Probiotics, prebiotics, and synbiotics regulate the intestinal microbiota differentially and restore the relative abundance of specific gut microorganisms.

Fermented milk is an effective carrier for probiotics, the consumption of which improves host health. The beneficial effects of probiotics, prebiotics, and synbiotics on gut dysbiosis have been reported previously. However, the way in which specific probiotics, prebiotics, and synbiotics regulate intestinal microbes remains unclear. Therefore, the probiotics Lactobacillus rhamnosus AS 1.2466 and Lactobacillus delbrueckii ssp. bulgaricus ATCC 11842 and the prebiotics xylooligosaccharide and red ginseng extracts were fed to mice to determine their effects on the intestinal microbiota. Then, mice were administered xylooligosaccharide and L. rhamnosus (synthesis) by gavage, and the number of L. rhamnosus was determined in the intestine at different times. The results show that probiotics and prebiotics can quickly reduce the Firmicutes/Bacteroidetes ratio, inhibit harmful bacteria (such as Klebsiella and Escherichia coli), and accelerate the recovery of beneficial intestinal microorganisms (such as Lactobacillus). In a complex intestinal microecology, different probiotics and prebiotics have different effects on specific intestinal microorganisms that cannot be recovered in the short term. In addition, after 20 d of intragastric xylooligosaccharide addition at 0.12 g/kg of body weight, L. rhamnosus colonization in the mouse ileum was 7.48 log cfu/mL, which was higher than in the low-dose group, prolonging colonization time and increasing the number of probiotics in the intestine. Therefore, this study demonstrated that probiotics and prebiotics can promote the balance of intestinal microbiota by regulating specific microbes in the intestine, and the effects of a suitable combination of synbiotics are beneficial, laying the foundation for the development of new dairy products rich in synbiotics.

Association between vitamin D status and asthma control: A meta-analysis of randomized trials.

BACKGROUND: There is a controversy in terms of the efficacy of vitamin D supplementation in improving asthma symptom control. Moreover, whether there is a difference in the treatment effect with respect to baseline vitamin D status remains unknown. This meta-analysis was to assess the correlations of vitamin D status with asthma-related respiratory outcomes. METHODS: PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials of vitamin D supplementation in patients with asthma. Primary outcomes were the rate of asthma exacerbation and predicted percentage of forced expiratory volume in first second (FEV1%). Secondary outcomes were asthma control test (ACT) scores, fractional exhaled nitric oxide (FeNO), interleukin-10 (IL-10) and adverse events. RESULTS: A total of 14 randomized controlled trials (1421 participants) fulfilled the inclusion. Vitamin D supplementation was associated with a significant reduction in the rate of asthma exacerbation by 27% (RR: 0.73 95%Cl (0.58-0.92)). In subgroup analysis, the protective effect of exacerbation was restricted in patients with vitamin D insufficiency (vitamin D < 30 ng/ml) (RR: 0.76 95%Cl (0.61-0.95)). An improvement of FEV1% was demonstrated in patients with vitamin D insufficiency and air limitation (FEV1% < 80%) (MD: 8.3 95%Cl (5.95-10.64). No significant difference was observed in ACT scores, FeNO, IL-10 and adverse events. CONCLUSIONS: Vitamin D supplementation reduced the rate of asthma exacerbation, especially in patients with vitamin D insufficiency. Additionally, the benefit of vitamin D had a positive effect on pulmonary function in patients with air limitation and vitamin D insufficiency.

Comparison of equiosmolar hypertonic saline and mannitol for brain relaxation during craniotomies: A meta-analysis of randomized controlled trials.

There is a controversy about the effects of hypertonic saline (HS) used for brain relaxation in patients requiring craniotomies. We conducted a meta-analysis to compare the efficacy of equiosmolar hypertonic saline with mannitol on intraoperative brain relaxation in patients undergoing craniotomies. We searched PubMed, EMBASE, Cochrane Library databases, and Web of Science for randomized controlled trials (RCTs). The outcome indicators included brain relaxation, hemodynamic status, fluid volume, and blood chemistry. A total of nine RCTs involving 665 patients were identified and included. There was a greater increase in the odds of good intraoperative brain relaxation in the HS group (odds ratio (OR) 2.05, 95% confidence interval (CI) 1.40~3.01; P = 0.0002) compared with mannitol. In comparison with HS, mannitol slightly reduced the central venous pressure (CVP) (mean difference (MD) 1.03, 95% CI 0.03~2.03; P = 0.04) as well as significantly increasing the diuretic effect regardless of the dosage of HS (standardized mean difference (SMD) -0.86, 95% CI -1.35~-0.37; P = 0.0006). HS increased the plasma sodium level significantly (MD 7.86, 95% CI 2.78 ~ 12.95, P = 0.002) but reduced the intraoperative fluid intake (SMD -0.56, 95% CI -0.98~-0.15, P = 0.008). However, there were no significant differences in plasma osmolality and mean arterial pressure (MAP). Our results suggest that there appears to be better brain relaxation without a significant increase in urine volume in the HS group compared with mannitol in patients requiring craniotomies. High-quality RCTs with larger sample sizes will be required in the future to confirm the conclusions.

Evodiamine exerts anti-tumor effects against hepatocellular carcinoma through inhibiting ß-catenin-mediated angiogenesis.

Hepatocellular carcinoma (HCC) is a highly vascular tumor with high microvessel density and high levels of circulating vascular endothelial growth factor (VEGF). Thus, the angiogenesis pathway is an attractive therapeutic target for HCC. The anti-tumor effects of evodiamine, a quinolone alkaloid isolated from Euodia rutaecarpa (Juss.) Benth. (Rutaceae), were investigated in a mouse xenograft model using BALB/c nude mice, various HCC cell lines (HepG2, SMMC-7721, H22), and human umbilical vein endothelial cells (HUVECs). The effects of evodiamine on tumor volumes and weights, levels of tumor markers, angiogenesis in vivo and in vitro, cell viability, and cell migration and invasion were measured, and the mechanism through which its effects are achieved was investigated. Transcriptional regulation of VEGFa via interaction with ß-catenin was established by luciferase activity assays and electrophoretic mobility shift assays. In a subcutaneous H22 xenograft model, evodiamine inhibited tumor growth and reduced serum tumor markers and the levels of ß-catenin and VEGFa. It also blocked VEGF-induced angiogenesis in a Matrigel plug assay. Evodiamine suppressed cellular proliferation, invasion, and migration and inhibited tube formation of HUVECs. Moreover, in a concentration-dependent manner, evodiamine reduced the number of capillary sprouts from Matrigel-embedded rat thoracic aortic rings. Also, evodiamine suppressed various biomarkers of angiogenesis and the expression of ß-catenin. Evodiamine decreased ß-catenin levels activated by LiCl, which led to reduced expression of VEGFa. In addition, ß-catenin interacted with VEGFa and transcriptionally regulated VEGFa, an effect inhibited by evodiamine in HCCs. Moreover, in an SMMC-7721 xenograft model, evodiamine suppressed tumor growth, various biomarkers of angiogenesis, and the levels of ß-catenin and VEGFa. Evodiamine has anti-tumor effects on HCCs through inhibiting ß-catenin, which interacts with and reduces VEGFa expression, thus inhibiting angiogenesis. These results indicate that evodiamine, which inhibits cellular invasion and migration and blocks angiogenesis, is a potential therapeutic agent for HCCs.

Liprosomes loading paclitaxel for brain-targeting delivery by intravenous administration: in vitro characterization and in vivo evaluation.

In this study, a lipid-protein nanocomplex (liprosome) was evaluated for its potential use for brain-targeting drug delivery. Liprosome was fabricated with the desolvation-ultrasonication method and characterized in terms of particle size, size distribution, zeta potential, morphology, crystal state of the drug, and in vitro release. The in vivo distribution of paclitaxel loading lipid-protein nanocomplex (PTX-liprosome) and Taxol were compared after i.v. administration in mice. The prepared PTX-liprosome has a high entrapment efficiency (>90%), small particle size (approximately 110 nm), and narrow distribution (P.I.<0.2). Transmission electron microscopy (TEM) indicated that liprosome had a spherical multilayer structure. X-ray photoelectron spectroscopy (XPS) showed that the conjugate of PTX and BSA was in the interior of the PTX-liprosome. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) demonstrated that the drug existed in a molecular or amorphous state. Fourier transform infrared spectroscopy (FTIR) suggested that the hydrophobic interactions, electrostatic interactions and hydrogen bonds among of the PTX, lipid and protein play an important role during the formation of the PTX-liprosome. The hemolysis test showed a good safety profile for the intravenous administration of liprosome. The result of the in vivo distribution suggested that liprosome increased the drug uptake by the brain tissue and decreased drug accumulation in non-target organs. Therefore, liprosome is a potential drug delivery system for transporting PTX to the brain.

Enhanced mucosal and systemic immune responses obtained by porous silica nanoparticles used as an oral vaccine adjuvant: effect of silica architecture on immunological properties.

Three different kinds of silica (S2, S1 and SBA-15) with different particle sizes (130, 430 nm and 1-2 µm) and different pore characteristics (i.e. pore size and shape) were developed as oral vaccine immunological adjuvants and the relationship between the silica architecture and immunological properties was investigated. The silica particles were characterized using SEM, TEM and nitrogen adsorption. Model antigen bovine serum albumin (BSA) was successfully entrapped into the silica pores to produce a sustained release vaccine delivery system. Compared with the responsiveness induced by parenteral administration of BSA emulsified in Freund's complete adjuvant (FCA), oral immunization with the silica/BSA formulation produced a stimulated humoral and mucosal (sIgA) response. The IgG and IgA titers induced by loading BSA was as follows: S1>S2>SBA-15. The highest IgG and IgA titers of S1 were attributed to its large honeycombed pores and the optimal particle diameter of 430 nm. The corresponding IgG1 and IgG2a titers were also investigated to confirm that BSA loaded in nanoparticles by oral immunization can induce both T-helper 1- and T-helper 2- (Th1 or Th2) mediated responses. We believe that the results of our research will open up new avenues for the formulation of oral vaccines.

Discriminatory dissolution method for quality control measurements of carbamazepine immediate release tablets based on in vitro--in vivo investigations.

The purpose of this study was to identify a discriminatory dissolution method able to predict the in vivo performance of tablet formulations designed for carbamazepine (CBZ). After evaluation of dissolution medium and rotation speed using a 25 central composite design and investigation of the in vivo release behaviors in beagle dogs, the dissolution method of CBZ 100 mg tablets was validated using a USP apparatus II, at a rotation speed of 75 rpm, and 900 ml deaerated water with 0.5% sodium lauryl sulfate (w/v) as the dissolution medium. Dissolution profiles were evaluated by the Weibull parameters and the modified fit factor, ƒ^(1,area). The in vitro-in vivo relationship of CBZ tablets was examined. Compared with the results from the USP and Chinese Pharmacopoeia monograph, the proposed system provides a superior discriminatory method. Since the dissolution method in pharmacopoeia for CBZ tablets is unable to distinguish between a good and a bad product, the method presented here can be used for the quality control testing of CBZ tablets.

Effect of diallyl trisulfide on the pharmacokinetics of dipyridamole in rats.

This study was aimed to evaluate the effect of diallyl trisulfide (DATS), a major component derived from garlic used to inhibit platelet thromboxane formation, on the pharmacokinetics of dipyridamole. Pharmacokinetic parameters of dipyridamole were determined in rats following intragastric (80 mg/kg suspension or 40 mg/kg solution) or intravenous (3 mg/kg) administration of dipyridamole with coadministration (20 mg/kg) and long-term pretreatment of DATS (10 or 20 mg/kg/day for 15 consecutive days). In addition, everted gut sac models were used to assess transepithelial transport of dipyridamole and the effect of DATS on the intestinal absorption of dipyridamole. After coadministration and long-term pretreatment of DATS, significantly lower Cmax and AUC(0-24 h) were observed for intragastric administration of dipyridamole, whereas little change was noted after intravenous dipyridamole administration. After adding DATS (10 and 50 µg/mL) in the everted gut sacs, absorption of dipyridamole was remarkably decreased in the ileum and jejunum (p < 0.01). In conclusion, DATS reduced the oral exposure of dipyridamole in rats likely by the modification of the dissolution rate and intestinal absorption of dipyridamole, indicating that combined use of DATS or DATS-containing supplements with dipyridamole may require caution as low plasma concentrations of dipyridamole may lead to a subtherapeutic effect of this agent.

Synthesis of a novel kind of carbon nanoparticle with large mesopores and macropores and its application as an oral vaccine adjuvant.

The purpose of this study is to develop a novel kind of adjuvant for oral vaccine delivery. In order to effectively prevent the degradation of antigens in the gastrointestinal tract and optimize the uptake for M cells, a novel kind of hydrophobic carbon nanoparticle (C1) with the size of 470nm was synthesized by taking silica as a template and sucrose as a carbon source. Notably, there were large mesopores and macropores mainly of 40-60nm, which made it to be excellent candidate as an antigen carrier. C1 was characterized using SEM, TEM and nitrogen adsorption. Following oral immunization with BSA loaded in C1, the IgG titer reached to a level almost equal to that of parenteral administration of antigen emulsified in Freund's complete adjuvant (FCA). Mucosal IgA was also detected in intestinal, salivary and vaginal secretions, suggesting an effective stimulation of mucosal immune response. Besides, both T-helper 1 and T-helper 2 (Th1 or Th2) mediated responses were induced. We believe that the research will help in the design of novel vaccine adjuvant for improvement their potential on modulation of immune response.

Effect of diallyl trisulfide on the pharmacokinetics of nifedipine in rats.

This study aimed to evaluate the effect of diallyl trisulfide (DATS), a major component derived from garlic, on the pharmacokinetics of nifedipine. Pharmacokinetic parameters of nifedipine were determined in rats following an oral gavage (3 mg/kg) or intravenous administration (0.75 mg/kg) of nifedipine with co-administration of DATS (20 mg/kg) and long-term pretreatment of DATS (20 mg/kg/d for 15 consecutive days). Compared to the control groups, higher C(max) and AUC(0-24 h) were observed for oral gavage of nifedipine after short-term and long-term pretreatment of DATS, whereas those for intravenous nifedipine were little changed. The oral bioavailabilities of nifedipine were remarkably enhanced via the concomitant use of DATS. In conclusion, DATS increased the oral exposure of nifedipine in rats likely by the modification of intestinal metabolism of nifedipine, indicating that combined use of DATS or DATS-containing supplement with nifedipine may require caution because high plasma concentrations may lead to an undesired toxicity of this agent. Practical Application: Patients suffering from cardiovascular disease should take caution in combined use of DATS or DATS-rich garlic supplement with nifedipine because long-term treatment of DATS could lead high plasma concentrations of nifedipine.

The photosensitive phs1 mutant is impaired in the riboflavin biogenesis pathway.

A photosensitive (phs1) mutant of Arabidopsis thaliana was isolated and characterized. The PHS1 gene was cloned using a map-based approach. The gene was found to encode a protein containing a deaminase-reductase domain that is involved in the riboflavin pathway. The phenotype and growth of the phs1 mutant were comparable to that of the wild-type when the plants were grown under low light conditions. When the light intensity was increased, the mutant was characterized by stunted growth and bleached leaves as well as a decrease in FNR activity. The NADPH levels declined, whereas the NADP(+) levels increased, leading to a decrease in the NADPH/NADP(+) ratio. The mutant suffered from severe photooxidative damage with an increase in antioxidant enzyme activity and a drastic reduction in the levels of chlorophyll and photosynthetic proteins. Supplementing the mutant with exogenous FAD rescued the photosensitive phenotype, even under increasing light intensity. The riboflavin pathway therefore plays an important role in protecting plants from photooxidative damage.

Wogonin potentiates the antitumor effects of low dose 5-fluorouracil against gastric cancer through induction of apoptosis by down-regulation of NF-kappaB and regulation of its metabolism.

Traditional Chinese medicines have been recognized as a new source of anticancer drugs or chemotherapy adjuvant to enhance the efficacy of chemotherapy and to ameliorate the side effects. Wogonin (WOG) has a potential for therapeutic use in the treatment of antitumor and chemoprophylaxis. 5-Fluorouracil (5-FU) is a key systemic chemotherapy drug and widely use in the treatment of solid tumors. In this study, we found that combination of WOG and 5-FU inhibited the viability of MGC-803 cells in a concentration-dependent manner and exhibited a synergistic anticancer effect (CI<1) when 5-FU was used at relatively low concentrations. The pro-apoptotic activity of two-drug combination was much stronger than single. Furthermore, WOG could decrease the mRNA levels of dihydropyrimidine dehydrogenase (DPD), the metabolic enzymes of 5-FU. WOG could inhibit the NF-kappaB nuclear translocation and I-kappaB phosphorylation. Moreover, combined treatment caused significantly growth inhibition of human tumor xenografts. In addition, WOG markedly enhanced the antitumor activity of low dose 5-FU (i.p. 10mg/kg/day), however there is no toxicity and influence on diet consumption in experimental animals. Taken together, our data's showed that WOG increased 5-FU retention for a prolonged catabolism by modulating 5-FU metabolic enzymes and sensitized the MGC-803 cells to 5-FU induced apoptosis by inhibiting the NF-kappaB nuclear translocation. The anti-gastric cancer effect of two-drug combination was much stronger than that of WOG or 5-FU alone. These results may be relevant to design new clinical therapeutic strategies against gastric cancer in future.

Wax-matrix tablet for time-dependent colon-specific delivery system of sophora flavescens Aiton: preparation and in vivo evaluation.

A wax-matrix time-dependent colon-specific tablet (WM-TDCS) was studied. Wax-matrix tablet core consisting of semi-synthetic glycerides, as a wax polymeric expanding agent, carboxymethyl starch sodium (CMS-Na), and NaCl was prepared, and Sophora flavescens Aiton (ASF, extracts of traditional Chinese medicine) was used as model drug. The wax-matrix ASF tablets core was coated with Eudragit NE 30 D as the inner coating materials and with Opadry OY-P-7171 as the outer coating materials. The in vitro release behaviors of the coated tablets were examined and then in vivo absorption kinetics of the coated tablets in dogs was further investigated. The volume of the tablet core was markedly increased at 37 degrees C because of the expand effect of polymer semi-synthetic glycerides and CMS-Na. The drug release from WM-TDCS was more stable than TDCS in vitro and in vivo. The lag time of ASF release was also controlled by the thickness of the inner coating layer. In vivo evaluation demonstrated that in vivo lag time of absorption was in a good agreement with in vitro lag time of release. ASF wax-matrix tablets coated with Eudragit NE 30 D and Opadry OY-P-7171 using the regular coating technique could be designed to achieve a lag time of 3 h in the small intestinal tract.