Browsing by Author "Thaned Kangsamaksin"

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    Angiogenesis and vascular remodelling: New perspectives
    (2014-12-01) Thaned Kangsamaksin; Ian W. Tattersall; Jan Kitajewski; Mahidol University; Columbia University Medical Center
    © The Authors Journal compilation © 2014 Biochemical Society. The Notch signalling pathway is a key regulator of developmental and tumour angiogenesis. Inhibition of Delta-like 4 (Dll4)-mediated Notch signalling results in hyper-sprouting, demonstrating that Notch regulates tip-stalk cell identity in developing tissues and tumours. Paradoxically, Dll4 blockade leads to reduced tumour growth because the newly growing vessels are poorly perfused. To explore the potential for targeting Notch, we developed Notch inhibitors, termed the Notch1 decoys. A Notch1 decoy variant containing all 36 epidermal growth factor (EGF)-like repeats of the extracellular domain of rat Notch1 has been shown to inhibit both Dll and Jagged class Notch ligands. Thus this Notch1 decoy functions differently than Dll4-specific blockade, although it has the potential to inhibit Dll4 activity. Expression of the Notch1 decoy in mice disrupted tumour angiogenesis and inhibited tumour growth. To understand the mechanism by which Notch blockade acts, it is important to note that Notch can function in multiple cell types that make up the vasculature, including endothelial cells and perivascular cells. We investigated Notch function in retinal microglia and determined how myeloid-expressed Notch can influence macrophages and angiogenesis. We found that myeloid-specific loss of Notch1 reduced microglia recruitment and led to improper microglia localization during retinal angiogenesis. Thus either pharmacological inhibition of Notch signalling or genetic deficiencies of Notch function in microglia leads to abnormal angiogenesis.
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    Aptamer-functionalized DNA nanosphere as a stimuli-responsive nanocarrier
    (2018-03-01) Supattra Chaithongyot; Nusara Chomanee; Komgrid Charngkaew; Anuttara Udomprasert; Thaned Kangsamaksin; Mahidol University; Faculty of Medicine, Siriraj Hospital, Mahidol University; Burapha University
    © 2017 Elsevier B.V. Smart nanocarriers that can respond to specific signals have recently gained attention in clinical research. Through the scaffolded DNA origami technique, we developed an aptamer-functionalized DNA nanosphere that could change its conformation upon binding to cancer-specific Mucin 1 protein (MUC1). A MUC1 aptamer was added into the lock-and-key system of the DNA nanosphere, and specific binding of the aptamer and MUC1 triggered the opening of the structure. A decrease in FRET signals demonstrated that the DNA nanosphere underwent structural change to the open conformation in response to the MUC1-containing cell lysate. Gold nanoparticles were also successfully encapsulated inside the cavity, implicating its loading ability. Our data confirmed that the aptamer-modified DNA nanosphere has proved to be a responsive nanocarrier and may serve as a promising candidate for cancer theranostic purposes.
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    DNA origami applications in cancer therapy
    (2017-08-01) Anuttara Udomprasert; Thaned Kangsamaksin; Burapha University; Mahidol University
    © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Due to the complexity and heterogeneity of cancer, the development of cancer diagnosis and therapy is still progressing, and a complete understanding of cancer biology remains elusive. Recently, cancer nanomedicine has gained much interest as a promising diagnostic and therapeutic strategy, as a wide range of nanomaterials possess unique physical properties that can render drug delivery systems safer and more effective. Also, targeted drug delivery and precision medicine have now become a new paradigm in cancer therapy. With nanocarriers, chemotherapeutic drugs could be directly delivered into target cancer cells, resulting in enhanced efficiency with fewer side-effects. DNA, a biomolecule with molecular self-assembly properties, has emerged as a versatile nanomaterial to construct multifunctional platforms; DNA nanostructures can be modified with functional groups to improve their utilities as biosensors or drug carriers. Such applications have become possible with the advent of the scaffolded DNA origami method. This breakthrough technique in structural DNA nanotechnology provides an easier and faster way to construct DNA nanostructures with various shapes. Several experiments proved that DNA origami nanostructures possess abilities to enhance efficacies of chemotherapy, reduce adverse side-effects, and even circumvent drug resistance. Here, we highlight the principles of the DNA origami technique and its applications in cancer therapeutics and discuss current challenges and opportunities to improve cancer detection and targeted drug delivery.
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    Downregulation of abca1 and abcg1 transporters by simvastatin in cholangiocarcinoma cells
    (2019-01-01) Pattaya Seeree; Tavan Janvilisri; Thaned Kangsamaksin; Rutaiwan Tohtong; Supeecha Kumkate; Mahidol University
    © 2019 Spandidos Publications. All rights reserved. Disturbances in cholesterol homeostasis of the bile duct epithelium, including transport interruption and the hyperaccumulation of intracellular cholesterol can lead to the initiation and progression of cholangiocarcinoma (CCA). Statins, which are lipid-lowering drugs, have been previously documented to exhibit anti-cancer properties. The role of statins in CCA cell cholesterol transport through the expression and function of ATP-binding cassette (ABC) A1 and ABCG1 was investigated in the current study. In four CCA cell lines, ABCA1 and ABCG1 expression was identified. However, neither ABCG5 nor ABCG8 expression was observed. Immunocytochemistry revealed that the expression of ABCA1 was localized in the proximity of the nucleus, while ABCG1 was more dispersed throughout the cytoplasm of KKU-100 cells. A cholesterol efflux assay was performed using bodipy cholesterol, and the translocation of cholesterol via ABCA1 and ABCG1 to Apo-A1 and high density lipoprotein was confirmed, respectively. Simvastatin and atorvastatin demonstrated the inhibitory effects on CCA cell viability. A reduction in intracellular lipid level and a lower expression of ABCA1 and ABCG1 were observed in KKU-100 cells under simvastatin treatment. The pre-exposure of KKU-100 cells to cholesterol diminished the statin effect. Furthermore, when KKU-100 cells were pre-loaded with cholesterol, ABCA1 and ABCG1-mediated exports were unaffected even though they were treated with simvastatin. The results of the current study indicated the limitations of the use of statin in CCA therapy, particularly under hypercholesterolemia conditions.
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    Effects of Heteroatom Doping of Carbon Dots from Sugar on Optical Properties, Phenolic Content, Antioxidant Activity, Photostability, and Cytotoxicity
    (2021-04-22) Monthakarn Supjaroenpisan; Rattanavinan Hanchaina; Thaned Kangsamaksin; Peerasak Paoprasert; Mahidol University; Thammasat University
    Carbon dots (CDs) are fascinating nanomaterials with technologically relevant properties; however, the effects of heteroatom doping on several properties of CDs have not been studied. In this work, a facile method for the synthesis and heteroatom doping of carbon dots from table sugar was developed using nitric acid, phosphoric acid, and sulfuric acid as simultaneous catalysts and dopants. The optical properties, phenolic content, antioxidant activity, photostability, and cytotoxicity of the CDs were measured and compared. L-ascorbic acid, a well-known antioxidant, and avobenzone and oxybenzone, common UV absorbers in sunscreens, were used for comparison. Interestingly, heteroatom doping has adverse effects on several properties of the CDs as the undoped CDs yielded the highest UV-vis absorption, phenolic content, antioxidant activity, photostability, and biocompatibility. Only fluorescence quantum yields were improved by heteroatom doping. These findings will be crucial for choosing precursors for the synthesis of CDs because heteroatoms inherently present in precursors can have negative effects on the properties of the resulting CDs.
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    Identification of Biomarkers in Burkholderia Pseudomallei using Whole-Cell Maldi-TOF MS
    (Mahidol University. Mahidol University Library and Knowledge Center, 2023) Suthamat Niyompanich; Sumalee Tungpradabkul; Wilai Noonpakdee; Thaned Kangsamaksin; Jamorn Somana
    Burkholderia pseudomallei is a pathogenic bacterium causing melioidosis, which is a serious human infectious disease with high mortality rates. Rapid identification and classification of B. pseudomallei from various sources could be advantageous for epidemiological tracking, medical prevention, and treatment of melioidosis. The whole-cell matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (whole- cell MALDI-TOF MS), a recently developed proteomics-based bacterial identification approach, could be employed for a rapid, robust, and accurate identification of B. pseudomallei. In this study, eleven isolates of B. pseudomallei collected from environmental and clinical sources were initially used for the whole-cell MALDI-TOF MS analyses; these included five environmental and six clinical isolates. The morphological appearance of most of these bacterial samples was purple, dry, and rough and was classified as morphotype I B. pseudomallei. By whole- cell MALDI-TOF MS approach, these bacteria were reliably identified as B. pseudomallei, based on five taxon- specific biomarkers and the identification scores obtained from BioTyper analysis. Cluster analysis of the environmental and clinical isolates revealed that six out of eleven isolates were correctly clustered according to their isolation sources. Upon further analysis using ClinProTools software, ten source-specific biomarkers were obtained according to their respective sources. Among these, six biomarkers (m/z 4056, 4214, 5814, 7545, 7895, and 8112 Da) were detected specific for the isolates of environmental source, and four (m/z 3658, 6322, 7035, and 7984 Da) were specific for clinical source. The clinical isolate-specific biomarkers were also observed in three laboratory-constructed rpoS, ppk, and bpsI mutants of clinical isolates that possessed single gene mutations in their respective gene locations, confirming their source of origin. Cluster analysis indicated that the wild-type PP844 reference strain, rpoS, ppk, and bpsI strains were separately dispersed. Thus the whole-cell MALDI-TOF MS method could distinguish B. pseudomallei isolates originated from either environmental or clinical sources as well as mutants bearing genetic changes. Moreover, subsequent ClinProTools analysis could identify the potential biomarkers specific to each of the three mutants. In this respect, a total of twelve candidate biomarkers were discovered, specific for each of the three mutant strains. These biomarkers included m/z 2721 and 2748 Da which were specific for the rpoS mutant, m/z 3150, 3378, and 7994 Da for ppk, and seven mass peaks at m/z 3420, 3520, 3587, 3688, 4623, 4708, and 5450 Da for bpsI. The present study is thus the first to establish and identify the source-specific and mutant-specific biomarkers for the identification and classification of B. pseudomallei based on whole-cell MALDI-TOF MS approach. These findings have also broadened the applicability of the whole-cell MALDI-TOF as a laboratory-based tool to rapidly, accurately, and reproducibly identify extensive libraries of the genetically modified bacteria.
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    Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability
    (2013-08-01) Utpal B. Pajvani; Li Qiang; Thaned Kangsamaksin; Jan Kitajewski; Henry N. Ginsberg; Domenico Accili; Columbia University in the City of New York; Mahidol University
    Increased hepatic lipid content is an early correlate of insulin resistance and can be caused by nutrient-induced activation of mammalian target of rapamycin (mTor). This activation of mTor increases basal Akt activity, leading to a self-perpetuating lipogenic cycle. We have previously shown that the developmental Notch pathway has metabolic functions in adult mouse liver. Acute or chronic inhibition of Notch dampens hepatic glucose production and increases Akt activity and may therefore be predicted to increase hepatic lipid content. Here we now show that constitutive liver-specific ablation of Notch signaling, or its acute inhibition with a decoy Notch1 receptor, prevents hepatosteatosis by blocking mTor complex 1 (mTorc1) activity. Conversely, Notch gain of function causes fatty liver through constitutive activation of mTorc1, an effect that is reversible by treatment with rapamycin. We demonstrate that Notch signaling increases mTorc1 complex stability, augmenting mTorc1 function and sterol regulatory element binding transcription factor 1c (Srebp1c)-mediated lipogenesis. These data identify Notch as a therapeutically actionable branch point of metabolic signaling at which Akt activation in the liver can be uncoupled from hepatosteatosis. © 2013 Nature America, Inc. All rights reserved.
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    Lupeol and stigmasterol suppress tumor angiogenesis and inhibit cholangiocarcinoma growth in mice via downregulation of tumor necrosis factor-a
    (2017-12-01) Thaned Kangsamaksin; Supattra Chaithongyot; Chanida Wootthichairangsan; Rattanavinan Hanchaina; Chayada Tangshewinsirikul; Jisnuson Svasti; Mahidol University; Chulabhorn Research Institute
    © 2017 Kangsamaksin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Lupeol and stigmasterol, major phytosterols in various herbal plants, possess anti-inflammatory activities and have been proposed as candidates for anti-cancer agents, but their molecular mechanisms are still unclear. Here, we investigated the effects of lupeol and stigmasterol on tumor and endothelial cells in vitro and their anti-cancer activities in vivo. Our results demonstrated that lupeol and stigmasterol suppressed cell viability, migration, and morphogenesis of human umbilical vein endothelial cells (HUVECs) but not cholangiocarcinoma (CCA) cells. Expression analyses showed that the treatment of both compounds significantly reduced the transcript level of tumor necrosis factor-a (TNF-a), and Western blot analyses further revealed a decrease in downstream effector levels of VEGFR-2 signaling, including phosphorylated forms of Src, Akt, PCL, and FAK, which were rescued by TNF-a treatment. In vivo, lupeol and stigmasterol disrupted tumor angiogenesis and reduced the growth of CCA tumor xenografts. Immunohistochemical analyses confirmed a decrease in CD31-positive vessel content and macrophage recruitment upon treatment. These findings indicate that lupeol and stigmasterol effectively target tumor endothelial cells and suppress CCA tumor growth by their anti-inflammatory activities and are attractive candidates for anticancer treatment of CCA tumors.
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    NOTCH1 regulates the viability of cholangiocarcinoma cells via 14-3-3 theta
    (2019-06-06) Nongnuch Singrang; Suthathip Kittisenachai; Sittiruk Roytrakul; Jisnuson Svasti; Thaned Kangsamaksin; Chulabhorn Research Institute; Mahidol University; Thailand National Center for Genetic Engineering and Biotechnology
    © 2018, The International CCN Society. Notch signaling has been reported to correlate with tumor progression and metastasis in several types of cancer. In cholangiocarcinoma (CCA), it has recently been shown that NOTCH1 is overexpressed in both nucleus and cytoplasm of CCA cells; however, the complete understanding of Notch signaling in CCA is still lacking. Here, we aimed to understand the functions of NOTCH1 in CCA cells and the molecular mechanisms that underlie those functions. We used retroviral vectors to overexpress active forms of NOTCH1, the NOTCH1 intracellular domain (N1ICD) and N1ICD that lacks the RBP-J-associated module (RAM), in human CCA cell lines RMCCA-1 and HuCCA-1. Our results showed that activation of Notch signaling by both N1ICD variants enhanced CCA cell proliferation and survival via upregulation of pro-survival protein Mcl-1 and Bcl-xL. Moreover, our LC-MS/MS proteomic studies demonstrated that NOTCH1 may cooperate with 14-3-3 theta to promote CCA cell survival. Knockdown of 14-3-3 theta in RMCCA-1 cells overexpressing N1ICD, diminished pro-survival effects of N1ICD under gemcitabine treatment. In conclusion, these data demonstrated that NOTCH1 plays a role in CCA cell proliferation and survival via the regulation of 14-3-3 theta in a RAM-independent fashion.
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    Novel solution- and paper-based sensors based on label-free fluorescent carbon dots for the selective detection of pyrimethanil
    (2021-10-30) Preeyanuch Supchocksoonthorn; Rattanavinan Hanchaina; Ma Concepcion Alvior Sinoy; Mark Daniel G. de Luna; Thaned Kangsamaksin; Peerasak Paoprasert; University of the Philippines Diliman; Mahidol University; Thammasat University
    Novel sensors based on fluorescent carbon dots were developed for a rapid, selective, and sensitive detection of pyrimethanil, a fungicide widely used in many agricultural crops. The carbon dots were synthesized from maleic anhydride and triethylenetetramine via a facile one-pot pyrolysis. A quenched fluorescence intensity of carbon dots in the presence of pyrimethanil occurred via inner filter effect and strong π-π interaction. The carbon dots were sensitive to pyrimethanil across a linear range from 0.5 to 75 µM with a low detection limit of 14 nM. The sensing results could be generated in 30 s. The fluorescent carbon dots showed excellent stability and selectivity to pyrimethanil in the presence of interferences, including fungicides and metal ions. They were also successfully employed for pyrimethanil detection in apples, cucumbers, and drinking water, yielding 98.6–107.1% recovery. The practical, portable, and reusable paper-based sensor was also developed. The cytotoxicity of carbon dots was tested to demonstrate that they are sufficiently safe to use. The novel pyrimethanil sensor based on fluorescent carbon dots developed in this work can be used as a high-performance sensor and a rapid tool for quality control in food, agricultural, and environmental monitoring.
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    Selective delivery of doxorubicin using the biomarker-specific, aptamer-functionalized DNA nanosphere
    (2020-02-01) Supattra Chaithongyot; Ratchanee Duangrat; Chanida Wootthichairangsan; Rattanavinan Hanchaina; Anuttara Udomprasert; Thaned Kangsamaksin; Mahidol University; Burapha University
    © 2019 Elsevier B.V. Targeted drug delivery systems have attracted much attention as they can enhance treatment efficiency and minimize cytotoxicity of chemotherapeutic drugs. Several nanomaterials with biological advantages have been explored for novel drug carrier invention. Here, a DNA origami nanosphere modified with a specific aptamer was developed for selective doxorubicin delivery. The specificity of the targeted nanocarrier was investigated against three cell lines with different levels of Mucin 1 (MUC1) expression. Our data showed that the doxorubicin-loaded, MUC1 aptamer-functionalized nanosphere (Dox-Apt-sphere) preferentially delivered drugs and exhibited cytotoxic effects at low Dox concentration in MUC1-high MCF-7 cells. These results also proved that the aptamer-modified DNA nanostructure may serve as a promising candidate for targeted drug delivery.
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    Terrein inhibits migration of human breast cancer cells via inhibition of the Rho and Rac signaling pathways
    (2018-03-01) Anongnard Kasorn; Fabien Loison; Thaned Kangsamaksin; Suchada Jongrungruangchok; Mathurose Ponglikitmongkol; Rangsit University; Vajira Hospital; Mahidol University
    Breast cancer is the most common cancer in women worldwide. Progression and aggressiveness of breast cancer is usually associated with its migration and invasion abilities. Recently, natural products with potential anticancer activity have become attractive candidates for alternative treatment of cancer. A fungal metabolite, terrein, isolated from the Aspergillus terreus has been revealed to exhibit selective anticancer activity; although this molecule has a variety of biological activities. The inhibitory effect on cell proliferation in hepatoma, keratinocytes, and lung cancer cells was due to cell cycle arrest without induction of apoptosis. In contrast, its effects on cervical and breast cancer cells were mediated through activation of the apoptotic process. However, the effect of terrein on cell migration and invasion has not been explored. In the present study we analyzed the molecular effects of terrein on cell adhesion, cell migration, and cell invasion using two breast cancer cell lines, MCF-7 and MDA-MB-231, which exhibit different levels of invasiveness. Terrein induced apoptosis in both breast cancer cell lines in a dose-dependent manner. In addition, at a non-toxic concentration terrein exhibited a weak inhibition of cell adhesion, using either fibronectin or type IV collagen as substrates. Notably, terrein significantly inhibited both the migration and invasion abilities of MDA-MB-231 cells at the same non-toxic concentration. A marked decrease in MMP-2 and MMP-9 transcripts, as evaluated by real-time PCR, confirmed the anti-invasion effect of terrein at the transcriptional level. Western blot analyses revealed that terrein treatment suppressed RhoB expression and reduced Rac1 phosphorylation, leading to Rho GTPase inhibition. In addition, terrein-treated MCF-7 and MDA-MB-231 cells both displayed a scattered pattern of migration, suggesting that the suppression of RhoB and Racl disturbed the collective migration processes of breast cancer cells.
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    Tetrahedral DNA nanostructures as drug delivery and bioimaging platforms in cancer therapy
    (2020-01-01) Ratchanee Duangrat; Anuttara Udomprasert; Thaned Kangsamaksin; Mahidol University; Burapha University
    © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Structural DNA nanotechnology enables DNA to be used as nanomaterials for novel nanostructure construction with unprecedented functionalities. Artificial DNA nanostructures can be designed and generated with precisely controlled features, resulting in its utility in bionanotechnological and biomedical applications. A tetrahedral DNA nanostructure (TDN), the most popular DNA nanostructure, with high stability and simple synthesis procedure, is a promising candidate as nanocarriers in drug delivery and bioimaging platforms, particularly in precision medicine as well as diagnosis for cancer therapy. Recent evidence collectively indicated that TDN successfully enhanced cancer therapeutic efficiency both in vitro and in vivo. Here, we summarize the development of TDN and highlight various aspects of TDN applications in cancer therapy based on previous reports, including anticancer drug loading, photodynamic therapy, therapeutic oligonucleotides, bioimaging platforms, and other molecules and discuss a perspective in opportunities and challenges for future TDN-based nanomedicine.