Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia.

INTRODUCTION: Synapse dysfunction is emerging as an early pathological event in frontotemporal dementia (FTD), however biomarkers are lacking. We aimed to investigate the value of cerebrospinal fluid (CSF) neuronal pentraxins (NPTXs), a family of proteins involved in homeostatic synapse plasticity, as novel biomarkers in genetic FTD. METHODS: We included 106 presymptomatic and 54 symptomatic carriers of a pathogenic mutation in GRN, C9orf72 or MAPT, and 70 healthy non-carriers participating in the Genetic Frontotemporal dementia Initiative (GENFI), all of whom had at least one CSF sample. We measured CSF concentrations of NPTX2 using an in-house ELISA, and NPTX1 and NPTX receptor (NPTXR) by Western blot. We correlated NPTX2 with corresponding clinical and neuroimaging datasets as well as with CSF neurofilament light chain (NfL) using linear regression analyses. RESULTS: Symptomatic mutation carriers had lower NPTX2 concentrations (median 643 pg/mL, IQR (301-872)) than presymptomatic carriers (1003 pg/mL (624-1358), p<0.001) and non-carriers (990 pg/mL (597-1373), p<0.001) (corrected for age). Similar results were found for NPTX1 and NPTXR. Among mutation carriers, NPTX2 concentration correlated with several clinical disease severity measures, NfL and grey matter volume of the frontal, temporal and parietal lobes, insula and whole brain. NPTX2 predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale plus FTD modules. In longitudinal CSF samples, available in 13 subjects, NPTX2 decreased around symptom onset and in the symptomatic stage. DISCUSSION: We conclude that NPTX2 is a promising synapse-derived disease progression biomarker in genetic FTD.

Gene expression analyses identify Narp contribution in the development of L-DOPA-induced dyskinesia.

In Parkinson's disease, long-term dopamine replacement therapy is complicated by the appearance of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID results from an aberrant transcriptional program in striatal neurons induced by L-DOPA and triggered by the activation of ERK. To identify these genes, we performed transcriptome analyses in the striatum in 6-hydroxydopamine-lesioned mice. A time course analysis (0-6 h after treatment with L-DOPA) identified an acute signature of 709 genes, among which genes involved in protein phosphatase activity were overrepresented, suggesting a negative feedback on ERK activation by l-DOPA. l-DOPA-dependent deregulation of 28 genes was blocked by pretreatment with SL327, an inhibitor of ERK activation, and 26 genes were found differentially expressed between highly and weakly dyskinetic animals after treatment with L-DOPA. The intersection list identified five genes: FosB, Th, Nptx2, Nedd4l, and Ccrn4l. Nptx2 encodes neuronal pentraxin II (or neuronal activity-regulated pentraxin, Narp), which is involved in the clustering of glutamate receptors. We confirmed increased Nptx2 expression after L-DOPA and its blockade by SL327 using quantitative RT-PCR in independent experiments. Using an escalating L-DOPA dose protocol, LID severity was decreased in Narp knock-out mice compared with their wild-type littermates or after overexpression of a dominant-negative form of Narp in the striatum. In conclusion, we have identified a molecular signature induced by L-DOPA in the dopamine-denervated striatum that is dependent on ERK and associated with LID. Here, we demonstrate the implication of one of these genes, Nptx2, in the development of LID.

A review of experimental research on herbal compounds in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease worldwide, leading to progressive muscle atrophy and paralysis. The limited success of conventional treatment for ALS has prompted investigations into complementary and alternative therapies. Herbal remedies provide good prospects of ALS prevention and treatment, with advantages such as multiple targets, multiple links, and few side effects. Studies in vitro and in vivo have shown that herbs have a great potential for treatment of ALS, with therapeutic effects against oxidative stress, excitatory amino acid toxicity, neuroinflammation, and calcium cytotoxicity. Active monomers or ingredients extracted from herbs are considered promising candidates for ALS. Therefore, we review recent experimental research on monomers and compounds isolated from herbal remedies for preventing and treating ALS.

[Application of factor analysis to evaluate deformation behaviors of frequently-used tablet excipients].

The present work is to investigate the correlation between physical properties and deformation behaviors of tablet excipients, and rank them according to their plastic performances during compaction. The excipients selected were compacted using Korsch XP1 after measuring their physical properties where the compression parameters for evaluating deformation behaviors were Heckle equation, compression work and elastic stretch in die. The correlations between compaction descriptors and physical parameters were analyzed by canonical correlation analysis, and factor analysis was simultaneously employed to synthetically assess deformation behaviors for all our samples. The canonical variables show that true density (Pa) correlated negatively with plastic coefficient (PL) and positively with yield pressure (YP); compression degree (Cp) correlated negatively with fast elastic stretch (FES) as well as YP and positively with PL. When factor scores were used in combination with original data, the plasticity of our samples was sorted and ranked as high (-0.56 < F' < 0.21), intermediate (-0.16 < F' < 0.36), or low (0.38 < F' < 0.84), which are in accord with plasticity rankings previously reported in literature. This study indicates factor analysis can be an approach to evaluate deformation behaviors of pharmaceutical powders.

[Discrimination of traditional Chinese medicinal materials with different tastes based on electronic tongue].

OBJECTIVE: To investigate the use of the electronic tongue in the evaluation of traditional Chinese medicinal materials with sour, bitter, sweet or salty tastes, and assess the possible application of the sensor in the evaluation of different tastes of traditional Chinese medicinal materials. METHOD: Aqueous extracts of 22 traditional Chinese medicinal materials were measured by the electronic tongue. The data collected with the tongue was evaluated for discrimination of the samples with multivariate statistical methods: principal component analysis (PCA) and discriminant factor analysis (DFA). RESULT: The electronic tongue was capable of discriminating between samples with different taste modalities and could also distinguish different samples eliciting the same basic taste. Twenty-two traditional Chinese medicinal materials could be classified into five clusters based on PCA. These differences seem to derive from the different tastes. DFA was applied to construct a model to discriminate traditional Chinese medicinal materials with different tastes. And the samples yielded about 88.2% accuracy for cross-validation. CONCLUSION: We confirmed that the electronic tongue may provide an analytical procedure for classification of the samples with respect to tastes of the traditional Chinese medicinal materials.

Highly Active Manganese Oxide from Electrolytic Manganese Anode Slime for Efficient Removal of Antibiotics Induced by Dissociation of Peroxymonosulfate.

In this paper, high-activity manganese oxide was prepared from electrolytic manganese anode slime to realize the efficient removal of antibiotics. The effects of sulfuric acid concentration, ethanol dosage, liquid-solid ratio, leaching temperature and leaching time on the leaching of manganese from electrolytic manganese anode slime were systematically studied. Under the optimal conditions, the leaching rate of manganese reached 88.74%. In addition, a Mn3O4 catalyst was synthesized and used to activate hydrogen persulfate (PMS) to degrade tetracycline hydrochloride (TCH). The synthesized Mn3O4 was characterized by XRD, XPS, Raman, SEM and HRTEM. As a result, the prepared Mn3O4 is spherical, with high purity and crystallinity. The catalytic activity of Mn3O4 for PMS to degrade TCH was increased to 82.11%. In addition, after four cycles, the performance remained at 78.5%, showing excellent stability and recyclability. In addition, O2- and 1O2 are the main active species in the degradation reaction. The activity of Mn3O4 is attributed to it containing Mn(II) and Mn(III) at the same time, which can quickly realize the transformation of high-valence and low-valence manganese, promote the transfer of electrons and realize the degradation of organic pollutants.

Increased expression of EMMPRIN and VEGF in the rat brain after gamma irradiation.

The extracellular matrix metalloproteinase inducer (EMMPRIN) has been known to play a key regulatory role in pathological angiogenesis. A elevated activation of vascular endothelial growth factor (VEGF) following radiation injury has been shown to mediate blood-brain barrier (BBB) breakdown. However, the roles of EMMPRIN and VEGF in radiation-induced brain injury after gamma knife surgery (GKS) are not clearly understood. In this study, we investigated EMMPRIN changes in a rat model of radiation injury following GKS and examined potential associations between EMMPRIN and VEGF expression. Adult male rats were subjected to cerebral radiation injury by GKS under anesthesia. We found that EMMPRIN and VEGF expression were markedly upregulated in the target area at 8-12 weeks after GKS compared with the control group by western blot, immunohistochemistry, and RT-PCR analysis. Immunofluorescent double staining demonstrated that EMMPRIN signals colocalized with caspase-3 and VEGF-positive cells. Our data also demonstrated that increased EMMPRIN expression was correlated with increased VEGF levels in a temporal manner. This is the first study to show that EMMPRIN and VEGF may play a role in radiation injuries of the central nervous system after GKS.

Characterization using LC/MS of the absorption compounds and metabolites in rat plasma after oral administration of a single or mixed decoction of Shaoyao and Gancao.

Shaoyao-Gancao decoction (SGD), a traditional Chinese formulation containing Paeoniae Radix (SY) and Glycyrrhizae Radix (GC), is commonly used to relieve abdominal pain. However, the absorption and metabolites of the characteristic constituents of the two herbs in vivo have been reported rarely. The purpose of this study was to investigate the compatibility rationality and the mechanism of the enhanced efficiency of SGD. A single or a mixed decoction (SG and S+G, respectively) was orally administered to rats. Blood samples were collected at different intervals following treatment and analyzed by liquid LC/MS. A total of fifteen ingredients (denoted as M1 to M15) were found in both rat plasma after treatment with the two decoctions. Furthermore, the proposed structures of the remained twelve ingredients were obtained except M9, M10 and M15. The quality of the ingredients in the rat plasma showed no significant difference between the two decoctions. However, the quantity of twelve ingredients differed greatly, indicating that the absorption of SG was greater than that of S+G except M7, M12 and M15. As the compositions associated with the efficacy of SG and S+G were inconsistent, the degree of the absorption of the 15 ingredients by the gastrointestinal tract were different, which caused a significantly enhanced efficacy of certain ingredients. This study presents an exploration of the mechanism behind the improved efficacy of individual components in traditional Chinese medicine therapies through combination with other components.

Pharmacokinetics of characteristic effective ingredients from individual and combination Shaoyao and Gancao treatment in rats using HPLC fingerprinting.

Shaoyao-Gancao decoction, a traditional Chinese formulation composed of Paeoniae Radix and Glycyrrhizae Radix, is commonly used to relieve abdominal pain. In this paper, the compatibility rationality of this decoction was investigated. Shaoyao-Gancao decoction, Shaoyao decoction and Gancao decoction were orally administered to rats, respectively. Blood samples were collected at pre-determined times after administration and analyzed by high-performance liquid chromatography (HPLC). The pharmacokinetic parameters of characteristic peaks were analyzed and the statistical significance of the obtained parameters was determined. Paeoniflorin (12.0 min) and compounds at retention times of 4.7 and 5.2 min were all significantly higher in the Shaoyao-Gancao decoction than in the Shaoyao decoction (P < 0.05). In contrast, in the Gancao decoction, the compound at a retention time of 14.6 min was significantly lower than in the Shaoyao-Gancao decoction (P < 0.01). However, the compounds at retention times of 17.1 and 18.1 min were significantly higher in the Gancao decoction than in the Shaoyao-Gancao decoction (P < 0.05). These results indicate that poor compatibility of the compounds in the Shaoyao-Gancao decoction could result in poor absorption. The compatibility of the component compounds of the Shaoyao-Gancao decoction was revealed in the pharmacokinetic characteristics of the decoction. Generally, the absorption of Shaoyao components was increased in the Shaoyao-Gancao decoction, while the absorption of Gancao components was time dependent. In the Shaoyao-Gancao decoction, the increased absorption of some Shaoyao components may be related to a reduction in absorption of some Gancao components.

Comparative pharmacokinetics of senkyunolide I in a rat model of migraine versus normal controls.

Senkyunolide I is an active ingredient of Rhizoma Chuanxiong, a Chinese medicinal herb commonly used for the treatment of cardiovascular ailments. In the present paper, we describe the isolation and elucidation of senkyunolide I from the ethanol extract of Rhizoma Chuanxiong and its pharmacokinetic behavior after intravenous and oral administration to normal and migrainous rats. After intravenous administration, senkyunolide I was rapidly distributed (V ( z )/F 2.07 ± 0.43 L/kg) and eliminated from the plasma (CL( z ) 2.56 ± 0.29 L/h/kg and t (1/2z ) 0.56 ± 0.13 h). After administration orally to normal rats at two dosages (20 and 72 mg/kg), the pharmacokinetic parameters of senkyunolide I were as follows: T (max) 0.25 ± 0.06 and 0.38 ± 0.11 h, C (max) 5,236.3 ± 802.8 and 22,071.9 ± 3,456.1 mg/L, Area under the curve(AUC)((0-t)) 5,217.5 ± 1,029.5 and 21,480.2 ± 3,003.1 µg h/L, respectively. Its oral absolute bioavailability at the two dosages was 67.2 and 76.9%, respectively. Intriguingly, migraine caused some significant changes in its pharmacokinetic parameter. For example, when compared with its pharmacokinetic behavior in normal rats at the two dosages, on average, its clearance decreased by 68% and volume of distribution increased by 342% in migrainous rats, both of which contributed to its several-fold increase in t (1/2z) and AUC. C (max) and AUC of senkyunolide I increased almost proportionally with dose between 20 and 72 mg/kg and the pharmacokinetics fit linear kinetic feature. The pharmacokinetic parameters of senkyunolide I were significantly different in normal and migrainous rats, which should be taken into account during the design of a clinical dosage regimen for senkyunolide I.

Comparison of the effects of fungal endophyte Gilmaniella sp. and its elicitor on Atractylodes lancea plantlets.

The effects of the endophytic fungus Gilmaniella sp. and its elicitor on the defense and metabolic responses of host plants Atractylodes lancea were investigated, in order to understand how to utilize endophytic fungi and their elicitor resources better. The results showed that the promotion effect of the fungus on the growth of host plantlets was much better than that of its elicitor. Both fungus and elicitor enhanced defense-related enzyme activities. In fungus-inoculated groups, phenylalanine ammonia lyase and polyphenol oxidase activities increased slowly, and reached a maximum level during the later stages, whereas peroxidase activity peaked in the first few days. Additionally, the activities of chitinase and ß-1,3-glucanase were significantly higher than those of the control plants. In elicitor-treated groups, however, most of the enzymes were activated during the early stage, and their highest levels were generally lower than those of the fungus-inoculated groups. Compared with the elicitor, fungal infection improved the photosynthetic rate of the host, and increased carbohydrate levels as well as chlorophyll content in host leaves. The total content of the four main components of volatile oil was also increased in elicitor-treated groups, but there was no particular pattern in this increase. Meanwhile, in the fungus-inoculated groups, the content of atractylone significantly increased with time, while the content of ß-eudesmol decreased. These results indicated that fungal elicitor could substantially improve the total content of volatile oil, while the fungus could more effectively enhance the quality of herbal medicines.

[Characterization of flowability of pharmaceutical powders based on multivariate analysis method].

The main methods of characterizing the flowability of pharmaceutical powders include repose angle method, HR method, Carr's index method, Jenike flow function method, fractal dimension method, and mass flow rate method, etc. Regarding powders with different flowabilities as the research subject, comprehensive features of pharmaceutical materials were investigated and characterized. The multivariate analysis method was employed to evaluate and analyze flowability values of the tested pharmaceutical materials. Comparing with the method of the mass flow rate, it was feasible to use multivariate analysis method to evaluate the flowability of powders. Simultaneously, the flowability of pharmaceutical materials could be ranked and definitely quantified, and critical values be determined according to the actual production, which has promoted the previous methods dependent only on the single parameter, i.e. repose angle and compression degree methods. A relatively objective standard method of evaluating flowability of powders is formed.

[Multivariate analysis of relationships between material properties and hygroscopicity of Chinese medicine raw materials].

Material properties and hygroscopicity were determined. Principal component analysis and partial least squares regression were applied to evaluate relationships between material properties and hygroscopicity of Chinese medicine raw materials. The results showed that hygroscopicity was correlated with water content, particle size distribution, water soluble characteristic and cohesion. Balanced moisture content was positively correlated with water content, particle size distribution, water soluble characteristic and cohesion. Moisture absorption velocity was negatively correlated with particle size distribution, protruding degree and positively correlated with water soluble characteristic and cohesion. Moisture absorption acceleration was positively correlated with water content, particle size distribution and negatively correlated with water soluble characteristic and cohesion. Hygroscopicity of Chinese medicine raw materials is interpreted in terms of physics.

[Pharmacokinetics effect of shaoyao gancao compound with different decocting methods on characteristic ingredients in rat plasma after oral administration].

OBJECTIVE: To observe the pharmacokinetic effect of Shaoyao Gancao compound on rats using different decocting methods, and to pharmacokinetically detect the the compatibility of the component compounds of the Shaoyao Gancao compound from the pharmacokinetic viewpoint. METHOD: Based on the established HPLC analytical method of plasma effective constituents, rats were orally administered with a single or mixed decoction of Shaoyao and Gancao. Blood at different times after administering these decoctions were collected, and then variance analysis was made for pharmacokinetic parameters. RESULT: The results of all six rats indicated that the absorption of the mixed decoction of Shaoyao and Gancao was greater than that of the single decoction. While, the absorption of the characteristic peaks at the retention time of 5.2, 11.0, 12.0, 14.6 min had statistical significance. CONCLUSION: Shaoyao Gancao compound was proved better than that of the single decoction from the pharmacokinetic viewpoint.

[Characterization methods of flowability of traditional Chinese medicine powders].

OBJECTIVE: To characterize the flowability of traditional Chinese medicine (TCM) powders by using appropriate methods. METHOD: With highly flowable direct compression excipients and Chinese traditional medicine powder as raw materials, the flowability of material powders is determined by the Carr method and the Jenike method. RESULT: The Carr method and the Jenike method for the determination of the flowability of Chinese herb extract powder and direct-pressing excipients have no obvious difference. But the flowability of Chinese herb extract powder is not as good as direct compression excipients. CONCLUSION: From the characterization results of both methods, we can find that the Carr method better reflects the actual flowability of TCM extracts, while the Jenike method can be used for guiding the design of the hopper device.

[Study on HPLC characteristic fingerprint of active components of dachuanxiong fang in plasma and cerebrospinal fluid].

OBJECTIVE: To establish an accurate and simple qualitative analytical method in vivo in the study on HPLC characteristic fingerprint of active components of dachuanxiong fang in plasma and cerebrospinal fluid, in order to lay a foundation for studies on components found in plasma and cerebrospinal fluid and provide basis for compatible regularity of initiators. METHOD: HPLC characteristic fingerprint of active components of dachuanxiong fang in plasma and cerebrospinal fluid was established. RESULT: The similarity of fingerprints of all of six batches of samples was above 0.85, RSD of their relative retention times in common peaks was less than 2. 0%. CONCLUSION: The fingerprints of active components of dachuanxiong fang in plasma and cerebrospinal fluid were stable and accurate that they can be used in qualitative analysis on in vivo components.

Highly Dispersion Cu2O QDs Decorated Bi2WO6 S-Scheme Heterojunction for Enhanced Photocatalytic Water Oxidation.

Developing suitable photocatalysts for the oxygen evolution reaction (OER) is still a challenging issue for efficient water splitting due to the high requirements to create a significant impact on water splitting reaction kinetics. Herein, n-type Bi2WO6 with flower-like hierarchical structure and p-type Cu2O quantum dots (QDs) are coupled together to construct an efficient S-scheme heterojunction, which could enhance the migration efficiency of photogenerated charge carriers. The electrochemical properties are investigated to explore the transportation features and donor density of charge carriers in the S-scheme heterojunction system. Meanwhile, the as-prepared S-scheme heterojunction presents improved photocatalytic activity towards water oxidation in comparison with the sole Bi2WO6 and Cu2O QDs systems under simulated solar light irradiation. Moreover, the initial O2 evolution rate of the Cu2O QDs/Bi2WO6 heterojunction system is 2.3 and 9.7 fold that of sole Bi2WO6 and Cu2O QDs systems, respectively.

Construction of plasmonic Bi/Bismuth oxycarbonate/Zinc bismuth oxide ternary heterojunction for enhanced charge carrier separation and photocatalytic performances.

In this work, a novel plasmonic ternary Bi/Bismuth oxycarbonate/Zinc bismuth oxide (Bi-Bi2O2CO3-ZnBi2O4) is synthesized synergistically by a one-step hydrothermal method. The results show that the metallic Bi spheres and ZnBi2O4 nanoparticles are uniformly distributed on the surface of flower-like Bi2O2CO3 layer. Compared with the bare ZnBi2O4 and Bi-Bi2O2CO3, the ternary Bi-Bi2O2CO3-ZnBi2O4 heterojunction displays a significantly improved solar energy harvesting efficiency and enhanced photocatalytic degradation activity for environmental organic pollutants. The degradation efficiency of organics reaches to 98.4% under simulated solar light illumination. The degradation kinetics indicates that the photocatalytic reaction rate constant of ternary system is about 4.4 and 29.5 times higher than that of pure ZnBi2O4 and Bi-Bi2O2CO3, respectively. Moreover, O2- and h+ are the main active species in the photodegradation reaction. The improvement of the photocatalytic activity of the composites is attributed to the synergistic effect of ternary heterostructure and surface plasmon resonance (SPR), which promotes charge transfer and effectively inhibits the recombination of photogenerated carriers.

[Pharmacokinetics of a long-circulating PEGylated Radix Ophiopogonis polysaccharide].

The pharmacokinetics of a long-circulating PEGylated Radix Ophiopogonis polysaccharide (ROP) was investigated in rats following i.v. or s.c. administration at three dose levels (9, 20, 50 mg x kg(-1)). A moderate coupling reaction between the hydroxyl-activated ROP and the amino-terminated mPEG was chosen to produce PEGylate ROP. The grafting degree of the prepared conjugate was 1.03, and the molecular mass of mPEG used was 20 kDa. High-performance gel permeation chromatorgraphy with fluorescein isothiocyanate prelabeling was established to determine levels of the conjugate in plasma. The results showed that the elimination half-life of the conjugate following s.c. administration was basically identical to that after iv administration. An accurate linear correlation was observed between administration doses and areas under the curve of plasma conjugate level vs. time profile, regardless of the administration route. The absolute bioavailability of the conjugate following sc administration was approximately 56%, and the mean in vivo residence time was 52.1 h, increased 2.4 times compared to those of iv administration. In general, linear pharmacokinetics was observed for the conjugate within the dose range studied, and sc should be a promising administration route for the conjugate.

[Pharmacokinetics study on characteristic ingredients of different-dose herbs of shaoyao-gancao decoction].

The paper is to report the observation of pharmacokinetic changes of the characteristic ingredients in the combinations of different-dose herbs of Shaoyao-Gancao decoction. After the establishment of HPLC analytical method of plasma effective constituents, rats were orally administered with different-dose herbs of Shaoyao-Gancao decoction. Blood samples at different times after administering these decoctions were collected, and then were analyzed by HPLC fingerprints technology. Pharmacokinetic parameters of characteristic peaks were analyzed by SPSS 15.0 software and DAS 2.0. At last, we looked for the correlation of those pharmacokinetic parameters and the dosage of Gancao. The best dose of Shaoyao-Gancao decoction was at the ratio of 4 to 4, which was consistent with the dose commonly used in ancient times. The absorption of characteristic peaks from Shaoyao-Gancao decoction was related with the dosage of Gancao, and there existed interaction between each characteristic ingredients. There existed the right dose-ratio of Shaoyao and Gancao to get the best effect. The absorptions of effective constitutents were mutual waxing and waning in order to increase biological effects together. It's demonstrated the compatibility connotation at a right dose-ratio of Shaoyao-Gancao decoction through the angle of pharmacokinetics.