期刊：
Phytomedicine : international journal of phytotherapy and phytopharmacology,2010年17(3-4):233-240 ISSN：0944-7113
通讯作者：
Deng, CQ
作者机构：
[Deng, Chang-Qing] Hunan Univ Tradit Chinese Med, Sch Integrated Chinese & Western Med, Pathophysiol Lab, Changsha, Hunan, Peoples R China.;[Chen, Bei-Yang; Zhang, Guo-Min; Li, Hua] Hunan Univ Tradit Chinese Med, Dept Pathol, Changsha, Hunan, Peoples R China.;[Tang, Ying-Hong] Hunan Univ Tradit Chinese Med, Dept Pharmacol, Changsha, Hunan, Peoples R China.;[Wu, Lu] Hunan Univ Tradit Chinese Med, Affiliated Tradit & Western Med Hosp 2, Changsha, Hunan, Peoples R China.
通讯机构：
[Deng, CQ] Hunan Univ Tradit Chinese Med, Sch Integrated Chinese & Western Med, Pathophysiol Lab, Xiangzui Rd, Changsha, Hunan, Peoples R China.
关键词：
Total saponins of "panax notoginseng root";Atorvastatin;Vascular smooth muscle cell;Proliferating cell nuclear antigen;Cyclind D(1);Cycline;Extracellular matrix;Collagen I;Fibronectin;Matrix metalloproteinase-9;Tissue inhibitor metalloproteinase-1
摘要：
Aim of the study: the effect of total saponins of "panax notoginseng root" on aortic intimal hyperplasia and the expressions of cell cycle protein and extracellular matrix in rats Materials and methods: Sprague-Dawley rats were randomly divided into sham-operated, control, TSPN and atorvastatin group. Rat aorta intima in all groups were injured by insertion of domestic balloon catheter into the aortae except sham-operated rats. Drugs were administrated orally from the second day after vascular injury and continued for 14 days. The injured segments of aortae were collected on the sixteenth day after operation to observe the morphological changes of vascular structure and to examine the expressions of proliferating cell nuclear antigen(PCNA), cyclinD1, cyclinE, collagen I(Col-I), fibronect(FN), matrix metalloproteinase-9(MMP-9) and tissue inhibitor metalloproteinase-1(TIMP-1). Results: TPNS significantly inhibited the vascular intimal hyperplasia. TPNS significantly lowered the expression of PCNA, cyclinE, cyclinD1, FN and MMP-9. TPNS had no significant impacts on the expression of Col-I and TIMP-1. Conclusions: Our studies indicated that TSPN could inhibit vessel restenosis after vascular intimal injury, and its mechanisms may be related to the blockage of the excessive proliferation of VSMC, the reduction of ECM protein deposition in the endometrium, and the degradation of ECM protein. (C) 2009 Elsevier GmbH. All rights reserved.
作者：
Liu, S. J.;Sun, Y. M.;Tian, D. F.;He, Y. C.;Zeng, L.;He, Y.;Ling, C. Q.;Sun, S. H.
期刊：
British journal of cancer,2008年98(2):363-369 ISSN：0007-0920
通讯作者：
Tian, DF
作者机构：
[Zeng, L.] Huan Provincial Tumor Hosp, Dept Pathol, Changsha, Peoples R China.;[Sun, Y. M.] Chinese Acad Sci, Inst Genet & Dev Biol, Beijing, Peoples R China.;[He, Y. C.; Tian, D. F.; Liu, S. J.] Tradit Chinese Med Univ Hunan, Fac Integrat Med, Changsha 410007, Peoples R China.;[He, Y.; Sun, S. H.] Second Mil Med Univ, Dept Med Genet, Shanghai, Peoples R China.;[Liu, S. J.; Ling, C. Q.] Changhai Hosp, Dept Tradit Chinese Med, Shanghai, Peoples R China.
通讯机构：
[Tian, DF] Tradit Chinese Med Univ Hunan, Fac Integrat Med, 113 Shaoshan Middle Rd, Changsha 410007, Peoples R China.
摘要：
Because the focus of nasopharyngeal carcinoma (NPC) is very close to intracranial organs, it often makes incursions into cranial cavity. Identification of intracranial invasion-associated indicators will provide potential therapeutic targets for NPC patients with intracranial invasion. In this regard, Human Xpro(TM) HC-plus cancer-related gene chip was utilised to screen intracranial invasion-associated genes for NPC from the biopsied primary focus tissue samples. In all, 8 upregulated and 23 downregulated genes were obtained. VEGF165 and MMP-9, the two upregulated genes, and NM23-H1, the downregulated one, were further confirmed by immunohistochemistry, quantitative real-time PCR and western blot. Invasion-associated cellular and nude mouse models were subsequently employed to study the biological properties of NM23-H1. NM23-H1 expression was significantly lower in 5-8F cells compared with that in 6-10B cells. Moreover, patch-clamp and transwell chamber were adopted to investigate the invading potential-associated biological dynamic mechanisms in the two cell lines, and Ca2+ current and motility were significantly elevated in 5-8F cells compared with that in 6-10B cells. Berberine, an inhibitor of Ca2+ current, could substantially increase the expression of NM23-H1 and decrease 5-8F cell motility. The specificity of berberine on NM23-H1 and cell motility was confirmed by RNAi assay.
期刊：
The American journal of Chinese medicine,2015年43(7):1419-1438 ISSN：0192-415X
通讯作者：
Deng, CQ
作者机构：
[Huang, Xiao-Ping; Deng, Chang-Qing] * Molecular Pathology Laboratory, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, P.R. China;[Ding, Huang; Tang, Ying-Hong] dagger Key Laboratory of Hunan Province for Prevention and Treatment of Integrated, Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Changsha 410208, Hunan Province, P.R. China;[Lu, Jin-Dong; Deng, Bing-Xiang] double dagger Key Laboratory of Hunan Universities for Cell biology and Molecular Techniques, Changsha 410208, Hunan Province, P.R. China
通讯机构：
[Deng, CQ] Hunan Univ Chinese Med, Mol Pathol Lab, Changsha 410208, Hunan, Peoples R China.
摘要：
Astragalus and Panax notoginseng are commonly used to treat cardio-cerebrovascular diseases in China and are often combined together to promote curative effect. We speculate that the enhancement of the combination on anticerebral ischemia injury may come from the main active components. The purpose of this work was to probe the effects and mechanisms of Astragaloside IV (the active component of Astragalus) combined with Ginsenoside Rg1, Ginsenoside Rb1, and Notoginsenoside R1 (the active components of P. notoginseng) to antagonize ischemia/reperfusion (I/R) injury via inflammation and apoptosis. C57BL/6 mice were randomly divided into sham, model, Astragaloside IV, Ginsenoside Rg1, Ginsenoside Rb1, Notoginsenoside R1, four active components combination, and Edaravone groups. After administration for 3 days, bilateral common carotid arteries (CCA) were occluded with artery clip for 20[Formula: see text]min followed by reperfusion for 24[Formula: see text]h. Our results showed that the survival rate of nerve cell in hippocampal CA1 decreased while the apoptotic rate increased, and the level of caspase-3 protein in brain tissues was elevated, the expressions of TNF-a, IL-1, and ICAM-1 mRNA as well as phosphorylated nuclear factor kappa B (NF-kappaB) inhibitor protein alpha (p-IkappaBa) in brain tissues were up-regulated, and the nuclear translocation rate of NF-kappaB was raised. Additionally, the protein expressions of phosphorylated tyrosine kinase 1 (p-JAK1), phosphorylated signal transducer and activator of transcription-1 (p-STAT1), glucose regulated protein 78 (GRP78), caspase-12, and phosphorylated c-Jun N-terminal kinases 1/2 (p-JNK1/2) in brain tissues were also significantly strengthened after I/R for 24 h. All drugs could increase neurocyte survival rate in hippocampal CA1, decrease the apoptotic rate, and inhibit caspase-3 protein expression, in contrast, the effects of four active components combination were better than those of active components alone. In addition, Astragaloside IV and Ginsenoside Rg1 could down-regulate the level of TNF-alpha, and ICAM-1 mRNA, respectively, Notoginsenoside R1 reduced both TNF-alpha and ICAM-1 mRNA, and the combination of the 4 effective components had inhibitory effects on the expressions of TNF-alpha, IL-1beta, and ICAM-1 mRNA. Astragaloside IV, Ginsenoside Rg1, Notoginsenoside R1, and 4 effective components combination were able to restrain the phosphorylation of IkappaBalpha, and relieve the nuclear translocation rate of NF-kappaB. Moreover, the effects of the combination are greater than those of active components alone. All drugs could suppress the phosphorylation of JAK1 induced by I/R; meanwhile the expression of p-STAT1 exhibited a decrease in Ginsenoside Rg1 and four active components combination groups. The decreases of p-JAK1 and p-STAT1 in the four active components combination group were more obvious than those in active components alone groups. Astragaloside IV, Ginsenoside Rg1, and Notoginsenoside R1 further augmented GRP78 expression caused by I/R, Notoginsenoside R1 attenuated caspase-12 protein expression, Astragaloside IV and Ginsenoside Rg1 lessened the phosphorylation of JNK1/2, and the four active components combination was capable of up-regulating GRP78 protein while down-regulating the expressions of caspase-12 and p-JNK1/2. Similarly, the effects of the four active components combination were greater than those of effective components alone. These suggested that the combination of the main active components of Astragalus and Panax notoginseng could strengthen protective effects on cerebral ischemia injury via anti-apoptosis and anti-inflammation, and the mechanisms might be associated with restraining the activation of NF-kappaB and JAK1/STAT1 signal pathways and regulating endoplasmic reticulum stress (ERS) after cerebral ischemia.
摘要：
Background: Astragalus and Panax notoginseng are traditional Chinese Medicines used for the treatments of ischemic cerebrovascular disease, being often combined together in China and achieving a good effect. Objective: The objective of this study is to investigate the effects of astragaloside-IV (AST-IV) (the effective component of Astragalus) combined with ginsenoside Rg1, ginsenoside Rb1, notoginsenoside R1 (the effective components of P. notoginseng) on oxidative stress injury after cerebral ischemia-reperfusion in mice, and to explore the mechanisms through nuclear factor-erythroid 2-related factor-2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway. Materials and Methods: C57BL/6 mice were randomly grouped after treated for 3 days, the model of cerebral ischemia-reperfusion injury was established, and the brain tissues were detected. Results: AST-IV combined with ginsenoside Rg1, ginsenoside Rb1, notoginsenoside R1 could increase significantly the survival rate of nerve cell; decrease the contents of malondialdehyde, nitric oxide, increase the activity of superoxide dismutase and the level of glutathione; Nrf2 was down-regulated in the cytoplasm while up-regulated in nucleus, nuclear translocation rate raised as well as HO-1 messenger ribonucleic acid and protein expressions increased. The effects of four active components combination were better than those of the active components alone. Conclusion: Active components of Astragalus and P. notoginseng had the effects against cerebral ischemia-reperfusion injury, which were related to the antioxidative stress after cerebral ischemia-reperfusion. AST-IV combined with ginsenoside Rg1, ginsenoside Rb1, notoginsenoside R1 could strengthen the antagonism effects on ischemia-reperfusion and oxidative stress injury, the mechanism underlying might be associated with jointly activating Nrf2/HO-1 signaling pathway after cerebral ischemia-reperfusion.
作者机构：
[Liao, Duan-fang; Tuo, Qin-hui] School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China;[He, Xiaochen; Chen, Jian-xiong; Zeng, Heng] Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, 39216, USA;[Zhang, Guo-qiang] Emergency Department of China-Japan Friendship Hospital, Beijing, 100029, China
通讯机构：
[Chen, JX] Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, Sch Med, Jackson, MS 39216 USA.
摘要：
Recent studies reveal a crucial role of pericyte loss in sepsis-associated microvascular dysfunction. Sirtuin 3 (SIRT3) mediates histone protein post-translational modification related to aging and ischemic disease. This study investigated the involvement of SIRT3 in LPS-induced pericyte loss and microvascular dysfunction. Mice were exposed to LPS, expression of Sirt3, HIF-2 alpha, Notch3 and angiopoietins/Tie-2, pericyte/endothelial (EC) coverage and vascular permeability were assessed. Mice treated with LPS significantly reduced the expression of SIRT3, HIF-2 alpha and Notch3 in the lung. Furthermore, exposure to LPS increased Ang-2 while inhibited Ang-1/Tie-2 expression with a reduced pericyte/EC coverage. Intriguingly, knockout of Sirt3 upregulated Ang-2, but downregulated Tie-2 and HIF-2 alpha/Notch3 expression which resulted in a dramatic reduction of pericyte/EC coverage and exacerbation of LPS-induced vascular leakage. Conversely, overexpression of Sirt3 reduced Ang-2 expression and increased Ang-1/Tie-2 and HIF-2 alpha/Notch3 expression in the LPS treated mice. Overexpression of Sirt3 further prevented LPS-induced pericyte loss and vascular leakage. This was accompanied by a significant reduction of the mortality rate. Specific knockout of prolyl hydroxylase-2 (PHD2) increased HIF-2 alpha/Notch3 expression, improved pericyte/EC coverage and reduced the mortality rate in the LPS-treated mice. Our study demonstrates the importance of SIRT3 in preserving vascular integrity by targeting pericytes in the setting of LPS-induced sepsis.
摘要：
Cantharidin (CTD), a chemical compound secreted by blister beetles, has been shown with anti-tumor property in many cancer cells. In this study, our data showed that CTD exerts potent anti-angiogenesis activity in a dose-dependent manner. CTD dose dependently suppressed human umbilical vascular endothelial cells proliferation, migration, and tube formation in vitro. Furthermore, CTD concentration dependently inhibited angiogenesis in chick embryo CAM model in vivo. At the molecular level, CTD abrogated VEGF-induced activation of STAT3 and suppressed the phosphorylation of JAK1 and ERK in a dose-dependent manner. Furthermore, CTD blocked the phosphorylation of AKT in a time-dependent manner. Taken together, these findings clearly demonstrate for the first time that CTD can inhibit angiogenesis and may have applications in the development of new anti-angiogenesis drugs.
关键词：
Active components combinations;AMP-activated protein kinase;Astragalus and Panax notoginseng;cerebral ischemia;energy metabolism;glucose transporter 3
摘要：
Background: Astragalus and Panax notoginseng are traditional Chinese medicines used for the treatments of cardio-cerebrovascular ischemic diseases, astragaloside IV (AST IV) and ginsenoside Rg1 (Rg1), ginsenoside Rb1 (Rb1), notoginsenoside R1 (R1) are their active components. Objective: The purpose of this work was to investigate the effect of AST IV combined with Rg1, Rb1, R1 on energy metabolism in brain tissues after cerebral ischemia-reperfusion in mice. Materials and Methods: C57BL/6 mice were randomly divided into 11 groups, treated for 3 days. At 1 h after the last administration, the model of cerebral ischemia-reperfusion injury was established, and brain tissues were detected. Results: All drugs increased the contents of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and the level of total adenine nucleotides (TAN), the combinations increased energy charge (EC), the effects of four active components combination were better. The phosphorylation of AMP-activated protein kinase1/2 (p-AMPK1/2) was increased in AST IV, R1, four active components combination, AST IV Rg1 and AST IV R1 groups, the increased effect of four active components combination was greater than that of the active components alone and AST IV Rb1. All drugs increased glucose transporter 3 (GLUT3) mRNA and protein, and the increases of four active components combination were more obvious than those of the active components alone or some two active components combinations. Conclusion: Four active components combination of Astragalus and P. notoginseng have the potentiation on improving of energy metabolism, the mechanism underlying might be associated with promoting the activation of AMPK1/2, enhancing the expression of GLUT3, thus mediating glucose into nerve cells, increasing the supply and intake of glucose.
作者机构：
[Tao, Yong-Kang; Xie, Xue-Jiao; He, Xiaochen; Roman, Richard J.; Chen, Jian-Xiong; Zeng, Heng; Wang, Shuo] Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, Sch Med, Jackson, MS 39216 USA.;[Xie, Xue-Jiao; Chen, Jian-Xiong] Hunan Univ Chinese Med, Sch Integrated Chinese & Western Med, Changsha, Hunan, Peoples R China.;[Aschner, Judy L.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA.;[Aschner, Judy L.] Childrens Hosp Montefiore, Bronx, NY USA.
通讯机构：
[Chen, JX] Hunan Univ Chinese Med, Sch Integrated Chinese & Western Med, Changsha, Hunan, Peoples R China.;Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, Sch Med, Jackson, MS 39216 USA.
摘要：
Pulmonary arterial hypertension (PAH) is a leading cause of heart failure. Although pulmonary endothelial dysfunction plays a crucial role in the progression of the PAH, the underlying mechanisms are poorly understood. The HIF-alpha hydroxylase system is a key player in the regulation of vascular remodeling. Knockout of HIF-2 alpha has been reported to cause pulmonary hypertension. The present study examined the role of endothelial cell specific prolyl hydroxylase-2 (PHD2) in the development of PAH and pulmonary vascular remodeling. The PHD2(f/f) mouse was crossbred with VE-Cadherin-Cre promoter mouse to generate an endothelial specific PHD2 knockout (Cdh5-Cre-PHD2(EC)KO) mouse. Pulmonary arterial pressure and the size of the right ventricle was significantly elevated in the PHD2(EC)KO mice relative to the PHD2(f/f) controls. Knockout of PHD2 in EC was associated with vascular remodeling, as evidenced by an increase in pulmonary arterial media to lumen ratio and number of muscularized arterioles. The pericyte coverage and vascular smooth muscle cells were also significantly increased in the PA. The increase in vascular pericytes was associated with elevated expression of fibroblast specific protein-1 (FSP-1). Moreover, perivascular interstitial fibrosis of pulmonary arteries was significantly increased in the PHD2(EC)KO mice. Mechanistically, knockout of PHD2 in EC increased the expression of Notch3 and transforming growth factor (TGF-beta) in the lung tissue. We conclude that the expression of PHD2 in endothelial cells plays a critical role in preventing pulmonary arterial remodeling in mice. Increased Notch3/TGF-beta signaling and excessive pericyte coverage may be contributing to the development of PAH following deletion of endothelial PHD2.
摘要：
The main active components extracted from Panax notoginseng are total saponins. They have been shown to inhibit platelet aggregation, increase cerebral blood flow, improve neurological behavior, decrease infarct volume and promote proliferation and differentiation of neural stem cells in the hippocampus and lateral ventricles. However, there is a lack of studies on whether total saponins of Panax notoginseng have potential benefits on immature neuroblasts in the olfactory bulb following ischemia and reperfusion. This study established a rat model of global cerebral ischemia and reperfusion using four-vessel occlusion. Rats were administered total saponins of Panax notoginseng at 75 mg/kg intraperitoneally 30 minutes after ischemia then once a day, for either 7 or 14 days. Total saponins of Panax notoginseng enhanced the number of doublecortin (DCX)~+ neural progenitor cells and increased co-localization of DCX with neuronal nuclei and phosphorylated cAMP response element-binding/DCX~+ neural progenitor cells in the olfactory bulb at 7 and 14 days post ischemia. These findings indicate that following global brain ischemia/reperfusion, total saponins of Panax notoginseng promote differentiation of DCX~+ cells expressing immature neuroblasts in the olfactory bulb and the underlying mechanism is related to the activation of the signaling pathway of cyclic adenosine monophosphate response element binding protein.
期刊：
MOLECULAR MEDICINE REPORTS,2015年11(6):4047-4052 ISSN：1791-2997
通讯作者：
Ge, JW
作者机构：
[Ge, Jin-Wen; Wang, Guo-Zuo] College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China;[Liao, Jun; Shi, Yong-Mei] Department of Anatomy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China;[Xia, Xing] Campus Network Center, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
通讯机构：
[Ge, JW] Hunan Univ Chinese Med, Coll Integrated Tradit Chinese & Western Med, 300 Xueshi St, Changsha 410208, Hunan, Peoples R China.
摘要：
The expression of Ferroportin (Fpn) was examined at different time points in rats following focal cerebral ischemia treated with or without the traditional Chinese medicine Naotaifang. Initially, rats were randomly divided into 2, 6, 12, 24 and 72 h groups following middle cerebral artery occlusion (MCAO) and the mRNA and protein level of Fpn was detected by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) at the above time points. Secondly, the rats were randomly divided into five groups as follows: Sham surgery group, model group, low-dose group (3 g/kg NTE), medium dose group (9 g/kg NTE) and the high-dose group (27 g/kg NTE). After 3 days of corresponding therapy by intragastric administration once a day, the regional cerebral ischemia model was reproduced by the MCAO suture method. On the third day, the neurological behavior of the rats was analyzed by neurobehavioral assessment. Fpn in the hippocampal CA2 region was measured by immunohistochemistry and the mRNA level of Fpn was detected by RT-PCR. Expression of Fpn in the hippocampal CA2 region reached a peak 12 h after surgery (P<0.05, compared with the model group). The high-dose group (27 g/kg NTE) exhibited a lower neurological behavior score (P<0.05) and a higher level of expression of Fpn at the mRNA and protein level compared with the sham surgery group and model group (P<0.05). Dysregulation of intracellular iron balance is possibly a new mechanism underlying cerebral ischemia. NTE can protect the neuronal population in the hippocampal CA2 region by adjusting the expression of Fpn to balance iron levels following cerebral ischemia.
摘要：
Objective： To explore the effects and molecular mechanisms of the combination between total Astragalus extract （TAE） and total Panax notoginseng saponins （TPNS） against cerebral ischemia- reperfusion injury. Methods： C57BL/6 mice were randomly divided into sham-operated group, model group, TAE （110 mg/kg） group, TPNS （115 mg/kg） group, TAE-TPNS combination group and Edaravone （4 mg/kg） group, treated for 4 days, then, cerebral ischemia-repeffusion injury was established by bilateral common carotid artery （CCA） ligation for 20 min followed by reperfusion for 1 and 24 h. Results： TPNS could increase adenosine triphosphate （ATP） level, TAE and TAE-TPNS combination increased ATP, adenosine diphosphate （ADP） contents and Na＋-K＋-ATPase activity, and the effects of TAE-TPNS combination were stronger than those of TAE or TPNS alone after reperfusion for 1 h. After reperfusion for 24 h, TAE, TPNS and TAE-TPNS combination significantly increased neurocyte survival rate and decreased the apoptosis rate as well as down-regulated the expression of phosphorylated c-June N-terminal kinasel/2 （p-JNK1/2）, cytochrome C （Cyt C）, cysteine aspartic acid-specific protease （Caspase）-9 and Caspase-3. Furthermore, the effects in TAE-TPNS combination were better than those in TAE or TPNS alone. Conclusion： The combination of TAE 110 mg/kg and TPNS 115 mg/kg could strengthen protective effects on cerebral ischemia injury, the mechanism underlying might be related to improving jointly the early energy metabolism, and relieving the delayed apoptosis via inhibiting the mitochondrial apoptosis pathway of JNK signal transduction.
关键词：
protein prenylation;geranylgeranyltransferase;knockout mouse models;small GTPases;synaptic plasticity;dendritic spine density
摘要：
Isoprenoids and prenylated proteins regulate a variety of cellular functions, including neurite growth and synaptic plasticity. Importantly, they are implicated in the pathogenesis of several diseases, including Alzheimer's disease (AD). Recently, we have shown that two protein prenyltransferases, farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT), have differential effects in a mouse model of AD. Haplodeficiency of either FT or GGT attenuates amyloid-beta deposition and neuroinflammation but only reduction in FT rescues cognitive function. The current study aimed to elucidate the potential mechanisms that may account for the lack of cognitive benefit in GGT-haplodeficient mice, despite attenuated neuropathology. The results showed that the magnitude of long-term potentiation (LTP) was markedly suppressed in hippocampal slices from GGT-haplodeficient mice. Consistent with the synaptic dysfunction, there was a significant decrease in cortical spine density and cognitive function in GGT-haplodeficient mice. To further study the neuron-specific effects of GGT deficiency, we generated conditional forebrain neuron-specific GGT-knockout (GGT(f/f)Cre+) mice using a Cre/LoxP system under the CAMKII alpha promoter. We found that both the magnitude of hippocampal LTP and the dendritic spine density of cortical neurons were decreased in GGT(f/f)Cre+ mice compared with GGT(f/f)Cre- mice. Immunoblot analyses of cerebral lysate showed a significant reduction in cell membrane-associated (geranylgeranylated) Rac1 and RhoA but not (farnesylated) H-Ras, in GGT(f/f)Cre+ mice, suggesting that insufficient geranylgeranylation of the Rho family of small GTPases may underlie the detrimental effects of GGT deficiency. These findings reinforce the critical role of GGT in maintaining spine structure and synaptic/cognitive function in development and in the mature brain. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
期刊：
Journal of Zhejiang University. Science. B,2009年10(03):172-179 ISSN：1673-1581
通讯作者：
He, YC
作者机构：
[HE; TIAN] Chinese Med Univ Hunan, Fac Integrat Med, Changsha 410007, Peoples R China.;[TANG] Cent S Univ, Dept Clin Lab, Xiangya Hosp 1, Changsha 410008, Peoples R China.;[Fang-guo] Chinese Med Univ Hunan, Fac Basic Med, Changsha 410007, Peoples R China.
通讯机构：
[He, YC] Chinese Med Univ Hunan, Fac Integrat Med, Changsha 410007, Peoples R China.
摘要：
OBJECTIVE: To investigate the enhancive effect of N,N'-dinitrosopiperazine (DNP) on induced carcinogenesis in nasal and/or nasopharyngeal epithelia among TgN(p53mt-LMP1)/HT transgenic mice to examine the underlying mechanism for the development of nasopharyngeal carcinoma (NPC). METHODS: TgN(p53mt-LMP1)/HT transgenic mice and the same strain of C(57)BL/6J wild-type mice both at the age of 5 months were randomly divided into 2 groups in parallel, respectively, i.e., TgN(p53mt-LMP1)/HT cancerous lesion-inducing group (TI), TgN(p53mt-LMP1)/HT control group (TC), C57BL/6J cancerous lesion-inducing group (CI), and C57BL/6J control group (CC). TI and CI mice were treated only with DNP for 16 weeks, twice each week, while TC and CC mice were given the same volume of saline as controls. At the end of treatment, animals were sacrificed to collect epithelial tissue samples from nasal cavity and nasopharynx for pathohistological evaluation by haematoxylin and eosin (HE) staining and for determination on the expression of TRAF2, c-Jun, and p16 by immunohistochemistry. RESULTS: Atypical hyperplasia was more significant in the samples of TI than in those of TC, CI, and CC, with the rates of lesions being 90%, 10%, 0, and 0 (P<0.01) respectively, though DNP was used alone in a much shortened inducing period at less dosage and without the use of carcinogenic promoter 12-O-tetradecanoylphorbol-13-acetate as usual. The expressions of tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and c-Jun in these samples were significantly up-regulated in TI (P<0.01), while the expression of p16 was significantly lower in TI than in the other groups (P<0.01). CONCLUSION: TgN(p53mt-LMP1)/HT mice hold inherited constitutional defect in immune surveillance function, which can be aggravated by environmental carcinogens, such as DNP used even though in a much less strength. The enhanced carcinogenesis-inducing effect of DNP on TgN(p53mt-LMP1)/HT mice should be closely associated with abnormal signaling of activator protein-1 (AP-1) pathway, especially up-regulated expressions of TRAF2 and c-Jun, and down-regulated expression of p16.
作者机构：
[Tang, Biao; Liu, Xiao-Dan; Tang, Ying-Hong] Hunan Education Department's Key Laboratory of Cell Biology and Molecular Technology, Hunan University of Chinese Medicine, Changsha, Hunan 410208, PR China;[Huang, Xiao-Ping; Li, Jing-Xian; Yang, Xiao-Qian; Ding, Huang] Molecular Pathology Laboratory, Hunan Provincial Key Laboratory for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, Hunan 410208, PR China;[Deng, Chang-Qing] Molecular Pathology Laboratory, Hunan Provincial Key Laboratory for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, Hunan 410208, PR China. Electronic address: dchangq@sohu.com
通讯机构：
[Deng, Chang-Qing] Molecular Pathology Laboratory, Hunan Provincial Key Laboratory for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, Hunan 410208, PR China. Electronic address:
摘要：
The aim of this study was to explore the effect by which the combination of Astragaloside IV (AST IV) and Ginsenoside Rg1 (Rg1) resisted autophagic injury in PC12 cells induced by oxygen glucose deprivation/reoxygenation (OGD/R). We studied the nature of the interaction between AST IV and Rg1 that inhibited autophagy through the Isobologram method, and investigated the synergistic mechanism via the PI3K I/Akt/mTOR and PI3K III/Becline-1/Bcl-2 signaling pathways. Our results showed that, based on the 50% inhibiting concentration (IC50), AST IV combined with Rg1 at a 1:1 ratio resulted in a synergistic effect, whereas the combination of the two had an antagonistic effect on autophagy at ratios of 1:2 and 2:1. Meanwhile, AST IV and Rg1 alone increased cell survival and decreased lactate dehydrogenase (LDH) leakage induced by OGD/R, reduced autophagosomes and the LC3 II positive patch, down-regulated the LC3 II/LC3 I ratio and up-regulated the p62 protein; the 1:1 combination enhanced these effects. Mechanistic study showed that Rg1 and the 1:1 combination increased the phosphorylation of PI3K I, Akt and mTOR; the effects of the combination were greater than those of the drugs alone. AST IV and the 1:1 combination suppressed the expression of PI3K III and Becline-1, and the combination elevated Bcl-2 protein expression; the effects of the combination were better than those of the drugs alone. These results suggest that after 2 h-OGD followed by reoxygenation for 24 h, PC12 cells suffer excessive autophagy and damage, which are blocked by AST IV or Rg1; moreover, the combination of AST IV and Rg1 at a 1:1 ratio of their IC50 concentrations has a synergistic inhibition on autophagic injury. The synergistic mechanism may be associated with the PI3K I/Akt/mTOR and PI3K III/Becline-1/Bcl-2 signaling pathways. (C) 2017 Elsevier Masson SAS. All rights reserved.
