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Microcystin-LR (MC-LR) is widely distributed in the natural environment and causes hepatotoxicity. However, whether MC-LR promotes liver tumor progression remains controversial. kras V12 transgenic zebrafish were used as an inducible liver tumor model to evaluate the potential tumor-promoting effect of MC-LR. First, kras V12 transgenic larvae were exposed to 0, 0.1 and 1 mg/L MC-LR with 20 mg/L doxycycline (Dox) for 4 d. The gray values and histopathological examinations of the liver demonstrated that MC-LR aggravated liver tumor progression, which could be inhibited by the Protein arginine methyltransferase 5 (Prmt5) inhibitor compound 5 (CMP5). Second, 1-month-old juvenile transgenic zebrafish were exposed to 0, 20 mg/L Dox, 1 μg/L MC-LR, and 20 mg/L Dox with 0.1 or 1 μg/L MC-LR for 15 d to determine whether the exposure to environmental concentrations of MC-LR promoted hepatocellular carcinoma (HCC) progression. We found that environmental concentrations of MC-LR increased the hepatosomatic index (HSI) and gray value (intensity/area) and promoted HCC progression. The results indicate that environmental concentrations of MC-LR have the potential to promote liver tumor progression. Taken together, the present study demonstrates that MC-LR can promote tumor in kras V12 transgenic zebrafish and that the upregulation of prmt5 expression might contribute to MC-LR-mediated promotion of liver tumorigenesis. [Display omitted] • KrasV12 transgenic zebrafish were used to evaluate the potential tumor-promoting effect of MC-LR. • MC-LR promotes tumor progression in the kras V12 zebrafish larvae, which could be eliminated by the inhibitor compound 5. • Exposure to environmental concentrations of MC-LR can promote HCC progression in the krasV12 zebrafish juveniles. [ABSTRACT FROM AUTHOR]

As a common organophosphorus flame retardant, tris (2-butoxyethyl) phosphate (TBOEP) is detected in water environment and aquatic animals extensively. Despite previous researches have reported the developmental toxicity of TBOEP in zebrafish (Danio rerio) larvae, few research focused on its underlying mechanisms. In this study, zebrafish embryos were exposed to 0, 20, 200, 1000 and 2000 µg/L TBOEP from 2 until 120 h post-fertilization (hpf) to determine potential mechanisms of developmental toxicity of this compound. Early developmental stage parameters such as body length, survival rate, hatching rate and heart rate were decreased, while malformation rate was ascended. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay was carried out at 12, 24, 72 and 120 hpf to demonstrate alterations in expression of genes of Wnt signaling pathway. The results indicated that axin1 was significantly up-regulated, while β-catenin, pkc and wnt11 were down-regulated. Correlation analysis indicated that expression of these genes was significantly correlated with body length. Furthermore, apoptosis was detected in heart region by acridine orange (AO) staining and terminal deoxynucleotide transferase-mediated deoxy-UTP nick end labeling (TUNEL) assay. In addition, at 120 hpf, occurrence of oxidative stress was observed in zebrafish larvae. Moreover, 6-Bromoindirubin-3′-oxime (BIO)， an activator of Wnt pathway, was found to alleviate the inhibiting effects of TBOEP on zebrafish growth. The overall outcomes offered novel viewpoints in toxic effects of TBOEP, and down-regulating Wnt signaling pathway were able to reveal some potential mechanisms of developmental toxicity of TBOEP in zebrafish larvae. ga1 • TBOEP caused significant inhibition of growth in early developmental stage of zebrafish. • TBOEP decreased heart rate and induced apoptosis. • TBOEP could down-regulate Wnt signaling pathway. • Some toxicity effects of TBOEP could be recovered by the Wnt pathway activator. [ABSTRACT FROM AUTHOR]

Ubiquitinlation of proteins is prevalent and important in both normal and pathological cellular processes. Deubiquitinating enzymes (DUBs) can remove the ubiquitin tags on substrate proteins and dynamically regulate the ubiquitination process. The PPPDE family proteins were predicted to be a novel class of deubiquitinating peptidase, but this has not yet been experimentally proved. Here we validated the deubiquitinating activity of PPPDE1 and revealed its isopeptidase activity against ubiquitin conjugated through Lys 48 and Lys 63. We also identified ribosomal protein S7, RPS7, as a substrate protein of PPPDE1. Moreover, PPPDE1 could mediate the ubiquitin chain editing of RPS7, deubiquitinating Lys 48-linked ubiquitination, and finally stabilize RPS7 proteins. Taken together, we report that PPPDE1 is a novel deubiquitinase that belongs to a cysteine isopeptidase family. [ABSTRACT FROM AUTHOR]