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ABSTRACT:
PROVIDER: PRJNA99299 | ENA |
REPOSITORIES: ENA
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Project description:This SuperSeries is composed of the following subset Series:; GSE6960: Synthesis and Anticancer Properties of Water-Soluble Zinc Ionophores 1; GSE6962: Synthesis and Anticancer Properties of Water-Soluble Zinc Ionophores 2 Experiment Overall Design: Refer to individual Series
2008-06-15 | E-GEOD-6972 | biostudies-arrayexpress
Project description:Synthesis and Anticancer Properties of Water-Soluble Zinc Ionophores 2
| PRJNA104131 | ENA
Project description:Synthesis and Anticancer Properties of Water-Soluble Zinc Ionophores 1
| PRJNA104129 | ENA
Project description:We have demonstrated that water-soluble zinc ionophores can be administered to mice at relatively high doses and inhibit the growth of A549 lung cancer cells grown in xenograft models. Gene expression profiles of tumor specimens harvested from mice four hours after treatment confirmed that the activation of stress responsive genes occurs in vivo. These findings lead us to propose that the pharmacologic delivery of zinc to tumors using water solubilized ionophores is a potential approach to cancer therapy. Keywords: Dose response
2007-02-07 | GSE6962 | GEO
Project description:We have shown that water solubilized versions of a zinc ionophore increase intracellular concentrations of free zinc and have antiproliferative activity in exponential phase A549 lung cancer cultures. The gene expression profiles of A549 lung cancer cultures treated with the lead compound PCI-5002 reveal the activation of stress response pathways. Medium supplementation with zinc (25 μM) led to activation of additional oxidative stress response as well as apoptotic pathways. We propose that the pharmacologic delivery of zinc to tumors using water solubilized ionophores is a potential approach to cancer therapy. Keywords: Dose response
2007-02-07 | GSE6960 | GEO
Project description:Zinc (Zn) is a major elemental component of respirable ambient particulate matter (PM) detected often at alarming levels in urban air. Exposure to PM has been widely associated with increased cardiovascular morbidity and mortality, however, it is not known what components or sources of PM are causative. We recently demonstrated that long-term episodic inhalation of combustion PM, having similar amount of Zn found in urban PM, caused myocardial lesions in rats. We further demonstrated that a single pulmonary exposure to Zn at high concentration is associated with disturbances in cardiac mitochondrial function, ion channel regulation, calcium homeostasis, and cell signaling. Therefore, in this study we investigated the role of PM-associated Zn in cardiac injury using multiple exposure scenarios. Male Wistar-Kyoto (WKY) rats of 12-14 wks age were intratracheally exposed (once per wk x 8 or16 wks) to either (1) saline (control); (2) PM having no soluble Zn; (3) combustion PM suspension containing 14.5 ug/mg water-soluble Zn at high and (4) low dose levels, (5) the aqueous fraction of this suspension devoid of solid insoluble particulate fraction (14.5 ug/mg soluble Zn), or (6) Zn sulfate. Zn concentrations were identical in groups 3, 5 and 6. Pulmonary toxicity was apparent in all exposure groups when compared to saline as determined by recovery of cells in bronchoalveolar lavage fluid. Long-term exposure to PM with or without soluble Zn, or Zn sulfate caused distinct myocardial lesions characterized by subepicardial and randomly distributed myocardial inflammation, degeneration, and fibrosis. The lesion severity was higher in those groups receiving Zn PM. Because cardiac mitochondria are likely the primary target of inhaled metal or other absorbed PM components, we analyzed mitochondrial DNA damage using QPCR and found that all exposure groups except those exposed to PM without Zn caused variable degree of damage. Aconitase activity, sensitive to inhibition by oxidative stress was inhibited slightly but significantly in rats receiving zinc sulfate. Although modest, microarray (Affymetrix) analysis revealed expression changes in the heart reflective of effects on cell signaling, inflammation/oxidative stress, mitochondrial fatty acid metabolisms and cell cycle regulation in rats exposed to zinc sulfate. However, these changes were minimal following exposure to PM devoid of soluble metals. We demonstrate that episodic subchronic pulmonary exposure to zinc sulfate causes cardiac injury and mitochondrial DNA damage. Thus, water-soluble PM-associated zinc may be one of the PM components responsible for cardiovascular morbidity. Experiment Overall Design: Group 1 received Saline to serve as a control. Group 2 received Mount St. Helenâs ash, which does not contain any water-soluble zinc or other metals such that we can delineate any cardiac effect secondary to pulmonary deposition of these particles as these fine mode particles themselves are not likely to translocate to the heart. Group 3 received whole saline suspension of the same fugitive oil combustion particle sample used in the previous study, which contained insoluble components plus water-soluble zinc (Kodavanti et al., 2003; 14.5 ug/mg zinc) and also a small amount of water-soluble nickel (3.0 µg/mg). Elemental composition of this PM is comparable to Ottawa urban PM (Kodavanti et al., 2003). Group 4 also received same particle sample but at half the dose than group 3. Group 5 received saline-soluble or leachable fraction of PM-HD devoid of any solid material but contained soluble components including zinc and nickel. And, group 6 received zinc sulfate at concentration that was present in groups 3 or 5. This design allowed us to test if cardiac injury in rats was due to leached of zinc or solid particles. There were 4 replicates per treatment group.
2008-06-14 | E-GEOD-6541 | biostudies-arrayexpress
Project description:This study reports on the co-administration of a zinc ionophore (PBT-2) and ampicillin to break antibiotic resistance of Streptococcus pneumoniae in a murine pneumonia model. The molecular mechanism for this heightened antimicrobial activity was identified through transcriptomic and metabolomic analyses of a wild type strain and a zinc efflux mutant to identify cellular targets of zinc intoxication. This revealed that zinc intoxication induces numerous cellular disruptions, which when combined with frontline antibiotics, can break antibiotic resistance and potentially preclude further resistance from emerging.
2022-02-01 | GSE159901 | GEO
Project description:<p><em>Streptococcus pneumoniae</em> is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multi-drug resistance exceeding 80% and 40%, respectively. The innate immune response generates a variety of antimicrobial agents to control infection including zinc stress. Here, we characterized the impact of zinc intoxication on <em>S. pneumoniae</em>, revealing disruptions in central carbon metabolism, lipid biogenesis and peptidoglycan biosynthesis. Characterization of the pivotal peptidoglycan biosynthetic enzyme GlmU revealed an exquisite sensitivity to zinc inhibition. Disruption of the sole zinc efflux pathway, czcD, rendered <em>S. pneumonia</em>e highly susceptible to β-lactam antibiotics. To dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human use ionophore PBT2. PBT2 rendered wild-type <em>S. pneumoniae</em> strains sensitive to a range of antibiotics. Using an invasive ampicillin-resistant strain, we demonstrate in a murine pneumonia infection model the efficacy of PBT2+ampicillin treatment. These findings present a therapeutic modality to break resistance of drug-resistant <em>S. pneumoniae</em>.</p>
2022-02-23 | MTBLS318 | MetaboLights
Project description:High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers for women, with a low survival rate, no early markers, a high rate of recurrence, and few therapeutic options. Forskolin, an activator of cyclic AMP signaling, has several anticancer activities, including against HGSOC, but has limited use in vivo. Its water-soluble derivative, colforsin daropate, has the same mechanism of action as forskolin and is used to treat acute heart failure. Here, we investigated the potential of colforsin daropate as a treatment for HGSOC. We found that colforsin daropate induced cell cycle arrest and apoptosis in cultured HGSOC cells and spheroids, but not in normal fallopian tube secretory cells and ovarian surface epithelial cells. Colforsin daropate also prevented HGSOC cells from invading ovarian surface cell layers in culture. In vivo, colforsin daropate reduced tumor growth, synergized with cisplatin (a standard chemotherapy in ovarian cancer care), and improved host survival in a subcutaneous xenograft model. These anti-tumor effects of colforsin daropate were mediated in part by its reduction in the abundance and transcriptional activity of the oncoprotein c-MYC, which is often increased in HGSOC. Our findings demonstrate that colforsin daropate may be a promising therapeutic that could be combined with conventional therapies to treat HGSOC.
2024-11-19 | GSE280516 | GEO
Project description:Hexafluoro-2-propanol (HFIP), a water-soluble primary metabolite of the volatile anesthetic sevoflurane, has recently been shown to have favorable properties, improving overall survival in a chronic model of murine peritonitis. The mechanisms of protection provided by HFIP are currently unknown. We therefore performed a gene expression analysis in an in vitro model of endotoxin-induced endothelial cell injury to gain insight into involved molecular mechanisms. Pathway analysis was subsequently performed using the GeneGo Metacore Framework.
2017-03-14 | GSE56256 | GEO