Antifatigue Effect of Millettiae speciosae Champ (Leguminosae) Extract in Mice

Purpose: To evaluate whether Millettiae Speciosae Champ. (Leguminosae) can enhance exercise performance as well as ascertain if it a potential functional food material.Methods: The extract of Millettia speciosa Champ. (MSE) was orally administered to mice in 500, 1000, 2000 mg/kg doses to investigate its anti-fatigue effect in both forced swimming and climbing tests. Glycogen, triglyceride (TG), blood urea nitrogen (BUN) and creatine phosphokinase (CK) levels in plasma which can indicate alterations in energy utilization during exercise performance, were determined to analyze the operating exercise mechanisms.Results: The results showed that swimming time to exhaustion was longer in all treated groups (41.06 ± 1.92, 47.84 ± 1.60, 54.00 ± 2.45 min for 500, 10000 and 2000 mg/kg doses, respectively) than for control (19.45 ± 0.62 min, p < 0.05). The middle and high doses of MSE-treated groups significantly prolonged the climbing time compared with control (p < 0.05). Furthermore, MSE reduced the content of TG significantly by increasing fat utilization, delayed the accumulation of BUN and decreased the level of CK (p < 0.05). In addition, administration of MSE significantly protected the depletion of muscle glycogen when compared with control (p < 0.05).Conclusion: The results show for the first time that Millettia speciosa Champ. (Leguminosae) has significant anti-fatigue activity, and also suggest that it is a potential functional food material.Keywords: Radix millettiae speciosae, Anti-fatigue activity, Exercise performance, Serum urea nitrogen, Gastrocnemius muscle glycogen, Triglyceride, Functional foo

Determination and Distribution Study of Pogostone in Rat Tissues by Ultra-Fast Liquid Chromatography

Purpose: To develop and validate a rapid, sensitive and reliable ultra-fast liquid chromatography (UFLC) method with photodiode array (PDA) detection for the determination of pogostone (PO) in rat tissues using honokiol as internal standard (IS).Methods: Rats were randomly divided into two groups (intravenous administration group and oral administration group) and given of a single dose of 10 mg/kg PO by intravenous administration and oral administration, respectively. After intravenous injection, the rats were sacrificed at 15, 60 and 360 min, while rats, after oral administration, were euthanasized at 30, 90 and 360 min, respectively. For the analysis of the preparation, optimal chromatographic conditions were determined using Acquity UPLC BEH C18 column with acetonitrile-water containing 0.1 % formic acid (55:45, v/v) as the mobile phase, at a flow rate of 400 μL/min. UV detection wavelength was set at 310 nm with temperature maintained at 30 °C.Results: Good linear relationship of calibration curve (r > 0.9984) was achieved over the range of 0.1 - 40 μg/mL for all the tissue samples. The limit of quantification (LOQ) and limit of detection (LOD) were 0.1 and 0.05 μg/mL, respectively. This method proved to have good precision, accuracy, stability, extraction recovery and matrix effect for tissue distribution studies of PO in rats.Conclusion: The developed method is suitable for tissue distribution studies in rats following intravenous and oral administration of PO at a dose of 10 mg/kg.Keywords: Ultra-fast liquid chromatography, Tissue distribution, Pogostone, Honokiol, Rat

Coalescence Behavior of Gold Nanoparticles

The tetraoctylammonium bromide (TOAB)-stabilized gold nanoparticles have been successfully fabricated. After an annealing of the as-synthesized nanoparticles at 300 °C for 30 min, the coalescence behavior of gold nanoparticles has been investigated using high-resolution transmission electron microscopy in detail. Two types of coalescence, one being an ordered combination of two or more particles in appropriate orientations through twinning, and the other being an ordered combination of two small particles with facets through a common lattice plane, have been observed

Errors in recall of age at first sex

Aims: To measure the degree and direction of errors in recall of age at first sex. Method: Participants were initially recruited in 1994–1995 (Wave I) with 3 subsequent follow-ups in: 1996 (Wave II); 2001– 2002 (Wave III); and 2007–2008 (Wave IV). Participants' individual errors in recall of their age at first sex at Wave IV were estimated by the paired difference between responses given for age at first sex in Wave I and Wave IV (recalled age at first sex obtained at Wave IV minus the age at first sex obtained at Wave I). Results: The mean of the recall-estimation of age at first sex at Wave IV was found to be slightly increased comparing to the age at first sex at Wave I (less than 1 year). The errors in the recalled age at first sex tended to increase in participants who had their first sex younger or older than the average, and the recalled age at first sex tended to bias towards the mean (i.e. participants who had first sex younger than the average were more likely to recall an age at first sex that was older than the age, and vice versa). Conclusions: In this U.S. population-based sample, the average recall error for age at first sex was small. However, the accuracy of recalled information varied significantly among subgroup populations

In-plane surface plasmonics integrated with THz Quantum cascade lasers for high collimation

We report planar integration of tapered Terahertz (THz) quantum cascade lasers (QCLs) with spoof surface plasmon (SSP) structures. The SSP structure consists of one plasmonic coupler and periodically arranged scatters. The resulting surface-emitting THz beam is highly collimated with a beam divergence as narrow as 3.6°×9.7°. As the beam divergence is inverse proportional to the light emission area, this low divergence indicates a good waveguiding property of the SSP structure, while the low optical background of the beam implies a high coupling efficiency of the THz wave from the laser cavity to the SSPs. Since all the structures are in-plane, this scheme provides a promising platform where the well-established SP techniques can be employed to engineer the THz QCL beam with high flexibilities

Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations

Inhaled corticosteroids (ICS) are often prescribed as first-line therapy for patients with asthma Despite their efficacy and improved safety profile compared with oral corticosteroids, the potential for systemic side effects continues to cause concern. In order to reduce the potential for systemic side effects, the pharmaceutical industry has begun efforts to generate new drugs with pulmonary-targeted topical efficacy. One of the major challenges of this approach is to differentiate both efficacy and side effects (pulmonary vs. systemic) in a preclinical animal model. In this study, fluticasone and ciclesonide were used as tool compounds to explore the possibility of demonstrating both efficacy and side effects in a rat model using pulmonary delivery via intratracheal (IT) instillation with nanosuspension formulations. The inhibition of neutrophil infiltration into bronchoalveolar lavage fluid (BALF) and cytokine (TNFα) production were utilized to assess pulmonary efficacy, while adrenal and thymus involution as well as plasma corticosterone suppression was measured to assess systemic side effects. Based on neutrophil infiltration and cytokine production data, the ED50s for ciclesonide and fluticasone were calculated to be 0.1 and 0.03 mg, respectively. At the ED50, the average adrenal involution was 7.6 ± 5.3% for ciclesonide versus 16.6 ± 5.1% for fluticasone, while the average thymus involution was 41.0 ± 4.3% for ciclesonide versus 59.5 ± 5.8% for fluticasone. However, the differentiation became less significant when the dose was pushed to the EDmax (0.3 mg for ciclesonide, 0.1 mg for fluticasone). Overall, the efficacy and side effect profiles of the two compounds exhibited differentiation at low to mid doses (0.03–0.1 mg ciclesonide, 0.01–0.03 mg fluticasone), while this differentiation diminished at the maximum efficacious dose (0.3 mg ciclesonide, 0.1 mg fluticasone), likely due to overdosing in this model. We conclude that the rat LPS model using IT administration of nanosuspensions of ICS is a useful tool to demonstrate pulmonary-targeted efficacy and to differentiate the side effects. However, it is only suitable at sub-maximum efficacious levels

Identification and Characterization of Paramyosin from Cyst Wall of Metacercariae Implicated Protective Efficacy against Clonorchis sinensis Infection

Human clonorchiasis has been increasingly prevalent in recent years and results in a threat to the public health in epidemic regions, motivating current strategies of vaccines to combat Clonorchis sinensis (C. sinensis). In this study, we identified C. sinensis paramyosin (CsPmy) from the cyst wall proteins of metacercariae by proteomic approaches and characterized the expressed recombinant pET-26b-CsPmy protein (101 kDa). Bioinformatics analysis indicated that full-length sequences of paramyosin are conserved in helminthes and numerous B-cell/T-cell epitopes were predicted in amino acid sequence of CsPmy. Western blot analysis showed that CsPmy was expressed at four life stages of C. sinensis, both cyst wall proteins and soluble tegumental components could be probed by anti-CsPmy serum. Moreover, immunolocalization results revealed that CsPmy was specifically localized at cyst wall and excretory bladder of metacercaria, as well as the tegument, oral sucker and vitellarium of adult worm. Both immunoblot and immunolocalization results demonstrated that CsPmy was highly expressed at the stage of adult worm, metacercariae and cercaria, which could be supported by real-time PCR analysis. Both recombinant protein and nucleic acid of CsPmy showed strong immunogenicity in rats and induced combined Th1/Th2 immune responses, which were reflected by continuous high level of antibody titers and increased level of IgG1/IgG2a subtypes in serum. In vaccine trials, comparing with control groups, both CsPmy protein and DNA vaccine exhibited protective effect with significant worm reduction rate of 54.3% (p<0.05) and 36.1% (p<0.05), respectively. In consistence with immune responses in sera, elevated level of cytokines IFN-γ and IL-4 in splenocytes suggested that CsPmy could induce combined cellular immunity and humoral immunity in host. Taken together, CsPmy could be a promising vaccine candidate in the prevention of C. sinensis regarding its high immunogenicity and surface localization

Cellular Mechanisms Underlying the Laxative Effect of Flavonol Naringenin on Rat Constipation Model

BACKGROUND & AIMS: Symptoms of constipation are extremely common, especially in the elderly. The present study aim to identify an efficacious treatment strategy for constipation by evaluating the secretion-promoting and laxative effect of a herbal compound, naringenin, on intestinal epithelial anion secretion and a rat constipation model, respectively. METHODS/PRINCIPAL FINDINGS: In isolated rat colonic crypts, mucosal addition of naringenin (100 microM) elicited a concentration-dependent and sustained increase in the short-circuit current (I(SC)), which could be inhibited in Cl- free solution or by bumetanide and DPC (diphenylamine-2-carboxylic acid), but not by DIDS (4, 4'- diisothiocyanatostilbene-2, 2'-disulfonic acid). Naringenin could increase intracellular cAMP content and PKA activity, consisted with that MDL-12330A (N-(Cis-2-phenyl-cyclopentyl) azacyclotridecan-2-imine-hydrochloride) pretreatment reduced the naringenin-induced I(SC). In addition, significant inhibition of the naringenin-induced I(SC) by quinidine indicated that basolateral K+ channels were involved in maintaining this cAMP-dependent Cl- secretion. Naringenin-evoked whole cell current which exhibited a linear I-V relationship and time-and voltage- independent characteristics was inhibited by DPC, indicating that the cAMP activated Cl- conductance most likely CFTR (cystic fibrosis transmembrane conductance regulator) was involved. In rat constipation model, administration of naringenin restored the level of fecal output, water content and mucus secretion compared to loperamide-administrated group. CONCLUSIONS: Taken together, our data suggest that naringenin could stimulate Cl- secretion in colonic epithelium via a signaling pathway involving cAMP and PKA, hence provide an osmotic force for subsequent colonic fluid secretion by which the laxative effect observed in the rat constipation model. Naringenin appears to be a novel alternative treatment strategy for constipation

SIRT2 Ablation Has No Effect on Tubulin Acetylation in Brain, Cholesterol Biosynthesis or the Progression of Huntington's Disease Phenotypes In Vivo

Huntington's disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. The molecular pathogenesis of HD is complex and many mechanisms and cellular processes have been proposed as potential sites of therapeutic intervention. However, prior to embarking on drug development initiatives, it is essential that therapeutic targets can be validated in mammalian models of HD. Previous studies in invertebrate and cell culture HD models have suggested that inhibition of SIRT2 could have beneficial consequences on disease progression. SIRT2 is a NAD[superscript +]-dependent deacetylase that has been proposed to deacetylate α-tubulin, histone H4 K16 and to regulate cholesterol biogenesis – a pathway which is dysregulated in HD patients and HD mouse models. We have utilized mice in which SIRT2 has been reduced or ablated to further explore the function of SIRT2 and to assess whether SIRT2 loss has a beneficial impact on disease progression in the R6/2 mouse model of HD. Surprisingly we found that reduction or loss of SIRT2 had no effect on the acetylation of α-tubulin or H4K16 or on cholesterol biosynthesis in the brains of wild type mice. Equally, genetic reduction or ablation of SIRT2 had no effect on HD progression as assessed by a battery of physiological and behavioural tests. Furthermore, we observed no change in aggregate load or levels of soluble mutant huntingtin transprotein. Intriguingly, neither the constitutive genetic loss nor acute pharmacological inhibition of SIRT2 affected the expression of cholesterol biosynthesis enzymes in the context of HD. Therefore, we conclude that SIRT2 inhibition does not modify disease progression in the R6/2 mouse model of HD and SIRT2 inhibition should not be prioritised as a therapeutic option for HD.American Parkinson Disease Association, Inc. (Fellowship)Johnson & Johnson. Pharmaceutical Research & Development (Fellowship

MTF-1-Mediated Repression of the Zinc Transporter Zip10 Is Alleviated by Zinc Restriction

The regulation of cellular zinc uptake is a key process in the overall mechanism governing mammalian zinc homeostasis and how zinc participates in cellular functions. We analyzed the zinc transporters of the Zip family in both the brain and liver of zinc-deficient animals and found a large, significant increase in Zip10 expression. Additionally, Zip10 expression decreased in response to zinc repletion. Moreover, isolated mouse hepatocytes, AML12 hepatocytes, and Neuro 2A cells also respond differentially to zinc availability in vitro. Measurement of Zip10 hnRNA and actinomycin D inhibition studies indicate that Zip10 was transcriptionally regulated by zinc deficiency. Through luciferase promoter constructs and ChIP analysis, binding of MTF-1 to a metal response element located 17 bp downstream of the transcription start site was shown to be necessary for zinc-induced repression of Zip10. Furthermore, zinc-activated MTF-1 causes down-regulation of Zip10 transcription by physically blocking Pol II movement through the gene. Lastly, ZIP10 is localized to the plasma membrane of hepatocytes and neuro 2A cells. Collectively, these results reveal a novel repressive role for MTF-1 in the regulation of the Zip10 zinc transporter expression by pausing Pol II transcription. ZIP10 may have roles in control of zinc homeostasis in specific sites particularly those of the brain and liver. Within that context ZIP10 may act as an important survival mechanism during periods of zinc inadequacy