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.
作者机构:
[Peng, Tingting; Tang, Qianli; Liao, Xianjiu] Youjiang Med Univ Nationalities, West Guangxi Key Lab Prevent & Treatment High Inc, 98 Chengxiang Rd, Baise 533000, Guangxi, Peoples R China.;[Li, Liqing; Ge, Bin; Tang, Qianli; Liao, Xianjiu] Hunan Univ Chinese Med, Sch Integrated Chinese & Western Med, Changsha, Hunan, Peoples R China.;[Pan, Jianbin] Nanjing Univ, Sch Chem & Chem Engn, State Key Lab Analyt Chem Life Sci, Nanjing, Jiangsu, Peoples R China.
通讯机构:
[Tang, Qianli] Y;Youjiang Med Univ Nationalities, West Guangxi Key Lab Prevent & Treatment High Inc, 98 Chengxiang Rd, Baise 533000, Guangxi, Peoples R China.
关键词:
carbon nitride nanosheet;catalytic hairpin assembly;intracellular signal amplification;microRNA;nanoprobe
摘要:
In this study, an ultrasensitive fluorescence turn-on assay for in situ sensing of intracellular microRNA (miRNA) was developed utilizing a carbon nitride nanosheet (CNNS) and a catalytic hairpin assembly (CHA). The CHA showed favourable signal amplification for low-level biomarkers, and CNNS was an excellent candidate as a fluorescence quencher and gene vector. Moreover, the hairpin DNA of CHA could be adsorbed onto the surface of CNNS. An enzyme-free fluorescence biosensor for ultrasensitive sensing of intracellular miRNA in cells based on CHA and CNNS was designed. When faced with target miRNA, the fluorescence was recovered due to the miRNA, which could trigger cycling of CHA circuits, leading to the production of a marked enhanced fluorescence signal. Compared with traditional methods, the proposed method is convenient, with low cytotoxicity, and high specificity and ultrasensitivity. It has promising potential for detection low-level biomarkers.
作者机构:
[何清湖; 朱闽] School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;[朱闽; 戴芳; 徐楠] Department of Andrology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi 530011, China;[赵自垒; 荀建宁] Graduate School, Guangxi University of Chinese Medicine, Nanning, Guangxi 530001, China;[荀建宁] Department of Andrology, Yucheng People's Hospital, Yucheng, Henan 476300, China
关键词:
total Astragalus extract;total Panax notoginseng saponins;combination;cerebral ischemiareperfusion;energy metabolism;C-Jun N-terminal kinase signal transduction;mitochondrial apoptosis pathway;Chinese medicine
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 ischemiareperfusion 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-reperfusion 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 kinase1/2 (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.
摘要:
Danggui Buxue Tang (DBT), a combination of Astragalus and Angelica at a 5 : 1 ratio, mainly promotes hematopoiesis. However, in the clinic, the combination ratio of Astragalus and Angelica to treat low hematopoietic function is not an absolute 5 : 1 ratio, suggesting that the herbs may promote hematopoiesis better after being combined at a certain range of ratios. The objective of this study is to investigate the effect of different ratio combinations of Astragalus and Angelica on bone marrow hematopoiesis suppression induced by cyclophosphamide (CTX) and to probe the interaction and mechanism of Astragalus combined with Angelica in promoting hematopoiesis. Following establishment of the model, mice were administered with Astragalus (6.00 g.kg(-1)), Angelica (3.00 g.kg(-1)), and combinations of Astragalus and Angelica at different ratios, including 10 : 1 (Astragalus 9.81 g.kg(-1)+Angelica 0.98 g.kg(-1)), 5 : 1 (Astragalus 9.00 g.kg(-1)+Angelica 1.80 g.kg(-1)), 2 : 1 (Astragalus 7.71 g.kg(-1)+Angelica 3.08 g.kg(-1)), 1 : 1 (Astragalus 5.40 g.kg(-1)+Angelica 5.40 g.kg(-1)), 1 : 2.5 (Astragalus 3.08 g.kg(-1)+Angelica 7.71 g.kg(-1)), 1 : 5 (Astragalus 1.80 g.kg(-1)+Angelica 9.00 g.kg(-1)), and 1 : 10 (Astragalus 0.98 g.kg(-1)+Angelica 9.81 g.kg(-1)). Our results suggested that Astragalus mixed with Angelica synergistically promoted hematopoiesis best when the combination ratio of Astragalus and Angelica was 1 : 1, 1 : 2.5 or 1 : 5; moreover, the effect of Angelica was greater than that of Astragalus. The potential mechanisms of the combinations of Astragalus and Angelica that promote hematopoiesis include the dissolution of the effective components, promoting the synthesis and secretion of hematopoietic growth factor (HGF) and the proliferation of hematopoietic progenitor cells (HPCs).
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.
作者机构:
[魏歆然] The First Affiliated Hospital, Hunan University of Traditional Chinese Medicine, Changsha 410208, China;[魏高文] College of Integrated Traditional Chinese and Western Medicine, Hunan University of Traditional Chinese Medicine, Changsha 410208, China;[文琪琦; 刘丽; 谢莉娜; 吴雪芬; 陈小丽; 郑雪娜; 谢志强] College of Acupuncture and Moxibustion, Hunan University of Traditional Chinese Medicine, Changsha 410208, China;[岳增辉] College of Acupuncture and Moxibustion, Hunan University of Traditional Chinese Medicine, Changsha 410208, China. 624755064@qq.com
作者机构:
[林群芳; 刘慧英; 黄培] Graduate School, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;[商学军] Department of Andrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu,210002, China;[田雪飞; 张国民] School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;[周青; 高瑞松; 周兴] Department of Andrology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China
作者机构:
[Zeng, Heng; Chen, Jian-xiong; He, Xiaochen] Univ Mississippi, Med Ctr, Dept Pharmacol & Toxicol, Sch Med, Jackson, MS 39216 USA.;[Liao, Duan-fang; Tuo, Qin-hui] Hunan Univ Chinese Med, Sch Integrated Chinese & Western Med, Changsha 410208, Hunan, Peoples R China.;[Zhang, Guo-qiang] China Japan Friendship Hosp, Emergency Dept, Beijing 100029, Peoples R China.
通讯机构:
[Chen, Jian-xiong] U;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-2α, 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-2α 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-2α/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-2α/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-2α/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:
Ethnopharmacological relevance: Liuwei Dihaung decoction (LWDHT) is a well-known classic traditional Chinese medicine formula, consists of six herbs including Rehmannia glutinosa Libosch.(family: Scrophulariaceae), Cornus officinalis Sieb.(family: Cornaceae), Dioscorea opposite Thunb.(family: Dioscoreaceae), Alisma orientale(G. Samuelsson) Juz (family: Alismataceae), Poria cocos (Schw.) Wolf (family: Polyporaceae) and Paeonia suffruticosa Andrews (family: Paeoniaceae). It has been used in the treatment of many types of diseases with signs of deficiency of Yin in the kidneys in China clinically. This study is aimed at investigating the effect of Liuwei dihuang decoction on PI3K/Akt signaling pathway in liver of T2DM rats with insulin resistance. Materials and methods: T2DM model was induced in male Sprague-Dawley (SD) rats by high sugar and high fat diets combined with small dose of streptozocin (STZ) injection. The successful T2DM rats were randomly allocated three group-vehicle group, positive control group and Liuwei Dihuang decoction group. After 12-weeks treatment with distilled water, rosiglitazone and LWDHT by intragastric administration respectively, the rats were put to death in batches. The variance of fasting blood glucose (FBG) and fasting insulin (FINS) in serum were determined, the pathological changes of each rats' liver were observed by hematoxylin-eosin (HE) staining, the expression of insulin receptor substrate 2(IRS2), phosphatidylinositol 3-kinase (PI3K) and protein kinas B (Akt) involving the canonical PI3K/Akt signaling pathway were detected by Real-time fluorescent quantitative PCR (RT-PCR), and the expression level of IRS2, PI3K, Akt protein and phosphorylated IRS2, PI3K, Akt protein were evaluated by Western Blot. All the data were analyzed by SPSS 17.0. Results: Four weeks of treatment with LWDHT could significantly decrease the level of FBG and FINS in serum, improve the cellular morphology of liver, kidney, pancreas tissue, and the expression of IRS2, PI31<, Akt mRNA and phosphorylated IRS2, PI3K, Akt protein involved in the canonical PI31</Akt signaling pathway of T2DM rats in liver were significantly up-regulated, while the total IRS2, PI31<, and Akt protein had no obvious changes. Conclusions: The results suggest that Liuwei Dihuang decoction could intervene insulin resistance of T2DM, in part, through regulation of canonical PI3K/Akt signaling pathway of T2DM rats in liver. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
作者机构:
[周青] Department of Traditional Chinese Medicine Surgery, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China;[何清湖; 刘朝圣; 宾东华; 陈虹历; 韩忠; 李迎秋] School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
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.
作者机构:
[Chang-qing Deng; Xiao-ping Huang] Molecular Pathology Laboratory, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China;[Huang Ding; Ying-hong Tang] Key Laboratory of Hunan Province for Prevention and Treatment of Integrated Traditional Chinese and Western Medicine on Cardio-cerebral Diseases, Changsha 410208, Hunan Province, China;[Bing-xiang Deng; Jin-dong Lu] Key Laboratory of Hunan Universities for Cell Biology and Molecular Techniques, Changsha 410208, Hunan Province, China;[Chang-qing Deng] E-mail: dchangq@sohu.com
关键词:
autophagy;brain ischemia;drugs, Chinese herbal;medicine, traditional Chinese;review
摘要:
Autophagy is a lysosome-mediated degradation process for non-essential or damaged cellular constituents, playing an important homeostatic role in cell survival, differentiation and development to maintain homeostasis. Autophagy is involved in tumors as well as neurodegenerative, cardiovascular and cerebrovascular diseases. Recently, active compounds from traditional Chinese medicine (TCM) have been found to modulate the levels of autophagy in tumor cells, nerve cells, myocardial cells and endothelial cells. Ischemic stroke is a major cause of neurological disability and places a heavy burden on family and society. Regaining function can significantly reduce dependence and improve the quality of life of stroke survivors. In healthy cells, autophagy plays a key role in adapting to nutritional deprivation and eliminating aggregated proteins, however inappropriate activation of autophagy may lead to cell death in cerebral ischemia. This paper reviews the process and the molecular basis of autophagy, as well as its roles in cerebral ischemia and the roles of TCM in modulating its activity.