Publications by authors named "Xiumei Huang"

30 Publications

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PCNA inhibition enhances the cytotoxicity of β-lapachone in NQO1-Positive cancer cells by augmentation of oxidative stress-induced DNA damage.

Cancer Lett 2021 Oct 27;519:304-314. Epub 2021 Jul 27.

Department of Radiation Oncology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. Electronic address:

β-Lapachone is a classic quinone-containing antitumor NQO1-bioactivatable drug that directly kills NQO1-overexpressing cancer cells. However, the clinical applications of β-lapachone are primarily limited by its high toxicity and modest lethality. To overcome this side effect and expand the therapeutic utility of β-lapachone, we demonstrate the effects of a novel combination therapy including β-lapachone and the proliferating cell nuclear antigen (PCNA) inhibitor T2 amino alcohol (T2AA) on various NQO1 cancer cells. PCNA has DNA clamp processivity activity mediated by encircling double-stranded DNA to recruit proteins involved in DNA replication and DNA repair. In this study, we found that compared to monotherapy, a nontoxic dose of the T2AA synergized with a sublethal dose of β-lapachone in an NQO1-dependent manner and that combination therapy prevented DNA repair, increased double-strand break (DSB) formation and promoted programmed necrosis and G1 phase cell cycle arrest. We further determined that combination therapy enhanced antitumor efficacy and prolonged survival in Lewis lung carcinoma (LLC) xenografts model. Our findings show novel evidence for a new therapeutic approach that combines of β-lapachone treatment with PCNA inhibition that is highly effective in treating NQO1 solid tumor cells.
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http://dx.doi.org/10.1016/j.canlet.2021.07.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403654PMC
October 2021

A Hybrid Visual Tracking Algorithm Based on SOM Network and Correlation Filter.

Sensors (Basel) 2021 Apr 19;21(8). Epub 2021 Apr 19.

College of Computer & Information Science, Southwest University, Chongqing 400715, China.

To meet the challenge of video target tracking, based on a self-organization mapping network (SOM) and correlation filter, a long-term visual tracking algorithm is proposed. Objects in different videos or images often have completely different appearance, therefore, the self-organization mapping neural network with the characteristics of signal processing mechanism of human brain neurons is used to perform adaptive and unsupervised features learning. A reliable method of robust target tracking is proposed, based on multiple adaptive correlation filters with a memory function of target appearance at the same time. Filters in our method have different updating strategies and can carry out long-term tracking cooperatively. The first is the displacement filter, a kernelized correlation filter that combines contextual characteristics to precisely locate and track targets. Secondly, the scale filters are used to predict the changing scale of a target. Finally, the memory filter is used to maintain the appearance of the target in long-term memory and judge whether the target has failed to track. If the tracking fails, the incremental learning detector is used to recover the target tracking in the way of sliding window. Several experiments show that our method can effectively solve the tracking problems such as severe occlusion, target loss and scale change, and is superior to the state-of-the-art methods in the aspects of efficiency, accuracy and robustness.
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http://dx.doi.org/10.3390/s21082864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072667PMC
April 2021

Efficacy and Safety of Mulberry Twig Alkaloids Tablet for the Treatment of Type 2 Diabetes: A Multicenter, Randomized, Double-Blind, Double-Dummy, and Parallel Controlled Clinical Trial.

Diabetes Care 2021 Apr 8. Epub 2021 Apr 8.

Department of Endocrinology, West China Hospital, Sichuan University, Sichuan, China.

Objective: This study aimed to evaluate the efficacy and safety of mulberry twig alkaloids (Sangzhi alkaloids [SZ-A]) in the treatment of type 2 diabetes (T2D).

Research Design And Methods: This was a multicenter, randomized, double-blind, double-dummy, and parallel controlled noninferiority clinical trial that was conducted for 24 weeks. A total of 600 patients were randomly allocated to the SZ-A group ( 360) or acarbose group ( 240). The primary efficacy end point was the change of glycosylated hemoglobin (HbA) compared with baseline. In addition, adverse events (AEs), severe AEs (SAEs), treatment-related AEs (TAEs), and gastrointestinal disorders (GDs) were monitored.

Results: After treatment for 24 weeks, the change in HbA was -0.93% (95% CI -1.03 to -0.83) (-10.2 mmol/mol [-11.3 to -9.1]) and -0.87% (-0.99 to -0.76) (-9.5 mmol/mol [-10.8 to -8.3]) in the SZ-A and acarbose groups, respectively, and the least squares mean difference was -0.05% (95% CI -0.18 to 0.07) (-0.5 mmol/mol [-2.0 to 0.8]) between the two groups, with no significant difference on the basis of covariance analysis ( > 0.05). The incidence of TAEs and GDs was significantly lower in the SZ-A group than the acarbose group ( < 0.01), but no differences for AEs or SAEs between the two groups were observed ( > 0.05).

Conclusions: SZ-A exhibited equivalent hypoglycemic effects to acarbose in patients with T2D. Nevertheless, the incidence of TAEs and GDs was lower following SZ-A treatment than acarbose treatment, suggesting good safety.
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http://dx.doi.org/10.2337/dc20-2109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247493PMC
April 2021

Changes in antibiotic resistance of Escherichia coli during the broiler feeding cycle.

Poult Sci 2020 Dec 1;99(12):6983-6989. Epub 2020 Aug 1.

Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control, College of Animal Science and Technology, Anhui Agricultural University, Hefei, Anhui, China.

The purpose of this study was to investigate the drug-resistant phenotypes and genes of Escherichia coli in animal, environmental, and human samples before and after antibiotic use at a large-scale broiler farm to understand the respective effects on E. coli resistance during the broiler feeding cycle. The antibiotic use per broiler house was 143.04 to 183.50 mg/kg, and included tilmicosin, florfenicol, apramycin, and neomycin. All strains isolated on the first day the broilers arrived (T1; day 1) were antibiotic-resistant bacteria. E. coli strains isolated from animal samples were resistant to ampicillin, tetracycline, and sulfamethoxazole (100%), and those isolated from environmental samples were resistant to 5 different drugs (74.07%, 20 of 27). E. coli strains isolated on the last day before the broilers left (T2; day 47) had a higher resistance rate to florfenicol (100%, 36 of 36) than at T1 (P < 0.05). Multidrug resistance increased from T1 (84.21%, 32 of 38) to T2 (97.22%, 35 of 36). Most strains were resistant to 5 classes of antibiotics, and 2 strains were resistant to 6 classes of antibiotics. Among 13 identified drug resistance genes, 11 and 13 were detected at T1 and T2, respectively. NDM-1 was detected in 4 environmental samples and 1 animal sample. In conclusion, the use of antibiotics during breeding increases E. coli resistance to antibacterial drugs. Drug-resistant bacteria in animals and the environment proliferate during the feeding cycle, leading to the widespread distribution of drug resistance genes and an increase in the overall resistance of bacteria.
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http://dx.doi.org/10.1016/j.psj.2020.06.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704736PMC
December 2020

Targeting Base Excision Repair in Cancer: NQO1-Bioactivatable Drugs Improve Tumor Selectivity and Reduce Treatment Toxicity Through Radiosensitization of Human Cancer.

Front Oncol 2020 19;10:1575. Epub 2020 Aug 19.

Department of Biochemistry and Molecular Biology, IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States.

Ionizing radiation (IR) creates lethal DNA damage that can effectively kill tumor cells. However, the high dose required for a therapeutic outcome also damages healthy tissue. Thus, a therapeutic strategy with predictive biomarkers to enhance the beneficial effects of IR allowing a dose reduction without losing efficacy is highly desirable. NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in the majority of recalcitrant solid tumors in comparison with normal tissue. Studies have shown that NQO1 can bioactivate certain quinone molecules (e.g., ortho-naphthoquinone and β-lapachone) to induce a futile redox cycle leading to the formation of oxidative DNA damage, hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1), and catastrophic depletion of NAD and ATP, which culminates in cellular lethality via NAD-Keresis. However, NQO1-bioactivatable drugs induce methemoglobinemia and hemolytic anemia at high doses. To circumvent this, NQO1-bioactivatable agents have been shown to synergize with PARP1 inhibitors, pyrimidine radiosensitizers, and IR. This therapeutic strategy allows for a reduction in the dose of the combined agents to decrease unwanted side effects by increasing tumor selectivity. In this review, we discuss the mechanisms of radiosensitization between NQO1-bioactivatable drugs and IR with a focus on the involvement of base excision repair (BER). This combination therapeutic strategy presents a unique tumor-selective and minimally toxic approach for targeting solid tumors that overexpress NQO1.
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http://dx.doi.org/10.3389/fonc.2020.01575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468503PMC
August 2020

Risk Prevention and Control Points Through Quantitative Evaluation of in a Large Broiler Slaughterhouse.

Front Vet Sci 2020 22;7:172. Epub 2020 Apr 22.

Department of Pathogenic Microorganisms, China Animal Health and Epidemiology Center, Qingdao, China.

Chickens contaminated with are a major risk factor for human disease. As a result of the slaughter process, infections should be strictly controlled due to complete exposure of the chickens and the cross-contamination of pathogens. Using @RISK software, quantitative evaluation models of contamination during slaughtering in a large broiler slaughterhouse were constructed. Broiler scalding was set as the starting point of evaluation and four major processes including defeathering, eviscerating, pre-cool rinsing, and splitting-transmission were included. Through the simulation of the constructed model, 90% probability of in 100 g chickens after slaughtering were distributed between 0.3 and 50.2 MPN, which was consistent with simulated actual monitoring data 0-16.6 MPN, indicating that the model shows high credibility. In addition, growth curves of during whole slaughtering showed that contamination significantly increased after defeathering, and increased again after pre-cool rinsing. Using correlation coefficients to analyze the sensitivity of each parameter in the model, it was determined that the concentration of in the pre-cool pond water (correlation coefficient: 0.95) was the most critical risk point of sanitary control in this slaughterhouse. In conclusion, this study is the first to incorporate environmental factors during broiler slaughtering into the risk evaluation of contamination, which provides guidance for the sanitary control and risk management of contamination during broiler slaughtering.
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http://dx.doi.org/10.3389/fvets.2020.00172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188754PMC
April 2020

NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance.

Nat Commun 2019 07 19;10(1):3251. Epub 2019 Jul 19.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA.

Lack of proper innate sensing inside tumor microenvironment (TME) limits T cell-targeted immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly enriched in multiple tumor types and has emerged as a promising target for direct tumor-killing. Here, we demonstrate that NQO1-targeting prodrug β-lapachone triggers tumor-selective innate sensing leading to T cell-dependent tumor control. β-Lapachone is catalyzed and bioactivated by NQO1 to generate ROS in NQO1 tumor cells triggering oxidative stress and release of the damage signals for innate sensing. β-Lapachone-induced high mobility group box 1 (HMGB1) release activates the host TLR4/MyD88/type I interferon pathway and Batf3 dendritic cell-dependent cross-priming to bridge innate and adaptive immune responses against the tumor. Furthermore, targeting NQO1 is very potent to trigger innate sensing for T cell re-activation to overcome checkpoint blockade resistance in well-established tumors. Our study reveals that targeting NQO1 potently triggers innate sensing within TME that synergizes with immunotherapy to overcome adaptive resistance.
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http://dx.doi.org/10.1038/s41467-019-11238-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642086PMC
July 2019

NQO1-dependent, Tumor-selective Radiosensitization of Non-small Cell Lung Cancers.

Clin Cancer Res 2019 04 7;25(8):2601-2609. Epub 2019 Jan 7.

Department of Biochemistry and Molecular Biology, Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana.

Purpose: Development of tumor-specific therapies for the treatment of recalcitrant non-small cell lung cancers (NSCLC) is urgently needed. Here, we investigated the ability of β-lapachone (β-lap, ARQ761 in clinical form) to selectively potentiate the effects of ionizing radiation (IR, 1-3 Gy) in NSCLCs that overexpress NAD(P)H:Quinone Oxidoreductase 1 (NQO1).

Experimental Design: The mechanism of lethality of low-dose IR in combination with sublethal doses of β-lap was evaluated in NSCLC lines and validated in subcutaneous and orthotopic xenograft models . Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus cotreatments were performed to validate therapeutic efficacy and mechanism of action.

Results: β-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD/ATP levels, and increased double-strand break (DSB) lesions over time . Radiosensitization of orthotopic, as well as subcutaneous, NSCLCs occurred with high apparent cures (>70%), even though 1/8 β-lap doses reach subcutaneous versus orthotopic tumors. No methemoglobinemia or long-term toxicities were noted in any normal tissues, including mouse liver that expresses the highest level of NQO1 (∼12 units) of any normal tissue. PK/PD responses confirm that IR + β-lap treatments hyperactivate PARP activity, greatly lower NAD/ATP levels, and dramatically inhibit DSB repair in exposed NQO1 cancer tissue, whereas low NQO1 levels and high levels of catalase in associated normal tissue were protective.

Conclusions: Our data suggest that combination of sublethal doses of β-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + β-lap against patients with NQO1 NSCLCs.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788754PMC
April 2019

Modulators of Redox Metabolism in Head and Neck Cancer.

Antioxid Redox Signal 2018 12 20;29(16):1660-1690. Epub 2017 Dec 20.

1 Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine , Winston-Salem, North Carolina.

Significance: Head and neck squamous cell cancer (HNSCC) is a complex disease characterized by high genetic and metabolic heterogeneity. Radiation therapy (RT) alone or combined with systemic chemotherapy is widely used for treatment of HNSCC as definitive treatment or as adjuvant treatment after surgery. Antibodies against epidermal growth factor receptor are used in definitive or palliative treatment. Recent Advances: Emerging targeted therapies against other proteins of interest as well as programmed cell death protein 1 and programmed death-ligand 1 immunotherapies are being explored in clinical trials.

Critical Issues: The disease heterogeneity, invasiveness, and resistance to standard of care RT or chemoradiation therapy continue to constitute significant roadblocks for treatment and patients' quality of life (QOL) despite improvements in treatment modality and the emergence of new therapies over the past two decades.

Future Directions: As reviewed here, alterations in redox metabolism occur at all stages of HNSCC management, providing opportunities for improved prevention, early detection, response to therapies, and QOL. Bioinformatics and computational systems biology approaches are key to integrate redox effects with multiomics data from cells and clinical specimens and to identify redox modifiers or modifiable target proteins to achieve improved clinical outcomes. Antioxid. Redox Signal.
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http://dx.doi.org/10.1089/ars.2017.7423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207163PMC
December 2018

Using a novel NQO1 bioactivatable drug, beta-lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer.

J Surg Oncol 2017 Jul 27;116(1):83-88. Epub 2017 Mar 27.

Harold Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor versus associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H O ) levels; normal tissues are spared by low NQO1 and high catalase expression. DNA damage created by ARQ761 in pancreatic cancer cells "hyperactivates" PARP1, causing metabolic catastrophe and NAD ± keresis cell death. NQO1: catalase levels (high in tumor, low in normal tissue) are an attractive therapeutic window to treat pancreatic cancer. Based on a growing body of literature, we are leading a clinical trial to evaluate the combination of ARQ761 and chemotherapy in patients with pancreatic cancer.
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http://dx.doi.org/10.1002/jso.24624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509448PMC
July 2017

Isolation, Identification, and Characterization of Foodborne Pathogens Isolated from Egg Internal Contents in China.

J Food Prot 2016 12;79(12):2107-2112

Laboratory of Quality and Safety Risk Assessment for Animal Products of Ministry of Agriculture, China Animal Health and Epidemiology Center, Qingdao, Shandong 266032, People's Republic of China.

Eggs continue to be significant in terms of the world economy and human nutrition. The aim of this study was to estimate the prevalence of foodborne pathogens in a cross section of egg production types in China and to examine the virulence features of the isolated pathogens. Three hundred eggs from three provinces were tested for Salmonella , Escherichia coli , Staphylococcus aureus , and Campylobacter . Two eggs were positive for Salmonella , one was positive for both E. coli and S. aureus , and none were positive for Campylobacter . When comparing different egg laying systems, there were no significant differences in findings between packaged and unpackaged eggs and between battery cage and cage-free eggs, but there were significant differences in the findings among pathogens and among provinces. Other potential foodborne pathogens were identified in addition to the targeted pathogens. The virulence of Serratia marcescens was higher than that of the isolated Salmonella Typhimurium, and the virulence of Staphylococcus saprophyticus was comparable to that of the isolated S. aureus . These findings are important for local risk assessments concerning possible human foodborne infections via cross-contamination of eggs.
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http://dx.doi.org/10.4315/0362-028X.JFP-16-168DOI Listing
December 2016

Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors.

Cancer Cell 2016 Dec;30(6):940-952

Departments of Pharmacology and Radiation Oncology, Simmons Comprehensive Cancer Center (SCCC), UT Southwestern Medical Center (UTSW), Dallas, TX 75390, USA. Electronic address:

Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1 cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.
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http://dx.doi.org/10.1016/j.ccell.2016.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161231PMC
December 2016

RPS23RG1 reduces Aβ oligomer-induced synaptic and cognitive deficits.

Sci Rep 2016 Jan 6;6:18668. Epub 2016 Jan 6.

Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is generally believed that β-amyloidogenesis, tau-hyperphosphorylation, and synaptic loss underlie cognitive decline in AD. Rps23rg1, a functional retroposed mouse gene, has been shown to reduce Alzheimer's β-amyloid (Aβ) production and tau phosphorylation. In this study, we have identified its human homolog, and demonstrated that RPS23RG1 regulates synaptic plasticity, thus counteracting Aβ oligomer (oAβ)-induced cognitive deficits in mice. The level of RPS23RG1 mRNA is significantly lower in the brains of AD compared to non-AD patients, suggesting its potential role in the pathogenesis of the disease. Similar to its mouse counterpart, human RPS23RG1 interacts with adenylate cyclase, activating PKA/CREB, and inhibiting GSK-3. Furthermore, we show that human RPS23RG1 promotes synaptic plasticity and offsets oAβ-induced synaptic loss in a PKA-dependent manner in cultured primary neurons. Overexpression of Rps23rg1 in transgenic mice consistently prevented oAβ-induced PKA inactivation, synaptic deficits, suppression of long-term potentiation, and cognitive impairment as compared to wild type littermates. Our study demonstrates that RPS23RG1 may reduce the occurrence of key elements of AD pathology and enhance synaptic functions to counteract oAβ-induced synaptic and cognitive deficits in AD.
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http://dx.doi.org/10.1038/srep18668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702092PMC
January 2016

Nanotechnology-enabled delivery of NQO1 bioactivatable drugs.

J Drug Target 2015 ;23(7-8):672-80

a Department of Pharmacology , Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center , Dallas , TX , USA.

Unlabelled: Current cancer chemotherapy lacks specificity and is limited by undesirable toxic side-effects, as well as a high rate of recurrence. Nanotechnology has the potential to offer paradigm-shifting solutions to improve the outcome of cancer diagnosis and therapy. β-Lapachone (β-lap) is a novel anticancer agent whose mechanism of action is highly dependent on

Nad(p)h: quinone oxidoreductase 1 (NQO1), a phase II detoxifying enzyme overexpressed in solid tumors from a variety of cancer types. However, the poor water solubility of β-lap limits its clinical potential. A series of drug formulations were developed for systemic administration in preclinical evaluations. Encapsulation of β-lap into polymeric micelles showed less side-effects and higher maximum tolerated dose (MTD), prolonged blood circulation time and preferential accumulation in tumors with greatly improved safety and antitumor efficacy. The prodrug strategy of β-lap further decreases the crystallization of β-lap by introducing esterase degradable side chains to the rigid fused ring structure. β-Lap prodrugs considerably increased the stability, drug-loading content and delivery efficiency of nanoparticles. The optimized formulation of β-lap-dC3 prodrug micelles showed excellent antitumor efficacy in treating orthotopic non-small cell lung tumors that overexpress NQO1, with target validation using pharmacodynamic endpoints.
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http://dx.doi.org/10.3109/1061186X.2015.1073296DOI Listing
July 2016

Molecular classification and drug resistance analysis of Escherichia coli isolated from poultry in China.

Int J Clin Exp Med 2015 15;8(1):836-44. Epub 2015 Jan 15.

Laboratory of Quality and Safety Risk Assessment for Animal Products of Ministry of Agriculture, China Animal Health and Epidemiology Center Qingdao, Shandong, China.

We aimed to understand the distribution of Escherichia coli in poultry and to reveal the virulence factors, the drug resistance and molecular epidemic regularity and characteristics of isolate strains from 6 provinces in China and to complete the characteristics of E. coli for the risk assessment. A total of 87 E. coli isolates were analyzed with 7 virulence genes by PCR drug sensitivity test in 13 kinds of antimicrobial agents and analyzed with PFGE and MLST genotyping. The PFGE genotyping of 87 isolates yielded 75 PFGE type. MLST analysis of isolates identified the 39 STs, the 7 housekeeping genes had the different variation. The most prevalent virulence genes were iucD (74.7%), followed by iss (55.2%), Irp2 (43.7%), tsh (28.7%), cva (19.5%), papC (9.2%) and vat (8.1%). All isolates were resistant to two or three antimicrobial agents highly resistant to SXT, TE (85.06%), SF (83.91%), AM (66. 67%), to fluoroquinolones (ENR, 63.22%, NOR, 50.57%) and to GM (57.47%). E. coli strains resistant spectrum was wide gene was polymorphism the distribution had a certain timeliness and regional in part region of China. These were a solid foundation for the epidemiological investigation and traceability laid.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358519PMC
March 2015

Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy.

J Control Release 2015 Feb 24;200:201-11. Epub 2014 Dec 24.

Department of Pharmacology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA. Electronic address:

Unlabelled: Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, β-lapachone (β-lap) was shown to be highly efficacious in killing non-small cell lung cancer (NSCLC) cells regardless of their p53, cell cycle and caspase status. Pre-clinical and clinical use of β-lap (clinical form, ARQ501 or 761) is hampered by poor pharmacokinetics and toxicity due to hemolytic anemia. Here, we report the development and preclinical evaluation of β-lap prodrug nanotherapeutics consisting of diester derivatives of β-lap encapsulated in biocompatible and biodegradable poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-b-PLA) micelles. Compared to the parent drug, diester derivatives of β-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered β-lap-dC3 and -dC6 prodrugs were converted to β-lap. Cytotoxicity assays using A549 and H596 lung cancer cells showed that both micelle formulations maintained

Nad(p)h: quinone oxidoreductase 1 (NQO1)-dependent cytotoxicity. However, antitumor efficacy study of β-lap-dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over β-lap-dC6 micelles or β-lap-HPβCD complexes. Improved therapeutic efficacy of β-lap-dC3 micelles correlated with higher area under the concentration-time curves of β-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γH2AX, and ATP depletion). β-Lap-dC3 prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy.
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http://dx.doi.org/10.1016/j.jconrel.2014.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803448PMC
February 2015

Studies on the anti-inflammatory effect and its mechanisms of sophoridine.

J Anal Methods Chem 2014 9;2014:502626. Epub 2014 Apr 9.

National Institutes for Food and Drug Control, Beijing 100050, China.

This work is to study the anti-inflammatory effect and its mechanisms of sophoridine in vitro and in vivo. For this aim, the influences of sophoridine on several inflammatory mediators were investigated. Excessive inflammatory response in vitro model was developed by using lipopolysaccharide (LPS) to stimulate the mouse peritoneal macrophages and HL-60 cells to produce IL-6 and IL-8. Carrageenin-induced mouse paw edema model was used as inflammatory response in vivo model. MTT method, ultraviolet spectrophotometric method, and radioimmunoassay were used to measure the changes of TNF α , IL-6, PGE2, and IL-8 in in vitro cell culture supernatant or in the local inflammatory exudates. The results showed that sophoridine inhibited the production of IL-8 in in vitro cell culture supernatant and inhibited the production of TNF α , PGE2, and IL-8 in the local inflammatory exudates but had no significant effects on the production of IL-6 in vitro and in vivo. It is demonstrated that sophoridine's anti-inflammatory effect was due to its ability to inhibit the production of cytokine and inflammatory mediators.
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http://dx.doi.org/10.1155/2014/502626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000653PMC
May 2014

Prodrug strategy to achieve lyophilizable, high drug loading micelle formulations through diester derivatives of β-Lapachone.

Adv Healthc Mater 2014 Aug 14;3(8):1210-6. Epub 2014 Feb 14.

Departments of Pharmacology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX, 75390-8807, USA.

β-Lap prodrug micelle strategy improves the formulation properties of β-lap therapeutics. The resulting micelles yield apparent high β-lap solubility (>7 mg mL(-1) ), physical stability, and ability to reconstitute after lyophilization. In the presence of esterase, β-lap prodrugs are efficiently converted into parent drug (i.e., β-lap), resulting in NQO1-dependent lethality of NSCLC cells.
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http://dx.doi.org/10.1002/adhm.201300590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133338PMC
August 2014

Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration.

J Neurosci 2012 Oct;32(44):15565-76

Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research and Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China.

Apoptosis is an essential cellular process in multiple diseases and a major pathway for neuronal death in neurodegeneration. The detailed signaling events/pathways leading to apoptosis, especially in neurons, require further elucidation. Here we identify a β-amyloid precursor protein (APP)-interacting protein, designated as appoptosin, whose levels are upregulated in brain samples from Alzheimer's disease and infarct patients, and in rodent stroke models, as well as in neurons treated with β-amyloid (Aβ) and glutamate. We further demonstrate that appoptosin induces reactive oxygen species release and intrinsic caspase-dependent apoptosis. The physiological function of appoptosin is to transport/exchange glycine/5-amino-levulinic acid across the mitochondrial membrane for heme synthesis. Downregulation of appoptosin prevents cell death and caspase activation caused by glutamate or Aβ insults. APP modulates appoptosin-mediated apoptosis through interaction with appoptosin. Our study identifies appoptosin as a crucial player in apoptosis and a novel pro-apoptotic protein involved in neuronal cell death, providing a possible new therapeutic target for neurodegenerative disorders.
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http://dx.doi.org/10.1523/JNEUROSCI.3668-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509748PMC
October 2012

Alzheimer's β-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of β-amyloid.

J Neurosci 2012 Aug;32(33):11390-5

Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China.

β-Amyloid protein (Aβ), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from proteolytic cleavages of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. BACE1 is the rate-limiting enzyme for Aβ production, and an increase in BACE1 level/activity contributes to the pathogenesis of sporadic AD. In addition to cleaving APP for Aβ generation, BACE1 plays multiple physiological roles including the regulation of synaptic functions. Here, we found that overexpression of BACE1 reduces cAMP response element binding protein (CREB) phosphorylation, protein kinase A (PKA) activity, and cAMP levels, whereas downregulation of BACE1 has the opposite effect. We showed that BACE1's effect is independent of its activity for Aβ production, which is corroborated by the observation that BACE1 transgenic mice have impaired learning/memory in the absence of neurotoxic human Aβ. Furthermore, we demonstrated that BACE1 interacts via its transmembrane domain with adenylate cyclase, resulting in reduction of cellular cAMP levels and thus PKA inactivation and reduced CREB phosphorylation. Our study suggests that in addition to its function as the β-secretase to produce Aβ, BACE1 may contribute to the memory and cognitive deficits typical of AD by regulating the cAMP/PKA/CREB pathway, which is important for memory functions.
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http://dx.doi.org/10.1523/JNEUROSCI.0757-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446780PMC
August 2012

An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis.

Cancer Res 2012 Jun 24;72(12):3038-47. Epub 2012 Apr 24.

Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.

Agents, such as β-lapachone, that target the redox enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), to induce programmed necrosis in solid tumors have shown great promise, but more potent tumor-selective compounds are needed. Here, we report that deoxynyboquinone kills a wide spectrum of cancer cells in an NQO1-dependent manner with greater potency than β-lapachone. Deoxynyboquinone lethality relies on NQO1-dependent futile redox cycling that consumes oxygen and generates extensive reactive oxygen species (ROS). Elevated ROS levels cause extensive DNA lesions, PARP1 hyperactivation, and severe NAD+ /ATP depletion that stimulate Ca2+ -dependent programmed necrosis, unique to this new class of NQO1 "bioactivated" drugs. Short-term exposure of NQO1+ cells to deoxynyboquinone was sufficient to trigger cell death, although genetically matched NQO1- cells were unaffected. Moreover, siRNA-mediated NQO1 or PARP1 knockdown spared NQO1+ cells from short-term lethality. Pretreatment of cells with BAPTA-AM (a cytosolic Ca2+ chelator) or catalase (enzymatic H2O2 scavenger) was sufficient to rescue deoxynyboquinone-induced lethality, as noted with β-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to β-lapachone, but at a 6-fold greater potency. PARP1 hyperactivation and dramatic ATP loss were noted in the tumor, but not in the associated normal lung tissue. Our findings offer preclinical proof-of-concept for deoxynyboquinone as a potent chemotherapeutic agent for treatment of a wide spectrum of therapeutically challenging solid tumors, such as pancreatic and lung cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-3135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795165PMC
June 2012

Salubrinal attenuates β-amyloid-induced neuronal death and microglial activation by inhibition of the NF-κB pathway.

Neurobiol Aging 2012 May 5;33(5):1007.e9-17. Epub 2011 Nov 5.

Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, College of Medicine, Xiamen University, Xiamen, Fujian, China.

Alzheimer's disease (AD) is characterized by the deposition of β-amyloid (Aβ) peptides in the brain, inducing neuronal cell death and microglial activation. Endoplasmic reticulum (ER) stress has been proposed to be a mediator of Aβ neurotoxicity. In this study, we test whether salubrinal, an ER stress inhibitor, can protect against Aβ-mediated neurotoxicity. We show in rat primary cortical neurons and mouse microglial BV-2 cells that short-term treatment with salubrinal attenuates Aβ-induced neuronal death and microglial activation. Remarkably, our results show that salubrinal's neuroprotective effects are not due to inhibition of ER stress. Rather, we demonstrate that salubrinal exerts its effects through the inhibition of IκB kinase (IKK) activation, IκB degradation, and the subsequent nuclear factor-kappa B (NF-κB) activation. These results elucidate inhibition of the NF-κB pathway as a new mechanism responsible for the protective effects of salubrinal against Aβ neurotoxicity. This study also suggests that modulation of Aβ-induced NF-κB activation could be a potential therapeutic strategy for Alzheimer's disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2011.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3294262PMC
May 2012

[Recycle of spent cells from anaerobic succinate fermentation].

Sheng Wu Gong Cheng Xue Bao 2010 Sep;26(9):1276-80

State Key Laboratory of Materials-Oriented Chemical Engineering, College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing 210009, China.

Spent cells recovered from anaerobic fermentation by Actinobacillus succinogenes were used as nitrogen source for succinic acid production. Three methods were investigated for cell wall-breaking. The results showed that enzymatic hydrolysis was more effective for higher succinic acid yield. When the enzymatic hydrolysate of spent cells was added to reach a total nitrogen concentration 1.11 g/L (equivalent to 10 g/L yeast extract), the succinic acid concentration was 42.0 g/L, but it increased slightly when enhancing the level of enzymatic hydrolysate. However, when 5 g/L yeast extract was supplemented with the enzymatic hydrolysate of spent cells, the succinic acid concentration reached 75.5 g/L after 36 hours and, the succinic acid productivity was 2.10 g/(L x h), which increased by 66.7% compared with the fermentation using 10 g/L yeast extract. Therefore, enzymatic hydrolysate of spent cells could replace 50% yeast extract in the original medium for succinic acid production.
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September 2010

[Effect of adding intermediate metabolites on succinate production by Actinobacillus succinogenes].

Sheng Wu Gong Cheng Xue Bao 2010 Sep;26(9):1249-56

State Key Laboratory of Materials-oriented Chemical Engineering, College of Life Science and Pharmacy, Nanjing University of Technology, Nanjing 210009, China.

We investigated the effect of adding intermediate metabolites on cell growth and succinate production. The yield of succinic acid achieved to the highest when 0.5 g/L phosphoenolpyruvic acid (PEP) was added. According to the metabolic network of Actinobaccilus succinogenes NJ113, the metabolic flux was calculated by metabolic flux analysis. The ratio of hexose monophosphate pathway to glycolytic pathway increased from 39.4:60.3 to 76.8:22.6 after adding 0.5 g/L PEP, thus the reducing power was better balanced. The flux of PEP to oxaloacetate was 23.8% higher, which made the succinic acid flux improve from 99.8 mmol/(g DCW x h) to 124.4 mmol/(g DCW x h) and the flux of acetic acid and formic acid decreased by 22.9% and 15.4%, respectively. The key enzyme activity analysis showed that the specific activity of PEP carboxykinase reached to 1910 U/mg with 0.5 g/L PEP addition, which was 74.7% higher than the control; and the specific activity of pyruvate kinase decreased by 67.5%. Finally, the concentration of succinic acid was 29.1 g/L with the yield of 76.2%.
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September 2010

[Measurement and analysis of phased-array focused ultrasound field of two-foci pattern].

Zhongguo Yi Liao Qi Xie Za Zhi 2010 May;34(3):172-4

Biomedical Instrument Institute of Shanghai Jiao Tong University. Shanghai, 200030.

This paper introduces the simulation and measurement results of the phased-array focused ultrasound field of two-foci pattern.
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May 2010

The Rps23rg gene family originated through retroposition of the ribosomal protein s23 mRNA and encodes proteins that decrease Alzheimer's beta-amyloid level and tau phosphorylation.

Hum Mol Genet 2010 Oct 22;19(19):3835-43. Epub 2010 Jul 22.

Institute for Biomedical Research and Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Xiamen University, Xiamen 361005, China.

Retroposition is an important mechanism for gene origination. However, studies to elucidate the functions of new genes originated through retroposition, especially the functions related to diseases, are limited. We recently identified a mouse gene, Rps23 retroposed gene 1 (Rps23rg1), that regulates beta-amyloid (Abeta) level and tau phosphorylation, two major pathological hallmarks of Alzheimer's disease (AD), and found that Rps23rg1 originated through retroposition of the mouse ribosomal protein S23 (Rps23) mRNA. Here we show that retroposition of Rps23 mRNA occurred multiple times in different species but only generated another functionally expressed Rps23rg1-homologous gene, Rps23rg2, in mice, whereas humans may not possess functional Rps23rg homologs. Both Rps23rg1 and Rps23rg2 are reversely transcribed relative to the parental Rps23 gene, expressed in various tissues and encode proteins that interact with adenylate cyclases. Similar to the RPS23RG1 protein, RPS23RG2 can upregulate protein kinase A activity to reduce the activity of glycogen synthase kinase-3, Abeta level and tau phosphorylation. However, the effects of RPS23RG2 are weaker than those of RPS23RG1 and such a difference could be attributed to the extra carboxyl-terminal region of RPS23RG2, which may have an inhibitory effect. In addition, we show that the transmembrane domain of RPS23RG1 is important for its function. Together, our results present a new gene family, whose products and associated signaling pathways might prevent mice from developing AD-like pathologies.
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http://dx.doi.org/10.1093/hmg/ddq302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935860PMC
October 2010

A protease-based strategy for the controlled release of therapeutic peptides.

Angew Chem Int Ed Engl 2010 Jul;49(29):4930-3

Department of Biotechnology, Jinan University, Guangzhou, Guangdong 510632, China.

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http://dx.doi.org/10.1002/anie.201000287DOI Listing
July 2010

[Breeding of ammonium-tolerant mutants of Actinobacillus succinogenes for succinic acid production and effect of ammonium].

Sheng Wu Gong Cheng Xue Bao 2010 Feb;26(2):183-8

State Key Laboratory of Materials-oriented Chemical Engineering, College of Life Science and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing, China.

An ammonium-tolerant mutant of Actinobacillus succinogenes, YZ25, was obtained in the medium containing 61-242 mmol/L NH4+ after DES mutagenesis. Succinic acid produced by the mutant YZ25 reached 32.68 g/L when the medium contains 50 g/L glucose and 121 mmol/L ammonium, which was increased by 180.5% compared with that of the parent strain. The effects of different ammonium salts on the growth of the mutant and its metabolic response to high ammonium concentrations were investigated. The results showed that low ammonium concentration could improve the specific growth rates of the mutants, while high ammonium concentration inhibited cell growth. The ammonia-nitrogen half-inhibition constants (Ki) for different ammonium salts were as follows: 215 mmol/L for (NH4)2SO4, 265 mmol/L for NH4HCO3, 235 mmol/L for NH4Cl, and 210 mmol/L for NH4NO3. The process of ammonium inhibition on the mutant YZ25 was investigated in 3.0 L stirred fermenter. When NH4OH was used to buffer the pH, cell growth was not inhibited. However, production of succinic acid and consumption of glucose gradually decreased when cells entered the stationary phase, and the glucose could not be utilized completely at the end of fermentation. The possible ammonium inhibition mechanism was discussed based on the metabolic pathway of A. succinogenes.
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February 2010

A functional mouse retroposed gene Rps23r1 reduces Alzheimer's beta-amyloid levels and tau phosphorylation.

Neuron 2009 Nov;64(3):328-40

Institute for Biomedical Research, Xiamen University, Xiamen, China.

Senile plaques consisting of beta-amyloid (Abeta) and neurofibrillary tangles composed of hyperphosphorylated tau are major pathological hallmarks of Alzheimer's disease (AD). Elucidation of factors that modulate Abeta generation and tau hyperphosphorylation is crucial for AD intervention. Here, we identify a mouse gene Rps23r1 that originated through retroposition of ribosomal protein S23. We demonstrate that RPS23R1 protein reduces the levels of Abeta and tau phosphorylation by interacting with adenylate cyclases to activate cAMP/PKA and thus inhibit GSK-3 activity. The function of Rps23r1 is demonstrated in cells of various species including human, and in transgenic mice overexpressing RPS23R1. Furthermore, the AD-like pathologies of triple transgenic AD mice were improved and levels of synaptic maker proteins increased after crossing them with Rps23r1 transgenic mice. Our studies reveal a new target/pathway for regulating AD pathologies and uncover a retrogene and its role in regulating protein kinase pathways.
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http://dx.doi.org/10.1016/j.neuron.2009.08.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846276PMC
November 2009

Retinoid X receptor-alpha mediates (R )-flurbiprofen's effect on the levels of Alzheimer's beta-amyloid.

J Neurochem 2009 Oct 29;111(1):142-9. Epub 2009 Jul 29.

Institute for Biomedical Research and School of Life Sciences, Xiamen University, Xiamen, China.

Alzheimer's disease (AD) is characterized by the formation of extracellular senile plaques in the brain, whose major component is a small peptide called beta-amyloid (Abeta). Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has been found beneficial for AD and several reports suggest that NSAIDs reduce the generation of Abeta, especially the more amyloidogenic form Abeta42. However, the exact mechanism underlying NSAIDs' effect on AD risk remains largely inconclusive and all clinical trials using NSAIDs for AD treatment show negative results so far. Recent studies have shown that some NSAIDs can bind to certain nuclear receptors, suggesting that nuclear receptors may be involved in NSAID's effect on AD risk. Here we find that (R)-flurbiprofen, the R-enantiomer of the racemate NSAID flurbiprofen, can significantly reduce Abeta secretion, but at the same time, increases the level of intracellular Abeta. In addition, we find that a nuclear receptor, retinoid X receptor alpha (RXRalpha), can regulate Abeta generation and that down-regulation of RXRalpha significantly increases Abeta secretion. We also show that (R)-flurbiprofen can interfere with the interaction between RXRalpha and 9-cis-retinoid acid, and that 9-cis-retinoid acid decreases (R)-flurbiprofen's reduction of Abeta secretion. Moreover, the modulation effect of (R)-flurbiprofen on Abeta is abolished upon RXRalpha down-regulation. Together, these results suggest that RXRalpha can regulate Abeta generation and is also required for (R)-flurbiprofen-mediated Abeta generation.
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http://dx.doi.org/10.1111/j.1471-4159.2009.06312.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401643PMC
October 2009
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