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：
Acute pancreatitis (AP) is defined as an acute inflammation of pancreas that may cause damage to other tissues and organs depending upon the severity of symptoms. The diagnosis of AP is usually made by detection of raised circulating pancreatic enzyme levels, but there are occasional false positive and false negative diagnoses and such tests are often normal in delayed presentations. More accurate biomarkers would help in such situations. In this study, the global metabolites' changes of AP patients (APP) were profiled by using gas chromatography-mass spectrometry (GC-MS). Multivariate pattern recognition techniques were used to establish the classification models to distinguish APP from healthy participants (HP). Some significant metabolites including 3-hydroxybutyric acid, phosphoric acid, glycerol, citric acid, D-galactose, D-mannose, D-glucose, hexadecanoic acid and serotonin were selected as potential biomarkers for helping clinical diagnosis of Ap. Furthermore, the metabolite changes in APP with severe and mild symptoms were also analyzed. Based on the selected biomarkers, some relevant pathways were also identified. Our results suggested that GC-MS based serum metabolomics method can be used in the clinical diagnosis of AP by profiling potential biomarkers. (C) 2017 LAP and EPC. Published by Elsevier B.V. All rights reserved.
作者机构：
[Yang, Xiudeng; Tang, Yamei; Tang, Aiguo] Cent S Univ, Xiangya Hosp 2, Dept Lab Med, Changsha 410011, Hunan, Peoples R China.;[Wei, Qinling] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Psychiat, Guangzhou 510631, Guangdong, Peoples R China.;[Lang, Bing; Zhang, Xianghui; Liu, Yong] Cent S Univ, Xiangya Hosp 2, Dept Psychiat, Changsha 410011, Hunan, Peoples R China.;[Lang, Bing; Zhang, Xianghui; Liu, Yong] Cent S Univ, Mental Hlth Inst, Changsha, Hunan, Peoples R China.;[Lang, Bing; Zhang, Xianghui; Liu, Yong] Hunan Key Lab Psychiat & Mental Hlth, Changsha, Hunan, Peoples R China.
通讯机构：
[Liu, Yong] C;[Liu, Yong] H;Cent S Univ, Xiangya Hosp 2, Dept Psychiat, Changsha 410011, Hunan, Peoples R China.;Cent S Univ, Mental Hlth Inst, Changsha, Hunan, Peoples R China.;Hunan Key Lab Psychiat & Mental Hlth, Changsha, Hunan, Peoples R China.
关键词：
AVP/AVPR1a;CD38;FES;OXT/OXTR;mRNA
摘要：
Schizophrenia (SZ) is a severe neuropsychiatric disorder with significant social cognition impairment. Increasing evidence has suggested that neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are important mediators of complex social cognition and behavior associates with SZ. In the present study, forty-three first-episode schizophrenia (FES) patients and forty-seven healthy controls (HC) were included. The peripheral mRNA expression of OXT, OXT receptor (OXTR), AVP, AVP 1a receptor (AVPR1a) and CD38 was determined by real-time quantitative polymerase chain reaction (RT-qPCR). The FES patients have a relatively higher mRNA level of OXT and OXTR genes and lower expression of AVP and CD38 genes than HC. No difference was found for AVPR1a between FES patients and HC. As for the sex difference, the mRNA expression of OXT and OXTR showed no difference in both male and female FES patients compared to HC group. The AVP and CD38 genes in female FES patients showed decreased mRNA expression than female HC. Our findings support disrupted OXT and AVP systems in the FES patients.
摘要：
This study was conducted to determine the effect of 200 ng mL−1 and 2000 ng mL−1 deoxynivalenol (DON) on apoptosis, barrier function, nutrient transporter gene expression, and free amino acid variation as well as on mitochondrial biogenesis and function-related gene expression in the intestinal porcine epithelial cell line J2 (IPEC-J2) for 6 h, 12 h, and 24 h. Exposure to 200 ng mL−1 DON inhibited the cell viability and promoted cell cycle progression from the G2/M phase to the S phase (P < 0.05). The data showed that the IPEC-J2 cell content of free amino acids, such as valine, methionine, leucine, and phenylalanine, was increased (P < 0.05) after treatment for 6 h; the aspartate, threonine, and lysine contents increased (P < 0.05) after treatment for 12 h; and the aspartate, serine, glycine, alanine, isoleucine, leucine, and lysine contents decreased (P < 0.05) after treatment for 24 h. The expression levels of barrier function genes, including zonula occludens 1 (ZO-1), occludin (OCLN), and claudin 1 (CLDN1), showed a significant reduction (P < 0.05). Moreover, the expression levels of differently regulated nutrient transporter genes, including B0,+ amino acid transporter (B0,+AT) and sodium-glucose transporter 1 (SGLT1) genes, showed a significant decrease (P < 0.05), while the Na+-dependent neutral amino acid transporter 2 (ASCT2) and glucose transporter type 2 (GLUT2) showed a significant increase (P < 0.01). The expression levels of cytokine genes, including IL-8, and IL-1β genes, showed a significant increase (P < 0.05). Furthermore, the expression levels of mitochondrial biogenesis and function-related genes, including mitochondrial transcription factor A (TFAM) and nuclear respiratory factor-1 (NRF), mitochondrial single-strand DNA-binding protein (mt SSB) and mitochondrial polymerase r (mt polr), NADH dehydrogenase subunit 4 (ND4) and cytochrome c oxidase (CcOX) IV, CcOX V and cytochrome c (Cyt c), mammalian silencing information regulator-2α (SIRT-1), glucokinase and citrate synthase (CS), showed a significant increase (P < 0.05). Taken together, the present study indicated that 200 and 2000 ng mL−1 DON could affect proliferation and cell cycle progression from the G2/M phase to the S phase and could mediate the expression levels of differently regulated barrier function, nutrient transport, and mitochondrial biogenesis and function-related genes.
期刊：
Biochemical and Biophysical Research Communications,2017年483(2):847-854 ISSN：0006-291X
通讯作者：
Deng Le
作者机构：
[Cheng Lijuan; Deng Le; Yan Xing; Wu Minxi; Li Wenkai] Hunan Normal Univ, Coll Life Sci, Dept Microbiol, Changsha 410081, Hunan, Peoples R China.;[Cheng Lijuan] Hunan Univ Chinese Med, Dept Biochem & Mol Biol, Changsha 410208, Hunan, Peoples R China.;[Li Wenkai] Cent S Univ, State Key Lab Med Genet, Dept Biochem, Changsha 410013, Hunan, Peoples R China.;[Li Wenkai] Cent S Univ, Sch Life Sci, Changsha 410013, Hunan, Peoples R China.
通讯机构：
[Deng Le] H;Hunan Normal Univ, Coll Life Sci, Dept Microbiol, Changsha 410081, Hunan, Peoples R China.
摘要：
Host-microbe interactions determine the outcome of host responses to commensal and pathogenic microbes. Previously, two epithelial cell-binding peptides were found to be homologues of two sites (B, aa168-174; F, aa303-309) in the flagellar hook protein FlgE of Pseudomonas aeruginosa. Tertiary modeling predicted these sites at the interface of neighboring FlgE monomers in the fully formed hook. Recombinant FlgE protein stimulated proinflammatory cytokine production in a human cell line and in murine lung organoid culture as detected with real-time RT-PCR and ELISA assays. When administered to mice, FlgE induced lung inflammation and enhanced the Th2-biased humoral response to ovalbumin. A pull-down assay performed with FlgE-saturated resin identified caveolin-1 as an FlgE-binding protein, and caveolin-1 deficiency impaired FlgE-induced inflammation and downstream Erk1/2 pathway activation in lung organoids. Intact flagellar hooks from bacteria were also proinflammatory. Mutations to sites B and F impaired bacteria motility and proinflammatory potency of FlgE without altering adjuvanticity of FlgE. These findings suggest that the flagellar hook and FlgE are novel players in host-bacterial interactions at immunological level. Further studies along this direction would provide new opportunities for understanding and management of diseases related with bacterial infection.
摘要：
Advanced osteosarcoma (OS) is usually treated by preoperative and postoperative chemotherapy, but there are a very limited number of active agents. Celecoxib (Cel) is a COX-2-selective nonsteroidal anti-inflammatory drug and its antitumoral effect has been shown widely in a variety of cancers including OS cells in vitro. However, the potential combinational effect of Cel with other biological therapy has not been reported in OS cells. In this study, the effects of Cel, miR-34a mimics, and their combination on cell proliferation (MTT assay), migration (in-vitro scratch assay), invasion (transwell assay), mRNA (real-time PCR), and protein (Western blot) expression of associated signal transductions were investigated in cultured MG63 cells. The results showed that miR-34a mimics transfection and Cel treatment significantly decreased cell viability, migration, and invasion in MG63 cells, with their combination being more effective. In contrast, miR-34a inhibitors transfection exerted an effect opposite to miR-34a mimics on cell viability, migration, and invasion. The antitumoral effects of miR-34a, Cel, and their combination were observed in significant up-regulated expression of PTEN and GSK-3β, down-regulated expression of ROCK1, Notch1, and MMP9 as well as Akt Ser473 phosphorylation. Our data suggested that miR-34a exerts a combinational effect with Cel on the cell proliferation, migration, and invasion in OS cells through regulating Notch1/ROCK1–PTEN–Akt–GSK-3β signaling and MMP9 gene expression.
摘要：
IMM-H004, a 3-piperazinylcoumarin compound derived from coumarin, has been proved effective against CA1 cell loss and spatial learning impairments resulting from transient global ischemia/reperfusion (TGCI/R), while the mechanism is still largely unknown. Here, we confirmed that treatment of rats with IMM-H004 immediately after TGCI/R ameliorated delayed neuronal death (DND) in the CA1 of hippocampus and cortex. Further study suggested that IMM-H004 contributed to the expression of antiapoptotic protein survivin through the activation of PI3K-dependent protein kinase B (PKB/Akt), which led to the phosphorylation of forkhead box O1 (FoxO1), then relieved the inhibiting effect on survivin promoter. Additionally, IMM-H004 also enhanced the expression of hepatitis B X-interacting protein (HBXIP), which formed a complex with survivin to prevent the activation of caspase death cascade, thereby halting apoptotic cell death. Finally, we injected a HBXIP siRNA into hippocampus and performed microelectroporation before ischemia/reperfusion, which abolished the protective effect of IMM-H004. Further study revealed that HBXIP maintained the high expression of Akt and survivin. Collectively, our findings demonstrated that DND after TGCI/R was alleviated by IMM-H004 through promoting the formation of survivin-HBXIP complex, which further emphasized the importance of endogenous protein involved in self-repair after stroke.
摘要：
Peptide toxins often have divergent pharmacological functions and are powerful tools for a deep review on the current understanding of the structure-function relationships of voltage-gated sodium channels (VGSCs). However, knowing about the interaction of site 3 toxins from tarantula venoms with VGSCs is not sufficient. In the present study, using whole-cell patch clamp technique, we determined the effects of Jingzhaotoxin-I (JZTX-I) on five VGSC subtypes expressed in HEK293 cells. The results showed that JZTX-I could inhibit the inactivation of rNav1.2, rNav1.3, rNav1.4, hNav1.5 and hNav1.7 channels with the IC50 of 870 +/- 8 nM, 845 +/- 4 nM, 339 +/- 5 nM, 335 +/- 9 nM, and 348 +/- 6 nM, respectively. The affinity of the toxin interaction with subtypes (rNav1.4, hNav1.5, and hNav1.7) was only 2-fold higher than that for subtypes (rNav1.2 and rNav1.3). The toxin delayed the inactivation of VGSCs without affecting the activation and steady-state inactivation kinetics in the physiological range of voltages. Site-directed mutagenesis indicated that the toxin interacted with site 3 located at the extracellular S3 S4 linker of domain IV, and the acidic residue Asp at the position1609 in hNav1.5 was crucial for JZTX-I activity. Our results provide new insights in single key residue that allows toxins to recognize distinct ion channels with similar potency and enhance our understanding of the structure-function relationships of toxin-channel interactions. (C) 2015 Elsevier Ltd. All rights reserved.
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.
摘要：
Multi-target drugs, such as the cocktail therapy used for treating AIDS, often show stronger efficacy than single target drugs in treating complicated diseases. This review will focus on clausenamide (clau), a small molecule compound originally isolated from the traditional Chinese herbal medicine, Clausenalansium. The finding of four chiral centers in clau molecules predicted the presence of 16 clau enantiomers, including (-)-dau and (+)-clau. All of the predicted enantiomers have been successfully synthesized via innovative chemical approaches, and pharmacological studies have demonstrated (-)-clau as a eutomer and (+)-clau as a distomer in improving cognitive function in both normal physiological and pathological conditions. Mechanistically, the nootropic effect of (-)-clau is mediated by its multi-target actions, which include mild elevation of intracellular Ca2+ concentrations, modulation of the cholinergic system, regulation of synaptic plasticity, and activation of cellular and molecular signaling pathways involved in learning and memory. Furthermore, (-)-clau suppresses the pathogenesis of Alzheimer's disease by inhibiting multiple etiological processes: (1) beta amyloid protein-induced intracellular Ca2+ overload and apoptosis and (2) tau hyperphosphorylation and neurodegeneration. In conclusion, the nature of the multi-target actions of (-)-clau substantiates it as a promising chiral drug candidate for enhancing human cognition in normal conditions and treating memory impairment in neurodegenerative diseases. (C) 2016 Elsevier Inc. All rights reserved.
摘要：
Rg1 has shown multiple pharmacological activities and been considered to be evaluated for hepatic protective activity, as Rg1 could modulate different pathways in various diseases. Herein we assessed its effect and potential mechanism in a newly modified ethanol model. C57BL/6 mice were fed with Lieber-DeCarli liquid diet containing ethanol or isocaloric maltose dextrin as control diet with or without Rg1. Meanwhile, bicyclol was treated as positive drug to compare the efficacy of Rg1 against alcoholic hepatotoxicity. According to our data, Rg1 indeed improved the survival rate and lowered the abnormal high levels of serum parameters. H&E and Oil Red O staining indicated that the condition of liver damage was mitigated by Rg1 administration. Furthermore, AMPK and Nrf2 pathways were all modulated at both RNA and protein levels. In accordance with these findings, Rg1 effectively protected against alcoholic liver injury, possibly by modulating metabolism, suppressing oxidative stress, and enhancing oxidant defense systems of Nrf2 pathway. In vitro, Rg1 has no cell toxicity and promotes Nrf2 translocate into nuclear. In summary, we demonstrate that Rg1 is a potent activator of Nrf2 pathway, and could therefore be applied for prevention of hepatic damage.
摘要：
We report on a photometric method for the determination of the metallothioneins (MTs). It is known that citrate capped gold nanoparticles (AuNPs) coated with traces of mercury possess peroxidase-like properties that can catalyze the oxidation of 2,2′-azino-bis(3-ethylbenzothiazoline- 6-sulfonate) (ABTS) to form a blue product in acetate buffer of pH 4.5. It is found that if the AuNPs are first aggregated by the cysteine-rich metallothioneins, the peroxidase-like properties of the resulting aggregates (AuNP-Hg-MTs) cause a largely accelerated oxidation of ABTS. The effect of adding MTs to such a solution is used to quantify the MTs by a kinetic assay. Changes in absorbance at 416 nm are linearly correlated to the concentration of MTs in the 4.3 to 49 nM range, and the detection limit is 1.3 nM. The method was successfully applied to the determination of MTs in (spiked) human urine. The strategy may pave the way for related detection platforms. Graphical Abstract The gold nanoparticle (AuNP)-Hg-metallothionein (MT) hybrid possesses a stronger peroxidase-like activity than the AuNP-Hg complex. It can catalyze H2O2-mediated oxidation of ABTS along with the change of the absorbance of the assay system, which is directly proportional to the concentration of MTs in the linear range.
期刊：
Molecular and Cellular Neuroscience,2016年71(1):102-113 ISSN：1044-7431
通讯作者：
Chen, Nai-Hong
作者机构：
[Wang, Zhen-Zhen; Mou, Zheng; Gao, Yan; Chen, Nai-Hong; Zhang, Zhao] Chinese Acad Med Sci, Peking Union Med Coll, Ctr Neurosci, Inst Mat Med,State Key Lab Bioact Subst & Funct N, Beijing 100730, Peoples R China.;[Chu, Shi-Feng] Hunan Univ Chinese Med, Coll Pharm, Collaborat Innovat Ctr Digital Tradit Chinese Med, Key Lab Diagnost Tradit Chinese Med, Changsha, Hunan, Peoples R China.;[Wei, Gui-Ning] Guangxi Inst Chinese Med & Pharmaceut Sci, Dept Pharmacol, Nanning, Peoples R China.
通讯机构：
[Chen, Nai-Hong] C;Chinese Acad Med Sci, Peking Union Med Coll, Ctr Neurosci, Inst Mat Med,State Key Lab Bioact Subst & Funct N, Beijing 100730, Peoples R China.
摘要：
Growing evidence indicates that GQ1b, one of the gangliosides members, contributes to synaptic transmission and synapse formation. Previous studies have shown that GQ1b could enhance depolarization induced neurotransmitter release, while the role of GQ1b in asynchronous release is still largely unknown. Here in our result, we found low concentration of GQ1b, but not GT1b or GD1b (which were generated from GQ1b by plasma membrane-associated sialidases), evoked asynchronous dopamine (DA) release from both clonal rat pheochromocytoma PC12 cells and rat striatal slices significantly. The release peaked at 2 min after GQ1b exposure, and lasted for more than 6 min. This effect was caused by the enhancement of intracellular Ca2+ and the activation of Pyk2. Inhibition of Pyk2 by PF-431396 (a dual inhibitor of Pyk2 and FAR) or Pyk2 siRNA abolished DA release induced by GQ1b. Moreover, Pyk2 Y402, but not other tyrosine site, was phosphorylated at the peaking time. The mutant of Pyk2 Y402 (Pyk2-Y402F) was built to confirm the essential role of Y402 activation. Further studies revealed that activated Pyk2 stimulated ERK1/2 and p-38, while only the ERK1/2 activation was indispensable for GQ1b induced DA release, which interacted with Synapsin I directly and led to its phosphorylation, then depolymerization of F-actin, thus contributed to DA release. In conclusion, low concentration of GQ1b is able to enhance asynchronous DA release through Pyk2/ERK/Synapsin I/actin pathway. Our findings provide new insights into the role of GQ1b in neuronal communication, and implicate the potential application of GQ1b in neurological disorders. (C) 2015 Elsevier Inc. All rights reserved.
