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Biomimetic enzyme nanocomplexes and their use as antidotes and preventive measures for alcohol intoxication.

ABSTRACT: Organisms have sophisticated subcellular compartments containing enzymes that function in tandem. These confined compartments ensure effective chemical transformation and transport of molecules, and the elimination of toxic metabolic wastes. Creating functional enzyme complexes that are confined in a similar way remains challenging. Here we show that two or more enzymes with complementary functions can be assembled and encapsulated within a thin polymer shell to form enzyme nanocomplexes. These nanocomplexes exhibit improved catalytic efficiency and enhanced stability when compared with free enzymes. Furthermore, the co-localized enzymes display complementary functions, whereby toxic intermediates generated by one enzyme can be promptly eliminated by another enzyme. We show that nanocomplexes containing alcohol oxidase and catalase could reduce blood alcohol levels in intoxicated mice, offering an alternative antidote and prophylactic for alcohol intoxication.

SUBMITTER: Liu Y

PROVIDER: S-EPMC3670615 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Biomimetic enzyme nanocomplexes and their use as antidotes and preventive measures for alcohol intoxication.

Liu Yang Y Du Juanjuan J Yan Ming M Lau Mo Yin MY Hu Jay J Han Hui H Yang Otto O OO Liang Sheng S Wei Wei W Wang Hui H Li Jianmin J Zhu Xinyuan X Shi Linqi L Chen Wei W Ji Cheng C Lu Yunfeng Y

Nature nanotechnology 20130217 3

Organisms have sophisticated subcellular compartments containing enzymes that function in tandem. These confined compartments ensure effective chemical transformation and transport of molecules, and the elimination of toxic metabolic wastes. Creating functional enzyme complexes that are confined in a similar way remains challenging. Here we show that two or more enzymes with complementary functions can be assembled and encapsulated within a thin polymer shell to form enzyme nanocomplexes. These ...[more]

PMID: 23416793

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Project description:BackgroundSelf-reported consumption is pervasive in alcohol research, though retrospective recall bias is a concern. Fine-grained methods are designed to limit retrospection; yet, discrepancies can arise when comparing responses on fine-grained surveys with responses to retrospective surveys across weeks or months. Many fine-grained studies use both repeated daily surveys (RDS) and end-of-day (EOD) summaries, but little research has examined whether these survey types are consistent. The purpose of this study was to quantify the magnitude and directionality of discrepancy between EOD summaries and RDS and identify alcohol-related predictors of discrepancy.MethodsAs a part of a larger study, college student alcohol and cannabis users (N = 341; 53% women; Mage = 19.79 years) were recruited to complete 56 days of data collection, including 5 daily assessments of their substance use and related constructs, one of which included an EOD summary of the previous day. Generalized linear mixed-effects models were used to examine between- and within-person predictors of a 5-category, discrepancy outcome: no discrepancy, low discrepancy where RDS < EOD, low discrepancy where EOD < RDS, high discrepancy where RDS < EOD, and high discrepancy where EOD < RDS.ResultsDiscrepancies between EOD and RDS were observed in both directions. Alcohol problems predicted more alcohol consumption reported on the EOD survey than across RDS. Within-person alcohol quantity and hourly rate of consumption were most strongly related to less alcohol consumption reported on the EOD survey. Between- and within-person peak subjective intoxication and within-person liquor consumption were associated with discrepancies in both directions.ConclusionsSurveys requiring more retrospection may overestimate alcohol consumption in problematic drinkers and underestimate consumption on days where more alcohol is consumed than typical. Evidence also suggests that greater day-to-day instability in alcohol behavior is linked to less consistent reporting overall. More research is needed to discern factors contributing to inconsistent reporting on fine-grained surveys to maximize the validity of reports.

Project description:BackgroundAlcohol intoxication can increase inflammation and worsen injury, yet the mechanisms involved are not clear. We investigated whether acute alcohol intoxication increases microvascular permeability and investigated potential signaling mechanisms in endothelial cells that may be involved.MethodsConscious rats received a 2.5 g/kg alcohol bolus via gastric catheters to produce acute intoxication. Microvascular leakage of intravenously administered fluorescein isothiocyanate (FITC)-conjugated albumin (FITC-albumin) from the mesenteric microcirculation was assessed by intravital microscopy. Endothelial-specific mechanisms were studied using cultured endothelial cell monolayers. Transendothelial electrical resistance (TER) served as an index of barrier function, before and after treatment with alcohol or its metabolite acetaldehyde. Pharmacologic agents were used to test the roles of alcohol metabolism, oxidative stress, p38 mitogen-activated protein kinase (MAPK), myosin light-chain kinase (MLCK), rho kinase (ROCK), and exchange protein activated by cAMP (Epac). VE-cadherin localization was investigated to assess junctional integrity. Rac1 and RhoA activation was assessed by ELISA assays.ResultsAlcohol significantly increased FITC-albumin extravasation from the mesenteric microcirculation. Alcohol also significantly decreased TER and disrupted VE-cadherin organization at junctions. Acetaldehyde significantly decreased TER, but inhibition of alcohol dehydrogenase or application of a superoxide dismutase mimetic failed to prevent alcohol-induced decreases in TER. Inhibition of p38 MAPK, but not MLCK or ROCK, significantly attenuated the alcohol-induced barrier dysfunction. Alcohol rapidly decreased GTP-bound Rac1 but not RhoA during the drop in TER. Activation of Epac increased TER, but did not prevent alcohol from decreasing TER. However, activation of Epac after initiation of alcohol-induced barrier dysfunction quickly resolved TER to baseline levels.ConclusionsOur results suggest that alcohol intoxication increases microvascular permeability to plasma proteins. The data also suggest the endothelial-specific mechanism involves the p38 MAPK, Rac1, and reorganization of VE-cadherin at junctions. Last, activation of Epac can quickly resolve alcohol-induced endothelial barrier dysfunction.

Dataset Information

Biomimetic enzyme nanocomplexes and their use as antidotes and preventive measures for alcohol intoxication.

Publications

Biomimetic enzyme nanocomplexes and their use as antidotes and preventive measures for alcohol intoxication.

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