http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2013 , Hindawi Publishing Corporation . All rights reserved. Thu, 23 May 2013 17:40:02 +0000 http://www.hindawi.com/journals/mi/2013/102457/ Chlamydia trachomatis, the agent of bacterial sexually transmitted infections, can manifest itself as either acute cervicitis, pelvic inflammatory disease, or a chronic asymptomatic infection. Inflammation induced by C. trachomatis contributes greatly to the pathogenesis of disease. Here we evaluated the anti-inflammatory capacity of naringenin, a polyphenolic compound, to modulate inflammatory mediators produced by mouse J774 macrophages infected with live C. trachomatis. Infected macrophages produced a broad spectrum of inflammatory cytokines (GM-CSF, TNF, IL-1β, IL-1α, IL-6, IL-12p70, and IL-10) and chemokines (CCL4, CCL5, CXCL1, CXCL5, and CXCL10) which were downregulated by naringenin in a dose-dependent manner. Enhanced protein and mRNA gene transcript expressions of TLR2 and TLR4 in addition to the CD86 costimulatory molecule on infected macrophages were modulated by naringenin. Pathway-specific inhibition studies disclosed that p38 mitogen-activated-protein kinase (MAPK) is involved in the production of inflammatory mediators by infected macrophages. Notably, naringenin inhibited the ability of C. trachomatis to phosphorylate p38 in macrophages, suggesting a potential mechanism of its attenuation of concomitantly produced inflammatory mediators. Our data demonstrates that naringenin is an immunomodulator of inflammation triggered by C. trachomatis, which possibly may be mediated upstream by modulation of TLR2, TLR4, and CD86 receptors on infected macrophages and downstream via the p38 MAPK pathway. Abebayehu N. Yilma, Shree R. Singh, Lisa Morici, and Vida A. Dennis Copyright © 2013 Abebayehu N. Yilma et al. All rights reserved. Thu, 23 May 2013 15:36:02 +0000 http://www.hindawi.com/journals/mi/2013/608187/ Interleukin (IL)-33 is a recently identified cytokine belonging to the IL-1 family that is widely expressed throughout the body and has the ability to induce Th2 immune responses. In addition, IL-33 plays a key role in promoting host defenses against parasites through the expansion of a novel population of innate lymphoid cells. In recent years, a growing body of evidence has shown that the proinflammatory properties displayed by IL-33 are detrimental in several experimental models of inflammation; in others, however, IL-33 appears to have protective functions. In 2010, four different research groups consistently described the upregulation of IL-33 in patients with inflammatory bowel disease (IBD). Animal models of IBD were subsequently utilized in order to mechanistically determine the precise role of IL-33 in chronic intestinal inflammation, without, however, reaching conclusive evidence demonstrating whether IL-33 is pathogenic or protective. Indeed, data generated from these studies suggest that IL-33 may possess dichotomous functions, enhancing inflammatory responses on one hand and promoting epithelial integrity on the other. This review focuses on the available data regarding IL-33/ST2 in the physiological and inflammatory states of the gut in order to speculate on the possible roles of this novel IL-1 family member in intestinal inflammation. Luca Pastorelli, Carlo De Salvo, Maurizio Vecchi, and Theresa T. Pizarro Copyright © 2013 Luca Pastorelli et al. All rights reserved. Wed, 22 May 2013 15:14:30 +0000 http://www.hindawi.com/journals/mi/2013/156053/ We studied the influence of PON1 on metabolic alterations induced by oxidized LDL when incubated with endothelial cells. HUVEC cells were incubated with native LDL, oxidized LDL, oxidized LDL plus HDL from wild type mice, and oxidized LDL plus HDL from PON1-deficient mice. Results showed alterations in carbohydrate and phospholipid metabolism and increased apoptosis in cells incubated with oxidized LDL. These changes were partially prevented by wild type mouse HDL, but the effects were less effective with HDL from PON1-deficient mice. Our results suggest that PON1 may play a significant role in endothelial cell survival by protecting cells from alterations in the respiratory chain induced by oxidized LDL. These results extend current knowledge on the protective role of HDL and PON1 against oxidation and apoptosis in endothelial cells. Anabel García-Heredia, Judit Marsillach, Anna Rull, Iris Triguero, Isabel Fort, Bharti Mackness, Michael Mackness, Diana M. Shih, Jorge Joven, and Jordi Camps Copyright © 2013 Anabel García-Heredia et al. All rights reserved. Wed, 22 May 2013 10:51:44 +0000 http://www.hindawi.com/journals/mi/2013/501430/ Recent investigations have indicated that reactive metabolites and AGE-RAGE-mediated inflammation might play an important role in the pathogenesis of ischemia-reperfusion injury in liver transplantation. In this observational clinical study, 150 patients were enrolled following liver transplantation from deceased donors. The occurrence of short-term complications within 10 days of transplantation was documented. Blood samples were collected prior to transplantation, immediately after transplantation, and at consecutive time points, for a total of seven days after transplantation. Plasma levels of methylglyoxal were determined using HPLC, whereas plasma levels of L-arginine, asymmetric dimethylarginine, advanced glycation endproducts-carboxylmethyllysine, soluble receptor for advanced glycation endproducts, and total antioxidant capacity were measured by ELISA. Patients following liver transplantation were shown to suffer from increased RAGE-associated inflammation with an AGE load mainly dependent upon reactive carbonyl species-derived AGEs. In contrast, carboxylmethyllysine-derived AGEs were of a minor importance. As assessed by the ratio of L-arginine/asymmetric dimethylarginine, the bioavailability of nitric oxide was shown to be reduced in hepatic IRI, especially in those patients suffering from perfusion disorders following liver transplantation. For the early identification of patients at high risk of perfusion disorders, the implementation of asymmetric dimethylarginine measurements in routine diagnostics following liver transplantation from deceased donors should be taken into consideration. Thorsten Brenner, Thomas H. Fleming, David Spranz, Peter Schemmer, Thomas Bruckner, Florian Uhle, Eike O. Martin, Markus A. Weigand, and Stefan Hofer Copyright © 2013 Thorsten Brenner et al. All rights reserved. Tue, 21 May 2013 10:25:10 +0000 http://www.hindawi.com/journals/mi/2013/920214/ Identifying rare human metabolic disorders that result from a single-gene defect has not only enabled improved diagnostic and clinical management of such patients, but also has resulted in key biological insights into the pathophysiology of the increasingly prevalent metabolic syndrome. Insulin resistance and type 2 diabetes are linked to obesity and driven by excess caloric intake and reduced physical activity. However, key events in the causation of the metabolic syndrome are difficult to disentangle from compensatory effects and epiphenomena. This review provides an overview of three types of human monogenic disorders that result in (1) severe, non-syndromic obesity, (2) pancreatic beta cell forms of early-onset diabetes, and (3) severe insulin resistance. In these patients with single-gene defects causing their exaggerated metabolic disorder, the primary defect is known. The lessons they provide for current understanding of the molecular pathogenesis of the common metabolic syndrome are highlighted. Rinki Murphy, Richard W. Carroll, and Jeremy D. Krebs Copyright © 2013 Rinki Murphy et al. All rights reserved. Mon, 20 May 2013 14:21:08 +0000 http://www.hindawi.com/journals/mi/2013/863036/ To test the hypothesis that brain-derived neurotrophic factor-(BDNF-) mediated neuroprotection is reduced by high-mobility group box-1 (HMGB1) in diabetic retina, paired vitreous and serum samples from 46 proliferative diabetic retinopathy and 34 nondiabetic patients were assayed for BDNF, HMGB1, soluble receptor for advanced glycation end products (sRAGE), soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and TBARS. We also examined retinas of diabetic and HMGB1 intravitreally injected rats. The effect of the HMGB1 inhibitor glycyrrhizin on diabetes-induced changes in retinal BDNF expressions was studied. Western blot, ELISA, and TBARS assays were used. BDNF was not detected in vitreous samples. BDNF levels were significantly lower in serum samples from diabetic patients compared with nondiabetics, whereas HMGB1, sRAGE, sICAM-1, and TBARS levels were significantly higher in diabetic serum samples. MCP-1 levels did not differ significantly. There was significant inverse correlation between serum levels of BDNF and HMGB1. Diabetes and intravitreal administration of HMGB1 induced significant upregulation of the expression of HMGB1, TBARS, and cleaved caspase-3, whereas the expression of BDNF and synaptophysin was significantly downregulated in rat retinas. Glycyrrhizin significantly attenuated diabetes-induced downregulation of BDNF. Our results suggest that HMGB1-induced downregulation of BDNF might be involved in pathogenesis of diabetic retinal neurodegeneration. Ahmed M. Abu El-Asrar, Mohd Imtiaz Nawaz, Mohammad Mairaj Siddiquei, Abdullah S. Al-Kharashi, Dustan Kangave, and Ghulam Mohammad Copyright © 2013 Ahmed M. Abu El-Asrar et al. All rights reserved. Mon, 20 May 2013 10:47:07 +0000 http://www.hindawi.com/journals/mi/2013/864319/ This paper reviews the impact of genetic variability of drug metabolizing enzymes, transporters, receptors, and pathways involved in chronic pain perception on the efficacy and safety of analgesics and other drugs used for chronic pain treatment. Several candidate genes have been identified in the literature, while there is usually only limited clinical evidence substantiating for the penetration of the testing for these candidate biomarkers into the clinical practice. Further, the pain-perception regulation and modulation are still not fully understood, and thus more complex knowledge of genetic and epigenetic background for analgesia will be needed prior to the clinical use of the candidate genetic biomarkers. Svatopluk Světlík, Karolína Hronová, Hana Bakhouche, Olga Matoušková, and Ondřej Slanař Copyright © 2013 Svatopluk Světlík et al. All rights reserved. Thu, 16 May 2013 12:30:31 +0000 http://www.hindawi.com/journals/mi/2013/982383/ Poly-γ-glutamic acid (γ-PGA), naturally secreted from various strains of Bacillus, has anti-inflammatory activity. In inflammatory bowel disease (IBD), inflammation is promoted and sustained by angiogenesis; however, the role played by γ-PGA in this condition is unclear. Therefore, we evaluated γ-PGA effects on angiogenesis and inflammation in a dextran sulfate sodium- (DSS-) induced mouse colitis model. Experimental colitis was induced in male C57BL/6 mice by administering 3% DSS. Disease activity index (DAI), histopathological scores, microvascular density, myeloperoxidase activity, and VEGF-A and VEGFR2 expression were compared among control mice, DSS-treated mice, and mice receiving 3% DSS along with γ-PGA at 50 mg/kg body weight per day or 3% DSS with γ-PGA at 200 mg/kg body weight per day. We found that γ-PGA significantly attenuated weight loss, DAI, and colon shortening. γ-PGA also significantly reduced histopathological evidence of injury. Moreover, γ-PGA significantly attenuated DSS-induced blood vessel densities. Furthermore, γ-PGA attenuated DSS-induced expression of VEGF-A and its receptor, VEGFR2. In addition, γ-PGA treatment led to reduced recruitment of leukocytes to the inflamed colon. Therefore, our results indicate that γ-PGA has potential application in conditions marked by inflammatory-driven angiogenesis and mucosal inflammation. Munkhtugs Davaatseren, Jin-Taek Hwang, Jae Ho Park, Myung-Sunny Kim, Shuaiyu Wang, and Mi Jeong Sung Copyright © 2013 Munkhtugs Davaatseren et al. All rights reserved. Thu, 16 May 2013 09:01:39 +0000 http://www.hindawi.com/journals/mi/2013/862628/ The lipoxins are the first proresolution mediators to be recognized and described as the endogenous “braking signals” for inflammation. We evaluated the anti-inflammatory and proresolution bioactions of lipoxin A4 in our lipopolysaccharide (LPS-)induced lung injury model. We demonstrated that lipoxin A4 significantly improved histology of rat lungs and inhibited IL-6 and TNF-α in LPS-induced lung injury. In addition, lipoxin A4 increased alveolar fluid clearance (AFC) and the effect of lipoxin A4 on AFC was abolished by (a specific inhibitor of CFTR). Moreover, lipoxin A4 could increase cystic fibrosis transmembrane conductance regulator (CFTR) protein expression in vitro and in vivo. In rat primary alveolar type II (ATII) cells, LPS decreased CFTR protein expression via activation of PI3K/Akt, and lipoxin A4 suppressed LPS-stimulated phosphorylation of Akt. These results showed that lipoxin A4 enhanced CFTR protein expression and increased AFC via PI3K/Akt pathway. Thus, lipoxin A4 may provide a potential therapeutic approach for acute lung injury. Yi Yang, Yang Cheng, Qing-Quan Lian, Li Yang, Wei Qi, De-Rong Wu, Xia Zheng, Yong-Jian Liu, Wen-Juan Li, Sheng-Wei Jin, and Fang Gao Smith Copyright © 2013 Yi Yang et al. All rights reserved. Mon, 13 May 2013 18:27:53 +0000 http://www.hindawi.com/journals/mi/2013/927636/ Background. Procalcitonin (PCT) is a useful surrogate marker for the differentiation of postoperative infection and unspecific inflammatory reaction after surgery. It is known that postoperative course of the PCT serum level varies with type of surgery. No data exists about the postoperative course of serum PCT levels after primary total hip replacement (THR). Purpose. To characterize early postoperative serum PCT levels in uneventful primary THR compared to postoperative levels of different frequently used inflammatory blood parameters. Method. We prospectively investigated 31 patients. Blood samples were taken preoperatively and for 5 days postoperatively. PCT levels were compared with C-reactive protein (CRP), interleukin-6 (IL-6), and blood leucocyte counts (WBC). Results. In uneventful THR PCT levels showed a uniform low-level course with a peak at the second postoperative day. At the fifth day values returned to almost preoperative levels. On contrary, CRP levels remained high during the entire observational period. Only IL-6 levels showed a peak at postoperative day one with a quick and uniform return to preoperative levels. Conclusion. Similar to observations in cardiothoracic, intestinal, and neural surgeries, postoperative course of PCT after primary THR showed a uniform low-level course with a peak at the second postoperative day but below expected levels in systemic infections. Samy Bouaicha, Samuel Blatter, Beat K. Moor, Katharina Spanaus, Claudio Dora, and Clément M. L. Werner Copyright © 2013 Samy Bouaicha et al. All rights reserved. Sun, 12 May 2013 17:36:07 +0000 http://www.hindawi.com/journals/mi/2013/963748/ Multiple sclerosis (MS) is an inflammatory disease in which the myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. It is caused by an autoimmune response to self-antigens in a genetically susceptible individual induced by unknown environmental factors. Principal cells of the immune system that drive the immunopathological processes are T cells, especially of TH1 and TH17 subsets. However, in recent years, it was disclosed that regulatory T cells took part in, too. Subsequently, there was endeavour to develop ways how to re-establish their physiological functions. In this review, we describe known mechanisms of action, efficacy, and side-effects of contemporary and emerging MS immunotherapeutical agents on Treg cells and other cells of the immune system involved in the immunopathogenesis of the disease. Furthermore, we discuss how laboratory immunology can offer physicians its help in the diagnosis process and decisions what kind of biological therapy should be used. Milan Buc Copyright © 2013 Milan Buc. All rights reserved. Sun, 12 May 2013 08:02:42 +0000 http://www.hindawi.com/journals/mi/2013/713284/ Acylation stimulating protein (ASP) is an adipokine derived from the immune complement system, which stimulates fat storage and is typically increased in obesity, type 2 diabetes, and cardiovascular disease. Using a diet-induced obesity (DIO) mouse model, the acute effects of ASP on energy metabolism and inflammatory processes in vivo were evaluated. We hypothesized that ASP would specifically exert proinflammatory effects. C57Bl/6 wild-type mice were put on a high-fat-high-sucrose diet for 12 weeks. Mice were then subjected to both glucose and insulin tolerance tests, each manipulation being preceded by recombinant ASP or vehicle (control) bolus injection. ASP supplementation increased whole-body glucose excursion, and this was accomplished with reduced concomitant insulin levels. However, ASP did not directly alter insulin sensitivity. ASP supplementation induced a proinflammatory phenotype, with higher levels of cytokines including IL-6 and TNF- in plasma and in adipose tissue, liver, and skeletal muscle mRNA. Additionally, ASP increased M1 macrophage content of these tissues. ASP exerted a direct concentration-dependent role in the migration and M1 activation of cultured macrophages. Altogether, the in vivo and in vitro experiments demonstrate that ASP plays a role in both energy metabolism and inflammation, with paradoxical whole-body glucose-sensitizing yet proinflammatory effects. Alexandre Fisette, Pegah Poursharifi, Katerina Oikonomopoulou, Mercedes N. Munkonda, Marc Lapointe, and Katherine Cianflone Copyright © 2013 Alexandre Fisette et al. All rights reserved. Thu, 09 May 2013 13:43:10 +0000 http://www.hindawi.com/journals/mi/2013/279781/ Introduction. Inflammation and endothelium-derived superoxides are important pathomechanisms in atherothrombotic diseases. We could previously show that the tyrosine phosphatase SHP-1 acts as a negative regulator in endothelial superoxide production. In this study we investigated the influence of SHP-1 on platelet-endothelium interaction and arterial thrombosis in TNFα-induced endothelial inflammation in vivo. Methods. Arteriolar thrombosis and platelet rolling in vivo were investigated in C57BL/6 mice using intravital microscopy in the dorsal skinfold chamber microcirculation model. Results. Inhibition of SHP-1 by the specific pharmacological inhibitor sodium stibogluconate did not significantly enhance platelet-endothelium interaction in vivo under physiological conditions but led to an augmented fraction of rolling platelets in TNFα-induced systemic inflammation. Accordingly, ferric-chloride-induced arteriolar thrombus formation, which was already increased by SHP-1 inhibition, was further enhanced in the setting of TNFα-induced inflammation. Platelet aggregation in vitro as well as ex vivo was not influenced by SHP-1-inhibition. In cultured endothelial cells, sodium stibogluconate increased TNFα-induced surface expression of p-selectin and von Willebrand factor. Additionally, TNFα increased SHP-1 activity and protein expression. Conclusions. The endothelial tyrosine phosphatase SHP-1 plays an important role for vascular hemostasis in vivo, which is crucial in TNFα-induced endothelial inflammation where it may serve as an autoinhibitory molecule to prevent excess inflammatory response and thrombus formation. Elisabeth Koch, Joachim Pircher, Thomas Czermak, Erik Gaitzsch, Stefan Alig, Hanna Mannell, Markus Niemeyer, Florian Krötz, and Markus Wörnle Copyright © 2013 Elisabeth Koch et al. All rights reserved. Wed, 08 May 2013 16:38:37 +0000 http://www.hindawi.com/journals/mi/2013/751068/ The physiology and pathology of the respiratory and gastrointestinal tracts are closely related. This similarity between the two organs may underlie why dysfunction in one organ may induce illness in the other. For example, smoking is a major risk factor for COPD and IBD and increases the risk of developing Crohn’s disease. Probiotics have been defined as “live microorganisms which, when administered in adequate amounts, confer health benefits on the host.” In model systems probiotics regulate innate and inflammatory immune responses. Commonly used probiotics include lactic acid bacteria, particularly Lactobacillus, Bifidobacterium, and Saccharomyces, and these are often used as dietary supplements to provide a health benefit in gastrointestinal diseases including infections, inflammatory bowel disease, and colon cancer. In this respect, probiotics probably act as immunomodulatory agents and activators of host defence pathways which suggest that they could influence disease severity and incidence at sites distal to the gut. There is increasing evidence that orally delivered probiotics are able to regulate immune responses in the respiratory system. This review provides an overview of the possible role of probiotics and their mechanisms of action in the prevention and treatment of respiratory diseases. Esmaeil Mortaz, Ian M. Adcock, Gert Folkerts, Peter J. Barnes, Arjan Paul Vos, and Johan Garssen Copyright © 2013 Esmaeil Mortaz et al. All rights reserved. Wed, 08 May 2013 15:11:18 +0000 http://www.hindawi.com/journals/mi/2013/391473/ Inflammatory bowel disease (IBD) is a chronic inflammatory condition characterized by an abnormal immune response against food or bacterial antigens in genetically predisposed individuals. Several factors of innate and adaptive immune system take part in the inflammatory process, probably actively contributing in endoscopic and histological healing at molecular level. Although it is difficult to discriminate whether they are primary factors in determining these events or they are secondarily involved, it would be interesting to have a clear map of those factors in order to have a restricted number of potentially “good candidates” for mucosal healing. The present review will present a class of these factors and their modulation in course of therapy, starting from pathogenic studies involving several treatments associated with good clinical outcomes. This approach is meant to help in the difficult task of identifying “good candidates” for healing signatures, which could also be possible new therapeutic targets for clinical management of IBD patients. F. Scaldaferri, V. Petito, L. Lopetuso, G. Bruno, V. Gerardi, G. Ianiro, A. Sgambato, A. Gasbarrini, and G. Cammarota Copyright © 2013 F. Scaldaferri et al. All rights reserved. Wed, 08 May 2013 15:04:06 +0000 http://www.hindawi.com/journals/mi/2013/515048/ Background. Inflammation mediators related to radiation proctitis are partially elucidated, and neovascularization is thought to play a key role. Objectives. To investigate the expression of vascular endothelial growth factor (VEGF) and CD31 as angiogenetic markers in postradiation rectal tissue. Methods. Rectal mucosa biopsies from 11 patients who underwent irradiation for prostate cancer were examined immunohistochemically for the expression of VEGF and CD31 at three time settings—before, at the completion of, and 6 months after radiotherapy. VEGF expressing vascular endothelial cells and CD31 expressing microvessels were counted separately in 10 high-power fields (HPFs). VEGF vascular index (VEGF-VI) and microvascular density (MVD) were calculated as the mean number of VEGF positive cells per vessel or the mean number of vessels per HPF, respectively. Histological features were also evaluated. Results. VEGF-VI was significantly higher at the completion of radiotherapy ( versus , ) declining 6 months after. MVD increased significantly only 6 months after radiotherapy ( versus , ). The histopathological examination revealed inflammatory changes at the completion of radiotherapy regressing in the majority of cases 6 months after. Conclusions. Our results showed that in postradiation rectal biopsy specimens neoangiogenesis seems to be inflammation-related and constitutes a significant postradiation component of the tissue injury. G. Karamanolis, I. Delladetsima, V. Kouloulias, K. Papaxoinis, I. Panayiotides, D. Haldeopoulos, K. Triantafyllou, N. Kelekis, and S. D. Ladas Copyright © 2013 G. Karamanolis et al. All rights reserved. Wed, 08 May 2013 13:33:33 +0000 http://www.hindawi.com/journals/mi/2013/298326/ Neuropathic pain is a frequent chronic presentation in autoimmune diseases of the nervous system, such as multiple sclerosis (MS) and Guillain-Barre syndrome (GBS), causing significant individual disablement and suffering. Animal models of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN) mimic many aspects of MS and GBS, respectively, and are well suited to study the pathophysiology of these autoimmune diseases. However, while much attention has been devoted to curative options, research into neuropathic pain mechanisms and relief has been somewhat lacking. Recent studies have demonstrated a variety of sensory abnormalities in different EAE and EAN models, which enable investigations of behavioural changes, underlying mechanisms, and potential pharmacotherapies for neuropathic pain associated with these diseases. This review examines the symptoms, mechanisms, and clinical therapeutic options in these conditions and highlights the value of EAE and EAN animal models for the study of neuropathic pain in MS and GBS. David H. Tian, Chamini J. Perera, and Gila Moalem-Taylor Copyright © 2013 David H. Tian et al. All rights reserved. Tue, 07 May 2013 11:45:34 +0000 http://www.hindawi.com/journals/mi/2013/895651/ It is widely accepted that cells serving immune functions in the brain, namely, microglia and astrocytes, are important mediators of pathological phenomena observed in Alzheimer’s disease. However, it is unknown how these cells initiate the response that results in cognitive impairment and neuronal degeneration. Here, we review the participation of the immune response mediated by glial cells in Alzheimer’s disease and the role played by scavenger receptors in the development of this pathology, focusing on the relevance of class A scavenger receptor (SR-A) for Aβ clearance and inflammatory activation of glial cell, and as a potential target for Alzheimer’s disease therapy. Francisca Cornejo and Rommy von Bernhardi Copyright © 2013 Francisca Cornejo and Rommy von Bernhardi. All rights reserved. Tue, 07 May 2013 10:44:30 +0000 http://www.hindawi.com/journals/mi/2013/641851/ NAG-1/GDF15 is a TGF-β superfamily member with poorly characterized biological activity proposed to inhibit inflammatory cytokine production. Transgenic mice expressing human NAG-1/GDF15 () are leaner with lower body weight and are resistant to chemically or genetically induced intestinal tumors. Because of the link between obesity, inflammation, and cancer, we examined whether these mice exhibit a reduced response to inflammatory stimuli. The mice had a reduced inflammatory response to LPS based on the serum levels of cytokines KC, IL-6, MCP-1, and TNFα. In contrast to literature reports and our in vivo results, NAG-1 did not inhibit LPS-induced cytokine expression in vitro in RAW264.7 cells, mouse peritoneal macrophages, or mouse liver Kupffer cells, suggesting that NAG-1/GDF15 does not directly inhibit LPS-induced inflammatory cytokine production. However, mice have less white adipose tissue, the major source of inflammatory adipokines including leptin. Basal and LPS-treated serum leptin and mRNA levels in the adipose tissue of mice were lower than those in WT mice. We propose that the reduced white adipose tissue and reduced leptin expression may be responsible, in part, for the reduced inflammatory response to LPS and the decrease in intestinal tumors observed in mice. J. M. Kim, J. P. Kosak, J. K. Kim, G. Kissling, D. R. Germolec, D. C. Zeldin, J. A. Bradbury, S. J. Baek, and T. E. Eling Copyright © 2013 J. M. Kim et al. All rights reserved. Tue, 07 May 2013 10:24:58 +0000 http://www.hindawi.com/journals/mi/2013/329494/ Prostaglandin (PG)D2 has been shown to be an active agent in the resolution of experimentally induced inflammation. This study was undertaken to determine the presence of PGD2 in chronic joint effusions and to explore the potential contributions of dendritic cells (DC) and monocytes to the intra-articular synthesis of PGD2. Synovial fluid (SF) was obtained from patients with inflammatory arthritis and knee effusions. PGD2 and PGE2 were detected in SF by ultrahigh-performance tandem mass spectrometry. Cellular fractions in SF were separated by density-gradient centrifugation and flow cytometry. The expression of hematopoietic prostaglandin D-synthase (hPGDS) and PGE-synthase (PGES) mRNA was determined by RT-PCR. Both PGD2 and PGE2 were detected in blood and SF, with PGD2 being more abundant than PGE2 in SF. mRNA for hPGDS was more abundant in SF mDCs than SF monocytes () or PB monocytes (). SF mDC expressed significantly more hPGDS than PGES. Expressions of PGD2 and hPGDS were inversely associated with serum C-reactive protein () and erythrocyte sedimentation rate (). The findings suggest that synovial DCs may be an important source of hPGDS and that systemic disease activity may be influenced by actions of PGD2 in RA and other arthropathies. Mahin Moghaddami, Enzo Ranieri, Michael James, Janice Fletcher, and Leslie G. Cleland Copyright © 2013 Mahin Moghaddami et al. All rights reserved. Thu, 02 May 2013 12:09:31 +0000 http://www.hindawi.com/journals/mi/2013/750540/ The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes. This narrative review will update evidence from the recently identified molecular regulators preserving beta-cell mass and function recovery in order to suggest potential therapeutic targets against diabetes. This review will also highlight the relevance for novel molecular pathways potentially improving beta-cell dysfunction. Alessandra Puddu, Roberta Sanguineti, François Mach, Franco Dallegri, Giorgio Luciano Viviani, and Fabrizio Montecucco Copyright © 2013 Alessandra Puddu et al. All rights reserved. Mon, 29 Apr 2013 15:03:44 +0000 http://www.hindawi.com/journals/mi/2013/510212/ Hyperglycemia-induced oxidative stress has been concerned in the development of diabetic nephropathy (DN), which may cause kidney damage associated with inflammation and fibrosis. This study has been conducted to investigate the role of genistein supplementation in an acute DN state. Mice with FBG levels more than 250 mg/dL after alloxan injection (single i.p., 150 mg/kg) were considered as diabetic. Diabetic mice (DM) were further subdivided according to their FBG levels, medium-high FBG (DMMH < 450 mg/dL) and high FBG (DMH; 450 mg/dL) and were administrated by an AIG-93G diet supplemented with different doses of genistein (0, 0.025 or 0.1%). After 2 weeks’ treatment, the levels of kidney malondialdehyde (MDA), blood urea nitrogen (BUN), and plasma creatinine and lipid profiles, as well as oxidative stress and inflammation-related markers, were measured (). Genistein supplementation improved levels of FBG in the DMMH groups, but not in the DMH group, regardless of the treatment dose. Moreover, the supplementation attenuated kidney oxidative stress indicated by MDA, BUN, and plasma creatinine. In addition, genistein treatment decreased inflammatory markers such as nuclear factor kappa B (p65), phosphorylated inhibitory kappa B alpha, C-reactive protein, monocyte chemotactic protein-1, cyclooxygenase-2, and tumor necrosis factor-alpha and improved oxidative stress markers (nuclear-related factor E2, heme oxygenase-1, glutathione peroxidase, and superoxide dismutase isoforms) in treatment groups, regardless of the genistein treatment dose. Furthermore, genistein supplementation inhibited the fibrosis-related markers (protein kinase C, protein kinase C-beta II, and transforming growth factor-beta I) in the DN state. However, 0.1% genistein supplementation in diabetes with high FBG levels selectively showed a preventive effect on kidney damage. These results suggest that genistein might be a good protective substance for DN through regulation of oxidative stress and inflammation. In particular, genistein is more efficient in diabetes patients with medium-high blood glucose levels. Finally, it is required to establish the beneficial dosage of genistein according to blood glucose levels. Min Ju Kim and Yunsook Lim Copyright © 2013 Min Ju Kim and Yunsook Lim. All rights reserved. Mon, 29 Apr 2013 10:05:30 +0000 http://www.hindawi.com/journals/mi/2013/495848/ The role of cytokines in relation to clinical manifestations, disease severity, and outcome of children with H1N1 virus infection remains thus far unclear. The aim of this study was to evaluate interleukin IL-1β and IL-6 plasma expressions and their association with clinical findings, disease severity, and outcome of children with H1N1 infection. We prospectively evaluated 15 children with H1N1 virus infection and 15 controls with lower respiratory tract infections (LRTI). Interleukin plasma levels were measured using immunoenzymatic assays. Significantly higher levels of IL-1β and IL-6 were detected in all patients with H1N1 virus infection compared to controls. It is noteworthy to mention that in H1N1 patients with more severe clinical manifestations of disease IL-1β and IL-6 expressions were significantly upregulated compared to H1N1 patients with mild clinical manifestations. In particular, IL-6 was significantly correlated with specific clinical findings, such as severity of respiratory compromise and fever. No correlation was found between interleukin expression and final outcome. In conclusion, H1N1 virus infection induces an early and significant upregulation of both interleukins IL1β and IL-6 plasma expressions. The upregulation of these cytokines is likely to play a proinflammatory role in H1N1 virus infection and may contribute to airway inflammation and bronchial hyperreactivity in these patients. Antonio Chiaretti, Silvia Pulitanò, Giovanni Barone, Pietro Ferrara, Valerio Romano, Domenico Capozzi, and Riccardo Riccardi Copyright © 2013 Antonio Chiaretti et al. All rights reserved. Mon, 29 Apr 2013 08:06:14 +0000 http://www.hindawi.com/journals/mi/2013/317120/ Advanced glycation end products (AGEs) might play a pathophysiological role in the development of diabetes and its complications. AGEs negatively affect pancreatic beta-cell function and the expression of transcriptional factors regulating insulin gene. Glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates glucose homeostasis, might counteract the harmful effects of AGEs on the beta cells in culture. The aim of this study was to identify the intracellular mechanisms underlying GLP-1-mediated protection from AGE-induced detrimental activities in pancreatic beta cells. HIT-T15 cells were cultured for 5 days with glycated serum (GS, consisting in a pool of AGEs), in the presence or absence of 10 nmol/L GLP-1. After evaluation of oxidative stress, we determined the expression and subcellular localization of proteins involved in maintaining redox balance and insulin gene expression, such as nuclear factor erythroid-derived 2 (Nrf2), glutathione reductase, PDX-1, and MafA. Then, we investigated proinsulin production. The results showed that GS increased oxidative stress, reduced protein expression of all investigated factors through proteasome activation, and decreased proinsulin content. Furthermore, GS reduced ability of PDX-1 and MafA to bind DNA. Coincubation with GLP-1 reversed these GS-mediated detrimental effects. In conclusion, GLP-1, protecting cells against oxidants, triggers protective intercellular pathways in HIT-T15 cells exposed to GS. Alessandra Puddu, Roberta Sanguineti, Arianna Durante, Alessio Nencioni, François Mach, Fabrizio Montecucco, and Giorgio L. Viviani Copyright © 2013 Alessandra Puddu et al. All rights reserved. Sat, 27 Apr 2013 12:14:25 +0000 http://www.hindawi.com/journals/mi/2013/345217/ Background. Allergic rhinitis is a disease with polarization towards Th2 and a defect of regulatory T cells. Immunological changes have been reported after immunotherapy treatment. However, there is not much known about the natural course of allergic rhinitis with respect to clinical manifestation and the relation with immunological responses. Objective. To evaluate clinical symptoms of allergic rhinitis, in relation to in vivo allergen-specific skin responses and in vitro allergen-specific effector and regulatory T cells determined at baseline and after two years. Methods. From a large trial, 59 children were randomly selected. The following variables were compared: clinical symptoms, allergen skin tests, specific IgE, T-cell proliferation, IL-5, IL-13, IFN-gamma, IL-10, TGF-beta, cells, and Foxp3 expression. Results. Allergic symptoms had decreased after two years. Whereas skin test reactions correlated between years 0 and 2, there was no change in the size of the reaction. Also, proinflammatory reactions did not change after two years, with a positive correlation between years 0 and 2. No relevant changes were observed with respect to regulatory cells. Conclusion. Whereas, comparable to immunotherapy, allergic complaints decrease, the immunological changes of specific T-cell activity (both effector cells and regulator cells) which are observed after immunotherapy, do not change. Heleen Moed, Roy Gerth van Wijk, Rudi W. Hendriks, and J. C. van der Wouden Copyright © 2013 Heleen Moed et al. All rights reserved. Tue, 23 Apr 2013 15:07:40 +0000 http://www.hindawi.com/journals/mi/2013/216402/ Microglia are the immune cells in the central nervous system. After injury microglia release bioactive molecules, including cytokines and ATP, which modify the functional state of hemichannels (HCs) and gap junction channels (GJCs), affecting the intercellular communication via extracellular and intracellular compartments, respectively. Here, we studied the role of extracellular ATP and several cytokines as modulators of the functional state of microglial HCs and GJCs using dye uptake and dye coupling techniques, respectively. In microglia and the microglia cell line EOC20, ATP advanced the TNF-/IFN--induced dye coupling, probably through the induction of IL-1 release. Moreover, TNF-/IFN-, but not TNF- plus ATP, increased dye uptake in EOC20 cells. Blockade of Cx43 and Panx1 HCs prevented dye coupling induced by TNF-/IFN-, but not TNF- plus ATP. In addition, IL-6 prevented the induction of dye coupling and HC activity induced by TNF-/IFN- in EOC20 cells. Our data support the notion that extracellular ATP affects the cellular communication between microglia through autocrine and paracrine mechanisms, which might affect the timing of immune response under neuroinflammatory conditions. Pablo J. Sáez, Kenji F. Shoji, Mauricio A. Retamal, Paloma A. Harcha, Gigliola Ramírez, Jean X. Jiang, Rommy von Bernhardi, and Juan C. Sáez Copyright © 2013 Pablo J. Sáez et al. All rights reserved. Mon, 22 Apr 2013 08:42:00 +0000 http://www.hindawi.com/journals/mi/2013/950981/ Prostaglandins act as mediators of inflammation and, similar to cytokines, function as immune modulators during innate and adaptive immune responses. Therefore, using a pharmacological inhibitor, celecoxib, we investigated the role of prostaglandins in host defense against Histoplasma capsulatum infection in C57BL/6 mice. Our results showed that treatment with celecoxib inhibited cyclooxygenase 2, reduced the total fungal burden, and reduced the concentration of PGE2, cytokines, lymphocytes, neutrophils, and mononuclear cells in the bronchoalveolar space and lung parenchyma. In addition, celecoxib treatment increased the synthesis of nitric oxide, IFN-γ, LTB4, and the phagocytic capacity of alveolar macrophages. Moreover, celecoxib treatment increased the survival of mice after infection with a lethal inoculum of H. capsulatum. These results suggest that prostaglandins alter the host immune response and play an important role in the pathogenesis of histoplasmosis. Thus, the inhibition of prostaglandins could be a valuable immunomodulatory strategy and antifungal therapy for histoplasmosis treatment. Priscilla Aparecida Tartari Pereira, Bruno Caetano Trindade, Adriana Secatto, Roberto Nicolete, Camila Peres-Buzalaf, Simone Gusmão Ramos, Ruxana Sadikot, Claudia da Silva Bitencourt, and Lúcia Helena Faccioli Copyright © 2013 Priscilla Aparecida Tartari Pereira et al. All rights reserved. Sun, 21 Apr 2013 11:00:30 +0000 http://www.hindawi.com/journals/mi/2013/620837/ It remains unclear whether etanercept penetrates directly into the contused brain and improves the outcomes of TBI by attenuating brain contents of TNF-α and/or stimulating newly formed neurogenesis. Rats that sustained TBI are immediately treated with etanercept. Acute neurological and motor injury is assessed in all rats the day prior to and 7 days after surgery. The numbers of the colocalizations of 5-bromodeoxyuridine and doublecortin specific markers in the contused brain injury that occurred during TBI were counted by immunofluorescence staining. Enzyme immunoassay for quantitative determination of TNF-α or etanercept in brain tissues is also performed. Seven days after systemic administration of etanercept, levels of etanercept can be detected in the contused brain tissues. In addition, neurological and motor deficits, cerebral contusion, and increased brain TNF-α contents caused by TBI can be attenuated by etanercept therapy. Furthermore, the increased numbers of the colocalizations of 5-bromodeoxyuridine and doublecortin specific markers in the contused brain tissues caused by TBI can be potentiated by etanercept therapy. These findings indicate that systemically administered etanercept may penetrate directly into the contused brain tissues and may improve outcomes of TBI by reducing brain contents of TNF-α and by stimulating newly formed neurogenesis. Chong-Un Cheong, Ching-Ping Chang, Chien-Ming Chao, Bor-Chih Cheng, Chung-Zhing Yang, and Chung-Ching Chio Copyright © 2013 Chong-Un Cheong et al. All rights reserved. Thu, 18 Apr 2013 17:54:57 +0000 http://www.hindawi.com/journals/mi/2013/340473/ The involvement of serotonin (5-HT) in chronic pain mechanisms is established. 5-HT inhibits central painful stimuli, but recent data suggests that 5-HT could also enhance pain stimulus from the periphery, where mast cells play an important role. We aimed in our study to clarify the influence of selected tricyclic antidepressants (TCAs) on mast cell function: secretion, uptake, and reuptake of 5-HT, that could interfere with 5-HT levels and in this way contribute to the generation of pain. As an experimental model, we used isolated rat peritoneal mast cells and incubated them with selected TCAs (clomipramine, amitriptyline, doxepin, and imipramine) under different experimental conditions. 5-HT release, uptake, and reuptake were determined spectrofluorometrically. We showed that TCAs were able to inhibit 5-HT secretion from mast cells, as well as uptake of exogenous 5-HT and reuptake of secreted 5-HT back into mast cells. The effects of TCAs were concentration dependent; higher concentrations of TCAs inhibited the secretion of 5-HT induced by compound 48/80, whereas lower concentrations of TCAs inhibited 5-HT uptake. The most effective TCA was halogenated clomipramine. As TCAs are well introduced in chronic pain treatment, the insight into mechanisms of action is important for an understanding of their effect in various pain conditions. Ilonka Ferjan and Metoda Lipnik-Štangelj Copyright © 2013 Ilonka Ferjan and Metoda Lipnik-Štangelj. All rights reserved. Thu, 18 Apr 2013 15:20:47 +0000 http://www.hindawi.com/journals/mi/2013/135984/ Fabrizio Montecucco, François Mach, and Aldo Pende Copyright © 2013 Fabrizio Montecucco et al. All rights reserved.