Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Inflammatory Biomarkers in Cancer Sun, 23 Oct 2016 07:56:16 +0000 Tomoki Nakamura, Czar L. Gaston, Krishna Reddy, Shintaro Iwata, and Jun Nishio Copyright © 2016 Tomoki Nakamura et al. All rights reserved. Indoxyl Sulfate Induces Mesangial Cell Proliferation via the Induction of COX-2 Sun, 23 Oct 2016 07:40:35 +0000 Indoxyl sulfate (IS) is one of important uremic toxins and is markedly accumulated in the circulation of end stage renal disease (ESRD) patients, which might contribute to the damage of residual nephrons and progressive loss of residual renal function (RRF). Thus this study was undertaken to investigate the role of IS in modulating mesangial cell (MC) proliferation and the underlying mechanism. The proliferation of MCs induced by IS was determined by cell number counting, DNA synthase rate, and cell cycle phase analysis. COX-2 expression was examined by Western blotting and qRT-PCR, and a specific COX-2 inhibitor NS398 was applied to define its role in IS-induced MC proliferation. Following IS treatment, MCs exhibited increased total cell number, DNA synthesis rate, and number of cells in S and G2 phases paralleled with the upregulation of cyclin A2 and cyclin D1. Next, we found an inducible inflammation-related enzyme COX-2 was remarkably enhanced by IS, and the inhibition of COX-2 by NS398 significantly blocked IS-induced MC proliferation in line with a blockade of PGE2 production. These findings indicated that IS could induce MC proliferation via a COX-2-mediated mechanism, providing new insights into the understanding and therapies of progressive loss of RRF in ESRD. Shuzhen Li, Sijie Cheng, Zhenzhen Sun, Harr-keshauve Mungun, Wei Gong, Jing Yu, Weiwei Xia, Yue Zhang, Songming Huang, Aihua Zhang, and Zhanjun Jia Copyright © 2016 Shuzhen Li et al. All rights reserved. MMP8 Is Increased in Lesions and Blood of Acne Inversa Patients: A Potential Link to Skin Destruction and Metabolic Alterations Sun, 23 Oct 2016 07:20:10 +0000 Acne inversa (AI; also designated as hidradenitis suppurativa) is a chronic inflammatory disease with still unknown pathogenesis that affects the intertriginous skin of perianal, inguinal, and axillary sites. It leads to painful nodules, abscesses, and fistulas with malodorous secretion and is frequently associated with metabolic alterations. Here, we demonstrate that one of the most highly upregulated molecules in AI lesions is matrix metalloproteinase 8 (MMP8), an enzyme specialized in the degradation of extracellular matrix components and the HDL component apolipoprotein A-I. Granulocytes, which were present in AI lesions, secreted high amounts of MMP8 especially after TNF-α stimulation. Furthermore, activated fibroblasts but not keratinocytes were found to express MMP8. The high lesional MMP8 levels were accompanied by elevated blood levels that positively correlated with TNF-α blood levels and disease severity assessed by Sartorius score, especially with the number of regions with inflammatory nodules/abscesses and fistulas. Additionally, we found a negative correlation between blood MMP8 and HDL-cholesterol levels, suggesting a contributory role of MMP8 in metabolic alterations in AI. In summary, we demonstrate elevated MMP8 levels in AI lesions, suggest their role in skin destruction and metabolic alterations, and recommend the use of MMP8 as blood biomarker for AI disease activity assessment. Athanasia Tsaousi, Ellen Witte, Katrin Witte, Hans-Joachim Röwert-Huber, Hans-Dieter Volk, Wolfram Sterry, Kerstin Wolk, Sylke Schneider-Burrus, and Robert Sabat Copyright © 2016 Athanasia Tsaousi et al. All rights reserved. Interaction between ANXA1 and GATA-3 in Immunosuppression of CD4+ T Cells Wed, 19 Oct 2016 12:49:50 +0000 Decreased Th1/Th2 ratio is one of the major characteristics of immunosuppression in sepsis. Both membrane adhesive protein Annexin-A1 (ANXA1) and transcription factor GATA-3 have been reported to play important roles in T cell differentiation. However, the relationship between ANXA1 and GATA-3 in Th1/Th2 shift is unknown. Our study investigated the interaction effects of ANXA1 and GATA-3 to influence T cell differentiation in CD4+ T cells. We found that GATA-3 and ANXA1 were coexpressed on Th0/Th1/Th2 cytoplasm and nuclear. Overexpressed ANXA1 significantly increased the expression of IFNγ and reduced IL-4 expression in T cells, while ANXA1-silenced T cells exhibited decreased production of IFNγ and increased production of IL-4. Knockdown of ANXA1 promoted higher expression level of GATA-3 and low level of T-box transcription factor (T-bet/Tbx21). Further study demonstrated that ANXA1 regulated GATA-3 expression through the formyl peptide receptor like-1 (FPRL-1) downstream signaling pathways ERK and PKB/Akt. These results suggested that ANXA1 modulates GATA-3/T-bet expression induced Th0/Th1 differentiation. Moreover, we found that GATA-3 inhibited ANXA1 expression by binding to its promoter for the first time. It is proposed that the interactions between ANXA1 and GATA-3 may provide clues to understand the immunosuppression and have potential as new therapeutic targets in immunotherapy after sepsis. Peng Huang, Yuxiang Zhou, Zan Liu, and Pihong Zhang Copyright © 2016 Peng Huang et al. All rights reserved. Interleukin-22 Might Act as a Double-Edged Sword in Type 2 Diabetes and Coronary Artery Disease Tue, 18 Oct 2016 09:06:47 +0000 Type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) are both characterized by chronic low-grade inflammation. The role of Th17 and its related cytokines in T2DM and CAD is unclear. Here we investigated the serum levels of five Th17-related cytokines (IL-17, IL-22, MIP-3α, IL-9, and IL-27) in T2DM, CAD, and T2DM-CAD comorbidity patients. IL-22 was found to be elevated in all three conditions. Elevated serum IL-22 was independently associated with the incidence of T2DM and CAD. Conversely, IL-22 was found to protect endothelial cells from glucose- and lysophosphatidylcholine- (LPC-) induced injury, and IL-22R1 expression on endothelial cells was increased upon treatment with high glucose and LPC. Blocking of IL-22R1 with IL-22R1 antibody diminished the protective role of IL-22. Our results suggest that IL-22 functions as a double-edged sword in T2DM and CAD and that IL-22 may be used in the treatment of chronic inflammatory diseases such as T2DM and CAD. Fangchen Gong, Jin Wu, Ping Zhou, Mengyao Zhang, Jingning Liu, Ying Liu, Xiang Lu, and Zhengxia Liu Copyright © 2016 Fangchen Gong et al. All rights reserved. Corrigendum to “Irbesartan Ameliorates Diabetic Nephropathy by Suppressing the RANKL-RANK-NF-κB Pathway in Type 2 Diabetic db/db Mice” Tue, 18 Oct 2016 08:00:13 +0000 Xiao-Wen Chen, Xiao-Yan Du, Yu-Xian Wang, Jian-Cheng Wang, Wen-Ting Liu, Wen-Jing Chen, Hong-Yu Li, Fen-Fen Peng, Zhao-Zhong Xu, Hong-Xin Niu, and Hai-Bo Long Copyright © 2016 Xiao-Wen Chen et al. All rights reserved. Effect of Topical Administration of Fractions and Isolated Molecules from Plant Extracts on Skin Wound Healing: A Systematic Review of Murine Experimental Models Mon, 17 Oct 2016 09:20:23 +0000 Background and Purpose. Skin wound healing is a dynamic process driven by molecular events responsible for the morphofunctional repair of the injured tissue. In a systematic review, we analyzed the relevance of plant fractions and isolates on skin wound healing. By revising preclinical investigations with murine models, we investigated if the current evidence could support clinical trials. Methods. Studies were selected in the MEDLINE/PubMed and Scopus databases according to the PRISMA statement. All 32 identified studies were submitted to data extraction and the methodological bias was investigated according to ARRIVE strategy. Results. The studies demonstrated that plant fractions and isolates are able to modulate the inflammatory process during skin wound healing, being also effective in attenuating the oxidative tissue damage in the scar tissue and stimulating cell proliferation, neoangiogenesis, collagen synthesis, granulation tissue expansion, reepithelialization, and the wound closure rate. However, we identified serious methodological flaws in all studies, such as the high level of reporting bias and absence of standardized experimental designs, analytical methods, and outcome measures. Conclusion. Considering these limitations, the current evidence generated from flawed methodological animal studies makes it difficult to determine the relevance of herbal medicines to treat skin wounds and derails conducting clinical studies. Mariáurea Matias Sarandy, Fernanda Barbosa Lopes, Sérgio Luis Pinto da Matta, Marcus Vinicius Mello Pinto, Sirlene Souza Rodrigues Sartori, Rômulo Dias Novaes, and Reggiani Vilela Golçalves Copyright © 2016 Mariáurea Matias Sarandy et al. All rights reserved. Apoptosis of Endothelial Cells by 13-HPODE Contributes to Impairment of Endothelial Barrier Integrity Wed, 12 Oct 2016 14:34:44 +0000 Inflammation is an essential host response during bacterial infections such as bovine mastitis. Endothelial cells are critical for an appropriate inflammatory response and loss of vascular barrier integrity is implicated in the pathogenesis of Streptococcus uberis-induced mastitis. Previous studies suggested that accumulation of linoleic acid (LA) oxygenation products derived from 15-lipoxygenase-1 (15-LOX-1) metabolism could regulate vascular functions. The initial LA derivative from the 15-LOX-1 pathway, 13-hydroperoxyoctadecadienoic acid (HPODE), can induce endothelial death, whereas the reduced hydroxyl product, 13-hydroxyoctadecadienoic acid (HODE), is abundantly produced during vascular activation. However, the relative contribution of specific LA-derived metabolites on impairment of mammary endothelial integrity is unknown. Our hypothesis was that S. uberis-induced LA-derived 15-LOX-1 oxygenation products impair mammary endothelial barrier integrity by apoptosis. Exposure of bovine mammary endothelial cells (BMEC) to S. uberis did not increase 15-LOX-1 LA metabolism. However, S. uberis challenge of bovine monocytes demonstrated that monocytes may be a significant source of both 13-HPODE and 13-HODE during mastitis. Exposure of BMEC to 13-HPODE, but not 13-HODE, significantly reduced endothelial barrier integrity and increased apoptosis. Changing oxidant status by coexposure to an antioxidant during 13-HPODE treatment prevented adverse effects of 13-HPODE, including amelioration of apoptosis. A better understanding of how the oxidant status of the vascular microenvironment impacts endothelial barrier properties could lead to more efficacious treatments for S. uberis mastitis. Valerie E. Ryman, Nandakumar Packiriswamy, and Lorraine M. Sordillo Copyright © 2016 Valerie E. Ryman et al. All rights reserved. Peroxisome Proliferator-Activated Receptor α Reduces Endothelin-1-Caused Cardiomyocyte Hypertrophy by Inhibiting Nuclear Factor-κB and Adiponectin Tue, 11 Oct 2016 08:01:35 +0000 Peroxisome proliferator-activated receptor α (PPARα) plays a role in the pathogenesis of cardiac hypertrophy, although its underlying mechanism remains unclear. The purpose of this study was to evaluate the effect of PPARα activation on endothelin-1- (ET-1-) caused cardiomyocyte hypertrophy and explore its underlying mechanisms. Human cardiomyocytes (HCMs) were cultured with or without ET-1, whereafter the inhibitory effects of fenofibrate, a PPARα activator, on cell size and adiponectin protein were tested. We examined the activation of extracellular signal-regulated kinase (ERK) and p38 proteins caused by ET-1 and the inhibition of the ERK and p38 pathways on ET-1-induced cell size and adiponectin expression. Moreover, we investigated the interaction of PPARα with adiponectin and nuclear factor-κB (NF-κB) by electrophoretic mobility shift assays and coimmunoprecipitation. ET-1 treatment significantly increased cell size, suppressed PPARα expression, and enhanced the expression of adiponectin. Pretreatment with fenofibrate inhibited the increase in cell size and enhancement of adiponectin expression. ET-1 significantly activated the ERK and p38 pathways, whereas PD98059 and SB205380, respectively, inhibited them. Our results suggest that activated PPARα can decrease activation of adiponectin and NF-κB and inhibit ET-1-induced cardiomyocyte hypertrophy. Hsu-Lung Jen, Po-Len Liu, Yung-Hsiang Chen, Wei-Hsian Yin, Jaw-Wen Chen, and Shing-Jong Lin Copyright © 2016 Hsu-Lung Jen et al. All rights reserved. Corrigendum to “Ethyl Pyruvate Ameliorates Hepatic Ischemia-Reperfusion Injury by Inhibiting Intrinsic Pathway of Apoptosis and Autophagy” Tue, 11 Oct 2016 06:26:04 +0000 Miao Shen, Jie Lu, Weiqi Dai, Fan Wang, Ling Xu, Kan Chen, Lei He, Ping Cheng, Yan Zhang, Chengfen Wang, Dong Wu, Jing Yang, Rong Zhu, Huawei Zhang, Yingqun Zhou, and Chuanyong Guo Copyright © 2016 Miao Shen et al. All rights reserved. ATP Induces IL-1β Secretion in Neisseria gonorrhoeae-Infected Human Macrophages by a Mechanism Not Related to the NLRP3/ASC/Caspase-1 Axis Mon, 10 Oct 2016 13:36:31 +0000 Neisseria gonorrhoeae (Ngo) has developed multiple immune evasion mechanisms involving the innate and adaptive immune responses. Recent findings have reported that Ngo reduces the IL-1β secretion of infected human monocyte-derived macrophages (MDM). Here, we investigate the role of adenosine triphosphate (ATP) in production and release of IL-1β in Ngo-infected MDM. We found that the exposure of Ngo-infected MDM to ATP increases IL-1β levels about ten times compared with unexposed Ngo-infected MDM (). However, we did not observe any changes in inflammasome transcriptional activation of speck-like protein containing a caspase recruitment domain (CARD) (ASC, ) and caspase-1 (CASP1, ). In addition, ATP was not able to modify caspase-1 activity in Ngo-infected MDM but was able to increase pyroptosis (). Notably ATP treatment defined an increase of positive staining for IL-1β with a distinctive intracellular pattern of distribution. Collectively, these data demonstrate that ATP induces IL-1β secretion by a mechanism not related to the NLRP3/ASC/caspase-1 axis and likely is acting at the level of vesicle trafficking or pore formation. Killen García, Gisselle Escobar, Pablo Mendoza, Caroll Beltran, Claudio Perez, Sergio Arancibia, Rolando Vernal, Paula I. Rodas, Claudio Acuña-Castillo, and Alejandro Escobar Copyright © 2016 Killen García et al. All rights reserved. Serum Amyloid A Promotes E-Selectin Expression via Toll-Like Receptor 2 in Human Aortic Endothelial Cells Wed, 05 Oct 2016 09:36:13 +0000 Periodontitis is a chronic inflammatory disease that affects the periodontium. Recent studies suggest an association between periodontal and cardiovascular diseases. However, the detailed molecular mechanism is unknown. A previous study has demonstrated that experimental periodontitis induces serum amyloid A (SAA) in the liver and peripheral blood of ApoE-deficient mice as an atherosclerosis model. SAA is an acute-phase protein that affects systemic inflammation. The aim of this study is to investigate the atherosclerosis-onset mechanism using human aortic endothelial cells (HAECs) stimulated by SAA in vitro. Atherosclerosis PCR array and qPCR analyses showed upregulation of adhesion molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in HAECs upon SAA stimulation. In addition, the results demonstrated that Toll-like receptor, TLR2, could serve as an important receptor of SAA in HAECs. Furthermore, small interfering RNA (siRNA) against TLR2 inhibited the upregulation of adhesion molecules in HAECs stimulated by SAA. Our results suggest that SAA stimulates the expression of adhesion molecules via TLR2. SAA could be an important molecule for atherosclerosis induced by periodontal disease. Eisaku Nishida, Makoto Aino, Shu-ichiro Kobayashi, Kosuke Okada, Tasuku Ohno, Takeshi Kikuchi, Jun-ichiro Hayashi, Genta Yamamoto, Yoshiaki Hasegawa, and Akio Mitani Copyright © 2016 Eisaku Nishida et al. All rights reserved. Placental Growth Factor, Soluble fms-Like Tyrosine Kinase 1, Soluble Endoglin, IL-6, and IL-16 as Biomarkers in Preeclampsia Wed, 05 Oct 2016 07:34:45 +0000 Preeclampsia (PE), an important cause of maternal and perinatal morbidity and mortality worldwide, is a pregnancy-related disease characterized by hypertension and proteinuria after 20 weeks of gestation. The aim of our study was to find a practical panel of biomarkers useful in early diagnosis of PE. This study was carried out at the Obstetrics and Gynecology Department in Tîrgu Mureș University Hospital, Romania, between January 2014 and July 2015 and included 68 pregnant women (47 preeclamptic women and 21 controls) with gestational age between 16 and 20 weeks at enrollment. The biomarkers PlGF, sFlt-1, sEng, IL-6, and IL-16 were determined by ELISA test. We compared the serum levels of soluble markers analysed in preeclamptic women and controls during the second and third trimesters of pregnancy and we found that the best predictor for PE was PlGF with a sensitivity of 100% at a concentration threshold of 120.16 pg/mL, a diagnosis accuracy of 70.8%, and AUC of 0.684 (). We also estimated the risk for PE according to BMI and we found that pregnant women with weight >90 kg had 7 times higher risk for PE. Second-trimester PlGF serum level may serve as an early biomarker for the diagnosis of PE. Carmen Rădulescu, Anca Bacârea, Adina Huțanu, Rozalia Gabor, and Minodora Dobreanu Copyright © 2016 Carmen Rădulescu et al. All rights reserved. Antileishmanial Activity and Inducible Nitric Oxide Synthase Activation by RuNO Complex Tue, 04 Oct 2016 09:22:52 +0000 Parasites of the genus Leishmania are capable of inhibiting effector functions of macrophages. These parasites have developed the adaptive ability to escape host defenses; for example, they inactivate the NF-κB complex and suppress iNOS expression in infected macrophages, which are responsible for the production of the major antileishmanial substance nitric oxide (NO), favoring then its replication and successful infection. Metal complexes with NO have been studied as potential compounds for the treatment of certain tropical diseases, such as ruthenium compounds, known to be exogenous NO donors. In the present work, the compound cis-[Ru(bpy)2SO3(NO)]PF6, or RuNO, showed leishmanicidal activity directly and indirectly on promastigote forms of Leishmania (Leishmania) amazonensis. In addition, treatment with RuNO increased NO production by reversing the depletion of NO caused by Leishmania. We also found increased expression of Akt, iNOS, and NF-κB in infected and treated macrophages. These results demonstrated that RuNO was able to kill the parasite by NO release and modulate the transcriptional capacity of the cell. Tatiane Marcusso Orsini, Natalia Yoshie Kawakami, Carolina Panis, Ana Paula Fortes dos Santos Thomazelli, Fernanda Tomiotto-Pellissier, Allan Henrique Depieri Cataneo, Danielle Kian, Lucy Megumi Yamauchi, Florêncio S. Gouveia Júnior, Luiz Gonzaga de França Lopes, Rubens Cecchini, Idessânia Nazareth Costa, Jean Jerley Nogueira da Silva, Ivete Conchon-Costa, and Wander Rogério Pavanelli Copyright © 2016 Tatiane Marcusso Orsini et al. All rights reserved. CCR9 Is a Key Regulator of Early Phases of Allergic Airway Inflammation Tue, 04 Oct 2016 07:40:08 +0000 Airway inflammation is the most common hallmark of allergic asthma. Chemokine receptors involved in leukocyte recruitment are closely related to the pathology in asthma. CCR9 has been described as a homeostatic and inflammatory chemokine receptor, but its role and that of its ligand CCL25 during lung inflammation remain unknown. To investigate the role of CCR9 as a modulator of airway inflammation, we established an OVA-induced allergic inflammation model in CCR9-deficient mice. Here, we report the expression of CCR9 and CCL25 as early as 6 hours post-OVA challenge in eosinophils and T-lymphocytes. Moreover, in challenged CCR9-deficient mice, cell recruitment was impaired at peribronchial and perivenular levels. OVA-administration in CCR9-deficient mice leads to a less inflammatory cell recruitment, which modifies the expression of IL-10, CCL11, and CCL25 at 24 hours after OVA challenge. In contrast, the secretion of IL-4 and IL-5 was not affected in CCR9-deficient mice compared to WT mice. These results demonstrate for the first time that CCR9 and CCL25 expressions are induced in the early stages of airway inflammation and they have an important role modulating eosinophils and lymphocytes recruitment at the first stages of inflammatory process, suggesting that they might be a potential target to regulate inflammation in asthma. C. López-Pacheco, G. Soldevila, G. Du Pont, R. Hernández-Pando, and E. A. García-Zepeda Copyright © 2016 C. López-Pacheco et al. All rights reserved. Effects of Glutamate and Aspartate on Serum Antioxidative Enzyme, Sex Hormones, and Genital Inflammation in Boars Challenged with Hydrogen Peroxide Thu, 29 Sep 2016 13:33:02 +0000 Background. Oxidative stress is associated with infertility. This study was conducted to determine the effects of glutamate and aspartate on serum antioxidative enzymes, sex hormones, and genital inflammation in boars suffering from oxidative stress. Methods. Boars were randomly divided into 4 groups: the nonchallenged control (CON) and H2O2-challenged control (BD) groups were fed a basal diet supplemented with 2% alanine; the other two groups were fed the basal diet supplemented with 2% glutamate (GLU) or 2% aspartate (ASP). The BD, GLU, and ASP groups were injected with hydrogen peroxide (H2O2) on day 15. The CON group was injected with 0.9% sodium chloride solution on the same day. Results. Dietary aspartate decreased the malondialdehyde (MDA) level in serum () compared with the BD group. Additionally, aspartate maintained serum luteinizing hormone (LH) at a relatively stable level. Moreover, glutamate and aspartate increased transforming growth factor-β1 (TGF-β1) and interleukin-10 (IL-10) levels in the epididymis and testis () compared with the BD group. Conclusion. Both glutamate and aspartate promoted genital mRNA expressions of anti-inflammatory factors after oxidative stress. Aspartate more effectively decreased serum MDA and prevented fluctuations in serum sex hormones after H2O2 challenge than did glutamate. Hengjia Ni, Lu Lu, Jinpin Deng, Wenjun Fan, Tiejun Li, and Jiming Yao Copyright © 2016 Hengjia Ni et al. All rights reserved. The Role of Endocrine System in the Inflammatory Process Thu, 29 Sep 2016 08:36:34 +0000 Christian Bowman-Colin, Luis A. Salazar, and Joilson O. Martins Copyright © 2016 Christian Bowman-Colin et al. All rights reserved. IL-33 Effect on Quantitative Changes of CD4+CD25highFOXP3+ Regulatory T Cells in Children with Type 1 Diabetes Wed, 28 Sep 2016 14:10:24 +0000 IL-33 is an IL-1 cytokine family member, with ability to induce both Th1 and Th2 immune responses. It binds to ST2 receptor, whose deficiency is associated with enhanced inflammatory response. The most recent studies have shown the immunoregulatory effect of IL-33 on Tregs in animal models. As type 1 diabetes is an autoimmune, inflammatory disease, where Treg defects have been described, we aimed to analyze the in vitro influence of recombinant IL-33 on quantitative properties of regulatory CD4+CD25highFOXP3+ T cells. CD4+CD25highFOXP3+ as well as CD4+CD25highFOXP3+ST2+ Tregs were analyzed by flow cytometry. In a group of patients with type 1 diabetes in vitro IL-33 treatment induced regulatory CD4+CD25highFOXP3+ cell frequencies as well as upregulating the surface expression of ST2 molecule. In addition, the number of CD4+CD25highFOXP3+ cells carrying ST2 receptor increased significantly. Similar effect was observed in case of the FOXP3 expression. We did not observe any significant changes in IL-33 treated cells of healthy controls. The level of ST2 was higher in serum of patients with type 1 diabetes in comparison to their healthy counterparts. We propose that IL-33 becomes an additional immunostimulatory factor used to induce Treg expansion in future clinical trials of adoptive therapy in type 1 diabetes. Monika Ryba-Stanisławowska, Paulina Werner, Maria Skrzypkowska, Agnieszka Brandt, and Jolanta Myśliwska Copyright © 2016 Monika Ryba-Stanisławowska et al. All rights reserved. Dietary Chitosan Supplementation Increases Microbial Diversity and Attenuates the Severity of Citrobacter rodentium Infection in Mice Wed, 28 Sep 2016 11:23:28 +0000 C57BL/6 mice were tested in order to investigate the effects of dietary chitosan (COS) supplements on intestinal microflora and resistance to Citrobacter rodentium infection. The findings reveal that, after consuming a 300 mg/kg COS diet for 14 days, microflora became more diverse as a result of the supplement. Mice receiving COS exhibited an increase in the percentage of Bacteroidetes phylum and a decrease in the percentage of Firmicutes phylum. After Citrobacter rodentium infection, the histopathology scores indicated that COS feeding resulted in less severe colitis. IL-6 and TNF-α were significantly lower in colon from COS-feeding mice than those in the control group. Furthermore, mice in COS group were also found to experience inhibited activation of nuclear factor-kappa B (NF-κB) in the colonic tissue. Overall, the findings revealed that adding 300 mg/kg COS to the diet changed the composition of the intestinal microflora of mice, resulting in suppressed NF-κB activation and less production of TNF-α and IL-6; and these changes led to better control of inflammation and resolution of infection with C. rodentium. Guiping Guan, Hongbing Wang, Shuai Chen, Gang Liu, Xia Xiong, Bie Tan, Veeramuthu Duraipandiyan, Naif Abdullah Al-Dhabi, and Jun Fang Copyright © 2016 Guiping Guan et al. All rights reserved. Clinical Application of Autologous Adipose Stem Cells in Patients with Multiple Sclerosis: Preliminary Results Wed, 28 Sep 2016 11:13:12 +0000 The clinical outcome of autologous adipose stem cell (ASC) treatment of patients with multiple sclerosis (MS) was investigated following one year of observation. Methods. The clinical and MRI outcomes of 16 ASC-treated patients with RRMS and SPMS are reported after a one-year follow-up period. Results. At 18 months of follow-up, some patients showed “enticing” improvements on some exploratory efficacy measures, although a significant benefit was not observed for any measure across the entire group. Neither the progression of disability nor relapses were observed in any cases. In four patients, we found new gadolinium+ (Gd+) lesions on MRI. Our results indicate that ASC therapy is safe and does not produce any substantial side effects. Disease progression-free survival (PFS) of 18 months was seen in all patients with RRMS and SPMS. In these patients, EDSS scores did not progress above baseline scores. Gd-enhancing lesions were observed in two cases with RRMS, but these patients did not exhibit changes in EDSS score. Conclusion. Intrathecal treatment with ASCs is an attractive form of therapy for patients with MS but should be reserved for cases with aggressive disease progression, for cases that are still in the inflammatory phase, and for the malignant form. Adam Stepien, Natalia L. Dabrowska, Marzena Maciagowska, Renata Piusinska Macoch, Aleksandra Zolocinska, Slawomir Mazur, Katarzyna Siennicka, Emilia Frankowska, Rafał Kidzinski, Małgorzata Chalimoniuk, and Zygmunt Pojda Copyright © 2016 Adam Stepien et al. All rights reserved. Inhibitory Effect of Loranthus parasiticus on IgE-Mediated Allergic Responses in RBL-2H3 Cells Tue, 27 Sep 2016 12:20:19 +0000 The mistletoe Loranthus parasiticus has been used as a compound for traditional medicine in Northeast Asia for a long time and is known to possess neuroprotective action. Nonetheless, the effect of Loranthus parasiticus on allergic responses remains unknown. In the present study, we evaluated whether the water extract of Loranthus parasiticus (LPE) could inhibit IgE-mediated allergic responses in RBL-2H3 cells. LPE inhibited the release of β-hexosaminidase (IC50, 184.5 μg/mL) and the formation of tumor necrosis factor-α (IC50, 84.27 μg/mL), interleukin-4 (IC50, 93.43 μg/mL), prostaglandin E2 (IC50, 84.10 μg/mL), prostaglandin D2, and leukotriene C4 (IC50, 43.27 μg/mL) in a concentration-dependent manner. Moreover, LPE inhibited phosphorylation of Syk, PLCγ1/2, PKCδ, ERK, JNK, p38, and Akt. In the late phase, LPE decreased 5-lipoxygenase phosphorylation and COX-2 expression but not cPLA2 phosphorylation. Additionally, LPE included total phenolic compounds (10.72 mg/g dry weight) and total flavonoids (56.20 mg/g dry weight). These results suggest that the phenolic compounds or flavonoids contained in LPE may be associated with antiallergic activity. The phenolic compounds and flavonoids in LPE are antiallergic phytochemicals capable of inhibiting the activation of the FcεRI signaling cascade in mast cells. Such effects may provide further information for the development of a phytomedicine for allergic diseases. Jae-Myung Yoo, Ju-Hye Yang, Young Soo Kim, Won-Kyung Cho, and Jin Yeul Ma Copyright © 2016 Jae-Myung Yoo et al. All rights reserved. Addition of Sodium Pyruvate to Stored Red Blood Cells Attenuates Liver Injury in a Murine Transfusion Model Mon, 26 Sep 2016 16:37:42 +0000 RBCs undergo numerous changes during storage and stored RBCs may induce adverse effects, ultimately resulting in organ injury in transfusion recipients. We tested the hypothesis that the addition of SP to stored RBCs would improve the quality of the stored RBCs and mitigate liver injury after transfusion in a murine model. RBCs were harvested from C57BL/6J mice and stored for 14 days in CPDA-1 containing either a solution of SP in saline or saline alone. Haemolysis, the 24-hour posttransfusion recovery, the oxygen-carrying capacity, and the SOD activity of stored RBCs were evaluated. The plasma biochemistry, hepatic MDA level, MPO activity, IL-6, TNF-α concentrations, and histopathology were measured two hours after the transfusion of stored RBCs. Compared with RBCs stored in CPDA-1 and saline, the addition of SP to stored RBCs restored their oxygen-carrying capacity and SOD activity, reduced the AST activity, BUN concentrations, and LDH activity in the plasma, and decreased the MDA level, MPO activity, and concentrations of IL-6 and TNF-α in the liver. These data indicate that the addition of SP to RBCs during storage has a beneficial effect on storage lesions in vitro and subsequently alleviates liver injury after the transfusion of stored RBCs in vivo. Sha Xia, Gan Chen, Bo Wang, Yujing Yin, Zhenwei Sun, Jingxiang Zhao, Penglong Li, Lian Zhao, and Hong Zhou Copyright © 2016 Sha Xia et al. All rights reserved. mTORC1-Activated Monocytes Increase Tregs and Inhibit the Immune Response to Bacterial Infections Mon, 26 Sep 2016 08:58:52 +0000 The TSC1/2 heterodimer, a key upstream regulator of the mTOR, can inhibit the activation of mTOR, which plays a critical role in immune responses after bacterial infections. Monocytes are an innate immune cell type that have been shown to be involved in bacteremia. However, how the mTOR pathway is involved in the regulation of monocytes is largely unknown. In our study, TSC1 KO mice and WT mice were infected with E. coli. When compared to WT mice, we found higher mortality, greater numbers of bacteria, decreased expression of coactivators in monocytes, increased numbers of Tregs, and decreased numbers of effector T cells in TSC1 KO mice. Monocytes obtained from TSC1 KO mice produced more ROS, IL-6, IL-10, and TGF-β and less IL-1, IFN-γ, and TNF-α. Taken together, our results suggest that the inhibited immune functioning in TSC1 KO mice is influenced by mTORC1 activation in monocytes. The reduced expression of coactivators resulted in inhibited effector T cell proliferation. mTORC1-activated monocytes are harmful during bacterial infections. Therefore, inhibiting mTORC1 signaling through rapamycin administration could rescue the harmful aspects of an overactive immune response, and this knowledge provides a new direction for clinical therapy. Lijun Fang, Huaijun Tu, Wei Guo, Shixuan Wang, Ting Xue, Fei Yang, Xiaoyan Zhang, Yazhi Yang, Qian Wan, Zhexin Shi, Xulong Zhan, and Jian Li Copyright © 2016 Lijun Fang et al. All rights reserved. From Placenta to Polycystic Ovarian Syndrome: The Role of Adipokines Mon, 26 Sep 2016 06:16:10 +0000 Adipokines are cytokines produced mainly by adipose tissue, besides many other tissues such as placenta, ovaries, peripheral-blood mononuclear cells, liver, muscle, kidney, heart, and bone marrow. Adipokines play a significant role in the metabolic syndrome and in cardiovascular diseases, have implications in regulating insulin sensitivity and inflammation, and have significant effects on growth and reproductive function. The objective of this review was to analyze the functions known today of adiponectin, leptin, resistin, and visfatin from placenta throughout childhood and adolescence. It is well known now that their serum concentrations during pregnancy and lactation have long-term effects beyond the fetus and newborn. With regard to puberty, adipokines are involved in the regulation of the relationship between nutritional status and normal physiology or disorders of puberty and altered gonadal function, as, for example, premature pubarche and polycystic ovarian syndrome (PCOS). Cytokines are involved in the maturation of oocytes and in the regular progression of puberty and pregnancy. Chiara Sartori, Pietro Lazzeroni, Silvia Merli, Viviana Dora Patianna, Francesca Viaroli, Francesca Cirillo, Sergio Amarri, and Maria Elisabeth Street Copyright © 2016 Chiara Sartori et al. All rights reserved. Exosomes and Exosomal miRNA in Respiratory Diseases Sun, 25 Sep 2016 13:42:26 +0000 Exosomes are nanosized vesicles released from every cell in the body including those in the respiratory tract and lungs. They are found in most body fluids and contain a number of different biomolecules including proteins, lipids, and both mRNA and noncoding RNAs. Since they can release their contents, particularly miRNAs, to both neighboring and distal cells, they are considered important in cell-cell communication. Recent evidence has shown their possible importance in the pathogenesis of several pulmonary diseases. The differential expression of exosomes and of exosomal miRNAs in disease has driven their promise as biomarkers of disease enabling noninvasive clinical diagnosis in addition to their use as therapeutic tools. In this review, we summarize recent advances in this area as applicable to pulmonary diseases. Shamila D. Alipoor, Esmaeil Mortaz, Johan Garssen, Masoud Movassaghi, Mehdi Mirsaeidi, and Ian M. Adcock Copyright © 2016 Shamila D. Alipoor et al. All rights reserved. High-Methionine Diet Attenuates Severity of Arthritis and Modulates IGF-I Related Gene Expressions in an Adjuvant Arthritis Rats Model Sun, 25 Sep 2016 13:33:26 +0000 Rheumatoid arthritis, a synthesized form of adjuvant arthritis exhibited throughout many animal species, inhibits liver function and circulation of IGF-I and contributes to the degradation of skeletal muscle mass. One of the primary goals of the present study is determining whether a high-Methionine (high-Met) diet is capable of reducing the adverse effects of arthritis, namely, loss of body mass. Following adjuvant injection, forty arthritic rats were randomly assigned to either a control group with a basal diet or a high-Met group with the same basal diet + 0.5% Methionine. After 14 days all rats were terminated. The high-Met group exhibited an increase in body weight and food intake in comparison with the control group (). High-Met diet debilitated arthritis-induced surges in the gastrocnemius in both atrogin-1 and the MuRF1 expressions; however, it was observed to have little to no effect on atrogin-1 and MuRF1 gene expression in soleus. At the same time, high-Met diet rats experienced a rise in IGF-I, with lowering of IGFBP-3 gene expression in the gastrocnemius and the soleus. These data suggest that arthritis severity can be partly attenuated by high-Met diet. Mingxin Li, Lidong Zhai, and Wanfu Wei Copyright © 2016 Mingxin Li et al. All rights reserved. Resolvin E1 Inhibits Substance P-Induced Potentiation of TRPV1 in Primary Sensory Neurons Sun, 25 Sep 2016 11:54:05 +0000 The neuropeptide substance P (SP) is expressed in primary sensory neurons and is commonly regarded as a “pain” neurotransmitter. Upon peripheral inflammation, SP activates the neurokinin-1 (NK-1) receptor and potentiates activity of transient receptor potential vanilloid subtype 1 (TRPV1), which is coexpressed by nociceptive neurons. Therefore, SP functions as an important neurotransmitter involved in the hypersensitization of inflammatory pain. Resolvin E1 (RvE1), derived from omega-3 polyunsaturated fatty acids, inhibits TRPV1 activity via activation of the chemerin 23 receptor (ChemR23)—an RvE1 receptor located in dorsal root ganglion neurons—and therefore exerts an inhibitory effect on inflammatory pain. We demonstrate here that RvE1 regulates the SP-induced potentiation of TRPV1 via G-protein coupled receptor (GPCR) on peripheral nociceptive neurons. SP-induced potentiation of TRPV1 inhibited by RvE1 was blocked by the Gαi-coupled GPCR inhibitor pertussis toxin and the G-protein inhibitor GDPβ-S. These results indicate that a low concentration of RvE1 strongly inhibits the potentiation of TRPV1, induced by the SP-mediated activation of NK-1, via a GPCR signaling pathway activated by ChemR23 in nociceptive neurons. RvE1 might represent a new therapeutic target for the treatment of inflammatory pain as a prospective endogenous inhibitor that strongly inhibits TRPV1 activity associated with peripheral inflammation. Youn Yi Jo, Ji Yeon Lee, and Chul-Kyu Park Copyright © 2016 Youn Yi Jo et al. All rights reserved. CYLD Promotes TNF-α-Induced Cell Necrosis Mediated by RIP-1 in Human Lung Cancer Cells Sun, 25 Sep 2016 09:24:26 +0000 Lung cancer is one of the most common cancers in the world. Cylindromatosis (CYLD) is a deubiquitination enzyme and contributes to the degradation of ubiquitin chains on RIP1. The aim of the present study is to investigate the levels of CYLD in lung cancer patients and explore the molecular mechanism of CYLD in the lung cancer pathogenesis. The levels of CYLD were detected in human lung cancer tissues and the paired paracarcinoma tissues by real-time PCR and western blotting analysis. The proliferation of human lung cancer cells was determined by MTT assay. Cell apoptosis and necrosis were determined by FACS assay. The results demonstrated that low levels of CYLD were detected in clinical lung carcinoma specimens. Three pairs of siRNA were used to knock down the endogenous CYLD in lung cancer cells. Knockdown of CYLD promoted cell proliferation of lung cancer cells. Otherwise overexpression of CYLD induced TNF-α-induced cell death in A549 cells and H460 cells. Moreover, CYLD-overexpressed lung cancer cells were treated with 10 μM of z-VAD-fmk for 12 hours and the result revealed that TNF-α-induced cell necrosis was significantly enhanced. Additionally, TNF-α-induced cell necrosis in CYLD-overexpressed H460 cells was mediated by receptor-interacting protein 1 (RIP-1) kinase. Our findings suggested that CYLD was a potential target for the therapy of human lung cancers. Xing Lin, Qianshun Chen, Chen Huang, and Xunyu Xu Copyright © 2016 Xing Lin et al. All rights reserved. Folic Acid Is Able to Polarize the Inflammatory Response in LPS Activated Microglia by Regulating Multiple Signaling Pathways Sun, 25 Sep 2016 07:25:57 +0000 We investigated the ability of folic acid to modulate the inflammatory responses of LPS activated BV-2 microglia cells and the signal transduction pathways involved. To this aim, the BV-2 cell line was exposed to LPS as a proinflammatory response inducer, in presence or absence of various concentrations of folic acid. The production of nitric oxide (NO) was determined by the Griess test. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-10 were determined by ELISA. Inducible NO synthase (iNOS), nuclear transcription factor-kappa B (NF-κB) p65, MAPKs protein, and suppressors of cytokine signaling (SOCS)1 and SOCS3 were analyzed by western blotting. TNF-α and IL-1β, as well as iNOS dependent NO production, resulted significantly inhibited by folic acid pretreatment in LPS-activated BV-2 cells. We also observed that folic acid dose-dependently upregulated both SOCS1 and SOCS3 expression in BV-2 cells, leading to an increased expression of the anti-inflammatory cytokine IL-10. Finally, p-IκBα, which indirectly reflects NF-κB complex activation, and JNK phosphorylation resulted dose-dependently downregulated by folic acid pretreatment of LPS-activated cells, whereas p38 MAPK phosphorylation resulted significantly upregulated by folic acid treatment. Overall, these results demonstrated that folic acid was able to modulate the inflammatory response in microglia cells, shifting proinflammatory versus anti-inflammatory responses through regulating multiple signaling pathways. Antonia Cianciulli, Rosaria Salvatore, Chiara Porro, Teresa Trotta, and Maria Antonietta Panaro Copyright © 2016 Antonia Cianciulli et al. All rights reserved. Is Low Serum Vitamin D Associated with Early Dental Implant Failure? A Retrospective Evaluation on 1625 Implants Placed in 822 Patients Thu, 22 Sep 2016 12:45:38 +0000 Aim. To investigate whether there is a correlation between early dental implant failure and low serum levels of vitamin D. Methods. All patients treated with dental implants in a single centre, in the period 2003–2015, were considered for enrollment in this study. The main outcome was early implant failure. The influence of patient-related variables on implant survival was calculated using the Chi-square test. Results. 822 patients treated with 1625 implants were selected for this study; 27 early failures (3.2%) were recorded. There was no link between gender, age, smoking, history of periodontitis, and an increased incidence of early failures. Statistical analysis reported 9 early failures (2.2%) in patients with serum levels of vitamin D > 30 ng/mL, 16 early failures (3.9%) in patients with levels between 10 and 30 ng/mL, and 2 early failures (9.0%) in patients with levels <10 ng/mL. Although there was an increasing trend in the incidence of early implant failures with the worsening of vitamin D deficiency, the difference between these 3 groups was not statistically significant (). Conclusions. This study failed in proving an effective link between low serum levels of vitamin D and an increased risk of early implant failure. Further studies are needed to investigate this topic. Francesco Mangano, Carmen Mortellaro, Natale Mangano, and Carlo Mangano Copyright © 2016 Francesco Mangano et al. All rights reserved.