Synthesis and Application of Porous Carbon Nanomaterials from Pomelo Peels: A Review.

Advanced carbon nanomaterials have been widely applied in various fields such as microelectronics, energy storage, catalysis, adsorption, biomedical engineering, and material strengthening. With the increasing demand for porous carbon nanomaterials, many studies have explored obtaining porous carbon nanomaterials from biomass, which is highly abundant. Pomelo peel, a type of biomass rich in cellulose and lignin, has been widely upgraded into porous carbon nanomaterials with large yield and significant applications. Here, we systematically review the recent progress in pyrolysis, activation, and applications of synthesizing porous carbon nanomaterials from waste pomelo peels. Moreover, we provide a perspective on the remaining challenges and potential future research directions.

Non-IgE-mediated hypersensitivity induced by multivitamins containing Tween-80.

Multivitamins have been widely used for years. Adverse reactions, especially hypersensitivity, to multivitamins are becoming noteworthy. However, the classification of hypersensitivity is confusing, and the trigger is unknown. Multivitamins consist of two vials labelled vial 1 containing Tween-80 and vial 2. Multivitamins without Tween-80 were used as a contrast. Behaviouristics, histamine, IgE, and blood pressure of beagle dogs and guinea-pigs were investigated by observation, ELISA and sphygmomanometer, and degranulation and apoptotic of RBL-2H3 cells were assayed by spectrophotometry and flow cytometry. The results showed that dogs suffered from multiorgan anaphylactoid symptoms, and dramatically decreased blood pressure, and high plasma concentrations of histamine after the first administration of multivitamins and multivitamins vial 1, which contains Tween-80, compared to the control, multivitamins vial 2 or multivitamins without Tween-80. In anaphylaxis assay, guinea-pigs did not display any anaphylaxis symptoms and there were no changes in plasma histamine and IgE concentrations in the multivitamins and multivitamins vial 1 groups or in the multivitamins vial 2 and multivitamins without Tween-80 groups except ovalbumin. Compared to the control, the release of ß-hexosaminidase and histamine, and the apoptosis of non-antigen-sensitized RBL-2H3 cells significantly increased in the Tween-80 and multivitamins and multivitamins vial 1 groups in a concentration-dependent manner. However, there was no alteration in multivitamins vial 2 and multivitamins without Tween-80 groups. The results indicate that the hypersensitivity induced by multivitamins may be anaphylactoid reaction, but not anaphylaxis. Multivitamin-induced release of inflammatory factors is triggered by Tween-80 through a non-IgE-mediated pathway.

Living Artificial Skin: Photosensitizer and Cell Sandwiched Bacterial Cellulose for Chronic Wound Healing.

Chronic wounds pose a significant global public health challenge due to their suboptimal treatment efficacy caused by bacterial infections and microcirculatory disturbances. Inspired by the biofunctionality of natural skin, an artificial skin (HV@BC@TBG) is bioengineered with bacterial cellulose (BC) sandwiched between photosensitizers (PS) and functionalized living cells. Glucose-modified PS (TBG) and vascular endothelial growth factor (VEGF)-functionalized living cells (HV) are successively modified on each side of BC through biological metabolism and bio-orthogonal reaction. As the outermost layer, the TBG layer can generate reactive oxygen species (ROS) upon light illumination to efficiently combat bacterial infections. The HV layer is the inner layer near the diabetic wound, which servs as a living factory to continuously secrete VEGF to accelerate wound repair by promoting fibroblast proliferation and angiogenesis. The sandwiched structural artificial skin HV@BC@TBG is nontoxic, biocompatible, and demonstrated its ability to significantly accelerate the healing process of infected diabetic wounds, rendering it a promising next-generation medical therapy for chronic wound management.

A novel antibiotic: the antimicrobial effects of CFBSA and its application on electronspun wound dressing.

N-chloro-N-fluorobenzenesulfonylamide (CFBSA), was a novel chlorinating reagent, which exhibits potential antibacterial activities. In this study, CFBSA was confirmed as a wide-broad antimicrobial and bactericidal drug against different gram-negative bacteria, gram-positive bacteria and fungi, while it was found to have low cytotoxicity for eukaryotic cells. In addition, microorganism morphology assay and oxidative stress test was used to determine the antimicrobial mechanisms of CFBSA. According to the results, CFBSA probably had a target on cell membrane and killed microorganism by disrupting its cell membrane. Then, CFBSA was first combined with poly(L-lactide-co-caprolactone) (PLCL)/SF via electrospinning and applied in wound dressings. The characterization of different PLCL/SF of CFBSA-loaded nanofibrous mats was investigated by SEM, water contact angle, Fourier transform infrared spectroscopy, cell compatibility and antimicrobial test. CFBSA-loaded PLCL/SF nanofibrous mats showed excellent antimicrobial activities. In order to balance of the biocompatibility and antibacterial efficiency, SP-2.5 was selected as the ideal loading concentration for further application of CFBSA-loaded PLCL/SF. In conclusion, the electrospun CFBSA-loaded PLCL/SF nanofibrous mat with its broad-spectrum antimicrobial and bactericidal activity and good biocompatibility showed enormous potential for wound dressing.

Development of lignin-based 3D-printable light responsive shape memory materials: Design of optically controlled devices.

This study employs simple approaches involving melt blending and Fused Deposition Modeling (FDM) 3D printing to fabricate a light-responsive shape memory composite. And, this composite material is used for the design of optically controlled devices that mimics the blooming of flowers in the natural environment. The composite material utilizes poly(ε-caprolactone) (PCL) and thermoplastic polyurethane (TPU) as the matrix, with lignin (L) serving as a functional filler. The analysis indicates that, due to the excellent photothermal conversion efficiency of lignin, under constant illumination the shape memory materials heat up to 50 °C within 40 s, the shape recovery rate exceeds 95.06 %. Lignin ameliorated the rheological deficiencies of TPU, with the composite material viscosity decreasing from 103 to 101 at an angular frequency of 100 rad/s, enhancing its compatibility with FDM processes. This research offers greater economic efficiency compared to conventional light-responsive materials and a simpler production method.

Improved therapeutic index of the liposomal docetaxel-glutathione prepared by active click loading.

The clinical usage of docetaxel (DTX) is severely hindered by the dose-limiting neutropenia and peripheral neurotoxicity of polysorbate 80-solubilized DTX injection, and there are no alternative formulations until now. In this study, we developed a new liposomal formulation of DTX to reduce its toxicities, accompanying with the greatly improved antitumor activity. The DTX was encapsulated into liposomes in the form of hydrophilic glutathione (GSH)-conjugated prodrugs using a click drug loading method, which achieved a high encapsulation efficiency (∼95 %) and loading capacity (∼30 % wt). The resulting liposomal DTX-GSH provided a sustained and efficient DTX release (∼50 % within 48 h) in plasma, resulting in a greatly improved antitumor activities as compared with that of polysorbate 80-solubilized DTX injection in the subcutaneous and orthotopic 4T1 breast tumor bearing mice. Even large tumors > 500 mm3 could be effectively inhibited and shrunk after the administration of liposomal DTX-GSH. More importantly, the liposomal DTX-GSH significantly decreased the neutropenia and peripheral neurotoxicity as compared with that of polysorbate 80-solubilized DTX injection at the equivalent dose. These data suggested that the liposomal DTX-GSH might become a superior alternative formulation to the commercial DTX injection.

Organic functional substance engineered living materials for biomedical applications.

Modifying living materials with organic functional substances (OFS) is a convenient and effective strategy to control and monitor the transport, engraftment, and secretion processes in living organisms. OFSs, including small organic molecules and organic polymers, own the merit of design flexibility, satisfying performance, and excellent biocompatibility, which allow for living materials functionalization to realize real-time sensing, controlled drug release, enhanced biocompatibility, accurate diagnosis, and precise treatment. In this review, we discuss the different principles of OFS modification on living materials and demonstrate the applications of engineered living materials in health monitoring, drug delivery, wound healing, and tissue regeneration.

[Research Progress on Distribution Characteristics and Formation Mechanisms of Microplastics in the Environment].

The extensive application of plastic products leads to the increasingly significant harm of plastic wastes to the ecological environment, which is also a focus of global environmental issues. Due to the lack of a sound plastic waste management system, most plastic waste is still treated by the traditional mode or remains in the environment, with low recycling efficiency, and the plastic life cycle has not yet formed. Plastics in the environment will age and degrade under the actions of physical (wear, waves), chemical (ultraviolet radiation, hydrolysis), and biological (fungi, bacteria) factors for a long time and generate micro (nano) plastics. Due to their small particle size, large specific surface area, and charged characteristics, in addition to their own toxicity, they can also be used as carriers or covert carriers of pollutants (heavy metals, persistent organic pollutants, polycyclic aromatic hydrocarbons, bacteria, etc.) to migrate in the environment through runoff, sewage discharge, and hydrometeorology, causing ecological environmental pollution. MPs pollution has been listed as the second largest scientific problem in the field of environmental and ecological science by the United Nations Environment Programme. MPs are widely distributed, and there are different degrees of MPs pollution in the global water (freshwater, ocean), soil, and atmospheric environment. Traces of MPs have also been found in human placentas, human breastmilk, living lungs, and blood in recent years. Therefore, the formation mechanisms of MPs under the actions of physics, chemistry, and microorganisms, as well as their abundance levels and migration characteristics in water, soil, and atmosphere environment were comprehensively reviewed, with the hope of providing reference for monitoring the pollution levels of MPs in the environment, exploring their transport laws in the environment, proposing the management strategy of MPs pollution, and revealing the degradation mechanisms of MPs under different effects.

Remote drug loading into liposomes via click reaction.

The development of liposome-based drugs was severely limited due to inefficient loading strategies. Herein, we developed a click reaction-mediated loading procedure by designing an enzyme-sensitive maleimide (MAL) tag for ferrying chemotherapeutics into preformed liposomes containing glutathione (GSH). Based on this strategy, various hydrophobic drugs could be encapsulated into liposomes within 5-30 min with encapsulation efficiency >95% and loading capacity of 10-30% (w/w). The entrapped cargo could be slowly released from the liposomes, followed by rapid enzyme-mediated conversion into active drugs to exert antitumor activity under physiological conditions. The resulting drug-loaded liposomes significantly prolonged the blood circulation of cargos and displayed more potent in vivo antitumor efficacy than free drugs at the equitoxic dose. More importantly, this method is a remote drug loading strategy in nature, which is suitable for industrial production. This is the first demonstration of active loading of MAL-tagged chemotherapeutics in liposomes for improved antitumor efficacies, which has the potential to serve as a universal drug loading strategy for the development of liposomal formulations of chemotherapeutics.

Application of moving bed biofilm reactor - nanofiltration - membrane bioreactor with loose nanofiltration hollow fiber membranes for synthetic roxithromycin-containing wastewater treatment: Long-term performance, membrane fouling and microbial community.

The present study operated the novel moving bed biofilm reactor-nanofiltration-membrane bioreactor (MBBR-NF-MBR) with loose polyamide NF membranes for the first time to treat roxithromycin (ROX) wastewater. Results showed that both MBBR-NF-MBRs achieved superior COD removal of 98.4% and 97.2% and excellent removal of ROX at 74.1% and 65.5%, respectively. The main membrane fouling mechanism was reversible fouling caused by the combination of abundant polysaccharides, proteins and Ca-P precipitates, which could be effectively removed by acidic cleaning. Sorption and biodegradation were the main removal routes of ROX in MBBR. Partial retention of loose NF membrane contributed to microbial metabolism and increased microbial diversity, especially the genera Hyphomicrobium in attached biofilm, which was reasonable for ROX removal. The cleavage of cladinose, demethylation, phosphorylation and ß-oxidation in macrolactone ring were the main biotransformation reactions of ROX. This study provides novel insights for micropollutants wastewater treatment by using loose NF membrane in MBR.

Introduction to biodegradable polylactic acid ureteral stent application for treatment of ureteral war injury.

OBJECTIVE: • To study the operability and effectiveness of a biodegradable ureteral stent for clinical treatment of ureteral war injury using a canine model. MATERIALS AND METHODS: • A device was designed and employed to generate firearm fragment wounds in unilateral ureters (on randomly chosen sides) of nine beagles (Group A). The wounded ureters were then debrided and sutured. • Intravenous pyelography (IVP) and radioactive renography were performed 40, 80 and 120 days postoperatively. In Group B, firearm fragment wounds were made to the bilateral ureters in nine beagles. A polylactic acid stent was placed unilaterally (on a randomly chosen side) whereas the ureter on the other side was debrided and sutured without stenting. • Both IVP and radioactive renography were performed 40, 80 and 120 days postoperatively. The operability and effectiveness of the biodegradable ureteral stent were studied thereafter. RESULTS: • In Group A, hydronephrosis and hydroureter occurred and worsened postoperatively on the wounded sides in all nine beagles. The ratio of the renal partial concentration indices (RPCI) between the kidneys (unwounded side : wounded side) increased. • The ratio of the kidney washout half-time between the kidneys (unwounded side : wounded side) decreased. In Group B, neither hydronephrosis nor hydroureter was found postoperatively in the stented ureters but both occurred in the unstented ureters in all nine beagles. • The ratio of RPCI between kidneys (stented side : unstented side) increased whereas the kidney washout half-time ratio between the stented and unstented sides decreased. Differences were significant. CONCLUSION: • In Group A, the new canine model for firearm fragment wounds was tested and proved to be operable and effective. In Group B, hydronephrosis and hydroureter were effectively prevented in ureters by biodegradable stent placement compared with the non-stented ureters where hydronephrosis and hydroureter occurred. The renal concentration capacity was effectively protected and the half-time of kidney washout was shortened.

Cross-linked PEG via degradable phosphate ester bond: synthesis, water-swelling, and application as drug carrier.

A new series of degradable and water-swellable cross-linked PEG phosphoester polymers (CPPs) based on a facile cross-linked reaction between diphosphoesters of polyethylene glycol (P-PEG-P) and diglycidyl ether of polyethylene glycol (E-PEG-E) has been prepared and characterized. The molecular weights and ratios of the prepolymers played an important role for the properties of CPPs polymers, such as mechanical property, swelling, and degradation rates. In the curing process, the glycidyl ether was consumed by both hydroxyl of the phosphoester (P-OH) and hydroxyl generated from the opened glycidyl ethers (C-OH) with the presence of acid, which generated degradable phosphate esters as cross-linked points and ether bonds as the short branches, respectively. Drug entrapment and release test and biological cytotoxicity studies in vitro suggested that the polymers and generated hydrogels have great potential applications in drug delivery system and biological materials.

The application of locking-taper implants in posterior area implant restoration with insufficient occlusal-gingival distances.

OBJECTIVE: We aimed to investigate the effect of locking-taper implants on restoration in the posterior teeth area with insufficient occlusal-gingival distances. METHODS: Forty-five patients undergoing dental implants in our hospital with occlusal-gingival distances under 5 mm in the posterior teeth area were recruited for this retrospective study. A total of 78 locking-taper implants were implanted in these patients. The patients were followed up for two years to observe the implant retention rate, the implant bone heights at different time points after the restoration, and the effects of the different implant placement depths on the marginal bone mass at the implants. Meanwhile, we evaluated the peri-implant soft tissue status by measuring the modified plaque index, the gingival index, and probing the depths. The postoperative complications and the patient satisfaction levels were also analyzed. RESULTS: During the 2-year follow-up, the patients' implant retention rate was 100.00%. The implant placement depths did not affect the marginal bone masses at the implants at T0-T1 or T1-T2 (T0: the day after the restoration, T1: at one year after the restoration, T2: at two years after the restoration, all P>0.05). The peri-implant soft tissues in most of the patients were in good condition, and only a few patients had a small amount of plaque or slight gingival swelling. The average probe depth was 3.23±1.20 mm during the follow-up. Only one patient had abutment loosening, and one had a dental prosthesis fall off. The patients did not feel any numbness, continuous pain, or other abnormalities during the follow-up, and the overall patient satisfaction rate was over 97.78%. CONCLUSION: Locking-taper implants can achieve good clinical outcomes in the restoration of the posterior area with insufficient occlusal-gingival distances. The implants can achieve a high implant retention rate, have no adverse effects on the peri-implant soft tissues, have a low complication rate, cause no significant marginal bone mass loss at the implants, and have a high patient satisfaction rate.

A Portable Digital Loop-Mediated Isothermal Amplification Platform Based on Microgel Array and Hand-Held Reader.

Digital polymerase chain reaction (dPCR) has found widespread applications in molecular diagnosis of various diseases owing to its sensitive single-molecule detection capability. However, the existing dPCR platforms rely on the auxiliary procedure to disperse DNA samples, which needs complicated operation, expensive apparatus, and consumables. Besides, the complex and costly dPCR readers also impede the applications of dPCR for point-of-care testing (POCT). Herein, we developed a portable digital loop-mediated isothermal amplification (dLAMP) platform, integrating a microscale hydrogel (microgel) array chip for sample partition, a miniaturized heater for DNA amplification, and a hand-held reader for digital readout. In the platform, the chip with thousands of isolated microgels holds the capability of self-absorption and partition of DNA samples, thus avoiding auxiliary equipment and professional personnel operations. Using the integrated dLAMP platform, λDNA templates have been quantified with a good linear detection range of 2-1000 copies/µL and a detection limit of 1 copy/µL. As a demonstration, the epidermal growth factor receptor L858R gene mutation, a crucial factor for the susceptibility of the tyrosine kinase inhibitor in non-small-cell lung cancer treatment, has been accurately identified by the dLAMP platform with a spiked plasma sample. This work shows that the developed dLAMP platform provides a low-cost, facile, and user-friendly solution for the absolute quantification of DNA, showing great potential for the POCT of nucleic acids.

The periodontal status of removable appliances vs fixed appliances: A comparative meta-analysis.

BACKGROUND: Although several researchers have analyzed the dental identity of patients experience with corrective methods using fixed and removable appliances, the consequences stay debatable. This meta-analysis intended to verify whether the periodontal status of removable appliances is similar to that of the conventional fixed appliances. METHODS: Relevant literature was retrieved from the database of Cochrane library, PubMed, EMBASE, and CNKI until December 2019, without time or language restrictions. Comparative clinical studies assessing periodontal conditions between removable appliances and fixed appliances were included for analysis. The data was analyzed using the Stata 12.0 software. RESULTS: A total of 13 articles involving 598 subjects were selected for this meta-analysis. We found that the plaque index (PLI) identity of the removable appliances group was significantly lower compared to the fixed appliances group at 3 months (OR = -0.57, 95% CI: -0.98 to -0.16, P = .006) and 6 months (OR = -1.10, 95% CI: -1.60 to -0.61, P = .000). The gingival index (GI) of the removable appliances group was lower at 6 months (OR = -1.14, 95% CI: -1.95 to -0.34, P = .005), but the difference was not statistically significant at 3 months (OR = -0.20, 95% CI: -0.50 to 0.10, P = .185) when compared with that of the fixed appliances group. The sulcus probing depth (SPD) of the removable appliances group was lower compared to the fixed appliances group at 3 months (OR = -0.26, 95% CI: -0.52 to -0.01, P = .047) and 6 months (OR = -0.42, 95% CI: -0.83 to -0.01, P = .045). The shape of the funnel plot was symmetrical, indicating no obvious publication bias in the Begg test (P = .174); the Egger test also indicated no obvious publication bias (P = .1). CONCLUSION: Our meta-analysis demonstrated that malocclusion patients treated with the removable appliances demonstrated a better periodontal status as compared with those treated with fixed orthodontic appliances. However, the analyses of more numbers of clinical trials are warranted to confirm this conclusion.

PLGA/chitosan-heparin composite microparticles prepared with microfluidics for the construction of hMSC aggregates.

Incorporating poly(lactic-co-glycolic) acid (PLGA) microparticles into human mesenchymal stem cells (hMSC) aggregates has shown promising application prospects. However, the acidic degradation products and burst release of PLGA microparticles still need to be ameliorated. In this study, the PLGA/chitosan-heparin (P/C-h) composite microparticles were successfully fabricated by integrating the double emulsion and microfluidic technology through the precise manipulation of the emulsion composition and flow rate of the two-phase in a flow-focusing chip. The P/C-h microparticles were highly monodispersed with a diameter of 23.45 ± 0.25 µm and shell-core structure of the PLGA encapsulated C-h complex, which were suitable for the fabrication of hMSC aggregates. When the mass ratio of PLGA to the C-h complex was optimized to 2 : 1, the pH of the leach liquor of P/C-h microparticles remained neutral. Compared with those of PLGA microparticles, the cytotoxicity and the initial burst release (loaded FGF-2 and VEGF) were both significantly reduced in P/C-h microparticles. Furthermore, the survival, stemness, as well as secretion and migration abilities of cells in hMSC aggregates incorporating P/C-h microparticles were also enhanced. In summary, the P/C-h composite microparticles prepared by the droplet microfluidic technique support the optimal biological and functional profile of the hMSC aggregates, which may facilitate the clinical applications of MSC-based therapy.

DOX-loaded peptide dendritic copolymer nanoparticles for combating multidrug resistance by regulating the lysosomal pathway of apoptosis in breast cancer cells.

Multidrug resistance (MDR) is a common phenomenon in clinical oncology and is a major obstacle to cancer chemotherapy. Many nanoparticle (NP)-based drug delivery systems have been developed to overcome MDR depending on increasing intracellular drug concentrations via increased cellular uptake and rapid drug release. The objective of this work was to investigate the performance and possible mechanisms of enzyme-sensitive mPEGylated dendron-GFLG-DOX conjugate based nanoparticles for blockading the MDR phenotype of MCF-7/ADR. In vitro, mPEGylated dendron-GFLG-DOX conjugate based nanoparticles could significantly promote cellular uptake and accumulation, potent cytotoxicity and apoptosis compared to free DOX in resistant cells. mPEGylated dendron-GFLG-DOX conjugate based nanoparticles were found to translocate across the membranes of resistant cells via active endocytic pathways leading to more DOX accumulating in the nuclei of MCF-7/ADR cells. Importantly, we found that mPEGylated dendron-GFLG-DOX conjugate based nanoparticles could induce cathepsin B in the cytoplasm and enhance lysosomal-mediated cell death compared to free DOX. Furthermore, mPEGylated dendron-GFLG-DOX conjugate based nanoparticles enhanced the drug's penetration, toxicity, and growth inhibition compared to free DOX in the three-dimensional multicellular tumor spheroid model. In vivo, mPEGylated dendron-GFLG-DOX conjugate based nanoparticles significantly improved the therapeutic efficacy against MDR xenograft tumors, and showed better biocompatibility than free DOX. These results indicated that mPEGylated dendron-GFLG-DOX conjugate based nanoparticles could be used as an alternative drug delivery system for MDR tumor treatment through initiating the lysosomal apoptosis pathway.

Label-Free Quantitative Proteomic Profiling of LAD2 Mast Cell Releasates Reveals the Mechanism of Tween-80-Induced Anaphylactoid Reaction.

PURPOSE: Tween-80 is one of the most important causes resulting in anaphylactoid reaction. However, its mechanism remains unclear. Proteomic characterizations of mast cells' excreta in response to Tween-80 are assayed to investigate the mechanism of anaphylactoid reaction. EXPERIMENTAL DESIGN: A label-free LCMS/MS-based proteomics is used to analyze Tween-80-stimulated Laboratory of Allergic Diseases 2 (LAD2) mast cells releasates. The results of proteomic are analyzed by bioinformatics analysis. Western blotting is used to verify the expression of proteins. RESULTS: Overall, endocytosis, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and calcium signaling pathways play important roles in Tween-80-induced LAD2 cells activation by bioinformatics analysis. The expressions of relative proteins including actin-related protein 2/3 complexes, vacuolar protein sorting-associated protein, phosphorylation of transcription factor of P105 and P65, phosphorylation of inositol 1,4,5-trisphosphate receptor (IP3 R), phosphoinositide phospholipase Cγ (PLCγ), and protein kinase C (PKC), are significantly increased in Tween-80 group compared to control. Tween-80 might be internalized via endocytosis, which induces degranulation by PLCγ/PKC pathways mediated calcium influx, and promotes the generation of inflammatory mediators via NF-κB pathway resulting in anaphylactoid reaction.

Construction of multicellular aggregate by E-cadherin coated microparticles enhancing the hepatic specific differentiation of mesenchymal stem cells.

The differentiation of human mesenchymal stem cells (hMSCs) into hepatocyte-like cells in vitroprovides a promising candidate for cell therapy of liver diseases, and cell aggregates have been proposed to improve the efficiency of expansion and differentiation. Previously, we engineered multicellular aggregates incorporating human E-cadherin fusion protein (hE-cad-Fc)-coated poly(lactic-co-glycolic acid) (PLGA) microparticles (hE-cad-PLGAs), and a significant improvement was obtained in both cellular proliferation of and cytokine secretion by hMSCs. In this study, hepatic differentiation of hMSCs was induced by a biomimetic microenvironment consisting of these engineered aggregates and a cocktail of specific cytokines. The ratio of hE-cad-PLGAs to hMSCs in engineered hMSCs aggregates was optimized to 1:3 for hepatic differentiation. The expressions of hepatic-specific markers were significantly promoted, and cell polarity and activated drug metabolism enzymes were established in MSC/hE-cad-PLGA aggregates compared with MSC and MSC/PLGA aggregates. Moreover, the expressions of stemness and definitive endoderm markers confirmed effectively induced endoderm differentiation in MSC/hE-cad-PLGA aggregates, which was consistent with the pattern of embryonic development. After pre-differentiation for 1 week, the MSC/hE-cad-PLGA aggregates continuously progressed the hepatic phenotype expression in healthy rat peritoneum. Therefore, the biomimetic microenvironment constructed by hE-cad-PLGAs in engineered multicellular aggregates was able to promote the process of endoderm differentiation and the subsequent hepatic differentiation of hMSCs. It would be appropriate for applied research in hepatotoxic drug screening and cell-based treatment of liver diseases. By optimizing with other cytokine cocktail, the engineered multicellular aggregates can be applied to the construction of other endoderm-derived organs. STATEMENT OF SIGNIFICANCE: The differentiation of mesenchymal stem cells (MSCs) into hepatocyte-like cells in vitroprovides a promising for cell therapy for liver diseases, and cell aggregates have been proposed to improve the expansion and differentiation efficiency. Here, engineered multicellular aggregates were constructed by E-cadherin modified microparticles (hE-cad-PLGAs) construct a biomimetic microenvironment to promote the process of endoderm differentiation and the subsequent hepatic differentiation of hMSCs. Furthermore, after pre-differentiation for 1 week, the MSC/hE-cad-PLGA aggregates continuously progressed the hepatic phenotype expression in healthy rat peritoneum. Therefore, engineered multicellular aggregates with hE-cad-PLGAs would be appropriate for applied research in hepatotoxic drug screening and cell-based treatment of liver diseases, and provide a promising method in the construction of other endoderm-derived organs.

[Effect of polyoxyl ether analogous surfactants on the activity of cytochromes P450 3A in rats in vivo].

To evaluate the effects of p-octyl polyethylene glycol phenyl ether (Triton X-100), polyoxyl 35 caster oil (EL35) and polyoxyl 40 hydrogenated caster oil (RH40) on the activity of Cytochrome P450 3A (CYP3 As) in vivo. Rats were administered with saline, ketoconazole (75 mg x kg(-1) x d(-1)), Triton X-100 (30 mg x kg(-1) x d(-1)), EL35 (150 mg x kg(-1) x d(-1)) and RH40 (150 mg x kg(-1) x d(-1)) intragastrically for 5 consecutive days, and then given midazolam 10 mg x kg(-1) 20 min after the last treatment of ketoconazole or three surfactants with the same dose through duodenal administration. Pharmacokinetics parameters for midazolam and its metabolite 1'-hydroxymidazolam were estimated from the plasma concentration-time data by a noncompartmental approach. The results showed that multiple dose administration of Triton X-100, EL35 and RH40 decreased the ratios of 1'-hydroxymidazolam and midazolam AUC0-infinity from 1.14 to 0.90, 1.03 and 0.64, respectively. In contrast, multiple dose administration of ketoconazole caused the ratios of 1'-hydroxymidazolam and midazolam a significant decrease to 0.50. This study indicated that Triton X-100 and EL35 would have no inhibition on CYP3A, while RH40 had significant inhibition on CYP3A. Therefore, RH40 might be used to prepare drug formulations in pharmaceutical industry and would increase the bioavailability of some drugs transformed by CYP3As and further lead to significant clinical pharmacologic effects.