Cartilage formation in growth plate and arteries: from physiology to pathology

Vascular calcifications are the consequence of several pathological conditions such as atherosclerosis, diabetes, hypercholesterolemia and chronic renal insufficiency. They are associated with risks of amputation, ischemic heart disease, stroke and increased mortality. A growing body of evidence indicates that vascular smooth muscle cells (VSMCs) undergo chondrogenic commitment eventually leading to vascular calcification, by mechanisms similar to those governing ossification in the cartilage growth plate. Our knowledge of the formation of cartilage growth plate can therefore help us to understand why and how arteries calcify and, consequently, develop new therapeutic strategies. Reciprocally, thorough consideration of the events leading to ectopic chondrocyte differentiation appears crucial to further increase our understanding of growth plate formation. In this context, we will review the effects of known or suspected factors that promote chondrogenic differentiation in growth plate and arteries.     

Recent insights into body weight control: from physiology to pathology.

Over the past several years, new modulators of feeding and body weight have been discovered, and our knowledge of the mechanisms and neurohumoral interactions between anorexigenic and orexigenic compounds has increased dramatically. This review aims to summarize the present knowledge of the role of leptin and several hypothalamic neuropeptides, such as neuropeptide Y (NPY), corticotropin-releasing hormone (CRH) and melanocortins, in the regulation of appetite and body weight. It also presents the progress made in the design of interactions between leptin and hypothalamic peptides in the regulation of feeding. The role of these compounds in the pathogenesis of obesity in animals and humans, and their potential usefulness in the treatment of this disorder, are discussed.     

The flagellum: from cell motility to morphogenesis

Flagella and cilia are elaborate cytoskeletal structures conserved from protists to mammals, where they fulfil functions related to motility or sensitivity. We demonstrate a novel role for the flagellum in the control of cell morphogenesis and division of Trypanosoma brucei. To investigate flagellum functions, its formation was perturbed by inducible RNA interference silencing of components required for intraflagellar transport (IFT), a dynamic process necessary for flagellum assembly. First, we show that down-regulation of IFT leads to assembly of a shorter flagellum. Strikingly, cells with a shorter flagellum are smaller, with a direct correlation between flagellum length and cell size. Detailed morphogenetic analysis reveals that the tip of the new flagellum defines the point where cytokinesis is initiated. Furthermore, when new flagellum formation is completely blocked, non-flagellated cells are very short, lose their normal shape and polarity and fail to undergo cytokinesis. We show that flagellum elongation controls formation of cytoskeletal structures present in the cell body that act as molecular organisers of the cell.     

DNA methylation in states of cell physiology and pathology

DNA methylation is one of epigenetic mechanisms regulating gene expression. The methylation pattern is determined during embryogenesis and passed over to differentiating cells and tissues. In a normal cell, a significant degree of methylation is characteristic for extragenic DNA (cytosine within the CG dinucleotide) while CpG islands located in gene promoters are unmethylated, except for inactive genes of the X chromosome and the genes subjected to genomic imprinting. The changes in the methylation pattern, which may appear as the organism age and in early stages of cancerogenesis, may lead to the silencing of over ninety endogenic genes. It has been found, that these disorders consist not only of the methylation of CpG islands, which are normally unmethylated, but also of the methylation of other dinucleotides, e.g. CpA. Such methylation has been observed in non-small cell lung cancer, in three regions of the exon 5 of the p53 gene (so-called "non-CpG" methylation). The knowledge of a normal methylation process and its aberrations appeared to be useful while searching for new markers enabling an early detection of cancer. With the application of the Real-Time PCR technique (using primers for methylated and unmethylated sequences) five new genes which are potential biomarkers of lung cancer have been presented.     

Liver autophagy: physiology and pathology

Autophagy has long been thought of as a bulk degradation system in which cytoplasmic components are sequestered by double-membrane structures called autophagosomes, and the contents are then degraded after autophagosomes fuse with lysosomes. Genetic experiments in yeast identified a set of Autophagy-related (ATG) genes that are essential for autophagy. We have since elucidated many of the molecular underpinnings of autophagy and the physiologic roles of these processes in various systems. This review summarizes the physiologic roles of autophagy with a particular focus on liver autophagy based on analyses of knockout mice lacking Atg genes.     

CLC chloride channels and transporters: from genes to protein structure, pathology and physiology

CLC genes are expressed in species from bacteria to human and encode Cl(-)-channels or Cl(-)/H(+)-exchangers. CLC proteins assemble to dimers, with each monomer containing an ion translocation pathway. Some mammalian isoforms need essential beta -subunits (barttin and Ostm1). Crystal structures of bacterial CLC Cl(-)/H(+)-exchangers, combined with transport analysis of mammalian and bacterial CLCs, yielded surprising insights into their structure and function. The large cytosolic carboxy-termini of eukaryotic CLCs contain CBS domains, which may modulate transport activity. Some of these have been crystallized. Mammals express nine CLC isoforms that differ in tissue distribution and subcellular localization. Some of these are plasma membrane Cl(-) channels, which play important roles in transepithelial transport and in dampening muscle excitability. Other CLC proteins localize mainly to the endosomal-lysosomal system where they may facilitate luminal acidification or regulate luminal chloride concentration. All vesicular CLCs may be Cl(-)/H(+)-exchangers, as shown for the endosomal ClC-4 and -5 proteins. Human diseases and knockout mouse models have yielded important insights into their physiology and pathology. Phenotypes and diseases include myotonia, renal salt wasting, kidney stones, deafness, blindness, male infertility, leukodystrophy, osteopetrosis, lysosomal storage disease and defective endocytosis, demonstrating the broad physiological role of CLC-mediated anion transport.     

Vascular physiology and pathology of circulating xanthine oxidoreductase: from nucleotide sequence to functional enzyme

The evolutionarily conserved, cofactor-dependent, enzyme xanthine oxidoreductase exists in both cell-associated and circulatory forms. The exact role of the circulating form is not known; however, several putative physiological and pathological functions have been suggested that range from purine catabolism to a mediator of acute respiratory distress syndrome. Regulation of gene expression, cofactor synthesis and insertion, post-translational conversion, entry into the circulation, and putative physiological and pathological roles for human circulating xanthine oxidoreductase are discussed.     

Rhes: a GTP-binding protein integral to striatal physiology and pathology

Rhes, the Ras Homolog Enriched in Striatum, is a GTP-binding protein whose gene was discovered during a screen for mRNAs preferentially expressed in rodent striatum. This 266 amino acid protein is intermediate in size between small Ras-like GTP-binding proteins and α-subunits of heterotrimeric G proteins. It is most closely related to another Ras-like GTP-binding protein termed Dexras1 or AGS1. Although subsequent studies have shown that the rhes gene is expressed in other brain areas in addition to striatum, the striatal expression level is relatively high, and Rhes protein is likely to play a vital role in striatal physiology and pathology. Indeed, it has recently been shown to interact with the Huntingtin protein and play a pivotal role in the selective vulnerability of striatum in Huntington's disease (HD). Not surprisingly, Rhes can interact with multiple proteins to affect striatal physiology at multiple levels. Functional studies have indicated that Rhes plays a role in signaling by striatal G protein-coupled receptors (GPCR), although the details of the mechanism remain to be determined. Rhes has been shown to bind to both α- and β-subunits of heterotrimeric G proteins and to affect signaling by both Gi/o- and Gs/olf-coupled receptors. In this context, Rhes can be classified as a member of the family of accessory proteins to GPCR signaling. With documented effects in dopamine- and opioid-mediated behaviors, an interaction with thyroid hormone systems and a role in HD pathology, Rhes is emerging as an important protein in striatal physiology and pathology.     

Stem cell research: from molecular physiology to therapeutic applications

Stem cell research promises remedies to many devastating diseases that are currently incurable, ranging from diabetes and Parkinson’s disease to paralysis. Totipotent embryonic stem cells have great potential for generating a wide     

Inositide signaling in the nucleus: From physiology to pathology

A inositide-dependent signaling exists in the nucleus. In this review we focused to the nuclear PI-PLC signaling activity, its downstream effects and its role in haematological malignancies. PI-PLC β1 is involved in the physiological control of the cell cycle and by acting on the Cylin D3 promoter plays a crucial role in the process of C2C12 myoblast differentiation. In hematological malignancies recent studies showed that PI-PLC β1 mono-allelic deletion correlates with a higher risk of AML evolution. Moreover it has been shown that PI-PLC β1 promoter is hypermethylated in high-risk MDS patients and that the amount of PI-PLC β1 mRNA could predict the clinical response to azacitidine, a well known demethylating drug.All in all the data reviewed here pave the way to a new prognostic and therapeutic strategy in some haematological malignancies.