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Aims: Although diabetes mellitus (DM) is a common co-morbidity in chronic heart failure (HF) patients, European data on concurrent HF and DM treatment are lacking. Therefore, we have studied the HF treatment of patients with and without DM. Additionally, with the recent breakthrough of sodium–glucose cotransporter 2 (SGLT2) inhibitors in the field of HF, we studied the potential impact of this new drug in a large cohort of HF patients. Methods and results: A total of 7488 patients with chronic HF with a left ventricular ejection fraction 2, P Conclusions: In this large real-world HF registry, a high prevalence of DM was observed and diabetics more often received guideline-recommended target doses. Based on current evidence, the majority of patients would fulfil the enrichment criteria of SGLT2 trials in HF and the impact of this new drug class will be large.

Contains fulltext : 287050.pdf (Publisher’s version ) (Closed access) Catestatin (CST) is a bioactive cleavage product of the neuroendocrine prohormone chromogranin A (CgA). Recent findings show that CST can exert anti-inflammatory and antiadrenergic effects by suppressing the inflammatory actions of mammalian macrophages. However, recent findings also suggest that macrophages themselves are major CST producers. Here, we hypothesize that macrophages produce CST in an inflammation-dependent manner and thereby might self-regulate inflammation in an autocrine fashion. CST is associated with pathological conditions hallmarked by chronic inflammation, including autoimmune, cardiovascular, and metabolic disorders. Since intraperitoneal injection of CST in mouse models of diabetes and inflammatory bowel disease has been reported to be beneficial for mitigating disease, we posit that CST should be further investigated as a candidate target for treating certain inflammatory diseases.

Vitamin D requires activation to show its pharmacological effect. While most studies investigate the association between vitamin D and disease, only a few focus on the impact of vitamin D metabolism gene polymorphisms (vitDMGPs). This bibliometric study aims to provide an overview of current publications on vitDMGPs (CYP27B1, CYP24A1, CYP2R1, CYP27A1, CYP2R1, DHCR7/NADSYN1), compare them across countries, affiliations, and journals, and inspect keywords, co-citations, and citation bursts to identify trends in this research field. CiteSpace© (version 6.1.R3, Chaomei Chen), Bibliometrix© (R version 4.1.3 library, K-Synth Srl, University of Naples Federico II, Naples, Italy), VOSviewer© (version 1.6.1, Nees Jan van Eck and Ludo Waltman, Leiden University, Leiden, Netherlands) and Microsoft® Excel 365 (Microsoft, Redmond, Washington, USA) classified and summarized Web of Science articles from 1998 to November 2022. We analyzed 2496 articles and built a timeline of co-citations and a bibliometric keywords co-occurrence map. The annual growth rate of vitDMGPs publications was 18.68%, and their relative research interest and published papers were increasing. The United States of America leads vitDMGPs research. The University of California System attained the highest quality of vitDMGPs research, followed by the American National Institutes of Health and Harvard University. The three productive journals on vitDMGPs papers are J. Steroid. Biochem. Mol. Biol., PLOS ONE, and J. Clin. Endocrinol. Metab. We highlighted that the vitDMGPs domain is relatively new, and many novel research opportunities are available, especially those related to studying single nucleotide polymorphisms or markers in a specific gene in the vitamin D metabolism cycle and their association with disease. Genome-wide association studies, genetic variants of vitDMGPs, and vitamin D and its role in cancer risk were the most popular studies. CYP24A1 and CYB27A1 were the most-studied genes in vitDMGPs. Insulin was the longest-trending studied hormone associated with vitDMGPs. Trending topics in this field relate to bile acid metabolism, transcriptome and gene expression, biomarkers, single nucleotide polymorphism, and fibroblast growth factor 23. We also expect an increase in original research papers investigating the association between vitDMGPs and coronavirus disease 2019, hypercalcemia, Smith–Lemli–Opitz syndrome, 27-hydroxycholesterol, and mendelian randomization. These findings will provide the foundations for innovations in the diagnosis and treatment of a vast spectrum of conditions.

Objective: Vaso-occlusive crisis (VOC) is a common clinical manifestation of sickle cell anemia (SCA) and is associated with increased proinflammatory mediators. Copeptin is the C-terminal part of the prohormone for provasopressin and seems clinically relevant in various clinical conditions. Right ventricular (RV) dysfunction significantly appears in SCA patients due to pulmonary hypertension. This study aimed to investigate the association of copeptin levels in VOC patients and evaluate RV dysfunction. Materials and Methods: A total of 108 patients were enrolled in the study. Twenty-eight SCA patients in steady state (30.2 ± 0.9 years), 25 SCA patients in VOC (36.8 ± 11.8 years), and 55 healthy individuals (31.9 ± 9.4 years) with HbAA genotype were included. Clinical, echocardiographic, and laboratory data were recorded. ELISA was used for the determination of serum levels of copeptin. Results: VOC patients had significantly higher copeptin level compared both with controls and SCA subjects in steady state (22.6 ± 13.0 vs. 11.3 ± 5.7 pmol/L, 22.6 ± 13.0 vs. 12.4 ± 5.8 pmol/L, p = 0.009 for both). Additionally, the copeptin level was significantly higher in SCA patients with RV dysfunction than those without RV dysfunction (23.2 ± 12.2 vs. 15.3 ± 9.5 pmol/L, p = 0.024). Multiple logistic regression analysis revealed that high-sensitivity C-reactive protein and copeptin levels were found to be associated with VOC. Conclusion: This study showed that copeptin and hs-CRP levels were increased in patients with VOC, and it was found that RV dysfunction was more common in SCA patients with VOC than in the control group. Copeptin can be considered for use as a potential biomarker in predicting VOC crisis in SCA patients and in the early detection of patients with SCA who have the potential to develop RV dysfunction.

Aim. To compare the effectiveness of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin II receptor antagonist valsartan in patients with heart failure with mid-range ejection fraction (HFmrEF) from the standpoint of the effect on the clinical picture, echocardiographic parameters and the level of the N-terminal fragment of the prohormone brain-type sodium (NT-proBNP). Methods. 110 patients with heart failure with mid-range ejection fraction were included in the study based on the City Clinical Hospital named after N.I. Pirogov of Orenburg between 2018 and 2020. All patients were divided into two randomized groups. Patients of the first group (n=55) were prescribed enalapril, the second group (n=55) valsartan. Each patient was followed up for 1 year. The six-minute walk test, NT-pro-brain natriuretic peptide level, echocardiography parameters were assessed in dynamics. Statistical analysis was performed by using Statistica 10.0 software, ShapiroWilk, MannWhitney, Wilcoxon tests. Results. During the year of observation in both groups, there was a significant decrease in the functional class of chronic heart failure (p 0.005) without a statistical difference between the groups (p=0.251). The distance during the six-minute walk test increased from 350 (310400) m to 490 (420530) m (p 0.001) in the first group, from 360 (330400) m to 510 (450520) m (p 0.001) in the second group, also without significant differences (p=0.361). The NT-pro-brain natriuretic peptide level decreased from 491 (410610) pg/ml to 286 (187350) pg/ml (p 0.001) in the first group, and from 446 (376534) pg/ml to 210 (143343) pg/ml (p 0.001) in the second, with a more significant change in the second group (p=0.020). The dynamics of echocardiography parameters were comparable in the groups (p 0.05), while ejection fraction normalized in 89.1% of patients received enalapril and 92.7% of patients received valsartan. Conclusion. The efficacy of enalapril and valsartan in heart failure with mid-range ejection fraction is comparable in its effect on the clinical picture and echocardiography parameters with a more pronounced decrease in NT-pro-brain natriuretic peptide when taking valsartan during a year of follow up.

Improvements in both liquid chromatography (LC) and mass spectrometry (MS) instrumentation have greatly enhanced proteomic and small molecule metabolomic analysis in recent years. Less focus has been on the improved capability to detect and quantify small bioactive peptides, even though the exact sequences of the peptide species produced can have important biological consequences. Endogenous bioactive peptide hormones, for example, are generated by the targeted and regulated cleavage of peptides from their prohormone sequence. This process may include organ specific variants, as proglucagon is converted to glucagon in the pancreas but glucagon-like peptide-1 (GLP-1) in the small intestine, with glucagon raising, whereas GLP-1, as an incretin, lowering blood glucose. Therefore, peptidomics workflows must preserve the structure of the processed peptide products to prevent the misidentification of ambiguous peptide species. The poor in vivo and in vitro stability of peptides in biological matrices is a major factor that needs to be considered when developing methods to study them. The bioinformatic analysis of peptidomics data sets requires the inclusion of specific post-translational modifications, which are critical for the function of many bioactive peptides. This review aims to discuss and contrast the various extraction, analytical, and bioinformatics approaches used for human peptidomics studies in a multitude of matrices.

Aims Risk stratification in patients with advanced chronic heart failure (HF) is an unmet need. Circulating microRNA (miRNA) levels have been proposed as diagnostic and prognostic biomarkers in several diseases including HF. The aims of the present study were to characterize HF‐specific miRNA expression profiles and to identify miRNAs with prognostic value in HF patients. Methods and results We performed a global miRNome analysis using next‐generation sequencing in the plasma of 30 advanced chronic HF patients and of matched healthy controls. A small subset of miRNAs was validated by real‐time PCR (P

Doege-Potter syndrome (DPS) is a rare paraneoplastic condition characterized by hypoinsulinemic hypoglycemia from a solitary fibrous tumor. The underlying mechanism is the secretion of a prohormone form of insulin-like growth factor II (IGF-II) by the tumor, which causes decreased release of glucose into the circulation. We report the case of a 27-year-old Filipino male with presumptive DPS from a recurrent right temporo-zygomatic hemangiopericytoma (HPC). The complexity of DPS requires a multidisciplinary approach. Early screening for metastases from HPC may prevent the undesirable sequelae of the disease process.

Background: Thyroxine (T4) is generally considered to be a prohormone that requires conversion to triiodothyronine (T3) to exert biological activity. Although evidence suggests that T4 has intrinsic activity, it is questionable if this activity has any physiological relevance. Methods: To answer this question, triple knockout (KO) mice (Triples) that cannot express the types 1 (D1) and 2 (D2) deiodinase and the Pax8 genes were generated. Thus, they lack a thyroid and cannot convert T4 to T3. Triples were injected on alternate days with either vehicle or physiological doses of T4, T3, or T3+T4 from postnatal days 2–14. They were euthanized at P15, and RNA-seq was employed to profile gene expression in the liver. In another experiment, Pax8KO mice were injected with T3, T4, or T4+T3, and growth rate and survival to P84 were determined. Results: The growth retardation of Triples was not improved by either T3 or T4 alone but was significantly improved by T4+T3. In the liver, T4 significantly regulated the expression of genes that were also regulated by T3, but the proportion of genes that were negatively regulated was higher in mice treated with T4 than in mice treated with T3. Treatment with T4+T3 identified genes that were regulated synergistically by T3 and T4, and genes that were regulated only by T4+T3. Analysis of these genes revealed enrichment in mechanisms related to cell proliferation and cholesterol physiology, suggesting a unique contribution of T4 to these biological functions. Pax8KO mice all survived to P84 when injected with T4 or T4+T3. However, survival rate with T3 was only 50% and 10% at 3.5 and 12 weeks of life, respectively. Conclusions: T4 has intrinsic activity in vivo and is critical for survival and growth. At a physiological level, T4 per se can upregulate or downregulate many T3 target genes in the neonatal liver. While most of these genes are also regulated by T3, subsets respond exclusively to T4 or demonstrate enhanced or normalized expression only in the presence of both hormones. These studies demonstrate for the first time a complex dependency on both T4 and T3 for normal mammalian growth and development.

Vitamin D can be obtained from diet, direct sunlight, or supplementation. The most common form is synthesized in the skin after exposure to ultraviolet B radiation. Nevertheless, the thought is that vitamin D is more of a multifunctional hormone or prohormone. This is because vitamin D plays contributes to many processes in the body. Calcitriol has been shown to have enhancing effects on the immune system, the cardiovascular system, the endocrine system, and other metabolic pathways. There is evidence that vitamin D has also a role in depression, pain, and cancer.

Proopiomelanocortin (POMC) neurons contribute to the regulation of many physiological processes; the majority of which have been attributed to the release of peptides produced from the POMC prohormone such as α-MSH, which plays key roles in food intake and metabolism. However, it is now clear that POMC neurons also release amino acid transmitters that likely contribute to the overall function of POMC cells. Recent work indicates that constitutive deletion of these transmitters can affect metabolic phenotypes, but also that the expression of GABAergic or glutamatergic markers changes throughout development. The goal of the present study was to determine whether the release of glutamate or GABA from POMC neurons in the adult mouse contributes notably to energy balance regulation. Disturbed release of glutamate or GABA specifically from POMC neurons in adult mice was achieved using a tamoxifen-inducible Cre construct ( Pomc-CreERT2) expressed in mice also carrying floxed versions of Slc17a6 (vGlut2) or Gad1 and Gad2, encoding the vesicular glutamate transporter type 2 and GAD67 and GAD65 proteins, respectively. All mice in the experiments received tamoxifen injections, but control mice lacked the tamoxifen-inducible Cre sequence. Body weight was unchanged in Gad1- and Gad2- or vGlut2-deleted female and male mice. Additionally, no significant differences in glucose tolerance or refeeding after an overnight fast were observed. These data collectively suggest that the release of GABA or glutamate from POMC neurons in adult mice does not significantly contribute to the metabolic parameters tested here. In light of prior work, the data also suggest that amino acid transmitter release from POMC cells may contribute to separate functions in the adult versus the developing mouse.

Bronchopulmonary dysplasia (BPD) is a combined pulmonary vascular and parenchymal disease, representing the most common cause of chronic lung disease (CLD) in infancy. Pulmonary hypertension (PH) is frequently associated with BPD and—if persistent—substantially increases mortality. We report on a 4-month-old, former preterm infant with BPD, severe PH and right heart failure who greatly and rapidly improved clinical status and right ventricular (RV) function by means of blood biomarkers [N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP), cardiac troponin T] and transthoracic echocardiography, following the addition of spironolactone and hydrochlorothiazide to the treatment regimen.

Atrial Fibrillation (AF) is a growing public health issue, associated with significant morbidity and mortality. In addition to pharmacological therapy, catheter ablation is an effective strategy in restoring and maintaining sinus rhythm. However, ablation is not without risk, and AF recurs in a significant proportion of patients. Non-invasive, easily accessible markers or indices that could stratify patients depending on the likelihood of a successful outcome following ablation would allow us to select the most appropriate patients for the procedure, reducing the AF recurrence rate and exposure to potentially life-threatening risks. : There has been much attention paid to Brain Natriuretic Peptide (BNP) and N-Terminal prohormone of Brain Natriuretic Peptide (NT-proBNP) as possible predictive markers of successful ablation. Several studies have demonstrated an association between higher pre-ablation levels of these peptides, and a greater likelihood of AF recurrence. Therefore, there may be a role for measuring brain natriuretic peptides levels when selecting patients for catheter ablation.

Aims Efforts to improve access to antiretroviral therapy (ART) have shifted morbidity and mortality among persons living with HIV (PLWH) from AIDS to non‐communicable diseases, such as cardiovascular disease (CVD). However, contemporary data on CVD among PLWH in sub‐Saharan Africa in the current ART era are lacking. The aim of this study was to assess the burden of cardiac stress among PLWH in South Africa via measurement of N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP). Methods and results NT‐proBNP was measured at baseline in 224 PLWH enrolled in a sub‐study of a tuberculosis vaccine trial in Khayelitsha township near Cape Town, South Africa. Thresholds were applied at the assay's limit of detection (≥137 pg/mL) and a level indicative of symptomatic heart failure in the acute setting (>300 pg/mL). Mean (SD) age of participants was 39 (6) years, 86% were female, and 19% were hypertensive. Mean (SD) duration of HIV diagnosis was 8.3 (3.9) years and CD4 + count was 673 (267) with 79% prescribed ART for a duration of 5.6 (2.7) years. Thirty‐one percent of participants had NT‐proBNP > 300 pg/mL. Elevated vs. undetectable NT‐proBNP level was associated with older age (P = 0.04), no ART (P = 0.03), and higher plasma tumour necrosis factor‐α (P = 0.01). Conclusions Among South African PLWH largely free of known CVD and on ART with high CD4 + counts and few comorbidities, we observed a high proportion with elevated NT‐proBNP levels, suggesting the burden of cardiac stress in this population may be high. This observation underscores the need for more in‐depth research, including the current effect of HIV on heart failure risk among a growing ART‐treated population in sub‐Saharan Africa.

Background: Increased plasma concentration of N-terminal-prohormone B-type natriuretic peptide (NT-proBNP) can be detected in cats with cardiac disease. Potential effects of feline characteristics on NT-proBNP concentration may influence clinical usefulness. Objectives: To evaluate potential effects of feline characteristics on NT-proBNP plasma concentration and to compare NT-proBNP plasma concentrations in healthy cats with results in hypertrophic cardiomyopathy (HCM) cats with or without left atrial enlargement (LAE) using an ELISA and a point-of-care test (POCT), and assess if POCT results reflect ELISA results. Animals: One hundred healthy cats of 3 breeds and 39 HCM cats were included. Methods: Diseases other than HCM were excluded by physical examination, blood pressure measurement, echocardiography, hematology, and serum biochemistry.Results Higher NT-proBNP concentrations were found in males than in females in healthy (P = .005) and in HCM cats (P = .0021), but breed had no effect on NT-proBNP concentrations. Using >= 100 pmol/L as a cutoff for abnormal samples, ELISA and POCT had similar sensitivity (SE; 72 and 74%) and specificity (SP; 97 and 98%) for detecting cats with HCM, cats with HCM and LAE (SE, both 100%; SP, 97 versus 98%), and cats with HCM without LAE (SE, both 69%; SP, 97 versus 98%), respectively, when compared to healthy cats. Conclusions and Clinical Importance: Breed had no effect on plasma NT-proBNP concentrations, but higher concentrations were found in male than in female cats. The ELISA and POCT had similar SE and SP for detecting HCM. Both tests could identify all HCM cats with LAE but not all HCM cats without LAE.

BACKGROUND Heart failure is characterized by a tissue damage that progressively leads to mechanical cardiac dysfunction and remodeling. A recent investigation showed that α-1 antitripsin, an antiprotease, able to inhibit metalloproteinases, provides prognostic information about heart failure and mortality postacute myocardial infarction. Therefore, we conducted a study to establish if α-1 antitrypsin (AAT) could be considered a marker of severity of heart failure. METHODS A total of 182 heart failure patients (Group 1) were enrolled and AAT values were compared with controls (Group 2). RESULTS In Group 1 a significant increment of AAT levels respect to Group 2 was observed (P

Cigarettes are the biggest health problem around the world. Nicotine in cigarettes has been proved insulin receptor resistance and can reduce insulin secretion in pancreatic β cells, which causes an increase in blood glucose levels. One of the efforts to reduce blood glucose levels is to consume vitamin D3. Vitamin D3 is a prohormone that plays a role in metabolic functions in cells and repair functions of cells. Purpose: to know the effect of vitamin D3 toward glucose blood level of male Rattus norvegicus Wistar exposed by cigarette smoke. Methods: This research conducted with pure experimental pre- and post-test with control group design. The samples used were 24 male rats. The sample divided into four groups, including K1, K2, K3, and P1. K1, which is not exposed by cigarette smoke and not given of vitamin D3. K2 is a group exposed by cigarette smoke but not given vitamin D3. K3 is a group that is not exposed by cigarette smoke but given vitamin D3 a dose of 0.2 µgr /head. P1 is a group exposed by cigarette smoke and given a vitamin D3 dose of 0.2 µgr /head. Results: Paired T-test showed increased blood glucose levels that are meaningful (p

Background : Multiple Sclerosis is a neurologic disease that effect Central Nervous System(CNS). Vitamin D is a liposoluble prohormone. It is thought that vitamin D deficiency is responsible for Lots of diseases which includes MS . In this study, we aimed to show the relationship between serum vitamin D level and MS. Objective : In our research we wanted to show the serum vitamin D levels in MS patients. Methods : We included 106 patients (76 female, 30 male) to our study. Participants were divided into two groups as patient and control group. Serum vitamin D levels were evaluated. We excluded patients with known liver or renal disease. Liver enzymes and blood creatinine of the patients included in the study were normal. Results: There was a statistically significant difference when comparing two groups of serum vitamin D results. Serum vitamin D levels were lower in the control group. No correlation was found between vitamin D and age. There was no correlation between vitamin D and gender. According to the vitamin D level reference interval in the MS group, 28 patients had deficiency, 17 patients had failure, and 12 patients were normal. In the control group, according to the vitamin D level reference range, 35 patients had deficiency, 11 patients had failure and 3 patients were normal. Conclusion: In this study conducted with limited facilities, lower vitamin D levels in the control group suggested that vitamin D levels may be low when the population is examined in general. Vitamin D support throughout the population may reduce the prevalence of other diseases thought to be caused by vitamin D deficiency as well as MS.

Neuropeptides are a diverse class of signalling molecules in metazoans. They occur in all animals with a nervous system and also in neuron-less placozoans. However, their origin has remained unclear because no neuropeptide shows deep homology across lineages and none have been found in sponges. Here, we identify two neuropeptide precursors, phoenixin and nesfatin, with broad evolutionary conservation. By database searches, sequence alignments and gene-structure comparisons we show that both precursors are present in bilaterians, cnidarians, ctenophores and sponges. We also found phoenixin and a secreted nesfatin precursor homolog in the choanoflagellate Salpingoeca rosetta. Phoenixin in particular, is highly conserved, including its cleavage sites, suggesting that prohormone processing occurs also in choanoflagellates. In addition, based on phyletic patterns and negative pharmacological assays we question the originally proposed GPR-173 (SREB3) as a phoenixin receptor. Our findings indicate that signalling by secreted neuropeptide homologs has pre-metazoan origins and thus evolved before neurons.

Aging is associated with the development of metabolic disorders, including insulin resistance and hypertension. Young mice that are negative for the neuroendocrine prohormone Chromogranin A (CgA knockout, CgA-KO) display two opposite aging phenotypes: hypertension but heightened insulin sensitivity. We determined these phenotypes in aging CgA mice. In comparison, aging wild-type (WT) mice gradually lost glucose tolerance and insulin sensitivity. Moreover, while aging WT mice had increased inflammation with higher plasma TNF-α, IFN-γ and CCL2 and increased mitochondrial fission, these phenotypes were the opposite in aging CgA-KO mice. CgA-KO mice also showed increased expression of mitochondrial and nuclear-encoded complex I genes, implying that they were healthier than WT mice. Most intriguingly, the hypertension in CgA-KO mice was spontaneously reversed with aging. Supplementation of CgA-KO mice with pancreastatin, a hyperglycemic peptide produced from CgA by proteolysis, increased both blood glucose levels and blood pressure, implicating hyperglycemia, and hypertension. We conclude that age-related insulin resistance and hypertension are caused by CgA.

Objective. To explore the role of conjunctival microvasculation combined with echocardiography in evaluating the prognosis of pulmonary arterial hypertension in systemic lupus erythematosus (SLE-PAH). Methods. We prospectively compared the conjunctival microvascular changes in 17 SLE-PAH patients and 34 SLE patients without PAH in our hospital from January 2020 to December 2020, and we observed the characteristics of conjunctival microvascular changes in SLE-PAH patients. We analyzed the correlation between the corresponding conjunctival microvascular changes and cardiopulmonary function and evaluated the predictive value of the vessel density (VD) and the microvascular flow index (MFI) of conjunctival microvasculation combined with echocardiography in SLE-PAH. Results. Compared with SLE patients without PAH, the ischemic areas in conjunctival microvasculation were significantly increased in SLE-PAH patients. The VD and MFI of conjunctival microvasculation are significantly correlated with N-terminal prohormone of brain natriuretic peptide and 6-minute walking distance. Combined with the VD and MFI, it can improve the accuracy of echocardiography in assessing the risk of death due to SLE-PAH (94.1% vs. 82.2%). Conclusion. The ischemic area, VD, and MFI of conjunctival microvasculation in SLE-PAH patients can indicate the occurrence of severe SLE-PAH and improve the accuracy of echocardiography in evaluating the prognosis of SLE-PAH.

Autologous pancreatic islet transplantation is an established therapy for patients with chronic pancreatitis. However, the long-term transplant outcomes are modest. Identifying indicators of graft function will aid the preservation of transplanted islets and glycemic control. To this end, we analyzed beta cell prohormone peptide levels in a retrospective cohort of total pancreatectomy autologous islet transplant patients (n=28). Proinsulin-to-C-peptide (PI/C) and proIAPP-to-total IAPP (proIAPP/IAPP) ratios measured at 3 months post-transplant were significantly higher in patients who remained insulin dependent at 1 year follow-up. In a mouse model of human islet transplantation, recipient mice that later became hyperglycemic displayed significantly higher PI/C ratios than mice that remained normoglycemic. Histological analysis of islet grafts showed reduced insulin- and proinsulin-positive area, but elevated glucagon-positive area in grafts that experienced greater secretory demand. Increased prohormone convertase 1/3 was detected in glucagon-positive cells, and glucagon-like peptide 1 (GLP-1) area was elevated in grafts from mice that displayed hyperglycemia or elevated plasma PI/C ratios, demonstrating intra-islet incretin production in metabolically challenged human islet grafts. These data indicate that in failing grafts, alpha cell prohormone processing is likely altered, and incomplete beta cell prohormone processing may be an early indicator of insulin dependency.

Thyroid hormones (THs) play a critical role in the regulation of biological processes, such as growth, metabolism, and development, in various animal species. Prohormone L-thyroxine (T4) is secreted from the thyroid gland and carried to peripheral tissues. T4 is then biotransformed to several metabolites which play different roles, mainly by iodothyronine deiodinases. Determination of deiodinated TH metabolites in key organs such as liver and brain would help to understand tissue-specific TH metabolism and homeostasis. In this study, we thus developed a highly sensitive method for the determination of six THs [T4, 3,5,3'-triodo-L-thyronine (T3), 3,3',5'-triiodo-L-thyronine (rT3), 3,5-diiodo-l-thyronine (3,5-T2), 3,3'-diiodo-l-thyronine (3,3'-T2), and 3-iodo-l-thyronine (3-T1)] in the brain and liver by using stored dog samples. The analytical method consisted of ultrasonic-assisted extraction in acetone acidified with formic acid, cleanup with a EVOLUTE® EXPRESS CX cartridge (reversed-phase combined with strong cation-exchange cartridge), and quantification with liquid chromatography-tandem mass spectrometry. Acceptable accuracy (internal standard-corrected recovery: 80%-120%) and intra- and inter-day precision (coefficient of variation:6% and15%, respectively) (n = 3/ batch, three days) were obtained for both brain and liver samples. In addition, low method detection limits were achieved for both brain (0.013-0.12 ng g

BackgroundBiopurification has been used to disclose an evolutionarily conserved inhibitory reproductive hormone involved in tissue mass determination. A (rat) bioassay-guided physicochemical fractionation using ovine materials yielded via Edman degradation a 14-residue amino acid (aa) sequence. As a 14mer synthetic peptide (EPL001) this displayed antiproliferative and reproduction-modulating activity, while representing only a part of the native polypeptide. Even more unexpectedly, a scrambled-sequence control peptide (EPL030) did likewise.MethodsReproduction has been investigated in the nematode Steinernema siamkayai, using a fermentation system supplemented with different concentrations of exogenous hexapeptides. Peptide structure-activity relationships have also been studied using prostate cancer and other mammalian cells in vitro, with peptides in solution or immobilized, and via the use of mammalian assays in vivo and through molecular modelling.ResultsReproduction increased (x3) in the entomopathogenic nematode Steinernema siamkayai after exposure to one synthetic peptide (IEPVFT), while fecundity was reduced (x0.5) after exposure to another (KLKMNG), both effects being dose-dependent. These hexamers are opposite ends of the synthetic peptide KLKMNGKNIEPVFT (EPL030). Bioactivity is unexpected as EPL030 is a control compound, based on a scrambled sequence of the test peptide MKPLTGKVKEFNNI (EPL001). EPL030 and EPL001 are both bioinformatically obscure, having no convincing matches to aa sequences in the protein databases. EPL001 has antiproliferative effects on human prostate cancer cells and rat bone marrow cells in vitro. Intracerebroventricular infusion of EPL001 in sheep was associated with elevated growth hormone in peripheral blood and reduced prolactin. The highly dissimilar EPL001 and EPL030 nonetheless have the foregoing biological effects in common in mammalian systems, while being divergently pro- and anti-fecundity respectively in the nematode Caenorhabditis elegans. Peptides up to a 20mer have also been shown to inhibit the proliferation of human cancer and other mammalian cells in vitro, with reproductive upregulation demonstrated previously in fish and frogs, as well as nematodes. EPL001 encodes the sheep neuroendocrine prohormone secretogranin II (sSgII), as deduced on the basis of immunoprecipitation using an anti-EPL001 antibody, with bespoke bioinformatics. Six sSgII residues are key to EPL001’s bioactivity : MKPLTGKVKEFNNI. A stereospecific bimodular tri-residue signature is described involving simultaneous accessibility for binding of the side chains of two specific trios of amino acids, MKP & VFN. An evolutionarily conserved receptor is conceptualised having dimeric binding sites, each with ligand-matching bimodular stereocentres. The bioactivity of the 14mer control peptide EPL030 and its hexapeptide progeny is due to the fortuitous assembly of subsets of the novel hormonal motif, MKPVFN, a default reproductive and tissue-building OFF signal.NOTEPlease see the end of the paper for links to ten files of supplementary information and for an independent peer review.KEY POINTSSynthetic hexapeptides have upregulated and downregulated nematode reproduction, following similar work in other nematode species and in fish and frogs.Peptides up to a 20mer have also been shown to inhibit the proliferation of human cancer and other mammalian cells in vitro and influence circulating levels of ovine pituitary hormones in vivo via intracerebroventricular peptide infusion.The amino acid sequence of the 14mer master peptide arose from a (rat) bioassay- guided fractionation using ovine materials, whose aim was to disclose an evolutionarily conserved inhibitory reproductive hormone involved in tissue mass determination.The bioactive peptides mimic the non-contiguous six-residue receptor-binding active face of a polypeptide hormone, which in mammals is a derivative of the secretory vesicle prohormone secretogranin II (SgII), taking the form of a novel, structually complex 70mer dubbed ‘SgII-70’.The ability has been gained to reinforce or block a default reproductive and tissue- building OFF signal, using peptide mimetics.

IntroductionNucleobindin-2 (NUCB2) was identified as a DNA/Ca2+ binding protein with multiple functions in humans. Prohormone convertase-mediated NUCB2 processing produced nesfatin-1 - a biologically active. Nesfatin-1, an 82-amino acid peptide, was extracted from the N-terminus of nucleobindin-2. Recently, it was described as an anorexia peptide related to weight loss, malnutrition, and appetite regulation in type 2 diabetes mellitus patients.Research design and methodsIn this study, we collected samples and divided them into groups of patients with long-term type 2 diabetes and newly diagnosed type 2 diabetes group. Serum nesfatin-1 level and mRNA NUCB2 gene expression level of the groups were analyzed and compared with those of the healthy group.Biometric parameters and biochemical indices were also analyzed to determine the correlation with nesfatin-1 level.ResultsLevels of nesfatin-1 were found to be higher in the newly diagnosed group than in the other groups. Similar results were also reported in the analysis of mRNA NUCB2 gene expression by Realtime-PCR. Meanwhile, no significant difference was found in both analyzes of nesfatin-1 levels and NUCB2 mRNA expression in subjects with long-term type 2 diabetes compared with the control group. This result can be explained by the effects of long-term treatment. In the correlation of anthropometric parameters and biochemical indices, nesfatin-1 exhibited a significant correlation with BMI (r=0.569), HbA1c (r=-0.468), HDL-C (r=0.731), LDL-C (r=-0.482), Creatinine serum (r=0.525), and Creatinine urine (r=0.592), with pConclusionsThese results indicate that the serum nesfatin-1 level and the NUCB2 mRNA gene expression level may be associated with newly diagnosed type 2 diabetes in Vietnamese patients. However, more specific studies with larger sample sizes were still needed in future studies.

To characterize the impact of metabolic disease on the peptidome of human and mouse pancreatic islets, LC-MS was used to analyze extracts of human and mouse islets, purified mouse alpha, beta, and delta cells, supernatants from mouse islet incubations, and plasma from patients with type 2 diabetes. Islets were obtained from healthy and type 2 diabetic human donors, and mice on chow or high fat diet. All major islet hormones were detected in lysed islets as well as numerous peptides from vesicular proteins including granins and processing enzymes. Glucose-dependent insulinotropic peptide (GIP) was not detectable. High fat diet modestly increased islet content of proinsulin-derived peptides in mice. Human diabetic islets contained increased content of proglucagon-derived peptides at the expense of insulin, but no evident prohormone processing defects. Diabetic plasma, however, contained increased ratios of proinsulin and des-31,32-proinsulin to insulin. Active GLP-1 was detectable in human and mouse islets but 100-1000-fold less abundant than glucagon. LC-MS offers advantages over antibody-based approaches for identifying exact peptide sequences, and revealed a shift toward islet insulin production in high fat fed mice, and toward proglucagon production in type 2 diabetes, with no evidence of systematic defective prohormone processing.

Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors, of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues defines prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic α-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, pro-islet amyloid polypeptide (proIAPP), and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin-to-C-peptide ratio for progression to type 2 diabetes, and elevated proinsulin or proinsulin-to-C-peptide ratio is predictive for development of type 1 diabetes in at-risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP, and proinsulin may be an autoantigen in type 1 diabetes. Furthermore, preclinical studies reveal that α-cells have altered proglucagon processing during diabetes, leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology.

The thyroid hormone system is a main target of endocrine disruptor compounds (EDC) at all levels of its intricately fine-tuned feedback regulation, synthesis, distribution, metabolism and action of the 'prohormone' thyroxine and its active metabolites. Apart from classical antithyroid effects of EDC on the gland, the majority of known and suspected effects occurs at the pre-receptor control of T3 ligand availability to T3 receptors exerting ligand modulated thyroid hormone action. Tissue-, organ- and cell-specific expression and function of thyroid hormone transporters, deiodinases, metabolizing enzymes and T3-receptor forms, all integral components of the system, may mediate adverse EDC effects. Established evidence from nutritional, pharmacological and molecular genetic studies clearly support the functional, biological, and clinical relevance of these targets. Iodine-containing thyroid hormones and the organization of this system are highly conserved during evolution from primitive aquatic life forms, amphibia, birds throughout all vertebrates including humans. Mechanistic studies from various animal experimental models strongly support cause-effect relationships upon EDC exposure, hazards and adverse effects of EDC across various species. Retrospective case-control, cohort and population studies linking EDC exposure with epidemiological data on thyroid hormone-related (dys-)functions provide clear evidence that human development, especially of the fetal and neonatal brain, growth, differentiation and metabolic processes in adult and aging humans are at risk for adverse EDC effects. Considering that more than half of the world population still lives on inadequate iodine supply, the additional ubiquitous exposure to EDC and their mixtures is an additional threat for the essential thyroid hormone system, the health of the human population and their future progenies, animal life forms and our global environment.

Funding Acknowledgements Type of funding sources: None. Introduction Pulmonary arterial hypertension (PAH) is a rare disease, with an incidence of 15–50 cases per million annually. The disease is associated with further progress and worsening of symptoms despite pharmacotherapy. The severity of PAH symptoms and their effects reduce the patients" quality of life (QoL). Numerous studies show that the quality of life is related to the therapeutic effect of the treatment. Available studies demonstrate that patients QoL deteriorates as the condition progresses. Consequently, the goals of PAH therapy have expanded from increasing survival to improving health-related quality of life. The aim of the study was to determine the clinical and sociodemographic factors influencing the quality of life in PAH patients. Methods The study involved 55 patients with PAH who were examined using the Polish version of the PAH-SYMPACT quality of life questionnaire. The PAH-SYMPACT questionnaire results were correlated with several variables. Results It was shown that the quality of life correlates significantly (p˂0,05) with WHO Functional Class, NT-pro BNP (N-terminal prohormone of brain natriuretic peptide) value, elderly age (the higher the value, the worse the QoL). On the other hand, the lower the 6MWT (6 minuts walk test) result, the worse the QoL. Moreover, the intensity of the accompanying PAH symptoms, such as chest pain, dyspnoea, arrhythmias, fatigue and weakness were associated with a lower quality of life in patients (p Conclusion Patients" quality of life correlates with many variables, both clinical and sociodemographic. In addition, there is a correlation between the quality of life of patients with PAH and the severity of several symptoms associated with this condition. Determination of factors affecting the quality of life of patients with PAH enables the selection of a more comprehensive therapy.