Abstract Background and Aims Antibiotics (ATBx) and acetaminophen (APAP) are widely used worldwide. APAP is the most common cause of acute liver injury (ALI) and might be used in combination with ATBx in clinics. However, the impact of ATBx on APAP‐induced ALI has rarely been studied. Methods First, we compared the effects of seven ATBx on APAP‐induced ALI. Then, we analysed faecal, serum and liver samples to investigate the impact of the gut microbiota on this process. Finally, we assessed the role of short‐chain fatty acids in this process. Results In this work, we found that the ALI was significantly aggravated in the mice treated with ampicillin (Amp) instead of other ATBx. Amp exposure reduced the diversity and altered the composition of gut microbiota. The altered gut microbiota aggravated APAP‐induced ALF, which was proven by faecal microbiota transplantation from ATBx‐treated mice. Metagenomic analysis showed a significantly decreased Lactobacillus abundance in Amp‐treated mice. Gavage with Lactobacillus , especially Lactobacillus rhamnosus , significantly reversed the severer ALF induced by APAP and Amp. Moreover, Lactobacillus supplementation increased butyrate‐producing clostridia and lowered butyrate levels in Amp‐treated mice. In accordance, butyrate supplementation could also alleviate Amp‐aggravated ALI. In addition, inhibition of nuclear factor erythroid 2–related factor 2 counteracted the protective effect of butyrate on aggravated ALI induced by Amp and APAP. Conclusion Together, this study revealed a potential health impact of Amp that may exacerbate liver damage when co‐exposed to excess APAP.
Abstract Background Hypoxia‐inducible factors (HIFs) are thought to play important roles in the carcinogenesis and progression of VHL‐deficient clear cell renal cell carcinoma (ccRCC). Methods The roles of HIF‐1/2α in VHL‐deficient clear cell renal cell carcinoma were evaluated by bioinformatics analysis, immunohistochemistry staining and Kaplan‐Meier survival analysis. The downstream genes that counteract the cancer‐promoting effect of HIF were analysed by unbiased proteomics and verified by in vitro and in vivo assays. Results There was no correlation between the high protein level of HIF‐1/2α and the poor prognosis of ccRCC patients in our large set of clinical data. Furthermore, NDRG1 was found to be up‐regulated by both HIF‐1α and −2α at the cellular level and in ccRCC tissues. Intriguingly, the high NDRG1 expression was correlated with lower Furman grade, TNM stage and longer survival for ccRCC patients compared with the low NDRG1 expression. In addition, NDRG1 suppressed the expression of series oncogenes as well as the proliferation, metastasis and invasion of VHL‐deficient ccRCC cells in vitro and vivo. Conclusions Our study demonstrated that HIF downstream gene of NDRG1 may counteract the cancer‐promoting effect of HIF. These results provided evidence that NDRG1 may be a potential prognostic biomarker as well as a therapeutic target in ccRCC.
Background Calorie restriction (CR) is a therapeutically effective method for nonalcoholic fatty liver disease. However, the compliance of the CR method is relatively poor. New CR methods are needed. Methods and Results Each week, mice are given a 5‐day high‐fat diet (HFD) ad libitum plus 2 days of an intermittent calorie restriction (ICR) diet (50% calorie restriction) consisting of yogurt, fruit, and vegetables, for 16 weeks. The effect of the ICR diet model on the fatty liver of mice is examined. Compared with continuous HFD‐fed mice, the mice feeding HFD+ICR have lower body weight and hepatic steatosis, reduced serum lipid and transaminase levels, increased fatty acid oxidation gene of Cpt1a , and decreased hepatic lipid synthesis gene of Pparγ and Srebf‐1c , as well as improved insulin resistance and lower level of inflammation. Moreover, ICR reverses the dysbacteriosis in HFD group, including the lower Shannon diversity indexes and lower abundance of Lactobacillus . Conclusion An ICR diet consisting of yogurt, fruit, and vegetables attenuates the development of HFD‐induced hepatic steatosis in mice. Furthermore, HFD+ICR diet is associated with a different fecal microbiota that tends to be more similar to normal diet controls.
Tumour cell proliferation requires high metabolism to meet the bioenergetics and biosynthetic needs. Dauer in Caenorhabditis elegans is characterized by lower metabolism, and we established an approach with C elegans to find potential tumour therapy targets.RNAi screening was used to find dauer-related genes, and these genes were further analysed in glp-1(-) mutants for tumour-suppressing testing. The identified tumour-related genes were verified in clinical tumour tissues.The lifespan of glp-1(-) mutants was found to be extended by classical dauer formation signalling. Then, 61 of 287 kinase-coding genes in Caenorhabditis elegans were identified as dauer-related genes, of which 27 were found to be homologous to human oncogenes. Furthermore, 12 dauer-related genes were randomly selected for tumour-suppressing test, and six genes significantly extended the lifespan of glp-1(-) mutants. Of these six genes, F47D12.9, W02B12.12 and gcy-21 were newly linked to dauer formation. These three new dauer-related genes significantly suppressed tumour cell proliferation and thus extended the lifespan of glp-1(-) mutants in a longevity- or dauer-independent manner. The mRNA expression profiles indicated that these dauer-related genes trigged similar low metabolism pattern in glp-1(-) mutants. Notably, the expression of homolog gene DCAF4L2/F47D12.9, TSSK6/W02B12.12 and NPR1/gcy-21 was found to be higher in glioma compared with adjacent normal tissue. In addition, the high expression of TSSK6/W02B12.12 and NPR1/gcy-21 correlated with a worse survival in glioma patients.Dauer gene screening in combination with tumour-suppressing test in glp-1(-) mutants provided a useful approach to find potential targets for tumour therapy via suppressing tumour cell proliferation and rewiring tumour cell metabolism.
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