Chemical upcycling of polyethylene, polypropylene, and mixtures to high-value surfactants.

Conversion of plastic wastes to fatty acids is an attractive means to supplement the sourcing of these high-value, high-volume chemicals. We report a method for transforming polyethylene (PE) and polypropylene (PP) at ~80% conversion to fatty acids with number-average molar masses of up to ~700 and 670 daltons, respectively. The process is applicable to municipal PE and PP wastes and their mixtures. Temperature-gradient thermolysis is the key to controllably degrading PE and PP into waxes and inhibiting the production of small molecules. The waxes are upcycled to fatty acids by oxidation over manganese stearate and subsequent processing. PP ꞵ-scission produces more olefin wax and yields higher acid-number fatty acids than does PE ꞵ-scission. We further convert the fatty acids to high-value, large-market-volume surfactants. Industrial-scale technoeconomic analysis suggests economic viability without the need for subsidies.

Evaluation potential effects of Picroside II on cytochrome P450 enzymes in vitro and in vivo.

ETHNOPHARMACOLOGY RELEVANCE: Picrorhiza scrophulariiflora Pennell, a well-known Chinese herb, has been traditionally utilized as an antioxidant and anti-inflammatory agent. One of its main bioactive components is Picroside II, a glycoside derivative. However, there is limited information on the effects of Picroside II on the activity of cytochrome P450 (CYP) enzymes nor on potential herb-drug interactions are rarely studied. AIM OF THE STUDY: The purpose of the study was to investigate the effects of Picroside II on the activity of cytochrome P450 enzymes in vitro and in vivo and its potential herb-drug interactions. MATERIALS AND METHODS: Specific probe substrates were employed to assess the effect of Picroside II on the activity of P450 enzymes. The inhibitory effects of Picroside II on CYP enzymes were assayed both in human (i.e., 1A, 2C9, 2C19, 2D6, 2E1, and 3A) and rat (i.e., 1A, 2C6/11, 2D1, 2E1, and 3A) liver microsomes in vitro. The inductive effects were investigated in rats following oral gavage of 2.5 mg/kg and 10 mg/kg Picroside II. A specific Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) method was developed to determine the formation of specific metabolites. RESULTS: Enzyme inhibition results showed that Picroside II (0.5-200 µM) had no evident inhibitory effects on rat and human liver microsomes in vitro. Interestingly, the administration of multiple doses of 10 mg/kg Picroside II inhibited the activity of CYP2C6/11 by reducing the rate of formation of 4-hydroxydiclofenac and 4-hydroxymephenytoin, while Picroside II at 2.5 mg/kg increased the activity of CYP3A by promoting the formation of 1-hydroxymidazolam and 6-hydroxychlorzoxazone in rats. In addition, there were negligible effects on CYP1A, CYP2D1, and CYP2E1 in rats. CONCLUSIONS: The results indicated that Picroside II modulated the activities of CYP enzymes and was involved in CYP2C and CYP3A medicated herb-drug interactions. Therefore, careful monitoring is necessary when Picroside II is used in combination with related conventional drugs.

Oxytocin promotes prefrontal population activity via the PVN-PFC pathway to regulate pain.

Neurons in the prefrontal cortex (PFC) can provide top-down regulation of sensory-affective experiences such as pain. Bottom-up modulation of sensory coding in the PFC, however, remains poorly understood. Here, we examined how oxytocin (OT) signaling from the hypothalamus regulates nociceptive coding in the PFC. In vivo time-lapse endoscopic calcium imaging in freely behaving rats showed that OT selectively enhanced population activity in the prelimbic PFC in response to nociceptive inputs. This population response resulted from the reduction of evoked GABAergic inhibition and manifested as elevated functional connectivity involving pain-responsive neurons. Direct inputs from OT-releasing neurons in the paraventricular nucleus (PVN) of the hypothalamus are crucial to maintaining this prefrontal nociceptive response. Activation of the prelimbic PFC by OT or direct optogenetic stimulation of oxytocinergic PVN projections reduced acute and chronic pain. These results suggest that oxytocinergic signaling in the PVN-PFC circuit constitutes a key mechanism to regulate cortical sensory processing.

Characterization of Preclinical Pharmacokinetic Properties and Prediction of Human PK Using a Physiologically Based Pharmacokinetic Model for a Novel Anti-Arrhythmic Agent Sulcardine Sulfate.

PURPOSE: Sulcardine sulfate (Sul) is a novel antiarrhythmic agent with promising pharmacological properties, which is currently being evaluated in several clinical trials as an oral formulation. To meet the medication needs of patients with acute conditions, the injection formulation of Sul has been developed. The objective of this study was to systemically investigate the pharmacokinetic profiles of Sul after intravenous infusion. METHODS: This research included the plasma protein binding and metabolic stability studies in vitro, plasma pharmacokinetics, biodistribution, excretion studies in animals, and the prediction of the clinical PK of Sul injection using a physiologically based pharmacokinetics (PBPK) model. RESULTS: The metabolic stability was similarly in dogs and humans but lower in rats. The plasma protein binding rates showed a concentration-dependent manner and species differences. The pharmacokinetic behavior after intravenous administration was linear in rats within the dose range of 30-90 mg/kg, but nonlinear in dogs within 30-60 mg/kg. Sul could be rapidly and widely distributed in multiple tissues after intravenous administration. About 12% of the parent compound were excreted via the urine and only a small fraction via bile and feces,and eight metabolites were found and identified in the rat excretion. The PBPK models were developed and simulated the observed PK date well in both rats and dogs. The PBPK model refined with human data predicted the PK characteristics of the first intravenous infusion of Sul in human. CONCLUSIONS: Our study systematically explored the pharmacokinetic characteristics of Sul and successfully developed the PBPK model to predict of its clinical PK.

Salvianolic acid B improves autophagic dysfunction and decreases the apoptosis of cholesterol crystal­induced macrophages via inhibiting the Akt/mTOR signaling pathway.

Progressive macrophage dysfunction and apoptosis are some of the major events that occur during atherogenesis. To further investigate the intrinsic association between atherosclerosis (AS) and macrophage apoptosis and autophagy, cholesterol crystals (CHCs) were used to stimulate RAW264.7 macrophages to establish a macrophage model of advanced AS. Cells in the CHC group were treated with salvianolic acid B (Sal B) to evaluate its protective effects and reveal its underlying molecular mechanism. The results demonstrated that treatments with Sal B significantly improved autophagy dysfunction and reduced the apoptotic rate of CHC­induced macrophages. Furthermore, Sal B significantly attenuated CHC­induced release of proinflammatory factors (TNF­α and IL­6) by macrophages. Treatment of macrophages with a specific inhibitor of autophagy (3­methyladenine) significantly reversed Sal B­mediated effects on autophagy, suggesting that Sal B­induced autophagy may display a protective effect in CHC­induced macrophages. Furthermore, pretreatment of CHC­induced macrophages with insulin significantly decreased Sal B­induced autophagy, indicating that the Akt/mTOR signaling pathway may serve as a critical mediator in regulating Sal B­mediated cell death. Taken together, the present study demonstrated that Sal B improved autophagic dysfunction and reduced the apoptosis of CHC­induced macrophages via inhibiting the Akt/mTOR signaling pathway.

Metabolomic characteristics of hepatotoxicity in rats induced by silica nanoparticles.

Silica nanoparticles (SiNPs) have become one of the most widely studied nanoparticles in nanotechnology for environmental health and safety. Although many studies have devoted to evaluating the hepatotoxicity of SiNPs, it is currently impossible to predict the extent of liver lipid metabolism disorder by identifying changes in metabolites. In the present study, 40 male Sprague-Dawley (SD) rats were randomly divided into control group and 3 groups with different doses (1.8 mg/kg body weight (bw), 5.4 mg/kg bw, 16.2 mg/kg bw), receiving intratracheal instillation of SiNPs. Liver tissue was taken for lipid level analysis, and serum was used for blood biochemical analysis. Then, the metabolites changes of liver tissue in rats were systematically analyzed using 1H nuclear magnetic resonance (1H NMR) techniques in combination with multivariate statistical analysis. SiNPs induced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride (TG) elevation in treated groups; TG and low-density lipoprotein cholesterol (LDL-C) were significantly higher in SiNPs-treated groups of high-dose, however high-density lipoprotein cholesterol (HDL-C) showed a declining trend in liver tissue. The orthogonal partial least squares discriminant analysis (OPLS-DA) scores plots revealed different metabolic profiles between control and high-dose group (Q2 =0.495, R2Y=0.802, p = 0.037), and a total of 11 differential metabolites. Pathway analysis indicated that SiNPs treatment mainly affected 10 metabolic pathways including purine metabolism, glucose-alanine cycle and metabolism of various amino acids such as glutamate, cysteine and aspartate (impact value>0.1, false discovery rate (FDR)< 0.05). The result indicated that exposure to SiNPs caused liver lipid metabolism disorder in rats, the biochemical criterions related to lipid metabolism changed significantly. The obviously changed metabolomics in SiNPs-treated rats mostly occurred in amino acids, organic acids and nucleosides.

Cancer Cell-Erythrocyte Hybrid Membrane Coated Gold Nanocages for Near Infrared Light-Activated Photothermal/Radio/Chemotherapy of Breast Cancer.

BACKGROUND: The combination of radiotherapy (RT) and chemotherapy, as a standard treatment for breast cancer in the clinic, is unsatisfactory due to chemoradioresistance and severe side effects. METHODS AND RESULTS: To address these issues, a cancer cell-erythrocyte hybrid membrane-coated doxorubicin (DOX)-loaded gold nanocage (CM-EM-GNCs@DOX) was constructed for near-infrared light (NIR)-activated photothermal/radio/chemotherapy of breast cancer. CM-EM-GNCs@DOX inherited an excellent homologous target ability from the cancer cell membrane and an immune evasion capability from the erythrocyte membrane, together resulting in highly efficient accumulation in the tumor site with decreased clearance. Following the highly efficient uptake of CM-EM-GNCs@DOX in cancer cells, the RT efficacy was remarkably amplified due to the radiosensitization effect of CM-EM-GNCs@DOX, which reduced the needed radiotherapeutic dose. Importantly, with NIR irradiation, CM-EM-GNCs@DOX exerted a high photothermal effect, which not only ruptured CM-EM-GNCs@DOX to release DOX for precise and controllable chemotherapy, but also potentiated chemo/radiotherapy by photothermal therapy. CONCLUSION: Therefore, a highly efficient and safe combined photothermal/radio/chemotherapy approach was achieved in vitro and in vivo by CM-EM-GNCs@DOX, which provided a promising strategy for treating breast cancer.

Protective effects of salvianolic acid B against hydrogen peroxide­induced apoptosis of human umbilical vein endothelial cells and underlying mechanisms.

Salvianolic acid B (Sal B) is a water­soluble active component of Danshen and has anti­atherosclerotic effects. The present study aimed to evaluate the cytoprotective effects of Sal B against hydrogen peroxide (H2O2)­induced oxidative stress damage in human umbilical vein endothelial cells (HUVECs) and investigate the underlying mechanisms. It was revealed that Sal B protected the cells from H2O2­induced damage, as indicated by MTT results showing enhanced cell viability and by flow cytometric analysis showing reduced apoptosis of cells challenged with H2O2. Furthermore, as an underlying mechanism, the enhancement of autophagy was indicated to be accountable for the decrease in apoptosis, as Sal B caused the upregulation of light chain 3­â…¡ and Beclin­1, and downregulation of p62 under H2O2­induced oxidative stress. Finally, Sal B increased the phosphorylation of AMP kinase (AMPK) and decreased the phosphorylation of mammalian target of rapamycin (mTOR), but had no effect on the phosphorylation of AKT. In conclusion, the present study revealed that Sal B protects HUVECs from oxidative stress, at least partially by promoting autophagy via activation of the AMPK pathway and downregulation of the mTOR pathway.

Ginsenoside Rh2 improves learning and memory in mice.

A wide range of plant foods and dietary supplements are able to modify the functioning of the central nervous system. In the present study, we observed that oral administration of ginsenoside Rh2 (10 mg/mL) for 3 weeks significantly improved spatial learning and memory. Spatial memory and learning was evaluated in mice by hippocampus-dependent tasks (Morris water maze test) and immunohistochemical marker of cell genesis bromodeoxyuridine. Ginsenoside Rh2 treatment (30 days) promoted cell survival and genesis. Further, ginsenoside Rh2 treatment in enriched condition had no significant effects on cell survival compared with standard condition exposure. These results revealed that ginsenoside Rh2-mediated spatial learning and memory improvement was associated with cell genesis and survival and may be parallel to the mechanism of environmental enrichment. Therefore, ginsenoside Rh2 may have efficacy as a dietary supplement for spatial learning and memory improvement.