Exosomes as a novel cell-free therapeutic approach in gastrointestinal diseases

Cell communication through extracellular vesicles (EVs) has been defined for many years and it is not limited only to neighboring cells, but also distant ones in organisms receive these signals. These vesicles are secreted from the variety of cells and are composed of a distinctive component such as proteins, lipids, and nucleic acids. EVs have different classified subgroups regarding their cell origin, in this context, exosomes are the most appealing particles in cell biology, especially clinical in recent years and are represented as novel therapeutic agents with numerous advantages alongside and/or over cell therapy. However, cell therapy had a hopeful outcome in gastrointestinal diseases which have minimal alternatives in their treatments. Inflammatory bowel disease (IBD), liver fibrosis, gastrointestinal cancers are the examples that cell therapy and immunotherapy were applied in their treatment, therefore, the cell products like exosomes are the beneficial option in their treatment even cancers with promising results in animal models. In this review, we consider the main defined biogenesis, function, and component of secreted exosomes in different cells with a specific focus on the potential application of these exosomes as a cell-free therapeutic approach in gastrointestinal diseases like IBD, gastric cancer, and colon cancer. Additionally, exosomes role as therapeutic reagents mainly mesenchymal stem cells and dendritic cell-derived exosomes in different studies have been under intense investigation and even they are being studied in different clinical trials. Therefore, all these striking functions described for secretome implies the importance of these biocarriers.     

Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis

Dimethyl fumarate (DMF) is an important oral treatment option for various autoimmune diseases, such as multiple sclerosis (MS) and psoriasis. DMF and its dynamic metabolite, monomethyl fumarate (MMF) are the major compounds that exert therapeutic effects on several pathologic conditions in part, through downregulation of immune responses. The exact mechanism of DMF is yet to be fully understood even though its beneficial effects on the immune system are extensively studied. It has been shown that DMF/MMF can affect various immune cells, which can get involved in both the naive and adaptive immune systems, such as T cells, B cells, dendritic cells, macrophages, neutrophils, and natural killer cells. It is suggested that DMF/MMF may exert their effect on immune cells through inhibition of nuclear factor-κB translocation, upregulation of nuclear factor erythroid-derived 2(E2)-related factor antioxidant pathway, and activation of hydroxyl carboxylic acid receptor 2. In this review, the mechanisms underlying the modulatory functions of DMF or MMF on the main immune cell populations involved in the immunopathogenesis of MS are discussed.     

Diagnostic biomarker and therapeutic target applications of miR-326 in cancers: A systematic review

MicroRNAs (miRNAs) are endogenous mediators of RNA interference and have key roles in the modulation of gene expression under healthy, inflamed, stimulated, carcinogenic, or other cells, and tissues of a pathological state. Many studies have proved the association between miRNAs and cancer. The role of miR-326 as a tumor suppressor miRNA in much human cancer confirmed. We will explain the history and the role of miRNAs changes, especially miR-326 in cancers and other pathological conditions. Attuned with these facts, this review highlights recent preclinical and clinical research performed on miRNAs as novel promising diagnostic biomarkers of patients at early stages, prediction of prognosis, and monitoring of the patients in response to treatment. All related publications retrieved from the PubMed database, with keywords such as epigenetic, miRNA, microRNA, miR-326, cancer, diagnostic biomarker, and therapeutic target similar terms from 1899 to 2018 with limitations in the English language. Recently, researchers have focused on the impacts of miRNAs and their association in inflammatory, autoinflammatory, and cancerous conditions. Recent studies have suggested a major pathogenic role in cancers and autoinflammatory diseases. Investigations have explained the role of miRNAs in cancers, autoimmunity, and autoinflammatory diseases, and so on. The miRNA-326 expression has an important role in cancer conditions and other diseases.     

Inflammation and pericarditis: Are neutrophils actors behind the scenes?

The morbidity of acute pericarditis is increasing over time impacting on patient quality of life. Recent clinical trials focused especially on clinical aspects, with a modest interest in pathophysiological mechanisms. This narrative review, based on papers in English language obtained via PubMed up to April 2018, aims at focusing on the role of the innate immunity in pericarditis and discussing future potential therapeutic strategies impacting on disease pathophysiology. In developed countries, most cases of pericarditis are referred to as idiopathic, although etiological causes have been described, with autoreactive/lymphocytic, malignant, and infectious ones as the most frequent causes. Apart the known impairment of the adaptive immunity, recently a large body evidence indicated the central role of the innate immune system in the pathogenesis of recurrent pericarditis, starting from similarities with autoinflammatory diseases. Accordingly, the “inflammasome” has been shown to behave as an important player in pericarditis development. Similarly, the beneficial effect of colchicine in recurrent pericarditis confirms that neutrophils are important effectors as colchicine, which can block neutrophil chemotaxis, interferes with neutrophil adhesion and recruitment to injured tissues and abrogate superoxide production. Anyway, the role of the adaptive immune system in pericarditis cannot be reduced to a black or white issue as mechanisms often overlap. Therefore, we believe that more efficient therapeutic strategies have to be investigated by targeting neutrophil-derived mediators (such as metalloproteinases) and disentangling the strict interplay between neutrophils and platelets. In this view, some progress has been done by using the recombinant human interleukin-1 receptor antagonist anakinra.     

Machado–Joseph disease/spinocerebellar ataxia type 3: lessons from disease pathogenesis and clues into therapy

This editorial highlights a study by Rodriguez, Sanchez‐Moran et al. (2019) in the current issue of the Journal of Neurochemistry, in which the authors describe a microcephalic boy carrying the novel heterozygous de novo missense mutation c.560A> G; p.Asp187Gly in Cdh1/Fzr1 encoding the APC/C E3‐ubiquitin ligase cofactor CDH1. A functional characterization of mutant APC/C^CDH1 confirms an aberrant division of neural progenitor cells, a condition known to determine the mouse brain cortex size. These data suggest that APC/C^CDH1 may contribute to the regulation of the human brain size.

     

The cis-Regulatory Atlas of the Mouse Immune System

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Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases

The chemokine receptor CXCR2 and its ligands are implicated in the progression of tumours and various inflammatory diseases. Activation of the CXCLs/CXCR2 axis activates multiple signalling pathways, including the PI3K, p38/ERK, and JAK pathways, and regulates cell survival and migration. The CXCLs/CXCR2 axis plays a vital role in the tumour microenvironment and in recruiting neutrophils to inflammatory sites. Extensive infiltration of neutrophils during chronic inflammation is one of the most important pathogenic factors in various inflammatory diseases. Chronic inflammation is considered to be closely correlated with initiation of cancer. In addition, immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) against T cells attenuate the anti-tumour effects of T cells and promote tumour invasion and metastasis. Over the last several decades, many therapeutic strategies targeting CXCR2 have shown promising results and entered clinical trials. In this review, we focus on the features and functions of the CXCLs/CXCR2 axis and highlight its role in cancer and inflammatory diseases. We also discuss its potential use in targeted therapies.     

Mesenchymal stem cells improve platelet counts in mice with immune thrombocytopenia

Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder. The breakdown of immune tolerance (regulatory T [Treg] cells and suppressor cytokines) plays an important role in ITP pathophysiology, especially in refractory ITP. Bone marrow–derived mesenchymal stem cells (BM-MSCs) show immunomodulatory properties and have been extensively utilized for autoimmune diseases. However, it has not been fully elucidated how BM-MSCs affect ITP. In this study, we explore the therapeutic mechanism of BM-MSCs on ITP in mice. Dose-escalation passive ITP mice were inducted by injection of MWReg30. BALB/c mice were randomly divided into two groups: ITP with BM-MSC transplantation and ITP controls. The serum levels of cytokines (interleukin 10 [IL-10] and transforming growth factor-β1 [TGF-β1]) were examined by enzyme-linked immunosorbent assays. The frequency of Treg cells in both peripheral blood and spleen mononuclear cells was analyzed by flow cytometry, and the forkhead box P3 (Foxp3) messenger RNA (mRNA) level was measured by real-time polymerase chain reaction. After BM-MSC treatment, the platelet (PLT) counts were significantly elevated. Meanwhile, cytokines (TGF-β1 and IL-10), the ratios of Treg cells, and the Foxp3 mRNA expression level were significantly higher in the BM-MSC group. Our results show that BM-MSCs can improve PLT counts mainly by secreting suppressive cytokines and upregulating Tregs, which may provide new therapeutic potential for human ITP.     

Downregulation of microRNA-214 improves therapeutic potential of allogeneic bone marrow–derived mesenchymal stem cell by targeting PIM-1 in rats with acute liver failure

Acute liver failure (ALF) is a disease resulted from diverse etiology, which generally leads to a rapid degenerated hepatic function. However, transplantation bone marrow–derived mesenchymal stem cells (BMSCs) transplantation has been suggested to relieve ALF. Interestingly, microRNA-214 (miR-214) could potentially regulate differentiation and migration of BMSCs. The present study aims to inquire whether miR-214 affects therapeutic potential of BMSCs transplantation by targeting PIM-1 in ALF. 120 male Wistar rats were induced as ALF model rats and transplanted with BMSCs post-alteration of miR-214 or PIM-1 expression. Further experiments were performed to detect biochemical index (alanine aminotransferase [ALT], aspartate transaminase [AST], total bilirubin [TBiL]), and expression of miR-214, PIM-1, hepatocyte growth factor (HGF), caspase 3, tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) in rat serum. Apart from the above detection, apoptosis of hepatocytes and Ki67 protein expression in hepatic tissues of rats were additionally assessed. After BMSCs transplantation with miR-214 inhibition, a decreased expression of ALT, AST, and TBiL yet an increased expression of HGF was shown, coupled with a decline in the expression of caspase 3, TNF-α, and IL-10. Meanwhile, alleviated hepatic injury and decreased apoptotic index of hepatic cells were observed and the positive rate of Ki67 protein expression was significantly increased. Moreover, miR-214 and caspase 3, TNF-α, and IL-10 decreased notably, while PIM-1 was upregulated in response to miR-214 inhibition. Strikingly, the inhibition of PIM-1 reversed effects triggered by miR-214 inhibition. These findings indicated that downregulation of miR-214 improves therapeutic potential of BMSCs transplantation by upregulating PIM-1 for ALF.