CYP3A4-mediated metabolism of artemisinin to 10ß-hydroxyartemisinin with comparable anti-malarial potency.

BACKGROUND: The most widely used anti-malarial drug artemisinin (ART) is metabolized extensively, but the therapeutic capacity of its major metabolite remains unknown. Whether the major metabolite of ART (ART-M) contributes to its antiplasmodial potency was investigated in this study. METHODS: The metabolite identification and enzyme phenotyping of ART were performed using human liver microsomes (HLMs). The stereostructure of the major metabolite ART-M was elucidated by spectroscopic and X-ray crystallographic analysis. The anti-malarial activity of ART-M against two reference Plasmodium strains (Pf3D7 and PfDd2) was evaluated. The pharmacokinetic profiles of ART and its metabolite ART-M were investigated in healthy Chinese subjects after a recommended two-day oral dose of ART plus piperaquine. Pharmacodynamic parameters based on minimum inhibitory concentration (MIC50) and free plasma concentration were employed to evaluate the therapeutic potency of ART-M, including fAUC0-t/MIC50, fCmax/MIC50 and T > MIC50. RESULTS: A major metabolite 10ß-hydroxyartemisinin (ART-M) was found for ART in human, and CYP3A4/3A5 was the major enzymes responsible for ART 10ß-hydroxylation. Compared with ART (MIC50, 10.1 nM against Pf3D7), weaker antiplasmodial activity was found for ART-M (MIC50, 61.4 nM against Pf3D7). However, a 3.5-fold higher maximal free plasma concentration was achieved for ART-M (fCmax, 180.0 nM vs. 51.8 nM for ART). ART-M displayed comparable antiplasmodial potency to ART, in terms of fAUC0-t/MIC50 (12.5 h), fCmax/MIC50 (2.8) and T > MIC50 (5 h). CONCLUSIONS: The major metabolite 10ß-hydroxyartemisinin contributes to the antiplasmodial efficacy of ART, which should be considered when evaluation of ART dosing regimens and/or clinical outcomes.

Critical impact of pressure regulation on carbon dioxide biosynthesis.

Carbon dioxide (CO2) biosynthesis is a promising alternative to traditional chemical synthesis. However, its application in engineering is hampered by poor gas mass transfer rates. Pressurization is an effective method to enhance mass transfer and increase synthesis yield, although the underlying mechanisms remain unclear. This review examines the effects of high pressure on CO2 biosynthesis, elucidating the mechanisms behind yield enhancement from three perspectives: microbial physiological traits, gas mass transfer and synthetic pathways. The critical role of pressurization in improving microbial activity and gas transfer efficiency is emphasized, with particular attention to maintaining pressure within microbial tolerance limits to maximize yield without compromising cell structure integrity.

Biocathode-anode cascade system in PRB: Efficient degradation of p-chloronitrobenzene in groundwater.

The consistent presence of p-chloronitrobenzene (p-CNB) in groundwater has raised concerns regarding its potential harm. In this study, we developed a biocathode-anode cascade system in a permeable reactive barrier (BACP), integrating biological electrochemical system (BES) with permeable reactive barrier (PRB), to address the degradation of p-CNB in the groundwater. BACP efficiently accelerated the formation of biofilms on both the anode and cathode using the polar periodical reversal method, proving more conducive to biofilm development. Notably, BACP demonstrated a remarkable p-CNB removal efficiency of 94.76 % and a dechlorination efficiency of 64.22 % under a voltage of 0.5 V, surpassing the results achieved through traditional electrochemical and biological treatment processes. Cyclic voltammetric results highlighted the primary contributing factor as the synergistic effect between the bioanode and biocathode. It is speculated that this system primarily relies on bioelectrocatalytic reduction as the predominant process for p-CNB removal, followed by subsequent dechlorination. Furthermore, electrochemical and microbiological tests demonstrated that BACP exhibited optimal electron transfer efficiency and selective microbial enrichment ability under a voltage of 0.3-0.5 V. Additionally, we investigated the operational strategy for initiating BACP in engineering applications. The results showed that directly introducing BACP technology effectively enhanced microbial film formation and pollutant removal performance.

Influence of concrete material of runoff collection containers on monitoring of nitrogen and phosphorus pollutants.

The accurate monitoring of N and P surface runoff losses from farmland is crucial to control agricultural nonpoint source pollution. A pond constructed with concrete material (CM) is a common collection container used during field experiments in China, but the adsorption characteristics of concrete may cause a considerable underestimation of surface runoff losses from farmland. To characterize any neglected error caused by the collection container material, a laboratory experiment was conducted comparing the N and P contents of runoff samples collected from CM and plastic material (PM) containers. The results indicated that CM containers significantly lowered N and P sample contents compared with PM containers, which was attributed to the adsorption capacity of pollutants by CM containers. This was confirmed by scanning electron microscopy (SEM) images of particles retained in CM containers. In an attempt to alleviate this error, three common water-repellent materials were applied to CM containers that significantly limited the pollutant adsorption of CM containers. Moreover, it was shown that there was no significant difference between the calculated concentration of runoff losses and the total amount of pollutants. To calibrate the observational error from CM containers, stepwise multiple regression models of different forms of N and P pollutants were developed. The results of this study suggest that treating CM containers with water repellent is an effective measure for improving the accuracy of new-built monitor points of agricultural nonpoint source pollutants. In addition, the calibration of observational error from CM containers and delayed sampling is essential to estimate agricultural nonpoint source pollution load via the surface runoff from farmland based on data from monitor points.

Preparation and Multitarget Anti-AD Activity Study of Chondroitin Sulfate Lithium in AD Mice Induced by Combination of D-Gal/AlCl3.

Previous studies have demonstrated that both CS and LiCl possess anti-Alzheimer's disease (AD) activities. We prepared chondroitin sulfate-Li (CS-Li) and investigated its effect on AD and explored the possible mechanisms both in vitro and in vivo. We found that CS-Li could inhibit amyloid ß (Aß) aggregation and protect SH-SY5Y cells from Aß 1-42-induced cytotoxicity in vitro. In D-gal and AlCl3-induced AD mouse model, CS-Li improves the spatial learning and memory abilities of AD mice, reverses the nuclear pyknosis and cell edema, and increases the survival rate of neurons in hippocampus of mice. Moreover, CS-Li significantly increased the levels of GSH-Px, Na+/K+-ATPase, and ChAT and decreased the levels of MDA and AchE in AD mice. Western blot results demonstrated that CS-Li could decrease the hyperphosphorylation of tau (Ser396/Ser404) by regulating the expression of p-GSK-3ß (Ser9) and PP2A and inhibit the expression of proinflammatory factors through inhibiting NF-κB nuclear translocation by activating the MAPK signaling pathways. In a word, CS-Li can delay AD development through multitarget processes, including Aß aggregation inhibition, oxidative stress damage, tau hyperphosphorylation, and inflammatory response, thereby improves learning and memory abilities.

High-Flux Ultrafiltration Membranes Combining Artificial Water Channels and Covalent Organic Frameworks.

Artificial water channels (AWCs) have been well investigated, and the imidazole-quartet water channel is one of the representative channels. In this work, covalent organic frameworks (COFs) composite membranes were fabricated through assembling COF layers and imidazole-quartet water channel. The membranes were synthesized by interfacial polymerization and self-assembly process, using polyacrylonitrile (PAN) ultrafiltration substrates with artificial water channels (HC6H) as modifiers. Effective combination of COF layers and imidazole-quartet water channels provide the membrane with excellent performance. The as-prepared membrane exhibits a water permeance above 271.7 L·m−2·h−1·bar−1, and high rejection rate (>99.5%) for CR. The results indicated that the composite structure based on AWCs and COFs may provide a new idea for the development of high-performance membranes for dye separation.

Facile Strategy to Fabricate the Flame Retardant Polyamide 66 Fabric Modified with an Inorganic-Organic Hybrid Structure.

Recently, traditional flame retardant finishing with a single metal compound has been rarely applied owing to its low effectiveness and durability. This study reports metal ion finishing in combination with surface photografting modification (M/P technology) as a novel approach to incorporate an inorganic-organic hybrid structure containing an Fe3+ ion onto the surface of the polyamide (PA) 66 fabric. Specifically, the PA fabric was first surface-modified in the presence of acrylic acid (AA) and N,N'-methylene bisacrylamide (MBAAn) during photografting pretreatment under UV irradiation (step I), then further reacted with the Fe3+ ion in the metal ion finishing (step II). After treatment with M/P technology, the fabric exhibits the required excellent flame retardancy and dripping resistance. Here, flame retardant tests show that the treated PA fabric has the highest limiting oxygen index (LOI) value of 33.4 and no melt dripping during combustion. An interesting inorganic/organic composite thermal barrier consisting of an inorganic iron oxide nanoparticle (NP) outer layer and an organic micro-intumescent inner layer can be observed on the surface of the burnt fabric. This structure could be responsible for the significant enhancement in the fire performance of the treated fabric. Importantly, the treated fabric is also highly stable during the laundering procedure, which could retain a high Fe/C ratio and an acceptable LOI value of 27.8 after washing 45 times. This confirms the achievement of durable flame retardancy after treatment with M/P technology, and its possible interaction mechanism has been discussed here.

Preparation and evaluation of the adjuvant effect of curdlan sulfate in improving the efficacy of dendritic cell-based vaccine for antitumor immunotherapy.

Dendritic cell (DC) vaccine immunotherapy applies tumor antigens or tumor cell lysate (TCL)-pulsed DCs to induce an antigen-specific immune response to attack cancer cells. However, tumor antigen alone has limited immunostimulatory effects, and so immunostimulants are needed to prepare mature DCs. In our previous study, curdlan sulfate (CS) showed potent adjuvant properties with the HBV vaccine; therefore, we attempted to use CS to mature TCL-pulsed DCs. We first prepared four CSs (CS1-CS4) with different sulfation (S) degrees and molecular weights (MWs), then studied the structure-activity relationship of CS in vitro and finally screened CS3 (14.316% S content and 30.66 kDa MW) as the DC vaccine adjuvant. An in vivo study showed that a DC vaccine adjuvanted with CS3 significantly prolonged the survival of tumor-bearing mice, reduced tumor burden and inhibited tumor growth. The CS3-adjuvanted DC vaccine increased CD80, MHC-I and MHC-II expression, promoted CD8+ T cell infiltration, upregulated TNF-α and IFN-γ transcription, and downregulated TGF-ß transcription in tumor tissues. A preliminary mechanism study showed that CS activated DCs mainly via the TLR4 and TLR2 signalling pathways. Based on these results, we concluded that CS3 is a potential adjuvant for DC vaccines and is worth studying for tumor immunotherapy.

Pharmacokinetics and vasodilating effect study of beraprost sodium in healthy volunteers.

Currently beraprost sodium (BPS) is widely proposed to ameliorate the symptoms caused by chronic arterial occlusive disease. The objective of this study is to investigate the BPS pharmacokinetic characteristics, its vasodilating effect and the relationship between plasma concentration vs response effect. 12 healthy Chinese volunteers (6 male, 6 female) were chosen to participate in a single center, random, and open design study. After overnight fasting, BPS (dose = 40µg) was administrated orally to each volunteer. The blood samples were collected at different time points (from 0 to 5 h after administration) and BPS concentration was analyzed by LC-MS/MS method. The vasodilating effect was evaluated by detecting the skin microcirculation blood flow of volunteers' fingers with laser Doppler fluxmetry. The Cmax of BPS was (601.14 ± 214.81) pg/mL, the Tmax was (0.58 ± 0.48) h, and AUC0-t was (1020.41±214.63) pg/mL•h. BPS exhibited significant vasodilating effect since the skin microcirculation blood flow increased definitely at 0.25, 0.5, and 0.75 h (all p<0.05) after drug administration, and a positive correlation was presented between the pharmacokinetics and the vasodilating effect, which would be beneficial for guiding BPS dosage in clinical.

Characteristics and Performance Evaluation of QZSS Onboard Satellite Clocks.

In the Global Navigation Satellite System (GNSS) community, the Quasi-Zenith Satellite System (QZSS) is an augmentation system for users in the Asia-Pacific region. However, the characteristics and performance of four QZSS satellite clocks in a long-term scale are unknown at present. However, it is crucial to the positioning, navigation and timing (PNT) services of users, especially in Asia-Pacific region. In this study, the characteristics and performance variation of four QZSS satellite clocks, which including the phase, frequency, frequency drift, fitting residuals, frequency accuracy, periodic terms, frequency stability and short-term clock prediction, are revealed in detail for the first time based on the precise satellite clock offset products of nearly 1000 days. The important contributions are as follows: (1) It is detected that the times of phase and frequency jump are 2.25 and 1.5 for every QZSS satellite clock in one year. The magnitude of the frequency drift is about 10-18. The periodic oscillation of frequency drift of J01 and J02 satellite clocks is found. The clock offset model precision of QZSS is 0.33 ns. (2) The two main periods of QZSS satellite clock are 24 and 12 hours, which is the influence of the satellite orbit; (3) The frequency stability of 100, 1000 and 10,000 s are 1.98 × 10-13, 6.59 × 10-14 and 5.39 × 10-14 for QZSS satellite clock, respectively. The visible "bump" is found at about 400 s for J02 and J03 satellite clocks. The short-term clock prediction accuracy of is 0.12 ns. This study provides a reference for the state monitoring and performance variation of the QZSS satellite clock.

Curdlan sulfate/O-linked quaternized chitosan nanoparticles acting as potential adjuvants promote multiple arms of immune responses.

Nasal immunization to prevent and treat diseases caused by infection through the respiratory tract cannot be actualized because of the lack of effective adjuvants. We have proven that compared with antigens loaded on CS or O-HTCC alone in nasal vaccination, antigens loaded on the nanoparticles of curdlan sulfate/O-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (CS/O-HTCC) can induce stronger systemic and mucosal immune responses. In this study, we evaluated the immunostimulatory activity and mechanisms of CS/O-HTCC nanoparticles. The results showed that CS/O-HTCC nanoparticles can improve the activation of antigen-presenting cells, upregulate the production of inflammatory factors and cytokines, induce cross-presentation, and simultaneously activate type I interferon-related genes. CS/O-HTCC nanoparticles also activated the PI3K/AKT and MAPK pathways and significantly promoted IL-2 transcription to induce the proliferation of lymphocytes. The results revealed that CS/O-HTCC nanoparticles as a type of multifunctional adjuvant can improve multiple arms of immune responses.

The Impact of Antiepileptic Drugs on Vitamin Levels in Epileptic Patients.

BACKGROUND: The impact of antiepileptics on serum vitamin levels is controversial and uncertain. With no clear conclusions on the impact of antiepileptics on serum levels of vitamins, there is a need for further clinical studies in order to ascertain the impact of old and newer antiepileptic drugs on serum levels of vitamins in epileptic patients, thus accomplishing a suitable usage of vitamins supplementation. OBJECTIVE: The intention of the present research is to confirm the hypothesis of whether or not vitamin levels are altered with antiepileptic drugs. The study also aims to reveal which vitamin levels are particularly more altered, are vitamin levels affected by gender and the type and number of antiepileptics used. METHODS: The present research was piloted in collaboration with the Department of Neurology in Qilu Hospital of Shandong University. A total of 63 serum samples of epileptic patients receiving antiepileptics as monotherapy or polytherapy were requested for analysis of nine vitamin serum levels. Total nine vitamins (B1, B2, B6, B9, B12, A, C, D and E) in epileptic patients receiving antiepileptic drugs were analyzed. The serum results of all vitamins were compiled and evaluated with SPSS. RESULTS: It was alarmingly found that serum levels of vitamin D were particularly very low in almost all (90%) epileptic patients in this study. Notably, serum levels of vitamin C and vitamin B1 were also below reference range in 72% and 46% epileptic patients, respectively. The remaining vitamins were almost in reference range for most of the patients. In our study, mean and frequency of vitamin D, C and B1 levels do not vary too much among different gender groups. The patients receiving newer antiepileptic drugs displayed a slightly increased serum vitamin D levels in comparison to the patients receiving older antiepileptic drugs. We found low vitamin D, C and B1 serum levels in patients who were on monotherapy as in comparison with patients on polytherapy. CONCLUSION: The most significant and surprising finding of this study revealed that serum vitamin D levels in particular were very low in almost all patients and in some patients' vitamin B1 serum levels were also below the reference range. More importantly, it is first time reported here that vitamin C serum levels were also below reference range in the majority of these Chinese epileptic patients. It is recommended that all these vitamins should be regularly monitored in addition to therapeutic drug monitoring of antiepileptic drugs. Additional clinical trials are required for further evaluation. It is also recommended that epileptic patients with low serum levels of these vitamins may be prescribed vitamins supplementations with antiepileptic drugs in order to control their seizures more effectively and efficiently.

ß-glucans as potential immunoadjuvants: A review on the adjuvanticity, structure-activity relationship and receptor recognition properties.

ß-glucans, a group of polysaccharides exist in many organism species such as mushrooms, yeasts, oats, barley, seaweed, but not mammalians, have a variety of biological activities and applications in drugs and other healthcare products. In recent years, ß-glucans have been studied as adjuvants in anti-infection vaccines as well as immunomodulators in anti-cancer immunotherapy. ß-glucans can regulate immune responses when administered alone and can connect innate and adaptive immunity to improve immunogenicity of vaccines. When ß-glucans act as immunostimulants or adjuvants, a set of receptors have been revealed to recognize ß-glucans, including dectin-1, complement receptor 3 (CR3), CD5, lactosylceramide, and so on. Therefore, this review is mainly focused on the application of ß-glucans as immune adjuvants, the receptors of ß-glucans, as well as their structure and activity relationship which will benefit future research of ß-glucans.

Curdlan sulfate-O-linked quaternized chitosan nanoparticles: potential adjuvants to improve the immunogenicity of exogenous antigens via intranasal vaccination.

INTRODUCTION: The development of ideal vaccine adjuvants for intranasal vaccination can provide convenience for many vaccinations. As an ideal intranasal vaccine adjuvant, it should have the properties of assisting soluble antigens to pass the mucosal barrier and potentiating both systemic and mucosal immunity via nasal administration. METHODS: By using the advantages of polysaccharides, which can promote both T-helper 1 and 2 responses, curdlan sulfate (CS)-O-(2-hydroxyl)propyl-3-trimethyl ammonium chitosan chloride (O-HTCC) nanoparticles were prepared by interacting CS with O-HTCC, and the adjuvancy of the nanoparticles was investigated. RESULTS: The results showed that the polysaccharide-based nanoparticles induced the proliferation and activation of antigen-presenting cells. High protein-loading efficiency was obtained by testing with the model antigen ovalbumin (Ova), and the Ova adsorbed onto the cationic CS/O-HTCC complexes was taken up easily by the epithelium. To evaluate the capacity of the Ova/CS/O-HTCC nanoparticles for immune enhancement in vivo, we collected and analyzed immunocytes, serum, and mucosal lavage fluid from intranasally vaccinated mice. The results showed that Ova/CS/O-HTCC nanoparticles induced activation and maturation of antigen-presenting cells and provoked the proliferation and differentiation of lymphocytes more significantly compared to the immunization of Ova mixed with aluminum hydroxide gel. Furthermore, CS/O-HTCC evoked a significantly higher level of Ova-specific antibodies. CONCLUSION: Therefore, these results suggest that CS/O-HTCC nanoparticles are ideal vaccine adjuvants for soluble antigens used in intranasal or mucosal vaccination.

Comparison of New Liquid Chromatography-Mass Spectrometry Method and Enzyme-Multiplied Immunoassay Technique for Routine Therapeutic Drug Monitoring of Vancomycin in Chinese Patients.

BACKGROUND: Therapeutic drug monitoring of vancomycin is very valuable due to the good correlation between trough levels and clinical outcome. Therefore, it is important to accurately determine the concentration of vancomycin in patient plasma for adequate dose-adjustment. The objective of this study was to develop a new liquid chromatography-mass spectrometry (LC-MS) method for determination of vancomycin in patient plasma and compare the results with those obtained from enzyme-multiplied immunoassay technique (EMIT). METHODS: After extraction by simple protein precipitation, vancomycin and bergenin (internal standard) were separated on a C18 column (150×4.6 mm, 5 µm) at 40°C by gradient elution with 0.1% formic acid and acetonitrile as the mobile phase and measured by electrospray ionization source in positive selective ion monitoring mode. Seventy-nine plasma samples from patients with severe infection were analyzed by enzyme-multiplied immunoassay technique and LC-MS method. MedCalc 15.2 software with Bland-Altman analysis and Passing-Bablok regression analysis was used for statistical analysis. RESULTS: The weighted (1/x2) calibration curve of the validated LC-MS was linear within the concentration range of 0.25 - 40 µg/mL. The inter- and intra-day precisions (%RSD) were less than 10.0%. No significant matrix effect was observed in the relevant time ranges. Comparison of the two methods indicated that results of the LC-MS were close to that of EMIT with a correlation coefficient of 0.957. Upon Bland-Altman analysis, the bias amounted to 2.9 µg/mL (95% confidence intervals of -3.4 - 9.2 µg/mL). CONCLUSIONS: The established LC-MS method and EMIT were both suitable for routine TDM of vancomycin.

A comparison of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and enzyme-multiplied immunoassay technique (EMIT) for the determination of the cyclosporin A concentration in whole blood from Chinese patients.

Cyclosporin A (CyA) is an immunosuppressive agent widely used in clinical therapy. In the therapeutic process, the blood concentration of CyA should be monitored to avoid or prevent rejection and toxicity. The objectives of this study were to compare the correlation of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and enzyme-multiplied immunoassay technique (EMIT) for the determination of the CyA concentration in human blood and to provide evidence for the rational usage of EMIT in clinical practice. Blood samples collected from 132 patients undergoing a liver or kidney transplant or patients with aplastic anemia at Qilu Hospital of Shandong University were tested using the two methods. The calibration curve was linear from 25-500 ng·mL-1 for LC-MS/MS and from 50-450 ng·mL-1 for EMIT. The inter- and intra-day RSDs were less than 15%. The CyA blood concentration according to EMIT was 3.5 ng·mL-1 more than that according to LC-MS/MS. The 95% confidence interval was -10.0~16.9 ng·mL-1. The CyA blood concentration according to the two methods did not differ significantly (p > 0.05). LC-MS/MS and EMIT were suitable methods for determining the CyA blood concentration. The two methods were closely correlated (r2 = 0.969), but the CyA blood concentration according to EMIT was slightly higher than that according to LC-MS/MS. The clinical significance of this finding needs to be further evaluated.

Comparison of the docetaxel concentration in human plasma measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and a nanoparticle immunoassay and clinical applications of that assay.

To determine the feasibility of using a nanoparticle immunoassay for clinical therapeutic drug monitoring (TDM) of docetaxel concentrations, a sensitive and simple method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) was established to measure the docetaxel concentration in human plasma and the results of LC-MS/MS and the immunoassay were compared. Docetaxel and paclitaxel (the internal standard, or IS) in human plasma were extracted through protein precipitation, separated on a Diamonsil C18 column (150 mm × 4.6 mm, 5 µm), ionized with positive ions, and detected with LC-MS/MS in multi-reaction monitoring (MRM) mode. Plasma samples from 248 cancer patients were assayed with LC-MS/MS and a nanoparticle immunoassay. Data from the samples were analyzed with the statistical software SPSS and the software MedCalc. Results indicated that the calibration curve of the validated method of LC-MS/MS was linear over the range of 10-2,000 ng/mL, with an lowest limit of quantitation (LLOQ) of 10 ng/mL, and the intra- and inter- day precision and accuracy were both < ± 15%. Comparison of the two methods indicated that results of the LC-MS/MS were closely related to those of the nanoparticle immunoassay, with a correlation coefficient (R) of 0.965 and acceptable 95% confidence intervals (CI) of ‒ 231.7-331.1 ng/mL. Overall, the established method of LC-MC/MS and the nanoparticle immunoassay were both suitable for measurement of the docetaxel concentration in human plasma, and the immunoassay was far more cost-effective and better at clinical TDM of docetaxel in clinical practice.

Effect of α-linolenic acid-modified low molecular weight chondroitin sulfate on atherosclerosis in apoE-deficient mice.

METHODS: 8-week-age male ApoE(-/-) mice were fed with the atherogenic diet together with or without tested compounds (rosuvastatin calcium, α-LNA-LMWCS, LMWCS and α-LNA) for 16 weeks. When the animals were killed, blood plasma was isolated to test the level of TC, LDL-C, TNF-α, IL-6 and CRP by biochemistry analysis and ELISA method. The whole aorta and aortic root sections were also collected to study atherogenesis level and reveal the possible mechanism by histological examination, real-time PCR and Western blot analysis. RESULTS: The level of TC, LDL-C, TNF-α, IL-6 and CRP in plasma in H-LNA-LMWCS group were significantly lower than those of the control group (rosuvastatin calcium). Plaques in H-LNA-LMWCS group showed higher content of smooth muscle cells, lower content of lipid and macrophages, and lower mRNA levels of TNF-α, IL-6, CRP, MCP-1, VCAM-1 and ICAM-1 than those in the control group. In addition, α-LNA-LMWCS could reduce the nuclear translocation of NF-κB, inhibit expressions of p-ERK1/2, p-p38, MCP-1, VCAM-1 and ICAM-1 in mice aorta. CONCLUSION: α-LNA-LMWCS exhibited anti-atherosclerosis effect through regulating the lipid metabolism and diminishing the synthesis of pro-inflammatory cytokines. The possible mechanism may be that α-LNA-LMWCS could influence MAPK/ NF-κB related signal pathway. GENERAL SIGNIFICANCE: The results may provide significant suggestions for the application of α-LNA-LMWCS in anti-atherosclerosis.

Impact of the CYP2C19 Gene Polymorphism on Clopidogrel Personalized Drug Regimen and the Clinical Outcomes.

BACKGROUND: Although the relationship between CYP2C19 genotype and clopidogrel metabolism has been studied clearly, we have not seen the report that clopidogrel was administered at a dose adjusted based on genotyping. The two main polymorphism loci of CYP2C19 gene were detected by the CYP2C19 genetic testing. ADP platelet aggregation technology was used to investigate the correlation between clinical effect and the clopidogrel dose, genetic metabolic type, physiological, pathological and other factors, to provide new ideas for clopidogrel therapy for percutaneous coronary intervention postoperation patients. METHODS: A total of 48 patients were enrolled. All patients were given clopidogrel routine maintenance dose treatment and underwent CYP2C19 genotyping and platelet function testing. Patients were divided into extensive metabolizers, intermediate metabolizers, and poor metabolizers based on the different CYP2C19 genotypes. The clopidogrel dosage was adjusted to double the maintenance dose for the ineffective patients. RESULTS: The study showed that all patients had no toxic side effects. The low responsiveness to clopidogrel in patients with diabetes is closely related to insulin resistance. Patients with hypertension and hyperlipidemia may increase the risk of clopidogrel resistance. The occurrence of clopidogrel resistance is associated with the CYP2C19 polymorphism in the < 65-year-old female patients. CONCLUSIONS: For percutaneous coronary intervention in postoperative patients, research data is still lacking regarding clopidogrel dosage on the basis of different CYP2C19 genotypes. Looking forward, more rigorous research programs need to be designed to bring more guidance for clinical application.

Polysaccharides: Candidates of promising vaccine adjuvants.

Aluminium-based adjuvants remain the only adjuvants approved for human use in the USA for over 80 years because of alum's simplicity, tolerability, safety and cost-efficiency. Recent development of vaccines, especially the increasing applications of recombinant subunit and synthetic vaccines, makes aluminium adjuvants cannot stimulate enough immunity to the antigens, since aluminium adjuvants can only induce Th2 type immune responses. So, novel adjuvants are urgent to make up the disadvantages of aluminium adjuvants. However, some major hurdles need to be overcome, not only the scientific knowledge of adjuvants but also unacceptable side-effects and toxicity. A number of carbohydrate-based polysaccharides from plant, bacterial, yeast and synthetic sources can act as pathogen-associated molecular patterns (PAMPs) and recognize pattern recognition receptors (PRRs) on immune cells, followed by triggering innate immunity and regulating adaptive immunity. What is more, polysaccharides are safe and biodegradable without tissue deposits as observed in aluminium adjuvants. Therefore, polysaccharide-based compounds and formulations are potential vaccine adjuvant candidates. Here, we mainly review polysaccharide-based adjuvants investigated in recent years.