Toxins

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Open AccessReview

by Antonella Antignani and David FitzGerald

Toxins 2013, 5(8), 1486-1502; https://doi.org/10.3390/toxins5081486 - 21 Aug 2013

Cited by 103 | Viewed by 15564

Immunotoxins are antibody-toxin bifunctional molecules that rely on intracellular toxin action to kill target cells. Target specificity is determined via the binding attributes of the chosen antibody. Mostly, but not exclusively, immunotoxins are purpose-built to kill cancer cells as part of novel treatment [...] Read more.

Immunotoxins are antibody-toxin bifunctional molecules that rely on intracellular toxin action to kill target cells. Target specificity is determined via the binding attributes of the chosen antibody. Mostly, but not exclusively, immunotoxins are purpose-built to kill cancer cells as part of novel treatment approaches. Other applications for immunotoxins include immune regulation and the treatment of viral or parasitic diseases. Here we discuss the utility of protein toxins, of both bacterial and plant origin, joined to antibodies for targeting cancer cells. Finally, while clinical goals are focused on the development of novel cancer treatments, much has been learned about toxin action and intracellular pathways. Thus toxins are considered both medicines for treating human disease and probes of cellular function. Full article

(This article belongs to the Special Issue Toxins and Carcinogenesis)

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Open AccessArticle

Effects of Decreased Vitamin D and Accumulated Uremic Toxin on Human CYP3A4 Activity in Patients with End-Stage Renal Disease

by Masayuki Tsujimoto, Yui Nagano, Satomi Hosoda, Asuka Shiraishi, Ayaka Miyoshi, Shima Hiraoka, Taku Furukubo, Satoshi Izumi, Tomoyuki Yamakawa, Tetsuya Minegaki and Kohshi Nishiguchi

Toxins 2013, 5(8), 1475-1485; https://doi.org/10.3390/toxins5081475 - 19 Aug 2013

Cited by 17 | Viewed by 6750

Abstract

In patients with end-stage renal disease, not only renal clearance but also hepatic clearance is known to be impaired. For instance, the concentration of erythromycin, a substrate of cytochrome P450 3A4 (CYP3A4), has been reported to be elevated in patients with end-stage renal [...] Read more.

In patients with end-stage renal disease, not only renal clearance but also hepatic clearance is known to be impaired. For instance, the concentration of erythromycin, a substrate of cytochrome P450 3A4 (CYP3A4), has been reported to be elevated in patients with end-stage renal disease. The purpose of this study is to elucidate the reason for the decrease in hepatic clearance in patients with end-stage renal disease. Deproteinized pooled sera were used to assess the effects of low-molecular-weight uremic toxins on CYP3A4 activity in human liver microsomes and human LS180 cells. Four uremic toxins (3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, hippuric acid, indole-3-acetic acid, and 3-indoxyl sulfate) present at high concentrations in uremic serum were also studied. Simultaneous treatment of uremic serum (less than 10%) or uremic toxins did not affect testosterone 6β-hydroxylation in human liver microsomes. On the other hand, pretreatment of each serum activates CYP3A4 in LS180 cells, and the increased CYP3A4 activity in uremic serum-treated cells was smaller than normal serum-treated cells. In addition, CYP3A4 and CYP24A1 mRNA levels also increased in LS180 cells exposed to normal serum, and this effect was reduced in uremic serum-treated cells and in cells exposed to uremic serum added to normal serum. Furthermore, addition of 1,25-dihydroxyvitamin D to uremic serum partially restored the serum effect on CYP3A4 expression. The present study suggests that the decrease of 1,25-dihydroxyvitamin D and the accumulation of uremic toxins contributed to the decreased hepatic clearance of CYP3A4 substrates in patients with end-stage renal disease. Full article

(This article belongs to the Special Issue Uremic Toxins)

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Open AccessReview

The Cytotoxic Necrotizing Factor 1 from E. Coli: A Janus Toxin Playing with Cancer Regulators

by Alessia Fabbri, Sara Travaglione, Giulia Ballan, Stefano Loizzo and Carla Fiorentini

Toxins 2013, 5(8), 1462-1474; https://doi.org/10.3390/toxins5081462 - 14 Aug 2013

Cited by 32 | Viewed by 8670

Abstract

Certain strains of Escherichia coli have been indicated as a risk factor for colon cancer. E. coli is a normal inhabitant of the human intestine that becomes pathogenic, especially in extraintestinal sites, following the acquisition of virulence factors, including the protein toxin CNF1. [...] Read more.

Certain strains of Escherichia coli have been indicated as a risk factor for colon cancer. E. coli is a normal inhabitant of the human intestine that becomes pathogenic, especially in extraintestinal sites, following the acquisition of virulence factors, including the protein toxin CNF1. This Rho GTPases-activating toxin induces dysfunctions in transformed epithelial cells, such as apoptosis counteraction, pro-inflammatory cytokines’ release, COX2 expression, NF-kB activation and boosted cellular motility. As cancer may arise when the same regulatory pathways are affected, it is conceivable to hypothesize that CNF1-producing E. coli infections can contribute to cancer development. This review focuses on those aspects of CNF1 related to transformation, with the aim of contributing to the identification of a new possible carcinogenic agent from the microbial world. Full article

(This article belongs to the Special Issue Toxins and Carcinogenesis)

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Open AccessArticle

Non-Linear Relationships between Aflatoxin B₁ Levels and the Biological Response of Monkey Kidney Vero Cells

by Reuven Rasooly, Bradley Hernlem, Xiaohua He and Mendel Friedman

Toxins 2013, 5(8), 1447-1461; https://doi.org/10.3390/toxins5081447 - 14 Aug 2013

Cited by 12 | Viewed by 7406

Abstract

Aflatoxin-producing fungi contaminate food and feed during pre-harvest, storage and processing periods. Once consumed, aflatoxins (AFs) accumulate in tissues, causing illnesses in animals and humans. Most human exposure to AF seems to be a result of consumption of contaminated plant and animal products. [...] Read more.

Aflatoxin-producing fungi contaminate food and feed during pre-harvest, storage and processing periods. Once consumed, aflatoxins (AFs) accumulate in tissues, causing illnesses in animals and humans. Most human exposure to AF seems to be a result of consumption of contaminated plant and animal products. The policy of blending and dilution of grain containing higher levels of aflatoxins with uncontaminated grains for use in animal feed implicitly assumes that the deleterious effects of low levels of the toxins are linearly correlated to concentration. This assumption may not be justified, since it involves extrapolation of these nontoxic levels in feed, which are not of further concern. To develop a better understanding of the significance of low dose effects, in the present study, we developed quantitative methods for the detection of biologically active aflatoxin B₁ (AFB1) in Vero cells by two independent assays: the green fluorescent protein (GFP) assay, as a measure of protein synthesis by the cells, and the microculture tetrazolium (MTT) assay, as a measure of cell viability. The results demonstrate a non-linear dose-response relationship at the cellular level. AFB1 at low concentrations has an opposite biological effect to higher doses that inhibit protein synthesis. Additional studies showed that heat does not affect the stability of AFB1 in milk and that the Vero cell model can be used to determine the presence of bioactive AFB1 in spiked beef, lamb and turkey meat. The implication of the results for the cumulative effects of low amounts of AFB1 in numerous foods is discussed. Full article

(This article belongs to the Special Issue Advances in Toxin Detection)

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Open AccessArticle

Deletion and Gene Expression Analyses Define the Paxilline Biosynthetic Gene Cluster in Penicillium paxilli

by Barry Scott, Carolyn A. Young, Sanjay Saikia, Lisa K. McMillan, Brendon J. Monahan, Albert Koulman, Jonathan Astin, Carla J. Eaton, Andrea Bryant, Ruth E. Wrenn, Sarah C. Finch, Brian A. Tapper, Emily J. Parker and Geoffrey B. Jameson

Toxins 2013, 5(8), 1422-1446; https://doi.org/10.3390/toxins5081422 - 14 Aug 2013

Cited by 24 | Viewed by 9926

Abstract

The indole-diterpene paxilline is an abundant secondary metabolite synthesized by Penicillium paxilli. In total, 21 genes have been identified at the PAX locus of which six have been previously confirmed to have a functional role in paxilline biosynthesis. A combination of bioinformatics, [...] Read more.

The indole-diterpene paxilline is an abundant secondary metabolite synthesized by Penicillium paxilli. In total, 21 genes have been identified at the PAX locus of which six have been previously confirmed to have a functional role in paxilline biosynthesis. A combination of bioinformatics, gene expression and targeted gene replacement analyses were used to define the boundaries of the PAX gene cluster. Targeted gene replacement identified seven genes, paxG, paxA, paxM, paxB, paxC, paxP and paxQ that were all required for paxilline production, with one additional gene, paxD, required for regular prenylation of the indole ring post paxilline synthesis. The two putative transcription factors, PP104 and PP105, were not co-regulated with the pax genes and based on targeted gene replacement, including the double knockout, did not have a role in paxilline production. The relationship of indole dimethylallyl transferases involved in prenylation of indole-diterpenes such as paxilline or lolitrem B, can be found as two disparate clades, not supported by prenylation type (e.g., regular or reverse). This paper provides insight into the P. paxilli indole-diterpene locus and reviews the recent advances identified in paxilline biosynthesis. Full article

(This article belongs to the Special Issue Evolutionary/Phylogenetic Studies of Mycotoxin Biosynthetic Pathways 2013)

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Open AccessReview

Bacterial Toxins Fuel Disease Progression in Cutaneous T-Cell Lymphoma

by Andreas Willerslev-Olsen, Thorbjørn Krejsgaard, Lise M. Lindahl, Charlotte Menne Bonefeld, Mariusz A. Wasik, Sergei B. Koralov, Carsten Geisler, Mogens Kilian, Lars Iversen, Anders Woetmann and Niels Odum

Toxins 2013, 5(8), 1402-1421; https://doi.org/10.3390/toxins5081402 - 14 Aug 2013

Cited by 73 | Viewed by 10729

Abstract

In patients with cutaneous T-cell lymphoma (CTCL) bacterial infections constitute a major clinical problem caused by compromised skin barrier and a progressive immunodeficiency. Indeed, the majority of patients with advanced disease die from infections with bacteria, e.g., Staphylococcus aureus. Bacterial toxins such [...] Read more.

In patients with cutaneous T-cell lymphoma (CTCL) bacterial infections constitute a major clinical problem caused by compromised skin barrier and a progressive immunodeficiency. Indeed, the majority of patients with advanced disease die from infections with bacteria, e.g., Staphylococcus aureus. Bacterial toxins such as staphylococcal enterotoxins (SE) have long been suspected to be involved in the pathogenesis in CTCL. Here, we review links between bacterial infections and CTCL with focus on earlier studies addressing a direct role of SE on malignant T cells and recent data indicating novel indirect mechanisms involving SE- and cytokine-driven cross-talk between malignant- and non-malignant T cells. Full article

(This article belongs to the Special Issue Toxins and Carcinogenesis)

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Open AccessReview

Earthworm-Derived Pore-Forming Toxin Lysenin and Screening of Its Inhibitors

by Neelanun Sukumwang and Kazuo Umezawa

Toxins 2013, 5(8), 1392-1401; https://doi.org/10.3390/toxins5081392 - 8 Aug 2013

Cited by 17 | Viewed by 9384

Abstract

Lysenin is a pore-forming toxin from the coelomic fluid of earthworm Eisenia foetida. This protein specifically binds to sphingomyelin and induces erythrocyte lysis. Lysenin consists of 297 amino acids with a molecular weight of 41 kDa. We screened for cellular signal transduction [...] Read more.

Lysenin is a pore-forming toxin from the coelomic fluid of earthworm Eisenia foetida. This protein specifically binds to sphingomyelin and induces erythrocyte lysis. Lysenin consists of 297 amino acids with a molecular weight of 41 kDa. We screened for cellular signal transduction inhibitors of low molecular weight from microorganisms and plants. The purpose of the screening was to study the mechanism of diseases using the obtained inhibitors and to develop new chemotherapeutic agents acting in the new mechanism. Therefore, our aim was to screen for inhibitors of Lysenin-induced hemolysis from plant extracts and microbial culture filtrates. As a result, we isolated all-E-lutein from an extract of Dalbergia latifolia leaves. All-E-lutein is likely to inhibit the process of Lysenin-membrane binding and/or oligomer formation rather than pore formation. Additionally, we isolated tyrosylproline anhydride from the culture filtrate of Streptomyces as an inhibitor of Lysenin-induced hemolysis. Full article

(This article belongs to the Special Issue Pore-Forming Toxins)

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Open AccessArticle

A Label Free Colorimetric Assay for the Detection of Active Botulinum Neurotoxin Type A by SNAP-25 Conjugated Colloidal Gold

by Jennifer Halliwell and Christopher Gwenin

Toxins 2013, 5(8), 1381-1391; https://doi.org/10.3390/toxins5081381 - 6 Aug 2013

Cited by 14 | Viewed by 7918

Abstract

Botulinum neurotoxins are one of the most potent toxins known to man. Current methods of detection involve the quantification of the toxin but do not take into account the percentage of the toxin that is active. At present the assay used for monitoring [...] Read more.

Botulinum neurotoxins are one of the most potent toxins known to man. Current methods of detection involve the quantification of the toxin but do not take into account the percentage of the toxin that is active. At present the assay used for monitoring the activity of the toxin is the mouse bioassay, which is lengthy and has ethical issues due to the use of live animals. This report demonstrates a novel assay that utilises the endopeptidase activity of the toxin to detect Botulinum neurotoxin in a pharmaceutical sample. The cleaving of SNAP-25 is monitored via UV-Visible spectroscopy with a limit of detection of 373 fg/mL and has been further developed into a high throughput method using a microplate reader detecting down to 600 fg/mL of active toxin. The results show clear differences between the toxin product and the placebo, which contains the pharmaceutical excipients human serum albumin and lactose, showing that the assay detects the active form of the toxin. Full article

(This article belongs to the Special Issue Advances in Toxin Detection)

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Open AccessReview

pH-Triggered Conformational Switching along the Membrane Insertion Pathway of the Diphtheria Toxin T-Domain

by Alexey S. Ladokhin

Toxins 2013, 5(8), 1362-1380; https://doi.org/10.3390/toxins5081362 - 6 Aug 2013

Cited by 54 | Viewed by 12288

Abstract

The translocation (T)-domain plays a key role in the action of diphtheria toxin and is responsible for transferring the catalytic domain across the endosomal membrane into the cytosol in response to acidification. Deciphering the molecular mechanism of pH-dependent refolding and membrane insertion of [...] Read more.

The translocation (T)-domain plays a key role in the action of diphtheria toxin and is responsible for transferring the catalytic domain across the endosomal membrane into the cytosol in response to acidification. Deciphering the molecular mechanism of pH-dependent refolding and membrane insertion of the T-domain, which is considered to be a paradigm for cell entry of other bacterial toxins, reveals general physicochemical principles underlying membrane protein assembly and signaling on membrane interfaces. Structure-function studies along the T-domain insertion pathway have been affected by the presence of multiple conformations at the same time, which hinders the application of high-resolution structural techniques. Here, we review recent progress in structural, functional and thermodynamic studies of the T-domain archived using a combination of site-selective fluorescence labeling with an array of spectroscopic techniques and computer simulations. We also discuss the principles of conformational switching along the insertion pathway revealed by studies of a series of T-domain mutants with substitutions of histidine residues. Full article

(This article belongs to the Special Issue Diphtheria Toxin)

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Open AccessCommunication

Occurrence of Deoxynivalenol in Wheat in Slovakia during 2010 and 2011

by Svetlana Šliková, Soňa Gavurníková, Valéria Šudyová and Edita Gregová

Toxins 2013, 5(8), 1353-1361; https://doi.org/10.3390/toxins5081353 - 2 Aug 2013

Cited by 18 | Viewed by 5593

Abstract

In this study, a total of 299 grain samples of wheat were collected from four production regions: the maize, sugar beet, potato and feed sectors of Slovakia. The samples were analyzed for deoxynivalenol (DON) content by using an enzyme-linked immunosorbent assay Ridascreen^® [...] Read more.

In this study, a total of 299 grain samples of wheat were collected from four production regions: the maize, sugar beet, potato and feed sectors of Slovakia. The samples were analyzed for deoxynivalenol (DON) content by using an enzyme-linked immunosorbent assay Ridascreen^® Fast DON. Analysis of variance revealed a significant difference between years in DON contents (p < 0.027). The occurrence of samples with DON was 82.2% in 2010, with maximum DON content of 7.88 mg kg⁻¹, and 70.7% in 2011, with maximum DON content of 2.12 mg·kg⁻¹. The total mean DON content was 0.62 mg·kg⁻¹; in the feed region 0.22 mg·kg⁻¹; 0.63 mg·kg⁻¹ in the maize region; 0.78 mg·kg⁻¹ in the sugar beet region; 0.45 mg·kg⁻¹ the potato region. The limit of 1.25 mg·kg⁻¹ imposed by the European Union (EU) for DON content was exceeded in 13.7% of the studied samples. The average monthly rainfall for May to June played a critical role in DON content of wheat grains for maize and sugar beet producing regions. The present results indicate that DON content was at a high level in grains from wheat grown during 2010. Full article

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Open AccessReview

Clinical Marine Toxicology: A European Perspective for Clinical Toxicologists and Poison Centers

by Corinne Schmitt and Luc De Haro

Toxins 2013, 5(8), 1343-1352; https://doi.org/10.3390/toxins5081343 - 2 Aug 2013

Cited by 21 | Viewed by 7275

Abstract

Clinical marine toxicology is a rapidly changing area. Many of the new discoveries reported every year in Europe involve ecological disturbances—including global warming—that have induced modifications in the chorology, behavior, and toxicity of many species of venomous or poisonous aquatic life including algae, [...] Read more.

Clinical marine toxicology is a rapidly changing area. Many of the new discoveries reported every year in Europe involve ecological disturbances—including global warming—that have induced modifications in the chorology, behavior, and toxicity of many species of venomous or poisonous aquatic life including algae, ascidians, fish and shellfish. These changes have raised a number of public issues associated, e.g., poisoning after ingestion of contaminated seafood, envenomation by fish stings, and exposure to harmful microorganism blooms. The purpose of this review of medical and scientific literature in marine toxicology is to highlight the growing challenges induced by ecological disturbances that confront clinical toxicologists during the everyday job in the European Poison Centers. Full article

(This article belongs to the Collection Marine and Freshwater Toxins)

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Open AccessArticle

The Effects of a Chactoid Scorpion Venom and Its Purified Toxins on Rat Blood Pressure and Mast Cells Histamine Release

by Keren Ettinger, Gadi Cohen, Tatjana Momic and Philip Lazarovici

Toxins 2013, 5(8), 1332-1342; https://doi.org/10.3390/toxins5081332 - 29 Jul 2013

Cited by 4 | Viewed by 6425

Abstract

The effect of the venom of the Chactoid family of scorpions on blood pressure was scantly investigated and was addressed in the present study using the venom of the Israeli scorpion, Scorpio maurus palmatus. Blood pressure in rats was monitored via cannulated [...] Read more.

The effect of the venom of the Chactoid family of scorpions on blood pressure was scantly investigated and was addressed in the present study using the venom of the Israeli scorpion, Scorpio maurus palmatus. Blood pressure in rats was monitored via cannulated femoral artery, while venom and toxins were introduced into femoral vein. Venom injection elicited a biphasic effect, expressed first by a fast and transient hypotensive response, which lasted up to 10 min, followed by a hypertensive response, which lasted up to one hour. It was found that these effects resulted from different venom components. Phospholipase A₂ produced the hypotensive effect, while a non-enzymatic neurotoxic polypeptide fraction produced the hypertensive effect. Surprisingly, the main neurotoxic polypeptide to mice had no effect on blood pressure. In vitro experiments indicated that the hypertensive factors caused histamine release from the peritoneal mast cells, but this effect is assumed to be not relevant to their in vivo effect. In spite of the cytotoxic activity of phospholipase A₂, it did not release histamine. These findings suggest that the effects of venom and isolated fractions on blood pressure parameters are mediated by different mechanisms, which deserve further pharmacological investigation. Full article

(This article belongs to the Special Issue Scorpion Toxins 2013)

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Toxins, Volume 5, Issue 8 (August 2013) – 12 articles , Pages 1332-1502

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