Adriamycin induces cardiac fibrosis in mice via PRMT5-mediated cardiac fibroblast activation.

Long-term treatment with adriamycin (ADR) is associated with higher incidences of cumulative cardiotoxicity manifest as heart failure. ADR-induced cardiomyopathy is characterized by extensive fibrosis that is caused by cardiac fibroblast activation. To date, however, no specific treatment is available to alleviate ADR-induced cardiotoxicity. Protein arginine methyltransferase 5 (PRMT5), a major enzyme responsible for methylation of arginine, regulates numerous cellular processes such as cell differentiation. In the present study we investigated the role of PRMT5 in cardiac fibrosis. Mice were administered ADR (3 mg/kg, i.p., every 2 days) for 2 weeks. We showed that aberrant PRMT5 expression was largely co-localized with α-SMA-positive activated cardiac fibroblasts in ADR-injected mice and in ADR-treated cardiac fibroblasts in vitro. PRMT5-overexpression exacerbated, whereas PRMT5 knockdown alleviated ADR-induced cardiac fibrosis in vivo and TGF-ß1-induced cardiac fibroblast activation in vitro. We demonstrated that PRMT5-overexpression enhanced methylated-Smad3 levels in vivo and in vitro. Pretreatment with a specific PRMT5 inhibitor EPZ015666 (5 nM) or overexpression of a catalytically inactive mutant of PRMT5, PRMT5(E444Q), reduced PRMT5-induced methylation of Smad3, thus suppressing PRMT5-mediated cardiac fibroblast activation in vitro. Furthermore, ADR activated cardiac fibroblasts was depending on autocrine TGF-ß1. Taken together, our results demonstrate that PRMT5 promotes ADR-induced cardiac fibrosis via activating cardiac fibroblasts, suggesting that it may be a potential therapeutic target of ADR-caused cardiotoxicity.

Cathelicidin-related antimicrobial peptide protects against enteric pathogen-accelerated type 1 diabetes in mice.

Rationale: Gut barrier disruption caused by enteric pathogen infection results in activated diabetogenic T cells and accelerated type 1 diabetes (T1D). Cathelicidin-related antimicrobial peptide (CRAMP) maintains intestinal barrier integrity, regulates the microbiome, and exerts positive immune-modulatory effects on pancreatic diseases. Methods: The model enteric pathogen Citrobacter rodentium (C. rodentium) was adopted to represent clinical colonic infection with gut barrier disruption. The protective role and gut-pancreas pathophysiological mechanism of CRAMP in enteric pathogen-accelerated T1D were investigated in spontaneous non-obese diabetic (NOD) mice and streptozotocin-induced diabetic mice. Results: Colonic CRAMP production was defective in C. rodentium infection-accelerated T1D. C. rodentium infection triggered the recruitment of interferon-gamma (IFN-γ)+ T cells and accelerated T1D. In the C. rodentium-accelerated T1D mice, CRAMP deficiency further aggravated gut barrier disruption, gut dysbiosis, and diabetic phenotype, which could be reversed by CRAMP treatment. The protective effect of CRAMP may be due to CRAMP inhibiting C. rodentium-aggravated gut immune dysregulation, gut dysbiosis, and migration of gut-primed IFN-γ+ T cells to the pancreas, thus contributing to gut barrier protection and pancreatic-intestinal immune homeostasis. Conclusion: CRAMP plays a pivotal role in pancreatic-gut crosstalk during C. rodentium-accelerated T1D by gut barrier-protective, immune- and microbial-modulatory mechanisms. Cathelicidin supplementation to restore a healthy gut barrier may represent a novel therapeutic strategy for T1D.

[Analysis of food sources of Eriocheir sinensis in rice-crab integrated ecosystem based on stable isotopes in saline-alkali land of the Yellow River Delta]. / åŸºäºŽç¨³å®šåŒä½ç´ çš„é»„æ²³ä¸‰è§’æ´²ç›ç¢±åœ°ç¨»èŸ¹ç§å »ç³»ç»Ÿä¸­åŽç»’èž¯èŸ¹é£Ÿç‰©æºåˆ†æž.

To explore food composition of Chinese mitten crab (Eriocheir sinensis) in rice-crab integrated ecosystem in saline-alkali land of the Yellow River Delta, we analyzed carbon and nitrogen stable isotope ratios (δ13C and δ15N) in the crab and that in food sources, including plants (Elodea, Potamogeton crispus, Ceratophyllum demersum, Lemna minor, Oryza sativa stem and leaf, rice grain), animals (benthos, zooplankton), organic debris and artificial feed (compound feed, corn meal) in Kenli District, Dongying, Shandong Province in June to October of 2020. Substantial differences in δ13C and δ15N were found among food sources. The δ13C and δ15N values of different food sources were in a range of -30.09‰--11.24‰ and 0.03‰-12.78‰, respectively, while those of the crab muscle were in range of -24.61‰--20.08‰ and 4.74‰-9.21‰, respectively, indicating diverse food sources for the crab. During the experiment, the contribution rate of different food sources followed the order: plant (46.7%-57.1%)>animal (21.5%-24.5%)>artificial feed (10.9%-21.3%)>organic detritus (7.1%-7.9%). It suggested that the natural bait of the paddy field could meet the feeding needs of Chinese mitten crabs in saline-alkali land. Even the crabs were fed with non-animal artificial feed, the contribution rates of the main food sources were not altered.

UGT1A1*6 polymorphisms are correlated with irinotecan-induced toxicity: a system review and meta-analysis in Asians.

PURPOSE: Previous studies confirmed that genotyping uridine diphosphate glucuronosyltransferase (UGT) 1A1*28 polymorphisms could predict the side effects in cancer patients using irinotecan (IRI) and then reduce IRI-induced toxicity by preventative treatment or decrease in dose. However, the association between UGT1A1*6 polymorphisms and IRI-induced severe toxicity in Asian patients is still unclear. The aim of this study was to evaluate the association between UGT1A1*6 polymorphisms and IRI-induced severe neutropenia as well as diarrhea in Asian patients. METHODS: We searched all papers on PubMed and Embase from February 1998 to August 2013. Then we assessed the methodologies quality, extracted data and made statistics analysis using STATA software. To uncover the sources of heterogeneity, subgroup meta-analysis was conducted according to the dosage of IRI. RESULTS: Eleven papers were included according to the inclusion and exclusion criteria after searching Pubmed and Embase. Overall, an increased risk of severe toxicity in Asian patients with UGT1A1*6 polymorphisms was found. Patients with heterozygous variant of UGT1A1*6 showed an increased risk [odds ratio (OR) = 1.98, 95 % confidence intervals (CI) 1.45-2.71, P < 0.001], and homozygous mutation showed an even higher risk (OR = 4.44, 95 % CI 2.42-8.14, P < 0.001) for severe neutropenia. For severe diarrhea, heterozygous variant of UGT1A1*6 showed no significant risk, while the homozygous variant performed a notable risk (OR = 3.51, 95 % CI 1.41-8.73, P = 0.007). Subgroup meta-analysis indicated that for patients harboring either heterozygous or homozygous variant, low dose of IRI also presented comparably increased risk in suffering severe neutropenia. CONCLUSION: In this meta-analysis, UGT1A1*6 polymorphisms were revealed as potential biomarkers, predicting IRI-induced severe toxicity in patients from Asia, and increased incidences of severe neutropenia could occur in both high/medium and low doses of IRI.