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Publisher: John Wiley and Sons   (Total: 1579 journals)

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Showing 1 - 200 of 1579 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 12, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 65, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 46, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 51, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 152, SJR: 0.101, h-index: 9)
Acta Geologica Sinica (English Edition)     Hybrid Journal   (Followers: 3, SJR: 0.552, h-index: 41)
Acta Neurologica Scandinavica     Hybrid Journal   (Followers: 5, SJR: 1.203, h-index: 74)
Acta Obstetricia et Gynecologica Scandinavica     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 5, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 56, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 6, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 35, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 6, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 4)
Addiction     Hybrid Journal   (Followers: 35, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 13, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 26, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 26, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 50, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 259, SJR: 9.021, h-index: 345)
Advanced Materials Interfaces     Hybrid Journal   (Followers: 6, SJR: 1.177, h-index: 10)
Advanced Optical Materials     Hybrid Journal   (Followers: 5, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 5)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 19)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 12)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 9)
African Development Review     Hybrid Journal   (Followers: 34, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 15, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 10, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 6, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 16, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 45, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 30, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 33, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 50, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 140, SJR: 0.951, h-index: 61)
American Business Law J.     Hybrid Journal   (Followers: 24, SJR: 0.205, h-index: 17)
American Ethnologist     Hybrid Journal   (Followers: 90, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 28, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 33, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 12, SJR: 1.018, h-index: 58)
American J. of Industrial Medicine     Hybrid Journal   (Followers: 16, SJR: 0.993, h-index: 85)
American J. of Medical Genetics Part A     Hybrid Journal   (Followers: 16, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 6, SJR: 2.315, h-index: 79)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 37, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 269, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 17, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 130, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 10, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 16)
Anatomia, Histologia, Embryologia: J. of Veterinary Medicine Series C     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 27)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1, SJR: 0.633, h-index: 24)
Andrologia     Hybrid Journal   (Followers: 2, SJR: 0.528, h-index: 45)
Andrology     Hybrid Journal   (Followers: 2, SJR: 0.979, h-index: 14)
Angewandte Chemie     Hybrid Journal   (Followers: 168)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 215, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 38, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 6, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 7, SJR: 0.816, h-index: 56)
Annals of Clinical and Translational Neurology     Open Access   (Followers: 1)
Annals of Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 47, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 2, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 9, SJR: 0.336, h-index: 23)
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5, SJR: 2.389, h-index: 189)
Annual Bulletin of Historical Literature     Hybrid Journal   (Followers: 13)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 25, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 17, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 15)
Anthropology of Consciousness     Hybrid Journal   (Followers: 11, SJR: 0.172, h-index: 5)
Anthropology of Work Review     Hybrid Journal   (Followers: 11, SJR: 0.256, h-index: 5)
Anthropology Today     Hybrid Journal   (Followers: 90, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 47, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 7, SJR: 0.432, h-index: 59)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apmis     Hybrid Journal   (Followers: 1, SJR: 0.855, h-index: 73)
Applied Cognitive Psychology     Hybrid Journal   (Followers: 69, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 177, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 49, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 14, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 31, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 36, SJR: 1.047, h-index: 57)
Arabian Archaeology and Epigraphy     Hybrid Journal   (Followers: 11, SJR: 0.453, h-index: 11)
Archaeological Prospection     Hybrid Journal   (Followers: 12, SJR: 0.922, h-index: 21)
Archaeology in Oceania     Hybrid Journal   (Followers: 13, SJR: 0.745, h-index: 18)
Archaeometry     Hybrid Journal   (Followers: 27, SJR: 0.809, h-index: 48)
Archeological Papers of The American Anthropological Association     Hybrid Journal   (Followers: 15, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 25, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 4, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 4)
Archives of Insect Biochemistry and Physiology     Hybrid Journal   (SJR: 0.768, h-index: 54)
Area     Hybrid Journal   (Followers: 12, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 237, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 51, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 27, SJR: 2.256, h-index: 114)
Artificial Organs     Hybrid Journal   (Followers: 1, SJR: 0.872, h-index: 60)
ASHE Higher Education Reports     Hybrid Journal   (Followers: 14)
Asia & the Pacific Policy Studies     Open Access   (Followers: 15)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 313, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (Followers: 1, SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 8, SJR: 0.345, h-index: 20)
Asia-pacific J. of Clinical Oncology     Hybrid Journal   (Followers: 6, SJR: 0.554, h-index: 14)
Asia-Pacific J. of Financial Studies     Hybrid Journal   (SJR: 0.241, h-index: 7)
Asia-Pacific Psychiatry     Hybrid Journal   (Followers: 4, SJR: 0.377, h-index: 7)
Asian Economic J.     Hybrid Journal   (Followers: 8, SJR: 0.234, h-index: 21)
Asian Economic Policy Review     Hybrid Journal   (Followers: 4, SJR: 0.196, h-index: 12)
Asian J. of Control     Hybrid Journal   (SJR: 0.862, h-index: 34)
Asian J. of Endoscopic Surgery     Hybrid Journal   (SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 5, SJR: 1.443, h-index: 19)
Asian J. of Social Psychology     Hybrid Journal   (Followers: 5, SJR: 0.665, h-index: 37)
Asian Politics and Policy     Hybrid Journal   (Followers: 12, SJR: 0.207, h-index: 7)
Asian Social Work and Policy Review     Hybrid Journal   (Followers: 5, SJR: 0.318, h-index: 5)
Asian-pacific Economic Literature     Hybrid Journal   (Followers: 5, SJR: 0.168, h-index: 15)
Assessment Update     Hybrid Journal   (Followers: 4)
Astronomische Nachrichten     Hybrid Journal   (Followers: 2, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 14, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 9, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 8, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 7, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 13, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 4, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 46, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 7, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 4, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 29, SJR: 0.23, h-index: 9)
Australian Economic Review     Hybrid Journal   (Followers: 6, SJR: 0.357, h-index: 21)
Australian Endodontic J.     Hybrid Journal   (Followers: 3, SJR: 0.513, h-index: 24)
Australian J. of Agricultural and Resource Economics     Hybrid Journal   (Followers: 3, SJR: 0.765, h-index: 36)
Australian J. of Grape and Wine Research     Hybrid Journal   (Followers: 5, SJR: 0.879, h-index: 56)
Australian J. of Politics & History     Hybrid Journal   (Followers: 14, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 18, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 404, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 5, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 71, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 12, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 19, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 32, SJR: 2.126, h-index: 39)
Autonomic & Autacoid Pharmacology     Hybrid Journal   (SJR: 0.371, h-index: 29)
Banks in Insurance Report     Hybrid Journal   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 10, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 5, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 9, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 24, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 9, SJR: 0.11, h-index: 5)
Beton- und Stahlbetonbau     Hybrid Journal   (Followers: 2, SJR: 0.493, h-index: 14)
Biochemistry and Molecular Biology Education     Hybrid Journal   (Followers: 6, SJR: 0.311, h-index: 26)
Bioelectromagnetics     Hybrid Journal   (Followers: 1, SJR: 0.568, h-index: 64)
Bioengineering & Translational Medicine     Open Access  
BioEssays     Hybrid Journal   (Followers: 10, SJR: 3.104, h-index: 155)
Bioethics     Hybrid Journal   (Followers: 14, SJR: 0.686, h-index: 39)
Biofuels, Bioproducts and Biorefining     Hybrid Journal   (Followers: 1, SJR: 1.725, h-index: 56)
Biological J. of the Linnean Society     Hybrid Journal   (Followers: 16, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 3, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 6, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 36, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 45, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 174, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 14, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 20, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 37, SJR: 0.763, h-index: 64)
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 2, SJR: 0.727, h-index: 77)
Birth Defects Research Part B: Developmental and Reproductive Toxicology     Hybrid Journal   (Followers: 5, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)
BJOG : An Intl. J. of Obstetrics and Gynaecology     Partially Free   (Followers: 233, SJR: 2.083, h-index: 125)

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Journal Cover Acta Physiologica
  [SJR: 1.69]   [H-I: 88]   [6 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1748-1708 - ISSN (Online) 1748-1716
   Published by John Wiley and Sons Homepage  [1579 journals]
  • Functional interaction of Junctophilin 2 with small conductance
    • Authors: Hong K. Fan; Tian X. Luo, Wei D. Zhao, Yong H. Mu, Yang Yang, Wen J. Guo, Hui Y. Tu, Qian Zhang
      Abstract: AimJunctophilins (JPs), a protein family of the junctional membrane complex, maintain the close conjunction between cell surface and intracellular membranes in striate muscle cells mediating the cross talk between extracellular Ca2+ entry and intracellular Ca2+ release. The small conductance Ca2+-activated K+ channels are activated by the intracellular calcium and play an essential role in the cardiac action potential profile. Molecular mechanisms of regulation of the SK channels are still uncertain. Here we sought to determine whether there is a functional interaction of junctophilin type 2(JP2) with the SK channels and whether JP2 gene silencing might modulate the SK channels function in cardiac myocytes.MethodsAssociation of JP2 with SK2 channel in mouse heart tissue as well as HEK 293 cells was studied using in vivo and in vitro approaches. siRNA knockdown of JP2 gene was assessed by Real time PCR. The expression of proteins was analyzed by Western blotting. Ca2+-activated K+ current (IK,Ca) in infected adult mouse cardiac myocytes was recorded using whole-cell voltage-clamp technique. The intracellular Ca2+ transient was measured using an IonOptix photometry system.ResultsWe showed for the first time that JP2 associates with the SK2 channel in native cardiac tissue. JP2, via the Membrane Occupation and Recognition Nexus (MORN motifs) in its N terminus, directly interacted with SK2 channels. A co-localization of the SK2 channel with its interaction protein of JP2 was found in the cardiac myocytes. Moreover, we demonstrated that JP2 is necessary for the proper cell-surface expression of the SK2 channel inHEK293. Functional experiments indicated that knockdown of JP2 caused a significant decrease in the density of IK,Ca and reduced the amplitude of the Ca2+ transient in infected cardiomyocytes.ConclusionsThe present data provide evidence that the functional interaction between JP2 and SK2 channels is present in the native mouse heart tissue. Junctophilin 2, as junctional membrane complex (JMC)protein, is an important regulator of the cardiac SK channels.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-21T03:45:23.256275-05:
      DOI: 10.1111/apha.12986
  • Acute mitogen activated protein kinase 1/2 inhibition improves functional
           recovery and vascular changes after ischemic stroke in rat- monitored by
           9.4 T Magnetic Resonance Imaging
    • Authors: Maryam Mostajeran; Friedrich Wetterling, Frank W Blixt, Lars Edvinsson, Saema Ansar
      Abstract: AimThe aim was to evaluate the beneficial effect of early mitogen activated protein kinase (MEK)1/2 inhibition administered at a clinical relevant time-point using the transient middle cerebral artery occlusion model and a dedicated rodent magnetic resonance imaging system (9.4T) to monitor cerebrovascular changes non-invasively for two weeks.MethodTransient middle cerebral artery occlusion was induced in male rats for two hours followed by reperfusion. The specific MEK1/2 inhibitor U0126 was administered i.p at 6 and 24 hours post-reperfusion. Neurological functions were evaluated by 6- and 28-point tests. 9.4 T magnetic resonance imaging was used to monitor morphological infarct changes at day 2, 8 and 14 after stroke and to evaluate cerebral perfusion at day 14.Immunohistochemistry evaluation of Ki67 was performed 14 days post-stroke.ResultsU0126 improved long-term behavioral outcome and significantly reduced infarct size. In addition, cerebral perfusion in U0126-treated animals was improved compared to the vehicle group. Immunohistochemistry showed a significant increase of Ki67+ cells in U0126 treated animals compared to the vehicle group.ConclusionEarly MEK1/2 inhibition improves long-term functional outcome, promotes recovery processes after stroke and most importantly provides a realistic time window for therapy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-21T03:15:23.531766-05:
      DOI: 10.1111/apha.12985
  • Our best 2015-2017
    • Authors: P. B. Persson
      Abstract: Publishing, as everything else these days, is living in the fast lane. From writing to printing these words, our topmost original articles will have changed. Citations bode very well for Acta Physiologica, suggesting another stark increase in our impact factor after the large leap the impact factor took last year.1 Yet, what may interest authors and readers even more are the prospects for our Acta-Physiologica-Award, which is probably the greatest prize ever to be presented in recognition of scientific publishing.2 Being lean and muscular, Acta Physiologica rather publishes fewer, but better, manuscripts.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-21T02:35:26.700847-05:
      DOI: 10.1111/apha.12983
  • Can we make physiological research better'
    • Authors: P. B. Persson; Anja Bondke Persson
      Abstract: Let us assume that scientists, being on average smart individuals, come with an intrinsic drive to, constantly and based on analytical results, improve the quality of their work and their professional environment. So how can we make science in general and physiological research in particular, better' Answering that question is more than a hypothetical pastime from some ivory tower.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-21T00:05:27.948701-05:
      DOI: 10.1111/apha.12987
  • Good Publication Practice in Physiology 2017
    • Authors: P. B. Persson
      Abstract: ICMJE is a non-profit working group of biomedical journal editors. In their annual meetings, ICMJE members work on and update the Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals (ICMJE guidelines). In 1978, the first edition was published as Uniform Requirements for Manuscripts Submitted to Biomedical Journals (URMs).This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-20T18:00:24.029358-05:
      DOI: 10.1111/apha.12984
  • Uteroplacental insufficiency in rats induces renal apoptosis and delays
           nephrogenesis completion
    • Authors: James SM Cuffe; Jessica F. Briffa, Shannyn Rosser, Andrew L Siebel, Tania Romano, Deanne H. Hryciw, Mary E Wlodek, Karen M Moritz
      Abstract: AimUteroplacental insufficiency in rats reduces nephron endowment, leptin concentrations and programs cardiorenal disease in offspring. Cross-fostering growth restricted (Restricted) offspring onto a mother with normal lactation restores leptin concentrations and nephron endowment. This study aimed to determine if the reduced nephron endowment in Restricted offspring is due to delayed glomerular formation and dysregulation of renal genes regulating branching morphogenesis, apoptosis or leptin signalling. Furthermore, we aimed to investigate if cross-fostering Restricted offspring onto Control mothers could improve glomerular maturation and restore renal gene abundance.MethodsUteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on gestation day 18 (E18). Kidneys were collected at E20, postnatal day 1 (PN1) and PN7. An additional cohort was cross-fostered onto separate mothers at birth and kidneys collected at PN7.ResultsKidneys were lighter in the Restricted group, but weight was restored with cross-fostering. At E20, Bax, Flt1 and Vegfa abundance were increased in Restricted offspring, while Ret and Bcl2 transcripts were increased only in Restricted females. At PN7, Gdnf and Ret abundance were higher in Restricted offspring, as was Casp3. Restricted offspring had a wider nephrogenic zone with more immature glomeruli suggesting a delayed or extended nephrogenic period. Cross-fostering had subtle effects on gene abundance and glomerular maturity.ConclusionUteroplacental insufficiency induced apoptosis in the developing kidney and delayed and extended nephrogenesis. Cross-fostering Restricted offspring onto Control mothers had beneficial effects on kidney growth and renal maturity, which may contribute to the restoration of nephron endowment.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-19T03:10:26.116075-05:
      DOI: 10.1111/apha.12982
  • Knock-out of histamine receptor H3 alters adaptation to sudden darkness
           and monoamine levels in the zebrafish
    • Authors: Henri A. J. Puttonen; Maria Sundvik, Svetlana Semenova, Yukako Shirai, Yu-Chia Chen, Pertti Panula
      Abstract: AimHistamine receptor H3 has substantial neuropharmacological potential. Currently, knock-out models of this receptor have been investigated only in mice. We characterized the expression of this receptor in the zebrafish and generated a zebrafish histamine receptor H3 knock-out line. Using this model, we studied the role of histamine receptor H3 in important behaviours. We also analyzed the effect of histamine receptor H3 knock-out on monoaminergic systems, which has not been thoroughly studied in any animal model.MethodsGeneration of a mutant zebrafish line using the CRISPR/Cas9 system. Analysis of locomotor and social behaviour. Expression of histamine receptor H3 was characterized using in situ hybridization. Analysis of monoamine networks using HPLC, immunohistochemistry and quantitative PCR.ResultsWe found that histamine receptor H3 knock-out zebrafish larvae showed a shorter period of increased locomotion after a sudden onset of darkness, while the knock-out larvae had a wild type like acute response to sudden darkness. Adult knock-out fish showed decreased swimming velocity, although locomotor activity of knock-out larvae was unaltered. Additionally, levels of dopamine and serotonin were significantly decreased in the knock-out fish, while monoamine-related gene expression and immunohistochemistry patterns were unchanged.ConclusionsOur results show that histamine receptor H3 knock-out larvae adapt faster to sudden darkness, suggesting a role for this receptor in regulating responses to changes in the environment. The decreased levels of dopamine and serotonin provides the first direct evidence that knock-out of histamine receptor H3 alters these systems.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-16T17:41:00.407356-05:
      DOI: 10.1111/apha.12981
  • Muscle specific differences in expression and phosphorylation of the Janus
           kinase 2/ Signal Transducer and Activator of Transcription 3 following
           long-term mechanical ventilation and immobilization in rats
    • Authors: Heba Salah; Wen Fury, Jesper Gromada, Yu Bai, Tamar Tchkonia, James L. Kirkland, Lars Larsson
      Abstract: AimMuscle wasting is one of the factors most strongly predicting mortality and morbidity in critically ill intensive care unit (ICU). This muscle wasting affects both limb and respiratory muscles but the understanding of underlying mechanisms and muscle-specific differences remains incomplete. This study aims at investigating the temporal expression and phosphorylation of the Janus kinase / signal transducer and activator of transcription (JAK/STAT) pathway in muscle wasting associated with the ICU condition in order to characterize the JAK/STAT proteins and the related changes leading or responding to their activation during exposure to the ICU condition.MethodsA novel experimental ICU model allowing long-term exposure to the ICU condition, immobilization and mechanical ventilation, was used in this study. Rats were pharmacologically paralyzed by post-synaptic neuromuscular blockade and mechanically ventilated for durations varying between 6 hours and 14 days to study muscle-specific differences in the temporal activation of the JAK/STAT pathway in plantaris, intercostal and diaphragm muscles.ResultsThe JAK2/STAT3 pathway was significantly activated irrespective of muscle, but muscle-specific differences were observed in the temporal activation pattern between plantaris, intercostal, and diaphragm muscles.ConclusionThe JAK2/STAT3 pathway was differentially activated in plantaris, intercostal, and diaphragm muscles in response to the ICU condition. Thus, JAK2/STAT3 inhibitors may provide an attractive pharmacological intervention strategy in immobilized ICU patients, but further experimental studies are required in the study of muscle-specific effects on muscle mass and function in response to both short- and long-term exposure to the ICU condition prior to the translation into clinical research and practice.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-15T09:15:25.130559-05:
      DOI: 10.1111/apha.12980
  • Baroreflex sensitivity: an algebraic dilemma
    • Authors: Anna Taboni; Nazzareno Fagoni, Giovanni Vinetti, Guido Ferretti
      Abstract: The baroreflex system is a complex mechanism for short-term regulation of arterial blood pressure, involving the heart rate (HR), the heart contractility and the vascular tone in its efferent branches. The study of arterial baroreflexes relies on two different experimental approaches. On one hand, the closed-loop approach analyses the mutual relationship between HR and arterial blood pressure, both in steady state and in dynamic conditions.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-11T02:15:19.631188-05:
      DOI: 10.1111/apha.12979
  • Molecular pathways of Estrogen receptors and β-adrenergic receptors in
           cardiac cells: Recognition of their similarities, interactions and
           therapeutic value
    • Authors: Machuki Ong'achwa Jeremiah; Hong-Yuan Zhang, Sian Harding, Hong Sun
      Abstract: Estrogen receptors (ERs) and β-adrenergic receptors (βARs) play important roles in the cardiovascular system. Moreover, these receptors are expressed in cardiac myocytes and vascular tissues. Numerous experimental observations support the hypothesis that similarities and interactions exist between the signaling pathways of ERs (ERα, ERβ, GPR30) and βARs (β1, β2, and β3AR). The recently discovered estrogen receptor GPR30 shares structural features with the βARs, and this forms the basis for the interactions and functional overlap. GPR30 possess protein kinase A (PKA) phosphorylation sites, PDZ binding motifs, and interacts with A-kinase anchoring protein 5 (AKAP5), all of which enable its interaction with the βARs pathways. The interactions between ERs and βARs occur downstream of the G protein-coupled receptor, through the Gαs and Gαi proteins. This review presents an up-to-date description of ERs and βARs and demonstrates functional synergism and interactions between these receptors in cardiac cells. We explore their signaling cascades and the mechanisms that orchestrate their interactions and propose new perspectives on the signaling patterns for the GPR30 based on its structural resemblance to the βARs. In addition, we explore the relevance of these interactions to cell physiology, drugs (especially β-blockers and calcium channels blockers), and cardioprotection. Furthermore, a receptor-independent mechanism for estrogen and its influence on the expression of βARs and calcium-handling proteins are discussed. Finally, we highlight promising therapeutic avenues that can be derived from the shared pathways, especially the phosphatidylinositol-3-OH kinase (PI3K/Akt) pathway.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-09T20:10:35.444901-05:
      DOI: 10.1111/apha.12978
  • Effects of manipulating tetanic calcium on the curvature of the
           force-velocity relationship in isolated rat soleus muscles
    • Authors: A. M. Kristensen; O. B. Nielsen, K Overgaard
      Abstract: AimIn dynamically contracting muscles, increased curvature of the force-velocity relationship contributes to the loss of power during fatigue. It has been proposed that fatigue-induced reduction in [Ca++]i causes this increased curvature. However, earlier studies on single fibers have been conducted at low temperatures. Here, we investigated the hypothesis that curvature is increased by reductions in tetanic [Ca++]i in isolated skeletal muscle at near-physiological temperatures.MethodsRat soleus muscles were stimulated at 60 Hz in standard Krebs–Ringer buffer and contraction force and velocity were measured. Tetanic [Ca++]i was in some experiments either lowered by addition of 10 μmol L−1 dantrolene or use of submaximal stimulation (30 Hz) or increased by addition of 2 mmol L−1 caffeine.Force-velocity curves were constructed by fitting shortening velocity at different loading forces to the Hill equation. Curvature was determined as the ratio a/F0 with increased curvature reflecting decreased a/F0.ResultsCompared to control levels, lowering tetanic [Ca++]i with dantrolene or reduced stimulation frequency decreased the curvature slightly as judged from increase in a/F0 of 13 ± 1% (P = < 0.001) and 20 ± 2% (P = < 0.001) respectively. In contrast, increasing tetanic [Ca++]i with caffeine increased the curvature (a/F0 decreased by 17 ± 1%; P = < 0.001).ConclusionContrary to our hypothesis, interventions that reduced tetanic [Ca++]i caused a decrease in curvature, while increasing tetanic [Ca++]i increased the curvature. These results reject a simple causal relation between [Ca++]i and curvature of the force-velocity relation during fatigue.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-03T10:40:23.372542-05:
      DOI: 10.1111/apha.12977
  • Mitochondrial increase in volume density with exercise training: more,
           larger or better'
    • Authors: Niels Ørtenblad
      Abstract: In this issue of Acta Physiologica, a paper by Meinild and colleagues1 aims to verify if the increase in mitochondrial content with endurance training is explained by mitochondrial remodelling (hypertrophy) or by a distinct biogenesis of new organelle structures. Mitochondria are membrane-enclosed organelles found in most cells, with a double membrane separating the mitochondrial matrix from the cytosol. This allows a permeability barrier enabling the electrochemical gradient, which in turn powers the cell aerobic ATP synthesis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-30T09:20:21.108244-05:
      DOI: 10.1111/apha.12976
  • Chemokine (C-X-C motif) ligand 1 is a myokine induced by palmitate and is
           required for myogenesis in mouse satellite cells
    • Authors: Shinya Masuda; Masashi Tanaka, Takayuki Inoue, Ryuji Kitano, Hajime Yamakage, Kazuya Muranaka, Toru Kusakabe, Akira Shimatsu, Koji Hasegawa, Noriko Satoh-Asahara
      Abstract: AimThe functional significance of the myokines, cytokines and peptides produced and released by muscle cells, has not been fully elucidated. The purpose of the present study was to identify a myokine with increased secretion levels in muscle cells due to saturated fatty acids and to examine the role of the identified myokine in the regulation of myogenesis.MethodsHuman primary myotubes and mouse C2C12 myotubes were used to identify the myokine; its secretion was stimulated by palmitate loading. The role of the identified myokine in the regulation of the activation, proliferation, differentiation and self-renewal was examined in mouse satellite cells (skeletal muscle stem cells).ResultsPalmitate loading promoted the secretion of chemokine (C-X-C motif) ligand 1 (CXCL1) in human primary myotubes, and it also increased CXCL1 gene expression level in C2C12 myotubes in a dose- and time-dependent manner. Palmitate loading increased the production of reactive oxygen species along with the activation of nuclear factor-kappa B (NF-κB) signalling. Pharmacological inhibition of NF-κB signalling attenuated the increase in CXCL1 gene expression induced by palmitate and hydrogen peroxide. Palmitate loading significantly increased CXC receptor 2 gene expression in undifferentiated cells. CXCL1 knockdown attenuated proliferation and myotube formation by satellite cells, with reduced self-renewal. CXCL1 knockdown also significantly decreased the Notch intracellular domain protein level.ConclusionThese results suggest that secretion of the myokine CXCL1 is stimulated by saturated fatty acids and that CXCL1 promotes myogenesis from satellite cells to maintain skeletal muscle homeostasis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-28T10:45:27.372643-05:
      DOI: 10.1111/apha.12975
  • SUMO co-expression modifies KV11.1 channel activity
    • Authors: Annette Buur Steffensen; Martin Nybo Andersen, Nancy Mutsaers, Amer Mujezinovic, Nicole Schmitt
      Abstract: AimThe voltage-gated potassium channel KV11.1 is the molecular basis for the IKr current which plays an important role in cardiac physiology. Its malfunction is associated with both inherited and acquired cardiac arrhythmias. Native currents differ from those in experimental models, suggesting additional regulatory mechanisms. We hypothesised that the post-translational modification sumoylation finetunes channel activity.MethodsThe functional effects of sumoylation on KV11.1 were addressed by employing two-electrode voltage-clamp (TEVC) experiments in Xenopus laevis oocytes. Site-directed mutagenesis enabled a further analyse of the SUMO-target amino acids. We assessed protein expression levels and used confocal imaging for localization studies.ResultsCo-expression with Ubc9 and SUMO alters the electrophysiological properties of KV11.1 leading to a decrease in steady-state current amplitude largely due to faster inactivation and alteration of deactivation kinetics. We identified three lysines (K21, K93, and K116) in the PAS-domain as the putative SUMO-targets.ConclusionThis study indicates KV11.1 as a sumoylation target, and offers the three main targets; K21, K93, and K116. Furthermore, it proposes an underlying mechanism for the observed kinetic impact of the PAS domain.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-09T10:40:24.684403-05:
      DOI: 10.1111/apha.12974
  • MicroRNA-214-3p: A Link between Autophagy and Endothelial Cell Dysfunction
           in Atherosclerosis
    • Authors: Jing Wang; Wei-Na Wang, Shuang-Bin Xu, Hong Wu, Bing Dai, Dong-Dong Jian, Mei Yang, Yu-Tao Wu, Qiang Feng, Jian-Hua Zhu, Lei Zhang, Li Zhang
      Abstract: AimEndothelial cell injury assumes a fundamental part in the pathogenesis of atherosclerosis, and endothelial cell autophagy has protective effects on the development of atherosclerosis, though the underlying molecular regulation mechanism is indistinct. This study is aimed to investigate whether microRNA-214-3p (miR-214-3p) is involved in the endothelial cell autophagy regulation of atherosclerosis.MethodsWe utilized ApoE-/- mice provided with a high-fat diet (HFD) as atherosclerosis model. We analyzed the level of miR-214-3p and the levels of autophagy-related protein 5 (ATG5) and autophagy-related protein 12 (ATG12) in the purified CD31+ endothelial cells from mouse aorta. Bioinformatics analysis and a dual luciferase reporter assay were performed to confirm the binding target of miR-214-3p. In vitro study, human umbilical vein endothelial cells (HUVECs) were transfected with miR-214-3p mimics/inhibitor and stimulated with 100 μg/mL oxidized low-density lipoprotein (ox-LDL) for 12 hours to initiate a stress-repairing autophagic process.ResultsIn mouse models, we identified an inverse correlation between miR-214-3p, ATG5 and ATG12. We observed that in young HUVECs, ox-LDL initiated autophagy where repressed by miR-214-3p overexpression, as evaluated by autophagic protein analysis, microtubule-associated protein 1 light chain 3B-II (LC3B-II) immunofluorescence assay, and transmission electron microscopy (TEM). Also, miR-214-3p promoted ox-LDL accumulation in HUVECs and THP-1 monocyte adhesion. Conversely, in old HUVECs, suppression of miR-214-3p preserved the ability to initiate a protective autophagy reaction to the ox-LDL stimulation.ConclusionmiR-214-3p regulates ox-LDL-initiated autophagy in HUVECs by directly targeting the 3'UTR of ATG5, and may have a suitable role in the pathogenesis of atherosclerosis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-09T10:10:21.526414-05:
      DOI: 10.1111/apha.12973
  • Top scorers of 2015
    • Authors: P. B. Persson
      Abstract: Over 25% of the articles published in 2015 received double digit citations. Not surprisingly, slightly more than half of our reviews published in Acta Physiologica exceed this citation level. Obviously, Acta Physiologica is on the rise and attracts ever more readers. It is with satisfaction that we discovered that this high-quality is distributed throughout all fields published in Acta Physiologica.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-09T05:05:22.886755-05:
      DOI: 10.1111/apha.12970
  • Sphingosine-1-phosphate and renal vasoconstriction
    • Authors: Boye L Jensen
      Abstract: In the present issue of Acta Physiologica, Guan et al. in their article “Mechanisms of sphingosine-1-phosphate-mediated vasoconstriction of rat afferent arterioles” 1 address the signaling events associated with sphingosine-1-phosphate (S1P)-mediated renal afferent vasoconstriction and show in, technically demanding, blood-perfused juxtamedullary nephron preparation that S1P signaling relies predominantly on transmembrane calcium influx from the extracellular fluid through L-type calcium channels with contribution from oxidative stress metabolites1. So not only is new information on S1P signaling of potential therapeutic relevance obtained but the general concept is confirmed that renal preglomerular vascular reactivity relies significantly on calcium influx through voltage gated calcium channels.
      Authors showed previously, that S1P caused selective renal afferent but not efferent vasoconstriction2 and in conjunction with increased S1P release in pathophysiological situations like sepsis and ischemia-reperfusion incidents, this effect could be relevant in acute kidney injury with parallel decreases in renal blood flow and GFR.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-09T05:05:21.443658-05:
      DOI: 10.1111/apha.12971
  • Evaluating the essential role of RONS in vivo in exercised human muscle
    • Authors: Enrique Jaimovich; Mariana Casas
      Abstract: An article by Margaritelis et al.,1 (this issue) addresses an important issue in exercise physiology, as it is the actual role of reactive oxygen and nitrogen species (RONS) in exercise-induced adaptations in humans. The authors designed a procedure that allowed them to avoid the use of exogenous anti-oxidants and redox agents that will normally alter metabolism and have multiple undesired effects. We discuss here in the context of the necessary balance between the beneficial role of reactive oxygen and nitrogen species as intracellular signals for muscle adaptation and the deleterious effects of these species in oxidative stress.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-09T05:00:24.033232-05:
      DOI: 10.1111/apha.12972
  • ARMAX: A method for assessment of the dynamic response of the arterial
    • Authors: Morten T Lund; Max Salomonsson, Thomas E N Jonassen, Niels-Henrik Holstein-Rathlou
      Abstract: AimThe baroreflex is a key mechanism in cardiovascular regulation and alterations in baroreceptor function are seen in many diseases, including heart failure, obesity and hypertension. We propose a new method for analyzing baroreceptor function from continuous blood pressure and heart rate in both health and disease.Methods48-hour data series of blood pressure and heart rate were collected with telemetry. Sprague-Dawley rats on standard chow (n=11) served as controls, while rats on a high-fat, high-fructose diet (n=6) constituted the obese-hypertensive model. A third group of rats underwent autonomic blockade (n=6). An autoregressive–moving-average with exogenous inputs (ARMAX)-model was applied to the data and compared with the α-coefficient.ResultsAutonomic blockade caused a significant reduction in the strength of the baroreflex as estimated by ARMAX (ARMAX-BRS -0.03±0.01 vs. -0.19±0.04 bpm heartbeat-1). Both methods showed a ~50% reduction in BRS in the obese-hypertensive group compared with control (body weight 531±27 vs. 458±19 g, p
      PubDate: 2017-09-05T02:50:55.959159-05:
      DOI: 10.1111/apha.12962
  • Orexin A increases sympathetic nerve activity through promoting expression
           of proinflammatory cytokines in Sprague-Dawley rats
    • Authors: Yuanyuan Fan; Enshe Jiang, Taija Hahka, Qinghui Chen, Jianqun Yan, Zhiying Shan
      Abstract: AimAccumulating evidence suggests that orexin signaling is involved in the regulation of blood pressure and cardiovascular function. However, the underlying mechanisms are not clear. Here we test the hypothesis that upregulated orexin A signaling in the paraventricular nucleus (PVN) increases sympathetic nerve activity (SNA) through stimulating expression of proinflammatory cytokines (PICs).MethodsIn vivo sympathetic nerve recordings were performed to test the impact of PVN orexin signaling on sympathetic outflow in Sprague-Dawley (SD) rats. Real-time PCR was carried out to assess effects of central administration of orexin A on PVN PICs expression in SD rats. To test whether orexin A induced increases in PICs were exclusively mediated by orexin receptor 1 (OX1R), OX1R expressing PC12 (PC12-OX1R) cells were incubated with different dose of orexin A, then PICs mRNA and immunoreactivity were measured.ResultsOrexin A microinjection (25 pmol) into the PVN significantly increased splanchnic SNA (93.5%) and renal SNA (83.3%) in SD rats, and these increases were attenuated by OX1R antagonist SB408124. Intracerebroventricular injection of orexin A (0.2 nmol) into SD rats increased mRNA levels of PICs including IL1-β (2.7-fold), IL6 (1.7-fold) and TNF-α (1.5-fold), as well as Fra1 (1.6-fold) in the PVN. Orexin A treatment in PC12-OX1R cells resulted in a dose- and time-dependent increase in the expression of PICs and Fra1, a subunit of AP1 transcriptional factor. The increase in the PICs was blocked by AP1 blocker curcumin.ConclusionPVN orexin system activation is involved in SNA regulation maybe through triggering AP1-PICs pathway.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-05T02:45:28.061316-05:
      DOI: 10.1111/apha.12963
  • Arginase – A novel target for cardioprotection by vagal nerve
    • Authors: A. Uitterdijk; D.J. Duncker
      Abstract: The elegant study of Kiss et al.1 in this issue of Acta Physiologica entitled ‘Vagal nerve stimulation reduces infarct size via a mechanism involving the alpha-7 nicotinic acetylcholine receptor and down-regulation of cardiac and vascular arginase’ explores the role of arginase in myocardial ischemia-reperfusion damage, and in the myocardial infarct-size limitation by vagal nerve stimulation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-21T07:00:41.095512-05:
      DOI: 10.1111/apha.12946
  • TRPM5 in the battle against diabetes and obesity
    • Authors: Rudi Vennekens; Margot Mesuere, Koenraad Philippaert
      Abstract: TRPM5 is a nonselective monovalent cation channel activated by increases of intracellular Ca2+. It has a distinct expression pattern: expression is detected in chemosensitive tissues from solitary chemosensory cells to the taste receptor cells and in pancreatic β-cells. The role of TRPM5 has been investigated with the use of knockout mouse models. Trpm5-/- mice have a lack of type II taste perception and show reduced glucose-induced insulin secretion. Expression levels of TRPM5 are reduced in obese, leptin signaling deficient mice and mutations in TRPM5 have been associated with type II diabetes and metabolic syndrome. In this review we aim to give an overview of the activation, selectivity, modulation and physiological roles of TRPM5.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-21T03:35:22.752212-05:
      DOI: 10.1111/apha.12949
  • High-doses of anti-inflammatory drugs compromise muscle strength and
           hypertrophic adaptations to resistance training in young adults
    • Authors: Mats Lilja; Mirko Mandić, William Apró, Michael Melin, Karl Olsson, Staffan Rosenborg, Thomas Gustafsson, Tommy R Lundberg
      Abstract: AimsThis study tested the hypothesis that high doses of anti-inflammatory drugs would attenuate the adaptive response to resistance training compared with low doses.MethodsHealthy men and women (aged 18-35 years) were randomly assigned to daily consumption of ibuprofen (IBU; 1200 mg; n=15) or acetylsalicylic acid (ASA; 75 mg; n=16) for 8 weeks. During this period, subjects completed supervised knee-extensor resistance training where one leg was subjected to training with maximal volitional effort in each repetition using a flywheel ergometer (FW), while the other leg performed conventional (work-matched across groups) weight-stack training (WS). Before and after training, muscle volume (MRI) and strength were assessed, and muscle biopsies were analysed for gene and protein expression of muscle growth regulators.ResultsThe increase in m. quadriceps volume was similar between FW and WS, yet was (averaged across legs) greater in ASA (7.5%) compared with IBU (3.7%, group difference 34 cm3; P=0.029). In the WS leg, muscle strength improved similarly (11-20%) across groups. In the FW leg, increases (10-23%) in muscle strength were evident in both groups yet they were generally greater (interaction effects P
      PubDate: 2017-08-21T02:40:24.716468-05:
      DOI: 10.1111/apha.12948
  • Contribution of Mitochondria-Derived Free Radicals to Endothelial
           Dysfunction in Human Skeletal Muscle Feed Arteries: Another Hazard of the
           Aging Process
    • Authors: Julian H. Lombard
      Abstract: Earlier studies by a number of laboratories 1-3 have demonstrated impaired endothelium-dependent vasodilation in arterioles of aged animals and humans; and older humans exhibit significantly attenuated hyperemic responses to moderate exercise1 and endothelium-dependent vasodilator stimuli 3 compared to younger controls, emphasizing the need for carefully targeted research to understand the mechanisms underlying compromised blood flow with age and its consequences. The current paper by Park and coworkers4 is a follow-up to an earlier study by this group,3 in which they demonstrated a significant attenuation of endothelium-dependent dilation in older subjects, compared to young subjects, which was accompanied by reductions in phospho-eNOS/eNOS (p-eNOS/eNOS) ratio and elevations in vascular superoxide (O2-) levels. The current study extends the authors’ earlier findings by investigating an important question, namely, whether mitochondria-derived free radicals are the mechanism responsible for the impaired endothelium-dependent vasodilator responses in the older individuals.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-21T02:35:19.491793-05:
      DOI: 10.1111/apha.12947
  • Autophagic dysfunction and autophagosome escape in the mdx mus musculus
           model of Duchenne muscular dystrophy
    • Authors: Hannah R. Spaulding; Ellen M. Kelly, John C. Quindry, Joel B. Sheffield, Matthew B. Hudson, Joshua T. Selsby
      Abstract: AimDuchenne muscular dystrophy is caused by the absence of functional dystrophin protein and results in a host of secondary effects. Emerging evidence suggests that dystrophic pathology includes decreased pro-autophagic signaling and suppressed autophagic flux in skeletal muscle, but the relationship between autophagy and disease progression is unknown. The purpose of this investigation was to determine the extent to which basal autophagy changes with disease progression. We hypothesized that autophagy impairment would increase with advanced disease.MethodsTo test this hypothesis, seven week old and 17 month old dystrophic diaphragms were compared to each other and age-matched controls.ResultsChanges in protein markers of autophagy indicate impaired autophagic stimulation through AMPK, however, robust pathway activation in dystrophic muscle, independent of disease severity. Relative protein abundance of p62, an inverse correlate of autophagic degradation, was dramatically elevated with disease regardless of age. Likewise, relative protein abundance of Lamp2, a lysosome marker, was decreased 2-fold at 17 months of age in dystrophic muscle and was confirmed, along with mislocalization, in histological samples, implicating lysosomal dysregulation in this process. In dystrophic muscle autophagosome-sized p62 positive foci were observed in the extracellular space. Moreover, we found that autophagosomes were released from both healthy and dystrophic diaphragms into the extracellular environment, and the occurrence of autophagosome escape was more frequent in dystrophic muscle.ConclusionThese findings suggest autophagic dysfunction proceeds independent of disease progression, blunted degradation of autophagosomes is due in part to decreased lysosome abundance, and contributes to autophagosomal escape to the extracellular space.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-19T05:05:23.182214-05:
      DOI: 10.1111/apha.12944
  • Nephropathies
    • Authors: Anika Westphal; Stefanie Reuter, Ralf Mrowka
      Abstract: Origins and progresses of nephropathies are manifold and include inflammatory or non-inflammatory causes. The incidence of nephropathies increases all over the world, supported by the growing elderly population. Nowadays there are about two million fatalities per year due to acute kidney injury (AKI) 1. Clinical outcomes of AKI have not improved over the past 50 years 2. Renal tissue hypoperfusion and hypoxia are thought to be the main elements causing AKI and the progression to chronic kidney disease (CKD) and end stage renal disease (ESRD) 1. Moreover renal disorders often coincide with systemic diseases like hypertension, which also has a high mortality, or with diabetes.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-18T22:35:24.661514-05:
      DOI: 10.1111/apha.12945
  • Comments on the Review “Biomarkers in acute kidney injury –
           pathophysiological basis and clinical performance” Acta Physiol 2017,
           219, 556–574: An update on kidney localization of IGFBP7 and TIMP2
    • Authors: David R. Emlet; Xiaoyan Wen, John A. Kellum
      Abstract: In March of 2017, Acta Physiologica published a special series on renoprotection, and one of the publications in that series was a review entitled “Biomarkers in acute kidney injury – pathophysiological basis and clinical performance”. This review described very well the current understanding of the pathophysiology, cellular localization, and clinical performance of the most important currently proposed biomarkers of AKI, to include insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases 2 (TIMP2). At the time that this review was accepted, no work had yet clearly identified the cellular localization of IGFBP7 and TIMP2 in the kidney, and that fact was correctly commented on in the review.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-09T07:55:19.786859-05:
      DOI: 10.1111/apha.12934
  • Study of termination of postprandial gastric contractions in humans, dogs,
           and Suncus murinus: role of motilin- and ghrelin- induced strong
    • Authors: Takashi Mikami; Kazuma Ito, Hetzel Tartera Diaz, Per M. Hellström, Erito Mochiki, Shota Takemi, Toru Tanaka, Sachiko Tsuda, Takamichi Jogahara, Ichiro Sakata, Takafumi Sakai
      Abstract: AimStomach contractions show two types of specific patterns in many species, i.e., migrating motor contraction (MMC) and postprandial contractions (PPCs), in the fasting and fed state, respectively. We found gastric PPCs terminated with migrating strong contractions in humans, dogs, and suncus. In this study, we reveal the detailed characteristics and physiological implications of these strong contractions of PPC.MethodsHuman, suncus, and canine gastric contractions were recorded with a motility-monitoring ingestible capsule and a strain-gauge force transducer. The response of motilin and ghrelin and its receptor antagonist on the contractions were studied by using free-moving suncus.ResultsStrong gastric contractions were observed at the end of a PPC in human, dog, and suncus models, and we tentatively designated this contraction to be a postprandial giant contraction (PPGC). In the suncus, the PPGC showed the same property as those of a phase III contraction of MMC (PIII-MMC) in the duration, motility index, and response to motilin- or ghrelin-antagonist administration. Ghrelin antagonist administration in the latter half of the PPC (LH-PPC) attenuated gastric contraction prolonged the duration of occurrence of PPGC, as found in PII-MMC.ConclusionIt is thought that the first half of the PPC changed to PII-MMC and then terminated with PIII-MMC, suggesting that PPC consists of a digestive phase (the first half of the PPC) and a discharge phase (LH-PPC), and that LH-PPC is coincident with MMC. In this paper, we propose a new approach for the understanding of postprandial contractions.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-08T04:05:19.880144-05:
      DOI: 10.1111/apha.12933
  • Overexpression of Integrin α11 Induces Cardiac Fibrosis in Mice
    • Authors: Andreas Romaine; Ida W. Sørensen, Cédric Zeltz, Ning Lu, Pugazendhi Murugan Erusappan, Arne Olav Melleby, Lili Zhang, Bård Bendiksen, Emma Louise Robinson, Jan Magnus Aronsen, Kate M Herum, Håvard Danielsen, Ivar Sjaastad, Geir Christensen, Donald Gullberg
      Abstract: AimTo understand the role of the collagen-binding integrin α11 in vivo we have used a classical approach of creating a mouse strain overexpressing integrin α11. A transgenic mouse strain overexpressing α11 in muscle tissues was analysed in the current study with special reference to the heart tissue.MethodsWe generated and phenotyped integrin α11 transgenic (TG) mice by echocardiography, magnetic resonance imaging and histology. Wild-type (WT) mice were subjected to aortic banding (AB) and the expression of integrin α11 was measured in flow cytometry sorted cardiomyocytes and non-myocytes.ResultsTG mice developed left ventricular concentric hypertrophy by 6 months, with increased collagen deposition and reactivation of mRNA encoding foetal genes associated with cardiovascular pathological remodelling compared to WT mice. Masson's trichrome staining revealed interstitial fibrosis, confirmed additionally by magnetic resonance imaging, and was found to be most prominent in the cardiac septum of TG but not WT mice. TG hearts expressed increased levels of transforming growth factor-β2 and -β3 and upregulated smooth muscle actin. Macrophage infiltration coincided with increased NFκB signalling in TG but not WT hearts. Integrin α11 expression was increased in both cardiomyocytes and non-myocyte cells from WT AB hearts compared to sham operated animals.ConclusionWe report for the first time that overexpression of integrin α11 induces cardiac fibrosis and left ventricular hypertrophy. This is a result of changes in intracellular hypertrophic signalling and secretion of soluble factors that increase collagen production in the heart.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-03T09:50:24.308619-05:
      DOI: 10.1111/apha.12932
  • The importance of the functional network between endothelial
           microparticles and late endothelial progenitor cells for understanding the
           physiological aspects of this new vascular repair system
    • Authors: Rosita A. Condorelli; Aldo E. Calogero, Sandro La Vignera
      Abstract: The article by Alexandru and colleagues, entitled “Microparticles of healthy origins improves endothelial progenitor cell dysfunction via microRNA transfer in an atherosclerotic hamster model”, represent an important advance in the physiology of the late endothelial progenitor cells (EPCs), documenting the complementary role played by endothelial microparticles (MPs) that play an active role in this repair system.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-03T09:45:21.182972-05:
      DOI: 10.1111/apha.12931
  • Distribution of muscle fiber conduction velocity for representative
           samples of motor units in the full recruitment range of the tibialis
           anterior muscle
    • Authors: Alessandro Del Vecchio; Francesco Negro, Francesco Felici, Dario Farina
      Abstract: AimMotor units are recruited in an orderly manner according to the size of motor neurons. Moreover, because larger motor neurons innervate fibers with larger diameters than smaller motor neurons, motor units should be recruited orderly according to their conduction velocity (MUCV). Because of technical limitations, these relations have been previously tested either indirectly or in small motor unit samples that revealed weak associations between motor unit recruitment threshold (RT) and MUCV. Here we analyze the relation between MUCV and RT for large samples of motor units.MethodsTen healthy volunteers completed a series of isometric ankle dorsiflexions at forces up to 70% of the maximum. Multi-channel surface electromyographic signals recorded from the tibialis anterior muscle were decomposed into single motor unit action potentials, from which the corresponding motor unit RT, MUCV, and action potential amplitude were estimated. Established relations between muscle fiber diameter and CV were used to estimate the fiber size.ResultsWithin individual subjects, the distributions of MUCV and fiber diameters were unimodal and did not show distinct populations. MUCV was strongly correlated with RT (mean (SD) R2 = 0.7 (0.09), p
      PubDate: 2017-08-01T09:05:52.096688-05:
      DOI: 10.1111/apha.12930
  • Different Solutions to Restoring Oxygen Delivery at Altitude
    • Authors: William .K. Milsom
      Abstract: Populations resident to high altitude have adapted to the demands of performance in low oxygen environments in different ways. The article by Ivy et al.1 provides new data allowing the authors to speculate on what specifically may have led to these alternate solutions.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-28T02:32:27.31023-05:0
      DOI: 10.1111/apha.12926
  • Genetic ablation of carbonic anhydrase IX disrupts gastric barrier
           function via claudin-18 downregulation and acid backflux
    • Authors: Taolang Li; Xuemei Liu, Brigitte Riederer, Katerina Nikolovska, Anurag Kumar Singh, Kari A. Mäkelä, Anna Seidler, Yongjian Liu, Gerolf Gros, Helmut Bartels, Karl Heinz Herzig, Ursula Seidler
      Abstract: AimThe study aims to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX).MethodsWe assessed the ability of CAIX knockout and WT gastric surface epithelial cells to withstand luminal acid load by measuring the pHi of exteriorized gastric mucosa in vivousing two photon confocal laser scanning microscopy. Cytokines and claudin-18A2 expression was analyzed by RT-PCR.ResultsCAIX knockout gastric surface epithelial cells showed significantly faster pHi-decline after luminal acid load compared to WT. Increased gastric mucosal IL-1β and iNOSexpression,but decreased claudin-18A2 (which confer acid resistance) were observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin-18 expression was different between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL-11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent theclaudin-18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL-1β. The treatment reduced the parietal cell loss in CAIX KO mice in the subsequent months.ConclusionsWe propose that CAIX converts protons that are either backflux or extruded from the cells rapidly to CO2 and H2O, contributing to tight junction protection and gastric epithelial pHi regulation. Lack of CAIX results in persistent acid backflux via claudin-18 downregulation, causing loss of parietal cells, hypergastrinemia and foveolar hyperplasia.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-27T03:05:37.721075-05:
      DOI: 10.1111/apha.12923
  • Extravasal albumin concentration modulates contractile responses of renal
           afferent arterioles
    • Authors: Xiang Gao; Zhi Zhao Liu, Hayar Mohammed, Zhengbing Zhuge, Ming Liu, En Yin Lai, Leif Jansson, Mattias Carlström, Andreas Patzak, A. Erik G Persson
      Abstract: AimAfferent arterioles (AA) hold a key position in the regulation of renal blood flow and glomerular filtration rate. Being the effector site of tubuloglomerular feedback the afferent arteriole contributes to the renal handling of sodium and fluid. Dehydration goes along with increased renal interstitial protein concentration. Here, the hypothesis was tested that extravasal protein concentration directly modulates afferent arteriolar tone; a mechanism which may contribute to body fluid volume control.MethodThe effect of increased extravasal albumin concentration on the vascular reactivity was investigated in renal AA and interlobar arteries of mice, rat renal AA, and in pancreatic islet arterioles.ResultsAlbumin (2% and 4% in the bath solution) significantly potentiated the contractile response of renal afferent arterioles induced by angiotensin II and adenosine, as well as their combination, compared to the control situation (0.1% albumin). Albumin did not influence the contractility of larger renal vessels or pancreatic islet arterioles. Mimicking the increase of the osmolality induced by 4% albumin by applying mannitol to the bath solution also increased the response of renal arterioles to Ang II. However, the effect was smaller compared to that of albumin. The nitric oxide bioavailability, measured by DAF-FM fluorescence, was reduced in afferent arterioles exposed to 4% albumin.ConclusionThe protein-induced modulation of AA tone is mediated by the increased osmolality as well as by NO scavenging. The results suggest a possible contribution of these mechanisms to the control of extracellular fluid volume via adjustment of renal blood flow and glomerular filtration rate.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-27T03:05:32.89983-05:0
      DOI: 10.1111/apha.12925
  • Apelin-induced Cardioprotection Against Ischemia/Reperfusion Injury: Roles
           of Epidermal Growth Factor and Src
    • Authors: Anna Folino; Lisa Accomasso, Claudia Giachino, Pier Giorgio Montarolo, Gianni Losano, Pasquale Pagliaro, Raffaella Rastaldo
      Abstract: AimApelin, the ligand of the G-protein-coupled-receptor (GPCR) APJ, exerts a postconditioning-like protection against ischemia-reperfusion injury through activation of PI3K-Akt-NO signalling. The pathway connecting APJ to PI3K is still unknown. Since other GPCR ligands act through transactivation of epidermal growth factor receptor (EGFR) via a matrix-metalloproteinase (MMP) or Src kinase, we investigated whether EGFR transactivation is involved in the following three features of apelin-induced cardioprotection: limitation of infarct size, suppression of contracture, and improvement of post-ischemic contractile recovery.MethodIsolated rat hearts underwent 30-min of global ischaemia and 2-hours of reperfusion. Apelin (0.5 μM), was infused during the first 20-min of reperfusion. EGFR, MMP or Src were inhibited to study the pathway connecting APJ to PI3K. Key components of RISK pathway, namely PI3K, guanylyl-cyclase or mitochondrial K+-ATP channels were also inhibited. Apelin-induced EGFR and PTEN phosphorylation were assessed. Left ventricular pressure and infarct size were measured.ResultsApelin-induced reductions of infarct size and myocardial contracture were prevented by inhibition of EGFR, Src, MMP, or RISK pathway. The involvement of EGFR was confirmed by its phosphorylation. However, neither direct EGFR nor MMP inhibition affected apelin-induced improvement of early post-ischemic contractile recovery, which was suppressed by Src and RISK inhibitors only. Apelin also increased PTEN-phosphorylation, which was removed by Src inhibition.ConclusionWhile EGFR and MMP limit infarct size and contracture, Src or RISK pathway inhibition abolishes the three features of cardioprotection. Src does not only transactivate EGFR, but also inhibits PTEN by phosphorylation, thus playing a crucial role in apelin-induced cardioprotection.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-27T03:05:29.92916-05:0
      DOI: 10.1111/apha.12924
  • MICAL2 Promotes Breast Cancer Cell Migration by Maintaining EGFR Stability
           and EGFR/P38 Signaling Activation
    • Authors: Yueyuan Wang; Wenjie Deng, Yujie Zhang, Shixiu Sun, Shuo Zhao, Yan Chen, Xuyang Zhao, Lei Liu, Jun Du
      Abstract: AimMICAL2, a cytoskeleton dynamics regulator, is identified associated with survival and metastasis of several types of cancers recently. The present study was designed to investigate the role of MICAL2 in breast cancer cell migration as well as its underlying mechanisms.MethodsThe relationship between MICAL2 and EGF/EGFR signaling was analyzed by using gene overexpression and knockdown techniques. Cell migration was measured by wound healing assays. Activation of EGF/EGFR singaling pathways were evaluated by immunofluorescence, qPCR, Western blotting and zymography techniques. Rac1 activity was assessed by pulldown assay. Correlation of MICAL2 and EGFR in breast cancer specimens was examined by using immunohistochemical analysis.ResultsEctopic expression of MICAL2 in MCF-7 cells augmented EGFR protein level, accompanied by the promotion of cell migration. Silencing MICAL2 in MDA-MB-231 cells destabilized EGFR and inhibited cell migration. In mechanism, the maintaining effect of MICAL2 on EGFR protein content was due to a delay in EGFR degradation. Expression of MICAL2 was also shown positively correlated with the activation of P38/HSP27 and P38/MMP9 signalings, which are the main downstream signaling cascades of EGF/EGFR involved in cell migration. Further analysis indicated that Rac1 activation contributed to the maintaining effect of MICAL2 on EGFR stability. In addition, analysis of breast cancer specimens revealed a positive correlation between MICAL2 and EGFR levels and an association between MICAL2 expression and worse prognosis.ConclusionMICAL2 is a major regulator of breast cancer cell migration, maintaining EGFR stability and subsequent EGFR/P38 signaling activation through inhibiting EGFR degradation in a Rac1-dependent manner.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:29:42.157585-05:
      DOI: 10.1111/apha.12920
  • Discovering Long-Term Potentiation (LTP) - Recollections and Reflections
           on what came after
    • Authors: Terje Lømo
      Abstract: Chance events led me to a lifelong career in scientific research. They paved the way for being the first to see long-term potentiation of synaptic efficiency (LTP) in Per Andersen's lab in Oslo in 1966. Here I describe my way to this discovery and the experiments with Tim Bliss in 1968-1969 that led to Bliss and Lømo, 1973. Surprisingly, we later failed to reproduce these results. I discuss possible reasons for this failure, which made us both leave LTP research, in my case for good, in Tim's case for several years.After 30 years of work in a different field, I renewed my interest in the hippocampus and LTP in the early 2000's and published, for the first time, results that I had obtained 40 years earlier. Here I present my take on how interest in and research on LTP evolved after the early years. This includes a discussion of the functions of hippocampus as seen in those early days, the case of patient H.M., Donald Hebb's place in the story, the search for “memory molecules” such as PKMζ, and the primary site for LTP expression (pre- and/or postsynaptic'). Throughout, I reflect on my life in science, how science is done, and what drives it. The reflections are quite personal and I admit to mixed feelings about broadcasting them.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:29:36.153794-05:
      DOI: 10.1111/apha.12921
  • Serotonergic paraneurons in the female mouse urethral epithelium and their
           potential role in peripheral sensory information processing
    • Authors: F. Aura Kullmann; Huiyi H. Chang, Christian Gauthier, Bronagh M. McDonnell, Jih-Chao Yeh, Dennis R Clayton, Anthony J. Kanai, William C. de Groat, Gerard L. Apodaca, Lori A. Birder
      Abstract: AimThe mechanisms underlying detection and transmission of sensory signals arising from visceral organs, such as the urethra, are poorly understood. Recently, specialized ACh-expressing cells embedded in the urethral epithelium have been proposed as chemosensory sentinels for detection of bacterial infection. Here we examined the morphology and potential role in sensory signaling of a different class of specialized cells that express serotonin (5-HT), termed paraneurons.MethodsUrethrae, dorsal root ganglia neurons and spinal cords were isolated from adult female mice and used for immunohistochemistry and calcium imaging. Visceromotor reflexes (VMRs) were recorded in vivo.ResultsWe identified two morphologically distinct groups of 5-HT+ cells with distinct regional locations: bipolar-like cells predominant in the mid-urethra and multipolar-like cells predominant in the proximal and distal urethra. Sensory nerve fibers positive for calcitonin gene-related peptide, substance P and TRPV1 were found in close proximity to 5-HT+ paraneurons. In vitro 5-HT (1 μM) stimulation of urethral primary afferent neurons, mimicking 5-HT release from paraneurons, elicited changes in the intracellular calcium concentration ([Ca2+]i) mediated by 5-HT2 and 5-HT3 receptors. Approximately 50% of 5-HT responding cells also responded to capsaicin with changes in the [Ca2+]i. In vivo intra-urethral 5-HT application increased VMRs induced by urethral distention and activated pERK in lumbosacral spinal cord neurons.ConclusionThese morphological and functional findings provide insights into a putative paraneuron-neural network within the urethra that utilizes 5-HT signaling, presumably from paraneurons, to modulate primary sensory pathways carrying nociceptive and non-nociceptive (mechano-sensitive) information to the central nervous system.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T09:05:18.960261-05:
      DOI: 10.1111/apha.12919
  • Can Principles of the Surface Potential be Combined with Knowledge of
           Natural Products to Reduce Atrial Rhythm Disturbances'
    • Authors: H. Ni; K. Narsingani, H. Zhang, W. R. Giles
      Abstract: Long lasting or chronic electrophysiological abnormalities in human atria are significant contributors to morbidity during healthy aging. Although both paroxysmal (brief) and chronic atrial fibrillation (AF) were considered to be benign; the notable association between maintained AF and stroke has resulted in AF now being a target for surgical intervention (ablation) and/or drug therapy. An interesting, forward looking paper from the Elinder Group1 in this issue of Acta Physiologica reveals novel pharmacological agents and principles that could be the basis for more effective antiarrhythmic therapies for AF.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T08:50:18.868108-05:
      DOI: 10.1111/apha.12918
  • Cerebrocortical activity during self-paced exercise in temperate, hot and
           hypoxic conditions
    • Authors: Julien D. Périard; Kevin De Pauw, Frank Zanow, Sébastien Racinais
      Abstract: AimHeat stress and hypoxia independently influence cerebrocortical activity and impair prolonged exercise performance. This study examined the relationship between electroencephalography (EEG) activity and self-paced exercise performance in control (CON, 18°C, 40% RH), hot (HOT, 35°C, 60%RH) and hypoxic (HYP, 18°C, 40%RH FiO2: 0.145) conditions.MethodsEleven well-trained cyclists completed a 750 kJ cycling time trial in each condition on separate days in a counter-balanced order. EEG activity was recorded with α and β activity evaluated in the frontal (F3 and F4) and central (C3 and C4) areas. Standardised low-resolution brain electromagnetic tomography (sLORETA) was also utilised to localise changes in cerebrocortical activity.ResultsBoth α and β activity decreased in the frontal and central areas during exercise in HOT relative to CON (P
      PubDate: 2017-07-07T01:55:59.855483-05:
      DOI: 10.1111/apha.12916
  • Astroglial vesicular network: Evolutionary trends, physiology and
    • Authors: Robert Zorec; Vladimir Parpura, Alexei Verkhratsky
      Abstract: Intracellular organelles, including secretory vesicles, emerged when eukaryotic cells evolved some 3 billion years ago. The primordial organelles that evolved in Archaea were similar to endolysosomes, which developed, arguably, for specific metabolic tasks, including uptake, metabolic processing, storage and disposal of molecules. In comparison to prokaryotes, cell volume of eukaryotes increased by several orders of magnitude and vesicle traffic emerged to allow for communication between distant intracellular locations. Lysosomes, first described in 1955, a prominent intermediate of endo- and exocytotic pathways, operate virtually in all eukaryotic cells including astroglia, the most heterogeneous type of homeostatic glia in the central nervous system. Astrocytes support neuronal network activity in particular through elaborated secretion, based on a complex intracellular vesicle network dynamics. Deranged homeostasis underlies disease and astroglial vesicle traffic contributes to the pathophysiology of neurodegenerative (Alzheimer's disease, Huntington's disease), neurodevelopmental diseases (intellectual deficiency, Rett's disease) and neuroinfectious (Zika virus) disorders. This review addresses astroglial cell-autonomous vesicular traffic network, classified into primary and secondary vesicular network defects in diseases, targets for developing new therapies for neurologic conditions.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-30T10:10:20.755867-05:
      DOI: 10.1111/apha.12915
  • Endothelial colony forming cells and proangiogenic cells: clarifying
           definitions and their potential role in mitigating acute kidney injury
    • Authors: David P. Basile; Jason A. Collett, Mervin C. Yoder
      Abstract: Acute kidney injury (AKI) represents a significant clinical concern that is associated with high mortality rates and also represents a significant risk factor for the development of chronic kidney disease (CKD). This article will consider alterations in renal endothelial function in the setting of AKI that may underlie impairment in renal perfusion and how inefficient vascular repair may manifest post-AKI and contribute to the potential transition to CKD. We provide updated terminology for cells previously classified as “endothelial progenitor” that may mediate vascular repair such as pro-angiogenic cells and endothelial colony forming cells. We consider how endothelial repair may be mediated by these different cell types following vascular injury, particularly in models of AKI. We further summarize the potential ability of these different cells to mitigate the severity of AKI, improve perfusion and maintain vascular structure in pre-clinical studies.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-28T02:30:19.465209-05:
      DOI: 10.1111/apha.12914
  • Mechanisms of Sphingosine-1-phosphate-mediated Vasoconstriction of Rat
           Afferent Arterioles
    • Authors: Zhengrong Guan; Fuchenchu Wang, Xiangqin Cui, Edward W. Inscho
      Abstract: AimSphingosine-1-phosphate (S1P) influences resistance vessel function and is implicated in renal pathological processes. Previous studies revealed that S1P evoked potent vasoconstriction of the preglomerular microvasculature, but the underlying mechanisms remain incompletely defined. We postulated that S1P-mediated preglomerular microvascular vasoconstriction involves activation of voltage-dependent L-type calcium channels (L-VDCC) and the rho/rho kinase pathway.MethodsAfferent arteriolar reactivity was assessed in vitro using the blood-perfused rat juxtamedullary nephron preparation and diameter was measured during exposure to physiological and pharmacological agents.ResultsExogenous S1P (10-9-10-5 mol L−1) evoked concentration-dependent vasoconstriction of afferent arterioles. Superfusion with nifedipine, a L-VDCC blocker, increased arteriolar diameter by 39 ± 18% of baseline and significantly attenuated the S1P-induced vasoconstriction. Superfusion with the rho kinase inhibitor, Y-27632, increased diameter by 60 ± 12% of baseline and also significantly blunted vasoconstriction by S1P. Combined nifedipine and Y-27632 treatment significantly inhibited S1P-induced vasoconstriction over the entire concentration range tested. In contrast, depletion of intracellular Ca2+ stores with the Ca2+-ATPase inhibitors, thapsigargin or cyclopiazonic acid, did not alter the S1P-mediated vasoconstrictor profile. Scavenging reactive oxygen species (ROS) or inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity significantly attenuated S1P-mediated vasoconstriction.ConclusionExogenous S1P elicits potent vasoconstriction of rat afferent arterioles. These data also demonstrate that S1P-mediated preglomerular vasoconstriction involves activation of L-VDCC, the rho/rho kinase pathway and ROS. Mobilization of Ca2+ from intracellular stores is not required for S1P-mediated vasoconstriction. These studies reveal a potential role for S1P in modulation of renal microvascular tone.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-22T12:10:25.509061-05:
      DOI: 10.1111/apha.12913
  • Control of breathing and ventilatory acclimatization to hypoxia in deer
           mice native to high altitudes
    • Authors: Catherine M. Ivy; Graham R. Scott
      Abstract: AimWe compared the control of breathing and heart rate by hypoxia between high- and low-altitude populations of Peromyscus mice, to help elucidate the physiological specializations that help high-altitude natives cope with O2 limitation.MethodsDeer mice (P. maniculatus) native to high altitude and congeneric mice native to low altitude (P. leucopus) were bred in captivity at sea level. The F1 progeny of each population were raised to adulthood and then acclimated to normoxia or hypobaric hypoxia (12 kPa, simulating hypoxia at ~4300 m) for 5 months. Responses to acute hypoxia were then measured during step-wise reductions in inspired O2 fraction.ResultsLowlanders exhibited ventilatory acclimatization to hypoxia (VAH), in which hypoxia acclimation enhanced the hypoxic ventilatory response, made breathing pattern more effective (higher tidal volumes and lower breathing frequencies at a given total ventilation), increased arterial O2 saturation and heart rate during acute hypoxia, augmented respiratory water loss, and led to significant growth of the carotid body. In contrast, highlanders did not exhibit VAH – exhibiting a fixed increase in breathing that was similar to hypoxia acclimated lowlanders – and they maintained even higher arterial O2 saturations in hypoxia. However, the carotid bodies of highlanders were not enlarged by hypoxia acclimation and were similar in size to those of normoxic lowlanders. Highlanders also maintained consistently higher heart rates than lowlanders during acute hypoxia.ConclusionsOur results suggest that highland deer mice have evolved high rates of alveolar ventilation and respiratory O2 uptake without the significant enlargement of the carotid bodies that is typical of VAH in lowlanders, possibly to adjust the hypoxic chemoreflex for life in high-altitude hypoxia.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-22T12:10:23.911072-05:
      DOI: 10.1111/apha.12912
  • Acta Physiologica Award: Outperforming original articles from 2015 –
    • Authors: P. B. Persson
      Abstract: Recently we announced what maybe the highest award in scientific publishing, the Acta Physiologica Award. The Scandinavian Physiological Society, as the owner of Acta Physiologica, sponsors the prize in recognition of your efforts that have increased the journal's performance. Here is an update of some outstanding original articles from 2015 and 2017.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-22T12:10:20.150339-05:
      DOI: 10.1111/apha.12911
  • Cardiac heterogeneity and drug-provoked arrhythmias
    • Authors: Ursula Ravens; Christian Aalkjaer
      Abstract: Functioning of the heart as a mechanical pump depends on electrical impulse formation in the sinus node, conduction of the excitatory wave along its preformed pathways, and orderly repolarisation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-14T10:15:18.148281-05:
      DOI: 10.1111/apha.12907
  • Myoendothelial coupling through Cx40 contributes to EDH-induced
           vasodilation in murine renal arteries: Evidence from experiments and
    • Authors: Jens Christian Brasen; Cor de Wit, Charlotte Mehlin Sorensen
      Abstract: Regulation of renal vascular resistance plays a major role in controlling arterial blood pressure. The endothelium participates in this regulation as endothelial derived hyperpolarization plays a significant role in smaller renal arteries and arterioles but the exact mechanisms are still unknownAimto investigate the role of vascular gap junctions and potassium channels in the renal endothelial derived hyperpolarization.Methodsin interlobar arteries from wild-type and connexin40 knock-out mice we assessed the role of calcium activated small (SK) and intermediate (IK) conductance potassium channels. The role of inward rectifier potassium channels (Kir) and Na+/K+-ATPases was evaluated as was the contribution from gap junctions. Mathematical models estimating diffusion of ions and electrical coupling in myoendothelial gap junctions were used to interpret the results.Resultslack of connexin40 significantly reduces renal endothelial hyperpolarization. Inhibition of SK and IK channels significantly attenuated renal EDH to a similar degree in wild-type and knock-out mice. Inhibition of Kir and Na+/K+-ATPases affected the response in wild-type and knock-out mice but at different levels of stimulation. The model confirms that activation of endothelial SK and IK channels generates a hyperpolarizing current that enters the vascular smooth muscle cells. Also, extracellular potassium increases sufficiently to activate Kir and Na+/K+-ATPases.Conclusionrenal endothelial hyperpolarization is mainly initiated by activation of IK and SK channels. The model shows that hyperpolarization can spread through myoendothelial gap junctions but enough potassium is released to activate Kir and Na+/K+-ATPases. Reduced coupling seems to shift the signaling pathway towards release of potassium. However, an alternative pathway also exists and needs to be investigated.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-14T10:10:19.549879-05:
      DOI: 10.1111/apha.12906
  • Exercise training increases skeletal muscle mitochondrial volume density
           by enlargement of existing mitochondria and not de novo biogenesis
    • Authors: Anne-Kristine Meinild Lundby; Robert A. Jacobs, Saskia Gehrig, Jeroen Leur, Moritz Hauser, Thomas C. Bonne, Daniela Flück, Sune Dandanell, Niels Kirk, Andreas Kaech, Urs Ziegler, Steen Larsen, Carsten Lundby
      Abstract: Aims1) determine whether exercise induced increases in muscle mitochondrial volume density (MitoVD) is related to enlargement of existing mitochondria or de novo biogenesis, 2) establish if measures of mitochondrial-specific enzymatic activities are valid biomarkers for exercise induced increases in MitoVD.MethodSkeletal muscle samples were collected from twenty-one healthy males prior to and following 6 weeks of endurance training. Transmission electron microscopy was used for estimation of mitochondrial densities and profiles. Biochemical assays, western blotting and high resolution respirometry were applied to detect changes in specific mitochondrial functions.ResultMitoVD increased with 55 ± 9% (P < 0.001), whereas the number of mitochondrial profiles per area of skeletal muscle remained unchanged following training. Citrate synthase activity (CS) increased (44 ± 12%, P < 0.001) however, there were no functional changes in oxidative phosphorylation capacity (OXPHOS, CI+IIP) or cytochrome c oxidase (COX) activity. Correlations were found between MitoVD and CS (P=0.01; r=0.58), OXPHOS, CI+CIIP (P=0.01; R=0.58) and COX (P=0.02; R=0.52) before training, after training a correlation was found between MitoVD and CS activity only (P=0.04; R=0.49). Intrinsic respiratory capacities decreased (P < 0.05) with training when respiration was normalized to MitoVD. This was not the case when normalized to CS activity although the percentage change was comparable.ConclusionsMitoVD was increased by inducing mitochondrial enlargement rather than de novo biogenesis. CS activity may be appropriate to track training induced changes in MitoVD.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-05T02:55:50.811228-05:
      DOI: 10.1111/apha.12905
  • Isolated pulmonary regurgitation causes decreased right ventricular
           longitudinal function and compensatory increased septal pumping in a
           porcine model
    • Authors: Sascha Kopic; Sigurdur S Stephensen, Einar Heiberg, Håkan Arheden, Philipp Bonhoeffer, Mads Ersbøll, Niels Vejlstrup, Lars Søndergaard, Marcus Carlsson
      Abstract: AimLongitudinal ventricular contraction is a parameter of cardiac performance with predictive power. Right ventricular longitudinal function is impaired in patients with free pulmonary regurgitation (PR) following corrective surgery for Tetralogy of Fallot (TOF). It remains unclear whether this is a consequence of the surgical repair, or whether it is inherent to PR. The aim of this study was to assess the relationship between longitudinal, lateral and septal pumping in a porcine model of isolated PR.MethodsPiglets were divided into a control (n=8) and a treatment (n=12) group, which received a stent in the pulmonary valve orifice, inducing PR. After two to three months animals were subjected to cardiac magnetic resonance imaging. A subset of animals (n=6) then underwent percutaneous pulmonary valve replacement (PPVR) with follow-up one month later. Longitudinal, lateral and septal contributions to stroke volume (SV) were quantified by measuring volumetric displacements from end-diastole to end-systole in the cardiac short- and long-axis.ResultsPR resulted in a lower longitudinal contribution to right ventricular (RV) stroke volume, compared to controls (60.0±2.6% vs. 73.6±3.8%; p=0.012). Furthermore, a compensatory increase in septal contribution to RVSV was observed (11.0±1.6% vs. -3.1±1.5%; p
      PubDate: 2017-06-05T02:17:36.424399-05:
      DOI: 10.1111/apha.12904
  • Obesity gets on your renal nerves
    • Authors: Boye L Jensen
      Abstract: In the present issue of Acta Physiologica1, Khan et al. in their article “Improvement in baroreflex control of renal sympathetic nerve activity in obese Sprague-Dawley rats following immunosuppression” confirm that obesity-related hypertension involves resetting of the arterial baroreceptor to a state of less sensitivity and relate this mechanistically to inflammation-induced altered renal afferent nerve activity 1. Pharmocological treatment with the calcineurin phosphatase inhibitor-type immunosuppressant tacrolimus attenuated inflammation, reversed, paradoxically, the hypertension and restored baroreceptor sensitivity similar to the effect of renal denervation. The paper not only points attention towards a mechanistic understanding of the baroreceptor resetting associated with chronic arterial hypertension but also demonstrates a pharmacological approach to remedy obesity-associated hypertension.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-26T06:40:25.11641-05:0
      DOI: 10.1111/apha.12900
  • Acute Toll-like Receptor 4 Activation Impairs Rat Renal Microvascular
           Autoregulatory Behaviour
    • Authors: Justin P. Van Beusecum; Shali Zhang, Anthony K. Cook, Edward W. Inscho
      Abstract: AimLittle is known about how toll-like receptor 4 (TLR4) influences the renal microvasculature. We hypothesized that acute TLR4 stimulation with lipopolysaccharide (LPS) impairs afferent arteriole autoregulatory behaviour, partially through reactive oxygen species (ROS).MethodsWe assessed afferent arteriole autoregulatory behaviour after LPS treatment (1 mg kg−1; i.p.) using the in vitro blood perfused juxtamedullary nephron preparation. Autoregulatory behaviour was assessed by measuring diameter responses to step-wise changes in renal perfusion pressure. TLR4 expression was assessed by immunofluorescence, immunohistochemistry and western blot analysis in the renal cortex and vasculature.ResultsBaseline arteriole diameter at 100 mmHg averaged 15.2 ± 1.2 μm and 12.2 ± 1.0 μm for control and LPS groups (P
      PubDate: 2017-05-25T09:10:49.143406-05:
      DOI: 10.1111/apha.12899
  • Adaptations to endurance training depend on exercise-induced oxidative
           stress: exploiting redox inter-individual variability
    • Authors: Nikos V. Margaritelis; Anastasios A. Theodorou, Vassilis Paschalis, Aristidis S. Veskoukis, Konstantina Dipla, Andreas Zafeiridis, George Panayiotou, Ioannis S. Vrabas, Antonios Kyparos, Michalis G. Nikolaidis
      Abstract: AimThe aim of the present study was to reveal the role of reactive oxygen and nitrogen species (RONS) in exercise adaptations under physiological in vivo conditions and without the interference from other exogenous redox agents (e.g., a pro-oxidant or antioxidant).MethodsWe invented a novel methodological set-up that exploited the large redox inter-individual variability in exercise responses. More specifically, we used exercise-induced oxidative stress as the “classifier” measure (i.e., low, moderate and high) and investigated the physiological and redox adaptations after a 6-wk endurance training protocol.ResultsWe demonstrated that the group with the low exercise-induced oxidative stress exhibited the lowest improvements in a battery of classic adaptations to endurance training (VO2max, time trial and Wingate test) as well as in a set of redox biomarkers (oxidative stress biomarkers and antioxidants), compared to the high and moderate oxidative stress groups.ConclusionThe findings of the present study substantiate, for the first time in a human in vivo physiological context, and in the absence of any exogenous redox manipulation, the vital role of RONS produced during exercise in adaptations. The stratification approach, based on a redox phenotype, implemented in the present study could be a useful experimental strategy to reveal the role of RONS and antioxidants in other biological manifestations as well.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-24T03:30:31.293588-05:
      DOI: 10.1111/apha.12898
  • Temporal overexpression of SIRT1 in skeletal muscle of adult mice does not
           improve insulin sensitivity or markers of mitochondrial biogenesis
    • Authors: Kristoffer Svensson; Samuel A. LaBarge, Vitor F. Martins, Simon Schenk
      Abstract: AimsActivation of the NAD+ dependent protein deacetylase SIRT1 has been proposed as a therapeutic strategy to treat mitochondrial dysfunction and insulin resistance in skeletal muscle. However, life-long overexpression of SIRT1 in skeletal muscle does not improve parameters of mitochondrial function and insulin sensitivity. In this study we investigated whether temporal overexpression of SIRT1 in muscle of adult mice would affect skeletal muscle mitochondrial function and insulin sensitivity.MethodsTo circumvent potential effects of germline SIRT1 overexpression, we utilized an inducible model of SIRT1 overexpression in skeletal muscle of adult mice (i-mOX). Insulin sensitivity was assessed by 2-deoxyglucose uptake, muscle maximal respiratory function by high-resolution respirometry and systemic energy expenditure was assessed by whole body calorimetry.ResultsAlthough SIRT1 was highly, and specifically, overexpressed in skeletal muscle of i-mOX compared to WT mice, glucose tolerance and skeletal muscle insulin sensitivity were comparable between genotypes. Additionally, markers of mitochondrial biogenesis, muscle maximal respiratory function and whole body oxygen consumption were also unaffected by SIRT1 overexpression.ConclusionThese results support previous work demonstrating that induction of SIRT1 in skeletal muscle, either at birth or in adulthood, does not impact muscle insulin action or mitochondrial function.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-22T12:31:09.254751-05:
      DOI: 10.1111/apha.12897
  • Microparticles of healthy origins improve endothelial progenitor cell
           dysfunction via microRNA transfer in an atherosclerotic hamster model
    • Authors: Nicoleta Alexandru; Eugen Andrei, Loredan Niculescu, Emanuel Dragan, Violeta Ristoiu, Adriana Georgescu
      Abstract: AimIn this study we aimed: (1) to obtain and functionally characterize the cultures of late endothelial progenitor cells (EPCs) from the animal blood; (2) to investigate the potential beneficial effects of circulating microparticles (MPs) of healthy origins on EPC dysfunctionality in atherosclerosis as well as involved mechanisms.MethodsLate EPCs were obtained and expanded in culture from peripheral blood isolated from two animal groups: hypertensive-hyperlipidemic (HH) and control (C) hamsters. In parallel experiments, late EPC cultures from HH were incubated with MPs from C group.ResultsThe results showed that late EPCs display endothelial cell phenotype: (1) have ability to uptake Dil-Ac-LDL and UEA-1; (2) express CD34, CD133, KDR, CD144, vWF, Tie-2. Late EPCs from HH exhibited different morphological and functional characteristics compared to control: (1) are smaller and irregular in shape; (2) present decreased endothelial surface marker expression; (3) display reduced proliferation, migration and adhesion; (4) lose ability to organize themselves into tubular structures and integrate into vascular network; (5) have diminished function of inward rectifier potassium channels. The incubation of late EPCs with MPs improved EPC functionality by miR-10a, miR-21, miR-126, miR-146a, miR-223 transfer and IGF-1 expression activation; the kinetic study of MP incorporation into EPCs demonstrated MP uptake by EPCs followed by the miRNA transfer.ConclusionThe data reveal that late EPCs from atherosclerotic model exhibit distinctive features and are dysfunctional, and their function recovery can be supported by MP ability to transfer miRNAs. These findings bring a new light on the vascular repair in atherosclerosis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-17T09:25:34.275274-05:
      DOI: 10.1111/apha.12896
  • Isopimaric acid – a multi-targeting ion channel modulator reducing
           excitability and arrhythmicity in a spontaneously beating mouse atrial
           cell line
    • Authors: Sajjad Salari; Malin Silverå Ejneby, Johan Brask, Fredrik Elinder
      Abstract: AimAtrial fibrillation is the most common persistent cardiac arrhythmia, and it is not well controlled by present drugs. Because some resin acids open voltage-gated potassium channels and reduce neuronal excitability, we explored the effects of the resin acid isopimaric acid (IPA) on action potentials and ion currents in cardiomyocytes.MethodsSpontaneously beating mouse atrial HL-1 cells were investigated with the whole-cell patch-clamp technique.Results1-25 μmol L‒1 IPA reduced the action potential frequency by up to 50%. The effect of IPA on six different voltage-gated ion channels was investigated; most voltage-dependent parameters of ion-channel gating were shifted in the negative direction along the voltage axis, consistent with an hypothesis that a lipophilic and negatively charged compound binds to the lipid membrane close to the positively charged voltage sensor of the ion channels. The major finding was that IPA inactivated sodium channels and L- and T-type calcium channels, and activated the rapidly activating potassium channel and the transient outward potassium channel. Computer simulations of IPA effects on all of the ion currents were consistent with a reduced excitability, and they also showed that effects on the Na channel played the largest role to reduce the action potential frequency. Finally, induced arrhythmia in the HL-1 cells was reversed by IPA.ConclusionLow concentrations of IPA reduced the action potential frequency and restored regular firing by altering the voltage dependencies of several voltage-gated ion channels. These findings can form the basis for a new pharmacological strategy to treat atrial fibrillation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-17T09:20:37.453343-05:
      DOI: 10.1111/apha.12895
  • Age-related endothelial dysfunction in human skeletal muscle feed
           arteries: The role of free radicals derived from mitochondria in the
    • Authors: Song-Young Park; Oh Sung Kwon, Robert H. I. Andtbacka, John R. Hyngstrom, Van Reese, Michael P. Murphy, Russell S. Richardson
      Abstract: AimThis study sought to determine the role of free radicals derived from mitochondria in the vasculature in the recognized age-related endothelial dysfunction of human skeletal muscle feed arteries (SMFAs).MethodsA total of 44 SMFAs were studied with and without acute exposure to the mitochondria-targeted antioxidant MitoQ and nitric oxide synthase (NOS) blockade. The relative abundance of proteins from the electron transport chain, phosphorylated (p-) to endothelial (e) NOS ratio, manganese superoxide dismutase (MnSOD), and the mitochondria-derived superoxide (O2-) levels were assessed in SMFA. Endothelium-dependent and -independent SMFA vasodilation was assessed in response to flow-induced shear stress, acetylcholine (ACh), and sodium nitroprusside (SNP).ResultsMitoQ restored endothelium-dependent vasodilation in the old to that of the young when stimulated by both flow (Young: 68±5; Old: 25±7; Old+MitoQ 65±9%) and ACh (Young: 97±4; Old: 59±10; Old+MitoQ: 98±5%), but did not alter, the initially uncompromised, endothelium-independent vasodilation (SNP). Compared to the young, MitoQ in the old diminished the initially elevated mitochondria-derived O2- levels and appeared to attenuate the breakdown of MnSOD. Furthermore, MitoQ increased the ratio of p-eNOS/NOS and the restoration of endothelium-dependent vasodilation in the old by MitoQ was ablated by NOS blockade.ConclusionThis study demonstrated that MitoQ reverses age-related vascular dysfunction by what appears to be an NO-dependent mechanism in human SMFAs. These findings suggest that mitochondrial-targeted antioxidants may have utility in terms of counteracting the attenuated blood flow and vascular dysfunction associated with advancing age.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-11T10:05:32.235067-05:
      DOI: 10.1111/apha.12893
  • Neurological and Neuropsychological Effects of Low and Moderate Prenatal
           Alcohol Exposure
    • Authors: Erika Comasco; Jenny Rangmar, Ulf J. Eriksson, Lars Oreland
      Abstract: Several explanations for the diverse results in research on Foetal Alcohol Spectrum Disorders (FASD) or Alcohol-Related Neuro-developmental Disorder (ARND) might be at hand: timing, amount and patterns of alcohol exposure, as well as complex epigenetic responses. The genetic background of the offspring and its interaction with other prenatal and postnatal environmental cues are likely also of importance. In the present report, key findings about the possible effects of low and moderate doses of maternal alcohol intake on the neuropsychological development of the offspring are reviewed and plausible mechanisms discussed. Special focus is put on the serotonergic system within developmental and gene-environment frameworks. The review also suggests guidelines for future studies, as well as summarises some of to be-answered questions of relevance to clinical practice.Contradictory findings and paucity of studies on the effects of exposure to low alcohol levels during foetal life for the offspring's neuropsychological development call for large prospective studies, as well as for studies including neuroimaging and multi-omics analyses to dissect the neurobiological underpinnings of alcohol exposure-related phenotypes and to identify biomarkers. Finally, it remains to be investigated whether any safe threshold of alcohol drinking during pregnancy can be identified.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-04T03:00:28.570201-05:
      DOI: 10.1111/apha.12892
  • Improvement in baroreflex control of renal sympathetic nerve activity in
           obese Sprague-Dawley rats following immunosuppression
    • Authors: Safia Akhtar Khan; Munavvar Zubaid Abdul Sattar, Nor Azizan Abdullah, Hassaan Anwer Rathore, Ashfaq Ahmad, Mohammed Hadi Abdulla, Edward James Johns
      Abstract: AimThis investigation explored the hypothesis that in obesity an inflammatory response in the kidney contributed to a renal nerve-dependent blunting of the baroreflex regulation of renal sympathetic nerve activity.MethodsRats received a normal (12%Kcal) or high-fat (45%Kcal) diet for 8 weeks plus daily injections of vehicle (0.9% NaCl i.p) or tacrolimus (0.25mg kg−1day−1i.p) from weeks 3-8. Following anaesthesia, left renal sympathetic nerve activity was recorded, baroreflex gain curves were generated, by infusing phenylephrine and sodium nitroprusside, and cardiopulmonary baroreceptors challenged by infusing a saline load.ResultsThe high-fat diet elevated weight gain and adiposity index by 89 and 129% (both, P
      PubDate: 2017-04-29T04:59:42.379893-05:
      DOI: 10.1111/apha.12891
  • Inhibitory action of oxytocin on spontaneous contraction of rat distal
           colon by nitrergic mechanism: involvement of cyclic GMP and
           apamin-sensitive K+ channels
    • Authors: R Wang; MT Han, XL LV, YA Yu, SQ Chai, CM Qu, CY Liu
      Abstract: AimThe mechanisms underlying the inhibitory effects of oxytocin (OT) on colon tone are not totally understood. We explore the mechanisms of OT on spontaneous contractility in rat distal colon, and identify the mediators involved in this action.MethodsIn rat distal colon strips, mechanical activity was analyzed and the production of nitric oxide (NO) in tissue loaded with the fluorochrome DAF-FM was visualized by confocal microscopy. OT receptor (OTR) expression was determined by western blotting and immunofluorescence.ResultsIn rat distal colon, OT produced a concentration-dependent reduction of the spontaneous contraction, which was abolished by the OTR antagonist atosiban, the neural blocker tetrodotoxin and the inhibitor of neuronal nitric oxide synthase (nNOS) NPLA. The inhibitory effects of OT were not affected by propranolol, atropine, the nicotinic cholinoceptor blocker hexamethonium, the vasoactive intestinal peptide receptor antagonist VIPHyb, the P2 purinoceptor antagonist PPADS, the adenosine A1 receptors antagonist DPCPX and the prostacyclin receptor antagonist Ro1138452. The soluble guanylyl cyclase (sGC) inhibitor ODQ and the small conductance Ca2+-activated K+ (CaK+) channels blocker apamin significantly reduced the relaxation induced by OT, nicotine, sodium nitroprusside and the sGC activator BAY 41-2272. The neural release of NO elicited by OT was prevented by NPLA, tetrodotoxin, and atosiban. The presence of the OTR and its co-localization with nNOS was detected by immunohistochemistry and western blotting experiments.ConclusionThese results demonstrate the NO release from enteric neurons induced by activation of OTR mediates distal colon relaxation. sGC and small conductance CaK+ channels are involved in this relaxation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-26T10:30:44.519742-05:
      DOI: 10.1111/apha.12890
  • Weak by the Machines: Muscle Motor Protein Dysfunction -NDASH- a side
           Effect of Intensive Care Unit Treatment
    • Authors: O Friedrich; S Diermeier, L Larsson
      Abstract: Intensive care interventions involve periods of mechanical ventilation, sedation and complete mechanical silencing of patients. Critical illness myopathy (CIM) is an ICU-acquired myopathy that is associated with limb muscle weakness, muscle atrophy, electrical silencing of muscle and motor-proteinopathy. The hallmark of CIM is a preferential muscle myosin loss due to increased catabolic and reduced anabolic activity. The ubiquitin-proteasome pathway plays an important role, apart from recently identified novel mechanisms affecting nonlysosomal protein degradation or autophagy. CIM is not reproduced by pure disuse atrophy, denervation atrophy, steroid-induced atrophy or septic myopathy, although combinations of high-dose steroids and denervation can mimic CIM. Novel animal models of critical illness and ICU-treatment (i.e. mechanical ventilation and complete immobilization) provide novel insights regarding the time course of protein synthesis and degradation alterations, and the role of protective chaperone activities in the process of myosin loss. Altered mechano-signaling seems involved in triggering a major part of myosin loss in experimental CIM models and passive loading of muscle potently ameliorates the CIM phenotype. We provide a systematic overview of similarities and distinct differences in the signaling pathways involved in triggering muscle atrophy in CIM and isolated trigger factors. Since preferential myosin loss is mostly determined from biochemistry analyses providing no spatial resolution of myosin loss processes within myofibres, we also provide first results monitoring myosin signal intensities during experimental ICU-intervention using multiphoton Second harmonic Generation microscopy. Our results confirm that myosin loss is an evenly distributed process within myofibres rather than being confined to hot spots.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-07T02:37:01.268769-05:
      DOI: 10.1111/apha.12885
  • The role of neuropeptide W in energy homeostasis
    • Authors: Hui Li; Stephen J Kentish, Gary A Wittert, Amanda J Page
      Abstract: Neuropeptide W is the endogenous ligand for G-protein-coupled receptors GPR7 and GPR8. In this review, we summarize findings on the distribution of neuropeptide W and its receptors in the central nervous system and the periphery, and discuss the role of NPW in food intake and energy homeostasis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-04T15:05:24.623783-05:
      DOI: 10.1111/apha.12884
  • Transcriptional regulation of voltage-gated Ca2+ channels
    • Authors: Ricardo González-Ramírez; Ricardo Felix
      Abstract: The transcriptional regulation of voltage-gated Ca2+ (CaV) channels is an emerging research area that promises to improve our understanding of how many relevant physiological events are shaped in the central nervous system, the skeletal muscle, and other tissues. Interestingly, a picture of how transcription of CaV channel subunit genes is controlled is evolving with the identification of the promoter regions required for tissue-specific expression, and the identification of transcription factors that control their expression. These promoters share several characteristics that include multiple transcriptional start sites, lack of a TATA box, and the presence of elements conferring tissue-selective expression. Likewise, changes in CaV channel expression occur throughout development, following ischemia, seizures, or chronic drug administration. This review focuses on insights achieved regarding the control of CaV channel gene expression. To further understand the complexities of expression and to increase the possibilities of detecting CaV channel alterations causing human disease, a deeper knowledge on the structure of the 5’ upstream regions of the genes encoding these remarkable proteins will be necessary.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-31T18:40:23.72669-05:0
      DOI: 10.1111/apha.12883
  • Exercise and epigenetic inheritance of disease risk
    • Authors: Joshua Denham
      Abstract: Epigenetics is the study of gene expression changes that occur in the absence of altered genotype. Current evidence indicates a role for environmentally induced alterations to epigenetic modifications leading to health and diseases changes across multiple generations. This phenomenon is called intergenerational or transgenerational epigenetic inheritance of health or disease.Environmental insults, in the form of toxins, plastics and particular dietary interventions, perturb the epigenetic landscape and influence the health of F1 through to F4 generations in rodents. There is, however, the possibility that healthy lifestyles and environmental factors, such as exercise training, could lead to favourable, heritable epigenetic modifications that augment transcriptional programs protective of disease, including metabolic dysfunction, heart disease and cancer. The health benefits conferred by regular physical exercise training are unquestionable, yet many of the molecular changes may have heritable health implications for future generations. Similar to other environmental factors, exercise modulates the epigenome of somatic cells and researchers are beginning to study exercise epigenetics in germ cells. The germ cell epigenetic modifications affected by exercise offer a molecular mechanism for the inheritance of health and disease risk.The aims of this review are to: 1) provide an update on the expanding field of exercise epigenetics; 2) offer an overview of data on intergenerational/transgenerational epigenetic inheritance of disease by environmental insults; 3) to discuss the potential of exercise-induced intergenerational inheritance of health and disease risk; and finally, outline potential mechanisms and avenues for future work on epigenetic inheritance through exercise.This article is protected by copyright. All rights reserved.
      PubDate: 2017-03-30T06:16:01.520992-05:
      DOI: 10.1111/apha.12881
  • Modeling vision: computational science for understanding human visual
    • Authors: Ralf Mrowka; Alexander Freytag, Stefanie Reuter
      Abstract: Human visual perception system is complex and involves a considerable portion of the brain's cortex. Hence, the wish to understand complex neuronal function is obvious, and the idea to model this by means of artificial neuronal networks might have been born at the time when first computational machines were constructed (Alan Turing, Intelligent machinery, 1948, h t t p: // article is protected by copyright. All rights reserved.
      PubDate: 2017-03-25T00:07:32.619018-05:
      DOI: 10.1111/apha.12875
  • Vagal nerve stimulation reduces infarct size via a mechanism involving the
           alpha-7 nicotinic acetylcholine receptor and down-regulation of cardiac
           and vascular arginase
    • Authors: Attila Kiss; Yahor Tratsiakovich, Ali Mahdi, Jiangning Yang, Adrian T Gonon, Bruno K Podesser, John Pernow
      Abstract: AimsVagal nerve stimulation (VNS) protects from myocardial and vascular injury following myocardial ischemia and reperfusion (IR) via a mechanism involving activation of alpha-7 nicotinic acetylcholine receptor (α7 nAChR) and reduced inflammation. Arginase is involved in development of myocardial IR injury driven by inflammatory mediators. The aim of the study was to clarify whether VNS downregulates myocardial and vascular arginase via a mechanism involving activation of α7 nAChR following myocardial IRMethodsAnaesthetized rats were randomized to (1) sham operated, (2) control IR (30 min ischemia and 2 h reperfusion, (3) VNS throughout IR, (4) the arginase inhibitor nor-NOHA+IR, (5) nor-NOHA+VNS+IR, (6) selective α7 nAChR blockade by methyllycaconitine (MLA) followed by VNS throughout IR and (7) MLA+IR.ResultsInfarct size was reduced by VNS compared to control IR (41±3% vs. 67±2% of the myocardium at risk, P
      PubDate: 2017-02-26T20:05:25.318276-05:
      DOI: 10.1111/apha.12861
  • Mind the gap: mechanisms regulating the endothelial barrier
    • Authors: Mariya Y. Radeva; Jens Waschke
      Abstract: The endothelial barrier consists of intercellular contacts localized in the cleft between endothelial cells, which is covered by the glycocalyx in a sieve-like manner. Both types of barrier-forming junctions, i.e. the adherens junction (AJ) serving mechanical anchorage and mechanotransduction and the tight junction (TJ) sealing the intercellular space to limit paracelullar permeability, are tethered to the actin cytoskeleton. Under resting conditions, the endothelium thereby builds a selective layer controlling the exchange of fluid and solutes with the surrounding tissue. However, in the situation of an inflammatory response such as in anaphylaxis or sepsis intercellular contacts disintegrate in postcapillary venules leading to intercellular gap formation. The resulting edema can cause shock and multi-organ failure. Therefore, maintenance as well as coordinated opening and closure of interendothelial junctions is tightly regulated. The two principle underlying mechanisms comprise spatiotemporal activity control of the small GTPases Rac1 and RhoA and the balance of the phosphorylation state of AJ proteins. In the resting state, junctional Rac1 and RhoA activity is enhanced by junctional components, actin-binding proteins (ABPs), cAMP signaling and extracellular cues such as sphingosine-1-phosphate (S1P) and angiopoitin-1 (Ang-1). In addition, phosphorylation of AJ components is prevented by junction-associated phosphatases including vascular endothelial protein tyrosine phosphatase (VE-PTP). In contrast, inflammatory mediators inhibiting cAMP/Rac1 signaling cause strong activation of RhoA and induce AJ phosphorylation finally leading to endocytosis and cleavage of VE-cadherin. This results in dissolution of TJs the outcome of which is endothelial barrier breakdown.This article is protected by copyright. All rights reserved.
      PubDate: 2017-02-23T17:35:35.883579-05:
      DOI: 10.1111/apha.12860
  • Repeated maximal-intensity hypoxic exercise superimposed to hypoxic
           residence boosts skeletal muscle transcriptional responses in elite
           team-sport athletes
    • Authors: F. Brocherie; G. P. Millet, G. D'Hulst, R. Van Thienen, L. Deldicque, O. Girard
      Abstract: AimTo determine whether repeated maximal-intensity hypoxic exercise induces larger beneficial adaptations on the hypoxia-inducible factor-1α pathway and its target genes than similar normoxic exercise, when combined with chronic hypoxic exposure.MethodsLowland elite male team-sport athletes underwent 14 days of passive normobaric hypoxic exposure [≥14 h·day−1 at inspired oxygen fraction (FiO2) 14.5–14.2%] with the addition of six maximal-intensity exercise sessions either in normobaric hypoxia (FiO2 ~14.2%; LHTLH; n = 9) or in normoxia (FiO2 20.9%; LHTL; n = 11). A group living in normoxia with no additional maximal-intensity exercise (LLTL; n = 10) served as control. Before (Pre), immediately after (Post-1) and 3 weeks after (Post-2) the intervention, muscle biopsies were obtained from the vastus lateralis.ResultsHypoxia-inducible factor-1α subunit, vascular endothelial growth factor, myoglobin, peroxisome proliferator-activated receptor-gamma coactivator 1-α and mitochondrial transcription factor A mRNA levels increased at Post-1 (all P ≤ 0.05) in LHTLH, but not in LHTL or LLTL, and returned near baseline levels at Post-2. The protein expression of citrate synthase increased in LHTLH (P 
      PubDate: 2017-02-22T00:15:33.898929-05:
      DOI: 10.1111/apha.12851
  • Issue Information
    • Pages: 149 - 150
      PubDate: 2017-10-14T03:11:27.357775-05:
      DOI: 10.1111/apha.12790
  • Sprint exercise enhances skeletal muscle p70S6k phosphorylation and more
           so in females than in males
    • Authors: Mona Esbjörnsson; Håkan C Rundqvist, Henrik Mascher, Ted Österlund, O. Rooyackers, Eva Blomstrand, Eva Jansson
      Abstract: Aim:Sprint exercise is characterized by repeated sessions of brief intermittent exercise at a high relative workload. However, little is known about the effect on mTOR pathway, an important link in regulation of muscle protein synthesis. An earlier training study showed a greater increase in muscle fibre cross sectional area in females than males. Therefore, we tested the hypothesis that activation of mTOR signalling is more pronounced in females than in males. Healthy males (n=9) and females (n=8) performed three bouts of 30-s sprint exercise with 20 min rest between.Methods:Multiple blood samples were collected over time and muscle biopsy specimens were obtained at rest and 140 min after the last sprint.Results:Serum insulin increased by sprint exercise and more so in females than in males (gender (g) x time (t):P=0.04. In skeletal muscle, phosphorylation of Akt increased by 50% (t, P=0.001) and mTOR by 120% (t, P=0.002) independent of gender. The elevation in p70S6k phosphorylation was larger in females (g x t, P=0.03) and averaged 230% (P=0.006) as compared to 60% in males (P=0.04). Phosphorylation rpS6 increased by 660% over time independent of gender (t, P=0.003). Increase in phosphorylation of p70S6k was directly related to increase in serum insulin (r=0.68, P=0.004).Conclusion:It is concluded that repeated 30-s all out bouts of sprint exercise separated by 20 min of rest, increases Akt/mTOR signalling in skeletal muscle. Secondly, signalling downstream of mTOR was stronger in females than in males after sprint exercise indicated by increased phosphorylation of p70S6k.
      PubDate: 2011-12-26T22:40:26.6469-05:00
      DOI: 10.1111/j.1748-1716.2011.02404.x
  • The effects of early exercise on brain damage and recovery after focal
           cerebral infarction in rats
    • Authors: Fumiyo Matsuda; Harutoshi Sakakima, Yoshihiro Yoshida
      Abstract: Aim:  Exercise can be used to enhance neuroplasticity and facilitate motor recovery after a stroke in rats. We investigated whether treadmill running could reduce brain damage and enhance the expression of midkine (MK) and nerve growth factor (NGF), increase angiogenesis, and decrease the expression of caspase-3.Methods:  77 Wistar rats were split unto 3 experimental groups (ischemia-control: 36, ischemia-exercise: 36, sham-exercise: 5). Stroke was induced by 90 min left middle cerebral artery occlusion using an intraluminal filament. Beginning on the following day, the rats were made to run on a treadmill for 20 min once a day for a maximum of 28 consecutive days. Functional recovery after ischemia was assessed using the beam walking test and a neurological evaluation scale in all rats. Infarct volume, and the expression of MK, NGF, PECAM-1, and caspase-3 were evaluated at 1, 3, 5, 7, 14, and 28 days after the induction of ischemia.Results:  Over time motor coordination and neurological deficits improved more in the exercised group than in the non-exercised group. The infarct volume in the exercised group (12.4 ± 0.8%) subjected to treadmill running for 28 days was significantly decreased compared with that in the control group (19.8 ± 4.2%, P
      PubDate: 2010-08-17T12:31:06.031647-05:
      DOI: 10.1111/j.1748-1708.2010.02174.x
  • Effects of exercise training on adipogenesis of stromal-vascular fraction
           cells in rat epididymal white adipose tissue
    • Authors: Takuya Sakurai; Satohiro Endo, Daisuke Hatano, Junetsu Ogasawara, Takako Kizaki, Shuji Oh-ishi, Tetsuya Izawa, Hitoshi Ishida, Hideki Ohno
      Abstract: Aim:  Previous studies have shown that exercise training reduced white adipose tissue (WAT) mass compared to that in sedentary controls, and that the smaller mass contained fewer adipocytes. However, the effect of exercise training on adipogenesis is not completely clear. Therefore, we reexamined the effect of exercise training on adipocyte numbers in WAT and, if such an effect was found tested the adipogenic responses of stromal-vascular fraction (SVF) cells containing adipose tissue-derived stem cells (ADSC) in epididymal WAT from exercise-trained (TR) rats.Methods:  Wistar male rats were divided into two groups: control (C) and TR. The TR rats were subjected to exercise on a treadmill for 9 weeks. SVF cells containing ADSC were separated from epididymal WAT by centrifugation. Expression of adipocyte differentiation-related genes and adipogenesis of SVF cells were examined.Results:  In SVF cells of TR rats, the expression of peroxisome proliferator-activated receptor γ (PPARγ) and that of PPARγ target lipogenic genes were dramatically downregulated, whereas that of preadipocyte factor-1 gene was significantly upregulated. Lipid accumulation in SVF cells of TR rats after the induction of adipocyte differentiation was significantly suppressed in comparison to that of C rats. Moreover, increased expression of hypoxia inducible factor-1α (HIF-1α) protein was observed in SVF cells of TR rats. Pretreatment of YC-1, a potent HIF-1α inhibitor, in SVF cells of TR rats restored adipogenesis.Conclusion:  These results suggest that exercise training suppresses the ability of SVF cells to differentiate into adipocytes, and that underlying mechanisms involve the upregulation of HIF-1α expression.
      PubDate: 2010-06-28T00:00:00-05:00
      DOI: 10.1111/j.1748-1708.2010.02159.x
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