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Publisher: Elsevier   (Total: 3157 journals)

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Showing 1201 - 1400 of 3157 Journals sorted alphabetically
Groundwater for Sustainable Development     Full-text available via subscription   (Followers: 3, SJR: 0.329, CiteScore: 1)
Growth Factors and Cytokines in Health and Disease     Full-text available via subscription   (Followers: 1)
Growth Hormone & IGF Research     Hybrid Journal   (Followers: 16, SJR: 1.059, CiteScore: 2)
Gynecologic Oncology     Hybrid Journal   (Followers: 25, SJR: 2.339, CiteScore: 4)
Gynecologic Oncology Reports     Open Access   (Followers: 10, SJR: 0.307, CiteScore: 1)
Gynécologie Obstétrique & Fertilité     Full-text available via subscription   (Followers: 1)
Habitat Intl.     Hybrid Journal   (Followers: 6, SJR: 1.336, CiteScore: 3)
Hand Clinics     Full-text available via subscription   (Followers: 5, SJR: 0.556, CiteScore: 1)
Hand Surgery and Rehabilitation     Full-text available via subscription   (Followers: 4, SJR: 0.358, CiteScore: 1)
Handai Nanophotonics     Full-text available via subscription  
Handbook of Adhesives and Sealants     Full-text available via subscription   (Followers: 2)
Handbook of Agricultural Economics     Full-text available via subscription   (Followers: 3)
Handbook of Algebra     Full-text available via subscription  
Handbook of Analytical Separations     Full-text available via subscription   (Followers: 3)
Handbook of Behavioral Neuroscience     Full-text available via subscription   (Followers: 3)
Handbook of Biological Physics     Full-text available via subscription  
Handbook of Chemical Neuroanatomy     Full-text available via subscription  
Handbook of Clinical Neurology     Full-text available via subscription   (Followers: 2, SJR: 1.007, CiteScore: 2)
Handbook of Clinical Neurophysiology     Full-text available via subscription  
Handbook of Complex Analysis     Full-text available via subscription  
Handbook of Computational Economics     Full-text available via subscription   (Followers: 1, SJR: 4.16, CiteScore: 2)
Handbook of Defense Economics     Full-text available via subscription   (Followers: 1)
Handbook of Development Economics     Full-text available via subscription   (Followers: 7)
Handbook of Differential Equations: Evolutionary Equations     Full-text available via subscription  
Handbook of Differential Equations: Ordinary Differential Equations     Full-text available via subscription  
Handbook of Differential Equations: Stationary Partial Differential Equations     Full-text available via subscription   (Followers: 2)
Handbook of Differential Geometry     Full-text available via subscription  
Handbook of Dynamical Systems     Full-text available via subscription   (Followers: 1)
Handbook of Econometrics     Full-text available via subscription   (Followers: 8)
Handbook of Economic Forecasting     Full-text available via subscription   (Followers: 1)
Handbook of Economic Growth     Full-text available via subscription   (Followers: 2)
Handbook of Environmental Economics     Full-text available via subscription   (Followers: 2)
Handbook of Experimental Economics Results     Full-text available via subscription   (Followers: 4)
Handbook of Exploration and Environmental Geochemistry     Full-text available via subscription   (Followers: 2)
Handbook of Exploration Geochemistry     Full-text available via subscription   (Followers: 1)
Handbook of Ferromagnetic Materials     Full-text available via subscription   (Followers: 1)
Handbook of Game Theory with Economic Applications     Full-text available via subscription   (Followers: 1)
Handbook of Geophysical Exploration: Seismic Exploration     Full-text available via subscription  
Handbook of Health Economics     Full-text available via subscription   (Followers: 10)
Handbook of Immunohistochemistry and in Situ Hybridization of Human Carcinomas     Full-text available via subscription   (Followers: 1)
Handbook of Income Distribution     Full-text available via subscription   (Followers: 2)
Handbook of Industrial Organization     Full-text available via subscription   (Followers: 3)
Handbook of Intl. Economics     Full-text available via subscription  
Handbook of Labor Economics     Full-text available via subscription   (Followers: 14)
Handbook of Law and Economics     Full-text available via subscription   (Followers: 17)
Handbook of Macroeconomics     Full-text available via subscription   (Followers: 6, SJR: 0, CiteScore: 2)
Handbook of Magnetic Materials     Full-text available via subscription   (Followers: 2, SJR: 0.467, CiteScore: 2)
Handbook of Mathematical Economics     Full-text available via subscription  
Handbook of Mathematical Fluid Dynamics     Full-text available via subscription   (Followers: 2)
Handbook of Metal Physics     Full-text available via subscription  
Handbook of Monetary Economics     Full-text available via subscription   (Followers: 5)
Handbook of Natural Resource and Energy Economics     Full-text available via subscription   (Followers: 3)
Handbook of Numerical Analysis     Full-text available via subscription   (Followers: 4)
Handbook of Perception and Action     Full-text available via subscription   (Followers: 2)
Handbook of Petroleum Exploration and Production     Full-text available via subscription   (Followers: 2)
Handbook of Population and Family Economics     Full-text available via subscription   (Followers: 4)
Handbook of Powder Technology     Full-text available via subscription   (Followers: 6)
Handbook of Public Economics     Full-text available via subscription   (Followers: 1)
Handbook of Regional and Urban Economics     Full-text available via subscription   (Followers: 1)
Handbook of Sensors and Actuators     Full-text available via subscription   (Followers: 10)
Handbook of Social Choice and Welfare     Full-text available via subscription   (Followers: 3)
Handbook of Statistics     Full-text available via subscription   (Followers: 7, SJR: 0.102, CiteScore: 0)
Handbook of Surface Science     Full-text available via subscription   (Followers: 4, SJR: 0.193, CiteScore: 0)
Handbook of Systemic Autoimmune Diseases     Full-text available via subscription   (Followers: 2)
Handbook of the Economics of Art and Culture     Full-text available via subscription   (Followers: 1)
Handbook of the Economics of Education     Full-text available via subscription   (Followers: 9, SJR: 0, CiteScore: 2)
Handbook of the Economics of Finance     Full-text available via subscription   (Followers: 6)
Handbook of the Economics of Giving, Altruism and Reciprocity     Full-text available via subscription  
Handbook of the Geometry of Banach Spaces     Full-text available via subscription   (Followers: 1)
Handbook of the History of Logic     Full-text available via subscription   (Followers: 1)
Handbook of Thermal Analysis and Calorimetry     Full-text available via subscription   (Followers: 1)
Handbook of Thermal Conductivity     Full-text available via subscription   (Followers: 4)
Handbook of Vapor Pressure     Full-text available via subscription  
Handbook on the Physics and Chemistry of Rare Earths     Full-text available via subscription   (Followers: 3, SJR: 0.755, CiteScore: 3)
Handbooks of Management Accounting Research     Full-text available via subscription   (Followers: 4)
HardwareX     Open Access  
Harmful Algae     Hybrid Journal   (Followers: 5, SJR: 1.531, CiteScore: 4)
HBRC J.     Open Access   (Followers: 2)
Health & Place     Hybrid Journal   (Followers: 15, SJR: 1.506, CiteScore: 3)
Health Outcomes Research in Medicine     Hybrid Journal   (Followers: 3)
Health Policy     Hybrid Journal   (Followers: 43, SJR: 1.252, CiteScore: 2)
Health Policy and Technology     Hybrid Journal   (Followers: 4, SJR: 0.322, CiteScore: 1)
Health Professions Education     Open Access   (Followers: 3)
Healthcare : The J. of Delivery Science and Innovation     Full-text available via subscription   (Followers: 1)
Hearing Research     Hybrid Journal   (Followers: 11, SJR: 1.35, CiteScore: 3)
Heart & Lung: The J. of Acute and Critical Care     Hybrid Journal   (Followers: 11, SJR: 0.757, CiteScore: 2)
Heart Failure Clinics     Full-text available via subscription   (Followers: 2, SJR: 1.153, CiteScore: 2)
Heart Rhythm     Hybrid Journal   (Followers: 11, SJR: 3.231, CiteScore: 4)
Heart, Lung and Circulation     Full-text available via subscription   (Followers: 9, SJR: 0.599, CiteScore: 1)
HeartRhythm Case Reports     Open Access   (SJR: 0.232, CiteScore: 0)
Heliyon     Open Access   (SJR: 0.355, CiteScore: 1)
Hellenic J. of Cardiology     Open Access   (Followers: 1, SJR: 0.479, CiteScore: 1)
Hematology, Transfusion and Cell Therapy     Open Access   (Followers: 1)
Hematology/Oncology and Stem Cell Therapy     Open Access   (Followers: 4, SJR: 0.532, CiteScore: 1)
Hematology/Oncology Clinics of North America     Full-text available via subscription   (Followers: 6, SJR: 1.282, CiteScore: 3)
Hepatobiliary & Pancreatic Diseases Intl.     Full-text available via subscription   (Followers: 2, SJR: 0.711, CiteScore: 2)
High Energy Density Physics     Hybrid Journal   (Followers: 2, SJR: 0.933, CiteScore: 2)
Hipertensión y Riesgo Vascular     Full-text available via subscription   (SJR: 0.115, CiteScore: 0)
Historia Mathematica     Full-text available via subscription   (Followers: 1, SJR: 0.174, CiteScore: 0)
History of CERN     Full-text available via subscription   (Followers: 1)
History of Neuroscience in Autobiography     Full-text available via subscription   (Followers: 3)
HIV & AIDS Review     Full-text available via subscription   (Followers: 12, SJR: 0.134, CiteScore: 0)
Homeopathy     Hybrid Journal   (Followers: 6, SJR: 0.678, CiteScore: 1)
HOMO - J. of Comparative Human Biology     Hybrid Journal   (Followers: 2, SJR: 0.335, CiteScore: 1)
Hong Kong J. of Nephrology     Open Access   (Followers: 2, SJR: 0.137, CiteScore: 0)
Hong Kong J. of Occupational Therapy     Open Access   (Followers: 42, SJR: 0.237, CiteScore: 1)
Hong Kong Physiotherapy J.     Open Access   (Followers: 13, SJR: 0.183, CiteScore: 0)
Hormigón y Acero     Full-text available via subscription  
Hormones and Behavior     Hybrid Journal   (Followers: 13, SJR: 1.638, CiteScore: 4)
Horticultural Plant J.     Open Access   (Followers: 5)
Hospital Medicine Clinics     Full-text available via subscription   (Followers: 2, SJR: 0.107, CiteScore: 0)
Human Factors in Information Technology     Full-text available via subscription   (Followers: 35)
Human Immunology     Hybrid Journal   (Followers: 17, SJR: 0.856, CiteScore: 2)
Human Movement Science     Hybrid Journal   (Followers: 15, SJR: 0.756, CiteScore: 2)
Human Pathology     Hybrid Journal   (Followers: 26, SJR: 1.304, CiteScore: 3)
Human Pathology : Case Reports     Open Access   (Followers: 2, SJR: 0.136, CiteScore: 0)
Human Resource Management Review     Hybrid Journal   (Followers: 50, SJR: 1.675, CiteScore: 4)
Hydrometallurgy     Hybrid Journal   (Followers: 13, SJR: 1.208, CiteScore: 3)
IATSS Research     Open Access   (SJR: 0.37, CiteScore: 1)
Icarus     Hybrid Journal   (Followers: 74, SJR: 2.037, CiteScore: 3)
ICT Express     Open Access   (SJR: 0.234, CiteScore: 1)
IDCases     Open Access   (SJR: 0.344, CiteScore: 1)
IERI Procedia     Open Access   (Followers: 1)
IFAC-PapersOnLine     Open Access   (SJR: 0.26, CiteScore: 1)
IIMB Management Review     Open Access   (Followers: 9, SJR: 0.24, CiteScore: 1)
IJC Heart & Vessels     Open Access   (Followers: 1)
IJC Heart & Vasculature     Open Access   (Followers: 1, SJR: 0.342, CiteScore: 1)
IJC Metabolic & Endocrine     Open Access   (Followers: 1, SJR: 0.4, CiteScore: 1)
Image and Vision Computing     Hybrid Journal   (Followers: 15, SJR: 0.612, CiteScore: 3)
Imagen Diagnóstica     Full-text available via subscription   (SJR: 0.106, CiteScore: 0)
Imagerie de la Femme     Full-text available via subscription   (Followers: 1, SJR: 0.124, CiteScore: 0)
Immunity     Full-text available via subscription   (Followers: 55, SJR: 13.393, CiteScore: 16)
Immuno-analyse & Biologie Spécialisée     Full-text available via subscription   (Followers: 2)
Immunobiology     Hybrid Journal   (Followers: 9, SJR: 1.1, CiteScore: 3)
Immunology and Allergy Clinics of North America     Full-text available via subscription   (Followers: 6, SJR: 1.132, CiteScore: 3)
Immunology Letters     Hybrid Journal   (Followers: 12, SJR: 1.168, CiteScore: 3)
Immunotoxicology of Drugs and Chemicals: an Experimental and Clinical Approach     Full-text available via subscription   (Followers: 1)
Implantodontie     Full-text available via subscription  
Indagationes Mathematicae     Open Access   (Followers: 1, SJR: 0.685, CiteScore: 1)
Indian Heart J.     Open Access   (Followers: 4, SJR: 0.333, CiteScore: 1)
Indian J. of Medical Specialities     Hybrid Journal   (SJR: 0.118, CiteScore: 0)
Indian J. of Tuberculosis     Full-text available via subscription   (SJR: 0.221, CiteScore: 0)
Indian Pacing and Electrophysiology J.     Open Access   (SJR: 0.273, CiteScore: 0)
Industrial Chemistry Library     Full-text available via subscription   (Followers: 3)
Industrial Crops and Products     Hybrid Journal   (Followers: 6, SJR: 1.091, CiteScore: 4)
Industrial Marketing Management     Hybrid Journal   (Followers: 23, SJR: 1.663, CiteScore: 4)
Industrial Safety Series     Full-text available via subscription   (Followers: 16)
Infant Behavior and Development     Hybrid Journal   (Followers: 14, SJR: 0.784, CiteScore: 2)
Infectio     Open Access   (SJR: 0.133, CiteScore: 0)
Infection, Disease & Health     Open Access   (Followers: 8, SJR: 0.23, CiteScore: 1)
Infection, Genetics and Evolution     Hybrid Journal   (Followers: 5, SJR: 1.278, CiteScore: 3)
Infectious Disease Clinics of North America     Full-text available via subscription   (Followers: 5, SJR: 2.359, CiteScore: 5)
Informatics in Medicine Unlocked     Open Access   (SJR: 0.224, CiteScore: 1)
Information & Management     Hybrid Journal   (Followers: 57, SJR: 1.628, CiteScore: 5)
Information and Computation     Hybrid Journal   (Followers: 4, SJR: 0.504, CiteScore: 1)
Information and Organization     Hybrid Journal   (Followers: 39, SJR: 1.202, CiteScore: 3)
Information and Software Technology     Hybrid Journal   (Followers: 6, SJR: 0.581, CiteScore: 4)
Information Economics and Policy     Hybrid Journal   (Followers: 4, SJR: 0.63, CiteScore: 1)
Information Fusion     Hybrid Journal   (Followers: 2, SJR: 1.832, CiteScore: 7)
Information Processing & Management     Hybrid Journal   (Followers: 353, SJR: 0.92, CiteScore: 4)
Information Processing in Agriculture     Open Access   (SJR: 0.352, CiteScore: 2)
Information Processing Letters     Hybrid Journal   (Followers: 6, SJR: 0.412, CiteScore: 1)
Information Sciences     Hybrid Journal   (Followers: 413, SJR: 1.635, CiteScore: 5)
Information Security Technical Report     Full-text available via subscription   (Followers: 12)
Information Systems     Hybrid Journal   (Followers: 13, SJR: 0.805, CiteScore: 4)
Infosecurity     Full-text available via subscription   (Followers: 11)
Infrared Physics & Technology     Hybrid Journal   (Followers: 12, SJR: 0.54, CiteScore: 2)
Injury     Hybrid Journal   (Followers: 18, SJR: 0.99, CiteScore: 2)
Injury Extra     Open Access   (Followers: 2)
Inmunología     Full-text available via subscription   (Followers: 2)
Innovative Food Science & Emerging Technologies     Hybrid Journal   (Followers: 5, SJR: 1.201, CiteScore: 3)
Inorganic Chemistry Communications     Hybrid Journal   (Followers: 13, SJR: 0.43, CiteScore: 2)
Inorganica Chimica Acta     Hybrid Journal   (Followers: 9, SJR: 0.485, CiteScore: 2)
Insect Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 3, SJR: 1.912, CiteScore: 4)
Instabilities in Silicon Devices     Full-text available via subscription   (Followers: 1)
Insulin     Full-text available via subscription   (Followers: 5)
Insurance: Mathematics and Economics     Hybrid Journal   (Followers: 9, SJR: 1.083, CiteScore: 2)
Integration, the VLSI J.     Hybrid Journal   (Followers: 6, SJR: 0.223, CiteScore: 1)
Integrative Medicine Research     Open Access   (Followers: 3)
Intellectual Economics     Open Access  
Intelligence     Hybrid Journal   (Followers: 7, SJR: 1.633, CiteScore: 3)
Intensive and Critical Care Nursing     Hybrid Journal   (Followers: 31, SJR: 0.611, CiteScore: 2)
Interdisciplinary Neurosurgery     Open Access   (SJR: 0.164, CiteScore: 0)
Interface Science and Technology     Full-text available via subscription  
Intermetallics     Hybrid Journal   (Followers: 22, SJR: 1.568, CiteScore: 4)
Internet Interventions : The application of information technology in mental and behavioural health     Open Access   (Followers: 4, SJR: 1.962, CiteScore: 4)
Interventional Cardiology Clinics     Full-text available via subscription   (Followers: 3, SJR: 0.156, CiteScore: 0)
Intl. Biodeterioration & Biodegradation     Hybrid Journal   (Followers: 1, SJR: 1.086, CiteScore: 4)
Intl. Business Review     Hybrid Journal   (Followers: 10, SJR: 1.012, CiteScore: 3)
Intl. Communications in Heat and Mass Transfer     Hybrid Journal   (Followers: 21, SJR: 1.553, CiteScore: 5)
Intl. Comparative Jurisprudence     Open Access   (Followers: 2)
Intl. Dairy J.     Hybrid Journal   (Followers: 6, SJR: 1.051, CiteScore: 2)
Intl. Economics     Hybrid Journal   (Followers: 3, SJR: 0.451, CiteScore: 1)
Intl. Emergency Nursing     Hybrid Journal   (Followers: 10, SJR: 0.461, CiteScore: 1)
Intl. Geophysics     Full-text available via subscription   (Followers: 3)
Intl. Immunopharmacology     Hybrid Journal   (Followers: 2, SJR: 1.051, CiteScore: 3)
Intl. J. for Parasitology     Hybrid Journal   (Followers: 11, SJR: 1.638, CiteScore: 4)
Intl. J. for Parasitology : Drugs and Drug Resistance     Open Access   (Followers: 4, SJR: 1.556, CiteScore: 4)
Intl. J. for Parasitology : Parasites and Wildlife     Open Access   (Followers: 2, SJR: 1.455, CiteScore: 3)
Intl. J. of Accounting     Hybrid Journal   (Followers: 1)

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Journal Cover
International Immunopharmacology
Journal Prestige (SJR): 1.051
Citation Impact (citeScore): 3
Number of Followers: 2  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1567-5769
Published by Elsevier Homepage  [3157 journals]
  • Immune checkpoint blockade therapy for cancer: An overview of FDA-approved
           immune checkpoint inhibitors
    • Abstract: Publication date: September 2018Source: International Immunopharmacology, Volume 62Author(s): Kristian M. Hargadon, Coleman E. Johnson, Corey J. Williams Although T lymphocytes have long been appreciated for their role in the immunosurveillance of cancer, it has been the realization that cancer cells may ultimately escape a response from tumor-reactive T cells that has ignited efforts to enhance the efficacy of anti-tumor immune responses. Recent advances in our understanding of T cell immunobiology have been particularly instrumental in informing therapeutic strategies to overcome mechanisms of tumor immune escape, and immune checkpoint blockade has emerged as one of the most promising therapeutic options for patients in the history of cancer treatment. Designed to interfere with inhibitory pathways that naturally constrain T cell reactivity, immune checkpoint blockade releases inherent limits on the activation and maintenance of T cell effector function. In the context of cancer, where negative T cell regulatory pathways are often overactive, immune checkpoint blockade has proven to be an effective strategy for enhancing the effector activity and clinical impact of anti-tumor T cells. Checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 have yielded unprecedented and durable responses in a significant percentage of cancer patients in recent years, leading to U.S. FDA approval of six checkpoint inhibitors for numerous cancer indications since 2011. In this review, we highlight the clinical success of these FDA-approved immune checkpoint inhibitors and discuss current challenges and future strategies that must be considered going forward to maximize the efficacy of immune checkpoint blockade therapy for cancer.Graphical abstractUnlabelled Image
  • Neutrophils contribute to the pathogenesis of hemorrhagic cystitis induced
           by ifosfamide
    • Abstract: Publication date: September 2018Source: International Immunopharmacology, Volume 62Author(s): Amílcar Figueiredo Dornelas-Filho, Venúcia Bruna Magalhães Pereira, Deysi Viviana Tenazoa Wong, Lívia Maria Soares Nobre, Anielle Torres Melo, Camila Meirelles Souza Silva, Carlos Wagner Souza Wanderley, Mariana Lima Nour, Lis Caetano Nobrega Costa Araújo, Renan Oliveira Silva, Francisco Maxwell Martins Pinto, Rudy Diavila Bingana, Marcellus Henrique Loiola Ponte Souza, Nylane Maria Nunes Alencar, Paulo Goberlânio Barros Silva, Ana Paula Negreiros Nunes Alves, Paulo Roberto Carvalho Almeida, Fernando Queiroz Cunha, Roberto César Pereira Lima-Júnior Ifosfamide (IFO) is an antineoplastic drug that is commonly used to treat gynecological and breast cancers. Hemorrhagic cystitis (HC) is a common side effect associated with IFO injection, which courses with neutrophil accumulation and affects 6–50% of patients depending on dose intensity. Here, we investigated the role of neutrophils in this inflammatory process. Female Swiss mice (n = 8/group) were injected with saline, IFO (400 mg/kg, i.p.), fucoidan (a P- and L-selectins inhibitor, 100 mg/kg, i.v.) or IFO + fucoidan (1–100 mg/kg) alone or combined with mesna (80 mg/kg i.p.). Another group of mice received anti-Ly6G antibody (500 μg/mouse, once daily for 2 days) for neutrophil depletion before IFO injection. In another experimental setting, animals received granulocyte colony-stimulating factor (G-CSF, 400 μg/kg), IFO (200 mg/kg), G-CSF (25–400 μg/kg, for 5 days) + IFO (200 mg/kg, i.p.) or fucoidan + G-CSF + IFO. Bladder injury was evaluated 12 h after IFO injection. IFO 400 mg/kg significantly increased visceral hyperalgesia, bladder edema, hemorrhage, vascular permeability, MPO, IL-1β and IL-6 tissue levels, and COX-2 immunostaining and expression versus the saline group (P 
  • A systematic investigation on animal models of cyclosporine A combined
           with Escherichia coli to simulate the immunosuppressive status of sepsis
           patients before onset
    • Abstract: Publication date: September 2018Source: International Immunopharmacology, Volume 62Author(s): Xianbin Kong, Jingjing Zhang, Jingrui Huo, Lei Wang, Lei Guo, Ying Liu, Tao He, Zhonglei Sun, Xuyi Chen, Zhenjiang Hou, Xiaohui Yang, Yi Tian, Shizhong Sun, Feng Chen, Yingfu Liu Immunosuppression is an important mechanism for the development of sepsis pathology, and is the key to the high mortality of sepsis. However, patients appear to be immunocompromised before sepsis onset due to lack of enough attention. Present sepsis models cannot fully mimic the onset of sepsis in patients. Hence, effective treatments in animal experiments could not be transformed into clinical application. In the present study, we improved the animal model of sepsis and used cyclosporine A immunosuppressive mice to make it closer to immune status before the onset of sepsis, followed by the intraperitoneal injection of Escherichia coli (E. coli) CMCC (B) 44,102 standard strain to produce the immunocompromised sepsis model. This trial systematically evaluates the new immunosuppressive sepsis model. Compared with routine sepsis models, the release of inflammatory factors in the new sepsis model was insufficient, blood bacteria were more cultured, diffuse intravascular coagulation (DIC) was more severe, lung, liver and kidney damage were heavier, and mortality rate was higher. In conclusion, the new sepsis model can mimic the patient's pre-onset immunocompromised state, is suitable for the development and evaluation of new methods of sepsis, and solves the controversy of sepsis treatment, providing new ideas and direction.
  • Recovery of circulating CD56dim NK cells and the balance of Th17/Treg
           after nucleoside analog therapy in patients with chronic hepatitis B and
           low levels of HBsAg
    • Abstract: Publication date: September 2018Source: International Immunopharmacology, Volume 62Author(s): Nianqiu Liu, Bin Liu, Li Zhang, Hu Li, Zhiwei Chen, Aoran Luo, Min Chen, Mingli Peng, Wenwei Yin, Hong Ren, Peng Hu Background and aimsMuch evidence indicates that the soluble antigens secreted by hepatitis B virus (HBV) inhibit the function of the immune system. The aim of this study is to investigate, after treatment with nucleoside (acid) analogs (NAs) and the inhibition of viral replication, whether the immune systems of patients with a peripheral blood HBV-DNA level
  • Efficacy and safety of biologics targeting IL-17 and IL-23 in the
           treatment of moderate-to-severe plaque psoriasis: A systematic review and
           meta-analysis of randomized controlled trials
    • Abstract: Publication date: September 2018Source: International Immunopharmacology, Volume 62Author(s): Lian Cui, Rongfen Chen, Smriti Subedi, Qian Yu, Yu Gong, Zeyu Chen, Yuling Shi Numerous biologics are currently licensed for the treatment of psoriasis, including new drugs targeting interleukin-17 (IL-17) and interleukin-23 (IL-23). This meta-analysis evaluated the short-term (12–16 weeks) efficacy and safety of biologics targeting IL-17 and IL-23 in the treatment of moderate-to-severe plaque psoriasis. Twenty-one randomized clinical trials met the defined inclusion criteria. Our results showed that Ixekizumab (160 mg wk0 + 80 mg q2w) had the greatest probability of achieving both PASI 75 (RR 21.32, 95% CI 15.48–29.36, P 
  • A novel CXCL8-IP10 hybrid protein is effective in blocking pulmonary
           pathology in a mouse model of Klebsiella pneumoniae infection
    • Abstract: Publication date: September 2018Source: International Immunopharmacology, Volume 62Author(s): Zhangbo Chen, Xiangyu Chen, Fang Li, Jya-Wei Cheng, Hsi-Tsung Cheng, Shu-Chi Yeh, Hui-Yuan Yu Klebsiella pneumoniae (K. pneumoniae) is a hospital-acquired infectious agent that causes a range of diseases. Herein we have developed a novel CXCL8-IP10 hybrid protein and evaluated its efficacy in an animal model of K. pneumoniae infection. Neutrophil chemotaxis data revealed that CXCL8-IP10 could inhibit human neutrophil chemotactic responses induced by the ELR-CXC chemokine CXCL8. To evaluate the effect of CXCL8-IP10 on K. pneumoniae infection, C57BL/6 mice were challenged with K. pneumoniae followed by treatment with CXCL8-IP10 (500 μg/kg, i.p.), or dexamethasone (0.8 mg/kg, s.c.), or ceftazidime (200 mg/kg, s.c.) individually. CXCL8-IP10, dexamethasone or ceftazidime markedly inhibit Klebsiella-induced pulmonary inflammation as assessed by gross examination and histopathology. Moreover, the chemotactic responses of neutrophils was blocked by CXCL8-IP10 rather than dexamethasone or ceftazidime. Furthermore, the levels of inflammatory factors IL-1β, IFN-γ and TNF-α were decreased after CXCL8-IP10, dexamethasone or ceftazidime treatment. Together, these results suggest that CXCL8-IP10 may provide a novel strategy for treating K. pneumoniae infection.
  • Nootkatone, a neuroprotective agent from Alpiniae Oxyphyllae Fructus,
           improves cognitive impairment in lipopolysaccharide-induced mouse model of
           Alzheimer's disease
    • Abstract: Publication date: September 2018Source: International Immunopharmacology, Volume 62Author(s): Yunlong Wang, Mengshi Wang, Mengjie Xu, Tongde Li, Kaiyue Fan, Tingxu Yan, Feng Xiao, Kaishun Bi, Ying Jia Neuroinflammatory responses play a crucial role in the pathogenesis of Alzheimer's disease (AD). Our previous study demonstrated that petroleum ether extracts from Alpiniae Oxyphyllae Fructus(AOF) could attenuate lipopolysaccharide (LPS)-induced learning and memory impairment in mice, which could be associated with its inhibitory effect on neuroinflammation. Therefore, our present study is to investigate the potential therapeutic neuroprotective effects of nootkatone (NKT) on an AD mouse model induced by intracerebroventricular injection of LPS. We found that NKT (10 mg/kg) group showed good performance in behavior experiments including Y-maze test and Morris water maze test. The results of histopathological examination and immunohistochemical analysis showed that LPS induced degeneration of neurons and activation of microglia particularly in hippocampus and NKT (10 mg/kg) reversed these changes. Enzyme linked immunosorbent assay and western blot analysis also demonstrated that the model group had increased expression of IL-1β, IL-6, TNF-α, NLRP3 and NF-κB p65, especially in hippocampus relative to sham-operated group, and NKT (10 mg/kg) decreased the high expression of these inflammatory cytokines. Collectively, these data indicated that LPS-induced learning and memory impairments in mice could be improved by NKT, which was associated with attenuating neuroinflammatory responses. Our study indicated that NKT could act as a potential therapeutic agent for the treatment of neuroinflammation and AD.
  • Melatonin attenuates airway inflammation via SIRT1 dependent inhibition of
           NLRP3 inflammasome and IL-1β in rats with COPD
    • Abstract: Publication date: September 2018Source: International Immunopharmacology, Volume 62Author(s): Zhenyu Peng, Wenxuan Zhang, Jianfeng Qiao, Baimei He Chronic airway inflammation is a characteristic feature of chronic obstructive pulmonary disease (COPD). Previous studies demonstrated that melatonin had a protective effect against COPD. In addition, silent information regulator 1 (SIRT1) was reported to be beneficial in COPD. However, whether SIRT1 is involved in the protective effect of melatonin against COPD remains unclear. In this study, we investigated the effect of melatonin on a rat model of COPD and explored the potential mechanisms. Twenty eight male Wistar rats were randomly assigned to four groups: control group, COPD group, COPD+Mel group and COPD+Mel+EX527 group. Rats were challenged with cigarette smoke and lipopolysaccharide (LPS) for 28 days with or without melatonin or EX527. The pulmonary function, lung histopathology, inflammatory cells count and the concentration of IL-1β in the BALF as well as the protein expressions of SIRT1, NLRP3, cleaved caspase-1 and ASC in the lung tissues were measured. The results demonstrated that melatonin prevented the development of COPD, which was attributed to the inhibition of airway inflammation by attenuating NLRP3 inflammasome and IL-1β. Furthermore, melatonin increased the expression of SIRT1 in lung tissues of rats with COPD, while inhibition of SIRT1 by EX527 abolished the protective effect of melatonin against COPD. In conclusion, these findings suggested that melatonin attenuated airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1β in rats with COPD.
  • Pogostone attenuates TNF-α-induced injury in A549 cells via inhibiting
           NF-κB and activating Nrf2 pathways
    • Abstract: Publication date: September 2018Source: International Immunopharmacology, Volume 62Author(s): Hong-Mei Yang, Jian-Yi Zhuo, Chao-Yue Sun, Juan Nie, Jie Yuan, Yan-Lu Liu, Rong-Feng Lin, Xiao-Ping Lai, Zi-Ren Su, Yu-Cui Li Pogostone (PO), a major component of Pogostemon cablin, displays potent protective effects against lipopolysaccharide-induced acute lung injury (ALI) in mice. This study aimed to investigate the protective effect of PO on TNF-α-induced cell injury in human alveolar epithelial cells in vitro and its underlying mechanism. The cell viability was measured using the MTS method. The cell apoptosis was determined using flow cytometry. The activities of reactive oxygen species (ROS) were detected using a fluorescence microscope. The pro-inflammatory cytokines and antioxidant genes were assessed using reverse transcription–polymerase chain reaction. The protein expression of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2–related factor 2 (Nrf2), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha (IκBα), and nuclear factor–kappa B (NF-κB) p65 was analyzed using the Western blot analysis. PO alleviated cell apoptosis and inhibited ROS production. It alleviated TNF-α-induced cell injury, suppressed the levels of inflammatory cytokines [interleukin (IL)-6, IL-1β, and IL-8], and enhanced the expression of antioxidant genes (quinine oxidoreductase 1, glutamate cysteine ligase catalytic subunit, heme oxygenase-1). It increased the expression of Keap1 and promoted the activation of Nrf2. However, the phosphorylation of IκBα and the nuclear expression of NF-κB p65 decreased. The anti-inflammatory and antioxidant effects of PO were abrogated following Nrf2 and NF-κB p65 knockdown. The results indicated a protective effect of PO against TNF-α-induced cell injury in A549 cells by modulating the balance between Nrf2 and NF-κB p65 signaling pathways. They verified PO as a promising anti-inflammatory adjuvant drug for treating ALI.Graphical abstractUnlabelled Image
  • Protective effect of pioglitazone on ovarian ischemia reperfusion injury
           of female rats via modulation of peroxisome proliferator activated
           receptor gamma and heme-oxygenase 1
    • Abstract: Publication date: September 2018Source: International Immunopharmacology, Volume 62Author(s): Marwa M.M. Refaie, Maram El-Hussieny Ovarian torsion is a dangerous gynecological emergency condition. Early diagnosis of this case is necessary to preserve the function of the ovaries and fallopian tubes and prevent further damage. Ovarian torsion means complete or partial rotation of the adnexa with ischemia followed by reperfusion period. Ovarian torsion affects 2%–15% of patients who have surgical treatment of adnexal masses. We investigated the effect of pioglitazone (PIO) on induced ovarian ischemia reperfusion (OIR). PIO (10, 30 mg/kg) was administered orally in the presence or absence of induced OIR. We measured ovarian tissue malondialdehyde (MDA), total nitrites (NOx), reduced glutathione (GSH), heme-oxygenase 1 (HO-1), and gene expressions of peroxisome proliferator activated receptor gamma (PPARγ), tumor necrosis factor alpha (TNFα), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS). Moreover, expression of p53 and histopathological changes were also evaluated. Results showed increase in the ovarian tissue levels of MDA and NOx and gene expressions of p53, TNFα, and iNOS in the induced OIR group. The induced OIR group showed the histopathological changes associated with cell injury, marked ovarian edema, hemorrhage and congestion. In addition, there was reduction in the GSH, HO-1 levels and PPARγ, eNOS gene expressions. PIO was able to reduce these induced OIR changes to levels insignificant from control group. This protective effect of PIO may be attributed to its PPARγ agonist effect, anti-inflammatory, anti-apoptotic and anti-oxidant properties.
  • Interaction of PEGylated interferon-beta with antibodies to recombinant
    • Abstract: Publication date: September 2018Source: International Immunopharmacology, Volume 62Author(s): Francesca Gilli, Adrianna L. De La Torre, Darlene B. Royce, Andrew R. Pachner Because PEGylated molecules exhibit different physicochemical properties from those of the parent molecules, PEGylated interferonβ-1a (pegIFNβ-1a) may be able to be used with retained bioactivity in Multiple Sclerosis (MS) patients who have previously developed neutralizing antibodies (NABs) to recombinant interferonβ (rIFNβ). Hence, the objective of the present study was to test whether pegIFNβ-1a is less antigenic for NABs in vitro than rIFNβ. Two in vitro assays were used to quantitate NABs in 115 sera obtained from MS patients included in the INSIGHT study: the cytopathic effect (CPE) assay, and the MxA protein induction assay. NABs cross-reactivity was assessed by comparing dilutions of serum with fixed doses of rIFNβ-1a Avonex® and pegIFNβ-1a Plegridy®. NABs were shown to cross-react in both assays. The y-intercept (c), the slope of the line of agreement (b), the Pearson coefficients as well as the Bland-Altman analysis, indicated that there is good level of agreement between NAB titers against the two IFNβ-1a formulations, with both the CPE (c = 0.1044 ± 0.1305; b = 0.8438 ± 0.06654; r2 = 0.587; bias index ± SD = −0.01702 ± 0.6334), and the MxA protein induction (c = 0.08246 ± 0.1229; b = 0.8878 ± 0.06613; r2 = 0.615; bias index ± SD = −0.09965 ± 0.6467) assays. Until further in vivo evidence is established, clinicians should consider the current in vitro data demonstrating NAB cross-reactivity between pegIFNβ-1a and rIFNβ when discussing new treatment options with MS patients.
  • Genistein reduces proliferation of EP3-expressing melanoma cells through
           inhibition of PGE2-induced IL-8 expression
    • Abstract: Publication date: September 2018Source: International Immunopharmacology, Volume 62Author(s): Isabella Venza, Maria Visalli, Rosaria Oteri, Concetta Beninati, Diana Teti, Mario Venza Genistein, a natural isoflavone found in soybean products, is considered as a powerful anti-cancer agent, although the involved mechanisms are not fully understood. There is a growing body of evidence that, among the genes inhibited by genistein and responsible for cell cycle progression, invasion, metastasis, and angiogenesis, IL-8 occupies a relevant place. On the other hand, it is equally well documented that IL-8 is upregulated by prostaglandin E2 (PGE2) in different pathological conditions, particularly in neoplastic disease. Here we investigated whether genistein could affect cell growth in a panel of oral, uveal and cutaneous melanoma cell lines by interfering with basal or PGE2-induced IL-8 production. To this end, experiments were performed to evaluate the effect of PGE2 treatment on IL-8 levels, the expression and the role of PGE2 receptors and whether genistein could be able to interfere with these events. Finally, it was evaluated whether the inhibition of oral, uveal and cutaneous melanoma cell proliferation in the presence of genistein could be related to a reduction of IL-8 levels. We show that PGE2 enhances IL-8 synthesis via the EP3 receptor and that genistein is able to down-regulate the latter, as well as to decrease IL-8 mRNA and protein expression, thereby inhibiting oral, uveal and cutaneous melanoma cell proliferation. Taken together, our data provide new insights into the anti-cancer properties of genistein by showing that this flavonoid may affect the development and growth of melanoma at oral, uveal and cutaneous sites. Moreover, these results provide evidence that genistein may exert its therapeutic activity through its ability to prevent PGE2-mediated IL-8 induction.Graphical abstractUnlabelled Image
  • Investigation of the interaction of allergens of Glycine max with
           IgE-antibody for designing of peptidomimetics based anti-allergen
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Vishvanath Tiwari, Debarghya Mitra, Monalisa Tiwari Allergen induced IgE dependent type I hypersensitivity is the main cause of the allergy, which would be a burden on medical setup in coming years. Allergens of Glycine max have been isolated, and their disease relationships are documented. Therefore, it becomes important to investigate the interaction of different allergens of Glycine max with IgE and also screen suitable therapeutics to prevent this interaction. The amino acid sequences of all allergens of Glycine max and their isoallergens have been taken, and 3D structure of allergens (Gly m 3, Gly m 4, Gly m 5, Gly m 6 and Gly m 8) and their isoallergens were generated using Modeller v9.17. The modeled structures were further validated using PSVS, ProSA, RAMPAGE, and PDBsum. HL domain of Fab region of human IgE (PDBID: 2R56) was generated using UCSFchimera. The HL domain was minimized by Schrodinger software using the OPLS_2005 force field. SiteMap identified epitope binding site of the minimized domain. All the predicted epitopes of different allergens were docked to the binding site of HL domain using the Patchdock server. We have also designed a peptidomimetics based inhibitor targeted at interaction interface of Gly m8 and IgE, using in-silico virtual screening, molecular mechanics, and molecular dynamics simulation studies. These studies identified BDE32166344 ((N-(1-{[1-(1-aminocyclopentanecarbonyl)-3-hydroxypyrrolidin-3-yl]methyl}piperidin-4-yl)acetamide) as a peptidomimetics based lead with binding energy of −72.77 kcal/mol. Therefore, the present study investigates the interaction between different Gly m allergens and IgE antibody and identifies peptidomimetics based lead that might be developed as a suitable therapeutics against allergy caused by allergen of Glycine max.
  • Nasal vaccination with pneumococcal surface protein A in combination with
           cationic liposomes consisting of DOTAP and DC-chol confers
           antigen-mediated protective immunity against Streptococcus pneumoniae
           infections in mice
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Rui Tada, Hidehiko Suzuki, Saeko Takahashi, Yoichi Negishi, Hiroshi Kiyono, Jun Kunisawa, Yukihiko Aramaki Infectious diseases are the second leading cause of death worldwide, suggesting that there is still a need for the development of new and improved strategies for combating pathogens effectively. Streptococcus pneumoniae is the most virulent bacteria causing pneumonia with high mortality, especially in children and the elderly. Because of the emergence of antibiotic resistance in S. pneumoniae, employing a serotype-independent mucosal vaccine would be the best approach to prevent and treat the diseases caused by S. pneumoniae. In this study, we have developed a pneumococcal nasal vaccine, consisting of pneumococcal surface protein A (PspA) and cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and cholesteryl 3β-N-(dimethylaminoethyl)­carbamate (DC-chol) (DOTAP/DC-chol liposome). The efficiency of this cationic liposome-based PspA nasal vaccine was examined in a murine model of S. pneumoniae infection. Intranasal vaccination with PspA and DOTAP/DC-chol liposomes conferred protective immunity against lethal inhalation of S. pneumoniae, improving the survival rate of infected mice. Moreover, intranasal immunization with PspA and DOTAP/DC-chol liposomes not only induced the production of PspA-specific IgA and IgG by both mucosal and systemic compartments but also elicited PspA-specific Th17 responses, which play a pivotal role in controlling S. pneumoniae infection by host innate immune response. We further demonstrated that DOTAP/DC-chol liposomes enhanced PspA uptake by nasal dendritic cells (DCs), which might be a mechanism for the induction of protective immune responses to S. pneumoniae infection. These results show that DOTAP/DC-chol liposome would be an efficient mucosal vaccine system for a serotype-independent universal nasal vaccine against pneumococcal infection.Graphical abstractUnlabelled Image
  • Comparison of lactate and β-hydroxybutyrate in the treatment of
           concanavalin-A induced hepatitis
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Sara H. Hazem, Mohamed F. Hamed, Mohamed-Ahdy A. Saad, Nariman M. Gameil Simple metabolites released during physical exercise and fasting like lactate (Lac) and β-hydroxybutyrate (BHB) have recently been shown to possess anti-inflammatory properties. However, the effects of these metabolites in immune mediated hepatitis are still unknown. Accordingly, we investigated the role of Lac, BHB and their combination on experimentally induced hepatic inflammation. Adult male mice were administered concanavalin A (Con A, 15 mg/kg, intravenous) for 12 h. In the treatment groups, mice were treated 1 h after Con A-intoxication with Lac (500 mg/kg, intraperitoneal), BHB (300 mg/kg, intraperitoneal) and their combination. The results demonstrated that Lac and BHB, especially when combined together, alleviated Con A-induced hepatocellular injury (ALT, AST and LDH) and necrosis (hematoxylin-eosin and electron microscopy). These beneficial effects correlated with attenuating Con A-induced elevation in hepatic oxidative stress parameters (MDA and NOx). Mechanistically, administration of Lac and BHB led to inhibition of Con A-induced phosphorylation of JNK and AMPK proteins in the liver to the same extent. These effects were concordant with curbing Con A-mediated overexpression of the pro-inflammatory cytokines TNF-α, IL-6 and IL-12 and activation of the transcription factor NF-κB. The marked anti-inflammatory properties of combining Lac and BHB were attributed to their cooperation in repressing immune cells (monocytes and neutrophils) infiltration to the liver. Unlike BHB, Lac administration markedly induced the reparative STAT3 and ERK phosphorylation in the livers of Con A-intoxicated mice at the early time point. In conclusion, the simultaneous use of Lac and BHB might be an auspicious strategy for limiting immune mediated hepatitis.Graphical abstractUnlabelled Image
  • Trigonelline mitigates lipopolysaccharide-induced learning and memory
           impairment in the rat due to its anti-oxidative and anti-inflammatory
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Mohsen Khalili, Mitra Alavi, Elham Esmaeil-Jamaat, Tourandokht Baluchnejadmojarad, Mehrdad Roghani Brain inflammation is associated with cognitive dysfunction, especially in elderly. Trigonelline is a plant alkaloid and a major component of coffee and fenugreek with anti-diabetic, antioxidant, anti-inflammatory, and neuroprotective effects. In this study, the beneficial effect of trigonelline against lipopolysaccharide (LPS)-induced cognitive decline was assessed in the rat. LPS was injected i.p. at a dose of 500 μg/kg to induce neuroinflammation and trigonelline was administered p.o. at doses of 20, 40, or 80 mg/kg/day 1 h after LPS that continued for one week. Trigonelline-treated LPS-challenged rats showed improved spatial recognition memory in Y maze, discrimination ratio in novel object discrimination test, and retention and recall in passive avoidance paradigm. Additionally, trigonelline lowered hippocampal malondialdehyde (MDA) and acetylcholinesterase (AChE) activity and improved superoxide dismutase (SOD), catalase, and glutathione (GSH). Furthermore, trigonelline depressed hippocampal nuclear factor-kappaB (NF-κB), toll-like receptor 4 (TLR4), and tumor necrosis factor α (TNF α) in LPS-challenged rats. All of the effects of trigonelline followed a dose-dependent pattern and in some aspects, it acted even better than the routinely-used anti-inflammatory drug dexamethasone. Collectively, trigonelline is capable to diminish LPS-induced cognitive decline via suppression of hippocampal oxidative stress and inflammation and appropriate modulation of NF-κB/TLR4 and AChE activity.
  • Over-expressed miRNA-200b ameliorates ulcerative colitis-related
           colorectal cancer in mice through orchestrating epithelial-mesenchymal
           transition and inflammatory responses by channel of AKT2
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Shuangjiao Deng, Hongfei Wang, Heng Fan, Lijuan Zhang, Jianli Hu, Qing Tang, Zhexing Shou, Xingxing Liu, Dongmei Zuo, Jia Yang, Meng Xu, Qianyun Chen, Yalan Dong, Zhen Nan, Hui Wu, Yujin Liu Our study was to explore the potential role of miRNA-200b in modulating tumorigenesis in the model of ulcerative colitis-related colorectal cancer (UCRCC) and, further, to decipher the underlying mechanisms associated with this effect. In this study, we examined a greater number of polyps or adenomas, a higher grade of epithelial dysplasia accompanied with a decrease in survival ratio in azoxymethane (AOM)/dextran sulfate sodium (DSS) model mice compared to mice treated with over-expressed miRNA-200b. Surprisingly, enforced miRNA-200b expression significantly suppressed AOM/DSS-induced up-regulation of oncologic markers including β-catenin and CD133. Independent of this, treatment with miRNA-200b obviously attenuated inflammatory responses, as indicated by down-regulating tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β) and blockade of AKT2-mediated NF-κB/IL-6/STAT3 signaling pathway. Furthermore, a simultaneous shift in epithelial-mesenchymal transition (EMT) markers such as E-cadherin and N-cadherin were observed to be increased and decreased, respectively. Coupled with the associated influence of over-expressed miRNA-200b were change in colorectal cell morphology shown by Transmission electron microscope (TEM) and a decrease in expression of rho-kinase2 (ROCK2) together with AKT2 phosphorylation (p-AKT2). Moreover, mice which were transfected with negative control of miRNA-200b possessed results that were in line with that obtained from AOM/DSS model mice. Additionally, we demonstrated that the 3′untranslated region (UTR) of AKT2 was a direct target of miRNA-200b through bioinformatics analysis and dual-luciferase assay. Collectively, these findings suggest that miRNA-200b's contribution to tumor-suppressing program was correlated with EMT and inflammatory responses in a AKT2-dependent manner.
  • Changes in inflammatory factors and protein expression in sulfur mustard
           (1LD50)-induced acute pulmonary injury in rats
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Yuan-yuan Jiang, Zun-shan Li, Dan Yu, Jian-wei Xie, Xiao-ji Zhu, Yu-xu Zhong
  • Formononetin inhibits neuroinflammation and increases estrogen receptor
           beta (ERβ) protein expression in BV2 microglia
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Abdelmeniem El-Bakoush, Olumayokun A. Olajide Formononetin is a bioactive non-steroidal polyphenol found in a variety of plants. In this study we evaluated the effects of formononetin on neuroinflammation in LPS-stimulated BV2 microglia. Results showed that formononetin significantly reduced the production of TNF-α, IL-6 and IL-1β, nitrite and PGE2, as well as protein levels of iNOS and COX-2. Reporter gene assays showed that formononetin produced inhibition of NF-κB luciferase activity in HEK293 cells stimulated with TNF-α. Immunoblotting experiments revealed an inhibition of IKKα phosphorylation, with the resultant attenuation of phosphorylation and degradation of IκBα following LPS stimulation. Formononetin also produced an inhibition of nuclear translocation and DNA binding by NF-κB following LPS stimulation. RNAi experiments showed that transfection of BV2 microglia with ERβ siRNA resulted in the loss of anti-inflammatory action of formononetin. MTT assay and MAP2 immunoreactivity experiments showed that formononetin produced significant neuroprotective activity by preventing BV2 microglia conditioned media-induced toxicity to HT22 neurons. Investigations on the effect of formononetin on MCF7 breast cancer cells revealed that, while the compound significantly increased ER-luciferase activity, its effects on proliferation were modest. This study has established that formononetin inhibits neuroinflammation by targeting NF-κB signalling pathway in BV2 microglia, possibly through mechanisms involving ERβ. Formononetin appears to modulate ERβ in MCF7 breast cancer cells with limited proliferative effect. Formononetin could therefore serve as a chemical scaffold for the development of novel compounds which have selective neuroprotective actions in the brain.
  • Heat treatment improves the immunomodulatory and cellular antioxidant
           behavior of a natural flavanone: Eriodictyol
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Rihab Khlifi, Zaineb Dhaouefi, Mouna Maatouk, Aicha Sassi, Najet Boudhiba, Irina Ioannou, Kamel Ghedira, Leila Chekir-Ghedira, Soumaya Kilani-Jaziri Plants and natural molecules are generally consumed not in raw state but after different processing conditions (heating, mechanical agitation or cooking). The understanding of the chemistry and biological outcome of thermal treatment is still scarce. In the current study, Eriodictyol, a natural flavanone, has undergone heat treatment, generating hence three different products ((3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid, (3-(3,4-dihydroxyphenyl) propanal) and an unidentified component).The consequences of aforementioned treatment on the immunomodulatory behavior of resulted molecules were evaluated. The amount of nitric oxide production and the lysosomal enzyme activity were determined in vitro on mouse peritoneal macrophages. The kinetic of cellular antioxidant activity in splenocytes and macrophages was measured. The present investigation demonstrates that heat-processed eriodictyol significantly enhanced the proliferation of lymphocytes B and T compared to native eriodictyol. Indeed, this compound showed an important improvement on cytotoxic T lymphocyte (CTL) and natural killer (NK) activities. In addition, the production of nitric oxide (NO) and suppression of phagocytic activity of activated macrophages have been increasingly important after thermal processing. Furthermore, it was also revealed that heat-treated Erio in comparison with the native (non heat-treated) molecule has a highest cellular anti-oxidant activity in splenocytes and macrophages cells. These findings highlight the importance of heat-process as feasible and effective strategy to improve the immunomodulatory and the antioxidant efficiency of an known flavanone Eriodictyol.Graphical abstractUnlabelled Image
  • Attenuation of inflammatory pain by puerarin in animal model of
           inflammation through inhibition of pro-inflammatory mediators
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Muhammad Zia Ullah, Ashraf Ullah Khan, Ruqayya Afridi, Hina Rasheed, Sidra Khalid, Muhammad Naveed, Hussain Ali, Yeong Shik Kim, Salman Khan In the current study, the puerarin was investigated for both acute Carrageenan and chronic CFA-induced inflammatory pain models. The Puerarin treatment significantly attenuated (P 
  • Phenotype analyses of IL-10-producing Foxp3− CD4+ T cells increased by
           subcutaneous immunotherapy in allergic airway inflammation
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Masaya Matsuda, Yuki Morie, Hirotaka Oze, Kana Doi, Tatsuya Tsutsumi, Junpei Hamaguchi, Miki Inaba, Takeshi Nabe IntroductionThe mechanisms of allergen immunotherapy are not fully elucidated. Here, we sought to develop a murine model to demonstrate the effectiveness of subcutaneous immunotherapy (SCIT) for allergic responses. As excessive antigen dosages may induce immune tolerance in sensitized mice, the effects of SCIT were assessed by varying the antigen dosage. The mechanisms of SCIT were analyzed by focusing on the induction of Foxp3+ Treg cells and IL-10-producing Foxp3− CD4+ T cells, as well as on the phenotype of the latter cells.MethodsOvalbumin (OVA) + Al(OH)3-sensitized mice received subcutaneous dosages of OVA at 0.01, 0.1 or 1 mg/animal for SCIT, followed by intratracheal challenges with OVA at 5, 50 or 500 μg/animal.ResultsThe maximum effects of SCIT were observed with 1 mg/animal of OVA for airway inflammation induced by 5 μg/animal of OVA, in which airway eosinophilia and Th2 cytokine production were markedly suppressed. The increase in the OVA-specific IgE level was significantly suppressed by SCIT. The development of bronchial epithelial thickening and mucus accumulation were also suppressed by SCIT. Concomitantly, IL-10-producing Foxp3− CD4+ T cells were increased in the lungs by SCIT, but Foxp3+ Treg cells were not. Most of the induced IL-10-producing Foxp3− CD4+ T cells were negative for either IL-5 or LAG-3, but positive for CD49b.ConclusionWe successfully developed an airway allergic model for SCIT. It was suggested that most of IL-10-producing Foxp3− CD4+ regulatory T cells increased by SCIT in the lungs were CD49b+ CD4+ regulatory T cells, but neither Th2 cells nor Tr1 cells.
  • Treatment of Guillain-Barré syndrome with Bifidobacterium infantis
           through regulation of T helper cells subsets
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Peng Shi, Hongdang Qu, Di Nian, Yuhua Chen, Xiaolin Liu, Qiang Li, Qianqian Li, Chun Wang, Ming Ye, Bo Ma BackgroundGuillain-Barré syndrome (GBS) is a rare, autoimmune-mediated disease. The use of Bifidobacterium is reportedly effective in alleviating GBS since they act by regulating T helper (Th) cells.ObjectivesIn this study, we explored the differentiation of T helper cell subsets in patients with GBS. We also evaluated the effect of GBS on Bifidobacterium levels in patients and the likely protective influence of this bacterium in alleviating the disease in an animal model.Materials and methodsWe used flow cytometry, and real-time polymerase chain reaction (PCR) to determine the T cell subsets differentiation among 30 GBS patients and 20 healthy controls (HC). The concentration of Bifidobacterium was assayed by real-time PCR. Experimental autoimmune neuritis (EAN) animal model was established to support the protective role of Bifidobacterium in GBS.ResultsThe expression of Th cells, Th2 and Th17 in the patients was significantly higher than that in the HC, while Treg cells decreased substantially. Moreover, the levels of Bifidobacterium in the GBS patients were considerably lower than those in the HC, the concentration of Bifidobacterium correlating with Th2 and Th17 subsets negatively. Treatment with Bifidobacterium significantly reduced the levels of Th2 and Th17 and promoted the levels of Treg cells.ConclusionsWe concluded from this study that Bifidobacterium alleviated GBS by regulating Th cells, although in-depth studies might be required to fully understand the mechanism of action.
  • Costunolide ameliorates lipoteichoic acid-induced acute lung injury via
           attenuating MAPK signaling pathway
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Zhengxu Chen, Dan Zhang, Man Li, Baolong Wang Lipoteichoic acid (LTA)-induced acute lung injury (ALI) is an experimental model for mimicking Gram-positive bacteria-induced pneumonia that is a refractory disease with lack of effective medicines. Here, we reported that costunolide, a sesquiterpene lactone, ameliorated LTA-induced ALI. Costunolide treatment reduced LTA-induced neutrophil lung infiltration, cytokine and chemokine production (TNF-α, IL-6 and KC), and pulmonary edema. In response to LTA challenge, treatment with costunolide resulted less iNOS expression and produced less inflammatory cytokines in bone marrow derived macrophages (BMDMs). Pretreatment with costunolide also attenuated the LTA-induced the phosphorylation of p38 MAPK and ERK in BMDMs. Furthermore, costunolide treatment reduced the phosphorylation of TAK1 and inhibited the interaction of TAK1 with Tab1. In conclusion, we have demonstrated that costunolide protects against LTA-induced ALI via inhibiting TAK1-mediated MAPK signaling pathway, and our studies suggest that costunolide is a promising agent for treatment of Gram-positive bacteria-mediated pneumonia.Graphical abstractUnlabelled Image
  • Xanthohumol attenuates cisplatin-induced nephrotoxicity through inhibiting
           NF-κB and activating Nrf2 signaling pathways
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Fan Li, Yunyi Yao, Hui Huang, Hua Hao, Mingzhong Ying Cisplatin is a chemotherapeutic agent that widely used in the treatment of cancer. However, cisplatin has been reported to induce nephrotoxicity by directly inducing inflammatory response and oxidative stress. In this study, we aimed to investigate the protective effects and mechanism of xanthohumol on cisplatin-induced nephrotoxicity. The model of nephrotoxicity was induced by intraperitoneal injection of cisplatin and xanthohumol was given intraperitoneally for three consecutive days. The results showed that xanthohumol significantly attenuated kidney histological changes and serum creatinine and BUN production. The levels of TNF-α, IL-1ß and IL-6 in kidney tissues were suppressed by xanthohumol. The levels of malondialdehyde (MDA) and ROS were suppressed by treatment of xanthohumol. The activities of glutathione (GSH) and superoxide dismutase (SOD) decreased by cisplatin were reversed by xanthohumol. Furthermore, the expression of TLR4 and the activation of NF-κB induced by cisplatin were significantly inhibited by xanthohumol. The expression of Nrf2 and HO-1 were dose-dependently up-regulated by the treatment of xanthohumol. In conclusion, xanthohumol protects against cisplatin-induced nephrotoxicity by ameliorating inflammatory and oxidative responses.
  • d-galactosamine-induced+acute+liver+injury+in+mice+through+inhibiting+toll-like+receptor+4+signaling+pathway&rft.title=International+Immunopharmacology&rft.issn=1567-5769&">Protective effects of ginsenoside Rg1 against
           lipopolysaccharide/d-galactosamine-induced acute liver injury in mice
           through inhibiting toll-like receptor 4 signaling pathway
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Chenqing Ning, Xiaoguang Gao, Changyuan Wang, Xiaokui Huo, Zhihao Liu, Huijun Sun, Xiaobo Yang, Pengyuan Sun, Xiaodong Ma, Qiang Meng, Kexin Liu Acute liver injury (ALI) is a dramatic liver disease characterized by large areas of inflammation in the liver. This study aimed to investigate the protective effects of ginsenoside Rg1 (Rg1), a biologically active component in Panax ginseng, on lipopolysaccharide/d-galactosamine (LPS/D-GalN)-induced ALI in mice, and meanwhile explore the molecular mechanism in vivo and in vitro. Mice were pretreated with Rg1 for three days prior to LPS (40 μg/kg)/D-GalN (700 mg/kg) administration. The results showed that Rg1 improved the survival rate and reduced the liver to body weight ratios in mice. Rg1 also reduced the production of oxidative markers such as MDA and MPO induced by LPS/D-GalN. In addition, Rg1 significantly decreased the production of inflammatory cytokines including TNF-α, IL-6, IL-1β, Mip-2, Mcp-1, iNOS, and increased the activity of anti-inflammatory cytokine IL-10. Moreover, Rg1 inhibited the protein expression of TLR4 and its downstream genes including NF-κB and MAPKs, which are involved in inflammatory response. Rg1 dramatically reduced oxidative stress by regulating the expression of efflux transporters Mrp2 and various enzymes including GCLC, GCLM, HO-1 and NQO1. However, the changes in these genes and protein induced by Rg1 were abrogated by TLR4 antagonist TAK-242 in vitro. In conclusion, Rg1 had hepatoprotective effect on LPS/D-GalN-induced ALI in mice. The protection may be associated with the inhibition of TLR4. These findings suggest that Rg1 may be a promising agent for prevention against ALI.
  • Development of a new approach of immunotherapy against scorpion
           envenoming: Avian IgYs an alternative to equine IgGs
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Amina Sifi, Sonia Adi-Bessalem, Fatima Laraba-Djebari Antivenom treatment has been largely used against scorpion stings. Despite their efficacy, the use of mammalian antivenoms may cause adverse effects due to the immune system activation. IgYs from hyperimmunized laying hens against venoms could be a promising alternative to equine IgGs due to the various benefits that these antibodies can provide. Here we report the preparation of specific IgYs by immunizing laying hens with Aah (Androctonus australis hector) scorpion venom.IgYs were isolated from egg yolks by water dilution and salt precipitation methods; they were characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis, western blot and ELISA. The efficiency of these immunoglobulins on the pathophysiological effects induced by Aah venom was assessed by histological and metabolical analysis of the aorta and the heart. The inflammatory response was assessed by evaluating the granulocyte tissue infiltration and oxidative/nitrosative status.Results revealed high IgYs titers against Aah venom by ELISA. Overall, these IgYs seem to protect efficiently mice against envenomation and neutralized the lethal effects of scorpion venom with a high efficacy; the median effective dose (ED50) was 221 μl/2 LD50; i.e. an amount of 79.23 mg of IgY scan neutralize 1 mg of Aah venom. IgY antibodies neutralize effectively the Aah venom lethality and could prevent severe pathological effects induced by scorpion venom and could be used as an effective alternative to equine IgGs against scorpion envenoming.
  • d-galactosamine+in+mice&rft.title=International+Immunopharmacology&rft.issn=1567-5769&">Dopamine alleviated acute liver injury induced by
           lipopolysaccharide/d-galactosamine in mice
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Honghong Zhou, Li Tang, Yongqiang Yang, Ling Lin, Jie Dai, Pu Ge, Qing Ai, Rong Jiang, Li Zhang Dopamine (DA), a crucial neurotransmitter, not only functions in the central nervous system but also plays important roles in the modulation of inflammation. Several studies suggest that DA might suppress the inflammatory response both in vitro and in vivo. In the present study, the potential effects of DA in a mouse model with lipopolysaccharide (LPS)/d-galactosamine (D-Gal)-induced acute liver injury were investigated. The results show that DA-treated LPS/D-Gal-exposed mice had reduced incidence of histologic lesions, lower plasma aminotransferases and improved the survival rates compared to LPS/D-Gal-exposed mice. Treatment with DA also suppressed LPS/D-Gal-induced production of TNF-α, phosphorylation of c-jun-N-terminal kinase (JNK), cleavage of caspase-3, up-regulation of hepatic caspase-3, caspase-8, and caspase-9 activities and reduced the count of TUNEL-positive hepatocytes. These data indicate that DA attenuated LPS/D-Gal-induced fulminant liver injury in mice, which implies that DA might have value for the prevention of inflammatory liver disease.
  • Against NF-κB/thymic stromal lymphopoietin signaling pathway, catechin
           alleviates the inflammation in allergic rhinitis
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Zengfeng Pan, Yuan Zhou, Xia Luo, Yan Ruan, Lian Zhou, Qing Wang, Ya jie Yan, Qi Liu, Jinyan Chen BackgroundThe prevalence of allergic rhinitis has risen sharply. Previous work has demonstrated the anti-inflammatory effect of catechin, including in models of allergic disease. However, the molecular mechanisms underlying this therapeutic effect remain unclear. Thymic stromal lymphopoietin(TSLP), as a molecule from epithelial cell, has been identified that plays a significant role in the development of allergic disease, and the production of TSLP is related to activation of the NF-κB signaling pathway. For that, we try to research the treatment of catechin for allergic rhinitis and found out possible mechanism under this effect, which was based on TSLP factor.Materials and methodsHere, the anti-inflammatory effects of catechin were studied in an ovalbumin-induced allergic rhinitis murine model and a vitro experiments using poly(I:C)-stimulated human nasal epithelial cells(HNEpCs). The pharmacological effects of catechin in allergic rhinitis mice were assessed by observing the allergic symptoms, performing hematoxylin and eosin staining and Giemsa staining of the nasal tissues. Additionally, the TSLP expression in epithelial cells was tested by enzyme-linked immunosorbent assays, immunohistochemistry, and western blots. The serum levels of interleukin-5, interleukin-13, and ovalbumin-specific immunoglobulin-E were detected by enzyme-linked immunosorbent assays, and the balance between T helper type 1 and T helper type 2 cells was assessed by flow cytometry. The expression levels of phospho-NF-κBp65, IκBα, and NF-κBp65 proteins were further investigated by western blots or immunofluorescence.ResultsOur results reveal that catechin, in doses of 75, 150, or 300 mg/kg, remitted the allergic symptoms in mice with allergic rhinitis, like sneezing and nasal rubbing. Catechin could reduce the levels of interleukin-5, interleukin-13, and ovalbumin-specific immunoglobulin-E in the serum and restored the T helper type 2/T helper type 1 cell balance and also had anti-thymic stromal lymphopoietin effects. Moreover, as an upstream regulator of TSLP, the NF-κB signal pathway was also suppressed after catechin treatment, which was demonstrated by the observed decrease in phospho-NF-κBp65 and NF-κBp65 levels and the reduction of IκBα degradation and NF-κBp65 nuclear translocation.ConclusionsCatechin effectively reduced the inflammation in allergic rhinitis. The underlying mechanism is that catechin inhibited the expression of TSLP in epithelial cells by influencing NF-κB/TSLP pathway.
  • Phytochemicals inhibit the immunosuppressive functions of myeloid-derived
           suppressor cells (MDSC): Impact on cancer and age-related chronic
           inflammatory disorders
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Antero Salminen, Kai Kaarniranta, Anu Kauppinen Traditional herbal medicine has provided natural remedies against cancers and many age-related inflammatory diseases for thousands of years. Modern drug discovery techniques have revealed several active ingredients and their medicinal targets have been characterized. Concurrently, there has been great progress in understanding the pathological mechanisms underpinning cancers and inflammatory diseases. These studies have demonstrated that immature myeloid-derived suppressor cells (MDSCs) have a crucial role in the immune escape of cancer cells thus promoting tumor growth. Inflammatory factors stimulate the recruitment, expansion, and activation of MDSCs in tumors and inflamed tissues. The immunosuppression generated by MDSCs has an important role in the resolution of acute inflammation but in chronic inflammatory disorders, the activation of MDSCs suppresses the innate and adaptive immune responses thus aggravating the disease processes in association with tumors, chronic infections, and many degenerative diseases. Currently, MDSCs are important drug discovery targets in cancers and chronic inflammatory diseases. Interestingly, there are promising reports that certain phytochemicals can function as potent inhibitors of the immunosuppressive MDSCs that could partially explain the therapeutic benefits of herbal medicine. We will briefly describe the immune suppressive functions of MDSCs in cancers and age-related inflammatory diseases and then review in detail the chemically characterized phytochemicals of different herbal categories, e.g. flavonoids, terpenoids, retinoids, curcumins, and β-glucans, which possess the MDSC-dependent antitumor and anti-inflammatory properties.
  • Emodin ameliorates cartilage degradation in osteoarthritis by inhibiting
           NF-κB and Wnt/β-catenin signaling in-vitro and in-vivo
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Qian-Hai Ding, Chen-Yi Ye, Er-Man Chen, Wei Zhang, Xiang-Hua Wang The overproduction of MMPs (matrix metalloproteinases) and members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family plays an important role in the pathogenesis of osteoarthritis (OA). The potential of selective MMPs or ADAMTS inhibitors as chemopreventive agents for OA has been demonstrated in several studies. In this study, we investigated the protective effects of emodin (1,3,8-trihydroxy-6-methylanthaquinone), isolated from the root of Rheum palmatum L., in the inhibition of MMP and ADAMTS expression in both rat chondrocytes and an animal model of OA. The expression of MMP-3, MMP-13, ADAMTS-4, ADAMTS-5, aggrecan, and collagen II mRNA and protein in interleukin-1beta (IL-1β)-induced rat chondrocytes was followed by quantitative real-time PCR and western blot. The activation of the NF-κB and Wnt/β-catenin pathways by IL-1β was assessed by western blot. The in vivo effects of emodin were evaluated by intra-articular injection in rats in an experimental model of OA induced by anterior cruciate ligament transection. Emodin dose-dependently down-regulated the expression of MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 at both the mRNA and protein level in IL-1β-stimulated rat chondrocytes. In addition, the IL-1β-induced activation of NF-κB and Wnt signals was attenuated by emodin, as determined by western blotting. The intra-articular injection of emodin in a rat OA model ameliorated OA progression, as determined in morphological and histological analyses in vivo. Taken together, our findings demonstrate that emodin is a promising therapeutic agent for the prevention and treatment of OA.
  • Montelukast inhibits inflammatory response in rheumatoid arthritis
           fibroblast-like synoviocytes
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Hongyu Dong, Feng Liu, Fengyun Ma, Lianna Xu, Linna Pang, Xuyan Li, Bo Liu, Liang Wang Montelukast, a potent selective antagonist of cysteinyl leukotriene (cysLT) receptors, has displayed its important anti-oxidative and anti-inflammatory effects in various tissues and organs. Rheumatoid arthritis (RA) is an immune disease defined by hyperplastic synovitis and joint destruction. Fibroblast-like synoviocytes in RA (RA-FLSs) are the main cell component of the hyperplastic synovium. Whether montelukast can protect against the inflammatory milieu of RA remains unclear. Here, it is shown that cysLT1R is present in FLSs and unregulated in RA-FLSs. Montelukast has an inhibitory effect on the inflammatory microenvironment of RA by decreasing the secretion of IL-6, IL-8, MMP-3 and MMP-13 in FLSs induced by IL-1β. Notably, treatment with montelukast attenuated IL-1β-induced phosphorylation of IκBα, IκBα degradation, nuclear translocation of p65 and NF-κB activity to express a luciferase reporter gene in FLSs. The findings of the current study provide evidence for a novel therapeutic strategy for RA using montelukast.
  • A synthetic diosgenin primary amine derivative attenuates LPS-stimulated
           inflammation via inhibition of NF-κB and JNK MAPK signaling in microglial
           BV2 cells
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Bangrong Cai, Kyung-Joo Seong, Sun-Woong Bae, Changju Chun, Won-Jae Kim, Ji-Yeon Jung Diosgenin, a precursor of steroid hormones in plants, is known to exhibit diverse pharmacological activities including anti-inflammatory properties. In this study, (3β, 25R)‑spirost‑5‑en‑3‑oxyl (2‑((2((2‑aminoethyl)amino)ethyl)amino)ethyl) carbamate (DGP), a new synthetic diosgenin derivative incorporating primary amine was used to investigate its anti-inflammatory effects and underlying mechanisms of action in lipopolysaccharide (LPS)-stimulated microglial BV2 cells. Pretreatment with DGP resulted in significant inhibition of nitric oxide (NO) synthesis, and down-regulation of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated microglial BV2 cells. In addition, DGP decreased the production of reactive oxygen species (ROS) and pro-inflammatory cytokines such as interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNF-α). The inhibitory effects of DGP on these inflammatory mediators in LPS-stimulated microglial BV2 cells were regulated by NF-κB signaling through blocking p65 nuclear translocation and NF-κB p65/DNA binding activity. DGP also blocked the phosphorylation of c-Jun amino-terminal kinase (JNK), but not p38 kinase or extracellular signal-regulated kinases (ERK). The NF-κB inhibitor JSH-23 and JNK-specific inhibitor SP600125 significantly decreased NO production and IL-6 release in LPS-stimulated BV2 cells, respectively. The overall results demonstrate that DGP has anti-inflammatory effects on LPS-stimulated BV2 cells via inhibition of NF-κB and JNK activation, suggesting that DGP is a potential prophylactic agent in various neurodegenerative disorders.Graphical abstractUnlabelled Image
  • Emergent nanotherapies in microcrystal-induced arthritis
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Yessica Zamudio-Cuevas, Javier Fernández-Torres, Gabriela Angélica Martínez-Nava, Karina Martínez-Flores, Alberto López-Reyes The anti-inflammatory and immunomodulatory effects of nanoparticles in several chronic diseases have been extensively researched. The aim of this review is to examine how nanoparticles modulate the inflammatory pathways that characterize the most prevalent forms of microcrystal-induced arthritis, including gout, pseudogout, and BCP-induced arthritis. The nanoparticles of chitosan-coated calcium phosphate, uricase, aceclofenac, and gold have been investigated in crystal-inducedarthritis. The most important results of the studies outlined in this review show that nanoparticles can inhibit the expression and the release of some pro-inflammatory mediators and proteolytic enzymes, and the activity of different transcriptional factors in vitro, as well as decrease the uric acid levels in several studies of in vitro and in vivo models of gout, which show interesting results in terms of decreasing the amount of crystals and tissue damage, respectively. In view of their multiple beneficial effects, nanoparticles can be considered a valuable therapy that contributes to the pharmacological treatment in crystalinduced arthritis.
  • Study of the allergenic potential of Bacillus thuringiensis Cry1Ac toxin
           following intra-gastric administration in a murine model of food-allergy
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Karla I. Santos-Vigil, Damaris Ilhuicatzi-Alvarado, Ana L. García-Hernández, Juan S. Herrera-García, Leticia Moreno-Fierros Cry1Ac toxin, from Bacillus thuringiensis, is widely used as a biopesticide and expressed in genetically modified (GM) plants used for human and animal consumption. Since Cry1Ac is also immunogenic and able to activate macrophages, it is crucial to thoroughly evaluate the immunological effects elicited after intra-gastric administration. The allergenic potential of purified Cry1Ac was assessed and compared with that induced in a murine model of food-allergy to ovalbumin (OVA), in which animals are sensitized with the adjuvant Cholera toxin (CT). Mice were weekly intragastrically administered with: i) vehicle phosphate-buffered saline (PBS), ii) OVA, iii) OVA plus CT iv) Cry1Ac or v) OVA plus Cry1Ac. Seven weeks after, mice were intragastrically challenged and allergic reactions along with diverse allergy related immunological parameters were evaluated at systemic and intestinal level. The groups immunized with, Cry1Ac, OVA/Cry1Ac or OVA/CT developed moderate allergic reactions, induced significant IgE response and increased frequencies of intestinal granulocytes, IgE+ eosinophils and IgE+ lymphocytes. These same groups also showed colonic lymphoid hyperplasia, notably in humans, this has been associated with food allergy and intestinal inflammation. Although the adjuvant and allergenic potential of CT were higher than the effects of Cry1Ac, the results show that applied intra-gastrically at 50 μg doses, Cry1Ac is immunogenic, moderately allergenic and able to provoke intestinal lymphoid hyperplasia. Moreover, Cry1Ac is also able to induce anaphylaxis, since when mice were intragastrically sensitized with increasing doses of Cry1Ac, with every dose tested, a significant drop in rectal temperature was recorded after intravenous challenge.Graphical abstractUnlabelled Image
  • Low-dose naltrexone (LDN): A promising treatment in immune-related
           diseases and cancer therapy
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Zijian Li, Yue You, Noreen Griffin, Juan Feng, Fengping Shan Naltrexone, a non-selective antagonist of opioid receptors, is mainly used as rehabilitation therapy for discharged opiate addicts to eliminate addiction in order to maintain a normal life and prevent or reduce relapse. In recent years, there have been some novel and significant findings on the off-label usage of naltrexone. Within a specific dosage window, LDN can act as an immunomodulator in multiple autoimmune diseases and malignant tumors as well as alleviate the symptoms of some mental disorders. The results of increasing studies indicate that LDN exerts its immunoregulatory activity by binding to opioid receptors in or on immune cells and tumor cells. These new discoveries indicate that LDN may become a promising immunomodulatory agent in the therapy for cancer and many immune-related diseases. In this article, we review the pharmacological functions and mechanisms of LDN as well as its clinical therapeutic potential as revealed by our team and other researchers.Graphical abstractUnlabelled Image
  • Paeonol attenuates acute lung injury by inhibiting HMGB1 in
           lipopolysaccharide-induced shock rats
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Xia Liu, Qin Xu, Liyan Mei, Hang Lei, Quan Wen, Jifei Miao, Huina Huang, Dongfeng Chen, Shaohui Du, Saixia Zhang, Jianhong Zhou, Rudong Deng, Yiwei Li, Chun Li, Hui Li High-mobility group box 1 (HMGB1) is a highly conserved DNA-binding nuclear protein that facilitates gene transcription and the DNA repair response. However, HMGB1 may be released by necrotic cells as well as activated monocytes and macrophages following stimulation with lipopolysaccharide (LPS), interleukin-1β (IL-1β), or tumor necrosis factor-α (TNF-α). Extracellular HMGB1 plays a critical role in the pathogenesis of acute lung injury (ALI) through activating the nuclear transcription factor κB (NF-κB) P65 pathway, thus, it may be a promising therapeutic target in shock-induced ALI. Paeonol (Pae) is the main active component of Paeonia suffruticosa, which has been used to inhibit the inflammatory response in traditional Chinese medicine. We have proven that Pae inhibits the expression, relocation and secretion of HMGB1 in vitro. However, the role of Pae in the HMGB1-NF-κB pathway remains unknown. We herein investigated the role of Pae in LPS-induced ALI rats. In this study, LPS induced a marked decrease in the mean arterial pressure (MAP) and survival rate (only 25% after 72 h), and induced severe pathological changes in the lung tissue of rats, which was accompanied by elevated expression of HMGB1 and its downstream protein NF-κB P65. Treatment with Pae significantly improved the survival rate (>60%) and MAP, and attenuated the pathological damage to the lung tissue in ALI rats. Western blotting revealed that Pae also inhibited the total expression of HMGB1, NF-κB P65 and TNF-α in the lung tissue of ALI rats. Moreover, Pae increased the expression of HMGB1 in the nucleus, inhibited the production of HMGB1 in the cytoplasm, and decreased the expression of P65 both in the nucleus and cytoplasm of lung tissue cells in LPS-induced ALI rats. The results were in agreement with those observed in the in vitro experiment. These findings indicate that Pae may be a potential treatment for ALI through its repression of the HMGB1-NF-κB P65 signaling pathway.
  • Bone marrow derived M2 macrophages protected against
           lipopolysaccharide-induced acute lung injury through inhibiting oxidative
           stress and inflammation by modulating neutrophils and T lymphocytes
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Fang Wang, Xiazhen Fu, Xinwan Wu, Jianhai Zhang, Jiali Zhu, Yun Zou, Jinbao Li Acute lung injury (ALI) is characterized by aggravated inflammatory responses and the subsequent alveolar-capillary injury for which there are no specific therapies available currently. The present study was designed to investigate the protective roles of bone marrow derived M2 macrophages (M2 BMDMs) in lipopolysaccharide (LPS) induced ALI. M2 BMDMs were obtained from bone marrow cells stimulated with M-CSF and IL-4. Mice received M2 BMDMs intratracheally 3 h after LPS administration. Histology and wet/dry (W/D) weight ratio, activated immune cells and total protein were detected. Cytokines production were measured in vivo and vitro study. The effects of PD-L1 blockade on M2 BMDMs were calculated. The results showed that M2 BMDMs administration reduced the infiltration of neutrophils, inhibited the oxidative stress, while increased the counts of CD3+T lymphocytes as well as CD4+CD25+ regulatory T lymphocytes. Further, M2 BMDMs suppressed the TNF-α, IL-1β and IL-6 production, while increased the IL-10 production. Blockade of PD-L1/PD-1 pathway reversed cytokines production of M2 BMDMs in the BALF. These findings indicated that M2 BMDMs might be a promising therapeutic strategy for LPS-induced ALI through inhibiting oxidative stress and inflammation by modulating neutrophils and T lymphocytes responses.
  • Leonurine ameliorates the inflammatory responses in
           lipopolysaccharide-induced endometritis
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Haichong Wu, Ailing Dai, Xingxing Chen, Xiaoyan Yang, Xiaohua Li, Cuiqin Huang, Kangfeng Jiang, Ganzhen Deng Endometritis is the inflammation of the endometrium that is associated with lower conception rates, increased intervals from calving to first service, and more culls for failure to conceive, which leads to serious economic losses in the dairy industry. Leonurine, a natural active compound of Leonurus cardiaca, has been proved to possess various biological activities. However, there is still no study about its anti-inflammatory effects on LPS-induced endometritis. The present study aimed to demonstrate the underlying mechanism responsible for the anti-inflammatory effects of leonurine on LPS induced endometritis in mice and in bovine endometrial epithelial cells (bEECs). The results of pathological section displayed that leonurine alleviated LPS induced uterine injury. qRT-PCR and ELISA experiments suggested that leonurine inhibited the expression levels of TNF-α and IL-1β in uterus tissues and bEECs. Molecular studies showed that TLR4 expression and nuclear factor (NF)-κB activation were both inhibited by leonurine treatment. These results suggested that the therapeutic effects of leonurine on LPS-induced endometritis in mice and bEECs may act by inhibiting the expression of TLR4 and its downstream mediated NF-κB pathway. Accordingly, leonurine may serve as an effective drug in preventing and treating LPS induced endometritis.
  • A flavonoids compound inhibits osteoclast differentiation by attenuating
           RANKL induced NFATc-1/c-Fos induction
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Ke Zhang, Jun Lei, Yuan He, Xiaobin Yang, Zhen Zhang, Dingjun Hao, Biao Wang, Baorong He Function studies of pectolinarigenin demonstrated that, as a natural product, it possesses the regulatory effects on transcription factors (TFs) such as: signal transducer and activator of transcription 3 (STAT3). Herein, we aimed to identify the regulatroy effects of pectolinarigenin on the osteoclastogenesis TFs such as: NFATc1 and c-Fos, and further identify the relevant up-stream signals activity. We initially found pectolinarigenin inhibited receptor activator of nuclear factor-kappa B ligand (RANKL) induced osteoclast formation during the bone marrow-derived macrophages (BMMs) cultures, suggesting that this natural product could act on osteoclast precursors by inhibiting the down signaling cascades of RANKL signaling. Moreover, mechanistical investigation showed pectolinarigenin inhibits RANKL-mediated osteoclastogenesis by attenuating the nuclear factor of activated T cells cytoplasmic 1 (NFATc-1) and c-Fos following the Akt and mitogen activated protein kinases (MAPKs) signaling costimulatory. These findings identify that pectolinarigenin may act as an anti-resorption agent by blocking osteoclast activation.
  • Formyl peptide receptor activation inhibits the expansion of effector T
           cells and synovial fibroblasts and attenuates joint injury in models of
           rheumatoid arthritis
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Dragana Odobasic, Yuan Jia, Wenping Kao, Huapeng Fan, Xuemin Wei, Ran Gu, Devi Ngo, A. Richard Kitching, Stephen R. Holdsworth, Eric F. Morand, Yuan H. Yang The effects of formyl peptide receptors (FPRs) on effector T cells and inflammation-causing tissue-resident cells are not well known. Here, we explored the effect of FPR activation on efferent T cell responses in models of rheumatoid arthritis (RA) and on the expansion of fibroblast-like synoviocytes (FLS). Compound 43 (Cpd43; FPR1/2 agonist) was administered to mice with collagen-induced arthritis (CIA) or antigen-induced arthritis (AIA) after disease onset. Joint inflammation/damage and immunity were assessed. FLS were cultured with Cpd43 to test its effects on cell apoptosis and proliferation. To explore the effects of endogenous FPR2 ligands on FLS proliferation, FLS FPR2 was blocked or Annexin A1 (AnxA1) expression silenced. Cpd43 reduced arthritis severity in both models. In CIA, Cpd43 decreased CD4 T cell proliferation and survival and increased the production of the protective cytokine, IFNγ, in lymph nodes. In AIA, Cpd43 increased CD4 apoptosis and production of the anti-inflammatory IL-4, while augmenting the proportion of splenic regulatory T cells and their expression of IL-2Rα. In both models, Cpd43 increased CD4 IL-17A production, without affecting humoral immunity. FPR2 inhibitors reversed Cpd43-mediated effects on AIA and T cell immunity. Cpd43 decreased TNF-induced FLS proliferation and augmented FLS apoptosis in association with intracellular FPR2 accumulation, while endogenous AnxA1 and FPR2 reduced FLS proliferation via the ERK and NFκB pathways. Overall, FPR activation inhibits the expansion of arthritogenic effector CD4 T cells and FLS, and reduces joint injury in experimental arthritis. This suggests the therapeutic potential of FPR ligation for the treatment of RA.
  • The prevalence and function of CD4+CXCR5+Foxp3+ follicular regulatory T
           cells in diffuse large B cell lymphoma
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Zhanshan Cha, Haihui Gu, Yan Zang, Zi Wang, Jinqi Li, Weihua Huang, Aihua Qin, Lishuang Zhu, Xiaohua Tu, Ning Cheng, Haihan Song, Baohua Qian CD4+CXCR5+Foxp3+ follicular regulatory T (Tfr) cells possess critical roles in suppressing the germinal center reaction, B cell activation, and follicular helper T cell (Tfh) cytokine secretion. Since diffuse large B cell lymphoma (DLBCL) can arise from B cells undergoing germinal center reaction and/or differentiation, we hypothesized that Tfr cells might be involved in DLBCL. In the present study, we recruited thirty-five DLBCL patients and twenty-five healthy controls. Data showed that DLBCL patients presented an enrichment of circulating CD4+CXCR5+Foxp3+ Tfr cells compared to controls. In the primary tumor isolated from enlarged lymph nodes, Tfr cells made up of roughly 3% to 16% of infiltrating T cells. Higher levels of tumor-infiltrating Tfr cells were observed in patients with less advanced DLBCL stages, and in patients that stayed in remission 24 months after the initial R-CHOP treatment. High BCL6 and high FOXP3 expression was observed in Tfr cells ex vivo. After anti-CD3/CD28 and IL-2 stimulation, the Tfr cells more closely resembled Treg cells and presented high IL10 and TGFB1 expression. CD4+CD25+CXCR5+ Tfr cells and CD4+CD25+CXCR5− non-Tfr Treg cells could suppress CD4+CD25− Tconv cell and CD8+ T cell proliferation with similar capacity. However, Tfr cells were less capable of suppressing IFNG expression than Treg cells, and although both cell types supported CD19+ tumor cell proliferation, Tfr cells were less supportive than the non-Tfr Treg cells. Overall, this study suggested that Tfr cells were involved in intratumoral immunity, were likely beneficial to DLBCL patients, and were functionally distinctive from non-Tfr Treg cells. The distribution pattern and the prognostic value of Tfr cells in DLBCL should be examined in further studies.
  • Component resolved diagnostic study of cow's milk allergy in infants and
           young children in northern China
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Junpu Li, Jiayi Zhang, Cuiya Qiong, Tiantian She, Ying Bian, Shuxiang Lin, Huiqiang Li BackgroundIncreasing dairy consumption in China has been accompanied by rising incidence of milk allergy. Here we analyzed profiles of specific immunoglobulin E (sIgE) against cow's milk proteins, and assessed their value for milk allergy diagnosis among infants and young children from northern China.MethodsSera collected from 48 patients with milk allergy and 27 negative control subjects was analyzed by enzyme-linked immunosorbent assay to measure sIgE to α-lactalbumin (Bos d 4), β-lactoglobulin (Bos d 5), α-casein (Bos d 9), β-casein (Bos d 11), and κ-casein (Bos d 12).ResultsAmong milk-allergic individuals, most were sensitized to at least one milk protein; about half were sensitized to Bos d 5, Bos d 9, Bos d 11 and Bos d 12, respectively, while few had positive serum sIgE against Bos d 4. Bos d 12 sIgE had the largest area under curve (AUC) (0.878; 95% CI, 0.800–0.957) and thus showed the best diagnostic performance in discriminating between milk-allergic and non-milk allergic patients, with a sensitivity of 92.6% and specificity of 72.9% using a statistically optimal cut-off value (OD450nm, 0.191). The combinations of Bos d 5 + Bos d 12 showed an AUC of 0.926, which was larger than for any individual components.ConclusionsOur results revealed inter-individual variation in the sensitization to different milk allergen component. Bos d 12 sIgE showed best performance in diagnosing milk allergy. Milk allergy diagnostic accuracy was further improved using combinations of milk allergen components by application of ROC curves based on logistic regression.
  • IL-34 regulates IL-6 and IL-8 production in human lung fibroblasts via
           MAPK, PI3K-Akt, JAK and NF-κB signaling pathways
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Jie Zhou, Xiaoyu Sun, Juan Zhang, Yang Yang, Dapeng Chen, Ju Cao IL-34 plays diverse roles in disease due to its inflammatory and immunosuppressive properties. Elevated IL-34 expression has been observed in lung cancers and pulmonary infections although its role is unclear. We found that IL-34 addition to primary lung fibroblasts significantly promoted IL-6 and IL-8 expression in a dose and time dependent manner. These effects were reversed when JAK, NF-κB, Akt and p38 inhibitors were included before IL-34 addition. Protein phosphorylation in these pathways was also observed through western-blotting. Stimulation of human lung fibroblasts with IL-34 in combination with TNF-α, IL-17A and IL-4 enhanced inflammatory cytokine production. Our data confirmed the inflammatory effect of IL-34 on human lung fibroblasts and suggested that the IL-34/CSF-1R axis may be a novel therapeutic target in pulmonary disease.
  • MSCs protect endothelial cells from inflammatory injury partially by
           secreting STC1
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Meimei Shi, Yujia Yuan, Jingping Liu, Younan Chen, Lan Li, Shuyun Liu, Xingxing An, Ruixi Luo, Dan Long, Bo Chen, Xiaojiong Du, Jingqiu Cheng, Yanrong Lu Inflammatory factors play an important role in the pathogenesis of diabetic vascular complications. Considerable interest in the therapeutic potential of mesenchymal stem cells (MSCs) has recently arisen. The purposes of this study were to investigate the effects of MSCs on endothelial cells under inflammatory conditions and to determine the relevant mechanism underlying these effects. In vitro, after TNF-α stimulation, MSCs-CM treatment significantly restored cell viability, reduced THP-1 cell adhesion and enhanced tube formation capacity via inhibiting ROS overproduction and NF-κB activation, subsequently down-regulating adhesion molecules and chemokines. These effects may be partially due to the up-regulation of uncoupling protein 2 (UCP2) in HUVECs that was induced by the secretion of stanniocalcin 1 (STC1) from MSCs. In vivo, MSCs transplantation ameliorated the progression of diabetes-associated vascular dysfunction by reducing ROS production and down-regulating the expression of adhesion molecules. These results suggest that MSCs protect HUVECs from inflammatory injury partially by secreting STC1. MSCs may be a potential therapeutic approach for the treatment of diabetic vascular complications.
  • Prophylactic herpes simplex virus type 2 vaccine adjuvanted with a
           universal CD4 T cell helper peptide induces long-term protective immunity
           against lethal challenge in mice
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Xiaoquan Li, Shouhua Zhang, Jun Lei, Ying Zhu, Xin Zhou, Juhua Xiao, Tianxin Xiang Induction of robust and long-term immune responses at the portal of entry remains a big challenge for HSV-2 vaccine development. The adoption of a CD4 T cell helper peptide in the vaccine is thought to be beneficial for the enhancement of immune responses, however, its effect on HSV-2 vaccines has not yet been studied. In this study, we designed a DNA vaccine (gD-TpD) simultaneously expressing HSV-2 gD ectodomain and a universal CD4 T cell helper peptide (TpD), and tested its efficacy on a murine model. Mice were immunized 3 times with gD-TpD or control DNA formulations, and then were rested until Day 150 when they were vaginally challenged with lethal doses of HSV-2. Our data showed that gD-TpD significantly increased gD-specific IgG and IgA in both sera and vaginal washes. Furthermore, the increased antibody responses showed enhanced neutralization activity in vitro. In addition, gD-TpD induced balanced Th1/2 cellular responses and CD8+ T cell-dependent CTL activity. Although immune responses dropped over time after the final immunization, robust and rapid antibody and T cell responses were induced upon virus challenge in gD-TpD group. Moreover, gD-TpD provided full protection against lethal viral challenge in immunized mice. Together, our findings indicate that the inclusion of the CD4 T cell helper peptide TpD in HSV-2 gD subunit vaccine could induce long-term protective immunity, providing information for a rational design of vaccines against HSV-2 or even other viruses.
  • Protective role of β-carotene against oxidative stress and
           neuroinflammation in a rat model of spinal cord injury
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Lihui Zhou, Lian Ouyang, Shuangzhi Lin, Song Chen, YingJie Liu, Wei Zhou, Xucan Wang Acute spinal cord injury (SCI) results in long-lasting functional impairments through both mechanical damage as well as secondary mechanisms, with limited available therapeutic options. β-Carotene has been demonstrated to exert biological and pharmacological activities. We aimed to examine the protective effects of β-carotene in a SCI rat model. We tested the hind-limb locomotor function, neuro-inflammation, oxidative stress, astrocyte activation and nuclear factor–κB (NF-κB) pathway activation of SCI rats, with or without β-carotene treatment. β-Carotene substantially improved locomotion that was reduced by SCI. β-Carotene also relieved SCI-induced oxidative stress via regulation of reactive oxygen species, malondialdehyde, nitric oxide, and superoxide dismutase, as well as restored SCI-suppressed protein expressions of Nrf2 and HO-1. Additionally, β-carotene decreased the generation of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-18 and cyclooxygenase-2, and inhibited the activation of astrocyte in the spinal cord. Furthermore, β-carotene treatment markedly inhibited the NF-κB pathway activation. Our findings demonstrated that β-carotene effectively reduced the progression of secondary injury events following SCI through preventing NF-κB pathway activation. Therefore, β-carotene may be an effective candidate for treating SCI.
  • Design, synthesis and investigation of potential anti-inflammatory
           activity of O-alkyl and O-benzyl hesperetin derivatives
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Ai-Ling Huang, Yi-Long Zhang, Hai-Wen Ding, Bo Li, Cheng Huang, Xiao-Ming Meng, Jun Li Hesperetin has been known to exert several activities such as anti-oxidant, antitumor and anti-inflammatory. To find hesperetin derivatives showing better activity, sixteen novel hesperetin derivatives were designed and synthesized. The new obtained compounds were investigated for their anti-inflammatory activity by inhibiting interleukin-1β (IL-1β), interleukin-6 (IL-6) and production of nitric oxide (NO) in mouse RAW264.7 macrophages, and the structure-activity relationship of them was discussed. Among them, the compound 1l, 2c demonstrated more effective inhibitory activity of IL-1β and IL-6, meanwhile, the compound 1l showed the best inhibition of NO production. The results of NO inhibition study were basically accord with the molecular docking results of inducible nitric oxide synthase (iNOS). Furthermore, the expression of LPS-induced iNOS and components of NF-κB signaling pathway were reduced by compound 1l. Our results suggest that the inhibitory effect of compound 1l on LPS-stimulated inflammatory mediator production in RAW 264.7 cells is associated with the suppression of NF-κB signaling pathway and inhibition of iNOS protein and iNOS activity. From in vivo study, it was also observed that compound 1l had hepato-protective and anti-inflammatory effects in CCl4-induced acute liver injury mouse models.Graphical abstractUnlabelled Image
  • Changes in Th17 cells function after nanocurcumin use to treat multiple
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Sanam Dolati, Majid Ahmadi, Reza Rikhtegar, Zohreh Babaloo, Hormoz Ayromlou, Leili Aghebati-Maleki, Mohammad Nouri, Mehdi Yousefi BackgroundMS is a chronic inflammatory disease that causes to brain inflammation and Th17 cells are considered to be important in multiple sclerosis pathogenesis. In the current study, we aimed to identify nanocurcumin effects on Th17 cells frequency, cytokines secretion, and expression of transcription factor of patients with relapsing-remitting multiple sclerosis (RRMS).MethodsIn this study we investigated frequency of Th17 lymphocytes; the expression of transcription factor, associated cytokines and the concentration of them in 35 healthy controls, and from 25 patients at baseline and after 6 months of nanocurcumin treatment and also from 25 patients whose received placebo by flowcytometry, real-time PCR and ELISA, respectively.ResultsOur analysis revealed that the proportions of Th17 were increased dramatically, along with increases in the levels of IL-17A, IL-23, and RORγt expression in MS patients in compared with healthy control group. Post-treatment evaluation of the nanocurcumin group revealed a significant decrease in Th17 associated parameters such as Th17 frequency (p = 0.029), expression levels of RORγt (p 
  • Targeting RAW 264.7 macrophages (M1 type) with Withaferin-A decorated
           mannosylated liposomes induces repolarization via downregulation of NF-κB
           and controlled elevation of STAT-3
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Manoj Kumar Neog, Farhath Sultana, Mahaboobkhan Rasool In the present study, we intend to gain an insight into the mechanism of Withaferin-A (WA), a steroidal lactone with reference to repolarization of RAW 264.7 macrophages (M1 to M2 type). We found that successful internalization of WA via mannosylated liposomal delivery system (ML-WA) reduced the RAW 264.7 macrophage (M1) mediated pro-inflammatory cytokines (IL-1β, IL-6, IL-23, and TNF-α) through the attenuation of transcription factor NF-κB-p65 expression. Whereas, ML-WA treatment induced a controlled upregulation of p-STAT3, and ablated the key oxidative stress markers (NO, iNOS, and ROS) in M1 → M2 RAW 264.7 macrophage repolarization, which suggested the recalibration of M1 macrophage metabolic function. Further, the elevated expression of M2 macrophage associated CD163 over the M1 macrophage related CD86 concluded that ML-WA induces an anti-inflammatory response by repolarizing the M1 → M2 RAW 264.7 macrophage.
  • Combination of TLR8 and TLR4 agonists reduces the degrading effects of
           nicotine on DC-NK mediated effector T cell generation
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Mahyar Nouri-Shirazi, Saba Tamjidi, Erika Nourishirazi, Elisabeth Guinet The magnitude of immune responses to vaccination is a critical factor in determining protection from disease. It is known that cigarette smoke dampens the immune system and increases the risk of vaccine-preventable diseases. We reported that nicotine, the immunosuppressive component of cigarette smoke, disrupts the differentiation and functional properties of DC, which are pivotal in the initiation of immune response to vaccines. We also reported that TLR agonists act in synergy and boost DC maturation, DC-NK crosstalk and ultimately naïve T cell polarization into effector Th1 and Tc1 cells. Here, we investigated whether the combination of TLR agonists could diminish the degrading effects of nicotine on DC-NK mediated effector T cell generation.We found that none of TLR agonists, single or combined, were able to diminish completely the adverse effects of nicotine on DC. However, TLR3, TLR4, and TLR8 agonists acted as the most effective adjuvants to increase the expression levels of antigen-presenting, costimulatory molecules and production of cytokines by nicotine-exposed DC (nicDC). When combined, TLR3 + 8 and TLR4 + 8 synergistically optimized nicDC maturation and IFN-γ secretion from nicotine-exposed NK (nicNK) during co-cultures. Interestingly, in contrast to DC-NK-T, co-cultures of nicDC-nicNK-T treated with TLR3 + 8 or TLR4 + 8 agonists produced a similar frequency of effector memory Th1 and Tc1 cells. However, the effector cells from TLR4 + 8 followed by TLR3 + 8 treated nicDC-nicNK-T co-cultures produced significantly more IFN-γ when compared with aluminum salt treated co-culture. Our data suggest that addition of appropriate TLR agonists to vaccine formulation could potentially augment the immune response to vaccination in smokers.
  • Combination of 4-hydroperoxy cyclophosphamide and methotrexate inhibits
           IL-6/sIL-6R-induced RANKL expression in fibroblast-like synoviocytes via
           suppression of the JAK2/STAT3 and p38MAPK signaling pathway
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Hong-Qing Niu, Wen-Peng Zhao, Xiang-Cong Zhao, Jing Luo, Kai-Li Qin, Kai-Lin Chen, Xiao-Feng Li Although conventional combination therapy is effective for most patients with rheumatoid arthritis (RA), many still do not respond to current therapies. Therefore, novel combination regimens that better target cellular processes involved in RA pathogenesis are required. Preliminary studies have demonstrated the beneficial effects of a combination of cyclophosphamide (CTX) and methotrexate (MTX) in models of RA. Using western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assays, and immunofluorescent staining, we demonstrated that the combination of 4-hydroperoxy CTX (4-H-CTX) and MTX inhibited the expression of receptor activator of nuclear factor-κB ligand (RANKL) in fibroblast-like synoviocytes (FLS) treated with the interleukin (IL)-6/soluble IL-6 receptor (sIL-6R) complex. To elucidate the mechanisms underlying this effect, we treated RA-FLS with the JAK2/STAT3 inhibitor AG490 or p38MAPK inhibitor SB203580. The results showed that IL-6/sIL-6R-induced RANKL upregulation required phosphorylation-mediated activation of STAT3 and p38 signaling, and that 4-H-CTX and/or MTX inhibited RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing JAK2/STAT3 and p38MAPK signaling. This study demonstrated for the first time the inhibitory effects of 4-H-CTX and MTX on RANKL expression in IL-6/sIL-6R-stimulated FLS via suppression of STAT3 and p38MAPK phosphorylation. These results identify promising therapeutic agents that might have clinical applications in patients with RA who are at high risk of bone erosion or do not respond well to conventional therapy.
  • DNA damage and telomere length shortening in the peripheral blood
           leukocytes of 20 years SM-exposed veterans
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Hossein Behboudi, Sakineh Kazemi Noureini, Tooba Ghazanfari, Sussan K. Ardestani Sulfur mustard (SM) is a vesicant chemical warfare agent, and a very potent alkylating agent. SM exerts its cytotoxicity via direct alkylation of biomacromolecules, and overproduction of reactive oxygen species (ROS). Previous studies have shown that SM-induced oxidative stress has adverse effects on antioxidant defense system, and damages lipids and proteins. The aim of this study was to investigate the effect of SM-induced oxidative stress on DNA damage, and cellular senescence in SM-exposed victims. For this purpose, MDA levels as a measure of oxidative stress in the serum, 8-oxo-dG content of the genomic DNA, and OGG1 expression as two biomarkers of oxidative DNA damage, as well as, telomere length, and p16INK4a expression as two biomarkers of cellular senescence were measured in the peripheral blood leukocytes of 215 males who were exposed to SM 20 to 25 years ago, and 53 unexposed healthy males as the control group. Our results indicated that the levels of 8-oxo-dG, and OGG1 mRNA expression were significantly higher in SM-exposed individuals. Furthermore, a significant increase in the expression of p16INK4a was observed in SM-exposed patients, and leukocyte telomere length (LTL) was also significantly shorter in severe/very severe cases of SM-exposed patients when compared with unexposed controls. In conclusion, our data indicate that oxidative DNA damage is higher in SM-exposed patients, and their immune system has subjected to cellular senescence.
  • The effect of natural antioxidants in cyclophosphamide-induced
           hepatotoxicity: Role of Nrf2/HO-1 pathway
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Iman O. Sherif Hepatotoxicity induced by cyclophosphamide (Cyclo) is a major concern in clinical practice. This study was designed to investigate the possible cytoprotective effect of natural antioxidants as oleuropein and quercetin against Cyclo induced hepatotoxicity via the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Male Wistar rats were randomly divided into six groups and treated for 10 days as follow: Group I (Normal control) received saline, group II (Oleu control): received orally oleuropein 30 mg/kg/day, group III (Quer control): administered orally quercetin 50 mg/kg/day, group IV (Cyclo): received saline and injected with single intraperitoneal (i.p) dose of Cyclo 200 mg/kg at day 5, group V (Oleu ttt): treated with oleuropein plus Cyclo i.p. injection at day 5, and group VI (Quer ttt): treated with quercetin plus Cyclo i.p. injection at day 5. Injection of Cyclo showed marked increase in serum transaminases and alkaline phosphatase, hepatic malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-⍺) levels along with significant reduction in hepatic reduced glutathione (GSH), superoxide dismutase (SOD), and catalase levels in addition to downregulation of hepatic Nrf2 and HO-1 expressions and reduction in hepatic nuclear Nrf2 binding activity when compared with normal group. Histopathological examination of Cyclo treated rats revealed hepatic damage. Both oleuropein and quercetin exhibited an improvement in the biochemical and histopathological findings. In conclusion, the natural antioxidants oleuropein and quercetin counteract the Cyclo induced hepatotoxicity through activation of Nrf2/HO-1 signaling pathway with subsequent suppression of oxidative stress and inflammation.
  • Inhibition of acetaminophen-induced hepatotoxicity in mice by exogenous
           thymosinβ4 treatment
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Lei Wang, Xiankui Li, Cai Chen ObjectiveTo study the effects of exogenous thymosinβ4 (Tβ4) treatment in acetaminophen (APAP)-induced hepatotoxicity.MethodsLiver injury was induced in mice by a single intraperitoneal injection of APAP (500 mg/kg). Exogenous Tβ4 was intraperitoneally administrated at 0 h, 2 h and 4 h after APAP injection. Chloroquine (CQ) (60 mg/kg) was intraperitoneally injected 2 h before APAP administration to inhibit autophagy. Six hours after APAP injection liver injury was evaluated by histological examinations, biochemical measurements and enzyme linked immunosorbent assay (ELISAs). Western blots were performed to detect proteins expression.ResultsSerum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were significantly increased 6 h after APAP administration, but were significantly reduced by co-administration of Tβ4. Histological examinations demonstrated that Tβ4 reduced necrosis and inflammation induced by APAP. Immunofluorescence showed that Tβ4 suppressed APAP-induced translocation of high mobility group box-1 protein (HMGB1) from the nucleus to cytosol and intercellular space. Hepatic glutathione (GSH) depletion, malondialdehyde (MDA) formation and decreased superoxide dismutase (SOD) activities induced by APAP were all attenuated by Tβ4. APAP-induced increases in hepatic nuclear factor-κB (NF-κB) p65 protein expression and inflammatory cytokines production including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were reduced by Tβ4 treatment. Increased LC3 and p62 proteins in the liver tissues of APAP-treated mice were decreased by Tβ4 treatment, which indicated the enhancement of autophagy flux by Tβ4. Furthermore, inhibiting autophagy by CQ abrogated the protective effects of Tβ4 against APAP hepatotoxicity.ConclusionExogenous Tβ4 treatment exerts protective effects against APAP-induced hepatotoxicity in mice. The underneath molecular mechanisms may involve autophagy enhancement and inhibition of oxidative stress by Tβ4.
  • Renoprotective effect of the isoflavonoid biochanin A against cisplatin
           induced acute kidney injury in mice: Effect on inflammatory burden and p53
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Faiha A. Suliman, Dina M. Khodeer, Afaf Ibrahiem, Eman T. Mehanna, Mohamed K. El-Kherbetawy, Hala M.F. Mohammad, Sawsan A. Zaitone, Yasser M. Moustafa Cisplatin is a potent widely-used chemotherapeutics; however, its clinical use is associated with nephrotoxicity. Renoprotective approaches are being discovered to halt the tubular cell death due to inflammatory and apoptotic burdens. In the present study, the renoprotective effects of different doses of biochanin A (10, 20 or 40 mg/kg) in mice treated with a single injection of cisplatin (10 mg/kg) were reported. Cisplatin administration resulted in marked increases in serum creatinine and blood urea nitrogen. Further, renal homogenates showed increased level of inflammatory cytokines and upregulation of the expression of p53 up-regulated modulator of apoptosis (PUMA), p53 and caspase 3 but downregulation in Nrf2 expression. Furthermore, cisplatin group showed marked necrosis and degenerated tubular lining epithelial cells with frequently detected apoptotic bodies. Mice treated with biochanin A (10, 20 or 40 mg/kg) for 14 days prior to cisplatin abrogated cisplatin-mediated damage. Furthermore, the elevated serum creatinine and urea levels were lessened by some doses of biochanin A, indicating protection against renal injury. Similarly, the changes in apoptosis and inflammatory markers have ameliorated to significant levels (P 
  • Curcumin attenuates sepsis-induced acute organ dysfunction by preventing
           inflammation and enhancing the suppressive function of Tregs
    • Abstract: Publication date: August 2018Source: International Immunopharmacology, Volume 61Author(s): Longwang Chen, Yang Lu, Linjun Zhao, Lili Hu, Qiaomeng Qiu, Zhuoling Zhang, Mengfang Li, Guangliang Hong, Bing Wu, Guangju Zhao, Zhongqiu Lu Sepsis is characterized by the extensive release of cytokines and other mediators. It results in a dysregulated immune response and can lead to organ damage and death. Curcumin has anti-inflammatory properties and immunoregulation functions in various disorders such as sepsis, cancer, rheumatoid arthritis, cardiovascular diseases, lung fibrosis, gallstone formation, and diabetes. This paper investigates the effects of curcumin on immune status and inflammatory response in mice subjected to cecal ligation and puncture (CLP). Inflammatory tissue injury was evaluated by histological observation. Magnetic microbeads were used to isolate splenic CD4+CD25+regulatory T cells (Tregs), and phenotypes were then analyzed by flow cytometry. The levels of Foxp3 were detected by Western blot and real-time PCR and cytokine levels were determined by enzyme-linked immunosorbent assay. We found that the administration of curcumin significantly alleviated inflammatory injury of the lung and kidney in septic mice. The suppressive function of Treg cells was enhanced and the plasma levels of IL-10 increased after treatment with curcumin. Furthermore, the secretion of plasma TNF-α and IL-6 was notably inhibited in septic mice treated with curcumin and administration with curcumin could improve survival after CLP. These data suggest that curcumin could be used as a potential therapeutic agent for sepsis.
  • Corrigendum to “Emodin ameliorates ulcerative colitis by the
           flagellin-TLR5 dependent pathway in mice” [Int. Immunopharmacol. 59
           (2018) 269–275]
    • Abstract: Publication date: Available online 6 July 2018Source: International ImmunopharmacologyAuthor(s): Shuang Luo, Xiangliang Deng, Qi Liu, Zengfeng Pan, Zhongxiang Zhao, Lian Zhou, Xia Luo
  • Quercetin in collagen-induced arthritis. Some comments
    • Abstract: Publication date: Available online 30 June 2018Source: International ImmunopharmacologyAuthor(s): Salvatore Chirumbolo, Geir Bjørklund
  • Corrigendum to “Endocytosis of particulate matter induces cytokine
           production by neutrophil via toll-like receptor 4” [Int. Immunol. 57
           (2018) 190–199]
    • Abstract: Publication date: Available online 29 June 2018Source: International ImmunopharmacologyAuthor(s): Tadahiro Miyake, Duo Wang, Hidetada Matsuoka, Kentaro Morita, Hiroshi Yasuda, Kazuhiro Yatera, Tamotsu Kanazawa, Yasuhiro Yoshida
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