Mediators of Inflammation The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. HaCaT Cells as a Reliable In Vitro Differentiation Model to Dissect the Inflammatory/Repair Response of Human Keratinocytes Sun, 17 Dec 2017 00:00:00 +0000 Cultured primary human keratinocytes are frequently employed for studies of immunological and inflammatory responses; however, interpretation of experimental data may be complicated by donor to donor variability, the relatively short culture lifetime, and variations between passages. To standardize the in vitro studies on keratinocytes, we investigated the use of HaCaT cells, a long-lived, spontaneously immortalized human keratinocyte line which is able to differentiate in vitro, as a suitable model to follow the release of inflammatory and repair mediators in response to TNFα or IL-1β. Different treatment conditions (presence or absence of serum) and differentiation stimuli (increase in cell density as a function of time in culture and elevation of extracellular calcium) were considered. ELISA and Multiplex measurement technologies were used to monitor the production of cytokines and chemokines. Taken together, the results highlight that Ca2+ concentration in the medium, cell density, and presence of serum influences at different levels the release of proinflammatory mediators by HaCaT cells. Moreover, HaCaT cells maintained in low Ca2+ medium and 80% confluent are similar to normal keratinocytes in terms of cytokine production suggesting that HaCaT cells may be a useful model to investigate anti-inflammatory interventions/therapies on skin diseases. Irma Colombo, Enrico Sangiovanni, Roberta Maggio, Carlo Mattozzi, Stefania Zava, Yolanda Corbett, Marco Fumagalli, Claudia Carlino, Paola Antonia Corsetto, Diletta Scaccabarozzi, Stefano Calvieri, Angela Gismondi, Donatella Taramelli, and Mario Dell’Agli Copyright © 2017 Irma Colombo et al. All rights reserved. The Role of Lower Airway Dysbiosis in Asthma: Dysbiosis and Asthma Wed, 13 Dec 2017 06:39:26 +0000 With the development of culture-independent techniques, numerous studies have demonstrated that the lower airway is not sterile in health and harbors diverse microbial communities. Furthermore, new evidence suggests that there is a distinct lower airway microbiome in those with chronic respiratory disease. To understand the role of lower airway dysbiosis in the pathogenesis of asthma, in this article, we review the published reports about the lung microbiome of healthy controls, provide an outlook on the contribution of lower airway dysbiosis to asthma, especially steroid-resistant asthma, and discuss the potential therapies targeted for lower airway dysbiosis. Junying Lu, Lingxin Xiong, Xiaohao Zhang, Zhongmin Liu, Shiji Wang, Chao Zhang, Jingtong Zheng, Guoqiang Wang, Ruipeng Zheng, Jodie L. Simpson, and Fang Wang Copyright © 2017 Junying Lu et al. All rights reserved. Different Dietary Proportions of Fish Oil Regulate Inflammatory Factors but Do Not Change Intestinal Tight Junction ZO-1 Expression in Ethanol-Fed Rats Wed, 13 Dec 2017 00:00:00 +0000 Sixty male Wistar rats were fed a control or an ethanol-containing diet in groups C or E. The fat compositions were adjusted with 25% or 57% fish oil substituted for olive oil in groups CF25, CF57, EF25, and EF57. Hepatic thiobarbituric acid-reactive substance (TBARS) levels, cytochrome P450 2E1 protein expression, and tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-10 levels, as well as intracellular adhesion molecule (ICAM)-1 levels were significantly elevated, whereas plasma adiponectin level was significantly reduced in group E (). Hepatic histopathological scores of fatty change and inflammation, in group E were significantly higher than those of group C (). Hepatic TBARS, plasma ICAM-1, and hepatic TNF-α, IL-1β, and IL-10 levels were significantly lower, and plasma adiponectin levels were significantly higher in groups EF25 and EF57 than those in group E (). The immunoreactive area of the intestinal tight junction protein, ZO-1, showed no change between groups C and E. Only group CF57 displayed a significantly higher ZO-1 immunoreactive area compared to group C (). 25% or 57% fish oil substituted for dietary olive oil could prevent ethanol-induced liver damage in rats, but the mechanism might not be related to intestinal tight junction ZO-1 expression. Yi-Wen Chien, Hsiang-Chi Peng, Ya-Ling Chen, Man-Hui Pai, Hsiao-Yun Wang, Hsiao-Li Chuang, and Suh-Ching Yang Copyright © 2017 Yi-Wen Chien et al. All rights reserved. HIF1α-Induced Glycolysis Metabolism Is Essential to the Activation of Inflammatory Macrophages Wed, 13 Dec 2017 00:00:00 +0000 Hypoxia-inducible factor (HIF) 1α is a metabolic regulator that plays an important role in immunologic responses. Previous studies have demonstrated that HIF1α participates in the M1 polarization of macrophages. To clarify the mechanism of HIF1α-induced polarization of M1 macrophage, myeloid-specific HIF1α overexpression (Lysm HIF1α lsl) mice were employed and the bone marrow-derived and peritoneal macrophages were isolated. RT-PCR results revealed that HIF1α overexpression macrophage had a hyperinflammatory state characterized by the upregulation of M1 markers. Cellular bioenergetics analysis showed lower cellular oxygen consumption rates in the Lysm HIF1α lsl mice. Metabolomics studies showed that HIF1α overexpression led to increased glycolysis and pentose phosphate pathway intermediates. Further results revealed that macrophage M1 polarization, induced by HIF1α overexpression, was via upregulating the mRNA expression of the genes related to the glycolysis metabolism. Our results indicate that HIF1α promoted macrophage glycolysis metabolism, which induced M1 polarization in mice. Ting Wang, Huiying Liu, Guan Lian, Song-Yang Zhang, Xian Wang, and Changtao Jiang Copyright © 2017 Ting Wang et al. All rights reserved. Gene Expression, Oxidative Stress, and Senescence of Primary Coronary Endothelial Cells Exposed to Postprandial Serum of Healthy Adult and Elderly Volunteers after Oven-Cooked Meat Meals Tue, 12 Dec 2017 05:06:19 +0000 Epidemiological studies have linked high consumption of meat with major age-related diseases including cardiovascular diseases. Abnormal postprandial increases in plasma lipids after a meat meal have been hypothesized among the pathogenetic mechanisms. However, it is still unknown if the postprandial serum derived after a normal meat meal is able to affect endothelial function, and if the type of meat and the age of the donors are critical factors. Here, we show the effects of postprandial sera derived from healthy adults and elderly volunteers who consumed meat meals on human coronary artery endothelial cell (HCAEC) oxidative stress, gene expression, DNA damage, and cellular senescence. We observed that a single exposure to postprandial serum induces a slight increase in ROS that is associated with modulation of gene expression pathways related to oxidative stress response and metabolism. The postprandial-induced increase in ROS is not associated with a measurable DNA oxidative damage. However, repeated exposure to postprandial serum induces an acceleration of cellular senescence. Taking into account the deleterious role of cellular senescence in age-related vascular diseases, the results suggest a new mechanism by which excessive meat consumption and time spent in postprandial state may affect health status during aging. Costarelli Laura, Giacconi Robertina, Francesco Piacenza, Andrea Basso, Deborah Pacetti, Michele Balzano, Riccardo Gagliardi, Natale Giuseppe Frega, Eugenio Mocchegiani, Mauro Provinciali, and Marco Malavolta Copyright © 2017 Costarelli Laura et al. All rights reserved. Small Intestinal Bacterial Overgrowth Affects the Responsiveness to Colchicine in Familial Mediterranean Fever Tue, 12 Dec 2017 00:00:00 +0000 Objective. Familial Mediterranean fever (FMF) is an autosomal recessive disease due to a MEFV gene mutation. Since Helicobacter pylori infection has been described to increase the severity and frequency of FMF attacks, we evaluate if overgrowth of small intestinal bacterial (SIBO), associated with a release of bacterial products, can affect the response to colchicine in FMF patients poorly responsive to colchicine. Methods. We revised our Periodic Fever Centre database to detect FMF patients who were poorly responsive to colchicine, without a well-defined cause of drug resistance. They were evaluated for SIBO presence, then treated with decontamination therapy. Results. Among 223 FMF patients, 49 subjects show colchicine resistance, and no other known causes of colchicine unresponsiveness has been found in 25 patients. All 25 patients underwent glucose breath test; 20 (80%) of them were positive, thus affected by SIBO. After a successful decontamination treatment, 11 patients (55%) did not show FMF attacks during the following three months (), while 9 of them revealed a significant reduction of the number of attacks compared to three months before (). Conclusion. The SIBO eradication improves laboratory and clinical features of FMF patients. Thus, patients with unresponsiveness to colchicine treatment should be investigated for SIBO. E. Verrecchia, L. L. Sicignano, M. La Regina, G. Nucera, I. Patisso, L. Cerrito, M. Montalto, A. Gasbarrini, and R. Manna Copyright © 2017 E. Verrecchia et al. All rights reserved. Nuclear Translocation of SGPP-1 and Decrease of SGPL-1 Activity Contribute to Sphingolipid Rheostat Regulation of Inflammatory Dendritic Cells Mon, 11 Dec 2017 10:00:09 +0000 A balanced sphingolipid rheostat is indispensable for dendritic cell function and survival and thus initiation of an immune response. Sphingolipid levels are dynamically maintained by the action of sphingolipid enzymes of which sphingosine kinases, S1P phosphatases (SGPP-1/2) and S1P lyase (SGPL-1), are pivotal in the balance of S1P and sphingosine levels. In this study, we present that SGPP-1 and SGPL-1 are regulated in inflammatory dendritic cells and contribute to S1P fate. TLR-dependent activation caused SGPL-1 protein downregulation with subsequent decrease of enzymatic activity by two-thirds. In parallel, confocal fluorescence microscopy revealed that endogenous SGPP-1 was expressed in nuclei of naive dendritic cells and was translocated into the cytoplasmatic compartment upon inflammatory stimulation resulting in dephosphorylation of S1P. Mass spectrometric determination showed that a part of the resulting sphingosine was released from the cell, increasing extracellular levels. Another route of diminishing intracellular S1P was possibly taken by its export via ATP-binding cassette transporter C1 which was upregulated in array analysis, while the S1P transporter, spinster homolog 2, was not relevant in dendritic cells. These investigations newly describe the sequential expression and localization of the endogenous S1P regulators SGPP-1 and SGPL-1 and highlight their contribution to the sphingolipid rheostat in inflammation. Anja Schwiebs, Dominique Thomas, Burkhard Kleuser, Josef M. Pfeilschifter, and Heinfried H. Radeke Copyright © 2017 Anja Schwiebs et al. All rights reserved. Corrigendum to “Metalloproteinases and Their Tissue Inhibitors in Comparison between Different Chronic Pneumopathies in the Horse” Mon, 11 Dec 2017 00:00:00 +0000 Ann Kristin Barton, Tarek Shety, Angelika Bondzio, Ralf Einspanier, and Heidrun Gehlen Copyright © 2017 Ann Kristin Barton et al. All rights reserved. Mouse Thyroid Gland Changes in Aging: Implication of Galectin-3 and Sphingomyelinase Mon, 11 Dec 2017 00:00:00 +0000 Prevalence of thyroid dysfunction and its impact on cognition in older people has been demonstrated, but many points remain unclarified. In order to study the effect of aging on the thyroid gland, we compared the thyroid gland of very old mice with that of younger ones. We have first investigated the changes of thyroid microstructure and the possibility that molecules involved in thyroid function might be associated with structural changes. Results from this study indicate changes in the height of the thyrocytes and in the amplitude of interfollicular spaces, anomalous expression/localization of thyrotropin, thyrotropin receptor, and thyroglobulin aging. Thyrotropin and thyrotropin receptor are upregulated and are distributed inside the colloid while thyroglobulin fills the interfollicular spaces. In an approach aimed at defining the behavior of molecules that change in different physiopathological conditions of thyroid, such as galectin-3 and sphingomyelinase, we then wondered what was their behavior in the thyroid gland in aging. Importantly, in comparison with the thyroid of young animals, we have found a higher expression of galectin-3 and a delocalization of neutral sphingomyelinase in the thyroid of old animals. A possible relationship between galectin-3, neutral sphingomyelinase, and aging has been discussed. Giovanna Traina, Samuela Cataldi, Paola Siccu, Elisabetta Loreti, Ivana Ferri, Angelo Sidoni, Michela Codini, Chiara Gizzi, Marzia Sichetti, Francesco Saverio Ambesi-Impiombato, Tommaso Beccari, Francesco Curcio, and Elisabetta Albi Copyright © 2017 Giovanna Traina et al. All rights reserved. A Prospective, Double-Blind, Randomized, Controlled Clinical Trial in the Gingivitis Prevention with an Oligomeric Proanthocyanidin Nutritional Supplement Sun, 10 Dec 2017 00:00:00 +0000 Aim. To evaluate the effectiveness on tissue response of the new nutritional supplement made of oligomeric proanthocyanidins in induced gingivitis after 21 days of use. Material and Methods. A prospective, double-blind, randomized, controlled clinical trial was carried out on 20 patients; it is divided into an experimental group and a control group after fulfilling the selection criteria. Patients had to come 4 times during the study to register the Silness and Löe index, the gingival bleeding index, the plaque index, the inflammatory crevicular fluid study (IL6), and the changes in the brightness of the gingiva. No complementary hygiene methods were allowed during the 21 days. Results. The Silness and Löe index was higher in the control group than in the experimental group, reaching a twofold difference between the groups (). The gingival bleeding index also supports this fact, since the bleeding was lower in the experimental group (). However, the dental plaque on the tooth surface according to the plaque index was 33% higher in the experimental group (). Some differences in the IL-6 were found in the crevicular fluid (). Conclusion. Oligomeric proanthocyanidins have an effect on the periodontal tissue’s health. No effects on the accumulation of plaque on the tooth surface were found, so further studies are needed to determine the nature of the plaque. R. M. Díaz Sánchez, G. Castillo-Dalí, A. Fernández-Olavarría, R. Mosquera-Pérez, J. M. Delgado-Muñoz, J. L. Gutiérrez-Pérez, and D. Torres-Lagares Copyright © 2017 R. M. Díaz Sánchez et al. All rights reserved. Granulocyte Colony-Stimulating Factor and Its Potential Application for Skeletal Muscle Repair and Regeneration Thu, 07 Dec 2017 00:00:00 +0000 Granulocyte colony-stimulating factor (G-CSF) was originally discovered in the context of hematopoiesis. However, the identification of the G-CSF receptor (G-CSFR) being expressed outside the hematopoietic system has revealed wider roles for G-CSF, particularly in tissue repair and regeneration. Skeletal muscle damage, including that following strenuous exercise, induces an elevation in plasma G-CSF, implicating it as a potential mediator of skeletal muscle repair. This has been supported by preclinical studies and clinical trials investigating G-CSF as a potential therapeutic agent in relevant disease states. This review focuses on the growing literature associated with G-CSF and G-CSFR in skeletal muscle under healthy and disease conditions and highlights the current controversies. Craig R. Wright, Alister C. Ward, and Aaron P. Russell Copyright © 2017 Craig R. Wright et al. All rights reserved. Visfatin Triggers Anorexia and Body Weight Loss through Regulating the Inflammatory Response in the Hypothalamic Microglia Thu, 07 Dec 2017 00:00:00 +0000 Visfatin is an adipokine that is secreted from adipose tissue, and it is involved in a variety of physiological processes. In particular, visfatin has been implicated in metabolic diseases, such as obesity and type 2 diabetes, which are directly linked to systemic inflammation. However, the potential impacts of visfatin on the hypothalamic control of energy homeostasis, which is involved in microglial inflammation, have not fully been investigated. In this study, we found that treatment with exogenous recombinant visfatin protein led to the activation of the inflammatory response in a microglial cell line. In addition, we observed that central administration of visfatin led to the activation of microglia in the hypothalamus. Finally, we found that visfatin reduced food intake and body weight through activating POMC neurons in association with microglia activation in mice. These findings indicate that elevation of central visfatin levels may be associated with homeostatic feeding behavior in response to metabolic shifts, such as increased adiposity following inflammatory processes in the hypothalamus. Thai Hien Tu, Il Seong Nam-Goong, Jisung Lee, Sunggu Yang, and Jae Geun Kim Copyright © 2017 Thai Hien Tu et al. All rights reserved. Role of Cathepsin S in Periodontal Inflammation and Infection Wed, 06 Dec 2017 09:51:10 +0000 Cathepsin S is a cysteine protease and regulator of autophagy with possible involvement in periodontitis. The objective of this study was to investigate whether cathepsin S is involved in the pathogenesis of periodontal diseases. Human periodontal fibroblasts were cultured under inflammatory and infectious conditions elicited by interleukin-1β and Fusobacterium nucleatum, respectively. An array-based approach was used to analyze differential expression of autophagy-associated genes. Cathepsin S was upregulated most strongly and thus further studied in vitro at gene and protein levels. In vivo, gingival tissue biopsies from rats with ligature-induced periodontitis and from periodontitis patients were also analyzed at transcriptional and protein levels. Multiple gene expression changes due to interleukin-1β and F. nucleatum were observed in vitro. Both stimulants caused a significant cathepsin S upregulation. A significantly elevated cathepsin S expression in gingival biopsies from rats with experimental periodontitis was found in vivo, as compared to that from control. Gingival biopsies from periodontitis patients showed a significantly higher cathepsin S expression than those from healthy gingiva. Our findings provide original evidence that cathepsin S is increased in periodontal cells and tissues under inflammatory and infectious conditions, suggesting a critical role of this autophagy-associated molecule in the pathogenesis of periodontitis. S. Memmert, A. Damanaki, A. V. B. Nogueira, S. Eick, M. Nokhbehsaim, A. K. Papadopoulou, A. Till, B. Rath, S. Jepsen, W. Götz, C. Piperi, E. K. Basdra, J. A. Cirelli, A. Jäger, and J. Deschner Copyright © 2017 S. Memmert et al. All rights reserved. Evidence for the Involvement of Lipid Rafts and Plasma Membrane Sphingolipid Hydrolases in Pseudomonas aeruginosa Infection of Cystic Fibrosis Bronchial Epithelial Cells Sun, 03 Dec 2017 00:00:00 +0000 Cystic fibrosis (CF) is the most common autosomal genetic recessive disease caused by mutations of gene encoding for the cystic fibrosis transmembrane conductance regulator. Patients with CF display a wide spectrum of symptoms, the most severe being chronic lung infection and inflammation, which lead to onset of cystic fibrosis lung disease. Several studies indicate that sphingolipids play a regulatory role in airway inflammation. The inhibition and downregulation of GBA2, the enzyme catabolizing glucosylceramide to ceramide, are associated with a significant reduction of IL-8 production in CF bronchial epithelial cells. Herein, we demonstrate that GBA2 plays a role in the proinflammatory state characterizing CF cells. We also report for the first time that Pseudomonas aeruginosa infection causes a recruitment of plasma membrane-associated glycosphingolipid hydrolases into lipid rafts of CuFi-1-infected cells. This reorganization of cell membrane may be responsible for activation of a signaling cascade, culminating in aberrant inflammatory response in CF bronchial epithelial cells upon bacterial infection. Taken together, the presented data further support the role of sphingolipids and their metabolic enzymes in controlling the inflammatory response in CF. Domitilla Schiumarini, Nicoletta Loberto, Giulia Mancini, Rosaria Bassi, Paola Giussani, Elena Chiricozzi, Maura Samarani, Silvia Munari, Anna Tamanini, Giulio Cabrini, Giuseppe Lippi, Maria Cristina Dechecchi, Sandro Sonnino, and Massimo Aureli Copyright © 2017 Domitilla Schiumarini et al. All rights reserved. S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling Sun, 03 Dec 2017 00:00:00 +0000 Sphingosine-1-phosphate (S1P) is a potent lipid signaling molecule that regulates pleiotropic biological functions including cell migration, survival, angiogenesis, immune cell trafficking, inflammation, and carcinogenesis. It acts as a ligand for a family of cell surface receptors. S1P concentrations are high in blood and lymph but low in tissues, especially the thymus and lymphoid organs. S1P chemotactic gradients are essential for lymphocyte egress and other aspects of physiological cell trafficking. S1P is irreversibly degraded by S1P lyase (SPL). SPL regulates lymphocyte trafficking, inflammation and other physiological and pathological processes. For example, SPL located in thymic dendritic cells acts as a metabolic gatekeeper that controls the normal egress of mature T lymphocytes from the thymus into the circulation, whereas SPL deficiency in gut epithelial cells promotes colitis and colitis-associated carcinogenesis (CAC). Recently, we identified a complex syndrome comprised of nephrosis, adrenal insufficiency, and immunological defects caused by inherited mutations in human SGPL1, the gene encoding SPL. In the present article, we review current evidence supporting the role of SPL in thymic egress, inflammation, and cancer. Lastly, we summarize recent progress in understanding other SPL functions, its role in inherited disease, and SPL targeting for therapeutic purposes. Ashok Kumar, Jesus Zamora-Pineda, Emilie Degagné, and Julie D. Saba Copyright © 2017 Ashok Kumar et al. All rights reserved. Association Study of Tumor Necrosis Factor Receptor 1 (TNFR1) Gene Polymorphisms with Schizophrenia in the Polish Population Wed, 29 Nov 2017 11:55:15 +0000 Schizophrenia is a devastating mental disorder with undetermined aetiology. Previous research has suggested that dysregulation of proinflammatory cytokines and their receptors plays a role in developing schizophrenia. We examined the association of the three single nucleotide polymorphisms (SNPs; rs4149576, rs4149577, and rs1860545) in the tumor necrosis factor receptor 1 (TNFR1) gene with the development and psychopathology of paranoid schizophrenia in the Polish Caucasian sample consisting of 388 patients and 657 control subjects. The psychopathology was assessed using a five-factor model of the Positive and Negative Syndrome Scale (PANSS). SNPs were genotyped using the TaqMan 5-exonuclease allelic discrimination assay. The SNPs tested were not associated with a predisposition to paranoid schizophrenia in either the entire sample or after stratification according to gender. However, rs4149577 and rs1860545 SNPs were associated with the intensity of the PANSS excitement symptoms in men, which may contribute to the risk of violent behavior. Polymorphisms in the TNFR1 gene may have an impact on the symptomatology of schizophrenia in men. Renata Suchanek-Raif, Krzysztof Kucia, Małgorzata Kowalczyk, Paweł Raif, Monika Paul-Samojedny, Anna Fila-Daniłow, and Jan Kowalski Copyright © 2017 Renata Suchanek-Raif et al. All rights reserved. Regulation of Ghrelin Receptor by Periodontal Bacteria In Vitro and In Vivo Wed, 29 Nov 2017 00:00:00 +0000 Ghrelin plays a major role in obesity-related diseases which have been shown to be associated with periodontitis. This study sought to analyze the expression of the functional receptor for ghrelin (GHS-R1a) in periodontal cells and tissues under microbial conditions in vitro and in vivo. The GHS-R1a expression in human periodontal cells challenged with the periodontopathogen Fusobacterium nucleatum, in gingival biopsies from periodontally healthy and diseased individuals, and from rats with and without ligature-induced periodontitis was analyzed by real-time PCR, immunocytochemistry, and immunofluorescence. F. nucleatum induced an initial upregulation and subsequent downregulation of GHS-R1a in periodontal cells. In rat experimental periodontitis, the GHS-R1a expression at periodontitis sites was increased during the early stage of periodontitis, but significantly reduced afterwards, when compared with healthy sites. In human gingival biopsies, periodontally diseased sites showed a significantly lower GHS-R1a expression than the healthy sites. The expression of the functional ghrelin receptor in periodontal cells and tissues is modulated by periodontal bacteria. Due to the downregulation of the functional ghrelin receptor by long-term exposure to periodontal bacteria, the anti-inflammatory actions of ghrelin may be diminished in chronic periodontal infections, which could lead to an enhanced periodontal inflammation and tissue destruction. Marjan Nokhbehsaim, Anna Damanaki, Andressa Vilas Boas Nogueira, Sigrun Eick, Svenja Memmert, Xiaoyan Zhou, Shanika Nanayakkara, Werner Götz, Joni Augusto Cirelli, Andreas Jäger, and James Deschner Copyright © 2017 Marjan Nokhbehsaim et al. All rights reserved. Reclamation of Herb Residues Using Probiotics and Their Therapeutic Effect on Diarrhea Wed, 29 Nov 2017 00:00:00 +0000 Residues from herbal medicine processing in pharmaceutical plants create a large amount of waste (herb residues), which consists mainly of environmental pollution and medicinal waste. In order to resolve this problem, probiotics of Bacillus (B.) subtilis, Aspergillus (A.) oryzae, and Lactobacillus (L.) plantarum M3 are selected to reuse herb residue of Jianweixiaoshi tablets (JT), and an antibiotic-associated diarrhea (AAD) mouse model was established to evaluate the therapeutic effects of the herb residue fermentation supernatant. Our results indicated that the fermentation supernatant had scavenged 77.8% of 2,2-diphenyl-1-picrylhydrazyl (DPPH), 78% of O2•−, 36.7% of •OH, 39% of Fe2+ chelation, and 716 mg/L reducing power. The inhibition zones for Salmonella (S.) typhimurium, S. enteritidis, Shigella (Sh.) flexneri, Escherichia (E.) coli, Listeria (L.) monocytogenes, Sh. dysenteriae 301, and Staphylococcus (S.) aureus were 17, 14, 19, 18, 20, 19, and 20 mm, respectively. The in vivo results indicated that the fermentation supernatant resulted in a high diarrhea inhibition rate (56%, ), greatly enhanced the disruption of bacterial diversity caused by antibiotics, and restored the dominant position of L. johnsonii in the treatment and recovery stages. Therefore, the combination of the herb residue and probiotics suggests a potential to explore conversion of these materials for the possible development of therapies for AAD. Fanjing Meng, Tingtao Chen, Dongwen Ma, Xin Wang, Xiaoxiao Zhao, Puyuan Tian, Huan Wang, Zhiwen Hai, Liang Shen, Xianyao Tang, Xiaolei Wang, and Hongbo Xin Copyright © 2017 Fanjing Meng et al. All rights reserved. Protective Effects of Gemigliptin, a Dipeptidyl Peptidase-4 Inhibitor, against Cisplatin-Induced Nephrotoxicity in Mice Tue, 28 Nov 2017 00:00:00 +0000 Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used antihyperglycemic agents for the treatment of type 2 diabetes mellitus. Recently, the pleiotropic actions of DPP-4 inhibitors have drawn much attention. In the present study, we aimed to examine whether gemigliptin, a recently developed DPP-4 inhibitor, could protect against cisplatin-induced nephrotoxicity. We showed that pretreatment with gemigliptin attenuated cisplatin-induced renal dysfunction, as shown by analysis of plasma creatinine levels and blood urea nitrogen and histological damage. Elevated plasma levels of active glucagon-like peptide-1 were observed in gemigliptin-pretreated mice after cisplatin treatment, compared to that in cisplatin alone-treated mice. Gemigliptin attenuated cisplatin-induced apoptotic cell death, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Western blot analysis in the kidneys. Gemigliptin also decreased the plasma levels of tumor necrosis factor-α and monocyte chemoattractant protein-1 and attenuated nuclear staining of nuclear factor kappa-B p65 in the kidneys. In addition, gemigliptin increased the protein expression of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) in the kidneys of cisplatin-treated mice. Taken together, these results suggest that pretreatment with gemigliptin protects against cisplatin-induced nephrotoxicity in mice, possibly via inhibition of apoptotic cell death and inflammatory responses through induction of HO-1 and NQO1 expression. Seung Hee Choi, Jaechan Leem, and In-Kyu Lee Copyright © 2017 Seung Hee Choi et al. All rights reserved. Overexpression of Cholesteryl Ester Transfer Protein Increases Macrophage-Derived Foam Cell Accumulation in Atherosclerotic Lesions of Transgenic Rabbits Tue, 28 Nov 2017 00:00:00 +0000 High levels of plasma high-density lipoprotein-cholesterol (HDL-C) are inversely associated with the risk of atherosclerosis and other cardiovascular diseases; thus, pharmacological inhibition of cholesteryl ester transfer protein (CETP) is considered to be a therapeutic method of raising HDL-C levels. However, many CETP inhibitors have failed to achieve a clinical benefit despite raising HDL-C. In the study, we generated transgenic (Tg) rabbits that overexpressed the human CETP gene to examine the influence of CETP on the development of atherosclerosis. Both Tg rabbits and their non-Tg littermates were fed a high cholesterol diet for 16 weeks. Plasma lipids and body weight were measured every 4 weeks. Gross lesion areas of the aortic atherosclerosis along with lesional cellular components were quantitatively analyzed. Overexpression of human CETP did not significantly alter the gross atherosclerotic lesion area, but the number of macrophages in lesions was significantly increased. Overexpression of human CETP did not change the plasma levels of total cholesterol or low-density lipoprotein cholesterol but lowered plasma HDL-C and increased triglycerides. These data revealed that human CETP may play an important role in the development of atherosclerosis mainly by decreasing HDL-C levels and increasing the accumulation of macrophage-derived foam cells. Shoucui Gao, Xiaojing Wang, Daxing Cheng, Jiayan Li, Lu Li, Linwu Ran, Sihai Zhao, Jianglin Fan, and Enqi Liu Copyright © 2017 Shoucui Gao et al. All rights reserved. Tabetri™ (Tabebuia avellanedae Ethanol Extract) Ameliorates Osteoarthritis Symptoms Induced by Monoiodoacetate through Its Anti-Inflammatory and Chondroprotective Activities Sun, 26 Nov 2017 00:00:00 +0000 Although osteoarthritis (OA), a degenerative joint disease characterized by the degradation of joint articular cartilage and subchondral bones, is generally regarded as a degenerative rather than inflammatory disease, recent studies have indicated the involvement of inflammation in OA pathogenesis. Tabebuia avellanedae has long been used to treat various diseases; however, its role in inflammatory response and the underlying molecular mechanisms remain poorly understood. In this study, the pharmacological effects of Tabetri (Tabebuia avellanedae ethanol extract (Ta-EE)) on OA pathogenesis induced by monoiodoacetate (MIA) and the underlying mechanisms were investigated using experiments with a rat model and in vitro cellular models. In the animal model, Ta-EE significantly ameliorated OA symptoms and reduced the serum levels of inflammatory mediators and proinflammatory cytokines without any toxicity. The anti-inflammatory activity of Ta-EE was further confirmed in a macrophage-like cell line (RAW264.7). Ta-EE dramatically suppressed the production and mRNA expressions of inflammatory mediators and proinflammatory cytokines in lipopolysaccharide-stimulated RAW264.7 cells without any cytotoxicity. Finally, the chondroprotective effect of Ta-EE was examined in a chondrosarcoma cell line (SW1353). Ta-EE markedly suppressed the mRNA expression of matrix metalloproteinase genes. The anti-inflammatory and chondroprotective activities of Ta-EE were attributed to the targeting of the nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) signaling pathways in macrophages and chondrocytes. Jae Gwang Park, Young-Su Yi, Yo Han Hong, Sulgi Yoo, Sang Yun Han, Eunji Kim, Seong-Gu Jeong, Adithan Aravinthan, Kwang Soo Baik, Su Young Choi, Young-Jin Son, Jong-Hoon Kim, and Jae Youl Cho Copyright © 2017 Jae Gwang Park et al. All rights reserved. Anti-Interleukin-22-Neutralizing Antibody Attenuates Angiotensin II-Induced Cardiac Hypertrophy in Mice Wed, 22 Nov 2017 00:00:00 +0000 Background. Interleukin- (IL-) 22 is considered a proinflammatory cytokine. Recent evidence has demonstrated that it plays a role in cardiovascular diseases. In the recent study, we investigate whether IL-22 is involved in cardiac hypertrophy. Methods. Angiotensin II was used to build hypertrophy model and the IL-22 and IL-22 receptor 1 (IL-22R1) levels in heart tissue were measured. In addition, angiotensin II-treated mice received an injection of anti-IL-22-neutralizing antibody (nAb) to investigate the effects of IL-22 nAb on myocardial hypertrophy, cardiac function, and cardiac fibrosis; the activation of the signaling pathway and the prohypertrophic inflammatory cytokine mRNA levels was detected. Furthermore, the effect of IL-22 nAb on angiotensin II-induced hypertrophy in vitro was also determined. Results. IL-22 and IL-22R1 levels were significantly increased after angiotensin II infusion. Anti-IL-22 nAb significantly alleviated the severity of hypertrophy, prevented systolic and diastolic abnormalities, reduced cardiac fibrosis, STAT3 and ERK phosphorylation, and downregulated the mRNA expression of IL-17, IL-6, IL-1β, IFN-γ, and TNF-α. In addition, IL-22 nAb attenuated angiotensin II-induced hypertrophy in H9C2 cells. Conclusion. Our data demonstrated that neutralization of IL-22 alleviated angiotensin II-induced cardiac hypertrophy. The downregulation of IL-22 may be a novel therapeutic strategy to prevent cardiac hypertrophy. Jing Ye, Ling Liu, Qingwei Ji, Ying Huang, Ying Shi, Lei Shi, Jianfang Liu, Menglong Wang, Yao Xu, Huimin Jiang, Zhen Wang, Yingzhong Lin, and Jun Wan Copyright © 2017 Jing Ye et al. All rights reserved. Tomatidine Attenuates Airway Hyperresponsiveness and Inflammation by Suppressing Th2 Cytokines in a Mouse Model of Asthma Tue, 21 Nov 2017 00:00:00 +0000 Tomatidine is isolated from the fruits of tomato plants and found to have anti-inflammatory effects in macrophages. In the present study, we investigated whether tomatidine suppresses airway hyperresponsiveness (AHR) and eosinophil infiltration in asthmatic mice. BALB/c mice were sensitized with ovalbumin and treated with tomatidine by intraperitoneal injection. Airway resistance was measured by intubation analysis as an indication of airway responsiveness, and histological studies were performed to evaluate eosinophil infiltration in lung tissue. Tomatidine reduced AHR and decreased eosinophil infiltration in the lungs of asthmatic mice. Tomatidine suppressed Th2 cytokine production in bronchoalveolar lavage fluid. Tomatidine also blocked the expression of inflammatory and Th2 cytokine genes in lung tissue. In vitro, tomatidine inhibited proinflammatory cytokines and CCL11 production in inflammatory BEAS-2B bronchial epithelial cells. These results indicate that tomatidine contributes to the amelioration of AHR and eosinophil infiltration by blocking the inflammatory response and Th2 cell activity in asthmatic mice. Chieh-Ying Kuo, Wen-Chung Huang, Chian-Jiun Liou, Li-Chen Chen, Jiann-Jong Shen, and Ming-Ling Kuo Copyright © 2017 Chieh-Ying Kuo et al. All rights reserved. Luteolin Treatment Protects against Renal Ischemia-Reperfusion Injury in Rats Tue, 21 Nov 2017 00:00:00 +0000 Renal ischemia-reperfusion (I/R) injury is a common but severe scientific problem. Luteolin has great anti-inflammatory and antioxidant effects. In this study, we studied the effect of luteolin on renal I/R injury in rats. Intragastric administration of luteolin or saline was performed in Sprague-Dawley rats before (40 mg/kg for three days) and after (one day) renal I/R modeling. Kidney and blood samples were harvested to detect the severity of renal injury 24 hours after operation. The results showed that luteolin-treated rats exhibited milder histomorphological changes with lower scores of renal histological lesions; lower blood urea nitrogen and creatinine levels; lower renal malondialdehyde (MDA), 8-oxo-deoxyguanosine (8-OHdG), and myeloperoxidase (MPO) levels; and higher superoxide dismutase (SOD) and catalase (CAT) activities in the kidney. Luteolin attenuated the increased levels of serum and renal tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, renal high mobility group box-1 (HMGB1), and nuclear factor kappa β (NF-κB) expression levels in I/R rats. Furthermore, luteolin treatment significantly reduced renal cell apoptosis and endoplasmic reticulum (ER) stress caused by renal I/R injury. In conclusion, luteolin improved renal function in I/R rats by reducing oxidative stress, neutrophil infiltration, inflammation, renal cell apoptosis, and expression of HMGB1 and NF-κB, and ER stress. Xin Hong, Xiaojing Zhao, Gang Wang, Zhengliang Zhang, Honghong Pei, and Zhong Liu Copyright © 2017 Xin Hong et al. All rights reserved. Antilipotoxicity Activity of Osmanthus fragrans and Chrysanthemum morifolium Flower Extracts in Hepatocytes and Renal Glomerular Mesangial Cells Mon, 20 Nov 2017 00:00:00 +0000 The excess influx of free fatty acids (FFAs) into nonadipose tissues, such as those of liver and kidney, induces lipotoxicity leading to hepatic steatosis and renal dysfunction. The aim of this study was to investigate the protective effects of methanolic flower extracts of Osmanthus fragrans (OF) and Chrysanthemum morifolium (CM) against FFA-induced lipotoxicity in hepatocytes (human HepG2 cells) and renal glomerular mesangial cells (mouse SV40-Mes13 cells). The results showed that OF and CM significantly suppressed FFA-induced intracellular triacylglycerol accumulation via partially inhibiting the gene expression of sterol regulatory element-binding protein-1c (SREBP-1c) and glycerol-3-phosphate acyltransferase (GPAT) in HepG2 cells. Both extracts inhibited reactive oxygen species (ROS) generation by FFA-stimulated HepG2 cells. OF and CM also suppressed the mRNA expression of interleukin- (IL-) 1β, IL-6, IL-8, tumor necrosis factor- (TNF-) α, and transforming growth factor- (TGF-) β by HepG2 cells treated with conditioned medium derived from lipopolysaccharide-treated THP-1 monocytes. Furthermore, OF and CM effectively inhibited oleate-induced cellular lipid accumulation, TGF-β secretion, and overexpression of fibronectin in mesangial cells. In conclusion, OF and CM possess hepatoprotective activity by inhibiting hepatic fat load and inflammation and renal protection by preventing FFA-induced mesangial extracellular matrix formation. Po-Jung Tsai, Mei-Ling Chang, Ching-Mei Hsin, Chung-Chieh Chuang, Lu-Te Chuang, and Wen-Huey Wu Copyright © 2017 Po-Jung Tsai et al. All rights reserved. Mitofusin 2 Promotes Apoptosis of CD4+ T Cells by Inhibiting Autophagy in Sepsis Sun, 19 Nov 2017 00:00:00 +0000 Apoptosis of CD4+ T cells is a primary pathophysiological mechanism of immune dysfunction in the pathogenesis of sepsis. Mitofusin 2 (Mfn2), an integral mitochondrial outer membrane protein, has been confirmed to be associated with cellular metabolism, proliferation, and apoptosis. The function of Mfn2 in CD4+ T cell apoptosis in sepsis is poorly understood. Here, we discovered increased in vivo Mfn2 expression, autophagy deficiency, and elevated cell apoptosis in murine splenic CD4+ T cells after cecal ligation and puncture (CLP). We also observed almost identical results in splenic CD4+ T cells upon lipopolysaccharide (LPS) stimulation in vitro. Furthermore, overexpression of Mfn2 resulted in impaired autophagy and increased apoptosis in Jurkat cells. Pharmacological inhibition of autophagy with 3-methyladenine enhanced Mfn2 overexpression-induced cell apoptosis. In addition, overexpression of Mfn2 downregulated phorbol myristate acetate (PMA)/ionomycin-, rapamycin- and starvation-induced autophagy in Jurkat T cells. Taken together, these data indicate a critical role of Mfn2 in CD4+ T cell apoptosis in sepsis and the underlying mechanism of autophagy deficiency. Lan Ying, Guang-Ju Zhao, You Wu, He-Liang Ke, Guang-Liang Hong, Hui Zhang, Ning Dong, Yao Wu, Yong-Ming Yao, and Zhong-Qiu Lu Copyright © 2017 Lan Ying et al. All rights reserved. Changes in Etiologies of Hospitalized Patients with Liver Cirrhosis in Beijing 302 Hospital from 2002 to 2013 Sun, 19 Nov 2017 00:00:00 +0000 Background. Over the last 20 years, the prevalence of hepatitis B virus (HBV) infection in China has decreased gradually due to the application of a national HBV vaccination program. In contrast, the prevalence of alcoholic liver disease (ALD), nonalcoholic fatty liver disease, autoimmune liver disease, and drug-induced liver injury has markedly increased. Methods. We conducted a retrospective review of 82,562 hospitalized patients diagnosed with liver cirrhosis in Beijing 302 Hospital from 2002 to 2013. Results. The top four etiologies of cirrhosis were HBV, HCV, ALD, and autoimmune liver disease. The percentage of HBV cirrhosis decreased from 81.53% in 2002 to 66.0% in 2013, whereas the frequency of alcoholic cirrhosis increased from 3.34% in 2002 to 8.40% in 2013. Females (84.34%) accounted for the majority of cirrhotic patients with autoimmune liver diseases. Males accounted for 80.16% of HBV cirrhosis patients and 98.02% of alcoholic cirrhosis patients. Conclusion. In Beijing 302 Hospital, the top four etiologies of cirrhosis were HBV, HCV, ALD, and autoimmune liver disease. Over the last 12 years, the prevalence of HBV cirrhosis has decreased gradually, whereas that of alcoholic cirrhosis has increased significantly. Binxia Chang, Baosen Li, Ying Sun, Guangju Teng, Ang Huang, Jin Li, and Zhengsheng Zou Copyright © 2017 Binxia Chang et al. All rights reserved. Platelet-Released Growth Factors Modulate the Secretion of Cytokines in Synoviocytes under Inflammatory Joint Disease Sun, 19 Nov 2017 00:00:00 +0000 The etiology and pathogenesis of rheumatoid arthritis (RA) are marked by a complex interplay of various cell populations and is mediated by different signaling pathways. Traditionally, therapies have primarily focused on pain relief, reducing inflammation and the recovery of joint function. More recently, however, researchers have discussed the therapeutic efficacy of autologous platelet-rich plasma (PRP). The main objective of this work is to examine the influences of platelet-released growth factor (PRGF) on human synoviocytes under inflammatory conditions. Additionally, it is checked to which extend treatment with platelet concentrate influences the release of cytokines form synoviocytes. For this purpose, an in vitro RA model was created by stimulating the cells with the TNF-α. The release of cytokines was measured by ELISA. The cytokine gene expression was analyzed by real-time PCR. It has been observed that the stimulation concentration of 10 ng/ml TNF-α resulted in a significantly increased endogenous secretion and gene expression of IL-6 and TNF-α. The anti-inflammatory effect of PRGF could be confirmed through significant reduction of TNF-α and IL-1β. An induced inflammatory condition seems to cause PRGF to inhibit the release of proinflammatory cytokines. Further study is required to understand the exact effect mechanism of PRGF on synoviocytes. Mersedeh Tohidnezhad, Andreas Bayer, Biljana Rasuo, Jennifer Vanessa Phi Hock, Nisreen Kweider, Athanassios Fragoulis, Tolga Taha Sönmez, Holger Jahr, Thomas Pufe, and Sebastian Lippross Copyright © 2017 Mersedeh Tohidnezhad et al. All rights reserved. Stimulation of Alpha7 Nicotinic Acetylcholine Receptor Attenuates Nicotine-Induced Upregulation of MMP, MCP-1, and RANTES through Modulating ERK1/2/AP-1 Signaling Pathway in RAW264.7 and MOVAS Cells Thu, 16 Nov 2017 10:40:37 +0000 Vagus nerve stimulation through alpha7 nicotine acetylcholine receptors (α7-nAChR) signaling had been demonstrated attenuation of inflammation. This study aimed to determine whether PNU-282987, a selective α7-nAChR agonist, affected activities of matrix metalloproteinase (MMP) and inflammatory cytokines in nicotine-treatment RAW264.7 and MOVAS cells and to assess the underlying molecular mechanisms. RAW264.7 and MOVAS cells were treated with nicotine at different concentrations (0, 1, 10, and 100 ng/ml) for 0–120 min. Nicotine markedly stimulated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and c-Jun in RAW264.7 cells. Pretreatment with U0126 significantly suppressed phosphorylation of ERK1/2 and further attenuated nicotine-induced activation of c-Jun and upregulation of MMP-2, MMP-9, monocyte chemotactic protein- (MCP-) 1, and regulated upon activation normal T cell expressed and secreted (RANTES). Similarly, nicotine treatment also increased phosphorylation of c-Jun and expressions of MMP-2, MMP-9, MCP-1, and RANTES in MOVAS cells. When cells were pretreated with PNU-282987, nicotine-induced activations of ERK1/2 and c-Jun in RAW264.7 cells and c-Jun in MOVAS cells were effectively inhibited. Furthermore, nicotine-induced secretions of MMP-2, MMP-9, MCP-1, and RANTES were remarkably downregulated. Treatment with α7-nAChR agonist inhibits nicotine-induced upregulation of MMP and inflammatory cytokines through modulating ERK1/2/AP-1 signaling in RAW264.7 cells and AP-1 in MOVAS cells, providing a new therapeutic for abdominal aortic aneurysm. Liping Liu, Hongxian Wu, Qunan Cao, Zhenzhen Guo, Anmin Ren, and Qiuyan Dai Copyright © 2017 Liping Liu et al. All rights reserved. Neutral Sphingomyelinase Behaviour in Hippocampus Neuroinflammation of MPTP-Induced Mouse Model of Parkinson’s Disease and in Embryonic Hippocampal Cells Thu, 16 Nov 2017 00:00:00 +0000 Neutral sphingomyelinase is known to be implicated in growth arrest, differentiation, proliferation, and apoptosis. Although previous studies have reported the involvement of neutral sphingomyelinase in hippocampus physiopathology, its behavior in the hippocampus during Parkinson’s disease remains undetected. In this study, we show an upregulation of inducible nitric oxide synthase and a downregulation of neutral sphingomyelinase in the hippocampus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced mouse model of Parkinson’s disease. Moreover, the stimulation of neutral sphingomyelinase activity with vitamin 1,25-dihydroxyvitamin D3 reduces specifically saturated fatty acid sphingomyelin by making sphingomyelin a less rigid molecule that might influence neurite plasticity. The possible biological relevance of the increase of neutral sphingomyelinase in Parkinson’s disease is discussed. Samuela Cataldi, Cataldo Arcuri, Stéphane Hunot, François-Pierre Légeron, Carmen Mecca, Mercedes Garcia-Gil, Andrea Lazzarini, Michela Codini, Tommaso Beccari, Anna Tasegian, Bernard Fioretti, Giovanna Traina, Francesco Saverio Ambesi-Impiombato, Francesco Curcio, and Elisabetta Albi Copyright © 2017 Samuela Cataldi et al. All rights reserved.