scholarly journals Entropy-driven binding of gut bacterial β-glucuronidase inhibitors ameliorates irinotecan-induced toxicity

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hsien-Ya Lin ◽  
Chia-Yu Chen ◽  
Ting-Chien Lin ◽  
Lun-Fu Yeh ◽  
Wei-Che Hsieh ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Glucuronic Acid ◽  
Intestinal Epithelial Cells ◽  
Primary Treatment ◽  
Water Molecules ◽  
Intestinal Epithelial ◽  
E Coli ◽  
Severe Diarrhea ◽  
Coordinated Water ◽  
Consequent Increase

AbstractIrinotecan inhibits cell proliferation and thus is used for the primary treatment of colorectal cancer. Metabolism of irinotecan involves incorporation of β-glucuronic acid to facilitate excretion. During transit of the glucuronidated product through the gastrointestinal tract, an induced upregulation of gut microbial β-glucuronidase (GUS) activity may cause severe diarrhea and thus force many patients to stop treatment. We herein report the development of uronic isofagomine (UIFG) derivatives that act as general, potent inhibitors of bacterial GUSs, especially those of Escherichia coli and Clostridium perfringens. The best inhibitor, C6-nonyl UIFG, is 23,300-fold more selective for E. coli GUS than for human GUS (Ki = 0.0045 and 105 μM, respectively). Structural evidence indicated that the loss of coordinated water molecules, with the consequent increase in entropy, contributes to the high affinity and selectivity for bacterial GUSs. The inhibitors also effectively reduced irinotecan-induced diarrhea in mice without damaging intestinal epithelial cells.

scholarly journals P fimbriae and other adhesins enhance intestinal persistence of Escherichia coli in early infancy

1998 ◽  
Vol 121 (3) ◽  
pp. 599-608 ◽  
Author(s):  
I. ADLERBERTH ◽  
C. SVANBORG ◽  
B. CARLSSON ◽  
L. MELLANDER ◽  
L.-Å. HANSON ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Cell Line ◽  
Intestinal Epithelial Cells ◽  
Antigen Expression ◽  
Intestinal Epithelial ◽  
E Coli ◽  
O Antigen ◽  
Ht 29 ◽  
Intestinal Persistence

Resident and transient Escherichia coli strains were identified in the rectal flora of 22 Pakistani infants followed from birth to 6 months of age. All strains were tested for O-antigen expression, adhesin specificity (P fimbriae, other mannose-resistant adhesins or type 1 fimbriae) and adherence to the colonic cell line HT-29. Resident strains displayed higher mannose- resistant adherence to HT-29 cells, and expressed P fimbriae (P=0·0036) as well as other mannose-resistant adhesins (P=0·012) more often than transient strains. In strains acquired during the first month of life, P fimbriae were 12 times more frequent in resident than in transient strains (P=0·0006). The O-antigen distribution did not differ between resident and transient strains, and none of the resident P-fimbriated strains belonged to previously recognized uropathogenic clones. The results suggest that adhesins mediating adherence to intestinal epithelial cells, especially P fimbriae, enhance the persistence of E. coli in the large intestine of infants.

Immunogenicity Evaluation of Chimeric Subunit Vaccine Comprising Adhesion Coli Surface Antigens from Enterotoxigenic Escherichia coli

2019 ◽  
Vol 29 (1-6) ◽  
pp. 91-100
Author(s):  
Dorna Khoobbakht ◽  
Shohreh Zare Karizi ◽  
Mohammad Javad  Motamedi ◽  
Rouhollah Kazemi ◽  
Pooneh Roghanian ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Epithelial Cells ◽  
Subunit Vaccine ◽  
Fusion Gene ◽  
Intestinal Epithelial Cells ◽  
High Titer ◽  
Chimeric Protein ◽  
Amino Acid Sequences ◽  
Intestinal Epithelial ◽  
E Coli

Enterotoxigenic <i>Escherichia coli</i> (ETEC) is the most common agent of diarrhea morbidity in developing countries. ETEC adheres to host intestinal epithelial cells via various colonization factors. The CooD and CotD proteins play a significant role in bacteria binding to the intestinal epithelial cells as adhesin tip subunits of CS1 and CS2 pili. The purpose here was to design a new construction containing <i>cooD</i> and <i>cotD</i> genes and use several types of bioinformatics software to predict the structural and immunological properties of the designed antigen. The fusion gene was synthesized with codon bias of <i>E. coli</i> in order to increase the expression level of the protein. The amino acid sequences, protein structure, and immunogenicity properties of potential antigens were analyzed in silico. The chimeric protein was expressed in <i>E. coli</i>BL21 (DE3). The antigenicity of the recombinant proteins was verified by Western blotting and ELISA. In order to assess the induced immunity, the immunized mice were challenged with wild-type ETEC by an intraperitoneal route. Immunological analyses showed the production of a high titer of IgG serum with no sign of serum-mucosal IgA antibody response. The result of the challenge assay showed that 30% of immunized mice survived. The results of this study showed that CooD-CotD recombinant protein can stimulate immunity against ETEC. The designed chimera could be a prototype for the subunit vaccine, which is worthy of further consideration.

scholarly journals Protecting intestinal epithelial cells against deoxynivalenol and E. coli damage by recombinant porcine IL-22

2019 ◽  
Vol 231 ◽  
pp. 154-159 ◽  
Author(s):  
Yunyun Li ◽  
Jinquan Wang ◽  
Yuchen Li ◽  
Haiqin Wu ◽  
Shiyi Zhao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
E Coli

Activation of NF-κB in intestinal epithelial cells by enteropathogenicEscherichia coli

1997 ◽  
Vol 273 (4) ◽  
pp. C1160-C1167 ◽  
Author(s):  
Suzana D. Savkovic ◽  
Athanasia Koutsouris ◽  
Gail Hecht
Keyword(s):  
Transcription Factor ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Bacterial Flora ◽  
Inflammatory Cells ◽  
Initial Response ◽  
Intestinal Epithelial ◽  
E Coli ◽  
Normal Bacterial Flora ◽  
First Time

The initial response to infection is recruitment of acute inflammatory cells to the involved site. Interleukin (IL)-8 is the prototypical effector molecule for this process. Transcription of the IL-8 gene is primarily governed by the nuclear transcription factor (NF)-κB. Intestinal epithelial cells produce IL-8 in response to infection by enteric pathogens yet remain quiescent in a milieu where they are literally bathed in normal bacterial flora. We therefore sought to investigate NF-κB activation in response to enteropathogenic Escherichia coli (EPEC), nonpathogenic E. coli, and bacterial lipopolysaccharide in an intestinal epithelial cell (T84) model and to determine whether EPEC-induced activation of NF-κB factor is causally linked to IL-8 production. We report herein that NF-κB is activated by EPEC, yet such a response is not extended to nonpathogenic organisms or purified E. coli lipopolysaccharide. Transcription factor decoys significantly diminished IL-8 production in response to EPEC, demonstrating a causal relationship. Furthermore, deletion of specific EPEC virulence genes abrogates the NF-κB-activating property of this pathogen, suggesting that specific bacterial factors are crucial for inducing this response. These studies show for the first time that infection of intestinal epithelial cells with EPEC activates NF-κB, which in turn initiates IL-8 transcription, and highlight the differential response of these cells to bacterial pathogens vs. nonpathogens.

Solid-state structure and antimicrobial and cytotoxicity studies of a cucurbit[6]uril-like Cu6 L 4 constructed from 3,5-bis[(1H-tetrazol-5-yl)methyl]-4H-1,2,4-triazol-4-amine

2018 ◽  
Vol 74 (11) ◽  
pp. 1413-1419
Author(s):  
Serhii Vasylevskyi ◽  
Anja Holzheu ◽  
Katharina M. Fromm
Keyword(s):  
Solid State ◽  
Distorted Octahedral Geometry ◽  
Water Molecules ◽  
State Structure ◽  
Sulfate Anion ◽  
E Coli ◽  
Cytotoxicity Studies ◽  
Distorted Octahedral ◽  
Sulfate Hydrate ◽  
Coordinated Water

3,5-Bis[(1H-tetrazol-5-yl)methyl]-4H-1,2,4-triazol-4-amine (H2 L) associates under deprotonation with CuSO4 in aqueous medium to form a new waisted barrel-shaped M 6 L 4 cluster, namely hexaaquatetrakis{μ4-3,5-bis[(1H-tetrazol-5-yl)methyl]-4H-1,2,4-triazol-4-amine}-μ4-sulfato-hexacopper(II) sulfate hydrate, [Cu6(SO4)(C6H6N12)4(H2O)6]SO4·nH2O (n = ∼23) (1). Cluster 1 resembles concave cucurbit[6]uril and has one disordered sulfate anion trapped inside the cage, which additionally stabilizes the Cu6 unit. The CuII ions have either a square-pyramidal or a distorted octahedral geometry. The equatorial positions are filled by N atoms from the L 2− ligand, while the axial positions are occupied by coordinated water molecules and O atoms of the sulfate counter-ion. In the solid state, the Cu6 clusters are connected through a large number of hydrogen bonds formed by uncoordinated water molecules and an additional sulfate anion. The compound shows good antimicrobial activity against E. coli tested with the Kirby Bauer approach. In addition, the cell viability towards HeLa and L-929 cells was studied.

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