Genetic and molecular data have implicated theAlternative splicing is a widespread mechanism of gene expression regulation frequently used during cell differentiation and development (1-3). Deficiencies in splice site selection have significant implications for a variety of diseases, including tumor progression, muscular dystrophy, and inflammatory responses (4, 5). The mechanisms underlying the control of splice site usage, however, are still poorly understood.Drosophila sex determination offers a system in which the factors involved in cascades of RNA processing events have been identified genetically. The gene Sxl controls the processes of sex determination, dosage compensation, and sexual behavior (6). It encodes an RNA-binding protein (SXL) 1 that is present exclusively in female flies and that induces female-specific patterns of alternative splicing of target genes. Female somatic differentiation and sexual behavior, for example, depend upon activation by SXL of a female-specific 3Ј splice site in the gene transformer (7-12). Use of the non-sex-specific 3Ј splice site results in mRNAs with little coding capacity because of the presence of premature stop codons. The stop codons are skipped when the female-specific 3Ј splice site is used, thus generating mRNAs that encode full-length TRA protein. In addition SXL controls splicing of its own pre-mRNA in an autoregulatory loop essential for the maintenance of sexual identity throughout the life of the fly (13). Genetic analyses have revealed three additional genes involved in at least some of the splicing events regulated by SXL: snf (sans-fille) (14), vir (virilizer) (15), and fl (2) (16). snf encodes the Drosophila homolog of two human splicing factors, U1A and U2BЉ, which are components of the U1 and U2 small nuclear ribonucleoprotein particles, respectively (14, 17). vir and fl (2)d encode nuclear proteins without significant homologies to characterized proteins in data bases (18,19).fl (2)d is required throughout development and adult life and is important for splicing regulation of Sxl and tra (transformer) pre-mRNAs (16,20), and these activities can account for the sex-specific phenotype associated with certain fl (2)d mutant alleles. The non-sex-specific lethal phenotype of other fl (2)d alleles suggests an additional function for the gene (21). The molecular mechanisms underlying these genetic interactions, however, have remained elusive. In this report we show that the FL (2)D protein forms complexes with SXL and VIR and that depletion of a FL (2)D human homolog from nuclear extracts affects tra splicing in vitro. These results argue that FL (2)D has a biochemical role in splicing regulation.Interestingly, hFL (2)D was independently identified as a protein that interacts with the WT1 (Wilms' tumor 1) protein (22). The tumor suppressor gene WT1 is important for genitourinary development, and its mutation is associated with Wilms' tumor, a common form of pediatric kidney cancer (23,24). The gene encodes various isoforms of a protein containing four z...
Consistent evidence from both experimental and human studies indicates that Type 2 diabetes mellitus (T2DM) is a complex disease resulting from the interaction of genetic, epigenetic, environmental, and lifestyle factors. Nutrients and dietary patterns are important environmental factors to consider in the prevention, development and treatment of this disease. Nutritional genomics focuses on the interaction between bioactive food components and the genome and includes studies of nutrigenetics, nutrigenomics and epigenetic modifications caused by nutrients. There is evidence supporting the existence of nutrient-gene and T2DM interactions coming from animal studies and family-based intervention studies. Moreover, many case-control, cohort, cross-sectional cohort studies and clinical trials have identified relationships between individual genetic load, diet and T2DM. Some of these studies were on a large scale. In addition, studies with animal models and human observational studies, in different countries over periods of time, support a causative relationship between adverse nutritional conditions during in utero development, persistent epigenetic changes and T2DM. This review provides comprehensive information on the current state of nutrient-gene interactions and their role in T2DM pathogenesis, the relationship between individual genetic load and diet, and the importance of epigenetic factors in influencing gene expression and defining the individual risk of T2DM.
Two milliliters of a fermented, pasteurized orange juice containing ~1% alcohol and 2.3 μmol of (poly)phenolic compounds was fed to rats by gavage after which plasma and urine collected over a 36 h period were analyzed by UHPLC-mass spectrometry. The main constituents in the juice were hesperetin and naringenin-O-glycosides, apigenin-6,8-C-diglucoside, and ferulic acid-4'-O-glucoside. Plasma contained seven flavanone glucuronides, with the principal metabolites, naringenin-7-O-glucuronide, naringenin-4'-O-glucuronide, and an isosakuranetin-O-glucuronide, peaking 6 h after intake at concentrations of ~10 nmol/L. Urinary excretion of four hesperetin glucuronides was equivalent to 0.28% of intake while that of the two naringenin glucuronides was 2.8% of intake. The plasma and urine data suggest that while some absorption occurred in the small intestine, the main site of uptake was the colon. Urine also contained dihydroferulic acid-4'-O-glucuronide and dihydroferulic acid-4'-O-sulfate which were excreted in quantities corresponding to 48.2% of the ingested ferulic acid-4'-glucoside. This indicates that the hydroxycinnamate is much more bioavailable than the flavanones in the rat model. Conversion of the ferulic acid glucoside to the dihydroferulic acid metabolites involves the action of colonic microbial glycosidases and reductases/hydrogenases followed by postabsorption phase II metabolism before renal excretion.
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