Cardioprotection by the adiponectin receptor agonist ALY688 in a preclinical mouse model of heart failure with reduced ejection fraction (HFrEF).

AIMS: Adiponectin has been shown to mediate cardioprotective effects and levels are typically reduced in patients with cardiometabolic disease. Hence, there has been intense interest in developing adiponectin-based therapeutics. The aim of this translational research study was to examine the functional significance of targeting adiponectin signaling with the adiponectin receptor agonist ALY688 in a mouse model of heart failure with reduced ejection fraction (HFrEF), and the mechanisms of cardiac remodeling leading to cardioprotection. METHODS AND RESULTS: Wild-type mice were subjected to transverse aortic constriction (TAC) to induce left ventricular pressure overload (PO), or sham surgery, with or without daily subcutaneous ALY688-SR administration. Temporal analysis of cardiac function was conducted via weekly echocardiography for 5 weeks and we observed that ALY688 attenuated the PO-induced dysfunction. ALY688 also reduced cardiac hypertrophic remodeling, assessed via LV mass, heart weight to body weight ratio, cardiomyocyte cross sectional area, ANP and BNP levels. ALY688 also attenuated PO-induced changes in myosin light and heavy chain expression. Collagen content and myofibroblast profile indicated that fibrosis was attenuated by ALY688 with TIMP1 and scleraxis/periostin identified as potential mechanistic contributors. ALY688 reduced PO-induced elevation in circulating cytokines including IL-5, IL-13 and IL-17, and the chemoattractants MCP-1, MIP-1ß, MIP-1alpha and MIP-3α. Assessment of myocardial transcript levels indicated that ALY688 suppressed PO-induced elevations in IL-6, TLR-4 and IL-1ß, collectively indicating anti-inflammatory effects. Targeted metabolomic profiling indicated that ALY688 increased fatty acid mobilization and oxidation, increased betaine and putrescine plus decreased sphingomyelin and lysophospholipids, a profile indicative of improved insulin sensitivity. CONCLUSION: These results indicate that the adiponectin mimetic peptide ALY688 reduced PO-induced fibrosis, hypertrophy, inflammation and metabolic dysfunction and represents a promising therapeutic approach for treating HFrEF in a clinical setting.

Flexible, robust, and high-performance gas sensors based on lignocellulosic nanofibrils.

Gas detection in flexible electronics demands novel materials with superior sensing performance that have high mechanically strength, are flexible, low-cost, and sustainable. We explore a composite sensing nanopaper based on lignocellulosic cellulose nanofibrils (LCNF) as a renewable and mechanically strong substrate that enables the fabrication of flexible, and highly sensitive gas sensors. In the system the hydrophobic lignin covalently bonds to cellulose in the nanofibrils, increasing the nanopaper water-resistance and limiting sensing materials response to humidity. The sensor is composed of polyaniline (PANI) grown on flexible LCNF and reduced graphene oxide (rGO) nanosheets. The proposed structure, at 10 wt% rGO, demonstrated a 10-fold improvement in sensitivity to volatile amines (i.e. ammonia detection down to 1 ppm) while maintaining an acceptable selectivity. Furthermore, we demonstrated the application of the sensing nanopaper in a microwave sensor that paves the path toward flexible, wireless, and high-performance sensing devices.