Anaphylaxis after ingestion of gummy bears.
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Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia.
Knockout studies have shown that the transcription factor Nrf1 is essential for embryonic development. Nrf1 has been implicated to play a role in mediating activation of oxidative stress response genes through the antioxidant response element (ARE). Because of embryonic lethality in knockout mice, analysis of this function in the adult knockout mouse was not possible. We report here that mice with somatic inactivation of nrf1 in the liver developed hepatic cancer. Before cancer development, mutant livers exhibited steatosis, apoptosis, necrosis, inflammation, and fibrosis. In addition, hepatocytes lacking Nrf1 showed oxidative stress, and gene expression analysis showed decreased expression of various ARE-containing genes, and up-regulation of CYP4A genes. These results suggest that reactive oxygen species generated from CYP4A-mediated fatty acid oxidation work synergistically with diminished expression of ARE-responsive genes to cause oxidative stress in mutant hepatocytes. Thus, Nrf1 has a protective function against oxidative stress and, potentially, a function in lipid homeostasis in the liver. Because the phenotype is similar to nonalcoholic steatohepatitis, these animals may prove useful as a model for investigating molecular mechanisms of nonalcoholic steatohepatitis and liver cancer.
Animals↗
The E3 ubiquitin ligase Itch controls the protein stability of p63.
p63, a member of the p53 family of transcription factors, plays an important role in epithelial development, regulating both cell cycle and apoptosis. Even though p63 activity is regulated mainly at the posttranslational level, the control of p63 protein stability is far from being fully understood. Here, we show that the Hect (homologous to the E6-associated protein C terminus)-containing Nedd4-like ubiquitin protein ligase Itch binds, ubiquitylates, and promotes the degradation of p63. The physical interaction occurs at the border between the PY and the SAM (sterile alpha motif) domains; a single Y504F mutation significantly affects p63 degradation. Itch and p63 are coexpressed in the epidermis and in primary keratinocytes where Itch controls the p63 protein steady-state level. Accordingly, p63 protein levels are significantly increased in Itch knockout keratinocytes. These data suggest that Itch has a fundamental role in the mechanism that controls endogenous p63 protein levels and therefore contributes to regulation of p63 in physiological conditions.
Animals↗
A highly conserved lysine residue on the head domain of type II keratins is essential for the attachment of keratin intermediate filaments to the cornified cell envelope through isopeptide crosslinking by transglutaminases.
We have addressed the question of how keratin intermediate filaments are associated with the cell envelope at the periphery of cornified epidermal cells. Many peptides from human epidermal cell envelopes containing isopeptide crosslinks inserted by transglutaminases in vivo have been characterized. A major subset involves the type II keratin chains keratin 1, 2e, 5, or 6 crosslinked to several protein partners through a lysine residue located in a conserved region of the V1 subdomain of their head domains. This sequence specificity was confirmed in in vitro crosslinking experiments. Previously the causative mutation in a family with diffuse nonepidermolytic palmar-plantar keratoderma was shown to be the loss in one allele of the same lysine residue of the keratin 1 chain. Ultrastructural studies of affected palm epidermis have revealed abnormalities in the organization of keratin filaments subjacent to the cell envelope and in the shape of the cornified cells. Together, these data suggest a mechanism for the coordination of cornified cell structure by permanent covalent attachment of the keratin intermediate filament cytoskeleton to the cell envelope by transglutaminase crosslinking. Furthermore, these studies identify the essential role of a conserved lysine residue on the head domains of type II keratins in the supramolecular organization of keratin filaments in cells.
Amino Acid Sequence↗
Biochemical, structural, and transglutaminase substrate properties of human loricrin, the major epidermal cornified cell envelope protein.
Loricrin is the major protein of the cornified cell envelope of terminally differentiated epidermal keratinocytes which functions as a physical barrier. In order to understand its properties and role in cornified cell envelope, we have expressed human loricrin from a full-length cDNA clone in bacteria and purified it to homogeneity. We have also isolated loricrin from newborn mouse epidermis. By circular dichroism and fluorescence spectroscopy, the in vivo mouse and bacterially expressed human loricrins possess no alpha or beta structure but have some organized structure in solution associated with their multiple tyrosines and can be reversibly denatured by either guanidine hydrochloride or temperature. The transglutaminase (TGase) 1, 2, and 3 enzymes expressed during epidermal differentiation utilized loricrin in vitro as a complete substrate, but the types of cross-linking were different. The TGase 3 reaction favored certain lysines and glutamines by forming mostly intrachain cross-links, whereas TGase 1 formed mostly large oligomeric complexes by interchain cross-links involving different lysines and glutamines. Together, the glutamines and lysines used in vitro are almost identical to those seen in vivo. The data support a hypothesis for the essential and complementary roles of both TGase 1 and TGase 3 in cross-linking of loricrin in vivo. Failure to cross-link loricrin by TGase 1 may explain the phenotype of lamellar ichthyosis, a disease caused by mutations in the TGase 1 gene.
Amino Acid Sequence↗
The cell-binding domain of intimin from enteropathogenic Escherichia coli binds to beta1 integrins.
Bacteria interact with mammalian cells surface molecules, such as integrins, to colonize tissues and evade immunological detection. Herein, the ability of intimin, an outer membrane protein from enteropathogenic Escherichia coli, to bind beta1 integrins was investigated. Solid-phase binding assays revealed binding of the carboxyl-terminal 280 amino acids of intimin (Int280) to alpha4beta1 and alpha5beta1 integrins. The binding required divalent ions (in particular, it was enhanced by Mn2+) and was inhibited by an RGD-containing peptide. Nonderivatized Int280, but not Int280CS (like Int280 but with Cys-937 replaced by Ser) blocked the binding of biotinylated Int280 to integrins. Int280 did not efficiently inhibit beta1 integrin binding of invasin from Yersinia pseudotuberculosis. Both intimin and invasin, immobilized on plastic surfaces, mediated adherence of resting or phorbol 12-myristate 13-acetate-activated human CD4(+) T cells, whereas fibronectin mediated the adherence of only activated T cells. T cell binding to intimin and invasin was integrin mediated because it was specifically blocked by an RGD-containing peptide and by antibodies directed against the integrin subunits beta1, alpha4, and alpha5. These results demonstrate a specific integrin binding activity for intimin that is related to, but distinct from, that of invasin.
Adhesins, Bacterial↗
The fate of trichohyalin. Sequential post-translational modifications by peptidyl-arginine deiminase and transglutaminases.
Trichohyalin (THH) is a major structural protein of the inner root sheath cells and medulla layer of the hair follicle and, to a lesser extent, of other specialized epithelia. THH is a high molecular weight insoluble alpha-helix-rich protein that forms rigid structures as a result of postsynthetic modifications by two Ca2+-dependent enzymes, transglutaminases (TGases) (protein cross-linking) and peptidyl-arginine deiminase (conversion of arginines to citrullines with loss of organized structure). The modified THH is thought to serve as a keratin intermediate filament matrix protein and/or as a constituent of the cell envelope. In this paper, we have explored in vitro the order of processing of THH to fulfill these functions, using an expressed truncated, more soluble form THH-8. THH-8 is a complete substrate for three known TGases expressed in epithelia, but the kinetic efficiency with TGase 3 is by far the greatest. Following maximal conversion of its arginines to citrullines, THH-8 is cross-linked even more efficiently by TGase 3, using most glutamines partially and all lysines. In addition, we show that insoluble aggregates of THH-8 or native pig tongue THH can be solubilized following peptidyl-arginine deiminase modification. Together, these data suggest an in vivo model in which THH located in insoluble cytoplasmic droplets is first modified by peptidyl-arginine deiminase which denatures it and makes it more soluble. This renders it available for efficient cross-linking by TGase 3 to form highly cross-linked rigid structures in the cells. This temporal order of reaction is supported by the observation that THH is expressed in hair follicle cells before the TGase 3 enzyme.
Amino Acid Sequence↗
Transglutaminase 1 mutations in lamellar ichthyosis. Loss of activity due to failure of activation by proteolytic processing.
Lamellar ichthyosis is a congenital recessive skin disorder characterized by generalized scaling and hyperkeratosis. It is caused by mutations in the TGM1 gene that encodes the transglutaminase 1 (TGase 1) enzyme, which is critical for the assembly of the cornified cell envelope in terminally differentiating keratinocytes. TGase 1 is a complex enzyme existing as both cytosolic and membrane-bound forms. Moreover, TGase 1 is proteolytically processed, and the major functionally active form consists of a membrane-bound 67/33/10-kDa complex with a myristoylated and palmitoylated amino-terminal 10-kDa membrane anchorage fragment. To understand better how point mutations, deletions, and truncations found in lamellar ichthyosis disease affect the structure and function of TGase 1, we have expressed in baculovirus and keratinocytes a number of reported TGase 1 mutants. The structural implications of these mutations were examined using a homology-derived three-dimensional model of TGase 1 generated from the known x-ray structure of the related coagulation factor XIIIa enzyme. The present studies demonstrate that loss of TGase 1 activity is not restricted to mutations that directly affect the enzymatic activity. We report a new class of mutations that impair the subsequent post-synthetic processing of the protein into its highly active functional forms.
Amino Acid Sequence↗
Structural and transglutaminase substrate properties of the small proline-rich 2 family of cornified cell envelope proteins.
The small proline-rich (SPR) proteins are components of the cornified cell envelope of stratified squamous epithelia and become cross-linked to other proteins by transglutaminases (TGases). The SPR2 family is the most complex, as it consists of several differentially expressed members of the same size. To explore their physical and cross-linking properties, we have expressed in bacteria a human SPR2 family member, and purified it to homogeneity. By circular dichroism, it possesses no alpha or beta structure but has some organized structure associated with the central peptide repeat domain. The TGase 1, 2, and 3 enzymes expressed in epithelia use the recombinant SPR2 protein as a complete substrate in vitro, but with widely differing kinetic efficiencies, and in different ways. With TGase 1, only one glutamine on the head domain and one lysine on the tail domain were used for limited interchain cross-linking. With TGase 3, multiple head and tail domain residues were used for extensive interchain cross-linking. The total usage of glutamine and lysine residues in vitro by TGase 3 was similar to that seen in earlier in vivo studies. We conclude that SPR2 proteins are cross-linked in epithelia primarily by the TGase 3 enzyme, a minor extent by TGase 1, and probably not by TGase 2.
Amino Acid Sequence↗
Transglutaminase cross-linking properties of the small proline-rich 1 family of cornified cell envelope proteins. Integration with loricrin.
Small proline-rich 1 (SPR1) proteins are important for barrier function in stratified squamous epithelia. To explore their properties, we expressed in bacteria a recombinant human SPR1 protein and isolated native SPR1 proteins from cultured mouse keratinocytes. By circular dichroism, they possess no alpha or beta structure but have some organized structure associated with their central peptide repeat domain. The transglutaminase (TGase) 1 and 3 enzymes use the SPR1 proteins as complete substrates in vitro but in different ways: head domain A sequences at the amino terminus were used preferentially for cross-linking by TGase 3, whereas those in head domain B sequences were used for cross-linking by TGase 1. The TGase 2 enzyme cross-linked SPR1 proteins poorly. Together with our data base of 141 examples of in vivo cross-links between SPRs and loricrin, this means that both TGase 1 and 3 are required for cross-linking SPR1 proteins in epithelia in vivo. Double in vitro cross-linking experiments suggest that oligomerization of SPR1 into large polymers can occur only by further TGase 1 cross-linking of an initial TGase 3 reaction. Accordingly, we propose that TGase 3 first cross-links loricrin and SPRs together to form small interchain oligomers, which are then permanently affixed to the developing CE by further cross-linking by the TGase 1 enzyme. This is consistent with the known consequences of diminished barrier function in TGase 1 deficiency models.
Amino Acid Sequence↗
Transglutaminase 5 cross-links loricrin, involucrin, and small proline-rich proteins in vitro.
Transglutaminases (TGases) are seven enzymes, cross-linking proteins by gamma-glutamil-epsilon-lysine bonds, four of which are expressed in the skin. A new member of the TGase family, TGase 5, has been identified recently, and in the present study we evaluated its role in keratinocyte differentiation in vitro. In addition to the previously described isoforms, full-length TGase 5 and Delta3 (deletion of exon 3), we identified two new splicing variants, Delta11 and Delta3Delta11 (deletion of exons 11 or 3, 11). We expressed full-length TGase 5, Delta3, Delta11, and Delta3Delta11 isoforms in the keratinocyte and baculovirus systems. The results indicate that both full-length TGase 5 and Delta11 are active, whereas Delta3 and Delta3Delta11 have very low activity. Expression studies show that full-length TGase 5 is induced during the early stages of keratinocyte differentiation and is differently regulated in comparison with the other epidermal TGases. Kinetic and in vitro cross-linking experiments indicate that full-length TGase 5 is very efficient in using specific epidermal substrates (loricrin, involucrin, and SPR3). In keratinocyte expression system, TGase 5 isoforms are retained in an intermediate filament-enriched fraction, suggesting its association with insoluble proteins. Indeed, TGase 5 co-localize with vimentin and it is able to cross-link vimentin in vitro.
Baculoviridae↗
Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress.
Nrf1 and Nrf2 are members of the CNC family of bZIP transcription factors that exhibit structural similarities, and they are co-expressed in a wide range of tissues during development. Nrf2 has been shown to be dispensable for growth and development in mice. Nrf2-deficient mice, however, are impaired in oxidative stress defense. We previously showed that loss of Nrf1 function in mice results late gestational embryonic lethality. To determine whether Nrf1 and Nrf2 have overlapping functions during early development and in the oxidative stress response, we generated mice that are deficient in both Nrf1 and Nrf2. In contrast to the late embryonic lethality in Nrf1 mutants, compound Nrf1, Nrf2 mutants die early between embryonic days 9 and 10 and exhibit extensive apoptosis that is not observed in the single mutants. Loss of Nrf1 and Nrf2 leads to marked oxidative stress in cells that is indicated by elevated intracellular reactive oxygen species levels and cell death that is reversed by culturing under reduced oxygen tension or the addition of antioxidants. Compound mutant cells also show increased levels of p53 and induction of Noxa, a death effector p53 target gene, suggesting that cell death is potentially mediated by reactive oxygen species activation of p53. Moreover, we show that expression of genes related to antioxidant defense is severely impaired in compound mutant cells compared with single mutant cells. Together, these findings indicate that the functions of Nrf1 and Nrf2 overlap during early development and to a large extent in regulating antioxidant gene expression in cells.
Animals↗
Polyols in confectionery: the route to sugar-free, reduced sugar and reduced calorie confectionery.
Polyol-containing confectionery offers considerable advantages over traditional sucrose-based confectionery in terms of reduced energy content and reduced cariogenicity. However, over-consumption of polyol confectionery may lead to gastrointestinal symptoms in some individuals. Rather than consider this as a distinct disadvantage to the consumer, this article discusses how careful consideration of the physico-chemical properties of polyols and advances in product development and formulation can provide suitable polyol-based products for the consumer. Furthermore. food legislation and ingredient pricing issues are just some of the factors that must be taken into account when designing new polyol-containing products if their functional benefits and good product quality are to be delivered to the consumer.
Candy↗
The prebiotic effects of biscuits containing partially hydrolysed guar gum and fructo-oligosaccharides--a human volunteer study.
Prebiotics are non-digestible food ingredients that target selected groups of the human colonic microflora, thus having the ability to alter the composition towards a more 'beneficial' community, i.e. selectively increasing populations of bifidobacteria and/or lactobacilli. In the present study the prebiotic potential of partially hydrolysed guar gum (PHGG) and fructo-oligosaccharides (FOS) in a biscuit was assessed in human volunteers. Fluorescent in situ hybridization using oligonucleotide probes targeting Bacteroides spp., Bifidobacterium spp., Clostridium spp. and Lactobacillus-Enterococcus spp. were used for the bacteriology and total bacteria were enumerated using the fluorescent stain 4',6-diamidino-2-phenylindole. Thirty-one volunteers consumed daily either three experimental biscuits (providing a total (g/d) of 6.6 FOS and 3.4 PHGG) or three placebo biscuits for two 21-d crossover periods. Bifidobacteria significantly increased in number on ingestion of the experimental biscuits compared with pre-treatment and placebo population levels. Bifidobacterial numbers returned to pretreatment levels within 7 d of the cessation of intake of experimental biscuits. A correlation was observed between the initial faecal bifidobacterial numbers and the magnitude of bifidogenesis, with volunteers who possessed low initial population levels of bifidobacteria experiencing the greatest increase in bifidogenesis. No changes were observed in the other bacterial groups monitored during the trial. Thus, the prebiotic nature of FOS and PHGG was maintained in a final food product as evidenced from the selective increase in bifidobacterial numbers.
Adult↗
Comparison of methods to estimate non-milk extrinsic sugars and their application to sugars in the diet of young adolescents.
Consistent information on the non-milk extrinsic sugars (NMES) content of foods and the NMES intake by the population is required in order to allow comparisons between dietary surveys. A critical appraisal of methods of NMES estimation was conducted to investigate whether the different published methods for estimating the NMES content of foods lead to significantly different values for the dietary intake of NMES by children and to consider the relative practicality of each method. NMES values of foods were calculated using three different published descriptions of methods of NMES estimation, and the values were compared within food groups. Dietary intake values for English children aged 11-12 years were calculated using each method and compared in terms of overall NMES intake and the contribution of different food groups to NMES intake. There was no significant difference in the dietary intake of NMES in children between the method used in the National Diet and Nutrition Surveys (NDNS) (81.9 g/d; 95 % CI 79.0, 84.7) and a method developed by the Human Nutrition Research Centre (84.3 g/d; 95 % CI 81.4, 87.2) at Newcastle University, UK, although the latter gave slightly higher values. An earlier method used by the Ministry of Agriculture, Food and Fisheries gave significantly higher values than the other two methods (102.5 g/d; 95 % CI 99.3, 105.6; P<0.05). The method used in the NDNS surveys and the method used by the Human Nutrition Research Centre at Newcastle University are both thorough and detailed methods that give consistent results. However, the method used in the NDNS surveys was more straightforward to apply in practice and is the best method for a single uniform approach to the estimation of NMES.
Candy↗
Adolescents' food habits: results of the Health Behaviour in School-aged Children survey.
The present study describes food habits in adolescents in thirty-five countries and regions (European countries/regions, Israel, Canada and the USA), based on the food-frequency questions from the cross-sectional Health Behaviour in School-aged Children survey of the year 2001-2. A total of 162,305 pupils of 11, 13 or 15 years of age completed an anonymous standardised questionnaire on health and lifestyle factors during one school hour. Large differences in food habits between countries were found: the consumption frequency of fruit varied from on average 2.8 to 5 d/week, the consumption of vegetables varied from on average 2.4 to 5.5 d/week, the consumption of soft drinks varied from 2.1 to 5 d/week and sweet consumption from 2.6 to 5 d/week. Methodological problems in comparing between countries are discussed. Nonetheless, the results indicate a need for national and international health promotion programmes to improve adolescents' food habits.
Adolescent↗
Glycaemic index and glycaemic load in the diet of healthy schoolchildren: trends from 1990 to 2002, contribution of different carbohydrate sources and relationships to dietary quality.
Despite intense discussion of the glycaemic index (GI) and glycaemic load (GL) concepts, data on the GI or GL levels in the diet of children are scarce. The present analysis determined trends in the levels of GI or GL of healthy children from 1990 to 2002 and examined the contribution of carbohydrate (CHO) sources to the overall GL, and the relationships of the GI and GL to the overall dietary quality. The analysis includes three cohorts of participants from the Dortmund Nutritional and Anthropometrical Longitudinally Designed study, aged 7-8 years in 1990 (n 53), 1996 (n 46) and 2002 (n 56). A GI value was assigned to all CHO foods recorded over three consecutive days. In comparison with 1990, 7-8-year-old children in 2002 had slightly higher GI (56.5 v. 55.1 %; P=0.03) and GL (17.5 v. 16.7 g/MJ; P=0.04) levels. In all three time periods the combined contribution of the 'tolerated food groups' (i.e. sweets, soft drinks, cakes and cookies, and salty snacks) to the overall GL exceeded that of bread and rolls (1990, 31 v. 24 %; 1996, 29 v. 31 %; 2002, 28 v. 25 %). Conversely, rice and fried or mashed potatoes had only a minor impact. Children in the lowest GI tertile, but not those in the lowest GL tertile, had a better nutrient profile and a more favourable food choice. In conclusion, partial replacement of high-GI 'tolerated food groups' for low-GI foods would help to reverse the slight recent increases in GI and GL, and to improve the overall dietary quality of 7-8-year-old children.
Animals↗
Whole-grain intake of British young people aged 4-18 years.
Inverse associations between whole-grain food consumption and risk of CVD, some cancers and type 2 diabetes have been reported. However, there are few reports of whole-grain intake, particularly among young people. The objective of the present study was to estimate whole-grain intake in a nationally representative sample of young people aged 4-18 years living in Great Britain. Whole-grain intake was estimated using 7 d weighed dietary records from 1583 young people who participated in the cross-sectional National Diet and Nutrition Survey in 1997. Whole-grain intake was quantified from the consumption of all foods containing > or =10 % whole-grain content. Median whole-grain intake was 7 g/d (interquartile range 0-19 g/d), with a corresponding mean of 13 (sd 18) g/d. Intake was significantly lower among young people whose head of household had a manual occupation, but did not differ significantly by sex, age, region or season. There was no whole-grain intake for 27 % of participants. The percentages for less than one and less than three 16 g amounts of whole-grain intake per d were 70 and 94, respectively, while corresponding percentages based on 20 g amounts were 76 and 97. Foods with <51 % whole-grain content provided 28 % of whole-grain intake overall, with a higher percentage in older adolescents. The main sources of whole-grain intake were breakfast cereals (56 %) and bread (25 %). The present study provides the first quantification of absolute whole-grain intake from all significant food sources in any representative age group in the UK. Although there is some debate regarding the quantity of whole grains required for good health, whole-grain intake among British young people is low.
Adolescent↗