Publications by authors named "Yuling Liang"

36 Publications

Highly Sensitive Fluorescence Detection of Global 5-Hydroxymethylcytosine from Nanogram Input with Strongly Emitting Copper Nanotags.

Anal Chem 2021 Oct 12. Epub 2021 Oct 12.

School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China.

Quantitative analysis of 5-hydroxymethylcytosine (5hmC) has remarkable clinical significance to early cancer diagnosis; however, it is limited by the requirement in current assays for large amounts of starting material and expensive instruments requring expertise. Herein, we present a highly sensitive fluorescence method, termed hmC-TACN, for global 5hmC quantification from several nanogram inputs based on terminal deoxynucleotide transferase (TdT)-assisted formation of fluorescent copper (Cu) nanotags. In this method, 5hmC is labeled with click tags by T4 phage β-glucosyltransferase (β-GT) and cross-linked with a random DNA primer via click chemistry. TdT initiates the template-free extension along the primer at the modified 5hmC site and then generates a long polythymine (T) tail, which can template the production of strongly emitting Cu nanoparticles (CuNPs). Consequently, an intensely fluorescent tag containing numerous CuNPs can be labeled onto the 5hmC site, providing the sensitive quantification of 5hmC with a limit of detection (LOD) as low as 0.021% of total nucleotides (/ = 3). With only a 5 ng input (∼1000 cells) of genomic DNA, global 5hmC levels were accurately determined in mouse tissues, human cell lines (including normal and cancer cells of breast, lung, and liver), and urines of a bladder cancer patient and healthy control. Moreover, as few as 100 cells can also be distinguished between normal and cancer cells. The hmC-TACN method has great promise of being cost effective and easily mastered, with low-input clinical utility, and even for the microzone analysis of tumor models.
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http://dx.doi.org/10.1021/acs.analchem.1c03266DOI Listing
October 2021

The Combined Impact of Female and Male Body Mass Index on Cumulative Pregnancy Outcomes After the First Ovarian Stimulation.

Front Endocrinol (Lausanne) 2021 17;12:735783. Epub 2021 Sep 17.

Center of Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Objectives: To evaluate the combined impact of male and female BMI on cumulative pregnancy outcomes after the first ovarian stimulation.

Design: Retrospective cohort study.

Setting: University-affiliated reproductive medicine center.

Patients: A total of 15,972 couples undergoing their first ovarian stimulations from June 2009 to June 2016 were included. During the follow-up period between June 2009 and June 2018, 14,182 couples underwent a complete ART cycle involving fresh embryo transfer and subsequent frozen embryo transfers (FETs) after their first ovarian stimulations. Patients with a BMI <24 kg/m served as the reference group. Patients with a BMI ≥ 24 kg/m were considered to be overweight, and those with a BMI ≥28 kg/m were considered to be obese.

Interventions: None.

Primary Outcome Measure: The primary outcome was the cumulative live birth rate (CLBR), which defined as the delivery of at least one live birth in the fresh or in the subsequent FET cycles after the first ovarian stimulation.

Results: In the analyses of females and males separately, compared with the reference group, overweight and obese females had a reduced CLBR (aOR 0.83, 95% CI 0.7.92 and aOR 0.76, 95% CI 0.64-0.90). Similarly, overweight males had a reduced CLBR (aOR 0.91, 95% CI 0.83-0.99) compared with that of the reference group. In the analyses of couples, those in which the male was in the reference or overweight group and the female was overweight or obese had a significantly lower CLBR than those in which both the male and female had a BMI <24 kg/m.

Conclusions: The CLBR is negatively impacted by increased BMI in the female and overweight status in the male, both individually and together.
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http://dx.doi.org/10.3389/fendo.2021.735783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486084PMC
September 2021

A MOF-Shell-Confined I-Motif-Based pH Probe (MOFC-i) Strategy for Sensitive and Dynamic Imaging of Cell Surface pH.

ACS Appl Mater Interfaces 2021 Sep 20;13(38):45291-45299. Epub 2021 Sep 20.

School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China.

Dynamic imaging of cell surface pH is extremely challenging due to the slight changes in pH and the fast diffusion of secreted acid to the extracellular environment. In this work, we construct a novel metal-organic framework (MOF)-shell-confined i-motif-based pH probe (MOFC-i) strategy that enables sensitive and dynamic imaging of cell surface pH. The CY3- and CY5-labeled i-motif, which is hybridized via its short complementary chain with two-base mismatches, is optimized for sensing at physiological pH. After efficiently anchoring the optimized pH probes onto the cell membrane with the aid of cholesterol groups, a biocompatible microporous MOF shell is then formed around the cell by cross-linking ZIF-8 nanoparticles via tannic acid. The microporous MOF shell can confine secreted acid without inhibiting the normal physiological activities of cells; thus, the MOFC-i strategy can be used to monitor dynamic changes in the cell surface pH of living cells. Furthermore, this method can not only clearly distinguish the different metabolic behaviors of cancer cells and normal cells but also reveal drug effects on the cell surface pH or metabolism, providing promising prospects in pH-related diagnostics and drug screening.
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http://dx.doi.org/10.1021/acsami.1c13720DOI Listing
September 2021

Adaptive Bipartite Output Tracking Consensus in Switching Networks of Heterogeneous Linear Multiagent Systems Based on Edge Events.

IEEE Trans Neural Netw Learn Syst 2021 Jul 13;PP. Epub 2021 Jul 13.

This article focuses on the problem of adaptive bipartite output tracking for a class of heterogeneous linear multiagent systems (MASs) by asynchronous edge-event-triggered communications under jointly connected signed topologies. By designing the observers to estimate the states of followers and the dynamic compensators to estimate the states of zero input and nonzero input leader, respectively, the fully distributed edge-event-triggered control protocol is presented. Moreover, it is proven that the bipartite output tracking problem is implemented, and the systems do not exhibit Zeno behavior under a fully distributed control strategy with edge-event-triggered mechanisms. Compared with the existing works, one of the highlights of this article is the design of triggering mechanisms, under which the leader avoids continuous information transmission and any pair of followers that make up the edge asynchronously transmit information through the edge. The methods greatly avoid unnecessary information transmission in the systems. Finally, several simulation examples are introduced to demonstrate the theoretical results obtained in this article.
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http://dx.doi.org/10.1109/TNNLS.2021.3089596DOI Listing
July 2021

Integrative Multi-Omics Analysis of Identified NUF2 as a Candidate Oncogene Correlates With Poor Prognosis and Immune Infiltration in Non-Small Cell Lung Cancer.

Front Oncol 2021 10;11:656509. Epub 2021 Jun 10.

Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China.

Background: Lung cancer is one of the most common malignant tumors and the leading causes of cancer-related deaths worldwide. As a component of the nuclear division cycle 80 complex, NUF2 is a part of the conserved protein complex related to the centromere. Although the high expression of NUF2 has been reported in many different types of human cancers, the multi-omics analysis in non-small cell lung cancer (NSCLC) of NUF2 remains to be elucidated.

Methods: In this analysis, NUF2 expression difference analysis in non-small cell lung cancer was evaluated by Oncomine, TIMER, GEO, and TCGA database. And the prognosis analysis of NUF2 based on Kaplan-Meier was performed. R language was used to analyze the differential expression genes, functional annotation and protein-protein interaction (PPI). GSEA analysis of differential expression genes was also carried out. Mechanism analysis about exploring the characteristic of NUF2, multi-omics, and correlation analysis was carried out using UALCAN, cBioportal, GEPIA, TIMER, and TISIDB, respectively.

Results: The expression of NUF2 in NSCLC, both lung adenocarcinoma (LUAD) and squamous lung cancer (LUSC), was significantly higher than that in normal tissues. The analysis of UALCAN database samples proved that NUF2 expression was connected with stage and smoking habits. Meanwhile, the overall survival curve also validated that high expression of NUF2 has a poorer prognosis in NSCLC. GO, KEGG, GSEA, subcellular location from COMPARTMENTS indicated that NUF2 may regulate the cell cycle. Correlation analysis also showed that NUF2 was mainly positively associated with cell cycle and tumor-related genes. NUF2 altered group had a poorer prognosis than unaltered group in NSCLC. Immune infiltration analysis showed that the NUF2 expression mainly have negatively correlation with immune cells and immune subtypes in LUAD and LUSC. Furthermore, quantitative PCR was used to validate the expression difference of NUF2 in LUAD and LUSC.

Conclusion: Our findings elucidated that NUF2 may play an important role in cell cycle, and significantly associated with tumor-related gene in NSCLC; we consider that NUF2 may be a prognostic biomarkers in NSCLC.
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http://dx.doi.org/10.3389/fonc.2021.656509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222979PMC
June 2021

The only conserved microsatellite in coding regions of ebolavirus is the editing site.

Biochem Biophys Res Commun 2021 Aug 4;565:79-84. Epub 2021 Jun 4.

Bioinformatics Center, College of Biology, Hunan University, Changsha, 410082, China. Electronic address:

Lots of viral genomes were found to contain microsatellites (SSRs) including Ebolavirus, and majority of Ebolavirus microsatellite sites are distributed in protein-coding regions of the genomes. Here, we totally identified 212 reserved microsatellite sites in the protein-coding regions of 213 genomic sequences from five Ebolavirus species. In these reserved microsatellite sites, there is only one significantly conserved microsatellite site among the sample Ebolavirus genomic sequences, and this microsatellite is located at RNA editing site of the GP gene, indicating the selective relevance with RNA editing there. This analysis may help to further explore the biological significance of various microsatellites in Ebolavirus genomes.
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http://dx.doi.org/10.1016/j.bbrc.2021.05.093DOI Listing
August 2021

A growth-factor-activated lysosomal K channel regulates Parkinson's pathology.

Nature 2021 03 27;591(7850):431-437. Epub 2021 Jan 27.

Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.

Lysosomes have fundamental physiological roles and have previously been implicated in Parkinson's disease. However, how extracellular growth factors communicate with intracellular organelles to control lysosomal function is not well understood. Here we report a lysosomal K channel complex that is activated by growth factors and gated by protein kinase B (AKT) that we term lysoK. LysoK consists of a pore-forming protein TMEM175 and AKT: TMEM175 is opened by conformational changes in, but not the catalytic activity of, AKT. The minor allele at rs34311866, a common variant in TMEM175, is associated with an increased risk of developing Parkinson's disease and reduces channel currents. Reduction in lysoK function predisposes neurons to stress-induced damage and accelerates the accumulation of pathological α-synuclein. By contrast, the minor allele at rs3488217-another common variant of TMEM175, which is associated with a decreased risk of developing Parkinson's disease-produces a gain-of-function in lysoK during cell starvation, and enables neuronal resistance to damage. Deficiency in TMEM175 leads to a loss of dopaminergic neurons and impairment in motor function in mice, and a TMEM175 loss-of-function variant is nominally associated with accelerated rates of cognitive and motor decline in humans with Parkinson's disease. Together, our studies uncover a pathway by which extracellular growth factors regulate intracellular organelle function, and establish a targetable mechanism by which common variants of TMEM175 confer risk for Parkinson's disease.
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http://dx.doi.org/10.1038/s41586-021-03185-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979525PMC
March 2021

-GFP Knock-In Mice Reflect Patterns of Endogenous Expression and Pathological Seeding.

eNeuro 2020 Jul/Aug;7(4). Epub 2020 Aug 27.

Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-4283

α-Synuclein (aSyn) participates in synaptic vesicle trafficking and synaptic transmission but its misfolding is also strongly implicated in Parkinson's disease (PD) and other neurodegenerative synucleinopathies in which misfolded aSyn accumulates in different regions of the central and peripheral nervous systems. Although increased aSyn expression levels or altered aggregation propensities likely underlie familial PD with amplification or mutations, the majority of synucleinopathies arise sporadically, indicating that disease can develop under normal levels of wild-type (wt) aSyn. We report here the development and characterization of a mouse line expressing an aSyn-green fluorescence protein (GFP) fusion protein under the control of native regulatory elements. Regional and subcellular localization of the aSyn-GFP fusion protein in brains and peripheral tissues of knock-in (KI) mice are indistinguishable from that of wt littermates. Importantly, similar to wt aSyn, aSyn-GFP disperses from synaptic vesicles on membrane depolarization, indicating that the tag does not alter normal aSyn dynamics at synapses. In addition, intracerebral injection of aSyn pre-formed fibrils into KI mice induced the formation of aSyn-GFP inclusions with a distribution pattern similar to that observed in wt mice, albeit with attenuated kinetics because of the GFP-tag. We anticipate that this new mouse model will facilitate and studies requiring detection of endogenous aSyn, thereby providing new insights into aSyn function in health and disease.
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http://dx.doi.org/10.1523/ENEURO.0007-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470929PMC
June 2021

Pediatric Donor Glomerulopathy Is a Possible Cause of Abnormal Urinalysis in Adults Receiving Small Pediatric Donor Kidneys.

Transplantation 2020 08;104(8):1695-1702

Department of Pathology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: Reports about prognosis of adults receiving small pediatric-donor kidneys (PDK) as compared to those receiving elder pediatric or adult donor kidneys (ADKs) are controversial. This study aimed to examine the outcomes of adults receiving small PDK and possible prognostic factors.

Methods: The records of adults who received kidneys from donors < 10 years old at our center from July 1, 2011 to June 30, 2018 were reviewed.

Results: A total of 121 adults were small PDK recipients. Twenty-three patients received 29 biopsies or nephrectomy between 6 and 896 days posttransplantation days. Seven patients (30.4%) had pediatric donor glomerulopathy (PDG), which developed from 113 to 615 days posttransplantation. The incidence of proteinuria and hematuria was significantly higher in the PDG group. The characteristic pathological finding in PDG was irregular lamination and splintering of the glomerular basement membrane (GBM). Donor age, donor weight, and donor kidney volume were significantly less in PDG cases compared with the non-PDG cases. For the risk factors of PDG, increasing urinary RBC count during follow-up was an independent predictor, while increasing donor age and body weight were protective factors. PDG was not a significant risk factor for Scr increasing of PDKs.

Conclusions: PDG is a potential cause of abnormal urinalysis in adults receiving small PDKs. The pathological characteristic change of PDG is splitting and lamination of GBM. Persistent hematuria after transplantation in recipients of PDK is a predictor of PDG development.
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http://dx.doi.org/10.1097/TP.0000000000003038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373488PMC
August 2020

[Analysis of clinical effects of early enteral nutrition standardized treatment process management on patients with acute exacerbation of chronic obstructive pulmonary disease on invasive mechanical ventilation].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2020 Jan;32(1):67-71

Department of Emergence Medicine, Shenzhen Baoan District People's Hospital (Second Affiliated Hospital of Shenzhen University), Shenzhen 518000, Guangdong, China. Corresponding author: Dou Qingli, Email:

Objective: To investigate the effect of early enteral nutrition (EN) standardized treatment process management on the ventilation treatment effect and prognosis of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) on invasive mechanical ventilation.

Methods: Forty-three patients with AECOPD on invasive mechanical ventilation admitted to Shenzhen Baoan District People's Hospital from January 2017 to December 2018 were enrolled. According to the start time of the continuous quality improvement project of nutritional support treatment for critically ill patients in the hospital, 20 patients from January 1st to December 31st in 2017 were enrolled in the routine EN group, and 23 patients from January 1st to December 31st in 2018 were enrolled in the early EN group. In the early EN group, when the patient was hemodynamically stable within 24 hours after intensive care unit (ICU) admission and there was no contraindication for EN, early trans nasal intestinal EN was started, and the infusion rate was adjusted or parenteral nutrition was added according to the EN tolerance score. The target feeding amount was 104.6-125.5 kJ×kg×d, and achieve complete EN. The conventional EN group started EN after patients had experienced the early stress stage, the vital signs were stable, and 48 hours after ICU admission. The management process was the same as the early EN group. The ventilation indicators including rapid shallow breathing index (RSBI), arterial blood pH value, arterial oxygen partial pressure (PaO), arterial partial pressure of carbon dioxide (PaCO), and base excess (BE) at weaning, PaCO, CO retention rate at 2 hours after weaning, as well as critical management indicators including the incidence of ventilator-associated pneumonia (VAP), duration of invasive mechanical ventilation, length of ICU stay, total hospitalization cost and re-intubation rate between the two groups were compared.

Results: After the early EN standardized treatment process management, the RSBI at weaning of the patients in the early EN group was significantly lower than that in the conventional EN group (times×min×L: 36.68±16.12 vs. 52.63±14.81, P < 0.05), but no significant difference in pH value, PaO, PaCO or BE was found as compared with the conventional EN group. The PaCO and CO2 retention rate at 2 hours after weaning in the early EN group were significantly lower than those in the conventional EN group [PaCO (mmHg, 1 mmHg = 0.133 kPa): 52.48±7.62 vs. 58.32±8.43, CO retention rate: (10.25±2.86)% vs. (18.46±3.21)%, both P < 0.05]. Compared with the conventional EN group, the incidence of VAP [8.7% (2/23) vs. 15.0% (3/20)], duration of invasive mechanical ventilation (hours: 52.64±14.81 vs. 53.78±12.75), length of ICU stay (days: 4.92±1.26 vs. 5.24±1.84), total hospitalization costs (thousand Yuan: 20.9±4.8 vs. 21.0±6.9) and re-intubation rate [13.0% (3/23) vs. 20.0% (4/20)] were slightly decreased in the early EN group without statistically significance (all P > 0.05).

Conclusions: The management of early EN standardized treatment process for patients with AECOPD on invasive mechanical ventilation may alleviate the respiratory muscle fatigue status, and does not increase the complications.
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http://dx.doi.org/10.3760/cma.j.cn121430-20190927-00012DOI Listing
January 2020

High-yield synthesis of monodisperse gold nanorods with a tunable plasmon wavelength using 3-aminophenol as the reducing agent.

Nanoscale 2019 Dec 25;11(47):22890-22898. Epub 2019 Nov 25.

College of Chemistry and Materials, Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, Nanning Normal University, Nanning 530001, P. R. China. and College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. China.

Facile synthesis of high quality gold nanorods (AuNRs) with a tunable size is of great value for applications of AuNRs in various fields and for the study of the growth mechanism of such anisotropic nanostructures. However, limitations usually exist in a specific synthetic protocol. In this work, using 3-aminophenol as the reducing agent, we present a AuNR synthetic strategy with an excellent comprehensive performance, which includes an exceptional monodispersity, a AuNR shape purity of around 99%, a conversion ratio of the gold precursor of about 91%, and an easily tuned longitudinal surface plasmon resonance wavelength ranging from 580 to ∼1050 nm. Studies on the impacts of the experimental parameters including silver ions, gold seeds, reducing agent, and cetyltrimethylammonium bromide (CTAB) revealed a profound recognition of the significant effect of the reductive atmosphere, in synergy with other parameters, in directing the growth and structural evolution of the gold seeds, thus deeply affecting the size, shape yield, monodispersity, and morphology of the final structure. These results could be immensely useful for the application and revelation of the growth mechanism of AuNRs.
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http://dx.doi.org/10.1039/c9nr07949aDOI Listing
December 2019

High-beta/low-gamma frequency activity reflects top-down predictive coding during a spatial working memory test.

Exp Brain Res 2019 Jul 15;237(7):1881-1888. Epub 2019 May 15.

Department of Psychiatry and Behavioral Sciences, University of Southern California, 2250 Alcazar St., Los Angeles, CA, 90033, USA.

Numerous mental health disorders are characterized by cognitive impairments that result in poor vocational and social outcomes. Among the cognitive domains commonly affected, working memory deficits have been noted in patients with attention-deficit/hyperactivity disorder (Martinussen et al. in J Am Acad Child Adolesc Psychiatry 44:377-384, 2005), post-traumatic stress disorder (Honzel et al. in Cogn Affect Behav Neurosci 14:792-804, 2014), and consistently with schizophrenia patients (Callicott et al. in Cereb Cortex 10:1078-1092, 2000; Lewis et al. in Front Hum Neurosci 10:85, 2005; Amann et al. in Brain Res Bull 83:147-161, 2010; Limongi et al. in Schizophr Res 197:386-391, 2018). Oscillations in neural activity from electroencephalogram (EEG) recordings are decomposed by frequency, and band-specific decreases in gamma power (> 30 Hz) have been correlated with working memory ability. This study examined within-subject changes in power of frequency-specific bands during sample versus choice trials during a spatial working memory paradigm (T-maze). EEG was recorded using a relatively novel wireless EEG telemetry system fully implanted within the mouse, enabling uninhibited movement during behavioral tasks. No significant differences were found between sample and correct choice phases in the alpha, theta or gamma frequency ranges. Evoked power was significantly higher during the choice phase than the sample phase in the high-beta/low-gamma frequency range. This frequency range has been implicated in the propagation of cortical predictions to lower levels of stimuli encoding in a top-down hierarchical manner. Results suggest there is an increase in brain activity during correct trials when the mouse enters the opposite arm during the choice phase compared to the sample phase, likely due to prediction error resulting from a discrepancy between present and prior experience. Future studies should identify specific cortical networks involved and investigate neural activity at the neuronal level.
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http://dx.doi.org/10.1007/s00221-019-05558-3DOI Listing
July 2019

[Galectin-3 induces differentiation of rat bone marrow mesenchymal stem cells into hepatocyte-like cells].

Nan Fang Yi Ke Da Xue Xue Bao 2018 Aug;38(9):1076-1082

Second Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.

Objective: To investigate the effect of galectin-3 in inducing the differentiation of rat bone marrow mesenchymal stem cells (BMSCs) into hepatocyte- like cells and explore the involvement of the signaling pathways in the induced cell differentiation.

Methods: The third passage of cultured rat femoral BMSCs were treated with 0.5 μg/mL galectin-3, 20 ng/mL hepatocyte growth factor (HGF) or both to induce their differentiation, with untreated rat BMSCs and hepatocytes as controls. At 7, 14, 21 and 28 days of induction, the cells were examined for morphological changes followed by glycogen staining, quantitative real-time PCR and Western blotting. Gene microarray technique was used to examine the mRNA expression profile of the BMSCs induced with galectin-3. The BMSCs were also induced with galectin-3 in combination with XMU-MP-1, a Hippo signaling pathway inhibitor, after which Western blotting was performed to detect the expressions of YAP, P-YAP, ALB, AFP and CK-18 in the cells.

Results: The cells isolated from the femoral bone marrow of SD rats showed a consistent surface marker phenotype with the BMSCs. Induction with galectin-3, HGF, or both all resulted in gradual morphological changes of the BMSCs into hepatocyte-like cells, and the cells with a combined induction for 28 days showed the highest morphological similarity with hepatocytes. The cells induced with galectin-3, HGF, or their combination for 28 days all showed increased positivity rate of glycogen staining, which was the highest in the cells with combined induction ( < 0.05) without significant difference between the cells induced with galectin-3 and HGF alone ( > 0.05). Induction with galectin-3 and HGF alone both increased the expressions of AFP, ALB and CK-18 mRNAs in the cells, and their expression levels were similar between the cells at 28 days ( > 0.05). Galectin-3 and HGF did not show an interactive effect on the mRNA expressions of AFP (=0.236, =0.640) or ALB (=50.639, =0.000), but had a synergistic effect on CK-18 mRNA expression (=50.639, =0.000). The protein expressions of AFP, ALB and CK18 were also increased in the induced cells but not detected in the cells without induction. Gene microarray results revealed 27 up-regulated genes and 62 down-regulated genes in galectin-3-induced BMSCs involving TGF-β, PI3K-Akt and Hippo signal pathways. Induction with galectin-3 and galectin-3+XMU-MP-1 increased YAP expression in the cells, and galectin-3+XMU-MP-1 was more efficient to induce the differentiation of the BMSCs.

Conclusions: Galectin-3 can induce the differentiation of rat BMSCs into hepatocyte-like cells, and the combination with HGF increases the efficiency of induced differentiation of the cells. TGF-β, PI3K-Akt and Hippo pathways are involved in the induced differentiation of the BMSCs, and inhibiting Hippo pathway can improve the induction efficiency.
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http://dx.doi.org/10.12122/j.issn.1673-4254.2018.09.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744192PMC
August 2018

Advanced oxidation protein products inhibit the autophagy of renal tubular epithelial cells.

Exp Ther Med 2018 Apr 15;15(4):3908-3916. Epub 2018 Feb 15.

Department of Nephrology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, P.R. China.

It is well known that autophagy serves a crucial role in renal tubular epithelial cell (RTEC) injury in the pathogenesis of chronic kidney disease (CKD). The accumulation of advanced oxidation protein products (AOPPs) also participates in the progression of CKD. However, the effects of AOPPs on autophagy remain unknown. To clarify the underlying mechanism of RTEC injury in CKD, the effect of AOPPs on HK-2 cells, an RTEC cell line, was investigated. The results of the present study revealed that AOPP exposure downregulated the expression of B-cell lymphoma-2-interacting myosin-like coiled-coil protein 1, reduced the conversion of microtubule-associated proteins 1 light chain 3B (LC3)-I to LC3-II and the formation of autophagosomes, and lead to an accumulation of p62. These results suggest that AOPPs may inhibit the autophagic activity of HK-2 cells. Furthermore, the aforementioned changes were mediated by the AOPP-phosphorylated phosphoinositide 3-kinase3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway; this was verified by treatment with LY294002, a PI3K inhibitor, which reversed the AOPP-induced changes. The present study also demonstrated that the activation of autophagy with rapamycin led to an improvement in the AOPP-induced overexpression of kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin, two biomarkers of RTEC injury, whereas inhibiting autophagy with chloroquine further increased their expression during AOPP treatment. Collectively, these results indicate that AOPPs may inhibit autophagy in RTECs via activation of the PI3K/AKT/mTOR pathway and that autophagy inhibition serves a role in AOPP-induced RTEC injury.
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http://dx.doi.org/10.3892/etm.2018.5875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844045PMC
April 2018

Pyramidal cell-selective GluN1 knockout causes impairments in salience attribution and related EEG activity.

Exp Brain Res 2018 03 19;236(3):837-846. Epub 2018 Jan 19.

Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Schizophrenia is a disabling psychiatric disease characterized by symptoms including hallucinations, delusions, social withdrawal, loss of pleasure, and inappropriate affect. Although schizophrenia is marked by dysfunction in dopaminergic and glutamatergic signaling, it is not presently clear how these dysfunctions give rise to symptoms. The aberrant salience hypothesis of schizophrenia argues that abnormal attribution of motivational salience to stimuli is one of the main contributors to both positive and negative symptoms of schizophrenia. The proposed mechanisms for this hypothesis are overactive striatal dopaminergic and hypoactive glutamatergic signaling. The current study assessed salience attribution in mice (n = 72) using an oddball paradigm in which an infrequent stimulus either co-occurred with shock (conditioned group) or was presented alone (non-conditioned group). Behavioral response (freezing) and electroencephalogram (whole brain and amygdala) were used to assess salience attribution. Mice with pyramidal cell-selective knockout of ionotropic glutamate receptors (GluN1) were used to reproduce a prominent physiological change involved in schizophrenia. Non-conditioned knockout mice froze significantly more in response to the unpaired stimulus than non-conditioned wild-type mice, suggesting that this irrelevant cue acquired motivational salience for the knockouts. In accordance with this finding, low-frequency event-related spectral perturbation was significantly increased in non-conditioned knockout mice relative to both conditioned knockout and non-conditioned wild-type mice. These results suggest that pyramidal cell-selective GluN1 knockout leads to inappropriate attribution of salience for irrelevant stimuli as characterized by abnormalities in both behavior and brain circuitry functions.
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http://dx.doi.org/10.1007/s00221-017-5152-8DOI Listing
March 2018

Emulsion Hydrogel Soft Motor Actuated by Thermal Stimulation.

ACS Appl Mater Interfaces 2017 Dec 1;9(49):43211-43219. Epub 2017 Dec 1.

Research Institute of Materials Science, South China University of Technology , Guangzhou 510640, China.

An emulsion hydrogel motor (E-H motor), constituted by low-boiling-point oil fuel and a hydrogel matrix, is prepared through a simple yet versatile oil-in-water (O/W) emulsion template method. The E-H motor can be efficiently propelled by the bubbles generated under a thermal stimulus. As thermally induced explosion occurs inside the E-H motor (diameter ∼4.0 mm and length ∼6.0 mm), the gas bubbles resulting from thermotropic phase transition are violently ejected from one side, leading to a fast speed of 14.78 ± 4.82 mm s in a 60 °C aqueous solution. Additionally, multiple water-insoluble organic solvents can serve as the fuel for self-propulsion, which demonstrates the favorable universality of the E-H motor. The magnetic navigation and near-infrared propulsion can be realized through incorporating hydrophilic iron oxide (FeO) nanoparticles and graphene oxide (GO) into the aqueous phase. Moreover, the synchronous integration of GO and enrofloxacin bactericide can enable intelligent targeted cargo transportation and delivery. The attractive self-propulsion performance, precise locomotion control, and formidable integration ability of the emulsion hydrogel-based miniaturized soft motor hold great promise for numerous practical applications.
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http://dx.doi.org/10.1021/acsami.7b08661DOI Listing
December 2017

Functional diversity of jasmonates in rice.

Rice (N Y) 2015 Dec 29;8(1):42. Epub 2015 Jan 29.

College of Life Sciences, Hebei University, Baoding, China,

Phytohormone jasmonates (JA) play essential roles in plants, such as regulating development and growth, responding to environmental changes, and resisting abiotic and biotic stresses. During signaling, JA interacts, either synergistically or antagonistically, with other hormones, such as salicylic acid (SA), gibberellin (GA), ethylene (ET), auxin, brassinosteroid (BR), and abscisic acid (ABA), to regulate gene expression in regulatory networks, conferring physiological and metabolic adjustments in plants. As an important staple crop, rice is a major nutritional source for human beings and feeds one third of the world's population. Recent years have seen significant progress in the understanding of the JA pathway in rice. In this review, we summarize the diverse functions of JA, and discuss the JA interplay with other hormones, as well as light, in this economically important crop. We believe that a better understanding of the JA pathway will lead to practical biotechnological applications in rice breeding and cultivation.
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http://dx.doi.org/10.1186/s12284-015-0042-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773313PMC
December 2015

Mice with subtle reduction of NMDA NR1 receptor subunit expression have a selective decrease in mismatch negativity: Implications for schizophrenia prodromal population.

Neurobiol Dis 2015 Jan 22;73:289-95. Epub 2014 Oct 22.

Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Reductions in glutamate function are regarded as an important contributory factor in schizophrenia. However, there is a paucity of animal models characterized by developmental and sustained reductions in glutamate function. Pharmacological models using NMDA antagonists have been widely used but these typically produce only transient changes in behavior and brain function. Likewise, mice with homozygous constitutive reductions in glutamate receptor expression show stable brain and behavioral changes, but many of these phenotypes are more severe than the human disease. The current study examines a variety of schizophrenia-related EEG measures in mice with a heterozygous alteration of the NMDA receptor NR1 subunit gene (NR1) that is known to result in reduced NR1 receptor expression in the homozygous mouse (NR1-/-). (NR1+/-) mice showed a 30% reduction in NR1 receptor expression and were reared after weaning in either group or isolated conditions. Outcome measures include the response to paired white noise stimuli, escalating inter-stimulus intervals (ISIs) and deviance-related mismatch negativity (MMN). In contrast to what has been reported in (NR1-/-) mice and mice treated with NMDA antagonists, (NR1+/-) mice showed no change on obligatory Event Related Potential (ERP) measures including the murine P50 and N100 equivalents (P20 and N40), or measures of baseline or evoked gamma power. Alternatively, (NR1+/-) mice showed a marked reduction in response to a deviant auditory tone during MMN task. Data suggest that EEG response to deviant, rather than static, stimuli may be more sensitive for detecting subtle changes in glutamate function. Deficits in these heterozygous NR1 knockdown mice are consistent with data demonstrating MMN deficits among family members of schizophrenia patients and among prodromal patients. Therefore, the current study suggests that (NR1+/-) mice may be among the most sensitive models for increased vulnerability to schizophrenia.
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http://dx.doi.org/10.1016/j.nbd.2014.10.010DOI Listing
January 2015

Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability.

Biol Psychiatry 2015 Mar 18;77(6):556-68. Epub 2014 Jul 18.

Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Background: Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear.

Methods: In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neuron specific NMDA receptor 1 knockout mice.

Results: The mice displayed increased baseline gamma power, as well as sociocognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increased neuronal excitability.

Conclusions: Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological, and behavioral changes related to SZ.
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http://dx.doi.org/10.1016/j.biopsych.2014.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297754PMC
March 2015

Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits.

Neuropsychopharmacology 2014 Jun 14;39(7):1603-13. Epub 2014 Feb 14.

Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.

NMDA-receptor (NMDAR) hypofunction is strongly implicated in the pathophysiology of schizophrenia. Several convergent lines of evidence suggest that net excitation propagated by impaired NMDAR signaling on GABAergic interneurons may be of particular interest in mediating several aspects of schizophrenia. However, it is unclear which behavioral domains are governed by a net increase of excitation and whether modulating downstream GABAergic signaling can reverse neural and thus behavioral deficits. The current study determines the selective contributions of NMDAR dysfunction on PV-containing interneurons to electrophysiological, cognitive, and negative-symptom-related behavioral phenotypes of schizophrenia using mice with a PVcre-NR1flox-driven ablation of NR1 on PV-containing interneurons. In addition, we assessed the efficacy of one agent that directly modulates GABAergic signaling (baclofen) and one agent that indirectly modifies NMDAR-mediated signaling through antagonism of mGluR5 receptors (2-methyl-6-(phenylethynyl) pyridine (MPEP)). The data indicate that loss of NMDAR function on PV interneurons impairs self-care and sociability while increasing N1 latency and baseline gamma power, and reducing induction and maintenance of long-term potentiation. Baclofen normalized baseline gamma power without corresponding effects on behavior. MPEP further increased N1 latency and reduced social behavior in PVcre/NR1+/+ mice. These two indices were negatively correlated before and following MPEP such that as N1 latency increases, sociability decreases. This finding suggests a predictive role for N1 latency with respect to social function. Although previous data suggest that MPEP may be beneficial for core features of autism spectrum disorders, current data suggest that such effects require intact function of NMDAR on PV interneurons.
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http://dx.doi.org/10.1038/npp.2014.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023157PMC
June 2014

Two faces of narcissism and romantic attraction: evidence from a collectivistic culture.

Psychol Rep 2012 Aug;111(1):1-12

Department of Psychology, Sun Yat-sen University, Guangzhou, China.

The present study was aimed to extend the self-orientation model (Campbell, 1999) to vulnerable narcissism in a collectivistic culture. Two hundred and twenty-seven college students were recruited from China. Participants reported their ratings on measures of vulnerable and grandiose narcissism, attractions to different (caring vs perfect) targets, and their choices of potential romantic partners. Results indicated that those participants classified as grandiose or vulnerable narcissists were more attracted to perfect targets than non-narcissists. In addition, grandiose narcissists preferred to choose perfect targets as their romantic partners, while vulnerable narcissists did not show such a preference when choosing potential partners. These results suggested that culture could influence the function of narcissism. The self-orientation model could not fully explain the choices of vulnerable narcissists.
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http://dx.doi.org/10.2466/09.02.20.pr0.111.4.1-12DOI Listing
August 2012

Subchronic ketamine treatment leads to permanent changes in EEG, cognition and the astrocytic glutamate transporter EAAT2 in mice.

Neurobiol Dis 2012 Sep 22;47(3):338-46. Epub 2012 May 22.

Department of Psychiatry, Translational Neuroscience Program, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

Ketamine is an NMDA receptor antagonist with psychotomimetic, dissociative, amnestic and euphoric effects. When chronically abused, ketamine users display deficits in cognition and information processing, even following long-term abstinence from the drug. While animal studies have shown evidence of behavioral changes and cognitive deficits that mimic those seen in humans within the period immediately following subchronic ketamine, a few animal studies have assessed long-term changes following cessation of ketamine exposure. To this end, the present study assessed event related potentials (ERPs) and EEG oscillations in mice exposed to subchronic ketamine following a 6month period of abstinence from the drug. Ketamine-treated mice showed no change in P20, but did show marked reductions in amplitude of the later N40 and P80 components, consistent with previous studies of acute ketamine exposure. Additionally, ketamine-treated animals showed a significant reduction in stimulus evoked theta oscillations. To assess the functional significance of these changes, mice were also assessed on a series of behavioral and cognitive tests, including progressive ratio (motivation), extinction (behavioral flexibility) and win-shift radial maze (spatial memory). Subchronic ketamine produced marked disruptions in reversal learning and spatial memory. Analysis of brains from ketamine-treated mice failed to show evidence of neuronal degeneration as determined by NueN immunohistochemistry, but did show increased astrocyte proliferation and decreased expression of the glial specific glutamate transporter, GLT-1. These results strongly suggest: 1) that subchronic ketamine induces significant changes in brain function that long exceed exposure to the drug; 2) that ketamine exposure in mice induces lasting cognitive impairments closely resembling those observed in human ketamine abusers; 3) that ERP and EEG measures are highly sensitive to alterations in brain function associated with reduced cognitive function; and 4) that the brain changes induced by chronic ketamine treatment are suggestive of long-term adaptive or plastic, rather than degenerative, changes.
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http://dx.doi.org/10.1016/j.nbd.2012.05.003DOI Listing
September 2012

Nicotine normalizes event related potentials in COMT-Val-tg mice and increases gamma and theta spectral density.

Behav Neurosci 2012 Apr 6;126(2):332-43. Epub 2012 Feb 6.

ranslational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, PA, USA.

Regulation of dopamine neurotransmission is essential for cognitive processes. In humans and rodents, the relationship between dopamine signaling and cognitive performance is described as a dose-dependent, inverted-U curve whereby excess or insufficiency of dopamine in prefrontal cortex has detrimental effects. Previous studies have indicated that prefrontal dopamine levels are associated with genetic variation in catechol-O-methyltransferase (COMT), a regulatory enzyme that controls dopamine availability. Furthermore, smokers who carry the high-activity COMT-Val allele are more prone to cognitive deficits and have an increased risk of smoking relapse. The present study employed transgenic mice expressing the human COMT-Val variant to determine the effects of the high-activity COMT allele on electrophysiological markers, including the P20, N40, and P80 components of the auditory event-related potential, as well as baseline and auditory event-related power and phase-synchrony in theta and gamma ranges. We also examined the effects of nicotine on these measures to investigate the potential effects of smoking on COMT-mediated electrophysiological activity. COMT-Val-tg mice displayed increased N40 latency and decreased P80 amplitude as well as reduced baseline theta and gamma power. Nicotine increased P20 and P80 amplitudes, decreased N40 amplitude, increased P20 and N40 latencies, and reduced P80 latency. Nicotine also increased the event-related power and phase synchrony, yielding an increase in signal-to-noise ratio across theta and gamma ranges. COMT activity specifically alters long-latency components of the event-related response. Nicotine restored normal event-related activity among COMT-Val-tg mice, suggesting one mechanism through which nicotine may normalize cognitive function among people with the high-activity allele.
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http://dx.doi.org/10.1037/a0027047DOI Listing
April 2012

In vitro-in vivo correlations of scalable PLGA-risperidone implants for the treatment of schizophrenia.

Pharm Res 2010 Aug 27;27(8):1730-7. Epub 2010 Apr 27.

Translational Neuroscience Program, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Purpose: Nonadherence to antipsychotic medications is a major obstacle preventing optimal outcomes for patients with schizophrenia. Extended release systems exist in the form of depot injections, but these formulations exhibit several disadvantages. To address these concerns, we previously demonstrated proof of concept for an antipsychotic implant containing risperidone and the biodegradable polymer poly(lactic-co-glycolic) acid (PLGA).

Methods: We build upon recently published data by utilizing a scalable single-screw extrusion system for the production of PLGA-risperidone implants. Implants were composed of 40% risperidone and 60% PLGA, with varying ratios of lactide to glycolide (50:50, 65:35, 75:25 or 85:15). Risperidone release was assessed in vitro and in vivo in rats, and Level A, B and C correlations (IVIVCs) attempted for all. Bioavailability was verified with locomotor testing

Results: Level B analysis yielded the greatest correlation between in vitro and in vivo data (R (2) = 0.9425), while Level C yielded the lowest (R (2) = 0.8336). Although, based on qualitative results, a Level A correlation was not achieved, it did produce an R (2) of 0.9261. Locomotor testing demonstrated that peak serum concentrations coincide with significant reductions in activity.

Conclusion: Data demonstrate the applicability of our modeling system and advance long-term, implantable antipsychotics toward clinical application.
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http://dx.doi.org/10.1007/s11095-010-0152-4DOI Listing
August 2010

A rapid method for creating drug implants: translating laboratory-based methods into a scalable manufacturing process.

J Biomed Mater Res B Appl Biomater 2010 May;93(2):562-72

Stanley Center for Experimental Therapeutics, Department of Psychiatry, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Low compliance with medication is the major cause of poor outcome in schizophrenia treatment. While surgically implantable solvent-cast pellets were produced to improve outcome by increased compliance with medication, this process is laborious and time-consuming, inhibiting its broader application (Siegel et al., Eur J Pharm Biopharm 2006;64:287-293). In this study, the previous fabrication process was translated to a continuous and scalable extrusion method. Extrusion processes were modified based on in vitro release studies, drug load consistency examination, and surface morphology analysis using scanning electron microscopy. Afterward, optimized haloperidol implants were implanted into rats for preliminary analysis of biocompatibility. Barrel temperature, screw speed and resulting processing pressure influenced surface morphology and drug release. Data suggest that fewer surface pores shift the mechanism from bulk to surface PLGA degradation and longer lag period. Results demonstrate that extrusion is a viable process for manufacturing antipsychotic implants.
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http://dx.doi.org/10.1002/jbm.b.31617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049914PMC
May 2010

Isolation of herbicide-resistant 4-hydroxyphenylpyruvate dioxygenase from cultured Coptis japonica cells.

Biosci Biotechnol Biochem 2008 Nov 7;72(11):3059-62. Epub 2008 Nov 7.

State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, PR China.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) catalyzes the formation of homogentisate from 4-hydroxyphenylpyruvate and O(2). In plants, HPPD has been identified as a molecular target for herbicides. We report the isolation and characterization of a cDNA encoding a HPPD from cultured Coptis japonica cells. Recombinant CjHPPD showed significantly higher half-maximum inhibitory concentration (IC(50)) values for the HPPD-inhibiting herbicide destosyl pyrazolate than other plant HPPDs.
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http://dx.doi.org/10.1271/bbb.80466DOI Listing
November 2008

Evaluation of in vitro release and in vivo efficacy of mPEG-PLA-haloperidol conjugate micelle-like structures.

J Biomed Mater Res B Appl Biomater 2007 Nov;83(2):422-30

Department of Chemical and Biological Engineering, Biomaterials and Drug Delivery Laboratory, Drexel University, Philadelphia, Pennsylvania 19104, USA.

Polymeric prodrugs of mPEG-PLA-haloperidol (methoxy poly(ethylene glycol)-b-poly (lactic acid)), self-assemble into nanoscale micelle-like structures in aqueous solutions. The micelles range in size from 28 to 52 nm in diameter and have been shown to be spherical in shape using cryogenic transmission electron microscopy. In this current work there is evidence shown that suggests these micelle-like structures do not dissociate below their critical micelle concentration (CMC) when the PEG weight percent is at least 68, releasing physically entrapped drug from intact micelles over a 3-day period. However, 55 wt % PEG micelles dissociate below their CMC, and release their physically entrapped drug within 8 h. Conjugate polymer micelles most closely approach a linear release profile over a 5-day period. Conjugate micelles with free drug incorporated, known as combination micelle-like structures, release drug over 4 days. However, these combination micelles have the fastest burst release indicating that free drug was potentially dominating the first 8 h of release, after which hydrolysis of covalently linked drug took over. In vivo behavioral studies can assess haloperidol bioactivity from drug loaded micelle-like structures on ketamine induced hyperlocomotion. Results are consistent with in vitro release data, showing that conjugate and combination micelles continue to release haloperidol 4 days post injection, attenuating the effects of the ketamine induced hyperlocomotion. Furthermore, results indicate that the sedative side effects of haloperidol were reduced with the micelle delivery systems as compared to the acute haloperidol injection.
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http://dx.doi.org/10.1002/jbm.b.30812DOI Listing
November 2007

Pharmacokinetic and behavioral characterization of a long-term antipsychotic delivery system in rodents and rabbits.

Psychopharmacology (Berl) 2007 Feb 21;190(2):201-11. Epub 2006 Nov 21.

Stanley Center for Experimental Therapeutics in Psychiatry, Translational Research Laboratories, University of Pennsylvania, Philadelphia, PA 19104, USA.

Rationale: Non-adherence with medication remains the major correctable cause of poor outcome in schizophrenia. However, few treatments have addressed this major determinant of outcome with novel long-term delivery systems.

Objectives: The aim of this study was to provide biological proof of concept for a long-term implantable antipsychotic delivery system in rodents and rabbits.

Materials And Methods: Implantable formulations of haloperidol were created using biodegradable polymers. Implants were characterized for in vitro release and in vivo behavior using prepulse inhibition of startle in rats and mice, as well as pharmacokinetics in rabbits.

Results: Behavioral measures demonstrate the effectiveness of haloperidol implants delivering 1 mg/kg in mice and 0.6 mg/kg in rats to block amphetamine (10 mg/kg) in mice or apomorphine (0.5 mg/kg) in rats. Additionally, we demonstrate the pattern of release from single polymer implants for 1 year in rabbits.

Conclusions: The current study suggests that implantable formulations are a viable approach to providing long-term delivery of antipsychotic medications in vivo using animal models of behavior and pharmacokinetics. In contrast to depot formulations, implantable formulations could last 6 months or longer. Additionally, implants can be removed throughout the delivery interval, offering a degree of reversibility not available with depot formulations.
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http://dx.doi.org/10.1007/s00213-006-0616-8DOI Listing
February 2007

Effects of nicotine vary across two auditory evoked potentials in the mouse.

Biol Psychiatry 2007 Jan 21;61(1):23-30. Epub 2006 Feb 21.

Stanley Center for Experimental Therapeutics in Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Background: Schizophrenia patients display sensory processing deficits, reduced alpha7-nicotine receptor expression, and increased incidence of smoking, prompting investigation of nicotine receptor agonists as possible treatments. We evaluated the effects of acute and chronic nicotine, using an animal model that incorporates genetic variation for sensory processing and nicotine sensitivity.

Methods: C57BL/6J and DBA/2Hsd mice received 2 weeks of 4.2 mg/kg chronic nicotine or saline. Auditory evoked potentials were recorded before and after acute nicotine injection of 1.05 mg/kg on day 14, with a paired-click paradigm (S1/S2). Amplitude and gating of the P20 and N40 were compared between conditions.

Results: Acute nicotine increased the amplitude and gating of the P20 and decreased the amplitude and gating of the N40 across all groups, primarily by acting on S1. Chronic nicotine attenuated the effects of acute nicotine on the N40.

Conclusions: Our data support the notion that the mouse P20 shares pharmacological response properties with the human P50. In addition, findings suggest that nicotine might increase the initial sensory response (S1), with a resulting improvement in gating of some components.
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http://dx.doi.org/10.1016/j.biopsych.2005.12.011DOI Listing
January 2007
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