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Special Issue "Tumor Necrosis Factor (TNF) II"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 29 February 2020.

Special Issue Editor

Guest Editor
Prof. Dr. Daniela Basso Website E-Mail
Laboratory Medicine, Department of Medicine—DIMED, University of Padova, Via Giustiniani 2, 35128 Padova, Italy

Special Issue Information

Dear Colleagues,

Tumor Necrosis Factor (TNF) and its receptors TNFR1 and TNFR2 are the best-characterized members of the TNFSF and TNFRSF superfamilies, which include, to date, 19 ligands and 29 receptors. TNFSF members have in common the ability to promote pro-inflammatory signals, but they might regulate other cellular functions, such as cell-to-cell communication, differentiation, survival, apoptosis, and necroptosis. TNF activates several intracellular signaling pathways, including NF-kB, JNK, apoptosis (caspase 8 activation), and necroptosis (phosphorylation of RIPK1, RIPK3, and MLKL), of which constant balance regulates the opposite cell fates proliferation and death.

TNF, which is mainly produced by macrophages, NK, and Th1 T lymphocytes, plays a central role in innate and adaptive immunity and in chronic inflammatory diseases, such as those of the joints, including rheumatoid arthritis and spondiloarthris, and those of the intestine, namely the inflammatory bowel diseases. Chronic inflammation, including the TNF–TNFR pathway’s activation, is increasingly being recognized as involved in cancer, obesity, diabetes, cardiovascular diseases, and neurodegenerative disorders. Five drugs blocking TNF–TNFR signaling have been approved for the therapy of chronic inflammatory rheumatic and intestinal diseases. However, the number of these drugs and the number of individuals with diseases that might benefit from this type of treatment, are expected to increase greatly in the near future. This Special Issue on “Tumor Necrosis Factor (TNF)” aims to address the biology of the TNF–TNFR pathway and present the newest knowledge on its role in diseases characterized by chronic inflammation and on established and emerging therapies that target TNF signaling.

Prof. Dr. Daniela Basso
Guest Editor

Manuscript Submission Information

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Keywords

  • Tumor Necrosis Factor (TNF);
  • TNF receptors;
  • Inflammation;
  • Signaling;
  • Arthritis;
  • Cancer;
  • Metabolic syndrome;
  • Anti-TNF agents.

Published Papers (2 papers)

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Research

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Open AccessArticle
Mechanism of Action of the Tumor Vessel Targeting Agent NGR-hTNF: Role of Both NGR Peptide and hTNF in Cell Binding and Signaling
Int. J. Mol. Sci. 2019, 20(18), 4511; https://doi.org/10.3390/ijms20184511 - 12 Sep 2019
Abstract
NGR-hTNF is a therapeutic agent for a solid tumor that specifically targets angiogenic tumor blood vessels, through the NGR motif. Its activity has been assessed in several clinical studies encompassing tumors of different histological types. The drug’s activity is based on an improved [...] Read more.
NGR-hTNF is a therapeutic agent for a solid tumor that specifically targets angiogenic tumor blood vessels, through the NGR motif. Its activity has been assessed in several clinical studies encompassing tumors of different histological types. The drug’s activity is based on an improved permeabilization of newly formed tumor vasculature, which favors intratumor penetration of chemotherapeutic agents and leukocyte trafficking. This work investigated the binding and the signaling properties of the NGR-hTNF, to elucidate its mechanism of action. The crystal structure of NGR-hTNF and modeling of its interaction with TNFR suggested that the NGR region is available for binding to a specific receptor. Using 2D TR-NOESY experiments, this study confirmed that the NGR-peptides binds to a specific CD13 isoform, whose expression is restricted to tumor vasculature cells, and to some tumor cell lines. The interaction between hTNF or NGR-hTNF with immobilized TNFRs showed similar kinetic parameters, whereas the competition experiments performed on the cells expressing both TNFR and CD13 showed that NGR-hTNF had a higher binding affinity than hTNF. The analysis of the NGR-hTNF-triggered signal transduction events showed a specific impairment in the activation of pro-survival pathways (Ras, Erk and Akt), compared to hTNF. Since a signaling pattern identical to NGR-hTNF was obtained with hTNF and NGR-sequence given as distinct molecules, the inhibition observed on the survival pathways was presumably due to a direct effect of the NGR-CD13 engagement on the TNFR signaling pathway. The reduced activation of the pro survival pathways induced by NGR-hTNF correlated with the increased caspases activation and reduced cell survival. This study demonstrates that the binding of the NGR-motif to CD13 determines not only the homing of NGR-hTNF to tumor vessels, but also the increase in its antiangiogenic activity. Full article
(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) II)
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Review

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Open AccessReview
Different Original and Biosimilar TNF Inhibitors Similarly Reduce Joint Destruction in Rheumatoid Arthritis—A Network Meta-Analysis of 36 Randomized Controlled Trials
Int. J. Mol. Sci. 2019, 20(18), 4350; https://doi.org/10.3390/ijms20184350 - 05 Sep 2019
Abstract
The effect of five approved tumour necrosis factor inhibitors (TNFi: infliximab, etanercept, adalimumab, certolizumab, and golimumab) on joint destruction in rheumatoid arthritis (RA) have been compared versus methotrexate (MTX) in randomized controlled trials (RCTs) but have not been compared directly to each other [...] Read more.
The effect of five approved tumour necrosis factor inhibitors (TNFi: infliximab, etanercept, adalimumab, certolizumab, and golimumab) on joint destruction in rheumatoid arthritis (RA) have been compared versus methotrexate (MTX) in randomized controlled trials (RCTs) but have not been compared directly to each other or to an otherwise untreated placebo control. The present analysis compares effects of standard doses, high doses, and low doses of TNFis on radiographic joint destruction in RA and relate these effects to MTX and placebo by means of a Bayesian network meta-analysis. We identified 31 RCTs of the effect of TNFis on joint destruction and 5 RCTs with controls, which indirectly could link otherwise untreated placebo controls to the TNFi treatments in the network. The previously untested comparison with placebo was performed to estimate not only the effect relative to another drug, but also the absolute attainable effect. Compared to placebo there was a highly significant inhibitory effect on joint destruction of infliximab, etanercept, adalimumab, certolizumab, and golimumab, which was about 0.9% per year as monotherapy and about 1.2% per year when combined with MTX. Although significantly better than MTX and placebo, golimumab seemed inferior to the remaining TNFis. There was no difference between original reference drugs (Remicade, Enbrel) and the almost identical copy drugs (biosimilars). Full article
(This article belongs to the Special Issue Tumor Necrosis Factor (TNF) II)
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