Urolithin A attenuates hexavalent chromium-induced small

Overview

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Key numbers

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• epithelium-specific knock out of Ppp2r1a (encoding PP2A Aa chromium in Chinese populations was 1.74 mg/L in 2009 to
• 5, 20, and 80 mg/l for 28 successive days. Cr(VI) treatment led chromium in digestive system mainly occurs in small intestine,
• contains two isoforms, Aa and Ab, which are 86% identical same breeding were used as WT control (Fig. 1A). As
• (17). Aa scaffold subunit is responsible for 90% of PP2A ho- expected, PP2A Aa mRNA expression in small intestinal
• loenzyme assemblies. PP2A dysregulation have been linked to tissues from HE and HO mice exhibited 54.43% and 87.9%
• ease, and Alzheimer’s disease (18, 19). The genetic variants in protein levels of HE and HO mice exhibited 45% and 98%
• testine tissue upon Cr(VI) exposure (unpublished data), lead- 58.5% in HE mice, and Aa only existed in lamina propria
• stasis (25, 26). Besides, we previously also showed the PP2A-attributable phosphatase activity (29). Therefore, to
• subunit) and characterized the regulatory role of PP2A in small mice were treated with Cr(VI) at dose of 0, 5, 20, and 80 mg/l
• involved in modulating the destruction or repair of gut barrier in Table S3. There was no significant difference in term of
• Especially, urolithin A could alleviate Cr(VI)-induced disrup- mice following 28 days Cr(VI) exposure (Table S4). H&E
• 825 bp), and HO (825 bp) mice by PCR analysis. B, relative mRNA levels of PP2A Aa in small intestinal tissues from WT, HE, and HO mice (n = 5). C, protein
• occupied compared with WT mice (n = 3). F, representative panoramic images of H&E-stained small intestinal sections from WT, HE, and HO mice (40× and
• dance, the intestinal villi length was decreased by 5.3%, 10.9%, of crypt is regarded as a signature of cell proliferation
• and 19.6%, respectively, in WT mice compared with that in (30). As shown in Figure 2A, the elongation of crypt was
• was more profound than that in WT mice (Fig. 2B), indicating 20 and 80 mg/l Cr(VI) group. Notably, HE mice at 20 and
• that HE mice with PP2A Aa deficiency were more susceptible 80 mg/l Cr(VI) group displayed more apparent structural
• Figure 2. PP2A was involved in Cr(VI)-induced small intestinal injury. WT and HE mice were treated with 0, 5, 20, and 80 mg/l Cr(VI) in drinking water,
• respectively, for 28 days (n = 811). A, representative panoramic images of small intestinal tissues sections stained with H&E in mice (40× and
• 200× magnification). B, the length of intestinal villi (n = 3), (C) depth of intestinal crypt (n = 3), and (D) ratio of intestinal villi length/crypt depth were
• quantified by ImageJ, a total of 45 randomized areas were analyzed in each group. Results were shown as mean ± SD. *p < 0.05, compared with WT control
• Figure 3. The effects of PP2A Aa deficiency on the intestinal barrier function upon Cr(VI) exposure. WT and HE mice treated with 0, 5, 20, and 80 mg/l
• B, the number of goblet cells in indicated group (n = 3) was quantified by ImageJ. C, relative mRNA levels of Muc2 in WT and HE mice treated with Cr(VI) at
• HE mice, even in 5 mg/l group. These observations 6022 genes regarding Cr(VI) exposure in vitro and 1511
• barrier function of intestinal epithelium. We next examined by 42.32% in WT mice upon Cr(VI) exposure, which were
• the intestinal barrier function following Cr(VI) exposure. abolished in HE mice (Fig. 4, A and B). Meanwhile, Cr(VI)
• As illustrated in Figure 3, A and B, the goblet cell counts treatment led to 39.93% increase in transcriptional coac-
• were decreased by 21.3%, 34.30%, and 47.9%, respectively, tivator with PDZ-binding motif (TAZ) protein level. By
• in WT mice with 5, 20, or 80 mg/l Cr(VI) treatment contrast, there was no obvious change in HE mice (Fig. 4, C
• mice, the goblet cell counts were declined by 19.7%, 52.1%, Cry61, Ctgf, and Tnfrsf12a mRNA level were increased in WT
• and 62.0%, respectively, indicating that the impaired in- mice upon Cr(VI) exposure, whereas the induction was
• intestinal secretory protein Muc2 was decreased by 28.0% Prior studies have reported the phosphorylation of YAP1 at
• in WT mice, whereas showed a 38.8% decrease in HE mice Ser127 resulted in the cytoplasmic retention or proteasome
• (Fig. 3D). Meanwhile, occludin expression was decreased by participated in Cr(VI)-induced intestinal toxicity by affecting
• exhibited a lower abundance of occludin and ZO1 were increased by 20.56%, 55.08%, and 77.60%, respectively,
• resulted in 8.78% and 24.39% increase in intestinal cells were mainly located in epithelial layer of villi (Fig. 5, C
• by control (n = 3). F, the intestinal permeability was determined by the concentration of FITC-dextran in serum (n = 3). *p < 0.05, compared with WT control
• immunofluorescence staining with an antibody against YAP1 (green) in small intestinal sections from WT and HE mice treated with 20 mg/l Cr(VI) (40× and
• centage of small intestinal fields occupied (n = 3). *p < 0.05, compared with WT control mice. p < 0.05, compared with HE control mice. Cr(VI), hexavalent
• images of staining with (A) Ki-67 and (C) TUNEL in small intestinal sections WT and HE mice upon 20 mg/l Cr(VI) treatment (200× magnification). The nuclei
• ing (Table S5). Among of them, urolithin A have the lowest The maintenance of apical-basal polarity of IECs depends
• with 20 mg/l Cr(VI) in presence or absence of urolithin A for networks (38). Disruption of intestinal mucosal homeostasis

Methods (brief)

• tivator with PDZ-binding motif protein driving epithelial crypt damage via an in vitro gastrointestinal digestion model (9).
• Cr(VI)-induced impairment of intestinal barrier function. were collected after centrifugation at 3000 rpm for 15 min at 4
• mass spectrometry (Agilent Technologies Co Ltd). tibodies were used: rabbit anti-PP2A Aa, anti-LATS1, anti-p-
• 2018). Four hours thereafter, blood was collected via puncture.
• in vitro gastrointestinal digestion model. Toxicol. Appl. Pharmacol. 436,
• by regulating stability of HuR. Mol. Cell Biol. 38, e00631-17 63. Beaumont, J. J., Sedman, R. M., Reynolds, S. D., Sherman, C. D., Li, L. H.,

Implications

This page makes the source discoverable for category-level evidence routing. Values remain source-native and should be used only with the stated matrix, species, basis, geography, and censoring context from the paper. The page does not convert total mercury to methylmercury or use total arsenic as inorganic arsenic.

Wiki pages this source may touch

• Fish — marine, non-predatory (sardines, anchovies, salmon, cod)
• Arsenic
• Chromium

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