Thematic Review Series: Bile Acids: Bile acids: regulation of apoptosis by ursodeoxycholic acid

Bile acids are a group of molecular species of acidic steroids with peculiar physical-chemical and biological characteristics. At high concentrations they become toxic to mammalian cells, and their presence is pertinent in the pathogenesis of several liver diseases and colon cancer. Bile acid cytoxicity has been related to membrane damage, but also to nondetergent effects, such as oxidative stress and apoptosis. Strikingly, hydrophilic ursodeoxycholic acid (UDCA), and its taurine-conjugated form (TUDCA), show profound cytoprotective properties. Indeed, these molecules have been described as potent inhibitors of classic pathways of apoptosis, although their precise mode of action remains to be clarified. UDCA, originally used for cholesterol gallstone dissolution, is currently considered the first choice therapy for several forms of cholestatic syndromes. However, the beneficial effects of both UDCA and TUDCA have been tested in other experimental pathological conditions with deregulated levels of apoptosis, including neurological disorders, such as Alzheimer''s, Parkinson''s, and Huntington''s diseases. Here, we review the role of bile acids in modulating the apoptosis process, emphasizing the anti-apoptotic effects of UDCA and TUDCA, as well as their potential use as novel and alternate therapeutic agents for the treatment of apoptosis-related diseases.     

Outcome of pregnancy in underweight women after spontaneous and induced ovulation

Low maternal weight before pregnancy and poor weight gain during pregnancy are known to result in an increased prevalence of low birthweight infants. Low body weight is also an important cause of amenorrhoea. The hypothesis that amenorrhoeic underweight women who become pregnant after induction of ovulation are more at risk of delivering low birthweight infants than underweight women who ovulate spontaneously was investigated. Forty one pregnant women in whom ovulation had been induced and 1212 in whom ovulation was spontaneous were studied. Women ovulating spontaneously whose weight was normal and who showed good weight gain during pregnancy (>450 g a week) had the lowest incidence (6%) of babies who were small for gestational age. Underweight women (body mass index <19·1) who ovulated spontaneously had a threefold increased risk of delivering babies who were small for gestational age (18%). Overall, the women in whom ovulation had been induced had an even higher risk of babies who were small for dates (25%), and this risk was greatest (54%) in those who were underweight.The outcome of pregnancy is related to weight before conception, which in many cases reflects nutritional state; lack of spontaneous ovulation indicates an increased risk of producing a small for dates infant. The most suitable treatment for infertility secondary to weight related amenorrhoea is therefore dietary rather than induction of ovulation.     

RepSeq – A database of amino acid repeats present in lower eukaryotic pathogens

Background  

Amino acid repeat-containing proteins have a broad range of functions and their identification is of relevance to many experimental biologists. In human-infective protozoan parasites (such as the Kinetoplastid and Plasmodium species), they are implicated in immune evasion and have been shown to influence virulence and pathogenicity. RepSeq is a new database of amino acid repeat-containing proteins found in lower eukaryotic pathogens. The RepSeq database is accessed via a web-based application which also provides links to related online tools and databases for further analyses.     

Game and players: mitochondrial apoptosis and the therapeutic potential of ursodeoxycholic acid

Apoptosis represents a universal and exquisitely efficient cellular suicide pathway essential for a variety of normal biological processes ranging from embryonic development to ageing. In fact, tissue homeostasis is dependent on the perfect balance between positive and negative signals that determines the decision between life and death. Therefore, any imbalance can result in a wide range of pathologic disorders associated with unwanted apoptosis or cell growth. During the apoptotic process, the molecular players interact closely with each other in ways relevant to accelerate or interrupt the cellular death process. In addition, two major pathways of apoptosis activation have been recognized as the "intrinsic" mitochondrial pathway and the "extrinsic" death receptor pathway. Although these pathways act independently to initiate apoptosis, a delicate balance and cross-talk between the extrinsic and intrinsic pathways is thought to occur in many cell types. Interestingly, we have shown that ursodeoxycholic acid (UDCA), an endogenous hydrophilic bile acid, is a potent inhibitor of apoptosis by either stabilizing the mitochondrial membrane or modulating the expression of specific upstream targets. Herein, we review the main effectors involved in the death machinery, describe how they interact to regulate apoptosis, and discuss the main pathways that control cell death and survival. Further, we address multiple interesting targets as well as the potential application of UDCA as a therapeutic modality for apoptosis-related disorders.     

The ecology of Helicoverpa spp. (Lepidoptera: Noctuidae) in the Riverina region of south-eastern Australia and the implications for tactical and strategic management

Decisions on the choice of appropriate tactical and strategic control techniques require an understanding of the seasonal distribution and ecology of the target species. To address this need, data were collected from 1997 to 2000 using crop surveys, field sampling and pheromone trapping to monitor the population trends of Helicoverpa armigera (Hübner) and H. punctigera (Wallengren) in the Riverina region of south-eastern Australia. The data gathered are compared to predictions from the HElicoverpa Armigera and Punctigera Simulation (HEAPS) model, that simulates Helicoverpa population dynamics to assist in identifying the drivers of regional populations and provide a framework to make informed decisions. The results highlight the contrasting seasonal dynamics of H. punctigera and H. armigera within the region. Helicoverpa punctigera populations peak in the spring, driven by large scale spring migration into the region and subsequently decline. Helicoverpa armigera populations, conversely, are characterized by a period of spring recruitment of adults from overwintering pupae within the region, followed by a within-season population increase leading to severe late season pressure. The within-season increase of H. armigera is a result of the succession of crop and non-crop hosts with the main driver being sequentially sown, unsprayed maize. Tactical and strategic management options are discussed in light of these findings.     

Moraxella catarrhalis stimulates the release of proinflammatory cytokines and prostaglandin E from human respiratory epithelial cells and monocyte-derived macrophages

The outer membrane proteins of Moraxella catarrhalis, a bacterial pathogen which causes disease in both children and adults, play an important role in its phenotypic properties. However, their proinflammatory potential with regard to respiratory epithelium and macrophages is unclear. To this end, we examined the cytokine- and mediator-inducing capacity of a heat-killed wild-type M. catarrhalis strain and a nonautoagglutinating mutant as well as their outer membrane proteins and secretory/excretory products using the A549 respiratory epithelial cell line. The outer membrane proteins and secretory/excretory products from both isolates as well as the heat-killed bacteria all induced interleukin (IL)-6, IL-8 and prostaglandin E2, but not IL-1beta, from the A549 cell line in a dose- and time-dependent manner. Heat-killed bacteria and secretory/excretory products stimulated the release of IL-1beta, IL-6, IL-8 and prostaglandin E2 from human monocyte-derived macrophages. Both heat-killed isolates also stimulated nuclear translocation and transactivation of nuclear factor-kappaB. The heat-killed wild-type autoagglutinating isolate induced significantly greater amounts of IL-6 and IL-8 from A549 cells than the nonautoagglutinating mutant compared with the monocyte-derived macrophages but no significant differences in the amounts induced by the two strains were observed. These differences were also evident when the respiratory cell line was stimulated with outer membrane proteins as well as in the degree of nuclear factor-kappaB transactivation. There was little difference in the stimulatory activity of the secretory/excretory products. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis analyses revealed some differences in the outer membrane proteins and secretory excretory products between the two isolates. Combined, these data show that M. catarrhalis secretory excretory products and outer membrane proteins are associated with the induction of inflammatory responses in both respiratory epithelium and macrophages.