Inflammation can not only cause a cerebral infarction, but it can also further activate the inflammatory response, creating a vicious circle (15–18). Tu et al. developed a mouse model of cerebral infarction and found that TPPU could significantly promote the recovery of neurological function and reduce the infarct volume and the expression of inflammatory cytokines IL-1βmRNA and TNF-αmRNA, revealing that TPPU may reduce the inflammatory response after infarction and promote the recovery of neurological function (19). Yu et al. used endothelial human Nox4 dominant-negative (EDN) transgenic mice in an ApoE deficient background to mimic the dysfunction of endothelial Nox4 in atherosclerosis-prone conditions. sEH and the inflammatory marker vascular cell adhesion molecule 1 (VCAM1) were upregulated in EDN aortic endothelium. TPPU reduced atherosclerotic lesions in EDN mice. In EDN endothelial cells (ECs), the endoplasmic reticulum stress inhibitor, 4-phenyl butyric acid (4-PBA), downregulated the expression of sEH and VCAM1 and suppressed inflammation. Moreover, its application in vivo reduced atherosclerotic lesions of EDN mice (20). In a study by Schmelzer et al., lipopolysaccharide (LPS, 10 mg/kg) was injected into C57BL/6 mice to cause celiac inflammation 24 h before and after the subcutaneous TPPU injection (20 mg/kg) and at the same dose of processed palm in the control group. The findings revealed that all the mice in the experimental group survived, and their blood pressure was restored to pre-LPS levels 24 h later, while all the mice in the control group developed severe hypotension (systolic pressure <40 mmHg) and died within 4 days. Studies have shown that TPPU increases the EET indirect inhibition of nitric oxide synthase, reduces NO produce, hypotension due to reduce inflammation, and inhibits non-specific inflammation index COX-2 (Cyclooxygenase-2) expression. Simultaneously, suppressing TNF alpha, IL-6, and monocyte chemotactic factor may reduce inflammation, improve lipid oxygen element A4 production, and increase inflammation abreaction (21). TPPU can simulate the role of EET in hemodynamics and anti-inflammatory activities and regulate growth, utility, and the forecast for new atherosclerosis compounds (22) (Figure 3).

Homeostasis of vascular structure and function is the basis of human physiological activities. If the vascular homeostasis is unbalanced, it may lead to the occurrence of various diseases (23). Vascular injury is one of the reasons for the imbalance of vascular homeostasis. After cerebral infarction, a vascular injury will inevitably occur, and the adventitia of blood vessels will undergo corresponding changes. Studies have shown that neutrophils can be detected in the adventitia 0.5 h following balloon stretch injury in the coronary arteries of the pig, while the intima-media can be detected later. The vascular endothelial growth factor can be detected in the adventitia at the earliest after balloon-stretch injury to the carotid artery of rats (24). The above findings suggest that the adventitia is the origin and active participant of vascular diseases and is one of the novel targets for treating abnormal vascular function. Protecting adventitia may reduce the imbalance of vascular homeostasis, thereby facilitating disease repair. Angiotensin II inhibitor competes with Ang II for AT1. Furthermore, it inhibits vasoconstriction, promotes aldosterone secretion, reverses hypertrophic cardiomyocytes, and lowers blood pressure. However, AngII-related preparations can result in vascular wall thickening and collagen deposition, affecting the remodeling of the vascular adventitia and causing an imbalance in vascular homeostasis. Researchers have found that TPPU intervention in AngII model mice could significantly prevent AngII-induced vascular adventitia damage. Furthermore, in vitro studies have also found that TPPU may affect collagen synthesis via the Ca₂₊-calmodulin/NFATc3 signaling pathway, suggesting that TPPU may be one of the novel ways to treat vascular adventitial injury (25).

Tight-junction proteins between endothelial cells, basement membrane, the foot process of astrocytes, and pericytes are the key structures that maintain the integrity of the blood-brain barrier (BBB). The main pathogenic changes in the early stages of cerebral ischemia are increased BBB permeability and damage of tight junction protein, which causes brain edema, directly or indirectly leading to neurological function damage. Hence, preventing ischemic stroke requires protecting the BBB, inhibiting increased permeability, and alleviating cerebral edema (26). Yi et al. found that TPPU can significantly reduce BBB damage in model rats following cerebral infarction by increasing the expression of ZO-1, Occludin, and Claudin-5, the subunits of tight junction proteins related to BBB (24). Claudin-5 regulates the normal and disturbed states of the BBB. The down-regulation of claudin-5 can directly cause an increase in BBB permeability. ZO-1, a regulator of tight junction proteins, plays an important role in maintaining cytoskeleton formation, cell polarity, and paracellular barrier (27). Multiple studies have reported that tight junction proteins are crucial in regulating BBB integrity and permeability, and the downregulation of tight junction protein expression is associated with increased BBB permeability (28, 29). Yi et al. found that a higher dose of TPPU (2 mg/kg) had a better protective effect on cerebral edema than a lower dose. However, the mechanism may be related to the pharmacokinetics of TPPU, as higher doses did not improve the protective effect (25). TPPU is readily absorbed and slowly eliminated, allowing it to remain in the bloodstream longer than other sEH inhibitors due to its metabolic stability. Previous studies have demonstrated that even at the lowest dose of 0.1 mg/kg, the concentration of TPPU in vitro is higher than the IC50 value. When the TPPU dose exceeds 1 mg/kg, the EET/DHET ratio is lower than the TPPU dose of 1 mg/kg, indicating that TPPU should not be overused (13). Furthermore, studies have shown that TPPU can also reduce the damage to the BBB by reducing the damage to vascular endothelial cells. However, there are few studies on this aspect, and the detailed mechanism is unclear (30).

The decrease in perfusion volume after cerebral infarction is the primary reason for the aggravation of neurological function. Low perfusion can not only stimulate the intensification of the local inflammatory response but also result in the activation of excessive oxygen free radicals, causing the aggravation of the disease (31). Hao et al. established a coil-type carotid artery stenosis model. They found that the neurological function of mice was significantly improved after TPPU intervention compared with the control group. Furthermore, basic research has shown that the neuroprotective effect of TPPU on cerebral hypoperfusion may be associated with the activation of the Neuregulin-1 (NRG 1)/ErbB 4 signaling pathway, which can further trigger the PI3K-Akt pathway, implying that TPPU can play a multi-targeted protective effect and reduce the degree of nerve damage in mice with chronic cerebral hypoperfusion (32). However, the increase in cerebral perfusion after cerebral infarction is a reason for the deterioration of neurological function; hence, it is particularly important to explore the appropriate dose of TPPU to achieve a balance between the two. Currently, there are limited reports on TPPU improving ischemic stroke perfusion, and more studies are required to demonstrate the specific mechanism in the future.

Apoptosis is one of the primary reasons for brain injury after ischemic stroke, and oxidative stress is the main pathway of apoptosis. Studies have shown that TPPU can reduce the production of reactive oxygen species (ROS) after ischemic stroke, increase the expression of Bcl-2 protein, and decrease the expression of Bax protein, implying that TPPU can inhibit cell apoptosis after ischemic stroke (33). ROS production plays a key role in the breakdown of the blood-brain barrier during cerebral ischemia/reperfusion (34). After cerebral ischemia, the expression of ROS and inflammatory cytokines increases, causing mitochondrial damage, activation of pro-apoptotic protein Bax, and stimulation of cytochrome c cascade reaction. Moreover, the Bcl-2 protein can inhibit the downstream apoptotic cascade and block the release of cytochrome C (35).