Publications by authors named "Limei Han"

44 Publications

Comparative analysis of ketone body metabolism in BALB/c mice infected with Trypanosoma evansi and Toxoplasma gondii.

Res Vet Sci 2021 Dec 20;143:134-141. Epub 2021 Dec 20.

Key Laboratory of Livestock Infectious Diseases, Ministry of Education, China; College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China. Electronic address:

KBs (ketone bodies), i.e., acetoacetate, acetone, and (R)-3-Hydroxybutanoate, constitute the intermediate products of the incomplete oxidative degradation of fatty acids. These KBs are used as a source of energy in the hosts' brain, skeletal muscles, and heart. Additionally, they regulate inflammation and oxidative stress of the host by acting as signaling mediators. Parasitic infection is known to result in abnormal physiological and biochemical metabolism, ketoacidosis, and other damage to the host. In this study, we investigated the effects of Trypanosoma evansi and Toxoplasma gondii on ketone body metabolism in mice, as well as the KB levels in the brain, liver, and peripheral blood. T. gondii was found to significantly increase the KB levels, resulting in ketonemia; T. evansi was found to stabilize KB levels in mice. Further investigations showed that T. evansi downregulated the expression of genes encoding enzymes involved in KBs synthesizing pathway and enhanced KBs synthesizing to eliminate ketonemia. Conversely, T. gondii significantly increased the expression of genes encoding enzymes involved in KBs synthesizing pathway and decreased KBs metabolism pathway ones and resulting in increased KBs levels in peripheral blood, culminating in ketonemia. These findings elucidate the differences in the KBs metabolism resulting from infection with T. evansi and T. gondii.
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http://dx.doi.org/10.1016/j.rvsc.2021.12.016DOI Listing
December 2021

Intelligent SERS Navigation System Guiding Brain Tumor Surgery by Intraoperatively Delineating the Metabolic Acidosis.

Adv Sci (Weinh) 2022 Jan 12:e2104935. Epub 2022 Jan 12.

Key Laboratory of Smart Drug Delivery Ministry of Education, State Key Laboratory of Medical Neurobiology, School of Pharmacy, Fudan University, Shanghai, 201203, China.

Surgeons face challenges in intraoperatively defining margin of brain tumors due to its infiltrative nature. Extracellular acidosis caused by metabolic reprogramming of cancer cells is a reliable marker for tumor infiltrative regions. Although the acidic margin-guided surgery shows promise in improving surgical prognosis, its clinical transition is delayed by having the exogenous probes approved by the drug supervision authority. Here, an intelligent surface-enhanced Raman scattering (SERS) navigation system delineating glioma acidic margins without administration of exogenous probes is reported. With assistance of this system, the metabolites at the tumor cutting edges can be nondestructively transferred within a water droplet to a SERS chip with pH sensitivity. Homemade deep learning model automatically processes the Raman spectra collected from the SERS chip and delineates the pH map of tumor resection bed with increased speed. Acidity correlated cancer cell density and proliferation level are demonstrated in tumor cutting edges of animal models and excised tissues from glioma patients. The overall survival of animal models post the SERS system guided surgery is significantly increased in comparison to the conventional strategy used in clinical practice. This SERS system holds the promise in accelerating clinical transition of acidic margin-guided surgery for solid tumors with infiltrative nature.
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http://dx.doi.org/10.1002/advs.202104935DOI Listing
January 2022

Discovery of Polar Ozonation Byproducts via Direct Injection of Effluent Organic Matter with Online LC-FT-ICR-MS.

Environ Sci Technol 2022 Jan 10. Epub 2022 Jan 10.

Department of Analytical Chemistry, Helmholtz Centre for Environmental Research-UFZ, Permoserstrasse 15, 04318 Leipzig, Germany.

Effluent organic matter (EfOM), a major ozone consumer during wastewater ozonation, is a complex mixture of natural and anthropogenic organic molecules. Ozonation of EfOM adds to molecular complexity by introducing polar and potentially mobile ozonation byproducts (OBPs). Currently, nontargeted direct infusion (DI) ultrahigh resolution mass spectrometry (e.g. FT-ICR-MS) is used to study OBPs but requires sample extraction, limiting the accessible polarity range of OBPs. To better understand the impact of ozonation on EfOM and the formation of polar OBPs, nonextracted effluent was analyzed by direct injection onto a reversed-phase liquid chromatography system (RP-LC) online hyphenated with an FT-ICR-MS. Over four times more OBPs were detected in nonextracted EfOM compared to effluent extracted with solid phase extraction and measured with DI-FT-ICR-MS (13817 vs 3075). Over 1500 highly oxygenated OBPs were detected exclusively in early eluting fractions of nonextracted EfOM, indicating polar OBPs. Oxygenation of these newly discovered OBPs is higher than previously found, with an average molecular DBE-O value of -3.3 and O/C ratio of 0.84 in the earliest eluting OBP fractions. These polar OBPs are consistently lost during extraction but may play an important role in understanding the environmental impact of ozonated EfOM. Moreover, 316 molecular formulas classified as nonreactive to ozone in DI-FT-ICR-MS can be identified with LC-FT-ICR-MS as isomers with varying degrees of reactivity, providing for the first time experimental evidence of differential reactivity of complex organic matter isomers with ozone.
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http://dx.doi.org/10.1021/acs.est.1c04310DOI Listing
January 2022

Design and Characterization of HY-038 Solid Dispersions via Spray Drying Technology: In Vitro and In Vivo Evaluations.

AAPS PharmSciTech 2021 Nov 8;22(8):267. Epub 2021 Nov 8.

Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai, 201203, People's Republic of China.

The aim of this study was to prepare HY-038 solid dispersions (SDs) with single carrier at high drug loading and then forming a tablet to enhance solubility, dissolution, and bioavailability via spray drying technology. At the same time, we hope to develop a more convenient in vitro method to predict the absorption behavior of different formulations in vivo. Different solid dispersions, varying in drug/polymer ratios, were prepared. Infrared spectroscopy, differential scanning calorimetry, scanning electron microscope, and X-ray diffraction were used to perform solid-state characterizations of the pure drug and SDs. Contact angle of water, dissolution in pH = 6.8 phosphate buffer, and in vivo absorption in dogs were studied. As a result, solid-state characterization demonstrated the transformation of the crystalline HY-038 to an amorphous state in the solid dispersions, and the in vivo exposure followed with the trend of the dissolution curve combined with contact angle. Compared with the prototype formulation, the C and AUC of optimized formulation SD2 (HY-038-HPMCAS 3:1) increased by about 5 ~ 9 times at the same dose. More importantly, the SD2 formulation showed approximately linear increases in C and AUC as the dose increased from 50 to 100 mg, while the prototype formulation reached absorption saturation at 50 mg. SD2 (HY-038-HPMCAS 3:1) was selected as the best formulation for the downstream development.
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http://dx.doi.org/10.1208/s12249-021-02135-2DOI Listing
November 2021

A Novel Real-Time Reverse Transcription Loop-Mediated Isothermal Amplification Detection Platform: Application to Diagnosis of COVID-19.

Front Bioeng Biotechnol 2021 22;9:748746. Epub 2021 Oct 22.

Central and Clinical Laboratory of Sanya People's Hospital, Sanya, China.

The ongoing Corona virus disease (COVID-19) outbreak has become a huge global health concern. Here, we reported a novel detection platform based on the loop-mediated isothermal amplification (LAMP), termed real-time reverse transcription LAMP (rRT-LAMP) and applied it for the diagnosis of COVID-19 (COVID-19 rRT-LAMP). rRT-LAMP integrates reverse transcription, LAMP amplification, restriction endonuclease cleavage and real-time fluorescence detection into one-pot reaction, and facilitates the diagnosis of COVID-19 at 64°C for only 35 min. The ORF1ab (opening reading frame 1a/b) and NP (nucleoprotein) genes of SARS-CoV-2 were detected for diagnosing COVID-19. The limit of detection (LoD) of COVID-19 rRT-LAMP assay was 14 copies (for each marker) per vessel, and no positive results were obtained from non-SARS-CoV-2 templates. To demonstrate its feasibility, a total of 33 oropharynx swab samples collected from COVID-19 patients also were diagnosed as SARS-CoV-2 infection using COVID-19 rRT-LAMP protocol. No cross-reactivity was yielded from 41 oropharynx swab samples collected from non-COVID-19 patients. These data suggesting that the COVID-19 rRT-LAMP assay is a potential detection tool for the diagnosis of SARS-CoV-2 infection in clinical, field and disease control laboratories, and will be valuable for controlling the COVID-19 epidemic.
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http://dx.doi.org/10.3389/fbioe.2021.748746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8569142PMC
October 2021

Role of microRNA and long non-coding RNA in Marek's disease tumorigenesis in chicken.

Res Vet Sci 2021 Mar 8;135:134-142. Epub 2021 Jan 8.

Department of Bioscience, Changchun Normal University, Changchun 130032, China. Electronic address:

Marek's disease virus (MDV), the causative agent of Marek's disease (MD), results in highly infectious phymatosis, lymphatic tissue hyperplasia, and neoplasia. MD is associated with high morbidity and mortality rate. Non-coding RNAs (ncRNAs) entails long non-coding RNA (lncRNA) and microRNA (miRNA). Numerous studies have reported that specific miRNAs and lncRNAs participate in multiple cellular processes, such as proliferation, migration, and tumor cell invasion. Specialized miRNAs and lncRNAs militate a similar role in MD tumor oncogenesis. Despite its growing popularity, only a few reviews are available on ncRNA in MDV tumor oncogenes. Herein, we summarized the role of the miRNAs and lncRNAs in MD tumorigenesis. Altogether, we brought forth the research issues, such as MD prevention, screening, regulatory network formation, novel miRNAs, and lncRNAs analysis in MD that needs to be explored further. This review provides a theoretical platform for the further analysis of miRNAs and lncRNAs functions and the prevention and control of MD and malignancies in domestic animals.
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http://dx.doi.org/10.1016/j.rvsc.2021.01.007DOI Listing
March 2021

Online Counter Gradient LC-FT-ICR-MS Enables Detection of Highly Polar Natural Organic Matter Fractions.

Anal Chem 2021 01 28;93(3):1740-1748. Epub 2020 Dec 28.

Department of Analytical Chemistry, Helmholtz Centre for Environmental Research (UFZ), 04318 Leipzig, Germany.

Natural organic matter (NOM) is a highly complex mixture of natural organic molecules. The recent developments in NOM molecular characterization methods have shown that ESI-FT-ICR hyphenated with liquid chromatography (LC) is a promising approach to also obtain chemical information (such as polarity and molecular size) about NOM molecules. However, due to changing solvent composition during gradient elution in LC-FT-ICR-MS, ionization conditions also change throughout the chromatographic separation process. In this study, we applied a post-LC column counter gradient (CG) to ensure stable solvent conditions for transient ESI-MS signals. Suwanee River Fulvic Acid (SRFA) standard and a peat pore water were used as representative dissolved NOM samples for method development and validation. Our results show that in polar NOM fractions (which elute with <50% methanol) the TIC intensity and number of assigned molecular formulas were increased by 48% and 20%, as compared to the standard gradient (SG) method. Further application of a Q-isolation and selective ion accumulation for low abundance fractions revealed over 3 times more molecular formulas (especially for CHNO, CHOS, CHNOS formula classes) than in full scan mode. The number of detected highly polar NOM compounds (with elemental ratios H/C < 1, O/C > 0.6) were more than 20 times larger for CG-LC mode as compared to direct infusion (DI) (5715 vs 266 MF). We conclude that the application of a postcolumn counter gradient in LC-FT-ICR-MS analyses of NOM offers novel insight into the most polar fractions of NOM which are inaccessible in conventional DI measurements.
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http://dx.doi.org/10.1021/acs.analchem.0c04426DOI Listing
January 2021

Georgenia faecalis sp. nov. isolated from the faeces of Tibetan antelope.

J Microbiol 2020 Sep 24;58(9):734-740. Epub 2020 Jul 24.

Central & Clinical Laboratory of Sanya People's Hospital, Sanya, Hainan, 572000, P. R. China.

Two aerobic, Gram-stain-positive, non-motile, non-sporulating coccoid strains, designated ZLJ0423 and ZLJ0321, were isolated from the faeces of Tibetan antelope (Pantholops hodgsonii). Their optimal temperature, NaCl concentration and pH for growth were 28°C, 0.5% (w/v) NaCl and pH 7.5, respectively. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strains ZLJ0423 and ZLJ0321 were very similar to each other (99.8%) and had a sequence similarity of 97.0% with Georgenia satyanarayanai NBRC 107612 and Georgenia subflava CGMCC 1.12782. Phylogenomic analysis based on 688 core genes indicated that these strains formed a clade with G. satyanarayanai NBRC 107612 and Georgenia wutianyii Z294. The predominant cellular fatty acids were anteiso-C, anteiso-C and C. The major menaquinone was MK-8(H). The cell-wall amino acids consisted of alanine, lysine, glycine and aspartic acid, with lysine as the diagnostic diamino acid. Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannosides and two unidentified lipids formed the polar lipid profile. The DNA G + C content of both isolates was 73.9 mol%. The digital DNA-DNA hybridization value between strains ZLJ0423 and ZLJ0321 was 91.2%, but their values with closely related species and other available type strains of the genus Georgenia were lower than the 70% threshold. On the basis of polyphasic taxonomic data, strains ZLJ0423 and ZLJ0321 represent a novel species within the genus Georgenia, for which the name Georgenia faecalis sp. nov. is proposed. The type strain is ZLJ0423 (= CGMCC 1.13681 = JCM 33470).
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http://dx.doi.org/10.1007/s12275-020-0060-1DOI Listing
September 2020

Multiplex reverse transcription loop-mediated isothermal amplification combined with nanoparticle-based lateral flow biosensor for the diagnosis of COVID-19.

Biosens Bioelectron 2020 Oct 15;166:112437. Epub 2020 Jul 15.

Department of Respiratory Disease, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 10045, PR China; Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Key Laboratory of Pediatric Respiratory Infection Disease, National Clinical Research Center for Respiratory Diseases, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 10045, PR China. Electronic address:

The ongoing global pandemic (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a huge public health issue. Hence, we devised a multiplex reverse transcription loop-mediated isothermal amplification (mRT-LAMP) coupled with a nanoparticle-based lateral flow biosensor (LFB) assay (mRT-LAMP-LFB) for diagnosing COVID-19. Using two LAMP primer sets, the ORF1ab (opening reading frame 1a/b) and N (nucleoprotein) genes of SARS-CoV-2 were simultaneously amplified in a single-tube reaction, and detected with the diagnosis results easily interpreted by LFB. In presence of FITC (fluorescein)-/digoxin- and biotin-labeled primers, mRT-LAMP produced numerous FITC-/digoxin- and biotin-attached duplex amplicons, which were determined by LFB through immunoreactions (FITC/digoxin on the duplex and anti-FITC/digoxin on the test line of LFB) and biotin/treptavidin interaction (biotin on the duplex and strptavidin on the polymerase nanoparticle). The accumulation of nanoparticles leaded a characteristic crimson band, enabling multiplex analysis of ORF1ab and N gene without instrumentation. The limit of detection (LoD) of COVID-19 mRT-LAMP-LFB was 12 copies (for each detection target) per reaction, and no cross-reactivity was generated from non-SARS-CoV-2 templates. The analytical sensitivity of SARS-CoV-2 was 100% (33/33 oropharynx swab samples collected from COVID-19 patients), and the assay's specificity was also 100% (96/96 oropharynx swab samples collected from non-COVID-19 patients). The total diagnostic test can be completed within 1 h from sample collection to result interpretation. In sum, the COVID-19 mRT-LAMP-LFB assay is a promising tool for diagnosing SARS-CoV-2 infections in frontline public health field and clinical laboratories, especially from resource-poor regions.
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http://dx.doi.org/10.1016/j.bios.2020.112437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361114PMC
October 2020

Four Cysteine Residues Contribute to Homodimerization of Chicken Interleukin-2.

Int J Mol Sci 2019 Nov 15;20(22). Epub 2019 Nov 15.

College of Animal Science, Jilin University, 5333 XiAn Road, Changchun, Jilin 130062, China.

Interleukin-2 (IL-2) is a pleiotropic cytokine regulating the immune and nervous systems. Mammalian and bird IL-2s have different protein sequences, but perform similar functions. In the current study, two bands were detected by immunoblotting using an antibody against freshly purified chicken IL-2 (chIL-2). The molecular weight of the larger band was approximately twice as much of the chIL-2 monomer, although a chIL-2 complex or homodimer has never been reported. To explain this intriguing result, several dissociation reagents were used to examine the intermolecular forces between components of the proposed chIL-2 complex. It was found that intermolecular disulphide bond promotes homodimerization of chIL-2. Subsequently, mutation of Cys residues of chIL-2 revealed that mutation of all four Cys residues disrupted homodimerization, but a single, dual, or triple Cys mutation failed to disrupt homodimerization, suggesting that all four Cys residues on chIL-2 contribute to this dimerization. Functional analysis showed that both monomeric and dimeric chIL-2 consisting of either wild type or mutant chIL-2 were able to stimulate the expansion of CD4 T cell in vivo or in vitro, and effectively bind to chIL-2 receptor. Overall, this study revealed that the recombinant chIL-2 purified from either () or (Sf9) cells could homodimerize in vitro, with all four Cys residues on each chIL-2 protein contributing to this homodimerization, and dimerization and Cys mutation not impacting chIL-2 induced stimulation of chicken CD4 T cells.
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http://dx.doi.org/10.3390/ijms20225744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888268PMC
November 2019

Morphology, Loadability, and Releasing Profiles of CalliSpheres Microspheres in Delivering Oxaliplatin: An Study.

Technol Cancer Res Treat 2019 Jan-Dec;18:1533033819877989

Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, China.

Objectives: This study aimed to explore the morphology, loadability, and releasing profiles of CalliSpheres microspheres in delivering oxaliplatin.

Methods: Varied amount (20, 40, 60, and 80 mg oxaliplatin) and concentration (1.25, 2.5, 5.0 mg/mL oxaliplatin) of oxaliplatin were mixed with CalliSpheres microspheres with 3 sizes (50-150 μm, 100-300 μm, and 300-500 μm) to measure the loadability. Of all, 20 mg oxaliplatin-loaded CalliSpheres microspheres with 3 sizes was prepared to measure the releasing profiles, meanwhile, fetal bovine serum was added to determine the effect of serum on oxaliplatin releasing. The morphology and size distribution of CalliSpheres microspheres with 3 sizes before and after 20 mg oxaliplatin loading were detected.

Results: Oxaliplatin amount was negatively correlated with loading efficiency with highest loadability in 20 mg oxaliplatin group (maximum 40% in 50-100 µm CalliSpheres microspheres, 52% in 100-300 µm CalliSpheres microspheres, and 52% in 300-500 µm CalliSpheres microspheres), while oxaliplatin concentration was positively associated with loading efficiency. Similar drug-releasing profiles were observed among oxaliplatin-loaded CalliSpheres microspheres with 3 sizes, and a rapid drug release was discovered in CalliSpheres microspheres with 3 sizes as well. We also found that fetal bovine serum did not affect the drug-releasing profiles of oxaliplatin-loaded CalliSpheres microspheres. In addition, CalliSpheres microspheres was modified a little to ellipse shape and less smooth after oxaliplatin loading, and it was enlarged to some extent.

Conclusion: This study discloses drug loadability, releasing profiles, and morphology change of CalliSpheres microspheres for delivering oxaliplatin, which provides potential evidences for application of oxaliplatin-loaded drug-eluting beads in clinical practice.
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http://dx.doi.org/10.1177/1533033819877989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801889PMC
May 2020

Tau-TCHF Inhibits Spleenic Apoptosis via PI3K-Akt Signaling Pathway in Chickens.

Adv Exp Med Biol 2019 ;1155:555-563

Liaoning Provincial Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, People's Republic of China.

Taurine plays an important role in improving immunity, regulating cell proliferation and differentiation, apoptosis and so on. Traditional Chinese herb formula (TCHF) is a wealth of medicine materials for diseases control. There are many studies on Chinese herb formula in inducing cell apoptosis, differentiation and improving animal immunity. The factors in phosphatidylinositol 3-kinase/Protein Kinase (PI3K-Akt) signaling pathway are central regulators of normal cells, which integrates extra-cellular signals into cells and activates affects cell activities including cell proliferation, differentiation and apoptosis. We find the key factors (PIK3CA, PDPK1, AKT1, MDM2, ITGA2B, ITGB1, FAK and p53) in PI3K-Akt signaling pathway by RNA-Seq analysis in our previous research. The overall goal of this study to investigate the influence of taurine TCHF (Tau-TCHF) on cell proliferation, differentiation and apoptosis by estimating the factors above. The layers were fed with normal diet plus 1% of Tau-TCHF and the control group with normal diet to 42 days old. The spleen tissue samples from individual layers were used to analyze the influence of Tau-TCHF on the factors PIK3CA, PDPK1, AKT1, MDM2, ITGA2B, ITGB1, FAK and p53 in PI3K-Akt signaling pathway. The levels of transcription and protein expression of various factors were assessed by quantitative PCR (qPCR) and Western Blot. The results showed that the transcription levels of itgb1, fak, pik3ca, akt1 and mdm2 on 42-day-old chicken spleen tissues were increased significantly in Tau-TCHF group comparing with control group (P < 0.01); the transcription levels of itga2b, pdpk1 and p53 were no significant difference (P > 0.05). The protein levels of PDPK1 and AKT (Ser437) were increased significantly (P < 0.05), but ITGA2B, ITGB1, FAK, PIK3CA, AKT1, MDM2 and p53 had no significant difference (P > 0.05). The results suggest that Tau-TCHF may influence proliferation and differentiation of chickens spleen via regulating PI3K-Akt signaling pathway. And Tau-TCHF may be provided as feed additives in improving the immunity of animals. AKT (Ser473) and PDPK1 may be considered as further targets to study mechanism of Tau-TCHF on anti-apoptosis via PI3K-Akt signaling pathway.
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http://dx.doi.org/10.1007/978-981-13-8023-5_51DOI Listing
September 2019

A three chamber bioelectrochemical system appropriate for in-situ remediation of nitrate-contaminated groundwater and its reaction mechanisms.

Water Res 2019 Jul 26;158:401-410. Epub 2019 Apr 26.

School of Environment, Tsinghua University, Beijing, 10084, China. Electronic address:

A novel laboratory experiment of three chamber bioelectrochemical (surface water-sediment-groundwater, SSG) system was established in this study, which combined a sediment microbial fuel cell (SMFC) reactor and biofilm electrode reactor (BER) and was self-driven. Simulated groundwater was firstly used to explore the reaction mechanisms of this system. The simulated groundwater conditions were static and the surface water and the groundwater systems were isolated. The results showed that the SMFC continuously supplied a stable voltage of 622 mV ± 20 mV, driving the BER and the related nitrate removal process. Compared to the control systems, the SSG system had higher nitrate removal with a denitrification rate of 3.87 mg N/(L·h). In addition, the sediment organic matter in the SMFC reactor decreased by 66.2%. Based on the electrochemical analysis and microbial community analysis, the SMFC reactor and BER worked synergistically to enhance the performance of both reactors in this system. The presence of microorganisms accelerated the electron transfer efficiency throughout the system, and the microcurrent helped a more fixed community structure to develop and stimulated the growth of denitrifying bacteria. The dominant genera detected in the mature biofilm samples were all microorganisms common in soil and groundwater, indicating that this system may be environmentally friendly. The nitrate removal efficiency for actual groundwater was higher than that for the simulated groundwater, indicating that the elements in the actual groundwater promote the nitrate removal efficiency. These results indicate that the SSG system has the potential for in-situ nitrate bioremediation, with minimal maintenance and health risk.
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http://dx.doi.org/10.1016/j.watres.2019.04.047DOI Listing
July 2019

Surface-Enhanced Resonance Raman Scattering-Guided Brain Tumor Surgery Showing Prognostic Benefit in Rat Models.

ACS Appl Mater Interfaces 2019 May 17;11(17):15241-15250. Epub 2019 Apr 17.

Minhang Hospital and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy , Fudan University , Shanghai 201203 , China.

Glioma is the most frequent form of malignant brain tumors. Surgical debulking is a major strategy for glioma treatment. However, there is a great challenge for the neurosurgeons to intraoperatively identify the true margins of glioma because of its infiltrative nature. Tumor residues or microscopic satellite foci left in the resection bed are the main reasons leading to early recurrence as well as poor prognosis. In this study, a surface-enhanced resonance Raman scattering (SERRS) probe was developed to intraoperatively guide glioma resection. In this probe, molecular reporters with absorptive maxima at the near-infrared wavelength range were covalently functionalized on the surface of gold nanostars. This SERRS probe demonstrated an ultrahigh sensitivity with a detection limit of 5.0 pM in aqueous solution. By the development of glioma xenografts in a mouse dorsal skin window chamber, extravasation of this probe from leaky tumor vasculature as functions of time and distance to tumor boundary was investigated. Importantly, the invasive margin of the tumor xenograft was demarcated by this probe with a high signal-to-background ratio. Preoperative magnetic resonance imaging (MRI) first defined the position of orthotopic glioma xenografts in the brain of rat models, and the craniotomy plan was designed. The brain tumor was then excised intraoperatively step-by-step with the assistance of a handheld Raman scanner till the Raman signals of the probe completely disappeared in the resection bed. Notably, longitudinal MRI showed that SERRS-guided surgery significantly reduced the tumor recurrence rate and improved the overall survival of rat models compared with the white light-guided surgery. Overall, this work demonstrates the prognostic benefit of SERRS-guided glioma surgery in animal models. Because delineation of tumor-invasive margins is a common challenge faced by the surgeons, this SERRS probe with a picomolar detection limit holds the promise in improving the surgical outcome of different types of infiltrated tumors.
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http://dx.doi.org/10.1021/acsami.9b00227DOI Listing
May 2019

Enterococcal isolates from bovine subclinical and clinical mastitis: Antimicrobial resistance and integron-gene cassette distribution.

Microb Pathog 2019 Apr 22;129:82-87. Epub 2019 Jan 22.

Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, 110866, PR China. Electronic address:

Bovine mastitis is one of the most prevalent and costly diseases, and can be caused by a variety of bacterial pathogens including enterococci. Unfortunately, comprehensive studies about the prevalence and antimicrobial resistance profiles of entercocci are scarcely reported. This study aimed to investigate the occurrence of enterococci associated with bovine clinical mastitis and subclinical mastitis, to assess their antimicrobial resistance profiles, and to detect the distribution of integrons and gene cassette arrays in Liaoning of China. Our results indicated subclinical mastitis occurred in 34.3% of bovine, and 21.4% of bovine were positive for clinical mastitis, meanwhile Enterococcus faecium is the predominant pathogen in both clinical mastitis and subclinical mastitis. More than 50% of the total isolates were resistant to penicillin, ceftiofur, tylosin, lincomycin, and oxytetracycline. Class I integrons was detected in enterococcal isolates from both clinical and subclinical mastitis with 57.1% and 45.3%, respectively. Meanwhile, class II integrons only were observed in enterococcal isolates from subclinical mastitis. Multidrug resistance has become prevalent in enterococci isolated from clinical mastitis and subclinical mastitis in Liaoning, northeast of China. This study revealed that enterococcal isolates had shown resistant to β-lactam antibiotics including penicillin, and different therapeutic programs should be carried out in Liaoning of China.
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http://dx.doi.org/10.1016/j.micpath.2019.01.031DOI Listing
April 2019

Serum Metabolomics Analysis in Wasp Sting Patients.

Biomed Res Int 2018 25;2018:5631372. Epub 2018 Dec 25.

Emergency Department, Taihe Hospital, Shiyan 442000, China.

To analyze the dynamic changes of serum metabolomics in wasp sting victims, we collected serum from 10 healthy volunteers and 10 patients who had been stung 3 hours, 24 hours, and 72 hours before sample collection. We analyzed the metabolomics by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) techniques and then performed enrichment analysis. A total of 838 metabolites were identified. Serum metabolomics analysis using MetaboAnalyst revealed 289 metabolites that were significantly different among patients in the 3-hour group versus healthy controls (P<0.001). Pathway analysis of those metabolites indicated that those metabolic sets were associated with sphingolipid metabolism. Based on the differences among the control, 3-hour, 24-hour, and 72-hour groups, we classified serum metabolites into different categories. The first and second categories included 297 and 280 metabolites that were significantly different in terms of concentration among healthy controls versus the participants whose sera were analyzed 3 hours, 24 hours, and 72 hours after wasp stings. Pathway analysis of those metabolites indicated that those metabolic sets were associated with thiamine metabolism. The third category included 269 significant metabolites. The fourth category included 28 significant metabolites. Pathway analysis of the metabolites in third and fourth categories indicated that those metabolic sets were associated with phenylalanine, tyrosine, and tryptophan biosynthesis. The fifth category included 31 metabolites, which were not significantly different between the control and 3-hour groups but were higher in concentration in the 24-hour and 72-hour groups. Pathway analysis of the fifth category of significant metabolites identified linoleic acid metabolism. In conclusion, multiple metabolic pathways are associated with wasp stings, and these might provide a basis for exploring mechanisms of wasp sting injury and potential targets for therapy.
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http://dx.doi.org/10.1155/2018/5631372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323449PMC
May 2019

Biopanning of allergens from wasp sting patients.

Biosci Rep 2018 10 17;38(5). Epub 2018 Oct 17.

Emergency Department, Taihe Hospital, Shiyan 442000, China

Objective: Wasp venom is a potentially important natural drug, but it can cause hypersensitivity reactions. The purpose of the present study was to systematically study the epitopes of wasp venom.

Methods: Using a random 12-peptide phage library, we performed antibody-binding epitope panning on ten serum samples from wasp sting victims at 3 h and 4 days after the sting. The panning epitopes were identified by high-throughput sequencing and matched with wasp venom proteins by BLAST. The panned antibody-binding epitopes were verified by ELISA.

Results: A total of 35 specific potential wasp venom epitopes in 4 days were identified. Amongst them, twelve peptide epitopes were matched with nine wasp venom proteins, namely, vitellogenin precursor, hexamerin 70b precursor, venom carboxylesterase-6 precursor, MRJP5, major royal jelly protein 8 precursor, venom acid phosphatase Acph-1 precursor, phospholipase A2, venom serine protease 34 precursor, and major royal jelly protein 9 precursor. The changes in serum IgM antibodies induced by wasp venom were confirmed by ELISA based on the 12 peptide epitopes.

Conclusion: The nine wasp venom proteins are potential allergens, which should be excluded or modified in the potential biomedical applications of wasp venom.
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http://dx.doi.org/10.1042/BSR20181113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200702PMC
October 2018

Image-guided chemotherapy with specifically tuned blood brain barrier permeability in glioma margins.

Theranostics 2018 30;8(11):3126-3137. Epub 2018 Apr 30.

Minhang Branch, Zhongshan Hospital and Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.

Blood-brain barrier (BBB) disruption is frequently observed in the glioma region. However, the tumor uptake of drugs is still too low to meet the threshold of therapeutic purpose. A tumor vasculature-targeted nanoagonist was developed. Glioma targeting specificity of the nanoagonist was evaluated by optical imaging. BBB permeability at the glioma margin was quantitatively measured by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Single-photon emission computed tomography imaging/computed tomography (SPECT/CT) quantitatively determined the glioma uptake of the radiolabeled model drug. T2-weighted MRI monitored the tumor volume. Immunostaining studies demonstrated that the BBB remained partially intact in the invasive margin of patients' gliomas regardless of their malignancies. DCE-MRI showed that vascular permeability in the glioma margin reached its maximum at 45 min post nanoagonist administration. optical imaging indicated the high glioma targeting specificity of the nanoagonist. SPECT/CT showed the significantly enhanced glioma uptake of the model drug after pre-treatment with the nanoagonist. Image-guided paclitaxel injection after nanoagonist-mediated BBB modulation more efficiently attenuated tumor growth and extended survival than in animal models treated with paclitaxel or temozolomide alone. Thus, image-guided drug delivery following BBB permeability modulation holds promise to enhance the efficacy of chemotherapeutics to glioma.
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http://dx.doi.org/10.7150/thno.24784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996359PMC
May 2019

Taurine Reverses Atrial Structural Remodeling in Ach-Cacl Induced Atrial Fibrillation Rats.

Adv Exp Med Biol 2017;975 Pt 2:831-841

Liaoning Provincial Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, 110866, People's Republic of China.

Taurine has been reported to have anti-arrhythmia effects, but the anti-atrial fibrillation (AF) effects and its mechanism remain incompletely understood. In the present study, the therapy effects and partly mechanisms were investigated. AF animal model was established by intravenous administered with the mixture of acetylcholine (Ach) and CaCl (66 μg/mL + 10 mg/mL) (i.v.) for 7 days. The actions of taurine (99 mg/kg∙d, introgastric administration) on the levels of Hs-CRP, IL-6, TNF-α, MMP-9, AngII, the extent of the fibrosis and ultrastructural changes in left atrial were studied. The data showed that the serum levels of TNF-α, IL-6, AngII and the plasma levels of Hs-CRP and MMP-9 were significantly elevated in automatic recovery group relative to the control group (p < 0.01), which were all decreased by taurine administration (p < 0.01) similar to Verapamil treatment. Masson's trichrome staining of the left atrial tissue showed an obvious interstitial fibrosis in rats of automatic recovery group. The alteration could be reversed by additional taurine. Electron microscopy revealed that taurine administration could significantly alleviate the ultrastructural damage of atrial cells, and the effects were similar to the Verapamil treatment. In conclusion, the results suggested that taurine could inhibit the structural remodeling of AF in rats partly by decreasing the levels of inflammatory factors and profibrotic molecules, attenuating the extent of myocardial fibrosis and protecting the integrity of myocardial ultrastructure.
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http://dx.doi.org/10.1007/978-94-024-1079-2_65DOI Listing
October 2018

Antibacterial and antioxidant properties of various solvents extracts of Abutilon theophrasti Medic. leaves.

Pak J Pharm Sci 2017 May;30(3):767-772

Department of Animal Pharmacy, Colloge of Animal Husbandry and Veterinary, Shenyang Agricultural University, No.120, Dongling Road Shenhe Dist, Shenyang Liaoning Prov., People's Republic of China.

This paper described the extraction procedure of six extracts from Abutilon theophrasti Medic. leaves and evaluated antioxidant and antibacterial activity of different extracts by hydroxyl radical, DPPH radical scavenging, broth micro-dilution and agar-well diffusion methods. The six extracts were prepared by the two extraction procedures: (I) water was the extraction solvent; (II) 90% alcohol extract was extracted by petroleum ether, chloroform, ethyl acetate and n-butanol in turn. Extract yields were 7.34%, 7.31%, 0.45%, 0.12%, 2.70% and 5.68% for extract I to VI. It was revealed that the various extracts had effective antibacterial activity against four test strains from Staphylococcus aureus (ATCC 25923), Streptococcus (ATCC 49619), Escherichia coli (ATCC 25922) and Salmonella (ATCC 01303); meanwhile, the six extracts demonstrated potent antioxidant activity, achieved by hydroxyl radical and DPPH radical scavenging assay. Minimum inhibitory concentrations (MICs) for the bacterial species ranged from 2.21 to 539.46 mg/ml, diameter of inhibition zone ranged from 2.08 to 15.05mm. The scavenging •OH and DPPH• rates were 62.37% to 81.86% with the concentration 0.06 to 1.89mg/ml and 37.80% to 81.23% with the concentration 1.07 to 35.52mg/ml. According to the results, these extracts have antioxidant and antibacterial activity. In view of all the facts collectively, the six extracts will become natural and nontoxic antioxidant and antibacterial agent, and be applied in food and pharmaceutical industries for the prevention or treatment caused by microorganisms and free radicals.
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May 2017

A novel strategy to achieve effective drug delivery: exploit cells as carrier combined with nanoparticles.

Drug Deliv 2017 Nov;24(1):83-91

a Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University , Shanghai , China and.

Cell-mediated drug delivery systems employ specific cells as drug vehicles to deliver drugs to targeted sites. Therapeutics or imaging agents are loaded into these cells and then released in diseased sites. These specific cells mainly include red blood cells, leukocytes, stem cells and so on. The cell acts as a Trojan horse to transfer the drug from circulating blood to the diseased tissue. In such a system, these cells keep their original properties, which allow them to mimic the migration behavior of specific cells to carry drug to the targeted site after in vivo administration. This strategy elegantly combines the advantages of both carriers, i.e. the adjustability of nanoparticles (NPs) and the natural functions of active cells, which therefore provides a new perspective to challenge current obstacles in drug delivery. This review will describe a fundamental understanding of these cell-based drug delivery systems, and discuss the great potential of combinational application of cell carrier and NPs.
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http://dx.doi.org/10.1080/10717544.2016.1230903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241159PMC
November 2017

Exploiting macrophages as targeted carrier to guide nanoparticles into glioma.

Oncotarget 2016 Jun;7(24):37081-37091

Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China.

The restriction of anti-cancer drugs entry to tumor sites in the brain is a major impediment to the development of new strategies for the treatment of glioma. Based on the finding that macrophages possess an intrinsic homing property enabling them to migrate to tumor sites across the endothelial barriers in response to the excretion of cytokines/chemokines in the diseased tissues, we exploited macrophages as 'Trojan horses' to carry drug-loading nanoparticles (NPs), pass through barriers, and offload them into brain tumor sites. Anticancer drugs were encapsulated in nanoparticles to avoid their damage to the cells. Drug loading NPs was then incubated with RAW264.7 cells in vitro to prepare macrophage-NPs (M-NPs). The release of NPs from M-NPs was very slow in medium of DMEM and 10% FBS and significantly accelerated when LPS and IFN-γ were added to mimic tumor inflammation microenvironment. The viability of macrophages was not affected when the concentration of doxorubicin lower than 25 μg/ml. The improvement of cellular uptake and penetration into the core of glioma spheroids of M-NPs compared with NPs was verified in in vitro studies. The tumor-targeting efficiency of NPs was also significantly enhanced after loading into macrophages in nude mice bearing intracranial U87 glioma. Our results provided great potential of macrophages as an active biocarrier to deliver anticancer drugs to the tumor sites in the brain and improve therapeutic effects of glioma.
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http://dx.doi.org/10.18632/oncotarget.9464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095060PMC
June 2016

Enhancing insulin oral absorption by using mucoadhesive nanoparticles loaded with LMWP-linked insulin conjugates.

J Control Release 2016 07 10;233:181-90. Epub 2016 May 10.

Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA. Electronic address:

Although significant progress has been achieved, effective oral delivery of protein drugs such as insulin by nanoparticle-based carrier systems still faces certain formidable challenges. Considerable amount of protein drug is released from the nanoparticles (NPs) in the gastrointestinal (GI) tract. Because of their low permeability through the intestinal mucosa, the released protein would be soon degraded by the large amount of proteases in the GI tract. Herein, we report an oral insulin delivery system that can overcome the above-mentioned problems by mucoadhesive NPs (MNPs) loaded with cell penetrating peptide-linked insulin conjugates. On one hand, after conjugation with low molecular weight protamine (LMWP), a cell penetrating peptide (CPP), insulin showed greatly improved permeability through intestinal mucus layer and epithelia. On the other hand, the mucoadhesive N-trimethyl chitosan chloride-coated PLGA nanoparticles (MNPs) that were loaded with conjugates enhanced the retention in the intestinal mucus layer. By adopting this delivery strategy, the LMWP-insulin conjugates released from the MNPs could be deprived from enzymatic degradation, due to the short distance in reaching the epithelia and the high permeation of the conjugates through epithelia. The oral delivery system of insulin designed by us showed a long-lasting hypoglycemia effect with a faster onset in diabetic rats. The pharmacological availability of orally delivered conjugates-loaded MNPs was 17.98±5.61% relative to subcutaneously injected insulin solution, with a 2-fold higher improvement over that by MNPs loaded with native insulin. Our results suggested that conjugation with CPP followed by encapsulation in MNPs provides an effective strategy for oral delivery of macromolecular therapeutics.
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http://dx.doi.org/10.1016/j.jconrel.2016.05.015DOI Listing
July 2016

Effects of borneol on the pharmacokinetics of 9-nitrocamptothecin encapsulated in PLGA nanoparticles with different size via oral administration.

Drug Deliv 2016 Nov 1;23(9):3417-3423. Epub 2016 Jun 1.

a Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University , Shanghai , China and.

Context: Although nanocarriers provide promising potential for oral drug delivery, the delivery efficiency remains unsatisfactory and needs to be improved. Size is considered to be the most important characteristic of nanoparticles related to their oral absorption. Borneol has been proved to have the ability to enhance the penetration and transport of many drugs through various physical barriers.

Objective: To investigate the effect of the particle size and coadministration of borneol on the pharmacokinetics and bioavailability of entrapped drug in different size poly(lactic-co-glycolic acid) (PLGA) nanoparticles.

Materials And Methods: 9-Nitrocamptothecin (9-NC)-loaded PLGA nanoparticles with three different range of size (50-100 nm, 100-200 nm, 200-300 nm) were prepared by emulsion solvent-evaporation method. The pharmacokinetic study in rats of these nanoparticles with borneol was carried out.

Results: The experiments showed that the encapsulation drug in nanoparticles with size below 200 nm could improve the oral bioavailability of 9-NC. The small size nanoparticles (50-100 nm) had a better improvement efficacy. As for borneol, it played a significant promotion effect only on the small nanoparticles. Moreover, there was no significant influence on the nanoparticles with size more than 100 nm.

Discussion And Conclusion: The study indicated that both entrapping drug in nanoparticles with the size below 100 nm and coadministrating with borneol could enhance the gastrointestinal absorption of water insoluble drug. The combination of the two strategies provides a potential approach to improve the oral bioavailability of drug.
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http://dx.doi.org/10.1080/10717544.2016.1189466DOI Listing
November 2016

Processing by MRE11 is involved in the sensitivity of subtelomeric regions to DNA double-strand breaks.

Nucleic Acids Res 2015 Sep 23;43(16):7911-30. Epub 2015 Jul 23.

Department of Radiation Oncology, University of California, San Francisco, 2340 Sutter St. San Francisco, CA 94143-1330, USA

The caps on the ends of chromosomes, called telomeres, keep the ends of chromosomes from appearing as DNA double-strand breaks (DSBs) and prevent chromosome fusion. However, subtelomeric regions are sensitive to DSBs, which in normal cells is responsible for ionizing radiation-induced cell senescence and protection against oncogene-induced replication stress, but promotes chromosome instability in cancer cells that lack cell cycle checkpoints. We have previously reported that I-SceI endonuclease-induced DSBs near telomeres in a human cancer cell line are much more likely to generate large deletions and gross chromosome rearrangements (GCRs) than interstitial DSBs, but found no difference in the frequency of I-SceI-induced small deletions at interstitial and subtelomeric DSBs. We now show that inhibition of MRE11 3'-5' exonuclease activity with Mirin reduces the frequency of large deletions and GCRs at both interstitial and subtelomeric DSBs, but has little effect on the frequency of small deletions. We conclude that large deletions and GCRs are due to excessive processing of DSBs, while most small deletions occur during classical nonhomologous end joining (C-NHEJ). The sensitivity of subtelomeric regions to DSBs is therefore because they are prone to undergo excessive processing, and not because of a deficiency in C-NHEJ in subtelomeric regions.
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http://dx.doi.org/10.1093/nar/gkv714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652756PMC
September 2015

N-trimethyl chitosan chloride-coated PLGA nanoparticles overcoming multiple barriers to oral insulin absorption.

ACS Appl Mater Interfaces 2015 Jul 9;7(28):15430-41. Epub 2015 Jul 9.

‡Department of Pharmaceutics, School of Pharmacy, Heilongjiang University of Chinese Medicine, Haerbin, Heilongjiang 150040, China.

Although several strategies have been applied for oral insulin delivery to improve insulin bioavailability, little success has been achieved. To overcome multiple barriers to oral insulin absorption simultaneously, insulin-loaded N-trimethyl chitosan chloride (TMC)-coated polylactide-co-glycoside (PLGA) nanoparticles (Ins TMC-PLGA NPs) were formulated in our study. The Ins TMC-PLGA NPs were prepared using the double-emulsion solvent evaporation method and were characterized to determine their size (247.6 ± 7.2 nm), ζ-potential (45.2 ± 4.6 mV), insulin-loading capacity (7.8 ± 0.5%) and encapsulation efficiency (47.0 ± 2.9%). The stability and insulin release of the nanoparticles in enzyme-containing simulated gastrointestinal fluids suggested that the TMC-PLGA NPs could partially protect insulin from enzymatic degradation. Compared with unmodified PLGA NPs, the positively charged TMC-PLGA NPs could improve the mucus penetration of insulin in mucus-secreting HT29-MTX cells, the cellular uptake of insulin via clathrin- or adsorption-mediated endocytosis in Caco-2 cells and the permeation of insulin across a Caco-2 cell monolayer through tight junction opening. After oral administration in mice, the TMC-PLGA NPs moved more slowly through the gastrointestinal tract compared with unmodified PLGA NPs, indicating the mucoadhesive property of the nanoparticles after TMC coating. Additionally, in pharmacological studies in diabetic rats, orally administered Ins TMC-PLGA NPs produced a stronger hypoglycemic effect, with 2-fold higher relative pharmacological availability compared with unmodified NPs. In conclusion, oral insulin absorption is improved by TMC-PLGA NPs with the multiple absorption barriers overcome simultaneously. TMC-PLGA NPs may be a promising drug delivery system for oral administration of macromolecular therapeutics.
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http://dx.doi.org/10.1021/acsami.5b03555DOI Listing
July 2015

Lymphatic transport of orally administered probucol-loaded mPEG-DSPE micelles.

Drug Deliv 2016 Jul 27;23(6):1955-61. Epub 2015 Mar 27.

a Department of Pharmaceutics , School of Pharmacy, Fudan University , Shanghai , People's Republic of China and.

Context: Transporting drugs through the lymphatic system has attracted increasing attention. Lipid-based formulations have been proved to be an effective way to improve systemic bioavailability of highly lipophilic drugs by increasing intestinal lymphatic transport.

Objective: The formulation of polymer micelle was developed for probucol to improve its intestinal lymphatic transport.

Materials And Methods: Methoxy-polyethylenelglycol-distearyl phosphatidyl-ethanolamine (mPEG-DSPE) polymer was chosen to develop the micelles for probucol. The physicochemical properties were characterized. Caco-2 cell model, unconscious and conscious lymph duct cannulated rat models were established for in vitro and in vivo evaluation of lymphatic transport.

Results: In vitro evaluation in the Caco-2 cell model showed that the micellar formulation could significantly increase the uptake and transport of probucol. The study in unconscious and conscious lymph duct cannulated rat models further verified the significant enhancement of lymphatic transport of probucol by mPEG-DSPE micelles.

Discussion And Conclusion: These results suggested that mPEG-DSPE micellar formulation could provide a useful alternative approach for improving the lymphatic transport of hydrophobic compounds.
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http://dx.doi.org/10.3109/10717544.2015.1028600DOI Listing
July 2016

Development of an LC-MS/MS method for determining the pharmacokinetics of clonidine following oral administration of Zhenju antihypertensive compound.

Biomed Chromatogr 2015 Jul 16;29(7):1068-75. Epub 2014 Dec 16.

Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education, Fudan University, Shanghai, 201203, China.

Zhenju antihypertensive compound (ZJAHC) is a combined Chinese-Western medicine formula including clonidine (CLO), hydrochlorothiazide (HCT), rutin, Chrysanthemum indicum extract and pearl powder. Compared with CLO preparations, ZJAHC shows improved activities and decreased adverse effects. It is believed that the side effects of CLO are caused by its high peak plasma concentration. Hence, study of the influence of ZJAHC on the pharmacokinetic behaviors of clonidine seems essential. In present study, the plasma concentrations of CLO were determined with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The MS/MS transitions monitored for clonidine and internal standard were 230.2 → 213.1 and 152.2 → 110.2, respectively. The analyte was quantified in a single run within 3 min. The pharmacokinetic study showed that the area under the plasma concentration-time curve of CLO in ZJAHC (60 µg/kg CLO) was similar to that of CLO-HCT-high (120 µg/kg CLO) but the peak concentration was much lower than that in CLO-HCT-high. ZJAHC could enhance the bioavailability without greatly increasing peak concentration of clonidine. This comprehensive effect of enhancing the bioavailability and avoiding the high peak plasma concentration for CLO might mainly result from the co-contribution of Western medicine and traditional Chinese medicine (TCM), while the effect of TCM was stronger than that of Western medicine.
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http://dx.doi.org/10.1002/bmc.3393DOI Listing
July 2015

Enhanced absorption and bioavailability of hydrochlorothiazide by Chinese medicines in the Zhenju antihypertensive compound.

J Pharm Pharmacol 2014 Jun 7;66(6):855-64. Epub 2014 Jan 7.

Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Fudan University, Shanghai, China.

Objectives: This study was performed to investigate the influence of traditional Chinese medicines in the Zhenju antihypertensive compound (ZJAHC) on the oral absorption of hydrochlorothiazide (HCT) both in vitro and in vivo.

Methods: Caco-2 cells and the in situ closed loop system were used to investigate the possible mechanism of the Chinese-Western medicine interaction on the transepithelial transport and uptake of HCT. The influence of TCMs on the pharmacokinetics and bioavailability of HCT was also studied to reveal the possible interaction in vivo.

Key Findings: In an in situ intestinal perfusion study, the cumulative amount of HCT of ZJAHC group (506.05 μg ± 96.03) was 2.2-fold, 2.18-fold and 1.38-fold higher compared to that of the HCT group (228.29 μg ± 23.39), HCT-clonidine (CLO) group (232.13 ± 54.79 μg) and HCT-rutin (RT) group (366.08 ± 21.97 μg), respectively, after 120 min of perfusion. A pharmacokinetic analysis showed a significant increase in area under the plasma concentration-time curve (AUC) of HCT in the ZJAHC group by 2.14-fold, 2.01-fold and 1.32-fold compared to the HCT, HCT-CLO and HCT-RT groups, respectively. As a P-gp inhibitor, RT could contribute to the enhanced oral absorption of HCT in ZJAHC.

Conclusion: The combination of traditional Chinese medicines and chemical drugs may provide a promising strategy and unique advantages to reduce the dosage and side effects of chemical drugs while maintaining an effect on hypertension.
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http://dx.doi.org/10.1111/jphp.12207DOI Listing
June 2014

Kinase AKT controls innate immune cell development and function.

Immunology 2013 Oct;140(2):143-52

Department of Immunology, Shanghai Medical College, Fudan University, Shanghai, China; Shenyang Agriculture University, Shenyang, China.

The critical roles of kinase AKT in tumour cell proliferation, apoptosis and protein synthesis have been widely recognized. But AKT also plays an important role in immune modulation. Recent studies have confirmed that kinase AKT can regulate the development and functions of innate immune cells (neutrophil, macrophage and dendritic cell). Studies have shown that different isoforms of kinase AKT have different effects in regulating immunity-related diseases, mainly through the mammalian target of rapamycin-dependent or -independent pathways. The purpose of this review is to illustrate the immune modulating effects of kinase AKT on innate immune cell development, survival and function.
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http://dx.doi.org/10.1111/imm.12123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784161PMC
October 2013
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