Podocalyxin enhances the adherence of cells to platelets

Podocalyxin (PODXL) is a mucin protein of the CD34 family expressed in kidney glomerular podocytes, vascular endothelium, progenitor bone marrow and tumor cells. It is assumed that PODXL plays an anti-adherent role in kidney podocytes. CHO cells stably expressing human PODXL (CHO-PODXL) or human tumor cells (Tera-1) inherently expressing PODXL showed increased adherence to platelets. The adherence of cells was inhibited (70%) by blockers of platelet P-selectin, prevented by the soluble ectodomain of human PODXL (PODXL-Δ) or by the arginine-glycine-aspartate (RGDS) peptide and partially impeded by inhibition of integrin αVβ3/αVβ5, suggesting a coordinated action of P-selectin and integrins. Colocalization of platelet P-selectin and PODXL expressed on CHO cells was demonstrated by confocal immunofluorescence. No adherence to platelets was observed when PODXL was expressed in glycomutant CHO cells deficient in sialic acid. Received 14 August 2007; received after revision 12 September 2007; accepted 13 September 2007     

Cardiovascular development: towards biomedical applicability

Advances in our understanding of cardiac development have fuelled research into cellular approaches to myocardial repair of the damaged heart. In this collection of reviews we present recent advances into the basic mechanisms of heart development and the resident and non-resident progenitor cell populations that are currently being investigated as potential mediators of cardiac repair. Together these reviews illustrate that despite our current knowledge about how the heart is constructed, caution and much more research in this exciting field is essential. The current momentum to evaluate the potential for cardiac repair will in turn accelerate research into fundamental aspects of myocardial biology.     

Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer

The fraction of pyruvate dehydrogenase complex (PDC) in the active form is reduced by the activities of dedicated PD kinase isozymes (PDK1, PDK2, PDK3 and PDK4). Via binding to the inner lipoyl domain (L2) of the dihydrolipoyl acetyltransferase (E2 60mer), PDK rapidly access their E2-bound PD substrate. The E2-enhanced activity of the widely distributed PDK2 is limited by dissociation of ADP from its C-terminal catalytic domain, and this is further slowed by pyruvate binding to the N-terminal regulatory (R) domain. Via the reverse of the PDC reaction, NADH and acetyl-CoA reductively acetylate lipoyl group of L2, which binds to the R domain and stimulates PDK2 activity by speeding up ADP dissociation. Activation of PDC by synthetic PDK inhibitors binding at the pyruvate or lipoyl binding sites decreased damage during heart ischemia and lowered blood glucose in insulin-resistant animals. PDC activation also triggers apoptosis in cancer cells that selectively convert glucose to lactate. Received 25 August 2006; received after revision 20 November 2006; accepted 20 December 2006     

How plants recognize pathogens and defend themselves

Plants have an innate immunity system to defend themselves against pathogens. With the primary immune system, plants recognize microbe-associated molecular patterns (MAMPs) of potential pathogens through pattern recognition receptors (PRRs) that mediate a basal defense response. Plant pathogens suppress this basal defense response by means of effectors that enable them to cause disease. With the secondary immune system, plants have gained the ability to recognize effector-induced perturbations of host targets through resistance proteins (RPs) that mediate a strong local defense response that stops pathogen growth. Both primary and secondary immune responses in plants depend on germ line-encoded PRRs and RPs. During induction of local immune responses, systemic immune responses also become activated, which predispose plants to become more resistant to subsequent pathogen attacks. This review gives an update on recent findings that have enhanced our understanding of plant innate immunity and the arms race between plants and their pathogens. Received 24 June 2007; received after revision 18 July 2007; accepted 15 August 2007     

Phytanic acid impairs mitochondrial respiration through protonophoric action

Refsum disease is a rare, inherited neurodegenerative disorder characterized by accumulation of the dietary branched-chain fatty acid phytanic acid in plasma and tissues caused by a defect in the alphaoxidation pathway. The accumulation of phytanic acid is believed to be the main pathophysiological cause of the disease. However, the exact mechanism(s) by which phytanic acid exerts its toxicity have not been resolved. In this study, the effect of phytanic acid on mitochondrial respiration was investigated. The results show that in digitonin-permeabilized fibroblasts, phytanic acid decreases ATP synthesis, whereas substrate oxidation per se is not affected. Importantly, studies in intact fibroblasts revealed that phytanic acid decreases both the mitochondrial membrane potential and NAD(P)H autofluorescence. Taken together, the results described here show that unesterified phytanic acid exerts its toxic effect mainly through its protonophoric action, at least in human skin fibroblasts. Received 4 August 2007; received after revision 26 September 2007; accepted 10 October 2007 J. C. Komen, F. Distelmaier: These authors contributed equally to this work.     

Drugs of the future: the hormone relaxin

The peptide hormone relaxin is emerging as a multi-functional factor in a broad range of target tissues including several non-reproductive organs, in addition to its historical role as a hormone of pregnancy. This review discusses the evidence that collectively demonstrates the many diverse and vital roles of relaxin: the homeostatic role of endogenous relaxin in mammalian pregnancy and ageing; its gender-related effects; the therapeutic effects of relaxin in the treatment of fibrosis, inflammation, cardioprotection, vasodilation and wound healing (angiogenesis) amongst other pathophysiological conditions, and its potential mechanism of action. Furthermore, translational issues using experimental models (to humans) and its use in various clinical trials, are described, each with important lessons for the design of future trials involving relaxin. The diverse physiological and pathological roles for relaxin have led to the search for its significance in humans and highlight its potential as a drug of the future. Received 12 December 2006; received after revision 12 February 2007; accepted 15 March 2007     

tRNase Z: the end is not in sight

Although the enzyme tRNase Z has only recently been isolated, a plethora of data has already been acquired concerning the enzyme. tRNase Z is the endonuclease that catalyzes the removal of the tRNA 3′ trailer, yielding the mature tRNA 3′ end ready for CCA addition and aminoacylation. Another substrate cleaved by tRNase Z is the small chromogenic phosphodiester bis(p-nitrophenyl)phosphate (bpNPP), which is the smallest tRNase Z substrate known so far. Hitherto the biological function as tRNA 3′-end processing enzyme has been shown only in one prokaryotic and one eukaryotic organism, respectively. This review summarizes the present information concerning the two tRNase Z substrates pre-tRNA and bpNPP, as well as the metal requirements of tRNase Z enzymes. Received 29 March 2007; received after revision 15 May 2007; accepted 21 May 2007     

The molecular role of the Rothmund-Thomson-, RAPADILINO- and Baller-Gerold-gene product, RECQL4: recent progress

The RecQ family of DNA helicases is highly conserved throughout evolution and plays an important role in the maintenance of genomic stability in all organisms. Mutations in three of the five known family members in humans, BLM, WRN and RECQL4, give rise to disorders that are characterized by predisposition to cancer and premature aging, emphasizing the importance of studying the RecQ proteins and their cellular activities. Interestingly, three autosomal recessive disorders have been associated with mutations in the RECQL4 gene: Rothmund-Thomson, RAPADILINO, and Baller-Gerold syndromes, thus making RECQL4 unique within the RecQ family of DNA helicases. To date, however, the molecular function of RECQL4 and the possible cellular pathways in which it is involved remain poorly understood. Here, we present an overview of recent findings in connection with RECQL4 and try to highlight different directions the field could head, helping to clarify the role of RECQL4 in preventing tumorigenesis and maintenance of genome integrity in humans. Received 31 October 2006; received after revision 4 January 2007; accepted 5 February 2007     

Telomeres and meiosis in health and disease

Beyond their role in replication and chromosome end capping, telomeres are also thought to function in meiotic chromosome pairing, meiotic and mitotic chromosome segregation as well as in nuclear organization. Observations in both somatic and meiotic cells suggest that the positioning of telomeres within the nucleus is highly specific and believed to be dependent mainly on telomere interactions with the nuclear envelope either directly or through chromatin interacting proteins. Although little is known about the mechanism of telomere clustering, some studies show that it is an active process. Recent data have suggested a regulatory role for telomere chromatin structure in telomere movement. This review will summarize recent studies on telomere interactions with the nuclear matrix, telomere chromatin structure and factors that modify telomere chromatin structure as related to regulation of telomere movement.