Proteinase-activated receptors (PARs) were discovered more than 25 years ago and since then, their role in cancer has been under investigation. Research has primarily focused on the receptors located on the membrane of cancer cells and their impact on metabolism, intracellular signalling, and proliferation. Regarding the host response to cancer, studies have predominantly examined the relationship of thrombin receptors (PAR-1, PAR-3, and PAR-4) with blood clotting in distant metastatic spread. However, limited studies have examined the role of PARs, especially PAR-2, in the host anti-tumor immunity. This review article provides insights into the role of PAR-2 on cancer cells and immune competent cells involved in cancer development and progression. It also discussed the current knowledge of the importance of PAR-2 activation at various stages of cancer progression and its association with cancer-related pain.

• MeSH
• lidé MeSH
• nádory * metabolismus   MeSH
• receptor PAR-1 metabolismus   MeSH
• receptor PAR-2 * metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

It has been 30 years since the first member of the protease-activated receptor (PAR) family was discovered. This was followed by the discovery of three other receptors, including PAR2. PAR2 is a G protein-coupled receptor activated by trypsin site-specific proteolysis. The process starts with serine proteases acting between arginine and serine, creating an N-terminus that functions as a tethered ligand that binds, after a conformational change, to the second extracellular loop of the receptor, leading to activation of G-proteins. The physiological and pathological functions of this ubiquitous receptor are still elusive. This review focuses on PAR2 activation and its distribution under physiological and pathological conditions, with a particular focus on the pancreas, a significant producer of trypsin, which is the prototype activator of the receptor. The role in acute or chronic pancreatitis, pancreatic cancer, and diabetes mellitus will be highlighted.

• MeSH
• lidé MeSH
• nemoci slinivky břišní * diagnóza   MeSH
• pankreas metabolismus   MeSH
• receptor PAR-2 * metabolismus   MeSH
• receptory spřažené s G-proteiny MeSH
• trypsin metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The mechanisms of inflammatory pain need to be identified in order to find new superior treatments. Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) are highly co-expressed in dorsal root ganglion neurons and implicated in pain development. Here, we examined the role of spinal PAR2 in hyperalgesia and the modulation of synaptic transmission in carrageenan-induced peripheral inflammation, using intrathecal (i.t.) treatment in the behavioral experiments and recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs and eEPSCs) in spinal cord slices. Intrathecal PAR2-activating peptide (AP) administration aggravated the carrageenan-induced thermal hyperalgesia, and this was prevented by a TRPV1 antagonist (SB 366791) and staurosporine i.t. pretreatment. Additionally, the frequency of the mEPSC and sEPSC and the amplitude of the eEPSC recorded from the superficial dorsal horn neurons were enhanced after acute PAR2 AP application, while prevented with SB 366791 or staurosporine pretreatment. PAR2 antagonist application reduced the thermal hyperalgesia and decreased the frequency of mEPSC and sEPSC and the amplitude of eEPSC. Our findings highlight the contribution of spinal PAR2 activation to carrageenan-induced hyperalgesia and the importance of dorsal horn PAR2 and TRPV1 receptor interactions in the modulation of nociceptive synaptic transmission.

• MeSH
• anilidy farmakologie   MeSH
• buňky zadních rohů míšních účinky léků   metabolismus   fyziologie   MeSH
• cinnamáty farmakologie   MeSH
• excitační postsynaptické potenciály MeSH
• hyperalgezie etiologie   metabolismus   patofyziologie   MeSH
• karagenan farmakologie   toxicita   MeSH
• kationtové kanály TRPV antagonisté a inhibitory   metabolismus   MeSH
• krysa rodu rattus MeSH
• miniaturní postsynaptické potenciály MeSH
• nocicepce MeSH
• potkani Wistar MeSH
• receptor PAR-2 metabolismus   MeSH
• staurosporin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Proteinase-activated receptor 2 (PAR2) is suspected to modulate the pathogenesis of various neurodegenerative conditions. We previously described delayed onset of clinical symptoms and prolonged survival of PAR2-deficient mice after intracerebral inoculation with prions. Here we report the results from a refined blinded study that aimed to investigate the effects of PAR2 deletion on scrapie pathogenesis after peripheral infection. This study failed to confirm that PAR2 deficiency impacts on the length of the incubation period, with PAR2-/- and PAR2+/+ littermates developing scrapie at the same time. To clarify the discrepancy between the two observations, we repeated the intracerebral inoculation study while utilizing our refined protocol, which aimed to limit possible sources of experimental bias. The study again failed to confirm the significant effect of PAR2 expression on the course of prion infection. Our report emphasizes and discusses the importance of unbiased experimental design and the selection of proper genetic controls when using genetically altered animal models for prion pathogenesis studies.

• MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované MeSH
• myši MeSH
• receptor PAR-2 nedostatek   metabolismus   MeSH
• scrapie patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Spinal cord injury (SCI) is an extremely serious type of physical trauma observed in clinics. Especially, neuropathic pain resulting from SCI has a lasting and significant impact on most aspects of daily life. Thus, a better understanding of the molecular pathways responsible for the cause of neuropathic pain observed in SCI is important to develop effectively therapeutic agents and treatment strategies. Proteinase-activated receptors (PARs) are a family member of G-protein-coupled receptors and are activated by a proteolytic mechanism. One of its subtypes PAR2 has been reported to be engaged in mechanical and thermal hyperalgesia. Thus, in this study we specifically examined the underlying mechanisms responsible for SCI evoked-neuropathic pain in a rat model. Overall, we demonstrated that SCI increases PAR2 and its downstream pathways TRPV1 and TRPA1 expression in the superficial dorsal horn of the spinal cord. Also, we showed that blocking spinal PAR2 by intrathecal injection of FSLLRY-NH2 significantly inhibits neuropathic pain responses induced by mechanical and thermal stimulation whereas FSLLRY-NH2 decreases the protein expression of TRPV1 and TRPA1 as well as the levels of substance P and calcitonin gene-related peptide. Results of this study have important implications, i.e. targeting one or more of these signaling molecules involved in activation of PAR2 and TRPV1/TRPA1 evoked by SCI may present new opportunities for treatment and management of neuropathic pain often observed in patients with SCI.

• MeSH
• acetanilidy aplikace a dávkování   MeSH
• anilidy aplikace a dávkování   MeSH
• cinnamáty aplikace a dávkování   MeSH
• krysa rodu rattus MeSH
• neuralgie farmakoterapie   metabolismus   MeSH
• oligopeptidy aplikace a dávkování   MeSH
• poranění míchy farmakoterapie   metabolismus   MeSH
• potkani Wistar MeSH
• puriny aplikace a dávkování   MeSH
• receptor PAR-2 antagonisté a inhibitory   metabolismus   MeSH
• spinální injekce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) receptors in the peripheral nerve endings are implicated in the development of increased sensitivity to mechanical and thermal stimuli, especially during inflammatory states. Both PAR2 and TRPV1 receptors are co-expressed in nociceptive dorsal root ganglion (DRG) neurons on their peripheral endings and also on presynaptic endings in the spinal cord dorsal horn. However, the modulation of nociceptive synaptic transmission in the superficial dorsal horn after activation of PAR2 and their functional coupling with TRPV1 is not clear. To investigate the role of spinal PAR2 activation on nociceptive modulation, intrathecal drug application was used in behavioural experiments and patch-clamp recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs, eEPSCs) were performed on superficial dorsal horn neurons in acute rat spinal cord slices. Intrathecal application of PAR2 activating peptide SLIGKV-NH2 induced thermal hyperalgesia, which was prevented by pretreatment with TRPV1 antagonist SB 366791 and was reduced by protein kinases inhibitor staurosporine. Patch-clamp experiments revealed robust decrease of mEPSC frequency (62.8 ± 4.9%), increase of sEPSC frequency (127.0 ± 5.9%) and eEPSC amplitude (126.9 ± 12.0%) in dorsal horn neurons after acute SLIGKV-NH2 application. All these EPSC changes, induced by PAR2 activation, were prevented by SB 366791 and staurosporine pretreatment. Our results demonstrate an important role of spinal PAR2 receptors in modulation of nociceptive transmission in the spinal cord dorsal horn at least partially mediated by activation of presynaptic TRPV1 receptors. The functional coupling between the PAR2 and TRPV1 receptors on the central branches of DRG neurons may be important especially during different pathological states when it may enhance pain perception.

• MeSH
• alergie metabolismus   patologie   MeSH
• anilidy farmakologie   MeSH
• buňky zadních rohů míšních účinky léků   fyziologie   MeSH
• chování zvířat účinky léků   MeSH
• cinnamáty farmakologie   MeSH
• excitační postsynaptické potenciály účinky léků   MeSH
• hyperalgezie etiologie   prevence a kontrola   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• kationtové kanály TRPV antagonisté a inhibitory   metabolismus   MeSH
• krysa rodu rattus MeSH
• metoda terčíkového zámku MeSH
• mícha metabolismus   MeSH
• nervový přenos fyziologie   MeSH
• oligopeptidy farmakologie   MeSH
• potkani Wistar MeSH
• receptor PAR-2 agonisté   metabolismus   MeSH
• staurosporin farmakologie   MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Protease-activated receptors (PARs) belong to the G-protein-coupled receptor family, that are expressed in many body tissues especially in different epithelial cells, mast cells and also in neurons and astrocytes. PARs play different physiological roles according to the location of their expression. Increased evidence supports the importance of PARs activation during nociceptive signaling and in the development of chronic pain states. This short review focuses on the role of PAR2 receptors in nociceptive transmission with the emphasis on the modulation at the spinal cord level. PAR2 are cleaved and subsequently activated by endogenous proteases such as tryptase and trypsin. In vivo, peripheral and intrathecal administration of PAR2 agonists induces thermal and mechanical hypersensitivity that is thought to be mediated by PAR2-induced release of pronociceptive neuropeptides and modulation of different receptors. PAR2 activation leads also to sensitization of transient receptor potential channels (TRP) that are crucial for nociceptive signaling and modulation. PAR2 receptors may play an important modulatory role in the development and maintenance of different pathological pain states and could represent a potential target for new analgesic treatments.

• MeSH
• kationtové kanály TRP metabolismus   MeSH
• lidé MeSH
• mícha metabolismus   MeSH
• nádorová bolest metabolismus   MeSH
• neuralgie metabolismus   MeSH
• nocicepce * MeSH
• nociceptivní bolest metabolismus   MeSH
• proteinkinasy metabolismus   MeSH
• receptor PAR-2 metabolismus   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• MeSH
• lidé MeSH
• lymfangiogeneze fyziologie   MeSH
• lymfatické metastázy patologie   MeSH
• nádorové mikroprostředí fyziologie   MeSH
• nádory slinivky břišní patologie   MeSH
• receptor PAR-2 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• dopisy MeSH
• komentáře MeSH
• práce podpořená grantem MeSH

BACKGROUND: Proteinase-activated receptor 2 (PAR-2) has been shown to promote both neurotoxic and neuroprotective effects. Similarly, other routinely used nonspecific markers of neuronal damage can be found in cerebrospinal fluid (CSF) and can be used as biomarkers for different neurodegenerative disorders. METHODS: Using enzyme-linked immunosorbent assays and western blotting we assessed PAR-2, total-tau, phospho-tau, beta-amyloid levels, and protein 14-3-3 in the CSF of former patients who had undergone a neuropathological autopsy after death and who had been definitively diagnosed with a prion or other neurodegenerative disease. RESULTS: We did not find any significant correlation between levels of PAR-2 and other biomarkers, nor did we find any differences in PAR-2 levels between prion diseases and other neurodegenerative conditions. However, we confirmed that very high total-tau levels were significantly associated with definitive prion diagnoses and exhibited greater sensitivity and specificity than protein 14-3-3, which is routinely used as a marker. CONCLUSIONS: Our study showed that PAR-2, in CSF, was not specifically altered in prion diseases compared to other neurodegenerative conditions. Our results also confirmed that very high total-tau protein CSF levels were significantly associated with a definitive Creutzfeldt-Jakob disease (CJD) diagnosis and should be routinely tested as a diagnostic marker. Observed individual variability in CSF biomarkers provide invaluable feedback from neuropathological examinations even in "clinically certain" cases.

• MeSH
• Alzheimerova nemoc diagnóza   MeSH
• amyloidní beta-protein MeSH
• biologické markery MeSH
• Creutzfeldtova-Jakobova nemoc diagnóza   MeSH
• diferenciální diagnóza MeSH
• dospělí MeSH
• ELISA MeSH
• fosfoproteiny MeSH
• frontotemporální lobární degenerace diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• neurodegenerativní nemoci diagnóza   MeSH
• pitva MeSH
• progresivní supranukleární obrna diagnóza   MeSH
• proteiny 14-3-3 MeSH
• proteiny tau MeSH
• receptor PAR-2 metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• vaskulární demence diagnóza   MeSH
• western blotting MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIM: We investigated differences of metastatic spread of normal proteinase-activated receptor-2 (Par2+/+) melanoma B16 in Par2-/- (knock-out) animals compared to C57Bl6 mice. MATERIALS AND METHODS: Nine knock-out mice B6.Cg-F2rl1tm1Mslb/J (Par2-/-) and nine C57Bl6/J controls were subcutaneously inoculated with B16 melanoma tissue cells. Twelve days after inoculation, all primary tumors were removed. Survival and metastatic spread was followed for up to 100 days after primary tumor extirpation. RESULTS: Excised primary tumors were on average larger in Par2-/- mice (360 mm3 vs. 221 mm3 in C57Bl6/J). Distant spontaneous metastases developed in only 3 of 9 of Par2-/- mice in comparison to 6 of 9 controls. The average survival time was 84 days in Par2-/- animals compared to 63 days in C57Bl6/J mice. CONCLUSION: Host Par2 melanoma model contributes to the limitation of local cancer progression in one area, while on the other hand is important for enhancing distant metastatic spread.

• MeSH
• imunohistochemie MeSH
• melanom experimentální genetika   metabolismus   patologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• receptor PAR-2 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH