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The cholesterol biosynthesis represents a crucial metabolic pathway for cellular homeostasis. The end products of this pathway are sterols, such as cholesterol, which are essential components of cell membranes, precursors of steroid hormones, bile acids, and other molecules such as ubiquinone. Furthermore, some intermediates of this metabolic system perform biological activity in specific cellular compartments, such as isoprenoid molecules that can modulate different signal proteins through the prenylation process. The defects of prenylation represent one of the main causes that promote the activation of inflammation. In particular, this mechanism, in association with oxidative stress, induces a dysfunction of the mitochondrial activity. The purpose of this review is to describe the pleiotropic role of prenylation in neuroinflammation and to highlight the consequence of the defects of prenylation.

Janus kinases (JAK) are a family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) that transduce cytokine-mediated signals through the JAK–STAT metabolic pathway. These kinases act by regulating the transcription of specific genes capable of inducing biological responses in several immune cell subsets. Inhibition of Janus kinases interferes with the JAK–STAT signaling pathway. Besides being used in the treatment of cancer and inflammatory diseases, in recent years, they have also been used to treat inflammatory conditions, such as graft-versus-host disease (GVHD) and cytokine release syndrome as complications of allogeneic hematopoietic stem cell transplantation and cell therapy. Recently, the FDA approved the use of ruxolitinib, a JAK1/2 inhibitor, in the treatment of acute steroid-refractory GVHD (SR-aGVHD), highlighting the role of JAK inhibition in this immune deregulation. Ruxolitinib was initially used to treat myelofibrosis and true polycythemia in a high-dose treatment and caused hematological toxicity. Since a lower dosage often could not be effective, the use of ruxolitinib was suspended. Subsequently, ruxolitinib was evaluated in adult patients with SR-aGVHD and was found to achieve a rapid and effective response. In addition, its early low-dose use in pediatric patients affected by GVHD has proved effective, safe, and reasonably preventive. The review aims to describe the potential properties of ruxolitinib to identify new therapeutic strategies.

Background and Aims Cardiovascular disease is the main cause of death worldwide, but the collective efforts to prevent this pathological condition are directed exclusively to individuals at higher risk due to hypercholesterolemia, hypertension, obesity, diabetes. Recently, vitamin D deficiency was identified as a risk factor for cardiovascular disease in healthy people, as it predisposes to different vascular dysfunctions that can result in plaque development and fragility. In this scenario, the fundamental aim of the study was to reproduce a disease model inducing vitamin D deficiency and atheromatosis in ApoE-/- mice and then to evaluate the impact of this vitamin D status on the onset/progression of atheromatosis, focusing on plaque formation and instability. Methods and Results In our murine disease model, vitamin D deficiency was achieved by 3 weeks of vitamin D deficient diet along with intraperitoneal paricalcitol injections, while atheromatosis by western-type diet. Under these experimental conditions, vitamin D deficient mice developed more unstable atheromatous plaques with reduced or absent fibrotic cap. Since calcium and phosphorus metabolism and also cholesterol and triglycerides systemic concentration were not affected by vitamin D level, our results highlighted the role of vitamin D deficiency in the formation/instability of atheromatous plaque and, although further studies are needed, suggested a possible intervention with vitamin D to prevent or delay the atheromatous disease. Conclusions The data obtained open the question about the potential role of the vitamins in the pharmacological treatments of cardiovascular disorders as coadjutant of the primary drugs used for these pathologies., Graphical abstract Image 1, Highlights • The vitamin D deficiency represents a risk factor for cardiovascular disease. • The vitamin D deficiency has been correlated to atheromatosis progression. • A model of vitamin D deficiency was fundamental to evaluate the role of the vitamin D the onset/progression of atheromatosis. • The vitamin D deficiency was clearly involved in an early formation of atherosclerotic lesions. • The vitamins play a potential role in the pharmacological treatments of cardiovascular disorders.

// Rebecca Voltan 1, * , Erika Rimondi 2, * , Elisabetta Melloni 1 , Gian Matteo Rigolin 3 , Fabio Casciano 1 , Maria Vittoria Arcidiacono 1 , Claudio Celeghini 2 , Antonio Cuneo 3 , Giorgio Zauli 1 , Paola Secchiero 1 1 Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy 2 Department of Life Sciences, University of Trieste, Trieste, Italy 3 Department of Medical Sciences, Section of Hematology, University of Ferrara, Ferrara, Italy * These authors have contributed equally to this work Correspondence to: Paola Secchiero, email: paola.secchiero@unife.it Keywords: B leukemic cells, Ibrutinib, MDM-2 inhibitors, apoptosis, combination therapy Received: July 20, 2016 Accepted: September 09, 2016 Published: September 20, 2016 ABSTRACT Objective: The aim of this study was to investigate the anti-leukemic activity of the Bruton tyrosine kinase inhibitor Ibrutinib in combination with the small molecule MDM-2 inhibitor Nutlin-3 in preclinical models. Methods: The potential efficacy of the Ibrutinib/Nutlin-3 combination was evaluated in vitro in a panel of B leukemic cell lines (EHEB, JVM-2, JVM-3, MEC-1, MEC-2) and in primary B-chronic lymphocytic leukemia (B-CLL) patient samples, by assessing cell viability, cell cycle profile, apoptosis and intracellular pathway modulations. Validation of the combination therapy was assessed in a B leukemic xenograft mouse model. Results: Ibrutinib exhibited variable anti-leukemic activity in vitro and the combination with Nutlin-3 synergistically enhanced the induction of apoptosis independently from the p53 status. Indeed, the Ibrutinib/Nutlin-3 combination was effective in promoting cytotoxicity also in primary B-CLL samples carrying 17p13 deletion and/or TP53 mutations, already in therapy with Ibrutinib. Molecular analyses performed on both B-leukemic cell lines as well as on primary B-CLL samples, while confirming the switch-off of the MAPK and PI3K pro-survival pathways by Ibrutinib, indicated that the synergism of action with Nutlin-3 was independent by p53 pathway and was accompanied by the activation of the DNA damage cascade signaling through the phosphorylation of the histone protein H2A.X. This observation was confirmed also in the JVM-2 B leukemic xenograft mouse model. Conclusions: Taken together, our data emphasize that the Ibrutinib/Nutlin-3 combination merits to be further evaluated as a therapeutic option for B-CLL.

The mitochondrial kinase inhibitor dichloroacetate (DCA) has recently received attention in oncology due to its ability to target glycolysis. However, DCA molecule exhibits poor bioavailability and cellular uptake with limited ability to reach its target mitochondria. To overcome these biases, we have synthesized novel DCA-loaded compounds. The selection of the most promising therapeutic molecule was evaluated by combining in vitro assays, to test the antitumoral potential on leukemic cells, and a preliminary characterization of the molecule stability in vivo, in mice. Among the newly synthesized compounds, we have selected the multiple DCA-loaded compound 10, characterized by a tertiary amine scaffold, because it exhibited enhanced (>30-fold) in vitro antitumor activity with respect to DCA and increased in vivo stability. On the basis of these results, we believe that compound 10 should be considered for further preclinical evaluations for the treatment of cancers and/or other diseases characterized by altered metabolic origin.

Squamous cell carcinoma (SCC) of the head and neck is a common malignancy accounting for over 300,000 cases worldwide every year [1] and occurring at all ages including in children [2]. Of all malignancies locaded in the head and neck region (i.e., oral cavity, pharynx, larynx and paranasal sinuses), the OSCC in its strictest definition (i.e. in front of the tonsils) accounts for the vast majority of cases [1–4]. Surgery remains the first line of treatment for oral cancer, in combination with radiotherapy or chemotherapy [3]. Nevertheless, the poor outcome of many patients affected by OSCC underline the urgent need for innovative therapeutic approaches. In this respect, the development of selective tumor-biology based therapies, that can improve current therapy and allow more tolerable treatment regimens, has become a main field of interest in cancer research. Previous studies have shown that the TNF-family member TRAIL exhibits selective anti-tumor activity due to its unique ability to induce apoptosis in a variety of continuous cancer cell lines and primary tumor cells, displaying minimal or absent toxicity on most normal cells and tissues [5]. Like other members of the TNF family of proteins, TRAIL can be expressed as type II transmembrane protein or as a soluble protein [6] and, besides inducing apoptosis of cancer cells, it plays a variety of biological functions on immune cells and on other cells of hematopoietic origin [6]. There are several ongoing phase I and phase II clinical trials to evaluate the potential anti-cancer activity of soluble recombinant TRAIL in both solid tumors [7] and hematological malignancies [8]. On these bases, the aim of the present study was to investigate the expression of TRAIL in a large sample (n = 134) of paraffin-embedded OSCC specimens and to assess whether this has a prognostic significance for the survival of patients suffering from OSCC. In addition, by using three continuous cell lines (PE15D, PE46 and PE49) of OSCC origin, we analyzed the potential biological significance of the high TRAIL expression in OSCC cells and the response of OSCC cells to treatment in vitro with soluble recombinant TRAIL.