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2019, Gastroenterology
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Butt et al 1 observed an increased risk of developing colon rectal cancer in individuals possessing circulating antibodies to the vacuolating toxin (VacA) of Helicobacter pylori. Such a risk was particularly high for African Americans. 1 Indeed, VacA forms chloride (Cl-) channels that become inserted into the cell and mitochondrial membranes, 2 thereby reducing the membrane potential and mitochondrial energy production. The paradigm of altered Clhandling is cystic fibrosis, and it is well-known that patients with this disease have a 5to 10-fold increased risk of colon rectal cancer, 3 as well of other gastrointestinal tract cancers, 4 owing to the irregular activity of Clexchange by the cystic fibrosis transmembrane regulator. The transmembrane ionic equilibrium controls membrane potential, which in turn was shown to control cell proliferation. 5 In fact, the manipulation of Clconcentrations in the environment was shown to control carcinogenesis in tadpoles. 6 It is also known that entry of Clinto the cells, cancer cells in particular, increases cell energy, 7 that cells can spend to increase their growth. 7 Therefore, it is biologically plausible that the VacA toxin of H pylori could increase the risk of colon cancer, by chronically altering ionic equilibrium of enterocytes exposed to the toxin. In turn, this might open the opportunity for a strategy of noninvasively checking the risk of colon cancer in patients with cystic fibrosis and in the general population.
Helicobacter, 2018
Helicobacter pylori is a gram negative, spiral shaped, and microaerophilic bacteria. H. pylori colonizes the stomach of more than half of the world population. Previously, it was believed that because of the uncongenial acidic environment bacteria cannot grow in the stomach. However, after the confirmation of the presence of H. pylori in the human stomach was reported, various colonization strategies through virulence factors were studied. H. pylori is classified as a Class-1 carcinogen. H. pylori colonization in the gastric environment causes chronic inflammation through invading the inner lining of stomach which leads to the development of gastric ulcer. Despite the acidic environment of gastric mucosa of the host cell, bacteria come across the barrier of the epithelial cells. The presence of H. pylori is mostly associated with the development of various gastric diseases including peptic ulcers, gastric ulcers, adenocarcinoma, MALT lymphoma, and gastric cancer. H. pylori finds multiple ways for its survival in the human host which is performed by various virulence factors. Over the period of time, these virulence factors are collectively responsible for persistence and colonization. One of the major virulence factors produced by H. pylori is Vacuolating cytotoxin A (VacA). VacA is one of the most studied toxins of H pylori. As
Journal of Infectious Diseases, 2014
Carriage of Helicobacter pylori strains producing more active (s1/i1) forms of VacA is strongly associated with gastric adenocarcinoma. To our knowledge, we are the first to determine effects of different polymorphic forms of VacA on inflammation and metaplasia in the mouse stomach. Bacteria producing the less active s2/i2 form of VacA colonized mice more efficiently than mutants null for VacA or producing more active forms of it, providing the first evidence of a positive role for the minimally active s2/i2 toxin. Strains producing more active toxin forms induced more severe and extensive metaplasia and inflammation in the mouse stomach than strains producing weakly active (s2/i2) toxin. We also examined the association in humans, controlling for cagPAI status. In human gastric biopsy specimens, the vacA i1 allele was strongly associated with precancerous intestinal metaplasia, with almost complete absence of intestinal metaplasia in subjects infected with i2-type strains, even in a vacA s1, cagA + background.
The Journal of Infectious Diseases, 1998
Preliminary clinical evidence suggests that Helicobacter pylori may be associated with diarrhea through its vacuolating toxin (VacA). To establish whether VacA induces intestinal secretion, epithelial damage, or both, purified pH-activated VacA was added to Caco-2 cell monolayers mounted in Ussing chambers, and electrical parameters were monitored. Mucosal addition of VacA induced an increase in short circuit current, consistent with enterotoxic effect. The effect was time-and dose-dependent and saturable. It was not found if the toxin was not pH-activated, added to the serosal side, or preheated. In cells preloaded with the Ca2 ϩ buffering compound BAPTA/AM or with the Cl Ϫ channel inhibitor 5-nitro-2-3-(3phenylpropylamino)benzoic acid, short circuit current did not change, indicating that VacA induces activation of Ca2 ϩ-dependent Cl Ϫ channels. VacA did not show cytopathic effects, as judged by tissue resistance. These results support the hypothesis that H. pylori may be associated with diarrhea through production of VacA.
Frontiers in Cellular and Infection Microbiology, 2012
More than 50% of the world's population is infected with Helicobacter pylori (H. pylori). Chronic infection with this Gram-negative pathogen is associated with the development of peptic ulcers and is linked to an increased risk of gastric cancer. H. pylori secretes many proteinaceous factors that are important for initial colonization and subsequent persistence in the host stomach. One of the major protein toxins secreted by H. pylori is the Vacuolating cytotoxin A (VacA). After secretion from the bacteria via a type V autotransport secretion system, the 88 kDa VacA toxin (comprised of the p33 and p55 subunits) binds to host cells and is internalized, causing severe "vacuolation" characterized by the accumulation of large vesicles that possess hallmarks of both late endosomes and early lysosomes. The development of "vacuoles" has been attributed to the formation of VacA anion-selective channels in membranes. Apart from its vacuolating effects, it has recently become clear that VacA also directly affects mitochondrial function. Earlier studies suggested that the p33 subunit, but not the p55 subunit of VacA, could enter mitochondria to modulate organelle function. This raised the possibility that a mechanism separate from pore formation may be responsible for the effects of VacA on mitochondria, as crystallography studies and structural modeling predict that both subunits are required for a physiologically stable pore. It has also been suggested that the mitochondrial effects observed are due to indirect effects on pro-apoptotic proteins and direct effects on mitochondrial morphology-related processes. Other studies have shown that both the p55 and p33 subunits can indeed be efficiently imported into mammalian-derived mitochondria raising the possibility that they could reassemble to form a pore. Our review summarizes and consolidates the recent advances in VacA toxin research, with focus on the outstanding controversies in the field and the key remaining questions that need to be addressed.
Frontiers in cellular and infection microbiology, 2012
Virulence mechanisms underlying Helicobacter pylori persistence and disease remain poorly understood, in part, because the factors underlying disease risk are multifactorial and complex. Among the bacterial factors that contribute to the cumulative pathophysiology associated with H. pylori infections, the vacuolating cytotoxin (VacA) is one of the most important. Analogous to a number of H. pylori genes, the vacA gene exhibits allelic mosaicism, and human epidemiological studies have revealed that several families of toxin alleles are predictive of more severe disease. Animal model studies suggest that VacA may contribute to pathogenesis in several ways. VacA functions as an intracellular-acting protein exotoxin. However, VacA does not fit the current prototype of AB intracellular-acting bacterial toxins, which elaborate modulatory effects through the action of an enzymatic domain translocated inside host cells. Rather, VacA may represent an alternative prototype for AB intracellula...
Proceedings of the National Academy of Sciences, 1998
The Helicobacter pylori toxin VacA causes vacuolar degeneration in mammalian cell lines in vitro and plays a key role in peptic ulcer disease. Two alleles, m1 and m2, of the mid-region of the vacA gene have been described, and the m2 cytotoxin always has been described as inactive in the in vitro HeLa cell assay. However, the m2 allele is associated with peptic ulcer and is prevalent in populations in which peptic ulcer and gastric cancer have high incidence. In this paper, we show that, despite the absence of toxicity on HeLa cells, the m2 cytotoxin is able to induce vacuolization in primary gastric cells and in other cell lines such as RK-13. The absence of Hela cell activity is due to an inability to interact with the cell surface, suggesting a receptor-mediated interaction. This result is consistent with the observation that the m2 allele is found in a population that has a high prevalence of peptic ulcer disease and gastric cancer. VacA is the first bacterial toxin described for which the same active subunit can be delivered by different receptor binding domains.
FEBS Letters, 2001
The protein vacuolating toxin A (VacA) of Helicobacter pylori converts late endosomes into large vacuoles in the presence of permeant bases. Here it is shown that this phenomenon corresponds to an accumulation of permeant bases and Cl 3 3 in HeLa cells and requires the presence of extracellular Cl 3 3 . The net influx of Cl 3 3 is due to electroneutral, Na + , K + , 2Cl 3 3 cotransporter-mediated transport. Cell vacuolation leads to cell volume increase, consistent with water flux into the cell, while hyper-osmotic media decreased vacuole formation. These data represent the first evidence that VacA-treated cells undergo an osmotic unbalance, reinforcing the hypothesis that the VacA chloride channel is responsible for cell vacuolation. ß 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.
Microbiology, 1999
Polarized epithelial monolayers of Madin-Darby canine kidney (MDCK) cells were used to study the pathogenicity of Helicobacterpylori, with an emphasis on the effect of VacA. The adherence of H. pylori to MDCK monolayers resulted in a decrease in trans-epithelial resistance (TER) across the cell monolayer. lsogenic vacA mutants did not lower the TER, demonstrating that the effect is strictly linked to the action of the toxin. A similar effect was observed with all VacA-producing strains, including those producing m2 toxins that are inactive in the vacuolating assay. In contrast to that seen with purified toxin, TER decrease was not enhanced by acid pH, which may indicate that the toxin associated to the bacterial surface is possibly in a monomeric state and therefore does not require a pH-induced conformation to be active. These data raise the possibility that one role of VacA in ulcerogenesis may consist of increasing the paracellular permeability of the gastric epithelium. Montecucco, C. (1997). Helicobacter pylori toxin VacA induces vacuole formation by acting in the cell cytosol. Mol Mic-rohiol26, 665474. Blaser, M. J. (1993). Helicobacter pylori: microbiology o f a 'slow' bacterial infection. Trends Microhiol 1, 255-260.
Journal of Biological Chemistry, 2003
Helicobacter pylori vacuolating toxin (VacA) is a secreted toxin that is reported to produce multiple effects on mammalian cells. In this study, we explored the relationship between VacA-induced cellular vacuolation and VacA-induced cytochrome c release from mitochondria. Within intoxicated cells, vacuolation precedes cytochrome c release and occurs at lower VacA concentrations, indicating that cellular vacuolation is not a downstream consequence of cytochrome c release. Conversely, bafilomycin A1 blocks VacA-induced vacuolation but not VacA-induced cytochrome c release, which indicates that cytochrome c release is not a downstream consequence of cellular vacuolation. Acid activation of purified VacA is required for entry of VacA into cells, and correspondingly, acid activation of the toxin is required for both vacuolation and cytochrome c release, which suggests that VacA must enter cells to produce these two effects. Single amino acid substitutions (P9A and G14A) that ablate vacuolating activity and membrane channel-forming activity render VacA unable to induce cytochrome c release. Channel blockers known to inhibit cellular vacuolation and VacA membrane channel activity also inhibit cytochrome c release. These data indicate that cellular vacuolation and mitochondrial cytochrome c release are two independent outcomes of VacA intoxication and that both effects are dependent on the formation of anion-selective membrane channels.
Tropical Journal of Applied Natural Science, 2024
Diabetes remains one of the major causes of untimely death globally. Over 11% of the global population is diabetic, possibly due to late disease detection, inadequate interventions, and lifestyle choices etc. The growing severity of diabetes is driving scientific interest in leveraging Digital Health Technologies (DHTs) for improved management and treatment. Early diagnosis of diabetes is essential for effective interventions, reducing complications, and lowering the mortality rate associated with the disease. Thus, this study focuses on prediction of diabetes using supervised machine learning technique, specifically Random Forest Algorithm (RFA) for timely detection and prevention of the disease. The model was trained using Pima Indian dataset (diabetes), which is freely available on Kaggle database. Trial result indicate that the model was promising, with an accuracy of 92%, 89% precision, 88% recall, and a 90% F1-score. The study shows that applying the Random Forest algorithm significantly improves the accuracy and efficiency of early diabetes detection and diagnosis. However, in spite of the prospects of ML models in diabetes management, there are still concerns about its drawbacks including algorithmic bias, legal and ethical issues, and implementation challenges in clinical environment. Thus, we recommend that legal framework should be put in place to guide the use of ML algorithms, and other digital health technologies in clinical diabetes care delivery.
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