Ya-Ling Hsu

Kaohsiung Medical University, Kao-hsiung-shih, Kaohsiung, Taiwan

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Publications (97)353.91 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic airway diseases, such as asthma and chronic obstructive pulmonary disease, are characterized by airway remodeling. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis and vascular remodeling, important components of airway remodeling. The aryl hydrocarbon receptor (AhR) is the principle receptor for many environmental toxicants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which may contribute to the pathogenesis of asthma and chronic obstructive pulmonary disease. However, the regulatory role of AhR on the expression of VEGF in bronchial epithelial cells (BECs) remains elusive. This study was conducted to determine the role of AhR in regulating bronchial epithelial VEGF expression, which might contribute to angiogenesis of airway remodeling. The plasma VEGF levels of asthmatic patients and healthy subjects were compared. By treating HBE-135, Beas-2B, and primary human BECs with AhR agonists, the mechanisms through which AhR modulated VEGF expression in human BECs were investigated. The plasma VEGF level was significantly higher in asthmatic patients than in healthy subjects. AhR agonists significantly upregulated VEGF secretion from human BECs, which promoted the migratory and tube-forming ability of human umbilical vein endothelial cells. The secretion of VEGF was increased via a canonical AhR pathway, followed by the 15-LOX/15-HETE/STAT3 pathway. C57BL/6JNarl mice treated with TCDD intratracheally also showed increased VEGF expression in BECs. This hitherto unrecognized pathway may provide a potential target for the treatment of airway remodeling in many pulmonary diseases, especially those related to environmental toxicants. AhR agonists increase VEGF secretion from bronchial epithelial cells. The mechanism involves the canonical AhR pathway and 15-LOX/15-HETE/STAT3 pathway. Asthmatic patients have higher plasma VEGF level. Mice treated with intratracheal TCDD show increased VEGF expression in BECs. This novel regulatory pathway is a potential target for treating asthma and COPD.
    Journal of Molecular Medicine 06/2015; DOI:10.1007/s00109-015-1304-0 · 4.74 Impact Factor
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    ABSTRACT: Bone metastasis in lung cancer results in an unfavorable outcome for patients by not only impairing the quality of life, yet also increasing the cancer-related death rates. In the present study, we discuss a novel treatment strategy that may benefit these patients. Human CD14+ monocytes treated with macrophage-colony stimulating factor (M-CSF)/receptor activator of nuclear factor κB ligand (RANKL) differentiated into osteoclasts, whereas syringetin (SGN), a flavonoid derivative found in both grapes and wine, suppressed the osteoclastogenesis in vitro in a dose‑dependent manner. In addition, SGN inhibited osteoclast formation induced by human lung adenocarcinoma A549 and CL1-5 cells. The associated signaling transduction pathway in osteoclastogenesis and SGN inhibition was found to be via the AKT/mammalian target of rapamycin (mTOR) signaling pathway. Blocking AKT and mTOR by respective inhibitors significantly decreased lung adenocarcinoma-mediated osteoclastogenesis. Moreover, SGN regulated the lung adenocarcinoma-mediated interaction between osteoblasts and osteoclasts by suppressing the stimulatory effect of lung adenocarcinoma on M-CSF and RANKL production in osteoblasts, and reversing the inhibitory effect of the lung adenocarcinoma on OPG production in osteoblasts. The present study has two novel findings. It is the first to illustrate lung adenocarcinoma-mediated interaction between osteoblasts and osteoclasts, leading to osteolytic bone metastasis. It also reveals that SGN, a flavonoid derivative, directly inhibits osteoclastogenesis and reverses lung adenocarcinoma‑mediated osteoclastogenesis. In conclusion, the present study suggests that SGN, a natural compound, prevents and treats bone metastasis in patients with lung cancer.
    Oncology Reports 06/2015; DOI:10.3892/or.2015.4028 · 2.19 Impact Factor
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    ABSTRACT: This is the first study to demonstrate that benzo(a)-pyrene (BaP) was able to enhance the production of parathyroid hormone‑related protein (PTHrP) by human non‑small cell lung cancer H460 cells. Such effect would further contribute to bone metastasis of lung cancer by increasing osteoclastogenesis. This study is also the first to reveal that tricetin (TCN), a flavonoid derivative found in Myrtaceae pollen and Eucalyptus honey, was able to reverse BaP‑mediated bone resorption activity of lung cancer cells. Human non‑small cell lung cancer H460 cells were treated with BaP to generate conditioned medium. When osteoblasts were cultured with BaP‑H460‑CM, their expression of osteoclastogenesis activator macrophage colony‑stimulating factor (M‑CSF) and receptor activator of nuclear factor κB ligand (RANKL) was increased. BaP‑H460‑CM reduced the production of osteoprotegerin (OPG), an osteoclastogenesis inhibitor, in osteoblasts. Osteoclastogenesis and bone resorption activity of H460 cells were increased by BaP‑H460‑CM. With BaP‑mediated PTHrP upregulation, IL‑8 secretion in H460 cells was increased contributing to human non‑small cell lung cancer‑mediated osteoclast differentiation and bone resorption. Moreover, TCN suppressed BaP‑mediated bone resorption. Therefore, TCN may be a novel agent for treatment of non‑small cell lung cancer patients with bone metastasis.
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    ABSTRACT: This study has two novel findings: it is not only the first to demonstrate that tumor-associated dendritic cells (TADCs) facilitate lung and breast cancer metastasis in vitro and in vivo by secreting inflammatory mediator CC-chemokine ligand 2 (CCL2), but it is also the first to reveal that 6-shogaol can decrease cancer development and progression by inhibiting the production of TADC-derived CCL2. Human lung cancer A549 and breast cancer MDA-MB-231 cells increase TADCs to express high levels of CCL2, which increase cancer stem cell features, migration and invasion, as well as immuno-suppressive tumor-associated macrophage infiltration. 6-Shogaol decreases cancer-induced up-regulation of CCL2 in TADCs, preventing the enhancing effects of TADCs on tumorigenesis and metastatic properties in A549 and MDA-MB-231 cells. A549 and MDA-MB-231 cells enhance CCL2 expression by increasing the phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the activation of STAT3 induced by A549 and MDA-MB-231 is completed inhibited by 6-shogaol. 6-Shogaol also decreases the metastasis of lung and breast cancers in mice. 6-Shogaol exerts significant anti-cancer effects on lung and breast cells in vitro and in vivo by targeting the CCL2 secreted by TADCs. Thus, 6-shogaol may have the potential of being an efficacious immuno-therapeutic agent for cancers.
    Journal of Agricultural and Food Chemistry 01/2015; 63(6). DOI:10.1021/jf504934m · 3.11 Impact Factor
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    ABSTRACT: This study is the first to demonstrate that parathyroid hormone-related protein (PTHrP), produced by human breast cancer cells after exposure to phthalate esters, contributes to bone metastasis by increasing osteoclastogenesis. This is also the first to reveal that obtusifolin reverses phthalate esters-mediated bone resorption. Human breast cancer cells were treated with dibutyl phthalate (DBP), harvested in conditioned medium, and cultured to osteoblasts or osteoclasts. Cultures of osteoblasts with DBP-MDA-MB-231-CM increased the osteoclastogenesis activator RANKL (receptor activator of nuclear factor kappa-B ligand) and M-CSF (macrophage colony-stimulating factor). PTHrP was secreted in MDA-MB-231 cells. DBP-MDA-MB-231-CM reduced osteoblasts to produce osteoprotegerin, an osteoclastogenesis inhibitor, while DBP mediated PTHrP up-regulation, increasing IL-8 secretion in MDA-MB-231 and contributing to breast cancer-mediated osteoclast differentiation and bone resorption. Obtusifolin, a major bioactive compound present in Cassia tora L., suppressed phthalate esters-mediated bone resorption. Therefore, obtusifolin may be a novel anti-breast cancer bone metastasis agent.
    Journal of Agricultural and Food Chemistry 11/2014; 62(49). DOI:10.1021/jf5042905 · 3.11 Impact Factor
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    ABSTRACT: The bone is the most common metastatic site of breast cancer. Bone metastasis causes pain, pathologic fractures, and severely reduces the quality of life. Breast cancer causes osteolytic bone metastasis, which is dependent on osteoclast-mediated bone resorption. While current treatments rely on palliative anti-resorptive agents, there is a need to develop a drug based on potential alternative therapies. This study is the first to determine that wedelolactone (WDL), a natural coumarin isolated from plants, can inhibit breast cancer-mediated osteoclastogenesis. Osteoclasts were generated from human CD14+ monocytes cultured with M-CSF/RANKL and WDL suppressed human osteoclast differentiation and activity in vitro in a dose-dependent manner. Moreover, WDL inhibited the upregulation of osteoclasts stimulated by MDA‑MB‑231 breast cancer cells. The activity of WDL on osteoclasts and breast cancer-mediated osteoclastogenesis was associated with the inhibition of Akt/mammalian target of the rapamycin signaling pathway (mTOR). Blocking Akt and mTOR by specific inhibitors significantly decreased osteoclast differentiation and bone resorption. Furthermore, WDL regulated breast cancer-enhanced interaction of osteoblasts and osteoclasts by decreasing M-CSF expression in MDA‑MB‑231-stimulated osteoblasts. Thus, this study suggests that WDL may be a potential natural agent for preventing and treating bone destruction in patients with bone metastasis due to breast cancer.
    International Journal of Oncology 11/2014; 46(2). DOI:10.3892/ijo.2014.2769 · 3.03 Impact Factor
  • Yung-Yu Liang, Po-Lin Kuo, Ya-Ling Hsu
    Cancer Research 10/2014; 74(19 Supplement):5265-5265. DOI:10.1158/1538-7445.AM2014-5265 · 9.28 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):3688-3688. DOI:10.1158/1538-7445.AM2014-3688 · 9.28 Impact Factor
  • Po-Lin Kuo, Jen-Yu Hung, Ya-Ling Hsu
    Cancer Research 10/2014; 74(19 Supplement):2464-2464. DOI:10.1158/1538-7445.AM2014-2464 · 9.28 Impact Factor
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    ABSTRACT: Tumor-associated dendritic cells (TADCs) are important in tumor immune surveillance, and it has been reported that the secretion of interleukin (IL)-10 by cancer cells is a major factor involved in the induction of TADCs in the tumor microenvironment. In the present study, IL-10 was found to activate cluster of differentiation (CD)45 protein tyrosine phosphatase (PTPase), inducing a TADC-like phenomenon. The PTPase inhibitor, phenylarsine oxide, and a CD45 inhibitor reversed the IL-10-induced impaired differentiation of the DCs, and also reversed the induction of the TADCs by A549, MDA-MB-231 and SW480 conditioned media, which thus represents a novel therapy to reduce immune surveillance in the tumor microenvironment. The present study is the first to identify that CD45 is involved in IL-10-activated signaling in myeloid lineage cells.
    Oncology letters 08/2014; 8(2):620-626. DOI:10.3892/ol.2014.2161 · 0.99 Impact Factor
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    Cancer Letters 07/2014; 349(2):154. DOI:10.1016/j.canlet.2013.07.001 · 5.02 Impact Factor
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    Cancer Letters 07/2014; 349(2):153. DOI:10.1016/j.canlet.2013.07.002 · 5.02 Impact Factor
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    ABSTRACT: The interaction between cancer cells and their microenvironment is a paradoxical cycle that exacerbates cancer progression and results in metastasis. The current study investigated the mechanism underlying the synergistic enhancement of release of soluble factors from tumor-associated dendritic cells and its effect on cancer development. The combination of HB-EGF and CXCL5 produced a strong synergistic effect on cancer proliferation, epithelial-mesenchymal transition, migration and invasion. CXCL5 not only potentiated the classical EGFR pathway and the AKT and ERK/RSK1/2 signaling pathways, but also increased the phosphorylation of heat shock protein 27 (HSP27), which was slightly increased in A549 cells treated with either HB-EGF or CXCL5 only. Phosphorylated HSP27 stabilized sustained AKT activity by direct interaction, leading to enhanced tumor spheroid formation. Knockdown of HSP27 by shRNA decreased HB-EGF plus CXCL5-mediated tumor spheroid formation in a 3D culture system, suggesting that AKT/HSP27 was required for HB-EGF/CXCL5-mediated cancer progression. Inhibiting RSK also reduces the modulation of c-Fos phosphorylation, Snail up-regulation and cell migration by HB-EGF plus CXCL5, suggesting a synergistic effect of ERK/RSK and HB-EGF plus CXCL5 on cell migration. In mice, CXCL5 antibody synergistically enhances the efficiency of the tyrosine kinase inhibitor, gefitinib, without increasing its toxicity. These results provide evidence that elucidates potential cross-points between extracellular signals affecting lung cancer progression. Targeting CXCL5 may provide therapeutic benefits for lung cancer chemo- or immuno-therapy. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 07/2014; 135(1). DOI:10.1002/ijc.28673 · 5.01 Impact Factor
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    ABSTRACT: It is believed that endometrial miRNAs contribute to the etiology of endometriosis in stem cells, however, but the mechanisms remains unclear. Here we collected serum samples from patients with or without endometriosis and characterized the miRNA expression profiles of these two groups. MicroRNA-199a-5p (miR-199a-5p) was dramatically down-regulated in patients with endometriosis compared with control patients. In addition, we found that the tumor suppressor gene, SMAD4, could elevate miR-199a-5p expression in ectopic endometrial mesenchymal stem cells. Up-regulation of miR-199a-5p suppressed cell proliferation, motility, and angiogenesis of these ectopic stem cells by targeting the 3' untranslated region of VEGFA. Furthermore, we established an animal model of endometriosis and found that miR-199a-5p could decrease the size of endometriotic lesions in vivo. Taken together, this newly identified miR-199a-5p module provides a new avenue to the understanding of the processes of endometriosis development, especially proliferation, motility as well as angiogenesis, and may facilitate the development of potential therapeutics against endometriosis.
    The Journal of Pathology 02/2014; 232(3). DOI:10.1002/path.4295 · 7.33 Impact Factor
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    ABSTRACT: Tolerogenic dendritic cells (tDCs) play important roles in immune tolerance, autoimmune disease, tissue transplantation, and the tumor micro-environment. Factors that induce tDCs have been reported, however the intracellular mechanisms involved are rarely discussed. Circulating CD14(+)CD16(+) of breast cancer patients and induced CD14(+)CD16(+) DCs were identified as tDCs by treating CD14(+) monocytes with galectin-1 and cancer cell-derived medium combined with IL-4 and GM-CSF. In addition, the 4T1 breast cancer syngeneic xenograft model was used to investigate the effect of galectin-1 in vivo. The CD14(+)CD16(+) tDC population in the breast cancer patients was comparatively higher than that in the healthy donors, and both the MDA-MB-231 conditioned medium and galectin-1 could induce tDC differentiation. In a BALB/c animal model, the 4T1 breast cancer cell line enhanced IL-10 expression in CD11c(+) DCs which was down-regulated after knocking down the galectin-1 expression of 4T1 cells. Analysis of galectin-1 interacting proteins showed that myosin IIa was a major target of galectin-1 after internalization through a caveolin-dependent endocytosis. Myosin IIa specific inhibitor could diminish the effects of galectin-1 on monocyte-derived tDCs and also blocked the 4T1 cells induced CD11c(+)Ly6G(+)IL-10(+) in the BALB/c mice. Galectin-1 can induce tDCs after internalizing into CD14+ monocytes through the caveolae-dependent pathway and activating myosin IIa. For the breast cancer patients with a high galectin-1 expression, blebbistatin and genistein show potential in immune modulation and cancer immunotherapy. General significance myosin IIa activation and galectin-1 endocytosis are important in tumor associated tDC development.
    Biochimica et Biophysica Acta 01/2014; 1840(6). DOI:10.1016/j.bbagen.2014.01.026 · 4.66 Impact Factor
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    ABSTRACT: Gemifloxacin (GMF) is an orally administered broad-spectrum fluoroquinolone antimicrobial agent used to treat acute bacterial exacerbation of pneumonia and bronchitis. Although fluoroquinolone antibiotics have also been found to have anti-inflammatory and anticancer effects, studies on the effect of GMF on treating colon cancer have been relatively rare. To the best of our knowledge, this is the first report to describe the antimetastasis activities of GMF in colon cancer and the possible mechanisms involved. Results have shown that GMF inhibits the migration and invasion of colon cancer SW620 and LoVo cells and causes epithelial mesenchymal transition (EMT). In addition, GMF suppresses the activation of NF- κ B and cell migration and invasion induced by TNF- α and inhibits the TAK1/TAB2 interaction, resulting in decreased I κ B phosphorylation and NF- κ B nuclear translocation in SW620 cells. Furthermore, Snail, a critical transcriptional factor of EMT, was downregulated after GMF treatment. Overexpression of Snail by cDNA transfection significantly decreases the inhibitory effect of GMF on EMT and cell migration and invasion. In conclusion, GMF may be a novel anticancer agent for the treatment of metastasis in colon cancer.
    12/2013; 2013:159786. DOI:10.1155/2013/159786
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    ABSTRACT: This study investigates the anticancer effect of arctigenin (ATG), a natural lignan product of Arctium lappa L., in human breast cancer MDA-MB-231 cells. Results indicate that ATG inhibits MDA-MB-231 cell growth by inducing apoptosis in vitro and in vivo. ATG triggers the mitochondrial caspase-independent pathways, as indicated by changes in Bax/Bcl-2 ratios, resulting in AIF and Endo G nuclear translocation. ATG increased cellular reactive oxygen species (ROS) production by increasing p22(phox)/ NADPH oxidase 1 (NOX1) interaction and decreasing glutathione level. ATG clearly increases the activation of p38 MAPK, but not JNK and ERK1/2. Antioxidant EUK-8, a synthetic catalytic superoxide and hydrogen peroxide scavenger, significantly decreases ATG-mediated p38 activation and apoptosis. Blocking p38 by specific inhibitor suppresses ATG-mediated Bcl-2 downregulation and apoptosis. Moreover, ATG activates ATF-2, a transcription factor activated by p38, then upregulates histone H3K9 trimethylation in the Bcl-2 gene promoter region, resulting in Bcl-2 downregulation. Taken together, the results demonstrate that ATG induces apoptosis of MDA-MB-231 cells via the ROS/p38 MAPK pathway, and epigenetic regulation of Bcl-2 by upregulation of histone H3K9 trimethylation.
    Free Radical Biology and Medicine 10/2013; 67. DOI:10.1016/j.freeradbiomed.2013.10.004 · 5.71 Impact Factor
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    ABSTRACT: [This corrects the article , PMID: 23533526.].
    Evidence-based Complementary and Alternative Medicine 10/2013; 2013:687142. DOI:10.1155/2013/687142 · 1.88 Impact Factor
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    ABSTRACT: Gemifloxacin (GMF) is a fluoroquinolone antibiotic that inhibits bacterial DNA gyrase and topoisomerase IV. The aim of this study was to investigate the anti-metastatic activities of GMF and its possible mechanisms of action, with a special focus on the induction of mesenchymal-epithelial transition (MET). The human breast adenocarcinoma cell lines MDA-MB-231 and MDA-MB-453 were used to assess the anti-metastatic activity of GMF on cell migration and invasion and in scratch wound-healing assays. The effects of GMF on the MET and its regulatory nuclear factor κB (NF-κB)/Snail pathway were assessed. The in vivo anti-metastatic effect of GMF was also evaluated in an animal model. This study demonstrated that GMF inhibited the migration and invasion of MDA-MB-231 and MDA-MB-453 cells and induced the MET. GMF suppressed the activation of NF-κB, as well as the cell migration and invasion induced by tumor necrosis factor α (TNF-α). GMF was shown to inhibit the phosphorylation of the inhibitor of κB (IκB) and the translocation of NF-κB/Snail in both cancer cell lines. This study showed that the Raf kinase inhibitor protein (RKIP), an inhibitor of IκB kinase, is upregulated after GMF treatment. Inhibition of RKIP by small hairpin RNA transfection significantly decreased the inhibitory effect of GMF on the NF-κB/Snail pathway and also inhibited cell migration and invasion. Overexpression of Snail suppressed GMF-mediated metastasis inhibition and E-cadherin upregulation. An animal model revealed that GMF effectively inhibits lipopolysaccharide-mediated metastasis in mice. This study has demonstrated that GMF might be a novel anticancer agent for the prevention and treatment of metastasis in breast cancer. GMF inhibits the migration and invasion of human breast adenocarcinoma cells. GMF induces MET by reducing NF-κB and Snail activation and by increasing RKIP levels. GMF has potential clinical implication as an anti-metastatic agent for breast cancer.
    Journal of Molecular Medicine 09/2013; 92(1). DOI:10.1007/s00109-013-1083-4 · 4.74 Impact Factor
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    ABSTRACT: BACKGROUND: Bone is a common site of metastasis for lung cancer, and is associated with significant morbidity and a dismal prognosis. MicroRNAs (miRNAs) are increasingly implicated in regulating the progression of malignancies. METHODS: The efficacy of miR-33a or anti-miR-33a plasmid was assessed by Real-time PCR. Luciferase assays were using One-Glo Luciferase Assay System. Measurement of secreted factors was determined by ELISA kit. RESULTS: We have found that miR-33a, which is downregulated in lung cancer cells, directly targets PTHrP (parathyroid hormone-related protein), a potent stimulator of osteoclastic bone resorption, leading to decreased osteolytic bone metastasis. We also found that miR-33a levels are inversely correlated with PTHrP expression between human normal bronchial cell line and lung cancer cell lines. The reintroduction of miR-33a reduces the stimulatory effect of A549 on the production of osteoclastogenesis activator RANKL (receptor activator of nuclear factor kappa-B ligand) and M-CSF (macrophage colony-stimulating factor) on osteoblasts, while the expression of PTHrP is decreased in A549 cells. miR-33a overexpression also reduces the inhibitory activity of A549 on the production of OPG (osteoprotegerin), an osteoclastogenesis inhibitor. In addition, miR-33a-mediated PTHrP downregulation results in decreased IL-8 secretion in A549, which contributes to decreased lung cancer-mediated osteoclast differentiation and bone resorption. CONCLUSIONS: These findings have led us to conclude that miR-33a may be a potent tumor suppressor, which inhibits direct and indirect osteoclastogenesis through repression of PTHrP. GENERAL SIGNIFICANCE: miR-33a may even predict a poor prognosis for lung cancer patients.
    Biochimica et Biophysica Acta 02/2013; 1830(6). DOI:10.1016/j.bbagen.2013.02.022 · 4.66 Impact Factor

Publication Stats

2k Citations
353.91 Total Impact Points

Institutions

  • 2004–2015
    • Kaohsiung Medical University
      • • College of Medicine
      • • Institute of Medicine
      • • Institute of Natural Products
      Kao-hsiung-shih, Kaohsiung, Taiwan
  • 2005–2008
    • Chia Nan University of Pharmacy and Science
      • • Department of Biotechnology
      • • Department of Pharmacy
      臺南市, Taiwan, Taiwan