Background: SGLT2 (sodium/glucose cotransporter 2) inhibitors exert robust cardioprotective effects against heart failure in patients with diabetes, and there is intense interest to identify the underlying molecular mechanisms that afford this protection. Because the induction of the late component of the cardiac sodium channel current (late- I _Na ) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late- I _Na . Methods: Electrophysiological, in silico molecular docking, molecular, calcium imaging, and whole heart perfusion techniques were used to address this question. Results: The SGLT2 inhibitor empagliflozin reduced late- I _Na in cardiomyocytes from mice with heart failure and in cardiac Nav1.5 sodium channels containing the long QT syndrome 3 mutations R1623Q or ΔKPQ. Empagliflozin, dapagliflozin, and canagliflozin are all potent and selective inhibitors of H ₂ O ₂ -induced late- I _Na (half maximal inhibitory concentration = 0.79, 0.58, and 1.26 µM, respectively) with little effect on peak sodium current. In mouse cardiomyocytes, empagliflozin reduced the incidence of spontaneous calcium transients induced by the late- I _Na activator veratridine in a similar manner to tetrodotoxin, ranolazine, and lidocaine. The putative binding sites for empagliflozin within Nav1.5 were investigated by simulations of empagliflozin docking to a three-dimensional homology model of human Nav1.5 and point mutagenic approaches. Our results indicate that empagliflozin binds to Nav1.5 in the same region as local anesthetics and ranolazine. In an acute model of myocardial injury, perfusion of isolated mouse hearts with empagliflozin or tetrodotoxin prevented activation of the cardiac NLRP3 (nuclear-binding domain-like receptor 3) inflammasome and improved functional recovery after ischemia. Conclusions: Our results provide evidence that late- I _Na may be an important molecular target in the heart for the SGLT2 inhibitors, contributing to their unexpected cardioprotective effects.

The hnRNP A/B family of proteins is canonically central to cellular RNA metabolism, but due to their highly conserved nature, the functional differences between hnRNP A1, A2/B1, A0, and A3 are often overlooked. In this review, we explore and identify the shared and disparate homeostatic and disease-related functions of the hnRNP A/B family proteins, highlighting areas where the proteins have not been clearly differentiated. Herein, we provide a comprehensive assembly of the literature on these proteins. We find that there are critical gaps in our grasp of A/B proteins’ alternative splice isoforms, structures, regulation, and tissue and cell-type-specific functions, and propose that future mechanistic research integrating multiple A/B proteins will significantly improve our understanding of how this essential protein family contributes to cell homeostasis and disease.

In the search for green CO₂-capture technology to combat global warming, bioengineering of carbonic anhydrases (CAs) is being sought for with target adaptabilities of extreme temperatures and alkaline pH conditions. The modern in silico screening of protein engineering complements the conventional in vitro high-throughput via generation of iteratively cumulating e-library of diverse beneficial mutations. As identified through various studies of randomized and rationalized mutagenesis, different features have been explored to engineer stability in CAs, including improving structural contacts in the protein quaternary architecture with disulfide bonds and salt-bridge networks, as well as enhancing the protein surface electrostatics. Advanced molecular dynamic simulation techniques and progressive training of machine learning-assisted databases are now being used to unravel wild-type CA properties and predict stable variants thereof with greater accuracy than ever before. The best fit CA achieved so forth demonstrates tolerances of up to 107°C at pH >10 with 25-fold enhancement in CO₂ mass transfer. This review will provide an overview of different approaches that have been utilized for engineering CAs and will highlight potential challenges and strategies for developing CA-based CO₂-capture and sequestration.

: Microtubule-Associated Protein Tau (also known as tau) has been shown to accumulate into paired helical filaments and neurofibrillary tangles, which are known hallmarks of Alzheimer’s disease (AD) pathology. Decades of research have shown that tau protein undergoes extensive post-translational modifications (PTMs), which can alter the protein's structure, function, and dynamics and impact the various properties such as solubility, aggregation, localization, and homeostasis. There is a vast amount of information describing the impact and role of different PTMs in AD pathology and neuroprotection. However, the complex interplay between these PTMs remains elusive. Therefore, in this review, we aim to comprehend the key post-translational modifications occurring in tau and summarize potential connections to clarify their impact on the physiology and pathophysiology of tau. Further, we describe how different computational modeling methods have helped in understanding the impact of PTMs on the structure and functions of the tau protein. Finally, we highlight the tau PTM-related therapeutics strategies that are explored for the development of AD therapy.