Signal transducer and activator of transcription (STAT) proteins are second messengers in the JAK/STAT signaling pathway. The activation mechanism of STAT proteins involves phosphorylation on a single tyrosine residue by Janus-activated family kinases (JAK) in response to the binding of a series of extracellular proteins, such as cytokines, growth factors, hormones and membrane receptors. Activated via phosphorylation, STATs dissociate from the receptor, undergo dimerization and translocate to the nucleus, where they induce the transcription of target genes, commonly referred to as Interferon stimulated genes (ISGs). The family of STAT proteins has been documented to participate in normal cellular events, such as differentiation, proliferation, cell survival, apoptosis and angiogenesis. Constitutively activated STATs are involved in an aberrant signaling pathway which has transforming properties and occurs in cancer development. This review describes the mechanisms of JAK/STAT activation in normal and cancer cells. Moreover, it outlines the role of the JAK/STAT pathway in the inflammatory process as well as in oncogenesis. Additionally, the contribution of STAT and JAK proteins in molecular targeted cancer therapy is discussed. Keywords: STAT proteins, JAK/STAT signaling pathway, inflammation, targeted therapy, cancer development, dimerization, phosphorylation, oligomerization, β-isoform, docking site

Bladder cancer is the second most common malignancy of urinary tract. Normal bladder urothelium is a transitional epithelium which consist of 3-7 layers and three different types of cells. The question is what kind of cells is responsible for bladder cancer development, probably stem cells? Stem cells can be sensitive to changes in their environment including toxic substances related to smoking. These changes within stem cells may potentially induce carcinogenesis by limiting their differentiating potential but expanding their proliferative potential. This process is directly connected with stem cell senescence in which DNA alterations play an important role. Cancer stem cells have become the target in treating various cancers. Tumor initiating cells within bladder cancer have been isolated. It has to be tested what connections are between cancer stem cells and tumor initiating cells. Characteristic markers and proteins may help to identify bladder cancer stem cells and thus early stages of bladder cancer. Moreover, bladder cancer stem cells undergo signaling pathways which play critical role both in normal and cancer stem cells. Keywords: Cancer stem cell, tumor biology, urinary bladder, carcinogenesis, phenotypic, metastatic, Neoplastic cells, post-mitotic, glycoproteins, lymphocyte

Hepatic encephalopathy (HE) is a common clinical complication in patients with severe liver disease. While the pathogenesis of HE is incompletely understood, ammonia has been strongly implicated as an important etiological factor, and astrocytes appear to be the primary target of its neurotoxicity. In addition to ammonia, infection and inflammation have increasingly been implicated in the pathogenesis of HE. Nuclear factor-kappa B (NF-κB), a major signaling molecule involved in inflammation and immune responses, is activated in cultured astrocytes treated with ammonia, as well as in brains of experimental animals with HE. Such activation may be a consequence of systemic inflammatory events, or as a result of hyperammonemia-induced central nervous system inflammation. Once activated, NF-κB stimulates the transcription of genes involved in immune responses and inflammation, that produce factors which may contribute to cellular dysfunction such as astrocyte swelling and glutamate transport impairment as occurs in HE. This review summarizes the evidence for NF-κB activation in HE, the signaling pathways involved in its activation, and consequences of such activation.

When fluoxetine, the first of the presently used serotonin-specific reuptake inhibitors (SSRIs), was approved in 1987, two effects of the drug had been established: inhibition of serotonin reuptake by the serotonin transporter (SERT), and partial displacement of serotonin binding to cultured astrocytes, which have no SERT expression. At that time astrocytes were generally assumed to be unimportant for brain function. Accordingly, inhibition of SERT has since been regarded as the mechanism responsible for SSRIs effects in spite of several problems: the delay in therapeutic activity, although the inhibition of serotonin uptake is immediate; lack of quantitative correlation between potency of inhibition by different SSRIs and their therapeutic plasma levels (even considering protein binding); and 80% SERT occupancy at minimum-effective doses. Moreover, little information has been obtained about the molecular mechanisms alleviating major depression and obsessive-compulsive disorder (OCD). In 1987 the 5-HT2B receptor was unknown, but it is now established to have the highest affinity between 5-HT receptors for SSRIs, with especially high affinity during chronic treatment. Here we summarize data from cultured mouse astrocytes and astrocytes obtained from the brains of fluoxetinetreated mice, supporting the role of the astrocytic binding: only small differences in affinity for the 5-HT2B receptor between different SSRIs; a week-long-delayed upregulation of the phospholipase, cPLA2a, and the kainate receptor GluK2, with simultaneous increased editing of the latter, reducing its possible stimulation of neuronal glutamatergic signaling. These effects are genetically and functionally correlated with major depression and OCD, including the therapeutic potential of drugs inhibiting glutamatergic activity. Keywords: astrocyte-to neuron signaling, calcium, gene editing, glutamate receptor GluK2, phospholipase cPLA2, serotonin specific reuptake inhibiotr, major depression, SERT, fluoxetine, OCD

Despite the advancements in diagnosis and therapy for hepatocellular carcinoma (HCC) that currently permit to treat with tailored strategies the disease in early stages, for intermediate and advanced stages the therapeutic options are far from optimal. In recent years, new targets have been searched by exploring the molecular pathways involved in hepatocarcinogenesis, leading to multiple trials on new agents interfering in these mechanisms. In this article we revised the principal agents that raised major interest, from the one already established as gold standard for advanced HCC (sorafenib) to the new molecules still in preclinical or early clinical studies. The extensive investigation on the field will identify the best agents and the subsets of patients that will benefit most from their application.

Hepatocyte growth factor/scatter factor (HGF/SF) acts as a mitogen, motogen and morphogen as well as an important angiogenic factor. In cancer cells, HGF/SF acts mainly as an inducer of cell migration and invasion with multiple motility signals mediated by the HGF receptor, c-MET. An important component in this signalling chain is the Rho/ROCK pathway, with resultant changes in cytoskeletal arrangement leading to cell motility/migration. This article outlines knowledge of HGF/SF in relation to cancer cell motility from previous reviews and focuses on more recent studies on the effect of HGF/SF in relation to RhoC GTPase and ROCK in breast cancer cells.

In steroidogenic tissue the first and rate limiting step of steroid hormone synthesis is the transport of cholesterol from the outer mitochondrial membrane to the inner membrane where it is enzymatically converted by cytochrome P450 side chain cleavage (P450scc) to pregnenolone, which is the metabolic precursor for all steroid hormones. This step is accelerated by steroidogenic hormones but how the signal from the periphery is transmitted to the mitochondria is only partially established. The steroidogenic acute regulatory protein (StAR) is known to accelerate the export of cholesterol from the outer mitochondrial membrane. StAR may bind cholesterol in its hydrophobic pocket and then transport or propel cholesterol towards the inner membrane. This action is thought to be dependent on interaction with proteins in the contact sites between the inner and outer mitochondrial membranes, such as the translocator protein and the voltage-dependent anion channel. Mutations in StAR often rob the protein of its steroidogenic properties and result in lipoid congenital adrenal hyperplasia (LCAH), a condition that is characterized by a build up of cholesterol and cholesterol esters in steroidogenic cells, deficiencies in mineralocorticoids and glucocorticoids and XY genetic males with female phenotypic external genitalia. StAR expression in healthy individuals is known to be regulated by protein kinase A and the transcription factor Nurr77. A complete understanding the workings of the signal transduction machinery in steroidogenic cells may allow future plans to combat LCAH by using gene therapy to restore appropriate activity to StAR gene products.

Cerebral ischemia is the third leading cause of death in industrialized countries and an important health system problem with no efficient treatment to date. The reduction in oxygen and glucose supply triggers a cascade of events such as excitotoxicity, oxidative stress, inflammation, apoptosis, and an adjustment of the gene expression program. The hypoxia inducible factor-1 (HIF-1) is a transcription factor that mediates the adaptive responses to the reduction in oxygen availability. HIF-1 activation in hypoxic conditions promotes the survival of cells through the induction of adaptive genes involved in glucose and energy production, glucose transport, cell proliferation, cell survival, iron homeostasis, erythropoiesis, angiogenesis and vascular reactivity. In recent years, biomedical research has focused on the oxygen regulated α subunit of HIF-1 as a potential therapy in medical events that involve hypoxic conditions. In this review we summarize current knowledge on the use of HIF-1α as a therapeutic target against cerebral ischemia through two different strategies: 1) the use of ischemic preconditioning to induce the HIF-1 pathway regulation, and 2) the pharmacological inhibition of prolyl and asparaginyl hydroxylases. Both strategies appear as attractive options for protection in ischemia in which signaling pathway activation could contribute to the establishment of tolerance in brain. Keywords: Hypoxia inducible factor, ischemic preconditioning, prolyl hydroxylase, cerebral ischemia

The dynamic cross-talk between bench – based research and clinical practice is the fundamental characteristic of modern oncology. Colorectal cancer, the second most common cause of cancer – related death in the Western world, is the paradigm of the revolutionary use of targeted sophisticated therapies. The continuous unraveling of the molecular identity of signaling pathways that govern sub-cellular decisions reveals candidate targets. The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) signaling pathways are considered major tumor-promoting cascades. Three monoclonal antibodies have been approved for the management of metastatic colorectal cancer. Cetuximab and panitumumab target the EGFR-signaling pathway, inhibiting the aberrant transduction of tumor – proliferating signals, as well as promoting tumor cell apoptosis. Bevacizumab is the first antibody inhibiting VEGF – driven formation of new blood vessels, a critical component of tumor metastasis. Randomized clinical trials in patients with colorectal cancer have shown significant clinical benefit and tolerable toxicity with the use of these antibodies. At the era of clinical bioinformatics, better selection of patient subpopulations with tumor-over-expressing specific clinical biomarkers could result in significant enhancement of signal transduction targeting success. This review discusses characteristics of cancer-associated signaling, describes the mechanism of action of the three monoclonal antibodies, focusing on their current role in the management of colorectal cancer.

Cyclooxygenase (COX) and nitric oxide synthase (NOS) are two isoenzyme families that both implicated in the inflammatory process. Indeed, the activities of both enzymes are so important that two of the most important classic drugs, Aspirin and Nitroglycerin, are directly related to the COX pathway and NO pathway, respectively. Although Aspirin has been used as an anti-inflammatory drug since 1876, it was not until 1970s that its action has been shown to be involved in inhibition of the Cox enzyme, being a class of drugs known as non-steroidal anti-inflammatory drugs(NSAIDs). This signaling pathway has led to extensive research led by a number of pharmaceutical companies in the race to make more effective anti-inflammatory drugs, such as ibuprofen and colecoxib to name but a few. Similarly, the nitroglycerin has been used to treat angina more than a hundred years, its only until late 1980s its drug action by releasing nitric oxide gas have been recognized. There are not however, many anti-inflammatory drugs that specially target NOS or more specifically, iNOS, although there are various studies and trial that are investigating the effect of iNOS inhibition in various inflammatory conditions such as sepsis and other chronic illness including cancer. More recently, COX pathway has been found to be regulated by NO pathway and therapeutic potentials of NO-releasing aspirin hybrid drugs has been developed. In this review, we will discuss both pathways and their cross talk and pharmaceutical potentials for future therapeutic development based on these signaling transduction pathways. Keywords: Cyclooxygenase, NSAIDs, prostaglandin, nitric oxide, iNOS, septic shock