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1.
J Crohns Colitis ; 15(9): 1528-1541, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-33609354

RESUMO

BACKGROUND AND AIMS: Intestinal epithelial cells [IECs] from inflammatory bowel disease [IBD] patients exhibit an excessive induction of endoplasmic reticulum stress [ER stress] linked to altered intestinal barrier function and inflammation. Colonic tissues and the luminal content of IBD patients are also characterized by increased serine protease activity. The possible link between ER stress and serine protease activity in colitis-associated epithelial dysfunctions is unknown. We aimed to study the association between ER stress and serine protease activity in enterocytes and its impact on intestinal functions. METHODS: The impact of ER stress induced by Thapsigargin on serine protease secretion was studied using either human intestinal cell lines or organoids. Moreover, treating human intestinal cells with protease-activated receptor antagonists allowed us to investigate ER stress-resulting molecular mechanisms that induce proteolytic activity and alter intestinal epithelial cell biology. RESULTS: Colonic biopsies from IBD patients exhibited increased epithelial trypsin-like activity associated with elevated ER stress. Induction of ER stress in human intestinal epithelial cells displayed enhanced apical trypsin-like activity. ER stress-induced increased trypsin activity destabilized intestinal barrier function by increasing permeability and by controlling inflammatory mediators such as C-X-C chemokine ligand 8 [CXCL8]. The deleterious impact of ER stress-associated trypsin activity was specifically dependent on the activation of protease-activated receptors 2 and 4. CONCLUSIONS: Excessive ER stress in IECs caused an increased release of trypsin activity that, in turn, altered intestinal barrier function, promoting the development of inflammatory process.


Assuntos
Colite Ulcerativa/patologia , Doença de Crohn/patologia , Estresse do Retículo Endoplasmático/fisiologia , Enterócitos/fisiologia , Absorção Intestinal/fisiologia , Tripsina/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Colite Ulcerativa/etiologia , Colite Ulcerativa/metabolismo , Doença de Crohn/etiologia , Doença de Crohn/metabolismo , Humanos , Organoides , Tapsigargina
2.
J Crohns Colitis ; 14(8): 1149-1161, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32090263

RESUMO

Crohn's disease [CD] and ulcerative colitis [UC] are the two main forms of inflammatory bowel disease [IBD]. Previous studies reported increased levels of proteolytic activity in stool and tissue samples from IBD patients, whereas the re-establishment of the proteolytic balance abrogates the development of experimental colitis. Furthermore, recent data suggest that IBD occurs in genetically predisposed individuals who develop an abnormal immune response to intestinal microbes once exposed to environmental triggers. In this review, we highlight the role of proteases in IBD pathophysiology, and we showcase how the main cellular pathways associated with IBD influence proteolytic unbalance and how functional proteomics are allowing the unambiguous identification of dysregulated proteases in IBD, paving the way to the development of new protease inhibitors as a new potential treatment.


Assuntos
Colite Ulcerativa , Doença de Crohn , Imunidade nas Mucosas/genética , Peptídeo Hidrolases/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/enzimologia , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/enzimologia , Doença de Crohn/genética , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Farmacogenética , Inibidores de Proteases/farmacologia , Fatores de Risco
3.
Artigo em Inglês | MEDLINE | ID: mdl-31708870

RESUMO

Protease-activated receptors (PARs) belong to the G protein-coupled receptor (GPCR) family. Compared to other GPCRs, the specificity of the four PARs is the lack of physiologically soluble ligands able to induce their activation. Indeed, PARs are physiologically activated after proteolytic cleavage of their N-terminal domain by proteases. The resulting N-terminal end becomes a tethered activation ligand that interact with the extracellular loop 2 domain and thus induce PAR signal. PARs expression is ubiquitous and these receptors have been largely described in chronic inflammatory diseases and cancer. In this review, after describing their discovery, structure, mechanisms of activation, we then focus on the roles of PARs in the intestine and the two main diseases affecting the organ, namely inflammatory bowel diseases and cancer.

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