Inhibition effect of choline and parecoxib sodium on chronic constriction nerve injury-induced neuropathic pain in rats

Abstract Purpose The simultaneous use of drugs with different mechanisms of analgesic action is a strategy for achieving effective pain control while minimizing dose-related side effects. Choline was described to potentiate the analgesic action of parecoxib sodium at small doses in several inflammatory pain models. However, these findings are still very limited, and more associated data are required to confirm the effectiveness of the combined choline and parecoxib sodium therapy against inflammatory pain. Methods Adult rats were randomly divided into 9 groups (N = 6/group). The sham surgery group received an intraperitoneal (i.p.) injection of saline. Rats with chronic constriction injury (CCI) of the sciatic nerve received saline, choline (cho, 6, 12 and 24 mg/kg), parecoxib sodium (pare, 3, 6, and 12 mg/kg), or a combination of choline 6 mg/kg and parecoxib sodium 3 mg/kg. Mechanical and heat pain thresholds were measured at 30 min after drug treatment at Days 3, 5, 7, 10, and 14 after CCI. Another 30 rats were divided into 5 groups (N = 6/group): the sham, CCI + saline, CCI + cho-6 mg/kg, CCI + pare-3 mg/kg, and CCI + cho-6 mg/kg + pare-3 mg/kg groups. After repeated drug treatment for 7 days, five rats were randomly selected from each group, and the lumbar dorsal root ganglia (DRGs) (L4–6) were harvested for western blot analysis. Results Choline significantly attenuated mechanical and heat hypersensitivity in CCI rats at 12 and 24 mg/kg doses (P < 0.05) but was not effective at the 6 mg/kg dose. Parecoxib sodium exerted significant pain inhibitory effects at the 6 and 12 mg/kg doses (P < 0.05) but not at the 3 mg/kg dose. Combining a low dose of choline (6 mg/kg) and parecoxib sodium (3 mg/kg) produced significant pain inhibition in CCI rats and reduced the expression of high mobility group protein 1 (HMGB1) and nuclear factor-kappa Bp65 (NF-κBp65) in L4–6 DRGs. Conclusion 1. In a rat model of chronic neuropathic pain (CCI), at a certain dose, choline or parecoxib sodium can alleviate mechanical pain and thermal hyperalgesia caused by CCI. 2. The combination of choline and parecoxib sodium in nonanalgesic doses can effectively relieve neuropathic pain, and its mechanism may be related to the inhibition of the high mobility group protein 1 (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway

Targeting the autophagy promoted antitumor effect of T-DM1 on HER2-positive gastric cancer

Abstract Trastuzumab emtansine (T-DM1), an antibody-drug conjugate consisted of the HER2-targeted monoclonal antibody trastuzumab and the tubulin inhibitor emtansine, has shown potent therapeutic value in HER2-positive breast cancer (BC). However, a clinical trial indicated that T-DM1 exerts a limited effect on HER2-positive gastric cancer (GC), but the underlying mechanism is inconclusive. Our research attempted to reveal the probable mechanism and role of autophagy in T-DM1-treated HER2-positive GC. In this study, our results showed that T-DM1 induced apoptosis and exhibited potent therapeutic efficacy in HER2-positive GC cells. In addition, autophagosomes were observed by transmission electron microscopy. Autophagy was markedly activated and exhibited the three characterized gradations of autophagic flux, consisting of the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and the deterioration of autophagosomes in autolysosomes. More importantly, autophagic inhibition by the suppressors 3-methyladenine (3-MA) and LY294002 significantly potentiated cytotoxicity and apoptosis in HER2-positive GC cells in vitro, while the combined use of LY294002 and T-DM1 elicited potent anti-GC efficacy in vivo. In mechanistic experiments, immunoblot analysis indicated the downregulated levels of Akt, mTOR, and P70S6K and confocal microscopy analysis clearly showed that autophagic inhibition promoted the fusion of T-DM1 molecules with lysosomes in GC cells. In conclusion, our research demonstrated that T-DM1 induced apoptosis as well as cytoprotective autophagy, and autophagic inhibition could potentiate the antitumor effect of T-DM1 on HER2-positive GC. Furthermore, autophagic inhibition might increase the fusion of T-DM1 with lysosomes, which might accelerate the release of the cytotoxic molecule emtansine from the T-DM1 conjugate. These findings highlight a promising therapeutic strategy that combines T-DM1 with an autophagy inhibitor to treat HER-positive GC more efficiently

Effect of Indium Doping on Surface Optoelectrical Properties of Cu₂ZnSnS₄ Photoabsorber and Interfacial/Photovoltaic Performance of Cadmium Free In₂S₃/Cu₂ZnSnS₄ Heterojunction Thin Film Solar Cell

Maximum conversion efficiency of 6.9% was obtained over an electrodeposited Cu₂ZnSnS₄-based thin film solar cell with a Cd-free In₂S₃ buffer layer by applying a rapid post-heat treatment to the In₂S₃/Cu₂ZnSnS₄ stacked layer. It was found that post-heating of the In₂S₃/Cu₂ZnSnS₄ stack promoted an increment of the acceptor density of the Cu₂ZnSnS₄ layer close to the In₂S₃–Cu₂ZnSnS₄ heterointerface of the In₂S₃/Cu₂ZnSnS₄ stack. Moreover, the diffusion of In also resulted in a red-shift of the band gap energy of Cu₂ZnSnS₄ from 1.47 to 1.40 eV. Due to extension of external quantum efficiency response of the solar cell to the long wavelength region, the solar cell based on the post-heated In₂S₃/Cu₂ZnSnS₄ stack reached appreciably large short circuit current density of more than 20 mA cm^–2. The energy difference between the conduction band minimum of In₂S₃ and that of Cu₂ZnSnS₄ at the In₂S₃/Cu₂ZnSnS₄ heterointerface was determined to be a slightly positive value of 0.11 eV, indicating formation of a “notch-type” conduction band offset for efficient suppression of the interface recombination

Additional file 1: of Regional anesthesia and lipid resuscitation for local anesthetic systemic toxicity in China: results of a survey by the orthopedic anesthesia group of the chinese society of anesthesiology

Survey questionnaire. (DOC 53 kb