Patulin triggers NRF2-mediated survival mechanisms in kidney cells

Pillay, Yogan; Phulukdaree, Alisa; Nagiah, Savania; Chuturgoon, Anil A.

doi:10.1016/j.toxicon.2015.03.004

Cited by 21 publications

(8 citation statements)

References 24 publications

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“…The highest concentration used in our study (2.5 μM) is below the upper range cited in previous PAT exposure investigations-but within range of concentrations reported in incidence studies. Previously, a range of PAT concentrations (0-100 μM) was tested on HEK293 cell viability (using the MTT assay) following 24 h exposure 33 . The MTT assay indicated 100 µM PAT reduced HEK293 cell viability to 2% following 24 h exposure and an IC 50 of 2.5 μM was determined.…”

Section: Methodsmentioning

confidence: 99%

“…Preliminary experiments used toxic exposure (2.5 µM PAT) determined from cytotoxic assays in previous studies using the same model 33 , 34 . Concentrations relevant to environmental and safety levels (0.2 µM; 0.5 µM; 1 µM PAT)—determined from incidence, monitor studies and literature were used to validate findings and molecular mechanisms in subsequent assays 2 , 3 .…”

Section: Methodsmentioning

confidence: 99%

“…1). Hence, the effects of 2.5 µM PAT 33,34 on AMPK signalling gene expression was measured using a Super Array Profiler of 84 relevant genes. Fold change > 2 was considered significant (Full array results listed in Supplementary Data S3).…”

Section: Cytotoxic Levels Of Pat Alter α-Adrenergic Receptor Expressimentioning

confidence: 99%

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Patulin suppresses α1-adrenergic receptor expression in HEK293 cells

Pillay

Nagiah

Phulukdaree

et al. 2020

Sci Rep

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Patulin (PAT) is a common mycotoxin contaminant of apple products linked to impaired metabolic and kidney function. Adenosine monophosphate activated protein kinase (AMPK), abundantly expressed in the kidney, intercedes metabolic changes and renal injury. The alpha-1-adrenergic receptors (α1-AR) facilitate Epinephrine (Epi)-mediated AMPK activation, linking metabolism and kidney function. Preliminary molecular docking experiments examined potential interactions and AMPK-gamma subunit 3 (PRKAG3). The effect of PAT exposure (0.2–2.5 µM; 24 h) on the AMPK pathway and α1-AR was then investigated in HEK293 human kidney cells. AMPK agonist Epi determined direct effects on the α1-AR, metformin was used as an activator for AMPK, while buthionine sulphoximine (BSO) and N-acetyl cysteine (NAC) assessed GSH inhibition and supplementation respectively. ADRA1A and ADRA1D expression was determined by qPCR. α1-AR, ERK1/2/MAPK and PI3K/Akt protein expression was assessed using western blotting. PAT (1 µM) decreased α1-AR protein and mRNA and altered downstream signalling. This was consistent in cells stimulated with Epi and metformin. BSO potentiated the observed effect on α1-AR while NAC ameliorated these effects. Molecular docking studies performed on Human ADRA1A and PRKAG3 indicated direct interactions with PAT. This study is the first to show PAT modulates the AMPK pathway and α1-AR, supporting a mechanism of kidney injury.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Patulin suppresses α1-adrenergic receptor expression in HEK293 cells

Pillay

Nagiah

Phulukdaree

et al. 2020

Sci Rep

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“…Nuclear erythroid 2-related factor (NFE2L2) regulates the expression of several antioxidant enzymes, such as glutathione and SOD, via the antioxidant response element (ARE), which confers on this transcription factor a major role in the defense against ROM damage (Kansanen et al, 2013;Pillay et al, 2015). It is noteworthy that Zn has been associated with the activation of the NFE2L2-ARE pathway.…”

Section: Gene Related To Oxidative Stressmentioning

confidence: 99%

Corium molecular biomarkers reveal a beneficial effect on hoof transcriptomics in peripartal dairy cows supplemented with zinc, manganese, and copper from amino acid complexes and cobalt from cobalt glucoheptonate

Osorio

Batistel

Garrett

et al. 2016

Journal of Dairy Science

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Supplying trace minerals in more bioavailable forms such as amino acid complexes (AAC) could help ameliorate the incidence of hoof disorders in peripartal dairy cows. The aim of this study was to evaluate the effects of supplementing metal AAC during the peripartal period on expression of 28 genes in corium tissue related to claw composition, oxidative stress, inflammation, chemotaxis, and transcriptional regulation. Forty-four multiparous Holstein cows received a common diet from -30 to 30 d relative to parturition and were assigned to receive an oral bolus containing either inorganic trace minerals (INO) or AAC (i.e., organic) Zn, Mn, Cu, and Co to achieve supplemental levels of 75, 65, 11, and 1 ppm, respectively, in the total diet dry matter. Inorganic trace minerals were provided in sulfate form, and AAC were supplied via Availa Zn, Availa Mn, Availa Cu, and COPRO (Zinpro Corp., Eden Prairie, MN). Locomotion score was recorded before enrollment and weekly throughout the experiment. Incidence of hoof health problems at 30 d in milk was evaluated before a hoof biopsy in a subset of cows (INO=10; AAC=9). Locomotion score did not differ between treatments in the prepartum or postpartum period. The incidence of heel horn erosion was lower in AAC cows, but the incidence of sole ulcers did not differ. Downregulation of KRT5, CTH, CALML5, and CYBB, and upregulation of BTD in AAC cows indicated a decrease in the need for activation of cellular pathways to regenerate corium tissue and increase biotin availability in the sole claw. These molecular changes in the sole could have been triggered by the lower incidence of heel erosion in response to AAC. Among the genes associated with oxidative stress, the AAC cows had greater expression of NFE2L2, a transcription factor that regulates the antioxidant response, and the antioxidant enzyme SOD1. Among genes associated with inflammation, AAC cows had greater expression of TLR4, and lower expression of TLR2, IL1B, and TNF compared with INO cows. Supplementation with metal AAC during the peripartal period affected the expression of genes involved in composition, oxidative stress, and inflammation status in the corium. The hoof biopsy procedure used in the present study should be further perfected and implemented in future lameness research to expand our understanding of hoof biology in dairy cows.

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“…Additionally, intestinal cell lines (HT-29-D4 and Caco-2-14) exposed to PAT (15 to 100 µM) showed a significant decrease of transepithelial resistance (TER) without major signs of toxicity (Mahfoud et al, 2002). On the other hand, toxic effects were reported in kidney cell lines (Riley and Showker, 1991;Pillay et al, 2015), chinese hamster ovary cell line (CHO-K1) (Ferrer et al, 2009) and human promyelocytic leukaemia (HL-60) cells (Liu et al, 2007) exposed to 0.1 to 100 µM of PAT.…”

Section: Introductionmentioning

confidence: 99%

Effects of patulin and ascladiol on porcine intestinal mucosa: An ex vivo approach

Maidana

Gerez

Khoury

et al. 2016

Food and Chemical Toxicology

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Patulin (PAT) is a secondary metabolite mainly produced by Aspergillus and Penicillium that is frequently found contaminating apples and rotten fruits. Patulin can be transformed in potencially less toxic compounds such as ascladiol (ASC). Toxic effects of patulin were described in rats and in in vitro models, however concerning ascladiol, data are restricted to metabolic pathways. The aim of the present study was to evaluate the effects of different concentrations of PAT (10 μM, 30 μM, 100 μM) and ASC (30 μM, 100 μM) on intestinal tissue using the jejunal explant model. Explants from pigs were exposed for 4 h to PAT and ASC and after this period were processed for histological, morphometrical and immunohistochemical analysis. Mild histological changes were observed in jejunal explants exposed to PAT and ASC, however no significant difference in the lesional score or villi height was observed between the PAT/ASC-groups and the control. Also, explants exposed to 100 μM of PAT showed a significant decrease in goblet cells density and a significant increase in cell apoptosis. These results indicate that high levels of patulin can induce mild toxic effects on intestinal mucosa whereas ascladiol apparently is non-toxic to intestinal tissue.

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Patulin triggers NRF2-mediated survival mechanisms in kidney cells

Cited by 21 publications

References 24 publications

Patulin suppresses α1-adrenergic receptor expression in HEK293 cells

Patulin suppresses α1-adrenergic receptor expression in HEK293 cells

Corium molecular biomarkers reveal a beneficial effect on hoof transcriptomics in peripartal dairy cows supplemented with zinc, manganese, and copper from amino acid complexes and cobalt from cobalt glucoheptonate

Effects of patulin and ascladiol on porcine intestinal mucosa: An ex vivo approach

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