Publications by authors named "Chien-Liang Lin"

52 Publications

Effect of diabetes mellitus comorbidity on outcomes in stages II and III colorectal cancer.

Asia Pac J Clin Oncol 2021 Nov 24. Epub 2021 Nov 24.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Aim: The effects of diabetes mellitus (DM) on the outcomes of colorectal cancer (CRC) are controversial. This retrospective study evaluated the effects of DM on American Joint Committee on Cancer (AJCC, 7th) Stages II and III CRC patients who received curative surgery.

Methods: We reviewed the records of CRC patients who were treated from January 2008 to December 2014 and identified the presence of DM and hypertension prior to CRC diagnosis. Cox proportional hazards analyses were used for prognostic factor determination, and survival was analyzed using the Kaplan-Meier method with the log-rank test.

Results: Total of 1066 consecutive eligible patients with stage II/III CRC were enrolled. There were 326 (30.6%) patients diagnosed with DM, and 311 (29.2%) CRC patients had recurrence. Patients with DM did not have a higher recurrence risk (p = 0.183) but had higher mortality (adjusted hazard ratio [aHR] = 1.381; 95% conference interval [CI], 1.069-1.782). In addition, HbA1c (≥7 vs. <7) was not associated with recurrence (p = 0.365). Patients with DM had more hypertension than patients without DM (69.1% vs. 37.6%, p < 0.001). A lower recurrence risk was noted in patients with hypertension (p = 0.002), but the overall survival (OS) did not reach statistical significance (aHR = 0.910; 95% CI, 0.707-1.169).

Conclusion: In our study, DM was a poor prognostic factor for survival in curative CRC patients. More studies are required to elucidate the effects that DM and other metabolic disorders, such as hypertension, have on the prognosis of patients with CRC.
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http://dx.doi.org/10.1111/ajco.13639DOI Listing
November 2021

Inclusive Leadership and Career Sustainability: Mediating Roles of Supervisor Developmental Feedback and Thriving at Work.

Front Psychol 2021 6;12:671663. Epub 2021 Jul 6.

College of Science and Technology, Ningbo University, Ningbo, China.

Career sustainability is a well-researched issue in academics and other sectors. Technology advancements and COVID-19 have jeopardized career sustainability. Numerous studies have explored the influence of individual characteristics on career sustainability, but few have focused on leadership. In addition, cultural factors must be considered because leadership is rooted in culture. In particular, inclusive leadership reflects traditional Chinese culture. Therefore, based on self-determination social exchange theories, we analyzed the effects of inclusive leadership on career sustainability as well as the roles of thriving at work and supervisor developmental feedback (SDF) in career sustainability. In total, 363 samples were collected from China. The results revealed that inclusive leadership improves career sustainability through SDF and thriving at work. Theoretically, our study fills the research gap and establishes a mechanism and theoretical framework for inclusive leadership and career sustainability. Practically, we offer guidance for enterprises to cultivate inclusive leadership and improve career sustainability.
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http://dx.doi.org/10.3389/fpsyg.2021.671663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291222PMC
July 2021

Age as a modifier of the effects of chemoradiotherapy with infusional 5-fluorouracil after D2 dissection in gastric cancer.

Aging (Albany NY) 2021 07 5;13(13):17337-17348. Epub 2021 Jul 5.

Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan.

Adjuvant concurrent chemoradiotherapy (CCRT) is the standard care for patients with resected advanced gastric cancer, but its survival benefits remain undetermined in patients undergoing D2 lymph node dissection (D2 dissection). We evaluated safety and efficacy of adjuvant CCRT with 5-fluorouracil (5-FU) versus chemotherapy alone in 110 gastric cancer patients with D2 dissection treated in Taiwan between January 2009 and January 2013. All the 71 patients receiving adjuvant CCRT were treated with daily infusional 5-FU and radiotherapy. Adjuvant CCRT was associated with higher risks of major hematologic (56.3% vs. 23.8%, = 0.002) and gastrointestinal (46.9% vs. 14.3%, = 0.027) toxicities and death (12.5% vs. 0.0%, = 0.041) in patients above 70 years old, but this was not the case in those ≤70 years of age. Univariate Cox proportional regressions identified adjuvant CCRT as a factor for better overall survival (OS) (hazard ratio [HR]=0.52; 95% confidence interval [CI]: 0.27-0.99) and disease-free survival (DFS) (HR=0.46, 95% CI: 0.24-0.88), but it was not a significant factor for OS or DFS after adjusting for other factors in the multivariate analysis. However, in stratified analyses by age, we found adjuvant CCRT was an independent prognostic factor for better OS (HR=0.07; 95% CI: 0.01-0.38) in patients ≤70 years old, but not in those above 70 years of age. Therefore, it was concluded that age may to be a modifier of the effects of adjuvant CCRT.
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http://dx.doi.org/10.18632/aging.203223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312439PMC
July 2021

Safe Sexual Behavior Intentions among College Students: The Construction of an Extended Theory of Planned Behavior.

Int J Environ Res Public Health 2021 06 11;18(12). Epub 2021 Jun 11.

Department of Computer Science and Engineering, National Taiwan Ocean University, Keelung 20224, Taiwan.

Sexual health education is an essential part of quality-oriented education for college students. It aims to help these students to acquire knowledge of sexual physiology, sexual psychology, and sexual social norms that is consistent with the maturity of the students. Along with college students'attitudes toward sex, their perceptions regarding sexual behavior have also undergone profound changes. The importance of safe sexual behavior, sexual taboos, and sexual autonomy are gaining increasing attention as Chinese society is becoming more open. For college students who have just reached adulthood and have full autonomy of themselves, however, are they really going to have sexual behavior without careful consideration? Or is it something they have planned to do in the first place? To answer the above questions, this study was conducted to understand the relationship between college students' attitudes toward sex, subjective norms, and behavioral control of their sexual behavior intentions by applying the Theory of Planned Behavior. In this study, 460 valid questionnaires were collected from Chinese college students and analyzed with partial least squares structural equation modeling (PLS-SEM). This study analyzes the relationship of multiple factors, including those influencing college students' sexual behavior intentions. Meanwhile, it also compares the differences in factors affecting sexual behavior intentions between college students with or without sexual experience and those of different genders. Based on the results of the study, it was found that, first, subjective norms and perceived behavioral control of college students had a significant effect on safe sexual behavior intentions, while attitudes did not have a significant effect on safe sexual behavior intentions. Second, the gender and sexual experience of college students had a significant effect on safe sexual behavior intentions. Third, non-sexually experienced college students were more likely to be influenced by external factors. Relevant future research suggestions will be proposed based on the results of this study. Finally, this study helps to provide substantive suggestions for enhancing safe sexual behavior among college students in the context of universal higher education, as well as strengthening the self-protection of college students and providing practical advice for the development of sex education in China.
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http://dx.doi.org/10.3390/ijerph18126349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296178PMC
June 2021

Emerging role of glutamate in the pathophysiology and therapeutics of Gulf War illness.

Life Sci 2021 Sep 13;280:119609. Epub 2021 May 13.

Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA. Electronic address:

Gulf War illness (GWI) is a chronic and multi-symptomatic disorder affecting veterans who served in the Gulf War. The commonly reported symptoms in GWI veterans include mood problems, cognitive impairment, muscle and joint pain, migraine/headache, chronic fatigue, gastrointestinal complaints, skin rashes, and respiratory problems. Neuroimaging studies have revealed significant brain structure alterations in GWI veterans, including subcortical atrophy, decreased volume of the hippocampus, reduced total grey and white matter, and increased brain white matter axial diffusivity. These brain changes may contribute to or increase the severities of the GWI-related symptoms. Epidemiological studies have revealed that neurotoxic exposures and stress may be significant contributors to the development of GWI. However, the mechanism underlying how the exposure and stress could contribute to the multi-symptomatic disorder of GWI remains unclear. We and others have demonstrated that rodent models exposed to GW-related agents and stress exhibited higher extracellular glutamate levels, as well as impaired structure and function of glutamatergic synapses. Restoration of the glutamatergic synapses ameliorated the GWI-related pathological and behavioral deficits. Moreover, recent studies showed that a low-glutamate diet reduced multiple symptoms in GWI veterans, suggesting an important role of the glutamatergic system in GWI. Currently, growing evidence has indicated that abnormal glutamate neurotransmission may contribute to the GWI symptoms. This review summarizes the potential roles of glutamate dyshomeostasis and dysfunction of the glutamatergic system in linking the initial cause to the multi-symptomatic outcomes in GWI and suggests the glutamatergic system as a therapeutic target for GWI.
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http://dx.doi.org/10.1016/j.lfs.2021.119609DOI Listing
September 2021

The Implementation of the 2020 Roadmap to Promote Good Registration Management (GRM) in APEC Region.

Ther Innov Regul Sci 2021 07 26;55(4):872-880. Epub 2021 Apr 26.

Division of Medicinal Products, Taiwan Food and Drug Administration, Ministry of Health and Welfare, Taipei, Taiwan, R.O.C.

Background: To promote the efficiency and quality of registration for medical products, the Asia-Pacific Economic Cooperation (APEC) Regulatory Harmonization Steering Committee (RHSC) has implemented a 2020 roadmap to promote the concept of GRM since 2011. Key outcomes of this roadmap are discussed in this article to provide recommendations for improved regulatory practices and accelerated regulatory convergence.

Methods: Adoption of relevant guidelines and delivery of training programs from the APEC Training Centers of Excellence for Regulatory Science (CoEs) have played a key role to promote capacity building, cooperation and convergence in good review practices (GRevPs) and good submission practices (GSubPs) for medical products among APEC economies. A key performance indicator (KPI) survey among the drug regulatory authorities (RAs) of APEC economies was conducted to understand the progress of this roadmap.

Results: The CoE programs have provided a unique opportunity to promote dialogues between regulatory authorities and industry and efficiently disseminated the concept of GRM among APEC economies. The results of the KPI survey indicated significant progress in the status of implementing GRevPs over the last ten years.

Conclusions: To accelerate regulatory convergence among APEC economies, it is necessary to promote mutual trust and cooperation in approval of medical products over the time. Continuous training in GRevPs and GSubPs through the CoE platform would set the stage to achieve the goal in the next decade.
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http://dx.doi.org/10.1007/s43441-021-00287-8DOI Listing
July 2021

A Study on Traditional Teaching Method Transferring to E-Learning Under the Covid-19 Pandemic: From Chinese Students' Perspectives.

Front Psychol 2021 11;12:632787. Epub 2021 Mar 11.

Department of Computer Science and Engineering, National Taiwan Ocean University, Keelung City, Taiwan.

In response to the Covid-19 pandemic, online learning has been carried out in many countries with different types of online learning models being promoted and implemented. In the global pandemic continues, the education environment is forced to change from traditional classroom or blended teaching mode to online learning teaching model. With the outbreak of COVID-19, China was the first to announce that online courses are to be implemented in February 2020. In China, whether online learning can replace traditional offline teaching has become a topic worth discussing. Therefore, this study investigates university students in China by questionnaires and discussions of this topic. The study is based on the Push-Pull Mooring model. Based on 854 valid responses collected from an online survey questionnaire, structural equation modeling was employed to examine the research model. The results show that push effects (Perceived security risk, Learning convenience, and Service quality), pull effects (Usefulness, Ease of use, Teacher's Teaching Attitude, Task-technology Fit), and mooring effects (habit) all significantly influence users' switching intentions from offline to online learning platform. Finally, this study explores whether push-pull-mooring can be a reference for promoting and implementing online learning courses in Chinese colleges and universities in the future after the pandemic.
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http://dx.doi.org/10.3389/fpsyg.2021.632787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991594PMC
March 2021

TFDA takes actions to expedite the development of COVID-19 vaccines.

J Formos Med Assoc 2021 Mar 3. Epub 2021 Mar 3.

Division of Medicinal Products, Taiwan Food and Drug Administration (TFDA), Ministry of Health and Welfare, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.jfma.2021.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927646PMC
March 2021

Nanostructured Molybdenum Trioxide Layer on the Silver Anode of a Top-Incident Organic Photovoltaic Device.

J Nanosci Nanotechnol 2021 Mar;21(3):1659-1666

Department of Electrical Engineering, Yuan Ze University, Taoyuan 32003, Taiwan.

A nanostructured molybdenum trioxide (MoO₃) layer was successfully fabricated utilizing various deposition rates, employed as an anodic buffer layer to separate the active layer from a silver anode and modifying the anodic surface to facilitate hole transportation for top-incident organic photovoltaic (TIOPV) devices. The deposition rate and thickness of the MoO₃ layer were crucial parameters for determining the surface morphology and work function, and the internal optical field distribution, respectively. These factors affected the performance of the devices in terms of their open-circuit voltage (), short-circuit current density (), and fill factor (FF). The baseline TIOPV device without a buffer layer had a power conversion efficiency (PCE) of only 0.47%. By contrast, with a smooth 20-nm MoO₃ buffer layer fabricated using a deposition rate of 1 Å/s (which prevented problems caused by the Ag anode), another fabricated TIOPV device had substantially higher , and FF values, which improved the PCE by a factor of 6.2 to 2.92%. When an additional 5-nm nanostructured MoO₃ layer was deposited at a deposition rate of 0.5 Å/s, the most efficient TIOPV device had an even greater PCE, a factor of 7.5 times higher at 3.53%.
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http://dx.doi.org/10.1166/jnn.2021.18985DOI Listing
March 2021

Restoring tripartite glutamatergic synapses: A potential therapy for mood and cognitive deficits in Gulf War illness.

Neurobiol Stress 2020 Nov 13;13:100240. Epub 2020 Jul 13.

Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA.

Gulf War illness is associated with a combination of exposure to war-related chemical agents and traumatic stress. Currently, there are no effective treatments, and the pathophysiology remains elusive. Neurological problems are among the most commonly reported symptoms. In this study, we investigated the glutamatergic system in the hippocampi of mice exposed to war-related chemical agents and stress. Mice developed Gulf War illness-like symptoms, including mood deficits, cognitive impairments, and fatigue. They exhibited the following pathological changes in hippocampi: elevated extracellular glutamate levels, impaired glutamatergic synapses, astrocyte atrophy, loss of interneurons, and decreased neurogenesis. LDN/OSU-215111 is a small-molecule that can strengthen the structure and function of both the astrocytic processes and the glutamatergic synapses that together form the tripartite synapses. We found that LDN/OSU-215111 effectively prevented the development of mood and cognitive deficits in mice when treatment was implemented immediately following the exposure. Moreover, when symptoms were already present, LDN/OSU-215111 still significantly ameliorated these deficits; impressively, benefits were sustained one month after treatment cessation, indicating disease modification. LDN/OSU-215111 effectively normalized hippocampal pathological changes. Overall, this study provides strong evidence that restoration of tripartite glutamatergic synapses by LDN/OSU-215111 is a potential therapy for Gulf War illness.
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http://dx.doi.org/10.1016/j.ynstr.2020.100240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739039PMC
November 2020

Genetic Variants of lncRNA Exert Diverse Impacts on the Risk and Clinicopathologic Characteristics of Patients with Hepatocellular Carcinoma.

J Clin Med 2019 Sep 6;8(9). Epub 2019 Sep 6.

Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.

The long noncoding (lnc)RNA, (), plays a crucial role in the development of hepatocellular carcinoma (HCC). However, potential genetic variants (single nucleotide polymorphisms, SNPs) in that affect the susceptibility and progression of HCC have rarely been explored. Three tagging SNPs, viz., rs3200401 C > T, rs619586 A > G, and rs1194338 C > A, in MALAT1 were genotyped by a TaqMan allelic discrimination assay in 394 HCC patients and 1199 healthy controls. A stratified analysis showed that younger patients (<55 years) with the MALAT1 rs619586 G allele had a decreased risk of HCC under a codominant model (AOR = 0.289, 95% CI: 0.108-0.773, p = 0.013) and dominant model (AOR = 0.286, 95% CI: 0.107-0.765, p = 0.013). Female patients and patients with a smoking habit who carried the CA + AA genotype of rs1194338 had a lower risk of developing vascular invasion (p = 0.049) and a high Child-Pugh grade (B or C) (p = 0.036), respectively. Under the dominant model, smokers with the MALAT1 rs3200401 CT + TT genotype had a higher frequency of hepatitis B virus (HBV) infection (p = 0.034). Moreover, the aspartate aminotransferase was higher in patients with the rs3200401 CT + TT genotype. Furthermore, analyses of clinical datasets revealed that MALAT1 expression level was gradually unregulated during HCC development from normal liver, cirrhotic liver, dysplastic liver to HCC and correlated with poor survival rates in HCC patients, especially in the hepatitis virus-infected population.
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http://dx.doi.org/10.3390/jcm8091406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780489PMC
September 2019

Enhancement of tripartite synapses as a potential therapeutic strategy for Alzheimer's disease: a preclinical study in rTg4510 mice.

Alzheimers Res Ther 2019 08 23;11(1):75. Epub 2019 Aug 23.

Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA.

Background: The lack of effective treatment options for Alzheimer's disease (AD) is of momentous societal concern. Synaptic loss is the hallmark of AD that correlates best with impaired memory and occurs early in the disease process, before the onset of clinical symptoms. We have developed a small-molecule, pyridazine-based series that enhances the structure and function of both the glial processes and the synaptic boutons that form the tripartite synapse. Previously, we have shown that these pyridazine derivatives exhibit profound efficacy in an amyloid precursor protein AD model. Here, we evaluated the efficacy of an advanced compound, LDN/OSU-0215111, in rTg4510 mice-an aggressive tauopathy model.

Methods: rTg4510 mice were treated orally with vehicle or LDN/OSU-0215111 (10 mg/kg) daily from the early symptomatic stage (2 months old) to moderate (4 months old) and severe (8 months old) disease stages. At each time point, mice were subjected to a battery of behavioral tests to assess the activity levels and cognition. Also, tissue collections were performed on a subset of mice to analyze the tripartite synaptic changes, neurodegeneration, gliosis, and tau phosphorylation as assessed by immunohistochemistry and Western blotting. At 8 months of age, a subset of rTg4510 mice treated with compound was switched to vehicle treatment and analyzed behaviorally and biochemically 30 days after treatment cessation.

Results: At both the moderate and severe disease stages, compound treatment normalized cognition and behavior as well as reduced synaptic loss, neurodegeneration, tau hyperphosporylation, and neuroinflammation. Importantly, after 30 days of treatment cessation, the benefits of compound treatment were sustained, indicating disease modification. We also found that compound treatment rapidly and robustly reduced tau hyperphosphorylation/deposition possibly via the inhibition of GSK3β.

Conclusions: The results show that LDN/OSU-0215111 provides benefits for multiple aspects of tauopathy-dependent pathology found in Alzheimer's disease including tripartite synapse normalization and reduction of toxic tau burden, which, in turn, likely accounted for normalized cognition and activity levels in compound-treated rTg4510 mice. This study, in combination with our previous work regarding the benefit of pyridazine derivatives against amyloid-dependent pathology, strongly supports pyridazine derivatives as a viable, clinically relevant, and disease-modifying treatment for many of the facets of Alzheimer's disease.
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http://dx.doi.org/10.1186/s13195-019-0530-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706914PMC
August 2019

Subsequent thyroid disorders associated with treatment strategy in head and neck cancer patients: a nationwide cohort study.

BMC Cancer 2019 May 16;19(1):461. Epub 2019 May 16.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 138, Shengli Road, Tainan, Taiwan.

Background: We investigated the risk of thyroid disorders, namely hypothyroidism, thyrotoxicosis and thyroiditis, in head and neck cancer patients undergoing multimodal treatment.

Methods: A cohort study design using Taiwan's National Health Insurance Research Database was used to assess head and neck cancer patients over 20 years old. The cohort was divided into one group who underwent primary tumor excision only (PTE) and another with additional neck dissection (PTE + ND). The tumor sites were stratified to estimate the tumor-site-specific risk of thyroid disorders. The effect of subsequent resurgery, radiotherapy (RT), chemotherapy (CT), and concomitant (CCRT) or sequential chemoradiation therapy (sequential CT+ RT) on the risk of thyroid disorders was explored.

Results: For 1999-2012, 7460 patients who underwent PTE + ND and 3730 who underwent PTE were enrolled and followed-up until the end of 2013. There were 122 and 50 patients in the two groups, respectively, who developed thyroid disorders, with no statistical difference between the groups. Patients with hypopharyngeal, oropharyngeal, or laryngeal cancer in the PTE + ND group had a higher risk of thyroid disorders (adjusted HR: 1.50, 95% CI: 0.67-3.38) than those in the PTE group when adjusted for covariates and mortality. Patients who underwent subsequent RT (adjusted HR: 3.64, 95% CI: 1.05-2.77) and CCRT (adjusted HR: 1.70, 95% CI: 1.05-2.77) after PTE + ND had a significantly higher risk of thyroid disorders.

Conclusion: RT results in a major risk of subsequent thyroid disorders, and ND may exacerbate this effect. Physicians should monitor thyroid function from two years after treatment initiation, especially in patients who undergo ND and subsequent RT.
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http://dx.doi.org/10.1186/s12885-019-5697-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524259PMC
May 2019

Effectiveness of the Multidisciplinary Team Model in Treating Colorectal Cancer.

Gastroenterol Nurs 2018 Nov/Dec;41(6):491-496

Wen-Li Lin, MSN, Cancer Center, Chi Mei Medical Center, Liouying, Taiwan. Jia-Ling Sun, PhD, Department of Nursing, National Taichung University of Science and Technology, Taichung, Taiwan. Shu-Chan Chang, MSN, Cancer Center, Chi Mei Medical Center, Liouying, Taiwan. Tsung-Chih Tsai, MD, Department of Surgery, Chi Mei Medical Center, Liouying, Taiwan. Pei-Hua Wu, MSN, Cancer Center, Chi Mei Medical Center, Liouying, Taiwan. Wen-Tsung Huang, MD, Department of Hematology and Oncology, Chi Mei Medical Center, Liouying, Taiwan. Chao-Jung Tsao, MD, Department of Hematology and Oncology, Chi Mei Medical Center, Liouying, Taiwan. Chien-Liang Lin, MD, Department of Hematology and Oncology, Chi Mei Medical Center, Liouying, Taiwan.

The multidisciplinary team (MDT) model involves multiple medical professionals providing integrated medical care. Colorectal cancer (CRC) has the highest prevalence of cancer in Taiwan. This study examines and evaluates the survival rates of CRC patients treated under the MDT model. In this retrospective and prospective study, 651 CRC patients were recruited. They were divided into 2 groups: the MDT group and the traditional care (TC) group. The MDT group comprised 326 patients who received care from a MDT. The TC group comprised 325 patients who received care from a TC. The outcome variables were survival rates, follow-up appointment compliance, and 14-day readmission rates. Adopting the MDT model for CRC care increased patient follow-up appointment compliance rates at the first week, first month, and third month (p = .032, p = .007, p = .001, respectively). The model also effectively reduced patients' 14-day readmission rates. The results indicated that the survival rates of the MDT care were superior to those of TC. The adoption of the MDT model to treat CRC effectively enhanced clinical treatment adherence, increased survival rates, and reduced the 14-day readmission rate.
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http://dx.doi.org/10.1097/SGA.0000000000000348DOI Listing
April 2019

Pyridazine-derivatives Enhance Structural and Functional Plasticity of Tripartite Synapse Via Activation of Local Translation in Astrocytic Processes.

Neuroscience 2018 09 27;388:224-238. Epub 2018 Jul 27.

Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, United States. Electronic address:

Excitatory amino acid transporter 2 (EAAT2) is primarily located in perisynaptic astrocytic processes (PAP) where it plays a critical role in synaptic glutamate homeostasis. Dysregulation of EAAT2 at the translational level has been implicated in a myriad of neurological diseases. We previously discovered that pyridazine analogs can activate EAAT2 translation. Here, we sought to further refine the site and mechanism of compound action. We found that in vivo, compound treatment increased EAAT2 expression only in the PAP of astrocytes where EAAT2 mRNA also was identified. Direct application of compound to isolated PAP induced de novo EAAT2 protein synthesis, indicating that compound activates translation locally in the PAP. Using a screening process, we identified a set of PAP proteins that are rapidly up-regulated following compound treatment and a subset of these PAP proteins may be locally synthesized in the PAP. Importantly, these identified proteins are associated with the structural and functional capacity of the PAP, indicating compound enhanced plasticity of the PAP. Concomitantly, we found that pyridazine analogs increase synaptic protein expression in the synapse and enhance hippocampal long-term potentiation. This was not dependent upon compound-mediated local translation in neurons. This suggests that compound enhances the structural and functional capacity of the PAP which in turn facilitates enhanced plasticity of the tripartite synapse. Overall, this provides insight into the mechanism action site of pyridazine derivatives as well as the growing appreciation of the dynamic regulation and functional aspects of the PAP at the tripartite synapse.
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http://dx.doi.org/10.1016/j.neuroscience.2018.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667176PMC
September 2018

Chemopreventive Potential of 2,3,5,4'-Tetrahydroxystilbene-2-O--D-glucoside on the Formation of Aberrant Crypt Foci in Azoxymethane-Induced Colorectal Cancer in Rats.

Biomed Res Int 2017 7;2017:3634915. Epub 2017 Nov 7.

Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

2,3,5,4'-Tetrahydroxystilbene-2---D-glucoside (THSG) has been shown to have antioxidative and anti-inflammatory effects. Oxidative and inflammatory reactions are related to the development of colorectal carcinoma (CRC). In the present study, we characterized the preventive activities of THSG on colon carcinogenesis using the azoxymethane- (AOM-) mediated rat colon carcinogenesis model. F344 male rats were randomly divided into 5 groups (untreated and AOM model rats treated with or without THSG at 30, 150, or 250 mg/kg) after which the numbers of aberrant crypt foci (ACF) were assessed in the colon tissues of all rats. The expressions of nuclear factor-B (NF-B), cyclooxygenase-2 (COX-2), matrix metalloproteinase proteins (MMPs), and carcinoembryonic antigen (CEA) were measured as effective early predictors of CRC using western blot analysis. Treatment with THSG (150 or 250 mg/kg) induced a 50% reduction in total colonic ACF formation ( < 0.05). Furthermore, our results revealed a downregulation of CEA and NF-B protein levels in the reduced number of ACF elicited by treatment with THSG, whereas levels of COX-2 and MMPs proteins were not changed. Collectively, THSG may be a promising natural lead compound or drug candidate for treating early phases of CRC.
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http://dx.doi.org/10.1155/2017/3634915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697369PMC
July 2018

Associations between interventions for urolithiasis and urinary tract cancer among patients in Taiwan: The effect of early intervention.

Medicine (Baltimore) 2016 Dec;95(49):e5594

Division of Hematology and Oncology Division of Urology, Chi-Mei Medical Center, Liouying Campus Min-Hwei Junior College of Health Care Management Department of Nursing Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Biostatistics Consulting Center, National Cheng Kung University Hospital, Tainan, Taiwan.

The aim of this study was to investigate cancer risk in patients with a history of urolithiasis and to determine whether intervention for calculi attenuated the risk of subsequent urinary tract cancer (UTC).Using data from the National Health Insurance Research Database in Taiwan, we performed a nationwide cohort study enrolling participants (n = 42,732) aged > 30 years who were diagnosed with urinary tract calculi between 2000 and 2009. Age- and gender-matched insured individuals (n = 213,660) found in the health service records over the same period were recruited as the control group. The Cox proportional hazards model and competing risks regression model were used to examine the relationship between urolithiasis and UTC, as well as whether early intervention for urolithiasis decreased the subsequent cancer risk relative to late intervention.Participants with a previous diagnosis of urolithiasis (n = 695) had a 1.82-fold (95% CI: 1.66-1.99, P < 0.001) increased risk of developing UTC. Furthermore, the risk of UTC associated with urolithiasis was higher in women (adjusted HR: 2.43, 95% CI: 1.94-3.05) than in men (adjusted HR: 1.72, 95% CI: 1.55-1.90). When stratified by cancer site, the adjusted HR for bladder, renal pelvis/ureter, renal, and prostate cancers were 1.94 (95% CI: 1.62-2.33), 2.94 (95% CI: 2.24-3.87), 2.94 (95% CI: 2.29-3.77), and 1.45 (95% CI: 1.27-1.65), respectively. Patients who received interventions for urolithiasis within 3 months of detection had a decreased risk of subsequent UTC (adjusted HR: 0.53, 95% CI: 0.40-0.71, P < 0.001).The present study demonstrated that urolithiasis increased the risk of subsequent UTC, especially upper UTC. Hence, it is recommended that physicians administer the appropriate interventions as early as possible upon diagnosis of urolithiasis.
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http://dx.doi.org/10.1097/MD.0000000000005594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266053PMC
December 2016

2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside suppresses human colorectal cancer cell metastasis through inhibiting NF-κB activation.

Int J Oncol 2016 Aug 9;49(2):629-38. Epub 2016 Jun 9.

Department of Nutrition and Health Sciences, Chang Jung Christian University, Tainan 711, Taiwan, R.O.C.

2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (THSG), a major component of Polygonum multiflorum Thunb (He-Shou-Wu), has been reported to exhibit antioxidant and anti-inflammatory effects. However, its anti-metastatic effect against colorectal cancer is still unclear. In this study, cell migration, invasion and adhesion abilities as well as metastasis-associated protein and NF-κB pathway signaling factor expression were analyzed after treating HT-29 cells with THSG. According to the results, the migration and invasiveness of HT-29 cells were reduced after treatment with 5 or 10 mM THSG (p<0.05). Additionally, the levels of matrix metalloproteinase-2 (MMP-2) and phosphorylated VE-cadherin in HT-29 cells were reduced and the transepithelial electrical resistance (TEER) of EA.hy926 endothelial cell monolayers was increased after incubation in THSG for 24 h (p<0.05). Cell adhesion ability and the E-selectin and intercellular adhesion molecule-1 (ICAM-1) protein levels were reduced when EA.hy926 endothelial cells were treated with THSG (p<0.05). In addition, the cytoplasmic phosphorylation of IκB, the nuclear p65 level and the DNA-binding activity of NF-κB were reduced after treating HT-29 or EA.hy926 cells with 5 or 10 mM THSG (p<0.05). These results suggest that THSG inhibits HT-29 cell metastasis by suppressing cell migration, invasion and adhesion. Furthermore, THSG inhibits metastasis-associated protein expression by suppressing NF-κB pathway activation.
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http://dx.doi.org/10.3892/ijo.2016.3574DOI Listing
August 2016

Regulation of Cell and Gene Therapy Medicinal Products in Taiwan.

Adv Exp Med Biol 2015 ;871:181-94

Division of Medicinal Products, Taiwan Food and Drug Administration, 161-2, Kunyang Street, Nangang, Taipei, 11561, Taiwan.

Owing to the rapid and mature development of emerging biotechnology in the fields of cell culture, cell preservation, and recombinant DNA technology, more and more cell or gene medicinal therapy products have been approved for marketing, to treat serious diseases which have been challenging to treat with current medical practice or medicine. This chapter will briefly introduce the Taiwan Food and Drug Administration (TFDA) and elaborate regulation of cell and gene therapy medicinal products in Taiwan, including regulatory history evolution, current regulatory framework, application and review procedures, and relevant jurisdictional issues. Under the promise of quality, safety, and efficacy of medicinal products, it is expected the regulation and environment will be more flexible, streamlining the process of the marketing approval of new emerging cell or gene therapy medicinal products and providing diverse treatment options for physicians and patients.
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http://dx.doi.org/10.1007/978-3-319-18618-4_10DOI Listing
December 2015

Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease.

Cell Mol Life Sci 2015 Sep 2;72(18):3489-506. Epub 2015 Jun 2.

Department of Neuroscience, The Ohio State University, 333 West 10th Avenue, Columbus, OH, 43210, USA.

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Excitatory amino acid transporter 2 (EAAT2) is primarily responsible for clearance of extracellular glutamate to prevent neuronal excitotoxicity and hyperexcitability. EAAT2 plays a critical role in regulation of synaptic activity and plasticity. In addition, EAAT2 has been implicated in the pathogenesis of many central nervous system disorders. In this review, we summarize current understanding of EAAT2, including structure, pharmacology, physiology, and functions, as well as disease relevancy, such as in stroke, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, major depressive disorder, and addiction. A large number of studies have demonstrated that up-regulation of EAAT2 protein provides significant beneficial effects in many disease models suggesting EAAT2 activation is a promising therapeutic approach. Several EAAT2 activators have been identified. Further understanding of EAAT2 regulatory mechanisms could improve development of drug-like compounds that spatiotemporally regulate EAAT2.
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http://dx.doi.org/10.1007/s00018-015-1937-8DOI Listing
September 2015

Risk of breast cancer recurrence in patients receiving manual lymphatic drainage: a hospital-based cohort study.

Ther Clin Risk Manag 2015 27;11:349-58. Epub 2015 Feb 27.

Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Background: This retrospective cohort study evaluated whether manual lymphatic drainage (MLD) therapy increases the risk of recurrence of breast cancer.

Methods: We analyzed 1,106 women who were diagnosed with stage 0-3 breast cancer between 2007 and 2011 and experienced remission after surgery and adjuvant therapy. The patients were divided into two groups: group A (n=996), in which patients did not participate in any MLD therapy, regardless of whether they developed breast cancer-related lymphedema (BCRL) after cancer treatment; and group B (n=110), in which patients participated in MLD therapy for BCRL. All patients were monitored until October 2013 to determine whether breast cancer recurrence developed, including local or regional recurrence and distant metastasis. Patients who developed cancer recurrence prior to MLD therapy were excluded from analysis. Risk factors associated with cancer recurrence were evaluated using Cox proportional hazards models.

Results: During the monitoring period, 166 patients (15.0%) developed cancer recurrence, including 154 (15.5%) in group A and 12 (10.9%) in group B. The median period from surgery to cancer recurrence was 1.85 (interquartile range 1.18-2.93) years. Independent risk factors for cancer recurrence were tumor histological grading of grade 3, high number (≥3) of axillary lymph node invasion, and a large tumor size (>5 cm). Factors protecting against recurrence were positive progesterone receptor status and receiving radiation therapy. Receiving MLD therapy was not an outcome factor in multivariate analyses (hazard ratio 0.71, 95% confidence interval 0.39-1.29, P=0.259).

Conclusion: MLD is a gentle procedure that does not increase the risk of breast cancer recurrence in patients who develop BCRL.
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http://dx.doi.org/10.2147/TCRM.S79118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354455PMC
March 2015

Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer's disease.

J Exp Med 2015 Mar 23;212(3):319-32. Epub 2015 Feb 23.

Department of Neuroscience, The Ohio State University, Columbus, OH 43210

Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer's disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD.
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http://dx.doi.org/10.1084/jem.20140413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354363PMC
March 2015

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection.

J Clin Invest 2014 Mar 24;124(3):1255-67. Epub 2014 Feb 24.

Glial glutamate transporter EAAT2 plays a major role in glutamate clearance in synaptic clefts. Several lines of evidence indicate that strategies designed to increase EAAT2 expression have potential for preventing excitotoxicity, which contributes to neuronal injury and death in neurodegenerative diseases. We previously discovered several classes of compounds that can increase EAAT2 expression through translational activation. Here, we present efficacy studies of the compound LDN/OSU-0212320, which is a pyridazine derivative from one of our lead series. In a murine model, LDN/OSU-0212320 had good potency, adequate pharmacokinetic properties, no observed toxicity at the doses examined, and low side effect/toxicity potential. Additionally, LDN/OSU-0212320 protected cultured neurons from glutamate-mediated excitotoxic injury and death via EAAT2 activation. Importantly, LDN/OSU-0212320 markedly delayed motor function decline and extended lifespan in an animal model of amyotrophic lateral sclerosis (ALS). We also found that LDN/OSU-0212320 substantially reduced mortality, neuronal death, and spontaneous recurrent seizures in a pilocarpine-induced temporal lobe epilepsy model. Moreover, our study demonstrated that LDN/OSU-0212320 treatment results in activation of PKC and subsequent Y-box-binding protein 1 (YB-1) activation, which regulates activation of EAAT2 translation. Our data indicate that the use of small molecules to enhance EAAT2 translation may be a therapeutic strategy for the treatment of neurodegenerative diseases.
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http://dx.doi.org/10.1172/JCI66163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938250PMC
March 2014

Glutamate transporter EAAT2: a new target for the treatment of neurodegenerative diseases.

Future Med Chem 2012 Sep;4(13):1689-700

Department of Neuroscience, The Ohio State University, Columbus, OH, USA.

Glutamate is the primary excitatory amino acid neurotransmitter in the CNS. The concentration of glutamate in the synaptic cleft is tightly controlled by interplay between glutamate release and glutamate clearance. Abnormal glutamate release and/or dysfunction of glutamate clearance can cause overstimulation of glutamate receptors and result in neuronal injury known as excitotoxicity. The glial glutamate transporter EAAT2 plays a major role in glutamate clearance. Dysfunction or reduced expression of EAAT2 has been documented in many neurodegenerative diseases. In addition, many studies in animal models of disease indicate that increased EAAT2 expression provides neuronal protection. Here, we summarize these studies and suggest that EAAT2 is a potential target for the prevention of excitotoxicity. EAAT2 can be upregulated by transcriptional or translational activation. We discuss current progress in the search for EAAT2 activators, which is a promising direction for the treatment of neurodegenerative diseases.
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http://dx.doi.org/10.4155/fmc.12.122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580837PMC
September 2012

Protective effect of caffeic acid on paclitaxel induced anti-proliferation and apoptosis of lung cancer cells involves NF-κB pathway.

Int J Mol Sci 2012 21;13(5):6236-45. Epub 2012 May 21.

Department of Life Science and Institute of Zoology, National Taiwan University, Taipei 106, Taiwan; E-Mails: (C.-L.L.); (R.-F.C.).

Caffeic acid (CA), a natural phenolic compound, is abundant in medicinal plants. CA possesses multiple biological effects such as anti-bacterial and anti-cancer growth. CA was also reported to induce fore stomach and kidney tumors in a mouse model. Here we used two human lung cancer cell lines, A549 and H1299, to clarify the role of CA in cancer cell proliferation. The growth assay showed that CA moderately promoted the proliferation of the lung cancer cells. Furthermore, pre-treatment of CA rescues the proliferation inhibition induced by a sub-IC(50) dose of paclitaxel (PTX), an anticancer drug. Western blot showed that CA up-regulated the pro-survival proteins survivin and Bcl-2, the down-stream targets of NF-κB. This is consistent with the observation that CA induced nuclear translocation of NF-κB p65. Our study suggested that the pro-survival effect of CA on PTX-treated lung cancer cells is mediated through a NF-κB signaling pathway. This may provide mechanistic insights into the chemoresistance of cancer calls.
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http://dx.doi.org/10.3390/ijms13056236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382759PMC
November 2015

Increased glial glutamate transporter EAAT2 expression reduces epileptogenic processes following pilocarpine-induced status epilepticus.

Neurobiol Dis 2012 Aug 6;47(2):145-54. Epub 2012 Apr 6.

Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.

Several lines of evidence indicate that glutamate plays a crucial role in the initiation of seizures and their propagation; abnormal glutamate release causes synchronous firing of large populations of neurons, leading to seizures. In the present study, we investigated whether enhanced glutamate uptake by increased glial glutamate transporter EAAT2, the major glutamate transporter, could prevent seizure activity and reduce epileptogenic processes. EAAT2 transgenic mice, which have a 1.5-2 fold increase in EAAT2 protein levels as compared to their non-transgenic counterparts, were tested in a pilocarpine-induced status epilepticus (SE) model. Several striking phenomena were observed in EAAT2 transgenic mice compared with their non-transgenic littermates. First, the post-SE mortality rate and chronic seizure frequency were significantly decreased. Second, neuronal degeneration in hippocampal subfields after SE were significantly reduced. Third, the SE-induced neurogenesis and mossy fiber sprouting were significantly decreased. The severity of cell loss in epileptic mice was positively correlated with that of mossy fiber sprouting and chronic seizure frequency. Our results suggest that increased EAAT2 expression can protect mice against SE-induced death, neuropathological changes, and chronic seizure development. This study suggests that enhancing EAAT2 protein expression is a potential therapeutic approach.
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http://dx.doi.org/10.1016/j.nbd.2012.03.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572547PMC
August 2012

Structure-activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators.

Bioorg Med Chem Lett 2011 Oct 8;21(19):5774-7. Epub 2011 Aug 8.

Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne St., Cambridge, MA 02139, USA.

Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter and functions to remove glutamate from synapses. A thiopyridazine derivative has been found to increase EAAT2 protein levels in astrocytes. A structure-activity relationship study revealed that several components of the molecule were required for activity, such as the thioether and pyridazine. Modification of the benzylthioether resulted in several derivatives (7-13, 7-15 and 7-17) that enhanced EAAT2 levels by >6-fold at concentrations < 5 μM after 24h. In addition, one of the derivatives (7-22) enhanced EAAT2 levels 3.5-3.9-fold after 24h with an EC(50) of 0.5 μM.
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http://dx.doi.org/10.1016/j.bmcl.2011.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172717PMC
October 2011

Effects of axon degeneration on oligodendrocyte lineage cells: dorsal rhizotomy evokes a repair response while axon degeneration rostral to spinal contusion induces both repair and apoptosis.

Glia 2010 Aug;58(11):1304-19

Department of Neuroscience, The Ohio State University College of Medicine, Columbus, Ohio, USA.

Wallerian degeneration in the dorsal columns (DC) after spinal cord injury (SCI) is associated with microglial activation and prolonged oligodendrocyte (OL) apoptosis that may contribute to demyelination and dysfunction after SCI. But, there is an increase in OL lineage cells after SCI that may represent a reparative response, and there is evidence for remyelination after SCI. To assess the role of axonal degeneration per se in OL apoptosis and proliferation, we cut the L2-S2 dorsal roots producing massive axonal degeneration and microglial activation in the DC, and found no evidence of OL loss or apoptosis. Rather, the numbers of OL-lineage cells positive for NG2 and APC (CC1) increased, and BrdU studies suggested new OL formation. We then tested contusion SCI (cSCI) that results in comparable degeneration in the DC rostral to the injury, microglial activation, and apoptosis of DC OLs by eight days. NG2+ cell proliferation and oligodendrogenesis was seen as after rhizotomy. The net result of this combination of proliferation and apoptosis was a reduction in DC OLs, confirming earlier studies. Using an antibody to oxidized nucleic acids, we found rapid and prolonged RNA oxidation in OLs rostral to cSCI, but no evidence of oxidative stress in DC OLs after rhizotomy. These results suggest that signals associated with axonal degeneration are sufficient to induce OL proliferation, and that secondary injury processes associated with the central SCI, including oxidative stress, rather than axonal degeneration per se, are responsible for OL apoptosis.
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http://dx.doi.org/10.1002/glia.21009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3045846PMC
August 2010

Identification of translational activators of glial glutamate transporter EAAT2 through cell-based high-throughput screening: an approach to prevent excitotoxicity.

J Biomol Screen 2010 Jul 27;15(6):653-62. Epub 2010 May 27.

Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.

Excitotoxicity has been implicated as the mechanism of neuronal damage resulting from acute insults such as stroke, epilepsy, and trauma, as well as during the progression of adult-onset neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. One potential approach to protect against excitotoxic neuronal damage is enhanced glutamate reuptake. The glial glutamate transporter EAAT2 is the quantitatively dominant glutamate transporter and plays a major role in clearance of glutamate. Expression of EAAT2 protein is highly regulated at the translational level. In an effort to identify compounds that can induce translation of EAAT2 transcripts, a cell-based enzyme-linked immunosorbent assay was developed using a primary astrocyte line stably transfected with a vector designed to identify modulators of EAAT2 translation. This assay was optimized for high-throughput screening, and a library of approximately 140,000 compounds was tested. In the initial screen, 293 compounds were identified as hits. These 293 hits were retested at 3 concentrations, and a total of 61 compounds showed a dose-dependent increase in EAAT2 protein levels. Selected compounds were tested in full 12-point dose-response experiments in the screening assay to assess potency as well as confirmed by Western blot, immunohistochemistry, and glutamate uptake assays to evaluate the localization and function of the elevated EAAT2 protein. These hits provide excellent starting points for developing therapeutic agents to prevent excitotoxicity.
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http://dx.doi.org/10.1177/1087057110370998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016154PMC
July 2010
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