Limei Sun,Ming Gao,Qiuhui Qian,Ziyi Guo,Peng Zhu,Xuedong Wang,Huili Wang
Chronic exposure of triclosan (TCS) to zebrafish triggers high incidence of fatty liver and hepatitis; however, the underlying molecular mechanisms remain unclear. Herein, we identified miR-30b as a sensitive biomarker to TCS stress, reflecting in that its decreased expression caused metabolic toxicity, abnormal development and behavior, and lipid-metabolism disorder. By microinjecting the inhibitor and mimic experiments, miR-30b was proved to regulate lipid metabolism by its main target gene fto . Over-expression of FTO resulted in fat accumulation, elevation of the TG and TC levels and up-regulation of the PPARγ and CEBPα, as well as decrease of the global m 6 A level in larvae. On the contrary, the knock-down of FTO using MO caused the anti-lipogenic effect, decrease of the TG and T-CHO levels, and abnormal changes of cebpɑ , acsl 5, fasn , ppap 2c and ppar γ etc. Further fortification tests of cycloleucine and betaine evidenced that the toxic effect was strongly dependent on regulation of the m 6 A level. The toxicity effects in the treatments of methylated donors and receptors were consistent with the changes in physiological functions of FTO knockdown and overexpression. The effects of cycloleucine on m 6 A level and lipid metabolism generally consisted with those of FTO, but this was not the case for betaine, reflecting in increased m 6 A level and lipid accumulation in larval liver. Consequently, we posit that TCS exposure caused zebrafish lipid-metabolism disorder by decreasing miR-30b expression to regulate fto-mediated m 6 A methylation level. These findings contribute to our deep understanding of the underlying molecular mechanisms regarding contaminant-originating fatty liver and hepatocellular carcinoma, and also have practical significance in pollution warning and target therapy for related diseases.
Bei Sun,Hao Ou,Fei Ren,Yujiao Guan,Ye Huan,Hongwei Cai
Cerebral ischemia-reperfusion (CI/R) injury is a serious central nervous system disease. Propofol (PPF) exerts a neuroprotective effect in CI/R injury; the underlying cause is still unclear. Here, we cultured mouse hippocampal neuron (HT22 cells) in oxygen-glucose deprivation/reoxygenation (OGD/R) conditions to mimic CI/R injury in vitro. PPF treatment promoted cell viability and reduced apoptotic cells in the OGD/R-treated HT22 cells, which was effectively abrogated by SNHG14 overexpression. Moreover, we constructed a CI/R injury mouse model on C57BL/6J mice by middle cerebral artery occlusion/reperfusion (MCAO/R), followed by administration of PPF. PPF reduced neuronal damage and loss, enhanced glial cell hyperplasia, and ameliorated cerebral cortex tissue damage and brain infarct in MCAO/R-induced mice. SNHG14 overexpression aggravated MCAO/R-induced CI/R injury in mice. Furthermore, SNHG14 promoted the expression of Atg5 and Beclin 1 via competitively binding miR-30b-5p, which contributed to activate autophagy and apoptosis in HT22 cells. In addition, the levels of p-p38 and p-SP1 were reduced in the OGD/R-treated HT22 cells in the presence of PPF. SP1 interacted with the promoter of SNHG14 and elevated the expression of SNHG14. PPF treatment inhibited the SP1-mediated up-regulation of SNHG14. In conclusion, this work demonstrates that PPF inhibits SNHG14 expression though the p38 MAPK signaling pathway. SNHG14 promotes Atg5 and Beclin 1 expression by sponging miR-30b-5p and thus activates autophagy and aggravates CI/R injury.
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