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AbstractDeriving active pharmaceutical agents from renewable resources is crucial to increasing the economic feasibility of modern biorefineries and promises to alleviate critical supply‐chain dependencies in pharma manufacturing. Our multidisciplinary approach combines research in lignin‐first biorefining, sustainable catalysis, and alternative solvents with bioactivity screening, an in vivo efficacy study, and a structural‐similarity search. The resulting sustainable path to novel anti‐infective, anti‐inflammatory, and anticancer molecules enabled the rapid identification of frontrunners for key therapeutic indications, including an anti‐infective against the priority pathogen Streptococcus pneumoniae with efficacy in vivo and promising plasma and metabolic stability. Our catalytic methods provided straightforward access, inspired by the innate structural features of lignin, to synthetically challenging biologically active molecules with the core structure of dopamine, namely, tetrahydroisoquinolines, quinazolinones, 3‐arylindoles and the natural product tetrahydropapaveroline. Our diverse array of atom‐economic transformations produces only harmless side products and uses benign reaction media, such as tunable deep eutectic solvents for modulating reactivity in challenging cyclization steps.

Platelet aggregation, secretion of serotonin, and formation of thromboxane B2 induced by platelet-activating factor (1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) were studied in plasma containing physiological concentrations of ionized calcium in eight alcoholics after cessation of heavy drinking. Responses of platelets of four nonalcoholic volunteers, matched with a subgroup of the alcoholics by age and sex, were also investigated. Aggregation of platelets from alcoholics was significantly less throughout the 6-day detoxification period compared with controls. Secretion of serotonin (5-hydroxy-tryptamine) was negligible and the production of thromboxane B2 was not detectable. Decreased platelet aggregability in response to aggregating agents, including platelet-activating factor, may be important in the development of hemorrhagic complications in alcoholics.

The actuation of micro- and nanostructures controlled by external stimuli remains one of the exciting challenges in nanotechnology due to the wealth of fundamental questions and potential applications in energy harvesting, robotics, sensing, biomedicine, and tunable metamaterials. Photoactuation utilizes the conversion of light into motion through reversible chemical and physical processes and enables remote and spatiotemporal control of the actuation. Here, we report a fast light-to-motion conversion in few-nanometer thick bare polydopamine (PDA) membranes stimulated by visible light. Light-induced heating of PDA leads to desorption of water molecules and contraction of membranes in less than 140 μs. Switching off the light leads to a spontaneous expansion in less than 20 ms due to heat dissipation and water adsorption. Our findings demonstrate that pristine PDA membranes are multiresponsive materials that can be harnessed as robust building blocks for soft, micro-, and nanoscale actuators stimulated by light, temperature, and moisture level.

The ability of drugs of abuse to increase mesolimbic levels of dopamine is a characteristic associated with their rewarding effects. Exactly how these effects are produced by different substances is not as well characterised. Our previous work in rats has demonstrated that accumbal glycine receptors (GlyRs) are involved in mediating the dopamine-activating effects of ethanol, and in modulating ethanol intake. In this study the investigation of GlyR involvement was extended to include several different drugs of abuse. By using microdialysis and electrophysiology we compared effects of addictive drugs, with and without the GlyR antagonist strychnine, on dopamine levels and neurotransmission in nucleus accumbens. The dopamine-increasing effect of systemic ethanol and the drug-induced change in neurotransmission in vitro, as measured by microdialysis and field potential recordings, were dependent on GlyRs in nAc. Accumbal GlyRs were also involved in the actions of tetrahydrocannabinol and nicotine, but not in those of cocaine or morphine. These data indicate that accumbal GlyRs play a key role in ethanol-induced dopamine activation and contribute also to that of cannabinoids and nicotine.

Identification of ethanol's (EtOH) primary molecular brain targets and determination of their functional role is an ongoing, important quest. Pentameric ligand‐gated ion channels, that is, the nicotinic acetylcholine receptor, the γ‐aminobutyric acid type A receptor, the 5‐hydroxytryptamine3, and the glycine receptor (GlyR), are such targets. Here, aspects of the structure and function of these receptors and EtOH's interaction with them are briefly reviewed, with special emphasis on the GlyR and the importance of this receptor and its ligands for EtOH pharmacology. It is suggested that GlyRs are involved in (i) the dopamine‐activating effect of EtOH, (ii) regulating EtOH intake, and (iii) the relapse preventing effect of acamprosate. Exploration of the GlyR subtypes involved and efforts to develop subtype specific agonists or antagonists may offer new pharmacotherapies for alcohol use disorders.

Abstract: Phosphatidylethanol is formed by phospholipase D in animal cells exposed to ethanol. Previous reports have demonstrated that the degradation of phosphatidylethanol is slow, indicating that this lipid may be present in the cells after ethanol itself has disappeared. Accumulation of an abnormal alcohol metabolite may influence cellular functions. In the present study, cultivation of NG108–15 neuroblastoma × glioma hybrid cells in the presence of ethanol resulted in an accumulation of phosphatidylethanol and a simultaneous increase in basal inositol 1,4,5‐trisphosphate levels. The direct effects of phosphatidylethanol on the phosphoinositide signal transduction system were examined through incorporation of exogenous phosphatidylethanol into membranes of ethanol‐naive cells. An incorporation amounting to 2.8% of cellular phospholipids was achieved after a 5‐h incubation with 30 μM phosphatidylethanol. Phosphatidylethanol was found to cause a time‐and dose‐dependent increase in the basal levels of inositol 1,4,5‐trisphosphate. The effects on inositol 1,4,5‐trisphosphate levels of exogenously added phosphatidylethanol and ethanol exposure for 2 days were not additive. No effect on bradykinin‐stimulated inositol 1,4,5‐trisphosphate production could be detected. However, the increase in basal inositol 1,4,5‐trisphosphate levels indicates that phosphatidylethanol affects inositol 1,4,5‐trisphosphate turnover and emphasizes the importance of considering phosphatidylethanol as a possible mediator of ethanol‐induced effects on cellular processes.

The mechanism of phosphatidyl [14C]ethanol formation was studied in rat brain microsomal fraction. Phospholipase D and base-exchange enzymes were assayed with [14C]ethanol as substrate. Phospholipase D was found to catalyse the formation of phosphatidylethanol. The reaction was dependent on sodium-oleate as activating factor. Phosphatidylethanol formation by phospholipase D has previously only been reported to occur in plant tissues. Stimulation of base-exchange enzymes with calcium in the presence of [14 C]ethanol did not induce any formation of phosphatidylethanol. These findings indicate that phosphatidylethanol formation in ethanol intoxicated rats is catalysed by phospholipase D.