The Mechanism of BIPN Intervention by Strychnine Based on lncRNA ZFAS1(XIST)/FAK Signaling Pathway / 浙江中医药大学学报

ABSTRACT

[Objective]To assess the effectiveness of prepared strychnine in the treatment of bortezomib-induced peripheral neuropathy(BIPN)and explore the mechanism of intervention of BIPN based on long noncoding RNA(lncRNA)X inactivated specific transcript(XIST)/ZNFX1 antisense RNA 1(ZFAS1).[Methods]Twenty patients diagnosed as multiple myeloma who received bortezomib(BTZ)and developed BIPN and received strgchnine treatment were collected by prospective non-randomized controlled study method.The traditional Chinese medicine(TCM)symptom score,neurotoxicity score,peripheral neuropathy(PN)grade,and partial peripheral nerve conduction velocity were compared with patients who did not receive strychnine treatment.Using self-control,peripheral blood samples were collected from patients in the treatment group,and enzyme-linked immunosorbent assay(ELISA)was used to detect the expression of inflammation-related factors.DRG 50B11 cells were cultured and screened by cell counting kit-8(CCK-8)for the optimal acting concentration and time of strychnine and the optimal acting time of BTZ,and the cases were randomly divided into normal control group,BTZ group,and strychnine+BTZ group.Real-time quantitative polymerase chain reaction(Real-time qPCR)was used to detect the expression levels of inflammation-related factors and total RNA related indexes,and it analyzed the differences and correlations.[Results]The clinical study showed that compared with control group,PN,TCM syndrome scores and neurotoxicity score were decreased after treatment,while peripheral nerve conduction velocity was increased(P＜0.05),and there were no significant adverse effects.The experimental results showed that compared with those before treatment,the expression of interleukin-17(IL-17),tumor necrosis factor-α(TNF-α),IL-1β,IL-6,nerve growth factor(NGF)and brain-derived neurotrophic factor(BDNF)were reduced(P＜0.05),and there was a significant negative correlation with time(P＜0.01).Compared with BTZ group,the expression levels of IL-17,TNF-α,IL-1β,IL-6,NGF,BDNF,the lncRNA XIST,fibronectin 1(FN1)and phospho-focal adhesion kinase(p-FAK)were decreased in strychnine+BTZ group(P＜0.05),while the expressions of miR-96-5P and miR-1271-5P increased(P＜0.05),without significant difference in the expression of lncRNA ZFAS1(P＞0.05).lncRNA XIST expression levels were significantly positively correlated with the expressions of IL-17,TNF-α,IL-1β,IL-6,NGF,BDNF,FN1 and p-FAK(P＜0.01),but no moderate negative correlated with miR-96-5P(P＜0.05),or very weakly correlated or no correlated with miR-1271-5P(P＞0.05).[Conclusion]Prepared strychnine capsule can alleviate BIPN to a certain extent and is relatively safe,and its mechanism may be related to the regulation of lncRNA XIST for promoting the expression of miR-96-5P/FN1 and inhibit p-FAK-mediated neuroinflammation.