What diseases are caused by alpha toxin,

Implicaţiile microbiomului în iniţierea şi promovarea carcinogenezei

Through the new techniques and establishment of novel protocols, especially in the field of molecular bio­lo­gy, together with the results from in vitro, in vivo pre­cli­ni­cal and clinical studies carried out on an im­pres­sive number of patients with various pathologies, scien­tists have established ample associations between the microbiome composition and certain cancers or the treat­ment response.

In some types of cancer, the role of microorganisms has been incriminated, which by their presence can activate certain signaling pathways or produce some metabolites that ultimately affect the cel­lular functioning.

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For some microorganisms such as Fu­so­bac­te­rium nucleatum or toxigenic Bacteroides fragilis in colorectal cancer, the possible mechanisms of action have been already described. Despite this fact, numerous stu­dies are still needed in order to determine whether bac­te­rial presence triggers the neoplastic process or the gut microbial abundance in affected patients is the result of other changes taking place.

Keywords microbiome, carcinogenesis, diagnosis Rezumat În ultima perioadă, microbiomul a primit tot mai multă aten­ţie, fiind o temă de cercetare frecvent abordată în numeroase studii. Prin noile tehnici şi stabilirea de pro­to­coa­le ino­va­toare, în special în domeniul biologiei mo­le­cu­lare, ală­turi de coroborarea rezultatelor cu ob­ser­va­ţii­le pro­ve­nite din studiile preclinice in vitro, in vivo şi clinice efec­tua­te la un număr impresionant de pacienţi cu diverse pa­to­lo­gii, cercetătorii au constatat asocieri între anumite pa­to­lo­gii neoplazice sau modul de răspuns la tratament şi com­po­zi­ţia microbiomului.

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În anumite tipuri de cancer a fost in­cri­mi­nat rolul unor microorganisme care prin prezenţa lor pot activa diverse căi de semnalizare sau pot produce me­ta­bo­liţi care în final afectează funcţionarea celulară.

Deşi pentru microorganisme precum Fusobacterium nu­cleatum sau Bacteroides fragilis toxigen în cancerul co­lo­rec­tal au fost descrise posibile mecanisme de acţiune, sunt în con­ti­nuare necesare numeroase studii pentru a sta­bili dacă pre­zenţa acestor bacterii declanşează procesul neo­pla­zic sau abundenţa lor la pacienţii afectaţi este doar re­zul­ta­tul celorlalte modificări care au loc.

Acta Microbiologica 34. (1987)

Cuvinte what diseases are caused by alpha toxin microbiom cancinogeneză diagnostic Introduction Tissue homeostasis, density, architecture and function can normally be maintained by a balance between cell growth and programmed cell death signals, together with other cellular control mechanisms 1. Microorganisms have been proven to be involved in the etiopathogenesis of some neoplasms 2.

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For example, Helicobacter pylori interacts through the cytotoxin-associated gene A CagA protein with E-cadherin, an intercellular adhesion molecule, leading to the dissociation of b-catenin from E-cadherin and thus to the cytoplasmic and nuclear accumulation of the first.

Moreover, by prolonged activity of the vacuolating cytotoxin protein VacAmany alterations happen at endosomal, mitochondrial, permeability and signaling level 4leading to the impediment of autophagy 3. Autophagy is a degradation process that involves the formation of autophagosomes, which include cytoplasmic components, and subsequently fuse with lysosomes, but due to the signals of mitochondrial destruction, the cell tries to reduce damage and triggers apoptosis instead of autophagy 5.

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Oncoviruses also present many mechanisms by which they can be involved in carcinogenesis through negii plantari rănesc după azot main paths: directly by genes insertion or indirectly by sustained inflammation 3.

For some types of cancers, parasitic etiologies have been suggested: Schistosoma haematobium, Schistosoma what diseases are caused by alpha toxin and Schistosoma mansoni through inflammation and oxidative stress; Opistorchis viverrini, Opistorchis felineus and Clonorchis sineses through inflammation, oxidative stress and cell proliferation 6.

At the same time, the presence of some parasites seems to have a beneficial, antineoplastic effect: Echinococcus spp.

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The microbiota represents all the microorganisms that are physiologically located in and on the surface of the human body, while the microbiome comprises their genetic material 8. In recent years, the growing interest for the microbiota and its implications in various pathologies has been observed through the multitude of studies, publications, but also scientific meetings on this topic.

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The role of the microbiota has been highlighted in numerous molecular mechanisms of what diseases are caused by alpha toxin body development, autoimmune diseases, hypersensitivity pathologies, and in many others, including neoplastic disorders 9. The microbiota can contribute to tumor genesis by direct mechanisms, producing toxins and acting on DNA denaturation, or indirectly, by modifying the tumor microenvironment, promoting unrestricted cell proliferation 9.

In both of these mechanisms, it should be taken into account the numerous effects of the microbiota on the immune system 9. Colorectal cancer A. Microorganisms with procarcinogenic effect The involvement of microbiota in the carcinogenesis of colon and rectum has been explained through several ways, such as altering cell proliferation, influencing the immune system or metabolizing food factors.

Enterotoxigenic Bacteroides fragilis Bacteroides fragilis colonizes between 0.


So far, two strains have been identified: one toxigenic and the what diseases are caused by alpha toxin one non-toxigenic The latter strain has what diseases are caused by alpha toxin effects in protective mechanisms against cancer 11while the first one, enterotoxigenic B. This toxin promotes the cleavage of E-cadherin and leads to nuclear translocation of b-catenin and c-myc proto-oncogene transcription, resulting in colonic epithelial cells hyperplasia, increased spermine oxidase expression and reactive oxygen species production, which promote cell injury and carcinogenesis 1.

Another toxin-mediated mechanism is achieved with the implication of the immune system: the accumulation of regulatory T lymphocytes in the intestinal lamina propria, the suppression of mucosal immune response by T helper-1 lymphocytes, the increased interleukin IL secretion, ultimately leading to tumor genesis. Increased MDSC can lead to increase in nitric oxide NO and arginase 1 levels, thus being responsible for inhibiting T lymphocytes and avoiding the antitumor immune what diseases are caused by alpha toxin According to the alpha-bug hypothesis, ETBF remodels the colonic microbiota and cooperates with environmental factors and host genetics to induce colon cancer 1.

Fusobacterium nucleatum Fusobacterium nucleatum is an opportunistic anaerobic commensal of the oral cavity, which may be involved in the production of periodontal disease, but it can also cause diseases in other areas of the body, such as intrauterine infections with major pregnancy complications Recently, F. One of the virulence factors expressed on its surface is FadA, which exists in two forms: the intact form pre-FadAanchored in the membrane, and the secreted mature FadA mFadA.

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Only the pairing of the two forms represents an active complex the pre-FadA-mFadA complexwhich has the ability to attach to the endothelial cells through E-cadherin and activate signaling pathways through b-catenin This process leads to increased expression of transcription factors, oncogenes, inflammatory genes and stimulates the development of cancer cells Fusobacterium varum may also what diseases are caused by alpha toxin through the same mechanism Several mechanisms have been proposed regarding the involvement of Smoothie concombre pomme banane. This protein appears to be involved in the adhesion of tumor cells, which overexpress Gal-GalNAc molecules This process is followed by what diseases are caused by alpha toxin interaction between F.

When a Wnt ligand binds to the transmembrane domain of Frizzled proteins family of G protein-coupled receptor proteins and its coreceptors, low-density lipoprotein receptor related protein 5 or 6 LRPthey form a complex together with the recruitment of the Dishevelled protein, which results in the phosphorylation and activation of LRP6.

Moreover, in the infection with F. In papilloma squamoso ugola to this, studies on F. Another possible involved mechanism is inflammation, with high levels of TNF-a and IL being observed in people with concurrent colonic adenomas and F.

In those with colon cancer, increased levels of IL-6 and IL-8 have been noticed in the presence of F. The presence of this bacterium has been associated with poor survival in patients with colon cancer and also with resistance to chemotherapy Escherichia coli Escherichia coli is a widespread Gram-negative bacterium, also part of the human gut microbiota. It is divi­ded into 5 phylogenetic groups, but the most commonly involved in human pathologies is the one belonging to B2 group The mechanism by which this leads to the development of colon condiloame și antiseptice is not exactly known, but there are two main pathways currently under investigation: one indirectly by inflammation and the other one directly through molecular mechanisms For example, both adherent invasive E.

Colibactin induces apoptosis of immune cells and chromosomal instability with DNA damage in the epithelial cells, leading to their senescence secretory phenotype of senescent cells Although the cells are no longer dividing, they may secrete growth factors which allow tumor development EspF may decrease the level of repair proteins MLH1 and MLH2 11 and it may also contribute to metastasis process by acting on the intercellular tight junction proteins occludin and claudin-1 Other proteins produced by E.

Salmonella spp. Salmonella enterica comprises several serotypes, such as Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis and Salmonella typhimurium In recent years, cancers of the cancer plamani doare, gall bladder and other cancers of the gastrointestinal tract have been correlated with infections caused by S.

The mechanism of cancer transformation can also be direct and indirect, as in the case of other pathogens described There are two identified toxins responsible for these mechanisms: typhoid toxin a cyclomodulin similar to the one produced by E. Typhoid toxin can increase cell survival and promote intestinal dysbiosis AvrA has been identified in the stool samples from colon cancer patients and several possible mechanisms of action have been suggested, including the inhibition of NF-kB signaling pathway, inhibition of IL, INF-g, TNF-a secretion, What diseases are caused by alpha toxin transcription and stimulation of IL transcription By its activity of acetyl transferase, AvrA can affect p53 activity, decreasing apoptosis It has been observed that the higher incidence of gallbladder cancer in some geographical areas corresponds to the increased incidence of Salmonella spp.

Microbiome implications in carcinogenesis initiation and promotion

Enterococcus faecalis By producing increased amounts of superoxide at the luminal level of the colonic mucosa, Enterococcus faecalis can lead to DNA damage, point mutations 2chromosome instability and cellular aneuploidy 1.

In vitro studies have proven that E. However, some studies even suggest a possible protective role of E. Streptococcus gallolyticus Streptococcus gallolyticus formerly known as S.

Although frequently reported, the mechanism of action is not yet fully elucidated, but carcinogenic effect is most likely produced by inflammatory effects In vitro studies have shown that mucosal exposure to this bacterium leads to increased IL-1 16but also IL-8, the latter being involved in carcinogenesis processes by increasing oxidative stress, promoting angiogenesis, tumor proliferation and overexpression of COX-2 Another recent theory mentions the ability of S.

In this case, it acts by activating the Wnt pathway, then decreasing Slc10A2 protein production Solute Carrier Family 10 Member 2, a bile acid transporterwhich leads to the accumulation of bile acids.

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Moreover, bacteriocine production is activated, allowing S. Clostridium septicum Due to its ability to produce alpha-toxin that binds to GPI glycosylphosphatidylinositol receptors on the cell surface, including folate receptors, Clostridium septicum has been associated in some studies with carcinogenesis Microorganisms with possible protective effect Some studies have pointed out that certain bacteria may play a protective role in neoplastic processes through numerous mechanisms, including the production of short-chain fatty acids 1.

They are produced in the intestine by microbial fermentation of the dietary fibres, representing the primary energy source for the colon epithelial cells, as opposed to the cancer cells, which are based on carbon source metabolism, especially on glucose 1. Eubacterium rectale and Faecalibacterium prausnitzii may be involved in the butyrate production, having an anti-inflammatory role by inducing IL expression Furthermore, the intracellular increased level of détoxifiant foie concentration may act as an inhibitor of histone deacetylation, which stimulates apoptosis and inhibits cell proliferation 1.

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Through their components, probiotics may have implications in modulating the immune system. For example, the lipopolysaccharide from the bacterial membrane of Gram-negative bacteria may activate the TLR4 surface receptor, which stimulates the T-cell-mediated immune response against cancer cells Bifidobacterium, Bacteroides thetaiotamicron and non-toxigenic B.

Lactobacillus casei BL23 has immunomodulatory effects by lowering IL and also antiproliferative influence by increasing caspase-7 and caspase-9 In addition to this, it produces ferrichrome, a tumour-suppressive molecule, by which it can trigger apoptosis in tumor cells Clostridium nexile may contribute to the anticancer effects of Pseudomonas aeruginosa Monophosphoryl lipid A, a modified synthetic form of lipid A, derivatived from Salmonella enterica Salmonella minnesotahas been used as an adjuvant in anticancer vaccines The composition of gut microbiota in oncology One of the studies that compared the composition of the microbiota of healthy people with the one of those with different types of cancers identified the following five most frequent phyla: Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria and Verrucomicrobia The abundance of Firmicutes was high in all groups, but this bacterium was predominant in healthy individuals, those with hyperplastic polips and low-risk or high-risk adenomas, compared with adenocarcinoma group, where it was found in a lower proportion