Publications by authors named "Yongmei Wu"

37 Publications

Analysis of biopharmaceutical formulations by Time Domain Nuclear Magnetic Resonance (TD-NMR) spectroscopy: A potential method for detection of counterfeit biologic pharmaceuticals.

J Pharm Sci 2021 Mar 18. Epub 2021 Mar 18.

Drug Product Development, Bristol-Myers Squibb, New Brunswick, New Jersey 08903, United States. Electronic address:

H Time-Domain Nuclear Magnetic Resonance (TD-NMR) is used to characterize solutions of antibodies that simulate biologic pharmaceutical formulations. The results from these measurements are compared with those from solutions in which the concentration or identity of the antibody has been altered. TD-NMR is shown to be very sensitive to differences in the amount of antibody in solution, with the ability to detect variations in as low as 2 mg/mL. It is therefore capable, by comparison with data from known formulations, of determining whether a particular sample is likely to be of an authentic biologic formulation. This method expands on the previous use of HPLC, UV/VIS, Near-IR and High-Resolution NMR to detect adulterated pharmaceutical materials. While the sensitivity of the method is high, it is a fingerprinting methodology, illustrating differences but not elucidating their origin. The extracted relaxation times reflect the combined effect of all solutes (antibody, buffer components, etc.) on the solvent (water).
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http://dx.doi.org/10.1016/j.xphs.2021.03.011DOI Listing
March 2021

Moderating Role of Perceived Social Support in the Relationship Between Emotion Regulation and Quality of Life in Chinese Ocean-Going Fishermen.

Front Psychol 2020 26;11:954. Epub 2020 May 26.

Department of Public Health, Hainan Medical University, Haikou, China.

Perceived social support (PSS) has been shown to be positively related to self-reported quality of life (QoL) as well as to emotion regulation strategy. In the present study, we compared a QoL index between Chinese fishermen ( = 507) and local villagers ( = 192) and examined whether PSS moderates the relationship between emotion regulation and QoL in our sample of Chinese ocean-going fishermen. Fishermen's QoL was found to be poorer than that of local villagers. Structural equation modeling (SEM) confirmed that cognitive reappraisal of emotion regulation had a positive predictive effect on QoL, while expression suppression of emotion regulation had a negative predictive effect on QoL. Using, latent moderated structural equations (LMS), we further confirmed that PSS moderates the relationship between emotion regulation and QoL. Simple slope analysis revealed that emotional regulation can predict QoL in a high-PSS context but not in a low-PSS context.
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http://dx.doi.org/10.3389/fpsyg.2020.00954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265168PMC
May 2020

Peptide-conjugated hemin/G-quadruplex as a versatile probe for "signal-on" electrochemical peptide biosensor.

Talanta 2020 Mar 2;209:120611. Epub 2019 Dec 2.

The First Affiliated Hospital, Department of Chemistry, Zhengzhou University, Zhengzhou, 450001, China. Electronic address:

In this work, a novel "signal-on" electrochemical peptide biosensor based on peptide-conjugated hemin/G-quadruplex (DNAzyme-peptide) hybrid and rosebud-like MoSe@reduced graphene oxide (MoSe@rGO) nanocomposite, was developed for detection of prostate-specific antigen (PSA). Interestingly, the peptide not only served as recognition probe to detect PSA, but also acted as the enhancer to improve the enzyme activity of hemin/G4, which promoted the detection sensitivity. Up addition of PSA, FeO-labeled DNAzyme-peptide probe was cleaved, followed by the magnetic separation. The cleaved DNAzyme-peptide was then captured onto the cysteine-modified electrode via the interaction between carboxyl groups of peptide and amino group of cysteine. A strong electrochemical signal was obtained from hemin and further was amplified by the enhanced electrocatalysis of DNAzyme-peptide. Compared to the original DNAzyme, DNAzyme-peptide exhibited more than 3-fold enhancement in signal amplification. And MoSe@rGO amplified the electrochemical signal due to its good conductivity and large surface area. So the proposed strategy detected PSA down to 0.3 fg/mL, and it showed the advantages of simplicity, low cost by avoiding the use of expensive protein enzyme and additional electroactive species. Therefore, the proposed biosensor potentially provided a very effective tool for early diagnosis of cancer by the detection of PSA.
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http://dx.doi.org/10.1016/j.talanta.2019.120611DOI Listing
March 2020

Aplnra/b Sequentially Regulate Organ Left-Right Patterning via Distinct Mechanisms.

Int J Biol Sci 2019 11;15(6):1225-1239. Epub 2019 May 11.

Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, Chengdu Medical College, Chengdu 610500, China.

The G protein-coupled receptor APJ/Aplnr has been widely reported to be involved in heart and vascular development and disease, but whether it contributes to organ left-right patterning is largely unknown. Here, we show that in zebrafish, coordinates organ LR patterning in an ligand-dependent manner using distinct mechanisms at different stages. During gastrulation and early somitogenesis, loss of function results in heart and liver LR asymmetry defects, accompanied by disturbed KV/cilia morphogenesis and disrupted left-sided expression in the LPM. In this process, only loss of function results in KV/cilia morphogenesis defect. In addition, only works as the early endogenous ligand to regulate KV morphogenesis, which then contributes to left-sided expression and subsequent organ LR patterning. The cascade regulates KV morphogenesis by enhancing the expression of , but not or , during KV development. At the late somite stage, both and contribute to the expression of in the trunk midline but do not regulate KV formation, and this role is possibly mediated by both endogenous ligands, and . In conclusion, our study is the first to identify a role for and their endogenous ligands in LR patterning, and it clarifies the distinct roles of and in orchestrating organ LR patterning.
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http://dx.doi.org/10.7150/ijbs.30100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567806PMC
April 2020

Representative Scale-Down Lyophilization Cycle Development Using a Seven-Vial Freeze-Dryer (MicroFD).

J Pharm Sci 2019 04 20;108(4):1486-1495. Epub 2018 Nov 20.

Bristol-Myers Squibb Company, Drug Product Science and Technologies, New Brunswick, New Jersey 08901.

We have implemented the use of a small-scale, 7-vial Micro Freeze Dryer (MicroFD; Millrock Technology, Inc.) that has the capability to accurately control heat transfer during lyophilization. We demonstrate the ability to fine-tune the MicroFD vial heat transfer coefficient (K) to match the K of vials in a LyoStar III laboratory-scale unit. When the MicroFD is run under conditions that match the K of the LyoStar III, the resulting lyophilization performance between scales results in equivalent product temperature profiles and critical quality attributes for the same drying process. The proposed workflow demonstrates how exploitation of K control in the MicroFD enables cycle development of at-scale lyophilization processes using only 7 product vials. By changing the MicroFDK, laboratory and, potentially, manufacturing cycles may be simulated using only 7 product vials for tremendous active pharmaceutical ingredient savings, as long as at-scale heat transfer coefficients are well characterized.
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http://dx.doi.org/10.1016/j.xphs.2018.11.018DOI Listing
April 2019

Combined use of bFGF/EGF and all-trans-retinoic acid cooperatively promotes neuronal differentiation and neurite outgrowth in neural stem cells.

Neurosci Lett 2019 01 6;690:61-68. Epub 2018 Oct 6.

Development and Regeneration Key Lab of Sichuan Province, Department of Anatomy and Histology and Embryology, Chengdu Medical College, Chengdu 610500, Sichuan, China; Chengdu Medical College Infertility Hospital, Chengdu 610000, Sichuan, China. Electronic address:

Neural stem cells (NSCs) as sources of new neurons in brain injuries or diseases are required to not only elicit neurons for neuronal repair, but also to enhance neurite outgrowth for neuronal network reestablishment. Various trophic or chemotropic factors have been shown to cooperatively improve NSC neurogenesis. However, effects of combined treatment of all-trans-retinoic acid (RA) with GF (Basic fibroblast growth factor and epidermal growth factor, bFGF/EGF) on neurogenesis of NSCs are poorly understood. To address this question, NSCs were isolated from the forebrains of embryonic mice, and treated with GF and RA either alone or in combination for differentiation in vitro. Neurons and astrocytes differentiated from NSCs were stained for MAP2 and GFAP separately by immunofluorescence. The results indicated that GF displayed superior efficacy in promoting neuronal differentiation, and RA showed better efficacy in advancing neurite outgrowth by increasing both neurite length and number. In addition, higher differentiation efficiency of neurons to astrocytes in RA or GF, or both acted at the early stage. However, more importantly, compared with RA alone, GF and RA in combination enhanced neuronal differentiation. Moreover, the combined use of GF and RA increased the length and number of neurites compared with GF, as well as the relative expression level of Smurf1. In addition, astrocytes induced by GF, RA, or both exhibited a radial glia-like morphology with long processes differing from serum effects, which might in part attribute to the total numbers of neurons. These findings for the first time unveil the roles of combined use of GF and RA on the neurogenesis of NSCs, suggesting that the use of this combination could be a comprehensive strategy for the functional repair of the nervous system through promoting neuronal differentiation, and advancing neurite outgrowth.
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http://dx.doi.org/10.1016/j.neulet.2018.10.002DOI Listing
January 2019

Co-administration of biocompatible self-assembled polylactic acid-hyaluronic acid block copolymer nanoparticles with tumor-penetrating peptide-iRGD for metastatic breast cancer therapy.

J Mater Chem B 2018 May 2;6(19):3163-3180. Epub 2018 May 2.

School of Pharmacy, Chengdu Medical College, No. 783 Xindu Avenue, Chengdu 610500, China.

The safe and efficient targeted delivery of chemotherapeutic drugs has remained a challenge in metastatic breast cancer therapy. Herein, we report a rational drug delivery strategy of co-administering tumor-penetrating peptide-iRGD with self-assembled amphiphilic block copolymer nanoparticles (HA-PLA) to inhibit tumor growth and lung metastasis in 4T1 breast cancer xenograft bearing mice through increasing drug accumulation in the tumors, inducing receptor-mediated tumor cell targeting without causing severe side effects. In vitro, HA-PLA displayed sustained and pH-sensitive release behavior. The cellular uptake of HA-PLA on high CD44-expressing 4T1 cells was significantly higher than the endocytosis on low CD44-expressing L929 fibroblast cells. In vivo, HA-PLA significantly extended the blood circulation time of DOX, displayed no "accelerated blood clearance (ABC) phenomenon" after repeated injection and decreased the side effects of DOX. When combined with iRGD, the drug distribution and penetration of HA-PLA in tumors were remarkably increased, resulting in better antitumor efficacy and the longest whole survival. In particular, the co-administration of iRGD with HA-PLA greatly increased drug distribution in the lung, which contributed to the effective inhibition of the lung metastasis of breast cancer. Therefore, co-administering iRGD with HA-PLA is a promising approach for metastatic breast cancer therapy.
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http://dx.doi.org/10.1039/c8tb00319jDOI Listing
May 2018

Ratiometric fluorescence sensing of mercuric ion based on dye-doped lanthanide coordination polymer particles.

Anal Chim Acta 2018 Jul 6;1014:85-90. Epub 2018 Feb 6.

College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450001, PR China. Electronic address:

This work focused on the development of a novel ratiometric fluorescence sensor for detection of Hg by using dye-doped lanthanide infinite coordination polymer (Ln-ICP) particles. The dye-doped Ln-ICP used herein was prepared by self-assemble of adenosine monophosphate (AMP) with Ce and Tb (Ce/Tb-AMP) through self-adaptive chemistry, in which the fluorescent dye coumarin was encapsulated during the assembly process as a guest molecule. Under 310 nm irradiation, the obtained coumarin@Ce/Tb-AMP itself emitted characteristic green luminescence of Tb, accompanied with a weak fluorescence at 445 nm originated from coumarin encapsulated in the Ce/Tb-AMP networks. The fluorescence emission of coumarin became strong when it was released to the solution. In the presence of Hg, the coumarin@Ce/Tb-AMP was destroyed due to the specific coordination interaction between AMP and Hg, which leaded to the release of coumarin to the solution meanwhile. Consequently, the fluorescence of Ce/Tb-AMP was quenched, while that of coumarin enhanced. On the basis of this strategy, we developed a novel ratiometric fluorescent sensor for the detection of Hg by measuring the ratio of fluorescent intensity of the coumarin@Ce/Tb-AMP suspension, which showed a wide linear range from 0.08 to 1000 nM and detection limit of 0.03 nM with high selectivity and sensitivity. Furthermore, the constructed ratiometric fluorescent sensor was successfully applied in detecting Hg in drinking water and human blood serum (HBS) with satisfactory results.
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http://dx.doi.org/10.1016/j.aca.2018.01.065DOI Listing
July 2018

Notoginsenoside R1 ameliorates diabetic encephalopathy by activating the Nrf2 pathway and inhibiting NLRP3 inflammasome activation.

Oncotarget 2018 Feb 16;9(10):9344-9363. Epub 2018 Jan 16.

Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Numerous researches supported that oxidative stress and inflammation play important roles in the development of diabetic encephalopathy (DEP). Notoginsenoside R1 (NGR1), one major component of , is believed to have anti-oxidative, anti-inflammatory and neuroprotective properties. However, its neuroprotective effects against DEP and underlying mechanisms are still unknown. In this study, db/db mice as well as high-glucose (HG)-treated HT22 hippocampal neurons were used as and models to estimate NGR1 neuroprotection. NGR1 administration for 10 weeks could ameliorate cognitive dysfunction, depression-like behaviors, insulin resistance, hyperinsulinemia, dyslipidemia, and inflammation in db/db mice. NGR1 markedly decreased the oxidative stress induced by hyperglycemia in hippocampal neurons. NGR1 significantly activated the protein kinase B (Akt)/nuclear factor-erythroid 2-related factor2 (Nrf2) pathway, and inhibited NLRP3 inflammasome activation in hippocampal neurons, which might be essential for the neuroprotective effects of NGR1. Further supporting these results, we observed that pretreatment with the phosphatidylinositol 3-kinase inhibitor LY294002 abolished NGR1-mediated neuroprotective effects against oxidative stress and NLRP3 inflammasome activation in HG-treated HT22 hippocampal neurons. In conclusion, the present study demonstrates the neuroprotective effects of NGR1 on DEP by activating the Akt/Nrf2 pathway and inhibiting NLRP3 inflammasome activation. This study also provides a novel strategy for the application of NGR1 as a therapeutic agent for patients with DEP.
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http://dx.doi.org/10.18632/oncotarget.24295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823646PMC
February 2018

An Unexpected Degradation Pathway of a 1,2,4-Triazolo[4,3-a]pyridine Derivative: The Formation of 2 Cationic Pseudodimers of an 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Drug Candidate in a Stressed Capsule Formulation.

J Pharm Sci 2018 06 17;107(6):1633-1641. Epub 2018 Feb 17.

Drug Product Science & Technology, Global Product Development & Supply, Bristol-Myers Squibb Company, New Brunswick, New Jersey.

Degradation of an active pharmaceutical ingredient (API), a 2-(3-(1-(4-chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-ol hydrochloride salt, was observed in a capsule formulation stressed at 50°C or 40°C/75% relative humidity conditions for 1 month. Two unknown degradants were identified as cationic pseudodimers of the API via accurate mass liquid chromatography-mass spectrometry and 1- and 2-dimensional NMR analyses. A plausible degradation pathway of the API was postulated which led to the identification of 2 key N-oxide degradants in the stressed capsule formulation at trace levels. It was hypothesized that the N-oxide degradants could be protonated and undergo further transformation so as to react with another API free base to form pseudodimeric N-oxide intermediates, followed by protonation/dehydration to yield the cationic pseudodimers of the API. The proposed degradation pathway was further supported by formulation screening studies: (1) the removal of magnesium stearate (base/lubricant) from the formulation to reduce the formation of API free base, which is susceptible to oxidation to form N-oxides; (2) the replacement of API hydrochloride salt by its free base form to eliminate the proton source for protonation of the N-oxides so as to prevent their further transformation; and (3) the addition of anti-oxidants to minimize the oxidation of API free base to N-oxides.
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http://dx.doi.org/10.1016/j.xphs.2018.02.009DOI Listing
June 2018

Novel electrochemical biosensor based on cationic peptide modified hemin/G-quadruples enhanced peroxidase-like activity.

Biosens Bioelectron 2018 Jun 9;107:178-183. Epub 2018 Feb 9.

College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address:

This work designed an artificial substrate peptide to synthesize peptide-hemin/G-quadruplex (peptide-DNAzyme) conjugates. In addition to enhancing catalytic activity of hemin/G-quadruplex, the peptide could also be induced and cleaved by prostate specific antigen (PSA). It was the first report on peptide-DNAzyme conjugates in application of the peptide biosensor. The polyethyleneimine-reduced graphene oxide@hollow platinum nanotubes (PEI-rGO@PtNTs) nanocomposites were cast on the glassy carbon electrode in order to form the interface of biocompatibility and huge surface area for bioprobes immobilization. In absence of PSA, the peptide-DNAzyme conjugates retained intact on the surface of the electrode to produce a strong response signal. But in presence of PSA, the peptide-DNAzyme conjugates were destroyed to release electron mediators, resulting in dramatical decrease of the electrochemicl signal. Therefore, the method had high sensitivity and super selectivity with the limit of detection calculated as 2.0 fg/mL. Furthermore, the strategy would be promising to apply for other proteases by transforming the synthetic peptide module of target.
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http://dx.doi.org/10.1016/j.bios.2018.02.014DOI Listing
June 2018

Highly sensitive electrochemical thrombin aptasensor based on peptide-enhanced electrocatalysis of hemin/G-quadruplex and nanocomposite as nanocarrier.

Biosens Bioelectron 2017 Nov 11;97:317-324. Epub 2017 Jun 11.

College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address:

In this work, we first conjugated a short peptide to thrombin binding aptamer (TBA) and bond hemin to the hybrid, effectively rendering hemin/G4-peptide more active over the original hemin/G4, so that a highly sensitive electrochemical thrombin (TB) aptasensor was developed based on it and PtNTs@rGO nanocomposite. It was the first report on the application of hemin/G4-peptide in electrochemical aptasensor. PtNTs@rGO with large surface area served as excellent nanocarrier for high loading of hemin/G4-peptide hybrids, resulting in the formation of hemin/G4-peptide-PtNTs@rGO bioconjugate as the secondary aptamer and further signal enhancement. The specific affinity of aptamer for target TB made the secondary aptamer go into the sensing interface, and then a noticeable current signal was obtained from hemin without additional redox mediators. Due to the collaborative electrocatalysis of hemin/G4-peptide and PtNTs toward HO, which was formed in situ during the process of hemin/G4-peptide-catalyzed oxidation of NADH with dissolved O, the current intensity increased dramatically. Such an electrochemical aptasensing system could be used to detect TB with a linear range of 0.05 pM-60nM and very lower detection limit of 15fM. Notably, this method exhibited a higher sensitivity than that of many hemin/G4-based electrochemical strategies for TB detection due to the improvement of the catalytic activity of hemin/G4-peptide. The present works opened a new way for expanding the application of hemin/G4 in biological detection. With the mediator-free, proteinous enzyme-free yet high-sensitivity advantages, this electrochemical aptasensor held great promise for other biomarker detections in clinical diagnostics.
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http://dx.doi.org/10.1016/j.bios.2017.06.023DOI Listing
November 2017

The Impact of Disintegrant Type, Surfactant, and API Properties on the Processability and Performance of Roller Compacted Formulations of Acetaminophen and Aspirin.

AAPS J 2017 09 12;19(5):1387-1395. Epub 2017 Jun 12.

Drug Product Science and Technology, Bristol-Myers Squibb, 1 Squibb Dr, New Brunswick, New Jersey, 08903, USA.

In formulation development, certain excipients, even though used in small quantities, can have a significant impact on the processability and performance of the dosage form. In this study, three common disintegrants, croscarmellose sodium (CCS), crospovidone (xPVP), and sodium starch glycolate (SSG) as well as the surfactant sodium lauryl sulfate (SLS) were evaluated for their impact on the processability and performance of a typical dry granulation formulation. Two model compounds, the mechanically brittle and chemically inert acetaminophen and the mechanically ductile carboxylic acid aspirin, were used for the evaluation. It was found that the disintegrants were generally identical in their impact on the processability and little difference was observed in the granulation and compression processes. The exception is that when xPVP was used in the formulation of the brittle acetaminophen, lower compression forces were needed to reach the same tablet hardness, suggesting a binding effect of xPVP for such systems. In general, CCS and xPVP tend to provide slightly better disintegration than SSG. However, in the case of aspirin, a strong hydrogen bonding interaction between the carboxylic acid group of aspirin and the carbonyl group of xPVP was observed, resulting in slower release of the drug after fast disintegration. SLS was found to have a significant impact on the processability due to its lubricating effect, resulting in higher compression forces needed to achieve the target tablet hardness. Due to the higher degree of compression, the disintegration and dissolution of both drugs became slower despite the wetting effect of SLS.
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http://dx.doi.org/10.1208/s12248-017-0104-6DOI Listing
September 2017

TIR-Domain-Containing Adapter-Inducing Interferon-β (TRIF) Is Essential for MPTP-Induced Dopaminergic Neuroprotection via Microglial Cell M1/M2 Modulation.

Front Cell Neurosci 2017 22;11:35. Epub 2017 Feb 22.

Development and Regeneration Key Lab of Sichuan Province, Department of Pathology, Department of Anatomy and Histology and Embryology, Chengdu Medical CollegeChengdu, China; Research Center, Chengdu Medical College Infertility HospitalChengdu, China.

Dynamic changes of two phenotypes of microglia, M1 and M2, are critically associated with the neurodegeneration of Parkinson's disease. However, the regulation of the M1/M2 paradigm is still unclear. In the MPTP induced neurodegeneration model, we examined the concentration of dopamine (DA) related metabolites and the survival of tyrosine hydroxylase (TH) positive cells in WT and mice. In experiments, MN9D cells were co-cultured with BV2 cells to mimic the animal experiments. Inhibition of TRIF aggravated TH+ cell loss, and DA-related metabolites decreased. TRIF inhibition was able to interrupt the microglial M1/M2 dynamic transformation. More BV2 cells were activated and migrated across the membrane of transwell plates by siTRIF treatment. Also, TRIF interruption inhibits the transformation of BV2 cells from the M1 to M2 phenotype which played a beneficial role in neuronal degenerative processes, and increased MN9D apoptosis. Moreover, MPP+ treatment decreases the (DAT) dopamine transporter and TH synthesis by MN9D. Taken together, the current results suggest that TRIF plays a key switch function in contributing to the microglial M1/M2 phenotype dynamic transformation. The interruption of TRIF may decrease the survival of MN9D cells as well as DAT and TH protein production. The current study sheds some light on the PD mechanism research by innate inflammation regulation.
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http://dx.doi.org/10.3389/fncel.2017.00035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319955PMC
February 2017

Palladium Nanoparticles Supported on Titanium-Doped Graphitic Carbon Nitride for Formic Acid Dehydrogenation.

Chem Asian J 2017 Apr 29;12(8):860-867. Epub 2017 Mar 29.

Graduate School of Engineering, Osaka University, Osaka, 565-0871, Japan.

Pd nanoparticles (NPs) supported on Ti-doped graphitic carbon nitride (g-C N ) were synthesized by a deposition-precipitation route and a subsequent reduction with NaBH . The features of the NPs were studied by XRD, TEM, FTIR, XPS, EXAFS and N -physisorption measurements. It was found that the NPs had an average size of 2.9 nm and presented a high dispersion on the surface of Ti-doped g-C N . Compared to Pd loaded on pristine g-C N , the Pd NPs supported on Ti-doped g-C N exhibited a high catalytic activity in formic acid dehydrogenation in water at room temperature. The enhanced activity could be attributed to the small Pd NPs size, as well as the strong interaction between Pd NPs and Ti-doped g-C N .
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http://dx.doi.org/10.1002/asia.201700041DOI Listing
April 2017

Spatial and Temporal Distribution of Dopaminergic Neurons during Development in Zebrafish.

Front Neuroanat 2016 28;10:115. Epub 2016 Nov 28.

Development and Regeneration Key Lab of Sichuan Province, Department of Anatomy and Histology and Embryology, Department of Pathology, Chengdu Medical CollegeChengdu, China; Chengdu Medical College Infertility HospitalChengdu, China.

As one of the model organisms of Parkinson's disease (PD) research, the zebrafish has its advantages, such as the 87% homology with human genome and transparent embryos which make it possible to observe the development of dopaminergic neurons in real time. However, there is no midbrain dopaminergic system in zebrafish when compared with mammals, and the location and projection of the dopaminergic neurons are seldom reported. In this study, Vmat2:GFP transgenic zebrafish was used to observe the development and distribution of dopaminergic neurons in real time. We found that diencephalons (DC) 2 and DC4 neuronal populations were detected at 24 h post fertilization (hpf). All DC neuronal populations as well as those in locus coeruleus (LC), raphe nuclei (Ra) and telencephalon were detected at 48 hpf. Axons were detected at 72 hpf. At 96 hpf, all the neuronal populations were detected. For the first time we reported axons from the posterior tubercle (PT) of ventral DC projected to subpallium . However, when compared with results from whole mount tyrosine hydroxylase (TH) immunofluorescence staining in wild type (WT) zebrafish, we found that DC2 and DC4 neuronal populations were mainly dopaminergic, while DC1, DC3, DC5 and DC6 might not. Neurons in pretectum (Pr) and telencephalon were mainly dopaminergic, while neurons in LC and Ra might be noradrenergic. Our study makes some corrections and modifications on the development, localization and distribution of zebrafish dopaminergic neurons, and provides some experimental evidences for the construction of the zebrafish PD model.
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http://dx.doi.org/10.3389/fnana.2016.00115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124710PMC
November 2016

Enzyme spheres as novel tracing tags coupled with target-induced DNAzyme assembly for ultrasensitive electrochemical microRNA assay.

Anal Chim Acta 2016 12 14;948:1-8. Epub 2016 Oct 14.

College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450001, PR China. Electronic address:

In this work, an ultrasensitive electrochemical microRNA detection strategy was developed based on porous palladium-modified horseradish peroxidase sphere (Pd@HRP) and target-induced assembly of DNAzyme. A highly loaded HRP sphere was prepared by covalent layer-by-layer assembly with CaCO as sacrificial template for the first time, and was further modified with porous Pd. Notably, Pd@HRP composite showed a good redox activity of HRP and electrocatalytic activity toward HO. The utilization of Pd@HRP as electrochemical signal indicator and enhancer to fabricate biosensor could avoid the need for additional redox mediator and amplify the detection sensitivity. Moreover, target recycling amplification was achieved by Pb-induced cleavage of ternary "Y" structure, circumventing the use of labile nuclease. Subsequent DNA concatamer synthesized through rolling circle amplification (RCA) reaction with cleaved hairpin probe as primer, hybridized with plentiful Pd@HRP-DNA probes, which led to the increased loading of redox-active and electrocatalytic Pd@HRP for sensitivity improvement. So the proposed electrochemical biosensor detected miRNA-24 down to 0.2 fM (S/N = 3) with a wide linear range from 3 fM to 1 nM. With bifunctional Pd@HRP tag, DNAzyme-aided target recycle and programmable junction probe, this strategy possessed the advantages of high efficiency, high sensitivity, low cost and versatility, and thus held great promise for other low-abundance nucleic acids determination.
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http://dx.doi.org/10.1016/j.aca.2016.10.005DOI Listing
December 2016

RNA-sequencing Reveals Global Transcriptomic Changes in Nicotiana tabacum Responding to Topping and Treatment of Axillary-shoot Control Chemicals.

Sci Rep 2015 Dec 16;5:18148. Epub 2015 Dec 16.

Kentucky Tobacco Research and Development Center , University of Kentucky, Lexington, KY 40546, U.S.A.

Removal of terminal buds (topping) and control of the formation of axillary shoots (suckers) are common agronomic practices that significantly impact the yield and quality of various crop plants. Application of chemicals (suckercides) to plants following topping is an effective method for sucker control. However, our current knowledge of the influence of topping, and subsequent suckercide applications, to gene expression is limited. We analyzed the differential gene expression using RNA-sequencing in tobacco (Nicotiana tabacum) that are topped, or treated after topping by two different suckercides, the contact-localized-systemic, Flupro(®) (FP), and contact, Off-Shoot-T(®). Among the differentially expressed genes (DEGs), 179 were identified as common to all three conditions. DEGs, largely related to wounding, phytohormone metabolism and secondary metabolite biosynthesis, exhibited significant upregulation following topping, and downregulation after suckercide treatments. DEGs related to photosynthetic processes were repressed following topping and suckercide treatments. Moreover, topping and FP-treatment affect the expression of auxin and cytokinin signaling pathway genes that are possibly involved in axillary shoot formation. Our results provide insights into the global change of plant gene expression in response to topping and suckercide treatments. The regulatory elements of topping-inducible genes are potentially useful for the development of a chemical-free sucker control system.
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http://dx.doi.org/10.1038/srep18148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680964PMC
December 2015

An amplified electrochemical aptasensor for thrombin detection based on pseudobienzymic Fe3O4-Au nanocomposites and electroactive hemin/G-quadruplex as signal enhancers.

Analyst 2014 Apr;139(7):1756-61

Education Ministry Key Laboratory on Luminescence and Real-TimeAnalysis, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People's Republic of China.

A sensitive and selective electrochemical aptasensor for thrombin detection was constructed based on hemin/G-quadruplex as the signal label and Fe3O4-Au nanocomposites with glucose oxidase (GOx-) and peroxide-mimicking enzyme activity as the signal enhancers. Due to their large surface area and good biocompatibility, Fe3O4-Au nanocomposites were employed to immobilize electroactive hemin/G-quadruplex, which was formed by the conjugation between a single-stranded guanine-rich nucleic acid and hemin. Based on the GOx-mimicking enzyme activity, Au nanoparticles on the surface of the Fe3O4-Au nanocomposites effectively catalyzed the oxidization of glucose in the presence of dissolved O2, accompanied by the production of H2O2. Both the Fe3O4 cores of Fe3O4-Au nanocomposites and hemin/G-quadruplex with H2O2-mimicking enzyme activity could catalyze the reduction of the generated H2O2, which promoted the electron transfer of hemin and amplified the electrochemical signal. The proposed electrochemical aptasensor had a wide dynamic linear range of 0.1 pM to 20 nM with a lower detection limit of 0.013 pM, which provided a promising method for a sensitive assay for the detection of proteins in electrochemical aptasensors.
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http://dx.doi.org/10.1039/c3an02237dDOI Listing
April 2014

Porous platinum nanotubes modified with dendrimers as nanocarriers and electrocatalysts for sensitive electrochemical aptasensors based on enzymatic signal amplification.

Chem Commun (Camb) 2014 Feb;50(12):1451-3

Chongqing Key Laboratory of Analytical Chemistry, Education Ministry Key Laboratory on Luminescence and Real-Time Analysis, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China.

A highly sensitive electrochemical aptasensor for thrombin detection is developed and demonstrated by using porous platinum nanotubes modified with polyamidoamine dendrimers as nanocarriers and electrocatalysts. The proposed strategy affords a low detection limit of 0.03 pM based on enzyme-based signal amplification.
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http://dx.doi.org/10.1039/c3cc46725bDOI Listing
February 2014

A pseudo triple-enzyme cascade amplified aptasensor for thrombin detection based on hemin/G-quadruplex as signal label.

Biosens Bioelectron 2014 Apr 18;54:415-20. Epub 2013 Nov 18.

Key Laboratory on Luminescence and Real-Time Analysis, School of Chemistry and Chemical Engineering, Southwest University, The Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Chongqing 400715, PR China.

In this work, a pseudo triple-enzyme cascade amplified electrochemical aptasensor based on hemin/G-quadruplex as signal label for thrombin (TB) was constructed and the amplified electrochemical signal was achieved by the corporate catalysis of alcohol dehydrogenase-graphene sheets (ADH-GSs) bionanocomposite and hemin/G-quadruplex, which simultaneously acted as NADH oxidase and HRP-mimicking DNAzyme. Through "sandwich" reaction, hemin/G-quadruplex labeled gold nanoparticles-ADH-GSs bionanocomposite (AuNPs-ADH-GSs) was captured on electrode surface and thus obtained the electrochemical signal. After the addition of ethanol into the electrolytic cell, ADH availably catalyzed the oxidation of ethanol with the reduction of NAD(+) to NADH. Then, hemin/G-quadruplex as NADH oxidase catalyzed the oxidization of NADH, accompanying with the production of H2O2. Simultaneously, hemin/G-quadruplex as HRP-mimicking DNAzyme catalyzed the reduction of the generated H2O2. Such a catalysis strategy greatly promoted the electron transfer of hemin and resulted in the specific enhancement of electrochemical signal. The proposed TB aptasensor achieved a linear range of 1 pM-50 nM with a detection limit of 0.3 pM (defined as S/N=3). In addition, it showed satisfying stability and reproducibility, good specificity and sensitivity, indicating promising application for the detection of various proteins in clinical analysis.
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http://dx.doi.org/10.1016/j.bios.2013.11.036DOI Listing
April 2014

Transcriptional regulation of secondary metabolite biosynthesis in plants.

Biochim Biophys Acta 2013 Nov 7;1829(11):1236-47. Epub 2013 Oct 7.

Department of Plant and Soil Sciences, Kentucky Tobacco Research and Development Center, University of Kentucky, Lexington, KY 40546, USA.

Plants produce thousands of secondary metabolites (a.k.a. specialized metabolites) of diverse chemical nature. These compounds play important roles in protecting plants under adverse conditions. Many secondary metabolites are valued for their pharmaceutical properties. Because of their beneficial effects to health, biosynthesis of secondary metabolites has been a prime focus of research. Many transcription factors have been characterized for their roles in regulating biosynthetic pathways at the transcriptional level. The emerging picture of transcriptional regulation of secondary metabolite biosynthesis suggests that the expression of activators and repressors, in response to phytohormones and different environmental signals, forms a dynamic regulatory network that fine-tune the timing, amplitude and tissue specific expression of pathway genes and the subsequent accumulation of these compounds. Recent research has revealed that some metabolic pathways are also controlled by posttranscriptional and posttranslational mechanisms. This review will use recent developments in the biosynthesis of flavonoids, alkaloids and terpenoids to highlight the complexity of transcriptional regulation of secondary metabolite biosynthesis.
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http://dx.doi.org/10.1016/j.bbagrm.2013.09.006DOI Listing
November 2013

[Expression of yeast acyl-delta9 desaturase for fatty acid biosynthesis in tobacco].

Sheng Wu Gong Cheng Xue Bao 2013 May;29(5):630-45

Institute of Molecular Agriculture and Bioenergy, Shanxi Agricultural University, Taigu 030801, Shanxi, China.

Palmitoleic acid (16:1delta9), an unusual monounsaturated fatty acid, is highly valued for human nutrition, medication and industry. Plant oils containing large amounts of palmitoleic acid are the ideal resource for biodiesel production. To increase accumulation of palmitoleic acid in plant tissues, we used a yeast (Saccharomyees cerevisiae) acyl-CoA-delta9 desaturase (Scdelta9D) for cytosol- and plastid-targeting expression in tobacco (Nicotiana tabacum L.). By doing this, we also studied the effects of the subcellular-targeted expression of this enzyme on lipid synthesis and metabolism in plant system. Compared to the wild type and vector control plants, the contents of monounsaturated palmitoleic (16:1delta9) and cis-vaccenic (18:1delta11) were significantly enhanced in the Scdelta9D-transgenic leaves whereas the levels of saturated palmitic acid (16:0) and polyunsaturated linoleic (18:2) and linolenic (18:3) acids were reduced in the transgenics. Notably, the contents of 16:1delta9 and 18:1delta11 in the Scdelta9D plastidal-expressed leaves were 2.7 and 1.9 folds of that in the cytosolic-expressed tissues. Statistical analysis appeared a negative correlation coefficient between 16:0 and 16:1delta9 levels. Our data indicate that yeast cytosolic acyl-CoA-delta9 desaturase can convert palmitic (16:0) into palmitoleic acid (16:1delta9) in high plant cells. Moreover, this effect of the enzyme is stronger with the plastid-targeted expression than the cytosol-target expression. The present study developed a new strategy for high accumulation of omega-7 fatty acids (16:1delta9 andl8:1delta11) in plant tissues by protein engineering of acyl-CoA-delta9 desaturase. The findings would particularly benefit the metabolic assembly of the lipid biosynthesis pathway in the large-biomass vegetative organs such as tobacco leaves for the production of high-quality biodiesel.
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May 2013

Ultrasensitive thrombin detection based on direct electrochemistry of highly loaded hemoglobin spheres-encapsulated platinum nanoparticles as labels and electrocatalysts.

Biosens Bioelectron 2013 Dec 19;50:50-6. Epub 2013 Jun 19.

Education Ministry Key Laboratory on Luminescence and Real-Time Analysis, College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People's Republic of China.

For the first time, a sandwich-type electrochemical method was proposed for ultrasensitive thrombin (TB) detection based on direct electrochemistry of highly loaded hemoglobin spheres-encapsulated platinum nanoparticles (PtNPs@Hb) as labels and electrocatalysts. The prepared PtNPs@Hb not only exhibited good biocompatibility, excellent electrocatalytic activity, but also presented redox activity of Hb. Thus, it was employed for the fabrication of aptasensor without any extraneous redox mediators, leading to a simple preparation process for the aptasensor. The high loading of Hb spheres as redox mediators could enhance the electrochemical signal. Importantly, the synergetic electrocatalytic behavior of Hb and PtNPs toward H2O2 reduction greatly amplified the electrochemical signal, resulting in the high sensitivity of aptasensor. Consequently, under optimal conditions, the designed aptasensor exhibited a lower detection limit of 0.05 pM and wide dynamic linear range from 0.15 pM to 40 nM for TB detection. Additionally, the proposed mediator-free and signal-amplified electrochemical aptasensor showed great potential in portable and cost-effective TB sensing devices.
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http://dx.doi.org/10.1016/j.bios.2013.06.021DOI Listing
December 2013

A sensitive electrochemical aptasensor for thrombin detection based on exonuclease-catalyzed target recycling and enzyme-catalysis.

Biosens Bioelectron 2013 Sep 2;47:368-72. Epub 2013 Apr 2.

Key Laboratory on Luminescence and Real-Time Analysis, School of Chemistry and Chemical Engineering, Southwest University, The Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Chongqing 400715, PR China.

In the present study, a sensitive electrochemical aptasensor based on exonuclease-catalyzed target recycling and enzyme-catalysis was developed for thrombin (TB) detection. Firstly, the alcohol dehydrogenase (ADH) was abundantly embedded in the 3-(mercaptopropyl)trimethoxysilane (MPTS) sol with a 3-D network that exhibited tunable porosity and high thermal stability. ADH, as an alcohol oxidase, catalyzed the conversation of alcohol into acetaldehyde coupling with the production of NADH in the presence of NAD(+). Then the immobilized gold nanoparticles (AuNPs) could electrocatalyze the oxidation of NADH, finally promoting the redox reaction of the electroactive material methylene blue (MB) labeled on the hybrid double strand DNA (dsDNA). Furthermore, when the mixture of TB and RecJf exonuclease was introduced, TB combined with the thrombin aptamer II (TBA II) and the aptamer-TB complex was formed. And then, the RecJf exonuclease selectively degraded the TBA II from 5'→3', releasing the target TB into the solution. The free TB was reused to combine with other TBA II to accomplish the target recycling and realize the electrochemical signal amplification. In this way, excellent sensitivity of the aptasensor was obtained. The thrombin aptasensor achieved a detection limit of 1.7pM (defined as S/N=3) with a linear range from 5pM to 100nM. In addition, the proposed aptasensor had good stability and sensitivity, and would become a promising choice for the protein diagnostics in clinical analysis.
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http://dx.doi.org/10.1016/j.bios.2013.03.045DOI Listing
September 2013

Soybean oil biosynthesis: role of diacylglycerol acyltransferases.

Funct Integr Genomics 2013 Mar 16;13(1):99-113. Epub 2013 Jan 16.

Shanxi Agricultural University, Taigu 030801, China.

Diacylglycerol acyltransferase (DGAT) catalyzes the acyl-CoA-dependent acylation of sn-1,2-diacylglycerol to form seed oil triacylglycerol (TAG). To understand the features of genes encoding soybean (Glycine max) DGATs and possible roles in soybean seed oil synthesis and accumulation, two full-length cDNAs encoding type 1 diacylglycerol acyltransferases (GmDGAT1A and GmDGAT1B) were cloned from developing soybean seeds. These coding sequences share identities of 94 % and 95 % in protein and DNA sequences. The genomic architectures of GmDGAT1A and GmDGAT1B both contain 15 introns and 16 exons. Differences in the lengths of the first exon and most of the introns were found between GmDGAT1A and GmDGAT1B genomic sequences. Furthermore, detailed in silico analysis revealed a third predicted DGAT1, GmDGAT1C. GmDGAT1A and GmDGAT1B were found to have similar activity levels and substrate specificities. Oleoyl-CoA and sn-1,2-diacylglycerol were preferred substrates over vernoloyl-CoA and sn-1,2-divernoloylglycerol. Both transcripts are much more abundant in developing seeds than in other tissues including leaves, stem, roots, and flowers. Both soybean DGAT1A and DGAT1B are highly expressed at developing seed stages of maximal TAG accumulation with DGAT1B showing highest expression at somewhat later stages than DGAT1A. DGAT1A and DGAT1B show expression profiles consistent with important roles in soybean seed oil biosynthesis and accumulation.
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http://dx.doi.org/10.1007/s10142-012-0306-zDOI Listing
March 2013

Biosynthesis and metabolic engineering of palmitoleate production, an important contributor to human health and sustainable industry.

Prog Lipid Res 2012 Oct 29;51(4):340-9. Epub 2012 May 29.

Shanxi Agricultural University, Taigu 030801, China.

Palmitoleate (cis-Δ9-16:1) shows numerous health benefits such as increased cell membrane fluidity, reduced inflammation, protection of the cardiovascular system, and inhibition of oncogenesis. Plant oils containing this unusual fatty acid can also be sustainable feedstocks for producing industrially important and high-demand 1-octene. Vegetable oils rich in palmitoleate are the ideal candidates for biodiesel production. Several wild plants are known that can synthesize high levels of palmitoleate in seeds. However, low yields and poor agronomic characteristics of these plants limit their commercialization. Metabolic engineering has been developed to create oilseed crops that accumulate high levels of palmitoleate or other unusual fatty acids, and significant advances have been made recently in this field, particularly using the model plant Arabidopsis as the host. The engineered targets for enhancing palmitoleate synthesis include overexpression of Δ9 desaturase from mammals, yeast, fungi, and plants, down-regulating KASII, coexpression of an ACP-Δ9 desaturase in plastids and CoA-Δ9 desaturase in endoplasmic reticulum (ER), and optimizing the metabolic flux into triacylglycerols (TAGs). This review will mainly describe the recent progress towards producing palmitoleate in transgenic plants by metabolic engineering along with our current understanding of palmitoleate biosynthesis and its regulation, as well as highlighting the bottlenecks that require additional investigation by combining lipidomics, transgenics and other "-omics" tools. A brief review of reported health benefits and non-food uses of palmitoleate will also be covered.
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http://dx.doi.org/10.1016/j.plipres.2012.05.001DOI Listing
October 2012

Formation of reactive impurities in aqueous and neat polyethylene glycol 400 and effects of antioxidants and oxidation inducers.

J Pharm Sci 2012 Sep 18;101(9):3305-18. Epub 2012 May 18.

Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903, USA.

A 2,4-dinitrophenylhydrazine (DNPH) precolumn derivatization high-performance liquid chromatography-ultraviolet detection (HPLC-UV) method was developed to quantify levels of formaldehyde and acetaldehyde in polyethylene glycol (PEG) solutions. Formic acid and acetic acid were quantified by HPLC-UV. Samples of neat and aqueous PEG 400 solutions were monitored at 40°C and 50°C to determine effects of excipient source, water content, pH, and trace levels of hydrogen peroxide or iron metal on the formation of reactive impurities. The effects of antioxidants were also evaluated. Formic acid was the major degradation product in nearly all cases. The presence of water increased the rate of formation of all impurities, especially formic acid as did the presence of hydrogen peroxide and trace metals. Acidic pH increased the formation of acetaldehyde and acetic acid. A distribution of unidentified degradation products formed in neat PEG 400 disappeared upon addition of HCl with corresponding increase of formic acid, indicating they were likely to be PEG-formyl esters. Other unidentified degradation products reacted with DNPH to form a distribution of derivatized products likely to be PEG aldehydes. Antioxidants butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate d-alpha tocopheryl polyethylene glycol-1000 succinate, and sodium metabisulfite were effective in limiting reactive impurity formation, whereas ascorbic acid and acetic acid were not.
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http://dx.doi.org/10.1002/jps.23198DOI Listing
September 2012

Vernonia DGATs can complement the disrupted oil and protein metabolism in epoxygenase-expressing soybean seeds.

Metab Eng 2012 Jan 12;14(1):29-38. Epub 2011 Nov 12.

Department of Plant and Soil Science, University of Kentucky, KY 40546-0312, USA.

Plant oils can be useful chemical feedstocks such as a source of epoxy fatty acids. High seed-specific expression of a Stokesia laevis epoxygenase (SlEPX) in soybeans only results in 3-7% epoxide levels. SlEPX-transgenic soybean seeds also exhibited other phenotypic alterations, such as altered seed fatty acid profiles, reduced oil accumulation, and variable protein levels. SlEPX-transgenic seeds showed a 2-5% reduction in total oil content and protein levels of 30.9-51.4%. To address these pleiotrophic effects of SlEPX expression on other traits, transgenic soybeans were developed to co-express SlEPX and DGAT (diacylglycerol acyltransferase) genes (VgDGAT1 & 2) isolated from Vernonia galamensis, a high accumulator of epoxy fatty acids. These side effects of SlEPX expression were largely overcome in the DGAT co-expressing soybeans. Total oil and protein contents were restored to the levels in non-transgenic soybeans, indicating that both VgDGAT1 and VgDGAT2 could complement the disrupted phenotypes caused by over-expression of an epoxygenase in soybean seeds.
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http://dx.doi.org/10.1016/j.ymben.2011.11.004DOI Listing
January 2012

Reactive impurities in excipients: profiling, identification and mitigation of drug-excipient incompatibility.

AAPS PharmSciTech 2011 Dec 27;12(4):1248-63. Epub 2011 Sep 27.

Bristol-Myers Squibb, Co., New Brunswick, New Jersey 08901, USA.

Reactive impurities in pharmaceutical excipients could cause drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants. The levels of reactive impurities in excipients may vary between lots and vendors. Screening of excipients for these impurities and a thorough understanding of their potential interaction with drug candidates during early formulation development ensure robust drug product development. In this review paper, excipient impurities are categorized into six major classes, including reducing sugars, aldehydes, peroxides, metals, nitrate/nitrite, and organic acids. The sources of generation, the analytical method for detection, the stability of impurities upon storage and processing, and the potential reactions with drug candidates of these impurities are reviewed. Specific examples of drug-excipient impurity interaction from internal research and literature are provided. Mitigation strategies and corrective measures are also discussed.
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http://dx.doi.org/10.1208/s12249-011-9677-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225520PMC
December 2011