Compressible Hydrogels with Stabilized Chirality from Thermoresponsive Helical Dendronized Poly(phenylacetylene)s.

Fabrication of chiral hydrogels from thermoresponsive helical dendronized phenylacetylene copolymers (PPAs) carrying three-fold dendritic oligoethylene glycols (OEGs) is reported. Three different temperatures, i.e. below or above cloud point temperatures (Tcps) of the copolymers, and under freezing condition, were utilized, affording thermoresponsive hydrogels with different morphologies and mechanical properties. At room temperature, transparent hydrogels were obtained through crosslinking among different copolymer chains. Differently, opaque hydrogels with much improved mechanical properties were formed at elevated temperatures through crosslinking from the thermally dehydrated and collapsed copolymer aggregates, leading to heterogeneity for the hydrogels with highly porous morphology. While crosslinking at freezing temperature synergistically through ice templating, these amphiphilic dendronized copolymers formed hydrogels with highly porous lamellar structures, which exhibited remarkable compressible properties as human articular cartilage with excellent fatigue resistance. Amphiphilicity of the dendronized copolymers played a pivotal role in modulating the network formation during the gelation, as well as morphology and mechanical performance of the resulting hydrogels. Through crosslinking, these dendronized copolymers featured with typical dynamic helical conformations were transformed into hydrogels with unprecedently stabilized helicities due to the restrained chain mobilities in the three-dimensional networks.

A State-of-the-Science Review of Interactions of Per- and Polyfluoroalkyl Substances (PFAS) with Renal Transporters in Health and Disease: Implications for Population Variability in PFAS Toxicokinetics.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous in the environment and have been shown to cause various adverse health impacts. In animals, sex- and species-specific differences in PFAS elimination half-lives have been linked to the activity of kidney transporters. However, PFAS molecular interactions with kidney transporters are still not fully understood. Moreover, the impact of kidney disease on PFAS elimination remains unclear. OBJECTIVES: This state-of-the-science review integrated current knowledge to assess how changes in kidney function and transporter expression from health to disease could affect PFAS toxicokinetics and identified priority research gaps that should be addressed to advance knowledge. METHODS: We searched for studies that measured PFAS uptake by kidney transporters, quantified transporter-level changes associated with kidney disease status, and developed PFAS pharmacokinetic models. We then used two databases to identify untested kidney transporters that have the potential for PFAS transport based on their endogenous substrates. Finally, we used an existing pharmacokinetic model for perfluorooctanoic acid (PFOA) in male rats to explore the influence of transporter expression levels, glomerular filtration rate (GFR), and serum albumin on serum half-lives. RESULTS: The literature search identified nine human and eight rat kidney transporters that were previously investigated for their ability to transport PFAS, as well as seven human and three rat transporters that were confirmed to transport specific PFAS. We proposed a candidate list of seven untested kidney transporters with the potential for PFAS transport. Model results indicated PFOA toxicokinetics were more influenced by changes in GFR than in transporter expression. DISCUSSION: Studies on additional transporters, particularly efflux transporters, and on more PFAS, especially current-use PFAS, are needed to better cover the role of transporters across the PFAS class. Remaining research gaps in transporter expression changes in specific kidney disease states could limit the effectiveness of risk assessment and prevent identification of vulnerable populations. https://doi.org/10.1289/EHP11885.

Absorption, distribution, and toxicity of per- and polyfluoroalkyl substances (PFAS) in the brain: a review.

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals colloquially known as "forever chemicals" because of their high persistence. PFAS have been detected in the blood, liver, kidney, heart, muscle and brain of various species. Although brain is not a dominant tissue for PFAS accumulation compared to blood and liver, adverse effects of PFAS on brain functions have been identified. Here, we review studies related to the absorption, accumulation, distribution and toxicity of PFAS in the brain. We summarize evidence on two potential mechanisms of PFAS entering the brain: initiating blood-brain barrier (BBB) disassembly through disrupting tight junctions and relying on transporters located at the BBB. PFAS with diverse structures and properties enter and accumulate in the brain with varying efficiencies. Compared to long-chain PFAS, short-chain PFAS may not cross cerebral barriers effectively. According to biomonitoring studies and PFAS exposure experiments, PFAS can accumulate in the brain of humans and wildlife species. With respect to the distribution of PFAS in specific brain regions, the brain stem, hippocampus, hypothalamus, pons/medulla and thalamus are dominant for PFAS accumulation. The accumulation and distribution of PFAS in the brain may lead to toxic effects in the central nervous system (CNS), including PFAS-induced behavioral and cognitive disorders. The specific mechanisms underlying such PFAS-induced neurotoxicity remain to be explored, but two major potential mechanisms based on current understanding are PFAS effects on calcium homeostasis and neurotransmitter alterations in neurons. Based on the information available about PFAS uptake, accumulation, distribution and impacts on the brain, PFAS have the potential to enter and accumulate in the brain at varying levels. The balance of existing studies shows there is some indication of risk in animals, while the human evidence is mixed and warrants further scrutiny.

Dendronized polydiacetylenes via photo-polymerization of supramolecular assemblies showing thermally tunable chirality.

Transformation of supramolecular chiral assemblies into covalent polymers integrates characteristics of supramolecular chemistry together with covalent entities, leading to fabrication of covalent chiral materials through versatile supramolecular chiral assemblies. Here, we report supramolecular assembly of an amphiphilic dendronized 10,12-pentacosadiynoic amide (PCDA) in aqueous solutions to form twisted ribbons, which were transferred into covalent dendronized polydiacetylenes (PDAs) via photopolymerization. These supramolecular dendronized PCDA and the corresponding covalent dendronized PDAs showed unprecedent thermoresponsive properties. The thermally-induced dehydration and aggregations tuned reversibly their chiralities, which can be visually inspected through colour changes.

Thermoresponsive Supramolecular Assemblies from Dendronized Amphiphiles To Form Fluorescent Spheres with Tunable Chirality.

Balance between self-association of structural units and self-repulsion from crowding-induced steric hindrance accounts for the supramolecular assembly of the amphiphilic entities to form ordered structures, and solvation provides a toolbox to conveniently modulate the assemblies through differential interactions to various structural units. Here we report solvation-modulated supramolecular chiral assembly in aqueous solutions of amphiphilic dendronized tetraphenylethylenes (TPEs) with three-folded dendritic oligoethylene glycols (OEGs) through dipeptide Ala-Gly linkage. These dendronized amphiphiles can form supramolecular spheres with enhanced supramolecular chirality, which is tunable and dependent on solvation. These nanosized spherical aggregates exhibit thermoresponsive behavior, and their cloud point temperatures are dependent on mixed solvent of water and THF. The phase transition temperatures increase with water fractions due to water-driven shifting of OEG moieties from interiors of the aggregates to their peripheries. Furthermore, the thermally induced dehydration and collapse of OEG moieties mediate the reversible aggregation and deaggregation between the spheres, imparting tunable aggregation-induced fluorescent emission (AIE) and supramolecular chirality. Both experimental results and molecular dynamic simulations have highlighted that reversible chirality transformations of the amphiphilic dendronized assemblies mediated by solvation through change solvent quality or thermally dehydration are dependent on the balance between interactions of OEG dendrons with TPE moieties and with the solvent molecules.

Inhibition of human endothelial cell nitric oxide synthesis by advanced glycation end-products but not glucose: relevance to diabetes.

Endothelial dysfunction, with decreased NO (nitric oxide) biosynthesis, may play a pathophysiological role in diabetic vasculopathy. The aim of the present study was to determine the relative contributions of glucose and AGE (advanced glycation end-product) accumulation in suppressing NOS-3 (the endothelial isoform of NO synthase). Cultured HUVECs (human umbilical vein endothelial cells) were incubated with different concentrations of glucose, unmodified albumin or AGE-modified albumin for different times. NOS activity was measured from the conversion of L-[(3)H]arginine into L-[(3)H]citrulline, and the expression, serine phosphorylation and O-glycosylation of NOS-3 were determined by Western blotting. High (25 mmol/l) glucose, for up to 12 days of incubation, had no effect on the activity or expression of NOS-3, nor on its degree of serine phosphorylation or O-glycosylation, compared with physiological (5 mmol/l) glucose. By contrast, AGE-modified albumin exerted a concentration- and time-dependent suppression of NOS-3 expression in HUVECs at a range of concentrations (0-200 mg/l) found in diabetic plasma; this was evident after 24 h, whereas inhibition of NOS activity was seen after only 3 h incubation with AGE-modified albumin, consistent with our previous observations of rapid suppression of NOS-3 serine phosphorylation and NOS-3 activity by AGE-modified albumin. In conclusion, AGE-modified albumin suppresses NOS-3 activity in HUVECs through two mechanisms: one rapid, involving suppression of its serine phosphorylation, and another slower, involving a decrease in its expression. We also conclude that, in the context of the chronic hyperglycaemia in diabetes, the effects of AGEs on endothelial NO biosynthesis are considerably more important than those of glucose.