Recent evidence suggested that ClC-3 channel/antiporter is involved in regulation of nuclear factor (NF)-κB activation. However, the mechanism explaining how ClC-3 modulates NF-κB signaling is not well understood. We hypothesized that ClC-3-dependent alteration of intracellular chloride concentration ([Cl(-)](i)) underlies the effect of ClC-3 on NF-κB activity in endothelial cells. Here, we found that reduction of [Cl(-)](i) increased tumor necrosis factor-α (TNFα)-induced expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 and adhesion of monocytes to endothelial cells (P<0.05; n=6). In Cl(-) reduced solutions, TNFα-evoked IκB kinase complex β and inhibitors of κBα phosphorylation, inhibitors of κBα degradation, and NF-κB nuclear translocation were enhanced. In addition, TNFα and interleukin 1β could activate an outward rectifying Cl(-) current in human umbilical vein endothelial cells and mouse aortic endothelial cells. Knockdown or genetic deletion of ClC-3 inhibited or abolished this Cl(-) conductance. Moreover, Cl(-) channel blockers, ClC-3 knockdown or knockout remarkably reduced TNFα-induced intercellular adhesion molecule 1 and vascular cell adhesion molecule 1expression, monocytes to endothelial cell adhesion, and NF-κB activation (P<0.01; n=6). Furthermore, TNFα-induced vascular inflammation and neutrophil infiltration into the lung and liver were obviously attenuated in ClC-3 knockout mice (P<0.01; n=7). Our results demonstrated that decrease of [Cl(-)](i) induced by ClC-3-dependent Cl(-) efflux promotes NF-κB activation and thus potentiates TNFα-induced vascular inflammation, suggesting that inhibition of ClC-3-dependent Cl(-) current or modification of intracellular Cl(-) content may be a novel therapeutic approach for inflammatory diseases.

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To study the epidemiological characteristics of sudden unexplained nocturnal death syndrome (SUNDS) in the southern Chinese Han population during 2007 to 2013, we gathered 879 SUNDS victims from Dongguan City and in the Longgang District in Shenzhen City as the case group then selected 879 all-cause death cases, adopting a 1:1 pair method, as the control group I and collected 8142 all-cause death cases from the Bao'an District in Shenzhen City as the control group II, simultaneously. Case information collected was statistically analyzed. The annual incidence of SUNDS is 1.02 and 2.23 per 100,000 person-years for Dongguan City and in the Longgang District, respectively. The number of male and female victims is drastically different, with a ratio of 13.92:1, whereas the incidence between the 2 sexes is significantly different (χ2 = 78.734, P < 0.01), with an odds ratio value of 11.32 (95% confidence interval, 5.75-22.28). The age of death of SUNDS cases ranges from 17 to 55 years with a median age of 35 years; furthermore, the difference of distribution of age of death between the SUNDS victims and the all-cause death population is significant (χ2 = 767.12, P < 0.001). The birthplace of SUNDS victims is distributed throughout 27 provinces of China, but the difference between the SUNDS victims and the all-cause death population is not significant (χ2 = 27.273, P > 0.05). The monthly incidence of SUNDS is relatively higher from March to June, whereas the difference of monthly distribution between SUNDS victims and all-cause death population is significant (χ2 = 9.869, P < 0.05), with an odds ratio value of 1.42 (95% confidence interval, 1.14-1.76). Although the majority of SUNDS occurred during midnight sleep, they were mostly discovered from 7 to 9 am once the inmates or spouses woke in the morning. A total of 97.74% of the SUNDS victims were blue-collar factory workers with a high-intensity labor and poor education background. This investigation confirmed the stability of epidemiological characteristics of SUNDS in South China and implicated that risk factors of this fatal disease still exist. The efficient strategy of early identification such as molecular diagnosis for SUNDS is extremely urgently required.

Vinpocetine is a clinically used drug for cerebrovascular disorders as well as age-related memory impairment. Of note, vinpocetine has been recently identified as a novel anti-inflammatory agent; however, its effects on cancer cells remain to be investigated. In the present study, we found that vinpocetine potently inhibited proliferation of multiple types of human breast cancer cells by arresting cell cycle at G(0)/G(1) phase. It was also revealed that vinpocetine induced cell apoptosis via mitochondria-dependent pathway. Moreover, vinpocetine impaired the migration of the strongly metastatic cell MDA-MB-231. In xenograft model of human breast cancer in nude mice, both systemic and local administration of vinpocetine significantly suppressed the tumor growth without observed toxicity. Interestingly, vinpocetine markedly attenuated the activation of Akt and signal transducer and activator of transcription factor 3 (STAT3), but had no effects on MAP kinases pathways. Collectively, the data suggest that vinpocetine possesses significant yet previously unknown antitumor properties that may be utilized for the treatment of breast cancer.

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