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Biomedicines Feb 2022The 2019 coronavirus (COVID-19) pandemic is still in progress, and a significant number of patients have presented with severe illness. Recently introduced vaccines,... (Review)
Review
The 2019 coronavirus (COVID-19) pandemic is still in progress, and a significant number of patients have presented with severe illness. Recently introduced vaccines, antiviral medicines, and antibody formulations can suppress COVID-19 symptoms and decrease the number of patients exhibiting severe disease. However, complete avoidance of severe COVID-19 has not been achieved, and more importantly, there are insufficient methods to treat it. Adrenomedullin (AM) is an endogenous peptide that maintains vascular tone and endothelial barrier function. The AM plasma level is markedly increased during severe inflammatory disorders, such as sepsis, pneumonia, and COVID-19, and is associated with the severity of inflammation and its prognosis. In this study, exogenous AM administration reduced inflammation and related organ damage in rodent models. The results of this study strongly suggest that AM could be an alternative therapy in severe inflammation disorders, including COVID-19. We have previously developed an AM formulation to treat inflammatory bowel disease and are currently conducting an investigator-initiated phase 2a trial for moderate to severe COVID-19 using the same formulation. This review presents the basal AM information and the most recent translational AM/COVID-19 study.
PubMed: 35327335
DOI: 10.3390/biomedicines10030533 -
Neural Regeneration Research Jul 2020Adrenomedullin, a peptide with multiple physiological functions in nervous system injury and disease, has aroused the interest of researchers. This review summarizes the... (Review)
Review
Adrenomedullin, a peptide with multiple physiological functions in nervous system injury and disease, has aroused the interest of researchers. This review summarizes the role of adrenomedullin in neuropathological disorders, including pathological pain, brain injury and nerve regeneration, and their treatment. As a newly characterized pronociceptive mediator, adrenomedullin has been shown to act as an upstream factor in the transmission of noxious information for various types of pathological pain including acute and chronic inflammatory pain, cancer pain, neuropathic pain induced by spinal nerve injury and diabetic neuropathy. Initiation of glia-neuron signaling networks in the peripheral and central nervous system by adrenomedullin is involved in the formation and maintenance of morphine tolerance. Adrenomedullin has been shown to exert a facilitated or neuroprotective effect against brain injury including hemorrhagic or ischemic stroke and traumatic brain injury. Additionally, adrenomedullin can serve as a regulator to promote nerve regeneration in pathological conditions. Therefore, adrenomedullin is an important participant in nervous system diseases.
PubMed: 31960799
DOI: 10.4103/1673-5374.272567 -
Frontiers in Immunology 2018Sepsis remains a major medical challenge, for which, apart from improvements in supportive care, treatment has not relevantly changed over the last few decades.... (Review)
Review
Sepsis remains a major medical challenge, for which, apart from improvements in supportive care, treatment has not relevantly changed over the last few decades. Vasodilation and vascular leakage play a pivotal role in the development of septic shock, with vascular leakage being caused by disrupted endothelial integrity. Adrenomedullin (ADM), a free circulating peptide involved in regulation of endothelial barrier function and vascular tone, is implicated in the pathophysiology of sepsis. ADM levels are increased during sepsis, and correlate with extent of vasodilation, as well as with disease severity and mortality. and preclinical data show that administration of ADM exerts anti-inflammatory, antimicrobial, and protective effects on endothelial barrier function during sepsis, but other work suggests that it may also decrease blood pressure, which could be detrimental for patients with septic shock. Work has been carried out to negate ADMs putative negative effects, while preserving or even potentiating its beneficial actions. Preclinical studies have demonstrated that the use of antibodies that bind to the N-terminus of ADM results in an overall increase of circulating ADM levels and improves sepsis outcome. Similar beneficial effects were obtained using coadministration of ADM and ADM-binding protein-1. It is hypothesized that the mechanism behind the beneficial effects of ADM binding involves prolongation of its half-life and a shift of ADM from the interstitium to the circulation. This in turn results in increased ADM activity in the blood compartment, where it exerts beneficial endothelial barrier-stabilizing effects, whereas its detrimental vasodilatory effects in the interstitium are reduced. Up till now, data on ADM-targeted treatments in humans are lacking; however, the first study in septic patients with an N-terminus antibody (Adrecizumab) is currently being conducted.
Topics: Adrenomedullin; Animals; Anti-Inflammatory Agents; Antibodies; Blood Pressure; Capillary Permeability; Humans; Molecular Targeted Therapy; Sepsis; Vasodilation
PubMed: 29520277
DOI: 10.3389/fimmu.2018.00292 -
Frontiers in Immunology 2022To evaluate adrenomedullin mRNA levels in the peripheral blood mononuclear cells (PBMCs) of patients with dermatomyositis (DM) as well as their correlation with the...
OBJECTIVE
To evaluate adrenomedullin mRNA levels in the peripheral blood mononuclear cells (PBMCs) of patients with dermatomyositis (DM) as well as their correlation with the severity of interstitial lung disease (ILD).
METHODS
A total of 41 DM patients and seven immune-mediated necrotizing myopathy (IMNM) patients were recruited, in addition to 21 healthy controls (HCs). The adrenomedullin mRNA levels in PBMCs were measured quantitative reverse-transcription real-time polymerase chain reaction (qRT-PCR). The associations between adrenomedullin expression levels and major clinical, laboratory, pulmonary function parameters and the prognosis of patients with DM-related ILD (DM-ILD) were analyzed. Immunohistochemical analysis was performed on lung tissues of DM-ILD patients to determine adrenomedullin expression.
RESULTS
Adrenomedullin mRNA levels in PBMCs were significantly higher in DM patients than in IMNM patients and HCs (p = 0.022 and p<0.001, respectively). Among DM patients, the levels were significantly higher in those with rapidly progressive ILD (RP-ILD) than in those with chronic ILD (p = 0.002) or without ILD (p < 0.001). The adrenomedullin mRNA levels in DM-ILD were positively correlated with serum ferritin (r =0.507, p =0.002), lactate dehydrogenase (LDH) (r =0.350, p =0.045), and lung visual analog scale (VAS) (r=0.392, p=0.021) and were negatively correlated with pulmonary function test parameters, including predicted forced vital capacity (FVC)% (r = -0.523, p = 0.025), forced expiratory volume in 1 s (FEV1)% (r = -0.539, p = 0.020), and diffusing capacity of carbon monoxide (DLco)% (r = -0.495, p = 0.036). Immunohistochemical analysis of adrenomedullin confirmed higher expression in the alveolar epithelial cells and macrophages of DM patients with RP-ILD. Among the DM patients with ILD, the six decedents exhibited higher adrenomedullin levels than the 28 survivors (p = 0.042). The cumulative survival rate was significantly lower (62.5% . 100%, P = 0.005) in patients with an adrenomedullin level > 0.053 than in those with a level <0.053.
CONCLUSIONS
Adrenomedullin levels are upregulated in DM patients with RP-ILD and are associated with ILD severity and poor prognosis. Adrenomedullin may be a potential prognostic biomarker in DM patients with ILD, although need further investigation.
Topics: Adrenomedullin; Dermatomyositis; Humans; Leukocytes, Mononuclear; Lung Diseases, Interstitial; Prognosis; RNA, Messenger
PubMed: 35720354
DOI: 10.3389/fimmu.2022.885142 -
Cellular & Molecular Immunology Sep 2014The immunology of pregnancy is complex and incompletely understood. Aberrant immune activity in the decidua and in the placenta is believed to play a role in diseases of... (Review)
Review
The immunology of pregnancy is complex and incompletely understood. Aberrant immune activity in the decidua and in the placenta is believed to play a role in diseases of pregnancy, such as infertility, miscarriage, fetal growth restriction and preeclampsia. Here, we briefly review the endocrine control of uterine natural killer cell populations and their functions by the peptide hormone adrenomedullin. Studies in genetic animal models have revealed the critical importance of adrenomedullin dosage at the maternal-fetal interface, with cells from both the maternal and fetal compartments contributing to essential aspects underlying appropriate uterine receptivity, implantation and vascular remodeling of spiral arteries. These basic insights into the crosstalk between the endocrine and immune systems within the maternal-fetal interface may ultimately translate to a better understanding of the functions and consequences of dysregulated adrenomedullin levels in clinically complicated pregnancies.
Topics: Adrenomedullin; Animals; Disease Models, Animal; Embryo Implantation; Endocrine System; Female; Humans; Immunity, Cellular; Killer Cells, Natural; Neovascularization, Physiologic; Pre-Eclampsia; Pregnancy
PubMed: 25132453
DOI: 10.1038/cmi.2014.71 -
European Review For Medical and... Oct 2014Heart failure (HF) results from the impaired ability of heart to fill or pump out blood. HF is a common health problem with a multitude of causes and affects ~30 million... (Review)
Review
Heart failure (HF) results from the impaired ability of heart to fill or pump out blood. HF is a common health problem with a multitude of causes and affects ~30 million people worldwide. Since ageing is a major risk factor for HF and as several treatment options are currently available to prolong the patients' survival, the number of affected patients is expected to grow. Even though traditional methods of assessment have been in use for managing HF, these are limited by time consuming and costly subjective interpretation and also by their invasive nature. Comparatively, biomarkers offer an objective and biologically relevant information that in conjunction with the patients' clinical findings provides optimal picture regarding the status of the HF patient and thus helps in diagnosis and prognosis. The current gold standard biomarkers for the diagnosis and prognosis of HF are B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP). Additional novel biomarkers (e.g., mid-regional pro atrial natriuretic peptide (MR-proANP), mid-regional pro adrenomedullin (MR-proADM), troponins, soluble ST2 (sST2), growth differentiation factor (GDF)-15 and galectin-3) can potentially identify different pathophysiological processes such as myocardial insult, inflammation and remodeling as the causes for the development and progression of HF. Different biomarkers of HF not only reflect the underlying mechanisms/pathways of HF and also its progression and also point specific therapy options. A multi-biomarker approach for personalized medical care is not too far fetched and such approach can greatly enhance diagnosis, prognostication, and therapy guidance for HF. In this review we describe the current status of HF biomarkers in clinical use and in laboratory research and the efforts aimed at the identification of novel biomarkers for HF.
Topics: Adrenomedullin; Animals; Atrial Natriuretic Factor; Biomarkers; Disease Progression; Galectin 3; Heart Diseases; Humans; Myocardium; Natriuretic Peptide, Brain; Peptide Fragments; Risk Factors
PubMed: 25339488
DOI: No ID Found -
Children (Basel, Switzerland) Aug 2022Adrenomedullin has several properties. It acts as a potent vasodilator, has natriuretic effects, and reduces endothelial permeability. It also plays a role in initiating... (Review)
Review
Adrenomedullin has several properties. It acts as a potent vasodilator, has natriuretic effects, and reduces endothelial permeability. It also plays a role in initiating the early hyperdynamic phase of sepsis. Since its discovery, many articles have been published studying the uses and benefits of this biomarker. The aim of this review is to determine the usefulness of adrenomedullin in pediatric patients. Relevant studies covering adrenomedullin in pediatrics (<18 years) and published up until August 2021 were identified through a search of MEDLINE, PubMed, Embase, Web of Science, Scopus, and Cochrane. Seventy studies were included in the present review, most of them with a low level of evidence (IV to VI). Research on adrenomedullin has primarily been related to infection and the cardiovascular field. The performance of adrenomedullin to quantify infection in children seems satisfactory, especially in sepsis. In congenital heart disease, this biomarker seems to be a useful indicator before, during, and after cardiopulmonary bypass. Adrenomedullin seems to be useful in the pediatric population for a large variety of pathologies, especially regarding infection and cardiovascular conditions. However, it should be used in combination with other biomarkers and clinical or analytical variables, rather than as a single tool.
PubMed: 36010070
DOI: 10.3390/children9081181 -
Journal of Atherosclerosis and... Jul 2015Vascular endothelial cells play key roles in maintaining vascular and organ homeostasis. Adrenomedullin (AM), originally identified as a vasodilating peptide, is now... (Review)
Review
Vascular endothelial cells play key roles in maintaining vascular and organ homeostasis. Adrenomedullin (AM), originally identified as a vasodilating peptide, is now recognized to be a pleiotropic molecule involved in both circulatory homeostasis and the pathogenesis of cardiovascular diseases. We have reported that knockout mice deficient in AM or receptor activity-modifying protein 2 (RAMP2), an AM-receptor accessory protein, show vascular endothelial cell deformities that are embryonically lethal. To directly clarify the pathophysiological functions of the vascular AM-RAMP2 system, we generated vascular endothelial cell-specific RAMP2 knockout mice. Using these mice, we found that the AM-RAMP2 system is a key determinant of vascular integrity and homeostasis from prenatal stages through adulthood. This review highlights the functions of AM-RAMP2 in vascular endothelial cells.
Topics: Adrenomedullin; Animals; Endothelial Cells; Humans; Mice, Knockout; Receptor Activity-Modifying Protein 2
PubMed: 26040754
DOI: 10.5551/jat.29967 -
PloS One 2023Atypical chemokine receptor 3 (ACKR3) is a scavenger of the chemokines CXCL11 and CXCL12 and of several opioid peptides. Additional evidence indicates that ACKR3 binds...
Atypical chemokine receptor 3 (ACKR3) is a scavenger of the chemokines CXCL11 and CXCL12 and of several opioid peptides. Additional evidence indicates that ACKR3 binds two other non-chemokine ligands, namely the peptide hormone adrenomedullin (AM) and derivatives of the proadrenomedullin N-terminal 20 peptide (PAMP). AM exhibits multiple functions in the cardiovascular system and is essential for embryonic lymphangiogenesis in mice. Interestingly, AM-overexpressing and ACKR3-deficient mouse embryos both display lymphatic hyperplasia. Moreover, in vitro evidence suggested that lymphatic endothelial cells (LECs), which express ACKR3, scavenge AM and thereby reduce AM-induced lymphangiogenic responses. Together, these observations have led to the conclusion that ACKR3-mediated AM scavenging by LECs serves to prevent overshooting AM-induced lymphangiogenesis and lymphatic hyperplasia. Here, we further investigated AM scavenging by ACKR3 in HEK293 cells and in human primary dermal LECs obtained from three different sources in vitro. LECs efficiently bound and scavenged fluorescent CXCL12 or a CXCL11/12 chimeric chemokine in an ACKR3-dependent manner. Conversely, addition of AM induced LEC proliferation but AM internalization was found to be independent of ACKR3. Similarly, ectopic expression of ACKR3 in HEK293 cells did not result in AM internalization, but the latter was avidly induced upon co-transfecting HEK293 cells with the canonical AM receptors, consisting of calcitonin receptor-like receptor (CALCRL) and receptor activity-modifying protein (RAMP)2 or RAMP3. Together, these findings indicate that ACKR3-dependent scavenging of AM by human LECs does not occur at ligand concentrations sufficient to trigger AM-induced responses mediated by canonical AM receptors.
Topics: Humans; Adrenomedullin; Chemokine CXCL11; Endothelial Cells; HEK293 Cells; Hyperplasia; Receptors, Adrenomedullin; Receptors, CXCR
PubMed: 37252916
DOI: 10.1371/journal.pone.0285597 -
Journal of the American Heart... Aug 2023Background Premature and early menopause are independently associated with greater risk of cardiovascular disease (CVD). However, mechanisms linking age of menopause...
Background Premature and early menopause are independently associated with greater risk of cardiovascular disease (CVD). However, mechanisms linking age of menopause with CVD remain poorly characterized. Methods and Results We measured 71 circulating CVD protein biomarkers in 1565 postmenopausal women enrolled in the FHS (Framingham Heart Study). We examined the association of early menopause with biomarkers and tested whether early menopause modified the association of biomarkers with incident cardiovascular outcomes (heart failure, major CVD, and all-cause death) using multivariable-adjusted linear regression and Cox models, respectively. Among 1565 postmenopausal women included (mean age 62 years), 395 (25%) had a history of early menopause. Of 71 biomarkers examined, we identified 7 biomarkers that were significantly associated with early menopause, of which 5 were higher in women with early menopause including adrenomedullin and resistin, and 2 were higher in women without early menopause including insulin growth factor-1 and CNTN1 (contactin-1) (Benjamini-Hochberg adjusted <0.1 for all). Early menopause also modified the association of specific biomarkers with incident cardiovascular outcomes including adrenomedullin (<0.05). Conclusions Early menopause is associated with circulating levels of CVD protein biomarkers and appears to modify the association between select biomarkers with incident cardiovascular outcomes. Identified biomarkers reflect several distinct biological pathways, including inflammation, adiposity, and neurohormonal regulation. Further investigation of these pathways may provide mechanistic insights into the pathogenesis, prevention, and treatment of early menopause-associated CVD.
Topics: Female; Humans; Middle Aged; Cardiovascular Diseases; Adrenomedullin; Menopause, Premature; Menopause; Biomarkers; Risk Factors
PubMed: 37548169
DOI: 10.1161/JAHA.122.028849