Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with pro-tumor inflammation playing a critical role in its initiation and progression. Chronic inflammation acts as a major driving force and a distinct mechanism underlying tumorigenesis. Although previous studies have demonstrated the importance of the VEGF/p38MAPK and p38MAPK/HSP27 signaling pathways in CRC-associated inflammation, a comprehensive understanding of the entire pro-tumor inflammatory mechanism remains incomplete.Methods: This study combined network pharmacology analysis and in vivo pharmacodynamic experiments using a p38MAPK pathway inhibitor to systematically identify and validate the VEGF/p38MAPK/HSP27 pro-tumor inflammatory signaling pathway. Western blotting was used to confirm key target proteins. Molecular docking and microscale thermophoresis (MST) experiments were conducted to screen active compounds from Patrinia villosa (PV). Molecular dynamics (MD) simulations evaluated the stability and drug-likeness of compound-target interactions.Results: Key proteins VEGF, p38MAPK, and HSP27 were identified as critical components of the signaling pathway. Three active compounds rutin, nicotiflorin, and 4,5-dicaffeoylquinic acid (4,5-Dicqa) were found to bind these targets with high affinity. MD simulations supported the stability of these interactions and their potential as drug candidates.Conclusion: This study provides theoretical and experimental evidence for pharmacological targets involved in pro-tumor inflammation in CRC. The findings offer valuable insights for developing novel anti-inflammatory therapeutics targeting the VEGF/p38MAPK/HSP27 signaling pathway.
Research suggests that ischemic glycolysis improves myocardial tolerance to anoxia and low-flow ischemia. The rate of glycolysis during ischemia reflects the severity of the injury caused by ischemia and subsequent functional recovery following reperfusion. Histone H2AK119 ubiquitination ( H2Aub ) is a common modification that is primarily associated with gene silencing. Recent studies have demonstrated that H2Aub contributes to the development of cardiovascular diseases. However, the underlying mechanism remains unclear. This study identified Hsp27 (heat shock protein 27) as a H2Aub binding protein and explored its involvement in mediating glycolysis and mitochondrial function. Functional studies revealed that inhibition of PRC1 (polycomb repressive complex 1) decreased H2Aub occupancy and promoted Hsp27 expression through inhibiting ubiquitination. Additionally, it increased glycolysis by activating the NF-κB / PFKFB3 signaling pathway during myocardial ischemia. Furthermore, Hsp27 reduced mitochondrial ROS production by chaperoning COQ9 , and suppressed ferroptosis during reperfusion. A delivery system was developed based on PCL-PEG-MAL (PPM)-PCM-SH (CWLSEAGPVVTVRALRGTGSW) to deliver PRT4165 (PRT), a potent inhibitor of PRC1 , to damaged myocardium, resulting in decreased H2Aub . These findings revealed a novel epigenetic mechanism connecting glycolysis and ferroptosis in protecting the myocardium against ischemia/reperfusion injury.
Skin flap transfer is an important method to repair and reconstruct various tissue defects; however, avascular necrosis largely affects the success of flap transfer. The sphingosine 1-phosphate receptor 1 (S1PR1) agonist SEW2871 has been proven to ameliorate ischemic injury; however, its effect on flap survival has not been reported. In this study, an experimental skin flap model was established in rats to investigate the roles of SEW2871. The results indicated that SEW2871 greatly increased the survival of the skin flap, alleviated pathological injury, promoted the angiogenesis, and inhibited cells apoptosis in skin flap tissues. SEW2871 activated S1PR1 downstream signaling pathways, including heat shock protein 27 (HSP27), extracellular regulated protein kinases (ERK), and protein kinase B (Akt). In addition, SEW2871 promoted the expression of S1PR1. These findings may provide novel insights for skin flap transfer.
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