Molecular features of biguanides required for targeting of mitochondrial respiratory complex I and activation of AMP-kinase.

BACKGROUND: The biguanides are a family of drugs with diverse clinical applications. Metformin, a widely used anti-hyperglycemic biguanide, suppresses mitochondrial respiration by inhibiting respiratory complex I. Phenformin, a related anti-hyperglycemic biguanide, also inhibits respiration, but proguanil, which is widely used for the prevention of malaria, does not. The molecular structures of phenformin and proguanil are closely related and both inhibit isolated complex I. Proguanil does not inhibit respiration in cells and mitochondria because it is unable to access complex I. The molecular features that determine which biguanides accumulate in mitochondria, enabling them to inhibit complex I in vivo, are not known. RESULTS: Here, a family of seven biguanides are used to reveal the molecular features that determine why phenformin enters mitochondria and inhibits respiration whereas proguanil does not. All seven biguanides inhibit isolated complex I, but only four of them inhibit respiration in cells and mitochondria. Direct conjugation of a phenyl group and bis-substitution of the biguanide moiety prevent uptake into mitochondria, irrespective of the compound hydrophobicity. This high selectivity suggests that biguanide uptake into mitochondria is protein mediated, and is not by passive diffusion. Only those biguanides that enter mitochondria and inhibit complex I activate AMP kinase, strengthening links between complex I and the downstream effects of biguanide treatments. CONCLUSIONS: Biguanides inhibit mitochondrial complex I, but specific molecular features control the uptake of substituted biguanides into mitochondria, so only some biguanides inhibit mitochondrial respiration in vivo. Biguanides with restricted intracellular access may be used to determine physiologically relevant targets of biguanide action, and for the rational design of substituted biguanides for diverse clinical applications

Adjustable hydro-thermochromic green nanofoams and films obtained from shapable hybrids of cellulose nanofibrils and ionic liquids for smart packaging

Abstract Engendering stimuli-responsive and green shapable materials is a critical aspect of intelligent, responsive packaging technologies. Thermochromism, i.e., the optical response of materials to thermal stimuli, merges the visual appearance of the packaging with the temperature of the surroundings and cargo. Herein, sustainable, functional two-dimensional (2D) and three-dimensional (3D) hybrids of natural nanoribbons, i.e., cellulose nanofibrils (CNFs) and ionic liquids (ILs), were introduced as highly porous hydrothermochromic nanofoams, spheres, and flexible films. Hygroscopic ILs of nickel (II) or chromium (III) salts and imidazolium derivatives (1-ethyl-3-methylimidazolium chloride) were incorporated into the nanofibrils network, driving reversible color-switching via moisture adsorption controlled by temperature (hydrothermochromism, HTC). Multicolored HTC hybrids with a vast and adjustable color range from pale green to blue and from green to red with a color transition at 20 °C–80 °C were obtained by tailoring the composition (nickel and chromium chloride chemistry) and shape of the CNF–IL samples. These humidity- and temperature-responsive hybrids derived from biobased nanomaterials can pave the way toward future green smart packaging, which meets the requirements of sustainable development. The hybrids also provide advanced performance by monitoring and responding to the conditions of items and the surroundings