Adrenomedullin Levels Research Articles

Plasma Endothelin-1 and Adrenomedullin are Associated with Coronary Artery Function and Cardiovascular Outcomes in Humans

Abstract Background Endothelin-1 (ET-1) is a vasoconstrictor associated with cardiovascular disease, whereas adrenomedullin (ADM) is a vasorelaxant with cardioprotective properties. We sought to determine the relationship between plasma ET-1 and ADM with coronary circulatory function and long-term major adverse cardiovascular events (MACE). Methods Thirty-two patients undergoing coronary angiography for chest pain were recruited. Baseline plasma ET-1 and ADM levels were measured. The index of microcirculatory resistance (IMR), coronary flow mediated dilatation (cFMD) and coronary flow reserve (CFR) were measured in a non-obstructed coronary artery. Patients were assessed for MACE over a median period of 8.8 years. Results Plasma ET-1 levels correlated with IMR (r = 0.57; p Conclusions Plasma ET-1 and ADM were associated with measures of coronary microvascular and coronary conduit vessel function, respectively. Increased cFMD and elevated plasma ADM were associated with a cardioprotective effect.

Serum Levels of Adrenomedullin in Women with PCOS before and after Rosuvastatin Treatment

Serum Levels of Adrenomedullin in Women with PCOS before and after Rosuvastatin Treatment

Follicular Fluid Levels of Adrenomedullin 2, Vascular Endothelial Growth Factor and its Soluble Receptors Are Associated with Ovarian Response During ART Cycles.

Introduction Adrenomedullin 2 (ADM2) and vascular endothelial growth factor (VEGF) affect ovarian function, especially angiogenesis and follicular development. The actions of VEGF can be antagonized by its soluble receptors, soluble Fms-like tyrosine kinase-1 (sFlt-1) and soluble VEGF receptor 2 (sVEGFR-2), as they decrease its free form. In the present study, we evaluated the relationship between follicular fluid (FF) levels of AMD2, VEGF and its soluble receptors, and ICSI outcomes. Materials and Methods ICSI cycle outcomes were evaluated and FF levels of VEGF, sFlt-1, sVEGFR-2 and ADM2 were determined using ELISA kits. Results FF levels of ADM2, VEGF, and sVEGFR-2 were significantly higher in non-responders compared to other ovarian response groups (p < 0.05). There were significant correlations between ADM2, VEGF and sVEGFR-2 levels as well as VEGF/sFlt-1 and VEGF/sVEGFR-2 ratios (r = 0.586, 0.482, 0.260, and − 0.366, respectively). Based on the ROC curve, the cutoff value for ADM2 as a non-responder predictor was 348.55 (pg/ml) with a sensitivity of 67.7% and a specificity of 94.6%. Conclusions For the first time we measured FF ADM2 levels to determine the relationship to VEGF and its soluble receptors. We suggest that ADM2 could be a potential predictive marker for non-responders. Although the exact function of ADM2 in ovarian angiogenesis is not yet understood, our study may shed light on the possible role of ADM2 in folliculogenesis and ovulation.

Association of brain natriuretic peptide and adrenomedullin plasma levels with left ventricular filling pressures in end-stage renal disease patients on hemodialysis.

Adrenomedullin (ADM) and brain natriuretic peptide (BNP) are known to be associated with elevated left ventricular filling pressures. However, little is known about this association in hemodialysis (HD) patients with preserved left ventricular ejection fraction (LVEF). Our objective was to evaluate the potential association between E/e' ratio and plasma levels of BNP and ADM in end-stage renal disease (ESRD) patients with preserved LVEF undergoing chronic hemodialysis. The study group enrolled 62 ESRD patients treated with hemodialysis three times weekly. BNP and ADM plasma concentration measurements and echocardiographic examination were performed 30 minutes after hemodialysis. E/e' ratio, evaluated by Tissue Doppler imaging and measured at the basal septum, was used as a surrogate marker for assessing left ventricular filling pressures. The mean age of patients was 62 ± 25 years. The mean BNP and ADM values after hemodialysis were 0.40 ± 6.73 ng/ml and 0.06 ± 2.12 ng/ml, respectively. Elderly patients with hypertrophied left ventricles and larger left atria displayed higher E/e' values. BNP (r = 0.324. p = 0.018) and ADM (r = 0.319, p = 0.042) plasma levels were positively and significantly associated with E/e΄. Multivariate regression analysis including BNP, ADM, age, hemodialysis duration, left ventricular end-systolic volume index, LVEF, left ventricular mass index and left atrium volume index, revealed that ADM (p-value 0.025) but not BNP levels, were independently associated with the E/e' ratio. ADM, but not BNP, was independently associated with septal E/e' in HD patients with preserved LVEF. ADM plasma levels can be used as a surrogate index to assess left ventricular filling pressures in HD patients.

Circulating Adrenomedullin Is Elevated in Gestational Diabetes and Its Role in Impaired Insulin Production by β-Cells.

Defective pancreatic β-cell adaptation in pregnancy plays an important role in the pathophysiology of gestational diabetes mellitus (GDM), but the molecular basis remains unclear. Objectives of this study were to determine if circulating levels of adrenomedullin (ADM) in women with GDM are elevated and to assess the effects of ADM on insulin synthesis and secretion by human pancreatic β-cells. A stable gene product of ADM precursor, midregional pro-adrenomedullin(MR-proADM), was measured in plasma of pregnant women with normal glucose tolerance (NGT, n = 10) or GDM (n = 11). The β-Lox5 cell line, derived from human pancreatic β-cells, was transduced with homeodomain transcription factor pancreatic-duodenal homeobox (PDX) factor 1 (PDX1) encoding lentiviral vector and treated with different doses of ADM. mRNA for insulin, ADM, and its receptor components in β-Lox5 cells and insulin in media were measured. Plasma MR-proADM levels were significantly higher in GDM compared with patients with NGT. Pancreatic β-Lox5 cells express mRNA for insulin, ADM, and its receptor components. PDX1 transduction and cell-cell contact synergistically promote β-Lox5 cells insulin mRNA and secretion. Furthermore, ADM dose-dependently inhibited mRNA and secretion of insulin in β-Lox5 cell aggregates. These inhibitory effects were blocked by ADM antagonist ADM22-52, cAMP-dependent protein kinase A inhibitor KT5720, and Erk inhibitor PD98059, but not by PI-3K the inhibitor wortmannin. Circulating ADM concentrations were elevated in pregnant women with GDM. ADM suppresses insulin synthesis and secretion by pancreatic β-cells in vitro. Thus, increased circulating ADM may contribute to the defective adaptation of β-cells in diabetic pregnancies, and blockade of ADM actions with its antagonists may improve β-cell functions.

Assessment of adrenomedullin and proadrenomedullin as predictors of mortality in septic patients: A systematic review and meta-analysis

ObjectiveTo ascertain the ability of adrenomedullin (ADM) and proadrenomedullin (proADM) to predict mortality in sepsis patients. DesignA systematic literature search was made of the PubMed, EMBASE, Cochrane and China National Knowledge Infrastructure (CNKI) databases before May 2017, supplemented by manual searches of references. A meta-analysis of high-quality clinical studies was subsequently performed to assess the association between ADM/proADM and mortality risk among patients with sepsis. PatientsThirteen studies involving 2556 patients were included in the study. InterventionsTwo reviewers independently identified articles, extracted data, assessed quality and cross-checked the results. The predictive values of ADM and proADM referred to mortality were assessed by relative risk (RR). The overall diagnostic accuracy of ADM and proADM in application to sepsis was pooled according to a bivariate model. Publication bias was assessed using Deek's funnel plot asymmetry test. ResultsElevated ADM or proADM levels were associated with increased mortality (pooled RR=3.31; 95%CI 2.31–4.75). Subgroup analyses indicated the pooled RRs were 3.12 (95%CI 1.75–5.56) and 3.43 (95%CI 2.21–5.31) for ADM and proADM, respectively. The pooled sensitivity and specificity were 0.72 (95%CI 0.64–0.78) and 0.77 (95%CI 0.69–0.83), respectively. The overall area under the summary receiver operating characteristic (SROC) curve was 0.80 (95%CI 0.77–0.84). Publication bias was not statistically significant. ConclusionsBoth ADM and proADM might serve as useful markers for predicting the prognosis of sepsis.

PS01.118: THE EFFECTS OF THE HERBAL MEDICINE DAIKENCHUTO (TJ-100) AFTER ESOPHAGEAL CANCER RESECTION, OPEN-LABEL, RANDOMIZED CONTROLLED TRIAL

Abstract Background Daikenchuto (TJ-100), a traditional Japanese herbal medicine, is widely used in Japan. Its effects on gastrointestinal motility, microcirculation and its anti-inflammatory effect are known. The purpose of this prospective randomized controlled trial was to investigate the effect of TJ-100 after esophagectomy in esophageal cancer patients. Methods Forty patients to whom subtotal esophagectomy for esophageal cancer was planned at our institute from March 2011 to August 2013 were enrolled and divided into two groups at the point of determination of the operation schedule after informed consent: TJ-100 treated group (n = 20) and Control group (n = 20). The primary end-points were maintenance of the nutrition condition and the recovery of gastrointestinal function. The secondary end-points were the serum C-reactive protein (CRP) level and adrenomedullin level during the postoperative course, the incidence of postoperative complications, and the length of hospital stay after surgery. Results We examined 39 patients because one patient in TJ-100 group couldn’t perform a curative surgery. The mean age of the TJ-100 group patients was significantly older than that of the control group. The rate of body weight decrease at postoperative day 21 was significantly suppressed in the TJ-100 group (3.6% vs. 7.0%, P = 0.014), but the serum albumin levels were not significantly different between the groups. The recovery of gastrointestinal function regarding flatus, defecation, and oral intake showed no significant between the groups, but postoperative bowel ill symptoms tended to be rare in the TJ-100 group. There was no significant difference in hospital stay after surgery. The serum CRP levels at postoperative day 3 tended to be suppressed in the TJ-100 group (P = 0.126). The rate of increase in adrenomedullin levels tended to be high postoperatively in the TJ-100 group, but there was no significant difference. Conclusion TJ-100 treatment after esophagectomy prompts the recovery of gastrointestinal motility and minimizes body weight loss. Those effects might suppress the excess inflammatory reaction related to surgery Disclosure All authors have declared no conflicts of interest.

Precursor proadrenomedullin influences cardiomyocyte survival and local inflammation related to myocardial infarction

Increased adrenomedullin (ADM) levels are associated with various cardiac diseases such as myocardial infarction (MI). ADM is cleaved off from the full-length precursor protein proadrenomedullin (ProADM) during its posttranslational processing. To date, no biological effect of ProADM is reported, while ADM infusion leads to antiapoptotic effects and improved cardiac function. Using an MI mouse model, we found an induction of ProADM gene as well as protein expression during the early phase of MI. This was accompanied by apoptosis and increasing inflammation, which substantially influence the post-MI remodeling processes. Simulating ischemia in vitro, we demonstrate that ProADM expression was increased in cardiomyocytes and cardiac fibroblasts. Subsequently, we treated ischemic cardiomyocytes with either ProADM or ADM and found that both proteins increased survival. This effect was diminishable by blocking the ADM1 receptor. To investigate whether ProADM and ADM play a role in the regulation of cardiac inflammation, we analyzed chemokine expression after treatment of cells with both proteins. While ProADM induced an expression of proinflammatory cytokines, thus promoting inflammation, ADM reduced chemokine expression. On leukocytes, both proteins repressed chemokine expression, revealing antiinflammatory effects. However, ProADM but not ADM dampened concurrent activation of leukocytes. Our data show that the full-length precursor ProADM is biologically active by reducing apoptosis to a similar extent as ADM. We further assume that ProADM induces local inflammation in affected cardiac tissue but attenuates exaggerated inflammation, whereas ADM has low impact. Our data suggest that both proteins are beneficial during MI by influencing apoptosis and inflammation.

Elevated levels of adrenomedullin in eutopic endometrium and plasma from women with endometriosis

To test adrenomedullin (Adm, ADM) as a downstream target of signal transducer and activator of transcription 3 (STAT3) in endometrial cells and to test midregional proadrenomedullin (MR-proADM) as a biomarker of endometriosis. Cross-sectional analysis of Adm expression in eutopic endometrium and of MR-proADM in plasma from women with and without endometriosis; and prospective study of MR-proADM levels in women with endometriosis undergoing surgical resection of ectopic lesions. Academic medical centers. Fifteen patients with endometriosis and 11 healthy control subjects who donated eutopic endometrial biopsies; and 28 patients with endometriosis and 19 healthy control subjects who donated plasma for MR-proADM analysis. None. Adm mRNA levels according to quantitative real-time polymerase chain reaction after activation of STAT3 by interleukin-6 (IL-6) in Ishikawa cells; immunohistochemistry for ADM in eutopic endometrial biopsies from women with endometriosis compared with healthy donors; and MR-proADM levels measured by commercial immunoassay in plasma from healthy women and women with endometriosis who subsequently underwent surgical resection of ectopic lesions. Activation of STAT3 by IL-6 up-regulated Adm mRNA expression in Ishikawa cells. ADM protein levels were elevated in the eutopic endometrium of women with endometriosis. MR-proADM concentrations were higher in women with endometriosis but were not correlated with disease stage, corrected by surgery, or predictive of fertility outcome. MR-proADM may be able to serve as a biomarker of endometriosis, but it is unknown whether elevated MR-proADM levels are secondary to the estrogenic and inflammatory properties of endometriosis or an inciting pathogenic factor.

A transcriptomics study of hereditary angioedema attacks

Hereditary angioedema (HAE) caused by C1-inhibitor deficiency is a lifelong illness characterized by recurrent acute attacks of localized skin or mucosal edema. Activation of the kallikrein/bradykinin pathway at the endothelial cell level has a relevant pathogenetic role in acute HAE attacks. Moreover, other pathways are involved given the variable clinical expression of the disease in different patients. We sought to explore the involvement of other putative genes in edema formation. We performed a PBMC microarray gene expression analysis on RNA isolated from patients with HAE during an acute attack and compared them with the transcriptomic profile of the same patients in the remission phase. Gene expression analysis identified 23 genes significantly modulated during acute attacks that are involved primarily in the natural killer cell signaling and leukocyte extravasation signaling pathways. Gene set enrichment analysis showed a significant activation of relevant biological processes, such as response to external stimuli and protein processing (q<0.05), suggesting involvement of PBMCs during acute HAE attacks. Upregulation of 2 genes, those encoding adrenomedullin and cellular receptor for urokinase plasminogen activator (uPAR), which occurs during an acute attack, was confirmed in PBMCs of 20 additional patients with HAE by using real-time PCR. Finally, invitro studies demonstrated the involvement of uPAR in the generation of bradykinin and endothelial leakage. Our study demonstrates the increase in levels of adrenomedullin and uPAR in PBMCs during an acute HAE attack. Activation of these genes usually involved in regulation of vascular tone and in inflammatory response might have a pathogenic role by amplifying bradykinin production and edema formation in patients with HAE.

Reduced Adrenomedullin Parallels Microtubule Dismantlement in Frontotemporal Lobar Degeneration.

Tau is a microtubule-associated protein highly expressed in neurons with a chief role in microtubule dynamics and axonal maintenance. Adrenomedullin gene (ADM) codifies for various peptides that exert broad range of actions in the body. Previous works in our groups have shown that increased ADM products are positively correlated to microtubule disruption and tau pathology in Alzheimer's disease brains. In the present study, we explore the involvement of ADM in the neuropathology of frontotemporal lobar degeneration that presents with primary tauopathy (FTLD-tau). Proteins from frontal cortices of FTLD-tau patients and age- and sex-matched non-demented controls were analyzed with antibodies against different microtubule components, including adrenomedullin, and synaptic markers. Tau pathology in frontal cortex from FTLD patients was confirmed. Levels of total βIII-tubulin as well as acetylated and detyrosinated tubulins, two markers of stabilized and aged microtubules, were significantly reduced and directly correlated with PSD95 and proBDNF in FTLD-tau patients when compared to non-demented controls. In contrast, no change in actin cytoskeleton was found. Interestingly, changes in microtubule elements, indicators of disturbed axonal preservation, were accompanied by decreased levels of free adrenomedullin, although no association was found. Altogether, reduced levels of adrenomedullin might not be directly linked to the microtubule pathology of FTLD-tau, but based on previous works, it is suggested that downregulation of ADM might be an adaptive attempt of neurons to mitigate microtubule disruption.

Evaluation of the role of adrenomedullin in febrile neutropenia

Objective The aim of this study was to evaluate the role of adrenomedullin (ADM) as a new marker in febrile neutropenia (FN). Background ADM has an effective role in FN episode in pediatric patients with acute lymphoblastic leukemia (ALL). Patient and methods This is a prospective study of 25 patients with ALL, recruited from the Hematology and Oncology Unit, Menoufia University Hospital, Egypt, from January to June 2016 diagnosed with ALL and suffering from FN episode. Complete blood count with differential count, C-reactive protein (CRP), ADM, Na, K, Ca, creatinine, and serum glutamate-pyruvate transaminase level were evaluated on the first and fifth days of FN. Results ADM level was higher on the fifth day than on the first day of FN. It showed higher sensitivity and specificity compared with CRP and has greater area under the curve compared with CRP, with a cutoff of point 6 for CRP and 50 for ADM. CRP level was higher on the first than on the fifth day of FN. Conclusion ADM was higher on the fifth day than on first day of FN episode and has higher sensitivity and specificity compared with CRP and has greater area under the curve. Therefore, it can be considered as a new diagnostic marker in FN episode in patients with ALL. Nevertheless, CRP is still an effective cheap marker that should be used in FN episode.

Overexpression of adrenomedullin protects mesenchymal stem cells against hypoxia and serum deprivation‑induced apoptosis via the Akt/GSK3β and Bcl‑2 signaling pathways.

The poor survival rate of transplanted mesenchymal stem cells (MSCs) within the ischemic heart limits their therapeutic potential for cardiac repair. Adrenomedullin (ADM) has been identified as a potent apoptotic inhibitor. The present study aimed to investigate the protective effects of ADM on MSCs against hypoxia and serum deprivation (H/SD)-induced apoptosis, and to determine the potential underlying mechanisms. In the present study, a recombinant adenovirus expressing the ADM gene was established and was infected into MSCs. The infection rate was determined via microscopic detection of green fluorescence and flow cytometric analysis. The mRNA expression levels of ADM were detected by reverse transcription-polymerase chain reaction. In addition, a model of H/SD was generated. The MSCs were randomly separated into six groups: Control, enhanced green fluorescent protein (EGFP)-Adv, EGFP-ADM, H/SD, EGFP-Adv + H/SD and EGFP-ADM + H/SD. Cell viability and proliferation were determined using the Cell Counting kit-8 assay. Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated-dUTP nick-end labeling assay and flow cytometric analysis using Annexin V-phycoerythrin/7-aminoactinomycin D staining. The protein expression levels of total protein kinase B (Akt), phosphorylated (p)-Akt, total glycogen synthase kinase (GSK)3β, p-GSK3β, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3 and cleaved caspase-3 were detected by western blot analysis. The results indicated that ADM overexpression could improve MSC proliferation and viability, and protect MSCs against H/SD-induced apoptosis. In addition, ADM overexpression increased Akt and GSK3β phosphorylation, and Bcl-2/Bax ratio, and decreased the activation of caspase-3. These results suggested that ADM protects MSCs against H/SD-induced apoptosis, which may be mediated via the Akt/GSK3β and Bcl-2 signaling pathways.

Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis.

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. In vitro and preclinical in vivo 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, in vivo 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.

Sustained increase in angiopoietin-2, heparin-binding protein, and procalcitonin is associated with severe sepsis

PurposeThe identification of infection at its early stage in vulnerable patients is challenging. This study aimed to investigate potential biomarkers to distinguish patients progressing to severe sepsis from those with uncomplicated sepsis. Materials and methodsSerum samples were collected from sepsis patients admitted to the emergency department. The mRNA and protein levels of angiopoietin-2 (Ang-2), interleukin-10 (IL-10), heparin-binding protein (HBP), procalcitonin (PCT), adrenomedullin (ADM), and interleukin-6 (IL-6) were evaluated. ResultsCompared to those of healthy individuals (n = 47), mRNA levels of ANG2, IL10, HBP, PCT, and ADM were increased in patients who eventually developed sepsis. ANG2 was the only gene whose expression was significantly increased in patients developing severe sepsis than in those with uncomplicated sepsis. Serum levels of Ang-2, IL-10, HBP, PCT, and IL-6 were also increased in sepsis patients, but only Ang-2, HBP, and PCT were elevated in the serum of patients developing severe septic shock than in those with uncomplicated sepsis. Serum levels of Ang-2, HBP, and PCT were closely associated with the sequential organ failure assessment (SOFA) score of the patients. ConclusionsThese findings indicated that sustained elevation of Ang-2, HBP, and PCT were associated with severe infection in critically ill patients.

The effects of the herbal medicine Daikenchuto (TJ-100) after esophageal cancer resection, open-label, randomized controlled trial

BackgroundDaikenchuto (TJ-100), a traditional Japanese herbal medicine, is widely used in Japan. Its effects on gastrointestinal motility and microcirculation and its anti-inflammatory effect are known. The purpose of this prospective randomized controlled trial was to investigate the effect of TJ-100 after esophagectomy in esophageal cancer patients.MethodsForty patients for whom subtotal esophageal resection for esophageal cancer was planned at our institute from March 2011 to August 2013 were enrolled and divided into two groups at the point of determination of the operation schedule after informed consent was obtained: a TJ-100 (15 g/day)-treated group (n = 20) and a control group (n = 20). The primary efficacy end-points were maintenance of the nutrition condition and the recovery of gastrointestinal function. The secondary efficacy end-points were the serum C-reactive protein (CRP) level and adrenomedullin level during the postoperative course, the incidence of postoperative complications, and the length of hospital stay after surgery.ResultsWe examined 39 patients because one patient in the TJ-100 group was judged as having unresectable cancer after surgery. The mean age of the TJ-100 group patients was significantly older than that of the control group patients.The rate of body weight decrease at postoperative day 21 was significantly suppressed in the TJ-100 group (3.6% vs. the control group: 7.0%, p = 0.014), but the serum albumin level was not significantly different between the groups. The recovery of gastrointestinal function regarding flatus, defecation, and oral intake showed no significant between-group differences, but postoperative bowel symptoms tended to be rare in the TJ-100 group. There was no significant between-group difference in the length of hospital stay after surgery. The serum CRP level at postoperative day 3 was 4.9 mg/dl in the TJ-100 group and 6.9 mg/dl in the control group, showing a tendency of a suppressed serum CRP level in the TJ-100 group (p = 0.126). The rate of increase in adrenomedullin tended to be high postoperatively, but there was no significant difference between the two groups.ConclusionsTJ-100 treatment after esophageal cancer resection has the effects of prompting the recovery of gastrointestinal motility and minimizing body weight loss, and it might suppress the excess inflammatory reaction related to surgery.

Assessment of adrenomedullin and proadrenomedullin as predictors of mortality in septic patients: A systematic review and meta-analysis

ObjectiveTo ascertain the ability of adrenomedullin (ADM) and proadrenomedullin (proADM) to predict mortality in sepsis patients. DesignA systematic literature search was made of the PubMed, EMBASE, Cochrane and China National Knowledge Infrastructure (CNKI) databases before May 2017, supplemented by manual searches of references. A meta-analysis of high-quality clinical studies was subsequently performed to assess the association between ADM/proADM and mortality risk among patients with sepsis. PatientsThirteen studies involving 2556 patients were included in the study. InterventionsTwo reviewers independently identified articles, extracted data, assessed quality and cross-checked the results. The predictive values of ADM and proADM referred to mortality were assessed by relative risk (RR). The overall diagnostic accuracy of ADM and proADM in application to sepsis was pooled according to a bivariate model. Publication bias was assessed using Deek's funnel plot asymmetry test. ResultsElevated ADM or proADM levels were associated with increased mortality (pooled RR=3.31; 95%CI 2.31–4.75). Subgroup analyses indicated the pooled RRs were 3.12 (95%CI 1.75–5.56) and 3.43 (95%CI 2.21–5.31) for ADM and proADM, respectively. The pooled sensitivity and specificity were 0.72 (95%CI 0.64–0.78) and 0.77 (95%CI 0.69–0.83), respectively. The overall area under the summary receiver operating characteristic (SROC) curve was 0.80 (95%CI 0.77–0.84). Publication bias was not statistically significant. ConclusionsBoth ADM and proADM might serve as useful markers for predicting the prognosis of sepsis.

Adrenomedullin Contributes to Age-Related Memory Loss in Mice and Is Elevated in Aging Human Brains.

Memory decline is common in elderly individuals and is the hallmark of Alzheimer’s disease (AD). Memory failure follows the loss of synaptic contacts in the cerebral cortex and hippocampus, caused in part by cytoskeleton disruption. Adrenomedullin (AM) and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), are microtubule-associated proteins (MAP) whose expression has been identified as a potential biomarker for predicting progression from predementia to clinical AD. Here we analyze the connection between AM levels and memory preservation. Mice lacking neuronal AM and PAMP (knockout, KO) and their wild type (WT) littermates were subjected, at different ages, to the novel object recognition test and the contextual fear conditioned test. Aged KO mice have significantly better retention memory than their WT counterparts. This feature was more prominent in females than in males. Prefrontal cortex and hippocampus samples from these animals were subjected to Western blotting for phospho-Tau and acetylated tubulin. Aged female KO mice had significantly less accumulation of phospho-Tau than their WT littermates. In addition, protein extracts from the frontal cortex of non-demented mature (65.10 ± 3.86 years) and aged (77.14 ± 2.77 years) human donors were analyzed by Western blotting. Aged human brains had significantly higher levels of AM and lower levels of acetylated tubulin than younger donors. These observations suggest that drugs or interventions that reduce AM/PAMP expression may constitute a new avenue to prevent memory decline during normal aging and in patients suffering moderate AD in high risk of rapid cognitive decline.

Human Milk Adrenomedullin Is Unstable During Cold Storage at 4°C

Under some circumstances human milk (HM) extraction and refrigerated storage may be necessary. Depending on the length and on the type of cold storage, milk may lose some important properties, but current advices on safe HM storage are discordant. Moreover until now no data in literature were present on the effect of prolonged cold storage on biologically active components of the HM such as adrenomedullin (AM). This important peptide is involved in response to hypoxia and inflammation, associated with neovascularization, in several tissues. The aim is to evaluate: (a) the presence of AM in preterm and term HM and (b) the concentration of AM in refrigerated milk at 4°C at 24-hour intervals, up to 96 hours of storage. The experiment was repeated four times. Immediately after collection, each HM sample deriving from each mother was divided into two parts as follows: "Pool" line and "Single Mother" line. One part (Pool line) was pooled and then divided into five aliquots. The other part (Single Mother line) was divided into five aliquots. From each line, one aliquot was analyzed within 3 hours, while the others were stored in the refrigerator for 24, 48, 72, and 96 hours, respectively, and then analyzed. AM levels were determined using a specific ELISA test. AM was detectable in all samples. Its concentration was significantly higher in preterm milk with respect to term milk (p < 0.05). Significant differences were observed during the cold storage: the AM levels decreased steadily during the storage and the remaining concentration at 96 hours is ∼2%. This study provides evidences regarding the presence of AM in HM, regardless of the gestational age. In particular, the refrigeration of fresh HM in controlled conditions significantly affected its bioactivity and nutritional quality related with AM, already at 24 hours.

Increased Levels of Brain Adrenomedullin in the Neuropathology of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the loss of synaptic contacts caused in part by cytoskeleton disruption. Adrenomedullin (AM) is involved in physiological functions such as vasodilation, hormone secretion, antimicrobial activity, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins, causing microtubule destabilization. Here, we describe the relationships between AM and other signs of AD in clinical specimens. Frontal cortex from AD patients and controls were studied for AM, acetylated tubulin, NCAM, Ox-42, and neurotransmitters. AM was increased in AD compared with controls, while levels of acetylated tubulin, NCAM, and neurotransmitters were decreased. Interestingly, increases in AM statistically correlated with the decrease in these markers. Furthermore, Ox42 overexpression in AD correlated with levels of AM. It is proposed that AD patients may have neural cytoskeleton failure associated with increase of AM levels, resulting in axon transport collapse and synaptic loss. These observations suggest that reducing AM expression may constitute a new avenue to prevent/treat AD.