Heart failure with preserved ejection fraction (HFpEF) roughly represents half of the cardiac failure events in developed countries. The proposed 'systemic microvascular paradigm' has been used to explain HFpHF presentation heterogeneity. The lack of effective treatments with few evidence-based therapeutic recommendations makes HFpEF one of the greatest unmet clinical necessities worldwide. The endogenous levels of the purine nucleoside, adenosine, increase significantly following cardiovascular events. Adenosine exerts cardioprotective, neuromodulatory, and immunosuppressive effects by activating plasma membrane-bound P1 receptors that are widely expressed in the cardiovascular system. Its proven benefits have been demonstrated in preclinical animal tests. Here, we provide a comprehensive and up-to-date critical review about the main therapeutic advantages of tuning adenosine signalling pathways in HFpEF, without discounting their side effects and how these can be seized.
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http://dx.doi.org/10.3389/fphar.2021.724320 | DOI Listing |
Nat Commun
January 2025
National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
Epitranscriptomic modifications, particularly N6-methyladenosine (mA), are crucial regulators of gene expression, influencing processes such as RNA stability, splicing, and translation. Traditional computational methods for detecting mA from Nanopore direct RNA sequencing (DRS) data are constrained by their reliance on experimentally validated labels, often resulting in the underestimation of modification sites. Here, we introduce pum6a, an innovative attention-based framework that integrates positive and unlabeled multi-instance learning (MIL) to address the challenges of incomplete labeling and missing read-level annotations.
View Article and Find Full Text PDFNat Chem Biol
January 2025
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
Nucleoside triphosphate (NTP)-dependent protein assemblies such as microtubules and actin filaments have inspired the development of diverse chemically fueled molecular machines and active materials but their functional sophistication has yet to be matched by design. Given this challenge, we asked whether it is possible to transform a natural adenosine 5'-triphosphate (ATP)-dependent enzyme into a dissipative self-assembling system, thereby altering the structural and functional mode in which chemical energy is used. Here we report that FtsH (filamentous temperature-sensitive protease H), a hexameric ATPase involved in membrane protein degradation, can be readily engineered to form one-dimensional helical nanotubes.
View Article and Find Full Text PDFInt J Mol Sci
December 2024
Hefei National Laboratory for Physical Sciences at the Microscale, MOE Key Laboratory for Membrane-Less Organelles & Cellular Dynamics, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.
Mitochondrial function is essential for synaptic function. ATAD1, an AAA+ protease involved in mitochondrial quality control, governs fission-fusion dynamics within the organelle. However, the distribution and functional role of ATAD1 in neurons remain poorly understood.
View Article and Find Full Text PDFCells
December 2024
Centre for Health and Life Sciences, Coventry University, Coventry CV1 5FB, UK.
The adenosine A1 receptor (AR) is a promising target for pain treatment. However, the development of therapeutic agonists is hampered by adverse effects, mainly including sedation, bradycardia, hypotension, or respiratory depression. Recently discovered molecules able to overcome this impediment are the positive allosteric modulator MIPS521 and the A1R-selective agonist BnOCPA, which are both potent and powerful analgesics with fewer side effects.
View Article and Find Full Text PDFNat Commun
December 2024
PSI Center for Life Sciences, Villigen PSI, Switzerland.
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans. The binding and dissociation of ligands tunes the inherent conformational flexibility of these important drug targets towards distinct functional states. Here we show how to trigger and resolve protein-ligand interaction dynamics within the human adenosine A receptor.
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