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Publisher: Springer-Verlag   (Total: 2355 journals)

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Showing 1 - 200 of 2355 Journals sorted alphabetically
3D Research     Hybrid Journal   (Followers: 19, SJR: 0.214, h-index: 10)
4OR: A Quarterly J. of Operations Research     Hybrid Journal   (Followers: 9, SJR: 1.073, h-index: 25)
AAPS J.     Hybrid Journal   (Followers: 20, SJR: 1.192, h-index: 74)
AAPS PharmSciTech     Hybrid Journal   (Followers: 6, SJR: 0.718, h-index: 54)
Abdominal Imaging     Hybrid Journal   (Followers: 14, SJR: 0.723, h-index: 60)
Abhandlungen aus dem Mathematischen Seminar der Universitat Hamburg     Hybrid Journal   (Followers: 2, SJR: 0.447, h-index: 12)
Academic Psychiatry     Full-text available via subscription   (Followers: 22, SJR: 0.492, h-index: 32)
Academic Questions     Hybrid Journal   (Followers: 7, SJR: 0.135, h-index: 6)
Accreditation and Quality Assurance: J. for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26, SJR: 0.378, h-index: 30)
Acoustical Physics     Hybrid Journal   (Followers: 11, SJR: 0.355, h-index: 20)
Acoustics Australia     Hybrid Journal  
Acta Analytica     Hybrid Journal   (Followers: 7, SJR: 0.387, h-index: 6)
Acta Applicandae Mathematicae     Hybrid Journal   (Followers: 1, SJR: 0.624, h-index: 34)
Acta Biotheoretica     Hybrid Journal   (Followers: 5, SJR: 0.419, h-index: 25)
Acta Diabetologica     Hybrid Journal   (Followers: 14, SJR: 1.318, h-index: 46)
Acta Endoscopica     Hybrid Journal   (Followers: 1, SJR: 0.113, h-index: 8)
acta ethologica     Hybrid Journal   (Followers: 4, SJR: 0.465, h-index: 23)
Acta Geochimica     Hybrid Journal   (Followers: 3)
Acta Geodaetica et Geophysica     Hybrid Journal   (Followers: 1, SJR: 0.294, h-index: 13)
Acta Geotechnica     Hybrid Journal   (Followers: 7, SJR: 1.818, h-index: 22)
Acta Informatica     Hybrid Journal   (Followers: 5, SJR: 0.524, h-index: 32)
Acta Mathematica     Hybrid Journal   (Followers: 11, SJR: 8.021, h-index: 47)
Acta Mathematica Hungarica     Hybrid Journal   (Followers: 2, SJR: 0.53, h-index: 29)
Acta Mathematica Sinica, English Series     Hybrid Journal   (Followers: 5, SJR: 0.406, h-index: 30)
Acta Mathematica Vietnamica     Hybrid Journal   (SJR: 0.451, h-index: 5)
Acta Mathematicae Applicatae Sinica, English Series     Hybrid Journal   (SJR: 0.22, h-index: 20)
Acta Mechanica     Hybrid Journal   (Followers: 19, SJR: 0.898, h-index: 52)
Acta Mechanica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.426, h-index: 29)
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5, SJR: 0.525, h-index: 18)
Acta Meteorologica Sinica     Hybrid Journal   (Followers: 3, SJR: 0.524, h-index: 14)
Acta Neurochirurgica     Hybrid Journal   (Followers: 6, SJR: 0.833, h-index: 73)
Acta Neurologica Belgica     Hybrid Journal   (SJR: 0.348, h-index: 27)
Acta Neuropathologica     Hybrid Journal   (Followers: 3, SJR: 6.61, h-index: 117)
Acta Oceanologica Sinica     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 17)
Acta Parasitologica     Hybrid Journal   (Followers: 9, SJR: 0.581, h-index: 28)
Acta Physiologiae Plantarum     Hybrid Journal   (Followers: 2, SJR: 0.551, h-index: 39)
Acta Politica     Hybrid Journal   (Followers: 13, SJR: 0.658, h-index: 20)
Activitas Nervosa Superior     Hybrid Journal  
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5, SJR: 0.103, h-index: 4)
ADHD Attention Deficit and Hyperactivity Disorders     Hybrid Journal   (Followers: 20, SJR: 0.871, h-index: 15)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 7)
Administration and Policy in Mental Health and Mental Health Services Research     Partially Free   (Followers: 15, SJR: 0.795, h-index: 40)
Adsorption     Hybrid Journal   (Followers: 4, SJR: 0.774, h-index: 52)
Advances in Applied Clifford Algebras     Hybrid Journal   (Followers: 3, SJR: 0.319, h-index: 15)
Advances in Atmospheric Sciences     Hybrid Journal   (Followers: 34, SJR: 0.959, h-index: 44)
Advances in Computational Mathematics     Hybrid Journal   (Followers: 15, SJR: 1.255, h-index: 44)
Advances in Contraception     Hybrid Journal   (Followers: 3)
Advances in Data Analysis and Classification     Hybrid Journal   (Followers: 53, SJR: 1.113, h-index: 14)
Advances in Gerontology     Partially Free   (Followers: 9, SJR: 0.141, h-index: 3)
Advances in Health Sciences Education     Hybrid Journal   (Followers: 23, SJR: 1.397, h-index: 42)
Advances in Manufacturing     Hybrid Journal   (Followers: 3, SJR: 0.2, h-index: 4)
Advances in Polymer Science     Hybrid Journal   (Followers: 41, SJR: 0.637, h-index: 89)
Advances in Therapy     Hybrid Journal   (Followers: 5, SJR: 0.79, h-index: 44)
Aegean Review of the Law of the Sea and Maritime Law     Hybrid Journal   (Followers: 7)
Aequationes Mathematicae     Hybrid Journal   (Followers: 2, SJR: 0.882, h-index: 23)
Aerobiologia     Hybrid Journal   (Followers: 1, SJR: 0.511, h-index: 36)
Aesthetic Plastic Surgery     Hybrid Journal   (Followers: 9, SJR: 0.821, h-index: 49)
African Archaeological Review     Hybrid Journal   (Followers: 15, SJR: 0.612, h-index: 24)
Afrika Matematika     Hybrid Journal   (Followers: 1, SJR: 0.248, h-index: 6)
AGE     Hybrid Journal   (Followers: 7, SJR: 1.358, h-index: 33)
Ageing Intl.     Hybrid Journal   (Followers: 7, SJR: 0.337, h-index: 10)
Aggiornamenti CIO     Hybrid Journal   (Followers: 1)
Aging Clinical and Experimental Research     Hybrid Journal   (Followers: 3, SJR: 0.529, h-index: 55)
Agricultural Research     Hybrid Journal   (Followers: 3)
Agriculture and Human Values     Hybrid Journal   (Followers: 12, SJR: 1.197, h-index: 49)
Agroforestry Systems     Hybrid Journal   (Followers: 19, SJR: 0.64, h-index: 56)
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 10, SJR: 1.732, h-index: 59)
AI & Society     Hybrid Journal   (Followers: 6, SJR: 0.171, h-index: 19)
AIDS and Behavior     Hybrid Journal   (Followers: 13, SJR: 2.006, h-index: 71)
Air Quality, Atmosphere & Health     Hybrid Journal   (Followers: 3, SJR: 0.706, h-index: 19)
Akupunktur & Aurikulomedizin     Full-text available via subscription   (Followers: 1)
Algebra and Logic     Hybrid Journal   (Followers: 3, SJR: 0.566, h-index: 18)
Algebra Universalis     Hybrid Journal   (Followers: 2, SJR: 0.388, h-index: 22)
Algebras and Representation Theory     Hybrid Journal   (Followers: 1, SJR: 0.868, h-index: 20)
Algorithmica     Hybrid Journal   (Followers: 7, SJR: 0.898, h-index: 56)
Allergo J.     Full-text available via subscription   (Followers: 1, SJR: 0.183, h-index: 20)
Allergo J. Intl.     Hybrid Journal   (Followers: 2)
Alpine Botany     Hybrid Journal   (Followers: 4, SJR: 0.729, h-index: 20)
ALTEX : Alternatives to Animal Experimentation     Open Access   (Followers: 3, SJR: 1.392, h-index: 32)
AMBIO     Hybrid Journal   (Followers: 15, SJR: 1.094, h-index: 87)
American J. of Cardiovascular Drugs     Hybrid Journal   (Followers: 11, SJR: 0.864, h-index: 39)
American J. of Community Psychology     Hybrid Journal   (Followers: 24, SJR: 1.237, h-index: 83)
American J. of Criminal Justice     Hybrid Journal   (Followers: 6, SJR: 0.634, h-index: 13)
American J. of Cultural Sociology     Hybrid Journal   (Followers: 11, SJR: 0.283, h-index: 3)
American J. of Dance Therapy     Hybrid Journal   (Followers: 4, SJR: 0.175, h-index: 13)
American J. of Potato Research     Hybrid Journal   (Followers: 2, SJR: 0.558, h-index: 35)
American J. of Psychoanalysis     Hybrid Journal   (Followers: 21, SJR: 0.293, h-index: 13)
American Sociologist     Hybrid Journal   (Followers: 12, SJR: 0.18, h-index: 13)
Amino Acids     Hybrid Journal   (Followers: 8, SJR: 1.362, h-index: 83)
AMS Review     Partially Free   (Followers: 4)
Analog Integrated Circuits and Signal Processing     Hybrid Journal   (Followers: 5, SJR: 0.21, h-index: 37)
Analysis and Mathematical Physics     Hybrid Journal   (Followers: 3, SJR: 0.665, h-index: 7)
Analysis in Theory and Applications     Hybrid Journal  
Analysis of Verbal Behavior     Hybrid Journal   (Followers: 4)
Analytical and Bioanalytical Chemistry     Hybrid Journal   (Followers: 28, SJR: 1.096, h-index: 123)
Anatomical Science Intl.     Hybrid Journal   (Followers: 2, SJR: 0.301, h-index: 26)
Angewandte Schmerztherapie und Palliativmedizin     Hybrid Journal  
Angiogenesis     Hybrid Journal   (Followers: 3, SJR: 2.212, h-index: 69)
Animal Cognition     Hybrid Journal   (Followers: 16, SJR: 1.122, h-index: 55)
Annales françaises de médecine d'urgence     Hybrid Journal   (Followers: 1, SJR: 0.156, h-index: 4)
Annales Henri Poincaré     Hybrid Journal   (Followers: 3, SJR: 1.377, h-index: 32)
Annales mathématiques du Québec     Hybrid Journal   (Followers: 4)
Annali dell'Universita di Ferrara     Hybrid Journal   (SJR: 0.504, h-index: 14)
Annali di Matematica Pura ed Applicata     Hybrid Journal   (Followers: 1, SJR: 1.167, h-index: 26)
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 11, SJR: 2.112, h-index: 98)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18, SJR: 1.182, h-index: 94)
Annals of Combinatorics     Hybrid Journal   (Followers: 3, SJR: 0.849, h-index: 15)
Annals of Data Science     Hybrid Journal   (Followers: 8)
Annals of Dyslexia     Hybrid Journal   (Followers: 9, SJR: 0.857, h-index: 40)
Annals of Finance     Hybrid Journal   (Followers: 28, SJR: 0.686, h-index: 14)
Annals of Forest Science     Hybrid Journal   (Followers: 4, SJR: 0.929, h-index: 57)
Annals of Global Analysis and Geometry     Hybrid Journal   (Followers: 1, SJR: 1.136, h-index: 23)
Annals of Hematology     Hybrid Journal   (Followers: 14, SJR: 1.117, h-index: 62)
Annals of Mathematics and Artificial Intelligence     Hybrid Journal   (Followers: 6, SJR: 0.593, h-index: 42)
Annals of Microbiology     Hybrid Journal   (Followers: 9, SJR: 0.402, h-index: 26)
Annals of Nuclear Medicine     Hybrid Journal   (Followers: 5, SJR: 0.68, h-index: 45)
Annals of Operations Research     Hybrid Journal   (Followers: 8, SJR: 1.186, h-index: 78)
Annals of Ophthalmology     Hybrid Journal   (Followers: 9)
Annals of Regional Science     Hybrid Journal   (Followers: 7, SJR: 0.405, h-index: 42)
Annals of Software Engineering     Hybrid Journal   (Followers: 12)
Annals of Solid and Structural Mechanics     Hybrid Journal   (Followers: 10, SJR: 0.553, h-index: 8)
Annals of Surgical Oncology     Hybrid Journal   (Followers: 11, SJR: 1.902, h-index: 127)
Annals of Telecommunications     Hybrid Journal   (Followers: 7, SJR: 0.315, h-index: 25)
Annals of the Institute of Statistical Mathematics     Hybrid Journal   (Followers: 1, SJR: 0.931, h-index: 31)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5, SJR: 0.992, h-index: 87)
Apidologie     Hybrid Journal   (Followers: 4, SJR: 1.14, h-index: 57)
APOPTOSIS     Hybrid Journal   (Followers: 8, SJR: 1.554, h-index: 87)
Applicable Algebra in Engineering, Communication and Computing     Hybrid Journal   (Followers: 2, SJR: 0.354, h-index: 27)
Applications of Mathematics     Hybrid Journal   (Followers: 1, SJR: 0.274, h-index: 20)
Applied Biochemistry and Biotechnology     Hybrid Journal   (Followers: 44, SJR: 0.575, h-index: 80)
Applied Biochemistry and Microbiology     Hybrid Journal   (Followers: 17, SJR: 0.267, h-index: 26)
Applied Cancer Research     Open Access  
Applied Categorical Structures     Hybrid Journal   (Followers: 2, SJR: 0.361, h-index: 21)
Applied Composite Materials     Hybrid Journal   (Followers: 47, SJR: 0.705, h-index: 35)
Applied Entomology and Zoology     Partially Free   (Followers: 2, SJR: 0.554, h-index: 34)
Applied Geomatics     Hybrid Journal   (Followers: 3, SJR: 0.323, h-index: 9)
Applied Geophysics     Hybrid Journal   (Followers: 7, SJR: 0.541, h-index: 13)
Applied Intelligence     Hybrid Journal   (Followers: 12, SJR: 0.777, h-index: 43)
Applied Magnetic Resonance     Hybrid Journal   (Followers: 3, SJR: 0.358, h-index: 34)
Applied Mathematics & Optimization     Hybrid Journal   (Followers: 4, SJR: 0.955, h-index: 33)
Applied Mathematics - A J. of Chinese Universities     Hybrid Journal   (SJR: 0.275, h-index: 8)
Applied Mathematics and Mechanics     Hybrid Journal   (Followers: 4, SJR: 0.37, h-index: 26)
Applied Microbiology and Biotechnology     Hybrid Journal   (Followers: 60, SJR: 1.262, h-index: 161)
Applied Physics A     Hybrid Journal   (Followers: 7, SJR: 0.535, h-index: 121)
Applied Physics B: Lasers and Optics     Hybrid Journal   (Followers: 23, SJR: 0.983, h-index: 104)
Applied Psychophysiology and Biofeedback     Hybrid Journal   (Followers: 8, SJR: 0.677, h-index: 47)
Applied Research in Quality of Life     Hybrid Journal   (Followers: 10, SJR: 0.288, h-index: 15)
Applied Solar Energy     Hybrid Journal   (Followers: 17, SJR: 0.251, h-index: 6)
Applied Spatial Analysis and Policy     Hybrid Journal   (Followers: 4, SJR: 0.351, h-index: 9)
Aquaculture Intl.     Hybrid Journal   (Followers: 22, SJR: 0.613, h-index: 40)
Aquarium Sciences and Conservation     Hybrid Journal   (Followers: 1)
Aquatic Ecology     Hybrid Journal   (Followers: 30, SJR: 0.646, h-index: 44)
Aquatic Geochemistry     Hybrid Journal   (Followers: 3, SJR: 0.764, h-index: 39)
Aquatic Sciences     Hybrid Journal   (Followers: 12, SJR: 1.172, h-index: 53)
Arabian J. for Science and Engineering     Hybrid Journal   (Followers: 5, SJR: 0.345, h-index: 20)
Arabian J. of Geosciences     Hybrid Journal   (Followers: 1, SJR: 0.417, h-index: 16)
Archaeological and Anthropological Sciences     Hybrid Journal   (Followers: 21, SJR: 1.056, h-index: 15)
Archaeologies     Hybrid Journal   (Followers: 12, SJR: 0.397, h-index: 13)
Archiv der Mathematik     Hybrid Journal   (Followers: 1, SJR: 0.597, h-index: 29)
Archival Science     Hybrid Journal   (Followers: 53, SJR: 0.804, h-index: 22)
Archive for History of Exact Sciences     Hybrid Journal   (Followers: 7, SJR: 0.28, h-index: 15)
Archive for Mathematical Logic     Hybrid Journal   (Followers: 1, SJR: 0.946, h-index: 23)
Archive for Rational Mechanics and Analysis     Hybrid Journal   (SJR: 4.091, h-index: 66)
Archive of Applied Mechanics     Hybrid Journal   (Followers: 4, SJR: 0.865, h-index: 40)
Archives and Museum Informatics     Hybrid Journal   (Followers: 119)
Archives of Computational Methods in Engineering     Hybrid Journal   (Followers: 4, SJR: 2.841, h-index: 40)
Archives of Dermatological Research     Hybrid Journal   (Followers: 6, SJR: 0.9, h-index: 65)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 10, SJR: 0.846, h-index: 84)
Archives of Gynecology and Obstetrics     Hybrid Journal   (Followers: 17, SJR: 0.695, h-index: 47)
Archives of Microbiology     Hybrid Journal   (Followers: 8, SJR: 0.702, h-index: 85)
Archives of Orthopaedic and Trauma Surgery     Hybrid Journal   (Followers: 8, SJR: 1.039, h-index: 56)
Archives of Osteoporosis     Hybrid Journal   (Followers: 2, SJR: 1.092, h-index: 13)
Archives of Sexual Behavior     Hybrid Journal   (Followers: 9, SJR: 1.198, h-index: 74)
Archives of Toxicology     Hybrid Journal   (Followers: 16, SJR: 1.595, h-index: 76)
Archives of Virology     Hybrid Journal   (Followers: 5, SJR: 1.086, h-index: 90)
Archives of Women's Mental Health     Hybrid Journal   (Followers: 13, SJR: 1.264, h-index: 50)
Archivio di Ortopedia e Reumatologia     Hybrid Journal  
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2, SJR: 1.2, h-index: 42)
ArgoSpine News & J.     Hybrid Journal   (SJR: 0.102, h-index: 3)
Argumentation     Hybrid Journal   (Followers: 5, SJR: 0.295, h-index: 18)
Arid Ecosystems     Hybrid Journal   (Followers: 3)
Arkiv för Matematik     Hybrid Journal   (Followers: 1, SJR: 0.948, h-index: 22)
Arnold Mathematical J.     Hybrid Journal   (Followers: 1)
Arthropod-Plant Interactions     Hybrid Journal   (Followers: 1, SJR: 0.797, h-index: 17)
Arthroskopie     Hybrid Journal   (Followers: 1, SJR: 0.145, h-index: 8)
Artificial Intelligence and Law     Hybrid Journal   (Followers: 9, SJR: 0.288, h-index: 25)
Artificial Intelligence Review     Hybrid Journal   (Followers: 14, SJR: 0.948, h-index: 48)
Artificial Life and Robotics     Hybrid Journal   (Followers: 7, SJR: 0.231, h-index: 14)
Asia Europe J.     Hybrid Journal   (Followers: 4, SJR: 0.247, h-index: 9)
Asia Pacific Education Review     Hybrid Journal   (Followers: 9, SJR: 0.371, h-index: 17)
Asia Pacific J. of Management     Hybrid Journal   (Followers: 12, SJR: 1.676, h-index: 50)
Asia-Pacific Education Researcher     Hybrid Journal   (Followers: 11, SJR: 0.353, h-index: 13)
Asia-Pacific Financial Markets     Hybrid Journal   (Followers: 2, SJR: 0.19, h-index: 15)
Asia-Pacific J. of Atmospheric Sciences     Hybrid Journal   (Followers: 20, SJR: 1.006, h-index: 14)
Asian Business & Management     Hybrid Journal   (Followers: 7, SJR: 0.41, h-index: 10)
Asian J. of Business Ethics     Hybrid Journal   (Followers: 7)
Asian J. of Criminology     Hybrid Journal   (Followers: 5, SJR: 0.263, h-index: 8)
AStA Advances in Statistical Analysis     Hybrid Journal   (Followers: 2, SJR: 0.681, h-index: 15)
AStA Wirtschafts- und Sozialstatistisches Archiv     Hybrid Journal   (Followers: 5, SJR: 0.195, h-index: 5)
ästhetische dermatologie & kosmetologie     Full-text available via subscription  

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Journal Cover APOPTOSIS
  [SJR: 1.554]   [H-I: 87]   [8 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1573-675X - ISSN (Online) 1360-8185
   Published by Springer-Verlag Homepage  [2355 journals]
  • Role of glycogen synthase kinase following myocardial infarction and
    • Authors: S. Ghaderi; N. Alidadiani; N. Dilaver; H. R. Heidari; R. Parvizi; R. Rahbarghazi; J. Soleimani-Rad; B. Baradaran
      Pages: 887 - 897
      Abstract: Glycogen synthase kinase-3 beta (GSK3β) is principally is a glycogen synthase phosphorylating enzyme that is well known for its role in muscle metabolism. GSK3β is a serine/threonine protein Kinase, which is responsible for several essential roles in mammalian cells. This enzyme is implicated in the pathophysiology of many conditions involved in homeostasis and cellular immigration. GSK3β is involved in several pathways leading to neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Increasing evidence has shown the potential importance of GSK3β in ischemic heart disease and ischemia–reperfusion pathologies. Reperfusion injury may occur in tissues after prolonged ischemia following reperfusion. Reperfusion injury can be life threatening. Reperfusion injury occurs due to a change in ionic homeostasis, excess free radical production, mitochondrial damage and cell death. There are however clear, cardiac-protective signals; although the molecular pathophysiology is not clearly understood. In normal physiology, GSK3β has a critical role in the cytoprotective pathway. However, it`s controversial role in ischemia and ischemia–reperfusion is a topic of current interest. In this review, we have opted to focus on GSK3β interactions with mitochondria in ischemic heart disease and expand on the therapeutic interventions.
      PubDate: 2017-07-01
      DOI: 10.1007/s10495-017-1376-0
      Issue No: Vol. 22, No. 7 (2017)
  • Overcoming chemotherapy drug resistance by targeting inhibitors of
           apoptosis proteins (IAPs)
    • Authors: Rama Rathore; Jennifer E. McCallum; Elizabeth Varghese; Ana-Maria Florea; Dietrich Büsselberg
      Pages: 898 - 919
      Abstract: Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the control of programmed cell death (PCD). PCD is essential to maintain healthy cell turnover within tissue but also to fight disease or infection. Uninhibited, IAPs can suppress apoptosis and promote cell cycle progression. Therefore, it is unsurprising that cancer cells demonstrate significantly elevated expression levels of IAPs, resulting in improved cell survival, enhanced tumor growth and subsequent metastasis. Therapies to target IAPs in cancer has garnered substantial scientific interest and as resistance to anti-cancer agents becomes more prevalent, targeting IAPs has become an increasingly attractive strategy to re-sensitize cancer cells to chemotherapies, antibody based-therapies and TRAIL therapy. Antagonism strategies to modulate the actions of XIAP, cIAP1/2 and survivin are the central focus of current research and this review highlights advances within this field with particular emphasis upon the development and specificity of second mitochondria-derived activator of caspase (SMAC) mimetics (synthetic analogs of endogenously expressed inhibitors of IAPs SMAC/DIABLO). While we highlight the potential of SMAC mimetics as effective single agent or combinatory therapies to treat cancer we also discuss the likely clinical implications of resistance to SMAC mimetic therapy, occasionally observed in cancer cell lines.
      PubDate: 2017-07-01
      DOI: 10.1007/s10495-017-1375-1
      Issue No: Vol. 22, No. 7 (2017)
  • Pro-apoptotic signaling induced by Retinoic acid and dsRNA is under the
           control of Interferon Regulatory Factor-3 in breast cancer cells
    • Authors: Ana R. Bernardo; José M. Cosgaya; Ana Aranda; Ana M. Jiménez-Lara
      Pages: 920 - 932
      Abstract: Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic–polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by a member of the pathogen recognition receptors, Toll-like receptor-3 (TLR3), since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent. Our results highlight the importance of IRF3 and type-I IFNs signaling for the pro-apoptotic effects induced by RA and synthetic dsRNA in breast cancer cells.
      PubDate: 2017-07-01
      DOI: 10.1007/s10495-017-1377-z
      Issue No: Vol. 22, No. 7 (2017)
  • AP-2α reverses vincristine-induced multidrug resistance of SGC7901
           gastric cancer cells by inhibiting the Notch pathway
    • Authors: Wei Lian; Li Zhang; Long Yang; Wensheng Chen
      Pages: 933 - 941
      Abstract: Multidrug resistance (MDR) remains a major clinical obstacle in the treatment of gastric cancer (GC) since it causes tumor recurrence and metastasis. The transcription factor activator protein-2α (AP-2α) has been implicated in drug-resistance in breast cancer; however, its effects on MDR of gastric cancer are far from understood. In this study, we aimed to explore the effects of AP-2α on the MDR in gastric cancer cells selected by vincristine (VCR). Decreased AP-2α levels were markedly detected by RT-PCR and Western blot in gastric cancer cell lines (BGC-823, SGC-7901, AGS, MKN-45) compared with that in the gastric epithelial cell line (GES-1). Furthermore, we found that the expression of AP-2α in SGC7901/VCR or SGC7901/adriamycin (ADR) cells was lower than in SGC7901 cells. Thus, a vector overexpressing AP-2α was constructed and used to perform AP-2α gain-of-function studies in SGC7901/VCR cells. The decreased IC50 values of the anti-cancer drugs in sensitive and resistant cells after transfect with pcDNA3.1/AP-2α were determined in SGC7901/VCR cells by MTT assay. Moreover, flow cytometry analysis indicated that overexpressed AP-2α induced cell cycle arrest in the G0/G1 phase and promoted cell apoptosis of VCR-selected SGC7901/VCR cells. RT-PCR and Western blot demonstrated that overexpressed AP-2α can significantly induce the down-regulation of Notch1, Hes-1, P-gp and MRP1 in SGC7901/VCR cells. Similar effects can be observed when Numb (Notch inhibitor) was introduced. In addition, the intracellular ADR accumulation was markedly detected in AP-2α overexpressed or Numb cells. In conclusion, our results indicate that AP-2α can reverse the MDR of gastric cancer cells, which may be realized by inhibiting the Notch signaling pathway.
      PubDate: 2017-07-01
      DOI: 10.1007/s10495-017-1379-x
      Issue No: Vol. 22, No. 7 (2017)
  • Diallyl trisulfide ameliorates myocardial ischemia–reperfusion injury by
           reducing oxidative stress and endoplasmic reticulum stress-mediated
           apoptosis in type 1 diabetic rats: role of SIRT1 activation
    • Authors: Liming Yu; Shu Li; Xinlong Tang; Zhi Li; Jian Zhang; Xiaodong Xue; Jinsong Han; Yu Liu; Yuji Zhang; Yong Zhang; Yinli Xu; Yang Yang; Huishan Wang
      Pages: 942 - 954
      Abstract: Diallyl trisulfide (DATS) protects against apoptosis during myocardial ischemia-reperfusion (MI/R) injury in diabetic state, although the underlying mechanisms remain poorly defined. Previously, we and others demonstrated that silent information regulator 1 (SIRT1) activation inhibited oxidative stress and endoplasmic reticulum (ER) stress during MI/R injury. We hypothesize that DATS reduces diabetic MI/R injury by activating SIRT1 signaling. Streptozotocin (STZ)-induced type 1 diabetic rats were subjected to MI/R surgery with or without perioperative administration of DATS (40 mg/kg). We found that DATS treatment markedly improved left ventricular systolic pressure and the first derivative of left ventricular pressure, reduced myocardial infarct size as well as serum creatine kinase and lactate dehydrogenase activities. Furthermore, the myocardial apoptosis was also suppressed by DATS as evidenced by reduced apoptotic index and cleaved caspase-3 expression. However, these effects were abolished by EX527 (the inhibitor of SIRT1 signaling, 5 mg/kg). We further found that DATS effectively upregulated SIRT1 expression and its nuclear distribution. Additionally, PERK/eIF2α/ATF4/CHOP-mediated ER stress-induced apoptosis was suppressed by DATS treatment. Moreover, DATS significantly activated Nrf-2/HO-1 antioxidant signaling pathway, thus reducing Nox-2/4 expressions. However, the ameliorative effects of DATS on oxidative stress and ER stress-mediated myocardial apoptosis were inhibited by EX527 administration. Taken together, these data suggest that perioperative DATS treatment effectively ameliorates MI/R injury in type 1 diabetic setting by enhancing cardiac SIRT1 signaling. SIRT1 activation not only upregulated Nrf-2/HO-1-mediated antioxidant signaling pathway but also suppressed PERK/eIF2α/ATF4/CHOP-mediated ER stress level, thus reducing myocardial apoptosis and eventually preserving cardiac function.
      PubDate: 2017-07-01
      DOI: 10.1007/s10495-017-1378-y
      Issue No: Vol. 22, No. 7 (2017)
  • Checkpoint kinase 2 is dispensable for regulation of the p53 response but
           is required for G 2 /M arrest and cell survival in cells with p53 defects
           under heat stress
    • Authors: Yukihiro Furusawa; Yuka Yamanouchi; Takashi Iizumi; Qing-Li Zhao; Yohei Mitsuhashi; Akinori Morita; Atushi Enomoto; Yoshiaki Tabuchi; Takashi Kondo
      Abstract: Hyperthermia induced by heat stress (HS) is known to inhibit proliferation and induce cell death in cancer. We previously demonstrated that checkpoint kinase 1 (Chk1) contributes to G2/M arrest and cell survival under HS; however, the role of Chk2, a functional analog of Chk1, in regulation of the cell cycle and cell death under HS is still unknown. Here, we addressed the role of Chk2 using Molt-4 cells with p53-targeted shRNA (Molt-4/shp53) and parental control cells (Molt-4/V). Chk2 inhibition suppressed C-terminal acetylation of p53 and delayed the induction of p53-target genes in Molt-4/V cells under HS; however, Chk2 inhibition failed to inhibit apoptosis induced by HS, indicating that Chk2 was dispensable for p53-dependent apoptosis under HS. In contrast, Chk2 inhibition abrogated G2/M arrest and promoted cell death induced by HS in HeLa cells and Molt-4/shp53 cells. Thus, we demonstrated for the first time that Chk2 was required for cell cycle arrest and cell survival, particularly in cells with p53 defects under HS. These findings indicated that Chk2 may be a selective target for p53-mutated or -deficient cancer treated with hyperthermia.
      PubDate: 2017-07-21
      DOI: 10.1007/s10495-017-1402-2
  • Etoposide and doxorubicin enhance the sensitivity of triple negative
           breast cancers through modulation of TRAIL-DR5 axis
    • Authors: Sarita Das; Neha Tripathi; Sumit Siddharth; Anmada Nayak; Deepika Nayak; Chinmayee Sethy; Prasad V. Bharatam; Chanakya Nath Kundu
      Abstract: Death receptor 5 (DR5) is an important target for development of anticancer agents against triple-negative breast cancer (TNBC). Recently, we reported the molecular level details for the modulation of TRAIL-DR5 axis by quinacrine (QC) in breast cancer cells. In this work, the DR5 mediated anticancer potential of topoisomerase inhibitor etoposide (ET) and doxorubicin (DOX) against TNBC has been evaluated. ET and DOX enhanced the DR5 expression in TNBC cells, whereas non-topoisomerase inhibitors pifithrin-α (PIF) and dexamethasone (DEX) failed to do so. In the TRAIL pre-treated cells, ET and DOX induced higher apoptosis, indicating their synergistic effect with TRAIL. The molecular docking and molecular dynamics studies showed their ability to stabilize the TRAIL-DR5 complex, whereas PIF and DEX failed to do so. The binding energy for TRAIL-DR5 complexation in the ternary complexes containing ET (−111.08 kcal/mol) and DOX (−76.35 kcal/mol) were higher than reported binding energy of binary complex (−53.70 kcal/mol). The in silico and in vitro mutational studies highlighted the importance of DR5 residue SerB68 in mediating the receptor-drug interaction. ET and DOX failed to enhance apoptosis in DR5 knockdown (DR5-KD) cells. On the other hand, TRAIL+ET exhibited induction of DR5 and subsequent apoptosis in WT-DR5 overexpressed DR5-KD cells, by modulating the mitochondrial intrinsic apoptosis cascade. An induction of apoptosis and DR5 expression was noticed in xenograft mice and in TNBC patient-derived metastatic cells after TRAIL+ET treatment. Thus, data suggests ET and DOX act as DR5 agonistic ligands and enhance the cellular apoptosis in TNBC.
      PubDate: 2017-07-12
      DOI: 10.1007/s10495-017-1400-4
  • KH-TFMDI, a novel sirtuin inhibitor, alters the cytoskeleton and
           mitochondrial metabolism promoting cell death in Leishmania amazonensis
    • Authors: Brunno Renato Farias Verçoza; Joseane Lima Prado Godinho; Sara Teixeira de Macedo-Silva; Kilian Huber; Franz Bracher; Wanderley de Souza; Juliany Cola Fernandes Rodrigues
      Abstract: Treatment of leishmaniasis involves the use of antimonials, miltefosine, amphotericin B or pentamidine. However, the side effects of these drugs and the reports of drug-resistant parasites demonstrate the need for new treatments that are safer and more efficacious. Histone deacetylase inhibitors are a new class of compounds with potential to treat leishmaniasis. Herein, we evaluated the effects of KH-TFMDI, a novel histone deacetylase inhibitor, on Leishmania amazonensis promastigotes and intracellular amastigotes. The IC50 values of this compound for promastigotes and intracellular amastigotes were 1.976 and 1.148 μM, respectively, after 72 h of treatment. Microscopic analyses revealed that promastigotes became elongated and thinner in response to KH-TFMDI, indicating changes in cytoskeleton organization. Immunofluorescence microscopy, western blotting and flow cytometry using an anti-acetylated tubulin antibody revealed an increase in the expression of acetylated tubulin. Furthermore, transmission electron microscopy revealed several ultrastructural changes, such as (a) mitochondrial swelling, followed by the formation of many vesicles inside the matrix; (b) presence of lipid bodies randomly distributed through the cytoplasm; (c) abnormal chromatin condensation; and (d) formation of blebs on the plasma membrane. Physiological studies for mitochondrial function, flow cytometry with propidium iodide and TUNEL assay confirmed the alterations in the mitochondrial metabolism, cell cycle, and DNA fragmentation, respectively, which could result to cell death by mechanisms related to apoptosis-like. All these together indicate that histone deacetylases are promising targets for the development of new drugs to treat Leishmania, and KH-TFMDI is a promising drug candidate that should be tested in vivo.
      PubDate: 2017-07-06
      DOI: 10.1007/s10495-017-1397-8
  • Amelioration of bleomycin-induced pulmonary fibrosis by chlorogenic acid
           through endoplasmic reticulum stress inhibition
    • Authors: Yi-Chun Wang; Jing Dong; Jing Nie; Ji-Xiang Zhu; Hui Wang; Qiong Chen; Jun-Yi Chen; Jia-Mei Xia; Wei Shuai
      Abstract: To investigate the inhibitory effects of chlorogenic acid on pulmonary fibrosis and the internal mechanisms in vivo and in vitro. 30 male BALB/C mice were randomized into 5 groups: control group, pulmonary fibrosis model group, low, middle and high dose of chlorogenic acid groups. Mice in pulmonary fibrosis model group were administered 5.0 mg/kg bleomycin with intracheal instillation and mice in 3 chlorogenic acid groups were treated with chlorogenic acid every day for 28 days after bleomycin administration. Lung tissue histology was observed using HE staining. Primary pulmonary fibroblasts were isolated and cultured. The expressions of fibrosis related factors (α-SMA and collagen I), as well as ER stress markers (CHOP and GRP78) were determined by both real-time PCR assay and Western blotting, while the expressions of other ER stress signaling pathway factors PERK, IRE-1, ATF-6 and protein levels of caspase-12, caspase-9, caspase-3, PARP were determined by Western blotting. RLE-6TN cell line induced by TGF-β1 was also used to verify the amelioration effects in vitro study. In both in vivo and in vitro studies, TUNEL staining was used to evaluate cell apoptosis. Expressions of collagen I, α-SMA, GRP78, and CHOP were significantly inhibited by chlorogenic acid in dose-dependent manner. Similarly, decreasing levels of cleaved caspase-12, caspase-9, caspase-3 and increasing level of uncleaved PARP were observed in chlorogenic acid groups compared with those in the fibrosis group both in vivo and in vitro. Chlorogenic acid could also significantly down-regulate the level of phosphorylation of PERK and cleaved ATF-6 in vivo study. Moreover, MTT assay demonstrated chlorogenic acid could enhance proliferation of RLE-6TN cells induced by TGFβ1 in vitro. And the apoptosis assays indicated that chlorogenic acid could significantly inhibit cell apoptosis both in vivo and in vitro studies. Chlorogenic acid could inhibit the pulmonary fibrosis through endoplasmic reticulum stress inhibition in vivo and in vitro.
      PubDate: 2017-07-04
      DOI: 10.1007/s10495-017-1393-z
  • Structural aspects of transglutaminase 2: functional, structural, and
           regulatory diversity
    • Authors: Chang Sup Lee; Hyun Ho Park
      Abstract: Transglutaminase 2 (TG2) is a multi-functional protein that has both protein cross-linking and guanosine 5′-triphosphate (GTP) hydrolysis activities. The activities of this protein are controlled by many cellular factors, including calcium (Ca2+) and GTP, and have been implicated in several physiological activities, including apoptosis, angiogenesis, wound healing, cellular differentiation, neuronal regeneration, and bone development. TG2 is linked to many human diseases such as inflammatory disease, celiac disease, neurodegenerative disease, diabetes, tissue fibrosis, and various cancers and is one of the most dynamic enzymes in terms of its functions, structures, and regulatory mechanisms. The aim of this review was to summarize the functional, structural, and regulatory diversity of TG2, with a particular focus on the structure of TG2.
      PubDate: 2017-07-04
      DOI: 10.1007/s10495-017-1396-9
  • Bisdemethoxycurcumin sensitizes cisplatin-resistant lung cancer cells to
           chemotherapy by inhibition of CA916798 and PI3K/AKT signaling
    • Authors: Hai-Jing Wang; Zai-Xing Yang; Xiao-Tian Dai; Yong-Feng Chen; He-Ping Yang; Xiang-Dong Zhou
      Abstract: Curcumin, a dietary supplement or herbal medicine from Curcuma longa, has shown antitumor activity in different cancer cell lines and clinical trials. CA916798, a novel protein, is overexpressed in multidrug-resistant tumor cells. This study aimed to assess the effects of curcumin on regulating chemosensitivity in cisplatin-resistant non-small cell lung cancer (NSCLC) cells in vitro and to explore the underlying molecular mechanisms. Human cisplatin-sensitive A549 and cisplatin-resistant A549/CDDP lung adenocarcinoma cells were treated with curcumin to assess cell viability and gene modulations using quantitative reverse transcription–polymerase chain reaction (qRT-PCR) and western blotting. CA916798 shRNA and point mutations were used to assess the CA916798 functions and phosphorylation sites. Bisdemethoxycurcumin sensitized cisplatin-resistant lung cancer cells to various chemotherapeutic agents, including cisplatin. Bisdemethoxycurcumin reduced the levels of CA916798 mRNA and protein in A549 and A549/CDDP cells, while it also suppressed phosphatidylinositol-3-kinase (PI3K)/AKT signaling. CA916798, as a downstream gene, interacted with AKT after bisdemethoxycurcumin treatment in A549 and A549/CDDP cells. Moreover, A549/CDDP cells expressing the point-mutated CA916798-S20D protein were more resistant to cisplatin and bisdemethoxycurcumin, whereas tumor cells expressing CA916798-S20A, CA916798-S31A, CA916798-S60A, CA916798-S93A, or CA916798-T97A (different sites of amino acid phosphorylation) showed similar sensitivity or resistance to cisplatin and bisdemethoxycurcumin, compared with the control cells. Bisdemethoxycurcumin is able to sensitize cisplatin-resistant NSCLC cells to chemotherapeutic agents by inhibition of CA916798 and PI3K/AKT activities. Moreover, phosphorylation of CA916798 at the S20 residue plays a critical role in mediating bisdemethoxycurcumin antitumor activity.
      PubDate: 2017-07-04
      DOI: 10.1007/s10495-017-1395-x
  • Astragalus polysaccharides inhibits cell growth and pro-inflammatory
           response in IL-1β-stimulated fibroblast-like synoviocytes by enhancement
           of autophagy via PI3K/AKT/mTOR inhibition
    • Authors: Qingliang Meng; Xuzhao Du; Huilian Wang; Huimin Gu; Junping Zhan; Zipeng Zhou
      Abstract: The hyperplastic growth of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) and inflammatory response are pathological hallmarks of RA. It has been reported that Astragalus polysaccharides (APS) possess appreciable anti-inflammatory activity against adjuvant-induced arthritis. Nevertheless, little is known about the role and detailed mechanism underlying the therapeutic effects of APS in RA. This study demonstrated that administration of APS dose-dependently impaired cell viability, increased cell apoptosis by decreasing Bcl-2 expression, increasing Bax expression and Caspase3 activity in IL-1β-stimulated RSC-364 cells and RA-FLS. Simultaneously, IL-1β-induced production of pro-inflammatory cytokines IL-6 and TNF-α was significantly decreased after APS treatment. Furthermore, preconditioning with APS dramatically enhanced autophagy activity by increasing Beclin-1 and LC3II/LC3I expression coupled with decreasing p62 expression and augmenting the number of LC3 puncta in IL-1β-stimulated RSC-364 cells. More importantly, autophagy inhibitor 3-methyladenine (3-MA) partly abolished APS-triggered inhibitory effects on cell growth and production of pro-inflammatory cytokines. APS also repressed the activation of PI3K/Akt/mTOR signaling pathway in IL-1β-stimulated RSC-364 cells. Moreover, treatment with insulin-like growth factor-1 (IGF-1), an activator of PI3K/Akt signaling, partly reversed the therapeutic effects of APS in IL-1β-stimulated RSC-364 cells. Collectively, we concluded that APS might attenuate the pathological progression of RA by exerting the pro-apoptotic and anti-inflammatory effects in IL-1β-stimulated FLSs by regulating the PI3K/AKT/mTOR-autophagy pathway.
      PubDate: 2017-06-28
      DOI: 10.1007/s10495-017-1387-x
  • Urokinase plasminogen activator protects cardiac myocytes from oxidative
           damage and apoptosis via hOGG1 induction
    • Authors: Philipp J. Hohensinner; Nikol Takacs; Christoph Kaun; Barbara Thaler; Konstantin A. Krychtiuk; Stefan Pfaffenberger; Arezu Aliabadi; Andreas Zuckermann; Kurt Huber; Johann Wojta
      Abstract: The role of uPA in tissue remodeling and cell migration is already well established. In addition, uPA was reported to stabilize p53, a key cell cycle control, DNA repair and apoptosis initiation protein. We aimed to determine the role of uPA-uPAR signaling towards cell survival or apoptosis in human adult cardiac myocytes (HACM). HACM were stimulated with uPA and DNA damage was inflicted by incubating cells with 200 µM H2O2. To analyze for apoptotic cells we applied TUNEL staining. Oxidative damage foci were analyzed by staining for 8-oxoguanine base pairs. In vivo qPCR analysis from RNA extracted from failing human hearts demonstrated a close relation of uPA with apoptosis and the p53 pathway. Furthermore, we observed a close correlation of uPA and p53 protein in homogenized tissue lysates. In vitro studies revealed that uPA preincubation protected HACM from oxidative damage induced cell death and reduced oxidative damage foci. uPA protection is independent of its catalytic activity, as the amino terminal fragment of uPA showed similar protection. A key enzyme for repairing oxidative DNA damage is the p53 target hOGG1. We found a significant increase of hOGG1 after pretreatment of HACM with uPA. Knockdown of hOGG1 completely abrogated the protective effect of uPA. We conclude that uPA might have a tissue protective role in human hearts besides its role in tissue remodeling. Tissue protection is mediated by the DNA repair protein hOGG1. This might be beneficial during tissue remodeling and thus could be a target for therapeutic approaches in the diseased heart.
      PubDate: 2017-06-22
      DOI: 10.1007/s10495-017-1388-9
  • Genetic variants in cell death pathway genes and HBV-related
           hepatocellular carcinoma among a Chinese Han population
    • Authors: Fei Liu; Fuqiang Li; Limei Luo; Hanteng Yang; Yonggang Wei; Wentao Wang; Lvnan Yan; Tianfu Wen; Jiayin Yang; Bo Li
      Abstract: Cell death pathway plays an important role in apoptosis, and corruption of this signaling pathway has been shown to participate in carcinogenesis. We aimed at determining whether genetic variants in CASP8, CASP10 and CFLAR influence the development and clinical outcomes of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). A hospital-based case-control study, including 600 HCC cases and 600 HBsAg positive controls without HCC, was conducted to assess the relationship between 11 tagging SNPs in CASP8, CASP10 and CFLAR and HBV-related HCC risk and prognosis in a Chinese Han population. Among the 11 polymorphisms, only CASP8 rs3834129 (−652 6N ins/del) modified HCC risk. Compared with CASP8 −652 insins genotype, the deldel (adjusted OR 0.717, 95% CI 0.553–0.930) and insdel (adjusted OR 0.731, 95% CI 0.554–0.964) genotypes had a significantly decreased HCC risk. Furthermore, this polymorphism was significantly associated with decreased portal vein tumor thrombosis (adjusted OR 0.554; P = 0.044) and reduced postoperative recurrence (adjusted OR 0.356; P < 0.001) of resected HCC. In addition, the multivariate analysis showed that the −652 6N ins/del polymorphism was significantly associated with improved overall survival and recurrence-free survival of resected HCC patients. The expression levels of CASP8 in HCC tumor tissues were significantly lower than those in paracancerous liver tissues, although no significant association between −652 6N ins/del genotypes and the expression levels of CASP8 were observed in these tissues. These results suggest that the CASP8 −652 6N ins/del polymorphism may play a protective role in the development, progression, and survival of HBV-related HCC among the Chinese Han population.
      PubDate: 2017-06-22
      DOI: 10.1007/s10495-017-1385-z
  • Phosphatidylethanolamine targeting for cell death imaging in early
           treatment response evaluation and disease diagnosis
    • Authors: Filipe Elvas; Sigrid Stroobants; Leonie Wyffels
      Abstract: Phosphatidylethanolamine (PE) is one of the most abundant phospholipids in mammalian plasma membranes. In healthy cells, PE resides predominantly in the inner leaflet of the cell membrane. In dead or dying cells on the other hand, PE is externalized to the outer leaflet of the plasma membrane. The exposure of PE on the cell surface has therefore become an attractive target for the molecular imaging of cell death using single-photon emission computed tomography (SPECT) and positron emission tomography (PET). This has motivated the development of PE-specific probes to measure cell death in vitro and non-invasively in vivo. In this review, we highlight the biological roles of PE on cell membranes, and PE exposure as a biomarker of cell death in disease processes, along with the use of PE-binding molecular probes to target PE for the characterization of cell death on a cellular and tissue level. We specifically emphasize the preclinical applications of radiolabeled duramycin for the non-invasive imaging of cell death in animal models of disease and in tumors after therapy. In addition, we discuss the clinical relevance, limitations and future perspectives of this imaging approach of cell death.
      PubDate: 2017-06-16
      DOI: 10.1007/s10495-017-1384-0
  • Perifosine enhances bevacizumab-induced apoptosis and therapeutic efficacy
           by targeting PI3K/AKT pathway in a glioblastoma heterotopic model
    • Authors: Sara Ramezani; Nasim Vousooghi; Fatemeh Ramezani Kapourchali; Mohammad Taghi Joghataei
      Abstract: Bevacizumab (BVZ) as an antiangiogenesis therapy leads to a transient therapeutic efficacy in high-grade glioma. However, the proapoptotic potential of BVZ has not been well elucidated, yet. There is also a tumor resistance to BVZ that is linked to post-treatment metalloproteinases and AKT activities. Herein, the association between therapeutic efficacy and putative proapoptotic activity of low-dose BVZ either alone or in combination with a specific inhibitor of AKT called perifosine (PRF), in a glioma model was investigated. BALB/c mice bearing C6 glioma tumor were treated with BVZ and PRF either alone or combined for 13 days (n = 11/group). At the end of treatments, apoptosis, proliferation and vascular density, in the xenografts (3/group) were detected by TUNEL staining, Ki67 and CD31 markers, respectively. Relative levels of cleaved-caspase3, phospho-AKT (Ser473) and matrix metalloproteinase2 (MMP2) were measured using western blotting. PRF and BVZ separately slowed down tumor growth along with the cell apoptosis induction associated with a profound increase in caspase3 activity through an AKT inhibition-related pathway for PRF but not BVZ. Unlike PRF, BVZ significantly increased the intratumor MMP2 and phospho-AKT (Ser473) levels coupled with the slight antiproliferative and significant antivascular effects. Co-administration of PRF and BVZ versus monotherapies potentiated the proapoptotic effects and reversed the BVZ-induced upregulation of phospho-AKT (Ser473) and MMP2 levels in C6 xenografts, leading to the optimal antiproliferative activity and tumor growth regression and longer survival. In conclusion, BVZ plus PRF renders a paramount proapoptotic effect, leading to a major therapeutic efficacy and might be a new substitute for GBM therapy in the clinic.
      PubDate: 2017-06-14
      DOI: 10.1007/s10495-017-1382-2
  • Dihydromyricetin protects human umbilical vein endothelial cells from
           injury through ERK and Akt mediated Nrf2/HO-1 signaling pathway
    • Authors: Yun Luo; Shan Lu; Xi Dong; Lijia Xu; Guibo Sun; Xiaobo Sun
      Abstract: Atherosclerosis-related cardiovascular disease is the predominant cause of death worldwide. Ox-LDL-induced vascular endothelial cell injury is a major factor in the pathogenesis of atherosclerosis. Dihydromyricetin (DMY) is a flavonoid extracted from vine tea that exerts multiple pharmacological activities, including cardio-protective, anti-tumor, and anti-oxidative effects. However, it is unreported that DMY shows protective effects on ox-LDL-induced endothelial cell injury. In this study, we used an ox-LDL injured human umbilical vein endothelial cell (HUVEC) in vitro model to explore the protective effects and mechanism of DMY. HUVECs were pretreatment with DMY and then exposed to ox-LDL, the cell viability was measured. Then, the anti-oxidative enzymes were tested by commercial kits and intracellular reactive oxygen species (ROS) was measured by flow cytometry, cell apoptosis was determined by Annexin-V/PI assay and apoptosis-related proteins were detected by western blot. Our results showed that DMY pretreatment provided cytoprotective effects by suppressing ox-LDL-induced endothelial cell apoptosis, mitochondrial membrane depolarization, caspase-3 activation, and modulation of oxidative enzymes, thereby inhibiting ROS generation. The anti-oxidative and anti-apoptotic effects of DMY were abrogated by the transfection of Nrf2 siRNAs and HO-1 inhibitor ZnPP. Furthermore, DMY might activate the Nrf2/HO-1 pathway through activation of the Akt and ERK1/2 pathways, as shown by the inhibition of Nrf2/HO-1 signaling by the inhibitors PD98059 or LY294002 and the transfection of ERK, Akt siRNAs. In this study, DMY protects HUVECs from ox-LDL-induced oxidative injury by activating Akt and ERK1/2, which subsequently activates Nrf2/HO-1 signaling, thereby up-regulating antioxidant enzymes and anti-apoptotic proteins.
      PubDate: 2017-06-13
      DOI: 10.1007/s10495-017-1381-3
  • Fludarabine inhibits STAT1-mediated up-regulation of caspase-3 expression
           in dexamethasone-induced osteoblasts apoptosis and slows the progression
           of steroid-induced avascular necrosis of the femoral head in rats
    • Authors: Zhenhua Feng; Wenhao Zheng; Qian Tang; Liang Cheng; Hang Li; Wenfei Ni; Xiaoyun Pan
      Abstract: Steroid-induced avascular necrosis of the femoral head (SANFH) is a major limitation of long-term or excessive clinical administration of glucocorticoids. Fludarabine, which is a compound used to treat various hematological malignancies, such as chronic lymphocytic leukemia, acts by down-regulating signal transducer and activator of transcription 1 (STAT1) by inhibiting STAT1 phosphorylation in both normal and cancer cells. This study assessed the effects of fludarabine in vitro (primary murine osteoblasts) and in vivo (rat SANFH model). In vitro, pretreatment with fludarabine significantly inhibited Dexamethasone (Dex)-induced apoptosis in osteoblasts, which was examined by TUNEL staining. Treatment with Dex caused a remarkable decrease in the expression of Bcl-2; an increase in cytochrome c release; activation of BAX, caspase-9, and caspase-3; and an obvious enhancement in STAT1 phosphorylation. However, treatment resulted in the up-regulation of caspase-3 expression. Enhanced P-STAT1 activity and up-regulation of caspase-3 expression were also observed in osteoblasts. In vivo, the subchondral trabeculae in fludarabine-treated rats exhibited less bone loss and a lower ratio of empty lacunae. Taken together, our results suggest that STAT1-mediated up-regulation of caspase-3 is involved in osteoblast apoptosis induced by Dex and indicates that fludarabine may serve as a potential agent for the treatment of SANFH.
      PubDate: 2017-06-10
      DOI: 10.1007/s10495-017-1383-1
  • Role of a novel benzoxazine derivative in the chemosensitization of colon
    • Authors: Rejitha Suraj; Suraj Radhamani; Terri Meehan-Andrews; Christopher Bradley
      Abstract: The concept to fight against tumour resistance is to use chemosensitizers that selectively sensitize tumour cells to chemotherapeutic drugs without affecting normal tissue. In this study, the chemosensitizing potential of a novel benzoxazine derivative in combination with Doxorubicin, a DNA damaging chemotherapeutic drug was evaluated. The results of this study showed that the compound LTUR6 is a potent chemosensitizer of Doxorubicin in colon cancer cell lines, HCT116 and HT29. It was also observed that LTUR6 delayed the resolution of Doxorubicin-induced γH2AX, a specific marker of unrepaired DNA DSB, and prolonged cell cycle arrest in both cell lines. This eventually led to DNA fragmentation, caspase activation and ultimately apoptosis in LTUR6 treated cell lines. Results of western blot analysis revealed that LTUR6 significantly inhibited the phosphorylation of DSB repair enzyme AKT, in response to Doxorubicin-induced DSB. We propose that the chemosensitization observed following inhibition of PI3K is likely due to the involvement of a number of downstream targets of AKT.
      PubDate: 2017-06-02
      DOI: 10.1007/s10495-017-1380-4
  • Augmenter of liver regeneration regulates autophagy in renal
           ischemia–reperfusion injury via the AMPK/mTOR pathway
    • Authors: Tao Pu; Xiao-hui Liao; Hang Sun; Hui Guo; Xiao Jiang; Jun-bo Peng; Ling Zhang; Qi Liu
      Abstract: Autophagy may have protective effects in renal ischemia–reperfusion (I/R) injury, although the underlying mechanisms remain unclear. Augmenter of liver regeneration (ALR), a widely distributed multifunctional protein that is originally identified as a hepatic growth factor, may participate in the process of autophagy. To investigate the role of ALR in autophagy, ALR expression is knocked-down in human kidney 2 (HK-2) cells with short hairpin RNA lentivirals. Then, the level of autophagy is measured in the shRNA/ALR group and the shRNA/control group in an in vitro model of ischemia–reperfusion (I/R). The results indicate that the level of autophagy in two groups increase, accompanied by increased reactive oxygen species production, especially in the shRNA/ALR group. The AMPK/mTOR signaling pathway is hyperactive in the shRNA/ALR group. Inhibition of autophagy with the AMPK inhibitor compound C induce apoptosis, especially in the shRNA/ALR group. These findings collectively indicate that ALR negatively regulates the autophagy process through an association with the AMPK/mTOR signaling pathway. Autophagy inhibit apoptosis and play a protective role under conditions of oxidative stress.
      PubDate: 2017-05-02
      DOI: 10.1007/s10495-017-1370-6
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