Identifying Modulators of hERG Channel Activity Using the PatchXpress® Planar Patch Clamp

Leung, Stewart; Holbrook, April; King, Beverly; Lu, Hong; Evans, V.; Miyamoto, Neil G.; Mallari, Cornell; Harvey, Susan; Davey, Dave; Ho, Elena; Li, Weiwei; Parkinson, John F.; Horuk, Richard; Jaroch, Stefan; Berger, Markus; Skuballa, Werner; West, Christopher M.; Pulk, Rebecca; Phillips, Gary; Bryant, Judi; Subramanyam, Babu; Schaefer, Caralee; Salamon, Hugh; Lyons, Eric; Schilling, Daniela; Seidel, Henrik; Kraetzschmar, Joern; Snider, M E; Pérez, Daniel I.

doi:10.1177/1087057104272394

Cited by 39 publications

(25 citation statements)

References 50 publications

(38 reference statements)

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“…Our findings are consistent with previous studies demonstrating that iron overload suppresses cell-mediated immune responses and inflammation, including production of canonical Th1 cytokines such as IFN-γ or IL-12 (29)(30)(31). However, reduction of iron levels with chelators other than deferasirox has also been shown to suppress Th1 polarization and inflammatory responses and to favor Th2 responses (32,33), so the effects of intracellular iron levels and iron chelation on host immune responses appear to be protean.…”

Section: Figuresupporting

confidence: 82%

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

Ibrahim¹,

Gebermariam²,

Fu³

et al. 2007

J. Clin. Invest.

286

270

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Mucormycosis causes mortality in at least 50% of cases despite current first-line therapies. Clinical and animal data indicate that the presence of elevated available serum iron predisposes the host to mucormycosis. Here we demonstrate that deferasirox, an iron chelator recently approved for use in humans by the US FDA, is a highly effective treatment for mucormycosis. Deferasirox effectively chelated iron from Rhizopus oryzae and demonstrated cidal activity in vitro against 28 of 29 clinical isolates of Mucorales at concentrations well below clinically achievable serum levels. When administered to diabetic ketoacidotic or neutropenic mice with mucormycosis, deferasirox significantly improved survival and decreased tissue fungal burden, with an efficacy similar to that of liposomal amphotericin B. Deferasirox treatment also enhanced the host inflammatory response to mucormycosis. Most importantly, deferasirox synergistically improved survival and reduced tissue fungal burden when combined with liposomal amphotericin B. These data support clinical investigation of adjunctive deferasirox therapy to improve the poor outcomes of mucormycosis with current therapy. As iron availability is integral to the pathogenesis of other infections (e.g., tuberculosis, malaria), broader investigation of deferasirox as an antiinfective treatment is warranted.

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Section: Figuresupporting

confidence: 82%

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

Ibrahim¹,

Gebermariam²,

Fu³

et al. 2007

J. Clin. Invest.

286

270

View full text Add to dashboard Cite

show abstract

“…In addition to reducing iron-catalyzed oxidative damage, iron chelation may suppress some immune functions relevant to EAE and MS. For example, iron chelation was found to suppress TNF␣ production following LPS administration [53], limit mononuclear cell activation in allografts [53], inhibit DNA synthesis in B and T lymphocytes [54] and restrict cytokine-mediated T-cell proliferation [55]. Deferiprone was found to affect T-cell activity in the present study, ie, it suppressed proliferation and decreased viability of stimulated T cells while not affecting unstimulated cells, which was similar to that seen by Hileti et al [56].…”

Section: Discussionmentioning

confidence: 99%

Deferiprone, an orally deliverable iron chelator, ameliorates experimental autoimmune encephalomyelitis

et al. 2007

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The iron chelator, Desferal, suppressed disease activity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), and it has been tested in pilot trials for MS. The administration regimen of Desferal is cumbersome and prone to complications. Orally-deliverable, iron chelators have been developed that circumvent these difficulties, and the objective of this study was to test an oral chelator in EAE. SJL mice with active EAE were randomly assigned to receive deferiprone (150 mg/kg) or vehicle (water) 2x/day via gavage. EAE mice given deferiprone had significantly less disease activity and lower levels of inflammatory cell infiltrates (revealed by H&E staining) than EAE mice administered vehicle. T-cell infiltration, assessed by anti-CD3 immunohistochemical staining, also was reduced, although not significantly. Splenocytes cultured from naïve SJL mice were stimulated with anti-CD3 and anti-CD28 with or without 250 microM deferiprone. While approximately 39% of costimulated splenocytes without deferiprone underwent division, only approximately 2.8% of costimulated splenocytes with deferiprone divided and the latter cells were only 53% as viable as the former. Deferiprone had no effect on proliferation or viability of cells that were not costimulated. In summary, deferiprone effectively suppressed active EAE disease and it inhibited T-cell function.

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“…Th1 cells are sensitive to iron limitation as application of an antibody toward Tfr1 or an iron chelator (Fig. 2) result in reduced proliferation in response to IL-12 and IL-18 and reduced secretion of IFN-␥ (Leung et al, 2005;Thorson et al, 1991). Similarly, Hpx inhibits the expansion of Th17 cells thus ameliorating the course of EAE, but whether or not iron chelators also affect Th17 cell or regulatory T cell proliferation or activity remains unknown (Rolla et al, 2013).…”

Section: Additional Aspects Of Interactions Between Iron and Immune Cmentioning

confidence: 97%

‘Ride on the ferrous wheel’ – The cycle of iron in macrophages in health and disease

et al. 2015

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Identifying Modulators of hERG Channel Activity Using the PatchXpress® Planar Patch Clamp

Cited by 39 publications

References 50 publications

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

The iron chelator deferasirox protects mice from mucormycosis through iron starvation

Deferiprone, an orally deliverable iron chelator, ameliorates experimental autoimmune encephalomyelitis

‘Ride on the ferrous wheel’ – The cycle of iron in macrophages in health and disease

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