Browsing by Author "Liang, Mei-Chih"

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An Improved Drugs Screening System Reveals that Baicalein Ameliorates the A beta/AMPA/NMDA-Induced Depolarization of Neurons
(2017-01-01)
Lin, Tian-Syuan
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Tsai, Han-Jung
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Lee, Chih-Han
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Song, Yan-Qing
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Huang, Rih-Sheng
The presence of amyloid-beta (A beta) plaque and tau protein hyperphosphorylation in brain tissue is the pathological hallmark of Alzheimer's disease (AD). At least some A beta neurotoxicity is caused by the presence of excess glutamate that has been induced by A beta accumulation. Memantine is currently the only NMDA receptor inhibitor approved for treating moderate-to-severe AD patients. We utilized primary cortical neurons and DiBAC4(3), a slow-response voltage sensitive fluorescence dye, to create a novel system for screening herbal medicines that allows the identification of pure compounds able to ameliorate A beta-induced abnormal depolarization. The intensity of DiBAC4(3) fluorescence was increased when primary neurons were stimulated by A beta; furthermore, pre-treatment with memantine abolished this change. Using this system, we identified six crude extracts made from herbal medicines that effectively alleviated this A beta-induced abnormal depolarization. Among these herbal medicines, one pure compound, baicalein, which was known to be present in Scutellaria baricalensis and is known to improve memory using an AD mouse model, was identified by our assay. However, the compound's molecular mechanism remained unknown. We found that baicalein, in addition to inhibiting A beta-induced depolarization, possibly functions as an antagonist of AMPA and NMDA receptors. Taken together, we have established a system/platform to identify herbal medicines that ameliorate A beta-induced depolarization of neurons. Equally important, baicalein is a candidate drug with great potential for the treatment of AD patients.
Heterogeneous nuclear ribonucleoprotein M associates with mTORC2 and regulates muscle differentiation
(2017-01-20)
Chen, Wei-Yen
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Lin, Chia-Lung
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Chuang, Jen-Hua
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Chiu, Fu-Yu
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Sun, Yun-Ya
Mammalian target of rapamycin (mTOR) plays a range of crucial roles in cell survival, growth, proliferation, metabolism, and morphology. However, mTOR forms two distinct complexes, mTOR complex 1 and mTOR complex 2 (mTORC1 and mTORC2), via association with a series of different components; this allows the complexes to execute their wide range of functions. This study explores further the composition of the mTORC2 complex. Utilizing Rictor knock-out cells, immunoprecipitation and mass spectrometry, a novel Rictor associated protein, heterogeneous nuclear ribonucleoprotein M (hnRNP M), was identified. The association between hnRNP M and Rictor was verified using recombinant and endogenous protein and the binding site was found to be within aa 1 similar to 532 of hnRNP M. The presence of hnRNP M significantly affects phosphorylation of SGK1 S422, but not of Akt S473, PKC alpha S657 and PKC zeta T560. Furthermore, hnRNP M also plays a critical role in muscle differentiation because knock-down of either hnRNP M or Rictor in C2C12 myoblasts reduced differentiation. This decrease is able to be rescued by overexpression SGK S422D in hnRNP M knockdown C2C12 myoblasts. Taken together, we have identified a novel Rictor/mTOR binding molecule, hnRNP M, that allows mTORC2 signaling to phosphorylate SGK1 thus regulating muscle differentiation.
Highly efficient drug delivery systems based on functional supramolecular polymers: In vitro evaluation
(2016-03-15)
Cheng, Chih-Chia
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Chang, Feng-Chih
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Kao, Wan-Yi
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Hwang, Shiaw-Min
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Liao, Li-Chuan
The novel concept of modifying and enhancing the properties of existing functional micelles through self-complementary interactions has significant potential. In this study, a practical approach to living polymerization of functionalized thermoresponsive monomers enabled the incorporation of self constituted multiple hydrogen bonded groups into micelles that have potential as supramolecular drug-delivery systems. Phase transitions and morphological studies in aqueous solution showed that the microstructure can be controlled to achieve well-defined vesicle-like micelles with respect to the strength of the hydrogen bond segment. Thus, the resulting micelles have a very low critical micellization concentration and very high loading capacity (16.1%), making the loading process extremely stable and efficient. Incorporation of the anticancer drug doxorubicin (DOX) affected the micellization process in aqueous solution and enabled fine-tuning of drug loading and precise control of drug release rate with excellent sensitivity. Release studies in vitro showed that DOX-loaded micelles exerted dose dependent cytotoxicity against human liver carcinoma (HepG2) cells at the physiological temperature of 37 degrees C. In addition, DOX-loaded micelles were efficiently endocytosed by the cancer cells, which may enable the micelles to serve as suitable vehicles for effective delivery of anticancer drugs to primary tumors and metastatic disease. This newly developed material may provide a potential route towards next-generation drug delivery vehicles. Statement of Significance A breakthrough innovation in water-based thermo-responsive polymers has enabled significant progress in developing smart stimuli-responsive nanocarriers by generating novel "supramolecular polymeric micelles" via self-complementary hydrogen-bonding interactions. These newly developed micelles exhibit extremely high micellar stability and drug loading capacity (up to 16%), excellent thermo-responsive behavior and precise control of drug release rate due to hydrogen-bond-induced physical cross-linking. In addition, doxorubicin-loaded micelles were efficiently endocytosed by the cancer cells, which allows them to serve as suitable vehicles for effective delivery of anticancer drugs to primary tumors and metastatic disease. Thus, this work provides a potential route for the development of next generation multifunctional nanocarriers that have improved safety and to increase the therapeutic efficacy of anticancer therapy. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
Nucleobase-grafted polycaprolactones as reversible networks in a novel biocompatible material
(2013)
Lin, I. -Hong
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Cheng, Chih-Chia
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Huang, Cheng-Wei
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Liang, Mei-Chih
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Chen, Jem-Kun
A series of nucleobase-grafted polycaprolactones have been prepared which exhibits a high complementary ability in solution and solid states owing to the formation of uracil-adenine pairs by induced hierarchical self-assembly. In addition, they can self-organize into spherical structure and result in excellent biomaterial properties.
Self-Assembled Supramolecular Nanogels as a Safe and Effective Drug Delivery Vector for Cancer Therapy
(2017-05-01)
Cheng, Chih-Chia
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Liang, Mei-Chih
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Liao, Zhi-Sheng
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Huang, Jyun-Jie
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Lee, Duu-Jong
Simple construction and manipulation of low-molecular-weight supramolecular nanogels, based on the introduction of multiple hydrogen bonding interactions, with the desired physical properties to achieve effective and safe delivery of drugs for cancer therapy remain highly challenging. Herein, a novel supramolecular oligomer cytosine (Cy)-polypropylene glycol containing self-complementary multiple hydrogen-bonded Cy moieties is developed, which undergoes spontaneous self-assembly to form nanosized particles in an aqueous environment. Phase transitions and scattering studies confirm that the supramolecular nanogels can be readily tailored to obtain the desired phase-transition temperature and temperature-induced release of the anticancer drug doxorubicin (DOX). The resulting nanogels exhibit an extremely high load carrying capacity (up to 24.8%) and drug-entrapment stability, making the loading processes highly efficient. Importantly, in vitro cytotoxicity assays indicate that DOX-loaded nanogels possess excellent biosafety for drug delivery applications under physiological conditions. When the environmental temperature is increased to 40 degrees C, DOX-loaded nanogels trigger rapid DOX release and exert cytotoxic effects, significantly reducing the dose required compared to free DOX. Given its simplicity, low cost, high reliability, and efficiency, this newly developed temperature-responsive nanocarrier has highly promising potential for controlled release drug delivery systems.
Telescoped Synthesis of 2-Acyl-1-aryl-1,2-dihydroisoquinolines and Their Inhibition of the Transcription Factor NF-kappa B
(2015-08-01)
Chung, Tsai-Wen
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Hung, Yi-Tzu
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Thikekar, Tushar
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Paike, Vijaykumar V.
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Lo, Fu Yuan
A sequential single-flask multicomponent reactions is highly effective for the synthesis of 1,2-dihydroisoquinolines through amidealkylation from intermediate N-acylisoquinolinium salts under mild conditions. N-Acylisoquinolinium ions and trichloromethyl-1-(1H-indol-3-yl)isoquinoline-2(1H)-carboxylate have demonstrated their reactivity toward aromatic and aliphatic pi-nucleophiles. One of the 1,2-dihydroisoquinoline derivatives was found to be a potent inhibitor for transcription factor NF-kappa B by blocking I kappa B alpha degradation, p65 nuclear translocation, and NF-kappa B DNA binding in TNF-alpha-induced NIH 3T3 cells.
Vorinostat enhances the cisplatin-mediated anticancer effects in small cell lung cancer cells
(2016-11-07)
Pan, Chun-Hao
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Chang, Ying-Fang
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Lee, Ming-Shuo
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Wen, B-Chen
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Ko, Jen-Chung
Background: Vorinostat, a histone deacetylase (HDAC) inhibitor, is a promising agent for cancer therapy. Combining vorinostat with cisplatin may relax the chromatin structure and facilitate the accessibility of cisplatin, thus enhancing its cytotoxicity. Studies have not yet investigated the effects of the combination of vorinostat and cisplatin on small cell lung cancer (SCLC). Methods: We first assessed the efficacy of vorinostat with etoposide/cisplatin (EP; triple combination) and then investigated the effects of cotreatment with vorinostat and cisplatin on H209 and H146 SCLC cell lines. The anticancer effects of various combinations were determined in terms of cell viability, apoptosis, cell cycle distribution, and vorinostat-regulated proteins. We also evaluated the efficacy of vorinostat/cisplatin combination in H209 xenograft nude mice. Results: Our data revealed that the triple combination engendered a significant reduction of cell viability and high apoptotic cell death. In addition, vorinostat combined with cisplatin enhanced cell growth inhibition, induced apoptosis, and promoted cell cycle arrest. We observed that the acetylation levels of histone H3 and a-tubulin were higher in combination treatments than in vorinostat treatment alone. Moreover, vorinostat reduced the expression of thymidylate synthase (TS), and TS remained inhibited after cotreament with cisplatin. Furthermore, an in vivo study revealed that the combination of vorinostat and cisplatin significantly inhibited tumor growth in xenograft nude mice (tumor growth inhibition T/C% = 20.5 %). Conclusions: Combined treatments with vorinostat promote the cytotoxicity of cisplatin and induce the expression of vorinostat-regulated acetyl proteins, eventually enhancing antitumor effects in SCLC cell lines. Triple combinations with a low dosage of cisplatin demonstrate similar therapeutic effects. Such triple combinations, if applied clinically, may reduce the undesired adverse effects of cisplatin. The effects of the combination of vorinostat and cisplatin should be evaluated further before conducting clinical trials for SCLC treatment.