RESUMO
BACKGROUND: Activated protein C (APC) has anticoagulant and cytoprotective cell-signaling activities, which often require protease-activated receptor (PAR) 1 and PAR3 and PAR cleavages at noncanonical sites (R46-N47 and R41-G42, respectively). Some PAR1-derived (P1) peptides and PAR3-derived (P3) peptides, eg, P1-47-66 and P3-42-65, mimic APC's cell signaling. In anti-inflammatory assays, these 2 peptides at low concentrations synergistically attenuate cellular inflammation. OBJECTIVES: To determine whether a P1 peptide covalently linked to a P3 peptide mimics APC's anti-inflammatory and endothelial barrier stabilization activities. METHODS: Anti-inflammatory assays employed stimulated THP-1 cells and caspase-1 measurements. Cultured human EA.hy926 or murine aortic endothelial cells (ECs) exposed to thrombin were monitored for transendothelial electrical resistance. Bivalent covalently linked P1:P3 peptides were studied for APC-like activities. RESULTS: In anti-inflammatory assays, P1-47-55 was as active as P1-47-66 and some P3 peptides (eg, P3-44-54 and P3-51-65) were as active as P3-42-65. The bivalent P1:P3 peptide comprising P1-47-55-(Gly[10 residues])-P3-51-65 (designated "G10 peptide") was more potently anti-inflammatory than the P1 or P3 peptide alone. In transendothelial electrical resistance studies of thrombin-challenged ECs, P1-47-55 and the G10 peptide mimicked APC's protective actions. In dose-response studies, the G10 peptide was more potent than the P1-47-55 peptide. In murine EC studies, the murine PAR-sequence-derived G10 peptide mimicked murine APC's activity. Anti-PAR1 and anti-PAR3 antibodies, but not anti-endothelial protein C receptor antibodies, abated G10's cytoprotection, showing that G10's actions involve PAR1:PAR3. G10 significantly increased survival in murine endotoxemia. CONCLUSION: The PAR-sequence-derived G10 peptide is a bivalent agonist that mimics APC's cytoprotective, anti-inflammatory, and endothelial barrier-stabilizing actions and APC's protection against endotoxemic mortality.
Assuntos
Células Endoteliais , Proteína C , Receptor PAR-1 , Proteína C/metabolismo , Proteína C/química , Humanos , Animais , Receptor PAR-1/agonistas , Receptor PAR-1/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Camundongos Endogâmicos C57BL , Células THP-1 , Trombina/metabolismo , Receptor de Proteína C Endotelial/metabolismo , Receptores de Trombina/agonistas , Receptores de Trombina/metabolismo , Transdução de Sinais , Receptores Ativados por Proteinase/agonistas , Receptores Ativados por Proteinase/metabolismo , Peptídeos/farmacologia , Peptídeos/química , Endotoxemia/tratamento farmacológico , Endotoxemia/metabolismo , Fragmentos de Peptídeos/farmacologia , Masculino , Modelos Animais de DoençasRESUMO
Pruritus or itch is a defining symptom of atopic dermatitis (AD). The origins of itch are complex, and it is considered both a defense mechanism and a cause of disease that leads to inflammation and psychological stress. Considerable progress has been made in understanding the processes that trigger itch, particularly the pruritoceptive origins that are generated in the skin. This perspective review discusses the implications of a recent observation that the V8 protease expressed by Staphylococcus aureus can directly trigger sensory neurons in the skin through activation of protease-activated receptor 1. This may be a key to understanding why itch is so common in AD because S. aureus commonly overgrows in this disease owing to deficient antimicrobial defense from both the epidermis and the cutaneous microbiome. Increased understanding of the role of microbes in AD provides increased opportunities for safely improving the treatment of this disorder.
Assuntos
Dermatite Atópica , Prurido , Staphylococcus aureus , Dermatite Atópica/microbiologia , Dermatite Atópica/complicações , Dermatite Atópica/imunologia , Humanos , Prurido/microbiologia , Prurido/imunologia , Animais , Pele/microbiologia , Pele/patologia , Células Receptoras Sensoriais/fisiologia , Células Receptoras Sensoriais/metabolismo , Receptores Ativados por Proteinase/metabolismo , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/microbiologiaRESUMO
BACKGROUND: Protease-activated receptor 4 (PAR4) mediates thrombin signaling on platelets and other cells. Our recent structural studies demonstrated that a single nucleotide polymorphism in extracellular loop 3 and PAR4-P310L (rs2227376) leads to a hyporeactive receptor. OBJECTIVES: The goal of this study was to determine how the hyporeactive PAR4 variant in extracellular loop 3 impacts platelet function in vivo using a novel knock-in mouse model (PAR4-322L). METHODS: A point mutation was introduced into the PAR4 gene F2rl3 via CRISPR/Cas9 to create PAR4-P322L, the mouse homolog to human PAR4-P310L. Platelet response to PAR4 activation peptide (AYPGKF), thrombin, ADP, and convulxin was monitored by αIIbß3 integrin activation and P-selectin translocation using flow cytometry or platelet aggregation. In vivo responses were determined by the tail bleeding assay and the ferric chloride-induced carotid artery injury model. RESULTS: PAR4-P/L and PAR4-L/L platelets had a reduced response to AYPGKF and thrombin measured by P-selectin translocation or αIIbß3 activation. The response to ADP and convulxin was unchanged among genotypes. In addition, both PAR4-P/L and PAR4-L/L platelets showed a reduced response to thrombin in aggregation studies. There was an increase in the tail bleeding time for PAR4-L/L mice. The PAR4-P/L and PAR4-L/L mice both showed an extended time to arterial thrombosis. CONCLUSION: PAR4-322L significantly reduced platelet responsiveness to AYPGKF and thrombin, which is in agreement with our previous structural and cell signaling studies. In addition, PAR4-322L had prolonged arterial thrombosis time. Our mouse model provides a foundation to further evaluate the role of PAR4 in other pathophysiological contexts.
Assuntos
Plaquetas , Camundongos Endogâmicos C57BL , Agregação Plaquetária , Complexo Glicoproteico GPIIb-IIIa de Plaquetas , Receptores de Trombina , Trombina , Animais , Plaquetas/metabolismo , Receptores de Trombina/genética , Receptores de Trombina/metabolismo , Trombina/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Modelos Animais de Doenças , Venenos de Crotalídeos/farmacologia , Venenos de Crotalídeos/toxicidade , Difosfato de Adenosina/metabolismo , Difosfato de Adenosina/farmacologia , Selectina-P/metabolismo , Selectina-P/genética , Mutação Puntual , Técnicas de Introdução de Genes , Transdução de Sinais , Trombose/genética , Trombose/sangue , Masculino , Cloretos , Camundongos , Ativação Plaquetária , Sistemas CRISPR-Cas , Humanos , Fenótipo , Compostos Férricos , Oligopeptídeos , Lectinas Tipo C , Receptores Ativados por ProteinaseRESUMO
Platelets are well-known players in several cardiovascular diseases such as atherosclerosis and venous thrombosis. There is increasing evidence demonstrating that reactive oxygen species (ROS) are generated within activated platelets. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a major source of ROS generation in platelets. Ligand binding to platelet receptor glycoprotein (GP) VI stimulates intracellular ROS generation consisting of a spleen tyrosine kinase-independent production involving NOX activation and a following spleen tyrosine kinase-dependent generation. In addition to GPVI, stimulation of platelet thrombin receptors (protease-activated receptors [PARs]) can also trigger NOX-derived ROS production. Our recent study found that mitochondria-derived ROS production can be induced by engagement of thrombin receptors but not by GPVI, indicating that mitochondria are another source of PAR-dependent ROS generation apart from NOX. However, mitochondria are not involved in GPVI-dependent ROS generation. Once generated, the intracellular ROS are also involved in modulating platelet function and thrombus formation; therefore, the site-specific targeting of ROS production or clearance of excess ROS within platelets is a potential intervention and treatment option for thrombotic events. In this review, we will summarize the signaling pathways involving regulation of platelet ROS production and their role in platelet function and thrombosis, with a focus on GPVI- and PAR-dependent platelet responses.
Assuntos
Plaquetas , Oxirredução , Espécies Reativas de Oxigênio , Transdução de Sinais , Trombose , Humanos , Plaquetas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Trombose/sangue , Glicoproteínas da Membrana de Plaquetas/metabolismo , Animais , Ativação Plaquetária , Mitocôndrias/metabolismo , NADPH Oxidases/metabolismo , Receptores de Trombina/metabolismo , Receptores Ativados por Proteinase/metabolismoRESUMO
Enhanced mucosal sealing around titanium implants can reduce complications such as peri-implantitis. The present study aims to investigate the mucosal healing at the early stage around the protease activated receptor 4-agonist peptide (PAR4-AP)- or perpendicularly protruded type I collagen (pCol)-treated titanium implants. A total of 72 implants were placed in 36 rats in the study. Following extractions, two tissue-level implants among the following three different surfaces, PAR4-AP-coated (PAR4 group, n = 24), pCol-treated (pCol group, n = 24) and non-treated (control group, n = 24) ones, were placed in the maxillae of each rat based on a split-mouth design. The specimens retrieved at 8 h (n = 8 per group), 3 days (n = 8 per group), and 2 weeks (n = 8 per group), were immunostained and tissue-cleared, and the signals of laminin-5 and collagen fibers were observed under multiphoton microscopy. Statistical analyses were performed using linear mixed model with post hoc tests to compare differences between the groups. While there was no intergroup difference at 8 h, the laminin-5 at 3 days was more abundant near the PAR4-group-surface, and its area was significantly larger in the PAR4 group (0.0204 ± 0.0194 mm2 ) than the control (0.0019 ± 0.0025 mm2 , p = .001) and pCol (0.0023 ± 0.0022 mm2 , p < .001) groups. The pCol group showed a significantly larger area of collagen fibers (0.0230 ± 0.0148 mm2 ) compared to the control (0.0035 ± 0.0051 mm2 , p = .002) and PAR4 (0.0031 ± 0.0057 mm2 , p < .001) groups at 3 days. At 3 days and 2 weeks, the collagen fiber orientation of the pCol group showed a more perpendicular manner compared to the control and PAR4 groups. The signal of basal lamina and collagen fibers were stronger around the PAR4-AP- and pCol-treated titanium surfaces, respectively during the early healing stage. This could have implications for improved mucosal sealing around dental implants, potentially reducing complications such as peri-implantitis.
Assuntos
Implantes Dentários , Peri-Implantite , Ratos , Animais , Colágeno Tipo I/farmacologia , Titânio/farmacologia , Propriedades de Superfície , Peptídeos , Receptores Ativados por ProteinaseRESUMO
The activation and mobilization of immune cells play a crucial role in immunotherapy. Existing therapeutic interventions, such as cytokines administration, aim to enhance immune cell activity. However, these approaches usually result in modest effectiveness and toxic side effects, thereby restricting their clinical application. Protease-activated receptors (PARs), a subfamily of G protein-coupled receptors, actively participate in the immune system by directly activating immune cells. The activation of PARs by proteases or synthetic ligands can modulate immune cell behavior, signaling, and responses to treat immune-related diseases, suggesting the significance of PARs agonism in immunotherapy. However, the agonism of PARs in therapeutical applications remains rarely discussed, since it has been traditionally considered that PARs activation facilitates disease progressions. This review aims to comprehensively summarize the activation, rather than inhibition, of PARs in immune-related physiological responses and diseases. Additionally, we will discuss the emerging immunotherapeutic potential of PARs agonism, providing a new strategic direction for PARs-mediated immunotherapy.
Assuntos
Imunoterapia , Receptores Ativados por Proteinase , Peptídeo Hidrolases/metabolismo , Receptores Acoplados a Proteínas G , Receptores Ativados por Proteinase/agonistas , Receptores Ativados por Proteinase/metabolismo , Transdução de Sinais , Neoplasias/imunologia , Neoplasias/terapia , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Humanos , AnimaisRESUMO
Background: Factor Xa (FXa) not only plays an active role in the coagulation cascade but also exerts non-hemostatic signaling through the protease-activated receptors (PARs). This study aimed to investigate whether the FXa inhibitor, Rivaroxaban (RIV), attenuates adverse cardiac remodeling in rats with myocardial infarction (MI) and to identify the underlying molecular mechanisms it uses. Methods: An MI model was induced in eight-week-old, male Wistar rats, by permanent ligation of the left anterior descending coronary artery. MI rats were randomly assigned to receive RIV or protease-activated receptors 2-antagonist (PAR-2 antagonist, FSLLRY) treatment for four weeks. Histological staining, echocardiography and hemodynamics were used to assess the cardioprotective effects of RIV. Meanwhile, pharmacological approaches of agonist and inhibitor were used to observe the potential pathways in which RIV exerts antifibrotic effects in neonatal rat cardiac fibroblasts (CFs). In addition, real-time PCR and western blot analysis were performed to examine the associated signaling pathways. Results: RIV presented favorable protection of left ventricular (LV) cardiac function in MI rats by significantly reducing myocardial infarct size, ameliorating myocardial pathological damage and improving left ventricular (LV) remodeling. Similar improvements in the PAR-2 antagonist FSLLRY and RIV groups suggested that RIV protects against cardiac dysfunction in MI rats by ameliorating PAR-2 activation. Furthermore, an in vitro model of fibrosis was then generated by applying angiotensin II (Ang II) to neonatal rat cardiac fibroblasts (CFs). Consistent with the findings of the animal experiments, RIV and FSLLRY inhibited the expression of fibrosis markers and suppressed the intracellular upregulation of transforming growth factor ß1 (TGFß1), as well as its downstream Smad2/3 phosphorylation effectors in Ang II-induced fibrosis, and PAR-2 agonist peptide (PAR-2 AP) reversed the inhibition effect of RIV. Conclusions: Our findings demonstrate that RIV attenuates MI-induced cardiac remodeling and improves heart function, partly by inhibiting the activation of the PAR-2 and TGF-ß1 signaling pathways.
Assuntos
Infarto do Miocárdio , Rivaroxabana , Ratos , Animais , Masculino , Rivaroxabana/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Fator Xa/metabolismo , Remodelação Ventricular , Ratos Wistar , Transdução de Sinais , Infarto do Miocárdio/tratamento farmacológico , Fibrose , Receptores Ativados por ProteinaseRESUMO
Blood coagulation is initiated in response to blood vessel injury or proinflammatory stimuli, which activate coagulation factors to coordinate complex biochemical and cellular responses necessary for clot formation. In addition to these critical physiologic functions, plasma protein factors activated during coagulation mediate a spectrum of signaling responses via receptor-binding interactions on different cell types. In this review, we describe examples and mechanisms of coagulation factor signaling. We detail the molecular basis for cell signaling mediated by coagulation factor proteases via the protease-activated receptor family, considering new insights into the role of protease-specific cleavage sites, cofactor and coreceptor interactions, and distinct signaling intermediate interactions in shaping protease-activated receptor signaling diversity. Moreover, we discuss examples of how injury-dependent conformational activation of other coagulation proteins, such as fibrin(ogen) and von Willebrand factor, decrypts their signaling potential, unlocking their capacity to contribute to aberrant proinflammatory signaling. Finally, we consider the role of coagulation factor signaling in disease development and the status of pharmacologic approaches to either attenuate or enhance coagulation factor signaling for therapeutic benefit, emphasizing new approaches to inhibit deleterious coagulation factor signaling without impacting hemostatic activity.
Assuntos
Fármacos Hematológicos , Trombina , Humanos , Trombina/metabolismo , Fatores de Coagulação Sanguínea , Coagulação Sanguínea , Fator de von Willebrand/metabolismo , Receptores Ativados por ProteinaseRESUMO
Protease-activated receptors (PARs) are a class of integral membrane proteins that are cleaved by a variety of proteases, most notably thrombin, to reveal a tethered ligand and promote activation. PARs are critical mediators of platelet function in hemostasis and thrombosis, and therefore are attractive targets for anti-platelet therapies. Animal models studying platelet PAR physiology have relied heavily on genetically modified mouse strains, which have provided ample insight but have some inherent limitations. The current review aims to summarize the notable PAR expression and functional differences between the mouse and human, in addition to highlighting some recently developed tools to further study human physiology in mouse models.
Assuntos
Receptores Ativados por Proteinase , Receptores de Trombina , Humanos , Camundongos , Animais , Receptores Ativados por Proteinase/metabolismo , Receptores de Trombina/metabolismo , Especificidade da Espécie , Plaquetas/metabolismo , Trombina/metabolismoRESUMO
Colorectal cancer (CRC) is one of the common malignancies with a global trend of increasing incidence and mortality. There is an urgent need to identify new predictive markers and therapeutic targets for the treatment of CRC. Protease-activated receptors (PARs) are a class of G-protein-coupled receptors, with currently identified subtypes including PAR1, PAR2, PAR3 and PAR4. Increasingly, studies suggest that PARs play an important role in the growth and metastasis of CRC. By targeting multiple signaling pathways may contribute to the pathogenesis of CRC. In this review, we first describe recent studies on the role of PARs in CRC inflammation-cancer transformation, focusing on the important role of PARs in signaling pathways associated with inflammation-cancer transformation, and summarize the progress of research on PARs-targeted drugs (AU)
Assuntos
Humanos , Neoplasias Colorretais/metabolismo , Receptores Ativados por Proteinase/metabolismo , Receptores de Trombina/metabolismo , Transdução de Sinais , InflamaçãoRESUMO
BACKGROUND: Thromboelastography (TEG) is used for real-time determination of hemostatic status in patients with acute risk of bleeding. Thrombin is thought to drive clotting in TEG through generation of polymerized fibrin and activation of platelets through protease-activated receptors (PARs). However, the specific role of platelet agonist receptors and signaling in TEG has not been reported. OBJECTIVES: Here, we investigated the specific receptors and signaling pathways required for platelet function in TEG using genetic and pharmacologic inhibition of platelet proteins in mouse and human blood samples. METHODS: Clotting parameters (R time, α-angle [α], and maximum amplitude [MA]), were determined in recalcified, kaolin-triggered citrated blood samples using a TEG 5000 analyzer. RESULTS: We confirmed the requirement of platelets, platelet contraction, and αIIbß3 integrin function for normal α and MA. Loss of the integrin adaptor Talin1 in megakaryocytes/platelets (Talin1mKO) also reduced α and MA, but only minimal defects were observed in samples from mice lacking Rap1 GTPase signaling. PAR4mKO samples showed impaired α but normal MA. However, impaired TEG traces similar to those in platelet-depleted samples were observed with samples from PAR4mKO mice depleted of glycoprotein VI on platelets or with addition of a Syk inhibitor. We reproduced these results in human blood with combined inhibition of PAR1, PAR4, and Syk. CONCLUSION: Our results demonstrate that standard TEG is not sensitive to platelet signaling pathways critical for integrin inside-out activation and platelet hemostatic function. Furthermore, we provide the first evidence that PARs and glycoprotein VI play redundant roles in platelet-mediated clot contraction in TEG.
Assuntos
Plaquetas , Hemostáticos , Animais , Humanos , Camundongos , Plaquetas/metabolismo , Glicoproteínas/metabolismo , Integrinas/metabolismo , Receptores Ativados por Proteinase/metabolismo , Receptores de Trombina/genética , Receptores de Trombina/metabolismo , Tromboelastografia/métodosAssuntos
Mastocitose Cutânea , Mastocitose Sistêmica , Mastocitose , Transtornos da Pigmentação , Humanos , Mastócitos/patologia , Mastocitose/patologia , Mastocitose Cutânea/patologia , Transtornos da Pigmentação/patologia , Pigmentação , Receptores Ativados por Proteinase , Peptídeo Hidrolases , Mastocitose Sistêmica/patologiaRESUMO
Colorectal cancer (CRC) is one of the common malignancies with a global trend of increasing incidence and mortality. There is an urgent need to identify new predictive markers and therapeutic targets for the treatment of CRC. Protease-activated receptors (PARs) are a class of G-protein-coupled receptors, with currently identified subtypes including PAR1, PAR2, PAR3 and PAR4. Increasingly, studies suggest that PARs play an important role in the growth and metastasis of CRC. By targeting multiple signaling pathways may contribute to the pathogenesis of CRC. In this review, we first describe recent studies on the role of PARs in CRC inflammation-cancer transformation, focusing on the important role of PARs in signaling pathways associated with inflammation-cancer transformation, and summarize the progress of research on PARs-targeted drugs.
Assuntos
Neoplasias , Receptores Ativados por Proteinase , Humanos , Receptores Ativados por Proteinase/metabolismo , Receptores de Trombina/metabolismo , Transdução de Sinais , InflamaçãoRESUMO
Proteases are signaling molecules that specifically control cellular functions by cleaving protease-activated receptors (PARs). The four known PARs are members of the large family of G protein-coupled receptors. These transmembrane receptors control most physiological and pathological processes and are the target of a large proportion of therapeutic drugs. Signaling proteases include enzymes from the circulation; from immune, inflammatory epithelial, and cancer cells; as well as from commensal and pathogenic bacteria. Advances in our understanding of the structure and function of PARs provide insights into how diverse proteases activate these receptors to regulate physiological and pathological processes in most tissues and organ systems. The realization that proteases and PARs are key mediators of disease, coupled with advances in understanding the atomic level structure of PARs and their mechanisms of signaling in subcellular microdomains, has spurred the development of antagonists, some of which have advanced to the clinic. Herein we review the discovery, structure, and function of this receptor system, highlight the contribution of PARs to homeostatic control, and discuss the potential of PAR antagonists for the treatment of major diseases.
Assuntos
Receptores Ativados por Proteinase , Transdução de Sinais , Humanos , Transdução de Sinais/fisiologia , Receptores Acoplados a Proteínas G , Peptídeo Hidrolases/metabolismo , HomeostaseRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Libidibia ferrea (Mart. ex. Tul.) L.P. Queiroz is a Brazilian native tree locally known as jucá and pau-ferro, and it has been used in folk medicine for relieving, asthma, bronchitis, sore throat, rheumatism, enterocolitis and fever. The anti-inflammatory properties of L. ferrea were confirmed for its stem, fruit, leaves, bark and seeds extracts, however little is known about the natural compounds that may be associated with that response. AIM OF THIS STUDY: In a normal physiological condition, many enzymes play an important role in catalyzing biological functions. Among them, proteases are of great interest. Although they take part of many biological systems, as the inflammatory process, when deregulated, proteases may cause system malfunctions, such as under- or overproduction of cytokines, or immune cells activation. Thus, protease inhibitors prevent these immune responses by regulating proteases. The objective of this study was to evaluate the anti-inflammatory and anti-nociceptive response of a protease inhibitor purified from L. ferrea seeds (LfTI). MATERIALS AND METHODS: In vitro (5, 50 and 250 µg/mL of LfTI) and in vivo (0.6, 3 e 15 mg/kg of LfTI) assays were performed. Male Swiss mice weighing 18-25 g were used for cell harvesting and for the in vivo assays. The anti-inflammatory activity was analyzed in vitro by macrophage cytotoxicity, hydrogen peroxide (H2O2) production, and cell adhesion assays; and in vivo by leukocyte recruitment, nitric oxide (NO) production, vascular permeability, paw edema and mast cell degranulation assays. The anti-nociceptive activity was evaluated through abdominal writhing test induced by acetic acid and formalin sensitization. RESULTS: Our results showed that, in vitro, LfTI is not cytotoxic. Also, LfTI (50 µg/mL) inhibited macrophage H2O2 production (48.2%), and adhesion (48.4%). LfTI (0.6, 3 e 15 mg/kg) decreased polymorphonuclear cell recruitment dose-dependently, and it inhibited NO production (53%), vascular permeability (40.7%) and paw edema at 3 mg/kg at different time, but it did not inhibit mast cell degranulation. Besides, LfTI did not inhibit either the number of writhing or the licking time in the formalin test in the second phase (inflammatory). However, LfTI (3 mg/kg) inhibited licking time at the first phase (neurogenic) in the formalin sensitization (46.1%). CONCLUSIONS: Our results show that LfTI has anti-inflammatory and antinociceptive (neurogenic pain) effects, and these effects might be associated with the inhibition of inflammatory proteases and/or protease-activated receptors activation hindering.
Assuntos
Anti-Infecciosos , Caesalpinia , Analgésicos/efeitos adversos , Animais , Anti-Infecciosos/uso terapêutico , Anti-Inflamatórios/efeitos adversos , Citocinas , Edema/tratamento farmacológico , Formaldeído , Peróxido de Hidrogênio , Camundongos , Óxido Nítrico , Peptídeo Hidrolases , Extratos Vegetais/efeitos adversos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Receptores Ativados por Proteinase/uso terapêutico , SementesRESUMO
Acute Coronary Syndrome (ACS) is a term that describes pathologies related to myocardial ischemia, and is comprised of unstable angina, non-ST elevation myocardial infarction, and ST elevation myocardial infarction. Urgent management of ACS is typically necessary to prevent future morbidity and mortality. Current medical recommendations of ACS management involve use of dual antiplatelet therapy, typically with aspirin and clopidogrel. However, newer therapies are being designed and researched to improve outcomes for patients with ACS. Vorapaxar is a novel antiplatelet therapy that inhibits thrombin-mediated platelet aggregation to prevent recurrence of ischemic events. It has been Food and Drug Administration approved for reduction of thrombotic cardiovascular events in patients with a history of MI or peripheral arterial disease with concomitant use of clopidogrel and/or aspirin, based upon the findings of the TRA 2°P-TIMI 50 trial. However, Vorapaxar was also found to have a significantly increased risk of bleeding, which must be considered when administering this drug. Based upon further subgroup analysis of both the TRA 2°P-TIMI 50 trial and TRACER trial, Vorapaxar was found to be potentially beneficial in patients with peripheral artery disease, coronary artery bypass grafting, and ischemic stroke. There are current trials in progress that are further evaluating the use of Vorapaxar in those conditions, and future research and trials are necessary to fully determine the utility of this drug.
Assuntos
Síndrome Coronariana Aguda , Infarto do Miocárdio , Doença Arterial Periférica , Acidente Vascular Cerebral , Humanos , Clopidogrel/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Receptores Ativados por Proteinase , Aspirina , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/tratamento farmacológico , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/induzido quimicamente , Infarto do Miocárdio/prevenção & controle , Resultado do TratamentoRESUMO
Introduction-Le diabète est un véritable problème de santé publique du fait de ses nombreuses complications potentielles, notamment cardiovasculaires. Notre objectif était de décrire le profil clinico-biologique chez une population de diabé tique type 2 et d'étudier la relation entre l'équilibre glycémique et les anomalies lipidiques avec les complications micro et macroangiopathiques. Matériels et méthodes -Nous avons mené une étude rétrospective portant sur 341 pa tients diabétiques type 2.Les données ont été analysées par le logiciel IBM® SPSS statis tics 20.0. Seules, les associations significatives (p ≤ 5%) étaient retenues. Résultats - quatre-vingt deux pourcent et demi des patients ont un taux d'HbA1c ≥7 %. Plus de 60 % ont une dyslipidémie. Cinquante deux pourcent des patients ont un taux du LDLc ≤ 1 g/l, et 64,4 % ont un taux du Non-HDLc >1g/l. Environ 66 % des patients ont une hypertension artérielle. quarante pourcent des patients ont présenté une macroangio pathie et 66,8 % une microangiopathie (p=0,0001). L'analyse par régression logistique, a montré que l'HbA1c est le paramètre biologique le plus associé aux complications macroangiopathiques (p=0,008), alors que pour les complications micro-angiopathiques, l'HTA était le seul facteur associé (p = 0,03). Pour la cardiopathie ischémique, la dyslipi démie et l'HTA étaient les facteurs les plus associés. Conclusion -Notre étude a montré une fréquence élevée des complications micro et macroangiopathiques et des anomalies lipidiques, ainsi qu'un très mauvais équilibre glycémique. L'HbA1c, la dyslipidémie et l'HTA sont les facteurs les plus associés au risque cardiovasculaire.
Background-Diabetes is a real health public problem because of its many potential complications, particularly the cardiovascular ones.The aim of this work was to describe the clinical and biological profile in type 2 diabetic population, then to study the relationship between glycemic control and lipid abnormalities with micro and macro vascular complications. Methods - It was about a retrospective study of 341 type 2 diabetes patients' with an average age of 60.1 ± 11.71 years.The IBM® SPSS statistics 20.0 software was used for analyzing data. Only significant associations (p ≤ 5%) were retained. Results -An HbA1c level ≥7% was observed in 82,5% of patients, More than 60% have dyslipidemia. 52,8% of them have an LDLc level ≤ 1 g/l, and 64,4% have a Non-HDLc level >1g/l. Sixty-six percent of patients have high blood pressure. The macrovascular disorders were observed on 30,9% of patients and microvascular ones on 66,8% of them (p = 0.0001).The logistic regression analysis showed that HbA1c was the most significant biological parameter (p=0,008). while for micro-vascular complications, high blood pressure was the only associated factor (p = 0.03). For ischemic heart disease, dyslipidemia and high blood pressure were the most associated factors. Conclusion - this study showed a high frequency of micro and macrovascular complications, lipid abnormalities and a very poor glycemic control. The elevation of HbA1c level, the high blood pressure and dyslipidemia are the most associated factors with a high cardiovascular risk.
Assuntos
Saúde Pública , Estudos Retrospectivos , Receptores Ativados por Proteinase , Diabetes Mellitus Tipo 2 , Dislipidemias , Fatores de Risco de Doenças Cardíacas , Diabetes Mellitus , Controle Glicêmico , HipertensãoRESUMO
Matriptases are cell surface proteolytic enzymes belonging to the type II transmembrane serine protease family that mediate inflammatory skin disorders and cancer progression. Matriptases may affect the development of periodontitis via protease-activated receptor-2 activity. However, the cellular mechanism by which matriptases are involved in periodontitis is unknown. In this study, we examined the antiperiodontitis effects of matriptase on Porphyromonas gingivalis-derived lipopolysaccharide (PG-LPS)-stimulated human gingival fibroblasts (HGFs). Matriptase small interfering RNA-transfected HGFs were treated with PG-LPS. The mRNA and protein levels of proinflammatory cytokines and matrix metalloproteinase 1 (MMP-1) were evaluated using the quantitative real-time polymerase chain reaction (qRT-PCR) and an enzyme-linked immunosorbent assay (ELISA), respectively. Western blot analyses were performed to measure the levels of Toll-like receptor 4 (TLR4)/interleukin-1 (IL-1) receptor-associated kinase (IRAK)/transforming growth factor ß-activated kinase 1 (TAK1), p65, and p50 in PG-LPS-stimulated HGFs. Matriptase downregulation inhibited LPS-induced proinflammatory cytokine expression, including the expression of IL-6, IL-8, tumor necrosis factor-α (TNF-α), and IL-Iß. Moreover, matriptase downregulation inhibited PG-LPS-stimulated MMP-1 expression. Additionally, we confirmed that the mechanism underlying the effects of matriptase downregulation involves the suppression of PG-LPS-induced IRAK1/TAK1 and NF-κB. These results suggest that downregulation of matriptase PG-LPS-induced MMP-1 and proinflammatory cytokine expression via TLR4-mediated IRAK1/TAK1 and NF-κB signaling pathways in HGFs.
Assuntos
Fibroblastos , Metaloproteinase 1 da Matriz , Periodontite , Serina Endopeptidases , Citocinas/metabolismo , Regulação para Baixo , Fibroblastos/metabolismo , Humanos , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/toxicidade , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , NF-kappa B/metabolismo , Periodontite/genética , Periodontite/metabolismo , Porphyromonas gingivalis , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores Ativados por Proteinase/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Protease activated receptors (PARs) are among the first receptors shown to transactivate other receptors: noticeably, these interactions are not limited to members of the same family, but involve receptors as diverse as receptor kinases, prostanoid receptors, purinergic receptors and ionic channels among others. In this review, we will focus on the evidence for PAR interactions with members of their own family, as well as with other types of receptors. We will discuss recent evidence as well as what we consider as emerging areas to explore; from the signalling pathways triggered, to the physiological and pathological relevance of these interactions, since this additional level of molecular cross-talk between receptors and signaling pathways is only beginning to be explored and represents a novel mechanism providing diversity to receptor function and play important roles in physiology and disease.
Assuntos
Receptores Ativados por Proteinase , Transdução de Sinais , Receptores Ativados por Proteinase/metabolismo , Transdução de Sinais/fisiologiaRESUMO
The outcome of ischemic stroke can be improved by further refinements of thrombolysis and reperfusion strategies. Factor VII activating protease (FSAP) is a circulating serine protease that could be important in this context. Its levels are raised in patients as well as mice after stroke and a single nucleotide polymorphism (SNP) in the coding sequence, which results in an inactive enzyme, is linked to an increased risk of stroke. In vitro, FSAP cleaves fibrinogen to promote fibrinolysis, activates protease-activated receptors, and decreases the cellular cytotoxicity of histones. Based on these facts, we hypothesized that FSAP can be used as a treatment for ischemic stroke. A combination of tissue plasminogen activator (tPA), a thrombolytic drug, and recombinant serine protease domain of FSAP (FSAP-SPD) improved regional cerebral perfusion and neurological outcome and reduced infarct size in a mouse model of thromboembolic stroke. FSAP-SPD also improved stroke outcomes and diminished the negative consequences of co-treatment with tPA in the transient middle cerebral artery occlusion model of stroke without altering cerebral perfusion. The inactive MI-isoform of FSAP had no impact in either model. FSAP enhanced the lysis of blood clots in vitro, but in the tail transection model of hemostasis, FSAP-SPD treatment provoked a faster clotting time indicating that it also has pro-coagulant actions. Thus, apart from enhancing thrombolysis, FSAP has multiple effects on stroke progression and represents a promising novel therapeutic strategy in the treatment of ischemic stroke.