Enhancing both oral bioavailability and anti-ischemic stroke efficacy of ginkgolide B by preparing nanocrystals self-stabilized Pickering nano-emulsion.

Ginkgolide B (GB), which has been demonstrated as the most efficacious naturally occurring platelet-activating factor (PAF) antagonist, is extensively utilized for the management of cardiovascular and cerebrovascular ailments. Nevertheless, its limited oral bioavailability is hindered by its low solubility in gastric acid and inadequate stability in intestinal fluid, thereby constraining its practical application. This study aimed to develop GB nanocrystals (GB-NCs) and GB nanocrystals self-stabilized Pickering nano-emulsion (GB-NSSPNE) using a miniaturized wet bead milling method. Comparative evaluations were conducted in vivo and in vitro to assess their effectiveness. The findings revealed that GB-NSSPNE, with its intact nanoparticle slow release and absorption, was more effective in enhancing the oral bioavailability of GB compared to the rapid release and absorption of GB-NCs. This finding suggests a potential novel strategy for the oral delivery of GB.

UWB Low-Profile Boat-Radiator Antenna (BRA) with Dual C-Shape Co-Radiative Ground for Multi-Standard Communication Networks.

Multiple standard communication networks operate in the frequency band of 1.8-6 GHz, which makes lots of antennas available in the limited space. To solve the problem of interference and improve the performance of these antennas, an ultra-wideband (UWB) antenna is presented. It consists of a boat-radiator and a dual C-shape co-radiative ground (DCCRG). One half of the DCCRG plays a role of the ground of a co-planar waveguide fed to the proposed boat-radiator antenna (BRA), while the other half works as a multiple order L-resonant circuit to broaden the lower operating band. Uniform bidirectional radiation is presented with the size of 0.25 λ × 0.375 λ × 0.0063 λ over the frequency band of 1.7-6.3 GHz (115%). The proposed antenna achieves around twice the bandwidth (60%) of the same structured antenna without the structure acting as a multiple order L-resonant circuit. Moreover, the stable boresight gain of 3.6 dBi ± 1.25 dBi is realized over the operating band.

ARCS: Active Radar Cross Section for Multi-Radiator Problems in Complex EM Environments.

In order to analyze the scattering properties in multi-radiator problems, the active radar cross section (ARCS) concept is proposed under complex electromagnetic (EM) environments. The corresponding calculation methods and formulation are proposed by incorporating the monostatic radar cross section (RCS) concept with external disturbances. By introducing the phase characteristics into the ARCS concept, the coherent problems can be accurately solved. Through analyzing the external disturbance and the radar waves by employing the finite element method, the coherent and the incoherent characteristics of the external disturbance can be simulated in complex structures. Numerical examples and an experiment are carried out to further demonstrate the effectiveness of the proposed ARCS concept. The results demonstrate that the proposed ARCS concept obtains better universality compared with the existing incoherent multi-radiator formulation. Meanwhile, the ARCS can be identical with the solution which is obtained by the single radar wave. Compared with the existing incoherent methods for external disturbances calculations, the proposed ARCS concept is more rational. Through the experiment, the effectiveness of the calculation method and formulation is further demonstrated and validated.

[Analysis of projects funded by NSFC in field of pharmacology of traditional Chinese medicine in 2019].

The projects which supported by National Natural Science Foundation of China(NSFC) including General Program, Young Scientist Fund, and Fund for Less Developed Regions, in field of pharmacology of traditional Chinese medicine in 2019 were reviewed. Based on these research items, the main contents and characteristics, as well as the main problems from academic and non-academic point of view, were summarized for reference.

Estradiol Protects Neuropeptide Y/Agouti-Related Peptide Neurons against Insulin Resistance in Females.

When it comes to obesity, men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage wanes in postmenopausal women. A key diagnostic of the metabolic syndrome is insulin resistance in both peripheral tissues and brain, especially in the hypothalamus. Since the anorexigenic hormone 17ß-estradiol (E2) regulates food intake in part by inhibiting the excitability of the hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons, we hypothesized that E2 would protect against insulin resistance in NPY/AgRP neurons with diet-induced obesity (DIO). Therefore, we did whole-cell recordings and single cell quantitative polymerase chain reaction in arcuate NPYGFP neurons from both female and male mice to test the efficacy of insulin with DIO. The resting membrane potential and input resistance of NPY/AgRP neurons were significantly increased in DIO versus control-diet fed males. Most notably, the efficacy of insulin to activate KATP channels in NPY/AgRP neurons was significantly attenuated, although the KATP channel opener diazoxide was fully effective in NPY/AgRP neurons from DIO males, indicating that the KATP channels were expressed and functional. In contrast, insulin was fully efficacious to activate KATP channels in DIO females, and the response was reversed by the KATP channel blocker tolbutamide. However, the ability of insulin to activate KATP channels was abrogated with ovariectomy but fully restored with E2 replacement. Insulin resistance in obese males was likely mediated by an increase in suppressor of cytokine signaling-3 (SOCS-3), protein tyrosine phosphatase B (PTP1B) and T-cell protein tyrosine phosphatase (TCPTP) activity, since the expression of all 3 mRNAs were upregulated in the obese males but not in females. As proof of principle, pre-incubation of hypothalamic slices from DIO males with the PTP1B/TCPTP inhibitor CX08005 completely rescued the effects of insulin. Therefore, E2 protects NPY/AgRP neurons in females against insulin resistance through, at least in part, attenuating phosphatase activity. The neuroprotective effects of E2 may explain sex differences in the expression of metabolic syndrome that disappears with the loss of E2 in aging.

Two new alkaloids from Portulaca oleracea L. and their bioactivities.

Two new indole alkaloids, identified as (E)-1-(5,6-dihydroxy-1H-indol-1-yl)-3-(4-hydroxyphenyl)prop-2-en-1-one, named oleraindole A (1), and (E)-1-(5,6-dihydroxy-1H-indol-1-yl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one, named oleraindole B (2), together with five known indole alkaloids, (-)-neoechinulin A (3), neoechinulin D (4), isoechinulin A (5), MT-6 (6) and echinulin (7) were isolated from the aqueous extract of Portulaca oleracea L. for the first time, using various chromatographic techniques. The structures of seven alkaloids were elucidated by the 1D and 2D NMR and HR-ESI-TOF-MS spectroscopic methods. Oleraindole A (1) and oleraindole B (2) exhibited a relatively high anticholinesterase activity with IC50 values of 55.12 ±â€¯0.20 µΜ and 46.76 ±â€¯0.08 µM, and antioxidant activities with the IC50 values of 16.20 ±â€¯0.11 µM and 13.88 ±â€¯0.06 µM among seven alkaloids.

Association of MMP-8 rs2012390 and rs11225394 polymorphisms with osteonecrosis of the femoral head risks: Evidence from a meta-analysis.

BACKGROUND: The association of MMP-8 rs2012390 and rs11225394 polymorphisms with osteonecrosis of the femoral head (ONFH) risks was investigated in several studies with conflicting results. We performed the meta-analysis to evaluate the association between them. METHODS: Potentially relevant literatures were searched from the electronic databases of PubMed, Web of Science, and Cochrane Library. All databases were searched up to May 6, 2018. The strength of associations of the MMP-8 rs2012390 and rs11225394 polymorphisms with ONFH risk was assessed by crude odds ratios (ORs) with their 95% confidence intervals (CIs) under different genetic models. RESULTS: A total of 1469 cases diagnosed with ONFH and 1211 healthy controls were included in the current meta-analysis. A remarkable association between rs11225394 in the MMP-8 gene and an increased risk of ONFH was found (allele model: OR = 1.33, 95% CI = 1.09-1.61, P = .005; heterozygote model: OR = 1.39, 95% CI = 1.13-1.71, P = .002; dominant model: OR = 1.40, 95% CI = 1.14-1.73, P = .002, respectively). Meanwhile, a significant association between MMP-8 rs2012390 and the decreased risk of ONFH was found in heterozygote model (OR = 0.63, 95% CI = 0.51-0.77, P < .00001). CONCLUSION: The meta-analysis results showed a remarkable association between rs11225394 in MMP-8 gene and an increased risk of ONFH and a significant association between MMP-8 rs2012390 and the decreased risk of ONFH.

Hyaluronic acid and carbon dots-gated hollow mesoporous silica for redox and enzyme-triggered targeted drug delivery and bioimaging.

In this work, a redox and enzyme dual-stimuli responsive drug delivery system (DDS) with tracking function (HMSN-SS-CDPEI@HA) based on carbon dots capped hollow mesoporous silica nanoparticles (HMSN) has been developed for targeted drug delivery. The positively charged CDPEI nanoparticles prepared by polyethylenimine (PEI) were grafted on the pore openings of HMSN through disulfide bonds and were used as "gatekeepers" to trap the drugs within the hollow cavity. The hyaluronic acid (HA), a natural polysaccharide, was further grafted on the surface of HMSN to realize targeted drug delivery, controlled drug release and improved the stability. Doxorubicin (DOX) was chosen as a model drug due to its wide clinical application. In vitro drug release profiles demonstrated that DOX-loaded HMSN-SS-CDPEI@HA exhibited redox and enzyme dual-responsive drug release property. In addition, the prepared HMSN-SS-CDPEI@HA exhibited excellent fluorescent properties and biocompatibility. Confocal laser scanning microscope (CLSM) and flow cytometry (FCM) illustrated that HMSN-SS-CDPEI@HA exhibited a higher cellular uptake via the CD44 receptor-mediated endocytosis by CD44-receptor over-expressed A549 cells than NIH-3T3 (receptor-negative) cells, leading to higher cytotoxicity against A549 cells than NIH 3T3 cells. This work suggested an exploration of dual-stimuli responsive as well as real-time imaging targeted drug delivery system based on HMSN and the prepared HMSN-SS-CDPEI@HA could be a promising platform for cancer therapy.

Effects of alfalfa flavonoids on the production performance, immune system, and ruminal fermentation of dairy cows.

OBJECTIVE: The objective of this study was to examine the effects of alfalfa flavonoids on the production performance, immunity, and ruminal fermentation of dairy cows. METHODS: The experiments employed four primiparous Holstein cows fitted with ruminal cannulas, and used a 4×4 Latin square design. Cattle were fed total mixed ration supplemented with 0 (control group, Con), 20, 60, or 100 mg of alfalfa flavonoids extract (AFE) per kg of dairy cow body weight (BW). RESULTS: The feed intake of the group receiving 60 mg/kg BW of AFE were significantly higher (p<0.05) than that of the group receiving 100 mg/kg BW. Milk yields and the fat, protein and lactose of milk were unaffected by AFE, while the total solids content of milk reduced (p = 0.05) linearly as AFE supplementation was increased. The somatic cell count of milk in group receiving 60 mg/kg BW of AFE was significantly lower (p<0.05) than that of the control group. Apparent total-tract digestibility of neutral detergent fiber and crude protein showed a tendency to increase (0.05

Design and evaluation of an innovative floating and bioadhesive multiparticulate drug delivery system based on hollow structure.

In this study a gastric-retentive delivery system was prepared by a novel method which is reported here for the first time. An innovative floating and bioadhesive drug delivery system with a hollow structure was designed and prepared. The floating and bioadhesive drug delivery system was composed of a hollow spherical shell, a waterproof layer (Stearic acid), a drug layer (Ofloxacin), a release retarding film (the novel blended coating materials) and a bioadhesive layer (Carbomer 934P) prepared by using a liquid multi-layering process. A novel blended coating material was designed and investigated to solve the problem of the initial burst release of the formulation and the release mechanism of the novel material was analyzed in this study. The optimized formulation provided the sustained release characteristic and was able to float for 24h. The SEM cross-section images showed that the particulates were hollow with a spherical shell. X-ray images and pharmacokinetic studies (Frel = 124.1 ± 28.9%) in vivo showed that the gastric-retentive delivery system can be retained in the stomach for more than 6h. The floating and bioadhesive particulate drug delivery system based on a hollow structure with a dual function presented here is a viable alternative to other for gastroretentive drug delivery system.

Application of an ultra-performance liquid chromatography method with tandem mass spectrometry to pharmacokinetics, tissue distribution and excretion in the study of DAT-230, a novel tubulin-binding agent candidate, in rats.

A rapid, sensitive and high-throughput ultra-performance liquid chromatography method with tandem mass spectrometry (UPLC-MS/MS) has been developed for the determination of DAT-230 in rat plasma, urine, feces and tissues (heart, liver, spleen, lung, kidney, stomach, intestine and brain). The biological samples were prepared by protein precipitation, and separation was achieved on an ACQUITY™ UPLC BEH C18 column (50 mm × 2.1mm, 1.7 µm) with a mobile phase that consisted of methanol - 0.2% formic acid water (80:20, v/v) at a flow rate of 0.2 mL/min. The MS/MS ion transitions were monitored at m/z 372.17 → 357.17 for DAT-230 and m/z 406.08 → 345.16 for COH-203 (internal standard, IS). The calibration curve was linear in the range of 0.1-5200 ng/mL for all biological matrices (r(2) ≥ 0.996), and it had the same value for the lower limit of quantification. The validated method was successfully applied to the pharmacokinetics, tissue distribution and excretion study after intravenous administration of a 5mg/kg dose of DAT-230 to healthy Sprague-Dawley rats. The mean pharmacokinetic parameters of t1/2 and AUC0-12 were (1.1 ± 0.4)h and (861.0 ± 281.2) ng h/mL, respectively. Tissue distribution results indicated that DAT-230 exhibited rapid distribution and high liver, kidney, spleen, stomach and intestine uptake; these organs were indicated as the major target organs of the drug. In total, 5.3% of the administered DAT-230 was excreted in an unconverted form in urine, feces and bile, which implies that DAT-230 was excreted primarily in the form of metabolites.

Estimation of left ventricular stroke volume based on pressure waves measured at the wrist: a method aimed at home-based use.

Continuous monitoring of stroke volume (SV) or cardiac output (CO) has long been the subject of numerous studies. The majority of existing methods are calibration-dependent, requiring invasive measurements of CO to initialize the estimation algorithms, thus limiting their application to the clinical setting. In the present study, a new calibration-free method aimed at home-based use has been developed, which allows noninvasive estimation of SV from oscillometric signals measured at the wrist. The estimation equation was constructed based on the PRAM method, with significant modifications to incorporate more patient-specific information. Furthermore, the estimation equation was optimized based on the clinical data acquired from 96 patients (the 'Training' group) to obtain the best comparison of estimated SV with echocardiographic SV. The resulting estimation equation was then applied directly to another patient group (the 'Testing' group) to examine its validity. Obtained results demonstrate that our estimations correlated closely with the measurements in both patient groups. In addition to being noninvasive and calibration-free, the proposed method can be fully automated, which may be valuable for the future development of home-based cardiac monitoring systems.

Application and functional characterization of POVACOAT, a hydrophilic co-polymer poly(vinyl alcohol/acrylic acid/methyl methacrylate) as a hot-melt extrusion carrier.

OBJECTIVE: The aim of this study was to evaluate the applicability of POVACOAT™, a hydrophilic PVA copolymer, as a solid dispersion (SD) carrier for hot-melt extrusion (HME). METHODS: Bifendate (DDB), a water-insoluble drug, was chosen as the model drug. DDB was hot-melt extruded by a co-rotating twin screw extruder with POVACOAT™. The SD formability of POVACOAT™ was investigated by varying the composition ratios. Solid state characterization was evaluated by differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy and Fourier transformation infrared spectroscopy. In order to have a better knowledge of the mechanism of dissolution enhancement, dissolution study, phase solubility study and crystallization study of DDB from supersaturated solutions were performed. In addition, the storage stability of the extrudate containing 10% DDB was investigated. RESULTS: Physical characterizations showed that DDB was amorphous up to 15% drug loading. The phase solubility study revealed an AL-type curve. Moreover, POVACOAT™ was found to have an inhibitory effect on crystallization from supersaturated solutions. Compared with the pure DDB and physical mixture, the dissolution rate and solubility of extrudates were significantly enhanced and the drug loading markedly affected the dissolution of SDs. Furthermore, the stability test indicated that 10% DDB-SD was stable during storage (40 °C/75% RH). CONCLUSION: The results of this study demonstrate that POVACOAT™ is a valuable excipient for the formulation of solid dispersions prepared by HME to improve dissolution of poorly water-soluble drugs.

Improving cabazitaxel chemical stability in parenteral lipid emulsions using cholesterol.

Intravenous lipid emulsions of cabazitaxel (CLEs) with a high stability were prepared by adding cholesterol (CH) to provide a new and more suitable delivery system for its administration. The factors affecting CLEs, such as the solubility of cabazitaxel in various oils, different kinds of lecithin, pH, different types of oil phases, and different concentrations of lipoid E80®, CH and poloxamer 188 were investigated systematically. The degradation of cabazitaxel in aqueous solution and lipid emulsion both followed pseudo first-order kinetics. A degradation mechanism was suggested by the U-shaped pH-rate profile of cabazitaxel. A formulation containing 0.5% (w/v) CH and another formulation without CH were made to investigate the protective influence of CH on the chemical stability of CLEs. The activation energy of the two formulations was calculated to be 65.74±6.88 and 54.24±1.43 kJ/mol (n=3), respectively. Compared with the untreated CH, the shelf-life of cabazitaxel with added CH was longer, namely 134.0±23.4 days versus 831.4±204.4 days (n=3) at 4 °C. This indicates that the addition of CH significantly improved the lifetime of cabazitaxel in intravenous lipid emulsions. The hydrogen bonding that takes place between cabazitaxel and CH accounts for the protective effect of CH on the chemical stability of CLEs in two ways: preventing cabazitaxel from leaking and hydrolyzing in aqueous solution and hindering hydrolysis in the oil phase. Finally, the hypothesis was confirmed by LC/TOFMS and Fourier-transform infrared-spectroscopy. As a result, CLEs were obtained successfully by the addition of CH and were stable enough to allow further research.

[Analysis of primary metabolites of ranolazine in dog urine by LC-MS(n)].

Ranolazine and metabolites in dog urine were identified by LC-MS(n). Dog urine samples were collected after ig 30 mg x kg(-1) ranolazine, then the samples were enriched and purified through solid-phase extraction cartridge. The purified samples were analyzed by LC-MS(n). The possible metabolites were discovered by comparing the full scan and SIM chromatograms of the test samples with the corresponding blanks. Seventeen phase I metabolites and fourteen phase II metabolites were identified in dog urine. Three metabolites were identified by comparing with the control article. The metabolites were formed via the following metabolic pathways: O-demethylation, O-dearylation, hydroxylation, N-dealkylation, amide hydrolysis, glucuronidation and sulfation. The LC-MS(n) method is suitable for the rapid identification of drug and its metabolites in biologic samples.

Preparation of lipid aspirin sustained-release pellets by solvent-free extrusion/spheronization and an investigation of their stability.

A novel solvent-free extrusion/spheronization technique was investigated for preparing stable aspirin sustained-release pellets. Lipids as binders and the matrix in this technique were extruded below their melting points, and spheronized in a thermomechanical process. Four types of lipids (adeps solidus, Compritol(®) 888 ATO, Precirol(®) ATO5 and Compritol(®) HD5 ATO) and their admixture in different ratios were used to obtain spherical and extended-release pellets. Pellets containing 80% aspirin, 15% adeps solidus and 5% Compritol(®) 888 ATO had the best spherical geometry and met the dissolution requirements of aspirin extended-release tablets in USP 31. Storage stability studies showed that the content of free salicylic acid increased sharply in the traditional pellets produced by wet extrusion/spheronization, from 1.91 to 7.84%, whereas there was little increase in the lipid pellets (from 0.48 to 1.08%). The dissolution rate from the optimal pellets (F11) stored at 26°C did not change, but became faster at 40°C/RH75% after 5 months. Powder X-ray diffraction, scanning electron microscopy (SEM) and differential scanning calorimetry were used to investigate the physical properties of the pellets during stability testing. The increase in the rate of drug release from aged pellets (40°C/RH75%) may result from the partially melted adeps solidus observed in SEM photographs. This study suggests that it is possible to prepare sustained-release pellets by solvent-free extrusion/spheronization using an appropriate mixture of lipids with high stability. In particular, this novel technique is excellent for hygroscopic drugs.

A floating multiparticulate system for ofloxacin based on a multilayer structure: In vitro and in vivo evaluation.

The purpose of this research was to develop a novel gastroretentive multiparticulate system with floating ability. This system was designed to provide drug-loaded pellets coated with three successive coatings-the retarding film (ethyl cellulose), the effervescent layer (sodium bicarbonate) and the gas-entrapped polymeric membrane (Eudragit RL 30D). The floating pellets were evaluated for SEM, floating characteristic parameters, in vitro release and bioavailability in New Zealand rabbits. The zero-order release theory model is designed to interpret the release processes. Due to the swelling property, high flexibility and high water permeability, Eudragit RL 30D was used as a gas-entrapped polymeric membrane. The obtained pellets exhibit excellent floating ability and release characteristics. Analysis of the release mechanism showed a zero-order release for the first 8h because of the osmotic pressure of the saturated solution inside of the membrane, which was in accordance with that predicted. Abdominal X-ray images showed that the gastroretention period of the floating barium sulfate-labeled pellets was no less than 6h. The relative bioavailability of the floating pellets compared with reference tablets was 113.06 ± 23.83%. All these results showed that the floating pellets are a feasible approach for the gastroretentive drug delivery system.

Biomechanical comparison of double-row versus transtendon single-row suture anchor technique for repair of the grade III partial articular-sided rotator cuff tears.

BACKGROUND: For partial-thickness tears of the rotator cuff, double-row fixation and transtendon single-row fixation restore insertion site anatomy, with excellent results. We compared the biomechanical properties of double-row and transtendon single-row suture anchor techniques for repair of grade III partial articular-sided rotator cuff tears. METHODS: In 10 matched pairs of fresh-frozen sheep shoulders, the infraspinatus tendon from 1 shoulder was repaired with a double-row suture anchor technique. This comprised placement of 2 medial anchors with horizontal mattress sutures at an angle of ≤ 45° into the medial margin of the infraspinatus footprint, just lateral to the articular surface, and 2 lateral anchors with horizontal mattress sutures. Standardized, 50% partial, articular-sided infraspinatus lesions were created in the contralateral shoulder. The infraspinatus tendon from the contralateral shoulder was repaired using two anchors with transtendon single-row mattress sutures. Each specimen underwent cyclic loading from 10 to 100 N for 50 cycles, followed by tensile testing to failure. Gap formation and strain over the footprint area were measured using a motion capture system; stiffness and failure load were determined from testing data. RESULTS: Gap formation for the transtendon single-row repair was significantly smaller (P < 0.05) when compared with the double-row repair for the first cycle ((1.74 ± 0.38) mm vs. (2.86 ± 0.46) mm, respectively) and the last cycle ((3.77 ± 0.45) mm vs. (5.89 ± 0.61) mm, respectively). The strain over the footprint area for the transtendon single-row repair was significantly smaller (P < 0.05) when compared with the double-row repair. Also, it had a higher mean ultimate tensile load and stiffness. CONCLUSIONS: For grade III partial articular-sided rotator cuff tears, transtendon single-row fixation exhibited superior biomechanical properties when compared with double-row fixation.

Association of production factors with milk IgA and IgM concentrations in normal lactating cows.

Concentrations of IgA and IgM in milk from normal lactating cows were measured to determine whether they were affected by lactation number, lactation stage, daily milk production, milk composition and somatic cell score (SCS). A total of 284 Chinese Holstein cows showing no signs of mastitis were selected from more than 1600 cows from one farm. Concentrations of IgA and IgM in normal milk were determined by ELISA. Results revealed that average milk IgA and IgM concentrations were 235±11 and 32±3 µg/ml, respectively. IgA and IgM concentrations in milk were found to have an association with lactation number, stage of lactation, daily milk production and SCS. Both SCS and daily milk production were found to be strong significant (P<0·01) direct factors correlating to IgA concentration. Stage of lactation and SCS were found to be strong significant (P<0·01) direct factors correlating to IgM concentration.