Visfatin: the missing link between intra-abdominal obesity and diabetes?

Human obesity-related diabetes and the accompanying metabolic disorders have been specifically linked to increased visceral adipose tissue mass. Understanding the differences in biology of the two human fat depots (visceral and subcutaneous) might hold the key to therapeutic strategies aimed at reducing obesity-induced insulin resistance and alleviating symptoms of the metabolic syndrome. Visfatin (pre-B-cell colony-enhancing factor, PBEF) is a novel adipokine that appears to be preferentially produced by visceral adipose tissue and has insulin-mimetic actions. Could this molecule hold the key to future treatments for type 1 and 2 diabetes? This article discusses the pros and cons of visfatin action and how it might affect future therapeutic strategies.     

Siderosomal ferritin. The missing link between ferritin and haemosiderin?

A minor electrophoretically fast component was found in ferritin from iron-loaded rat liver in addition to a major electrophoretically slow ferritin similar to that observed in control rats. The electrophoretically fast ferritin showed immunological identity with the slow component, but on electrophoresis in SDS it gave a peptide of 17.3 kDa, in contrast with the electrophoretically slow ferritin, which gave a major band corresponding to the L-subunit (20.7 kDa). Thus the electrophoretically fast ferritin resembles that reported by Massover [(1985) Biochim. Biophys. Acta 829, 377-386] in livers of mice with short-term parenteral iron overload. The electrophoretically fast ferritin had a lower iron content (2000 Fe atoms/molecule) than the electrophoretically slow ferritin (3000 Fe atoms/molecule). Removal and re-incorporation of iron was possible without effect on the electrophoretic mobility of either ferritin species. On subcellular fractionation the electrophoretically fast ferritin was enriched in pellet fractions and was the sole soluble ferritin isolated from iron-laden secondary lysosomes (siderosomes). The amount and relative proportion of the electrophoretically fast species increased with iron loading. Haemosiderin isolated from siderosomes was found to contain a peptide reactive to anti-ferritin serum and corresponding to the 17.3 kDa peptide of the electrophoretically fast ferritin species. Unlike the electrophoretically slow ferritin, the electrophoretically fast ferritin did not become significantly radioactive in a 1 h biosynthetic labelling experiment. We conclude that the minor ferritin is not, as has been suggested for mouse liver ferritin, 'a completely new species of smaller holoferritin that represents a shift in the ferritin phenotype' in response to siderosis, but a precursor of haemosiderin, in agreement with the proposal by Richter [(1984) Lab. Invest. 50, 26-35] concerning siderosomal ferritin.     

CFTR: a missing link between exocrine and endocrine pancreas?

<正>Cystic fibrosis(CF),a life-shortening hereditary disease mainly afflicting people of Caucasian origins,is caused by loss-of-function mutations in the CFTR(Cystic Fibrosis Transmembrane conductance Regulator)gene,which encodes a phosphorylation-activated,but ATP-gated anion channel expressed primarily in epithelial cells.To date,nearly 2000 mutations have been identified as pathogenic,     

Is urodilatin the missing link in exercise-dependent renal sodium retention?

Schmidt, W., A. Bub, M. Meyer, T. Weiss, D. Schneider, N. Maassen, and W. G. Forssmann. Is urodilatin the missing link inexercise-dependent renal sodium retention? J. Appl.Physiol. 84(1): 123-128, 1998.The purpose of thepresent study was to investigate the behavior of plasma atrialnatriuretic peptide [ANP-(99126)] concentration([ANP]) and renal urodilatin [Uro; ANP-(95126)] excretion during and after exercise and theirpossible effects on renal Na⁺retention. Ten male subjects performed a cycle ergometer test for 60 min at 60% of maximum workload. Blood and urine samples were collectedbefore, during, and up to 24 h after exercise. During exercise, plasma[ANP] and renal Uro excretion were oppositely affected:whereas [ANP] increased from 46.5 ± 5.1 to 124.1 ± 10.6 pg/ml, urinary Uro excretion decreased from 120.8 ± 16.0 to49.5 ± 9.8 fmol/min and remained at a lower level until 1 h afterexercise. Glomerular filtration rate showed lowest values duringexercise (from 164.9 ± 15.3 to 75.8 ± 10.1 ml/min), and urineflow and the fractional excretion rate ofNa⁺(FE_Na⁺) andCl()had their nadir during the first hour after exercise. Positiverelationships were observed between Uro excretion andFE_Na⁺(P < 0.05) and, whereas a tendency toward a negative correlation was obtained between[ANP] andFE_Na⁺. It seemspossible that Uro may be, among other factors, involved in theexercise-related regulation of renalNa⁺ retention. The specific rolesUro and ANP play during exercise, however, remain to be investigated.

     

Polyoxovanadates: The missing link between simple paramagnets and bulk magnets?

Oxovanadium clusters provide novel examples of large magnetic clusters, which may showin nuce the typical behavior of bulk magnetic materials.The paper reviews the magnetic properties of V₁₅, comprising fifteen oxovanadium(IV); V₁₄, comprising fourteen oxovanadium(IV); V₃₊₁, comprising three localized oxovanadium(IV), six localized oxovanadium(V), and one oxovanadium(IV) delocalized over three sites; V₄₊₂ and V₄₊₄ which comprise four localized and two and four delocalized oxovanadium(IV), respectively. The different observed magnetic behaviors are discussed on the basis of several models of different sophistication.     

Is there a link between telomere maintenance and radiosensitivity?

Several recent studies point to the possibility that telomere maintenance may constitute a potential genetic marker of radiosensitivity. For example, the human diseases ataxia telangiectasia and Nijmegen breakage syndrome, which are characterized by clinical radiosensitivity, show alterations in telomere maintenance. In addition, Fanconi's anemia patients, who are characterized by mild cellular radiosensitivity and in some cases marked clinical radiosensitivity, have altered telomere maintenance. Similarly, a correlation between telomere maintenance and cellular radiosensitivity was reported in a group of breast cancer patients. Another study demonstrated that radiosensitivity may be more pronounced in human fibroblasts with short telomeres than in their counterparts with long telomeres. Several mouse models including mice deficient in Ku, DNA-PKcs (Prkdc), Parp and Atm, all of which are radiosensitive in vivo, show clear telomere alterations. The link between telomere maintenance and radiosensitivity is also apparent in mice genetically engineered to have dysfunctional telomeres. Finally, studies using non-mammalian model systems such as C. elegans and yeast point to the link between radiosensitivity and telomere maintenance. These results warrant further investigation to identify the extent to which these two phenotypes, namely radiosensitivity and telomere maintenance, are linked.     

Is immune cell activation the missing link in the pathogenesis of post-diarrhoeal HUS?

Haemolytic uraemic syndrome (HUS), which is caused by Shiga toxin (Stx)-producing Escherichia coli, is the commonest cause of acute renal failure in childhood. It is widely believed that HUS develops following the release of Stx, an AB5 toxin that inhibits protein synthesis and has a direct toxic effect on the kidney endothelium. There remains, however, a mismatch between the current understanding of the pathogenesis of HUS and the evolution of the clinical signs of the disease. Our hypothesis is that Stx-mediated immune cell activation in the gut is the missing link in the pathogenesis of this condition, initiating the characteristic renal pathology of HUS either alone or in synergy with Stx. Validation of this hypothesis could lead to a targeted anti-inflammatory approach aimed at modulating immune cell function in HUS.     

Innate immunity: the missing link in neuroprotection and neurodegeneration?

Innate immunity was previously thought to be a nonspecific immunological programme that was engaged by peripheral organs to maintain homeostasis after stress and injury. Emerging evidence indicates that this highly organized response also takes place in the central nervous system. Through the recognition of neuronal fingerprints, the long-term induction of the innate immune response and its transition to an adaptive form might be central to the pathophysiology and aetiology of neurodegenerative disorders. Paradoxically, this response also protects neurons by favouring remyelination and trophic support afforded by glial cells.     

Apoptosis in Parkinson's disease: is p53 the missing link between genetic and sporadic Parkinsonism?

Parkinson's disease (PD) is a major age-related neurodegenerative disorder characterized by a massive and specific loss of dopaminergic neurons of the substantia nigra pars compacta. The cellular alterations are clinically translated into an invalidating movement disability associated to three canonical symptoms that are bradykinesia, resting tremor and rigidity. The exact causes of this neuronal loss are unknown, but a network of evidences indicates a major contribution of orchestrated cell death processes, also known as apoptosis. Apoptotic cell death is a normal process, the alteration of which triggers several pathologies including cancer and neurodegenerative disorders. Exhaustive work has been done to delineate the cellular mechanisms responsible for the exacerbated cell death of dopaminergic neurons observed in PD. Overall, the oncogene p53 has been identified as a key effector protein.This review will focus on the clues linking p53 to the etiology of PD and the evidences that this protein may be at the center of multiple signaling cascades not only altered by mutations of various proteins responsible for familial cases of PD but also on more general sporadic cases of this devastating disease.     

Interleukin-17: the missing link between T-cell accumulation and effector cell actions in rheumatoid arthritis?

The prominence of T cells and monocyte/macrophages in rheumatoid synovium suggests T cells may localize and amplify the effector functions of monocyte/macrophages in rheumatoid disease. However, while T cells are abundant in rheumatoid joints, classic T-cell derived cytokines are scarce, especially when compared to the levels of monokines IL-1 beta and TNF-alpha. For this reason, it has been speculated that monocyte/macrophages may act independently of T cells in rheumatoid disease and that the role of T cells may be more or less irrelevant to core disease mechanisms. The question of T-cell influence requires re-evaluation in light of the characterization of IL-17, a T-cell derived cytokine that is abundant in rheumatoid synovium and synovial fluid. IL-17 has a number of pro-inflammatory effects, both directly and through amplification of the effects of IL-1 beta and TNF-alpha. IL-17 is able to induce expression of pro-inflammatory cytokines and stimulate release of eicosanoids by monocytes and synoviocytes. Furthermore, IL-17 has been implicated in the pathogenesis of inflammatory bone and joint damage through induction of matrix metalloproteinases and osteoclasts, as well as inhibition of proteoglycan synthesis. In animal models of arthritis, intra-articular injection of IL-17 results in joint inflammation and damage. The recognition of IL-17 as a pro-inflammatory T cell derived cytokine, and its abundance within rheumatoid joints, provides the strongest candidate mechanism to date through which T cells can capture and localize macrophage effector functions in rheumatoid arthritis. As such, IL-17 warrants consideration for its potential as a therapeutic target in rheumatoid arthritis.     

Hyperinsulinemia: the missing link among oxidative stress and age-related diseases?

Mounting evidence supports Harman’s hypothesis that aging is caused by free radicals and oxidative stress. Although it is known that oxidant species are produced during metabolic reactions, it is largely unknown which factor(s), of physiological or pathophysiological significance, modulate their production in vivo. In this hypothesis paper, it is postulated that hyperinsulinemia may have such function and therefore promote aging, independently of elevations of glycemia. Hyperinsulinemia is secondary to impaired insulin stimulated glucose metabolism at the level of skeletal muscle (insulin resistance) and is seen in about one third of glucose tolerant humans following dietary carbohydrate intake. If other insulin-stimulated (or inhibited) pathways retain normal sensitivity to the hormone, hyperinsulinemia could, by its effects on antioxidative enzymes and on free radical generators, enhance oxidative stress. Other proaging effects of insulin involve the inhibition of proteasome and the stimulation of polyunsaturated fatty acid (PUFA) synthesis and of nitric oxide (NO). The hypothesis that hyperinsulinemia accelerates aging also offers a metabolic explanation for the life-prolonging effect of calorie restriction and of mutations decreasing the overall activity of insulin-like receptors in the nematode Caenorhabditis elegans.     

Is time on our side? Strengthening the link between field efforts and conservation needs

The collection and organization of distributional data is the first crucial stage of any conservation planning action: therefore the decline in field research has implications in both the systematic, floristic and conservation fields. The aim of this paper is to analyze the effects of data updating on conservation planning and priorities. Focusing on the short time frame ranging from 2006 to 2011, we present a case study showing the rate of increase of collected data (taxa and records) and the consequential effects on the definition of areas of priority interest for plant conservation (Important Plant Areas—IPAs). We gathered data on a total of 193 taxa and 849 records with a mean rate of increase of +97 % for taxa and +166 % for records (2006/2011). This increase caused a positive rate of change in high ranking cells (+78 %) defining IPAs, while the number of low ranking cells and no data cells slightly decreased (?12 and ?8 %, respectively). Our results suggest that specific investment to complete the knowledge on the distribution of selected taxa (e.g. 193 taxa represent the 7.5 % of the total vascular flora of Sardinia) would dramatically reduce both the Linnean and Wallacean shortfalls and would allow robust conservation programs to preserve the diversity of the island. Updating the IPAs on a regular basis is a good example of a process that has a low impact as well as a big potential gain especially when field research can only be performed with low intensity and small monetary investments.     

Calcium influx: is Homer the missing link?

Calcium signals in cells can arise via release from intracellular stores or influx across the plasma membrane. Recent studies have shed new light on the multi-protein signalling complexes that mediate communication between calcium stores and plasma membrane calcium channels.     

Is crossover between the X and Y a regular feature of meiosis in mouse and man?

There has long been an assumption that normal disjunction of the sex chromosomes of all mammals is assured by synapsis of a region of homology between the X and Y and that an obligatory crossover with chiasmata formation follows. Evidence is presented here that much (if not all) observed synapsis between the X and Y in mouse and man is nonhomologous and that crossing over most likely does not occur as a normal event in these organisms. The X and Y have desynapsed to a mere terminal association by the time of pachytene DNA synthesis, generally considered to be associated with crossing over. Recombination nodules or bars observed on the X and Y of human spermatocytes are also present at the wrong substage of pachytene and are insufficient in frequency to accounf for an obligatory crossover between the X and Y and thus assure normal disjunction. Instead it is suggested that orientation and disjunction of the sex chromosomes is mediated in these species by an achiasmatic telomeric association.     

A relation between TGF-β and mast cell tryptase in experimental emphysema models

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by emphysema and/or chronic bronchitis. The aim of this study was to investigate the effect of cigarette smoke exposure on mast cells and mast cell function in vitro and in vivo in order to get further insight in the role of mast cells in the pathogenesis of emphysema. Cigarette smoke conditioned medium (CSM) induced the expression of mast cell tryptase (MMCP-6) in primary cultured mast cells. This tryptase expression was caused by the CSM-stimulated production of TGF-β in culture and neutralization of TGF-β suppressed the CSM-induced expression of tryptase in mast cells. An increase in mast cell tryptase expression was also found in an experimental model for emphysema. Exposure of mice to cigarette smoke increased the number of mast cells in the airways and the expression of mast cell tryptase. In accordance with the in vitro findings, TGF-β in bronchoalveolar lavage fluid of smoke-exposed animals was significantly increased. Our study indicates that mast cells may be a source of TGF-β production after cigarette smoke exposure and that in turn TGF-β may change the tryptase expression in mast cells.