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. 2005 34 875 878 Jin, D. Y.: Molecular pathogenesis of hepatitis C virus-associated hepatocellular

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Wong, C-M., Ng, I. O. L.: Molecular pathogenesis of hepatocellular carcinoma. Liver Intern., 2008, 28 , 160–174. Ng I. O. L. Molecular pathogenesis of hepatocellular carcinoma

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Abstract

The serine protease HtrA of C. jejuni has been identified as a novel secreted virulence factor which opens cell-to-cell junctions by cleaving E-cadherin. Efficient C. jejuni transmigration across polarized human epithelial cells requires the intact flagellum and HtrA; however, the mechanism of HtrA secretion into the supernatant is unknown. Here we show that HtrA secretion is highly efficient and does not require its proteolytic activity because the protease-inactive S197A mutant is secreted like wild-type HtrA. In addition, the flagellar mutants ΔflaA/B, ΔfliI, ΔflgH, ΔflhA, ΔflhB, and ΔflgS were also able to secrete HtrA in high amounts, while they were strongly attenuated in secreting the well-known invasion antigen CiaB. We also tested several culture media and cell lines of different origin such as human, mouse, hamster, dog, and chicken for their ability to influence HtrA secretion. Interestingly, HtrA was effectively secreted in the presence of most but not all cell lines and media, albeit at different levels, but secretion was significantly higher when fetal calf serum (FCS) was added. These results demonstrate that HtrA secretion by Campylobacter proceeds independent of HtrA's protease activity, the flagellum and origin of cell lines, but can be strongly enhanced by molecular compound(s) present in FCS.

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European Journal of Microbiology and Immunology
Authors: Manja Boehm, Daniel Simson, Ulrike Escher, Anna-Maria Schmidt, Stefan Bereswill, Nicole Tegtmeyer, Steffen Backert and Markus M. Heimesaat

Campylobacter jejuni is a major food-borne zoonotic pathogen, responsible for a large proportion of bacterial gastroenteritis cases, as well as Guillian-Barré and Miller-Fisher syndromes. During infection, tissue damage is mainly caused by bacteria invading epithelial cells and traversing the intestinal barrier. C. jejuni is able to enter the lamina propria and the bloodstream and may move into other organs, such as spleen, liver, or mesenteric lymph nodes. However, the involved molecular mechanisms are not fully understood. C. jejuni can transmigrate effectively across polarized intestinal epithelial cells mainly by the paracellular route using the serine protease high-temperature requirement A (HtrA). However, it appears that HtrA has a dual function, as it also acts as a chaperone, interacting with denatured or misfolded periplasmic proteins under stress conditions. Here, we review recent progress on the role of HtrA in C. jejuni pathogenesis. HtrA can be transported into the extracellular space and cleaves cell-to-cell junction factors, such as E-cadherin and probably others, disrupting the epithelial barrier and enabling paracellular transmigration of the bacteria. The secretion of HtrA is a newly discovered strategy also utilized by other pathogens. Thus, secreted HtrA proteases represent highly attractive targets for anti-bacterial treatment and may provide a suitable candidate for vaccine development.

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Campylobacter jejuni is an important pathogen of foodborne illness. Transmigration across the intestinal epithelial barrier and invasion are considered as primary reasons for tissue damage triggered by C. jejuni. Using knockout mutants, it was shown that the serine protease HtrA may be important for stress tolerance and physiology of C. jejuni. HtrA is also secreted in the extracellular environment, where it can cleave junctional host cell proteins such as E-cadherin. Aim of the present study was to establish a genetic complementation system in two C. jejuni strains in order to introduce the wild-type htrA gene in trans, test known htrA phenotypes, and provide the basis to perform further mutagenesis. We confirm that reexpression of the htrA wild-type gene in ΔhtrA mutants restored the following phenotypes: 1) C. jejuni growth at high temperature (44 °C), 2) growth under high oxygen stress conditions, 3) expression of proteolytically active HtrA oligomers, 4) secretion of HtrA into the supernatant, 5) cell attachment and invasion, and 6) transmigration across polarized epithelial cells. These results establish a genetic complementation system for htrA in C. jejuni, exclude polar effects in the ΔhtrA mutants, confirm important HtrA properties, and permit the discovery and dissection of new functions.

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Orvosi Hetilap
Authors: Zsuzsa Schaff, Ilona Kovalszky, Gábor Lotz and András Kiss

6 674 687 Thorgeirsson, S. S., Grisham, J. W.: Molecular pathogenesis of human hepatocellular carcinoma. Nat. Genet., 2002, 31

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A nyelőcsőrák a kilencedik leggyakoribb rosszindulatú daganat. Több mint 90%-ban előrehaladott állapotban kerül felismerésre. A sebészi beavatkozás, a kemo-, illetve radioterápia lehetőségei korlátozottak. Napjainkban a génterápia került az érdeklődés előterébe. A szerzők a nyelőcsőlaphámrák genetikai és molekuláris hátterét és a génterápiával elért kezdeti tapasztalatokat tekintik át. Ismertetik a komplementer nukleinsavak (antisense terápia), a génpótlás, a kis interferáló RNS-k alkalmazásának lehetőségeit.

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A szív-ér rendszeri megbetegedések világszerte a leggyakoribb halálozási okok közé tartoznak. Az utóbbi évek tudományos eredményei arra utalnak, hogy a hyperhomocystinaemia a szív-ér rendszeri betegségek egyik jelentős kockázati tényezője. A homocisztein és a folsav metabolizmusát befolyásoló gének közül a metilén-tetrahidrofolát-reduktáz (MTHFR) polimorfizmusai – az MTHFR C677T és az MTHFR A1298C – összefüggésbe hozhatóak a cardiovascularis betegségekkel. A magas vérnyomás kialakulásában az MTHFR C677T polimorfizmusa is hajlamosító tényező lehet. Nem egyértelmű ugyanakkor az összefüggés a hyperhomocystinaemia és az MTHFR említett génvariánsai között. A legújabb kutatási eredmények szerint az 5-metil-tetrahidrofolát (5-MTHF) is befolyásolja az endothelfunkciókat. Így valószínűsíthető, hogy az MTHFR polimorfizmusai a homociszteintől függetlenül is hajlamosítanak a magas vérnyomásra és a szív-ér rendszeri megbetegedések kialakulására. Ennek tükrében kiemelkedő fontosságú lehet a folsavanyagcserében részt vevő génpolimorfizmusok és a cardiovascularis kockázati tényezők közötti kapcsolat vizsgálata és a molekuláris patomechanizmusok feltárása. Orv. Hetil., 2012, 153, 445–453.

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2989 2996 Puccio, H., Koenig, M.: Recent advances in the molecular pathogenesis of Friedreich ataxia. Hum. Mol. Genet., 2000, 9 , 887

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pheochromocytomas and extra-adrenal paragangliomas. Arch. Pathol. Lab. Med., 2014, 138 (2), 182–188. 7 Galan, S. R., Kann, P. H.: Genetics and molecular pathogenesis

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