Harpagide alleviate neuronal apoptosis and blood-brain barrier leakage by inhibiting TLR4/MyD88/NF-κB signaling pathway in Angiotensin II-induced microglial activation in vitro.

Angiotensin II, the effector peptide of the renin-angiotensin system, is not only a pivotal peptide implicated in the regulation of blood pressure but also a key mediator of the inflammatory processes that play an important role in the pathology of hypertension-related cSVD. Harpagide is the major bioactive constituent of Scrophulariae Radix widely used in traditional Chinese medicine for numerous diseases including hypertension. The present study aimed to investigate the effect of harpagide on Ang II-induced neuroinflammation and the potential mechanism. Pretreated with harpagide or resatorvid (the TLR4 pathway inhibitor), BV2 cells were treated with Ang II or LPS (the TLR4 activator). NO, pro-inflammatory cytokines, the proteins on TLR4/MyD88/NF-κB signaling pathway and the expression of CD86, CD206, TREM2 in BV2 cells were detected respectively. Subsequently, the effects of harpagide on neurotoxicity and BBB destruction triggered by Ang II-induced neuroinflammation were investigated in the co-cultures of BV2 microglia/HT22 hippocampal neurons, BV2 microglia/bEnd.3 endotheliocyte and BV2 microglia/BBB monolayer model. We found that Ang II converted microglia into M1 state and resulted in neuroinflammation through activating TLR4/MyD88/NF-κB signaling pathway. It also triggered the imbalance of TLR4/TREM2 in microglia. Ang II-mediated inflammation microglia further led to neuronal apoptosis and BBB damage. Harpagide showed the effect of alleviating Ang II-mediated neuroinflammation as well as the resulting neurotoxicity and BBB destruction through inhibiting the TLR4/MyD88/NF-κB pathway. The anti-inflammatory and neuroprotective effect of harpagide suggested that it might be a potential therapeutic strategy in hypertensive cSVD.

[Predicting value of dynamic alteration of blood neutrophil/lymphocyte ratio on recurrence-free survival in patients with advanced colon cancer after operation and chemotherapy].

OBJECTIVE: To evaluate whether neutrophil-lymphocyte ratio(NLR) predicts risk of recurrence in patients with advanced colon cancer undergoing curative resection followed by adjuvant chemotherapy. METHODS: A total of 149 patients with advanced colon cancer undergoing curative resection followed by adjuvant chemotherapy(FOLFOX6 protocol) were included. NLR was calculated preoperatively and before chemotherapy. The changes in NLR and the predictive value of NLR for prognosis were analyzed. RESULTS: The NLR of 149 patients was 2.8±1.5. NLR of 3.5 was identified according to the ROC curve. NLR<3.5 and NLR≥3.5 were classified as low and high NLR group, respectively. The 5-year recurrence-free survival(RFS) of patients with high preoperative NLR(n=22) was significantly worse than that of those with low preoperative NLR(n=127)(50.9% vs. 76.4%, P=0.025). The difference of 5-year RFS between high pre-chemotherapy NLR group(n=34) and low pre-chemotherapy NLR group(n=115) was statistically significant(50.1% vs. 71.4%, P=0.032). The 5-year RFS was 79.5% in patients with low preoperative NLR converting to high pre-chemotherapy NLR(n=16), similar to the group with high pre-chemotherapy group(P=0.077). The 5-year RFS was 17.7% in patients with high preoperative NLR reverting to low pre-chemotherapy NLR(n=12), similar to the group with low pre-chemotherapy group(P=0.978). There was significant difference in 5-year RFS between the postoperatively elevated group and postoperatively decreased group(P=0.036). CONCLUSION: An elevated blood NLR may be a biomarker of poor RFS in patients with advanced colon cancer after curative resection and chemotherapy.