Regulation of Epithelial Cell Tight Junctions by Protease-Activated Receptor          2

Enjoji, Shuhei; Sato, Koichi

doi:10.1292/jvms.14-0191

Cited by 28 publications

(28 citation statements)

References 19 publications

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“…This similar trend in different models may be due to the fact that during exercise, the blood flow is diverted from the gut to the periphery, creating an I/R-like scenario (92) with the potential consequent activation of PAR-2. It has been reported that PAR-2 activation may directly affect cytoskeleton contraction by triggering the phosphorylation of MLCK with subsequent changes in TJ permeability, as demonstrated in in vitro epithelial models (19,20). However, the unchanged expression level of OCLN suggests that the PAR-2 receptor activation in our model is insufficient to induce damage at the TJ level, and so we were unable to predict the impairment of barrier permeability.…”

Section: Discussionmentioning

confidence: 69%

“…Gut permeability is also influenced by protease-activated receptor-2 (PAR-2) expressed in the apical and basolateral membranes of intestinal epithelial cells (17). As described by a review (17), its activation induces an increase in permeability by means of impairment of the TJ functions, as shown in several epithelial and endothelial cell models (18)(19)(20)(21). In different models including colitis and ischemia and reperfusion (I/R), PAR-2 transcription was upregulated in mouse, rodent, and horse models (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

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Non-invasive Assessment of Fecal Stress Biomarkers in Hunting Dogs During Exercise and at Rest

et al. 2020

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Intense exercise causes to organisms to have oxidative stress and inflammation at the gastrointestinal (GI) level. The reduction in intestinal blood flow and the exercise-linked thermal damage to the intestinal mucosa can cause intestinal barrier disruption, followed by an inflammatory response. Furthermore, the adaptation to exercise may affect the gut microbiota and the metabolome of the biofluids. The aim of the present research was to evaluate the presence of a GI derangement in hunting dogs through a non-invasive sampling as a consequence of a period of intense exercise in comparison with samples collected at rest. The study included nine dogs that underwent the same training regime for hunting wild boar. In order to counterbalance physiological variations, multiple-day replicates were collected and pooled at each experimental point for each dog. The samples were collected immediately at rest before the training (T0), after 60 days of training (T1), after 60 days of hunting wild boar (T2), and finally, at 60 days of rest after hunting (T3). A number of potential stress markers were evaluated: fecal cortisol metabolites (FCMs) as a major indicator of altered physiological states, immunoglobulin A (IgA) as an indicator of intestinal immune protection, and total antioxidant activity [total antioxidant capacity (TAC)]. Since stool samples contain exfoliated cells, we investigated also the presence of some transcripts involved in GI permeability [occludin (OCLN), protease-activated receptor-2 (PAR-2)] and in the inflammatory mechanism [interleukin (IL)-8, IL-6, IL-1b, tumor necrosis factor alpha (TNFα), calprotectin (CALP), heme oxygenase-1 (HO-1)]. Finally, the metabolome and the microbiota profiles were analyzed. No variation in FCM and IgA content and no differences in OCLN and CALP gene expression between rest and training were observed. On the contrary, an increase in PAR-2 and HO-1 transcripts, a reduction in total antioxidant activity, and a different profile of microbiota and metabolomics data were observed. Collectively, the data in the present study indicated that physical exercise in our model could be considered a mild stressor stimulus.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Non-invasive Assessment of Fecal Stress Biomarkers in Hunting Dogs During Exercise and at Rest

et al. 2020

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“…NF‐κB upregulates intercellular adhesion molecule‐1 (ICAM‐1). In addition, PAR‐2 activation breaks tight junctions via the p38 MAP kinase (p38 MAPK), suggesting that PAR‐2 can induce barrier instability and thereby create openings for new exogenous inducers of CNI. Both PAR‐2 and PAR‐4 could enhance or maintain a CNI‐related vicious cycle by upregulating specific pro‐inflammatory genes, although these genes have not yet been completely described.…”

Section: Role Of Parsmentioning

confidence: 99%

Self‐maintenance of neurogenic inflammation contributes to a vicious cycle in skin

Gouin

Lebonvallet

L’Hérondelle

et al. 2015

Experimental Dermatology

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Cutaneous neurogenic inflammation (CNI) is frequently associated with skin disorders. CNI is not limited to the retrograde signalling of nociceptive sensory nerve endings but can instead be regarded as a multicellular phenomenon. Thus, soluble mediators participating in communication among sensory nerves, skin and immune cells are key components of CNI. These interactions induce the self-maintenance of CNI, promoting a vicious cycle. Certain G protein-coupled receptors (GPCRs) play a prominent role in these cell interactions and contribute to selfmaintenance. Protease-activated receptors 2 and 4 (PAR-2 and PAR-4, respectively) and Mas-related G protein-coupled receptors (Mrgprs) are implicated in the synthesis and release of neuropeptides, proteases and soluble mediators from most cutaneous cells. Regulation of the expression and release of these mediators contributes to the vicious cycle of CNI. The authors propose certain hypothetical therapeutic options to interrupt this cycle, which might reduce skin symptoms and improve patient quality of life.

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“…Src1 is also a component of the focal adhesion complex [31]. The activation of PAR2 has been shown to result in the phosphorylation of p38 [32]. Moreover, studies have reported that β1-integrin has the ability to induce FAK auto-phosphorylation at Tyr397, which in turn binds to the SH2 domain of Src1 protein [33,34].…”

Section: Introductionmentioning

confidence: 99%

Accumulation of tissue factor in endothelial cells promotes cellular apoptosis through over-activation of Src1 and involves β1-integrin signalling

et al. 2019

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Accumulation of tissue factor (TF) within cells leads to cellular apoptosis mediated through p38 and p53 pathways. In this study, the involvement of Src1 in the induction of TF-mediated cell apoptosis, and the mechanisms of Src1 activation were investigated. Human coronary artery endothelial cell (HCAEC) were transfected with plasmids to express the wild-type TF (TF Wt-tGFP), or a mutant (Ser253 → Ala) which is incapable of being released from cells (TF Ala253-tGFP). The cells were then activated with PAR2-agonist peptide (SLIGKV-NH) and the phosphorylation of Src and Rac, and also the kinase activity of Src were assessed. Transfected cells were also pre-incubated with pp60c Src inhibitor, FAK inhibitor-14, or a blocking anti-β1-integrin antibody prior to activation and the phosphorylation of p38 as well as cellular apoptosis was examined. Finally, cells were co-transfected with the plasmids, together with a Src1-specific siRNA, activated as above and the cellular apoptosis measured. Activation of PAR2 lead to the phosphorylation of Src1 and Rac1 proteins at 60 min regardless of TF expression. Moreover, Src phosphorylation and kinase activity was prolonged up to 100 min in the presence of TF, with a significantly higher magnitude when the non-releasable TF Ala253-tGFP was expressed in HCAEC. Inhibition of Src with pp60c, or suppression of Src1 expression in cells, reduced p38 phosphorylation and prevented cellular apoptosis. In contrast, inhibition of FAK had no significant influence on Src kinase activity or cellular apoptosis. Finally, pre-incubation of cells with an inhibitory anti-β1-integrin antibody reduced both Src1 activation and cellular apoptosis. Our data show for the first time that the over-activation of Src1 is a mediator of TF-induced cellular apoptosis in endothelial cells through a mechanism that is dependent on its interaction with β1-integrin.

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Regulation of Epithelial Cell Tight Junctions by Protease-Activated Receptor 2

Cited by 28 publications

References 19 publications

Non-invasive Assessment of Fecal Stress Biomarkers in Hunting Dogs During Exercise and at Rest

Non-invasive Assessment of Fecal Stress Biomarkers in Hunting Dogs During Exercise and at Rest

Self‐maintenance of neurogenic inflammation contributes to a vicious cycle in skin

Accumulation of tissue factor in endothelial cells promotes cellular apoptosis through over-activation of Src1 and involves β1-integrin signalling

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