Combined histomorphometric and gene-expression profiling applied to toxicology

Kriete, Andres; Anderson, Mary; Love, Brad; Freund, John M.; Caffrey, James L.; Young, M Brook; Sendera, Timothy J.; Magnuson, Scott R.; Braughler, J Mark

doi:10.1186/gb-2003-4-5-r32

Cited by 25 publications

(1 citation statement)

References 31 publications

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“…Body weight gain and histology of major organs were indistinguishable from controls. Toxicogenetics is a powerful method to predict possible toxicity of the drug by analyzing changes in gene expression after administration of a drug 64,65 . We compared the transcriptome of livers of rats treated with 10 mg/kg of C9, i.p.…”

Section: Discussionmentioning

confidence: 99%

Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound

Stefanovic

Manojlovic

Vied

et al. 2019

Sci Rep

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Fibrosis is characterized by excessive production of type I collagen. Biosynthesis of type I collagen in fibrosis is augmented by binding of protein LARP6 to the 5′ stem-loop structure (5′SL), which is found exclusively in type I collagen mRNAs. A high throughput screen was performed to discover inhibitors of LARP6 binding to 5′SL, as potential antifibrotic drugs. The screen yielded one compound (C9) which was able to dissociate LARP6 from 5′ SL RNA in vitro and to inactivate the binding of endogenous LARP6 in cells. Treatment of hepatic stellate cells (liver cells responsible for fibrosis) with nM concentrations of C9 reduced secretion of type I collagen. In precision cut liver slices, as an ex vivo model of hepatic fibrosis, C9 attenuated the profibrotic response at 1 μM. In prophylactic and therapeutic animal models of hepatic fibrosis C9 prevented development of fibrosis or hindered the progression of ongoing fibrosis when administered at 1 mg/kg. Toxicogenetics analysis revealed that only 42 liver genes changed expression after administration of C9 for 4 weeks, suggesting minimal off target effects. Based on these results, C9 represents the first LARP6 inhibitor with significant antifibrotic activity.

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Section: Discussionmentioning

confidence: 99%

Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound

Stefanovic

Manojlovic

Vied

et al. 2019

Sci Rep

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Toxicogenomics

Cunningham

Shah

2010

Pharmaceutical Sciences Encyclopedia

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Cytomics—New technologies: Towards a human cytome project

2004

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Wilson's disease results from mutations in the P‐type Cu2+‐ATPase causing Cu2+ toxicity. We previously demonstrated that exposure of mixed neuronal/glial cultures to 20μM Cu2+ induced ATP loss and death that were attenuated by mitochondrial substrates, activators, and cofactors. Here, we show differential cellular sensitivity to Cu2+ that was equalized to 5 μM in the presence of the copper exchanger/ionophore, disulfiram. Because Cu2+ facilitates formation of oxygen radicals (ROS) which inhibit pyruvate dehydrogenase (PDH) and alpha‐ketoglutarate dehydrogenase (KGDH), we hypothesized that their inhibition contributed to Cu2+‐induced death. Toxic CU2+ exposure was accompanied by early inhibition of neuronal and hepatocellular PDH and KGDH activities, followed by reduced mitochondrial transmembrane potential, ΔΨM. Thiamine (1–6mM), and dihydrolipoic acid (LA, 50μM), required cofactors for PDH and KGDH, attenuated this enzymatic inhibition and subsequent death in all cell types. Furthermore, liver PDH and KGDH activities were reduced in the Atp7b mouse model of Wilson's disease prior to liver damage, and were partially restored by oral thiamine supplementation. These data support our hypothesis that Cu2+‐induced ROS may inhibit PDH and KGDH resulting in neuronal and hepatocellular death. Therefore, thiamine or lipoic acid may constitute potential therapeutic agents for Wilson's disease.

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Combined histomorphometric and gene-expression profiling applied to toxicology

Cited by 25 publications

References 31 publications

Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound

Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound

Toxicogenomics

Cytomics—New technologies: Towards a human cytome project

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