Multi-omics reveals that 5-O-methylvisammioside prevention acute liver injury in mice by regulating the TNF/MAPK/NF-κB/arachidonic acid pathway.

BACKGROUND: The pathogenesis of acute liver injury (ALI) has been a pressing issue in the medical scientific community. We previously found that 5-O-methylvisammioside (MeV) from Saposhnikovia divaricata (Turcz.) Schischk has excellent anti-inflammatory properties. However, the mechanism by which MeV protects against ALI still needs to be deeply investigated. PURPOSE: In the present study, we established an acetaminophen (APAP) -induced ALI mouse model and pre-protected the mice with MeV. METHODS & RESULTS: Our findings indicate that MeV (5 and 10 mg/kg) lowered the blood levels of alanine aminotransferase and aspartate aminotransferase and reduced the infiltration of inflammatory cells in the liver. MeV initially showed an inhibitory effect on ALI. We then analyzed the molecular mechanisms underlying the effects of MeV by transcriptomic and metabolomic analyzes. Through transcriptomic analysis, we identified 4675 differentially expressed genes between the APAP+MeV group and the APAP-induced ALI group, which were mainly enriched in the MAPK pathway, the TNF pathway, and the NF-κB pathway. Through metabolomic analysis, we found that 249 metabolites in the liver were differentially regulated between the APAP+MeV group and the APAP- induced ALI group, which were mainly enriched in the arachidonic acid pathway. The mRNA expression levels of key genes (encoding TNF-α, p38, AP-1, RelB, IL-1ß, and Ptges), as determined by RT-PCR analysis, were consistent with the RNA-seq data. The ELISA results indicate that MeV markedly decreased the serum levels of TNF-α and IL-1ß in mice. Finally, the key proteins in the NF-κB and MAPK pathways were examined using immunoblotting. The results showed that MeV decreased IκB-α phosphorylation and inhibited the nuclear translocation of NF-κB. In addition, MeV reduced the hepatic inflammatory burst mainly by inhibiting the phosphorylation of p38 and JNK in the MAPK pathway. CONCLUSION: The present study demonstrated (i) that MeV could ameliorate APAP-induced ALI by inhibiting arachidonic acid metabolism and the TNF, MAPK, and NF-κB pathways, and (ii) that MeV is a promising drug candidate for the prevention of ALI.

Study on the antidepressant effect of panaxynol through the IκB-α/NF-κB signaling pathway to inhibit the excessive activation of BV-2 microglia.

Panaxynol (PAL) mainly comes from Umbelliferae plants, which has anti-inflammatory and neuroprotective activities. Lipopolysaccharide (LPS)-induced depression in mice was a classic model for studying the effects of drugs on depression in mice. The purpose of this study was to investigate the mechanism and effect of PAL on depression by LPS induced in mice. In the tail suspension test (TST) and forced swimming test (FST) results, PAL significantly reduced the immobility time of mice. In the result of the open field test (OFT) and the elevated plus maze test (EPM), improved their exploration ability. According to the results of ELISA, PAL could significantly reduce the tumor necrosis factor-α (TNF-α) and interleukin- 6 (IL-6) levels in serum. Increase the superoxide dismutase (SDO) level and decrease the malondialdehyde (MDA) level in hippocampus. According to Western blotting analysis results, PAL increased the protein expression of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB), decreased the nuclear transport of nuclear factor kappa-Bp65 (NF-κBp65) and phosphorylation of inhibitor of NF-κB (IκB-α). Meanwhile, PAL also inhibited the production of nitric oxide in BV-2 microglia and decreased the level of inflammatory factors. PAL also reduced levels of oxidative stress and inhibited protein expression in the NF-κB/IκB-α inflammatory pathway and increased the protein expression of BDNF/TrkB, thereby inhibiting the over-activation of BV-2 microglia. In conclusion, according to the results of the behavioral text, it is proved that PAL could effectively alleviate LPS induced depression behavior in mice. The mechanism may be that the anti-inflammatory and anti-oxidative stress effects of PAL reduce the release of inflammatory factors in the mouse brain. Meanwhile, PAL could improve brain neurotrophic factors, inhibit the excessive activation of BV-2 microglia, and further inhibit the depressive state of the mice.

Study on antidepressant-like effect of protoilludane sesquiterpenoid aromatic esters from Armillaria Mellea.

Armillaria mellea, also known as Hazel mushroom, is a delicious food material and traditional herbal medicine in East Asia. Protoilludane sesquiterpenoid aromatic esters from A. mellea (PSAM) are the main active components with antibacterial and anticancer activities. This study explored the antidepressant-like activities of PSAM and its possible mechanisms of action using the open field test (OFT), tail suspension test (TST) and forced swimming test (FST) in mice for the first time. The results revealed that PSAM (1 mg/kg, i.p.) exhibited markedly antidepressant-like activity, which could be reversed by pretreatment with haloperidol (a non-selective D2 receptor antagonist), bicuculline (a competitive GABA antagonist), NMDA (an agonist at the glutamate site). Meanwhile, PSAM also effectively increased the hippocampus dopamine (DA) and γ-aminobutyric acid (GABA) and decreased the hippocampus glutamate (Glu) levels of mice, indicating that the antidepressant-like effect of PSAM might be mediated by the DAergic, GABAergic and Gluergic systems.

The protective effect of 5-O-methylvisammioside on LPS-induced depression in mice by inhibiting the over activation of BV-2 microglia through Nf-κB/IκB-α pathway.

BACKGROUND: 5-O-methylvisammioside (MeV), also known as 4'-O-ß-D-glucosyl-5-O-methylvisamminol, is a conventional marker compound for quality control of roots of Saposhnikovia diviaricata (Radix Saposhnikoviae), which exhibits anti-inflammatory and neuroprotective activities. PURPOSE: According to the activity of MeV, we speculated that MeV may have antidepressant effect on LPS induced depression, and further explored its mechanism. STUDY DESIGN: First, to explore the effect and mechanism of MeV on LPS-induced depression in mice, and then to further explore the effect and mechanism of MeV on LPS-activated BV-2 microglia. METHODS: By the OFT, EPM, TST and FST behavioral tests, to explore the effect of MeV pretreatment on the behavior of LPS-induced depression mice. ELISA and Griess method were used to detect the changes of the serum TNF-α and IL-6 levels, the hippocampus SOD and MDA levels, and the NO, SOD, MDA, TNF-α and IL-6 levels in the culture medium of LPS-stimulated BV-2 microglia. Western blot was used to analyze the protein expression in the Nf-κB/IκB-α and BDNF/TrkB pathway in the hippocampus of mice and BV-2 microglia. RESULTS: MeV (4 mg/kg, i.p.) pretreatment significantly improves the activity and exploration ability of LPS-induced depression mice, and reduces the immobility time. MeV inhibited the production of pro-inflammatory cytokines in the serum of mice induced by LPS, such as IL-6 and TNF-α. MeV also increased the levels of SOD and reduces the expression of MDA in the hippocampus, thus promoting the alleviation of depressive symptoms in mice. Western blotting analysis showed that the antidepressant activity of MeV was related to the decrease of Nf-κB nuclear transport, the inhibition of IκB-α phosphorylation, and the increase of BDNF and TrkB expression. MeV (40 µM) significantly reduced the contents of NO, MDA, TNF-α and IL-6 in the culture medium of LPS-stimulated BV-2 microglia, and increased the content of SOD. CONCLUSION: MeV can regulate the neurotrophic factors in the mouse brain, reduce the content of inflammatory factors by the Nf-κB/IκB-α pathway, improve oxidative stress, and inhibit the excessive activation of LPS-stimulated BV -2 microglia. It effectively reversed the depression-like behAavior induced by LPS in mice.