Exploring the mechanism of safflower in treating ischemic stroke based on network pharmacology and molecular docking technology
In recent years, the disability and mortality rates of ischemic stroke have continued to rise. Ischemic stroke is the most common type of stroke, which occurs when blood vessels in the neck or brain are blocked, causing local ischemia and hypoxia in brain tissue, leading to neurological disorders such as softening or even necrosis of brain tissue. At present, Western medicine treatments for ischemic stroke include antiplatelet therapy, acute phase antihypertensive treatment, skull resection for hematoma removal, intraventricular tube drainage, minimally invasive puncture hematoma clearance, etc. These methods are rapid and effective, but also come with some side effects, such as postoperative bleeding, infection and nerve damage, and risks of insufficient cerebral perfusion pressure. At present, the main effects of traditional Chinese medicine in improving ischemic stroke include combating cell apoptosis after ischemic stroke, reducing bleeding volume, and alleviating complications such as cerebral vasospasm, cerebral edema, and neurological dysfunction, thereby reducing inflammatory reactions.

Red flower is the dried flower of Carthamus tinctorius L. in the Asteraceae family, which has the effects of promoting blood circulation, clearing meridians, dispersing blood stasis, and relieving pain. Its main chemical components include flavonoids, steroids, phenolic acids, lignans, chalcones, and volatile oils. In recent years, the anti ischemic stroke effect of safflower has received attention. It mainly exerts neuroprotective effects by inhibiting the production of free radicals, inhibiting thrombus formation, inhibiting cell apoptosis and inflammatory response, protecting nerve cells, antioxidant capacity, and regulating some signaling pathways. However, traditional Chinese medicine has the characteristics of multi-component and multi-target effects, so the mechanism of safflower’s anti ischemic stroke effect is also multifaceted. However, at present, there is a lack of overall understanding of the active ingredients and mechanisms of safflower’s anti ischemic stroke effect. Therefore, this study adopts a combination of network pharmacology and molecular docking technology to construct a network relationship between “safflower active ingredient brain ischemia common target”, and to verify the stronger targets in safflower’s anti ischemic stroke effect. From a holistic perspective, the complex relationship of safflower’s anti ischemic stroke effect is elucidated, and the pharmacological mechanisms of safflower’s multi-component, multi-target, and multi pathway effects are explained.

Ischemic stroke can cause a series of adverse effects, including oxidative stress, inflammatory response, neuronal apoptosis, and cognitive impairment. Traditional Chinese medicine believes that the main pathogenesis of stroke lies in the imbalance of yin and yang, the disorder of qi and blood, and the treatment principles mainly focus on dispelling wind and unblocking collaterals, promoting blood circulation and removing blood stasis. Red flower is a traditional Chinese medicine in China, belonging to the category of promoting blood circulation and removing blood stasis, and is often found in compound formulas of promoting blood circulation and removing blood stasis. In recent years, safflower has been widely used in cerebrovascular diseases, but its mechanism of action is still unclear. Therefore, this article uses network pharmacology and molecular docking technology for the first time to explore the mechanism of safflower in treating ischemic stroke.

Through network pharmacology, it was found that quercetin, kaempferol, stigmasterol, luteolin, and hydroxysafflower yellow pigment A (HSYA) are the main active ingredients in safflower, with the majority of targets being quercetin, kaempferol, stigmasterol, luteolin, and HSYA. Quercetin, kaempferol, stigmasterol, luteolin, and hydroxysafflower yellow pigment A all have anti-inflammatory and antioxidant effects, with the potential to act as adjunctive treatments for inflammation and oxidative stress. kaempferol and hydroxysafflower yellow pigment A also have the ability to inhibit cell apoptosis, improve microcirculation, and correct damaged metabolic pathways. Therefore, it is speculated that these components may be the key to the treatment of ischemic stroke with safflower.

By analyzing the interaction relationship between targets and screening through degree values, it was found that TNF, VEGFA, IL6, CXCL8, ICAM1, and CCL2 targets have a strong relationship with the active ingredients of safflower, and are key targets for safflower treatment of ischemic stroke. Research has found that tumor necrosis factor – α (TNF – α) regulates the expression of intercellular adhesion molecule 1 (ICAMI), leading to vasculitis and inducing the transfer of inflammatory cells from blood vessels to neural tissue. Interleukin-6 (IL-6), CXCL8, and chemokine ligand 2 (CCL2) play important roles in the occurrence and development of inflammation after ischemic stroke, while vascular endothelial growth factor A (VEGFA) mainly participates in the process of angiogenesis after ischemic stroke. Through GO and KEGG enrichment analysis, it was found that the AGE-RAGE, PI3K Akt, TNF, HIF-1, and IL-17 signaling pathways are the main pathways for safflower treatment of ischemic stroke. PI3K Akt is an important signal transduction pathway for cell survival and anti apoptosis. The AGE-RAGE signaling pathway can promote the expression and release of inflammatory factors, induce cell apoptosis, and promote angiogenesis. The HIF-1 signaling pathway can be activated during acute cerebral ischemia, mediating the expression of vascular endothelial growth factor VEGF, indicating that vascular endothelial growth factor is enriched in the AGE-RAGE and HIF-1 signaling pathways. Previous studies by the research team have shown that HSYA can treat ischemic stroke by stimulating VEGF signaling, which is consistent with the predicted results of network pharmacology. Therefore, safflower is used to treat ischemic stroke by exerting anti-inflammatory, antioxidant, anti apoptotic, and promoting angiogenesis effects through multiple components, targets, and pathways.

Through molecular docking technology, the mechanism of action of safflower in treating ischemic stroke disease was further revealed. The results showed that the key targets had good docking effects with safflower active ingredients. Among them, the binding energies of TNF and the five main active ingredients of safflower were all ≤ -7.0 kcal/mol, indicating strong binding activity. IL6 also had strong binding activity with quercetin, kaempferol, and luteolin, while CXCL8 and VEGFA had binding energies ≤ -5.0 kcal/mol with quercetin, kaempferol, and luteolin, indicating good binding activity. Therefore, it is speculated that the binding of the main active ingredients of safflower to key targets may be the key to the therapeutic effect of safflower on ischemic stroke.

In summary, this study elucidates the complex relationship between safflower and ischemic stroke from a holistic perspective, analyzes the mechanism of safflower in treating ischemic stroke through network pharmacology methods, and verifies key targets using molecular docking technology. Research has found that safflower mainly acts on key targets such as TNF, VEGFA, IL6, CXCL8 through active ingredients such as quercetin, kaempferol, and luteolin, regulating inflammatory response, oxidative stress, cell apoptosis, and angiogenesis, thereby regulating signaling pathways such as AGE-RAGE, TNF, and IL-17 to treat ischemic stroke. The research results provide theoretical guidance for the mechanism of action of safflower in treating ischemic stroke, and also provide reference for drug development of ischemic stroke.