Thursday, January 19, 2012

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1.
Int J Obes (Lond). 2012 Jan 17. doi: 10.1038/ijo.2011.265. [Epub ahead of print]

Hindbrain leptin and glucagon-like-peptide-1 receptor signaling interact to suppress food intake in an additive manner.

Source

1] Department of Physiology and Pathophysiology, School of Medicine, Xi'an Jiaotong University, Xi'an, People's Republic of China [2] Department of Psychology, School of Art and Science University of Pennsylvania, Philadelphia, PA, USA.

Abstract

Background:The physiological control of feeding behavior involves modulation of the intake inhibitory effects of gastrointestinal satiation signaling via endogenous hindbrain leptin receptor (LepR) and glucagon-like-peptide-1 receptor (GLP-1R) activation.Design and Results:Using a variety of dose-combinations of hindbrain delivered (4th intracerebroventricular; i.c.v.) leptin and the GLP-1R agonist exendin-4, experiments demonstrate that hindbrain LepR and GLP-1R signaling interact to control food intake and body weight in an additive manner. In addition, the maximum intake suppressive response that could be achieved by 4th i.c.v. leptin alone in non-obese rats (∼33%) was shown to be further suppressed when exendin-4 was co-administered. Importantly, it was determined that the interaction between hindbrain LepR signaling and GLP-1R signaling is relevant to endogenous food intake control, as hindbrain GLP-1R blockade by the selective antagonist exendin-(9-39) attenuated the intake inhibitory effects of hindbrain leptin delivery.Conclusions:Collectively, the findings reported here show that hindbrain LepR and GLP-1R activation interact in at least an additive manner to control food intake and body weight. As evidence is accumulating that combination pharmacotherapies offer greater sustained food intake and body weight suppression in obese individuals when compared with mono-drug therapies or lifestyle modifications alone, these findings highlight the need for further examination of combined central nervous system GLP-1R and LepR signaling as a potential drug target for obesity treatment.International Journal of Obesity advance online publication, 17 January 2012; doi:10.1038/ijo.2011.265.

PMID:
22249232
[PubMed - as supplied by publisher]
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2.
Pediatr Int. 2012 Jan 16. doi: 10.1111/j.1442-200X.2012.03559.x. [Epub ahead of print]

R2 Predicting Scores for Left Ventricular Dysfunction in Duchenne Muscular Dystrophy.

Source

Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan. Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, Kobe, Japan. Department of Internal Medicine, Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

Abstract

Objective:  To predict left ventricular (LV) dysfunction and the timing to perform echocardiography in patients with Duchenne muscular dystrophy (DMD), we developed a scoring system using clinical parameters and examined its efficacy. Background:  It is indispensable to utilize echocardiogram for evaluating myocardial damage of DMD patients, but there is no established guideline for determining the clinical conditions which require echocardiographic examination. Methods:  We retrospectively analyzed 86 patients with DMD who were treated in Kobe University Hospital from 2007 to 2009. The multiple logistic regression analysis on routine clinical data was performed to identify parameters which can find abnormal LV contraction, and to develop weighted scoring system. Echocardiogram was performed as the gold standard for detecting LV dysfunction. Results:  Four parameters were associated with abnormal LV contraction, (1) brain natriuretic peptide, (2) creatine kinase, (3) scoliosis and (4) body surface area. When BNP was used as the only predictor to evaluate of LV systolic dysfunction, sensitivity and specificity were 36.4% and 92.1 %, respectively. In contrast, abnormal LV contraction was detected in high accuracy (sensitivity; 95.5%, specificity; 68.3%) when we used a two step scoring system in which BNP is combined with the other three factors, raising the sensitivity of compared to using BNP levels as the single parameter (P = 0.008). Conclusion:  Our scoring system detects the early heart dysfunction of DMD patients, especially when BNP level is not elevated. This system is useful to determine the timing for echocardiographic examination and consulting cardiologists. © 2012 The Authors. Pediatrics International © 2012 Japan Pediatric Society.

© 2012 The Authors. Pediatrics International © 2012 Japan Pediatric Society.

PMID:
22248373
[PubMed - as supplied by publisher]
3.
Int J Biochem Cell Biol. 2012 Jan 9. [Epub ahead of print]

Presence of urotensin-II receptors at the cell nucleus: Specific tissue distribution and hypoxia induced modulation.

Source

Laboratoire d'études moléculaires et pharmacologiques des peptides, Université du Québec, INRS-Institut Armand-Frappier, Ville de Laval, Qc, Canada; Laboratoire International Associé Samuel de Champlain (INSERM-INRS-Université de Rouen), Canada.

Abstract

Urotensin II (UII) and its receptor UT, is widely expressed in the cardiovascular and central nervous system, where they exert regulatory actions under both physiological and pathological conditions. Our study, aimed at investigating the presence of functional nuclear UT in various rat and monkey tissues as well as in human cell lines, demonstrated for the first time by western blot analysis and confocal immunofluorescence a tissue-specific nuclear expression of this receptor (heart and central nervous system). This nuclear UT was further characterized pharmacologically through radioligand binding studies using specific ligands of the urotensinergic system, as well as somatostatin. In 2D-gel experiments, we have observed the presence of different post-translational modifications between membrane and nuclear UT receptors in brain extracts. Transcription initiation assays showed de novo RNA synthesis caused by UII and Urotensin-related peptide (URP) which were inhibited by an UT antagonist urantide. In hypoxic/ischemic conditions, UT receptors were differentially modulated in regard to subcellular localization. Thus, the unique regiospecificity of the nuclear UT receptor along with its particular modulation under hypoxic conditions could indicate a specific and complementary physiological role that could be correlated with pro-angiogenic and/or neuromodulatory actions of UII, both in the cardiovascular and central nervous system.

Copyright © 2012. Published by Elsevier Ltd.

PMID:
22245063
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4.
FEBS J. 2012 Jan 13. doi: 10.1111/j.1742-4658.2012.08483.x. [Epub ahead of print]

Role of polar and nonpolar residues at the active site for PPIase activity of FKBP22 from Shewanella sp. SIB1.

Source

Department of Material and Life Science, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, JapanInternational College, Osaka University, 1-30 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan.

Abstract

FKBP22 from the psychotropic bacterium Shewanella sp. SIB1 is a homodimeric protein with peptidyl prolyl cis-trans isomerase (PPIase) activity. According to a tertiary model, several nonpolar residues including Trp157 and Phe197 form a substrate-binding cavity, and Asp137 and Arg142, which form a salt bridge, are located at the edge of this cavity. To analyze the role of these residues, nine single (D137A, R142A, W157A/F/Y, F197A/L/Y/W) and one double (D137A/R142A) mutant proteins of SIB1 FKBP22 were constructed. The far- and near-UV CD spectra of these mutant proteins suggest that the mutations at Asp137 and Arg142 do not seriously affect the protein structure, while those at W157 and Phe197 cause a local conformational change around the mutation site. Each mutation decreased the PPIase activities of SIB1 FKBP22 for peptide and protein substrates similarly without seriously affecting chaperone function. This result indicates that SIB1 FKBP22 does not require PPIase activity for chaperone function. The PPIase activities of R142A, D137A, and D137A/R142A decreased in this order, suggesting that Asp137 and Arg142 play a principal and auxiliary role in catalytic function, respectively, but Arg142 can function as a substitute of Asp137. Because the PPIase activity of SIB1 FKBP22 was not fully lost by the removal of all polar residues around the active site, the desolvation effect may also contribute to the enzymatic activity. However, the mutations of Trp157 to Phe or Phe197 to Leu greatly decrease the enzymatic activity, suggesting that a shape of the substrate-binding cavity is also important for enzymatic activity.

Journal compilation © 2012 Federation of European Biochemical Societies.

PMID:
22244380
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5.
Physiol Plant. 2012 Jan 13. doi: 10.1111/j.1399-3054.2012.01573.x. [Epub ahead of print]

Root proteases: reinforced links between nitrogen uptake and mobilization and drought tolerance.

Source

Plant Breeding, Genetics, and Biotechnology Division Crop and Environmental Sciences Division, International Rice Research Institute, DAPO Box 7777, Metro Manila, Philippines.

Abstract

Integral sub-cellular and cellular functions ranging from gene expression, protein targeting and nutrient supply to cell differentiation and cell death require proteases. Plantshave unique organelles such as chloroplasts composed of unique proteins that carry out the unique process of photosynthesis.Hence, along with proteases common across kingdoms plants contain unique proteases. Improved knowledge on proteases can lead to a better understanding of plant development, differentiation and death. Because of their importance in multiple processes, plant proteases are actively studied. However, root proteases specifically are not as well studied. The associated rhizosphere, organic matter, and/or inorganic matter make roots a difficult system. However, recent research strongly supported the occurrence of endocytosis of proteins, peptides and even microbes by root cells, which, hitherto known for specialized pathogenesis or symbiosis, was unsuspected for nutrient uptake. These results reinforced the importance of root proteases in endocytosis or root exudate-mediated nutrient uptake. Rhizoplane, rhizosphere or in planta protease action on proteins,peptides and microbes generates sources of nitrogen, especially during abiotic stresses such as drought. This review highlights the recent research on root proteases for nitrogen uptake and the connection of the two to drought-tolerance mechanisms. Drought-induced proteases in rice roots, as known from rice expression databases, are discussed for future research on certain M50, Deg, FtsH, AMSH and deubiquitination proteases. The recent emphasis on linking drought and plant hydraulics to nutrient metabolism is illustrated and connected to the value of a systematic study of root proteases in crop improvement.

Copyright © Physiologia Plantarum 2012.

PMID:
22242864
[PubMed - as supplied by publisher]
6.
J Vet Med Sci. 2012 Jan 12. [Epub ahead of print]

Plasma Adrenomedullin Concentration in Dogs with Myxomatous Mitral Valvular Disease.

Source

Laboratory of Veterinary Surgery, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University.

Abstract

Adrenomedullin (AM), a peptide identified to have vasodilating and natriuretic effects, is involved in the regulation of the cardiovascular system. To evaluate plasma AM concentration in dogs with myxomatous mitral valvular disease (MMVD), and to investigate the associations between the concentrations of plasma AM and natriuretic peptides and the echocardiographic data, we evaluated plasma AM concentrations in 31 healthy control dogs and 57 dogs with MMVD. Plasma AM concentrations in dogs with MMVD were higher than that in the control subjects. Plasma AM concentration increased in population to the severity of heart failure according to the International Small Animal Cardiac Health Council (ISACHC). AM concentrations were respectively 25.1 ± 5.0 fmol/ml (ISACHC class Ia), 29.9 ± 11.0 fmol/ml (ISACHC class Ib), 43.4 ± 19.8 fmol/ml (ISACHC class II) and 73.5 ± 21.7 fmol/ml (ISACHC class III) and 7.5 ± 5.1 fmol/ml (control group). The response-operating characteristics (ROC) curve indicated an area of 0.93 (95% CI, 0.8801-0.9889; < 0.0001), a cutoff value of 30.5 fmol/ml, a sensitivity of 87.1 %, and a specificity of 82.5 % for the determination of congestive heart failure. Plasma AM concentrations correlated with atrial natriuretic peptide concentrations, LA/Ao ratio, and left ventricular diameter. In conclusion, AM may be potential diagnostic marker for canine MMVD and possibly plays a pathophysiological role in collaboration with the other neurohumoral factors such as natriuretic peptides.

PMID:
22240987
[PubMed - as supplied by publisher]
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7.
J Neurochem. 2012 Jan 12. doi: 10.1111/j.1471-4159.2012.07657.x. [Epub ahead of print]

Minimal essential length of Clostridium botulinum C3 peptides to enhance neuronal regenerative growth and connectivity in a non-enzymatic mode.

Source

Center for Anatomy, Functional Cell Biology, Charité-Universitätsmedizin Berlin, Germany Department of Morphology & BIOMED Institute, Hasselt University, Belgium Université Pierre et Marie Curie, Institut de la Vision, Paris, France) Institute of Toxicology, Hannover Medical School (MHH), Germany.

Abstract

C3 ADP-ribosyltransferase is a valuable tool to study Rho-dependent cellular processes. In the current study we investigated the impact of enzyme-deficient peptides derived from Clostridium botulinum C3 transferase in the context of neuronal process elongation and branching, synaptic connectivity, and putative beneficial effects on functional outcome following traumatic injury to the CNS. By screening a range of peptidic fragments we identified three short peptides from C3bot that promoted axon and dendrite outgrowth in cultivated hippocampal neurons. Furthermore, one of these fragments, a 26-amino acid peptide covering the residues 156-181 enhanced synaptic connectivity in primary hippocampal culture. This peptide was also effective to foster axon outgrowth and re-innervation in organotypical brain slice culture. To evaluate the potential of the 26mer to foster repair mechanisms after CNS injury we applied this peptideto mice subjected to spinal cord injury by either compression impact or hemisection. A single local administration at the site of the lesion improved locomotor recovery. In addition, histological analysis revealed an increased serotonergic input to lumbar motoneurons in treated compared to control mice. Pull-down assays showed that lesion-induced up-regulation of RhoA activity within the spinal cord was largely blocked by C3bot peptides despite the lack of enzymatic activity. © 2012 The Authors Journal of Neurochemistry© 2012 International Society for Neurochemistry.

© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

PMID:
22239108
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8.
Vector Borne Zoonotic Dis. 2012 Jan 4. [Epub ahead of print]

Optimization of Peptide-Based ELISA for Serological Diagnostics: A Retrospective Study of Human Monkeypox Infection.

Source

1 Najít Technologies, Inc. , Portland, Oregon.

Abstract

Abstract Although smallpox has been eradicated, other diseases caused by virulent orthopoxviruses such as monkeypox virus (MPV) remain endemic in remote areas of western and central sub-Saharan Africa, and represent a potential biothreat due to international travel and/or inadvertent exposure. Unfortunately, extensive antigenic cross-reactivity among orthopoxviruses presents a challenge to serological diagnosis. We previously reported a 20mer peptide-based ELISA that identified recent MPV infection with >90% sensitivity and >90% specificity. However, the sensitivity of this approach was not determined with samples obtained at later time points after antibody titers had declined from their peak levels. To improve assay sensitivity for detecting MPV-specific antibodies at later time points, we compared diagnostic 20mer peptides to 30mer peptides. In addition, optimal 30mer peptides were tested in combination or after conjugating selected peptides to a carrier protein (bovine serum albumin) to further improve assay performance. An optimized combination of four unconjugated 30mer peptides provided 100% sensitivity for detecting MPV infection at 2-6 months post-infection, 45% sensitivity for detecting MPV infection at >2 years post-infection, and 99% specificity. However, an optimized combination of two peptide conjugates provided 100% sensitivity for detecting MPV infection at 2-6 months post-infection, 90% sensitivity for detecting MPV infection at >2 years post-infection, and 97% specificity.Peptide-based ELISA tests provide a relatively simple approach for serological detection of MPV infection. Moreover, the systematic approach used here to optimize diagnostic peptide reagents is applicable to developing improved diagnostics to a broad range of other viruses, and may be particularly useful for distinguishing between closely-related viruses within the same genus or family.

PMID:
22217169
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9.
Cytometry A. 2011 Dec 28. doi: 10.1002/cyto.a.22009. [Epub ahead of print]

Isolation of synaptic terminals from Alzheimer's disease cortex.

Source

UCLA School of Nursing, Los Angeles, California 90095; UCLA Center for the Advancement of Gerontological Nursing Sciences, Los Angeles, California 90095; UCLA Brain Research Institute, Los Angeles, California 90095. ssokolow@sonnet.ucla.edu.

Abstract

Amyloid beta (Aβ) oligomers and phosphorylated tau (p-tau) aggregates are increasingly identified as potential toxic intermediates in Alzheimer's disease (AD). In cortical AD synapses, p-tau co-localizes with Aβ, but the Aβ and p-taupeptide species responsible for synaptic dysfunction and demise remains unclear. The present experiments were designed to use high-speed cell sorting techniques to purify synaptosome population based on size, and then extend the method to physically isolate Aβ-positive synaptosomes with the goal of understanding the nature of Aβ and tau pathology in AD synapses. To examine the purity of size-gated synaptosomes, samples were first gated on size; particles with sizes between 0.5 and 1.5 microns were collected. Electron microscopy documented a homogenous population of spherical particles with internal vesicles and synaptic densities. Next, size-gated synaptosomes positive for Aβ were collected by fluorescence activated sorting and then analyzed by immunoblotting techniques. Sorted Aβ-positive synaptosomes were enriched for amyloid precursor protein (APP) and for Aβ oligomers and aggregates; immunolabeling for p-tau showed a striking accumulation of p-tau aggregates compared to the original homogenate and purified synaptosomes. These results confirm co-localization of Aβ and p-tau within individual synaptic terminals and provide proof of concept for the utility of flow sorting synaptosomes. © 2011 International Society for Advancement of Cytometry.

Copyright © 2011 International Society for Advancement of Cytometry.

PMID:
22213704
[PubMed - as supplied by publisher]
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10.
Clin Chem. 2011 Dec 28. [Epub ahead of print]

Growth-Differentiation Factor-15 in the Early Diagnosis and Risk Stratification of Patients with Acute Chest Pain.

Source

Department of Internal Medicine.

Abstract

BACKGROUND:

Growth-differentiation factor-15 (GDF-15) is a stress-responsive marker that might aid in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction (AMI).

METHODS:

In a prospective, international multicenter study, GDF-15, high-sensitivity cardiac troponin T (hs-cTnT), and B-type natriuretic peptide (BNP) were measured in 646 unselected patients presenting to the emergency department with acute chest pain. The final diagnosis was adjudicated by 2 independent cardiologists. The primary prognostic end point was all-cause mortality during a median follow-up of 26 months.

RESULTS:

AMI was the adjudicated final diagnosis in 115 patients (18%). GDF-15 concentrations at presentation were significantly higher in AMI patients compared to patients with other diagnoses. The diagnostic accuracy of GDF-15 at presentation for the diagnosis of AMI as quantified by the area under the ROC curve (AUC) was lower (AUC 0.69, 95% CI 0.64-0.74) compared to hs-cTnT (AUC 0.96, 95% CI 0.94-0.98, P < 0.001) and BNP (AUC 0.74, 95% CI 0.69-0.80, P = 0.02). A total of 55 deaths occurred during follow-up. GDF-15 predicted all-cause mortality independently of and more accurately than hs-cTnT [AUC 0.85 (95% CI 0.81-0.90) vs 0.77 (95% CI 0.72-0.83), P = 0.002] and BNP (AUC 0.75, 95% CI 0.68-0.82, P = 0.007). Net reclassification improvement was 0.15 (P = 0.01), and the absolute integrated discrimination improvement was 0.07, yielding a relative integrated discrimination improvement of 0.36 (P = 0.07).

CONCLUSIONS:

GDF-15 predicts all-cause mortality in unselected patients with acute chest pain independently of and more accurately than hs-cTnT and BNP. However, GDF-15 does not seem to help in the early diagnosis of AMI.

PMID:
22205695
[PubMed - as supplied by publisher]
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11.
J Alzheimers Dis. 2011 Dec 27. [Epub ahead of print]

Fibrillar Amyloid-β1-42 Modifies Actin Organization Affecting the Cofilin Phosphorylation State: A Role for Rac1/cdc42 Effector Proteins and the Slingshot Phosphatase.

Source

Laboratory of Cellular and Molecular Neurosciences, University of Chile and International Center for Biomedicine (ICC), Santiago, Chile.

Abstract

The neuronal cytoskeleton regulates numerous processes that occur in normal homeostasis. Under pathological conditions such as those of Alzheimer's disease (AD), major alterations in cytoskeleton organization have been observed and changes in both microtubules and actin filaments have been reported. Many neurodegenerative consequences of AD are linked to the production and accumulation of amyloid peptides (Aβ) and their oligomers, produced from the internal cleavage of the amyloid-β protein precursor. We previously reported that fibrillar Aβ1-42 (fAβ) treatment of hippocampal neurons induced an increase in Rac1 and Cdc42 activities linking fAβ effects with changes in actin dynamics. Here we show fAβ-induces increased activity of PAK1 and cyclin-dependent kinase 5, and that p21-activated kinase (PAK1) activation targets the LIMK1-cofilin signaling pathway. Increased cofilin dephosphorylation under conditions of enhanced LIM-Kinase 1 (LIMK1) activity suggests that fAβ co-stimulates bifurcating pathways impacting cofilin phosphorylation. Overexpression of slingshot (SSH) prevents the augment of F-actin induced by fAβ after 24 h, suggesting that fAβ-induced changes in actin assembly involve both LIMK1 and SSH. These results suggest that fAb may alter the PAK1/LIMK1/cofilin axis and therefore actin organization in AD.

PMID:
22204905
[PubMed - as supplied by publisher]
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12.
Resuscitation. 2011 Dec 23. [Epub ahead of print]

Novel biomarkers in diagnosing cardiac ischemia in the emergency department: A systematic review.

Source

Division of Emergency Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Rescu, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Health Policy, Management & Evaluation, University of Toronto, Toronto, Ontario, Canada.

Abstract

BACKGROUND:

Novel biomarkers of myocardial ischemia and inflammatory processes have the potential to improve diagnostic accuracy of acute coronary syndrome (ACS) within a shorter time interval after symptom onset.

OBJECTIVE:

The objective was to review the recent literature and evaluate the evidence for use of novel biomarkers in diagnosing ACS in patients presenting with chest pain or symptoms suggestive of cardiac ischemia to the emergency department or chest pain unit.

METHODS:

A literature search was performed in MEDLINE, EMBASE, Cochrane DSR, ACP Journal Club, DARE, CCTR, CMR, HTA, and NHSEED for studies from 2004 to 2010. We used the inclusion criteria: (1) human subjects, (2) peer-reviewed articles, (3) enrolled patients with ACS, acute myocardial infarction or undifferentiated signs and symptoms suggestive of ACS, and (4) English language or translated manuscripts. Two reviewers conducted a hierarchical selection and assessment using a scale developed by the International Liaison Committee on Resuscitation.

RESULTS:

Out of a total 3194 citations, 58 articles evaluating 37 novel biomarkers were included for final review. Forty-one studies did not support the use of their respective biomarkers. Seventeen studies supported the use of 5 biomarkers, particularly when combined with cardiac-specific troponin: heart fatty acid-binding protein, ischemia-modified albumin, B-type natriuretic peptide, copeptin, and matrix metalloproteinase-9.

CONCLUSION:

In patients presenting to the emergency department with chest pain or symptoms suggestive of cardiac ischemia, there is inadequate evidence to suggest the routine testing of novel biomarkers in isolation. However, several novel biomarkers have the potential to improve the sensitivity of diagnosing ACS when combined with cardiac-specific troponin.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

PMID:
22200578
[PubMed - as supplied by publisher]
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13.
Biochem Pharmacol. 2011 Dec 16. [Epub ahead of print]

Urocontrin, a novel UT receptor ligand with a unique pharmacological profile.

Source

Laboratoire d'études moléculaires et pharmacologiques des peptides, Université du Québec, INRS - Institut Armand-Frappier, Ville de Laval, Québec, Canada; Laboratoire International Associé Samuel de Champlain (INSERM - INRS - Université de Rouen), Canada.

Abstract

In recent years, several studies have demonstrated that urotensin II (UII) and urotensin II-related peptide (URP) can exhibit differential biological activity. So far, known antagonists of the urotensin II receptor (UT) are of limited usefulness for investigating the specific pathophysiological role of UII or URP. Therefore, identification of new compounds able to discriminate UII- and URP-associated biological activities is crucially needed. In the present study, we report preliminary data regarding the pharmacological properties of a novel UT ligand termed urocontrin, i.e. [Bip(4)]URP, that is able to reduce the ex vivo efficacy of hUII- but not URP-induced vasoconstriction in rat aortic rings. In vivo studies support the pharmacological profile described above. Although urocontrin exert some residual agonist activity, this compound should be useful for the rational design of potent molecules that would allow discriminating specific biological action mediated by UII or URP.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22197588
[PubMed - as supplied by publisher]
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14.
J Neurochem. 2011 Dec 22. doi: 10.1111/j.1471-4159.2011.07633.x. [Epub ahead of print]

Nicotine stimulates secretion of corticosterone via both CRH and AVP receptors.

Source

Division of Endocrinology, Molecular Medicine and Metabolism, Department of Internal Medicine, Charles R. Drew University of Medicine & Sciences-David Geffen School of Medicine at UCLA, Los Angeles, CA 90059 College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766.

Abstract

Corticosterone-releasing hormone (CRH) and arginine vasopressin (AVP) are crucial components of the hypothalamic-pituitary-adrenal (HPA) axis that stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary and mediate the stress response. CRH binds to two subtypes of CRH receptors (CRH-R1 and CRH-R2) that are present in both central and peripheral tissues. We used the CRH-R1 specific antagonist, antalarmin (ANT), the CRH-R1 and CRH-R2 peptide antagonist, astressin (AST), and the CRH-R2 specific peptide antagonist, astressin2b (AST2b), to determine which CRH receptor is involved in the nicotine-stimulated secretion of corticosterone. Male C57BL/6 mice were administered ANT (20 mg/kg, i.p.), AST (0.3 mg/kg, i.p.), AST2b (0.3 mg/kg, i.p.) or vehicle prior to administration of nicotine (1.0 mg/kg, s.c.), CRH (10 μg/kg, s.c.), AVP (10 μg/kg, s.c.) or saline (SAL) (s.c.), sacrificed 15 min later and trunk blood collected and assayed for corticosterone plasma levels. We found that CRH enhanced corticosterone release, and this response was blocked by both AST and ANT. Nicotine also increased corticosterone secretion, but this effect persisted in the presence of either CRH antagonist. Furthermore, AST but not ANT or AST2b decreased corticosterone levels associated with stress of handling and injection. We also assessed the role of AVP V(1b) specific receptor antagonist, SSR149415 alone and in combination with AST and AST2b. Although the AVP antagonist did not alter basal or nicotine-stimulated corticosterone secretion, it attenuated the AVP-induced stimulation of corticosterone and its combination with AST but not AST2b completely abolished nicotine-mediated stimulation of corticosterone secretion. Our results demonstrate that the nicotine-induced stimulation of the hypothalamic-pituitary adrenal axis (HPA) is mediated by both the CRH-R and the AVP V(1b) receptor and when the CRH receptor is blocked, nicotine may utilize the AVP V(1b) receptor to mediate secretion of corticosterone. These results argue in favor of the development of specific antagonists that block both AVP and CRH receptors to decrease the pleasurable component of nicotine, which may be mediated by corticosterone © 2011 The Authors Journal of Neurochemistry© 2011 International Society for Neurochemistry.

© 2011 The Authors Journal of Neurochemistry © 2011 International Society for Neurochemistry.

PMID:
22191943
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15.
J Interv Card Electrophysiol. 2011 Dec 23. [Epub ahead of print]

Clinical features of patients with left atrial thrombus undergoing anticoagulant therapy.

Source

Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.

Abstract

PURPOSE:

Left atrial (LA) thrombus was sometimes found by transesophageal echocardiography (TEE) in non-valvular atrial fibrillation (AF), even in the setting of continuous warfarin therapy. A D-dimer cutoff level of 0.50 μg/mL appears to be a useful marker to rule out venous vein thrombosis. This study analyzed the clinical features of patients with LA thrombi who received anticoagulant therapy and whether the D-dimer test is useful to exclude LA thrombus.

METHODS:

Two hundred twenty-five consecutive patients with AF (149 with paroxysmal and 76 with persistent) were enrolled. All patients received continuous warfarin therapy with the prothrombin time-international normalized ratio (PT-INR) between 1.6 and 3.0 for more than 3 months and TEE was performed.

RESULTS:

LA thrombi were present in 23 and absent in 202 patients. Age, gender, and PT-INR (1.96 ± 0.59 vs. 1.98 ± 0.53) were not different between the two groups. Persistent AF (65 vs. 30%; p < 0.005), LA diameter (44 ± 5 vs. 40 ± 7 mm; p < 0.005), ejection fraction (57 ± 13 vs. 65 ± 9%; p < 0.005), brain natriuretic peptide levels (203 ± 209 vs. 105 ± 166 pg/mL; p < 0.05), D-dimer (0.55 ± 0.70 vs. 0.16 ± 0.20 μg/mL; p < 0.001), LA appendage flow velocity (33 ± 15 vs. 54 ± 19 cm/s; p < 0.001), CHADS(2) scores (2 ± 1 vs. 1 ± 1; p < 0.005), and CHA(2)DS(2)-VASc scores (3 ± 2 vs. 2 ± 1; p < 0.005) were significantly different in both groups. Although multivariate analysis showed that D-dimer and LA appendage flow velocity were significant independent predictors of LA thrombus, D-dimer levels below 0.5 μg/mL were found in 19 of 23 patients with LA thrombi.

CONCLUSION:

D-dimer levels below 0.5 μg/mL is not enough to rule out LA thrombus in AF patients with well-controlled anticoagulation.

PMID:
22190167
[PubMed - as supplied by publisher]
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16.
Curr Opin Pharmacol. 2011 Dec 19. [Epub ahead of print]

Neurotherapeutics to inhibit exocytosis from sensory neurons for the control of chronic pain.

Source

International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland.

Abstract

There is a pressing unmet need for long-acting and effective therapeutics to alleviate symptoms of the varied forms of chronic pain. As many sufferers do not respond satisfactorily to non-addictive anti-nociceptives, a new treatment has emerged using inhibitors for the release of pain mediators from peripheral sensory nerves to give prolonged benefit. This strategy relies on proteolytically inactivating intra-neuronal SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptors) proteins which are essential for regulated exocytosis of transmitters, peptides and other pain signalling molecules. Success has been achieved with botulinum neurotoxin A (BoNT/A) which targets neuronal acceptors via its heavy chain, becomes endocytosed and translocated into the cytosol where the long-lived protease of its light chain potently and specifically cleaves SNAP-25 (synaptosomal-associated protease of Mr=25k). Encouragingly, clinical trials have shown that local injections of BOTOX(®) (BoNT/A complex) reduce chronic migraine symptoms including frequency and intensity for many months. Several serotypes of the neurotoxin moiety alone have been prepared recombinantly using Escherichia coli, which exhibit optimal neuroparalysis. Moreover, an engineered chimera of BoNT/E in which its binding domain was replaced with that from /A efficaciously inhibits the TRPV1 (transient receptor potential vanilloid type 1)-triggered release of CGRP (calcitonin gene-related peptide) from cultured sensory neurons, and suppresses the resultant excitatory effects in brain slices. A longer acting composite toxin, containing the protease of type E attached to BoNT/A, displays prolonged amelioration of pain symptoms in an animal model of inflammatory pain. This provides proof of principle that therapeutically advantageous features of /E (most robust inhibitor of CGRP release) and /A (targeting to sensory neurons and dramatic extension of the longevity of E protease) can be incorporated into a single synergistically active anti-nociceptive.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID:
22188874
[PubMed - as supplied by publisher]
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17.
Bioanalysis. 2011 Dec;3(24):2709-15.

Conference report: the 19th international reid bioanalytical forum.

Source

Huntingdon Life Sciences, Woolley Road, Alconbury, Huntingdon, Cambridgeshire, PE16 5HS, UK. hillh@ukorg.huntingdon.com.

Abstract

The 19th International Reid Bioanalytical Forum was attended by over 120 participants. The Forum divided into approximately eight broad topics, although not always in the same session. The meeting commenced with a discussion on metabolites in safety testing, with emphasis on enabling technologies and philosophies. This was followed by a variety of regulatory-based issues initiated by Brian Booth of the US FDA. The next day started with a review of developing technologies in LC-MS and some anecdotal troubleshooting experiences. Interspersed among the sessions were experiences with bioanalysis in the discovery environment, biomarker-based topics and the rapidly developing field of the quantitation of proteins and peptides using LC-MS. The meeting finished with the best-attended session of the Forum on developing trends in using dried blood spots.

PMID:
22185269
[PubMed - in process]
Free full text
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18.
Int J Obes (Lond). 2011 Dec 20. doi: 10.1038/ijo.2011.256. [Epub ahead of print]

Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesity-related insulin resistance.

Source

Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain.

Abstract

Objective:Lipopolysaccharide-binding protein (LBP) is a 65-kDa acute-phase protein present in blood at high concentrations, known to be derived from the liver. We aimed to gain insights into the association of circulating LBP with insulin resistance in humans and mice.Methods, design and measurements:We studied the cross-sectional (n=222) and weight loss-induced (n=34) associations of LBP (enzyme-linked immunosorbent assay) with inflammatory and metabolic parameters (including minimal model-measured insulin sensitivity), and the effects of high-fat diet (HFD), metformin and genetic insulin sensitization (glucagon-like peptide 1 receptor knockout model) in mice.Results:Circulating LBP concentration was significantly increased in subjects with type 2 diabetes and dramatically increased in subjects with morbid obesity. LBP was significantly associated with insulin sensitivity and different inflammatory markers and decreased after weight loss (22.2±5.8 vs 16.2±9.3 μg ml(-1), P<0.0001) in association with changes in body mass index and insulin sensitivity. Circulating LBP concentration was increased in HFD mice, whereas decreased in glucagon-like peptide 1 receptor knockout mice (significantly more insulin sensitive than wild-type mice) and after metformin administration.Conclusion:LBP is an inflammatory marker associated with obesity-related insulin resistance.International Journal of Obesity advance online publication, 20 December 2011; doi:10.1038/ijo.2011.256.

PMID:
22184060
[PubMed - as supplied by publisher]
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19.
Biochim Biophys Acta. 2011 Dec 13;1823(2):206-214. [Epub ahead of print]

The SH2-domain of SHIP1 interacts with the SHIP1 C-terminus: Impact on SHIP1/Ig-α interaction.

Source

RWTH Aachen University, Medical Faculty, Department of Biochemistry and Molecular Immunology, Institute of Biochemistry and Molecular Biology, 52074 Aachen, Germany; International Max Planck Research School, 79108 Freiburg, Germany.

Abstract

The SH2-containing inositol 5'-phosphatase, SHIP1, negatively regulates signal transduction from the B cell antigen receptor (BCR). The mode of coupling between SHIP1 and the BCR has not been elucidated so far. In comparison to wild-type cells, B cells expressing a mutant IgD- or IgM-BCR containing a C-terminally truncated Ig-α respond to pervanadate stimulation with markedly reduced tyrosine phosphorylation of SHIP1 and augmented activation of protein kinase B. This indicates that SHIP1 is capable of interacting with the C-terminus of Ig-α. Employing a system of fluorescence resonance energy transfer in S2 cells, we can clearly demonstrate interaction between the SH2-domain of SHIP1 and Ig-α. Furthermore, a fluorescently labeled SH2-domain of SHIP1 translocates to the plasma membrane in an Ig-α-dependent manner. Interestingly, whereas the SHIP1 SH2-domain can be pulled-down with phospho-peptidescorresponding to the immunoreceptor tyrosine-based activation motif (ITAM) of Ig-α from detergent lysates, no interaction between full-length SHIP1 and the phosphorylated Ig-α ITAM can be observed. Further studies show that the SH2-domain of SHIP1 can bind to the C-terminus of the SHIP1 molecule, most probably by inter- as well as intra-molecular means, and that this interaction regulates the association between different forms of SHIP1 and Ig-α.

Copyright © 2011 Elsevier B.V. All rights reserved.

PMID:
22182704
[PubMed - as supplied by publisher]
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20.
PLoS Negl Trop Dis. 2011 Dec;5(12):e1419. Epub 2011 Dec 13.

In Vivo Expression of Salmonella enterica Serotype Typhi Genes in the Blood of Patients with Typhoid Fever in Bangladesh.

Source

International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh.

Abstract

BACKGROUND:

Salmonella enterica serotype Typhi is the cause of typhoid fever. It is a human-restricted pathogen, and few data exist on S. Typhi gene expression in humans.

METHODOLOGY/PRINCIPAL FINDINGS:

We applied an RNA capture and amplification technique, Selective Capture of Transcribed Sequences (SCOTS), and microarray hybridization to identify S. Typhi transcripts expressed in the blood of five humans infected with S. Typhi in Bangladesh. In total, we detected the expression of mRNAs for 2,046 S. Typhi genes (44% of the S. Typhi genome) in human blood; expression of 912 genes was detected in all 5 patients, and expression of 1,100 genes was detected in 4 or more patients. Identified transcripts were associated with the virulence-associated PhoP regulon, Salmonella pathogenicity islands, the use of alternative carbon and energy sources, synthesis and transport of iron, thiamine, and biotin, and resistance to antimicrobial peptides and oxidative stress. The most highly represented group were genes currently annotated as encoding proteins designated as hypothetical, unknown, or unclassified. Of the 2,046 detected transcripts, 1,320 (29% of the S. Typhi genome) had significantly different levels of detection in human blood compared to in vitro cultures; detection of 141 transcripts was significantly different in all 5 patients, and detection of 331 transcripts varied in at least 4 patients. These mRNAs encode proteins of unknown function, those involved in energy metabolism, transport and binding, cell envelope, cellular processes, and pathogenesis. We confirmed increased expression of a subset of identified mRNAs by quantitative-PCR.

CONCLUSIONS/SIGNIFICANCE:

We report the first characterization of bacterial transcriptional profiles in the blood of patients with typhoid fever. S. Typhi is an important global pathogen whose restricted host range has greatly inhibited laboratory studies. Our results suggest that S. Typhi uses a largely uncharacterized genetic repertoire to survive within cells and utilize alternate energy sources during infection.

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