Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD.
© 2023. The Author(s).

Although two-dimensional hydrogel thin films have been applied across many biomedical applications, creating higher dimensionality structured hydrogel interfaces would enable potentially improved and more biomimetic hydrogel performance in biosensing, bioseparations, tissue engineering, drug delivery, and wound healing applications. Herein, we present a new and simple approach to control the structure of hydrogel thin films in 2.5D. Hybrid suspensions containing cellulose nanocrystals (CNCs) and aldehyde- or hydrazide-functionalized poly(oligoethylene glycol methacrylate) (POEGMA) were spin-coated onto prestressed polystyrene substrates to form cross-linked hydrogel thin films. The films were then structured via thermal shrinking, with control over the direction of shrinking leading to the formation of biaxial, uniaxial, or hierarchical wrinkles. Notably, POEGMA-only hydrogel thin films (without CNCs) did not form uniform wrinkles due to partial dewetting from the substrate during shrinking. Topographical feature sizes of CNC-POEGMA films could be tuned across 2 orders of magnitude (from ∼300 nm to 20 μm) by varying the POEGMA concentration, the length of poly(ethylene glycol) side chains in the polymer, and/or the overall film thickness. Furthermore, by employing adhesive masks during the spin-coating process, structured films with gradient wrinkle sizes can be fabricated. This precise control over both wrinkle size and wrinkle topography adds a level of functionality that to date has been lacking in conventional hydrogel networks.

Most of the bacteria are on the verge of becoming resistant to available potential antibiotics. Novel approaches to combat these drug resistant bacteria are turning out to be crucial. This study aimed to synthesize novel fatty acid based cationic amphiphiles (FCA) that would serve as nano-drug carrier having intrinsic antibacterial activity. Three fatty acids oleic acid, linoleic acid and linolenic acid based cationic amphiphiles were synthesized and evaluated for antibacterial activity and cytotoxicity. The application in the delivery of vancomycin (VCM) was demonstrated using oleic based cationic amphiphilic (OCA). OCA was self-assembled in aqueous media to prepare VCM loaded OCA vesicles. The particle size, polydispersity index, zeta potential and entrapment efficiency were found to be 132.9 ± 2.5 nm, 0.167 ± 0.02, 18.9 ± 1.2 mV and 61.24 ± 1.8% respectively. The images from transmission electron microscopy (TEM) revealed that the vesicles were spherical and bilayered. The release of VCM from OCA vesicles was sustained throughout the studied period of 72 h. From in vitro studies, a significant antibacterial activity was observed for all three FCAs and it was found that, VCM loaded OCA vesicles displayed indifference and synergism against Gram positive methicillin susceptible and resistant staphylococcus aureus respectively (MRSA). In contrast to minimum inhibitory concentration (MIC) of VCM against Gram negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa), the synthesized FCAs were more potent against both the strains, further there was no synergism observed against either of the strains when VCM was encapsulated in OCA vesicles. The synergism against MRSA was further confirmed in in vivo studies using mouse infection model. These findings therefore suggest that, FCAs can make promising nano-carrier systems for the delivery of antibiotics to treat infections caused by multi drug resistant bacteria.
Copyright © 2018 Elsevier B.V. All rights reserved.

Cladrin, an isoflavone is a major bioactive constituent found in stem bark of Butea monosperma with remarkable osteogenic activity. A speedy and sensitive UPLC coupled tandem mass spectrometry (UPLC-MS/MS) method was developed, validated and successfully applied to bioavailability, blood partitioning, plasma protein binding, intravenous and multiple-dose oral pharmacokinetics of cladrin in rats. Separation was done on C18 column (5.0 μm, 4.6 × 50 mm) using mobile phase containing acetonitrile and 0.10% formic acid in the ratio of 65:35 (v/v) with 0.60 mL/min flow rate. The method was highly sensitive and has a short run time of 2.50 min with an excellent linearity (R2 > 0.99) in the range of 0.20-200 μg/L. Absolute bioavailability was found to be 16.58, 19.04 and 6.76% at oral doses of 5, 10, and 20 mg/Kg, respectively. Cladrin was rapidly absorbed (Tmax 3.0 h) with a high apparent volume of distribution (15.03 ± 1.79L/Kg), high clearance (2.27 ± 0.30L/h/Kg) and high plasma protein binding. The present study is a first comprehensive in-vitro as well as the in-vivo preclinical pharmacokinetic report of cladrin giving insights about its drug-likeness and further development as a potential therapeutic agent.
Copyright © 2018 Elsevier B.V. All rights reserved.

Graft copolymers based on carboxymethylcellulose (CMC) and thermosensitive polyetheramines (ethylene oxide/propylene oxide = 33/10 and 1/9) were prepared in water, at room temperature, by using a carbodiimide and N-hydroxysuccinimide as activators. SLS was applied to obtain Mw, A2 and Rg of CMC and its derivatives. Amide linkages were evidenced by FTIR and grafting percentage was determined by 1H NMR. TGA demonstrated that copolymers were thermally more stable than their precursors. DLS, UV-vis and rheological measurements revealed that properties were salt- and thermo-responsive and linked to the polysaccharide/polyetheramine ratio and the hydrophobicity of the graft. None of the copolymers showed cloud point temperature (Tcp) in water, but they turned turbid in saline media when heated. Copolymers exhibited thermothickening behaviour at 60 °C (>Tcp) in saline media. Below their Tcp, they showed the ability of keeping constant viscosity or even slight increase it, which was interpreted in terms of intermolecular hydrophobic associations.
Copyright © 2017 Elsevier Ltd. All rights reserved.