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1.
Intensive Care Med ; 47(11): 1284-1294, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34605947

RESUMO

PURPOSE: Investigate safety and tolerability of adrecizumab, a humanized monoclonal adrenomedullin antibody, in septic shock patients with high adrenomedullin. METHODS: Phase-2a, double-blind, randomized, placebo-controlled biomarker-guided trial with a single infusion of adrecizumab (2 or 4 mg/kg b.w.) compared to placebo. Patients with adrenomedullin above 70 pg/mL, < 12 h of vasopressor start for septic shock were eligible. Randomization was 1:1:2. Primary safety (90-day mortality, treatment emergent adverse events (TEAE)) and tolerability (drug interruption, hemodynamics) endpoints were recorded. Efficacy endpoints included the Sepsis Support Index (SSI, reflecting ventilator- and shock-free days alive), change in Sequential-related Organ Failure Assessment (SOFA) and 28-day mortality. RESULTS: 301 patients were enrolled (median time of 8.5 h after vasopressor start). Adrecizumab was well tolerated (one interruption, no hemodynamic alteration) with no differences in frequency and severity in TEAEs between treatment arms (TEAE of grade 3 or higher: 70.5% in the adrecizumab group and 71.1% in the placebo group) nor in 90-day mortality. Difference in change in SSI between adrecizumab and placebo was 0.72 (CI -1.93-0.49, p = 0.24). Among various secondary endpoints, delta SOFA score (defined as maximum versus minimum SOFA) was more pronounced in the adrecizumab combined group compared to placebo [difference at 0.76 (95% CI 0.18-1.35); p = 0.007]. 28-day mortality in the adrecizumab group was 23.9% and 27.7% in placebo with a hazard ratio of 0.84 (95% confidence interval 0.53-1.31, log-rank p = 0.44). CONCLUSIONS: Overall, we successfully completed a randomized trial evaluating selecting patients for enrolment who had a disease-related biomarker. There were no overt signals of harm with using two doses of the adrenomedullin antibody adrecizumab; however, further randomized controlled trials are required to confirm efficacy and safety of this agent in septic shock patients.


Assuntos
Adrenomedulina , Choque Séptico , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores , Método Duplo-Cego , Humanos , Choque Séptico/tratamento farmacológico , Resultado do Tratamento
2.
Medicina (Kaunas) ; 57(9)2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34577843

RESUMO

Sepsis and septic shock represent a leading cause of mortality in the Emergency Department (ED) and in the Intensive Care Unit (ICU). For these life-threating conditions, different diagnostic and prognostic biomarkers have been studied. Proadrenomedullin (MR-proADM) is a biomarker that can predict organ damage and the risk of imminent death in patients with septic shock, as shown by a large amount of data in the literature. The aim of our narrative review is to evaluate the role of MR-proADM in the context of Emergency Medicine and to summarize the current knowledge of MR-proADM as a serum indicator that is useful in the Emergency Department (ED) to determine an early diagnosis and to predict the long-term mortality of patients with sepsis and septic shock. We performed an electronic literature review to investigate the role of MR-proADM in sepsis and septic shock in the context of ED. We searched papers on PubMed®, Cochrane®, UptoDate®, and Web of Science® that had been published in the last 10 years. Data extracted from this literature review are not conclusive, but they show that MR-proADM may be helpful as a prognostic biomarker to stratify the mortality risk in cases of sepsis and septic shock with different degrees of organ damage, guiding emergency physicians in the diagnosis and the succeeding therapeutic workup. Sepsis and septic shock are conditions of high complexity and have a high risk of mortality. In the ED, early diagnosis is crucial in order to provide an early treatment and to improve patient survival. Diagnosis and prognosis are often the result of a combination of several tests. In our opinion, testing for MR-proADM directly in the ED could contribute to improving the prognostic assessment of patients, facilitating the subsequent clinical management and intensive treatment by the emergency physicians, but more studies are needed to confirm these results.


Assuntos
Sepse , Choque Séptico , Adrenomedulina , Biomarcadores , Serviço Hospitalar de Emergência , Humanos , Prognóstico , Precursores de Proteínas , Sepse/diagnóstico , Choque Séptico/diagnóstico
3.
J Crit Care ; 66: 173-180, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34340901

RESUMO

PURPOSE: We assessed the ability of mid-regional proadrenomedullin (MR-proADM) and C-terminal proendothelin-1 (CT-proET-1) to predict 28-day mortality in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. METHODS: Biomarkers were collected during the first seven days in this prospective observational cohort study. We investigated the relationship between biomarkers and mortality in a multivariable Cox regression model adjusted for age and SOFA score. RESULTS: In 105 critically ill patients with confirmed SARS-CoV-2 pneumonia 28-day mortality was 28.6%. MR-proADM and CT-proET-1 were significantly higher in 28-day non-survivors at baseline and over time. ROC curves revealed high accuracy to identify non-survivors for baseline MR-proADM and CT-proET-1, AUC 0.84, (95% CI 0.76-0.92), p < 0.001 and 0.79, (95% CI 0.69-0.89), p < 0.001, respectively. The AUC for prediction of 28-day mortality for MR-proADM and CT-proET-1 remained high over time. MR-proADM ≥1.57 nmol/L and CT-proET-1 ≥ 111 pmol/L at baseline were significant predictors for 28-day mortality (HR 6.80, 95% CI 3.12-14.84, p < 0.001 and HR 3.72, 95% CI 1.71-8.08, p 0.01). CONCLUSION: Baseline and serial MR-proADM and CT-proET-1 had good ability to predict 28-day mortality in critically ill patients with SARS-CoV-2 pneumonia. TRIAL REGISTRATION: NEDERLANDS TRIAL REGISTER, NL8460.


Assuntos
COVID-19 , Pneumonia , Adrenomedulina , Biomarcadores , Estado Terminal , Endotelina-1 , Endotélio , Humanos , Fragmentos de Peptídeos , Prognóstico , Estudos Prospectivos , Precursores de Proteínas , SARS-CoV-2
4.
Int J Infect Dis ; 111: 211-218, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34461254

RESUMO

OBJECTIVES: Thromboinflammation, resulting from a complex interaction between thrombocytopathy, coagulopathy, and endotheliopathy, contributes to increased mortality in COVID-19 patients. MR-proADM, as a surrogate of adrenomedullin system disruption, leading to endothelial damage, has been reported as a promising biomarker for short-term prognosis. We evaluated the role of MR-proADM in the mid-term mortality in COVID-19 patients. METHODS: A prospective, observational study enrolling COVID-19 patients from August to October 2020. A blood sample for laboratory test analysis was drawn on arrival in the emergency department. The primary endpoint was 90-day mortality. The area under the curve (AUC) and Cox regression analyses were used to assess discriminatory ability and association with the endpoint. RESULTS: A total of 359 patients were enrolled, and the 90-day mortality rate was 8.9%. ROC AUC for MR-proADM predicting 90-day mortality was 0.832. An optimal cutoff of 0.80 nmol/L showed a sensitivity of 96.9% and a specificity of 58.4%, with a negative predictive value of 99.5%. Circulating MR-proADM levels (inverse transformed), after adjusting by a propensity score including eleven potential confounders, were an independent predictor of 90-day mortality (HR: 0.162 [95% CI: 0.043-0.480]) CONCLUSIONS: Our data confirm that MR-proADM has a role in the mid-term prognosis of COVID-19 patients and might assist physicians with risk stratification.


Assuntos
COVID-19 , Trombose , Adrenomedulina , Biomarcadores , Humanos , Inflamação , Prognóstico , Estudos Prospectivos , Precursores de Proteínas , Medição de Risco , SARS-CoV-2
5.
J Endocrinol ; 251(1): 97-109, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34370692

RESUMO

Preterm birth is associated with immaturity of several crucial physiological functions notably those prevailing in the lung and kidney. Recently, a steroid secretion deficiency was identified in very preterm neonates, associated with a partial yet transient deficiency in 11ß-hydroxylase activity, sustaining cortisol synthesis. However, the P450c11ß enzyme is expressed in preterm adrenal glands, we hypothesized an inhibition of cortisol production by adrenomedullin (ADM), a peptide highly produced in neonates and whose effect on steroidogenesis remains poorly known. We studied the effects of ADM on three models: 104 cord-blood samples of the PREMALDO neonate cohort, genetically targeted mice overexpressing ADM, and two human adrenocortical cell lines (H295R and HAC15 cells). Mid-regional-proADM (MR-proADM) quantification in cord-blood samples showed strong negative correlation with gestational age (P = 0.0004), cortisol production (P < 0.0001), and 11ß-hydroxylase activity index (P < 0.0001). Mean MR-proADM was higher in very preterm than in term neonates (1.12 vs 0.60 nmol/L, P < 0.0001). ADM-overexpression mice revealed a lower 11ß-hydroxylase activity index (P < 0.05). Otherwise, aldosterone levels measured by LC-MS/MS were higher in ADM-overexpression mice (0.83 vs 0.46 ng/mL, P < 0.05). More importantly, the negative relationship between adrenal ADM expression and aldosterone production found in control was lacking in the ADM-overexpression mice. Finally, LC-MS/MS and gene expression studies on H295R and HAC15 cells revealed an ADM-induced inhibition of both cortisol secretion in cell supernatants and CYP11B1 expression. Collectively, our results converge toward an inhibitory effect of ADM on glucocorticoid synthesis in humans and should be considered to explain the steroid secretion deficiency observed at birth in premature newborns.


Assuntos
Adrenomedulina/metabolismo , Hidrocortisona/biossíntese , Recém-Nascido Prematuro/metabolismo , Adrenomedulina/sangue , Animais , Carcinoma Adenoide Cístico/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Sangue Fetal/metabolismo , Humanos , Recém-Nascido , Masculino , Camundongos , Fragmentos de Peptídeos/sangue , Precursores de Proteínas/sangue , Esteroide 11-beta-Hidroxilase/metabolismo
6.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205035

RESUMO

Hyperpigmentation is a dermatological condition characterized by the overaccumulation and/or oversecretion of melanin pigment. The efficacy of curcumin as an anti-melanogenic therapeutic has been recognized, but the poor stability and solubility that have limited its use have inspired the synthesis of novel curcumin analogs. We have previously reported on comparisons of the anti-melanogenic activity of four novel chemically modified curcumin (CMC) analogs, CMC2.14, CMC2.5, CMC2.23 and CMC2.24, with that of parent curcumin (PC), using a B16F10 mouse melanoma cell model, and we have investigated mechanisms of inhibition. In the current study, we have extended our findings using normal human melanocytes from a darkly pigmented donor (HEMn-DP) and we have begun to study aspects of melanosome export to human keratinocytes. Our results showed that all the CMCs downregulated the protein levels of melanogenic paracrine mediators, endothelin-1 (ET-1) and adrenomedullin (ADM) in HaCaT cells and suppressed the phagocytosis of FluoSphere beads that are considered to be melanosome mimics. All the three CMCs were similarly potent (except CMC2.14, which was highly cytotoxic) in inhibiting melanin production; furthermore, they suppressed dendricity in HEMn-DP cells. CMC2.24 and CMC2.23 robustly suppressed cellular tyrosinase activity but did not alter tyrosinase protein levels, while CMC2.5 did not suppress tyrosinase activity but significantly downregulated tyrosinase protein levels, indicative of a distinctive mode of action for the two structurally related CMCs. Moreover, HEMn-DP cells treated with CMC2.24 or CMC2.23 partially recovered their suppressed tyrosinase activity after cessation of the treatment. All the three CMCs were nontoxic to human dermal fibroblasts while PC was highly cytotoxic. Our results provide a proof-of-principle for the novel use of the CMCs for skin depigmentation, since at low concentrations, ranging from 5 to 25 µM, the CMCs (CMC2.24, CMC2.23 and CMC2.5) were more potent anti-melanogenic agents than PC and tetrahydrocurcumin (THC), both of which were ineffective at melanogenesis at similar doses, as tested in HEMn-DP cells (with PC being highly toxic in dermal fibroblasts and keratinocytes). Further studies to evaluate the efficacy of CMCs in human skin tissue and in vivo studies are warranted.


Assuntos
Curcumina/farmacologia , Hiperpigmentação/tratamento farmacológico , Melaninas/biossíntese , Melanoma Experimental/tratamento farmacológico , Adrenomedulina/genética , Animais , Curcumina/análogos & derivados , Curcumina/química , Endotelina-1/genética , Humanos , Hiperpigmentação/metabolismo , Hiperpigmentação/patologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Melaninas/antagonistas & inibidores , Melanócitos/efeitos dos fármacos , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Melanossomas/efeitos dos fármacos , Melanossomas/genética , Camundongos , Fagocitose/genética , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia
7.
Eur J Endocrinol ; 185(4): 507-514, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34324433

RESUMO

Background: Despite adequate presurgical management, blood pressure fluctuations are common during resection of pheochromocytoma or sympathetic paraganglioma (PPGL). To a large extent, the variability in blood pressure control during PPGL resection remains unexplained. Adrenomedullin and B-type natriuretic peptide, measured as MR-proADM and NT-proBNP, respectively, are circulating biomarkers of cardiovascular dysfunction. We investigated whether plasma levels of MR-proADM and NT-proBNP are associated with blood pressure fluctuations during PPGL resection. Methods: Study subjects participated in PRESCRIPT, a randomized controlled trial in patients undergoing PPGL resection. MR-proADM and NT-proBNP were determined in a single plasma sample drawn before surgery. Multivariable linear and logistic regression analyses were used to explore associations between these biomarkers and blood pressure fluctuations, use of vasoconstrictive agents during surgery as well as the occurrence of perioperative cardiovascular events. Results: A total of 126 PPGL patients were included. Median plasma concentrations of MR-proADM and NT-proBNP were 0.51 (0.41-0.63) nmol/L and 68.7 (27.9-150.4) ng/L, respectively. Neither MR-proADM nor NT-proBNP were associated with blood pressure fluctuations. There was a positive correlation between MR-proADM concentration and the cumulative dose of vasoconstrictive agents (03B2 0.44, P =0.001). Both MR-proADM and NT-proBNP were significantly associated with perioperative cardiovascular events (OR: 5.46, P =0.013 and OR: 1.54, P =0.017, respectively). Conclusions: plasma MR-proADM or NT-proBNP should not be considered as biomarkers for the presurgical risk assessment of blood pressure fluctuations during PPGL resection. Future studies are needed to explore the potential influence of these biomarkers on the intraoperative requirement of vasoconstrictive agents and the perioperative cardiovascular risk.


Assuntos
Neoplasias das Glândulas Suprarrenais , Adrenomedulina/sangue , Pressão Sanguínea/fisiologia , Peptídeo Natriurético Encefálico/sangue , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/sangue , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/cirurgia , Antagonistas Adrenérgicos/uso terapêutico , Adulto , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Estudos Transversais , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Complicações Intraoperatórias/sangue , Complicações Intraoperatórias/diagnóstico , Complicações Intraoperatórias/fisiopatologia , Complicações Intraoperatórias/prevenção & controle , Masculino , Pessoa de Meia-Idade , Feocromocitoma/sangue , Feocromocitoma/diagnóstico , Feocromocitoma/tratamento farmacológico , Feocromocitoma/cirurgia , Prognóstico , Medição de Risco , Resultado do Tratamento
8.
BMC Pediatr ; 21(1): 292, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34187408

RESUMO

BACKGROUND: Midregional-proadrenomedullin (MR-proADM) is a useful prognostic peptide in severe infectious pathologies in the adult population. However, there are no studies that analyze its utility in febrile urinary tract infection (fUTI) in children. An accurate biomarker would provide an early detection of patients with kidney damage, avoiding other invasive tests like renal scintigraphy scans. Our objective is to study the usefulness of MR-proADM as a biomarker of acute and chronic renal parenchymal damage in fUTI within the pediatric population. METHODS: A prospective cohort study was conducted in pediatric patients with fUTI between January 2015 and December 2018. Plasma and urine MR-proADM levels were measured at admission in addition to other laboratory parameters. After confirmation of fUTI, renal scintigraphy scans were performed during the acute and follow-up stages. A descriptive study has been carried out and sensitivity, specificity and ROC curves for MR-proADM, C-reactive protein, and procalcitonin were calculated. RESULTS: 62 pediatric patients (34 female) were enrolled. Scintigraphy showed acute pyelonephritis in 35 patients (56.5%). Of those patients, the median of plasmatic MR-proADM (P-MR-proADM) showed no differences compared to patients without pyelonephritis. 7 patients (11.3%) developed renal scars (RS). Their median P-MR-proADM levels were 1.07 nmol/L (IQR 0.66-1.59), while in patients without RS were 0.48 nmol/L (0.43-0.63) (p < 0.01). The AUC in this case was 0.92 (95% CI 0.77-0.99). We established an optimal cut-off point at 0.66 nmol/L with sensitivity 83.3% and specificity 81.8%. CONCLUSION: MR-ProADM has demonstrated a poor ability to diagnose pyelonephritis in pediatric patients with fUTI. However, P-MR-proADM proved to be a very reliable biomarker for RS prediction.


Assuntos
Infecções Urinárias , Adrenomedulina , Biomarcadores , Criança , Feminino , Humanos , Rim , Masculino , Prognóstico , Estudos Prospectivos , Precursores de Proteínas , Infecções Urinárias/diagnóstico
9.
Commun Biol ; 4(1): 776, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34163006

RESUMO

Agonist bias occurs when different ligands produce distinct signalling outputs when acting at the same receptor. However, its physiological relevance is not always clear. Using primary human cells and gene editing techniques, we demonstrate endogenous agonist bias with physiological consequences for the calcitonin receptor-like receptor, CLR. By switching the receptor-activity modifying protein (RAMP) associated with CLR we can "re-route" the physiological pathways activated by endogenous agonists calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2). AM2 promotes calcium-mediated nitric oxide signalling whereas CGRP and AM show pro-proliferative effects in cardiovascular cells, thus providing a rationale for the expression of the three peptides. CLR-based agonist bias occurs naturally in human cells and has a fundamental purpose for its existence. We anticipate this will be a starting point for more studies into RAMP function in native environments and their importance in endogenous GPCR signalling.


Assuntos
Adrenomedulina/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Hormônios Peptídicos/fisiologia , Receptores Acoplados a Proteínas G/agonistas , Proteína Semelhante a Receptor de Calcitonina/fisiologia , Células Cultivadas , AMP Cíclico/metabolismo , Células Endoteliais/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Receptores de Adrenomedulina/agonistas , Receptores de Adrenomedulina/análise , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia
10.
J Neurol Sci ; 427: 117533, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34111763

RESUMO

OBJECTIVES: Adrenomedullin (ADM) has been identified as a promising biomarker of mortality and outcome in sepsis, heart failure and after major surgery. A recently developed assay specific for bioactive adrenomedullin (bio-ADM) has not yet been assessed in aneurysmal subarachnoid hemorrhage (aSAH). The objective of this prospective trial was to assess the time course of bio-ADM after aSAH in relation to the development of delayed cerebral ischemia (DCI) and its association with clinical outcome. METHODS: Bio-ADM levels in plasma and cerebrospinal fluid (CSF) were measured during five predefined epochs, for up to 21 days in 30 aSAH patients: early, (day 0 to day 3); acute, (day 4 to day 8); early critical, (day 9 to day 12); late critical, (day 13 to day 15), and late (day 16 to day 21). DCI was diagnosed clinically or based on multimodal monitoring and imaging, and the occurrence of DCI-related cerebral infarction, and outcome after 12 months (extended Glasgow outcome scale), was noted. RESULTS: Higher median bio-ADM levels in plasma during the acute phase were predictive of long-term unfavorable outcome (AUC = 0.97; 95% CI 0.91 to 1.00; p < 0.001). Early critical bio-ADM levels during DCI were lower in CSF and confirmed DCI occurrence (AUC = 0.80; 95% CI 0.59 to 1.00; p = 0.044). CONCLUSION: The dynamics of bio-ADM levels in CSF present a fairly different course compared to plasma with observed higher bio-ADM concentrations in patients spared from DCI and/or developing favorable outcome.


Assuntos
Isquemia Encefálica , Hemorragia Subaracnóidea , Adrenomedulina , Isquemia Encefálica/complicações , Infarto Cerebral , Humanos , Estudos Prospectivos , Hemorragia Subaracnóidea/complicações
11.
Minerva Anestesiol ; 87(10): 1117-1127, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34134460

RESUMO

INTRODUCTION: The incidence and mortality of sepsis are high, and common biomarkers are not perfect. To identify a biomarker with high specificity and sensitivity for sepsis, we evaluated the current literature on the performance of mid-regional pro-adrenomedullin (MR-proADM) in the diagnosis of sepsis. EVIDENCE ACQUISITION: According to appropriate eligibility and exclusion criteria, PubMed, EMBASE, Cochrane Library, China Journal full-text Database, Wanfang Database and Chinese Journal Full Text Database were searched for "mid-regional pro-adrenomedullin," "MR-proADM," "sepsis," "pyemia," "pyohemia," "septicemia," and "blood poisoning." The publication dates considered for the search were from inception until August 31st, 2020. The risk of bias was assessed according to QUADAS-2 criteria. EVIDENCE SYNTHESIS: Eleven studies involving 2038 cases were included. MR-proADM had high sensitivity and specificity in the diagnosis of sepsis, with values of 0.83 (95% CI: 0.79-0.87) and 0.90 (95% CI: 0.83-0.94), respectively. The odds ratio of a combined diagnosis was 41.35, and the area under the curve (AUC) was 0.91. The best cut-off value for MR-proADM diagnosis of sepsis is 1-1.5 nmol/L. MR-proADM may also have value in distinguishing pathogens and identifying sepsis severity and organ failure. CONCLUSIONS: MR-proADM is an excellent biomarker for the diagnosis of sepsis with high sensitivity and specificity. The best cut-off value for MR-proADM diagnosis of sepsis is 1-1.5 nmol/L.


Assuntos
Adrenomedulina , Sepse , Área Sob a Curva , Biomarcadores , Humanos , Prognóstico , Sepse/diagnóstico
13.
Stem Cell Res Ther ; 12(1): 288, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33985585

RESUMO

BACKGROUND: Both advanced glycation end products (AGEs) and AGE-mediated M1 macrophage polarization contribute to bone marrow mesenchymal stem cell (BMSC) dysfunction, leading to impaired bone regeneration in type 1 diabetes mellitus (T1DM). Adrenomedullin 2 (ADM2), an endogenous bioactive peptide belonging to the calcitonin gene-related peptide family, exhibits various biological activities associated with the inhibition of inflammation and reduction of insulin resistance. However, the effects and underlying mechanisms of ADM2 in AGE-induced macrophage M1 polarization, BMSC dysfunction, and impaired bone regeneration remain poorly understood. METHODS: The polarization of bone marrow-derived macrophages was verified using flow cytometry analysis. Alkaline phosphatase (ALP) staining, ALP activity detection, and alizarin red staining were performed to assess the osteogenesis of BMSCs. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, and immunofluorescence staining were used to assess polarization markers, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, and osteogenic markers. In vivo, a distraction osteogenesis (DO) rat model with T1DM was established, and tibia samples were collected at different time points for radiological, biomechanical, and histological analyses, to verify the effects of ADM2 on bone regeneration and M2 polarization under diabetic conditions. RESULTS: ADM2 treatment reversed AGE-induced M1 macrophage polarization towards the M2 phenotype, which was partially achieved by the peroxisome proliferator-activated receptor γ (PPARγ)-mediated inhibition of NF-κB signaling. The PPARγ inhibitor GW9662 significantly attenuated the effects of ADM2. Besides, ADM2 treatment improved the AGE-impaired osteogenic potential of BMSCs in vitro. Furthermore, ADM2 accelerated bone regeneration, as revealed by improved radiological and histological manifestations and biomechanical parameters, accompanied by improved M2 macrophage polarization in diabetic DO rats, and these effects were partially blocked by GW9662 administration. CONCLUSIONS: These results indicate that ADM2 enhances diabetic bone regeneration during DO, by attenuating AGE-induced imbalances in macrophage polarization, partly through PPARγ/NF-κB signaling, and improving AGE-impaired osteogenic differentiation of BMSCs simultaneously. These findings reveal that ADM2 may serve as a potential bioactive factor for promoting bone regeneration under diabetic conditions, and imply that management of inflammation and osteogenesis, in parallel, may present a promising therapeutic strategy for diabetic patients during DO treatment.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Hormônios Peptídicos , Adrenomedulina , Animais , Regeneração Óssea , Diferenciação Celular , Células Cultivadas , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Humanos , Macrófagos , Osteogênese , Ratos
14.
Endocrinology ; 162(8)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33955458

RESUMO

Pulmonary fibrosis is an irreversible, potentially fatal disease. Adrenomedullin (AM) is a multifunctional peptide whose activity is regulated by receptor activity-modifying protein 2 (RAMP2). In the present study, we used the bleomycin (BLM)-induced mouse pulmonary fibrosis model to investigate the pathophysiological significance of the AM-RAMP2 system in the lung. In heterozygous AM knockout mice (AM+/-), hydroxyproline content and Ashcroft scores reflecting the fibrosis severity were significantly higher than in wild-type mice (WT). During the acute phase after BLM administration, FACS analysis showed significant increases in eosinophil, monocyte, and neutrophil infiltration into the lungs of AM+/-. During the chronic phase, fibrosis-related molecules were upregulated in AM+/-. Notably, nearly identical changes were observed in RAMP2+/-. AM administration reduced fibrosis severity. In the lungs of BLM-administered AM+/-, the activation level of Smad3, a receptor-activated Smad, was higher than in WT. In addition, Smad7, an antagonistic Smad, was downregulated and microRNA-21, which targets Smad7, was upregulated compared to WT. Isolated AM+/- lung fibroblasts showed less proliferation and migration capacity than WT fibroblasts. Stimulation with TGF-ß increased the numbers of α-SMA-positive myofibroblasts, which were more prominent among AM+/- cells. TGF-ß-stimulated AM+/- myofibroblasts were larger and exhibited greater contractility and extracellular matrix production than WT cells. These cells were α-SMA (+), F-actin (+), and Ki-67(-) and appeared to be nonproliferating myofibroblasts (non-p-MyoFbs), which contribute to the severity of fibrosis. Our findings suggest that in addition to suppressing inflammation, the AM-RAMP2 system ameliorates pulmonary fibrosis by suppressing TGF-ß-Smad3 signaling, microRNA-21 activity and differentiation into non-p-MyoFbs.


Assuntos
Adrenomedulina/uso terapêutico , Miofibroblastos/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Proteína 2 Modificadora da Atividade de Receptores/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adrenomedulina/metabolismo , Adrenomedulina/farmacologia , Animais , Bleomicina , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Infusões Intravenosas , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/metabolismo , Miofibroblastos/metabolismo , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/prevenção & controle , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta/farmacologia
15.
J Stroke Cerebrovasc Dis ; 30(6): 105761, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33813084

RESUMO

OBJECTIVES: Adrenomedullin (AM), a vasoactive peptide, has strong anti-inflammatory and angiogenic properties, which have been reported to ameliorate the consequences of ischemic stroke in several animal models. After a phase I study in healthy volunteers, two phase II trials of AM for inflammatory bowel diseases have been recently completed. The current AdrenoMedullin For Ischemic Stroke (AMFIS) study aims to assess the safety and efficacy of AM in patients with acute ischemic stroke. MATERIALS AND METHODS: The AMFIS study is an investigator-initiated, randomized, double-blind, phase-II trial. AM or placebo will be administered to patients with non-cardioembolic ischemic stroke within 24 h after stroke onset. In the first cohort of the AMFIS study, patients will be randomly allocated to the investigation treatment A (30 µg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10). In the second cohort, patients will be assigned to the investigation treatment B (56 µg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10). RESULTS: Serious adverse events related to the protocol treatment will be evaluated as the primary outcome. All adverse events will be analyzed as the secondary outcome. Regarding efficacy endpoints, the change in National Institutes of Health Stroke Scale and modified Rankin Scale scores will be compared between investigation treatment and placebo groups. CONCLUSIONS: AM is expected to be a safe and effective treatment for ischemic stroke.


Assuntos
Adrenomedulina/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , AVC Isquêmico/tratamento farmacológico , Adrenomedulina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Fármacos Cardiovasculares/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Método Duplo-Cego , Feminino , Humanos , AVC Isquêmico/diagnóstico , AVC Isquêmico/fisiopatologia , Japão , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto Jovem
16.
Neurology ; 96(20): e2488-e2499, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33827963

RESUMO

OBJECTIVE: To determine whether the IV infusion of adrenomedullin, a potent vasodilator belonging to calcitonin family of peptides, provokes attacks of migraine in patients. METHODS: Twenty patients with migraine without aura participated in a placebo-controlled and double-blind clinical study. In a randomized crossover design, the patients received an IV infusion of human adrenomedullin (19.9 pmol/kg/min) or placebo (saline) administrated via an automated IV pump (20 minutes). The patients participated in 2 study days with a washout period of minimum of 7 days. The primary outcome of the study was predefined as a difference in migraine incidence (0-12 hours), and the secondary outcomes were the area under curve (AUC0-12 hours) for the headache intensity score and AUC0-90 minutes for mean arterial blood pressure (MAP), flushing, and heart rate (HR). RESULTS: Eleven patients with migraine without aura (55%) fulfilled migraine attacks criteria after adrenomedullin infusion compared to only 3 patients who reported attack (15%) after placebo (p = 0.039). We found that patients reported in a period of 0 to 12 hours stronger headache intensity after adrenomedullin compared to placebo infusion (p = 0.035). AUC0-90 minutes value for HR and flushing (p < 0.05) was significant and for MAP (p = 0.502) remained unchanged. Common reported adverse events were facial flushing, heat sensation, and palpitation (p < 0.001). CONCLUSION: Our data implicate adrenomedullin in migraine pathogenesis. This suggests that adrenomedullin or its receptors are novel therapeutic targets for the treatment of migraine. However, we cannot discount the possibility that adrenomedullin may be acting through the canonical calcitonin gene-related peptide receptor. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT04111484.


Assuntos
Adrenomedulina/farmacologia , Pressão Arterial/efeitos dos fármacos , Rubor/induzido quimicamente , Cefaleia/induzido quimicamente , Frequência Cardíaca/efeitos dos fármacos , Enxaqueca sem Aura/induzido quimicamente , Vasodilatadores/farmacologia , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Projetos Piloto , Distribuição Aleatória , Índice de Gravidade de Doença , Adulto Jovem
17.
Eur J Intern Med ; 88: 89-95, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33888392

RESUMO

BACKGROUND: Adrenomedullin (AM) is a vasoactive peptide mostly secreted by endothelial cells with an important role in preserving endothelial integrity.  The relationship between AM and hereditary hemorrhagic telangiectasia (HHT) is unknown. We aimed to compare the serum levels and tissue expression of AM between HHT patients and controls. METHODS: Serum AM levels were measured by radioimmunoassay and compared between control and HHT groups. AM levels were also compared among HHT subgroups according to clinical characteristics. The single nucleotide polymorphism (SNP) rs4910118 was assessed by restriction analysis and sequencing. AM immunohistochemistry was performed on biopsies of cutaneous telangiectasia from eight HHT patients and on the healthy skin from five patients in the control group. RESULTS: Forty-five HHT patients and 50 healthy controls were included, mean age (SD) was 50.7 (14.9) years and 46.4 (9.9) years (p = 0.102), respectively. HHT patients were mostly female (60% vs 38%, p = 0.032). Median [Q1-Q3] serum AM levels were 68.3 [58.1-80.6] pg/mL in the HHT group and 47.7 [43.2-53.8] pg/mL in controls (p<0.001), with an optimal AM cut-off according to Youden's J statistic of 55.32 pg/mL (J:0.729). Serum AM levels were similar in the HHT subgroups. No patient with HHT had the SNP rs4910118. AM immunoreactivity was found with high intensity in the abnormal blood vessels of HHT biopsies. CONCLUSIONS: We detected higher AM serum levels and tissue expression in patients with HHT than in healthy controls. The role of AM in HHT, and whether AM may constitute a novel biomarker and therapeutic target, needs further investigation.


Assuntos
Telangiectasia Hemorrágica Hereditária , Adrenomedulina/genética , Biomarcadores , Células Endoteliais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Telangiectasia Hemorrágica Hereditária/genética
18.
Eur J Intern Med ; 88: 104-113, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33906810

RESUMO

INTRODUCTION: The midregional fragment of proadrenomedullin (MR-proADM) is known to provide accurate short-, mid- and long term prognostic information in the triage and multi-dimensional risk assessment of patients in the emergency department (ED). In two independent observational cohorts MR-proADM values identified low disease severity patients without risk of disease progression in the ED with no 28 days mortality that wouldn´t require hospitalization. In this interventional study we want to show that the combination of an MR-proADM algorithm with clinical assessment is able to identify low risk patients not requiring hospitalization to safely reduce the number of hospital admissions. METHODS: A randomized-controlled interventional multicenter study in 4 EDs in Spain. The study protocol was approved by Ethics Committees. Control arm patients received Standard Care. MR-proADM guided arm patients with low MR-proADM value (≤0.87 nmol/L) were treated as out-patients, with high MR-proADM value (>0.87 nmol/L) were hospitalized. The hospitalization rate was compared between the study arms. RESULTS: Two hundred patients with suspicion of infection were enrolled. In the MR-proADM guided arm the hospital admission rate in the intention-to-treat (ITT) population was 17% lower than in the control arm (40.6% vs. 57.6%, p=0.024) and 20% lower in the per protocol (PP) population (37.2% vs. 57.6%, p=0.009). No deaths of out-patients and no significant difference for the safety endpoints readmission and representation rates were observed. The readmission rate was only slightly higher in the MR-proADM guided arm compared to the control arm (PP population: at 14 days 9.3% vs. 7.1%, difference 2.1% (95% CI: -11.0% to 15.2%); and at 28 days 11.1% vs. 9.5%, difference 1.6% (95% CI: -12.2% to 15.4%)). The rate of 28 days representation was slightly lower in the MR-proADM guided arm compared to the control arm (20.4% vs. 26.2%, difference -5.8% (95% CI: -25.0% to 13.4%); PP population). CONCLUSIONS: Implementing a MR-proADM algorithm optimizes ED workflows efficiently and sustainably. Hospitals can highly benefit from a reduced rate of hospitalizations by 20% using MR-proADM. The safety in the MR-proADM guided study arm was similar to the Standard Care arm. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03770533.


Assuntos
Serviço Hospitalar de Emergência , Hospitalização , Adrenomedulina , Biomarcadores , Humanos , Projetos Piloto , Prognóstico , Precursores de Proteínas , Espanha
19.
Respir Res ; 22(1): 114, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879148

RESUMO

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) might lead to oxidative stress, inflammation and elevated circulating copeptin, proANP and proADM levels. We aimed to evaluate whether the levels of these prohormones are higher in patients with OSA and whether they might change under continuous positive airway pressure (CPAP) therapy, serving as potential proxies for the diagnosis and therapy-response in OSA. METHODS: A total of 310 patients with suspicion of OSA were recruited. Screening for OSA was performed using overnight pulse oximetry followed by polygraphy and a venous puncture in the morning. All patients diagnosed with OSA underwent CPAP adaptation. A venous puncture was conducted in the night before CPAP and in the following morning. At 1 and 6 months of treatment, polygraphy was performed, followed by a venous puncture in the morning. In the acquired blood, copeptin, proANP and proADM levels were measured. RESULTS: We analyzed 232 patients with OSA and 30 patients without OSA. Our results indicated that only copeptin levels differed significantly among patients with and without OSA at baseline. In OSA patients, the levels of proADM significantly changed after 1 and 6 months on CPAP therapy, when compared to baseline (p < 0.001 and p = 0.020). Additionally, proANP levels significantly decreased after 12 h on CPAP therapy, as compared to baseline levels (p < 0.001). CONCLUSIONS: Copeptin is significantly associated with the presence of OSA. ProANP levels might serve as a potential proxy for the acute response to non-invasive ventilation (12 h), while proADM reflects the long-term response (1 and 6 months).


Assuntos
Adrenomedulina/sangue , Fator Natriurético Atrial/sangue , Glicopeptídeos/sangue , Hipóxia/sangue , Precursores de Proteínas/sangue , Apneia Obstrutiva do Sono/sangue , Adulto , Idoso , Biomarcadores/sangue , Pressão Positiva Contínua nas Vias Aéreas , Feminino , Humanos , Hipóxia/diagnóstico , Hipóxia/terapia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/terapia , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
20.
Lab Med ; 52(5): 493-498, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33928380

RESUMO

OBJECTIVE: The aim of the study was to assess the role of midregional proadrenomedullin (MR-proADM) in patients with COVID-19. METHODS: We included 110 patients hospitalized for COVID-19. Biochemical biomarkers, including MR-proADM, were measured at admission. The association of plasma MR-proADM levels with COVID-19 severity, defined as a requirement for mechanical ventilation or in-hospital mortality, was evaluated. RESULTS: Patients showed increased levels of MR-proADM. In addition, MR-proADM was higher in patients who died during hospitalization than in patients who survived (median, 2.59 nmol/L; interquartile range, 2.3-2.95 vs median, 0.82 nmol/L; interquartile range, 0.57-1.03; P <.0001). Receiver operating characteristic curve analysis showed good accuracy of MR-proADM for predicting mortality. A MR-proADM value of 1.73 nmol/L was established as the best cutoff value, with 90% sensitivity and 95% specificity (P <.0001). CONCLUSION: We found that MR-proADM could represent a prognostic biomarker of COVID-19.


Assuntos
Adrenomedulina/sangue , COVID-19/diagnóstico , Hipertensão/diagnóstico , Pneumopatias/diagnóstico , Precursores de Proteínas/sangue , Idoso , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , COVID-19/sangue , COVID-19/mortalidade , COVID-19/virologia , Comorbidade , Feminino , Humanos , Hipertensão/sangue , Hipertensão/mortalidade , Hipertensão/virologia , Interleucina-6/sangue , Pneumopatias/sangue , Pneumopatias/mortalidade , Pneumopatias/virologia , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Prognóstico , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Análise de Sobrevida , Triagem/métodos
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