Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels. VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible. VPA is a widely used drug, particularly for children suffering from epilepsy. Due to the increasing number of clinical trials involving VPA, and interesting results obtained, this molecule will be implicated in an increasing number of therapies. However side effects of VPA are substantially described in the literature whereas they are poorly discussed in articles focusing on its therapeutic use. This paper aims to give an overview of the different clinical-trials involving VPA and its side effects encountered during treatment as well as its molecular properties.

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Heteronemin, a spongean sesterterpene, inhibits TNFα-induced NF-κB activation through proteasome inhibition and induces apoptotic cell death. Biochemical Pharmacology, Elsevier, 2009, 79 (4) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 AbstractIn this study, we investigated the biological effects of heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp. on chronic myelogenous leukemia cells. To gain further insight into the molecular mechanisms triggered by this compound, we initially performed DNA microarray profiling and determined which genes respond to heteronemin stimulation in TNF-treated cells and which genes display an interaction effect between heteronemin and TNF. Within the differentially regulated genes, we found that heteronemin was affecting cellular processes including cell cycle, apoptosis, mitogen-activated protein kinases (MAPKs) pathway and the nuclear factor B (NF-B) signaling cascade.We confirmed in silico experiments regarding NF-B inhibition by reporter gene analysis, electrophoretic mobility shift analysis and IB degradation. In order to assess the underlying molecular mechanisms, we determined that heteronemin inhibits both trypsin and chymotrypin-like proteasome activity at an IC 50 of 0.4 µM.Concomitant to the inhibition of the NF-B pathway, we also observed a reduction in cellular viability. Heteronemin induces apoptosis as shown by Annexin V/propidium iodide staining, nuclear morphology analysis, procaspase 3, -8 and -9 and poly(ADPribose) polymerase (PARP) cleavage as well as truncation of Bid. Altogether, resultsshow that this compound has potential as anti-inflammatory and anti-cancer agent.

Glucocorticoids (GCs) block inflammation via interference of the liganded glucocorticoid receptor (GR) with the activity of pro-inflammatory transcription factors NF-κB and AP-1, a mechanism known as transrepression. This mechanism is believed to involve the activity of GR monomers. Here, we explored how the GR monomer-favoring Compound A (CpdA) affects AP-1 activation and activity. Our results demonstrate that non-steroidal CpdA, unlike classic steroidal GCs, blocks NF-κB- but not AP-1-driven gene expression. CpdA rather sustains AP-1-driven gene expression, a result which could mechanistically be explained by the failure of CpdA to block upstream JNK kinase activation and concomitantly also phosphorylation of c-Jun. In concordance and in contrast to DEX, CpdA maintained the expression of the activated AP-1 target gene c-jun, as well as the production of the c-Jun protein. As for the underlying mechanism, GR is a necessary intermediate in the CpdA-mediated gene expression of AP-1-regulated genes, but seems to be superfluous to CpdA-mediated JNK phosphorylation prolongation. The latter phenomenon concurs with the inability of CpdA to stimulate DUSP1 gene expression. ChIP analysis demonstrates that DEX-activated GR, but not CpdA-activated GR, is recruited to AP-1-driven promoters. Furthermore, in mice we observed that CpdA instigates a strong enhancement of TNF-induced AP-1-driven gene expression. Finally, we demonstrate that this phenomenon coincides with an increased sensitivity towards TNF lethality, and implicate again a role for JNK2. In conclusion, our data support the hypothesis that a ligand-induced differential conformation of GR yields a different transcription factor cross-talk profile.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-013-1367-4) contains supplementary material, which is available to authorized users.

In this chapter we examine whether criteria usually defining adult tissue stem cells apply to mesenchymal stem cells (MSCs) that give rise to cells of the skeletal connective tissues. MSCs appear to constitute a heterogeneous population of undifferentiated and committed, lineage-primed cells, capable of: homing upon engraftment to a number of growth microenvironments, extensive proliferation, producing large numbers of differentiated progeny, and functional tissue repair after injury. In addition, MSCs are extensively distributed throughout tissues, and bone marrow MSCs provide the stromal component of the niche of hematopoietic stem cells. The capacity of apparently differentiated mesenchymal cells to shift their differentiation pathway with changing microenvironmental conditions (known as differentiation plasticity) may be due to de-differentiation and reprogramming in MSCs. Because they present several features setting them apart from other stem cells, MSCs may constitute another paradigm for stem cell systems, where self-renewal and hierarchy are no longer essential, but where plasticity is the major characteristic.