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Background Limited research studies with a large sample size were performed to evaluate the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) for in-hospital or long-term poor outcomes in patients with infective endocarditis. Methods A total of 703 patients with infective endocarditis were enrolled and divided into four groups according to admission NT-pro-BNP (pg/mL) quartiles: Q1 (258), Q2 (258-1054), Q3 (1055-3522) and Q4 (3522). Multivariate regression was used to determine independent risk of NT-proBNP for in-hospital and one-year death. Results In-hospital death occurred in 9.0% of patients. The in-hospital mortality was increased from the lowest to the highest NT-proBNP quartiles (1.1%, 3.4%, 9.1% and 22.3%, P 0.001, respectively). During the one-year follow-up period, 29 patients died: 0 in Q1, 7 (4.6%) in Q2, 8 (5.7%) in Q3 and 14 (12.0%) in Q4 ( P 0.001). Log-transformed (lg) NT-proBNP had a linear correlation with lg C-reactive protein ( r = 0.308, P 0.001). Multivariate analysis showed lgNT-proBNP was an independent predictor for both in-hospital (odds ratio 4.59, 95% confidence interval (CI) 2.45-8.61, P 0.001) and one-year mortality (hazard ratio 3.11, 95% CI 1.65-5.87, P 0.001). In addition, NT-proBNP had a higher predictive power for in-hospital death than C-reactive protein (area under the curve 0.797 vs. 0.670, P = 0.005). NT-proBNP 2260 pg/mL had 76.2% sensitivity and 69.1% specificity for predicting in-hospital death. Kaplan-Meier analysis showed that patients with NT-proBNP 2260 pg/ml had a worse prognosis than those without (log-rank test 18.84, P 0.001). Conclusion Increased NT-proBNP was independently associated with in-hospital and one-year mortality in patients with infective endocarditis.

Background/Aim. Patients with chronic renal failure (CRF) have increased cardiovascular morbidity and mortality. It is unknown which biomarkers best describe the degree of diastolic dysfunction in patients with CRF. The aim of this study was to determine the correlation between B-type natriuretic peptide (BNP), N-terminal prohormone brain natriuretic peptide (NTproBNP) and left ventricular diastolic dysfunction (DD-LV) with the degree of CRF. Methods. The study included 100 adult patients with CRF without major cardiac and cerebral incidents who did not start actively treating CRF. According to the degree of CRF, the patients were divided into two groups: G1 (moderate degree), glomerular filtration rate (GFR) ? 30 mL/min/1.73 m2, and G2 (more severe degree), GFR < 30 mL/min/1.73 m2. Blood concentrations of BNP and NTproBNP were measured and Doppler echocardiographic measurement performed to estimate diastolic dysfunction (DD-LV). According to the degree of DD-LV, all the patients were divided into two groups: DD-LV1 (mild diastolic dysfunction) and DD-LV2 (severe diastolic dysfunction). According to the degree of CRF and DD-LV, the patients were divided into four groups: I (G1, DD-LV1), II (G1, DD-LV2), III (G2, DD-LV1) and IV (G2, DD-LV2). Results. There was a highly significant statistical correlation between BNP and NTproBNP with GFR (p < 0.001), and DD-LV with BNP (p < 0.023) and NTproBNP (p = 0.035). In patients with DD-LV2, a statistically significantly higher BNP concentrations were registered in patients with G2 (p < 0.001). Unlike BNP in the patients with diastolic dysfunction DD-LV1 and those with diastolic dysfunction DD-LV2, significantly higher concentrations of NTproBNP were registered in the patients with G2 (DD- LV1: p = 0.006; DD-LV2: p < 0.001). Conclusion. Biomarkers BNP and NTproBNP are not the best predictors in the assessment of diastolic dysfunction because they are correlated with the degree of renal insufficiency.

Background: The N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) is a powerful predictor of adverse outcomes in patients with coronary artery disease (CAD). However, little is known regarding the prognostic significance of longitudinal changes in NT-proBNP levels. Methods: We evaluated the ability of 5-year changes in NT-proBNP levels to predict subsequent heart failure (HF) hospitalization or cardiovascular (CV) death in 635 participants with stable CAD enrolled in the Heart and Soul Study. Results: The median (IQR) 5-year change in NT-proBNP was 50 pg/mL (-5 to +222). During an average of 4.0 ± 1.4 years follow-up (i.e., 9 years from the baseline measurement), there were 67 events. Participants with 5-year changes in the highest quartile (≥ 223 pg/mL increase in NT-proBNP) had an almost 4-fold greater risk of subsequent HF or CV death than those in the lowest quartile of ≤-5 pg/mL (HR 3.8; 95% CI 2.0-7.3; p < 0.001). This association remained strong after adjustment for demographic variables, comorbidities, left ventricular mass index, systolic and diastolic function, and baseline and follow-up NT-proBNP levels (HR 3.9; 95% CI 1.1-13.4; p = 0.01). Conclusion: Changes in NT-proBNP levels at 5 years predict subsequent HF or CV death in patients with stable CAD, independent of other prognostic markers, including baseline and follow-up NT-proBNP levels. A stable NT-proBNP level predicts a low risk of subsequent events.

Herein, we report on an 82-year-old woman who presented with anorexia. The patient had hyponatremia with preserved urinary osmotic pressure. T1-weighted magnetic resonance imaging (MRI) showed a lack of high signal intensity (SI) in the posterior pituitary lobe. Based on the patient's high levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP), heart failure was suspected. The heart failure may have caused arginine vasopressin (AVP) secretion. The depletion of AVP secretory granules may therefore cause the posterior pituitary gland to disappear on T1-weighted MRI.

A contributor to beta cell failure in type 2 diabetes and islet transplants is amyloid formation by aggregation of the beta cell peptide, islet amyloid polypeptide (IAPP). Similar to the proinsulin processing pathway that generates insulin, IAPP is derived from a prohormone precursor, proIAPP, which requires cleavage by prohormone convertase (PC) 1/3 and PC2 in rodent pancreatic beta cells. We hypothesised that loss of PC2 would promote beta cell death and dysfunction in a rodent model of human beta cell proIAPP overexpression. We generated an islet transplant model wherein immune-deficient mouse models of diabetes received islets expressing amyloidogenic human proIAPP and lacking PC2, leading to restoration of normoglycaemia accompanied by increased secretion of human proIAPP. Blood glucose levels were analysed for up to 16 weeks in transplant recipients and grafts were assessed for islet amyloid and beta cell number and death. Hyperglycaemia (blood glucose >16.9 mmol/l) returned in 94% of recipients of islets expressing human proIAPP and lacking PC2, whereas recipients of islets that express human proIAPP and normal PC2 levels remained normoglycaemic for at least 16 weeks. Islet graft failure was accompanied by a ∼20% reduction in insulin-positive cells, yet the degree of amyloid deposition and beta cell apoptosis was similar to those of controls expressing human proIAPP with functional PC2 levels. PC2 deficiency in transplanted mouse islets expressing human proIAPP promotes beta cell loss and graft failure. Our data suggest that impaired NH2-terminal processing and increased secretion of human proIAPP promote beta cell failure.

Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell–derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p–/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p–/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p–/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH–releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.

Aim We analyzed atrial natriuretic peptide (ANP), N-terminal pro-brain natriuretic natriuretic peptide (NT-proBNP) and vector synthesis high-resolution electrocardiography (ECG), to estimate cardiac load with circulatory dynamic change from pregnancy through the post-partum period. Methods The subjects were singleton pregnant women (n = 19), who were divided into three stages: stage 1, 34–36 weeks of gestation; stage 2, 2–6 post-partum days; and stage 3, 1–3 months after delivery. Vector synthesis high-resolution ECG, ANP and NT-proBNP were analyzed for all subjects. Results A pregnant woman with massive uterin liomyoma expressed largest the corrected recover time (RTc) dispersion in I + II of tow Dimensional (2D) color distribution map ANP and NT-proBNP were significantly higher in stage 2 than in stages 1 and 3. Conclusions ANP, NT-proBNP and vector synthesis high-resolution ECG there might be able to evaluate cardiac load of normal pregnancy.

Maternal thyroid hormones (THs) are known to be crucial in embryonic development in humans, but their influence on other, especially wild, animals remains poorly understood. So far, the studies that experimentally investigated the consequences of maternal THs focused on short-term effects, while long-term organisational effects, as shown for other prenatal hormones, could also be expected. In this study, we aimed at investigating both the short- and long-term effects of prenatal THs in a bird species, the Japanese quail Coturnix japonica . We experimentally elevated yolk TH content (the prohormone T 4 , and its active metabolite T 3 , as well as a combination of both hormone) We analysed hatching success, embryonic development, offspring growth and oxidative stress as well as their potential organisational effects on reproduction, moult, and oxidative stress in adulthood. We found that eggs injected with both hormones had a higher hatching success compared with control eggs, suggesting conversion of T 4 into T 3 by the embryo. We detected no other short-term or organisational effects of yolk THs. Unfortunately, sex-specific responses could not be properly tested due to low sample sizes. These results suggest that yolk thyroid hormones are important in the embryonic stage of precocial birds, but may not have other short and long-term consequences, at least not in captivity. Research on maternal thyroid hormones will greatly benefit from studies investigating how embryos use and respond to this maternal signalling. Long-term studies on prenatal THs in other taxa in the wild are needed for a better understanding of this hormone-mediated maternal pathway. Summary statement Thyroid hormones are important hormones in all vertebrates, although overlooked in the context of maternal effect. We found short-term effects of prenatal THs but no evidence of programming effects.

The cardiac function critically depends on an adequate myocardial oxygenation and on a correct coronary blood flow. Endothelial, hormonal and extravascular factors work together generating a fine balance between oxygen supply and oxygen utilization through the coronary circulation. Among the regulatory factors that contribute to the coronary tone, increasing attention is paid to the cardiac endocrines, such as chromogranin A, a prohormone for many biologically active peptides, including vasostatin and catestatin. In this review, we will summarize the available evidences about the coronary effects of these molecules, and their putative mechanism of action. Laboratory and clinical data on chromogranin A and its derived fragments will be analyzed in relation to the scenario of the endocrine heart, and of its putative clinical perspectives.

BACKGROUND: Vitamin D (VitD) has important prohormone functions in a wide range of clinical processes. Although it is known that individuals with VitD deficiency have cardiac autonomic dysfunction, there are no convincing data regarding the effect of VitD replacement. We aimed to evaluate the impact of VitD replacement on cardiac autonomic dysfunction. METHODS: Fifty‐two apparently healthy subjects with VitD deficiency and 50 healthy control subjects were enrolled. Prior to VitD replacement, 24‐hr Holter recordings were obtained, and HRV parameters were recorded. VitD levels were measured 2 months later after replacement, and control 24‐hr Holter recordings were analyzed. RESULTS: The mean age of the patients was 36.04 ± 7.6 years, and 53.9% were female. SDNN (68.58 ± 13.53 vs. 121.02 ± 27.45 ms, p = .001), SDANN (95.96 ± 22.26 vs. 166.48 ± 32.97 ms, p = .001), RMSSD (23 vs. 59 ms, p

BackgroundThe double-blind OMEGA-REMODEL placebo-controlled randomized trial of high-dose omega-3 fatty acids (O-3FA) post-acute myocardial infarction (AMI) reported improved cardiac remodeling and attenuation of non-infarct myocardial fibrosis. Fatty acid desaturase 2 (FADS2) gene cluster encodes key enzymes in the conversion of essential omega-3 and omega-6 fatty acids into active arachidonic (ArA) and eicosapentaenoic acids (EPA), which influence cardiovascular outcomes.Methods and resultsWe tested the hypothesis that the genotypic status of FADS2 (rs1535) modifies therapeutic response of O-3FA in post-AMI cardiac remodeling in 312 patients. Consistent with known genetic polymorphism of FADS2, patients in our cohort with the guanine-guanine (GG) genotype had the lowest FADS2 activity assessed by arachidonic acid/linoleic acid (ArA/LA) ratio, compared with patients with the adenine-adenine (AA) and adenine-guanine (AG) genotypes (GG:1.62±0.35 vs. AA: 2.01±0.36, pConclusionGenetic profiling using FADS2 genotype can predict the therapeutic benefits of O-3FA treatment against adverse cardiac remodeling during the convalescent phase of AMI.Clinical trial registration informationclinicaltrials.gov Identifier: NCT00729430.

Purpose To evaluate the relationship of lipocalin 2 to inflammation and cardiac injury with increased aldosterone in human immunodeficiency virus (HIV). Methods A standardized 6-day low-sodium diet was used to stimulate renin-angiotensin-aldosterone system (RAAS) activation, and serum lipocalin 2 and biomarkers of inflammation and cardiac stretch were assessed among persons with or without HIV. Results Lipocalin 2 levels increased with RAAS activation compared with suppression in the HIV group (median level [interquartile range], 71.3 [59.2–99.7] vs 67.0 [51.8–86.3] ng/mL; P = .01). During RAAS activation, lipocalin 2 was related to biomarkers of inflammation (tumor necrosis factor α [P = .007]), monocyte/macrophage activation (soluble CD163 [P = .005] and chemokine [C-C motif] ligand 2 [P = .03]), and markers of cardiac stretch (brain natriuretic peptide [P < .001] and N-terminal fragment of the prohormone brain natriuretic peptide [P = .001]) in HIV. Conclusion Lipocalin 2 may be important in modulating aldosterone-induced inflammation, monocyte activation, and cardiac stretch during RAAS activation in HIV. Clinical Trial Registration NCT01407237

Significance The plant hormone auxin coordinates almost all aspects of plant development. Throughout plant life, the expression of hundreds of genes involved in auxin regulation is orchestrated via several combinatorial and cell-specific auxin perception systems. An effective approach to dissect these complex pathways is the use of synthetic molecules that target specific processes of auxin activity. Here, we describe synthetic auxins, RubNeddins (RNs), which act as selective auxin agonists. The RN with the greatest potential for dissecting auxin perception was RN4, which we used to reveal a role for the chromatin remodeling ATPase BRAHMA in apical hook development. Therefore, the understanding of RN mode of action paves the way to dissecting specific molecular components involved in auxin-regulated developmental processes., Auxin phytohormones control most aspects of plant development through a complex and interconnected signaling network. In the presence of auxin, AUXIN/INDOLE-3-ACETIC ACID (AUX/IAA) transcriptional repressors are targeted for degradation by the SKP1-CULLIN1-F-BOX (SCF) ubiquitin-protein ligases containing TRANSPORT INHIBITOR RESISTANT 1/AUXIN SIGNALING F-BOX (TIR1/AFB). CULLIN1-neddylation is required for SCFTIR1/AFB functionality, as exemplified by mutants deficient in the NEDD8-activating enzyme subunit AUXIN-RESISTANT 1 (AXR1). Here, we report a chemical biology screen that identifies small molecules requiring AXR1 to modulate plant development. We selected four molecules of interest, RubNeddin 1 to 4 (RN1 to -4), among which RN3 and RN4 trigger selective auxin responses at transcriptional, biochemical, and morphological levels. This selective activity is explained by their ability to consistently promote the interaction between TIR1 and a specific subset of AUX/IAA proteins, stimulating the degradation of particular AUX/IAA combinations. Finally, we performed a genetic screen using RN4, the RN with the greatest potential for dissecting auxin perception, which revealed that the chromatin remodeling ATPase BRAHMA is implicated in auxin-mediated apical hook development. These results demonstrate the power of selective auxin agonists to dissect auxin perception for plant developmental functions, as well as offering opportunities to discover new molecular players involved in auxin responses.

Carboxypeptidase E, also known as neurotrophic factor-α1 (CPE-NFα1), was first discovered as an exopeptidase and is known to work by cleaving C-terminal basic amino acids from prohormone intermediates to produce mature peptide hormones and neuropeptides in the endocrine and central nervous systems, respectively. CPE-NFα1 also plays a critical role in prohormone sorting and secretory vesicle transportation. Recently, emerging studies have indicated that CPE-NFα1 exerts multiple non-enzymatic physiological roles in maintaining normal central nervous system function and in neurodevelopment. This includes potent neuroprotective and anti-depressant activities, as well as stem cell differentiation functions. In addition, N-terminal truncated variants of CPE-NFα1 have been identified to regulate expression of important neurodevelopmental genes. This mini-review summarizes recent advances in understanding the mechanisms underlying CPE-NFα1’s function in neuroprotection during stress and aspects of neurodevelopment.

We recently described the persistence of detectable serum proinsulin in a large majority of individuals with longstanding type 1 diabetes (T1D), including individuals with undetectable serum C-peptide. Here, we sought to further explore the mechanistic etiologies of persistent proinsulin secretion in T1D at the level of the islet, using tissues obtained from human donors. Immunostaining for proinsulin and insulin was performed on human pancreatic sections from the Network for Pancreatic Organ Donors with Diabetes (nPOD) collection (n = 24). Differential proinsulin processing enzyme expression was analyzed using mass spectrometry analysis of human islets isolated from pancreatic sections with laser capture microdissection (n = 6). Proinsulin processing enzyme mRNA levels were assessed using quantitative real-time PCR in isolated human islets (n = 10) treated with or without inflammatory cytokines. Compared to nondiabetic controls, immunostaining among a subset (4/9) of insulin positive T1D donor islets revealed increased numbers of cells with proinsulin-enriched, insulin-poor staining. T1D donor islets also exhibited increased proinsulin fluorescence intensity relative to insulin fluorescence intensity. Laser capture microdissection followed by mass spectrometry revealed reductions in the proinsulin processing enzymes prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE) in T1D donors. Twenty-four hour treatment of human islets with inflammatory cytokines reduced mRNA expression of the processing enzymes PC1/3, PC2, and CPE. Taken together, these data provide new mechanistic insight into altered proinsulin processing in long-duration T1D and suggest that reduced β cell prohormone processing is associated with proinflammatory cytokine-induced reductions in proinsulin processing enzyme expression.

Insulin is first produced in pancreatic β-cells as the precursor prohormone proinsulin. Defective proinsulin processing has been implicated in the pathogenesis of both type 1 and type 2 diabetes. Though there is substantial evidence that mouse β-cells process proinsulin using prohormone convertase 1/3 (PC1/3) and then prohormone convertase 2 (PC2), this finding has not been verified in human β-cells. Immunofluorescence with validated antibodies revealed that there was no detectable PC2 immunoreactivity in human β-cells and little PCSK2 mRNA by in situ hybridization. Similarly, rat β-cells were not immunoreactive for PC2. In all histological experiments, PC2 immunoreactivity in neighboring α-cells acted as a positive control. In donors with type 2 diabetes, β-cells had elevated PC2 immunoreactivity, suggesting that aberrant PC2 expression may contribute to impaired proinsulin processing in β-cells of patients with diabetes. To support histological findings using a biochemical approach, human islets were used for pulse-chase experiments. Despite inhibition of PC2 function by temperature blockade, brefeldin A, chloroquine, and multiple inhibitors that blocked production of mature glucagon from proglucagon, β-cells retained the ability to produce mature insulin. Conversely, suppression of PC1/3 blocked processing of proinsulin but not proglucagon. By demonstrating that healthy human β-cells process proinsulin by PC1/3 but not PC2, we suggest that there is a need to revise the long-standing theory of proinsulin processing.

Background: Cardiac resynchronization therapy (CRT) is a valuable intracardiac device-based treatment option for a subgroup of patients with advanced heart failure (HF) and QRS prolongation. However, still a significant proportion of patients do not benefit from CRT implantation, labeled as non-responders. Objectives: The aim of the present study was to evaluate the N-terminal prohormone of brain natriuretic peptide (NT-pro BNP) and high sensitivity troponin T (cTnThs) value as predictors of CRT response in a 12-month observation. Materials and Methods: The study included 46 patients with HF and implanted CRT-D. Levels of NT-pro BNP and cTnThs were assessed during a 12 month follow up. Results: 46 consecutive patients (76% men) with a mean age of 64±8 were observed for 12 months. The CRT response criteria was met by 26 patients (56,5%). A significant decline in the NT-pro BNP concentrations was documented in responders (p=0.001). Moreover, ΔNT-pro BNP by at least 579 pg/ml had high sensitivity and specificity for identifying the CRT responders. There were no statistically significant differences in the results of cTnThs between the two study groups. Conclusion: The relative change in the level of NT-pro BNP by at least 43,5% allows to identify the responders to CRT after 12 months of follow-up. Serial measurements of NT-pro BNP can be a valuable tool for monitoring the effectiveness of CRT.

Pro-opiomelanocortin (POMC) is a member of prohormone family and has important functions in stress response, skin pigmentation, thermoregulation and reproduction. In this study, the single nucleotide polymorphisms (SNPs) of POMC gene exons were detected by direct sequencing in 317 Zhenning yellow chickens. The sequencing results indicated there were seven mutation sites (g.1140C T, g.1185 T C, g.2085 T C, g.3566A C, g.3572 G A, g.3594 G A and g.3628 G A) and all of these were synonymous. Furthermore, seven haplotypes were formed and sixteen diplotypes were obtained. The associations between the POMC gene polymorphisms or diplotypes and reproduction traits were also analyzed. The association analysis results indicated that the SNP of g.1140C T was associated with egg production at 300 d of age (E300), fertilization rate (FR), hatching rate of hatching eggs (HEHR) and hatching rate of fertilized eggs (FEHR; P 0.05). The SNP of g.3566AC was associated with FR (P 0.05), SNP of g.3594GA was associated with egg weight at 300d of age (EW300; P 0.05), and SNP of g.3628GA was associated with HEHR and FEHR (P 0.01), respectively. Furthermore, chickens with H2H3 diplotype had greater EW300 and FR than those with H1H7 and H3H4 diplotypes (P 0.05). These results indicate the expression of the POMC gene had significant genotype effects on the reproduction traits of Zhenning yellow chickens, and that the H2H3 diplotype could be used as a potential genetic marker to improve the reproduction traits in chicken breeding.

Aim: The usefulness of N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) as a predictor of perioperative hemodynamic instability is not fully elucidated. Methods: This prospective study was conducted on a group of 455 patients undergoing elective heart valve surgery. The primary end point at the 30-day follow-up was postoperative hemodynamic instability. The secondary end point was death from all causes in patients with postoperative hemodynamic instability. Results: The postoperative hemodynamic instability occurred in 85 patients. At multivariate analysis NT-proBNP, New York Heart Association classes and glomerular filtration rate remained independent predictors of the primary end point. Age and NT-proBNP were associated with an increased risk of death. Conclusion: The preoperative NT-proBNP can be used to predict a postoperative hemodynamic instability as well as death in the group of patients with postoperative hemodynamic instability.

Changes in the levels of serum creatinine and N-terminal of prohormone brain natriuretic peptide (NT-proBNP) are useful risk markers after cardiac resynchronization therapy (CRT). The diagnostic value of changes in serum uric acid levels has been established in chronic heart failure, but no data are available on the prognostic value of hyperuricemia in a CRT population.We measured markers of renal function [creatinine, blood urea nitrogen (BUN) and uric acid] and NT-proBNP levels of 129 heart failure patients undergoing CRT in a prospective, observational study. The 5-year all-cause mortality and the 6-month clinical response (≥ 15% increase in the left ventricular ejection fraction) were considered as study end points.In multivariable analyses, the uric acid was found to be a statistically significant predictor of the outcome. Uric acid levels exceeding 386 mmol/L before CRT increased the chances of mortality [n = 55, hazard ratio = 2.39 (1.30-4.39), p 0.01] and poor clinical response [n = 37, odds ratio = 2.89 (1.22-6.87), p = 0.01] independently of serum NT-proBNP and other factors.Elevated uric acid concentrations in patients with CRT are associated with an increased risk of mortality and poor clinical response independently of the NT-proBNP levels and other relevant clinical factors.

The tasks of the thyroid gland comprise (1) thyroid hormone (TH) generation via synthesis of the prohormone thyroglobulin (Tg), (2) import and organification of iodine resulting in the generation of preformed TH bound to Tg, (3) Tg storage in covalently cross-linked form in the extracellular follicle lumen, (4) TH demand-driven solubilization of Tg from its storage forms, (5) proteolytic processing of Tg for TH liberation by extra- and intracellular means, (6) complete degradation of Tg upon its re-internalization, and (7) TH release into the bloodstream. Therefore, this chapter focuses on thyroid cell biology and describes how classical thyroid hormones are generated, liberated, and released from thyroid follicles.

Patients with a recent coronary event are at high risk of further cardiovascular events, including hospitalization for heart failure (HFH).1,2 Knowledge of the pathophysiological changes preceding HFH provides insight into the temporal course of the progression of HF and may help identify those at imminent risk of this event. B-type natriuretic peptide (BNP) and NT-proBNP (N-terminal prohormone BNP) change rapidly in relation to changes in filling pressures and wall stress, making them useful for monitoring clinical status and response to treatment and clinical status in HF.3 Because there are limited data on temporal changes in natriuretic peptides (NPs) preceding HFH, we examined concentrations of NPs preceding HFH in patients with a recent coronary event and type 2 diabetes mellitus enrolled in the ELIXA trial [Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide); NCT01147250]. The design and primary findings of ELIXA have been published.4 A total of 6068 patients with type 2 diabetes mellitus and an acute coronary syndrome (index event) occurring within 180 days of randomization were enrolled. The trial was designed to assess the efficacy and safety of lixisenatide, a glucagon-like peptide-1 receptor agonist, with respect to cardiovascular morbidity and mortality.5 Sampling of BNP and NT-proBNP occurred at baseline and at weeks 24, 76, and 108 after randomization, yielding 19 585 samples. Samples were collected and analyzed at a core laboratory (Covance Central Laboratory Services, Meyrin, Switzerland). ELIXA was approved by appropriate institutional or central review boards. All participants provided …

Insulin gene coding sequence mutations are known to cause mutant INS-gene-induced diabetes of youth (MIDY), yet the cellular pathways needed to prevent misfolded proinsulin accumulation remain incompletely understood. Here, we report that Akita mutant proinsulin forms detergent-insoluble aggregates that entrap wild-type (WT) proinsulin in the endoplasmic reticulum (ER), thereby blocking insulin production. Two distinct quality-control mechanisms operate together to combat this insult: the ER luminal chaperone Grp170 prevents proinsulin aggregation, while the ER membrane morphogenic protein reticulon-3 (RTN3) disposes of aggregates via ER-coupled autophagy (ER-phagy). We show that enhanced RTN-dependent clearance of aggregated Akita proinsulin helps to restore ER export of WT proinsulin, which can promote WT insulin production, potentially alleviating MIDY. We also find that RTN3 participates in the clearance of other mutant prohormone aggregates. Together, these results identify a series of substrates of RTN3-mediated ER-phagy, highlighting RTN3 in the disposal of pathogenic prohormone aggregates.

Sepsis remains the leading cause of mortality and critical illness worldwide. Myocardial dysfunction is one of the most clinically relevant manifestations of sepsis and results from a complex interaction among genetic, molecular, metabolic, and structural changes. Despite the prominence given to the occurrence of systolic dysfunction during sepsis, the association between diastolic dysfunction and mortality is controversial, while diastolic dysfunction and right ventricular dysfunction are identified as independent predictors of mortality in the most recent studies. Elevation of biomarkers during sepsis may result from several mechanisms, and although the role of the B-type natriuretic peptide (BNP) and the N-terminal portion of its prohormone (NT-proBNP) as independent predictors of mortality is well defined, the same cannot be said about cardiac troponins due to conflicting results among currently available studies. The objective of the present review is to discuss the pathophysiological mechanisms of myocardial dysfunction induced by sepsis in adults and the role of echocardiography and cardiac biomarkers as tools for prognostic evaluation in this clinical setting.

In the context of genomic thyroid hormone actions in normal (noncancer) cells that involve primary interactions with nuclear thyroid hormone receptors (TRs), L-thyroxine (T4), and 3,3',5'-triiodo-L-thyronine (reverse T3, rT3) have little bioactivity. In terms of TRs, T4 is a prohormone from which the active nuclear ligand, 3,5,3'-triido-L-thyronine (T3), is generated by deiodination. Deaminated T4 and T3 metabolites have different genomic effects: tetraiodothyroacetic acid (tetrac) is a low grade thyromimetic derivative of T4, whereas triiodothyroacetic acid (triac), the acetic acid metabolite of T3, has substantial thyromimetic activity. In cancer cells, the cell surface receptor for thyroid hormone on integrin αvβ3 mediates non-genomic actions of thyroid hormone analogs. The integrin is expressed in large measure by cancer cells and dividing endothelial cells and has a substantially different panel of responses to thyroid hormone analogs. At αvβ3, T4 is a potent proliferative, anti-apoptotic and pro-angiogenic hormone and is the primary ligand. rT3 may also be proliferative at this site. In contrast, tetrac and triac are antagonists of T4 at αvβ3, but also have anticancer properties at this site that are independent of their effects on the binding of T4.

Proinsulin was first identified as the primary translation product of the insulin gene in Donald Steiner's laboratory in 1967, and was the first prohormone to be isolated and sequenced. While its role as an insulin precursor has been extensively studied in the field of endocrinology, the bioactivity of the proinsulin molecule itself has received much less attention. Insulin binds to isoforms A and B of the insulin receptor (IR) with high affinity. Proinsulin, in contrast, binds with high affinity only to IR-A, which is present in the nervous system, among other tissues and elicits antiapoptotic and neuroprotective effects in the developing and postnatal nervous system. Proinsulin specifically exerts neuroprotection in the degenerating retina in mouse and rat models of retinitis pigmentosa (RP), delaying photoreceptor and vision loss after local administration in the eye or systemic (intramuscular) administration of an adeno-associated viral (AAV) vector that induces constitutive proinsulin release. AAV-mediated proinsulin expression also decreases the expression of neuroinflammation markers in the hippocampus and sustains cognitive performance in a mouse model of precocious brain senescence. We have therefore proposed that proinsulin should be considered a functionally distinct member of the insulin superfamily. Here, we briefly review the legacy of Steiner's research, the neural expression of proinsulin, and the tissue expression patterns and functional characteristics of IR-A. We discuss the neuroprotective activity of proinsulin and its potential as a therapeutic tool in neurodegenerative conditions of the central nervous system, particularly in retinal dystrophies.

The prevalence of neurocognitive deficits remains high in patients with stage 5 chronic kidney disease (CKD5D). Major contributors to such deficits include stroke, cervical carotid artery disease (CCAD), and intracranial atherosclerotic disease (ICAD). The risk of developing these dysfunctional vascular processes is facilitated by the chronic inflammation associated with renal failure. Plasma levels of 10 circulating biomarkers in patients with CKD5D (n = 78-90) were quantified using the sandwich enzyme linked immune sorbent assay method. Biomarkers for this study included kidney injury molecule-1, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), neutrophil gelatinase-associated lipocalin, interleukin-18, endothelin 1, calcifediol, parathyroid hormone, platelet-derived growth factor, microparticles-expressing tissue factor, and lipoprotein(a) (Lp(a)). Of the 90 patients with CKD5D, 30 had CCAD, 24 had ICAD, and 22 had stroke. Lp(a) level was significantly elevated in patients with CKD5D with comorbid ICAD compared to those without (125.70 ± 10.03 ng/mL vs 97.16 ± 5.97 ng/mL; P = .0065). NT-proBNP level was also significantly elevated in patients with CKD5D with comorbid stroke diagnosis compared to those without stroke history, once patients with a diagnosis of heart failure (HF) were excluded (14.84 ± 2.80 ng/mL vs 9.06 ± 1.27 ng/mL; P = .0283). Profiling levels of Lp(a) and NT-ProBNP could thus be useful in the risk stratification of ICAD and stroke, respectively, in the CKD5D population.

BackgroundCardiac amyloidosis (CA) is a life-threatening restrictive cardiomyopathy. Identifying patients with a poor prognosis is essential to ensure appropriate care. The aim of this study was to compare myocardial work (MW) indices with standard echocardiographic parameters in predicting mortality among patients with CA.MethodsClinical, biological and transthoracic echocardiographic parameters were retrospectively compared among 118 patients with CA. Global work index (GWI) was calculated as the area of left ventricular pressure–strain loop. Global work efficiency (GWE) was defined as percentage ratio of constructive work to sum of constructive and wasted works. Sixty-one (52%) patients performed a cardiopulmonary exercise.ResultsGWI, GWE, global longitudinal strain (GLS), left ventricular ejection fraction (LVEF) and myocardial contraction fraction (MCF) were correlated with N-terminal prohormone brain natriuretic peptide (R=−0.518, R=−0.383, R=−0.553, R=−0.382 and R=−0.336, respectively; pConclusionIn CA population, MW indices are well correlated with known prognosis markers and are better than LVEF and MCF in predicting mortality. However, MW does not perform better than GLS.

We aimed to investigate the effects of thyroid hormone withdrawal on N-terminal prohormone forms of atrial natriuretic peptide (NT-proANP) and brain natriuretic peptide (NT-proBNP) during radioiodine therapy in female patients with differentiated thyroid cancer (DTC).Serum concentrations of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), NT-proANP and NT-proBNP were measured in 51 female patients with DTC (48.7 ± 4.2 years) at three time-points: day of radioiodine therapy (t1 - under acute hypothyroidism), 5 days after radioiodine (t2 - under acute hypothyroidism) and 3 months after radioiodine (t3 - under TSH suppression). Thirty healthy euthyroid women served as controls (42.8 ± 5.6 years).At t1/t2/t3, median NT-proANP was 5.2/1.7/487 pmol/L vs. 297.7 pmol/L in control group (p 0.001), median NT-proBNP was 50.1/36.5/79.5 pmol/L vs. 64.5 pmol/L (p 0.001) and median NT-proANP/NT-proBNP ratios was 0.20/0.18/4.81 vs. 4.14 (p 0.001). In acute hypothyroidism, FT3 levels were positively correlated with NT-proANP (r = 0.38, p = 0.005), NT-proANP/NT-proBNP ratios (r = 0.47, p = 0.001), heart rate (r = 0.39, p = 0.005), and negatively with mean arterial blood pressure (r = -0.58, p 0.001).Our results indicate that NT-proANP reflects more accurately direct thyroid hormone effects than NT-proBNP. Thyroid hormone-dependent hemodynamic effects seem to be overlapped on the direct stimulatory effect of thyroid hormones on NT-proANP secretion by cardiac myocytes.

Background Black populations exhibit lower concentrations of the cardioprotective peptide, insulin-like growth factor-1 (IGF-1), and are more prone to develop hypertensive heart disease than whites. We therefore determined whether lower IGF-1 in black individuals relates to a marker of cardiac overload and systolic dysfunction, namely N-terminal prohormone B-type natriuretic peptide (NT-proBNP). Materials and methods We included 160 black and 195 white non-diabetic South African men and women (aged 44.4 ± 9.81 years), and measured ambulatory blood pressure, NT-proBNP, IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3). Results Although the black group presented elevated ambulatory blood pressure accompanied by lower IGF-1 compared to the white group (all p

The aim of the experiment was to study the effect of exhaustive exercise on some cytokines and iron status parameters. We used 12 male, mongrel dogs divided into two groups – animals from experimental group were submitted to exercise at moderate intensity with exhaustion as the end-point; animals from control group did no exercise. Serum levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), hepcidin prohormone, serum iron (SI), total iron binding capacity (TIBC) and transferrin saturation (TS) were measured before exercise (BE), right after exercise (0 hour) and on 2, 4, 24, 48 and 72 hours after exercise. SI, TIBC and TS were measured also on day 7 and 14 after exercise. Serum levels of TNF-α increased after the exhaustive exercise. Serum levels of IL-6 demonstrated an increase at 0 hour, but increase was not statistically significant compared to BE level. Serum levels of hepcidin prohormone marked a slight increase 48 hours after the exercise, but change was insignificant. Levels of SI decreased on hour 72 (P

Biologically active vitamin D (1,25-dihydroxycholecalciferol or 1,25(OH)2D) is synthetized from inactive prohormone 25-hydroxycholecalciferol (25(OH)D) by the enzyme CYP27B1 1-α-hydroxylase in kidney and several extrarenal tissues including breast. Although the development of breast cancer has been linked to inadequate vitamin D status, the importance of bioactive vitamin D production within tumors themselves is not fully understood. To investigate the role of tumoral vitamin D production in mammary epithelial cell progression to breast cancer, we conducted a Cre-loxP-mediated Cyp27b1 gene ablation in the mammary epithelium of the polyoma middle T antigen-mouse mammary tumor virus (PyMT-MMTV) mouse breast cancer model. Targeted ablation of Cyp27b1 was accompanied by significant acceleration in initiation of spontaneous mammary tumorigenesis. In vivo, cell proliferation, angiogenesis, cell cycle progression, and survival markers were up-regulated in tumors by Cyp27b1 ablation, and apoptosis was decreased. AK thymoma (AKT) phosphorylation and expression of several components of nuclear factor κB (NF-κB), integrin, and signal transducer and activator of transcription 3 (STAT3) signaling pathways were increased in Cyp27b1-ablated tumors compared with nonablated controls. In vitro, 1,25(OH)2D treatment induced a strong antiproliferative action on tumor cells from both ablated and nonablated mice, accompanied by rapid disappearance of NF-κB p65 from the nucleus and segregation in the cytoplasm. In contrast, treatment with the metabolic precursor 25(OH)D was only effective against cells from nonablated mice. 25(OH)D did not inhibit growth of Cyp27b1-ablated cells, and their nuclear NF-κB p65 remained abundant. Our findings demonstrate that in-tumor CYP27B1 1-α-hydroxylase activity plays a crucial role in controlling early oncogene-mediated mammary carcinogenesis events, at least in part by modulating tumoral cell NF-κB p65 nuclear translocation.

Pro-opiomelanocortin (POMC) is a prohormone that encodes multiple smaller peptide hormones within its structure. These peptide hormones can be generated by cleavage of POMC at basic residue cleavage sites by prohormone-converting enzymes in the regulated secretory pathway (RSP) of POMC-synthesizing endocrine cells and neurons. The peptides are stored inside the cells in dense-core secretory granules until released in a stimulus-dependent manner. The complexity of the regulation of the biosynthesis, trafficking, and secretion of POMC and its peptides reflects an impressive level of control over many factors involved in the ultimate role of POMC-expressing cells, that is, to produce a range of different biologically active peptide hormones ready for action when signaled by the body. From the discovery of POMC as the precursor to adrenocorticotropic hormone (ACTH) and β-lipotropin in the late 1970s to our current knowledge, the understanding of POMC physiology remains a monumental body of work that has provided insight into many aspects of molecular endocrinology. In this article, we describe the intracellular trafficking of POMC in endocrine cells, its sorting into dense-core secretory granules and transport of these granules to the RSP. Additionally, we review the enzymes involved in the maturation of POMC to its various peptides and the mechanisms involved in the differential processing of POMC in different cell types. Finally, we highlight studies pertaining to the regulation of ACTH secretion in the anterior and intermediate pituitary and POMC neurons of the hypothalamus.

Tissue regeneration is a complex process that involves a mosaic of molecules that vary spatially and temporally. Insights into the chemical signaling underlying this process can be achieved with a multiplex and untargeted chemical imaging method such as mass spectrometry imaging (MSI), which can enable de novo studies of nervous system regeneration. A combination of MSI and multivariate statistics was used to differentiate peptide dynamics in the freshwater planarian flatworm Schmidtea mediterranea at different time points during cephalic ganglia regeneration. A protocol was developed to make S. mediterranea tissues amenable for MSI. MS ion images of planarian tissue sections allow changes in peptides and unknown compounds to be followed as a function of cephalic ganglia regeneration. In conjunction with fluorescence imaging, our results suggest that even though the cephalic ganglia structure is visible after 6 days of regeneration, the original chemical composition of these regenerated structures is regained only after 12 days. Differences were observed in many peptides, such as those derived from secreted peptide 4 and EYE53-1. Peptidomic analysis further identified multiple peptides from various known prohormones, histone proteins, and DNA- and RNA-binding proteins as being associated with the regeneration process. Mass spectrometry data also facilitated the identification of a new prohormone, which we have named secreted peptide prohormone 20 (SPP-20), and is up-regulated during regeneration in planarians.

Understanding the role of hypothalamic neuropeptides and hormones in energy balance is paramount in the search for approaches to mitigate the obese state. Increased hypothalamic-pituitary-adrenal axis activity leads to increased levels of glucocorticoids (GC) that are known to regulate body weight. The axis initiates the production and release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus. Levels of active CRH peptide are dependent on the processing of its precursor pro-CRH by the action of two members of the family of prohormone convertases 1 and 2 (PC1 and PC2). Here, we propose that the nutrient sensor sirtuin 1 (Sirt1) regulates the production of CRH post-translationally by affecting PC2. Data suggest that Sirt1 may alter the preproPC2 gene directly or via deacetylation of the transcription factor Forkhead box protein O1 (FoxO1). Data also suggest that Sirt1 may alter PC2 via a post-translational mechanism. Our results show that Sirt1 levels in the PVN increase in rats fed a high fat diet for 12 weeks. Furthermore, elevated Sirt1 increased PC2 levels, which in turn increased the production of active CRH and GC. Collectively, this study provides the first evidence supporting the hypothesis that PVN Sirt1 activates the hypothalamic-pituitary-adrenal axis and basal GC levels by enhancing the production of CRH through an increase in the biosynthesis of PC2, which is essential in the maturation of CRH from its prohormone, pro-CRH.

Objective The human prohormone chromogranin A (CHGA), an index member of the granin family is processed to generate catestatin, a peptide that is hypotensive in action and modulates catecholamine release within the sympathoadrenal system. Hypertensive patients with excess sympathetic activity have diminished catestatin. Often the study of physiological consequences of human genetic variation is confounded by elements such as other variations in obligatory linkage disequilibrium with the variant being studied. Also the phenotype of the variant may be influenced by genetic background that varies amongst individuals. This study addresses the effects of a human catestatin polymorphism (rs9658667) using humanized CHGA mouse models. Methods We created pertinent humanized mouse models wherein the mouse Chga gene locus was replaced by the human ortholog wild-type and the variant versions. This allowed for probing of the effects of catestatin variation in vivo with controls for other variations and global genetic background. Results Both the wild-type and variant human catestatin expressing mouse models were normotensive. The variant catestatin mouse model recapitulated physiological influence of the polymorphism on autonomic traits. These mice had diminished catecholamine, attenuated stress response and increased baroreceptor slopes that would suggest reduced risk of developing hypertension. Elevated plasma glucose, a trait observed in humans was not observed in mice expressing the variant catestatin. Conclusion This functional genomics approach of creating humanized mouse models to study rs9658667 polymorphism recapitulated and validated many of the human trait associations. This approach can also be applied in the study of other human gene polymorphisms.

Aim. To assess effects of quinapril on the regulatory-adaptive status (RAS) in patients with chronic heart failure (CHF) NYHA class 1 and arterial hypertension (HT). Material and methods. Patients (n=49) with CHF NYHA class I and HT stage I–II (25 men and 24 women, aged 52.5±8.4 years) were included into an open noncomparative study. A cardio-respiratory synchronization (CRS) test, 6 minute walk test, treadmill test with evaluation of the maximal oxygen uptake during exercise, ambulatory blood pressure monitoring, echocardiography , determination of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) plasma level were performed at baseline and after 6 months of quinapril therapy. Results. The quinapril treatment (average daily dose 17.3±7.9 mg) improved myocardium structural and functional parameters, increased the exercise tolerance, reduced neurohumoral activity , improved the RAS according to CRS test: increase in synchronization range of cardiorespiratory cycles per minute from 8.0±2.1 to 11.0±2.5 (Δ27.3%; p

The B-type natriuretic peptide prohormone (proBNP) is enzymatically cleaved into an inactive N-terminal peptide and a biologically active C-terminal peptide with many beneficial cardiorenal effects. The purpose of this study was to develop and test in cats with cardiomyopathy an immunoassay to quantify the concentrations of C-terminal proBNP in feline plasma. An anti-canine proBNP monoclonal antibody (UI-1021) was shown to have adequate binding affinity to proBNP 80-106 for use in a solid-phase immunoassay, and by epitope mapping to bind within positions 84-87 of feline proBNP. UI-1021 was paired with an affinity-purified rabbit polyclonal detection antibody to feline proBNP 100-106, in a sandwich ELISA with feline proBNP 80-106 standard. The linearity and analytical range and sensitivity of the assay were confirmed from 1.4 to 85 pmol/L. Spike recovery averaged 106.5% (95% confidence interval 78-135%). Within run and intra-assay coefficients of variation were

We investigated the biological significance of microRNA-126 (miR-126) expression in patients with atrial fibrillation (AF) and/or heart failure (HF) to examine the possible mechanism of miR-126-dependent AF and development of HF. A total of 103 patients were divided into three groups: AF group (18 men and 17 women, mean age: 65.62±12.72 years), HF group (17 men and 15 women, mean age: 63.95±19.71 years), and HF-AF group (20 men and 16 women, mean age: 66.56±14.37 years). Quantitative real-time PCR was used to measure relative miR-126 expression as calculated by the 2−ΔΔCt method. miR-126 was frequently downregulated in the 3 patient groups compared with controls. This reduction was significantly lower in permanent and persistent AF patients than in those with paroxysmal AF (P