Subjects -> ENGINEERING (Total: 2791 journals)
    - CHEMICAL ENGINEERING (248 journals)
    - CIVIL ENGINEERING (242 journals)
    - ELECTRICAL ENGINEERING (176 journals)
    - ENGINEERING (1402 journals)
    - ENGINEERING MECHANICS AND MATERIALS (452 journals)
    - HYDRAULIC ENGINEERING (56 journals)
    - INDUSTRIAL ENGINEERING (100 journals)
    - MECHANICAL ENGINEERING (115 journals)

ENGINEERING (1402 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 1205 Journals sorted alphabetically
3 Biotech     Open Access   (Followers: 2)
3D Research     Hybrid Journal   (Followers: 17)
AAPG Bulletin     Hybrid Journal   (Followers: 9)
Abstract and Applied Analysis     Open Access   (Followers: 1)
Aceh International Journal of Science and Technology     Open Access   (Followers: 3)
ACS Nano     Hybrid Journal   (Followers: 187)
Acta Geotechnica     Hybrid Journal   (Followers: 6)
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 8)
Acta Nova     Open Access  
Acta Polytechnica : Journal of Advanced Engineering     Open Access  
Acta Universitatis Cibiniensis. Technical Series     Open Access   (Followers: 1)
Active and Passive Electronic Components     Open Access   (Followers: 5)
Adaptive Behavior     Hybrid Journal   (Followers: 8)
Additive Manufacturing Letters     Open Access   (Followers: 5)
Adsorption     Hybrid Journal   (Followers: 4)
Advanced Energy and Sustainability Research     Open Access   (Followers: 4)
Advanced Engineering Forum     Full-text available via subscription   (Followers: 10)
Advanced Engineering Research     Open Access  
Advanced Journal of Graduate Research     Open Access   (Followers: 1)
Advanced Quantum Technologies     Hybrid Journal   (Followers: 1)
Advanced Science     Open Access   (Followers: 11)
Advanced Science Focus     Free   (Followers: 5)
Advanced Science Letters     Full-text available via subscription   (Followers: 8)
Advanced Science, Engineering and Medicine     Partially Free   (Followers: 3)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 19)
Advanced Theory and Simulations     Hybrid Journal   (Followers: 2)
Advances in Applied Energy     Open Access   (Followers: 4)
Advances in Catalysis     Full-text available via subscription   (Followers: 7)
Advances in Complex Systems     Hybrid Journal   (Followers: 10)
Advances in Engineering Software     Hybrid Journal   (Followers: 25)
Advances in Fuzzy Systems     Open Access   (Followers: 5)
Advances in Geosciences (ADGEO)     Open Access   (Followers: 19)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 27)
Advances in Natural Sciences : Nanoscience and Nanotechnology     Open Access   (Followers: 28)
Advances in Operations Research     Open Access   (Followers: 13)
Advances in OptoElectronics     Open Access   (Followers: 6)
Advances in Physics Theories and Applications     Open Access   (Followers: 12)
Advances in Polymer Science     Hybrid Journal   (Followers: 50)
Advances in Remote Sensing     Open Access   (Followers: 58)
Advances in Science and Research (ASR)     Open Access   (Followers: 8)
Aerobiologia     Hybrid Journal   (Followers: 2)
Aerospace Systems     Hybrid Journal   (Followers: 6)
African Journal of Science, Technology, Innovation and Development     Hybrid Journal   (Followers: 7)
AIChE Journal     Hybrid Journal   (Followers: 31)
Ain Shams Engineering Journal     Open Access   (Followers: 1)
Al-Nahrain Journal for Engineering Sciences     Open Access  
Al-Qadisiya Journal for Engineering Sciences     Open Access  
AL-Rafdain Engineering Journal     Open Access  
Alexandria Engineering Journal     Open Access   (Followers: 1)
AMB Express     Open Access   (Followers: 1)
American Journal of Applied Sciences     Open Access   (Followers: 21)
American Journal of Engineering and Applied Sciences     Open Access   (Followers: 7)
American Journal of Engineering Education     Open Access   (Followers: 13)
American Journal of Environmental Engineering     Open Access   (Followers: 6)
American Journal of Industrial and Business Management     Open Access   (Followers: 23)
Annals of Civil and Environmental Engineering     Open Access   (Followers: 1)
Annals of Combinatorics     Hybrid Journal   (Followers: 3)
Annals of Pure and Applied Logic     Open Access   (Followers: 4)
Annals of Regional Science     Hybrid Journal   (Followers: 7)
Annals of Science     Hybrid Journal   (Followers: 9)
Annual Journal of Technical University of Varna     Open Access  
Antarctic Science     Hybrid Journal   (Followers: 1)
Applicable Algebra in Engineering, Communication and Computing     Hybrid Journal   (Followers: 3)
Applicable Analysis: An International Journal     Hybrid Journal   (Followers: 1)
Applications in Energy and Combustion Science     Open Access   (Followers: 2)
Applications in Engineering Science     Open Access  
Applied Catalysis A: General     Hybrid Journal   (Followers: 7)
Applied Catalysis B: Environmental     Hybrid Journal   (Followers: 9)
Applied Clay Science     Hybrid Journal   (Followers: 6)
Applied Computational Intelligence and Soft Computing     Open Access   (Followers: 15)
Applied Energy     Partially Free   (Followers: 25)
Applied Engineering Letters     Open Access  
Applied Magnetic Resonance     Hybrid Journal   (Followers: 3)
Applied Nanoscience     Open Access   (Followers: 7)
Applied Network Science     Open Access   (Followers: 2)
Applied Numerical Mathematics     Hybrid Journal   (Followers: 4)
Applied Physics Research     Open Access   (Followers: 5)
Applied Spatial Analysis and Policy     Hybrid Journal   (Followers: 5)
Arab Journal of Basic and Applied Sciences     Open Access  
Arabian Journal for Science and Engineering     Hybrid Journal   (Followers: 1)
Archives of Computational Methods in Engineering     Hybrid Journal   (Followers: 5)
Archives of Foundry Engineering     Open Access  
Archives of Thermodynamics     Open Access   (Followers: 10)
Arctic     Open Access  
Arid Zone Journal of Engineering, Technology and Environment     Open Access  
Arkiv för Matematik     Hybrid Journal  
ArtefaCToS : Revista de estudios sobre la ciencia y la tecnología     Open Access  
Asian Journal of Applied Science and Engineering     Open Access  
Asian Journal of Applied Sciences     Open Access   (Followers: 2)
Asian Journal of Biotechnology     Open Access   (Followers: 8)
Asian Journal of Control     Hybrid Journal  
Asian Journal of Technology Innovation     Hybrid Journal   (Followers: 5)
Assembly Automation     Hybrid Journal   (Followers: 2)
ATZagenda     Hybrid Journal  
ATZextra worldwide     Hybrid Journal  
AURUM : Mühendislik Sistemleri ve Mimarlık Dergisi = Aurum Journal of Engineering Systems and Architecture     Open Access   (Followers: 1)
Australasian Journal of Engineering Education     Hybrid Journal   (Followers: 3)
Australasian Physical & Engineering Sciences in Medicine     Hybrid Journal   (Followers: 1)
Australian Journal of Multi-Disciplinary Engineering     Hybrid Journal  
Autocracy : Jurnal Otomasi, Kendali, dan Aplikasi Industri     Open Access  
Automotive and Engine Technology     Hybrid Journal  
Automotive Experiences     Open Access  
Automotive Innovation     Hybrid Journal  
Avances en Ciencias e Ingenierías     Open Access  
Avances: Investigación en Ingeniería     Open Access  
Balkan Region Conference on Engineering and Business Education     Open Access   (Followers: 2)
Bangladesh Journal of Scientific and Industrial Research     Open Access  
Basin Research     Hybrid Journal   (Followers: 6)
Batteries & Supercaps     Hybrid Journal   (Followers: 5)
Bautechnik     Hybrid Journal   (Followers: 1)
Bell Labs Technical Journal     Hybrid Journal   (Followers: 27)
Beni-Suef University Journal of Basic and Applied Sciences     Open Access  
Beyond : Undergraduate Research Journal     Open Access  
Bhakti Persada : Jurnal Aplikasi IPTEKS     Open Access  
Bharatiya Vaigyanik evam Audyogik Anusandhan Patrika (BVAAP)     Open Access  
Bilge International Journal of Science and Technology Research     Open Access   (Followers: 1)
Biointerphases     Open Access   (Followers: 1)
Biomaterials Science     Hybrid Journal   (Followers: 11)
Biomedical Engineering     Hybrid Journal   (Followers: 11)
Biomedical Engineering and Computational Biology     Open Access   (Followers: 10)
Biomedical Engineering Letters     Hybrid Journal   (Followers: 3)
Biomedical Engineering: Applications, Basis and Communications     Hybrid Journal   (Followers: 4)
Biomedical Microdevices     Hybrid Journal   (Followers: 8)
Biomedical Science and Engineering     Open Access   (Followers: 4)
Biomicrofluidics     Open Access   (Followers: 7)
Biotechnology Progress     Hybrid Journal   (Followers: 42)
Black Sea Journal of Engineering and Science     Open Access  
Botswana Journal of Technology     Full-text available via subscription   (Followers: 1)
Boundary Value Problems     Open Access  
Bulletin of Canadian Petroleum Geology     Full-text available via subscription   (Followers: 12)
Bulletin of Engineering Geology and the Environment     Hybrid Journal   (Followers: 15)
Bulletin of the Crimean Astrophysical Observatory     Hybrid Journal  
Cahiers Droit, Sciences & Technologies     Open Access   (Followers: 1)
Calphad     Hybrid Journal  
Canadian Geotechnical Journal     Hybrid Journal   (Followers: 28)
Canadian Journal of Remote Sensing     Full-text available via subscription   (Followers: 51)
Carbon Resources Conversion     Open Access   (Followers: 2)
Carpathian Journal of Electronic and Computer Engineering     Open Access  
Case Studies in Thermal Engineering     Open Access   (Followers: 9)
Catalysis Communications     Hybrid Journal   (Followers: 7)
Catalysis Letters     Hybrid Journal   (Followers: 3)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 9)
Catalysis Science and Technology     Hybrid Journal   (Followers: 9)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 4)
Catalysis Today     Hybrid Journal   (Followers: 4)
CEAS Space Journal     Hybrid Journal   (Followers: 6)
Cell Reports Physical Science     Open Access  
Cellular and Molecular Neurobiology     Hybrid Journal   (Followers: 2)
CFD Letters     Open Access   (Followers: 7)
Chaos : An Interdisciplinary Journal of Nonlinear Science     Hybrid Journal   (Followers: 3)
Chaos, Solitons & Fractals     Hybrid Journal   (Followers: 1)
Chaos, Solitons & Fractals : X     Open Access   (Followers: 1)
Chinese Journal of Catalysis     Full-text available via subscription   (Followers: 2)
Chinese Journal of Engineering     Open Access   (Followers: 1)
Chinese Journal of Population, Resources and Environment     Open Access  
Chinese Science Bulletin     Open Access  
Ciencia e Ingenieria Neogranadina     Open Access  
Ciencia en su PC     Open Access   (Followers: 1)
Ciencia y Tecnología     Open Access  
Ciencias Holguin     Open Access   (Followers: 1)
CienciaUAT     Open Access  
Cientifica     Open Access  
CIRP Annals - Manufacturing Technology     Hybrid Journal   (Followers: 10)
CIRP Journal of Manufacturing Science and Technology     Hybrid Journal   (Followers: 12)
City, Culture and Society     Hybrid Journal   (Followers: 23)
Clay Minerals     Hybrid Journal   (Followers: 7)
Cleaner Engineering and Technology     Open Access   (Followers: 3)
Cleaner Environmental Systems     Open Access   (Followers: 3)
Coastal Engineering     Hybrid Journal   (Followers: 15)
Coastal Engineering Journal     Hybrid Journal   (Followers: 7)
Coastal Engineering Proceedings : Proceedings of the International Conference on Coastal Engineering     Open Access   (Followers: 1)
Coastal Management     Hybrid Journal   (Followers: 29)
Cogent Engineering     Open Access   (Followers: 1)
Cognitive Computation     Hybrid Journal   (Followers: 2)
Color Research & Application     Hybrid Journal   (Followers: 1)
COMBINATORICA     Hybrid Journal  
Combustion Theory and Modelling     Hybrid Journal   (Followers: 18)
Combustion, Explosion, and Shock Waves     Hybrid Journal   (Followers: 21)
Communications Faculty of Sciences University of Ankara Series A2-A3 Physical Sciences and Engineering     Open Access  
Communications in Numerical Methods in Engineering     Hybrid Journal   (Followers: 2)
Components, Packaging and Manufacturing Technology, IEEE Transactions on     Hybrid Journal   (Followers: 27)
Composite Interfaces     Hybrid Journal   (Followers: 6)
Composite Structures     Hybrid Journal   (Followers: 243)
Composites Part A : Applied Science and Manufacturing     Hybrid Journal   (Followers: 176)
Composites Part B : Engineering     Hybrid Journal   (Followers: 220)
Composites Part C : Open Access     Open Access  
Composites Science and Technology     Hybrid Journal   (Followers: 148)
Comptes Rendus : Mécanique     Open Access   (Followers: 2)
Computational Geosciences     Hybrid Journal   (Followers: 17)
Computational Optimization and Applications     Hybrid Journal   (Followers: 9)
Computer Applications in Engineering Education     Hybrid Journal   (Followers: 6)
Computer Science and Engineering     Open Access   (Followers: 15)
Computers & Geosciences     Hybrid Journal   (Followers: 29)
Computers & Mathematics with Applications     Full-text available via subscription   (Followers: 8)
Computers and Electronics in Agriculture     Hybrid Journal   (Followers: 7)
Computers and Geotechnics     Hybrid Journal   (Followers: 11)
Computing and Visualization in Science     Hybrid Journal   (Followers: 6)
Computing in Science & Engineering     Full-text available via subscription   (Followers: 31)
Conciencia Tecnologica     Open Access  
Concurrent Engineering     Hybrid Journal   (Followers: 3)

        1 2 3 4 5 6 7 8 | Last

Similar Journals
Journal Cover
Advances in Calculus of Variations
Number of Followers: 5  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1864-8258 - ISSN (Online) 1864-8266
This journal is no longer being updated because:
    RSS feed has been removed by publisher
  • High-Content Single-Cell Förster Resonance Energy Transfer Imaging of
           Cultured Striatal Neurons Reveals Novel Cross-Talk in the Regulation of
           Nuclear Signaling by Protein Kinase A and Extracellular Signal-Regulated
           Kinase 1/2 [Articles]

    • Free pre-print version: Loading...

      Authors: Jones-Tabah, J; Martin, R. D, Tanny, J. C, Clarke, P. B. S, Hebert, T. E.
      Pages: 526 - 539
      Abstract: Genetically encoded biosensors can be used to track signaling events in living cells by measuring changes in fluorescence emitted by one or more fluorescent proteins. Here, we describe the use of genetically encoded biosensors based on Förster resonance energy transfer (FRET), combined with high-content microscopy, to image dynamic signaling events simultaneously in thousands of neurons in response to drug treatments. We first applied this approach to examine intercellular variation in signaling responses among cultured striatal neurons stimulated with multiple drugs. Using high-content FRET imaging and immunofluorescence, we identified neuronal subpopulations with unique responses to pharmacological manipulation and used nuclear morphology to identify medium spiny neurons within these heterogeneous striatal cultures. Focusing on protein kinase A (PKA) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in the cytoplasm and nucleus, we noted pronounced intercellular differences among putative medium spiny neurons, in both the magnitude and kinetics of signaling responses to drug application. Importantly, a conventional "bulk" analysis that pooled all cells in culture yielded a different rank order of drug potency than that revealed by single-cell analysis. Using a single-cell analytical approach, we dissected the relative contributions of PKA and ERK1/2 signaling in striatal neurons and unexpectedly identified a novel role for ERK1/2 in promoting nuclear activation of PKA in striatal neurons. This finding adds a new dimension of signaling crosstalk between PKA and ERK1/2 with relevance to dopamine D1 receptor signaling in striatal neurons. In conclusion, high-content single-cell imaging can complement and extend traditional population-level analyses and provides a novel vantage point from which to study cellular signaling.SIGNIFICANCE STATEMENTHigh-content imaging revealed substantial intercellular variation in the magnitude and pattern of intracellular signaling events driven by receptor stimulation. Since individual neurons within the same population can respond differently to a given agonist, interpreting measures of intracellular signaling derived from the averaged response of entire neuronal populations may not always reflect what happened at the single-cell level. This study uses this approach to identify a new form of cross-talk between PKA and ERK1/2 signaling in the nucleus of striatal neurons.
      PubDate: 2021-11-19T08:26:30-08:00
      DOI: 10.1124/molpharm.121.000290
      Issue No: Vol. 100, No. 6 (2021)
       
  • Characterization of VU0468554, a New Selective Inhibitor of Cardiac G
           Protein-Gated Inwardly Rectifying K+ Channels [Articles]

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      Authors: Anderson, A; Vo, B. N, de Velasco, E. M. F, Hopkins, C. R, Weaver, C. D, Wickman, K.
      Pages: 540 - 547
      Abstract: G protein–gated inwardly rectifying K+ (GIRK) channels are critical mediators of excitability in the heart and brain. Enhanced GIRK-channel activity has been implicated in the pathogenesis of supraventricular arrhythmias, including atrial fibrillation. The lack of selective pharmacological tools has impeded efforts to investigate the therapeutic potential of cardiac GIRK–channel interventions in arrhythmias. Here, we characterize a recently identified GIRK-channel inhibitor, VU0468554. Using whole-cell electrophysiological approaches and primary cultures of sinoatrial nodal cells and hippocampal neurons, we show that VU0468554 more effectively inhibits the cardiac GIRK channel than the neuronal GIRK channel. Concentration-response experiments suggest that VU0468554 inhibits Gβ-activated GIRK channels in noncompetitive and potentially uncompetitive fashion. In contrast, VU0468554 competitively inhibits GIRK-channel activation by ML297, a GIRK-channel activator containing the same chemical scaffold as VU0468554. In the isolated heart model, VU0468554 partially reversed carbachol-induced bradycardia in hearts from wild-type mice but not Girk4–/– mice. Collectively, these data suggest that VU0468554 represents a promising new pharmacological tool for targeting cardiac GIRK channels with therapeutic implications for relevant cardiac arrhythmias.SIGNIFICANCE STATEMENTAlthough cardiac GIRK–channel inhibition shows promise for the treatment of supraventricular arrhythmias, the absence of subtype-selective channel inhibitors has hindered exploration into this therapeutic strategy. This study utilizes whole-cell patch-clamp electrophysiology to characterize the new GIRK-channel inhibitor VU0468554 in human embryonic kidney 293T cells and primary cultures. We report that VU0468554 exhibits a favorable pharmacodynamic profile for cardiac over neuronal GIRK channels and partially reverses GIRK-mediated bradycardia in the isolated mouse heart model.
      PubDate: 2021-11-19T08:26:30-08:00
      DOI: 10.1124/molpharm.121.000311
      Issue No: Vol. 100, No. 6 (2021)
       
  • Remdesivir and EIDD-1931 Interact with Human Equilibrative Nucleoside
           Transporters 1 and 2: Implications for Reaching SARS-CoV-2 Viral Sanctuary
           Sites [Articles]

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      Authors: Miller, S. R; McGrath, M. E, Zorn, K. M, Ekins, S, Wright, S. H, Cherrington, N. J.
      Pages: 548 - 557
      Abstract: Equilibrative nucleoside transporters (ENTs) are present at the blood-testis barrier (BTB), where they can facilitate antiviral drug disposition to eliminate a sanctuary site for viruses detectable in semen. The purpose of this study was to investigate ENT-drug interactions with three nucleoside analogs, remdesivir, molnupiravir, and molnupiravir’s active metabolite, β-d-N4-hydroxycytidine (EIDD-1931), and four non-nucleoside molecules repurposed as antivirals for coronavirus disease 2019 (COVID-19). The study used three-dimensional pharmacophores for ENT1 and ENT2 substrates and inhibitors and Bayesian machine learning models to identify potential interactions with these transporters. In vitro transport experiments demonstrated that remdesivir was the most potent inhibitor of ENT-mediated [3H]uridine uptake (ENT1 IC50: 39 μM; ENT2 IC50: 77 μM), followed by EIDD-1931 (ENT1 IC50: 259 μM; ENT2 IC50: 467 μM), whereas molnupiravir was a modest inhibitor (ENT1 IC50: 701 μM; ENT2 IC50: 851 μM). Other proposed antivirals failed to inhibit ENT-mediated [3H]uridine uptake below 1 mM. Remdesivir accumulation decreased in the presence of 6-S-[(4-nitrophenyl)methyl]-6-thioinosine (NBMPR) by 30% in ENT1 cells (P = 0.0248) and 27% in ENT2 cells (P = 0.0054). EIDD-1931 accumulation decreased in the presence of NBMPR by 77% in ENT1 cells (P = 0.0463) and by 64% in ENT2 cells (P = 0.0132), which supported computational predictions that both are ENT substrates that may be important for efficacy against COVID-19. NBMPR failed to decrease molnupiravir uptake, suggesting that ENT interaction is likely inhibitory. Our combined computational and in vitro data can be used to identify additional ENT-drug interactions to improve our understanding of drugs that can circumvent the BTB.SIGNIFICANCE STATEMENTThis study identified remdesivir and EIDD-1931 as substrates of equilibrative nucleoside transporters 1 and 2. This provides a potential mechanism for uptake of these drugs into cells and may be important for antiviral potential in the testes and other tissues expressing these transporters.
      PubDate: 2021-11-19T08:26:30-08:00
      DOI: 10.1124/molpharm.121.000333
      Issue No: Vol. 100, No. 6 (2021)
       
  • Decoding the Cardiac Actions of Protein Kinase D Isoforms [Minireview]

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      Authors: Steinberg S. F.
      Pages: 558 - 567
      Abstract: Protein kinase D (PKD) consists of a family of three structurally related enzymes that play key roles in a wide range of biological functions that contribute to the evolution of cardiac hypertrophy and heart failure. PKD1 (the founding member of this enzyme family) has been implicated in the phosphorylation of substrates that regulate cardiac hypertrophy, contraction, and susceptibility to ischemia/reperfusion injury, and de novo PRKD1 (protein kinase D1 gene) mutations have been identified in patients with syndromic congenital heart disease. However, cardiomyocytes coexpress all three PKDs. Although stimulus-specific activation patterns for PKD1, PKD2, and PKD3 have been identified in cardiomyocytes, progress toward identifying PKD isoform-specific functions in the heart have been hampered by significant gaps in our understanding of the molecular mechanisms that regulate PKD activity. This review incorporates recent conceptual breakthroughs in our understanding of various alternative mechanisms for PKD activation, with an emphasis on recent evidence that PKDs activate certain effector responses as dimers, to consider the role of PKD isoforms in signaling pathways that drive cardiac hypertrophy and ischemia/reperfusion injury. The focus is on whether the recently identified activation mechanisms that enhance the signaling repertoire of PKD family enzymes provide novel therapeutic strategies to target PKD enzymes and prevent or slow the evolution of cardiac injury and pathological cardiac remodeling.SIGNIFICANCE STATEMENTPKD isoforms regulate a large number of fundamental biological processes, but the understanding of the biological actions of individual PKDs (based upon studies using adenoviral overexpression or gene-silencing methods) remains incomplete. This review focuses on dimerization, a recently identified mechanism for PKD activation, and the notion that this mechanism provides a strategy to develop novel PKD-targeted pharmaceuticals that restrict proliferation, invasion, or angiogenesis in cancer and prevent or slow the evolution of cardiac injury and pathological cardiac remodeling.
      PubDate: 2021-11-19T08:26:30-08:00
      DOI: 10.1124/molpharm.121.000341
      Issue No: Vol. 100, No. 6 (2021)
       
  • {beta}-Arrestin-Biased Allosteric Modulator Potentiates
           Carvedilol-Stimulated {beta} Adrenergic Receptor Cardioprotection
           [Articles]

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      Authors: Wang, J; Pani, B, Gokhan, I, Xiong, X, Kahsai, A. W, Jiang, H, Ahn, S, Lefkowitz, R. J, Rockman, H. A.
      Pages: 568 - 579
      Abstract: β1 adrenergic receptors (β1ARs) are central regulators of cardiac function and a drug target for cardiac disease. As a member of the G protein–coupled receptor family, β1ARs activate cellular signaling by primarily coupling to Gs proteins to activate adenylyl cyclase, cAMP-dependent pathways, and the multifunctional adaptor-transducer protein β-arrestin. Carvedilol, a traditional β-blocker widely used in treating high blood pressure and heart failure by blocking β adrenergic receptor–mediated G protein activation, can selectively stimulate Gs-independent β-arrestin signaling of β adrenergic receptors, a process known as β-arrestin–biased agonism. Recently, a DNA-encoded small-molecule library screen against agonist-occupied β2 adrenergic receptors (β2ARs) identified Compound-6 (Cmpd-6) to be a positive allosteric modulator for agonists on β2ARs. Intriguingly, it was further discovered that Cmpd-6 is positively cooperative with the β-arrestin–biased ligand carvedilol at β2ARs. Here we describe the surprising finding that at β1ARs unlike β2ARs, Cmpd-6 is cooperative only with carvedilol and not agonists. Cmpd-6 increases the binding affinity of carvedilol for β1ARs and potentiates carvedilol-stimulated, β-arrestin–dependent β1AR signaling, such as epidermal growth factor receptor transactivation and extracellular signal-regulated kinase activation, whereas it does not have an effect on Gs-mediated cAMP generation. In vivo, Cmpd-6 enhances the antiapoptotic, cardioprotective effect of carvedilol in response to myocardial ischemia/reperfusion injury. This antiapoptotic role of carvedilol is dependent on β-arrestins since it is lost in mice with myocyte-specific deletion of β-arrestins. Our findings demonstrate that Cmpd-6 is a selective β-arrestin–biased allosteric modulator of β1ARs and highlight its potential clinical utility in enhancing carvedilol-mediated cardioprotection against ischemic injury.SIGNIFICANCE STATEMENTThis study demonstrates the positive cooperativity of Cmpd-6 on β1ARs as a β-arrestin–biased positive allosteric modulator. Cmpd-6 selectively enhances the affinity and cellular signaling of carvedilol, a known β-arrestin–biased β-blocker for β1ARs, whereas it has minimal effect on other ligands tested. Importantly, Cmpd-6 enhances the β-arrestin–dependent in vivo cardioprotective effect of carvedilol during ischemia/reperfusion injury–induced apoptosis. The data support the potential therapeutic application of Cmpd-6 to enhance the clinical benefits of carvedilol in the treatment of cardiac disease.
      PubDate: 2021-11-19T08:26:30-08:00
      DOI: 10.1124/molpharm.121.000359
      Issue No: Vol. 100, No. 6 (2021)
       
  • Potential Use of Senolytics for Pharmacological Targeting of Precancerous
           Lesions [Emerging Concepts]

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      Authors: Saleh, T; Carpenter, V. J.
      Pages: 580 - 587
      Abstract: Senescence is a cell state that contributes to several homeostatic and pathologic processes. In addition to being induced in somatic cells in response to replicative exhaustion (replicative senescence) as part of organismal aging, senescence can also be triggered prematurely by oncogene hyperactivation or tumor suppressor dysfunction [oncogene-induced senescence (OIS)]. Consequently, senescent cells comprise a major component of precancerous lesions of skin, oral mucosa, nasopharynx, prostate, gut, and lung. Unfortunately, invasive (or minimally invasive) interventions are currently the only available approach employed to eradicate premalignant lesions that carry the potential for cancer progression. Senolytics are a newly emerging drug class capable of selectively eliminating senescent cells. Although senolytics have been successfully demonstrated to mitigate a myriad of aging-related pathologies and to cull senescent cancer cells, there is a paucity of evidence for the potential use of senolytics as a novel approach to eliminate oncogene-induced senescent cells. This Emerging Concepts commentary will 1) summarize evidence in established models of OIS including B-Raf–induced nevi, transgenic lung cancer, and pancreatic adenocarcinoma models, as well as evidence from clinical precancerous lesions; 2) suggest that OIS is targetable; and 3) propose the utilization of senolytic agents as a revolutionary means to interfere with the ability of senescent premalignant cells to progress to cancer in vitro and in vivo. If proven to be effective, senolytics will represent an emerging tool to pharmacologically treat precancerous lesions.SIGNIFICANCE STATEMENTThe treatment of premalignant lesions is largely based on the utilization of invasive (or minimally invasive) measures. Oncogene-induced senescence (OIS) is one form of senescence that occurs in response to oncogene overexpression in somatic cells and is present in precancerous lesions. Although the contribution of OIS to disease progression is undetermined, recent evidence suggests that senescent cells are permissive for malignant transformation. Accordingly, the pharmacological targeting of oncogene-induced senescent cells could potentially provide a novel, less invasive, means for the treatment of premalignant disease.
      PubDate: 2021-11-19T08:26:30-08:00
      DOI: 10.1124/molpharm.121.000361
      Issue No: Vol. 100, No. 6 (2021)
       
  • Naturally Occurring Mutations to Muscle-Type Creatine Kinase Impact Its
           Canonical and Pharmacological Activities in a Substrate-Dependent Manner
           In Vitro [Articles]

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      Authors: Mosher, E. P; Eberhard, C. D, Bumpus, N. N.
      Pages: 588 - 596
      Abstract: Tenofovir (TFV) is a key component of human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP). TFV is a nucleotide analog reverse-transcriptase inhibitor prodrug that requires two separate phosphorylation reactions by intracellular kinases to form the active metabolite tenofovir-diphosphate (TFV-DP). Muscle-type creatine kinase (CKM) has previously been demonstrated to be the kinase most responsible for the phosphorylation of tenofovir-monophosphate (TFV-MP) to the active metabolite in colon tissue. Because of the importance of CKM in TFV activation, genetic variation in CKM may contribute to interindividual variability in TFV-DP levels. In the present study, we report 10 naturally occurring CKM mutations that reduced TFV-MP phosphorylation in vitro: T35I, R43Q, I92M, H97Y, R130H, R132C, F169L, Y173C, W211R, V280L, and N286I. Interestingly, of these 10, only 4—R130H, R132C, W211R, and N286I—reduced both canonical CKM activities: ADP phosphorylation and ATP dephosphorylation. Although positions 130, 132, and 286 are located in the active site, the other mutations that resulted in decreased TFV-MP phosphorylation occur elsewhere in the protein structure. Four of these eight mutations—T35I, R43Q, I92M, and W211R—were found to decrease the thermal stability of the protein. Additionally, the W211R mutation was found to impact protein structure both locally and at a distance. These data suggest a substrate-specific effect such that certain mutations are tolerated for canonical activities while being deleterious toward the pharmacological activity of TFV activation, which could influence PrEP outcomes.SIGNIFICANCE STATEMENTMuscle-type creatine kinase (CKM) is important to the activation of tenofovir, a key component of HIV prophylaxis. This study demonstrates that naturally occurring CKM mutations impact enzyme function in a substrate-dependent manner such that some mutations that do not reduce canonical activities lead to reductions in the pharmacologically relevant activity. This finding at the intersection of drug metabolism and energy metabolism is important to the perspective on pharmacology of other drugs acted on by atypical drug-metabolizing enzymes.
      PubDate: 2021-11-19T08:26:30-08:00
      DOI: 10.1124/molpharm.121.000348
      Issue No: Vol. 100, No. 6 (2021)
       
  • Correction to "Unique Positive Cooperativity Between the
           {beta}-Arrestin-Biased {beta}-Blocker Carvedilol and a Small Molecule
           Positive Allosteric Modulator of the {beta}2-Adrenergic Receptor"
           [ERRATUM]

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      Pages: 597 - 597
      PubDate: 2021-12-03T07:26:48-08:00
      DOI: 10.1124/molpharm.121.000363err
      Issue No: Vol. 100, No. 6 (2021)
       
  • Correction to "{beta}2-Adrenoceptor Agonists Promote Extracellular
           Signal-Regulated Kinase 1/2 Dephosphorylation in Human Airway Epithelial
           Cells by Canonical, cAMP-Driven Signaling Independently of {beta}-Arrestin
           2" [ERRATUM]

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      Pages: 598 - 598
      PubDate: 2021-12-03T07:26:48-08:00
      DOI: 10.1124/molpharm.121.000294err
      Issue No: Vol. 100, No. 6 (2021)
       
  • Identification of Key Amino Acids that Impact Organic Solute Transporter
           {alpha}/{beta} (OST{alpha}/{beta}) [Articles]

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      Authors: Murphy, W. A; Beaudoin, J. J, Laitinen, T, Sjöstedt, N, Malinen, M. M, Ho, H, Swaan, P. W, Honkakoski, P, Brouwer, K. L. R.
      Pages: 599 - 608
      Abstract: Organic solute transporter α/β (OSTα/β) is a bidirectional bile acid transporter localized on the basolateral membrane of hepatic, intestinal, and renal epithelial cells. OSTα/β plays a critical role in intestinal bile acid reabsorption and is upregulated in hepatic diseases characterized by elevated bile acids, whereas genetic variants in SLC51A/B have been associated with clinical cholestasis. OSTα/β also transports and is inhibited by commonly used medications. However, there is currently no high-resolution structure of OSTα/β, and structure-function data for OSTα, the proposed substrate-binding subunit, are lacking. The present study addressed this knowledge gap and identified amino acids in OSTα that are important for bile acid transport. This was accomplished using computational modeling and site-directed mutagenesis of the OSTα subunit to generate OSTα/β mutant cell lines. Out of the 10 OSTα/β mutants investigated, four (S228K, T229S, Q269E, Q269K) exhibited decreased [3H]-taurocholate (TCA) uptake (ratio of geometric means relative to OSTα/β wild type (WT) of 0.76, 0.75, 0.79, and 0.13, respectively). Three OSTα/β mutants (S228K, Q269K, E305A) had reduced [3H]-TCA efflux % (ratio of geometric means relative to OSTα/β WT of 0.86, 0.65, and 0.79, respectively). Additionally, several OSTα/β mutants demonstrated altered expression and cellular localization when compared with OSTα/β WT. In summary, we identified OSTα residues (Ser228, Thr229, Gln269, Glu305) in predicted transmembrane domains that affect expression of OSTα/β and may influence OSTα/β-mediated bile acid transport. These data advance our understanding of OSTα/β structure/function and can inform future studies designed to gain further insight into OSTα/β structure or to identify additional OSTα/β substrates and inhibitors.SIGNIFICANCE STATEMENTOSTα/β is a clinically important transporter involved in enterohepatic bile acid recycling with currently no high-resolution protein structure and limited structure-function data. This study identified four OSTα amino acids (Ser228, Thr229, Gln269, Glu305) that affect expression of OSTα/β and may influence OSTα/β-mediated bile acid transport. These data can be utilized to inform future investigation of OSTα/β structure and refine molecular modeling approaches to facilitate the identification of substrates and/or inhibitors of OSTα/β.
      PubDate: 2021-12-03T07:26:48-08:00
      DOI: 10.1124/molpharm.121.000345
      Issue No: Vol. 100, No. 6 (2021)
       
  • Correction to "Tacrine Induces Endoplasmic Reticulum-Stressed Apoptosis
           via Disrupting the Proper Assembly of Oligomeric Acetylcholinesterase in
           Cultured Neuronal Cells" [ERRATUM]

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      Pages: 609 - 609
      PubDate: 2021-12-08T07:51:29-08:00
      DOI: 10.1124/molpharm.121.000269err
      Issue No: Vol. 100, No. 6 (2021)
       
 
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