Effects of resveratrol on the levels of ATP, 5-HT and GAP-43 in the hippocampus of mice exposed to chronic unpredictable mild stress.

Growing evidence suggested that energy deficiency might be involved in the pathophysiological mechanism of depression. Energy deficiency, mainly results from mitochondrial damage, can lead to the dysfunction of synaptic neurotransmission, and further cause depressive-like behavior. The antidepressant effect of resveratrol had been widely demonstrated in previous studies; however, the underlying mechanism remains poorly understood. The present study aimed to investigate whether the antidepressant effects of resveratrol involved in the energy levels and neurotransmission in the hippocampus. We found that resveratrol and fluoxetine significantly attenuated depressive-like behaviors induced by chronic unpredictable mild stress (CUMS), which evidenced by the increased sucrose preference and the reduced immobility time in a forced swimming test. In addition, resveratrol increased hippocampal ATP levels, decreased Na+-K+-ATPase and pyruvate levels, and upregulated the levels of mitochondrial DNA (mtDNA), mRNA expression of sirtuin (SIRT)1 and peroxisome proliferator-activated receptor γ coactivator (PGC)1α. Furthermore, resveratrol and fluoxetine increased serotonin (5-HT) levels and downregulated the mRNA expression of 5-HT transporter (SERT) in the hippocampus. The decreased protein expression of growth-associated protein (GAP)-43 induced by CUMS was also ameliorated by resveratrol and fluoxetine. These findings demonstrated the antidepressant effects of resveratrol and suggested that resveratrol was able to promote mitochondrial biogenesis, enhance ATP and 5-HT levels, as well as upregulate GAP-43 expression in the hippocampus.

Depressive-like behaviors are induced by chronic liver injury in male and female mice.

Depression is a highly prevalent mental disease and increasingly become a global public health problem. Recent studies have shown that the dysfunction of liver was associated with depression. However, the previous studies have not been fully explained the relationship between depression and liver injury. The present study was aimed to investigate whether chronic liver injury could induce depressive-like behavior. Chronic liver injury was induced by intraperitoneal injection of carbon (CCl4), D-galactosamine (D-GalN) and thioacetamide (TAA), respectively. And the results showed that the serum activities of ALT in CCl4, D-GalN and TAA groups were significantly increased in both male and female mice compared with the control group, while the activities of AST increased only in CCl4 group. Meanwhile, H&E staining showed that CCl4, D-GalN and TAA induced hepatocytes injury in both male and female mice. Moreover, the sucrose preference was significantly decreased and the immobility time in forced swimming test and tail suspension test were significantly prolonged in CCl4 and D-GalN group compared with control group. Our findings demonstrated that chronic liver injury induced by CCl4 and D-GalN could induce depressive-like behaviors in mice.

Transcriptomic analysis reveals the mechanism of sulfasalazine-induced liver injury in mice.

Liver injury is one of the main toxic effect of sulfasalazine (SASP). However, the toxicological mechanism of SASP-induced liver injury remains unclear. In the present study, the liver injury was induced by orally treatment with SASP for 4 weeks in mice. The hepatic mRNA profiles were detected by RNA sequencing and the differentially expressed genes (DEGs) were analyzed by bioinformatics methods. The elevated serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TBIL), combined with the hepatic histopathological features verified that liver injury was successfully caused by SASP. Transcriptomic results showed that 187 genes (fold change > 1.5 and P < 0.05) were differentially expressed, of which 106 genes were up-regulated and 81 genes were down-regulated in SASP-treated group. Moreover, the further analysis showed that these 187 differentially expressed genes (DEGs) were enriched in 123 GO terms, which mainly including oxidation-reduction process, oxidoreductase activity and epoxygenase P450 pathway. KEGG pathway analysis showed 30 pathways including chemical carcinogenesis, retinol metabolism, arachidonic acid metabolism, linoleic acid metabolism and glutathione metabolism. Among these 187 DEGs, the top 22 hub genes were screened from network of protein-protein interaction (PPI) and verified by qRT-PCR. The results showed that the mRNA levels of hepatic drug-metabolizing enzymes, including cyp2b50, cyp2c50, cyp2c39, cyp2c38, cyp2c29, cyp2c54, cyp2c55, cyp2a5, gsta1, gsta2, gstt2, gstm2 and ephx1, were significantly up-regulated, while egfr and egr1 were down-regulated in SASP-treated group. Moreover, the mRNA levels of egfr and cyp2c55 exhibited a dose-dependent changes in SASP groups. Western blotting verified that the changes of protein levels of EGFR and CYP2C55 were consistent with mRNA levels. Considering that egfr has the highest score in PPI degree and cyp2c55 has the largest fold change in qPCR analysis, our present results suggested that the toxicological mechanisms of SASP-induced liver injury might be related to multi-biological processes and pathways, and egfr and cyp2c55 may play important roles in SASP-induced liver injury. The present study would be helpful for better understanding the hepatotoxic mechanism of SASP. However, the precise mechanism still needs further research.