Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Potential Biomarkers of Fat Loss as a Feature of Cancer Cachexia Mon, 05 Oct 2015 09:50:11 +0000 Fat loss is associated with shorter survival and reduced quality of life in cancer patients. Effective intervention for fat loss in cachexia requires identification of the condition using prognostic biomarkers for early detection and prevention of further depletion. No biomarkers of fat mass alterations have been defined for application to the neoplastic state. Several inflammatory cytokines have been implicated in mediating fat loss associated with cachexia; however, plasma levels may not relate to adipose atrophy. Zinc-α2-glycoprotein may be a local catabolic mediator within adipose tissue rather than serving as a plasma biomarker of fat loss. Plasma glycerol and leptin associate with adipose tissue atrophy and mass, respectively; however, no study has evaluated their potential as a prognostic biomarker of cachexia-associated fat loss. This review confirms the need for further studies to identify valid prognostic biomarkers to identify loss of fat based on changes in plasma levels of biomarkers. Maryam Ebadi and Vera C. Mazurak Copyright © 2015 Maryam Ebadi and Vera C. Mazurak. All rights reserved. Interactions between Myc and Mediators of Inflammation in Chronic Liver Diseases Mon, 05 Oct 2015 09:34:53 +0000 Most chronic liver diseases (CLDs) are characterized by inflammatory processes with aberrant expressions of various pro- and anti-inflammatory mediators in the liver. These mediators are the driving force of many inflammatory liver disorders, which often result in fibrosis, cirrhosis, and liver tumorigenesis. c-Myc is involved in many cellular events such as cell growth, proliferation, and differentiation. c-Myc upregulates IL-8, IL-10, TNF-α, and TGF-β, while IL-1, IL-2, IL-4, TNF-α, and TGF-β promote c-Myc expression. Their interactions play a central role in fibrosis, cirrhosis, and liver cancer. Molecular interference of their interactions offers possible therapeutic potential for CLDs. In this review, current knowledge of the molecular interactions between c-Myc and various well known inflammatory mediators is discussed. Ting Liu, Yu Zhou, Kwang Suk Ko, and Heping Yang Copyright © 2015 Ting Liu et al. All rights reserved. Cancer as a Proinflammatory Environment: Metastasis and Cachexia Mon, 05 Oct 2015 08:39:52 +0000 The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines. Nelson Inácio Pinto, June Carnier, Lila M. Oyama, Jose Pinhata Otoch, Paulo Sergio Alcântara, Flavio Tokeshi, and Claudia M. Nascimento Copyright © 2015 Nelson Inácio Pinto et al. All rights reserved. N-Acetyl-seryl-aspartyl-lysyl-proline Alleviates Renal Fibrosis Induced by Unilateral Ureteric Obstruction in BALB/C Mice Mon, 05 Oct 2015 08:36:53 +0000 To expand the armamentarium of treatment for chronic kidney disease (CKD), we explored the utility of boosting endogenously synthesized N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is augmented by inhibition of the angiotensin converting enzyme. Male BALB/c mice underwent unilateral ureteral ligation (UUO) or sham operation and received exogenously administered Ac-SDKP delivered via a subcutaneous osmotic minipump or Captopril treatment by oral gavage. Seven days after UUO, there were significant reductions in the expression of both collagen 1 and collagen 3 in kidneys treated with Ac-SDKP or Captopril, and there was a trend towards reductions in collagen IV, α-SMA, and MCP-1 versus control. However, no significant attenuation of interstitial injury or macrophage infiltration was observed. These findings are in contrary to observations in other models and underscore the fact that a longer treatment time frame may be required to yield anti-inflammatory effects in BALB/c mice treated with Ac-SDKP compared to untreated mice. Finding an effective treatment regimen for CKD requires fine-tuning of pharmacologic protocols. Gary C. W. Chan, Wai Han Yiu, Hao Jia Wu, Dickson W. L. Wong, Miao Lin, Xiao Ru Huang, Hui Yao Lan, and Sydney C. W. Tang Copyright © 2015 Gary C. W. Chan et al. All rights reserved. Role of Inflammation in Muscle Homeostasis and Myogenesis Mon, 05 Oct 2015 08:36:36 +0000 Skeletal muscle mass is subject to rapid changes according to growth stimuli inducing both hypertrophy, through increased protein synthesis, and hyperplasia, activating the myogenic program. Muscle wasting, characteristic of several pathological states associated with local or systemic inflammation, has been for long considered to rely on the alteration of myofiber intracellular pathways regulated by both hormones and cytokines, eventually leading to impaired anabolism and increased protein breakdown. However, there are increasing evidences that even alterations of the myogenic/regenerative program play a role in the onset of muscle wasting, even though the precise mechanisms involved are far from being fully elucidated. The comprehension of the links potentially occurring between impaired myogenesis and increased catabolism would allow the definition of effective strategies aimed at counteracting muscle wasting. The first part of this review gives an overview of skeletal muscle intracellular pathways determining fiber size, while the second part considers the cells and the regulatory pathways involved in the myogenic program. In both parts are discussed the evidences supporting the role of inflammation in impairing muscle homeostasis and myogenesis, potentially determining muscle atrophy. Domiziana Costamagna, Paola Costelli, Maurilio Sampaolesi, and Fabio Penna Copyright © 2015 Domiziana Costamagna et al. All rights reserved. Proinflammatory Cytokines and Potassium Channels in the Kidney Mon, 05 Oct 2015 08:36:35 +0000 Proinflammatory cytokines affect several cell functions via receptor-mediated processes. In the kidney, functions of transporters and ion channels along the nephron are also affected by some cytokines. Among these, alteration of activity of potassium ion (K+) channels induces changes in transepithelial transport of solutes and water in the kidney, since K+ channels in tubule cells are indispensable for formation of membrane potential which serves as a driving force for the transepithelial transport. Altered K+ channel activity may be involved in renal cell dysfunction during inflammation. Although little information was available regarding the effects of proinflammatory cytokines on renal K+ channels, reports have emerged during the last decade. In human proximal tubule cells, interferon-γ showed a time-dependent biphasic effect on a 40 pS K+ channel, that is, delayed suppression and acute stimulation, and interleukin-1β acutely suppressed the channel activity. Transforming growth factor-β1 activated KCa3.1 K+ channel in immortalized human proximal tubule cells, which would be involved in the pathogenesis of renal fibrosis. This review discusses the effects of proinflammatory cytokines on renal K+ channels and the causal relationship between the cytokine-induced changes in K+ channel activity and renal dysfunction. Kazuyoshi Nakamura, Hikaru Hayashi, and Manabu Kubokawa Copyright © 2015 Kazuyoshi Nakamura et al. All rights reserved. Live or Die: Choice Mechanisms in Stressed Cells Mon, 05 Oct 2015 07:39:49 +0000 Francesco Cecconi, Laura Soucek, Dennis D. Taub, and Elio Ziparo Copyright © 2015 Francesco Cecconi et al. All rights reserved. Increased NHC Cells in the Peritoneal Cavity of Plasmacytoma Susceptible BALB/c Mouse Sun, 04 Oct 2015 13:57:54 +0000 BALB/c strain mice are unique in that they develop murine plasmacytoma (MPC) as a consequence of the inflammation induced by pristane oil injection in the peritoneal cavity. In this work the Treg, Th17, B1, B2, and NHC lymphocyte populations from the peritoneal environment of BALB/c, the susceptible strain, and C57BL/6 mice, which do not develop MPC after oil treatment, were studied. Both oil-treated strains showed decreased levels of Th17 lymphocytes, no significant variation in Treg lymphocytes, and a drastic decrease of all B lymphocyte populations. However, only oil-induced BALB/c showed increased levels of natural helper cells (NHC) which could be important in the myeloma induction. Berenice Sánchez-González, Francisco Javier García-Vázquez, José Eduardo Farfán-Morales, and Luis Antonio Jiménez-Zamudio Copyright © 2015 Berenice Sánchez-González et al. All rights reserved. Increased Risk of Cancer in relation to Gout: A Review of Three Prospective Cohort Studies with 50,358 Subjects Sun, 04 Oct 2015 11:41:03 +0000 Gout is a common inflammatory disease characterized by acute arthritis and hyperuricemia. A number of epidemiological studies have suggested the critical role of gout in carcinogenesis. The aim of this study was to estimate the association between gout and cancer risk by meta-analysis of all relevant studies published to date. A comprehensive literature search in PubMed and Embase databases from their inception up to July 1, 2014, was performed to identify eligible studies. The strength for relationship between gout and the risk of different cancers was evaluated by calculating pooled relative risks (RRs) with 95% confidence intervals (95% CIs). All analyses were carried out by STATA 12.0 software. Gout patients were at an increased risk of cancer, particularly urological cancers, digestive system cancers, and lung cancer. No such significant association between gout and the risk of breast or brain cancers was observed. Sensitivity analysis did not materially alter the pooled results. Gout is a risk factor of cancer, particularly that of urological cancers, digestive system cancers, and lung cancer. The pooled data further support the hypothesis of a link between gout and carcinogenesis. Weijie Wang, Donghua Xu, Bin Wang, Shushan Yan, Xiaochen Wang, Yin Yin, Xuehao Wang, Beicheng Sun, and Xiaoyang Sun Copyright © 2015 Weijie Wang et al. All rights reserved. Serum Uric Acid Increases Risk of Cancer Incidence and Mortality: A Systematic Review and Meta-Analysis Sun, 04 Oct 2015 11:27:47 +0000 SUA is a potent antioxidant and thus may play a protective role against cancer. Many epidemiological studies have investigated this hypothesis but provided inconsistent and inconclusive findings. We aimed to precisely elucidate the association between SUA levels and cancer by pooling all available publications. Totally, 5 independent studies with 456,053 subjects and 12 with 632,472 subjects were identified after a comprehensive literature screening from PubMed, Embase, and Web of Science. The pooled RRs showed that individuals with high SUA levels were at an increased risk of total cancer incidence (, 95% CI 1.01–1.05, ). Positive association between high SUA levels and total cancer incidence was observed in males but not females (for men: , 95% CI 1.02–1.08, ; for women, , 95% CI 0.98–1.04, ). Besides, high SUA levels were associated with an elevated risk of total cancer mortality (, 95% CI 1.04–1.32, ), particularly in females (, 95% CI 1.07–1.45, ). The study suggests that high SUA levels increase the risk of total cancer incidence and mortality. The data do not support the hypothesis of a protective role of SUA in cancer. Shushan Yan, Pengjun Zhang, Wei Xu, Yuqing Liu, Bin Wang, Tao Jiang, Changjiang Hua, Xuan Wang, Donghua Xu, and Beicheng Sun Copyright © 2015 Shushan Yan et al. All rights reserved. Cancer Cachexia and MicroRNAs Sun, 04 Oct 2015 11:22:29 +0000 Cancer cachexia is a paraneoplastic syndrome compromising quality of life and survival, mainly characterized by involuntary weight loss, fatigue, and systemic inflammation. The syndrome is described as a result of tumor-host interactions characterized by an inflammatory response by the host to the presence of the tumor. Indeed, systemic inflammation is considered a pivotal feature in cachexia progression and maintenance. Cytokines are intimately related to chronic systemic inflammation and the mechanisms underlying the release of these factors are not totally elucidated, the etiology of cachexia being still not fully understood. Therefore, the understanding of cachexia-related mechanisms, as well as the establishment of markers for the syndrome, is very relevant. MicroRNAs (miRNAs) are a class of noncoding RNAs interfering with gene regulation. Different miRNA expression profiles are associated with different diseases and inflammatory processes. miRNAs modulate adipose and skeletal muscle tissue metabolism in cancer cachexia and also tumor and tissue derived inflammation. Therefore, we propose a possible role for miRNAs in the modulation of the host inflammatory response during cachexia. Moreover, the establishment of a robust body of evidence in regard to miRNAs and the mechanisms underlying cachexia is mandatory, and shall contribute to the improvement of its diagnosis and treatment. Rodolfo Gonzalez Camargo, Henrique Quintas Teixeira Ribeiro, Murilo Vieira Geraldo, Emídio Matos-Neto, Rodrigo Xavier Neves, Luiz Carlos Carnevali Jr., Felipe Fedrizzi Donatto, Paulo S. M. Alcântara, José P. Ottoch, and Marília Seelaender Copyright © 2015 Rodolfo Gonzalez Camargo et al. All rights reserved. 25-OH Vitamin D and Interleukin-8: Emerging Biomarkers in Cutaneous Melanoma Development and Progression Sun, 04 Oct 2015 11:22:12 +0000 Background. There are several circulatory biomarkers that are involved in forecasting the clinical outcome of cutaneous melanoma. Serum/plasma vitamin D status is one of the markers intensively studied in this type of cutaneous cancer. The combination of validated serum biomarkers (like LDH) with new biomarkers such as IL-8, angiogenic factor, and vitamin D is still at the dawn of research. Hence, we are aiming to establish the predictive power of inflammatory biomarkers, such as IL-8, and metabolic ones, such as vitamin D. These candidate biomarkers are intended to aid classical biomarkers, such as LDH, in the prognosis of cutaneous melanoma. Methods. Serum vitamin D and IL-8 were quantified in melanoma patients and in matching healthy controls. Results. Median serum vitamin D concentrations were significantly lower () in melanoma patients as compared to healthy control subjects, while around 65% of the investigated patients have proven a severe circulatory deficiency of this vitamin. IL-8 was found increased () in melanoma patients as compared to controls. Conclusion. Upregulation of proangiogenic factors associated with vitamin D deficiency can prove to be potent future biomarkers candidates, enhancing the predictive power of classical LDH. Corina-Daniela Ene, Amalia-Elena Anghel, Monica Neagu, and Ilinca Nicolae Copyright © 2015 Corina-Daniela Ene et al. All rights reserved. Contribution of Neuroinflammation to the Pathogenesis of Cancer Cachexia Sun, 04 Oct 2015 09:42:13 +0000 Inflammation characterizes the course of acute and chronic diseases and is largely responsible for the metabolic and behavioral changes occurring during the clinical journey of patients. Robust data indicate that, during cancer, functional modifications within brain areas regulating energy homeostasis contribute to the onset of anorexia, reduced food intake, and increased catabolism of muscle mass and adipose tissue. In particular, functional changes are associated with increased hypothalamic concentration of proinflammatory cytokines, which suggests that neuroinflammation may represent the adaptive response of the brain to peripheral challenges, including tumor growth. Within this conceptual framework, the vagus nerve appears to be involved in conveying alert signals to the hypothalamus, whereas hypothalamic serotonin appears to contribute to triggering catabolic signals. Alessio Molfino, Gianfranco Gioia, Filippo Rossi Fanelli, and Alessandro Laviano Copyright © 2015 Alessio Molfino et al. All rights reserved. Modulation of Voltage-Gated Sodium Channels by Activation of Tumor Necrosis Factor Receptor-1 and Receptor-2 in Small DRG Neurons of Rats Sun, 04 Oct 2015 09:21:18 +0000 Tumor necrosis factor- (TNF-) α is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain. Its effects are mediated by two receptors, TNF receptor-1 (TNFR-1) and TNF receptor-2 (TNFR-2). These receptors play a crucial role in the sensitization of voltage-gated sodium channels (VGSCs), a key mechanism in the pathogenesis of chronic pain. Using the whole-cell patch-clamp technique, we examined the influence of TNFR-1 and TNFR-2 on VGSCs and TTX-resistant NaV1.8 channels in isolated rat dorsal root ganglion neurons by using selective TNFR agonists. The TNFR-1 agonist R32W (10 pg/mL) caused an increase in the VGSC current (INa(V)) by 27.2 ± 5.1%, while the TNFR-2 agonist D145 (10 pg/mL) increased the current by 44.9 ± 2.6%. This effect was dose dependent. Treating isolated NaV1.8 with R32W (100 pg/mL) resulted in an increase in INaV(1.8) by 18.9 ± 1.6%, while treatment with D145 (100 pg/mL) increased the current by 14.5 ± 3.7%. Based on the current-voltage relationship, 10 pg of R32W or D145 led to an increase in INa(V) in a bell-shaped, voltage-dependent manner with a maximum effect at −30 mV. The effects of TNFR activation on VGSCs promote excitation in primary afferent neurons and this might explain the sensitization mechanisms associated with neuropathic and inflammatory pain. M. Leo, S. Argalski, M. Schäfers, and T. Hagenacker Copyright © 2015 M. Leo et al. All rights reserved. Polymorphisms of Tumor Necrosis Factor Alpha in Moroccan Patients with Gastric Pathology: New Single-Nucleotide Polymorphisms in TNF-α−193 (G/A) Sun, 04 Oct 2015 09:16:12 +0000 Polymorphisms in tumor necrosis factor alpha (TNF-α) gene are emerging as key determinants of gastric diseases. The TNF-α−308 (G/A) and TNF-α−238 (G/A) single-nucleotide polymorphisms SNPs are the most extensively studied. However, all these studies are conducted in Caucasian and Asian populations. Thus, for the first time in Africa, we sought to investigate whether polymorphisms in TNF-α gene were associated with the development of gastric pathology in Morocco. Two SNPs located in the promoter region (positions −308 and −238) in TNF-α gene were genotyped in 244 individuals (170 patients and 74 healthy controls). Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression analysis. The TNF-α−238 (G/A) genotype was significantly associated with a high risk of gastritis and gastric cancer (GC) ( and , resp.). Furthermore, a new polymorphism located in the promoter region at position −193 in TNF-α gene was identified. The distribution of this SNP was markedly different in patients suffering from ulcers. The association between TNF-α−193 (G/A) genotype and high risk of ulcer was significant (). These results suggest that the TNF-α−193 (G/A) allele has a protective function against gastric cancer by developing ulcer. A. Essadik, H. Jouhadi, T. Rhouda, S. Nadifiyine, A. Kettani, and F. Maachi Copyright © 2015 A. Essadik et al. All rights reserved. A Survey of Attitudes towards the Clinical Application of Systemic Inflammation Based Prognostic Scores in Cancer Sun, 04 Oct 2015 08:56:59 +0000 Introduction. The systemic inflammatory response (SIR) plays a key role in determining nutritional status and survival of patients with cancer. A number of objective scoring systems have been shown to have prognostic value; however, their application in routine clinical practice is not clear. The aim of the present survey was to examine the range of opinions internationally on the routine use of these scoring systems. Methods. An online survey was distributed to a target group consisting of individuals worldwide who have reported an interest in systemic inflammation in patients with cancer. Results. Of those invited by the survey (), 65% routinely measured the SIR, mainly for research and prognostication purposes and clinically for allocation of adjuvant therapy or palliative chemotherapy. 40% reported that they currently used the Glasgow Prognostic Score/modified Glasgow Prognostic Score (GPS/mGPS) and 81% reported that a measure of systemic inflammation should be incorporated into clinical guidelines, such as the definition of cachexia. Conclusions. The majority of respondents routinely measured the SIR in patients with cancer, mainly using the GPS/mGPS for research and prognostication purposes. The majority reported that a measure of the SIR should be adopted into clinical guidelines. David G. Watt, Campbell S. Roxburgh, Mark White, Juen Zhik Chan, Paul G. Horgan, and Donald C. McMillan Copyright © 2015 David G. Watt et al. All rights reserved. Lung Epithelial TRPA1 Transduces the Extracellular ROS into Transcriptional Regulation of Lung Inflammation Induced by Cigarette Smoke: The Role of Influxed Ca2+ Sun, 04 Oct 2015 07:45:00 +0000 The mechanism underlying the inflammatory role of TRPA1 in lung epithelial cells (LECs) remains unclear. Here, we show that cigarette smoke extract (CSE) sequentially induced several events in LECs. The Ca2+ influx was prevented by decreasing extracellular reactive oxygen species (ROS) with the scavenger N-acetyl-cysteine, removing extracellular Ca2+ with the chelator EGTA, or treating with the TRPA1 antagonist HC030031. NADPH oxidase activation was abolished by its inhibitor apocynin, EGTA, or HC030031. The increased intracellular ROS was halted by apocynin, N-acetyl-cysteine, or HC030031. The activation of the MAPKs/NF-κB signaling was suppressed by EGTA, N-acetyl-cysteine, or HC030031. IL-8 induction was inhibited by HC030031 or TRPA1 siRNA. Additionally, chronic cigarette smoke (CS) exposure in wild-type mice induced TRPA1 expression in LECs and lung tissues. In CS-exposure trpa1−/− mice, the increased BALF level of ROS was similar to that of CS-exposure wild-type mice; yet lung inflammation was lessened. Thus, in LECs, CSE may initially increase extracellular ROS, which activate TRPA1 leading to an increase in Ca2+ influx. The increased intracellular Ca2+ contributes to activation of NADPH oxidase, resulting in increased intracellular ROS, which activate the MAPKs/NF-κB signaling leading to IL-8 induction. This mechanism may possibly be at work in mice chronically exposed to CS. An-Hsuan Lin, Meng-Han Liu, Hsin-Kuo Ko, Diahn-Warng Perng, Tzong-Shyuan Lee, and Yu Ru Kou Copyright © 2015 An-Hsuan Lin et al. All rights reserved. Comprehensive Screening of Gene Function and Networks by DNA Microarray Analysis in Japanese Patients with Idiopathic Portal Hypertension Sun, 04 Oct 2015 07:03:50 +0000 The functions of genes involved in idiopathic portal hypertension (IPH) remain unidentified. The present study was undertaken to identify the functions of genes expressed in blood samples from patients with IPH through comprehensive analysis of gene expression using DNA microarrays. The data were compared with data from healthy individuals to explore the functions of genes showing increased or decreased expression in patients with IPH. In cluster analysis, no dominant probe group was shown to differ between patients with IPH and healthy controls. In functional annotation analysis using the Database for Annotation Visualization and Integrated Discovery tool, clusters showing dysfunction in patients with IPH involved gene terms related to the immune system. Analysis using network-based pathways revealed decreased expression of adenosine deaminase, ectonucleoside triphosphate diphosphohydrolase 4, ATP-binding cassette, subfamily C, member 1, transforming growth factor-β, and prostaglandin E receptor 2; increased expression of cytochrome P450, family 4, subfamily F, polypeptide 3, and glutathione peroxidase 3; and abnormalities in the immune system, nucleic acid metabolism, arachidonic acid/leukotriene pathways, and biological processes. These results suggested that IPH involved compromised function of immunocompetent cells and that such dysfunction may be associated with abnormalities in nucleic acid metabolism and arachidonic acid/leukotriene-related synthesis/metabolism. Kohei Kotani, Joji Kawabe, Hiroyasu Morikawa, Tomohiko Akahoshi, Makoto Hashizume, and Susumu Shiomi Copyright © 2015 Kohei Kotani et al. All rights reserved. CXCR6 Expression Is Important for Retention and Circulation of ILC Precursors Thu, 01 Oct 2015 13:43:12 +0000 Innate lymphoid cells are present at mucosal sites and represent the first immune barrier against infections, but what contributes to their circulation and homing is still unclear. Using Rag2−/−Cxcr6Gfp/+ reporter mice, we assessed the expression and role of CXCR6 in the circulation of ILC precursors and their progeny. We identify CXCR6 expressing ILC precursors in the bone marrow and characterize their significant increase in CXCR6-deficient mice at steady state, indicating their partial retention in the bone marrow after CXCR6 ablation. Circulation was also impaired during embryonic life as fetal liver from CXCR6-deficient embryos displayed decreased numbers of ILC3 precursors. When injected, fetal CXCR6-deficient ILC3 precursors also fail to home and reconstitute ILC compartments in vivo. We show that adult intestinal ILC subsets have heterogeneous expression pattern of CXCR6, integrin α4β7, CD62L, CD69, and CD44, with ILC1 and ILC3 being more likely tissue resident lymphocytes. Intestinal ILC subsets were unchanged in percentages and numbers in both mice. We demonstrate that the ILC frequency is maintained due to a significant increase of ILC peripheral proliferation, as well as an increased proliferation of the in situ ILC precursors to compensate their retention in the bone marrow. Sylvestre Chea, Cécilie Possot, Thibaut Perchet, Maxime Petit, Ana Cumano, and Rachel Golub Copyright © 2015 Sylvestre Chea et al. All rights reserved. Virological Mechanisms in the Coinfection between HIV and HCV Thu, 01 Oct 2015 08:32:50 +0000 Due to shared transmission routes, coinfection with Hepatitis C Virus (HCV) is common in patients infected by Human Immunodeficiency Virus (HIV). The immune-pathogenesis of liver disease in HIV/HCV coinfected patients is a multifactorial process. Several studies demonstrated that HIV worsens the course of HCV infection, increasing the risk of cirrhosis and hepatocellular carcinoma. Also, HCV might increase immunological defects due to HIV and risk of comorbidities. A specific cross-talk among HIV and HCV proteins in coinfected patients modulates the natural history, the immune responses, and the life cycle of both viruses. These effects are mediated by immune mechanisms and by a cross-talk between the two viruses which could interfere with host defense mechanisms. In this review, we focus on some virological/immunological mechanisms of the pathogenetic interactions between HIV and HCV in the human host. Maria Carla Liberto, Emilia Zicca, Grazia Pavia, Angela Quirino, Nadia Marascio, Carlo Torti, and Alfredo Focà Copyright © 2015 Maria Carla Liberto et al. All rights reserved. Semiannual Imaging Surveillance Is Associated with Better Survival in Patients with Non-B, Non-C Hepatocellular Carcinoma Thu, 01 Oct 2015 07:39:05 +0000 Since it remains elusive whether and how the imaging surveillance affects the survival in patients with non-B, non-C hepatocellular carcinoma (NBNC-HCC), we conducted this retrospective study which investigated the association between the semiannual surveillance prior to HCC diagnosis and the survival in patients with the initial diagnosis of HCC induced by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections () and non-B, non-C etiology (). It was demonstrated that surveillance was less frequently performed in the NBNC-HCC patients compared to that in HCC patients with HBV and/or HCV infections (B/C-HCC patients), and the survival was unfavorable in NBNC-HCC patients. On the other hand, the survival of NBNC-HCC patients with semiannual surveillance was significantly favorable than those patients without semiannual surveillance, and the survival was similar between B/C-HCCs and NBNC-HCCs with semiannual surveillance. In conclusion, though NBNC-HCC patients compared to B/C-HCC patients had poorer prognosis overall, these NBNC-HCC patients with semiannual surveillance had a better survival almost equivalent to the survival of B/C-HCC patients with semiannual surveillance, demonstrating the clinical utility of the semiannual imaging surveillance program for NBNC-HCCs. Kuniaki Shindo, Shinya Maekawa, Nobutoshi Komatsu, Akihisa Tatsumi, Mika Miura, Mitsuaki Sato, Yuichiro Suzuki, Shuya Matsuda, Masaru Muraoka, Fumitake Amemiya, Mitsuharu Fukasawa, Tatsuya Yamaguchi, Yasuhiro Nakayama, Tomoyoshi Uetake, Taisuke Inoue, Minoru Sakamoto, Tadashi Sato, and Nobuyuki Enomoto Copyright © 2015 Kuniaki Shindo et al. All rights reserved. Liver Cirrhosis: Evaluation, Nutritional Status, and Prognosis Thu, 01 Oct 2015 06:28:35 +0000 The liver is the major organ for the metabolism of three major nutrients: protein, fat, and carbohydrate. Chronic hepatitis C virus infection is the major cause of chronic liver disease. Liver cirrhosis (LC) results from different mechanisms of liver injury that lead to necroinflammation and fibrosis. LC has been seen to be not a single disease entity but one that can be graded into distinct clinical stages related to clinical outcome. Several noninvasive methods have been developed for assessing liver fibrosis and these methods have been used for predicting prognosis in patients with LC. On the other hand, subjects with LC often have protein-energy malnutrition (PEM) and poor physical activity. These conditions often result in sarcopenia, which is the loss of skeletal muscle volume and increased muscle weakness. Recent studies have demonstrated that PEM and sarcopenia are predictive factors for poorer survival in patients with LC. Based on these backgrounds, several methods for evaluating nutritional status in patients with chronic liver disease have been developed and they have been preferably used in the clinical field practice. In this review, we will summarize the current knowledge in the field of LC from the viewpoints of diagnostic method, nutritional status, and clinical outcomes. Hiroki Nishikawa and Yukio Osaki Copyright © 2015 Hiroki Nishikawa and Yukio Osaki. All rights reserved. Endothelial-Leukocyte Interaction in Severe Malaria: Beyond the Brain Wed, 30 Sep 2015 13:06:04 +0000 Malaria is the most important parasitic disease worldwide, accounting for 1 million deaths each year. Severe malaria is a systemic illness characterized by dysfunction of brain tissue and of one or more peripheral organs as lungs and kidney. The most severe and most studied form of malaria is associated with cerebral complications due to capillary congestion and the adhesion of infected erythrocytes, platelets, and leukocytes to brain vasculature. Thus, leukocyte rolling and adhesion in the brain vascular bed during severe malaria is singular and distinct from other models of inflammation. The leukocyte/endothelium interaction and neutrophil accumulation are also observed in the lungs. However, lung interactions differ from brain interactions, likely due to differences in the blood-brain barrier and blood-air barrier tight junction composition of the brain and lung endothelium. Here, we review the importance of endothelial dysfunction and the mechanism of leukocyte/endothelium interaction during severe malaria. Furthermore, we hypothesize a possible use of adjunctive therapies to antimalarial drugs that target the interaction between the leukocytes and the endothelium. Mariana C. Souza, Tatiana A. Padua, and Maria G. Henriques Copyright © 2015 Mariana C. Souza et al. All rights reserved. Cardiac-Restricted IGF-1Ea Overexpression Reduces the Early Accumulation of Inflammatory Myeloid Cells and Mediates Expression of Extracellular Matrix Remodelling Genes after Myocardial Infarction Wed, 30 Sep 2015 09:05:07 +0000 Strategies to limit damage and improve repair after myocardial infarct remain a major therapeutic goal in cardiology. Our previous studies have shown that constitutive expression of a locally acting insulin-like growth factor-1 Ea (IGF-1Ea) propeptide promotes functional restoration after cardiac injury associated with decreased scar formation. In the current study, we investigated the underlying molecular and cellular mechanisms behind the enhanced functional recovery. We observed improved cardiac function in mice overexpressing cardiac-specific IGF-1Ea as early as day 7 after myocardial infarction. Analysis of gene transcription revealed that supplemental IGF-1Ea regulated expression of key metalloproteinases (MMP-2 and MMP-9), their inhibitors (TIMP-1 and TIMP-2), and collagen types (Col 1α1 and Col 1α3) in the first week after injury. Infiltration of inflammatory cells, which direct the remodelling process, was also altered; in particular there was a notable reduction in inflammatory Ly6C+ monocytes at day 3 and an increase in anti-inflammatory CD206+ macrophages at day 7. Taken together, these results indicate that the IGF-1Ea transgene shifts the balance of innate immune cell populations early after infarction, favouring a reduction in inflammatory myeloid cells. This correlates with reduced extracellular matrix remodelling and changes in collagen composition that may confer enhanced scar elasticity and improved cardiac function. Enrique Gallego-Colon, Robert D. Sampson, Susanne Sattler, Michael D. Schneider, Nadia Rosenthal, and Joanne Tonkin Copyright © 2015 Enrique Gallego-Colon et al. All rights reserved. Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms Tue, 29 Sep 2015 13:12:40 +0000 The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs) showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34+ cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV) and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF) patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET) and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34+ cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs. Vladan P. Čokić, Olivera Mitrović-Ajtić, Bojana B. Beleslin-Čokić, Dragana Marković, Marijana Buač, Miloš Diklić, Nada Kraguljac-Kurtović, Svetozar Damjanović, Pavle Milenković, Mirjana Gotić, and Puri K. Raj Copyright © 2015 Vladan P. Čokić et al. All rights reserved. Downregulation of Lung Toll-Like Receptor 4 Could Effectively Attenuate Liver Transplantation-Induced Pulmonary Damage at the Early Stage of Reperfusion Tue, 29 Sep 2015 11:42:25 +0000 Acute lung injury (ALI) is a severe complication of orthotopic liver transplantation (OLT) with unclear underline mechanism. Toll-like receptor 4 (TLR4) has been identified as a key receptor mediating inflammation. We hypothesized that TLR4-mediated pulmonary inflammation may contribute to development of ALI during OLT. Patients with or without ALI were observed for serum cytokines and expression of TLR4 on peripheral blood polymorphonuclear leukocytes (PMNs). Next, rats which underwent orthotopic autologous liver transplantation (OALT) were divided into sham and model groups. Pulmonary function and the level of TLR4 expression and cytokines were analyzed. Furthermore, the role of TLR4 in OALT-mediated ALI was assessed in rats treated with TLR4-siRNA before OALT. The PMNs TLR4 expression and the serum TNF-α and IL-β level were higher in patients with ALI than those with non-ALI. Interestingly, lung TLR4 expression was significantly increased after 8 hours of OALT with increased levels of TNF-α and IL-β, which lead to lung pathological damage and an increase of lung myeloperoxidase content. Moreover, knockdown of TLR4 reduced lung cytokines release and reversed the above pathologic changes after OALT and finally improved rats’ survival rate. In conclusion, TLR4 overexpression, potentially by stimulating proinflammatory cytokine overproduction, contributes to the development of ALI after OLT. Xinjin Chi, Weifeng Yao, Ailan Zhang, Mian Ge, Jun Cai, Shaoli Zhou, Zhengyuan Xia, Gangjian Luo, and Ziqing Hei Copyright © 2015 Xinjin Chi et al. All rights reserved. Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI Mon, 28 Sep 2015 11:13:07 +0000 Drug induced liver injury (DILI) is an idiosyncratic adverse drug reaction leading to severe liver damage. Kupffer cells (KC) sense hepatic tissue stress/damage and therefore could be a tool for the estimation of consequent effects associated with DILI. Aim of the present study was to establish a human in vitro liver model for the investigation of immune-mediated signaling in the pathogenesis of DILI. Hepatocytes and KC were isolated from human liver specimens. The isolated KC yield was cells/g liver tissue with a purity of >80%. KC activation was investigated by the measurement of reactive oxygen intermediates (ROI, DCF assay) and cell activity (XTT assay). The initial KC activation levels showed broad donor variability. Additional activation of KC using supernatants of hepatocytes treated with hepatotoxic drugs increased KC activity and led to donor-dependent changes in the formation of ROI compared to KC incubated with supernatants from untreated hepatocytes. Additionally, a compound- and donor-dependent increase in proinflammatory cytokines or in anti-inflammatory cytokines was detected. In conclusion, KC related immune signaling in hepatotoxicity was successfully determined in a newly established in vitro liver model. KC were able to detect hepatocyte stress/damage and to transmit a donor- and compound-dependent immune response via cytokine production. Victoria Kegel, Elisa Pfeiffer, Britta Burkhardt, Jia L. Liu, Katrin Zeilinger, Andreas K. Nüssler, Daniel Seehofer, and Georg Damm Copyright © 2015 Victoria Kegel et al. All rights reserved. Postmitotic Expression of SOD1G93A Gene Affects the Identity of Myogenic Cells and Inhibits Myoblasts Differentiation Mon, 28 Sep 2015 06:47:21 +0000 To determine the role of mutant SOD1 gene (SOD1G93A) on muscle cell differentiation, we derived C2C12 muscle cell lines carrying a stably transfected SOD1G93A gene under the control of a myosin light chain (MLC) promoter-enhancer cassette. Expression of MLC/SOD1G93A in C2C12 cells resulted in dramatic inhibition of myoblast differentiation. Transfected SOD1G93A gene expression in postmitotic skeletal myocytes downregulated the expression of relevant markers of committed and differentiated myoblasts such as MyoD, Myogenin, MRF4, and the muscle specific miRNA expression. The inhibitory effects of SOD1G93A gene on myogenic program perturbed Akt/p70 and MAPK signaling pathways which promote differentiation cascade. Of note, the inhibition of the myogenic program, by transfected SOD1G93A gene expression, impinged also the identity of myogenic cells. Expression of MLC/SOD1G93A in C2C12 myogenic cells promoted a fibro-adipogenic progenitors (FAPs) phenotype, upregulating HDAC4 protein and preventing the myogenic commitment complex BAF60C-SWI/SNF. We thus identified potential molecular mediators of the inhibitory effects of SOD1G93A on myogenic program and disclosed potential signaling, activated by SOD1G93A, that affect the identity of the myogenic cell population. Martina Martini, Gabriella Dobrowolny, Michela Aucello, and Antonio Musarò Copyright © 2015 Martina Martini et al. All rights reserved. Multidrug Resistance Protein-4 Influences Aspirin Toxicity in Human Cell Line Sun, 27 Sep 2015 14:16:23 +0000 Overexpression of efflux transporters, in human cells, is a mechanism of resistance to drug and also to chemotherapy. We found that multidrug resistance protein-4 (MRP4) overexpression has a role in reducing aspirin action in patients after bypass surgery and, very recently, we found that aspirin enhances platelet MRP4 levels through peroxisome proliferator activated receptor-α (PPARα). In the present paper, we verified whether exposure of human embryonic kidney-293 cells (Hek-293) to aspirin modifies MRP4 gene expression and its correlation with drug elimination and cell toxicity. We first investigated the effect of high-dose aspirin in Hek-293 and we showed that aspirin is able to increase cell toxicity dose-dependently. Furthermore, aspirin effects, induced at low dose, already enhance MRP4 gene expression. Based on these findings, we compared cell viability in Hek-293, after high-dose aspirin treatment, in MRP4 overexpressing cells, either after aspirin pretreatment or in MRP4 transfected cells; in both cases, a decrease of selective aspirin cell growth inhibition was observed, in comparison with the control cultures. Altogether, these data suggest that exposing cells to low nontoxic aspirin dosages can induce gene expression alterations that may lead to the efflux transporter protein overexpression, thus increasing cellular detoxification of aspirin. Isabella Massimi, Ambra Ciuffetta, Flavia Temperilli, Francesca Ferrandino, Alessandra Zicari, Fabio M. Pulcinelli, and Maria Pia Felli Copyright © 2015 Isabella Massimi et al. All rights reserved. The Link between Fetal Programming, Inflammation, Muscular Strength, and Blood Pressure Sun, 27 Sep 2015 13:37:15 +0000 Hypertension affects one billion individuals worldwide and is considered the leading cause of cardiovascular death, stroke, and myocardial infarction. This increase in the burden of hypertension and cardiovascular diseases (CVD) is principally driven by lifestyle changes such as increased hypercaloric diets and reduced physical activity producing an increase of obesity, insulin resistance, and low-grade inflammation. Visceral adipocytes are the principal source of proinflammatory cytokines and systemic inflammation participates in several steps in the development of CVD. However, maternal and infant malnutrition also persists as a major public health issue in low- to middle-income regions such as Latin America (LA). We propose that the increased rates of cardiovascular and metabolic diseases in these countries could be the result of the discrepancy between a restricted nutritional environment during fetal development and early life, and a nutritionally abundant environment during adulthood. Maternal undernutrition, which may manifest in lower birth weight offspring, appears to accentuate the relative risk of chronic disease at lower levels of adiposity. Therefore, LA populations may be more vulnerable to the pathogenic consequences of obesity than individuals with similar lifestyles in high-income countries, which may be mediated by higher levels of proinflammatory markers and lower levels of muscle mass and strength observed in low birth weight individuals. Jose Lopez-Lopez, Patricio Lopez-Jaramillo, Paul A. Camacho, Diego Gomez-Arbelaez, and Daniel D. Cohen Copyright © 2015 Jose Lopez-Lopez et al. All rights reserved.