Retinoids, vitamin A derivatives, are natural or synthetic molecules with pleiotropic effects, which regulate cell differentiation, proliferation and apoptosis. In target cell, the active natural metabolites retinoic acid (RA) and 9-cis-retinoic acid are synthetized from retinol by a two-step process with intermediate metabolite retinaldehyde. In 1987, the identification of the nuclear retinoic acid receptors that belong to the superfamily of nuclear receptors led to a significant progress in the comprehension of the mechanism of action of retinoids. There are two families of Retinoid Nuclear Receptors (RNR), the RA receptors (RAR), which natural ligand is RA, and the Retinoid X Receptors (RXR), which natural ligand is 9-cis-retinoic acid. Among synthetic retinoids, isotretinoin, acitretin, tazarotene and adapalene are ligands of the RAR, bexarotene is the first rexinoid (ligand of the RXR), alitretinoin the first panagonist (RAR+ RXR). For each family, there are 3 isotypes (α, β, γ), and for each isotype several isoforms. Each NRR is composed of 6 regions (A-F). 3 regions are of importance: the A/B region has a ligand-independent transcriptional activation function, the C region harbors the DNA binding domain, the E region harbors the ligand binding domain. To regulate the expression of target genes, NRR have to dimerize. RXR are obligatory in dimers (heterodimers RAR-RXR, homodimers RXR-RXR). Dimers binds specific sequences of DNA, present in the promoters of target genes. When the ligand, natural or synthetic, bind to RNR, coactivators are recruited and transcription factors are activated. In target cell, retinoids not utilized are degradated in polar metabolites by enzymes of cytochrome P450.

HDAC, by modifiing relations between DNA and histones, are major proteins of the epigenetic regulation. They play part in the signal transduction and in many cellular processes: cell cycle control, apoptosis, protein degradation, angiogenesis, invasion and cell motility. In several models of cancer HDAC inhibitors (HDACIs) are able to up regulate tumor suppressing gene (p53, p21, pRB...) and to down regulate oncogenes (SRC, HIF-Ialpha,HER2...). Many inhibitors are currently in clinical development and promising results have been reported in cutaneous T cell lymphoma, Hodgkin's disease and non-hodgkin lymphoma. Combination with chemotherapy and molecular targeted agents seem to be effective in myeloma, lung cancer and myeloïd neoplasms. In this review, we focus on recent biologic and clinical data that highlitght the anti-neoplastic role of HDACIs.

Endoplasmic reticulum (ER) stress is a situation caused by the accumulation of unfolded proteins in the endoplasmic reticulum, triggering an evolutionary conserved adaptive response termed the unfolded protein response. When adaptation fails, excessive and prolonged ER stress triggers cell suicide. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including diabetes, hypoxia, ischemia/reperfusion injury, neurodegenerative and heart diseases. The implication of the ER stress is not well recognized in solid organ transplantation, but increasing evidence suggests its implication in mediating allograft injury. The purpose of this review is to summarize the mechanisms of ER stress and to discuss its implication during tissue injury in solid organ transplantation. The possible implications of the ER stress in the modifications of cell functional properties and phenotypic changes are also discussed beyond the scope of adaptation and cell death. Increasing the understanding of the cellular and molecular mechanisms of acute and chronic allograft damages could lead to the development of new biomarkers and to the discovery of new therapeutic strategies to prevent the initiation of graft dysfunction or to promote the tissue regeneration after injury.

Trisomy 21 was first described as a syndrome in the middle of the nineteenth century and associated to a chromosomic anomaly one hundred years later: the most salient feature of this syndrome is a mental retardation of variable intensity. Molecular mapping and DNA sequencing have allowed identifying the gene content of chromosome 21. Molecular quantitative analyses indicated that trisomy is inducing an overexpression for a large part of the triplicated genes and deregulates also pathways involving non HSA21 genes. Together with the physiological description of murine models overexpressing orthologous genes, these data have allowed to elaborate hypotheses on the cause of cognitive impairment. From these hypotheses and using murine models it is now possible to assess the efficiency of various therapeutic strategies. This paper reviews these new perspectives starting from the strategies targeting the level of HSA21 RNAs or HSA21 proteins; then it describes methods targeting activities either of proteins involved in cell cycle pathways or of proteins controlling the synaptic plasticity. It is promising that strategies targeting specific genes or specific pathways are already giving positive results.

Activating mutations of the oncogene K-ras are found in one third of all human cancers. Much of our knowledge on K-ras signal transduction and its influence on tumor initiation and progression come from in vitro studies with cell lines. However, mouse models of human cancer allow a much more faithful recapitulation of the human disease, and the in vivo perspective is crucial for our understanding of neoplasia. In recent years, several new murine models for K-ras-induced tumorigenesis have been described. They allow new insights into the specific role that oncogenic K-ras proteins play in different solid tumors, and they permit the molecular dissection of the pathways that are initiated by somatic mutations in subsets of cells. Key advances have been made by the use of tissue-specific and inducible control of expression, which is achieved by the Cre/loxP technology or the tetracycline system. From these sophisticated models, a common picture emerges: the effects of K-ras on tumor initiation depend strongly on the cellular context, and different tissues vary in their susceptibility to K-ras transformation.

Angiogenesis is a basic process during development and in pathology as well. The molecular networks involved in angiogenesis are not totally understood. We have recently developed a new model for tumoral angiogenesis in the chicken embryo, which allows large scale studies. On the other hand we have uncovered a new induction pathway, which involves stress of the endoplasmic reticulum. These investigations open up novel prospects for the future.

Generation of transgenic mice have identified new pathophysiological mechanisms in sickle disease, including a permanent proinflammatory state and dysregulation of vascular tone. Treatment is no longer solely symptomatic. New agents target red cell hydration and the kinetics of deoxyhemoglobin S polymerization. Hydroxyurea, which reactivates fetal hemoglobin synthesis, is now widely used. Anti-adhesion molecules and agents modulating vascular tone are being tried in sickle mice. Bone marrow transplantation is widely used to cure patients with HLA-identical siblings, and gene therapy looks promising for those without a donor.

Discovered 10 years ago, survivin has a dual role in the smooth progress of mitosis and in apoptosis resistance. Survivin plays an important physiological role in development, but is absent in differentiated adult tissues. In contrast, aberrant survivin expression is found in most human cancers because of the activation of various signalling pathways. A complex survivin network appears to intersect multiple pathways in cell biology, related to several molecular partners and fine subcellular localizations. Based on its pro-oncogenic properties, basic and translational studies have shown a growing interest in survivin that has led to consider survivin as a prognostic marker and a promising target for anti-tumoral therapies.

Tau interferon (IFN-tau) was shown to inhibit human immunodeficiency virus (HIV) replication in vitro more strongly than human IFN-alpha, particularly in human macrophages. IFN-tau efficiently inhibited the early steps of HIV biological cycle, decreasing intracellular HIV RNA and inhibiting the initiation of the reverse transcription of viral RNA into proviral DNA. In this study, the in vitro immunomodulatory effects of IFN-tau were explored in human macrophages. We found that IFN-tau increased the synthesis of the cellular antiviral factors, such as 2',5'-oligoadenylate synthetase/RNase L and MxA protein. These results suggested that IFN-tau induces the same antiviral pathways in macrophages as other type I IFNs. We found that IFN-tau increased the production of interleukins (IL)-10 and IL-6, but not of IL-1ss or TNF-alpha, in not infected and in in vitro HIV-1/Ba-L-infected macrophages. We also found that the neutralization of IL-6 biological activity in the cell culture supernatants of IFN-tau-treated macrophages led to a decrease in the antiretroviral effects of IFN-tau towards HIV RNA. In conclusion, anti-HIV effects of IFN-tau are mediated by several modes of action, mediated either directly by IFN-tau or via other cytokines, such as IL-6, also known to be induced by IFN-alpha.

Amphibian metamorphosis is an excellent model to study the diverse effects of thyroid hormones (TH). TH modulate target gene expression via thyroid hormone receptors (TR). Generally, unliganded TR repress transcription, whereas liganded TR activate transcription. During metamorphosis, these dual effects of TR are evident. Moreover, we show that gene specific response to TH can underline the multiple effects of TH. Finally, studies of unliganded-thyroid hormone receptor function reveal a physiological role in eye development.

Cartilage has a limited capacity for healing after trauma. Autologous chondrocyte implantation is widely used for the treatment of patients with focal damage to articular cartilage. Chondrocytes are isolated from biopsy specimen, cultured in monolayers on plastic then transplanted over the cartilage defect. However, chondrocyte amplification on plastic triggers their dedifferentiation. This phenomenon is characterized by loss of expression of type II collagen, the most abundant cartilage protein. The challenge for autologous chondrocyte implantation is to provide patients with well-differentiated cells. The aim of the present study was to test the capability of bone morphogenetic protein (BMP)-2 to promote redifferentiation of human chondrocytes after their expansion on plastic.

Deciphering the mechanisms underlying skeletal muscle differentiation in mammals is an important challenge. Cell differentiation involves complex pathways regulated at both transcriptional and post-transcriptional levels. Recent observations have revealed the importance of small (20-25 base pairs) non-coding RNAs (microRNAs or miRNAs) that are expressed in both lower organisms and in mammals. miRNAs modulate gene expression by affecting mRNA translation or stability. In lower organisms, miRNAs are essential for cell differentiation during development; some miRNAs are involved in maintenance of the differentiated state. We have shown that miR-181, a microRNA that is strongly upregulated during differentiation, participates in establishing the muscle phenotype. Moreover, our results suggest that miR-181 downregulates the homeobox protein Hox-A11 (a repressor of the differentiation process), thus establishing a functional link between miR-181 and the complex process of mammalian skeletal muscle differentiation. Therefore, miRNAs can be involved in the establishment of a differentiated phenotype - even when they are not expressed in the corresponding fully differentiated tissue.

Neurodegenerative diseases are more and more prevalent in our aging societies. A rapid overview of the etiology of many neurodegenerative diseases like Alzheimer, Parkinson, Huntington disease and amyotrophic lateral sclerosis suggests a tight link with mitochondrial dysfunction. Since it has been recently demonstrated that activation of the SIRT1/PGC-1 pathway, in a metabolic context promotes mitochondrial function, we performed a detailed literature review on the implication of this pathway in neurodegeneration. Interestingly, transgenic mice with impaired PGC-1 expression have neurodegenerative lesions and show behavioural abnormalities. As evidenced from independent investigations, enhanced SIRT1 activity has been demonstrated to protect against axonal degeneration and to decrease the accumulation of amyloid beta peptides, the hallmark of Alzheimer disease, in cultured murine embryonic neurons. In addition, several studies suggest that resveratrol, a specific activator of SIRT1, could have protective effects in animal models of neurodegenerative diseases. Taken together, these results strongly suggest that the modulation of the SIRT1/PGC-1 pathway, which has not been well documented in the central nervous system, could become the cornerstone for new therapeutical approaches to combat neurodegeneration.