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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >HYS-32, a novel analogue of combretastatin A-4, enhances connexin43 expression and gap junction intercellular communication in rat astrocytes
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HYS-32, a novel analogue of combretastatin A-4, enhances connexin43 expression and gap junction intercellular communication in rat astrocytes

机译：HYS-32，一种康普他汀A-4的新型类似物，可增强大鼠星形胶质细胞中连接蛋白43的表达和间隙连接的细胞间通讯

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摘要

HYS-32 [4-(3,4-dimethoxyphenyl)-3-(naphthalen-2-yl)-2(5H)-furanone] is a new analogue of the anti-tumor compound combretastatin A-4 containing a cis-stilbene moiety. In this study, we investigated its effects on Cx43 gap junction intercellular communication (GJIC) and the signaling pathway involved in rat primary astrocytes. Western blot analyses showed that HYS-32 dose- and time-dependently upregulated Cx43 expression. A confocal microscopic study and scrape-loading/dye transfer analyses demonstrated that HYS-32 (5 μM) induced microtubule coiling, accumulation of Cx43 in gap junction plaques, and increased GJIC in astrocytes. The HYS-32-induced microtubule coiling and Cx43 accumulation in gap junction plaques was reversed when HYS-32 was removed. Treatment of astrocytes with cycloheximide resulted in time-dependent degradation of by co-treatment with HYS-32 by increasing the half-life of Cx43. Co-treatment with HYS-32 also prevented the LPS-induced downregulation of Cx43 and inhibition of GJIC in astrocytes. HYS-32 induced activation of PKC, ERK, and JNK, and co-treatment with the PKC inhibitor Go6976 or the ERK inhibitor PD98059, but not the JNK inhibitor SP600125, prevented the HYS-32-induced increase in Cx43 expression and GJIC. Go6976 suppressed the HYS-32-induced PKC phosphorylation and increase in phospho-ERK levels, while PD98059 did not prevent the HYS-32-induced increase in phospho-PKC levels, suggesting that PKC is an upstream effector of ERK. In conclusion, our results show that HYS-32 increases the half-life of Cx43 and enhances Cx43 expression and GJIC in astrocytes via a PKC-ERK signaling cascade. These novel biological effects of HYS-32 on astrocyte gap junctions support its potential for therapeutic use as a protective agent for the central nervous system.
机译：HYS-32 [4-（3,4-二甲氧基苯基）-3-（萘-2-基）-2（5H）-呋喃酮]是抗肿瘤化合物康维他汀A-4的新类似物，该化合物包含顺-sti部分。在这项研究中，我们调查了其对大鼠原代星形胶质细胞中Cx43间隙连接细胞间通讯（GJIC）和信号通路的影响。蛋白质印迹分析表明，HYS-32剂量和时间依赖性上调了Cx43的表达。共聚焦显微镜研究和刮擦载荷/染料转移分析表明，HYS-32（5μM）引起微管卷曲，间隙连接斑块中Cx43的积累以及星形胶质细胞中GJIC的增加。当去除HYS-32时，HYS-32诱导的微管卷曲和间隙连接斑块中的Cx43积累被逆转。用环己酰亚胺处理星形胶质细胞可通过增加Cx43的半衰期与HYS-32共同处理，导致时间依赖性降解。与HYS-32共同治疗还可以防止LPS诱导的星形胶质细胞Cx43的下调和GJIC的抑制。 HYS-32诱导PKC，ERK和JNK的活化，并与PKC抑制剂Go6976或ERK抑制剂PD98059共同治疗，但不与JNK抑制剂SP600125共同治疗，阻止了HYS-32诱导的Cx43表达和GJIC升高。 Go6976抑制了HYS-32诱导的PKC磷酸化和磷酸化ERK水平的升高，而PD98059并未阻止HYS-32诱导的磷酸化PKC水平的升高，表明PKC是ERK的上游效应物。总之，我们的结果表明，HYS-32通过PKC-ERK信号级联增加星形胶质细胞中Cx43的半衰期并增强Cx43表达和GJIC。 HYS-32对星形胶质细胞间隙连接的这些新颖的生物学作用支持了其作为中枢神经系统保护剂的治疗用途的潜力。

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