Efforts to extend nanoparticle residence time in vivo have inspired many strategies in particle surface modifications to bypass macrophage uptake and systemic clearance. Here we report a top-down biomimetic approach in particle functionalization by coating biodegradable polymeric nanoparticles with natural erythrocyte membranes, including both membrane lipids and associated membrane proteins for long-circulating cargo delivery. The structure, size and surface zeta potential, and protein contents of the erythrocyte membrane-coated nanoparticles were verified using transmission electron microscopy, dynamic light scattering, and gel electrophoresis, respectively. Mice injections with fluorophore-loaded nanoparticles revealed superior circulation half-life by the erythrocytemimicking nanoparticles as compared to control particles coated with the state-of-the-art synthetic stealth materials. Biodistribution study revealed significant particle retention in the blood 72 h following the particle injection. The translocation of natural cellular membranes, their associated proteins, and the corresponding functionalities to the surface of synthetic particles represents a unique approach in nanoparticle functionalization.biomimetic nanoparticle | drug delivery | long circulation | red blood cell membrane
During speech perception, linguistic elements such as consonants and vowels are extracted from a complex acoustic speech signal. The superior temporal gyrus (STG) participates in high-order auditory processing of speech, but how it encodes phonetic information is poorly understood. We used high-density direct cortical surface recordings in humans while they listened to natural, continuous speech to reveal the STG representation of the entire English phonetic inventory. At single electrodes, we found response selectivity to distinct phonetic features. Encoding of acoustic properties was mediated by a distributed population response. Phonetic features could be directly related to tuning for spectrotemporal acoustic cues, some of which were encoded in a nonlinear fashion or by integration of multiple cues. These findings demonstrate the acoustic-phonetic representation of speech in human STG.
In humans, listening to speech evokes neural responses in the motor cortex. This has been controversially interpreted as evidence that speech sounds are processed as articulatory gestures. However, it is unclear what information is actually encoded by such neural activity. We used high-density direct human cortical recordings while participants spoke and listened to speech sounds. Motor cortex neural patterns during listening were substantially different than during articulation of the same sounds. During listening, we observed neural activity in the superior and inferior regions of ventral motor cortex. During speaking, responses were distributed throughout somatotopic representations of speech articulators in motor cortex. The structure of responses in motor cortex during listening was organized along acoustic features similar to auditory cortex, rather than along articulatory features as during speaking. Motor cortex does not contain articulatory representations of perceived actions in speech, but rather, represents auditory vocal information.DOI: http://dx.doi.org/10.7554/eLife.12577.001
The peroxisome proliferator-activated receptor-alpha (PPARalpha), first identified in 1990 as a member of the nuclear receptor superfamily, has a central role in the regulation of numerous target genes encoding proteins that modulate fatty acid transport and catabolism. PPARalpha is the molecular target for the widely prescribed lipid-lowering fibrate drugs and the diverse class of chemicals collectively referred to as peroxisome proliferators. The lipid-lowering function of PPARalpha occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPARalpha agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPARalpha also mediates this effect. There is no strong evidence that the low-affinity fibrate ligands are associated with cancer in humans, but it still remains a possibility that chronic activation with high-affinity ligands could be carcinogenic in humans. It is now established that the species difference between rodents and humans in response to peroxisome proliferators is due in part to PPARalpha. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPARalpha target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPARalpha in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPARalpha agonist-induced hepatocarcinogenesis.
Lipid-lowering fibrate drugs function as agonists for the nuclear receptor peroxisome proliferator-activated receptor ␣ (PPAR␣). Sustained activation of PPAR␣ leads to the development of liver tumors in rats and mice. However, humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by fibrate drugs. The molecular basis of this species difference is not known. To examine the mechanism determining species differences in peroxisome proliferator response between mice and humans, a PPAR␣-humanized mouse line was generated in which the human PPAR␣ was expressed in liver under control of the tetracycline responsive regulatory system. The PPAR␣-humanized and wild-type mice responded to treatment with the potent PPAR␣ ligand Wy-14643 as revealed by induction of genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and resultant decrease of serum triglycerides. However, surprisingly, only the wild-type mice and not the PPAR␣-humanized mice exhibited hepatocellular proliferation as revealed by elevation of cell cycle control genes, increased incorporation of 5-bromo-2-deoxyuridine into hepatocyte nuclei, and hepatomegaly. These studies establish that following ligand activation, the PPAR␣-mediated pathways controlling lipid metabolism are independent from those controlling the cell proliferation pathways. These findings also suggest that structural differences between human and mouse PPAR␣ are responsible for the differential susceptibility to the development of hepatocarcinomas observed after treatment with fibrates. The PPAR␣-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators.
The aim of this study was to investigate the effects of (-)-epigallocatechin-3-gallate (EGCG) on a newly developed high-fat/Western-style diet-induced obesity and symptoms of metabolic syndrome. Male C57BL/6J mice were fed a high fat/Western-style (HFW; 60% energy as fat and lower levels of calcium, vitamin D3, folic acid, choline bitartrate, and fiber) or HFW with EGCG (HFWE; HFW with 0.32% EGCG) diet for 17 wk. As a comparison, two other groups of mice fed a low-fat (LF; 10% energy as fat) and high-fat (HF; 60% energy as fat) were also included. HFW group developed more body weight gain and severe symptoms of metabolic syndrome than the HF group. EGCG treatment significantly reduced body weight gain associated with increased fecal lipids, and decreased blood glucose and alanine aminotransferase (ALT) levels compared to the HFW group. Fatty liver incidence, liver damage and liver triglyceride levels were also decreased by EGCG treatment. Moreover, EGCG treatment attenuated insulin resistance and levels of plasma cholesterol, monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP), interlukin-6 (IL-6), and granulocyte colony-stimulating factor (G-CSF). Our results demonstrate that the HFW diet produces more severe symptoms of metabolic syndrome than the HF diet and EGCG treatment can alleviate these symptoms and body fat accumulation. The beneficial effects of EGCG are associated with decreased lipid absorption and reduced levels of inflammatory cytokines.
ABSTRACT:The cytochrome P450 (P450) CYP2E1 enzyme metabolizes and activates a wide array of toxicological substrates, including alcohols, the widely used analgesic acetaminophen, acetone, benzene, halothane, and carcinogens such as azoxymethane and dimethylhydrazine. Most studies on the biochemical and pharmacological actions of CYP2E1 are derived from studies with rodents, rabbits, and cultured hepatocytes; therefore, extrapolation of the results to humans can be difficult. Creating "humanized" mice by introducing the human CYP2E1 gene into Cyp2e1-null mice can circumvent this disadvantage. A transgenic mouse line expressing the human CYP2E1 gene was established. Western blot and high-performance liquid chromatography/mass spectrometry analyses revealed human CYP2E1 protein expression and enzymatic activity in the liver of CYP2E1-humanized mice. Treatment of mice with the CYP2E1 inducer acetone demonstrated that human CYP2E1 was inducible in this transgenic model. The response to the CYP2E1 substrate acetaminophen was explored in the CYP2E1-humanized mice. Hepatotoxicity, resulting from the CYP2E1-mediated activation of acetaminophen, was demonstrated in the livers of CYP2E1-humanized mice by elevated serum alanine aminotransferase levels, increased hepatocyte necrosis, and decreased P450 levels. These data establish that in this humanized mouse model, human CYP2E1 is functional and can metabolize and activate different CYP2E1 substrates such as chlorzoxazone, p-nitrophenol, acetaminophen, and acetone. CYP2E1-humanized mice will be of great value for delineating the role of human CYP2E1 in ethanol-induced oxidative stress and alcoholic liver damage. They will also function as an important in vivo tool for predicting drug metabolism and disposition and drug-drug interactions of chemicals that are substrates for human CYP2E1.The cytochrome P450 (P450) family of enzymes play an important role in the metabolic activation of chemicals to cytotoxic or carcinogenic products, as well as the oxidation of therapeutically used drugs and endogenous steroids (Guengerich et al., 1991;Lieber, 1997). In particular, CYP2E1 is of interest since it metabolizes and activates a wide array of toxicologically important substrates, including acetaminophen (APAP), acetone, benzene, halothane, ethanol, carbon tetrachloride, and carcinogens such as the low molecular weight nitrosamines (Kessova and Cederbaum, 2003). CYP2E1 metabolizes a small number of clinically employed drugs such as disulfiram and the muscle relaxant chlorzoxazone, which undergoes 6-hydroxylation (Peter et al., 1990;Carriere et al., 1993). CYP2E1 also oxidizes a significant number of important occupational and industrial chemicals, including alkanes, alkenes, solvents, and aromatic and halogenated hydrocarbons (Bolt et al., 2003).APAP is a widely used analgesic and is considered safe at therapeutic doses; hepatotoxicity occurs at low frequency. Metabolism of APAP was shown to be primarily contributed by CYP2E1 (Raucy et al., 1989;Snawder et al., 1994a;Kostrubsky et al...
ABSTRACT:The most common clinical implication for the activation of the human pregnane X receptor (PXR) is the occurrence of drug-drug interactions mediated by up-regulated cytochromes P450 3A (CYP3A) isozymes. Typical rodent models do not predict drug-drug interactions mediated by human PXR because of species differences in response to PXR ligands. In the current study, a PXRhumanized mouse model was generated by bacterial artificial chromosome (BAC) transgenesis in Pxr-null mice using a BAC clone containing the complete human PXR gene and 5-and 3-flanking sequences. In this PXR-humanized mouse model, PXR is selectively expressed in the liver and intestine, the same tissue expression pattern as CYP3A. Treatment of PXR-humanized mice with the PXR ligands mimicked the human response, since both hepatic and intestinal CYP3As were strongly induced by rifampicin, a human-specific PXR ligand, but not by pregnenolone 16␣-carbonitrile, a rodent-specific PXR ligand. In rifampicin-pretreated PXRhumanized mice, an ϳ60% decrease was observed for both the maximal midazolam serum concentration (C max ) and the area under the concentration-time curve, as a result of a 3-fold increase in midazolam 1-hydroxylation. These results illustrate the potential utility of the PXR-humanized mice in the investigation of drug-drug interactions mediated by CYP3A and suggest that the PXR-humanized mouse model would be an appropriate in vivo tool for evaluation of the overall pharmacokinetic consequences of human PXR activation by drugs.
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