181 results on '"Petersen JS"'
Search Results
2. Pharmacological characterization of the novel nociceptin/orphanin FQ receptor ligand, ZP120: In vitro and in vivo studies in mice
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Rizzi, Anna, Rizzi, D, Marzola, G, Regoli, Domenico, Larsen, Bd, Petersen, Js, and Calo', Girolamo
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NOP receptor ,In vitro and in vivo assays ,Mice ,Nociceptin/orphanin FQ ,ZP120 - Published
- 2002
3. THE INFLUENCE OF PORCINE GROWTH-HORMONE ON MUSCLE-FIBER CHARACTERISTICS, METABOLIC POTENTIAL AND MEAT QUALITY
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OKSBJERG, N, PETERSEN, JS, SORENSEN, MT, HENCKEL, P, AGERGAARD, N, BEJERHOLM, C, and ERLANDSEN, E
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LIPOGENESIS ,SOMATOTROPIN PST ,SEX ,WEIGHT ,PERFORMANCE ,FIBER CHARACTERISTICS ,TRAITS ,GROWING PIGS ,KILOGRAMS - Published
- 1995
4. Antihypertensive action of non-natriuretic doses of furosemide in Dahl salt-sensitive rats.
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Haugan K, Petersen JS, Spannow J, Shalmi M, Christensen S, Haugan, K, Petersen, J S, Spannow, J, Shalmi, M, and Christensen, S
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- 1997
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5. An auto-ethnographic study of co-produced health research in a patient organisation: unpacking the good, the bad, and the unspoken.
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Janssens A, Drachmann D, Barnes-Cullen K, Carrigg A, Christesen HT, Futers B, Lavery YO, Palms T, Petersen JS, Shah P, Thornton P, and Wolfsdorf J
- Abstract
Background: In rare diseases, limited access to services and rare disease experts may force families to act as medical advocates for their child; they can volunteer to support clinician-initiated research or initiate and lead research themselves. Ketotic Hypoglycemia International (KHI) is a new, global organization for families affected by idiopathic ketotic hypoglycemia (IKH) and is run solely by volunteers. Doing research together, families and international experts in a collaborative process such as at KHI, also referred to as patient and public involvement and engagement (PPIE) or extreme citizen science, is often praised for its positive effects on the research and the stakeholders involved., Methods: We used auto-ethnographic narratives from parents and medical professionals in KHI to report on their experiences with co-produced health research. All co-authors wrote down their experiences in relation to three topics: time invested, work invested and power dynamics., Results: Whilst the parents and health care professionals felt a new hope for (their) children with IKH, they also felt pressure to contribute time or to be flexible in how and when they dedicated time towards the organization. The power dynamics were characterised by a change in the relationship between the parents and medical experts; the parent being taught by the expert shifted to the expert learning from the lived experience of the parent. Both parents and medical experts struggled with maintaining boundaries and safeguarding their mental health., Conclusion: Our findings call for the need to secure and prioritize funding for patient organizations, to enable them to create the sustainable architecture required for meaningful PPIE within these organizations. The morals and often deeply personal reasons for engaging with voluntary work in health research, can lead to overstepping of boundaries. As a result of our research, we call for the development of ethics of care guidelines within collaborative health research., (© 2024. The Author(s).)
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- 2024
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6. Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity.
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Cornelius P, Mayes BA, Petersen JS, Turnquist DJ, Dufour PJ, Dannenberg AJ, Shanahan JM, and Carver BJ
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- Humans, Animals, Mice, Cell Line, Tumor, Methionyl Aminopeptidases antagonists & inhibitors, Metalloendopeptidases antagonists & inhibitors, Neoplasm Metastasis, Sesquiterpenes pharmacology, Sesquiterpenes chemistry, Cyclohexanes pharmacology, Cyclohexanes chemistry, Female, Neoplasms drug therapy, Neoplasms pathology, Cell Proliferation drug effects, Aminopeptidases antagonists & inhibitors, Aminopeptidases metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry
- Abstract
Methionine aminopeptidase type 2 (METAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. METAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of METAP2-specific substrates whose biological activity may be altered following METAP2 inhibition, and additionally, that METAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of METAP2 using fumagillin analogues has established the anti-angiogenic and anti-tumor characteristics of these derivatives; however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting central nervous system (CNS) toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer-drug conjugate of the novel METAP2 inhibitor (METAP2i) SDX-7539. In vitro binding, enzyme, and cell-based assays demonstrated that SDX-7539 is a potent and selective METAP2 inhibitor. In utilizing a high molecular weight, water-soluble polymer to conjugate the novel fumagillol-derived, cathepsin-released, METAP2i SDX-7539, limitations observed with prior generation, small molecule fumagillol derivatives were ameliorated including reduced CNS exposure of the METAP2i, and prolonged half-life enabling convenient administration. Multiple xenograft and syngeneic cancer models were utilized to demonstrate the anti-tumor and anti-metastatic profile of SDX-7320. Unlike polymer-drug conjugates in general, reductions in small molecule-equivalent efficacious doses following polymer conjugation were observed. SDX-7320 has completed a phase I clinical safety study in patients with late-stage cancer and is currently being evaluated in multiple phase Ib/II clinical studies in patients with advanced solid tumors., (©2024 The Authors; Published by the American Association for Cancer Research.)
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- 2024
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7. Deaths Among Ambulance Patients Released from the Emergency Department Within the First 24 Hours With Nonspecific Diagnoses - Expected or Not?
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Harðardóttir GH, Petersen JS, Krarup AL, Christensen EF, and Søvsø MB
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- Humans, Female, Retrospective Studies, Male, Aged, Aged, 80 and over, Denmark epidemiology, Middle Aged, Adult, Cause of Death trends, International Classification of Diseases, Ambulances statistics & numerical data, Emergency Service, Hospital statistics & numerical data, Emergency Service, Hospital organization & administration
- Abstract
Background: Emergency patients are frequently assigned nonspecific diagnoses. Nonspecific diagnoses describe observations or symptoms and are found in chapters R and Z of the International Classification of Diseases, 10
th edition (ICD-10). Patients with such diagnoses have relatively low mortality, but due to patient volume, the absolute number of deaths is substantial. However, information on cause of short-term mortality is limited., Objectives: To investigate whether death could be expected for ambulance patients brought to the emergency department (ED) after a 1-1-2 call, released with a nonspecific ICD-10 diagnosis within 24 h, and who subsequently died within 30 days., Methods: Retrospective medical record review of adult 1-1-2 emergency ambulance patients brought to an ED in the North Denmark Region during 2017-2021. Patients were divided into three categories: unexpected death, expected death (terminal illness), and miscellaneous. Charlson Comorbidity Index (CCI) was assessed., Results: We included 492 patients. Mortality was distributed as follows: Unexpected death 59.2% (n = 291), expected death (terminal illness) 25.8% (n = 127), and miscellaneous 15.0% (n = 74). Patients who died unexpectedly were old (median age of 82 years) and had CCI 1-2 (58.1%); 43.0% used at least five daily prescription drugs, and they were severely acutely ill upon arrival (24.7% with red triage, 60.1% died within 24 h)., Conclusions: More than half of ambulance patients released within 24 h from the ED with nonspecific diagnoses, and who subsequently died within 30 days, died unexpectedly. One-fourth died from a pre-existing terminal illness. Patients dying unexpectedly were old, treated with polypharmacy, and often life-threateningly sick at arrival., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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8. First-in-human study of a pharmacological duodenal exclusion therapy shows reduced postprandial glucose and insulin and increased bile acid and gut hormone concentrations.
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Fineman MS, Bryant CLN, Colbert K, Jozefiak TH, Petersen JS, Horowitz M, Vora J, Rayner CK, Wabnitz P, and Nimgaonkar A
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- Humans, Insulin therapeutic use, Bile Acids and Salts, Blood Glucose metabolism, Insulin, Regular, Human therapeutic use, Glucose therapeutic use, Obesity drug therapy, Double-Blind Method, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 metabolism
- Abstract
Aims: To address the need for noninvasive alternatives to metabolic surgery or duodenal exclusion devices for the management of type 2 diabetes (T2D) and obesity by developing an orally administered therapeutic polymer, GLY-200, designed to bind to and enhance the barrier function of mucus in the gastrointestinal tract to establish duodenal exclusion noninvasively., Materials and Methods: A Phase 1, randomized, double-blind, placebo-controlled, single- (SAD) and multiple-ascending-dose (MAD) healthy volunteer study was conducted. In the SAD arm, four cohorts received a single dose of 0.5 g up to 6.0 g GLY-200 or placebo, while in the MAD arm, four cohorts received 5 days of twice-daily or three-times-daily dosing (total daily dose 2.0 g up to 6.0 g GLY-200 or placebo). Assessments included safety and tolerability (primary) and exploratory pharmacodynamics, including serum glucose, insulin, bile acids and gut hormones., Results: No safety signals were observed; tolerability signals were limited to mild to moderate dose-dependent gastrointestinal events. In the MAD arm (Day 5), reductions in glucose and insulin and increases in bile acids, glucagon-like peptide-1, peptide YY and glicentin, were observed following a nonstandardized meal in subjects receiving twice-daily dosing of 2.0 g GLY-200 (N = 9) versus those receiving placebo (N = 8)., Conclusions: GLY-200 is safe and generally well tolerated at doses of ≤2.0 g twice daily. Pharmacodynamic results mimic the biomarker signature observed after Roux-en-Y gastric bypass and duodenal exclusion devices, indicating a pharmacological effect in the proximal small intestine. This study represents the first clinical demonstration that duodenal exclusion can be achieved with an oral drug and supports further development of GLY-200 for the treatment of obesity and/or T2D., (© 2023 Glyscend Therapeutics. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
- Published
- 2023
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9. Elucidating complex triplet-state dynamics in the model system isopropylthioxanthone.
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Liaros N, Gutierrez Razo SA, Thum MD, Ogden HM, Zeppuhar AN, Wolf S, Baldacchini T, Kelley MJ, Petersen JS, Falvey DE, Mullin AS, and Fourkas JT
- Abstract
We introduce techniques for probing the dynamics of triplet states. We employ these tools, along with conventional techniques, to develop a detailed understanding of a complex chemical system: a negative-tone, radical photoresist for multiphoton absorption polymerization in which isopropylthioxanthone (ITX) is the photoinitiator. This work reveals that the same color of light used for the 2-photon excitation of ITX, leading to population of the triplet manifold through intersystem crossing, also depletes this triplet population via linear absorption followed by reverse intersystem crossing (RISC). Using spectroscopic tools and kinetic modeling, we identify the reactive triplet state and a non-reactive reservoir triplet state. We present compelling evidence that the deactivation channel involves RISC from an excited triplet state to a highly vibrationally excited level of the electronic ground state. The work described here offers the enticing possibility of understanding, and ultimately controlling, the photochemistry and photophysics of a broad range of triplet processes., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)
- Published
- 2021
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10. Children with acute pyelonephritis need medical re-evaluation when home-treated with oral antibiotics.
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Sehested LT, Kamperis K, Winding L, Bjerre CK, Neland M, Hagstrøm S, Wilms LK, Andersen MLE, Kuhne-Qvist L, Hoffmann-Petersen JS, Nørgaard H, and Cortes D
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- Acute Disease, Administration, Oral, Amoxicillin-Potassium Clavulanate Combination therapeutic use, Anti-Bacterial Agents therapeutic use, Child, Humans, Infant, Bacterial Infections drug therapy, Pyelonephritis drug therapy
- Abstract
Aim: To investigate the efficacy and safety of home-treatment with oral piv-mecillinam or amoxicillin-clavulanate in children with acute pyelonephritis., Methods: Children aged over 6 months diagnosed with culture confirmed pyelonephritis at Danish Paediatric Departments were home-treated with piv-mecillinam (tablets) or amoxicillin-clavulanate (liquid or tablets). Follow-up was performed by phone (second treatment day) and clinical review of the patients in the hospital (day three)., Results: Four hundred eighteen children were included. In total, 333/418 (80%) responded well to the initial oral antibiotic treatment. 85/418 (20%) were changed to another treatment of these 47/418 (11%) to a second-line oral antibiotic and 38/418 (9%) to intravenous antibiotics due to insufficient clinical improvement or bacterial resistance. Bacterial resistance was similar for piv-mecillinam and amoxicillin-clavulanate: 4/74 (5%) versus 33/333 (10%) (p = 0.22). Insufficient clinical improvement, despite no resistance, primarily occurred in children treated with piv-mecillinam: 16/74 (22%) versus 28/344 (8%) (p < 0.001), and predominantly occurred in piv-mecillinam treated children <5 years: 7/20 (35%) versus 9/54 (17%) (p < 0.05), potentially because of problems with piv-mecillinam tablets. In the study population no cases of death or septicemia developed after start of initial oral treatment., Conclusion: A home-treatment regime for pyelonephritis in children >6 months is safe; however, during treatment, clinical re-evaluation is required as in 20% of cases a change in treatment was necessary., (©2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)
- Published
- 2021
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11. Ketotic hypoglycemia in patients with Down syndrome.
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Drachmann D, Carrigg A, Weinstein DA, Petersen JS, and Christesen HT
- Abstract
Background: Ketotic hypoglycemia (KH) without an identifiable underlying metabolic or hormonal disease is historically named idiopathic KH. The prevalence is unknown, but idiopathic KH is considered the most frequent cause of hypoglycemia beyond the neonatal period. KH in Down syndrome (DS) has not been reported., Methods: We conducted a web-based survey on KH in DS through the non-profit patient organization Ketotic Hypoglycemia International. The responses were evaluated for consistency with KH by two authors. Two DS patient histories with documented KH were shared in more details., Results: Survey data on 139 DS patients were obtained. After validation, 10 patients (7.2%) had reported episodes of documented hypoglycemia, ketosis, and/or symptoms compatible with KH beyond the neonatal period. Glucose concentrations ranged 1.2-2.9 mmol/L; betahydroxybutyrate was up to 5.5 mmol/L during hypoglycemia. One girl had trisomy 21 with no response to i.m. glucagon also had a heterozygous Xp22.23 deletion including GYG2 , which protein, glycogenin 2, is a substrate for glycogen synthase. Treatment with extended release cornstarch was effective., Conclusion: This is the first demonstration of a possible high prevalence of KH in DS. Even though this finding needs to be confirmed in other research settings, identification of KH in DS could have a dramatic impact, as simple treatments with cornstarch, protein and frequent meals may prevent KH attacks and, analogous to other conditions with KH, improve growth, stamina and prevent overeating and obesity. GYG2 deletion may contribute to KH in DS, resembling glycogen storage disease type 0., Competing Interests: The authors declare that they have no competing interests., (© 2021 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)
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- 2021
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12. Towards enhanced understanding of idiopathic ketotic hypoglycemia: a literature review and introduction of the patient organization, Ketotic Hypoglycemia International.
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Drachmann D, Hoffmann E, Carrigg A, Davis-Yates B, Weaver V, Thornton P, Weinstein DA, Petersen JS, Shah P, and Christesen HT
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- Adult, Blood Glucose, Fasting, Fatty Acids, Humans, Hypoglycemia diagnosis
- Abstract
Background: Idiopathic Ketotic hypoglycemia (IKH) is a diagnosis of exclusion. Although considered as the most frequent cause of hypoglycemia in childhood, little progress has been made to advance the understanding of IKH since the medical term was coined in 1964. We aimed to review the literature on ketotic hypoglycemia (KH) and introduce a novel patient organization, Ketotic Hypoglycemia International (KHI)., Results: IKH may be diagnosed after the exclusion of various metabolic and hormonal diseases with KH. Although often mild and self-limiting, more severe and long-lasting IKH occurs. We therefore divide IKH in physiological KH and pathological KH, the latter defined as recurrent symptomatic, or occasionally symptomatic, episodes with beta-hydroxybutyrate ≥ 1.0 mmol/L and blood glucose < 70 mg/dL (3.9 mol/L), in the absence of prolonged fasting, acute infections and chronic diseases known to cause KH. Pathological KH may represent undiscovered diseases, e.g. glycogen storage disease IXa, Silver-Russel syndrome, and ketone transporter defects, or suggested novel disease entities identified by exome sequencing. The management of KH aims to prevent hypoglycemia, fatty acid oxidation and protein deficiency by supplying adequate amounts of carbohydrates and protein, including nutritional therapy, uncooked cornstarch, and sometimes continuous tube feeding by night. Still, intravenous dextrose may be needed in acute KH episodes. Failure to acknowledge that IKH can be more than normal variation may lead to under-treatment. KHI is a non-profit, patient-centric, global organization established in 2020. The organization was created by adult IKH patients, patient family members, and volunteers. The mission of KHI is to enhance the understanding of IKH while advocating for patients, their families and the continued research into KH., Conclusion: IKH is a heterogeneous disorder including physiological KH and pathological KH. IKH may represent missed diagnoses or novel disease entities, but shares common management principles to prevent fatty acid oxygenation. KHI, a novel patient organization, aims to enhance the understanding of IKH by supporting IKH families and research into IKH.
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- 2021
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13. Case Reports of Pre-clinical Replication Studies in Metabolism and Diabetes.
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von Herrath M, Pagni PP, Grove K, Christoffersson G, Tang-Christensen M, Karlsen AE, and Petersen JS
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- Animals, Case-Control Studies, Humans, Reproducibility of Results, Diabetes Mellitus metabolism
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Recent articles have highlighted the lack of reproducibility of data from scientific publications. Here we would argue that a better way to describe and also tackle this matter is to use the term "lack of robustness," since it points toward potential solutions. Presenting several case reports, we highlight examples with common underlying issues from Novo Nordisk's experience: animal model variability, reagent quality, and inter-lab variability. We discuss means to prevent these issues and argue for increased collaborative work and transparent manuscript revision procedures. Collectively, we believe these measures will help promote a more rapid and efficient self-corrective process in diabetes drug target research., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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14. First trimester pregnancy ultrasound findings as a function of method of conception in an infertile population.
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von Versen-Höynck F, Petersen JS, Chi YY, Liu J, and Baker VL
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- Adult, Cryopreservation, Embryo Transfer methods, Female, Fertilization, Fertilization in Vitro, Humans, Infertility, Female diagnostic imaging, Insemination, Artificial, Pregnancy, Pregnancy Trimester, First, Ultrasonography, Prenatal methods, Crown-Rump Length, Gestational Sac diagnostic imaging, Infertility, Female therapy
- Abstract
Purpose: The aim of this study was to determine whether first trimester ultrasound measurements of crown rump length (CRL) and gestational sac diameter (GSD) differ depending on the method of conception among infertile women., Method: Infertile women, ages 21-50 years old, who conceived viable, singleton pregnancies via fresh embryo transfer (ET), frozen ET, non-in vitro fertilization (IVF) fertility treatment, or spontaneously were included in this observational cohort study at an academic fertility practice. Embryonic growth trajectories defined by the CRL and GSD at 6 and 8 weeks' gestation were analyzed and compared among the methods of conception., Results: Crown rump length at 6 weeks' gestation was smaller for conceptions achieved via fresh ET compared with frozen ET in a natural cycle (1.50 vs. 2.50 mm, p = 0.017). Crown rump length was smaller at 8 weeks' gestation in conceptions achieved via fresh ET compared to frozen ET in a programmed cycle (16.13 vs. 17.02 mm, p = 0.039)., Conclusion: Among infertile women, embryo growth may differ between fresh and frozen ET as early as 6 and 8 weeks' gestation.
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- 2018
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15. Systems Signatures Reveal Unique Remission-path of Type 2 Diabetes Following Roux-en-Y Gastric Bypass Surgery.
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Li QR, Wang ZM, Wewer Albrechtsen NJ, Wang DD, Su ZD, Gao XF, Wu QQ, Zhang HP, Zhu L, Li RX, Jacobsen S, Jørgensen NB, Dirksen C, Bojsen-Møller KN, Petersen JS, Madsbad S, Clausen TR, Diderichsen B, Chen LN, Holst JJ, Zeng R, and Wu JR
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- Blood Proteins metabolism, Diabetes Mellitus, Type 2 blood, Gastric Bypass, Gene Regulatory Networks, Humans, Metabolome, Obesity genetics, Principal Component Analysis, Weight Loss, Diabetes Mellitus, Type 2 surgery, Systems Biology
- Abstract
Roux-en-Y Gastric bypass surgery (RYGB) is emerging as a powerful tool for treatment of obesity and may also cause remission of type 2 diabetes. However, the molecular mechanism of RYGB leading to diabetes remission independent of weight loss remains elusive. In this study, we profiled plasma metabolites and proteins of 10 normal glucose-tolerant obese (NO) and 9 diabetic obese (DO) patients before and 1-week, 3-months, 1-year after RYGB. 146 proteins and 128 metabolites from both NO and DO groups at all four stages were selected for further analysis. By analyzing a set of bi-molecular associations among the corresponding network of the subjects with our newly developed computational method, we defined the represented physiological states (called the edge-states that reflect the interactions among the bio-molecules), and the related molecular networks of NO and DO patients, respectively. The principal component analyses (PCA) revealed that the edge states of the post-RYGB NO subjects were significantly different from those of the post-RYGB DO patients. Particularly, the time-dependent changes of the molecular hub-networks differed between DO and NO groups after RYGB. In conclusion, by developing molecular network-based systems signatures, we for the first time reveal that RYGB generates a unique path for diabetes remission independent of weight loss., (Copyright © 2018. Published by Elsevier B.V.)
- Published
- 2018
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16. The influence of feeding crimped kernel maize silage on broiler production, nutrient digestibility and meat quality.
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Ranjitkar S, Karlsson AH, Petersen MA, Bredie WL, Petersen JS, and Engberg RM
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- Animals, Chickens growth & development, Chickens metabolism, Diet veterinary, Dietary Supplements analysis, Dose-Response Relationship, Drug, Male, Random Allocation, Animal Nutritional Physiological Phenomena drug effects, Chickens physiology, Digestion drug effects, Meat analysis, Silage analysis, Zea mays chemistry
- Abstract
Two experiments were carried out in parallel with male Ross 308 broilers over 37 d. An experiment with a total of 736 broilers was performed to study the effect of dietary inclusion of crimped kernel maize silage (CKMS) on broiler production and meat quality. Another study with 32 broilers was carried out from 21 to 25 d to investigate the inclusion of CKMS on nutrient digestibility. In both trials, 4 dietary treatments were used: wheat-based feed (WBF), maize-based feed (MBF), maize-based feed supplemented with 15% CKMS (CKMS-15) and maize-based feed supplemented with 30% CKMS (CKMS-30). Compared with MBF, the dry matter (DM) intakes of broilers receiving CKMS-15 and CKMS-30, respectively, were numerically 7.5 and 6.2% higher and feed conversion ratio 6 and 12% poorer (significant for 30% CKMS), although there were no significant differences in AME content between the three diets. At 37 d, the body weight of birds receiving 15% CKMS was similar to birds fed with MBF. However, the inclusion of 30% CKMS decreased broiler growth. Dietary supplementation with CKMS significantly reduced the apparent digestibility of phosphorus. The fat digestibility was significantly lower for CKMS-30 than for the other three diets. Broiler mortality decreased significantly when CKMS was added to the diet. The consumption of drinking water was significantly lower in all maize-based diets as compared to WBF and was lowest in broilers fed with CKMS-30. An improved litter quality in terms of DM content and a lower frequency of foot pad lesions was observed with broilers supplemented with both dietary levels of CKMS. The addition of CKMS to maize-based diets increased juiciness, tenderness and crumbliness of the meat. In conclusion, the dietary supplementation of 15% CKMS had no negative effect on broiler growth and positively influenced bird welfare in terms of mortality and foot pad health. Therefore, the addition of 15% CKMS to maize-based diets is considered an advantageous feeding strategy in broiler production.
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- 2016
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17. Partial remission definition: validation based on the insulin dose-adjusted HbA1c (IDAA1C) in 129 Danish children with new-onset type 1 diabetes.
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Max Andersen ML, Hougaard P, Pörksen S, Nielsen LB, Fredheim S, Svensson J, Thomsen J, Vikre-Jørgensen J, Hertel T, Petersen JS, Hansen L, and Mortensen HB
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- Adolescent, Age Factors, C-Peptide blood, Child, Child, Preschool, Cohort Studies, Denmark, Diabetes Mellitus, Type 1 blood, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 1 metabolism, Diagnosis, Differential, Female, Glycated Hemoglobin analysis, Humans, Infant, Insulin Secretion, Insulin-Secreting Cells metabolism, Male, Prediabetic State blood, Prediabetic State drug therapy, Prediabetic State metabolism, Remission Induction, Sensitivity and Specificity, Diabetes Mellitus, Type 1 diagnosis, Hyperglycemia prevention & control, Hypoglycemic Agents administration & dosage, Insulin administration & dosage, Insulin metabolism, Insulin Resistance, Insulin-Secreting Cells drug effects, Prediabetic State diagnosis
- Abstract
Objective: To validate the partial remission (PR) definition based on insulin dose-adjusted HbA1c (IDAA1c)., Subjects and Methods: The IDAA1c was developed using data in 251 children from the European Hvidoere cohort. For validation, 129 children from a Danish cohort were followed from the onset of type 1 diabetes (T1D). Receiver operating characteristic curve (ROC) analysis was used to evaluate the predictive value of IDAA1c and age on partial C-peptide remission (stimulated C-peptide, SCP > 300 pmol/L)., Results: PR (IDAA1c ≤ 9) in the Danish and Hvidoere cohorts occurred in 62 vs. 61% (3 months, p = 0.80), 47 vs. 44% (6 months, p = 0.57), 26 vs. 32% (9 months, p = 0.32) and 19 vs. 18% (12 months, p = 0.69). The effect of age on SCP was significantly higher in the Danish cohort compared with the Hvidoere cohort (p < 0.0001), likely due to higher attained Boost SCP, so the sensitivity and specificity of those in PR by IDAA1c ≤ 9, SCP > 300 pmol/L was 0.85 and 0.62 at 6 months and 0.62 vs. 0.38 at 12 months, respectively. IDAA1c with age significantly improved the ROC analyses and the AUC reached 0.89 ± 0.04 (age) vs. 0.94 ± 0.02 (age + IDAA1c) at 6 months (p < 0.0004) and 0.76 ± 0.04 (age) vs. 0.90 ± 0.03 (age + IDAA1c) at 12 months (p < 0.0001)., Conclusions: The diagnostic and prognostic power of the IDAA1c measure is kept but due to the higher Boost stimulation in the Danish cohort, the specificity of the formula is lower with the chosen limits for SCP (300 pmol/L) and IDAA1c ≤9, respectively., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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18. Disease progression among 446 children with newly diagnosed type 1 diabetes located in Scandinavia, Europe, and North America during the last 27 yr.
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Max Andersen ML, Nielsen LB, Svensson J, Pörksen S, Hougaard P, Beam C, Greenbaum C, Becker D, Petersen JS, Hansen L, and Mortensen HB
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- Body Mass Index, Child, Child, Preschool, Cohort Studies, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 1 epidemiology, Europe, Female, Glutamate Decarboxylase metabolism, Humans, Infant, Insulin Antibodies metabolism, Male, North America, Scandinavian and Nordic Countries, White People, C-Peptide metabolism, Diabetes Mellitus, Type 1 physiopathology, Disease Progression
- Abstract
Objective: To clarify whether the rate of decline in stimulated C-peptide (SCP) from 2 to 15 months after diagnosis has changed over an interval of 27 yr., Research Design and Methods: The rate of decline in SCP levels at 1, 2, 3, 6, 9, 12, and 15 months after diagnosis was compared in four paediatric cohorts from Scandinavian and European countries including 446 children with new onset type 1 diabetes (T1D, 1982-2004). Findings were evaluated against 78 children (2004-2009) from the TrialNet studies., Results: The mean rate of decline [%/month (±SEM)] in SCP for a 10-yr-old child was 7.7%/month (±1.5) in the 1982-1985 Cohort, 6.3%/month (±1.7) in the 1995-1998 Cohort, 7.8%/month (±0.7) in the 1999-2000 Cohort, and 10.7%/month (±0.9) in the latest 2004-2005 Cohort (p = 0.05). Including the TrialNet Cohort with a rate of decline in SCP of 10.0%/month (±0.9) the differences between the cohorts are still significant (p = 0.039). The rate of decline in SCP was negatively associated with age (p < 0.0001), insulin antibodies (IA) (p = 0.003), and glutamic acid decarboxylase-65 (GAD65A) (p = 0.03) initially with no statistically significant effect of body mass index (BMI) Z-score at 3 months. Also, at 3 months the time around partial remission, the effect of age on SCP was significantly greater in children ≤5 yr compared with older children (p ≤ 0.0001)., Conclusions: During the past 27 yr, initial C-peptide as well as the rate of C-peptide decline seem to have increased. The rate of decline was affected significantly by age, GAD65A, and IA, but not BMI Z-score or initial C-peptide., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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19. Characterization of Novel PI3Kδ Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies.
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Haselmayer P, Camps M, Muzerelle M, El Bawab S, Waltzinger C, Bruns L, Abla N, Polokoff MA, Jond-Necand C, Gaudet M, Benoit A, Bertschy Meier D, Martin C, Gretener D, Lombardi MS, Grenningloh R, Ladel C, Petersen JS, Gaillard P, and Ji H
- Abstract
SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP(®)) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis.
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- 2014
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20. 2-Colour photolithography.
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Fourkas JT and Petersen JS
- Abstract
Photolithography is a crucial technology for both research and industry. The desire to be able to create ever finer features has fuelled a push towards lithographic methods that use electromagnetic radiation or charged particles with the shortest possible wavelength. At the same time, the physics and chemistry involved in employing light or particles with short wavelengths present great challenges. A new class of approaches to photolithography on the nanoscale involves the use of photoresists that can be activated with one colour of visible or near-ultraviolet light and deactivated with a second colour. Such methods hold the promise of attaining lithographic resolution that rivals or even exceeds that currently sought by industry, while at the same time using wavelengths of light that are inexpensive to produce and can be manipulated readily. The physical chemistry of 2-colour photolithography is a rich area of science that is only now beginning to be explored.
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- 2014
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21. Complex multi-block analysis identifies new immunologic and genetic disease progression patterns associated with the residual β-cell function 1 year after diagnosis of type 1 diabetes.
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Andersen ML, Rasmussen MA, Pörksen S, Svensson J, Vikre-Jørgensen J, Thomsen J, Hertel NT, Johannesen J, Pociot F, Petersen JS, Hansen L, Mortensen HB, and Nielsen LB
- Subjects
- Adolescent, Age of Onset, Alleles, Autoantibodies blood, C-Peptide blood, Cation Transport Proteins immunology, Child, Diabetes Mellitus, Type 1 blood, Disease Progression, Female, Genetic Predisposition to Disease, Glycated Hemoglobin metabolism, Humans, Insulin-Secreting Cells pathology, Male, Models, Biological, Polymorphism, Single Nucleotide, Prospective Studies, Risk, Zinc Transporter 8, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 immunology, Insulin-Secreting Cells physiology
- Abstract
The purpose of the present study is to explore the progression of type 1 diabetes (T1D) in Danish children 12 months after diagnosis using Latent Factor Modelling. We include three data blocks of dynamic paraclinical biomarkers, baseline clinical characteristics and genetic profiles of diabetes related SNPs in the analyses. This method identified a model explaining 21.6% of the total variation in the data set. The model consists of two components: (1) A pattern of declining residual β-cell function positively associated with young age, presence of diabetic ketoacidosis and long duration of disease symptoms (P = 0.0004), and with risk alleles of WFS1, CDKN2A/2B and RNLS (P = 0.006). (2) A second pattern of high ZnT8 autoantibody levels and low postprandial glucagon levels associated with risk alleles of IFIH1, TCF2, TAF5L, IL2RA and PTPN2 and protective alleles of ERBB3 gene (P = 0.0005). These results demonstrate that Latent Factor Modelling can identify associating patterns in clinical prospective data--future functional studies will be needed to clarify the relevance of these patterns.
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- 2013
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22. Murine extracellular superoxide dismutase is converted into the inactive fold by the Ser195Cys mutation.
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Scavenius C, Petersen JS, Thomsen LR, Poulsen ET, Valnickova-Hansen Z, Bowler RP, Oury TD, Petersen SV, and Enghild JJ
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- Amino Acid Substitution, Animals, CHO Cells, Cricetinae, Cricetulus, Cysteine chemistry, HEK293 Cells, Humans, Kinetics, Mice, Mice, Transgenic, Mutagenesis, Site-Directed, Protein Folding, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Spectrometry, Mass, Electrospray Ionization, Superoxide Dismutase metabolism, Tandem Mass Spectrometry, Superoxide Dismutase chemistry, Superoxide Dismutase genetics
- Abstract
We have previously shown that human extracellular superoxide dismutase (EC-SOD) exists as two variants with differences in their disulfide bridge patterns: one form is the active enzyme (aEC-SOD), and the other is inactive (iEC-SOD). The availability of both active and inactive folding variants significantly reduces the specific activity of EC-SOD in vivo. Both forms are produced during biosynthesis, but the underlying folding mechanisms remain unclear. To address this issue, we expressed EC-SOD in heterologous systems that do not endogenously express iEC-SOD. Rodents express only aEC-SOD because they lack Cys195 (human EC-SOD sequence numbering), which is essential for the formation of iEC-SOD. However, cultured hamster cells and transgenic mice expressing human EC-SOD were able to produce both human a- and iEC-SOD variants, which led us to hypothesize that the folding was sequence-dependent rather than a property of the expression system. To substantiate this hypothesis, we expressed murine EC-SOD in a human cell line, and as expected, only aEC-SOD was produced. Significantly, when Cys195 was introduced, both murine aEC-SOD and a novel murine iEC-SOD were generated, and the specific activity of the murine EC-SOD was significantly reduced by the mutation. Collectively, these data suggest that Cys195 actuates the formation of iEC-SOD, independent of the expression system or host. In addition, the dual-folding pathway most likely requires biosynthesis factors that are common to both humans and rodents.
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- 2013
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23. Effects of 12 weeks' treatment with a proton pump inhibitor on insulin secretion, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind prospective placebo-controlled study.
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Hove KD, Brøns C, Færch K, Lund SS, Petersen JS, Karlsen AE, Rossing P, Rehfeld JF, and Vaag A
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- Aged, Biomarkers blood, Blood Pressure Monitoring, Ambulatory, Cardiovascular Diseases epidemiology, Combined Modality Therapy, Denmark epidemiology, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 diet therapy, Diabetes Mellitus, Type 2 metabolism, Double-Blind Method, Drug Therapy, Combination adverse effects, Esomeprazole administration & dosage, Esomeprazole adverse effects, Gastrins blood, Gastrins metabolism, Glycated Hemoglobin analysis, Humans, Hypertension prevention & control, Insulin blood, Insulin Secretion, Male, Middle Aged, Placebo Effect, Proton Pump Inhibitors administration & dosage, Proton Pump Inhibitors adverse effects, Risk Factors, Yogurt, Cardiovascular Diseases prevention & control, Diabetes Mellitus, Type 2 drug therapy, Esomeprazole therapeutic use, Hyperglycemia prevention & control, Insulin metabolism, Proton Pump Inhibitors therapeutic use
- Abstract
Aims/hypothesis: Recent studies suggest that proton pump inhibitor treatment may increase insulin secretion and improve glucose metabolism in type 2 diabetes. In a randomised double-blind prospective placebo-controlled 2 × 2 factorial study, we examined the effect of esomeprazole on insulin secretion, HbA(1c) and cardiovascular risk factors in type 2 diabetes., Methods: Forty-one patients with type 2 diabetes using dietary control or oral glucose-lowering treatment were randomised to receive add-on esomeprazole 40 mg (n = 20) or placebo (n = 21) for 12 weeks. Randomisation was carried out prior to inclusion on the basis of a computer-generated random-number list. The allocation sequence was concealed in sealed envelopes from the researcher enrolling and assessing participants. The study was undertaken at Steno Diabetes Center, Gentofte, Denmark. The primary outcome was change in AUC for insulin levels during a meal test. Secondary outcomes were the levels of HbA(1c) and biochemical markers of cardiovascular risk, including lipids, coagulation factors, inflammation markers, markers of endothelial function and 24 h ambulatory BP measurements., Results: Forty-one participants were analysed. In the esomeprazole-treated group the AUC for insulin did not change (before vs after treatment: 28,049 ± 17,659 vs 27,270 ± 32,004 pmol/l × min (p = 0.838). In the placebo group AUC for insulin decreased from 27,392 ± 14,348 pmol/l × min to 22,938 ± 11,936 pmol/l × min (p = 0.002). Esomeprazole treatment (n = 20) caused a ninefold increase in the AUC for gastrin. HbA(1c) increased from 7.0 ± 0.6% (53 ± 5 mmol/mol) to 7.3 ± 0.8% (56 ± 6 mmol/mol) in the esomeprazole-treated group and from 7.0 ± 0.6% (53 ± 5 mmol/mol) to 7.4 ± 0.8% (57 ± 6 mmol/mol) in the placebo group (n = 21) (p for difference in change >0.05). Except for BP, there were no differences between the groups in the markers of cardiovascular risk (p > 0.05). Monitoring of 24 h ambulatory BP showed a significant decrease in daytime systolic BP, daytime diastolic BP and 24 h diastolic BP in the placebo group (p < 0.05). No change in BP was seen in the patients treated with esomeprazole., Conclusions/interpretation: Treatment with esomeprazole over 12 weeks did not improve insulin secretion, glycaemic control or cardiovascular disease biomarkers in patients with type 2 diabetes.
- Published
- 2013
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24. Proinsulin, GLP-1, and glucagon are associated with partial remission in children and adolescents with newly diagnosed type 1 diabetes.
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Kaas A, Andersen ML, Fredheim S, Hougaard P, Buschard K, Petersen JS, de Beaufort C, Robertson KJ, Hansen L, Mortensen HB, and Nielsen LB
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- Adolescent, Age of Onset, Blood Glucose analysis, C-Peptide analysis, C-Peptide blood, Child, Child, Preschool, Cohort Studies, Diabetes Mellitus, Type 1 diagnosis, Female, Follow-Up Studies, Glucagon analysis, Glucagon-Like Peptide 1 analysis, Humans, Infant, Infant, Newborn, Male, Proinsulin analysis, Remission, Spontaneous, Diabetes Mellitus, Type 1 blood, Diabetes Mellitus, Type 1 epidemiology, Glucagon blood, Glucagon-Like Peptide 1 blood, Proinsulin blood
- Abstract
Objective: Proinsulin is a marker of beta-cell distress and dysfunction in type 2 diabetes and transplanted islets. Proinsulin levels are elevated in patients newly diagnosed with type 1 diabetes. Our aim was to assess the relationship between proinsulin, insulin dose-adjusted haemoglobin A1c (IDAA1C), glucagon-like peptide-1 (GLP-1), glucagon, and remission status the first year after diagnosis of type 1 diabetes., Methods: Juvenile patients (n = 275) were followed 1, 6, and 12 months after diagnosis. At each visit, partial remission was defined as IDAA1C ≤ 9%. The patients had a liquid meal test at the 1-, 6-, and 12-month visits, which included measurement of C-peptide, proinsulin, GLP-1, glucagon, and insulin antibodies (IA)., Results: Patients in remission at 6 and 12 months had significantly higher levels of proinsulin compared to non-remitting patients (p < 0.0001, p = 0.0002). An inverse association between proinsulin and IDAA1C was found at 1 and 6 months (p = 0.0008, p = 0.0022). Proinsulin was positively associated with C-peptide (p < 0.0001) and IA (p = 0.0024, p = 0.0068, p < 0.0001) at 1, 6, and 12 months. Glucagon (p < 0.0001 and p < 0.02) as well as GLP-1 (p = 0.0001 and p = 0.002) were significantly lower in remitters than in non-remitters at 6 and 12 months. Proinsulin associated positively with GLP-1 at 1 month (p = 0.004) and negatively at 6 (p = 0.002) and 12 months (p = 0.0002)., Conclusions: In type 1 diabetes, patients in partial remission have higher levels of proinsulin together with lower levels of GLP-1 and glucagon compared to patients not in remission. In new onset type 1 diabetes proinsulin level may be a sign of better residual beta-cell function., (© 2011 John Wiley & Sons A/S.)
- Published
- 2012
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25. Characterization of a novel peripheral pro-lipolytic mechanism in mice: role of VGF-derived peptide TLQP-21.
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Possenti R, Muccioli G, Petrocchi P, Cero C, Cabassi A, Vulchanova L, Riedl MS, Manieri M, Frontini A, Giordano A, Cinti S, Govoni P, Graiani G, Quaini F, Ghè C, Bresciani E, Bulgarelli I, Torsello A, Locatelli V, Sanghez V, Larsen BD, Petersen JS, Palanza P, Parmigiani S, Moles A, Levi A, and Bartolomucci A
- Subjects
- Adipocytes cytology, Adipocytes drug effects, Animals, Body Composition, Dietary Fats adverse effects, Dietary Fats metabolism, Male, Mice, NIH 3T3 Cells, Nerve Growth Factors, Obesity chemically induced, Obesity metabolism, Protein Binding, Protein Transport, Receptors, Cell Surface, Neuropeptides metabolism, Peptide Fragments pharmacology
- Abstract
The peptides encoded by the VGF gene are gaining biomedical interest and are increasingly being scrutinized as biomarkers for human disease. An endocrine/neuromodulatory role for VGF peptides has been suggested but never demonstrated. Furthermore, no study has demonstrated so far the existence of a receptor-mediated mechanism for any VGF peptide. In the present study, we provide a comprehensive in vitro, ex vivo and in vivo identification of a novel pro-lipolytic pathway mediated by the TLQP-21 peptide. We show for the first time that VGF-immunoreactivity is present within sympathetic fibres in the WAT (white adipose tissue) but not in the adipocytes. Furthermore, we identified a saturable receptor-binding activity for the TLQP-21 peptide. The maximum binding capacity for TLQP-21 was higher in the WAT as compared with other tissues, and selectively up-regulated in the adipose tissue of obese mice. TLQP-21 increases lipolysis in murine adipocytes via a mechanism encompassing the activation of noradrenaline/β-adrenergic receptors pathways and dose-dependently decreases adipocytes diameters in two models of obesity. In conclusion, we demonstrated a novel and previously uncharacterized peripheral lipolytic pathway encompassing the VGF peptide TLQP-21. Targeting the sympathetic nerve-adipocytes interaction might prove to be a novel approach for the treatment of obesity-associated metabolic complications.
- Published
- 2012
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26. ZP2307, a novel, cyclic PTH(1-17) analog that augments bone mass in ovariectomized rats.
- Author
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Neerup TS, Stahlhut M, Petersen JS, Daugaard JR, Jensen JE, Peng Z, Morko J, and Thorkildsen C
- Subjects
- Absorptiometry, Photon, Animals, Bone Density Conservation Agents pharmacokinetics, Calcium blood, Cyclic AMP metabolism, Female, Rats, Rats, Inbred F344, Tomography, X-Ray Computed, Bone Density drug effects, Bone Density Conservation Agents pharmacology, Bone and Bones drug effects, Organ Size drug effects, Ovariectomy, Parathyroid Hormone pharmacology, Peptide Fragments pharmacology
- Abstract
Daily injections of human parathyroid hormone (1-34), hPTH(1-34), provide a highly effective treatment option for severe osteoporosis. However, PTH analogs shorter than 28 amino acids do not retain any bone augmenting potential. Here, we present ZP2307 ([Ac₅c¹, Aib³, Leu⁸, Gln¹⁰, Har¹¹, Ala¹², Trp¹⁴, Asp¹⁷]PTH(1-17)-NH₂), a novel, chemically modified and cyclized hPTH(1-17) analog, that augments bone mass in ovariectomized, osteopenic rats. Subcutaneous administration of this structurally constrained, K¹³-D¹⁷ side-chain-to-side-chain cyclized peptide reversed bone loss and increased bone mineral density (BMD) up to or above baseline levels in rat long bones and vertebrae. Highly significant effects of ZP2307 were achieved at doses of 40-320 nmol/kg. Micro-CT and histomorphometric analyses showed that ZP2307 improved quantitative and qualitative parameters of bone structure. Biomechanical testing of rat femora confirmed that ZP2307 dramatically increased bone strength. Over a broad maximally effective dose range (40-160 nmol/kg) ZP2307 did not increase serum concentrations of ionized free calcium above normal levels. Only at the highest dose (320 nmol/kg) ZP2307 induced hypercalcemic calcium levels in the ovariectomized rats. To our knowledge ZP2307 is the smallest PTH peptide analog known to exert augmentation of bone. Our findings suggest that ZP2307 has the potential to effectively augment bone mass over a broad dose range without a concomitant increase in the serum concentration of ionized free calcium above the normal range., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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27. Treatment with a proton pump inhibitor improves glycaemic control in type 2 diabetic patients - a retrospective analysis.
- Author
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Hove KD, Færch K, Bödvarsdóttir TB, Karlsen AE, Petersen JS, and Vaag A
- Subjects
- Aged, Aged, 80 and over, Blood Glucose, Female, Glycated Hemoglobin metabolism, Humans, Hypoglycemic Agents therapeutic use, Male, Middle Aged, Retrospective Studies, Diabetes Mellitus, Type 2 drug therapy, Esomeprazole therapeutic use, Proton Pump Inhibitors therapeutic use
- Abstract
We retrospectively studied whether treatment with esomeprazole improved HbA₁(c) levels in type 2 diabetic patients. We selected 21 patients who had been treated with esomeprazole for 11 ± 3 months and 21 controls. HbA₁(c) levels decreased in the esomeprazole-treated group. Our data indicate that proton pump inhibitors may improve glycaemic control in type 2 diabetic patients., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2010
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28. Advances in pemphigus research, signaling, and acantholysis.
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Bektas M, Runager K, Petersen JS, and Rubenstein DS
- Subjects
- Animals, Apoptosis, Biomedical Research, Cell Adhesion, HSP27 Heat-Shock Proteins physiology, Humans, Signal Transduction, p38 Mitogen-Activated Protein Kinases physiology, Acantholysis immunology, Pemphigus complications, Pemphigus immunology
- Abstract
Pemphigus is a family of human autoimmune blistering diseases in which pathogenic autoantibodies induce blistering in skin and mucosa. The mechanisms by which pemphigus autoantibodies induce disease in the skin is under active investigation. A large number of cellular events induced in the target keratinocytes by pemphigus IgG have been described and suggest that pemphigus IgG binding to desmogleins trigger a complicated cascade of intracellular signaling and regulatory events. Targeting these intracellular events may prove useful therapeutically.
- Published
- 2010
29. Treatment with a proton pump inhibitor improves glycaemic control in Psammomys obesus, a model of type 2 diabetes.
- Author
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Bödvarsdóttir TB, Hove KD, Gotfredsen CF, Pridal L, Vaag A, Karlsen AE, and Petersen JS
- Subjects
- 2-Pyridinylmethylsulfinylbenzimidazoles administration & dosage, Analysis of Variance, Animals, Blood Glucose metabolism, Diabetes Mellitus, Type 2 metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors therapeutic use, Female, Gastrins blood, Gerbillinae, Immunohistochemistry, Insulin metabolism, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells metabolism, Lansoprazole, Male, 2-Pyridinylmethylsulfinylbenzimidazoles therapeutic use, Blood Glucose drug effects, Diabetes Mellitus, Type 2 drug therapy, Hyperglycemia drug therapy, Proton Pump Inhibitors
- Abstract
Aims/hypothesis: Gastrin has been implicated in islet growth/neogenesis, and proton pump inhibitors (PPIs) have been shown to increase endogenous gastrin levels in animals and humans. Therefore, we investigated the effect of PPIs in a model of type 2 diabetes, Psammomys obesus., Methods: P. obesus (morning blood glucose [mBG] 16.9 +/- 0.6 mmol/l) were treated with vehicle or different doses (1-15 mg/kg) of lansoprazole for 17 days., Results: Treatment with lansoprazole resulted in up to ninefold dose-dependent increases in endogenous gastrin levels (p < 0.05 for 10 mg/kg lansoprazole vs vehicle). There was a significant reduction in mBG levels in all animals in the high-dose lansoprazole groups during the 17 day treatment period, whereas there was no significant improvement in mBG in animals in the vehicle groups. The mBG at end of study was 18.2 +/- 2.1, 8.7 +/- 2.2 (p < 0.01), and 6.1 +/- 2.3 (p < 0.001) mmol/l for vehicle and lansoprazole 10 and 15 mg/kg, respectively. The animals treated with 15 mg/kg lansoprazole, compared with vehicle, had a 2.3-fold increase in the intensity of insulin staining in beta cells (p=0.0002) and 50% higher beta cell mass (p=0.04)., Conclusions/interpretations: The PPI lansoprazole had significant glucose-lowering effects in an animal model of type 2 diabetes, an effect that is most likely mediated through an increase in endogenous gastrin levels.
- Published
- 2010
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30. The concentration of extracellular superoxide dismutase in plasma is maintained by LRP-mediated endocytosis.
- Author
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Petersen SV, Thøgersen IB, Valnickova Z, Nielsen MS, Petersen JS, Poulsen ET, Jacobsen C, Oury TD, Moestrup SK, Crapo JD, Nielsen NC, Kristensen T, and Enghild JJ
- Subjects
- Animals, COS Cells, Chlorocebus aethiops, Endocytosis genetics, Female, Hep G2 Cells, Humans, Low Density Lipoprotein Receptor-Related Protein-1 genetics, Low Density Lipoprotein Receptor-Related Protein-1 metabolism, Metabolic Clearance Rate, Mice, Osmolar Concentration, Oxidation-Reduction, Protein Binding physiology, Superoxide Dismutase chemistry, Superoxide Dismutase genetics, Endocytosis physiology, Low Density Lipoprotein Receptor-Related Protein-1 physiology, Superoxide Dismutase blood, Superoxide Dismutase metabolism
- Abstract
In this study, we show that human extracellular superoxide dismutase (EC-SOD) binds to low-density lipoprotein receptor-related protein (LRP). This interaction is most likely responsible for the removal of EC-SOD from the blood circulation via LRP expressed in liver tissue. The receptor recognition site was located within the extracellular matrix-binding region of EC-SOD. This region encompasses the naturally occurring Arg213Gly amino acid substitution, which affects the affinity of EC-SOD for ligands in the extracellular space. Interestingly, the binding between LRP and Arg213Gly EC-SOD was significantly reduced, thus clarifying the observation that hetero- or homozygous carriers present with a significant increase in EC-SOD in their blood. On the basis of our results, we speculate that EC-SOD synthesized locally in tissues diffuses slowly into the circulation, from where it is removed by binding to LRP present in the liver. The interaction between LRP and EC-SOD is thus likely to be important for maintaining redox balance in the circulation., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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31. Cardiac and metabolic changes in long-term high fructose-fat fed rats with severe obesity and extensive intramyocardial lipid accumulation.
- Author
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Axelsen LN, Lademann JB, Petersen JS, Holstein-Rathlou NH, Ploug T, Prats C, Pedersen HD, and Kjølbye AL
- Subjects
- AMP-Activated Protein Kinases metabolism, Animals, Blood Pressure drug effects, Glucose metabolism, Heart drug effects, Insulin blood, Lipids blood, Liver metabolism, Male, Metabolic Syndrome metabolism, Myocardium metabolism, Rats, Rats, Sprague-Dawley, Fats pharmacology, Fructose pharmacology, Obesity metabolism
- Abstract
Metabolic syndrome and obesity-related diseases are affecting more and more people in the Western world. The basis for an effective treatment of these patients is a better understanding of the underlying pathophysiology. Here, we characterize fructose- and fat-fed rats (FFFRs) as a new animal model of metabolic syndrome. Sprague-Dawley rats were fed a 60 kcal/100 kcal fat diet with 10% fructose in the drinking water. After 6, 12, 18, 24, 36, and 48 wk of feeding, blood pressure, glucose tolerance, plasma insulin, glucose, and lipid levels were measured. Cardiac function was examined by in vivo pressure volume measurements, and intramyocardial lipid accumulation was analyzed by confocal microscopy. Cardiac AMP-activated kinase (AMPK) and hepatic phosphoenolpyruvate carboxykinase (PEPCK) levels were measured by Western blotting. Finally, an ischemia-reperfusion study was performed after 56 wk of feeding. FFFRs developed severe obesity, decreased glucose tolerance, increased serum insulin and triglyceride levels, and an initial increased fasting glucose, which returned to control levels after 24 wk of feeding. The diet had no effect on blood pressure but decreased hepatic PEPCK levels. FFFRs showed significant intramyocardial lipid accumulation, and cardiac hypertrophy became pronounced between 24 and 36 wk of feeding. FFFRs showed no signs of cardiac dysfunction during unstressed conditions, but their hearts were much more vulnerable to ischemia-reperfusion and had a decreased level of phosphorylated AMPK at 6 wk of feeding. This study characterizes a new animal model of the metabolic syndrome that could be beneficial in future studies of metabolic syndrome and cardiac complications.
- Published
- 2010
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32. Metabolic and cardiac changes in high cholesterol-fructose-fed rats.
- Author
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Axelsen LN, Pedersen HD, Petersen JS, Holstein-Rathlou NH, and Kjølbye AL
- Subjects
- Animals, Blood Glucose drug effects, Blood Glucose metabolism, Cholesterol blood, Cholesterol, HDL blood, Dietary Carbohydrates administration & dosage, Dietary Carbohydrates blood, Dietary Fats administration & dosage, Dietary Fats blood, Fructose blood, Insulin blood, Liver drug effects, Liver pathology, Male, Organ Size drug effects, Organ Size physiology, Rats, Rats, Sprague-Dawley, Cardiovascular Physiological Phenomena drug effects, Cholesterol administration & dosage, Fructose administration & dosage, Liver metabolism
- Abstract
Introduction: High cholesterol-fructose (HCF) fed rats have previously been described as an animal model of impaired cardiac insulin signaling and decreased contractile performance. In this study, we evaluated the metabolic and cardiac effects of a HCF diet in rats., Methods: Male Sprague-Dawley rats received a HCF diet for 16 to 17weeks. Body weight was measured weekly and mean arterial blood pressure, fasting blood glucose, fasting plasma insulin, glucose tolerance, and blood lipid levels were measured following 15weeks of feeding. One to 2weeks later, while still on the HCF diet, cardiac function was examined by in vivo pressure-volume measurements in the left ventricle. Finally, protein and glucose content in the urine was measured and all organs were weighed at the end of the study., Results: Rats fed a HCF diet showed increased cholesterol and decreased high-density lipoprotein (HDL) levels in serum compared to control fed rats and they had more than a twofold increase in liver weight. However, in contrast to what has previously been reported, HCF diet had no effect on body weight, blood pressure, fasting blood glucose, fasting plasma insulin, glucose tolerance, or cardiac function during unstressed conditions., Discussion: We were unable to reproduce previous findings that a HCF diet causes changes in glucose tolerance and cardiac contractile performance. Therefore, further studies are warranted to evaluate specific interactions between genetic, environmental, and dietary factors on metabolic and cardiovascular disease progression associated with intake of a westernized diet., (2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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33. Amylin(1-8) is devoid of anabolic activity in bone.
- Author
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Ellegaard M, Thorkildsen C, Petersen S, Petersen JS, Jørgensen NR, Just R, Schwarz P, Ramirez MT, and Stahlhut M
- Subjects
- Amyloid therapeutic use, Anabolic Agents therapeutic use, Animals, Animals, Newborn, Binding Sites drug effects, Binding Sites physiology, Bone Diseases, Metabolic drug therapy, Bone Diseases, Metabolic metabolism, Bone Diseases, Metabolic physiopathology, Bone Regeneration physiology, Cell Line, Cell Line, Tumor, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Humans, Intracellular Signaling Peptides and Proteins drug effects, Intracellular Signaling Peptides and Proteins metabolism, Islet Amyloid Polypeptide, Membrane Proteins drug effects, Membrane Proteins metabolism, Mice, Osteoblasts drug effects, Osteoblasts metabolism, Osteogenesis physiology, Ovariectomy, Peptide Fragments therapeutic use, Peptides pharmacology, Peptides therapeutic use, Rats, Rats, Sprague-Dawley, Receptor Activity-Modifying Protein 1, Receptor Activity-Modifying Proteins, Receptors, Calcitonin drug effects, Receptors, Calcitonin metabolism, Amyloid pharmacology, Anabolic Agents pharmacology, Bone Regeneration drug effects, Osteogenesis drug effects, Peptide Fragments pharmacology
- Abstract
Amylin(1-8), a cyclic peptide consisting of the eight N-terminal amino acids of the 37-amino acid peptide amylin, has been shown to induce proliferation of primary osteoblasts and to induce bone formation in healthy male mice, whereas no data on efficacy in bone disease-related models have been reported. Therefore, we evaluated any effects of amylin(1-8) in ovariectomized rats with established osteopenia, a model for postmenopausal osteoporosis. At doses up to 100 nmol/kg/day, a dose highly effective in healthy mice, amylin(1-8) was unable to increase bone mineral density in ovariectomized rats during an 8-week treatment period. Histomorphometric analysis of the tibia indicated that amylin(1-8) did not change bone histomorphometric parameters. In an attempt to verify any potential biological effects of amylin(1-8), we investigated the efficacy of this peptide in various in vitro assays. Experiments designed to confirm previously published results on the proliferative effects of amylin(1-8) on primary osteoblasts failed to show any response. Amylin(1-8) was able to partially displace (125)I-rat amylin(1-37) from amylin receptors composed of the calcitonin receptor and RAMP1, indicating specific interaction of the peptide with the amylin binding site. However, in vitro efficacy assays with amylin(1-8) in calcitonin receptor-RAMP-positive HEK293T and MCF7 cells failed to reveal any agonist activity of amylin(1-8), whereas amylin(1-37) showed the expected agonist activity. In conclusion, our results indicate that amylin(1-8) does not show agonist activity on amylin receptors, does not affect osteoblast proliferation, and is devoid of anabolic activity in bone.
- Published
- 2010
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34. GAP-134 ([2S,4R]-1-[2-aminoacetyl]4-benzamidopyrrolidine-2-carboxylic acid) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs.
- Author
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Hennan JK, Swillo RE, Morgan GA, Rossman EI, Kantrowitz J, Butera J, Petersen JS, Gardell SJ, and Vlasuk GP
- Subjects
- Animals, Anti-Arrhythmia Agents administration & dosage, Benzamides administration & dosage, Coronary Circulation drug effects, Disease Models, Animal, Dogs, Dose-Response Relationship, Drug, Infusions, Intravenous, Myocardial Infarction etiology, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardial Reperfusion Injury complications, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury physiopathology, Proline administration & dosage, Proline pharmacology, Tachycardia, Ventricular etiology, Tachycardia, Ventricular pathology, Tachycardia, Ventricular physiopathology, Time Factors, Ventricular Premature Complexes etiology, Ventricular Premature Complexes pathology, Ventricular Premature Complexes physiopathology, Anti-Arrhythmia Agents pharmacology, Benzamides pharmacology, Myocardial Infarction prevention & control, Myocardial Reperfusion Injury drug therapy, Myocardium pathology, Proline analogs & derivatives, Tachycardia, Ventricular prevention & control, Ventricular Premature Complexes prevention & control
- Abstract
The antiarrhythmic dipeptide, GAP-134, ([2S,4R]-1[2-aminoacetyl]-4-benzamido-pyrrolidine-2-carboxylic acid) was evaluated in canine ischemia/reperfusion model. In dogs subjected to 60-minute ischemia and 4-hour reperfusion, GAP-134 was administered 10 minutes before reperfusion as a bolus + intravenous (IV) infusion. The doses administered were 0.25 microg/kg bolus + 0.19 microg/kg per hour infusion; 2.5 microg/kg + 1.9 microg/kg per hour; 25 mg/kg + 19 mg/kg per hour; 75 mg/kg + 57 mg/kg per hour. Ventricular ectopy was quantified during reperfusion, including premature ventricular contractions (PVC) and ventricular tachycardia (VT). Total incidence of VT was reduced significantly with the 2 highest doses of GAP-134 (1.7 + 0.8; 2.2 + 1.4 events; P < .05) compared to controls (23.0 + 6.1). Total PVCs were reduced significantly from 11.1 + 1.6% in control animals to 2.0% + 0.7% and 1.8% + 0.8% after the 2 highest doses of GAP-134. Infarct size, expressed as percentage of left ventricle, was reduced significantly from 19.0% + 3.5% in controls to 7.9% + 1.5% and 7.1% + 0.8% (P < .05) at the 2 highest doses of GAP-134. GAP-134 is an effective antiarrhythmic agent with potential to reduce ischemia/reperfusion injury.
- Published
- 2009
- Full Text
- View/download PDF
35. The anti-arrhythmic peptide AAP10 remodels Cx43 and Cx40 expression and function.
- Author
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Easton JA, Petersen JS, and Martin PE
- Subjects
- Benzophenanthridines pharmacology, Blotting, Western, Cell Membrane drug effects, Cell Membrane metabolism, Connexin 26, Connexin 43 genetics, Connexin 43 metabolism, Connexins genetics, Connexins metabolism, Fluorescent Dyes metabolism, Gap Junctions drug effects, Gap Junctions metabolism, Gene Expression Regulation drug effects, HeLa Cells, Humans, Protein Kinase C metabolism, RNA, Messenger drug effects, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Gap Junction alpha-5 Protein, Anti-Arrhythmia Agents pharmacology, Connexin 43 drug effects, Connexins drug effects, Oligopeptides pharmacology
- Abstract
The anti-arrhythmic peptide AAP10 has previously been shown to acutely upregulate electrical cell-to-cell coupling mediated via connexin 43 gap junctions. In the present work, we have further examined the connexin (Cx) specificity and mechanism of action of this peptide in HeLa cells expressing Cx43, Cx40 or Cx26. The ability of cells to transfer the small fluorescent dyes Alexa 488 (MW 570) or Alexa 594 (MW 759), as markers for metabolic coupling mediated via gap junctions, before and after exposure to AAP10 and/or the protein kinase C inhibitor chelerythrine for 5 h was determined by microinjection analysis. Immunofluorescence analysis assessed the effect of AAP10 on the spatial localisation of each Cx sub-type. Cell extracts were isolated for Western blot and reverse transcription polymerase chain reaction analysis at 0, 5, 10, 18 and 24 h following exposure to AAP10 and the relative Cx expression profiles determined. AAP10 enhanced the ability of Cx43 and, to a lesser extent, Cx40 to transfer Alexa 488. It also enhanced the ability of Cx43 to transfer Alexa 594 but not Cx40. Inhibition of protein kinase C blocked this enhanced response in both Cx sub-types. Western blot analysis determined that AAP10 induced Cx40 protein expression over periods of up to 24 h with an associated increase in the localisation of Cx40 at points of cell-to-cell contact following 24-h exposure. Cx43 expression was transiently induced following exposure to the peptide for 5-10 h, with an associated increase in Cx43 at points of cell-to-cell contact, returning to control levels by 18-24 h, via a post-translational mechanism independent of chelerythrine. A transient increase in Cx40 mRNA expression but not Cx43 mRNA expression was also observed. By contrast, AAP10 had no effect on the ability of Cx26 gap junctions to transfer the dyes or on the level of Cx26 expression. We propose that AAP10 is a versatile peptide that remodels metabolic coupling via Cx43 and to a lesser extent Cx40 gap junction channels via an initial protein-kinase-C-dependent pathway modifying local responses at the plasma membrane. This is followed by enhanced Cx43 or Cx40 protein expression.
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- 2009
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36. The gap junction modifier, GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], improves conduction and reduces atrial fibrillation/flutter in the canine sterile pericarditis model.
- Author
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Rossman EI, Liu K, Morgan GA, Swillo RE, Krueger JA, Gardell SJ, Butera J, Gruver M, Kantrowitz J, Feldman HS, Petersen JS, Haugan K, and Hennan JK
- Subjects
- Animals, Anti-Arrhythmia Agents pharmacology, Anti-Arrhythmia Agents therapeutic use, Atrial Fibrillation physiopathology, Atrial Flutter physiopathology, Benzamides pharmacology, Connexin 43 metabolism, Dipeptides adverse effects, Dipeptides pharmacology, Disease Models, Animal, Dogs, Electric Conductivity, Female, Gap Junctions physiology, Heart Atria drug effects, Heart Atria metabolism, Heart Atria physiopathology, Heart Conduction System physiology, Male, Molecular Structure, Oligopeptides pharmacology, Oligopeptides therapeutic use, Pericarditis physiopathology, Postoperative Complications drug therapy, Postoperative Complications physiopathology, Proline pharmacology, Proline therapeutic use, Rats, Rats, Sprague-Dawley, Refractory Period, Electrophysiological drug effects, Atrial Fibrillation drug therapy, Atrial Flutter drug therapy, Benzamides therapeutic use, Dipeptides therapeutic use, Gap Junctions drug effects, Heart Conduction System drug effects, Pericarditis drug therapy, Proline analogs & derivatives
- Abstract
Gap junction uncoupling can alter conduction pathways and promote cardiac re-entry mechanisms that potentiate many supraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL). Our objective was to determine whether GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], a small dipeptide gap junction modifier, can improve conduction and ultimately prevent AF/AFL. In rat atrial strips subjected to metabolic stress, GAP-134 prevented significantly conduction velocity slowing at 10 nM compared with vehicle (p < 0.01). In the canine sterile pericarditis model, conduction time (CT; n = 5), atrial effective refractory period (AERP; n = 3), and AF/AFL duration/inducibility (n = 16) were measured 2 to 3 days postoperatively in conscious dogs. CT was significantly faster after GAP-134 infusion (average plasma concentration, 250 nM) at cycle lengths of 300 ms (66.2 +/- 1.0 versus 62.0 +/- 1.0 ms; p < 0.001) and 200 ms (64.4 +/- 0.9 versus 61.0 +/- 1.3 ms; p < 0.001). No significant changes in AERP were noted after GAP-134 infusion. The mean number of AF/AFL inductions per animal was significantly decreased after GAP-134 infusion (2.7 +/- 0.6 versus 1.6 +/- 0.8; p < 0.01), with total AF/AFL burden being decreased from 12,280 to 6063 s. Western blot experiments showed no change in connexin 43 expression. At concentrations exceeding those described in the AF/AFL experiments, GAP-134 had no effect on heart rate, blood pressure, or any electrocardiogram parameters. In conclusion, GAP-134 shows consistent efficacy on measures of conduction and AF/AFL inducibility in the canine sterile pericarditis model. These findings, along with its oral bioavailability, underscore its potential antiarrhythmic efficacy.
- Published
- 2009
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37. [Future breakthroughs in medical treatment of age-related conditions].
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Vaag A and Petersen JS
- Subjects
- Aged, Epigenesis, Genetic, Humans, Inflammation drug therapy, Oxidative Stress drug effects, Primary Prevention, Sirtuins genetics, Telomere drug effects, Aging genetics, Aging metabolism, Aging physiology, Drug Therapy trends, Pharmaceutical Preparations administration & dosage, Pharmacogenetics trends
- Abstract
Significant progress in our understanding of age-related diseases including the metabolic syndrome, type 2 diabetes, arteriosclerosis and cancer have been achieved in recent years. Novel disease-causing mechanisms and, therefore, drug targets, include epigenetics, inflammation, telomeres, mitochondrial function, oxidative stress and sirtuins. There is a need for individualized treatments, and future medical interventions may be initiated in a primary preventive setting by targeting mechanisms similar to those influenced by calorie restriction and physical exercise.
- Published
- 2009
38. Discovery of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride (GAP-134)13, an orally active small molecule gap-junction modifier for the treatment of atrial fibrillation.
- Author
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Butera JA, Larsen BD, Hennan JK, Kerns E, Di L, Alimardanov A, Swillo RE, Morgan GA, Liu K, Wang Q, Rossman EI, Unwalla R, McDonald L, Huselton C, and Petersen JS
- Subjects
- Administration, Oral, Animals, Anti-Arrhythmia Agents pharmacology, Anti-Arrhythmia Agents therapeutic use, Benzamides chemistry, Benzamides therapeutic use, Dipeptides chemistry, Dipeptides pharmacology, Dipeptides therapeutic use, Disease Models, Animal, Drug Discovery, Mice, Peptide Library, Proline chemistry, Proline pharmacology, Proline therapeutic use, Structure-Activity Relationship, Anti-Arrhythmia Agents chemistry, Atrial Fibrillation drug therapy, Benzamides pharmacology, Gap Junctions drug effects, Proline analogs & derivatives
- Abstract
Rotigaptide (3) is an antiarrhythmic peptide that improves cardiac conduction by modifying gap-junction communication. Small molecule gap-junction modifiers with improved physical properties were identified from a Zealand Pharma peptide library using pharmaceutical profiling, established SAR around 3, and a putative pharmacophore model for rotigaptide. Activity of the compounds was confirmed in a mouse cardiac conduction block model of arrhythmia. Dipeptide 9f (GAP-134) was identified as a potent, orally active gap-junction modifier for clinical development.
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- 2009
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39. Further studies on the pharmacological features of the nociceptin/orphanin FQ receptor ligand ZP120.
- Author
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Fischetti C, Rizzi A, Gavioli EC, Marzola G, Trapella C, Guerrini R, Petersen JS, and Calo G
- Subjects
- Animals, Electric Stimulation, Ligands, Male, Mice, Mice, Knockout, Motor Activity, Narcotic Antagonists, Rats, Rats, Sprague-Dawley, Receptors, Opioid genetics, Receptors, Opioid metabolism, Vas Deferens drug effects, Vasodilator Agents pharmacology, Nociceptin, Oligopeptides pharmacology, Opioid Peptides pharmacology
- Abstract
ZP120 is a nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) ligand. In previous studies, the effects of ZP120 were found to be sensitive to J-113397 in mouse tissues while resistant to UFP-101 in rat tissues. The aim of this study was to further investigate the ZP120 pharmacological profile using mouse and rat preparations, J-113397 and UFP-101, as well as NOP receptor knockout (NOP(-/-)) mice. Electrically stimulated mouse and rat vas deferens were used to characterize the pharmacology of ZP120 in vitro. For in vivo studies the tail-withdrawal assay was performed in wild type (NOP(+/+)) and NOP knockout (NOP(-/-)) mice. In the mouse and rat vas deferens ZP120 mimicked the effects of N/OFQ showing higher potency but lower maximal effects. In both preparations, J-113397 antagonized N/OFQ and ZP120 effects showing similar pK(B) values ( approximately 7.8). UFP-101 antagonized the actions of N/OFQ (pK(B) values approximately 7.3) but did not modify the effects of ZP120. The inhibitory effects of N/OFQ and ZP120 were no longer evident in vas deferens tissues taken from NOP(-/-) mice. In NOP(+/+) mice subjected to the tail-withdrawal assay, ZP120 (1 nmol) mimicked the pronociceptive action of N/OFQ (10 nmol), producing longer lasting effects. The effects of both peptides were absent in NOP(-/-) animals. The NOP receptor ligand ZP120 is a high potency NOP selective partial agonist able to evoke long-lasting effects; its diverse antagonist sensitivity in comparison with N/OFQ may derive from different modality of binding to the NOP receptor.
- Published
- 2009
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40. Nociceptin/orphanin FQ peptide receptor agonist Ac-RYYRWKKKKKKK-NH2 (ZP120) induces antinatriuresis in rats by stimulation of amiloride-sensitive sodium reabsorption.
- Author
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van Deurs US, Hadrup N, Petersen JS, Christensen S, and Jonassen TE
- Subjects
- Absorption physiology, Animals, Drug Interactions, Immunohistochemistry, Natriuresis physiology, Opioid Peptides pharmacology, Rats, Rats, Wistar, Nociceptin Receptor, Nociceptin, Absorption drug effects, Amiloride pharmacology, Natriuresis drug effects, Oligopeptides pharmacology, Receptors, Opioid agonists, Sodium metabolism
- Abstract
The aim of the present study was to examine the mechanisms responsible for the antinatriuretic effect of the selective, peripherally acting, nociceptin/orphanin FQ peptide (NOP) receptor partial agonist Ac-RYYRWKKKKKKK-NH(2) (ZP120). Using immunohistochemistry, we showed that in the cortex NOP receptors are expressed in the distal convoluted tubules, the connecting tubules, and the collecting ducts. Using clearance techniques, we evaluated renal excretory function during acute administration of ZP120 (1 nmol/kg/min) in chronically catheterized, conscious rats (n = 8/group). To examine the hypothesis that ZP120 induces direct renal effects by modifying the activity of sodium transporters in the distal convoluted tubules or in the collecting ducts, ZP120-induced antinatriuresis was examined during coadministration of an inhibitor of the NaCl cotransporter, bendroflumethiazide, or a blocker of the epithelial sodium channel, amiloride, respectively. ZP120 produced a marked antinatriuresis [fractional excretion of sodium (FE(Na)): ZP120, 0.3 +/- 0.1% versus control, 0.9 +/- 0.1%; p < 0.05] in sodium-replete rats. The natriuretic response to amiloride was significantly increased in ZP120-treated rats compared with controls (DeltaFE(Na): ZP120, 1.1 +/- 0.2% versus control, 0.5 +/- 0.2%; p < 0.01), whereas the effect of BFTZ was equal in ZP120-treated rats and controls. These results suggest that ZP120 exerts a direct renal NOP receptor-mediated stimulatory effect on the epithelial sodium channel in the collecting ducts.
- Published
- 2009
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- View/download PDF
41. Enhancement of ventricular gap-junction coupling by rotigaptide.
- Author
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Lin X, Zemlin C, Hennan JK, Petersen JS, and Veenstra RD
- Subjects
- Action Potentials, Animals, Animals, Newborn, Cells, Cultured, Computer Simulation, Dose-Response Relationship, Drug, Gap Junctions metabolism, Heart Ventricles drug effects, Heart Ventricles metabolism, Kinetics, Mice, Mice, Inbred C57BL, Models, Cardiovascular, Myocytes, Cardiac metabolism, Anti-Arrhythmia Agents pharmacology, Cell Communication drug effects, Gap Junctions drug effects, Myocytes, Cardiac drug effects, Oligopeptides pharmacology
- Abstract
Aims: Rotigaptide is proposed to exert its anti-arrhythmic effects by improving myocardial gap-junction communication. To directly investigate the mechanisms of rotigaptide action, we treated cultured neonatal murine ventricular cardiomyocytes with clinical pharmacological doses of rotigaptide and directly determined its effects on gap-junctional currents., Methods and Results: Neonatal murine ventricular cardiomyocytes were enzymatically isolated and cultured for 1-4 days. Primary culture cell pairs were subjected to dual whole cell patch-clamp procedures to directly measure gap-junctional currents (I(j)) and voltage (V(j)). Rotigaptide (0-350 nM) was applied overnight or acutely perfused into 35 mm culture dishes. Rotigaptide (35-100 nM) acutely and chronically increased the resting gap-junction conductance (g(j)), and normalized steady-state minimum g(j) (G(min)) by 5-20%. Higher concentrations produced a diminishing response, which mimics the observed therapeutic efficacy of the drug. The inactivation kinetics was similarly slowed in a therapeutic concentration-dependent manner without affecting the V(j) dependence of inactivation or recovery. The effects of 0-100 nM rotigaptide on ventricular g(j) during cardiac action potential propagation were accurately modelled by computer simulations which demonstrate that clinically effective concentrations of rotigaptide can partially reverse conduction slowing due to decreases in g(j) and inactivation., Conclusion: These results demonstrate that therapeutic concentrations of rotigaptide increase the resting gap-junction conductance and reduce the magnitude and kinetics of steady-state inactivation in a concentration-dependent manner. Rotigaptide may be effective in treating re-entrant forms of cardiac arrhythmias by improving conduction and preventing the formation of re-entrant circuits in partially uncoupled myocardium.
- Published
- 2008
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42. The folding of human active and inactive extracellular superoxide dismutases is an intracellular event.
- Author
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Petersen SV, Kristensen T, Petersen JS, Ramsgaard L, Oury TD, Crapo JD, Nielsen NC, and Enghild JJ
- Subjects
- Amino Acid Substitution, Base Sequence, Cell Line, Disulfides, Enzyme Activation physiology, Humans, Molecular Sequence Data, Protein Biosynthesis physiology, Superoxide Dismutase genetics, Superoxides metabolism, Extracellular Space enzymology, Protein Folding, Superoxide Dismutase metabolism
- Abstract
Human extracellular superoxide dismutase (EC-SOD) is a tetrameric glycoprotein responsible for the removal of superoxide generated in the extracellular space. Two different folding variants of EC-SOD exist based on the disulfide bridge connectivity, resulting in enzymatically active (aEC-SOD) and inactive (iEC-SOD) subunits. As a consequence of this, the assembly of the EC-SOD tetramers produces molecules with variable activity and may represent a way to regulate the antioxidant level in the extracellular space. To determine whether the formation of these two folding variants is an intra- or extracellular event, we analyzed the biosynthesis in human embryonic kidney 293 cells expressing wild-type EC-SOD. These analyses revealed that both folding variants were present in the intra- and extracellular spaces, suggesting that the formation is an intracellular event. To further analyze the biosynthesis, we constructed mutants with the capacity to generate only aEC-SOD (C195S) or iEC-SOD (C45S). The expression of these suggested that the cellular biosynthetic machinery supported the secretion of aEC-SOD but not iEC-SOD. The coexpression of these two mutants did not affect the expression pattern. This study shows that generation of the EC-SOD folding variants is an intracellular event that depends on a free cysteine residue not involved in disulfide bonding.
- Published
- 2008
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43. The future of diabetes treatment.
- Author
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Petersen JS
- Subjects
- Animals, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 2 drug therapy, Glucagon-Like Peptide 1 pharmacology, Humans, Insulin-Secreting Cells drug effects, Diabetes Mellitus drug therapy, Hypoglycemic Agents therapeutic use
- Published
- 2008
- Full Text
- View/download PDF
44. ZP120 causes relaxation by pre-junctional inhibition of noradrenergic neurotransmission in rat mesenteric resistance arteries.
- Author
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Simonsen U, Laursen BE, and Petersen JS
- Subjects
- Adenosine Triphosphate pharmacology, Animals, Electric Stimulation, In Vitro Techniques, Isometric Contraction, Male, Mesenteric Arteries metabolism, Norepinephrine pharmacology, Oligopeptides administration & dosage, Opioid Peptides administration & dosage, Opioid Peptides pharmacology, Peptide Fragments administration & dosage, Peptide Fragments pharmacology, Rats, Rats, Wistar, Sympathetic Nervous System drug effects, Sympathetic Nervous System metabolism, Vasoconstriction drug effects, Nociceptin Receptor, Mesenteric Arteries drug effects, Oligopeptides pharmacology, Receptors, Opioid agonists, Vasodilation drug effects
- Abstract
Background and Purpose: ZP120 (Ac-RYYRWKKKKKKK-NH(2)), is a new partial nociceptin/orphanin FQ (NOP) receptor agonist with sodium-potassium sparing aquaretic effects. The mechanisms of vasodilatation of ZP120 were examined in rat mesenteric resistance arteries., Experimental Approach: Arterial segments (internal diameters 206+/-4 microm, n=224) were mounted in microvascular myographs for isometric tension recordings and electrical field stimulation (EFS)., Key Results: ZP120 and the endogenous NOP receptor ligand, N/OFQ, did not relax arteries contracted with noradrenaline or adenosine-triphosphate. EFS-evoked contractions were inhibited by a purinoceptor antagonist, suramin, and the alpha(1)-adrenoceptor antagonist prazosin. N/OFQ inhibited, concentration-dependently, EFS-evoked contractions with a maximal effect of 52+/-3% (n=8) at 1 microM. The maximal effect of 1 microM ZP120 was lower (27+/-5%, P<0.05, n=9) than for N/OFQ. Endothelial removal or pretreatment with capsaicin did not influence the vasodilator effects of ZP120 and N/OFQ. ZP120 and N/OFQ responses were preserved in the presence of suramin. The alpha(2)-adrenoceptor antagonist, rauwolscine, antagonized the effect of clonidine and brimonidine, but ZP120 and N/OFQ inhibition of EFS-evoked contraction was unaltered. The competitive NOP receptor antagonist, UFP-101 (10 microM), prevented the inhibitory effect of N/OFQ, but not ZP120 suggesting that N/OFQ and ZP120 have distinct modes of interaction with the NOP receptor., Conclusions and Implications: Our findings suggest that the vasodilator effect of ZP120 and N/OFQ in rat mesenteric resistance arteries is mediated by prejunctional inhibition of adrenergic neurotransmission. These properties, that promote diuresis and attenuate the cardiovascular consequences of increased sympathetic nerve activity, make ZP120 a promising drug candidate.
- Published
- 2008
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45. Differential down-regulation of aquaporin-2 in rat kidney zones by peripheral nociceptin/orphanin FQ receptor agonism and vasopressin type-2 receptor antagonism.
- Author
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Hadrup N, Petersen JS, Windfeld S, Risom L, Andersen CB, Nielsen S, Christensen S, and Jonassen TE
- Subjects
- Animals, Antidiuretic Hormone Receptor Antagonists, Aquaporin 2 genetics, Aquaporin 2 physiology, Benzazepines pharmacology, Diuresis drug effects, Down-Regulation, Kidney metabolism, Male, RNA, Messenger analysis, Rats, Rats, Wistar, Receptors, Opioid agonists, Sodium metabolism, Nociceptin Receptor, Aquaporin 2 antagonists & inhibitors, Kidney drug effects, Receptors, Opioid physiology, Receptors, Vasopressin physiology
- Abstract
We previously showed that aquaresis induced by the peripherally acting nociceptin/orphanin FQ receptor agonist ZP120 is associated with a decreased protein level of aquaporin-2 (AQP2) in whole-kidney homogenates. We now examined the effects of Ac-RYYRWKKKKKKK-NH(2) (ZP120) (1 nmol/kg/min i.v. for 4 h) on renal regional expression (cortex/outer stripe of outer medulla, inner stripe of outer medulla, and inner medulla) and subcellular localization of aquaporin-2. Responses to ZP120 were compared to the effects of an equi-aquaretic dose ( approximately 40% inhibition of distal water reabsorption) of the vasopressin type-2 receptor antagonist 5-dimethylamine-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzapine (OPC31260) (32 nmol/kg/min). ZP120 decreased the aquaporin-2 protein level in the rat cortex/outer stripe of outer medulla and decreased apical plasma membrane localization of aquaporin-2 in the cortex (P = 0.002) and in the inner medulla (P = 0.06). These effects were not accompanied by a decrease in the aquaporin-2 mRNA level. OPC31260-induced aquaresis was associated with a decreased aquaporin-2 protein level in both the cortex/outer stripe of outer medulla and in the inner stripe of outer medulla. Apical localization of aquaporin-2 was decreased throughout all kidney zones, and OPC31260 decreased the AQP2 mRNA level in the inner medulla. We conclude that equi-aquaretic doses of ZP120 and OPC31260 produce different patterns of aquaporin-2 down-regulation, suggesting different signaling pathways.
- Published
- 2007
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46. Pharmacological modulation of gap junction function with the novel compound rotigaptide: a promising new principle for prevention of arrhythmias.
- Author
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Kjølbye AL, Haugan K, Hennan JK, and Petersen JS
- Subjects
- Animals, Arrhythmias, Cardiac physiopathology, Atrial Fibrillation physiopathology, Atrial Fibrillation prevention & control, Gap Junctions physiology, Humans, Tachycardia, Ventricular physiopathology, Tachycardia, Ventricular prevention & control, Anti-Arrhythmia Agents adverse effects, Anti-Arrhythmia Agents pharmacology, Anti-Arrhythmia Agents therapeutic use, Arrhythmias, Cardiac prevention & control, Gap Junctions drug effects, Oligopeptides adverse effects, Oligopeptides pharmacology, Oligopeptides therapeutic use
- Abstract
Existing anti-arrhythmic therapy is hampered by lack of efficacy and unacceptable side effects. Thus, ventricular tachycardia and fibrillation remains the strongest predictor of in-hospital mortality in patients with myocardial infarction. In atrial fibrillation, rhythm control with conventional ion channel blockers provide no therapeutic benefit relative to rate control. Several lines of research indicate that impaired gap junctional cell-to-cell coupling between neighbouring cardiomyocytes is critical for the development of cardiac re-entry arrhythmias. Rotigaptide is the first drug that has been developed to prevent arrhythmias by re-establishing gap junctional intercellular communication. During conditions with acute cardiac ischaemia, rotigaptide effectively prevents induction of both ventricular and atrial tachyarrhythmia. Moreover, rotigaptide effectively prevents ischaemia reperfusion arrhythmias. At the cellular level, rotigaptide inhibits ischaemia-induced dephosphorylation of Ser297 and Ser368, which is considered important for the gating of connexin43 gap junction channels. No drug-related toxicity has been demonstrated at plasma concentrations 77,000 times above therapeutic concentrations. In rats and dogs, rotigaptide reduces infarct size following myocardial infarction. A series of phase I trials has been completed in which rotigaptide has been administered intravenously to ~200 healthy persons. No drug-related side effects have been demonstrated in healthy human beings. Clinical safety, tolerability and efficacy in patients with heart disease are being evaluated in ongoing clinical trials. Rotigaptide represents a pioneering pharmacological principle with a highly favourable preclinical and clinical safety profile, which makes this molecule a promising drug candidate for the prevention of cardiac arrhythmias.
- Published
- 2007
- Full Text
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47. Increasing gap junctional coupling: a tool for dissecting the role of gap junctions.
- Author
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Axelsen LN, Haugan K, Stahlhut M, Kjølbye AL, Hennan JK, Holstein-Rathlou NH, Petersen JS, and Nielsen MS
- Subjects
- Animals, Arrhythmias, Cardiac physiopathology, Atrial Fibrillation physiopathology, Bone and Bones drug effects, Cell Communication drug effects, Connexin 43 physiology, Female, Gap Junctions drug effects, Homeostasis physiology, Humans, Ion Channel Gating drug effects, Myocardial Ischemia physiopathology, Oligopeptides pharmacology, Osteoblasts drug effects, Anti-Arrhythmia Agents pharmacology, Cell Communication physiology, Gap Junctions physiology, Oligopeptides physiology
- Abstract
Much of our current knowledge about the physiological and pathophysiological role of gap junctions is based on experiments where coupling has been reduced by either chemical agents or genetic modification. This has brought evidence that gap junctions are important in many physiological processes. In a number of cases, gap junctions have been implicated in the initiation and progress of disease, and experimental uncoupling has been used to investigate the exact role of coupling. The inverse approach, i.e., to increase coupling, has become possible in recent years and represents a new way of testing the role of gap junctions. The aim of this review is to summarize the current knowledge obtained with agents that selectively increase gap junctional intercellular coupling. Two approaches will be reviewed: increasing coupling by the use of antiarrhythmic peptide and its synthetic analogs and by interfering with the gating of gap junctional channels.
- Published
- 2007
- Full Text
- View/download PDF
48. Small-molecule agonists for the glucagon-like peptide 1 receptor.
- Author
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Knudsen LB, Kiel D, Teng M, Behrens C, Bhumralkar D, Kodra JT, Holst JJ, Jeppesen CB, Johnson MD, de Jong JC, Jorgensen AS, Kercher T, Kostrowicki J, Madsen P, Olesen PH, Petersen JS, Poulsen F, Sidelmann UG, Sturis J, Truesdale L, May J, and Lau J
- Subjects
- Animals, Cells, Cultured, Cricetinae, Drug Evaluation, Preclinical, Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptides chemistry, Glucagon-Like Peptides metabolism, Humans, Insulin metabolism, Insulin Secretion, Mice, Mice, Knockout, Molecular Structure, Pancreas drug effects, Pancreas metabolism, Pancreas surgery, Perfusion, Quinoxalines chemistry, Receptors, Glucagon genetics, Receptors, Glucagon metabolism, Sulfones chemistry, Thiadiazoles chemistry, Quinoxalines pharmacology, Receptors, Glucagon agonists, Sulfones pharmacology, Thiadiazoles pharmacology
- Abstract
The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been described and none in the B family of the G protein coupled receptors to which the GLP-1 receptor belongs. We have discovered a series of small molecules known as ago-allosteric modulators selective for the human GLP-1 receptor. These compounds act as both allosteric activators of the receptor and independent agonists. Potency of GLP-1 was not changed by the allosteric agonists, but affinity of GLP-1 for the receptor was increased. The most potent compound identified stimulates glucose-dependent insulin release from normal mouse islets but, importantly, not from GLP-1 receptor knockout mice. Also, the compound stimulates insulin release from perfused rat pancreas in a manner additive with GLP-1 itself. These compounds may lead to the identification or design of orally active GLP-1 agonists.
- Published
- 2007
- Full Text
- View/download PDF
49. Antigen-based prediction and prevention of type 1 diabetes.
- Author
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Petersen JS
- Subjects
- Animals, Autoantibodies blood, Diabetes Mellitus, Type 1 metabolism, Disease Models, Animal, Humans, Mice, Rats, Autoantigens physiology, Diabetes Mellitus, Type 1 etiology, Diabetes Mellitus, Type 1 prevention & control, Glutamate Decarboxylase immunology, Immunotherapy, Isoenzymes immunology
- Published
- 2006
50. Intrarenal octreotide treatment prevents sodium retention in liver cirrhotic rats: evidence for direct effects within the thick ascending limb of Henle's loop.
- Author
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Jonassen TE, Christensen S, Marcussen N, and Petersen JS
- Subjects
- Animals, Female, Furosemide pharmacology, Hemodynamics drug effects, Hypertrophy, Kidney drug effects, Kidney pathology, Loop of Henle pathology, Octreotide administration & dosage, Rats, Rats, Wistar, Specific Pathogen-Free Organisms, Liver Cirrhosis, Biliary drug therapy, Liver Cirrhosis, Experimental drug therapy, Loop of Henle drug effects, Octreotide therapeutic use, Sodium metabolism
- Abstract
We have previously shown that systemic treatment with the somatostatin analog octreotide has marked beneficial effects on renal function in rats with liver cirrhosis induced by common bile duct ligation (CBL; Jonassen TEN, Christensen S, Sørensen AM, Marcussen N, Flyvbjerg A, Andreasen F, and Petersen JS. Hepatology 29: 1387-1395, 1999). In the present study, we tested the hypothesis that octreotide has a direct effect on renal tubular function. Rats (CBL or Sham-CBL) were intrarenally treated with low-dose octreotide in a long-acting release formulation, which had no systemic actions (100 microg/kg body wt as a single dose). Rats receiving low-dose octreotide (sc) were used as controls. The rats were chronically instrumented, and renal function was examined 4 wk after CBL or Sham-CBL. Intrarenal octreotide administration (IROA) prevented sodium retention in CBL rats without changes in renal plasma flow, glomerular filtration rate, or circulating levels of aldosterone and vasopressin. Renal clearance studies revealed that IROA normalized the increased natriuretic efficacy of furosemide found in CBL rats. Furthermore, IROA protected against the development of hypertrophy of the inner stripe of the outer medulla and thereby the increased the volume of thick ascending limb of Henle's loop (TAL) epithelium found in CBL rats. Finally, Western blot analyses of outer medullary homogenates showed increased abundance of the furosemide-sensitive Na-K-2Cl (NKCC2) cotransporter. IROA did not affect the abundance of NCKK2 within the outer medulla. Together with the histological findings, these results indicate that IROA reduces the total number of NKCC2 within the outer medulla. In conclusion, the results indicate a direct intrarenal effect of octreotide on TAL function and morphology in cirrhotic rats.
- Published
- 2006
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