The specific mechanism of gingerol in cerebral ischemia remains unknown. A neuroprotective function for miR‐210 in cerebral ischemia has been identified. The brain‐derived neurotrophic factor (BDNF)‐mediated signaling pathway protects against cerebral ischemic injury. This investigation aimed to determine whether gingerol plays a neuroprotective role in cerebral ischemia via the miR‐210/BDNF axis. N2a cells subjected to 10 h of hypoxia and 4 h of reoxygenation were treated with 5, 10, or 20 μmol/L gingerol. The levels of viability, apoptosis, and proteins in N2a cells were determined using MTT assays, flow cytometry, and western blotting, respectively. The binding relationship between BDNF and miR‐210 was studied using a dual luciferase reporter assay. The expression levels of miR‐210 and BDNF were determined using qPCR. Gingerol repressed the increase in apoptosis and decrease in viability observed in response to hypoxia/reoxygenation. Gingerol increased Bcl‐2, BDNF, and TrkB levels and reduced Bax and cleaved caspase 3 levels after hypoxia/reoxygenation. Gingerol evoked decreased expression of miR‐210. Inhibition of miR‐210 resulted in increased viability and reduced apoptosis along with increased levels of Bcl‐2, BDNF, and TrkB and reduced levels of Bax and cleaved caspase 3 after hypoxia/reoxygenation. Additionally, the miR‐210 mimic reversed changes induced by gingerol. The cotransfection of the miR‐210 mimic and wild type BDNF led to decreased luciferase activity. BDNF was negatively regulated by miR‐210. BDNF siRNA reversed these changes evoked by miR‐210 inhibition. Gingerol ameliorated hypoxia/reoxygenation‐stimulated neuronal damage by regulating the miR‐210/BDNF axis, indicating that gingerol is worthy of further application in cerebral ischemia therapy.
Pachymic acid (PA) plays a neuroprotective role during cerebral ischemia/reperfusion. However, the protective mechanisms of PA in cerebral ischemia/reperfusion have been not fully determined. This investigation aims to explore the neuroprotective role of PA in ischemia/reperfusion via miR‑155/NRF2/HO‑1 axis. The N2a cell line was induced by hypoxia/reoxygenation (H/R) to simulate the neuronal damage that occurs during cerebral ischemia/reperfusion. PA was used to treat H/R‑induced N2a cells. An MTT assay was used to determine cell viability. The protein levels of Bcl‑2, Bax, heme oxygenase‑1 (HO‑1) and nuclear factor E2‑related factor 2 (NRF2) were measured via Western blot analysis. The level of apoptosis of N2a cells was determined by flow cytometry. The expression levels of miR‑155 and NRF2 were quantified by real‑ti me PCR. PA treatment inhibits the increase in apoptosis induced by H/R and also enhances the viability of cells exposed to H/R. PA reverses the increased expression of miR‑155 caused by H/R. Furthermore, H/R does not change the expression of HO‑1 and NRF2, but PA upregulates the expressions of HO‑1 and NRF2. Additionally, NRF2 is the target of miR‑155. Inhibiting miR‑155 contributes to increased cell viability and decreased apoptosis via targeting the NRF2/HO‑1 pathway. Overall, PA prevents neuronal cell damage induced by hypoxia/reoxygenation via miR‑155/ NRF2/HO‑1 axis.
Accumulation of amyloid-β (Aβ) is implicated in the pathogenesis and development of Alzheimer's disease (AD) and it is a prime suspect for causing neuronal loss and cognitive deficits during AD. To explore the mechanisms of Aβ-induced neurodegeneration, we used Aβ-treated primary cortical neuron culture as a cell model of AD and investigated the function of miR-137 in this process. qRT-PCR and western blot were used to examine levels of miR-137, AMPA receptors (AMPARs), p-ERK1/2, and ERK1/2. MTT assay and caspases 3 activity assay were employed to examine cell viability and apoptosis. Dual-luciferase assay was used to validate the interaction between miR-137 and ERK1/2. We found that Aβ decreased cell viability, AMPAR and miR-137 levels, but increased caspase 3 activity in a dose-and time-dependent manner. Overexpression of miR-137 suppressed the Aβ-induced neurotoxicity. MiR-137 directly bound to ERK1/2 mRNA and negatively regulated its expression. Further, overexpression of ERK1/2 blocked the effects of miR-137 mimics on Aβ-induced neurotoxicity. These results provide strong evidence that miR-137 protects neurons against Aβ-induced neurotoxicity via targeting ERK1/2.
Background: The standardized treatment of ischemic stroke (IS) with Shuanglu Tongnao Compound Recipe (SLTNCR) combined with Western medicine has improved the life quality and neurological function of patients and achieved a satisfactory clinical effect. However, the underlying mechanisms of SLTNCR in the treatment of IS remain unclear.Methods: A rat model of IS was prepared using Longa's wire bolus method. SLTNCR was administered by gavage with following doses: low dose, 7.16 g•kg −1 ; middle dose, 14.33 g•kg −1 ; high dose, 28.66 g•kg −1 .The expressions of toll-like receptor 4 (TLR4), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), IL-6, nuclear factor-κB (NF-κB), etc., brain neuron damage, small intestine structure, and the structure of intestinal flora of rats in the high, medium, and low dose SLTNCR groups as well as the Injury + Clostridium butyricum and Injury + Edaravone groups were detected by 16SrRNA gene sequencing, western blot, hematoxylin-eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), and polymerase chain reaction (PCR).Results: SLTNCR significantly reduced the brain water content, decreased the cerebral infarct size, and improved the neurological deficits, neuronal damage, small bowel tissue damage, and expression of inflammatory factors [B-cell CLL/lymphoma 2 (Bcl-2), BCL2 associated agonist of cell death (Bad), cleavedcaspase-3] in brain tissue. SLTNCR administration significantly inhibited expressions of TLR4, NF-κB, and inhibitor of nuclear factor kappa B (IκB), and decreased phosphorylation levels of NF-κB and IκB in the small intestinal tissues of IS rats. Moreover, SLTNCR also significantly upregulated the expression of intestinal barrier function-related molecules [zona occludens 1 (ZO-1), occludin, claudin-5] and regulated the expression of colonic TLR4, TNF-α, IL-6, and IL-1β. SLTNCR can improve the symptoms of IS rats by improving brain and small intestinal function, particularly by regulating the TLR4/NF-κB signaling pathway, apoptotic proteins, and inflammatory factors in brain tissue. Gut microbiota analysis helped to identify the pharmacological mechanisms underlying the effects of SLTNCR on intestinal bacterial diversity and flora structure in IS rats.Conclusions: SLTNCR can alleviate symptoms of IS and the potential mechanism of its effect is to protect brain tissue by suppressing inflammation. SLTNCR can also alter the structure and diversity of the bacterial community in IS.
Objective To explore the mechanism of Wenyang Huayu Formula in the treatment of ischemic stroke based on network pharmacology, molecular docking and experimental verification. Methods The chemical components and potential targets in Wenyang Huayu Formula were obtained by network pharmacology, and the targets related to the pathological process of cerebral ischemia-reperfusion were obtained, and the "drug-component-target-disease" was drawn by Cytoscape software,protein interaction network map was drawn based on STRING database.Gene enrichment analysis was using the Metascape database, and the Autodock vina software was using for molecular docking to determine the pathways and targets of Wenyang Huayu Formula, which were verified by vivo experiments in rats. Results 277 drug targets and 3777 disease targets of Wenyang Huayu Formula were retrieved. The core components were Quercetin, kaempferol, luteolin, etc., and the core targets were AKT1, TP53, IL6, CASP3, IL1β, etc.Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis yielded 222 entries, involving Cellular senescence, TNF signaling pathway, Toll-like receptor signaling pathway, etc. Molecular docking results showed that the core component and the core protein had good binding energy. Vivo experiments results shown that: Stigmasterol, C-Homoerythrinan, luteolin and other components in Wenyang Huayu Formula may act on targets such as IL-6, IL-1β and TNF-α through the TLR4/NF-κB signaling pathway, and play roles in neural protection, reduce reperfusion injury, inhibit apoptosis, anti-inflammatory and other effects. Conclusion The mechanism of ischemic stroke by Wenyang Huayu Formula was the result of multi-component, multi-target and multi-channel interaction, and its mean mechanism may inhibit cell apoptosis, reduce inflammation and promote blood vessels through the TLR4/NF-κB signaling pathway.
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