Fibulins and cancer: friend or foe?

The fibulins are a family of secreted glycoproteins, which are characterised by repeated epidermal-growth-factor-like domains and a unique C-terminal structure. Six distinct fibulin genes, encoding at least nine protein products generated by alternative splicing, have been identified. Considerable evidence is available pointing towards a structural role for fibulins within the extracellular matrix. Fibulins have been shown to modulate cell morphology, growth, adhesion and motility. The dysregulation of certain fibulins occurs in a range of human disorders, including cancer. Indeed, both tumour suppressive and oncogenic activities have been proposed for members of the fibulin family. Herein, we discuss the possible roles of fibulins in cancer, in addition to their diagnostic and therapeutic potential.     

Cardiac fibroblasts: friend or foe?

Cardiac function is determined by the dynamic interaction of various cell types and the extracellular matrix that composes the heart. This interaction varies with the stage of development and the degree and duration of mechanical, chemical, and electrical signals between the various cell types and the ECM. Understanding how these complex signals interact at the molecular, cellular, and organ levels is critical to understanding the function of the heart under a variety of physiological and pathophysiological conditions. Quantitative approaches, both in vivo and in vitro, are essential to understand the dynamic interaction of mechanical, chemical, and electrical stimuli that govern cardiac function. The fibroblast can thus be a friend in normal function or a foe in pathophysiological conditions.     

Alcohol: friend or foe to the cardiovascular system?

Epidemiological data show that light-to-moderate drinkers, especially those over 50 years of age, are more healthy in every way than non-drinkers. Although the J-shaped all-cause mortality curves may indicate that small quantities of alcohol (for some age groups) can confer good health, researchers are beginning to realize that drinking habits also reflect far more powerful underlying risk factors such as socio-economic class, education and general ill-health. Epidemiologists, cardiologists, statisticians, public health experts and sociologists met at the Novartis Foundation in London in October 1997 to discuss this vexed question in light of the new clinical, biochemical and sociological data that have emerged in recent months. In the red corner, statisticians and sociologists, such as Professor Kaye Fillimore (Institute of Health and Ageing, San Francisco, CA, USA) showed that outdated, ineffectual questionnaires, unreliable reporting and poor statistical classification have probably vastly exaggerated the so-called `beneficial' effect of alcohol. Furthermore, Dr Gerry Shaper (Mill Hill, London, UK) pointed out, vital information about changes in drinking pattern over time and the effects of heavy drinking in youth are being lost by the practice of lumping together lifelong teetotallers and ex-drinkers as one all purpose category, `non-drinkers'. But the biochemists in the blue corner were far more enthusiastic. Professor Ian Puddey (University of Western Australia, Perth, Australia) reviewed the possible role of the free radicals and antioxidants in alcoholic beverages in protecting against coronary heart disease. His in vitro studies have shown that polyphenolic compounds, such as flavonoids and phenolic acids, can dose-dependently inhibit serum and low-density lipoprotein (LDL) oxidation. Beverages containing high levels of polyphenols, such as red wine and dark beers, have a greater antioxidant effect than white wine and other substances with a low polyphenol content. However, Puddey was careful to point out that these findings are not sufficient to send us reaching for the Bordeaux—for two reasons. First, there have not as yet been any convincing in vivo studies of this phenomenon and, second, the much-vaunted flavonoids and polyphenolics are in fact present in a large number of plant products including tea, fruit, onions, and olive oil. So assuming for a moment that much of the `beneficial' effect of alcohol arises from the antioxidant effect of the polyphenolic compounds therein, why don't we all switch to red grape juice instead and save ourselves from possible cirrhosis, cancers, haemorrhagic strokes, memory loss, addiction, violence and suicide? Well, quite apart from the fact that many people actually enjoy the taste of `a real drink', it is the ethanol, explained Michael Gaziano (Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA) that does a lot of good, regardless of beverage type. Ethanol raises high-density lipoprotein (HDL) levels. HDL has long been known to protect against heart disease; it is involved in transporting cholesterol from artery walls back to the liver and might interfere with platelet aggregation and stimulate fibrinolysis. `It may not be the only mechanism at play' he conceded, `but I do think it is most likely to be the most important mechanism.' But given that alcohol's `protective effect' only really applies to the over fifties and is probably in the region of 1–3 fewer heart attacks per 1000 person years, `what we need now,' said Gaziano, `is more data on free-living humans so that we can learn about the risk: benefit ratio in different populations.' Until then the symposiasts agreed that it would be sheer folly to plug the so-called beneficial effects of drinking alcohol as though it were some amazing new prophylactic. `Not only could positive public health messages increase heavy drinking,' warned Dr Peter Anderson (WHO), `but they would also present a very misleading image of alcohol to developing world societies unaccustomed to drinking.' `We must not just extrapolate from epidemiological data to public health messages,' cautioned chairman Professor Tim Peters (King's College School of Medicine and Dentistry, London, UK). `To move forward from here', he concluded, `we need some viable animal models, more biochemistry, more genetics, and a good, easy-to-measure, non-invasive blood-alcohol marker so that we can find out once and for all how much people really drink!'     

Luminal sulfide and large intestine mucosa: friend or foe?

Hydrogen sulfide (H₂S) is present in the lumen of the human large intestine at millimolar concentrations. However, the concentration of free (unbound) sulfide is in the micromolar range due to a large capacity of fecal components to bind the sulfide. H₂S can be produced by the intestinal microbiota from alimentary and endogenous sulfur-containing compounds including amino acids. At excessive concentration, H₂S is known to severely inhibit cytochrome c oxidase, the terminal oxidase of the mitochondrial electron transport chain, and thus mitochondrial oxygen (O₂) consumption. However, the concept that sulfide is simply a metabolic troublemaker toward colonic epithelial cells has been challenged by the discovery that micromolar concentration of H₂S is able to increase the cell respiration and to energize mitochondria allowing these cells to detoxify and to recover energy from luminal sulfide. The main product of H₂S metabolism by the colonic mucosa is thiosulfate. The enzymatic activities involved in sulfide oxidation by the colonic epithelial cells appear to be sulfide quinone oxidoreductase considered as the first and rate-limiting step followed presumably by the action of sulfur dioxygenase and rhodanese. From clinical studies with human volunteers and experimental works with rodents, it appears that H₂S can exert mostly pro- but also anti-inflammatory effects on the colonic mucosa. From the available data, it is tempting to propose that imbalance between the luminal concentration of free sulfide and the capacity of colonic epithelial cells to metabolize this compound will result in an impairment of the colonic epithelial cell O₂ consumption with consequences on the process of mucosal inflammation. In addition, endogenously produced sulfide is emerging as a prosecretory neuromodulator and as a relaxant agent toward the intestinal contractibility. Lastly, sulfide has been recently described as an agent involved in nociception in the large intestine although, depending on the experimental design, both pro- and anti-nociceptive effects have been reported.     

Inflammation in viral myocarditis: friend or foe?

Viral myocarditis is an important cause of heart failure for which no specific treatments are available. Direct viral injury to cardiac cells provokes an inflammatory response that significantly contributes to cardiac damage and ensuing morbidity. Despite the central pathogenic role of autoimmune injury, broad inhibition of the inflammatory response does not result in patient benefit. Many preclinical studies collectively emphasize that modulating distinct inflammatory signaling pathways may yield effective viral clearance while preserving cardiac structure. This review aims to provide an overview of the sometimes contrasting observations from experimental viral myocarditis models and to translate the lessons learned into opportunities for future investigations and therapies.     

Parasites in biodiversity conservation: friend or foe?

Parasites stabilise food webs and facilitate species coexistence but can also lead to population- or species-level extinctions. So, in biodiversity conservation, are parasites friends or foes? This question is misleading: it implies that parasites are not part of biodiversity. Greater integration of parasites into global biodiversity and ecosystem conservation efforts is required.     

Amyloid in neurodegenerative diseases: friend or foe?

Accumulation of amyloid-like aggregates is a hallmark of numerous neurodegenerative disorders such as Alzheimer's and polyglutamine disease. Yet, whether the amyloid inclusions found in these diseases are toxic or cytoprotective remains unclear. Various studies suggest that the toxic culprit in the amyloid folding pathway is actually a soluble oligomeric species which might interfere with normal cellular function by a multifactorial mechanism including aberrant protein-protein interactions. Molecular chaperones suppress toxicity of amyloidogenic proteins by inhibiting aggregation of non-native disease substrates and targeting them for refolding or degradation. Paradoxically, recent studies also suggest a protective action of chaperones in their promotion of the assembly of large, tightly packed, benign aggregates that sequester toxic protein species.