tilianin and Inflammation

Although vascular dementia (VaD) is the second most prevalent form of dementia, there is currently a lack of effective treatments. Tilianin, isolated from the traditional drug. Rats with 2-vessel occlusion (2VO), a standard model of VaD, were treated with tilianin, vehicle control, and target overexpression or downregulation. High-throughput sequencing, qRT-PCR, and western blot analyses were utilized to identify the downstream target genes and signaling pathways of tilianin involved in VaD.. Our results showed that tilianin ameliorated cognitive deficits, neurodegeneration, and microglial and astrocytic activation in rats with 2VO. Subsequent high-throughput sequencing and qRT-PCR analyses revealed that tilianin increased the downregulated miR-193b-3p and miR-152-3p levels in the cortex and hippocampus of 2VO rats. Mechanistically, miR-193b-3p targeting CaM and miR-152-3p targeting CaMKIIα were identified to play a role in VaD-associated pathology, inhibiting the p38 MAPK/NF--κB p65 pathway and decreasing TNF-α and IL-6 levels. Further gain- and loss-of-function experiments for these key genes showed that tilianin-exerted cognitive improvement by activating the p38 MAPK/NF--κB p65 and Bcl-2/Bax/caspase-3/PARP pathways in the brain of 2VO rats was abolished by miR-193b-3p and miR-152-3p inhibition. Moreover, CaM and CaMKIIα overexpression eliminated the elevated effects of miR-193b-3p and miR-152-3p on tilianin's protection against ischemic injury through increased inflammatory reactions and apoptotic signaling.. Together, these findings indicate that tilianin improves cognition by regulating the miR-193b-3p/CaM- and miR-152-3p/CaMKIIα-mediated inflammatory and apoptotic pathways, suggesting a potential small-molecule regulator of miRNA associated with inflammatory signaling for VaD treatment.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cognition; Dementia, Vascular; Inflammation; MicroRNAs; p38 Mitogen-Activated Protein Kinases; Rats

We investigated the effect of tilianin upon inducible nitric oxide synthesis in the plasma of low-density lipoprotein receptor knock-out (Ldlr-/-) mice fed with high cholesterol diet and in primary peritoneal macrophages of Ldlr-/- mice. High cholesterol diet induced nitric oxide production in the plasma of Ldlr-/- mice. Tilianin reduced the level of nitric oxide (NO) in plasma from Ldlr-/- mice induced by the high cholesterol diet. Tilianin also inhibited the NO production from the primary culture of peritoneal macrophages treated with lipopolysaccharide. The inhibition of NO production was caused by the suppression of inducible nitric oxide synthase (iNOS) gene expression in peritoneal macrophages isolated from Ldlr-/- mice. Moreover, tilianin inhibited the transcriptional activation of iNOS promoter that has NF-kappaB binding element. Thus, these results provide the first evidence that tilianin inhibit iNOS expression and production of NO and may act as a potential anti-inflammatory agent.

Topics: Animals; Atherosclerosis; Down-Regulation; Flavonoids; Glycosides; Inflammation; Male; Mice; Mice, Knockout; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Promoter Regions, Genetic; Receptors, LDL; Sinus of Valsalva; Tissue Distribution; Tyrosine