Regorafenib (REGO) is a synthetic oral multi-kinase inhibitor with potent antitumor activity. In this study, we investigate the molecular mechanisms by which REGO induces apoptosis. REGO induced cytotoxicity, inhibited the proliferation and migration ability of cells, and induced nuclear condensation, and reactive oxygen species (ROS)-dependent apoptosis in cancer cells. REGO downregulated PI3K and p-AKT level, and prevented FOXO3a nuclear export. Most importantly, AKT agonist (SC79) not only inhibited REGO-induced FOXO3a nuclear localization and apoptosis but also restored the proliferation and migration ability of cancer cells, further demonstrating that REGO prevented FOXO3a nuclear export by deactivating PI3K/AKT. REGO treatment promotes Bim expression via the FOXO3a nuclear localization pathway following PI3K/AKT inactivation. REGO induced Bim upregulation and translocation into mitochondria as well as Bim-mediated Bax translocation into mitochondria. Fluorescence resonance energy transfer (FRET) analysis showed that REGO enhanced the binding of Bim to Bak/Bax. Knockdown of Bim, Bak and Bax respectively almost completely inhibited REGO-induced apoptosis, demonstrating the key role of Bim by directly activating Bax/Bak. Knockdown of Bax but not Bak inhibited REGO-induced Drp1 oligomerization in mitochondria. In conclusion, our data demonstrate that REGO promotes apoptosis via the PI3K/AKT/FOXO3a/Bim-mediated intrinsic pathway.
Objectives. The objective of this study is to compare the safety and effectiveness of the temporary spinal cord stimulation (SCS) versus pulsed radiofrequency (PRF) in treating postherpetic neuralgia (PHN). Methods. From September 1, 2019, to May 30, 2020, 44 PHN patients admitted to the Pain Department of the Foshan First People’s Hospital, China were enrolled in this study. The patients were randomly assigned to SCS and PRF groups in a ratio of 1 : 1 and were given respective therapy for 8 days. Rash, in all patients, was located in the trunk and extremities of the spinal nerve (C4-L5), and the pain intensity was greater than or equal to 7 points on the VAS scale. Subsequently, we evaluated the visual analogue scale (VAS), efficiency rate (ER), complete remission rate (CRR), daily sleep interference score (SIS), patient health questionnaire (PHQ-9), generalized anxiety disorder assessment (GAD-7), bodily pain (BP), and physical function (PF) sections of the 36-item short-form health survey (SF-36) at the following time points: presurgery, as well as 1 week, 1 month, 3 months, and 6 months postsurgery. Results. The final analysis was performed on 40 patients (n = 20 SCS cohort, and n = 20 PRF cohort). Both cohorts exhibited comparable baseline values ( P > 0 : 05 ). Particularly, they were similar in age, sex, pain duration, involved dermatome, and comorbidity. Among the variables that demonstrated marked improvements from presurgical data to 1 week postsurgery were VAS, ER, CRR, SIS, PHQ-9, GAD-7, as well as BP and PF of the SF-36 in both cohorts. In addition, this improvement persisted for 6 months. There was no complication related to surgery in any of our patients. Conclusion. Based on our analysis, SCS exhibited better efficacy and safety than PRF. This study was prospectively registered in the Chinese Clinical Trial Registry (ChiCTR2100050647).
Temporary spinal cord stimulation (tSCS) can effectively reduce the pain and severity of postherpetic neuralgia (PHN). However, there are no effective and objective methods for predicting the effects of tSCS on PHN. Laser speckle contrast imaging (LSCI) is frequently used in neurology to evaluate the effectiveness of treatment. To assess the accuracy of LSCI in predicting the impact of tSCS on PHN, 14 adult patients receiving tSCS treatments for spinal nerve-innervated (C6-T2) PHN participated in this observational study. Visual analog scale (VAS) assessments and LSCI blood flow images of the fingers were recorded after the tSCS procedure. The results showed that the VAS scores of all patients decreased significantly. Moreover, the blood flow index (BFI) values were significantly higher than they were before the procedure. Increased blood flow and pain alleviation were positively correlated. The findings indicated that spinal nerve PHN (C6-T2) was significantly reduced by tSCS. Pain alleviation by tSCS was positively correlated with increased blood flow in the hand. The effect of tSCS on PHN may thus be predicted using an independent and consistent indicator such as LSCI.
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