Tuesday, January 17, 2012

peptide 2.0 | What is peptide 2.0|Papers on peptide 2.0|Research on peptide 2.0| Publications on peptide 2.0

    Results: 1 to 20 of 23388

    1.
    J Control Release. 2012 Jan 5. [Epub ahead of print]

    Positron emission tomography evaluation of somatostatin receptor targeted (64)Cu-TATE-liposomes in a human neuroendocrine carcinoma mouse model.

    Source

    Technical University of Denmark, DTU Nanotech, Department of Micro- and Nanotechnology, Center for Nanomedicine and Theranostics, Building 423, 2800 Lyngby, Denmark; Technical University of Denmark, Hevesy Laboratory, Risø National Laboratory for Sustainable Energy, Frederiksborgvej 399, 4000 Roskilde, Denmark.

    Abstract

    Targeted therapeutic and diagnostic nanocarriers functionalized with antibodies, peptides or other targeting ligands that recognize over-expressed receptors or antigens on tumor cells have potential in the diagnosis and therapy of cancer. Somatostatin receptors (SSTRs) are over-expressed in a variety of cancers, particularly neuroendocrine tumors (NETs) and can be targeted with somatostatin peptide analogs such as octreotate (TATE). In the present study we investigate liposomes that target SSTR in a NET xenograft mouse model (NCI-H727) by use of TATE. TATE was covalently attached to the distal end of DSPE-PEG(2000) on PEGylated liposomes with an encapsulated positron emitter (64)Cu that can be utilized for positron emission tomography (PET) imaging. The biodistribution and pharmacokinetics of the (64)Cu-loaded PEGylated liposomes with and without TATE was investigated and their ability to image NETs was evaluated using PET. Additionally, the liposome accumulation and imaging capability was compared with free radiolabelled TATE peptide administered as (64)Cu-DOTA-TATE. The presence of TATE on the liposomes resulted in a significantly faster initial blood clearance in comparison to control-liposomes without TATE. PEGylated liposomes with or without TATE accumulated at significantly higher quantities in NETs (5.1±0.3 and 5.8±0.2 %ID/g, respectively) than the free peptide (64)Cu-DOTA-TATE (1.4±0.3 %ID/g) 24h post-injection. Importantly, (64)Cu-loaded PEGylated liposomes with TATE showed significantly higher tumor-to-muscle (T/M) ratio (12.7±1.0) than the control-liposomes without TATE (8.9±0.9) and the (64)Cu-DOTA-TATE free peptide (7.2±0.3). The higher T/M ratio of the PEGylated liposomes with TATE suggests some advantage of active targeting of NETs, although no absolute benefit in tumor accumulation over the non-targeted liposomes was observed. Collectively, these data showed that (64)Cu-loaded PEGylated liposomes with TATE conjugated to the surface could be promising new imaging agents for visualizing tumor tissue and especially NETs using PET.

    Copyright © 2011. Published by Elsevier B.V.

    PMID:
    22245688
    [PubMed - as supplied by publisher]
    2.
    J Agric Food Chem. 2012 Jan 9. [Epub ahead of print]

    Purification of a Novel Angiotensin-I-Converting Enzyme (ACE) InhibitoryPeptide with Antihypertensive Effect from Loach (Misgurnus anguillicaudatus).

    Abstract

    In order to isolate and characterize novel angiotensin-I-converting enzyme (ACE) inhibitory peptide from loach (Misgurnus anguillicaudatus), six proteases of pepsin, -chymotrypsin, bromelain, papain, alcalase and neutrase, were used to hydrolyze loach protein. The hydrolysate (LPH) generated by bromelain (ratio of enzyme to substrate, 3:1000 (w/w)) was found to have the highest ACE inhibitory activity (IC50, 613.2 ± 8.3 g/mL). Therefore, it was treated by ultrafiltration to afford fraction of LPH-IV (MW < 2.5 kDa) with an IC50 of 231.2 ± 3.8 g/mL, having higher activity than the other fractions. Then, LPH-IV was isolated and purified by consecutive purification steps of gel filtration chromatography and reverse-phase HPLC to afford a purified peptide with an IC50 of 18.2 ± 0.9 g/mL, an increase of 33.7-fold in ACE inhibitory activity compared with that of LPH. The purified peptide was identified as Ala-His-Leu-Leu (452 Da) by Q-TOF mass spectrometry and amino acid analyzer. Antihypertensive effect in spontaneously hypertensive rats revealed that oral administration of LPH-IV could decrease systolic blood pressure significantly.

    PMID:
    22224920
    [PubMed - as supplied by publisher]
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    3.
    J Nucl Med. 2012 Jan;53(1):138-45.

    Quantitative PET of Human Urokinase-Type Plasminogen Activator Receptor with 64Cu-DOTA-AE105: Implications for Visualizing Cancer Invasion.

    Source

    The Danish Chinese Center for Proteases and Cancer, Copenhagen, Denmark.

    Abstract

    Expression levels of the urokinase-type plasminogen activator receptor (uPAR) represent an established biomarker for poor prognosis in a variety of human cancers. The objective of the present study was to explore whether noninvasive PET can be used to perform a quantitative assessment of expression levels of uPAR across different human cancer xenograft models in mice and to illustrate the clinical potential of uPAR PET in future settings for individualized therapy.

    METHODS:

    To accomplish our objective, a linear, high-affinity uPAR peptide antagonist, AE105, was conjugated with DOTA and labeled with (64)Cu ((64)Cu-DOTA-AE105). Small-animal PET was performed in 3 human cancer xenograft mice models, expressing different levels of human uPAR, and the tumor uptake was correlated with the uPAR expression level determined by uPAR enzyme-linked immunosorbent assay. The tumor uptake pattern of this tracer was furthermore compared with (18)F-FDG uptake, and finally the correlation between sensitivity toward 5-fluorouracil therapy and uPAR expression level was investigated.

    RESULTS:

    The uPAR-targeting PET tracer was produced in high purity and with high specific radioactivity. A significant correlation between tumor uptake of (64)Cu-DOTA-AE105 and uPAR expression was found (R(2) = 0.73; P < 0.0001) across 3 cancer xenografts, thus providing a strong argument for specificity. A significantly different uptake pattern of (64)Cu-DOTA-AE105, compared with that of (18)F-FDG, was observed, thus emphasizing the additional information that can be obtained on tumor biology using (64)Cu-DOTA-AE105 PET. Furthermore, a significant correlation between baseline uPAR expression and sensitivity toward 5-fluorouracil was revealed, thus illustrating the possible potentials of uPAR PET in a clinical setting.

    CONCLUSION:

    Our results clearly demonstrate that the peptide-based PET tracer (64)Cu-DOTA-AE105 enables the noninvasive quantification of uPAR expression in tumors in vivo, thus emphasizing its potential use in a clinical setting to detect invasive cancer foci and for individualized cancer therapy.

    PMID:
    22213823
    [PubMed - in process]
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    4.
    Inflammation. 2011 Dec 29. [Epub ahead of print]

    The Efficiency of a Urotensin II Antagonist in an Experimental Lung Fibrosis Model.

    Source

    Department of Rheumatology, Sahinbey Medical Center, School of Medicine, Gaziantep University, Gaziantep, 27310, Turkey.

    Abstract

    Pulmonary fibrosis is a chronic disease. Urotensin II (U-II) is a new peptide with angiogenic and profibrotic features. Therefore, we aim to evaluate the antagonism of U-II with palosuran in an animal model and plan to measure U-II, endothelin-1 (ET-1), and transforming growth factor-β1 (TGF-β1) and their association with lung fibrosis. Thirty Wistar male rats were used in the study and were divided into three groups: group 1, control; group 2, bleomycin-induced lung fibrosis group; and group 3, bleomycin-induced lung fibrosis with treatment palosuran group. U-II level (nanograms per milliliter) was 2.957 ± 0.159 in group1, 3.188 ± 0.122 in group 2, and 2.970 ± 0.165 in group 3 (p = 0.002). The ET-1 level (picograms per milliliter) was 4.486 ± 0.376 in group 1, 9.086 ± 1.850 in group 2, and 4.486 ± 0.376 in group 3 (p < 0.001). The TGF-β1 (nanograms per milliliter) level was 73.143 ± 9.96 in group 1, 84.81 ± 4.73 in group 2, and 77.86 ± 5.77 in group 3 (p = 0.006). Finally, the fibrosis score was 0.7 ± 0.48 in group 1, 4.4 ± 1.34 in group 2, and 3.2 ± 0.63 in group 3 (p < 0.001). There is a statistically significant positive relationship between fibrosis scores and the UT-II, ET-1, and TGF-β1 levels of the experimental lung fibrosis model. We believe U-II is an important mediator in lung fibrosis models, and its antagonism with palosuran could be a new treatment choice for interstitial lung fibrosis, but further studies need to be conducted to verify the findings of the current study.

    PMID:
    22205238
    [PubMed - as supplied by publisher]
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    5.
    Gan To Kagaku Ryoho. 2011 Nov;38(12):1903-5.

    [The development of a novel cancer vaccine using Peptide vaccine for patients with advanced pancreatic cancer].

    [Article in Japanese]

    Source

    Second Dept. of Surgery, Wakayama Medical University.

    Abstract

    Vascular endothelial growth factor receptor 2( VEGFR2) is an essential factor in tumor angiogenesis and the growth of pancreatic cancer. In addition, it is overexpressed in tumor blood vessels, however, VEGFR2 is not expressed in normal vessels, which makes an attractive candidate as a molecular target for antiangiogenic cancer immunotherapy. Furthermore, the tumor cell-indirect immunotherapy targeting VEGFR2 is expected to overcome tumor immune escape. The phase I clinical trial using VEGFR2-169 peptide that successfully induced specific CTLs in cancer patients, combined with gemcitabine (GEM), was conducted for patients with advanced pancreatic cancer. VEGFR2-169 was subcutaneously injected weekly in a dose-escalation manner( doses of 0.5, 1.0, 2.0 mg/body, 6 patients/1 cohort). GEM was administered at a dose of 1,000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. No dose limiting toxicity was observed. Specific CTLs reacting to VEGFR2-169 were induced in 11(61%)of the 18 patients. Our protocol was safe and well-tolerated. VEGFR2-169 was immunogenic under the condition with GEM treatment. From an immunological point of view, the optimal dose might be 2.0 mg/body. A randomized phase II/III clinical trial started in January 2009 to demonstrate the clinical benefits of VEGFR2-169 for advanced pancreatic cancer patients.

    PMID:
    22202233
    [PubMed - in process]
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    6.
    Nan Fang Yi Ke Da Xue Xue Bao. 2011 Dec;31(12):2002-5.

    [Cloning, prokaryotic expression and antifungal assay of Tenecin gene encoding an antibacterial peptide from Tenebrio molitor].

    [Article in Chinese]

    Source

    School of Basic Medicine, Wannan Medical College, Wuhu 241002, China. E-mail: liuyingwuhu @wnmc.edu.cn.

    Abstract

    OBJECTIVE:

    To clone tenecin gene, an antibacterial peptide gene, from Tenebrio molitor for its prokaryotic expression and explore the molecular mechanism for regulating the expression of antibacterial peptide in Tenebrio molitor larvae.

    METHODS:

    The antibacterial peptide was induced from the larvae of Tenebrio molitor by intraperitoneal injection of Escherichia coli DH-5α (1×10(8)/ml). RT-PCR was performed 72 h after the injection to clone Tenecin gene followed by sequencing and bioinformatic analysis. The recombinant expression vector pET-28a(+)-Tenecin was constructed and transformed into E. coli BL21(DE3) cells and the expression of tenecin protein was observed after IPTG induction.

    RESULTS:

    Tenecin expression was detected in transformed E.coli using SDS-PAGE after 1 mmol/L IPTG induction. Tenecin gene, which was about 255 bp in length, encoded Tenecin protein with a relative molecular mass of 9 kD. Incubation of E.coli with 80, 60, 40, and 20 µg/ml tenecin for 18 h resulted in a diameter of the inhibition zone of 25.1∓0.03, 20.7∓0.06, 17.2∓0.11 and 9.3∓0.04 mm, respectively.

    CONCLUSIONS:

    Tenecin protein possesses strong antibacterial activity against E. coli DH-5α, which warrants further study of this protein for its potential as an antibacterial agent in clinical application.

    PMID:
    22200700
    [PubMed - in process]
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    7.
    Reprod Biomed Online. 2011 Nov 27. [Epub ahead of print]

    Neurotrophins (BDNF and NGF) in follicular fluid of women with different infertility diagnoses.

    Source

    Deptartment of Obstetrics and Gynecology, Health Sciences Centre, McMaster University, Hamilton, Ontario, Canada.

    Abstract

    Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are intra-ovarian signalling peptides that are important in follicle development and oocyte maturation. In the ovary, neurotrophin expression is regulated by gonadotrophins. Therefore, this study postulates that aetiology of infertility will affect follicular-fluid BDNF and NGF concentrations. Follicular fluid from the first follicle aspirated from 190 infertile women attending a university-affiliated fertility programme (McMaster University and ONE Fertility, Burlington, Ontario) was collected between February 2004 and November 2010. The relationship between follicular-fluid BDNF and NGF concentration and age, day-3 FSH and peak serum oestradiol concentrations and antral follicle count was determined. Participants were aged between 24 and 44years (mean±SEM, 35.2±0.3years) of age. The median concentrations of BDNF and NGF in the follicular fluid was 19.4pg/ml and 344.6ng/ml, respectively. The concentrations of BDNF and NGF were significantly related (P=0.028) but only the BDNF concentration was significantly higher (P<0.05) in women with unexplained infertility compared with other causes of infertility. It is concluded that, apart from unexplained infertility, the underlying cause of infertility did not affect ovarian output of BDNF and NGF in response to ovulation induction. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are proteins that are produced in the brain, where they play a role in the development and survival of brain cells. Emerging evidence has shown that these proteins are also made in the ovary, where they are thought to be important in the recruitment and development of a woman's oocytes (eggs). In the ovary, the hormones responsible for controlling the production of female hormones, such as oestradiol, are believed to also regulate the production of BDNF and NGF. Therefore, we proposed that the concentrations of these proteins in the fluid surrounding the developing egg (follicular fluid) could be affected by the underlying causes of infertility. Therefore we measured the concentration of these proteins in the follicular fluid collected from 190 infertile women attending a university-affiliated fertility programme (McMaster University and ONE Fertility, Burlington, Ontario). In this study, the concentrations of BDNF and NGF were significantly related but only the BDNF concentration was significantly higher in women with unexplained infertility compared with other causes of infertility. We conclude that, apart from unexplained infertility, the underlying cause of infertility did not affect ovarian output of these proteins.

    Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

    PMID:
    22197602
    [PubMed - as supplied by publisher]
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    8.
    Rheumatol Int. 2011 Dec 21. [Epub ahead of print]

    Serum anti-cyclic citrullinated peptide antibodies may predict disease activity in rheumatoid arthritis.

    Source

    Internal Medicine Ward, Division of Rheumatology, Shahid Beheshti Hospital, Kashan University of Medical Sciences, Kashan, Iran.

    Abstract

    To define the relationship between serum anti-cyclic citrullinated peptide antibodies (anti-CCP) and disease activity, and to construct a new disease activity index by using anti-CCP in rheumatoid arthritis (RA). One hundred and five RA patients were included. Disease activity based on DAS28-ESR and serum anti-CCP was measured. There was correlation between serum anti-CCP and DAS28-ESR. (R (2) = 0.71, P value < 0.01). New disease activity index was developed by replacing anti-CCP with ESR in DAS28-ESR. There was correlation between new model and DAS28-ESR. (R (2) = 0.91, P value < 0.01) The new composite index best cut-off values corresponding to DAS28-ESR values of 2.6, 3.2, and 5.1 were 3.21, 3.38, and 4.74, respectively. There was agreement between new model and DAS28-ESR for determination of patients in different disease activity categories. (Kappa = 0.71, P value < 0.01). The new disease activity index that applies serum anti-CCP may predict disease activity in RA.

    PMID:
    22187060
    [PubMed - as supplied by publisher]
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    9.
    Zhonghua Nei Ke Za Zhi. 2011 Sep;50(9):781-4.

    [The protection of islet β-cells in db/db mice by combination pioglitazone and glucagon like peptide-1 treatment].

    [Article in Chinese]

    Source

    Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China. Email: ywy_1010@yahoo.com.cn.

    Abstract

    OBJECTIVES:

    To evaluate the effect of combination of liraglutide, a glucagon-like peptide-1 analogue and pioglitazone, an insulin sensitizer, on diabetic db/db mice.

    METHODS:

    Thirty-five 8-week old male db/db mice were divided into control group (n = 8), pioglitazone group (n = 9), liraglutide group (n = 9) and combined therapeutic group (n = 9), which was given normal saline 0.1 ml, 2/d, pioglitazone 24 mg×kg(-1)×d(-1) (feed contained 0.02% pioglitazone) + normal saline 0.1 ml, 2/d, liraglutide 300 mg/kg, 2/d, and pioglitazone 20 mg×kg(-1)×d(-1) (feed contained 0.02% pioglitazone) + liraglutide 300 mg/kg, 2/d, respectively. Liraglutide were given at 8:00 and 16:00 via subcutaneous injection after having been diluted with sterilized normal saline. Effect on glucose, lipid metabolism and islet β-cell preservation were assessed after 4 weeks. Oneway ANOVA was adopted for statistical analysis.

    RESULTS:

    Combination therapy displayed promising anti-hyperglycemic [glycosylated hemoglobin A1c: (4.5 ± 0.6)% vs. (7.3 ± 0.4)%, P < 0.001]. Glucose tolerance were improved assessed by area under curve (AUC) of glucose by intraperitoneal glucose tolerance test (IPGTT) [(1814 ± 91) mmol×min×L(-1) vs. (4042 ± 183) mmol×min×L(-1), P < 0.001]; insulin release response to glucose were also preserved as AUC of insulin by IPGTT was higher [(1639 ± 372) µg×min×L(-1) vs.(834 ± 201) µg×min×L(-1)]. Combination therapy also reduced circulated free fatty acids and TG [(202.0 ± 20.4) µmol/L vs. (272.5 ± 21.7) µmol/L, (0.81 ± 0.28) mmol/L vs. (1.35 ± 0.21) mmol/L], and increased plasma adiponectin [(16.7 ± 2.0) mg/L vs. (10.2 ± 1.8) mg/L]. All P value < 0.05. Islet immunohistochemistry showed that combination therapy significantly increased insulin positive area were [(59.5 ± 1.5)% vs. (22.4 ± 1.5)%] and ratio of Brdu positive β-cells was three folds than vehicle-treated mice [(2.4 ± 0.5)% vs. (0.8 ± 0.3)%], both greater than each single treatment. Combined therapy significantly improved islet β cell/α cell distribution, which led to islet recovery.

    CONCLUSIONS:

    Combined therapy improves glucose and lipid metabolism, preserves islet β-cell function and stimulates β-cell proliferation, greater than either liraglutide or pioglitazone treatment alone.

    PMID:
    22176969
    [PubMed - in process]
    10.
    Nucl Med Biol. 2011 Dec 13. [Epub ahead of print]

    (68)Ga-labeling and in vivo evaluation of a uPAR binding DOTA- and NODAGA-conjugated peptide for PET imaging of invasive cancers.

    Source

    The Danish-Chinese Center for Proteases and Cancer, Denmark; Department of Clinical Physiology, Nuclear Medicine and PET, Center for Diagnostic Investigations, Rigshospitalet, 2100-Copenhagen, Denmark; Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, 2100-Copenhagen, Denmark.

    Abstract

    INTRODUCTION:

    The urokinase-type plasminogen activator receptor (uPAR) is a well-established biomarker for tumor aggressiveness and metastatic potential. DOTA-AE105 and DOTA-AE105-NH(2) labeled with (64)Cu have previously been demonstrated to be able to noninvasively monitor uPAR expression using positron emission tomography (PET) in human cancer xenograft mice models. Here we introduce (68)Ga-DOTA-AE105-NH(2) and (68)Ga-NODAGA-AE105-NH(2) and evaluate their imaging properties using small-animal PET.

    METHODS:

    Synthesis of DOTA-AE105-NH(2) and NODAGA-AE105-NH(2) was based on solid-phase peptide synthesis protocols using the Fmoc strategy. (68)GaCl(3) was eluted from a (68)Ge/(68)Ga generator. The eluate was either concentrated on a cation-exchange column or fractionated and used directly for labeling. For in vitro characterization of both tracers, partition coefficient, buffer and plasma stability, uPAR binding affinity and cell uptake were determined. To characterize the in vivo properties, dynamic microPET imaging was carried out in nude mice bearing human glioma U87MG tumor xenograft.

    RESULTS:

    In vitro experiments revealed uPAR binding affinities in the lower nM range for both conjugated peptides and identical to AE105. Labeling of DOTA-AE105-NH(2) and NODAGA-AE105-NH(2) with (68)Ga was done at 95°C and room temperature, respectively. The highest radiochemical yield and purity were obtained using fractionated elution, whereas a negative effect of acetone on labeling efficiency for NODAGA-AE105-NH(2) was observed. Good stability in phosphate-buffered saline and mouse plasma was observed. High cell uptake was found for both tracers in U87MG tumor cells. Dynamic microPET imaging demonstrated good tumor-to-background ratio for both tracers. Tumor uptake was 2.1% ID/g and 1.3% ID/g 30 min postinjection and 2.0% ID/g and 1.1% ID/g 60 min postinjection for (68)Ga-NODAGA-AE105-NH(2) and (68)Ga-DOTA-AE105-NH(2), respectively. A significantly higher tumor-to-muscle ratio (P<.05) was found for (68)Ga-NODAGA-AE105-NH(2) 60 min postinjection.

    CONCLUSIONS:

    The use of (68)Ga-DOTA-AE105-NH(2) and (68)Ga-NODAGA-AE105-NH(2) as the first gallium-68 labeled uPAR radiotracers for noninvasive PET imaging is reported, which combine versatility with good imaging properties. These new tracers thus constitute an interesting alternative to the (64)Cu-labeled version ((64)Cu-DOTA-AE105 and 64Cu-DOTA-AE105-NH(2)) for detecting uPAR expression in tumor tissue. In our hands, the fractionated elution approach was superior for labeling of peptides, and (68)Ga-NODAGA-AE105-NH(2) is the favored tracer as it provides the highest tumor-to-background ratio.

    Copyright © 2011 Elsevier Inc. All rights reserved.

    PMID:
    22172391
    [PubMed - as supplied by publisher]
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    11.
    Xenotransplantation. 2011 Nov;18(6):328-42. doi: 10.1111/j.1399-3089.2011.00676.x.

    Species incompatibilities in the pig-to-macaque islet xenotransplant model affect transplant outcome: a comparison with allotransplantation.

    Source

    Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.

    Abstract

    Graham ML, Bellin MD, Papas KK, Hering BJ, Schuurman H-J. Species incompatibilities in the pig-to-macaque islet xenotransplant model affect transplant outcome: a comparison with allotransplantation. Xenotransplantation 2011; 18: 328-342. © 2011 John Wiley & Sons A/S. Abstract:  Background:  Porcine islet transplantation into diabetic non-human primates is considered most relevant in translational research supporting a clinical application. Most studies have focused on immunosuppressive protocols, while metabolic aspects have mainly been utilized in graft monitoring. We evaluated data from our group regarding human and non-human primate (NHP) allotransplantation and pig-to-NHP xenotransplantation to identify incompatibilities in metabolic factors and their consequences for transplant outcomes. Methods:  Basic gluco-metabolic parameters (fasting blood glucose, C-peptide, and response to stimulation with arginine or glucose) were derived from literature (humans), 72 macaques, and 47 adult Landrace pigs. Islet preparations from 15 human deceased donors, 61 macaques, and 23 adult pigs were compared with respect to yield, fractional viability assessed by oxygen consumption normalized for DNA, and in vitro glucose-induced insulin release. Metabolic parameters at day 75 after a single islet transplantation in the liver were compared for 19 patients and 9 macaques receiving an allotransplant and 11 macaques receiving a porcine xenotransplant: recipients received chronic immunosuppression. Results:  Pigs differ from NHPs and humans by a much lower C-peptide level (0.42 vs. 1.3 to2.0 ng/ml, respectively) and a 2- to 7-fold lower C-peptide response to arginine stimulation. In contrast, NHPs have the highest metabolic demand as evidenced by a high C-peptide and high C-peptide response to arginine stimulation; values are about twice higher than in humans. For manufactured islet preparations, these differences are reflected by glucose-stimulated insulin release (the stimulation index for pigs is 1.5, for humans 3.8, and for macaques 7.7), but not by fractional viability, which was in the same range. The day 75 outcome after transplantation assessed by C-peptide was similar for allotransplanted humans and NHPs (80 to 90% good graft function) and lower in xenografted NHPs (36% good graft function); gluco-metabolic parameters were in accordance with graft function, albeit different between species because normoglycemia under exogenous insulin is maintained more aggressively in patients than in NHPs. In xenografted NHPs, the shift in glycemic control with respect to normal values, combined with low values of circulating porcine C-peptide, resembled more the normal condition in a pig than that in a macaque. Conclusions:  The substantially lower glucose-induced insulin response in adult porcine islet preparations as opposed to islets manufactured from humans or macaques combined with the much higher need for insulin in macaques than in humans creates an imbalance between the metabolic demand and the engrafted islet mass in the pig-to-NHP xenograft recipient. Engrafted islet mass is affected by dose, suggesting that a much higher dose level of islets is necessary in the xenogeneic setting than in human or NHP allotransplantation, and pig islets need to be given at a higher dose in macaques than the anticipated effective dose in humans. To cope with differences in metabolic demand and presumably also metabolic dynamics, a liberal regime in supportive exogenous insulin might be essential to achieve long-term survival. These intrinsic characteristics of the NHP model deserve consideration to optimally design experimental studies with the perspective of translational value of results.

    © 2011 John Wiley & Sons A/S.

    PMID:
    22168140
    [PubMed - in process]
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    12.
    Analyst. 2012 Feb 7;137(3):601-7. Epub 2011 Dec 8.

    Colorimetric assay for parallel detection of Cd(2+), Ni(2+) and Co(2+) usingpeptide-modified gold nanoparticles.

    Source

    Lab of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Meilong RD 130, Shanghai, 200237, China. bcye@ecust.edu.cn.

    Abstract

    A colorimetric assay has been developed for parallel detection of Cd(2+), Ni(2+) and Co(2+) utilizing peptide-modified gold nanoparticles (P-AuNPs) as a sensing element based on its unique surface plasmon resonance properties. The functional peptide ligand, CALNNDHHHHHH, was self-assembled on gold nanoparticles (AuNPs) to produce P-AuNPs probe. The P-AuNPs probe could be used to simultaneously detect and showed different responses to the three ions Cd(2+), Ni(2+) and Co(2+) in an aqueous solution based on the aggregation-induced color change of AuNPs. The method showed good selectivity for Cd(2+), Ni(2+) and Co(2+) over other metal ions, and detection limit as low as 0.05 μM Cd(2+), 0.3 μM Ni(2+) or 2 μM Co(2+). To simultaneously (or parallel) detect the three metal ions coexisting in a sample, EDTA and imidazole were applied to mask Co(2+) and Ni(2+) for detecting Cd(2+), glutathione and EDTA were applied to mask Cd(2+) and Co(2+) for detecting Ni(2+), and glutathione and imidazole were applied to mask Cd(2+) and Ni(2+) for detecting Co(2+). Finally, the simple and cost-effective probe could be successfully applied for simultaneously detecting Cd(2+), Ni(2+), and Co(2+) in river water. Because this novel P-AgNPs-based probe design offers many advantages, including simplicity of preparation and manipulation compared with other methods that employ specific strategies, the sensing system shows potential application in the developing region for monitoring water quality.

    PMID:
    22158918
    [PubMed - in process]
    13.
    Biochemistry (Mosc). 2011 Dec;76(12):1337-41.

    Interaction of synthetic Peptide octarphin with rat myocardium membranes.

    Source

    Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia. navolotskaya@fibkh.serpukhov.su.

    Abstract

    A selective agonist of non-opioid β-endorphin receptor synthetic peptide octarphin (TPLVTLFK, specific activity 28 Ci/mmol) was prepared. The [3H]octarphin binding to rat myocardium membranes before and after experimental myocardial infarction (EMI) was studied. It was found that [3H]octarphin with high affinity and specificity binds to non-opioid β-endorphin receptor of rat myocardium membranes before EMI: K(d1) value of the [3H]octarphin specific binding to membranes was 1.8 ± 0.2 nM. In 3 h after EMI a sharp lowering in affinity of the binding is observed (K(d2) = 13.3 ± 0.4 nM), and in 48 h its almost complete restoration (K(d4) = 2.2 ± 0.3 nM). The results indicate participation of non-opioid β-endorphin receptor in the regulation of myocardial activity.

    PMID:
    22150278
    [PubMed - in process]
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    14.
    J Am Chem Soc. 2012 Jan 11;134(1):103-6. Epub 2011 Dec 14.

    Structure of the Stapled p53 Peptide Bound to Mdm2.

    Source

    Max Planck Institute for Biochemistry , Am Klopferspitz 18, 82152 Martinsried, Germany.

    Abstract

    Mdm2 is a major negative regulator of the tumor suppressor p53 protein, a protein that plays a crucial role in maintaining genome integrity. Inactivation of p53 is the most prevalent defect in human cancers. Inhibitors of the Mdm2-p53 interaction that restore the functional p53 constitute potential nongenotoxic anticancer agents with a novel mode of action. We present here a 2.0 Å resolution structure of the Mdm2 protein with a bound stapled p53 peptide. Suchpeptides, which are conformationally and proteolytically stabilized with all-hydrocarbon staples, are an emerging class of biologics that are capable of disrupting protein-protein interactions and thus have broad therapeutic potential. The structure represents the first crystal structure of an i, i + 7 stapled peptide bound to its target and reveals that rather than acting solely as a passive conformational brace, a staple can intimately interact with the surface of a protein and augment the binding interface.

    PMID:
    22148351
    [PubMed - in process]
    Click here to read
    15.
    Reproduction. 2011 Dec 5. [Epub ahead of print]

    Immunization with Ovarian Autoantigens leads to Reduced Fertility in Mice following Follicular dysfunction.

    Source

    P Mande, Gamete Immuno Biology, National Institute for Research in Reproductive Health, Mumbai, India.

    Abstract

    Immunoproteomics using sera of women with ovarian autoimmune diseases such as Primary Ovarian Insufficiency and In Vitro Fertilization Embryo Transfer recruits led to identification of three proteins namely Alpha Actinin 4 (α-ACTN4), Heat Shock 70 Protein 5 (HSPA5) and Actin beta (ACTB). The present study deals with the establishment of a peptideELISA for screening sera of Anti-ovarian Antibody (AOA) positive patients and further delves into understanding the role of these three proteins in ovarian autoimmunity in a mouse model. Using in silico approach, antigenic peptides of these proteins were identified and used for peptide ELISA. ELISA results indicated that AOA positive sera showed reactivity with only specific peptides. The functional significance of the dominant peptides was studied by active immunization of female mice with these peptides. All immunized mice generated high antibody titers and profound effect on ovaries with few primordial (2.4±0.1,2.4±0.2,2±0.1), primary (2.4±0.5,1.7±0.3,2.4±0.3), preantral (2.3±0.5,3.4±0.3,2.9±0.3), antral (0.9±0.2,1.6±0.8,2.3±0.6) follicles and corpora lutea (2.8±0.8,2.9±1.7,4.6±2.3) and increased number of atretic follicles (5.5±0.4,4.9±1.8,7.5±1.0) in ACTN4, HSPA5, ACTB immunized mice as compared to control animals (3.0±0.2,3.5±0.6,3±0.1,3.6±0.2,4.7±0.3,1.5±0.3) respectively. These mice when mated with fertile male mice showed an overall 25-43% reduction in fertility as compared to controls. The data clearly suggest that the dominant antigenic epitopes of the three proteins play critical role in fertility and could possibly be the key autoimmune targets. These epitopes could be used to develop a more specific and sensitive diagnostic test for women with ovarian autoimmune diseases and to design therapy for disease management for reinstatement of ovarian function.

    PMID:
    22143970
    [PubMed - as supplied by publisher]
    Click here to read
    16.
    N Engl J Med. 2011 Dec 1;365(22):2055-66.

    Interleukin-2 and regulatory T cells in graft-versus-host disease.

    Source

    Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA 02215, USA. john_koreth@dfci.harvard.edu

    Abstract

    BACKGROUND:

    Dysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD.

    METHODS:

    In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×10(6), 1×10(6), or 3×10(6) IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period.

    RESULTS:

    A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×10(6) IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (P<0.001 for both comparisons with baseline values), then declined when the patients were not receiving interleukin-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received interleukin-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60% (range, 25 to 100).

    CONCLUSIONS:

    Daily low-dose interleukin-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients. (Funded by a Dana-Farber Dunkin' Donuts Rising Star award and others; ClinicalTrials.gov number, NCT00529035.).

    PMID:
    22129252
    [PubMed - indexed for MEDLINE]
    Click here to read
    17.
    Clin Exp Nephrol. 2011 Nov 30. [Epub ahead of print]

    Aliskiren-associated acute kidney injury in a patient with pre-existing chronic kidney disease and dilated cardiomyopathy.

    Source

    Department of Nephrology and Hypertension, St. Marianna University Hospital, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan, yamauchizz-ycu@umin.ac.jp.

    Abstract

    We report a case of acute kidney injury (AKI) caused by a novel direct renin inhibitor, aliskiren. A 43-year-old Japanese man with dilated cardiomyopathy on cardiac resynchronization therapy with defibrillator and chronic kidney disease (CKD) was started on aliskiren in addition to enalapril, carvedilol, furosemide, and spironolactone for worsening cardiac function suggested by the elevation of serum brain natriuretic peptide. After 1 month, he noticed general malaise, loss of appetite and his serum creatinine level increased from 2.0 to 7.24 mg/dL. He had no evidence of exacerbation of hemodynamic instability (heart failure or hypotension) or post-renal cause of AKI. Although a cessation of aliskiren did not ameliorate AKI, renal function returned to baseline after withholding enalapril. Careful monitoring is necessary when aliskiren is used in patients with CKD and/or significant systolic dysfunction since it can cause normotensive ischemic AKI, especially when there is a concomitant use of other renin-angiotensin-aldosterone system inhibitors.

    PMID:
    22127400
    [PubMed - as supplied by publisher]
    Click here to read
    18.
    Diabetes Care. 2012 Jan;35(1):42-6. Epub 2011 Nov 28.

    Magnitude and Variability of the Glucagon-Like Peptide-1 Response in Patients With Type 2 Diabetes up to 2 Years Following Gastric Bypass Surgery.

    Source

    Corresponding author: Blandine Laferrère, bbl14@columbia.edu.

    Abstract

    OBJECTIVE To characterize the magnitude and variance of the change of glucose and glucagon-like peptide-1 (GLP-1) concentrations, and to identify determinants of glucose control up to 2 years after gastric bypass (GBP). RESEARCH DESIGN AND METHODS Glucose and GLP-1 concentrations were measured during an oral glucose challenge before and 1, 12, and 24 months after GBP in 15 severely obese patients with type 2 diabetes. RESULTS Glucose area under the curve from 0 to 180 min (AUC(0-180)) started decreasing in magnitude (P < 0.05) 1 month after surgery. GLP-1 AUC(0-180) increased in magnitude 1 month after GBP (P < 0.05), with increased variance only after 1 year (P(σ)(2) ≤ 0.001). GLP-1 AUC(0-180) was positively associated with insulin AUC(0-180) (P = 0.025). CONCLUSIONS The increase in variance of GLP-1 at 1 and 2 years after GBP suggests mechanisms other than proximal gut bypass to explain the enhancement of GLP-1 secretion. The association between GLP-1 and insulin concentrations supports the idea that the incretins are involved in glucose control after GBP.

    PMID:
    22124715
    [PubMed - in process]
    Click here to read
    19.
    J Neurosci. 2011 Nov 23;31(47):17007-16.

    Calcium/calmodulin kinase II in the pedunculopontine tegmental nucleus modulates the initiation and maintenance of wakefulness.

    Source

    Laboratory of Sleep and Cognitive Neuroscience, and Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, USA. Subimal@bu.edu

    Abstract

    The pedunculopontine tegmentum nucleus (PPT) is critically involved in the regulation of wakefulness (W) and rapid eye movement (REM) sleep, but our understanding of the mechanisms of this regulation remains incomplete. The present study was designed to determine the role of PPT intracellular calcium/calmodulin kinase (CaMKII) signaling in the regulation of W and sleep. To achieve this aim, three different concentrations (0.5, 1.0, and 2.0 nmol) of the CaMKII activation inhibitor, KN-93, were microinjected bilaterally (100 nl/site) into the PPT of freely moving rats, and the effects on W, slow-wave sleep (SWS), REM sleep, and levels of phosphorylated CaMKII (pCaMKII) expression in the PPT were quantified. These effects, which were concentration-dependent and affected wake-sleep variables for 3 h, resulted in decreased W, due to reductions in the number and duration of W episodes; increased SWS and REM sleep, due to increases in episode duration; and decreased levels of pCaMKII expression in the PPT. Regression analyses revealed that PPT levels of pCaMKII were positively related with the total percentage of time spent in W (R(2) = 0.864; n = 28 rats; p < 0.001) and negatively related with the total percentage of time spent in sleep (R(2) = 0.863; p < 0.001). These data provide the first direct evidence that activation of intracellular CaMKII signaling in the PPT promotes W and suppresses sleep. These findings are relevant for designing a drug that could treat excessive sleepiness by promoting alertness.

    PMID:
    22114270
    [PubMed - indexed for MEDLINE]
    PMCID: PMC3229030
    [Available on 2012/11/23]
    Click here to read
    20.
    J Oral Implantol. 2011 Nov 21. [Epub ahead of print]

    Eight-years results of site retention of anorganic bovine bone and anorganic bovine matrix added to a synthetic peptiden.

    Source

    University of Chieti-Pescara, Oral Science, Nano and Biotechnology, University of Chieti-Pescara.

    Abstract

    Abstract The long term fate of some biomaterials is still unknown and the reports present in the literature are not conclusive whether these biomaterials are resorbed over time or not. Different reports can be found about the resorption behavior of anorganic bovine bone (ABB). The aim of the present study was a comparative histological and histomorphometrical evaluation, in the same patient, of two specimens retrieved from a sinus augmented with ABB and with anorganic bovine matrix added to a cell-binding peptide (PepGen P-15), respectively after a healing period of 6-months and after 8-years implant loading, to evaluate the resorption of both biomaterials. A unilateral sinus augmentation procedure with ABB (50%) and with PepGen P-15 (50%) was performed in a 54-year-old male patient. Two titanium dental implants with a sandblasted and acid-etched surface were inserted after 6-months. During this procedure, two tissue cores were retrieved from the sinus with a trephine, before implant insertion. After an additional 6-months, a fixed prosthetic restoration was fabricated. One of these implants, after a loading period of 8-years, fractured in the coronal portion and was removed. Both specimens, one retrieved after a 6-months healing period and the other after 8-years loading period, were treated to obtain thin ground sections. In the 6-months specimen, the histomorphometry showed that the percentage of newly formed bone was 27.2% ± 3.6%, marrow spaces 35.6% ± 2.3%, residual ABB particles 25.1% ± 1.2%, residual PepGen P-15 particles 12.1% ± 2.2%. In the 8-years specimen, the histomorphometry showed that the percentage of newly formed bone was 51.4% ± 4.8%, marrow spaces 40% ± 7.1%, residual ABB particles 6.2% ± 0.7%, residual PepGen P-15 particles 2.4% ± 0.5%. Both biomaterials underwent significant resorption over the course of this study.

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