Current Molecular Pharmacology - Volume 4, Issue 1, 2011

Cerebral complications of liver failure either due to chronic or acute manifestations lead to a neurological disorder known as Hepatic encephalopathy (HE). Neurosteroids, synthesized in the brain mainly by astrocytes but also in other brain cells independently from peripheral steroidal sources such as adrenal and gonads, are suggested to play a role in the pathogenesis of HE. The mechanisms by which neurosteroids affect brain function are not totally elucidated but may involve both genomic and non genomic effects. On the one hand, neurosteroids bind and modulate different types of neuronal memebrane receptors. While neurosteroids may affect directly postsynaptic receptors including GABAA, 5-HT3, NMDA, glycine, and opioid receptors which have been involved in HE, neurosteroids effects through GABAA receptors may also compromise indirectly the function of neurons networking with GABAergic interneurons. On the other hand, some neurosteroids bind to intracellular receptors through which they also regulate gene expression, and there is substantial evidence confirming that expression of genes coding for key astrocytic and neuronal proteins is altered in HE. The mechanisms that trigger brain neurosteroid changes in HE are not yet established, but could involve (i) ammonia and manganese (in chronic HE)-induced translocator protein (TSPO) activation, (ii) neuroinflammation or (iii) blood-brain transfer of lipophylic neuroactive steroids. The present review summarizes evidence for the involvement of neurosteroids in HE and possible mechanisms for their altered brain production and central effects in human and experimental HE.

The Wnt pathway plays a critical role in development and differentiation of many tissues, such as the gut, hair follicles, and bone. Increasing evidence indicates that Wnts may function as key regulators in osteogenic differentiation of mesenchymal stem cells and bone formation. Conversely, aberrant Wnt signaling is associated with many osteogenic pathologies. For example, genetic alterations in the Wnt signaling pathway lead to osteoporosis and osteopenia, while inactivating mutations of Wnt inhibitors result in a hyperostotic skeleton with increased bone mineral density. Hyperparathyroidism causes osteopenia via induction of the Wnt signaling pathway. Lithium, often used to treat bipolar disorder, blocks a Wnt antagonist, decreasing the patient's risk of fractures. Thus, manipulating the Wnt pathway may offer plenty therapeutic opportunities in treating bone disorders. In fact, induction of the Wnt signaling pathway or inhibition of Wnt antagonists has shown promise in treating bone metabolic disorders, including osteoporosis. For example, antibodies targeting the Wnt inhibitor Sclerostin lead to increased bone mineral density in post-menopausal women. However, such therapies targeting the Wnt pathway are not without risk, as genetic alternations may lead to over-activation of Wnt/β- catenin and its association with many tumors. It is conceivable that targeting Wnt inhibitors may predispose the individuals to tumorigenic phenotypes, at least in bone. Here, we review the roles of Wnt signaling in bone metabolic and pathologic processes, as well as the therapeutic potential for targeting Wnt pathway and its associated risks in bone diseases.

Thalidomide is a powerful treatment for inflammatory and cancer-based diseases. However, its clinical use remains limited due to its teratogenic properties, which primarily affect limb development. A prerequisite for overcoming these limitations is to understand the cellular and molecular mechanisms underlying thalidomide teratogenicity, which involve induction of oxidative stress, suppression of ubiquitin-mediated protein degradation and disruption of angiogenesis. Here, we discuss the hypothesis that thalidomide-induced limb teratogenicity is primarily based on the generation of nuclear oxidative stress with subsequent induction of transient apoptosis in the outgrowing limb bud. To this end, we establish a model of the signaling network regulating cell proliferation, survival and endogenous apoptosis-induction required for correct limb outgrowth and patterning. We then summarize data showing how thalidomide interferes with this signaling network: thalidomide inhibits the activity of the redox-sensitive transcription factor NF-κB, shifts the balance of fibroblast growth factors and bone morphogenetic proteins (Bmps) towards pro-apoptotic Bmps, and suppresses Wnt/β- catenin- and Akt-dependent survival signaling in the limb bud. Consequently, prechondrogenic precursor cells that determine skeletal elements are eliminated leading to the development of truncated limbs. We further discuss the involvement of thalidomide effects on ubiquitin-mediated protein degradation and angiogenesis in the induction of apoptosis in the limb bud. Finally, we discuss the paradox that the embryonic molecular pathology induced by thalidomide suggests this drug as a candidate for therapeutic application in idiopathic pulmonary fibrosis (IPF), a chronic and fatal lung disease characterized by downregulation of Bmp signaling, increased Wnt and Akt activity, and apoptosis resistance.

Cells in rapidly growing solid tumors are commonly exposed to chronic or intermittent hypoxia. Hypoxia can induce cell death by multiple mechanisms; however, some cells may adapt by orchestrating dramatic changes in gene expression patterns. In addition, hypoxia exerts a powerful selective pressure on tumor cells, resulting in the emergence of clonal populations whose defects in DNA repair mechanisms favor genomic instability and tumor progression, whereas disabling of apoptotic pathways makes them more resistant to both environmental stresses and therapeutic interventions. The transcription factor HIF-1 (Hypoxia-Inducible Factor 1) is generally considered as the major regulator of the hypoxic adaptive response, and as such it is viewed as a viable prospective target for novel pharmacologic approaches to the clinical management of solid tumors. Several agents have been identified that inhibit HIF-1 transcriptional activity, and some of them are currently undergoing clinical trials, mostly based on their antiangiogenic properties. This article reviews the role played by HIF-1 in tumorigenesis and chemoresistance and provides an overview of current and prospective pharmacologic strategies designed to inhibit HIF-1 activity, emphasizing their direct and indirect effects on tumor growth, as well as their potential for chemoprevention and chemosensitization.