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Objective Recently, blueberry has been identified as a candidate for the treatment of liver fibrosis. Given the role of gut-liver axis in liver fibrosis and the importance of the gut microbiota homeostasis to the maintenance of the intestinal epithelial barrier, this study aimed to investigate whether blueberry could attenuate liver fibrosis and protect the intestinal epithelial barrier by maintaining the homeostasis of the gut microbiota. Method A CCl4-induced rat liver fibrosis model was used to detect the roles of blueberry in liver fibrosis and intestinal epithelial barrier. The liver weight and body weight were measured, the liver function was monitored by ALT and AST activity, protein and mRNA were determined by western blot and RT-qPCR, and the gut microbiome was detected by Miseq. Results The results showed that blueberry could reduce the rate of liver weight/body weight gain (p < 0.05), ALT (p < 0.01) and AST (p < 0.05) activity, and the expression of collagen I (p < 0.01), collagen IV (p < 0.01), and α-SMA (p < 0.01) expression in CCl4-induced rat liver. CCl4 impaired the intestinal epithelial barrier and decreased the expression of the tight junction protein. Blueberry restored the intestinal epithelial barrier and increased the expression of the tight junction protein. The gut microbiota homeostasis was impaired by CCl4, but after treatment with blueberry, the intestinal flora returned to normal. Conclusion Blueberry attenuated liver fibrosis, protected intestinal epithelial barrier, and maintained the homeostasis of the gut microbiota in a CCl4-induced injury rat model.

To determine the effects ofanthocyanins from blueberries on hepatic stellate cell (HSCs-T6) and on histone acetylation during liver fibrosis induced by CCl4 in rats. Fifty male SD rats weighing 180 ± 20g were randomly placed into a control group, a hepatic fibrosis group, a blueberry treatment group, a blueberry intervention group, and a natural recovery group. After the rats were sacrificed, the livers and the liver indexes were measured, and the pathological changes were observed by HE staining and Masson staining. The blood was analyzed for the four indexes of liver fibrosis and liver function; nucleoprotein from liver tissues and karyoplasm were isolated to determine the expression of acH3K9, acH3K14, and acH3K18 by Western blotting.Compared with the lethal rate of the control group, the median lethal rate of HSCs-T6 cells treated with a the 50μmol/L concentration was 66.94% (P < 0.05). The protein expression on α-SMA, type I collagen, TIMP1 significantly decreased (P < 0.05) following treatment with 50 ug/ml of anthocyanin for 36 h; moreover, the expression of acH3K9, acH3K14 and acH3K18 modification were up-regulated (P < 0.05). Furthermore, compared with the liver in the model group, the liver in the intervention group showed the most obvious improvement (P < 0.01), and its karyoplasm had increased expression of acH3K9, acH3K14 and acH3K18 (P<0.01).Regulating histone acetylation could improve liver function and liver fibrosis indexes in rats with hepatic fibrosis. The mechanism might be related to certain genes that promote apoptosis, so as to inhibit the effect of anti hepatic fibrosis.

ABSTRACT. The objective of this study was to investigate the effects of blueberry treatment on histone acetylation modification of carbon tetrachloride (CCl 4 )-induced liver disease in rats. Laboratory rats were randomly divided into control, hepatic fibrosis, blueberry treatment, blueberry intervention, and natural recovery groups. Rats in the model groups were treated with CCl 4 administered subcutaneously at 4-and 8-week intervals, and then executed. Both the 4-and 8-week treatment groups were treated with blueberry juice for 8 weeks, and then executed after 12 and 16 weeks, respectively. Following the experiment, four liver function and hepatic fibrosis indices were measured. Liver index was calculated, hematoxylin-eosin staining was conducted, and H3K9, H3K14, and H3K18 expressions were evaluated among the nuclear proteins of the liver tissues. No differences in alanine transaminase were noted between the control and intervention groups, but significant differences were detected among the model, treatment, and natural recovery groups (P < 0.01). Significant differences were also observed in aspartate transaminase, hyaluronic acid, and collagen IV among the model, treatment, intervention, and natural recovery groups (P < 0.01, P < 0.01, P < 0.01). Liver index, and H3K9 and H3K14 expression were significantly different among the model groups (P < 0.05 and P < 0.01), whereas H3K18 expression was dramatically different among model, treatment, intervention, and natural recovery groups (P < 0.01). Following blueberry treatment, rat liver function and hepatic fibrosis improved, potentially indicating that blueberry components could regulate histone acetylation and improve liver pathologic changes in rats with CCl 4 -induced disease.

Abstract. The aim of the present study was to investigate the effects of blueberry consumption on the migration, invasion, proliferation, cell cycle and apoptosis in human hepatocellular carcinoma (HCC) cells, in order to provide clinical treatment and prevention strategies for liver cancer using anticancer therapeutic agents. Rabbiteye blueberry was prepared as fresh juice and fed to rats at low, moderate and high dosages (25, 50 and 100%, respectively) by daily gastric gavage. Seven days later, the rats were sacrificed and the blood serum was obtained for co-culture with HEPG2 cells. The MTT assay was used for detecting cell proliferation, Transwell assay was performed for migration and invasion evaluation, and cell cycle and apoptosis were assessed by flow cytometry. After co-culturing with the blood serum of rats that were fed different dosages of blueberry juice, the inhibition rate of HEPG2 cells in the three groups was significantly lower than that in the control group at 48 and 72 h (P<0.05). The number of migrated and transmembrane HEPG2 cells in the three groups was significantly lower than that in the control group at 48 and 72 h (P<0.05). The number of migrated HEPG2 cells in the high dosage group was significantly lower than that in the low dosage group at 48 h, and the numbers of migrated HEPG2 cells in the high and moderate dosage groups were significantly lower than that in the low dosage group at 72 h (P<0.05). The number of transmembrane HEPG2 cells in the high dosage group was significantly lower than that in the low dosage group at 48 h (P<0.05). The numbers of HEPG2 cells at the G 2 /M stage in the three groups were significantly lower than that in the control group, and the number of HEPG2 cells in the high dosage group was significantly lower than that in the low dosage group, at 48 and 72 h (P<0.05). The apoptosis rate in the three groups was significantly higher than that in the control group, and the apoptosis rate in the high dosage group was significantly higher than that in the low dosage group at 48 and 72 h (P<0.05). Thus, blueberries may facilitate the clinical treatment of HCC, providing a novel therapeutic and prevention strategy for HCC as an anticancer therapeutic agent.