserved. Pretreatment Liver Injury Predicts Poor Prognosis of DLBCL Patients Sun, 17 Sep 2017 00:00:00 +0000 Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of lymphoma, with different clinical manifestation and prognosis. The International Prognostic Index (IPI), an index designed during the prerituximab era for aggressive lymphoma, showed variable values in the prediction of patient clinical outcomes. The aim of this study was to analyze the prognostic value and causes of pretreatment liver injury in 363 de novo DLBCL patients in our institution. Pretreatment liver impairment, commonly detected in lymphoma patients, showed significant association with poor outcomes and increased serum inflammatory cytokines in DLBCL patients but had no relation to hepatitis B virus replication nor lymphomatous hepatic infiltration. Multivariate analysis revealed that liver dysfunction, advanced Ann Arbor stage, and elevated lactate dehydrogenase (LDH) were independent adverse prognostic factors of both PFS and OS. Accordingly, a new liver-IPI prognostic model was designed by adding liver injury as an important factor in determining IPI score. Based on Kaplan-Meier curves for PFS and OS, the liver-IPI showed better stratification in DLBCL patients than either the IPI or the revised IPI in survival prediction. Qing Shi, Rong Shen, Chao-Fu Wang, Xing Fan, Ying Qian, Bin-Shen Ou-Yang, Yan Zhao, Christophe Leboeuf, Anne Janin, Shu Cheng, Li Wang, and Wei-Li Zhao Copyright © 2017 Qing Shi et al. All rights reserved. Middermal Elastolysis: Dermal Fibroblasts Cooperate with Inflammatory Cells to the Elastolytic Disorder Sun, 17 Sep 2017 00:00:00 +0000 Little is known about the cause and pathophysiology of middermal elastolysis (MDE). In this condition, variable inflammatory infiltrate may be present or not together with loss of elastic fibres in the middermis that spares both papillary and lower reticular dermis. MDE may be a consequence of abnormal extracellular matrix degradation related to an imbalance between elastolytic enzymes released from inflammatory and resident cells and their naturally occurring inhibitors. However, the cause of this imbalance is still an object of investigation. In order to shed light on the role of fibroblasts in MDE, we used fibroblast cultures from MDE and control subjects to evaluate matrix metalloproteinases (MMPs) and their major inhibitor TIMP-1, which in combination with neutrophil or macrophage proteases released in inflamed areas may influence the elastolytic burden. We demonstrate that fibroblasts derived from MDE produce in vitro low levels of TIMP-1, the major inhibitor of MMPs. Elevated levels of MMP-2, MMP-14, and TIMP-2 capable to activate in a cooperative manner pro-MMP-2 are present in MDE tissue samples. Additionally, significant reaction for MMP-1 is present in the same MDE areas. These data all together suggest that ECM changes in MDE are due to cooperation of different cell populations (i.e., inflammatory cells and fibroblasts). Giovanna De Cunto, Arianna Lamberti, Maria Margherita de Santi, Clelia Miracco, Michele Fimiani, Giuseppe Lungarella, and Eleonora Cavarra Copyright © 2017 Giovanna De Cunto et al. All rights reserved.