Gene/Protein Disease Symptom Drug Enzyme Compound
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The human intestinal pathogen, enteropathogenic Escherichia coli (EPEC), causes diarrhoeal disease by a mechanism that is dependent on the injection of effector proteins into the host cell. One effector, EspF, is reported to be required for EPEC to disrupt tight junction integrity of intestinal cells and increase the paracellular movement of molecules, which is likely to contribute to diarrhoea. Here, we show that not one but three EPEC-encoded factors play important roles in this process. Thus, the Map (Mitochondria-associated protein) effector is shown to: (i) be as essential as EspF for disrupting intestinal barrier function, (ii) be able to function independently of EspF, (iii) alter tight junction structure and (iv) mediate these effects in the absence of mitochondrial targeting. Additionally, the outer membrane protein Intimin is shown to be crucial for EspF and Map to disrupt the intestinal barrier function. This function of Intimin is completely independent of its interaction with its known receptor Tir, revealing a physiologically relevant requirement for Intimin interaction with alternative receptor(s). This work demonstrates that EPEC uses multiple multifunctional proteins to elicit specific responses in intestinal cells and that EPEC can control the activity of its injected effector molecules from its extracellular location.
Mol Microbiol 2004 Nov
PMID:Intestinal barrier dysfunction by enteropathogenic Escherichia coli is mediated by two effector molecules and a bacterial surface protein. 1549 58

Bacillus cereus is the causative agent of two distinct forms of gastroenteritic disease connected to food-poisoning. It produces one emesis-causing toxin and three enterotoxins that elicit diarrhea. Due to changing lifestyles and eating habits, B. cereus is responsible for an increasing number of food-borne diseases in the industrial world. In the past, most studies concentrated on the diarrhoeal type of food-borne disease, while less attention has been given to the emetic type of the disease. The toxins involved in the diarrhoeal syndrome are well-known and detection methods are commercially available, whereas diagnostic methods for the emetic type of disease have been limited. Only recently, progress has been made in developing identification methods for emetic B. cereus and its corresponding toxin. We will summarize the data available for the emetic type of the disease and discuss some new insights in emetic strain characteristics, diagnosis, and toxin synthesis.
Mol Nutr Food Res 2004 Dec
PMID:Bacillus cereus, the causative agent of an emetic type of food-borne illness. 1553 9

Subtyping of Shiga toxin (Stx)-encoding genes by conventional polymerase chain reaction (PCR) is time-consuming. We developed a single step real-time fluorescence PCR with melting curve analysis to distinguish rapidly stx1 from its variants, stx1c and stx1d. Melting temperatures (Tm) of 206 Stx-producing Escherichia coli (STEC) identified to harbor stx1 or stx1c were analyzed using a specific hybridization probe over the variable region. 170 of 171 stx1-harboring STEC displayed Tm of 69 degrees C to 70 degrees C, whereas 34 of 35 strains containing stx1c had Tm of 65 degrees C-66 degrees C. This constant and reproducible difference of 4 degrees C demonstrated that melting curve analysis is a reliable technique to differentiate stx1 from stx1c. Two isolates displayed atypical Tm. Sequence analysis showed that one of them was 100% identical to stx1d within a 511 bp DNA stretch. Our data demonstrate that real-time PCR is a rapid and reliable tool to differentiate stx1 from stx1c and stx1d and to detect new stx1 variants. Because stx1-harboring STEC cause diarrhoea and hemolytic-uremic syndrome, whereas those containing stx1c are often shed asymptomatically, a rapid differentiation between stx1 and its variants using the procedure developed here has both clinical implications and a direct significance for the risk assessment analysis of STEC isolated from foods.
Mol Nutr Food Res 2004 Dec
PMID:A rapid method for the discrimination of genes encoding classical Shiga toxin (Stx) 1 and its variants, Stx1c and Stx1d, in Escherichia coli. 1553 10

We compared the effect of diets containing different nondigestible carbohydrates: cellulose (C), inulin (IN) and carboxymethylcellulose (CMC) as single supplements or in dietary combination on caecal physiology of rats. Sixty male Wistar rats (Rattus norvegicus) were divided into five groups and for 4 weeks were fed a casein diet with the compared carbohydrates (4% of diet) or a combination of IN+C or IN+CMC (both 4+4%). Diet intake and FCR index remained unaffected by the treatments, whereas IN improved the body weight gain of rats compared to CMC. Compared to C group, all diets containing IN and CMC decreased the caecal pH as well as enlarged the caecum, thus increasing the weights of contents and tissue, especially upon CMC treatment. Rats given carboxymethylcellulose (CMC and IN+CMC groups) had watery caecal digesta, and some of them suffered from diarrhoea. In the case of CMC, the caecal enlargement was due to tissue hypertrophy and digesta accumulation mostly in response to an increased bulk of contents. Unlike C+IN, the dietary combination of CMC- and inulin-enhanced fermentation in the caecum of rats, however the proportion of acetate, propionate and butyrate was less beneficial. Compared to CMC, inulin gave a higher concentration of SCFA, especially of butyrate and propionate. The action of inulin in the caecum of rats could be pronounced by dietary treatment combined with CMC.
Comp Biochem Physiol A Mol Integr Physiol 2004 Dec
PMID:Effects of cellulose, carboxymethylcellulose and inulin fed to rats as single supplements or in combinations on their caecal parameters. 1559 97

Clostridium difficile (C.difficile) is a nosocomially acquired intestinal bacillus which can cause chronic diarrhea and life-threatening colitis. The pathogenic effects of the bacillus are mediated by the release of two toxins, A and B. The C-terminal portions of both toxins are composed of 20 and 30 residue repeats known as cell wall binding (CWB) domains. We have cloned and expressed the CWB-domains of toxins A and B and several truncated CWB-domain constructs to investigate their structure and function. The smallest CWB-domain that folded in a cooperative manner was an 11 repeat construct of toxin A. This differentiates the C-terminal domains of toxins A and B from the CWB-domain of Streptococcus pneumoniae LytA, which only requires six repeats to fold. The 11 repeat toxin A construct bound Ca2+ directly with millimolar affinity and interacted with mammalian cell surfaces in a concentration and Ca2+-dependent fashion. Millimolar Ca2+ levels also accelerated toxin mediated CHO cell killing in an in vitro cell assay. Together, the data suggest a role for extracellular Ca2+ in the sensitization of toxin A/cell-surface interactions.
J Mol Biol 2005 Mar 11
PMID:Structural characterization of the cell wall binding domains of Clostridium difficile toxins A and B; evidence that Ca2+ plays a role in toxin A cell surface association. 1571 74

The major class of mycotoxins produced by Fusarium moulds are trichothecenes, a large group of sesquiterpenes sharing the same basic chemical structure, a 12,13-epoxytrichothec-9-ene ring system. Their toxic effects range from causing diarrhoea, vomiting and gastro-intestinal inflammation to noncompetitive inhibition of the biosynthesis of proteins in eukaryotic cells. Trichothecenes in general are relatively stable compounds, their degradation is observed only at high temperatures and prolonged heating time. In order to investigate the stability of the trichothecene nivalenol (NIV) under food processing conditions such as cooking or baking, we performed model heating experiments and screened the residue for degradation products using gas chromatography-mass spectrometry (GC-MS). Heating of nivalenol, especially under mild alkaline conditions, gave a mixture of four compounds (norNIV A, norNIV B, norNIV C, and NIV lactone), which where isolated and identified by nuclear magnetic resonance (NMR) and MS experiments. Although their formation was also demonstrated in heating experiments with spiked flour samples, only norNIV B was detectable in a screening of several commercially available samples, possibly due to the very low contamination with nivalenol. Furthermore, cell culture experiments using immortalized human kidney epithelial (IHKE) cells showed that the four compounds are less cytotoxic (formazan dye cytotoxicity assay) compared to nivalenol. Whereas nivalenol revealed an EC50 at 0.9 micromol, all other compounds did not show any significant effect up to 100 micromol.
Mol Nutr Food Res 2005 Apr
PMID:Structural elucidation and analysis of thermal degradation products of the Fusarium mycotoxin nivalenol. 1574 14

Surveyed in the paper are published data on properties, biological activity, genetic determinants and action mechanisms of recently known toxins produced by different strains of Vibrio cholerae irrespectively of their capacity for the synthesis of choleric toxin--the main virulence factor. Their possible importance both for the general clinical pattern of cholera provoked by cholerogenic agents and as independent virulence factors causing diarrhea without cholera is elucidated. The sets and levels of expression of additional toxins can differ for different pathogenic clones and they can correspondingly condition degrees of their epidemic and etiological safety.
Mol Gen Mikrobiol Virusol 2005
PMID:[Toxins of Vibrio cholerae]. 1579 27

Clostridium perfringens type A isolates carrying an enterotoxin (cpe) gene are an important cause of human gastrointestinal diseases, including food poisoning, antibiotic-associated diarrhoea (AAD) and sporadic diarrhoea (SD). Using polymerase chain reaction (PCR), the current study determined that the cpb2 gene encoding the recently discovered beta2 toxin is present in <15% of food poisoning isolates, which typically carry a chromosomal cpe gene. However, >75% of AAD/SD isolates, which usually carry a plasmid cpe gene, tested cpb2(+) by PCR. Western blot analysis demonstrated that >97% of those cpb2(+)/cpe(+) AAD/SD isolates can produce CPB2. Additional PCR analyses, sequencing studies and pulsed field gel electrophoresis experiments determined that AAD/SD isolates carry cpb2 and cpe on the same plasmid when IS1151 sequences are present downstream of cpe, but cpb2 and cpe are located on different plasmids in AAD/SD isolates where IS1470-like sequences are present downstream of cpe. Those analyses also demonstrated that two different CPB2 variants (named CPB2h1 or CPB2h2) can be produced by AAD/SD isolates, dependent on whether IS1470-like or IS1151 sequences are present downstream of their cpe gene. CPB2h1 is approximately 10-fold more cytotoxic for CaCo-2 cells than is CPB2h2. Collectively, these results suggest that CPB2 could be an accessory toxin in C. perfringens enterotoxin (CPE)-associated AAD/SD.
Mol Microbiol 2005 May
PMID:Association of beta2 toxin production with Clostridium perfringens type A human gastrointestinal disease isolates carrying a plasmid enterotoxin gene. 1581 29

Gastrointestinal symptoms are often an early and prominent manifestation of Fabry disease, an X-linked inborn error of metabolism caused by the deficient activity of the lysosomal enzyme, alpha-galactosidase A. This enzyme deficiency results in the progressive accumulation of globotriaosylceramide and other glycosphingolipids in tissue lysosomes throughout the body. In classically affected patients, glycosphingolipid accumulation in the vascular endothelium eventually culminates in life-threatening renal, cardiac, and cerebrovascular disease. In addition, over 50% of patients experience post-prandial abdominal pain and diarrhea that interferes with the ability to work and quality of life. Here, we describe four males aged 17-40 years with classic Fabry disease and severe gastrointestinal symptoms who participated in clinical trials of enzyme replacement therapy with agalsidase beta (Fabrazyme, 1 mg/kg every 2 weeks). Before therapy, the three adult patients experienced post-prandial abdominal pain, bloating, and severe diarrhea with 7-10 bowel movements per day every day and the 17-year-old had weekly episodes of diarrhea with six bowel movements per day. Other symptoms included vomiting, food intolerance, and poor weight gain. All patients took medications for these symptoms (diphenoxylate-atropine [Lomotil], ranitidine hydrochloride [Zantac], or sulfasalazine). After 6-7 months of agalsidase beta therapy, all patients reported "no or only occasional" abdominal pain or diarrhea, had discontinued their gastrointestinal medications, and had gained 3-8 kg. These marked improvements in gastrointestinal symptoms have persisted for over 3 years of treatment. In such patients, enzyme replacement at 1 mg/kg effects an early and significant clinical improvement in the gastrointestinal manifestations of Fabry disease.
Mol Genet Metab 2005 Aug
PMID:Gastrointestinal manifestations of Fabry disease: clinical response to enzyme replacement therapy. 1593 45

Lactoferrin is a metal-binding glycoprotein exhibiting multifunctional immunoregulation of antibacterial, antioxidant, anti-endotoxin and antiviral activities. Uptake of porcine lactoferrin (PLF) has been shown to enhance resistance to diarrhea and anemia in neonatal piglets. In this study, the methylotrophic yeast, Pichia pastoris, was used to express a recombinant PLF (rPLF) gene from swine mammary gland. A synthetic secretion cassette was constructed using the inducible promoter of the alcohol oxidase-1 gene (AOX1) and the yeast alpha-mating factor signal peptide. After electroporation and Zeocin selection, several clones expressed high levels of rPLF protein which constitutes more than 30% of the total protein. A time-course study showed that rPLF mRNA transcripts are stably expressed during 120 h of culture induction. rPLF was exported into the culture supernatant at approximately 87 mg/l and a large portion of rPLF was accumulated in the cell cytoplasm at approximately 760 mg/l after 72 h of methanol induction. Recombinant PLF protein was purified via a heparin column using a fast protein liquid chromatography system. The glycosylation of P. pastoris-derived rPLF was analyzed and similar patterns to milk PLF were observed. Pepsin hydrolysate of rPLF displayed high bactericidal activity against Escherichia coli ATCC 25922 under scanning electron microscopy observation and minimal inhibitory concentration and minimal bactericidal concentration tests. Our results suggested that the methylotrophic yeast-inducible system is suitable for large-scale production of active antibacterial rPLF glycoprotein.
J Mol Microbiol Biotechnol 2004
PMID:Production of recombinant porcine lactoferrin exhibiting antibacterial activity in methylotrophic yeast, Pichia pastoris. 1608 16


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