Lipid-lowering drugs

Although a change in life-style is often the method of first choice for lipid lowering, lipid-lowering drugs, in general, help to control elevated levels of different forms of lipids in patients with hyperlipidemia. While one group of drugs, statins, lowers cholesterol, the other group, fibrates, is known to take care of fatty acids and triglycerides. In addition, other drugs, such as ezetimibe, colesevelam, torcetrapib, avasimibe, implitapide, and niacin are also being considered to manage hyperlipidemia. As lipids are very critical for cardiovascular diseases, these drugs reduce fatal and nonfatal cardiovascular abnormalities in the general population. However, a number of recent studies indicate that apart from their lipidlowering activities, statins and fibrates exhibit multiple functions to modulate intracellular signaling pathways, inhibit inflammation, suppress the production of reactive oxygen species, and modulate T cell activity. Therefore, nowadays, these drugs are being considered as possible therapeutics for several forms of human disorders including cancer, autoimmunity, inflammation, and neurodegeneration. Here I discuss these applications in the light of newly discovered modes of action of these drugs. Received 5 September 2005; received after revision 29 December 2005; accepted 26 January 2006     

Phytanic acid: production from phytol, its breakdown and role in human disease

Phytanic acid is a branched-chain fatty acid that accumulates in a variety of metabolic disorders. High levels of phytanic acid found in patients can exceed the millimolar range and lead to severe symptoms. Degradation of phytanic acid takes place by α-oxidation inside the peroxisome. A deficiency of its breakdown, leading to elevated levels, can result from either a general peroxisomal dysfunction or from a defect in one of the enzymes involved in α-oxidation. Research on Refsum disease, belonging to the latter group of disorders and characterized by a deficiency of the first enzyme of α-oxidation, has extended our knowledge of phytanic acid metabolism and pathology of the disease greatly over the past few decades. This review will centre on this research on phytanic acid: its origin, the mechanism by which its α-oxidation takes place, its role in human disease and the way it is produced from phytol. Received 4 October 2005; received after revision 24 February 2006; accepted 26 April 2006     

Understanding the importance of selenium and selenoproteins in muscle function

Selenium is an essential trace element. In cattle, selenium deficiency causes dysfunction of various organs, including skeletal and cardiac muscles. In humans as well, lack of selenium is associated with many disorders, but despite accumulation of clinical reports, muscle diseases are not generally considered on the list. The goal of this review is to establish the connection between clinical observations and the most recent advances obtained in selenium biology. Recent results about a possible role of selenium-containing proteins in muscle formation and repair have been collected. Selenoprotein N is the first selenoprotein linked to genetic disorders consisting of different forms of congenital muscular dystrophies. Understanding the muscle disorders associated with selenium deficiency or selenoprotein N dysfunction is an essential step in defining the causes of the disease and obtaining a better comprehension of the mechanisms involved in muscle formation and maintenance. Received 13 July 2005; received after revision 9 September 2005; accepted 4 October 2005     

Memory

Memories become stabilized through a time-dependent process that requires gene expression and is commonly known as consolidation. During this time, memories are labile and can be disrupted by a number of interfering events, including electroconvulsive shock, trauma and other learning or the transient effect of drugs such as protein synthesis inhibitors. Once consolidated, memories are insensitive to these disruptions. However, they can again become fragile if recalled or reactivated. Reactivation creates another time-dependent process, known as reconsolidation, during which the memory is restabilized. Here we discuss some of the questions currently debated in the field of memory consolidation and reconsolidation, the molecular and anatomical requirements for both processes and, finally, their functional relationship.     

CXorf6 is a causative gene for hypospadias

46,XY disorders of sex development (DSD) refer to a wide range of abnormal genitalia, including hypospadias, which affects approximately 0.5% of male newborns. We identified three different nonsense mutations of CXorf6 in individuals with hypospadias and found that its mouse homolog was specifically expressed in fetal Sertoli and Leydig cells around the critical period for sex development. These data imply that CXorf6 is a causative gene for hypospadias.     

Differentiated cells are more efficient than adult stem cells for cloning by somatic cell nuclear transfer

Since the creation of Dolly via somatic cell nuclear transfer (SCNT), more than a dozen species of mammals have been cloned using this technology. One hypothesis for the limited success of cloning via SCNT (1%-5%) is that the clones are likely to be derived from adult stem cells. Support for this hypothesis comes from the findings that the reproductive cloning efficiency for embryonic stem cells is five to ten times higher than that for somatic cells as donors and that cloned pups cannot be produced directly from cloned embryos derived from differentiated B and T cells or neuronal cells. The question remains as to whether SCNT-derived animal clones can be derived from truly differentiated somatic cells. We tested this hypothesis with mouse hematopoietic cells at different differentiation stages: hematopoietic stem cells, progenitor cells and granulocytes. We found that cloning efficiency increases over the differentiation hierarchy, and terminally differentiated postmitotic granulocytes yield cloned pups with the greatest cloning efficiency.     

Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration

Age-related macular degeneration (AMD) is a common, late-onset disease with seemingly typical complexity: recurrence ratios for siblings of an affected individual are three- to sixfold higher than in the general population, and family-based analysis has resulted in only modestly significant evidence for linkage. In a case-control study drawn from a US-based population of European descent, we have identified a previously unrecognized common, noncoding variant in CFH, the gene encoding complement factor H, that substantially increases the influence of this locus on AMD, and we have strongly replicated the associations of four other previously reported common alleles in three genes (P values ranging from 10(-6) to 10(-70)). Despite excellent power to detect epistasis, we observed purely additive accumulation of risk from alleles at these genes. We found no differences in association of these loci with major phenotypic categories of advanced AMD. Genotypes at these five common SNPs define a broad spectrum of interindividual disease risk and explain about half of the classical sibling risk of AMD in our study population.