ABSTRACT
BACKGROUND: Baicalin, which is isolated from Radix Scutellariae, possesses strong biological activities including an anti-inflammation property. Recent studies have shown that the anti-inflammatory effect of baicalin is linked to toll-like receptor 4 (TLR4), which participates in pathological changes of central nervous system diseases such as depression. In this study, we explored whether baicalin could produce antidepressant effects via regulation of TLR4 signaling in mice and attempted to elucidate the underlying mechanisms. METHODS: A chronic unpredictable mild stress (CUMS) mice model was performed to explore whether baicalin could produce antidepressant effects via the inhibition of neuroinflammation. To clarify the role of TLR4 in the anti-neuroinflammatory efficacy of baicalin, a lipopolysaccharide (LPS) was employed in mice to specially activate TLR4 and the behavioral changes were determined. Furthermore, we used LY294002 to examine the molecular mechanisms of baicalin in regulating the expression of TLR4 in vivo and in vitro using western blot, ELISA kits, and immunostaining. In the in vitro tests, the BV2 microglia cell lines and primary microglia cultures were pretreated with baicalin and LY292002 for 1 h and then stimulated 24 h with LPS. The primary microglial cells were transfected with the forkhead transcription factor forkhead box protein O 1 (FoxO1)-specific siRNA for 5 h and then co-stimulated with baicalin and LPS to investigate whether FoxO1 participated in the effect of baicalin on TLR4 expression. RESULTS: The administration of baicalin (especially 60 mg/kg) dramatically ameliorated CUMS-induced depressive-like symptoms; substantially decreased the levels of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in the hippocampus; and significantly decreased the expression of TLR4. The activation of TLR4 by the LPS triggered neuroinflammation and evoked depressive-like behaviors in mice, which were also alleviated by the treatment with baicalin (60 mg/kg). Furthermore, the application of baicalin significantly increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and FoxO1. The application of baicalin also promoted FoxO1 nuclear exclusion and contributed to the inhibition of the FoxO1 transactivation potential, which led to the downregulation of the expression of TLR4 in CUMS mice or LPS-treated BV2 cells and primary microglia cells. However, prophylactic treatment of LY294002 abolished the above effects of baicalin. In addition, we found that FoxO1 played a vital role in baicalin by regulating the TLR4 and TLR4-mediating neuroinflammation triggered by the LPS via knocking down the expression of FoxO1 in the primary microglia. CONCLUSION: Collectively, these results demonstrate that baicalin ameliorated neuroinflammation-induced depressive-like behaviors through the inhibition of TLR4 expression via the PI3K/AKT/FoxO1 pathway.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Depression/immunology , Flavonoids/pharmacology , Signal Transduction/drug effects , Toll-Like Receptor 4/drug effects , Animals , Depression/etiology , Forkhead Box Protein O1/metabolism , Inflammation/metabolism , Male , Mice , Mice, Inbred ICR , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Psychological Distress/complications , Psychological Distress/immunology , Toll-Like Receptor 4/biosynthesisABSTRACT
OBJECTIVE: To assess the association of interleukin 10 (IL10) gene -592C/A polymorphism with morbidity of coronary heart disease in a southern Chinese Han population. METHODS: Frequencies of various genotypes and alleles for the IL10 -592C/A polymorphism (rs1800872) were determined by the means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) in 249 patients and 132 unaffected controls. RESULTS: The frequencies of both IL10 -592C/A site and different alleles have reached statistical significance (P<0.05) after correcting the difference in clinical data by logistic regression analysis. The risk of coronary heart disease in the patients with A gene (AA+CA) was 2.449 times greater than those without (95%CI:1.214-4.940, P=0.012). CONCLUSION: IL10 gene -592C/A polymorphism is associated with the risk of coronary heart disease. Allele A may be a risk factor for this disease in the studied population.