Outcomes following major dysvascular lower limb amputation: an updated systematic review.

In forensic practice, cases involving the evaluation of mental disorders resulting from positional restraint, intimidation, or other stressful events are commonly observed (). Acute restraint stress (ARS) has been shown to enhance the secretion of pro-inflammatory cytokines within the cerebral cortex, thereby precipitating cerebral dysfunction and culminating in neuronal injury (). Stressful events trigger a neuroendocrine cascade in which the hypothalamic-pituitary-adrenal (HPA) axis becomes activated. This activation drives the systemic release of glucocorticoids and catecholamines (). HPA axis hyperactivity is frequently associated with depression (). Stress is also a commonly used model in depression-related research (–). Current research on stress has largely focused on the central nervous system. However, stress elicits systemic effects, underscoring the importance of investigating its impact on peripheral vital organs. Previous studies have demonstrated that intense or prolonged stress can induce systemic damage, thereby impairing normal psychological and physiological functions, and leading to pathological injury in vital organs such as the central nervous system (), heart (), liver (), and kidneys (). Inflammation is closely associated with psychiatric disorders such as depression and schizophrenia (, ), and Soluble epoxide hydrolase (sEH) plays a role in the pathogenesis of inflammation-related diseases (). The expression and enzymatic activity of sEH vary across different tissues, with the liver exhibiting the highest sEH expression and the strongest enzymatic activity (). sEH possesses bifunctional enzyme characteristics, exhibiting both epoxyeicosatrienoic acids (EETs) hydrolase activity and lipid phosphatase activity (). Through these dual pathways, sEH may exacerbate stress-induced behavioral abnormalities: on one hand, the reduction of EETs leads to neuroinflammation and impaired synaptic plasticity (). On the other hand, dysregulation of lipid phosphate metabolism may affect lipid signal transmission along the liver-brain axis (). sEH serves as a key metabolic regulatory hub in stress-induced depression (), hydrolyzing neuroprotective EETs and participating in the regulation of stress responses. Studies have confirmed that interleukin-6 (IL-6) serves as a key proinflammatory node downstream of this regulatory pathway, with its expression closely correlated with sEH activity and EETs levels (, ). TPPU is the most commonly used sEH inhibitor (), characterized by a longer half-life and higher efficacy. The protective effects of TPPU have been validated in various disease models (–). Its core mechanism involves inhibition of sEH activity to maintain endogenous EETs levels, thereby exerting significant anti-inflammatory and anti-injury effects. Moreover, studies have confirmed that TPPU effectively alleviates sepsis-associated acute liver injury by precisely modulating the immune microenvironment (), indicating its targeted potential in hepatic protection. Previous studies have demonstrated that chronic stress selectively upregulates hepatic sEH expression (). However, whether acute stress-induced hepatic dysfunction () is accompanied by elevated sEH expression, and the underlying mechanism of sEH in stress-induced neurological injury, remain to be further elucidated. Studies have revealed that sEH plays a key regulatory role in neuroinflammation and mood disorders (). Upregulation of hepatic sEH expression induces significant pathological changes in hepatocytes, while specific inhibition of hepatic sEH alleviates neurological injury symptoms (). Microglia, as the primary immune effector cells in the central nervous system (), regulate neuroinflammation through M1/M2 phenotypic polarization () and release proinflammatory cytokines and reactive oxygen species (). Microglia serve as a core hub mediating inflammation-associated neurological damage, and their functional dysregulation directly exacerbates neuronal injury. ARS has been shown to induce significant hepatic dysfunction and pathological changes in the liver (). Preliminary experiments confirmed that 24 hours of restraint stress significantly upregulated hepatic sEH expression and activated microglia in the hypothalamus.