CRC Press Online - Series: Cellular and Molecular Mechanisms of Toxic Action. Secretory Systems and Toxins. 1st Edition. Michal Linial, Alfonso Grasso.
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- Mechanisms of Toxicity
- The Comprehensive Sourcebook of Bacterial Protein Toxins
However, if a chemical accumulates in a particular cell or organ, that may signal a reason to further examine its potential toxicity in that organ. More recently, mathematical models have been developed to extrapolate pharmacokinetic variables from animals to humans. These pharmacokinetic models are extremely useful in generating hypotheses and testing whether the experimental animal may be a good representation for humans.
Numerous chapters and texts have been written on this subject Gehring et al. A simplified example of a physiological model is depicted in figure 1. Toxicity can be described at different biological levels. Injury can be evaluated in the whole person or animal , the organ system, the cell or the molecule. Organ systems include the immune, respiratory, cardiovascular, renal, endocrine, digestive, muscolo-skeletal, blood, reproductive and central nervous systems.
Some key organs include the liver, kidney, lung, brain, skin, eyes, heart, testes or ovaries, and other major organs. Adverse effects at the molecular level include alteration of the normal function of DNA-RNA transcription, of specific cytoplasmic and nuclear receptor binding, and of genes or gene products. Ultimately, dysfunction in a major organ system is likely caused by a molecular alteration in a particular target cell within that organ.
However, it is not always possible to trace a mechanism back to a molecular origin of causation, nor is it necessary. Intervention and therapy can be designed without a complete understanding of the molecular target. However, knowledge about the specific mechanism of toxicity increases the predictive value and accuracy of extrapolation to other chemicals.
Figure 2 is a diagrammatic representation of the various levels where interference of normal physiological processes can be detected. Mechanisms of toxicity can be straightforward or very complex. Frequently, there is a difference among the type of toxicity, the mechanism of toxicity, and the level of effect, related to whether the adverse effects are due to a single, acute high dose like an accidental poisoning , or a lower-dose repeated exposure from occupational or environmental exposure.
Classically, for testing purposes, an acute, single high dose is given by direct intubation into the stomach of a rodent or exposure to an atmosphere of a gas or vapour for two to four hours, whichever best resembles the human exposure. The animals are observed over a two-week period following exposure and then the major external and internal organs are examined for injury.
Repeated-dose testing ranges from months to years. For rodent species, two years is considered a chronic lifetime study sufficient to evaluate toxicity and carcinogenicity, whereas for non-human primates, two years would be considered a subchronic less than lifetime study to evaluate repeated dose toxicity. Following exposure a complete examination of all tissues, organs and fluids is conducted to determine any adverse effects. The following examples are specific to high-dose, acute effects which can lead to death or severe incapacitation.
However, in some cases, intervention will result in transient and fully reversible effects. The dose or severity of exposure will determine the result. The mechanism of toxicity for inert gases and some other non-reactive substances is lack of oxygen anoxia. These chemicals, which cause deprivation of oxygen to the central nervous system CNS , are termed simple asphyxiants. If a person enters a closed space that contains nitrogen without sufficient oxygen, immediate oxygen depletion occurs in the brain and leads to unconsciousness and eventual death if the person is not rapidly removed.
In extreme cases near zero oxygen unconsciousness can occur in a few seconds. Rescue depends on rapid removal to an oxygenated environment. Survival with irreversible brain damage can occur from delayed rescue, due to the death of neurons, which cannot regenerate.
Carbon monoxide CO competes with oxygen for binding to haemoglobin in red blood cells and therefore deprives tissues of oxygen for energy metabolism; cellular death can result. Intervention includes removal from the source of CO and treatment with oxygen. The direct use of oxygen is based on the toxic action of CO. Another potent chemical asphyxiant is cyanide. The cyanide ion interferes with cellular metabolism and utilization of oxygen for energy.
Treatment with sodium nitrite causes a change in haemoglobin in red blood cells to methaemoglobin. Methaemoglobin has a greater binding affinity to the cyanide ion than does the cellular target of cyanide. Consequently, the methaemoglobin binds the cyanide and keeps the cyanide away from the target cells. This forms the basis for antidotal therapy.
Central nervous system CNS depressants. Acute toxicity is characterized by sedation or unconsciousness for a number of materials like solvents which are not reactive or which are transformed to reactive intermediates. If sufficient dose is administered by ingestion or inhalation the animal can die due to respiratory arrest. If anaesthetic death does not occur, this type of toxicity is usually readily reversible when the subject is removed from the environment or the chemical is redistributed or eliminated from the body.
Adverse effects to the skin can range from irritation to corrosion, depending on the substance encountered. Strong acids and alkaline solutions are incompatible with living tissue and are corrosive, causing chemical burns and possible scarring. Scarring is due to death of the dermal, deep skin cells responsible for regeneration. Lower concentrations may just cause irritation of the first layer of skin.
Another specific toxic mechanism of skin is that of chemical sensitization. As an example, sensitization occurs when 2,4-dinitrochlorobenzene binds with natural proteins in the skin and the immune system recognizes the altered protein-bound complex as a foreign material. This is the same reaction of the immune system when exposure to poison ivy occurs. Immune sensitization is very specific to the particular chemical and takes at least two exposures before a response is elicited.
The first exposure sensitizes sets up the cells to recognize the chemical , and subsequent exposures trigger the immune system response. Removal from contact and symptomatic therapy with steroid-containing anti-inflammatory creams are usually effective in treating sensitized individuals. In serious or refractory cases a systemic acting immunosuppresant like prednisone is used in conjunction with topical treatment. An immune sensitization response is elicited by toluene diisocyanate TDI , but the target site is the lungs.
TDI over-exposure in susceptible individuals causes lung oedema fluid build-up , bronchial constriction and impaired breathing. This is a serious condition and requires removing the individual from potential subsequent exposures. Treatment is primarily symptomatic. Skin and lung sensitization follow a dose response. Exceeding the level set for occupational exposure can cause adverse effects.
Injury to the eye ranges from reddening of the outer layer swimming-pool redness to cataract formation of the cornea to damage to the iris coloured part of the eye. Eye irritation tests are conducted when it is believed serious injury will not occur. Many of the mechanisms causing skin corrosion can also cause injury to the eyes. Materials corrosive to the skin, like strong acids pH less than 2 and alkali pH greater than In addition, surface active agents like detergents and surfactants can cause eye injury ranging from irritation to corrosion.
A group of materials that requires caution is the positively charged cationic surfactants, which can cause burns, permanent opacity of the cornea and vascularization formation of blood vessels. Another chemical, dinitrophenol, has a specific effect of cataract formation. This appears to be related to concentration of this chemical in the eye, which is an example of pharmacokinetic distributional specificity.
While the listing above is far from exhaustive, it is designed to give the reader an appreciation for various acute toxicity mechanisms. When given as a single high dose, some chemicals do not have the same mechanism of toxicity as when given repeatedly as a lower but still toxic dose. Alcohol is a good example. High doses of alcohol lead to primary central nervous system effects, while lower repetitive doses result in liver injury.
Most organophosphate pesticides, for example, have little mammalian toxicity until they are metabolically activated, primarily in the liver. The primary mechanism of action of organophosphates is the inhibition of acetylcholinesterase AChE in the brain and peripheral nervous system. AChE is the normal enzyme that terminates the stimulation of the neurotransmitter acetylcholine. Slight inhibition of AChE over an extended period has not been associated with adverse effects. At high levels of exposure, inability to terminate this neuronal stimulation results in overstimulation of the cholinergic nervous system.
Cholinergic overstimulation ultimately results in a host of symptoms, including respiratory arrest, followed by death if not treated. The primary treatment is the administration of atropine, which blocks the effects of acetylcholine, and the administration of pralidoxime chloride, which reactivates the inhibited AChE. Therefore, both the cause and the treatment of organophosphate toxicity are addressed by understanding the biochemical basis of toxicity.
Many chemicals, including carbon tetrachloride, chloroform, acetylaminofluorene, nitrosamines, and paraquat are metabolically activated to free radicals or other reactive intermediates which inhibit and interfere with normal cellular function. While the specific interactions and cellular targets remain unknown, the organ systems which have the capability to activate these chemicals, like the liver, kidney and lung, are all potential targets for injury.
Specifically, particular cells within an organ have a greater or lesser capacity to activate or detoxify these intermediates, and this capacity determines the intracellular susceptibility within an organ. Metabolism is one reason why an understanding of pharmacokinetics, which describes these types of transformations and the distribution and elimination of these intermediates, is important in recognizing the mechanism of action of these chemicals. Cancer is a multiplicity of diseases, and while the understanding of certain types of cancer is increasing rapidly due to the many molecular biological techniques that have been developed since , there is still much to learn.
However, it is clear that cancer development is a multi-stage process, and critical genes are key to different types of cancer. Exposure to natural chemicals in cooked foods like beef and fish or synthetic chemicals like benzidine, used as a dye or physical agents ultraviolet light from the sun, radon from soil, gamma radiation from medical procedures or industrial activity are all contributors to somatic gene mutations.
However, there are natural and synthetic substances such as anti-oxidants and DNA repair processes which are protective and maintain homeostasis. It is clear that genetics is an important factor in cancer, since genetic disease syndromes such as xeroderma pigmentosum, where there is a lack of normal DNA repair, dramatically increase susceptibility to skin cancer from exposure to ultraviolet light from the sun.
It is known that certain viruses such as rubella , bacterial infections and drugs such as thalidomide and vitamin A will adversely affect development. Recently, work by Khera , reviewed by Carney , show good evidence that the abnormal developmental effects in animal tests with ethylene glycol are attributable to maternal metabolic acidic metabolites.
This occurs when ethylene glycol is metabolized to acid metabolites including glycolic and oxalic acid. The subsequent effects on the placenta and foetus appear to be due to this metabolic toxication process. The intent of this article is to give a perspective on several known mechanisms of toxicity and the need for future study.
It is important to understand that mechanistic knowledge is not absolutely necessary to protect human or environmental health. The actual techniques used in elucidating any particular mechanism depend upon the collective knowledge of the scientists and the thinking of those who make decisions regarding human health.
Virtually all of medicine is devoted to either preventing cell death, in diseases such as myocardial infarction, stroke, trauma and shock, or causing it, as in the case of infectious diseases and cancer. It is, therefore, essential to understand the nature and mechanisms involved.
Cell injury and cell death are, therefore, important both in physiology and in pathophysiology. Physiological cell death is extremely important during embryogenesis and embryonic development. The study of cell death during development has led to important and new information on the molecular genetics involved, especially through the study of development in invertebrate animals. In these animals, the precise location and the significance of cells that are destined to undergo cell death have been carefully studied and, with the use of classic mutagenesis techniques, several involved genes have now been identified.
In adult organs, the balance between cell death and cell proliferation controls organ size. In some organs, such as the skin and the intestine, there is a continual turnover of cells. In the skin, for example, cells differentiate as they reach the surface, and finally undergo terminal differentiation and cell death as keratinization proceeds with the formation of crosslinked envelopes. Many classes of toxic chemicals are capable of inducing acute cell injury followed by death. These include anoxia and ischaemia and their chemical analogues such as potassium cyanide; chemical carcinogens, which form electrophiles that covalently bind to proteins in nucleic acids; oxidant chemicals, resulting in free radical formation and oxidant injury; activation of complement; and a variety of calcium ionophores.
Cell death is also an important component of chemical carcinogenesis; many complete chemical carcinogens, at carcinogenic doses, produce acute necrosis and inflammation followed by regeneration and preneoplasia. Cell injury is defined as an event or stimulus, such as a toxic chemical, that perturbs the normal homeostasis of the cell, thus causing a number of events to occur figure 1. The principal targets of lethal injury illustrated are inhibition of ATP synthesis, disruption of plasma membrane integrity or withdrawal of essential growth factors.
Lethal injuries result in the death of a cell after a variable period of time, depending on temperature, cell type and the stimulus; or they can be sublethal or chronic—that is, the injury results in an altered homeostatic state which, though abnormal, does not result in cell death Trump and Arstila ; Trump and Berezesky ; Trump and Berezesky ; Trump, Berezesky and Osornio-Vargas In the case of a lethal injury, there is a phase prior to the time of cell death. This is the phase known as necrosis. During the prelethal phase, several principal types of change occur, depending on the cell and the type of injury.
These are known as apoptosis and oncosis. Apoptosis is derived from the Greek words apo , meaning away from, and ptosis , meaning to fall. The term falling away from is derived from the fact that, during this type of prelethal change, the cells shrink and undergo marked blebbing at the periphery. The blebs then detach and float away. Apoptosis occurs in a variety of cell types following various types of toxic injury Wyllie, Kerr and Currie It is especially prominent in lymphocytes, where it is the predominant mechanism for turnover of lymphocyte clones.
The resulting fragments result in the basophilic bodies seen within macrophages in lymph nodes. In other organs, apoptosis typically occurs in single cells which are rapidly cleared away before and following death by phagocytosis of the fragments by adjacent parenchymal cells or by macrophages. Apoptosis occurring in single cells with subsequent phagocytosis typically does not result in inflammation. Prior to death, apoptotic cells show a very dense cytosol with normal or condensed mitochondria. The endoplasmic reticulum ER is normal or only slightly dilated. The nuclear chromatin is markedly clumped along the nuclear envelope and around the nucleolus.
The nuclear contour is also irregular and nuclear fragmentation occurs. The chromatin conden- sation is associated with DNA fragmentation which, in many instances, occurs between nucleosomes, giving a characteristic ladder appearance on electrophoresis. Injuries that totally inhibit ATP synthesis, therefore, are more likely to result in apoptosis.
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Endonuclease activation results in single and double DNA strand breaks which, in turn, stimulate increased levels of p53 and in poly-ADP ribosylation, and of nuclear proteins which are essential in DNA repair. Activation of proteases modifies a number of substrates including actin and related proteins leading to bleb formation. Such kinases are involved in activation of transcription factors which initiate transcription of immediate-early genes, for example, c-fos, c-jun and c-myc, and in activation of phospholipase A 2 which results in permeabilization of the plasma membrane and of intracellular membranes such as the inner membrane of mitochondria.
Oncosis, derived from the Greek word onkos , to swell, is so named because in this type of prelethal change the cell begins to swell almost immediately following the injury Majno and Joris The reason for the swelling is an increase in cations in the water within the cell. The principal cation responsible is sodium, which is normally regulated to maintain cell volume. However, in the absence of ATP or if Na-ATPase of the plasmalemma is inhibited, volume control is lost because of intracellular protein, and sodium in the water continuing to increase. This results in swelling of the cytosol, swelling of the endoplasmic reticulum and Golgi apparatus, and the formation of watery blebs around the cell surface.
The mitochondria initially undergo condensation, but later they too show high-amplitude swelling because of damage to the inner mitochondrial membrane. In this type of prelethal change, the chromatin undergoes condensation and ultimately degradation; however, the characteristic ladder pattern of apoptosis is not seen.
Necrosis refers to the series of changes that occur following cell death when the cell is converted to debris which is typically removed by the inflammatory response. Two types can be distinguished: Oncotic necrosis typically occurs in large zones, for example, in a myocardial infarct or regionally in an organ after chemical toxicity, such as the renal proximal tubule following administration of HgCl 2.
Broad zones of an organ are involved and the necrotic cells rapidly incite an inflammatory reaction, first acute and then chronic. In the event that the organism survives, in many organs necrosis is followed by clearing away of the dead cells and regeneration, for example, in the liver or kidney following chemical toxicity. In contrast, apoptotic necrosis typically occurs on a single cell basis and the necrotic debris is formed within the phagocytes of macrophages or adjacent parenchymal cells.
The earliest characteristics of necrotic cells include interruptions in plasma membrane continuity and the appearance of flocculent densities, representing denatured proteins within the mitochondrial matrix. In some forms of injury that do not initially interfere with mitochondrial calcium accumulation, calcium phosphate deposits can be seen within the mitochondria.
Other membrane systems are similarly fragmenting, such as the ER, the lysosomes and the Golgi apparatus. Ultimately, the nuclear chromatin undergoes lysis, resulting from attack by lysosomal hydrolases.
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Following cell death, lysosomal hydrolases play an important part in clearing away debris with cathepsins, nucleolases and lipases since these have an acid pH optimum and can survive the low pH of necrotic cells while other cellular enzymes are denatured and inactivated. In the case of lethal injuries, the most common initial interactions resulting in injury leading to cell death are interference with energy metabolism, such as anoxia, ischaemia or inhibitors of respiration, and glycolysis such as potassium cyanide, carbon monoxide, iodo-acetate, and so on.
As mentioned above, high doses of compounds that inhibit energy metabolism typically result in oncosis. The other common type of initial injury resulting in acute cell death is modification of the function of the plasma membrane Trump and Arstila ; Trump, Berezesky and Osornio-Vargas In some cases, the pattern in the prelethal change is apoptosis; in others, it is oncosis. With many types of injury, mitochondrial respiration and oxidative phosphorylation are rapidly affected.
In some cells, this stimulates anaerobic glycolysis, which is capable of maintaining ATP, but with many injuries this is inhibited. Positive and negative regulation of chloride secretion in T84 cells. Nucleotide sequence of Clostridium difficile toxin B gene. Cloning of a gene zot encoding a new toxin produced by Vibrio cholerae. Phosphatase inhibitors activate normal and defective CFTR chloride channels. A novel bicomponent hemolysin from Bacillus cereus. Characterization of the components of hemolysin BL from Bacillus cereus.
Enterotoxic activity of hemolysin BL from Bacillus cereus. Improved purification and characterization of hemolysin BL, a hemolytic dermonecrotic vascular permeability factor from Bacillus cereus. Interactions between membranes and cytolytic peptides. Fibroblasts modulate intestinal secretory responses to inflammatory mediators. Staphylococcal enterotoxin A is encoded by phage. Involvement of arachidonic acid in the chloride secretory response of intestinal epithelial cells.
Experimental Campylobacter jejuni infection in humans. A review of human salmonellosis: Biological and immunological properties of the carboxyl terminus of staphylococcal enterotoxin C1. Incidence of toxigenic Campylobacter strains in South Africa. Regulation of taurine transport by Escherichia coli heat-stable enterotoxin and guanylin in human intestinal cell lines. Effect of toxigenic Escherichia coli on myoelectric activity of small intestine.
Alteration of myoelectric activity of small intestine by invasive Escherichia coli. Campylobacter jejuni chromosomal sequences that hybridize to Vibrio cholerae and Escherichia coli LT enterotoxin genes. Enteropathogenic Escherichia coli decreases the transepithelial electrical resistance of polarized epithelial monolayers. Partial purification and characterization of an escherichia coli toxic factor that induces morphological cell alterations.
The Escherichia coli heat-stable enterotoxin is a long-lived superagonist of guanylin. Synergistic action of cyclic adenosine monophosphate- and calcium-mediated chloride secretion in a colonic epithelial cell line. Release of vasoactive intestinal polypeptide from the cat small intestine exposed to cholera toxin. The effect of nicotinic and muscarinic receptor blockade on cholera toxin induced intestinal secretion in rats and cats.
The involvement of intramural nerves in cholera toxin induced intestinal secretion. Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum. Cloning of enterotoxin gene from Aeromonas hydrophila provides conclusive evidence of production of a cytotonic enterotoxin. Interleukins 1 and 3 stimulate anion secretion in chicken intestine. Phorbol ester stimulation of active anion secretion in intestine. Differential activation by atrial and brain natriuretic peptides of two different receptor guanylate cyclases. Type II heat-labile enterotoxin of Escherichia coli activates adenylate cyclase in human fibroblasts by ADP ribosylation.
Activation of intestinal mucosal adenylate cyclase by Shigella dysenteriae I enterotoxin. Location of the enterotoxin gene from Salmonella typhimurium and characterization of the gene products. Evidence for protein kinase C stimulation in rat enterocytes pretreated with heat stable enterotoxin of Escherichia coli. Effect of amphotericin B on sodium and water movement across normal and cholera toxin-challenged canine jejunum. The protein kinase domain of the ANP receptor is required for signaling.
Purification and partial characterization of a cytotonic enterotoxin produced by Aeromonas hydrophila. Cloning, expression, and sequence analysis of a cytolytic enterotoxin gene from Aeromonas hydrophila. Cloning and expression of the Salmonella enterotoxin gene. Molecular characterization of an enterotoxin from Salmonella typhimurium.
Cloning and expression of putative cytotonic enterotoxin-encoding genes from Aeromonas hydrophila. Mechanism of action of a cytotonic enterotoxin produced by Aeromonas hydrophila. Epithelial secretory response to inflammation. Ann N Y Acad Sci.
Mechanisms of Toxicity
Shiga-like cytotoxin production by enteropathogenic Escherichia coli serogroups. Age-related differences in receptors for Escherichia coli heat-stable enterotoxin in the small and large intestine of children. Receptors for Escherichia coli heat stable enterotoxin in human intestine and in a human intestinal cell line Caco A gradient in expression of the Escherichia coli heat-stable enterotoxin receptor exists along the villus-to-crypt axis of rat small intestine.
Biochem Biophys Res Commun. Differences in jejunal and ileal response to E. Safety, immunogenicity, and efficacy of live attenuated Vibrio cholerae O vaccine prototype. Production of cholera-like enterotoxin by a Vibrio cholerae non-O1 strain isolated from the environment. Carbachol mimics phorbol esters in its ability to enhance cyclic GMP production by STa, the heat-stable toxin of Escherichia coli. Regulation of intestinal guanylate cyclase by the heat-stable enterotoxin of Escherichia coli STa and protein kinase C. Cloning, nucleotide sequencing, and expression of the Clostridium perfringens enterotoxin gene in Escherichia coli.
Partial purification and characterization of the enterotoxin produced by Campylobacter jejuni. Enterotoxicity of bacteria-free culture-filtrate of Vibrio cholerae. Globotetraosylceramide is recognized by the pig edema disease toxin. Role of Yersinia enterocolitica Yst toxin in experimental infection of young rabbits. Nucleotide sequence of yst, the Yersinia enterocolitica gene encoding the heat-stable enterotoxin, and prevalence of the gene among pathogenic and nonpathogenic yersiniae. Localization of cystic fibrosis transmembrane conductance regulator in chloride secretory epithelia.
Evidence for two types of cytotoxic necrotizing factor in human and animal clinical isolates of Escherichia coli. Characterization of the recombinant human receptor for Escherichia coli heat-stable enterotoxin. Rat guanylyl cyclase C expressed in COS-7 cells exhibits multiple affinities for Escherichia coli heat-stable enterotoxin. Multiple calcium-mediated effector mechanisms regulate chloride secretory responses in Tcells. Established intestinal cell lines as model systems for electrolyte transport studies. Mechanism of chloride secretion induced by carbachol in a colonic epithelial cell line.
A study of intercellular spaces in the rabbit jejunum during acute volume expansion and after treatment with cholera toxin. Phospholipase C-induced anion secretion and its interaction with carbachol in the rat colonic mucosa. Involvement of Ras-related Rho proteins in the mechanisms of action of Clostridium difficile toxin A and toxin B. Identification of errors among database sequence entries and comparison of correct amino acid sequences for the heat-labile enterotoxins of Escherichia coli and Vibrio cholerae. A plasmid-encoded type IV fimbrial gene of enteropathogenic Escherichia coli associated with localized adherence.
Role of the eaeA gene in experimental enteropathogenic Escherichia coli infection. A second chromosomal gene necessary for intimate attachment of enteropathogenic Escherichia coli to epithelial cells. Calcium dependence of serotonin-induced changes in rabbit ileal electrolyte transport. Effects of phorbol esters on sodium and chloride transport in rat colon. Detection of heat-labile Escherichia coli enterotoxin with the use of adrenal cells in tissue culture. Binding of class II Escherichia coli enterotoxins to mouse Y1 and intestinal cells.
Molecular characterization of the Clostridium difficile toxin A gene. Chemical properties of heat-stable enterotoxins produced by enterotoxigenic Escherichia coli of different host origins. Characterization of the mechanism of action of Escherichia coli heat-stable enterotoxin. Purification of the STB enterotoxin of Escherichia coli and the role of selected amino acids on its secretion, stability and toxicity. Enterotoxin-induced fluid accumulation during experimental salmonellosis and cholera: Pathogenesis of Escherichia coli diarrhea. N Engl J Med. Inoculum size in shigellosis and implications for expected mode of transmission.
Signal transduction in human epithelial cells infected with attaching and effacing Escherichia coli in vitro. Epithelial cells secrete the chemokine interleukin-8 in response to bacterial entry. Effect of 5-hydroxytryptamine antagonists on cholera toxin-induced secretion in the human jejunum. Eur J Clin Invest. The enteric nervous system participates in the secretory response to the heat stable enterotoxins of Escherichia coli in rats and cats. Influence of staphylococcal enterotoxin on water and electrolyte transport in the small intestine.
Modulation of host response to Escherichia coli o H7 infection by anti-CD18 antibody in rabbits. Mechanisms of oral staphylococcal enterotoxin B-induced emesis in the monkey Proc Soc Exp Biol Med. H7 and of Shiga toxin on eukaryotic ribosomes. RNA N-glycosidase activity of the toxins. Differentiated Caco-2 cells as a model for enteric invasion by Campylobacter jejuni and C. Pathological changes in the rabbit ileal loop model caused by Campylobacter jejuni from human colitis. Isolation and nucleotide sequence of the gene encoding cytotoxic necrotizing factor 1 of Escherichia coli.
Induction of phagocytic behaviour in human epithelial cells by Escherichia coli cytotoxic necrotizing factor type 1. Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions. Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. Enterotoxin and cytotoxin production by enteroinvasive Escherichia coli.
Culture supernatants of Campylobacter jejuni induce a secretory response in jejunal segments of adult rats. Molecular cloning of a Salmonella typhi LT-like enterotoxin gene. Heat-stable enterotoxin of Escherichia coli: Cytoskeletal composition of attaching and effacing lesions associated with enteropathogenic Escherichia coli adherence to HeLa cells. Cytoskeletal changes induced in HEp-2 cells by the cytotoxic necrotizing factor of Escherichia coli. Escherichia coli cytotoxic necrotizing factor 1: Clostridium difficile toxin A and its effects on cells.
Production of enterotoxin and cytotoxin in Campylobacter jejuni strains isolated in Costa Rica. Lysosomal involvement in cellular intoxication with Clostridium difficile toxin B. Role of Shiga toxin in the pathogenesis of bacillary dysentery, studied by using a Tox- mutant of Shigella dysenteriae 1. Role of platelet activating factor in the inflammatory and secretory effects of Clostridium difficile toxin A. J Lipid Mediat Cell Signal. Guanylin stimulation of Cl- secretion in human intestinal T84 cells via cyclic guanosine monophosphate. Stimulation of intestinal Cl- transport by heat-stable enterotoxin: The eaeB gene of enteropathogenic Escherichia coli is necessary for signal transduction in epithelial cells.
A diarrheal pathogen, enteropathogenic Escherichia coli EPEC , triggers a flux of inositol phosphates in infected epithelial cells. Ruffles induced by Salmonella and other stimuli direct macropinocytosis of bacteria. Infection of gnotobiotic pigs with an Escherichia coli O H7 strain associated with an outbreak of hemorrhagic colitis. Ion transport across isolated ileal mucosa invaded by salmonella. Purification and characterization of Escherichia coli heat-stable enterotoxin II. Effect of alterations of basic amino acid residues of Escherichia coli heat-stable enterotoxin II on enterotoxicity.
Forskolin- but not ionomycin-evoked Cl- secretion in colonic epithelia depends on intact microtubules. Involvement of the epidermal growth factor receptor in the invasion of cultured mammalian cells by Salmonella typhimurium. Role of Vibrio cholerae neuraminidase in the function of cholera toxin. Effect of iron on production of a possible virulence factor by Plesiomonas shigelloides. Importance of disulfide bridges in the structure and activity of Escherichia coli enterotoxin ST1b.
Structure of the toxic domain of the Escherichia coli heat-stable enterotoxin ST I. Activation of particulate guanylate cyclase by Escherichia coli heat-stable enterotoxin is regulated by adenine nucleotides. Importance of the intestinal inflammatory reaction in salmonella-mediated intestinal secretion. Studies of fluid secretion, mucosal invasion, and morphologic reaction in the rabbit ileum. Pathogenesis of Salmonella-mediated intestinal fluid secretion.
Activation of adenylate cyclase and inhibition by indomethacin. Effect of a recA mutation on cholera toxin gene amplification and deletion events.
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Shigella subversion of the cellular cytoskeleton: Escherichia coli heat-stable enterotoxin-mediated colonic Cl- secretion is absent in cystic fibrosis. A plasmid-encoded regulatory region activates chromosomal eaeA expression in enteropathogenic Escherichia coli. Isolation and purification of Aeromonas sobria cytotonic enterotoxin and beta-haemolysin.
The Comprehensive Sourcebook of Bacterial Protein Toxins
Sphingomyelinase is part of the 'enterotoxin complex' produced by Bacillus cereus. Inhibition of Escherichia coli heat-stable enterotoxin effects on intestinal guanylate cyclase and fluid secretion by quinacrine. Inhibition of Escherichia coli heat-stable enterotoxin by indomethacin and chlorpromazine. Lanthanum chloride inhibition of the secretory response to Escherichia coli heat-stable enterotoxin. T84 cell receptor binding and guanyl cyclase activation by Escherichia coli heat-stable toxin.
Small and large intestinal guanylate cyclase activity in children: Cyclic adenosine monophosphate and alteration of Chinese hamster ovary cell morphology: Role of platelet activating factor in the intestinal epithelial secretory and Chinese hamster ovary cell cytoskeletal responses to cholera toxin.
Role of toxigenic and invasive bacteria in acute diarrhea of childhood. Production of a unique cytotoxin by Campylobacter jejuni. A 56 kDa binding protein for Escherichia coli heat-stable enterotoxin isolated from the cytoskeleton of rat intestinal membrane does not possess guanylate cyclase activity. Apical membrane chloride channels in a colonic cell line activated by secretory agonists.
Neurological manifestations of hemorrhagic colitis in the outbreak of Escherichia coli O H7 infection in Japan. A recombinant C-terminal toxin fragment provides evidence that membrane insertion is important for Clostridium perfringens enterotoxin cytotoxicity. Localization of the receptor-binding region of Clostridium perfringens enterotoxin utilizing cloned toxin fragments and synthetic peptides. The 30 C-terminal amino acids define a functional binding region. Mapping of functional regions of Clostridium perfringens type A enterotoxin.
Involvement of 5-hydroxytryptamine and prostaglandin E2 in the intestinal secretory action of Escherichia coli heat-stable enterotoxin B. Clostridium difficile toxin B disrupts the barrier function of T84 monolayers.
Clostridium difficile toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers. Reversible disassembly of an intestinal epithelial monolayer by prolonged exposure to phorbol ester. Molecular cloning and characterization of the hblA gene encoding the B component of hemolysin BL from Bacillus cereus.
Cellular internalisation of Clostridium difficile toxin A. In vitro and in vivo pathogenicity of Plesiomonas shigelloides. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Search in this book. The Comprehensive Sourcebook of Bacterial Protein Toxins 4 th Edition, contains chapters written by internationally known and well-respected specialists. This book contains chapters devoted to individual toxins, as well as chapters that consider the different applications of these toxins.
Considerable progress has been made in understanding the structure, function, interaction and trafficking into cells, as well as mechanism of action of toxins. Bacterial toxins are involved in the pathogenesis of many bacteria, some of which are responsible for severe diseases in human and animals, but can also be used as tools in cell biology to dissect cellular processes or used as therapeutic agents. Novel recombinant toxins are already proposed in the treatment of some diseases, as well as new vaccines.
Alternatively, certain toxins are also considered as biological weapons or bioterrorism threats.