A Kawabata

..These findings demonstrate that endothelial PAR-1 and PAR-2, upon activation, dilate the gastric artery via NO and prostanoid formation and also EDHF mechanisms including gap junctions, which would enhance GMBF...

..pylori extracts in A549 and HCT-15 cells or rat platelets, and suggests that they are not mediated by any PAR-activating proteinases, but may involve the other pathogenic factors including LPS...

..7. Thus, 2-furoyl-LIGRL-NH(2) is considered a potent and orally available gastric mucosal protective agent. Our data also substantiate a role for PAR(2) in gastric mucosal protection and the selective nature of 2-furoyl-LIGRL-NH(2)...

..PARs thus appear to play critical roles in the respiratory systems, and the agonists/antagonists for PARs may serve as the novel therapeutic strategy for treatment of certain respiratory diseases including asthma...

..Our study thus provides a novel mouse model for PAR-2-mediated nociception, and suggests that NMDA receptors are involved in PAR-2-triggered nociception and hyperalgesia, while NO contributes only to the latter...

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..There is also fundamental and clinical evidence for involvement of PAR2 in colonic pain. PARs are thus considered key molecules in regulation of GI functions and targets for development of drugs for treatment of various GI diseases...

..PAR-2 is thus involved in a variety of physiological and pathophysiological functions. PAR-2 is now considered one of the most important molecules as a target for drug development...

..6. Our data suggest involvement of apamin/charybdotoxin-sensitive K+ channels in the PAR-2-triggered hypotension and increased GMBF, predicting a role of EDHF-like factors...

..Thus, PAR-2 would appear to be a therapeutic target for treatment of gastric mucosal injury. Agonists and/or antagonists for PAR-2 might also be applicable to the clinical treatment of patients with inflammatory diseases in other organs...

..Thus, PARs, especially PAR-1 and PAR-2, play extensive roles in modulating the gastrointestinal functions...

..The role of PAR-1, a thrombin receptor, in the stomach remains unknown. We thus examined if the PAR-1 agonist could protect against gastric mucosal injury in rats...

..Our data thus reveal that activation of PAR-2 in the parotid gland can cause activation of trigeminal nociceptive neurons via capsaicin-sensitive sensory nerves most probably by a non-inflammatory mechanism...

..Furthermore, the data from PAR-2-deficient mice provide ultimate evidence for involvement of PAR-2 in salivation and the selective nature of the 2-furoylated peptides...

..Protease-activated receptors (PARs) 1 and 2 are expressed in various blood vessels including rat aorta, modulating vascular tone. We investigated the roles of PAR-1 and PAR-2 in vasomotor modulation in rat superior mesenteric artery...

..In contrast, the PAR-2-mediated salivary exocrine secretion appears to be independent of capsaicin-sensitive sensory neurons...

..3. Thus, activation of VR1 is responsible, at least in part, for the neurally mediated mucosal cytoprotection following activation of PAR2...

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..These findings indicate the development of cross tolerance to prolonged environmental stress and endotoxin, implying involvement of a common mechanism...

..Thus, PAR-2 is expressed by the three distinct salivary glands in the rat, and sublingual PAR-2 appears to play a role in triggering mucin secretion, at least in part, via activation of tyrosine kinase...

..Our results indicate that in addition to a potential role in regulating cardiovascular and respiratory functions, PAR-2 may also play a general role in vivo for the direct regulation of glandular exocrine secretion...

..Our data could provide evidence for a novel role of PAR-4 as opposed to PAR-1, although the underlying mechanisms are still open to question...

..Furthermore, non-adrenergic, non-cholinergic nerve neurotransmitter candidates that may modulate K+ channels do not appear to contribute to the relaxation by PAR-1 activation...

..Our study thus provides novel evidence for the physiological and/or pathophysiological roles of PARs 1 and 2 in the digestive systems, most probably during inflammation...

..Thus, PGE(2) has a great impact on pain signals, and pharmacological intervention in upstream and downstream signals of PGE(2) may serve as novel therapeutic strategies for the treatment of intractable pain...

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..Thus, H(2)S appears to function as a novel nociceptive messenger through sensitization of T-type Ca(2+) channels in the peripheral tissues, particularly during inflammation...

..Our data demonstrate that repeated etidronate as well as alendronate exhibits antiallodynic activity in arthritic rats, which might be clinically relevant, and suggest involvement of K+ ATP channels in the underlying mechanisms...

..The factor Xa-PAR-2 pathway might thus contribute to the severe hypotension during sepsis, in which multiple coagulation factors including factor X would become activated and PAR-2 would be induced...

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..Our data thus provide ultimate evidence for role of PAR2 in colonic hypersensitivity, and suggest involvement of the bradykinin-B2 pathway...

..Recently, a pronociceptive role for H(2)S in the processing of somatic pain was identified. Here, the involvement of H(2)S in pancreatic pain is examined...

..These data provide novel evidence that activation of peripheral PAR-2 is pro-nociceptive, producing thermal hyperalgesia and also triggering pain sensation, by itself, independently of mast cell degranulation...

..2 T-type Ca(2+) channels that are upregulated in the early stage of colitis, leading to colonic mucosal cytoprotection in rats...

..Our study thus clarifies the multiple mechanisms for gastrointestinal motility modulation by PAR-1 and -2, and also provides ultimate evidence for involvement of PAR-2...

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..Together with the in vivo results, our study implies that H2S plays multiple complex roles in regulation of gastric circulation...

..Given recent evidence that hydrogen sulfide (H(2)S), a gasotransmitter, promotes somatic pain through redox modulation of T-type Ca(2+) channels, the roles of colonic luminal H(2)S in visceral nociceptive processing in mice were examined...

..2 and CSE at protein levels, differing from the previous evidence for the neuropathic pain model induced by spinal nerve cutting in which Ca(v)3.2 was dramatically upregulated in DRG...

..Collectively, a functional linkage of PAR1 and/or PAR2 to PGs is considered important in the gastrointestinal system...

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..Further, HPLC-ESI-MS revealed that all the tissues examined in mice and rats commonly contained highly acetylated sialic acids and 8-O-sulfated N-acetylneuraminic acid...

..5. Our study thus provides novel evidence that PAR-2 is localized in mucosal chief cells and facilitates gastric pepsin secretion in the rats, most probably by a direct mechanism...

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..Given evidence for contribution of PAR2 to pancreatic pain, the present study aimed at clarifying the involvement of TRPV1 in processing of pancreatic pain by the proteinase/PAR2 pathway in mice...

..We thus propose that Ca(v)3.2 and CSE could be targets for the development of therapeutic drugs for the treatment of neuropathic pain...

..t. L-NAME. Thus, ONO-1714 is considered a potent inhibitor of nNOS in addition to iNOS. The distinct relative antinociceptive activities of systemic and i.t. ONO-1714 are attributable to its possible poor blood-brain barrier permeability...

..pl. SLIGRL-NH2 were attenuated by capsazepine. Our data imply that trans-activation of capsaicin receptors by PAR-2 might be involved in the PAR-2-triggered thermal hyperalgesia, but not nociception...

..2 T-type Ca2+ channels expressed in the primary afferents and/or spinal nociceptive neurons, leading to sensitization of nociceptive processing and hyperalgesia...

..Most interestingly, our data demonstrate direct inhibition of eNOS by NaHS, probably responsible for its contractile activity, being evidence for a novel function of H(2)S...

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..2 isoform. Hence, endogenous Zn(2+) is considered to play a critical role in modulating visceral pain...

..Vasculatures in the wound proliferated in PAI-1 deficient mice. Our study shows that uPA affects BBB disruption. PA enhances angiogenesis after brain injury...

..Based on the these findings, PAR-1 and PAR-2 are attracting interest as target molecules for new drug development...

..Together, PAR2 triggers IL-8 release via two independent signaling pathways, MEK/ERK and PI3-kinase/Akt, suggesting a role of PAR2 as a pro-inflammatory receptor in the GI tract...

..PAR-2 would thus appear to be primarily protective in gastric mucosa, but may also have an aggressive property in certain conditions. Finally, functions of PARs other than PAR-2 in gastric mucosa are also discussed...

..The thrombin-PAR-1 system might thus act to attenuate nociception during inflammatory hyperalgesia...

..Thus, specific expression of spinal Fos following peripheral PAR-2 activation is detectable in mast cell-depleted rats, suggesting activation of spinal nociceptive neurons, which is partially mediated by activation of PKC...

..The future perspective of studies on PARs is also discussed, focusing on the possibility of clinical application of PAR-targeted drugs...

..The delayed enhancement of rhodanese activity in RBCs, a possible compensative event, might be available as a disease marker for IBD...

..In addition, our data also indicate involvement of COX-1, PKC and p38 MAPK in PAR1-triggered PGE(2) formation. PAR1, thus stimulates complex multiple signaling pathways responsible for PGE(2) formation in RGM1 cells...

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..Thus, NaHS evokes bronchodilation in mice, suggesting a possible role for H(2)S in the respiratory system...

..These results suggest that NaHS/H(2)S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of MAP kinase pathways, a therapeutic dose range being very narrow...

..PAR2 thus appears to trigger specific up-regulation of mPGES-1 that is dependent on prostanoids formed via the MEK/ERK/cPLA(2)/COX-1 pathway, being critical for PGE(2) formation...

..In contrast, the control peptide FTLLR-NH(2), given in the same manner, had no such effect. Thus, PAR-1, like PAR-2, might function to facilitate pepsinogen secretion, suggesting a novel role of the thrombin-PAR-1-pathway in the stomach...

..Together, our data reveal that Src kinase participates in the T-type Ca(2+) channel-dependent neuronal differentiation caused by NaHS/H(2)S in NG108-15 cells...

..In conclusion, ciglitazone and troglitazone, exert opposite effects on the PAR1-triggered PGE(2) production and COX-2 upregulation by targeting molecules other than PPARgamma...

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..Our data thus demonstrate inhibition of three NOS isoforms by NaHS/H(2)S, and suggest involvement of interaction of NaHS/H(2)S with BH(4) in inhibition of nNOS and eNOS, but not iNOS...

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..These dual actions of PAR-2 would result in gastric mucosal cytoprotection...

..These results suggest that activation of SII-medullary fibers suppress nociceptive information from the oro-facial regions...

..These data suggest that camostat mesilate prevents and/or depresses pancreatitis-induced pain and/or referred hyperalgesia/allodynia, in which proteinases including trypsin would play a critical role...

..7 These studies indicate that [(3)H]2-furoyl-LIGRL-NH(2) binds to human PAR2 at its ligand-binding site. The use of this radioligand will be valuable for characterising chemicals that interact to PAR2...

..Also, the PAR-2-gene-deficient mice and the potent and metabolically stable agonists are shown to be useful tools for evaluating the potency of PAR-2 as a therapeutic target...