Aloin promotes cell apoptosis by targeting HMGB1-TLR4-ERK axis in human melanoma cells

Aloin (ALO) is the major anthraquinone glycoside purified from the Aloe species. It is well known for its anti-tumor effects. However, the protective effects of ALO in melanoma cancer and underlying molecular mechanism remain unclear. High-mobility group protein B1 (HMGB1) is an intracellular protein, which has closely association with cell survival, proliferation and metastasis in various cancers. In this study, we explored the effect of ALO on cell survival and apoptosis by targeting HMGB1 signal pathway. We confirmed that ALO exerts a strong effect on promoting cell apoptosis of melanoma cells in vitro. Furthermore, HMGB1 release was significantly inhibited in melanoma cancer cells treated with ALO. Knockdown of HMGB1 could enhance melanoma cell death that is induced by ALO treatment. Moreover, HMGB1 facilitated ALO mediated melanoma cell apoptosis by binding to its receptor, Toll-like receptor 4 and activating extracellular regulated protein kinases (ERK) signal pathway. Altogether, our study demonstrated that ALO plays an important role in promoting apoptosis of melanoma cells by inhibiting HMGB1 release and activation of downstream ERK signal pathway

Pharmacokinetic Interaction between Magnolol and Piperine in Rats

Purpose: To investigate the pharmacokinetic mechanism of interaction between magnolol and piperine when co-administered to rats.Methods: The rats were divided into five groups as follows: magnolol group (625 mg/kg); low dose of piperine group (20 mg/kg); high dose of piperine group (40 mg/kg); low dose of piperine + magnolol group; or high dose of piperine + magnolol group. Plasma samples were collected at regular time intervals after administration of a single dose of magnolol (625 mg/kg, p.o.) alone or piperine (20 or 40 mg/kg, p.o.) in the presence or absence of magnolol (625 mg/kg, p.o.). The concentrations of magnolol and piperine in plasma were measured by a validated high performance liquid chromatography (HPLC) method.Results: Compared with control, the groups given magnolol alone, concomitant administration of piperine and magnolol resulted in significant decrease (p < 0.01) in the AUC and Cmax of magnolol. Interestingly, compared with administration of piperine alone (20 mg/kg), co-administration with magnolol did not significantly (p > 0.05) alter the pharmacokinetic parameters of piperine. However, at high dose (40 mg/kg) of piperine, Cmax of piperine significantly decreased from 4.30 ± 1.47 to 2.50 ± 0.78 μg/mL (p < 0.05).Conclusion: Co-administration of magnolol and piperine decreases plasma concentration of either drug in rats, suggesting that concurrent use of magnolol with piperine or piperine-containing diets would require close monitoring for potential interactions.Keywords: Magnolol, Piperine, Pharmacokinetic interaction, Co administratio

Epigenetic modification and inheritance in sexual reversal of fish

Environmental sex determination (ESD) occurs in divergent, phylogenetically unrelated taxa, and in some species, co-occurs with genetic sex determination (GSD) mechanisms. Although epigenetic regulation in response to environmental effects has long been proposed to be associated with ESD, a systemic analysis on epigenetic regulation of ESD is still lacking. Using half-smooth tongue sole (Cynoglossus semilaevis) as a model—a marine fish that has both ZW chromosomal GSD and temperature-dependent ESD—we investigated the role of DNA methylation in transition from GSD to ESD. Comparative analysis of the gonadal DNA methylomes of pseudomale, female, and normal male fish revealed that genes in the sex determination pathways are the major targets of substantial methylation modification during sexual reversal. Methylation modification in pseudomales is globally inherited in their ZW offspring, which can naturally develop into pseudomales without temperature incubation. Transcriptome analysis revealed that dosage compensation occurs in a restricted, methylated cytosine enriched Z chromosomal region in pseudomale testes, achieving equal expression level in normal male testes. In contrast, female-specific W chromosomal genes are suppressed in pseudomales by methylation regulation. We conclude that epigenetic regulation plays multiple crucial roles in sexual reversal of tongue sole fish. We also offer the first clues on the mechanisms behind gene dosage balancing in an organism that undergoes sexual reversal. Finally, we suggest a causal link between the bias sex chromosome assortment in the offspring of a pseudomale family and the transgenerational epigenetic inheritance of sexual reversal in tongue sole fish

Superconductivity and Charge-density-wave-like Transition in Th2Cu4As5

We report the synthesis, crystal structure, and physical properties of a novel ternary compound, Th$_2$Cu$_4$As$_5$. The material crystallizes in a tetragonal structure with lattice parameters $a=4.0716(1)$ {\AA} and $c=24.8131(4)$ {\AA}. Its structure can be described as an alternating stacking of fluorite-type Th$_2$As$_2$ layers with antifluorite-type double-layered Cu$_4$As$_3$ slabs. The measurement of electrical resistivity, magnetic susceptibility and specific heat reveals that Th$_2$Cu$_4$As$_5$ undergoes bulk superconducting transition at 4.2 K. Moreover, all these physical quantities exhibit anomalies at 48 K, where the Hall coefficient change the sign. These findings suggest a charge-density-wave-like (CDW) transition, making Th$_2$Cu$_4$As$_5$ a rare example for studying the interplay between CDW and superconductivity.Comment: 11 pages, 6 figures, and 1 tabl

White Pepper and Piperine Have Different Effects on Pharmacokinetics of Puerarin in Rats

This study attempted to explore the effects of white pepper and its major component piperine on puerarin administered to rats. Pharmacokinetic parameters of puerarin in rats were determined by oral administration (400 mg/kg) or intravenous injection (40 mg/kg) of puerarin, pretreated with or without white pepper and piperine given orally. Compared to the control group given oral puerarin only, the combined use of piperine (10 or 20 mg/kg) increased the Cmax of puerarin by 1.30-fold or 1.64-fold and the AUC0–∞ by 133% or 157%, respectively. In contrast, coadministration of white pepper (125 or 250 mg/kg) decreased oral absorption of puerarin to 83% or 74%, respectively. On the other hand, pretreatment with piperine orally did not alter the intravenous pharmacokinetics of puerarin, while the AUC of puerarin after intravenous administration was increased by pretreatment with white pepper. The results indicate that pretreatment with piperine or pepper exerts different effects on pharmacokinetics of puerarin administrated via intragastric and intravenous routes. Therefore, it is suggested that the combined application of piperine or white pepper with puerarin should be carefully monitored for potential diet-drug interactions

Targeting of the Human Coagulation Factor IX Gene at rDNA Locus of Human Embryonic Stem Cells

BACKGROUND: Genetic modification is a prerequisite to realizing the full potential of human embryonic stem cells (hESCs) in human genetic research and regenerative medicine. Unfortunately, the random integration methods that have been the primary techniques used keep creating problems, and the primary alternative method, gene targeting, has been effective in manipulating mouse embryonic stem cells (mESCs) but poorly in hESCs. METHODOLOGY/PRINCIPAL FINDINGS: Human ribosomal DNA (rDNA) repeats are clustered on the short arm of acrocentric chromosomes. They consist of approximately 400 copies of the 45S pre-RNA (rRNA) gene per haploid. In the present study, we targeted a physiological gene, human coagulation factor IX, into the rDNA locus of hESCs via homologous recombination. The relative gene targeting efficiency (>50%) and homologous recombination frequency (>10(-5)) were more than 10-fold higher than those of loci targeted in previous reports. Meanwhile, the targeted clones retained both a normal karyotype and the main characteristics of ES cells. The transgene was found to be stably and ectopically expressed in targeted hESCs. CONCLUSION/SIGNIFICANCE: This is the first targeting of a human physiological gene at a defined locus on the hESC genome. Our findings indicate that the rDNA locus may serve as an ideal harbor for transgenes in hESCs

Causative agent distribution and antibiotic therapy assessment among adult patients with community acquired pneumonia in Chinese urban population

<p>Abstract</p> <p>Background</p> <p>Knowledge of predominant microbial patterns in community-acquired pneumonia (CAP) constitutes the basis for initial decisions about empirical antimicrobial treatment, so a prospective study was performed during 2003–2004 among CAP of adult Chinese urban populations.</p> <p>Methods</p> <p>Qualified patients were enrolled and screened for bacterial, atypical, and viral pathogens by sputum and/or blood culturing, and by antibody seroconversion test. Antibiotic treatment and patient outcome were also assessed.</p> <p>Results</p> <p>Non-viral pathogens were found in 324/610 (53.1%) patients among whom <it>M. pneumoniae </it>was the most prevalent (126/610, 20.7%). Atypical pathogens were identified in 62/195 (31.8%) patients carrying bacterial pathogens. Respiratory viruses were identified in 35 (19%) of 184 randomly selected patients with adenovirus being the most common (16/184, 8.7%). The nonsusceptibility of <it>S. pneumoniae </it>to penicillin and azithromycin was 22.2% (Resistance (R): 3.2%, Intermediate (I): 19.0%) and 79.4% (R: 79.4%, I: 0%), respectively. Of patients (312) from whom causative pathogens were identified and antibiotic treatments were recorded, clinical cure rate with β-lactam antibiotics alone and with combination of a β-lactam plus a macrolide or with fluoroquinolones was 63.7% (79/124) and 67%(126/188), respectively. For patients having mixed <it>M. pneumoniae </it>and/or <it>C. pneumoniae </it>infections, a better cure rate was observed with regimens that are active against atypical pathogens (e.g. a β-lactam plus a macrolide, or a fluoroquinolone) than with β-lactam alone (75.8% vs. 42.9%, <it>p </it>= 0.045).</p> <p>Conclusion</p> <p>In Chinese adult CAP patients, <it>M. pneumoniae </it>was the most prevalent with mixed infections containing atypical pathogens being frequently observed. With <it>S. pneumoniae</it>, the prevalence of macrolide resistance was high and penicillin resistance low compared with data reported in other regions.</p

Does or did the supernova remnant Cassiopeia A operate as a PeVatron?

For decades, supernova remnants (SNRs) have been considered the prime sources of Galactic Cosmic rays (CRs). But whether SNRs can accelerate CR protons to PeV energies and thus dominate CR flux up to the knee is currently under intensive theoretical and phenomenological debate. The direct test of the ability of SNRs to operate as CR PeVatrons can be provided by ultrahigh-energy (UHE; $E_\gamma \geq 100$~TeV) $\gamma$-rays. In this context, the historical SNR Cassiopeia A (Cas A) is considered one of the most promising target for UHE observations. This paper presents the observation of Cas A and its vicinity by the LHAASO KM2A detector. The exceptional sensitivity of LHAASO KM2A in the UHE band, combined with the young age of Cas A, enabled us to derive stringent model-independent limits on the energy budget of UHE protons and nuclei accelerated by Cas A at any epoch after the explosion. The results challenge the prevailing paradigm that Cas A-type SNRs are major suppliers of PeV CRs in the Milky Way.Comment: 11 pages, 3 figures, Accepted by the APJ