作者: Zhang, Yunxiao ; Zhou, Xi ; He, Xi ; Zhong, Guyu ; Zhu, Bo ; Peng, Dezheng ; Zhong, Jie ; Wang, Jia ; Wu, Hang ; Liu, Zhonghua ; Yin, Yekui ; Hu, Zhaotun ; Wang, Wenxing ; Wang, Yin ; Chen, Minzhi ; Zhou, Qing ; Hao, Xinlong

The voltage-gated sodium channel Na_V1.7 is a pivotal therapeutic target for the developing novel, potent, and specific analgesics. HWTX-I, a peptide isolated from the venom of the tarantula Ornithoctonus huwena, is known to inhibit N-type calcium channels and has also been demonstrated to block tetrodotoxin-sensitive Na_V channels in dorsal root ganglion neurons. In this study, we show that HWTX-I potently inhibits Na_V1.7 currents with an IC₅₀ value of 40.6 ± 16.1 nM, but it does not significantly affect the voltage dependence of Na_V1.7 steady-state activation and inactivation. Alanine-scanning mutagenesis revealed that residues K3, V5, F6, P11, N14, E15, W28, and K30 are critical for HWTX-I's inhibitory activity against Na_V1.7. Furthermore, site-directed mutagenesis analysis demonstrated that HWTX-I binds to the S3-S4 linker in domain II of Na_V1.7, and the D816K mutation in Na_V1.7 significantly abrogates the efficacy of the HWTX-I-Na_V1.7 interaction. Molecular dynamics simulations combined with free energy decomposition analysis identified Na_V1.7-D816 and HWTX-I-K3 as dominant energetic contributors to binding, consistent with a role for long-range electrostatic steering rather than a persistent short-range salt bridge. Collectively, these findings elucidate the structural basis of HWTX-I-Na_V1.7 binding, identify the pharmacophore of the toxin, and provide valuable insights into the interactions between peptide toxins and Na_V1.7. Therefore, this research may guide the future development of specific, safe, and efficacious Na_V1.7 inhibitors for pain relief.

2020-08-30·Nan fang yi ke da xue xue bao = Journal of Southern Medical University

[Aerobic exercise combined with huwentoxin-I upregulates phase-Ⅱ detoxification enzymes to alleviate obstructive jaundice-induced central nervous system injury in mice].

Article

作者: Chen, Jiaqin ; Chen, Wei ; Liang, Wei

OBJECTIVE:

To explore the effects of aerobic exercise combined with huwentoxin-I (HWTX-I)-mediated Keap1-Nrf2-ARE pathway on phase II detoxification enzymes HO-1 and NQO1 and their protective effects against obstructive jaundice (OJ)-induced central nervous system injury in mice.

METHODS:

50 male KM mice were randomly divided into blank group (GO), model group (M), aerobic exercise group (T), HWTX-I group (H), and aerobic exercise combined with HWTX-I group (TH). Mouse models of OJ were established with surgical suture for 72 h in the mice in all the groups except for the blank control group. The mice received interventions by aerobic exercise and tail vein injection of HWTX-I (0.05 μg/g) and were assessed by behavioral observation, Clark's neurological function scores, enzyme-linked immunosorbent assay (ELISA), brain tissue Nissl staining, hippocampal tissue Western blotting, and liver tissue mRNA expression profiling and sequencing.

RESULTS:

The mice in group M had obvious jaundice symptoms after the operation with significantly increased Clark's neurological score (P < 0.01). Compared with those in group M, the mice in group T, group H, and group TH showed significantly decreased serum levels of ALT, AST, TBIL, and TBA (P < 0.01) with increased contents of 5-HT and BDNF and decreased contents of S100B and NSE in the hippocampus (P < 0.01). Synergistic effects between aerobic exercise and HWTX-I were noted on the above parameters except for the liver function indicators. Interventions with aerobic exercise and HWTX-I, alone or in combination, obviously lessened pathologies in the brain tissue induced by OJ, and the combined treatment produced the strongest effect. The treatment also increased the expression levels of Nrf2, HO-1, and NQO1 mRNA and protein in brain tissues (P < 0.01 or 0.05) with a synergistic effect between aerobic exercise and HWTX-I. Illumina high-throughput sequencing showed that the differentially expressed factors participated mainly in such neural regulatory pathways as neuroactive ligand-receptor interaction, GABAergic synapses, dopaminergic synapses, synaptic vesicle circulation, and axon guidance, involving tissue cell neuronal signal transduction, apoptosis inhibition, immune response, and toxicity. Aerobic exercise and HWTX-I synergistically increased the accumulation of the signal pathways related with neuron damage repair and proliferation.

CONCLUSIONS:

Aerobic exercise combined with HWTX-I can up-regulate the expression of phase Ⅱ detoxification enzymes HO-1 and NQO1 through the Keap1-Nrf2-ARE pathway to protect the central nervous system against OJ-induced damage in mice.

2017-01-01·Neural regeneration research2区 · 医学

Aerobic exercise combined with huwentoxin-I mitigates chronic cerebral ischemia injury

2区 · 医学

ArticleOA

作者: Hai-feng Mao ; Rui Chen ; Wei Chen ; Bo-cun Zhou ; Chu-zu Wu ; Jia-qin Chen ; Chang-fa Tang ; Jun Xie ; Hong-lin Qu

Ca²⁺ channel blockers have been shown to protect neurons from ischemia, and aerobic exercise has significant protective effects on a variety of chronic diseases. The present study injected huwentoxin-I (HWTX-I), a spider peptide toxin that blocks Ca²⁺ channels, into the caudal vein of a chronic cerebral ischemia mouse model, once every 2 days, for a total of 15 injections. During this time, a subgroup of mice was subjected to treadmill exercise for 5 weeks. Results showed amelioration of cortical injury and improved neurological function in mice with chronic cerebral ischemia in the HWTX-I + aerobic exercise group. The combined effects of HWTX-I and exercise were superior to HWTX-I or aerobic exercise alone. HWTX-I effectively activated the Notch signal transduction pathway in brain tissue. Aerobic exercise up-regulated synaptophysin mRNA expression. These results demonstrated that aerobic exercise, in combination with HWTX-I, effectively relieved neuronal injury induced by chronic cerebral ischemia via the Notch signaling pathway and promoting synaptic regeneration.

100 项与虎纹镇痛肽相关的药物交易

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