The n-butanolic extract of Opuntia ficus-indica var. saboten enhances long-term memory in the passive avoidance task in mice

Opuntia ficus-indica var. saboten Makino (Cactaceae) is used to treat burns, edema, dyspepsia, and asthma in traditional medicine. The present study investigated the beneficial effects of the n-butanolic extract of O. ficus-indica var. saboten (BOF) on memory performance in mice and attempts to uncover the mechanisms underlying its action. Memory performance was assessed with the passive avoidance task, and western blotting and immunohistochemistry were used to measure changes in protein expression and cell survival. After the oral administration of BOF for 7 days, the latency time in the passive avoidance task was significantly increased relative to vehicle-treated controls (P < 0.05). Western blotting revealed that the expression levels of brain-derived neurotrophic factor (BDNF), phosphorylated cAMP response element binding-protein (pCREB), and phosphorylated extracellular signal-regulated kinase (pERK) 1/2 were significantly increased in hippocampal tissue after 7 days of BOF administration (P < 0.05). Doublecortin and 5-bromo-2-deoxyuridine immunostaining also revealed that BOF significantly enhanced the survival of immature neurons, but did not affect neuronal cell proliferation in the subgranular zone of the hippocampal dentate gyrus. These results suggest that the subchronic administration of BOF enhances long-term memory, and that this effect is partially mediated by ERK-CREB-BDNF signaling and the survival of immature neurons.     

NR2B-ERK-CREB信号途径参与了大鼠逃避性长期记忆

目的明确NR2B-ERK-CREB途径是否参与了大鼠Y迷宫逃避性长期记忆。方法雄性SD大鼠45只（第一军医大学实验动物中心提供）,共分为4组：ifenprodil腹腔注射组14只,DMSO腹腔注射组15只,此2组中分别有7只动物在Y-迷宫训练后立即处死,用来进行免疫组织化学染色;ifenprodil脑室注射组和DMSO脑室注射组各8只,分别在Y-迷宫记忆测试后立即脑室注射ifen-prodil（2.0μg/μl,注射量0.5μl/侧）或等量DMSO,并于记忆再巩固测试后立即断颈取脑,进行Westernblot蛋白免疫印迹检测。结果训练前15min腹腔注射ifenprodil组动物的Y迷宫学习成绩与DMSOip组相比,没有明显差异（P〉0.05）,但是在24h后测试动物的Y迷宫记忆,ifenprodilip组成绩差于DMSOip组成绩（P〈0.05）。Y迷宫训练后ifenprodilip组各脑区pERK1/2和pCREB表达普遍下降,其中pERK1/2在海马、纹状体、杏仁核下降最为明显,pCREB在海马、纹状体、小脑最为明显,与DMSOip组相比差异显著（P〈0.01）。第一次Y迷宫测试ifenprodilic组与DMSOic组成绩没有明显差异（P〉0.05）,测试后立即脑室注射并在术后6h测试动物对Y迷宫的记忆再巩固,ifenprodilic组成绩下降,与DMSOic组相比有明显差异（P〈0.05）,同时ifenprodilic组动物各被检测脑区pERK1/2和pCREB表达与DMSOic组相比均普遍下降。结论 NR2B-ERK-CREB途径参与了大鼠Y迷宫的习得、长期记忆形成、记忆的再巩固等过程,而且该途径对于长期记忆的形成和记忆提取是必要的。     

Role of the extracellular signal-regulated kinase 1/2 signaling pathway in the process of thrombin-promoting airway remodeling in ovalbumin-allergic rats

Abstract

Context: Although it is recognized that thrombin plays a key role in airway remodeling during chronic asthma. In a previous study, we have proved that thrombin promotes airway remodeling via PAR-1 in OVA-allergic rats, but little is known about intracellular signaling pathway involved in the event.

Objective: In this study, we intend to explore the impact of pERK1/2 signaling pathway on the process of thrombin-induced airway remodeling in OVA-allergic rats.

Materials and methods: A rat model of chronic asthma was set up by systemic sensitization and repeated challenge to OVA. The doses of thrombin, recombinant hirudin, PAR-1 inhibitor ER-112780-06, and pERK1/2 inhibitor PD98059 varied for different groups. The expression of pERK1/2 was analyzed by western blot and RT-PCR. Secretion of TGF-β1 and IL-6 was detected by ELISA.

Results: The expression of pERK1/2 was higher in the airway of asthmatic rats than those of normal rats, and was significantly increased by thrombin treatment but decreased by thrombin-inhibitor treatment. Airway remodeling was enhanced by thrombin but weakened by pERK1/2 inhibitor. Expression of growth factors and IL-6 in asthmatic rats was significantly increased by thrombin treatment and decreased by thrombin-inhibitor treatment and pERK1/2 inhibitor treatment.

Conclusion: These results suggest that ERK1/2 signaling pathway may play an important role in the process of thrombin-promoting airway remodeling in OVA-allergic rats, and pERK1/2 inhibitor effectively inhibits the process.     

Effect of Vestibulosympathetic Reflex and Baroreflex on Expression of pERK in the Nucleus Tractus Solitarius following Acute Hypotension in Conscious Rats

Control of blood pressure is maintained by the interaction between the arterial baroreflex and vestibulosympathetic reflex during postural changes. In this study, the contributions of vestibular receptors and baroreceptors to the maintenance of blood pressure following acute hypotension were compared in terms of phosphorylated extracellular regulated protein kinase (pERK) expression in the nucleus tractus solitaries (NTS). Expression of pERK in the NTS was measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD) 5, 10, 20, and 40 min following acute hypotension induced by sodium nitroprusside (SNP) infusion. Expression of pERK increased significantly in the NTS in the control group following SNP infusion, and the expression peaked at 10 min after SNP infusion. The number of pERK positive neurons increased following SNP infusion in BL, SAD, and BL+SAD groups, although the increase was smaller than in control group. The BL group showed a relatively higher reduction in pERK expression than the SAD group, and the pERK expression in the NTS was localized to the caudal portion of the nuclei in the BL and SAD groups. These results suggest that the vestibular receptors may play a key role in maintaining blood pressure following acute hypotension; thus, the vestibular system may contribute to compensate for orthostatic hypotension.     

Recent advances in delivery of drug–nucleic acid combinations for cancer treatment

Cancer treatment that uses a combination of approaches with the ability to affect multiple disease pathways has been proven highly effective in the treatment of many cancers. Combination therapy can include multiple chemotherapeutics or combinations of chemotherapeutics with other treatment modalities like surgery or radiation. However, despite the widespread clinical use of combination therapies, relatively little attention has been given to the potential of modern nanocarrier delivery methods, like liposomes, micelles, and nanoparticles, to enhance the efficacy of combination treatments. This lack of knowledge is particularly notable in the limited success of vectors for the delivery of combinations of nucleic acids with traditional small molecule drugs. The delivery of drug–nucleic acid combinations is particularly challenging due to differences in the physicochemical properties of the two types of agents. This review discusses recent advances in the development of delivery methods using combinations of small molecule drugs and nucleic acid therapeutics to treat cancer. This review primarily focuses on the rationale used for selecting appropriate drug–nucleic acid combinations as well as progress in the development of nanocarriers suitable for simultaneous delivery of drug–nucleic acid combinations.     

鞘内注射GABA转运体-1抑制剂NO-711对CCI大鼠脊髓背角pERK表达的影响

目的 观察γ-氨基丁酸(GABA)转运体-1(GAT-1)抑制剂NO-711对坐骨神经慢性松结扎(OCI)大鼠机械和热痛阈及脊髓背角神经元磷酸化细胞外信号调节激酶(pERK)表达的影响,探讨NO-711在脊髓水平抗痛敏的机制.方法 雄性SD大鼠126只,随机均分为六组(n=21):CCI+NO-711 50μg组(N50组)、CCI+NO-711 100 μg组(N100组)、CCI+NO-711 200 μg组(N200组)、CCI+生理盐水组(CN组)、CCI组、假手术组(S组).CCI组和S组在术前、术后1、3、5、7、14、21 d测定大鼠机械缩腿阈值(MWT)和热缩腿潜伏期(TWL);其余各组大鼠在手术前5 d先进行鞘内置管,CCI手术后5 d鞘内注射不同剂量的NO-711或生理盐水,测定给药前、给药后30 min、1、2、4、8 h大鼠MWT、TWL及脊髓背角pERK表达的变化.结果 CCI组MWT和TWL术后3 d后各时点较术前2 d均降低和缩短、且相应时点均低于和短于S组(P＜0.01);与给药前比较,CN组大鼠各时点MWT和TWL,差异无统计学意义,而NO-711各剂量组大鼠给药后MWT和TWL均呈剂量依赖性增加;与CCI组和NS组比较,NO-711对脊髓背角pERK表达呈剂量依赖性抑制.结论 鞘内注射NO-711能明显抑制CCI大鼠机械痛敏和热痛敏及脊髓背角pERK表达,提示pERK介导NO-711在脊髓水平具有抗痛敏效应.     

100Hz电刺激肩胛间区对家兔胆囊痛及其脊髓后角磷酸化细胞外信号调节蛋白激酶表达的影响

目的 探讨100 Hz电刺激肩胛间区对家兔胆囊痛及脊髓后角磷酸化细胞外信号调节蛋白激酶(phosphorylate extracellular signal-regulated kinases,pERK1/2)表达的影响.方法 家兔采用随机数字表法随机分为5组:对照组、生理盐水组、甲醛溶液组、肩胛间区电刺激组和非肩胛间...     

Role of Sigma-1 Receptors in Paclitaxel-Induced Neuropathic Pain in Mice

Sigma-1 (σ₁) receptors play a role in different types of pain and in central sensitization mechanisms; however, it is unknown whether they are involved in chemotherapy-induced neuropathic pain. We compared the ability of paclitaxel to induce cold (acetone test) and mechanical (electronic Von Frey test) allodynia in wild-type (WT) and σ₁ receptor knockout (σ₁-KO) mice. We also tested the effect on paclitaxel-induced painful neuropathy of BD-1063 (16–64 mg/kg, subcutaneously) and S1RA (32–128 mg/kg, subcutaneously), 2 selective σ₁ receptor antagonists that bind to the σ₁ receptor with high affinity and competitively. The responses to cold and mechanical stimuli were similar in WT and σ₁-KO mice not treated with paclitaxel; however, treatment with paclitaxel (2 mg/kg, intraperitoneally, once per day during 5 consecutive days) produced cold and mechanical allodynia and an increase in spinal cord diphosphorylated extracellular signal-regulated kinase (pERK) in WT but not in σ₁-KO mice. The administration of BD-1063 or S1RA 30 minutes before each paclitaxel dose prevented the development of cold and mechanical allodynia in WT mice. Moreover, the acute administration of both σ₁ receptor antagonists dose dependently reversed both types of paclitaxel-induced allodynia after they had fully developed. These results suggest that σ₁ receptors play a key role in paclitaxel-induced painful neuropathy.