Compatibility of ingredients of Danshen (Radix Salviae Miltiorrhizae) and Honghua (Flos Carthami) and their protective effects on cerebral ischemia-reperfusion injury in rats.

Danshen (Radix Salviae Miltiorrhizae) and Honghua (Flos Carthami) (Danhong) are two drugs commonly prescribed together, which are often used in the treatment of cerebrovascular diseases in China. Due to the complexity of the ingredients of Danhong, the present study focused on performing the orthogonal compatibility method on the primary effective molecules of this drug: Tanshinol, salvianolic acid A, salvianolic acid B and hydroxysafflor yellow A. These four molecules were studied to determine their protective effects and to screen for the most compatible ingredients to improve cerebral ischemia-reperfusion injury (IR) in rats. Focal middle cerebral artery occlusion was performed to establish the cerebral IR model in rats. Male Sprague-Dawley rats were randomly divided into sham operation group, IR group and nine orthogonal administration groups with different ratios of Danhong effective ingredients and Danhong injection group. Neurological deficit score and cerebral infarction volume were measured postoperatively. Morphological pathological alterations were observed via H&E staining. Bcl-2 and Bax were quantified using ELISA. Immunohistochemistry was conducted to analyze the expression of caspase-3 in the hippocampus. The expression levels of cytochrome c, apoptotic peptidase activating factor 1 (apaf-1), caspase-9, caspase-3 and p53 mRNA in the hippocampus were assessed via reverse transcription-quantitative PCR. The results demonstrated that different compatibility groups significantly reduced the neurological function score and decreased the volume of cerebral infarct compared with the IR group. These groups were also indicated to improve the pathological damage to the brain tissue. In addition, certain compatibility groups significantly decreased the number of caspase-3 positive cells in the hippocampus and the expression levels of cytochrome c, apaf-1, caspase-9, caspase-3 and p53 mRNA in the brain tissue. Orthogonal group 4 (30 mg/kg tanshinol; 2.5 mg/kg salvianolic acid A; 16 mg/kg salvianolic acid B; 8 mg/kg hydroxysafflor yellow A) was indicated to be the most effective. The four effective ingredients of Danhong exhibited a protective effect on rats with cerebral IR injury, potentially through the inhibition of apoptosis via the downregulation of key targets upstream of the caspase-3 pathway. In addition, the present study provided novel insights for the continued study of the drug compatibility rules of TCM.

The recycling endosome protein Rab25 coordinates collective cell movements in the zebrafish surface epithelium.

In emerging epithelial tissues, cells undergo dramatic rearrangements to promote tissue shape changes. Dividing cells remain interconnected via transient cytokinetic bridges. Bridges are cleaved during abscission and currently, the consequences of disrupting abscission in developing epithelia are not well understood. We show that the Rab GTPase Rab25 localizes near cytokinetic midbodies and likely coordinates abscission through endomembrane trafficking in the epithelium of the zebrafish gastrula during epiboly. In maternal-zygotic Rab25a and Rab25b mutant embryos, morphogenic activity tears open persistent apical cytokinetic bridges that failed to undergo timely abscission. Cytokinesis defects result in anisotropic cell morphologies that are associated with a reduction of contractile actomyosin networks. This slows cell rearrangements and alters the viscoelastic responses of the tissue, all of which likely contribute to delayed epiboly. We present a model in which Rab25 trafficking coordinates cytokinetic bridge abscission and cortical actin density, impacting local cell shape changes and tissue-scale forces.

Pharmacokinetic-Pharmacodynamic Modeling of the Antioxidant Activity of Quzhou Fructus Aurantii Decoction in a Rat Model of Hyperlipidemia.

BACKGROUND: Quzhou Fructus Aurantii (QFA) is an herb that is commonly used to alleviate inflammation in individuals dealing with obesity.To date, however, no systematic pharmacokinetic (PK) or pharmacodynamic (PD) analyses of the clinical efficacy of QFA under hyperlipemia-associated oxidative stress conditions have been conducted. The present study, was therefore designed to construct a PK-PD model for this herb, with the goal of linking QFA PK profiles to key therapeutic outlines to guide the therapeutic use of this herb in clinical settings. METHODS: Rats were fed a high-fat diet in order to establish a model of hyperlipidemia, after which they were randomized into a normal control group (NCG), a normal treatment group (NTG), a model control group (MCG), and a model treated group (MTG) (n = 6 each). QAF decoction was used to treat rats in the NTG and MTG groups (25 g/kg), while equivalent volumes of physiological saline were administered to rats in the NCG and MCG groups. Plasma samples were collected from the mandibular vein for animals at appropriate time points and analyzed via high-performance liquid chromatography (HPLC). We evaluated PK properties for three QAF components and compared these dynamics between the NTG and MTG groups, while also measuring levels of lipid peroxidation (LPO) in the plasma of rats in all four treatment groups. We then constructed a PK-PD model based upon plasma neohesperidin, luteolin, and nobiletin concentrations and LPO levels using a three-compartment PK model together with a Sigmoid Emax PD model. This model thereby enabled us to assess the antioxidative impact of neohesperidin, luteolin, and nobiletin on hyperlipidemia in rats. RESULTS: When comparing the NTG and MTG groups, we detected significant differences in the following parameters pertaining to neohesperidin, luteolin, and nobiletin:t1/2ß, V1, t1/2γ, CL1 (p < 0.01) and AUC0-t, Tmax, Cmax (p < 0.05). Relative to NTG group rats, AUC0-t, TmaxandCmaxvalues significantly higher for MTG group rats (p < 0.01), while t1/2ß, V1, and t1/2γ values were significantly lower in MTG group rats (p < 0.01) in MTG rats. QAF decoction also exhibited excellent PD efficacy in MTG rats, with significant reductions in plasma LPO levels relative to NTG rats (p < 0.01) following treatment. This therapeutic efficacy may be attributable to the activity of neohesperidin, luteolin, and nobiletin, as LPO levels and plasma concentrations of these compounds were negatively correlated in treated rats. Based upon Akaike Information Criterion (AIC) values, we determined that neohesperidin, luteolin, and nobiletin PK processes were consistent with a three-compartment model. Together, these findings indicated that three active components in QAF decoction (neohesperidin, luteolin, and nobiletin) may exhibit antioxidant activity in vivo. CONCLUSION: Our in vivo data indicated that neohesperidin, luteolin and nobiletin components of QAF decoctions exhibit distinct PK and PD properties. Together, these findings suggest that hyperlipidemia-related oxidative stress can significantly impact QFA decoction PK and PD parameters. Our data additionally offer fundamental insights that can be used to design appropriate dosing regimens for individualized clinical QAF decoction treatment.

A Super-Stretchable Liquid Metal Foamed Elastomer for Tunable Control of Electromagnetic Waves and Thermal Transport.

It is remarkably desirable and challenging to design a stretchable conductive material with tunable electromagnetic-interference (EMI) shielding and heat transfer for applications in flexible electronics. However, the existing materials sustained a severe attenuation of performances when largely stretched. Here, a super-stretchable (800% strain) liquid metal foamed elastomer composite (LMF-EC) is reported, achieving super-high electrical (≈104 S cm-1) and thermal (17.6 W mK-1) conductivities under a large strain of 400%, which also exhibits unexpected stretching-enhanced EMI shielding effectiveness of 85 dB due to the conductive network elongation and reorientation. By varying the liquid and solid states of LMF, the stretching can enable a multifunctional reversible switch that simultaneously regulates the thermal, electrical, and electromagnetic wave transport. Novel flexible temperature control and a thermoelectric system based on LMF-EC is furthermore developed. This work is a significant step toward the development of smart electromagnetic and thermal regulator for stretchable electronics.

Ferromagnetic Liquid Metal Putty-Like Material with Transformed Shape and Reconfigurable Polarity.

It is remarkably desirable and challenging to design reconfigurable ferromagnetic materials with high electrical conductivity. This has attracted great attention due to promising applications in many fields such as emerging flexible electronics and soft robotics. However, the shape and magnetic polarity of existing ferromagnetic materials with low conductivity are both hard to be reconfigured, and the magnetization of insulative ferrofluids is easily lost once the external magnetic field is removed. A novel reconfigurable ferromagnetic liquid metal (LM) putty-like material (FM-LMP) with high electrical conductivity and transformed shape, which is prepared through homogenously mixing neodymium-iron-boron microparticles into the gallium-based LM matrix, and turning this liquid-like suspension into the solid-like putty-like material by magnetization, is reported to achieve this. The induction magnetic field of FM-LMP is mainly attributed to the magnetic alignment of the dispersed ferromagnetic microparticles, which can be conveniently demagnetized by mechanical disordering and reversibly reconfigured through microparticle realignment by applying a weak magnetic field. FM-LMP with a low fraction of microparticles can be used as printable conductive ink for paper electronics, which are further exploited for applications including magnetic switching, flexible erasable magnetic recording paper, and self-sensing paper-based soft robotics using magnetic actuation.

Pharmacokinetics of seven major active components of Mahuang decoction in rat blood and brain by LC-MS/MS coupled to microdialysis sampling.

A new highly specific high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method coupled to microdialysis sampling was developed and validated for simultaneous determination of L-ephedrine, D-pseudoephedrine, L-methyl-ephedrine, cinnamic acid, liquiritin, amygdalin, and glycyrrhizic acid both in rat blood and brain after oral administration of Mahuang decoction in this paper. An Agilent Zorbax SB-C18 using the 0.1% formic acid water solution and acetonitrile as mobile phase with a gradient elution was applied to the chromatographic separation. The ion transitions were quantified in positive mode for D-pseudoephedrine, L-ephedrine, L-methylephedrine, and diphenhydramine (internal standard), while negative mode for liquiritin, glycyrrhizic acid, amygdalin, cinnamic acid, and prednisolone (internal standard). Several parameters of the method including linearity, accuracy, precision, stability, and matrix effect were within acceptable ranges. The results showed the LC-MS/MS method coupled to microdialysis sampling can be utilized for the pharmacokinetic studies of these seven ingredients in vivo. According to the pharmacokinetic results, the pharmacokinetic parameters of L-ephedrine, D-pseudoephedrine, L-methylephedrine, glycyrrhizic acid, cinnamic acid, liquiritin, and amygdalin were totally different in rat blood and brain, the bioavailability of ephedrine and amygdalin in the blood and brain was higher, while the MRT of ephedrine was the shortest. In the rat brain, the elimination rate of three Ephedra alkaloids was lower than that of the remaining four components. This research offered more basic pharmacokinetic information on the safety mechanisms of Mahuang decoction.

A cargo model of yolk syncytial nuclear migration during zebrafish epiboly.

In teleost fish, the multinucleate yolk syncytial layer functions as an extra-embryonic signaling center to pattern mesendoderm, coordinate morphogenesis and supply nutrients to the embryo. External yolk syncytial nuclei (e-YSN) undergo microtubule-dependent movements that distribute the nuclei over the large yolk mass. How e-YSN migration proceeds, and the role of the yolk microtubules, is not understood, but it is proposed that e-YSN are pulled vegetally as the microtubule network shortens from the vegetal pole. Live imaging revealed that nuclei migrate along microtubules, consistent with a cargo model in which e-YSN are moved down the microtubules by direct association with motor proteins. We found that blocking the plus-end directed microtubule motor kinesin significantly attenuated yolk nuclear movement. Blocking the outer nuclear membrane LINC complex protein Syne2a also slowed e-YSN movement. We propose that e-YSN movement is mediated by the LINC complex, which functions as the adaptor between yolk nuclei and motor proteins. Our work provides new insights into the role of microtubules in morphogenesis of an extra-embryonic tissue and further contributes to the understanding of nuclear migration mechanisms during development.