Inhibitors of tumour necrosis factor (TNF) are among the most successful protein-based drugs (biologics) and have proven to be clinically efficacious at reducing inflammation associated with several autoimmune diseases. As a result, attention is focusing on the therapeutic potential of additional members of the TNF superfamily of structurally related cytokines. Many of these TNF-related cytokines or their cognate receptors are now in preclinical or clinical development as possible targets for modulating inflammatory diseases and cancer as well as other indications. This Review focuses on the biologics that are currently in clinical trials for immune-related diseases and other syndromes, discusses the successes and failures to date as well as the expanding therapeutic potential of modulating the activity of this superfamily of molecules.
"The inhibition of TNF-α is an emerging and promising strategy to overcome chronic inflammatory processes in human diseases like rheumatoid arthritis and inflammatory bowel diseases (Laveti et al., 2013). Indeed, several TNF-α inhibitors have been proven to be clinically effective (Croft et al., 2013). Presently, commercially available anti-TNF-α drugs are immunobiological which require intra-articular administration and are costly (Khanna et al., 2007). "
"The tumor necrosis factor-(TNF-) í µí»¼ is a key proinflammatory cytokine that mediates apoptosis, inflammation, and immunity and is believed to play a role in various chronic inflammatory diseases including RA, psoriasis, inflammatory bowel disease (IBD), diabetes, cancer, and sepsis   . "
[Show abstract][Hide abstract] ABSTRACT: Several plant species are traditionally used in Brazil to treat various inflammatory diseases. Tumor necrosis factor- (TNF-) α and chemokine (C-C motif) ligand 2 (CCL2) are key inflammatory mediators in diseases like rheumatoid arthritis and atherosclerosis, respectively; nevertheless, only a few extracts have been assayed against these targets. We herein report the effect of 19 plant extracts on TNF-α and CCL2 release by lipopolysaccharide- (LPS-) stimulated THP-1 cells, a human monocytic leukemia cell line, along with their radical scavenging activity on DPPH. The extracts of Caryocar brasiliense, Casearia sylvestris, Coccoloba cereifera, and Terminalia glabrescens inhibited TNF-α production in a concentration-dependent manner. Fractionation of these extracts potentiated the anti-TNF-α effect, which was shown to concentrate in polar fractions, mainly composed by polyphenols. Significant CCL2 inhibition was elicited by Lippia sidoides and Terminalia glabrescens extracts, whose fractionation resulted in highly active low polar fractions. All assayed extracts showed strong radical scavenging activity, but antioxidant activity did not correlate with inhibition of TNF-α or CCL2 production. Our results allowed identifying extracts with selective capacity to block cytokine production; therefore, further purification of these extracts may yield molecules that could be useful in the treatment of chronic inflammatory diseases.
Evidence-based Complementary and Alternative Medicine 04/2015; 2015:497123. DOI:10.1155/2015/497123 · 1.88 Impact Factor
"Equipped with a tool that distinguishes stem from non-stem cells and knowing that chronic inflammation predisposes tissues to cancer [9,13], we aimed to determine whether inflammation affects the SC pool in melanoma, thus providing a missing link between inflammation and tumor development. The most prominent and best-characterized pro-inflammatory cytokine present in the site of inflammation is TNF [24,25], and reversible quiescence is one of the hallmarks of SCs. TNF dramatically decreased the proportion of melanosphere cells resting in the quiescent G0 phase of the cell cycle, reaching the level of adherent monolayer cultures (Figure 3A). "
[Show abstract][Hide abstract] ABSTRACT: Background
It is well established that inflammation promotes cancer, including melanoma, although the exact mechanisms involved are less known. In this study, we tested the hypothesis that inflammatory factors affect the cancer stem cell (CSC) compartment responsible for tumor development and relapse.ResultsUsing an inducible histone 2B-GFP fusion protein as a tracer of cell divisional history, we determined that tumor necrosis factor (TNF), which is a classical pro-inflammatory cytokine, enlarged the CSC pool of GFP-positive label-retaining cells (LRCs) in tumor-like melanospheres. Although these cells acquired melanoma stem cell markers, including ABCB5 and CD271, and self-renewal ability, they lost their capacity to differentiate, as evidenced by the diminished MelanA expression in melanosphere cells and the loss of pigmentation in a skin equivalent model of human melanoma. The undifferentiated cell phenotype could be reversed by LY294002, which is an inhibitor of the PI3K/AKT signaling pathway, and this reversal was accompanied by a significant reduction in CSC phenotypic markers and functional properties. Importantly, the changes induced by a transient exposure to TNF were long-lasting and observed for many generations after TNF withdrawal.Conclusions
We conclude that pro-inflammatory TNF targets the quiescent/slow-cycling melanoma SC compartment and promotes PI3K/AKT-driven expansion of melanoma SCs most likely by preventing their asymmetrical self-renewal. This TNF effect is maintained and transferred to descendants of LRC CSCs and is manifested in the absence of TNF, suggesting that a transient exposure to inflammatory factors imprints long-lasting molecular and/or cellular changes with functional consequences long after inflammatory signal suppression. Clinically, these results may translate into an inflammation-triggered accumulation of quiescent/slow-cycling CSCs and a post-inflammatory onset of an aggressive tumor.
Cell Communication and Signaling 09/2014; 12(1):52. DOI:10.1186/PREACCEPT-1668207151340493 · 3.38 Impact Factor
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