The interferon (IFN)‐induced double‐stranded RNA (dsRNA)‐activated Ser/Thr protein kinase (PKR) plays a role in the antiviral and antiproliferative effects of IFN. PKR phosphorylates initiation factor eIF2α, thereby inhibiting protein synthesis, and also activates the transcription factor, nuclear factor‐κB (NF‐κB), by phosphorylating the inhibitor of NF‐κB, IκB. Mice devoid of functional PKR (Pkr^°/°) derived by targeted gene disruption exhibit a diminished response to IFN‐γ and poly(rI:rC) (pIC). In embryo fibroblasts derived from Pkr^°/° mice, interferon regulatory factor 1 (IRF‐1) or guanylate binding protein (Gbp) promoter–reporter constructs were unresponsive to IFN‐γ or pIC but response could be restored by co‐transfection with PKR. The lack of responsiveness could be attributed to a diminished activation of IRF‐1 and/or NF‐κB in response to IFN‐γ or pIC. Thus, PKR acts as a signal transducer for IFN‐stimulated genes dependent on the transcription factors IRF‐1 and NF‐κB.

Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs). It becomes clinically apparent in >30% of patients with Crohn's disease (CD) and in about 5% with ulcerative colitis (UC). Fibrosis is a consequence of local chronic inflammation and is characterized by excessive extracellular matrix (ECM) protein deposition. ECM is produced by activated myofibroblasts, which are modulated by both, profibrotic and antifibrotic factors. Fibrosis depends on the balance between the production and degradation of ECM proteins. This equilibrium can be impacted by a complex and dynamic interaction between profibrotic and antifibrotic mediators. Despite the major therapeutic advances in the treatment of active inflammation in IBD over the past two decades, the incidence of intestinal strictures in CD has not significantly changed as the current anti-inflammatory therapies neither prevent nor reverse the established fibrosis and strictures. This implies that control of intestinal inflammation does not necessarily affect the associated fibrotic process. The conventional view that intestinal fibrosis is an inevitable and irreversible process in patients with IBD is also gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the mechanisms of intestinal fibrosis is thus vital and may pave the way for the developments of antifibrotic agents and new therapeutic approaches in IBD.

Fibrosis is a chronic and progressive disorder characterized by excessive deposition of extracellular matrix, which leads to scarring and loss of function of the affected organ or tissue. Indeed, the fibrotic process affects a variety of organs and tissues, with specific molecular background. However, two common hallmarks are shared: the crucial role of the transforming growth factor-beta (TGF-β) and the involvement of the inflammation process, that is essential for initiating the fibrotic degeneration. TGF-β in particular but also other cytokines regulate the most common molecular mechanism at the basis of fibrosis, the Epithelial-to-Mesenchymal Transition (EMT). EMT has been extensively studied, but not yet fully explored as a possible therapeutic target for fibrosis. A deeper understanding of the crosstalk between fibrosis and EMT may represent an opportunity for the development of a broadly effective anti-fibrotic therapy. Here we report the evidences of the relationship between EMT and multi-organ fibrosis, and the possible therapeutic approaches that may be developed by exploiting this relationship.

Members of the suppressor of cytokine signaling (SOCS) family of signaling molecules regulate the activation of cytokine signaling. Experimental evidence indicates that SOCS expression is induced by cytokines and pro-inflammatory stimuli and is controlled at both the transcriptional and post-transcriptional levels. SOCS proteins are unstable and seem to be rapidly degraded by proteasomal pathways. However, the mechanisms by which SOCS protein levels are regulated remain unclear. Here, we show that TRIM8/GERP, a RING finger protein, interacts with SOCS-1 in vitro andin vivo. TRIM8/GERP, previously identified as a new member of the family of proteins containing a tripartite motif (TRIM), is a 551-amino acid RING finger protein conserved across species. TRIM8/GERP expression can be induced by interferon-γ in epithelial and lymphoid cells. Coexpression of TRIM8/GERP with SOCS-1 decreases SOCS-1 protein stability and levels. Functionally, expression of TRIM8/GERP decreases the repression of interferon-γ signaling mediated by SOCS-1. These data suggest that TRIM8/GERP may be a regulator of SOCS-1 function.

Metabolic alterations have been observed in many cancer types. The deregulated metabolism has thus become an emerging hallmark of the disease, where the metabolism is frequently rewired to aerobic glycolysis. This has led to the concept of "metabolic reprogramming", which has therefore been extensively studied. Over the years, it has been characterized the enhancement of aerobic glycolysis, where key mutations in some of the enzymes of the TCA cycle, and the increased glucose uptake, are used by cancer cells to achieve a "metabolic phenotype" useful to gain a proliferation advantage. Many studies have highlighted in detail the signaling pathways and the molecular mechanisms responsible for the glycolytic switch. However, glycolysis is not the only metabolic process that cancer cells rely on. Oxidative Phosphorylation (OXPHOS), gluconeogenesis or the beta-oxidation of fatty acids (FAO) may be involved in the development and progression of several tumors. In some cases, these metabolisms are even more crucial than aerobic glycolysis for the tumor survival. This review will focus on the contribution of these alterations of metabolism to the development and survival of cancers. We will also analyze the molecular mechanisms by which the balance between these metabolic processes may be regulated, as well as some of the therapeutical approaches that can derive from their study.

Different Stat proteins are activated through phosphorylation of unique tyrosine residues in response to different cytokines and growth factors. Interferon-γ activates Stat1 molecules that form homodimers and bind cognate DNA elements. Here we show that treatment of permeabilized cells with 200-500 μM peroxo-derivatives of vanadium, molybdenum, and tungsten results in the accumulation of constitutively phosphorylated Stat1α molecules. In contrast, treatment of permeabilized cells with orthovanadate, vanadyl sulfate, molybdate, and tungstate at the same range of concentrations does not result in the accumulation of activated Stat1α molecules in the absence of ligand. However, these compounds inhibit the inactivation of interferon-γ-induced DNA-binding activity of Stat1α. A 4-6-h exposure of the permeabilized cells to orthovanadate, molybdate, and tungstate, but not vanadyl sulfate, results in a ligand-independent activation of Stat1α, which is blocked by the inhibition or depletion of NADPH oxidase activity in the cells, indicating that NADPH oxidase-catalyzed superoxide formation is required for the bioconversion of these metal oxides to the corresponding peroxo-compounds. Interestingly, ligand-independent Stat1α activation by peroxo-derivatives of these transition metals does not require Jak1, Jak2, or Tyk2 kinase activity, suggesting that other kinases can phosphorylate Stat1α on tyrosine 701.