Identification of miRNA and Their Regulatory Effects Induced by Total Flavonoids From Dracocephalum moldavica in the Treatment of Vascular Dementia

Abstract

Vascular dementia (VaD) is a general term used to describe difficulties in memory, reasoning, judgment, and planning caused by a reduced blood flow to the brain and consequent brain damage, in which microRNAs (miRNAs) are involved. Dracocephalum moldavica L. (D. moldavica) is traditionally used in the treatment of cardiovascular diseases as well as VaD, but the biomolecular mechanisms underlying its therapeutic effect are obscure. In the present study, the molecular mechanisms involved in the treatment of VaD by the total flavonoids from Dracocephalum moldavica L. (TFDM) were explored by the identification of miRNA profiling using bioinformatics analysis and experimental verification. A total of 2,562 differentially expressed miRNAs (DEMs) and 3,522 differentially expressed genes (DEGs) were obtained from the GSE120584 and GSE122063 datasets, in which the gene functional enrichment and protein-protein interaction network of 93 core targets, originated from the intersection of the top DEM target genes and DEGs, were established for VaD gene profiling. One hundred and eighty-five targets interacting with 42 flavonoids in the TFDM were included in a compound-target network, subsequently found that they overlapped with potential targets for VaD. These 43 targets could be considered in the treatment of VaD by TFDM, and included CaMKII, MAPK, MAPT, PI3K, and KDR, closely associated with the vascular protective effect of TFDM, as well as anti-oxidative, anti-inflammatory, and anti-apoptotic properties. The subsequent analysis of the compound-target gene-miRNA network indicated that eight miRNAs that mediated 43 targets had a close interaction with TFDM, suggesting that the neuroprotective effects were principally due to kaempferol, apigenin, luteolin, and quercetin, which were mostly associated with the miR-3184-3p/ESR1, miR-6762-3p/CDK1, miR-6777-3p/ESRRA, and other related axes. Furthermore, the in vitro oxygen-glucose deprivation (OGD) model demonstrated that the dysregulation of miR-3184-3p and miR-6875-5p found by qRT-PCR was consistent with the changes in the bioinformatics analysis. TFDM and its active compounds involving tilianin, luteolin, and apigenin showed significant effects on the upregulation of miR-3184-3p and downregulation of miR-6875-5p in OGD-injured cells, in line with the improved cell viability. In conclusion, our findings revealed the underlying miRNA-target gene network and potential targets of TFDM in the treatment of VaD.

Tilianin improves cognition in a vascular dementia rodent model by targeting miR-193b-3p/CaM- and miR-152-3p/CaMKIIα-mediated inflammatory and apoptotic pathways

“…With various pharmacological effects that include promoting blood circulation, removing blood stasis, clearing heat, and detoxifying, D. moldavica has a long history as a traditional Chinese medicine for treating cardiovascular and cerebrovascular diseases. In a previous study, we performed comprehensive miRNA profiling and constructed a compound-target gene-miRNA network of TFDM for cerebral ischemic treatment ( 30 ). We also showed that TFDM and its active compounds, namely tilianin, luteolin, and apigenin, protect against OGD injury by upregulating miR-3184-3p and downregulating miR-6875-5p in neuronal cells ( 30 ).…”

“…In a previous study, we performed comprehensive miRNA profiling and constructed a compound-target gene-miRNA network of TFDM for cerebral ischemic treatment ( 30 ). We also showed that TFDM and its active compounds, namely tilianin, luteolin, and apigenin, protect against OGD injury by upregulating miR-3184-3p and downregulating miR-6875-5p in neuronal cells ( 30 ). These findings provide a foundation that dysregulated miRNAs play a role in the therapeutic effect of TFDM and its active components against brain ischemia.…”

“…Tilianin with 99.02% purity, shown by high-performance liquid chromatography (HPLC) was isolated from D. moldavica ( 30 , 36 ). Briefly, the above-ground parts of D. moldavica were ground to powder and refluxed three times with 40% ethanol at 100 °C.…”

“…MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression ( 5 ). Some miRNAs, such as miR-15a/16-1 ( 28 ), miR-93 ( 29 ), miR-3184-3p, miR-6875-5p ( 30 ), and miR-126 ( 31 ), play a role in the pathological process of VaD since they have been involved in cognitive impairment, vascular dysfunction, neuroinflammatory response, blood-brain barrier destruction, and synaptic loss. There is also evidence that miRNAs play a regulatory role in aberrant CaM/CaMKII cascades in ischemia and reperfusion.…”

Role of traditional Chinese medicine in ameliorating mitochondrial dysfunction via non-coding RNA signaling: Implication in the treatment of neurodegenerative diseases

“…Traditional Chinese medicine (TCM) has become one of the most important sources for exploring and developing modern medicines due to their application in treating various diseases for more than 5,000 years (Wang et al, 2018). Additionally, TCM can be further optimized to treat complex diseases due to its multicomponent, multi-target, and multi-pathway synergistic effects (Liu et al, 2021a;Cai et al, 2022a). Over the past few years, TCM has received increasing attention in treating NDs, and many NDs treatments of TCM origin are in different clinical trial stages (Shan et al, 2018).…”