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Involvement of bradykinin and bradykinin B1 receptor in patients with endometriosis.

ABSTRACT: Endometriosis (EM), a benign aseptic inflammatory disease, is associated with the presence of endometrial foci. Pain, one of its typical symptoms, has been reported as a constant stressor, but the etiology and pathogenesis of EM-associated pain are unclear. In the present study, eutopic and ectopic endometrium samples from women with EM (n=50) and normal endometrium samples from control subjects (n=20) were collected. Serum levels of prostaglandin E₂ (PGE₂), prostaglandin F2α (PGF2α) and bradykinin (BK) were measured using commercial ELISA kits. The expression of the BKB1 receptor (BKB1R) protein was evaluated by immunohistochemical staining and western blot assay. The mRNA expression of BKB1R was measured by reverse transcription-quantitative PCR. The results revealed that there was a substantial increase in the protein and mRNA expression of BKB1R, as well as the release of PGE₂, PGF2α and BK in the blood, in the EM group compared with that in the control group. Moreover, PGE₂, PGF2α and BK levels were significantly correlated with each other, as well as with the pain intensity of EM. The increased expression levels of BKB1R protein and mRNA were positively correlated with the pain degree of EM. Thus, these data indicated that BK and BKB1R were involved in the pathological onset of EM-associated pain and that they may play an important role in EM-related pain by inducing PGE₂ and PGF2α. The data indicate a potential new therapeutic target for EM-related pain.

SUBMITTER: Meng X

PROVIDER: S-EPMC8438668 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Biotechnological Fluorescent Ligands of the Bradykinin B1 Receptor: Protein Ligands for a Peptide Receptor.

Project description:The bradykinin (BK) B1 receptor (B1R) is a peculiar G protein coupled receptor that is strongly regulated to the point of being inducible in immunopathology. Limited clinical evidence suggests that its expression in peripheral blood mononuclear cells is a biomarker of active inflammatory states. In an effort to develop a novel imaging/diagnostic tool, we report the rational design and testing of a fusion protein that is a ligand of the human B1R but not likely to label peptidases. This ligand is composed of a fluorescent protein (FP) (enhanced green FP [EGFP] or mCherry) prolonged at its N-terminus by a spacer peptide and a classical peptide agonist or antagonist (des-Arg9-BK, [Leu8]des-Arg9-BK, respectively). The design of the spacer-ligand joint peptide was validated by a competition assay for [3H]Lys-des-Arg9-BK binding to the human B1R applied to 4 synthetic peptides of 18 or 19 residues. The labeling of B1R-expressing cells with EGFP or mCherry fused with 7 of such peptides was performed in parallel (microscopy). Both assays indicated that the best design was FP-(Asn-Gly)n-Lys-des-Arg9-BK; n = 15 was superior to n = 5, suggesting benefits from minimizing steric hindrance between the FP and the receptor. Cell labeling concerned mostly plasma membranes and was inhibited by a B1R antagonist. EGFP-(Asn-Gly)15-Lys-des-Arg9-BK competed for the binding of [3H]Lys-des-Arg9-BK to human recombinant B1R, being only 10-fold less potent than the unlabeled form of Lys-des-Arg9-BK to do so. The fusion protein did not label HEK 293a cells expressing recombinant human BK B2 receptors or angiotensin converting enzyme. This study identifies a modular C-terminal sequence that can be adapted to protein cargoes, conferring high affinity for the BK B1R, with possible applications in diagnostic cytofluorometry, histology and drug delivery (e.g., in oncology).

| S-EPMC4742067 | biostudies-literature

Involvement of Bradykinin Receptor 2 in Nerve Growth Factor Neuroprotective Activity.

Project description:Neurotrophin nerve growth factor (NGF) has been demonstrated to upregulate the gene expression of bradykinin receptor 2 (B2R) on sensory neurons, thus facilitating nociceptive signals. The aim of the present study is to investigate the involvement of B2R in the NGF mechanism of action in nonsensory neurons in vitro by using rat mixed cortical primary cultures (CNs) and mouse hippocampal slices, and in vivo in Alzheimer's disease (AD) transgenic mice (5xFAD) chronically treated with NGF. A significant NGF-mediated upregulation of B2R was demonstrated by microarray, Western blot, and immunofluorescence analysis in CNs, indicating microglial cells as the target of this modulation. The B2R involvement in the NGF mechanism of action was also demonstrated by using a selective B2R antagonist which was able to reverse the neuroprotective effect of NGF in CNs, as revealed by viability assay, and the NGF-induced long-term potentiation (LTP) in hippocampal slices. To confirm in vitro observations, B2R upregulation was observed in 5xFAD mouse brain following chronic intranasal NGF treatment. This study demonstrates for the first time that B2R is a key element in the neuroprotective activity and synaptic plasticity mediated by NGF in brain cells.

| S-EPMC7763563 | biostudies-literature

P2X3 receptor involvement in endometriosis pain via ERK signaling pathway.

Project description:The purinergic receptor P2X ligand-gated ion channel 3 (P2X3) is crucially involved in peripheral nociceptive processes of somatic and visceral pain. Endometriosis pain is considered as a kind of inflammatory and neuropathic pain. However, whether P2X3 is involved in endometriosis pain has not been reported up to date. Here, we aimed to determine whether P2X3 expression in endometriotic lesions is involved in endometriosis pain, which is regulated by inflammatory mediators through extracellular regulated protein kinases (ERK) signalling pathway. We found that P2X3 expressions in endometriosis endometrium and endometriotic lesions were both significantly higher as compared with control endometrium (P<0.05), and both positively correlated with pain (P<0.05). The expression levels of phosphorylated -ERK (p-ERK), phosphorylated-cAMP-response element binding protein (p-CREB), and P2X3 in endometriotic stromal cells (ESCs) were all significantly increased in comparison to the initial levels after treated with interleukin (IL)-1β (P<0.05) or adenosine triphosphate (ATP) (P<0.05), respectively, and did not increase after the ESCs were pre-treated with ERK1/2 inhibitor. Additionally, P2X3 and calcitonin gene related peptide (CGRP) were co-expressed in endometriotic lesions. These obtained results suggest that P2X3 might be involved in endometriosis pain signal transduction via ERK signal pathway.

| S-EPMC5595329 | biostudies-literature

Nociceptive tolerance is improved by bradykinin receptor B1 antagonism and joint morphology is protected by both endothelin type A and bradykinin receptor B1 antagonism in a surgical model of osteoarthritis.

Project description:Endothelin-1, a vasoconstrictor peptide, influences cartilage metabolism mainly via endothelin receptor type A (ETA). Along with the inflammatory nonapeptide vasodilator bradykinin (BK), which acts via bradykinin receptor B1 (BKB1) in chronic inflammatory conditions, these vasoactive factors potentiate joint pain and inflammation. We describe a preclinical study of the efficacy of treatment of surgically induced osteoarthritis with ETA and/or BKB1 specific peptide antagonists. We hypothesize that antagonism of both receptors will diminish osteoarthritis progress and articular nociception in a synergistic manner.Osteoarthritis was surgically induced in male rats by transection of the right anterior cruciate ligament. Animals were subsequently treated with weekly intra-articular injections of specific peptide antagonists of ETA and/or BKB1. Hind limb nociception was measured by static weight bearing biweekly for two months post-operatively. Post-mortem, right knee joints were analyzed radiologically by X-ray and magnetic resonance, and histologically by the OARSI histopathology assessment system.Single local BKB1 antagonist treatment diminished overall hind limb nociception, and accelerated post-operative recovery after disease induction. Both ETA and/or BKB1 antagonist treatments protected joint radiomorphology and histomorphology. Dual ETA/BKB1 antagonism was slightly more protective, as measured by radiology and histology.BKB1 antagonism improves nociceptive tolerance, and both ETA and/or BKB1 antagonism prevents joint cartilage degradation in a surgical model of osteoarthritis. Therefore, they represent a novel therapeutic strategy: specific receptor antagonism may prove beneficial in disease management.

| S-EPMC3218886 | biostudies-other

The Effects of Bradykinin B1 Receptor Antagonism on the Myocardial and Vascular Consequences of Hypertension in SHR Rats.

Project description:It is known that non-steroidal anti-inflammatory drugs increase cardiovascular (CV) morbidity and mortality. In this study, we examined whether a novel anti-inflammatory drug, bradykinin B1 receptor antagonist (FGY-1153) treatment could influence the development of hypertensive organ damages in spontaneously hypertensive rats (SHR). SHRs were treated with low (FGY-120) or high dose FGY-1153 (FGY-400) and with placebo (Control) for 26 weeks. Wistar-Kyoto rats were used as aged-matched, normotensive controls (WKY). Body weight, food consumption and blood pressure were measured regularly. Echocardiography was performed at the beginning and at the end of the study. Light and electron microscopic analysis of heart and great vessels were performed, and the extent of fibrotic areas was measured. The phosphorylation state of prosurvival Akt-1/glycogen synthase kinase (GSK)-3β pathway and the activation of signaling factors playing part in the fibrotic processes - mitogen activated protein kinases (MAPKs), and TGF-β/Smad2 - were monitored using Western-blot. Body weight and food consumption as well as the elevated blood pressure in SHRs was not influenced by FGY-1153 treatment. However, both doses of FGY-1153 treatment decreased left ventricular (LV) hypertrophy and diastolic dysfunction in hypertensive animals. Moreover systolic LV function was also preserved in FGY-120 group. Increased intima-media thickness and interstitial fibrosis were not significantly diminished in great vessels. FGY-1153 treatment inhibited the expression of TGFβ and the phosphorylation of SMAD2 in the heart. Our results suggest that the tested novel anti-inflammatory compound has no deleterious effect on CV system, moreover it exerts moderate protective effect against the development of hypertensive cardiopathy.

| S-EPMC6537226 | biostudies-literature

Involvement of B2 receptor in bradykinin-induced proliferation and proinflammatory effects in human nasal mucosa-derived fibroblasts isolated from chronic rhinosinusitis patients.

Project description:Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the sinonasal mucosa either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). CRSsNP accounts for the majority of CRS cases and is characterized by fibrosis and neutrophilic inflammation. However, the pathogenesis of CRS, especially CRSsNP, remains unclear. Immunohistochemistry of CRSsNP specimens in the present study showed that the submucosa, perivascular areas, and the mucous glands were abundant in fibroblasts. Therefore, we investigated the effects bradykinin (BK), an autacoid known to participate in inflammation, on human CRSsNP nasal mucosa-derived fibroblasts (NMDFs). BK increased CXCL1 and -8 secretion and mRNA expression with EC50 ranging from 0.15~0.35 μM. Moreover, BK enhanced cell proliferation and upregulated the expressions of proinflammatory molecules, including cell adhesion molecules (CAMs) and cyclooxygenase (COX)-1 and -2. These functionally caused an increase in monocyte adhesion to fibroblast monolayer. Using pharmacological intervention and BKR siRNA knockdown, we demonstrated that the BK-induced CXCL chemokine release, cell proliferation and COX and CAM expressions were mainly through the B2 receptor (B2R). Accordingly, the B2R was preferentially expressed in the NMDFs than B1R. The B2R was highly expressed in the CRSsNP than the control specimens, while the B1R and kininogen (KNG)/BK expression slightly increased in the CRSsNP mucosa. Collectively, we report here for the first time that fibroblasts, KNG/BK, and BKRs are overexpressed in CRSsNP mucosa and BK upregulates chemokine expression, proliferation, and proinflammatory molecule expression in NMDFs via B2R activation, which lead to a functional increase in monocyte-fibroblast interaction. Our findings reveal a critical role of fibroblast, KNG/BK, and BKRs in the development of CRSsNP.

| S-EPMC4430235 | biostudies-literature

Endogenous bradykinin and B1-B5 during angiotensin-converting enzyme inhibitor-associated angioedema.

Project description: Not available

| S-EPMC6226317 | biostudies-literature

FSH RECEPTOR AND FSH BETA CHAIN POLYMORPHISM INVOLVEMENT IN INFERTILITY AND ENDOMETRIOSIS DISEASE.

Project description:ObjectivesThe purpose of this study was to evaluate the association between the follicle-stimulating hormone (FSH) receptor (c.-29G>A) and FSH beta chain (c.-280G>T) polymorphisms and endometriosis in Romanian women.Material and methodsWe performed the polymorphic analysis of the FSH receptor gene and FSH beta chain in 44 patients with endometriosis and 34 controls. Genomic DNA was obtained from peripheral blood and polymorphisms were investigated using restriction fragment length polymorphism analysis (RFLP).ResultsThere were no significant differences in genotype frequencies of FSH receptor gene between endometriosis patients and controls. For the heterozygous type of the FSH receptor polymorphism (c.-29G>A) we did not find a significant difference in its frequency between patients with minimal/mild and moderate/severe endometriosis (p = 0.136). Also, the FSH beta chain (c.-280G> T) polymorphism frequency was not significantly associated with the severity of endometriosis (p = 0.966).ConclusionsFSH receptor and FSH beta chain polymorphisms do not seem to influence the severity of endometriosis, but they could be correlated with female infertility (primary or secondary), therefore further studies are required to debate this topic.

| S-EPMC7535885 | biostudies-literature

Bradykinin receptor expression and bradykinin-mediated sensitization of human sensory neurons.

Project description:Bradykinin is a peptide implicated in inflammatory pain in both humans and rodents. In rodent sensory neurons, activation of B1 and B2 bradykinin receptors induces neuronal hyperexcitability. Recent evidence suggests that human and rodent dorsal root ganglia (DRG), which contain the cell bodies of sensory neurons, differ in the expression and function of key GPCRs and ion channels; whether BK receptor expression and function are conserved across species has not been studied in depth. In this study, we used human DRG tissue from organ donors to provide a detailed characterization of bradykinin receptor expression and bradykinin-induced changes in the excitability of human sensory neurons. We found that B2 and, to a lesser extent, B1 receptors are expressed by human DRG neurons and satellite glial cells. B2 receptors were enriched in the nociceptor subpopulation. Using patch-clamp electrophysiology, we found that acute bradykinin increases the excitability of human sensory neurons, while prolonged exposure to bradykinin decreases neuronal excitability in a subpopulation of human DRG neurons. Finally, our analyses suggest that donorâ€™s history of chronic pain and age may be predictors of higher B1 receptor expression in human DRG neurons. Together, these results indicate that acute BK-induced hyperexcitability, first identified in rodents, is conserved in humans and provide further evidence supporting BK signaling as a potential therapeutic target for treating pain in humans.

| S-EPMC10081334 | biostudies-literature

A Systematic Review of Molecular Imaging Agents Targeting Bradykinin B1 and B2 Receptors.

Project description:Kinins, bradykinin and kallidin are vasoactive peptides that signal through the bradykinin B1 and B2 receptors (B1R and B2R). B2R is constitutively expressed in healthy tissues and mediates responses such as vasodilation, fluid balance and retention, smooth muscle contraction, and algesia, while B1R is absent in normal tissues and is induced by tissue trauma or inflammation. B2R is activated by kinins, while B1R is activated by kinins that lack the C-terminal arginine residue. Perturbations of the kinin system have been implicated in inflammation, chronic pain, vasculopathy, neuropathy, obesity, diabetes, and cancer. In general, excess activation and signaling of the kinin system lead to a pro-inflammatory state. Depending on the disease context, agonism or antagonism of the bradykinin receptors have been considered as therapeutic options. In this review, we summarize molecular imaging agents targeting these G protein-coupled receptors, including optical and radioactive probes that have been used to interrogate B1R/B2R expression at the cellular and anatomical levels, respectively. Several of these preclinical agents, described herein, have the potential to guide therapeutic interventions for these receptors.

| S-EPMC7464927 | biostudies-literature

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