Preclinical Bioavailability, Tissue Distribution, and Protein Binding Studies of Erinacine A, a Bioactive Compound from Hericium erinaceus Mycelia Using Validated LC-MS/MS Method.

Erinacine A, derived from the mycelia of Hericium erinaceus, has attracted much attention due to its neuroprotective properties. However, very few studies have been conducted on the bioavailability, tissue distribution, and protein binding of erinacine A. This study aimed to investigate the bioavailability, tissue distribution, and protein binding of erinacine A in Sprague-Dawley rats. After oral administration (po) and intravenous administration (iv) of 2.381 g/kg BW of the H. erinaceus mycelia extract (equivalent to 50 mg/kg BW of erinacine A) and 5 mg/kg BW of erinacine A, respectively, the absolute bioavailability of erinacine A was estimated as 24.39%. Erinacine A was detected in brain at 1 h after oral dosing and reached the peak at 8 h. Protein binding assay showed unbound erinacine A fractions in brain to blood ratio is close to unity, supporting passive diffusion as the dominating transport. Feces was the major route for the elimination of erinacine A. This study is the first to show that erinacine A can penetrate the blood-brain barrier of rats by the means of passive diffusion and thus support the development of H. erinaceus mycelia for the improvement of neurohealth.

Single Mesopores with High Surface Charges as Ultrahigh Performance Osmotic Power Generators.

Numerous studies on osmotic power generators with nanoscale pores are conducted. However, their performance output is limited because of the finite osmotic current and conductance from such tiny pores. Here, a proof-of-concept study demonstrating that the rectified mesopore (sub-micrometer-scale pore) with high surface charges can be applied in osmotic energy conversion is reported. A single conical mesopore of ≈405 nm in tip diameter, which can reach an osmotic conductance as high as 0.284 µS (corresponding to a current of 27.5 nA and voltage of 97 mV), enables a record-high power of 667 pW under a 1000-fold salinity gradient, more than doubling all of the state-of-the-art single-pore osmotic power generators reported. This work extends the knowledge of osmotic energy with solid-state pores from nanoscale to mesoscale and opens up a promising avenue toward ultrahigh performance osmotic power.

Decoding the evolutionary response to prostate cancer therapy by plasma genome sequencing.

BACKGROUND: Investigating genome evolution in response to therapy is difficult in human tissue samples. To address this challenge, we develop an unbiased whole-genome plasma DNA sequencing approach that concurrently measures genomic copy number and exome mutations from archival cryostored plasma samples. This approach is applied to study longitudinal blood plasma samples from prostate cancer patients, where longitudinal tissue biopsies from the bone and other metastatic sites have been challenging to collect. RESULTS: A molecular characterization of archival plasma DNA from 233 patients and genomic profiling of 101 patients identifies clinical correlations of aneuploid plasma DNA profiles with poor survival, increased plasma DNA concentrations, and lower plasma DNA size distributions. Deep-exome sequencing and genomic copy number profiling are performed on 23 patients, including 9 patients with matched metastatic tissues and 12 patients with serial plasma samples. These data show a high concordance in genomic alterations between the plasma DNA and metastatic tissue samples, suggesting the plasma DNA is highly representative of the tissue alterations. Longitudinal sequencing of 12 patients with 2-5 serial plasma samples reveals clonal dynamics and genome evolution in response to hormonal and chemotherapy. By performing an integrated evolutionary analysis, minor subclones are identified in 9 patients that expanded in response to therapy and harbored mutations associated with resistance. CONCLUSIONS: This study provides an unbiased evolutionary approach to non-invasively delineate clonal dynamics and identify clones with mutations associated with resistance in prostate cancer.

Thermal Dependence of the Mesoscale Ionic Diode: Modeling and Experimental Verification.

Mesoscale ionic diodes, which can rectify ionic current at conditions at which their pore size is larger than 100 nm and thus over 100 times larger than the Debye length, have been recently discovered with potential applications in ionic circuits as well as osmotic power generation. Compared with the conventional nanoscale ionic diodes, the mesoscale ionic diodes can offer much higher conductance, ionic current resolution, and power generated. However, the thermal response, which has been proven playing a crucial role in nanofluidic devices, of the mesoscale ionic diode remains significantly unexplored. Here, we report the thermal dependence of the mesoscale ionic diode comprising a conical pore with a tip opening diameter of ∼400 nm. To capture its underlying physics more accurately, our model takes into account the practical equilibrium chemistry reaction of functional carboxyl groups on the pore surface. Modeling results predict that in the mesoscale ionic diode prepared currents increase but the performance decreases with the increase of temperature, which is consistent with our experimental data and indicates that the ion transport properties apparently depend on the presence of highly mobile hydroxide ions. The results gathered can provide important guidance for the design of new mesoscale ionic diodes, enriching their applications in thermoelectric power and thermoresponsive chemical sensors.

The Efficacy of Metacognitive Training for Delusions in Patients With Schizophrenia: A Meta-Analysis of Randomized Controlled Trials Informs Evidence-Based Practice.

BACKGROUND: Metacognitive training (MCT) was developed in 2007 and widely used to modify the delusions for patient with schizophrenia. However, its effectiveness remains unclear. AIMS: To investigate the overall effectiveness of MCT for delusion in schizophrenia patients from 2007 to 2016, and to investigate the variables (intervention approach, intervention dose, and participant factors) of an MCT study that could influence the effect size. METHODS: Parallel-arm design of MCT for delusions published from 2007 to 2016 were collected and then cross-referenced using these keywords: delusion (psychosis or psychotic or schizophrenia) and metacognitive (training or therapy or intervention). The quality of the studies was evaluated and the effect size and the moderating variables of MCT on delusion were determined. RESULTS: A total of 11 studies on the effect of MCT for delusion were investigated. The MCT had a moderate immediate postintervention effect (g = -0.38) and a lasting effect after 6 months (g = -0.35). In terms of immediate effect, moderating variables with significant differences between them were (a) individual approach versus group-based approach and mixed approach, and (b) eastern country versus western country. LINKING EVIDENCE TO ACTION: MCT could be used as a valuable nonpharmacologic intervention to reduce delusions in clinical settings. The individual modularized MCT approach had a beneficial effect and is recommended to healthcare professionals as an application for patients with schizophrenia or delusional disorder.

Punctuated copy number evolution and clonal stasis in triple-negative breast cancer.

Aneuploidy is a hallmark of breast cancer; however, knowledge of how these complex genomic rearrangements evolve during tumorigenesis is limited. In this study, we developed a highly multiplexed single-nucleus sequencing method to investigate copy number evolution in patients with triple-negative breast cancer. We sequenced 1,000 single cells from tumors in 12 patients and identified 1-3 major clonal subpopulations in each tumor that shared a common evolutionary lineage. For each tumor, we also identified a minor subpopulation of non-clonal cells that were classified as metastable, pseudodiploid or chromazemic. Phylogenetic analysis and mathematical modeling suggest that these data are unlikely to be explained by the gradual accumulation of copy number events over time. In contrast, our data challenge the paradigm of gradual evolution, showing that the majority of copy number aberrations are acquired at the earliest stages of tumor evolution, in short punctuated bursts, followed by stable clonal expansions that form the tumor mass.

Development of chitosan/heparin nanoparticle-encapsulated cytolethal distending toxin for gastric cancer therapy.

AIM: The aim of this work was to develop pH-responsive nanoparticles encapsulating CdtB and to demonstrate that these particles represent a potential therapeutic agent for gastric cancer. MATERIALS & METHODS: Chitosan/heparin nanoparticle-encapsulated CdtB was prepared and the delivery efficiency was monitored by confocal laser scanning microscopy. The molecular basis of the nanoparticle-encapsulated CdtB-mediated p53 activation pathway was explored by immunoblot analysis. Antitumoral activities were investigated by analyzing the cell cycle and apoptosis. RESULTS: Chitosan/heparin nanoparticle-encapsulated CdtB preferentially inhibited the proliferation of cells derived from gastric cancer, but not in primary gastric epithelial cells. Treatment of cells with nanoparticle-encapsulated CdtB enhanced cell-cycle arrest at G2/M, followed by apoptosis. Moreover, our data showed that the mechanism for nanoparticle-encapsulated CdtB-induced cell death was mediated by ATM-dependent DNA damage checkpoint responses. CONCLUSION: These findings indicate that chitosan/heparin nanoparticle-encapsulated CdtB could represent a new CdtB delivery strategy for the treatment of gastric cancer.

Metabolic protein patterns and monascorubrin production revealed through proteomic approach for Monascus pilosus treated with cycloheximide.

Monascus species have the unique ability to economically produce many secondary metabolites. However, most metabolic regulation processes in the production of secondary metabolites in Monascus remain unclear. We found that the translational inhibitor cycloheximide induced different expression patterns between the monascorubrin pigment production and the growth in Monascus pilosus. Here, we used the proteomic approach of two-dimensional gel electrophoresis, matrix-assisted laser desorption ionization time-of-flight/time-of-flight liquid chromatography-mass spectrometry (MALDI-TOF/TOF LC-MS), and tandem mass spectrometry (MS/MS) to identify the intracellular and mitochondrial proteins of M. pilosus between the cycloheximide treatment and the control. These results revealed that the cycloheximide-induced down-regulated proteins were involved in transcriptional regulation, peptide synthesis, and other metabolic processes, such as methylation of secondary metabolites. In contrast, the energy-related proteins, such as the transcriptional regulator rosAr and 1,4-alpha-glucan branching enzyme, were up-regulated as compared to the control.

Novel borane reduction of ether-protected aromatic lactams.

Borane reduction of ether-protected aromatic lactams produces 1-alkyl-1,2,3,4-tetrahydroquinolines (5 and 6) in excellent yields. This reaction provides a novel one-pot tandem process for reduction of amide group and N-protected groups. Experimental results demonstrate that the reaction proceeds through two consecutive elimination and reductions via two C-O bond cleavages to form the foresaid products.