Folic acid and colorectal cancer prevention: molecular mechanisms and epidemiological evidence (Review)

Epidemiological studies suggest that a diet rich in fruits and vegetables protects against colorectal cancer. This effect may result from their high levels of folic acid (pteroylglutamic acid). Folic acid holds a key position in DNA synthesis and mitosis as well as DNA methylation and regulation of gene expression. Folic acid deficiency has been associated with site- and gene specific DNA hypo- and hypermethylation. Furthermore thymidylate synthesis is restricted by folic acid deficiency which causes misincorporation of nucleotides and DNA strand breaks. Much epidemiological evidence supports the hypothesis that insufficient folic acid supply favors the development of colorectal tumors, particularly prospective studies have supported this connection. However, the data from case-control studies are less consistent. Functional polymorphisms in folate-metabolizing genes, especially the methylenetetrahydrofolate reductase (MTHFR) are capable of modifying the risk of colorectal cancer. Observational studies show that individuals with the homozygote genotype for the MTHFR (677C-->T) polymorphism are at higher risk when folic acid supply is low. Currently there are only few human intervention trials which show that folic acid can modify and inhibit the development of colorectal tumors. Additional studies are required in order to determine whether folic acid will be a useful agent in colorectal cancer prevention.     

Expression of the Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) in EBV-associated nasopharyngeal carcinoma

The Epstein-Barr virus (EBV) is associated with virtually all cases of undifferentiated nasopharyngeal carcinoma (NPC) and has been classified as a group I carcinogen. In addition to its potential role in the pathogenesis of NPC, EBV also provides a possible target for immunotherapy of NPC, since a limited number of viral genes are expressed in the neoplastic cells. The EBV-encoded latent membrane protein 2A (LMP2A) is considered a promising target since it provides epitopes recognized by EBV-specific T-cells. Using immunohistochemistry, the present study shows that LMP2A is expressed at the protein level in the neoplastic cells of 16 of 35 (45.7%) NPC biopsies. This finding provides further evidence suggesting that NPC tumour cells may be susceptible to lysis by cytotoxic T-cells directed against LMP2A and should encourage efforts to develop immunotherapeutic approaches for the treatment of NPC.     

Early administration of tiapride to young rats without long-lasting changes in the development of the dopaminergic system

BACKGROUND: The benzamide tiapride, a selective dopamine D2/D3-receptor antagonist, can be used effectively in children to treat tic disorders and stuttering. Tiapride is a clinically safe substance (even during long-term treatment and when given to young children). Unfortunately, its probable effects on general brain development and the maturation of the dopaminergic system have not been investigated. Thus, important information for drug treatment in children is missing. Therefore, this study in rats describes tiapride's effects on several parameters of dopaminergic activity (dopamine transporter, D2 receptor, dopamine, DOPAC, and homovanillic acid in the striatum) seen after tiapride administration (30 mg/kg/day) to prepubertal (from day 25-39) and postpubertal (from day 50-64) rats. METHODS: Three groups of rats (n = 6) received tiapride within their drinking water for 14 days. Two groups were treated before puberty; one of those was killed at day 50, the other at day 90. The group treated after puberty was measured at day 90. A fourth group (n = 6) was treated from day 50 to day 53 and measured under tiapride at day 53. Changes were measured by ligand-binding assays (KD and Bmax values of dopamine transporter by [3H]-GBR binding and D2 receptor by [3H]- spiperone binding) and by HPLC (concentrations of dopamine, DOPAC, and homovanillic acid). RESULTS: The density of dopamine transporters and D2 receptors remained unaffected after early (day 25) and late (day 50) tiapride administration. Only during the treatment period could a significant reduction of D2-receptor binding (displacement of spiperone) and of dopamine and DOPAC levels be stated. CONCLUSIONS: These data suggest that tiapride treatment during postnatal brain development causes no long-lasting changes in the development of the central dopaminergic system and is in line with clinical experience in children.     

Amniotic air insufflation during minimally invasive fetoscopic fetal cardiac interventions is safe for the fetal brain in sheep

BACKGROUND: Amniotic air insufflation during experimental fetoscopic fetal cardiac interventions greatly improves the visualization of intra-amniotic contents. The purpose of this study was to assess any histologically discernible effects from this approach on the fetal brain after short-term studies and long-term survival in sheep. METHODS: Thirty pregnant ewes between 80 and 110 days of gestation underwent amniotic air insufflation during various fetoscopic fetal cardiac interventions. After 18 short-term and 12 long-term studies, the brains of the operated fetuses and-if available-their unoperated siblings were examined for hemorrhage, embolism, infarctions, inflammatory changes, and abnormal cortical maturation. RESULTS: Amniotic air insufflation during minimally invasive fetoscopic fetal cardiac interventions did not result in any histologically discernible damage to the brain in short-term and long-term studies in any but 2 sibling sheep. In the 2 affected siblings, a small area of chronic cortical frontal lobe infarction was observed after long-term survival. CONCLUSIONS: Amniotic air insufflation during minimally invasive percutaneous fetoscopic fetal cardiac interventions is safe for the fetal brain and does not compromise maternal hemodynamics in sheep. These findings encourage further investigation of the role this technique might play during fetoscopic fetal cardiac interventions in humans.     

Characterization of plasminogen variants in healthy subjects and plasminogen mutants in patients with inherited plasminogen deficiency by isoelectric focusing gel electrophoresis

Plasmin(ogen) plays an important role in fibrinolysis and wound healing. Severe hypoplasminogenemia has recently been linked to ligneous conjunctivitis. Plasminogen (plg) is known as a polymorphic protein and most of these variants have been identified using isoelectric focusing (IEF) gel electrophoresis. Here, we studied common plg variants from healthy subjects and plg mutants from three patients with hypoplasminogenemia and three subjects with dysplasminogenemia by molecular genetic analysis and IEF. Analysis of 24 healthy subjects showed that subjects with the most common IEF plg phenotype A (n=12) were homozygous for aspartate at position 453 (453D), while both subjects with IEF plg phenotype B were homozygous for asparagine at this position (453N). Subjects with IEF plg phenotype AB (n=10) were compound-heterozygous for 453D/453N. Three patients with severe hypoplasminogenemia and different plg gene mutations exhibited characteristic "abnormal" IEF band patterns when compared with IEF plg phenotypes A and B. In all heterozygous family members the observed IEF plg phenotype was derived from the wild type plg molecule only, probably due to low concentration of the mutant plg molecule in plasma. In contrast, in three unrelated subjects with heterozygous dysplasminogenemia an equal "mixture" of wild type and mutant plg was found by IEF analysis. In conclusion, plg phenotyping by IEF in combination with molecular analysis of the plg gene seems to be a useful method for characterization of plg variants and mutants.     

Effects of acute psychological stress on adhesion molecules,interleukins and sex hormones: implications for coronary heart disease

Abstract Rationale. Subjects with high levels of daily stress suffer from an increased risk of coronary heart disease. Increased concentrations of the intercellular adhesion molecule-1 (ICAM-1) contribute to atherosclerosis. Cell adhesion molecules may be activated by psychological stress exposure, depending on their interaction with the interleukin network, sex hormones and cortisol secretion. Objectives. To assess effects of acute psychological stress on the interaction between cell adhesion molecules, interleukins, sex hormones and cortisol in healthy male subjects. Methods. Cell adhesion molecules, interleukin-1 beta (IL-1β), IL-2, IL-6, sex hormones and cortisol levels of 18 healthy male physicians were measured before and after an academic oral presentation and on a control day. Results. The oral presentation was perceived as a stressful event and was accompanied by a significant increase in cortisol secretion in all volunteers. Soluble ICAM-1 and IL-1β also increased in all subjects after psychological stress exposure. The stress-associated increase in IL-2 concentrations approached statistical significance and correlated negatively with luteinizing hormone plasma levels. Estradiol concentrations correlated positively with IL-6 levels. Conclusions. Subjective ratings and the increase in cortisol plasma concentrations support the validity of the chosen stress model. Acute stress exposure was followed by an increase in IL-1β, IL-2 and soluble ICAM-1 plasma concentrations, which can contribute to coronary heart disease and immunological disorders. Electronic Publication     

Tartrolone C: a novel insecticidal macrodiolide produced by Streptomyces sp. CP1130

A new member of the tartrolone series of macrodiolides, tartrolone C (1), was isolated from a Streptomyces species on the basis of its insecticidal activity. Metacycloprodigiosin (2) and undecylprodigiosin (3) were also isolated on the same basis. The structure of all compounds was established by spectroscopic data (NMR, MS, and UV).