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Sultana N.,Research Institute of Pharmaceutical science | Naz A.,Research Institute of Pharmaceutical science | Naz A.,Ziauddin University | Arayne M.S.,University of Karachi | Mesaik M.A.,University of Karachi
Journal of Molecular Structure | Year: 2010

Gatifloxacin is a potent fluoroquinolone antibacterial agent. It is reported and our previous work has also proved that availability of gatifloxacin is reduced by co-administration of metallic supplements. For better understanding of these interactions, complexes of gatifloxacin were synthesized with Mg(II), Ca(II), Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) (usually present in human body) and their structures were established with the help of spectroscopic studies like IR, UV, and NMR. The IR spectra of the complexes suggest that the gatifloxacin behaves as a monoanionic bidentate ligand. In vitro antibacterial, antifungal, anti-inflammatory and immunosuppressive activities of the gatifloxacin and the complexes were tested. GTX-Ni and GTX-Cu has excellent anti-inflammatory activity. © 2010 Elsevier B.V. All rights reserved.


Lee W.,Research Institute of Pharmaceutical science | Kim K.-M.,Kyungpook National University | Bae J.-S.,Research Institute of Pharmaceutical science
American Journal of Chinese Medicine | Year: 2015

The ubiquitous nuclear protein, high mobility group box 1 (HMGB1), is released by activated macrophages and human umbilical vein endothelial cells (HUVECs) and functions as a late mediator of experimental sepsis. Aspalathin (Asp) and nothofagin (Not), which have been reported to have anti-oxidant activity, are the two major active dihydrochalcones found in green rooibos. In this study, we investigated the antiseptic effects and underlying mechanisms of Asp and Not against HMGB1-mediated septic responses in HUVECs and mice. The anti-inflammatory activities of Asp and Not were determined by measuring permeability, monocyte adhesion and migration, and activation of proinflammatory proteins in HMGB1-activated HUVECs and mice. According to the results, Asp and Not effectively inhibited lipopolysaccharide (LPS)-induced release of HMGB1, and suppressed HMGB1-mediated septic responses, such as hyperpermeability, adhesion and migration of leukocytes, and expression of cell adhesion molecules. In addition, Asp and Not suppressed the production of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), the activation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) by HMGB1. Collectively, these results indicate that Asp and Not could be potential therapeutic agents for the treatment of various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway. © 2015 World Scientific Publishing Company & Institute for Advanced Research in Asian Science and Medicine.


Seok J.-K.,Research Institute of Pharmaceutical science | Seok J.-K.,Kyungpook National University | Lee S.H.,Research Institute of Pharmaceutical science | Kim M.J.,Research Institute of Pharmaceutical science | And 3 more authors.
Nucleic Acids Research | Year: 2014

Recent studies have revealed that microRNAs (miRs) play important roles in the regulation of angiogenesis. In this study, we have characterized miR-382 upregulation by hypoxia and the functional relevance of miR-382 in tumor angiogenesis. miRs induced by hypoxia in MKN1 human gastric cancer cells were investigated using miRNA microarrays. We selected miR-382 and found that the expression of miR-382 was regulated by HIF-1α. Conditioned media (CM) from MKN1 cells transfected with a miR-382 inhibitor (antagomiR-382) under hypoxic conditions significantly decreased vascular endothelial cell (EC) proliferation, migration and tube formation. Algorithmic programs (Target Scan, miRanda and cbio) predicted that phosphatase and tensin homolog (PTEN) is a target gene of miR-382. Deletion of miR382-binding sequences in the PTEN mRNA 3'-untranslated region (UTR) diminished the luciferase reporter activity. Subsequent study showed that the overexpression of miR-382 or antagomiR-382 down- or upregulated PTEN and its downstream target AKT/mTOR signaling pathway, indicating that PTEN is a functional target gene of miR-382. In addition, PTEN inhibited miR-382-induced in vitro and in vivo angiogenesis as well as VEGF secretion, and the inhibition of miR-382 expression reduced xenograft tumor growth and microvessel density in tumors. Taken together, these results suggest that miR-382 induced by hypoxia promotes angiogenesis and acts as an angiogenic oncogene by repressing PTEN. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.


Lee H.-J.,Inje University | Kim K.-W.,Research Institute of Pharmaceutical science | Kim K.-W.,Seoul National University of Science and Technology
Biomolecules and Therapeutics | Year: 2012

The developing embryo naturally experiences relatively low oxygen conditions in vivo. Under in vitro hypoxia, mouse embryonic stem cells (mESCs) lose their self-renewal activity and display an early differentiated morphology mediated by the hypoxiainducible factor-1α (HIF-1α). Previously, we demonstrated that histone deacetylase (HDAC) is activated by hypoxia and increases the protein stability and transcriptional activity of HIF-1α in many human cancer cells. Furthermore HDAC1 and 3 mediate the differentiation of mECSs and hematopoietic stem cells. However, the role of HDACs and their inhibitors in hypoxia-induced early differentiation of mESCs remains largely unknown. Here, we examined the effects of several histone deacetylase inhibitors (HDACIs) on the self-renewal properties of mESCs under hypoxia. Inhibition of HDAC under hypoxia effectively decreased the HIF-1α protein levels and substantially improved the expression of the LIF-specific receptor (LIFR) and phosphorylated-STAT3 in mESCs. In particular, valproic acid (VPA), a pan HDACI, showed dramatic changes in HIF-1α protein levels and LIFR protein expression levels compared to other HDACIs, including sodium butyrate (SB), trichostatin A (TSA), and apicidin (AP). Importantly, our RTPCR data and alkaline phosphatase assays indicate that VPA helps to maintain the self-renewal activity of mESCs under hypoxia. Taken together, these results suggest that VPA may block the early differentiation of mESCs under hypoxia via the destabilization of HIF-1α. © 2012 The Korean Society of Applied Pharmacology.


Park Y.-J.,Research Institute of Pharmaceutical science | Song B.,Seoul National University of Science and Technology | Kim Y.-S.,Research Institute of Pharmaceutical science | Kim E.-K.,Research Institute of Pharmaceutical science | And 8 more authors.
Cancer Research | Year: 2013

How myeloid-derived suppressor cells (MDSC) emerge in the tumor environment remains unclear. Here, we report that GM-CSF can convert natural killer (NK) cells into MDSCs. When transferred into tumor-bearing mice, adoptively transferred NK cells lost their NK phenotype and were converted into Ly6ChighLy6Ghigh MDSC. This conversion was abolished by exposure to IL-2 either in vitro or in vivo. Notably, we found that of the 4 maturation stages based on CD11b/CD27 expression levels, only the CD11bhighCD27high NK cells could be converted into CD11bGr1MDSCex vivo. Transfer of CD27highNKcells from tumor-bearing mice into tumor-bearing recipients was associated with conversion to MDSC in a manner associated with reduced numbers of CD11bhighCD27high and CD11bhighCD27lowNKcell populations in the recipients. Our results identify a pathway ofMDSCdevelopment from immature NK cells in tumor-bearing hosts, providing new insights into how tumor cells modulate their host immune microenvironment to escape immune surveillance. © 2013 American Association for Cancer Research.


Won H.Y.,Center for Cell Signaling and Drug Discovery Research | Min H.J.,Center for Cell Signaling and Drug Discovery Research | Lee W.H.,Research Institute of Pharmaceutical science | Kim S.G.,Research Institute of Pharmaceutical science | Hwang E.S.,Center for Cell Signaling and Drug Discovery Research
Biochemical and Biophysical Research Communications | Year: 2010

G12 family have been known to modulate a variety of cellular events such as cell migration, B cell activation and maturation, cytokine production, and cell differentiation. In particular, Gα12 modulates IgG production, thus induces IgG antibody-mediated immune responses. However, it is largely unknown whether Gα12 is required for T cell-mediated immune functions. In this study, we investigated the effects of Gα12 in the activation and differentiation of CD4+ T cells. While PMA plus ionomycin induced equal levels of IL-2 production in WT and Gα12-deficient lymphocytes, TCR-triggered IL-2 production was significantly attenuated in Gα12 KO lymphocytes. In particular, CD4+ T cells and effector Th cells lacking of Gα12 revealed diminished IL-2 production, but not IFNγ production, upon TCR stimulation. In addition, supplement of IL-2 preferentially induced Gα12-deficient CD4+ T cells into Th2 and Th17 cells; however, the expression of specific transcription factors was unchanged in Gα12 KO Th cells. While IL-2 expression was still diminished by the re-stimulation with anti-CD3, PMA plus ionomycin restored IL-2 production in Gα12-deficient Th1 and Th2 cells. These results suggest that Gα12 may be a critical signaling molecule in TCR-induced IL-2 production and also relay a signal to suppress Th2 and Th17 cell differentiation. © 2010 Elsevier Inc. All rights reserved.


Ozek G.,Anadolu University | Demirci F.,Anadolu University | Ozek T.,Anadolu University | Tabanca N.,University of Mississippi | And 5 more authors.
Journal of Chromatography A | Year: 2010

Four different isolation techniques, conventional hydrodistillation (HD), microwave-assisted hydrodistillation (MWHD), microdistillation (MD) and micro-steam distillation-solid-phase microextraction (MSD-SPME), have been used to analyze the volatile constituents from the aerial parts of Salvia rosifolia Sm. by gas chromatography and gas chromatography coupled to mass spectrometry. HD and MWHD techniques produced quantitatively (yield, 0.39% and 0.40%) and qualitatively (aromatic profile) similar essential oils. α-Pinene (15.7-34.8%), 1,8-cineole (16.6-25.1%), β-pinene (6.7-13.5%), β-caryophyllene (1.4-5.0%) and caryophyllene oxide (1.4-4.4%) were identified as major constituents of this Turkish endemic species. Besides, the hydrodistilled oil of S. rosifolia was evaluated for antibacterial, antifungal, anticancer, antioxidant and cytotoxic activities. The hydrodistilled oil of S. rosifolia showed antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA) with a MIC value of 125 μg/mL. Other human pathogenic microorganisms (Escherichia coli, Pseudomonas aeruginosa, Enterobacter aerogenes, Salmonella typhimurium, Staphylococcus epidermidis, Candida albicans) were also inhibited within a moderate range (MIC = 125-1000 μg/mL). Antifungal activity of the oil was also observed against the strawberry anthracnose-causing fungal plant pathogens Colletotrichum acutatum, C. fragariae and C. gloeosporioides. No cytotoxicity was observed for S. rosifolia oil up to 25 mg/mL against malignant melanoma, epidermal, ductal and ovary carcinoma. © 2009 Elsevier B.V.


Sultana N.,Research Institute of Pharmaceutical science | Arayne M.S.,University of Karachi | Gul S.,Research Institute of Pharmaceutical science | Shamim S.,Research Institute of Pharmaceutical science
Journal of Molecular Structure | Year: 2010

Metal complexes with the third-generation quinolone antibacterial agent sparfloxacin (SPFX) or 5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8,di-fluoro-1-4-dihydro-4-oxo-3-quinocarboxylic acid have been synthesized and characterized with physicochemical and spectroscopic techniques such as TLC, IR, NMR and elemental analyses. In these complexes, sparfloxacin acts as bidentate deprotonated ligands bound to the metal through the pyridone oxygen and one carboxylate oxygen. The antimicrobial activity of these complexes has been evaluated against four Gram-positive and seven Gram-negative bacteria. Antifungal activity against five different fungi has been evaluated and compared with reference drug sparfloxacin. Fe2+-SPFX and Cd2+-SPFX complexes showed remarkable potency as compared to the parent drug. © 2010 Elsevier B.V. All rights reserved.


Lee S.H.,Research Institute of Pharmaceutical science | Jung Y.D.,Research Institute of Pharmaceutical science | Choi Y.S.,Research Institute of Pharmaceutical science | Lee Y.M.,Research Institute of Pharmaceutical science
Oncotarget | Year: 2015

Mature microRNAs (miRNAs) are 21 to 23 nucleotide noncoding RNA molecules that can downregulate multiple gene expression by mRNA degradation or translational repression. miRNAs are considered to play important roles in cell proliferation, apoptosis, and differentiation during mammalian development. The Runt-related transcription factor 3 (RUNX3) expression and activity are frequently downregulated by various mechanisms in gastric cancer. We have reported that RUNX3 inactivation is crucial for early tumorigenesis. In this study, we investigated the role of miRNAs targeting RUNX3 in early tumorigenesis. miR-130a and miR-495 upregulated under hypoxic conditions that bind to the RUNX3 3'-untranslated region (3'-UTR) were identified in gastric cancer cells by using microarray analysis and bioinformatics programs. Combination of miR-130a and miR-495 inhibited RUNX3 expression at the protein level, but not at the mRNA level. miR-130a and miR-495 significantly inhibited the RUNX3-3'UTR-luciferase activity. Combination of miR-130a and miR- 495 significantly decreased apoptosis determined by Annexin V-FITC/propidium iodide staining and flow cytometric analysis, and the expression of Bim in SNU484 gastric cancer cells. In addition, p21 and Bim, RUNX3 target genes, were completely downregulated by the combination of miR-130a and miR-495. Using matrigel plug assay, we found that antagomiRs specific for miR-130a and miR-495 significantly reduced angiogenesis in vivo. In conclusion, targeting miR-130a and miR-495 could be a potential therapeutics to recover RUNX3 expression under hypoxic conditions and in early tumorigenic progression.


Choi S.H.,Research Institute of Pharmaceutical science | Kim Y.W.,Research Institute of Pharmaceutical science | Kim S.G.,Research Institute of Pharmaceutical science
Biochemical Pharmacology | Year: 2010

Isoliquiritigenin (ILQ), a flavonoid compound originated from Glycyrrhiza species, is known to activate SIRT1. Arachidonic acid (AA) in combination with iron (a catalyst of auto-oxidation) leads cells to produce excess reactive species with a change in mitochondrial permeability transition. In view of the importance of oxidative stress in cell death and inflammation, this study investigated the potential of ILQ to protect cells against the mitochondrial impairment induced by AA + iron and the underlying basis for this cytoprotection. Treatment with ILQ inhibited apoptosis induced by AA + iron, as evidenced by alterations in the levels of the proteins associated with cell viability: ILQ prevented a decrease in Bcl-xL, and cleavage of poly(ADP-ribose)polymerase and procaspase-3. Moreover, ILQ inhibited the ability of AA + iron to elicit mitochondrial dysfunction. In addition, superoxide generation in mitochondria was attenuated by ILQ treatment. Consistently, ILQ prevented cellular H2O2 production increased by AA + iron, thereby enabling cells to restore GSH content. ILQ treatment enhanced inhibitory phosphorylation of glycogen synthase kinase-3β (GSK3β), and prevented a decrease in the GSK3β phosphorylation elicited by AA + iron, which contributed to protecting cells and mitochondria. GSK3β phosphorylation by ILQ was preceded by AMP-activated protein kinase (AMPK) activation, which was also responsible for mitochondrial protection, as shown by reversal of its effect in the experiments using a dominant negative mutant of AMPK and compound C. Moreover, the AMPK activation led to GSK3β phosphorylation. These results demonstrate that ILQ has the ability to protect cells from AA + iron-induced H2O2 production and mitochondrial dysfunction, which is mediated with GSK3β phosphorylation downstream of AMPK. © 2009 Elsevier Inc. All rights reserved.

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