期刊：
Journal of Molecular Neuroscience,2013年50(1):70-77 ISSN：0895-8696
通讯作者：
Tang, Xiao-Qing
作者机构：
[Ren, Yan-Kai; Chen, Rong-Qian; Tang, Xiao-Qing] Univ South China, Coll Med, Inst Cognit & Nervous Syst Dis, Hengyang 421001, Hunan, Peoples R China.;[Ren, Yan-Kai; Tang, Xiao-Qing] Univ South China, Coll Med, Dept Physiol, Hengyang 421001, Hunan, Peoples R China.;[Liao, Duan-Fang] Hunan Univ Chinese Med, Div Stem Cell Regulat & Applicat, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha 420108, Hunan, Peoples R China.;[Del Soldato, Piero] CTG Pharma, I-20131 Milan, Italy.;[Sparatore, Anna] Univ Milan, Dept Pharmaceut Sci Pietro Pratesi, Milan, Italy.
通讯机构：
[Tang, Xiao-Qing] U;Univ South China, Coll Med, Inst Cognit & Nervous Syst Dis, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
H2S-releasing sildenafil;Homocysteine;Neurotoxicity;Paraoxonase-1;Reactive oxygen species
摘要：
ACS6, a novel hydrogen sulfide (H2S)-releasing sildenafil, has been demonstrated to inhibit superoxide formation through donating H2S. We have previously found that ACS6 antagonizes homocysteine-induced apoptosis and cytotoxicity. The aim of the present study is to explore the molecular mechanisms underlying ACS6-exerted protective action against the neurotoxicity of homocysteine. In the present work, we used PC12 cells to explore whether paraoxonase-1 (PON-1) is implicated in ACS6-induced neuroprotection against homocysteine neurotoxicity. We show that ACS6 treatment results in prevention of homocysteine-caused neurotoxicity and overproduction of reactive oxygen species (ROS). Homocysteine downregulates the expression and activity of PON-1; however, this effect is significantly blocked by co-treatment with ACS6. The specific inhibitor of PON-1 2-hydroxyquinoline reverses the inhibitory effect of ACS6 on homocysteine-induced neurotoxicity and intracellular ROS accumulation. These results indicate that ACS6 protects PC12 cells against homocysteine-induced neurotoxicity by upregulating PON-1 and suggest a promising role of PON-1 as a novel therapeutic strategy for homocysteine-induced toxicity.
作者机构：
[Gu Hong-Feng] Univ South China, Dept Physiol, Hengyang 421001, Peoples R China.;[Gu Hong-Feng; Yang Yong-Zong] Key Lab Arteriosclerol Hunan Prov, Hengyang 421001, Peoples R China.;[Jiang Jian-Hong] Nanhua Univ, Chuanshan Coll, Hengyang 421001, Peoples R China.;[Tong Qiao-Zhen; Liao Duan-Fang] Hunan Univ Chinese Med, Div Stem Cell Regulat & Applicat, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Gu Hong-Feng] U;Univ South China, Dept Physiol, Hengyang 421001, Peoples R China.
关键词：
GP Ⅱb/Ⅲa;atherosclerosis;HMGB-1;TLR4;NF-κB
摘要：
The effects of glycoprotein (GP) Ⅱb/Ⅲa inhibitors on the development of the atherosclerotic process has received scant attention. To investigate whether GP Ⅱb/Ⅲa blockade influences atherosclerosis lesion and HMGB-1/TLR4 signaling, we compared plaque formation in ApoE~(-/-) mice: control group (n=10); IgG group (n=10, 50 μg) and GP Ⅱb/Ⅲa mAb group (n=10, 50 μg). All mice were fed on a Western diet (10% fat and 1.25% cholesterol) for 10 weeks. GP Ⅱb/Ⅲa blockade significantly decreased the atherosclerotic lesion and platelet adhesion to the vessel wall. Immunohistochemistry analysis showed that blocking GP Ⅱb/Ⅲa diminished MOMA-2 and VCAM-1 expression in aortic plaque in ApoE~(-/-) mice. Western blot results indicated that HMGB-1, TLR4, and NF-κB levels were markedly reduced in arteries of ApoE-/- mice treated with GP Ⅱb/Ⅲa mAb (P < 0.05). Moreover, GP Ⅱb/Ⅲa mAb decreased plasma HMGB-1, IL-1β, TNF-α and MCP-1 concentrations. Our findings demonstrated that GP Ⅱb/Ⅲa mAb significantly decreased atherosclerotic lesions and HMGB-1, TLR4 and NF-κB expression in ApoE~(-/-) mice (P < 0.05). The present study has suggested a possibility that GP Ⅱb/Ⅲa blockade attenuates atherosclerosis by inhibiting the HMGB-1/TLR4 pathway..
