Cysteinyl leukotrienes synthesis is involved in aristolochic acid I-induced apoptosis in renal proximal tubular epithelial cells

Yang, Hongyu; Dou, Yuan; Zheng, Xuehua; Tan, Yun; Cheng, Jiajun; Li, Lü; Du, Yue; Zhu, Danyan; Lou, Yijia

doi:10.1016/j.tox.2011.05.014

Cited by 28 publications

(24 citation statements)

References 35 publications

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“…Shunting glucose into the pentose phosphate pathway instead of mitochondrial oxidative phosphorylation allows cells to generate NADPH, a key molecule in anti-oxidant defense [76]. The concomitant down-regulation of anti-oxidant proteins such as Sod2 and Gsr (as well as peroxisomal Cat) may be overcome by sufficient dampening of mitochondrial activity, as well as by the up-regulation of oxidative stress-reducing proteins such as Mgst3 [79], and Gpx2 [24]. Other proteins that we found to be differential may also contribute to the detoxification of harmful compounds, such as Nit2 [80], Cbr1, Aldh1a1, as well as other up-regulated dehydrogenases in our dataset (Additional file 5: Table S2) [81,82].…”

Section: Resultsmentioning

confidence: 99%

Colorectal cancer derived organotypic spheroids maintain essential tissue characteristics but adapt their metabolism in culture

et al. 2014

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BackgroundOrganotypic tumor spheroids, a 3D in vitro model derived from patient tumor material, preserve tissue heterogeneity and retain structural tissue elements, thus replicating the in vivo tumor more closely than commonly used 2D and 3D cell line models. Such structures harbour tumorigenic cells, as revealed by xenograft implantation studies in animal models and maintain the genetic makeup of the original tumor material. The aim of our work was a morphological and proteomic characterization of organotypic spheroids derived from colorectal cancer tissue in order to get insight into their composition and associated biology.ResultsMorphological analysis showed that spheroids were of about 250 μm in size and varied in structure, while the spheroid cells differed in shape and size and were tightly packed together by desmosomes and tight junctions. Our proteomic data revealed significant alterations in protein expression in organotypic tumor spheroids cultured as primary explants compared to primary colorectal cancer tissue. Components underlying cellular and tissue architecture were changed; nuclear DNA/ chromatin maintenance systems were up-regulated, whereas various mitochondrial components were down-regulated in spheroids. Most interestingly, the mesenchymal cells appear to be substantial component in such cellular assemblies. Thus the observed changes may partly occur in this cellular compartment. Finally, in the proteomics analysis stem cell-like characteristics were observed within the spheroid cellular assembly, reflected by accumulation of Alcam, Ctnnb1, Aldh1, Gpx2, and CD166. These findings were underlined by IHC analysis of Ctnnb1, CD24 and CD44, therefore warranting closer investigation of the tumorigenic compartment in this 3D culture model for tumor tissue.ConclusionsOur analysis of organotypic CRC tumor spheroids has identified biological processes associated with a mixture of cell types and states, including protein markers for mesenchymal and stem-like cells. This 3D tumor model in which tumor heterogeneity is preserved may represent an advantageous model system to investigate novel therapeutic approaches.

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Section: Resultsmentioning

confidence: 99%

Colorectal cancer derived organotypic spheroids maintain essential tissue characteristics but adapt their metabolism in culture

et al. 2014

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“…The H&E staining was carried out as previously described [32]. Generally, tumor sections from DMSO and AAI groups were embedded with paraffin, and then cut into 5 μm-thick slices.…”

Section: Methodsmentioning

confidence: 99%

Premalignant alteration assessment in liver-like tissue derived from embryonic stem cells by aristolochic acid I exposure

Jin

Zhu

et al. 2016

Oncotarget

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The in vitro predictive evaluation of chemical carcinogenicity based on hepatic premalignance has so far not been established. Here, we report a novel approach to investigate the premalignant events triggered by human carcinogen aristolochic acid I (AAI) in the liver-like tissue derived from mouse embryonic stem cells. By AAI exposure, the liver-like tissue exhibited the paracrine interleukin-6 phenotypic characteristics. Hepatocytes expressed STAT3/p-STAT3, c-Myc and Lin28B in parallel. Some of them displayed the dedifferentiation characteristics, such as full of α-fetoprotein granules, increase in size, and nucleocytoplasmic shuttle of Oct4. When these cells were injected into mice, the xenografts mostly displayed the uniform area of hepatic-like tissue with malignant nuclei. The hepatic malignant markers, α-fetoprotein, cytokeratin 7 and cytokeratin 19, were co-expressed in albumin-positive areas, respectively. In conclusion, we established an approach to predict the hepatic premalignance triggered by carcinogen AAI. This premalignant assay system might aid to evaluate the effects of potential carcinogens in liver, and probably to screen the protecting against hepatocarcinogenic efficacy of pharmaceuticals in vitro.

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“…5). FLAP and cysLT generation are increased renal proximal tubular LLC-PK1 cells in response to aristolochic acid and appear to contribute to apoptosis (142). The FLAP inhibitor decreased aristolochic acid activation of ERK and significantly protected LLC-PK1 cells from apoptosis (142).…”

Section: Renal Inflammation and Apoptosismentioning

confidence: 99%

“…FLAP and cysLT generation are increased renal proximal tubular LLC-PK1 cells in response to aristolochic acid and appear to contribute to apoptosis (142). The FLAP inhibitor decreased aristolochic acid activation of ERK and significantly protected LLC-PK1 cells from apoptosis (142). On the whole, the actions of 12(S)-HETE contribute to renal inflammation and the recent findings of a 12(S)-HETE receptor suggest that receptor antagonists could be beneficial in combating renal injury associated with diabetes.…”

Section: Renal Inflammation and Apoptosismentioning

confidence: 99%

Cytochrome P450 and Lipoxygenase Metabolites on Renal Function

Imig

Khan

2015

Comprehensive Physiology

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Arachidonic acid metabolites have a myriad of biological actions including effects on the kidney to alter renal hemodynamics and tubular transport processes. Cyclooxygenase metabolites are products of an arachidonic acid enzymatic pathway that has been extensively studied in regards to renal function. Two lesser-known enzymatic pathways of arachidonic acid metabolism are the lipoxygenase (LO) and cytochrome P450 (CYP) pathways. The importance of LO and CYP metabolites to renal hemodynamics and tubular transport processes is now being recognized. LO and CYP metabolites have actions to alter renal blood flow and glomerular filtration rate. Proximal and distal tubular sodium transport and fluid and electrolyte homeostasis are also significantly influenced by renal CYP and LO levels. Metabolites of the LO and CYP pathways also have renal actions that influence renal inflammation, proliferation, and apoptotic processes at vascular and epithelial cells. These renal LO and CYP pathway actions occur through generation of specific metabolites and cell-signaling mechanisms. Even though the renal physiological importance and actions for LO and CYP metabolites are readily apparent, major gaps remain in our understanding of these lipid mediators to renal function. Future studies will be needed to fill these major gaps regarding LO and CYP metabolites on renal function.

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Cysteinyl leukotrienes synthesis is involved in aristolochic acid I-induced apoptosis in renal proximal tubular epithelial cells

Cited by 28 publications

References 35 publications

Colorectal cancer derived organotypic spheroids maintain essential tissue characteristics but adapt their metabolism in culture

Colorectal cancer derived organotypic spheroids maintain essential tissue characteristics but adapt their metabolism in culture

Premalignant alteration assessment in liver-like tissue derived from embryonic stem cells by aristolochic acid I exposure

Cytochrome P450 and Lipoxygenase Metabolites on Renal Function

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