ABSTRACT
Rheumatoid arthritis(RA) is a debilitating chronic inflammatory disease. Suppressors of Cytokine Signaling(SOCS) proteins regulate homeostasis and pathogenesis in several diseases. The intersection between RA pathophysiology and SOCS2 is unclear. Herein, we investigated the roles of SOCS2 during the development of an experimental antigen-induced arthritis(AIA). In wild type mice, joint SOCS2 expression was reduced during AIA development. At the peak of inflammation, SOCS2-/- mice presented with reduced numbers of infiltrated cells in their joints. At the late phase of AIA, however, exhibited increased adhesion/infiltration of neutrophils, macrophages, CD4+-T cells, CD4+CD8+-T cells, and CD4-CD8--T cells associated with elevated IL-17 and IFN-γ levels, joint damage, proteoglycan loss, and nociception. SOCS2 deficiency resulted in lower numbers of apoptotic neutrophils and reduced efferocytosis. The present study demonstrated the vital role of SOCS2 during the development and resolution of an experimental RA model. Hence, this protein may be a novel therapeutic target for this disorder.
Subject(s)
Arthritis, Experimental/etiology , Suppressor of Cytokine Signaling Proteins/immunology , Adaptive Immunity , Animals , Arthritis, Experimental/immunology , Arthritis, Experimental/pathology , Cell Adhesion , Disease Progression , Endocytosis/immunology , Immunity, Innate , Leukocytes/immunology , Leukocytes/pathology , Macrophages/immunology , Macrophages/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Spleen/immunology , Spleen/pathology , Suppressor of Cytokine Signaling Proteins/deficiency , Suppressor of Cytokine Signaling Proteins/geneticsABSTRACT
The World Health Organization (WHO) has been warning about the importance of developing new drugs against superbugs. Antimicrobial peptides are an alternative in this context, most of them being involved in innate immunity, acting in various ways, and some even showing synergism with commercial antimicrobial agents. LyeTx I-b is a synthetic peptide derived from native LyeTx I, originally isolated from Lycosa erythrognatha spider venom. Although LyeTx I-b is active against several multidrug-resistant bacteria, it shows some hemolytic and cytotoxic effects. To overcome this hindrance, in the present study we PEGylated LyeTx I-b and evaluated its toxicity and in vitro and in vivo activities on pneumonia caused by multi-resistant Acinetobacter baumannii. PEGylated LyeTx I-b (LyeTx I-bPEG) maintained the same MIC value as the non- PEGylated peptide, showed anti-biofilm activity, synergistic effect with commercial antimicrobial agents, and did not induce resistance. Moreover, in vivo experiments showed its activity against pneumonia. Additionally, LyeTx I-bPEG reduced hemolysis up to 10 times, was approximately 2 times less cytotoxic to HEK-293 cells and 4 times less toxic to mice in acute toxicity models, compared to LyeTx I-b. Our results show LyeTx I-bPEG as a promising antimicrobial candidate, significantly active against pneumonia caused by multidrug-resistant A. baumannii.
Subject(s)
Acinetobacter baumannii , Antimicrobial Cationic Peptides , Peptide Fragments , Pneumonia , Animals , Carbapenems , Drug Resistance, Bacterial , Drug Synergism , Gentamicins/pharmacology , HEK293 Cells , Humans , Mice , Microbial Sensitivity Tests , Peptide Fragments/pharmacology , Peptides , Polyethylene Glycols , Receptors for Activated C KinaseABSTRACT
trans-Aconitic acid (TAA) is the main constituent of the leaves from the medicinal plant Echinodorus grandiflorus, used to treat different inflammatory diseases. TAA induces a potent but short-lasting biological response, credited to its high polarity and unfavorable pharmacokinetics. Here we developed, characterized and evaluated the anti-inflammatory activity of mucoadhesive microspheres loaded with TAA. Seven batches of mucoadhesive microspheres were prepared by the emulsification/solvent evaporation method, employing different proportions of TAA and Carbopol 934 or/and hydroxypropylmethylcellulose. All batches were characterized for their particle medium size, polydispersity index and entrapment percentage. The batch coded F3c showed highest entrapment percentage and was characterized by infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermogravimetric analyses (TGA) and zeta potential. The anti-inflammatory activity of F3c was assessed in a model of acute arthritis induced by injection of LPS in the knee joint of Swiss mice. The granulometric analyses indicated heterogeneous size distribution for F3c. SEM characterization indicated microspheres with slightly irregular shape and rough surface. Results from ATR-FTIR and thermal analyses (DSC and TGA) pointed out absence of incompatibility between the components of the formulation; thermal events related to the constituents were isolated and randomly located, suggesting amorphous distribution of TAA in the formulation matrix. The zeta potential of the formulations varied from -30 to -34â¯mV, which may contribute to good stability. When given orally to mice, F3c induced a prolonged anti-inflammatory response by reducing total cell count and neutrophilic accumulation in the joint cavity even when given 48 and 36â¯h before the stimulus, respectively, in comparison to free TAA (up to 24 and 6â¯h, respectively). Therefore, the encapsulation of TAA in mucoadhesive microspheres provided its sustained release, indicating that this drug delivery system is a potential agent to treat inflammatory diseases by regulating cell influx.
