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Nature Communications Jun 2023Phosphodiesterase type 5 inhibitors (PDE5is) constitute the primary therapeutic option for treating erectile dysfunction (ED). Nevertheless, a substantial proportion of...
Phosphodiesterase type 5 inhibitors (PDE5is) constitute the primary therapeutic option for treating erectile dysfunction (ED). Nevertheless, a substantial proportion of patients, approximately 30%, do not respond to PDE5i treatment. Therefore, new treatment methods are needed. In this study, we identified a pathway that contributes to male erectile function. We show that mechano-regulated YAP/TAZ signaling in smooth muscle cells (SMCs) upregulates adrenomedullin transcription, which relaxed the SMCs to maintain erection. Using single-nucleus RNA sequencing, we investigated how penile erection stretches the SMCs, inducing YAP/TAZ activity. Subsequently, we demonstrate that YAP/TAZ plays a role in erectile function and penile rehabilitation, using genetic lesions and various animal models. This mechanism relies on direct transcriptional regulation of adrenomedullin by YAP/TAZ, which in turn modulates penile smooth muscle contraction. Importantly, conventional PDE5i, which targets NO-cGMP signaling, does not promote erectile function in YAP/TAZ-deficient ED model mice. In contrast, by activating the YAP/TAZ-adrenomedullin cascade, mechanostimulation improves erectile function in PDE5i nonrespondent ED model rats and mice. Furthermore, using clinical retrospective observational data, we found that mechanostimulation significantly promotes erectile function in patients irrespective of PDE5i use. Our studies lay the groundwork for exploring the mechano-YAP/TAZ-adrenomedullin axis as a potential target in the treatment of ED.
Topics: Animals; Humans; Male; Mice; Rats; Adrenomedullin; Erectile Dysfunction; Penile Erection; Penis; Retrospective Studies; YAP-Signaling Proteins; Transcriptional Coactivator with PDZ-Binding Motif Proteins
PubMed: 37353497
DOI: 10.1038/s41467-023-39009-z -
European Heart Journal Feb 2023Albuminuria is common in patients with heart failure and associated with worse outcomes. The underlying pathophysiological mechanism of albuminuria in heart failure is...
AIMS
Albuminuria is common in patients with heart failure and associated with worse outcomes. The underlying pathophysiological mechanism of albuminuria in heart failure is still incompletely understood. The association of clinical characteristics and biomarker profile with albuminuria in patients with heart failure with both reduced and preserved ejection fractions were evaluated.
METHODS AND RESULTS
Two thousand three hundred and fifteen patients included in the index cohort of BIOSTAT-CHF were evaluated and findings were validated in the independent BIOSTAT-CHF validation cohort (1431 patients). Micro-albuminuria and macro-albuminuria were defined as urinary albumincreatinine ratio (UACR) 30 mg/gCr and 300 mg/gCr in spot urines, respectively. The prevalence of micro- and macro-albuminuria was 35.4 and 10.0, respectively. Patients with albuminuria had more severe heart failure, as indicated by inclusion during admission, higher New York Heart Association functional class, more clinical signs and symptoms of congestion, and higher concentrations of biomarkers related to congestion, such as biologically active adrenomedullin, cancer antigen 125, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (all P 0.001). The presence of albuminuria was associated with increased risk of mortality and heart failure (re)hospitalization in both cohorts. The strongest independent association with log UACR was found for log NT-proBNP (standardized regression coefficient 0.438, 95 confidence interval 0.350.53, P 0.001). Hierarchical clustering analysis demonstrated that UACR clusters with markers of congestion and less with indices of renal function. The validation cohort yielded similar findings.
CONCLUSION
In patients with new-onset or worsening heart failure, albuminuria is consistently associated with clinical, echocardiographic, and circulating biomarkers of congestion.
Topics: Humans; Prognosis; Albuminuria; Heart Failure; Biomarkers; Natriuretic Peptide, Brain; Hospitalization; Peptide Fragments; Stroke Volume
PubMed: 36148485
DOI: 10.1093/eurheartj/ehac528 -
Frontiers in Immunology 2022Mas-related G protein-coupled receptor-X2 (MRGPRX2) expressed on mast cells (MCs) contributes to hypersensitivity reactions to cationic US-Food and Drug Administration...
Mas-related G protein-coupled receptor-X2 (MRGPRX2) expressed on mast cells (MCs) contributes to hypersensitivity reactions to cationic US-Food and Drug Administration (FDA) approved drugs such as the neuromuscular blocking agent, rocuronium. In addition, activation of MRGPRX2 by the neuropeptide substance P (SP) and the pro-adrenomedullin peptide (PAMP-12) is associated with a variety of cutaneous conditions such as neurogenic inflammation, pain, atopic dermatitis, urticaria, and itch. Thus, small molecules aimed at blocking MRGPRX2 constitute potential options for modulating IgE-independent MC-mediated disorders. Two inverse MRGPRX2 agonists, named C9 and C9-6, have recently been identified, which inhibit basal G protein activation and agonist-induced calcium mobilization in transfected HEK293 cells. Substance P serves as a balanced agonist for MRGPRX2 whereby it activates both G protein-mediated degranulation and β-arrestin-mediated receptor internalization. The purpose of this study was to determine if C9 blocks MRGPRX2's G protein and β-arrestin-mediated signaling and to determine its specificity. We found that C9, but not its inactive analog C7, inhibited degranulation in RBL-2H3 cells stably expressing MRGPRX2 in response to SP, PAMP-12 and rocuronium with an IC value of ~300 nM. C9 also inhibited degranulation as measured by cell surface expression of CD63, CD107a and β-hexosaminidase release in LAD2 cells and human skin-derived MCs in response to SP but not the anaphylatoxin, C3a or FcϵRI-aggregation. Furthermore, C9 inhibited β-arrestin recruitment and MRGPRX2 internalization in response to SP and PAMP-12. We found that a G protein-coupling defective missense MRGPRX2 variant (V282M) displays constitutive activity for β-arrestin recruitment, and that this response was significantly inhibited by C9. Rocuronium, SP and PAMP-12 caused degranulation in mouse peritoneal MCs and these responses were abolished in the absence of MrgprB2 or cells treated with pertussis toxin but C9 had no effect. These findings suggest that C9 could provide an important framework for developing novel therapeutic approaches for the treatment of IgE-independent MC-mediated drug hypersensitivity and cutaneous disorders.
Topics: Mice; Animals; Humans; Receptors, Neuropeptide; Cell Degranulation; Adrenomedullin; Receptors, IgE; Substance P; Calcium; Rocuronium; Pertussis Toxin; HEK293 Cells; Nerve Tissue Proteins; Receptors, G-Protein-Coupled; Mast Cells; Neuropeptides; Drug Hypersensitivity; beta-N-Acetylhexosaminidases; beta-Arrestins; Anaphylatoxins; Immunoglobulin E
PubMed: 36275683
DOI: 10.3389/fimmu.2022.1033794 -
Science Advances Nov 2023Early-onset preeclampsia (EOPE) is a severe pregnancy complication associated with defective trophoblast differentiation and functions at implantation, but manifestation...
Early-onset preeclampsia (EOPE) is a severe pregnancy complication associated with defective trophoblast differentiation and functions at implantation, but manifestation of its phenotypes is in late pregnancy. There is no reliable method for early prediction and treatment of EOPE. Adrenomedullin (ADM) is an abundant placental peptide in early pregnancy. Integrated single-cell sequencing and spatial transcriptomics confirm a high ADM expression in the human villous cytotrophoblast and syncytiotrophoblast. The levels of ADM in chorionic villi and serum were lower in first-trimester pregnant women who later developed EOPE than those with normotensive pregnancy. ADM stimulates differentiation of trophoblast stem cells and trophoblast organoids in vitro. In pregnant mice, placenta-specific ADM suppression led to EOPE-like phenotypes. The EOPE-like phenotypes in a mouse PE model were reduced by a placenta-specific nanoparticle-based forced expression of ADM. Our study reveals the roles of trophoblastic ADM in placental development, EOPE pathogenesis, and its potential clinical uses.
Topics: Pregnancy; Female; Mice; Humans; Animals; Pre-Eclampsia; Trophoblasts; Adrenomedullin; Placenta; Cell Differentiation
PubMed: 37922358
DOI: 10.1126/sciadv.adi4777 -
The Journal of Allergy and Clinical... Nov 2023Endogenous inhibitory mechanisms promote resolution of inflammation, enhance tissue repair and integrity, and promote homeostasis in the lung. These mechanisms include... (Review)
Review
Endogenous inhibitory mechanisms promote resolution of inflammation, enhance tissue repair and integrity, and promote homeostasis in the lung. These mechanisms include steroid hormones, regulatory T cells, IL-10, prostaglandin E, prostaglandin I, lipoxins, resolvins, protectins, maresins, glucagon-like peptide-1 receptor, adrenomedullin, nitric oxide, and carbon monoxide. Here we review the most recent literature regarding these endogenous inhibitory mechanisms in asthma, which remain a promising target for the prevention and treatment of asthma.
PubMed: 37781649
DOI: 10.1016/j.jacig.2023.100135 -
Biomolecules Jan 2022Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are two bioactive peptides derived from the same precursor with several biological functions... (Review)
Review
Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are two bioactive peptides derived from the same precursor with several biological functions including vasodilation, angiogenesis, or anti-inflammation, among others. AM and PAMP are widely expressed throughout the gastrointestinal (GI) tract where they behave as GI hormones, regulating numerous physiological processes such as gastric emptying, gastric acid release, insulin secretion, bowel movements, or intestinal barrier function. Furthermore, it has been recently demonstrated that AM/PAMP have an impact on gut microbiome composition, inhibiting the growth of bacteria related with disease and increasing the number of beneficial bacteria such as or . Due to their wide functions in the GI tract, AM and PAMP are involved in several digestive pathologies such as peptic ulcer, diabetes, colon cancer, or inflammatory bowel disease (IBD). AM is a key protective factor in IBD onset and development, as it regulates cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function and mucosal epithelial repair, and promotes a beneficial gut microbiome composition. AM and PAMP are relevant GI hormones that can be targeted to develop novel therapeutic agents for IBD, other GI disorders, or microbiome-related pathologies.
Topics: Adrenomedullin; Gastrointestinal Tract; Intestinal Mucosa; Peptide Fragments; Proteins
PubMed: 35204657
DOI: 10.3390/biom12020156 -
Gastroenterology Apr 2021Recent literature has implicated a key role for mast cells in murine models of colonic inflammation, but their role in human ulcerative colitis (UC) is not well...
BACKGROUND & AIMS
Recent literature has implicated a key role for mast cells in murine models of colonic inflammation, but their role in human ulcerative colitis (UC) is not well established. A major advance has been the identification of mrgprb2 (human orthologue, MRGPX2) as mediating IgE-independent mast cell activation. We sought to define mechanisms of mast cell activation and MRGPRX2 in human UC.
METHODS
Colon tissues were collected from patients with UC for bulk RNA sequencing and lamina propria cells were isolated for MRGPRX2 activation studies and single-cell RNA sequencing. Genetic association of all protein-altering G-protein coupled receptor single-nucleotide polymorphism was performed in an Ashkenazi Jewish UC case-control cohort. Variants of MRGPRX2 were transfected into Chinese hamster ovary (CHO) and human mast cell (HMC) 1.1 cells to detect genotype-dependent effects on β-arrestin recruitment, IP-1 accumulation, and phosphorylated extracellular signal-regulated kinase.
RESULTS
Mast cell-specific mediators and adrenomedullin (proteolytic precursor of PAMP-12, an MRGPRX2 agonist) are up-regulated in inflamed compared to uninflamed UC. MRGPRX2 stimulation induces carboxypeptidase secretion from inflamed UC. Of all protein-altering GPCR alleles, a unique variant of MRGPRX2, Asn62Ser, was most associated with and was bioinformatically predicted to alter arrestin recruitment. We validated that the UC protective serine allele enhances β-arrestin recruitment, decreases IP-1, and increases phosphorylated extracellular signal-regulated kinase with MRGPRX2 agonists. Single-cell RNA sequencing defines that adrenomedullin is expressed by activated fibroblasts and epithelial cells and that interferon gamma is a key upstream regulator of mast cell gene expression.
CONCLUSION
Inflamed UC regions are distinguished by MRGPRX2-mediated activation of mast cells, with decreased activation observed with a UC-protective genetic variant. These results define cell modules of UC activation and a new therapeutic target.
Topics: Adrenomedullin; Animals; CHO Cells; Case-Control Studies; Cell Degranulation; Colitis, Ulcerative; Colon; Cricetulus; Extracellular Signal-Regulated MAP Kinases; Genetic Variation; Humans; Inositol Phosphates; Ligands; Mast Cells; Nerve Tissue Proteins; Phosphorylation; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; beta-Arrestin 2
PubMed: 33421512
DOI: 10.1053/j.gastro.2020.12.076 -
Annals of Translational Medicine May 2020Community-acquired pneumonia (CAP) is one of the respiratory infectious diseases caused by not only bacteria, but also viruses. Antibiotic agents are needed to treat... (Review)
Review
Community-acquired pneumonia (CAP) is one of the respiratory infectious diseases caused by not only bacteria, but also viruses. Antibiotic agents are needed to treat only bacterial but not viral CAP. In addition, there are some non-infectious respiratory diseases in the differential diagnosis of CAP, such as malignant diseases, interstitial lung diseases, pulmonary edema, and pulmonary hemorrhage. We usually diagnose patients having CAP by comprehensive evaluation of symptoms, vital signs, laboratory examinations, and radiographic examinations. However, symptoms and vital signs are not specific for the diagnosis of CAP; therefore, we also use inflammatory biomarkers for differentiating bacterial from viral CAP and non-infectious respiratory diseases. We have used the white blood cell count, C-reactive protein (CRP), and erythrocyte sedimentation rate as common inflammatory biomarkers, but they are not specific for bacterial infection because they could be increased by malignant diseases and collagen diseases. Recently, some inflammatory biomarkers such as procalcitonin (PCT), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), pro-adrenomedullin (proADM), and presepsin have been developed as relatively specific biomarkers for bacterial infection. Many reports have evaluated the usefulness of PCT for diagnosing CAP. In this review, the characteristics of each biomarker are discussed based on previous studies.
PubMed: 32566635
DOI: 10.21037/atm.2020.02.182 -
Trends in Pharmacological Sciences Apr 2020Receptor activity-modifying proteins (RAMPs) interact with G-protein-coupled receptors (GPCRs) to modify their functions, imparting significant implications upon their... (Review)
Review
Receptor activity-modifying proteins (RAMPs) interact with G-protein-coupled receptors (GPCRs) to modify their functions, imparting significant implications upon their physiological and therapeutic potentials. Resurging interest in identifying RAMP-GPCR interactions has recently been fueled by coevolution studies and orthogonal technological screening platforms. These new studies reveal previously unrecognized RAMP-interacting GPCRs, many of which expand beyond Class B GPCRs. The consequences of these interactions on GPCR function and physiology lays the foundation for new molecular therapeutic targets, as evidenced by the recent success of erenumab. Here, we highlight recent papers that uncovered novel RAMP-GPCR interactions, human RAMP-GPCR disease-causing mutations, and RAMP-related human pathologies, paving the way for a new era of RAMP-targeted drug development.
Topics: Animals; Antibodies, Monoclonal, Humanized; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Molecular Targeted Therapy; Mutation; Receptor Activity-Modifying Proteins; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 32115276
DOI: 10.1016/j.tips.2020.01.009 -
Cancers Mar 2023The roles played by the peptides belonging to the tachykinin (neurokinin A and B) and calcitonin/calcitonin gene-related peptide (adrenomedullin, adrenomedullin 2,... (Review)
Review
The roles played by the peptides belonging to the tachykinin (neurokinin A and B) and calcitonin/calcitonin gene-related peptide (adrenomedullin, adrenomedullin 2, amylin, and calcitonin gene-related peptide (CGRP)) peptide families in cancer development are reviewed. The structure and dynamics of the neurokinin (NK)-2, NK-3, and CGRP receptors are studied together with the intracellular signaling pathways in which they are involved. These peptides play an important role in many cancers, such as breast cancer, colorectal cancer, glioma, lung cancer, neuroblastoma, oral squamous cell carcinoma, phaeochromocytoma, leukemia, bladder cancer, endometrial cancer, Ewing sarcoma, gastric cancer, liver cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma, and thyroid cancer. These peptides are involved in tumor cell proliferation, migration, metastasis, angiogenesis, and lymphangiogenesis. Several antitumor therapeutic strategies, including peptide receptor antagonists, are discussed. The main research lines to be developed in the future are mentioned.
PubMed: 36980580
DOI: 10.3390/cancers15061694